Abstract
The past decade has witnessed significant advances in C–H bond functionalizations with the discovery of new mechanisms. Non-precious transition-metal-catalysed radical oxidative coupling for C(sp3)–H bond transformations is an appealing strategy for C–C bond formations. The radical oxidative C(sp3)–H/C(sp3)–H cross-coupling reactions of α-C(sp3)–H bonds of amines with free radicals represent a conceptual and practical challenge. We herein develop the coordinating activation strategy to illustrate the nickel-catalysed radical oxidative cross-coupling between C(sp3)–H bonds and (hetero)arylmethyl free radicals. The protocol can tolerate a rich variety of α-amino acids and (hetero)arylmethanes as well as arylmethylenes and arylmethines, affording a large library of α-tertiary and α-quaternary β-aromatic α-amino acids. This process also features low-cost metal catalyst, readily handled and easily removable coordinating group, synthetic simplicity and gram-scale production, which would enable the potential for economical production at commercial scale in the future.
Highlights
The past decade has witnessed significant advances in C–H bond functionalizations with the discovery of new mechanisms
A number of strategies have been used for the preparation of non-proteinogenic amino acids, traditional methodologies typically encounter highly hazardous reagents, tedious multiple synthesis and purification, rigorous reaction conditions such as very strong bases that may be intolerant of sensitive functionalities, and/or limited substrate scope[16]
It should be possible to perform the cross-coupling between a-C(sp3)–H bonds of a-amino acids and arylmethyl free radicals, generated from arylmethyl C(sp3)–H bond by peroxide via single-electron transfer (SET), to produce b-arylalanine derivatives (Fig. 1c, right)
Summary
The past decade has witnessed significant advances in C–H bond functionalizations with the discovery of new mechanisms. One of the main disadvantages of these strategies is the use of noble metal catalysts typically in combination with stoichiometric silver salts as the additive, which would diminish the appeal of practical application Given that both a-amino acids and benzylic units[27,28,29,30,31,32] are among the most widespread scaffolds, we surmised that the oxidative benzylation of a-C(sp3)–H bonds of a-amino acids with benzylic C(sp3)–H bonds would be a distinct, straightforward gateway to long-range unnatural b-arylalanine derivatives involving both a-tertiary and a-quaternary carbon centers (Fig. 1b, right). In this work, using the coordinating activation strategy, we demonstrate a practical gateway to b-aromatic a-amino-acid derivatives through the nickel-catalysed radical oxidative
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