Synlett 2014; 25(20): 2918-2922
DOI: 10.1055/s-0034-1379475
letter
© Georg Thieme Verlag Stuttgart · New York

A Simple Synthesis of Alkyl 2-Aminobenzo[b]thiophene-3-carboxylates via an Unexpected Dehydrogenation of Alkyl 2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylates

Mehdi Adib*
a  School of Chemistry, College of Science, University of Tehran, P. O. Box 14155-6455 Tehran, Iran   Fax: +98(21)66495291   Email: madib@khayam.ut.ac.ir
,
Maryam Bayanati
a  School of Chemistry, College of Science, University of Tehran, P. O. Box 14155-6455 Tehran, Iran   Fax: +98(21)66495291   Email: madib@khayam.ut.ac.ir
,
Mehdi Soheilizad
a  School of Chemistry, College of Science, University of Tehran, P. O. Box 14155-6455 Tehran, Iran   Fax: +98(21)66495291   Email: madib@khayam.ut.ac.ir
,
Helia Janatian Ghazvini
a  School of Chemistry, College of Science, University of Tehran, P. O. Box 14155-6455 Tehran, Iran   Fax: +98(21)66495291   Email: madib@khayam.ut.ac.ir
,
Mahmood Tajbakhsh
b  Department of Organic Chemistry, Faculty of Chemistry, Mazandaran University, Babolsar, Iran
,
Massoud Amanlou
c  Pharmaceutical Sciences Research Center and Department of Medicinal Chemistry, Tehran University of Medical Sciences, Tehran, Iran
› Author Affiliations
Further Information

Publication History

Received: 25 August 2014

Accepted: 21 September 2014

Publication Date:
14 November 2014 (online)


Abstract

A simple method for the preparation of alkyl 2-aminobenzo[b]thiophene-3-carboxylates is described. Alkyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylates, generated from the Gewald three-component reaction between cyclohexanones, alkyl cyanoacetates and sulfur, undergo dehydrogenation in benzonitrile under an air atmosphere to afford alkyl 2-aminobenzo[b]thiophene-3-carboxylates in good to excellent yields.

 
  • References and Notes

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  • 23 General Procedure for the Preparation of Alkyl 2-Aminobenzo[b]thiophene-3-carboxylates 7a–j, Exemplified with 7a: A mixture of cyclohexanone (0.196 g, 2.0 mmol), methyl cyanoacetate (0.198 g, 2.0 mmol), elemental sulfur (0.064 g, 2.0 mmol) and morpholine (0.174 g, 2.0 mmol) was heated at 75 °C for 1 h. After nearly complete conversion to the corresponding 2-aminothiophene, as was indicated by TLC monitoring, the reaction mixture was cooled to r.t. and the solid residue was recrystallized from EtOH to afford methyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (6a). Then a solution of 6a (0.211 g, 1 mmol) in benzonitrile (2 mL) was heated within a flask equipped with an air-filled balloon at 200 °C for 24 h in a silicone oil bath. Progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was cooled to r.t. and the excess of benzonitrile was removed under the reduced pressure. The crude product was purified by column chromatography using n-hexane–EtOAc (8:1) as eluent. The solvent was evaporated under the reduced pressure and the residue was crystallized from n-hexane–EtOAc (5:1) to afford the pure product 7a as pale yellow crystals. Yield: 0.188 g, 91% (on the basis of 6a). IR (KBr): 3395, 3280, 3167 (NH), 1647 (C=O) cm–1. 1H NMR (500.1 MHz, CDCl3): δ = 3.97 (s, 3 H, Me), 6.55 (br s, 2 H, NH2), 7.16 (td, J = 7.6, 1.2 Hz, 1 H, CH), 7.34 (td, J = 7.8, 1.2 Hz, 1 H, CH), 7.52 (d, J = 8.0 Hz, 1 H, CH), 8.10 (d, J = 8.0 Hz, 1 H, CH). 13C NMR (100.6 MHz, CDCl3): δ = 51.1 (OMe), 99.7 (CCO2), 121.4, 122.4, 122.5, 125.5 (4 × CH), 128.8, 137.3 (2 × C), 164.5 (SCN), 166.7 (C=O). MS: m/z (%) = 207 (95) [M+], 175 (100). Anal. Calcd for C10H9NO2S (207.25): C, 57.95; H, 4.38; N, 6.76. Found: C, 58.08; H, 4.42; N, 6.68. 7b: pale yellow crystals. Yield: 0.205 g (93%). IR (KBr): 3395, 3277, 3159 (NH), 1641 (C=O) cm–1. 1H NMR (400.1 MHz, CDCl3): δ = 1.49 (t, J = 7.2 Hz, 3 H, Me), 4.44 (q, J = 7.2 Hz, 2 H, CH2), 6.56 (br s, 2 H, NH2), 7.16 (td, J = 7.6, 1.2 Hz, 1 H, CH), 7.34 (td, J = 7.8, 1.2 Hz, 1 H, CH), 7.52 (d, J = 7.8 Hz, 1 H, CH), 8.13 (d, J = 8.2 Hz, 1 H, CH). 13C NMR (100.6 MHz, CDCl3): δ = 14.6 (Et), 59.9 (OEt), 99.7 (CCO2), 121.3, 122.4, 122.5, 125.5 (4 × CH), 128.8, 137.4 (2 × C), 164.4 (SNC), 166.4 (C=O). MS: m/z (%) = 221 (83) [M+], 175 (100). Anal. Calcd for C11H11NO2S (221.28): C, 59.71; H, 5.01; N, 6.33. Found: C, 59.69; H, 5.13; N, 6.27. 7c: pale yellow crystals. Yield: 0.199 g, 90%. IR (KBr): 3411, 3298 (NH), 1650 (C=O) cm–1. 1H NMR (400.1 MHz, CDCl3): δ = 2.41 (s, 3 H, Me), 3.96 (s, 3 H, OMe), 6.50 (br s, 2 H, NH2), 7.15 (d, J = 8.4 Hz, 1 H, CH), 7.33 (br s, 1 H, CH), 7.97 (d, J = 8.4 Hz, 1 H, CH). 13C NMR (100.6 MHz, CDCl3): δ = 21.2 (Me), 51.0 (OMe), 99.5 (CCO2), 121.4, 122.2, 126.8 (3 × CH), 129.0, 132.2, 134.7 (3 × C), 163.9 (CNS), 166.7 (C=O). MS: m/z (%) = 221 (72) [M+], 189 (100). Anal. Calcd for C11H11NO2S (221.28): C, 59.71; H, 5.01; N, 6.33. Found: C, 59.86; H, 5.04; N, 6.30. 7d: pale yellow crystals. Yield: 0.211 g, 90%. IR (KBr): 3410, 3294 (NH), 1643 (C=O) cm–1. 1H NMR (400.1 MHz, CDCl3): δ = 1.48 (t, J = 7.2 Hz, 3 H, Me), 2.41 (s, 3 H, Me), 4.43 (q, J = 7.2 Hz, 2 H, CH2), 6.48 (br s, 2 H, NH2), 7.15 (d, J = 8.4 Hz, 1 H, CH), 7.33 (br s, 1 H, CH), 8.00 (d, J = 8.4 Hz, 1 H, CH). 13C NMR (100.6 MHz, CDCl3): δ = 14.6 (Et), 21.2 (Me), 59.9 (OEt), 99.6 (CCO2), 121.4, 122.2, 126.8 (3 × CH), 129.0, 132.1, 134.9 (3 × C), 163.8 (CNS), 166.3 (C=O). MS: m/z (%) = 235 (66) [M+], 189 (100). Anal. Calcd for C12H13NO2S (235.31): C, 61.25; H, 5.57; N, 5.95. Found: C, 61.24; H, 5.46; N, 5.91. 7e: yellow oil. Yield: 0.245 g, 88%. IR (KBr): 3426, 3320 (NH), 1713, 1674 (C=O) cm–1. 1H NMR (500.1 MHz, CDCl3): δ = 1.36 (t, J = 7.2 Hz, 3 H, Et), 3.83 (s, 3 H, OMe), 4.34 (q, J = 7.2 Hz, 2 H, OEt), 6.35 (br s, 2 H, NH2), 7.18 (t, J = 7.6 Hz, 1 H, CH), 7.61 (dd, J = 7.6, 1.2 Hz, 1 H, CH), 7.62 (dd, J = 7.6, 1.2 Hz, 1 H, CH). 13C NMR (100.6 MHz, CDCl3): δ = 14.2 (Et), 51.0 (OMe), 60.9 (OEt), 101.0 (CCO2), 121.9, 124.0, 126.8 (3 × CH), 127.0, 130.4, 134.5 (3 × C), 163.3 (CNS), 165.8, 169.5 (2 × C=O). MS: m/z (%) = 279 (85) [M+], 175 (100). Anal. Calcd for C13H13NO4S (279.32): C, 55.90; H, 4.69; N, 5.01. Found: C, 55.78; H, 4.75; N, 4.84. 7f: yellow oil. Yield: 0.258 g, 88%. IR (KBr): 3428, 3322, 3179 (NH), 1714, 1670 (C=O) cm–1. 1H NMR (500.1 MHz, CDCl3): δ = 1.34 (t, J = 7.2 Hz, 3 H, Et), 1.35 (t, J = 7.2 Hz, 3 H, Et), 4.31 (q, J = 7.2 Hz, 2 H, OEt), 4.33 (q, J = 7.2 Hz, 2 H, OEt), 6.26 (br s, 2 H, NH2), 7.18 (t, J = 7.6 Hz, 1 H, CH), 7.61 (dd, J = 7.6, 1.2 Hz, 1 H, CH), 7.64 (dd, J = 7.6, 1.2 Hz, 1 H, CH). 13C NMR (100.6 MHz, CDCl3): δ = 14.2, 14.2 (2 × Et), 60.4, 60.8 (2 × OEt), 99.9 (CCO2), 121.8, 124.1 (2 × CH), 126.9 (C), 127.0 (CH), 130.5, 134.9 (2 × C), 163.3 (CNS), 165.6, 169.3 (2 × C=O). MS: m/z (%) = 293 (72) [M+], 175 (100). Anal. Calcd for C14H15NO4S (293.34): C, 57.32; H, 5.15; N, 4.77. Found: C, 57.49; H, 5.26; N, 4.58. 7g: yellow oil. Yield: 0.188 g, 85%. IR (KBr): 3391, 3286, 3171 (NH), 1647 (C=O) cm–1. 1H NMR (400.1 MHz, CDCl3): δ = 2.51 (s, 3 H, Me), 3.92 (s, 3 H, Me), 6.10 (br s, 2 H, NH2), 7.09 (t, J = 7.6 Hz, 1 H, CH), 7.14 (d, J = 7.5 Hz, 1 H, CH), 7.38 (d, J = 7.5 Hz, 1 H, CH). 13C NMR (100.6 MHz, CDCl3): δ = 23.2 (Me), 50.9 (OMe), 101.8 (CCO2), 119.0, 122.6, 128.7 (3 × CH), 129.9, 132.8, 135.9 (3 × C), 162.2 (CNS), 166.2 (C=O). MS: m/z (%) = 221 (13) [M+], 64 (100). Anal. Calcd for C11H11NO2S (221.28): C, 59.71; H, 5.01; N, 6.33. Found: C, 59.63; H, 4.90; N, 6.21. 7h: yellow oil. Yield: 0.200 g, 85%. IR (KBr): 3433, 3327 (NH), 1660 (C=O) cm–1. 1H NMR (500.1 MHz, CDCl3): δ = 1.42 (t, J = 7.2 Hz, 3 H, Et), 2.54 (s, 3 H, Me), 4.40 (q, J = 7.2 Hz, 2 H, OEt), 6.11 (br s, 2 H, NH2), 7.09 (t, J = 7.6 Hz, 1 H, CH), 7.14 (d, J = 7.6 Hz, 1 H, CH), 7.38 (d, J = 7.6 Hz, 1 H, CH). 13C NMR (100.6 MHz, CDCl3): δ = 14.5 (2 × Et), 23.5 (Me), 60.3 (OEt), 102.2 (CCO2), 119.0, 122.6, 128.6 (3 ×× CH), 129.9, 131.8, 136.0 (3 × C), 162.1 (CNS), 166.0 (C=O). MS: m/z (%) = 235 (87) [M+], 189 (100). Anal. Calcd for C12H13NO2S (235.31): C, 61.25; H, 5.57; N, 5.95. Found: C, 61.40; H, 5.72; N, 5.76. 7i: pale yellow crystals. Yield: 0.269 g, 95. IR (KBr): 3458, 3344 (NH), 1660 (C=O) cm–1. 1H NMR (500.1 MHz, CDCl3): δ = 3.40 (s, 3 H, OMe), 6.59 (br s, 2 H, NH2), 7.36 (tt, J = 7.6, 1.2 Hz, 1 H, CH), 7.47 (t, J = 7.6 Hz, 2 H, 2 × CH), 7.59 (dd, J = 8.4, 1.6 Hz, 1 H, CH), 7.64 (dd, J = 7.6, 1.2 Hz, 2 H, 2 × CH), 7.76 (d, J = 1.6 Hz, 1 H, CH), 8.15 (d, J = 8.4 Hz, 1 H, CH). 13C NMR (100.6 MHz, CDCl3): δ = 51.1 (OMe), 99.5 (CCO2), 119.7, 122.6, 124.8 (3 × CH), 126.9 (2 × CH), 127.0 (CH), 128.8 (2 × CH), 129.5, 135.7, 136.4, 140.9 (4 × C), 164.7 (SNC), 166.6 (C=O). MS: m/z (%) = 283 (99) [M+], 251 (100). Anal. Calcd for C16H13NO2S (283.35): C, 67.82; H, 4.62; N, 4.94. Found: C, 67.83; H, 4.64; N, 4.92. 7j: yellow oil. Yield: 0.282 g, 95%. IR (KBr): 3400, 3312 (NH), 1657 (C=O) cm–1. 1H NMR (500.1 MHz, CDCl3): δ = 1.52 (t, J = 7.2 Hz, 3 H, Et), 4.48 (q, J = 7.2 Hz, 2 H, OEt), 6.66 (br s, 2 H, NH2), 7.37 (t, J = 7.6 Hz, 1 H, CH), 7.48 (t, J = 7.6 Hz, 2 H, 2 × CH), 7.61 (dd, J = 8.4, 1.6 Hz, 1 H, CH), 7.65 (dd, J = 7.6, 1.2 Hz, 2 H, 2 × CH), 7.76 (d, J = 1.6 Hz, 1 H, CH), 8.19 (d, J = 8.4 Hz, 1 H, CH). 13C NMR (100.6 MHz, CDCl3): δ = 14.6 (Me), 60.0 (OCH2), 99.6 (CCO2), 119.7, 122.7, 124.8 (3 × CH), 126.9 (2 × CH), 127.0 (CH), 128.8 (2 × CH), 129.6, 135.5, 136.6, 141.0 (4 × C), 164.7 (SCN), 166.3 (C=O). MS: m/z (%) = 297 (51) [M+], 57 (100). Anal. Calcd for C17H15NO2S (297.38): C, 68.66; H, 5.08; N, 4.71. Found: C, 68.79; H, 5.23; N, 4.57.
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