Cu-Promoted ipso-Hydroxylation of sp2 Bonds with Concomitant Aromatic 1,2-Rearrangement Involving a Cu-oxyl-hydroxo Species

Herein, we report the first example of Cu-promoted β ipso-hydroxylation of substituted benzophenones using a bidentate directing group (DG) and H2O2 as an oxidant. In addition to the new C–O bond formed, the ipso-oxidation induces a very unusual 1,2-rearrangement of the iminyl group to the vicinal γ position. This transformation is highly dependent on the substrate utilized (favored for 4-methoxy-substituted benzophenones) and on the DG used (2-picolylamine leads to selective γ-C–H functionalization, while β ipso-oxidation requires 2-(2-aminoethyl)pyridine). An analysis of the oxidation of substrate–ligands derived from 2-(2-aminoethyl)pyridine and unsymmetrical 4-MeO-substituted benzophenones indicates high regioselectivity (up to 89:11 for the MeO-substituted arene ring and up to 92:8 for β ipso- vs γ-C–H hydroxylation). Mechanistic studies (which include spectroscopic characterization of reaction intermediates, kinetics, and calculations) suggest the formation of a mononuclear CuIIOOH species before the rate-determining step (rds) of the reaction. DFT calculations suggest that the γ-C–H hydroxylation pathway involves a one-step concerted O–O cleavage and electrophilic aromatic attack. Conversely, β ipso-hydroxylation occurs in a stepwise fashion, in which O–O bond cleavage produces a CuIII(O·)(OH) before electrophilic aromatic attack. Calculations also shed light on the mechanism of the 1,2-rearrangement step, which involves strain release from a spiro 5-membered to a 6-membered Cu chelate.本文首次报道了以双齿导向基团（bidentate directing group，DG）与过氧化氢（H₂O₂）为氧化剂，在铜促进下实现取代二苯甲酮的β-本位羟基化反应的实例。除生成新的C-O键外，本位氧化还会引发亚胺基向邻位γ位的极为罕见的1,2-重排反应。该转化反应高度依赖所选用的底物（对于4-甲氧基取代的二苯甲酮反应更易进行）以及所使用的导向基团：2-吡啶甲胺可实现选择性γ-C-H官能化，而β-本位羟基化则需要使用2-(2-氨基乙基)吡啶。对由2-(2-氨基乙基)吡啶与不对称4-甲氧基取代二苯甲酮衍生的底物-配体体系的氧化反应分析显示，该反应具有较高的区域选择性：对于甲氧基取代的芳烃环，区域选择性最高可达89:11；而对于β-本位羟基化与γ-C-H羟基化的竞争反应，区域选择性最高可达92:8。机理研究（涵盖反应中间体的光谱表征、动力学分析与理论计算）表明，在反应的决速步（rate-determining step，rds）之前，会生成单核CuIIOOH物种。密度泛函理论（DFT）计算结果表明，γ-C-H羟基化路径涉及一步协同的O-O键断裂与亲电芳香进攻过程。与之相反，β-本位羟基化则以分步方式进行：O-O键断裂先生成CuIII(O·)(OH)物种，随后再发生亲电芳香进攻。计算结果还阐明了1,2-重排步骤的反应机理：该过程涉及螺环五元铜螯合物的张力释放，并转化为六元铜螯合物。