Palladium-catalyzed Suzuki Reaction At Room-temperature And Product Structure-based Virtual Screening Of Potential Targets

In this research, Pd/NiXantphos-catalyzed Suzuki reaction adopting aryl chlorides and arylboronic acids as raw materials were conducted under room temperature, and for the first time, the virtual screening of potential targets for the products obtained from cross-coupling reaction was conducted to explore the potential druggability of the products, which may provide useful information for further research.Firstly, we optimized the solvents and bases used in the following reaction, and determined the optimum conditions as follows:aryl chlorides (0.2mmol,1equiv) and arylboronic acids (1.2equiv) as raw materials, K2CO3 (2equiv) as base, THF/H2O (2:1) as solvents,2% Pd(OAc)2-3%NiXantphos (1:1.5) as the catalytic system. Then, under the optimum conditions,4-tert-butyl phenylboronic acid was chosen as the arylboronic acid substrate to investigate the scope of aryl chlorides substrates suitable for suzuki reaction, and on the other side,2-chloro-5-(trifluoromethyl) pyridine and 3-chloropyridine were chosen as the aryl chlorides substrate to investigate the scope of arylboronic acids substrates for suzuki cross-coupling reaction. Afterwards, two series of designed suzuki reaction were conducted in 6h at room temperature, and obtained 7 and 12 products, respectively. In total, we got 19 products.To make the purification and isolation step easier, reaction with yields lower than 90% were repeated under higher temperature to increase the yields. And under 65 ℃, the yield of reaction adopting 3-chloropyridine and 4-tert-butylphenylboronic acid as raw materials was increased from 65% to 90%; yields of reaction adopting 2-chloro-5-(trifluoromethyl) pyridine and furan-2-ylboronic acid,2-chloro-5-(trifluoromethyl) pyridine and m-tolylboronic acid,3-chloropyridine and p-tolylboronic acid as raw materials were increased from 70%,80%,60% to 95%,100%,80%, respectively.Through the structure analysis of the products, it could be seen that when the substrate scope of aryl chlorides with 4-tert-butylphenylboronic acid was tested under the optimized reaction conditions, heterocyciic chlorides with pyridine framework were preferable substrates. Furthermore, the reaction could be facilitated when adopting aryl chlorides with strongly electron-withdrawing groups like trifluoromethyl, cyano group, nitro group, etc. On the other hand, the reaction could be suppressed when adopting aryl chlorides with strongly electron-donating groups like amino group, etc. And it was also discovered that reactions adopting 2-substituted pyridine chlorides as substrate were easier than adopting 3-substituted pyridine chlorides as substrate. Similarly, when the substrate scope of arylboronic acids with 2-chloro-5-(trifluoromethyl) pyridine was tested under the optimized reaction conditions, the reaction could be facilitated when adopting arylboronic acids with strongly electron-withdrawing groups like trifluoromethyl, etc. And the reaction could be suppressed when adopting arylboronic acids with strongly electron-donating groups like ether group, thioether group, etc.Later, the products A1 and B7 were chosen for the the virtual screening research of potential receptors, and tens of receptors with △Gpred<-8 kcal/mol were listed as good results. Then the two targets of 3IIF and 1RM8 with best affinity with the products Al and B7, respectively, were selected to conduct further research on all of the products.In this part of research, through structure clustering, products of A1, A2, A3, A4, A5, A6, A7, B1, B2, B3, B4, B5, B8, B9, B10, B11, B12 were chosen as ligands to conduct Autodock vina docking research and Surflex-Dock docking research on 3IIF. As a result, A1 and B11 were determined to be the best two ligands with best affinity and structural recognition with 3IIF. At the same time, Autodock vina docking research and Surflex-Dock docking research on 1RM8 were conducted adopting B6 and B7 as ligands. According to the results, both structures of 2-(furan-2-yl)-5-(trifluoromethyl) pyridine and 2-(thiophen-2-yl)-5-(trifluoromethyl) pyridine showed good affinity with 1RM8. However, because of the overly small frameworks, both of the two compounds showed weak structural recognition with 1RM8. In further research, the polar bond and structural recognition with 1RM8 of the two compounds could be increased through structural modification of adding electron-donating groups like tertiary butyl, ester group, etc.As 1RM8 was known to have vital function in tumor invasion and metastasis, if we could promote the structural recognition of B6 and B7 with 1RM8 through structural modification in synthetic research, good anti-tumor agents might be obtained.