Regioselectivity of the nucleophilic additions and substitutions of 3-(4ʹ,4ʹ-dimethyl-2ʹ-oxazolinyl)pyridine by organolithium compounds

Abstract

Procedures for preparing 3-(4',4'-dimethyl-2'-oxazolinyl)pyridine and 4-(4',4'-dimethyl-2'-oxazolinyl)pyridine were developed. The nucleophilic heteroaromatic addition reactions of 3-(4',4'~ dimethyl-2'-oxazolinyl)pyridine with methyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium and phenyllithium as nucleophilic reagents were investigated. Stable crystalline 4-substituted 3-- (4',4'-- dimethyl-2'-oxazolinyl)-1,4-dihydropyridine addition products were isolated in good yields. The dihydropyridines could be oxidized to the corresponding 3,4-disubstituted pyridines by a variety of oxidizing agents. Thus, the regiochemistry of the addition indicated that the gamma rather than the alpha position of the pyridine ring was preferentially attacked. The analogous nucleophilic heteroaromatic substitution reactions were also studied. The reaction of 3-(4',4'-dimethyl-2'-oxazolinyl)- pyridine with n-butyllithium gave a mixture of products, namely, 2-nbutyl-, 4-n-butyl and 6-n-butyl-3-(4',4'-diemthyl-2'-oxazolinyl)- pyridine; however, the predominant product was 4-n-butyl-3-(4',4'- dimethyl-2'-oxazolinyl)pyridine. With sec-butyllithium, 2-sec-butyl and 4-sec-butyl-3-(4',4'-dimethyl-2'-oxazolinyl)pyridine were obtained; again, the 4-sec-butyl derivative was the major isomer. With methyllithium or phenyllithium, the 3,4-isomer was also the predominant product. With tert-butyllithium. the 3,4-isomeric product was not isolated; instead, considerable amounts of the starting compound, 3- (4',4'-dimethyl-2'-oxazolinyl)pyridine, was recovered. The expected 4-product could have been formed in the reaction, but there was evidence that it was dealkylated to the starting compound..