Retro-Claisen benzylation: direct use of benzyl alcohols in Pd-catalyzed couplings with nitriles

Abstract

A new strategy has been developed for the benzylation of nitriles directly from benzyl alcohols. In this process benzyl alcohols undergo retro-Claisen activation with cyanoacetic esters to generate an active electrophile and a carbanionic nucleophile. In the presence of Pd(0) these intermediates undergo catalytic coupling to generate a new C-C bond, resulting in the formation of phenyl propionitriles.

Production of Csp3–Csp3 Bonds through Palladium‐Catalyzed Tsuji–Trost‐Type Reactions of (Hetero)Benzylic Substrates

“…[36] Whereas (1-chloropropyl)benzene and (chloromethylene)di- benzene were unreactive [Equation (35)], 1-(1-chloropropyl)-naphthalene afforded a mixture of the benzylation product and diethyl 2-(1-propylidene-1,2-dihydronaphthalen-2-yl)malonate [Equation (36)]. The dearomatization product was selectively obtained when the ethyl substituent of the substrate was exchanged for a phenyl group [Equation (36)].…”

“…[35] This allowed the coupling to be performed with benzyl alcohol [Equation (33)] because this is transformed into the corresponding carbonate in situ through a retro-Claisen pathway (Scheme 9). It seems, however, that this procedure is limited to the decarboxylative benzylation of α-cyano α-aryl esters.…”

“…Nevertheless, interesting Pd-catalyzed three-component couplings have been carried out in the presence both of a benzylic alcohol and of allyl acetate [Equation (34)]. [35] Scheme 9. In situ formation of the leaving group.…”

“…In 2011, Bao and co-workers disclosed the Pd-catalyzed nucleophilic substitution of benzyl chloride and 1-chloromethyl naphthalene with diethyl malonate anion [Equation (35)]. [36] Whereas (1-chloropropyl)benzene and (chloromethylene)di- benzene were unreactive [Equation (35)], 1-(1-chloropropyl)-naphthalene afforded a mixture of the benzylation product and diethyl 2-(1-propylidene-1,2-dihydronaphthalen-2-yl)malonate [Equation (36)].…”

“…[26] The synthesis of 2,2-dimethyl-3-(pyridin-3-yl)propanenitrile from diethyl (pyridin-3-ylmethyl) phosphate and potassium 2-cyano-2-methylpropanoate has been carried out by Fu's procedure [Equation (72)], [33] whereas furanylmethanols and (indol-3-yl)methanol were coupled with ethyl 2-cyano-2-arylpent-4-enoates under Tunge's conditions [Equation (73)]. [35] When ethyl 2-cyano-2-phenylpent-4-enoate was treated with a 1:1 mixture of 3-indolylmethanol and (4-methoxyphenyl)methanol, the reaction exclusively occurred with the former compound [Equation (74)], again indicating the decisive role of the resonance energy of the aromatic unit with regard to the reactivity.…”