Published on Web 05/01/2003
New Strategic Reactions for Organic Synthesis: Catalytic
Asymmetric C-H Activation r to Nitrogen as a Surrogate for
the Mannich Reaction
Huw M. L. Davies,* Chandrasekar Venkataramani, Tore Hansen, and
Darrin W. Hopper
Contribution from the Department of Chemistry, UniVersity at Buffalo, State UniVersity of
New York, Buffalo, New York 14260-3000
Received October 18, 2002; E-mail: hdavies@acsu.buffalo.edu
Abstract: The asymmetric C-H activation reactions of methyl aryldiazoacetates are readily induced by
the rhodium prolinate catalyst Rh2(S-DOSP)4 (1) or the bridged prolinate catalysts Rh2(S-biDOSP)2 (2a)
and Rh2(S-biTISP)2 (2b). The C-H activation of N-Boc-protected cyclic amines demonstrates that the donor/
acceptor-substituted carbenoids display remarkable chemoselectivity, which allows for highly regioselective,
diastereoselective, and enantioselective reactions to be achieved. Furthermore, the reactions can display
high levels of double stereodifferentiation and kinetic resolution. The C-H activation is caused by a rhodium
carbenoid induced C-H insertion. The potential of this chemistry is demonstrated by a very direct synthesis
of threo-methylphenidate.
The development of practical methods that would achieve
functionalization of unactivated C-H bonds is of considerable
current interest.1,2 Recently, we reported a very general method
for intermolecular C-H activation by means of a rhodium
carbenoid induced C-H insertion.3,4 High asymmetric induction
can be achieved in this C-H activation process when these
reactions are catalyzed by dirhodium tetraprolinates. The
reaction is applicable to a wide range of substrates, and because
of subtle steric and electronic effects it is highly chemoselective.
We have previously communicated that asymmetric C-H
activation can occur R to N-Boc-protected cyclic amines (eq
1).3c,d This paper will give a full description of the scope of
this chemistry, with particular emphasis on the effect of ring
size and the factors that control the chemoselectivity and
diastereoselectivity. A further focus will be on the robust double
diastereoselection and kinetic resolution that is achievable with
this system. A particularly attractive feature of this methodology
is that the products are â-amino acid derivatives, and so it may
be considered as a new strategic reaction that is a surrogate for
the Mannich reaction.5
(1) For reviews on other methods for C-H activation, see: (a) Shilov, A. E.;
Shul’pin, G. B. Chem. ReV. 1997, 97, 2879. (b) Dyker, G. Angew. Chem.,
Int. Ed. 1999, 28, 1698. (c) Arndsten, B. A.; Bergman, R. G. Science 1995,
270, 1970. (d) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001,
34, 633. (e) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. ReV. 2002, 102, 1731.
(f) Labinger, J. A.; Bercaw, J. E. Nature 2002, 417, 507.
The successful development of the asymmetric intermolecular
C-H activation by rhodium carbenoids required much more
chemoselective carbenoid intermediates than the carbenoids
derived from diazoacetates, which had been typically used.6,7
(2) For recent representative examples of C-H activation, see: (a) Chen, H.;
Schlecht, S.; Semple, T. C.; Hartwig, J. F. Science 2000, 287, 1995. (b)
Waltz, K. M.; Hartwig, J. F. J. Am. Chem. Soc. 2000, 122, 11358. (c)
Johnson, J. A.; Li, N.; Sames, D. J. Am. Chem. Soc. 2002, 124, 6900. (d)
Dangel, B. D.; Godula, K.; Youn, S. W.; Sezen, B.; Sames, D. J. Am.
Chem. Soc. 2002, 124, 11856. (e) Karig, G.; Moon, M.-T.; Thasana, N.;
Gallagher, T. Org. Lett. 2002, 4, 3115. (f) Saaby, S.; Bayon, P.; Aburel, P.
S.; Jorgensen, K. A. J. Org. Chem. 2002, 67, 4352. (g) Tan, K. L.; Bergman,
R. G.; Ellman, J. A. J. Am. Chem. Soc. 2002, 124, 3202. (h) Zhong, H. A.;
Labinger, J. A.; Bercaw, J. E. J. Am. Chem. Soc. 2002, 124, 1378.
(3) (a) Davies, H. M. L.; Hansen, T. J. Am. Chem. Soc. 1997, 119, 9075. (b)
Davies, H. M. L.; Stafford, D. G.; Hansen, T. Org. Lett. 1999, 1, 233. (c)
Davies, H. M. L.; Antoulinakis, E. G.; Hansen, T. Org. Lett. 1999, 1, 383.
(d) Davies, H. M. L.; Hansen, T.; Hopper, D.; Panaro, S. A. J. Am. Chem.
Soc. 1999, 121, 6509. (e) Davies, H. M. L.; Hansen, T.; Churchill, M. R.
J. Am. Chem. Soc. 2000, 122, 3063. (f) Davies, H. M. L.; Antoulinakis, E.
G. Org. Lett. 2000, 2, 4153. (g) Davies, H. M. L.; Ren, P. J. Am. Chem.
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(5) For reviews and recent references on the catalytic asymmetric Mannich
reaction, see: (a) Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069.
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(i) Cordova, A.; Watanabe, S.-i.; Tanaka, F.; Notz, W.; Barbas, C. F., III.
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(6) (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for
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(4) For recent reviews, see: (a) Davies, H. M. L.; Antoulinakis, E. G. J.
Organomet. Chem. 2001, 617-618, 45. (b) Davies, H. M. L. J. Mol. Catal.
A 2002, 189, 125.
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10.1021/ja0290072 CCC: $25.00 © 2003 American Chemical Society