ORGANIC
LETTERS
2007
Vol. 9, No. 23
4909-4912
Cyclic Sulfamidates as Precursors to
Alkylidene Pyrrolidines and Piperidines
John F. Bower,† Peter Szeto,‡ and Timothy Gallagher*,†
School of Chemistry, UniVersity of Bristol, Bristol BS8 1TS, U.K., and Synthetic
Chemistry, GlaxoSmithKline, Medicines Research Centre, SteVenage SG1 2NY, U.K.
Received September 8, 2007
ABSTRACT
The reaction of the dienolate of ethyl acetoacetate (and related dienolates) with a range of 1,2- and 1,3-cyclic sulfamidates provides an entry
to substituted and enantiopure alkylidenated pyrrolidines and piperidines. These heterocycles function as convenient precursors to heterocyclic
â
-amino acid derivatives.
Alkylidene variants of pyrrolidines and piperidines (1 and
2) represent a versatile family of N-heterocycles which have
found numerous applications in a variety of synthetic
settings.1 The most common route to members of this class
of compound involves alkylidenation of a lactam precursor
by activation of the otherwise unreactive carbonyl unit. In
this regard, the classical Eschenmoser sulfide contraction of
thiolactams has found widespread application2 as has lactam
activation via the corresponding iminoether.3,4 While ef-
ficient, these approaches necessarily rely on first obtaining
a suitably substituted (and enantiopure) lactam precursor.
We are interested in heterocyclic alkylidenes 1 and 2 as
suitable intermediates for the synthesis of substituted (and
enantioenriched) homoproline and homopipecolinic acid
derivatives, respectively. Accordingly, we sought a direct
but flexible entry which would provide access to range of
substitution patterns, and in this paper, we disclose our
studies in this area. We have explored the reactivity of 1,2-
and 1,3-cyclic sulfamidates 3 with both heteroatom and
carbon-based nucleophiles to provide a variety of N-
heterocyclic scaffolds, including 4 and 5 (Scheme 1).5,6
† University of Bristol.
‡ GlaxoSmithKline.
(1) For a review on the synthesis and reactivity of alkylidene pyrrolidines,
see: Elliott, M. C.; Wood, J. L.; Wordingham, S. V. Trends Heterocycl.
Chem. 2005, 10, 73-95.
(2) (a) Fischli, A.; Eschenmoser, A. Angew. Chem., Int. Ed. 1967, 6,
866-868. (b) Yamada, Y.; Miljkovic, D.; Wehrli, P.; Golding, B.; Lo¨liger,
P.; Keese, R.; Mu¨ller, K.; Eschenmoser, A. Angew. Chem., Int. Ed. 1969,
8, 343-348. (c) Roth, M.; Dubs, P.; Go¨tschi, E.; Eschenmoser, A. HelV.
Chim. Acta, 1971, 54, 710-734. For other selected examples of this method,
see: (d) Gossauer, A.; Hinze, R.-P.; Zilch, H. Angew. Chem., Int. Ed. 1977,
16, 418-418. (e) Shiosaki, K.; Rapoport, H. J. Org. Chem. 1985, 50, 1229-
1239. (f) Honda, T.; Kimura, M. Org. Lett. 2000, 2, 3925-3927.
(3) For selected examples of lactam alkylidenation via the intermediacy
of imino ethers, see: (a) Ce´le´rier, J.-P.; Deloisy, E.; Lhommet, G.; Maitte,
P. J. Org. Chem. 1979, 44, 3089-3089. (b) Coppola, G. M.; Damon, R. E.
A. J. Heterocyclic Chem. 1990, 27, 815-817. (c) Millet, R.; Domarkas, J.;
Rombaux, P.; Rigo, B.; Houssin, R.; He´nichart, J.-P. Tetrahedron Lett. 2002,
43, 5087-5088.
(4) For other selected approaches to alkylidene pyrrolidines, see: (a)
Breuer, E.; Zbaida, S. J. Org. Chem. 1977, 42, 1904-1910. (b) Hannick,
S. M.; Kishi, Y. J. Org. Chem. 1983, 48, 3833-3835. (c) Lambert, P. H.;
Vaultier, M.; Carrie´, R. J. Org. Chem. 1985, 50, 5352-5356. (d) Shaw, K.
J.; Luly, J. R.; Rapoport, H. J. Org. Chem. 1985, 50, 4515-4523. (e)
Michael, J. P.; Hosken, G. D.; Howard, A. S. Tetrahedron 1988, 44, 3025-
3036. (f) Jacobi, P. A.; Brielmann, H. L.; Hauck, S. I. J. Org. Chem. 1996,
61, 5013-5023. (g) Jacobi, P. A.; Buddhu, S. C.; Fry, D.; Rajeswari, S. J.
Org. Chem. 1997, 62, 2894-2906. (h) Langer, P.; Freifeld, I. Chem.
Commun. 2002, 2668-2669. (i) Elliott, M. C.; Wordingham, S. V. Synthesis
2006, 1162-1170.
(5) For a review on the synthesis and reactivity of cyclic sulfamidates,
see: Mele´ndez, R. E.; Lubell, W. D. Tetrahedron 2003, 59, 2581-2616.
10.1021/ol7022104 CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/20/2007