Cytotoxic compounds. Part 23. Reactions of the methanesulphonates of 2-(N-aryl-N-methylamino)propan-1-ols and of 1-(N-aryl-N-methylamino) propan-2-ols with nucleophiles

Abstract

Syntheses of the primary alcohols p-RC₆H₄·NMe·CHMe·CH₂·OH (from ethyl 2-bromopropanoate) and of the secondary isomers p-RC₆H₄·NMe·CH₂·CHMe·OH (from propylene oxide) are described (R = H, Cl, OMe, or NO₂). In solution, the primary methanesulphonates rearrange to the secondary isomers, a process facilitated by an electrondonating aryl substituent. Reactions of the primary and the secondary methanesulphonates with methanol, sodium methoxide, acetic acid, potassium acetate, tetramethylammonium acetate, sodium phenyl sulphide, sodium benzyl sulphide, lithium bromide, and sodium azide show that with weak nucleophiles the intermediate aziridinium ion is opened almost exclusively to give the secondary substitution product; with more powerful nucleophiles some sterically-controlled opening occurs to give also some primary product. When the formation of the aziridinium ion is retarded by the presence of an electron-attracting aryl substituent, strong nucleophiles can effect direct S_N2 substitution on the methanesulphonates to give unrearranged products. The N-methyl resonances in the ¹H n.m.r. spectra of the primary compounds are consistently at higher field than those of the secondary isomers.