Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
Chemical and Synthetic Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey 08903, United States.
J Am Chem Soc. 2020 Apr 8;142(14):6786-6799. doi: 10.1021/jacs.0c01666. Epub 2020 Mar 25.
Experimental, spectroscopic, and computational studies are reported that provide an evidence-based mechanistic description of an intermolecular reductive C-N coupling of nitroarenes and arylboronic acids catalyzed by a redox-active main-group catalyst (1,2,2,3,4,4-hexamethylphosphetane -oxide, i.e., ·[O]). The central observations include the following: (1) catalytic reduction of ·[O] to P phosphetane is kinetically fast under conditions of catalysis; (2) phosphetane represents the catalytic resting state as observed by P NMR spectroscopy; (3) there are no long-lived nitroarene partial-reduction intermediates observable by N NMR spectroscopy; (4) the reaction is sensitive to solvent dielectric, performing best in moderately polar solvents (viz. cyclopentylmethyl ether); and (5) the reaction is largely insensitive with respect to common hydrosilane reductants. On the basis of the foregoing studies, new modified catalytic conditions are described that expand the reaction scope and provide for mild temperatures ( ≥ 60 °C), low catalyst loadings (≥2 mol%), and innocuous terminal reductants (polymethylhydrosiloxane). DFT calculations define a two-stage deoxygenation sequence for the reductive C-N coupling. The initial deoxygenation involves a rate-determining step that consists of a (3+1) cheletropic addition between the nitroarene substrate and phosphetane ; energy decomposition techniques highlight the biphilic character of the phosphetane in this step. Although kinetically invisible, the second deoxygenation stage is implicated as the critical C-N product-forming event, in which a postulated oxazaphosphirane intermediate is diverted from arylnitrene dissociation toward heterolytic ring opening with the arylboronic acid; the resulting dipolar intermediate evolves by antiperiplanar 1,2-migration of the organoboron residue to nitrogen, resulting in displacement of ·[O] and formation of the target C-N coupling product upon hydrolysis. The method thus described constitutes a mechanistically well-defined and operationally robust main-group complement to the current workhorse transition-metal-based methods for catalytic intermolecular C-N coupling.
实验、光谱和计算研究报告提供了一种基于证据的机制描述，即由氧化还原活性主族催化剂（1,2,2,3,4,4-六甲基膦氧化物，即·[O]）催化的硝基芳烃和芳基硼酸之间的分子间还原 C-N 偶联。主要观察结果包括以下几点：（1）在催化条件下，·[O]催化还原为膦烷是动力学快速的；（2）膦烷通过 P NMR 光谱观察到是催化的静止状态；（3）通过 N NMR 光谱观察不到长寿命的硝基芳烃部分还原中间体；（4）该反应对溶剂介电常数敏感，在中等极性溶剂（即环戊基甲基醚）中表现最佳；（5）该反应对常见的硅烷还原剂基本不敏感。基于上述研究，描述了新的改良催化条件，扩大了反应范围，并提供了温和的温度（≥60°C）、低催化剂负载（≥2 mol%）和无害的末端还原剂（聚甲基氢硅氧烷）。DFT 计算为还原 C-N 偶联定义了两步脱氧序列。初始脱氧步骤涉及一个速率决定步骤，该步骤由硝基芳烃底物和膦烷之间的（3+1）螯合加成组成；能量分解技术突出了膦烷在这一步骤中的两性特征。尽管动力学上不可见，但第二步脱氧步骤被认为是关键的 C-N 产物形成事件，其中假定的氮杂磷杂环戊烷中间体偏离芳基氮烯离解，向与芳基硼酸的异裂环打开；所得偶极中间体通过有机硼残基的反式平面 1,2-迁移向氮进化，导致·[O]的取代和目标 C-N 偶联产物的形成，随后水解。该方法构成了对当前催化分子间 C-N 偶联的主力过渡金属基方法的一种机制上定义明确且操作稳健的主族补充。
