4-bromoisoindoline-1,3-dione

To a mixture of Int-A (82 mg, 0.4 mmol) and compound 2 (120 mg, 0.5 mmol) in 1, 4- dioxane (5.0 mL) was added Pd2(dba)3 (18 mg, 0.02 mmol), xantphos (23 mg, 0.04 mmol) and K2C03 (110 mg, 0.8 mmol). The reaction mixture was heated at 100 °C under a N2 atmosphere for 16 h. The mixture was cooled to rt and partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layers washed with water, brine, then dried (Na2S04), filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (eluting with 5percent MeOH in DCM) to afford compound 3 (75 mg, 51percent) as a yellow solid. 1H MR (400 MHz, DMSO-i): delta 9.24 (s, 1H), 8.89 (s, 1H), 8.35 (m, 1H), 7.89 (m, 1H), 7.72 (m, 1H), 7.65 (m, 1H), 7.42 (m, 1H), 7.27 (m, 1H), 5.33 (m, 1H), 3.02 (s, 3H), 1.36 - 1.37 (m, 6H); LCMS Mass: 363.1 (M++l).[00287] To a solution of 4-bromoisoindole-l, 3-dione 1 (226 mg, 1.0 mmol) in DMF (8 mL) was added Cs2C03 (652 mg, 2.0 mmol). The mixture was cooled to 0-5 °C and PMB-Br (302 mg, 1.5 mmol) was added dropwise. The reaction was allowed to warm to rt and stirred for 16 h. The mixture was partitioned between water and EtOAc, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried (Na2S04), filtered and concentrated under reduced pressure. The residue was purified (silica gel; eluting with 20percent EtOAc in hexanes) to afford compound 2 (208 mg, 74percent) as a yellow solid. 1H NMR (400 MHz, CDC13): delta 7.80 - 7.83 (m, 2H), 7.60 (m, 1H), 7.53 - 7.57 (m, 2H), 6.85 - 6.90 (m, 2H), 4.80 (s, 2H), 3.79 (s, 3H).[00290] To a solution of 4-bromoisoindole-l, 3-dione 1 (226 mg, 1.0 mmol) in MeCN (5 mL) was added CS2CO3 (652 mg, 2.0 mmol). The reaction mixture was stirred at rt for 15 min then cooled to 0-5 °C. lodomethane (0.2 mL, 3.0 mmol) added dropwise and the reaction mixture was allowed to warm to rt and stirred for a further 16 h. The mixture was partitioned between EtOAc and water and the aqueous layer extracted with EtOAc. The combined organic layers were washed with water, brine, then dried (Na2S04), filtered and concentrated under reduced pressure. The residue was purified (silica gel; eluting with 20percent EtOAc in hexanes) to afford the compound 2 (220 mg, 92percent) as a yellow solid. 1H MR (400 MHz, DMSO-i): delta 7.97 (m, 1H), 7.86 (m, 1H), 7.70 (m, 1H), 3.03 (s, 3H).Step b. A mixture of 7-bromo-3-hydroxy-3-methylisoindolin-l-one and 4-bromo-3-hydroxy-3 -methyl isoindolin-l-one (12.00 g, 49.8 mmol) in DCM (100 ml) was cooled to -40°C. Triethylsilane (80.4 ml, 498 mmol) was added to the reaction mixture at -40°C under N2 atmosphere. Boron trifluoride diethyletherate (18.7 ml, 149.4 mmol) was added to the reaction mixture at -40°C under N2 atmosphere. The reaction mixture was stirred at 0°C for 1 h. The resulting reaction mixture was combined with two other batches prepared on the same scale by an identical method. The resulting reaction mixture was poured into NaHC03 solution (500 ml) and extracted with the DCM (3 x 1000 ml). The combined organic phase was dried over Na2S04, filtered and concentrated under reduced pressure. The crude material obtained was purified by column chromatography (3percent EtOAc in DCM) yielding 7-bromo-3-methylisoindolin-l-one (9.200 g, 40.9 mmol). LCMS: Method A, 1.521 min, MS: ES+ 226.11, 228.11; NMR (400 MHz, CDC13) delta ppm 7.61 (dd, J=7.2, 1.2 Hz, 1 H), 7.43 - 7.38 (m, 3 H), 7.68 - 7.63 (m, 1 H), 1.52 (d, J=6.8 Hz, 3 H).Step a. To a solution of 4-bromoisoindoline-l, 3-dione (CAS Number 70478-63-6, 15.00 g, 66.4 mmol) in DCM (150 ml) was dropwise added methyl magnesium bromide (1 M in THF) (199 ml, 199 mmol) at 0°C under N2 atmosphere. The reaction mixture was stirred at rt for 2 h. The reaction mixture was combined with three other batches prepared on the same scale by an identical method. The resulting reaction mixture was poured in to NH4C1 solution (500 ml) and extracted with the DCM (3 x 1 L). The combined organic phases was dried over Na2S04, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (30-32 percent EtOAc in hexane) yielding a mixture of 7-bromo-3-hydroxy-3-methylisoindolin-1-one and 4-bromo-3-hydroxy- 3-methylisoindolin-1-one (37.00 g, 153.6 mmol). LCMS: Method A, 1.435 min, MS: ES+ 242.33, 244.33.

Molecular Weight:226.03
XLogP3:1.4
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Exact Mass:224.94254
Monoisotopic Mass:224.94254
Topological Polar Surface Area:46.2
Heavy Atom Count:12
Complexity:241
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes