2-(benzyloxy)-4-fluorobenzaldehyde

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a slurry of magnesium (9.52 g, 0.39 mol) in THF (25 mL) in a 1 L round bottom flask fitted with a condenser was added the intermediate obtained in Step A (1 g). A vigorous reflux commenced at once. To this refluxing mixture was added a solution of the intermediate from Step A (109 g) at a rate which maintained reflux. After completion of addition the reaction was allowed to proceed until it cooled to 25° C. and was then heated at reflux for 1 h. The reaction was allowed to cool to 25° C. and DMF (48 mL) was then added portionwise. The reaction was allowed to cool to 25° C. and was then filtered through a plug of Celite. The THF was removed under reduced pressure and the residue was dissolved in ethyl acetate (500 mL) and washed sequentially with water (100 mL), 10% HCl (100 mL), saturated sodium bicarbonate solution (100 mL), and brine (100 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The resultant residue was purified by flash chromatography (10% ethyl acetate-hexane) to provide 77.3 g of 2-benzyloxy-4-fluorobenzaldehyde. 1H NMR (300 MHz, CDCl3): δ 5.16 (s, 2 H), 6.70-6.76 (m, 2 H), 7.34-7.44 (m, 5 H), 7.87-7.92 (m, 1 H), 10.43 (s, 1 H). FAB-MS: calcd for (C14H11O2F) 230; found 231 (M+1). A vigorous reflux maintained reflux After completion of addition the reaction was then heated at reflux for 1 h to cool to 25° C. to cool to 25° C. was then filtered through a plug of Celite The THF was removed under reduced pressure the residue was dissolved in ethyl acetate (500 mL) washed sequentially with water (100 mL), 10% HCl (100 mL), saturated sodium bicarbonate solution (100 mL), and brine (100 mL) The organic layer was dried (Na2SO4) concentrated under reduced pressure The resultant residue was purified by flash chromatography (10% ethyl acetate-hexane)

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: A mixture of 2-(benzyloxy)-4-fluorobenzyl alcohol (6.54 g) and manganese(IV) oxide (9.04 g) in chloroform (70 ml) was refluxed and stirred for 2 hr. The insoluble material was removed by filtration and washed with chloroform. The filrate was evaporated and the residue (6.7 g) was chromatographed over silica gel (90 g) eluting with a mixture of hexane and dichloromethane (5:1) to dichloromethane to give a colorless oil of 2-(benzyloxy)-4-fluorobenzaldehyde (3.8 g, 59%). was refluxed The insoluble material was removed by filtration washed with chloroform The filrate was evaporated the residue (6.7 g) was chromatographed over silica gel (90 g) eluting with a mixture of hexane and dichloromethane (5:1) to dichloromethane

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

Procedure: Sodium borohydride (0.223 g) was added to a solution of the product from step (ii) (1.07 g) in dry ethanol (30 ml) and the mixture was stirred at RT overnight. The mixture was partitioned between 2M hydrochloric acid/ethyl acetate, the organics separated, dried and evaporated under reduced pressure, yield 1.08 g. The mixture was partitioned between 2M hydrochloric acid/ethyl acetate the organics separated, dried evaporated under reduced pressure, yield 1.08 g

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of the product from step (i) (3.0 g), potassium carbonate (4.42 g) and benzyl bromide (3.90 ml) in DMF (40 ml) was heated at 90° C. for 14 h. The mixture was partitioned between water/ethyl acetate, the organics separated, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with isohexane/diethylether 5:1, yield 6.3 g. The mixture was partitioned between water/ethyl acetate the organics separated, dried evaporated under reduced pressure The residue was purified by chromatography on silica eluting with isohexane/diethylether 5:1, yield 6.3 g

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of the product from step (i) (3.0 g), potassium carbonate (4.42 g) and benzyl bromide (3.90 ml) in DMF (40 ml) was heated at 90° C. for 14 h. The mixture was partitioned between water/ethyl acetate, the organics separated, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with isohexane/diethylether 5:1, yield 6.3 g. The mixture was partitioned between water/ethyl acetate the organics separated, dried evaporated under reduced pressure The residue was purified by chromatography on silica eluting with isohexane/diethylether 5:1, yield 6.3 g

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

Procedure: To a solution of 4-fluoro-2-hydroxy-benzaldehyde (560 mg, 4 mmol) in DMF (10 ml) were added benzyl chloride (0.5 ml, 4.33 mmol), and K2CO3 (860 mg, 6.22 mmol). After heating at reflux for an hour, the reaction mixture was allowed to cool to room temperature and was poured into a mixture of EtOAc/H2O. The organic layer was separated, washed with H2O and dried over MgSO4. The resulting oil was purified by flash chromatography to give 2-benzyloxy-4-fluoro-benzaldehyde as pale oil (628 mg, 68%), 1H NMR (CDCl3, 300 MHz) δ: 5.17 (s, 2H), 6.74 (m, 2H), 7.36 (m, 5H), 7.88 (m, 1H), 10.51 (s, 1H). After heating at reflux for an hour The organic layer was separated washed with H2O dried over MgSO4 The resulting oil was purified by flash chromatography

Conditions: temp:0.00; pressure:0.00; stir: