Unexpected Reactivity of Trifluoromethyl Diazomethane (CF 3 CHN 2 ): Electrophilicity of the Terminal N‑Atom Anton V. Arkhipov, †,‡ Viatcheslav V. Arkhipov, †,‡ Janine Cossy, § Volodymir O. Kovtunenko, ‡ and Pavel K. Mykhailiuk* ,†,‡,§ † Enamine Ltd., Chervonotkatska 78, Kyiv 02094, Ukraine ‡ Department of Chemistry, National Taras Shevchenko University of Kyiv, Volodymyrska 64, Kyiv 01033, Ukraine § Laboratoire de Chimie Organique, Institute of Chemistry, Biology and Innovation (CBI), UMR 8231, ESPCI ParisTech/CNRS/PSL Research University, 10 rue Vauquelin, Paris 75231 Cedex 05, France * S Supporting Information ABSTRACT: After more than 70 years since its discovery, CF 3 CHN 2 was found to possess a novel reactivity mode: N-terminal electrophile. With C-nucleophiles it gives hydrazones that are easily transformed into valuable CF 3 -heterocycles. D erivatization of organic compounds by fluorine-containing units often beneficially affects their physicochemical and biological properties. 1,2 Consequently, ca. 20% of pharmaceut- icals and agrochemicals contain at least one fluorine atom, the trifluoromethyl group being especially prevalent. 3 Therefore, innovative reactions toward CF 3 -bearing building blocks from cheap and available starting materials are at the heart of modern commercial needs. 4 In 1943, Gilman and Jones synthesized gaseous CF 3 CHN 2 (1) from trifluoroethylamine hydrochloride and sodium nitrite. 5 Since then, reagent 1 has been blossoming in chemistry. Especially, it became popular after 2010, when conditions for the in situ generation of compound 1 in solution were developed. 6 More than 100 publications already appeared on reagent 1, comprising roughly four reactivies: (1) CF 3 CH:- carbene insertion and [2+1]-cycloaddition (Scheme 1). 7-9 For example, recently the metal-catalyzed N-trifluoroethylation of anilines was developed. (2) [3+2]-cycloaddition of CF 3 CHN 2 with diverse polarized double/triple bonds to give five- membered heterocycles was also studied. 10 (3) C-Nucleophilic addition of CF 3 CHN 2 to boronic acids, ketones, aldehydes, and ketals was elaborated recently; 11 moreover, the latter method was already applied in flow. 11h (4) C-Electrophilic reaction of CF 3 CHN 2 with alcohols and sulfonic acids. 12 In this letter, we report a novel unexpected reactivity of CF 3 CHN 2 as a N-terminal electrophile. In 1847, Japp and Klingemann discovered a reaction in which positively charged aryldiazonium salts acted as N-electrophiles. They reacted with β-ketoesters under basic conditions to form arylhydrazones. 13 On the contrary, aliphatic diazo compounds are less active and their N-electrophilicity is far less known. There are several examples of diazocarbonyl compounds, where the diazo group is stabilized by conjugation with the carbonyl group. 14 For example, the common chemical reagent, ethyl diazoacetate (N 2 CHCO 2 Et), was recently shown to react as an N-electrophile in the presence of DBU. 14i In addition, cyclo- propyl diazomethane is known to possess N-electrophilic properties; the reaction, however, proceeds via a cyclopropyl diazonium cation. 15 In 2014, an “unexpected aldol product” of CF 3 CHN 2 under Japp-Klingemann conditions, with CuCl as a catalyst, was reported. 9b We were inspired by these results, but also surprised because the original reaction required no metal catalysis. Therefore, a model experiment was devised: a dry solution of CF 3 CHN 2 in dichloromethane was treated with a simple C- nucleophile, NaCH(CN)CO 2 Me (2). After 5 min, the color of the reaction mixture changed from yellow (diazo compound) to deep orange (conjugated anion). After 24 h at room temperature, the reaction was completed. Standard workup afforded the Received: May 31, 2016 Scheme 1. Known (eqs 1-4) and Novel (eq 5) Reactivity of 1 Letter pubs.acs.org/OrgLett © XXXX American Chemical Society A DOI: 10.1021/acs.orglett.6b01565 Org. Lett. XXXX, XXX, XXX-XXX