Scalable Synthesis of Trifluoromethylated Imidazo-Fused N-Heterocycles Using TFAA and Trifluoroacetamide as CF₃-Reagents

Abstract

A scalable synthesis of trifluoromethylated imidazo-fused N-heterocyles from heterocyclic benzylamines using TFAA as trifluoromethylating reagent is presented. The reaction proceeds via intermediate benzylic N-trifluoroacetamides followed by dehydrative cyclization to the products. To further broaden the scope and practicality, a new method for the preparation of benzylic N-trifluoroacetamides via alkylation of trifluoroacetamide with benzyl (pseudo)halides was developed. Both methods proceed under mild conditions, and their symbiosis provides access to a wide range of novel CF-heterocycles.

Luminescent Imidazo[1,5‐a]pyridine Scaffold: Synthetic Heterocyclization Strategies‐Overview and Promising Applications

“…The optimized conditions are also applicable to substituted heterocyclic benzylamines, and a wide range of novel trifluoromethylated imidazo-fused N-heterocycles to obtain a large variety of trifluoromethylated impy derivatives. [23,77] In Scheme 13 impy nucleus is obtained through oxidative desulfurization (iodine-mediated) cyclization of N-2pyridylmethyl thioamides (in Scheme 14 the reaction mechanism), this synthetic approach represents an efficient and versatile method to prepare impy products. [78] Similarly, in the last reaction of Scheme 13, the heterocyclization of a family of selenoamides is reported to obtain impy derivatives.…”

Aluminium Chloride‐Mediated Synthesis of 1‐Chloro‐2,2,2‐Trifluoroethylidene‐Substituted Pyrrolidones

“…General Information 1 H NMR, 19 F NMR and 13 C NMR spectra were recorded using Bruker AVIII 400 spectrometer. 1 H NMR and 13 C NMR chemical shifts were reported in parts per million (ppm) downfield from tetramethylsilane and 19 F NMR chemical shifts were determined relative to CFCl 3 as the external standard and low field is positive.…”

“…[13] Pyrrolidone derivatives are also used as 11-b-hydroxysteroid dehydrogenase inhibitors, [14] or monoamine oxidase B inhibitors [15] (Figure 1). [19] Despite these advancements, to the best of our knowledge, there is no literature precedence on the one-pot synthesis of 1-chloro-2,2,2-trifluoroethylidene-substituted pyrrolidone compounds using TFAA as 2,2,2-trifluoroethylidene source. The use of readily available, convenient, and inexpensive trifluoroacetic acid (TFA) and its anhydride (TFAA) as a trifluoromethyl source for trifluoromethylation reactions, would be an attractive approach to the synthesis of trifluoromethylated compounds.…”

“…Stephenson and co‐workers reported an elegant radical trifluoromethylation of arenes and heteroarenes using TFAA as the trifluoromethylating reagent and pyridine N ‐oxide and photoredox catalysis . Later, Schäfer and co‐workers also reported the synthesis of trifluoromethylated imidazo‐fused N ‐heterocyles using TFAA as trifluoromethylating reagent …”

Evaluating the Green Credentials of Flow Chemistry towards Industrial Applications

“…The process required an intermediate work-up and purification by column chromatography but with a strategic goal to increase safety margins the reaction was developed in a single step using TFAA as both the CF3 source and the dehydrative cyclization reagent. 60 An estimation of the green metrics including PMI and E-factor are reported in Table 1. The continuous flow one pot approach was more sustainable and cost effective than the two-step flow and two-step batch processes.…”