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CAS No. : | 693-95-8 | MDL No. : | MFCD00005340 |
Formula : | C4H5NS | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | QMHIMXFNBOYPND-UHFFFAOYSA-N |
M.W : | 99.15 | Pubchem ID : | 12748 |
Synonyms : |
|
Num. heavy atoms : | 6 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.25 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 27.08 |
TPSA : | 41.13 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.22 cm/s |
Log Po/w (iLOGP) : | 1.54 |
Log Po/w (XLOGP3) : | 0.97 |
Log Po/w (WLOGP) : | 1.45 |
Log Po/w (MLOGP) : | 0.05 |
Log Po/w (SILICOS-IT) : | 2.68 |
Consensus Log Po/w : | 1.34 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.68 |
Solubility : | 2.06 mg/ml ; 0.0208 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.42 |
Solubility : | 3.76 mg/ml ; 0.0379 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.6 |
Solubility : | 2.49 mg/ml ; 0.0251 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.78 |
Signal Word: | Danger | Class: | 3 |
Precautionary Statements: | P210-P233-P240-P241-P242-P243-P261-P264-P270-P271-P280-P301+P312+P330-P303+P361+P353-P304+P340+P312-P305+P351+P338-P332+P313-P337+P313-P370+P378-P403+P233-P403+P235-P405-P501 | UN#: | 1993 |
Hazard Statements: | H225-H302-H315-H319-H335 | Packing Group: | Ⅲ |
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 |
---|---|---|
37% | at 0 - 20℃; | Preparation 85 -Bromo-4-methylthiazoleAdd bromine (9.27 mL, 182 mmol) to a solution of 4-methylthiazole (15.0 g, 152 mmol) in acetic acid (30 mL) at 0 0C. Slowly warm the reaction mixture to room temperature and stir overnight. Dilute with dichloromethane and wash with 1 N NaOH and brine. Dry the organic layer over sodium sulfate, filter, and concentrate under vacuum. Purify the crude product by silica gel column chromatography, elueting with hexanes/ethyl acetate (5/1) to obtain the title compound (9.94 g, 37percent). 1H NMR (400 MHz, CDCl3): δ 8.69 (s, IH), 2.43 (s, 3H). |
22% | at 20℃; for 16 h; | 4-methyl-5-bromothiazole 4-methylthiazole (200 uL, 2. 2mmol) and bromine (112 pL, 2. 2mmol) in acetic acid (2 mL) were protected from the light and stirred for 16 hours at room temperature. The mixture was washed with 10percent aqueous sodium carbonate and extracted with ethyl acetate. The organic layers were washed with brine, dried over Na2SO4 and evaporated to give 4-methyl-5- bromothiazole (0.085 g, 22percent). 8 (1H, 400MHz, CDCl3) 2.45 (3H, s), 8.69 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.2% | With potassium permanganate In water at 55℃; for 22 h; | 4-methylthiazole (19.8 g, 0.2 mol),200 mL of water and potassium permanganate (173.8 g, 1.1 mol) were placed in a 500 mL three-neck reaction flask and heated to 55° C. for 22 h with stirring and heating.The reaction solution was then cooled and then filtered. The filter cake (manganese dioxide) was washed with hot water at 50°C, and the filtrate was adjusted to pH 3 with dilute hydrochloric acid.A solid precipitated and was filtered. The filter cake was washed with a small amount of water. The product was dried to give 18.1 g, yield 70.2percent, melting point 196-198°C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid; zinc |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With water; mercury(II) oxide | ||
With hydrogenchloride; dihydrogen peroxide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: 4-Methylthiazole With n-butyllithium In diethyl ether; n-heptane at -78 - -60℃; for 0.75h; Inert atmosphere; Stage #2: acetone In diethyl ether; n-heptane at -60℃; for 0.5h; Inert atmosphere; Stage #3: With ammonium acetate In diethyl ether; n-heptane Inert atmosphere; | |
With n-butyllithium 1.) -77 deg C, 45 min, 2.) 1.5 h; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.2% | With potassium permanganate; In water; at 55℃; for 22h; | 4-methylthiazole (19.8 g, 0.2 mol),200 mL of water and potassium permanganate (173.8 g, 1.1 mol) were placed in a 500 mL three-neck reaction flask and heated to 55° C. for 22 h with stirring and heating.The reaction solution was then cooled and then filtered. The filter cake (manganese dioxide) was washed with hot water at 50°C, and the filtrate was adjusted to pH 3 with dilute hydrochloric acid.A solid precipitated and was filtered. The filter cake was washed with a small amount of water. The product was dried to give 18.1 g, yield 70.2percent, melting point 196-198°C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: 4-Methylthiazole With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1h; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran; hexane at -78 - 20℃; for 3h; | |
72% | Stage #1: 4-Methylthiazole With n-butyllithium In tetrahydrofuran; diethyl ether at -78℃; for 1.5h; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran; diethyl ether at -78 - 16℃; for 12h; | |
60.8% | Stage #1: 4-Methylthiazole With n-butyllithium In tetrahydrofuran at -70℃; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at -70 - 20℃; | 94 PREPARATION 944-Methylthiazole-2-carbaldehydeTo a solution of 4-methylthiazole (9 g, 90.9 mmol) in dry THF (200 mL) was added n- BuLi (2.5 M, 54.5 mL, 136.4 mmol) drop-wise at -70°C, and the mixture was stirred at - 70°C for 1.5 hour, DMF (1 1 mL) was added to the slurry over 15 min, and the mixture was slowly warmed to room temperature and stirred overnight. TLC (petroleum ethenEtOAc 10:1 ) indicated the reaction was completed. The mixture was warmed to 0°C, and quenched by saturated NH4CI solution (100 mL). The mixture was acidified by 2N HCI to pH ~ 4, and extracted with EtOAc (100 mL χ 3). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate, and concentrated in vacuum to give the title compound as a brown oil (7.0 g, 60.8%). |
Stage #1: 4-Methylthiazole With n-butyllithium In tetrahydrofuran at -78℃; for 0.5h; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at 20℃; | 1.1 Example 1: Synthesis of Heterocycle AlcoholsExample 1.1: Methylthiazole Methanol; [0278] Methylthiazole (1.0 g, 10.1 mmol) in THF at - 78 0C was treated with n-BuLi (1.6 M, 7.56 niL) for 30 min, DMF (1.4 niL, 18.2 mmol) was added dropwise. The resulting reaction mixture was warmed to r.t. After the starting material was disappeared (by TLC), the reaction mixture was recooled to 0 0C and LAH (0.69 g, 18.5 mmol) was added. The mixture was warmed to r.t. and stirred for 1 h, the reaction was quenched with aquoues NH4Cl, diluted with EtOAc. The organic solution was separated, extracted twice with EtOAc, dried with Na2SO4, and concentrated. The residue was purified with flash chromatography to give the corresponding alcohol as a light yellow oil. 1H-NMR: (300 MHz, CDCl3), δ: 6.89 (s, 1 H); 4.95 (s, 2 H); 2.48 (s, 3 H). | |
Stage #1: 4-Methylthiazole With n-butyllithium In hexanes; diethyl ether at -78℃; for 1.5h; Stage #2: N,N-dimethyl-formamide In hexanes; diethyl ether at -78 - 20℃; | 1.1.6 [0284] To a solution of BuLi (1.6 M in hexanes, 12.6 mL, 20.2 mmol) in 25mL of diethyl ether at -78 °C, was added a solution of 5-methylthiazole (2.0 g, 20.2 mmol) in ether (6 mL), drop-wise and stirred at -78 °C for 1.5 h. A solution of DMF (2.33 mL, 30.3 mmol in ether (5 mL) was added at once and the reaction mixture was allowed to warm to room temperature and stirred overnight. Ice was added to the reaction mixture followed by the slow addition of 4N HC1. The mixture was taken up in a separating funnel, ether added (30 mL) and shaken. The organic layer was discarded. The aqueous layer was brought to pH -7.5 with solid NaHC03 and extracted with ether twice. The ether layer was dried over Na2S04 and concentrated, and the resulting crude 5- methylthiazole-2-carbaldehyde (1.6 g) was carried over to the next- step without purification. | |
With n-butyllithium In tetrahydrofuran at -70℃; | 9 Intermediate -94-Methyl-thiazole-2-carbaldehydeTo a cold solution of 4-methyl thiazole (1.0 g, 0.010 mol) in THF was added n-BuLi (0.775 g, 0.012 mol) at -70°C. The reaction mass was stirred for 30-40 mins. DMF was added and the reaction mixture was stirred for 2-3 hours at -70°C. The reaction mass was quenched in cold water and acidified with dil acetic acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 0.800 g of desired product. 'HNMR (DMSO-d6): δ 2.58 (s, 3H), 7.35 (s, 1H), 9.96 (s, 1H); MS [M+H]+ : 127.20. | |
Stage #1: 4-Methylthiazole With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 2h; Inert atmosphere; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran; hexane at -78 - 20℃; | I I. 4-Methylthiazole-2-carbaldehyde I. 4-Methylthiazole-2-carbaldehyde To a solution of 4-methylthiazole (30 g, 303 mmol) in anhydrous tetrahydrofuran (500 mL) stirred under nitrogen at -78 °C was added a solution of butyllithium (121 mL, 303 mmol) dropwise. The reaction mixture was stirred at -78 °C for 2 hours. Then anhydrous N,N- dimethylformamide (47.1 mL, 605 mmol) was added dropwise to the suspension. The reaction was warmed to room temperature slowly and stirred overnight. It was quenched by saturated solution of NH4CI (300 mL) and extracted with ethyl acetate (300 mL x 3). The organic layers were combined and dried over anhydrous Na2S04 and filtered. The filtrate was concentrated to give crude 4-methylthiazole-2-carbaldehyde (33.5 g, yield 87%) as brown oil without further purification: 1H NMR (400 MHz, CDC13) δ 9.95 (s, 1H), 7.33 (s, 1H), 2.57 (s, 3H). | |
Stage #1: 4-Methylthiazole With n-butyllithium In tetrahydrofuran at -60℃; for 1h; Inert atmosphere; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at -60℃; for 0.5h; | 54.1 Step 1 Synthesis of (4-methylthiazol-2-yl)methanol Step 1 Synthesis of (4-methylthiazol-2-yl)methanol To a solution of 4-methylthiazole (1.0 g, 10.1 mmol) in THF (30 mL) was added n-BuLi (7.56 mL, 13.48 mmol) dropwise under a nitrogen atmosphere at -60 °C. The reaction was stirred for 1 h; then DMF (1.4 ml, 18.2 mmol) was added dropwise while maintaining -60 °C. The resulting mixture was stirred at this temperature for 30 min. The reaction was quenched with aqueous saturated ammonium chloride (5 mL) and partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a yellow oil. This oil was dissolved in methanol (15 ml) and sodium borohydride (460 mg, 12.1 mmol) was added portionwise under nitrogen atmosphere at -60 °C. The mixture was stirred at this temperature for 1 h. The reaction mixture was quenched with acetone, warmed to room temperature, and concentrated. The residue was partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography eluting with petroleum ether/ ethyl acetate (3 : 1) to give (4-methylthiazol-2-yl)methanol (1 .3 g, 90.3%) as brown oil . LCMS retention time 0.375 min; LCMS MH+ 130. | |
Stage #1: 4-Methylthiazole With n-butyllithium In tetrahydrofuran at -60℃; for 1h; Inert atmosphere; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at -60℃; for 0.5h; Inert atmosphere; | 40.1 Synthesis of (4-methylthiazol-2-yl)methanol To a solution of 4-methylthiazole (1.0 g, 10.1 mmol) in tetrahydrofuran (30 mL) was added n-BuLi (7.56 mL, 13.48 mmol) dropwise under a nitrogen atmosphere at -60° C. The reaction was stirred for 1 hour; then DMF (1.4 ml, 18.2 mmol) was added dropwise while maintaining -60° C. The resulting mixture was stirred at this temperature for 30 min. The reaction was quenched with aqueous saturated ammonium chloride (5 mL). The mixture was partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a yellow oil. This yellow oil was dissolved in methanol (15 ml) and sodium borohydride (460 mg, 12.1 mmol) was added portionwise under nitrogen atmosphere at -60° C. The mixture was stirred at this temperature for 1 hour. The reaction mixture was quenched with acetone, warmed to room temperature, and concentrated. The residue was partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography eluting with petroleum ether/ethyl acetate (3:1) to give thiazol-2-ylmethanol (1.3 g, 90.3%) as brown oil. LCMS retention time 0.375 min; LCMS MH+ 130 | |
Stage #1: 4-Methylthiazole With n-butyllithium In diethyl ether; hexane at -78℃; for 2h; Stage #2: N,N-dimethyl-formamide In diethyl ether; hexane at 20℃; for 16h; | 1 Step 1 A three-necked round bottomed flask equipped with a teflon-coated stir bar was charged with diethyl ether (250 mL) and n-BuLi (241.98 mL, 604.96 mmol, 2.5 M in hexane) was transferred at -78° C. A solution of 4-methylthiazole (50.0 g, 504.13 mmol) in diethyl ether (200 mL) was added over a period of 30 min. The reaction mixture was turned into pale yellow suspension. After 1.5 hours, DMF (58.54 mL, 756.20 mmol) was added and stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was poured into cold aq. HC1 (400 mL, 4N) under stirring and separated the two layers. The organic layer was washed with cold aq. HC1 (2*80 mL, 4N)). The combined aq. layers were slowly basified with K2CO3 (pH 7) and extracted with diethyl ether (3*150 mL). The combined organic layers were dried over sodium sulfate and evaporated to dryness at room temperature under vacuum to afford 4-methylthiazole-2-carbaldehyde (60.0 g, crude) as a pale yellow liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With n-butyllithium In tetrahydrofuran; hexane at -80℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With bromine; acetic acid; at 0 - 20℃; | Preparation 85 -Bromo-4-methylthiazoleAdd bromine (9.27 mL, 182 mmol) to a solution of 4-methylthiazole (15.0 g, 152 mmol) in acetic acid (30 mL) at 0 0C. Slowly warm the reaction mixture to room temperature and stir overnight. Dilute with dichloromethane and wash with 1 N NaOH and brine. Dry the organic layer over sodium sulfate, filter, and concentrate under vacuum. Purify the crude product by silica gel column chromatography, elueting with hexanes/ethyl acetate (5/1) to obtain the title compound (9.94 g, 37%). 1H NMR (400 MHz, CDCl3): delta 8.69 (s, IH), 2.43 (s, 3H). |
22% | With bromine; acetic acid; at 20℃; for 16h; | 4-methyl-5-bromothiazole 4-methylthiazole (200 uL, 2. 2mmol) and bromine (112 pL, 2. 2mmol) in acetic acid (2 mL) were protected from the light and stirred for 16 hours at room temperature. The mixture was washed with 10% aqueous sodium carbonate and extracted with ethyl acetate. The organic layers were washed with brine, dried over Na2SO4 and evaporated to give 4-methyl-5- bromothiazole (0.085 g, 22%). 8 (1H, 400MHz, CDCl3) 2.45 (3H, s), 8.69 (1H, s). |
200 mg | With bromine; acetic acid; at 0℃; | Compound 47a (400 mg, 4.04 mmol) was dissolved in 10 mL of glacial acetic acid.Bromine (176 mg, 4.44 mmol) was added at 0 C.The TLC was monitored until the starting material was completely converted. After the reaction, the reaction was quenched with a saturated sodium sulfite solution.Extracted with EtOAc, the organic phases were combined and dried over anhydrous sodium sulfate, filtered and the solvent was distilled off under reduced pressure, purified by silica gel column chromatography to obtain compound 47b (200mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-Bromosuccinimide; | PREPARATION 141(1) 4-Bromomethylthiazole (1.80 g) was obtained as an oil from 4-methylthiazole (1.00 g) and N-bromosuccinimide (1.97 g) in a manner similar to Preparation 91(2). NMR (DMSO-d6, delta): 4.65 (2H, s), 7.37 (1H, d, J=2 Hz), 8.82 (1H, d, J=2 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; In tetrahydrofuran; methanol; diethyl ether; hexane; | a Methyl 4-methyl-2-thiazole carboxylate To a solution of 4-methylthiazole (10 g) in anhydrous tetrahydrofuran (200 ml) was added n-butyl lithium in hexane (34.65 ml of 1.6M solution) dropwise at -78 C. The solution was stirred at -78 C. for 1 hour, at which point carbon dioxide gas was passed through the solution for 20 mins at -78 C. The solution was then allowed to warm to room temperature over 2 hours, the precipitate was filtered off, dissolved in methanol (200 ml) and added to methanolic hydrogen chloride (200 ml). The solution was stirred at room temperature overnight. The solvent was removed under vacuum and diethyl ether was added to the residue. The resultant solid was filtered off to yield the title compound as a white solid (2.2 g). 1H NMR (250 MHz, DMSO) delta 2.44 (3H, s), 3.89 (3H, s), 7.74 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With n-butyllithium In tetrahydrofuran; <i>N</i>-methyl-acetamide; hexane | 25 4-Methylthiazole-2-carboxaldehyde Preparation 25 4-Methylthiazole-2-carboxaldehyde A solution of 4-methylthiazole (0.91 mL, 10.0 mmol) in tetrahydrofuran (30 mL) was chilled to -78° C. and butyllithium (6.0 mL, 15 mmol, 2.5 molar solution in hexane) was added dropwise over 15 min. The pale yellow solution was stirred 1 h at -78° C. and became thick slurry. Dimethylformamide (1.2 mL, 15 mmol) was added to the reaction via syringe over 5 min. The reaction was stirred an additional 2 h at -79° C., then allowed to warm at 0° C. and poured onto wet ice. The acidity of the mixture was adjusted to pH 4 with 1 N HCl and extracted with ether. The combined ether extracts were washed with brine, dried over sodium sulfate and concentrated afford 4-methylthiazole-2-carboxaldehyde (0.734 g, 57%) as a brown oil. NMR δ9.88 (s, 1H), 7.29 (s, 1H), 2.50 (s, 3H). The material was used without further purification. |
57% | With n-butyllithium In tetrahydrofuran; <i>N</i>-methyl-acetamide; hexane | 25 4-Methylthiazole-2-carboxaldehyde Preparation 25 4-Methylthiazole-2-carboxaldehyde A solution of 4-methylthiazole (0.91 mL, 10.0 mmol) in tetrahydrofuran (30 mL) was chilled to -78°C and butyllithium (6.0 mL, 15 mmol, 2.5 molar solution in hexane) was added dropwise over 15 min. The pale yellow solution was stirred 1 h at -78°C and became thick slurry. Dimethylformamide (1.2 mL, 15 mmol) was added to the reaction via syringe over 5 min. The reaction was stirred an additional 2 h at -79°C, then allowed to warm at 0°C and poured onto wet ice. The acidity of the mixture was adjusted to pH 4 with 1 N HCI and extracted with ether. The combined ether extracts were washed with brine, dried over sodium sulfate and concentrated afford 4-methylthiazole-2-carboxaldehyde (0.734 g, 57%) as a brown oil. NMR δ 9.88 (s, 1H), 7.29 (s, 1H), 2.50 (s, 3H). The material was used without further purification. |
57% | With n-butyllithium In tetrahydrofuran; <i>N</i>-methyl-acetamide; hexane | 25 4-Methylthiazole-2-carboxaldehyde Preparation 25 4-Methylthiazole-2-carboxaldehyde A solution of 4-methylthiazole (0.91 mL, 10.0 mmol) in tetrahydrofuran (30 mL) was chilled to -78° C. and butyllithium (6.0 mL, 15 mmol, 2.5 molar solution in hexane) was added dropwise over 15 min. The pale yellow solution was stirred 1 h at -78° C. and became thick slurry. Dimethylformamide (1.2 mL, 15 mmol) was added to the reaction via syringe over 5 min. The reaction was stirred an additional 2 h at -79° C., then allowed to warm at 0° C. and poured onto wet ice. The acidity of the mixture was adjusted to pH 4 with 1 N HCl and extracted with ether. The combined ether extracts were washed with brine, dried over sodium sulfate and concentrated afford 4-methylthiazole-2-carboxaldehyde (0.734 g, 57%) as a brown oil. 1H NMR δ9.88 (s,1 H), 7.29 (s, 1 H), 2.50 (s, 3H). The material was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,4-dioxane; acetone | N-(2-hydroxypropyl)-4-methylthiazolium chloride hydrochloride N-(2-hydroxypropyl)-4-methylthiazolium chloride hydrochloride To a mixture of 4-methylthiazole (10.0 g) and dioxane (20ml) was further added 1-bromo-2-propanol (containing 20% of 2-bromo-1-propanol) (15.3 g), and the mixture was heated under reflux for about 6 hours. After cooling, the reaction was added with acetone (30 ml) and ether (130 ml) and left standing. After the pale brown supernatant was discarded, ether (150 ml) was further added to the amorphous precipitate to solidify it. Pale brown powder thus crystallized was collected by filtration and dried under reduced pressure. Yield: 8.74 g. NMR (in DMSO-d6): δ10.04 (1H, d, J=3 Hz), 8.01 (1H, q), 4.52 (1H, dd), 4.28 (1H, dd), 4.00 (1H, m), 2.56 (3H, d, J=1 Hz), 1.19 (3H, d, J=6 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8.6 g (33.5%) | With n-butyllithium In hexane | 15.a EXAMPLE 15 (a) To a solution of n-butyllithium (96 ml, 0.24 mol, 2.5M in hexane) in 200 ml of ether under argon at -78° C. was added dropwise in 1 h a solution of 4-methylthiazole (20 g, 0.0202 mol) in 100 ml of ether. The mixture was stirred at -78° C. for 1 h, and then a solution of N-formyl-morpholine (22 ml, 0.22 mol) in 120 ml of ether was added within 15 min. The mixture was stirred for 1 h at -78° C., then at 0°--5° C. overnight. The reaction mixture was then extracted with 4N HCl (4*40 ml), the aqueous layers were combined, cooled in an ice-bath, and neutralized with sodium bicarbonate solution (pH 9). The aqueous layer was extracted with ether (4*80 ml), the organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was distilled (80°-85° C./25 mm) to afford 8.6 g (33.5%) of 4-methyl-2-thiazolylcarboxaldehyde. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic anhydride; 3-chloro-benzenecarboperoxoic acid; In hydrogenchloride; methanol; dichloromethane; | a 4-Hydroxymethylthiazole A solution of m-chloroperbenzoic acid (57-58%, 61.1 g, 0.2 mol) in dichloromethane (500 ml) was added dropwise to a stirred solution of 4-methylthiazole (20 g, 0.2 mol) in dichloromethane (200 ml) at 0 C. When addition was complete the mixture was allowed to warm to room temperature and stirred for 18 h. The solvent was evaporated in vacuo to half its volume and the m-chlorobenzoic acid filtered off. This was repeated five times to give the crude N-oxide (31 g). The N-oxide (33 g) was added slowly to acetic anhydride (60 ml) at 110 C. with stirring. The mixture was heated at this temperature for 18 h, then cooled to room temperature and concentrated in vacuo. The residue was distilled i-n vacuo to give the crude acetate (9.58 g), bp 106-110 C. at 4 Torr. A solution of the acetate (9.58 g) in methanol/HCl solution (1:1) was stirred at room temperature for 4 h. The solvent was evaporated in vacuo and the residue partitioned between sodium hydroxide solution (4M) and dichloromethane. The aqueous phase was extracted into dichloromethane (6*) and the combined extracts were dried (MgSO4) and evaporated in vacuo. Flash chromatography on silica gel, eluding with 3% methanol/dichloromethane, gave the title-alcohol (1.22 g, 23%), 1H NMR (250 MHz, CDCl3) delta 4.85 (2H, s, CH2), 7.27 (1H, m, Ar-H), 8.81 (1H, m, Ar-H); MS (ES30) m/e 115 [MH]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; dichloromethane; water addn. of Au-complex in dichloromethane to LiCl+HClO4 in methanol:water (95:5 v/v) at 25 °C; detected by UV; |
Yield | Reaction Conditions | Operation in experiment |
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Example 1Synthesis of Heterocycle AlcoholsExample 1.1; Methylthiazole Methanol Methylthiazole (1.0 g, 10.1 mmol) in THF at -78 C. was treated with n-BuLi (1.6 M, 7.56 mL) for 30 min, DMF (1.4 mL, 18.2 mmol) was added dropwise. The resulting reaction mixture was warmed to r.t. After the starting material was disappeared (by TLC), the reaction mixture was recooled to 0 C. and LAH (0.69 g, 18.5 mmol) was added. The mixture was warmed to r.t. and stirred for 1 h, the reaction was quenched with aqeuous NH4Cl, diluted with EtOAc. The organic solution was separated, extracted twice with EtOAc, dried with Na2SO4, and concentrated. The residue was purified with flash chromatography to give the corresponding alcohol as a light yellow oil. 1H-NMR: (300 MHz, CDCl3), delta: 6.89 (s, 1H); 4.95 (s, 2H); 2.48 (s, 3H). | ||
Example 1.1: Synthesis of Amine Building Blocks.; Example 1.1.1: (4-methylthiazol-2-yl)methanamine; Methylthiazole (1.0 g, 10.1 mmol) in THF at - 78 0C was treated with n-BuLi (1.6 M, 7.56 mL) for 30 min, DMF (1.4 rnL, 18.2 mmol) was added dropwise. The resulting reaction mixture was warmed to r.t. After the starting material disappeared (by TLC), the reaction mixture was recooled to 0 0C and LAH (0.69 g, 18.5 mmol) was added. The mixture was warmed to r.t. and stirred for 1 h, the reaction was quenched with aqueous NH4Cl, diluted with EtOAc. The organic solution was separated, extracted twice with EtOAc, dried with Na2SO4, and concentrated. The residue was purified with flash chromatography to give the corresponding alcohol as a light yellow oil. 1H-NMR: (300 MHz, CDCl3), d: 6.89 (s, 1 H); 4.95 (s, 2 H); 2.48 (s, 3 H). | ||
[0269] Methylthiazole (1.0 g, 10.1 mmol) in THF at - 78 C was treated with n-BuLi (1.6 M, 7.56 mL) for 30 min, DMF (1.4 mL, 18.2 mmol) was added dropwise. The resulting reaction mixture was warmed to r.t. After the starting material disappeared (by TLC), the reaction mixture was recooled to 0 C and LAH (0.69 g, 18.5 mmol) was added. The mixture was warmed to r.t. and stirred for 1 h, the reaction was quenched with aqueous NH4C1, diluted with EtOAc. The organic solution was separated, extracted twice with EtOAc, dried with Na2S04, and concentrated. The residue was purified with flash chromatography to give the corresponding alcohol as a light yellow oil. 1H-NMR: (300 MHz, CDC13), delta: 6.89 (s, 1 H); 4.95 (s, 2 H); 2.48 (s, 3 H). |
Methylthiazole (1.0 g, 10.1 mmol) in tetrahydrofuran (THF) at - 78 C was treated with n-BuLi (1.6 M, 7.56 mL) for 30 min, dimethylformamide (DMF) (1.4 mL, 18.2 mmol) was added dropwise. The resulting reaction mixture was warmed to r.t. After the starting material disappeared (by TLC), the reaction mixture was recooled to 0 C and lithium aluminum hydride (LAH) (0.69 g, 18.5 mmol) was added. The mixture was warmed to r.t. and stirred for 1 h, the reaction was quenched with aqueous NH4C1, diluted with ethyl acetate (EtOAc). The organic solution was separated, extracted twice with EtOAc, dried with Na2S04, and concentrated. The residue was purified with flash chromatography to give the corresponding alcohol as a light yellow oil. 1H-NMR: (300 MHz, CDC13), delta: 6.89 (s, 1 H); 4.95 (s, 2 H); 2.48 (s, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
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12% | With chlorosulfonic acid; phosphorus pentachloride at 20 - 140℃; for 4h; | 42.1 Step 1: 4-methylthiazole-5-sulfonyl chloride Sulfurochloridic acid (50 mL) was added dropwise to 4-methylthiazole (10 g, 99.85 mmol) with stirring, while maintaining the temperature at RT followed by addition of PCl5 (10 g, 47.54 mmol). The resulting solution was allowed to react, with stirring, for 4 h while the temperature was maintained at 140° C. (reaction progress monitored by TLC (EtOAc/PE=1:1)). The reaction mixture was then quenched by the adding 500 g of ice/salt. The resulting solution was extracted with EtOAc (3*500 mL), the organics were combined, and dried over Na2SO4. The solvent was removed to afford 2.5 g (12%) of 4-methylthiazole-5-sulfonyl chloride as a brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36.7% | Stage #1: 4-Methylthiazole With n-butyllithium In hexanes; diethyl ether for 0.766667h; Cooling with acetone-dry ice; Stage #2: C12H13O2(CH3)3(O)(OO) In tetrahydrofuran; hexanes; diethyl ether at -78℃; for 1.08333h; Cooling with acetone-dry ice; Stage #3: With boron trifluoride diethyl etherate; acetic anhydride more than 3 stages; | 2 Example 2: DART-4-Me-thiaz[0179] A flame-dried 2 dram vial was loaded with a stir-bar, diethyl ether (880 μL), and 4- methylthiazole (17 μL, 0.18 mmol). The vial was immersed in a dry ice/acetone bath and after several minutes, n-BuLi (110 μL, 1.6 M sol in hexanes, 0.18 mmol) was added over a one minute period. The mixture was stirred for 45 minutes at which time the thiazole solution was added to a cooled (-78 0C) solution of artemisinin (50 mg, 0.18 mmol) in THF (880 μL) over 5 minutes. After 60 minutes, acetic anhydride (125 μL, 1.3 mmol) was added and the dry ice/acetone bath was replaced with an ice water bath. After two hours, BF3 etherate (160 μL, 1.3 mmol) was added and the cooling bath was removed. The reaction was allowed to warm to room temperature, RT, and stir at RT for two hours at which time the colorless mixture had turned light yellow. The reaction mixture was then poured into a separatory funnel containing dichloromethane (10 mL) and saturated aqueous sodium bicarbonate (5 mL). The organic layer was washed two additional times with saturated aqueous sodium bicarbonate (5 mL), once with saturated aqueous sodium chloride (5 mL), dried with magnesium sulfate, filtered, and concentrated, in vacuo, at 40 0C to afford 73 mg of crude product. The residue was purified by flash column chromatography (8.6 grams of silica gel; packed with 100 % hexanes; eluted with 10% ethyl acetate in hexanes) to give the product as a white crystalline solid (24 mg, 0.07 mmol, 36.7%). 1H NMR (CDCl3, 400 MHz): δ 6.82 (s, IH), 5.75 (s, IH), 2.45-2.37 (m, 4H), 2.23 (s, 3H), 2.11-2.02 (m, 2H), 1.98- 1.88 (m, 2H), 1.73-1.69 (m, IH), 1.61-1.55 (m, IH), 1.46-1.44 (m, 4H), 1.36-1.24 (m, 2H), 1.19-1.09 (m, IH), 1.00-0.99 (d, J = 1.2 Hz, 3H). 13C NMR (CDCl3, 100 MHz): δ 164.1, 152.7, 138.2, 113.1, 110.3, 104.5, 90.3, 78.4, 50.7, 47.9, 37.6, 36.1, 34.2, 29.0, 25.6, 24.5, 20.1, 17.4, 17.1. |
Yield | Reaction Conditions | Operation in experiment |
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Example 1.1: Synthesis of Amine Building Blocks.; Example 1.1.1: (4-methylthiazol-2-yl)methanamine; Methylthiazole (1.0 g, 10.1 mmol) in THF at - 78 0C was treated with n-BuLi (1.6 M, 7.56 mL) for 30 min, DMF (1.4 rnL, 18.2 mmol) was added dropwise. The resulting reaction mixture was warmed to r.t. After the starting material disappeared (by TLC), the reaction mixture was recooled to 0 0C and LAH (0.69 g, 18.5 mmol) was added. The mixture was warmed to r.t. and stirred for 1 h, the reaction was quenched with aqueous NH4Cl, diluted with EtOAc. The organic solution was separated, extracted twice with EtOAc, dried with Na2SO4, and concentrated. The residue was purified with flash chromatography to give the corresponding alcohol as a light yellow oil. 1H-NMR: (300 MHz, CDCl3), d: 6.89 (s, 1 H); 4.95 (s, 2 H); 2.48 (s, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With C82H77Cl2N3O2Pd; potassium carbonate; Trimethylacetic acid; In N,N-dimethyl acetamide; at 130℃; for 4h; | General procedure: Typically, (hetero)aryl bromide (1.0 mmol), thiazole derivatives(2.0 mmol), Pd-PEPPSI complexes (0.01e0.5 mol%), base (2 mmol),acid additive (0.3 mmol), and 3mL of DMAc solvent were addedinto a parallel reactor. After heating at 130 C for 4 h, the resultingmixture was cooled to room temperature. Subsequently, 25mL ofwater and 20 mL of dichloromethane were added into the reactor,and the mixture was stirred for another several minutes, followedby extraction three times with dichloromethane (3 x 5 mL). Theorganic layer was then combined, dried over anhydrous sodiumsulfate, filtered, and evaporated under reduced pressure to give thecrude products. The crude products were then purified by silica-gelcolumn chromatography using petroleum etheredichloromethane(15/1) as the eluent. The obtained pure products were characterizedby 1H NMR and 13C NMR spectroscopy, and the spectra can be foundin the Supporting Information. And the isolated yields of productswere obtained based on the amounts of (hetero)aryl bromides. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | To a stirred solution of n-BuLi (2M in pentane ; 22.4 ML9 0.045 mol) in 70 ML of dry ether AT-78°C was added dropwise 4-METHYLTHIAZOLE (3.7 g, 0.037 mol) in 30 ML of ether over a period of 30 minutes. The mixture was stirred for LH, then N-METHOXY-N- methylacetamide (4.37 mL, 0.041 mol) was added dropwise over 10 minutes. After Ih of stirring AT-78°C THE REACTION MIXTURE WAS WASHED WITH SAT D NAHCO3 AND EXTRACTED WITH ether. The organic layer was dried with NA2S04 and concentrated in vacuo to give 4. 38 g (85percent) of 2a as an oil that was used directly for the next STEP. 1H NMR (CDC13) 6 7.2 (s, 1H), 2.75 (s, 3H), 2.5 (s, 3H). | |
39% | With n-butyllithium; In hexane; at -78℃; for 2.5h; | Step 1-Synthesis of 1-(4-methyl-1,3-thiazol-2-yl)ethan-1-oneTo a solution of n-butyllithium (2.5M in hexane, 14.4 mL) maintained under nitrogen at -78° C. was added a solution of 4-methyl-1,3-thiazole (3 g, 30.26 mmol) in ether (20 mL).The reaction mixture was stirred at -78° C. for 20 min. <strong>[78191-00-1]N-Methoxy-N-methylacetamide</strong> (3.4 g, 32.97 mmol) was then added dropwise to the reaction mixture over 10 min.The resulting solution was stirred at -78° C. for 2 hr and then quenched by the addition of aqueous sodium bicarbonate (20 mL).The resulting solution was extracted with ether (3*50 mL).The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo.The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1/5) to give 2.1 g (39percent) of 1-(4-methyl-1,3-thiazol-2-yl)ethan-1-one as a yellow oil: 1H NMR (300 MHz, CDCl3) delta 7.25 (s, 1H), 2.71 (s, 3H), 2.51 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With acetic acid; In N,N-dimethyl-formamide; at 105 - 110℃; for 8h;Green chemistry; | 14.6 g (0.1 mol, 98percent, Belling Technology Co., Ltd.) <strong>[20485-41-0]4-methylthiazole-5-carboxylic acid</strong> was dissolved in 45.0 g of N,N-dimethylformamide and 0.32 g of acetic acid (0.002 mol, 37percent). Heat 105-110 ° C, stir the reaction for 8 hours, The solvent was distilled off under reduced pressure to give 4-methylthiazole; The NMR data was consistent with the reported compound with a yield of 95percent and a purity of 98percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium acetate; palladium diacetate; In N,N-dimethyl acetamide; at 150℃; for 19h;Inert atmosphere; | Alternate Route: 4-bromobenzonitrile (5.1 g, 28 mmol, 1 eq), 4-methylthiazole (5.56 g, 56 mmol, 2 eq) potassium acetate (5.5 g, 56 mmol, 2 eq), palladium (II) acetate (63 mg, 0.28 mmol, 1 mol %) were dissolved in dimethylacetamide and stirred under argon. (CITE JOC, 2009, 74, 1179) The mixture was heated to 150 C. and stirred for 19 hours, then diluted with 500 mL EtOAc, and washed 4 times with 300 mL water. The first wash was then back extracted with 300 mL EtOAc, and then washed 4 times with 100 mL water. The combined organic layer was dried over sodium sulfate, filtered and concentrated under vacuum to give a beige solid (5.55 g, 27.7 mmol, 99%) that matched the reported spectral data.[8] The solid was then dissolved in MeOH (280 mL) and cooled to 4 C. Cobalt chloride (9.9 g, 41.6 mmol, 1.5 eq) was added, followed by the slow, portionwise addition of sodium borohydride (5.2 g, 139 mmol, 5 eq), which was accompanied by vigorous bubbling. After 90 minutes, the reaction was quenched by the addition of water and ammonium hydroxide. The mixture was extracted 4 times with chloroform, and purified by column chromatography (10 to 30% 0.5M NH3 (MeOH)/DCM) to give a darker oil (4.12 g, 20.2 mmol, 73%). |
99% | With potassium acetate; palladium diacetate; at 150℃; for 19h;Inert atmosphere; | Alternate Route: 4-bromobenzonitrile (5.1 g, 28 mmol, 1 eq), 4-methylthiazole (5.56 g, 56 mmol, 2 eq) potassium acetate (5.5 g, 56 mmol, 2 eq), palladium (II) acetate (63 mg, 0.28 mmol, 1 mol %) were dissolved in dimethylacetamide and stirred under argon (J. Org. Chem. 2009, 74:1179). The mixture was heated to 150 C. and stirred for 19 hours, then diluted with 500 mL EtOAc, and washed 4 times with 300 mL water. The first wash was then back extracted with 300 mL EtOAc, and then washed 4 times with 100 mL water. The combined organic layer was dried over sodium sulfate, filtered and concentrated under vacuum to give a beige solid (5.55 g, 27.7 mmol, 99%) that matched the reported spectral data. The solid was then dissolved in MeOH (280 mL) and cooled to 4 C. Cobalt chloride (9.9 g, 41.6 mmol, 1.5 eq) was added, followed by the slow, portionwise addition of sodium borohydride (5.2 g, 139 mmol, 5 eq), which was accompanied by vigorous bubbling. After 90 minutes, the reaction was quenched by the addition of water and ammonium hydroxide. The mixture was extracted 4 times with chloroform, and purified by column chromatography (10 to 30% 0.5M NH3 (MeOH)/DCM) to give a darker oil (4.12 g, 20.2 mmol, 73%). |
97% | With potassium acetate; palladium diacetate; In N,N-dimethyl acetamide; at 150℃; | To a solution of 4-bromobenzonitrile (1.5 g, 8.24 mmol, 1 equiv.) and Pd(OAc)2 (2 mg, 0.08mmol, 0.1mol%) in DMAc (8mL) were added KOAc (1.62g, 16.5 mmol, 2 equiv.) and 4-methylthiazole (1.63 g, 1.49 mL, 16.5 mmol, 2 equiv.). The resulting mixture was heated to 150 C and stirred overnight. The mixture was diluted with water and extracted with DCM (3x). The combined organic phases were dried over MgS04 and evaporated under reduced pressure to give the corresponding cyano derivate as a beige solid (1.67 g, 7.99 mmol, 97%) that matched the reported spectral data. A solution of the cyano-derivate product (270mg, 1.3mmol, 1 equiv.) in methanol (15mL) was cooled to 0C. CoCl (282 mg, 2.2 mmol, 1.5 equiv.) was added, followed by portion-wise addition of NaBH4 (274 mg, 7.2 mmol, 5 equiv.). The resulting mixture was stirred for 90 min, the reaction was quenched with water and ammonium hydroxide, and the mixture was extracted with chloroform (6x). The combined organic phases were dried over MgS04 and evaporated under reduced pressure to give a dark-brown oil which was purified by flash column chromatography to yield the desired product, preparative compound (4) as a yellow oil (76.5 mg, 0.40 mmol, 29% (isolated)) that matched the reported spectral data. |
95% | With C82H77Cl2N3O2Pd; potassium carbonate; Trimethylacetic acid; In N,N-dimethyl acetamide; at 130℃; for 4h; | General procedure: Typically, (hetero)aryl bromide (1.0 mmol), thiazole derivatives(2.0 mmol), Pd-PEPPSI complexes (0.01e0.5 mol%), base (2 mmol),acid additive (0.3 mmol), and 3mL of DMAc solvent were addedinto a parallel reactor. After heating at 130 C for 4 h, the resultingmixture was cooled to room temperature. Subsequently, 25mL ofwater and 20 mL of dichloromethane were added into the reactor,and the mixture was stirred for another several minutes, followedby extraction three times with dichloromethane (3 x 5 mL). Theorganic layer was then combined, dried over anhydrous sodiumsulfate, filtered, and evaporated under reduced pressure to give thecrude products. The crude products were then purified by silica-gelcolumn chromatography using petroleum etheredichloromethane(15/1) as the eluent. The obtained pure products were characterizedby 1H NMR and 13C NMR spectroscopy, and the spectra can be foundin the Supporting Information. And the isolated yields of productswere obtained based on the amounts of (hetero)aryl bromides. |
91% | With potassium acetate; palladium diacetate; In N,N-dimethyl acetamide; at 20 - 150℃; for 5h;Inert atmosphere; | [0400] Step 1: Synthesis of 4-(4-methyl-l,3-thiazol-5-yl)benzonitrile (G)[0401] To a stirred solution of 4-bromobenzonitrile (E, 20 g, 109.88 mmol) in DMA (250 mL) under a nitrogen atmosphere was added 4-methyl-l,3-thiazole (F, 21.88 g, 220.67 mmol), palladium (II) acetate (743 mg, 3.31 mmol) and potassium acetate (21.66 g, 220.71 mmol) at rt. The resulting solution was heated to 150 C and stirred at this temperature for 5 h, LC-MS indicated formation of the desired product. The reaction was cooled to rt, diluted with 1 L of water and extracted with ethyl acetate (300 mL x 3). The organic layers were combined, washed with saturated aqueous solution of sodium chloride (200 mL), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether, v: v = 1:5) to give the G (yield: 91%) as a white solid. |
91% | With potassium acetate; palladium diacetate; In N,N-dimethyl acetamide; at 150℃; for 5h;Inert atmosphere; | To a stirred solution of 4-bromobenzonitrile (20 g, 109.88 mmol) in DMA (250 mL) under a nitrogen atmosphere was added 4-methyl-1,3-thiazole (21.88 g, 220.67 mmol), palladium (II) acetate (743 mg, 3.31 mmol) and potassium acetate (21.66 g, 220.71 mmol) at rt. The resulting solution was heated to 150 C. and stirred at this temperature for 5 h, at which time LC-MS indicated completion of reaction. The reaction was cooled to rt, diluted with 1 L of water and extracted with ethyl acetate (300 mL*3). The organic layers were combined, washed with saturated aqueous solution of sodium chloride (200 mL), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether, v:v=1:5) to give the titled compound (yield: 91%) as a white solid. |
91% | With palladium diacetate; potassium carbonate; In N,N-dimethyl acetamide; at 150℃; for 5h;Inert atmosphere; | To a stirred solution of 4-bromobenzonitrile (20 g, 109.88 mmol) in DMA (250 mL) under a nitrogen atmosphere was added 4-methyl-l,3-thiazole (21.88 g, 220.67 mmol), palladium (II) acetate (743 mg, 3.31 mmol) and potassium acetate (21.66 g, 220.71 mmol) at rt. The resulting mixture was heated to 150 C and stirred at this temperature for 5 h, at which time LC-MS indicated completion of the reaction. The mixture was cooled to rt, diluted with 1 L of water and extracted with ethyl acetate (300 mL x 3). The organic layers were combined, washed with brine (200 mL), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel column chromatography (eluent: ethyl acetate/petroleum ether, v: v = 1:5) to give the titled compound (yield: 91%) as a white solid. |
91% | With potassium acetate; palladium diacetate; In N,N-dimethyl acetamide; at 150℃; for 5h;Inert atmosphere; | To a stirred solution of 4-bromobenzonitrile (E, 20 g, 109.88 mmol) in DMA (250 mL) under a nitrogen atmosphere was added 4-methyl-1,3-thiazole (F, 21.88 g, 220.67 mmol), palladium (II) acetate (743 mg, 3.31 mmol) and potassium acetate (21.66 g, 220.71 mmol) at rt. The resulting solution was heated to 150 C. and stirred at this temperature for 5 h, LC-MS indicated formation of the desired product. The reaction was cooled to rt, diluted with 1 L of water and extracted with ethyl acetate (300 mL*3). The organic layers were combined, washed with saturated aqueous solution of sodium chloride (200 mL), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether, v:v=1:5) to give the G (yield: 91%) as a white solid. |
91% | With potassium acetate; palladium diacetate; In N,N-dimethyl acetamide; at 150℃; for 5h; | Into a l-L round -bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-bromobenzonitrile (20 g, 109.88 mmol, LOO equiv) in DMA (250 mL), 4-methyl- 1, 3 -thiazole (21.88 g, 220.67 mmol, 2.00 equiv), Pd(OAc)2 (743 mg, 3.31 mmol, 0.03 equiv) and KOAc (21.66 g, 220.71 mmol, 2.00 equiv). The resulting solution was stirred for 5 hours at l50C. The reaction mixture was cooled with a water/ice bath and diluted with 1 L of water. The resulting solution was extracted with 3x300 mL of ethyl acetate. The combined organic layers were washed with 3x300 mL of water and 1x300 mL of brine, then dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on combi-flash with ethyl acetate/petroleum ether (1: 100-1:5). This resulted in 20 g (91%) of 4- (4-methyl-l,3-thiazol-5-yl)benzonitrile as a beige solid. |
91% | With potassium acetate; palladium diacetate; In N,N-dimethyl acetamide; at 150℃; for 5h;Inert atmosphere; | Into a 1-L round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-bromobenzonitrile (20 g, 109.88 mmol, 1.00 equiv) in DMA (250 mL), 4-methyl-1,3-thiazole (21.88 g, 220.67 mmol, 2.00 equiv), Pd(OAc)2 (743 mg, 3.31 mmol, 0.03 equiv) and KOAc (21.66 g, 220.71 mmol, 2.00 equiv). The resulting solution was stirred for 5 h at 150C. The reaction mixture was cooled with a water/ice bath and diluted with 1 L of water. The resulting solution was extracted with 3x300 mL of ethyl acetate. The combined organic layers were washed with 3x300 mL of water and 1x300 mL of brine, then dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on combi- flash with ethyl acetate/petroleum ether (1:100-1:5). This resulted in 20 g (91%) of 4-(4-methyl- 1,3-thiazol-5-yl)benzonitrile as a beige solid. |
82% | With palladium diacetate; In N,N-dimethyl acetamide; at 150℃; for 2h;Inert atmosphere; | To a mixture of 4-bromobenzonitrile (32.0 g, 176 mmol), 4-methylthiazole (34.86 g, 352 mmol) and KOAc (34.5 g, 352 mmol) in DMA (100 mL) was added Pd(OAc)2 (820 mg, 3.65 mmol). The mixture was stirred at 150 C. under nitrogen atmosphere for 2 hours. On completion, the mixture was diluted with water (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product. The crude product was triturated with PE (100 mL) and filtered to give the title compound (28.8 g, 82% yield) as a yellow solid. 1H NMR (400 MHz, MeOD-d4) delta 8.98 (s, 1H), 7.85-7.81 (m, 2H), 7.71-7.66 (m, 2H), 2.53 (s, 3H); LC-MS (ESI+) m/z 201.0 (M+H)+. |
77% | With copper(l) iodide; potassium acetate; palladium diacetate; In N,N-dimethyl acetamide; at 150℃;Inert atmosphere; | Measure 4-bromobenzonitrile (7.0g, 38.5mmol), Pd(OAc)2 (43.2mg, 0.19mmol) andKOAc (5.67g, 57.8mmol) was placed in a two-necked flask. After argon protection, DMAc (40mL) and 4-methylthiazole (5.3mL, 57.8mmol) were added and heated at 150C overnight.After cooling, the solvent DMAC was spin-dried, extracted with water and ethyl acetate, the organic layer was separated and washed with saturated brine,Dry with Na2SO4, spin-dry the solvent under reduced pressure, and pass through silica gel column chromatography (petroleum ether/ethyl acetate=5:1)Purification of the residue gave 38 as a white solid (5.9 g, 29.5 mmol, 77% yield): |
73% | With PdCl(C3H5)(1,4-bis(diphenylphosphino)butane); potassium acetate; In pentan-1-ol; at 150℃; for 20h;Inert atmosphere; | General procedure: In a typical experiment, the aryl bromide (1 mmol), heteroaromatic derivative (2 mmol), KOAc (0.196 g, 2 mmol) and PdCl(C3H5)(dppb)17 (0.012 g, 0.02 mmol) were dissolved in pentan-1-ol or 3-methylbutanol (5 mL) (see tables) in a Schlenk tube under an argon atmosphere. The reaction mixture was stirred at 150 for 20 h. The solvent was removed in vacuo, then the crude mixture was purified by silica gel column chromatography. |
55% | With potassium acetate; palladium diacetate; In N,N-dimethyl acetamide; at 20 - 130℃; for 18h; | To a solution of 4-bromobenzonitrile (1.0 g, 5.5 mmol) and palladium acetate (0.061 g, 2.75 mmol) in dimethyl acetamide (5 mL) was added potassium acetate (1.08 g, 11.0 mmol) and 4-methylthiazole (1 mL, 11.0 mmol) at rt. The reaction mixture was then heated and stirred at 130 C. for 18 h. The reaction mixture was transferred into ice water and the resulting mixture was extracted using DCM (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (10% EtOAc-hexane) to give 4-(4-methylthiazol-5-yl)benzonitrile as yellow solid (0.6 g, 55%). LC-MS (ESI+) m/z 200 (M+H)+. |
96%Chromat. | With C42H42Cl2N2Pd; potassium carbonate; Trimethylacetic acid; In N,N-dimethyl acetamide; at 100℃; for 24h; | General procedure: Aniline ligand (10.0mmol) and palladium dichloride (0.886g, 5.0mmol) were dissolved in 15mL of DMAc at room temperature. After the mixture was stirred for 0.5hat 80C, the methanol (50mL) was added and the precipitation was formed. The precipitate of palladium complexes was then dissolved in 5mL dichloromethane, then 20mL hexane was added. After crystallized from the mixture of ethanol and dichloromethylene, the palladium complex was obtained as light yellow crystals.1H NMR (400MHz, CDCl3): delta (ppm) 7.23 (t, JHH=7.6Hz, Ar-H, 2H), 7.12 (t, JHH=7.6Hz, Ar-H, 4H), 4.69 (s, NH2, 4H), 3.57 (m, CH(CH3)2, 4H), 1.36 (m, CH(CH3)2, 24H). 13C NMR (100MHz, CDCl3): delta (ppm) 139.8, 133.4, 126.5, 123.6, 28.2, 23.5. ESI-MS. m/z: 497, [2L1PdCl] +; 461, [2L2Pd] 2+; Anal. Calcd for: C24H38Cl2N2Pd: C, 54.19; H, 7.20; N, 5.27. Found: C, 54.01; H, 7.28; N, 5.16. Tm: 230.5C. |
3.2 g | With potassium acetate; palladium diacetate; In N,N-dimethyl-formamide; for 10h;Reflux; | Add KOAc (3.2g) to a 50ml single-mouth bottle and4-methylthiazole (3.24g),Add 15ml DMF to dissolve,Add p-bromobenzonitrile (3.0 g),Add Pd(OAc) 2 (16 mg),The outer bath was heated to reflux and stirred for 10 h.TLC detection of the raw material reaction is complete,Filtration, adding 50 ml of water, extracting three times with EA (20 mL×3), combining the organic phases, and washing with 50 ml of saturated aqueous sodium chloride solution.Dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give 3.2g of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With tert-Butyl peroxybenzoate In toluene at 100℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With C68H65Cl2N3Pd; potassium carbonate; Trimethylacetic acid In N,N-dimethyl acetamide at 130℃; for 12h; regioselective reaction; | |
97% | With C34H48Cl2N2Pd; potassium carbonate; Trimethylacetic acid In N,N-dimethyl acetamide at 100℃; for 8h; | |
92% | With C82H77Cl2N3O2Pd; potassium carbonate; Trimethylacetic acid In N,N-dimethyl acetamide at 130℃; for 4h; | 6.1. General procedure for direct arylation promoted by palladiumcomplexes General procedure: Typically, (hetero)aryl bromide (1.0 mmol), thiazole derivatives(2.0 mmol), Pd-PEPPSI complexes (0.01e0.5 mol%), base (2 mmol),acid additive (0.3 mmol), and 3mL of DMAc solvent were addedinto a parallel reactor. After heating at 130 °C for 4 h, the resultingmixture was cooled to room temperature. Subsequently, 25mL ofwater and 20 mL of dichloromethane were added into the reactor,and the mixture was stirred for another several minutes, followedby extraction three times with dichloromethane (3 x 5 mL). Theorganic layer was then combined, dried over anhydrous sodiumsulfate, filtered, and evaporated under reduced pressure to give thecrude products. The crude products were then purified by silica-gelcolumn chromatography using petroleum etheredichloromethane(15/1) as the eluent. The obtained pure products were characterizedby 1H NMR and 13C NMR spectroscopy, and the spectra can be foundin the Supporting Information. And the isolated yields of productswere obtained based on the amounts of (hetero)aryl bromides. |
91% | With C23H20ClFeN3Pd; potassium carbonate; Trimethylacetic acid In N,N-dimethyl acetamide at 140℃; for 10h; regioselective reaction; | |
80% | With palladium diacetate; potassium carbonate; tricyclohexylphosphine; Trimethylacetic acid In N,N-dimethyl-formamide at 180℃; for 0.166667h; Inert atmosphere; Microwave irradiation; | |
With C42H42Cl2N2Pd; potassium carbonate; Trimethylacetic acid In N,N-dimethyl acetamide at 100℃; for 24h; | General procedures for the synthesis of aniline palladium compounds General procedure: Aniline ligand (10.0mmol) and palladium dichloride (0.886g, 5.0mmol) were dissolved in 15mL of DMAc at room temperature. After the mixture was stirred for 0.5hat 80°C, the methanol (50mL) was added and the precipitation was formed. The precipitate of palladium complexes was then dissolved in 5mL dichloromethane, then 20mL hexane was added. After crystallized from the mixture of ethanol and dichloromethylene, the palladium complex was obtained as light yellow crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With potassium acetate; palladium diacetate; In N,N-dimethyl acetamide; at 20 - 150℃; for 2.5h;Inert atmosphere; | Step 1 : 2-(aminomethyl)-5-(4-methyl-l,3-thiazol-5-yl)phenol (BI)[0459] To a stirred solution of 2-hydroxy-4-(4-methyl- l,3-thiazol-5-yl)benzonitrile (BH,15.6 g, 72.14 mmol) in tetrahydrofuran (400 mL) under an atmosphere of nitrogen was added LiAlH4(11 g, 289.86 mmol) in several portions at 10 C. The resulting mixture was then heated to reflux for 3 h, LC-MS indicated formation of the desired product. The reaction was then cooled to 0 C, quenched by the water (10 mL, added slowly and drop wise), 15% NaOH (aq.) (30 mL) and water (10 mL). The solids precipitated were removed by filtration, the solution phase was concentrated under reduced pressure followed by high vacuum pump to give BI(yield: 65%). LC-MS (ES+): m/z 220.85 [MH+], tR= 1.02 min (2.6 minute run). |
73% | With potassium acetate; palladium diacetate; In 1-methyl-pyrrolidin-2-one; at 110℃; for 3h;Inert atmosphere; | -Hydroxy-4-(4-methylthiazol-5-yl)benzonitrile Under an atmosphere of nitrogen, a mixture of <strong>[288067-35-6]4-bromo-2-hydroxybenzonitrile</strong> (commercially available from for example Fluorochem) (15 g, 76 mmol), 4-methylthiazole (commercially available from for example Aldrich) (14 mL, 152 mmol), potassium acetate (14.9 g, 152 mmol) and palladium(II) acetate (0.34 g, 1.52 mmol) in l-methyl-2-pyrrolidone (125 mL) was heated at 110C for 3 hours. The mixture was then cooled to 50C, poured into water (300 mL) and extracted with ethyl acetate (3 x 350 mL). The combined organic fraction was filtered and the filtrate was then washed with brine (3 x 400 mL), filtered through a hydrophobic frit and evaporated to dryness. The residue was re-evaporated from toluene then from diethyl ether and then slurried in methanol to precipitate a yellow solid which was filtered off. The filtrate was evaporated to dryness and slurried in ice-cooled methanol to afford a second batch of yellow solid. The combined solid was dried under vacuum to afford the title compound (12 g, 56 mmol, 73 % yield). LCMS RT= 0.75 min, ES+ve m/z 217 [M+H]+. |
73% | With potassium acetate; palladium diacetate; In 1-methyl-pyrrolidin-2-one; at 110℃; for 3h;Inert atmosphere; | Under an atmosphere of nitrogen, a mixture of <strong>[288067-35-6]4-bromo-2-hydroxybenzonitrile</strong> (commercially available from for example Fluorochem) (15 g, 76 mmol), 4-methylthiazole (commercially available from for example Aldrich) (14 mL, 152 mmol), potassium acetate (14.9 g, 152 mmol) and palladium(II) acetate (0.34 g, 1.52 mmol) in 1-methyl-2-pyrrolidone (125 mL) was heated at 110 C. for 3 hours. The mixture was then cooled to 50 C., poured into water (300 mL) and extracted with ethyl acetate (3*350 mL). The combined organic fraction was filtered and the filtrate was then washed with brine (3*400 mL), filtered through a hydrophobic frit and evaporated to dryness. The residue was re-evaporated from toluene then from diethyl ether and then slurried in methanol to precipitate a yellow solid which was filtered off. The filtrate was evaporated to dryness and slurried in ice-cooled methanol to afford a second batch of yellow solid. The combined solid was dried under vacuum to afford the title compound (12 g, 56 mmol, 73% yield). LCMS RT=0.75 min, ES+ve m/z 217 [M+H]+. |
73% | With potassium acetate; palladium diacetate; In 1-methyl-pyrrolidin-2-one; at 110℃; for 3h;Inert atmosphere; | 2-Hydroxy-4-(4-methylthiazol-5-yl)benzonitrile Under an atmosphere of nitrogen, a mixture of <strong>[288067-35-6]4-bromo-2-hydroxybenzonitrile</strong> (Fluorochem) (15 g, 76 mmol), 4-methylthiazole (Aldrich) (14 mL, 152 mmol), potassium acetate (14.9 g, 152 mmol) and palladium(II) acetate (0.34 g, 1.52 mmol) in 1-methyl-2-pyrrolidone (125 mL) was heated at 110 C. for 3 hours. The mixture was then cooled to 50 C., poured into water (300 mL) and extracted with ethyl acetate (3*350 mL). The combined organic fraction was filtered and the filtrate was then washed with brine (3*400 mL), filtered through a hydrophobic frit and evaporated to dryness. The residue was reevaporated from toluene, then from diethyl ether, and then slurried in methanol to precipitate a yellow solid which was filtered off. The filtrate was evaporated to dryness and slurried in ice-cooled methanol to afford a second batch of yellow solid. The combined solid was dried under vacuum to afford the title compound (12 g, 56 mmol, 73% yield). LCMS RT=0.75 min, ES+ve m/z 217 [M+H]+. |
67% | With potassium acetate; palladium diacetate; In 1-methyl-pyrrolidin-2-one; at 110℃; for 6h; | To a solution of <strong>[288067-35-6]4-bromo-2-hydroxy-benzonitrile</strong> (15 g, 75.75 mmol, 1 eq) and 4- methylthiazole (20.28 g, 204.53 mmol, 19 mL, 2.7 eq) in N-methyl pyrrolidone (150 mL) was added potassium acetate (22.30 g, 227.25 mmol, 3 eq) and palladium acetate (1.70 g, 7.58 mmol, 0.1 eq) ), the mixture stirred at 110 C under nitrogen for 6 hours. The mixture was quenched with water (500 mL), the aqueous phase was extracted with ethyl acetate (300 mL x 3). The combined organic phase was washed with brine (200 mL, twice), dried with anhydrous sodium sulfate, filtered and concentrated under vacuum and then methyl tertiary butyl ether (500 mL) was added to the mixture and the organic phase was washed with water (100 mL) and brine (100 mL, twice). The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1 to 1/1). Compound 2-hydroxy-4-(4-methylthiazol-5-yl)benzonitrile (11 g, 50.87 mmol, 67% yield) was obtained as a yellow solid. |
64% | With potassium acetate; palladium diacetate; In 1-methyl-pyrrolidin-2-one; at 110℃; for 6h;Inert atmosphere; | A mixture of <strong>[288067-35-6]4-bromo-2-hydroxybenzonitrile</strong> (15 g, 76 mmol), 4-methylthiazole (14 mL, 152 mmol), KOAc (14.9 g, 152 mmol) and Pd(OAc)2 (0.34g, 1.52 mmol) in dry NMP (125 mL) was stirred at 110 C for 6 hours under nitrogen atmosphere. TLC showed the reaction was complete. The mixture was first cooled to room temperature, then partitioned between EtOAc and water. The combined organic fraction was filtered and the filtrate was washed with water, brine, dried over anhydrous Na2S04, and concentrated. The residue was dissolved in toluene (100 mL) and re-evaporated to afford the crude product. The crude product was treated with cold MeOH (80 mL). The resulting precipitate was collected by filtration, washed with MeOH (20 mL), and dried under vacuum to afford the title compound as a light yellow solid (10.5 g, 64 %). LC/MS: 217.2 [M+l]+. ^ MR (400 MHz, DMSO-d6): 52.49(s, 3H), 7.07(dd, J=8.0, 1.6Hz, 1H), 7.13(d, J=1.6Hz, 1H), 7.70(d, J=8.0 Etazeta,IotaEta), 9.07(s, 1H), 11.34 (s, 1H). |
50.77% | With potassium acetate; palladium diacetate; at 150℃; for 5h; | Into a 500-ml-3-necked round-bottom flask with an inert atmosphere of nitrogen were loaded <strong>[288067-35-6]4-bromo-2-hydroxybenzonitrile</strong> (26 g, 131.3 mmol, 1.00 equiv), DMA (300 ml),4- methylthiazole(26 g, 262.6 mmol, 2.00 equiv), KOAc (26 g, 262.6 mmol, 2.00 equiv ), Pd(OAc)2 (884.3 mg, 3.94 mmol, 0.03 equiv). The resulting solution was stirred for 5 hour at 150 oC. The reaction was then quenched by the addition of 1000 mL of water. The resulting mixture was washed with 3x500 mL of ethyl acetate and the organic layers combined, and washed with 3x500 mL of H2O. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 14.4g (66.66 mmol, 50.77%) of 2-hydroxy-4-(4-methylthiazol-5-yl) benzonitrile as a yellow solid.1HNMR (400MHz, DMSO-d6): delta 2.49 (s, 3H), 7.08(d, J = 8.0 Hz, 1H), 7.13(s, 1H), 7.71(d, J = 8.0 Hz, 1H), 9.07(s, 1H), 11.35 (s,1H). |
50.77% | With potassium acetate; palladium diacetate;Inert atmosphere; | Into a 500-ml-3-necked round-bottom flash with an inert atmosphere of nitrogen,4-bromo-2-hydroxybenzoni- trile (26 g,131.3 mmol, 1.00 equiv), DMA(300 ml),4-meth- ylthiazole(26, 262.6 mmol, 2.00 equiv), KOAc (26 g, 262.6 mmol, 2.00 equiv), Pd(OAc)2 (884.3 mg, 3.94 mmol, 0.03 equiv). The resulting solution was stirred for 5 hour at 150 C. The reaction was then quenched by the addition of 1000 mE of water. The resulting mixture was washed with 3x500 mE of ethyl acetate and the organic layers combined, and the organic layers was washed with 3x500 mE of H20. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel colunm with ethyl acetate/petroleum ether (1:1). This resulted in 14.4 g(66.66 mmol, 50.77%) of 2-hydroxy- 4-(4-methylthiazol-5-yl) benzonitrile as a yellow solid. 1HNMR (400 MHz,DMSO-d6): oe 2.49 (s, 3H), 7.08(d, J=8.0 Hz, 1H), 7.13(s, 1H), 7.71(d, J=8.0 Hz, 1H), 9.07(s, 1H), 11.35 (s,1H). |
With palladium diacetate; | Step 1: Preparation of 2-hydroxy-4-(4-methylthiazol-5-yl) benzonitrile A mixture of <strong>[288067-35-6]4-bromo-2-hydroxybenzonitrile</strong> (15 g, 76 mmol), 4-methylthiazole (14 mL, 152 mmol), KOAc (14.9 g, 152 mmol) and Pd(OAc)2 (0.34 g, 1.52 mmol) in dry NMP (125 mL) was stirred at 110 C. for 6 hours under nitrogen atmosphere. TLC showed the reaction was complete. The mixture was first cooled to room temperature, then partitioned between EtOAc and water. The combined organic fraction was filtered and the filtrate was washed with water, brine, dried over anhydrous Na2SO4, and concentrated. The residue was dissolved in toluene (100 mL) and re-evaporated to afford the crude product. The crude product was treated with cold MeOH (80 mL). The resulting precipitate was collected by filtration, washed with MeOH (20 mL), and dried under vacuum to afford the title compound as a light yellow solid (10.5 g, 64%). LC/MS: 217.2 [M+1]+. 1HNMR (400 MHz, DMSO-d6): delta2.49 (s, 3H), 7.07 (dd, J=8.0, 1.6 Hz, 1H), 7.13 (d, J=1.6 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 9.07 (s, 1H), 11.34 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Alternate Route: 4-bromobenzonitrile (5.1 g, 28 mmol, 1 eq), 4-methylthiazole (5.56 g, 56 mmol, 2 eq) potassium acetate (5.5 g, 56 mmol, 2 eq), palladium (II) acetate (63 mg, 0.28 mmol, 1 mol %) were dissolved in dimethylacetamide and stirred under argon. (CITE JOC, 2009, 74, 1 179) The mixture was heated to 150 C and stirred for 19 hours, then diluted with 500 mL EtOAc, and washed 4 times with 300 mL water. The first wash was then back extracted with 300 mL EtOAc, and then washed 4 times with 100 mL water. The combined organic layer was dried over sodium sulfate, filtered and concentrated under vacuum to give a beige solid (5.55 g, 27.7 mmol, 99%) that matched the reported spectral data.[S] The solid was then dissolved in MeOH (280 mL) and cooled to 4 C. Cobalt chloride (9.9 g, 41.6 mmol, 1.5 eq) was added, followed by the slow, portionwise addition of sodium borohydride (5.2 g, 139 mmol, 5 eq), which was accompanied by vigorous bubbling. After 90 minutes, the reaction was quenched by the addition of water and ammonium hydroxide. The mixture was extracted 4 times with chloroform, and purified by column chromatography (10 to 30% 0.5M NH3 (MeOH)/DCM) to give a darker oil (4.12 g, 20.2 mmol, 73%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With C31H33ClP2Pd; potassium acetate; In N,N-dimethyl acetamide; at 150℃; for 16h;Inert atmosphere; | General procedure: The reaction of the <strong>[49619-82-1]3-bromochromen-4-one</strong> (0.225 g, 1 mmol), heteroarene (2 mmol) and KOAc (0.196 g, 2 mmol) at 150 C during 16 h in DMAc (4 mL) with PdCl(C3H5)(dppb) (12.2 mg, 0.02 mmol), under argon affords the coupling product after evaporation of the solvent and purification on silica gel. 3-(2-Ethyl-4-methylthiazol-5-yl)-chromen-4-one (1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With palladium(II) trimethylacetate; caesium carbonate In N,N-dimethyl-formamide at 100℃; for 24h; Schlenk technique; Inert atmosphere; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With C82H77Cl2N3O2Pd; potassium carbonate; Trimethylacetic acid In N,N-dimethyl acetamide at 130℃; for 4h; | 6.1. General procedure for direct arylation promoted by palladiumcomplexes General procedure: Typically, (hetero)aryl bromide (1.0 mmol), thiazole derivatives(2.0 mmol), Pd-PEPPSI complexes (0.01e0.5 mol%), base (2 mmol),acid additive (0.3 mmol), and 3mL of DMAc solvent were addedinto a parallel reactor. After heating at 130 °C for 4 h, the resultingmixture was cooled to room temperature. Subsequently, 25mL ofwater and 20 mL of dichloromethane were added into the reactor,and the mixture was stirred for another several minutes, followedby extraction three times with dichloromethane (3 x 5 mL). Theorganic layer was then combined, dried over anhydrous sodiumsulfate, filtered, and evaporated under reduced pressure to give thecrude products. The crude products were then purified by silica-gelcolumn chromatography using petroleum etheredichloromethane(15/1) as the eluent. The obtained pure products were characterizedby 1H NMR and 13C NMR spectroscopy, and the spectra can be foundin the Supporting Information. And the isolated yields of productswere obtained based on the amounts of (hetero)aryl bromides. |
94% | With C23H20ClFeN3Pd; potassium carbonate; Trimethylacetic acid In N,N-dimethyl acetamide at 140℃; for 10h; regioselective reaction; | |
83% | With C34H48Cl2N2Pd; potassium carbonate; Trimethylacetic acid In N,N-dimethyl acetamide at 100℃; for 8h; |
47% | With palladium(II) trimethylacetate; caesium carbonate In N,N-dimethyl-formamide at 100℃; for 24h; Schlenk technique; Inert atmosphere; regioselective reaction; | |
With C42H42Cl2N2Pd; potassium carbonate; Trimethylacetic acid In N,N-dimethyl acetamide at 100℃; for 24h; | General procedures for the synthesis of aniline palladium compounds General procedure: Aniline ligand (10.0mmol) and palladium dichloride (0.886g, 5.0mmol) were dissolved in 15mL of DMAc at room temperature. After the mixture was stirred for 0.5hat 80°C, the methanol (50mL) was added and the precipitation was formed. The precipitate of palladium complexes was then dissolved in 5mL dichloromethane, then 20mL hexane was added. After crystallized from the mixture of ethanol and dichloromethylene, the palladium complex was obtained as light yellow crystals. | |
With potassium acetate; palladium diacetate In N,N-dimethyl acetamide at 150℃; for 15h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | for 8h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With C82H77Cl2N3O2Pd; potassium carbonate; Trimethylacetic acid In N,N-dimethyl acetamide at 130℃; for 4h; | 6.1. General procedure for direct arylation promoted by palladiumcomplexes General procedure: Typically, (hetero)aryl bromide (1.0 mmol), thiazole derivatives(2.0 mmol), Pd-PEPPSI complexes (0.01e0.5 mol%), base (2 mmol),acid additive (0.3 mmol), and 3mL of DMAc solvent were addedinto a parallel reactor. After heating at 130 °C for 4 h, the resultingmixture was cooled to room temperature. Subsequently, 25mL ofwater and 20 mL of dichloromethane were added into the reactor,and the mixture was stirred for another several minutes, followedby extraction three times with dichloromethane (3 x 5 mL). Theorganic layer was then combined, dried over anhydrous sodiumsulfate, filtered, and evaporated under reduced pressure to give thecrude products. The crude products were then purified by silica-gelcolumn chromatography using petroleum etheredichloromethane(15/1) as the eluent. The obtained pure products were characterizedby 1H NMR and 13C NMR spectroscopy, and the spectra can be foundin the Supporting Information. And the isolated yields of productswere obtained based on the amounts of (hetero)aryl bromides. |
89% | With C34H48Cl2N2Pd; potassium carbonate; Trimethylacetic acid In N,N-dimethyl acetamide at 100℃; for 8h; | |
78% | With tris [tris(3,5-bis(trifluoromethyl)phenyl)phosphine]palladium(0); potassium carbonate; Trimethylacetic acid In N,N-dimethyl acetamide at 140℃; for 3h; regioselective reaction; |
75% | With palladium diacetate; potassium carbonate; tricyclohexylphosphine tetrafluoroborate; Trimethylacetic acid In N,N-dimethyl acetamide at 100℃; for 20h; Inert atmosphere; | |
With C42H42Cl2N2Pd; potassium carbonate; Trimethylacetic acid In N,N-dimethyl acetamide at 100℃; for 24h; | General procedures for the synthesis of aniline palladium compounds General procedure: Aniline ligand (10.0mmol) and palladium dichloride (0.886g, 5.0mmol) were dissolved in 15mL of DMAc at room temperature. After the mixture was stirred for 0.5hat 80°C, the methanol (50mL) was added and the precipitation was formed. The precipitate of palladium complexes was then dissolved in 5mL dichloromethane, then 20mL hexane was added. After crystallized from the mixture of ethanol and dichloromethylene, the palladium complex was obtained as light yellow crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With potassium phosphate; bis(1,5-dicyclooctadiene)nickel; 1,2-bis-(dicyclohexylphosphino)ethane In tert-Amyl alcohol at 110℃; for 36h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With C82H77Cl2N3O2Pd; potassium carbonate; Trimethylacetic acid In N,N-dimethyl acetamide at 130℃; for 4h; | 6.1. General procedure for direct arylation promoted by palladiumcomplexes General procedure: Typically, (hetero)aryl bromide (1.0 mmol), thiazole derivatives(2.0 mmol), Pd-PEPPSI complexes (0.01e0.5 mol%), base (2 mmol),acid additive (0.3 mmol), and 3mL of DMAc solvent were addedinto a parallel reactor. After heating at 130 °C for 4 h, the resultingmixture was cooled to room temperature. Subsequently, 25mL ofwater and 20 mL of dichloromethane were added into the reactor,and the mixture was stirred for another several minutes, followedby extraction three times with dichloromethane (3 x 5 mL). Theorganic layer was then combined, dried over anhydrous sodiumsulfate, filtered, and evaporated under reduced pressure to give thecrude products. The crude products were then purified by silica-gelcolumn chromatography using petroleum etheredichloromethane(15/1) as the eluent. The obtained pure products were characterizedby 1H NMR and 13C NMR spectroscopy, and the spectra can be foundin the Supporting Information. And the isolated yields of productswere obtained based on the amounts of (hetero)aryl bromides. |
94% | With C34H48Cl2N2Pd; potassium carbonate; Trimethylacetic acid In N,N-dimethyl acetamide at 100℃; for 8h; | |
With C42H42Cl2N2Pd; potassium carbonate; Trimethylacetic acid In N,N-dimethyl acetamide at 100℃; for 24h; | General procedures for the synthesis of aniline palladium compounds General procedure: Aniline ligand (10.0mmol) and palladium dichloride (0.886g, 5.0mmol) were dissolved in 15mL of DMAc at room temperature. After the mixture was stirred for 0.5hat 80°C, the methanol (50mL) was added and the precipitation was formed. The precipitate of palladium complexes was then dissolved in 5mL dichloromethane, then 20mL hexane was added. After crystallized from the mixture of ethanol and dichloromethylene, the palladium complex was obtained as light yellow crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium acetate; palladium diacetate; In N,N-dimethyl acetamide; at 120℃; for 2h;Inert atmosphere; | A mixture of /er/-butyl N-[(lS)-l-(4-bromophenyl)ethyl]carbamate (15.0 g, 50.0 mmol), potassium acetate (9.81 g, 100 mmol) and Pd(OAc)2 (112 mg, 0.50 mmol) in DMA (100 mL) at it, was added 4-methylthiazole (9.10 mL, 100 mmol). The mixture was purged with nitrogen and put under vacuum (3 x cycle) and then stirred at 120 C for 2 h. The mixture was cooled to rt and diluted with water (250 mL). The resulting solid was filtered and washed with water (500 mL). The solid was dried in a vacuum oven at 65 C for 18 h to afford the title compound 15.6 g, 98%). MS (ESI) [M+H]+ 319.2. |
82.3% | With palladium diacetate; potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 18h;Inert atmosphere; | A mixture of (S)-tert-b ty -l-(4-bromophenyl)-ethyl carbamate (4.0 g, 13.3 mmol), 4- methylthiazole (2.64 g, 26.6 mmol), palladium (II) acetate (29.6 mg, 0.13 mmol) and potassium acetate (2.61 g, 26.6 mmol) in DMF(10 mL) was stirred at 90C under N2 for 18 h. After cooling to ambient temperature, the reaction mixture was filtered. To the filtrate was added H20 (50 mL) and the resulting mixture was stirred at ambient temperature for 4 h. The reaction mixture was filtered. The solid was collected by filtration and dried in oven at 50C to afford (S)-tert-b ty l-(4-(4-methylthiazol-5-yl)phenyl)ethylcarbamate (3.48 g, 82.3%) as gray solid. HNMR (400 MHz, DMSO-d6): delta 1.33 (d, / = 7.2 Hz, 3H), 1.38 (s, 9H), 2.46 (s, 3H), 4.64-4.68 (m, 1H), 7.23 (br d, 0.5H), 7.39 (d, J = 8 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.50 (br d, 0.5H), 8.99 (s, 1H); LC-MS [M+l]+: 319.5 [00205] This solid material (1.9 g, 6.0 mmol) was dissolved in 4N hydrochloride in methanol (5 mL, 20 mmol, prepared from acetyl chloride and methanol) and the mixture was stirred at ambient temperature for 3h then concentrated and triturated with ether. The mixture was filtered and the solid was collected and dried in oven at 60C to afford (5)-l-(4-(4- methylthiazol-5-yl)phenyl)ethanamine hydrochloride (1.3 g , 85%) as a light green solid. HNMR (400 MHz, DMSO-d6): 5 1.56 (d, = 6.8 Hz, 3H), 2.48 (s, 3H), 4.41-4.47 (m, 1H), 7.57 (d, = 8.4Hz, 2H), 7.67 (d, / = 8.4 Hz), 8.75 (s, 3H), 9.17 (s, 1H); LC-MS [M+l]+: 219.2 |
82.3% | With potassium acetate; palladium diacetate; In N,N-dimethyl acetamide; at 90℃; for 18h;Inert atmosphere; | A mixture of compound 2 (4.0 g, 13.3 mmol), 4-methylthiazole (2.64 g, 26.6 mmol), palladium (II) acetate (29.6 mg, 0.13 mmol) and potassium acetate (2.61 g, 26.6 mmol) in N,N-dimethylacetamide (10 mL) was stirred at 90 C. under N2 for 18 h. After cooling to ambient temperature, the reaction mixture was filtered. To the filtrate was added H2O (50 mL) and the resulting mixture was stirred at ambient temperature for 4 h. The reaction mixture was filtered. The solid was collected by filtration and dried in oven at 50 C. to afford (S)-tert-butyl 1-(4-(4-methylthiazol-5-yl)phenyl)ethylcarbamate (3.48 g, 82.3%) as gray solid. 1HNMR (400 MHz, DMSO-d6): delta 1.33 (d, J=7.2 Hz, 3H), 1.38 (s, 9H), 2.46 (s, 3H), 4.64-4.68 (m, 1H), 7.23 (br d, 0.5H), 7.39 (d, J=8 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H), 7.50 (br d, 0.5H), 8.99 (s, 1H); LC-MS [M+1]+: 319.5 This solid material (1.9 g, 6.0 mmol) was dissolved in 4N hydrochloride in methanol (5 mL, 20 mmol, prepared from acetyl chloride and methanol) and the mixture was stirred at ambient temperature for 3 h. the mixture was filtered and the solid was collected and dried in oven at 60 C. to afford (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethanamine hydrochloride (1.3 g, 85%) as a light green solid. 1HNMR (400 MHz, DMSO-d6): delta 1.56 (d, J=6.8 Hz, 3H), 2.48 (s, 3H), 4.41-4.47 (m, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.67 (d, J=8.4 Hz), 8.75 (s, 3H), 9.17 (s, 1H); LC-MS [M+1]+: 219.2 |
82.3% | With potassium acetate; palladium diacetate; In N,N-dimethyl-formamide; at 90℃; for 18h; | A mixture of intermediate compound 2 (4.0 g, 13.3 mmol), 4-methylthiazole (2.64 g, 26.6 mmol), palladium (II) acetate (29.6 mg, 0.13 mmol) and potassium acetate (2.61 g, 26.6 mmol) in N,N-dimethylacetamide (10 mL) was stirred at 90C under N2 for 18 h. After cooling to ambient temperature, the reaction mixture was filtered. To the filtrate was added H20 (50 mL) and the resulting mixture was stirred at ambient temperature for 4 h. The reaction mixture was filtered. The solid was collected by filtration and dried in oven at 50C to afford (S)-ieri-butyl 1- (4-(4-methylthiazol-5-yl)phenyl)ethylcarbamate (3.48 g, 82.3%) as gray solid. 1HNMR (400 MHz, DMSO-d6): delta 1.33 (d, J = 7.2 Hz, 3H), 1.38 (s, 9H), 2.46 (s, 3H), 4.64-4.68 (m, 1H), 7.23 (br d, 0.5H), 7.39 (d, J = 8 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.50 (br d, 0.5H), 8.99 (s, 1H); LC- MS [M+l]+: 319.5 |
66% | With potassium acetate; palladium diacetate; In N,N-dimethyl-formamide; at 120℃; for 16h; | To a stirred solution of tert-butyl (S)-(1-(4-bromophenyl)ethyl)carbamate (20.0 g, 66.66 mmol) and 4-methylthiazole (13.11 g, 133.32 mmol) in DMF (250 mL) was added KOAc (19.66 g, 99.98 mmol) and Pd(OAC)2 (0.75 g, 33.33 mmol). The reaction mixture was heated at 120 C for 16 h. After completion of the reaction (monitored by TLC) the reaction mixture was allowed to cool to RT and poured into ice cold water. The resulting mixture was extracted with ethyl acetate (2 X 500 mL). The combined organic layer was washed with water (200 mL), brine (200 mL), dried over anhydrous sodium sulphate and concentrated under vacuum to give the residue which was purified by combi flash column chomatography using 15 % ethyl acetate in hexane as eluent to afford the title compound (14.0 g, 66 %). 1H NMR (400 MHz, DMSO-d6): d 8.97 (s, 1H), 7.44 (d, J = 7.6 Hz, 2H), 7.38-7.35 (m, 3H), 4.63 (d, J = 6.8 Hz, 1H), 2.45 (s, 3H), 1.35 (s, 9H), 1.25 (d, / = 7.3 Hz, 3H), LC-MS: m/z 319.1 (M+l)+. |
47% | With potassium acetate; palladium diacetate; In N,N-dimethyl acetamide; at 20 - 120℃; for 2h;Inert atmosphere; | tep 2: Synthesis of tert-butyl N-[(lS)-l-[4-(4-methyl-l,3-thiazol-5- yl)phenyl] ethyl] carbamate (P)[0421] To a stirred solution of tert-butyl N-[(lS)-l-(4-bromophenyl)ethyl]carbamate (O,15.0 g, 49.97 mmol) in DMA (100 mL), under an atmosphere of nitrogen, was added 4-methyl- 1,3-thiazole (9.9 g, 99.84 mmol), potassium acetate (9.8 g, 99.86 mmol) and Pd(OAc)2(112.5 mg, 0.50 mmol) at rt. The resulting mixture was then stirred at 120C for 2h. The reaction mixture was then cooled to rt, diluted by water (120mL), and extracted with ethyl acetate (200 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether, v: v = 1:5) to give P (yield: 47%) as a white solid. LC-MS (ES+): m/z 319.13 [MH+], tR= 0.97 min (2.0 minute run). |
47% | With potassium acetate; palladium diacetate; In N,N-dimethyl acetamide; at 120℃; for 2h;Inert atmosphere; | To a stirred solution of tert-butyl N-[(1S)-1-(4-bromophenyl)ethyl]carbamate (0, 15.0 g, 49.97 mmol) in DMA (100 mL), under an atmosphere of nitrogen, was added 4-methyl-1,3-thiazole (9.9 g, 99.84 mmol), potassium acetate (9.8 g, 99.86 mmol) and Pd(OAc)2 (112.5 mg, 0.50 mmol) at rt. The resulting mixture was then stirred at 120 C. for 2 h. The reaction mixture was then cooled to rt, diluted by water (120 mL), and extracted with ethyl acetate (200 mL*3). The organic layers were combined, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether, v:v=1:5) to give P (yield: 47%) as a white solid. LC-MS (ES+): m/z 319.13 [MH+], tR=0.97 min (2.0 minute run). |
47% | With potassium acetate; palladium diacetate; In N,N-dimethyl acetamide; at 120℃; for 2h; | Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl N-[(lS)-l-(4-bromophenyl)ethyl]carbamate (15.0 g, 49.97 mmol, 1.00 equiv) in N,N-Dimethylaeetamide (100 mL), 4-methyl- l,3-thiazole (9.9 g, 99.84 mmol, 2.00 equiv), potassium acetate (9.8 g, 99.86 mmol, 2.00 equiv), palladium(II) acetate (112.5 mg, 0.50 mmol, 0.01 equiv). The resulting solution was stirred for 2 hours at l20C. The reaction mixture was quenched by the addition of water (500 mL). The resulting solution was extracted with ethyl acetate (200 mL x 3) and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 7.5 g (47%) of tert-butyl N-[(lS)-l-[4-(4-methyl- l,3-thiazol-5-yl)phenyl]ethyl]carbamate as a white solid. LC/MS (ESI) in/z: 319.13 [M+Na] +. |
47% | With potassium acetate; palladium diacetate; In N,N-dimethyl acetamide; at 120℃; for 2h;Inert atmosphere; | Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl N-[(1S)-1-(4-bromophenyl)ethyl]carbamate (15.0 g, 49.97 mmol, 1.00 equiv) in N,N-Dimethylacetamide (100 mL), 4-methyl-1,3-thiazole (9.9 g, 99.84 mmol, 2.00 equiv), potassium acetate (9.8 g, 99.86 mmol, 2.00 equiv), palladium(II) acetate (112.5 mg, 0.50 mmol, 0.01 equiv). The resulting solution was stirred for 2 h at 120C. The reaction mixture was quenched by the addition of water (500 mL). The resulting solution was extracted with ethyl acetate (200 mL x 3) and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 7.5 g (47%) of tert-butyl N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5- yl)phenyl]ethyl]carbamate as a white solid. LC/MS (ESI) m/z: 319.13 [M+Na] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With potassium acetate; | Step 1: Preparation of 4-(4-methyl-1,3-thiazol-5-yl)benzonitrile To a stirred solution of 4-bromobenzonitrile (20 g, 109.88 mmol) in DMA (250 mL) under a nitrogen atmosphere was added 4-methyl-1,3-thiazole (21.88 g, 220.67 mmol), palladium (II) acetate (743 mg, 3.31 mmol) and potassium acetate (21.66 g, 220.71 mmol) at room temperature. The resulting mixture was heated to 150 C. and stirred at this temperature for 5 hours, at which time LC-MS indicated completion of the reaction. The mixture was cooled to room temperature, diluted with 1 L of water and extracted with ethyl acetate (300 mL*3). The organic layers were combined, washed with brine (200 mL), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel column chromatography (eluent: ethyl acetate/petroleum ether, v: v=1:5) to give the titled compound (yield: 91%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: 4-methylthiazol-2-ylamine With sulfuric acid; sodium nitrite In water at -15 - -10℃; for 4h; Stage #2: With sodium hypophosphite In water at -10 - -5℃; for 6h; | 3.3.3 3.3) Synthesis of 4-Methylthiazole Take 68.4g (0.6mol) 2-amino-4-methylthiazole in a 2L three-necked flask, then add a mixture of 150mL water and 90mL concentrated sulfuric acid,The reaction mixture was cooled to -10 to -15°C, and an aqueous solution of sodium nitrite (45.5 g, 0.66 mol of sodium nitrite dissolved in 160 mL of water) was added dropwise at this temperature within 2.5 hours.After the addition is completed, the temperature is maintained for 1.5 hours, at which time the diazonium salt is obtained.Then, an aqueous solution of sodium hypophosphite (76.3 g, 0.72 mol) sodium hypophosphite was dissolved in 320 mL of water dropwise at -5 to -10°C.After the addition was complete, stirring was continued at this temperature for 6 h. Afterwards, the pH was adjusted to 9-10 with a 45% sodium hydroxide solution.Then it was extracted three times with 110 mL of dichloromethane, and the organic phases were combined and dried over anhydrous sodium sulfate.Distillation first distills off CH3Cl2 at low temperature of 30-40°C, and then raises the temperature to collect fractions at 133-135°C to obtain 43.2 g of a yellow liquid with a yield of 72%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With palladium diacetate; potassium carbonate; tricyclohexylphosphine tetrafluoroborate; Trimethylacetic acid In N,N-dimethyl acetamide at 100℃; for 20h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With palladium diacetate; potassium carbonate; tricyclohexylphosphine tetrafluoroborate; Trimethylacetic acid; In N,N-dimethyl acetamide; at 100℃; for 16h;Inert atmosphere; | To a solution of <strong>[121219-03-2]4-bromo-3-fluorophenol</strong> (1.000 g, 5.24 mmol), K2C03 (1.085 g, 7.85 mmol), PivOH (160.4 mg, 1.57 mmol), PCy3HBF4 (76.91 mg, 0.21 mmol), and 4- methylthiazole (622.9 mg, 6.28 mmol) in DMAc (20 mL) was added Pd(OAc)2 (23.51 mg, 0.10 mmol). The mixture was stirred at 100 C for 16 hours under N2. The mixture was filtered, concentrated, and diluted with water (50 mL). The resulting solution was extracted with EtOAc (50 mL x 3). The organic layer was dried over Na2SC>4, concentrated, and purified by flash chromatography on silica gel (0-50% EtOAc in petroleum ether, Rf = 0.4) to afford 3-fluoro-4- (4-methylthiazol-5-yl)phenol (228 mg, 21%) as gray solid. XH NMR (400 MHz, CDC13) delta 10.25 (s, 1 H), 9.04 (s, 1 H), 7.30 - 7.25 (m, 1 H), 6.73 - 6.72 (m, 1 H), 6.71 - 6.69 (m, 1 H), 2.29 (s, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With C82H77Cl2N3O2Pd; potassium carbonate; Trimethylacetic acid; In N,N-dimethyl acetamide; at 130℃; for 4h; | General procedure: Typically, (hetero)aryl bromide (1.0 mmol), thiazole derivatives(2.0 mmol), Pd-PEPPSI complexes (0.01e0.5 mol%), base (2 mmol),acid additive (0.3 mmol), and 3mL of DMAc solvent were addedinto a parallel reactor. After heating at 130 C for 4 h, the resultingmixture was cooled to room temperature. Subsequently, 25mL ofwater and 20 mL of dichloromethane were added into the reactor,and the mixture was stirred for another several minutes, followedby extraction three times with dichloromethane (3 x 5 mL). Theorganic layer was then combined, dried over anhydrous sodiumsulfate, filtered, and evaporated under reduced pressure to give thecrude products. The crude products were then purified by silica-gelcolumn chromatography using petroleum etheredichloromethane(15/1) as the eluent. The obtained pure products were characterizedby 1H NMR and 13C NMR spectroscopy, and the spectra can be foundin the Supporting Information. And the isolated yields of productswere obtained based on the amounts of (hetero)aryl bromides. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With C82H77Cl2N3O2Pd; potassium carbonate; Trimethylacetic acid; In N,N-dimethyl acetamide; at 130℃; for 4h; | General procedure: Typically, (hetero)aryl bromide (1.0 mmol), thiazole derivatives(2.0 mmol), Pd-PEPPSI complexes (0.01e0.5 mol%), base (2 mmol),acid additive (0.3 mmol), and 3mL of DMAc solvent were addedinto a parallel reactor. After heating at 130 C for 4 h, the resultingmixture was cooled to room temperature. Subsequently, 25mL ofwater and 20 mL of dichloromethane were added into the reactor,and the mixture was stirred for another several minutes, followedby extraction three times with dichloromethane (3 x 5 mL). Theorganic layer was then combined, dried over anhydrous sodiumsulfate, filtered, and evaporated under reduced pressure to give thecrude products. The crude products were then purified by silica-gelcolumn chromatography using petroleum etheredichloromethane(15/1) as the eluent. The obtained pure products were characterizedby 1H NMR and 13C NMR spectroscopy, and the spectra can be foundin the Supporting Information. And the isolated yields of productswere obtained based on the amounts of (hetero)aryl bromides. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With C82H77Cl2N3O2Pd; potassium carbonate; Trimethylacetic acid; In N,N-dimethyl acetamide; at 130℃; for 4h; | General procedure: Typically, (hetero)aryl bromide (1.0 mmol), thiazole derivatives(2.0 mmol), Pd-PEPPSI complexes (0.01e0.5 mol%), base (2 mmol),acid additive (0.3 mmol), and 3mL of DMAc solvent were addedinto a parallel reactor. After heating at 130 C for 4 h, the resultingmixture was cooled to room temperature. Subsequently, 25mL ofwater and 20 mL of dichloromethane were added into the reactor,and the mixture was stirred for another several minutes, followedby extraction three times with dichloromethane (3 x 5 mL). Theorganic layer was then combined, dried over anhydrous sodiumsulfate, filtered, and evaporated under reduced pressure to give thecrude products. The crude products were then purified by silica-gelcolumn chromatography using petroleum etheredichloromethane(15/1) as the eluent. The obtained pure products were characterizedby 1H NMR and 13C NMR spectroscopy, and the spectra can be foundin the Supporting Information. And the isolated yields of productswere obtained based on the amounts of (hetero)aryl bromides. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With palladium diacetate; potassium carbonate In N,N-dimethyl acetamide at 130℃; for 4h; Inert atmosphere; | Heck Coupling; General Procedure II General procedure: The corresponding bromoaryl compound 5 (25 mmol), Pd(OAc)2 (56 mg, 0.25 mmol), and anhyd K2CO3 (4.91 g, 50 mmol) were dissolved in N,N-dimethylacetamide (25 mL). 4-Methylthiazole (4.96 g, 4.55 mL,50 mmol) was added, and the solution was heated to 130 °C under an argon atmosphere for 4 h. Subsequently, the mixture was cooled to rt, diluted with H2O (100 mL), and extracted with CH2Cl2 (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried (Na2SO4), filtered, and concentrated in vacuo. |
60% | With anhydrous potassium acetate; palladium diacetate In N,N-dimethyl acetamide at 130℃; for 4h; Inert atmosphere; | tert-Butyl (2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)carbamate SI-2. Compound SI-1 (7.50 g, 25.0mmol), Pd(OAc)2 (55.0 mg, 0.24 mmol), and KOAc (4.90 g, 50.0mmol) were dissolved in N,Ndimethylacetamide(25 mL). 4-Methylthiazole (4.90 g, 50.0 mmol) was added, and the solution washeated to 130 °C for 4 h. Subsequently, the mixture was cooled to r.t., diluted with H2O (100 mL), andextracted with CH2Cl2 (100 mL 3). The combined organic layers were washed with brine (100 mL),dried with anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by purifiedby silica gel chromatography eluted with Hexane/EtOAc (from 5/1 to 2/1) to give SI-2 as white foam(4.80 g, 60%); Rf = 0.4, Hexane/EtOAc = 1/1; 1H NMR (400 MHz, CDCl3) d 9.43 (brs, 1H), 8.65 (s,1H), 7.12 (d, J = 8.0 Hz, 1H), 7.01 (s, 1H), 6.88 (dd, J = 7.6, 1.6 Hz, 1H), 5.55 (brs, 1H), 4.26 (d, J =6.4 Hz, 2H), 2.52 (s, 3H), 1.44 (s, 9H); 13C NMR (101 MHz, CDCl3) d 158.3, 155.9, 150.3, 148.2, 133.0,131.7, 130.7, 124.9, 120.6, 118.1, 81.1, 40.8, 28.3, 16.0; HRMS: m/z [M+H]+ Calcd. for C16H21N2O3S,321.1273 Found: 321.1266. |
60% | With anhydrous potassium acetate; palladium diacetate In N,N-dimethyl acetamide at 130℃; for 4h; Inert atmosphere; | tert-Butyl (2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)carbamate SI-2. Compound SI-1 (7.50 g, 25.0mmol), Pd(OAc)2 (55.0 mg, 0.24 mmol), and KOAc (4.90 g, 50.0mmol) were dissolved in N,Ndimethylacetamide(25 mL). 4-Methylthiazole (4.90 g, 50.0 mmol) was added, and the solution washeated to 130 °C for 4 h. Subsequently, the mixture was cooled to r.t., diluted with H2O (100 mL), andextracted with CH2Cl2 (100 mL 3). The combined organic layers were washed with brine (100 mL),dried with anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by purifiedby silica gel chromatography eluted with Hexane/EtOAc (from 5/1 to 2/1) to give SI-2 as white foam(4.80 g, 60%); Rf = 0.4, Hexane/EtOAc = 1/1; 1H NMR (400 MHz, CDCl3) d 9.43 (brs, 1H), 8.65 (s,1H), 7.12 (d, J = 8.0 Hz, 1H), 7.01 (s, 1H), 6.88 (dd, J = 7.6, 1.6 Hz, 1H), 5.55 (brs, 1H), 4.26 (d, J =6.4 Hz, 2H), 2.52 (s, 3H), 1.44 (s, 9H); 13C NMR (101 MHz, CDCl3) d 158.3, 155.9, 150.3, 148.2, 133.0,131.7, 130.7, 124.9, 120.6, 118.1, 81.1, 40.8, 28.3, 16.0; HRMS: m/z [M+H]+ Calcd. for C16H21N2O3S,321.1273 Found: 321.1266. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With palladium diacetate; potassium carbonate In N,N-dimethyl acetamide at 130℃; for 4h; Inert atmosphere; | Heck Coupling; General Procedure II General procedure: The corresponding bromoaryl compound 5 (25 mmol), Pd(OAc)2 (56 mg, 0.25 mmol), and anhyd K2CO3 (4.91 g, 50 mmol) were dissolved in N,N-dimethylacetamide (25 mL). 4-Methylthiazole (4.96 g, 4.55 mL,50 mmol) was added, and the solution was heated to 130 °C under an argon atmosphere for 4 h. Subsequently, the mixture was cooled to rt, diluted with H2O (100 mL), and extracted with CH2Cl2 (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried (Na2SO4), filtered, and concentrated in vacuo. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With palladium diacetate; potassium carbonate In 1-methyl-pyrrolidin-2-one at 120℃; for 12h; Inert atmosphere; | 11.1 Step 1: tert-butyl (S)-(5-(4-methylthiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)carbamate. To a solution of tert-butyl N-[(1S)-5-bromoindan-1-yl]carbamate (220 mg, 705 umol) and 4-methylthiazole (140 mg, 1.41 mmol) in NMP (6 mL) was added Pd(OAc)2 (15.8 mg, 70.5 umol) and K2CO3 (243 mg, 1.76 mmol) under nitrogen protection. Then the mixture was stirred at 120 °C for 12 hours. On completion, the reaction mixture was quenched by saturated ammonium chloride aqueous solution (30 mL) and ethyl acetate (30 mL). The black suspension mixture was filtered to give the filtrate and extracted with ethyl acetate (10 mL3). The organic layers were washed by brine (10 mL3) and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=20/1 to 2/1) to give the title compound (90 mg, 23% yield, 60% purity) as a yellow oil. LC-MS (ESI, m/z): [M +1]+ = 331.4. |
Tags: 693-95-8 synthesis path| 693-95-8 SDS| 693-95-8 COA| 693-95-8 purity| 693-95-8 application| 693-95-8 NMR| 693-95-8 COA| 693-95-8 structure
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P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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