Modular Access to 2-(Trifluoromethyl)pyrazolo[1,5-a]pyridines and Their Benzo Analogues through a Copper(I)-Catalyzed Radical Annulation

Abstract

A mechanistically distinctive copper-catalyzed radical annulation to valuable 2-(trifluoromethyl)­pyrazolo­[1,5-a]­pyridines and their benzo analogues has been described for the first time. Notably, the newly developed complementary process allows the synthesis of 4- or 6-substituted target molecular entities as a single product, which was previously challenging to access by existing methods. The utility of this process is further demonstrated by the facile construction of four different ring systems, a gram-scale synthesis, and the late-stage functionalization of bioactive molecules.

Recent advances in the synthesis of trifluoromethyl-containing heterocyclic compounds via trifluoromethyl building blocks

“…As shown in Scheme 71, a new transformation of 2-pyridyl derivatives with 2,2,2-trifluoroacetaldehyde O-(aryl)oxime using copper as the catalyst to produce 2-(trifluoromethyl)pyrazolo[1,5-a]pyridines and their benzo counterparts with great effectiveness was created by Weng's group 99 in 2022. It is worth noting that this supplementary strategy enables the synthesis of 4-or 6-substituted 2-(trifluoromethyl)pyrazolo [1,5-a] pyridines as a singular product, a feat previously unattainable using existing procedures.…”

Synthesis of 2-trifluoromethyl thiazoles via [3 + 2] cycloaddition of pyridinium 1,4-zwitterionic thiolates with CF3CN

“…27 The utility of pyridinium 1,4-zwitterionic thiolates in synthesis has been recently developed by Zhai's group in a variety of cycloaddition reactions. 28–30 On the basis of our recent studies on the synthesis of trifluoromethylated heterocycles using trifluoroacetonitrile generated from 2,2,2-trifluoroacetaldehyde O -(aryl)oxime, 31–34 we predicted a similar mechanistic pathway for the reaction of pyridinium 1,4-zwitterionic thiolates with CF 3 CN, to generate 2-trifluoromethyl thiazoles (Scheme 1b).…”

One-step synthesis of cyanated pyrazolo[1,5-a]pyridines utilizing N-aminopyridines as a 1,3-dipole and a nitrogen source

“…7,8 As a result, much attention has been paid to develop a handful of powerful approaches to build functionalized pyrazolo[1,5- a ]pyridines. 9 Typically, the [3 + 2] annulation reaction between pyridinium salts and electron-withdrawing alkenes/alkynes is proved to be an efficient and atom-economical protocol. However, the synthetic strategies toward cyanated pyrazolo[1,5- a ]pyridine derivatives are less explored.…”