2-Fluoro-4-methylbenzaldehyde

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 100.89 g of aluminum chloride (mol. Wt. 133.34; 756.6 mmol) and about 503.54 g of 3-fluorotoluene (mol. Wt. 110.13; 4,572 mmol) were charged to a 2 liter Parry -brand 4522 stainless steel reaction vessel. To this mixture was added 5 drops of concentrated HCl. The vessel was sealed, heated to 60° C., and purged three times with carbon monoxide with the pressure of the vessel increased to 200 psi for each purging. After the third purge, the vessel was vented and a final introduction of CO was made at a pressure of about 200 psi, the pressure at which the reaction was maintained for the total reaction time of about 17 hours (the reaction temperature was maintained at 60° C. for the duration as well). Once the reaction was complete, the resultant mixture (exhibiting a dark orange color) was poured into about 500 mL of ice water (which turned the solution a yellow color), to which was added 500 mL of cyclohexane. The top, organic layer was removed and washed three times with water using a separatory funnel and dried over magnesium sulfate. The residual organic phase was then distilled under vacuum to remove excess cyclohexane, 3-fluorotoluene, and left about 79.65 g of a benzaldehyde mixture consisting of 4-fluoro-2-methylbenzaldehyde (88.4%) and 2-fluoro-4-methylbenzaldehyde (11.6%) (mol. Wt. 138.14; 576.6 mmol; yield of approximately 76.2%). The vessel was sealed purged three times with carbon monoxide with the pressure of the vessel increased to 200 psi for each purging After the third purge the pressure at which the reaction was maintained for the total reaction time of about 17 hours (the reaction temperature was maintained at 60° C. for the duration as well) was poured into about 500 mL of ice water (which was added 500 mL of cyclohexane The top, organic layer was removed washed three times with water using a separatory funnel dried over magnesium sulfate The residual organic phase was then distilled under vacuum to remove excess cyclohexane, 3-fluorotoluene left about 79.65 g of a benzaldehyde mixture

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 100.89 g of aluminum chloride (mol. Wt. 133.34; 756.6 mmol) and about 503.54 g of 3-fluorotoluene (mol. Wt. 110.13; 4,572 mmol) were charged to a 2 liter Parr®-brand 4522 stainless steel reaction vessel. To this mixture was added 5 drops of concentrated HCl. The vessel was sealed, heated to 60° C., and purged three times with carbon monoxide with the pressure of the vessel increased to 200 psi for each purging. After the third purge, the vessel was vented and a final introduction of CO was made at a pressure of about 200 psi, the pressure at which the reaction was maintained for the total reaction time of about 17 hours (the reaction temperature was maintained at 60° C. for the duration as well). Once the reaction was complete, the resultant mixture (exhibiting a dark orange color) was poured into about 500 mL of ice water (which turned the solution a yellow color), to which was added 500 mL of cyclohexane. The top, organic layer was removed and washed three times with water using a separatory funnel and dried over magnesium sulfate. The residual organic phase was then distilled under vacuum to remove excess cyclohexane, 3-fluorotoluene, and left about 79.65 g of a benzaldehyde mixture consisting of 4-fluoro-2-methylbenzaldehyde (88.4%) and 2-fluoro-4-methylbenzaldehyde (11.6%) (mol. Wt. 138.14; 576.6 mmol; yield of approximately 76.2%). The vessel was sealed purged three times with carbon monoxide with the pressure of the vessel increased to 200 psi for each purging After the third purge the pressure at which the reaction was maintained for the total reaction time of about 17 hours (the reaction temperature was maintained at 60° C. for the duration as well) was poured into about 500 mL of ice water (which was added 500 mL of cyclohexane The top, organic layer was removed washed three times with water using a separatory funnel dried over magnesium sulfate The residual organic phase was then distilled under vacuum to remove excess cyclohexane, 3-fluorotoluene left about 79.65 g of a benzaldehyde mixture

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

Procedure: The solution of 3-fluorotoluene (2.91 g, 0.0266 mol) in anhydrous tetrahydrofuran was cooled to −78° C. and a 1.4M solution of n-butyllithium in hexanes (19 mL, 0.0266 mol) was added dropwise keeping the reaction mixture temperature below −75° C. Upon the completion of the addition, N,N,N′,N′,N″-pentamethyldiethylenetriamine was added dropwise and the stirring at −78° C. was continued under an atmosphere of nitrogen for an additional 2 hours. N,N-dimethylformamide (3.89 g, 0.0532 mol) was added dropwise and the reaction mixture was slowly warmed up while stirring for 0.5 hours. It was quenched by dropwise addition of 1N hydrochloric acid and the layers were separated. The aqueous phase was further extracted with ethyl acetate (2×150 mL) and the combined organic extracts were dried with magnesium sulfate. The organic phase was concentrated under reduced pressure and the residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (5:95) as mobile phase to yield 2-fluoro-4-methylbenzaldehyde (0.83 g, 0.006 mol) as a white solid. the reaction mixture temperature below −75° C was added dropwise the reaction mixture was slowly warmed up It was quenched by dropwise addition of 1N hydrochloric acid the layers were separated The aqueous phase was further extracted with ethyl acetate (2×150 mL) the combined organic extracts were dried with magnesium sulfate The organic phase was concentrated under reduced pressure the residue was purified by flash chromatography on silica

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

Procedure: To a solution of 2-bromo-4-methylpyridine (600 mg) in diethyl ether (20 mL) at −78° C. is added a 2.3M solution of butyllithium in hexanes (1.52 mL). After stirring at this temperature for 1 hour 2-fluoro-4-methylbenzaldehyde is added and the mixture allowed to warm at room temperature. The reaction mixture is then hydrolyzed with diluted aqueous hydrochloric acid, washed with diethyl ether, basified with concentrated sodium hydroxide and extracted with diethyl ether. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (heptane/ethyl acetate 2/1) to afford (2-fluoro-4-methylphenyl)(4-methyl-pyridin-2-yl)methanol as a pale yellow oil which solidifies on standing. is added hydrolyzed with diluted aqueous hydrochloric acid, washed with diethyl ether extracted with diethyl ether The pooled organic extracts are dried over magnesium sulfate concentrated under reduced pressure The residue is purified by chromatography over silica gel (heptane/ethyl acetate 2/1)

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

Procedure: The solution of 3-fluorotoluene (2.91 g, 0.0266 mol) in anhydrous tetrahydrofuran was cooled to −78° C. and a 1.4M solution of n-butyllithium in hexanes (19 mL, 0.0266 mol) was added dropwise keeping the reaction mixture temperature below −75° C. Upon the completion of the addition, N,N,N′,N′,N″-pentamethyldiethylenetriamine was added dropwise and the stirring at −78° C. was continued under an atmosphere of nitrogen for an additional 2 hours. N,N-dimethylformamide (3.89 g, 0.0532 mol) was added dropwise and the reaction mixture was slowly warmed up while stirring for 0.5 hours. It was quenched by dropwise addition of 1N hydrochloric acid and the layers were separated. The aqueous phase was further extracted with ethyl acetate (2×150 mL) and the combined organic extracts were dried with magnesium sulfate. The organic phase was concentrated under reduced pressure and the residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (5:95) as mobile phase to yield 2-fluoro-4-methylbenzaldehyde (0.83 g, 0.006 mol) as a white solid. the reaction mixture temperature below −75° C was added dropwise the reaction mixture was slowly warmed up It was quenched by dropwise addition of 1N hydrochloric acid the layers were separated The aqueous phase was further extracted with ethyl acetate (2×150 mL) the combined organic extracts were dried with magnesium sulfate The organic phase was concentrated under reduced pressure the residue was purified by flash chromatography on silica

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 100.89 g of aluminum chloride (mol. Wt. 133.34; 756.6 mmol) and about 503.54 g of 3-fluorotoluene (mol. Wt. 110.13; 4,572 mmol) were charged to a 2 liter Parry -brand 4522 stainless steel reaction vessel. To this mixture was added 5 drops of concentrated HCl. The vessel was sealed, heated to 60° C., and purged three times with carbon monoxide with the pressure of the vessel increased to 200 psi for each purging. After the third purge, the vessel was vented and a final introduction of CO was made at a pressure of about 200 psi, the pressure at which the reaction was maintained for the total reaction time of about 17 hours (the reaction temperature was maintained at 60° C. for the duration as well). Once the reaction was complete, the resultant mixture (exhibiting a dark orange color) was poured into about 500 mL of ice water (which turned the solution a yellow color), to which was added 500 mL of cyclohexane. The top, organic layer was removed and washed three times with water using a separatory funnel and dried over magnesium sulfate. The residual organic phase was then distilled under vacuum to remove excess cyclohexane, 3-fluorotoluene, and left about 79.65 g of a benzaldehyde mixture consisting of 4-fluoro-2-methylbenzaldehyde (88.4%) and 2-fluoro-4-methylbenzaldehyde (11.6%) (mol. Wt. 138.14; 576.6 mmol; yield of approximately 76.2%). The vessel was sealed purged three times with carbon monoxide with the pressure of the vessel increased to 200 psi for each purging After the third purge the pressure at which the reaction was maintained for the total reaction time of about 17 hours (the reaction temperature was maintained at 60° C. for the duration as well) was poured into about 500 mL of ice water (which was added 500 mL of cyclohexane The top, organic layer was removed washed three times with water using a separatory funnel dried over magnesium sulfate The residual organic phase was then distilled under vacuum to remove excess cyclohexane, 3-fluorotoluene left about 79.65 g of a benzaldehyde mixture

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 100.89 g of aluminum chloride (mol. Wt. 133.34; 756.6 mmol) and about 503.54 g of 3-fluorotoluene (mol. Wt. 110.13; 4,572 mmol) were charged to a 2 liter Parr®-brand 4522 stainless steel reaction vessel. To this mixture was added 5 drops of concentrated HCl. The vessel was sealed, heated to 60° C., and purged three times with carbon monoxide with the pressure of the vessel increased to 200 psi for each purging. After the third purge, the vessel was vented and a final introduction of CO was made at a pressure of about 200 psi, the pressure at which the reaction was maintained for the total reaction time of about 17 hours (the reaction temperature was maintained at 60° C. for the duration as well). Once the reaction was complete, the resultant mixture (exhibiting a dark orange color) was poured into about 500 mL of ice water (which turned the solution a yellow color), to which was added 500 mL of cyclohexane. The top, organic layer was removed and washed three times with water using a separatory funnel and dried over magnesium sulfate. The residual organic phase was then distilled under vacuum to remove excess cyclohexane, 3-fluorotoluene, and left about 79.65 g of a benzaldehyde mixture consisting of 4-fluoro-2-methylbenzaldehyde (88.4%) and 2-fluoro-4-methylbenzaldehyde (11.6%) (mol. Wt. 138.14; 576.6 mmol; yield of approximately 76.2%). The vessel was sealed purged three times with carbon monoxide with the pressure of the vessel increased to 200 psi for each purging After the third purge the pressure at which the reaction was maintained for the total reaction time of about 17 hours (the reaction temperature was maintained at 60° C. for the duration as well) was poured into about 500 mL of ice water (which was added 500 mL of cyclohexane The top, organic layer was removed washed three times with water using a separatory funnel dried over magnesium sulfate The residual organic phase was then distilled under vacuum to remove excess cyclohexane, 3-fluorotoluene left about 79.65 g of a benzaldehyde mixture

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

Procedure: 2-Fluoro-4-methyl-benzaldehyde (4 g) was added to a solution of 4-aminobutan-2-one ethylene acetal (3.8 g) in dry benzene (50 mL) and the solution was stirred at r.t. under a nitrogen atmosphere. After 1 hour the mixture was heated at reflux for 16 hours and then allowed to cool to r.t. This solution was slowly added to a refluxing solution of p-toluenesulphonic acid (10.6 g) in dry benzene (50 mL) previously refluxed for 1 hour with a Dean-Stark apparatus. After 3.5 hours the crude solution was cooled and made basic with a saturated potassium carbonate solution and taken up with AcOEt (50 mL). The aqueous phase was extracted with AcOEt (3×50 mL) and Et2O (2×50 mL). The organic layer was dried and concentrated in vacuo to a yellow thick oil as residue (7.23 g). A portion of the crude mixture (3 g) was dissolved in a 6N hydrochloric acid solution (20 mL) and stirred at 60° C. for 16 hours. The solution was basified with solid potassium carbonate and extracted with DCM (5×50 mL). The combined organic phases were washed with brine (50 mL), dried and concentrated in vacuo to give the title compound (2.5 g) as a thick yellow oil. After 1 hour the mixture was heated at reflux for 16 hours to cool to r.t previously refluxed for 1 hour with a Dean-Stark apparatus The aqueous phase was extracted with AcOEt (3×50 mL) and Et2O (2×50 mL) The organic layer was dried concentrated in vacuo to a yellow thick oil as residue (7.23 g) A portion of the crude mixture (3 g) was dissolved in a 6N hydrochloric acid solution (20 mL) stirred at 60° C. for 16 hours extracted with DCM (5×50 mL) The combined organic phases were washed with brine (50 mL) dried concentrated in vacuo

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

Procedure: The solution of 3-fluorotoluene (2.91 g, 0.0266 mol) in anhydrous tetrahydrofuran was cooled to −78° C. and a 1.4M solution of n-butyllithium in hexanes (19 mL, 0.0266 mol) was added dropwise keeping the reaction mixture temperature below −75° C. Upon the completion of the addition, N,N,N′,N′,N″-pentamethyldiethylenetriamine was added dropwise and the stirring at −78° C. was continued under an atmosphere of nitrogen for an additional 2 hours. N,N-dimethylformamide (3.89 g, 0.0532 mol) was added dropwise and the reaction mixture was slowly warmed up while stirring for 0.5 hours. It was quenched by dropwise addition of 1N hydrochloric acid and the layers were separated. The aqueous phase was further extracted with ethyl acetate (2×150 mL) and the combined organic extracts were dried with magnesium sulfate. The organic phase was concentrated under reduced pressure and the residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (5:95) as mobile phase to yield 2-fluoro-4-methylbenzaldehyde (0.83 g, 0.006 mol) as a white solid. the reaction mixture temperature below −75° C was added dropwise the reaction mixture was slowly warmed up It was quenched by dropwise addition of 1N hydrochloric acid the layers were separated The aqueous phase was further extracted with ethyl acetate (2×150 mL) the combined organic extracts were dried with magnesium sulfate The organic phase was concentrated under reduced pressure the residue was purified by flash chromatography on silica

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

Procedure: To a solution of 2-bromo-4-methylpyridine (600 mg) in diethyl ether (20 mL) at −78° C. is added a 2.3M solution of butyllithium in hexanes (1.52 mL). After stirring at this temperature for 1 hour 2-fluoro-4-methylbenzaldehyde is added and the mixture allowed to warm at room temperature. The reaction mixture is then hydrolyzed with diluted aqueous hydrochloric acid, washed with diethyl ether, basified with concentrated sodium hydroxide and extracted with diethyl ether. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (heptane/ethyl acetate 2/1) to afford (2-fluoro-4-methylphenyl)(4-methyl-pyridin-2-yl)methanol as a pale yellow oil which solidifies on standing. is added hydrolyzed with diluted aqueous hydrochloric acid, washed with diethyl ether extracted with diethyl ether The pooled organic extracts are dried over magnesium sulfate concentrated under reduced pressure The residue is purified by chromatography over silica gel (heptane/ethyl acetate 2/1)

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

Procedure: The solution of 3-fluorotoluene (2.91 g, 0.0266 mol) in anhydrous tetrahydrofuran was cooled to −78° C. and a 1.4M solution of n-butyllithium in hexanes (19 mL, 0.0266 mol) was added dropwise keeping the reaction mixture temperature below −75° C. Upon the completion of the addition, N,N,N′,N′,N″-pentamethyldiethylenetriamine was added dropwise and the stirring at −78° C. was continued under an atmosphere of nitrogen for an additional 2 hours. N,N-dimethylformamide (3.89 g, 0.0532 mol) was added dropwise and the reaction mixture was slowly warmed up while stirring for 0.5 hours. It was quenched by dropwise addition of 1N hydrochloric acid and the layers were separated. The aqueous phase was further extracted with ethyl acetate (2×150 mL) and the combined organic extracts were dried with magnesium sulfate. The organic phase was concentrated under reduced pressure and the residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (5:95) as mobile phase to yield 2-fluoro-4-methylbenzaldehyde (0.83 g, 0.006 mol) as a white solid. the reaction mixture temperature below −75° C was added dropwise the reaction mixture was slowly warmed up It was quenched by dropwise addition of 1N hydrochloric acid the layers were separated The aqueous phase was further extracted with ethyl acetate (2×150 mL) the combined organic extracts were dried with magnesium sulfate The organic phase was concentrated under reduced pressure the residue was purified by flash chromatography on silica

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 100.89 g of aluminum chloride (mol. Wt. 133.34; 756.6 mmol) and about 503.54 g of 3-fluorotoluene (mol. Wt. 110.13; 4,572 mmol) were charged to a 2 liter Parry -brand 4522 stainless steel reaction vessel. To this mixture was added 5 drops of concentrated HCl. The vessel was sealed, heated to 60° C., and purged three times with carbon monoxide with the pressure of the vessel increased to 200 psi for each purging. After the third purge, the vessel was vented and a final introduction of CO was made at a pressure of about 200 psi, the pressure at which the reaction was maintained for the total reaction time of about 17 hours (the reaction temperature was maintained at 60° C. for the duration as well). Once the reaction was complete, the resultant mixture (exhibiting a dark orange color) was poured into about 500 mL of ice water (which turned the solution a yellow color), to which was added 500 mL of cyclohexane. The top, organic layer was removed and washed three times with water using a separatory funnel and dried over magnesium sulfate. The residual organic phase was then distilled under vacuum to remove excess cyclohexane, 3-fluorotoluene, and left about 79.65 g of a benzaldehyde mixture consisting of 4-fluoro-2-methylbenzaldehyde (88.4%) and 2-fluoro-4-methylbenzaldehyde (11.6%) (mol. Wt. 138.14; 576.6 mmol; yield of approximately 76.2%). The vessel was sealed purged three times with carbon monoxide with the pressure of the vessel increased to 200 psi for each purging After the third purge the pressure at which the reaction was maintained for the total reaction time of about 17 hours (the reaction temperature was maintained at 60° C. for the duration as well) was poured into about 500 mL of ice water (which was added 500 mL of cyclohexane The top, organic layer was removed washed three times with water using a separatory funnel dried over magnesium sulfate The residual organic phase was then distilled under vacuum to remove excess cyclohexane, 3-fluorotoluene left about 79.65 g of a benzaldehyde mixture