Transition-Metal-Catalyzed DenitrogenativeTransannulation:

Converting Triazoles into OtherHeterocyclic Systems

杜宇鎏2012.10.13

Page 2 2

1. Introduction

In this PPT, recent progress of the transition metal catalyzed denitrogenative transannulation of a triazole ring, which was discovered in 2007, is discussed.

1,2,3-Triazoles are important heterocyclic units endowed with a broad spectrum of biological activities. They have been extensively used in medicinal chemistry, biochemistry, and in material science.

Page 3 3

◆The Dimroth rearrangement

N

NNN

Ph

R

H

H

N

NNN

Ph

R

H

H

N

NNN

H

R

H

Ph

N

NH

NN

R

H

Ph

1)Otto Dimroth, Justus Liebig’s Annalen der Chemie, 1909, 364, 183-226.2)Otto Dimroth, Walter Michaelis, Justus Liebig’s Annalen der Chemie, 1927, 459, 39-46.

Page 4 4

The position of this equilibrium depends upon several factors, such as temperature, solvent, and the nature of the substituent (R1) at C7 of the triazole ring.

The introduction of a halogen atom at C7 shifts the equilibrium to the right, which has been explained in terms of nonbonding repulsion between the lone pair of electrons on the halogen and nitrogen atom in the peri-position of the left.

1)G. Labb, Bull. Soc. Chim.Belg. 1990, 99, 281;2)B. Abarca-Gonzlez, R. Ballesteros, F. Mojarred, G. Jones, D. J. Mouat, J. Chem. Soc. Perkin Trans. 1 1987, 1865.

N NN

R1

R2

NN2

R1

R2

Page 5 5

2. Transannulation of Pyridotriazoles

1) S. Chuprakov, Frank, W. Hwang, V. Gevorgyan, Angew. Chem. 2007, 119, 4841; Angew. Chem. Int. Ed. 2007, 46, 4757.2) V. Bagheri, M. P. Doyle, J. Taunton, E. E. Claxton, J. Org. Chem. 1988, 53, 6158.

N NN

CO2Me

R

NN2

CO2Me

R

Rh2(OAc)4

1 mol% N[Rh]

CO2Me

R

2eq Et3SiHCH2Cl2, RT

N

CO2Me

R

SiEt3

a: R= Hb: R= Cl

a: 0%b: 88%

Page 6 6S. Chuprakov, Frank, W. Hwang, V. Gevorgyan, Angew. Chem. 2007, 119, 4841; Angew. Chem. Int. Ed. 2007, 46, 4757.

◆Transannulation with Alkynes and Nitriles

N NN

CO2Me

Cl

1 mol% Rh2(OAc)4

PhCH2Cl2, R.T.

NClCO2Me

Ph

+ N

CO2Me

PhCl

[Rh2(pfb)4]

Ph

X

68% 28%

78%

Page 7 7

N

CO2Me

Cl

N

CO2Me

Cl

N

CO2Me

Cl

OMe

N

CO2Me

Cl

N

CO2Me

Cl

N

CO2Me

Cl

CO2Me

80% 73% 85%

70% 65% 57%

Page 8 8

Proposed mechanism for transannulation of pyridotriazoles with alkynes and nitriles

N NN

R2

R1

+ R31 mol% Rh2(OAc)4

CH2Cl2, R.T. NN

R2

R1 R3

R1=Cl, R2=CO2Me, yield from 54% to 89%

NN

4-CF3C6H4

Cl Ph

NN

4-CF3C6H4

Br Ph

NN

OMe

OMe Ph

82% 73% 51%

Page 9 9

3. Transannulation of N-Sulfonyl-1,2,3-triazoles

NN

NS

O

O

R2

R1+ N R3 [Rh2(oct)4], CHCl3 N

N S

O

O

R2

R1

R3

yield from 42% to 99%

Microwave and conventional heating can be employed

3.1. Transannulation with Alkynes, Nitriles, and Alkenes

T. Horneff, S. Chuprakov, N. Chernyak, V. Gevorgyan, V. V. Fokin, J. Am. Chem. Soc. 2008, 130, 14972.

NN

NS

O

OPh

+Ph

1 mol% [Rh2(oct)4]DCE, 80¡æ

silica gel chromatography99%

PhPh

H

O

N

N2

PhTs

1 mol% [Rh2(oct)4]

N

[Rh]

PhTs Ph

PhPh

HN Ts

Page 10 10

T. Miura, M. Yamauchi, M. Murakami, Chem. Commun. 2009, 1470.

◆ Nickel-catalyzed denitrogenative transannulation reaction of Nsulfonyl-1,2,3-triazoles with internal alkynes.

P

N SNN

O

O

R2

R1

+ R3 R4

10 mol% [Ni(cod)2]20 mol% P(nBu)Ad2

5 mol% AlPh3, PhMe100 ℃

N

R4R3

R1

S

O

O

R2

yield from 5% to 75%

P(nBu)Ad2

Page 11 11

◆ Proposed reaction pathway

N TsNN

Ph

N

N2

Ts

Ph N2

Ni0 N

[Ni]

Ts

Ph

[Ni]

NTs

Ph

R R[Ni]N

Ts

Ph R

RNi0

reductiveelimination

N

RR

Ph

Ts

◆ Possible role of the Lewis acid:

A promotion of the ring–chain tautomerization, or an acceleration of the reductive elimination of nickel.

Page 12 12

◆ Transannulation of monocyclic triazoles with terminal alkynes into pyrroles

B. Chattopadhyay, V. Gevorgyan, Org. Lett. 2011, 13, 3746.

N TsNN

R1

+ R2

2.5 mol% [Rh2(oct)4]5.0 mol% AgOCOCF3

0.06M hexanes70¡æ, 3-20h

N Ts

R1

R2

R1= H, Ar, Alkyl

R2=Ar, Alkenyl, 26 examples

44-99%

Page 13 13

◆ Unique spot

◆ Deuterium labeling experiment

N NN

R1

Ts

D+N

Ph

Ts

D66% D incorporated

66% D observed

N NN

Ts

R

N2

Rh-cat[Rh]

N

R

Ts

NN

TsR1

NTs

R

R1

N R1

R1

AgOCOCF3-cat

N2

Ni/AlPh3-cat

[Ni]

NTs

R

R1R1

NTs

R

R1

R1

(this work)

Page 14 14

N NN

R1

Ts[Rh]

[Rh]

R1

NTs

NTs R1

[Rh]

H

R2

R2H

N R1

[Rh]

Ts

R2

H

R2Ag

NTs R1

[Rh]

R2

H

H-

NR1

Ts

R2

H

◆ Proposed Mechanism

The role of silver trifluoroacetate would probably activates the electrophilic rhodium carbene moiety toward the nucleophilic attack by an alkyne.

Page 15 15

◆ An efficient three-component semi-one-pot synthesis of the pyrrole

TsN3 +

1) 10 mol% CuI 1.2equiv 2,6-lutidine

0.5M CHCl3, 0¡æ, 12h

2) 2.5 mol% [Rh2(oct)4]5 mol% AgOCOCF3

0.06M hexanes, 70¡æ£¬15h

NOMe

Ts

59% (over 2 steps)

OMe1.5 equiv

Page 16 16

3.2 Synthesis of Rhodium(II) N-Triflyl Azavinyl Carbenes

◆Sulfonylation reaction of 4-phenyl-NH-1,2,3-triazole

N. Grimster, L. Zhang, V. V. Fokin, J. Am. Chem. Soc. 2010, 132, 2510.

N NN H

Ph

N

Me

tBuBut

(CF3SO2)ODCM

NN

N Tf

Ph

NN

N

Ph

Tf

NN

N

Ph

Tf

N

NN

N

R1

+R2

R3

1) 0.5 mol%[Rh2(S-NTTL)4]

2) 1 equiv (CF3SO2)2-30¡æ-RT, 3h

N

tBu

tBu

1.2 equiv

OR1

R3

R213 example

yield: 45%-96%ee: 0-96%

N

R1

Tf R

R=OMe; R1=Ph(92%, 72%ee)R=H; R1=CO2Et(75%, 0% ee)

dr>20:1

aq. work up

Page 17 17

NN

N

RO

N2

N

O R

+ R1 R2 Pd0

N

R2

R1

R

+ N2

X

NH

R

+ R1 R2Pd0

base N

R2

R1

R

+ HX base

◆Larock’s indole synthesis

1) I. Nakamura, T. Nemoto, N. Shiraiwa, M. Terada, Org. Lett. 2009, 11, 10552) R. C. Larock, E. K. Yum, J. Am. Chem. Soc. 1991, 113, 6689

4. Transannulation of N-Aroylbenzotriazoles

Page 18 18

Pd0

R4

R3

R2

R1

NN

N

OR

R4

R3

R2

R1

N

N2

RO

N2

R4

R3

R2

R1

N

Pd

O

R

R4

R3

R2

R1

N

Pd

RO

R5 R6

R4

R3

R2

R1

NPd

R5

R6

O R

R4

R3

R2

R1

N

OR

R5

R6

◆ Proposed Mechanism

Page 19 19

5. Transannulation of 1,2,3-Benzotriazinones

NN

N

O

R

+ Bun nBu

5 mol%[Ni(cod)2]

20 mol% PMe3 or PPh3THF, RT

N

O

R

nBu

nBu

NiLn

N

O

R NiLn

N

OR

BunnBu

Bun nBu

-Ni0Ni0 -N2

T. Miura, M. Yamauchi, M. Murakami, Org. Lett. 2008, 10, 3085

Page 20 20

NN

N

O

R

+ R1 R2

5 mol%[Ni(cod)2]

20 mol% PMe3 or PPh3THF, RT

N

O

R

R1

R2

N

O

Ph

Ph

Ph

N

O

Ph

OBn

OBnN

O

C6H4-4Me

Ph

Me

N

O

C6H4-4Me

C6H4-4CF3

Me

N

O

C6H4-4Me

C6H4-4OMe

Me

N

O

C6H4-4Me

Me

iPr

N

O

C6H4-4Me

CO2Et

nPr

N

O

C6H4-4Me

Bpin

nBu

N

O

C6H4-4Me

Bpin

TMS

N

O

C6H4-4Me

n-hexyl

N

O

C6H4-4Me

TMS

N

O

C6H4-4Me

nBu3Sn

98% 94% 99%(86:14) 99%(73:27)

99%(89:11) 97%(58:42) 99%(92:8) 93%(98:2)

94%(99:1) 99%(98:2) 94%(99:1) 92%(99:1)

Page 21 21

◆ Transannulation of 1,2,3-benzotriazinones with allenes

NN

N

O

Tol 1 equiv [Ni(cod)2]

1 equiv dppbenzTHF, RT, 3h

79%

NiN

O

Ph2PPPh2

Tol

THF, 60¡æ12h

•hexyl3 equiv

N

O

Tol

hexyl

N

O

Tol

hexyl

+

99%(54:46)

M. Yamauchi, M. Morimoto, T. Miura, M. Murakami, J. Am. Chem. Soc. 2010, 132, 54.

Page 22 22

NN

N

O

Tol

+

•

10 mol% [Ni(cod)2]40 mol% PMe3

THF, 60¡æ, 6h

10 mol% [Ni(cod)2]20 mol% (R,R)-Me-duphos

PhMe, 100¡æ, 6h

O

NTol

N

O

Tol

75%

99%

◆The nature of the product varied depending upon the type of the phosphine ligand

NN

N

O

R2

R3

R1

+ •R

[Ni(cod)2], PMe3 N

O

R2

R3

R1

R

+N

O

R2

R3

R1

RR1= tolyl, aryl; R2= H, OMe; R3=H, OMe,CO2Me

R4=hexyl, (CH2)2OBn, (CH2)2OSitBuMe2,

(CH2)2OH, (CH2)2CN, SitBuMe2

14 examplesyield: 76%-99%

selectiviy: up to 0:100

Page 23 23

◆Asymmetric version

NN

N

O

R2

R3

R1

+ •R

10-20 mol% [Ni(cod)2] N

O

R2

R3

R1

R

+N

O

R2

R3

R1

R

R1= tolyl, aryl, CONPh2; R2= H, OMe; R3=H, OMe,CO2MeR4=alkyl, protected alkyl

20 mol%chiral ligand

60-80 ¡æ

*

19 examplesyield: 76-99%ee: 78-97%

Page 24 24

◆ Transannulation of benzotriazinones with 1,3-dienes and activated alkenes

NiN

O

4-Tol

Ph2PPPh2

+

3 equiv

X equiv dppf

toluene, 110℃, 24h

X= 0 <5%X= 1 40%

N

O

4-Tol

NN

NR2

R3

O

R1

+R5

R4

Ni0 cat.

ligand

NR2

R3

O

R1

R5R4

+N

R2

R3

O

R1

R4R5

T. Miura, M. Morimoto, M. Yamauchi, M. Murakami, J. Org. Chem. 2010, 75, 5359.

Page 25 25

N

O

PhN

O

C6H4-4-OMeN

O

C6H4-4-CF3 N

O

Bn

N

O

PhMeO2C N

O

PhMeO

MeO

N

O

4-tolN

O

4-tol

87% 85% 88% 24%

74% 86% 81% 92%

◆With symmetrical 1,3-dienes

N

O

4-tol+

N

O

4-tol

66% (86:14)

N

O

4-tol N

O

4-tol

+

53% (83:17)

N

O

4-tol+ N

O

4-tol

85% (90:10)

◆With unsymmetrical 1,3-dienes

Page 26 26

◆ Transannulation with Isocyanides

T. Miura, Y. Nishida, M. Morimoto, M. Yamauchi, M. Murakami, Org. Lett. 2011, 13, 1429.

NN

NXR2

R3

O

R1

+ N

R4

C

5 mol% [CpPd(¦Ð-allyl)]10 mol% PMe3

1,4-dioxane, 110¡æ, 18h

R2

R3N

XO

R1

NR4

R1= aryl, heteroaryl

R2= H, OMe

R3= H, OMe, CO2Me

R4= 2,6-xylyl,

Cy, Bn, aryl, alkyl84% to 99%

X= C, SO

Page 27 27

6. Transannulation of 1,2,3,4-Benzothiazinones

◆ Transannulation with Allenes

NN

NS Me

O O

+ •R

10 mol% [Ni(cod)2]10 mol% quinap

1,4-dioxane100¡æ, 3h

NS

O OMe

R

+N

SO O

Me

R

Ni0 -N2

NiLn

NS

Me

OO

NS

O OMe

R

-Ni0

N

PPh2

8 examplesyield: 87-99%ee: 72-85%

T. Miura, M. Yamauchi, A. Kosaka, M. Murakami, Angew. Chem. 2010, 122, 5075; Angew. Chem. Int. Ed. 2010, 49, 4955.

Page 28 28

◆Highly diastereo- and enantioselective Rh(II)-catalyzed cyclopropanation

H

NRO2S R2

MLn

NN

N

H

RO2S

R2 R2

NN

NRO2S

NN

NMs

R

+ Ph

1. Rh2(S-NTTL)40.5 mol% DCE, H2O

2. K2CO3, H2OMeOH, rt

RO

Ph

dr= > 20:1

yield: 57%-94%ee: 93%-98%

N

O

O

Rh

RhO

O 4

Rh2(S-NTTL)4

Stepan Chuprakov, Sen Wai Kwok, Li Zhang, Lukas Lercher, and Valery V. Fokin, J. Am. Chem. Soc., 2009, 131, 18034–18035.

Page 29 29

◆Catalytic Asymmetric C-H Insertions of Rhodium(II) Azavinyl Carbenes

NN

N

R1

S

OO

R2

+ R5H

R3R4

1) 0.5 mol% Rh2(S-NTTL)4CHCl3, rt

2) LiAlH4, 1.2 equiv, 0¡æNH

R1

S

OO

R2

R5

R3 R4

H

yield: 61-98%, ee: 86-97%

Stepan Chuprakov, Jamal A. Malik, Mikhail Zibinsky, and Valery V. Fokin, J. Am. Chem. Soc. 2011, 133, 10352-10355

Page 30 30

◆Reactivity of N-(1,2,4-Triazolyl)-Substituted 1,2,3-Triazoles

N

RN N

N[Rh]

R2

CO2Et

NN N

N

R2

CO2EtNN

R1

1) CHCl365-75¡æ, 24h

2) NaBH4, EtOH 0¡æ to rt

HNN N

N

R2

CO2Et

R3

R1

R3

NN N

N

R2

CO2EtR1

R3

1) 1,2-DCE85¡æ, 5h N

N N

N

R2

CO2EtN

R1

R3N R3

NN N

N

R2

CO2Et

R1

[Rh] N

R351-91% yield

80-95% ee, dr> 20:168-76% yield

Mikhail Zibinsky and Valery V. Fokin, Org. Lett. 2011, 13, 4870-4872

Page 31 31

Conclusion

◆The PPT highlights the increasing interest in the development of transition metal catalyzed transannulation reactions.

◆ Triazoles serves as a complimentary methodology for construction of heterocycles as it allows a general and highly efficient synthesis of complex and highly functionalized aromatic nitrogen heterocycles with diverse substitution patterns.

◆Unsymmetrical approaches in this area have not been developed as complete as the symmetrical ones, which require more attentions and researches.

Thank You For Your Attention

Page 33 33

◆ Proposed mechanism for transannulation of pyridotriazoles with alkynes and nitriles

N NN

R1

R2

NR1N2

R2

[Rh2L4]

N2

NR1[Rh]

R2

Y R3

path c [2+2]

NR1Y [Rh]

R2

R3

NR1

R2 [Rh]

Y

R3

Y R3

path b

NY

R2 [Rh]

R3R1

NR1R2

Y

R3

[Rh]

Y=CH, N

NR1R2

YR3

Y R3

path a[2+1]

NY

R1

R2

R3

NR1R2

Y

R3

[Rh]

X

¦Ò-bond metathesis

Page 34 34

◆ Proposed mechanism for the transannulation of N-sulfonyl-1,2,3-triazoles 17 with nitriles

NN N

R1S

O

O

R2

NS

O

O

R2

[Rh]

R1

path a

R3

NS

O

O

R2 R1

[Rh]

N

R3

NS

O

O

R2

N[Rh]

R1

R3

NS

O

O

R2

[Rh] N

R1

R3

NN

R1S

O

O

R2

R3

path b [3+2]

R3

1,3-Rh shift