| 89% |
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In chloroform; for 16h;Heating / reflux; |
Example 53 2-(Oxalyl-amino)-5-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid; 2-Methyl-benzoic acid methyl ester (1.50 g 10 mmol), N-bromosuccinimide (1.96 g, 11 mmol) and 2,2'-azobis(2-methylpropionitrile) (AIBN) (25 mg, 0.15 mmol) were dissolved in chloroform (3 ml). The solution was heated at reflux for 16 h. cooled and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using a gradient of ethyl acetate/hexane (1-2%) as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 2.05 g (89%) of 2-bromomethyl-benzoic acid methyl ester as a solid.1H NMR (CDCl3): delta 7.97 (d, 1H, J=7.6 Hz), 7.45-7.52 (m, 2H), 7.38 (dt, 1H, J=1.2, 7.6 Hz), 4.96 (s, 2H), 3.95 (s, 1H).To a solution of 2-amino-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester (100 mg, 0.20 mmol) and pyridine (0.18 ml, 2.0 mmol) in acetonitrile (1 ml) at room temperature was added benzyl chloroformate (0.28 ml, 2.0 mmol) in 10 aliquots over 48 h. The solution was then taken into ethyl acetate (30 ml), washed with 0.5 N hydrochloric acid (3×10 ml), saturated sodium bicarbonate (3×10 ml), brine (10 ml), dried (MgSO4) and filtered. The solvent was evaporated in vacuo. The resulting oil crystallized upon standing for 2 days. The precipitate was filtered off and washed with diethyl ether (3×1 ml) affording after drying in vacuo 59 mg (47,%) of 2-benzyloxy-carbonylamino-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester as a solid.1H NMR (CDCl3): delta 10.60 (s, 1H), 7.60-7.92 (m, 4H), 7.38 (m, 5H), 5.26 (s, 2H), 4.30-5.10 (m, 3H), 3.40-4.00 (m, 2H), 1.57 (m, 9H), 1.15 (m, 9H).To a solution of 1N hydrochloric acid in ethyl acetate (1.0 ml) was added 2-benzyloxy-carbonylamino-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester (52 mg, 0.08 mmol). The solution was stirred at room temperature for 48 h. A precipitate was filtered off which afforded 42 mg (90%) of 2-benzyloxy-carbonylamino-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester hydrochloride as a solid.1H NMR (DMSO-d6): 810.45 (s, 1H), 9.40 (s, 1H), 9.25 (s, 1H), 7.89 (m, 4H), 7.39 (m, 5H), 5.22 (s, 2H), 4.39 (d, 1H, J=15 Hz), 4.28 (m, 1H), 3.95 (m, 2H), 3.79 (m, 1H), 3.20 (m, 1H), 2.70 (m, 1H), 1.48 (s, 9H).To a solution of the above 2-benzyloxy-carbonylamino-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester hydrochloride (42 mg, 0.072 mmol) in ethanol (0.5 ml) was added hydrazine (68 mul, 0.22 mmol). The solution was stirred at 80 C. for 5 h. and at room temperature for 16 h. The mixture was filtered and the filtrate evaporated in vacuo. The residue was extracted with dichloromethane (5×1 ml). The combined dichloromethane washes were evaporated in vacuo affording 20 mg (67%) of 5-aminomethyl-2-benzyloxy-carbonylamino-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.1H NMR (CDCl3): delta 10.55 (bs, 1H), 7.37 (m, 5H), 5.23 (s, 2H), 3.92 (s, 2H), 2.60-3.10 (m, 3H), 1.53 (s, 9H).To a solution of the above 5-aminomethyl-2-benzyloxy-carbonylamino-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (20 mg, 0.048 mmol) in acetonitrile (1 ml) at 0 C. was added diisopropylethylamine (18 mul, 0.15 mmol) and 2-bromomethyl-benzoic acid methyl (12 mg, 0.048 mmol). The solution was stirred at 0 C. for 3 hours and at room temperature for 16 h. Di-tert-butyl dicarbonate (21 mg, 0.096 mmol) was then added to the solution. The solution was then stirred at room temperature for 16 h. The solution was taken into ethyl acetate (30 ml), washed with 0.5 N hydrochloric acid (3×10 ml), saturated sodium bicarbonate (3×10 ml) and brine (10 ml), dried (MgSO4) and filtered. The solvent was evaporated in vacuo. The solid residue was purified by silica gel chromatography using a 5% mixture of ethyl acetate/hexane as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 10 mg (33%) of 2-benzyloxycarbonylamino-5-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester as a solid.1H NMR (CDCl3): delta 10.59 (s, 1H), 7.81 (m, 1H), 7.52 (m, 1H), 7.39 (m, 7H), 5.25 (s, 1H), 4.22-5.00 (m, 4H), 4.40-4.80 (m, 2H), 2.80-3.10 (m, 2H), 1.55 (s, 9H), 1.25 (s, 9H).To a solution of the above 2-benzyloxycarbonylamino-5-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester (9 mg, 0.014 mmol) in methanol (2 ml) was added 10% Pd/C (4 mg). The mixture was stirred under hydrogen (1 atm.) for 3 hours and then filtered. The filtrate was evapora... |
| 80% |
With N-Bromosuccinimide;2,2'-azobis(isobutyronitrile); In tetrachloromethane;Reflux; |
A solution of compound 18b (4.5 g, 30 mmol), NBS (5.9 g, 33 mmol) and AIBN (0.5 g, 3 mmol) in CCI4 (20 mL) was refluxed overnight. The mixture was taken up in H20 (20 mL) and extracted with DCM (100 mL). The organic layer was washed with brine, dried over Na2S04, filtered and concentrated. The crude product was purified by CC to give the compound 18c (5.5 g, 80% yield). |
| 77% |
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 4h;Heating / reflux; |
To a solution of methyl 2-methylbenzoate (5g, 0. 033mol) in carbon tetrachloride (85ml) was added n-bromosuccinimide (5.93g, 0. 033mol) and benzoyl peroxide (0.22g, 0. 9mol). The reaction was refluxed for 4 hr. The reaction was cooled to room temperature. The white precipitate was filtered and the solvent removed. The oil was dissolved in ET2O and cooled to-78C The product precipitated and collected yielding v (5. 86G, 77%). |
| 73% |
With N-Bromosuccinimide; |
Step A Preparation of Methyl-2-bromomethylbenzoate To a solution of 2.3 g (15.3 mmol) of methyl o-methylbenzoate (methyl o-toluate) in 20 mL of refluxing CCl4 was added 3 g of N-bromosuccinimide and 0.10 g AIBN. After 2.5 hours the mixture was cooled, diluted with 500 mL of CH2 Cl2 and washed with 200 mL of H2 O and 200 mL Of brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The resultant oil was flash chromatographed with 5:1 hexane/ethyl acetate to yield the titled compound (2.56 g, 73%). FAB-MS: m/e=230 (M+1) 1 H NMR (300 MHz, CDCl3, ppm) d 7.97 (d, 1H); 7.51 (d, 1H); 7.48 (d, 1H); 7.39 (dd, 1H); 4.96 (s, 2H); 3.93 (s, 3H). |
| 68% |
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 85℃; for 17h;Reflux; Inert atmosphere; |
A mixture of Methyl 2-methylbenzoate (1.00 mL, 7.20 mmol)and NBS (1.40 g, 7.90 mmol) in CCl4 (28 mL) was degassed. AIBN(24.0 mg, 0.140 mmol) was added and the mixture was heatedto 85 C for 16 h. Further NBS (0.130 g, 0.710 mmol) was addedand the whole was refluxed for 1 more hour. The mixture wasdiluted with CH2Cl2 and washed with sat. aq NaHCO3 solutionand water. The organic layer was dried (Na2SO4), filtered and concentratedin vacuo. Purification of the residue by flash chromatography(hexane/EtOAc 100:0?95:5) gave the title compound as anorange to pink liquid that solidifies on standing (68%). 1H NMR(300 MHz, CDCl3) d ppm 3.92 (s, 3H), 4.95 (s, 2H), 7.30-7.39 (m,1H), 7.41-7.53 (m, 2H), 7.89-8.01 (m, 1H). 13C NMR (75 MHz,CDCl3) d ppm 31.7, 52.4, 128.7, 129.2, 131.4, 131.8, 132.7, 139.4,167.2. |
| 67.6% |
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In chloroform; at 85℃;Reflux; |
A mixture of Methyl 2-methylbenzoate (1 mL, 7.2 mmol) and NBS (1.4 g, 7.9 mmol) in 0014 (28 mL) was degassed. AIBN (24 mg, 0.14 mmol) was added and the mixture was heated to 85 00 overnight. Eurther NBS (0.13 g, 0.71 mmol) was added and the whole was refluxed for 1 more hour. The mixture was diluted with 0H2012 and washed with sat. aq. NaHOO3 solution andwater. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash chromatography (hexane/EtOAc 100:0 -* 95:5) gave the title compound as an orange to pink liquid that solidifies on standing (67.6%). 1H NMR (300 MHz, ODd3) 6 ppm 3.92 (s, 3 H) 4.95 (s, 2 H) 7.30 - 7.39 (m, 1 H) 7.41 - 7.53 (m, 2 H) 7.89 - 8.01 (m, 1 H). 130 NMR (75 MHz, 0D013)6 ppm 31.7, 52.4, 128.7, 129.2, 131.4, 131.8, 132.7, 139.4, 167.2. |
| 65.7% |
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In acetonitrile; at 90℃; for 6h;Inert atmosphere; |
To a stirred solution of methyl 2-methylbenzoate 6- 1 A (5 g, 33.3 mmol) in ACN (200 mL) was added NBS (5.3 g, 30 mmol) and AIBN (547 mg, 3.33 mmol) at RT. The reaction mixture was warmed to 90 C for 6 hr under nitrogen atmosphere. The reaction mixture solvent was evaporated under reduced pressure and the crude residue washed with toluene (500 mL) and filtered the precipitate (NBS). Filtrate evaporated under reduced pressure and the crude residue was purified by flash column chromatography (100-200 silica) using 2% EtOAc/pet. ether to afford 6-2A (5 g, 22.1 mmol, 65.7 % yield) as a yellow thick liquid. |
| 62% |
With N-Bromosuccinimide;dibenzoyl peroxide; In chloroform;Reflux; |
To a solution of methyl 2-(methyl)benzoate 3a (9.46 g, 6.3 mmol) in chloroform (200 mL) were added NBS (13.8 g, 7.6 mmol) and benzoyl peroxide (760 mg, 0.32 mmol). The reaction mixture was stirred at reflux overnight. When the mixture was cooled to rt, filtered and concentrated. The residue was purified by CC, eluted with PE to give 3b as a colorless oil (9 g, 62% yield). |
| 62% |
With N-Bromosuccinimide; dibenzoyl peroxide; In chloroform;Reflux; |
To a solution of compound 3a (9.46 g, 6.3 mmol) in chloroform (200 mL) were added NBS (13.8 g, 7.6 mmol) and benzoyl peroxide (760 mg, 0.32 mmol). The reaction mixture was stirred at reflux overnight. When the mixture was cooled to room temperature, it was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography, eluted with petroleum ether to give 3b as a colorless oil (Yield: 9 g, 62%). |
| 37% |
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane;Heating / reflux; |
A mixture of methyl o-toluate (13.5 g, 89.9 mmol), NBS (17.6 g, 98.9 mmol), and benzoyl peroxide (50 mg, 0.2 mmol) in carbon tetrachloride (250 mL) was heated at reflux over the weekend. The reaction mixture was allowed to cool, and it was then filtered. The solvents were evaporated under reduced pressure and the residue was purified by chromatography, eluting with 3% ethyl acetate/hexanes to give 2-bromomethyl-benzoic acid methyl ester (7.7 g, 37%) as a white solid. 1HNMR (CDCl3): delta 7.97 (dd, J=1.5 Hz, 8.0 Hz, 1H), 7.49 (m, 2H), 7.38 (dt, J=1.5 Hz, 8.0 Hz, 1H), 4.96 (s, 2H), 3.94 (s, 3H). MS (APCI+): 231 (100), 229 (93). |
|
With azobisisobutyronitrile; In N-Bromosuccinimide; |
REFERENCE EXAMPLE 2 2-bromomethylbenzoic Acid Methyl Ester To a solution of 2-methylbenzoic acid methyl ester (33.0 g) in tetrachlorocarbon (440 ml) were added N-bromosuccinimide (43.0 g) and AIBN (2,2'-azobisisobutyronitrile, 361 mg) and the mixture was refluxed for 30 minutes. The reaction mixture was cooled down to 0 C. and cinnamoic acid that appeared were filtered off and the filtrate was concentrated. The residue was purified by distillation under reduced pressure to give the title compound having the following physical data (28.0 g, colorless oil). TLC: Rf 0.65 (n-hexane:ethyl acetate=4:1); NMR(CDCl3): delta 7.97 (d, J=7.4 Hz, 1H), 7.56-7.30 (m, 3H), 4.96 (s, 2H), 3.95 (s, 3H). |
|
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; |
Step B Synthesis of methyl 2-bromomethylbenzoate as an intermediate This compound was prepared in the manner of Example 6, Part A, using 42.6 grams (0.283 mole) of methyl 2-methylbenzoate, 50.4 grams (0.283 mole) of N-bromosuccinimide and 2.0 grams (0.008 mole) of benzoyl peroxide in 500 ml of carbon tetrachloride. The yield of methyl 2-bromomethylbenzoate was 64.2 grams as an oil. |
|
With N-Bromosuccinimide;dibenzoyl peroxide; In tetrachloromethane; hexane; ethyl acetate; |
Example 3 Synthesis of GERI-E3=Sodium R(+)-2-[(5,6-dichloro-2 3,9,9a-tetrahydro-3-oxo-9a-propyl-1H-fluoren-7-yl)oxymethyl]benzoate To prepare a methyl 2-(bromomethyl)benzoate reagent, methyl 2-methylbenzoate (Aldrich Chemical Co., 5.97 g, 40.0 mmol) was treated with N-bromosuccinimide (7.1 g, 40.0 mmol) in the presence of benzoyl peroxide (53 mg) in tetrachloromethane. The reaction mixture was refluxed overnight under N2 atmosphere, and was monitored by TLC using 5% EtOAc/hexane. After the reaction was completed, the solvent was removed by evaporation and the residue was separated between water and EtOAc. |
|
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 1.5h;Heating / reflux; |
To a mixture of methyl 2-methylbenzoate (5.0 g, 0.033 mmol) and N- bromosuccinimide (5.9 g, 0.033 mmol) in CCU (50 ml_) was added benzoyl peroxide (0.04 g, 0.00016 mmol). The mixture was heated to reflux for 1.5 h, cooled to room temperature, filtered through Celite, and concentrated to afford methyl 2- (bromomethyl)benzoate (7.2 g, ca. 94% mass recovery), which was contaminated with ca. 14% unreacted starting material and was used without purification. |
|
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 80℃; |
Example 106; 2-bromomethyl-benzoic acid methyl ester (Dvornikovs, V. ; Smithrud, D. B. ; J. Org. Chem.; 2002, 67, 2160 - 2167) was prepared, via the cited literature preparation, from methyl 2-methylbenzoate by alpha-bromination (NBS, benzoyl peroxide, CC14, 80C). |
|
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 90℃; for 1.5h; |
step 1 Production of 2-bromomethylbenzoic acid methyl ester 2-Methylbenzoic acid methyl ester (5 g) was dissolved in carbon tetrachloride (50 mL), N-bromosuccinimide (5.93 g) and alpha,alpha'-azobisisobutyronitrile (273 mg) were added, and the mixture was stirred with heating at 90 C. for 1.5 hr. The precipitated solid was removed by filtration, and the filtrate was concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate=20:1) to give the title compound (4.69 g) as a colorless oil. |
|
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In chloroform; at 65℃; for 5h;Reflux; |
Intermediate 7: Methyl 2-(bromomethyl)benzoateDissolve methyl 2-methylbenzoate (3.33×10-2 mol) in chloroform (30 ml). Add N-bromosuccinimide (3.50×10-2 mol), 2,2'-azobis(2-methylpropionitrile) (3.65×10-4 mol) and heat progressively to 65 C. to allow initiation of the free-radical reaction. Subsequently, reflux the reaction mixture for 5 hours. The mixture is then cooled to ambient temperature. Filter off the precipitate that has formed. Evaporate the filtrate to dryness under reduced pressure.The title product is obtained in the form of an orange-coloured oil which is used without subsequent purification. |
|
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In chloroform; at 65℃; for 16h; |
Example 41 : 2-((6-( 1 -Methyl- 1 H-pyrazo 1-4-ylamino)- 1 H-pyrazolo [3 ,4-d]pyrimidin- 1 - yl)methyl)benzoic acid Step (i)A solution of methyl-o-toluate (0.93mL, 6.6mmol), N-bromosuccinimide (1.25g, 7.0mmol) and azaisobutryonitrile (l lmg, 0.07mmol) in chloroform (lOmL) was heated at 65 for 16h. After cooling to rt, the mixture was diluted with dichloromethane and washed with H20 and then brine. The organic phase was collected, dried (MgS04) and concentrated in vacuo to give methyl 2-(bromomethyl)benzoate |
|
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 24h;Inert atmosphere; Reflux; |
2-(Azidomethyl)benzoic acid (21). To a solution of methyl 2-methylbenzoate (18, 85.0 g, 566 mmol) in anhydrous CCl4 (1.00 L) was added NBS (102 g, 572 mmol, 1.01 equiv) and benzoyl peroxide (1.37 g, 6.66 mmol, 0.01 equiv). CAUTION. This reaction is very exothermic, thus care must be taken in order to minimize the risks of runaway reaction. The mixture was stirred for 24 h at reflux under an argon atmosphere. Then, the temperature was lowered to 0 C and the precipitate was removed by filtration. The solvents were evaporated under reduced pressure to dryness to afford a residue, which was dissolved in anhydrous EtOH (1.59 L). NaN3 (37.2 g, 572 mmol, 1.01 equiv) was added and the mixture was stirred for 3 h at reflux under an argon atmosphere. The reaction was then quenched with brine (250 mL) and the mixture was concentrated (to 1/3 volume) under reduced pressure. The aqueous phase was extracted with CH2Cl2 (3×500 mL), the organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The resulting residue was dissolved in MeOH/H2O (1.19 L, 5:2 v/v) and NaOH (51.0 g) was added. The mixture was stirred for 2 h at room temperature, then concentrated (to 1/3 volume) under reduced pressure. The aqueous phase was extracted with CH2Cl2 (3×500 mL) and acidified with 6 N aqueous HCl. The precipitated acid was then extracted with CH2Cl2 (3×250 mL), the organic phases were pooled and concentrated to dryness to afford a yellow solid residue. The crude product was recrystallized from Chex to furnish 21 (77.3 g, 77%, 3 steps) as a white crystalline powder. Physical and analytical data of 2141 were in agreement with those published in the literature. |
|
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 1.5h;Reflux; |
A solution of o-Methyl methyl benzoate (15.0g, 100mmol) in carbon tetrachloride (800ml) added by NBS (19.8g, 110mmol) and BPO (0.48g, 2mmol), reflux for 1.5h, the unsolvable material was filtrated, The quantitative production was gained by evaporation. The obtained compound (9.16g, 40mmol) was dissolved in 200ml ethanol, and sodium azide was added (3.9g, 60mmol), The reaction mixtrue was stirred overnight at room temperature. After ethanol evaporation, the crude material was re-dissolved in ethyl acetate, and washed with water and brine. The organic layer was separated and diluted with 2M NaOH-CH3OH (1:1, v:v). This solution was stirred for half an hour at room temperature, followed by partial evaportion under vacuum. The solution was then acidified to pH?1 by 2.5M HCl, and the product was extracted with dichloromethane (X4). The combined organic layer were dried over sodium sulfate. After evaporation, the crude product was recrystallized by cyclohexane to give white crystal. The overall yield is 71%. This product was reflux in thionyl chloride and evaporated to give corresponding 2-(azidomethyl)benzoyl chloride before use. |
|
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 80℃; for 16h; |
Step I Methyl 2-(bromomethyl)benzoate To a solution of methyl 2-methylbenzoate (1.0 g, 6.66 mmol) in CCI4 (20 mL) was added NI3S (1.3 g, 7.32 mmol) and IWO (50 mg, 0.21 mmol). The mixture was heated at 80 C for 16 hrs. After cooling to room temperature, the reaction mixture was concentrated and the residue was dissloved in EtOAc (50 mL) and washed with 1120 (20 mL). The organic phase was dried over anhydrousNa2S0, filtered and concentrated. The residue was purified by flash column chromatography onsilica gel eluting with 0-10% EtOAc in hexanes to give the desired product (1.4 g crude) as acolorless oil. 111 NMR (400 MHz, CDCI3): 6 7.97 (d, J= 7.6 Hz, 1H), 7.52 - 7.47 (m, 2H), 7.40 -7.38 (m, IH), 4.96 (s, 211), 3.95 (s, 311). |
|
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 1.5h;Reflux; |
The picolin ester (56 g, 0.37 mol), 2,2?-azobisisobutyronitrile (2.43 g, 0.01 mol) and N bromosuccnmde (26.3 g, 0.15 mol) was dissolved in 0014 (500 ml) and heated under reflux for1.5 hours. On cooling the suspension was filtered and the filtrate evaporated. The crude bromide was dissolved in methanol (500 ml) and a mixture of the thioacetate (50.6 g, 0.15 mol) and potassium carbonate (24.5 g, 0.18 mol) in methanol (200 ml) was added drop wise under ice-bath cooling. The resulting mixture was stirred at room temperature overnight. The solvent was evaporated, the residue dissolved in ethyl acetate, washed with water, dried over anhydrous Na2504, filtered and evaporated. The excess picolin ester was recovered by distillation at 120 00, and 0.8 mbar. The crude sulfide (63.9 g, 96.2 %) was used as such in the next step. |
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With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 1h;Reflux; Irradiation; |
General procedure: Corresponding substituted toluene (12a-d, 70.0 mmol), N-bromosuccinimide (NBS) (70.0 mmol), and azobisisobutyronitrile (AIBN) (7.0 mmol) in carbon tetrachloride (108mL) were heated to reflux under irradiation conditions for 1 h. Cyclohexane (108 mL) was added to the mixture and the reaction was stirred for 10 min. After removal of precipitate by filtration, the filtrate was concentrated and recrystallized in ethanol to obtain substituted benzyl bromides 13a-d, yield 95-100%. |
|
With N-Bromosuccinimide; In Petroleum ether; at 15℃; for 2.5h; |
Placed in a 20L reaction vessel was petroleum ether, o-methyl benzoate, N- bromosuccinimide. Use a water bath to control temperature at 15 deg.C. Under stirring, react for 2.5h. Using known separation methods, separated o halomethyl benzoate. |
| 7 g |
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 2h;Reflux; |
The o-methylbenzoate (6 g, 39.95 mmol) was weighed into 60 mL of carbon tetrachloride and NBS(2.73 g, 47.94 mmol) and benzoyl peroxide (484 mg, 2 mmol) and refluxed for 2 h. TLC detectionAfter completion of the reaction, the reaction solution was cooled, filtered and the filtrate was dried to give intermediate o-bromomethylbenzoic acid methyl ester (7 g). |
|
With N-Bromosuccinimide; dibenzoyl peroxide; In chloroform; at 65℃; for 5h;Inert atmosphere; Schlenk technique; Reflux; |
General procedure: To a solution of 6.0 g (0.04 mol) of methyl 2-methylbenzoate derivatives in 38 mL of chloroform, 7.5 g (0.042 mol) of N-bromosuccinimide and 0.078 g of benzoyl peroxide were added and carefully warmed up to 65 C until reaction started. Then the mixture was refluxed for 5 h. After cooling down to room temperature, the deposit of succinimide was filtered. The solvent was removed under reduced pressure and the crude product was used in the next step without further purification. To a solution of functionalized methyl 2-(bromomethyl)benzoate (6.55 mmol), substituted phenol (8.5 mmol), K3PO4 (16.4 mmol) and toluene 20 mL were added to Schlenk under argon. The resulting solution was stirred to 110 C for 5 h. The progress of the reaction was monitored by TLC. The mixture was extracted with EtOAc, washed with water, brine and the combined organic layers were dried over anhydrous Na2SO4and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification. To the solution of the ester (0.015 mol) in MeOH (73 mL), was added 13 mL aqueous KOH (20%) and refluxed at 80C for 5 h. MeOH was removed and the aqueous phase was washed with DCM. After acidifying with HCl (10%) the deposit was collected and washed with water. |
|
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 0 - 80℃; for 3h;Inert atmosphere; |
A solution of compound 23E (30 g, 200 mmol) in CC14 (40 mL) was added drop-wise to a stirring mixture of benzoyl peroxide (1.45 g, 5.99 mmol) and NBS (35.6 g, 200 mmol) in CC14 (300 mL) at 0 C. The mixture was heated to reflux (80 C) and stirred for 3 hrs under nitrogen. The precipitated succinimide was removed by filtration and the filter cake was washed with carbon tetrachloride (30 mL x 2). The combined filtrates were washed successively with 2N NaOH (150 mL), and water (100 mL x 2), and the solution was dried over anhydrous MgS04, filtered (Celite), and evaporated under vacuum to afford compound 23F (45 g, crude) as yellow oil, which was used for next step without further purification. 1H NMR (400MHz, DMSO-d6) delta 7.88 (d, J = 7.6 Hz, 1H), 7.63 - 7.57 (m, 2H), 7.51 - 7.44 (m, 1H), 5.02 (s, 2H), 3.87 (s, 3H). |
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