Pinacol boronic esters

Boronic acids (5a) were among the first examples of low-molecular-weight, reversible inhibitors of serine proteinases [151, 152]. Significant inhibition was initially demonstrated against a-chymotrypsin. Unlike the carbonyl-derived reversible inhibitors, which require a polypeptide or peptide-like chain, activity was found with simple alkylboronic acids (e.g. the value for PhCH2CH2B(OH)2 with a-chymotrypsin was = 40 //M) [153], Weak inhibition of elastase (PPE) was first reported for a series of arylboronic acids, for example, (10-1) [123]. Some of the boron-based inhibitors Figure 2.5) were tested as either the difluoroboranes (5b) or as the pinacol boronate esters (5c). These modifications were employed because they were more readily synthesized and/or purified than the boronic acids. For both of these derivatives inhibition was shown to be due to in situ hydrolysis to the parent boronic acid (5a) [154, 155]. 

Figure 2.5. Boron derived inhibitors (5a) boronic acid (5b) difluoroborane (5c) pinacol boronate ester.

Ligands 5 and 6 are particularly efficacious for the borylation of aryl chlorides to pinacol boronate esters, thus allowing the direct one-pof synthesis of unsymmetrical biaryls from two aryl chlorides (Equation 2.23) [41]. Due to the wide breadth and scope that this family of biaryldialkylphosphine Hgands offers for palladium-catalyzed couplings of aryl chlorides, many are commercially available and aU are highly crystalline, air-stable solids, and hence easy to use. 

This monomer, also named 9,9-dihexylfluorene-2,7-diboronic acid bis(l,3-propanediol) ester, is commercially available. The propanediol or pinacol boronate esters of dialkylfluorenes with different alkyl chain lengths are also commercially available products, and these compounds can be used directly in the following Suzuki polymerization. However, the given synthetic procedures for boronate ester monomers will be useful for preparing new fluorene monomers, which are not commercially available. 

Scheme 3.2 Transesterification of a pinacol boronic ester. (Adapted with permission from ref. 26 2012 American Chemical Society.)...

Hydrolysis of 1,3,2-dioxaborolanes is thermodynamically disfavored, no doubt as a result of the same kinds of entropic factors that favor formation of cyclic acetals in preference to acyclic acetals. Hydrolysis of a 1,3,2-dioxaborolane (1) converts three molecules to two, but hydrolysis of a boronic acid dimethyl ester keeps the total number of molecules at three (Scheme 5). (It m be noted that hydrolysis of a cyclic acetal with one molecule of water keeps the number of reactant and product molecules equal at two, and hydrolysis of an acyclic acetal converts two molecules to three.) Adding base does almost nothing to the equilibrium, since hydroxide ion coordinates to the boronic ester 1 as well as to the boronic acid product. Furthermore, it spears that the trans R° substituents in 1 further stabilize the stmcture. Chiral boronic esters of this series are harder to hydrolyze than pinacol boronic esters, and treatment of pinacol boronic esters with DICHED results in liberation of the pinacol and formation of the DICHED boronic ester. 

Queiroz and coworkers [152] have used this reaction for the efficient synthesis of 6-(hetero)arylthieno[3,2-fo]pyridines (Figure 1.44) which have shown application in the growth inhibition of human tumor cell lines. The organoboron reagent varied between the pinacol boronic ester and potassium aryltrifluoroboronate salts, the yields were generally very good. 

Clary, J. W., Rettemnaier, T. J., Snelling, R., Bryks, W., Banwell, J., Wipke, W. T., and Singaram, B. (2011). Hydride as a leaving group in the reaction of pinacolborane with halides under ambient Grignard and Barbier conditions, one-pot s5Tithesis of alkyl, aryl, heteroaryl, vinyl, and aUyl pinacol-boronic esters. J. Org. Chem., 76, 9602-9610. 

A new protocol has been introduced to improve selectivity in allylboration of aldehydes. The readily available a-substituted allyl or crotyl pinacol boronic esters often give low A/Z-selectivity. Addition of -butyllithium followed by trapping of alkoxide with TFAA generates an allyl borinic acid, which gives very high -selectivity, and in some cases, this is the opposite of the standard conditions. The borinic ester intermediate was characterized by B-NMR. 

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