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a) Synthesis of 4-bromothiazol A solution of 10.0 g (41.2 mmol) 2,4-dibromothiazol in ether (210 ml) was cooled to -78° C. and 28.3 ml (45.3 mmol, 15percent in hexane) n-butyllithium was added in drops at this temperature. After 30 min of stirring, 3.3 ml (82.3 mmol) methanol was added at -78° C. to the reaction mixture. Heating was subsequently performed to RT over a period of 16 h. The reaction mixture was filtered over silica gel and washed with a n-hexane/AE mixture (2:1). The filtrate was concentrated in a vacuum, whereby 6.7 g (40.9 mmol, 99percent) 4-bromothiazol was obtained.
With sodium hydroxide; In dichloromethane; acetic acid;
Reference Example 2 4-Bromothiazole Following the procedure of M. Robba and R. C. Moreau, Annales pharm. franc. 22, #3, 201-210 (1965); 10 g of 2,4-dibromothiazole and 5 g of powdered zinc in 40 ml of glacial acetic acid is stirred at 60°-65° C. for 45 minutes. The mixture is cooled in an ice bath, as 40 ml of 10 N sodium hydroxide is added in portions. Stirring is continued for 30 minutes. Ten milliliters of 10 N sodium hydroxide is added and the reaction is extracted with diethyl ether followed by methylene chloride. The combined organic layers are dried over sodium sulfate, filtered and concentrated in vacuo to give 5.4 g of the product as a yellow oil.
2,4-Dibromothiazole (5.00 g, 20.7 mmol) is placed in a flask which has been back filled with Argon three times. Anhydrous ether (82 mL) is added and the solution is cooled to -78°C. n-Butyllithium (2.5 M in cyclohexane, 10.0 mL) is added and the reaction mixture is stirred for 90 minutes at -78°C before quenching with HCl/ether solution (2.0 m x 15 mL). The reaction mixture is warmed to room temperature. The mixture is washed with NaHCpsi3 (saturated aqueous solution, 60 mL) and the organic phase is dried with Na2SO4. After evaporation, 4-bromothiazole is obtained as a crude product.
A solution of 2,4-dibromothiazole B.31 (5.0128 g, 20.63 mmol) in ether (52 mL) was cooled to -78 0C. To the cooled solution was added n-BuLi (1.6 M sol. in hexane, 14.2 mL, 22.72 mmol) and the mixture was stirred at -78 0C for 30 minutes. To the cooled mixture was then added dropwise N-acetylmorpholine (3.1 mL, 26.83 mmol). The mixture was stirred at -78 0C for 1.5 hours and then room temperature for 18 hours. The mixture was diluted with ether (200 mL), washed with saturated aqueous NaHCO3 (100 mL x 1), dried over MgSO4, filtered, and concentrated under reduced pressure. The product was purified by silica gel column chromatography using 0% to 50% gradient of ethyl acetate in hexane as eluent to give 1 -(4- bromothiazol-2-yl)ethanone B.32 (3.383 g, 79.5% yield): 1H NMR (500 MHz, CHLOROFORM-d) 5 ppm 7.59 (1 H, s), 2.73 (3 H, s); Mass Spectrum (ESI) m/e = 205.9 [M+l (79Br)] and 207.9 [M+l (81Br)].
50%
To a solution of compound 21-2 (3.0 g, 12.35 mmol) in THF (25 ml) was added dropwise n-BuLi (2.5 M in hexane, 2.5 ml) at -78 C. After addition, the reaction mixture was stirred at -78 C for 30 min. N-acetyl morpholine (1.9 ml, 16.06 mmol) was added dropwise during 15 min at -78 C. After addition, the reaction mixture was stirred at -78 C for 4 h, quenched with saturated NaHCO3 (15 ml) and extracted with ethyl acetate (25 ml x 4). The combined organic layers were washed with brine (30 ml), dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (PE : EA = 50 : 1 to 10 : 1) to afford 21-3 as a white solid (1.28 g, yield 50%).
50%
Compound 22-3 (0435) To a solution of compound 22-2 (3.0 g, 12.35 mmol) in THF (25 mL) was added dropwise n-BuLi (2.5 M in hexane, 2.5 mL) at -78 C. After addition, the reaction mixture was stirred at -78 C. for 30 min. N-acetyl morpholine (1.9 mL, 16.06 mmol) was added dropwise during 15 min at -78 C. After addition, the reaction mixture was stirred at -78 C. for 4 h, then quenched with sat. NaHCO3 (15 mL) and extracted with ethyl acetate (25 mL×4). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (PE:EA=50:1 to 10:1) to afford 22-3-3 as a white solid (1.28 g, yield 50%).
33%
To a stirring solution of 2, 4-dibromothiazole 84 (50 g, 205.82 mmol) in anhydrous THF (500 mL) under inert atmosphere was added n-butyllithium (193 mL, 308.74 mmol) dropwise for 30 min at -40 oC and stirred for 1 h at the same temperature. To this was added 1- morpholinoethan-1-one (32 g, 248 mmol) in anhydrous THF (100 mL) dropwise for 20 min at -40 oC and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution and extracted using EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 1-2% EtOAc/ hexanes to afford compound 85 (14 g, 33%) as an off-white solid. TLC: 10% EtOAc/ hexanes (Rf: 0.8); 1H NMR (DMSO-d6, 400 MHz): delta 8.33 (s, 1H), 2.62 (s, 3H); LCMS Calculated for C5H4BrNOS: 204.92; LCMS observed: 208.0 (M+2)+.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of commercially available 2,4-dibromo-thiazole (3.50 g, 14.41 mmol) in dry Et2O (120 ml.) was treated with n-BuLi (5.9 ml. of a 2.5M solution in hexanes, 14.72 mmol) at -78 0C. The reaction mixture was stirred at this temperature for 30 min. lambda/,lambda/-Dimethylformamide (1.35 ml_, 14.47 mmol) was then added and the mixture allowed to warm to rt over a period of 1 h. The reaction was quenched by the addition of sat. aq. NH4CI (50 ml_). The layers were separated and the aq. layer extracted with Et2O (3 x 50 ml_). The combined org. extracts dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (10:1 -> 3:1 hept-EA) gave the title compound as a pale yellow solid. TLC: rf (1 :1 hept-EA) = 0.21. LC-MS-conditions 02: tR = 0.81 min.
With n-butyllithium; In diethyl ether; at -78 - 20℃; for 1.25h;
To a solution of 2,4-dibromothiazole (2.50 g, 10.28 mmol) in diethyl ether (50 ml) cooled to -78 C. was added n-butyl lithium (1.40 M, 8.80 ml, 12.38 mmol) and the resulting reaction mixture was stirred for 15 min at the same temperature followed by addition of DMF (5.0 ml, 64.30 mmol). The reaction mass was then allowed to come to room temperature and stirred for 1 h. After the completion of the reaction (TLC monitoring), the reaction mass was cooled to 0 C. and quenched with saturated NH4Cl solution (aqueous). Water was then added to the reaction mass and extracted with diethyl ether (3×100 ml). The combined organics was then dried over anhydrous Na2SO4, filtered and concentrated to get the desired product (2.10 g, quantitative crude yield) that was carried forward to the next step without further purification.
4-Bromo-thiazole-2-carbaldehyde:; In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of commercially available 2,4-dibromo-thiazole (3.50 g, 14.41 mmol) in dry Et2O (120 mL) was treated with n-BuLi (5.9 mL of a 2.5M solution in hexanes, 14.72 mmol) at -78 0C. The reaction mixture was stirred at this temperature for 30 min. Lambda/,Lambda/-Dimethylformamide (1.35 mL, 14.47 mmol) was then added and the mixture allowed to warm to rt over a period of 1 h. The reaction was quenched by the addition of sat. aq. NH4CI (50 mL). The layers were separated and the aq. layer extracted with Et2O (3 x 50 mL). The combined org. extracts dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (10:1 ->; 3:1 hept-EA) gave the title compound as a pale yellow solid. TLC: rf (1 :1 hept-EA) = 0.21. LC-MS-conditions 02: tR = 0.81 min.
(Example 30a) (4-bromo-1,3-thiazol-2-yl)methanol [Show Image] Under a nitrogen atmosphere at -78C, to a solution (20 mL) of 2,4-dibromothiazole (5 g, 20.6 mmol) in diethyl ether was added n-butyllithium (1.6 M hexane solution, 15.4 mL, 24.7 mmol), and the mixture was stirred at the same temperature for 30 min. N,N-Dimethylformamide (2.3 g, 30.9 mmol) was added to the reaction mixture at -78C, and the mixture was gradually warmed to room temperature. After confirmation of the termination of the reaction by TLC, hexane was added. The resulting salt was filtered and the solvent was evaporated under reduced pressure to give 4-bromo-1,3-thiazole-2-carbaldehyde as a crude product. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 7.68 (1 H, d, J=1.0 Hz), 9.95 (1 H, d, J=1.2 Hz)
General procedure: The reaction was carried out in a sealed tube under N2 using THF (4 mL) as the solvent. To the solution of tert-butyl 2-bromothiazole-4-carboxylate 1a (0.397 mmol), iPrMgCl·LiCl (1.3 M, 0.52 mmol) was added dropwise at -78 C. After 15 min the corresponding aldehyde (0.79-0.99 mmol) or N-formyl-morpholine (in the case of 2-formylthiazoles 3a-b) was added dropwise under stirring and the reaction mixture was stirred at -78 C for 10 min, then 1.5 h at 0 C. Saturated aqueous NH4Cl was added and the aqueous layer was extracted with Et2O (3 × 10 mL). The combined organic layers were washed with 5% aqueous HCl (10 mL), brine (10 mL), dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel using a mixture of EtOAc:P (petroleum ether) as eluent (see below) to give tert-butyl 2-(1-hydroxymethyl)thiazole-4-carboxylate derivatives rac-2a-h.
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