动力学分辨率
催化作用
亲核细胞
芳基
化学
吡啶
亲核取代
组合化学
半胺
药物化学
有机化学
对映选择合成
烷基
作者
Ming‐Sheng Xie,Shuxian Meng,Ning Li,Yang-Guang Chen,Xiaobing Wang,Xuan Cheng,Tian Yin,Xin Wu,Yun Deng,Gui‐Rong Qu,Hai‐Ming Guo
标识
DOI:10.1021/acscatal.1c04923
摘要
An efficient chiral 4-aryl-pyridine-N-oxide (ArPNO) nucleophilic organocatalyst was rationally designed, synthesized, and applied to the acylative dynamic kinetic resolution of azoles, aldehydes, and anhydride. The restriction of the pyridine’s C-4 position, where the dialkylamino group should be always present when using chiral pyridine-N-oxide as an acyl transfer catalyst, was overcome, thereby allowing structural diversity at this position. In the presence of 5 mol % 3,5-dimethylphenyl-derived ArPNO catalyst, the corresponding 2,5-disubstituted tetrazole hemiaminal esters were obtained in up to 93% yields, >20:1 rr, and 99% ee. Other N-heteroaromatics, including substituted pyrazole, imidazole, purine, benzimidazole, and benzotriazole, were also suitable substrates. Mechanistic studies by control experiments and density functional theory calculations indicated that an acyloxypyridinium cation was formed, and the nucleophilic substitution of azole hemiaminal with the acyloxypyridinium cation was the rate-determining step. Furthermore, the nucleophilic ability of oxygen in pyridine-N-oxide was higher than that of nitrogen in pyridine. This work provides an effective method for the utilization of the C-4 position of the pyridine ring, allowing the development of more varied chiral 4-substituted pyridine-N-oxides as efficient nucleophilic organocatalysts.
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