ORGANIC LETTERS
Azomethine Ylides from Tin-Substituted Cyclic Carbinol Amides: A New Route to Highly Substituted Pyrrolizidines
2004 Vol. 6, No. 6 1005-1008
William H. Pearson,*,† Amber Dietz, and Patrick Stoy Department of Chemistry, UniVersity of Michigan, 930 North UniVersity AVe., Ann Arbor, Michigan 48109-1055
[email protected] Received January 12, 2004
ABSTRACT
Addition of organolithium and organomagnesium reagents to N-(tri-n-butylstannylmethyl)phthalimides yields N-(tri-n-butylstannylmethyl) cyclic carbinol amides, which form azomethine ylides upon treatment with HF‚pyridine. This novel route to azomethine ylides allows rapid access to highly functionalized pyrrolizidines (1,2,3,9b-tetrahydropyrrolo[2,1-a]isoindol-5-ones).
We have a longstanding interest in N-(tri-n-butylstannylmethyl)phthalimides1 (e.g., 1) as intermediates in the synthesis of (2-azaallyl)stannanes,2 which are precursors to nonstabilized 2-azaallyllithiums2a,c,3 and nonstabilized azomethine ylides4 and also serve as R,R′-aminodication equivalents.2b We have also been interested in the chemistry of R-amino organolithiums generated by tin-lithium exchange of R-aminostannanes.5 In the course of attempting to generate the novel R-amino organolithium 2 from N-(tri-n-butylstannylmethyl)phthalimide 1, we observed that under typical tinlithium exchange conditions (n-BuLi, -78 °C, THF) the † Current address: Berry & Associates, Inc., 2434 Bishop Circle East, Dexter, MI, 48130. (1) Chong, J. M.; Park, S. B. J. Org. Chem. 1992, 57, 2220-2222. (2) (a) Pearson, W. H.; Stoy, P. Synlett 2003, 903-921. (b) Pearson, W. H.; Aponick, A. Org. Lett. 2001, 3, 1327-1330. (c) Pearson, W. H.; Postich, M. J. J. Org. Chem. 1992, 57, 6354-6356. (3) Pearson, W. H.; Szura, D. P.; Postich, M. J. J. Am. Chem. Soc. 1992, 114, 1329-1345. (4) (a) Pearson, W. H.; Clark, R. B. Tetrahedron Lett. 1999, 40, 44674471. (b) Clark, R. B.; Pearson, W. H. Org. Lett. 1999, 1, 349-351. (c) Pearson, W. H.; Mi, Y. Tetrahedron Lett. 1997, 38, 5441-5444. (d) Pearson, W. H.; Stoy, P.; Mi, Y. J. Org. Chem. 2004, in press. (5) (a) Pearson, W. H.; Lindbeck, A. C.; Kampf, J. W. J. Am. Chem. Soc. 1993, 115, 2622-2636. (b) Pearson, W. H.; Lindbeck, A. C. J. Am. Chem. Soc. 1991, 113, 8546-8548. (c) Pearson, W. H.; Lindbeck, A. C. J. Org. Chem. 1989, 54, 5651-5654.
10.1021/ol0499304 CCC: $27.50 Published on Web 02/25/2004
© 2004 American Chemical Society
addition of n-butyllithium to the imide group to give cyclic carbinol amide 3 is favored over tin-lithium exchange (Scheme 1). This observation is in contrast to the successful tin-lithium exchange of compounds bearing less electrophilic carbonyl groups such as ureas, carbamates, and amides.1,5,6 It was subsequently found that 3 formed an azomethine ylide upon treatment with HF‚pyridine, which underwent cycloaddition with N-methylmaleimide to form the pyrrolizidine cycloadduct 4 in excellent yield. Preliminary studies into the scope of this novel route to azomethine ylides and its application to a general synthesis of 1,2,3,9btetrahydropyrrolo[2,1-a]isoindol-5-one cycloadducts are described herein. The process by which an azomethine ylide is believed to be formed from cyclic carbinol amide 3 is outlined in Scheme 1. Treatment of 3 with HF‚pyridine in refluxing THF over 10 min induces the formation of N-acyliminium7 5, which (6) Some recent selected examples: (a) Christoph, G.; Hoppe, D. Org. Lett. 2002, 4, 2189-2192. (b) Clayden, J.; Helliwell, M.; Pink, J. H.; Westlund, N. J. Am. Chem. Soc. 2001, 123, 12449-12457. (c) Iula, D. M.; Gawley, R. E. J. Org. Chem. 2000, 65, 6196-6201. (7) N-Acyliminiums derived from cyclic carbinol amides have proved to be useful intermediates in the synthesis of nitrogen-containing heterocycles. See: Rashatasakhon, P.; Padwa, A. Org. Lett. 2003, 5, 189-191 and references therein.
Scheme 1
Table 1. Addition of Organometallics to Phthalimide 1
R-M
equiv
solvent
product
yielda
MeLi n-BuLi n-BuLi i-PrLi i-PrMgCl t-BuLi vinyl MgBr allyl MgBr PhLi PhMgBr
1.1 1.05 1.05 1.05 1.1 1.2 1.1 1.1 1.1 1.5
Et2O THF Et2O Et2O Et2O Et2O Et2O Et2O Et2O Et2O
7 3 3 8 8 9 10 11 12 12
93% 83% 95%
