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CAS No. : | 4122-56-9 | MDL No. : | MFCD00204231 |
Formula : | C9H8O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | YRMODRRGEUGHTF-UHFFFAOYSA-N |
M.W : | 164.16 | Pubchem ID : | 243003 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.11 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 43.11 |
TPSA : | 43.37 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.26 cm/s |
Log Po/w (iLOGP) : | 1.72 |
Log Po/w (XLOGP3) : | 1.47 |
Log Po/w (WLOGP) : | 1.29 |
Log Po/w (MLOGP) : | 1.28 |
Log Po/w (SILICOS-IT) : | 1.85 |
Consensus Log Po/w : | 1.52 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.96 |
Solubility : | 1.82 mg/ml ; 0.0111 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.99 |
Solubility : | 1.69 mg/ml ; 0.0103 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.41 |
Solubility : | 0.634 mg/ml ; 0.00386 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.28 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302+H312+H332-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 |
---|---|---|
With hydrogenchloride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With thionyl chloride at 20℃; for 0.666667h; Cooling with ice; | 1 Preparation of intermediate 2: 1.5 g (10 mmol) of compound 1 (o-carboxybenzaldehyde) was dissolved in 10 mL of thionyl chloride, and 10.0 mL of anhydrous methanol was slowly added dropwise under ice bath. After the addition was completed, the mixture was stirred for 10 min and then transferred to room temperature. After stirring for about 0.5 h, the reaction was completely monitored by TLC, and the solvent was evaporated under reduced pressure and purified by silica gel column to yield 1.31 g of colorless oily liquid 2 with a yield of 82%. |
80% | With thionyl chloride at 20℃; for 0.5h; | 4.1.3.13 Methyl 2-formylbenzoate (11) To the solution of compound 10 (750 mg, 5 mmol) in 5mL SOCl2, 5mL of MeOH was slowly added. The mixture was stirred at room temperature for 30 min. Then, solvent removal yielded the crude product, which was purified by silica gel column chromatography (petroleum ether/AcOEt=10:1) to provide 11. Colourless oil, yield: 80%. 1H NMR (400MHz, CDCl3) δ 10.57 (s, 1H), 7.98-7.81 (m, 2H), 7.72-7.56 (m, 2H), 3.94 (s, 3H). LC-MS(ESI): 165.0M+H+. |
With sulfuric acid |
With sulfuric acid at 70℃; | 1 Step 1: methyl 2-formylbenzoate (01) To a solution of H2504 (2 mL) in MeOH (100 mL) was added 2-formyl benzoic acid (10.0 g, 66.2 mmol). The resulting mixture was stirred at 70 °C overnight. After cooled toRT, the mixture was concentrated in vacuo, adjusted pH to 8 with aq. NaHCO3 and extractedwith EtOAc (10 mL x 3). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradientchromatography (10% EtOAc in petroleum ether) to give the title compound. LRMS m/z (M+H) 165.1 found, 165.1 required ‘H NMR (CDC13, 400MHz): ö 10.58 (s, 1H), 7.89-7.95 (m, 2H), 7.60-7.63 (m, 2H), 3.95 (s, 3H). | |
With sulfuric acid at 70℃; | 1 Step 1: methyl 2-formylbenzoate (B1) To a solution of H2SO4 (2 mL) in MeOH (100 mL) was added 2-formyl benzoic acid (10.0 g, 66.2 mmol). The resulting mixture was stirred at 70 °C overnight. After cooled to RT, the mixture was concentrated in vacuo, adjusted pH to 8 with aq. NaHCO3 and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (10% EtOAc in petroleum ether) to give the title compound as sm oil. LRMS m/z (M+H) 165.1 found, 165.1 required | |
With sulfuric acid at 70℃; | 1 Step 1: methyl 2-formylbenzoate (01) 2-(2,2,2-trifluoroethyl)benzoic IntermediateO Step 1: methyl 2-formylbenzoate (01) To a solution of H2S04 (2 mL) in MeOH (100 mL) was added 2-formyl benzoic acid (10.0 g, 66.2 mmol). The resulting mixture was stirred at 70 °C overnight. After cooled to RT, the mixture was concentrated in vacuo, adjusted pH to ~8 with aq. NaHC03 and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (10% EtOAc in petroleum ether) to give the title compound. LRMS m/z (M+H) 165.1 found, 165.1 required. XH NMR (CDC13, 400MHz): δ 10.58 (s, 1H), 7.89-7.95 (m, 2H), 7.60-7.63 (m, 2H), 3.95 (s, 3H). | |
4.80 g | With sulfuric acid at 70℃; | 1 Step 1: Methyl 24brniyihenzoate (Al) Step 1: Methyl 24brniyihenzoate (Al)To a solution of i-12S04 (2 mL) in MeOH (100 mL) was added 2-formyl benzoic acid (10.0 g, 66.2 mrnol), The resulting mixture was stirred at 70 °C overnight. After cooling to RI, the mixture was concentrated in vacuo, adjusted pH to 8 with aq. NaHCO3 and extracted withEtOAc (10 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradientchromatography (10% EtOAc in petroleum ether) to give the title compound (4.80 g) as yellow oil. LRMS m/z (M+H) 165.1 found, 165.1 required111 NMR (CDC13, 400MHz): ö 10.58 (s, lEt), 7.89-7.95 (rn, 2H), 7.60-7.63 (in, 2H), 3.95 (s, 3H). |
With sulfuric acid at 70℃; | 1 Step 1: methyl 2-formylbenzoate (Ii) To a solution of H2S04 (2 mL) in MeOH (100 mL) was added 2-formyl benzoic acid(10.0 g, 66.2 mmol). The resulting mixture was stirred at 70 °C overnight. After cooling to roomtemperature, the mixture was concentrated in vacuo, adjusted to pH8 with aq. NaHCO3 and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (10% EtOAc in petroleum ether) to give Ii as an oil. LRMS mlz (M+H) 165.1 found, 165.1 required. ‘H15 NMR (CDC13, 400MHz): ö 10.58 (s, 1H), 7.89-7.95 (m, 2H), 7.60-7.63 (m, 2H), 3.95 (s, 3H). | |
With sulfuric acid at 45℃; | 1; 3 A method for preparing 2- (4-chlorophenyl) -3-oxo-N- (tosylmethyl) isoindoline-1-carboxamide, including the following experimental steps: At room temperature, first add 2-aldehyde benzoic acid, ethanol, and concentrated sulfuric acid at 45 degrees Celsius to make it fully react, and then post-treatment to obtain methyl 2-aldehyde benzoate; second, at room temperature Next, methyl 2-aldehyde benzoate (164 mg, 1 mmol), a methanol solvent, and p-chloroaniline (127 mg, 1.0 mmol) were sequentially added to the reactor under stirring at room temperature to fully dissolve, and a MOF-Cu catalyst ( 0.1% mol), sulfonyl isocyanide (215 mg, 1.1 mmol), MeOH (5 ml). After being dissolved, the reaction was continued for 12 hours. After the reaction was detected by TLC, the MOF-Cu catalyst was filtered off first, and then removed under reduced pressure. The solvent was methanol, and the residue was subjected to column chromatography to obtain the target compound 4a in a yield of 90%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In acetone for 3h; Ambient temperature; Yield given. Yields of byproduct given. Title compound not separated from byproducts; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium cyanoborohydride 1.) MeOH, 5 min, 2.) MeOH, reflux, overnight; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 73% 2: 21% | With tri-n-butyl-tin hydride In tetrahydrofuran at 50℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 34% 2: 16% 3: 15% 4: 10% | With oxygen Further byproducts given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 12% 2: 16% 3: 15% 4: 34% 5: 10% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 12% 2: 16% 3: 15% 4: 34% | With oxygen Further byproducts given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate In N,N-dimethyl-formamide for 1h; Heating; | |
100% | With potassium carbonate In acetone at 20 - 56℃; | Synthesis of methyl 4-chloroisoquinoline-2-carboxylate Synthesis of 2-carboxymethylbenzaldehyde: 2-Carboxybenzaldehyde (4.53g, 30mmoles) was dissolved in acetone (100mls) and anhydrous potassium carbonate (4.14g, 30mmoles) was added. After stirring methyl iodide (5.6mls, 90mmoles) was added and the reaction was heated (560C) for 30 minutes. The reaction became very thick so further acetone was added (50mIs) and stirring continued at room temperature for a further 72 hours. The reaction mixture was filtered through Celite and then evaporated to leave a viscous oil. The oil was then partitioned between water (30ml) and ethyl acetate (30ml). The aqueous layer was washed with further ethyl acetate (2x3 OmIs) and all the ethyl acetate extracts combined and washed with brine (30mIs) and then water (3OmIs) dried over anhydrous magnesium sulphate and evaporated to leave a clear light yellow oil (4.9g, 100% yield). |
98% | With potassium carbonate In N,N-dimethyl-formamide for 1h; Reflux; Inert atmosphere; |
96% | With potassium carbonate In acetone | |
95% | With potassium carbonate In N,N-dimethyl-formamide at 150℃; for 0.166667h; Microwave irradiation; | 4.1.42. Methyl 2-formylbenzoate (28) A mixture of 27 (100 mg, 0.666 mmol), MeI (189 mg, 1.33 mmol), K2CO3 (55 mg, 0.400 mmol), and DMF (0.5 ml) was heated 10 min at 150 °C using Biotage Initiator microwave synthesizer. The resulting reaction mixture was dissolved in ethyl acetate (50 ml) and washed with HCl (1 M, 3× 50 ml). The organic phase was dried (Na2SO4) and evaporated to dryness. The crude product was purified by flash chromatography (silica gel) eluting with EtOAc/PE 1:10 to give 28 (104 mg, 95%). 1H NMR (DMSO-d6): δ 10.42 (s, 1H); 7.94-7.85 (m, 2H), 7.80-7.75 (m, 2H), 3.92 (s, 3H). 13C NMR (DMSO-d6): δ 192.8 (CHO); 166.9 (CO2Me); 136.7; 133.7; 132.8; 132.4; 130.2; 128.8; 53.1. |
95% | With potassium carbonate In N,N-dimethyl-formamide; acetone at 20℃; Heating; | Methyl 2-formylbenzoate (33). The mixture of 2-formylbenzoic acid (6.005 g, 40 mmol),iodomethane (4.63 mL, 74.4 mmol), and K2CO3 (2.981 g, 21.6 mmol) were heated inDMF/acetone (35 mL/5 mL) for 1 h and stirred at ambient temperature overnight. The reaction22mixture was filtered through celite and the filtrate was concentrated under reduced pressure toyield viscous oil. The oil was partitioned between water (40 mL) and DCM (40 mL). Theaqueous layer washed with DCM (20 mL 2). The combined organic layers were washed withbrine, dried over anhydrous magnesium sulphate and concentrated to give yellow oil, which wasfurther purified by flash chromatography (EA/PE = 1/12) to give 6.212 g light yellow oil, in 95%yield. 1H NMR (400 MHz, CDCl3) 10.62 (s, 1H), 7.987.93 (m, 2H), 7.667.64 (m, 2H), 3.98(s, 3H). |
95% | With potassium carbonate In N,N-dimethyl-formamide; acetone at 20℃; for 12h; Heating; | Methyl 2-formylbenzoate (40) Themixture of 2-formylbenzoic acid (6.005 g, 40 mmol), iodomethane (4.63 mL, 74.4mmol), and K2CO3 (2.981 g, 21.6 mmol) were heated inDMF/acetone (35 mL/5 mL) for 1 h and stirred at ambient temperature overnight.The reaction mixture was filtered through celite and the filtrate wasconcentrated under reduced pressure to yield viscous oil. The oil was partitionedbetween water (40 mL) and DCM (40 mL). The aqueous layer washed with DCM (20 mL2). The combined organic layers were washed with brine, dried over anhydrousmagnesium sulphate and concentrated to give yellow oil, which was furtherpurified by flash chromatography (EA/PE = 1/12) to give 6.212 g light yellowoil, in 95% yield. 1H NMR (400 MHz, CDCl3) d 10.62 (s, 1H), 7.98-7.93(m, 2H), 7.66-7.64 (m, 2H), 3.98 (s, 3H) |
95% | With potassium carbonate In acetone at 20℃; for 12h; | |
94% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 4h; | |
94% | With potassium carbonate In N,N-dimethyl-formamide at 20 - 60℃; for 18h; | |
93% | With potassium carbonate In acetone for 5h; Reflux; | 1.1 Preparation of intermediate ester (1) A two-necked flask was charged with phthalaldehyde acid4.0 g (27 * 10 mol),11.3 g of potassium carbonate (K 2 CO 3) and 4.1 g of methyl iodide (CH 3 I) were placed, dissolved in 100 ml of acetone, and refluxed for 5 hours. The product was filtered, concentrated, and dried under reduced pressure to obtain a yellow liquid of the intermediate ester (1) represented by the following formula (H-1) in a yield of 4.0 g in a yield of 93%. |
92% | With potassium carbonate In N,N-dimethyl-formamide for 2h; Reflux; | |
92% | With potassium carbonate In N,N-dimethyl-formamide for 4h; Reflux; | |
91% | With potassium carbonate In N,N-dimethyl-formamide at 20 - 60℃; for 14h; | |
90% | With potassium carbonate In acetone at 20℃; Inert atmosphere; Reflux; | |
90% | With potassium carbonate In acetone at 20℃; for 4h; Inert atmosphere; | |
90% | With potassium carbonate In acetone | |
90% | With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 5h; Inert atmosphere; | 3.2. Procedure for the Synthesis of methyl-2-formylbenzoate (10) To a stirred solution of 2-carboxy benzaldehyde in DMF (10 volume), K2CO3 (2 equiv.) and methyl iodide (1.2 equiv.) was added slowly into the reaction mixture and then refluxed the reaction at 100°C for 5 hrs. The completion ofthe reaction was monitored by the thin-layer chromatography technique. After completion of the reaction, the reaction mixture was allowed to cool and then at room temperature quenched with water and extraction done by using ethyl acetate solvent, combined organic layer brine washed, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a crude residue. The purification was done by using silica gel chromatography (100-200 mesh size silica) with 0-100% Ethyl acetate in Hexane solvent system to obtain the desired product with a 90% yield. |
84% | With sodium hydroxide In 1,4-dioxane; water at 70℃; for 16h; | 1.1 41 g (0.273 mol) of 2-carboxybenzaldehyde(Compound 5), 410 mL of dioxane, 80 mL of iodomethane, and 82 mL (0.328 mol) of a 4N aqueous solution of sodium hydroxide were added to a 1-L reaction vessel. The solution was vigorously stirred at 700C for 16 hours. Dioxane was removed under reduced pressure, and 200 mL of distilled water was added to the solution, followed by extraction with ethyl acetate (200 mL x twice) . An organic layer was collected, washed with saturated sodium bicarbonate water, distilled water, and a saturated salt solution, and dried with anhydrous MgSO4. After that, the solution was condensed, whereby 43 g of a colorless liquid was obtained. The liquid was purified by means of silica gel column chromatography (mobile phase; hexane : ethyl acetate = 3 : 1), whereby 37.7 g (0.230 mol, yield = 84%) of Compound 6 as a colorless liquid were obtained. |
80.4% | With potassium carbonate In N,N-dimethyl-formamide for 4h; Reflux; | |
80.4% | With potassium carbonate In N,N-dimethyl-formamide for 4h; Reflux; | 1 Representative procedure A: synthesis of alkyl 2-formylbenzoate General procedure: synthesis of alkyl 2-formylbenzoate. Iodomethane (0.6 mL, 9.5 mmol) was added toa stirred solution of 2-formylbenzoic acid (0.765 g, 5.1 mmol) andpotassium carbonate (0.387 g, 2.8 mmol) in DMF (4 mL). The reactionmixture was refluxed for 4 h, diluted with water (8 mL), andextracted with DCM. The combined organic phases were washedwith 1 N HCl (4 mL), saturated aqueous NaHCO3 (4 mL), and driedover Na2SO4. After filtration and evaporation of the solvents invacuum, the crude product was purified by column chromatographyon silica gel (n-hexane/EtOAc: 6/1) to yield 7a as a colorless oil(0.673 g, 80.4%). 2.2.1.1 Methyl 2-formylbenzoate (7a) 1H NMR (300 MHz, CDCl3): δ=10.59 (s, 1H), 7.97-7.90 (m, 2H), 7.65-7.62 (m, 2H), 3.96 (s, 3H). 13C NMR (75 MHz, CDCl3): δ=192.3, 166.9, 137.1, 134.5, 133.1, 132.5, 130.5, 128.5, 52.9. HRMS (EI): m/z calcd for C9H8O3 (M+): 164.0473; found: 164.0468. |
78% | With potassium carbonate In acetone for 4h; Heating; | |
76% | With potassium carbonate In acetone | |
70% | With potassium carbonate In acetonitrile for 24h; Heating; | |
55% | With potassium carbonate In N,N-dimethyl-formamide | |
With potassium carbonate In acetone | ||
With potassium carbonate In acetone for 4h; Heating; | ||
In acetonitrile | ||
With sodium; potassium carbonate In water; acetone | 2-Carbomethoxybenzaldehyde (Compound 43) 2-Carbomethoxybenzaldehyde (Compound 43) 4.5 g (30 mmol) of 2-carboxybenzaldehyde, 17.1 g (120 mmol) of iodomethane and 12.4 g (90 mmol) of potassium carbonate were stirred in 85 ml of acetone for 24 hours. The solvent was removed by evaporation and the residue was partioned between 50 ml of water and 50 ml of ether. The aqueous layer was washed with 3*50 ml portions of ether. The combined organic extracts were washed with 30 ml each of 1M sodium thiosufate and saturated sodium cloride solutions and dried over MgSO4. The solvent was removed by evaporation. The residue was subjected to flash chromatography (silica gel, 10% ethyl acetate/hexanes) to give the title compound as a clear colorles oil. PMR (CDCl3): d 3.98 (3H, s), 7.65-7.68 (2H, m), 7.94-8.00 (2H, m), 10.63 (1H, s). | |
With potassium carbonate In <i>N</i>-methyl-acetamide | R.9 REFERENCE EXAMPLE 9 REFERENCE EXAMPLE 9 6 Grams of 2-formylbenzoic acid and 6 g of potassium carbonate were added to 30 ml of dimethylformamide, then 6 g of methyl iodide were added dropwise thereto at room temperature with stirring. The reaction mixture was continuously stirred at room temperature overnight, then was concentrated. The residue obtained was extracted with chloroform, and the chloroform layer was washed with water, and was dried with anhydrous magnesium sulfate, then concentrated. The residue obtained was purified by distillation under reduced pressure to yield 3 g of methyl 2-formylbenzoate. Boiling point: 95° C. (at 0.5 mm-Hg). | |
With 1,8-diazabicyclo[5.4.0]undec-7-ene at 20℃; | ||
With potassium carbonate In N,N-dimethyl-formamide Reflux; | ||
With potassium carbonate In acetone at 20℃; for 12h; | ||
420 mg | With potassium carbonate In acetone for 4h; Inert atmosphere; Reflux; | 88 2-formylbenzoic acid methyl ester Under nitrogen, 600 mg (4 mmol) of 2-formylbenzoic acid,1.65 g (12 mmol) of potassium carbonate were mixed in anhydrous acetone,274 μl (4.4 mmol) of methyl iodide was added and refluxed for 4 hours.After cooling, the mixture was diluted with water and extracted with ethyl acetate.The ethyl acetate layer was washed three times with brine and dried over anhydrous magnesium sulfate. filter,The filtrate was concentrated in silica gel and flash column chromatography (0-10% ethyl acetate / petroleum ether) to give 420 mg of a colorless oil. |
With potassium carbonate | ||
With potassium carbonate In N,N-dimethyl-formamide at 60℃; Darkness; | ||
With potassium carbonate In acetone at 60℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1) Ar-MeOH matrix, 11 K, irradiation, 2) up to rt; Yield given. Multistep reaction. Yields of byproduct given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: o-carboxybenzaldehyde With thionyl chloride for 2h; Heating; Stage #2: methanol for 4h; Heating; Title compound not separated from byproducts; | ||
With bismuth(lll) trifluoromethanesulfonate Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | Stage #1: pyrrole; methyl o-formylbenzoate; 4-trimethylsilylbenzaldehyde With boron trifluoride diethyl etherate In chloroform at 20℃; for 0.666667h; Stage #2: With 2,3-dicyano-5,6-dichloro-p-benzoquinone In chloroform; benzene at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: 2-(1,3-dioxolan-2-yl)ethyl(triphenyl)phosphonium bromide With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: methyl o-formylbenzoate In tetrahydrofuran at 0℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 59% 2: 4% | Stage #1: naphthalene With oxygen; ozone In methanol Stage #2: With acetic acid; potassium iodide In methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | Stage #1: naphthalene With oxygen; ozone In methanol Stage #2: With acetic acid; potassium iodide In methanol for 1.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer In ethanol at 80℃; for 5.5h; Schlenk technique; | 4.2.17. 1,3-Dihydro-2-benzofuran-1-one (5). 4b (13.2 mg, 0.191 mmol) was reacted in 2a (2.0 mL) in the presence of [Cp*RhCl2]2 (2.7 mg, 4.4 μmol, 4.6 mol % Rh) for 5.5 h. Purification by preparative TLC on silica gel (hexane:AcOEt=5:1) afforded 5 (18.0 mg, 0.134 mmol, 70%). |
68% | With sodium tetrahydroborate In methanol at 0 - 5℃; for 3h; | |
28% | Stage #1: methyl o-formylbenzoate With 2,2'-bis(1,3,2-benzodioxaborole); water In N,N-dimethyl acetamide at 80℃; for 12h; Inert atmosphere; Sealed tube; Stage #2: With 2,3-dimethyl-2,3-butane diol; triethylamine In N,N-dimethyl acetamide at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With (IMes)CuCl; triphenylphosphine; isopropyl alcohol In 1,4-dioxane; diethyl ether at 60℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | Stage #1: 2-aminopyridine; methyl o-formylbenzoate; p-nitrophenyl isocyanide With perchloric acid In methanol at 20℃; Stage #2: With potassium <i>tert</i>-butylate In methanol at 20℃; for 2h; | 1.A Example 1: Scheme A: general Ugi procedureA mixture of 2-aminopyridine (II) (1.0 equiv., 5.30 mmol, 0.500 g), 4-nitrophenyl isocyanide (12) (1.1 equiv., 5.80 mmol, 0.870 g), methyl 2-formylbenzoate (13)(1.1 equiv., 5.80 mmol, 0.960 g) and perchloric acid (0.1 equiv., 0.53 mmol, 0.053 g) in methanol (25 ml) was stirred at room temperature until no starting material was left.The progress of the reaction was monitored by LCMS. Potassium tert-butoxide(1.1 equiv., 5.80 mmol, 0.660 g) was added and the reaction mixture was further stirred at room temperature for 2 h. The resulting precipitate was filtered off and washed with isopropanol and isopropyl ether to give 6-(4-nitrophenyl)-pyrido[2',r:2,3]imidazo-[4,5-c]isoquinolin-5(6H)-one (1) (1.20 g, yield = 63%, purity (LC) = 95%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | Stage #1: 6-aminopyridin-3-ol; methyl o-formylbenzoate; p-nitrophenyl isocyanide With perchloric acid In methanol at 20℃; Stage #2: With potassium <i>tert</i>-butylate In methanol at 20℃; for 2h; Stage #3: In methanol Acidic conditions; | 20.C A mixture of 2-aminopyridine (II) (1.0 equiv., 27.2 mmol, 3.00 g), 4-nitrophenyl isocyanide (1.1 equiv., 29.9 mmol, 4.40 g), methyl 2-formylbenzoate (1.1 equiv., 29.9 mmol, 4.9 g) and perchloric acid (0.2 equiv., 5.4 mmol, 0.55 g) in methanol was stirred at room temperature overnight. Potassium tert-butoxide (2.2 equiv., 59.8 mmol, 6.7 g) was added and the reaction mixture was further stirred at room temperature for 2 h. Acetic acid (2.0 ml) (or concentrated hydrochloric acid) was added, the resulting precipitate was filtered off and washed with isopropanol and isopropyl ether to give 9-hydroxy-6-(4-nitrophenyl)-pyrido[2',r:2,3]imidazo[4,5-c]isoquinolin-5(6H)-one (10) (6.80 g, yield = 67%, purity (LC) = 95%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | Stage #1: 6-chloro-pyridazin-3-ylamine; methyl o-formylbenzoate; p-nitrophenyl isocyanide With perchloric acid In tetrahydrofuran at 50℃; Stage #2: With sodium hydride In tetrahydrofuran at 0 - 20℃; Stage #3: With hydrogenchloride In tetrahydrofuran; water; acetonitrile | 26.D Example 26: Scheme DI22 I2 I3I23A mixture of 6-chloropyridazin-3 -amine (122) (1.0 equiv., 7.72 mmol, 1.00 g), 4-nitrophenyl isocyanide (12) (1.2 equiv., 9.26 mmol, 1.37 g) and methyl 2-formyl- benzoate (13) (1.2 equiv., 9.26 mmol, 1.52 g) and perchloric acid (0.1 equiv., 0.77 mmol, 0.078 g) in THF (40 ml) was heated at 50 0C overnight under Ar atmosphere. After the reaction mixture had been cooled in an ice-bath, sodium hydride (1.5 equiv., 11.58 mmol, 0.463 g (60%)) was added. The reaction mixture was stirred at room temperature overnight and then poured onto a mixture of acetonitrile (30 ml) and 1 M HCl (30 ml). The resulting precipitate was filtered off, washed with isopropanol and isopropyl ether successively to give 9-chloro-6-(4-nitrophenyl)-pyridazo[3',2':2,3]- imidazo[4,5-c]isoquinolin-5(6H)-one (123) (0.554 g, yield = 18 %) as a light green powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With piperidine In ethanol at 80℃; for 1h; | A solution of rpm281 (0.149 g, 0.586 mmol) and methyl 2-formylbenzoate (0.105 g, 0.645 mmol, 1.1 eq) in ethanol (10 ml) was stirred in presence of piperidine (1 drop) at 80 0C, under Ar for Ih. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (15 ml) and washed with HCl IM (10 ml). The organic extracts were collected, dried over Na2SO4 and the solvent removed under reduced pressure to afford a orange solid. The pure compound rpm347 was obtained after trituration with hexane/ethyl acetate mixture (6:4) (10 ml) as a off-white solid (0.135 g, 0.337 mmol, 60%), mp 271-273 0C. MS (API-ES): mJz 401 (M+H)+; HRMS (API- ES) mlz Found: 401.1 173 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With diethylamino-sulfur trifluoride In ethanol; dichloromethane at 20℃; | General Procedure I (Synthesis of difluoromethylarenes from arene carbaldehydes) General procedure: To a flame dried flask containing a solution of aryl aldehyde (1.0 eq.) in DCM (1.0 M) at room temperature was added EtOH (5-100 μL) and DAST (1.7 eq.). The reaction was stirred over night at room temperature before it was quenched with aq. NaHCO3 (sat.) and extracted with DCM. The combined organic fractions were washed with brine, dried over MgSO4, evaporated to dryness and loaded onto a silica gel column for purification. |
66% | With diethylamino-sulfur trifluoride In dichloromethane at 20℃; Inert atmosphere; | 1 Synthesis of compound 24 Diethylaminosulfur trifluoride (DAST) (3.8 mL; 31 mmol; 1.7 eq.) is added dropwise into a round-bottom flask under an inert atmosphere, which contains methyl 2- formylbenzoate 23. (3 g; 18 mmol; 1 eq.) in dichloromethane (20 mL). A drop of anhydrous methanol is then added to the reaction medium in order to catalyze the reaction. The mixture is stirred for 16 h at ambient temperature (82% conversion rate determined by GC) and then cooled to 00C prior to adding a saturated sodium bicarbonate solution until the neutral state is reached. The mixture is then extracted with dichloromethane, dried over magnesium sulphate and then concentrated. The residue is then purified on a chromatography column (95/5 cyclohexane/ethyl acetate eluent) to produce compound 24, in the form of a yellow oil, with a yield of 66%.24: C9H8F2O2 M = 186.16 g.mol"1Rf: 0.44 (cyclohexane/ethyl acetate) 9/1.NMR 19F (CDO1. 282.5 Mz): -114.2 (d, J= 56 Hz, 2F).Mass: (ESI +) : 187.07 (M + H). |
62% | With (bis-(2-methoxyethyl)amino)sulfur trufluoride In dichloromethane for 12h; Reflux; | 103.1 Synthesis of methyl 2-(difluoromethyl)benzoate: A solution of methyl 2-formylbenzoate (10.0 g, 61 mmol) and bis-(2-methoxyethyl)aminosulfur trifluoride (40.4 g, 183 mmol) in CH2Cl2 was heated at reflux for 12 h. The reaction mixture was cooled to room temp, concentrated and partitioned between EtOAc (500 mL)/ H2O (300 mL). NaHCO3 was added to adjust the pH to 8. The organic phase was separated, washed with brine, dried and concentrated. The residue was purified by flash chromatography to give methyl 2-(difluoromethyl)benzoate (7.0g, 62 % yield) |
62% | With (bis-(2-methoxyethyl)amino)sulfur trufluoride In dichloromethane for 12h; Reflux; | 103.1 Synthesis of methyl 2-(difluoromethyl)benzoate A solution of methyl 2-formylbenzoate (10.0 g, 61 mmol) and bis-(2-methoxyethyl)amino-sulfur trifluoride (40.4 g, 183 mmol) in CH2Cl2 was heated at reflux for 12 h. The reaction mixture was cooled to room temp, concentrated and partitioned between EtOAc (500 mL)/ H2O (300 mL). NaHCO3 was added to adjust the pH to 8. The organic phase was separated, washed with brine, dried and concentrated. The residue was purified by flash chromatography to give methyl 2-(difluoromethyl)benzoate (7.0g, 62 % yield). |
With (bis-(2-methoxyethyl)amino)sulfur trufluoride In dichloromethane for 12h; Heating / reflux; | Preparation of methyl 2-(difluoromethyl)benzoate A solution of methyl 2-formylbenzoate (1.0 g, 6.09 mmol) and bis(2-methoxyethyl)amino-sulfur trifluoride (4.04 g, 18.3 mmol) in methylene chloride (10 mL) was heated at reflux for twelve hours. The reaction was concentrated, diluted with ethyl acetate (200 mL) and water (100 mL). Sodium bicarbonate solid was used to neutralize the mixture slowly to pH of 8. The organic phase was then separated and washed with brine (50 mL), dried over sodium sulfate and concentrated. The residue was purified with silica gel chromatography to give methyl 2-(difluoromethyl)benzoate as an oil (700 mg). 1H NMR (400 MHz, CDCl3) δ 8.02 (d, 1H), 7.82 (d, 1H), 7.64 (t, 1H), 7.52 (m, 1H). 7.39 (t, 1H), 3.93 (s, 3H). | |
With diethylamino-sulfur trifluoride In methanol; dichloromethane at -5 - 25℃; for 16h; | 13.1 2-(Difluoromethyl)aniline hydrobromide Step 1: Into a 250 mL round bottom flask containing a solution of methyl 2-formylbenzoate (5.0 g, 30 mmol) in dichloromethane (80 mL) were added diethylaminosulfur trifluoride (7 mL, 52mmol) and methanol (1.5 mL) at-S °C and the reaction was stirred at room temperature for 16 h. The reaction mixture was diluted with dichloromethane (20 mL) and washed with saturated sodium bicarbonate solution, water and brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford methyl 2- (difluoromethyl)benzoate as an oil which was taken to the next step without further purification. | |
With diethylamino-sulfur trifluoride In methanol; dichloromethane at -5 - 25℃; for 16h; | 1 Step 1: Into a 250 mL round bottom flask containing a solution of methyl 2-formylbenzoate (5.0 g, 30 mmol) in dichloromethane (80 mL) were added diethylaminosulfur trifluoride (7 mL, 52 mmol) and methanol (1.5 mL) at-S °C and the reaction was stirred at room temperature for 16 h. The reaction mixture was diluted with dichloromethane (20 mL) and washed with saturated sodium bicarbonate solution, water and brine. The solution was dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to afford methyl 2-(difluoromethyl)benzoate as an oil which was taken to the next step without further purification. | |
With diethylamino-sulfur trifluoride In methanol; dichloromethane at -5 - 20℃; for 16h; | 1 Step 1: Into a 250 mL round bottom flask containing a solution of methyl 2-formylbenzoate (5.0 g, 30 mmol) in dichloromethane (80 mL) were added diethylaminosulfur trifluoride (7 mL, 52 mmol) and methanol (1.5 mL) at -5 °C and the reaction was stirred at room temperature for 16 h. The reaction mixture was diluted with dichloromethane (20 mL) and washed with saturated sodium bicarbonate solution, water and brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford methyl 2- (difluoromethyl)benzoate as an oil which was taken to the next step without further purification. | |
With diethylamino-sulfur trifluoride In methanol; dichloromethane at -5 - 20℃; for 16h; | 14.1 Step 1: Into a 250 mL round bottom flask containing a solution of methyl 2-formylbenzoate (5.0 g, 30 mmol) in dichloromethane (80 mL) were added diethylaminosulfur trifluoride (7 mL, 52 mmol) and methanol (1.5 mL) at -5 oC and the reaction was stirred at room temperature for 16 h. The reaction mixture was diluted with dichloromethane (20 mL) and washed with saturated sodium bicarbonate solution, water and brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford methyl 2- (difluoromethyl)benzoate as an oil which was taken to the next step without further purification | |
With diethylamino-sulfur trifluoride In dichloromethane at 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: p-toluene sulfonic acid / toluene / Heating 2: toluene / 1.) RT, 30 min; 2.) 100 deg C, 4 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | In methanol; at 20℃; for 24h; | A mixture of commercially available 2-formylbenzoic acid methyl ester (100 mg, 0.61 mmol) and <strong>[57497-39-9]N-(tert-butyl)hydroxylamine hydrochloride</strong> (109 mg, 0.732 mmol) in methanol (5 mL) was stirred at ambient temperature for 24 h. The mixture was then concentrated in vacuo and the crude product was dissolved in ethyl acetate (15 ml) and extracted with water (2*20 ml). After the combined organic layers were dried over Na2SO4 and concentrated in vacuo, chromatography on silica gel provided compound 1 (10 mg, 20percent). MS: m/z 236 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; for 3h; | 3-1 After adding methyl 2-formylbenzoate (254 mg, 1.55 mmol), acetic acid (89 µL, 1.55 mmol) and sodium triacetoxyborohydride (265 mg, 1.25 mmol) to a solution of N-[1-[2-[1-(2-aminoethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide (226 mg, 0.52 mmol) in 1,2-dichloroethane (3 mL), the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with chloroform and washed with saturated aqueous sodium hydrogencarbonate and saturated brine in that order. The organic layer was dried (anhydrous sodium sulfate) and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (10 g NH Silica Chromatorex DM2035, hexane:ethyl acetate = 7:3-1:1) to obtain the title compound as a colorless oil (194 mg, 0.26 mmol) (67% yield). 1H-NMR (CDCl3) δ: 1.30-1.60 (m, 16H), 1.87 (d, 2H, J = 12.2 Hz), 2.14 (t, 2H, J = 11.2 Hz), 2.31-2.36 (m, 2H), 3.02 (d, 2H, J = 11.7 Hz), 3.53-3.58 (m, 2H), 4.36 (s, 2H), 4.73-4.82 (m, 1H), 5.35 (brs, 1H), 6.13 (dd, 1H, J = 1.5 Hz, 2.9 Hz), 7.02 (d, 2H, J = 8.3 Hz), 7.18 (d, 2H, J = 8.3 Hz), 7.35 (d, 1H, J = 1.0 Hz), 7.42-7.47 (m, 2H), 7.50-7.54 (m, 1H), 7.83 (d, 1H, J = 7.3 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid; In toluene; | EXAMPLE 25 Preparation of methyl o-[N-(1-carbamoyl-1,2-dimethylpropyl)formimidoyl]benzoate STR77 A mixture containing 5.0 g methyl 2-formylbenzoate [C. Brown and M. V. Sargent, J. Chem. Soc. (C), 1818 (1969)] and 4.0 g <strong>[40963-14-2]2-amino-2,3-dimethylbutyramide</strong> and 50 mg p-toluenesulfonic acid in 100 mL toluene is heated under reflux under a Dean-Stark water separator for three hours. The mixture is filtered and concentrated in vacuo. The residue crystallizes on standing and is recrystallized from etherhexane to give analytically pure methyl o-[N-(1-carbamoyl-1,2-dimethylpropyl)formimidoyl]benzoate, mp 79-80.5 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: dimethyl sulfate; o-carboxybenzaldehyde With potassium carbonate In acetone at 20℃; for 2h; Inert atmosphere; Stage #2: In acetone for 1h; Reflux; | |
With nitrogen; triethylamine In dichloromethane; water | 4 EXAMPLE 4: EXAMPLE 4: Preparation of STR17 2-Carbomethoxybenzaldehyde Into a 3-neck 1 liter round bottom flask equipped with a magnetic stirrer, reflux condenser fitted with a drying tube, addition funnel with a septum and a nitrogen inlet, 100 g (0.659 mole) 2-carboxybenzaldehyde, about 140 ml methylene chloride and 162.8 g [122.2 ml (1.291 moles)] dimethylsulfate were placed. The mixture was heated to reflux 135.89 g [187.2 ml (1.343 moles)] triethylamine was added dropwise, maintaining a brisk reflux. After the addition was complete, the resulting gold-colored solution was allowed to cool to room temperature, and then washed with 400 ml water. After the layers were separated, the aqueous phase was extracted with 400 ml methylene chloride. The organic layers were combined and washed with 500 ml of a saturated aqueous sodium bicarbonate solution and with 500 ml water. The organic phase was dried over magnesium sulfate and then concentrated to give 111.5 g of the product as a gold liquid. | |
With triethylamine In dichloromethane; water | 9 2-Carbomethoxybenzaldehyde 2-Carbomethoxybenzaldehyde To a 3-neck 1-liter round-bottom flask equipped with a magnetic stirrer, reflux condenser and addition funnel was added 2-carboxybenzaldehyde (100.00 g, 0.659 moles), dimethylsulfate (162.8 g 1.291 moles) and 200 ml of dichloromethane under nitrogen. The mixture was heated to reflux and triethylamine (135.89 g, 1.343 moles) was added at such a rate to maintain a brisk reflux. After the addition was complete, the solution was allowed to cool to room temperature and stirred overnight. Water (400 ml) was then added and the layers separated. The aqueous layer was extracted with dichloromethane (1*200 ml) and the combined organic layers washed with saturated sodium bicarbonate solution (1*400 ml), dried over magnesium sulfate and concentrated in vacuo to give a golden oil. Vacuum distillation of this oil gave 88.7 g of the product as a pale yellow oil, bp 95°-98° C./0.4 mm. |
With potassium carbonate In acetone at 20℃; for 3h; Reflux; | ||
With potassium carbonate In acetone at 20℃; for 3h; Reflux; | ||
With potassium carbonate In acetone Reflux; | Synthesis of trans-o-Carboxybenzylidenepyruvate (6). The methyl ester of o-carboxybenzaldehyde [12 (Scheme 3)] was synthesized by mixing o-carboxybenzaldehyde (o-CBA, 10,1.5 g, 10 mM) and dimethyl sulfate (1.9 g, 15 mM) with 2 equiv of K2CO3. The reaction mixture was stirred at a gentlere flux in acetone (50 mL) overnight. After most of the acetone was removed under reduced pressure, the residue was diluted with ethyl acetate (∼100 mL) and filtered to remove salts. The ethyl acetate was washed with water, and the organic layer was collected, dried over anhydrous Na2SO4, and evaporated to dryness. For additional purity, the residue was purified by flash column chromatography (4:1 hexanes/ethyl acetate). Fractions containing 12 were combined, dried over anhydrous Na2SO4, and evaporated to dryness. | |
With potassium carbonate In acetone at 0 - 30℃; for 4h; | 2. Preparation of N-tert-butanesulfinylimines General Procedure: Step 2 General procedure: To a dried flask containing a magnetic stir bar under an atmosphere of dry argon was added the 2-formylbenzoic acid (1.0 equiv), K2CO3 (2.0 equiv) and acetone (0.2 M). The solution was cooled to 0 °C followed by drop-wise addition of Me2SO4 (1.3 equiv). The reaction mixture was allowed to warm to 30 °C for 4 h, and quenched by adding EtOAc and water. The organic phase was extracted with EtOAc, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by flash column chromatography (PE/EA: 25/1 to 5/1) to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium chloride; magnesium In tetrahydrofuran | XVI EXAMPLE XVI EXAMPLE XVI Preparation of 4-(4,4-dimethyl-3,4-dihydro-6-benzothiopyranyl) hydroxymethyl methyl benzoate. Compound of formula II wherein X=--S--, n=0, R'=OH, R"=H and R8 =OCH3. To a solution of 5 g (0.0195 mole) of 6-bromo-4,4-dimethyl-3,4-dihydro benzothiopyran in 50 cm3 of anhydrous THF, there is added 0.55 g of magnesium. The reaction is primed by heating. The reaction medium is maintained at the reflux of THF for about 1 hour until the total disappearance of magnesium. The reaction mixture is cooled to 0° C. and in the absence of air, the organomagnesium compound is decanted in a dropping funnel. The product is slowly added to a solution of 1.8 g of 4 formyl methyl benzoate in about 150 cm3 of anhydrous THF at 0° C. During the addition, the temperature must not exceed 5° C. At the end of the addition, the reaction mixture is maintained under stirring of 2 hours and then left overnight. The reaction mixture is poured into 100 cm3 of a saturated ammonium chloride solution and then extracted with 3*100 cm3 of ethyl ether. The organic phase is washed with a diluted solution of ammonium chloride, then with water, dried on magnesium sulfate and concentrated under reduced pressure. The expected product is purified by silica gel chromatography (eluant: 8/2, heptane/ethylacetate). acetate). 1.3 g of a pure yellow oil whose NMR1 H spectrum 80 MHz conforms to the expected structure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; for 18h; | 2 Example 2 2-{4-[4-(2-Ethyl-butyrylamino)-2-fluoro-phenyl]-piperazin-1-ylmethyl}-benzoic acid methyl ester To a solution of 2-ethyl-N-(3-fluoro-4-piperazin-1-yl-phenyl)-butyramide (0.05 mg, 0.17 mmol) and methyl-2-formyl benzoate (0.03 mg, 0.19 mmol) in DCM (10 mL) was added NaBH(OAc)3 (0.03 mg, 0.13 mmol). After 18 h, the mixture was diluted with 1 N NaOH (15 mL) and extracted with DCM (3*25 mL). The organic layers were combined, dried (Na2SO4), and concentrated. Chromatography of the resulting residue (SiO2; 2 M NH3 in MeOH/DCM) gave the title compound (0.70 g, 93%). MS (ESI) mass calcd. for C25H32FN3O3, 441.24; m/z found, 442.4 [M+H]+. 1H NMR (CDCl3): 7.70 (d, J=7.3, 1H), 7.48-7.43 (m, 2H), 7.34-7.30 (m, 1H), 7.14-7.08 (m, 2H), 6.88-6.84 (m, 1H), 3.90 (s, 3H), 3.00 (s, 4H), 2.61-2.58 (m, 4H), 2.00-1.97 (m, 1H), 1.74-1.47 (m, 4H), 0.96-0.93 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: 3-hydroxy-1(3H)-isobenzofuranone With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile for 0.166667h; Stage #2: methyl iodide In acetonitrile at 20℃; for 4h; | |
With potassium carbonate In N,N-dimethyl-formamide at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With (S)-3-ethylisobenzofuran-1(3H)-one In hexane; toluene at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 50% 2: 50% | With 1,1-diethyl-3-(3'-indolyl)-(2S)-(N-methyl-N-3'',3''-dimethylbutylamino)-1-propanol In hexane; toluene at -15℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 16% 2: 13% | With 1,1-diethyl-3-(3'-indolyl)-(2S)-(N-methyl-N-3'',3''-dimethylbutylamino)-1-propanol In hexane; toluene at -15℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 69% 2: 20% | With 1,1-diethyl-3-(3'-indolyl)-(2S)-(N-methyl-N-3'',3''-dimethylbutylamino)-1-propanol In hexane; toluene at -15℃; for 10h; Inert atmosphere; optical yield given as %ee; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 12% 2: 43% | With 1,1-diethyl-3-(3'-indolyl)-(2S)-(N-methyl-N-3'',3''-dimethylbutylamino)-1-propanol; zinc(II) chloride In hexane; toluene at -15℃; for 10h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With bis(η3-allyl-μ-chloropalladium(II)); C27H30N2S(1+)*Cl(1-); cesium fluoride In toluene at 80℃; for 1h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With bis(η3-allyl-μ-chloropalladium(II)); C27H30N2S(1+)*Cl(1-); cesium fluoride In toluene at 80℃; for 1h; Inert atmosphere; | |
91% | With potassium phosphate; chloro(1,5-cyclooctadiene)rhodium(I) dimer In tetrahydrofuran at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Stage #1: ethyltriphenylphosphonium bromide With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 1h; Stage #2: methyl o-formylbenzoate In tetrahydrofuran at 20℃; for 6h; | 1.2 Preparation of intermediate ester (2) In a two-necked flask, 10.0 g of the phosphonium salt represented by the formula (P)6.0 g of potassium ter-butoxide ((CH 3) 3 COK, t-BuOK) was placed, and further 40 mL of tetrahydrofuran was added, followed by mixing and stirring at room temperature for 1 hour.After stirring,4.0 g of the intermediate ester (1) obtained in (1) and 20 ml of tetrahydrofuran were charged,And further mixed and stirred at room temperature for 6 hours.After stirring, hydrochloric acid was added to stop the reaction,After extraction three times with dichloromethane and three times with water,Ethyl acetate and hexane were separated by column chromatography using a developing solvent of ethyl acetate / hexane = 1/5,A yellow liquid of the intermediate ester (2) shown in the following formula (H-2) was obtained in a yield of 3.3 g in a yield of 77%. |
76% | Stage #1: ethyltriphenylphosphonium bromide With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 20℃; for 5h; Stage #2: methyl o-formylbenzoate In tetrahydrofuran at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; chlorobis(ethylene)rhodium(I) dimer; 4-methylphenylboronic acid In tetrahydrofuran at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium acetate; acetic anhydride at 100℃; for 4h; | Synthesis of 2-carboxymethylbenzaldehyde hippuric acid adduct: 2-Carboxymethylbenzaldehyde (4.9g, and 30mmoles) with hippuric acid (5.9g, 33moles) and potassium acetate (2.94g, 30mmoles) were added to acetic anhydride (14.2mls, 150mmoles) and the reaction heated (1000C) for 4 hours. To the cooled reaction was added water (100mls) and stirred overnight. The resulting solid was collected by filtration and washed with water and dried (7.6g, 83% yield). |
73% | With potassium acetate In acetic anhydride | |
50% | With sodium acetate; acetic anhydride at 100℃; for 3h; | Methyl 2-[(5-oxo-2-phenyloxazol-4(5H)-ylidene)methyl]benzoate (34). The mixture of 33(6.205 g, 37.8 mmol), hippuric acid (6.773 g, 37.8 mmol), acetic anhydride (10.72 mL, 113.4mmol), and sodium acetate (3.101 g, 37.8 mmol) was heated at 100 °C for 3 h. After cooleddown, water (50 mL) was added and extracted with DCM (30 mL 3). The combined organiclayers were washed with brine, dried over MgSO4 and filtered. The filtrate was concentratedunder reduced pressure. The residue was crystallized with EtOAc/PE to give 5.827 g yellowgreen solid, in 50% yield. 1H NMR (400 MHz, CDCl3) 8.68 (d, J = 7.84 Hz, 1H), 8.188.15 (m,2H), 8.13 (s, 1H), 8.00 (dd, J = 1.12 Hz, 7.8 Hz, 1H), 7.677.60 (m, 2H), 7.557.48 (m, 3H),3.95 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.27, 167.17, 164.44, 134.61, 133.69, 133.49,132.92, 131.95, 131.50, 130.78, 130.05, 129.56, 128.94 ( 2), 128.49 ( 2), 125.55, 52.49. |
50% | With sodium acetate; acetic anhydride at 100℃; for 3h; | Methyl 2-[(5-oxo-2-phenyloxazol-4(5H)-ylidene)methyl]benzoate(41) Themixture of 40 (6.205 g, 37.8 mmol),hippuric acid (6.773 g, 37.8 mmol), acetic anhydride (10.72 mL, 113.4 mmol),and sodium acetate (3.101 g, 37.8 mmol) was heated at 100 °C for 3 h. Aftercooled down, water (50 mL) was added and extracted with DCM (30 mL 3). The combined organic layers were washed with brine, dried over MgSO4and filtered. The filtrate was concentrated under reduced pressure. The residuewas crystallized with EtOAc/PE to give 5.827 g yellow green solid, in 50%yield. 1H NMR (400 MHz, CDCl3) d 8.68 (d, J = 7.84 Hz, 1H), 8.18-8.15(m, 2H), 8.13 (s, 1H), 8.00 (dd, J =1.12 Hz, 7.8 Hz, 1H), 7.67-7.60 (m, 2H), 7.55-7.48(m, 3H), 3.95 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.27, 167.17, 164.44, 134.61,133.69, 133.49, 132.92, 131.95, 131.50, 130.78, 130.05, 129.56, 128.94 (2), 128.49 ( 2), 125.55, 52.49 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With Oxone In water; N,N-dimethyl-formamide at 20℃; for 1h; | 16 To a solution of 4-(2-amino-pyrimidin-5-yl)-N1-ieri-butyl-benzene- l,2-diamine (300 mg ,1.17 mmol) in DMF (10 mL) is added methyl-2-formybenzoate (287 mg, 1.75 mmol) at room temperature. Oxone (717 mg, 1.17 mmol) in H20 (2 mL) is added and the solution is stirred for 1 hour. Saturated sodium thiosulfate solution (5 mL) is added and the mixture is extracted with EtOAc (3 x 10 mL) and H20 (10 mL). The combined organic layer is dried with MgS04 and is filtered. The filtrate is concentrated and the residue is purified by silica gel flash column chromatography with 10% MeOH in CH2C12 as the eluent to afford 2-[5-(2-amino-pyrimidin-5-yl)-l-ieri-butyl- lH-benzimidazol-2-yl]- benzoic acid methyl ester (320 mg, 68%) as a pale brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: triphenylboroxine; methyl o-formylbenzoate With [2,2]bipyridinyl; sodium acetate; copper(l) chloride In o-xylene at 135℃; Stage #2: With hydrogenchloride In o-xylene; water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium carbonate In acetonitrile at 20℃; for 48h; | 3.2. General procedure for the synthesis of isobenzofuranones General procedure: To a solution of aldehyde (50 mg, 0.31 mmol, 1 equiv) and potassium carbonate (12.6 mg, 0.093 mmol, 0.3 equiv) methylene active compounds (0.34 mmol, 1.1 equiv) were added dropwise. The mixture was stirred until starting material disappeared. Purification consists of a filtration on a short pad of silica gel with hexane/ethyl acetate mixtures to give the products 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With triethylamine | |
96% | With potassium carbonate at 20℃; for 12h; Neat (no solvent); | 3.2. General procedure for the synthesis of isobenzofuranones General procedure: To a solution of aldehyde (50 mg, 0.31 mmol, 1 equiv) and potassium carbonate (12.6 mg, 0.093 mmol, 0.3 equiv) methylene active compounds (0.34 mmol, 1.1 equiv) were added dropwise. The mixture was stirred until starting material disappeared. Purification consists of a filtration on a short pad of silica gel with hexane/ethyl acetate mixtures to give the products 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium carbonate at 20℃; for 12h; Neat (no solvent); | 3.2. General procedure for the synthesis of isobenzofuranones General procedure: To a solution of aldehyde (50 mg, 0.31 mmol, 1 equiv) and potassium carbonate (12.6 mg, 0.093 mmol, 0.3 equiv) methylene active compounds (0.34 mmol, 1.1 equiv) were added dropwise. The mixture was stirred until starting material disappeared. Purification consists of a filtration on a short pad of silica gel with hexane/ethyl acetate mixtures to give the products 3. |
99% | With triethylamine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride; In methanol; at 20℃; | To a solution of methyl 2-formylbenzoate (1.3 g) and Compound I (1.45 g) in methanol was added sodium triacetoxy borohydride (1.35 g), and the resulting mixture was stirred overnight. Then, the mixture was allowed to warm up to room temperature and was stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was diluted with aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was dehydrated with sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/1) to give Compound II (930 mg).1H-NMR (CDCl3) delta 1.52 (s, 9H), 1.68-1.72 (m, 4H), 2.05-2.09 (m, 2H), 2.50 (s, 2H), 4.21-4.43 (m, 5H), 7.47-7.52 (m, 3H), 7.83 (d, 1H, J=7.5 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With silver fluoride; (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl; In methanol; at -20℃; for 5h; | General procedure: Representative procedure C: synthesis of substituted (R)-3-allylisobenzofuran-1(3H)-one A round-bottomed flask wrapped in aluminum foil was charged with AgF (7.75 mg, 0.061 mmol), (R)-BINAP (22.8 g, 0.035 mmol), anhydrous MeOH (0.2 mL), and stirred for 10 min at room temperature. The mixture was cooled to -20 C (dry ice/xylene bath) followed by dropwise addition of methyl 2-formylbenzoate 7a (100 mg, 0.61 mmol) and <strong>[2551-83-9]allyltrimethoxysilane</strong> (154 muL, 0.91 mmol). After 4 h, the reaction mixture was quenched with a mixture of 1 N HCl (3 mL) and KF (ca. 0.3 g) and stirred for 30 min. The resulting precipitate was filtered and the filtrate was dried over MgSO4. After evaporation of the solvents in vacuum, the crude product was purified by column chromatography on silica gel (n-hexane/EtOAc: 1/1) to yield 8a as a colorless oil (72.1 mg, 68% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: 4-iodobenzonitrile With TurboGrignard In tetrahydrofuran at -70 - -50℃; for 0.5h; Stage #2: methyl o-formylbenzoate In tetrahydrofuran at 20℃; | 4.3 General procedure B General procedure: A three-necked, round-bottomed flask equipped with a septum, nitrogen inlet adapter, and thermocouple was charged with the iodopyridine (1equiv) and THF (15mL per 1g of iodopyridine). The reaction mixture was cooled at -50 to -70°C while a solution of isopropylmagnesium chloride-lithium chloride (1.3M, 1.1-1.3equiv) was added and the reaction mixture stirred for 30min. The aldehyde or ketone (1.0-1.3equiv) was added in one portion and the reaction mixture was warmed to room temperature. After complete cyclization, water was added and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (EtOAc/hexanes) to give the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With trimethylsilylazide In methanol at 25℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.3% | Stage #1: methyl o-formylbenzoate; phenylmagnesium bromide In tetrahydrofuran at -40 - 0℃; for 1h; Stage #2: With trifluoroacetic acid In tetrahydrofuran at 25℃; for 1.5h; | General Procedure A: Synthesis of Symmetrical Diarylisobenzofuran General procedure: To a solution of methyl 2-formylbenzoate (50.5 mg, 0.308 mmol) in THF (2.0 mL) was added PhMgBr (1.0 M in THF, 0.72 mL, 0.72 mmol) at -40 °C, and the reaction was warmed to 0 °C. After 1 h, CF3CO2H (181 mg, 1.59 mmol) in THF (1 mL) was added to the mixture, and the reaction was stirred at 25 °C for further 1.5 h. The reaction was stopped by adding sat. aq. NaHCO3. The products were extracted with EtOAc (X3), washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by PTLC (hexane/Et2O = 9/1) to gived iphenylisobenzofuran 3a (70.9 mg, 85.3%). Recrystallization from hexane/EtOAc gave 3a as yellow needles. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran at -40 - 0℃; for 2h; | General Procedure B: Synthesis of Unsymmetrical Diarylisobenzofuran General procedure: To a solution of methyl 2-formylbenzoate (49.5 mg, 0.302 mmol) in THF (2.0 mL) was added PhMgBr (1.1 M in THF, 0.31 mL, 0.34 mmol) at -40 °C, and the reaction was warmed to 0 °C. After 2 h, (4-fluorophenyl)magnesium bromide (1.0 M in THF, 0.40 mL, 0.40 mmol) was added to the reaction mixture at -40 °C, and the reaction was warmed to 0 °C. After 45 min, CF3CO2H (193 mg, 1.69 mmol) in THF (1 mL) was added to the reaction mixture, and the reaction was stirred at 25 °C for 30 min. The reaction was stopped by adding sat. aq. NaHCO3. The products were extracted with EtOAc (X3), washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by PTLC (hexane/Et2O = 9/1) to give diarylisobenzofuran 4a (65.5 mg, 75.4%). Recrystallization from hexane/EtOAc gave 4a as yellow prisms. | |
In tetrahydrofuran at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.9% | Stage #1: methyl o-formylbenzoate; 4-methoxyphenyl magnesium bromide In tetrahydrofuran at -40 - 0℃; for 1h; Stage #2: With trifluoroacetic acid In tetrahydrofuran at 25℃; for 1.5h; | General Procedure A: Synthesis of Symmetrical Diarylisobenzofuran General procedure: To a solution of methyl 2-formylbenzoate (50.5 mg, 0.308 mmol) in THF (2.0 mL) was added PhMgBr (1.0 M in THF, 0.72 mL, 0.72 mmol) at -40 °C, and the reaction was warmed to 0 °C. After 1 h, CF3CO2H (181 mg, 1.59 mmol) in THF (1 mL) was added to the mixture, and the reaction was stirred at 25 °C for further 1.5 h. The reaction was stopped by adding sat. aq. NaHCO3. The products were extracted with EtOAc (X3), washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by PTLC (hexane/Et2O = 9/1) to gived iphenylisobenzofuran 3a (70.9 mg, 85.3%). Recrystallization from hexane/EtOAc gave 3a as yellow needles. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.3% | Stage #1: methyl o-formylbenzoate; 2-methoxyphenylmagnesium bromide In tetrahydrofuran at -40 - 0℃; for 1h; Stage #2: With trifluoroacetic acid In tetrahydrofuran at 25℃; for 1.5h; | General Procedure A: Synthesis of Symmetrical Diarylisobenzofuran General procedure: To a solution of methyl 2-formylbenzoate (50.5 mg, 0.308 mmol) in THF (2.0 mL) was added PhMgBr (1.0 M in THF, 0.72 mL, 0.72 mmol) at -40 °C, and the reaction was warmed to 0 °C. After 1 h, CF3CO2H (181 mg, 1.59 mmol) in THF (1 mL) was added to the mixture, and the reaction was stirred at 25 °C for further 1.5 h. The reaction was stopped by adding sat. aq. NaHCO3. The products were extracted with EtOAc (X3), washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by PTLC (hexane/Et2O = 9/1) to gived iphenylisobenzofuran 3a (70.9 mg, 85.3%). Recrystallization from hexane/EtOAc gave 3a as yellow needles. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.7% | Stage #1: methyl o-formylbenzoate; 4-flourophenylmagnesium bromide In tetrahydrofuran at -40 - 0℃; for 1h; Stage #2: With trifluoroacetic acid In tetrahydrofuran at 25℃; for 1.5h; | General Procedure A: Synthesis of Symmetrical Diarylisobenzofuran General procedure: To a solution of methyl 2-formylbenzoate (50.5 mg, 0.308 mmol) in THF (2.0 mL) was added PhMgBr (1.0 M in THF, 0.72 mL, 0.72 mmol) at -40 °C, and the reaction was warmed to 0 °C. After 1 h, CF3CO2H (181 mg, 1.59 mmol) in THF (1 mL) was added to the mixture, and the reaction was stirred at 25 °C for further 1.5 h. The reaction was stopped by adding sat. aq. NaHCO3. The products were extracted with EtOAc (X3), washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by PTLC (hexane/Et2O = 9/1) to gived iphenylisobenzofuran 3a (70.9 mg, 85.3%). Recrystallization from hexane/EtOAc gave 3a as yellow needles. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.9% | Stage #1: methyl o-formylbenzoate; thiophen-2-yl magnesium bromide In tetrahydrofuran at -40 - 0℃; for 1h; Stage #2: With trifluoroacetic acid In tetrahydrofuran at 25℃; for 1.5h; | General Procedure A: Synthesis of Symmetrical Diarylisobenzofuran General procedure: To a solution of methyl 2-formylbenzoate (50.5 mg, 0.308 mmol) in THF (2.0 mL) was added PhMgBr (1.0 M in THF, 0.72 mL, 0.72 mmol) at -40 °C, and the reaction was warmed to 0 °C. After 1 h, CF3CO2H (181 mg, 1.59 mmol) in THF (1 mL) was added to the mixture, and the reaction was stirred at 25 °C for further 1.5 h. The reaction was stopped by adding sat. aq. NaHCO3. The products were extracted with EtOAc (X3), washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by PTLC (hexane/Et2O = 9/1) to gived iphenylisobenzofuran 3a (70.9 mg, 85.3%). Recrystallization from hexane/EtOAc gave 3a as yellow needles. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | Stage #1: methyl o-formylbenzoate; 4-dimethylaminophenylmagnesium bromide In tetrahydrofuran at -40 - 0℃; for 2h; Stage #2: With trifluoroacetic acid In tetrahydrofuran at 25℃; for 0.5h; | Synthesis of isobenzofuran 1a To a solution of o-formyl benzoate 5 (50.1 mg, 0.305 mmol) in THF (2.0 mL) was added [p-(N,N-dimethylamino)phenyl]magnesium bromide 6 (0.50 M in THF, 2.0 mL, 1.0mmol) at -40 °C, and the reaction was gradually warmed to 0 °C. After stirring for 2 h, trifluoroacetic acid (0.24 mL, 3.2 mmol) was added to the reaction mixture, and the reactionwas further stirred for 30 min at 25 °C. The precipitates were filtered to give an orange solid,which were dissolved with CHCl3, washed with sat. aq. NaHCO3 and brine, and dried over Na2SO4. Evaporation of solvents gave essentially pure isobenzofuran 1a (68.1 mg, 63%). [1]Rf 0.30 (hexane/EtOAc = 9/1);Mp 143-145 °C (hexane/EtOAc);1H NMR (d6-acetone, 500 MHz) 3.02 (s, 12H), 6.88-6.93 (m, 6H), 7.78-7.84 (m, 6H);13C NMR (d6-acetone, 125 MHz) 40.4, 113.5, 120.9, 121.0, 121.2, 124.9, 126.2, 143.9, 150.3;IR (ATR, cm-1) 2886, 1606, 1509, 1441, 1351, 1168, 1061, 938, 809, 739, 651;HRMS (MALDI, TCNQ matrix) calcd for C24H24N2O [M]+ 356.1883; found 356.1895. |
62.6% | Stage #1: methyl o-formylbenzoate; 4-dimethylaminophenylmagnesium bromide In tetrahydrofuran at 0℃; for 2h; Stage #2: With trifluoroacetic acid In tetrahydrofuran at 25℃; for 0.5h; | A-1 Synthesis of diarylisobenzofuran 1a: To a solution of 2-formylbenzoate (50.1 mg, 0.305 mmol) in THF (2.0 mL) was added (4-dimethylaminophenyl)magnesium bromide (0.50 M in THF, 2.0 mL, 1.0 mmol) at -40 °C, and the reaction was stirred at 0 °C. After 2 h, CF3CO2H (0.24 mL, 3.2 mmol) was added to the reaction mixture, and the reaction was further stirred for 30 min at 25 °C. The product was gradually precipitated, and the reaction mixture was filtered to give orange solids, which were dissolved with CHCl3, washed with NaHCO3 aq. and brine, and dried (Na2SO4). Evaporation of the solvents gave essentially pure diarylisobenzofuran 1a (68.1 mg, 62.6 %). Recrystallization from hexane/EtOAc gave 1a as orange needles. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With BDMS In acetonitrile at 20℃; | 5.2.1. 2-(1,3-Diethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)benzoate (3) BDMS (0.101 g, 0.451 mmol, 0.9 equiv) was added to a stirringsolution of 1,3-diethyl-5,6-aminouracil 2 (0.100 g, 0.504 mmol,1.0 equiv) and methyl 2-formylbenzoate (0.070 mL, 0.504 mmol,1.0 equiv) in acetonitrile (10 mL). The reaction was stirred at roomtemperature overnight. The reaction mixture was concentrated invacuo and the resulting residue was purified via silica gel chromatography(9:1 hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate)to afford the product as a white crystalline solid (0.099 g, 57%).Mp = 198-201 C; 1H NMR (500 MHz, DMSO-d6): d 13.86 (br s,1H), 7.86 (d, J = 7.0 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.67 (d,J = 8.0 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 4.03 (q, J = 7.0 Hz, 2H), 3.95(q, J = 7.5 Hz, 2H), 1.24 (t, J = 7.0 Hz, 3H), 1.15 (t, J = 7.5 Hz, 3H);13C NMR (100 MHz, DMSO-d6): d 168.8, 154.6, 152.6, 152.4,150.8, 148.1, 132.9, 131.8, 130.0, 129.6, 108.5, 52.9, 38.7, 36.5,13.9, 13.8; HRMS (ESI) m/z C17H18N4O4 (M+H)+ calcd 343.1403,obsd 343.1406. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With sodium formate; In N,N-dimethyl-formamide; at 110℃; under 760.051 Torr; for 8h; | General procedure: A 50 mL round-bottomed flask, equipped with a gas inlet tube, a refluxcondenser and a magnetic stirring bar was charged with MCM-41-2PPdCl2 (102 mg, 0.05 mmol Pd), aryl halide (5.0 mmol) and HCOONa(7.5 mmol). The flask was flushed with CO. DMF (5 mL) was addedby syringe and a slow stream of CO was passed into the suspension.The mixture was vigorously stirred at 110-130 C for 2-20 h, cooledto room temperature and diluted with diethyl ether (50 mL). Thepalladium catalyst was separated from the mixture by filtration,washed with distilled water (2 × 10 mL), ethanol (2 × 10 mL) and ether(2 × 10 mL) and reused in the next run. The ethereal solution waswashed with water (3 × 20 mL), and dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (hexane-ethylacetate = 10 : 1). |
80% | With sodium formate; In N,N-dimethyl-formamide; at 100℃; under 760.051 Torr; for 20h; | General procedure: A 50mL round-bottomed flask equipped with a gas inlet tube, a reflux condenser, and a magnetic stirring bar was charged with MCM-41-S-PdCl2 (173mg, 0.05 mmol Pd), aryl halide (5.0 mmol) and HCOONa (7.5 mmol). The flask was flushed with carbon monoxide. DMF (5 mL) was added by syringe and a slow stream of CO was passed into the suspension. The mixture was vigorously stirred at 100-110C for 4-24h, cooled to room temperature, and diluted with diethyl ether (50 mL). The palladium catalyst was separated from the mixture by filtration, washed with distilled water (2×10 mL), ethanol (2×10 mL) and ether (2×10 mL) and reused in the next run. The ethereal solution was washed with water (3×20mL) and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexane-ethyl acetate=10:1). (0008) All formylation products were characterized by comparison of their spectra and physical data with authentic samples. IR spectra were determined on a Perkin-Elmer 683 instrument. 1H NMR (400MHz) and 13C NMR (100MHz) spectra were recorded on a Bruker Avance 400MHz spectrometer with TMS as an internal standard and CDCl3 as solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: [(4S)-4-methyl-2-oxo-1,3-oxazolidin-4-yl]methyl}(triphenyl)phosphonium iodide With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Stage #2: methyl o-formylbenzoate In tetrahydrofuran; hexane at -78 - 20℃; for 2h; diastereoselective reaction; | 4.2.7. (4R)-4-Methyl-4-[(E)-2-phenylethenyl]-1,3-oxazolidin-2-one(9a) and (4S)-4-(diphenylphosphorylmethyl)-4-methyl-oxazolidin-2-one (13eo) General procedure: 4.2.7. (4R)-4-Methyl-4-[(E)-2-phenylethenyl]-1,3-oxazolidin-2-one(9a) and (4S)-4-(diphenylphosphorylmethyl)-4-methyl-oxazolidin-2-one (13eo). Typical procedure of a Wittig reaction: To a suspensionof the phosphonium salt (13) (500 mg, 1.0 mmol, 2.0 equiv) in THF(5 mL) was added n-butyllithium (1.9 M in hexane, 1.0 mL,1.95 mmol, 3.9 equiv) at 78 C and then the solution was stirredfor 30 min at the same temperature. After the addition of benzaldehyde(54 mg, 0.5 mmol,1.0 equiv) at 78 C, the reaction mixturewas gradually warmed to ambient temperature and stirred for 2 h.After quenching with saturated aq NH4Cl (10 mL), the resultingbiphasic mixture was extracted with AcOEt (10 mL2). The combinedorganic layer was washed with water (10 mL) and brine(10 mL), dried over Na2SO4, filtered, and evaporated. Purification bysilica gel column chromatography (hexane:AcOEt3:1 to 1:1)provided 9a (101 mg, 99% yield, 98.6% ee) as a white solid, and 13-o(156 mg, 99% yield) as a white solid. The enantiomeric excess of 9awas determined by HPLC analysis by using the following condition.DAICEL CHIRALCEL IA column (4.6f150 mm), hexane:EtOH95:5(0 min)d50:50 (8.0 min), flow rate: 2.0 ml/min, temperature:25.0 C. The retention times of (S)-9a and (R)-9a were 4.6 min and5.3 min, respectively. (Compound 9a) mp: 155.6 C; [a]D20 61.0 (c0.27, CH3OH); 1H NMR (500 MHz, CDCl3) d ppm: 1.53 (s, 3H), 4.17 (d,1H, J8.3 Hz), 4.23 (d, 1H, J8.3 Hz), 5.09 (s, 1H), 6.21 (d, 1H,J16.1 Hz), 6.59 (d, 1H, J16.1 Hz), 7.26e7.36 (m, 5H); 13C NMR(126 MHz, CDCl3) d ppm; 25.6, 58.5, 76.5, 126.7, 128.3, 128.7, 130.1,131.2, 135.7, 159.0; IR (KBr) cm1: 3293, 1756, 1710, 1393, 1288, 1171,1042, 967, 751, 659; MS (ESI) m/z: 203 (M); Anal. Calcd forC12H13NO2: C, 70.92; H, 6.45; N, 6.89. Found: C, 70.80; H, 6.49; N,6.83. (Compound 13-o) mp: 181.4 C; [a]D20 9.1 (c 0.41, CH3OH); 1HNMR (500 MHz, CDCl3) d ppm: 1.34 (s, 3H), 4.09 (d, 1H, J8.8 Hz), 2.60e2.78 (m, 2H), 4.21 (d, 1H, J8.8 Hz), 6.44 (br s, 1H), 7.46e7.57(m, 5H), 7.67e7.71 (m, 2H), 7.78e7.82 (m, 2H); 13C NMR (126 MHz,CDCl3) d ppm; 26.7, 39.9 (d, J69.1 Hz), 57.3 (d, J4.8 Hz), 77.4 (d,J12.5 Hz), 128.9 (d, J3.6 Hz), 129.0 (d, J3.6 Hz), 130.3 (d,J9.5 Hz), 130.6 (d, J9.5 Hz), 132.2, 132.3, 132.8 (d, J90.6 Hz),133.6 (d, J93.0 Hz), 157.7; IR (KBr) cm1: 3308, 1758, 1439, 1255,1175, 1034, 930, 752, 699; HRMS (ESI): calcd for C17H19NO3P[MH] 316.1103; found 316.1105 |
75% | Stage #1: [(4S)-4-methyl-2-oxo-1,3-oxazolidin-4-yl]methyl}(triphenyl)phosphonium iodide With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Stage #2: methyl o-formylbenzoate In tetrahydrofuran; hexane at -78 - 20℃; for 2h; stereoselective reaction; | 4.2.7. (4R)-4-Methyl-4-[(E)-2-phenylethenyl]-1,3-oxazolidin-2-one(9a) and (4S)-4-(diphenylphosphorylmethyl)-4-methyl-oxazolidin-2-one (13-o). General procedure: Typical procedure of a Wittig reaction: To a suspension of the phosphonium salt (13) (500 mg, 1.0 mmol, 2.0 equiv) in THF(5 mL) was added n-butyllithium (1.9 M in hexane, 1.0 mL,1.95 mmol, 3.9 equiv) at 78 C and then the solution was stirred for 30 min at the same temperature. After the addition of benzaldehyde(54 mg, 0.5 mmol,1.0 equiv) at 78 C, the reaction mixture was gradually warmed to ambient temperature and stirred for 2 h. After quenching with saturated aq NH4Cl (10 mL), the resulting biphasic mixture was extracted with AcOEt (10 mL2). The combined organic layer was washed with water (10 mL) and brine(10 mL), dried over Na2SO4, filtered, and evaporated. Purification bysilica gel column chromatography (hexane:AcOEt3:1 to 1:1)provided 9a (101 mg, 99% yield, 98.6% ee) as a white solid, and 13-o(156 mg, 99% yield) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (R)-3,3'-bis(2,4,6-triisopropylphenyl)binol phosphoric acid In toluene at 25℃; for 24h; Molecular sieve; Inert atmosphere; Overall yield = 40 %; Overall yield = 8.9 mg; Optical yield = 29 %ee; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.3 g | To a suspension of(methoxymethyl)triphenylphosphonium bromide (9.44 g, 27.4mmol) in THF (50 mL) was added NaH (1.46 g, 36.6 mmol) at 0 C portion wise. The mixture was stirred at 0 C for 0.5 hand then a solution ofmethyl2-formylbenzoate (3.0 g, 18.3 mmol)in THF (15 mL) added dropwise and the reaction mixture stirred at RT for 12 h. The mixturewas diluted with water, extracted with EtOAc (30 mL x 2) and the combined organic layerswashed with brine, dried over MgS04, filtered, and concentrated in vacuo. The residue was5 purified by chromatography on silica (petroleum ether: EtOAc = 10: 1 to 3: 1) to give the titlecompound (2.3 g) as a colorless oil. | |
2.3 g | To a suspension of (methoxymethyl)triphenylphosphonium bromide (9.44 g, 27.4 mmol) in THF (50 mL) was added NaH (1.46 g, 36.6 mmol) at 0 C portion wise. The mixture was stirred at 0 C for 0.5 h and then a solution of methyl 2-formylbenzoate (3.0 g, 18.3 mmol) in THF (15 mL) added dropwise and the reaction mixture stirred at RT for 12 h. The mixture was diluted with water, extracted with EtOAc (30 mL x 2) and the combined organic layers washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica (petroleum ether: EtOAc = 10: 1 to 3: 1) to give the title compound (2.3 g) as a colorless oil. | |
To a suspension of (methoxymethyl)triphenylphosphoniumbromide (9.44 g, 27.4 mmol) in THF (50 mL) was added NaH (1.46 g,36.6 mmol) at 0C portion wise. The mixture was stirred at 0C for 0.5 h and then a solution of methyl 2-formylbenzoate (3.0 g, 18.3mmol) in THF (15 mL) added dropwise and the reaction mixture stirred at RT for 12 h. The mixture was diluted with water, extracted with EtOAc (30 mL x 2) and the combined organic layers washed with brine, dried over MgSO4, filtered, and concentrated invacuo. The residue was purified by chromatography on silica (petroleum ether: EtOAc = 10:1 to 3:1) to give the title compound as an oil. |
To a suspension of (methoxymethyl)triphenylphosphonium bromide (9.44 g, 27.4mmol) in THF (50 mL) was added NaH (i.46 g, 36.6 mmol) at 0 C portion wise. The mixturewas stirred at 0 C for 0.5 h. Then a solution of methyl 2-formylbenzoate (3.0 g, 18.3 mmol) in THF (15 mL) was added dropwise and the reaction mixture was stirred at RT for i2 h. The mixture was diluted with water and extracted with EtOAc (30 mL x 2). The combined organic layers was washed with brine, dried over Mg504, filtered, and concentrated in vacuo. Theresidue was purified by chromatography on silica (petroleum ether: EtOAc = 10: ito 3:1) to give the title compound. | ||
Intermediate L Step 1 : (EVMethyl 2-(2-methoxyvinyl)benzoate (LI) To a suspension of (methoxymethyl)triphenylphosphonium bromide (9.44 g, 27.4 mmol) in THF (50 mL) was added NaH (1.46 g, 36.6 mmol) at 0 C portion wise. The mixture was stirred at 0 C for 0.5 h. Then a solution of methyl 2-formylbenzoate (3.0 g, 18.3 mmol) in THF (15 mL) was added dropwise and the reaction mixture was stirred at RT for 12 h. The mixture was diluted with water and extracted with EtOAc (30 mL x 2). The combined organic layers was washed with brine, dried over MgSC>4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica (petroleum ether: EtOAc = 10: 1 to 3: 1) to give the title compound. | ||
To a suspension of (methoxymethyl)triphenylphosphonium bromide (9.44 g, 27.4 mmol) in THF (50 mL) was added NaH (1.46 g, 36.6 mmol) at 0 C portion wise. The mixture was stirred at 0 C for 0.5 h and then a solution of methyl 2-formylbenzoate (3.0 g, 18.3 mmol) in THF(15 mL) added dropwise and the reaction mixture stirred at room temperature for 12 h. The mixture was diluted with water, extracted with EtOAc (30 mL x 2) and the combined organic layers washed with brine, dried over Mg504, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 10:1 to 3:1) to give F las an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: methyl o-formylbenzoate; (E)-4-[2-(3,4-dimethoxyphenyl)ethenyl]aniline With sodium sulfate In ethanol at 20℃; for 3h; Stage #2: With sodium tetrahydroborate In ethanol at 0℃; for 1h; | 4.1.3.14 (E)-methyl 2-((4-(3,4-dimethoxystyryl)phenylamino)methyl)benzoate (12) Compound 4b (2 mmol) and compound 11 (2 mmol) were dissolved in ethanol, and the resulting mixture was stirred at room temperature for 3 h NaBH4 was then added at 0 °C. After the mixture was stirred for 1 h, water (10 mL) was added, and the mixture was extracted with ethyl acetate. The solvents were removed under reduced pressure to obtain the crude product, which was purified by recrystallisation or flash chromatography on silica gel to provide 12. Yellow solid, yield 65%. 1H NMR (400MHz, DMSO-d6) δ 7.84 (d, J=7.4 Hz, 1H), 7.51 (dd, J=6.5, 1.2Hz, 2H), 7.35 (s, 1H), 7.24 (d, J=8.6Hz, 2H), 7.10 (d, J=1.8Hz, 1H), 6.99-6.91 (m, 1H), 6.91-6.84 (m, 2H), 6.79 (d, J=16.3Hz, 1H), 6.51 (d, J=8.5Hz, 2H), 4.59 (d, J=4.8Hz, 2H), 3.83 (s, 3H), 3.77 (s, 3H), 3.72 (s, 3H). LC-MS(ESI): 404.0M+H+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With scandium tris(trifluoromethanesulfonate) In ethanol at 20℃; for 7h; | General procedure to prepare N-substituted 3-oxoisoindoline-1-carbonitrile derivatives General procedure: Methyl 2-formylbenzoate (0.5 mmol), amine (0.5 mmol), TMSCN (1.0 mmol) and 2.5 mol% Sc(OTf)3 were dissolved in EtOH (1 mL), and the homogeneous solution was stirred at room temperature for 7 h. After completing the reaction (judged by running TLC), the mixture was concentrated in vacuo and the crude product was purified over silica gel by column chromatography (20-30% EtOAc in hexane). |
93% | Stage #1: methyl o-formylbenzoate; 4-methoxy-aniline With zinc trifluoromethanesulfonate In chloroform at 25℃; Inert atmosphere; Stage #2: trimethylsilyl cyanide In chloroform at 25℃; for 12h; Inert atmosphere; Stage #3: With trifluoroacetic acid In chloroform Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With scandium tris(trifluoromethanesulfonate) In ethanol at 20℃; for 7h; | General procedure to prepare N-substituted 3-oxoisoindoline-1-carbonitrile derivatives General procedure: Methyl 2-formylbenzoate (0.5 mmol), amine (0.5 mmol), TMSCN (1.0 mmol) and 2.5 mol% Sc(OTf)3 were dissolved in EtOH (1 mL), and the homogeneous solution was stirred at room temperature for 7 h. After completing the reaction (judged by running TLC), the mixture was concentrated in vacuo and the crude product was purified over silica gel by column chromatography (20-30% EtOAc in hexane). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With scandium tris(trifluoromethanesulfonate) In ethanol at 20℃; for 7h; | General procedure to prepare N-substituted 3-oxoisoindoline-1-carbonitrile derivatives General procedure: Methyl 2-formylbenzoate (0.5 mmol), amine (0.5 mmol), TMSCN (1.0 mmol) and 2.5 mol% Sc(OTf)3 were dissolved in EtOH (1 mL), and the homogeneous solution was stirred at room temperature for 7 h. After completing the reaction (judged by running TLC), the mixture was concentrated in vacuo and the crude product was purified over silica gel by column chromatography (20-30% EtOAc in hexane). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With scandium tris(trifluoromethanesulfonate) In ethanol at 20℃; for 7h; | General procedure to prepare N-substituted 3-oxoisoindoline-1-carbonitrile derivatives General procedure: Methyl 2-formylbenzoate (0.5 mmol), amine (0.5 mmol), TMSCN (1.0 mmol) and 2.5 mol% Sc(OTf)3 were dissolved in EtOH (1 mL), and the homogeneous solution was stirred at room temperature for 7 h. After completing the reaction (judged by running TLC), the mixture was concentrated in vacuo and the crude product was purified over silica gel by column chromatography (20-30% EtOAc in hexane). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With scandium tris(trifluoromethanesulfonate) In ethanol at 20℃; for 7h; | General procedure to prepare N-substituted 3-oxoisoindoline-1-carbonitrile derivatives General procedure: Methyl 2-formylbenzoate (0.5 mmol), amine (0.5 mmol), TMSCN (1.0 mmol) and 2.5 mol% Sc(OTf)3 were dissolved in EtOH (1 mL), and the homogeneous solution was stirred at room temperature for 7 h. After completing the reaction (judged by running TLC), the mixture was concentrated in vacuo and the crude product was purified over silica gel by column chromatography (20-30% EtOAc in hexane). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With scandium tris(trifluoromethanesulfonate) In ethanol at 20℃; for 7h; | General procedure to prepare N-substituted 3-oxoisoindoline-1-carbonitrile derivatives General procedure: Methyl 2-formylbenzoate (0.5 mmol), amine (0.5 mmol), TMSCN (1.0 mmol) and 2.5 mol% Sc(OTf)3 were dissolved in EtOH (1 mL), and the homogeneous solution was stirred at room temperature for 7 h. After completing the reaction (judged by running TLC), the mixture was concentrated in vacuo and the crude product was purified over silica gel by column chromatography (20-30% EtOAc in hexane). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With scandium tris(trifluoromethanesulfonate) In ethanol at 20℃; for 7h; | General procedure to prepare N-substituted 3-oxoisoindoline-1-carbonitrile derivatives General procedure: Methyl 2-formylbenzoate (0.5 mmol), amine (0.5 mmol), TMSCN (1.0 mmol) and 2.5 mol% Sc(OTf)3 were dissolved in EtOH (1 mL), and the homogeneous solution was stirred at room temperature for 7 h. After completing the reaction (judged by running TLC), the mixture was concentrated in vacuo and the crude product was purified over silica gel by column chromatography (20-30% EtOAc in hexane). |
82% | Stage #1: methyl o-formylbenzoate; 2-methoxy-phenylamine With zinc trifluoromethanesulfonate In chloroform at 20℃; Inert atmosphere; Stage #2: trimethylsilyl cyanide In chloroform at 20℃; for 12h; Inert atmosphere; Stage #3: With trifluoroacetic acid In chloroform Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With scandium tris(trifluoromethanesulfonate); In ethanol; at 20℃; for 7h; | General procedure: Methyl 2-formylbenzoate (0.5 mmol), amine (0.5 mmol), TMSCN (1.0 mmol) and 2.5 molpercent Sc(OTf)3 were dissolved in EtOH (1 mL), and the homogeneous solution was stirred at room temperature for 7 h. After completing the reaction (judged by running TLC), the mixture was concentrated in vacuo and the crude product was purified over silica gel by column chromatography (20?30percent EtOAc in hexane). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With scandium tris(trifluoromethanesulfonate) In ethanol at 20℃; for 7h; | General procedure to prepare N-substituted 3-oxoisoindoline-1-carbonitrile derivatives General procedure: Methyl 2-formylbenzoate (0.5 mmol), amine (0.5 mmol), TMSCN (1.0 mmol) and 2.5 mol% Sc(OTf)3 were dissolved in EtOH (1 mL), and the homogeneous solution was stirred at room temperature for 7 h. After completing the reaction (judged by running TLC), the mixture was concentrated in vacuo and the crude product was purified over silica gel by column chromatography (20-30% EtOAc in hexane). |
92% | Stage #1: methyl o-formylbenzoate; benzylamine With indium(III) triflate In chloroform at 20℃; Inert atmosphere; Stage #2: trimethylsilyl cyanide In chloroform at 20℃; for 12h; Inert atmosphere; Stage #3: With trifluoroacetic acid In chloroform Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With scandium tris(trifluoromethanesulfonate) In ethanol at 20℃; for 7h; | General procedure to prepare N-substituted 3-oxoisoindoline-1-carbonitrile derivatives General procedure: Methyl 2-formylbenzoate (0.5 mmol), amine (0.5 mmol), TMSCN (1.0 mmol) and 2.5 mol% Sc(OTf)3 were dissolved in EtOH (1 mL), and the homogeneous solution was stirred at room temperature for 7 h. After completing the reaction (judged by running TLC), the mixture was concentrated in vacuo and the crude product was purified over silica gel by column chromatography (20-30% EtOAc in hexane). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With scandium tris(trifluoromethanesulfonate) In ethanol at 20℃; for 7h; | General procedure to prepare N-substituted 3-oxoisoindoline-1-carbonitrile derivatives General procedure: Methyl 2-formylbenzoate (0.5 mmol), amine (0.5 mmol), TMSCN (1.0 mmol) and 2.5 mol% Sc(OTf)3 were dissolved in EtOH (1 mL), and the homogeneous solution was stirred at room temperature for 7 h. After completing the reaction (judged by running TLC), the mixture was concentrated in vacuo and the crude product was purified over silica gel by column chromatography (20-30% EtOAc in hexane). |
Tags: 4122-56-9 synthesis path| 4122-56-9 SDS| 4122-56-9 COA| 4122-56-9 purity| 4122-56-9 application| 4122-56-9 NMR| 4122-56-9 COA| 4122-56-9 structure
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