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.

Key words

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

References and Notes

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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. 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.