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Paper | Special issue | Vol 47, No. 2, 1998, pp.811-827
Published online, 1st January, 1970
DOI: 10.3987/COM-97-S(N)84
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

Marcus V. Nora de Souza and Robert H. Dodd*

*Institut de Chimie des Substances Naturelles, Centre National de la Recherche Scientifique, Avenue de la Terrasse, Bat. 27, 91198 Gif-sur-Yvette Cedex, France

Abstract

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 allyl alkoxide, followed by treatment of the product (17) with tri-n-butyltin hydride, provided the 2-methylfuro[3,2-c]pyridine derivative (18) in 85% yield.