ortho-Directed Lithiation Studies of 4-Chloropicolinanilide : Introduction of Functional Groups at C-3 and Their Elaboration to Chain Extended Derivatives via Carbon-Carbon Bond Formation

An improved synthesis of 4-chloropicolinanilide (3) is presented.Treatment of 3 with lithium diisopropylamide (LDA) in THF, followed by addition of an electrophile (methyl iodide, iodine, carbon dioxide, trimethylstannyl chloride), gave exclusively the products of C-3 substitution (respectively, the 3-methyl-, 3-iodo, 3-carboxylic acid and 3-trimethylstannyl derivatives of 3).Further treatment of the 3-methyl derivative (7) with carbon dioxide or ethyl bromoacetate produced the one-and two-carbon homologues of 4-chloroquinolinanilide (8 and 9, respectively).The palladium acetate-catalyzed reaction of 4-chloro-3-iodopicolinanilide (10) with various unsaturated derivatives (trimethylsilylacetylene, tri-n-hutyl(vinyl)tin, styrene, acrylonitrile, methyl acrylate) afforded the corresponding C-3 cross-coupled products in 70-80% yield.Reaction of 10 with ally1 alkoxide, followed by treatment of the product (17) with tri-n-butyltin hydride, provided the 2-methylfuro[3,2-clpyridine derivative (18) in 85% yield.As part of a research program aimed at developing new agents acting on the central nervous system, we have been interested in synthesizing trifunctionalized derivatives of pyridine, in particular, those This paper is dedicated to Dr. Koji Nakanishi on the occasion of his 75th birthday