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

Abstract

N-CF 3 compounds constitute valuable targets in medicinal chemistry. Extensive studies have been reported for the preparation of N-CF 3 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-Ntrifluoromethyl hydroxylamine reagents by silver-mediated oxidative trifluoromethylation. These reagents have been successfully applied to the direct incorporation of a NCF 3 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-CF 3 compounds including N-CF 3 oxazolidinones and oxazolones were conveniently prepared with N-Boc-N-trifluoromethyl hydroxylamine reagents. Furthermore, diversification of the resulting α-trifluoromethylamino ketones afforded the largely underexplored N-alkenyl-and N-alkynyl-N-CF 3 compounds.

The advent of electrophilic hydroxylamine-derived reagents for the direct preparation of unprotected amines

“…133 More recently, the Xu and Huang groups reported the C-H amination of (hetero)arenes under photoredox catalysis to form protected trifluoromethylamines. 134 With the development of new Fe catalysed innate C-H amination reactions a variety of new aminating reagents was introduced, each tailored for different kinds of transformations. In 2017, Jiao and co-workers introduced a new aminating reagent 4-NO 2 -C 6 H 4 CO 2 NH 3 OTf (R8), which enabled the Fe catalysed C-H amination of electron-rich and -neutral arenes as well as heteroarenes (Scheme 6B).…”

“… 133 More recently, the Xu and Huang groups reported the C–H amination of (hetero)arenes under photoredox catalysis to form protected trifluoromethylamines. 134 …”

Electrochemical cyclization ofN-cyanamide alkenes with CF3SO2Na to access C,N-(bis)trifluoromethylated cyclic amidines and related compounds

“…5 However, relatively less attention has been paid to both the synthetic methods for direct N -trifluoromethylations and their biological applications, in sharp contrast to the well-developed C-trifluoromethylations. 1 a–c ,2 In addition to the typical methods which relied on the functional group interconversions with tedious N -prefunctionalizations and the emerging N -CF 3 synthon approaches, 6,7 several elegant works have been reported to achieve direct electrophilic N -trifluoromethylations (Scheme 1b). 8 Recently, Bolm et al and Selander et al have accomplished a transition metal (TM)-mediated radical N -trifluoromethylation of sulfoximines and aryl nitroso derivatives, respectively.…”

Synthesis of N-CF3 Amidines/Imidates/Thioimidates via N-CF3 Nitrilium Ions

“…Very recently, Huang, Xu, and co-workers reported the first trifluoromethylamination in which N-CF 3 hydroxylamines (s-1) were synthesized to be successfully used as N-CF 3 transfer reagents (Scheme 1-I, strategy C1). 13 The second mode is based on the transformation of a functional group in the N-CF 3 synthon (Scheme 1-I, strategy C2). The past few years have witnessed remarkable achievements in this field.…”

“…One includes an N -CF 3 transfer pathway from the N -CF 3 synthon to the substrate, namely, trifluoromethylamination. Very recently, Huang, Xu, and co-workers reported the first trifluoromethylamination in which N -CF 3 hydroxylamines ( s-1 ) were synthesized to be successfully used as N -CF 3 transfer reagents (Scheme - I , strategy C1) . The second mode is based on the transformation of a functional group in the N -CF 3 synthon (Scheme - I , strategy C2).…”