Selective boron-heteroatom group exchange reactions

De-Wei Gao's research group at ShanghaiTech University has developed a new method for efficient and highly selective boron-heteroatom functional group exchange reactions. Their method overcomes the inherent difficulty of primary radical instability in traditional free radical chemistry and can achieve highly selective conversion of primary carbon-boron bonds to a variety of heteroatom functional groups. This strategy has been successfully applied to a sugar-derived 1,n-diboron compound system, achieving modular modification and efficient synthesis of sugar molecules and has shown to have potential application in the rapid construction of bioactive molecules. These results were published as an open access article in CCS Chemistry, the flagship journal of the Chinese Chemical Society.

Background:

Small molecule drugs often contain two or more heteroatom functional groups that play key roles. Pinacol boronates (BPins) offer an important avenue for the efficient introduction of functional groups due to their facile transformation. Among the numerous boron-containing compounds, 1,n-diboron compounds have attracted considerable attention because they contain two C–B bonds with distinct reactivities in a single molecule. This structural property enables the introduction of bifunctional groups, significantly simplifying the synthetic routes for drugs and related functional molecules. However, due to the highly similar chemical environments of different C–B bonds, achieving precise control of site-specific reaction selectivity during the transformation of multiple carbon-boron bonds remains a significant challenge. While current research has achieved the selective transformation of 1,2- or 1,3-diboron compounds, these reactions typically require the participation of ortho-boron groups or the formation of specialized intermediates such as five- or six-membered rings. Consequently, they are only applicable to specific types of diboron systems (e.g., 1,2- or 1,3-diboron compounds), and their scope of application remains significantly limited. However, most current reaction systems still rely heavily on transition metal catalysts, organometallic reagents, photocatalysts, or reagents sensitive to air and moisture, which limits their practical application in synthetic applications. Of particular note, current research primarily focuses on the selective conversion of C–B bonds to C–C bonds, while the selective conversion of C–B bonds to C–X bonds (where X is a heteroatom or other functional group) remains underdeveloped (Figure 1).

Highlights of this article:

This study successfully initiated a free radical chain reaction using readily available catechol compounds, achieving highly selective boron-heteroatom functional group exchange. This strategy was successfully applied to a system of sugar-derived 1,n-diboron compounds, enabling modular modification and efficient synthesis of sugar molecules, while exhibiting excellent compatibility with complex stereochemical environments (Figure 2).

To explore the mechanism of this reaction, the authors conducted a series of mechanistic validation experiments. First, radical-trapping experiments demonstrated that the reaction proceeds via the generation of primary alkyl radicals and phenylsulfonyl radicals. Control experiments further confirmed the necessity of catechol for the reaction. The authors also synthesized a diboron compound containing a primary Bcat, 1f-Bcat , and conducted a series of control and comparison experiments. The results suggested that 1f-Bcat may be a key intermediate initiating the reaction, but subsequent reactions may require the participation of the bis(pinacol boronate)-substituted substrate 1. Further experiments confirmed that 1f-Bcat can independently initiate the reaction by generating a primary radical, while catechol accelerates this process by activating 1f-Bcat . However, in the subsequent step, the phenylsulfonyl radical directly activates the pinacol boronate substrate 1. Based on these findings, the authors proposed a radical chain reaction mechanism as shown in Figure 3.

Given the importance of organoboronates in synthetic and medicinal chemistry, the authors systematically investigated the subsequent transformation and application of this reaction product. In their initial exploration, they employed a tandem reaction strategy, sequentially carrying out phenylthiolation and photocatalytic deborylation in a one-pot process, and successfully synthesized the bifunctionalized product 21 in 43% isolated yield, achieving differential functionalization of the two C–B bonds. Building upon this bifunctionalized product, the authors further explored various transformations of the secondary C–B bond in the standard product, including Zweifel olefination, copper-catalyzed electrophilic coupling, and oxidation. Subsequently, they conducted a Mitsunobu azidation reaction on the oxidation product 26, successfully making the azide compound 27. This intermediate can be further derivatized: first, a triazole building block can be efficiently introduced via copper-catalyzed azide–alkyne cycloaddition (CuAAC) reaction; second, a Staudinger reduction–acylation tandem reaction can be used to construct a Boc-protected secondary amine derivative in a single step. In addition to the aforementioned transformations, the authors also applied this selective boron-heteroatom exchange strategy to the efficient synthesis of high-value-added bioactive molecules, further demonstrating the method's practical value in the construction of complex molecules. Starting from readily available diboron compounds, two important classes of bioactive molecules were efficiently synthesized in just a few transformation steps. The successful development of this selective boron-heteroatom exchange reaction provides a new strategy and approach for drug discovery and the efficient construction of related functional molecules (Figure 4).

Summary and Outlook:

This study employed a simple bisphenol-initiated boroester exchange strategy to initiate a free radical chain reaction, achieving efficient and highly selective boron-heteroatom functional group exchange in 1,n-diboron compounds. This synthetic method can be applied to the efficient construction of bioactive molecules, demonstrating its promising application in synthetic chemistry and drug discovery, as well as its potential value in the later functionalization of molecules.

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About the journal: CCS Chemistry is the Chinese Chemical Society’s flagship publication, established to serve as the preeminent international chemistry journal published in China. It is an English language journal that covers all areas of chemistry and the chemical sciences, including groundbreaking concepts, mechanisms, methods, materials, reactions, and applications. All articles are diamond open access, with no fees for authors or readers. More information can be found at https://www.chinesechemsoc.org/journal/ccschem.

About the Chinese Chemical Society: The Chinese Chemical Society (CCS) is an academic organization formed by Chinese chemists of their own accord with the purpose of uniting Chinese chemists at home and abroad to promote the development of chemistry in China. The CCS was founded during a meeting of preeminent chemists in Nanjing on August 4, 1932. It currently has more than 120,000 individual members and 184 organizational members. There are 7 Divisions covering the major areas of chemistry: physical, inorganic, organic, polymer, analytical, applied and chemical education, as well as 31 Commissions, including catalysis, computational chemistry, photochemistry, electrochemistry, organic solid chemistry, environmental chemistry, and many other sub-fields of the chemical sciences. The CCS also has 10 committees, including the Woman’s Chemists Committee and Young Chemists Committee. More information can be found at https://www.chinesechemsoc.org/.