Synthesis of 3,4-Disubstituted Pyridines Starting from Baylis-Hillman Adducts Using Schweizer Reaction

Abstract

Recently, we have reported the facile synthesis of polysubstituted pyridine derivatives from the Baylis-Hillman adducts. As shown in Scheme 1, the Baylis-Hillman adducts of alkyl vinyl ketone 1a could be converted easily into their tosylamide derivatives 2a. Sequential Michael addition of 2a to the appropriate Michael acceptor, aldol type cyclization, dehydration, elimination of p-toluenesulfinic acid, and the final isomerization afforded polysubstituted pyridines. In the reaction, compound 2a served threecarbons and one-nitrogen atom for the final pyridine while the Michael acceptor served two-carbon atoms. In this paper we wish to report the application of another two-carbon unit, vinyltriphenylphosphonium bromide (3a, Schweizer reagent), for the synthesis of 3,4-disubstituted pyridines. Extensive efforts have been devoted to the synthesis of 3,4-disubstituted pyridine derivatives due to their biological importance and the usefulness as synthetic intermediates. As shown in Scheme 2 and in Table 1, the reaction of 2a and 3a in CH3CN in the presence of DBU at 40-50 C for 16 h afforded 5a in 72% yield. Benzylidene derivative 5a must be formed via the successive Michael-Wittig reaction (Schweizer reaction). We could prepare 3-benzyl-4-methylpyridine (6a) from the reaction of 5a under K2CO3/DMF