methyl 5-bromo-2-formylbenzoate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 50 mL round-bottom flask was charged with methyl 5-bromo-2-formylbenzoate (1.00 g, 4.11 mmol, 1.00 equiv), lithium hydroxide (2.00 g, 83.5 mmol, 20.0 equiv), tetrahydrofuran (10 mL), and H2O (10 mL). The resulting solution was stirred for 3 h at room temperature. The pH value of the solution was adjusted to 6 with hydrogen chloride solution (2 mol/L). The solid were collected by filtration to yield 0.700 g (crude) of 5-bromo-2-formylbenzoic acid as a light yellow solid. LCMS (ESI, m/z): 227 [M−H]−. The solid were collected by filtration

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 50 mL round-bottom flask was charged with methyl 5-bromo-2-formylbenzoate (1.00 g, 4.11 mmol, 1.00 equiv), lithium hydroxide (2.00 g, 83.5 mmol, 20.0 equiv), tetrahydrofuran (10 mL), and H2O (10 mL). The resulting solution was stirred for 3 h at room temperature. The pH value of the solution was adjusted to 6 with hydrogen chloride solution (2 mol/L). The solid were collected by filtration to yield 0.700 g (crude) of 5-bromo-2-formylbenzoic acid as a light yellow solid. LCMS (ESI, m/z): 227 [M−H]−. The solid were collected by filtration

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (2-Methoxyphenyl)boronic acid (4.69 g, 30.9 mmol), methyl 5-bromo-2-formylbenzoate (5.00 g, 20.6 mmol; GLSyntech, LLC), tripotassium phosphate (17.5 g, 82.0 mmol) and THF (103 mL) were added to a pressure tube. The tube was purged with argon. Then chloro(1,5-cyclooctadiene)rhodium(I) dimer (0.507 g, 1.03 mmol) was added. The tube was sealed and stirred at rt. After 30 min, LCMS showed lactone product. TLC confirmed a complete conversion of methyl 5-bromo-2-formylbenzoate to a lower spot. The reaction was filtered with the aid of EtOAc. The filtrate was concentrated and the crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (120 g), eluting with a gradient of 0% to 30% EtOAc in hexanes, to provide 6-bromo-3-(2-methoxyphenyl)isobenzofuran-1(3H)-one (5.15 g, 78% yield). m/z (ESI) 319.0 (M+H)+, 321.0 (M+3H)+. The tube was purged with argon The tube was sealed The reaction was filtered with the aid of EtOAc The filtrate was concentrated the crude material was absorbed onto a plug of silica gel purified by chromatography through a Redi-Sep pre-packed silica gel column (120 g) eluting with a gradient of 0% to 30% EtOAc in hexanes

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Methoxy-4-(trifluoromethyl)phenyl boronic acid (2.05 g, 9.32 mmol; Combi-Blocks, San Diego, Calif.), methyl 5-bromo-2-formylbenzoate (1.51 g, 6.21 mmol; GLSyntech, LLC, Hatfield, Pa.), tripotassium phosphate (5.27 g, 24.9 mmol; freshly ground) and THF (31.1 mL) was added to a vial. The vial was purged with argon. Then chloro(1,5-cyclooctadiene)rhodium(i) dimer (0.153 g, 0.311 mmol; Strem Chemicals, Inc., Newburyport, Mass.) was added. The vial was sealed and stirred at RT. After 1 h, the reaction was filtered and the filtrate was concentrated under a vacuum. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column (80 g), eluting with a gradient of 0% to 10% EtOAc in heptane, to provide 6-bromo-3-(2-methoxy-4-(trifluoromethyl)phenyl)isobenzofuran-1(3H)-one (2.06 g, 86% yield) as a brown solid. 1H NMR (400 MHz, CDCl3) δ ppm 3.92 (s, 3H), 6.72 (s, 1H), 7.11-7.17 (m, 3H), 7.25 (dt, J=8.2, 0.7 Hz, 1H), 7.65 (dd, J=8.3, 1.7 Hz, 1H), 8.00 (d, J=1.8 Hz, 1H). m/z (ESI) 405.0 (M+H)+. This lactone was not stable on MS. The vial was purged with argon The vial was sealed the reaction was filtered the filtrate was concentrated under a vacuum The crude material was absorbed onto a plug of silica gel purified by chromatography through a silica gel column (80 g) eluting with a gradient of 0% to 10% EtOAc in heptane