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CAS No. : | 167366-05-4 | MDL No. : | MFCD06660122 |
Formula : | C4H2BrNOS | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | JDUXMFGFGCJNGO-UHFFFAOYSA-N |
M.W : | 192.03 | Pubchem ID : | 2763187 |
Synonyms : |
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Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H319 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
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) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With methanol; sodium tetrahydroborate; at 20℃; for 0.5h; | Sodium borohydride (99 mg, 2.60 mmol) was added to a stirring solution of 5- chlorothiazole-2-carboxaldehyde (500 mg, 2.60 mmol) in MeOH (5.2 mL) at RT. The mixture was stirred for 30 min at RT and then concentrated in vacuo. The residue was taken up in EtOAc (40 mL) and washed sequentially with water (30 mL) and brine (20 mL). The organic layer was then dried over Na2SO4, filtered and concentrated in vacuo to give (4-bromothiazol-2-yl)methanol as a brown oil that was used without further purification (406A, 499 mg, 99%). LC/MS (ESI+) m/z = 194.0 (M+H)+. 1H NMR (400 MHz, chloroform-d) delta 7.23 (s, 1 H), 4.97 (d, J=6.06 Hz, 2H), 2.51 (t, J=5.38 Hz, 1 H). |
95.2% | With sodium tetrahydroborate; | (4-Bromothiazol-2-yl)methanol (2) To a solution of <strong>[167366-05-4]4-bromothiazole-2-carbaldehyde</strong> (10.4 g, 0.0542 mol) in MeOH (150 mL) was added NaBH4 (4.10 g, 0.108 mol) at 0 C. The mixture was stirred at 25 C. for 2 hrs. TLC showed the reaction was completed and one new spot was observed. The mixture was quenched with water (70 mL), stirred for 0.5 hr and concentrated to remove most of MeOH. The aqueous layer was extracted with EtOAc (30 mL*3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SiO2, Petroleum ether/Ethyl acetate=10: to 3:1) to give (4-bromothiazol-2-yl)methanol (10.0 g, 0.0515 mol, yield: 95.2%) as white solid. 1H NMR (400 MHz, CDCl3) delta 7.23 (s, 1H), 4.96 (d, J=6.0 Hz, 2H), 2.79 (t, J=6.0 Hz, 1H). |
With sodium tetrahydroborate; In methanol; at 20℃; | 2,4-Dibromothiazole (4.31 g, 17.7 mmol) are dissolved in anhydrous diethyl ether (170 ml) and the solution is cooled to -78 C. (dry ice-acetone bath). n-Butyllithium (1.6 M in hexanes, 13 ml, 20.8 mmol) is added dropwise to the reaction mixture and the resulting solution is stirred at the same temperature for 30 minutes. Anhydrous DMF (ml, mmol) is then added at -78 C. and, after being stirred at the -78 C. for 30 minutes, the reaction mixture is warmed to room temperature over a period of 2 hours. Hexanes (300 ml), were added and the resulting mixture is passed through a short silica cake eluting with 30% EtOAc-hexanes. The solvents are evaporated to yield the crude aldehyde which is used directly in the next step. To a solution of the above aldehyde in MeOH (80 ml) is added sodium borohydride (g, mmol), and the resulting mixture is stirred room temperature for hours. Hexanes (300 ml) are added and the mixture is passed through a short silica cake eluting with EtOAc. The crude alcohol is further purified by flash chromatography on silica with 20-50% EtOAc-hexanes as an eluant to yield g (mmol, %) of the pure desired product. |
With sodium tetrahydroborate; In methanol; at 0 - 25℃;Inert atmosphere; | In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), <strong>[167366-05-4]4-bromo-thiazole-2-carbaldehyde</strong> (1.68 g, 8.75 mmol) was dissolved in MeOH (10 mL). NaBH4 (428 mg, 10.86 mmol) was added portionwise at 0 0C and the reaction mixture stirred at rt for 1 h. Water (10 mL) was added and the mixture extracted with EA (3 x 20 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (6:1 -> 2:1 hept-EA) gave the title compound as a pale yellow solid. TLC: rf (1 :1 hept-EA) = 0.31. LC-MS-conditions 02: tR = 0.62 min [M+H]+ = 194.31. | |
With sodium tetrahydroborate; In methanol; at 20℃; | To an ice-cold solution of <strong>[167366-05-4]4-bromothiazole-2-carbaldehyde</strong> (1.78 g, 9.27 mmol, crude obtained above), in methanol (30 ml) was added NaBH4 (1.76 g, 46.35 mmol) portion wise. The resulting reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (TLC monitoring), the reaction mass was cooled to 0 C., quenched it with 25 ml of water and concentrated under vacuum. Added 50 ml water and extracted with EtOAc (3×100 ml). The combined organics was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified over silica gel (60-120 M, 10% EtOAc-Hexane) to get the desired product (1.40 g, 78%). MS: 194.01 (M+H)+. | |
With sodium tetrahydroborate; In methanol; at 0 - 20℃;Inert atmosphere; | (4-Bromo-thiazol-2-yl)-methanol:; In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), <strong>[167366-05-4]4-bromo-thiazole-2-carbaldehyde</strong> (1.68 g, 8.75 mmol) was dissolved in MeOH (10 ml_). NaBH4 (428 mg, 10.86 mmol) was added portionwise at 0 0C and the reaction mixture stirred at rt for 1 h. Water (10 ml.) was added and the mixture extracted with EA (3 x 20 ml_). The combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (6:1 ->; 2:1 hept-EA) gave the title compound as a pale yellow solid. TLC: rf (1 : 1 hept-EA) = 0.31. LC-MS-conditions 02: tR = 0.62 min [M+H]+ = 194.31. | |
To a solution (20 mL) of crude <strong>[167366-05-4]4-bromo-1,3-thiazole-2-carbaldehyde</strong> in ethanol was added sodium tetrahydroborate (935 mg, 24.7 mmol), and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained crude product was purified by column chromatography (hexane - hexane/ethyl acetate=75/25) to give the title compound (1.8 g, 44%) as a pale-yellow oil. 1H NMR (300 MHz, CHLOROFORM-d) delta ppm 2.60 (1 H, t, J=6.2 Hz), 4.96 (2 H, d, J=6.2 Hz), 7.22 (1 H, s) | ||
865 mg | With methanol; sodium tetrahydroborate; In tetrahydrofuran; at 0 - 35℃; for 1h; | A) (4-bromothiazol-2-yl)methanol To a solution of <strong>[167366-05-4]4-bromothiazole-2-carbaldehyde</strong> (1.20 g) in THF (10 mL) were successively added sodium borohydride (236 mg) and methanol (1.0 mL) at 0C, and the mixture was stirred at room temperature for 1 hr. 1N Hydrochloric acid was added, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (865 mg) as a colorless oil. 1H NMR (300 MHz, DMSO-d6) delta 4.72 (2H, d, J = 6.0 Hz), 6.19 (1H, t, J = 5.9 Hz), 7.75 (1H, s). |
3.28 g | With sodium tetrahydroborate; In methanol; at 20℃; for 0.333333h; | Step 1: (4-Bromo-thiazol-2-yI)-methanol [00308] To a solution of <strong>[167366-05-4]4-bromo-2-formylthiazole</strong> (4.00 g, 20.8 mmol) in methanol (60.0 mL, 1480 mmol) was slowly added sodium tetrahydroborate (0.946 g, 25.0 mmol), and the reaction was stirred at rt for 20 min. The reaction was concentrated in vacuo, diluted with EtOAc, and washed with water 2x and then brine l x. Organic layer was dried over Na2S04, filtered and concentrated in vacuo. The residue was purified via column chromatograpy (40g column, 20% - 50% EtOAc in hexanes over 30min) to give a light yellow oil. Yield = 3.28 g. NMR (400 MHz, Chloroform-d) delta 7.22 (s, 1H), 4.95 (d, J = 6.2 Hz, 2H), 2.76 (t, J = 6.2 Hz, 1H). LCMS (FA): 196.0 m/z (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With toluene-4-sulfonic acid; In toluene; for 12h;Dean-Stark; Reflux; | A toluene (120 mL) solution of <strong>[167366-05-4]4-bromothiazole-2-carbaldehyde</strong> (7 g, 36.50 mmol) and ethyleneglycol (2.72 g, 43.7 mmol) in a RB flask was added catalytic amount of pTsOH (0.347 g, 1.823mmol). The RB flask was attached with Dean-Stark apparatus and reaction mixture was heated to reflux for 12h. The mixture was cooled to RT, and was partitioned with saturated aqueous NaHCO3 solution. The organic layer was separated, washed with saturated aqueous NaHCO3 (2 X 120 mL) solution and then once with brine (100 mL). The organic layer was dried over anhydroussodium sulphate, filtered and the filtrate concentrated under reduced pressure. The residue was purified by combiflash chromatography (40 g Redisep 5i02 column, eluting with 20% EtOAc in pet ether) to afford the title compound 137A (8 g, 97%) as a colourless liquid. LC-MS retention time = 1.557 mm; m/z = 236.0 [M+2Hj + K1NETIX XB-C18, (3 X 75) mm, 2.6 micron column; Flow rate: 1 mL/min; Mobile Phase A: 10mM HCO2NH4in 98% Water/ 2% ACN; Mobile PhaseB: 10 mM HCO2NH4 in 2% Water/ 98% ACN; 20% B to 100% B over 4.6 mm, then hold 0.5 mm. at 20% B with flow rate 1-1.5 mL/min; Detection: UV at 254 nm. ?H NMR (400 MHz, DMSO-d6) oe 7.94 (s, 1H), 6.08 (s, 1H), 3.99 -4.08 (m, 4H). |
With toluene-4-sulfonic acid; In benzene; for 3h;Heating / reflux; | To a rb flask with an attached Dean-Stark trap containing molecular sieves, 4A (0.25g) was added <strong>[167366-05-4]4-bromothiazole-2-carbaldehyde</strong> (4.4 g, 22.91 mmol). The starting material was dissolved in Benzene (45 ml) and Ethylene glycol (1.406 ml, 25.2 mmol) was added followed by pTsOH (0.218 g, 1.146 mmol). The mixture was heated to reflux for 3 h. The mixture was cooled to rt, and was partitioned with sat. aq. NaHCO3. The mixture was washed 2* with sat. NaHCO3 (40 mL), then once with sat. NaCl (40 mL). The organic layer was dried with Na2SO4. The drying agent was removed by filtration, and the mixture was concentrated under reduced pressure. The residue was purified by biotage flash chromatography using a 40+M column and a 0 to 20% EtOAc in hexanes gradient. The product, 4-bromo-2-(1,3-dioxolan-2-yl)thiazole (5.1 g, 21.60 mmol, 94% yield), was collected as a light-yellow oil. To a solution of 4-bromo-2-(1,3-dioxolan-2-yl)thiazole (5.09 g, 21.56 mmol) in Toluene (100 ml) was added Hexamethylditin (10 g, 30.5 mmol) followed by Tetrakis (2.491 g, 2.156 mmol). The mixture was attached to a reflux condenser, and was flushed with N2. The mixture was heated to 100 C. for 4 h. The mixture was cooled to rt, and was loaded onto a 40+M biotage cartridge that was pre-saturated with hexanes with 0.1% Et3N. The desired product was purified using a 0-20% EtOAc in hexanes with 0.1% Et3N gradient. After concentrating in vacuo, the product, 2-(1,3-dioxolan-2-yl)-4-(trimethylstannyl)thiazole (4.64 g, 14.50 mmol, 67.3% yield), was isolated as a light-yellow oil. LCMS: m/e 322.0 (M+H)+, ret time 2.23 min (method 7); 1H NMR (500 MHz, CDCl3) delta ppm 7.39 (s, 1H) 6.20 (s, 1H) 4.03-4.20 (m, 4H) 0.27-0.42 (m, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2,4-Dibromothiazole (4.31 g, 17.7 mmol) are dissolved in anhydrous diethyl ether (170 ml) and the solution is cooled to -78 C. (dry ice-acetone bath). n-Butyllithium (1.6 M in hexanes, 13 ml, 20.8 mmol) is added dropwise to the reaction mixture and the resulting solution is stirred at the same temperature for 30 minutes. Anhydrous DMF (ml, mmol) is then added at -78 C. and, after being stirred at the -78 C. for 30 minutes, the reaction mixture is warmed to room temperature over a period of 2 hours. Hexanes (300 ml), were added and the resulting mixture is passed through a short silica cake eluting with 30% EtOAc-hexanes. The solvents are evaporated to yield the crude aldehyde which is used directly in the next step. To a solution of the above aldehyde in MeOH (80 ml) is added sodium borohydride (g, mmol), and the resulting mixture is stirred room temperature for hours. Hexanes (300 ml) are added and the mixture is passed through a short silica cake eluting with EtOAc. The crude alcohol is further purified by flash chromatography on silica with 20-50% EtOAc-hexanes as an eluant to yield g (mmol, %) of the pure desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 4-bromo-1 ,3-thiazole-2-carbaldehyde (192 mg, 1.0 mmol) in DCM (4.0 ml_) was added acetic acid (3 drops) and 2,2,2-trifluoroethanamine (120 mul_, 1.5 mmol). The reaction was stirred overnight. Sodium triacetoxyborohydride (335 mg, 1.5 mmol) was then added and reaction was stirred for 6 h. It was then quenched with sodium bicarbonate to yield 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1/-/-indole-7-carboxamide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | N-((4-bromothiazol-2-yl)methyl)cyclopropanamine <strong>[167366-05-4]4-bromothiazole-2-carbaldehyde</strong> (2.5 g, 13 mmol) was dissolved in tetrahydrofuran (65 mL) and cyclopropylamine (3.72 mL, 53.7 mmol) and sodium triacetoxyborohydride (11.4 g, 53.7 mmol) added. The reaction mixture was stirred 20 h at RT and then hydrolyzed at 0 C. with sat. sodium hydrogencarbonate sol. (150 mL). The product was extracted with ethyl acetate (2*300 mL) and the organic phase dried. (Yield: 3.0 g, 97%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; acetic acid; In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; | Example 354 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-piperidinylmethyl)-1,3-thiazol-4-yl]-1H-indole-7-carboxamide To a solution of <strong>[167366-05-4]4-bromo-1,3-thiazole-2-carbaldehyde</strong> (192 mg, 1.0 mmol) in DCM (4.0 mL) was added piperidine (150 ul, 1.5 mmol) and 3 drops of AcOH. The mixture was stirred for 12 hr and then Na(OAc)3BH (0.335 g, 1.5 mmol) was added. After 6 hr. the mixture was quenched with Sat. NaHCO3 (4.0 mL) and brine (3.0 mL). The organic layer was separated and concentrated to give 166 mg of the title compound (64%). The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-[(2-methylpropyl)amino]methyl}-1,3-thiazol-4-yl)-1H-indole-7-carboxamide trifluoroacetate, substituting piperidine (78 mg, 0.3 mmol) for 2-methyl-1-propanamine to afford 15.5 mg of the title compound (51.6%). LC/MS=m/z 517.4 [M+H] Ret. Time: 1.29 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With sodium hydrogencarbonate; acetic acid; In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; | Example 351 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(4-morpholinylmethyl)-1,3-thiazol-4-yl]-1H-indole-7-carboxamide trifluoroacetate To a solution of <strong>[167366-05-4]4-bromo-1,3-thiazole-2-carbaldehyde</strong> (192 mg, 1.0 mmol) in DCM (4.0 mL) was added morpholine (130 ul, 1.5 mmol) and 3 drops of AcOH. The mixture was stirred for 12 hr and then Na(OAc)3BH (0.335 g, 1.5 mmol) was added. After 6 hr. the mixture was quenched with Sat. NaHCO3 (4.0 mL) and brine (3.0 mL). The organic layer was separated and concentrated to give 200 mg of 4-[(4-bromo-1,3-thiazol-2-yl)methyl]morpholine (76%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; potassium carbonate; acetic acid; dimethyl amine; In 1,4-dioxane; water; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; | Example 355 5-{2-[(dimethylamino)methyl]-1,3-thiazol-4-yl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate To a solution of <strong>[167366-05-4]4-bromo-1,3-thiazole-2-carbaldehyde</strong> (192 mg, 1.0 mmol) in DCM (4.0 mL) was added dimethyl amine (2.0M, 3.0 mL) and 3 drops of AcOH. The mixture was stirred for 48 hr and then Na(OAc)3BH (1.33 g, 6.0 mmol) was added. After 12 hr. the mixture was quenched with Sat. NaHCO3 (4.0 mL) and brine (3.0 mL) and separator was used to get the DCM organic layer. The organic layer was concentrated to give 90 mg of desired product (40%). To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (46 mg, 0.1 mmol), dimethylamine (69 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol) in dioxane (2 mL) and water (0.7 mL) was added triacetoxyborohydride (12 mg, 0.01 mmol). This mixture was degassed for 5 min. The mixture was then reacted in a microwave for 20 min at 160 C. The organic layers were separated and concentrated. It was then purified using Gilson Preparatory HPLC to afford 23 mg of the title compound (59%) LC/MS=m/z 474.4 [M+H] Ret. Time: 1.20 |
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