Recent Developments toward Synthesis of the …...* Rankings among top 200 drugs in 2008 6 N H...
Transcript of Recent Developments toward Synthesis of the …...* Rankings among top 200 drugs in 2008 6 N H...
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Recent Developments toward Synthesis of the “Privileged” Indole Scaffold
Dimitra KontokostaNovember 11, 2009N
H
N
N
O
O
O O
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• 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
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• 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.
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Indoles in Nature
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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
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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
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Fischer Indole Synthesis
Fischer, E.; Jourdan, F. Ber. Dtsch. Chem. Ges. 1883, 16, 2241.
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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.
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Japp-Klingemann Reaction
Japp, F. R.; Klingemann, F. Ber. 1887, 20, 2942.
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Larrock Heteroannulation
Limitation
• Iodoanilines required; low yields with 2-bromo- or 2-chloroanilines.
Larock, R. C. J. Am. Chem. Soc. 1991, 113, 6689.
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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.
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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?
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• 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
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3,3-Disubstituted Indolenine Rearrangement
Liu, K. G. et al. Organic Letters 2006, 8, 5769.
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3,3-Disubstituted Indolenine Rearrangement
Liu, K. G. et al. Organic Letters 2006, 8, 5769.
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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
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[1,2]-Aryl Rearrangement
Pei, T. et al. Angew. Chem. Int. Ed. 2008, 47, 4231.
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[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.
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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
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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.
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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.
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Control Experiment
Pei, T. et al. Angew. Chem. Int. Ed. 2008, 47, 4231.Wender, P. A. Tetrahedron, 1983, 39, 3767.
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Anionic N-Fries Rearrangement
Ding, F. et al. Organic Letters 2008, 10, 1067.
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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.
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McMurry Cyclization
Ding, F. et al. Organic Letters 2008, 10, 1067.
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McMurry Reaction Mechanism
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• 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
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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
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Curtius Rearrangement Mechanism
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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
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31Lebel, H. Angew. Chem. 2008, 120, 356.
Indole N-carboxamide Derivatives
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32Lebel, H. Angew. Chem. 2008, 120, 356.
Indole N-carboxamide Derivatives
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N-Aryl Amides and Ethyl Diazoacetate
Wang, Y. J. Am. Chem. Soc. 2008, 130, 13526.
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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
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Tandem C─N/Carbonylation/Suzuki
Alper, H. Org. Lett. 2008, 10, 4899.
Florent, J. Org. Lett. 2009, 11, 4608.
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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.
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Tandem C─N/Carbonylation/Suzuki
Florent, J. Org. Lett. 2009, 11, 4608.
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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
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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
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Azide Thermolysis
CO2Et
N3
CO2EtN
NH
CO2Et
Taniguchi, H. J. Chem. Soc., Chem. Commun. 1980, 1252.
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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.
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The Neber Route
Taber, D. J. Am. Chem. Soc. 2006, 128, 1058.
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The Neber Route
Taber, D. J. Am. Chem. Soc. 2006, 128, 1058.
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44
Mechanistic Studies
Taber, D. J. Am. Chem. Soc. 2006, 128, 1058.
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45
Mechanistic Studies
Taber, D. J. Am. Chem. Soc. 2006, 128, 1058.
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46
C─H Amination of Vinyl Azides
Driver, T. G. J. Am. Chem. Soc. 2007, 129, 7500.
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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.
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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
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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.
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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.
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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.
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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
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53
Intermolecular Cyclizations with Alkynes
Ackerman, L. Tetrahedron 2008, 64, 769.
Fagnou, K. J. Am. Chem. Soc. 2008, 130, 16474.
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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
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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%
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56
Proposed Mechanistic Cycle
Jiao, N. Angew. Chem. Int. Ed. 2009, 48, 4572.
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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
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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.
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59
Preparation of Fused Ring Components
Akiyama, T. Angew. Chem. Int. Ed. 2009, 48, 8070.
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60
Amination Reaction Pathway
Buchwald, S. J. Org. Chem. 2000, 65, 1144.
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61
Amination Reaction Pathway
Buchwald, S. J. Org. Chem. 2000, 65, 1144.
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62
Proposed Catalytic Cycle
Akiyama, T. Angew. Chem. Int. Ed. 2009, 48, 8070.
Driver, T. G. Angew. Chem. Int. Ed. 2009, 48, 7974.
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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
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