5264
S. Hesse et al. / Tetrahedron Letters 48 (2007) 5261–5264
9. (a) Gutschow, M.; Neumann, U. J. Med. Chem. 1998, 41,
General procedure for the synthesis of 2-aminothiophenes: A
mixture of 2,5-dihydroxy-1,4-dithiane (dimer of thioacet-
aldehyde) (5 mmol), activated nitrile (10 mmol), triethyl-
amine (0.5 mL) and two drops of DMF in methanol
(4 mL) was submitted to microwave irradiation for 2 min
at 50 ꢁC. After cooling, the reaction mixture was concen-
trated under reduced pressure and hydrolyzed. The
precipitate was filtered off.
2-Amino-thiophene-3-carboxylic acid phenylamide 8: Pale
brown solid. Mp 139 ꢁC. IR (KBr): 1616 (C@O), 3346,
3458 (NH2) cmÀ1. 1H NMR (250 MHz, DMSO-d6): d 6.32
(d, 1H, J = 5.8 Hz), 6.98–7.05 (m, 1H), 7.25–7.34 (m, 3H),
7.38 (br s, 2H), 7.66 (d, 2H, J = 7.5 Hz), 9.31 (br s, 1H).
13C NMR (62.9 MHz, DMSO-d6): d 105.6 (CH), 106.8
(C), 120.3 (CH), 122.8 (CH), 124.2 (CH), 128.4 (CH),
139.3 (C), 162.9 (C), 164.3 (C).
¨
1729 (synthesis of tert-butyl 2-aminothiophene-3-carbox-
ylate in 58% yield); (b) Gutschow, M.; Kuerschner, L.;
¨
Neumann, U.; Pietsch, M.; Lo¨ser, R.; Koglin, N.; Eger, K.
J. Med. Chem. 1999, 42, 5437 (synthesis of ethyl 2-
aminothiophene-3-carboxylate in 1 h in 80% yield); (c)
Tranberg, C. E.; Zickgraf, A.; Giunta, B. N.; Luetjens, H.;
Figler, H.; Murphee, L. J.; Falke, R.; Fleischer, H.;
Linden, J.; Scammells, P. J.; Olsson, R. A. J. Med. Chem.
2002, 45, 382 (synthesis of (2-aminothien-3-yl)(phenyl)-
methanone in 4 h in 64% yield).
10. Robba, M.; Lecomte, J. M.; Sevricourt, M. C. Bull. Soc.
Chim. Fr. 1974, 2864.
11. Perrissin, M.; Favre, M.; Luu-Duc, C.; Bakri-Logeais, F.;
Huguet, F.; Narcisse, G. Eur. J. Med. Chem. Chim. Ther.
1984, 5, 420.
12. (a) Wang, Y. D.; Johnson, S.; Powell, D.; McGinnis, J. P.;
Miranda, M.; Rabindran, S. K. Bioorg. Med. Chem. Lett.
2005, 15, 3763; (b) Jennings, L. D.; Kincaid, S. L.; Wang,
Y. D.; Krishnamurthy, G.; Beyer, C. F.; McGinnis, J. P.;
Miranda, M.; Discafani, C. M.; Rabindran, S. K. Bioorg.
Med. Chem. Lett. 2005, 15, 4731.
13. Munchhof, M. J.; Beebe, J. S.; Casavant, J. M.; Cooper,
B. A.; Doty, J. L.; Higdon, R. C.; Hillerman, S. M.;
Soderstrom, C. I.; Knauth, E. A.; Marx, M. A.; Rossi, A.
M. K.; Sobolov, S. B.; Sun, J. Bioorg. Med. Chem. Lett.
2004, 14, 21.
14. (a) Zheng, G. Z.; Bhatia, P.; Daanen, J.; Kolasa, T.; Patel,
M.; Latshaw, S.; El Kouhen, O. F.; Chang, R.; Uchic, M.
E.; Miller, L.; Nakane, M.; Lehto, S. G.; Honore, M. P.;
Moreland, R. B.; Brioni, J. D.; Stewart, A. O. J. Med.
Chem. 2005, 48, 7374; (b) Zheng, G. Z.; Bhatia, P.;
Kolasa, T.; Patel, M.; El Kouhen, O. F.; Chang, R.;
Uchic, M. E.; Miller, L.; Baker, S.; Lehto, S. G.; Honore,
M. P.; Wetter, J. M.; Marsh, K. C.; Moreland, R. B.;
Brioni, J. D.; Stewart, A. O. Bioorg. Med. Chem. Lett.
2006, 16, 4936.
1-(2-Amino-thien-3-yl)-2,2-dimethyl-propan-1-one 9: Yel-
low solid. Mp 101 ꢁC. IR (KBr): 1591 (C@O), 3266, 3370
1
(NH2) cmÀ1. H NMR (250 MHz, CDCl3): d 1.30 (s, 9H,
3CH3), 6.15 (d, 1H, J = 6 Hz), 6.87 (br s, 2H), 7.19 (d, 1H,
J = 6 Hz). 13C NMR (62.9 MHz, CDCl3): d 27.8 (CH3),
43.7 (C), 105.4 (CH), 112.8 (C), 126.3 (CH), 166.3 (C),
202.2 (C@O).
3H-Thieno[2,3-d]pyrimidin-4-one 10: Pale yellow solid.
Mp 245 ꢁC (dec) (lit.:15 264 ꢁC). IR (KBr): 1652 (C@O)
cmÀ1 1H NMR (250 MHz, DMSO-d6): d 7.39 (d, 1H,
.
J = 5.8 Hz), 7.57 (d, 1H, J = 5.8 Hz), 8.12 (s, 1H), 12.50
(br s, 1H). 13C NMR (62.9 MHz, DMSO-d6): d 121.8
(CH), 124.1 (CH), 124.7 (C), 145.3 (CH), 156.5 (C), 163.5
(C@O).
Methyl 2-formylaminothiophene-3-carboxylate 11: Pale
1
brown solid. Mp 88 ꢁC. H NMR (250 MHz, DMSO-d6):
d 3.85 (s, 3H), 7.03 (d, 1H, J = 5.9 Hz), 7.17 (d, 1H,
J = 5.9 Hz), 8.54 (s, 1H), 11.31 (br s, 1H). 13C
NMR (62.9 MHz, DMSO-d6): d 51.7 (CH3), 113.0 (C),
117.2 (CH), 123.8 (CH), 145.7 (C), 159.8 (C@O),
163.8(C@O).
15. (a) Robba, M.; Lecomte, J. M.; Sevricourt, M. C. Bull.
Soc. Chim. Fr. 1970, 3630; (b) Robba, M.; Lecomte, J. M.;
Sevricourt, M. C. Bull. Soc. Chim. Fr. 1975, 587.
16. In Pyo, J.; Ha Lee, S.; Cheong, C. S. J. Heterocycl. Chem.
2006, 43, 1129.
17. Wu et al. have observed the same kind of reactivity: thus
treating 2-amino-3-cyano-4-methylpyrrole with formic
acid in the presence of acetic anhydride gave the
corresponding N-formylpyrrole and not the pyrrolopyri-
midinone. Kanamarlapudi, R. C.; Bednarz, M.; Wu, W.;
Keyes, P. Org. Process Res. Dev. 2007, 11, 86.
2-Formylaminothiophene-3-carbonitrile 12: Brown solid.
Mp 195 ꢁC (dec). IR (KBr): 1678 (C@O), 2227 (CN), 3216
1
(NH2) cmÀ1. H NMR (250 MHz, DMSO-d6): d 7.18 (s,
2H), 8.41 (s, 1H), 12.04 (br s, 1H). 13C NMR (62.9 MHz,
DMSO-d6): d 92.8 (C), 114.4 (CN), 119.2 (CH), 124.6
(CH), 147.8 (C), 159.2 (CH).
2-Formylaminothiophene-3-carboxamide 13: Pale brown
solid. Mp 193 ꢁC (dec). IR (KBr): 1648 (C@O), 1673
.
(C@O), 3262, 3339, 3446 (NH2) cmÀ1 1H NMR
(250 MHz, DMSO-d6): d 6.98 (d, 1H, J = 5 Hz), 7.39 (d,
1H, J = 5 Hz), 7.49 (br s, 1H), 7.87 (br s, 1H), 8.51 (s, 1H),
12.03 (br s, 1H). 13C NMR (62.9 MHz, DMSO-d6): d
116.0 (C), 116.3 (CH), 123.1 (CH), 143.7 (C), 159.2 (CH),
166.3 (C).
18. Domarkas, J.; Dudouit, F.; Williams, C.; Qiyu, Q.;
Banerjee, R.; Brahimi, F.; Jean-Claude, B. J. J. Med.
Chem. 2006, 49, 3544.
19. El-Baih, F. E. M.; Al-Blowy, H. A. S.; Al-Hazimi, H. M.
Molecules 2006, 11, 498.
20. All reactions were performed in the Open Vessel mode
with a CEM Discover single mode microwave reactor
equipped with a 300 W power source.
4-Chlorothieno[2,3-d]pyrimidine 14: Pale brown solid. Mp
85 ꢁC. 1H NMR (250 MHz, DMSO-d6): d 7.57 (d, 1H,
J = 6 Hz), 8.10 (d, 1H, J = 6 Hz), 8.92 (s, 1H). 13C NMR
(62.9 MHz, DMSO-d6): d 119.6 (CH), 129.0 (C), 130.7
(CH), 152.8 (CH), 153.9 (C), 168.4 (C).