Bridgehead lithiation-substitution of bridged ketones, lactones, lactams, and imides: experimental observations and computational insights

Hayes, C. J., Simpkins, N. S., Kirk, D. T., Mitchell, L., Baudoux, J., Blake, A. J. and Wilson, C. (2009) Bridgehead lithiation-substitution of bridged ketones, lactones, lactams, and imides: experimental observations and computational insights. Journal of the American Chemical Society, 131(23), pp. 8196-8210. (doi: 10.1021/ja9009875) (PMID:19507906)

Abstract

The viability of bridgehead lithiation-substitution of bridged carbonyl compounds has been tested in the laboratory, and the results were rationalized with the aid of a computational study. Lithiation-substitution was found to be possible for ketones, lactones, lactams, and imides having small bridges, including examples having [3.2.1], [3.2.2], [3.3.1], [4.2.1], and [4.3.1] skeletons. Smaller systems, where the sum of the bridging atoms (S) was 5, for example [2.2.1] or [3.1.1] ketones or [2.2.1] lactams, did not undergo controlled bridgehead substitution. Ketones or lactams having a [2.2.2] structure also did not give bridgehead substitution. B3LYP calculations accurately predict this behavior with negative ΔErxn values being calculated for the successful deprotonations and positive ΔErxn values being calculated for the unsuccessful ones. NBO calculations were also performed on the anionic deprotonated species, and these show that some structures are best represented as bridgehead enolates and some are best represented as α-keto carbanions.

• Item Type: Articles
• Additional Information: We thank the Engineering and Physical Sciences Research Council (EPSRC) for support of L.M. and J.B. through funding of a postdoctoral fellowship. We also thank the University of Nottingham, and GlaxoSmithKline, Stevenage, U.K., for support of D.T.K. through funding of a research studentship.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Wilson, Dr Claire
• Authors: Hayes, C. J., Simpkins, N. S., Kirk, D. T., Mitchell, L., Baudoux, J., Blake, A. J., and Wilson, C.
• College/School: College of Science and Engineering > School of Chemistry
• Journal Name: Journal of the American Chemical Society
• Publisher: American Chemical Society
• ISSN: 0002-7863
• ISSN (Online): 1520-5126