Ruthenium/Iridium-Catalyzed C-2 Activation of Indoles with Bicyclic Olefins: An Easy Access to Functionalized Heterocyclic Motifs

^‡ These authors contributed equally

Abstract

Selective C-2 functionalization of N-protected and free indoles is reported. The ruthenium-catalyzed C-2 activation of indoles provided an easy access to cyclopentenylated indoles. Hydroheteroarylated bicyclic motifs were synthesized via iridium-catalyzed C-2 activation of NH indoles. The methodology was extended to different bicyclic adducts such as diaza- or urea-derived bicyclic olefins.

Key words

indole - diazabicyclic olefins - urea derived - iridium catalyzed - ruthenium catalyzed - C–H activation

• References and Notes

• 1 Van Order RB, Lindwall HG. Chem. Rev. 1942; 30: 69
• 2a Kochanowska-Karamyan AJ, Hamann MT. Chem. Rev. 2010; 110: 4489
• 2b Biswal S, Sahoo U, Sethy S, Kumar HK. S, Banerjee M. Asian J. Pharm. Clin. Res. 2012; 5: 1
• 2c Kaushik NK, Kaushik N, Attri P, Kumar N, Kim CH, Verma AK, Choi EH. Molecules 2013; 18: 6620
• 3a Kakiuchi F, Chatani N. Adv. Synth. Catal. 2003; 345: 1077
• 3b Satoh T, Miura M. Chem. Eur. J. 2010; 16: 11212
• 3c Gutekunst WR, Baran PS. Chem. Soc. Rev. 2011; 40: 1976
• 3d Chen Z, Wang B, Zhang J, Yu W, Liu Z, Zhang Y. Org. Chem. Front. 2015; 2: 1107
• 3e Gensch T, Hopkinson MN, Glorius F, Wencel-Delord J. Chem. Soc. Rev. 2016; 45: 2900

Selected references:
• 4a García-Rubia A, Arrayas RG, Carretero JC. Angew. Chem. Int. Ed. 2009; 48: 6511
• 4b Johansen MB, Kerr MA. Org. Lett. 2010; 12: 4956
• 4c Zhang D.-H, Tang X.-Y, Wei Y, Shi M. Chem. Eur. J. 2013; 19: 13668
• 4d Shi J, Zhao G, Wang X, Xu HE, Yi W. Org. Biomol. Chem. 2014; 12: 6831
• 4e Zhang Y, Zheng J, Cui S. J. Org. Chem. 2014; 79: 6490
• 4f Liang L, Fu S, Lin D, Zhang X.-Q, Deng Y, Jiang H, Zeng W. J. Org. Chem. 2014; 79: 9472
• 4g Yang Q, Choy PY, Fu WC, Fan B, Kwong FY. J. Org. Chem. 2015; 80: 11193
• 4h Xu L, Zhang C, He Y, Tan L, Ma D. Angew. Chem. Int. Ed. 2016; 55: 321
• 4i Pan S, Endo K, Shibata T. Org. Lett. 2011; 13: 4692
• 4j Pan S, Ryu N, Shibata T. J. Am. Chem. Soc. 2012; 134: 17474
• 4k Larsen MA, Hartwig JF. J. Am. Chem. Soc. 2014; 136: 4287
• 4l Shibata T, Ryu N, Takano H. Adv. Synth. Catal. 2015; 357: 1131
• 4m Kannaboina P, Anil Kumar K, Das P. Org. Lett. 2016; 18: 900
• 4n Kumar GS, Kapur M. Org. Lett. 2016; 18: 1112
• 4o Ge C, Liu R.-R, Gao J.-R, Jia Y.-X. Org. Lett. 2016; 18: 3122
• 4p Pirovano V, Facoetti D, Dell’Acqua M, Fontana ED, Abbiati G, Rossi E. Org. Lett. 2013; 15: 3812
• 4q Joucla L, Djakovitch L. Adv. Synth. Catal. 2009; 351: 673
• 4r Verma AK, Danodia AK, Saunthwal RK, Patel M, Choudhary D. Org. Lett. 2015; 17: 3658
• 4s Sevov CS, Hartwig JF. J. Am. Chem. Soc. 2013; 135: 2116
• 5a Stuart DR, Villemure E, Fagnou K. J. Am. Chem. Soc. 2007; 129: 12072
• 5b Zhou J, Hu P, Zhang M, Huang S, Wang M, Su W. Chem. Eur. J. 2010; 16: 5876
• 6 Grimster NP, Gauntlett C, Godfrey CR. A, Gaunt MJ. Angew. Chem. Int. Ed. 2005; 44: 3125
• 7 Yamashita M, Hirano K, Satoh T, Miura M. Org. Lett. 2009; 11: 2337
• 8 Lanke V, Prabhu KR. Org. Lett. 2013; 15: 2818
• 9a Liang L, Fu S, Lin D, Zhang X-Q, Deng Y, Jiang H, Zeng W. J. Org. Chem. 2014; 79: 9472
• 9b Gong B, Shi J, Wang X, Yan Y, Li Q, Meng Y, Xu HE, Yi W. Adv. Synth. Catal. 2014; 356: 137
• 9c Sharma S, Han S, Kim M, Mishra NK, Park J, Shin Y, Ha J, Kwak JH, Jung YH, Kim IS. Org. Biomol. Chem. 2014; 12: 1703
• 9d Zhang W, Wei J, Fu S, Lin D, Jiang H, Zeng W. Org. Lett. 2015; 17: 1349
• 10a Sajisha VS, Anas S, John J, Radhakrishnan KV. Synlett 2009; 2885
• 10b Bournaud C, Chung F, Luna AP, Pasco M, Errasti G, Lecourt T, Micouin L. Synthesis 2009; 869
• 10c Prasad BA. B, Buechele AE, Gilbertson SR. Org. Lett. 2010; 12: 5422
• 10d Gu P, Xu Q, Shi M. Organometallics 2013; 32: 7575

Selected references:
• 11a Storsberg J, Nandakumar MV, Sankaranarayanan S, Kaufmann DE. Adv. Synth. Catal. 2001; 343: 177
• 11b Luna AP, Bonin M, Micouin L, Husson H.-P. J. Am. Chem. Soc. 2002; 124: 12098
• 11c Yao M.-L, Adiwidjaja G, Kaufmann DE. Angew. Chem. Int. Ed. 2002; 41: 3375
• 11d Bertozzi F, Pineschi M, Macchia F, Arnold LA, Minnaard AJ, Feringa BL. Org. Lett. 2002; 4: 2703
• 11e Luna AP, Cesario M, Bonin M, Micouin L. Org. Lett. 2003; 5: 4771
• 11f Lautens M, Mancuso J. J. Org. Chem. 2004; 69: 3478
• 11g Bournaud C, Robic D, Bonin M, Micouin L. J. Org. Chem. 2005; 70: 3316
• 11h Pineschi M, Moro FD, Crotti P, Macchia F. Org. Lett. 2005; 7: 3605
• 11i Bournaud C, Bonin M, Micouin L. Org. Lett. 2006; 8: 3041
• 11j Cho Y, Zunic V, Senboku H, Olsen M, Lautens M. J. Am. Chem. Soc. 2006; 128: 6837
• 11k John J, Sajisha VS, Mohanlal S, Radhakrishnan KV. Chem. Commun. 2006; 3510
• 11l Palais L, Mikhel IS, Bournaud C, Micouin L, Falciola CA, Vuagnoux-d’Augustin M, Rosset S, Bernardinelli G, Alexakis A. Angew. Chem. Int. Ed. 2007; 46: 7462
• 11m Menard F, Weise CF, Lautens M. Org. Lett. 2007; 9: 5365
• 11n Crotti S, Bertolini F, Macchia F, Pineschi M. Chem. Commun. 2008; 3127
• 11o Menard F, Lautens M. Angew. Chem. Int. Ed. 2008; 47: 2085
• 11p Crotti S, Bertolini F, Macchia F, Pineschi M. Adv. Synth. Catal. 2009; 351: 869
• 11q Martins A, Lemouzy S, Lautens M. Org. Lett. 2009; 11: 181
• 11r Webster R, Böing C, Lautens M. J. Am. Chem. Soc. 2009; 131: 444
• 11s John J, Indu U, Suresh E, Radhakrishnan KV. J. Am. Chem. Soc. 2009; 131: 5042
• 11t Jijy E, Prakash P, Shimi M, Pihko PM, Joseph N, Radhakrishnan KV. Chem. Commun. 2013; 49: 7349
• 11u Chand SS, Jijy E, Prakash P, Szymoniak J, Preethanuj P, Dhanya BP, Radhakrishnan KV. Org. Lett. 2013; 15: 3338
• 11v Prakash P, Jijy E, Preethanuj P, Pihko PM, Chand SS, Radhakrishnan KV. Chem. Eur. J. 2013; 19: 10473
• 11w Prakash P, Jijy E, Aparna PS, Viji S, Radhakrishnan KV. Tetrahedron Lett. 2014; 55: 916
• 12a Prakash P, Aparna PS, Jijy E, Santhini PV, Varughese S, Radhakrishnan KV. Synlett 2013; 25: 275
• 12b Zhang Y, Wu Q, Cui S. Chem. Sci. 2014; 5: 297
• 12c Aparna PS, Prabha B, Prakash P, Jijy E, Luxmi Varma R, Radhakrishnan KV. Tetrahedron Lett. 2014; 55: 865
• 13 Ackermann L. Acc. Chem. Res. 2014; 47: 281
• 14 Typical Experimental Procedure for 3 A mixture of diazabicyclic olefin (60 mg, 0.2497 mmol, 1.5 equiv), indole (42 mg, 0.1665 mmol, 1.0 equiv), [RuCl₂(p-cymene)]₂ (3 mg, 0.0050 mmol, 3 mol%), and Cu(OAc)₂·H₂O (7 mg, 0.0333 mmol, 20 mol%) were weighed into a Schlenk tube and degassed for 10 min. Dry toluene (2 mL) was added, and the reaction mixture was purged with argon and allowed to stir at 110 °C for 12 h. The crude reaction mixture was purified by silica gel (100–200 mesh) column chromatography using an EtOAc–hexane mixture to yield the cyclopentane-substituted indoles.
• 15 Spectroscopic Data for 3a R_f = 0.85 (hexane–EtOAc = 7:3 ). IR (neat): ν_max = 3289, 2919, 1716, 1606, 1532, 1419, 1262, 1172, 1096, 1061, 758 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 9.99 (br s, 1 H), 7.49 (d, J = 8.0 Hz, 1 H), 7.34 (d, J = 8.0 Hz, 1 H), 7.08 (t, J = 7.0 Hz, 1 H), 7.01 (t, J = 7.5 Hz, 1 H), 6.57 (br s, 1 H), 6.19 (s, 1 H), 5.94 (s, 1 H), 5.88 (s, 1 H), 4.76 (br s, 1 H), 4.33–3.99 (m, 5 H), 2.57 (br s, 2 H), 1.37–1.25 (m, 4 H), 0.89–0.85 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 155.7, 138.8, 130.8, 128.1, 127.5, 120.9, 119.7, 118.8, 110.5, 99.7, 62.5, 34.7, 29.5, 14.4. ESI-HRMS: m/z calcd for C₁₉H₂₃N₃O₄Na: 380.15863; found: 380.15851.
• 16 Typical Experimental Procedure for 5 A mixture of bicyclic alkene (80 mg, 0.3329 mmol, 1.0 equiv), indole (35 mg, 0.2996 mmol, 0.9 equiv), [Ir(1,5-cod)Cl]₂ (11 mg, 0.0166 mmol, 5 mol%) and dppe (13 mg, 0.0333 mmol, 10 mol%) were weighed into a Schlenk tube and degassed for 10 min. Dry toluene (2 mL) was added, and the reaction mixture was purged with argon and allowed to stir at 110 °C for 16 h. The crude reaction mixture was purified by alumina column chromatography using EtOAc–hexane mixture to yield the hydroheteroarylated bicyclic olefins.
• 17 Spectroscopic Data for Compound 5a R_f = 0.28 (hexane–EtOAc = 7:3). IR (neat): ν_max = 3333, 3054, 2982, 2911, 1713, 1618, 1459, 1402, 1374, 1323, 1171 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 8.88–8.41 (m, 1 H), 7.53 (d, J = 8.0 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 7.15 (t, J = 7.0 Hz, 1 H), 7.07 (t, J = 7.0 Hz, 1 H), 6.21 (s, 1 H), 4.73–4.61 (m, 2 H), 4.27 (m, 4 H), 3.40 (br s, 1 H), 2.36–2.26 (m, 1 H), 2.11 (br s, 1 H), 1.92–1.90 (m, 1 H), 1.72 (br s, 1 H), 1.33–1.24 (m, 6 H). ¹³C NMR (125 MHz, CDCl₃): δ = 157.7, 139.3, 136.4, 128.1, 121.8, 120.0, 119.8, 110.8, 99.2, 64.4, 62.8, 60.2, 39.5, 35.6, 14.5. ESI-HRMS: m/z calcd for C₁₉H₂₃N₃O₄Na: 380.15863; found: 380.16012.
• 18a Seth PP, Ranken R, Robinson DE, Osgood SA, Risen LM, Rodgers EL, Migawa MT, Jefferson EA, Swayze EE. Bioorg. Med. Chem. Lett. 2004; 14: 5569
• 18b Reddy NS, Rao AS, Chari MA, Kumar VR, Jyothy V, Himabindu V. Int. J. Org. Chem. 2012; 2: 267
• 18c Lee T, Gong Y.-D, Min KH. Bull. Korean Chem. Soc. 2012; 33: 3857
• 19a Anumandla D, Little R, Je CS. Org. Lett. 2014; 16: 5112
• 19b Vijayan A, Baiju TV, Jijy E, Prakash P, Shimi M, Joseph N, Pihko PM, Varughese S, Radhakrishnan KV. Tetrahedron 2016; 72: 4007
• 20 CCDC 148823 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.