N-Heterocycle-Forming Amino/Carboperfluoroalkylations of Aminoalkenes by Using Perfluoro Acid Anhydrides: Mechanistic Studies and Applications Directed Toward Perfluoroalkylated Compound Libraries

Abstract

This work describes a practical and efficient method for synthesizing a diverse array of perfluoroalkylated amines, including N-heterocycles, to afford perfluoroalkylated chemical libraries as potential sources of drug candidates, agrochemicals, and probe molecules for chemical-biology research. Perfluoro acid anhydrides, which are commonly used in organic synthesis, were employed as a perfluoroalkyl source for intramolecular amino- and carbo-perfluoroalkylations of aminoalkenes, affording perfluoroalkylated N-heterocycles, including: aziridines, pyrrolidines, benzothiazinane dioxides, indolines, and hydroisoquinolinones. Diacyl peroxides were generated in situ from the perfluoro acid anhydrides with urea·HO, and allowed to react with aminoalkenes in the presence of copper catalyst to control the product selectivity between amino- and carbo-perfluoroalkylations. To illustrate the synthetic utility of bench-stable trifluoromethylated aziridine, which was prepared on a gram scale, we used it to synthesize a wide variety of trifluoromethylated amines including complex molecules, such as trifluoromethylated tetrahydroharmine and spiroindolone. A mechanistic study of the role of the copper catalyst in the aminotrifluoromethylation of allylamine suggested that Cu(I) accelerates CF radical formation via decomposition of diacyl peroxide, which appears to be the turnover-limiting step, while Cu(II) controls the product selectivity.

Evolution and Future of Hetero‐ and Hydro‐Trifluoromethylations of Unsaturated C−C Bonds

“…Copper-catalyzed amino-trifluoromethylation with TFAA. [134] Scheme 118. Metal-free intramolecular amino-trifluoromethylation of styrenes with TFAA.…”

“…The group of Kawamura and Sodeoka focused on the application of TFAA as an inexpensive and readily available trifluoromethylation agent in amino‐trifluoromethylation (Scheme 117). [134] The diacyl peroxide prepared in situ from TFAA and urea ⋅ H 2 O 2 efficiently generated CF 3 ‐containing aziridines and pyrrolidines from the corresponding alkenyl amines in the presence of a Cu(I) catalyst. Compared to Togni reagent, the diacyl peroxide showed a much higher reactivity and a wider substrate scope.…”

Understanding and Controlling Fluorinated Diacyl Peroxides and Fluoroalkyl Radicals in Alkene Fluoroalkylations

“…These conditions were successfully applied to intramolecular amino‐perfluoroalkylation of alkenes bearing a pendant amino group, providing easy and efficient access to a wide range of valuable molecules containing aziridine and pyrrolidine skeletons (Scheme 6). [6b] CF 3 ‐containing aziridines have proven to be excellent building blocks, with various ring‐opening nucleophilic substitutions available.…”

Synthesis of CF3CH2-Containing Indolines by Transition-Metal-Free Aryltrifluoromethylation of Unactivated Alkenes

“…Significant efforts have been directed toward the incorporation of a polyfluoroalkyl group into various organic systems . In this context, trifluoromethylative vicinal difunctionalization of activated alkenes has proven to be a powerful strategy to access molecule complexity, − while trifluoromethylation of unactivated ones remains more rudimentary. , …”

“…Very few examples of 3-(2,2,2-trifluoroethyl) indoline synthesis have been disclosed, and they are associated with tedious procedures, a narrow substrate scope, high cost, and/or harsh/toxic conditions (Scheme ). , The reduction of oxindoles might afford related indolines as well, yet it suffers from severe functional group intolerance . Therefore, it is highly desirable to develop a general, practical, and cost-effective method for the synthesis of the title CF 3 CH 2 -containing indolines.…”