PAPER
Microwave-Assisted Synthesis of 5-Substituted 2-Aminothiophenes
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1H NMR (250 MHz, DMSO-d6): d = 7.14–7.21 (m, 2 H, 2 CH),
1H NMR (250 MHz, DMSO-d6): d = 3.72 (s, 3 H, CH3), 3.78 (s, 3
H, CH3), 6.83 (dd, J = 8, 2 Hz, 2 H, 2 CH), 6.90 (d, J = 8 Hz, 1 H,
1 CH,), 6.98 (d, J = 2 Hz, 1 H, 1 CH,), 7.36 (s, 4 H, 2 NH2), 7.41 (s,
1 H, CH).
13C NMR (62.5 MHz, DMSO-d6): d = 55.3, 55.5, 107.5, 107.7,
112.2, 116.0, 120.0, 121.5, 127.2, 147.4, 148.9, 160.6, 167.3.
7.28–7.35 (m, 2 H, 2 CH), 7.39–7.44 (m, 4 H, 2 CH + NH2).
13C NMR (62.5 MHz, DMSO-d6): d = 83.8, 96.9, 116.3, 121.7,
124.1, 126.5, 127.9, 133.1, 164.4.
HRMS (ESI): m/z calcd for [C11H18N2S + Na]+: 223.0300; found:
223.1127.
HRMS (ESI): m/z calcd for [C13H14N2O3S + H]+: 278.0531; found:
2-Amino-5-(3,4-dimethoxyphenyl)-3-thiophenecarbonitrile
278.0530.
(7b)
Yield: 77%; yellow solid; mp 116 °C.
2-Amino-5-(4-methoxyphenyl)-3-thiophenecarboxamide (8c)
Yield: 59%; pale brown solid; mp 167 °C.
1H NMR (250 MHz, DMSO-d6): d = 3.72 (s, 3 H, CH3), 3.77 (s, 3
H, CH3), 6.80–6.87 (m, 2 H, 2 CH), 7.06 (s, 1 H, CH), 7.12 (s, 1 H,
CH), 7.31 (s, 2 H, NH2).
13C NMR (62.5 MHz, DMSO-d6): d = 55.5, 64.9, 83.5, 108.1, 112.0,
116.4, 120.4, 124.5, 126.2, 135.9, 147.9, 149.0, 163.9.
HRMS (ESI): m/z calcd for [C13H12N2O2S + Na]+: 283.1427; found:
283.1428.
1H NMR (250 MHz, DMSO-d6): d = 3.73 (s, 3 H, CH3), 6.90 (d,
J = 8.75 Hz, 2 H, 2 CH), 7.29 (d, J = 8.75 Hz, 2 H, 2 CH), 7.36 (s,
4 H, 2 NH2), 7.37 (s, 1 H, CH).
13C NMR (62.5 MHz, DMSO-d6): d = 54.9, 107.1, 113.6, 119.8,
121.3, 124.9, 126.9, 157.6, 160.6, 167.3.
HRMS (ESI): m/z calcd for [C12H12N2O2S + H]+: 247.0515; found:
247.0536.
2-Amino-5-(4-methoxyphenyl)-3-thiophenecarbonitrile (7c)
Yield: 53%; green solid; 102 °C.
2-Amino-5-(2-naphthyl)-3-thiophenecarboxamide (8e)
Yield: 74%; pale brown solid; mp 90 °C.
1H NMR (250 MHz, DMSO-d6): d = 3.73 (s, 3 H, CH3), 6.89 (d,
J = 8.75 Hz, 2 H, 2 CH), 7.04 (s, 1 H, CH), 7.30 (s, 2 H, NH2), 7.36
(d, J = 8.75 Hz, 2 H, 2 CH).
13C NMR (62.5 MHz, DMSO-d6): d = 55.1, 83.6, 114.3, 116.4,
119.9, 124.3, 125.5, 125.8, 158.1, 163.6.
HRMS (ESI): m/z calcd for [C12H10N2OS + Na]+: 220.1339; found:
220.1329.
1H NMR (250 MHz, DMSO-d6): d = 7.28–7.52 (m, 3 H, 3 CH), 7.57
(s, 1 H, CH), 7.63–7.67 (m, 2 H, 2 CH), 7.73 (s, 4 H, 2NH2), 7.81–
7.89 (m, 3 H, 3 CH).
13C NMR (62.5 MHz, DMSO-d6): d = 108.0, 120.7, 121.1, 122.3,
122.5, 125.2, 125.9, 126.6, 127.3, 128.3, 131.3, 132.4, 133.4, 161.6,
167.3.
HRMS (ESI): m/z calcd for [C15H12N2OS + H]+: 269.0743; found:
2-Amino-5-(2-thienyl)-3-thiophenecarbonitrile (7d)
269.0872.
Yield: 50%; green solid; mp 85 °C.
1H NMR (250 MHz, DMSO-d6): d = 6.95–7.04 (m, 3 H, 3 CH), 7.37
(s, 1 H, CH), 7.44 (s, 2 H, NH2).
Acknowledgment
We thank the ’Ministère de l’Enseignement Supérieur et de la Re-
cherche’ for a Ph.D. grant to G.R. We thank also Veronique Poddig
and Agnès Crepet for recording the NMR spectra.
13C NMR (62.5 MHz, DMSO-d6): d = 83.3, 115.9, 117.8, 121.6,
122.7, 124.1, 128.0, 136.0, 164.2.
HRMS (ESI): m/z calcd for [C9H6N2S2 + Na]+: 226.9509; found:
226.9521.
References
2-Amino-5-(2-naphthyl)-3-thiophenecarbonitrile (7e)
(1) (a) Sabnis, R. W.; Rangnekar, D. W.; Sonawane, N. D.
J. Heterocycl. Chem. 1999, 36, 333. (b) Puterová, Z.;
Kruto íková, A.; Végh, D. ARKIVOC 2010, (i), 209.
(2) Briel, D.; Rybak, A.; Kronbach, C.; Unverferth, K. Eur.
J. Med. Chem. 2010, 45, 69.
(3) Bowers, S.; Truong, A. P.; Neitz, R. J.; Neitzel, M.; Probst,
G. D.; Hom, R. K.; Peterson, B.; Galemmo, R. A. Jr.;
Konradi, A. W.; Sham, H. L.; Tóth, G.; Pan, H.; Yao, N.;
Artis, D. R.; Brigham, E. F.; Quinn, K. P.; Sauer, J. M.;
Powell, K.; Ruslim, L.; Ren, Z. Bioorg. Med. Chem. Lett.
2011, 21, 1838.
Yield: 94%; orange solid; mp 215 °C.
1H NMR (250 MHz, DMSO-d6): d = 7.38 (s, 1 H, CH), 7.43–7.48
(m, 2 H, 2 CH), 7.52 (s, 2 H, NH2), 7.69–7.73 (m, 1 H, CH), 7.82–
7.88 (m, 4 H, 4 CH).
13C NMR (62.5 MHz, DMSO-d6): d = 83.9, 116.2, 121.6, 122.5,
122.8, 124.0, 125.6, 126.6, 127.5, 127.6, 128.4, 130.7, 131.6, 133.2,
164.7.
HRMS (ESI): m/z calcd for [C15H10N2S + Na]+: 273.1377; found:
273.1382.
(4) Ye, P.; Kuhn, C.; Juan, M.; Sharma, R.; Connolly, B.; Alton,
G.; Liu, H.; Stanton, R.; Kablaoui, N. M. Bioorg. Med.
Chem. Lett. 2011, 21, 849.
(5) Thomae, D.; Perspicace, E.; Xu, Z.; Henryon, D.; Schneider,
S.; Hesse, S.; Kirsch, G.; Seck, P. Tetrahedron 2009, 65,
2982.
(6) Thomae, D.; Kirsch, G.; Seck, P. Synthesis 2007, 1027.
(7) Abdillahi, I.; Kirsch, G. Synthesis 2010, 1428.
(8) Hesse, S.; Perspicace, E.; Kirsch, G. Tetrahedron Lett. 2007,
48, 5261.
2-Amino-5-phenyl-3-thiophenecarboxamide (8a)
Yield: 80%; pale yellow solid; mp 211 °C (Lit.9 mp 218–220 °C).
1H NMR (250 MHz, DMSO-d6): d = 7.07–7.14 (m, 1 H, CH), 7.25–
7.41 (m, 4 H, 4 CH), 7.47 (s, 4 H, 2 NH2), 7.47 (s, 1 H, CH).
13C NMR (62.5 MHz, DMSO-d6): d = 107.9, 121.1, 121.4, 123.5,
125.7, 128.9, 134.2, 161.4, 167.4.
HRMS (ESI): m/z calcd for [C11H10N2OS + H]+: 219.0587; found:
219.0577.
(9) Gewald, K.; Schinke, E.; Böttcher, H. Chem. Ber. 1966, 99,
94.
(10) Chandrasekhar, S.; Kumar, M. S.; Muralidhar, B.
Tetrahedron Lett. 1998, 39, 909.
2-Amino-5-(3,4-dimethoxyphenyl)-3-thiophenecarboxamide
(8b)
Yield: 95%; pale brown solid; mp 91 °C.
Synthesis 2011, No. 18, 2935–2940 © Thieme Stuttgart · New York