Presentaci¾n Proyecto Pirroles definitiva
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Modular Three-ComponentOrganocatalytic Synthesis of
3,4-Disubstituted Pyrroles by aOne-Pot Domino Reaction
Carlos Jarava
Barrera
COMMUNICATIONS
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COMMUNICATIONS1.Introduction
Pyrroles represent one of the most widely used heterocycles due to theirpresence in several natural and non- natural products.
Pyrrole itself is readiliy available commercially, and is manufactured by
alumina-catalysed gas-phase interaction of furan and ammonia.
Degradation of the blood respiratory pigment haem, and chlorophyll, ledto the formation of mixtures of alkylpyrroles.
N
H
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COMMUNICATIONS1.Introduction
NH
H2N
CO 2HCO 2H
Phorphobilinogen(living cell)
Vitamin B 12
Chlorophyll
Haem
http://upload.wikimedia.org/wikipedia/commons/b/be/Heme_b.svg -
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COMMUNICATIONS1.Introduction
NN
Alkyl Me
Tetrapyrroles asChromophores
NH
Ar COAr
NR
Ar N
Ar
XN
(Antifungal Activity)
N
N
OHR1 R2
OHR2R2
IV Halitulin R 1=H, R 2=OHV Isohalitulin R 1=OH, R 2=H
I
II (COX inhibitors) III
3,4.disubstituted pyrroles represent important building blocks forthe synthesis of tetraporphyrines and several bioactive compounds
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COMMUNICATIONS1. Introduction
Tetrapyrroles as chromophores inthe plant photoreceptorphytochrome
U. Robben, I. Lindner, W. Grtner J. Am. Chem. Soc. 2008 , 130 , 11304
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COMMUNICATIONS1.Introduction
L. Knorr Ber. Dtsch. Chem. Ges. 1884 , 17 , 1635
Knorr synthesis
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COMMUNICATIONS1.Introduction
Paal-Knorr synthesis
C. Pall Ber. Dtsch. Chem. Ges. 1885 , 18 , 367
O
O
ammonia,benzenereflux
90%
RN
http://en.wikipedia.org/wiki/File:PKP_mechanism.svg -
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COMMUNICATIONS1.Introduction
Hantzsch synthesis
R1
NH O
R3
O
R4
O R 2
R1
NH2 O
O R 2
NH
R1
O
OR 2
R3
R4
R1
O
OOR2
NH3
R1
N
O
O
R2
R3R4
Cl
Cl
A. Hantzsch Ber. Dtsch. Chem. Ges. 1890 , 23 , 1474
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COMMUNICATIONS2.Disadvantages
Most of the syntheses for pyrroles are methods that involve multi-steproutes, expensive reagents, and rarely provide the 3,4-substitution pattern.
For these reasons, it would be highly desirable to develop a Lego methodthat could start from three different components, with each oneincorporating a desired substitution: one for 3-position, another for the 4-position, and finally the N-substitution.
We present a new catalytic method for the synthesis of 3,4-disubstitutedpyrroles.
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COMMUNICATIONS3.Objective
It would be highly desirableto have an alternativemethod for the synthesis of
3-4-pyrroles
N
R1 R2
R3
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COMMUNICATIONS4. Lego Method
ChemCatChem 2012 , DOI: cctc.201200104
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COMMUNICATIONS5. Screening
CHO1 Cat (mol%)
NO 2Ph
Br
+N
i- Pr Ph
N
HNH
NH
O
NH
CO 2H
1a 1b 1c 1d
Bn
CH 2Cl2
CHO
PhNO 2
Br
BnNH 2
(no isolated)Entry Catalyst Time (h) Conversion Yield (%)
1 1a (20 mol%) 24 20 -
2 1b (20 mol%) 1.5 50 -
3 1c (20 mol%) 1.5 100 65
4 1d (20 mol%) 1.5 70 -
5 1c (10 mol%) 1.5 100 90
6 1c (5 mol%) 1.5 100 88
7 1c (1 mol%) 24 100 72
8 1c (5 mol%) b 8 100 57
[a] All the reactions were carried out with 0.44 mmol of nitroalkene 3a , 0.88mmol of aldehyde 2a and 1.0 mmol of BnNH 2 in 0.9 mL of CH 2Cl2. [b] Inthis case the amount of aldehyde was reduce to 0.53 mmol.
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COMMUNICATIONS6. Kinetic studies
CHO(5 mol%)
NO 2Ph+
CH 2Cl2
CHO
Ph NO 2
Conversion:>99%
NH
CHO (5 mol%)
NO 2Ph+
NH
CH 2Cl2
CHO
Ph NO 2
Conversion:30%
Nitrostyrene preferspirrolidine
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COMMUNICATIONS6. Kinetic studies
Br-Nitrostyrene preferspiperidine
CHO(5 mol%)
NO 2
Ph+
NH
CH2Cl
2
CHO
Ph NO 2
Conversion: 89 %
Br
Br
CHO (5 mol%)
NO 2Ph
Br
+
NH
CH 2Cl2
CHO
Ph NO 2
Br Conversion: 58 %
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COMMUNICATIONS7. Scope
(88%) (76%) (85%) (large scale)
NBn
Ph
NBn
NBn
(62%) (20 mol% catalyst)
NBn
O
N
Bn
Cl
(58%)(57 %)
N
Bn
F
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COMMUNICATIONS7. Scope
(45%) (20 mol% catalyst) (79%)
NBn
NBn
Ph
(65%) (61%)
NBn
Ph
NBn
Bn Ph
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COMMUNICATIONS7. Scope
(88%) (90%) (>99%) (55%) (52%)
When R 3 = H, there is no reaction.
N
Ph
N
Ph
N
Ph
Ph
N
Ph
N
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COMMUNICATIONS8. Non racemization
PhNH2
CO 2Me
NO 2Ph
Br a) 1c (5 mol%)
b)CHO N
CO 2MePh
Ph
ee>98%(Yield= 72%) ee=96%
H
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COMMUNICATIONS9. Complex molecules
NH2
NHBoc
NHBoc
N
CHONO 2
Ph
Br
b)
a) 1c (5 mol%)
Ph
(61%) yield
a) TFA
b)
CHONO 2
Ph
Br a) 1c (5 mol%)
CHO
PhNO 2
Br
N
N
Ph
Ph
(36%) yield
( )2
( )3
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COMMUNICATIONS10. Mechanism
First stage
NH
N
H
N
H
NR1
H
R1CH 2CHO
R1
R1
R2 NO 2
Br
R2O2N
Br
OR1
H
R2O2N
Br
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COMMUNICATIONS10. Mechanism
Second stage
< >
NO 2Br
Br-nitrostyrene acts as a
tripositive synthon
R3-NH2
"One pot addition"
N
R1 H
R2O2N
Br
R3
HN
R1H
R3
Br NO 2
R2
NR3
N
R2 R 1
O
O
HNR3
R2 R 1
I
II
III
syn-elimination
OR1 H
R2O 2N
Br
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COMMUNICATIONS11. Conclusions
The use of trans -bromonitrostyrenes under enamine catalysis with theunexpensive piperidine, allows 1,4-Michael adduct intermediates which
are treated with the desired amine (R 3-NH2), and trigger the dominoreaction to the obtention of the final 3,4-disubstituted pyrrole derivative.
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COMMUNICATIONS12. Other Projects
Trienamine Catalysis
O
H
NH
Ph
OTMSPh
NO 2HOOC
CHCl 3
NO 2
40 C
O2N
CHO
N
HPh
OTMSPh
Chen et al. ACIE 2011
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COMMUNICATIONS12. Other Projects
Trienamine Catalysis
OHC
H
O
R1
R3X
H
O
MeO 2CCO 2Me
H
OEt
O
O
O
NO 2
Br
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COMMUNICATIONS12. Other Projects
Dienamine Catalysis of Ketones
O NO 2
Br
Chincona (10 mol%)
OFBA (20 mol%)Toluene 0,2M
40 C48h
O
NO 2
Br
Ph
NO
O
O
O
H OEt
O
O
OEt
O
NOH
Ph
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COMMUNICATIONS12. Other Projects
Cycloaddition [2+2]
Ph
O
NO 2Br
Ph PhPh
Br
NO 2OHC
CH 2Cl2
BifunctionalSquaramide
DEA (1eq)
NO
Catalyst
Problem: Derivation
COMMUNICATIONS13 C t P j t
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COMMUNICATIONS13. Current Project
Synthesis of 1,2-dihydronaphtho[2,1-]furanes
Entry Reaction Base Co-catalyst(mol%)
Conversion(%) (ee%)
ReactionTime
1 CJ88 DIPEA 20 31 24 h 2 CJ89:A Et3N 10 30 24h 3 CJ89:B NaOAc 10 26 24h 4 CJ89:C K2CO 3 10 12 24h 5 CJ89:D Pyridine 10 8 (66) 24h 6 CJ89:E NaHCO 3 10 0 24h 7 CJ89:F DMAP 10 37 4d 8 CJ89:G DBU 10 32 4d 9 CJ89:H Dimethylaniline 10 22 4d 10 CJ89:D Pyridine 10 41 4d
11 CJ90A Et 3N 100 100 (xx) 3d 12 CJ90B NaOAc 100 81 (xx) 3d 13 CJ91A DMAP 50 67 (xx) 3d 14 CJ91:B DBU 50 77 (xx) 3d 15 CJ91:C DIPEA 50 78 (xx) 3d 16
CJ94A Methilimidazole 10 27 24h
17 CJ94B DABCO 10 56 (xx) 24h 18 CJ94C Diethylamine 10 29 24h 19 CJ94D TMEDA 10 27 24h
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