General Synthesis of N-Trifluoromethyl Compounds with N-Trifluoromethyl Hydroxylamine Reagents

N-CF3 compounds constitute valuable targets in medicinal chemistry. Extensive studies have been reported for the preparation of N-CF3 compounds through fluorination and trifluoromethylation of N-containing compounds. The development of new synthetic methods from abundant and easily available substrates is highly desirable but still challenging. Herein, we report the design and synthesis of novel N-Cbz- and N-Boc-N-trifluoromethyl hydroxylamine reagents by silver-mediated oxidative trifluoromethylation. These reagents have been successfully applied to the direct incorporation of a NCF3 moiety into the commonly used unsaturated substrates under photoredox catalysis. This protocol enables the efficient and regioselective C-H trifluoromethylamination of various (hetero)arenes, including complex bioactive molecules. Furthermore, a variety of alkenes, dienes, and isonitriles undergo tandem trifluoromethylamination/functionalization delivering structurally diverse N-trifluoromethyl aliphatic and heteroaromatic amines. Notably, previously unknown cyclic N-CF3 compounds including N-CF3 oxazolidinones and oxazolones were conveniently prepared with N-Boc-N-trifluoromethyl hydroxylamine reagents. Furthermore, diversification of the resulting alpha-trifluoromethylamino ketones afforded the largely underexplored N-alkenyl- and N-alkynyl-N-CF3 compounds.

Automated summary

This study reports a method for the design and synthesis of novel N-Cbz- and N-Boc-N-trifluoromethyl hydroxylamine reagents using silver-mediated oxidative trifluoromethylation. These reagents have been successfully applied to incorporate a NCF3 moiety into commonly used unsaturated substrates, enabling efficient and regioselective C-H trifluoromethylamination. Additionally, a variety of substrates can undergo tandem trifluoromethylamination/functionalization to deliver structurally diverse N-trifluoromethyl aliphatic and heteroaromatic amines.