Recent Developments toward Synthesis of the …...* Rankings among top 200 drugs in 2008 6 N H Fischer (1883) N H NH 2 R 2 O + R 1 O O R 3 O N R 2 H + R 1 Nenitzescu (1929) N H R 2

Recent Developments toward Synthesis of the “Privileged” Indole Scaffold

Dimitra KontokostaNovember 11, 2009N

H

N

N

O

O

O O

2

• Introduction

Synthesis of substituted indoles via:

• Rearrangement Reactions • Multi-component, One-Pot Syntheses• C─H Amination of Azides• Pd-Catalyzed C─H Functionalization• Nb-Promoted C─F Functionalization• Conclusion

Contents

3

• Indole structure proposed in 1869.

• Used in dyes until the end of the 19th century.

• Special interest gained in 1930’s with the discovery of biologically important molecules.

Historical Background

• First synthesis by Adolf von Baeyer in 1866.

4

Indoles in Nature

5

Indoles in Pharmaceuticals

NH

NMe2S

MeN

O O

H

Imitrex (rank # 35)

NH

N

N

O

O

O O

Cialis (rank # 66)

NH

NMe2NNN

Maxalt (rank # 148)

NH

N

SO O

Relpax (rank # 151)

NH

NMe2

ONH

O

Zomig (rank # 196)

Serotonin receptor agonist;treatment of migraines

Phosphodiesterase inhibitor;treatment of erectile dysfuntion




http://www.chem.cornell.edu/jn96/outreach.html

* Rankings among top 200 drugs in 2008

6

NH

Fischer (1883)

NH

NH2 R2

OR1+

OOR3

O

R2NH

R1+

Nenitzescu (1929)

NH

R2

O

R1Madelung (1912)

NH2

Hegedus (1976)

I

HN

R1

R2

R3

+

Larock (1991)

R1

NO2

XMg

R3

R2+

Bartoli (1989)

NH

R1

S

R2Fukuyama (1999)

ORN3

OHemetsberger (1972)

Indole Synthesis: Classical Approaches

7

Fischer Indole Synthesis

Fischer, E.; Jourdan, F. Ber. Dtsch. Chem. Ges. 1883, 16, 2241.

8

Fischer Indole Synthesis

Limitations• Availability of certain substituted aryl hydrazines. • Unsymmetrical ketones give a mixture of regioisomers.• EWG groups on the aromatic ring are not well tolerated.• Slow reaction times with ortho-substituted arylhydrazines.

Fischer, E.; Jourdan, F. Ber. Dtsch. Chem. Ges. 1883, 16, 2241.

9

Japp-Klingemann Reaction

Japp, F. R.; Klingemann, F. Ber. 1887, 20, 2942.

10

Larrock Heteroannulation

Limitation

• Iodoanilines required; low yields with 2-bromo- or 2-chloroanilines.

Larock, R. C. J. Am. Chem. Soc. 1991, 113, 6689.

11

Larrock Heteroannulation

L2PdCl-I

HNR

PdL

L

ICl

PdL

ICl

R1 R2

HNR

HNR

R2R1

NPd

R

RL RS

ClL

L

NR

RL

PdII

Pd0 L2

Cl-

RS

Lbase

HI

NPd

R

RS RL

ClL

Lfavoredover

Larock, R. C. J. Org. Chem. 1998, 63, 7652.

12

Continuous interest in the development of synthetic routes that:

• Tolerate a wide variety of functional groups.

• Provide a variety of substitution patterns.

• Utilize readily available starting materials.

• Are economical, efficient, and take place under mild, “green” conditions.

Why New Methodologies?

13

• Introduction



Contents

14

3,3-Disubstituted Indolenine Rearrangement

Liu, K. G. et al. Organic Letters 2006, 8, 5769.

15

3,3-Disubstituted Indolenine Rearrangement

Liu, K. G. et al. Organic Letters 2006, 8, 5769.

16

Mechanism

NH NH2

H

OR1

R2

+H+

-H2O

NN H

H

R1

R2

NN H

HH

NN H

H

HH

NN H

R2

HH

HN

HH2N

-NH2H

R1 R2

P.T.R2

R1 R1 R1R2

NR1

R2

H+ NR1

R2

HN

R1

HR2N

R1

HR2

17

[1,2]-Aryl Rearrangement

Pei, T. et al. Angew. Chem. Int. Ed. 2008, 47, 4231.

18


NH

Cl

NH

Cl

O

O

NH

Cl

NH

Cl

NH

Cl

N

NH

Cl

S

NH

Cl

SiMe3NH

ClSiMe3 N

HCl

89% 86% 45%

91% 78% 72%

54% 70% 76%


19

NH

NH

NH

N

63% 68%

66%91%

OMe FF

F

Me

FMe

OCl

NH2Cl

R-M

PhMe, -40 to 22 oC NH

Cl

R



20

OCl

NH2

Cl

NH

R-MORM

NH

O

R NH

R- H2O

A

Proposed Mechanism


21

OCl

NH2

Cl

NH

R-MORM

NH

O

R NH

R- H2O

A

Proposed Mechanism


22

Control Experiment

Pei, T. et al. Angew. Chem. Int. Ed. 2008, 47, 4231.Wender, P. A. Tetrahedron, 1983, 39, 3767.

23

Anionic N-Fries Rearrangement

Ding, F. et al. Organic Letters 2008, 10, 1067.

24

Anionic N-Fries Rearrangement

I

NR1

R2

OX

1.

2.

iPrMgCl, THF, 0 oC

R3COCl, 0 to 25 oC NR1

X

R3O

R2

O


25

McMurry Cyclization


26

McMurry Reaction Mechanism

27

• Introduction



Contents

28

77%

NH

Ph

PhNH

Ph

TMS

82%

NH

Me

t-Bu

56%

One-pot Curtius Rearrangement/Pd-Cat. Indolization

Lebel, H. Angew. Chem. 2008, 120, 356.

I

CO2H

1. CBzCl, NaOtBu; NaN3DMF, 75 oC, 5 h

2. Pd(OAc)2, NaCO3, R1 R2DMF, 120 oC, 16 h

29

Curtius Rearrangement Mechanism

30

Pd-Catalyzed Indolization

L2PdCl-

R2R1

HN

R1

R2

I

NC

O

Pd

NC

O

Pd

NC

O

I

R2

R1I

Pd

N

ORO

R2

R1

RO

31Lebel, H. Angew. Chem. 2008, 120, 356.

Indole N-carboxamide Derivatives

32Lebel, H. Angew. Chem. 2008, 120, 356.

Indole N-carboxamide Derivatives

33

N-Aryl Amides and Ethyl Diazoacetate

Wang, Y. J. Am. Chem. Soc. 2008, 130, 13526.

34

Mechanism

HN R1

ON Cl

+Tf2O

HN R1

N Cl OTf

N ClClHN R1

NCl

ClOTf

N2 CO2Et N R1

CO2EtN2- 2,6-Cl2PyHOTf

NR1

CO2Et

-N2 NR1

CO2Et

1,3-H shiftHN

R1

CO2Et

35

Tandem C─N/Carbonylation/Suzuki

Alper, H. Org. Lett. 2008, 10, 4899.

Florent, J. Org. Lett. 2009, 11, 4608.

36


Br

BrN

X

B(OH)2

+Pd(PPh3)4, K2CO3

CO (12 bar)dioxane, 85 oC, 24 h

XNH

O

H2


37



38



Br

BrN

B(OH)2

+Pd(PPh3)4, K2CO3

CO (12 bar)dioxane, 85 oC, 24 h

NH

O

X XH2

39

• Introduction



Contents

40

Azide Thermolysis

CO2Et

N3

CO2EtN

NH

CO2Et

Taniguchi, H. J. Chem. Soc., Chem. Commun. 1980, 1252.

41

The Neber Route

Br

O

- H2O

H2N-OH

Br

N

MsCl

Et3N

Br

N

DBU

Br

N

Br

OH OMs

OMsN

NHBr

Taber, D. J. Am. Chem. Soc. 2006, 128, 1058.

42

The Neber Route


43

The Neber Route


44

Mechanistic Studies


45

Mechanistic Studies


46

C─H Amination of Vinyl Azides

Driver, T. G. J. Am. Chem. Soc. 2007, 129, 7500.

47

Rh2(O2CC3F7)4

CO2Me

N3

R

CO2Me

N

R

[Rh]N

N

CO2Me

N

R

[Rh]

R

NCO2Me

[Rh]H

R

NH

CO2Me

N2



48



CO2Me

N3

Rh2(O2CC3F7)4PhMe, 40 to 60 oC N

H

CO2Me

R1R2

R3

R1R2

R3

49

C─H Amination of Aryl Azides

X

R1R2

N3

[Rh2(O2CC3F7)4]

4 A M.S.o

PhMe, 60 oCNH

X

R1

R2

Sunberg, R. J. J. Org. Chem. 1972, 37, 719.

R

N3 NH

R

Driver, T. G. Angew. Chem. Int. Ed. 2008, 47, 5056.

50


X

R1R2

N3

[Rh2(O2CC3F7)4]

4 A M.S.o

PhMe, 60 oCNH

X

R1

R2

NH

H

Ph

94%

NH

H

PhMeO

89%

NH

H

PhF

99%

NH

H

PhMeO

88%

NH

H

PhF3C

89%

NH

H

Ph

Me72%


51


[Rh2(O2CC3F7)4]X

N3

R2

H

R1

R2X

R1

NN[Rh]

N

N2R2

X

R1

N

[Rh]

R2X

R1

N

[Rh]

H

H

XN H

[Rh]

R1

R2

XNH

R1

R2


52

• Introduction



Contents

53

Intermolecular Cyclizations with Alkynes

Ackerman, L. Tetrahedron 2008, 64, 769.

Fagnou, K. J. Am. Chem. Soc. 2008, 130, 16474.

54

Intermolecular Cyclizations with Alkynes

Ackerman, L. Tetrahedron 2008, 64, 769.

Fagnou, K. J. Am. Chem. Soc. 2008, 130, 16474.

Ortho-halogenated anilines required

Directing group (OAc) required

55

Pd-Catalyzed C─H Functionalization

+

120 oC, 12 hNH

R1

R2

R1

R2

Pd(OAc)2

O2 (1 atm)

DMA/PivOH (4:1)

NH2X X

Jiao, N. Angew. Chem. Int. Ed. 2009, 48, 4572.

NH

CO2Me

CO2MeMe

NH

CO2Me

CO2Me

93%

Me

95%

NH

CO2Me

CO2Me

Me72%

NH

CO2Me

CO2MeiPr

99%

NH

CO2Me

CO2MeMeO

99%

NH

CO2Me

CO2Me

OMe81%

NH

CO2Me

CO2Me

OMe

OMe

63%

NH

CO2Me

CO2MeMeO

MeO

93%

NH

CO2Me

CO2MeF3CO

NH

CO2iPr

CO2iPr

46%

EtO2C

60%

NH

CO2Et

CO2Et

75%

NH

CN

Ph

20%

56

Proposed Mechanistic Cycle

Jiao, N. Angew. Chem. Int. Ed. 2009, 48, 4572.

57

• Introduction



Contents

58

Ph CF3

NX

nNbCl5 (30 mol%)NaAlH4 (4 equiv)

1,4-dioxane, reflux

N

Ph

X

nN

Ph

X

n+

RuZr-P (8 mol%)O2

Nb-Promoted C─F Functionalization

Akiyama, T. Angew. Chem. Int. Ed. 2009, 48, 8070.

59

Preparation of Fused Ring Components


60

Amination Reaction Pathway

Buchwald, S. J. Org. Chem. 2000, 65, 1144.

61

Amination Reaction Pathway

Buchwald, S. J. Org. Chem. 2000, 65, 1144.

62

Proposed Catalytic Cycle



63

• The indole scaffold is of particular importance in nature and medicinal chemistry.

• New synthetic strategies target the efficient preparation of indoles that exhibit multiple substitution patterns.

• Novel developments have been made toward the functionalization of otherwise unreactivebonds.

Conclusion

THANK YOU

Recent Developments toward Synthesis of the …...* Rankings among top 200 drugs in 2008 6 N H Fischer (1883) N H NH 2 R 2 O + R 1 O O R 3 O N R 2 H + R 1 Nenitzescu (1929) N H R 2

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