Solid-Phase Parallel Synthesis of 5-Amino- and 5-Amido-1,2,4-thiadiazole Derivatives via Cyclization Reactions of a Carboxamidine Thiourea Linker

Abstract

A general method is described for the solid-phase parallel synthesis of 5-amino- and 5-amido-1,2,4-thiadiazoles. The sequence developed for this purpose is based on cyclization reactions of resin-bound carboxamidine thioureas promoted by p-toluenesulfonyl chloride. The resin-bound carboxamidine thioureas, produced by addition of arylcarboxamidines to a isothiocyanate terminated resin, serve as key intermediates that undergo cyclizations to generate 5-amino-1,2,4-thiadiazole resins. N-Alkylation or N-acylation reactions of 5-amino-1,2,4-thiadiazole resins yield the desired variously functionalized 1,2,4-thiadiazole resins. Finally, 5-amino- and 5-amido-1,2,4-thiadiazoles are then generated in good yields and purities by cleavage of the respective 1,2,4-thiadiazole resins under TFA in CH₂Cl₂.

Heterocyclic skeletons serve as ideal scaffolds on which pharmacophores can be appended to yield potent and selective drugs. [¹] This is especially true for five-membered-ring heterocycles, which are core components of a large number of substances that possess a wide range of interesting biological activities. In this respect, the potential of the thiadiazole scaffold to serve as a privileged structure for the generation of druglike libraries in drug-discovery programs has been amply demonstrated. [²] In this family of heterocycles, 1,2,4-thiadiazoles have been used as the basic framework for substances of interest in numerous therapeutic areas, such as antiimflammatory, [³] antimicrobial, [4] anticonvulsant, [5] and antihypertensive agents. [6] As a part of a research program aimed at drug discovery and high throughput organic synthesis, we needed to develop a facile and rapid parallel approach for the construction of druglike small heterocyclic molecules. [7] Our specific focus was on modulators of G-protein-coupled receptors (GPCR), which have been identified as allosteric modulators of a wide variety of untreated GPCR, including the human µ-, δ-, and κ- and β-adrenergic, muscarinic M₁ and M₂, and dopaminergic D₁ and D₂ receptors. [8] Since these types of modulators possess 3-phenyl with 5-amino and 5-amido functionalities, our efforts concentrated on the construction of GPCR focused on 5-amino- and 5-amido-substituted 1,2,4-thiadiazoles. However, methods to readily introduce 5-amine- and 5-amide functionalities onto a preexisting 1,2,4-thiadiazole backbone in the solid phase have not been fully explored. As a matter of fact, it is for this reason that most known 5-amino-substituted 1,2,4-thiadiazoles have been prepared by solution-phase reactions of phenylthiocyanate. This strategy severely limits the number of 5-amino-substituted 1,2,4-thiadiazoles that can be generated. Moreover, procedures to produce 5-­hydroxy or 5-mercapto-1,2,4-thiadiazoles starting with carbon disulfide are rare.

As a result of these limitations, we have undertaken an investigation aimed at developing efficient and simple parallel synthetic methods to produce various 5-amino- and 5-amido-substituted-1,2,4-thiadiazoles. Recently, we reported the results of a study that led to the development of a solution-phase parallel synthesis of various druglike 5-amino-1,2,4-thiadiazoles, which employs a key cyclization reaction of a carboxamidine dithiocarbazate induced by p-toluenesulfonyl chloride (p-TsCl). [9] The goal of the investigation described below was to uncover a simple and efficient solid-phase parallel synthetic method that would enable production of a variety of 5-amino- and 5-amido-1,2,4-thiadiazoles derived from a common intermediate. Selection of 5-amine and 5-amide substituents was guided by a consideration of physicochemical properties that would lead to increased biological activities (see Figure  [¹] ).

The strategy we have employed for the efficient solid-phase synthesis of various 5-amino- and 5-amido-functionalized 1,2,4-thiadiazole derivatives is given in the sequence illustrated in Scheme  [¹] . In the route, resin-bound carboxamidine thioureas 4 were used as key intermediates, which undergo cyclization to produce the 1,2,4-thiadiazole resin 5. N-Alkylation and N-acylation reactions of 5 then yield the respective resins 6 and 7, which are transformed to the 5-amino- and 5-amido-1,2,4-thiadiazoles 8 and 9, respectively.

The isothiocyanate terminated resin 2 was prepared from the amine resin 1 by reaction with thiophosgene (CSCl₂) in the presence of triethylamine (Et₃N) in CH₂Cl₂ at 0 ˚C to room temperature. Formation of the resin 2 was confirmed by inspection of its attenuated total reflection (ATR) single-bead FTIR spectrum, which showed the presence of the typical isothiocyanate band at 2071 cm^-¹. The resin-bound isothiocyanate reacts with phenylcarboxamidine (3a) in the presence of DBU in dichloroethane at 60 ˚C to give the resin-bound phenylcarboxamidine thiourea 4a, signaled by the absence of the isothiocyanate band for 2 at 2071 cm^-¹. To develop methods for solid-phase synthesis of various 5-functionalized 1,2,4-thiadi­azoles, cyclization of the phenylcarboxamidine thiourea resin 4a, and needed in the strategy we have devised, was investigated by using a number of different activating agents, including EDC˙HCl, DCC, TMSCl, p-TsCl, Ph₃P, SOCl₂, PCl₅, and diphenyl chlorophosphate. This effort demonstrated that the best cyclization condition involved the use of p-TsCl in the presence of Et₃N in dichloro­ethane at 60 ˚C. This process led to the formation of the 3-phenyl-5-amino-1,2,4-thiadiazole resin 5a, whose single bead FTIR spectrum contained stretching bands at 1558 and 1346 cm^-¹.

Alkylation reactions of the 3-phenyl-5-amino-1,2,4-thiadiazole resin 5a provided the desired 3-phenyl-5-(N-alkyl­amino)-1,2,4-thiadiazole resin 6a. In a similar manner, 3-phenyl-5-(N-acylamino)-1,2,4-thiadiazole resin 7a was produced by acylation reactions of resins 5 with acid chlorides. Importantly, resins 6a and 7a undergo smooth ­reactions to yield 3-phenyl-5-amino or 5-amido-functionalized 1,2,4-thiadiazoles 8a and 9a, respectively, in high yields and purities when treated with TFA in CH₂Cl₂ at room temperature. As shown by the spectra given in Figure  [²] , the progress of the reactions of resins 6a and 7a can be monitored by single-bead FTIR spectroscopy. The conversion of 5 into 6a is characterized by the disappearance of NH band at 3100 cm^-¹ and a red shift of the cyclic imines bands at 1544 and 1330 cm^-¹. And the conversion of resins 5 into 5-amide-substituted 1,2,4-thiadiazole resin 7a was checked by the appearance of an amide band at 1653 cm^-¹. As shown by the data given in Table  [¹] and Table  [²] , various 5-amino- and 5-amido-1,2,4-thiadiazoles 8 and 9 can be produced by this five-step route in high overall yields and purities. It was possible to introduce benzyl- (8a-m) and alkyl (8n-s) substituents on the 5-amino group. Finally, the general procedures used are given in detail [¹0] and Supporting Information.

Table 1 Yields and Purities of the 5-Amino-1,2,4-thiadiazoles
(continued)

Entry	Compd 8	R¹	R²	Yield (%)a	Purity (%)b
1	8a	Ph		28	90
2	8b	Ph		31	96
3	8c	Ph		19	98
4	8d	Ph		31	>99
5	8e	Ph		29	98
6	8f	Ph		26	93
7	8g	Ph		27	>99
8	8h	Ph		17	>99
9	8i	Ph		30	97
10	8j	Ph		23	95
11	8k	Ph		23	>99
12	8l	Ph		15	96
13	8m	Ph		24	93
14	8n	Ph		15	94
15	8o	Ph		19	93
16	8p	Ph		34	91
17	8q	Ph		27	>99
18	8r	Ph		33	96
19	8s	Ph	Me	29	>99
20	8t	3-O2NC6H4		20	95
21	8u	3-O2NC6H4		20	>99
22	8v	3-O2NC6H4		20	>99
a Five-step overall yields from BOMBA resin 1 (loading capacity of the resin 1 is 1.2 mmol/g). b All of the purified products were checked by LC-MS.

In conclusion, the results of the investigation described above demonstrate that 5-amino- and 5-amido-1,2,4-thiadiazoles can be efficiently synthesized by using an easily obtainable carboxamidine intermediate resin 4. Cyclization of resin 4, promoted by reaction with p-TsCl, followed by N-alkylation or N-acylation and liberation from the resin, leads to formation of the 5-amino-3-phenyl-1,2,4-thiadiazoles 8 and 5-amido-3-phenyl-1,2,4-thiadi­azoles 9 in high overall yields and purities.

Table 2 Yields and Purities of the 5-Amido-1,2,4-thiadiazoles

Entry	Compd 9	R¹	R³	Yield (%)a,b
1	9a	Ph		26
2	9b	Ph		7
3	9c	Ph		23
4	9d	Ph		20
5	9e	Ph		21
6	9f	Ph		6
7	9g	Ph		6
8	9h	Ph		14
9	9i	Ph		6
10	9j	Ph		13
11	9k	3-O2NC6H4		21
12	9l	3-O2NC6H4		6
a Five-step overall yield from BOMBA resin 1 (loading capacity of the resin 1 is 1.2 mmol/g). b The purities of all of the final products were determined >98% by LC-MS.

Acknowledgment

This investigation was supported by a grant (CBM32-B1000-01-00-00) from the Center for Biological Modulators of the 21^st Century Frontier R&D Program, the Ministry of Education Science and Technology, Korea and Korea Research Institute of Chemical Technology.

References and Notes

• 1a Krchňák V. Holladay MW. Chem. Rev.  2002,  102:  61 
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• 1b Thompson LA. Ellman JA. Chem. Rev.  1996,  96:  555 
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• 1c Terrett NK. Gardner M. Gordon DW. Kobylecki RJ. Steele J. Tetrahedron  1995,  51:  8135 
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• 2a Kumar H. Javed SA. Khan SA. Amir M. Eur. J. Med. Chem.  2008,  43:  2688 
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• 2b Shen L. Zhang Y. Wang A. Sieber-McMaster E. Chen X. Pelton P. Xu JZ. Yang M. Zhu P. Zhou L. Reuman M. Hu Z. Russell R. Gibbs AC. Ross H. Demarest K. Murray WV. Kuo G.-H. Bioorg. Med. Chem.  2008,  16:  3321 
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• 2c Castro A. Castaño T. Encinas A. Porcal W. Gil C. Bioorg. Med. Chem.  2006,  14:  1644 
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• 2d Teng X. Keys H. Jeevanandam A. Porco JA. Degterev A. Yuan J. Cuny GD. Bioorg. Med. Chem. Lett.  2007,  17:  6836 
  Search in Google Scholar
• 3a Mullican MD. Wilson MW. Connor DT. Kostlan CR. Schrier DJ. Dyer RD. J. Med. Chem.  1993,  36:  1090 
  Search in Google Scholar
• 3b Song Y. Connor DT. Sercel AD. Sorenson RJ. Doubleday R. Unangst PC. Roth BD. Beylin VG. Beylin VG. Gilbertsen RB. Chan K. Schrier DJ. Guglietta A. Bornemeier DA. Dyer RD. J. Med. Chem.  1999,  42:  1161 
  Search in Google Scholar
• 3c Labanauskas L. Kalcas V. UdrenaiteE . Gaidelis P. Brukstus A. Dauksas A. Pharmazie  2001,  56:  617 
  Search in Google Scholar
• 3d Boschelli DH. Connor DT. Bornemeier DA. Dyer RD. Kennedy JA. Kuipers PJ. Okonkwo GC. Schrier DJ. Wright CD. J. Med. Chem.  1993,  36:  1802 
  Search in Google Scholar
• 4a El-Emam AA. Al-Deeb OA. Al-Omar M. Lehmann J. Bioorg. Med. Chem.  2004,  12:  5107 
  Search in Google Scholar
• 4b Dogan HN. Duran A. Rollas S. Sener G. Uysal MK. Gülen D. Bioorg. Med. Chem.  2002,  10:  2893 
  Search in Google Scholar
• 4c Hollar BS. Gonsalves R. Shenoy S. Eur. J. Med. Chem.  2000,  35:  267 
  Search in Google Scholar
• 5a Chapleo CB. Myers M. Myers PL. Saville JF. Smith ACB. Stillings MR. Tulloch IF. Walter DS. Welbourn AP. J. Med. Chem.  1986,  29:  2273 
  Search in Google Scholar
• 5b Chapleo CB. Myers PL. Smith AC. Stillings MR. Tulloch IF. Walter DS. J. Med. Chem.  1988,  31:  7 
  Search in Google Scholar
• 5c Akbarzadeh T. Tabatabai SA. Khoshnoud MJ. Shafaghi D. Shafiee A. Bioorg. Med. Chem.  2003,  11:  769 
  Search in Google Scholar
• 5d Foroumadi A. Tabatabai SA. Gitinezhad G. Zarrindast MR. Shafiee A. Pharm. Pharmacol. Commun.  2000,  6:  1 
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• 6a Turner S. Myers M. Gadie B. Nelson AJ. Pape R. Saville JF. Doxey JC. Berridge TL. J. Med. Chem.  1988,  31:  902 
  Search in Google Scholar
• 6b Turner S. Myers M. Gadie B. Hale SA. Horsley A. Nelson AJ. Pape R. Saville JF. Doxey JC. Berridge TL. J. Med. Chem.  1988,  31:  907 
  Search in Google Scholar
• 6c Tyagi M. Kumar A. Oriental J. Chem.  2002,  18:  125 
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• 7a Yoo S.-e. Seo J.-s. Yi KY. Gong Y.-D. Tetrahedron Lett.  1997,  38:  1203 
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• 7b Yoo S.-e. Gong Y.-D. Seo J.-s. Sung M.-M. Lee S. Kim Y. J. Comb. Chem.  1999,  1:  177 
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• 7c Gong Y.-D. Yoo S.-e. Bull. Korean Chem. Soc.  2001,  21:  941 
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• 7d Gong Y.-D. Seo J.-s. Chon Y.-S. Hwang J.-Y. Park J.-Y. Yoo S.-e. J. Comb. Chem.  2003,  5:  577 
  Search in Google Scholar
• 7e Lee IY. Kim SY. Lee JY. Yu C.-M. Lee DH. Gong Y.-D. Tetrahedron Lett.  2004,  45:  9319 
  Search in Google Scholar
• 8a Fawzi AB. Macdonald D. Bendow LL. Smith Torhan A. Zhang HT. Weig BC. Ho G. Tulshian D. Linder ME. Graziano MP. Mol. Pharmacol.  2001,  59:  30 
  Search in Google Scholar
• 8b Lanzafame A. Christopoulos A. J. Pharmacol. Exp. Ther.  2004,  308:  830 
  Search in Google Scholar
• 8c Castro A. Castano T. Encinas A. Porcal W. Gil C. Bioorg. Med. Chem.  2006,  14:  1644 
  Search in Google Scholar
• 9 Park JY. Ryu IA. Park JH. Ha DC. Gong Y.-D. Synthesis  2009,  in press

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. 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. Preparation of 5-Benzylamino-3-phenyl-1,2,4-thiadi-azole Resin 6a 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 µL, 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 µL, 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, 1491, 1449, 1376, 1284, 1263, 1195, 1158, 1112, 1026, 1017, 819, 757, 733, 696 cm^-¹. Preparation of N -Benzyl-3-phenyl-1,2,4-thiadiazol-5-amine 8a from Resin 6a A mixture of 5-benzylamino-3-phenyl-1,2,4-thiadiazole resin 6a (203 mg, 0.20 mmol) and 3 mL of cleavage cocktail (TFA-CH₂Cl₂ = 1:4, v/v) was shaken at r.t. for 4 h. The resin was filtered and the filtrate was concentrated in vacuo giving a residue which was dissolved in CH₂Cl₂. The solution was eluted through a SAX cartridge (CH₂Cl₂). The eluent was concentrated in vacuo giving a residue which was subjected to SiO₂ column chromatography (n-hexane-EtOAc, 8:1) to afford 8a (15.3 mg, 28%; 90% purity). ^¹H NMR (500 MHz, CDCl₃): δ = 8.17-8.14 (m, 2 H), 7.43-7.39 (m, 3 H), 7.38-7.31 (m, 5 H), 6.47 (s, 1 H), 4.52 (d, 2 H, J = 5.6 Hz). ^¹³C NMR (125 MHz, CDCl₃): δ = 50.6, 127.8, 128.1, 128.4, 128.6, 129.1, 130.1, 133.4, 136.3, 170.0, 184.6 cm^-¹. LC-MS (ESI): m/z = 268 [M + 1]⁺. HRMS (EI): m/z [M]⁺ calcd for C₁₅H₁₃N₃S₁: 267.0830; found: 267.0829. Synthesis of N -(3-Phenyl-1,2,4-thiadiazol-5-yl)benz-amide 9a from Resin 7a A mixture of 3-phenyl-5-benzamide-1,2,4-thiadiazole resin 7a (206 mg, 0.20 mmol) and the cleavage cocktail (3 mL; TFA-CH₂Cl₂ = 1:4) was shaken at r.t. for 4 h. Filtration followed by washing the precipitate with CH₂Cl₂ gave a filtrate which was concentrated in vacuo to give a residue that was eluted through a SAX cartridge (CH₂Cl₂). The eluent was concentrated in vacuo to give a residue was subjected to SiO₂ column chromatography (n-hexane-EtOAc, 8:1) to afford 9a (14.6 mg, 26%; 99% purity). ^¹H NMR (500 MHz, CDCl₃): δ = 10.71 (s, 1 H), 8.19-8.14 (m, 2 H), 7.93-7.90 (m, 2 H), 7.60-7.56 (m, 1 H), 7.47-7.43 (m, 2 H), 7.42-7.38 (m, 3 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 127.8, 127.9, 128.8, 129.3, 130.4, 130.6, 132.8, 133.8, 165.8, 167.9, 175.8. LC-MS (ESI): m/z = 282 [M + 1]⁺. HRMS (EI): m/z [M]⁺ calcd for C₁₅H₁₁N₃O₁S₁: 281.0623; found: 281.0616.

References and Notes

• 1a Krchňák V. Holladay MW. Chem. Rev.  2002,  102:  61 
  Search in Google Scholar
• 1b Thompson LA. Ellman JA. Chem. Rev.  1996,  96:  555 
  Search in Google Scholar
• 1c Terrett NK. Gardner M. Gordon DW. Kobylecki RJ. Steele J. Tetrahedron  1995,  51:  8135 
  Search in Google Scholar
• 2a Kumar H. Javed SA. Khan SA. Amir M. Eur. J. Med. Chem.  2008,  43:  2688 
  Search in Google Scholar
• 2b Shen L. Zhang Y. Wang A. Sieber-McMaster E. Chen X. Pelton P. Xu JZ. Yang M. Zhu P. Zhou L. Reuman M. Hu Z. Russell R. Gibbs AC. Ross H. Demarest K. Murray WV. Kuo G.-H. Bioorg. Med. Chem.  2008,  16:  3321 
  Search in Google Scholar
• 2c Castro A. Castaño T. Encinas A. Porcal W. Gil C. Bioorg. Med. Chem.  2006,  14:  1644 
  Search in Google Scholar
• 2d Teng X. Keys H. Jeevanandam A. Porco JA. Degterev A. Yuan J. Cuny GD. Bioorg. Med. Chem. Lett.  2007,  17:  6836 
  Search in Google Scholar
• 3a Mullican MD. Wilson MW. Connor DT. Kostlan CR. Schrier DJ. Dyer RD. J. Med. Chem.  1993,  36:  1090 
  Search in Google Scholar
• 3b Song Y. Connor DT. Sercel AD. Sorenson RJ. Doubleday R. Unangst PC. Roth BD. Beylin VG. Beylin VG. Gilbertsen RB. Chan K. Schrier DJ. Guglietta A. Bornemeier DA. Dyer RD. J. Med. Chem.  1999,  42:  1161 
  Search in Google Scholar
• 3c Labanauskas L. Kalcas V. UdrenaiteE . Gaidelis P. Brukstus A. Dauksas A. Pharmazie  2001,  56:  617 
  Search in Google Scholar
• 3d Boschelli DH. Connor DT. Bornemeier DA. Dyer RD. Kennedy JA. Kuipers PJ. Okonkwo GC. Schrier DJ. Wright CD. J. Med. Chem.  1993,  36:  1802 
  Search in Google Scholar
• 4a El-Emam AA. Al-Deeb OA. Al-Omar M. Lehmann J. Bioorg. Med. Chem.  2004,  12:  5107 
  Search in Google Scholar
• 4b Dogan HN. Duran A. Rollas S. Sener G. Uysal MK. Gülen D. Bioorg. Med. Chem.  2002,  10:  2893 
  Search in Google Scholar
• 4c Hollar BS. Gonsalves R. Shenoy S. Eur. J. Med. Chem.  2000,  35:  267 
  Search in Google Scholar
• 5a Chapleo CB. Myers M. Myers PL. Saville JF. Smith ACB. Stillings MR. Tulloch IF. Walter DS. Welbourn AP. J. Med. Chem.  1986,  29:  2273 
  Search in Google Scholar
• 5b Chapleo CB. Myers PL. Smith AC. Stillings MR. Tulloch IF. Walter DS. J. Med. Chem.  1988,  31:  7 
  Search in Google Scholar
• 5c Akbarzadeh T. Tabatabai SA. Khoshnoud MJ. Shafaghi D. Shafiee A. Bioorg. Med. Chem.  2003,  11:  769 
  Search in Google Scholar
• 5d Foroumadi A. Tabatabai SA. Gitinezhad G. Zarrindast MR. Shafiee A. Pharm. Pharmacol. Commun.  2000,  6:  1 
  Search in Google Scholar
• 6a Turner S. Myers M. Gadie B. Nelson AJ. Pape R. Saville JF. Doxey JC. Berridge TL. J. Med. Chem.  1988,  31:  902 
  Search in Google Scholar
• 6b Turner S. Myers M. Gadie B. Hale SA. Horsley A. Nelson AJ. Pape R. Saville JF. Doxey JC. Berridge TL. J. Med. Chem.  1988,  31:  907 
  Search in Google Scholar
• 6c Tyagi M. Kumar A. Oriental J. Chem.  2002,  18:  125 
  Search in Google Scholar
• 7a Yoo S.-e. Seo J.-s. Yi KY. Gong Y.-D. Tetrahedron Lett.  1997,  38:  1203 
  Search in Google Scholar
• 7b Yoo S.-e. Gong Y.-D. Seo J.-s. Sung M.-M. Lee S. Kim Y. J. Comb. Chem.  1999,  1:  177 
  Search in Google Scholar
• 7c Gong Y.-D. Yoo S.-e. Bull. Korean Chem. Soc.  2001,  21:  941 
  Search in Google Scholar
• 7d Gong Y.-D. Seo J.-s. Chon Y.-S. Hwang J.-Y. Park J.-Y. Yoo S.-e. J. Comb. Chem.  2003,  5:  577 
  Search in Google Scholar
• 7e Lee IY. Kim SY. Lee JY. Yu C.-M. Lee DH. Gong Y.-D. Tetrahedron Lett.  2004,  45:  9319 
  Search in Google Scholar
• 8a Fawzi AB. Macdonald D. Bendow LL. Smith Torhan A. Zhang HT. Weig BC. Ho G. Tulshian D. Linder ME. Graziano MP. Mol. Pharmacol.  2001,  59:  30 
  Search in Google Scholar
• 8b Lanzafame A. Christopoulos A. J. Pharmacol. Exp. Ther.  2004,  308:  830 
  Search in Google Scholar
• 8c Castro A. Castano T. Encinas A. Porcal W. Gil C. Bioorg. Med. Chem.  2006,  14:  1644 
  Search in Google Scholar
• 9 Park JY. Ryu IA. Park JH. Ha DC. Gong Y.-D. Synthesis  2009,  in press

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. 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. Preparation of 5-Benzylamino-3-phenyl-1,2,4-thiadi-azole Resin 6a 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 µL, 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 µL, 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, 1491, 1449, 1376, 1284, 1263, 1195, 1158, 1112, 1026, 1017, 819, 757, 733, 696 cm^-¹. Preparation of N -Benzyl-3-phenyl-1,2,4-thiadiazol-5-amine 8a from Resin 6a A mixture of 5-benzylamino-3-phenyl-1,2,4-thiadiazole resin 6a (203 mg, 0.20 mmol) and 3 mL of cleavage cocktail (TFA-CH₂Cl₂ = 1:4, v/v) was shaken at r.t. for 4 h. The resin was filtered and the filtrate was concentrated in vacuo giving a residue which was dissolved in CH₂Cl₂. The solution was eluted through a SAX cartridge (CH₂Cl₂). The eluent was concentrated in vacuo giving a residue which was subjected to SiO₂ column chromatography (n-hexane-EtOAc, 8:1) to afford 8a (15.3 mg, 28%; 90% purity). ^¹H NMR (500 MHz, CDCl₃): δ = 8.17-8.14 (m, 2 H), 7.43-7.39 (m, 3 H), 7.38-7.31 (m, 5 H), 6.47 (s, 1 H), 4.52 (d, 2 H, J = 5.6 Hz). ^¹³C NMR (125 MHz, CDCl₃): δ = 50.6, 127.8, 128.1, 128.4, 128.6, 129.1, 130.1, 133.4, 136.3, 170.0, 184.6 cm^-¹. LC-MS (ESI): m/z = 268 [M + 1]⁺. HRMS (EI): m/z [M]⁺ calcd for C₁₅H₁₃N₃S₁: 267.0830; found: 267.0829. Synthesis of N -(3-Phenyl-1,2,4-thiadiazol-5-yl)benz-amide 9a from Resin 7a A mixture of 3-phenyl-5-benzamide-1,2,4-thiadiazole resin 7a (206 mg, 0.20 mmol) and the cleavage cocktail (3 mL; TFA-CH₂Cl₂ = 1:4) was shaken at r.t. for 4 h. Filtration followed by washing the precipitate with CH₂Cl₂ gave a filtrate which was concentrated in vacuo to give a residue that was eluted through a SAX cartridge (CH₂Cl₂). The eluent was concentrated in vacuo to give a residue was subjected to SiO₂ column chromatography (n-hexane-EtOAc, 8:1) to afford 9a (14.6 mg, 26%; 99% purity). ^¹H NMR (500 MHz, CDCl₃): δ = 10.71 (s, 1 H), 8.19-8.14 (m, 2 H), 7.93-7.90 (m, 2 H), 7.60-7.56 (m, 1 H), 7.47-7.43 (m, 2 H), 7.42-7.38 (m, 3 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 127.8, 127.9, 128.8, 129.3, 130.4, 130.6, 132.8, 133.8, 165.8, 167.9, 175.8. LC-MS (ESI): m/z = 282 [M + 1]⁺. HRMS (EI): m/z [M]⁺ calcd for C₁₅H₁₁N₃O₁S₁: 281.0623; found: 281.0616.

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