62nd Annual Report on Research 2017

Our PRF proposal put forth a novel borylation strategy for petrochemical-derived organic electrophiles employing nucleophilic hexaborate clusters. A sustained effort has been underway for decades to develop efficient and atom-economical methods to forge B–C bonds. In particular, with the utility of the Suzuki-Miyaura cross coupling method, borylated organics become valuable precursors for complex molecule synthesis and polymer science. Despite the consideration of boron as an electrophilic atom in a BR₃-type framework, we proposed that six-membered hexaborate clusters could be used as nucleophilic boron sources in order to form desired B – C linkages (Scheme 1) with simple organic electrophiles. These clusters, synthesized in a straightforward manner from NaBH₄ and BF₃·Et₂O, would be substituted with an organic electrophile at each vertex. We anticipated that these perfunctionalized clusters would be unstable towards oxidation, since each boron in the cage is formally B(I) and the sensitivity of these clusters to certain chemical conditions is known. Upon oxidation of the hexaborate core in the presence of a trapping agent, such as pinacol or KHF₂, we proposed that borylated organic species, such as alkylboron pinacol esters, could be isolated. Importantly, this process would circumvent the use of B₂pin₂ or HBpin as boron sources, which involve the use of elemental sodium and BBr₃ in their syntheses, and valorized petrochemicals would be obtained in a straightforward manner. We are pleased to report our progress toward this end.

Scheme 1. Proposed method for nucleophilic functionalization of the hexaborate core followed by controlled oxidative degradation to form desired alkyboron species.

A microwave-based synthetic route to hexaborate clusters of the type [NBu₄][B₆(CH₂Ar)₆H^fac] (Ar = C₆H₅, 4-Br-C₆H₄) was established by our group in a recent communication (see attached reference). This establishes, for the first time, a synthetic route for substituting each boron vertex with a carbon-based electrophile. For the ultimate goal of oxidative degradation (vide infra), this is crucial for maximum boron atom economy. Furthermore, we have expanded this method to include thermal methods that do not require microwave heating, as well as an expanded electrophile scope for the formation of additional, perfunctionalized hexaborate species (Figure 1). The desired compounds can be isolated by precipitation in good yields.

Figure 1. Complementary synthetic methods for the formation of perfunctionalized hexaborate clusters with benzyl electrophiles.

Given the forcing conditions for hexaborate perfunctionalization, we have also considered that certain electrophiles desirable for borylation may not be stable to high temperatures and long reaction times. We therefore set out to establish alternative protocols for single vertex functionalization under mild conditions. Expanding on previously established methodology, we find that monosubstitution is tolerant to potentially reactive groups such as cyclopropanes. These monosubstitution reactions proceed with electrophiles in a 1:1 ratio to the hexaborate nucleophile. The ¹¹B NMR of the monosubsituted products provide diagnostic chemical shift patterns that indicate conversion to the desired product. Importantly, these substitutions are not limited to alkyl or benzylbromides and are in fact compatible with alkyl and benzylchlorides and tosylates (Figure 2). We are currently in the process of further expanding the electrophile scope for these monosubstitution reactions.

Figure 2. Electrophile scope for the monosubsitution of the hexaborate dianion. Alkyl bromides, chlorides, and tosylates all react to form monofunctionalized hexaborates.

Ultimately, controlled cluster degradation in the presence of a trapping agent (e.g. pinacol) should furnish synthetically useful reagents such as alkylboron pinacol esters. The possibility of this goal is supported by the electrochemical behavior of the perfunctionalized clusters: irreversible oxidative waves are observed for both of our reported perfunctionalized derivatives (Figure 3A), suggesting that cage degradation is feasible via oxidation. We have found two synthetic routes that indicate formation of the desired alkylboron pinacol esters. In particular, treatment of [NBu₄][B₆R₆H^fac] with either I₂ or tetracyanoquinodimethane (TCNQ) in the presence of base and pinacol furnishes new products consistent with the formation of the desired compounds as judged ¹H and ¹¹B NMR spectroscopy and mass spectrometry (Figure 3B). We are currently in the process of optimizing the isolation protocols for these compounds and look forward to extending these oxidation procedures to the monofunctionalized hexaborate clusters (vide supra).

Figure 3. A) Electrochemical irreversibility of the benzyl-substituted hexaborate suggested accessible cluster degradation pathway. B) Complementary methods for controlled oxidative cage degradation using different oxidants to form desired alkylboron pinacol esters. Yields are unoptimized.

Overall, this method provides an alternative route to traditional borylation methods, many of which require transition metal catalysis. With the support of this grant in the upcoming year, we will expand this borylation methodology based on the encouraging leads disclosed above and further explore the potentially interesting chemical and electrochemical properties of the alkylated hexaborate species. We will also strive to develop a general method by which hexaborate–C_sp2 bonds may be formed, further expanding the classes of organic molecules that can be valorized with boron-based functional groups.