
%0 Journal Article
%A Eastwood, FW 
%A Gunawardana, D 
%A Wernert, GT 
%T Lithiation of bridgehead positions in 3,6-bridged piperazine-2,5-diones
%J Australian Journal of Chemistry
%D 1982/11/01
%V 35
%N 11
%P 2289-2298
%K 
%R https://doi.org/10.1071/CH9822289
%U https://www.publish.csiro.au/paper/CH9822289 
%X 2,5-Dimethyl-2,5 diazabicyclo[2,2,2]octane-3,6-dione can be lithiated at the 1,4 (bridgehead) positions with 2 equiv. of t-butyllithium at -78º and deuterated with D2O (Do, 11.2; Dl, 56.1 ; D2, 30.1%). With butyllithium and methyl iodide the 1,2,5-trimethyl and 1,2,4,5-tetramethyl derivatives are obtained. Treatment of dimethyl 2,6-diaminoheptanedioate dihydrochloride with sodium methoxide in boiling butanol gives 6,8-diazabicyclo[3,2,2]nonane-7,9-dione in 62% yield. N-Methylation of this compound yields 6,8-dimethyl-6,8-diazabicyclo[3,2,2]nonane-7,9-dione which can similarly be lithiated at the 1,5 (bridgehead) positions and deuterated with D2O (Do, 5.6; Dl, 70.8; D2, 23.6%). Lithiation with butyllithium and reaction with methyl iodide, benzyl iodide or bromomethyl methyl ether gives mono-and di-alkylated products at the 1,5-positions. The ability to lithiate the bridgehead positions in these compounds is attributed primarily to a combination of the inductive effect of the carbonyl group and dipole stabilization by the amide nitrogen. 
