A General Solution for the 2‐Pyridyl Problem

Abstract

Problem solved: An air‐stable 2‐pyridyl borane that can effectively couple to a wide range of aryl and heteroaryl halides and pseudohalides has evaded the synthesis community for decades. The discovery that Cu(DEA)2 powerfully enables palladium‐mediated cross‐couplings with air‐stable boronates 1 has finally provided a general solution to this problem. DEA=diethanolamine, DMF=N,N′‐dimethylformamide, Tf=trifluoromethanesulfonyl.

Towards the generalized iterative synthesis of small molecules

“…137 This mechanistic divergence is consistent with extensive reaction kinetics, kinetic isotope effects, 18 O labelling, and computational data. 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 …”

The Directed Ortho Metallation (DoM)–Cross‐Coupling Nexus. Synthetic Methodology for the Formation of Aryl–Aryl and Aryl–Heteroatom–Aryl Bonds

“…Nevertheless, this cross-coupling reaction, as others, may still be relegated partially to an art, requiring empirical observation, preferably by parallel synthesizer technology, of catalyst, ligand, base, temperature, and solvent variation to establish optimum conditions. The purity of the arylboronic acid 22 derived from 20 in the Li → B transmetallation, often uncertain either as prepared or purchased, may be ascertained by formation of either the usually crystalline and stable diethanolamine (DEA) 21a and N-methyliminodiacetic acid (MIDA) 21b [24] adducts (Scheme 14.6) [2] or, with less certainty of these properties, pinacolates 23a [25], neopentyl glycolates 23b [25f], and undoubtedly other boronates yet to be tested [26]. Current practice, however, is to hastily use the crude 22 in the cross-coupling reaction.…”

Transforming Suzuki–Miyaura Cross-Couplings of MIDA Boronates into a Green Technology: No Organic Solvents

“…Triethylamine, therefore, was chosen for further studies given both its low cost and effectiveness. Unlike traditional MIDA boronate couplings oftentimes run in organic media at low molarities ( e.g ., 0.07 M ), 8 a global concentration of 0.5 M was characteristic of all couplings preformed in these nanoreactors. Reactions could also be run at 1.0 M with similar yields, but on a small scale they were more difficult to monitor.…”

“…With notoriously unstable 2-heteroaromatic substituted systems, slow release to their corresponding boronic acids allows for couplings that otherwise have a history of either limited utility or complete failure. 8 …”

“…8,9 In some cases, the requirement for a solvent such as DMF makes the coupling highly undesirable from a safety, health, and environmental perspective. 8b And just as certain organic solvents have been essentially removed from use ( e.g ., benzene and CCl 4 ), and others such as chlorinated solvents discouraged, so is DMF apparently destined to realize a similar fate. 10 Hence, it behooves the synthesis community to work towards not only reliance on safer solvents, but on greener solvents.…”