Ag‐Catalyzed Trifluoromethylative Ring Expansion of Isatins and Isatin Ketimines with Trifluorodiazoethane

Abstract

A general method for the construction of trifluoromethylated 2‐quinolinones has been established herein by using a trifluoromethylative ring expansion of isatin with trifluorodiazoethane. The strategy provides a platform for the rapid synthesis of a wide range of substituted 3‐hydroxy‐4‐trifluoromethyl‐2‐quinolinones. This operationally simple and robust Ag‐catalyzed protocol successfully transforms isatin ketimines to 3‐amino‐4‐trifluoromethylquinolinones in excellent yields. The utility of this novel method is further illustrated by the conversion of the products into various synthetically and medicinally relevant molecules.

2,2,2-Trifluorodiazoethane (CF3CHN2): A Long Journey since 1943

“…In 2020, Mohanan reported on a reaction between in situ generated CF 3 CHN 2 (1) and isatines in the presence of AgOAc. 87 The reaction was performed at a room temperature and gave quinolinones of type 254−256 in 68−92% yield (Scheme 50). Detailed mechanistic studies were not undertaken, but the authors suggested that 2,2,2-trifluorodiazoethane reacted first with AgOAc to form intermediate 64 (Scheme 30), followed by a nucleophilic attack at the carbonyl group of isatine and the subsequent migration of the phenyl-substituent.…”

“…In 2020, Mohanan described an AgOAc-catalyzed reaction between in situ generated CF 3 CHN 2 (1) with isatine ketimines. 87 Quinolinones of type 264−266 were obtained in 68−92% yield (Scheme 53). Mechanistically, the authors proposed the formation of silver intermediate 64 (Scheme 30); however, an alternative activation of the imine moiety with Ag + could be also viable.…”

“…In 2020, Mohanan reported on a reaction between in situ generated CF 3 CHN 2 ( 1 ) and isatines in the presence of AgOAc . The reaction was performed at a room temperature and gave quinolinones of type 254 – 256 in 68–92% yield (Scheme ).…”

Trifluorodiazoethane: A versatile building block to access trifluoromethylated heterocycles

“…In 2020, we developed a silver‐catalyzed ring expansive trifluoromethylation reaction of isatin 86 employing CF 3 CHN 2 to synthesize a wide range of trifluoromethylated 2‐quinolinones 87 (Scheme 42) [60]. Several isatins 86 reacted smoothly under the reaction conditions to afford this important class of compounds.…”

An Overview of Ag‐catalyzed Synthesis of Six‐membered Heterocycles

“…(Scheme 22, Scheme 23). [33] A range of the above products were synthesized under the optimized conditions of 5 mol % AgOAc in 1,4‐dioxane at 25 °C for 2 h in good yields. The reaction was compatible with various substitutions on the aryl ring of isatins as well as isatin ketimines and also with their N‐substituted derivatives.…”