First! Intermolecular trans-bissilylation of terminal alkynes

Recently, the team of Zhao Dongbing from the State Key Laboratory of Elemental Organic Chemistry of Nankai University and the team of Hong Xin of Zhejiang University have made breakthroughs in the field of trans-bissilylation reaction between terminal alkyne molecules. On May 22, 2023, the relevant research results were published in the journal Nature Synthesis under the title “Intermolecular trans-bis-silylation of terminal alkynes”.

Researcher Zhao Dongbing from the State Key Laboratory of Elemental Organic Chemistry of Nankai University and researcher Hong Xin from Zhejiang University as the corresponding authors of this paper, doctoral students Zhao Shuang and Zhang Yun from Nankai University as co-first authors and master student Yin Kailin as the second author completed the main experimental work. Wu Rongkai, a master’s student at Zhejiang University, completed the theoretical calculation part as the co-first author.

Due to their special physical and chemical properties, organosilicon compounds are widely used in many fields such as organic chemical synthesis, material science and medicine, so it is of great significance to develop simple and efficient methods for synthesizing organosilicon compounds. Over the past few decades, transition metal-catalyzed bissilylation between alkynes and disilanes has been considered one of the most straightforward methods for stereoselective synthesis of 1,2-bissilylolefin compounds (Figure 1a). These 1,2-bissilylated olefins not only have many unique properties in their own right, but also serve as important synthetic intermediates for further conversion into many fine chemicals and bioactive molecules with polysubstituted olefin backbones (Figure 1b).

Although the bissilylation reaction of alkynes has made great progress in synthetic chemistry, there are still limitations that cannot be ignored: 1) the mechanism of such reactions includes processes such as oxidative addition/migration insertion/reduction elimination, so Z-type bissilylated products are usually obtained (Figure 1c), in fact, since the reaction was first reported in 1972, the trans-bissilylation reaction between terminal alkynes and disilanes catalyzed by transition metals has been a problem in the field and has not yet been solved; 2) At present, the efficient differentiation of the reactivity of two adjacent silicon groups in 1,2-bissilylolefin is also very difficult and challenging, which is not conducive to subsequent conversion applications; 3) When realizing the asymmetric silylation reaction of asymmetric alkynes, including terminal alkynes, poor regional selectivity is often obtained; Therefore, it is of great significance to develop convenient and efficient methods to realize the trans-bissilylation reaction between terminal alkynes and disilanes, and to achieve efficient differentiation of the reactivity of two adjacent silyl groups in subsequent conversion. It can be expected that the realization of terminal alkyne trans-bissilylation reaction and the efficient differentiation of two adjacent silicon-based reactivity in subsequent conversion will provide more possibilities for the synthesis of polysubstituted olefins.

Figure 1: Transition metal catalytic silicon? Research status of silicon bonds on alkyne addition.

In recent years, Zhao Dongbing’s research group of Nankai University has focused on the research of silicone chemistry, committed to the development of new reagents and new reactions to achieve efficient synthesis of silicone compounds, and on this basis, discover and regulate the properties of silicone molecules. In the early stage, they used the strong coordination strategy to develop a well-synthesized, air and moisture stable bissilane reagent TMDQ containing quinoline guide groups, and successfully realized cis-bissilylation of inactivated endoalkyne and benzyne (Nat. Commun, 2020, 12, 68.)。 In this study, trans-bissilylation products of small amounts of alkynes were always detected when terminal alkyne was used to react with the disilane reagent TMDQ. They were encouraged to screen disilane reagents, catalysts, additives, reactant proportions, temperature and other parameters to TMDQ as a disilane reagent, and achieved the first trans-bissilylation reaction between terminal alkyne molecules under palladium catalysis (Figure 2). The reaction has good functional group compatibility (good compatibility with substrates containing functional groups such as halogens, amines, methoxy, cyanogen) and substrate universality (compatible with terminal alkynes such as aryl, alkyl, alkenyl, alkyne, and pull-electron substituents). Subsequently, they also confirmed that the reaction can also be applied to the late functionalization of many bioactive molecule-derived alkynoides, providing opportunities for new drug development.

Figure 2: Range of trans-bissilylation reaction substrates for palladium-catalyzed terminal alkynes.

After completing substrate expansion, they first demonstrated that the activity of two different silica groups on the trans-bissilylated product can be regulated to achieve step-by-step recognition transformation using silicone coupling (Figure 3a). Subsequently, they used the trans-bissilylated olefin products obtained by this reaction as starting materials to achieve simple and efficient synthesis of many important bioactive molecules, such as the anti-cancer reagent CC5078, the long-acting nonsteroidal estrogen receptor modulator chlorotrianisene, and the chemopreventive cancer drug Temarotene. Compared with the traditional synthetic route of synthesizing these drug molecules, this route shortens the reaction step and improves the synthesis efficiency.

Figure 3: Example of a stepwise differentiation and synthesis application of adjacent silicon groups in a product.

Immediately afterwards, the authors carried out a series of control experiments, combined with DFT calculations, and studied the reaction mechanism in detail. Tracking the reaction using in situ Raman spectroscopy revealed that the reaction first underwent a process of cis-bissilylation, followed by Z/E isomerization of olefins, and finally obtained trans-bissilylation products (Figure 4). Notably, TMDQ as a disilane and excess terminal alkynes are key to the success of this reaction. Specifically, the nitrogen atom of 8-quinoline in TMDQ favors the cleavage of Si-Si bonds in disilanes and the Z/E isomerization of olefins. Excess terminal alkynes have a significant effect on the Z/E isomerization of olefins. Specifically, the palladium catalyst complexes and coordinates the nitrogen atom of 8-quinoline group and excess alkynes in the cis-product, and the resulting organometallic intermediate promotes the Z/E isomerization of olefins through oxidative addition/hydrogen metallization. The DFT calculation study is consistent with the reaction mechanism proposed by the research group.

Figure 4: Possible reaction mechanisms and catalytic cycling.

In short, Zhao Dongbing’s research group and Hong Xin’s research group realized the intermolecular trans-bissilylation reaction of terminal alkynes for the first time, and obtained trans-bissilylated olefin products concisely and efficiently. Further, the two non-equivalent silicon groups in the product can be fully differentiated and transformed in a stepwise manner, enabling modular synthesis of functionalized bioactive compounds. Mechanistic studies, including DFT calculations, have shown that TMDQ as a disilane reagent and stoichiometric excess terminal alkynes under reaction are critical to the success of this conversion. The strong coordination ability of N-atoms on the asymmetric disilane reagent TMDQ and the relatively strong acidity of the terminal alkynes make the reaction undergo cis-bissilylation and subsequent Z/E olefin isomerization during the reaction. The research group expects that this strategy will soon promote the addition of element-element bonds catalyzed by transition metals to different unsaturated bonds in a trans manner, opening up new reverse synthesis methods for complex molecular synthesis. (Source: Science Network)

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