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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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
Serotonin receptor agonist;treatment of migraines
Serotonin receptor agonist;treatment of migraines
Serotonin receptor agonist;treatment of migraines
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
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
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
[1,2]-Aryl Rearrangement
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%
Pei, T. et al. Angew. Chem. Int. Ed. 2008, 47, 4231.
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
Pei, T. et al. Angew. Chem. Int. Ed. 2008, 47, 4231.
[1,2]-Aryl Rearrangement
20
OCl
NH2
Cl
NH
R-MORM
NH
O
R NH
R- H2O
A
Proposed Mechanism
Pei, T. et al. Angew. Chem. Int. Ed. 2008, 47, 4231.
21
OCl
NH2
Cl
NH
R-MORM
NH
O
R NH
R- H2O
A
Proposed Mechanism
Pei, T. et al. Angew. Chem. Int. Ed. 2008, 47, 4231.
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
Ding, F. et al. Organic Letters 2008, 10, 1067.
25
McMurry Cyclization
Ding, F. et al. Organic Letters 2008, 10, 1067.
26
McMurry Reaction Mechanism
27
• 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
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
Tandem C─N/Carbonylation/Suzuki
Br
BrN
X
B(OH)2
+Pd(PPh3)4, K2CO3
CO (12 bar)dioxane, 85 oC, 24 h
XNH
O
H2
Florent, J. Org. Lett. 2009, 11, 4608.
37
Tandem C─N/Carbonylation/Suzuki
Florent, J. Org. Lett. 2009, 11, 4608.
38
Tandem C─N/Carbonylation/Suzuki
Florent, J. Org. Lett. 2009, 11, 4608.
Br
BrN
B(OH)2
+Pd(PPh3)4, K2CO3
CO (12 bar)dioxane, 85 oC, 24 h
NH
O
X XH2
39
• 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
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
Taber, D. J. Am. Chem. Soc. 2006, 128, 1058.
43
The Neber Route
Taber, D. J. Am. Chem. Soc. 2006, 128, 1058.
44
Mechanistic Studies
Taber, D. J. Am. Chem. Soc. 2006, 128, 1058.
45
Mechanistic Studies
Taber, D. J. Am. Chem. Soc. 2006, 128, 1058.
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
C─H Amination of Vinyl Azides
Driver, T. G. J. Am. Chem. Soc. 2007, 129, 7500.
48
C─H Amination of Vinyl Azides
Driver, T. G. J. Am. Chem. Soc. 2007, 129, 7500.
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
C─H Amination of Aryl Azides
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%
Driver, T. G. Angew. Chem. Int. Ed. 2008, 47, 5056.
51
C─H Amination of Aryl Azides
[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
Driver, T. G. Angew. Chem. Int. Ed. 2008, 47, 5056.
52
• 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
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
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
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
Akiyama, T. Angew. Chem. Int. Ed. 2009, 48, 8070.
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
Akiyama, T. Angew. Chem. Int. Ed. 2009, 48, 8070.
Driver, T. G. Angew. Chem. Int. Ed. 2009, 48, 7974.
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
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