Synlett 2019; 30(02): 156-160
DOI: 10.1055/s-0037-1611692
letter
© Georg Thieme Verlag Stuttgart · New York

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

a  School of Pharmacy, Faculty of Life Sciences, University College London, London, WC1N 1AX, UK   Email: ucnvcrm@ucl.ac.uk   Email: s.hilton@ucl.ac.uk
,
Lidia S. Konstantinova
b  N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, 119991, Russia
c  Nanotechnology Education and Research Center, South Ural State University, Lenina Ave. 76, Chelyabinsk, Russia
,
Graham J. Tizzard
d  School of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, UK
,
Tuomo Laitinen
e  School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, 70211, Finland
,
Simon J. Coles
d  School of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, UK
,
Oleg A. Rakitin
b  N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, 119991, Russia
c  Nanotechnology Education and Research Center, South Ural State University, Lenina Ave. 76, Chelyabinsk, Russia
,
Stephen T. Hilton*
a  School of Pharmacy, Faculty of Life Sciences, University College London, London, WC1N 1AX, UK   Email: ucnvcrm@ucl.ac.uk   Email: s.hilton@ucl.ac.uk
› Author Affiliations
Further Information

Publication History

Received: 08 October 2018

Accepted after revision: 19 November 2018

Publication Date:
19 December 2018 (online)


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.

 
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  • 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): νmax = 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, CHAr), 7.54 (1 H, d, J = 8.1 Hz, CHAr), 7.38 (1 H, t, J = 7.8 Hz, CHAr), 7.28 (1 H, s, CHAr), 7.17 (1 H, dq, J = 1.0, 8.1 Hz, CHAr), 7.14–7.11 (3 H, m, CHAr), 6.38 (1 H, s, CHAr), 5.43 (2 H, s, CH2), 2.37 (3 H, s, CH3). 13C NMR (100 MHz, CDCl3): δ = 139.6 (CAr), 136.9 (CAr), 136.1 (CAr), 131.2 (CHAr), 130.4 (CHAr), 129.7 (CHAr), 129.5 (CHAr), 128.3 (CAr), 121.2 (CHAr), 120.1 (CHAr), 120.0 (CHAr), 118.5 (CAr), 113.1 (C≡N), 108.8 (CHAr), 101.3 (CHAr), 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): νmax = 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, CHAr), 7.62–7.59 (1 H, m, CHAr), 7.40–7.34 (2 H, m, CHAr), 7.16–7.12 (3 H, m, CHAr), 6.52 (1 H, d, J = 6.3, CHAr), 6.41 (1 H, s, CHAr), 5.55 (2 H, s, CH2), 2.39 (3 H, s, CH3). 13C NMR (100 MHz, CDCl3): δ = 141.7 (CAr), 137.0 (CAr), 136.4 (CAr), 133.5 (CHAr), 132.9 (CHAr), 128.3 (CAr), 127.8 (CHAr), 126.5 (CHAr), 121.2 (CHAr), 120.0 (CHAr), 117.1 (CAr), 110.1 (C≡N), 108.9 (CHAr), 101.2 (CHAr), 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): νmax = 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, CHAr), 7.46 (2 H, ddd, J = 1.0, 4.8, 5.9 Hz, CHAr), 7.40–7.32 (3 H, m, CHAr), 7.24–7.19 (2 H, m, CHAr), 6.15 (2 H, s, CHAr). 13C NMR (100 MHz, CDCl3): δ = 195.9 (C=S), 146.9 (CAr), 142.2 (CAr), 149.4 (CAr), 139.0 (CAr), 131.4 (CHAr), 131.3 (CAr), 130.3 (CHAr), 129.6 (CHAr), 125.5 (CAr), 121.9 (CHAr), 121.7 (CHAr), 120.6 (CHAr), 114.3 (CHAr),113.0 (C≡N), 111.8 (CHAr), 44.0 (CH2).