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With N-iodo-succinimide; In dichloromethane; at 20℃; for 24.0h;
To a solution of ethyl 2-aminothiazole-4-carboxylate (2.92 g, 16.96 mmol) in dichloromethane (100 mL) was added NIS (5.00 g, 22.22 mmol). The resulting reaction mixture was stirred at room temperature for 24 h and then it was diluted with ethyl acetate, washed with water and brine, dried over MgS04, filtered and concentrated to give ethyl 2-amino-5-iodothiazole-4-carboxylate (4.75 g, 90%) that was used as such for the next step. LC (Method A): 1.549 min. LCMS (APCI): calcd for C6H8IN202S [M+H]+ m/z 298.94, found 299.0.
67%
With N-iodo-succinimide; In acetonitrile; at 80℃; for 2.0h;
A solution of ethyl 2-amino-l ,3-thiazole-4-carboxylate (3 g, 17.421 mmol, 1.00 equiv) and N-iodosuccinimide (4.689 g, 20.841 mmol, 1.20 equiv) in acetonitrile (50 mL) was stirred for 2 h at 80 C. The resulting solution was concentrated under vacuum and the residue was purified by a silica gel column chromatography eluted with dichloromethane/methanol (30: 1) to give the title compound (3.5 g, 67%) as a light yellow solid. LC-MS (ES, m/z): 299 [M+H]+.
With N-iodo-succinimide; In N,N-dimethyl-formamide; at 60℃;
Dissolve ethyl 2-amino-l,3-thiazole-4-carboxylate (5.00 g, 29.0 mmol) in DMF (40 mL) and add N-iodosuccmirnide (7.18 g, 31.9 minol). Heat the mixture at 6O0C overnight. Cool the mixture and add EtOAc (300 mL). Extract with IN NaOH (200 mL), H2O (2 x 200 mL) and brine (1 x 200 mL). Dry the organic layer over Na2SO4 and evaporate under reduced pressure. Purify the crude product by chromatography on silica gel eluting with EtOAc/hexanes (2:1) to yield the title compound. LOMS (MH+) 298.98.
With N-iodo-succinimide; In tetrahydrofuran; at 0℃; for 1.5h;
EXAMPLES; Example 1; 4-Hydroxymethyl-5-((Z)-2-tritylthioethen-1-yl)thiazole; a) 2-Amino-4-ethoxycarbonyl-5-iodothiazole; A solution of 14.53 g of 2-amino-4-ethoxycarbonylthiazole in 200 ml of THF was cooled in ice under an argon atmosphere, 20.0 g of N-iodosuccinimide was added to the cooled solution, and the mixture was stirred at the same temperature for 1.5 hr. Brine was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1 to 1:2) to give 21.12 g of 2-amino-4-ethoxycarbonyl-5-iodothiazole. NMR (CDCl3) δ: 1.41 (3H, t, J=7.2 Hz), 4.39 (2H, q, J=7.2 Hz), 5.4 (2H, br s)
With tert.-butylnitrite; In N,N-dimethyl-formamide; at 20℃; for 2.0h;Cooling with ice; Inert atmosphere;
A solution of <strong>[860646-12-4]ethyl 2-amino-5-iodothiazole-4-carboxylate</strong> (4.75 g, 15.93 mmol) in DMF (70 mL) was cooled in an ice bath under nitrogen and then tert- butylnitrite (2.74 mL, 23.04 mmol) was added and the mixture was stirred at room temperature for 2 h. The reaction mixture was poured into brine, and the mixture was extracted 3 times with ethyl acetate. The combined organic extracts were washed with brine, dried over MgS04, filtered and concentrated. The crude residue obtained was purified by column chromatography (Isco, 8g cartridge) eluting with a gradient of ethyl acetate in hexanes (from 0 to 50%>) to give the pure title compound (0.825 g, 18%). LC (Method A): 1.601 min. LCMS (APCI): calcd for C6H71N2S [M+H]+ m/z 283.92, found 283.9. 1H NMR (CDCl3, 400 MHz) δ ppm: 1.45 (t, J= 7.0 Hz, 3H), 4.46 (q, J= 7.0 Hz, 2H), 8.95 (s, 1H).
With tert.-butylnitrite; In tetrahydrofuran; at 20 - 50℃; for 2.0h;
Dissolve ethyl 2-amino-5-iodo-l,3-thiazole-4-carboxylate (3.53 g, 11.8 mmol) in dry THF (60 mL). Heat the solution to 500C. Add a solution of t-butyl nitrite (1.87 g, 18.1 mmol) in dry THF (12 mL) dropwise. Stir the mixture at 500C for 1 hour. Cool to room temperature and stir one additional hour.Add water (100 mL) and extract with EtOAc (2 x 100 mL). Combine organic extracts and extract with saturated NaHCO3 (aq) (100 ml) and brine (100 mL). Dry the organic layer over Na2SO4 and evaporate under reduced pressure. Purify the residue by chromatography on silica gel eluting with EtOAc/hexanes (1 :2) to yield the title compound. LC/MS (MH+) 283.95.
With tert.-butylnitrite; In N,N-dimethyl-formamide; at 0 - 20℃; for 0.5h;
b) 4-Ethoxycarbonyl-5-iodothiazole A solution of 10.68 g of 2-amino-4-ethoxycarbonyl-5-iodothiazole in 140 ml of DMF was cooled in ice under an argon atmosphere. t-Butylnitrite (6.15 ml) was added to the cooled solution, and the mixture was stirred at room temperature for 30 min. The reaction solution was poured into brine, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, followed by washing three times with brine. The organic layer was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1 to 3:1) to give 5.08 g of 4-ethoxycarbonyl-5-iodothiazole. NMR (CDCl3) δ: 1.45 (3H, t, J=7.2 Hz), 4.46 (2H, q, J=7.2 Hz), 8.94 (1H, s)
With zinc(II) chloride;tris-(dibenzylideneacetone)dipalladium(0); trifuran-2-yl-phosphane; In 1-methyl-pyrrolidin-2-one; at 20℃; for 2.5h;
Example 20; 2-Amino-4-carbamoyl-5-((Z)-2-tritylthioethen-1-yl)thiazole; a) 2-Amino-4-ethoxycarbonyl-5-ethynylthiazole; 2-Amino-4-ethoxycarbonyl-5-iodothiazole (1.40 g) prepared in step a) in Example 1 was dissolved in 20 ml of N-methyl-2-pyrrolidinone. tri-n-butylethynyltin (1.63 ml), 127 mg of tri(2-furyl)phosphine, 127 mg of tris(dibenzylideneacetone)dipalladium(0), and 1.27 g of zinc chloride were added to the solution under an argon atmosphere, and the mixture was stirred at room temperature for 2.5 hr. Brine and ethyl acetate were added to the reaction solution. The insolubles were removed by filtration through Celite, and the filtrate was extracted twice with ethyl acetate. The organic layers were combined, were washed with brine, were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1) to give 597 mg of 2-amino-4-ethoxycarbonyl-5-ethynylthiazole. NMR (CDCl3) δ: 1.39 (3H, t, J=6.9 Hz), 3.67 (1H, s), 4.39 (2H, q, J=6.9 Hz), 5.55 (2H, br s)
ethyl 2-chloro-5-iodothiazole-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
With tert.-butylnitrite; copper(l) chloride; In acetonitrile; at 80℃; for 2.0h;
A solution of <strong>[860646-12-4]ethyl 2-amino-5-iodothiazole-4-carboxylate</strong> (3 g, 10.067 mmol, 1.00 equiv), tert-butyl nitrite (1.24 g, 12.080 mmol, 1.20 equiv), cuprous chloride (1.19 g, 12.080 mmol, 1.20 equiv) in acetonitrile (50 mL) was stirred for 2 h at 80 C. The resulting solution was concentrated under vacuum and the residue was purified by a silica gel column chromatography eluted with dichloromethane/methanol (40:1) to give the title compound (1.8 g, 56%) as a white solid. LC-MS (ES, m/z): 318 [M+H]+.
ethyl 2-chloro-5-iodothiazole-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
25%
With tert.-butylnitrite; copper dichloride; In acetonitrile; at 80℃; for 0.333333h;Schlenk technique; Inert atmosphere;
In an inert Schlenk flask equipped with magnetic stirring bar ethyl 2-amino-5-iodothiazole-4- carboxylate (1.0 eq., 1.69 mmol, 505 mg) and CuCI2 (1.2 eq., 2.03 mmol, 271 mg) were dissolved in 8 mL MeCN anhydrous. The reaction mixture was heated to 80 C and fBuONO (1.2 eq. 2.03 mmol, 270 mI_) were added dropwise over 5 min. The reaction was stirred for another 15 min. When full conversion could be observed via TLC, the solvent was removed under reduced pressure. The residue was taken up in DCM (50 mL) and washed with water (5 x 200 H20). The organic phase was dried over Na2SC>4, filtered and the solvent was removed under reduced pressure. The crude product was purified via column chromatography (100 mL Si02, eluent CH/EA 12:1 ).Yield: 132 mg (416 pmoi, 25 %) light yellow solidC6H5CIIN02S [317.53]m.p.: 81 CRf: 0.88 (DCM/MeOH 30:1 )1H-NMR (300 MHz, CDCh): d (ppm) 4.44 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H).13C-NMR (75.5 MHz, CDC ): d (ppm) 160.5, 156.8, 146.6, 80.1 , 62.3, 14.4.
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