An Effective Route to Dithieno[3,2-b:2′,3′-d]thiophene-Based Hexaheteroacenes

Abstract

A series of 12H-[1]benzo[4′′,5′′]thieno[2′′,3′′:4′,5′]thieno[2′,3′:4,5]thieno[3,2-b]indoles were efficiently prepared in three steps starting from available benzo[b]thieno[2,3-d]thiophen-3(2H)-ones. These fused ketones were treated with the Vilsmeier reagent and hydroxylamine hydrochloride to give the corresponding 3-chlorobenzo[b]thieno[2,3-d]thiophene-2-carbonitriles, which then reacted with methyl sulfanylacetate to form methyl 3-aminobenzo[4′,5′]thieno[2′,3′:4,5]thieno[3,2-b]thiophene-2-carboxylates, in accordance with the Fiesselmann thiophene synthesis protocol. Finally, the desired N,S-heterohexacenes were obtained by conversion of these fused 3-aminothiophene-2-carboxylates into the corresponding 3-aminothiophene intermediates, which acted as synthetic equivalents of thiophen-3(2H)-ones, followed by their acid-promoted reaction with arylhydrazines, in accordance with the Fischer indolization procedure.

Keywords

benzothienothienothienoindoles - aminothiophenes - arylhydrazines - Fiesselmann reaction - Fischer indole synthesis

Publication History

Received: 03 February 2021

Accepted after revision: 24 February 2021

Accepted Manuscript online:
24 February 2021

Article published online:
22 March 2021

• References and Notes

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• 45 Thiophen-3(2H)-ones 5a–c; General Procedure All solvents were previously degassed. The appropriate ester 1a–c (6.0 mmol) was dissolved in DMSO (30 mL), and a solution of NaOH (4.8 g, 120.0 mmol) in H₂O (30.00 mL) was added. The resulting mixture was refluxed at 120 °С for 2 h under an inert atmosphere, then cooled to r.t. and poured into 1.0 M aq HCl (0.20 L). The resulting mixture was boiled with stirring until evolution of CO₂ ceased. The resulting precipitate was collected by filtration, washed with H₂O (2 × 0.10 L), and dried. 6-Methylthieno[3,2-b][1]benzothiophen-3(2H)-one (5c) Light-brown solid; yield: 1.59 g (98%); mp 211–212 °C. ¹H NMR (500 MHz, CDCl₃): δ = 7.74 (d, J = 8.1 Hz, 1 H), 7.66 (s, 1 H), 7.29 (dd, J = 8.1, 1.4 Hz, 1 H), 4.19 (s, 2 H), 2.52 (s, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 191.6, 160.9, 148.0, 140.4, 130.6, 127.1, 124.3, 123.2, 121.3, 44.2, 22.0. Anal. Calcd for C₁₁H₈OS₂: C, 59.97; H, 3.66. Found: C, 59.90; H, 3.58.
• 46 3-Chlorothiophene-2-carbonitriles 6a–c; General Procedure The appropriate thiophen-3(2H)-one 5a–c (5.0 mmol) was dissolved in DMF (50.00 mL) and the solution was cooled 15 °C. POCl₃ (10.0 mmol, 0.93 mL) in DMF (20.0 mmol, 1.55 mL) was added dropwise, and the mixture was heated to 60 °C for 3 h while a yellow precipitate of the iminium salt formed. The mixture was cooled to r.t. and a solution of hydroxylamine hydrochloride (10.0 mmol, 0.70 g) in DMF (10.00 mL) was added dropwise. The resulting mixture was stirred for 4 h at r.t., then heated at 60 °C for an additional 1 h. The mixture was diluted with H₂O (50.00 mL), and the residue that formed was collected by filtration, washed with water (2 × 25.00 mL), and dried. 3-Chloro-6-methylthieno[3,2-b][1]benzothiophene-2-carbonitrile (6c) Brown solid; yield: 0.87 g (66%); mp 221–222 °C. ¹H NMR (500 MHz, CDCl₃): δ = 7.76 (d, J = 8.2 Hz, 1 H), 7.70 (s, 1 H), 7.34–7.28 (m, 1 H), 2.52 (s, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 144.0, 138.0, 137.6, 135.6, 129.6, 129.4, 127.3, 124.2, 121.4, 112.5, 105.2, 21.8. Anal. Calcd for C₁₂H₆ClNS₂: C, 54.65; H, 2.29; N, 5.31. Found: C, 54.57; H, 2.21; N, 5.23.
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• 48 3-Aminothiophene-2-carboxylates 7a-c; General Procedure The appropriate nitrile 6a–c (4.0 mmol) was dissolved in 9:1 THF–MeOH (50.00 mL) under argon. Methyl sulfanylacetate (4.8 mmol, 0.43 mL) and DBU (6.0 mmol, 0.87 mL) were added, and the resultant mixture was refluxed for 15 h, then cooled and diluted with MeOH (40.00 mL). The precipitate that formed was collected by filtration and washed with MeOH (2 × 10.00 mL). Methyl 3-Amino-7-methylthieno[2′,3′:4,5]thieno[3,2-b][1]-benzothiophene-2-carboxylate (7c) Yellow solid (0.70 g, 53%); mp 270–271 °C. ¹H NMR (400 MHz, DMSO-d₆): δ = 7.99–7.91 (m, 2 H), 7.40–7.33 (m, 1 H), 7.21 (s, 2 H), 3.79 (s, 3 H).¹³C NMR (126 MHz, DMSO-d₆): δ = 164.2, 148.2, 142.0, 139.1, 135.8, 132.8, 130.5, 130.1, 128.3, 127.0, 124.2, 121.0, 97.6, 51.2, 21.1. Anal. Calcd for C₁₅H₁₁NO₂S₃: C, 54.03; H, 3.33; N, 4.20. Found: C, 53.95; H, 3.25; N, 4.12.
• 49 BTTTI derivatives 9a–l; General Procedure All solvents were previously degassed. The appropriate compound 7a–c (1.0 mmol) was dissolved in DMSO (5.00 mL), and a solution of NaOH (20.0 mmol, 0.80 g) in H₂O water (5.00 mL) was added. The mixture was refluxed at 120 °C for 3 h under an inert atmosphere, then cooled to r.t. and diluted with glacial HOAc (10.00 mL). The appropriate hydrazine 8a–d (1.5 mmol) was added. and the resultant mixture was refluxed at 120 °C for additional 3 h, then cooled again to r.t. The precipitate that formed was collected by filtration, washed successively with H₂O (2 × 10.00 mL) and MeOH (2 × 5.00 mL), and dried. Compounds 9d–i, and 9k–l were additionally purified by sublimation under reduced pressure (250 °C, 3 mbar). 3-Fluoro-12H-[1]benzothieno[2′′,3′′:4′,5′]thieno[2′,3′:4,5]-thieno[3,2-b]indole (9c) Light-brown solid (0.23 g, 64%); mp 401–402 °C. ¹H NMR (500 MHz, DMSO-d₆): δ = 12.11 (s, 1 H), 8.12 (d, J = 8.1 Hz, 1 H), 8.07 (d, J = 7.8 Hz, 1 H), 7.69 (dd, J = 9.7, 2.6 Hz, 1 H), 7.58 (dd, J = 8.9, 4.5 Hz, 1 H), 7.55–7.49 (m, 1 H), 7.49–7.42 (m, 1 H), 7.16–7.08 (m, 1 H). ¹³C NMR (126 MHz, DMSO-d₆): δ = 156.9 (d, J = 233.1 Hz), 140.6, 136.9, 136.8, 134.8, 132.7, 132.5, 130.4, 125.5, 125.1, 125.0, 124.4, 122.2 (d, J = 11.1 Hz), 120.7, 117.3 (d, J = 4.4 Hz), 113.5 (d, J = 9.9 Hz), 110.7 (d, J = 26.0 Hz), 103.6 (d, J = 25.1 Hz). ¹⁹F NMR (471 MHz, DMSO-d₆): δ = 39.24–39.17 (m). Anal. Calcd for C₁₈H₈FNS₃: C, 61.17; H, 2.28; N, 3.96. Found: C, 61.20; H, 2.31; N, 3.99.
• 50 12-Benzyl-12H-[1]benzothieno[2′′,3′′:4′,5′]thieno[2′,3′:4,5]-thieno[3,2-b]indole (10) Compound 9a (0.5 mmol, 0.17 g) was dissolved in DMSO (2.00 mL) at 100 °C, and a 60% dispersion of NaH in mineral oil (0.8 mmol, 0.03 g) was added. When the evolution of H₂ ceased, BnBr (0.8 mmol, 0.09 mL) was added, and the mixture was stirred at 100 °C for an additional 30 min. The mixture was then cooled to r.t. and diluted with H₂O (5.00 mL). The precipitate that formed was collected by filtration, washed with H₂O (2 ×10.00 mL) and MeOH (2 ×10.00 mL), and dried to give a white product; yield: 0.20 g (95%); mp 284–285 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.89–7.84 (m, 1 H), 7.82–7.73 (m, 2 H), 7.47–7.39 (m, 2 H), 7.37–7.33 (m, 1 H), 7.35–7.20 (m, 7 H), 5.64 (s, 2 H).¹³C NMR (126 MHz, CDCl₃): δ = 141.5, 141.0, 137.1, 136.9, 134.9, 133.4, 133.0, 131.3, 129.0, 127.9, 126.8, 125.0, 124.6, 124.5, 124.0, 123.0, 122.9, 120.3, 120.2, 118.8, 118.3, 110.4, 49.2. Anal. Calcd for C₂₅H₁₅NS₃: C, 70.56; H, 3.55; N, 3.29. Found: C, 70.59; H, 3.58; N, 3.32.
• 51 CCDC 2064036 contains the supplementary crystallographic data for compound 10. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures.