Copper-Catalyzed Synthesis of N-Aryl and N-Sulfonyl Indoles from 2-Vinyl­anilines with O₂ as Terminal Oxidant and TEMPO as Cocatalyst

Abstract

A copper-catalyzed intramolecular alkene oxidative ­amination that utilizes TEMPO as cocatalyst and O₂ as the terminal oxidant has been developed. The method furnishes N-aryl and N-sulfonyl indoles from N-aryl and N-sulfonyl 2-vinylanilines, ­respectively. Additionally, sequential copper-catalyzed reactions where initial Chan–Lam coupling of 2-vinylanilines with aryl­boronic acids is followed by oxidative amination of the alkene can generate N-aryl indoles in one pot.

Key words

copper - oxidation - indoles - oxygen - TEMPO

• References and Notes


For selected reviews on synthesis and bioactivity of indoles, see:
• 1a Cacchi S, Fabrizi G. Chem. Rev. 2011; 111: PR215
• 1b Humphrey GR, Kuethe JT. Chem. Rev. 2006; 106: 2875
• 1c Kochanowska-Karamyan AJ, Hamann MT. Chem. Rev. 2010; 110: 4489
• 1d Taber DF, Tirunahari PK. Tetrahedron 2011; 67: 7195

For classical indole syntheses, see:
• 2a Fischer E, Jourdan F. Ber. Dtsch. Chem. Ges. 1883; 16: 2241
• 2b Robinson B. Chem. Rev. 1963; 63: 373
• 2c Bartoli G, Palmieri G, Bosco M, Dalpozzo R. Tetrahedron Lett. 1989; 30: 2129
• 2d Larock RC, Yum EK. J. Am. Chem. Soc. 1991; 113: 6689

For selected recent indole synthesis methods, see:
• 3a Taddei M, Mura MG, Rajamäki S, Luca LD, Porcheddu A. Adv. Synth. Catal. 2013; 355: 3002
• 3b Muralirajan K, Cheng C.-H. Adv. Synth. Catal. 2014; 356: 1571
• 3c Dawande SG, Kanchupalli V, Kalepu J, Chennamsetti H, Lad BS, Katukojvala S. Angew. Chem. Int. Ed. 2014; 53: 4076
• 3d Stokes BJ, Liu S, Driver TG. J. Am. Chem. Soc. 2011; 133: 4702
• 3e Ackermann L, Lygin AV. Org. Lett. 2012; 14: 764
• 3f Yamaguchi M, Manabe K. Org. Lett. 2014; 16: 2386
• 3g Hao W, Geng W, Zhang W.-X, Xi Z. Chem. Eur. J. 2014; 20: 2605
• 3h Cacchi S, Fabrizi G, Goggiamani A, Molinaro C, Verdiglione R. J. Org. Chem. 2013; 79: 401
• 3i Wang Q, Huang L, Wu X, Jiang H. Org. Lett. 2013; 15: 5940
• 3j Zheng L, Hua R. Chem. Eur. J. 2014; 20: 2352
• 3k Miura T, Funakoshi Y, Murakami M. J. Am. Chem. Soc. 2014; 136: 2272
• 3l Liu B, Song C, Sun C, Zhou S, Zhu J. J. Am. Chem. Soc. 2013; 135: 16625
• 3m Kiruthika SE, Perumal PT. Org. Lett. 2013; 16: 484
• 3n Zhu C, Ma S. Org. Lett. 2013; 15: 2782
• 3o Jensen T, Petersen H, Bang-Andersen B, Madsen R, Jorgensen M. Angew. Chem. Int. Ed. 2008; 47: 888
• 3p Pena-Lopez M, Neumann H, Beller M. Chem. Eur. J. 2014; 20: 1818
• 3q Zhao D, Shi Z, Glorius F. Angew. Chem. Int. Ed. 2013; 52: 12426
• 3r Shi Z, Zhang C, Li S, Pan D, Ding S, Cui Y, Jiao N. Angew. Chem. Int. Ed. 2009; 48: 4572
• 3s Wei Y, Deb I, Yoshikai N. J. Am. Chem. Soc. 2012; 51: 9098
• 3t Wagaw S, Yang BH, Buchwald SL. J. Am. Chem. Soc. 1999; 121: 10251
• 3u Wang C, Huang Y. Org. Lett. 2013; 15: 5294
• 3v Varela-Fernandez A, Varela JA, Saa C. Synthesis 2012; 44: 3285
• 4a Harrington PJ, Hegedus LS. J. Org. Chem. 1984; 49: 2657
• 4b Harrington PJ, Hegedus LS, McDaniel KF. J. Am. Chem. Soc. 1987; 109: 4335
• 4c Larock RC, Hightower TR, Hasvold LA, Peterson KP. J. Org. Chem. 1996; 61: 3584
• 4d Izumi T, Nishimoto Y, Kohei K, Kasahara A. J. Heterocycl. Chem. 1990; 27: 1419
• 4e Tsvelikhovsky D, Buchwald SL. J. Am. Chem. Soc. 2010; 132: 14048
• 5a Maity S, Zheng N. Angew. Chem. Int. Ed. 2012; 51: 9562
• 5b Fra L, Millan A, Souto JA, Muniz K. Angew. Chem. Int. Ed. 2014; 53: 7349
• 6a Liwosz TW, Chemler SR. Chem. Eur. J. 2013; 19: 12771

For alternative copper-catalyzed indole syntheses, primarily using alkynes, see:
• 6b Ackermann L. Org. Lett. 2005; 7: 439
• 6c Oda Y, Hirano K, Satoh T, Miura M. Org. Lett. 2012; 14: 664
• 6d Frischmuth A, Knochel P. Angew. Chem. Int. Ed. 2013; 52: 10084
• 6e Zhu Z, Yuan J, Zhou Y, Qin Y, Xu J, Peng Y. Eur. J. Org. Chem. 2014; 511

For selected reviews and examples, see:
• 7a Allen SE, Walvoord RR, Padilla-Salinas R, Kozlowski MC. Chem. Rev. 2013; 113: 6234
• 7b Ortgies DH, Chen F, Forgione P. Eur. J. Org. Chem. 2014; 3917
• 7c Steves JE, Stahl SS. J. Am. Chem. Soc. 2013; 135: 15742
• 7d Han B, Yang X.-L, Wang C, Bai Y.-W, Pan T.-C, Chen X, Yu W. J. Org. Chem. 2011; 77: 1136
• 7e Liu J, Ma S. Org. Lett. 2013; 15: 5150
• 7f Yin W, Wang C, Huang Y. Org. Lett. 2013; 15: 1850
• 7g Chen C, Liu B, Chen W. Synthesis 2013; 45: 3387
• 7h Qifa L, Ming L, Fei Y, Wei W, Feng S, Zhenbang Y, Sufeng H. Synth. Commun. 2010; 40: 1106
• 7i Liwosz TW, Chemler SR. Org. Lett. 2013; 15: 3034
• 7j Paderes MC, Keister JB, Chemler SR. J. Org. Chem. 2012; 78: 506
• 7k Fuller PH, Kim J.-W, Chemler SR. J. Am. Chem. Soc. 2008; 130: 17638
• 7l Zeng W, Chemler SR. J. Am. Chem. Soc. 2007; 129: 12948
• 7m Sheldon RA, Arends IW. C. E. J. Mol. Catal. A: Chem. 2006; 251: 200

Recent example and review:
• 8a Antilla JC, Buchwald S. Org. Lett. 2001; 3: 2077
• 8b Qiao JX, Lam PY. S. Synthesis 2011; 829
• 8c Qiao JX, Lam PY. S. Boronic Acids . John Wiley and Sons; New York: 2011. 2nd ed
• 9 Representative Procedure for the Copper-Catalyzed Intramolecular Alkene C–H Amination An oven-dried 100 mL round-bottom flask was charged with 1a (50 mg, 0.174 mmol, 1 equiv), Cu(2-ethylhexanoate)₂ (9 mg, 0.026 mmol, 15 mol%), TEMPO (5 mg, 0.035 mmol, 20 mol%), and dry toluene (1.74 mL, 0.1 M). The flask was purged with O₂, put under an O₂ atmosphere using an O₂ balloon, and stirred for 24 h at 120 °C. Filtration of the cooled reaction mixture through a pad of silica gel with EtOAc (100 mL) and subsequent evaporation of the solvent in vacuo afforded the crude mixture. Flash chromatography of the resulting crude mixture on silica gel (0–20% EtOAc in hexanes gradient) afforded indole 2a (36 mg, 71% yield) as an off-white solid.^{6 1}H NMR (400 MHz, CDCl₃): δ = 7.99 (d, J = 8.4 Hz, 1 H), 7.74 (d, J = 8.0 Hz, 2 H), 7.45 (d, J = 7.2 Hz, 1 H), 7.34–7.29 (m, 2 H), 7.26–7.22 (m, 1 H), 7.19 (d, J = 8.4 Hz, 2 H), 2.32 (s, 3 H), 2.24 (d, J = 0.8 Hz, 3 H).