Proximity- and Chelation-Induced SNAr 1,4-Aromatic ortho-Substitution of ortho-Methoxyphenyl 2-Alkyl Ketones

Abstract

OMe X O R 1 R 2 MgBr R 2 X O R 1 13 examples 68-99% X = H, OMe, Br, Cl R 1 = alkyl, cycloalkyl R 2 = alkyl, alkenyl, aryl Abstract The direct displacement of an o-methoxy group in o-methoxyaryl ketones with aryl, alkyl, and alkenyl Grignard reagents to provide a series of o-substituted ketones is described. Application of this reaction to the synthesis of a C-methyl analogue of a cyclooxygenase inhibitor is shown. The scope and limitations are discussed.In the course of our synthetic studies on the diastereoselective arylation of 2-alkylbenzylic alcohols, 1 ketone 1a was treated with p-methoxyphenylmagnesium bromide with the intention of obtaining the corresponding benzylic tertiary alcohol 2a (Scheme 1).We were initially surprised to find that the biaryl adduct 3a was formed in 59% yield, in addition to the expected alcohol 2a (30%). In this reaction, we had effectively replaced the o-methoxy group with an aryl group. Intrigued by this result, we were led through a literature search to the pioneering work by Fuson and Speck, who in 1942 had reported that o-methoxybenzoylmesitylene reacted with phenylmagnesium bromide in refluxing benzene to afford 2-phenylbenzoylmesitylene in 35% yield. 2 The reaction was extended to o-methoxynaphthoylmesitylene with higher yields (Scheme 2). Further examples included the direct oarylation of hindered aromatic ketones and esters in what amounts to a replacement of an aromatic C-H with an aryl moiety provided by the Grignard reagent. 3 Since then, several examples of S N Ar displacement of o-methoxy groups with Grignard reagents in aromatic esters 4 and oxazolines 5 have been reported. In 2011, Shaw and co-workers 6 revisitScheme 1 Unexpected 1,4-aromatic substitution of o-methoxyaryl alkyl ketones MeO OMe O 1a OMe MgBr (2 equiv) MeO OMe 2a (30%) OMe OH + MeO 3a (59%) OMe O Et 2 O, 0 °C SYNTHESIS0 0 3 9 -7 8 8 1 1 4 3 7 -2 1 0 X © Georg Thieme Verlag Stuttgart · New York 2015, 47, 1091-1100 paper Downloaded by: University of Queensland. Copyrighted material.