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. 2024 Nov 15;89(22):16195-16202.
doi: 10.1021/acs.joc.4c00089. Epub 2024 Mar 14.

Rapid, Homogenous, B-Alkyl Suzuki-Miyaura Cross-Coupling of Boronic Esters

Matthew J Bock  1 , Scott E Denmark  1
Affiliations

Rapid, Homogenous, B-Alkyl Suzuki-Miyaura Cross-Coupling of Boronic Esters

Matthew J Bock et al. J Org Chem. .

Abstract

A rapid, anhydrous Suzuki-Miyaura cross-coupling of alkylboronic esters with aryl halides is described. Parallel experimentation revealed that the combination of AntPhos, an oxaphosphole ligand, neopentyldiol alkylboronic esters, and potassium trimethylsilanolate (TMSOK) enables successful cross-coupling. In general, reactions proceed in under 1 h with good yields and high linear/branched (l/b) selectivities. Crucially, two literature examples which previously took >20 h to reach completion were accomplished in a fraction of the time with the method described herein. Mechanistic studies revealed that the reaction proceeds through a stereoretentive pathway and identified the boronic ester skeleton as a predominant pathway for deleterious protodehalogenation.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
HTE survey using four, 24 well plates. (A) First-generation screen focusing on ligand space. (B) Second-generation screen focusing on solvents and refined ligand space. Reactions run with 0.20 mmol of aryl halide and 1.20 equiv of boronic ester. Yields were determined by GC-FID analysis using biphenyl as an internal standard.
Figure 2.
Figure 2.
(A). Plausible mechanism for the origin of protodehalogenation. (B). Hypothetical pathways for the source of the hydride. (C). Deuterium labeling experiments. Reactions run with 0.25 mmol of aryl halide and 1.20 equiv of boronic ester. Yields of isolated product after column chromatography. Deuterium incorporation was determined from mass spectrometry; see the Supporting Information for details.
Scheme 1.
Scheme 1.
Initial Investigation using n-Butylboronic Ester 2aa aReaction run with 0.20 mmol of aryl halide and 1.20 equiv of boronic ester. Yields determined by GC-FID analysis using biphenyl as internal standard.
Scheme 2.
Scheme 2.
Post-HTE Experimentsa aReaction run with 0.20 mmol of aryl halide and 1.20 equiv of boronic ester. Yields determined by GC-FID analysis using biphenyl as internal standard.
Scheme 3.
Scheme 3.
Stereospecificity of the Coupling Reaction aReactions run with 1.00 mmol of aryl halide and 1.20 equiv of boronic ester. Yields of isolated product after column chromatography. bProduct was further purified to analytical purity; see the Supporting Information.
See this image and copyright information in PMC

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