Alkyne-tetracoordinated boron modularly constructs tetrasubstituted halogenated olefins

Recently, Professor Song Qiuling’s research group designed and reported the multiple migration reaction of alkyne-tetracoordinated boron, and obtained a series of tetrasubstituted monohalogenated olefins. On February 6, 2023, the research results were published in the journal Chem under the title “Modular assembly of versatile tetrasubstituted alkenyl monohalides from alkynyl tetracoordinate borons”. The first author of the work is Ma Xingxing, a 20-level doctoral student at Fuzhou University, and the corresponding author is Professor Song Qiuling.

Tetrasubstituted olefins have received great attention for their wide range of applications in pharmaceuticals, natural products, chemical biology, polymer chemistry, and materials science. Among them, tetrasubstituted monohalogenated olefins (containing F, Cl, Br, I) are important molecular backbones in many bioactive natural products, drugs and agrochemicals (Figure 1a). In addition, these compounds are also very important chemical synthetics in the field of synthesis, and have been widely used in transition metal-catalyzed cross-coupling reactions to further produce a variety of other valuable tetrasubstituted olefins. Therefore, the construction of tetrasubstituted monohalogenated olefins has aroused great interest in various fields. The reaction of alkynes or alkenes with commonly used halogenation reagents is a typical strategy for the synthesis of tetrasubstituted alkenyl monohalides (shown in Figure 1a). However, this synthesis strategy has problems such as low reactivity, high toxicity, and harsh reaction conditions, so the efficient construction of tetrasubstituted alkenyl compounds still faces great challenges.

Due to their unique properties and rich and diverse subsequent transformation, organoboronic compounds have attracted extensive attention from chemists and have become an important research direction in the field of synthesis. Song Qiuling’s research group has been committed to the research of organic boron chemistry for many years (Acc. Chem. Res., 2021, 54, 2298-2312)。 Some attempts have also been made to construct polysubstituted olefins and some results have been achieved (Nat. Synth. 2023, DOI: 10.1038/s44160-022-00201-6; Chem, 2020, 6, 2347-2363; Sci. China Chem. 2022, 65, 912–917; Cell Rep. Phys. Sci. 2021, 2, 100629; Org. Lett. 2021, 23, 2994-2999; Sci. China Chem. 2019, 62, 62-66; Org. Lett. 2018, 20, 5153-5157)。 As the most important intermediate in boron chemistry, tetracoordinated boron compounds, 1,2-migration and metal conversion are the two most important types of reactions. At present, there are many studies on the reaction of alkyl substituted and alkenyl substituted tetracoordinated boron, while for alkyne tetracoordinated boron, there are fewer related studies, and the currently known transformation is the synthesis of trisubstituted olefins catalyzed by transition metals (Figure 1b). Therefore, the authors wonder whether such boron compounds can be used to cause two aryl migrations to obtain tetrasubstituted olefins (shown in Figure 1c).

Recently, Professor Song Qiuling’s research group designed and reported the multiple migration reaction of alkyne-tetracoordinated boron, and obtained a series of tetrasubstituted monohalogenated olefins. The electrophiles used in these reactions are inexpensive, easy to obtain, economical and practical, and the different halogen sources in this reaction allow two different modes of migration of alkyne tetracoordinated boron (two 1, 2- migrations for fluorine sources (Selectfluoro) and chlorine sources (TCCA), and one 1, 2- migration and one 1,3 migration for bromine sources (NBS) and iodine sources (NIS). At the same time, the corresponding tetrasubstituted monohalogenolefin compounds can achieve a variety of transformations by subsequent coupling reactions, and quickly and easily construct tetrasubstituted olefins containing C-B, C-N, C-P, C-O, C-Si bonds, etc. (Figure 1d).

Figure 1: Application of tetrasubstituted halogenated olefins in drug molecules and traditional synthesis methods, traditional conversion of alkyne tetracoordinated boron, the author’s vision, and this work

After a large number of conditional screening to obtain the best reaction conditions, the authors extended the reaction study of the substrate range of different alkynyl tetracoordinated borons with four halogen sources. In addition, for this system, the authors tried the one-pot method strategy, and they could also successfully synthesize tetrasubstituted monohalogenated olefins. Such reactions can be scaled up and converted, such as Suzuki coupling, borylation, and coupling reactions with alkynes and olefins, and the authors have successfully modified some complex drug molecules with this method (Figure 2).

Figure 2: One-pot synthesis of these compounds, scale-up reaction, and product transformation

Through a large number of mechanistic exploration experiments, the authors obtained the reaction intermediates, confirmed the migration mode of alkyne tetracoordinated boron, and proposed a reasonable reaction mechanism (Figure 3).

Figure 3: Proposed mechanism

The above research work has been strongly supported by Fuzhou University, the National Natural Science Foundation of China, and key projects of Fujian Province. Master’s students Li Luo, Tan Mengjiao, Zhong Zihao, Liang Jinchao and Li Puhui have also made great contributions to this work. (Source: Science Network)

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