trans-Haloboration of o-Alkynyl Phenols Generates Halogenated Bicyclic-Boronates Relevant to Broad Spectrum Beta-Lactamase Inhibitors

Benzoxaborinines are key intermediates on route to bicyclic boronates that are ultra-broad spectrum beta-lactamase inhibitors (BLIs). However, routes to benzoxaborinines are limited and substituents at C4 are not tolerated in the current key method. Herein, the haloboration of o-alkynyl-phenols using BX3 (X = Cl or Br) is disclosed as a simple route to form C4-halogenated benzoxaborinines. The functional group tolerance is excellent for an electrophilic borylation process, tolerating halides, ethers, esters, CF3 and an enolisable ketone. This methodology was extended to form benzoxaborinines with an ester at the C8 posi-tion (key for accessing highly active BLIs) in high yield by using BCl3 and [BCl4]−. The requirement for [BCl4]− as an exogenous chloride source indicated a switch in the haloboration mechanism and computational studies indicated that there are two similar in barrier mechanisms: (i) double alkyne haloboration followed by a retro-haloboration; (ii) concerted alkyne trans-haloboration with an exogenous chloride source ([BCl4]−). The C4-halide unit in these benzoxaborinines is useful, with a haloboration-Negishi cross coupling protocol used to form benzoxaborinines with an alkyl or an aryl group at C4. This simple trans-haloboration methodology represents a useful addition to the chemists toolbox for synthesizing bicyclic-boronates that are in-creasingly important active pharmaceutical ingredients.