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.

solid-phase parallel synthesis - 5-substituted 1,2,4-thiadiazole - thiourea carboxamidine linker

References and Notes

<A NAME="RU12908ST-1A">1a</A> Krchňák V. Holladay MW. Chem. Rev.  2002,  102:  61 

<A NAME="RU12908ST-1B">1b</A> Thompson LA. Ellman JA. Chem. Rev.  1996,  96:  555 

<A NAME="RU12908ST-1C">1c</A> Terrett NK. Gardner M. Gordon DW. Kobylecki RJ. Steele J. Tetrahedron  1995,  51:  8135 

<A NAME="RU12908ST-2A">2a</A> Kumar H. Javed SA. Khan SA. Amir M. Eur. J. Med. Chem.  2008,  43:  2688 

<A NAME="RU12908ST-2B">2b</A> 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 

<A NAME="RU12908ST-2C">2c</A> Castro A. Castaño T. Encinas A. Porcal W. Gil C. Bioorg. Med. Chem.  2006,  14:  1644 

<A NAME="RU12908ST-2D">2d</A> Teng X. Keys H. Jeevanandam A. Porco JA. Degterev A. Yuan J. Cuny GD. Bioorg. Med. Chem. Lett.  2007,  17:  6836 

<A NAME="RU12908ST-3A">3a</A> Mullican MD. Wilson MW. Connor DT. Kostlan CR. Schrier DJ. Dyer RD. J. Med. Chem.  1993,  36:  1090 

<A NAME="RU12908ST-3B">3b</A> 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 

<A NAME="RU12908ST-3C">3c</A> Labanauskas L. Kalcas V. UdrenaiteE . Gaidelis P. Brukstus A. Dauksas A. Pharmazie  2001,  56:  617 

<A NAME="RU12908ST-3D">3d</A> Boschelli DH. Connor DT. Bornemeier DA. Dyer RD. Kennedy JA. Kuipers PJ. Okonkwo GC. Schrier DJ. Wright CD. J. Med. Chem.  1993,  36:  1802 

<A NAME="RU12908ST-4A">4a</A> El-Emam AA. Al-Deeb OA. Al-Omar M. Lehmann J. Bioorg. Med. Chem.  2004,  12:  5107 

<A NAME="RU12908ST-4B">4b</A> Dogan HN. Duran A. Rollas S. Sener G. Uysal MK. Gülen D. Bioorg. Med. Chem.  2002,  10:  2893 

<A NAME="RU12908ST-4C">4c</A> Hollar BS. Gonsalves R. Shenoy S. Eur. J. Med. Chem.  2000,  35:  267 

<A NAME="RU12908ST-5A">5a</A> Chapleo CB. Myers M. Myers PL. Saville JF. Smith ACB. Stillings MR. Tulloch IF. Walter DS. Welbourn AP. J. Med. Chem.  1986,  29:  2273 

<A NAME="RU12908ST-5B">5b</A> Chapleo CB. Myers PL. Smith AC. Stillings MR. Tulloch IF. Walter DS. J. Med. Chem.  1988,  31:  7 

<A NAME="RU12908ST-5C">5c</A> Akbarzadeh T. Tabatabai SA. Khoshnoud MJ. Shafaghi D. Shafiee A. Bioorg. Med. Chem.  2003,  11:  769 

<A NAME="RU12908ST-5D">5d</A> Foroumadi A. Tabatabai SA. Gitinezhad G. Zarrindast MR. Shafiee A. Pharm. Pharmacol. Commun.  2000,  6:  1 

<A NAME="RU12908ST-6A">6a</A> Turner S. Myers M. Gadie B. Nelson AJ. Pape R. Saville JF. Doxey JC. Berridge TL. J. Med. Chem.  1988,  31:  902 

<A NAME="RU12908ST-6B">6b</A> 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 

<A NAME="RU12908ST-6C">6c</A> Tyagi M. Kumar A. Oriental J. Chem.  2002,  18:  125 

<A NAME="RU12908ST-7A">7a</A> Yoo S.-e. Seo J.-s. Yi KY. Gong Y.-D. Tetrahedron Lett.  1997,  38:  1203 

<A NAME="RU12908ST-7B">7b</A> Yoo S.-e. Gong Y.-D. Seo J.-s. Sung M.-M. Lee S. Kim Y. J. Comb. Chem.  1999,  1:  177 

<A NAME="RU12908ST-7C">7c</A> Gong Y.-D. Yoo S.-e. Bull. Korean Chem. Soc.  2001,  21:  941 

<A NAME="RU12908ST-7D">7d</A> Gong Y.-D. Seo J.-s. Chon Y.-S. Hwang J.-Y. Park J.-Y. Yoo S.-e. J. Comb. Chem.  2003,  5:  577 

<A NAME="RU12908ST-7E">7e</A> Lee IY. Kim SY. Lee JY. Yu C.-M. Lee DH. Gong Y.-D. Tetrahedron Lett.  2004,  45:  9319 

<A NAME="RU12908ST-8A">8a</A> 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 

<A NAME="RU12908ST-8B">8b</A> Lanzafame A. Christopoulos A. J. Pharmacol. Exp. Ther.  2004,  308:  830 

<A NAME="RU12908ST-8C">8c</A> Castro A. Castano T. Encinas A. Porcal W. Gil C. Bioorg. Med. Chem.  2006,  14:  1644 

<A NAME="RU12908ST-9">9</A> Park JY. Ryu IA. Park JH. Ha DC. Gong Y.-D. Synthesis  2009,  in press

<A NAME="RU12908ST-10">10</A>

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.