4-Bromo-2-methylisoindolin-1-one

< Step 3>; Methyl 3-bromo-2-(bromomethyl)benzoate (5.27 g, 17 mmol) obtained in Step 2 was dissolved in 50 mi of tetrahydrofuran, 40percent methylamine aqueous solution (7.5 mi, 86 mmol) was added thereto, and the mixture was allowed to react for 2 hours at room temperature. The solvent was removed under a low pressure, and the resulting residue was diluted with water and extracted with ethyl acetate. The resulting organic layer was washed with saturated sodium, dried over anhydrous magnesium sulfate, and the solvent was removed under a reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 4-bromo-2-methylisoindolin-l-one (3.36 g (87percent)).To a mixed solution of compound 3b (5 g, 22 mmol), bisboronic acid pinacol (8.5 g, 33 mmol) and KOAc (3.2g, 33 mmol) in 1, 4-dioxane (50 ml) was added Pd(dppf)2Cl2 (1g), and flushed with nitrogen. The reaction flask wassealed and the reaction was stirred overnight at 85C. After cooled to room temperature, an aqueous Na2CO3 solution (2.5M, 10ml), Pd(dppf)2Cl2 (1g) and 2, 5-dibromo-3-nitropyridine (9 g, 33 mmol) were added. After flushed with nitrogenfor 10 minutes, the reaction flask was sealed and the mixture was stirred overnight at 85C. The reaction was pouredinto water and extracted with ethyl acetate. The organic phase mixture was dried over Na2SO4, dried by suction andpurified by silica gel column chromatography (PE:EA=10:2 to 1:1) to provide compound 3c as a yellow solid.MS(ESI)m/z:347.9(M+H)+.2-methyl-l-oxoisoindoline-4-carbaldehyde: To a solution of 4-bromo-2- methylisoindolin-l-one (200mg, 0.89 mmol) in THF (3 mL), n-BuLi (0.78 mL, 1.95 mmol) was added to the solution at -78 C. After 30 minutes, DMF (0.273 mL, 3.57 mmol) was added to the solution. After 1 hour, the reaction was warmed up. Diluted with EtOAc and washed with brine. The organic layer was dried over sodium sulfate, and concentrated. The product was purified by chromatography on silica gel (eluent: EtOAc/hexanes) to yield the product after lyophilization from water / MeCN.Compound 1 L: 4-Bromo-2-methyl-7-nitro-2, 3-dihydro-1 H-isoindol-1 -oneAn 8M solution of methylamine in ethanol (10 mL, 80 mmol) was added to a solution of methyl 3-Bromo-2-(bromomethyl)benzoate in THF (30 mL) and allowed to stir for 2h. The reaction mixture was concentrated to dryness and the residue was triturated with water. The solids produced were collected by filtration and dried to afford 4-bromo-2-methyl-2, 3- dihydroisoindol-1-one which used immediately in the next step. To a cold suspension of 4- bromo-2-methyl-2, 3-dihydroisoindol-1 -one (60 g, 265 mmol) in concentrated sulfuric acid (60 mL) was added pre-cooled mixture of cone, nitric acid (12.5 mL, 265 mmol) and cone, sulfuric acid (60 mL) over 20 min. The reaction mixture was stirred for 30 min at 0 C and 2h at room temperature. The reaction mixture was poured into an ice-water mixture (300 mL) and the precipitate that formed was collected by filtration and washed with water (3x100 mL). The solids were suspended in isopropanol (200 mL) and heated on a steam bath for 10 minutes. The mixture was cooled and the solid was collected by filtration and air dried to afford 53 g of the title compound (74 %). 1H NMR (CDCI3, 300 MHz) delta 3.22 (s, 3H), 4.36 (s, 2H), 7.67 (d, J = 8.4= 8.4 Hz, 1 H).

Molecular Weight:226.07
XLogP3:1.6
Hydrogen Bond Acceptor Count:1
Exact Mass:224.97893
Monoisotopic Mass:224.97893
Topological Polar Surface Area:20.3
Heavy Atom Count:12
Complexity:207
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes