A Versatile One-Pot Strategy for the Synthesis of [1,4]Thiazepino[5,4-a]isoquinolines Containing Intramolecular Hydrogen Bonds

Abstract

A simple and efficient one-pot method is described for the construction of [1,4]thiazepino[5,4-a]isoquinolines containing intramolecular hydrogen bonds by a sequential four-component domino reaction of isoquinoline, a 2-bromoacetophenone, an aryl isothiocyanate, and dimethyl acetylenedicarboxylate.

Key words

heterocycles - polycycles - isoquinolines - hydrogen bonds - domino reactions - multicomponent reactions

• References and Notes

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• 16 [1,4]Thiazepino[5,4-a]isoquinolines 3a–g; General Procedure A mixture of the appropriate 2-bromoacetophenone 1 (1 mmol) and isoquinoline (1 mmol) in MeCN (2 mL) was stirred at r.t. for 30 min. Aryl isothiocyanate 2 (1 mmol) was added, followed by dropwise addition of Et₃N (1 mmol), and the mixture was stirred at r.t. for 20 min. Finally, DMAD (1 mmol) was added dropwise to the mixture. When the reaction was complete (2 h, TLC), the solvent was removed and the residue was purified by flash column chromatography [silica gel, hexane–EtOAc (1:6)]. Dimethyl 4-Anilino-5-benzoyl-12bH-[1,4]thiazepino[5,4-a]isoquinoline-1,2-dicarboxylate (3a) Yellow–orange crystals; yield: 0.39 g (75%); mp 179–180 °C; IR (KBr): 3445 (N–H), 1732 (C=O), 1586 and 1528 (Ar), 1375 (C–N), 1238 (C–O) cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 3.36 (s, 3 H, OCH₃), 3.63 (s, 3 H, OCH₃), 5.53 (s, 1 H, CH), 5.62 (d, ³ J _HH = 7.4 Hz, 1 H, CH⁸ of isoquinoline), 6.62 (d, ³ J _HH = 7.4 Hz, 1 H, CH⁷ of isoquinoline), 6.71 (d, ³ J _HH = 7.6 Hz, 1 H, CH of Ar), 6.93–6.95 (m, 2 H, 2 × CH of Ar), 7.07–7.20 (m, 4 H, 4 × CH of Ar), 7.25–7.33 (m, 5 H, 5 × CH of Ar), 7.51 (d, ³ J _HH = 7.6 Hz, 2 H, 2 × CH of Ar), 11.30 (s, 1 H, NH). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 52.2 (OCH₃), 53.5 (OCH₃), 60.3 (CH), 101.2 (CH⁸), 121.8 (C¹), 122.1 (CH of Ar), 122.9 (CH of Ar), 123.9 (C⁵), 124.4 (C²), 124.7 (CH of Ar), 126.3 (CH of Ar), 126.6 (2 × CH of Ph), 127.4 (CH of Ph), 127.7 (2 × CH of Ph), 128.3 (2 × CH of Ph), 128.9 (2 × CH of Ph), 129.0 (CH of Ar), 132.2 (C^8a), 137.0 (CH⁷), 138.7 (C⁴), 139.1 (C_ipso –CO), 144.1 (C _ipso –N), 162.0 (C^12a), 164.2 (CO₂Me), 165.3 (CO₂Me), 187.5 (C=O). MS (EI, 70 eV): m/z (%) = 395 (42), 337 (24), 303 (16), 275 (23), 172 (14), 129 (71), 105 (92), 77 (100). Anal. Calcd for C₃₀H₂₄N₂O₅S (524.59): C, 68.69; H, 4.61; N, 5.34. Found: C, 68.62; H, 4.66; N, 5.44. Crystal data for 3a: C₃₀H₂₃N₂O₅S: M_W = 523.56, monoclinic, P1, a = 9.5067(5), b = 21.4933(12), c = 12.8134(6) Å, β = 102.389(1), V = 2557.2(2) ų, Z = 2, D _calcd = 1.360 mg/m³, F (000) = 1092; crystal dimensions: 0.34 × 0.27 × 0.15 mm; radiation, Mo Kα (λ = 0.71073Å), 1.89 ≤ 2θ ≤ 25.10. Intensity data were collected at 295(2) K with a Bruker APEX area-detector diffractometer by employing the ω/2θ scanning technique in the range –11 ≤ h ≤ 11, –25 ≤ k ≤ 25, –15 ≤ l ≤ 15. The structure was solved by a direct method; all nonhydrogen atoms were positioned, and anisotropic thermal parameters refined from 3615 observed reflections with R(into) = 0.0565 by a full-matrix least-squares technique converged to R = 0.0413 and R _aw = 0.1177 [I > 2σ(I)]. Dimethyl 5-Benzoyl-4-[(3-bromophenyl)amino]-12bH-[1,4]thiazepino[5,4-a]isoquinoline-1,2-dicarboxylate (3b) Orange crystals; yield: 0.44 g (73%); mp 141–144 °C. IR (KBr): 3444 (N–H), 1728 (C=O), 1611 and 1549 (Ar), 1357 (C–N), 1239 (C–O) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ =3.37 (s, 3 H, OCH₃), 3.70 (s, 3 H, OCH₃), 5.34 (s, 1 H, CH), 5.73 (d, ³ J _HH = 7.2 Hz, 1 H, CH⁸ of isoquinoline), 6.43 (d, ³ J _HH = 7.2 Hz, 1 H, CH⁷ of isoquinoline), 6.67 (d, ³ J _HH = 7.5 Hz, 1 H, CH of Ar), 6.95 (t, ³ J _HH = 7.5 Hz, 1 H, CH of Ar), 6.98 (d, ³ J _HH = 7.5 Hz, 1 H, CH of Ar), 7.12 (d, ³ J _HH = 7.8 Hz, 1 H, CH of Ar), 7.16 (t, ³ J _HH = 8.7 Hz, 2 H, 2 × CH of Ar), 7.25–7.30 (m, 3 H, 3 × CH of Ar), 7.41 (d, ³ J _HH = 8.4 Hz, 1 H, CH of Ar), 7.45 (d, ⁴ J _HH = 1.5 Hz, 1 H, CH of Ar), 7.66 (d, ³ J _HH = 7.8 Hz, 2 H, 2× CH of Ar), 10.00 (br s, 1 H, NH). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 52.4 (OCH₃), 53.4 (OCH₃), 61.8 (CH), 102.2 (CH⁸), 122.5 (C¹), 122.7 (C⁵), 122.8 (C²), 123.3 (CH of Ar), 123.7 (CH of Ar), 123.8 (CH of Ar), 125.0 (CH of Ar), 126.3 (CH of Ar), 127.8 (2 × CH _meta of Ph), 127.9 (2 × CH _ortho of Ph), 128.2 (CH _para of Ph), 128.4 (CH of Ar), 129.5 (CH of Ar), 130.3 (CH), 130.9 (CH of Ar), 132.3 (C^8a), 136.3 (CH⁷), 138.3 (C⁴), 139.4 (C_ipso –CO), 145.7 (C _ipso –N), 161.7 (C^12a), 164.0 (CO₂Me), 166.3 (CO₂Me), 190.3 (C=O). MS (EI, 70 eV): m/z (%) = 473 (16), 415 (18), 374 (17), 220 (32), 129 (96), 105 (100), 77 (100). Anal. Calcd for C₃₀H₂₃BrN₂O₅S (603.48): C, 59.71; H, 3.84; N, 4.64. Found: C, 59.65; H, 3.27; N, 4.70. Dimethyl 5-Benzoyl-4-[(2,4-dichlorophenyl)amino]-12bH-[1,4]thiazepino[5,4-a]isoquinoline-1,2-dicarboxylate (3c) Orange crystals; yield: 0.40 g (68%); mp 172–174 °C. IR (KBr): 3445 (N–H), 1727 (C=O), 1617 and 1537 (Ar), 1363 (C–N), 1241 (C–O) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 3.34 (s, 3 H, OCH₃), 3.61 (s, 3 H, OCH₃), 5.38 (s, 1 H, CH), 5.73 (d, ³ J _HH = 7.2 Hz, 1 H, CH⁸ of isoquinoline), 6.43 (d, ³ J _HH = 7.2 Hz, 1 H, CH⁷ of isoquinoline), 6.70 (d, ³ J _HH = 7.5 Hz, 1 H, CH of Ar), 6.97 (t, ³ J _HH = 8.4 Hz, 1 H, CH of Ar), 6.98 (d, ³ J _HH = 7.8 Hz, 1 H, CH of Ar), 7.11–7.19 (m, 3 H, 3 × CH of Ar), 7.25–7.31 (m, 3 H, 3 × CH of Ar), 7.49 (s, 1 H, CH of Ar), 7.68 (d, ³ J _HH = 7.5 Hz, 2 H, 2 × CH of Ar), 10.00 (br s, 1 H, NH). ¹³C NMR (75 MHz, CDCl₃): δ =52.4 (OCH₃), 53.3 (OCH₃), 61.7 (CH), 102.4 (CH⁸ of isoquinoline), 123.0 (C¹), 123.3 (CH of Ar), 123.5 (C⁵), 123.7 (C²), 125.1 (CH of Ar), 126.4 (CH of Ar), 127.4 (CH of Ar), 127.6 (CH of Ar), 127.8 (2 × CH of Ar), 128.0 (2 × CH of Ar), 128.5 (CH of Ar), 129.9 (CH of Ar), 130.3 (C _ipso –Cl), 131.0 (CH of Ar), 132.0 (C^8a), 132.4 (C _ipso –Cl), 134.8 (C⁴), 136.0 (CH⁷), 137.9 (C _ipso –CO), 145.7 (C _ipso –N), 161.1 (C^12a), 163.9 (CO₂Me), 166.2 (CO₂Me), 189.9 (C=O); MS (EI, 70 eV): m/z (%) = 499 (3), 463 (56), 428 (67), 396 (61), 129 (38), 105 (98), 77 (100). Anal. Calcd for C₃₀H₂₂Cl₂N₂O₅S (593.48): C, 60.71; H, 3.74; N, 4.72. Found: C, 60.80; H, 3.68; N, 4.65.
• 17 Crystallographic data for compound 3a have been deposited with the accession number CCDC 1041246, and can be obtained free of charge from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: [phone]; E-mail: [e-mail]; Web site: www.ccdc.cam.ac.uk/conts/retrieving.html.
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