Exploration and Development of a C–H-Activated Route to Access the [1,2]Dithiolo[4,3-b]indole-3(4H)-thione Core and Related Derivatives

Abstract

A robust procedure for the production of [1,2]dithiolo[4,3-b]indole-3(4H)-thione analogues using a DABCO/S₂Cl₂ complex as a sulfur source via a C–H activated approach.

Key words

indole - indole sulfides - sulfur-nitrogen heterocycles - fused 3H-1,2-dithiole-3-thiones - C–H activation - disulfur dichloride

• References and Notes

• 1 Current address - Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, NC 27599, USA
• 2 de Sá Alves FR, Barreiro EJ, Fraga CA. Mini-Rev. Med. Chem. 2009; 9: 782
• 3a Rewcastle GW, Denny WA. Heterocycles 1994; 37: 701
• 3b Palmer BD, Rewcastle GW, Thompson AM, Boyd M, Showalter HD, Sercel AD, Fry DW, Kraker AJ, Denny WA. J. Med. Chem. 1995; 38: 58
• 3c Dobrusin EM, Showalter HD. H, Denny WA, Rewcastle GW, Tercel M, Thompson AM. US 5464861, 1994
• 4 Greenhouse RJ, Muchowski JM. US 4654360, 1987
• 5 Hosoi MK, Fumio NO, Ichikawa HT, Ichikawa KN, Okazaki SN. US 4743609, 1988
• 6 Asquith CR. M, Meli ML, Konstantinova LS, Laitinen T, Poso A, Rakitin OA, Hofmann-Lehmann R, Allenspach K, Hilton ST. Bioorg. Med. Chem. Lett. 2015; 25: 1352
• 7 Rewcastle GW, Janosik T, Bergman J. Tetrahedron 2001; 57: 7185
• 8a Friary RJ, Zhou G, Shih N, Chen L, Shu Y, Tong L, Lavey BJ, Wong MK. C, Kozlowski JA, Shankar BB. US 200410013, 2004
• 8b Shankar BB, Gilbert E, Huang C, Mccombie S, Shih N, Kozlowski JA, Rizvi RK. WO 20062133, 2006
• 9 Gao D, Sand R, Fu H, Sharmin N, Gallin WJ, Hall DG. Bioorg. Med. Chem. Lett. 2013; 23: 5503
• 10 Carpenter W, Grant MS, Snyder HR. J. Am. Chem. Soc. 1960; 82: 2739; and references within
• 11 Wawzonek S, Hansen GR. J. Org. Chem. 1966; 31: 3580
• 12 Harris RL. N. Aust J Chem. 1970; 23: 1199
• 13 Kobayashi K, Kobayashi A, Ezaki K. Tetrahedron 2013; 69: 7936
• 14 Zhang H, Bao X, Song Y, Qu J, Wang B. Tetrahedron 2015; 71: 8885
• 15a Hamel P, Préville P. J. Org. Chem. 1996; 61: 1573
• 15b Hamel P. J. Org. Chem. 2002; 67: 2854
• 15c Plate R, Nivard RJ. F, Ottenheijm HC. J. Tetrahedron 1986; 42: 4503
• 16a Prasad CD, Kumar S, Sattar M, Adhikary A, Kumar S. Org. Biomol. Chem. 2013; 11: 8036
• 16b Silveira CC, Mendes SR, Wolf L, Martins GM, Mühlen LV. Tetrahedron 2012; 68: 10464
• 16c Hamel P, Zajac N, Atkinson JG, Girard Y. J. Org. Chem. 1994; 59: 6372
• 16d Hamel P, Girard Y, Atkinson JG. J. Org. Chem. 1992; 57: 2694
• 16e Anzai KJ. Heterocycl. Chem. 1979; 16: 567
• 17 Yang FL, Tian SK. Angew. Chem. Int. Ed. 2013; 18: 4929
• 18 Halimehjani AZ, Shokrgozar S, Beier P. J. Org. Chem. 2018; 83: 5778
• 19a Konstantinova LS, Rakitin OA, Rees CW. Chem. Commun. 2002; 11: 1204
• 19b Amelichev SA, Konstantinova LS, Lyssenko KA, Rakitin OA, Rees CW. Org. Biomol. Chem. 2005; 19: 3496
• 19c Amelichev SA, Aysin RR, Konstantinova LS, Obruchnikova NV, Rakitin OA, Rees CW. Org Lett. 2005; 25: 5725
• 19d Konstantinova LS, Amelichev SA, Rakitin OA. Russ. Chem. Bull. 2006; 55: 2081
• 19e Janosik T, Bergman J, Stensland B, Stalhandsked C. J. Chem. Soc., Perkin Trans. 1. 2002; 330
• 19f Bergman J, Sthandske C. Tetrahedron Lett. 1994; 5279
• 19g Konstantinova LS, Amelichev SA, Rakitin OA. Russ. Chem. Rev. 2007; 76: 195
• 20 Jardine RV, Brown RK. Can. J. Chem. 1965; 43: 1293
• 21 Kobayashi G, Furukawa S, Matsuda Y, Natsuki R. Yakugaku Zasshi 1970; 90: 132
• 22 Rewcastle GW, Denny WA. Heterocycles 1994; 37: 701
• 23a Konstantinova LS, Rakitin OA, Rees CW, Amelichev SA. Mendeleev Commun. 2004; 91
• 23b Konstantinova LS, Rakitin OA. Mendeleev Commun. 2009; 55
• 24 Konstantinova LS, Lysov KA, Amelichev SA, Obruchnikova NV, Rakitin OA. Tetrahedron 2009; 65: 2178
• 25 CCDC 1517984–1517999 contain the supplementary crystallographic data for 14a,b,e–m and 14o–s. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures
• 26 Sambiagio C, Marsden SP, Blacker AJ, McGowan PC. Chem. Soc. Rev. 2014; Recent Ullman Coupling review: 10: 3525
• 27 Cremlyn RJ. An Introduction to Organosulfur Chemistry. John Wiley and Sons; Chichester: 1996
• 28 Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery JA. Jr, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas Ö, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ. Gaussian 09, Revision E.01,. Gaussian, Inc; Wallingford, CT: 2009
• 29 Schmitt J, Lespagnol A. Bull. Soc. Chim. Fr. 1950; 459
• 30 General ProceduresMethod A2-Methylindole (1.31 g, 10.0 mmol) in dry DMF (15 mL) was treated with powdered KOH (0.67 g, 12.0 mmol) and the mixture stirred for 30 min, where upon 3-(bromomethyl)benzonitrile (1.99 g, 10.0 mmol) was added in one portion. The reaction became exothermic and was cooled in an ice bath and after stirring for 96 h at r.t., the mixture was concentrated under vacuum and the residue taken up in EtOAc. The solution was washed with water, brine, dried (MgSO₄), and concentrated to dryness in vacuo. Purification via flash column chromatography on silica gel (hexanes/EtOAc, 1:1) to afford 3-[(2-methyl-1H-indol-1-yl)methyl]benzonitrile (12k, 1.95 g, 7.4 mmol, 74% yield) as colorless crystals; mp 120–121 °C. HMRS: m/z calcd for C₁₇H₁₄N₂ [M + H]⁺: 247.1235; found 247.1231. IR (film): ν_max = 3019 m (C–H), 2945 m (C–H), 2915 m (C–H), 2224 s (C≡N), 1552 m (C=C), 1457 m, 1426 w, 1395 w, 1136 w, 783 m 744 s, 686 m cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.60–7.57 (1 H, m, CH^Ar), 7.54 (1 H, d, J = 8.1 Hz, CH^Ar), 7.38 (1 H, t, J = 7.8 Hz, CH^Ar), 7.28 (1 H, s, CH^Ar), 7.17 (1 H, dq, J = 1.0, 8.1 Hz, CH^Ar), 7.14–7.11 (3 H, m, CH^Ar), 6.38 (1 H, s, CH^Ar), 5.43 (2 H, s, CH₂), 2.37 (3 H, s, CH₃). ¹³C NMR (100 MHz, CDCl₃): δ = 139.6 (C^Ar), 136.9 (C^Ar), 136.1 (C^Ar), 131.2 (CH^Ar), 130.4 (CH^Ar), 129.7 (CH^Ar), 129.5 (CH^Ar), 128.3 (C^Ar), 121.2 (CH^Ar), 120.1 (CH^Ar), 120.0 (CH^Ar), 118.5 (C^Ar), 113.1 (C≡N), 108.8 (CH^Ar), 101.3 (CH^Ar), 45.7 (CH₂), 12.7 (CH₃).Method BSodium hydride (0.5 g of a 60% dispersion in mineral oil, 12.5 mmol) was added portionwise to a solution of 2-methylindole (1.31 g, 10.0 mmol) in dry THF (20 mL). The mixture was stirred for 30 min, and then 2-(bromomethyl)benzonitrile (1.96 g, 10.0 mmol) was added in one portion, in addition to NaI (1.50 g, 10.0 mmol). The reaction became exothermic and was cooled in an ice bath and after stirring for 48 h at r.t., it was concentrated in vacuo and the residue taken up in EtOAc. The solution was washed with water, brine, dried (MgSO₄), and concentrated to dryness in vacuo. Purification via flash column chromatography on silica gel (hexanes/EtOAc, 1:1) to afford 2-[(2-methyl-1H-indol-1-yl)methyl]benzonitrile (12j, 1.28 g, 5.2 mmol, 52% yield) as colorless crystals; mp 124–125 °C. HMRS: m/z calcd for C₁₇H₁₅N₂ [M + H]⁺: 247.1235; found: 247.1233. IR (film): ν_max = 3055 m (C–H), 2920 m (C–H), 2851 m (C–H), 2220 s (C≡N), 1460 m (C=C), 1396 w, 747 s, 703 s cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.74 (1 H, dd, J = 1.2, 7.0 Hz, CH^Ar), 7.62–7.59 (1 H, m, CH^Ar), 7.40–7.34 (2 H, m, CH^Ar), 7.16–7.12 (3 H, m, CH^Ar), 6.52 (1 H, d, J = 6.3, CH^Ar), 6.41 (1 H, s, CH^Ar), 5.55 (2 H, s, CH₂), 2.39 (3 H, s, CH₃). ¹³C NMR (100 MHz, CDCl₃): δ = 141.7 (C^Ar), 137.0 (C^Ar), 136.4 (C^Ar), 133.5 (CH^Ar), 132.9 (CH^Ar), 128.3 (C^Ar), 127.8 (CH^Ar), 126.5 (CH^Ar), 121.2 (CH^Ar), 120.0 (CH^Ar), 117.1 (C^Ar), 110.1 (C≡N), 108.9 (CH^Ar), 101.2 (CH^Ar), 44.7(CH₂), 12.6 (CH₃).Method CDisulfur dichloride (0.4 mL, 5 mmol) was added dropwise at –35 °C to a stirred solution of DABCO (1.12 g, 10 mmol) in chloroform (25 mL) under nitrogen. The mixture was stirred at r.t. for 1 h. 3-[(2-Methyl-1H-indol-1-yl)methyl]benzonitrile (12j, 0.239 g, 1 mmol) in chloroform (5 mL) was added, and the mixture was stirred at r.t. for 48 h under nitrogen. Triethylamine (1.4 mL, 10 mmol) was then added to the resultant mixture at 0 °C, the mixture stirred at r.t. for 2 h, heated at reflux for 3 h, filtered, and solvents evaporated. Purification via flash column chromatography on silica gel (hexanes/CH₂Cl₂) to afford 3-{(3-thioxo-[1,2]dithiolo[4,3-b]indol-4(3H)-yl)methyl}benzonitrile (14l) (0.277 g, 0.82 mmol, 82% yield) as orange crystals; mp 190–191 °C. HMRS: m/z calcd for C₁₇H₁₁N₂S₃ [M + H]⁺: 339.0079; found: 339.0077. IR (film): ν_max = 3054 m (C–H), 2952 m (C–H), 2921 m (C–H), 2872 w (C–H), 2851 w (C–H), 2226 s (C≡N), 1472 s (C=C), 1330 s, 1258 w, 1122 w, 1060 s, 685 m cm^–1. (400 MHz, CDCl₃): δ = 7.77 (1 H, dt, J = 1.0, 8.0 Hz, CH^Ar), 7.46 (2 H, ddd, J = 1.0, 4.8, 5.9 Hz, CH^Ar), 7.40–7.32 (3 H, m, CH^Ar), 7.24–7.19 (2 H, m, CH^Ar), 6.15 (2 H, s, CH^Ar). ¹³C NMR (100 MHz, CDCl₃): δ = 195.9 (C=S), 146.9 (C^Ar), 142.2 (C^Ar), 149.4 (C^Ar), 139.0 (C^Ar), 131.4 (CH^Ar), 131.3 (C^Ar), 130.3 (CH^Ar), 129.6 (CH^Ar), 125.5 (C^Ar), 121.9 (CH^Ar), 121.7 (CH^Ar), 120.6 (CH^Ar), 114.3 (CH^Ar),113.0 (C≡N), 111.8 (CH^Ar), 44.0 (CH₂).