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To a stirring mixture of <strong>[1075-11-2]6-fluoroisoquinoline</strong> in H2SO4 (5 mL) at 0 0C was added solid NBS (1.5 EQ) slowly over 5 min. The reaction mixture was reacted at 0 0C for 1 h. To this reaction mixture was added NBS (0.5 EQ). The cold bath was then removed. The reaction mixture was reacted until all the starting material was consumed. To this reaction mixture was neutralized with a cold solution of NaOH (5N) until the pH of this mixture >;10. The white solid was filtered off and dissolved in DCM and washed with a solution of NaOH (IN). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified via a column to give 5-bromo-<strong>[1075-11-2]6-fluoroisoquinoline</strong>. Retention time (min) = 2.810, method [3], MS(ESI) 226.0 (M+H).
Step 1. methyl 2-(2-acetyl-5-bromo-6-fluoro-1,2-dihydroisoquinolin-1-yl)acetate To a stirred solution of <strong>[1239463-43-4]5-bromo-6-fluoroisoquinoline</strong> (43.9 g, 194 mmol) in DCM (880 mL) acetyl chloride (14.49 mL, 204 mmol) was dropped at RT and the solution was stirred for 60 min. The solution was cooled to -78 C. (yellow suspension) and then a solution of tert-butyl((1-methoxyvinyl)oxy)dimethylsilane (38.4 g, 204 mmol) in DCM (220 mL) was added in one portion. The resulting yellow solution was stirred at -78 C. for 1 h and then allowed to warm to rt overnight. 2N aqueous HCl was added and the reaction mixture was stirred for 10 min. The organic layer was separated and washed with brine (2*). The combined organic layers were dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was dissolved in diethyl ether, charcoal was added and the mixture was filtrated through a pad of celite. The solvent was evaporated and the crude product was dried under high vacuo overnight to yield the title compound (70.6 g) which was used without further purification. UPLC-MS: MS 342.2/344.2 (M+H+); UPLC rt 1.05 min.
To a stirred solution of <strong>[1239463-43-4]5-bromo-6-fluoroisoquinoline</strong> (43.9 g, 194 mmol) in DCM (880 mL) acetyl chloride (14.49 mL, 204 mmol) was dropped at RT and the solution was stirred for 60 min. The solution was cooled to -78C (yellow suspension) and then a solution of tert-butyl((1 - methoxyviny)oxy)dimethylsilane (38.4 g, 204 mmol) in DCM (220 mL) was added in one portion. The resulting yellow solution was stirred at -78C for 1 and then allowed to warm to rt overnight. 2N aqueous HCl was added and the reaction mixture was stirred for 10 min. The organic layer was separated and washed with brine (2x). The combined organic layers were dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was dissolved in diethyl ether, charcoal was added and the mixture was filtrated through a pad of celite. The solvent was evaporated and the crude product was dried under high vacuo overnight to yield the title compound (70.6 g) which was used without further purification. UPLC-MS: MS 342.2/344.2 (M+H*) ; UPLC rt 1.05 min.
5-bromo-6-fluoro-1,2,3,4-tetrahydroisoquinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium tetrahydroborate; In acetic acid; at 20℃; for 16.0h;
To a solution of <strong>[1239463-43-4]5-bromo-6-fluoroisoquinoline</strong> (1.0 g, 4.4 mmol) in acetic acid (20.0 mL) at room temperature was added sodium tetrahydroborate (592.0 mg, 15.65 mmol) portionwise. The mixture was stirred at room temperature for 16 h, and then concentrated. The residue was diluted with CH2Cl2 and washed with aqueous Na2CO3 (2 M). The separated organic phase was dried over anhydrous Na2SO4, filtered and concentrated to give a yellow oil which was used directly in the next step without further purification. LCMS calculated for C9H10BrFN (M+H)+ m/z=230.0; found 230.1.
With sodium tetrahydroborate; acetic acid; at 20℃; for 16.0h;
To a solution of <strong>[1239463-43-4]5-bromo-6-fluoroisoquinoline</strong> (1.002 g, 4.433 mmol) in acetic acid (20.0 mL) at room temperature was added sodium tetrahydroborate (592.0 mg, 15.65 mmol) portionwise. The mixture was stirred at room temperature for 16 h, and then concentrated. The residue was diluted with CH2Cl2 and washed with 2 M Na2CO3 (aq). The separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give a yellow oil, which was used directly in the next step without further purification. LCMS calculated for C9H10BrFN (M+H)+ m/z=230.0; found 230.1.
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