One-Pot Homologation of Boronic Acids: A Platform for Diversity-Oriented Synthesis

Abstract

Formal homologation of sp(2)-hybridized boronic acids is achieved via cross-coupling of boronic acids with conjunctive haloaryl BMIDA components in the presence of a suitably balanced basic phase. The utility of this approach to provide a platform for diversity-oriented synthesis in discovery medicinal chemistry is demonstrated in the context of the synthesis of a series of analogues of a BET bromodomain inhibitor.

Towards the generalized iterative synthesis of small molecules

“…In-situ slow release of MIDA boronates has been advantageous for many reactions including couplings of unstable heteroarylboronates, 138,139 polymerization reactions, 140–141 asymmetric methodologies, 142 the synthesis of organic photovoltaics, 143 and a one-pot homologation of boronic acids. 144 …”

Cyrene as a Bio-Based Solvent for the Suzuki–Miyaura Cross-Coupling

“…No particular difficulties were observed and chemical yields were consistent with both literature examples as well as those from our own laboratory in previous studies. [58][59][60][61][62] With a view to evaluate the utility of Cyrene within the context of synthesis on a more preparative scale, we selected 4′-methyl-2-biphenylcarbonitrile (OTBN, 4w) as a target. Compound 4w is a key intermediate in the synthesis of angiotensin II receptor antagonists (sartans), and can be easily accessed via the SM reaction.…”

A Convenient, Rapid, Conventional Heating Route to MIDA Boronates

“…Given that time is often a factor, and a significant cost to factor in, processes that are "plug and play" and carried out with little, or no, optimisation, are often de rigueur (Figure 1). MIDA boronates occupy a central role in organic synthesis with many app including, but not limited to, masked boronic acids in total synthesis [8][9][10]; catal 17], including iterative or telescopic couplings [17][18][19][20][21]; oxidation chemistry [22] or C2 building blocks [23,24]. Although traditionally made by a Dean-Stark proto ally employing DMSO as solvent [25][26][27][28], many recent methods have shifted milder reaction conditions, more convenient work-up, purification and isolati niques, notably to enable the synthesis of unstable esters such as 2-phenol [12] or 2 aryl MIDA analogues [29].…”

“…Hereafter, we have focused ou mainly on a group of "off the shelf" boronic acids that were readily available in ou atory at the time of the study. Indeed, the samples that were subjected to our new were rather broad in scope, encompassing boronic acids based on an aryl 1, isox MIDA boronates occupy a central role in organic synthesis with many applications including, but not limited to, masked boronic acids in total synthesis [8][9][10]; catalysis [11][12][13][14][15][16][17], including iterative or telescopic couplings [17][18][19][20][21]; oxidation chemistry [22] or as C1 or C2 building blocks [23,24]. Although traditionally made by a Dean-Stark protocol, usually employing DMSO as solvent [25][26][27][28], many recent methods have shifted towards milder reaction conditions, more convenient work-up, purification and isolation techniques, notably to enable the synthesis of unstable esters such as 2-phenol [12] or 2-hetero-aryl MIDA analogues [29].…”