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I. A. Ryu et al.
LETTER
5, 577. (e) Lee, I. Y.; Kim, S. Y.; Lee, J. Y.; Yu, C.-M.; Lee,
D. H.; Gong, Y.-D. Tetrahedron Lett. 2004, 45, 9319.
(8) (a) Fawzi, A. B.; Macdonald, D.; Bendow, L. L.;
Smith Torhan, A.; Zhang, H. T.; Weig, B. C.; Ho, G.;
Tulshian, D.; Linder, M. E.; Graziano, M. P. Mol.
Pharmacol. 2001, 59, 30. (b) Lanzafame, A.;
Christopoulos, A. J. Pharmacol. Exp. Ther. 2004, 308, 830.
(c) Castro, A.; Castano, T.; Encinas, A.; Porcal, W.; Gil, C.
Bioorg. Med. Chem. 2006, 14, 1644.
(9) Park, J. Y.; Ryu, I. A.; Park, J. H.; Ha, D. C.; Gong, Y.-D.
Synthesis 2009, in press.
(10) General Procedure for the Synthesis of 5-Amino-
substituted 1,2,4-Thiadiazoles (8a)
Preparation of Isothiocyanate-Terminated Resin 2
To a mixture of BOMBA resin 1 (5.00 g, 6.0 mmol) in
CH2Cl2 (120 mL) was added Et3N (3.35 mL, 24.0 mmol) and
CSCl2 (1.84 mL, 24.0 mmol) at 0 °C. The mixture was
stirred at r.t. for 5 h. The precipitate obtained by filtration of
the mixture was washed with CH2Cl2 and MeOH and dried
in a vacuum oven. This process gave resin 2 (5.24 g) as a
dark brown solid. Single-bead ATR-FTIR: 2071 (N=C=S),
1610, 1590, 1507, 1493, 1451, 1421, 1376, 1286, 1266,
1196, 1160, 1114, 1029, 1017, 943, 819, 757, 697 cm–1.
Preparation of Carboxamidine Thiourea Resin 4a
A mixture of isothiocyanate resin 2 (5.00 g, 5.71 mmol),
benzamidine hydrochloride (2.68 g, 17.1 mmol), and DBU
(5.12 mL, 34.3 mmol) in DCE (120 mL) was stirred at 60 °C
16 h. The resin was filtered and washed several times with
CH2Cl2 and MeOH and dried in a vacuum oven. Resin 4a
was obtained as a light brown solid (5.62 g). Single-bead
ATR-FTIR: 1611, 1505, 1492, 1448, 1375, 1284, 1195,
1158, 1113, 1029, 820, 756, 697 cm–1.
Figure 2 ATR-FTIR spectra on single beads of 1,2,4-thiadiazole re-
sins 1 (A), 2 (B), 4a (C), 5a (D), 6a (E) and 7a (F)
(3) (a) Mullican, M. D.; Wilson, M. W.; Connor, D. T.; Kostlan,
C. R.; Schrier, D. J.; Dyer, R. D. J. Med. Chem. 1993, 36,
1090. (b) Song, Y.; Connor, D. T.; Sercel, A. D.; Sorenson,
R. J.; Doubleday, R.; Unangst, P. C.; Roth, B. D.; Beylin,
V. G.; Beylin, V. G.; Gilbertsen, R. B.; Chan, K.; Schrier,
D. J.; Guglietta, A.; Bornemeier, D. A.; Dyer, R. D. J. Med.
Chem. 1999, 42, 1161. (c) Labanauskas, L.; Kalcas, V.;
UdrenaiteE, ; Gaidelis, P.; Brukstus, A.; Dauksas, A.
Pharmazie 2001, 56, 617. (d) Boschelli, D. H.; Connor,
D. T.; Bornemeier, D. A.; Dyer, R. D.; Kennedy, J. A.;
Kuipers, P. J.; Okonkwo, G. C.; Schrier, D. J.; Wright, C. D.
J. Med. Chem. 1993, 36, 1802.
Preparation of 5-Amino-3-phenyl-1,2,4-thiadiazole
Resin 5a
A mixture of carboxamidine thiourea resin 4a (5.00 g, 5.02
mmol), Et3N (2.10 mL, 15.1 mmol), and p-TsCl (2.87 g, 15.1
mmol) in DCE (120 mL) was stirred at 60 °C for 8 h.
Filtration gave a precipitate, which was washed several
times with CH2Cl2 and MeOH and dried in a vacuum oven.
Resin 5a was obtained as a light brown solid (4.87 g).
Single-bead ATR-FTIR: 1614, 1558, 1506, 1493, 1451,
1421, 1346, 1286, 1195, 1158, 1118, 1029, 816, 757, 697
cm–1.
(4) (a) El-Emam, A. A.; Al-Deeb, O. A.; Al-Omar, M.;
Lehmann, J. Bioorg. Med. Chem. 2004, 12, 5107.
(b) Dogan, H. N.; Duran, A.; Rollas, S.; Sener, G.; Uysal,
M. K.; Gülen, D. Bioorg. Med. Chem. 2002, 10, 2893.
(c) Hollar, B. S.; Gonsalves, R.; Shenoy, S. Eur. J. Med.
Chem. 2000, 35, 267.
Preparation of 5-Benzylamino-3-phenyl-1,2,4-thiadi-
azole Resin 6a
(5) (a) Chapleo, C. B.; Myers, M.; Myers, P. L.; Saville, J. F.;
Smith, A. C. B.; Stillings, M. R.; Tulloch, I. F.; Walter,
D. S.; Welbourn, A. P. J. Med. Chem. 1986, 29, 2273.
(b) Chapleo, C. B.; Myers, P. L.; Smith, A. C.; Stillings,
M. R.; Tulloch, I. F.; Walter, D. S. J. Med. Chem. 1988, 31,
7. (c) Akbarzadeh, T.; Tabatabai, S. A.; Khoshnoud, M. J.;
Shafaghi, D.; Shafiee, A. Bioorg. Med. Chem. 2003, 11,
769. (d) Foroumadi, A.; Tabatabai, S. A.; Gitinezhad, G.;
Zarrindast, M. R.; Shafiee, A. Pharm. Pharmacol. Commun.
2000, 6, 1.
(6) (a) Turner, S.; Myers, M.; Gadie, B.; Nelson, A. J.; Pape, R.;
Saville, J. F.; Doxey, J. C.; Berridge, T. L. J. Med. Chem.
1988, 31, 902. (b) Turner, S.; Myers, M.; Gadie, B.; Hale,
S. A.; Horsley, A.; Nelson, A. J.; Pape, R.; Saville, J. F.;
Doxey, J. C.; Berridge, T. L. J. Med. Chem. 1988, 31, 907.
(c) Tyagi, M.; Kumar, A. Oriental J. Chem. 2002, 18, 125.
(7) (a) Yoo, S.-e.; Seo, J.-s.; Yi, K. Y.; Gong, Y.-D. Tetrahedron
Lett. 1997, 38, 1203. (b) Yoo, S.-e.; Gong, Y.-D.; Seo, J.-s.;
Sung, M.-M.; Lee, S.; Kim, Y. J. Comb. Chem. 1999, 1,
177. (c) Gong, Y.-D.; Yoo, S.-e. Bull. Korean Chem. Soc.
2001, 21, 941. (d) Gong, Y.-D.; Seo, J.-s.; Chon, Y.-S.;
Hwang, J.-Y.; Park, J.-Y.; Yoo, S.-e. J. Comb. Chem. 2003,
To a mixture of 5-amino-1,2,4-thiadiazole resin 5a (200 mg,
0.20 mmol) in DMF (5 mL) was added NaH (24.0 mg, 0.6
mmol, 60% dispersion in mineral oil) at r.t. The resulting
mixture was stirred for 10 min. Benzyl chloride (115.1 mL,
1.0 mmol) was added, and the resulting mixture was stirred
at 60 °C for 24 h. The resin was filtered and washed several
times with DMF, H2O, MeOH, and CH2Cl2, and then the
resin was dried in a vacuum oven. Resin 6a was obtained as
a brown solid (203 mg). Single-bead ATR-FTIR: 1606,
1587, 1544, 1505, 1493, 1451, 1340, 1286, 1264, 1196,
1159, 1114, 1028, 820, 758, 733, 697 cm–1.
Preparation of 5-Benzamide-3-phenyl-1,2,4-thiadiazole
Resin 7a
To a mixture of the 5-amino-1,2,4-thiadiazole resin 5a (200
mg, 0.20 mmol) in THF (5 mL) was sequentially added
LiHMDS (1.0 mL, 1.0 mmol, 1.0 M solution in hexanes),
benzoyl chloride (116.1 mL, 1.0 mmol), and DMAP (12.2
mg, 0.1 mmol) at r.t. The mixture was stirred at 60 °C for 24
h. The resin was filtered and washed several times with
DMF, H2O, MeOH, and CH2Cl2 and then dried in a vacuum
oven. Resin 7a was obtained as a brown solid (206 mg).
Single-bead ATR-FTIR: 1653 (NC=O), 1602, 1586, 1504,
Synlett 2009, No. 6, 999–1003 © Thieme Stuttgart · New York