Li Yan, Li Zhilin, Zhang Zhiqiang
School of Chemical Engineering, University of Science and Technology Liaoning, Anshan 114051, P. R. China.
Phys Chem Chem Phys. 2021 Mar 18;23(10):6204-6212. doi: 10.1039/d1cp00369k.
Density functional theory (DFT) calculations (M06-2X) have been employed to disclose the mechanisms and regio- and stereo-selectivities of the N-heterocyclic carbene (NHC)-catalyzed reaction of 2-benzothiazolimines and α-chloroaldehydes. The preferred mechanism is initiated by the nucleophilic attack of NHC on α-chloroaldehyde (first step), followed by 1,2-proton transfer which was assisted by the Brønsted acid DABCO·H+ to generate the Breslow intermediate (second step). The cleavage of the C-Cl bond (third step) and deprotonation (fourth step) form the enolate intermediate. This further reacts with 2-benzothiazolimine which leads to the formation of a new C-C bond (fifth step). Subsequent cyclization takes place via the formation of a new C-N bond (sixth step). Catalyst regeneration completes the whole catalytic cycle and affords the final product (seventh step). The DFT results indicate that the fifth step determines the stereochemistry of the reaction and leads to benzothiazolopyrimidinone with the SS configuration, which agrees well with experimental observations. Intramolecular cyclization is found to be the regioselectivity-determining step, for which the [4+2] annulation pathway is more preferred than that via [2+2] annulation, which again agrees well with experimental observations. Based on the mechanism proposed, the origins of regio- and stereoselectivities have also been investigated by performing distortion/interaction, natural bond orbital (NBO) and non-covalent interaction (NCI) analyses. The mechanistic insights gained in this work should be helpful in the rational design of potential catalysts for analogous reactions.
采用密度泛函理论（DFT）计算（M06 - 2X）来揭示N - 杂环卡宾（NHC）催化2 - 苯并噻唑亚胺与α - 氯代醛反应的机理、区域选择性和立体选择性。优选的机理是由NHC对α - 氯代醛的亲核进攻引发（第一步），随后是在布朗斯特酸DABCO·H⁺的协助下进行1,2 - 质子转移以生成布雷斯洛中间体（第二步）。C - Cl键的断裂（第三步）和去质子化（第四步）形成烯醇盐中间体。该中间体进一步与2 - 苯并噻唑亚胺反应，导致形成新的C - C键（第五步）。随后通过形成新的C - N键进行环化（第六步）。催化剂再生完成整个催化循环并得到最终产物（第七步）。DFT结果表明，第五步决定了反应的立体化学，生成具有SS构型的苯并噻唑并嘧啶酮，这与实验观察结果非常吻合。发现分子内环化是区域选择性的决定步骤，对于该步骤，[4 + 2]环加成途径比[2 + 2]环加成途径更受青睐，这同样与实验观察结果相符。基于所提出的机理，还通过进行变形/相互作用、自然键轨道（NBO）和非共价相互作用（NCI）分析研究了区域选择性和立体选择性的起源。这项工作中获得的机理见解应有助于合理设计类似反应的潜在催化剂。
