Ketenimines as Intermediates To Access Difluoromethoxylated Scaffolds

Abstract

We report herein the in situ generation of difluoromethoxylated ketenimines. This novel intermediate is readily obtained from the corresponding oxime through a Beckmann rearrangement. The reactivity potential of this species is demonstrated as it easily undergoes addition of various nucleophiles, with a great modularity of the starting oxime. The broad applicability of this transformation leads to a chemical library of original molecules bearing −OCHF2, an Emergent Fluorinated Group (EFG).

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

“…General procedure for the synthesis of the starting difluoromethoxylated ketones, adapted from the literature: General procedures for the synthesis of 1 a-g, 2 a-g and 3 a-g have been described in our previous publication. [36] General Procedure A for the one-pot synthesis of pyrazoles 4 a-f: A mixture of 1-aryl-2-(difluoromethoxy)ethan-1-one 3 a-f (1 equiv., 0.30 mmol) and N,N-dimethylformamide dimethyl acetal (1.1 equiv., 44 μL, 0.33 mmol) was heated at 90 °C for 7 h. Excess DMFDMA was removed under vacuum. The obtained residue was dissolved in EtOH (0.20 mL).…”

“…General procedure for the synthesis of the starting difluoromethoxylated ketones, adapted from the literature : General procedures for the synthesis of 1 a – g , 2 a – g and 3 a – g have been described in our previous publication [36] …”

“…We have recently reported the preparation of difluoromethoxylated building‐blocks via F 2 HCO‐containing ketenimines, formed from α‐(F 2 HCO)‐ketoximes, themselves obtained from α‐(F 2 HCO)‐ketones. In fact, the latter ketones accessed via the route described in Scheme 1 (steps affording compounds 1–3 ), [36] as such, have a strong potential as difluoromethoxylated synthons and could be readily converted into heterocycles, where the −OCF 2 H group would be directly connected to the ring. Accordingly, we report herein an efficient synthesis of OCF 2 H‐bearing pyrazoles, isoxazoles and pyrimidines starting from α‐difluoromethoxylated ketones via an enaminone intermediate, [37] as well as an elegant Fischer indole synthesis using various hydrazine derivatives (Scheme 1).…”