This journal is © The Royal Society of Chemistry 2016 Chem. Commun. Cite this: DOI: 10.1039/c6cc03106d Double C–H amination by consecutive SET oxidations† Christopher J. Evoniuk, Sean P. Hill, Kenneth Hanson and Igor V. Alabugin* A new method for intramolecular C–H oxidative amination is based on a FeCl 3 -mediated oxidative reaction of anilines with activated sp 3 C–H bonds. The amino group plays multiple roles in the reaction cascade: (1) as the activating group in single-electron-transfer (SET) oxidation process, (2) as a directing group in benzylic/allylic C–H activation at a remote position, and (3) internal nucleophile trapping reactive intermediates formed from the C–H activation steps. These multielectron oxidation reactions proceed with catalytic amounts of Fe(III) and inexpensive reagents. C–N bonds can be formed in a variety of ways, from the venerable Hofmann–Loffler–Freytag N-haloamine homolysis to oxidation of C,N-dianions and nitrene insertion. 1 The recent advances in direct functionalization of C–H bonds expanded the list of available chemical strategies. 2,3 The new C–H func- tionalization approach suggests that the methods for carbon- nitrogen double bond formation can go beyond the traditional condensation of an amine with a carbonyl (Scheme 1). Transition-metal-mediated (TMM) C–H amination represents a valuable method for adding functionality 4 dating back to the early reports of Fe- and Rh-mediated nitrene formation by Breslow and Gellman. 5 Unlike the most commonly used Rh-catalyzed C–H aminations, 6 the Co-, 7 Cu-, 8 Mn-, 9 and Fe-mediated 10 C–H aminations are believed to proceed through a single electron pathway (recent works illustrated in Fig. 1). 11 Herein, we describe a direct intramolecular C–H amination involving o-substituted-anilines, FeCl 3 , and 2,3-dichloro-5,6- dicyano-1,4-benzoquinone (DDQ) for the preparation of aromatic N-heterocycles. When designing substrates for oxidative C–H amination, we started with o-functionalized anilines. When making this choice, we envisioned that the amino group can play three synergistic roles in the reaction cascade: (1) as the activating group in single-electron-transfer (SET) oxidation process, (2) as a directing group for C–H activation at a remote position, and (3) as the internal nucleophile trapping the cation formed from the C–H activation steps. Extended conjugation can stabilize the radical and cationic species formed after the initial SET oxidation/deprotonation steps (Scheme 2) (Table 1). 12 The desired o-functionalized anilines are readily accessible via multiple robust routes derived from the Wittig, Grignard and Suzuki reactions (Scheme 3, full details in ESI†). These methods allowed us to prepare a diverse library of substrates in moderate to good yields. With substrates in hand, we first investigated the oxidation potentials of substrates 1a and 1p to test the feasibility of the initial SET step. The oxidation potentials for 1a and 1p (0.52 V and 0.55 V, respectively, vs. Fc/Fc + ) suggesting that SET oxidation is a viable platform for the desired transformation. Scheme 1 Two general strategies for C QN bond formation. Fig. 1 Examples of intramolecular C–H aminations with present work. Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida 32306-4390, USA. E-mail: alabugin@chem.fsu.edu † Electronic supplementary information (ESI) available: Experimental procedures and characterization data for new compounds. See DOI: 10.1039/c6cc03106d Received 13th April 2016, Accepted 4th May 2016 DOI: 10.1039/c6cc03106d www.rsc.org/chemcomm ChemComm COMMUNICATION Published on 04 May 2016. Downloaded by Florida State University on 15/05/2016 20:58:01. View Article Online View Journal