Retropinacol rearrangement in the synthesis of 3,3,4-trimethyl-2-azaspiro[4.5]deca-1,6,9-trien-8-one derivatives

Abstract

In the recent years 2-azaspiro[4.5]deca-1,6,9-trien8-one derivatives have attracted researchers’ attention due to their biological activity [1, 2]. These compounds may be synthesized in different ways; for example, 7-methoxy-2-methyl-2-azaspiro[4.5]deca-6,9diene-3,8-dione was obtained by heating 2-[(3,4-dimethoxybenzyl)(methyl)amino]-2-oxoethyldiazonium salt for a short time [3]. The simplest procedure for the synthesis of 2-azaspiro[4.5]deca-1,6,9-trien-8-one derivatives is based on three-component condensation of substituted anisole with isobutyraldehyde and nitrile in concentrated sulfuric acid [4–7]. Generation of carbenium ion as key intermediate in the Ritter heterocyclization is also possible via retropinacol rearrangement of the corresponding alcohol [8]; in this way, 3,3,4-trimethyl-3,4-dihydroisoquinoline derivatives can be obtained. In fact, by reaction of anisole (I) or 1-methoxynaphthalene (II) with pivalaldehyde and nitriles (such as methyl thiocyanate and methyl and ethyl cyanoacetates) under the conditions described in [8] we obtained the corresponding 2-azaspiro[4.5]deca-1,6,9-trien-8-one derivatives III–VIII in 28–49% yield (Scheme 1). The reaction was accompanied by concurrent Danilov rearrangement [9], so that 2 equiv of pivalaldehyde was necessary.