Post on 30-Jul-2020
Utilisation du XtalFluor en synthèse organique et développement de réactifs de fluoration électrophile
Thèse
Mathilde Vandamme
Doctorat en chimie Philosophiæ Doctor (Ph. D.)
Québec, Canada
© Mathilde Vandamme, 2017
Utilisation du XtalFluor en synthèse organique et développement de réactifs de fluoration électrophile
Thèse
Mathilde Vandamme
Sous la direction de :
Jean-François Paquin, directeur de recherche
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Résumé
L’amélioration des méthodes de synthèse organique, que ce soit les réactions ou les
réactifs, retient continuellement l’intérêt des chimistes. Ceci est particulièrement vrai pour
les molécules fluorées, qui sont d’une grande utilité en chimie pharmaceutique, en
agrochimie et en sciences des matériaux.
À cet effet, la compagnie OmegaChem a récemment développé deux réactifs de fluoration
nucléophile capables de réaliser la déoxofluoration d’alcools, de cétones et d’acides
carboxyliques en fluorures d’alkyles, difluorométhylènes et fluorures d’acyles
respectivement. Il s’agit de tétrafluoroborate de diéthylaminodifluorosulfinium et de
tétrafluoroborate de morpholinodifluorosulfinium, appelés XtalFluor-E et XtalFluor-M.
Ceux-ci possèdent un pouvoir activant, mais une source externe de fluorure est nécessaire
pour que la déoxofluoration s’opère. En raison de leur facilité de manipulation et leur faible
coût, il s’est avéré intéressant d’utiliser cette nouvelle classe de réactifs dans d’autres
réactions de fluoration, mais également dans des transformations nécessitant un agent
activant. Dans le cadre des travaux de cette thèse, diverses réactions impliquant le
XtalFluor-E ont été développées. Ainsi, des isonitriles ont pu être synthétisés à partir de
formamides, puis impliqués dans des réactions multicomposantes. De la même manière,
une méthode permettant de former des nitriles à partir d’amides primaires ou d’aldoximes a
été développée. Des esters perfluorés ont également été synthétisés, à partir d’acides
carboxyliques et d’alcools perfluorés variés. Enfin, une réaction de déoxofluoration
éliminatrice a permis l’obtention de monofluoroalcènes cycliques.
La seconde partie du projet s’est focalisée sur la fluoration électrophile. Dans ce cas-là, le
substrat joue le rôle de nucléophile tandis que l’atome de fluor est fourni sous forme
électrophile. Au vu des limites des réactifs actuels (disponibilité commerciale, solubilité
dans les solvants organiques, réactivité, etc.), l’objectif consiste à élaborer de nouveaux
réactifs de fluoration électrophile comblant ces lacunes. Plus particulièrement, des dérivés
de N-fluorosquaramides ont été brièvement étudiés.
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Abstract
The improvement of synthetic methodologies, either reactions or reagents, continually
retains the interest of chemists. This is particularly true for fluorinated molecules, which
occupy a significant place in pharmaceutical chemistry, agrochemistry, and material
sciences.
To this end, OmegaChem recently commercialized two nucleophilic fluorinating reagents
allowing the deoxofluorination of alcohols, ketones and carboxylic acids into alkyl
fluorides, difluoromethylenes and acyl fluorides, respectively. These are
diethylaminodifluorosulfinium tetrafluoroborate and morpholinodifluorosulfinium
tetrafluoroborate, named XtalFluor-E and XtalFluor-M. They possess an activating power,
but an exogenous source of fluoride is required to perform deoxofluorination reactions.
Because of their ease of handle and low cost, it was advantageous to use this new class of
reagents in other fluorination reactions, but also in transformations requiring an activating
agent. As part of this thesis, various reactions involving XtalFluor-E have been developed.
Isocyanides could be synthesized from formamides and then involved in multi-component
reactions. In the same way, a method allowing the formation of nitriles from primary
amides or aldoximes has been developed. Perfluorinated esters have been also synthesized,
from carboxylic acids and various perfluorinated alcohols. Finally, an eliminative
deoxofluorination allowed the formation of cyclic monofluoroalkenes.
The second part of the project focused on electrophilic fluorination. In this case, the
substrate behaves as the nucleophile whereas the fluorine atom is delivered as an
electrophile. Given the limitations of the current reagents (commercial availability,
solubility in organic solvents, reactivity, etc.), the objective is to develop new electrophilic
fluorine sources that can address these issues. More particularly, N-fluorosquaramides
derivatives were briefly investigated.
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Table des matières
Résumé .................................................................................................................................. iiiAbstract ................................................................................................................................ ivTable des matières ................................................................................................................ vListe des figures ................................................................................................................. viiiListe des schémas ................................................................................................................. ixListe des tableaux ................................................................................................................. xiListe des abréviations ......................................................................................................... xiiRemerciements ................................................................................................................... xivAvant-propos ...................................................................................................................... xviCHAPITRE 1 Introduction .............................................................................................. 1
1.1 LE FLUOR EN CHIMIE ORGANIQUE ............................................................................... 11.1.1 Propriétés physico-chimiques ............................................................................. 11.1.2 Applications en chimie organique ....................................................................... 3
1.2 MÉTHODES DE FLUORATION ....................................................................................... 61.2.1 Fluoration nucléophile ........................................................................................ 61.2.2 Fluoration électrophile ..................................................................................... 101.2.3 Fluoration radicalaire ....................................................................................... 13
1.3 LE XTALFLUOR ........................................................................................................ 141.3.1 Découverte du XtalFluor ................................................................................... 141.3.2 Méthodes de synthèse ........................................................................................ 161.3.3 Propriétés .......................................................................................................... 181.3.4 Réactif de fluoration .......................................................................................... 201.3.5 Agent activant .................................................................................................... 26
1.4 OBJECTIFS DE LA THÈSE ............................................................................................ 351.4.1 Utilisation du XtalFluor-E en synthèse organique ........................................... 351.4.2 Développement de nouveaux réactifs de fluoration électrophile ...................... 37
CHAPITRE 2 Synthèse d’isonitriles par déshydratation de formamides en utilisant le XtalFluor-E Synthesis of isocyanides through dehydration of formamides using XtalFluor-E 38
2.1 RÉSUMÉ .................................................................................................................... 392.2 ABSTRACT ................................................................................................................ 392.3 INTRODUCTION ......................................................................................................... 392.4 RESULTS AND DISCUSSION ........................................................................................ 422.5 CONCLUSION ............................................................................................................. 492.6 ACKNOWLEDGMENTS ............................................................................................... 492.7 SUPPORTING INFORMATION AVAILABLE .................................................................... 49
2.7.1 General information .......................................................................................... 492.7.2 Synthesis of the new formamides ....................................................................... 502.7.3 Synthesis of isocyanides .................................................................................... 542.7.4 Multi-component reactions ............................................................................... 57
CHAPITRE 3 Synthèse de nitriles à partir d’aldoximes et d’amides primaires en utilisant le XtalFluor-E Synthesis of Nitriles from Aldoximes and Primary Amides Using XtalFluor-E ............................................................................................................... 63
3.1 RÉSUMÉ .................................................................................................................... 64
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3.2 ABSTRACT ................................................................................................................ 643.3 INTRODUCTION ......................................................................................................... 653.4 RESULTS AND DISCUSSION ........................................................................................ 673.5 CONCLUSION ............................................................................................................. 733.6 ACKNOWLEDGMENTS ............................................................................................... 733.7 SUPPORTING INFORMATION AVAILABLE .................................................................... 74
3.7.1 General information .......................................................................................... 743.7.2 Synthesis of aldoximes ....................................................................................... 743.7.3 Synthesis of amides ............................................................................................ 783.7.4 Synthesis of nitriles ............................................................................................ 80
CHAPITRE 4 Estérification directe d’acides carboxyliques avec des alcools perfluorés, effectuée par l’entremise de XtalFluor-E Direct Esterification of Carboxylic Acids with Perfluorinated Alcohols Mediated by XtalFluor-E .................. 88
4.1 RÉSUMÉ .................................................................................................................... 894.2 ABSTRACT ................................................................................................................ 894.3 INTRODUCTION ......................................................................................................... 904.4 RESULTS AND DISCUSSION ........................................................................................ 924.5 CONCLUSION ............................................................................................................. 994.6 ACKNOWLEDGMENTS ............................................................................................. 1004.7 ANNEXE .................................................................................................................. 100
4.7.1 Estérification de l’acide 5-phénylvalérique avec des alcools non fluorés ...... 1004.7.2 Étude du mécanisme par chimie computationnelle ......................................... 101
4.8 SUPPORTING INFORMATION AVAILABLE .................................................................. 1024.8.1 General information ........................................................................................ 1024.8.2 Esterification mediated by XtalFluor-E using perfluorinated alcohols .......... 1034.8.3 Control experiments ........................................................................................ 119
4.9 PARTIE EXPÉRIMENTALE DES RÉSULTATS NON PUBLIÉS (SECTION 4.7) .................... 1214.9.1 Estérification de l’acide 5-phénylvalérique avec des alcools non fluorés ...... 1214.9.2 Méthodes computationnelles ........................................................................... 123
CHAPITRE 5 Déoxofluoration éliminatrice au moyen de XtalFluor-E : Synthèse de monofluoroalcènes en une étape à partir de dérivés de cyclohexanone Eliminative Deoxofluorination Using XtalFluor-E: A One-Step Synthesis of Monofluoroalkenes from Cyclohexanone Derivatives .................................................................................... 124
5.1 RÉSUMÉ .................................................................................................................. 1255.2 ABSTRACT .............................................................................................................. 1255.3 INTRODUCTION ....................................................................................................... 1255.4 RESULTS AND DISCUSSION ...................................................................................... 1295.5 CONCLUSION ........................................................................................................... 1355.6 ACKNOWLEDGMENTS ............................................................................................. 1355.7 ANNEXE .................................................................................................................. 135
5.7.1 Optimisation : Résultats complémentaires ...................................................... 1355.7.2 Étendue de la réaction : discussion ................................................................. 138
5.8 SUPPORTING INFORMATION AVAILABLE .................................................................. 1405.8.1 General information ........................................................................................ 1405.8.2 Additional optimization results ....................................................................... 1425.8.3 Synthesis of monofluoroalkenes from cyclohexanone derivatives .................. 143
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CHAPITRE 6 Vers la synthèse de N-fluorosquaramides en tant que nouveaux réactifs de fluoration électrophile ................................................................................... 150
6.1 INTRODUCTION ....................................................................................................... 1506.1.1 Propriétés des squaramides ............................................................................ 1506.1.2 N-fluorosquaramides ....................................................................................... 1516.1.3 Potentiel de fluoration électrophile des N-fluorosquaramides ....................... 1526.1.4 Potentiel de fluoration radicalaire des N-fluorosquaramides ........................ 155
6.2 RÉSULTATS ET DISCUSSION ..................................................................................... 1566.3 CONCLUSION ........................................................................................................... 1616.4 MÉTHODES COMPUTATIONNELLES .......................................................................... 1626.5 PARTIE EXPÉRIMENTALE ......................................................................................... 162
6.5.1 Informations générales .................................................................................... 1626.5.2 Synthèse des produits de départ ...................................................................... 1636.5.3 Tentatives de fluoration, chloration et bromation des squaramides ............... 1666.5.4 Méthylation des squaramides .......................................................................... 1676.5.5 Expériences de deutération ............................................................................. 169
CHAPITRE 7 Conclusion et perspectives ................................................................... 1707.1 RETOUR SUR LES OBJECTIFS .................................................................................... 170
7.1.1 Utilisation du XtalFluor-E en synthèse organique ......................................... 1707.1.2 Développement de nouveaux réactifs de fluoration électrophile .................... 171
7.2 PERSPECTIVES ......................................................................................................... 1717.2.1 Étendre la liste des réactions utilisant le XtalFluor-E comme agent activant 1717.2.2 Réactifs de fluoration électrophile : concevoir de nouvelles structures ......... 173
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Liste des figures
Figure 1.1. Exemples de médicaments fluorés. ...................................................................... 4Figure 1.2. Exemples de produits agrochimiques fluorés. ..................................................... 5Figure 1.3. Exemples de réactifs de fluoration nucléophile. .................................................. 8Figure 1.4. Réactifs de déoxofluoration. .............................................................................. 10Figure 1.5. Exemples de réactifs de fluoration électrophile. ................................................ 12Figure 1.6. Réactifs de fluoration électrophile récents. ........................................................ 13Figure 1.7. Thermogrammes DSC du DAST, Deoxo-Fluor, XtalFuor-E et XtalFluor-M. Figure tirée de la référence 31b. ........................................................................................... 19Figure 1.8. Structure des N-fluorosquaramides. ................................................................... 37Figure 2.1. Activation of amides with [Et2NSF2]BF4 for the synthesis of 1,3,4-oxadiazoles and isocyanides. .................................................................................................................... 41Figure 2.2. Unproductive formamides. ................................................................................. 45Figure 2.3. Mechanistic proposal for the dehydration reaction. The BF4
- counter-ion has been omitted for clarity. ........................................................................................................ 46Figure 3.1. Activation of amides and aldoximes with XtalFluor-E for the synthesis of nitriles. .................................................................................................................................. 67Figure 5.1. Ensemble des cétones pour lesquelles la fluoration n’a pas été possible. ........ 139Figure 6.1. Structure des squaramides. ............................................................................... 151Figure 6.2. N-Fluorosquaramides et autres réactifs de fluoration électrophile. ................. 152Figure 6.3. Valeurs de FPD des principales classes de réactifs de fluoration électrophile dans le dichlorométhane. Figure tirée de la référence 241. ................................................ 153Figure 6.4. Comparaison des valeurs calculées de FPD (kcal/mol) des N-fluorosquaramides avec celles du NFSI et du Selectfluor dans le dichlorométhane et l’acétonitrile. .............. 154Figure 6.5. Valeurs de BDE des principales classes de réactifs de fluoration N–F dans l’acétonitrile. Figure tirée de la référence 243. ................................................................... 155Figure 6.6. Comparaison des valeurs calculées de BDE (kcal/mol) des N-fluorosquaramides avec celles du NFSI et du Selectfluor dans l’acétonitrile. .................................................. 156Figure 6.7. Squaramides modèles. ...................................................................................... 157Figure 7.1. Dérivés de N-fluorosulfonylhydrazine. ............................................................ 173
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Liste des schémas
Schéma 1.1. Fluoration nucléophile. ...................................................................................... 7Schéma 1.2. Réaction de déoxofluoration. ............................................................................. 9Schéma 1.3. Fluoration électrophile. .................................................................................... 11Schéma 1.4. Synthèse de sels de dialkylaminodifluorosulfinium au moyen de BF3·Et2O. . 14Schéma 1.5. Premier exemple d’utilisation d’un sel de dialkylaminodifluorosulfinium comme agent de déoxofluoration. ........................................................................................ 15Schéma 1.6. Méthodes de synthèse du XtalFluor-E. ............................................................ 17Schéma 1.7. Synthèse de sels de diéthylaminodifluorosulfinium à partir d’acides de Brønsted. ............................................................................................................................... 17Schéma 1.8. Synthèse de fluorures d’alkyle par déoxofluoration d’alcools. ....................... 21Schéma 1.9. Mécanismes de déoxofluoration d’un alcool avec le DAST et le XtalFluor-E. .............................................................................................................................................. 22Schéma 1.10. Formation de l’intermédiaire diéthylaminodifluorosulfane 1.3. .................... 23Schéma 1.11. Synthèse de difluorométhylènes par déoxofluoration de carbonyles. ........... 24Schéma 1.12. Synthèse de fluorures d’acyle par déoxofluoration d’acides carboxyliques. . 24Schéma 1.13. Synthèse de fluorures de glycosyle. ............................................................... 25Schéma 1.14. Synthèse d’un fluorure de sulfonyle. ............................................................. 26Schéma 1.15. Utilisation du XtalFluor-E comme agent activant. ........................................ 26Schéma 1.16. Expansion de cycles dérivés de prolinol. ....................................................... 27Schéma 1.17. Synthèse de 1,3,4-oxadiazoles à partir de 1,2-diacylhydrazines. .................. 28Schéma 1.18. Synthèse d’oxazolines à partir d’hydroxyamides. ......................................... 29Schéma 1.19. Synthèse d’oxazolines par désilylation in situ et cyclodéshydratation. ......... 29Schéma 1.20. Synthèse d’oxazolines par ouverture d’oxiranes. .......................................... 30Schéma 1.21. Halogénation d’alcools primaires. ................................................................. 30Schéma 1.22. Amidation d’acides carboxyliques décrite par le groupe de Cossy. .............. 31Schéma 1.23. Amidation d’acides carboxyliques décrite par le groupe de Paquin. ............. 31Schéma 1.24. Aminofluoration intramoléculaire catalysée au fer. ....................................... 32Schéma 1.25. Aminofluoration intermoléculaire catalysée au fer. ....................................... 33Schéma 1.26. Synthèse de dérivés d’imidazolidinone par ouverture d’aziridines. .............. 33Schéma 1.27. Synthèse de diaryl- et triarylméthanes par benzylation de Friedel-Crafts. .... 34Schéma 1.28. Allylation d’alcools benzyliques. ................................................................... 35Schéma 1.29. Synthèse d’isonitriles à partir de formamides. ............................................... 35Schéma 1.30. Synthèse de nitriles à partir d’amides primaires ou d’aldoximes. ................. 36Schéma 1.31. Synthèse d’esters perfluorés à partir d’acides carboxyliques et d’alcools perfluorés. ............................................................................................................................. 36Schéma 1.32. Synthèse de monofluoroalcènes à partir de cétones. ..................................... 37Scheme 2.1. Synthesis of N-formyl amides with crude isocyanides. ................................... 48Scheme 2.2. Ugi-Smiles with a crude isocyanide. ............................................................... 48Scheme 3.1. Initial results for the dehydration of 3.1 and 3.3 using XtalFluor-E. ............... 68Scheme 3.2. Synthesis of aromatic nitriles (3.6) from aldoximes (3.4) or primary amides (3.5). ...................................................................................................................................... 69Scheme 3.3. Synthesis of vinylic nitrile 3.9 from cinnamic acid derivatives 3.7 and 3.8. ... 70Scheme 3.4. Synthesis of aliphatic nitriles from aldoximes (3.10) or primary amides (3.11). .............................................................................................................................................. 71
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Scheme 3.5. Synthesis of chiral nonracemic nitriles from primary amides derived from protected amino acids. .......................................................................................................... 72Scheme 3.6. Synthesis of chiral nonracemic nitriles from L-mandelic acid and L-lactic acid and derivatives. ..................................................................................................................... 73Scheme 4.1. Previous Work and the Current Method. ......................................................... 91Scheme 4.2. Results for the Esterification of Various Carboxylic Acids with TFE Using XtalFluor-E.a,b ....................................................................................................................... 95Scheme 4.3. Selected Results for the Esterification of Various Carboxylic Acids with Perfluorinated Alcohols Using XtalFluor-E.a,b ..................................................................... 97Scheme 4.4. Control Experiments and Mechanistic Hypothesis.a ....................................... 99Schéma 4.5. Estérification de l’acide 5-phénylvalérique (4.2) avec des alcools non fluorés. ............................................................................................................................................ 101Schéma 4.6. Voies mécanistiques possibles. ...................................................................... 101Schéma 4.7. Équilibre de l’intermédiaire 5.57 avec sa forme dissociée 5.58. ................... 102Scheme 5.1. Previous and Current Work. .......................................................................... 127Scheme 5.2. Eliminative Deoxofluorination of Various Cyclohexanone Derivatives Using XtalFluor-E.a,b ..................................................................................................................... 132Scheme 5.3. Mechanistic Hypothesis.a ............................................................................... 134Schéma 5.4. Équilibre conformationnel entre les formes A et B de l’intermédiaire 5.6. ... 140Schéma 6.1. Réactivité attendue des N-fluorosquaramides envers les énolates. ................ 152Schéma 6.2. Dissociation hétérolytique de réactifs de fluoration électrophile de type N–F. ............................................................................................................................................ 153Schéma 6.3. Dissociation homolytique de réactifs de fluoration électrophile de type N–F. ............................................................................................................................................ 155Schéma 6.4. Stratégie de synthèse des squaramides. ......................................................... 157Schéma 6.5. Voies de fluoration des squaramides. ............................................................ 158Schéma 6.6. Méthylation des squaramides. ........................................................................ 160Schéma 6.7. Chloration des squaramides. .......................................................................... 160Schéma 6.8. Bromation du squaramide 6.4. ....................................................................... 161Schéma 6.9. Deutération du squaramide 6.4. ..................................................................... 161Schéma 7.1. Utilisation du XtalFluor-E pour la synthèse d’isonitriles, nitriles, esters perfluorés et monofluoroalcènes cycliques. ....................................................................... 171Schéma 7.2. Synthèse de monofluoroalcènes à partir de cétones. ..................................... 172Schéma 7.3. Benzylation de Friedel-Crafts par activation de dérivés de phénylcyclopropanol. ......................................................................................................... 172Schéma 7.4. Dissociation hétérolytique d’un dérivé de N-fluorosulfonylhydrazine. ......... 174
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Liste des tableaux
Tableau 1.1. Comparaison des propriétés atomiques de l’atome de fluor avec les atomes d’hydrogène, chlore, brome et iode. ....................................................................................... 2Tableau 1.2. Comparaison des caractéristiques des liaisons C–X. ......................................... 3Tableau 1.3. Comparaison des propriétés du DAST avec celles du XtalFluor-E. ............... 18Table 2.1. Selected optimization results for the dehydration of formamide 2.1. ................. 42Table 2.2. Scope of the dehydration of formamides with XtalFluor-E.a .............................. 44Table 2.3. Synthesis of α-acyloxyamide using crude isocyanides.a,b ................................... 47Table 4.1. Optimization Results for the Esterification of 5-Phenylvaleric acid (4.2) with TFE Using XtalFluor-E.a ...................................................................................................... 93Table 5.1. Key Optimization Results for the Eliminative Deoxofluorination of 5.1a Using XtalFluor-E.a ....................................................................................................................... 130Tableau 5.2. Étude de l’influence de la température. ......................................................... 136Tableau 5.3. Étude de l’influence du nombre d’équivalents de XtalFluor-E. .................... 137Tableau 5.4. Étude de l’influence de l’ordre et du temps d’ajout des réactifs. .................. 138Table 5.5. Additional Optimization Results for the Eliminative Deoxofluorination of 5.1a Using XtalFluor-E. ............................................................................................................. 142Tableau 6.1. Tentatives de fluoration des squaramides. ..................................................... 159
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Liste des abréviations
Ac acétyle Ar aryle BDE bond dissociation enthalpy Bn benzyle Boc tert-butoxycarbonyle Bu butyle Bz benzoyle Cbz carboxybenzyle Cys cystéine DAST trifluorure de diéthylaminosulfure DBU 1,8-diazabicyclo[5.4.0]undéc-7-ène DCE 1,2-dichloroéthane DIBAl-H hydrure de diisobutylaluminium DIPEA N,N-diisopropyléthylamine DMA diméthylacétamide DME 1,2-diméthoxyéthane DMF diméthylformamide DMPU 1,3-diméthyl-3,4,5,6-tétrahydro-2(1H)-pyrimidinone DMSO diméthylsulfoxyde DSC calorimétrie différentielle à balayage ee excès énantiomérique équiv. équivalent Et éthyle FPD fluorine plus detachment HFIP 1,1,1,3,3,3-hexafluoroisopropan-2-ol HMDS hexaméthyldisilamidure HPLC chromatographie en phase liquide à haute pression i-Pr iso-propyle Me méthyle MOM méthoxyméthyle MS tamis moléculaire NFSI N-fluorobenzènesulfonimide NMP N-méthyl-2-pyrrolidone NMR résonance magnétique nucléaire (nuclear magnetic resonance) Nu nucléophile Ph phényle PMB p-méthoxybenzyle PTFE polytétrafluoroéthylène RMN résonance magnétique nucléaire rt température ambiante (room temperature) Ser sérine SMD modèle de solvatation basé sur la densité SN substitution nucléophile t.a. température ambiante
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t-Bu tert-butyle TBAF fluorure de tétrabutylammonium TBS tert-butyldiméthylsilyle temp. température TES triéthylsilyle Tf trifluorométhylsulfonyle TFA acide trifluoroacétique TFE 2,2,2-trifluoroéthanol THF tétrahydrofurane Tr trityle TrisNHNH2 hydrazide de 2,4,6-triisopropylbenzènesulfonyle Ts tosyle
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Remerciements
Je tiens à remercier chaleureusement mon directeur de thèse, le professeur Jean-François
Paquin, de m’avoir accueillie dans son laboratoire afin que je puisse y réaliser ma thèse,
dans le domaine stimulant de la chimie des composés organofluorés. Je le remercie pour sa
grande disponibilité, son soutien et ses conseils judicieux, mais aussi de m’avoir partagé
son inestimable expérience dans ce domaine. Je souhaite également le remercier de m’avoir
donné l’occasion d’écrire des articles dans des journaux renommés, et d’assister à de
nombreux congrès.
Je remercie le professeur André Beauchemin d’avoir accepté d’évaluer cette thèse en tant
qu’examinateur externe, ainsi que les professeurs Denis Giguère et Thierry Ollevier en tant
qu’examinateurs internes.
Je souhaite ensuite remercier tous les membres du laboratoire, passés et présents, avec
lesquels j’ai partagé de bons moments et des discussions enrichissantes au quotidien. De
près ou de loin, ils m’ont tous aidée à devenir la chercheuse que je suis aujourd’hui. Un
énorme merci à Massaba, qui a grandement contribué au projet relatif au XtalFluor, ainsi
qu’à Eliane, Audrey et Léa, qui ont chacune apporté leur pierre à l’édifice. Un merci
particulier à Elsa, qui m’a très bien accueillie dès mon arrivée à Québec et avec qui j’ai
passé d’excellents moments, que ce soit au sein du labo ou en dehors. Merci aussi à
Myriam et Audrey, avec qui j’ai eu beaucoup de fun lors des nombreuses soirées et sorties
de lab, à PA et JD d’avoir toujours été disponibles lorsque j’avais des questions ou que je
doutais de moi, à Justine d’avoir été une super voisine de hotte tout au long de mon
doctorat, à Paul pour ses conseils en matière de calculs ab initio, à Majdouline pour sa
gentillesse infinie, et à Marius, toujours partant pour une bière ou un barbecue.
Je remercie aussi tous les employés du département, qui ont toujours été disponibles et
d’une aide précieuse. Je pense notamment à Pierre Audet, Christian Côté, Jean Laferrière,
Mélanie Tremblay, Denyse Michaud et Marie Tremblay.
Cette thèse étant la raison de ma présence à Québec, je me dois également de remercier
toutes les personnes qui m’ont entourée, encouragée, et ont formé ma « famille
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québécoise ». Je pense ici à JF, mon compatriote belge, mais aussi à tous les membres de
« Lundi BBQ », pour les très nombreuses soirées du vendredi, soirées film et sorties, ainsi
que les multiples brunchs de lendemain de veille, appart’athons, week-ends en nature, et …
barbecues du lundi. Merci donc à Alina, Laurence, Marjo, Arnaud, Fanny, Ben, Sean,
Sinen, Romain, Steph, PJ, Julia, Anne-So, Julien, Nizar, Larbi, les quatre Marseillais et
tous les autres. Je remercie également les nombreux colocs qui sont passés par le 524
Richelieu, et plus particulièrement Manon et Belén, qui ont toujours été là pour me
remonter le moral dans les instants plus difficiles, et avec qui j’ai partagé énormément de
moments inoubliables. J’espère sincèrement les revoir de l’autre côté de l’Atlantique : en
Belgique, en France ou en Espagne.
Je tiens aussi à adresser mes remerciements à mes amis de Belgique, qui m’ont toujours
soutenue à distance. Merci à Kala, Kiki et Pooka pour les nombreux skypes copines, et aux
Quentin’s de s’être inquiétés de ma survie au Canada depuis le début…
Enfin, je remercie ma famille pour leurs encouragements et leurs visites à Québec. Un
merci plus particulier à mes parents, qui m’ont constamment soutenue, que ce soit par e-
mail, whatsapp, skype, par l’envoi de cartes ou de chocolat, et qui ont traversé l’Atlantique
pour assister à la soutenance de ma thèse.
xvi
Avant-propos
Les travaux de recherche présentés ci-après font l’objet d’une collaboration avec la
compagnie québécoise OmegaChem, spécialisée dans le développement de molécules de
synthèse. Ces travaux sont financés par une subvention de recherche et développement
coopérative (RDC) du CRSNG.
Cette thèse est divisée en 7 chapitres. Une introduction générale présente d’abord l’état de
l’art de la chimie du fluor et du XtalFluor, et relie les différents chapitres qui vont suivre
entre eux. Les chapitres 2 à 5 sont constitués d’articles scientifiques auxquels j’ai contribué
de manière significative. Le texte et les figures de ces articles ont été recopiés sans
modifications, excepté la numérotation des schémas, tableaux, figures et molécules. Le
chapitre 6 décrit ensuite des résultats non publiés, qui nécessitent encore des recherches
plus approfondies. Enfin, la thèse se conclut par un retour aux objectifs et la mise en place
de perspectives.
Le chapitre 2 est tiré d’un article intitulé « Synthesis of isocyanides through dehydration of
formamides using XtalFluor-E » paru dans Tetrahedron Letters et publié en ligne le 4
décembre 2014. L’optimisation de la réaction a été effectuée par Massaba Keita et Olivier
Mahé, tous deux stagiaires postdoctoraux. J’ai réalisé une partie des expériences
nécessaires à l’étendue de la réaction, en partenariat avec Massaba. Nous avons également
toutes les deux contribué à la préparation du document d’informations supplémentaires. Le
manuscrit a été rédigé principalement par mon directeur de thèse, le professeur Jean-
François Paquin.
Le chapitre 3 provient d’un article intitulé « Synthesis of Nitriles from Aldoximes and
Primary Amides Using XtalFluor-E » paru dans Synthesis et publié en ligne le 20 août
2015. Les premiers tests ont été réalisés par Massaba Keita, puis les expériences
nécessaires à l’étendue de la réaction (synthèse des substrats de départ et formation des
nitriles) ont été partagées entre Massaba et moi-même. Nous avons également écrit la partie
expérimentale ensemble, tandis que le manuscrit a été rédigé principalement par mon
directeur Jean-François Paquin.
xvii
Le chapitre 4 est issu d’un article intitulé « Direct Esterification of Carboxylic Acids with
Perfluorinated Alcohols Mediated by XtalFluor-E » paru dans Organic Letters et publié en
ligne le 7 décembre 2016. Massaba Keita a participé à l’optimisation de la réaction, tandis
que Léa Bouchard et Audrey Gilbert, toutes deux stagiaires au baccalauréat, ont synthétisé
quelques esters perfluorés. Quant à moi, j’ai orchestré le projet en complétant
l’optimisation, et en effectuant la majeure partie des expériences nécessaires à l’étendue de
la réaction et à l’étude du mécanisme. J’ai également préparé le document d’informations
supplémentaires, avec la contribution de Léa et Audrey. Le manuscrit a été principalement
rédigé par mon directeur Jean-François Paquin. La partie annexe comporte les résultats de
Massaba et Audrey concernant les esters non fluorés, et l’étude du mécanisme de la
réaction par chimie computationnelle a été réalisée par moi-même.
Quant au chapitre 5, il est tiré d’un article intitulé « Eliminative Deoxofluorination Using
XtalFluor-E: A One-Step Synthesis of Monofluoroalkenes from Cyclohexanone
Derivatives » paru dans Organic Letters et publié en ligne le 27 juin 2017. J’ai réalisé
l’entièreté des expériences nécessaires à la publication de cet article, de même que la
préparation du document d’informations supplémentaires. Le manuscrit a été rédigé
principalement par mon directeur Jean-François Paquin. Les résultats annexes décrivent des
expériences effectuées par moi-même.
Enfin, le chapitre 6 est composé de résultats non publiés issus d’expériences que j’ai
réalisées seule, y compris les calculs ab initio. Même si ces expériences n’ont pas toutes
abouti à des résultats concluants, cela constitue néanmoins des données intéressantes à
prendre en compte lors d’une poursuite éventuelle du projet.
1
CHAPITRE 1
Introduction
1.1 LE FLUOR EN CHIMIE ORGANIQUE
Lorsque le fluor est évoqué, Monsieur Tout-le-Monde a tendance à penser au dentifrice, et
plus particulièrement aux fluorures qui permettent de renforcer l’émail des dents et limiter
l’apparition de caries. Selon certains, le fluor est même toxique, il est responsable de tous
les maux et les industries pharmaceutiques nous empoisonnent !1 C’est dans de telles
situations que le rôle du scientifique intervient : informer la population, discerner le vrai du
faux, et faire la distinction entre les ions fluorures et les molécules organofluorées. Ces
dernières comportent un atome de fluor lié de manière covalente au reste de la molécule et
peuvent s’avérer précieuses pour de multiples applications, au vu des propriétés
exceptionnelles de l’atome de fluor.
1.1.1 Propriétés physico-chimiques
L’intérêt porté par de nombreux chimistes sur l’atome de fluor s’explique par les propriétés
extrêmes de cet atome.2,3 Le fluor est l’élément le plus léger de la série des halogènes, mais
aussi le plus électronégatif du tableau périodique (3,98 sur l’échelle de Pauling) (Tableau
(1) Exemple typique d’information erronée circulant sur le web : Le fluor toxique règne dans la pharmacie. http://www.alterinfo.net/Le-fluor-toxique-regne-dans-la-pharmacie_a81311.html, consulté le 31 mai 2017. (2) Livres généraux sur la chimie des molécules organofluorées : (a) Kirsh, P. Introduction. Dans Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications; Wiley-VCH: Weinheim, Germany, 2013. (b) Hiyama, T. Organofluorine Compounds; Chemistry and Applications; Yamamoto, H. (Éd.): Springer, 2000. (3) Revues : (a) Smart, B. E. J. Fluorine Chem. 2001, 109, 3–11. (b) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308–319.
2
1.1).4 Selon les estimations de Bondi, son rayon de van der Waals est de 1,47 Å, ce qui en
fait le plus petit atome après l’hydrogène (1,2 Å).5 Il s’agit également de l’atome le moins
polarisable, avec une polarisabilité qui s’élève à 0,557 Å3.6
Tableau 1.1. Comparaison des propriétés atomiques de l’atome de fluor avec les atomes d’hydrogène, chlore, brome et iode.
Atome Électronégativité Rayon de van der Waals (Å) Polarisabilité (Å3)
H 2,2 1,2 0,667 F 3,98 1,47 0,557 Cl 3,16 1,75 2,18 Br 2,96 1,85 3,05 I 2,66 1,98 4,7
Les liaisons C–F sont également dotées de propriétés exceptionnelles grâce au
recouvrement presque optimal des orbitales 2s et 2p de l’atome de fluor avec celles du
carbone.3 De ce fait, le lien C–F (1,38 Å) se classe en deuxième position, juste après le lien
C–H (1,09 Å) en matière de longueur de liaison (Tableau 1.2). La liaison C–F comporte
également une très grande énergie de liaison (115,7 kcal/mol), ce qui en fait la liaison
simple la plus forte que peut faire le carbone avec n’importe quel autre atome. Ceci
s’explique par la grande différence d’électronégativité entre ces deux atomes, conférant
ainsi un caractère fortement ionique à la liaison. De la même façon, cela rend la liaison très
polarisée, avec un moment dipolaire typique qui avoisine 1,41 D.
(4) Sen, K. D.; Jorgensen, C. K. Electronegativity, Springer-Verlag, New York, 1987. (5) Bondi, A. J. Phys. Chem. 1964, 68, 441–451. (6) Nagle, J. K. J. Am. Chem. Soc. 1990, 112, 4741–4747.
3
Tableau 1.2. Comparaison des caractéristiques des liaisons C–X.
Atome X Longueur de liaison C–X (Å)
Énergie de liaison C–X (kcal/mol)
Moment dipolaire C–X (D)
H 1,09 98,0 0,4 F 1,38 115,7 1,41 Cl 1,77 77,2 1,46 Br 1,94 64,3 1,38 I 2,13 50,7 1,19
Les propriétés physiques extrêmes de l’atome de fluor énumérées ci-dessus mènent
également à des propriétés chimiques intéressantes.2,3 À cause de son effet inductif
électroattracteur non négligeable, l’introduction d’un atome de fluor dans une molécule
augmente de manière considérable l’acidité des groupements ionisables à proximité, tout en
diminuant la basicité des groupements fonctionnels voisins. On remarque aussi une
influence sur la lipophilie puisque d’une manière générale, les molécules fluorées auront
tendance à être plus lipophiles que leur analogue non fluoré. Enfin, l’atome de fluor peut
être impliqué dans des ponts hydrogène en tant qu’accepteur de liaisons hydrogène.7
Cependant, ces liaisons sont de faible énergie étant donné la petite polarisabilité de la
liaison C–F et des doublets du fluor, qui ne contribue ainsi que moindrement au transfert
d’électrons.
1.1.2 Applications en chimie organique
1.1.2.1 Chimie médicinale
Les molécules fluorées sont omniprésentes en chimie médicinale puisque environ 25 % des
médicaments actuellement sur le marché comportent au moins un atome de fluor (Figure
1.1).8 L’insertion d’un atome de fluor dans une molécule altère de manière significative ses
(7) Champagne, P. A.; Desroches, J.; Paquin, J.-F. Synthesis 2015, 47, 306–322. (8) Revues : (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320–330. (b) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359–4369. (c) Kirk, K. L. Org. Process. Res. Dev. 2008, 12, 305–321. (d) Wang, J.; Sánchez-Roselló, M.; Luis Aceña, J.; del Pozo, C.; Sorochinsky, A. E.; Fustero, S.;
4
propriétés chimiques et peut ainsi augmenter son affinité avec sa cible biologique (par des
interactions dipôle-dipôle, ponts H, etc.), mais également améliorer ses propriétés
pharmacocinétiques. Les molécules fluorées étant bien souvent plus lipophiles que leur
analogue non fluoré, le passage à travers les bicouches lipidiques sera facilité et le
médicament aura une meilleure biodisponibilité. D’autre part, la force de la liaison C–F
ainsi que l’effet électroattracteur de l’atome de fluor permettent à la molécule de mieux
résister aux divers processus métaboliques impliqués (métabolismes oxydatif et
hydrolytique).
Figure 1.1. Exemples de médicaments fluorés.
En outre, les molécules fluorées sont utilisées comme sondes biochimiques pour l’étude de
divers processus biologiques, et le fait que les noyaux 19F soient actifs en RMN permet
l’utilisation de l’imagerie par résonance magnétique (IRM) in vivo.9
Enfin, la tomographie par émission de positons (TEP) utilisant des molécules marquées au
fluor radioactif 18F permet de diagnostiquer, localiser et détecter la récurrence et la
progression de diverses maladies telles que le cancer.10
Soloshonok, V. A.; Liu, H. Chem. Rev. 2014, 114, 2432–2506. (e) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. J. Med. Chem. 2015, 58, 8315–8359. (9) Revues: (a) Bartusik, D.; Tomanek, B. Adv. Drug Deliv. Rev. 2013, 65, 1056–1064. (b) Chen, H.; Viel, S.; Ziarelli, F.; Peng, L. Chem. Soc. Rev. 2013, 42, 7971–7982.
N CO2HOHOH
Ph
PhHNO2C
i-Pr
F
AtorvastatineLipitor®
régulateur du métabolisme lipidique
MeHN O
Ph CF3NN
OCO2HF
HN
CiprofloxacineCiprobay®
antibactérien
FluoxétineProzac®
antidépresseur
5
1.1.2.2 Agrochimie
L’effet des substituants fluorés sur l’activité biologique des systèmes organiques a
également été largement utilisé dans le domaine de l’agrochimie.11 Ainsi, de nombreux
herbicides, insecticides et fongicides comportent au moins un atome de fluor au sein de leur
structure, bien souvent sous forme de fluorure d’aryle ou d’aryltrifluorométhyle (Figure
1.2).
Figure 1.2. Exemples de produits agrochimiques fluorés.
1.1.2.3 Chimie des matériaux
Depuis la découverte du polytétrafluoroéthylène (PTFE) en 1930, de nombreux polymères
fluorés ont été exploités dans le domaine des matériaux, grâce à leur grande stabilité
chimique et thermique.11e,12 Ceux-ci se retrouvent par exemple utilisés pour des
(10) Fletcher, J. W.; Djulbegovic, B.; Soares, H. P.; Siegel, B. A.; Lowe, V. J.; Lyman, G. H.; Coleman, R. E.; Wahl, R.; Paschold, J. C.; Avril, N.; Einhorn, L. H.; Suh, W. W.; Samson, D.; Delbeke, D.; Gorman, M.; Shields, A. F. J. Nucl. Med. 2008, 49, 480–508. (11) (a) Jeschke, P. ChemBioChem 2004, 5, 570–589. (b) Jeschke, P. Pest. Manag. Sci. 2010, 66, 10–27. (c) Giornal, F.; Pazenok, S.; Rodefeld, L.; Lui, N.; Vors, J.-P.; Leroux, F. R. J. Fluorine Chem. 2013, 152, 2–11. (d) Fujiwara, T.; O’Hagan, D. J. Fluorine Chem. 2014, 167, 16–29. (e) Harsanyi, A.; Sandford, G. Green Chem. 2015, 17, 2081–2086. (12) Berger, R.; Resnati, G.; Metrangolo, P.; Weber, E.; Hulliger, J. Chem. Soc. Rev. 2011, 40, 3496–3508.
NO2
F3C
NO2
NF
F
NH
O
NH
O
ClF
Cl
FNOMe
OMeO
O N
CF3
TeflubenzuronNomolt®
insecticide
TrifloxystrobineFlint®
fongicide
BenfluralineBalan®
herbicide
6
revêtements de poêles (PTFE, Teflon®), des vêtements imperméables (PTFE, Goretex®),
des réfrigérants (chlorofluorocarbones) et dans des cellules photovoltaïques.13
1.2 MÉTHODES DE FLUORATION
Les molécules organofluorées sont très peu abondantes naturellement : seuls 19 composés
ont été identifiés à ce jour.14 Ceci incite donc fortement les chimistes à consacrer leurs
recherches au développement de nouvelles méthodes de fluoration, qui sont maintenant
largement décrites dans la littérature.15
L’introduction d’un atome de fluor peut être réalisée par trois approches différentes, qui
varient selon la nature électronique du fluor (nucléophile, électrophile ou radicalaire). Les
réactions de fluoration électrophile et nucléophile sont les méthodes les plus courantes, bien
que la fluoration radicalaire émerge comme une alternative viable.16 Nous nous
consacrerons ici essentiellement aux fluorations nucléophile et électrophile.
1.2.1 Fluoration nucléophile
En fluoration nucléophile, l’atome de fluor est fourni sous forme de fluorure, tandis que le
substrat joue le rôle de l’électrophile.15,17 Il s’agit bien souvent d’une simple substitution
(13) Xu, X.-P.; Li, Y.; Luo, M.-M.; Peng, Q. Chin. Chem. Lett. 2016, 27, 1241–1249. (14) Walker, M. C.; Chang, M. C. Y. Chem. Soc. Rev. 2014, 43, 6527–6536. (15) Revues récentes : (a) Prakash, C. K. S.; Wang, F.; O’Hagan, D.; Hu, J.; Ding, K.; Dai, L.-X. Flourishing Frontiers in Organofluorine Chemistry. Dans Organic Chemistry – Breakthroughs and Perspectives; Ding, K., Dai, L.-X., Eds.; Wiley-VCH: Weinheim, Germany, 2012. (b) Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem., Int. Ed. 2013, 52, 8214–8264. (c) Yang, X.; Wu, T.; Phipps, R. J.; Toste, F. D. Chem. Rev. 2015, 115, 826–870. (d) Campbell, M. G.; Ritter, T. Chem. Rev. 2015, 115, 612–633. (e) Champagne, P. A.; Desroches, J.; Hamel, J.-D.; Vandamme, M.; Paquin, J.-F. Chem. Rev. 2015, 115, 9073–9174. (16) (a) Rueda-Becerril, M. ; Chatalova Sazepin, C. ; Leung, J. C. T. ; Okbinoglu, T. ; Kennepohl, P. ; Paquin, J.-F. ; Sammis, G. M. J. Am. Chem. Soc. 2012, 134, 4026–4029. (b) Sibi, M. P.; Landais, Y. Angew. Chem., Int. Ed. 2013, 52, 3570–3572. (c) Chatalova Sazepin, C.; Hemelaere, R.; Paquin, J.-F.; Sammis, G. Synthesis 2015, 47, 2554–2569. (17) Revues récentes consacrées à la fluoration nucléophile: (a) Hollingworth, C.; Gouverneur, V. Chem. Commun. 2012, 48, 2929–2942. (b) Wu, J. Tetrahedron Lett. 2014, 55, 4289–4294.
7
nucléophile au cours de laquelle une chaîne alkyle ou un cycle aromatique comportant un
groupe partant réagit avec une source de fluorure (Schéma 1.1).
Schéma 1.1. Fluoration nucléophile.
De nombreuses sources de fluorure ont été utilisées au fil des années. Ainsi, les réactifs de
fluoration traditionnels sont essentiellement des fluorures de métaux alcalins (KF, CsF), des
réactifs à base de HF (HF/pyridine, Et3N·3HF), des silicates et des stannates hypervalents
fluorés et des fluorures de tétraalkylammonium (fluorure de tétrabutylammonium, abrégé
TBAF) (Figure 1.3). Les dérivés d’halogène hypervalent constituent également une classe
importante de réactifs de fluoration nucléophile, comme le tétrafluoroborate de
bis(pyridine)iodonium(I) (IPy2BF4),18 le difluorure de para-iodotoluène (p-Tol-IF2)19 ou le
difluorure de para-trifluorométhylphénylbromonium (p-CF3-C6H4-BrF2).20 Enfin, plus
récemment, de nouveaux réactifs ont été développés de manière à étendre encore davantage
les possibilités de fluoration nucléophile de manière plus efficace et pour un large éventail
de substrats. Parmi ces nouveaux réactifs, on retrouve deux dérivés du TBAF (une version
anhydre du TBAF et le TBAF(t-BuOH)4),21,22 le IF5-pyridine-HF,23 le BrF3-KHF224 et le
DMPU/HF (complexe de 1,3-diméthyl-3,4,5,6-tétrahydro-2(1H)-pyrimidinone avec HF).25
(18) Barluenga, J.; Gonzalez, J. M.; Campos, P. J.; Asensio, G. Angew. Chem., Int. Ed. Engl. 1985, 24, 319–320. (19) Tsushima, T.; Kawada, K.; Tsuji, T. Tetrahedron Lett. 1982, 23, 1165–1168. (20) Frohn, H. J.; Giesen, M. J. Fluorine Chem. 1998, 89, 59–63. (21) Sun, H.; DiMagno, S. G. J. Am. Chem. Soc. 2005, 127, 2050–2051.
R2
R1 X
XR
source de F–R2
R1 F
FR
X = halogénure ou sulfonate
8
Figure 1.3. Exemples de réactifs de fluoration nucléophile.
La réaction de déoxofluoration est un cas particulier de fluoration nucléophile et est une des
stratégies les plus intéressantes pour l’introduction d’un atome de fluor au sein d’une
molécule organique. Ceci s’explique par l’abondance et l’accessibilité de précurseurs
comportant des fonctions alcools.26 Les produits fluorés sont obtenus en une synthèse
monotope au cours de laquelle l’alcool est d’abord activé, puis subit une substitution
nucléophile par un ion fluorure (Schéma 1.2).
(22) Kim, D. W.; Jeong, H.-J.; Lim, S. T.; Sohn, M.-H. Angew. Chem., Int. Ed. 2008, 47, 8404–8406. (23) Hara, S.; Monoi, M.; Umemura, R.; Fuse, C. Tetrahedron 2012, 68, 10145–10150. (24) Shishimi, T.; Hara, S. J. Fluorine Chem. 2014, 168, 55–60. (25) Okoromoba, O. E.; Han, J.; Hammond, G. B.; Xu, B. J. Am. Chem. Soc. 2014, 136, 14381–14384. (26) (a) Dax, K. Synthesis by Substitution of Hydroxy Groups in Alcohols. Dans Science of Synthesis; Percy, J. M., Éd.; Thieme Chemistry; Stuttgart, Germany, 2006; pp 71–148. (b) Al-Maharik, N.; O’Hagan, D. Aldrichimica Acta 2011, 44, 65–75. (c) Vandamme, M.; Paquin, J.-F. Synthesis by Substitution of Hydroxy Groups in Alcohols. Dans Science of Synthesis Knowledge Updates 2016/1; Paquin, J.-F., Éd.; Thieme Chemistry: Stuttgart, Germany, 2016; pp 395–408.
N
N
N
⋅ (HF)x n-Bu4N+F– n-Bu4N+Ph2SiF2–
I N I F
F
F3C
Br F
F
BF4–
IF5⋅ (HF) BrF3⋅KHF2 N NMe Me
O
⋅ (HF)x
HF/pyridine TBAF TBAT
DMPU/HFBrF3⋅KHF2IF5-pyridine-HF
IPy2BF4 p-Tol-IF2 p-CF3-C6H4-BrF2
9
Schéma 1.2. Réaction de déoxofluoration.
Parmi les nombreux réactifs capables d’effectuer cette transformation, le DAST27
(trifluorure de diéthylaminosulfure) et le Deoxo-Fluor28 (trifluorure de bis(2-
méthoxyéthyl)aminosulfure) sont les deux réactifs commerciaux les plus couramment
utilisés (Figure 1.4).29 Cependant, des inconvénients sont associés à leur utilisation. Il s’agit
notamment de leur instabilité thermique, leur mauvaise chimiosélectivité et la génération de
produits secondaires d’élimination. Ceci a mené ainsi au développement récent de
nouveaux réactifs de déoxofluoration (Figure 1.4), tels que le Fluolead30 (trifluorure de 4-
tert-butyl-2,6-diméthyl phénylsoufre), les XtalFluor-E et -M31 (sels de tétrafluoroborate
d’aminodifluorosulfinium), le PhenoFluor (1,3-bis(2,6-diisopropylphényl)-2,2-difluoro-2,3-
dihydro-1H-imidazole) utilisé pour les phénols32 et les alcools33, le PyFluor34 (fluorure de
2-pyridinesulfonyle) et le CpFluor35 (1,2-diaryl-3,3-difluorocyclopropène).
(27) Middleton, W. J. J. Org. Chem. 1975, 40, 574–578. (28) Lal, G. S.; Pez, G. P.; Pesaresi, R. J.; Prozonic, F. M. Chem. Commun. 1999, 215–216. (29) Revue: Singh, R. P. ; Shreeve, J. M. Synthesis 2002, 2561–2578. (30) Umemoto, T.; Singh, R. P.; Xu, Y.; Saito, N. J. Am. Chem. Soc. 2010, 132, 18199–18205. (31) (a) Beaulieu, F.; Beauregard, L.-P.; Courchesne, G.; Couturier, M.; Laflamme, F.; L’Heureux, A. Org. Lett. 2009, 11, 5050–5053. (b) L’Heureux, A.; Beaulieu, F.; Bennet, C.; Bill, D. R.; Clayton, S.; Laflamme, F.; Mirmehrabi, M.; Tadayon, S.; Tovell, D.; Couturier, M. J. Org. Chem. 2010, 75, 3401–3411. (c) Mahé, O.; L'Heureux, A.; Couturier, M.; Bennett, C.; Clayton, S.; Tovell, D.; Beaulieu, F.; Paquin, J.-F. J. Fluorine Chem. 2013, 153, 57–60. (32) Tang, P.; Wang, W.; Ritter, T. J. Am. Chem. Soc. 2011, 133, 11482–11484. (33) Sladojevich, F.; Arlow, S. I.; Tang, P.; Ritter, T. J. Am. Chem. Soc. 2013, 135, 2470–2473. (34) Nielsen, M. K.; Ugaz, C. R.; Li, W. P.; Doyle, A. G. J. Am. Chem. Soc. 2015, 137, 9571–9574. (35) Li, L.; Ni, C.; Wang, F.; Hu, J. Nature Commun. 2016, 7, 13320.
R2R1
OH
R2R1
FF–
R2R1
O [X][X]–F
alcool activé
10
Figure 1.4. Réactifs de déoxofluoration.
1.2.2 Fluoration électrophile
En fluoration électrophile, les rôles sont inversés puisque le substrat se comporte comme le
nucléophile tandis que l’atome de fluor est fourni sous forme d’un équivalent de « F+ ».15,36
Le nucléophile peut aussi bien se présenter sous la forme d’un carbanion (ex : réactifs de
Grignard), d’une insaturation riche en électrons (arène, alcène ou alcyne), ou d’un substrat
comportant un groupement labile lié à un nucléophile (Schéma 1.3). Bien que les sources
de fluor électrophile soient souvent considérées comme des sources de « F+ », elles ne
génèrent véritablement aucune espèce de cette sorte puisque cela serait très défavorable
d’un point de vue énergétique.
(36) Revue consacrée à la fluoration électrophile : Taylor, S. D.; Kotoris, C. C.; Hum, G. Tetrahedron 1999, 55, 12431–12477.
N SF3 N SF3
MeO
MeO
N SF
F
BF4–
N SF
F
BF4–
O
SF3Me
Met-Bu
N N
F F
i-Pr
i-Pr
i-Pr
i-Pr
DAST Deoxo-Fluor XtalFluor-E XtalFluor-M
Fluolead PhenoFluor
F F
Ar Ar
CpFluor
N
S F
O O
PyFluor
11
Schéma 1.3. Fluoration électrophile.
Les premiers réactifs de fluoration électrophile comportaient des liaisons O–F (ex : CH3OF,
HOF, CsSO4F), Xe–F (XeF2) ou F–F (F2), mais ces composés montraient une très grande
réactivité et une faible sélectivité. La plupart des sources de « F+ » utilisées de nos jours
sont des réactifs dans lesquels l’atome de fluor est lié à un atome d’azote, ce qui les rend
plus stables et dont la commercialisation est ainsi possible.37 Les sels de N-
fluoropyridinium (NFPy)38, le NFSI (N-fluorobenzènesulfonimide),39 le Selectfluor
(bis(tétrafluoroborate) de 1-chlorométhyl-4-fluoro-1,4-diazoniabicyclo[2,2,2]octane)40 et
son dérivé l’Accufluor (bis(tétrafluoroborate) de 1-fluoro-4-hydroxy-1,4-
diazoniabicyclo[2,2,2]octane)41 constituent les réactifs utilisés le plus couramment (Figure
1.5).
(37) Revues : (a) Lal, G. S.; Pez, G. P.; Syvret, R. G. Chem. Rev. 1996, 96, 1737–1756. (b) Baudoux, J.; Cahard, D. Org. React. 2007, 69, 1–326. (38) Umemoto, T.; Tomita, K. Tetrahedron Lett. 1986, 27, 3271–3274. (39) Differding, E.; Ofner, H. Synlett 1991, 187–189. (40) Banks, R. E.; Mohialdin-Khaffaf, S. N.; Lal, G. S.; Sharif, L.; Syvret, R. G. J. Chem. Soc., Chem. Commun. 1992, 595–596. (41) Stavber, S.; Zupan, M.; Poss, A. J.; Shia, G. A. Tetrahedron Lett. 1995, 36, 6769–6772.
Rsource de " F+ " F
R
X = SiR3, SnR3, BR2 ou BR3–
X F
R3C FR3C
12
Figure 1.5. Exemples de réactifs de fluoration électrophile.
Bien que ces réactifs aient démontré leur efficacité pour toutes sortes de transformations, il
subsiste toujours des réactions pour lesquelles ces sources de « F+ » ne se comportent pas
comme attendu (ou espéré). Ainsi, il a été observé dans certains cas un transfert de la
phényle sulfone du NFSI,42 et dans d’autres cas, la réactivité des quatre molécules
présentées ci-dessus diffère beaucoup. De hauts taux de conversion obtenus avec le
PhSO2N(F)t-Bu peuvent donner de mauvaises conversions et sélectivités en utilisant une
source commerciale de « F+ » telle que le NFSI.43 De subtiles différences dans la structure
du réactif de fluoration peuvent donc mener à des résultats très différents. Enfin, un
problème récurrent reste la question de la solubilité de la source de « F+ » dans le milieu
réactionnel. Le Selectfluor nécessite par exemple des solvants très polaires tels que
l’acétonitrile, l’eau ou le diméthylformamide (DMF), qui ne sont pas toujours compatibles
avec les réactions souhaitées.
La recherche de nouveaux réactifs de fluoration électrophile doit dès lors être poursuivie,
afin que ceux-ci possèdent une réactivité appropriée envers les substrats désirés et une
bonne solubilité dans les solvants organiques couramment utilisés (THF, toluène, etc.). De
plus, le développement de réactifs chiraux permettrait une fluoration énantiosélective. On a
ainsi assisté ces dernières années à l’apparition de nouvelles sources de « F+ », comme de
(42) Snieckus, V.; Beaulieu, F.; Mohri, K.; Han, W.; Murphy, C. K.; Davies, F. A. Tetrahedron Lett. 1994, 35, 3465–3468. (43) (a) Lee, S.-H.; Riediker, M.; Schwartz, J. Bull. Korean Chem. Soc. 1998, 19, 760–766. (b) Marterer, J.; Paquin, J.-F. Résultats non publiés.
NF
RNF
S SPhPh
O OO ONN
Cl
FNNOH
F2 BF4– 2 BF4–X–
X = BF4 ou TfONFPy NFSI Selectfluor Accufluor
13
nouveaux dérivés de NFSI,44 mais aussi des dérivés chiraux de Selectfluor45 et de NFSI46
(Figure 1.6).
Figure 1.6. Réactifs de fluoration électrophile récents.
1.2.3 Fluoration radicalaire
En fluoration radicalaire, la liaison C–F est formée par réaction d’un carbone radicalaire
(généré in situ de diverses manières) avec une source de fluor atomique.16 Les premiers
réactifs utilisés pour cette approche ont été le XeF2, l’hypofluorite et le fluor moléculaire.47
(44) NFBSI : (a) Yasui, H.; Yamamoto, T.; Ishimaru, T.; Fukuzumi, T.; Tokunaga, E.; Akikazu, K.; Shiro, M.; Shibata, N. J. Fluorine Chem. 2011, 132, 222–225. 4,4'-diF-NFSI : (b) Wang, F.; Li, J.; Hu, Q.; Yang, X.; Wu, X. Y.; He, H. Eur. J. Org. Chem. 2014, 3607–3613. (45) Wolstenhulme, J. R.; Rosenqvist, J.; Lozano, O.; Ilupeju, J.; Wurz, N.; Engle, K. M.; Pidgeon, G. W.; Moore, P. R.; Sandford, G.; Gouverneur, V. Angew. Chem., Int. Ed. 2013, 52, 9796–9800. (46) Zhu, C.-L.; Maeno, M.; Zhang, F.-G.; Shigehiro, T.; Kagawa, T.; Kawada, K.; Shibata, N.; Ma, J.-A.; Cahard, D. Eur. J. Org. Chem. 2013, 6501–6505. (47) (a) Grakauskas, V. J. Org. Chem. 1969, 34, 2446–2450. (b) Rozen, S. Acc. Chem. Res. 1988, 21, 307–312. (c) Patrick, T. B.; Khazaeli, S.; Nadji, S.; Hering-Smith, K.; Reif, D. J. Org. Chem. 1993, 58, 705–708.
NF
S SO OO O
NNMe
F2 TfO–
Dérivé chiraldu NFSI
NFBSI 4,4'-diF-NFSI
Dérivé chiraldu Selectfluor
CF3
CF3
FF
NF
S SO OO O
OMeMeO
t-Bu
t-But-Bu
t-Bu
S
SN
OOF
OO
14
De plus récentes contributions dans le domaine ont montré que des réactifs de fluoration
électrophile de type N–F16a ainsi que certains solvants fluorés48 pouvaient se comporter
comme des agents de transfert de fluor atomique.
1.3 LE XTALFLUOR
Parmi les réactifs de fluoration nucléophile, nous nous sommes intéressés plus
particulièrement au XtalFluor. Celui-ci possède un double rôle puisqu’il peut se comporter
à la fois comme agent de fluoration et comme agent activant.
1.3.1 Découverte du XtalFluor
Les premiers exemples de sels de dialkylaminodifluorosulfinium ont été rapportés dans la
littérature en 1977 par le groupe de Markovskii.49 Les auteurs décrivent que le DAST et ses
dérivés réagissent avec l’éthérate de trifluorure de bore (BF3·Et2O) pour donner les sels
d’aminodifluorosulfinium correspondants (Schéma 1.4). Dans ce cas-ci, le trifluorure de
bore n’est pas utilisé comme acide de Lewis, mais plutôt comme accepteur irréversible
d’ions fluorures pour former le tétrafluoroborate de manière irréversible.50
Schéma 1.4. Synthèse de sels de dialkylaminodifluorosulfinium au moyen de BF3·Et2O.
(48) Döbele, M.; Vanderheiden, S.; Jung, N.; Bräse, S. Angew. Chem., Int. Ed. 2010, 49, 5986–5988. (49) Markovskii, L. N.; Pashinnik, V. E.; Saenko, E. P. Zh. Org. Khim. 1977, 13, 1116–1117. (50) Minkwitz, R.; Molsbeck, W.; Oberhammer, H.; Weiss, I. Inorg. Chem. 1992, 31, 2104–2107.
N SR
R F
FF
BF3⋅Et2ON S
R
R F
FBF4-
R = Me, Et, –(CH2)5– –(CH2)2O(CH2)2–
15
D’autres sels de dialkylaminodifluorosulfinium ont ensuite été rapportés par différents
groupes, qui ont fait réagir un dérivé du DAST avec un accepteur d’ions fluorures, tel que
BF3, PF5, SeF4, SbF5 et AsF5.51,52,53,54
En 1996, la substitution d’un hydroxyle allylique par un fluorure dans des prostaglandines
représente le premier exemple de déoxofluoration qui emploie un sel de
dialkylaminodifluorosulfinium (Schéma 1.5).55 Plus précisément, le tétrafluoroborate de
morpholinodifluorosulfinium est utilisé en adjonction avec un dérivé de
triméthyldifluorosilicate de tris(morpholine)sulfonium comme source de fluorure pour
donner un mélange des deux épimères.
Schéma 1.5. Premier exemple d’utilisation d’un sel de dialkylaminodifluorosulfinium comme agent de déoxofluoration.
(51) Cowley, A. H.; Pagel, D. J.; Walker, M. L. J. Am. Chem. Soc. 1978, 100, 7065–7066. (52) Mews, R.; Henle, H. J. Fluorine Chem. 1979, 14, 495–510. (53) Pauer, F.; Erhart, M.; Mews, R.; Stalke, D. Z. Zeitschrift fuer Naturforsch., B: Chem. Sci. 1990, 45, 271–276. (54) Pashinnik, V. E.; Martynyuk, E. G.; Shermolovich, Y. G. Ukr. Khim. Zh. (Russ. Ed.) 2002, 68, 83–87. (55) Bezuglov, V. V.; Pashinnik, V. E.; Tovstenko, V. I.; Markovskii, L. N.; Freimanis, Y. A.; Serkov, I. V. Russ. J. Bioorg. Chem. 1996, 22, 814–822.
O O
OMe
OH
O O
OMe
F
ON S
F
F
BF4
CH3CN
source de F-
O
NS NN
OO
Me3SiF2-
source de F-
85 %
16
Enfin, c’est au cours de ces huit dernières années que la compagnie québécoise
OmegaChem a exploité le potentiel de déoxofluoration de ces composés en présence d’une
source externe de fluorure. OmegaChem a ainsi mis sur le marché deux nouveaux réactifs :
le tétrafluoroborate de diéthylaminodifluorosulfinium et le tétrafluoroborate de
morpholinodifluorosulfinium, appelés respectivement XtalFluor-E et XtalFluor-M (Figure
1.4).31
1.3.2 Méthodes de synthèse
La première méthode de synthèse a été décrite en 1977 par le groupe de Markovskii
(Schéma 1.6).49 Le XtalFluor-E est synthétisé par réaction du DAST avec BF3·Et2O dans
l’éther, puis recristallisé à chaud dans le 1,2-dichloroéthane (DCE) pour mener à la
formation de cristaux en forme d’aiguilles après un rapide refroidissement. Ces cristaux ont
un point de fusion compris entre 74 et 76 °C et sont sensibles à l’humidité.
En 2010, des chimistes de chez OmegaChem ont effectué une recristallisation à une
température plus élevée. Celle-ci ne conduit pas à des cristaux de même morphologie
puisque des flocons ont été obtenus à la place des aiguilles.31b Ce produit est plus dense,
plus propre, plus stable et moins hygroscopique. Son point de fusion s’élève à 83-85 °C.
Une diffraction par rayons X a pu démontrer la génération des deux polymorphes
différents. Le XtalFluor-E sous forme d’aiguilles est appelé polymorphe de type I, tandis
que celui sous forme de flocons correspond au polymorphe de type II.
Cette méthode de synthèse comporte un gros inconvénient, puisque le DAST est un réactif
qui nécessite d’être préalablement distillé. Cette distillation est dangereuse et requiert
d’importantes mesures de sécurité en raison du caractère très explosif du DAST à
température élevée. Une voie de synthèse alternative a ainsi été développée, dans laquelle
le DAST est formé in situ (Schéma 1.6). La diéthyltriméthylsilylamine réagit tout d’abord
avec le SF4 dans le dichlorométhane, puis le BF3·THF est ajouté directement sur le DAST
brut. Après filtration, le XtalFluor-E est obtenu avec un rendement de 90 % sous forme de
cristaux de type II (polymorphe désiré).
17
Schéma 1.6. Méthodes de synthèse du XtalFluor-E.
Enfin, les chimistes de chez OmegaChem ont également mis au point une méthode pour
accéder à la synthèse de triflates de dialkylaminodifluorosulfinium (Schéma 1.7). Il a en
effet été montré que le DAST réagit de manière très exothermique avec HBF4 pour former
le XtalFluor-E, avec élimination concomitante de HF. Ainsi, cette méthode par échange
d’acide de Brønsted donne accès à des sels de dialkylaminodifluorosulfinium comportant
d’autres types de contre-anions. Ces nouveaux sels peuvent posséder des propriétés
intéressantes, comme une augmentation de la température de fusion (97-101 °C pour le
dérivé triflate).
Schéma 1.7. Synthèse de sels de diéthylaminodifluorosulfinium à partir d’acides de Brønsted.
N SF
FF BF3⋅Et2O
Et2ON S
F
F
BF4
N SiMe31) SF4, CH2Cl2 2) BF3⋅THF N S
F
F
BF4N SF
FF
3) filtration
Synthèse décrite en 1977
Synthèse décrite en 2010
90 %
82 %
N SF
FF
HBF4⋅Et2O
Et2ON S
F
F
BF4
96 %
81 %
N SF
F
OTf
Et2O
HOTf
18
1.3.3 Propriétés
Le XtalFluor-E a été conçu comme alternative au DAST, dont l’utilisation comporte de
nombreux inconvénients. Parmi ceux-ci, nous pouvons citer une purification dangereuse,
une grande instabilité, la libération de HF, la génération de produits secondaires
d’élimination, un coût élevé et une manipulation difficile. En comparaison, le XtalFluor-E
se présente sous la forme d’un solide cristallin relativement stable et moins coûteux, qui ne
libère pas de HF libre et dont la quantité de produits secondaires d’élimination est
relativement limitée (Tableau 1.3).31
Tableau 1.3. Comparaison des propriétés du DAST avec celles du XtalFluor-E.
DAST XtalFluor-E
Purification Distillation sous vide Recristallisation
Stabilité Décomposition soudaine et très exothermique à 155 °C
Décomposition progressive aux alentours de 205 °C
Libération de HF Oui Non
Produits secondaires (élimination) Fréquents Peu fréquents
Coût56 1,97 $CAD/mmol 0,824 $CAD/mmol
Apparence Liquide fumant Solide cristallin
La stabilité du XtalFluor-E a été étudiée par des analyses de calorimétrie différentielle à
balayage (DSC), afin d’établir si celui-ci est sécuritaire d’un point de vue thermique (Figure
1.7). Le DAST possède un pic très étroit à 155 °C et dégage 1641 J/g, indiquant une
décomposition soudaine et très exothermique. Le Deoxo-Fluor montre une température de
décomposition similaire (158 °C), mais avec un pic plus large et un dégagement de
1031 J/g. Le XtalFluor-E, quant à lui, se décompose aux alentours de 205 °C avec un
dégagement exothermique de 1260 J/g. Une température de décomposition élevée et un (56) Les prix ont été calculés à partir de la plus grande quantité disponible chez Sigma-Aldrich (juillet 2017). Le DAST est sous forme de solution 1,0 M dans CH2Cl2.
19
faible dégagement d’énergie sont significatifs d’un composé plus stable, et donc plus
sécuritaire. Ainsi, le XtalFluor-E est plus stable que le DAST et le Deoxo-Fluor puisque sa
température de décomposition est supérieure d’environ 50 °C. De meilleurs résultats ont
encore été observés avec le XtalFluor-M, qui se décompose aux alentours de 243 °C et
dégage 773 J/g.
Figure 1.7. Thermogrammes DSC du DAST, Deoxo-Fluor, XtalFuor-E et XtalFluor-M. Figure tirée de la référence 31b.
En plus de cela, lorsque la température est fixée à 90 °C, le XtalFluor-E ne subit aucune
dégradation visible endéans la période de temps consacrée à l’expérience (5000 minutes),
contrairement au DAST et au Deoxo-Fluor qui se dégradent en moins de 300 et 1800
minutes respectivement.
20
1.3.4 Réactif de fluoration
Le XtalFluor a été développé initialement en tant que réactif de déoxofluoration pour des
transformations variées, telles que la formation de fluorures d’alkyle, de
difluorométhylènes ou de fluorures d’acyle.
1.3.4.1 Déoxofluoration d’alcools
La déoxofluoration d’alcools, par réaction avec le XtalFluor et un promoteur, permet
d’obtenir les fluorures d’alkyle correspondants (Schéma 1.8).31 Dans cette transformation,
le promoteur peut être une source de fluorures (Et3N·3HF ou Et3N·2HF), mais également
une base forte telle que le 1,8-diazabicyclo[5.4.0]undéc-7-ène (DBU) dans certains cas. Le
XtalFluor-E et le XtalFluor-M ont généralement une réactivité similaire, tandis que les
autres sels d’aminodifluorosulfinium étudiés n’ont pas fourni de meilleurs résultats.31c
Toutes sortes d’alcools ont été fluorés de cette manière, incluant des alcools primaires,
secondaires, tertiaires, allyliques et anomériques. Dans le cas d’alcools allyliques, la
réaction s’effectue cependant uniquement via un mécanisme SN2’. En outre, la formation de
produits secondaires d’élimination a été rapportée pour certains substrats. Les deux produits
ayant des propriétés physiques similaires, leur séparation demeure quelques fois difficile,
voire impossible.
21
Schéma 1.8. Synthèse de fluorures d’alkyle par déoxofluoration d’alcools.
Depuis cette découverte et avec la commercialisation des XtalFluor-E et -M, de nombreux
autres exemples ont été décrits dans la littérature.57
(57) (a) Srinivasarao, M.; Park, T.; Chen, Y.; Fuchs, P. L. Chem. Commun. 2011, 47, 5858–5860. (b) Lueg, C.; Schepmann, D.; Günther, R.; Brust, P.; Wünsch, B. Bioorg. Med. Chem. 2013, 21, 7481–7498. (c) Juncosa Jr.; J. I.; Groves, A. P.; Xia, G.; Silverman, R. B. Bioorg. Med. Chem. 2013, 21, 903–911. (d) Huchet, Q. A.; Kuhn, B.; Wagner, B.; Fischer, H.; Kansy, M.; Zimmerli, D.; Carreira, E. M.; Müller, K. J. Fluorine Chem. 2013, 152, 119–128. (e) Kardivel, M.; Fairclough, M.; Cawthorne, C.; Rowling, E. J.; Babur, M.; McMahon, A.; Birkket, P.; Smigova, A.; Freeman, S.; Williams, K. J.; Brown, G. Bioorg. Med. Chem. 2014, 22, 341–349. (f) Kardivel, M.; Fanimarvasti, F.; Forbes, S.; McBain, A.; Gardiner, J. M.; Brown, G. D.; Freeman, S. Chem. Commun. 2014, 50, 5000–5002. (g) Gagnon, M.-C.; Turgeon, B.; Savoie, J.-D.; Parent, J.-F.; Auger, M.; Paquin, J.-F. Org. Biomol. Chem. 2014, 12, 5126–5135. (h) Holl, K.; Schepmann, D.; Fischer, S.; Ludwig, F.-A.; Hiller, A.; Donat, C. K.; Deuther-Conrad, W.; Brust, P.; Wünsch, B. Pharmaceuticals 2014, 7, 78–112. (i) Khazaei, K.; Yeung, J. H. F.; Moore, M. M.; Bennet, A. J. Can. J. Chem. 2015, 93, 1207–1213. (j) Carpentier, C.; Godbout, R.; Otis, F.; Voyer, N. Tetrahedron Lett. 2015, 56, 1244–1246. (k) Davies, S. G.; Fletcher, A. M.; Frost, A. B.; Roberts, P. M.; Thomson, J. E. Org. Lett. 2015, 17, 2254–2257.
OH
R2R1
F
R2R1
XtalFluorpromoteur
promoteur = Et3N⋅3HF, Et3N⋅2HF ou DBU
Exemples représentatifs
OH
FSN2'
90 %
N
HO
CbzN
F
Cbz 86 %ee 98 %
fluoro/alcène = 6,9:1
NCbz
+
OH F
93 %
22
Le mécanisme de cette transformation est similaire à celui de la déoxofluoration d’un
alcool par le DAST, puisque ces deux réactions impliquent la formation d’un intermédiaire
diéthylaminodifluorosulfane (Schéma 1.9).27,31b Les différences notoires entre les deux
mécanismes sont, d’une part, la libération de HF pour la déoxofluoration au moyen de
DAST, et d’autre part, la nécessité d’une source externe de fluorure pour la réaction
utilisant le XtalFluor-E.
Schéma 1.9. Mécanismes de déoxofluoration d’un alcool avec le DAST et le XtalFluor-E.
Un intermédiaire diéthylaminodifluorosulfane a pu être isolé par le groupe de John Vederas
en 1999 lors de la déoxofluoration de l’alcool 1.1 par le DAST (Schéma 1.10).58 Cet
intermédiaire a été obtenu avec un rendement de 12 %, en plus du produit d’élimination
(7 %) et du produit fluoré (52 %).
(58) Sutherland, A.; Vederas, J. C. Chem. Commun. 1999, 1739–1740.
N SF
FF
HO R- HF
N SF
FO F
F R
Déoxofluoration d'un alcool avec le DAST
RN S
O
F
N SF
F
HF+ +
Déoxofluoration d'un alcool avec le XtalFluor-E
BF4 HO R- HBF4
N SF
FO F
F RR
N SO
F+
source externede fluorure
F+
23
Schéma 1.10. Formation de l’intermédiaire diéthylaminodifluorosulfane 1.3.
1.3.4.2 Déoxofluoration d’aldéhydes et cétones
La déoxofluoration d’aldéhydes et de cétones par le XtalFluor a été développée
parallèlement à la déoxofluoration des alcools (Schéma 1.11).31 Les conditions
réactionnelles sont semblables et une source de fluorure est également nécessaire
(Et3N·3HF ou Et3N·2HF). Ceci a conduit à la synthèse de difluorométhylènes variés,
décrits par OmegaChem31b ou plus tard par d’autres groupes.59 Tout comme pour la
déoxofluoration d’alcools, des produits secondaires d’élimination sont observés, dans ce
cas-ci des fluoroalcènes.
(59) En plus de la réf. 57d, voir : (a) Yu, L.-F.; Eaton, J. B.; Fedolak, A.; Zhang, H.-K.; Hanania, T.; Brunner, D.; Lukas, R. J.; Kozikowski, A. P. J. Med. Chem. 2012, 55, 9998–10009. (b) Nemoto, H.; Takubo, K.; Shimizu, K.; Akai, S. Synlett 2012, 23, 1978–1984. (c) Chernykh, A. V.; Feskov, I. O.; Chernykh, A. V.; Daniliuc, C. G.; Tolmachova, N. A.; Volochnyuk, D. M.; Radchenko, D. S. Tetrahedron 2016, 72, 1036–1041.
N
OMe
OMei-Pr
CO2MeO
NBoc2
SF2
NEt2
N
OMe
OMei-Pr
CO2Me
NBoc2
N
OMe
OMei-Pr
CO2MeF
NBoc2
+
+
1.2, 7 %
1.3, 12 %
1.4, 52 %
N
OMe
OMei-Pr
CO2MeOH
NBoc2
DAST
CH2Cl2, -78 °C
1.1
24
Schéma 1.11. Synthèse de difluorométhylènes par déoxofluoration de carbonyles.
1.3.4.3 Déoxofluoration d’acides carboxyliques
Le XtalFuor permet également d’effectuer la déoxofluoration d’acides carboxyliques
(Schéma 1.12).31 D’excellents rendements ont été obtenus, mais peu d’exemples ont été
rapportés.
Schéma 1.12. Synthèse de fluorures d’acyle par déoxofluoration d’acides carboxyliques.
XtalFluorsource de F-
R1 R2
O
R1 R2
F F
Exemples représentatifs
CO2Et
O
CO2Et
F F
87 %
N
O
Cbz NCbzNCbz
FF
F+
81 %produit difluoré/fluoroalcène = 13:1
XtalFluor-E (1,5 équiv.)Et3N⋅3HF (2 équiv.)
R OH
O
R F
O
R = Ph, (CH2)2Ph 2 exemples89-94 %
CH2Cl2, t.a., 3 h
25
1.3.4.4 Autres fluorations
Le groupe de Spencer Williams a rapporté en 2012 la synthèse de fluorures de glycosyle à
partir de thio-, séléno- et telluroglycosides et de sulfoxydes de glycosyle (Schéma 1.13).60
Des études mécanistiques ont montré que le fluorure est fourni par le tétrafluoroborate et
qu’aucune autre source externe de fluor n’est nécessaire. La réaction a été effectuée avec
plusieurs substrats et avec de bons rendements.
Schéma 1.13. Synthèse de fluorures de glycosyle.
En 2016, la formation d’un fluorure de sulfonyle au moyen de XtalFluor-M a été décrite par
le groupe de Rob Liskamp, en tant qu’étape clé de la synthèse d’inhibiteurs du protéasome
(Schéma 1.14).61 L’ester sulfonique 1.5 est d’abord clivé par l’iodure de
tétrabutylammonium (Bu4NI) pour obtenir le sulfonate 1.6, qui réagit ensuite avec le
XtalFluor-M en présence d’une quantité catalytique de Et3N·3HF.
(60) Tsegay, S.; Williams, R. J.; Williams, S. J. Carbohydr. Res. 2012, 357, 16–22. (61) Brouwer, A. J.; Álvarez, N. H.; Ciaffoni, A.; van de Langemheen, H.; Liskamp, R. M. Bioorg. Med. Chem. 2016, 24, 3429–3435.
O O
X F
RO RO
RO ROXtalFluor-EDCE, reflux
13 exemples45-95 %
X = S-aryle, S-alkyle, S(O)-aryle,S(O)-alkyle, SePh, TePh
26
Schéma 1.14. Synthèse d’un fluorure de sulfonyle.
1.3.5 Agent activant
Lors des réactions de déoxofluoration, le XtalFluor se comporte en réalité comme un agent
activant qui transforme l’alcool en un meilleur groupe partant. Par conséquent, une source
externe de fluorure permet la déoxofluoration, mais de la même manière, d’autres
nucléophiles peuvent réagir et d’autres fonctionnalités peuvent être activées (alcools, acides
carboxyliques, amides, etc.). Ceci ouvre la porte à une large gamme de nouvelles réactions
(Schéma 1.15).
Schéma 1.15. Utilisation du XtalFluor-E comme agent activant.
CbzHN S OOO
CbzHN S OOO
NBu4
CbzHN S FOO
Bu4NI (1 équiv.)acétonereflux
XtalFluor-M (2,1 équiv.)Et3N⋅3HF (5 %mol)CH2Cl2
30 % sur 2 étapes
1.5 1.6
Nu-R Nu
R OH
N SF
F
BF4
N SF
FO
R
R FF-
27
1.3.5.1 Synthèse énantiosélective de dérivés d’azidopipéridines et aminopipéridines à
partir de prolinols
Le premier exemple de réaction utilisant le XtalFluor-E comme agent activant a été décrit
en 2011 par le groupe de Janine Cossy.62 Il s’agit de l’expansion de cycles dérivés de
prolinol pour obtenir des azidopipéridines (Schéma 1.16). D’un point de vue mécanistique,
l’hydroxyle du prolinol est activé par le XtalFluor-E, permettant la formation d’un
intermédiaire aziridinium. Celui-ci peut réagir avec l’azoture de tétrabutylammonium pour
produire l’azidopipéridine correspondante avec de bons rendements et d’excellentes
diastéréo- et énantiosélectivités. En outre, des aminopipéridines peuvent être synthétisées à
partir des azotures par une réaction de Staudinger avec également de très bons rendements.
Schéma 1.16. Expansion de cycles dérivés de prolinol.
1.3.5.2 Synthèse d’oxadiazoles à partir de diacylhydrazines
À la suite du groupe de Janine Cossy, le groupe de Jean-François Paquin a également
investigué longuement sur la réactivité du XtalFluor. En 2012, son groupe a décrit la
synthèse de 1,3,4-oxadiazoles à partir de 1,2-diacylhydrazines (Schéma 1.17).63 Cette
(62) Cochi, A.; Gomez Pardo, D.; Cossy, J. Org. Lett. 2011, 13, 4442–4445. (63) Pouliot, M.-F.; Angers, L.; Hamel, J.-D.; Paquin, J.-F. Org. Biomol. Chem. 2012, 10, 988–993.
N∗∗
R1
OHXtalFluor-E (1,1 équiv.)nBu4NN3 (1,1 équiv.)
CH2Cl2 N
∗∗ N3
R1
R2
R2N
∗∗
R1
N3R2+
R1 = Bn, Tr, PMBR2 = NR2, OR, F
16 exemples55-88 %
N
∗∗ NH2
R1
R2N
∗∗
R1
NH2R2+
PPh3 (1,5 équiv.)H2O (7 équiv.)THF, reflux, 5 h
3 exemples68-91 %
28
réaction est habituellement effectuée avec des réactifs de cyclodéshydratation tels que
SOCl2 ou POCl3, mais le mécanisme reste très similaire. Le carbonyle le plus nucléophile
attaque le soufre électrophile du XtalFluor-E, puis la molécule se cyclise et le fluorure de
diéthylaminosulfinyle est expulsé. Les auteurs ont montré que l’ajout d’acide acétique
améliorait dans la majorité des cas les rendements obtenus sans ce dernier. La réaction peut
être étendue à divers substrats (10 exemples) avec de très bons rendements.
Schéma 1.17. Synthèse de 1,3,4-oxadiazoles à partir de 1,2-diacylhydrazines.
1.3.5.3 Synthèse d’oxazolines et analogues
Dans la foulée des oxadiazoles, d’autres hétérocycles ont été synthétisés par le groupe de
Jean-François Paquin.64 Ainsi, la formation d’oxazolines à partir d’hydroxyamides a été
rapportée en 2012 (Schéma 1.18). De la même manière que pour les oxadiazoles, le
XtalFluor-E est utilisé comme agent de cyclodéshydratation. Des oxazolines variées ont pu
être synthétisées, avec de très bons rendements dans l’ensemble.
(64) Pouliot, M.-F.; Angers, L.; Hamel, J.-D.; Paquin, J.-F. Tetrahedron Lett. 2012, 53, 4121–4123.
XtalFluor-E (1,5 équiv.)AcOH (0 ou 1,5 équiv.)
DCE, 90 °C, 12 h
R1 = alkyle, aryle, CF3, NHMeR2 = H, PhX = O, S
10 exemples54-92 %
N N
OR1 R2R1
X
HN N
HR2
O
29
Schéma 1.18. Synthèse d’oxazolines à partir d’hydroxyamides.
En 2015, le groupe de Nathan Luedtke a approfondi l’étude de cette réaction et a proposé
une synthèse d’oxazolines par une désilylation in situ et cyclodéshydratation de β-
hydroxyamides (Schéma 1.19).65 L’utilité de cette approche a été démontrée pour la
cyclodéshydratation de di- ou tripeptides, tels que le peptide Boc-Cys(Bn)-Ser(TES)-OMe
ou le peptide Boc-Ser(Bn)-Ser(TES)-Ser(TES)-OMe.
Schéma 1.19. Synthèse d’oxazolines par désilylation in situ et cyclodéshydratation.
(65) Brandstätter, M.; Roth, F.; Luedtke, N. W. J. Org. Chem. 2015, 80, 40–51.
XtalFluor-E (2 équiv.)
DCE, 90 °C, 18 h
R1 = alkyle, aryle, vinyleR2 = alkyle, benzyle, CO2MeX = O, Sn = 1, 2, 3
12 exemples55-95 %
R1 NH
X OH
nR2 X
NR1
nR2
R1 NH
O
R2
OSi
nR1 N
H
O
R2
HO
n
O
N R2R1
n
XtalFluor-E
(-H2O)
XtalFluor-E
[F-]
n = 1, 2
Exemple représentatif
NH
HN
OOMe
O
OSiEt3
OBn
O
O XtalFluor-E (2 équiv.)
CH2Cl2, -78 à 0 °C NH
OBn
O
O
O
N
OMe
O
56 %Boc-Ser(Bn)-Ser(TES)-OMe
30
La formation d’oxazolines a également été observée par le groupe de Loránd Kiss en 2016
alors que son groupe avait pour but d’obtenir des dérivés fluorés d’acides β-aminés par
ouverture d’oxiranes (Schéma 1.20).66
Schéma 1.20. Synthèse d’oxazolines par ouverture d’oxiranes.
1.3.5.4 Halogénation d’alcools
L’halogénation d’alcools au moyen de XtalFluor-E a été décrite en 2012 par le groupe de
Jean-François Paquin (Schéma 1.21).67 Cette méthode est une alternative intéressante à la
réaction d’Appel puisque aucun sous-produit organique n’est formé. L’halogénure est
fourni sous forme d’halogénure de tetraéthylammonium. La chloration et la bromation
d’alcools primaires ont montré de très bons rendements (jusqu’à 92 %), tandis que
l’iodation et l’halogénation d’alcools secondaires ont donné des rendements modérés.
Schéma 1.21. Halogénation d’alcools primaires.
(66) Remete, A. M.; Nonn, M.; Fustero, S.; Fülöp, F.; Kiss, L. Molecules 2016, 21, 1493–1502. (67) Pouliot, M.-F.; Mahé, O.; Hamel, J.-D.; Desroches, J.; Paquin, J.-F. Org. Lett. 2012, 14, 5428–5431.
CO2Et
NHCOPhO
n
mCO2Et
n
m
O N
Ph
XtalFluor-E (1 équiv.)EtOH (1 goutte)
1,4-dioxane, reflux
m = 1,2n = 0, 1
4 exemples37-85 %
HO
R OH R X
XtalFluor-E (1,5 équiv.)Et4N+X- (1,5 équiv.)2,6-lutidine (3 équiv.)
CH2Cl2, t.a., 12 h
R = alkyle, aryleX = Cl, Br, I
20 exemples48-92 %
31
Plus tard, cette procédure a été utilisée par d’autres groupes pour d’autres applications. En
2013, le groupe de Weihua Xue a rapporté la synthèse de per(6-déoxy-6-
halo)cyclodextrines,68 tandis que le groupe de Yongming Chen a décrit en 2017 la
bromation de polymères comportant des fonctions alcools.69
1.3.5.5 Amidation d’acides carboxyliques
En 2013, les groupes de Janine Cossy et Jean-François Paquin ont rapporté de manière
simultanée la synthèse d’amides à partir d’acides carboxyliques et d’amines (Schéma 1.22
et Schéma 1.23).70,71 Dans les deux cas, de très bons rendements ont été obtenus pour un
grand nombre d’exemples, comprenant des amides chiraux énantiopurs.
Schéma 1.22. Amidation d’acides carboxyliques décrite par le groupe de Cossy.
Schéma 1.23. Amidation d’acides carboxyliques décrite par le groupe de Paquin.
(68) Liu, X.; Cheng, S.; Wang, X.; Xue, W. Synthesis 2013, 45, 3103–3105. (69) Zhou, H.; Chen, Y.; Plummer, C. M.; Huang, H.; Chen, Y. Polym. Chem. 2017, 8, 2189–2196. (70) Orliac, A.; Gomez Pardo, D.; Bombrun, A.; Cossy, J. Org Lett. 2013, 15, 902–905. (71) Mahé, O.; Desroches, J.; Paquin, J.-F. Eur. J. Org. Chem. 2013, 4325–4331.
R2∗∗
CO2H
R1HN
∗∗
R5R4
R3
+XtalFluor-E (1,5 équiv.)
THF, 0 °C à t.a., 4 h R2∗∗
R1
N
O
∗∗
R5
R3
R4
R1, R2, R3, R4, R5 = alkyle, benzyle, aryle, allyle
30 exemples52-98 %
R1 OH
OR1 N
OR2
R3
1) XtalFluor-E (1 équiv.), 2 h2) R2R3NH (1,8 équiv.), 1 h
AcOEt, t.a.
R1, R2, R3 = alkyle, benzyle,aryle, sulfonyle, vinyle
29 exemples18-99 %
32
1.3.5.6 Aminofluoration catalysée au fer
Le groupe de Hao Xu a étudié en 2014 l’aminofluoration intramoléculaire d’alcènes par
catalyse au fer (Schéma 1.24).72 La réaction passe par un intermédiaire fer-nitrénoïde et le
XtalFluor-E est utilisé dans ce cas-ci pour piéger le benzoate et empêcher une
aminohydroxylation non désirée. Les produits fluorés ont été obtenus avec de très bons
rendements et leur stéréochimie dépend de la configuration de l’alcène de départ.
Schéma 1.24. Aminofluoration intramoléculaire catalysée au fer.
Deux ans plus tard, le même groupe a rapporté une version intermoléculaire de la réaction
précédemment développée (Schéma 1.25).73 De la même manière, le XtalFluor-E est utilisé
pour piéger le carboxylate généré lors du clivage de la liaison N–O. Une grande gamme de
composés aminofluorés ont pu être synthétisés avec de très bons rendements.
(72) Lu, D.-F.; Liu, G.-S.; Zhu, C.-L.; Yuan, B.; Xu, H. Org. Lett. 2014, 16, 2912–2915. (73) Lu, D.-F.; Zhu, C.-L.; Sears, J. D.; Xu, H. J. Am. Chem. Soc. 2016, 138, 11360–11367.
R2
R1O
NHO
R4O Fe(BF4)⋅6H2O (10 %mol)1.7 (10 %mol)
Et3N⋅3HF (1,4 équiv.)XtalFluor-E (1,2 équiv.)
CH2Cl2, t.a., 4Å MS FO
HNO
R2
R1 N N
O
1.7
14 exemples45-75 %
R1 = H, alkyle, aryle, alcynyleR2 = H, alkyle, aryle, alcynyleR3 = alkyleR4 = 3,5-(CF3)2-benzoyle
R3
R3
33
Schéma 1.25. Aminofluoration intermoléculaire catalysée au fer.
1.3.5.7 Synthèse de dérivés d’imidazolidinone par ouverture d’aziridines
L’ouverture d’aziridines par le XtalFluor-E a été décrite en 2015 par le groupe de Ferenc
Fülöp (Schéma 1.26).74 Une cyclisation intramoléculaire a donné lieu à la formation de
produits bicycliques fluorés comprenant un cycle imidazolidinone avec de très bons
rendements, mais pour un petit nombre d’exemples. Lorsque le substituant « NHBoc »
n’est pas présent, on assiste à une simple ouverture de l’aziridine et fluoration.
Schéma 1.26. Synthèse de dérivés d’imidazolidinone par ouverture d’aziridines.
(74) Nonn, M.; Kiss, L.; Haukka, M.; Fustero, S.; Fülöp, F. Org Lett. 2015, 17, 1074–1077.
Fe(BF4)2(H2O)2MeCN (10 %mol)1.8 (10 %mol)
Et3N⋅3HF (1,5 équiv.)XtalFluor-E (2,5 équiv.)
CH2Cl2, -30 à -15 °C
19 exemples62-88 %
R1, R2, R3 = alkyle, aryle, vinyle, alcynyle
NN
OO
N
MeMeMeMe
1.8
R2 R3R1F
HN
O
O CF3
CF3R2
R1 R3
F3C O
CF3
N
OOBz
H
+
CO2Et
NHBocTsN
H
H n
mCO2Et
n
mF
TsN NH
O
H HXtalFluor-E (4 équiv.)
1,4-dioxane, reflux, 10 min
m = 1, 2n = 0, 1
4 exemples75-95 %
34
1.3.5.8 Benzylation de Friedel-Crafts
Le XtalFluor-E peut également être utilisé pour réaliser des benzylations de Friedel-Crafts
en activant des alcools benzyliques in situ et en les faisant réagir avec des arènes (Schéma
1.27).75 Ces recherches ont été menées par le groupe de Jean-François Paquin en 2015 et
celui-ci a démontré ainsi la capacité du XtalFluor-E à induire une ionisation de la liaison
C–OH et effectuer des réactions de type SN1. Un grand nombre de diaryl- et
triarylméthanes ont été synthétisés de cette manière, avec des rendements modérés à
excellents.
Schéma 1.27. Synthèse de diaryl- et triarylméthanes par benzylation de Friedel-Crafts.
1.3.5.9 Allylation d’alcools benzyliques
Dans la poursuite de ses recherches sur la réactivité des alcools benzyliques, le groupe de
Jean-François Paquin a rapporté en 2017 l’allylation d’alcools benzyliques par activation
avec le XtalFluor-E et réaction avec l’allyltriméthylsilane (Schéma 1.28).76 En plus des
alcools benzyliques, la réaction a également été effectuée sur des diaryl- et
triarylméthanols. Les produits allylés ont été obtenus avec des rendements modérés à
excellents.
(75) Desroches, J.; Champagne, P. A.; Benhassine, Y.; Paquin, J.-F. Org. Biomol. Chem. 2015, 13, 2243–2246. (76) Lebleu, T.; Paquin, J.-F. Tetrahedron Lett. 2017, 58, 442–444.
X
OH
R1
X
Ar
R1XtalFluor-E (1,1 équiv.)
Ar-H (5 équiv.)
CH2Cl2/HFIP (9:1), t.a., 4 hR2
R1 = H, PhR2 = H, Cl, Br, NO2, OR, Ph, alkyleX = CH, N
27 exemples23-100 %
R2
35
Schéma 1.28. Allylation d’alcools benzyliques.
1.4 OBJECTIFS DE LA THÈSE
Les recherches effectuées au cours de cette thèse se divisent en deux parties : mettre au
point de nouvelles réactions utilisant le XtalFluor-E comme agent activant, et développer
de nouveaux réactifs de fluoration électrophile.
1.4.1 Utilisation du XtalFluor-E en synthèse organique
Depuis 2009, le XtalFluor-E s’est avéré un excellent agent activant, tant pour des réactions
de fluoration que d’autres réactions nécessitant habituellement un réactif activant. Ainsi, le
premier objectif de cette thèse consiste à étendre le champ d’application de ce réactif. Les
chapitres 2 à 5 décrivent la mise au point de quatre nouvelles transformations.
La première réaction étudiée sera la déshydratation de formamides par le XtalFluor-E afin
de former les isonitriles correspondants (Schéma 1.29). Des réactions multicomposantes,
comme la réaction de Passerini ou Ugi, seront également envisagées à partir des isonitriles
formés.
Schéma 1.29. Synthèse d’isonitriles à partir de formamides.
Ar1 OH
R2R1XtalFluor-E (1,1 équiv.)
allyltriméthylsilane (5 équiv.)
CH2Cl2/HFIP (9:1), t.a. Ar1R2R1
R1 = H, Ar2R2 = H, Ar3
28 exemples26-96 %
XtalFluor-ENH
O
HR N CR
36
Dans le chapitre 3, nous traiterons d’une réaction similaire à celle décrite au chapitre 2, à
savoir la déshydratation d’amides primaires et d’aldoximes pour la synthèse de nitriles
(Schéma 1.30).
Schéma 1.30. Synthèse de nitriles à partir d’amides primaires ou d’aldoximes.
La synthèse d’esters perfluorés par activation d’acides carboxyliques sera ensuite discutée
dans le chapitre 4 (Schéma 1.31). De nombreux alcools perfluorés seront testés, tels que le
trifluoroéthanol, l’hexafluoroisopropanol et des chaînes perfluorées à 2, 3, 7 ou 8 carbones.
Schéma 1.31. Synthèse d’esters perfluorés à partir d’acides carboxyliques et d’alcools perfluorés.
Nous décrirons également une réaction de déoxofluoration éliminatrice à partir de cétones
(Schéma 1.32). Les monofluoroalcènes sont des produits secondaires d’élimination
fréquemment observés lors de la déoxofluoration de cétones. Nous tenterons donc d’établir
des conditions réactionnelles favorables à leur formation.
C NRR
O
NH2 R H
Nou
OHXtalFluor-E
R f−OH
R OH
O
R ORf
OXtalFluor-E
37
Schéma 1.32. Synthèse de monofluoroalcènes à partir de cétones.
1.4.2 Développement de nouveaux réactifs de fluoration électrophile
Le dernier chapitre de cette thèse sera consacré à la mise au point de nouveaux réactifs de
fluoration électrophile, et plus particulièrement des N-fluorosquaramides (Figure 1.8).
L’objectif premier sera la synthèse de ces composés fluorés, alors qu’un objectif à plus long
terme sera l’étude des variations stériques et électroniques sur la puissance de fluoration à
partir de réactions tests (fluoration de RMgX, énolates, etc.).
Figure 1.8. Structure des N-fluorosquaramides.
R1 R1R2
OR2
FXtalFluor-E
OO
NNFR
R R
38
CHAPITRE 2
Synthèse d’isonitriles par déshydratation de formamides
en utilisant le XtalFluor-E
Synthesis of isocyanides through dehydration of formamides
using XtalFluor-E
Massaba Keita, Mathilde Vandamme, Olivier Mahé, Jean-François Paquin*
Canada Research Chair in Organic and Medicinal Chemistry, CCVC, PROTEO,
Département de chimie, Université Laval, 1045 avenue de la Médecine,
Québec, Québec, Canada, G1V 0A6
E-mail: jean-francois.paquin@chm.ulaval.ca
Reproduit à partir de Tetrahedron Letters 2015, 56, 461–464.
39
2.1 RÉSUMÉ
La formation d’isonitriles à partir de formamides en utilisant le XtalFluor-E, [Et2NSF2]BF4,
est présentée. Une large gamme de formamides peut être utilisée pour produire les
isonitriles correspondants avec des rendements allant jusqu’à 99 %. Dans plusieurs cas, les
produits bruts se sont avérés assez purs pour être utilisés directement dans des réactions
multicomposantes.
2.2 ABSTRACT
The formation of isocyanides from formamides using XtalFluor-E, [Et2NSF2]BF4, is
presented. A wide range of formamides can be used to produce the corresponding
isocyanides in up to 99% yield. In a number of cases, the crude products showed good
purity (generally >80% by NMR) allowing to be used directly in multi-component
reactions.
2.3 INTRODUCTION
Isocyanides (also called isonitriles)77 are key building blocks in organic synthesis.78 They
are well known for their use in the Ugi reaction (or other multi-component reactions),79 but
(77) Although still used, isonitrile is an obsolete term that should be replaced with isocyanides, see Moss, G. P.; Smith, P. A. S.; Tavernier, D. Pure Appl. Chem. 1995, 67, 1307–1375. (78) Isocyanide Chemistry: Applications in Synthesis and Materials Science, Nenajdenko, V., Ed.; Wiley-VCH: Weinheim, Germany, 2012.
40
they are also utilized in many other synthetic transformations.80 They can act as ligands for
transition metals.81 Finally, a few natural products contain this functionality.82
As isocyanides are somewhat unstable, they are normally prepared just before their use,
although some are commercially available. A straightforward approach for their preparation
consists in the dehydration of formamides.83 Numerous reagents can affect this
transformation including phosphoryl chloride,84 chlorophosphate derivatives,85 Vilsmeier
reagent,86 TsCl,87 Burgess reagents,88 chlorodimethylformiminium chloride,86 phosgene,89
CCl4/PPh3,90 cyanuric chloride,91 and TfOH.92 Unfortunately, some of these reagents are
expensive and not available on large scale, in addition most are either hygroscopic,
moisture sensitive, highly toxic or thermally unstable.
We have recently described the synthesis of various N-containing heterocycles93 through
dehydration using diethylaminodifluorosulfinium tetrafluoroborate ([Et2NSF2]BF4),
(79) Reviews: (a) Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–3210. (b) Ugi, I.; Werner, B.; Dömling, A. Molecules 2003, 8, 56–66. (c) Dömling, A. Chem. Rev. 2006, 106, 17–89. (d) Koopmanschap, G.; Ruijter, E.; Orru, R. V. A. Beilstein J. Org. Chem. 2014, 10, 544–598. (80) Reviews: (a) Lygin, A. V.; de Meijere, A. Angew. Chem., Int. Ed. 2010, 49, 9094–9124. (b) Gulevich, A. V.; Zhdanko, A.; Orru, R. V. A.; Nenajdenko, V. G. Chem. Rev. 2010, 110, 5235–5331. (c) Vlaar, T.; Ruijter, E.; Maes, B. U. W.; Orru, R. V. A. Angew. Chem., Int. Ed. 2013, 52, 7084–7097. (81) Reviews: (a) Yamamoto, Y. Coord. Chem. Rev. 1980, 32, 193–233. (b) Singleton, E.; Oosthuizen, H. E. Adv. Organomet. Chem. 1983, 22, 209–310. (c) Hahn, F. E. Angew. Chem., Int. Ed. Engl. 1993, 32, 650–665. (82) Review: Garson, M. J.; Simpson, J. S. Nat. Prod. Rep. 2004, 21, 164–179. (83) For selected alternative procedures, see (a) Atkinson, R. S.; Harger, M. J. P. J. Chem. Soc., Perkin Trans. 1 1974, 2619–2622. (b) Kitano, Y.; Manoda, T.; Miura, T.; Chiba, K.; Tada, M. Synthesis 2006, 405–410. (c) Pirrung, M. C.; Ghorai, S. J. Am. Chem. Soc. 2006, 128, 11772–11773. (d) Pirrung, M. C.; Ghorai, S.; Ibarra-Rivera, T. R. J. Org. Chem. 2009, 74, 4110–4117. (84) Ugi, I.; Meyr, R. Chem. Ber. 1960, 93, 239–248. (85) Kobayashi, G.; Saito, T.; Kitano, Y. Synthesis 2011, 3225–3234. (86) Walborsky, H. M.; Niznik, G. E. J. Org. Chem. 1972, 37, 187–190. (87) (a) Okada, I.; Kitano, Y. Synthesis 2011, 3997–4002. (b) Guchhait, S. K.; Priyadarshani, G.; Chaudhary, V.; Seladiya, D. R.; Shah, T. M.; Bhogayta, N. P. RSC Advances 2013, 3, 10867–10874. (88) Creedon, S. M.; Crowley, H. K.; McCarthy, D. G. J. Chem. Soc., Perkin Trans 1 1998, 1015–1017. (89) Ugi, I.; Fetzer, U.; Eholzer, U.; Knupfer, H.; Offermann, K. Angew. Chem., Int. Ed. Engl. 1965, 4, 472–484. (90) Maillard, M.; Faraj, A.; Frappier, F.; Florent, J.-C.; Grierson, D. S.; Monneret, C. Tetrahedron Lett. 1989, 30, 1955–1958. (91) Porcheddu, A.; Giacomelli, G.; Salaris, M. J. Org. Chem. 2005, 70, 2361–2363. (92) Baldwin, J. E.; O'Neil, I. A. Synlett 1900, 603–604. (93) (a) Pouliot, M.-F.; Angers, L.; Hamel, J.-D.; Paquin, J.-F. Org. Biomol. Chem. 2012, 10, 988–993. (b) Pouliot, M.-F.; Angers, L.; Hamel, J.-D.; Paquin, J.-F. Tetrahedron Lett. 2012, 53, 4121–4123.
41
XtalFluor-E,94 a crystalline solid initially developed as a deoxofluorinating agent with
enhanced thermal stability. In particular, we have reported the preparation of 1,3,4-
oxadiazoles from 1,2-diacylhydrazines (Figure 2.1).93a As a potential extension of this
work, we imagined that if formamides (i.e., R1 = H) were used as starting substrate, upon
activation with XtalFluor-E and in the presence of a base, isocyanides would be generated.
Figure 2.1. Activation of amides with [Et2NSF2]BF4 for the synthesis of 1,3,4-oxadiazoles and isocyanides.
Herein, we report the feasibility of this transformation. A wide range of formamides can be
used to produce the corresponding isocyanides in up to 99% yield. In a number of cases, the
crude products showed good purity (generally >80% by NMR) allowing to be used directly
in multi-component reactions.
(94) (a) Beaulieu, F.; Beauregard, L.-P.; Courchesne, G.; Couturier, M.; Laflamme, F.; L’Heureux, A. Org. Lett. 2009, 11, 5050–5053. (b) L’Heureux, A.; Beaulieu, F.; Bennet, C.; Bill, D. R.; Clayton, S.; Laflamme, F.; Mirmehrabi, M.; Tadayon, S.; Tovell, D.; Couturier, M. J. Org. Chem. 2010, 75, 3401–3411.
O
N N
R1 R1
R1 NHR2
O
R1
O
N
R1 = alkyl or arylR2 = NHC(O)R1
This work
[Et2NSF2]BF4(XtalFluor-E)
R1 = HR2 = alkyl or aryl
isocyanides
1,3,4-oxadiazoles
R2
SNEt2
FF
H+
NC R2base
BF4-
42
2.4 RESULTS AND DISCUSSION
We optimized the reaction conditions using 2.1 as the formamide and selected results are
shown in Table 2.1. First, using 1 equiv of XtalFluor-E and Et3N as the base, it was found
that 1.5 equiv of Et3N was optimal (entries 1-3). Other organic bases (entries 4-5) or an
inorganic base (entry 6) were less effective. Using Et3N as the base, other solvents were
examined but all proved less effective than CH2Cl2 (entries 7-10). Using a slight excess of
XtalFluor-E (1.1 equiv) provided almost a quantitative yield (entry 11). Finally, fine-tuning
of the reaction temperature (not shown) revealed that running the transformation at -40 °C
for 1 h provided a cleaner product (less side-products observed by 1H NMR analysis of the
crude product).
Table 2.1. Selected optimization results for the dehydration of formamide 2.1.
Entry Base Solvent Yield (%)a 1 Et3N (1.2 equiv) CH2Cl2 64 2 Et3N (1.5 equiv) CH2Cl2 90 3 Et3N (2.5 equiv) CH2Cl2 92 4 iPr2EtN (1.5 equiv) CH2Cl2 23 5 2,4,6-collidine (1.5 equiv) CH2Cl2 <20b 6 K2CO3 (1.5 equiv) CH2Cl2 0c 7 Et3N (1.5 equiv) THF 41 8 Et3N (1.5 equiv) CH3CN 36 9 Et3N (1.5 equiv) toluene 55
10 Et3N (1.5 equiv) EtOAc 50 11d Et3N (1.5 equiv) CH2Cl2 99
XtalFluor-E (1 equiv)base
solvent (1 M)0 °C, 1 h then rt, 2 h
2.1 2.2NH
H
OMeO
NC
MeO
43
a Determined by 1H NMR analysis of the crude using p-xylene as an internal standard. b Estimated value as spectral interferences prevented a more accurate measurement. c Starting material was recovered. d 1.1 equiv of XtalFluor-E was used.
These optimized conditions were then used to examine the scope of this reaction (Table
2.2). In a number of cases, the crude isocyanide was pure enough so that it could be used
directly in a subsequent transformation (vide infra). In those cases, no further purification
was performed and the estimated NMR purity is indicated in parentheses.95 When the crude
isocyanides showed numerous impurities, purification using flash chromatography was
performed; this often resulted in lower yields due, most likely, to the instability of the
product on silica gel. Hence, a wide range of isocyanides could be generated including ones
derived from aromatic (2.2-2.7), benzylic (2.8-2.9), aliphatic (2.10-2.12) or amino acid-
based formamides (2.13-2.15). Also, these results show that various functional groups
including ether, ester, and protected amines (benzyl, Cbz or Boc) are well tolerated. In the
case of the phenylalanine-based isocyanide (2.13), chiral HPLC analysis showed that
complete racemization occurred when starting from the enantioenriched formamide.96 For
the crude isocyanides with good purity, the crude yield varied between 72% and 99%. For
the isocyanides that required purification, the isolated yields were lower, that is, between
34% and 60%. Surprisingly, for a few formamides (Figure 2.2), no desired product could
be isolated. For N-pentylformamide and N-(4-trifluoromethylphenyl)formamide, complete
degradation was observed. With N-tert-butylformamide, no conversion was observed (even
at higher temperature) and the starting formamide could be fully recovered. Finally, for N-
formylglycine ethyl ester, the major product was not the desired isocyanide, although we
have not been able to isolate and characterize this compound. We suspect an intramolecular
reaction with the activated amide similarly to what has been observed with 1,2-
diacylhydrazines.93a This side-reaction may be slowed down with an α-substituent (c.f.
compounds 2.13-2.14).
(95) The impurities have not been structurally identified, but originate from XtalFluor-E as peaks most likely assigned to the diethyl portion of the reagent can be observed on the crude 1H NMR spectra. (96) Zhu, J.; Wu, X.; Danishefsky, S. J. Tetrahedron Lett. 2009, 50, 577–579.
44
Table 2.2. Scope of the dehydration of formamides with XtalFluor-E.a
a Crude yield after work-up with purity estimated by 1H NMR analysis in parenthesis. b Isolated yield. c Reaction time was 2 h.
R-NCO
HNH
R
XtalFluor-E (1.1 equiv)Et3N (1.5 equiv)
CH2Cl2 (1 M), -40 ̊ C, 1 h
MeO
NC
2.2; 97% (85%)
O2N
NC
2.3; 47%b
I
NC
2.4; 51%b
NC
2.5; 72% (92%)
CH3
MeO2.8; 99% (94%)
NC
NBn
2.9; 96% (93%)c
NC
2.10; 83% (89%)
MeO2C NC
2.14; 91% (86%)
2.12; 56%bF F
NC
NBoc
NC
FF
2.15; 60%b
2.2 - 2.15
NC
COOEt2.6; 39%b
CN
NCbz
CN
2.11; 95% (93%)
NC
2.7; 34%b
CNOMe
O2.13; 96% (71%)
45
Figure 2.2. Unproductive formamides.
With respect to the reaction mechanism, the formation of isocyanides would most likely
proceed with a mechanism similar to that which occurs for the cyclodehydration of 1,2-
diacylhydrazines (Figure 2.1 and Figure 2.3).93a Hence, nucleophilic attack of the amide
carbonyl group to [Et2NSF2]BF4 at the electrophilic sulfur would generate intermediate
2.16. Lost of HF and diethylaminosulfinyl fluoride97 would lead to the protonated
isocyanide (2.17) that would rapidly generate the isocyanide in the presence of Et3N.
(97) (a) D. H. Brown, K. D. Crosbie, J. I. Darragh, D. S. Ross and D. W. A. Sharp, J. Chem. Soc. A 1970, 914–917. (b) R. Keat, D. S. Ross and D. W. A. Sharp, Spectrochim. Acta 1971, 27A, 2219–2225.
HN H
O
HN H
O
F3C
HN H
O
HN H
OEtO
O
degradation
no reaction major side-reactionobserved
46
Figure 2.3. Mechanistic proposal for the dehydration reaction. The BF4- counter-ion has
been omitted for clarity.
Finally, we explored the possibility of using the crude isocyanides directly in multi-
component reactions. First, Passerini reaction98 using crude isocyanides 2.2, 2.5, 2.8, 2.9,
2.11, or 2.14 with a benzaldehyde and a carboxylic acid provided the corresponding α-
acyloxyamide 2.18-2.25 in moderate to good yield from formamides over two steps (Table
2.3). Using this particular protocol, a simple filtration allows the isolation of the final
product. This reaction is particularly effective with benzylic isocyanides. At this point, no
attempts were made to further improve the yield though additional product may be present
in the filtrate.99 This represents 57-87% per step, which is satisfactory considering the crude
yield and purity of isocyanides and the fact that the Passerini is not a quantitative reaction,
even with pure isocyanide.98
(98) Pirrung, M. C.; Das Sarma, K. J. Am. Chem. Soc. 2004, 126, 444–445. (99) For instance, in the case of 2.21, 1H NMR analysis of the filtrate showed the presence of ca. 20% of 2.21 along with numerous impurities.
H
O
S NEt2F
F +
N H
OR
SNEt2
FF
H
+
Et3N
N CR+ -
2.16
N C HR+
NR
H 2.17
47
Table 2.3. Synthesis of α-acyloxyamide using crude isocyanides.a,b
a See Supplementary Material for details on the reaction conditions. b Isolated yield by filtration over two steps.
Then, synthesis of N-formyl amide under conditions reported by Danishefsky100 with crude
isocyanides 2.8 or 2.9 and benzoic acid gave the desired products 2.26 and 2.27 in
moderate yields over two steps (Scheme 2.1).
(100) Li, X.; Danishefsky, D. J. Am. Chem. Soc. 2008, 130, 5446–5448.
RNH
H
O
crudeisocyanide
RNH
OO
Ar
R1
O
i) XtalFluor-E Et3N CH2Cl2, -40 °C
MeOOC NH
OO Ph
OPh
2.25 (36%)
NH
OO Ph
OPhCbzN
2.24 (39%)
NH
OO Ph
OPhMe
2.19 (34%)
NH
OO Ph
OPh
MeO
2.18 (33%)
ii) work-up H2O, rt
R1CO2HArCHO
NH
OO
Ar
R1
O
2.20; R = H, Ar = Ph, R1 = Ph (50%)2.21; R = OMe, Ar = Ph, R1 = Ph (74%)2.22; R = OMe, Ar = 4-NO2-C6H4, R1 = Ph (74%)2.23; R = OMe, Ar = Ph, R1 = 4-NO2-C6H4 (75%)
R
R-NC
48
Scheme 2.1. Synthesis of N-formyl amides with crude isocyanides.
(a) XtalFluor-E, Et3N, CH2Cl2 (1 M), -40 °C, 1-2 h followed by an aqueous work-up. (b) PhCO2H, CHCl3, 150 °C (MW), 30 min. Yields from products 2.26 and 2.27 are calculated from formamides (over two steps).
Finally, a phenol Ugi-Smiles reaction101 with crude isocyanide 2.8 is also possible albeit in
moderate yield (Scheme 2.2).
Scheme 2.2. Ugi-Smiles with a crude isocyanide.
(a) XtalFluor-E, Et3N, CH2Cl2 (1 M), -40 °C, 1 h followed by an aqueous work-up. (b) CH3CHO, BnNH2, 4-nitrophenol, rt, 16 h. The yield from products 2.28 is calculated from the formamide (over two steps).
Overall, the results obtained for those two multi-component reactions show that the
presence of minor impurities in the isocyanide does not affect significantly the subsequent
(101) El Kaïm, L.; Grimaud, L.; Oble, J. Angew. Chem., Int. Ed. 2005, 44, 7969–7964.
R
NH
H
O
acrude 2.8 or 2.9
R
N Ph
O
OH
2.26; R = H (53%)2.27; R = OMe (51%)
b
R
NH
H
Oa
crude 2.8
R
NH
O
2.28; R = OMe (35%)
b
Me
N Ph
NO2
49
transformation and suggest that extension to other multi-component reactions may be
possible.
2.5 CONCLUSION
We have reported the synthesis of isocyanides from formamides using XtalFluor-E. A
number of isocyanides can be prepared in up to 99% yield from readily available
formamides. In a number of cases, the crude products showed good purity (generally >80%
by NMR) allowing to be used directly in multi-component reactions.
2.6 ACKNOWLEDGMENTS
This work was supported by the Canada Research Chair Program, the Natural Sciences and
Engineering Research Council of Canada, the Canada Foundation for Innovation, FRQ-NT
Centre in Green Chemistry and Catalysis (CGCC), FRQ-NT Research Network on Protein
Function, Structure and Engineering (PROTEO), OmegaChem and the Université Laval.
OmegaChem is acknowledged for a generous gift of N-t-BOC-4,4-difluoro-(2S)-
aminomethylpyrrolidine benzensulfonate.
2.7 SUPPORTING INFORMATION AVAILABLE
2.7.1 General information
All reactions were carried out under a nitrogen or argon atmosphere with dry solvents under
anhydrous conditions. Unless otherwise noted, all commercial reagents were used without
further purification. Dichloromethane, toluene, tetrahydrofuran and acetonitrile were
purified by using a Vacuum Atmospheres Inc. Solvant Purification System. Thin-layer
chromatography (TLC) analysis of reaction mixtures was performed using Silicyle silica
gel 60Å F254 TLC plates, and visualized under UV or by staining with ceric ammonium
50
molybdate, phosphomolybdic acid or molybdenium blue. Flash column chromatography
was carried out on Silicycle Silica Gel 60 Å, 230 X 400 mesh. 1H, 13C, and 19F NMR
spectra were recorded on a Agilent DD2 500 or a Varian Inova 400 in CDCl3 at ambient
temperature using tetramethylsilane (1H NMR) or residual CHCl3 (1H and 13C NMR) as the
internal standard or CFCl3 (19F NMR) as the external standard. Coupling constants (J) are
measured in hertz (Hz). Multiplicities are reported using the following abbreviations: s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad resonance. High-
resolution mass spectra were obtained on a LC/MS-TOF Agilent 6210 using electrospray
ionization (ESI). Infrared spectra were recorded on a Thermo Scientific Nicolet 380 FT-IR
spectrometer Melting points were recorded on a Stanford ResearchSystem OptiMelt
capillary melting point apparatus and are uncorrected. The required formamides precursors
were either purchased or synthesized. The purity of the crude isocyanides was estimated by 1H NMR and in all cases, the major impurity seemed to be a derivative of XtalFluor-E (as
evidenced by the presence of CH3CH2 peaks). The purity was estimated by comparing the
integration of one isolated peak of the isocyanide with one peak of the impurity (either CH3
at ca. 1.3 ppm or CH2 at ca. 3.8 ppm), corrected for the number of hydrogens. When other
impurities were also present, their integration was also taken into the account.
2.7.2 Synthesis of the new formamides
1-benzylpiperidine-4-carboxamide. To a stirred suspension of isonipectamide
(5.0 g, 39 mmol) and K2CO3 (10.8 g, 78.0 mmol) in EtOH (210 mL) was added
benzylbromide (5.10 mL, 42.9 mmol) and the mixture was heated under reflux
overnight, cooled to room temperature and filtered. The filtrate was evaporated
under vacuum and H2O was added. The aqueous layer was extracted with CH2Cl2, the
organic layers combined and dried over MgSO4 and filtrated. The solvent was evaporated
under vacuum to give 1-benzylpiperidine-4-carboxamide as a yellowish solid (6.66 g,
78%). mp: 156-159 °C; IR (ATR, ZnSe) ν = 3329, 3151, 2922, 1627, 1494 cm-1; 1H NMR
(500 MHz, CDCl3) δ (ppm) 7.33-7.31 (m, 4H), 7.28-7.24 (m, 1H), 5.65 (bs, 1H), 5.52 (bs,
1H), 3.51 (s, 2H), 2.96-2.92 (m, 2H), 2.16 (tt, J = 11.8, 4.0 Hz, 1H), 2.01 (td, J = 11.7, 2.5
Hz, 2H), 1.89-1.84 (m, 2H), 1.80-1.71 (m, 2H); 13C NMR (126 MHz, CDCl3) δ (ppm)
NBn
O NH2
51
178.2, 138.1, 129.1, 128.2, 127.0, 63.1, 53.0, 42.7, 28.8; HRMS-ESI calcd for C13H19N2O
[M+H]+ 219.1492, found 219.1493.
(1-benzylpiperidin-4-yl)methanamine. To a suspension of 1-benzylpiperidine-
4-carboxamide (2.0 g, 9.2 mmol) in dry THF (24 mL) was added slowly to a
solution of LiAlH4 (520 mg, 13.7 mmol) in dry THF (30 mL). The mixture was
stirred under reflux and argon atmosphere for 6 h. After cooling, water was
added at 0 °C, the precipitate was filtered and washed with Et2O. The filtrate was extracted
with Et2O, dried over MgSO4 and the solvent was evaporated under vacuum to give (1-
benzylpiperidin-4-yl)methanamine as an orange solid (1.52 g, 81%). mp: 86-90 °C; IR
(ATR, ZnSe) ν = 3344, 3024, 2933, 1579, 1476 cm-1; 1H NMR (CDCl3) δ (ppm) 7.31-7.26
(m, 5H), 3.49 (s, 2H), 2.90 (d, J = 11.8 Hz, 2H), 2.57 (d, J = 5.9 Hz, 2H), 1.94 (t, J = 11.2
Hz, 2H), 1.70-1.67 (m, 2H), 1.29-1.21 (m, 5H); 13C NMR (CDCl3) δ (ppm) 138.6, 129.2,
128.1, 126.9, 63.5, 53.7, 48.2, 39.4, 30.0; HRMS-ESI calcd for C13H21N2 [M+H]+
205.1699, found 205.1699.
N-((1-benylpiperidin-4-yl)methyl)formamide. To a solution of (1-
benzylpiperidin-4-yl)methanamine (870 mg, 4.26 mmol) in formic acid (10 mL)
was added ZnCl2 (58 mg, 0.43 mmol). The mixture was stirred at reflux for 24
h. The reaction was dissolved in water and washed with EtOAc. The aqueous
layer was then basified until pH 10 and extracted with EtOAc (3 × 30 mL). The
organic layer dried over MgSO4 and concentrated under vacuum to give crude product. The
residue was purified by chromatography eluting with CH2Cl2/MeOH (9/1) to give N-((1-
benylpiperidin-4-yl)methyl)formamide (448 mg, 45%) as yellow oil. 1H NMR spectra
indicates the presence of rotamers at rt. Rf (CH2Cl2/MeOH: 9/1, SiO2) = 0.5; IR (ATR,
ZnSe) ν = 3277, 2920, 2800, 1659, 1537, 1494 cm-1; 1H NMR (500 MHz, CDCl3) δ (ppm)
8.14 (d, J = 1.8 Hz, 0.8H), 7.96 (d, J = 11.9 Hz, 0.2H), 7.36-7.18 (m, 5H), 6.28-6.25 (m,
1H), 3.51 (s, 1.5H), 3.49 (s, 0.5H), 3.16 (t, J = 6.5 Hz, 1.6H), 3.06 (t, J = 6.6 Hz, 0.4H),
2.90 (dd, J = 9.1, 2.7 Hz, 2H), 2.02-1.87 (m, 2H), 1.71-1.61 (m, 2H), 1.52 (qdd, J = 10.5,
NBn
NH2
NBn
HN
H O
52
6.9, 3.8 Hz, 1H), 1.36-1.29 (m, 2H); 13C NMR (126 MHz, CDCl3) δ (ppm) 164.9, 161.5,
138.0, 137.7, 129.3, 128.2, 127.2, 63.1, 53.1, 47.5, 43.6, 37.3, 35.8, 29.6; HRMS calcd for
C14H21N2O [M+H]+ 233.1648, found 233.1642.
Benzyl 4-(formamidomethyl)piperidine-1-carboxylate. To a solution of N-
((1-benylpiperidin-4-yl)methyl)formamide (940 mg, 4.05 mmol) in MeOH (20
ml) was added 10% Pd/C (94 mg, 10% m/m) and PdCl2 (94 mg, 10% m/m).
The mixture was stirred under hydrogen (20 bars) for 18 h. The reaction was
then filtered on a Celite pad and concentrated under vacuum. The residue was
dissolved in THF/H2O (1:1, 12 mL) followed by addition of benzylchloroformate (575 µl,
4.04 mmol) and NaHCO3 (729 mg, 6.88 mmol). The resulting solution was stirred at room
temperature for 3 h. The reaction was quenched with water and extracted with CH2Cl2. The
organic layer was dried over MgSO4 and concentrated under vacuum. The title compound
was obtained after purification by SiO2 chromatography eluting with EtOAc as an yellow
pale oil (691 mg, 2.50 mmol, 62%). 1H NMR spectra indicates the presence of rotamers at
rt. Rf (EtOAc, SiO2) = 0.2; IR (ATR, ZnSe) ν = 3297, 3056, 2921, 2855, 1661, 1533, 1429
cm-1; 1H NMR (500 MHz, CDCl3) δ (ppm) 8.19 (d, J = 1.7 Hz, 0.8H), 8.00 (d, J = 11.9 Hz,
0.3H), 7.37-7.27 (m, 5H), 5.96-5.87 (m, 1H), 5.12 (s, 2H), 4.21 (bs, 2H), 3.20 (bs, 2H),
2.76 (bs, 2H), 1.72-1.69 (m, 3H), 1.16 (d, J = 13.0 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ
(ppm) 164.8, 161.4, 155.2, 136.8, 128.5, 128.0 (2C), 127.9, 127.8, 67.1, 47.3, 43.7, 43.4,
37.6, 36.2, 29.6; HRMS calcd for C15H21N2O3 [M+H]+ 277.1500, found 277.1544.
N-((4,4-difluorocyclohexyl)methyl)formamide. 4,4-difluorocyclohexane
methylamine hydrochloride (1.0 g, 5.4 mmol) was dissolved in an aqueous
solution of NaHCO3. The aqueous phase was extracted with CH2Cl2, dried over
MgSO4 and the solvent evaporated under vacuum. To the resulting 4,4-
difluorocyclohexane methylamine was added formamide (230 µL, 7.00 mmol).
The solution was stirred for 24 h at 80 °C. The crude product was washed with aq. HCl (2
M), extracted with CH2Cl2, dried over MgSO4 and concentrated under vacuum to obtain the
NCbz
HN
H O
HN
H O
F F
53
desired formamide as a yellow oil (165 mg, 19%). 1H NMR spectra indicates the presence
of rotamers at rt. IR (ATR, ZnSe) ν = 3301, 2939, 2867, 1659, 1538, 1449 cm-1; 1H NMR
(500 MHz, CDCl3) δ (ppm) 8.11 (s, 0.8H), 7.94 (d, J = 11.7 Hz, 0.2H), 6.83 (bs, 0.2H),
6.61 (bs, 0.8H), 3.13 (t, J = 6.5 Hz, 1.5H), 3.06 (t, J = 6.6 Hz, 0.5H), 2.06-1.99 (m, 2H),
1.76-1.56 (m, 5H), 1.26-1.21 (m, 2H); 13C NMR (126 MHz, CDCl3) δ (ppm) 165.3, 161.8,
123.4 (t, J = 239.5 Hz), 123.2 (t, J = 239.5), 46.9 (d, J = 2.9 Hz), 42.8 (d, J = 2.9 Hz), 37.1
(d, J = 1.4 Hz), 35.8 (d, J = 1.3 Hz), 33.0 (d, J = 22.9 Hz), 32.8 (d, J = 22.9 Hz), 26.5 (d, J
= 9.7 Hz), 26.2 (d, J = 9.9 Hz); 19F NMR (376 MHz, CDCl3) δ -101.84 (d, J = 234.4 Hz,
1F), -91.91 (d, J = 236.1 Hz, 1F); HRMS calcd for C8H14F2NO [M+H]+ 178.1038, found
178.1035.
tert-Butyl 3,3-difluoro-4-(formamidomethyl)pyrrolidine-1-carboxylate.
N-Boc-4,4-difluoro-(2S)-aminomethylpyrrolidine benzensulfonate (1.0 g, 2.5
mmol) was dissolved in an aqueous solution of NaHCO3. The aqueous phase
was extracted with CH2Cl2, dried over MgSO4 and the solvent evaporated
under vacuum. To the resulting N-Boc-4,4-difluoro-(2S)-aminomethylpyrrolidine was
added formamide (113 µL, 3.00 mmol). The solution was stirred for 24 h at 80 °C. The
crude product was washed with aq. HCl (2 M), extracted with CH2Cl2, dried over MgSO4
and the solvent evaporated under vacuum to obtain formamide as yellow oil (482 mg,
73%). 1H NMR spectra indicates the presence of rotamers at rt. IR (ATR, ZnSe) ν = 3302,
2978, 1666, 1536, 1393 cm-1; 1H NMR (500 MHz, CDCl3) δ (ppm) 8.18 (s, 0.8H), 8.0 (d, J
= 11.8 Hz, 0.2H), 7.11 (bs, 1H), 4.21-4.18 (m, 1H), 3.81-3.79 (m, 1H), 3.65-3.62 (m, 2H),
3.42-3.41 (m, 1H), 2.57-2.52 (m, 1H), 2.21-2.16 (m, 1H), 1.47 (s, 9H); 13C NMR (126
MHz, CDCl3) δ (ppm), 161.5, 126.4 (t, J = 247.9 Hz), 81.4, 55.5, 55.4, 53.7, 53.4, 42.8,
37.8, 28.2; 19F NMR (376 MHz, CDCl3) δ -100.93 (d, J = 243.0 Hz, 1F), -97.75 (d, J =
235.9 Hz, 1F); HRMS calcd for C11H19F2N2O3 [M+H]+ 265.1358, found 265.1365.
NBoc
HN
H O
FF
54
2.7.3 Synthesis of isocyanides
General procedure – To a solution of formamide (1.0 mmol) and Et3N (1.5 mmol) in
CH2Cl2 (1 ml) at -40 °C was added XtalFluor-E (1.1 mmol) portion wise. The resulting
solution was stirred at -40 °C for 1 h. The reaction was quenched with saturated aqueous
solution of Na2CO3 and extracted with CH2Cl2 (2 × 10 mL). The organic layer was washed
with water, dried over MgSO4 and concentrated under vacuum to afford the crude
isocyanide.
1-Isocyano-4-methoxybenzene (2.2). Following the general protocol
on a 1.0 mmol scale, the crude isocyanide was isolated as a brown oil
(197 mg, 97% crude yield, 85% purity by 1H NMR analysis). Spectral
data for 2.2 were identical to those previously reported.91
1-Isocyano-4-nitrobenzene (2.3). Following the general protocol on a
1.0 mmol scale, the isocyanide was isolated as a yellow oil after
purification by flash chromatography using EtOAc/hexane (1/9) as the
eluent (71 mg, 47%). Spectral data for 2.3 were identical to those previously reported.91
1-Iodo-4-isocyanobenzene (2.4). Following the general protocol on a 1.0
mmol scale, the isocyanide was isolated as an orange foam after
purification by flash chromatography using EtOAc/hexane (1/9) as the
eluent (226 mg, 51%). Spectral data for 2.4 were identical to those previously reported.85
1-Isocyano-2-methylbenzene (2.5). Following the general protocol on a 1.0
mmol scale, the crude isocyanide was isolated as an orange oil (100 mg, 72%
crude yield, 92% purity by 1H NMR analysis). IR (ATR, ZnSe) ν = 2927,
MeO
NC
O2N
NC
I
NC
NCCH3
55
2119, 1725, 1633, 1595, 1459 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.35-7.21 (m, 4H), 2.45
(s, 3H); 13C NMR (126 MHz, CDCl3) δ 165.6, 134.9, 130.5, 129.2, 126.6, 126.5, 18.6;
HRMS calcd for C8H8N [M+H]+ 118.0633, found 118.0651.
Ethyl 3-isocyanobenzoate (2.6). Following the general protocol on a 1.0
mmol scale, the isocyanide was isolated as a yellow oil after purification
by flash chromatography using EtOAc/hexane (2/8) as the eluent (68 mg,
39%). Spectral data for 2.6 were identical to those previously reported.85
2-Isocyanonaphthalene (2.7). Following the general protocol on a 1.0
mmol scale, the isocyanide was isolated as a brown oil after purification
by flash chromatography using EtOAc/hexane (0.5/9.5) as the eluent (52 mg, 34%).
Spectral data for 2.7 were identical to those previously reported.102
1-(Isocyanomethyl)-4-methoxybenzene (2.8). Following the general
protocol on a 1.0 mmol scale, the crude isocyanide was isolated as a
yellow oil (148 mg, 99% crude yield, 94% purity by 1H NMR analysis). Spectral data for
2.8 were identical to those previously reported.91
(Isocyanomethyl)benzene (2.9). Following the general protocol on a 1.0
mmol scale, the crude isocyanide was isolated as a yellow pale oil (112 mg,
96% crude yield, 93% purity by 1H NMR analysis). Spectral data for 2.9 were identical to
those previously reported.103
(102) Soo, B.; Beebe, J. M.; Jun, Y.; Zhu, X.-Y.; Frisbie, C. D. J. Am. Chem. Soc. 2006, 128, 4970–4971. (103) Guirado, A.; Zapata, A.; Gómez, J. L.; Trabalón, L.; Gálvez, J. Tetrahedron 1999, 55, 9631–9640.
NC
COOEt
NC
MeO
NC
NC
56
1-Benzyl-4-(isocyanomethyl)piperidine (2.10). Following the general protocol
on a 1.0 mmol scale, the crude isocyanide was isolated as a yellow oil (178 mg,
83% crude yield, 89% purity by 1H NMR analysis). IR (ATR, ZnSe) ν = 2942,
2149, 1687, 1494, 1450, 1367 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.33-7.26 (m,
5H), 3.51 (s, 2H), 3.28 (dt, J = 6.6, 1.6 Hz, 2H), 2.93 (dt, J = 11.8, 2.4 Hz, 2H), 1.98 (td, J
= 11.9, 2.5 Hz , 2H), 1.77 (d, J = 11.7 Hz, 2H), 1.68-1.65 (m, 1H), 1.37 (qd, J = 12.7, 3.8
Hz, 2H), 13C NMR (126 MHz, CDCl3) δ 156.3, 138.3, 129.1, 128.2, 127.0, 63.1, 52.9, 47.3,
35.8, 29.4; HRMS calcd for C14H19N2 [M+H]+ 215.1548, found 215.1539.
Benzyl 4-(isocyanomethyl)piperidine-1-carboxylate (2.11). Following the
general protocol on a 1.0 mmol scale, the crude isocyanide was isolated as a
yellow oil (247 mg, 95% crude yield, 93% purity by 1H NMR analysis). IR
(ATR, ZnSe) ν = 2938, 2854, 2147, 1690, 1428 cm-1; 1H NMR (500 MHz,
CDCl3) δ 7.37-7.35 (m, 5H), 5.13 (s, 2H), 4.25 (bs, 2H), 3.30 (d, J = 6.2 Hz, 2H), 2.79 (bs,
2H), 1.85-1.76 (m, 3H), 1.28-1.24 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 161.4, 155.1,
136.7, 128.5, 128.0, 127.9, 67.2, 47.0, 43.7, 43.4, 36.2, 35.8, 29.1; HRMS calcd for
C15H19N2O2 [M+H]+ 259.1441, found 260.1431.
1,1-Difluoro-4-(isocyanomethyl)cyclohexane (2.12). Following the general
protocol on a 0.56 mmol scale in 1 mL of CH2Cl2, the isocyanide was isolated as
a colorless oil after purification by flash chromatography using EtOAc/hexane
(1/9) as the eluent (50 mg, 56%). IR (ATR, ZnSe) ν = 2942, 2149, 1450, 1385
cm-1; 1H NMR (500 MHz, CDCl3) δ 3.31 (dt, J = 6.5, 1.9 Hz, 2H), 2.60-2.14 (m, 2H), 1.91-
1.86 (m, 2H), 1.83- 1.63 (m, 3H), 1.40 (qd, J = 12.7, 3.6 Hz, 2H); 13C NMR (126 MHz,
CDCl3) δ 157.0, 122.8 (t, J = 242.6 Hz), 46.5 (d, J = 3.2 Hz), 35.5, 32.9 (d, J = 23.4 Hz),
32.7 (d, J = 23.4 Hz), 26.2, 26.1; 19F NMR (376 MHz, CDCl3) δ -102.4 (dt, J = 66.8, 33.8
Hz), -92.6 (d, J = 236.8 Hz); HRMS calcd for C8H12F2N [M+NH4]+ 177.1198, found
177.1222.
NBn
CN
NCbz
CN
F F
NC
57
Methyl 2-isocyano-3-phenylpropanoate (2.13). Following the general
protocol on a 1.0 mmol scale, the crude isocyanide was isolated as a
yellow oil (182 mg, 96% crude yield, 71% purity by 1H NMR analysis).
Spectral data for 2.13 were identical to those previously reported.96
Chiral HPLC analysis indicates complete racemization.
Methyl 2-isocyano-3-methylbutanoate (2.14). Following the general
protocol on a 1.0 mmol scale, the crude isocyanide was isolated as a
yellow oil (130 mg, 91% crude yield, 86% purity by 1H NMR analysis). Spectral data for
2.14 were identical to those previously reported.91 Based on the result obtained for 2.13, we
assume that 2.14 is also racemic.
tert-Butyl 3,3-difluoro-4-(formamidomethyl)pyrrolidine-1-
carboxylate (2.15). Following the general protocol on a 0.63 mmol scale
in 1 mL of CH2Cl2, the isocyanide was isolated as a yellow oil after
purification by flash chromatography using EtOAc/hexane (1/9) as the eluent (100 mg,
60%). [α]D20 -60.3 (c 1.0, MeOH); IR (ATR, ZnSe) ν = 2979, 2149, 1698, 1394, 1367 cm-1;
1H NMR (500 MHz, CDCl3) δ 4.18 (bs, 1H), 3.80-3.77 (m, 2H), 3.68-3.64 (m, 2H), 2.52-
2.43 (m, 2H), 1.45 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 158.6, 153.8, 123.4 (t, J = 248.1
Hz), 81.5, 54.1, 44.0, 43.3, 37.3, 37.0, 36.6, 36.4, 28.2; 19F NMR (376 MHz, CDCl3) -100.1
(m, 2F); HRMS calcd for C11H17F2N2O2 [M+H]+ 247.1253, found 247.1255.
2.7.4 Multi-component reactions
2.7.4.1 Passerini reaction
General procedure98 – A suspension of the crude isonitrile (1.0 mmol), the carboxylic acid
(1.0 mmol) and benzaldehyde (1.0 mmol) in water (20 mL) was stirred at room temperature
CNOMe
O
MeO2C NC
NBoc
NC
FF
58
for 16 h. The precipitate formed during the reaction was recovered by filtration and washed
with ether to give the pure product.
2-((4-methoxyphenyl)amino)-2-oxo-1-phenylethyl
benzoate (2.18). Following the general protocol using the
crude isocyanide 2.2 and benzoic acid, the desired product
was isolated (120 mg, 33% from the formamide). mp: 165-167 °C; IR (ATR, ZnSe) ν =
3295, 1730, 1672, 1560, 1516 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.16 (d, J = 6.9 Hz, 2H),
7.82 (s, 1H), 7.67-7.61 (m, 3H), 7.52 (t, J = 7.7 Hz, 2H), 7.45-7.41 (m, 5H), 6.85 (d, J = 9.0
Hz, 2H), 6.47 (s, 1H), 3.79 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 166.1, 164.9, 156.8,
135.3, 133.8, 129.9 (2C), 129.2, 129.1, 128.9, 128.7, 127.5, 121.9, 114.2, 76.0, 55.5;
HRMS calcd for C22H20NO4 [M+H]+ 362.1387, found 362.1403.
2-oxo-1-phenyl-2-(o-tolylamino)ethyl benzoate (2.19).
Following the general protocol using the crude isocyanide 2.5 and
benzoic acid, the desired product was isolated (87 mg, 34% from
the formamide). mp: 173-175 °C; IR (ATR, ZnSe) ν = 3293, 3067, 1716, 1662, 1530, 1450
cm-1; 1H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 6.8 Hz, 2H), 7.93 (d, J = 8.1 Hz, 1H), 7.87
(s, 1H), 7.65 (d, J = 6.6 Hz, 3H), 7.52 (t, J = 7.7 Hz, 3H), 7.45-7.43 (m, 3H), 7.21 (dd, J =
7.8, 1.6 Hz, 1H), 7.16 (d, J = 1.5 Hz, 1H), 7.08 (td, J = 7.5, 1.3 Hz, 1H), 6.53 (s, 1H), 2.19
(s, 3H); 13C NMR (126 MHz, CDCl3) δ 166.3, 164.8, 135.3, 134.8, 133.9, 130.5, 129.8,
129.2, 129.0, 128.7, 128.3, 127.4, 127.0, 125.4, 122.4, 76.2, 17.5; HRMS calcd for
C22H20NO3 [M+H]+ 346.1438, found 346.1451.
2-(benzylamino)-2-oxo-phenylethyl benzoate (2.20).
Following the general protocol using the crude isocyanide 2.9
and benzoic acid, the desired product was isolated (161 mg,
50% from the formamide). mp: 105-108 °C; IR (ATR, ZnSe) ν = 3287, 3029, 1749, 1635,
NH
OO Ph
OPh
MeO
NH
OO Ph
OPhMe
NH
OO
Ph
Ph
O
59
1540 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.10 (d, J = 7.2 Hz, 2H), 7.64-7.54 (m, 3H),
7.49-7.45 (m, 2H), 7.44-7.36 (m, 3H), 7.35-7.26 (m, 3H), 7.23 (d, J = 6.7 Hz, 2H), 6.57 (s,
1H), 6.40 (s, 1H), 4.54 (dd, J = 15.0, 5.9 Hz, 1H), 4.48 (dd, J = 15.0, 5.8 Hz, 1H); 13C
NMR (126 MHz, CDCl3) δ 168.4, 165.1, 137.7, 135.5, 133.7, 129.9, 129.2, 129.1, 128.9,
128.7, 128.7, 127.6, 127.5, 127.4, 76.0, 43.4; HRMS calcd for C22H20NO3 [M+H]+
346.1438, found 346.1445.
2-((4-methoxybenzyl)amino)-2-oxo-1-phenylethyl
benzoate (2.21). Following the general protocol using
the crude isocyanide 2.8 and benzoic acid, the desired
product was isolated (276 mg, 74% from the formamide). mp: 147-151 °C; IR (ATR, ZnSe)
ν = 3322, 1726, 1650, 1528, 1515 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.09 (dd, J = 7.4,
1.4 Hz, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.56 (dd, J = 7.1, 1.2 Hz, 2H), 7.46 (t, J = 8.0 Hz,
2H), 7.42-7.40 (m, 3H), 7.17 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 7.7 Hz, 2H), 6.43 (bs, 1H),
6.38 (s, 1H), 4.48 (dd, J = 14.7, 5.9 Hz, 1H), 4.42 (dd, J = 14.7, 5.7 Hz, 1H), 3.80 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 168.2, 165.0, 159.1, 135.5, 133.7, 129.9, 129.8, 129.2,
129.1, 129.0, 128.8, 128.6, 127.4, 114.1, 76.0, 55.3, 42.9; HRMS calcd for C23H22NO4
[M+H]+ 376.1543, found 375.1551.
2-((4-methoxybenzyl)amino)-1-(4-nitrophenyl)-2-
oxoethyl benzoate (2.22). Following the general
protocol using the crude isocyanide 2.8, benzoic acid and
4-nitrobenzaldehyde, the desired product was isolated
(309 mg, 74% from the formamide). mp: 87-90°C; IR
(ATR, ZnSe) ν = 3276, 3077, 2841, 1729, 1659, 1514 cm-1; 1H NMR (500 MHz, CDCl3) δ
8.25 (d, J = 8.3 Hz, 2H), 8.08 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H), 7.65 (t, J = 7.5
Hz, 1H), 7.50 (t, J = 7.8 Hz, 2H), 7.17 (d, J = 8.1 Hz, 2H), 6.85 (d, J = 8.2 Hz, 2H), 6.64 (s,
1H), 6.46 (s, 1H), 4.45 (dd, J = 8.2, 5.8 Hz, 2H), 3.79 (s, 3H); 13C NMR (126 MHz, CDCl3)
δ 167.0, 164.6, 159.2, 148.1, 142.4, 134.2, 133.6, 130.5, 130.1, 129.8, 129.3, 129.0, 128.8,
NH
OO
Ph
Ph
OMeO
NH
OO Ph
OMeO
NO2
60
128.5, 128.0, 124.3, 114.2, 74.8, 55.3, 43.1; HRMS calcd for C23H21N2O6 [M+H]+
421.1394, found 421.1386.
2-((4-methoxybenzyl)amino)-2-oxo-1-
phenylethyl 4-nitrobenzoate (2.23).
Following the general protocol using the crude
isocyanide 2.8 and 4-nitrobenzoic acid, the desired product was isolated (223 mg, 75%
from the formamide). mp: 144-147 °C; IR (ATR, ZnSe) ν = 3295, 2835, 1748, 1661, 1528
cm-1; 1H NMR (500 MHz, CDCl3) δ 8.27 (q, J = 8.8 Hz, 4H), 7.63-7.52 (m, 2H), 7.48-7.37
(m, 3H), 7.14 (d, J = 8.6 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 6.31 (s, 1H), 6.19 (t, J = 5.9 Hz,
1H), 4.47 (dd, J = 14.7, 5.8 Hz, 1H), 4.40 (dd, J = 14.7, 5.6 Hz, 1H), 3.79 (s, 3H); 13C
NMR (126 MHz, CDCl3) δ 167.5, 163.6, 159.1, 150.8, 134.7, 134.6, 131.0, 129.6, 129.5,
129.1, 129.0, 127.7, 123.7, 114.1, 76.8, 55.3, 43.1; HRMS calcd for C23H21N2O6 [M+H]+
421.1394, found 421.1403.
Benzyl 4-((2-(benzoyloxy)-2-phenylacetamido)methyl)
piperidine-1-carboxylate (2.24). Following the general
protocol using the crude isocyanide 2.11 and benzoic acid,
the desired product was isolated (153 mg, 39% from the formamide). mp: 99 °C (dec); IR
(ATR, ZnSe) ν = 3317, 2858, 1730, 1665, 1584 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.17-
7.98 (m, 2H), 7.73-7.14 (m, 13H), 6.32 (s, 1H), 6.28 (t, J = 6.1 Hz, 1H), 5.12 (s, 2H), 4.18
(bs, 2H), 3.21 (bs, 2H), 2.73 (bs, 2H), 1.69 (m, 3H), 1.12 (bs, 2H); 13C NMR (126 MHz,
CDCl3) δ 168.6, 165.0, 155.2, 136.8, 135.4, 133.8, 129.8, 129.1, 128.9, 128.7, 128.5, 128.0,
127.8, 127.2, 76.0, 67.0, 44.7, 43.7, 36.2, 29.6; HRMS calcd for C29H30N2O5 [M+H]+
487.2227, found 487.2238.
NH
OO
Ph OMeO
NO2
NH
OO Ph
OPhCbzN
61
2-((1-methoxy-3-methyl-1-oxobutan-2yl)amino)-2-oxo-1-
phenylethyl benzoate (2.25). Following the general protocol
using the crude isocyanide 2.14 and benzoic acid, the desired
product was isolated (120 mg, 36% from the formamide). mp 142 °C (dec); IR (ATR,
ZnSe) ν = 3271, 2961, 1740, 1661, 1661, 1603, 1567 cm-1; 1H NMR (500 MHz, CDCl3,
mixture of rotamers) δ 8.19-8.07 (m, 2H), 7.68-7.54 (m, 3H), 7.54-7.45 (m, 2H), 7.40 (m,
3H), 6.87 (d, J = 8.7 Hz, 0.75H), 6.76 (d, J = 8.9 Hz, 0.35H), 6.38 (s, 0.30H), 6.35 (s,
0.70H), 4.61 (dd, J = 8.6, 4.7 Hz, 1H), 3.76 (s, 0.70H), 3.72 (s, 2.3H), 2.22 (m, 1H), 0.93
(dd, J = 6.9, 3.5 Hz, 4H), 0.89 (d, J = 6.9 Hz, 1H), 0.81 (d, J = 6.8 Hz, 1H); 13C NMR (126
MHz, CDCl3, mixture of rotamers) δ 172.2, 172.0, 168.3, 165.0, 164.8, 135.5, 135.3, 133.7,
133.6, 129.8, 129.2, 129.1, 128.8, 128.7, 128.4, 127.5, 127.2, 76.1, 76.0, 56.9, 56.8, 52.3,
52.2, 31.8, 31.6, 18.9, 17.7, 17.4; HRMS calcd for C21H23NO5 [M+ H]+ 370.1649, found
370.1646.
2.7.4.2 Synthesis of N-formyl amides
General procedure100 – To a solution of crude isonitrile in CHCl3 (1 mL) was added
benzoic acid (1.0 equiv) under argon. The reaction mixture was heated to 150 °C in
microwave oven for 1 h and then applied onto flash chromatography column
(EtOAc/Hexane, 1/5) to afford the desired compound.
N-benzyl-N-formylbenzamide (2.26). Following the general protocol
on a 0.56 mmol scale using the crude isocyanide 2.9 the desired
product was isolated as yellow pale solid after purification by flash
chromatography (88 mg, 53% yield from the formamide). mp: 63-67 °C; IR (ATR, ZnSe) ν
= 1715, 1658, 1446 cm-1; 1H NMR (500 MHz, CDCl3) δ 9.01 (s, 1H), 7.63-7.42 (m, 7H),
7.38-7.26 (m, 3H), 5.08 (s, 2H); 13C NMR (126 MHz, CDCl3) δ 171.1, 164.1, 136.6, 133.5,
132.3, 130.2, 129.0, 128.8, 128.7, 128.6, 127.7, 43.8; HRMS calcd for C15H14NO2 [M+H]+
240.1019, found 240.1008.
MeOOC NH
OO Ph
OPh
N Ph
O
OH
62
N-formyl-N-(4-methoxybenzyl)benzamide (2.27). Following
the general protocol on a 1.0 mmol scale using the crude
isocyanide 2.8 the desired product was isolated as yellow foam
after purification by flash chromatography (100 mg, 51% yield from the formamide). IR
(ATR, ZnSe) ν = 2962, 2938, 1655, 1509 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.97 (s, 1H),
7.59-7.52 (m, 1H), 7.53-7.44 (m, 4H), 7.40 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H),
5.00 (s, 2H), 3.79 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 172.2, 164.1, 159.1, 133.6, 132.2,
130.4, 128.9, 128.9, 128.8, 113.9, 55.2, 43.2; HRMS calcd for C16H15NO3Na [M+Na]+
292.0944, found 292.0949.
2.7.4.3 Ugi-Smiles reaction101
2-(benzyl(4-nitrophenyl)amino)-N-(4-
methoxybenzyl)propanamide (2.28). To a solution of
the crude isocyanide 2.8 (1.0 mmol) in methanol (1 mL)
were successively added acetaldehyde (1.0 mmol),
benzylamine (1.0 mmol) and 4-nitrophenol (1.0 mmol)
under an inert atmosphere. The resulting mixture was
stirred at room temperature for 16 h. The solvent was evaporated and the crude product was
purified by flash chromatography column (EtOAc/Hexane, 3/7) to give compound 2.28
(147 mg, 35% yield from the formamide) as a yellow foam. IR (ATR, ZnSe) ν = 3299,
2916, 1650, 1592, 1507 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.96 (d, J = 9.5 Hz, 2H), 7.36-
7.23 (m, 3H), 7.16 (d, J = 6.7 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 6.79 (d, J = 8.6 Hz, 2H),
6.66 (d, J = 9.5 Hz, 2H), 6.42 (t, J = 5.8 Hz, 1H), 4.70 (d, J = 4.2 Hz, 2H), 4.52 (q, J = 7.1
Hz, 1H), 4.32 (dd, J = 14.5, 5.8 Hz, 1H), 4.27 (dd, J = 14.5, 5.8 Hz, 1H), 3.77 (s, 3H), 1.55
(d, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 170.9, 159.0, 152.9, 138.4, 137.0,
129.8, 129.1, 129.0, 127.6, 126.2, 125.9, 114.0, 112.5, 59.1, 55.3, 51.9, 43.2, 14.9; HRMS
calcd for C24H26N3O4 [M+H]+ 420.1918, found 420.1931.
MeO
N Ph
O
OH
MeO
NH
O
Me
N Ph
NO2
63
CHAPITRE 3
Synthèse de nitriles à partir d’aldoximes
et d’amides primaires en utilisant le XtalFluor-E
Synthesis of Nitriles from Aldoximes
and Primary Amides Using XtalFluor-E
Massaba Keita, Mathilde Vandamme, Jean-François Paquin*
CCVC, PROTEO, Département de chimie, Université Laval,
1045 avenue de la Médecine, Québec, Québec, Canada, G1V 0A6
E-mail: jean-francois.paquin@chm.ulaval.ca
Reproduit à partir de Synthesis 2015, 47, 3758–3766.
64
3.1 RÉSUMÉ
La réaction de déshydratation d’aldoximes et d’amides pour la synthèse de nitriles en
utilisant [Et2NSF2]BF4 (XtalFluor-E) est décrite. D’une manière générale, la réaction se
déroule rapidement (normalement <1 h) à température ambiante dans un solvant
respectueux de l’environnement (AcOEt) et avec seulement un léger excès d’agent
déshydratant (1,1 équiv). Une large gamme de nitriles peut être ainsi préparée, incluant des
produits chiraux non racémiques. De plus, dans certains cas, une purification
supplémentaire du nitrile après le traitement de la réaction n’a pas été requise.
3.2 ABSTRACT
The dehydration reaction of aldoximes and amides for the synthesis of nitriles using
[Et2NSF2]BF4 (XtalFluor-E) is described. Overall, the reaction proceeds rapidly (normally
<1 h) at room temperature in an environmentally–benign solvent (EtOAc) with only a slight
excess of the dehydrating agent (1.1 equiv). A broad scope of nitriles can be prepared,
including chiral nonracemic ones. In addition, in a number of cases, further purification of
the nitrile after the workup was not required.
26 examplesup to 99% yield
N
HR
OHO
NH2Ror
EtOAc, rt, 1 h
XtalFluor-EEt3N
R C N
• Fast reaction under mild conditions;• Environmentally-benign solvent;• Only 1.1 equiv of XtalFluor-E required; • Broad substrate scope (including chiral non-racemic precursors)
65
3.3 INTRODUCTION
Nitriles are key building-blocks in organic synthesis.104 In addition, a number of
pharmaceuticals or natural products contain this functional group.105,106 Due to their
importance, numerous approaches have been published recently.107 Nonetheless, the main
synthetic route remains arguably the dehydration of a suitable precursor. To that effect,
numerous protocols have been reported over the past years using either aldoximes108 or
primary amides109 as starting materials. However, most of these suffer from one or multiple
(104) Selected reviews/books on the use of nitrile-containing molecules in organic synthesis, see (a) Enders, D.; Shilvock, J. P. Chem. Soc. Rev. 2000, 29, 359–373. (b) Three carbon-heteroatom bonds: nitriles, isocyanides and derivatives; Shun’ichi, M., Ed.; Georg Thieme Verlag, 2004. (c) Ronald, M. R. Nitriles. In Kirk-Othmer Encyclopedia of Chemical Technology (5th Edition); Othmer K., Ed.; Hoboken, N.J. 2006; Vol. 17, pp 227. (d) Otto, N.; Opatz, T. Chem. Eur. J. 2014, 20, 13064–13077. (105) Review: Fleming, F. F.; Yao, L.; Ravikumar, P. C.; Funk, L.; Shook, B. C. J. Med. Chem. 2010, 53, 7902–7917. (106) Review: Fleming, F. F. Nat. Prod. Rep. 1999, 16, 597–606. (107) For other recent selected approaches to nitriles, see (a) Laulhé, S.; Gori, S. S.; Nantz, M. H. J. Org. Chem. 2012, 77, 9334–9337. (b) Tseng, K.-N. T.; Rizzi, A. M.; Szymczak, N. K. J. Am. Chem. Soc. 2013, 135, 16352–16355. (c) Powell, K. J.; Han, L.-C.; Sharma, P.; Moses, J. E. Org. Lett. 2014, 16, 2158–2161. (d) Nagase, Y.; Sugiyama, T.; Nomiyama, S.; Yonekura, K.; Tsuchimoto, T. Adv. Synth. Catal. 2014, 356, 347–352. (e) Cohen, D. T.; Buchwald, S. L. Org. Lett. 2015, 17, 202–205. (f) Lindsay-Scott, P. J.; Clarke, A.; Richardson, J. Org. Lett. 2015, 17, 476–479. (g) Wang, Y.-F.; Qiu, J.; Kong, D.; Gao, Y.; Lu, F.; Karmaker, P. G.; Chen, F.-X. Org. Biomol. Chem. 2015, 13, 365–368. (108) For recent selected approaches to nitriles from aldoximes, see (a) Yamaguchi, K.; Fujiwara, H.; Ogasawara, Y.; Kotani, M.; Mizuno, N. Angew. Chem., Int. Ed. 2007, 46, 3922–3925. (b) Campbell, J. A.; McDougald, G.; McNab, H.; Rees, L. V. C.; Tyas, R. G. Synthesis 2007, 3179–3184. (c) Saha, D.; Saha, A.; Ranu, B. C. Tetrahedron Lett. 2009, 50, 6088–6091. (d) Singh, M. K.; Lakshman, M. K. J. Org. Chem. 2009, 74, 3079–3084. (e) Jiang, N.; Ragauskas, A. J. Tetrahedron Lett. 2010, 51, 4479–4481. (f) Augustine, J. K.; Kumar, R.; Bombrun, A.; Mandal, A. B. Tetrahedron Lett. 2011, 52, 1074–1077. (g) Kalkhambkar, R. G.; Bunge, S. D.; Laali, K. K. Tetrahedron Lett. 2011, 52, 5184–5187. (h) Denton, R. M.; An, J.; Lindovska, P.; Lewis, W. Tetrahedron Lett. 2012, 68, 2899–2905. (i) Tambara, K.; Pantoş, G. D. Org. Biomol. Chem. 2013, 11, 2466–2472. (j) Rai, A.; Yadav, L. D. S. Eur. J. Org. Chem. 2013, 1889–1893. (k) Yadav, A. K.; Srivastava, V. P.; Yadav, L. D. S. RSC Adv. 2014, 4, 4181–4186. (l) Metzner, R.; Okazaki, S.; Asano, Y.; Gröger, H. ChemCatChem 2014, 6, 3105–3109. (m) Song, Y.; Shen, D.; Zhang, Q.; Chen, B.; Xu, G. Tetrahedron Lett. 2014, 55, 639–641. (n) Yu, L.; Li, H.; Zhang, X.; Ye, J.; Liu, J.; Xu, Q.; Lautens, M. Org. Lett. 2014, 16, 1346–1349. (109) For recent selected approaches to nitriles from primary amides, in addition to references 108b,j,k, see (a) Maffioli, S. I.; Marzorati, E.; Marazzi, A. Org. Lett. 2005, 7, 5237–5239. (b) Kuo, C.-W.; Zhu, J.-L.; Wu, J.-D.; Chu, C.-M.; Yao, C.-F.; Shia, K.-S. Chem. Commun. 2007, 301–303. (c) Hanada, S.; Motoyama, Y.; Nagashima, H. Eur. J. Org. Chem. 2008, 4097–4100. (d) Zhou, S.; Junge, K.; Addis, D.; Das, S.; Beller, M. Org. Lett. 2009, 11, 2461–2464. (e) Zhou, S.; Addis, D.; Das, S.; Junge, K.; Beller, M. Chem. Commun. 2009, 4883–4885. (f) Sueoka, S.; Mitsudome, T.; Mizugaki, T.; Jitsukawa, K.; Kaneda, K. Chem. Commun. 2010, 8243–8245. (g) Enthaler, S.; Weidauer, M. Catal. Lett. 2011, 141, 1079–1085. (h) Enthaler, S. Chem. Eur. J. 2011, 9316–9319. (i) Enthaler, S. Eur. J. Org. Chem. 2011, 4760–4763. (j) Enthaler, S.; Inoue, S. Chem.
66
drawbacks including high temperature and/or the use of an excess of the dehydration
reagent (>2 equiv). Finally, only a few methods are mild enough to allow the synthesis of
chiral nonracemic nitriles.110
We have recently reported the use of diethylaminodifluorosulfinium tetrafluoroborate
([Et2NSF2]BF4), XtalFluor-E,111 a crystalline solid initially developed as a
deoxofluorinating agent with enhanced thermal stability, for the synthesis of various
isocyanides through the dehydration of formamides.112 We envisioned that if primary
amides or aldoximes were used as the starting substrate instead, upon activation with
XtalFluor-E and in the presence of a base, nitriles would be obtained (Figure 3.1). Herein,
we report this transformation. Overall, the reaction proceeds rapidly at room temperature in
an environmentally–benign solvent with only a slight excess of the dehydrating agent. In a
number of cases, further purification of the nitrile after the workup is not necessary.
Finally, this method has a large scope, allowing the synthesis of aromatic, vinylic, aliphatic,
and benzylic nitriles including chiral nonracemic ones and tolerates typical oxygen or
nitrogen protecting groups.
Asian J. 2012, 169–175. (k) Itagaki, S.; Kamata, K.; Yamaguchi, K.; Mizuno, N. ChemCatChem 2013, 1725–1728. (110) For selected examples of chiral nonracemic nitriles obtained from dehydration, see (a) Claremon, D. A.; Phillips, B. T. Tetrahedron Lett. 1988, 29, 2155–2158. (b) Spero, D. M.; Kapadia, S. R. J. Org. Chem. 1996, 61, 7398–7401. (c) Maetz, P.; Rodriguez, M. Tetrahedron Lett. 1997, 38, 4221–4222. (d) Bose, D. S.; Jayalakshmi, B. Synthesis 1999, 64–65. (e) Bose, D. S.; Jayalakshmi, B. J. Org. Chem. 1999, 64, 1713–1714. (f) Bose, D. S.; Sunder, K. S. Synth. Commun. 1999, 29, 4235–4239. (g) Bose, D. S.; Jayalakshmi, B.; Goud, P. R. Synthesis 1999, 1724–1726. (h) Bose, D. S.; Kumar, K. K. Synth. Commun. 2000, 30, 3047–3052. (i) Bose, D. S.; Narsaiah, A. V. Synthesis 2001, 373–375. (j) Nakajima, N.; Saito, M.; Ubukata, M. Tetrahedron 2002, 58, 3561–3577. (k) Beaufort-Droal, V.; Pereira, E.; Théry, V.; Aitken, D. J. Tetrahedron 2006, 62, 11948–11954. (l) Tka, N.; Kraïem, J.; Ben Hassine, B. Synth. Commun. 2013, 43, 735–743. (111) (a) Beaulieu, F.; Beauregard, L.-P.; Courchesne, G.; Couturier, M.; Laflamme, F.; L’Heureux, A. Org. Lett. 2009, 11, 5050–5053. (b) L’Heureux, A.; Beaulieu, F.; Bennet, C.; Bill, D. R.; Clayton, S.; Laflamme, F.; Mirmehrabi, M.; Tadayon, S.; Tovell, D.; Couturier, M. J. Org. Chem. 2010, 75, 3401–3411. (c) Mahé, O.; L'Heureux, A.; Couturier, M.; Bennett, C.; Clayton, S.; Tovell, D.; Beaulieu, F.; Paquin, J.-F. J. Fluorine Chem. 2013, 153, 57–60. (112) Keita, M.; Vandamme, M.; Mahé, O.; Paquin, J.-F. Tetrahedron Lett. 2015, 56, 461–464.
67
Figure 3.1. Activation of amides and aldoximes with XtalFluor-E for the synthesis of nitriles.
3.4 RESULTS AND DISCUSSION
The initial tests were performed using aldoxime 3.1, derived from hydrocinnamaldehyde,
using the conditions developed for the synthesis of isocyanides (Scheme 3.1).112
Gratifyingly, performing the reaction at room temperature instead of -40 °C provided
within one hour reaction time, the desired nitrile 3.2 in 95% yield. At this point, since
CH2Cl2 has been identified as an undesirable solvent by various pharmaceutical solvent
selection guides,113 EtOAc was chosen as the optimal solvent. The use of the corresponding
primary amide, 3.3, provided, under the same reaction conditions, the nitrile 3.2 in 74%
(113) (a) Alfonsi, K.; Colberg, J.; Dunn, P. J.; Fevig, T.; Jennings, S.; Johnson, T. A.; Kleine, H. P.; Knight, C.; Nagy, M. A.; Perry, D. A.; Stefaniak, M. Green Chem. 2008, 10, 31–36. (b) Henderson, R. K.; Jiménez-González, C.; Constable, D. J. C.; Alston, S. R.; Inglis, G. G. A.; Fisher, G.; Sherwood, J.; Binks, S. P.; Curzons, A. D. Green Chem. 2011, 13, 854–862. (c) Prat, D.; Pardigon, O.; Flemming, H.-W.; Letestu, S.; Ducandas, V.; Isnard, P.; Guntrum, E.; Senac, T.; Ruisseau, S.; Cruciani, P.; Hosek, P. Org. Process Res. Dev. 2013, 17, 1517–1525.
R1 NHR2
O
R1
O
N
This work[Et2NSF2]BF4(XtalFluor-E)
R1 = HR2 = alkyl or aryl
isocyanides
R2
SNEt2
FF
H+
NC R2base
BF4-
R1 = alkyl or arylR2 = H
C NR1
nitriles
R1
N XtalFluor-EOH
H R1
NO
H
SNEt2
F F- HBF4
amides
aldoximes
base
+-
68
yield (Scheme 3.1). A better yield of 90% could be obtained in CH2Cl2. Nonetheless,
EtOAc was kept as the solvent for the rest of the studies.
Scheme 3.1. Initial results for the dehydration of 3.1 and 3.3 using XtalFluor-E.
a Reaction was performed on 6.7 mmol scale (i.e., 1.0 g) of 3.1.
Nearly identical results being obtained from both starting materials, we proceeded to study
the scope of this reaction in a comparative fashion to identify the strengths and weaknesses
of each precursor (i.e., aldoximes vs primary amides) for the various classes of substrates.
First, we examined the synthesis of aromatic nitriles (Scheme 3.2). The reaction proceeded
well with both aldoximes and primary amides, though the yields were always better for the
former (6-42% higher). Higher nucleophilicity of the aldoxime oxygen (not conjugated
with the aromatic ring) as opposed to the amide which is conjugated with the aromatic ring
may account for the difference of reactivity in some cases. Overall, both electron-
withdrawing and electron-donating groups were tolerated regardless of their position.
Interestingly, a free phenol was tolerated and nitrile 3.6i was obtained in 60% from the
corresponding aldoxime. In this case, the reaction of the primary amide provided a complex
mixture of products as shown by NMR analysis of the crude mixture. We hypothesized that
CNXtalFluor-E (1.1 equiv)
Et3N (1.5 equiv)
solvent (1 M), rt, 1 h3.1 3.2
CH2Cl2tolueneEtOAc
95%98%
99% (87%)a
NOH
H
NH2
XtalFluor-E (1.1 equiv)Et3N (1.5 equiv)
EtOAc (1 M), rt, 1 h3.3
3.2 (74%)
O
From aldoxime 3.1
From amide 3.3
69
the phenol competes with the less nucleophilic amide for the XtalFluor-E reagent, thus
leading to undesirable products. In the case of the more nucleophilic aldoxime, this
pathway does not compete. Finally, 3-cyanopyridine (3.6j), a heterocyclic nitrile, was
obtained from both precursors, although more efficiently from the aldoxime (87% vs 47%
from the amide). Practically, while most of the nitriles generated from primary amides
required purification by flash chromatography, the majority of the ones generated from the
aldoximes did not.
Scheme 3.2. Synthesis of aromatic nitriles (3.6) from aldoximes (3.4) or primary amides (3.5).
CNXtalFluor-E (1.1 equiv)
Et3N (1.5 equiv)
EtOAc (1 M), rt, 1 h
3.4a-j 3.6a-j
XR
XR
XR
NH2
ONOH
3.5a-j
orH
CN
3.6a; 87% (from 3.4a) 81% (from 3.5a)
CN CN
I
CN
MeO
CN
MeO2C
CNF3C
CF3
CN
O2N
CN
OPh
CN
HO N
CN
3.6b; 99% (from 3.4b) 61%b (from 3.5b)
3.6c; 99% (from 3.4c) 74% (from 3.5c)
3.6d; 85% (from 3.4d) 65% (from 3.5d)
3.6e; 97% (from 3.4e) 72% (from 3.5e)
3.6f; 86% (from 3.4f) -%c (from 3.5f)
3.6g; 95% (from 3.4g) 55% (from 3.5g)
3.6h; 97% (from 3.4h) 61%d (from 3.5h)
3.6i; 60% (from 3.4i) 6%e (from 3.5i)
3.6j; 87% (from 3.4j) 45% (from 3.5j)
70
a The reaction was run in toluene for 4 h. b The yield could not be determined as the desired product co-eluted with an unidentified side-product. Overlaps in the NMR spectrum prevented the estimation of an NMR yield. c The reaction time was 5 h. d The crude 1H NMR spectrum shows multiple unidentified products.
The synthesis of a vinylic nitrile, 3.9, proceeded both from the aldoxime (3.7) or the
primary amide (3.8), but a higher yield was observed with the former (Scheme 3.3). Here
again, the reaction could be performed on a larger scale (13.6 mmol of 3.8) with a similar
result.
Scheme 3.3. Synthesis of vinylic nitrile 3.9 from cinnamic acid derivatives 3.7 and 3.8.
a Reaction was performed on 13.6 mmol scale (i.e, 2.0 g) of 3.8.
We then turned our attention to the synthesis of aliphatic nitriles (Scheme 3.4). In this
series, the difference of reactivity between both precursors is less obvious. For instance, the
synthesis of caprylonitrile (3.12a) and glutaronitrile (3.12b) proceeded well from the
aldoximes, but poorly from the amides. On the other hand, better yields were obtained from
the amides for some nitriles (e.g., 3.12d, 3.12f, 3.12g). Benzylic nitriles 3.12c-d can be
prepared from both precursors although in the case of the nitro-containing precursors, the
crude NMR spectrum shows multiple non-identified products. Acid-labile alcohol
protecting groups such as TBS or MOM are well tolerated. Finally, a series of protected
piperidines were tested and showed that benzyl, Cbz and Boc protecting groups are all
tolerated under those reaction conditions.
CNXtalFluor-E (1.1 equiv)
Et3N (1.5 equiv)
EtOAc (1 M), rt, 1 h
3.7; R = CH=NOH3.8; R = C(O)NH2
3.9; 84% (from 3.7) 62% and 69%a (from 3.8)
R
71
Scheme 3.4. Synthesis of aliphatic nitriles from aldoximes (3.10) or primary amides (3.11).
a The crude 1H NMR spectrum shows multiple unidentified products. b Crude yield.
Considering the challenge that represents the synthesis of chiral nonracemic aliphatic
nitriles,110 we then investigated, whether or not, this methodology could be applied for their
preparation. We initially considered the use of aldoximes derived from L-valine or L-
phenylalanine. Unfortunately, under our conditions, none of them provided the desired
nitriles and a complex mixture was obtained in both cases. Unexpectedly, but fortunately,
the use of primary amides derived from L-valine (3.13) or L-phenylalanine (3.14) as the
precursor allowed for the synthesis of the corresponding nitriles (Scheme 3.5).114,115 In all
(114) For other examples of the synthesis of 3.16 from 3.13, see (a) Nakajima, N.; Ubukata, M. Tetrahedron Lett. 1997, 38, 2099–2102. (b) Nakajima, N.; Saito, M.; Ubukata, M. Tetrahedron 2002, 58, 3561–3577. (c) Hoang, C. T.; Bouillère, F.; Johannesen, S.; Zulauf, A.; Panel, C.; Pouilhès, A.; Gori, D.; Alezra. V.; Kouklovsky, C. J. Org. Chem. 2009, 74, 4177–4187. (115) For other examples of the synthesis of 3.17 from 3.14, see ref. 114c and (a) Hoang, C. T.; Alezra, V.; Guillot, R.; Kouklovsky, C. Org. Lett. 2007, 9, 2521–2524. (b) Sureshbabu, V. V.; Naik, S. A.; Hemanta, H.
XtalFluor-E (1.1 equiv)Et3N (1.5 equiv)
EtOAc (1 M), rt, 1 h
3.10a-j 3.12a-j
RR NH2
ONOH
3.11a-j
or R CNH
CN NC CNCN CN
MeO
CN
O2N
RO CN
2 NR
CN
3.12a; 82% (from 3.10a) 19%b (from 3.11a)
3.12b; 88% (from 3.10b) tracesb (from 3.11b)
3.12c; 52% (from 3.10c) 54% (from 3.11c)
3.12d; 90% (from 3.10d) 98% (from 3.11d)
3.12e; tracesb (from 3.10e) tracesb (from 3.11e)
3.12f (R = TBS); 65% (from 3.10f) 73% (from 3.11f)
3.12g (R = MOM); 72%c (from 3.10g) 98%c (from 3.11g)
3.12h (R = Bn); 80% (from 3.10h) 85% (from 3.11h)
3.12i (R = Cbz); 88% (from 3.10i) 63% (from 3.11i)
3.12j (R = Boc); 99% (from 3.10j) 98% (from 3.11j)
72
cases, no erosion of the enantiomeric purity was observed by chiral HPLC analyses. The
reaction was also possible with the threonine-derived amide 3.15, although in this case the
use of CH2Cl2 as the solvent was required to obtain the nitrile 3.18 in good yield.
Interestingly, some of these nitriles have been used as synthetic precursors for various
value-added products.115,116
Scheme 3.5. Synthesis of chiral nonracemic nitriles from primary amides derived from protected amino acids.
a Reaction was performed in CH2Cl2 for 2 h instead.
The synthesis of chiral nitriles was then extended to L-mandelic acid and L-lactic acid
derivatives (Scheme 3.6). The desired nitriles 3.21117 and 3.24118,119,120 were obtained in
moderate to excellent yields (38-99%) from both precursors. Again, in all cases, no erosion
of the enantiomeric purity was observed by chiral HPLC analyses.
P.; Narendra, N.; Das, U.; Row, N. G. J. Org. Chem. 2009, 74, 5260–5266. (c) Delacroix, S.; Bonnet, J.-P.; Courty, M.; Postel, D.; Van Nhien, A. N. Carbohydr. Res. 2013, 381, 12–18. (116) Demko, Z. P.; Sharpless, B. K. Org. Lett. 2002, 4, 2525–2527. (117) For another exemple of the synthesis of 3.21 from 3.19, see Singh, B.; Gupta, P.; Chaubey, A.; Parshad, R.; Sharma, S.; Taneja, S. C. Tetrahedron: Asymmetry 2008, 19, 2579–2588. (118) For the synthesis of 3.24 via the dehydration of tert-butanesulfinyl imines, see Tanuwidjaja, J.; Peltier, H. M.; Lewis, J. C.; Schenkel, L. B.; Ellman, J. A. Synthesis 2007, 3385–3389. (119) For a chiral Brønsted acid-mediated vinyl ether hydrocyanationenantio approach to 3.26, see Lu, C.; Su, X.; Floreancig, P. E. J Org. Chem. 2013, 78, 9366–9376. (120) For examples of application of 3.24 in organic synthesis, see (a) Charette, A. B.; Gagnon, A.; Janes, M.; Mellon, C. Tetrahedron Lett. 1998, 39, 5147–5150. (b) Tanaka, R.; Yuza, A.; Watai, Y.; Suzuki, D.; Takayama, Y.; Sato, F.; Urabe, H. J. Am. Chem. Soc. 2005, 127, 7774–7780.
CbzHN
R
O XtalFluor-E (1.1 equiv)Et3N (1.5 equiv)
EtOAc (1 M), rt, 1 h
CbzHN
R
CN
3.13; R = i-Pr3.14; R = Bn3.15; R = (R)-CH(OCH3)CH3
3.16; R = i-Pr (51%, >99% ee)3.17; R = Bn (70%, >99% ee)3.18; R = (R)-CH(OCH3)CH3 (62%, >99% ee)a
NH2
73
Scheme 3.6. Synthesis of chiral nonracemic nitriles from L-mandelic acid and L-lactic acid and derivatives.
3.5 CONCLUSION
In conclusion, we have described the dehydration reaction of aldoximes and amides for the
synthesis of nitriles using XtalFluor-E. The reaction proceeds normally within 1 h at room
temperature in EtOAc, an environmentally–benign solvent, with only a slight excess of the
dehydrating agent. In a number of cases, further purification of the nitrile after the workup
is not necessary. Finally, this method has a large scope, allowing the synthesis of aromatic,
vinylic, aliphatic, and benzylic nitriles including chiral nonracemic ones and tolerates
standard oxygen or nitrogen protecting groups.
3.6 ACKNOWLEDGMENTS
This work was supported by the Canada Research Chair Program, the Natural Sciences and
Engineering Research Council of Canada, the Canada Foundation for Innovation, Fonds de
recherche du Québec – Nature et technologies, OmegaChem and the Université Laval.
OMe
R
OMe
CN
3.19; R = CH=NOH3.20; R = C(O)NH2
3.21 (60%, >99% ee from 3.19) (57%, >99% ee from 3.20)
Me
OBn
R
XtalFluor-E (1.1 equiv)Et3N (1.5 equiv)
EtOAc (1 M), rt, 1 h
3.22; R = CH=NOH3.23; R = C(O)NH2
3.24 (38%, >99% ee from 3.22) (99%, >99% ee from 3.23)
Me
OBn
CN
74
3.7 SUPPORTING INFORMATION AVAILABLE
3.7.1 General information
All reactions were carried out under an argon atmosphere with dry solvents under
anhydrous conditions. Unless otherwise noted, all commercial reagents were used without
further purification. Thin-layer chromatography (TLC) analysis of reaction mixtures was
visualized under UV (λ = 254 nm) or by staining with a KMnO4 solution followed by
heating. 1H, 13C and 19F spectra were respectively recorded at 500, 125 and 470 MHz using
CDCl3 or DMSO-d6 as the solvent at ambient temperature using tetramethylsilane (1H and 13C NMR) or residual solvent (1H and 13C NMR) as the internal standards and CFCl3 (19F
NMR) as the external standard. Coupling constants (J) are measured in hertz (Hz).
Multiplicities are reported using the following abbreviations: s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet, br = broad resonance. Coupling constants J (Hz) were
taken directly from the spectra and are not averaged. High-resolution mass spectra were
obtained using electrospray ionization (ESI) on a time-of-flight (TOF) spectrometer.
Melting points were obtained on a melting point apparatus with open capillary tubes and
are uncorrected. IR spectra were measured on a FT-IR spectrometer. Optical rotation was
recorded on a digital polarimeter with a sodium lamp at ambient temperature. Amides 3.5c,
3.5d, 3.5f, 3.5g, 3.5i, 3.5j, 3.8, and 3.11d were obtained from commercial sources and used
as received.
3.7.2 Synthesis of aldoximes
General procedure – To a solution of the aldehyde in CH2Cl2 (0.2 M) was added
hydroxylamine hydrochloride (2.0 equiv) and triethylamine (4.2 equiv) and the mixture was
stirred at room temperature for 16 h. The reaction was quenched with sat. aq. NaHCO3 and
extracted with CH2Cl2. The organic layer was washed with HCl (1 M), dried over MgSO4
and concentrated to give the crude aldoxime, which was purified by flash chromatography.
The known aldoximes 3.1,121 3.4a,108i 3.4b,122 3.4c,123 3.4d,121 3.4e,124 3.4f,125 3.4g,121
(121) Minakata, S.; Okumura, S.; Nagamachi, T.; Takeda, Y. Org. Lett. 2011, 13, 2966–2969.
75
3.4h,126 3.4i,127 3.4j,123 3.7,128 3.10a,128 3.10b,129 3.10c,121 3.10d,130 3.10e,130 3.10f,131
3.10j,108i 3.19,132 were synthesized following the general procedure described above.
5-(Methoxymethoxy)pentanal oxime (3.10g). To a mixture of
methyl 5-hydroxypentanoate133 (2.0 g, 15.1 mmol, 1.0 equiv) and
diisopropylethylamine (7.90 mL, 45.3 mmol, 3.0 equiv) in CH2Cl2
(15 mL) at 0 °C was added chloromethyl methyl ether (3.4 mL, 45.3 mmol, 3 equiv). The
reaction mixture was stirred at room temperature for 16 h, diluted with ether, washed with
H2O, sat. aq. NH4Cl solution, brine, dried over Na2SO4, and concentrated to afford methyl
5-(methoxymethoxy)pentanoate (2.46 g, 92%) as a yellow oil. IR (ATR, ZnSe) ν = 2949,
1736, 1437, 1358 cm-1; 1H NMR (500 MHz, CDCl3) δ 4.61 (s, 2H), 3.67 (s, 3H), 3.54 (t, J
= 7.4 Hz, 2H), 3.36 (s, 3H), 2.36 (t, J = 7.4 Hz, 2H), 1.76-1.69 (m, 2H), 1.63-1.61 (m, 2H); 13C NMR (126 MHz, CDCl3) δ = 173.9, 96.4, 67.2, 55.1, 51.5, 33.7, 29.1, 21.7; HRMS-ESI
calcd for C13H19N2O [M+H]+ 219.1492, found 219.1493.
To a solution of methyl 5-(methoxymethoxy)pentanoate (1.0 g, 5.6 mmol, 1.0 equiv) in
CH2Cl2 (10 mL) at -78 °C was added dropwise DIBAl-H (8.4 mL, 1.5 equiv, 1 M in
toluene). The resulting solution was stirred at -78 °C for 2 h. The reaction was quenched
(122) Allen, C. L.; Davulcu, S.; Williams, J. M. J. Org. Lett. 2010, 12, 5096–5099. (123) Aakeroy, C. B.; Sinha, A. S.; Epa, K. N.; Chopade, P. D.; Smith, M. M., Desper, J. Cryst. Growth Des. 2013, 13, 2687–2695. (124) Kim, K. D.; Yu, Y.; Jeong, H. J.; Jung, H. M.; Kim, K. L.; Kim, A. N.; Dagvajantsan, O.; Park, G. S.; Kim, S. C. Bull. Korean Chem. Soc. 2012, 33, 4275–4276. (125) Liu, A.; Wang, X.; Ou, X.; Huang, M.; Chen, C.; Liu, S.; Huang, L.; Liu, X.; Zhang, C.; Zheng, Y.; Ren,Y.; He, L.; Yao, J. J. Agric. Food Chem. 2008, 56, 6562–6566. (126) Yonekawa, M.; Koyama, Y.; Kuwata, S.; Takata, T. Org. Lett. 2012, 14, 1164–1167. (127) Hou, Y.; Lu, S.; Liu, G. J. Org. Chem. 2013, 78, 8386–8395. (128) Yu, J.; Cao, X.; Lu, M. Tetrahedron Lett. 2014, 55, 5751–5755. (129) Maurer, C.; Pittenauer, E.; Puchberger, M.; Allmaier, G.; Schubert, U. ChemPlusChem 2013, 78, 343–351. (130) Castellano, S.; Kuck, D.; Viviano, M.; Yoo, J.; Lopez-Vallejo, F.; Conti, P.; Tamborini, L.; Pinto, A.; Medina-Franco, J. L.; Sbardella, G. J. Med. Chem. 2011, 54, 7663–7677. (131) Kozikowski, A. P.;ShumP.W.;Basu,A.;Lazo, J. S. J. Med. Chem. 1991, 34, 2420–2430. (132) Yang S. H.; Chang S.; Org. Lett. 2001, 3, 4209–4211. (133) Hickmann, V.; Kondoh, A.; Gabor, B.; Alcazaro, M.; Fürstner, A. J. Am. Chem. Soc. 2011, 133, 13471–13480.
MOMO2
N
H
OH
76
with MeOH (20 mL) and sat. aq. Rochelle’s salt solution. The aqueous layer was extracted
with CH2Cl2 (2 × 20 mL). The combined organic layer was washed with H2O, brine, dried
over MgSO4 and concentrated. To a solution of the resulting crude product in CH2Cl2 (15
mL) was added hydroxylamine hydrochloride (778 mg, 11.2 mmol) and Et3N (3.3 mL, 23.8
mmol). The mixture was stirred at room temperature for 16 h. The reaction was quenched
with sat. aq. NaHCO3 solution and extracted with CH2Cl2. The organic layer was washed
with HCl (1 M), dried over MgSO4 and concentrated to give the crude product. The residue
was purified by silica gel chromatography eluting with hexane/EtOAc (7/3) to give 3.10g
(365 mg, 40%) as a colorless oil. Rf (hexane/EtOAc: 7/3, SiO2) = 0.15; IR (ATR, ZnSe) ν =
3351, 2933, 1441, 1387 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.88 (bs, 0.5H), 8.45 (bs,
0.5H), 7.42 (td, J = 6.1, 1.4 Hz, 0.5H), 6.72 (td, J = 6.1, 1.2 Hz, 0.5H), 4.61 (s, 2H), 3.59-
3.47 (m, 2H), 3.49–3.01 (m, 3H), 2.43 (m, 1H), 2.24 (tdd, J = 7.3, 6.1, 1.2 Hz, 1H), 1.74-
1.52 (m, 4H); 13C NMR (126 MHz, CDCl3) δ 152.4, 151.8, 96.4, 67.2, 55.1, 29.4, 29.2,
29.1, 24.6, 23.3, 22.8; HRMS-ESI calcd for C7H15NO3Na [M+Na]+ 184.0944, found
184.0878.
1-Benzylpiperidine-4-carbaldehyde oxime (3.10h). A solution of tert-butyl 4-
((hydroxyimino)methyl)piperidine-1-carboxylate108i (300 mg, 1.3 mmol,
1.0 equiv) in HCl/dioxane (10 mL, 4 M solution) was stirred at room
temperature for 2 h. The solvent was evaporated. A mixture of the resulting
crude amine hydrochloride, benzaldehyde (148 µL, 1.4 mmol, 1.1 equiv), Et3N
(454 µL, 3.2 mmol, 2.5 equiv) and MgSO4 (313 mg, 2.0 equiv) in CH2Cl2 (15 mL) was
stirred at room temperature for 16 h. The CH2Cl2 was evaporated and the residue was
dissolved in MeOH (10 mL). NaBH4 (49 mg, 1.3 mmol, 1.0 equiv) was then added and the
mixture was stirred at room temperature for 1 h. The reaction was quenched with H2O, the
solvent was evaporated and the aqueous layer was extracted with EtOAc. The organic layer
was washed with brine, dried over MgSO4 and concentrated to give the crude product
which was purified by chromatography using hexane/EtOAc (1/1) as the eluent to give
3.10h (153 mg, 54%) as a white solid. Rf (hexane/EtOAc: 1/1, SiO2) = 0.1; mp: 85-88 °C;
IR (ATR, ZnSe) ν = 3061, 2920, 2818, 2767, 1496, 1449, 1395 cm-1; 1H NMR (500 MHz,
NBn
H NOH
77
CDCl3) δ 7.45-7.13 (m, 6H), 6.58 (d, J = 7.1 Hz, 0.5H), 3.52 (s, 2H), 2.99-2.84 (m, 2H),
2.22 (m, 1H), 2.10-2.01 (m, 2H), 1.77-1.74 (m, 2H), 1.69-1.56 (m, 2H); 13C NMR (126
MHz, CDCl3) δ 155.0, 138.0, 129.3, 128.2, 127.1, 63.4, 53.0, 52.8, 36.7, 29.3, 28.67;
HRMS-ESI calcd for C13H19N2O [M+H]+ 219.1445, found 219.1431.
Benzyl 4-((hydroxyimino)methyl)piperidine-1-carboxylate (3.10i). To a
solution of benzyl 4-formylpiperidine-1-carboxylate134 (850 mg, 3.4 mmol,
1.0 equiv) in CH2Cl2 (20 mL) was added hydroxylamine hydrochloride (474 mg,
6.8 mmol, 2.0 equiv) and Et3N (2 mL, 14.5 mmol, 4.2 equiv). The mixture was
stirred at room temperature for 16 h. The reaction was quenched with sat. aq.
NaHCO3 solution and extracted with CH2Cl2. The organic layer was washed with HCl (1
M), dried over MgSO4 and concentrated to give the crude product. The residue was purified
by chromatography using hexane/EtOAc (6/4) as the eluent to give 3.10i (851 mg, 95%) as
a colorless oil. Rf (hexane/EtOAc: 6/4, SiO2) = 0.4; IR (ATR, ZnSe) ν = 3342, 2940, 2856,
1671, 1497, 1429, 1362 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.37 (s, 0.5H), 7.99 (s, 1H),
7.59-7.26 (m, 5H), 6.55 (d, J = 6.9 Hz, 0.5H), 5.14 (s, 2H), 4.29-4.01 (m, 2H), 2.90 (bs,
2H), 2.43 (m, 1H), 1.80 (bs, 2H), 1.49-1.47 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 128.0,
127.9, 67.2, 43.4, 36.6, 32.0, 29.1; HRMS-ESI calcd for C14H19N2O3 [M+H]+ 263.1343,
found 263.1323.
(S)-2-(Benzyloxy)propanal oxime (3.22). To a solution of ethyl (S)-2-
(benzyloxy)propanoate135 (700 mg, 3.4 mmol, 1.0 equiv) in Et2O (10 mL) at
-78 °C was added dropwise DIBAl-H (1 M in toluene) (4.0 mL, 1.2 equiv).
The resulting solution was stirred at -78 °C for 2 h. The reaction was quenched with H2O
and the organic layer was washed with a sat. aq. NaHCO3 solution, brine and H2O, dried
over Na2SO4 and concentrated under reduced pressure. To a solution of the crude product in (134) Boyer, N.; Gloanec, P.; De Nanteuil, G.; Jubault, P.; Quirion, J.-C. Eur. J. Org. Chem. 2008, 4277–4295. (135) Yadav, J. S.; Mishra, A. K.; Dashavaram, S. S.; Kumar, S. G.; Das, S. Tetrahedron Lett. 2014, 55, 2921–2923.
NCbz
H NOH
Me
OBn
N
H
OH
78
CH2Cl2 (35 mL) was added hydroxylamine hydrochloride (467 mg, 6.7 mmol, 2.0 equiv)
and pyridine (1.1 mL, 13.4 mmol, 4.0 equiv) and stirred at room temperature for 16 h. The
reaction was quenched with aq. 1 M HCl solution and extracted with CH2Cl2. The organic
layer was dried over MgSO4 and concentrated to give the crude product which was purified
by chromatography using hexane/EtOAc (6/4) as the eluent to give (S)-2-
(benzyloxy)propanal oxime (275 mg, 46% over 2 steps) as a colorless oil. Rf
(hexane/EtOAc: 9/1, SiO2) = 0.21; IR (ATR, ZnSe) ν = 3320, 2978, 2869, 1749, 1496,
1454, 1324 cm-1; 1H NMR (500 MHz, CDCl3) δ 9.78 (s, 0.25H), 9.61 (s, 0.75H), 7.48 (d, J
= 7.5 Hz, 0.75H), 7.43-7.33 (m, 5H), 6.95 (d, J = 6.1 Hz, 0.25H), 4.92 (m, 0.25H), 4.60
(dd, J = 45.2, 11.7 Hz, 0.5H), 4.60 (dd, J = 62.5, 11.8 Hz, 1.5H), 4.22 (dq, J = 7.4, 6.6 Hz,
0.75H), 1.45 (d, J = 6.4 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 154.9, 152.9, 137.8,
137.8, 128.5, 128.0, 128.0, 128.0, 127.9, 72.2, 71.6, 70.8, 68.3, 19.5, 17.9; HRMS-ESI
calcd for C10H13NO2 [M+H]+ 180.1019, found 180.1024.
3.7.3 Synthesis of amides
General procedure – A 0.2 M solution of the corresponding methyl ester in aq.
ammonium hydroxide (28 to 30%) was stirred at room temperature for 16 h. The solvent
was evaporated to afford the amide, which was, in some cases, purified by silica gel
chromatography. The known amides 3.3,136 3.5a,137 3.5b,109c 3.5h,138 3.11a,139 3.11b,140
3.11c,139 3.11e,141 3.11h,112 3.11i,142 3.11j,142 3.13,143 3.14,144 3.20,145 3.23,146 were
(136) Koltunov, K. Y.; Walspurger, S.; Sommer, J. Eur. J. Org. Chem. 2004, 4039–4047. (137) Li, X.-Q.; Wang, W.-K.; Han, Y.-X.; Zhang, C. Adv. Synth. Cat. 2010, 352, 2588–2598. (138) Lou, Z.; Yang, S.; Li, P.; Zhou, P.; Han, K. Phys. Chem. Chem. Phys. 2014, 16, 3749–3756. (139) Bonne, D.; Dekhane, M.; Zhu, J. J. Am. Chem. Soc. 2005, 127, 6926–6927. (140) Shirota, H.; Ushiyama, H. J. Phys. Chem. B 2008, 112, 13542–13551. (141) Veisi, H.; Maleki, B.; Hamelian, M.; Ashrafi, S. RSC Adv. 2015, 5, 6365–6371. (142) Winkler, M.; Meischler, D.; Klempier, N. Adv. Synth. Catal. 2007, 349, 1475–1480. (143) Sawa, E.; Takahashi, M.; Kamishohara, M.; Tazunoki, T.; Kimura, K.; Arai, M.; Miyazaki, T.; Kataoka, S.; Nishitoba, T. J. Med. Chem. 1999, 42, 3289–3299. (144) Falorni, M.; Dettori, G.; Giacomelli, G. Tetrahedron: Asymmetry 1998, 9, 1419–1426. (145) Kimura, M.; Kuboki, A.; Sugai, T. Tetrahedron: Asymmetry 2002, 13, 1059–1068. (146) Kametani, T.; Loc, C. V.; Higa, T.; Ihara, M.; Fukumoto, K. J. Chem. Soc., Perkin Trans. 1 1977, 2347–2349.
79
synthesized following the general procedure described above. Compound 3.5e was
synthesized following the literature.147
5-((tert-Butyldimethylsilyl)oxy)pentanamide (3.11f). Following
the general procedure on a 3.2 mmol scale, 3.11f (167 mg, 23%)
was isolated after purification by silica gel chromatography
(CH2Cl2/MeOH: 95/5) as a white solid. Rf (CH2Cl2/MeOH: 95/5, SiO2) = 0.38; mp: 39-41
°C; IR (ATR, ZnSe) ν = 3356, 3189, 2953, 2857, 1661, 1471, 1389 cm-1; 1H NMR (500
MHz, DMSO-d6) δ 7.21 (s, 1H), 6.68 (s, 1H), 3.56 (t, J = 6.3 Hz, 2H), 2.02 (t, J = 7.3 Hz,
2H), 1.59-1.36 (m, 4H), 0.85 (s, 9H), 0.02 (s, 6H); 13C NMR (126 MHz, DMSO-d6) δ
174.6, 62.7, 35.2, 32.4, 26.3, 22.0, 18.4, -4.8; HRMS-ESI calcd for C11H25NO2Si [M+Na]+
254.1547, found 254.1549.
5-(Methoxymethoxy)pentanamide (3.11g). Following the
general procedure on a 2.8 mmol scale, 3.11g (442 mg, 92%) was
isolated as a yellow oil which was used without purification. IR
(ATR, ZnSe) ν = 3335, 3206, 2935, 1660, 1404 cm-1; 1H NMR (500 MHz, DMSO-d6) δ
7.22 (s, 1H), 6.69 (s, 1H), 4.53 (s, 2H), 3.42 (t, J = 7.1 Hz, 2H), 3.23 (s, 3H), 2.04 (t, J = 7.1
Hz, 1H), 1.54-1.46 (m, 4H); 13C NMR (126 MHz, DMSO-d6) δ 174.6, 96.0, 67.2, 54.9,
35.2, 29.3, 22.3; HRMS-ESI calcd for C7H15NNaO3 [M+Na]+ 184.0944, found 184.0938.
Benzyl ((2S,3R)-1-amino-3-methoxy-1-oxobutan-2-yl)carbamate (3.15).
To a solution of (2S,3R)-methyl 2-amino-3-methoxybutanoate
hydrochloride148 (280 mg, 1.5 mmol, 1.0 equiv) in THF/H2O (1:1, 10 mL)
was added Na2CO3 (318 mg, 3.0 mmol, 2.0 equiv) and benzyl chloroformate (238 µL, 1.7
(147) Ghosh,S.C.; Ngiam,J.S.Y.;Seayad, A. M.; Tuan, D. T.; Chai,C.L.L.;Chen, A. J. Org. Chem. 2012, 77, 8007–8015. (148) Nobuharu, A.; Yukio Y.; Jun’ichi O.; Yuzo I. Bull. Chem. Soc. Jpn. 1979, 52, 2369–2371.
TBSO2
O
NH2
MOMO2
O
NH2
OMe
NHCbz
O
NH2
80
mmol, 1.1 equiv). The mixture was stirred at room temperature for 16 h. The reaction was
quenched with H2O and extracted with EtOAc to give the crude product. The residue was
purified by chromatography using hexane/EtOAc (8/2) as the eluent to give (2S,3R)-methyl
2-(((benzyloxy)carbonyl)amino)-3-methoxybutanoate (420 mg, 99%) as a colorless oil. Rf
(hexane/EtOAc: 8/2, SiO2) = 0.2; IR (ATR, ZnSe) ν = 3432, 3031, 2950, 1720, 1511, 1436,
1317 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.49-7.31 (m, 5H), 5.47 (d, J = 9.5 Hz, 1H), 5.14
(d, J = 1.1 Hz, 1H), 4.35 (dd, J = 9.5, 2.4 Hz, 1H), 3.94 (qd, J = 6.3, 2.4 Hz, 1H), 3.77 (s,
3H), 3.28 (s, 3H), 1.21 (d, J = 6.3 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 171.4, 156.7,
136.3, 128.0, 128.1, 128.0, 127.6, 127.0, 67.0, 65.3, 58.5, 56.8, 52.5, 15.7; HRMS-ESI
calcd for C14H19NNaO5 [M+Na]+ 304.1155, found 304.1154.
Following the general procedure from (2S,3R)-methyl 2-(((benzyloxy)carbonyl)amino)-3-
methoxybutanoate on a 1.5 mmol scale, amide 3.15 (400 mg, 99%) was isolated as a white
solid which was used without purification. mp: 154-155 °C; IR (ATR, ZnSe) ν = 3370,
3304, 3199, 2979, 2930, 2822, 1660, 1612, 1539, 1422, 1360 cm-1; 1H NMR (500 MHz,
DMSO-d6) δ 7.43-7.25 (m, 5H), 7.13 (s, 1H), 7.00 (d, J = 9.1 Hz, 1H), 5.04 (d, J = 2.6 Hz,
2H), 3.97 (dd, J = 9.1, 4.5 Hz, 1H), 3.67-3.60 (m, 1H), 3.21 (s, 3H), 1.05 (d, J = 6.3 Hz,
3H); 13C NMR (126 MHz, DMSO-d6) δ 172.3, 156.6, 137.5, 128.8, 128.2, 128.0, 76.7,
65.9, 59.3, 56.7, 16.1; HRMS-ESI calcd for C13H18N2NaO4 [M+Na]+ 289.1159, found
289.1159.
3.7.4 Synthesis of nitriles
General procedure – To a solution of the aldoxime or the amide (1.0 mmol) and Et3N (1.5
mmol) in EtOAc (1 ml, 1 M) at room temperature was added XtalFluor-E (1.1 mmol)
portionwise (over ca. 2 minutes). The resulting solution was stirred at room temperature for
1 h. The reaction was quenched with sat. aq. Na2CO3 solution and extracted with CH2Cl2
(2 × 10 ml). The organic layer was washed with H2O, brine, dried over MgSO4 and
concentrated under vacuum to afford the crude nitrile, which was purified by flash
chromatography if required.
81
4-(tert-Butyl)benzonitrile (3.6a). From aldoxime 3.4a, nitrile 3.6a was
isolated as a colorless oil (139 mg, 87%) after purification by flash
chromatography using hexane/EtOAc (1/1) as the eluent. From amide
3.5a, 3.6a was isolated (99 mg, 81%) after purification through a pad of silica using CH2Cl2
as the eluent. Spectral data for 3.6a were identical to those previously reported.149
2-Naphtonitrile (3.6b). From aldoxime 3.4b, nitrile 3.6b was isolated as
a white solid without further purification (151 mg, 99%). From amide
3.5b, 3.6b was isolated (93 mg, 61%) after purification by flash chromatography using
hexane/EtOAc (1/1) as the eluent. Spectral data for 3.6b were identical to those previously
reported.149
4-Iodobenzonitrile (3.6c). From aldoxime 3.4c, nitrile 3.6c was isolated as
a yellow oil (227 mg, 99%) without further purification. From amide 3.5c,
3.6c was isolated (170 mg, 74%) after purification by flash chromatography
using hexane/EtOAc (9/1) as the eluent. Spectral data for 3.6c were identical to those
previously reported.149
4-Methoxybenzonitrile (3.6d). From aldoxime 3.4d, nitrile 3.6d was
isolated as a yellow oil (113 mg, 85%) after purification by flash
chromatography using hexane/EtOAc (8/2) as the eluent. From amide
3.5d, 3.6d was also isolated after purification by flash chromatography using the same
eluent (87 mg, 65%). Spectral data for 3.6d were identical to those previously reported.149
(149) Zhou, W.; Xu, J.; Zhang, L.; Jiao, N. Org. Lett. 2010, 12, 2888–2891.
CN
CN
CN
I
CN
MeO
82
Methyl 4-cyanobenzoate (3.6e). From aldoxime 3.4e, nitrile 3.6e
was isolated as a brown solid (157 mg, 97%) without further
purification. From amide 3.5e (0.5 mmol scale), 3.6e was also
isolated without further purification (58 mg, 72%). Spectral data for 3.6e were identical to
those previously reported.149
3,5-Bis(trifluoromethyl)benzonitrile (3.6f). From aldoxime 3.4f, nitrile
3.6f was isolated as a yellow oil (103 mg, 86%) without further
purification. Spectral data for 3.6f were identical to those previously
reported.150
4-Nitrobenzonitrile (3.6g). From aldoxime 3.4g, nitrile 3.6g was
isolated as a yellow solid (140 mg, 95%) without further purification.
From amide 3.5g, 3.6g was isolated (81 mg, 55%) after purification by
flash chromatography using hexane/EtOAc (9/1) as the eluent. Spectral data for 3.6g were
identical to those previously reported.150
2-Phenoxybenzonitrile (3.6h). From aldoxime 3.4h, nitrile 3.6h was
isolated as a colorless oil (190 mg, 97%) after purification by flash
chromatography using hexane/EtOAc (9/1) as the eluent. From amide 3.5h,
3.6g was also isolated after purification by flash chromatography using the same eluent
(118 mg, 61%). Spectral data for 3.6h were identical to those previously reported.151
(150) Schareina, T.; Zapf, A.; Mägerlein, W.; Müller, N.; Beller, M. Chem. Eur. J. 2007, 13, 6249–6254. (151) Arundhathi, R.; Damodara, D.; Likhar, P. R.; Kantam, M. L.; Saravanan, P.; Magdaleno, T.; Kwon, S. H. Adv. Synth. Catal. 2011, 353, 1591–1600.
CN
MeO2C
CNF3C
CF3
CN
O2N
CN
OPh
83
4-Hydroxybenzonitrile (3.6i). From aldoxime 3.4i, nitrile 3.6i was
isolated as a colorless oil (71 mg, 60%) after purification through a pad
of silica using CH2Cl2 as the eluent. Spectral data for 3.6i were identical
to those previously reported.152
3-Cyanopyridine (3.6j). From aldoxime 3.4j, nitrile 3.6j was isolated as a
pale yellow oil (91 mg, 87%) without further purification. From amide 3.5j,
3.6j was isolated (47 mg, 45%) after purification by flash chromatography
using hexane/EtOAc (8/2) as the eluent. Spectral data for 3.6j were identical to those
previously reported.150
Cinnamonitrile (3.9). From aldoxime 3.7, nitrile 3.9 was isolated as a
colorless oil (109 mg, 84%) after purification by flash chromatography
using hexane/EtOAc (1/1) as the eluent. From amide 3.8, 3.9 was also isolated after
purification by flash chromatography using the same eluent (80 mg, 62%). Spectral data for
3.9 were identical to those previously reported.149
3-Phenylpropanenitrile (3.2). From aldoxime 3.1, nitrile 3.2 was isolated
as a colorless oil (130 mg, 99%) without further purification. From amide
3.3, 3.2 was isolated (97 mg, 74%) after purification by flash chromatography using
hexane/EtOAc (9/1) as the eluent. Spectral data for 3.2 were identical to those previously
reported.153
Octanenitrile (3.12a). From aldoxime 3.10a, nitrile 3.12a was
(152) Yang, H.; Li, Y.; Jiang, M.; Wang, J.; Fu, H. Chem. Eur. J. 2011, 17, 5652–5660. (153) Mori, N.; Togo, H. Synlett 2005, 1456–1458.
CN
HO
N
CN
PhCN
PhCN
CN
84
isolated as a yellow oil (102 mg, 82%) after purification through a pad of silica using
CH2Cl2 as the eluent. From amide 3.11a, 3.12a was isolated (24 mg, 19%) after purification
by flash chromatography using hexane/EtOAc (95/5) as the eluent. Spectral data for 3.12a
were identical to those previously reported.154
Glutaronitrile (3.12b). From aldoxime 3.10b, nitrile 3.12b was isolated
as a yellow oil (83 mg, 88%) after purification through a pad of silica
using CH2Cl2 as the eluent. Spectral data for 3.12b were identical to those previously
reported.155
2-Phenylacetonitrile (3.12c). From aldoxime 3.10c, nitrile 3.12c was
isolated as a yellow oil (61 mg, 52%) after purification through a pad of
silica using CH2Cl2 as the eluent. From amide 3.11c, 3.12c was isolated (63 mg, 54%) after
purification by flash chromatography using hexane/EtOAc (9/1) as the eluent. Spectral data
for 3.12c were identical to those previously reported.156
2-(4-Methoxyphenyl)acetonitrile (3.12d). From aldoxime 3.10d,
nitrile 3.12d was obtained as a yellow oil (133 mg, 90%) without
further purification. From amide 3.11d, 3.12d was also obtained without further
purification (144 mg, 98%). Spectral data for 3.12d were identical to those previously
reported.157
(154) Cahiez, G.; Chaboche, C.; Duplais, C.; Giulliani, A.; Moyeux, A. Adv. Synth. Catal. 2008, 350, 1484–1488. (155) Choi, Y. M.; Kucharczyk, N.; Sofia, R. D. J. Label. Compd. Radiopharm. 1987, 24, 1–14. (156) Nambo,M.;Yar, M.; Smith, J. D.; Crudden, C. M. Org. Lett. 2015, 17, 50–53. (157) Wu, L.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 15824–15832.
NC CN
CN
CN
MeO
85
5-((tert-Butyldimethylsilyl)oxy)pentanenitrile (3.12f). From
aldoxime 3.10f, nitrile 3.12f was obtained as a yellow oil (138 mg,
65%) after purification through a pad of silica using CH2Cl2 as the eluent. From amide
3.11f, 3.12f was also obtained after purification through a pad of silica using the same
eluent (157 mg, 73%). Spectral data for 3.12f were identical to those previously reported.158
5-(Methoxymethoxy)pentanenitrile (3.12g). From aldoximes 3.10g,
nitrile 3.12g was obtained as a colorless oil (94 mg, 67%) after
purification through a pad of silica using CH2Cl2 as the eluent. From amide 3.11g, 3.12g
was also obtained after purification through a pad of silica using the same eluent (67 mg,
44%). IR (ATR, ZnSe) ν = 2938, 2245, 1456, 1387 cm-1; 1H NMR (500 MHz, CDCl3) δ
4.62 (s, 1H), 3.57 (t, J = 5.8 Hz, 2H), 3.36 (s, 3H), 2.44 (t, J = 5.8 Hz, 2H), 1.87-1.64 (m,
4H); 13C NMR (126 MHz, CDCl3) δ 119.6, 96.4, 66.5, 55.2, 28.6, 22.6, 17.0; HRMS-ESI
calcd for C7H12NO [M+H-H2O]+ 126.0913, found 126.0905.
1-Benzylpiperidine-4-carbonitrile (3.12h). From aldoxime 3.10h (0.5 mmol
scale), nitrile 3.12h was isolated as colorless oil (75 mg, 80%) after purification by
flash chromatography using hexane/EtOAc (1/1) as the eluent. From amide 3.11h,
3.10h was also isolated after purification by flash chromatography using the same
eluent (171 mg, 85%). Spectral data for 3.12h were identical to those previously
reported.159
Benzyl 4-cyanopiperidine-1-carboxylate (3.12i). From aldoxime 3.10i, nitrile
3.12i was obtained as a pale yellow oil (214 mg, 88%) after purification by flash
chromatography using hexane/EtOAc (1/1) as the eluent. From amide 3.11c, 3.12i
(158) Vatèle, J.-M. Synlett 2014, 1275–1278. (159) Honkanen, E.; Pippuri, A.; Kairisalo, P.; Nore, P.; Karppanen, H.; Paakkari, I. J. Med. Chem. 1983, 26, 1433–1438.
TBSO CN2
MOMO CN2
NBn
CN
NCbz
CN
86
was also obtained after purification by flash chromatography using the same eluent (154
mg, 63%). Spectral data for 3.12i were identical to those previously reported.142
tert-Butyl 4-cyanopiperidine-1-carboxylate (3.12j). From aldoxime 3.10j, nitrile
3.12j was obtained as a yellow oil (209 mg, 99%) without further purification.
From amide 3.11j, 3.12j was also obtained without further purification (206 mg,
98%). Spectral data for 3.12j were identical to those previously reported.142
Benzyl (S)-(1-cyano-2-methylpropyl)carbamate (3.16). From amide
3.13, nitrile 3.16 was obtained as a yellow oil (119 mg, 51%) after
purification by flash chromatography using hexane/EtOAc (8/2) as the eluent. HPLC
analysis: >99% ee [Daicel CHIRALPAK AD-H column, 20 °C, 254 nm, hexane/i-PrOH =
95:5, 1 mL/min, tr = 14.7 min]. Spectral data for 3.16 were identical to those previously
reported.115a
Benzyl (S)-(1-cyano-2-phenylethyl)carbamate (3.17). Fom amide
3.14 (0.5 mmol scale), nitrile 3.17 was obtained as a pale yellow oil (98
mg, 70%) after purification by flash chromatography using
hexane/EtOAc (8/2) as the eluent. HPLC analysis: >99% ee [Daicel CHIRALPAK AD-H
column, 20 °C, 254 nm, hexane/i-PrOH = 90:10, 0.8 mL/min, tr = 13.7 min]. Spectral data
for 3.17 were identical to those previously reported.115a
Benzyl ((1R,2R)-1-cyano-2-methoxypropyl)carbamate (3.18). From amide
3.15 (0.26 mmol scale), nitrile 3.18 was obtained as a pale yellow oil (40 mg,
62%) after purification through a pad of silica using CH2Cl2 as the eluent.
HPLC analysis: >99% ee [Daicel CHIRALPAK AD-H column, 20 °C, 254 nm, hexane/i-
PrOH = 95:5, 1 mL/min, tr = 22.3 min]; [α]D20
-22.5 (c 1.0, MeOH); IR (ATR, ZnSe) ν =
NBoc
CN
CbzHN CN
CbzHN CN
CNOMe
NHCbz
87
3316, 2937, 2877, 2251, 1707, 1511, 1454 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.59-7.30
(m, 5H), 5.41 (d, J = 9.3 Hz, 1H), 5.16 (s, 2H), 4.63 (dd, J = 9.3, 2.8 Hz, 1H), 3.71 (dd, J =
6.3, 2.8 Hz, 1H), 3.44 (s, 3H), 1.23 (d, J = 6.3 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ
155.6 , 135.5, 128.6, 128.5, 128.2, 117.7, 76.0, 67.8, 57.4, 47.1, 15.4; HRMS-ESI calcd for
C13H16N2NaO3 [M+Na]+ 271.1053, found 271.1024.
(R)-2-Methoxy-2-phenylacetonitrile (3.21). From aldoxime 3.19 (0.5 mmol
scale), nitrile 3.21 was obtained as a pale yellow oil (44 mg, 60%) after
purification through a pad of silica using CH2Cl2 as the eluent. From amide 3.20, 3.21 was
also isolated after purification through a pad of silica using the same eluent (84 mg, 57%).
HPLC analysis: >99% ee [Daicel CHIRALPAK OJ-H column, 20 °C, 220 nm, hexane/i-
PrOH = 95:5, 1 mL/min, tr = 11.2 min]. Spectral data for 3.21 were identical to those
previously reported.115a
(S)-2-(Benzyloxy)propanenitrile (3.24). From aldoxime 3.22 (0.7 mmol
scale), nitrile 3.24 was obtained as a colorless oil (43 mg, 38%) after
purification by flash chromatography using hexane/EtOAc (95/5) as the eluent. From amide
3.23 (0.56 mmol scale), 3.24 was isolated without further purification (90 mg, 99%). HPLC
analysis: >99% ee [Daicel CHIRALPAK OJ-H column, 20 °C, 254 nm, hexane/i-PrOH =
99:1, 1 mL/min, tr = 16.6 min]. Spectral data for 3.24 were identical to those previously
reported.160
(160) Cazes, B.; Julia, S. Tetrahedron 1979, 35, 2655–2660.
Ph
OMe
CN
Me
OBn
CN
88
CHAPITRE 4
Estérification directe d’acides carboxyliques avec des alcools
perfluorés, effectuée par l’entremise de XtalFluor-E
Direct Esterification of Carboxylic Acids with
Perfluorinated Alcohols Mediated by XtalFluor-E
Mathilde Vandamme, Léa Bouchard, Audrey Gilbert, Massaba Keita,
Jean-François Paquin*
CCVC, PROTEO, Département de chimie, Université Laval,
1045 avenue de la Médecine, Québec, Québec, Canada G1V 0A6
E-mail: jean-francois.paquin@chm.ulaval.ca
Reproduit à partir de Organic Letters 2016, 18, 6468–6471.
89
4.1 RÉSUMÉ
L’estérification directe d’acides carboxyliques avec des alcools perfluorés, effectuée par
l’entremise de XtalFluor-E, est rapportée. Les esters polyfluorés correspondants sont
obtenus avec des rendements modérés à excellents, pour une large gamme d’acides
carboxyliques, incluant des substrats aromatiques, hétéroaromatiques, aliphatiques et
chiraux non racémiques, en utilisant seulement un léger excès (2 équiv.) de l’alcool
perfluoré. Des expériences de contrôle indiquent que la réaction ne passe pas par la
formation du fluorure d’acyle, mais plus probablement par un intermédiaire
(diéthylamino)difluoro-λ4-sulfanyl carboxylate.
4.2 ABSTRACT
The direct esterification of carboxylic acids with perfluorinated alcohols mediated by
XtalFluor-E is reported. The corresponding polyfluorinated esters are obtained in moderate
to excellent yields with a broad range of carboxylic acids, including aromatic,
heteroaromatic, aliphatic, and nonracemic chiral substrates, using only a slight excess
(2 equiv) of the perfluorinated alcohol. Control experiments indicate that the reaction does
not proceed through the formation of an acyl fluoride but most likely through a
(diethylamino)difluoro-λ4-sulfanyl carboxylate intermediate.
90
4.3 INTRODUCTION
Perfluorination of an organic compound can profoundly modify its physicochemical
properties.161 Within the large family of perfluorinated molecules, polyfluorinated esters
with the fluorine located on the alkoxy chain (e.g., 4.1 in Scheme 4.1) have found
applications in medicinal chemistry,162 as monomers for the synthesis of perfluorinated
polymers,163 and in organic chemistry as substrates and/or reagents,164 as well as for other
usages.165
They are generally prepared through preactivation of the carboxylic acid (mostly as the acyl
chloride, i.e., X = Cl) prior to the reaction with the polyfluorinated alcohol (Scheme 4.1, eq
1).166 From a practical aspect, a method that would obviate this preactivation step would be
highly desirable. In that regard, the use of a Dean−Stark apparatus (Scheme 4.1, eq 2)167
and synthesis through a Fischer esterification reaction (Scheme 4.1, eq 3)168 have been
described occasionally. However, in the former case, the perfluorinated alcohol is used in (161) (a) Hiyama, T. In Organofluorine Compounds: Chemistry and Applications; Yamamoto, H., Ed.; Springer: New York, 2000 and references therein. (b) The Handbook of Fluorous Chemistry; Gladysz, J. A., Horváth, I., Curran, D. P., Eds.; Wiley-VCH: Weinheim, Germany, 2004 and references therein. (162) For selected examples, see: (a) Schroeder, G. K.; Wolfenden, R. Biochemistry 2007, 46, 4037–4044. (b) Yin, W.; Majumder, S.; Clayton, T.; Petrou, S.; VanLinn M. L.; Namjoshi, O. A.; Ma, C.; Cromer, B. A.; Roth, B. L.; Platt, D. M.; Cook J. M. Bioorg. Med. Chem. 2010, 18, 7548–7564. (c) Crocetti, L.; Giovannoni, M. P.; Schepetkin, I. A.; Quinn, M. T.; Khlebnikov, A. I.; Cilibrizzi, A.; Dal Piaz, V.; Graziano, A.; Vergelli, C. Bioorg. Med. Chem. 2011, 19, 4460–4472. (d) Fuchs, A. V.; Tse, B. W. C.; Pearce, A. K.; Yeh, M.-C.; Fletcher, N. L.; Huang, S. S.; Heston, W. D.; Whittaker, A. K.; Russell, P. J.; Thurecht, K. J. Biomacromolecules 2015, 16, 3235−3247. (e) Zhang, H.; Xu, X.; Chen, Y.; Qiu, Y.; Liu, X.; Liu, B.-F.; Zhang, G. Eur. J. Med. Chem. 2015, 89, 524–539. (163) For selected recent examples, see: (a) Guo, L.; Jiang, Y.; Qiu, T.; Meng, Y.; Li, X. Polymer 2014, 55, 4601–4610. (b) Nuhn, L.; Overhoff, I.; Sperner, M.; Kaltenberg, K.; Zentel. R. Polym. Chem., 2014, 5, 2484–2495. (c) Sun, Q.; Li, H.; Xian, C.; Yang, Y.; Song, Y.; Cong, P. Appl. Surf. Sci. 2015, 344, 17–26. (164) For selected examples, see: (a) Schmidt-Leithoff, J.; Brückner, R. Helv. Chim. Acta 2005, 88, 1943–1959. (b) Hamada, M.; Inami, Y.; Nagai, Y.; Higashi, T.; Shoji, M.; Ogawa, S.; Umezawa, K.; Sugai, T. Tetrahedron: Asymmetry 2009, 20, 2105–2111. (c) Monteiro, C. M.; Lourenço, N. M. T.; Afonso, C. A. M. Tetrahedron: Asymmetry 2010, 21, 952–956. (d) Fang, X.; Li, J.; Wang, C.-J. Org. Lett. 2013, 15, 3448–3451. (e) Conner, M. L.; Xu, Y.; Brown, M. K. J. Am. Chem. Soc. 2015, 137, 3482–3485. (f) Curiel Tejeda, J. E.; Irwin, L. C.; Kerr, M. A. Org. Lett. 2016, 18, 4738–4741. (165) For selected recent examples, see: (a) Lu, W.; Xie, K.; Chen, Z. x.; Pan, Y.; Zheng, C. m. J. Fluorine Chem. 2014, 161, 110–119. (b) Sevov, C. S.; Brooner, R. E. M.; Chénard, E.; Assary, R. S.; Moore, J. S.; Rodríguez-López, J.; Sanford, M. S. J. Am. Chem. Soc. 2015, 137, 14465–14472. (166) For example, see refs 162b,c, 163c, and 164c. (167) For example, see ref 164a. (168) For example, see refs 162a,e, 164f, and 165b.
91
large excess, while in the latter, it is used as the solvent, which limits the utility of this
approach to low-molecular-weight perfluoroalcohols. Finally, a Steglich esterification using
carbodiimide reagents has been explored (Scheme 4.1, eq 4).169 Although this approach is
more straightforward, the use of carbodiimide reagents leads to the formation of urea
byproducts that are sometimes difficult to separate from the desired product.
Scheme 4.1. Previous Work and the Current Method.
(169) For example, see ref 164d,e.
O
OHR1
Previous work
This work: In situ activation using XtalFluor-E
O
OHR1
O
ORfR1
pre-activation
4.1
4.1
XtalFluor-ERfOH
water-solubleside products
+
organic side product
+HF HBF4Et2NSO2H + +
O
OHR1
RfOH
4.1
Pre-activation of the carboxylic acid
Steglich esterification
O
R2HN NHR2
N C NR2 R2
(1)
(4)
(5)
RfOHO
XR1
Continuous removal of water (Dean-Stark)
Fischer esterification
O
OHR1
RfOH (large excess)(2)
Dean-Stark apparatus
4.1
O
OHR1
cat. H+
RfOH (solvent)(3)
4.1
92
A few years ago, the research team of Cossy and our group independently reported the
synthesis of amides from carboxylic acids mediated by (Et2NSF2)BF4 (XtalFluor-
E).170,171,172,173 In this reaction, XtalFluor-E served to activate the carboxylic acid in situ
prior to the attack by the amine. Although XtalFluor-E was primarily developed for the
deoxofluorination of alcohols, we hypothesized that because of the low nucleophilicity of
perfluorinated alcohols,174,175 selective activation of the carboxylic acid over the
perfluorinated alcohol with XtalFluor-E could be possible, thus leading to a direct synthesis
of 4.1 (Scheme 4.1, eq 5).173e Herein we report the direct esterification, mediated by
XtalFluor-E, of a broad range of carboxylic acids using only a slight excess of various
perfluorinated alcohols. Notably, and as opposed to the use of diimide reagents, this system
generates water-soluble side products, which facilitates purification.
4.4 RESULTS AND DISCUSSION
Selected optimization data using 5-phenylvaleric acid (4.2) with 2,2,2-trifluoroethanol
(TFE) are reported in Table 4.1. The use of a slight excess of XtalFluor-E with Et3N
(2.5 equiv) and TFE as the solvent provided the desired ester 4.3 in 68% yield (Table 4.1,
entry 1). Product 4.3 was obtained in 75% yield with a 1:1 TFE/CH2Cl2 mixture (Table 4.1,
entry 2). Further dilution to 1:9 provided an improved yield of 88% (Table 4.1, entry 3).
(170) (a) Beaulieu, F.; Beauregard, L.-P.; Courchesne, G.; Couturier, M.; Laflamme, F.; L’Heureux, A. Org. Lett. 2009, 11, 5050–5053. (b) L’Heureux, A.; Beaulieu, F.; Bennett, C.; Bill, D. R.; Clayton, S.; Laflamme, F.; Mirmehrabi, M.; Tadayon, S.; Tovell, D.; Couturier, M. J. Org. Chem. 2010, 75, 3401–3411. (c) Mahé, O.; L’Heureux, A.; Couturier, M.; Bennett, C.; Clayton, S.; Tovell, D.; Beaulieu, F.; Paquin, J.-F. J. Fluorine Chem. 2013, 153, 57–60. (171) Orliac, A.; Gomez Pardo, D. Bombrun, A.; Cossy, J. Org. Lett. 2013, 15, 902–905. (172) Mahé, O.; Desroches, J.; Paquin, J.-F. Eur. J. Org. Chem. 2013, 2013, 4325–4331. (173) For other contributions from our group using XtalFluor-E, see: (a) Pouliot, M.-F.; Angers, L.; Hamel, J.-D.; Paquin, J.-F. Org. Biomol. Chem. 2012, 10, 988–993. (b) Pouliot, M.-F.; Angers, L.; Hamel, J.-D.; Paquin, J.-F. Tetrahedron Lett. 2012, 53, 4121–4123. (c) Pouliot, M.-F.; Mahé, O.; Hamel, J.-D.; Desroches, J.; Paquin, J.-F. Org. Lett. 2012, 14, 5428–5431. (d) Keita, M.; Vandamme, M.; Mahé, O.; Paquin, J.-F. Tetrahedron Lett. 2015, 56, 461–464. (e) Desroches, J.; Champagne, P. A.; Benhassine, Y.; Paquin, J.-F. Org. Biomol. Chem. 2015, 13, 2243–2246. (f) Keita, M.; Vandamme, M.; Paquin, J.-F. Synthesis 2015, 47, 3758–3766. (174) Bégué, J.-P.; Bonnet-Delpon, D.; Crousse, B. Synlett 2004, 18–29. (175) For a review of the use of fluorinated alcohols as solvents, cosolvents or additives in homogeneous catalysis, see: Shuklov, I. A.; Dubrovina, N. V.; Börner, A. Synthesis 2007, 2007, 2925–2943.
93
Using other cosolvent (THF, toluene, EtOAc, and CH3CN) instead of CH2Cl2 provided
lower yields (58−80%) (Table 4.1, entries 4−7). Running the reaction in the absence of Et3N
provided a considerably lower yield as estimated by NMR analysis of the crude reaction
mixture (Table 4.1, entry 8), but 1.5 equiv seemed to be the optimal amount (Table 4.1,
entries 9 and 10). Finally, the amount of TFE could be reduced to 2 equiv without a major
effect on the outcome (Table 4.1, entry 11), although further reducing it to 1.2 equiv
resulted in a lower yield (Table 4.1, entry 12). The conditions shown in Table 4.1, entry 11
were chosen as the optimized ones.
Table 4.1. Optimization Results for the Esterification of 5-Phenylvaleric acid (4.2) with TFE Using XtalFluor-E.a
Entry y Solvent Yield (%)b 1 2.5 TFE 68 2 2.5 TFE/CH2Cl2 (1:1) 75 3 2.5 TFE/CH2Cl2 (1:9) 88 4 2.5 TFE/THF (1:9) 80 5 2.5 TFE/toluene (1:9) 60 6 2.5 TFE/EtOAc (1:9) 74 7 2.5 TFE/CH3CN (1:9) 58 8 0 TFE/CH2Cl2 (1:9) 60c 9 1 TFE/CH2Cl2 (1:9) 89
10 1.5 TFE/CH2Cl2 (1:9) 90 11 1.5 TFE (2 equiv) in CH2Cl2 84 12 1.5 TFE (1.2 equiv) in CH2Cl2 55
a See the Supporting Information for the detailed experimental procedures. The optimized conditions are shown in bold. b Isolated yields. c Estimated by NMR analysis of the crude reaction mixture.
Ph
TFE (x equiv)XtalFluor-E (1.1 equiv)
Et3N (y equiv)
OH
OPh
OCH2CF3
O
solvent (0.56 M), rt, 16 h4 4
4.2 4.3
94
With those conditions in hand, the esterification of other carboxylic acids was investigated,
and the results are shown in Scheme 4.2. Various aromatic carboxylic acids provided the
desired esters 4.4−4.8 in moderate to excellent yields. The reaction could also be performed
on a gramscale, as illustrated by the esterification of 1.00 g of 4-nitrobenzoic acid in 97%
yield. Interestingly, the TFE esters of all regioisomers of picolinic acid (4.9−4.11) could be
obtained in good yields (71−75%). A β-keto carboxylic acid such as phenylglyoxylic acid
reacted well, providing the ester 4.12 in 74% yield. Aliphatic carboxylic acids could also be
used as substrates for this transformation, as illustrated by the use of derivatives of
phenylacetic acid and isonipecotic acid. In the latter case, a Cbz protecting group is
preferred over a benzyl group, probably because of the reduced basicity of the nitrogen.
Phthalic acid and a benzylmalonic acid could both be bisesterified to provide 4.17 and 4.18,
respectively, in good yields when the stoichiometry of the reagents was adjusted
accordingly. The reaction could be extended to nonracemic chiral carboxylic acids. For
instance, Cbz-protected L-phenylalanine could be esterified with TFE to provide ester 4.19
in 85% yield. Likewise, the reactions of O-benzyl-(S)-lactic acid and O-methyl-(R)-
mandelic acid provided esters 4.20 and 4.21, respectively, in good yields. In all cases, chiral
HPLC analyses showed no loss of enantiopurity.
95
Scheme 4.2. Results for the Esterification of Various Carboxylic Acids with TFE Using XtalFluor-E.a,b
TFE (2.0 equiv)XtalFluor-E (1.1 equiv)
Et3N (1.5 equiv)
OH
O
OCH2CF3
O
CH2Cl2 (0.56 M), rt, 16 hR R
OCH2CF3
O
R
4.4, R = Ph (77%)4.5, R = OMe (50%)4.6, R = NO2 (95%, 97%c)
4.4-4.18
O
OCH2CF3Ph
4.13, R = H (62%)4.14, R = Ph (89%)
NR
OCH2CF3O
4.15, R = Bn (32%)4.16, R = Cbz (84%)
O
PhO
OCH2CF3
4.12 (74%)
OCH2CF3
O
Br
4.8 (78%)
R
N
O OCH2CF3
4.9 (71%)
OCH2CF3
O
4.7 (67%)
F3C
CF3
N
O OCH2CF3
4.10 (71%)
N
O OCH2CF3
4.11 (75%)
Aromatics
Heteroaromatics
Aliphatic and derivatives
F3CH2CO
O
O
OCH2CF3
4.17 (65%)d
OO
Ph
OCH2CF3F3CH2CO
4.18 (73%)d
Double esterification
96
a See the Supporting Information for the detailed experimental procedures. b Isolated yields are shown. c The reaction was performed on a 5.98 mmol scale (i.e., 1.00 g of the acid). d TFE (4.0 equiv), XtalFluor-E (2.2 equiv), and Et3N (3 equiv) were used instead.
To further extend the utility of this transformation, esterification with other perfluorinated
alcohols was explored, as shown in Scheme 4.3. For that purpose, 1,1,1,3,3,3-hexafluoro-2-
propanol (HFIP, 4.22), 2,2,3,3,3-pentafluoro-1-propanol (PFPOH, 4.23), 2,2,3,3,4,4,4-
heptafluoro-1-butanol (4.24), 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluoro-1-octanol (4.25),
and 2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,9-heptadecafluoro-1-nonanol (4.26) were used. A wide
range of carboxylic acids could be esterified (or bisesterified in the case of phthalic acid) to
provide the corresponding esters 4.27−4.46 in moderate to excellent yields (45−96%).
CbzHNO
OCH2CF3
Ph
4.19 (85%, > 99% ee) 4.20 (64%, > 99% ee)
MeO
OCH2CF3
OBn
4.21 (64%, > 99% ee)
PhO
OCH2CF3
OMe
Chiral non-racemic substrates
97
Scheme 4.3. Selected Results for the Esterification of Various Carboxylic Acids with Perfluorinated Alcohols Using XtalFluor-E.a,b
a See the Supporting Information for the detailed experimental procedures. b Isolated yields are shown. c 4.23 or 4.25 (4.0 equiv), XtalFluor-E (2.2 equiv), and Et3N (3 equiv) were used instead.
To gain insight into the reaction mechanism, a series of control experiments were run. First,
we reacted 4.25 with XtalFluor-E, omitting the carboxylic acid and Et3N (Scheme 4.4,
eq 1). A moderate conversion of 66% was obtained, and NMR analysis of the crude
RfOH (4.22-4.26) (2.0 equiv)XtalFluor-E (1.1 equiv)
Et3N (1.5 equiv)
OH
O
ORf
O
CH2Cl2 (0.56 M), rt, 16 hR R
4.27-4.46
CF3
CF3
HO
HO C7F15 HO C8F17
HOCF3
FFHO
FFCF3
FF4.22
4.25 4.26
4.23 4.24
NCbz
ORfO
4.42, Rf = CH(CF3)2 (72%)4.43, Rf = CH2C7F15 (85%)4.44, Rf = CH2C8F17 (81%)
O
ORf
O
RfO
4.45, Rf = CH2CF2CF3 (60%)c4.46, Rf = CH2C7F15 (54%)c
Ph
R
O
ORf
4.39, R = H, Rf = CH(CF3)2 (66%)4.40, R = Ph, Rf = CH(CF3)2 (80%)4.41, R = Ph, Rf = CH2C7F15 (74%)
ORf
O
O2N
4.29, Rf = CH(CF3)2 (90%)4.30, Rf = CH2CF2CF3 (90%)4.31, Rf = CH2(CF2)2CF3 (89%)4.32, Rf = CH2C7F15 (95%)4.33, Rf = CH2C8F17 (96%)
OCH(CF3)2
O
R
4.27, R = Ph (75%)4.28, R = OMe (45%)
OCH2CF2CF3
O
Br
4.34 (67%)
Ph
R
O
ORf
4.39, R = H, Rf = CH(CF3)2 (66%)4.40, R = Ph, Rf = CH(CF3)2 (80%)4.41, R = Ph, Rf = CH2C7F15 (74%)
O
PhO
OCH2CF2CF3
4.38 (70%)
N
ORfO
4.36, Rf = CH2C7F15 (85%)4.37, Rf = CH2C8F17 (69%)
98
reaction mixture revealed the formation of sulfinate 4.47 (20%) along with some
unidentified XtalFluor-E-related products.170b The fluoride176 corresponding to 4.25 was not
observed. For comparison, complete conversion in less than 5 min was reported with
hydrocinnamyl alcohol.170b The slower reaction of perfluorinated alcohols with XtalFluor-E
likely originates from their impaired nucleophilicity due to the powerful inductive effect of
the adjacent fluorine atoms.174 Next, in two separate experiments, we investigate whether
the reaction proceeds through an acyl fluoride, as it has been shown that XtalFluor-E is able
to convert a carboxylic acid to an acyl fluoride, albeit slowly in the absence of an external
source of fluoride.170b To this end, 4-nitrobenzoic acid 4.48177 was subjected to the reaction
conditions without any perfluorinated alcohol. After 16 h, a low conversion of ca. 40% to
the corresponding acyl fluoride 4.49 was determined by NMR analysis (Scheme 4.4, eq 2).
In addition to this slow formation of the acyl fluoride, which is not compatible with the
time required for the completion of the esterification reaction, no transformation was
observed when independently synthesized acyl fluoride 4.49 was allowed to react with
perfluorinated alcohol 4.25 (Scheme 4.4, eq 3). On the basis of those two observations, we
discarded the acyl fluoride pathway. Hence, our current working hypothesis is the
following: First, deprotonation of the carboxylic acid by Et3N would lead to the more
nucleophilic carboxylate.171 Reaction of the latter with XtalFluor-E would generate
(diethylamino)difluoro-λ4-sulfanyl carboxylate 4.50.171,172 Under the reaction conditions,
the formation of the acyl fluoride would be slower than the reaction of 4.50 with the
perfluorinated alcohol, which would generate the desired perfluorinated ester in addition to
diethylaminosulfinyl fluoride.178
(176) Raghavanpillai, A.; Burton, D. J. J. Fluorine Chem. 2006, 127, 456–470. (177) Ochiai, M.; Yoshimura, A.; Hoque, M. M.; Okubo, T.; Saito, M.; Miyamoto, K. Org. Lett. 2011, 13, 5568–5571. (178) (a) Brown, D. H.; Crosbie, K. D.; Darragh, J. I.; Ross, D. S.; Sharp, D. W. A. J. Chem. Soc. A 1970, 914–917. (b) Keat, R.; Ross, D. S.; Sharp, D. W. A. Spectrochim. Acta, Part A 1971, 27, 2219–2225.
99
Scheme 4.4. Control Experiments and Mechanistic Hypothesis.a
a See the Supporting Information for the detailed experimental procedures. b The counterions have been omitted for clarity.
4.5 CONCLUSION
In summary, we have reported the use of XtalFluor-E as an effective promoter for the direct
esterification of carboxylic acids using perfluorinated alcohols. The corresponding
polyfluorinated esters are obtained in moderate to excellent yields with a broad range of
O
F
O2N CH2Cl2, rt, 16 h
O
OCH2C7F15
O2N
O
OH
O2N CH2Cl2, rt, 16 h
O
F
O2N
XtalFluor-E (1.1 equiv)Et3N (1.5 equiv)
4.49 (ca. 40% by NMR)
O
R1 OH
O
R1 O-
Et3N O
R1 OS
N
FFXtalFluor-E
HO Rf
R
O
R1 O Rf
R slow O
R1 F- Et2NSOF
fast
Attempted reaction of acyl fluoride 4.49
Formation of an acyl fluoride from 4.48
Mechanistic hypothesisb
CH2Cl2, rt, 16 hca. 66% conversion
OHC7F15
Reaction of perfluorinated alcohol 4.25 with XtalFluor-E
XtalFluor-E (1.1 equiv)(1)
(2)
(3)
4.25
4.48
4.49 4.32
4.50
OHC7F15
4.25
OC7F15SO
O C7F15
4.47 (20%)
100
carboxylic acids, including aromatic, heteroaromatic, aliphatic, and nonracemic chiral
substrates, using only a slight excess (2 equiv) of the perfluorinated alcohol. Control
experiments indicated that the reaction does not proceed through the formation of an acyl
fluoride but most likely through a (diethylamino)difluoro-λ4-sulfanyl carboxylate
intermediate.
4.6 ACKNOWLEDGMENTS
This work was supported by the Natural Sciences and Engineering Research Council of
Canada, the Fonds de recherche du Québec – Nature et technologies, OmegaChem, and
Université Laval.
4.7 ANNEXE
4.7.1 Estérification de l’acide 5-phénylvalérique avec des alcools non fluorés
Parallèlement à la synthèse d’esters perfluorés, nous avons montré que l’estérification de
l’acide 5-phénylvalérique avec des alcools non fluorés fonctionnait tout aussi bien (Schéma
4.5). Des rendements modérés ont été obtenus pour des alcools aliphatiques (4.51-4.53), un
alcool allylique (4.55) et un alcool benzylique (4.56). L’encombrement stérique des alcools
a une influence sur le rendement de la réaction, puisque l’utilisation d’isopropanol a fourni
un faible rendement (4.53, 30 %) tandis qu’aucune réaction ne s’est produite avec le tert-
butanol (4.54, 0 %).
Ceci est intéressant afin de souligner que la réaction peut être généralisée à des alcools très
variés. Cependant, de nombreuses méthodes d’estérification utilisant des alcools non
fluorés existent déjà, telles que les estérifications bien connues de Fischer,179 Steglich,180
Mitsunobu181 et Yamaguchi.182
(179) Fischer, E.; Speier, A. Ber. Dtsch. Chem. Ges. 1895, 28, 3252–3258.
101
Schéma 4.5. Estérification de l’acide 5-phénylvalérique (4.2) avec des alcools non fluorés.
4.7.2 Étude du mécanisme par chimie computationnelle
Le mécanisme de la réaction d’estérification a également été étudié grâce à des calculs ab
initio. Deux voies de réaction sont en effet envisageables : une voie directe (voie 1) et une
voie indirecte passant par la formation d’un fluorure d’acyle in situ (voie 2) (Schéma 4.6).
Schéma 4.6. Voies mécanistiques possibles.
(180) Neises, B.; Steglich, W. Angew. Chem. Int. Ed. Engl. 1978, 17, 522–524. (181) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380–2382. (182) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989–1993.
Ph
R–OH (2 équiv.)XtalFluor-E (1,1 équiv.)
Et3N (1,5 equiv.)OH
OPh
O
O
CH2Cl2 (0,56 M), t.a., 16 h4 4
4.2 4.51-56
4.51, R = Me (61 %)4.52, R = Et (70 %)4.53, R = iPr (30 %)4.54, R = tBu (0 %)4.55, R = CH2CHCH2 (49 %)4.56, R = Bn (33 %)
R
O
R1 OH
O
R1 OS
N
FFEt3NXtalFluor-E
O
R1 OS
N
F
+ F–
O
R1 O Rf
R
O
R1 O Rf
R
HO Rf
R
- Et2NSOF
HO Rf
R
- Et2NSOF R1
O
F
Voie 1
Voie 2
102
Expérimentalement, nous avions montré qu’en absence de l’alcool, la formation du fluorure
d’acyle était possible mais plus lente, donc pas favorisée. La voie 1 semblait donc
l’explication la plus plausible du mécanisme de la réaction.
Des calculs ab initio ont ainsi été effectués dans le but d’appuyer cette hypothèse. Nous
avons cherché à calculer la variation d’enthalpie libre (ΔG) entre l’intermédiaire 5.57 et sa
forme dissociée 5.58 (Schéma 4.7) par des calculs au niveau de théorie B3LYP/6-
311++G(2d, p)//B3LYP/6-31+G(d) en utilisant le modèle de solvatation SMD pour tenir
compte des effets du dichlorométhane. La valeur obtenue s’élève à 23,0 kcal/mol, indiquant
ainsi que la dissociation ionique de l’intermédiaire 5.57 n’est pas favorable
thermodynamiquement. Par conséquent, ceci nous suggère que la réaction suit le
mécanisme décrit par la voie 1, et renforce ce que nous avions établi expérimentalement.
Schéma 4.7. Équilibre de l’intermédiaire 5.57 avec sa forme dissociée 5.58.
4.8 SUPPORTING INFORMATION AVAILABLE
4.8.1 General information
The following includes general experimental procedures, specific details for representative
reactions, and isolation and spectroscopic information for the new compounds prepared. All
reactions were carried out under an argon atmosphere with dry solvents. Et2O, THF,
CH3CN, CH2Cl2 and toluene were purified using a Vacuum Atmospheres Inc. Solvent
Purification System. All other commercially available compounds were used as received.
Thin-layer chromatography (TLC) analysis of reaction mixtures was performed using
Silicycle silica gel 60 Å F254 TLC plates, and visualized under UV or by staining with
O
Ph OS
N
FF O
Ph OS
N
F+ F–
ΔG = 23,0 kcal/mol5.57 5.58
103
either potassium permanganate or phosphomolybdic acid. Flash column chromatography
was carried out on Silicycle silica gel 60 Å, 230–400 mesh. 1H, 13C and 19F NMR spectra
were recorded in CDCl3 at ambient temperature using Agilent DD2 500 spectrometer. 1H
and 13C NMR chemical shifts are reported in ppm downfield of tetramethylsilane and are
respectively referenced to tetramethylsilane (δ = 0.00 ppm) and residual solvent (δ = 77.16
ppm for CDCl3). For 19F NMR, CFCl3 is used as the external standard. High-resolution
mass spectra were obtained on a LC/MS–TOF Agilent 6210 using electrospray ionization
(ESI) or atmospheric pressure photoionization source (APPI). Infrared spectra were
recorded using a Thermo Scientific Nicolet 380 FT-IR spectrometer. Melting points were
recorded on a Stanford Research System OptiMelt capillary melting point apparatus and are
uncorrected. 1-benzylpiperidine-4-carboxylic acid,183 1-((benzyloxy)carbonyl)-piperidine-
4-carboxylic acid,184 2-benzylmalonic acid,185 ((benzyloxy)carbonyl)-L-phenylalanine,186
(S)-2-(benzyloxy)propanoic acid,187 and (R)-2-methoxy-2-phenylacetic acid188 were
prepared according to literature procedures.
4.8.2 Esterification mediated by XtalFluor-E using perfluorinated alcohols
General procedure – To a solution of the carboxylic acid (0.56 mmol, 1 equiv) in CH2Cl2
(1 mL) at rt were successively added the fluorinated alcohol (1.12 mmol, 2 equiv),
triethylamine (0.84 mmol, 1.5 equiv), and XtalFluor-E (0.616 mmol, 1.1 equiv). The
resulting solution was stirred at rt for 16 hours. The reaction mixture was quenched with
water and extracted with CH2Cl2 (3×). The combined organic layers were dried (Na2SO4)
and concentrated under vacuum to give the crude ester, which was purified by flash
chromatography, if required.
(183) Manetti, D.; Di Cesare Mannelli, L.; Dei, S.; Guandalini, L.; Martini, E.; Banchelli, M.; Gherlardini, C. Bioorg. Med. Chem. Lett. 2009, 19, 2224–2229. (184) Imamura, S.; Nishikawa, Y.; Ichikawa, T.; Hattori, T.; Matsushita, Y.; Hashiguchi, S.; Kanzaki, N.; Iizawa, Y.; Baba, M.; Sugihara, Y. Bioorg. Med. Chem. 2005, 13, 397–416. (185) Rotthaus, O.; LeRoy, S.; Tomas, A.; Barkigia, K. M.; Artaud, I. Eur. J. Inorg. Chem. 2004, 1545–1551. (186) Shi, H.; Liu, K; Leong, W. W. Y.; Yao, S. Q. Bioorg. Med. Chem. Lett. 2009, 19, 3945–3948. (187) Matsumura, Y.; Suzuki, T.; Sakakura, A. Angew. Chem., Int. Ed. 2014, 53, 6131–6134. (188) Moreno-Dorado, F. J.; Guerra, F. M.; Ortega, M. J.; Zubia, E.; Massanet, G. M. Tetrahedron: Asymmetry 2003, 14, 503–510.
104
2,2,2-trifluoroethyl 5-phenylpentanoate (4.3). Using the
general protocol on 5-phenylpentanoic acid and 2,2,2-
trifluoroethan-1-ol, ester 4.3 was obtained as a colorless oil
(84 mg, 84%) after purification by flash chromatography using hexane/EtOAc (95:5) as the
eluent. IR (ATR, ZnSe) ν = 3028, 2937, 2862, 1756, 1709, 1412, 1279, 1162 cm-1; 1H
NMR (500 MHz, CDCl3) δ 7.30-7.26 (m, 2H), 7.20-7.16 (m, 3H), 4.45 (q, J = 8.5 Hz, 2H),
2.64 (t, J = 7.2 Hz, 2H), 2.44 (t, J = 7.2 Hz, 2H), 1.74-1.63 (m, 4H); 13C NMR (126 MHz,
CDCl3) δ 171.9, 141.9, 128.4 (3C), 125.9 (2C), 123.0 (q, J = 277.1 Hz), 60.1 (q, J = 36.5
Hz) 35.5, 33.5, 30.7, 24.3; 19F NMR (470 MHz, CDCl3) δ -73.9 (t, J = 8.4 Hz, 3F); HRMS-
ESI calcd for C13H19F3NO2 [M+NH4]+ 278.1362, found 278.1353.
2,2,2-trifluoroethyl [1,1’-biphenyl]-4-carboxylate (4.4). Using
the general protocol on [1,1'-biphenyl]-4-carboxylic acid and
2,2,2-trifluoroethan-1-ol, ester 4.4 was obtained as a white solid
(121 mg, 77%) after purification by flash chromatography using hexane/EtOAc (95:5) as
the eluent. Spectral data for 4.4 were identical to those previously reported.189
2,2,2-trifluoroethyl 4-methoxybenzoate (4.5). Using the
general protocol on 4-methoxybenzoic acid and 2,2,2-
trifluoroethan-1-ol, ester 4.5 was obtained as a colorless oil (65
mg, 50%) after purification by flash chromatography using hexane/EtOAc (95:5) as the
eluent. Spectral data for 4.5 were identical to those previously reported.190
2,2,2-trifluoroethyl 4-nitrobenzoate (4.6). Using the general
protocol on 4-nitrobenzoic acid and 2,2,2-trifluoroethan-1-ol,
(189) Crosignani, S.; Gonzalez, J.; Swinnen, D. Org. Lett. 2004, 6, 4579–4582. (190) Mori, N.; Togo, H. Tetrahedron 2005, 61, 5915–5925.
O
O
CF3
O
O
Ph
CF3
O
O
MeO
CF3
O
O
O2N
CF3
105
ester 4.6 was obtained as a yellow solid (132 mg, 95%) after purification through a pad of
silica using CH2Cl2 as the eluent. When the reaction was carried out on a 5.98 mmol (1.00
g) scale, 1.45 g of ester 4.6 was obtained (97% yield). mp: 48-50 °C; IR (ATR, ZnSe) ν =
3077, 2921, 1724, 1530, 1288, 1167 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.35-8.31 (m,
2H), 8.28-8.24 (m, 2H), 4.76 (q, J = 8.3 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 163.2,
151.1, 133.7, 131.2 (2C), 123.8 (2C), 122.9 (q, J = 277.16 Hz), 61.4 (q, J = 37.0 Hz); 19F
NMR (470 MHz, CDCl3) δ -73.6 (t, J = 8.3 Hz, 3F); HRMS-ESI calcd for C9H6F3NNaO4
[M+Na]+ 272.0141, found 272.0139.
2,2,2-trifluoroethyl 3,5-bis(trifluoromethyl)benzoate (4.7).
Using the general protocol on 3,5-bis(trifluoromethyl)benzoic
acid and 2,2,2-trifluoroethan-1-ol, ester 4.7 was obtained as a
colorless oil (127 mg, 67%) after purification by flash
chromatography using hexane/EtOAc (95:5) as the eluent. IR (ATR, ZnSe) ν = 3101, 2983,
1750, 1276, 1232, 1121 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.52 (s, 2H), 8.14 (s, 1H), 4.80
(q, J = 8.3 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 162.4, 132.6 (q, J = 34.3 Hz, 2C),
130.5, 130.0 (q, J = 3.4 Hz, 2C), 127.2 (hept, J = 3.6 Hz), 122.6 (q, J = 277.1 Hz, 2C),
122.6 (q, J = 272.9 Hz), 61.4 (q, J = 37.2 Hz); 19F NMR (470 MHz, CDCl3) δ -63.4 (s, 6F),
-73.9 (t, J = 8.2 Hz, 3F); HRMS-ESI calcd for C11H6F9O2 [M+H]+ 341.0219, found
341.0195.
2,2,2-trifluoroethyl 2-bromobenzoate (4.8). Using the general
protocol on 2-bromobenzoic acid and 2,2,2-trifluoroethan-1-ol, ester
4.8 was obtained as a colorless oil (123 mg, 78%) after purification by
flash chromatography using hexane/EtOAc (9:1) as the eluent. IR (ATR, ZnSe) ν = 3070,
2972, 1748, 1268, 1159, 1102 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.88 (m, 1H), 7.70 (m,
1H), 7.42-7.37 (m, 2H), 4.71 (q, J = 8.4 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 164.1,
134.7, 133.5, 131.9, 129.9, 127.3, 123.0 (q, J = 277.2 Hz), 122.4, 61.0 (q, J = 37.0 Hz); 19F
Br
O
O
CF3
CF3
F3C O
O
CF3
106
NMR (470 MHz, CDCl3) δ -73.4 (t, J = 8.3 Hz, 3F); HRMS-ESI calcd for C9H10BrF3NO2
[M+NH4]+ 299.9841, found 299.9864.
2,2,2-trifluoroethyl isonicotinate (4.9). Using the general protocol
on isonicotinic acid and 2,2,2-trifluoroethan-1-ol, ester 4.9 was
obtained as a colorless oil (82 mg, 71%) after purification by flash
chromatography using hexane/EtOAc (8:2) as the eluent. IR (ATR, ZnSe) ν = 3038, 2975,
1745, 1410, 1252, 1160, 1114 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.86-8.82 (m, 2H), 7.90-
7.87 (m, 2H), 4.75 (q, J = 8.3 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 163.6, 150.8 (2C),
135.5, 122.9 (2C), 122.7 (q, J = 277.2 Hz), 61.2 (q, J = 37.0 Hz); 19F NMR (470 MHz,
CDCl3) δ -73.7 (t, J = 8.2 Hz, 3F); HRMS-ESI calcd for C8H7F3NO2 [M+H]+ 206.0423,
found 206.0426.
2,2,2-trifluoroethyl nicotinate (4.10). Using the general protocol on
nicotinic acid and 2,2,2-trifluoroethan-1-ol, ester 4.10 was obtained
as a colorless oil (82 mg, 71%) after purification by flash
chromatography using hexane/EtOAc (7:3) as the eluent. IR (ATR, ZnSe) ν = 2978, 1740,
1592, 1418, 1294, 1257 cm-1; 1H NMR (500 MHz, CDCl3) δ 9.25 (s, 1H), 8.82 (dd, J = 5.0,
1.7 Hz, 1H), 8.32 (ddd, J = 8.0, 2.2, 1.7 Hz, 1H), 7.43 (ddd, J = 7.9, 4.9, 0.9 Hz, 1H), 4.73
(q, J = 8.3 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 163.7, 154.3, 151.2, 137.4, 126.2,
123.5, 122.8 (q, J = 277.2 Hz), 60.9 (q, J = 36.8 Hz); 19F NMR (470 MHz, CDCl3) δ -73.7
(t, J = 8.3 Hz, 3F); HRMS-ESI calcd for C8H7F3NO2 [M+H]+ 206.0423, found 206.0418.
2,2,2-trifluoroethyl picolinate (4.11). Using the general protocol on
picolinic acid and 2,2,2-trifluoroethan-1-ol, ester 4.11 was obtained
as a colorless oil (86 mg, 75%) after purification by flash
chromatography using hexane/EtOAc (7:3) as the eluent. IR (ATR, ZnSe) ν = 3061, 2976,
1738, 1585, 1439, 1414, 1269 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.82 (ddd, J = 4.7, 1.7,
N
O
O CF3
N
O
O CF3
N
O
O CF3
107
0.9 Hz, 1H), 8.17 (dt, J = 7.8, 1.0 Hz, 1H), 7.90 (td, J = 7.8, 1.8 Hz, 1H), 7.55 (ddd, J = 7.7,
4.7, 1.2 Hz, 1H), 4.81 (q, J = 8.3 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 163.5, 150.3,
146.5, 137.2, 127.6, 125.8, 122.9 (q, J = 277.5 Hz), 61.3 (q, J = 37.0 Hz); 19F NMR (470
MHz, CDCl3) δ -73.5 (t, J = 8.3 Hz, 3F); HRMS-ESI calcd for C8H7F3NO2 [M+H]+
206.0423, found 206.0423.
2,2,2-trifluoroethyl 2-oxo-2-phenylacetate (4.12). Using the general
protocol on 2-oxo-2-phenylacetic acid and 2,2,2-trifluoroethan-1-ol,
ester 4.12 was obtained as a colorless oil (97 mg, 74%) after
purification by flash chromatography using hexane/EtOAc (95:5) as the eluent. IR (ATR,
ZnSe) ν = 3070, 2977, 1756, 1686, 1270, 1153 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.01-
7.98 (m, 2H), 7.69 (m, 1H), 7.55-7.51 (m, 2H), 4.77 (q, J = 8.2 Hz, 2H); 13C NMR (126
MHz, CDCl3) δ 184.3, 161.8, 135.5, 131.9, 130.0 (2C), 129.1 (2C), 122.5 (q, J = 277.4 Hz),
61.0 (q, J = 37.5 Hz); 19F NMR (470 MHz, CDCl3) δ -73.5 (t, J = 7.8 Hz, 3F); HRMS-ESI
calcd for C10H8F3O3 [M+H]+ 233.0420, found 233.0426.
2,2,2-trifluoroethyl 2-phenylacetate (4.13). Using the general
protocol on 2-phenylacetic acid and 2,2,2-trifluoroethan-1-ol, ester
4.13 was obtained as a colorless oil (76 mg, 62%) after purification through a pad of silica
using CH2Cl2 as the eluent. Spectral data for 4.13 were identical to those previously
reported.191
2,2,2-trifluoroethyl 2,2-diphenylacetate (4.14). Using the general
protocol on 2,2-diphenylacetic acid and 2,2,2-trifluoroethan-1-ol,
ester 4.14 was obtained as a colorless oil (147 mg, 89%) after
purification by flash chromatography using hexane/EtOAc (96:4) as the eluent. IR (ATR,
ZnSe) ν = 3031, 2973, 1754, 1272, 1126 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.35-7.27 (m,
(191) Duggan, P. J.; Humphrey, D. G.; McCarl, V. Aust. J. Chem. 2004, 57, 741–745.
Ph
OO
O
CF3
O
O
CF3
O O CF3
108
10H), 5.13 (d, J = 3.2 Hz, 1H), 4.52 (qd, J = 8.4, 1.9 Hz, 2H); 13C NMR (126 MHz, CDCl3)
δ 171.0, 137.6 (2C), 128.7 (4C), 128.5 (4C), 127.6 (2C), 122.8 (q, J = 277.6 Hz), 60.7 (q, J
= 36.7 Hz), 56.4; 19F NMR (470 MHz, CDCl3) δ -73.6 (t, J = 8.5 Hz, 3F); HRMS-APPI
calcd for C16H13F3O2 [M*]+ 294.0862, found 294.0872.
2,2,2-trifluoroethyl 1-benzylpiperidine-4-carboxylate (4.15). Using the
general protocol on 1-benzylpiperidine-4-carboxylic acid and 2,2,2-
trifluoroethan-1-ol, ester 4.15 was obtained as a yellow oil (58 mg, 32%)
after purification by flash chromatography using hexane/EtOAc (8:2) as the
eluent. IR (ATR, ZnSe) ν = 2947, 2802, 2761, 1751, 1276, 1142 cm-1; 1H
NMR (500 MHz, CDCl3) δ 7.35-7.31 (m, 4H), 7.27 (m, 1H), 4.48 (q, J = 8.5 Hz, 2H), 3.51
(s, 2H), 2.88 (dt, J = 12.0, 3.8 Hz, 2H), 2.43 (tt, J = 11.1, 4.1 Hz, 1H), 2.07 (td, J = 11.5,
2.7 Hz, 2H), 1.97-1.88 (m, 2H), 1.86-1.78 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 173.5,
138.1, 129.1 (2C), 128.2 (2C), 127.1, 123.0 (q, J = 277.3 Hz), 63.1, 60.2 (q, J = 36.6 Hz),
52.6 (2C), 40.7, 28.0 (2C); 19F NMR (470 MHz, CDCl3) δ -73.9 (t, J = 8.3 Hz, 3F); HRMS-
APPI calcd for C15H18F3NO2 [M*]+ 301.1284, found 301.1286.
1-benzyl 4-(2,2,2-trifluoroethyl) piperidine-1,4-dicarboxylate (4.16).
Using the general protocol on 1-((benzyloxy)carbonyl)piperidine-4-
carboxylic acid and 2,2,2-trifluoroethan-1-ol, ester 4.16 was obtained as a
colorless oil (163 mg, 84%) after purification by flash chromatography using
hexane/EtOAc (8:2) as the eluent. IR (ATR, ZnSe) ν = 2954, 2862, 1752,
1693, 1426, 1145 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.38-7.31 (m, 5H), 5.13 (s, 2H), 4.48
(q, J = 8.4 Hz, 2H), 4.11 (bs, 2H), 2.96 (bs, 2H), 2.60 (tt, J = 10.9, 3.9 Hz, 1H), 1.94 (bs,
2H), 1.73-1.66 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 172.7, 155.1, 136.7, 128.5 (2C),
128.1, 127.9 (2C), 123.0 (q, J = 277.5 Hz), 67.2, 60.3 (q, J = 36.5 Hz), 43.1 (2C), 40.5,
27.7 (2C); 19F NMR (470 MHz, CDCl3) δ -73.9 (t, J = 8.4 Hz, 3F); HRMS-ESI calcd for
C16H19F3NO4 [M+H]+ 346.1261, found 346.1261.
NBn
O O
CF3
NCbz
O O
CF3
109
Bis(2,2,2-trifluoroethyl) terephthalate (4.17). Using
the general protocol on terephthalic acid and 2,2,2-
trifluoroethan-1-ol, ester 4.17 was obtained as a white
solid (121 mg, 65%) after purification by flash
chromatography using hexane/EtOAc (9:1) as the eluent. mp: 111-113 °C; IR (ATR, ZnSe)
ν = 2915, 1727, 1417, 1288, 1241 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.19 (s, 4H), 4.75
(q, J = 8.3 Hz, 4H); 13C NMR (126 MHz, CDCl3) δ 163.9 (2C), 132.9 (2C), 130.1 (4C),
122.9 (q, J = 277.2 Hz, 2C), 61.1 (q, J = 37.0 Hz, 2C); 19F NMR (470 MHz, CDCl3) δ -73.7
(t, J = 8.4 Hz, 6F); HRMS-ESI calcd for C12H8F6NaO4 [M+Na]+ 353.0219, found
353.0221.
Bis(2,2,2-trifluoroethyl) 2-benzylmalonate (4.18). Using the
general protocol on 2-benzylmalonic acid and 2,2,2-
trifluoroethan-1-ol, ester 4.18 was obtained as a colorless oil
(146 mg, 73%) after purification by flash chromatography using hexane/EtOAc (95:5) as
the eluent. IR (ATR, ZnSe) ν = 3035, 2977, 1755, 1411, 1279, 1158 cm-1; 1H NMR (500
MHz, CDCl3) δ 7.32-7.18 (m, 5H), 4.54-4.41 (m, 4H), 3.89 (t, J = 7.9 Hz, 1H), 3.29 (d, J =
7.9 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 166.5 (2C), 136.4, 128.8 (2C), 128.7 (2C),
127.3, 122.5 (q, J = 277.2 Hz, 2C), 61.1 (q, J = 37.2 Hz, 2C), 52.9, 34.4; 19F NMR (470
MHz, CDCl3) δ -73.9 (t, J = 8.1 Hz, 6F); HRMS-ESI calcd for C14H16F6NO4 [M+NH4]+
376.0978, found 376.0962.
2,2,2-trifluoroethyl ((benzyloxy)carbonyl)-L-phenylalaninate
(4.19). Using the general protocol on ((benzyloxy)carbonyl)-L-
phenylalanine and 2,2,2-trifluoroethan-1-ol, ester 4.19 was
obtained as a white solid (181 mg, 85%) after purification by flash chromatography using
hexane/EtOAc (9:1) as the eluent. mp: 78-79 °C; IR (ATR, ZnSe) ν = 3318, 3032, 2965,
1763, 1685, 1530, 1259 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.34-7.23 (m, 8H), 7.10-7.08
(m, 2H), 5.36 (bs, 1H), 5.06 (s, 2H), 4.73 (m, 1H), 4.50 (m, 1H), 4.38 (m, 1H), 3.14 (dd, J =
O
O
O
O
CF3F3C
O
O
O
O
Ph
CF3F3C
CbzHN O
O
CF3
Ph
110
14.1, 5.7 Hz, 1H), 3.05 (dd, J = 14.0, 6.8 Hz, 1H), ; 13C NMR (126 MHz, CDCl3) δ 170.4,
155.8, 136.1, 135.2, 129.2 (2C), 128.8 (2C), 128.6 (2C), 128.3, 128.1 (2C), 127.4, 122.7 (q,
J = 277.2 Hz), 61.2, 60.9 (q, J = 36.9 Hz), 54.7, 37.8; 19F NMR (470 MHz, CDCl3) δ -73.5
(t, J = 8.3 Hz, 3F); HRMS-ESI calcd for C19H19F3NO4 [M+H]+ 382.1261, found 382.1258;
HPLC: Daicel chiralpak AD-H, 20 °C, 220 nm, hexane-i-PrOH (95:5), 1 mL/min, tR = 16.8
min, >99% ee. Reaction on rac-((benzyloxy)carbonyl)phenylalanine provided the racemic
compound in 83% yield with identical spectroscopic data. HPLC: Daicel chiralpak AD-H,
20 °C, 220 nm, hexane-i-PrOH (95:5), 1 mL/min, tR = 16.8 min and 19.2 min.
2,2,2-trifluoroethyl (S)-2-(benzyloxy)propanoate (4.20). Using the
general protocol on (S)-2-(benzyloxy)propanoic acid and 2,2,2-
trifluoroethan-1-ol, ester 4.20 was obtained as a colorless oil (95 mg,
64%) after purification by flash chromatography using hexane/EtOAc (95:5) as the eluent.
IR (ATR, ZnSe) ν = 3032, 2991, 2872, 1769, 1454, 1280, 1164, 1124 cm-1; 1H NMR (500
MHz, CDCl3) δ 7.40-7.31 (m, 5H), 4.72 (d, J = 11.5 Hz, 1H), 4.63-4.49 (m, 2H), 4.49 (d, J
= 11.5 hz, 1H), 4.19 (q, J = 6.9 Hz, 1H), 1.51 (d, J = 6.9 Hz, 3H); 13C NMR (126 MHz,
CDCl3) δ 171.7, 137.1, 128.5 (2C), 128.0 (3C), 122.8 (q, J = 277.2 Hz), 73.5, 72.2, 60.3 (q,
J = 36.8 Hz), 18.6; 19F NMR (470 MHz, CDCl3) δ -73.8 (t, J = 8.3 Hz, 3F); HRMS-ESI
calcd for C12H14F3O3 [M+H]+ 263.0890, found 263.0884; HPLC: Daicel chiralpak OJ-H,
20 °C, 220 nm, hexane-i-PrOH (90:10), 1 mL/min, tR = 10.8 min, >99% ee. Reaction on 2-
(benzyloxy)propanoic acid provided the racemic compound in 63% yield with identical
spectroscopic data. HPLC: Daicel chiralpak OJ-H, 20 °C, 220 nm, hexane-i-PrOH (90:10),
1 mL/min, tR = 7.1 min and 10.8 min.
2,2,2-trifluoroethyl (R)-2-methoxy-2-phenylacetate (4.21).
Using the general protocol on (R)-2-methoxy-2-phenylacetic acid
and 2,2,2-trifluoroethan-1-ol, ester 4.21 was obtained as a colorless
oil (89 mg, 64%) after purification by flash chromatography using hexane/EtOAc (95:5) as
the eluent. IR (ATR, ZnSe) ν = 2936, 2833, 1769, 1456, 1281, 1148 cm-1; 1H NMR (500
Me
OBnO
O
CF3
O
O
CF3OMe
111
MHz, CDCl3) δ 7.46-7.36 (m, 5H), 4.87 (s, 1H), 4.55 (dq, J = 12.7, 8.3 Hz, 1H), 4.43 (dq, J
= 12.7, 8.3 Hz, 1H), 3.43 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 169.3, 135.2, 129.1, 128.8
(2C), 127.2 (2C), 122.6 (q, J = 277.4 Hz), 82.1, 60.6 (q, J = 37.0 Hz), 57.5; 19F NMR (470
MHz, CDCl3) δ -73.8 (t, J = 8.3 Hz, 3F); HRMS-ESI calcd for C11H15F3NO3 [M+NH4]+
266.0998, found 266.0996; HPLC: Daicel chiralpak AD-H, 20 °C, 220 nm, hexane-i-PrOH
(99:1), 1 mL/min, tR = 5.4 min, >99% ee. Reaction on 2-methoxy-2-phenylacetic acid
provided the racemic compound in 64% yield with identical spectroscopic data. HPLC:
Daicel chiralpak AD-H, 20 °C, 220 nm, hexane-i-PrOH (99:1), 1 mL/min, tR = 4.8 and 5.4
min.
1,1,1,3,3,3-hexafluoropropan-2-yl [1,1'-biphenyl]-4-
carboxylate (4.27). Using the general protocol on [1,1'-
biphenyl]-4-carboxylic acid and 1,1,1,3,3,3-hexafluoropropan-2-
ol, ester 4.27 was obtained as a white solid (146 mg, 75%) after purification by flash
chromatography using hexane/CH2Cl2 (1:9) as the eluent. mp: 67-69 °C; IR (ATR, ZnSe) ν
= 3029, 2978, 1752, 1357, 1232, 1097 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.27-8.05 (m,
2H), 7.78-7.71 (m, 2H), 7.69-7.61 (m, 2H), 7.55-7.47 (m, 2H), 7.44 (m, 1H), 6.06 (hept, J =
6.1 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 163.1, 147.6, 139.5, 131.0 (2C), 129.1 (2C),
128.6, 127.5 (2C), 127.3 (2C), 125.4, 120.6 (qq, J = 282.4, 2.2 Hz, 2C), 67.0 (hept, J = 35.0
Hz); 19F NMR (470 MHz, CDCl3) δ -73.2 (d, J = 6.4 Hz, 6F); HRMS-APPI calcd for
C16H10F6O2 [M*]+ 348.0579, found 348.0577.
1,1,1,3,3,3-hexafluoropropan-2-yl 4-methoxybenzoate
(4.28). Using the general protocol on 4-methoxybenzoic acid
and 1,1,1,3,3,3-hexafluoropropan-2-ol, ester 4.28 was obtained
as a white solid (77 mg, 45%) after purification by flash chromatography using
hexane/CH2Cl2 (75:25) as the eluent. mp: 39-41 °C; IR (ATR, ZnSe) ν = 2964, 2849, 1746,
1603, 1256, 1096 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.42-8.35 (m, 2H), 8.35-8.28 (m,
2H), 6.03 (hept, J = 6.0 Hz, 1H), 3.91 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 164.8, 162.8,
MeO
O
O
CF3
CF3
112
132.7 (2C), 120.6 (qq, J = 282.7, 2.2 Hz, 2C), 118.9, 114.2 (2C), 66.6 (hept, J = 34.6 Hz),
55.6; 19F NMR (470 MHz, CDCl3) δ -73.3 (d, J = 5.4 Hz, 6F); HRMS-APPI calcd for
C11H8F6O3 [M*]+ 302.0372, found 302.0381.
1,1,1,3,3,3-hexafluoropropan-2-yl 4-nitrobenzoate (4.29).
Using the general protocol on 4-nitrobenzoic acid and
1,1,1,3,3,3-hexafluoropropan-2-ol, ester 4.29 was obtained as a
yellow solid (160 mg, 90%) after purification by flash chromatography using CH2Cl2 as the
eluent. mp: 37-40 °C; IR (ATR, ZnSe) ν = 3079, 2983, 1754, 1527, 1257, 1182, 1098 cm-1;
1H NMR (500 MHz, CDCl3) δ 8.42-8.35 (m, 2H), 8.35-8.28 (m, 2H), 6.03 (hept, J = 6.0
Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 161.7, 151.6, 132.1, 131.7 (2C), 124.0 (2C), 120.3
(qq, J = 282.6, 2.2 Hz, 2C), 67.5 (hept, J = 35.0 Hz); 19F NMR (470 MHz, CDCl3) δ -73.1
(d, J = 6.4 Hz, 6F); HRMS-ESI calcd for C10H4F6NO4 [M-H]- 316.0050, found 316.0059.
2,2,3,3,3-pentafluoropropyl 4-nitrobenzoate (4.30). Using
the general protocol on 4-nitrobenzoic acid and 2,2,3,3,3-
pentafluoropropan-1-ol, ester 4.30 was obtained as a white
solid (151 mg, 90%) after purification by flash chromatography using hexane/EtOAc (9:1)
as the eluent. mp: 61-63 °C; IR (ATR, ZnSe) ν = 3117, 2971, 1739, 1518, 1347, 1274,
1195 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.37-8.30 (m, 2H), 8.27-8.22 (m, 2H), 4.83 (tq, J
= 12.6, 1.0 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 163.1, 151.1, 133.5, 133.1 (2C), 123.8
(2C), 118.4 (qt, J = 286.0, 34.6 Hz), 111.9 (tq, J = 255.6, 38.2 Hz), 60.2 (t, J = 28.5 Hz);
19F NMR (470 MHz, CDCl3) δ -83.8 (s, 3F), -123.4 (t, J = 12.5 Hz, 2F); HRMS-ESI calcd
for C10H6F5NNaO4 [M+Na]+ 322.0109, found 322.0104.
2,2,3,3,4,4,4-heptafluorobutyl 4-nitrobenzoate (4.31). Using
the general protocol on 4-nitrobenzoic acid and 2,2,3,3,4,4,4-
heptafluorobutan-1-ol, ester 4.31 was obtained as a colorless
O2N
O
O
CF3
CF3
O
O
C2F5
O2N
O2N
O
O
C3F7
113
oil (174 mg, 89%) after purification by flash chromatography using hexane/EtOAc (9:1) as
the eluent. IR (ATR, ZnSe) ν = 3114, 2973, 1743, 1530, 1223, 1101 cm-1; 1H NMR (500
MHz, CDCl3) δ 8.34-8.31 (m, 2H), 8.26-8.23 (m, 2H), 4.87 (tt, J = 13.1, 1.3 Hz, 2H); 13C
NMR (126 MHz, CDCl3) δ 163.1, 151.0, 133.5, 131.1 (2C), 123.8 (2C), 117.5 (qt, J =
287.4, 33.5 Hz), 113.8 (tt, J = 257.2, 31.1 Hz), 108.6 (tqt, J = 265.3, 38.7, 33.9 Hz), 60.4 (t,
J = 27.9 Hz); 19F NMR (470 MHz, CDCl3) δ -81.0 (t, J = 9.3 Hz, 3F), -120.4 (h, J = 11.7
Hz, 2F), -127.7 (s, 2F); HRMS-ESI calcd for C11H6F7NNaO4 [M+Na]+ 372.0077, found
372.0082.
2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluorooctyl 4-
nitrobenzoate (4.32). Using the general protocol on 4-
nitrobenzoic acid and 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-
pentadecafluorooctan-1-ol, ester 4.32 was obtained as a white solid (294 mg, 95%) after
purification by flash chromatography using hexane/EtOAc (97:3) as the eluent. mp: 64-66
°C; IR (ATR, ZnSe) ν = 3115, 2927, 1737, 1538, 1203, 1141 cm-1; 1H NMR (500 MHz,
CDCl3) δ 8.36-8.33 (m, 2H), 8.26-8.24 (m, 2H), 4.88 (t, J = 13.2 Hz, 2H); 13C NMR (126
MHz, CDCl3) δ 163.2, 151.1, 133.6, 131.2 (2C), 123.9 (2C), 118.6-108.1 (complex weak
signal, 7C), 60.7 (t, J = 27.6 Hz); 19F NMR (470 MHz, CDCl3) δ -80.8 (t, J = 10.1 Hz, 3F),
-119.3 (s, 2F), -122.0 (s, 4F), -122.8 (s, 2F), -123.2 (s, 2F), -126.2 (s, 2F); HRMS-ESI calcd
for C15H5F15NO4 [M-H]- 547.9985, found 548.0001.
2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,9-heptadecafluorononyl 4-
nitrobenzoate (4.33). Using the general protocol on 4-
nitrobenzoic acid and 2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9-
hexadecamethyldecan-1-ol, ester 4.33 was obtained as a white solid (324 mg, 96%) after
purification by flash chromatography using hexane/EtOAc (95:5) as the eluent. mp: 71-73
°C; IR (ATR, ZnSe) ν = 3113, 2963, 1737, 1607, 1538, 1196 cm-1; 1H NMR (500 MHz,
CDCl3) δ 8.37-8.32 (m, 2H), 8.29-8.24 (m, 2H), 4.89 (t, J = 13.2 Hz, 2H); 13C NMR (126
MHz, CDCl3) δ 163.1, 151.0, 133.5, 131.0 (2C), 123.7 (2C), 120.7-105.7 (complex weak
O2N
O
O
C7F15
O2N
O
O
C8F17
114
signal, 8C), 60.5 (t, J = 27.6 Hz); 19F NMR (470 MHz, CDCl3) δ -81.2 (t, J = 10.0 Hz, 3F),
-119.6 (s, 2F), -122.2 (bs, 6F), -123.0 (s, 2F), -123.4 (s, 2F), -126.5 (s, 2F); HRMS calcd
for C16H6F17NNaO4 [M+Na]+ 621.9918, found 621.9884.
2,2,3,3,3-pentafluoropropyl 2-bromobenzoate (4.34). Using the
general protocol on 2-bromobenzoic acid and 2,2,3,3,3-
pentafluoropropan-1-ol, ester 4.34 was obtained as a colorless oil
(126 mg, 67%) after purification by flash chromatography using hexane/EtOAc (96:4) as
the eluent. IR (ATR, ZnSe) ν = 2969, 1749, 1193, 1152 cm-1; 1H NMR (500 MHz, CDCl3)
δ 7.87 (m, 1H), 7.70 (m, 1H), 7.42-7.36 (m, 2H), 4.78 (tq, J = 12.8, 1.0 Hz, 2H); 13C NMR
(126 MHz, CDCl3) δ 164.0, 134.9, 133.7, 131.9, 129.7, 127.4, 122.7, 118.6 (qt, J = 285.8,
34.7 Hz), 112.2 (tq, J = 255.5, 38.2 Hz), 59.9 (t, J = 28.0 Hz); 19F NMR (470 MHz, CDCl3)
δ -83.8 (s, 3F), -123.3 (t, J = 12.8 Hz, 2F); HRMS-ESI calcd for C10H6BrF5O2 [M+H]+
332.9544, found 332.9548.
2,2,3,3,4,4,4-heptafluorobutyl 3,5-
bis(trifluoromethyl)benzoate (4.35). Using the general
protocol on 3,5-bis(trifluoromethyl)benzoic acid and
2,2,3,3,4,4,4-heptafluorobutan-1-ol, ester 4.35 was obtained as
a colorless oil (182 mg, 74%) after purification by flash chromatography using
hexane/EtOAc (97:3) as the eluent. IR (ATR, ZnSe) ν = 3096, 1752, 1279, 1225, 1119 cm-
1; 1H NMR (500 MHz, CDCl3) δ 8.51 (s, 2H), 8.14 (s, 1H), 4.91 (tt, J = 13.0, 1.3 Hz, 2H);
13C NMR (126 MHz, CDCl3) δ 162.4, 132.6 (q, J = 34.2 Hz, 2C), 130.4, 129.9 (q, J = 3.8
Hz, 2C), 127.2 (hept, J = 3.7 Hz), 122.6 (q, J = 272.7 Hz, 2C), 117.5 (qt, J = 278.1, 33.5
Hz), 113.7 (tt, J = 257.2 Hz, 31.1 Hz), 108.6 (tqt, J = 265.0, 38.8, 33.7 Hz), 60.4 (t, J = 27.7
Hz); 19F NMR (470 MHz, CDCl3) δ -63.6 (s, 6F), -81.2 (t, J = 9.2 Hz, 3F), -120.6 (h, J =
11.8 Hz, 2F), -127.9 (s, 2F); Under all conditions tested for MS analysis (HRMS-ESI(+).
HRMS-ESI(-), HRMS-APPI, GC-MS-EI and GC-MS-CI), we never could detect any
significant ions.
Br
O
O
C2F5
F3C
CF3
O
O
C3F7
115
2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluorooctyl isonicotinate
(4.36). Using the general protocol on isonicotinic acid and
2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluorooctan-1-ol, ester 4.36
was obtained as a white solid (241 mg, 85%) after purification by flash chromatography
using hexane/EtOAc (8:2) as the eluent. mp: 42-43 °C; IR (ATR, ZnSe) ν = 3059, 2976,
1747, 1411, 1200 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.86-8.84 (m, 2H), 7.88-7.87 (m,
2H), 4.86 (tt, J = 13.2, 1.3 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 163.5, 150.8 (2C),
135.4, 122.8 (2C), 120.7-105.7 (complex weak signal, 7C), 60.4 (t, J = 27.7 Hz); 19F NMR
(470 MHz, CDCl3) δ -81.2 (t, J = 10.3 Hz, 3F), -119.6 (s, 2F), -122.3 (s, 4F), -123.1 (s, 2F),
-123.5 (s, 2F), -126.5 (s, 2F); HRMS-ESI calcd for C14H7F15NO2 [M+H]+ 506.0232, found
506.0218.
2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,9-heptadecafluorononyl
isonicotinate (4.37). Using the general protocol on isonicotinic acid
and 2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9-hexadecamethyldecan-1-ol, ester
4.37 was obtained as a white solid (213 mg, 69%) after purification by flash
chromatography using hexane/EtOAc (8:2) as the eluent. mp: 60-61 °C; IR (ATR, ZnSe) ν
= 2923, 2359, 1748, 1412, 1333, 1200 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.87-8.83 (m,
2H), 7.89-7.86 (m, 2H), 4.87 (t, J = 13.2 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 163.6,
150.9 (2C), 135.4, 122.9 (2C), 120.5-106.9 (complex weak signal, 8C), 60.6 (t, J = 27.6
Hz); 19F NMR (470 MHz, CDCl3) δ -81.2 (t, J = 10.0 Hz, 3F), -119.6 (s, 2F), -122.2 (bs,
6F), -123.0 (s, 2F), -123.4 (s, 2F), -126.5 (s, 2F); HRMS-ESI calcd for C15H7F17NO2
[M+H]+ 556.0200, found 556.0183.
2,2,3,3,3-pentafluoropropyl 2-oxo-2-phenylacetate (4.38). Using
the general protocol on 2-oxo-2-phenylacetic acid and 2,2,3,3,3-
pentafluoropropan-1-ol, ester 4.38 was obtained as a colorless oil (78
mg, 49%) after purification by flash chromatography using hexane/EtOAc (95:5) as the
eluent. IR (ATR, ZnSe) ν = 3073, 2973, 1755, 1689, 1597, 1188, 1151 cm-1; 1H NMR (500
NO
O
C7F15
N
O
O C8F17
Ph
OO
O
C2F5
116
MHz, CDCl3) δ 8.02-7.98 (m, 2H), 7.70 (m, 1H), 7.57-7.52 (m, 2H), 4.85 (tq, J = 12.8, 1.0
Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 179.4, 157.0, 130.7, 127.1, 125.3 (2C), 124.3 (2C),
113.5 (qt, J = 286.1, 34.6 Hz), 106.9 (tq, J = 256.2, 38.4 Hz), 55.0 (t, J = 27.5 Hz); 19F
NMR (470 MHz, CDCl3) δ -83.8 (s, 3F), -123.2 (t, J = 12.8 Hz, 2F); HRMS-ESI calcd for
C11H8F5O3 [M+H]+ 283.0388, found 283.0394.
1,1,1,3,3,3-hexafluoropropan-2-yl 2-phenylacetate (4.39). Using
the general protocol on 2-phenylacetic acid and 1,1,1,3,3,3-
hexafluoropropan-2-ol, ester 4.39 was obtained as a colorless oil (106 mg, 66%) after
purification by flash chromatography using hexane/EtOAc (97:3) as the eluent. IR (ATR,
ZnSe) ν = 3035, 2968, 1781, 1386, 1287, 1224, 1196, 1105 cm-1; 1H NMR (500 MHz,
CDCl3) δ 7.40-7.28 (m, 5H), 5.78 (hept, J = 6.1 Hz, 1H), 3.84 (s, 2H); 13C NMR (126 MHz,
CDCl3) δ 168.4, 131.7, 129.2 (2C), 128.9 (2C), 127.8, 120.4 (qq, J = 281.6, 2.6 Hz, 2C),
66.7 (hept, J = 34.7 Hz), 40.1; 19F NMR (470 MHz, CDCl3) δ -73.3 (s, 6F); GC-MS-EI
calcd for C11H8O2F6 [M*]+ 286.04, found 286.00. All other MS analysis (HRMS-ESI(+).
HRMS-ESI(-), HRMS-APPI, and GC-MS-CI) failed.
1,1,1,3,3,3-hexafluoropropan-2-yl 2,2-diphenylacetate (4.40).
Using the general protocol on 2,2-diphenylacetic acid and 1,1,1,3,3,3-
hexafluoropropan-2-ol, ester 4.40 was obtained as a colorless oil (163
mg, 80%) after purification by flash chromatography using
hexane/EtOAc (96:4) as the eluent. IR (ATR, ZnSe) ν = 3033, 2968, 1777, 1497, 1385,
1357, 1285, 1226, 1199 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.35-7.26 (m, 10H), 5.82
(hept, J = 6.1 Hz, 1H), 5.20 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 169.6, 136.8 (2C),
128.9 (4C), 128.5 (4C), 127.9 (2C), 120.4 (qq, J = 282.3, 2.0 Hz, 2C), 66.9 (hept, J = 34.8
Hz), 56.2; 19F NMR (470 MHz, CDCl3) δ -73.1 (d, J = 6.2 Hz, 6F); HRMS-ESI calcd for
C17H12F6NaO2 [M+Na]+ 385.0634, found 385.0628.
O
O
CF3
CF3
O O CF3
CF3
117
2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluorooctyl 2,2-
diphenylacetate (4.41). Using the general protocol on 2,2-
diphenylacetic acid and 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-
pentadecafluorooctan-1-ol, ester 4.41 was obtained as a colorless oil (245 mg, 74%) after
purification by flash chromatography using hexane/toluene (8:2) as the eluent. IR (ATR,
ZnSe) ν = 3033, 2969, 1757, 1201, 1127 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.34-7.24 (m,
10H), 5.12 (s, 1H), 4.63 (t, J = 13.6 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 171.1, 137.6
(2C), 128.7 (4C), 128.5 (4C), 127.6 (2C), 120.8-105.8 (complex weak signal, 7C), 59.9 (t, J
= 26.6 Hz), 56.6; 19F NMR (470 MHz, CDCl3) δ -81.0 (t, J = 9.9 Hz, 3F), -119.5 (s, 2F), -
122.2 (s, 4F), -122.9 (s, 2F), -123.5 (s, 2F), -126.3 (s, 2F); HRMS-APPI calcd for
C22H13F15O2 [M*]+ 594.0670, found 594.0661.
1-benzyl 4-(1,1,1,3,3,3-hexafluoropropan-2-yl) piperidine-1,4-
dicarboxylate (4.42). Using the general protocol on 1-
((benzyloxy)carbonyl)piperidine-4-carboxylic acid and 1,1,1,3,3,3-
hexafluoropropan-2-ol, ester 4.42 was obtained as a white solid (166 mg,
72%) after purification by flash chromatography using CH2Cl2 as the eluent. mp: 46-49 °C;
IR (ATR, ZnSe) ν = 2966, 2885, 1760, 1688, 1442, 1167, 1106 cm-1; 1H NMR (500 MHz,
CDCl3) δ 7.42-7.30 (m, 5H), 5.78 (hept, J = 6.1 Hz, 1H), 5.14 (s, 2H), 4.12 (bs, 2H), 3.01
(bs, 2H), 2.73 (tt, J = 10.8, 3.9 Hz, 1H), 1.98 (bs, 2H), 1.79-168 (m, 2H); 13C NMR (126
MHz, CDCl3) δ 171.1, 155.1, 136.5, 128.5 (2C), 128.1, 128.0 (2C), 120.3 (qq, J = 282.2,
2.3 Hz, 2C) , 67.3, 66.3 (hept, J = 34.6 Hz), 42.8 (2C), 40.2, 27.4 (2C); 19F NMR (470
MHz, CDCl3) δ -73.4 (d, J = 6.0 Hz, 6F); HRMS-ESI calcd for C17H16F6NO4 [M-H]-
412.0989, found 412.1000.
1-benzyl 4-(2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluorooctyl)
piperidine-1,4-dicarboxylate (4.43). Using the general protocol on 1-
((benzyloxy)carbonyl)piperidine-4-carboxylic acid and
2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluorooctan-1-ol, ester 4.43 was
O O C7F15
NCbz
O O C7F15
118
obtained as a white solid (307 mg, 85%) after purification by flash chromatography using
hexane/EtOAc (8:2) as the eluent. mp: 48-50 °C; IR (ATR, ZnSe) ν = 2960, 2928, 1744,
1693, 1450, 1430 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.41-7.30 (m, 5H), 5.14 (s, 2H), 4.62
(t, J = 13.4 Hz, 2H), 4.12 (bs, 2H), 2.97 (bs, 2H), 2.61 (tt, J = 10.9, 3.9 Hz, 1H), 1.94 (bs,
2H), 1.77-1.64 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 172.7, 155.1, 136.7, 128.5 (2C),
128.1, 127.9 (2C), 118.5-107.9 (complex weak signal, 7C), 67.2, 59.6 (t, J = 27.1 Hz), 43.0
(2C), 40.6, 27.6 (2C); 19F NMR (470 MHz, CDCl3) δ -80.8 (t, J = 10.0 Hz, 3F), -119.5 (s,
2F), -122.0 (s, 4F), -122.7 (s, 2F), -123.3 (s, 2F), -126.1 (s, 2F); HRMS-ESI calcd for
C22H19F15NO4 [M+H]+ 646.1069, found 646.1053.
1-benzyl 4-(2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,9-heptadecafluorononyl)
piperidine-1,4-dicarboxylate (4.44). Using the general protocol on 1-
((benzyloxy)carbonyl)piperidine-4-carboxylic acid and
2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9-hexadecamethyldecan-1-ol, ester 4.44 was
obtained as a white solid (315 mg, 81%) after purification by flash chromatography using
hexane/EtOAc (8:2) as the eluent. mp: 55-58 °C; IR (ATR, ZnSe) ν = 2929, 2855, 1746,
1685, 1432, 1171, 1140 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.37-7.29 (m, 5H), 5.14 (s,
2H), 4.61 (t, J = 13.4 Hz, 2H), 4.12 (bs, 2H), 2.95 (bs, 2H), 2.59 (tt, J = 10.9, 3.9 Hz, 1H),
1.92 (bs, 2H), 1.73-1.65 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 172.6, 155.1, 136.7, 128.5
(2C), 128.0, 127.9 (2C), 120.8-105.8 (complex weak signal, 8C), 67.2, 59.4 (t, J = 27.0
Hz), 43.0 (2C), 40.5, 27.6 (2C); 19F NMR (470 MHz, CDCl3) δ -81.3 (t, J = 10.0 Hz, 3F), -
119.9 (s, 2F), -122.2 (bs, 6F), -123.0 (s, 2F), -123.0 (s, 2F), -123.5 (s, 2F), -126.5 (s, 2F);
HRMS calcd for C23H19F17NO4 [M+H]+ 696.1037, found 696.1024.
Bis(2,2,3,3,3-pentafluoropropyl) terephthalate
(4.45). Using the general protocol on terephthalic acid
and 2,2,3,3,3-pentafluoropropan-1-ol, ester 4.45 was
obtained as a white solid (145 mg, 60%) after
purification by flash chromatography using hexane/EtOAc (95:5) as the eluent. mp: 65-66
NCbz
O O C8F17
O
O
O
O
C2F5C2F5
119
°C; IR (ATR, ZnSe) ν = 2980, 1728, 1449, 1409, 1352, 1274, 1200 cm-1; 1H NMR (500
MHz, CDCl3) δ 8.16 (s, 4H), 4.81 (t, J = 12.5 Hz, 4H); 13C NMR (126 MHz, CDCl3) δ
163.8 (2C), 132.8 (2C), 130.1 (4C), 118.47 (qt, J = 285.7, 34.7 Hz, 2C), 112.04 (tq, J =
255.2, 38.2 Hz, 2C), 60.03 (t, J = 28.4 Hz, 2C); 19F NMR (470 MHz, CDCl3) δ -83.9 (s,
6F), -123.5 (t, J = 12.4 Hz, 4F); HRMS-ESI calcd for C14H8F10NaO4 [M+Na]+ 453.0155,
found 453.0151.
Bis(2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-
pentadecafluorooctyl) terephthalate (4.46). Using
the general protocol on terephthalic acid and
2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluorooctan-1-ol, ester 4.46 was obtained as a white
solid (284 mg, 54%) after purification by flash chromatography using hexane/toluene (6:4)
as the eluent. mp: 81-83 °C; IR (ATR, ZnSe) ν = 2924, 2855, 1732, 1199, 1103 cm-1; 1H
NMR (500 MHz, CDCl3) δ 8.18 (s, 4H), 4.87 (t, J = 13.2 Hz, 4H); 13C NMR (126 MHz,
CDCl3) δ 163.9 (2C), 132.9 (2C), 130.2 (4C), 118.5-107.6 (complex weak signal, 14C),
60.4 (t, J = 27.8 Hz, 2C); 19F NMR (470 MHz, CDCl3) δ -80.8 (t, J = 10.1 Hz, 6F), -119.2
(s, 4F), -122.0 (s, 8F), -122.7 (s, 4F), -123.2 (s, 4F), -126.1 (s, 4F); Under all conditions
tested for MS analysis (HRMS-ESI(+). HRMS-ESI(-), HRMS-APPI, GC-MS-EI and GC-
MS-CI), we never could detect any significant ions.
4.8.3 Control experiments
4.8.3.1 Reaction of perfluorinated alcohol 4.25 with XtalFluor-E
To a solution of 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluorooctan-1-ol (224 mg, 0.56
mmol, 1 equiv) in CH2Cl2 (1 mL) at rt was added XtalFluor-E (141 mg, 0.616 mmol,
CH2Cl2, rt, 16 hca. 66% conversion
OHC7F15
XtalFluor-E (1.1 equiv)
4.25
OC7F15SO
O C7F15
4.47 (20%)
O
O
O
O
C7F15C7F15
120
1.1 equiv). The resulting solution was stirred at rt for 16 hours. The reaction mixture was
quenched with water and extracted with CH2Cl2 (3×). The combined organic layers were
dried (Na2SO4) and 2-fluoro-4-nitrotoluene (87 mg, 0.56 mmol, 1 équiv) was added as a
standard for 1H and 19F NMR analyses. The resulting solution was concentrated under
vacuum to give the crude product. A conversion of 66% was obtained and analysis of the
crude mixture by NMR revealed the formation of sulfinate 4.47 (20%) along with some
unidentified XtalFluor-E related products. The fluoride176 corresponding to 4.25 was not
observed.
4.8.3.2 Formation of an acyl fluoride from 4.48
To a solution of 4-nitrobenzoic acid (94 mg, 0.56 mmol, 1 equiv) in CH2Cl2 (1 mL) at rt
were successively added triethylamine (117 µL, 0.84 mmol, 1.5 equiv) and XtalFluor-E
(141 mg, 0.616 mmol, 1.1 equiv). The resulting solution was stirred at rt for 16 hours, and
then concentrated under vacuum to give the crude product. Ethyltrifluoroacetate (67 µL,
0.56 mmol, 1 equiv) was added as a standard. The corresponding acyl fluoride 4.49177 was
obtained with ca. 40% NMR yield (determined by 1H and 19F NMR).
4.8.3.3 Attempted reaction of acyl fluoride 4.49
OH
O
O2N
XtalFluor-E (1.1 equiv)Et3N (1.5 equiv)
CH2Cl2, rt, 16 h
F
O
O2N4.48 4.49
C7F15 OH
CH2Cl2, rt, 16 hF
O
O2N
O
O
O2N
C7F15
4.49 4.32
121
2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluorooctan-1-ol (448 mg, 1.12 mmol, 2 equiv) was
added to a solution of 4-nitrobenzoyl fluoride (95 mg, 0.56 mmol, 1 equiv) in CH2Cl2 (1
mL) at rt. The resulting solution was stirred at rt for 16 hours. The reaction mixture was
quenched with water and extracted with CH2Cl2 (3×). The combined organic layers were
dried (Na2SO4) and concentrated under vacuum. Ethyltrifluoroacetate (67 µL, 0.56 mmol,
1 equiv, 67 µL) was added as a standard. 1H and 19F NMR analyses did not show the
appearance of the ester 4.32, but the recovery of the starting material in place.
4.9 PARTIE EXPÉRIMENTALE DES RÉSULTATS NON PUBLIÉS (SECTION 4.7)
4.9.1 Estérification de l’acide 5-phénylvalérique avec des alcools non fluorés
General procedure – To a solution of 5-phenylvaleric acid (100 mg, 0.56 mmol, 1 equiv)
in CH2Cl2 (1 mL) at rt were successively added the alcohol (1.12 mmol, 2 equiv),
triethylamine (117 µL, 0.84 mmol, 1.5 equiv), and XtalFluor-E (141 mg, 0.616 mmol,
1.1 equiv). The resulting solution was stirred at rt for 16 hours. The reaction mixture was
quenched with water and extracted with CH2Cl2 (3×). The combined organic layers were
dried (Na2SO4) and concentrated under vacuum to give the crude ester, which was purified
by flash chromatography.
Methyl 5-phenylpentanoate (4.51). Using the general protocol
on 5-phenylvaleric acid and methanol, ester 4.51 was obtained
as a colorless oil (66 mg, 61%) after purification by flash
chromatography using CH2Cl2 as the eluent. Spectral data for 4.51 were identical to those
previously reported.192
(192) Mandal, P. K.; McMurray, J. S. J. Org. Chem. 2007, 72, 6599–6601.
OMe
O
122
Ethyl 5-phenylpentanoate (4.52). Using the general protocol
on 5-phenylvaleric acid and ethanol, ester 4.52 was obtained as a
coloreless oil (81 mg, 70%) after purification by flash
chromatography using CH2Cl2 as the eluent. Spectral data for 4.52 were identical to those
previously reported.193
Isopropyl 5-phenylpentanoate (4.53). Using the general
protocol on 5-phenylvaleric acid and isopropanol, ester 4.53 was
obtained as a colorless oil (37 mg, 30%) after purification by
flash chromatography using CH2Cl2 as the eluent. 1H NMR (500 MHz, CDCl3) δ 7.29-7.25
(m, 2H), 7.19-7.16 (m, 3H), 5.00 (hept, J = 6.3 Hz, 1H), 2.64-2.61 (m, 2H), 2.31-2.27 (m,
2H), 1.68-1.64 (m, 4H), 1.22 (d, J = 6.3 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 173.2,
142.2, 128.4 (2C), 128.3 (2C), 125.7, 67.4, 35.6, 34.5, 30.9, 24.7, 21.9 (2C); HRMS-ESI
calcd for C14H20O2 [M+H]+ 221.1536, found 211.1540.
Allyl 5-phenylpentanoate (4.55). Using the general
protocol on 5-phenylvaleric acid and allyl alcohol, ester
4.55 was obtained as a colorless oil (60 mg, 49%) after
purification by flash chromatography using CH2Cl2 as the eluent. Spectral data for 4.55
were identical to those previously reported.194
Benzyl 5-phenylpentanoate (4.56). Using the general protocol
on 5-phenylvaleric acid and benzyl alcohol, ester 4.56 was
obtained as a colorless oil (50 mg, 33%) after purification by
flash chromatography using CH2Cl2 as the eluent. Spectral data for 4.56 were identical to
those previously reported.195
(193) Amézquita-Valencia, M.; Alper, H. J. Org. Chem. 2016, 81, 3860–3867. (194) Wang, Y.; Kang, Q. Org. Lett. 2014, 16, 4190–4193.
OEt
O
OiPr
O
O
O
OBn
O
123
4.9.2 Méthodes computationnelles
Geometry optimizations, vibrational frequencies, and thermal energy corrections were
performed with the B3LYP functional in conjunction with the standard 6-31+G(d) basis
set.196 The SMD solvatation model197 was used to account for the effects of
dichloromethane solution. To obtain more accurate electronic energies, single-point energy
calculations were performed at the SMD-B3LYP/6-311++G(2d, p) level of theory with the
B3LYP/6-31+G(d) optimized structures. Structures were generated using Avogadro. All
calculations were carried out with GAMESS-US.198
(195) Shukla, P.; Sharma, A.; Pallavi, B.; Cheng, C. H. Tetrahedron 2015, 71, 2260–2266. (196) Hehre, W. J.; Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab Initio Molecular Orbital Theory; Wiley: New York, 1986. (197) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B 2009, 113, 6378–6396. (198) Schmidt, M.W.; Baldridge, K. K.; Boatz, J. A.; Elbert, S. T.; Gordon, M. S.; Jensen, J. H.; Koseki, S.; Matsuraga, N.; Nguyen, K. A.; Su, S. J.; Windus, T. L.; Dupuis, M.; Montgomery, J. A. J. Comput. Chem. 1993, 14, 1347–1363.
124
CHAPITRE 5
Déoxofluoration éliminatrice au moyen de XtalFluor-E :
Synthèse de monofluoroalcènes en une étape à partir de dérivés de
cyclohexanone
Eliminative Deoxofluorination Using XtalFluor-E: A One-Step
Synthesis of Monofluoroalkenes from Cyclohexanone Derivatives
Mathilde Vandamme and Jean-François Paquin*
CGCC, PROTEO, Département de chimie, Université Laval,
1045 Avenue de la Médecine, Québec, Québec, G1V 0A6, Canada
E-mail: jean-francois.paquin@chm.ulaval.ca
Reproduit à partir de Organic Letters 2017, 19, 3604–3607.
125
5.1 RÉSUMÉ
La déoxofluoration éliminatrice de dérivés de cyclohexanone au moyen de XtalFluor-E est
décrite. Les monofluoroalcènes correspondants sont obtenus avec des rendements allant
jusqu’à 79 %. Notamment, cette procédure en une étape s’effectue à température ambiante
en utilisant des réactifs facilement accessibles et peu coûteux.
5.2 ABSTRACT
The eliminative deoxofluorination of cyclohexanone derivatives using XtalFluor-E is
described. The corresponding monofluoroalkenes are obtained in up to 79% yield. Notably,
this one-step procedure occurs at room temperature using readily accessible and cost-
effective reagents.
5.3 INTRODUCTION
Alkenes bearing one or more fluorine atoms represent a valuable subclass of fluorine-
containing molecules. Indeed, monofluoroalkenes are utilized in medicinal chemistry as,
among other things, amide isosteres199,200 and enol mimics.201 Fluoroalkenes also have
(199) (a) Taguchi, T.; Yanai, H. In Fluorine in Medicinal Chemistry and Chemical Biology, Ojima, I., Ed.; Blackwell Publishing Inc., 2009; pp 257–290. (b) Choudhary, A.; Raines, R. T. ChemBioChem 2011, 12, 1801–1807. (200) For selected recent applications, see: (a) Villiers, E.; Couve-Bonnaire, S.; Cahard, D.; Pannecoucke, X. Tetrahedron 2015, 71, 7054–7062. (b) Nadon, J.-F.; Rochon, K.; Grastilleur, S.; Langlois, G.; Dao, T. T. H.; Blais, V.; Guérin, B.; Gendron, L.; Dory, Y. L. ACS Chem. Neurosci. 2017, 8, 40–49. (201) Weintraub, P. M.; Holland, A. K.; Gates, C. A.; Moore, W. R.; Resvick, R. J.; Bey, P.; Peet, N. P. Bioorg. Med. Chem. 2003, 11, 427–431.
XtalFluor-EEt3N·2HF
DMA, rt X
F
RX
R
O
• one-step transformation• accessible and cost-effective reagents • 15 examples with up to 79% yield
126
potential applications in material sciences,202 and they can be used in synthetic organic
chemistry as fluorinated building blocks for further functionalization.203 The synthesis of
monofluorinated alkenes, despite their potential uses in various fields, still remains a
synthetic challenge.204 An attractive strategy would be the direct conversion of a ketone to
the corresponding fluoroalkene. Toward this end, three synthetic approaches have been
reported. In the first case, an alumina-promoted elimination of difluorocycloalcanes was
described (Scheme 5.1, eq 1).205 In the second approach, the Shapiro reaction was used as
the key step (Scheme 5.1, eq 2).206 Ketones were first transformed into hydrazones using
2,4,6-triisopropylbenzenesulfonyl hydrazide (TrisNHNH2). Reaction with n-BuLi followed
by fluorination of the resulting vinyl lithium species using NFSI afforded the fluoroalkenes.
More recently, the palladium-catalyzed fluorination of cyclic vinyl triflates was reported
(Scheme 5.1, eq 3).207 In this case, ketones were first converted to their corresponding vinyl
triflates, which were then fluorinated using a newly developed phosphine ligand, a
palladium source, TESCF3 as an additive, and KF as the fluoride source. While all reactions
represent key contributions, they suffer from issues limiting their applications. Indeed, in
the first case, the source of alumina was found to be critical. In the last two reactions, the
starting ketone must be transformed into an appropriate precursor which results in a lower
overall yield. Additionally, in the case of the Shapiro reaction, both the hydrazine and
(202) For selected examples, see: (a) Cardone, A.; Martinelli, C.; Losurdo, M.; Dilonardo, E.; Bruno, G.; Scavia, G.; Destri, S.; Cosma, P.; Salamandra, L.; Reale, A.; Di Carlo, A.; Aguirre, A.; Milián-Medina, B.; Gierschnerf, J.; Farinola, G. M. J. Mater. Chem. A 2013, 1, 715–727. (b) Milad, R.; Shi, J.; Aguirre, A.; Cardone, A.; Milián-Medina, B.; Farinola, G. M.; Abderrabba. M.; Gierschner, J. J. Mater. Chem. C 2016, 4, 6900–6906. (203) For selected recent examples, see: (a) Koh, M. J.; Nguyen, T. T.; Zhang, H.; Schrock, R. R.; Hoveyda, A. H. Nature 2016, 531, 459–465. (b) Nguyen, T. T.; Koh, M. J.; Shen, X.; Romiti, F.; Schrock, R. R.; Hoveyda, A. H. Science 2016, 352, 569–575. (c) Guérin, D.; Dez, I.; Gaumont, A.-C.; Pannecoucke, X.; Couve-Bonnaire, S. Org. Lett. 2016, 18, 3606–3609. (d) Rousée, K.; Schneider, C.; Bouillon, J.-P.; Levacher, V.; Hoarau, C.; Couve-Bonnaire, S.; Pannecoucke, X. Org. Biomol. Chem. 2016, 14, 353–357. (204) For reviews on their synthesis, see: (a) van Steenis, J. H.; van der Gen, A. J. Chem. Soc., Perkin Trans. 1 2002, 2117–2133. (b) Zajc, B.; Kumar, R. Synthesis 2010, 1822–1836. (c) Landelle, G.; Bergeron, M.; Turcotte-Savard, M.-O.; Paquin, J.-F. Chem. Soc. Rev. 2011, 40, 2867–2908. (d) Yanai, H.; Taguchi, T. Eur. J. Org. Chem. 2011, 5939–5954. (e) Hara, S. Top. Curr. Chem. 2012, 327, 59–86. (f) Pfund, E.; Lequeux, T.; Gueyrard, D. Synthesis 2015, 1534–1546. (g) Champagne, P. A.; Desroches, J.; Hamel, J.-D.; Vandamme, M.; Paquin, J.-F. Chem. Rev. 2015, 115, 9073–9174. (205) Strobach, D. R.; Boswell, Jr. G. A. J. Org. Chem. 1971, 36, 818–820. (206) Yang, M.-H.; Matikonda, S. S.; Altman, R. A. Org. Lett. 2013, 15, 3894–3897. (207) Ye, Y.; Takada, T.; Buchwald, S. L. Angew. Chem., Int. Ed. 2016, 55, 15559–15563.
127
fluorinating agent are expensive208 and the basic conditions employed limit the functional
groups tolerated. In the case of the Pd-catalyzed fluorination, not all the ligands employed
are commercially available, and the reaction requires 30 mol% of TESCF3, an expensive
additive,207 but most importantly, the fluorination step needs to be performed in a glovebox
under strictly anhydrous conditions. Given those limitations, the development of additional
complementary methods is necessary.
Scheme 5.1. Previous and Current Work.
(208) The price per mmol (in American dollars) for the following reagent was calculated using the largest amount available from a single provider (February 2017): TrisNHNH2 ($18.96), NFSI ($4.87), TESCF3 ($17.37), XtalFluor-E ($0.77), Et3N·3HF ($0.21).
Previous work
This work: Eliminative deoxofluorination of cyclohexanone derivatives
Shapiro reaction
R1
OR2
R1
NR2
R1
FR2
NHTris 1) n-BuLi2) NFSITrisNHNH2
25-79%(average 53%)
Palladium-catalyzed fluorination of cyclic enol triflates
0-93%(average 66%)
Pd cat./LKF
XR
O
XR
FXtalFluor-EEt3N·2HF
DMA, rt
(2)
(3)
(4)
R
O
R
OTf
R
F
Tf2O, base
(1)
n n n
Alumina-promoted elimination reaction
FF
n n
F
20-66%(average 48%)
Al2O3
128
Our inspiration for the present work was the report that fluoroalkenes were sometimes
observed as side products for the deoxofluorination of ketones using XtalFluor-E
([Et2NSF2]BF4)209,210 or with other related reagents.211,212,213 We imagine that if conditions
favoring the formation of the fluoroalkene could be found, it would represent a practical
one-step alternative to the above methods. Herein, we report the direct conversion of
cyclohexanone derivatives to monofluoroalkene using XtalFluor-E (Scheme 5.1, eq 4).214
Notably, this one-step procedure occurs at room temperature using readily accessible and
cost-effective reagents206 without the need for a glovebox.
(209) (a) Beaulieu, F.; Beauregard, L.-P.; Courchesne, G.; Couturier, M.; Laflamme, F.; L’Heureux, A. Org. Lett. 2009, 11, 5050–5053. (b) L’Heureux, A.; Beaulieu, F.; Bennett, C.; Bill, D. R.; Clayton, S.; Laflamme, F.; Mirmehrabi, M.; Tadayon, S.; Tovell, D.; Couturier, M. J. Org. Chem. 2010, 75, 3401–3411. (c) Mahe, O.; L’Heureux, A.; Couturier, M.; Bennett, C.; Clayton, S.; Tovell, D.; Beaulieu, F.; Paquin, J.-F. J. Fluorine Chem. 2013, 153, 57−60. (210) For other contributions from our group using XtalFluor-E, see: (a) Pouliot, M.-F.; Angers, L.; Hamel, J.-D.; Paquin, J.-F. Org. Biomol. Chem. 2012, 10, 988−993. (b) Pouliot, M.-F.; Angers, L.; Hamel, J.-D.; Paquin, J.-F. Tetrahedron Lett. 2012, 53, 4121−4123. (c) Mahé, O.; Desroches, J.; Paquin, J.-F. Eur. J. Org. Chem. 2013, 4325−4331. (d) Pouliot, M.- F.; Mahé, O.; Hamel, J.-D.; Desroches, J.; Paquin, J.-F. Org. Lett. 2012, 14, 5428−5431. (e) Keita, M.; Vandamme, M.; Mahé, O.; Paquin, J.-F. Tetrahedron Lett. 2015, 56, 461−464. (f) Desroches, J.; Champagne, P. A.; Benhassine, Y.; Paquin, J.-F. Org. Biomol. Chem. 2015, 13, 2243−2246. (g) Keita, M.; Vandamme, M.; Paquin, J.-F. Synthesis 2015, 47, 3758−3766. (h) Vandamme, M.; Bouchard, L.; Gilbert, A.; Keita, M.; Paquin, J.-F. Org. Lett. 2016, 18, 6468–6471. (i) Lebleu, T.; Paquin, J.-F. Tetrahedron Lett. 2017, 58, 442–444. (211) Monofluoroalkenes were observed when the deoxofluorination of cyclohexanone (72% GC yield) and 4-methoxyacetophenone (15% GC yield) were performed using 2,2-difluoro-1,3-dimethylimidazolidine (DFI); see Hayashi, H.; Sonoda, H.; Fukumura, K.; Nagata, T. Chem. Commun. 2002, 1618–1619. (212) A patent describing the eliminative deoxofluorination using DAST under strong acidic conditions was reported; see: Boswell Jr., G. A. Preparation of vinylene fluorides. U.S. Patent 4,212,815, 1980. (213) The deoxofluorination of β-diketones with N,N-diethyl-α,α-difluoro-m-methylbenzylamine provides β-fluoro-α,β-unsaturated ketones, see: (a) Sano, K.; Fukuhara, T.; Hara, S. J. Fluorine Chem. 2009, 130, 708–713. Reaction of cyclohexanone with the same reagent provides fluorocyclohexane in 58% yield along with 32% of difluorocyclohexane, see: (b) Hara, S.; Fukuhara, T. Method of fluorination. U.S. Patent 20060014972, 2006. (214) For selected recent alternative approaches to monofluoroalkene-containing cyclohexane derivatives, see: (a) Furuya, T.; Ritter, T. Org. Lett. 2009, 11, 2860–2863. (b) Alonso, P.; Pardo, P.; Fañanás, F. J.; Rodríguez, F. Chem. Commun. 2014, 50, 14364–14366. (c) Okoromoba, O. E.; Han, J.; Hammond, G. B.; Xu, B. J. Am. Chem. Soc. 2014, 136, 14381−14384. (d) Nihei, T.; Kubo, Y.; Ishihara, T.; Konno, T. J. Fluorine Chem. 2014, 167, 110–121. (e) Lou, S.-J.; Xu, D.-Q.; Xu, Z.-Y. Angew. Chem., Int. Ed. 2014, 53, 10330–10335. (f) Hamel, J.-D.; Cloutier, M.; Paquin, J.-F. Org. Lett. 2016, 18, 1852−1855.
129
5.4 RESULTS AND DISCUSSION
An extensive optimization of the reaction conditions was undertaken, and selected key
results are shown in Table 5.1.215 Under conditions reported for the deoxofluorination of
ketone using XtalFluor-E (Table 5.1, entry 1),207 a 13% NMR yield of the
monofluoroalkene 5.2a was observed, yet the major product was the difluoromethylene
compound 5.3a (ratio 5.2a/5.3a = 1:6.7). Next, different solvents were tested including
toluene, EtOAc, Et2O, THF, or CH3CN (Table 5.1, entries 2–6).214 For all of them, low
NMR yields of 5.2a were detected (13–24%), and in all cases, product 5.3a was the major
compound with the best 5.2a/5.3a observed with THF (1:1.8). Interestingly, when DMF
was ratio employed as the solvent, a reversal of the selectivity was observed, as 5.2a was
now the major product (5.2a/5.3a = 2.5:1) with an NMR yield of 33% (Table 5.1, entry 7).
Using a related solvent, dimethylacetamide (DMA), improved the 5.2a/5.3a ratio to 5:1, but
at the expense of the yield (15% by NMR) (Table 5.1, entry 8). Increasing the amount of
XtalFluor-E to 3 equiv (Table 5.1, entries 9–10) resulted in a 75% NMR yield of the
desired monofluoroalkene 5.2a with a 5.2a/5.3a ratio of 6.8:1. Diluting the reaction in
CH2Cl2 using various ratios (9:1, 1:1, or 1:9) of a CH2Cl2/DMA mixture did not furnish
better results (not shown). Similarly, conducting the reaction at 60 °C resulted in a lower
NMR yield of 5.2a (23%) (Table 5.1, entry 11). Reducing the amount Et3N·2HF to
1.5 equiv resulted in a much slower reaction. Nonetheless, after 5 days, a 73% NMR yield
of 5.2a was observed with a higher 5.2a/5.3a ratio of 9.1:1 (Table 5.1, entry 12). When
Et3N·3HF was used as the fluoride source, a slightly inferior NMR yield was observed
(70%) (Table 5.1, entry 13) most likely due to the lower nucleophilicity of Et3N·3HF
compared to Et3N·2HF.216 Replacing the added Et3N by other amine bases (DBU, i-Pr2EtN
or Me-imidazole) had limited effect on conversion and on the 5.2a/5.3a ratio (Table 5.1,
entries 14–16). Other fluoride sources such as TBAF (1 M soln in THF), TBAF·3H2O, or
DMPU·HF217 (with or without added Et3N) were ineffective (not shown). Also, various
additives214 were tested, but none offered significantly better results (not shown). Finally,
for comparison, Me-DAST and Deoxo-Fluor, two classical deoxofluorinating agents, were
(215) Additional optimization results can be found in the Supporting Information. (216) Giudicelli, M. B.; Picq, D.; Veyron, B. Tetrahedron Lett. 1990, 31, 6527–6530. (217) Okoromoba, O. E.; Han, J.; Hammond, G. B.; Xu, B. J. Am. Chem. Soc. 2014, 136, 14381–14384.
130
tested (Table 5.1, entries 17–18). In both cases, a low yield (19–29%) and lower selectivity
(up to 3.2:1) were obtained, demonstrating the unique reactivity of XtalFluor-E. Overall,
the conditions shown in Table 5.1, entry 10 were chosen to be optimal.
Table 5.1. Key Optimization Results for the Eliminative Deoxofluorination of 5.1a Using XtalFluor-E.a
Entry XtalFluor-E (equiv)
Fluoride source (equiv)b
Solvent Additive (equiv)
Temperature (°C)
Time (h)
Conversion (%)c
Ratio 5.2a/5.3ac
Yield (%)d
1 1.5 Et3N·2HF (3) CH2Cl2 – rt 16 100 1:6.7 13 2 1.5 Et3N·2HF (3) toluene – rt 16 100 1:2.4 22 3 1.5 Et3N·2HF (3) EtOAc – rt 16 90 1:4.7 14 4 1.5 Et3N·2HF (3) Et2O – rt 16 100 1:5.5 13 5 1.5 Et3N·2HF (3) THF – rt 16 86 1:1.8 24 6 1.5 Et3N·2HF (3) CH3CN – rt 16 100 1:2.9 12 7 1.5 Et3N·2HF (3) DMF – rt 16 100 2.5:1 33 8 1.5 Et3N·2HF (3) DMA – rt 16 100 5:1 15 9 2 Et3N·2HF (3) DMA – rt 16 87 5.7:1 34 10 3 Et3N·2HF (3) DMA – rt 16 100 6.8:1 75 (79)e 11 3 Et3N·2HF (3) DMA – 60 2 100 4.6:1 23 12 3 Et3N·2HF (1.5) DMA – rt 120 98 9.1:1 73 13 3 Et3N·3HF (3) DMA – rt 16 100 5.4:1 70 14 3 Et3N·3HF (2) DMA DBU (1) rt 16 94 5.5:1 60 15 3 Et3N·3HF (2) DMA i-Pr2EtN (1) rt 16 97 5.8:1 70 16 3 Et3N·3HF (2) DMA Me-imidazole (1) rt 16 97 5.5:1 44 17f 3 Et3N·3HF (2) DMA – rt 16 97 3.2:1 19 18g 3 Et3N·3HF (2) DMA – rt 16 89 2.9:1 29
a See the Supporting Information for the detailed experimental procedures. b Et3N·2HF is generated in situ by adding Et3N (1 equiv) to Et3N·3HF (2 equiv). c Determined by 19F NMR analysis of the crude mixture after workup. d Yield of 5.2a determined by 19F NMR analysis of the crude mixture after workup. e Isolated yield of 5.2a contaminated with inseparable 5.3a (5.2a/5.3a = 5.9:1). f Me-DAST was used instead of XtalFluor-E. g Deoxo-Fluor was used instead of XtalFluor-E.
5.1a 5.2a
solvent
XtalFluor-E ([Et2NSF2]BF4)fluoride source
additive
NCbz
O
NCbz
F
+
5.3a
NCbz
FF
131
We next evaluated the reactivity of various cyclohexanone derivatives under the optimized
conditions (Scheme 5.2). 4-Piperidone bearing various amine protecting groups performed
well. In this case, monofluoroalkenes bearing a carbamate or sulfonyl-based protecting
groups (5.2a–c) were isolated in better yields than the one having a benzyl group (5.2d).
Cbz-, Boc-, or Ts-protected 4-aminocyclohexanone also provided the corresponding
monofluoroalkenes (5.2e–g) in moderate yields. In the case of protected 4-
hydroxycyclohexanone, the use of a benzoyl group furnished the monofluoroalkene 5.2h in
a better yield than when using a benzyl group (5.2i). An ethyl ester substituent is well
tolerated at both the 4- and 3-position. In the former, monofluoalkene 5.2j is isolated in
76% yield. In the latter, the product 5.2k is isolated in moderate yield as a mixture of
inseparable monofluoroalkenes in a ratio of 1.2:1 favoring the alkene distal to the ester
moiety. Monofluoroalkenes derived from 1,4-cyclohexanedione monoacetal (5.2l and
5.2m) were obtained in good yield. Finally, cyclohexanone bearing a phenyl group or a n-
pentyl chain at the 4-position provided the desired products 5.2n and 5.2o in 38% and 14%
respectively.
132
Scheme 5.2. Eliminative Deoxofluorination of Various Cyclohexanone Derivatives Using XtalFluor-E.a,b
NCbz
F
5.2a (79%, 5.9:1)c,d
F
NHBoc
5.2f (48%)
F
Ph
5.2n (38%)
F
C5H11
5.2o (14%)
F
NHCbz
5.2e (53%)
F
5.2m (62%, 34:1)c
O O
F
5.2l (76%, 20:1)c
O O
F
CO2Et
5.2j (76%)
NBoc
F
5.2b (66%, 4.5:1)c
X
F
X
O
F
OBz
5.2h (49%)
NBn
F
5.2d (14%, 1.6:1)c
DMA, rt, 16 h
XtalFluor-E (3 equiv)Et3N·2HF (3 equiv)
NTs
F
5.1a-o 5.2a-o
5.2c (75%, 19:1)c
F
OBn
5.2i (27%)
O
n
5.4a (n = 1 or 2)
O
Me
O2N5.4b; R = Me5.4c; R = Ph 5.4d 5.4e
unsuitable ketones
F
5.2k (42%, 1.1:1)
CO2Et
F
CO2Et
F
NHTs
5.2g (51%)
R R
OR
NCbz
O
CO2Me
133
a See the Supporting Information for the detailed experimental procedures. b Isolated yield. c Monofluoroalkene/difluoromethylene ratio determined by 19F NMR in the purified product when complete separation by flash chromatography was not possible. d On a 1 mmol scale, 75% (ratio 5.2a/5.3a = 6.1:1) of 5.2a was obtained.
A number of other ketones were also tested, but did not provide the desired
monofluoroalkenes. For instance, for 1-tetralone, no conversion was observed whereas, for
1-indanone, < 20% conversion was observed by NMR, but no fluorinated products were
formed. When using α-substituted cyclohexanones, some conversion (23% and 72% for
5.4b and 5.4c respectively) was observed, but no fluorinated products could be detected. A
moderate conversion (69%) was obtained for a five-membered ring derivative (5.4d), but
no fluorinated products were formed. Finally, when using an acyclic ketone such as 5.4e,
only degradation was observed and no fluorinated products were observed.
Our current mechanistic hypothesis is shown in Scheme 5.3. First, the ketone (5.5) would
get converted to the fluoroalkoxy-N,N-diethylaminodifluorosulfane (5.6).218 This could
occur either through HF addition to the carbonyl and reaction of the resulting α-fluoro
alcohol with XtalFluor-E as claimed for DAST219 or, alternatively, via reaction of the
ketone with XtalFluor-E followed by addition of HF as proposed for SF4.220 In any case,
from intermediate 5.6, two related pathways would be possible for the formation of
difluoromethylene 5.7 and monofluoroalkene 5.9. For difluoromethylene 5.7, an SN2
reaction on intermediate 5.6 with HF would produce 5.7 directly. Alternatively, ionization
would lead to the fluorine-stabilized carbocation 5.8,221 which could then react with HF to
produce 5.7. For monofluoroalkene 5.9, the first possibility would involve an E2
mechanism triggered by Et3N conducting directly to 5.9. Or else, ionization to carbocation
5.8 followed by elimination (E1 pathway) would also lead to monofluoroalkene 5.9. While
(218) A related alkoxy-N,N-dialkylaminodifluorosulfane has been isolated and characterized; see: Sutherland, A.; Vederas, J. C. Chem. Commun. 1999, 1739–1740. (219) (a) Middleton, W. J. J. Org. Chem. 1975, 40, 574–578. (b) Singh, R. P.; Shreeve, J. M. Synthesis 2002, 2561–2578. (220) Pustovit, Y. M.; Nazaretian, V. P. J. Fluorine Chem. 1991, 55, 29–36. (221) (a) Blint, R. J.; McMahon, T. B.; Beauchamp, J. L. J. Am. Chem. Soc. 1974, 96, 1269–1278. (b) Williamson, A. D.; LeBreton, P. R.; Beauchamp, T. B. J. Am. Chem. Soc. 1976, 98, 2705–2709.
134
the current conditions do not allow us to discriminate between the two pathways, the
observation that substrates bearing an electron-withdrawing substituent performed better
suggest that the mechanism involving the carbocation is likely not the main pathway.
Concerning the role of DMA (or DMF) for the control of the selectivity between
monofluoroalkene (5.9) and difluoromethylene (5.7), our current hypothesis222 points
toward a possible role for the hydrogen bond acceptor ability of the solvent. Indeed, both
DMA and DMF are strong hydrogen bond acceptors (pKBHX = 2.44 and 2.10 respectively)
whereas all the other solvents are a significantly weaker hydrogen bond acceptor (pKBHX =
–0.36 (toluene) to 1.28 (EtOAc)).223 Hence, with HF being an excellent hydrogen bond
donor, a significant interaction between HF with DMA would slow down the SN2 attack of
HF onto intermediate 5.6 (to produce 5.7) and would thus favor the elimination pathway
instead (leading to 5.9).
Scheme 5.3. Mechanistic Hypothesis.a
a The BF4– counterion has been omitted for clarity.
(222) We cannot exclude the potential role of DMA (or DMF) as a weak base; see ref 217. (223) Laurence, C.; Brameld, K. A.; Graton, J.; Le Questel, J.-Y.; Renault, E. J. Med. Chem. 2009, 52, 4073–4086.
Et2NSF2, HF
XR
O
5.5X
R
FO
5.6
SEt2N
FF
SN2
HF
XR
FF
5.7
XR
5.9
F
E2Et3N
E1 XR
5.8
F
HF
Et3N
135
5.5 CONCLUSION
In summary, we have described the eliminative deoxofluorination of cyclohexanone
derivatives using XtalFluor-E. Notably, this one-step procedure for the synthesis of
monofluoroalkenes occurs at room temperature using readily accessible and cost-effective
reagents without the need for a glovebox. Overall, this new approach complements the
previous reported methods. Mechanistic studies and extension of the reaction to other
ketones, including acyclic ones, are currently underway and will be reported in due course.
5.6 ACKNOWLEDGMENTS
This work was supported by the Natural Sciences and Engineering Research Council of
Canada, the Fonds de recherche du Quebec–Nature et technologies, OmegaChem, and the
Université Laval. Eliane Soligo (Université Laval) is thanked for preliminary experiments.
5.7 ANNEXE
5.7.1 Optimisation : Résultats complémentaires
En plus des résultats d’optimisation décrits dans les sections 5.4 et 5.8.2, quelques
expériences supplémentaires ont été réalisées. Ainsi, l’influence de la température a été
étudiée pour divers solvants, et pas uniquement pour les réactions effectuées dans le DMA
(Tableau 5.2). Nous avions montré que dans le cas du DMA, une augmentation de la
température diminuait le rendement de la réaction de manière draconienne (entrée 11, Table
5.1). Concernant le toluène, l’AcOEt, le THF, le DMF, le DCE (1,2-dichloroéthane) et le
DME (1,2-diméthoxyéthane), les rendements ne sont globalement pas améliorés lors du
chauffage du milieu réactionnel, et le produit difluoré est même davantage favorisé.
136
Tableau 5.2. Étude de l’influence de la température.
Entrée Solvant Température (°C)
Temps (h)
Conversion (%)a
Ratio 5.2a/5.3aa
Rendement (%)b
1 toluène
t.a. 16 100 1 : 2,4 22 2 100 °C 2 100 1 : 4,1 14 3
AcOEt t.a. 16 90 1 : 4,7 14
4 reflux 2 97 1 : 4,6 14 5
THF t.a. 16 86 1 : 1,8 24
6 reflux 2 95 1 : 2 21 7
DMF t.a. 16 100 2,5 : 1 33
8 100 °C 2 96 3,7 : 1 11 9
DCE t.a. 16 100 1 : 3,2 14
10 reflux 2 99 1 : 3,6 15 11
DME t.a. 16 59 1 : 1,9 8
12 reflux 16 78 1 : 2,6 7 a Déterminé par une analyse RMN 19F du mélange réactionnel brut après traitement. b Rendement de 5.2a déterminé par une analyse RMN 19F du mélange réactionnel brut après traitement.
Nous avons également changé le nombre d’équivalents de XtalFluor-E, passant ainsi de 1,5
à 3 (Tableau 5.3). Pour le toluène et le THF, le rendement en fluoroalcène a diminué, tandis
que pour le DMF et le DME, celui-ci a augmenté. Par ailleurs, le ratio 5.2a/5.3a s’est
accentué dans tous les cas, rendant ainsi le toluène, le THF et le DME plus enclins à la
formation des produits difluorés, et le DMF à celle des fluoroalcènes.
5.1a 5.2a
solvant, temp., temps
XtalFluor-E (1,5 équiv.)Et3N⋅2HF (3 équiv.)
NCbz
O
NCbz
F
+
5.3a
NCbz
FF
137
Tableau 5.3. Étude de l’influence du nombre d’équivalents de XtalFluor-E.
Entrée Solvant XtalFluor-E (équiv.)
Conversion (%)a
Ratio 5.2a/5.3aa
Rendement (%)b
1 toluène
1,5 100 1 : 2,4 22 2 3 100 1 : 8 10 3
THF 1,5 86 1 : 1,8 24
4 3 91 1 : 2,4 19 5
DMF 1,5 100 2,5 : 1 33
6 3 96 5,3 : 1 42 7
DME 1,5 59 1 : 1,9 8
8 3 92 1 : 3,3 15 a Déterminé par une analyse RMN 19F du mélange réactionnel brut après traitement. b Rendement de 5.2a déterminé par une analyse RMN 19F du mélange réactionnel brut après traitement.
Enfin, nous avons étudié l’influence de l’ordre d’ajout des réactifs sur le rendement de la
réaction (Tableau 5.4). Dans les conditions optimales (entrée 1), un rendement de 75 %
avait été obtenu. En retardant l’ajout du XtalFluor-E d’une heure (entrée 2), le fluoroalcène
est formé avec 64 % de rendement. En commençant par l’ajout de la cétone 5.1a, le
rendement s’élève à 44 %, tandis que lorsque 5.1a est le dernier réactif ajouté, un
rendement de 8 % est observé.
5.1a 5.2a
solvant, t.a., 16 h
XtalFluor-EEt3N⋅2HF (3 équiv.)
NCbz
O
NCbz
F
+
5.3a
NCbz
FF
138
Tableau 5.4. Étude de l’influence de l’ordre et du temps d’ajout des réactifs.
Entrée Ordre d’addition Conversion (%)a
Ratio 5.2a/5.3aa
Rendement (%)b
1 Et3N·3HF + solvant + Et3N + 5.1a + XtalFluor-E 100 6,8 : 1 75
2 Le XtalFluor-E est ajouté 1 h après l’ajout de 5.1a 92 6,4 : 1 64
3 5.1a + solvant + Et3N·3HF + Et3N + XtalFluor-E 93 5,5 : 1 44
4 Et3N·3HF + solvant + Et3N + XtalFluor-E + 5.1a 99 4 : 1 8
a Déterminé par une analyse RMN 19F du mélange réactionnel brut après traitement. b Rendement de 5.2a déterminé par une analyse RMN 19F du mélange réactionnel brut après traitement.
5.7.2 Étendue de la réaction : discussion
La méthode de fluoration développée ci-dessus comporte l’inconvénient majeur de ne
pouvoir être généralisée qu’à une faible diversité de substrats. En effet, les cétones doivent
être incluses dans des cycles à 6 carbones, les substituants en position 2 sont à éviter, et les
substituants en position 3 ou 4 ne doivent pas posséder un effet inductif donneur trop
important. Pour arriver à cette conclusion, de nombreux substrats qui n’apparaissent pas
dans l’article ont été testés. Ceux-ci sont reportés à la Figure 5.1, accompagnés de leur
conversion, ratio fluoroalcène/produit difluoré et rendement RMN. Lorsque de faibles
conversions sont indiquées, les cétones correspondantes ne sont pas ou peu réactives. Bien
souvent dans ces cas-là, un groupement électrodonneur est présent sur la molécule, et
diminue le caractère électrophile du carbone du carbonyle. Cela rend ainsi l’attaque du
fluorure peu favorable. Quant aux conversions élevées, elles représentent dans tous les cas
la dégradation du produit de départ. Aucun produit difluoré et aucun produit secondaire
5.1a 5.2a
DMA, t.a., 16 h
XtalFluor-E (3 équiv.)Et3N⋅2HF (3 équiv.)
NCbz
O
NCbz
F
+
5.3a
NCbz
FF
139
identifiable n’ont été observés. Les sous-produits formés ont été éliminés lors du traitement
nécessaire au retrait du DMA (solvant de la réaction) et n’ont donc pas pu être identifiés. Il
s’agit probablement de dérivés d’intermédiaires réactionnels.
Figure 5.1. Ensemble des cétones pour lesquelles la fluoration n’a pas été possible. a Déterminé par une analyse RMN 19F du mélange réactionnel brut après traitement. b Ratio fluoroalcène/produit difluoré déterminé par une analyse RMN 19F du mélange réactionnel brut après traitement. c Rendement du fluoroalcène correspondant déterminé par une analyse RMN 19F du mélange réactionnel brut après traitement.
O O
O
N
O
Bn
OOPh
O
MeO
Me
H
HH
O
O
O
OEtPh
O2N
O
OO
NCbz
O
CO2MeN
O H
Cbz
O
Ph
ConversionaRatiobRendement RMNc
ConversionaRatiobRendement RMNc
ConversionaRatiobRendement RMNc
1 %-
0 %
100 %-
0 %
52 %-
0 %
23 %-
0 %
100 %-
0 %
8 %-
0 %
100 %6,1 : 13 %
21 %-
0 %
46 %-
0 %
100 %-
0 %
69 %-
0 %
100 %-
0 %
100 %-
0 %
3 %-
0 %
140
Lors de la déoxofluoration classique de cétones, les chimistes de chez OmegaChem avaient
observé des produits secondaires d’élimination uniquement pour des cas de cétones
incluses dans des cycles à 6 carbones.209b La formation de fluoroalcènes pour d’autres types
de cétones était donc un défi de taille majeure, qui n’a malheureusement pu être relevé. La
réactivité unique des cycles à 6 carbones s’explique par un positionnement forcé des
atomes, qui est favorable à une élimination de type E2. Dans la forme B de l’équilibre
conformationnel (Schéma 5.4), H2ax et H6ax sont parfaitement antipériplanaires au groupe
partant OSF2NEt2, facilitant ainsi grandement la réaction d’élimination. Ceci n’est pas le
cas pour les cycles à 5 carbones, et les cétones non cycliques n’ont pas de contrainte
géométrique. D’autre part, nous avons pu remarquer que les cétones possédant des
groupements électroattracteurs en position 4 (CO2Et, NCbz, etc.) fournissaient de meilleurs
rendements que celles qui comportent des groupements donneurs (chaîne alkyle, phényle,
etc.). Les groupements attracteurs rendent H2 et H6 plus acides, ce qui les rend par
conséquent plus enclins à être déprotonnés par la triéthylamine.
Schéma 5.4. Équilibre conformationnel entre les formes A et B de l’intermédiaire 5.6.
5.8 SUPPORTING INFORMATION AVAILABLE
5.8.1 General information
The following includes additional optimization results, general experimental procedures,
specific details for representative reactions, and isolation and spectroscopic information for
XH2
OSF2NEt2
H6
F
Et3N
XOSF2NEt2
F
A B
141
the new compounds prepared. All reactions were carried out under an argon atmosphere
with dry solvents. Et2O, THF, CH3CN, CH2Cl2 and toluene were purified using a Vacuum
Atmospheres Inc. Solvent Purification System. All other commercially available
compounds were used as received. Thin-layer chromatography (TLC) analysis of reaction
mixtures was performed using Silicycle silica gel 60 Å F254 TLC plates, and visualized
under UV or by staining with potassium permanganate. Flash column chromatography was
carried out on Silicycle silica gel 60 Å, 230–400 mesh. 1H, 13C and 19F NMR spectra were
recorded in CDCl3 at ambient temperature using Agilent DD2 500 spectrometer. 1H and 13C
NMR chemical shifts are reported in ppm downfield of tetramethylsilane and are
respectively referenced to tetramethylsilane (δ = 0.00 ppm) and residual solvent (δ = 77.16
ppm for CDCl3). For 19F NMR, CFCl3 is used as the external standard. High-resolution
mass spectra were obtained on a LC/MS–TOF Agilent 6210 using electrospray ionization
(ESI). Infrared spectra were recorded using a Thermo Scientific Nicolet 380 FT-IR
spectrometer. Melting points were recorded on a Stanford Research System OptiMelt
capillary melting point apparatus and are uncorrected. Benzyl 4-oxopiperidine-1-
carboxylate (5.1a),224 tert-butyl 4-oxopiperidine-1-carboxylate (5.1b),225 1-tosyl-piperidin-
4-one (5.1c),226 4-methyl-N-(4-oxo-cyclohexyl)benzenesulfonamide (5.1g),227 4-
oxocyclohexyl benzoate (5.1h),228 4-(benzyloxy)-cyclohexan-1-one (5.1i),229 and ethyl 3-
oxocyclohexane-1-carboxylate (5.1k)230 were prepared according to literature procedures.
(224) Masse, J.; Langlois, N. Heterocycles 2009, 77, 417–432. (225) Wang, Z.; Miller, E. J.; Scalia, S. J. Org. Lett. 2011, 13, 6540–6543. (226) Jiang, Z.; Zhao, J.; Gao, B.; Chen, S.; Qu, W.; Mei, X.; Rui, C.; Ning, J.; She, D. Phosphorus Sulfur Silicon Relat. Elem. 2013, 188, 1026–1037. (227) Tsuchiya, D.; Moriyama, K.; Togo, H. Synlett 2011, 2701–2704. (228) Kamijo, S.; Amaoka, Y.; Inoue, M. Synthesis 2010, 2475–2489. (229) Dibble, D. J.; Ziller, J. W.; Woerpel, K. A. J. Org. Chem. 2011, 76, 7706–7719. (230) De Lucca, G. V. et al. J. Med. Chem. 2016, 59, 7915–7935.
142
5.8.2 Additional optimization results
Table 5.5. Additional Optimization Results for the Eliminative Deoxofluorination of 5.1a Using XtalFluor-E.
Entry XtalFluor-E (equiv)
Fluoride source (equiv)a
Solvent Additive (equiv)
Conversion (%)b
Ratio 5.2a/5.3ab
Yield (%)c
1 1.5 Et3N·2HF (3) DCEd - 100 1:3.2 14 2 1.5 Et3N·2HF (3) DMEe - 59 1:1.9 8 3 1.5 Et3N·2HF (3) TFE - 48 - 0 4 1.5 Et3N·2HF (3) HFIP - 31 - 0 5 3 Et3N·2HF (3) NMP - 90 6:1 42 6 3 Et3N·2HF (3) DMPU - 80 13:1 39 7f 3 Et3N·2HF (3) DMA - 52 18:1 18 8 3 Et3N·2HF (3) CH2Cl2/DMA (9:1) - 100 1:2.4 25 9 3 Et3N·2HF (3) CH2Cl2/DMA (1:1) - 100 2.2:1 55 10 3 Et3N·2HF (3) CH2Cl2/DMA (1:9) - 100 5.3:1 64 11 3 TBAFg (3) DMA - 97 - 0 12 3 TBAF·3H2O (3) DMA - 71 - 0 13 3 DMPU·HF (3)h DMA - 28 2.7:1 16 14i 3 Et3N·2HF (3) DMA - 80 5.8:1 46 15 3 Et3N·2HF (3) DMA NaOAc (1) 79 8.4:1 42 16 3 Et3N·2HF (3) DMA NH4OAc (1) 1 - 0 17 3 Et3N·2HF (3) DMA AgOTf (1) 93 8:1 80 18 3 Et3N·2HF (3) DMA LiOTf (1) 91 10.4:1 73 19 3 Et3N·2HF (3) DMA AgOCOCF3 (1) 88 6.6:1 53 20 3 Et3N·2HF (3) DMA AcOH (1 drop) 79 6.8:1 56 21 3 Et3N·2HF (3) DMA AcOH (1) 67 9.4:1 15 22 3 Et3N·2HF (3) DMA TFA (1 drop) 88 7.6:1 55 23 3 Et3N·2HF (3) DMA TFA (1) 90 9.5:1 38 24 3 Et3N·2HF (3) DMA conc. H2SO4 (1 drop) 89 7.8:1 52 25 3 Et3N·2HF (3) DMA conc. H2SO4 (1) 81 12:1 31
5.1a 5.2a
solvent, rt, 16 h
XtalFluor-Efluoride source
additive
NCbz
O
NCbz
F
+
5.3a
NCbz
FF
143
a Et3N·2HF is generated in situ by adding Et3N (1 equiv) to Et3N·3HF (2 equiv). b Determined by 19F NMR analysis of the crude mixture after workup. c Yield of 5.2a determined by 19F NMR analysis of the crude mixture after workup. d 1,2-Dichloroethane. e 1,2-Dimethoxyethane. f Reaction was performed at 0.1 M concentration. g A 1 M solution in THF was used. h 3 Equiv. of Et3N was also added. i XtalFluor-M was used instead of XtalFluor-E.
5.8.3 Synthesis of monofluoroalkenes from cyclohexanone derivatives
General procedure – To a solution of Et3N·3HF (218 µL, 1.33 mmol, 2 equiv) in DMA (2
mL) were successively added triethylamine (94 µL, 0.67 mmol, 1 equiv), XtalFluor-E (460
mg, 2.00 mmol, 3 equiv) and the ketone (0.67 mmol, 1 equiv). After 16 hours stirring at
room temperature under inert atmosphere, the reaction mixture was quenched with an
aqueous saturated solution of NaHCO3 and extracted with CH2Cl2 (3×). The combined
organic layers were washed with brine and water, dried over Na2SO4 and filtered through a
pad of silica gel. Solvents were evaporated, and the resulting crude material was purified by
silica gel flash chromatography.
Benzyl 4-fluoro-3,6-dihydropyridine-1(2H)-carboxylate (5.2a). Using the
general procedure on benzyl 4-oxopiperidine-1-carboxylate (0.67 mmol),
fluoroalkene 5.2a was obtained as a colorless oil (124 mg, 79%) after purification
by flash chromatography using hexane/EtOAc (85:15) as the eluent. The title
compound was contaminated with benzyl 4,4-difluoropiperidine-1-carboxylate in a 5.9:1
ratio. Major compound: IR (ATR, ZnSe) ν = 2941, 1697, 1425, 1234, 1210, 1108 cm-1; 1H
NMR (500 MHz, CDCl3) δ 7.38-7.30 (m, 5H), 5.21-5.12 (m, 3H), 4.00 (bs, 2H), 3.68 (bs,
2H), 2.31 (bs, 2H); 13C NMR (126 MHz, CDCl3) δ 158.0 (d, J = 258.3 Hz), 155.3, 136.5,
128.5 (2C), 128.1, 128.0 (2C), 99.5 (d, J = 15.9 Hz), 67.4, 41.1, 40.5, 25.9 (d, J = 22.6 Hz); 19F NMR (470 MHz, CDCl3) δ -101.6 (s, 1F); HRMS-ESI calcd for C13H15FNO2 [M+H]+
236.1081, found 236.1098.
Procedure for the 1 mmol scale of benzyl 4-oxopiperidine-1-carboxylate. To a solution of
Et3N·3HF (326 µL, 2.00 mmol, 2 equiv) in DMA (3 mL) were successively added
N
F
Cbz
144
triethylamine (139 µL, 1.00 mmol, 1 equiv), XtalFluor-E (690 mg, 3.00 mmol, 3 equiv) and
benzyl 4-oxopiperidine-1-carboxylate (233 mg, 1.00 mmol, 1 equiv). After 16 hours
stirring at room temperature under inert atmosphere, the reaction mixture was quenched
with an aqueous saturated solution of NaHCO3 and extracted with CH2Cl2 (3×). The
combined organic layers were washed with brine and water, dried over Na2SO4 and filtered
through a pad of silica gel. Solvents were evaporated, and the resulting crude material was
purified by silica gel flash chromatography using hexane/EtOAc (85:15) as the eluent.
Benzyl 4-fluoro-3,6-dihydropyridine-1(2H)-carboxylate (5.2a) was obtained as a colorless
oil (177 mg, 75%) and was contaminated with benzyl 4,4-difluoropiperidine-1-carboxylate
in a 6.1:1 ratio. Spectral data for 5.2a were identical to those described above.
tert-Butyl 4-fluoro-3,6-dihydropyridine-1(2H)-carboxylate (5.2b). Using the
general procedure on tert-butyl 4-oxopiperidine-1-carboxylate (0.67 mmol),
fluoroalkene 5.2b was obtained as a colorless oil (60 mg, 66%) after purification
by flash chromatography using hexane/EtOAc (9:1) as the eluent. The title
compound was contaminated with tert-butyl 4,4-difluoropiperidine-1-carboxylate in a 4.5:1
ratio. Major compound: IR (ATR, ZnSe) ν = 2977, 2934, 1724, 1670, 1597, 1302 1147 cm-
1; 1H NMR (500 MHz, CDCl3) δ 5.19 (d, J = 14.9 Hz, 1H), 3.92 (bs, 2H), 3.60 (bs, 2H),
2.29 (bs, 2H), 1.47 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 158.0 (d, J = 251.9 Hz), 154.6,
100.0 (d, J = 39.6 Hz), 80.0, 41.0, 40.6, 28.4 (3C), 26.1 (d, J = 14.1 Hz); 19F NMR (470
MHz, CDCl3) δ -102.1 (s, 1F); HRMS-ESI calcd for C10H16FNNaO2 [M+Na]+ 224.1057,
found 224.1082.
4-Fluoro-1-tosyl-1,2,3,6-tetrahydropyridine (5.2c). Using the general procedure
on 1-tosyl-piperidin-4-one (0.67 mmol), fluoroalkene 5.2c was obtained as a white
solid (128 mg, 75%) after purification by flash chromatography using
hexane/EtOAc (9:1) as the eluent. The title compound was contaminated with 4,4-
difluoro-1-tosylpiperidine in a 19:1 ratio. Major compound: mp: 85-86 °C; IR (ATR, ZnSe)
ν = 3044, 2924, 2857, 1712, 1596, 1462, 1337, 1145 cm-1; 1H NMR (500 MHz, CDCl3) δ
N
F
Boc
NTs
F
145
7.69-7.66 (m, 2H), 7.35-7.32 (m, 2H), 5.17 (dtt, J = 14.8, 3.5, 1.3 Hz, 1H), 3.64 (ddt, J =
5.3, 3.6, 2.6 Hz, 2H), 3.31 (td, J = 5.9, 1.8 Hz, 2H), 2.43 (s, 3H), 2.37-2.33 (m, 2H); 13C
NMR (126 MHz, CDCl3) δ 157.4 (d, J = 258.2 Hz), 143.9, 133.4, 129.8 (2C), 127.5 (2C),
98.8 (d, J = 17.9 Hz), 42.8 (d, J = 3.3 Hz), 42.7 (d, J = 4.1 Hz), 26.0 (d, J = 24.2 Hz), 21.5; 19F NMR (470 MHz, CDCl3) δ -102.2 (d, J = 14.8 Hz, 1F); HRMS-ESI calcd for
C12H14FNNaO2S [M+Na]+ 278.0621, found 278.0634.
1-Benzyl-4-fluoro-1,2,3,6-tetrahydropyridine (5.2d). Using the general
procedure on 1-benzylpiperidine-4-one (0.67 mmol), fluoroalkene 5.2d was
obtained as a colorless oil (18 mg, 14%) after purification by flash chromatography
using hexane/EtOAc (95:5) as the eluent. The title compound was contaminated
with 1-benzyl-4,4-difluoropiperidine in a 1.6:1 ratio. Spectral data for 5.2d were identical
to those previously reported.231
Benzyl (4-fluorocyclohex-3-en-1-yl)carbamate (5.2e). Using the general
procedure on benzyl (4-oxocyclohexyl)carbamate (0.67 mmol), fluoroalkene
5.2e was obtained as a white solid (87 mg, 53%) after purification by flash
chromatography using hexane/EtOAc (85:15) as the eluent. mp: 49-50 °C; IR
(ATR, ZnSe) ν = 3003, 2950, 2849, 1682, 1541, 1264, 1131 cm-1; 1H NMR (500 MHz,
CDCl3) δ 7.35-7.28 (m, 5H), 5.11-5.06 (m, 3H), 4.90 (bs, 1H), 3.86 (bs, 1H), 2.40-2.19 (m,
3H), 1.95-1.90 (m, 2H), 1.79-1.72 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 158.9 (d, J =
255.5 Hz), 155.7, 136.5, 128.5 (3C), 128.2 (2C), 99.4 (d, J = 17.0 Hz), 66.7, 45.4, 29.1 (d, J
= 8.0 Hz), 27.8 (d, J = 9.1 Hz), 23.4 (d, J = 24.7 Hz); 19F NMR (470 MHz, CDCl3) δ -102.1
(d, J = 15.6 Hz, 1F); HRMS-ESI calcd for C14H16FNNaO2 [M+Na]+ 272.1057, found
272.1060.
(231) Yang, M.-H.; Matikonda, S. S.; Altman, R. A. Org. Lett. 2013, 15, 3894–3897.
NBn
F
F
NHCbz
146
tert-Butyl (4-fluorocyclohex-3-en-1-yl)carbamate (5.2f). Using the general
procedure on tert-butyl (4-oxocyclohexyl)carbamate (0.67 mmol), fluoroalkene
5.2f was obtained as a white solid (69 mg, 48%) after purification by flash
chromatography using hexane/EtOAc (9:1) as the eluent. mp: 79-80 °C; IR
(ATR, ZnSe) ν = 3306, 2969, 2930, 1673, 1521, 1364, 1124 cm-1; 1H NMR (500 MHz,
CDCl3) δ 5.13-5.08 (m, 1H), 4.62 (bs, 1H), 3.79 (bs, 1H), 2.40-2.22 (m, 3H), 1.96-1.92 (m,
2H), 1.78-1.70 (m, 1H), 1.45 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 158.9 (d, J = 255.3
Hz), 155.3, 99.5 (d, J = 19.0 Hz), 79.3, 44.9, 29.2 (d, J = 8.1 Hz), 28.4 (3C), 28.0 (d, J =
8.9 Hz), 23.50 (d, J = 24.7 Hz); 19F NMR (470 MHz, CDCl3) δ -102.4 (d, J = 14.4 Hz, 1F);
HRMS-ESI calcd for C11H19FNO2 [M+H]+ 216.1394, found 216.1392.
N-(4-fluorocyclohex-3-en-1-yl)-4-methylbenzenesulfonamide (5.2g). Using
the general procedure on 4-methyl-N-(4-oxocyclohexyl)benzenesulfonamide
(0.329 mmol) scale, fluoroalkene 5.2g was obtained as a white solid (45 mg,
51%) after purification by flash chromatography using hexane/EtOAc (8:2) as the
eluent. mp: 95-96 °C; IR (ATR, ZnSe) ν = 3235, 2931, 2903, 2845, 1705, 1425, 1322 cm-1;
1H NMR (500 MHz, CDCl3) δ 7.78-7.75 (m, 2H), 7.31 (d, J = 8.0 Hz, 2H), 5.01 (dt, J =
16.1, 4.0 Hz, 1H), 4.47 (d, J = 7.7 Hz, 1H), 3.51-3.45 (m, 1H), 2.44 (s, 3H), 2.24-2.21 (m,
3H), 1.91-186 (m, 1H), 1.84-1.79 (m, 1H), 1.75-1.71 (m, 1H); 13C NMR (126 MHz,
CDCl3) δ 158.8 (d, J = 256.0 Hz), 143.5, 137.8, 129.8 (2C), 127.0 (2C), 99.1 (d, J = 17.5
Hz), 48.0 (d, J = 1.9 Hz), 29.6 (d, J = 8.1 Hz), 28.5 (d, J = 9.3 Hz), 23.3 (d, J = 25.0 Hz),
21.5; 19F NMR (470 MHz, CDCl3) δ -101.8 (d, J = 11.8 Hz, 1F); HRMS-ESI calcd for
C13H16FNNaO2S [M+Na]+ 292.0778, found 292.0777.
4-Fluorocyclohex-3-en-1-yl benzoate (5.2h). Using the general procedure on 4-
oxocyclohexyl benzoate (0.67 mmol), fluoroalkene 5.2h was obtained as a
colorless oil (71 mg, 49%) after purification by flash chromatography using
hexane/EtOAc (97:3) as the eluent. IR (ATR, ZnSe) ν = 2934, 2851, 1712, 1269,
1109 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.05-8.02 (m, 2H), 7.57-7.54 (m, 1H), 7.45-7.42
F
NHBoc
F
NHTs
OBz
F
147
(m, 2H), 5.31-5.27 (m, 1H), 5.17-5.12 (m, 1H), 2.53-2.40 (m, 2H), 2.36-2.30 (m, 2H), 2.14-
2.06 (m, 1H), 2.05-2.00 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 166.0, 158.7 (d, J = 254.9
Hz), 133.0, 130.4, 129.6 (2C), 128.4 (2C), 98.7 (d, J = 17.5 Hz), 68.4, 28.2 (d, J = 8.0 Hz),
26.9 (d, J = 9.1 Hz), 22.7 (d, J = 25.3 Hz); 19F NMR (470 MHz, CDCl3) δ -102.2 (d, J =
16.0 Hz, 1F); HRMS-ESI calcd for C13H14FO2 [M+H]+ 221.0972, found 221.0972.
(((4-Fluorocyclohex-3-en-1-yl)oxy)methyl)benzene (5.2i). Using the general
procedure on 4-(benzyloxy)cyclohexan-1-one (0.67 mmol), fluoroalkene 5.2i was
obtained as a colorless oil (38 mg, 27%) after purification by flash
chromatography using hexane/EtOAc (95:5) as the eluent. IR (ATR, ZnSe) ν =
2929, 2850, 1703, 1453, 1373, 1093 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.38-7.35 (m,
4H), 7.33-7.29 (m, 1H), 5.10 (dtd, J = 16.1, 3.4, 1.7 Hz, 1H), 4.62-4.55 (m, 2H), 3.71-3.67
(m, 1H), 2.41-2.33 (m, 2H), 2.28-2.16 (m, 2H), 2.03-1.97 (m, 1H), 1.94-189 (m, 1H); 13C
NMR (126 MHz, CDCl3) δ 159.0 (d, J = 254.8 Hz), 138.7, 128.4 (2C), 127.6, 127.5 (2C),
99.0 (d, J = 17.2 Hz), 72.4 (d, J = 2.0 Hz), 70.3, 28.6 (d, J = 8.1 Hz), 27.3 (d, J = 9.4 Hz),
23.4 (d, J = 25.0 Hz); 19F NMR (470 MHz, CDCl3) δ -103.1 (d, J = 16.3 Hz, 1F); HRMS-
ESI calcd for C13H16FO [M+H]+ 207.1179, found 207.1144.
Ethyl 4-fluorocyclohex-3-ene-1-carboxylate (5.2j). Using the general
procedure on ethyl 4-oxocyclohexane-1-carboxylate (0.67 mmol), fluoroalkene
5.2j was obtained as a colorless oil (87 mg, 76%) after purification by flash
chromatography using hexane/EtOAc (85:15) as the eluent. Spectral data for
5.2j were identical to those previously reported.232
Ethyl 3-fluorocyclohexene-1-carboxylate (5.2k). Using
the general procedure on ethyl 3-oxocyclohexane-1-
(232) Umemoto, T.; Singh, R. P.; Xu, Y.; Saito, N. J. Am. Chem. Soc. 2010, 132, 18199–18205.
F
OBn
F
CO2Et
CO2Et
F
CO2Et
F
+
148
carboxylate (0.67 mmol), fluoroalkenes 5.2k were obtained in a 1.1:1 ratio as a colorless oil
(48 mg, 42%) after purification by flash chromatography using hexane/EtOAc (95:5) as the
eluent. The title compounds were contaminated with traces of unidentified side-products.
IR (ATR, ZnSe) ν = 2936, 2853, 1731, 1445, 1368, 1177, 1137 cm-1; 1H NMR (500 MHz,
CDCl3) δ 5.34 (ddt, J = 16.8, 3.3, 1.5 Hz, 1H), 5.21 (d, J = 16.8 Hz, 1.1H), 4.16 (q, J = 7.3
Hz, 2H), 4.15 (q, J = 7.3 Hz, 2.2H), 3.16 (bs, 1H), 2.72-2.66 (m, 1.1H), 2.49-1.59 (m,
12.6H), 1.27 (t, J = 7.1 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3.3H); 13C NMR (126 MHz, CDCl3)
δ 174.3, 173.8, 161.3 (d, J = 257.4 Hz), 157.9 (d, J = 252.8 Hz), 101.5 (d, J = 14.9 Hz),
100.9 (d, J = 19.2 Hz), 60.7, 60.6, 39.6 (d, J = 7.2 Hz), 39.5 (d, J = 8.1 Hz), 27.7, 27.5,
25.3, 25.1, 21.6, 21.5, 20.8, 20.7, 14.2; 19F NMR (470 MHz, CDCl3) δ -98.8 (d, J = 16.7
Hz, 1F), -102.8 (dd, J = 16.7, 5.9 Hz, 1.1F); HRMS-ESI calcd for C9H14FO2 [M+H]+
173.0972, found 173.0959.
8-Fluoro-1,4-dioxaspiro[4.5]dec-7-ene (5.2l). Using the general procedure on
1,4-dioxaspiro[4.5]decan-8-one (0.67 mmol), fluoroalkene 5.2l was obtained as a
colorless oil (80 mg, 76%) after purification by flash chromatography using
pentane/Et2O (9:1) as the eluent. The title compound was contaminated with 8,8-
difluoro-1,4-dioxaspiro[4.5]decane in a 20:1 ratio. Spectral data for 5.2l were identical to
those previously reported.233
9-Fluoro-3,3-dimethyl-1,5-dioxaspiro[5.5]undec-8-ene (5.2m). Using the
general procedure on 3,3-dimethyl-1,5-dioxaspiro[5.5]undecan-9-one (0.67
mmol), fluoroalkene 5.2m was obtained as a white solid (82 mg, 62%) after
purification by flash chromatography using hexane/EtOAc (9:1) as the eluent.
The title compound was contaminated with 9,9-difluoro-3,3-dimethyl-1,5-
dioxaspiro[5.5]undecane in a 34:1 ratio. Spectral data for 5.2m were identical to those
previously reported.234
(233) Tius, M. A.; Kawakami, J. K. Synth. Commun. 1992, 22, 1461–1471.
F
O O
F
O O
149
4-Fluoro-1,2,3,6-tetrahydro-1,1’-biphenyl (5.2n). Using the general procedure
on 4-phenylcyclohexan-1-one (0.67 mmol), fluoroalkene 5.2n was obtained as a
colorless oil (44 mg, 38%) after purification by flash chromatography using hexane
as the eluent. Spectral data for 5.2n were identical to those previously reported.234
1-Fluoro-4-pentylcyclohex-1-ene (5.2o). Using the general procedure on 4-
pentylcyclohexan-1-one (0.67 mmol), fluoroalkene 5.2o was obtained as a
colorless oil (16 mg, 14%) after purification by flash chromatography using
pentane as the eluent. Spectral data for 5.2o were identical to those previously
reported.234
(234) Ye, Y.; Takada, T.; Buchwald, S. L. Angew. Chem., Int. Ed. 2016, 55, 15559–15563.
F
Ph
F
C5H11
150
CHAPITRE 6
Vers la synthèse de N-fluorosquaramides en tant que
nouveaux réactifs de fluoration électrophile
6.1 INTRODUCTION
Étant donné l’intérêt des molécules organofluorées (voir section 1.1) ainsi que les limites
des réactifs de fluoration électrophile actuels (voir section 1.2.2), nous avons réfléchi à une
nouvelle classe de réactifs de fluoration. Les caractéristiques recherchées de ces nouveaux
composés sont principalement : une grande réactivité envers des substrats variés, une bonne
solubilité dans les solvants organiques couramment utilisés en fluoration électrophile (THF,
toluène), et la possibilité de fluorer de manière énantiosélective par l’utilisation de variantes
chirales. Dans ce contexte, nous avons envisagé l’utilisation de N-fluorosquaramides
comme nouvelle classe de réactifs de fluoration électrophile.
6.1.1 Propriétés des squaramides
Les squaramides sont des amides vinylogues aromatiques dérivés de l’acide squarique
(Figure 6.1). Ce sont d’excellents accepteurs (C=O) et donneurs (N–H) de liaisons
hydrogène, mais également de très bons acides et bases de Lewis, puisque l’aromaticité des
squaramides augmente lorsqu’ils établissent des liaisons hydrogène ou qu’ils se complexent
avec des cations ou des anions.235 Ainsi, le caractère d’acide/base de Brønsted et Lewis de
ces molécules a souvent été utilisé dans le domaine de la reconnaissance moléculaire, mais
(235) Quiñonero, D.; Prohens, R.; Garau, C.; Frontera, A.; Ballester, P.; Costa, A.; Deyà, P. M. Chem. Phys. Lett. 2002, 351, 115–120.
151
aussi plus récemment en catalyse organique.236 En termes de pKa, les squaramides ont le
même pKa que les ions ammonium (pKa = 10) et sont plus acides que les amides (pKa =
15).
Figure 6.1. Structure des squaramides.
6.1.2 N-fluorosquaramides
En prenant tout cela en compte, nous pouvons raisonnablement émettre l’hypothèse que des
dérivés N-fluorés des squaramides pourraient également être utilisés comme agents de
fluoration électrophile. Les amides237 et les amines quaternaires238,239 sont d’ailleurs déjà
utilisés à cet effet (Figure 6.2). Cependant, bien que les sels d’amines quaternaires, comme
le Selectfluor, soient de bons réactifs de fluoration, ils sont très peu solubles dans les
solvants organiques habituels. Les squaramides, dont la forme acide est neutre, devraient
quant à eux pouvoir bénéficier d’une bonne solubilité dans les solvants organiques, tout en
montrant une réactivité comparable au Selectfluor et à ses dérivés.
(236) (a) Aleman, J.; Parra, A.; Jiang, H.; Jørgensen, K. A. Chem. Eur. J. 2011, 17, 6890–6899. (b) Tsakos, M.; Kokotos, C. G. Tetrahedron 2013, 69, 10199–10222. (c) Chauhan, P.; Mahajan, S.; Kaya, U.; Hack, D.; Enders, D. Adv. Synth. Catal. 2015, 357, 253–281. (d) Žabka, M.; Šebesta, R. Molecules 2015, 20, 15500. (e) Held, F. E.; Tsogoeva, S. B. Catal. Sci. Technol. 2016, 6, 645–667. (f) Han, X.; Zhou, H.-B.; Dong, C. Chem. Rec. 2016, 16, 897–906. (g) Zhao, B.-L.; Li, J.-H.; Du, D.-M. Chem. Rec. 2017, 17, 1–26. (237) Tee, O. S.; Iyengar, N. R.; Paventi, M. J. Org. Chem. 1983, 48, 761–762. (238) Selectfluor: (a) Banks, R. E.; Mohialdin-Khaffaf, S. N.; Lal, G. S.; Sharif, L.; Syvret, R. G. J. Chem. Soc., Chem. Commun. 1992, 595–596. (b) Nyffeler, P. T.; Duron, S. G.; Burkart, M. D.; Vincent, S. P.; Wong, C. Angew. Chem., Int. Ed. 2005, 44, 192–212. (239) Accufluor: Stavber, S.; Zupan, M.; Poss, A. J.; Shia, G. A. Tetrahedron Lett. 1995, 36, 6769–6772.
OO
NNHH
R R
accepteur de liaison H
donneur de liaison H
152
Figure 6.2. N-Fluorosquaramides et autres réactifs de fluoration électrophile.
D’un point de vue réactionnel, notons que les N-fluorosquaramides peuvent potentiellement
montrer des réactivités élevées envers les énolates (Schéma 6.1). On s’attend en effet à ce
que les N-fluorosquaramides, en tant que bases de Lewis, se coordonnent à l’énolate lithié,
pour qu’il en résulte ainsi la fluorocétone et l’anion lithié du squaramide. Cette
méthodologie pourrait être étendue à des exemples asymétriques en utilisant des
squaramides chiraux qui peuvent être obtenus à partir d’amines chirales relativement bon
marché.
Schéma 6.1. Réactivité attendue des N-fluorosquaramides envers les énolates.
6.1.3 Potentiel de fluoration électrophile des N-fluorosquaramides
En plus de ces considérations d’ordre physico-chimique, il est possible d’évaluer
quantitativement la force de fluoration d’un réactif donné par le calcul de l’énergie de
dissociation hétérolytique de la liaison N–F (Schéma 6.2).240,241 Ce paramètre est appelé
(240) Christe, K. O.; Dixon, D. A. J. Am. Chem. Soc. 1992, 114, 2978–2985. (241) Xue, X.-S.; Wang, Y.; Li, M.; Cheng, J.-P. J. Org. Chem. 2016, 81, 4280–4289.
NN
Cl
FNNOH
F2 BF4– 2 BF4–
Selectfluor Accufluor
OO
NNFR
R R
N-Fluorosquaramides
NF
O
1-Fluoro-2-pyridone
O O
R3R2N NR1
F
OLiO O
R3R2N NR1
Li+
OF
153
Fluorine Plus Detachment (FPD) et permet ainsi une conception rationnelle de nouveaux
réactifs de fluoration électrophile, qui peuvent ensuite être utilisés dans des cas spécifiques
selon la réactivité désirée.
Schéma 6.2. Dissociation hétérolytique de réactifs de fluoration électrophile de type N–F.
De cette manière, le groupe de Xue et Cheng a calculé l’énergie de dissociation de 130
réactifs de fluoration électrophile.241 Ils ont obtenu des valeurs de FPD variant de 112,3 à
290,4 kcal/mol dans le dichlorométhane et de 110,9 à 278,4 kcal/mol dans l’acétonitrile
(Figure 6.3).
Figure 6.3. Valeurs de FPD des principales classes de réactifs de fluoration électrophile dans le dichlorométhane. Reproduced with permission from Xue, X.-S.; Wang, Y.; Li, M.; Cheng, J.-P. J. Org. Chem. 2016, 81, 4280–4289. Copyright 2017 American Chemical Society.
L’objectif poursuivi consiste ainsi à calculer les valeurs des FPD de N-fluorosquaramides
afin de les comparer à celles de réactifs bien connus et largement répandus tels que le N-
fluorobenzènesulfonimide (NFSI) et le Selectfluor (Figure 6.4). Les énergies de
N FR
RN
R
RF+
ΔH298
FPD
154
dissociation hétérolytique (FPD) ont été obtenues par des calculs ab initio au niveau de
théorie M06-2X/6-311++G(2d, p)//M05-2X/6-31+G(d) en utilisant le modèle de solvatation
SMD pour tenir compte des effets du dichlorométhane et de l’acétonitrile.
Figure 6.4. Comparaison des valeurs calculées de FPD (kcal/mol) des N-fluorosquaramides avec celles du NFSI et du Selectfluor dans le dichlorométhane et l’acétonitrile.
Les valeurs de FPD pour le NFSI et le Selectfluor, deux des réactifs de fluoration
électrophile les plus communs, s’élèvent respectivement à 242,4 et 225,5 kcal/mol dans le
dichlorométhane, et respectivement 229,6 et 229,8 kcal/mol dans l’acétonitrile. Dans le cas
du NFSI, une valeur moins élevée dans l’acétonitrile indique que le transfert du fluor
électrophile est plus favorable dans un solvant à constante diélectrique élevée, alors que la
tendance est inversée dans le cas du Selectfluor. Les calculs effectués sur les N-
fluorosquaramides 6.1 et 6.2 ont donné des résultats de respectivement 280,3 et
259,3 kcal/mol dans le dichlorométhane, et 268,5 et 253,7 kcal/mol dans l’acétonitrile. Les
meilleurs résultats obtenus pour le squaramide 6.2 comportant un phényle peuvent
s’expliquer par une meilleure stabilisation de l’anion résultant de la perte du fluor
électrophile par le groupement phényle. De la même manière, on peut imaginer que des
substituants électroattracteurs pourraient stabiliser l’anion et abaisser par conséquent
l’énergie de dissociation hétérolytique. Cela a d’ailleurs été démontré pour des dérivés de
N-fluorobenzènesulfonimides.241
OO
NNFMe
Me Me
OO
NNFMe
Me PhNF
SSO O O O
NN
F
Cl
NFSI Selectfluor
CH2Cl2 242,4 225,5 280,3 259,3
6.1 6.2
CH3CN 229,6 229,8 268,5 253,7
155
6.1.4 Potentiel de fluoration radicalaire des N-fluorosquaramides
En plus de pouvoir être impliqués dans des réactions de fluoration électrophile, les réactifs
de type N–F peuvent être utilisés en fluoration radicalaire.242 Dans le but de mieux
comprendre leur réactivité, le groupe de Xue et Cheng a calculé les enthalpies de
dissociation homolytique (Bond Dissociation Enthalpies, BDE) de 88 réactifs de fluoration
N–F (Schéma 6.3, Figure 6.5).243 Les valeurs obtenues oscillent entre 49,3 et 80,0 kcal/mol
dans l’acétonitrile, mais ne suivent pas les mêmes tendances que celles obtenues en
fluoration électrophile. Par exemple, ils ont montré que des N-fluorosulfonamides sont
potentiellement de bons réactifs en fluoration radicalaire, alors qu’ils se trouvent parmi les
plus faibles en fluoration électrophile.
Schéma 6.3. Dissociation homolytique de réactifs de fluoration électrophile de type N–F.
Figure 6.5. Valeurs de BDE des principales classes de réactifs de fluoration N–F dans l’acétonitrile. Reproduced with permission from Yang, J.-D.; Wang, Y.; Xue, X.-S.; Cheng, J.-P. J. Org. Chem. 2017, 82, 4129–4135. Copyright 2017 American Chemical Society.
(242) (a) Rueda-Becerril, M.; Chatalova Sazepin, C.; Leung, J. C. T.; Okbinoglu, T.; Kennepohl, P.; Paquin, J.-F.; Sammis, G. M. J. Am. Chem. Soc. 2012, 134, 4026–4029. (b) Chatalova Sazepin, C.; Hemelaere, R.; Paquin, J.-F.; Sammis, G. Synthesis 2015, 47, 2554–2569. (243) Yang, J.-D.; Wang, Y.; Xue, X.-S.; Cheng, J.-P. J. Org. Chem. 2017, 82, 4129–4135.
N FR
RN
R
RF+
ΔH298
BDE
156
De la même manière que précédemment, les enthalpies de dissociation homolytique des N-
fluorosquaramides 6.1 et 6.2 ont été calculées pour être comparées au NFSI et au
Selectfluor, qui affichent des valeurs de respectivement 63,4 et 64,0 kcal/mol dans
l’acétonitrile (Figure 6.6). Les résultats obtenus pour les N-fluorosquaramides sont bien
meilleurs : 55,5 kcal/mol pour le squaramide 6.1 et 46,5 pour le squaramide 6.2. Ceci
s’explique principalement par l’importante stabilisation des radicaux par résonance avec le
noyau du squaramide, ainsi qu’avec le phényle dans le second cas.
Figure 6.6. Comparaison des valeurs calculées de BDE (kcal/mol) des N-fluorosquaramides avec celles du NFSI et du Selectfluor dans l’acétonitrile.
Pour finir, cela vaut la peine de mentionner que les paramètres FPD et BDE sont des
paramètres thermodynamiques et peuvent donc seulement être bien appliqués dans des
réactions contrôlées thermodynamiquement. Dans le cas de l’intervention de facteurs
cinétiques, une analyse détaillée des états de transition est nécessaire.
6.2 RÉSULTATS ET DISCUSSION
Les squaramides sont aisément accessibles par une synthèse en deux étapes à partir de
l’acide squarique (Schéma 6.4).244 La première étape est la condensation de l’acide avec un
solvant alcool, puis les deux alcoolates sont substitués par des amines. Cette synthèse est
(244) Tietze, W. F. ; Arlt, M. ; Beller, M. ; Glüsenkamp, K.-H. ; Jähde, E. ; Rajewky, M. F. Chem. Ber. 1991, 124, 1215–1221.
OO
NNFMe
Me Me
OO
NNFMe
Me PhNF
SSO O O O
NN
F
Cl
NFSI Selectfluor
CH3CN 63,4 64,0 55,5 46,5
6.1 6.2
157
modulaire, puisqu’un équivalent d’amine peut être ajouté, suivi d’un autre équivalent d’une
amine différente.
Schéma 6.4. Stratégie de synthèse des squaramides.
De cette manière, trois squaramides modèles ont été synthétisés pour servir de substrat de
départ à la mise au point d’une méthode de fluoration (Figure 6.7). Ces squaramides ont été
choisis de telle sorte que le carbone porté par l’amine secondaire ne soit pas lié à un
hydrogène, puisque ceci pourrait engendrer une libération de HF lors de la réaction de
fluoration.
Figure 6.7. Squaramides modèles.
Deux manières d’introduire l’atome de fluor peuvent être envisagées (Schéma 6.5). La
première voie repose sur l’utilisation de fluor élémentaire après déprotonation préalable du
squaramide,245 tandis que la deuxième voie serait une fluoration par transfert en utilisant le
Selectfluor238 ou le XeF2246 comme source de fluor. Ces deux approches sont
(245) Sandford, G. J. Fluorine Chem. 2007, 128, 90–104. (246) Tius, M. A. Tetrahedron 1995, 51, 6605–6634.
O O
N NR2
R1
HR3
O O
HO OH
O O
N OEtR2
R1
O O
EtO OEt
EtOHR1R2NH(1 équiv.) R3NH2
OO
NEt2NH
Ph
6.3
OO
NPh2NH
Ph
OO
NNHPh
6.4 6.5
158
complémentaires en termes d’échelle et d’équipement nécessaire. Bien que la fluoration
directe soit souhaitable à grande échelle, elle nécessite des équipements spécialisés. La
fluoration par transfert, quant à elle, est limitée aux petites échelles (< 1 g), mais ne
nécessite pas de verrerie spéciale. Dans le cadre de ce projet, c’est la méthode par transfert
qui a initialement été explorée.
Schéma 6.5. Voies de fluoration des squaramides.
Un long travail d’optimisation pour l’introduction de l’atome de fluor a été réalisé et
quelques résultats clés ont été reportés dans le Tableau 6.1. Les conditions choisies
initialement correspondent à l’entrée 1 (entrées 9 et 10 pour les squaramides 6.4 et 6.5), où
la réaction a été effectuée dans l’acétonitrile pendant 16 heures en utilisant le NaH comme
base et le Selectfluor comme agent de fluoration. Des conversions de 0 à 54 % ont été
obtenues, mais aucun squaramide fluoré n’a été formé. D’autres solvants ont ensuite été
utilisés, à savoir le THF, le DMF et le DMA (diméthylacétamide) (entrées 2-4). Ceux-ci ont
donné des conversions de 32 à 64 %, mais aucun produit fluoré n’a été observé.
L’optimisation a été poursuivie en effectuant la réaction par chauffage aux micro-ondes
(entrée 5), en changeant de base (LiHMDS et NaHMDS, entrées 6 et 7), ainsi qu’en
utilisant le NFSI à la place du Selectfluor (entrée 8). Dans tous les cas, les spectres
RMN 19F n’ont pas montré l’apparition de squaramide fluoré. Les spectres RMN 1H
indiquent que les squaramides de départ ont été retrouvés en fin de réaction, en plus de
quelques dégradations.
O O
N NR2
R1
H
R3
O O
N NR2
R1
F
R3
1) NaH2) 10 % F2/N2
1) NaH2) Selectfluor
Fluorationdirecte
Fluorationpar transfert
159
Tableau 6.1. Tentatives de fluoration des squaramides.
a Déterminé par analyses RMN 1H et 19F du produit brut en utilisant le 2-fluoro-4-nitrotoluène comme standard interne. b Le NFSI est utilisé à la place du Selectfluor.
La réactivité de ces squaramides a ensuite été étudiée en les faisant réagir avec d’autres
électrophiles. Les réactions de méthylation ont montré de bons résultats, avec des
rendements isolés compris entre 47 et 82 % (Schéma 6.6), indiquant de cette manière le
potentiel caractère nucléophile des squaramides 6.3-6.5.
Selectfluor (1,1 équiv.)base (1,1 équiv.)
solvant (0,2 M)temps, temp.
OO
NNHR2
R1 R3
6.3-6.5
OO
NNFR2
R1 R3
Entrée Substrat Base Solvant Temps Température Conversion (%)a
Rendement RMN (%)a
1 6.3 NaH CH3CN 16 h 0 °C à t.a. 54 0 2 6.3 NaH THF 16 h 0 °C à t.a. 56 0 3 6.3 NaH DMF 16 h 0 °C à t.a. 64 0 4 6.3 NaH DMA 16 h 0 °C à t.a. 32 0 5 6.3 - CH3CN 10 min 150 °C (µW) 66 0 6 6.3 LiHMDS THF 16 h 0 °C à t.a. 54 0 7 6.3 NaHMDS THF 16 h 0 °C à t.a. 59 0 8b 6.3 NaH THF 16 h 0 °C à t.a. 70 0 9 6.4 NaH CH3CN 16 h 0 °C à t.a. 0 0
10 6.5 NaH CH3CN 16 h 0 °C à t.a. 30 0
160
Schéma 6.6. Méthylation des squaramides.
La chloration et la bromation des squaramides ont également été tentées, mais aucun
résultat fructueux n’a été obtenu (Schéma 6.7 et Schéma 6.8).247,248
Schéma 6.7. Chloration des squaramides.
(247) Conditions de chloration tirées de : Xu, C.; Ma, B.; Shen, Q. Angew. Chem., Int. Ed. 2014, 53, 9316–9320. (248) Conditions de bromation tirées de : Duhamel, L.; Plé, G.; Angibaud, P.; Desmurs, J. R. Synth. Commun. 1993, 23, 2423–2433.
OO
Et2N NPh
Me
OO
Ph2N NMe
Ph
OO
N NPh Me
MeI (1 équiv.)NaH (1,1 équiv.)
DMF, 0 °C à t.a., 6 h
OO
NNHR2
R1 R3
6.3-6.5
OO
NNMeR2
R1 R3
6.6-6.8
6.6; 47 % 6.7; 64 % 6.8; 82 %
t-BuOCl (1,35 équiv.)
MeOH, t.a., 24 h
OO
NNHR2
R1 R3
6.3-6.5
OO
NNClR2
R1 R3
161
Schéma 6.8. Bromation du squaramide 6.4.
En plus de cela, des expériences de deutération ont été réalisées. Celles-ci ont montré une
déprotonation quantitative quand le squaramide 6.4 réagit avec le NaH dans l’acétonitrile
ou le DMF (Schéma 6.9).
Schéma 6.9. Deutération du squaramide 6.4.
6.3 CONCLUSION
Nous avons pu calculer par des calculs ab initio les énergies de dissociation hétérolytique et
homolytique de dérivés de N-fluorosquaramides. Les valeurs obtenues nous ont encouragés
à consacrer nos efforts à la synthèse de ces composés dans le but de les utiliser comme
réactifs de fluoration électrophile. Malheureusement, aucune fluoration n’a été possible.
Seules la méthylation et la deutération se sont avérées fructueuses. D’autres types de
structures, telles que des N-fluorosulfonylhydrazines, restent encore à étudier.
AcOBr (1,5 équiv.)
CH2Cl2, t.a., 3 h
OO
NNHPh
6.4
OO
NNBrPh
1) NaH (1,1 équiv.)solvant, 0 °C, 30 min
2) D2O, 0 °C, 5 min
OO
NNHPh
6.4
OO
NNDPh
6.9quant.
162
6.4 MÉTHODES COMPUTATIONNELLES
Geometry optimizations, vibrational frequencies, and thermal energy corrections were
performed with the M05-2X functional249 in conjunction with the standard 6-31+G(d)250
basis set. The SMD solvatation model251 was used to account for the effects of
dichloromethane and acetonitrile solutions. To obtain more accurate electronic energies,
single-point energy calculations were performed at the SMD-M06-2X/6-311++G(2d, p)
level of theory with the M05-2X/6-31+G(d) optimized structures. The spin state of each
structure is a singlet except for that of F+, which is triplet, and for that of radicalar
compounds, which is a doublet. Structures were generated using Avogadro. All calculations
were carried out with GAMESS-US.252
6.5 PARTIE EXPÉRIMENTALE
6.5.1 Informations générales
All reactions were carried out under an argon atmosphere with dry solvents. THF, CH3CN
and CH2Cl2 were purified using a Vacuum Atmospheres Inc. Solvent Purification System.
All other commercially available compounds were used as received. Thin-layer
chromatography (TLC) analysis of reaction mixtures was performed using Silicycle silica
gel 60 Å F254 TLC plates, and visualized under UV or by staining with potassium
permanganate. Flash column chromatography was carried out on Silicycle silica gel 60 Å,
230–400 mesh. 1H, 13C and 19F NMR spectra were recorded in CDCl3 at ambient
temperature using Agilent DD2 500 spectrometer. 1H and 13C NMR chemical shifts are
reported in ppm downfield of tetramethylsilane and are respectively referenced to
(249) (a) Zhao, Y.; Truhlar, D. G. Acc. Chem. Res. 2008, 41, 157–167. (b) Zhao, Y.; Truhlar, D. G. Chem. Phys. Lett. 2011, 502, 1–13. (250) Hehre, W. J.; Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab Initio Molecular Orbital Theory; Wiley: New York, 1986. (251) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B 2009, 113, 6378–6396. (252) Schmidt, M.W.; Baldridge, K. K.; Boatz, J. A.; Elbert, S. T.; Gordon, M. S.; Jensen, J. H.; Koseki, S.; Matsuraga, N.; Nguyen, K. A.; Su, S. J.; Windus, T. L.; Dupuis, M.; Montgomery, J. A. J. Comput. Chem. 1993, 14, 1347–1363.
163
tetramethylsilane (δ = 0.00 ppm) and residual solvent (δ = 77.16 ppm for CDCl3). For 19F
NMR, CFCl3 is used as the external standard. High-resolution mass spectra were obtained
on a LC/MS–TOF Agilent 6210 using electrospray ionization (ESI). Infrared spectra were
recorded using a Thermo Scientific Nicolet 380 FT-IR spectrometer. Melting points were
recorded on a Stanford Research System OptiMelt capillary melting point apparatus and are
uncorrected.
6.5.2 Synthèse des produits de départ
6.5.2.1 Synthèse du squaramide 6.3
3,4-Diethoxycyclobut-3-ene-1,2-dione. Squaric acid (1.00 g, 8.77 mmol)
was refluxed in EtOH (10 mL) for 3 hours after which the solvent was
removed under vacuum. Another 10 mL of EtOH was added and it was
refluxed for another 30 min. This procedure was repeated 3 times to give the 3,4-
diethoxycyclobut-3-ene-1,2-dione as a colorless oil. The crude product was used without
purification for the second step.
3-(Diethylamino)-4-ethoxycyclobut-3-ene-1,2-dione. A solution of
diethylamine (0.333 mL, 3.22 mmol, 1.1 equiv) in diethyl ether (15 mL)
was added dropwise to a solution of 3,4-diethoxycyclobut-3-ene-1,2-dione
(500 mg, 2.93 mmol, 1 equiv) in 5 mL of diethyl ether, and the reaction was stirred at room
temperature for 20 hours. Then, the solvent was evaporated and the title compound was
obtained as a pale yellow solid (527 mg, 91% over 2 steps) after purification by flash
chromatography using EtOAc as the eluent. Spectral data were identical to those previously
reported.253
(253) Sanna, E.; López, C.; Ballester, P.; Rotger, C.; Costa, A. Eur. J. Org. Chem. 2015, 2015, 7656–7660.
OO
EtO OEt
OO
Et2N OEt
164
3-(Diethylamino)-4-(phenylamino)cyclobut-3-ene-1,2-dione (6.3). To
a solution of 3-(diethylamino)-4-ethoxycyclobut-3-ene-1,2-dione (2.29 g,
11.6 mmol, 1 equiv) in MeOH (100 mL) was added aniline (1.59 mL,
17.4 mmol, 1.5 equiv) and N,N-diisopropylethylamine (DIPEA) (15.2 mL, 87 mmol,
5 equiv). The reaction was stirred at 60 °C for 24 hours. Then, the solvent was evaporated
and the squaramide 6.3 was obtained as a pale yellow solid (1.791 g, 63%) after
purification by flash chromatography using hexane/EtOAc (1:1) as the eluent. mp: 139-140
°C; IR (ATR, ZnSe) ν = 3170, 2968, 2930, 1782, 1662, 1589, 1510, 1417, 1297 cm-1; 1H
NMR (500 MHz, DMSO-d6) δ 9.30 (s, 1H), 7.33-7.28 (m, 2H), 7.24-7.21 (m, 2H), 7.07-
7.03 (m, 1H), 3.67 (bs, 4H), 1.19 (t, J = 7.1 Hz, 6H); 13C NMR (126 MHz, DMSO-d6) δ
186.0, 181.0, 169.2, 163.8, 139.2, 128.9 (2C), 123.4, 120.9 (2C), 44.2 (2C), 15.2 (2C);
HRMS calcd for C14H16N2NaO2 [M+Na]+ 267.1104, found 267.1091.
6.5.2.2 Synthèse du squaramide 6.4
3,4-Bis(tert-butylamino)cyclobut-3-ene-1,2-dione. Diethyl squarate
(1.00 g, 5.88 mmol) was cooled to 0 °C, followed by the addition of 2
M tert-butyl amine in THF (8 mL). After the complete addition of tert-
butyl amine, the reaction was stirred at room temperature for 24 hours.
The precipitated solid was filtered, washed with diethyl ether (2×), and dried under vacuum
to give the pure title product as a pale yellow solid (926 mg, 70%). Spectral data were
identical to those previously reported.254
3-(tert-Butyl(phenyl)amino)-4-(tert-butylamino)cyclobut-3-ene-1,2-
dione (6.4). To a solution of CuI (189 mg, 0.99 mmol, 0.5 equiv) in
anhydrous DMF (2 mL) were added L-proline (114 mg, 0.99 mmol,
0.5 equiv) and K2CO3 (820 mg, 5.94 mmol, 3 equiv). The mixture was
stirred at room temperature for 20 minutes. Then, bromobenzene (633 µL, 5.94 mmol,
(254) Ramalingam, V.; Bhagirath, N.; Muthyala, R. S. J. Org. Chem. 2007, 72, 3976–3979.
OO
N NPh H
OO
N NH H
OO
Et2N N Ph
H
165
3 equiv) and 3,4-bis(tert-butylamino)cyclobut-3-ene-1,2-dione (444 mg, 1.98 mmol,
1 equiv) were added. The reaction temperature was increased to 120 °C and maintained for
18 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc,
filtered, and concentrated under vacuum. The squaramide 6.4 was obtained as a pale yellow
solid (386 mg, 65%) after purification by flash chromatography using hexane/EtOAc (6:4)
as the eluent. Spectral data for 6.4 were identical to those previously reported.254
6.5.2.3 Synthèse du squaramide 6.5
3,4-Diisopropoxycyclobut-3-ene-1,2-dione. Squaric acid (1.00 g, 8.77
mmol) was refluxed in i-PrOH (20 mL) for 3 days after which the
solvent was removed under vacuum. Another 20 mL of i-PrOH was
added and it was refluxed for another 16 hours. After evaporation of the solvent, crude 3,4-
diisopropoxycyclobut-3-ene-1,2-dione was obtained as a colorless oil and used without
purification for the second step.
3-(Diphenylamino)-4-isopropoxycyclobut-3-ene-1,2-dione. A solution
of diphenylamine (1.63 g, 9.65 mmol, 1.1 equiv) in i-PrOH was added to
a solution of 3,4-diisopropoxycyclobut-3-ene-1,2-dione (1.74 g, 8.77
mmol, 1 equiv) in the same solvent. Concentrated hydrochloric acid (0.18 mL) was added
to the mixture, which was refluxed for 7 days. Then, the solvent was evaporated and the
title compound was obtained as a yellow solid (2.172 g, 81% over 2 steps) after purification
by flash chromatography using hexane/EtOAc (6:4) as the eluent. mp: 153-154 °C; IR
(ATR, ZnSe) ν = 2985, 1796, 1720, 1576, 1488, 1392, 1348, 1268 cm-1; 1H NMR (500
MHz, DMSO-d6) δ 7.44-7.39 (m, 4H), 7.34-7.30 (m, 2H), 7.21-7.18 (m, 4H), 5.25 (hept, J
= 6.2 Hz, 1H), 1.23 (d, J = 6.2 Hz, 6H); 13C NMR (126 MHz, DMSO-d6) δ 187.3, 186.2,
179.2, 170.4, 141.3 (2C), 129.3 (4C), 127.3 (2C), 125.6 (2C), 78.0, 22.9 (2C); HRMS calcd
for C19H17NNaO3 [M+Na]+ 330.1101, found 330.1075.
OO
i-PrO Oi-Pr
OO
Ph2N Oi-Pr
166
3-(Diphenylamino)-4-(phenylamino)cyclobut-3-ene-1,2-dione (6.5).
To a solution of 3-(diphenylamino)-4-isopropoxycyclobut-3-ene-1,2-
dione (1.00 g, 3.26 mmol, 1 equiv) in MeOH (25 mL) was added aniline
(445 µL, 4.88 mmol, 1.5 equiv) and DIPEA (2.84 mL, 16.3 mmol,
5 equiv). The reaction was stirred at 60 °C for 4 days. Then, the solvent was evaporated and
the squaramide 6.5 was obtained as a yellow solid (352 mg, 32%) after purification by flash
chromatography using hexane/EtOAc (1:1) as the eluent. mp: 220-224 °C; IR (ATR, ZnSe)
ν = 3361, 1785, 1739, 1721, 1569, 1489, 1433 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 9.56
(bs, 1H), 7.32-7.28 (m, 4H), 7.16 (t, J = 7.4 Hz, 2H), 7.12 (t, J = 7.9 Hz, 2H), 7.09-7.06 (m,
4H), 6.98 (d, J = 7.8 Hz, 2H), 6.92 (t, J = 7.4 Hz, 1H); 13C NMR (126 MHz, DMSO-d6) δ
187.7, 185.3, 168.1, 165.6, 141.6 (2C), 138.7, 129.4 (4C), 129.0 (2C), 126.2 (2C), 124.5
(4C), 124.1, 120.8 (2C); HRMS calcd for C22H17N2O2 [M+H]+ 341.1284, found 341.1290.
6.5.3 Tentatives de fluoration, chloration et bromation des squaramides
6.5.3.1 Fluoration des squaramides
Typical procedure (entries 1, 9, 10) – To a solution of the squaramide (0.20 mmol,
1 equiv) in acetonitrile (1 mL) was added NaH 60% dispersion in mineral oil (0.22 mmol,
1.1 equiv) at 0 °C under inert atmosphere. After 1 hour of stirring at room temperature,
Selectfluor was added and stirring was continued at room temperature for 16 hours. The
reaction mixture was quenched with H2O and extracted with EtOAc (3×). The combined
organic layers were washed with brine and water, dried over Na2SO4, filtered and
concentrated under vacuum. 1H and 19F NMR analyses did not show the appearance of the
fluorinated product, but the recovery of the starting material with some degradations.
6.5.3.2 Chloration des squaramides
To a suspension of the squaramide (0.5 mmol, 1 equiv) in MeOH (1 mL) was added
tBuOCl (0.67 mmol, 1.35 equiv) under inert atmosphere. After 24 hours of stirring at room
OO
Ph2N NH
Ph
167
temperature, the reaction mixture was quenched with water and extracted with CH2Cl2
(3×). The combined organic layers were dried (Na2SO4) and concentrated under vacuum. 1H NMR analysis did not show the appearance of the chlorinated product, but the recovery
of the starting material with some degradations.
6.5.3.3 Bromation des squaramides
The squaramide 6.4 (50 mg, 0.166 mmol, 1 equiv) was dissolved in 1.9 mL of a solution
0.13 M of AcOBr in CH2Cl2 (0.250 mmol, 1.5 equiv) under inert atmosphere. After 3 hours
of stirring at room temperature and away from light, the reaction mixture was concentrated
under vacuum. 1H NMR analysis did not show the appearance of the brominated product,
but the recovery of the starting material in place.
6.5.4 Méthylation des squaramides
General procedure – To a solution of the squaramide (1 equiv) in DMF (0.2 M) was
added NaH 60% dispersion in mineral oil (1.1 equiv) at 0 °C under inert atmosphere. After
30 minutes of stirring at room temperature, iodomethane was added at 0 °C and stirring was
continued at room temperature for 6 hours. The reaction mixture was quenched with H2O
and extracted with EtOAc (3×). The combined organic layers were washed with brine and
water, dried over Na2SO4, filtered and concentrated under vacuum. The resulting crude
material was purified by silica gel flash chromatography.
3-(Diethylamino)-4-(methyl(phenyl)amino)cyclobut-3-ene-1,2-dione
(6.6). Using the general procedure on squaramide 6.3 (100 mg, 0.409
mmol), the methylated squaramide 6.6 was obtained as a pale yellow
solid (49 mg, 47%) after purification by flash chromatography using
hexane/EtOAc (7:3) as the eluent. mp: 100-101 °C; IR (ATR, ZnSe) ν = 2965, 2928, 2869,
1781, 1682, 1576, 1489, 1446, 1276 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.41-7.38 (m,
OO
Et2N N Ph
Me
168
2H), 7.20-7.17 (m, 1H), 7.04-7.01 (m, 2H), 3.77 (s, 3H), 3.15 (bs, 4H), 0.99 (t, J = 7.2 Hz,
6H); 13C NMR (126 MHz, CDCl3) δ 186.6, 185.2, 170.6, 166.0, 144.8, 129.7 (2C), 125.1,
121.0 (2C), 44.1, 39.1 (2C), 13.8 (2C); HRMS-ESI calcd for C15H18N2NaO2 [M+Na]+
281.1260, found 281.1255.
3-(tert-Butyl(methyl)amino)-4-(tert-butyl(phenyl)amino)cyclobut-
3-ene-1,2-dione (6.7). Using the general procedure on squaramide 6.4
(100 mg, 0.333 mmol), the methylated squaramide 6.7 was obtained as
a pale yellow solid (67 mg, 64%) after purification by flash
chromatography using hexane/EtOAc (75:25) as the eluent. mp: 141-142 °C; IR (ATR,
ZnSe) ν = 2978, 2916, 1766, 1686, 1537, 1380, 1363, 1159 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.36-7.32 (m, 3H), 7.18-7.15 (m, 2H), 2.34 (s, 3H), 1.51 (s, 9H), 1.17 (s, 9H); 13C
NMR (126 MHz, CDCl3) δ 187.0; 185.7, 177.5, 176.0, 141.1, 130.4 (2C), 128.2 (2C),
127.6, 59.9, 57.2, 35.8, 29.8 (3C), 28.0 (3C); HRMS-ESI calcd for C19H26N2NaO2 [M+Na]+
337.1886, found 377.1875.
3-(Diphenylamino)-4-(methyl(phenyl)amino)cyclobut-3-ene-1,2-
dione (6.8). Using the general procedure on squaramide 6.5 (100 mg,
0.294 mmol), the methylated squaramide 6.8 was obtained as a yellow
solid (85 mg, 82%) after purification by flash chromatography using hexane/EtOAc (7:3) as
the eluent. mp: 213-216 °C; IR (ATR, ZnSe) ν = 2927, 1777, 1703, 1570, 1486, 1409 cm-1;
1H NMR (400 MHz, CDCl3) δ 7.17-6.9 (m, 9H), 6.79-6.75 (m, 4H), 6.63-6.60 (m, 2H),
3.70 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 188.7, 185.3, 169.8, 166.0, 142.6, 141.3 (2C),
128.97 (4C), 128.95 (2C), 125.8 (2C), 125.4, 123.6 (4C), 121.7 (2C), 39.4; HRMS-ESI
calcd for C23H18N2NaO2 [M+Na]+ 377.1260, found 377.1239.
OO
N NPh Me
OO
Ph2N NMe
Ph
169
6.5.5 Expériences de deutération
To a solution of the squaramide 6.4 (50 mg, 0.166 mmol, 1 equiv) in the solvent (DMF or
THF) was added NaH 60% dispersion in mineral oil (7.3 mg, 0.183 mmol, 1.1 equiv) at 0
°C under inert atmosphere. After 30 minutes of stirring at 0 °C, 1 mL of D2O was added at
0 °C and stirring was continued for 5 minutes. The reaction mixture was extracted with
CH2Cl2 (3×) and the combined organic layers were washed with brine and water, dried
(Na2SO4) and concentrated under vacuum. The corresponding deuterated squaramide 6.9
was obtained with ca. 99% NMR yield.
170
CHAPITRE 7
Conclusion et perspectives
7.1 RETOUR SUR LES OBJECTIFS
7.1.1 Utilisation du XtalFluor-E en synthèse organique
Une grande partie des travaux de doctorat a été consacrée à la mise au point de nouvelles
méthodes de synthèse utilisant le XtalFluor-E comme agent activant. Les avantages de ce
réactif sont principalement une facilité d’utilisation, ainsi qu’un coût relativement faible en
comparaison avec d’autres agents activants.
Des méthodes simples ont été développées pour la synthèse d’isonitriles, de nitriles,
d’esters perfluorés et de monofluoroalcènes cycliques (Schéma 7.1). Des rendements
modérés à excellents ont été obtenus dans des conditions relativement douces, et ces
réactions ont été effectuées sur toutes sortes de substrats, que ce soit des aromatiques,
aliphatiques, benzyliques, vinyliques, etc.. Des produits chiraux énantiopurs ont également
pu être obtenus lors de la synthèse des nitriles et des esters perfluorés. Ainsi, le nombre
élevé d’exemples décrits dans chacun des cas souligne l’étendue des quatre réactions
développées.
Par ailleurs, nous avons démontré une fois de plus la grande utilité du XtalFluor en
synthèse organique et nous avons contribué à l’étude de sa réactivité avec des substrats
variés.
171
Schéma 7.1. Utilisation du XtalFluor-E pour la synthèse d’isonitriles, nitriles, esters perfluorés et monofluoroalcènes cycliques.
7.1.2 Développement de nouveaux réactifs de fluoration électrophile
La deuxième partie de cette thèse consistait à développer de nouvelles sources de fluor
électrophile, et plus particulièrement des N-fluorosquaramides. Par chimie
computationnelle, nous avons pu mettre en évidence le pouvoir de fluoration de ces
composés, mais la synthèse de ceux-ci a échoué. De la même manière, la chloration et la
bromation des squaramides n’ont pas été fructueuses, tandis que la méthylation et la
deutération ont montré de bons résultats. Ceci nous indique ainsi que la déprotonation est
possible, mais l’halogénation demeure problématique.
7.2 PERSPECTIVES
7.2.1 Étendre la liste des réactions utilisant le XtalFluor-E comme agent activant
Les perspectives relatives à l’utilisation du XtalFluor comme agent activant sont très
nombreuses. Une grande variété de fonctionnalités peuvent être activées et réagir avec
toutes sortes d’autres nucléophiles. Parmi les nombreuses possibilités, nous pouvons mettre
en évidence deux exemples de réactions envisageables.
R O
ORf
22-96 %40 exemples
C NR
N CR
R = aryle, alkyle, benzyle, vinyleRf = CH2CF3, CH(CF3)2, CH2C2F5, CH2C3F7, CH2C7F15, CH2C8F17
34-99 %14 exemples
38-99 %26 exemples
R OH
ORf OH+
NH
O
HR
R
O
NH2 R H
N OHou
N SF
F
BF4XtalFluor-E
X XO F14-79 %
15 exemples
172
Tout d’abord, il serait intéressant de se pencher sur la synthèse de monofluoroalcènes à
partir de cétones pour des composés non cycliques (Schéma 7.2). Des méthodes pour
effectuer cette transformation ont déjà été décrites dans la littérature, mais aucune d’entre
elles ne combine à la fois une facilité d’exécution, l’utilisation de réactifs peu coûteux, de
bons rendements et des conditions douces. Pour parvenir à cet objectif, une réoptimisation
complète de la réaction de déxofluoration éliminatrice décrite au Chapitre 5 serait
nécessaire. Le point de départ de cette nouvelle optimisation pourrait être l’ajout d’additifs,
étant donné les résultats positifs obtenus avec l’ajout de AgOTf.
Schéma 7.2. Synthèse de monofluoroalcènes à partir de cétones.
Ensuite, dans la continuité des travaux de benzylation de Friedel-Crafts par activation
d’alcools benzyliques,255 nous pourrions tenter la même réaction à partir de dérivés de
phénylcyclopropanol (Schéma 7.3). Le motif cyclopropyle est d’ailleurs très utile en chimie
médicinale puisqu’il apparaît fréquemment dans les médicaments de stades préclinique et
clinique.256
Schéma 7.3. Benzylation de Friedel-Crafts par activation de dérivés de phénylcyclopropanol.
(255) Desroches, J.; Champagne, P. A.; Benhassine, Y.; Paquin, J.-F. Org. Biomol. Chem. 2015, 13, 2243–2246. (256) Talele, T. T. J. Med. Chem. 2016, 59, 8712–8756.
R1 R1R2
OR2
FXtalFluor-E
X
OH
X
ArAr–H
XtalFluor-ERR
173
7.2.2 Réactifs de fluoration électrophile : concevoir de nouvelles structures
Alors que la synthèse des N-fluorosquaramides n’a pas été fructueuse, d’autres réactifs de
fluoration électrophile pourraient être proposés. Nous envisageons ainsi la synthèse de
dérivés de N-fluorosulfonylhydrazine (Figure 7.1). Il a en effet été démontré précédemment
dans la littérature que des N-chlorohydrazines trisubstituées étaient de bonnes sources de
« Cl+ ».257 Sachant cela, nous émettons l’hypothèse que des dérivés de N-
fluorosulfonylhydrazine pourraient, de la même manière, s’avérer être de bonnes sources de
fluor électrophile. Les avantages attendus de ces composés sont une réactivité ajustable par
la nature hautement modulaire de ce type de structure et une solubilité accrue dans les
solvants organiques courants dans lesquels les réactions de fluoration électrophile sont
généralement effectuées (THF, toluène, etc.).
Figure 7.1. Dérivés de N-fluorosulfonylhydrazine.
Comme travail préliminaire et de la même manière que nous l’avions fait pour les N-
fluorosquaramides (section 6.1.3), nous avons calculé l’énergie de dissociation
hétérolytique (FPD) (Schéma 7.4).258 Dans l’acétonitrile, une valeur de 234,3 kcal/mol a été
obtenue pour la dissociation du composé 7.1, alors que les valeurs de FPD du NFSI et du
Selectfluor s’élèvent à respectivement 229,6 et 229,8 kcal/mol. Ainsi, les dérivés de N-
fluorosulfonylhydrazine décrits à la Figure 7.1 constituent des réactifs de fluoration
(257) Benin, V.; Kaszynski, P.; Radziszewski, J. G. Tetrahedron 2002, 58, 2085–2090. (258) Xue, X.-S.; Wang, Y.; Li, M.; Cheng, J.-P. J. Org. Chem. 2016, 81, 4280–4289.
SNN
S
F
SR2
O OO O
O O
R1
modulations stériqueset électroniques
174
électrophile très prometteurs. Par ailleurs, l’ajout de substituants électroattracteurs pourrait
encore abaisser davantage leur valeur de FPD.
Schéma 7.4. Dissociation hétérolytique d’un dérivé de N-fluorosulfonylhydrazine.
SNN
S
F
SMe
O OO O
O OSNN
S SMe
O OO O
O O
F+ΔH298 = 234,3 kcal/mol
CH3CN
7.1