Protodeboronation of Heteroaromatic, Vinyl, and Cyclopropyl Boronic Acids: pH–Rate Profiles, Autocatalysis, and Disproportionation

Abstract

pH−rate profiles for aqueous−organic protodeboronation of 18 boronic acids, many widely viewed as unstable, have been studied by NMR and DFT. Rates were pH-dependent, and varied substantially between the boronic acids, with rate maxima that varied over 6 orders of magnitude. A mechanistic model containing five general pathways (k 1 −k 5 ) has been developed, and together with input of [B] tot , K W , K a , and K aH , the protodeboronation kinetics can be correlated as a function of pH (1−13) for all 18 species. Cyclopropyl and vinyl boronic acids undergo very slow protodeboronation, as do 3-and 4-pyridyl boronic acids (t 0.5 > 1 week, pH 12, 70 °C). In contrast, 2-pyridyl and 5-thiazolyl boronic acids undergo rapid protodeboronation (t 0.5 ≈ 25−50 s, pH 7, 70 °C), via fragmentation of zwitterionic intermediates. Lewis acid additives (e.g., Cu, Zn salts) can attenuate (2-pyridyl) or accelerate (5-thiazolyl and 5-pyrazolyl) fragmentation. Two additional processes compete when the boronic acid and the boronate are present in sufficient proportions (pH = pK a ± 1.6): (i) self-/autocatalysis and (ii) sequential disproportionations of boronic acid to borinic acid and borane.

Asymmetric Suzuki-Miyaura coupling of heterocycles via Rhodium-catalysed allylic arylation of racemates

“…Although we suspect the poor results with 3-pyrrole and indole boronic acids (Fig. 2) are due to competitive protodeboronation39, in the case of pyridines it is likely that the N -lone pairs interfere by binding to rhodium and shutting down a key step in the mechanistic cycle. The role of the 2-F or 2-Cl substituent would be to remove electron density, and hence Lewis basicity, from the pyridine ring.…”

“…At the 2-position of 5-membered O, S and N (Boc-protected) heterocycles, asymmetric addition was observed in >50% yield and very high ee (90–99%, 21 – 23 ). At the 3-position, furan 24 (98% ee) and thiophene 25 (97% ee) derivatives also worked well, but products from a protected 3-pyrrole 26 were never isolated, likely due to rapid base-mediated protodeboronation39. 2-Boronic acid substituted 5-membered heterocycles fused to a benzene ring gave excellent levels of ee (all >95%) with high yield in the case of benzofuran ( 27 , 75%) but low yields with benzothiophene 28 (23%) and protected indole 29 (20%).…”

Chemoselective Suzuki–Miyaura Cross‐Coupling via Kinetic Transmetallation

“…Importantly, the mass balance was generally returned starting material, with some protodeboronation observed in specific cases. 22 Reactions were halted at 1 h and the yields represent the efficiency of the boronic acid coupling over this time frame; however, increasing the reaction time did not negatively affect chemoselectivity. Electron-rich boronic acids delivered greater efficiency over those comparatively electron-poor, in agreement with previous studies.…”

A General Protocol for the Polycondensation of Thienyl N-Methyliminodiacetic Acid Boronate Esters To Form High Molecular Weight Copolymers

“…However, the utility of Suzuki–Miyaura polycondensation protocols in forming thienyl based copolymers is extremely challenging due to the propensity of thienyl boronic acids (and derivatives) to undergo protodeboronation. 8 This generally leads to low yields of pure borylated thienyl monomer or significant impurities in the crude monomer. The latter when combined with premature chain termination events caused by protodeboronation during the polymerization often leads to a reduction in polymer yield and lower than required molecular weights.…”