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

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.

Key words

2-aminobenzo[b]thiophene-3-carboxylates - Gewald reaction - cyclohexanones - cyanoacetates - benzonitrile - dehydrogenation - heterocycles

• References and Notes

• 1 Gai Z, Yu B, Wang X, Deng Z, Xu P. Microbiology 2008; 154: 3804
• 2a Malamas MS, Sredy J, Moxham C, Katz A, Xu W, McDevitt R, Adebayo FO, Sawicki DR, Seestaller L, Sullivan D, Taylor JR. J. Med. Chem. 2000; 43: 1293
• 2b Ellingboe JW, Alessi TR, Dolak TM, Nguyen TT, Tomer JD, Guzzo F, Bagli JF, McCaleb ML. J. Med. Chem. 1992; 35: 1176
• 3a Fouad I, Mechbal Z, Chane-Ching KI, Adenier A, Maurel F, Aaron JJ, Vodicka P, Cernovska K, Kozmik V, Svoboda J. J. Mater. Chem. 2004; 14: 1711
• 3b Jung KH, Kim KH, Lee DH, Jung DS, Park CE, Choi DH. Org. Electron. 2010; 11: 1584
• 4a Tietze LF, Lohmann JK, Stadler C. Synlett 2004; 1113
• 4b Tietze LF, Thede K, Schimpf R, Sannicolo F. Chem. Commun. 2000; 583
• 5 Raga MM, Moreno-Mañas M, Cuberes MR, Palacín C, Castelló JM, Ortiz JA. Arzneim. Forsch. 1992; 42: 691
• 6 Mourey RJ, Burnette BL, Brustkern SJ, Daniels JS, Hirsch JL, Hood WF, Meyers MJ, Mnich SJ, Pierce BS, Saabye MJ, Schindler JF, South SA, Webb EG, Zhang J, Anderson DR. J. Pharmacol. Exp. Ther. 2010; 333: 797
• 7 Black LJ, Jones CD, Falcone JF. Life Sci. 1983; 32: 1031
• 8 Romagnoli R, Baraldi PG, Kimatrai Salvador M, Preti D, Aghazadeh Tabrizi M, Bassetto M, Brancale A, Hamel E, Castagliuolo I, Bortolozzi R, Basso G, Viola G. J. Med. Chem. 2013; 56: 2606
• 9 Markwell RE, Smith SA, Ward RW. US Patent US4548948A, 1985
• 10 Burkart SE, Davis SG, Lutomski KA, Meier GA, Phillips RB, Roush DM. US Patent US5073564A, 1991
• 11 Tao ZF, Hasvold LA, Leverson JD, Han EK, Guan R, Johnson EF, Stoll VS, Stewart KD, Stamper G, Soni N, Bouska JJ, Luo Y, Sowin TJ, Lin NH, Giranda VS, Rosenberg SH, Penning TD. J. Med. Chem. 2009; 52: 6621
• 12 Rossi A, Pergola C, Koeberle A, Hoffmann M, Dehm F, Bramanti P, Cuzzocrea S, Werz O, Sautebin L. Br. J. Pharmacol. 2010; 161: 555
• 13 Qin Z, Kastrati I, Chandrasena RE. P, Liu H, Yao P, Petukhov PA, Bolton JL, Thatcher GR. J. J. Med. Chem. 2007; 50: 2682
• 14 Liu H, Liu J, van Breemen RB, Thatcher GR, Bolton JL. Chem. Res. Toxicol. 2005; 18: 162
• 15 Nakamaya J In Comprehensive Heterocyclic Chemistry II. Vol. 2. Katritzky AR, Rees CW, Scriven EF. V. Chap. 11 Pergamon Press; London: 1996: 607-677 ; and references therein
• 16 Sato O, Nakayama J In Comprehensive Heterocyclic Chemistry III. Vol. 3. Katritzky AR, Ramsden CA, Scriven EF. V, Taylor RJ. K. Chap. 11 Elsevier Science; Oxford: 2008: 843-922 ; and references therein
• 17a Kim S, Dahal N, Kesharwani T. Tetrahedron Lett. 2013; 54: 4373
• 17b Teplyakov FS, Vasileva TG, Petrov ML, Androsov DA. Org. Lett. 2013; 15: 4038
• 17c Romagnoli R, Baraldi PG, Lopez-Cara C, Preti D, Aghazadeh Tabrizi M, Balzarini J, Bassetto M, Brancale A, Fu XH, Gao Y, Li J, Zhang SZ, Hamel E, Bortolozzi R, Basso G, Viola G. J. Med. Chem. 2013; 56: 9296
• 17d Lyapunova AG, Androsov DA, Petrov ML. Tetrahedron Lett. 2013; 54: 3427
• 17e Hari DP, Hering T, König B. Org. Lett. 2012; 14: 5334
• 17f Han J, Wang Q, Chang X, Liu Y, Wang Y, Meng J. Tetrahedron 2011; 67: 8865
• 17g Mésangeau C, Fraise M, Delagrange P, Caignard DH, Boutin JA, Berthelot P, Yous S. Eur. J. Med. Chem. 2011; 46: 1835
• 18 Zhang X, Zhou X, Kisliuk RL, Piraino J, Cody V, Gangjee A. Bioorg. Med. Chem. 2011; 19: 3585
• 19 Seio K, Tanaka H, Kohara T, Hashimoto K, Fujimura M, Horiuchi H, Yasumatsu Y, Kimura K. US Patent US 6271225B1, 2001
• 20 Eiden F, Felbermeir G. Arch. Pharm. 1984; 317: 675
• 21 Gewald N, Neumann G, Böttcher H. Z. Chem. 1966; 6: 261
• 22a Adib M, Sheikhi E, Bijanzadeh HR, Zhu LG. Tetrahedron 2012; 68: 3377
• 22b Adib M, Sheikhi E, Bagheri M, Bijanzadeh HR, Amanlou M. Tetrahedron 2012; 68: 3237
• 22c Adib M, Sheikhi E, Rezaei N. Tetrahedron Lett. 2011; 52: 3191
• 22d Adib M, Ansari S, Bijanzadeh HR. Synlett 2011; 619
• 22e Adib M, Karimzadeh M, Mahdavi M, Sheikhi E, Mirzaei P. Synlett 2011; 834
• 22f Adib M, Mohamadi A, Sheikhi E, Ansari S, Bijanzadeh HR. Synlett 2010; 1606
• 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.
• 24a Fokin AA, Yurchenko AG, Rodionov VN, Gunchenko PA, Yurchenko RI, Reichenberg A, Wiesner J, Hintz M, Jomaa H, Schreiner PR. Org. Lett. 2007; 9: 4379
• 24b Adam W, Krebs O. Chem. Rev. 2003; 103: 4131