Studies on the copper hydride mediated reductive Claisen rearrangement & synthesis and synthetic applications of C- boron enolates

Abstract

The copper hydride catalyzed reductive Claisen rearrangement reaction was investigated for improvement of diastereoselectivity. The poor diastereoselectivity was ascribed to an undesirable E / Z isomerization of the boron enolate intermediates when pinacolborane was used as the stoichiometric reductant. By switching from pinacolborane to methyldiethoxysilane, the E / Z isomerization of the corresponding enol silanes do not occur and a dramatic improvement of the diastereoselectivity was achieved. The reaction has been demonstrated for a total of 18 substrates, and occur with excellent yields (up to 95 %) and good diastereoselectivities (up to >25 : 1).

The mechanism of the copper hydride catalyzed reductive Claisen rearrangement, using pinacolborane as the stoichiometric reductant, was found to involve a stereospecific rearrangement via a chair transition state. The identification of an unusual C- bound boron enolate in the reaction mixture led to the discovery of an unprecedented phosphine promoted isomerization of O- boron enolates to C- boron enolates.

The synthesis of C- bound boron enolates, via a phosphine promoted O to C isomerization, was demonstrated for 8 different a,b-unsaturated esters and 2 different a,b-unsaturated amides. One C- boron enolate, 3.130a, was isolated in pure form and fully characterized by 1H, 13C and 11B NMR spectroscopy, showing that C- boron enolates of esters are stable enough to exist alone without external stabilization. Mechanistic studies suggested that the isomerization required both phosphine and copper, and was proposed to proceed via copper enolates as intermediates.

The synthesis of C- bound boron enolates, via a phosphine promoted O to C isomerization, was demonstrated for 8 different a,b-unsaturated esters and 2 different a,b-unsaturated amides. One C- boron enolate, 3.130a, was isolated in pure form and fully characterized by 1H, 13C and 11B NMR spectroscopy, showing that C- boron enolates of esters are stable enough to exist alone without external stabilization. Mechanistic studies suggested that the isomerization required both phosphine and copper, and was proposed to proceed via copper enolates as intermediates.

C- Boron enolates were oxidized to afford lactate derivatives as products. Mechanistic understanding of the protodeboronation pathway led to the identification of N,N-dimethylaniline N-oxide as the oxidant of choice for this reaction. C- boron enolates can be generated and oxidized in one-pot. The whole reaction sequence, 1,4-reduction-isomerization-oxidation, constitutes an anti-Markovnikov hydration of a,b-unsaturated esters. The reaction was demonstrated for 8 different a,b-unsaturated esters, with excellent yields (up to 90 %) and regioselectivities. Combined with asymmetric 1,4-reduction using chiral phosphine, enantioselective hydrations were demonstrated on 2 different a,b-unsaturated esters, with excellent enantioselectivities of up to 96 % ee and moderate diastereoselectivities of up to 8:1. As a proof of principle, an enantioselective O to C isomerization was also demonstrated using a chiral phosphine for the isomerization, albeit with only 14.8 % ee.

Suzuki-Miyaura cross coupling of C- boron enolates with aryl bromides and aryl iodides were also developed. C- boron enolates can be generated and induced to undergo the Suzuki-Miyaura reaction without purification. The whole reaction sequence, 1,4-reduction-isomerization-cross coupling, constitutes a hydroarylation of a,b-unsaturated esters. The reaction was demonstrated for 5 different a,b-unsaturated esters and 8 different aryl halides, and moderate yields of up to 72 % were observed.

Amination of C- boron enolates was not compatible with phosphines and pinacolborane used for in situ generation of C- boron enolates. As a result, excess phosphine and pinacolborane had to be removed in vacuo before the amination. The whole reaction sequence, 1,4-reduction-isomerization-amination, constitutes a hydroamination of a,b-unsaturated esters. As a proof of principle, the reaction was demonstrated for ethyl acrylate in 40 % yield.