ORGANIC
LETTERS
2003
Vol. 5, No. 23
4417-4420
Highly Diastereoselective
Simmons−Smith Cyclopropanation of
Allylic Amines
Varinder K. Aggarwal,* Guang Yu Fang,† and Graham Meek‡
,†
Department of Chemistry, UniVersity of Bristol, Cantock’s Close, Bristol, U.K., and
Dowpharma, Chirotech Technology Ltd., Cambridge Science Park, Milton Road,
Cambridge, U.K.
Received September 8, 2003
ABSTRACT
Cyclopropanation of allylic tertiary amines using the Simmons−Smith reagent has been achieved by employing chelating groups in close
proximity to the amine. The chelating groups promote cyclopropanation at the expense of N-ylide formation. Using pseudoephedrine as the
chelating group, high diastereoselectivity is observed.
Simmons-Smith-type reagents1 are widely used to cyclo-
propanate a range of alkenes.2 Features that contribute to
their popularity include broad substrate generality, tolerance
of a variety of functional groups, stereospecificity with
respect to alkene geometry, and the syn-directing/rate-
enhancing effect observed with proximal oxygen atoms.
Much of the development of stereoselective cyclopro-
panation has relied on the directing effect of an allylic/
homoallylic oxygen functional group, which provides an
oxygen atom to chelate with the zinc reagent. Functional
groups involved in substrate-controlled diastereoselective
Simmons-Smith cyclopropanations include hydroxyl,3
acetal,4,5 amide,6 and borate7 groups. However, even though
amines have the same potential for binding with the zinc
reagent as oxygen functional groups, allylic amines have not
been explored in Simmons-Smith cyclopropanation;8 only
enamines9 and non-nucleophilic allylic amides10 have been
reported. The problem associated with the cyclopropanation
of allylic amines (or olefins containing an amino group) is
the competing ylide formation pathway. It has been reported
that trimethylamine reacted with Zn(CH2Cl)2 generating a
zinc-complexed ammonium ylide,11 and our group also found
that ylide formation was the predominant pathway when
simple allylic amines were treated with Zn(CH2I)2. The
resulting zinc-complexed ammonium ylides were rather
stable but upon addition of nBuLi were converted into
reactive zincate intermediates, which were capable of
undergoing [2,3] sigmatropic rearrangements (Scheme 1).12
† University of Bristol.
‡ Dowpharma, Chirotech Technology Ltd., a subsidiary of the Dow
Chemical Company.
(6) Tanaka, K.; Uno, H.; Osuga, H.; Suzuki, H. Tetrahedron: Asymmetry
1994, 5, 1175
(7) Imai, T.; Mineta, H.; Nishida, S. J. Org. Chem. 1990, 55, 4986.
(8) Although a single example of the cyclopropanation of an allylic amine
was reported, no details were provided. See: Perraud, R.; Arnaud, P. Bull.
Soc. Chim. Fr. 1968, 1540.
(9) (a) Kuehne, M. E.; DiVincenzo, G. J. Org. Chem. 1972, 37, 1023.
(b) Kuehne, M. E.; King, J. C. J. Org. Chem. 1973, 38, 304.
(10) (a) Wipf, P.; Kendall, C.; Stephenson, C. R. J. J. Am. Chem. Soc.
2003, 125, 761. (b) Russ, P.; Ezzitouni, A.; Marquez, V. E. Tetrahedron
Lett. 1997, 38, 723. (c) Ezzitouni, A.; Russ, P.; Marquez, V. E. J. Org.
Chem. 1997, 62, 4870.
(1) (a) Simmons, H. E.; Smith, R. D. J. Am. Chem. Soc. 1958, 80, 5323.
(b) Simmons, H. E.; Smith, R. D. J. Am. Chem. Soc. 1959, 81, 4256.
(2) For a review on Simmons-Smith cyclopropanation, see: Charette,
A.; Beauchemin, A. Org. React. 2001, 58, 1.
(3) (a) Sugimura, T.; Yoshikawa, M.; Futagawa, T.; Tai, A. Tetrahedron
1990, 46, 5955. (b) Charette, A. B.; Coˆte´, B.; Marcoux, J.-F. J. Am. Chem.
Soc. 1991, 113, 8166. (c) Charette, A. B.; Marcoux, J.-F. Tetrahedron Lett.
1993, 34, 7157.
(4) (a) Kaye, P. T.; Molema, W. E. Chem. Commun. 1998, 2479. (b)
Arai, I.; Mori, A.; Yamamoto, H. J. Am. Chem. Soc. 1985, 107, 8254.
(5) Mash, E. A.; Hemperly, S. B.; Nelson, K. A.; Heidt, P. C.; Deusen,
S. V. J. Org. Chem. 1990, 55, 2045.
(11) Wittig, G.; Schwarzenbach, K. Liebigs Ann. Chem. 1961, 650, 1.
10.1021/ol035713b CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/16/2003