High pressure vs. thermal activation in the conjugate addition of amines: a new access to spirocyclamines

Abstract

The reactions of methyl or ethyl 4-tert-butylcyclohexylidene bromoacetates 3-Me or 3-Et with amines afford various products depending on the experimental conditions and the nature of the amine. When the starting ester 3 is treated with benzylamine in refluxing methanol, the ester 5 and the corresponding amide 6 are isolated as the main reaction products. By contrast, the same reaction at room temperature and under high pressure leads to a spiro aziridine derivative 4 in good yield and high stereoselectivity. On the other hand, when ester 3 reacts with secondary amines in refluxing alcohol, the corresponding α-amino β,γ-unsaturated ester 7 is isolated as the sole product of the reaction in good yield. In toluene, the same reaction produces, in addition to the deconjugation–substitution compound 7, the isomeric γ-amino α,β-unsaturated ester 8. Finally, the hetero-Michael type addition of alcohol is the main reaction when substrate 3 is treated with methanol in the presence of a secondary or tertiary amine under high pressure, leading to β-substituted ester 9.