The N-cumyl group for facile manipulation of carboxamides, sulfonamides and aryl O-carbamates post-directed ortho metalation

Abstract

ortho-Substituted N-cumylbenzamides and aryl O-carbamates may be easily decumylated under a number of conditions. Treatment of secondary N-cumylbenzamides with a Lewis acid (BF3·OEt2/CH2Cl2/r.t.) gives primary amides in good yields, while application of Charette's conditions (Tf2O/pyridine/CH2Cl2-40°C) affords benzonitriles in one pot. Similarly, O-carbamates undergo rapid decumylation (TFA/r.t./6-10 min) to yield benzoxazines or secondary carbamates; the latter may be easily hydrolyzed to phenols (10% NaOH/EtOH/r.t.). Metalation of N-cumyl phthalimidine (2.2 equiv s-BuLi/TME-DA/THF/-78°C) followed by electrophile quench gives, after oxidation (PDC/DMF/r.t.) access to 3-substituted phthalimides that can be decumylated (TFA/50°C/9-16 h) in high yield. The method has been extended to TMS-protected sultams derived from N-cumylbenzenesulfonamide, to afford 7-substituted saccharins after simple desilylation (K2CO3/MeOH), oxidation (PDC/DMF/r.t.) and decumylation (CF3CH2OH/reflux/90 min). Alternatively, decumylation of 7-substituted TMS-protected sultams (CF3CH2OH/reflux) provide direct access to 7-substituted benzisothiazole-1,1-dioxides. Weinreb has shown that N-cumyl-N-(α-methoxy)benzylbenzamides may be used to generate N-acylimines (BF3·OEt2/CH2Cl2/r.t./ 18-21 h) which can be trapped with allyltrimethylsilane, with concomitant loss of the N-cumyl group, to afford N-homoallylic secondary benzamides. Clayden has used N-cumyl-N-benzylbenzamides to induce dearomatizing cyclization reactions, initiated by benzylic anion formation (2 equiv t-BuLi/12 equiv HMPA/THF/-40°C), to provide enone products after acidic workup. The use of cumyl as the N-protecting group in such systems was a key aspect to the successful synthesis of (±)-kainic acid, since the corresponding t-Bu analogue failed to dealkylate under identical conditions (TFA/reflux/6 h). Enantioselective applications are also possible. N-Cumyl-N-ethylferrocenecarboxamide sterically mimics N,N-diisopropylferrocenecarboxamide in (-)-sparteine-mediated metalation to provide 2-substituted ferrocenes in good yield. Unlike the original N,N-diisopropyl systems, the products are open to flexible manipulation by virtue of decumylation under very mild conditions (CF3CH2OH/reflux/5-12 h) to give, usually quantitatively, enantiomerically enriched secondary ferrocenecarboxamides for further transformations. For example, N-allylation of N-ethyl-2-vinylferrocenecarboxamide followed by olefin metathesis with Grubbs' catalyst gives, after hydrogenation, a planar chiral ferrocenyl azepinone. Subsequent metalation and electrophile quench (Ph2Cl) affords structurally novel phosphine ligands.