Rhodium‐Catalyzed Enantioselective 1,4‐Oxyamination of Conjugated gem‐Difluorodienes via Coupling with Carboxylic Acids and Dioxazolones

Abstract

The incorporation of fluorine atoms in organics improves their bioactivity and lipophilicity. Catalytic functionalization of gem‐difluorodienes represents one of the most straightforward approaches to access fluorinated alkenes. In contrast to the regular 1,3‐dienes that undergo diverse asymmetric di/hydrofunctionalizations, the regio‐ and enantioselective oxyamination of gem‐difluorodienes remains untouched. Herein, we report asymmetric 1,4‐oxyamination of gem‐difluorodiene by chiral rhodium‐catalyzed three‐component coupling with readily available carboxylic acid and dioxazolone, affording gem‐difluorinated 1,4‐amino alcohol derivatives. Our asymmetric protocol exhibits high 1,4‐regio‐ and enantioselectivity with utility in the late‐stage modification of pharmaceuticals and natural products. Stoichiometric experiments provide evidences for the π‐allylrhodium pathway. Related oxyamination was also realized when trifluoroethanol was used as an oxygen nucleophile.

Efficient Access to Enantioenriched gem-Difluorinated Heterocycles via Silver-Catalyzed Asymmetric Cycloaddition Reaction

“…15 So far, Li and Yu's group reported a seminal work on the enantioselective 1,4oxyamination of gem-difluorodienes via Rhodium catalysis (Figure 1b), which revealed the powerful reaction via diversely synthesizing gem-difluorinated 1,4-amino alcohol derivatives. 16 Given the unique chemical properties of 1,3-dienes, further exploration of the gem-difluoro-1,3-dienes is indispensable, which would pave a new avenue for applications of gemdifluorinated alkenes. Azo-Diels−Alder reactions between conjugated 1,3-dienes and azodicarboxylates is a powerful approach for the construction of functionalized hydropyridazines, which generally exhibited good biological activities and as the core scaffolds of drugs.…”

“…Zhang and co-workers reported an example of preparing fluorinated aryl compounds using gem -difluoro-1,3-dienes and N-(4-bromophenyl)­maleimide, but no gem -difluoro products were obtained because of the β-F elimination . So far, Li and Yu’s group reported a seminal work on the enantioselective 1,4-oxyamination of gem -difluorodienes via Rhodium catalysis (Figure b), which revealed the powerful reaction via diversely synthesizing gem -difluorinated 1,4-amino alcohol derivatives . Given the unique chemical properties of 1,3-dienes, further exploration of the gem -difluoro-1,3-dienes is indispensable, which would pave a new avenue for applications of gem -difluorinated alkenes.…”