Difluoromethoxylated Ketones as Building Blocks for the Synthesis of Challenging OCF₂H‐Bearing N‐Heterocycles

Abstract

We report herein an unprecedented synthesis of difluoromethoxylated nitrogen‐containing heterocycles from the corresponding α‐(difluoromethoxy)ketones as versatile building blocks. Pyrazoles, isoxazoles and pyrimidines could be obtained via an enaminone intermediate, whereas in the direct reaction of α‐(difluoromethoxy)ketones with arylhydrazines, a Fischer indole synthesis was achieved. All these scaffolds, which are uncommon, or even sometimes novel, due to the directly attached emerging fluorinated group (EFG) ‐OCF2H, might be of high potential in life sciences and appear as an interesting alternative to more and more controversial classical fluorinated groups, such as the ubiquitous trifluoromethyl group.

Rapid Multikilogram Scale-Up of Di- and Trifluoromethoxy Proline Derivatives

“…The difluoromethyl ether moiety has been found in several potential drug candidates due to the unique chemical and physical properties that enhance bioefficacy. − While synthetic strategies for difluoromethyl aryl ether synthesis have been developed, ,− very few have been applied to chiral secondary alcohols. Synthetic methods to prepare difluoromethyl ethers can be divided into four main groups: (a) C–O coupling reaction using a OCF 2 H synthon, , (b) transformation of esters and thioesters into difluoroethers, − (c) nucleophilic substitution pathways such as halogen displacement or nucleophilic attack of the alcohol to an electrophilic difluoromethyl source, ,− and (d) difluoromethylation of aryl and alkyl alcohols using a variety of difluorocarbene sources ,− (Figure ).…”

“…13 C NMR (101 MHz, DMSO-d 6 ) δ 168.3, 128.0−112.8 (m), 77.7 (q, J = 2.6 Hz), 57.6, 53.6, 50.9, 34.7 19. F NMR (376 MHz, DMSO-d 6 ) δ −57.32.…”