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CAS No. : | 59016-93-2 | MDL No. : | MFCD00792672 |
Formula : | C7H9BO3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | PZRPBPMLSSNFOM-UHFFFAOYSA-N |
M.W : | 151.96 | Pubchem ID : | 2734706 |
Synonyms : |
4-(Hydroxymethyl)benzeneboronic acid
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.14 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 3.0 |
Molar Refractivity : | 42.4 |
TPSA : | 60.69 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -7.27 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | -0.06 |
Log Po/w (WLOGP) : | -1.29 |
Log Po/w (MLOGP) : | -0.27 |
Log Po/w (SILICOS-IT) : | -0.91 |
Consensus Log Po/w : | -0.51 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.02 |
Solubility : | 14.6 mg/ml ; 0.0964 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.76 |
Solubility : | 26.2 mg/ml ; 0.172 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.1 |
Solubility : | 12.0 mg/ml ; 0.0793 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.46 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With C46H49BrClFeN3Pd; copper diacetate; caesium carbonate In 1,4-dioxane at 110℃; for 24 h; | General procedure: A 10 mL round-bottom flask was charged with the prescribedamount of catalyst Pd/Cu, aryl chlorides (0.5 mmol), phenylboronicacids containing hydroxymethyl (0.75 mmol), Cs2CO3 (1.0 mmol)and dioxane (5 mL) in air. The reaction mixture was then placedin an oil bath and heated at 110 C for 24 h. After removal of thesolvent, the resulting residue was purified by flash chromatographyon silica gel using CH2Cl2 as eluent. The products 4a–k, and4m are known compounds [6,9] except for 4l and 4n. |
88% | With C46H49BrClFeN3Pd; copper diacetate; caesium carbonate In 1,4-dioxane at 110℃; for 24 h; | General procedure: A 10 mL round-bottom flask was charged with the prescribedamount of catalyst Pd/Cu, aryl chlorides (0.5 mmol), phenylboronicacids containing hydroxymethyl (0.75 mmol), Cs2CO3 (1.0 mmol)and dioxane (5 mL) in air. The reaction mixture was then placedin an oil bath and heated at 110 C for 24 h. After removal of thesolvent, the resulting residue was purified by flash chromatographyon silica gel using CH2Cl2 as eluent. The products 4a–k, and4m are known compounds [6,9] except for 4l and 4n. |
88% | With C46H49BrClFeN3Pd; copper diacetate; caesium carbonate In 1,4-dioxane at 110℃; for 24 h; | General procedure: A 10 mL round-bottom flask was charged with the prescribedamount of catalyst Pd/Cu, aryl chlorides (0.5 mmol), phenylboronicacids containing hydroxymethyl (0.75 mmol), Cs2CO3 (1.0 mmol)and dioxane (5 mL) in air. The reaction mixture was then placedin an oil bath and heated at 110 C for 24 h. After removal of thesolvent, the resulting residue was purified by flash chromatographyon silica gel using CH2Cl2 as eluent. The products 4a–k, and4m are known compounds [6,9] except for 4l and 4n. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With sodium tetrahydroborate In methanol at 0℃; for 1 h; | j00699j A solution of (4-formylphenyl)boronic acid (1.5 g, 11 mmol.) in methanol (40mL), was charged with sodiumborohydride (0.38 g, 11 mmol) at 0°C and the reaction mixturewas stirred for 1 h. The reaction mixture was concentrated in vacuo resulting in a crude product was dissolved in water and cooled to 0-5°C and 5percent aqueous acetic acid solution was added up to pH=5. Precipitated solid was collected by filtration and dried to afford 1.2 (80 percent yield) the titled compound. ‘H NMR (400 MHz, CD3OD) 5 7.72 (d, J= 7.2 Hz, 1H), 7.59 (d, J= 7.6 Hz, 2H), 7.35 —7.30 (m, 2H), 4.60 (s, 2H); MS (ES+): m/z 542.15 , 544.35 [M+H] LCMS: tR =2.42 mm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | for 22 h; Reflux | A suspension of 4-(hydroxymethyl)phenylboronic acid (1.00 g, 6.6. mmol) and pinacol (0.79 g, 6.7 mmol) in tetrahydrofurane (40 mL) was refluxed over 22 h. During this time the starting materials were completely dissolved. The solvent was removed in vacuum (10 mbar), the residue redissolved in CH2Cl2 / EtOAc and purified by column chromatography on silica gel using the mixture of CH2Cl2 / EtOAc (9/1, v/v) as eluent. Yield 1.4 g (92percent). Rf= 0.3 (silica, eluent - CH2Cl2 / EtOAc, 9/1, v/v). 1H NMR (200 MHz, CDCl3), δ in ppm: 1.35 (s, 12H), 4.71 (s, 2H), 7.37 (d, 2H, 3J = 8.2 Hz), 7.81 (d, 2H, 3J = 8.2 Hz). |
92% | for 22 h; Reflux | Synthesis4-(Hvdroxymethyl)phenylboronic acid pinacol ester:A suspension of 4-(hydroxymethyl)phenylboronic acid (1.00 g, 6.6 mmol) and pinacol (0.79 g, 6.7 mmol) in tetrahydrofurane (40 ml_) was refluxed over 22 h. During this time the starting materials were completely dissolved. The solvent was removed in vacuum (10 mbar), the residue redissolved in CH2CI2 / EtOAc and purified by column chromatography on silica gel using the mixture of CH2CI2 / EtOAc (9/1 , v/v) as eluent. Yield 1.4 g (92percent). Rf= 0.3 (silica, eluent - CH2CI2 / EtOAc, 9/1 , v/v). H NMR (200 MHz, CDCI3), δ in ppm: 1.35 (s, 12H), 4.71 (s, 2H), 7.37 (d, 2H, 3J = 8.2 Hz), 7.81 (d, 2H, 3J = 8.2 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With C46H49BrClFeN3Pd; copper diacetate; caesium carbonate In 1,4-dioxane at 110℃; for 24 h; | General procedure: A 10 mL round-bottom flask was charged with the prescribedamount of catalyst Pd/Cu, aryl chlorides (0.5 mmol), phenylboronicacids containing hydroxymethyl (0.75 mmol), Cs2CO3 (1.0 mmol)and dioxane (5 mL) in air. The reaction mixture was then placedin an oil bath and heated at 110 C for 24 h. After removal of thesolvent, the resulting residue was purified by flash chromatographyon silica gel using CH2Cl2 as eluent. The products 4a–k, and4m are known compounds [6,9] except for 4l and 4n. |
90% | With C46H49BrClFeN3Pd; copper diacetate; caesium carbonate In 1,4-dioxane at 110℃; for 24 h; | General procedure: A 10 mL round-bottom flask was charged with the prescribedamount of catalyst Pd/Cu, aryl chlorides (0.5 mmol), phenylboronicacids containing hydroxymethyl (0.75 mmol), Cs2CO3 (1.0 mmol)and dioxane (5 mL) in air. The reaction mixture was then placedin an oil bath and heated at 110 C for 24 h. After removal of thesolvent, the resulting residue was purified by flash chromatographyon silica gel using CH2Cl2 as eluent. The products 4a–k, and4m are known compounds [6,9] except for 4l and 4n. |
90% | With C46H49BrClFeN3Pd; copper diacetate; caesium carbonate In 1,4-dioxane at 110℃; for 24 h; | General procedure: A 10 mL round-bottom flask was charged with the prescribedamount of catalyst Pd/Cu, aryl chlorides (0.5 mmol), phenylboronicacids containing hydroxymethyl (0.75 mmol), Cs2CO3 (1.0 mmol)and dioxane (5 mL) in air. The reaction mixture was then placedin an oil bath and heated at 110 C for 24 h. After removal of thesolvent, the resulting residue was purified by flash chromatographyon silica gel using CH2Cl2 as eluent. The products 4a–k, and4m are known compounds [6,9] except for 4l and 4n. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With palladium diacetate; sodium carbonate; tris-(m-sulfonatophenyl)phosphine In water; acetonitrile at 80℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; triethylamine;copper diacetate; In N,N-dimethyl-formamide; at 20℃; for 24h; | 3.04 g (20 mmol) of 4-(hydroxymethyl)phenylboronic acid, 1.44 g (10 mmol) of <strong>[670-95-1]4-phenylimidazole</strong>, 2.8 ml (20 mmol) of triethylamine and 1.64 ml (20 mmol) of pyridine are dissolved in 20 ml of dimethylformamide. 2.72 g (15 mmol) of copper diacetate are added and the mixture is stirred for 24 hours at ambient temperature. It is diluted with 200 ml of dichloromethane and 200 ml of aqueous 28% ammonia solution. After the phases have settled and been separated, the aqueous phase is extracted with 100 ml of dichloromethane. The organic phases are washed with 50 ml of saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated to dryness. The product is purified by chromatography on silica gel, eluting with a 97/3 then 95/5 mixture of dichloromethane and methanol. The product is recrystallized from a mixture of toluene and diisopropyl ether, to give 1.82 g of product in the form of white crystals. Melting point ( C.): 137-139 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 20 - 60℃; for 2h; | A solution of compound 52ii (100 mg, 0.48 mmol), 52iii (73 mg, 0.48 mmol), and KOAc (190 mg, 1.92 mmol) in DMF (5 ml) was degassed thrice and PdCl2(drhopf) (36 mg, 0.048 mmol) added to it at rt under an argon atmosphere. The reaction mixture was heated at 6O0C for two hours, diluted with ethyl acetate (EA) and washed with brine. The organic layer was dried, concentrated, and the residue separated by column chromatography on silica gel employing as eluent EA/Hex (0 - 80percent) to yield 52i. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;PdCl2[dppf]; In tetrahydrofuran; N,N-dimethyl-formamide; | Step 4. Preparation of (4'-Trifluoromethyl-biphenyl-4-yl)-methanol (compound 36D) 1-Bromo-4-trifluoromethyl-benzene (814 mg, 3.62 mmol), 4-hydroxymethylphenylboronic acid (600 mg, 3.98 mmol), cesium carbonate (2.36 g, 7.24 mmol), and PdCl2(dppf) (132 mg, 0.181 mmol) were added to 10 ml of a 1:1 solution of DMF/THF. The reaction was flushed with nitrogen and heated to 90 C. for 1 h. The reaction was cooled, poured into diethyl ether and washed with water (2*50 ml), brine (1*50 ml) and dried over anhydrous sodium sulfate. The crude product was filtered through silica gel, eluted with diethyl ether, and concentrated to provide the title compound. MS m/z 251 (M-1). | |
With caesium carbonate;palladium dichloride; In tetrahydrofuran; DMF (N,N-dimethyl-formamide); at 90℃; for 1h;Heating / reflux; | Step 1.Preparation of (4'-Trifluoromethyl-biphenyl-4-yl)-methanol (Compound 3A) 1-Bromo-4-trifluoromethyl-benzene (814 mg, 3.62 mmol), 4-hydroxymethylphenylboronic acid (600 mg, 3.98 mmol), cesium carbonate (2.36 g, 7.24 mmol), and PdCl2(dppf) (132 mg, 0.181 mmol) were added to 10 ml of a 1:1 solution of DMF/THF. The reaction was flushed with nitrogen and heated to 90 C. for 1 h.The reaction was cooled, poured into diethyl ether and washed with water (2*50 ml), brine (1*50 ml) and dried over anhydrous sodium sulfate.The crude product was filtered through silica gel, eluted with diethyl ether, and concentrated to provide the title compound. MS m/z 251 (M-1). | |
With bis-triphenylphosphine-palladium(II) chloride; caesium carbonate; In tetrahydrofuran; N,N-dimethyl-formamide; at 90℃; for 1h;Inert atmosphere; | A mixture of Compound 33A (450 mg, 2.0 mmol), 4- (hydroxymethyl)phenylboronic acid (334 mg, 2.2 mmol), CS2CO3 (1.30 g, 4.0 mmol), and Pd(PPh3)Cl2 (140 mg, 0.2 mmol) in DMF/THF (10 mL, 1 : 1 in volume) was heated at 90 C under nitrogen for 1 hour. The mixture was cooled down to room temperature, diluted with diethyl ether (50 mL), washed with water (50 mL x 2) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified with column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 10% v/v) to yield Compound 33B: LC-MS (ESI) m/z: 235 [M-OH]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With C37H44ClN2O3PPd; caesium carbonate In water at 100℃; for 12h; Schlenk technique; Inert atmosphere; | General procedure for Suzuki coupling General procedure: In a Schlenk tube, a mixture of the required amount of catalyst, plus the aryl chloride (1.0 mmol), aryl boronic acid (1.5 mmol) and the selected base (2.0 mmol) in water was evacuated and charged with nitrogen. The reaction mixture was heated at 100°C for 12 h. After cooling, the mixture was extracted with CH2Cl2 and the extract was evaporated. The resulting residue was purified by flash chromatography on silica gel using a mixture of CH2Cl2/ethyl acetate (5/1) as eluent. The known products 5, 6a [17,18], 6b [22], 6c [23], 6e [24], 6g [19], 6h [25] and 7a [26] were characterized by comparison of data with those in the literature. The products 6d, 6f and 7b-h were new compounds and characterized by elemental analysis, MS, 1H and 13C NMR. |
18 Preparation of [4-(5-Trifluoromethyl-pyridin-2-yl)-phenyl]-methanol (Compound 18A) The title compound was prepared from 2-Chloro-5-trifluoromethyl-pyridine and 4-(hydroxymethyl)boronic acid PdCl2(dppb) catalyst in the manner analogous to Example 3A. 400 MHz 1H NMR (DMSO-d6) δ 8.98 (s, 1H), 8.2 (dd, 1H, J=2.4 Hz, J'=8.4 Hz), 8.09 (m, 3H), 7.42 (d, 2H, J=8.54 Hz), 5.23 (t, 1H), 4.54 (d, 2H, J=6 Hz); MS m/z 254 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In methanol; water; toluene; at 70℃; for 16h; | Example 90; [4- (4, 6-Diphenylpyrimidin-2-yl) -phenyl]methanol; A mixture of 2-chloro-4, 6-diphenylpryimidine, 0.79g (2.96 mmol), 4- (hydroxylmethyl)phenylboronic acid, 0.45g (2.96 mmol), Pd (PPh3) 4, 342mg (0.296 mmol), in 2 mL of toluene and EPO <DP n="177"/>ImL of methanol was heated to obtain a clear solution. To the solution was added 2mL of 4.0M aq. Na2CO3. The reaction mixture refluxed for lbetah at 70 C. The mixture was cooled to room temperature and diluted with 10OmL ethyl acetate. The organic layer was washed with water, sat. aq. NaCl, and dried (MgSO4) . After the solution was concentrated, the residue was recrystallized with Et2O-Heptane (1:1) to afford the desired product in 0.38g (38%) as a yellow solid. |
38% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In methanol; water; toluene; at 70℃; for 16h; | A mixture of 2-chloro-4,6-diphenylpryimidine, 0. 79G (2.96 mmol), 4- (HYDROXYLMETHYL) phenylboronic acid, 0.45g (2.96 mmol), Pd (PPh3) 4,342mg (0.296 mmol), in 2 mL of toluene and 1ML of methanol was heated to obtain a clear solution. To the solution was added 2mL of 4. OM aq. NA2CO3. The reaction mixture refluxed for 16h at 70 C. The mixture was cooled to room temperature and diluted with LOOML ethyl acetate. The organic layer was washed with water, sat. aq. NaCl, and dried (MGSO4). After the solution was concentrated, the residue was recrystallized with Et20-Heptane (1 : 1) to afford the desired product in 0.38g (38%) as a yellow SOLID. 1H NMR (DMSO-d6) 8.72 (d, 2H, J = 9. 0HZ), 8.52-8. 47 (m, 4H), 8.45 (s, 1H), 7.64-7. 57 (m, 8H), 4.78 (d, 2H, J = 6.7Hz), 4.37 (t, 1H, J = 6.7Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,2-dimethoxyethane; water at 90℃; for 8h; Inert atmosphere; | 5.1.6. [4-(3-Methylpyridin-2-yl)phenyl]methanol (11a) Under argon gas atmosphere, to a mixture of 2-bromo-3-methylpyridine (9a; 860 mg, 5.00 mmol) and [4-(hydroxymethyl)phenyl]boronic acid (10; 836 mg, 5.50 mmol) in 1,2-dimethoxyethane (DME; 30 mL) were added Pd(PPh3)4 (289 mg, 0.25 mmol)and 1 M Na2CO3 aqueous solution (12.5 mL, 12.5 mm ol), and the mixture was stirred at 90 C for 8 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was concentrated in vacuo and purified by silica gel column chromatography (0-5% MeOH in CHCl3) to give 11a (906 mg, 91%) as a pale yellow solid. 1H NMR (DMSO-d6) d 2.32 (s, 3H), 4.56 (d, 2H, J = 5.7 Hz), 5.23(t, 1H, J = 5.7 Hz), 7.28 (dd, 1H, J = 7.6, 4.7 Hz), 7.40 (d, 2H,J = 8.3 Hz), 7.50 (d, 2H, J = 8.3 Hz), 7.69-7.73 (m, 1H), 8.45-8.48(m, 1H); MS (ESI) m/z 200 [M+H]+. |
47% | With sodium carbonate In water; toluene | Intermediate 14: 4-(3-methyl-2-pyridinyl)benzoic Acid Intermediate 14: 4-(3-methyl-2-pyridinyl)benzoic Acid A mixture of 2-bromo-3-methylpyridine (22.5 g, 0.1312 mol), 4-(hydroxymethyl)phenylboronic acid (25 g, 0.164 mol), Pd(PPh3)4 (9.5 g, 0.0082 mol), and sodium carbonate (200 g in 500 ml of water) in toluene (750 ml) were refluxed under nitrogen atmosphere for 15 h. Separated the toluene layer and distilled under reduced pressure to give a residue. The residue was then purified by column chromatography to yield [4-(3-methyl-2-pyridinyl)phenyl]methanol (12 g, 47%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With sodium tetrahydroborate In methanol at 0℃; for 1h; | j00698j (4-(Hydroxymethyl) phenyl) boronic acid: j00699j A solution of (4-formylphenyl)boronic acid (1.5 g, 11 mmol.) in methanol (40mL), was charged with sodiumborohydride (0.38 g, 11 mmol) at 0°C and the reaction mixturewas stirred for 1 h. The reaction mixture was concentrated in vacuo resulting in a crude product was dissolved in water and cooled to 0-5°C and 5% aqueous acetic acid solution was added up to pH=5. Precipitated solid was collected by filtration and dried to afford 1.2 (80 % yield) the titled compound. ‘H NMR (400 MHz, CD3OD) 5 7.72 (d, J= 7.2 Hz, 1H), 7.59 (d, J= 7.6 Hz, 2H), 7.35 -7.30 (m, 2H), 4.60 (s, 2H); MS (ES+): m/z 542.15 , 544.35 [M+H] LCMS: tR =2.42 mm. |
With hydrogenchloride; sodium borohydrid In methanol | 6 [4-(hydroxymethyl)-phenyl]-boronic acid PREPARATION 6 [4-(hydroxymethyl)-phenyl]-boronic acid 380 mg of sodium borohydride were added to a solution of 1.5 g of (4-formylphenyl)-boronic acid in 40 ml of methanol at 0° C. under an inert atmosphere, and after stirring for 30 minutes, 200 ml of 2N hydrochloric acid were added. After evaporation under reduced pressure, the crude product was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate, followed by filtration and evaporation under reduced pressure to obtain 1.5 g of the expected product with a Rf=0.15 (cyclohexane/ethyl acetate 50/50). IR (CHCl3) Aromatics 1614, 1565, 1518 cm-1 NMR (CDCl3) 4.50 (d) CH2 OH 7.92 (s) B(OH)2 7.26 and 7.74 aromatic H's 5.14 (t) CH2 OH | |
With sodium tetrahydroborate In tetrahydrofuran for 1h; |
With sodium tetrahydroborate; water In acetonitrile | ||
In tetrahydrofuran | 13 4-(Hydroxymethyl)phenylboronic Acid Example 13 4-(Hydroxymethyl)phenylboronic Acid 15 g (100 mmol) of 4-formylphenylboronic acid were dissolved in 200 ml of tetrahydrofuran, and 0.25 g of Raney nickel were added. A stream of hydrogen was passed through the reaction mixture for 8 hours, giving 14.8 g (97 mmol) of 4-(hydroxymethyl)phenylboronic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 124 4-(3,4-diethoxyphenyl)-N-{4-[4-(hydroxymethyl)phenyl]-6-phenylpyridin-2-yl}-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and (4-hydroxymethylphenyl)boronic acid (19.0 mg) as starting materials and in the same manner as in Example 119, 4-(3,4-diethoxyphenyl)-N-{4-[4-(hydroxymethyl)phenyl]-6-phenylpyridin-2-yl}-4-oxobutanamide (11.7 mg) was obtained. HPLC (220 nm) purity 95% (retention time 1.89 min) MS (ESI+, m/e) 525 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 156 4-(2,3-dihydro-1-benzofuran-5-yl)-N-{4-[4-(hydroxymethyl)phenyl]-6-phenylpyridin-2-yl}-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide obtained in Example 114-(1) (20.3 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and (4-hydroxymethylphenyl)boronic acid (19.0 mg) as starting materials and in the same manner as in Example 119, 4-(2,3-dihydro-1-benzofuran-5-yl)-N-{4-[4-(hydroxymethyl)phenyl]-6-phenylpyridin-2-yl}-4-oxobutanamide (12.9 mg) was obtained. HPLC (220 nm) purity 92% (retention time 1.82 min) MS (ESI+, m/e) 479 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium carbonate In acetonitrile at 160℃; for 0.116667h; Microwave irradiation; | 48 Synthesis of 4-(4-hvdroxymethyl-benzyl)-benzoic acid methyl ester (1). A mixture of 4-(hydroxymethyl)phenylboronic acid(304 mg, 2.0 mmol), methyl 4-(bromomethyl)-benzoate (229 mg, 1.0 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol) and 1 M aq. K2CO3 (400 μl) in ACN (800 μl) was irradiated in microwave oven (max. power 250W, 160° C) for 7 min and cooled to ambient temperature. Reaction mixture was diluted with EtOAc (100 ml) and extracted with 5% aq. NaHCO3 (30 ml) and brine (30 ml). Organic layer was dried over MgSO4 (anh.). Solvent was evaporated in vacuum. Residue was dried in vacuum overnight to provide target product (1) (224 mg, 88%) as yellow oil. |
67% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In tetrahydrofuran; water; N,N-dimethyl-formamide at 55℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium carbonate;tris-(dibenzylideneacetone)dipalladium(0); tri tert-butylphosphoniumtetrafluoroborate; In 1,4-dioxane; at 80 - 90℃;Product distribution / selectivity; | A solution of <strong>[460081-18-9]ethyl 2-chloro-1,3-oxazole-4-carboxylate</strong> (0.59 g, 3.36 mmol) in dioxane was treated with 4-(hydroxymethyl)phenyl boronic acid (0.766 g, 5.04 mmol), K2CO3 (0.929 g, 6.72 mmol), t-Bu3PhBF4 (0.049 g, 0.168 mmol) heated to 80 C. then treated with Pd2(dba)3 (0.154 g 0.168 mmol) and stirred overnight at 90 C. The reaction mixture was diluted with EtOAc, washed with water, saturated sodium chloride, dried over MgSO4 and concentrated in in vacuo. The resultant residue was purified by flash chromatography (silica, EtOAc:hexanes 20?50%) to give the title product in 70% yield, identified by NMR and mass spectral analyses. LCMS (ESI+) 248 (MH+). |
68% | With potassium carbonate;tris-(dibenzylideneacetone)dipalladium(0); tri tert-butylphosphoniumtetrafluoroborate; In 1,4-dioxane; water; at 86℃; for 2h;Product distribution / selectivity; | To a suspension of tris(dibenzylideneacetone)dipalladium (0) (0.025 eq) and tri-tert-butylphosphonium tetrafluoroborate (0.05 eq) a mixture of dioxane and 1N aqueous potassium carbonate (3:1) degassed with nitrogen was added chlorooxazole carboxylate (1 eq) followed by a suspension of 4-hydroxymethylphenylboronic acid (1 eq) in a mixture of dioxane and 1N aqueous potassium carbonate (8:1) continuing to degas with nitrogen and the resulting reaction mixture was stirred at 86 C. (reflux) until determined complete by HPLC (about 2 h). The reaction mixture was allowed to cool to room temperature and filtered through celite, the organic layer separated, and the aqueous layer extracted with ethyl acetate. The dioxane layer was concentrated (avoiding total evaporation to dryness) and combined with the ethyl acetate extract and washed with aq. sodium bicarbonate, brine, dried over sodium sulphate, filtered, evaporated, and triturated with MTBE. The isolated yield of the target compound was 68%. m. p. 99-101 C.; 1H NMR (300 MHz, CDCl3, delta): 8.27 (s, 1H), 8.10 (d, 2H, J=8.2 Hz), 7.47 (d, 2H, J=8.2 Hz), 4.77 (s, 2H), 4.43 (m, 2H, J=7.4 Hz), 1.41 (t, 3H, J=7.4 Hz). |
68% | With potassium carbonate;tris-(dibenzylideneacetone)dipalladium(0); tri tert-butylphosphoniumtetrafluoroborate; In 1,4-dioxane; water; at 86℃;Inert atmosphere; | Example 2; Step 1: Preparation of ethyl 2-[4-(hydroxymethyl)phenyl]-1,3-oxazole-4-carboxylate; To a suspension of tris(dibenzylideneacetone)dipalladium (0) (3.1 g, 3.36 mmol) and tri-tert-butylphosphonium tetrafluoroborate (1.95 g, 6.7 mmol) in a mixture of dioxane (500 ml) and 1N aqueous potassium carbonate (150 ml) degassed with nitrogen was added chlorooxazole carboxylate (23.5. g, 135 mmol) followed by a suspension of 4-hydroxymethylphenylboronic acid (21.3 g, 135 mmol) in a mixture of dioxane (200 ml, +50 ml wash) and 1N aqueous potassium carbonate (30 ml) continuing to degas with nitrogen and the resulting reaction mixture was stirred at 86 C. (reflux) until determined complete by HPLC (about 2 h). The reaction mixture was allowed to cool to room temperature and filtered through celite, the organic layer separated, and the aqueous layer extracted with ethyl acetate. The dioxane layer was concentrated (avoiding total evaporation to dryness) and combined with the ethyl acetate extract and washed with aq. sodium bicarbonate, brine, dried over sodium sulphate, filtered, evaporated, and triturated with MTBE. The isolated yield of the target compound 22.7 g (68%). m.p. 99-101 C.; 1H NMR (300 MHz, CDCl3, delta): 8.27 (s, 1H), 8.10 (d, 2H, J=8.2 Hz), 7.47 (d, 2H, J=8.2 Hz), 4.77 (s, 2H), 4.43 (m, 2H, J=7.4 Hz), 1.41 (t, 3H, J=7.4 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sodium hydroxide; water In tetrahydrofuran at 23℃; for 0.166667h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In benzene for 20h; Dean-Stark; Reflux; | 4-(Hydroxymethyl)phenylboronic Acid MIDA Ester 4 An oven-dried flask topped with a Dean-Stark apparatus and condenserwas charged sequentially with 4-(hydroxymethyl)phenylboronicacid (3; 200 mg, 1.32 mmol), MIDA (387 mg, 2.63 mmol), anhydbenzene (2.7 mL), and DMSO (0.3 mL). The Dean-Stark trap was filledwith benzene and the resulting mixture was heated at reflux for 20 h(reaction monitored by TLC). The solution was cooled to rt, concentratedunder reduced pressure, and the resulting residue was purifiedby flash column chromatography (silica gel, EtOAc/acetone 8:2) toprovide compound 4 (340 mg, 98%); Rf = 0.35 (EtOAc/acetone 8:2)1H NMR (400 MHz, CD3CN): = 2.49 (s, 3 H), 3.91 (d, J = 17.2 Hz, 2 H),4.11 (d, J = 17.2 Hz, 2 H), 4.57 (s, 2 H), 7.34 (d, J = 8.0 Hz, 2 H), 7.45 (d,J = 8.0Hz, 2 H).13C NMR (100 MHz, CD3CN): = 41.4, 62.8, 64.6, 127.2, 133.5, 144.2,169.6.11B NMR (128 MHz, CD3CN): = 11.59.HRMS (ESI+): m/z [M + H]+ calcd for C12H14NO5B: 264.1043; found:264.1039. |
94% | In dimethyl sulfoxide; toluene for 3h; Reflux; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In toluene; acetonitrile; at 150℃; for 0.25h;Inert atmosphere; Microwave irradiation; | 1.2 [4-(2-Phenylimidazo[1,2-a]pyridin-6-yl)phenyl]methanol; 150 mg of <strong>[4044-98-8]6-bromo-2-phenylimidazo[1,2-a]pyridine</strong>, 125 mg of 4-(hydroxymethyl)phenylboronic acid, 19 mg of tetrakis(triphenylphosphine)palladium and 2 ml of acetonitrile are placed in a microwave tube. Under a stream of nitrogen, 2 ml of nitrogen-degassed toluene and then 2 ml of a 2M solution of sodium carbonate are added thereto. The tube is placed in a microwave device and irradiated at 150 C. for 15 min. The organic phase is recovered, dried and then concentrated under reduced pressure. The residue is taken up with diisopropyl ether and the precipitate is recovered by filtration, washed and dried. It is purified by recrystallization from n-butanol. 52 mg of compound are obtained. Mp=238-240 C. 1H NMR (DMSO-d6, delta in ppm): 4.54 (d, J=5.5 Hz, 2H); 5.2 (t, J=5.6 Hz, 1H); from 7.24 to 7.73 (m, 9H); 7.96 (m, 2H); 8.36 (s, 1H); 8.84 (t, J=1.3 Hz, 1H). M+H=301. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In tetrahydrofuran; water at 20 - 64℃; Inert atmosphere; | |
90% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In tetrahydrofuran; water at 60℃; for 3h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With C37H44ClN2O3PPd; caesium carbonate In water at 100℃; for 12h; Schlenk technique; Inert atmosphere; | General procedure for Suzuki coupling General procedure: In a Schlenk tube, a mixture of the required amount of catalyst, plus the aryl chloride (1.0 mmol), aryl boronic acid (1.5 mmol) and the selected base (2.0 mmol) in water was evacuated and charged with nitrogen. The reaction mixture was heated at 100°C for 12 h. After cooling, the mixture was extracted with CH2Cl2 and the extract was evaporated. The resulting residue was purified by flash chromatography on silica gel using a mixture of CH2Cl2/ethyl acetate (5/1) as eluent. The known products 5, 6a [17,18], 6b [22], 6c [23], 6e [24], 6g [19], 6h [25] and 7a [26] were characterized by comparison of data with those in the literature. The products 6d, 6f and 7b-h were new compounds and characterized by elemental analysis, MS, 1H and 13C NMR. |
With potassium phosphate In 1,4-dioxane; water at 80℃; Inert atmosphere; | 1.27.A Step A: Preparation of (4-(Pyrazin-2-yl)phenyI)methanol.A mixture of 2-chloropyrazme (0.230 ml, 2.62 mmol), 4-(hydroxymethyl)phenylboronic acid (517 mg, 3.41 mmol), tetrakis(tϖphenylphosphine)palladium (0) (303 mg, 0.262 mmol) and 2 M potassium phosphate aqueous solution (2.62 ml, 5.24 mmol) in dioxane (10 mL) was heated at 80 0C overnight under nitrogen. The mixture was cooled down, poured into water and extracted with ethyl acetate. The combined organic layers were dried and concentrated. The residue was purified by preparative HPLC to give the title compound (350 mg) as an off-white solid. LCMS m/z = 187.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 4.79 (s, 2H), 7.52 (d, J= 8.1 Hz, 2H), 8.02 (d, J = 8.1 Hz, 2H), 8.51 (d, J= 2.5 Hz, IH), 8.63 (dd, J = 2.4 and 1.6 Hz, IH), 9.03 (d, J= 1.6 Hz, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium carbonate; In ethanol; water; toluene; at 88℃; for 1h; | A stirred mixture of 4-(hydroxymethyl)phenylboronic acid (34) (308 mg, 2.03 mmol) and Pd(dppf)Cl2 (191 mg, 0.261 mmol) in toluene (22 mL) and EtOH (11 mL) was degassed for 8 min (vacuum pump) and then N2 was added. An aqueous solution of 2M Na2CO3 (4.4 mL, 8.8 mmol) was added by syringe and the stirred mixture was again degassed for 8 min, and then N2 was added. 2-Chloro-l-iodo-4-(trifluoromethoxy)benzene (35) (585 mg, 1.81 mmol) was added by syringe and the resulting mixture was stirred at 88 0C for 60 min. The cooled mixture was then diluted with aqueous NaHCO3 (100 mL) and extracted with CH2Cl2 (5x 100 mL). The extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-50% CH2Cl2/petroleum ether firstly gave foreruns, and then further elution with 50% CH2Cl2/petroleum ether gave 2'-chloro-4'-(trifluoromethoxy)[l,r-biphenyl]-4-yl]methanol (37) (537 mg, 98%) as a white solid: mp (pentane) 38-39 C; 1H NMR (CDCl3) delta 7.46 (br d, J = 8.2 Hz, 2 H), 7.42 (dt, J = 8.3, 2.0 Hz, 2 H), 7.37 (br s, 1 H), 7.36 (d, J = 8.5 Hz, 1 H), 7.19 (m,I H), 4.77 (d, J = 5.9 Hz, 2 H), 1.70 (t, J = 5.9 Hz, 1 H); HREIMS calcd for C14H10ClF3O2 mlz (M+) 304.0292, 302.0321 , found 304.0294, 302.0317. |
98% | With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In ethanol; toluene; at 88℃; for 1h;Inert atmosphere; | EXAMPLE 2Methods of PreparationA. Synthesis of (6S)-6-[{2'-chloro-4'-(trifluoromethoxy)[1,1'-biphenyl]-4-yl]methoxy}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (1) by the method of Scheme 1 A stirred mixture of 4-(hydroxymethyl)phenylboronic acid (34) (308 mg, 2.03 mmol) and Pd(dppf)Cl2 (191 mg, 0.261 mmol) in toluene (22 mL) and EtOH (11 mL) was degassed for 8 min (vacuum pump) and then N2 was added. An aqueous solution of 2M Na2CO3 (4.4 mL, 8.8 mmol) was added by syringe and the stirred mixture was again degassed for 8 min, and then N2 was added. 2-Chloro-1-iodo-4-(trifluoromethoxy)benzene (35) (585 mg, 1.81 mmol) was added by syringe and the resulting mixture was stirred at 88 C. for 60 min. The cooled mixture was then diluted with aqueous NaHCO3 (100 mL) and extracted with CH2Cl2 (5×100 mL). The extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-50% CH2Cl2/petroleum ether firstly gave foreruns, and then further elution with 50% CH2Cl2/petroleum ether gave 2'-chloro-4'-(trifluoromethoxy)[1,1'-biphenyl]-4-yl]methanol (37) (537 mg, 98%) as a white solid: mp (pentane) 38-39 C.; 1H NMR (CDCl3) delta 7.46 (br d, J=8.2 Hz, 2H), 7.42 (dt, J=8.3, 2.0 Hz, 2H), 7.37 (br s, 1H), 7.36 (d, J=8.5 Hz, 1H), 7.19 (m, 1H), 4.77 (d, J=5.9 Hz, 2H), 1.70 (t, J=5.9 Hz, 1H); HREIMS calcd for C14H10ClF3O2 m/z (M+) 304.0292, 302.0321, found 304.0294, 302.0317. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; potassium carbonate In 1,4-dioxane; lithium hydroxide monohydrate at 90℃; for 1h; Inert atmosphere; | 3.3.1 Step 3.1 Preparation of Compound 5 N-[5-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (Int-1) (1.5 g, 5.34 mmol), [4- (Hydroxymethyl)phenyl]boronic acid (SM3) (1.62 g, 10.67 mmol) and potassium carbonate (2.21 g, 16.01 mmol) were dissolved in dioxane (15 mL) and water (3 mL) 3 times to replace nitrogen, then After adding 1,1-bis(diphenylphosphonium)ferrocene palladium chloride (195 mg, 0.267 mmol), nitrogen was replaced again 3 times and added to 90 degrees and stirred for 1 hour.The reaction mixture was added with water (20 mL) and extracted with ethyl acetate (20 mL×3). The organic phase was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was subjected to silica gel column chromatography ( Eluent: 2% to 5% methanol/dichloromethane) to give yellow solid N-[5-(4-(hydroxymethyl)phenyl]-[1,2,4]triazole[1,5-a] ]dopyridin-2-yl]cyclopropanecarboxamide (5) (1.4 g, 78% yield). |
68% | With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; potassium carbonate In 1,4-dioxane; lithium hydroxide monohydrate at 90℃; for 16h; Inert atmosphere; | 7.2 Step 2: Preparation of N-(5-(4-(hydroxymethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (Intermediate 7B) N-(5-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (2.8 g, 10 mmol),4-hydroxymethylphenylboronic acid (1.5g, 10mmol),1,1'-bisdiphenylphosphinoferrocene dichloropalladium (730 mg, 1 mmol),Potassium carbonate (2.8g, 20mmol) was sequentially added to the jar.Then 50 mL of 1,4-dioxane and 10 mL of water were added thereto.Under argon protection,The reaction was heated to 90 °C and stirred for 16 hours.Then, cool the reaction solution to room temperature.Add ethyl acetate extraction,Organic layer separation,Dry, concentrate.The residue was purified by column chromatography (eluent: dichloromethane:methanol = 25:1).The title product was obtained as a yellow solid 2.1 g, yield 68% |
With potassium carbonate In 1,4-dioxane; lithium hydroxide monohydrate at 90℃; for 16h; Inert atmosphere; | 1.1 Step 1:; 4-(Hydroxymethyl)phenylboronic acid (1.1 eq.) was added to a solution of cyclopropanecarboxylic acid (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide in 1,4-dioxane/water (4:1). K2CO3 (2 eq.) and PdCl2dppf (0.03 eq.) were added to the solution. The resulting mixture was then heated in an oil bath at 90° C. for 16 h under N2. Water was added and the solution was extracted with ethyl acetate. The organic layers were dried over anhyd. MgSO4 and evaporated in vacuo. The resulting mixture was used without further purification. |
With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; potassium carbonate In 1,4-dioxane; lithium hydroxide monohydrate at 90℃; | ||
With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; potassium carbonate In 1,4-dioxane; lithium hydroxide monohydrate at 90℃; for 16h; Inert atmosphere; | 1.2.1.1 1.2. Route 2 1.2.1. Step 1: cyclopropanecarboxylic acid [5-(4-hydroxymethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amide 1.2. Route 2 1.2.1. Step 1: cyclopropanecarboxylic acid [5-(4-hydroxymethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amide 4-(Hydroxymethyl)phenylboronic acid (1.1 eq.) is added to a solution of cyclopropanecarboxylic acid (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide in 1,4-dioxane/water (4:1). K2CO3 (2 eq.) and PdCl2dppf (0.03 eq.) are added to the solution. The resulting mixture is then heated in an oil bath at 90° C. for 16 h under N2. Water is added and the solution is extracted with ethyl acetate. The organic layers are dried over anhydrous MgSO4 and evaporated in vacuo. The resulting mixture is used without further purification. | |
With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; potassium carbonate In 1,4-dioxane; lithium hydroxide monohydrate at 90℃; for 16h; Inert atmosphere; | 1.2.1 1.2.1. Step 1: cyclopropanecarboxylic acid [5-(4- hydroxymethyl-phenyl)-[ 1 ,2,4]triazolo[ 1 ,5-a]pyri-din-2-yl] -amide Step 1: cyclopropanecarboxylic acid [5-(4-hydroxymethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amide 4-(Hydroxymethyl)phenylboronic acid (1.1 eq.) is added to a solution of cyclopropanecarboxylic acid (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide in 1,4-dioxane/water (4:1). K2CO3 (2 eq.) and PdCl2 dppf (0.03 eq.) are added to the solution. The resulting mixture is then heated in an oil bath at 90° C. for 16 h under N2. Water is added and the solution is extracted with ethyl acetate. The organic layers are dried over anhydrous MgSO4 and evaporated in vacuo. The resulting mixture is used without further purification. | |
With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; potassium carbonate In 1,4-dioxane; lithium hydroxide monohydrate at 90℃; for 16h; Inert atmosphere; | 1.2.1 Step 1: cyclopropanecarboxylic acid [5-(4-hydroxymethyl-phenyl)-[l,2,4]triazolo[l,5- aJpyridin-2-ylJ-am [0170] 4-(Hydroxymethyl)phenylboronic acid (l . l eq.) is added to a solution of cyclopropanecarboxylic acid (5-bromo-[l ,2,4]triazolo[l ,5-a]pyridin-2-yl)-amide in 1 ,4-dioxane/water (4: 1). K2C03 (2 eq.) and PdCl2dppf (0.03 eq.) are added to the solution. The resulting mixture is then heated in an oil bath at 90°C for 16h under N2. Water is added and the solution is extracted with ethyl acetate. The organic layers are dried over anhydrous MgS04 and evaporated in vacuo. The resulting mixture is used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In tetrahydrofuran; for 22h;Reflux; | A suspension of 4-(hydroxymethyl)phenylboronic acid (1.00 g, 6.6. mmol) and pinacol (0.79 g, 6.7 mmol) in tetrahydrofurane (40 mL) was refluxed over 22 h. During this time the starting materials were completely dissolved. The solvent was removed in vacuum (10 mbar), the residue redissolved in CH2Cl2 / EtOAc and purified by column chromatography on silica gel using the mixture of CH2Cl2 / EtOAc (9/1, v/v) as eluent. Yield 1.4 g (92%). Rf= 0.3 (silica, eluent - CH2Cl2 / EtOAc, 9/1, v/v). 1H NMR (200 MHz, CDCl3), delta in ppm: 1.35 (s, 12H), 4.71 (s, 2H), 7.37 (d, 2H, 3J = 8.2 Hz), 7.81 (d, 2H, 3J = 8.2 Hz). |
92% | In tetrahydrofuran; for 22h;Reflux; | Synthesis4-(Hvdroxymethyl)phenylboronic acid pinacol ester:A suspension of 4-(hydroxymethyl)phenylboronic acid (1.00 g, 6.6 mmol) and pinacol (0.79 g, 6.7 mmol) in tetrahydrofurane (40 ml_) was refluxed over 22 h. During this time the starting materials were completely dissolved. The solvent was removed in vacuum (10 mbar), the residue redissolved in CH2CI2 / EtOAc and purified by column chromatography on silica gel using the mixture of CH2CI2 / EtOAc (9/1 , v/v) as eluent. Yield 1.4 g (92%). Rf= 0.3 (silica, eluent - CH2CI2 / EtOAc, 9/1 , v/v). H NMR (200 MHz, CDCI3), delta in ppm: 1.35 (s, 12H), 4.71 (s, 2H), 7.37 (d, 2H, 3J = 8.2 Hz), 7.81 (d, 2H, 3J = 8.2 Hz). |
With magnesium sulfate; In acetonitrile; for 24h;Reflux; | To a stirred solution of 4-(hydroxymethyl) phenylboronic acid (0.4 g, 2.63 mmol) in acetonitrile (15 mL), MgS04 (3 g) and pinacol (0.37 g, 3.15 mmol) are added. The reaction mixture is heated up to about 80C and allowed to reflux for about 24 hours. After completion of the reaction, solvent is evaporated under vacuum. The crude mixture is dissolved in dichloromethane and filtered. The obtained product (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) methanol (i.e. compound 1) is used for further reaction without purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; at 170℃; for 0.166667h;microwave; | A mixture of <strong>[51676-74-5]5-chloro-2,4-dinitrotoluene</strong> (1.0 g), 4-(hydroxymethyl)phenylboronic acid (0.84 g), bis(triphenylphosphine)palladium(II) chloride (150 mg) and potassium carbonate (2.0 g) in a mixture of 1,4-dioxane and water (10/1, 11 mL) was heated at 170 C. in a microwave reactor for 10 minutes. The reaction mixture was then cooled and diluted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (acetone /DCM, 3/97) to give 0.6 g of (5'-methyl-2',4'-dinitro-biphenyl-4-yl)-methanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; at 80℃; for 0.25h;Inert atmosphere; | Nitrogen was bubbled through a mixture of 1-bromo-4-chloro-2-nitro-benzene (1.25 g, 5.3 mmol), bis(triphenylphosphine)palladium(II) chloride (90 mg, 0.13 mmol) and potassium phosphate tribasic (4.2 g, 19.7 mmol) in anhydrous 1,2-dimethoxyethane (30 mL) for 15 minutes. A solution of 4-(hydroxymethyl)phenylboronic acid (0.8 g, 5.3 mmol) in anhydrous 1,2-dimethoxyethane (1.5 mL) was added and the resulting mixture was heated at 80 C. overnight. The reaction mixture was then poured into water and extracted twice with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (hexane /EtOAc, 70/30) to give 0.367 g of (4'-chloro-2'-nitro-biphenyl-4-yl)-methanol as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium carbonate;palladium 10% on activated carbon; In ethanol; water; at 63℃; for 5h;Industry scale; Inert atmosphere; Reflux; | Step 1: 5-[4-(Hydroxymethyl)phenyl]-2-(ethyloxy)pyridine A suspension of 4-(hydroxymethyl)phenyl]boronic acid (14 kg), 5-bromo-2-(ethyloxy)pyridine (19.6 kg), sodium carbonate (11.4 kg) in ethanol (169.4L) and water (49.4L) was stirred under vacuum and then purged with nitrogen twice. A suspension of 10% palladium on carbon (50% wet, 4.6 kg) was added followed by water (7 L), and the suspension was degassed (3×) under nitrogen. The reaction mixture was heated to 63+/-3 C. and then heated to reflux and stirred for 5 h. The catalyst was filtered off at 57-63 C., and the cake washed with ethanol (28 L). The reaction was concentrated to ca.140 L by atmospheric distillation, cooled to 57+/-3 C. and water (28 L) added, maintaining >54 C. The reaction was cooled to 53+/-3 C. and seeded with 5-[4-(hydroxymethyl)phenyl]-2-(ethyloxy)pyridine (70 g) as a slurry in ethanol/water (1:1, 200 mL). After 2 h 10 min water (14 L) was added, maintaining the temperature at 53+/-3 C. and then cooled to 2+/-3 C. over about 4.5 hours followed by a 0.5h age. The product was isolated by filtration, washed with ethanol/water (1:1, 140 L) at 2+/-3 C., followed by water (3×93 L) and dried at 40-50 C. under vacuum to give the title product (19.0 kg, 90% th) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 4h;Inert atmosphere; | Example 113 Synthesis of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4'-(hydroxymethyl)-4-methyl-[1,1'-biphenyl]-3-carboxamide To a stirred solution of <strong>[1403257-80-6]5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide</strong> (200 mg, 0.42 mmol) and 4-(hydroxymethyl)phenylboronic acid (96 mg, 0.63 mmol) in dioxane (2.5 mL), aqueous 2M Na2CO3 solution (0.75 mL, 1.51 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (48 mg, 0.04 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100 C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (130 mg, 62%). LCMS: 504.15 (M+1)+; HPLC: 98.86% ( 254 nm) (Rt; 4.240; Method: Column: YMC ODS-A 150 mm*4.6 mm*5mu; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 muL, Col. Temp.: 30 C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) delta 11.45 (s, 1H), 8.19 (t, 1H), 7.57 (d, 2H, J=7.2 Hz), 7.39 (s, 1H), 7.37 (d, 2H), 7.21 (s, 1H), 5.85 (s, 1H), 5.20 (t, 1H, J=5.2 Hz), 4.52 (d, 2H, J=5.6 Hz), 4.28 (d, 2H, J=3.6 Hz), 3.81-3.84 (m, 2H), 3.22-3.32 (m, 2H), 3.08-3.09 (m, 2H), 3.01 (m, 1H), 2.24 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.65-1.67 (m, 2H), 1.51-1.53 (m, 2H), 0.83 (t, 3H, J=6.4 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With caesium carbonate;bis-triphenylphosphine-palladium(II) chloride; In tetrahydrofuran; at 70℃; for 2h;Inert atmosphere; | Step 1: Synthesis of methyl 2-chloro-6-(4-(hydroxymethyl)phenyl)isonicotinate A solution of <strong>[42521-09-5]methyl 2,6-dichloroisonicotinate</strong> (1 g, 4.85 mmol), boronic acid (0.73 g, 4.8 mmol) and PdCl2(PPh3)2 (0.15 g, 0.218 mmol) in THF (20 mL) was degassed for 15 min. Then Cs2CO3 was added and reaction mass purged again for 10 min. Reaction was heated at 70 C. for 2 h. On completion, reaction mass was concentrated and purified by column chromatography over silica gel affording methyl 2-chloro-6-(4-(hydroxymethyl)phenyl)isonicotinate (0.45 g, 33%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); potassium bromide; In 1,4-dioxane; at 85℃;Inert atmosphere; | General procedure: A stirred mixture of <strong>[51628-12-7]4-iodophenylacetonitrile</strong> (35), arylboronic acid (36-45) (1.1 equiv), Pd(PPh3)4 (0.03 equiv), KBr (1.1 equiv), and K3PO4 (2.5 equiv) in dioxane (5 mL/mmol) was purged with N2 for10 min at room temperature and then stirred overnight at 85 C under N2. The mixture was diluted with water and extracted with AcOEt. The organic phase was washed three times with water, dried (Na2SO4), and evaporated under vacuum. The residue was chromatographedon silica gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; | 4-((2-cyanobenzo[d]thiazol-6-yloxy)methyl)phenylboronic acid (6) 2-Cyano-6-hydroxybenzothiazole (2) (150 mg, 0.85 mmol, 1.1 equiv.) and 4-(hydroxymethyl)benzeneboronic acid (5) (166 mg, 0.77 mmol, 1 equiv.) were dissolved in 15 mL dry dimethylformamide (DMF) prior to the addition of cesium carbonate (277 mg, 0.85 mmol, 1 equiv.). The mixture was stirred at 60° C. for 45-50 minutes before it was allowed to cool to room temperature. 100 mL EtOAc was added to the reaction mixture, and the organic phase was washed three times with DI H2O. The aqueous layers were combined and washed three times with EtOAc. All of the organic layers were combined, washed twice with brine, dried over sodium sulfate, and concentrated. The crude material was purified on a silica column (90:10 EtOAc:methanol, dry loaded) to give 225 mg (94percent) of the pure product. 1H NMR (400 MHz, d6-Acetone): delta 5.33 (2H, s), 7.23 (2H, s), 7.45 (1H, dd, J=9.0, 2.6 Hz), 7.52 (2H, d, J=8.0 Hz), 7.93 (3H, m), 8.16 (1H, d, J=8.8 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 130℃; for 0.5h;Microwave irradiation; | A mixture of <strong>[14472-14-1]4-bromo-3-methylphenol</strong> (24b) (561 mg, 3.00 mmol), (4-(hydroxymethyl)phenyl) boronic acid (547 mg, 3.60 mmol), K2CO3 (912 mg, 6.60 mmol), Pd(dppf)Cl2?CH2Cl2 (122 mg, 0.149 mmol), water (1.5 mL) and 1,4-dioxane (13.5 mL) was heated in a sealed vial in a microwave reactor at 130C for 30 min. The same reaction was repeated once and combined. To the mixture was added EtOAc and water, and extracted with EtOAc. The organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography (hexane:EtOAc 5:1?2:1) to afford 4'-(hydroxymethyl)-2-methyl-[1,1'-biphenyl]-4-ol (25b) (1.10 g, 86% yield) as a yellow solid. 1H NMR (300 MHz, CDCl3) delta 8.69 (s, 1H), 7.44 - 7.35 (m, 3H), 7.25 (s, 1H), 7.03 (d, J = 8.1, 1H), 6.77 - 6.68 (m, 2H), 4.68 (d, J = 5.8, 2H), 4.14 (t, J = 5.8, 1H), 2.21 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 4h; Microwave irradiation; | |
95% | With urea hydrogen peroxide adduct In acetonitrile at 27 - 29℃; for 0.5h; Green chemistry; chemoselective reaction; | 2.1 Solution phase protocol: General procedure: To a stirred solution of aryl/alkyl boronic acid (1 mmol) in methanol or acetonitrile solvent (1 ml) was added 1 equiv. of Urea-Hydrogen peroxide (UHP) (2.5 equiv for alkyl boronic acids) at room temperature and the progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water and extracted with dichloromethane (DCM). The combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), evaporated and subjected to silica gel column chromatography for further purification. |
91% | With 1-carboxymethyl-3-methylimidazolium tetrachloroferrate; dihydrogen peroxide In neat (no solvent) at 20℃; for 0.133333h; |
74% | With 1,3-dimethyl-5-ethyl-4a-hydroperoxyalloxazine; oxygen; hydrazine hydrate In methanol; 2,2,2-trifluoroethanol at 20℃; for 2h; | |
61% | With graphite; air In water at 80℃; | |
Multi-step reaction with 2 steps 1: tetrahydrofuran / 24 h / 20 °C 2: dihydrogen peroxide; water / aq. phosphate buffer / 37 °C / pH 7.4 | ||
Multi-step reaction with 2 steps 1: sodium sulfate / tetrahydrofuran / 6 h / Reflux; Inert atmosphere 2: fluorescein free acid; sodium L-ascorbate / aq. phosphate buffer / 0.5 h / pH 7.4 / Irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In 1,2-dimethoxyethane; water; at 90℃; for 24h;Inert atmosphere; | General procedure: Under an argon atmosphere, to a stirring mixture of 4-methoxycarbonylphenylboronic acid (14.0 g, 77.9 mmol), 1-(Perfluorooctyl)-2-iodoethane (62.6 g, 109.0 mmol) and Pd(PPh3)4 (27.0 g, 23.4 mmol) was added DME (200 ml), then NaHCO3 solution (195.0 ml, 1.0 mol/L). The mixture was refluxed at 90oC for 24 h. The mixture was cooled to rt. After quenching the reaction with brine (200 ml), the mixture was extracted with ether (150 ml, three times). The combined organic phases were dried over anhydrous Na2SO4, concentrated under vacuum, the residue was purified by flash chromatography on silica gel to give 5 as white solid Compound 4 was prepared starting with 4-(Hydroxymethyl)phenylboronic acid (11.0 g, 72.1 mmol), 1-(Perfluorooctyl)-2-iodoethane (57.9 g, 100.9 mmol), and Pd(PPh3)4 (25.0 g, 21.6 mmol) by following the general procedure, as white wax (24 g, yield: 60%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With nickel(II) chloride hexahydrate; tetrabutyl ammonium fluoride; potassium carbonate; palladium dichloride In N,N-dimethyl-formamide at 100℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With C46H49BrClFeN3Pd; copper diacetate; caesium carbonate In 1,4-dioxane at 110℃; for 24h; | 2.4. General procedure for the one-pot oxidation/Suzuki coupling General procedure: A 10 mL round-bottom flask was charged with the prescribedamount of catalyst Pd/Cu, aryl chlorides (0.5 mmol), phenylboronicacids containing hydroxymethyl (0.75 mmol), Cs2CO3 (1.0 mmol)and dioxane (5 mL) in air. The reaction mixture was then placedin an oil bath and heated at 110 C for 24 h. After removal of thesolvent, the resulting residue was purified by flash chromatographyon silica gel using CH2Cl2 as eluent. The products 4a-k, and4m are known compounds [6,9] except for 4l and 4n. |
86% | With C46H49BrClFeN3Pd; copper diacetate; caesium carbonate In 1,4-dioxane at 110℃; for 24h; | General procedure for the one-pot oxidation/Suzuki coupling General procedure: A 10 mL round-bottom flask was charged with the prescribedamount of catalyst Pd/Cu, aryl chlorides (0.5 mmol), phenylboronicacids containing hydroxymethyl (0.75 mmol), Cs2CO3 (1.0 mmol)and dioxane (5 mL) in air. The reaction mixture was then placedin an oil bath and heated at 110 C for 24 h. After removal of thesolvent, the resulting residue was purified by flash chromatographyon silica gel using CH2Cl2 as eluent. The products 4a-k, and4m are known compounds [6,9] except for 4l and 4n. |
86% | With C46H49BrClFeN3Pd; copper diacetate; caesium carbonate In 1,4-dioxane at 110℃; for 24h; | General procedure for the one-pot oxidation/Suzuki coupling General procedure: A 10 mL round-bottom flask was charged with the prescribedamount of catalyst Pd/Cu, aryl chlorides (0.5 mmol), phenylboronicacids containing hydroxymethyl (0.75 mmol), Cs2CO3 (1.0 mmol)and dioxane (5 mL) in air. The reaction mixture was then placedin an oil bath and heated at 110 C for 24 h. After removal of thesolvent, the resulting residue was purified by flash chromatographyon silica gel using CH2Cl2 as eluent. The products 4a-k, and4m are known compounds [6,9] except for 4l and 4n. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With C46H49BrClFeN3Pd; copper diacetate; caesium carbonate; In 1,4-dioxane; at 110℃; for 24h; | General procedure: A 10 mL round-bottom flask was charged with the prescribedamount of catalyst Pd/Cu, aryl chlorides (0.5 mmol), phenylboronicacids containing hydroxymethyl (0.75 mmol), Cs2CO3 (1.0 mmol)and dioxane (5 mL) in air. The reaction mixture was then placedin an oil bath and heated at 110 C for 24 h. After removal of thesolvent, the resulting residue was purified by flash chromatographyon silica gel using CH2Cl2 as eluent. The products 4a-k, and4m are known compounds [6,9] except for 4l and 4n. |
80% | With C46H49BrClFeN3Pd; copper diacetate; caesium carbonate; In 1,4-dioxane; at 110℃; for 24h; | General procedure: A 10 mL round-bottom flask was charged with the prescribedamount of catalyst Pd/Cu, aryl chlorides (0.5 mmol), phenylboronicacids containing hydroxymethyl (0.75 mmol), Cs2CO3 (1.0 mmol)and dioxane (5 mL) in air. The reaction mixture was then placedin an oil bath and heated at 110 C for 24 h. After removal of thesolvent, the resulting residue was purified by flash chromatographyon silica gel using CH2Cl2 as eluent. The products 4a-k, and4m are known compounds [6,9] except for 4l and 4n. |
80% | With C46H49BrClFeN3Pd; copper diacetate; caesium carbonate; In 1,4-dioxane; at 110℃; for 24h; | General procedure: A 10 mL round-bottom flask was charged with the prescribedamount of catalyst Pd/Cu, aryl chlorides (0.5 mmol), phenylboronicacids containing hydroxymethyl (0.75 mmol), Cs2CO3 (1.0 mmol)and dioxane (5 mL) in air. The reaction mixture was then placedin an oil bath and heated at 110 C for 24 h. After removal of thesolvent, the resulting residue was purified by flash chromatographyon silica gel using CH2Cl2 as eluent. The products 4a-k, and4m are known compounds [6,9] except for 4l and 4n. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With C46H49BrClFeN3Pd; copper diacetate; caesium carbonate; In 1,4-dioxane; at 110.0℃; for 24h; | General procedure: A 10 mL round-bottom flask was charged with the prescribedamount of catalyst Pd/Cu, aryl chlorides (0.5 mmol), phenylboronicacids containing hydroxymethyl (0.75 mmol), Cs2CO3 (1.0 mmol)and dioxane (5 mL) in air. The reaction mixture was then placedin an oil bath and heated at 110 C for 24 h. After removal of thesolvent, the resulting residue was purified by flash chromatographyon silica gel using CH2Cl2 as eluent. The products 4a-k, and4m are known compounds [6,9] except for 4l and 4n. |
90% | With C46H49BrClFeN3Pd; copper diacetate; caesium carbonate; In 1,4-dioxane; at 110.0℃; for 24h; | General procedure: A 10 mL round-bottom flask was charged with the prescribedamount of catalyst Pd/Cu, aryl chlorides (0.5 mmol), phenylboronicacids containing hydroxymethyl (0.75 mmol), Cs2CO3 (1.0 mmol)and dioxane (5 mL) in air. The reaction mixture was then placedin an oil bath and heated at 110 C for 24 h. After removal of thesolvent, the resulting residue was purified by flash chromatographyon silica gel using CH2Cl2 as eluent. The products 4a-k, and4m are known compounds [6,9] except for 4l and 4n. |
90% | With C46H49BrClFeN3Pd; copper diacetate; caesium carbonate; In 1,4-dioxane; at 110.0℃; for 24h; | General procedure: A 10 mL round-bottom flask was charged with the prescribedamount of catalyst Pd/Cu, aryl chlorides (0.5 mmol), phenylboronicacids containing hydroxymethyl (0.75 mmol), Cs2CO3 (1.0 mmol)and dioxane (5 mL) in air. The reaction mixture was then placedin an oil bath and heated at 110 C for 24 h. After removal of thesolvent, the resulting residue was purified by flash chromatographyon silica gel using CH2Cl2 as eluent. The products 4a-k, and4m are known compounds [6,9] except for 4l and 4n. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; N-benzyl-N,N,N-triethylammonium chloride; cesium fluoride; In water; toluene; at 120℃; for 1h;Microwave irradiation; Inert atmosphere; | General procedure: Method A: In a20 mL microwave Biotage tube, a mixture of <strong>[71759-89-2]4-iodo-1H-imidazole</strong>(1a) (0.194 g, 1.0 mmol), a boronic acid 2(2.0 mmol), CsF (0.456 g,3.0 mmol), PdCl2(dppf)(0.041 g, 0.05 mmol) and BnEt3NCl(0.011 g, 0.05 mmol) in toluene(7 mL) and water (7 mL)was purged with argon andheated under microwaveirradiation. When the reaction was complete, the mixture was cooled toroom temperature and concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel to provide compounds 3a-3i and 3k-3o in yields ranging from 40 to 91%. Time and temperaturereactions were collected in Table 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 90℃; for 19h;Inert atmosphere; | 5.1.19 [4-(3-Methylquinolin-2-yl)phenyl]methanol (23) To a suspension of <strong>[57876-69-4]2-chloro-3-methylquinoline</strong> (21, 533 mg, 3.00 mmol) and [4-(hydroxymethyl)phenyl]boronic acid (22, 501 mg, 3.30 mmol) in 1,2-dimethoxyethane (20 mL) were added Pd(PPh3)4 (173 mg, 0.15 mmol) and 1 M Na2CO3 aqueous solution (7.5 mL), and the mixture was stirred at 90 C for 19 h under argon gas atmosphere. After cooling at room temperature, the mixture was partitioned between EtOAc and water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-5% MeOH in CHCl3) to give 23 as a pale yellow oil. 1H NMR (DMSO-d6) delta 2.46 (s, 3H), 4.60 (d, 2H, J = 5.7 Hz), 5.27 (t, 1H, J = 5.7 Hz), 7.45 (d, 2H, J = 8.3 Hz), 7.56-7.65 (m, 3H), 7.67-7.73 (m, 1H), 7.93 (d, 1H, J = 8.1 Hz), 7.98 (d, 1H, J = 8.2 Hz), 8.25 (s, 1H); MS (ESI) m/z 250 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,2-dimethoxyethane; water at 90℃; for 12h; Inert atmosphere; | 5.1.35 5.1.35. [4-(3-Ethylquinolin-2-yl)phenyl]methanol (27f) General procedure: 5.1.30 [4-(5-Fluoro-3-methylquinolin-2-yl)phenyl]methanol (27c) Under argon atmosphere, a mixture of 2-chloro-5-fluoro-3-methylquinoline (26c, 443 mg, 2.27 mmol) and 22 (379 mg, 2.49 mmol), and Pd(PPh3)4 (130 mg, 0.11 mmol) in 1 M Na2CO3 aqueous solution (5.7 mL) and DME (15 mL) was stirred at 90 °C for 12 h. The mixture was filtered through Celite pad and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-10% MeOH in CHCl3) to give 27c (432 mg, 71%) as a white solid. 5.1.35 [4-(3-Ethylquinolin-2-yl)phenyl]methanol (27f) Compound 27f was prepared from 2-chloro-3-ethylquinoline (26f) in a manner similar to that described for compound 27c, with a yield of 56% as a beige solid. 1H NMR (CDCl3) δ 1.20 (t, 3H, J = 7.5 Hz), 2.12 (t, 1H, J = 6.1 Hz), 2.76-2.84 (m, 2H), 4.77 (d, 2H, J = 6.1 Hz), 7.46 (d, 2H, J = 8.3 Hz), 7.51-7.56 (m, 3H), 7.63-7.70 (m, 1H), 7.81 (dd, 1H, J = 8.1, 1.2 Hz), 8.06 (s, 1H), 8.13 (d, 1H, J = 8.4 Hz); MS (ESI) m/z 264 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: ethidium Bromide With dmap; N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 0℃; for 0.5h; Inert atmosphere; Stage #2: phosgene In dichloromethane; N,N-dimethyl-formamide at 0℃; for 3h; Inert atmosphere; Stage #3: p-hydroxymethylphenylboronic acid In dichloromethane; N,N-dimethyl-formamide at 20℃; for 24h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 90℃; for 8h;Inert atmosphere; | Compound 11b was prepared from <strong>[92992-85-3]2-bromo-3,5-dimethylpyridine</strong> (9b) and 10 in a manner similar to that described for compound 11a, with a yield of 68% as a brown syrup. 1H NMR(DMSO-d6) d 2.29 (s, 3H), 2.30 (s, 3H), 4.55 (d, 2H, J = 5.7 Hz),5.21 (t, 1H, J = 5.7 Hz), 7.38 (d, 2H, J = 8.3 Hz), 7.47 (d, 2H,J = 8.3 Hz), 7.52 (br s, 1H), 8.30 (br s, 1H); MS (ESI) m/z 214 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,2-dimethoxyethane; water at 100℃; for 14h; Inert atmosphere; | [4-(Quinolin-2-yl)phenyl]methanol (11) Under argon gas atmosphere, to a mixture of 2-chloroquinoline (1.05 g, 6.42 mmol), [4-(hydroxymethyl)phenyl] boronic acid (10,976 mg, 6.42 mmol) and Pd(PPh3)4 (384 mg, 0.33 mmol) in 1,2-dimethoxyethane (15 mL) and water (5 mL) was added Na2CO3 (1.65 g, 15.6 mmol), and the mixture was stirred at 100°C for 14 h. After cooling at room temperature, the mixture was partitioned between EtOAc and water. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (10-100% EtOAc in hexane) to give 11 (1.50 g, 99%) as an off-white solid. 1H-NMR (DMSO-d6) δ: 4.60 (2H,d, J=5.7 Hz), 5.28 (1H, t, J=5.7 Hz), 7.50 (2H, d, J=8.2 Hz), 7.56-7.62 (1H, m), 7.75-7.61 (1H, m), 7.99 (1H, d, J=8.1 Hz), 8.07 (1H, d, J=8.5 Hz), 8.14 (1H, d, J=8.7 Hz). 8.25 (2H, d,J=8.2 Hz), 8.44 (1H, d, J=8.7 Hz); MS (ESI) m/z 236 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); In water; at 60℃; for 24h;Inert atmosphere; | A solution of <strong>[153463-65-1]3,5-dichloro-4-pyridinecarbonitrile</strong> (2.27 g, 13.12 mmol), 4- (hydroxymethyl)phenylboronic acid (1.99 g, 13.12 mmol), potassium phosphate tribasic (19.68 ml, 19.68 mmol) dissolved in water (17 mL) and XPhos (1.032 g, 1.312 mmol) in THF (100 ml) was flashed with N2. The mixture was heated at 60C under dry N2 for 4 hours. The reaction mixture was allowed to stir for a total of 24 hours. The reaction mixture was filtered and concentrated under vacuum. The crude product was purified on a silica gel column, RediSep Column, eluted with hexane and ethyl acetate to afford 3-chloro-5-(4- (hydroxymethyl)phenyl)isonicotinonitrile. LC/MS [M+H]+: 245. | |
With potassium phosphate; XPhos; In tetrahydrofuran; water; at 60℃; for 4h;Inert atmosphere; | Step A: 3-Chloro-5-(4-(hydroxymethyl)phenyl)isonicotinonitrile (0655) A solution of <strong>[153463-65-1]3,5-dichloro-4-pyridinecarbonitrile</strong> (2.27 g, 13.12 mmol), 4-(hydroxymethyl)phenylboronic acid (1.99 g, 13.12 mmol), potassium phosphate tribasic (19.68 ml, 19.68 mmol) dissolved in water (17 mL) and XPhos (1.032 g, 1.312 mmol) in THF (100 ml) was flashed with N2. The mixture was heated at 60 C. under dry N2 for 4 hours. The reaction mixture was allowed to stir for a total of 24 hours. The reaction mixture was filtered and concentrated under vacuum. The crude product was purified on a silica gel column, RediSep Column, eluted with hexane and ethyl acetate to afford 3-chloro-5-(4-(hydroxymethyl)phenyl)isonicotinonitrile. LC/MS [M+H]+: 245 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.4 g | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; for 16h;Inert atmosphere; Reflux; | A) [4-(l-methyl-lH-l,2,3-triazol-4-yl)phenyl]methanol A mixture of [ 4- (hydroxymethyl ) henyl] boronic acid (7.10 g) , 4-bromo-l-methyl-lH-l, 2-3-triazole (5.00 g) , sodium carbonate (6.59 g) and tetrakis (triphenylphosphine)palladium(O) (3.59 g) in a mixed solvent of water (30.0 mL) -1, 4-dioxane (100 mL) was heated with reflux for 16 hr under nitrogen atmosphere. The reaction mixture was allowed to be cooled to room temperature, the organic layer was concentrated under reduced pressure, and the residue was extracted with dichloromethane (x 3) . The combined extracts were dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (3.40 g) . MS: [M+H]+ 189.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃; for 16h; | A mixture of <strong>[5775-82-6]4-bromo-1,3-dimethyl-1H-pyrazole</strong> (200 mg, 1.14 mmol), [4-(hydroxymethyl)phenyl]boronic acid (260 mg, 1.71 mmol), potassium carbonate (474 mg, 3.43 mmol) and tetrakis(triphenylphosphine)palladium(0) (132 mg, 0.114 mmol) in 1,4-dioxane (12 mL) and water (3 mL) was heated at 100 00 for 16 hours. The reactionmixture was concentrated in vacuo; purification using silica gel chromatography (Gradient: 0% to 100% ethyl acetate in petroleum ether) provided the product (190 mg) as a yellow solid. By 1H NMR and mass spectroscopic analysis, this material was contaminated with tn phenyl phosphi ne oxide. Yield, corrected for triphenyl phospine oxide content: 120 mg, 0.59 mmol, 52%. LCMS m/z202.9 [M+H]. 1H NMR (400 MHz,ODd3), product peaks only: oe 7.43 (5, 1 H), 7.39 (br 5, 4H), 4.72 (5, 2H), 3.89 (5, 3H),2.40 (5, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃; | Aqueous potassium carbonate solution (3.0 M, 17 mL, 51 mmol) was added to a solution of [4-(hydroxymethyl)phenyl]boronic acid (96percent, 4.0 g, 25 mmol) and 4-bromo- 1 ,3-thiazole (96percent, 6.48 g, 37.9 mmol) in 1 ,4-dioxane (75 mL). Tetrakis(triphenylphosphine)palladium(0) (885 mg, 0.766 mmol) was added, and thereaction mixture was heated at 100 00 overnight. After cooling to room temperature, the reaction mixture was diluted with water and extracted several times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo; silica gel chromatography (Gradient: 25percent to 50percent ethyl acetate in heptane) provided the productas a cream-colored solid. Yield: 3.60 g, 18.8 mmol, 75percent. LCMS m/z 192.0 [M+H]. 1H NMR (400 MHz, ODd3) oe 8.92 (d, J=2.0 Hz, 1 H), 7.95 (br d, J=8.2 Hz, 2H), 7.56 (d, J=2.0 Hz, 1H), 7.46 (br d, J=8.3 Hz, 2H), 4.76 (5, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With C37H44ClN2O3PPd; caesium carbonate In water at 100℃; for 12h; Schlenk technique; Inert atmosphere; | General procedure for Suzuki coupling General procedure: In a Schlenk tube, a mixture of the required amount of catalyst, plus the aryl chloride (1.0 mmol), aryl boronic acid (1.5 mmol) and the selected base (2.0 mmol) in water was evacuated and charged with nitrogen. The reaction mixture was heated at 100°C for 12 h. After cooling, the mixture was extracted with CH2Cl2 and the extract was evaporated. The resulting residue was purified by flash chromatography on silica gel using a mixture of CH2Cl2/ethyl acetate (5/1) as eluent. The known products 5, 6a [17,18], 6b [22], 6c [23], 6e [24], 6g [19], 6h [25] and 7a [26] were characterized by comparison of data with those in the literature. The products 6d, 6f and 7b-h were new compounds and characterized by elemental analysis, MS, 1H and 13C NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With C37H44ClN2O3PPd; caesium carbonate; In water; at 100℃; for 12h;Schlenk technique; Inert atmosphere; | General procedure: In a Schlenk tube, a mixture of the required amount of catalyst, plus the aryl chloride (1.0 mmol), aryl boronic acid (1.5 mmol) and the selected base (2.0 mmol) in water was evacuated and charged with nitrogen. The reaction mixture was heated at 100C for 12 h. After cooling, the mixture was extracted with CH2Cl2 and the extract was evaporated. The resulting residue was purified by flash chromatography on silica gel using a mixture of CH2Cl2/ethyl acetate (5/1) as eluent. The known products 5, 6a [17,18], 6b [22], 6c [23], 6e [24], 6g [19], 6h [25] and 7a [26] were characterized by comparison of data with those in the literature. The products 6d, 6f and 7b-h were new compounds and characterized by elemental analysis, MS, 1H and 13C NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In ethanol; water; toluene at 100℃; for 4h; Inert atmosphere; | 5 3'-ethoxybiphenyl-4-ylmethanol General procedure: To 1.21 g (6.02 mmol) of 3-bromophenetole were added 15 mL of toluene, 15 mL of ethanol, and 4.5 mL (9.0 mmol) of 2 mol/L aqueous sodium carbonate solution, degassed under reduced pressure, and then substituted with argon gas. Thereafter, 1.37 g (9.02 mmol) of 4-(hydroxymethyl)phenylboronic acid and 347 mg (0.300 mmol) of tetrakis(triphenylphosphine)palladium were added and stirred for 4 hours at 100°C in an argon gas atmosphere. After the completion of the reaction, the reaction solution was concentrated under reduced pressure. Thereafter, water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane:ethyl acetate = 9:1 → 7:3 (V/V)), and fractions containing the target product were concentrated under reduced pressure to afford 1.23 g of the title compound as a pale yellow oil. (Yield: 90%) Mass spectrum (CI, m/z): 229 (M++1) 1H-NMR spectrum (CDCl3, δ ppm): 7.61-7.56 (m, 2H), 7.46-7.41 (m, 2H), 7.34 (dd, J = 8.0, 8.0 Hz, 1H,), 7.18-7.11 (m, 2H), 6.91-6.87 (m, 1H), 4.74 (d, J = 5.9 Hz, 2H), 4.10 (q, J = 7.0 Hz, 2H), 1.67 (t, J = 5.9 Hz, 1H), 1.45 (t, J = 7.0 Hz, 3H) |
90% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In ethanol; water; toluene at 100℃; for 4h; Inert atmosphere; | 5 3'-ethoxybiphenyl-4-ylmethanol 3-bromophenetole 1.21g (6.02mmol) in 15mL of toluene was added, an aqueous solution of sodium carbonate in ethanol 15mL and 2mol / L 4.5ml (9.0mmol) and, after evacuation to vacuum, argon gas was replaced. Subsequently, 4-(hydroxymethyl) phenylbornic acid under a 1.37g (9.02mmol) and tetrakistriphenylphosphine palladium was added to 347mg (0.300mmol), and an argon gas atmosphere, was stirred for 4 hours at 100°C . After the reaction, the reaction solution was concentrated under reduced pressure, water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent; n- hexane: ethyl acetate = 9: 1 → 7: 3 (V / V)) is applied to, by the fraction containing the target substance was concentrated under reduced pressure, the title compound 1.23g It was obtained as a light yellow oil (yield: 90%) |
90% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In ethanol; water; toluene at 100℃; for 4h; Inert atmosphere; | 5 3'-Ethoxybiphenyl-4-ylmethanol Reference Example 5 3'-Ethoxybiphenyl-4-ylmethanol 15 mL of toluene, 15 mL of ethanol and 4.5 mL (9.0 mmol) of 2 mol/L aqueous sodium carbonate solution were added to 1.21 g (6.02 mmol) of 3-bromophenetole followed by degassing under reduced pressure and substituting with argon gas. Next, 1.37 g (9.02 mmol) of 4-(hydroxymethyl)phenylboronic acid and 347 mg (0.300 mmol) of tetrakis(triphenylphosphine)palladium were added followed by stirring for 4 hours at 100° C. in an argon gas atmosphere. After completion of the reaction, the reaction solution was concentrated under reduced pressure and water was added to the residue followed by extracting with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=9:1→7:3 (V/V)) and the fractions containing the target product were concentrated under reduced pressure to obtain 1.23 g of the title compound in the form of a pale yellow oil (yield: 90%). mass spectrum (CI, m/z): 229 (M++1). 1H-NMR spectrum (CDCl3, δ ppm): 7.61-7.56 (m, 2H), 7.46-7.41 (m, 2H), 7.34 (dd, J=8.0, 8.0 Hz, 1H), 7.18-7.11 (m, 2H), 6.91-6.87 (m, 1H), 4.74 (d, J=5.9 Hz, 2H), 4.10 (q, J=7.0 Hz, 2H), 1.67 (t, J=5.9 Hz, 1H), 1.45 (t, J=7.0 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane; water at 90℃; for 12h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: Triphenylvinyl bromide; p-hydroxymethylphenylboronic acid With potassium carbonate In tetrahydrofuran; water at 25℃; for 0.5h; Inert atmosphere; Stage #2: With tetrakis(triphenylphosphine) palladium(0) In tetrahydrofuran; water for 24h; Reflux; Inert atmosphere; | 2.4 Synthesis of TPE-OH -Bromo-1,2,2-triphenylethylene (2.0g, 6.0mmol) and 4-(hydroxymethyl)phenylboronic acid (1.35g, 9.0mmol) were dissolved in the mixture of THF and 1.2M potassium carbonate aqueous solution. The mixture was stirred at room temperature for 30min under an argon atmosphere. Tetrakis (triphenylphosphine) palladium (Pd(PPh3)4, 0.05g, 0.004mmol) was added, and the reaction mixture was refluxed for 24h. After completion of the reaction, the resultant mixture was poured into 150mL of double distilled water and extracted three times with ethyl acetate. The organic layer was evaporated, and the crude reaction mixture was purified using column chromatography by eluting with ethyl acetate and dichloromethane (10:90) to obtain a white powder (yield=75%). 1H NMR (400MHz, CDCl3, δ): 4.60 (s, -CH2OH, 2H, benzylic protons), 6.98-7.15 (aromatic protons, 19H)·13C NMR (100MHz, CDCl3, δ): 65.11, 126.34, 126.45, 127.64, 127.67, 127.72, 131.30, 131.51, 138.88, 140.56, 141.07, 143.16, 143.68ppm. |
58% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In tetrahydrofuran; water at 64℃; for 20h; Inert atmosphere; | |
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In tetrahydrofuran; water for 18h; Inert atmosphere; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.3 g | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In ethanol; water; toluene; for 16h;Reflux; Inert atmosphere; | A) (4-(1-methyl-1H-pyrazol-3-yl)phenyl)methanol 4-(Hydroxymethyl)phenylboronic acid (3.68 g), <strong>[151049-87-5]<strong>[151049-87-5]3-bromo-1-methyl-1H-pyrazol</strong>e</strong> (3.00 g), sodium carbonate (4.54 g) and Pd(dppf)Cl2 DCM (1.97 g) were heated under reflux in a mixture of toluene (60 mL), ethanol (10 mL) and water (10 mL) under a nitrogen atmosphere for 16 hr. The reaction mixture was cooled to room temperature and diluted with ethyl acetate, and the organic layer was washed with water (twice) and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (2.30 g). 1H NMR (400 MHz, CDCl3) delta2.06 (1H, t, J = 5.6 Hz), 3.97 (3H, s), 4.72 (2H, d, J = 5.2 Hz), 6.56 (1H, d, J = 2.4 Hz), 7.38-7.41 (3H, m), 7.79 (2H, d, J = 8.4 Hz). |
1.1 g | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In ethanol; water; toluene; at 10 - 110℃;Inert atmosphere; | To a mixture of 3-bromo-1-methylpyrazole (0.91 g), toluene (18 mL), ethanol (3.0 mL) and water (3.0 mL) were added (4-(hydroxymethyl)phenyl)boronic acid (1.1 g), sodium carbonate (0.60 g) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (0.52 g) at room temperature, and the mixture was stirred under an argon atmosphere at 110 C. overnight. The reaction mixture was filtered, and the filtrate was diluted with ethyl acetate, washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) and triturated with ethyl acetate and hexane to give the title compound (1.1 g). MS: [M+H]+ 189.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II); potassium carbonate In 1,4-dioxane at 80℃; for 5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In methanol; water; toluene;Inert atmosphere; | General procedure: <strong>[405224-23-9]5-bromo-2-chloronicotinonitrile</strong> (5, 2.16 g, 10 mmol), aromatic boronic acid (10 mmol), (PPh3)2PdCl2 (175 mg, 0.25 mmol), Na2CO3 (2.12 g, 20 mmol) were dissolved in a mixed solvent (22 mL, toluene: ethanol: water = 10: 10: 2). Nitrogen gas was bubbled through the reaction mixture for 5 min, and then the mixture was heated to 60C under inert atmosphere for 6 h. The mixture was filtered and the filtrate was concentrated under vacuum. The crude product was extracted with ethyl acetate and the organic layer was concentrated, then the solid was washed with ethyl acetate and petroleum ether to give compounds 6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29.62% | With pyridine; copper diacetate; In 1-methyl-pyrrolidin-2-one; at 25℃; for 24h;Molecular sieve; | [1151] to a solution of <strong>[4027-57-0]ethyl 3-methyl-1H-pyrazole-5-carboxylate</strong> (2 g, 12.97 mmol), [4-(hydroxymethyl)phenyl]boronic acid (3.94 g, 25.94 mmol) in nmp (200 ml) was added pyridine (2.05 g, 25.94 mmol, 2.09 ml), Cu(OAc)2 (3.53 g, 19.45 mmol), 4a ms (20 g, 12.97 mmol). After stirred at 25 C for 24h, the mixture was filtered. The filtrate was washed with H2O (500 ml), extracted with ethyl acetate (50 ml x 3). The organic phase was washed brine (500 ml), dried over Na2SO4, concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 5/1 to 3/1) to obtain intermediate compound 227a (1 g, yield: 29.62%) as white solid. Compound 227a: 1H NMR (400mhz, CDCl3) delta 7.41 - 7.34 (m, 4h), 6.80 (s, 1h), 4.71 (s, 2h), 4.22 (q, 7 = 7.1 hz, 2h), 2.35 (s, 3h), 1.24 (t, 7 = 7.2 hz, 3h). MS (ESI) m/z (M+H)+ 261.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Methyl 2-(4-(hydroxymethyl)phenyl)-1-methyl-1H-imidazole-5-carboxylate (44). To a solution of methyl2-bromo-1-methyl-1H-imidazole-5-carboxylate5 (515 mg, 2.35 mmol, 1.0 eq) in dioxane (72 mL) was added Pd(PPh3)4 (133 mg, 0.115 mmol, 0.049 eq). The mixture was stirred for 15 min at room temperature before 4-hydroxymethylbenzeneboronic acid (357 mg, 2.35 mmol, 1.0 eq) in 22 mL H2O and K2CO3 (390mg, 2.82 mmol, 1.2 eq) were added. The reaction mixture was heated to 60 C and stirred for 16 h. The solvent was evaporated and the residue was diluted with EtOAc and H2O. The phases were separated and the product was extracted with EtOAc (3x 20 mL). The combined organic extracts were dried overNa2SO4 and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (10-100% EtOAc linear gradient in hexanes) providing the corresponding benzylicalcohol in 81% (470 mg) yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; bis[2-(diphenylphosphino)phenyl] ether In N,N-dimethyl-formamide at 120℃; for 24h; Inert atmosphere; | 7 Example 7; Preparation of (E)-(4-(2-(2-isopropylphenyl)-1,2-bis(4-methoxyphenyl)vinyl)phenyl)methanol 0.3 mmol of sodium carbonate and 0.1 mmol of 1,2-bis(4-methoxyphenyl)acetylene,Tetrakis(triphenylphosphine palladium) 0.005 mmol, bis(2-diphenylphosphinophenyl)ether 0.005 mmol,0.2 mmol of (4-(hydroxymethyl)phenyl)boronic acid, 0.3 mmol of 2-isopropyliodobenzene, and 1 mL of N,N-dimethylformamide were added to a 15 mL reaction tube.Nitrogen was repeatedly filled 10 times, placed in an oil bath at 120 ° C, and reacted for 24 hours;Cooled to room temperature, the reaction was diluted with ethyl acetate, washed with water three times, the organic phase dried over anhydrous Na2SO4, filtered, and concentratedPurification by thin layer chromatography gave 19 mg of the desired product, yield 41%. |
41% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; bis[2-(diphenylphosphino)phenyl] ether In N,N-dimethyl-formamide at 120℃; for 24h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With pyridine; oxygen; copper diacetate In dichloromethane at 20℃; for 12h; | 1 Step 1-1-[4-(Hydroxymethyl)phenyl]-4-nitro-pyrazole-3-carbonitrile To a mixture of 4-nitro-1H-pyrazole-3-carbonitrile (3.00 g, 21.7 mmol, CAS61241-07-4) and [4-(hydroxylmethyl)phenyl] boronic acid (2.20 g, 14.4 mmol, CAS59012-93-2) in mixed solvents of pyridine (25 mL) and DCM (75 mL) was added Cu(OAc)2 (3.94 g, 21.7 mmol) under O2 (15 psi), then the mixture was stirred at 20° C. for 12 hours. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2) to give the title compound (3.00 g, 78% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 7.95 (d, J=8.8 Hz, 2H), 7.56 (d, J=8.4 Hz, 2H), 4.62 (s, 2H), 4.39 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With chloro[1,3-bis(2,6-di-i-propylphenyl)imidazol-2-ylidene]copper(I); potassium methanolate; In N,N-dimethyl acetamide; at 70℃; for 24h;Schlenk technique; Sealed tube; | In the glove box, to a 50 mL Schlenk bottle equipped with a stir bar was added 4-hydroxymethylphenylboronic acid (1 mmol, 152.0 mg), potassium methoxide (2 mmol, 2 equivalents, 140.2 mg), Cu (IPr) Cl (0.03 mmol, 0.03 equivalents, 14.6 mg), 5 mL of solvent N, N-dimethylacetamide. Remove the capped Schlenk bottle from the glove box, fully evacuate, fill the reaction system with carbon dioxide and seal it well, and then stir the reaction mixture at 70 C. for 24 hours. After cooling to room temperature, it was acidified by adding 1 mol / L hydrochloric acid, and extracted with ethyl acetate, and washed once with brine. The organic phase was collected and concentrated in vacuo. The liquid mixture was dropped on a silica gel column and purified by column chromatography. As petroleum ether / ethyl acetate, the desired product 4-hydroxymethylbenzoic acid was obtained with a yield of 73%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In tetrahydrofuran at 70℃; for 8h; Inert atmosphere; | General procedure for the synthesis of 2-aryl-cyclohex-2-enones 13a-i General procedure: In an oven-dried round-bottm flask, under N2 atmosphere, 2-iodo-cyclohexenone 14 (0.22mmol, 1 equiv.) was taken in THF (3 mL) and 2(M) Na2CO3 solution (3 mL) and the reaction mixture was degassed for 5 mins to make it oxygen-free. To this solution arylboronic acid (0.33 mmol, 1.5 equiv.) was added followed by the addition of 5 mol% Pd(PPh3)4. Then the reaction mixture was kept in a preheated oil bath at 70°C and stirring was continued for 8 h. After completion of the reaction (as judged by running TLC), the reaction mixture was extracted with ethyl acetate (10 mL X 2). The crude material was purified through column chromatography by using ethyl acetate and petroleum ether as eluents. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A) (4-(5-methyl-1,3-thiazol-2-yl)phenyl)methanol The title compound was obtained from (4-(hydroxymethyl)phenyl)boronic acid and <strong>[41731-23-1]2-bromo-5-methyl-1,3-thiazole</strong> by a method similar to that in step F of Example 1. MS: [M+H]+ 206.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With palladium diacetate; | Step-1: Synthesis of 1-(4-(hydroxymethyl)phenyl)ethanone To a stirred solution 4-(hydroxymethyl)phenylboronic acid (1.0 g, 6.6 mmol, 1.0 eq.) in acetone (10 mL) was added Pd(OAc)2 (0.03 g, 0.13 mmol, 0.02 eq.) and DPPP (0.081 g, 0.19 mmol, 0.03 eq.). The reaction mixture purged with nitrogen for 10 min then added 1-(vinyloxy)butane (2.0 mL, 13.2 mmol, 2.0 eq.) The resulting mixture heated at 60 C. for 16 h. Following this, reaction was allowed to cool to RT and added 3N HCl (10 mL) and stirred for 1 h. To the reaction mixture diluted with water (20 mL) and extracted using DCM (3*30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to get the solid residue. The crude was purified by normal phase silica-gel column provided title compound (0.4 g, 40%). LCMS: 150.9 [M+1]+; 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 7.95 (m, J=8.33 Hz, 2H) 7.46 (m, J=7.89 Hz, 2H) 4.78 (s, 2H) 2.60 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis-(triphenylphosphine)-palladium; anhydrous sodium carbonate In 1,2-dimethoxyethane; lithium hydroxide monohydrate at 85℃; for 24h; |
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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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