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 DeltaE(rxn) values being calculated for the successful deprotonations and positive DeltaE(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 alpha-keto carbanions.
Hayes
Christopher J
CJ
School of Chemistry, The University of Nottingham, University Park, Nottingham, NG7 2RD United Kingdom.
Simpkins
Nigel S
NS
Kirk
Douglas T
DT
Mitchell
Lee
L
Baudoux
Jerome
J
Blake
Alexander J
AJ
Wilson
Claire
C
D001952:Bridged-Ring Compounds / Q000737:chemistry*; D003198:Computer Simulation; D007094:Imides / Q000737:chemistry*; D007659:Ketones / Q000737:chemistry*; D007769:Lactams / Q000737:chemistry*; D007783:Lactones / Q000737:chemistry*; D008094:Lithium / Q000737:chemistry*; D008432:Mathematical Computing; D008956:Models, Chemical; D015394:Molecular Structure
D001952:Bridged-Ring Compounds; D007094:Imides; D007659:Ketones; D007769:Lactams; D007783:Lactones; D008094:Lithium