In silico reaction screening with difluorocarbene for N-difluoroalkylative dearomatization of pyridines
In silico reaction screening with difluorocarbene for N-difluoroalkylative dearomatization of pyridines
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DOI：
10.1038/s44160-022-00128-y
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发表时间：
2022-10-01
期刊：
影响因子：
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通讯作者：
Mita, Tsuyoshi
中科院分区：
文献类型：
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作者：
Hayashi, Hiroki;Katsuyama, Hitomi;Mita, Tsuyoshi
量子化学计算主要被认为是有机化学中机理研究的一种方法，而它们用于模拟未知反应可以极大地帮助反应的发展。在这里，我们报告的基础上，计算反应模拟的结果开发多组分反应的策略。用人工力诱导反应方法对二氟卡宾的多组分反应进行了计算机模拟筛选，结果表明甲亚胺叶立德与多种偶联配体之间的环加成反应可生成相应的α，α-二氟代N-杂环化合物。预测的反应成功地实现了实验，导致多组分的N-二氟烷基化脱芳构化的吡啶涉及吡啶叶立德介导的1，3-偶极环加成与各种亲电试剂，如醛，酮，亚胺，烯烃和炔烃。此外，环加成反应的性能可以通过比较期望途径与竞争性非期望途径的能垒来解释，这也通过人工力诱导反应搜索来确定。
Quantum chemical calculations are mainly regarded as a method for mechanistic studies in organic chemistry, whereas their use for the simulation of unknown reactions could greatly assist in reaction development. Here we report a strategy for developing multicomponent reactions on the basis of the results of computational reaction simulations. In silico screening of multicomponent reactions with difluorocarbene using the artificial force induced reaction method suggested that cycloadditions between an azomethine ylide and a variety of coupling partners would proceed to generate the corresponding alpha,alpha-difluorinated N-heterocyclic compounds. The predicted reaction was successfully realized experimentally, leading to a multicomponent N-difluoroalkylative dearomatization of pyridines involving a pyridinium ylide-mediated 1,3-dipolar cycloaddition with a diverse range of electrophiles such as aldehydes, ketones, imines, alkenes and alkynes. Moreover, the performance of the cycloaddition could be explained by comparing the energy barrier of the desired pathway with that of the competitive undesired pathway, which was also identified by the artificial force induced reaction search.