Synthesis and rearrangement of 1-substituted 3,3,7-trimethyl-2-azaspiro[4.5]deca-1,6,9-trien-8-ones

Abstract

We previously synthesized 3,3-dimethyl-1-methylthio-2-azaspiro[4.5]deca-1,6,9-trien-8-one by threecomponent condensation of anisole, 1,2-epoxy-2methylpropane, and nitriles in the presence of concentrated sulfuric acid [1]. An analogous result was obtained in the reaction of anisole with isobutyraldehyde and nitriles [2]. Taking into account that the product composition strongly depends on the nature and position of substituents in the aromatic ring [3], we thought it reasonable to examine the same transformation of anisole homologs, in particular of methyl o-tolyl ether. We have fount that introduction of a methyl group into the ortho-position of anisole does not change the reaction direction. Addition of an equimolar mixture of methyl o-tolyl ether, isobutyraldehyde, and methyl thiocyanate to concentrated sulfuric acid at 035oC, followed by dilution of the reaction mixture with cold water and neutralization of the aqueous phase with ammonium carbonate, leads to formation of 3,3,7-trimethyl-1-methylthio-2-azaspiro[4.5]deca1,6,9-trien-8-one (IIa) in 67% yield. The isolated product was a single enantiomer whose configuration was not determined. The presence of an asymmetric spiro-carbon atom in molecule IIa is confirmed by the H NMR spectrum, where splitting of signals from diastereotopic protons of the CH2 and 3-CH3 groups is observed. Spiro compounds IIb and IIc, formed in the reactions with ethyl cyanoacetate and cyanoacetamide, undergo dienone3phenol rearrangement during isolation. As a result, amides III and IV were obtained. The relatively ready hydrolysis of structurally related ____________ * This study was financially supported by the Russian Foundation for Basic Research (project no. 01-03-96 479). spiro compounds with carbonyl-containing groups (derived from anisole) was noted by us previously [4]. 3,3,7-Trimethyl-1-methylthio-2-azaspiro[4.5]deca-1,6,9-trien-8-one (IIa). A mixture of 12.2 g (0.1 mol) of methyl o-tolyl ether, 7.2 g (0.1 mol) of isobutyraldehyde, and 7.3 g (0.1 mol) of methyl thiocyanate was added dropwise over a period of 15320 min to 50 ml of 96% sulfuric acid stirred at 035oC. The mixture was stirred for 30 min, poured into 300 ml of water, and extracted with 50 ml of toluene. The aqueous phase was separated and neutralized with (NH4)2CO3 to pH 839. The precipitate was filtered off, washed with water, dried, and recrystallized twice from methanol. Yield 15.75 g (67%), mp 63364oC. IR spectrum, n, cm: 1660 (CIO), 1630 (CIC), 1605 (CIN), 1580. H NMR spectrum, d, ppm: 1.36 s and 1.39 s (6H, 3-CH3), 1.82 s (3H, 7-CH3), 2.18 s and 2.20 s (2H, 4-H),