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

Christopher R. M. Asquith; Lidia S. Konstantinova; Graham J. Tizzard; Tuomo Laitinen; Simon J. Coles; Oleg A. Rakitin; Stephen T. Hilton

doi:10.1055/s-0037-1611692

Synlett, Table of Contents

Synlett 2019; 30(02): 156-160
DOI: 10.1055/s-0037-1611692

letter

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

Authors

Christopher R. M. Asquith *

^aSchool 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

^bN.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, 119991, Russia

^cNanotechnology Education and Research Center, South Ural State University, Lenina Ave. 76, Chelyabinsk, Russia
Graham J. Tizzard

^dSchool of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, UK
Tuomo Laitinen

^eSchool of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, 70211, Finland
Simon J. Coles

^dSchool of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, UK
Oleg A. Rakitin

^bN.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, 119991, Russia

^cNanotechnology Education and Research Center, South Ural State University, Lenina Ave. 76, Chelyabinsk, Russia
Stephen T. Hilton*

^aSchool of Pharmacy, Faculty of Life Sciences, University College London, London, WC1N 1AX, UK Email: ucnvcrm@ucl.ac.uk Email: s.hilton@ucl.ac.uk

Abstract

All articles of this category

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

Full Text

References

References and Notes
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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): 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).