4-bromoisoindolin-1-one

3-bromo-2-methylbenzoic acid (6.13 g, 28.5 mmol) was suspended in MeOH (52 ml) and concentrated HStep 3: To a solution of the 3-bromo-2-bromomethyl-benzoic acid methyl ester (2.74 g, 8.88 [MMOL)] in tetrahydrofuran (70 [ML)] at [0°C] was added 30 percent aq. ammonia (10 ml) and the mixture stirred at room temperature under nitrogen for 18 hours. The solvent was removed by evaporation under reduced pressure. The white residue was partitioned between ethyl acetate (50 mi) and 2M citric acid (50 [ML).] The ethyl acetate was dried magnesium sulfate, filtered and solvent removed by evaporation under reduced pressure. The orange oil was dissolved in minimum [DICHLOROMETHANE] and purified by flash chromatography on silica gel eluting with a solvent gradient of [DICHOROMETHANE/METHANOL] (9: 1) to give the title compound (1.5 g, 80 percent) as a white solid. [1H-NMR] (400 MHz, DMSO): [A] = 4.29 (s, 2H), 7.44 (t, [1H), ] 7.69 (d, [1H), ] 7.80 (d, [1H), ] 8.68 (brs, 1 H). LRMS (Electrospray) : m/z [M+ 2H] [+] 214. Microanalysis : Found: C, 45.20 ; H, 2.90 ; N, 6.67. C8H6NOBr requires C, 45.31 ; H, 2.85 ; N, 6.60percent.Step 3: Preparation of 4-bromoisoindolin-1-one (4) To a solution of methyl 3-bromo-2-(bromomethyl)benzoate 3 (8.3 g, 26.9 mmol) in THF (100 mL) was added concentrated NH3-bromo-2-methylbenzoic acid (6.13 g, 28.5 mmol) was suspended in MeOH (52 ml) and concentrated H2SO4 (10.0 ml) was added via syringe over 4 minutes at room temperature. The reaction was heated to 90 C, stirred for 4 hours, cooled in an ice water bath, and then quenched with saturated NaHCO3 (250 ml). The reaction was extracted with EtOAc (3 x 50 ml), and the organic layers were combined, dried over MgSO4, filtered, and concentrated to give methyl 3-bromo-2-methylbenzoate (6.43 g, 98%).Methyl 3-bromo-2-methylbenzoate (7.45 g, 32.5 mmol) was dissolved in CCl4 (94 ml) and N- bromosuccinimide (6.67 g, 37.5 mmol) and benzoyl peroxide (0.38 g, 1.6 mmol) were added. The reaction was heated to 75 C - 85 C, stirred for 3 hours and 45 minutes, cooled to room temperature, and filtered. The filtrate was concentrated and purified on SiO2 (Biotage instrument; 0% -> 20% EtOAc / hexanes) to give methyl 3-bromo-2-(bromomethyl)benzoate (10.07 g, 100%).Methyl 3-bromo-2-(bromomethyl)benzoate (10.30 g, 33.44 mmol) was dissolved in THF (93 ml) and cooled in an ice water bath. Then, NuH3 (60 ml, ~ 7N in MeOH) was added via syringe over 4.5 minutes. The reaction was warmed to room temperature, stirred for 7.5 hours, and then diluted with water. The aqueous phase was extracted repeatedly with CH2Cl2 and EtOAc. The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated to give title compound (6.99 g, EPO Step 3: 4-bromoisoindolin-1-one To a solution of methyl 3-bromo-2-(bromomethyl)benzoate (27 mmol) in THF (100 mmol) was added ammonium hydroxide (9 mL) dropwise at rt. The reaction mixture was allowed to stir overnight and then diluted with 30 mL of water. The solution was extracted with DCM, dried over Na2SO4, filtered and concentrated to give 4-bromoisoindolin-1-one (5.20 g, 91%).To a solution of the 3-bromo-2-bromomethyl-benzoic acid methyl ester (2.74 g, 8.88 [MMOL)] in tetrahydrofuran (70 [ML)] at [0C] was added 30 % aq. ammonia (10 ml) and the mixture stirred at room temperature under nitrogen for 18 hours. The solvent was removed by evaporation under reduced pressure. The white residue was partitioned between ethyl acetate (50 mi) and 2M citric acid (50 [ML).] The ethyl acetate was dried magnesium sulfate, filtered and solvent removed by evaporation under reduced pressure. The orange oil was dissolved in minimum [DICHLOROMETHANE] and purified by flash chromatography on silica gel eluting with a solvent gradient of [DICHOROMETHANE/METHANOL] (9: 1) to give the title compound (1.5 g, 80 %) as a white solid. [1H-NMR] (400 MHz, DMSO): [A] = 4.29 (s, 2H), 7.44 (t, [1H), ] 7.69 (d, [1H), ] 7.80 (d, [1H), ] 8.68 (brs, 1 H). LRMS (Electrospray) : m/z [M+ 2H] [+] 214. Microanalysis : Found: C, 45.20 ; H, 2.90 ; N, 6.67. C8H6NOBr requires C, 45.31 ; H, 2.85 ; N, 6.60%.(iii) Production of 4-bromo-1-isoindolinone Methyl 3-bromo-2-(bromomethyl)benzoate (1.28 g) was dissolved in a 11% solution of ammonia in methanol-THF mixed solution (3:2, 25 ml) and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated and the residue was washed with saturated brine. Recrystallization from ethyl acetate-hexane gave the title compound (671 mg, 76%) as colorless needle crystals. 1H-NMR (CDCl3) delta: 4.42 (2H, s), 7.42 (1H, dd, J=7.8, 7.8 Hz), 7.48 (1H, br s), 7.73 (1H, d, J=7.8 Hz), 7.85 (1H, d, J=7.8 Hz). IR (KBr): 3167, 1728, 1684, 1667, 1470, 1462, 1107, 745 cm-1.EXAMPLE 1C 4-bromo-1-isoindolinone A solution of Example 1B (8.3 g, 26.9 mmol) in THF (100 mL) was treated dropwise with concentrated NH4OH (9 mL, 135 mmol) stirred at room temperature for 2 days, diluted with 30 mL water, cooled to 0 C., and filtered. The filter cake was washed with water and ethyl acetate and dried to give 3.34 g of the desired product. MS (ESI(+)) m/e 212 (M+H)+.Step 3: Preparation of 4-bromoisoindolin-1-one (4) To a solution of methyl 3-bromo-2-(bromomethyl)benzoate 3 (8.3 g, 26.9 mmol) in THF (100 mL) was added concentrated NH4OH (9 mL) dropwise. After stirring them at room temperature overnight, the mixture was concentrated in vacuo to give the residue, which was then washed with water and MTBE, and dried to give the title product 4 (4.14 g). 1H NMR (400 Hz, CDCl3) delta 7.85-7.83 (d, J=7.5 Hz, 1H), 7.72-7.70 (d, J=7.9 Hz, 1H), 7.42-7.38 (t, J=7.7 Hz, 1H), 6.81 (s, 1H), 4.39 (s, 2H).A solution of Example IB (8.3g, 26.9mmol) in THF (100 mL) was treated dropwisewith concentrated NE^OH (9 mL, 135 mmol) stirred at room temperature for 2 days, diluted with 30 mL water, cooled to 0 C, and filtered. The filter cake was washed with water andethyl acetate and dried to give 3.34 g of the desired product.The compound III obtained in was added to a freshly prepared 10 M ammonia methanol solution and stirred overnight. When no white solid precipitated, it was filtered and dried to obtain 60 g of a white product.EXAMPLE 2A 4-bromo-7-nitro-1-isoindolinone A 0 C. solution of Example 1C (5 g, 23.6 mmol) in 10 mL sulfuric acid was treated with a solution of concentrated nitric acid (1.55 mL, 24.7 mmol) in 10 mL sulfuric acid via addition funnel. The resulting mixture was stirred at 0 C. for 1 hour, warmed to room temperature, stirred overnight, poured over ice, and filtered. The filter cake was washed with water and diethyl ether and then dried to give 5.39 g of the desired product. 1H NMR (300 MHz, DMSO-d6) delta 4.39 (s, 2H); 7.88 (d, J=8.1 Hz, 1H); 8.05 (d, J=8.5 Hz, 1H); 9.17 (s, 1H).Step 4: Preparation of 4-bromo-7-nitroisoindolin-1-one (5) To a solution of A 0 C solution of Example 1C (5g, 23.6 mmol) in 10 mL sulfuric acid was treatedwith a solution of concentrated nitric acid (1.55 mL, 24.7 mmol) in 10 mL sulfuric acid viaaddition funnel. The resulting mixture was stirred at 0 C for 1 hour, warmed to roomtemperature, stirred overnight, poured over ice, and filtered. The filter cake was washed withwater and diethyl ether and then dried to give 5.39g of the desired product.EXAMPLE 1D 4-(4-aminophenyl)-1-isoindolinone A suspension of Example 1C (2 g, 9.43 mmol), 4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxa-borolan-2-yl)aniline (2.5 g, 11.3 mmol), and Na2CO3 (2.2 g, 20.8 mmol) in DME (68 mL) and water (17 mL) was purged with nitrogen, treated with Pd(PPh3)4 (1 g, 0.9 mmol), and stirred at 90 C. for 19 hours. The reaction mixture was cooled to room temperature, concentrated to one-third its original volume, diluted with ethyl acetate (30 mL) and water (20 mL), and filtered. The filter cake was washed with water and ethyl acetate and dried to give 1.25 g of the desired product. MS (ESI(+)) m/e 225 (M+H)+.A suspension of Example 1C (2g, 9.43 mmol), 4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxa-borolan-2-yl)aniline (2.5g, 11.3 mmol), and Na2CO3 (2.2g, 20.8 mmol) in DME (68 mL) andwater (17 mL) was purged with nitrogen, treated with Pd(PPh3)4 (Ig, 0.9 mmol), and stirredat 90 C for 19 hours. The reaction mixture was cooled to room temperature, concentrated toone-third its original volume, diluted with ethyl acetate (30 mL) and water (20 mL), andfiltered. The filter cake was washed with water and ethyl acetate and dried to give 1.25g ofthe desired product.EXAMPLE 54A 4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1-isoindolinone A suspension of Example 1C (10.6 g, 50 mmol) and 4, 4, 5, 5, 4', 4', 5', 5'-octamethyl-[2, 2']bi[[1, 3, 2]dioxaborolanyl] (15.23 g, 60 mmol) in DMF (390 mL) was stirred until a clear yellow solution was obtained. The solution was then treated with potassium acetate (14.72 g, 150 mmol), degassed with nitrogen, treated with [1.1'-bis(diphenylphosphino)-ferrocene]dichloropalladium [II].CH2Cl2 (7 g, 8.5 mmol) and heated to 90 C. overnight. The reaction was cooled to room temperature and filtered through diatomaceous earth (Celite), and concentrated. The concentrate was partitioned between water and ethyl acetate and filtered through diatomaceous earth (Celite). The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by silica gel chromatography eluding with 100% ethyl acetate and triturated from hexanes to give 4.56 g (35% yield) of the desired product. m.p.: 189-191 C.A suspension of Example 1C (10.6g, 50 mmol) and 4, 4, 5, 5, 4', 4', 5', 5 -octamethyl-[2, 21bi[[l, 3, 2]dioxaborolanyl] (15.23g, 60 mmol) in DMF (390 mL) was stirred until a clearyellow solution was obtained. The solution was then treated with potassium acetate (14.72g, 150 mmol), degassed with nitrogen, treated with [1.1 -bis(diphenylphosphino)-ferrocene]dichloropalladium [H]-CH2C12 (7g, 8.5 mmol) and heated to 90 C overnight. The(R)reaction was cooled to room temperature and filtered through diatomaceous earth (Celite ), and concentrated. The concentrate was partitioned between water and ethyl acetate and/«filtered through diatomaceous earth (Celite ). The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by silica gel chromatographyeluting with 100% ethyl acetate and triturated from hexanes to give 4.56g (35% yield) of thedesired product

Molecular Weight:212.04
XLogP3:1.5
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:1
Exact Mass:210.96328
Monoisotopic Mass:210.96328
Topological Polar Surface Area:29.1
Heavy Atom Count:11
Complexity:183
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes