Brønsted Acid and H‐Bond Activation in Boronic Acid Catalysis

Abstract

Boronic acid catalysis has emerged as am ild method for promoting aw ide variety of reactions. It has been proposed that the mode of catalysis involves Lewis acid or covalent activation of hydroxyl groupsb yb oron, but limited mechanistic evidencee xists. In this work, representative boronic acid catalyzedr eactions of alcohols and oximes have been reinvestigated. As eries of control experiments with boronic and Brønsted acids were interpreted along with correlations between their reactivity and their acidity measured by the Gutmann-Beckett method. Overall,i tw as concluded that the major modes of catalysis involvee ither dual H-bondc atalysis or Brønsted acid catalysis. Strong Brønsted acids were shown to be generated in situ from covalenta ssembly of the boronic acids with hexafluoroisopropanol, explaining why the solvent had such am ajor impact on the reactivity.T his new insight should guide the future development of boronic acid catalysis, where the diverse and solvent-specific nature of catalytic modes has been overlooked. Scheme1.Representative boronic acid catalyzed transformations of alcohols and oximes.

Exploiting hexafluoroisopropanol (HFIP) in Lewis and Brønsted acid-catalyzed reactions

“…Indeed, we noticed that boronic acids were able to trigger a cyclopropane ring opening in HFIP, although no hydroxyl group was present (Scheme 8) (see part 5 for details). 21 Therefore, we reinvestigated a series of BAC reactions with alcohols and oximes. At the outset, we examined several boronic and Brønsted acids using the Gutmann-Beckett method, 22 which revealed that strong Brønsted acids are very likely to be produced by B1 and B3 in HFIP (Figure 2).…”

Brønsted Acid‐Catalysed Dehydrative Substitution Reactions of Alcohols

“…Increased understanding of the role of these solvents will facilitate the development of more industrially viable protocols. For example, recent work by Moran and co‐workers suggest the formation of supramolecular assemblies between BCF⋅H 2 O and nitro‐additives, [67] while many boronic acid catalysts are likely to form strong Brønsted acids in situ using the solvent [17] . These insights further highlight the importance of the solvent in such processes and will help in the design and study of future catalytic systems.…”

“…In most cases, these reactions work well with activated allylic alcohols or electron‐rich benzylic alcohols, but do not tolerate substrates bearing strongly electron‐withdrawing substituents. A recent study by Moran suggests that the mode of activation of alcohols using arylboronic acids is likely to be due to either Brønsted acid or H‐bond catalysis, rather than Lewis acid catalysis as initially postulated [17] . Building upon their seminal work in the area, [18] Hall and co‐workers discovered that a combination of 2,3,4,5‐tetrafluorophenylboronic acid 6 (10 mol %) and perfluoropinacol 7 (10 mol %) was effective for Friedel–Crafts alkylation reactions using a range of benzylic alcohols, including those bearing electron‐withdrawing substituents [19] .…”

“…Ar ecent study by Moran suggests that the mode of activation of alcohols using arylboronic acids is likely to be due to either Brønsted acid or H-bond catalysis, rather than Lewis acid catalysis as initially postulated. [17] Buildingu pon their seminal work in the area, [18] Hall and coworkers discoveredt hat ac ombination of 2,3,4,5-tetrafluorophenylboronic acid 6 (10 mol %) and perfluoropinacol 7 (10 mol %) wase ffective for Friedel-Crafts alkylation reactions using ar ange of benzylic alcohols, includingt hose bearing electron-withdrawing substituents. [19] Perfluoropinacol 7 is essentialf or the observed reactivity,f or example the reactiono f p-xylene with alcohol 5 gives product 8 in 88 %y ield under the standard reaction conditions (Scheme 6a), whereas no reaction is observedi nt he absence of 7.M echanistic experimentss uggest that boronic acid 6 reacts with 7 and the HFIP solventt oform hydronium boronate complex 9 as the active catalyst( Scheme 6b), whicha cts as aB rønsteda cid towards the alcohols ubstrate.…”

Arylboronic Acid Catalyzed C-Alkylation and Allylation Reactions Using Benzylic Alcohols

“…In solution, pentafluoro­phenyl­boronic acid 1 and oxalic acid 2 are in dynamic equilibrium with hydrated boronate 39 , which is likely to act as a Brønsted acid to protonate the secondary benzylic alcohol. This is consistent with recent work by Moran and co-workers, who found that various arylboronic acid promoted alcohol activation processes are likely to proceed via either a Brønsted acid or H-bond activation mode, as opposed to Lewis acid or covalent catalysis . Dissociation of ion pair 40 forms benzylic carbocation 41 , which can undergo nucleophilic addition from the enol tautomer of either the 1,3-diketone derivatives or 1,3-ketoesters to form the C -alkylation products and release water as the only byproduct.…”