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A photoinduced transient activating strategy for late-stage chemoselective C(sp3)–H trifluoromethylation of azines† † Electronic supplementary information (ESI) available. CCDC 2075782, 2075783 and 2126072. For ESI and crystallographic data in CIF or other electronic format see https://doi.org/10.1039/d2sc03989c

ABSTRACT: The direct functionalization of C(sp3)–H bonds is an ultimately ideal synthetic strategy with high atom economy and step efficiency. However, the direct trifluoromethylation of electron-deficient heteroaryl adjacent C(sp3)–H bonds remains a formidable challenge. We have described a transient activating strategy involving a Tf-shift process and π–π stacking interaction for catalyst-free direct benzylic C(sp3)–H trifluoromethylation of azines, such as pyridine, pyrimidine, quinoline, dihydropyridinone, tetrahydroisoquinoline and tetrahydroquinazoline, with an air-stable crystalline imidazolium sulfonate reagent IMDN-Tf. This bench-stable cationic reagent offers a scalable and practical protocol for the late-stage modification of drug molecules with high site selectivity, which avoids the prefunctionalization and the use of stoichiometric metals and strong oxidants. Furthermore, comprehensive mechanistic studies revealed the determining effect of π–π stacking for the activation of azinylic C(sp3)–H bonds. Late-stage C(sp3)–H functionalization of unactivated azines: the traceless Tf switching process offers ample opportunities for site-selective derivatization of heteroaryls, allowing for the rapid increase of molecular complexity.

SUBMITTER: Huang M

PROVIDER: S-EPMC9533475 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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