* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
for 0.0833333 h; Microwave irradiation; Green chemistry
CPAT was synthesized (Reaction 1) [22] by reacting 2'-chloroacetophenone (0.05 mol), iodine (0.1 mol) and thiourea (0.1 mol). They were mixed well with mortar-pestle and placed in small conical flask at room temperature. The mixture was then exposed to microwave irradiations for 5 min with 30 s pause at 180 W. Then 100 ml distilled water was added to the mixture and heated in microwave for 5–6 min at 270 W with 1 min pause till the precipitate dissolve. Filter the yellow solution and alkaline it with ammonia solution. Separate out the product and recrystallize with ethyl alcohol followed by diethyl ether and dried under reduced pressure.
66%
at 100℃; for 8 h;
General procedure: A mixture of thiourea (50 mmol), the corresponding acetophenone (25 mmol) and iodine (25 mmol) is stirred at 100 °C for 8 h.Then the reaction mixture is cooled, extracted with diethyl ether toremove excess of acetophenone, and then washed with aqueous sodium thiosulfate to remove excess iodine and later with cold water. The crude product is dissolved in hot water, filtered to remove sulphone, and the filtrate is basified with aqueous Na2CO3to yield the corresponding 2-amino-4-(substituted-phenyl)-1,3-thiazole. The crude product is purified by recrystallization from alcohol.
Reference：
[1] Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2013, vol. 115, p. 393 - 398
[2] Chemical and Pharmaceutical Bulletin, 2007, vol. 55, # 7, p. 1014 - 1017
[3] Journal of Heterocyclic Chemistry, 2002, vol. 39, # 6, p. 1133 - 1138
[4] European Journal of Medicinal Chemistry, 2013, vol. 66, p. 305 - 313
[5] Arzneimittel-Forschung/Drug Research, 1986, vol. 36, # 9, p. 1391 - 1393
[6] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 2, p. 692 - 702
[7] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 23, p. 5428 - 5431
[8] Chemical Biology and Drug Design, 2017, vol. 90, # 5, p. 778 - 790
[9] Chemical Biology and Drug Design, 2018, vol. 91, # 3, p. 728 - 734
2
[ 673477-11-7 ]
[ 21344-90-1 ]
Yield
Reaction Conditions
Operation in experiment
93%
With sodium carbonate In water; ethyl acetate
Thiourea (2.1 g, 27.45 mmol) was added to a solution 2-bromo-l-(2- chlorophenyl)ethanone (7 g, 27.45 mmol) in ethanol (10 mL) and reaction mixture was stirred at RT for 18h. The solvent was evaporated and refluxed for 5 minutes in DCM. Suspension was filtered to yield 7.84 g of 4-(2-chlorophenyl)thiazol-2- amine hydrobromide as a white powder. This powder was stirred in a mixture of aq. sat. Na2CO3 and AcOEt. Phases are separated and organic layer dried overMgSO4, concentrated in vacuo to yield title compound as a yellow oil which solidifies spontaneously. Y: 5.37 g (93percent), P=100percent, rt=2.84 mn (gradient A),(M+H)+ = 211.
General procedure: The crude 2-bromo-1-(2-chlorophenyl)ethanone (0.64 mL, 4.28 mmol) was dissolved in anhydrous ethanol (10 mL) and treated with thiourea (344 mg, 4.51 mmol). After heating at reflux for 2 h, the reaction mixture was cooled to room temperature, with a yellow precipitation. The solid obtained was filtered, washed with water and ethanol and vacuum dried to afford 4b as a yellow solid (884 mg, 98.0percent). 1H NMR (CDCl3, 400 MHz): δ 7.12 (s, 1H), 7.46-7.55 (m, 2H), 7.62 (s, 1H), 7.63 (d, 1H, J = 1.2 Hz), 8.94 (s, 1H), 9.15 (s, 1H).
Reference：
[1] European Journal of Medicinal Chemistry, 2012, vol. 52, p. 70 - 81
[2] Journal of the Chinese Chemical Society, 2017, vol. 64, # 12, p. 1408 - 1416
4
[ 2142-68-9 ]
[ 21344-90-1 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2012, vol. 52, p. 70 - 81
5
[ 577-16-2 ]
[ 21344-90-1 ]
Reference：
[1] Journal of the Chinese Chemical Society, 2017, vol. 64, # 12, p. 1408 - 1416
With iodine; for 0.0833333h;Microwave irradiation; Green chemistry;
CPAT was synthesized (Reaction 1) [22] by reacting 2'-chloroacetophenone (0.05 mol), iodine (0.1 mol) and thiourea (0.1 mol). They were mixed well with mortar-pestle and placed in small conical flask at room temperature. The mixture was then exposed to microwave irradiations for 5 min with 30 s pause at 180 W. Then 100 ml distilled water was added to the mixture and heated in microwave for 5?6 min at 270 W with 1 min pause till the precipitate dissolve. Filter the yellow solution and alkaline it with ammonia solution. Separate out the product and recrystallize with ethyl alcohol followed by diethyl ether and dried under reduced pressure.
66%
With iodine; at 100℃; for 8h;
General procedure: A mixture of thiourea (50 mmol), the corresponding acetophenone (25 mmol) and iodine (25 mmol) is stirred at 100 °C for 8 h.Then the reaction mixture is cooled, extracted with diethyl ether toremove excess of acetophenone, and then washed with aqueous sodium thiosulfate to remove excess iodine and later with cold water. The crude product is dissolved in hot water, filtered to remove sulphone, and the filtrate is basified with aqueous Na2CO3to yield the corresponding 2-amino-4-(substituted-phenyl)-1,3-thiazole. The crude product is purified by recrystallization from alcohol.
With iodine; at 100℃; for 8h;
General procedure: A mixture of thiourea (7, 50 mmol), the corresponding acetophenone (6, 25 mmol) and iodine(25 mmol) is stirred at 100 °C for 8 h. Then the reaction mixture is cooled, extracted with diethylether to remove excess of acetophenone, and then washed with aqueous sodium thiosulfate to remove excess iodine and later with cold water. The crude product is dissolved in hot water, filtered to remove sulphone, and the filtrate is basified with aqueous Na2CO3 to yield the corresponding 2-amino-4-(substituted-phenyl)-1,3-thiazole (5). The crude product is purified by recrystallization from alcohol. The synthesis and spectral data of compounds 5a-i have been reported by us earlier [2]. The data in respect of compounds 5j-l is described here.
295A N-[4-(2-chlorophenyl)-1,3-thiazol-2-yl][1,1'-biphenyl]-4-sulfonamide The title compound was prepared from <strong>[21344-90-1]4-(2-chlorophenyl)-1,3-thiazol-2-amine</strong> and 4-phenylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (31.8 mg) with purity >90percent. MS (pos) m/z 427.1.
4,5-Dichloro-N-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-2-thiophenesulfonamide The title compound was prepared from <strong>[21344-90-1]4-(2-chlorophenyl)-1,3-thiazol-2-amine</strong> (57 mg) and 2,3-dichlorothiophene-5-sulfonyl chloride (68 mg) as described in the synthetic METHOD B to give a white solid (56.6 mg) with purity >90percent: MS (pos) ml/z 425.3, 427.3; HRMS m/z 423.8737 (calc. of monoisotopic mass for C13H7Cl3N2O2S3 gives 423.8735).
276A N-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-4-propylbenzenesulfonamide The title compound was prepared from <strong>[21344-90-1]4-(2-chlorophenyl)-1,3-thiazol-2-amine</strong> and 4-n-propylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (30.9 mg) with purity >90percent. MS (pos) m/z 393.1.
2,3,4-Trichloro-N-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]benzenesulfonamide The title-compound was prepared from <strong>[21344-90-1]4-(2-chlorophenyl)-1,3-thiazol-2-amine</strong> (57 mg) and 2,3,4-trichlorobenzenesulfonyl chloride (76 mg) as described in the synthetic METHOD B to give a white solid (64.8 mg) with purity >90percent: MS (pos) m/z 453.3, 455.3, 457.2.
282A 3-Chloro-N-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-2-methylbenzenesulfonamide The title compound was prepared from <strong>[21344-90-1]4-(2-chlorophenyl)-1,3-thiazol-2-amine</strong> and 3-chloro-2-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (45.3 mg) with purity >90percent: MS (pos) m/z 399.1, 401.1; HRMS m/z 397.9711 (calc. of monoisotopic mass for C16H12Cl2N2O2S2 gives 397.9117).
289A 2,4,6-Trichloro-N-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]benzenesulfonamide The title compound was prepared from <strong>[21344-90-1]4-(2-chlorophenyl)-1,3-thiazol-2-amine</strong> and 2,4,6-trichlorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (38.7 mg) with purity >90percent. MS (pos) m/z 453.0, 455.0, 457.0.
2,4-dichloro-6-methylbenzene-1-sulfonyl chloride[ No CAS ]
[ 21344-90-1 ]
[ 376349-63-2 ]
Yield
Reaction Conditions
Operation in experiment
2,4-Dichloro-N-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-6-methylbenzenesulfonamide The title compound was prepared from <strong>[21344-90-1]4-(2-chlorophenyl)-1,3-thiazol-2-amine</strong> and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (40.3 mg) with purity >90%. MS (pos) m/z 435.0, 437.0.
3-Bromo-5-chloro-N-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-2-thiophenesulfonamide The title compound was prepared from <strong>[21344-90-1]4-(2-chlorophenyl)-1,3-thiazol-2-amine</strong> (57 mg) and 3-bromo-5-chlorothiophene-2-sulfonyl chloride (80 mg) as described in the synthetic METHOD B to give a white solid (43.7 mg) with purity >90percent: MS (pos) m/z 469.2, 471.2, 473.2.
To a solution of (R)-2-benzyl-4-tert-butoxy-4-oxobutanoic acid Ib (1.21 mmol, 320 mg) in anhydrous DMF (5mL) was added HATU (1.33mmol, 505mg). After 5 min was added 4-(2-chlorophenyl)thiazol-2-amine 2a (1.33 mmol, 279 mg) and DIEA (1.815 mmol, 300 muL). Reaction mixture was stirred at RT for 4 days. TLC (cyclohexane/AcOEt=8/2) indicated reaction was complete. Reaction mixture (rm) was diluted with AcOEt (2OmL) and washed with sat. aq. NaHCO3 (1OmL) and water (3x10 mL). The organic phase was dried over MgSO4 and evaporated. Crude was purified by flash chromatography (cyclohexane/ AcOEt= 9/1) (loading onto silica) to yield title compound as a yellow gum. Y: 370 mg (67percent), P>95percent, rt=5.24 mn (gradient A), (M+H)+ =457.1. ACN was also used instead of DMF
cis-2-methoxycarbonylcyclohex-4-ene-1-carboxylic acid[ No CAS ]
C18H17ClN2O3S[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide;
Example 98: compound n°98: cis-6-(4-(2-chlorophenyl)thiazol-2- ylcarbamoyl)cyclohex-3-enecarboxylic acid was synthesized from cis-3a,4,7,7a- tetrahydroisobenzofuran-l,3-dione and intermediate 2a as described in Scheme 14.
Thiourea (2.1 g, 27.45 mmol) was added to a solution 2-bromo-l-(2- chlorophenyl)ethanone (7 g, 27.45 mmol) in ethanol (10 mL) and reaction mixture was stirred at RT for 18h. The solvent was evaporated and refluxed for 5 minutes in DCM. Suspension was filtered to yield 7.84 g of 4-(2-chlorophenyl)thiazol-2- amine hydrobromide as a white powder. This powder was stirred in a mixture of aq. sat. Na2CO3 and AcOEt. Phases are separated and organic layer dried overMgSO4, concentrated in vacuo to yield title compound as a yellow oil which solidifies spontaneously. Y: 5.37 g (93percent), P=100percent, rt=2.84 mn (gradient A),(M+H)+ = 211.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In chloroform; for 24h;
General procedure: A mixture of <strong>[21344-90-1]4-(2-chlorophenyl)thiazol-2-amine</strong> (500 mg, 2.37 mmol), DMAP (13.27 mg, 0.12 mmol), EDCI (682.43 mg, 3.55 mmol) and 4-methoxy-4-oxobutanoic acid (470.3 mg, 3.55 mmol) in chloroform (20 mL) was stirred at room temperature for 24 h. The solution was filtered, and filtrate was washed with water. The organic phase was dried (Na2SO4) and evaporated to dryness. The residue was purified by flash chromatography over silica gel eluting with CH2Cl2:EtOAC (80:1) yielded 280 mg (36.3percent yield) to 5b.
General procedure: The crude 2-bromo-1-(2-chlorophenyl)ethanone (0.64 mL, 4.28 mmol) was dissolved in anhydrous ethanol (10 mL) and treated with thiourea (344 mg, 4.51 mmol). After heating at reflux for 2 h, the reaction mixture was cooled to room temperature, with a yellow precipitation. The solid obtained was filtered, washed with water and ethanol and vacuum dried to afford 4b as a yellow solid (884 mg, 98.0percent). 1H NMR (CDCl3, 400 MHz): delta 7.12 (s, 1H), 7.46-7.55 (m, 2H), 7.62 (s, 1H), 7.63 (d, 1H, J = 1.2 Hz), 8.94 (s, 1H), 9.15 (s, 1H).
General procedure: The general protocol followed by us in obtaining 2-(2,4-dioxo-1,3-thiazolidin-5-yl)acetamide compounds 4a-o is illustrated for the synthesis of N-(4-phenyl-1,3-thiazol-2-yl)-2-(2,4-dioxo-1,3-thiazolidin-5-yl)acetamide (4a) as an example. A solution of compound 1 (0.4 g, 2.55 mmol) in DCM (10 mL) is cooled to 0 °C and then charged with HOBT (0.36 g, 2.4 mmol), followed by HBTU (0.90 g, 2.4 mmol). The reaction mixture is stirred at 0 °C for 45 min. After that, a solution of 4-phenylthiazol-2-amine, 3a (0.29 g,1.70 mmol) and DIEA (0.8 mL, 5.1 mmol) in a mixture of DCM (5 mL) and DMF (2.5 mL) is added drop wise over 5 min. The reaction temperature is initially maintained at 0 °C for 1 h and later at RT for 10 h. Completion of reaction is evidenced by TLC analysis. After evaporating the DCM solvent on rotavapor, the reaction mixture is diluted with 40 mL of distilled water and extracted with (3 15 mL) of ethyl acetate. The combined organic layer is washed with saturated aqueous sodium bicarbonate solution (2 10 mL), followed by saturated aqueous sodium chloride solution (2 20 mL). After drying over anhydrous sodium sulfate, the organic layer is filtered and the filtrate is stripped off the solvent. The crude product thus obtained is purified by column chromatography over silica gel. The rest of the 2-(thiazolidinedion-5-yl)acetamide derivatives (4b-o) are prepared similarly by reacting 2,4-dioxo-1,3-thiazolidine-5-acetic acid (1) with the appropriate amine (3b-o).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;
General procedure: Iodine(18.80 g, 74.1 mmol) was added to 1-(2,5-dichlorophenyl)ethanone (10.67 ml,74.1 mmol) and thiourea (11.27 g, 148.0mmol). Thereaction mixture was stirred and heatedto 100 °C overnight. After cooling to room temperature, the reaction mixture was triturated with diethylether (about 50 mL) to remove any unreacted iodine and1-(2,5-dichlorophenyl)ethanone. Thesolid residue was put in cold distilled water (100 mL) and treated withammonium solution to pH 9-10. The precipitated thiazole was collected togive 4-(2,5-dichlorophenyl)-1,3-thiazol-2-amine (11.2 g, 62percentyield) as a yellow solid. MS(ES+) m/z 245.0, 247.0 (MH+).A solution of[4-(ethylsulfonyl)phenyl]acetic acid (0.239 g, 1.1 mmol), 4-(2,5-dichlorophenyl)-1,3-thiazol-2-amine(0.245 g, 1.0 mmol), EDC (0.230 g, 1.2 mmol) and HOBt (0.184 g, 1.2 mmol) in dichloromethane(DCM) (10 mL) was stirred at room temperature overnight. The mixture was pouredinto water, and extracted with DCM. The organic phase was washed with water andbrine, dried over anhydrous sodium sulfate, filtered and concentrated under reducedpressure to give the crude product. The crude was purified by mass directedautopreparation (MDAP) to afford N-[4-(2,5-dichlorophenyl)-1,3-thiazol-2-yl]-2-[4-(ethylsulfonyl)phenyl]acetamide(6a) (177 mg, 37percent yield) as a white solid.
3-(2-chlorophenyl)-6-phenylimidazo[2,1-b]thiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
In ethanol; at 100℃; under 12929.0 Torr;Sealed tube; Microwave irradiation;
General procedure: A mixture of 2 mmol each of the respective 4-(aryl)-1,3-thiazol-2-amine (5a-l) and 2-bromo-1-phenylethanone (6) in ethanol are taken in a 20 mL sealed pressure tube and subjected to microwave irradiation (CEM Discover, 180 W, 250 psi, 100 °C) for 5-6 min. The reaction mixture is cooled to room temperature and ethanol is evaporated under reduced pressure. The residue is suspended in water (5 mL) and a saturated aqueous solution of Na2CO3 is added dropwise under stirring to bring the pH of the medium to 8-9, before extracting the organics with 3 x15 mL portions of ethyl acetate. The organic phase is dried (anhydrous Na2SO4) and the solvent evaporated in vacuo. The crude product is purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to provide the corresponding 3-aryl-6-phenylimidazo[2,1-b]thiazole (4a-l) as solid.
4-(3-(4-(2-chlorophenyl)thiazol-2-ylamino)propoxy)benzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
23.1%
With potassium carbonate; In N,N-dimethyl-formamide; for 12h;Reflux;
General procedure: To a solution of 4-(3-bromopropoxy)benzaldehyde (200.00 mg, 0.82 mmol)and 4-phenylthiazol-2-amine (144.50 mg, 0.82 mmol) in DMF (15 mL),potassium carbonate (170.00 mg, 1.23 mmol) was added. The reaction mixturewas refluxed for 12 h. The reaction mixture was quenched with water,and extracted with toluene (20 mL*3). The combined organic layer waswashed with brine, dried with anhydrous sodium sulphate, concentratedunder vacuum, then purified by flash chromatography (petroleum ether:ethyl acetate = 3:1) to afford a colorless solid. Yield 32.3percent. The procedure described for the synthesis of compound 3a can also beapplied to the synthesis of compounds 3b-o.
3-(4-(4-(2-chlorophenyl)thiazol-2-ylamino)butoxy)-4-methoxybenzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30.6%
With potassium carbonate; In N,N-dimethyl-formamide; for 12h;Reflux;
General procedure: To a solution of 4-(4-bromobutoxy)benzaldehyde (400.00 mg, 1.56 mmol) and 4-phenylthiazol-2-amine (275.00 mg, 1.56 mmol) in DMF (15 mL), potassium carbonate (331.80 mg, 2.34 mmol) was added. The reaction mixture was refluxed for 12 h. The reaction mixture was quenched with water, and extracted with toluene (20 mL*3). The combined organic layer was washed with brine, dried with anhydrous sodium sulphate, concentrated under vacuum, then purified by flash chromatography (petroleum ether:ethyl acetate = 3:1) to afford a yellow oil.
tert-butyl 2-((4-(2-chlorophenyl)thiazol-2-yl)amino)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
29.2%
With caesium carbonate; In N,N-dimethyl-formamide; at 20 - 100℃; for 16h;
[0531] To a solution of <strong>[21344-90-1]4-(2-chlorophenyl)thiazol-2-amine</strong> (2.0 g, 9.5mmol) in DMF (80 mL) at rt was added tert-butyl 2-bromoacetate (2.78 g, 14.24 mmol) and Cs2CO3 (6.20 g, 19 mmol). The mixture was heated at 100°C for 16 hrs, cooled to rt, and the solvent was removed. The residue was diluted with water (50 mL) and extracted with EA (60 mL x 2). The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated providing the crude product, which was purified by chromatography on silica-gel eluted with petroleum ether/ EA (20/1 to 10/1) providing tert-butyl 2-((4-(2- chlorophenyl)thiazol-2-yl)amino)acetate (0.9 g, 29.2percent yield) as a yellow oil. MS (ESI) m/z 325.1[M+H]+.
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