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Structure of 41011-01-2 * 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.
Step 2: To a mixture of 2-bromo-1-(3-chlorophenyl)ethan-1-one (0.5 g, 2.1 mmol) and thiourea (0.2 g, 2.3 mmol) in anhydrous EtOH (5 mL) was heated at reflux for 1 h. After that, the solvent was removed in vacuo, and saturated aqueous NaHCO3 was added. The mixture was then extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 4-(3-chlorophenyl)thiazol-2-amine as a solid (0.4 g, 93percent).
23 g
Reflux
To a solution of 2-bromo-1-(3-chlorophenyl)ethanone (28 g) in ethanol (300 ml) was added thiourea (10.04 g). The reaction mixture was refluxed overnight. Solvent was removed, and the residue was triturated with diethyl ether to give the title compound (23 g) as a white solid. MS(ES+) m/z 211 (MH+).
Reference：
[1] Patent: US2016/257690, 2016, A1, . Location in patent: Paragraph 0727
[2] Medicinal Chemistry Research, 2014, vol. 23, # 1, p. 259 - 268
[3] Patent: WO2012/100734, 2012, A1, . Location in patent: Page/Page column 20
[4] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 17, p. 5293 - 5302
[5] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 15, p. 3669 - 3674
[6] Patent: WO2017/9650, 2017, A1, . Location in patent: Page/Page column 103
[7] European Journal of Medicinal Chemistry, 2018, vol. 144, p. 179 - 200
[8] Tetrahedron, 2018, vol. 74, # 27, p. 3602 - 3607
2
[ 99-02-5 ]
[ 41011-01-2 ]
Yield
Reaction Conditions
Operation in experiment
91%
With bromine In n-heptane; water
EXAMPLE 5 Under a nitrogen atmosphere, 3'-chloroacetophenone (154.6 g, 1 mol) and anhydrous methanol (310 ml) dried with molecular sieves were charged in a four-necked flask. Bromine (158.2 g, 0.99 mol) was added dropwise with stirring at a temperature in a range from 30° to 45° C. over one hour, and the mixture was maintained at the same temperature for 10 minutes. After water (160 g) was added, the solution was cooled to -10° C. to precipitate crystals which were filtered to obtain 250 g of a crude cake. This crude cake was dissolved in heptane (750 g), and the solution was washed twice with water (200 g), dried over anhydrous magnesium sulfate, filtered, washed and then concentrated to obtain 212.5 g of 2-bromo-3'-chloroacetophenone. The yield was 91.0percent and no impurity was detected.
91%
With bromine In n-heptane; water
Reference Example 1 3'-Chloroacetophenone (154.6 g) and anhydrous methanol (dried with a molecular sieves 4A) (310 ml) were charged in a flask, and bromine (158.2 g) was added dropwise under stirring at 30° to 45° C. over one hour. After continuous stirring at the same temperature for 10 minutes, water (160 g) was added and the mixture was stirred continuously for one hour. After cooling to -10° C., the crystal deposited was filtered to give 250 g of a solid. This solid was dissolved in heptane (750 g), and the resulting solution was washed twice with water (200 g), dried over anhydrous magnesium sulfate and filtered. Then, the filtrate was cooled to -30° C. and the crystal was filtered and dried to give 212.5 g of 2-bromo-3'-chloroacetophenone. It was analyzed by subjecting to gas chromatography. As a result, impurities were not observed, yield 91percent.
90%
With tetrabutylammomium bromide In acetonitrile at 150℃; for 0.0333333 h; Microwave irradiation; Sealed tube
Step 1 [Show Image] 1-(3-chlorophenyl)ethanone 25 (750 mg, 4.85 mmol) was dissolved in acetonitrile (11.5 ml). To the solution was added tetrabutylammonium bromide (2.34 g, 4.85 mmol) and the mixture was in sealed tubes and stirred by a microwave reactor for 2 minutes at 150 °C. The reactant was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate solution, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography to give the desired compound 26 (1.02 g, yield 90 percent). 1H-NMR (DMSO-d6) δ: 5.01 (s, 2H), 7.60-7.65 (m, 1H), 7.77-7.80 (m, 1H), 7.96-8.06 (m, 2H).
90%
With tetrabutylammomium bromide In acetonitrile at 150℃; for 0.0333333 h; Microwave irradiation; Sealed tubes
1-(3-chlorophenyl)ethanone 25 (750 mg, 4.85 mmol) was dissolved in acetonitrile (11.5 ml). To the solution was added tetrabutylammonium bromide (2.34 g, 4.85 mmol) and the mixture was in sealed tubes and stirred by a microwave reactor for 2 minutes at 150° C. The reactant was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate solution, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography to give the desired compound 26 (1.02 g, yield 90percent).1H-NMR (DMSO-d6) δ: 5.01 (s, 2H), 7.60-7.65 (m, 1H), 7.77-7.80 (m, 1H), 7.96-8.06 (m, 2H).
87%
With Oxone; ammonium bromide In methanol for 2 h; Reflux
General procedure: Oxone (1.352 g, 2.2 mmol) was added to the well stirred solution of substrate (2 mmol) and NH4Br (0.215 g, 2.2 mmol) in methanol (10 ml) and the reaction mixture was allowed to stir at room temperature (or reflux temperature). After completion of the reaction, as monitored by TLC, the reaction mixture was quenched with aqueous sodium thiosulfate, and extracted with ethyl acetate (3.x.25 ml). Finally, the combined organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and removal of solvent in vacuo yielded a crude residue, which was further purified by column chromatography over silica gel (finer than 200 mesh) to afford pure products. All the products were identified on the basis of 1H NMR and mass spectral data.
82.2%
With bromine In dichloromethane at 20 - 25℃; for 0.5 h;
Preparation No.M.l: 2-Bromo-l-(3-chIorophenyl)-ethanone; EPO <DP n="117"/>To a stirred solution of 3-chloroacetophenone (18.2 g, 0.118 mol) in DCM (150 mL, 2.3 mol), at about 20-25 0C was added drop-wise a solution of bromine (6.00 mL, 0.116 mol) in DCM (20 mL) over about 15 min. After the addition was complete the pale yellow solution was stirred at ambient temperature for about 15 min. Ice-cold water (100 mL) was added to the reaction solution and stirred for about 5 min. The organic layer was separated and washed with ice-cold water (2 x 150 mL). The organic layer was dried over MgSO4, filtered, and the solvent removed in vacuo to yield a pale yellow oil (31.0Ig). The oil residue was stirred with petroleum ether [bp 30-60 0C] (5OmL) at about 40 0C for about 5 min and almost all the oil had dissolved. A magnetic stirrer bar was added to the mixture and rapidly stirred whilst the internal temperature was reduced to about -10 to -5 0C. Held at about -5 0C for about 5 min before the off-white solid was collected. The crystalline solid was washed with ice-cold petroleum ether [bp 30-60 0C] (2 x 40 mL) and dried under reduced pressure to yield an off-white powdery solid (23.8 g, 82.2percent): 1H NMR (400 MHz5CDCl3) δ 7.96 (IH), δ 7.86 (IH), δ 7.59 (IH), δ 7.45 (IH), δ 4.42 (2H); TLC (EtOAc/heptane 1:1) Rf 0.59.
72.8%
With copper(I) bromide In ethyl acetate at 80℃;
A) 3-Chloroacetophenone (0.2 g, 1.294 mmol)And copper bromide (0.347 g, 1.552 mmol)Were successively dissolved in ethyl acetate (30 mL)The mixture was stirred overnight at 80 ° C,The reaction solution was cooled to room temperature,Further, 30 mL of ethyl acetate was added,The reaction mixture was washed with 100 mL of water,100 mL of saturated sodium chloride solution,The ethyl acetate layer was separated,Dried over anhydrous sodium sulfate,The organic solvent was distilled off under reduced pressure,The residue was purified by flash silica gel column chromatography,Eluting with petroleum ether / ethyl acetate (V / V = 10: 1)To obtain 220 mg of 2-bromo-1- (3-chlorophenyl) ethanone,As a white solid,Yield 72.8percent
18 g
With copper(ll) bromide In chloroform; ethyl acetateReflux
To a solution of 1-(3-chlorophenyl)ethanone (15 g) in chloroform (100 ml) and ethyl acetate (100 ml) was added copper(II) bromide (21.67 g), and the reaction mixture was refluxed overnight. The reaction mixture was concentrated to give the desired product (18 g) as a brown oil. MS(ES+) m/z 219 (MH+).
Reference：
[1] Tetrahedron, 1992, vol. 48, # 1, p. 67 - 78
[2] Journal of Medicinal Chemistry, 1992, vol. 35, # 16, p. 3045 - 3049
[3] Patent: US5717116, 1998, A,
[4] Patent: US5831132, 1998, A,
[5] Patent: EP2280000, 2011, A1, . Location in patent: Page/Page column 40-41
[6] Patent: US2011/28468, 2011, A1, . Location in patent: Page/Page column 26
[7] Tetrahedron Letters, 2012, vol. 53, # 2, p. 191 - 195
[8] Synthetic Communications, 2013, vol. 43, # 19, p. 2603 - 2614
[9] Patent: WO2007/28051, 2007, A2, . Location in patent: Page/Page column 115-116
[10] Journal of Organic Chemistry, 2013, vol. 78, # 14, p. 7312 - 7317
[11] Journal of Medicinal Chemistry, 2013, vol. 56, # 10, p. 3833 - 3851
[12] Patent: CN103833671, 2016, B, . Location in patent: Paragraph 0074; 0075; 0076; 0077
[13] RSC Advances, 2014, vol. 4, # 107, p. 62308 - 62320
[14] Tetrahedron Letters, 1999, vol. 40, # 24, p. 4551 - 4554
[15] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1986, vol. 25, p. 228 - 229
[16] Journal of the Indian Chemical Society, 2002, vol. 79, # 5, p. 469 - 471
[17] Journal of Medicinal Chemistry, 1971, vol. 14, # 10, p. 977 - 982
[18] Pharmazie, 1988, vol. 43, # 7, p. 470 - 472
[19] Journal of Pharmaceutical Sciences, 1982, vol. 71, # 5, p. 556 - 561
[20] Chemical & Pharmaceutical Bulletin, 1995, vol. 43, # 9, p. 1497 - 1504
[21] Journal of agricultural and food chemistry, 2002, vol. 50, # 12, p. 3486 - 3490
[22] Synthesis, 2004, # 11, p. 1750 - 1754
[23] Synthetic Communications, 2007, vol. 37, # 2, p. 199 - 207
[24] Bioscience, Biotechnology and Biochemistry, 2005, vol. 69, # 1, p. 79 - 86
[25] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 5, p. 1291 - 1295
[26] Patent: WO2008/64136, 2008, A2, . Location in patent: Page/Page column 43
[27] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 4, p. 1432 - 1435
[28] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 1, p. 182 - 185
[29] Patent: WO2012/27965, 2012, A1, . Location in patent: Page/Page column 20
[30] Patent: WO2012/100734, 2012, A1, . Location in patent: Page/Page column 19
[31] Synlett, 2012, vol. 23, # 12, p. 1797 - 1800
[32] European Journal of Medicinal Chemistry, 2012, vol. 54, p. 403 - 412
[33] European Journal of Medicinal Chemistry, 2012, vol. 57, p. 407 - 416
[34] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 1, p. 153 - 157
[35] Journal of Medicinal Chemistry, 2013, vol. 56, # 1, p. 84 - 96
[36] Journal of Organic Chemistry, 2013, vol. 78, # 12, p. 6276 - 6280
[37] Angewandte Chemie - International Edition, 2013, vol. 52, # 44, p. 11632 - 11636[38] Angew. Chem., 2013, vol. 125, # 44, p. 11846 - 11850,5
[39] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 24, p. 6764 - 6768
[40] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 2, p. 692 - 702
[41] Medicinal Chemistry Research, 2014, vol. 23, # 1, p. 259 - 268
[42] Patent: WO2014/70978, 2014, A1, . Location in patent: Page/Page column 34; 35
[43] Chemical Biology and Drug Design, 2015, vol. 86, # 4, p. 849 - 856
[44] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 17, p. 5293 - 5302
[45] MedChemComm, 2016, vol. 7, # 7, p. 1441 - 1448
[46] Phosphorus, Sulfur and Silicon and the Related Elements, 2016, vol. 191, # 8, p. 1166 - 1173
[47] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 15, p. 3669 - 3674
[48] Organic and Biomolecular Chemistry, 2016, vol. 14, # 34, p. 8026 - 8029
[49] Patent: CN105315279, 2016, A, . Location in patent: Paragraph 0156
[50] Patent: CN105669586, 2016, A, . Location in patent: Paragraph 0074
[51] Patent: WO2017/9651, 2017, A1, . Location in patent: Page/Page column 40; 41
[52] Journal of Medicinal Chemistry, 2017, vol. 60, # 4, p. 1591 - 1597
[53] Organic Letters, 2017, vol. 19, # 8, p. 1994 - 1997
[54] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 16, p. 3726 - 3732
[55] Organic and Biomolecular Chemistry, 2017, vol. 15, # 38, p. 8134 - 8139
[56] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 8, p. 1986 - 1995
[57] Tetrahedron Letters, 2018, vol. 59, # 33, p. 3214 - 3219
3
[ 99-02-5 ]
[ 25847-29-4 ]
[ 41011-01-2 ]
Yield
Reaction Conditions
Operation in experiment
80%
With N-Bromosuccinimide; silica gel In methanol for 0.366667 h; Reflux
General procedure: The α-bromination reaction was carried out using acetophenone (1200 mg, 10 mmol), N-bromosuccinimide (2136 mg, 12 mmol), 10percent (w/w) silica gel (120mg) in 10 mL of methanol at reflux conditions until the disappearance of the substrate. (Note: 2136mg of N-bromosuccinimide was added portion wise i.e. 356 mg for each time in six portions). The progress of the reaction was monitored by TLC. The reaction mass was filtered after the completion of the reaction as per TLC and the catalyst was collected for reuse. The filtrate was concentrated under vacuum. Double distilled water was added to the reaction mixture and quenched with aqueous sodium thiosulfate and the product extracted with dichloromethane (Caution: Severe burning sensation of eyes was observed during the work-up process). The layers were separated and the organic layer was collected and washed thrice with distilled water (3×50mL). The collected organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The obtained crude product was purified by column chromatography over silica gel (60–120 mesh) using n-hexane–EtOAc (99:1 ratio). With the aim of studying the recycling of the catalyst, the isolated catalyst was washed with ethyl acetate (5mL) after its filtration from the reaction medium, collected and dried in vacuum at 70°C to a constant weight. Subsequently it was reused for the α-bromination of acetophenone and achieved 95percent, 86percent and 83percent yields of product (2a) for first, second and third reuse of catalyst respectively. All products gave spectroscopic data in agreement with the literature [15,21,27–30]. The method is also very practical for scale up in process development. We attempted large scale (100 gram scale) synthesis of 2-bromo-1-phenylethanone 2a and obtained fruitful results with isolated yields ranging from 93percent to 96percent.
Reference：
[1] Chinese Chemical Letters, 2014, vol. 25, # 1, p. 179 - 182
4
[ 1616490-77-7 ]
[ 41011-01-2 ]
Reference：
[1] Chemical Communications, 2017, vol. 53, # 49, p. 6565 - 6568
5
[ 2039-85-2 ]
[ 41011-01-2 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2017, vol. 15, # 46, p. 9889 - 9894
[2] Tetrahedron, 2018, vol. 74, # 27, p. 3602 - 3607
6
[ 766-83-6 ]
[ 41011-01-2 ]
Reference：
[1] European Journal of Organic Chemistry, 2017, vol. 2017, # 4, p. 781 - 785
2-(3-chloro-phenyl)-imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With triethylamine In ethanol at 90℃; for 5h;
4 Procedure 4:
Synthesis of 2-(3-Chloro-phenyl)-imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester A solution of 2-amino-isonicotinic acid methyl ester (0.35 g, 1.98 mmol), meta-chlorophenyl-α-bromo ketone (1 eq., 1.98 mmol, 461 mg), Et3N (0.3 eq, 0.59 mmol, 0.083 mL) in ethanol (10 mL) was heated at 90° C. for 5 hours. The mixture was then evaporated to dryness. Ethyl acetate was added and removed in vacuo three times to afford 515 mg (91% yield) of 2-(3-chloro-phenyl)-imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester. m/z (M+H)=287.2.
Step 2: To a mixture of 2-bromo-1-(3-chlorophenyl)ethan-1-one (0.5 g, 2.1 mmol) and thiourea (0.2 g, 2.3 mmol) in anhydrous EtOH (5 mL) was heated at reflux for 1 h. After that, the solvent was removed in vacuo, and saturated aqueous NaHCO3 was added. The mixture was then extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 4-(3-chlorophenyl)thiazol-2-amine as a solid (0.4 g, 93%).
In ethanol;Reflux;
Step 2:; To a solution of 2-bromo-l-(3-chlorophenyl)ethanone (28 g) in ethanol (300 mL) was added thiourea (10.04 g). The reaction mixture was refluxed overnight. Solvent was removed, and the residue was triturated with diethyl ether to give 4-(3-chlorophenyl)thiazol-2-amine (23 g) as a white solid. MSfES4") m/z 211 (MH"t).
23 g
In ethanol;Reflux;
To a solution of 2-bromo-1-(3-chlorophenyl)ethanone (28 g) in ethanol (300 ml) was added thiourea (10.04 g). The reaction mixture was refluxed overnight. Solvent was removed, and the residue was triturated with diethyl ether to give the title compound (23 g) as a white solid. MS(ES+) m/z 211 (MH+).
In ethanol; for 3h;Reflux;
General procedure: (iii) A mixture of the above synthetic 9a-10n(calculate to yield 100% for last step, 4 mmol, 1.0 equiv.) and thiourea (4.4 mmol,1.1 equiv.) in anhydrous ethanol (50 mL) was refluxed for 3 h. After that, thesolvent was removed in vacuo andwashed with cold ether. Then the mixture was extracted dichloromethane (3*15mL) and washed with saturated aqueous NaHCO3. The combined organicphases were dried with anhydrous Na2SO4. Then removingthe solvent, the residue was purified by silica gel column (hexane/EtOAc=8:1 to4:1) and dried under vacuum to give 4-arylthiazol-2-amine 10a-10n, yieldwas 50~90%.
In ethanol; at 20℃; for 1h;
Step a. To a solution of 2-bromo-l-(3-chlorophenyl)ethan-l-one (CAS Number 41011-01-2) (0.3 g, 1.28 mmol) in ethanol (5ml) was added thiourea (0.108 g, 1.41 mmol) at rt. The resulting reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure. The obtained residue was poured into 1M NaOH solution (70 ml) and extracted with DCM (2 x 30 ml). The combined organic phase was dried over Na2S04, filtered and concentrated under reduced pressure yielding 4-(3-chlorophenyl) thiazol-2 -amine (0.350 g, quantitative). LCMS: Method C, 2.03 min; MS: ES+ 213.04.This material was used directly for the next step without further purification.
In ethanol;Reflux;
General procedure: Haloketones (1 eq) were conjugated with thioureas (1 eq) in anhydrous ethanol (EtOH) (1ml). Reaction was stirred at reflux from 2 to 24h until the reaction was judged complete (HPLC-MS). The mixture was then extracted with ethyl acetate (3×3ml). The organic phases were concentrated in vacuum and lyophilized. Products were verified by HPLC and MS and purified with preparative HPLC. Relevant fractions were collected and concentrated to afford the desired product in 40-95% yields, with purity of >95% as determined by HPLC-MS.
In ethanol; at 80℃; for 2h;
General procedure: To a mixture of olefin (0.5 mmol) and tween-80 (30 mL) in water (3 mL) was added DBH (214.5 mg, 0.75 mmol) at room temperature, and the mixture was stirred under the conditions as indicated in Table 1. After cooling to room temperature and removal of solvent under reduced pressure, EtOH (3 mL), thiourea (57.1 mg, 0.75 mmol) (or 0.75 mmol of N-methylthiourea/N-phenethylthiourea) were added to the mixture, and the obtained mixture was stirred for 2 h at 80 C. The mixture was diluted with ethyl acetate (60 mL). The organic phase was washed with brine (10mL x 3) and dried over Na2SO4. After concentrated under reduced pressure, the residue was purified by preparative thin layer chromatography to afford the corresponding 2-aminothiazoles.
4.4. Preparation of 1,2,4-triazolo[3,4-b][1,3,4]-thiadiazines (6aeh)
General procedure: A mixture of 4-amino-5-(pyridin-4-yl)-4H-[1,2,4]triazole-3-thiol 5 (1 mmol) and substituted phenacyl bromides (1.2 mmol) was refluxed in absolute ethanol (10 mL) for 6-7 h. The reactionmass was poured into crushed ice and neutralized with sodium bicarbonate. Solid product obtained was filtered, washed with water, dried and recrystallized from ethanol to afford conjugated products 6a-h [28].
In N,N-dimethyl-formamide at 100℃; for 1h; Inert atmosphere;
5.1. General procedure for compounds (2a-2i)
General procedure: A mixture of 1 (2.0 g, 10 mmol) and α-bromoacetophenone (2.0 g, 10 mmol) in N,N-dimethylformamide (DMF) (20 mL) was taken in a round bottom flask and was heated at 100 °C for 1 h. Contents were then cooled to room temperature and poured over ice cooled water (100 mL) resulting in the formation of a light yellow solid, which was filtered to give desired product 2a (2.5 g, yield: 83%). The rest of compounds were prepared by the similar procedure to 2a.
With tris(2,2'-bipyridyl)ruthenium dichloride; Bromoform; [bis(acetoxy)iodo]benzene; In 1,4-dioxane; at 20℃; for 8h;Irradiation;
General procedure: Under conditions B: A 5 mL oven-dried reaction vessel equipped with a magnetic stirrer bar was charged withstyrene (1a, 20.8 mg, 0.20 mmol), Ru(bpy)3Cl2 (1.28 mg, 0.002 mmol, 1.0 mol%), PhI(OAc)2 (64.0 mg, 1.0 equiv.),CHBr3 (2b, 0.20 mmol) and dioxane (2.0 mL). The reaction vessel was exposed to blue LED (450-455 nm, 3 W) atroom temperature in air with stirring for 8 h. After completion of the reaction, the mixture was concentrated to yieldthe crude product, which was further purified by flash chromatography (silica gel, petroleum ether/ethyl acetate =10:1 to 5:1) to give the desired product 4a.
With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; water; at 80℃; for 3h;
General procedure: To a mixture of olefin (0.5 mmol) and tween-80 (30 mL) in water (3 mL) was added DBH (214.5 mg, 0.75 mmol) at room temperature, and the mixture was stirred under the conditions as indicated in Table 1. After cooling to room temperature and removal of solvent under reduced pressure, EtOH (3 mL), thiourea (57.1 mg, 0.75 mmol) (or 0.75 mmol of N-methylthiourea/N-phenethylthiourea) were added to the mixture, and the obtained mixture was stirred for 2 h at 80 C. The mixture was diluted with ethyl acetate (60 mL). The organic phase was washed with brine (10mL x 3) and dried over Na2SO4. After concentrated under reduced pressure, the residue was purified by preparative thin layer chromatography to afford the corresponding 2-aminothiazoles.
With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; water; In acetone; at 70℃; for 0.138833h;
5 mmol (0.69 g) of <strong>[2039-85-2]3-chlorostyrene</strong> was dissolved in 10 mL of water/acetone solution (5 mL of water plus 5 mL of acetone mixed) to obtain a homogeneous solution A, which was added to the injection pump a; 8 mmol ( 2.29g) DBH is dissolved in lOmLl: 1 water / acetone solution (5ml water plus 5ml acetone mixed evenly), to obtain homogeneous solution B, added to the injection chestnut b; 6mmol (0.91g) DBU and 6mmol (1.10g ) pentafluorophenol is dissolved in 10 mL of acetone (acetone) to obtain a homogeneous solution C, which is added to the injection pump c; The injection flow rate of a and b is 0.3ml/min, the injection flow rate of injection c is 0.5ml/min; the reaction volume of the first microchannel reactor is V = 5ml, the reaction time is 8.33min, and the reaction volume of the second microchannel reactor is V = 5ml, reaction time 4.55min; first and second microchannel reactor inner diameter = 0.5first microchannel reactor temperature is 70 C, second microchannel reactor temperature is 70 C; After two cycles of the microchannel reactor reaction, the reaction liquid was collected, and the product yield was calculated by HPLC method to be 80%.After column chromatography separation, the product 3d is obtained;
4-(3-chlorophenyl)-2-(pyrimidine-2-yl)thiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
In ethanol at 20 - 78℃;
11 General procedure for the synthesis of 4-(aryl/heteroaryl)-2-(pyrimidin-2-yl)thiazole (1-21)
General procedure: In the synthesis process, different 1-(aryl/heteroaryl)ethanone(50 mmol) derivatives were brominated in the presence of copper(II) bromide (100 mmol) followed by a reaction with equimolarpyrimidine-2-carbothioamide (50 mmol). In the course of the reaction,the components were mixed in ethanol acetate for approximately1 h in room temperature and then refluxed at 77-78 Cfor 15-20 min. After cooling, the precipitate was filtered, neutralizedwith sodium acetate, and recovered from the HBr salt. Allthe synthesized compounds were purified twice by crystallizationfrom ethanol. Pyrimidine-2-carbonitrile and phosphorus pentasulfidewere mixed in dioxane for 48 h to obtain pyrimidine-2-carbothioamideas the starting material. This is the first time in theliterature that synthesis of pyrimidine thioamides has been undertakenwith this method.
2-(3-chlorophenyl)-7-methylimidazo[1,2-a]pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
In ethanol for 5h; Reflux;
4.1.53 General procedure VI - synthesis of 7-methyl-2-arylo-imidazo[1,2-a]pyrimidines (60a-60j)
General procedure: To a solution of 2-amino-4-methylpyrimidine (59, 1 eq.) in absolute EtOH (100 mL) the appropriate phenacyl bromide (1 eq.) was added and the whole was heated at reflux for 5 h. After cooling to RT water (100 mL) and CHCl3 (200 mL) were added and the organic phase was separated. Water phase was neutralized to pH 7 with aqueous NaOH, adjusted to pH 9 with aq. NaHCO3 extracted with chloroform (3×40 mL) and dried with Na2SO4. The solvent was evaporated and the residue was recrystallized from AcOEt/EtOH (2:1, v/v). The precipitate was filtered and washed with AcOEt, affording pure product.
4-(2-chlorophenyl)-N-[3-(trifluoromethyl)phenyl]thiazol-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
14.4%
With potassium fluoride; In water; acetonitrile; at 28℃; for 12h;
To a solution of 2-bromo-l-(2-chlorophenyl)ethanone (100 mg, 428.28 pmol, 62.50 pL,1.2 eq) and [3-(trifluoromethyl)phenyl]thiourea (90 mg, 367.82 pmol,1.03 eq) in ACN (3 mL) and ThO (3 mL) was added KF (40 mg, 688.47 pmol,1.93 eq). The mixture was stirred at 28 C for 12 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over NaiSCL, filtered and concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Welch Xtimate Cl 8 150*25mm*5um;mobile phase: [water(10mM NH4HC03)-ACN]; B%: 62%-92%,10 min), followed by lyophilization to yield 4-(2-chlorophenyl)-A-[3-(trifluoromethyl)phenyl]thiazol-2- amine (18.26 mg, 51.47 pmol,14.4% yield,100.0% purity) as a white solid.1HNMR (400 MHz, DMSO-di) d ppm 10.63 (br s,1H), 8.31 (s,1H), 7.87 (dd, J= 1.6, 7.7 Hz,1H), 7.76 (d, J= 8.3 Hz,1H), 7.56-7.52 (m,1H), 7.52-7.48 (m,1H), 7.45-7.40 (m,1H), 7.39 (s,1H), 7.38-7.32 (m,1H), 7.24 (d, J= 7.8 Hz,1H); ES-LCMS m/z 355.0 [M+H]+.
With potassium fluoride; In water; at 25℃; for 2h;Inert atmosphere;
A mixture of [3-(trifluoromethyl)phenyl]thiourea (705.05 mg, 3.17 mmol,1 eq), 2- bromo-l-(3-chlorophenyl)ethanone (740.08 mg, 3.17 mmol,1 eq), KF (184.15 mg, 3.17 mmol, 74.25 pL,1 eq) in MeCN (15 mL) and FLO (15 mL) was degassed and purged with N2 for 3 times and the mixture was stirred at 25 C for 2 h under N2 atmosphere. The reaction mixture was concentrated to yield a residue which was treated with EtOAc (30mL) and FLO (30mL). The combined organic layers was dried over Na2S04, filtered and the filtrate was concentrated to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 2/1, TLC: PE/EtOAc = 1/1, Rf = 0.5) to yield 4-(3 -chi orophenyl )-Af-[3 -(trill uoro ethyl )phenyl]thiazol - 2-amine (0.851 g, 2.36 mmol, 74.5% yield, 98.5% purity) was obtained as a yellow solid.1HNMR (400 MHz, DMSO- e) d ppm 10.72 (s,1H), 8.43 (s,1H), 7.97 (t, J = 1.8 Hz,1H), 7.89 (td, J = 1.2, 7.8 Hz,1H), 7.79 (dd, J = 1.6, 8.2 Hz,1H), 7.61 (s, 2H), 7.51-7.44 (m,1H), 7.41-7.36 (m,1H), 7.31 (d, J = 7.6 Hz,1H); ES-LCMS m/z 354.9, 356.9[M+H]+.
4-(3-chlorophenyl)-N-[3-(trifluoromethoxy)phenyl]thiazol-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium fluoride In water; acetonitrile at 30℃; for 12h;
1.3 Step 3 : 4-(3-Chlorophenyl)-A-[3-(trifluoromethoxy)phenyl]thiazol-2-amine
To a solution of [3-(trifluoromethoxy)phenyl]thiourea (170 mg, 719.69 pmol,1 eq) and 2-bromo-l-(3-chlorophenyl)ethanone (168.04 mg, 719.69 pmol,1 eq) in MeCN (5 mL) and H20 (5 mL) was added KF (83.62 mg,1.44 mmol, 33.72 pL, 2 eq). The mixture was stirred at 30 °C for 12 h. The reaction mixture was quenched by addition of water (50 mL), extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2S04, filtered and concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18 150*25mm*5pm; mobile phase: [water (0.04%NH3H20+10mM NH4HC03)-ACN]; B%: 70%-100%, lOmin), followed by lyophilization to yield 4-(3 -chi orophenyl)-/V-[3-(trifluoromethoxy)phenyl]thiazol -2-amine (19.08 mg, 48.58 pmol, 6.7% yield, 94.4% purity) as yellow oil. NMR (500 MHz, CD3OD) d ppm 8.12 (d, J = 0.9 Hz,1H), 7.94 (t, J = 1.8 Hz,1H), 7.83 (td, J = 1.2, 7.9 Hz,1H), 7.46-7.41 (m,1H), 7.40-7.35 (m, 2H), 7.30 (ddd, J = 1.0, 2.1, 7.9 Hz,1H), 7.21 (s,1H), 6.85 (td, J = 1.1, 8.0 Hz,1H); ES- LCMS m/z 370.9, 372.9 [M+H]+.
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