CuH-Catalyzed Regio- and Enantioselective Formal Hydroformylation of Vinyl Arenes

Abstract

A highly enantioselective formal hydroformylation of vinyl arenes enabled by copper hydride (CuH) catalysis is reported. Key to the success of the method was the use of the mild Lewis acid zinc triflate to promote the formation of oxocarbenium electrophiles through the activation of diethoxymethyl acetate. Using the newly developed protocol, a broad range of vinyl arene substrates underwent efficient hydroacetalization reactions to provide access to highly enantioenriched α-aryl acetal products in good yields with exclusively branched regioselectivity. The acetal products could be converted to the corresponding aldehydes, alcohols, and amines with full preservation of the enantiomeric purity. Density functional theory studies support that the key C-C bond-forming event between the alkyl copper intermediate and the oxocarbenium electrophile takes place with inversion of configuration of the Cu-C bond in a backside S_E2-type mechanism.

Figure 1.

(A) Precious metal-catalyzed asymmetric hydroformylation. (B) CuH and Lewis acid mediated hydroacetalization (formylation) of vinyl arenes.

Figure 2.

Computational studies of the mechanisms of electrophile activation and CuH-catalyzed hydroacetalization. Bond distances are in Å.

Scheme 1.. Derivatization of CuH-Catalyzed Asymmetric Hydroacetalization Products

^IReaction conditions: Pentane: Formic acid (1:1), rt, 1 h. ⁱⁱReaction conditions: NaBH₄ (5.0 equiv), methanol, rt, 1 h. ⁱⁱⁱReaction conditions: NaBH(OAc)₃ (2.0 equiv), amine (1.0 equiv), AcOH (1.0 equiv), DCE, rt, 8 h.