Bridgehead Lithiation-Substitution of Bridged Ketones, Lactones, Lactams, and Imides: Experimental Observations and Computational Insights

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 ΔE_rxn values being calculated for the successful deprotonations and positive ΔE_rxn 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.