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Chatani, N. et al., Org. Lett. 2007, 9, 3351-3353
Amol Kulkarni @ Wipf Group 1 10/29/2007
Ambiphilic Reactivity of IsocyanidesN R+-
N R
isocyanides
• Isocyanides possess unique reactivity due to the presence of a formally divalent carbon atom
• Nucleophilic reactions dominate; electrophilic reactions commonly observed with strong nuclephiles
Domling, A., Chem. Rev. 2006, 106, 17-89Amol Kulkarni @ Wipf Group 2 10/29/2007
Isocyanides As Nucleophiles
H R1
NHR2
+
R4CO2-
N R3
+-
Ugi Multicomponent Coupling Reaction
Ugi, I., Pure Appl. Chem. 2001, 73, 187-191
H R1
O
+ R2NH2 + N R3
+-+ R4CO2H
R4 NR2
O
NHR3
O
H R1solvent
Passerini Reaction
R1CO2H +R2 R3
O
N R4
+-+
apolar
solvent ONHR4
O
R1
R2 R3
O
Ostaszewski, R. et al., Pure Appl. Chem. 2003, 75, 413-419Amol Kulkarni @ Wipf Group 3 10/29/2007
Synthesis of substituted Furans
Nair, V.; Vinod, A. U., Chem. Commun. 2000, 1019-1020
Mechanistically…..
Amol Kulkarni @ Wipf Group 4 10/29/2007
Synthesis of Highly Substituted Furo[2,3-c]quinolines
0.1 M in tolueneRT to reflux, 15 h
Zhu, J.; Fayol, A., Angew. Chem. Int. Ed. 2002, 41, 3633-3635 Amol Kulkarni @ Wipf Group 5 10/29/2007
Isocyanides As ElectrophilesAddition of Alkyl Lithium and Alkyl Grignard Reagents
R-M + NR1
-+ pentane
rtN
R1 M
RH2O
N
R1 H
RH3O+
O
H
R
M = Li
= MgBr
Walborsky, H. M. et al., J. Org. Chem. 1974, 39, 600-604
Addition of Dialkyl Zinc Reagents
R2Zn +
N
C
toluene
rt
N
ZnRR
TMSCl, DMF
74%
N
TMSR
Ito, Y. et al., J. Org. Chem. 1988, 53, 4158-4159Amol Kulkarni @ Wipf Group 6 10/29/2007
Activation with Lewis Acids: s-cis ketones
Chatani, N. et al., J. Am. Chem. Soc. 2005, 127, 761-766
Isocyanides As Electrophiles
Activation with Lewis Acids: s-trans ketones
Winkler, J. D.; Asselin, S. M., Org. Lett. 2006, 8, 3975-3977
O
Nu N R
+-
O-LA
Nu
NR+
O
NR
Nu
Amol Kulkarni @ Wipf Group 7 10/29/2007
Initial Experiments
Chatani, N. et al., Org. Lett. 2007, 9, 3351-3353
2alewis acid
PhMe, rt3a
lewis acid
BF3.OEt2
GaCl3
In(OTf)3
yield (%)
68
86
90
entry
1
2
3
1 +
• A formal insertion of the isocyanide into the aromatic C-H bond• Group 13 elements: excellent promoters• Intermolecular reaction is unprecedented
N
NC
BF3.OEt2 (0.1 equiv)
CH2Cl2, 0 ˚CN
N
H
Kobayashi, K., et al., Chem. Lett. 1998, 9, 551-552
Amol Kulkarni @ Wipf Group 8 10/29/2007
Substrate Scope
• AlCl3-mediated insertion exhibits a wide substrate scope• Electron withdrawing groups on indole: not tolerated
Chatani, N. et al., Org. Lett. 2007, 9, 3351-3353
Ar = 2,6-dimethylphenyl
+ 3-subst.isomer (6%)
run at60 ˚C
run at60 ˚C
Heterocycle (1.0 mmole)
Isocyanide (1.2 mmole)
AlCl3 (1.2 mmole),
toluene, rt, 15 h
Amol Kulkarni @ Wipf Group 9 10/29/2007
Labeling Experiments
Chatani, N. et al., Org. Lett. 2007, 9, 3351-3353
GaCl3: more soluble inNon-polar solvents
1H-NMR experiment with GaCl3
• H at C-3 is transferred to the imino carbon in the product
Amol Kulkarni @ Wipf Group 10 10/29/2007
Proposed Mechanism
Chatani, N. et al., Org. Lett. 2007, 9, 3351-3353
Nucleophilic attack of the indole onto LA-activated isocyanideRearomatization via deprotonation and protonolysis of C-M bond
Alternative Mechanism
• Treatment of a solution of indole + isonitrile with LA: no interaction between indole and LA
Amol Kulkarni @ Wipf Group 11 10/29/2007
Further Structural Elaboration
Conclusions• A novel protocol for the α-addition of isocyanides to aromatic compounds promoted by inexpensive LAs has been developed
• This method provides a direct and practical access to a wide variety of imines via aromatic C-H bond functionalization
• Ongoing research seeks to explore this new isocyanide insertion process into other chemical bonds
Amol Kulkarni @ Wipf Group 12 10/29/2007
Isocyanides: Metal-Mediated MCRsSynthesis of allyl aryl cyanamides
Kamijo, S.; Yamamoto, Y., J. Am. Chem. Soc. 2002, 124, 11940-11945
Synthesis of N-cyanoindoles
Amol Kulkarni @ Wipf Group 13 10/29/2007
Kamijo, S.; Yamamoto, Y., J. Am. Chem. Soc. 2002, 124, 11940-11945
Mechanism of the formation of N-cyanoindoles
Amol Kulkarni @ Wipf Group 14 10/29/2007
