Abstract
Transition metal-catalyzed cross dehydrogenative coupling is an important tool for functionalization of the α Csp3-H bond of amines. Among this reaction category, copper-catalyzed selective C-C bond formation under atmospheric O2 is of considerable research interest and significant progress has been achieved in recent years. In comparison, development of the intramolecular version of this transformation is still in its infancy. Furthermore, diastereoselective cyclization with this transformation has not been achieved. Here, we describe the highly diastereoselective intramolecular dehydrogenative cyclization of N,N-disubstituted hydrazones by a copper-catalyzed sp3 C-H bond functionalization process. The reaction protocol utilizes O2 as the oxidant and shows great functional group compatibility. Computational studies suggest that a 5-center/6-electron disrotatory cyclization mechanism is probably involved in the process for controlling the diastereoselectivity. This work represents the first example of a copper-catalyzed, direct intramolecular diastereoselective coupling reaction via an iminium ion intermediate. Additionally, it provides an environmentally friendly and atom efficient approach to access substituted pyrazolines, an important structural unit in many biologically active compounds.
Highlights
Selective carbon–carbon (C–C) bond formation is a fundamental focus in chemical research due to its importance in organic, medicinal, agricultural, and material chemistry.[1]
Considerable efforts have been devoted in this area for selective C–C bond construction, and a variety of copper-catalyzed aerobic dehydrogenative coupling reactions have been reported via sp or sp[2] C–H bond functionalization
Representative examples, which have expanded product diversity, include oxidative dimerization of phenols, naphthols and electron-de cient arenes, cross coupling of terminal alkynes with electron-de cient arenes, and intramolecular dehydrogenative cyclization of anilides.4e,g,6 copper-catalyzed aerobic cross dehydrogenative coupling (CDC) via an sp[3] C–H bond functionalization process has been established on tertiary amines by Miura, Li, and others.4a,e,g It has been demonstrated that a wide range of nucleophiles, such as alkynes, nitroalkanes, malonic esters, ketones, and electron-richarenes, are compatible coupling partners under aerobic oxidative conditions
Summary
Selective carbon–carbon (C–C) bond formation is a fundamental focus in chemical research due to its importance in organic, medicinal, agricultural, and material chemistry.[1] Conventional methods for the construction of C–C bonds, such as nucleophilic addition and substitution reactions, Friedel– Cra s-type reactions, and transition-metal-catalyzed or -mediated cross coupling reactions, rely primarily on prefunctionalized reactants, which somehow limit the synthetic application of these transformations.[2] stoichiometric amounts of toxic metal waste are o en generated in the processes, which constitutes an environmental issue.
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