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Structure of 72505-21-6 * Storage: {[proInfo.prStorage]}
* 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.
With sodium hydrogensulfide In ethanol at 60℃; for 3 h;
500 mg (2.92 mmol) of 4-trifluorobenzonitrile was reacted with 702 mg (8.7 mmol) of sodium hydrosulfide at 60°C for 3 hours, and ethanol as a solvent was distilled off. Ethylacetate was added and the resulting solution was washed with water. An organic layer was dried over anhydrous magnesium sulfate and solvent was distilled off, then the residue was purified by column chromatography to give 517 mg (yield: 95percent) of the title compound. Without further purification, the next procedure was conducted. Mass (EI) 152 (M++1)
73%
With hydrogenchloride; thioacetamide In DMF (N,N-dimethyl-formamide) at 20 - 95℃; for 42 h;
[4-TRIFLUOROMETHYL-THIOBENZAMIDE] A solution of [A,] a, a-trifluoro-p-tolunitrile (603.5 g, 3.53 mol) in dry DMF (2 L) under N2 [WAS HEATED AT 70XB0;C AND THIOACETAMIDE (505 G, 1.9 EQ. ) ADDED. THE REACTION MIXTURE] was treated with HCI gas for 15 minutes and was stirred at [95XB0;C] for 6 hours. This treatment was repeated 3 times and the mixture stirred at rt for 24 hours. After cooling to [0XB0;C,] water was added and the residue was extracted with diethyl ether (4 L). The organic layer was washed with water (3 L), dried over [NA2SO4] and evaporated. The brownish powder was washed with pentane (3 L) to give the title compound (530.3g, 2.59 mol) as a brown solid in 73percent yield ; GC/MS: [M+] [C8H6F3NS] 205
70%
With sodiumsulfide nonahydrate In N,N-dimethyl-formamide at 130℃; for 2.5 h;
General procedure: Benzonitrile 1a (1 mmol), Na2S*9H2O (1.2 mmol) and DMF (1 mL) were added into a 10 mL bottle. The reactor was placed in a heating magnetic stirrer at 130 °C. After 2.5 h, by adding about 3 mL H2O after the reaction to disperse the solid product, the reaction mixture was extracted with EtOAc (3 x 3 mL), and the mixture was purified by column chromatography.
Reference：
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 8, p. 3213 - 3222
[2] Patent: WO2005/40127, 2005, A1, . Location in patent: Page/Page column 100-101
[3] Journal of Fluorine Chemistry, 2006, vol. 127, # 1, p. 63 - 67
[4] Patent: WO2004/6922, 2004, A1, . Location in patent: Page/Page column 27; 28
[5] RSC Advances, 2018, vol. 8, # 1, p. 170 - 175
[6] Heterocycles, 2018, vol. 96, # 3, p. 509 - 517
[7] Collection of Czechoslovak Chemical Communications, 1988, vol. 53, # 11B, p. 2957 - 2961
[8] Patent: US6011048, 2000, A,
[9] Patent: US4788207, 1988, A,
[10] Patent: US4889867, 1989, A,
[11] European Journal of Inorganic Chemistry, 2015, vol. 2015, # 29, p. 4935 - 4945
[12] Patent: WO2004/785, 2003, A2, . Location in patent: Page 20
2
[ 455-18-5 ]
[ 62-55-5 ]
[ 72505-21-6 ]
Yield
Reaction Conditions
Operation in experiment
73%
With hydrogenchloride In DMF (N,N-dimethyl-formamide) at 20 - 95℃; for 30 h;
A solution of α,α,α-trifluoro-p-tolunitrile (603.5 g, 3.53 mol) in dry DMF (2 l) under N2 [was heated at 70C and the thioacetamide (505 g, 1.9 eq) was added. The reaction mixture was treated with HCl gas for 15 minutes and stirred at 95C] for 6 hours. This treatment was repeated 3 times and the mixture stirred at rt for 24 hours. After cooling at 0C, water was added and the residue extracted with diethyl ether (4 l). The organic layer was washed with water (3 l), dried over Na2SO4 and the solvent evaporated. The brownish powder was washed with pentane (3 l) to give the title compound (530.3g, 2.59 mol) as a brown solid in a 73percent yield; GC/MS: M+ C8H6F3NS 205
With sodium hydrogensulfide; In ethanol; at 60℃; for 3h;
500 mg (2.92 mmol) of 4-trifluorobenzonitrile was reacted with 702 mg (8.7 mmol) of sodium hydrosulfide at 60C for 3 hours, and ethanol as a solvent was distilled off. Ethylacetate was added and the resulting solution was washed with water. An organic layer was dried over anhydrous magnesium sulfate and solvent was distilled off, then the residue was purified by column chromatography to give 517 mg (yield: 95%) of the title compound. Without further purification, the next procedure was conducted. Mass (EI) 152 (M++1)
73%
With hydrogenchloride; thioacetamide; In DMF (N,N-dimethyl-formamide); at 20 - 95℃; for 42h;
[4-TRIFLUOROMETHYL-THIOBENZAMIDE] A solution of [A,] a, a-trifluoro-p-tolunitrile (603.5 g, 3.53 mol) in dry DMF (2 L) under N2 [WAS HEATED AT 70XB0;C AND THIOACETAMIDE (505 G, 1.9 EQ. ) ADDED. THE REACTION MIXTURE] was treated with HCI gas for 15 minutes and was stirred at [95XB0;C] for 6 hours. This treatment was repeated 3 times and the mixture stirred at rt for 24 hours. After cooling to [0XB0;C,] water was added and the residue was extracted with diethyl ether (4 L). The organic layer was washed with water (3 L), dried over [NA2SO4] and evaporated. The brownish powder was washed with pentane (3 L) to give the title compound (530.3g, 2.59 mol) as a brown solid in 73% yield ; GC/MS: [M+] [C8H6F3NS] 205
70%
With sodiumsulfide nonahydrate; In N,N-dimethyl-formamide; at 130℃; for 2.5h;
General procedure: Benzonitrile 1a (1 mmol), Na2S*9H2O (1.2 mmol) and DMF (1 mL) were added into a 10 mL bottle. The reactor was placed in a heating magnetic stirrer at 130 C. After 2.5 h, by adding about 3 mL H2O after the reaction to disperse the solid product, the reaction mixture was extracted with EtOAc (3 x 3 mL), and the mixture was purified by column chromatography.
With hydrogen sulfide; triethylamine; In pyridine;
Step A. 4-(Trifluoromethyl)thiobenzamide 4-(Trifluoromethyl)benzonitrile (3.42 g) was treated with triethylamine (2.12 g) and hydrogen sulfide in pyridine solution as described in Example 2, Step A. The crude product was triturated with hexane (150 mL) and collected to afford 3.80 g of yellow powder: mp 133-136 C.; 1 H NMR (400 MHz, CDCl3) delta 7.92 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H).
With triethylamine; In pyridine; hydrogenchloride;
Step A (4-Trifluoromethylphenyl)thiocarboxamide To a stirred solution of 25.0 grams (0.146 mole) of 4-(trifluoromethyl)benzonitrile in 190 ml of pyridine was added 14.8 grams (0.146 mole) of triethylamine. During a two hour period, hydrogen sulfide gas was bubbled into the reaction mixture. The reaction mixture was stirred under a dry nitrogen atmosphere for 15 minutes and then was poured into ice-water. The aqueous mixture was extracted with three portions of diethyl ether. The organic extracts were combined and washed in succession with 10% hydrochloric acid, water, and an aqueous, saturated sodium chloride solution. The washed extract was dried over anhydrous sodium sulfate and was filtered. The filtrate was evaporated under reduced pressure to yield 28.3 grams of (4-trifluoromethylphenyl)thiocarboxamide as a solid.
With triethylamine; In pyridine; hydrogenchloride;
Step A (4-Trifluoromethylphenyl)thiocarboxamide To a stirred solution of 25.0 grams (0.146 mole) of 4-(trifluoromethyl)benzonitrile in 190 ml of pyridine was added 14.8 grams (0.146 mole) of triethylamine. During a two hour period, hydrogen sulfide gas was bubbled into the reaction mixture. The reaction mixture was stirred under a dry nitrogen atmosphere for 15 minutes and then was poured into ice-water. The aqueous mixture was extracted with three portions of diethyl ether. The organic extracts were combined and washed in succession with 10% hydrochloric acid, water, and an aqueous, saturated sodium chloride solution. The washed extract was dried over anhydrous sodium sulfate and was filtered. The filtrate was evaporated under reduced pressure to yield 28.3 grams of (4-trifluoromethylphenyl)thiocarboxamide as a solid.
With thioacetamide; In DMF (N,N-dimethyl-formamide); at 70 - 95℃; for 30.15h;
-Trifluoromethyl-thiobenzamide A solution of oc, a, [A-TRIFLUORO-P-TOLUNITRILE] (603.5 g, 3.53 mol) in dry DMF (2 L) under N2 was heated at [70C] and the Thioacetamide (505 g, 1.9 eq. ) was added. The reaction mixture was treated with HCI gas before 15 minutes and was stirred at [95C] for 6 hours. This treatment was operated 3 times and the mixture was stirred at rt for 24 hours. After cooling at [0C,] water was added and the residue was extracted with diethyl ether (4*1 L). The organic layer was washed with water (3*1 L), dried over [NA2SO4] and then evaporated off. The brownish powder was washed with pentane (3 L) to give the title compound (530.3 g, 2.59 mol) as brown solid in a 73% yield. GC/MS: [M+ C8H6F3NS] 205
To a stirred solution of 4-trifluoromethylthiobenzamide (205 g, 10 mmol) in acetone (10 mL) was added ethyl bromopyruvate (1.95 g, 10 mmol) in acetone (10 mL) dropwise. The mixture was stirred under reflux for 3 h. After cooling to room temperature, the solution was concentrated and purified by column chromatography to give 1.9 g (63%) of cpd Q1 as a white solid: 1H NMR (300 MHz, CDCl3) delta 8.23 (s, 1H), 8.14 (d, J=8.4 Hz, 2H), 7.72 (d, J=8.4 Hz, 2H), 4.46 (q, J=7.1 Hz, 2H) 1.44(t, J=7.1 Hz, 3H); MS (ES) m/z: 302 (M+H+).
2-(4-[(4-[4-(4-methoxyphenyl)piperazin-1-yl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl)methyl]sulfanyl}phenoxy)-2-methylpropanoic acid[ No CAS ]
2-{4-[4-[4-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenylsulfanylmethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-phenoxy}-2-methyl-propionic acid ethyl ester[ No CAS ]
(S)-2-Amino-1-((S)-3-fluoro-pyrrolidin-1-yl)-2-[2-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-benzothiazol-6-yl]-ethanone; compound with trifluoro-acetic acid[ No CAS ]
ethyl 4-METHYL-2-[4-(TRIFLUOROMETHYL) PHENYL]-THIAZOLE-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95.6%
In tetrahydrofuran; at 20 - 80℃; for 12.8333h;
4- (Trifluoromethyl) thiobenzamide (20.5 g, 0.1 mol) was dissolved in tetrahydrofuran (300 [UN)] at room temperature, and then methyl [2-CHLOROACETOACETATE] (12.2 [UN,] 0.1 mol) was added slowly for about 20 minutes therein while stirring. After completion of addition, the mixture was stirred again at room temperature for 30 minutes, and then the mixture was heated and refluxed at 78 to 80 C for 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature. Subsequently, 50% aqueous solution of sodium hydroxide [(150 NE)] was added and stirred for 20 minutes. The resultant organic layer was separated by extraction with ethyl acetate, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to thereby yield 28.8 g of the title compound (yield: 95. 6%). 'H-NMR (300 MHz, [CDCI3)] : 8.01 (d, 2H, [J =] 8.4 Hz), 7.64 (d, 2H, [J= 8. 3] Hz), 3. 84 [(S, 3H),] 2. [73] (s, [3H).]
95.6%
4-(Trifluoromethyl)thiobenzamide (20.5 g, 0.1 mol) was dissolved in tetrahydrofuran (300 mi) at room temperature, and then methyl 2-chloroacetoacetate (12.2 mi, 0.1 mol, 1.0 eq.) was added slowly for about 20 minutes therein while stirring. After completion of addition, the mixture was stirred again at room temperature for 30 minutes, and then the mixture was heated and refluxed at 75 to 80 C for 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature. Subsequently, 50% aqueous solution of sodium hydroxide (150 mi) was added and stirred for 20 minutes. The resultant organic layer was separated by extraction with brine and ethyl acetate, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to thereby yield 28.8 g of the title compound (yield: 95.6%).
In ethanol; for 24h;Inert atmosphere; Reflux;
General procedure: Appropriate thiobenzamides or thioacetamides (1 mmol) and alpha-chloroacetoacetate 3 (150 mg, 1.2 mmol) were added to absolute ethanol (15 mL). The reaction mixture was heated at reflux for 24 h. After removal of solvent under reduced pressure, the residue was purified by silica gel chromatography using hexanes-ethyl acetate (7:3) to provide the desired compounds.
2-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-benzothiazole-4-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30.6%
In ethanol;Heating / reflux;
4-trifluoromethyl-thiobenzamide (48.7 mmol, 10 g) is dissolved in denatured ethanol (200 mL) and 3-bromo-2-oxo- cyclohexanecarboxylic acid ethyl ester (12.4 g, 50 mmol) is added, then the reaction is heated under nitrogen to reflux. The reaction is monitored by TLC and HPLC to complete consumption of the thioamide, and then allowed to cool. The cooled reaction is concentrated and diluted with 250 mL ethyl acetate. The residue is washed with 100 mL saturated sodium bicarbonate followed by water and brine. The organic layer is dried over anhydrous sodium sulfate, then concentrated and purified by column chromatrography. The fractions that contained pure product are concentrated to yield 5.06 g (30. 6%) ester as a solid.
4-(Trifluoromethyl)benzene-1-carbothiamide (5.03 g, 24.5 mmol) was dissolved in 30 ml of EtOH and treated with 1.05 eq of 3-chloro-2,4-pentanedione (3.46 g, 25.7 mmol); the mixture was kept at 55-60 C. over night. Reducing the total volume to ~1/4 and cooling to 0 C. triggered crystallization. Filtration and washing with a tiny amount of cold EtOH afforded 5.49 g of 1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanone (79%) as yellow crystals of, MS: 285 (M+), MP: 89-90 C.
With hydrogenchloride; In DMF (N,N-dimethyl-formamide); at 20 - 95℃; for 30h;
A solution of alpha,alpha,alpha-trifluoro-p-tolunitrile (603.5 g, 3.53 mol) in dry DMF (2 l) under N2 [was heated at 70C and the thioacetamide (505 g, 1.9 eq) was added. The reaction mixture was treated with HCl gas for 15 minutes and stirred at 95C] for 6 hours. This treatment was repeated 3 times and the mixture stirred at rt for 24 hours. After cooling at 0C, water was added and the residue extracted with diethyl ether (4 l). The organic layer was washed with water (3 l), dried over Na2SO4 and the solvent evaporated. The brownish powder was washed with pentane (3 l) to give the title compound (530.3g, 2.59 mol) as a brown solid in a 73% yield; GC/MS: M+ C8H6F3NS 205
Intermediate Example P; EMI70.1Ethyl 4- (1-methylethyl)-2- [4- (trifluoromethyl) phenyl]-1, 3-thiazole-5-carboxylate(XI-5a) Ethyl isobutyrylacetate(XI-3a) (3.006 g, 19.0mmol) was dissolved in chloroform (20 mL). Sulfuryl chloride (1.70 mL, 21.2mmol) was added and the solution was stirred at RT for 18 hours, then was concentrated. The residue was dissolved in ethanol (50 mL).4- (Trifluoromethyl) benzenethioamide (4.234 g, 20.6mmol) was added and the solution was heated to reflux for 24 hours. The mixture was cooled to RT and filtered. The solid was washed with cold ethanol and dried to provide the title product (2.68 g, 32%) as a pale yellowsolid.'H NMR (400 MHz,CDCI3)6 8.09 (d, J= 8.1 Hz, 2H), 7.69 (d, J= 8.1 Hz, 2H), 4.35 (q, J= 7.1 Hz, 2H), 3.99 (qu, J= 6.8 Hz,1H), 1.39 (t, J= 7.1 Hz,3H), 1.35 (d, J= 6.8 Hz, 6H).
Example 1; Intermediate: r5-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yll -acetic acid ethyl ester; To a solution of 4-trifluoromethyl-benzene-thioamide (1.845g, 9mmol) in ethanol (15 mL, 200 proof) add ethyl-4-bromo-3-oxo-pentanoate (2.07g, 9 mmol). Seal this solution warm the solution to 170C in a Personal ChemistryNo. microwave oven and stir at this temperature for 20 min. Cool the resulting solution to room temperature, concentrate under reduced pressure and purify the residue by flash chromatography (elute with 30% ethyl acetate / 10% dichloromethane in heptane ) and obtain the title compound as a white solid (1.4g). MS (ESI) m/z 330 (M+H) ; H1 NMR (CDC13) No. 1.87 (bs, 1H), 2.49 (s, 3H), 4.86 (s, 2H), 7.67 (d, J = 8Hz, 2H), 8.02 (d, J = 8Hz, 2H).
Example 18; Intermediate: 4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5- carboxylic acid methyl ester; To a solution of 3-oxo-heptanoic acid methyl ester (5.0 g, 31.6 mmol) in dry dichloromethane (80 mL) add sulfurylchloride (2.82 mL). Stir the reaction mixture at room temperature for 30 minutes then add water (20 mL) and the reaction mixture extracted five times with portions of 30 mL of dichloromethane. Wash the combined organic extracts with water, saturated aqueous solution of NaHC03 and brine and then dry over MgS04. Remove the solvent under reduced pressure to give 2-chloro-3-oxo-heptanoic acid methyl ester (6.0 g), which was used in the next step without further purification. To a solution of 2-chloro-3-oxo- heptanoic acid methyl ester (6.0 g, 31.1 mmol) in ethanol (50 mL) add 4-(trifluoromethyl) thiobenzamide (6.4 g, 31.2 mmol). Heat the reaction mixture to reflux overnight. Remove the solvent under reduced pressure and purify the residue by chromatography on silica gel (eluting with a gradient of n-heptane:ethyl acetate (100:1 to 60:1)) to give 4-butyl-2-(4- trifluoromethyl-phenyl) -thiazol-5- carboxylic acid methyl ester (7.4 g) as a yellow oil. MS (ESI) m/z 344 (M+H).
In ethanol;Heating / reflux;
4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5- carboxylic acid methyl ester; 5.0 g 3-Oxo-heptanoic acid methyl ester were dissolved in 80 ml dry dichloromethane and 2.82 ml sulfurylchloride were added. The reaction mixture was stirred at room temperature for 30 minutes. 20 ml of water were added and the reaction mixture extracted five times with portions of 30 ml of dichloromethane. The combined organic extracts were washed with water and saturated NaHCO3 solution and brine and dried over MgSO4. The solvent was removed under reduced pressure to obtain 6.0 g 2- Chloro-3-oxo-heptanoic acid methyl ester as raw material. This material was used without further purification. 6.0 g 2-Chloro-3-oxo-heptanoic acid methyl ester were dissolved in 50 ml ethanol and 6.4 g 4-(Trifluoromethyl)thiobenzamide were added. The reaction mixture was heated under reflux overnight. The solvent was removed under reduced pressure and the residue purified by chromatography with the eluent n- heptane:ethyl acetate = 100:1 => 60:1. This gives 7.4 g 4-Butyl-2-(4-trifluoromethyl- phenyl)-thiazol-5- carboxylic acid methyl ester as yellow oil. C16H16F3NO2S (343.37), MS(ESI): 344.1 (M+H+), Rf(n-heptane: ethyl acetate = 4:1 ) = 0.62.
In ethanol; for 12h;Heating / reflux;
5.0 g of Methyl 3-oxoheptanoate were dissolved in 80 ml dry dichloromethane. 2.82 ml Sulfurylchloride was added and the reaction mixture was stirred at room temperature for thirty minutes. Water was added and the mixture was extracted five times with dichloromethane (30 ml). The combined organic extracts were washed with water and brine and dried over MgSO4. The solvent was evaporated in vacuo to obtain 6.0 g 2-Chloro-3-oxo-heptanoic acid methyl ester as crude material. 6.0g 2-Chloro-3-oxo-heptanoic acid methyl ester was dissolved in 50 ml ethanol and 6.4 g 4-(Trifluoromethyl)thiobenzamide was added. The mixture was heated under reflux overnight. The cooled reaction mixture was evaporated in vacuo and column chromatography (n-heptane:ethyl acetate = 100:1 => 60:1) of the residue gave 7.4 g 4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid methyl ester as yellow oil. C16H16F3NO2S (343.37), MS(ESI): 344.1 (M+H+), Rf(n-heptane:ethyl acetate = 4:1) = 0.62.
EXAMPLE 140 2-Phenyl-5(4-carboxyphenyl)thiazole A mixture of 4-trifluoromethylbenzamide (79 mM) and Lawesson's reagent (39 mM) in toluene (200 mL) was heated at reflux for 4 hours under N2. The reaction mixture was cooled and the resulting precipitate was isolated by filtration to give 4-trifluoromethylthiobenzamide as a solid: mp 125 C. (The following general procedure was used to synthesize the various substituted thiobenzamides (Tetrahedron 35,2433, (1979)):
6-cyclobutyl-2-[4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro-4H-[1,3]thiazolo[4,5-d]azepine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol; for 18h;Heating / reflux;
A crude mixture of 5-bromo-1-cyclobutylhexahydro-4H-azepin-4-one (may be prepared as described in Description 2) (1.2mmol) and <strong>[72505-21-6]4-(trifluoromethyl)benzenecarbothioamide</strong> (0.38g, 1.85mmol) in ethanol was heated under reflux for 18 hours. The reaction was then cooled, applied to an ion exchange cartridge (SCX) and washed with methanol and then a 2M ammonia in methanol solution. The basic fractions were then reduced and the residue purified using reverse phase chromatography to afford the product (E1); MS (ES+) m/e 353 [M+H]+.
The solution was washed in turn with one portion of water, two 150 ml portions of aqueous 10% hydrochloric acid solution and one portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate/magnesium carbonate and filtered. The filtrate was concentrated under reduced pressure, yielding 76.9 grams of 4-trifluoromethylbenzthioamide. The nmr spectrum was consistent with the proposed structure.
82
[ 7252-83-7 ]
[ 72505-21-6 ]
[ 119514-24-8 ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In ethanol; hexane; ethyl acetate;
Step B 2-(4-Trifluoromethylphenyl)thiazole A stirred solution of 5.0 grams (0.024 mole) of <strong>[72505-21-6]4-trifluoromethylbenzthioamide</strong>, 4.4 grams (0.026 mole) of bromoacetaldehyde dimethyl acetal, and 4 drops of concentrated hydrochloric acid in 50 ml of ethanol was heated at reflux for 18 hours. After this time the reaction mixture was subjected to column chromatography on silica gel. Elution was accomplished using 20% ethyl acetate in hexane. The appropriate fractions were combined and concentrated under reduced pressure, yielding 3.3 grams of 2-(4-trifluoromethylphenyl)thiazole. The nmr spectrum was consistent with the proposed structure.
In a manner similar to Step B of Example 1, the reaction of 10.0 grams (0.0487 mole) of (4-trifluoromethylphenyl)thiocarboxamide, 125 ml of ethanol, 8.35 grams (0.0490 mole) of bromoacetaldehyde, and 2 ml of concentrated hydrochloric acid produced 5.5 grams of 2-(4-trifluoromethylphenyl)thiazole as a solid.
In a manner similar to Step B of Example 1, the reaction of 10.0 grams (0.0487 mole) of (4-trifluoromethylphenyl)thiocarboxamide, 125 ml of ethanol, 8.35 grams (0.0490 mole) of bromoacetaldehyde, and 2 ml of concentrated hydrochloric acid produced 5.5 grams of 2-(4-trifluoromethylphenyl)thiazole as a solid.
To a solution of 1.15 g of 6-benzyloxy-2-chloro-3-oxo-hexanoic acid ethyl ester in 10 ml of ethanol was added 0.932 g of <strong>[72505-21-6]4-(trifluoromethyl)thiobenzamide</strong>. The reaction mixture was refluxed overnight. The solvent was removed under reduced pressure. The resulting residue was taken into ethyl acetate, washed with water. The aqueous layer was separated and extracted wih ethyl acetate. The combined organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (heptane 90/ethyl acetate 10) to give 1.15 g of 4-(3-benzyloxy-propyl)-2- (4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester as a colorless liquid. C23H22F3NO3S (449.49), MS(ESI): 450 (M+H+).
Intermediate 2. 2-(4-Trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine.[0055] Step A: 3-Bromo-pperidin-4-one hydrobromide 1 (1.5 g, 5.79 mmol) and4-trifluoromethyl-thiobenzamide (0.79 g, 3.96 mmol) are dissolved in DMF (2 mL) and heated to 100C for 8 h. After cooling to room temperature the mixture is diluted with EtOAc and extracted with water. The aqueous layer containing the protonated product is basified with aqueous saturated bicarbonate and extracted with DCM twice. The organic layers are combined and concentrated to afford 2 (0.45 g, 40%) as a reddish solid: 1H-NMR (400MHz5 CDCl3) delta = 8.01 (d, J = 8.1 Hz, 2H), 7.67 (d, J = 8.1 Hz, 2H), 4.12 (t, J = 1.7 Hz, 2H), 3.24 (t, J = 5.8 Hz, 2H), 2.91 (m, 2H). MS calcd. for C13Hi2F3N2S (M+H"1") 285.1, found 285.1.
Ethyl 4-[{tert-butyl(diphenyl)silyl]oxy}methyl)-2-(4-{trifluoromethyl}phenyl)-1,3-thiazole-5-carboxylate To a 500 ml round-bottom flask equipped with a magnetic stir-bar was mixed ethyl 4-[tert-butyl(diphenyl)silyl]oxy}2-chloro-3-oxobutanoate (20.4 g, 52.88 mmoles, 1 eq), 4-trifluoromethylthiobenzamide (12.29, 59.5 mmoles, 1.1 eq), 1,2-dichloroethane (150 ml, 0.44M) and H2O (3 ml). This mixture was refluxed for 12 hrs. After cooling to room temperature, the reaction mixture was diluted with CH2Cl2 (100 ml) and washed with sat. NaHCO3. Once the phases were separated, the organic phase was washed with water, brine and dried over Na2SO4. This was then filtered, concentrated in vacuo and purified via silica gel chromatography (5% EtOAc/Hexanes to 20% EtOAc/Hexanes) to yield 20.3 g (76%) of the titled compound. 1H NMR (CDCl3) 400 MHz delta 8.07 (d, 2H, J=8.37 Hz), 7.76 (m, 4H), 7.71 (d, 2H, J=8.37 Hz), 7.37 (m, 6H), 5.24 (s, 2H), 4.26 (q, 2H, J=7.18 Hz), 1.29 (t, 3H, J=7.18 Hz), 1.11 (s, 9H),
3-methyl-3-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-butyric acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In toluene; at 80℃; for 2h;
500 mg (1.99 mmol) of 5-bromo-3,3-dimethyl-4-oxo-pentanoic acid ethyl ester, 408.6 mg (1.99 mmol) of 4-trifluoromethyl-thiobenzamide and 403 mg (3.98 mmol) of triethylamine in 10 ml of toluene were stirred at 80 C for 2 h. After evaporation, water and dichloromethane were added, the organic phase was separated, washed with water, dried, and evaporated. The product was purified by chromatography (silica gel, n-heptane/ethyl acetate 8:1). Yield: 498.5 mg. MS: m/e = 358 (M+H)+
[ 4-METHYL-2- (4-TRIFLUOROMETHVL-PHENVL)-THIAZOLE-5-CARBOXYLIC ACID] To a solution of intermediate 4 (20 g, 0.1 mol) in EtOH (300 mL) was added the 2-Chloro-3-oxo-butyric acid ethyl ester (14 mL, [1EQ.).] The mixture was stirred to reflux overnight to give the [4-METHYL-2- (4-TRIFLUOROMETHYL-PHENYL)-THIAZOLE-5-CARBOXYLIC] acid ethyl ester and a 1 N [NAOH] solution (120 mL, 1.2eq) was added and heating for 3 hours. After evaporation the residue was diluted with water (50 mL) and 1 N HCI solution (120 mL). The precipitate was filtered off to give the title compound (26 g, 0.099 mol) as powder in a quantitative yield. ['H] NMR (300 MHz, [CDCI3)] [8] : 8.29 (d, 2H), 7.97 (d, 2H), 2.80 (s, 3H).
2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
To a solution of NaOEt (21% in EtOH, 215 ml, 584 mmol) were added ethyl formate (46.97 ml, 584 mmol) and then, with cooling (max. 28 C.), chloro acetic acid ethyl ester in Et2O (200 ml). The mixture was stirred at RT for 20 h and filtered after adding Et2O (200 ml). The resulting solid was dissolved in EtOH (400 ml) and after addition of 4-(trifluoromethyl)benzene-1-carbothioamide (11.98 g, 58.4 mmol) stirring to reflux was accomplished for 20 h. After filtration, the EtOH was removed under reduced pressure and extracted with CH2Cl2 (3x)/H2O. The organic phases were washed with H2O, dried (Na2SO4) and evaporated to give crude compound which was crystallized (Et2O/n-pentane) to give 12.43 g (71%) of 2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester as off-white crystals, MS: 301 (M+), MP: 98-110 C.
With methyl 2-bromo-2-cyanoacetate; In methanol; at 23℃; for 0.0166667h;
General procedure: Thioamide (1 mmol) was added to a solution of methyl bromocyanoacetate (1, 215 mg, 1.2 mmol) in absolute methanol (5 mL) at room temperature. The reaction mixture was stirred for 15 s to 1 min. The precipitate was collected by filtration, washed with methanol-water (5 mL), and dried. In the case of oily compound 3z, it was purified by silica gel chromatography using hexane-ethyl acetate (9:1).42 Compounds 3a, [43] and [44]3b, [45] and [46]3c,473d,483e,493f, 3g,503h,513s,523ff,533jj,543kk55 have previously been reported.
91%
With chloranil; In water; at 20℃; for 0.1h;Sonication; Green chemistry;
General procedure: A flask was charged with primary thiobenzamide 1a-j(1.0 mmol) and chloranil (270 mg, 1.1 mmol) in H2O(3 ml). The reaction mixture was irradiated with ultrasound at room temperature for appropriate time. The progress of reaction was monitored with TLC. After completion of thereaction, solvent was concentrated under reduced pressure,and the obtained residue was subjected to silica gel column chromatography purification (EtOAc-hexane) to obtain the desired products.
89%
With tert.-butylnitrite; In dichloromethane; at 27 - 29℃; for 0.5h;
General procedure: The primary thioamides (1a-1k) (1 mmol) was stirred in dichloromethane (2 mL) at room temperature to which 1.1 equiv. of tert-butyl nitrite (TBN) was added. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate (Na 2 SO 4 ), concentrated and subjected for silica gel (60-120 mesh) column chromatography purification (SiO 2 : ethyl acetate/hexane) to obtain the desired products (2a-2k).
79%
With nicotinamide; In acetonitrile; at 80℃; for 16h;
General procedure: A 10 mL round bottomed flask was charged with a mixture of selenocarboxamide 1a-h (1.0 mmol) or thiocarboxamides 3a-o (1.0 mmol), Vitamin-B3 (0.1 mmol) or Thiourea (0.1 mmol) and acetonitrile (2 mL). The reaction mixture was then heated at 80 C for 16 hours. After completion of the reaction (progress was monitored by TLC; SiO2, hexane / ethyl acetate = 9.5 : 0.5) the mixture was diluted with hot ethyl acetate (10 mL) and water (15 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layer was washed with brine (3 × 10 mL) and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and the remaining residue was purified by column chromatography over silica gel using hexane / ethyl acetate as an eluent to obtain the desired 1,2,4-selenadiazoles 2a-h or 1,2,4-thiadiazoles 4a-o in high yield.
56%
With sodiumsulfide nonahydrate; In dimethyl sulfoxide; acetonitrile; at 20℃; for 12h;Irradiation;
General procedure: To a 10 mL bottle were added 0.25 mmol of arylthioamide and Na2-eosin Y-TiO2 (8 mg) in MeCN 1.5 mL and DMSO 0.5 mL. The reaction mixturewas stirred at room temperature for 12 h. Next, by adding about 2 mL H2O after the reaction to dispersethe solid product, the reaction mixture was extracted with EtOAc, and the mixture was purified bycolumn chromatography.
Methyl 4-methyl-3-oxovalerate (19) (28.1 g, 195 mmol) was cooled to 5 C, and to this solution, SO2Cl2 (15.7 mL, 195 mmol) was added dropwise over 45 min, stirred for 30 min, and allowed to room temperature. To this solution, <strong>[72505-21-6]4-(trifluoromethyl)thiobenzamide</strong> (30.8 g, 150 mmol) in EtOH (15 mL) was added and refluxed for 2 h. The reaction mixture was cooled, and to this solution, IPA was added. The insoluble material was filtered and washed with IPA. Water was added to the filtrates, which were stirred at room temperature for 1 h. The precipitated product was filtered and washed with a solution of IPA/H2O = 1:2 (50 mL) and dried under a vacuum. The crude product was recrystallized from IPA/H2O to give the target compound as a pale brown crystal (34.9 g, yield 71%).1H NHR (400 MHz, CDCl3) delta: 1.35 (d, 6H, J = 7 Hz), 3.90 (s, 3H), 3.15 (m, 1H), 7.70 (d, 2H, J = 8 Hz), 8.10 (d, 2H, J = 8 Hz).
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