Time-Controlled Synthesis of Diverse Silicon Heterocycles via Palladium-Catalyzed CH Activation

Silicon heterocyclic compounds are widely used in organic synthesis, medicinal chemistry and material science, so it is of great significance to develop efficient synthesis methods. Transition metal-catalyzed C-Si bond construction is the most direct and effective method for the synthesis of silicon heterocycles. Typical strategies include: (1) pre-introduction of silicon groups into organic frameworks, followed by ring closure to synthesize silicon heterocycles; (2) ring expansion reactions of three- or four-membered silicon heterocycles; (3) intermolecular cyclization reactions between organic substrates and simple silicon reagents. Compared to the progress made by the first two strategies, the third strategy, although attractive, remains less reported. There are three main reasons: (1) silicon reagents are scarce; (2) the reaction mode is single, limited to cycloaddition reactions; (3) the types of substrates are limited. Therefore, it is highly necessary to develop new methods for the synthesis of silicon heterocycles using new silicon reagents and organic substrates. 1,4-dioxacyclohexasilane (ODCS) is easy to synthesize, but the research on its reactivity is very lagging behind. It was not until 2021 that the research group of Professor Shi Zhuangzhi of Nanjing University disclosed the application of ODCS as a silicon reagent for the first time, and synthesized silicon heterocyclic compounds through a C−H activation strategy assisted by P(III) directing groups (Figure 1b). In their report, ODCS reagents were used as disiloxane units to construct heteroarene-fused disiloxanes via two oxidative additions of Si–Si bonds to Pd(II). In view of the current progress, it is highly necessary to further explore the application of this tetrasilane reagent ODCS on other substrates.

The Liang Yun/Yang Yuan research group of Hunan Normal University has devoted themselves to the research on the conversion reaction of C,C -ring palladium species in recent years. Using a variety of coupling reagents to capture five-membered C,C- ring palladium species, a series of CH activation/decarboxylation cyclization reactions, CH activation/silylation reactions ( Chem . Sci . 2021 , 12 , 11756; Org. Lett . 2022 , 24 , 7282; Org. Lett. 2022 , 24 , 1400; 2021 , 23 , 7150; Org. Lett . 2021 , 23 , 5744; Org. Lett. 2021 , 23 , 2878 ; Org . Lett . 2021 , 23 , 2610; Org. Lett. 2019 , 21 , 9960; Org. Lett . 2019 , 21 , 7284; Org. Lett . 2019 , 21 , 2718; Org. Lett . 8 , 20 , 2997 ; Org . Chem . Front . 2022 , 9 , 3414; Org. Chem. Front . 2021 , 8 , 6535; Org. Chem . Front . 2021 , 8 , 5687 ; . 2020 , 7 , 2075; Org. Chem. Front. 2020 , 7 , 2016). On the basis of the previous research, the research group has recently made new progress in this area, and discovered a method for the time-controlled palladium-catalyzed CH activation of tetrasilane (ODCS) to synthesize silicon heterocyclic compounds . In this reaction, ODCS reagent is used to capture five-membered C,C -ring palladium species, and the reaction time is used as a control switch to realize the conversion of three different substrates, acrylamide, 2-halo-N- methacryloyl benzamide and 2-iodobiphenyl, thereby selectively synthesizing silicon heterocyclic compounds with different ring sizes, including ten-membered, seven-membered, and five-membered silicon heterocyclic compounds.

The optimal conditions were determined by adjusting the catalyst, ligand, base, solvent, temperature, time and so on. Subsequently, the author made a series of extensions to spirocyclic substrates, and the results showed that different functional groups ( CF 3 , COOCH 3 , NO 2 , etc.) showed good tolerance, and products 3 , 4 , and 5 were obtained in moderate to good yields at different times.

At the same time, the authors found that substrates 6 and 2 could efficiently assemble ten-membered or seven-membered fused silicon heterocycles at room temperature, and showed good substrate compatibility. This greatly expands the universality of Reagent 2.

In subsequent explorations, the authors found that 2-iodobiphenyl is also suitable for this strategy (Fig. 4a). The authors also performed some interesting transformations on some silane heterocyclic molecules. For example, 10-membered silicon heterocyclic rings can be followed by 11-membered silicon heterocyclic molecules 13-15 (Figure 4b); through simple deuterium experiments, heterocyclic molecules 16 and 17 with high deuteration rates can be obtained .

In order to clarify the course of the reaction, the authors conducted a series of control experiments (Figure 5), and the results indicated that the cyclopalladium species may be the intermediate of the reaction (Figure 5a). The generation of seven-membered and five-membered silicon heterocycles can be obtained from the corresponding ten-membered and seven-membered silicon heterocycles through intramolecular condensation with the assistance of K 2 CO 3 (Fig. 5b). The author also monitored the generation of various cyclic siloxane by-products through real-time GC-MS monitoring experiments, and these siloxanes showed specific changes with the prolongation of the reaction time. These results also demonstrate that the cleavage of Si-O and Si-C bonds occurs during the ring shrinkage process (Fig. 5d). Finally, the authors found that open-chain silanols cannot obtain the corresponding products with the assistance of K 2 CO 3 , which also indicates that the ring shrinkage process is an intramolecular cooperative process.

Based on the above experimental results and related literature, the author proposed a possible mechanism (Fig. 6). The oxidative addition of 1a to Pd(0) followed by intramolecular carbopalladiumation forms the σ-alkylpalladium intermediate A. Next, intermediate A undergoes CH activation to generate spirocyclic palladium heterocycle B , which leads to intermediates D or D′ through two possible pathways, including oxidative addition/reductive elimination (pathway a) and transmetalation/reductive elimination (pathway b). Subsequent reductive elimination of intermediates D or D’ yields Pd(0) and 3 . With the assistance of base K 2 CO 3 , the ten-membered silicon ring 3 was rapidly transformed into 4 and the intermediate G through the cleavage of two Si-O bonds and the formation of one Si-O bond . At the same time, intermediate G undergoes dimerization to generate 2, 2 is further converted to cyclosiloxane 21-23 in the presence of K 2 CO 3 and DMA . Finally, 4 undergoes a ring shrinkage reaction through Si-O/Si-C bond cleavage and formation of a Si-C bond to obtain 5 and H , HCyclosiloxanes 21-23 are formed by polymerization . Furthermore, in the transformation from 3 to 4 to 5 , another route by breaking another Si–O bond cannot be ruled out.

To sum up, the Liang Yun/Yang Yuan research group of Hunan Normal University developed a multifunctional tetrasilane for time-controlled palladium-catalyzed CH activation divergent tandem silicon cyclization reaction to construct silicon heterocycles, realizing the efficient synthesis of diverse silicon heterocycles. This method provides a new idea for the synthesis of organosilicon heterocycles.