1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 Triflic Acid as an Efficient Brønsted Acid Promoter for the Umpolung of N-Ac Indoles in Hydroarylation Reactions Raj Kumar Nandi, a Alejandro Perez-Luna, b Didier Gori, a Rodolphe Beaud, a Re ´ gis Guillot, a Cyrille Kouklovsky, a Vincent Gandon, a, c, * and Guillaume Vincent a, * a Institut de Chimie Mole ´culaire et des Mate ´riaux d’Orsay (ICMMO), Univ. Paris-Sud, Universite ´ Paris-Saclay, CNRS UMR 8182, 91405 Orsay cedex Phone number: + 33169157548 E-mail: vincent.gandon@u-psud.fr; guillaume.vincent@u-psud.fr b Sorbonne UniversitØs, UPMC Univ Paris 06, CNRS UMR 8232, Institut Parisien de Chimie MolØculaire (IPCM), FR 2769, Case 229, 4 place Jussieu, 75005 Paris, France c Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Univ. Paris-Sud, UniversitØ Paris-Saclay, 1, av. de la Terrasse, 91198 Gif-sur-Yvette, France Received: August 30, 2017; Revised: October 30, 2017; Published online: November 17, 2017 Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.201701074 Abstract: We report that triflic acid, a strong Brønsted acid, is a very powerful alternative to FeCl 3 to mediate the hydroarylation of N À Ac indoles, which delivers regioselectively 3-arylindo- lines, 3,3-spiroindolines or 2-arylindolines. Mecha- nistic explorations point towards the existence of a highly electrophilic intermediate by simultaneous activation of the acetyl and of the C2 = C3 bond by protons. Keywords: Indole; Umpolung; Hydroarylation; Brønsted acid; Friedel-Crafts The dearomative umpolung of the indole nucleus is an emerging topic with an important synthetic potential to access indoline derivatives of biological relevance. [1– 8] Most of the time, this reversal of polarity [2a] involves the oxidation of the indole nucleus [2b–j, 3] or the presence of strong electron-withdrawing groups. [2k–m] In this context, our group developed several meth- ods [3, 4] to generate electrophilic indoles to overturn the innate nucleophilicity of indoles, [1a, 5] including the C3-regioselective FeCl 3 -mediated hydroarylation of N À Ac indole 1 (Scheme 1) [3] which was inspired by preliminary findings from Nakatsuka and co-work- ers. [6] We have recently demonstrated that this reaction proceeds via a polyactivated intermediate, in which the acetyl is activated by FeCl 3 to favour the delocalization of the nitrogen lone pair into the carbonyl system, and in which the C2 = C3 bond is activated by a proton to induce a Friedel-Crafts reaction with arene 2 (Scheme 1). [7] During the optimization process of the hydro- arylation of N À Ac indoles, we screened several Lewis acids and FeCl 3 proved to be rather exclusive to promote the desired reaction. At that time, we ruled out the fact that a proton could be the sole promoter of the reaction. We recently started a more thorough evaluation of Brønsted acids as promoters (Table 1). We indeed envisioned that hydrogen chloride could be generated from FeCl 3 in the reaction medium. Therefore, HCl gas was bubbled through a mixture of N À Ac skatole 1a and anisole 2a, yet 3a was not detected (entry 1). We continued our study with strong Brønsted acids. Trifluoroacetic acid (entry 2) did not deliver any coupling product. However, 2.5 equiva- lents of sulfuric acid were able to promote the reaction and delivered 3a in 84% yield (entry 3). Triflic acid (TfOH) was even better and provided the hydro- arylated product in 95% yield (entry 4). [9] Other Scheme 1. Our FeCl 3 -mediated regioselective hydroarylation of N À Ac indoles via a polyactivated intermediate. UPDATES DOI: 10.1002/adsc.201701074 Adv. Synth. Catal. 2018, 360, 161 – 172 161  2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim