methyl 2-(bromomethyl)-5-fluorobenzoate

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

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

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-bromomethyl-5-fluoro-benzoic acid methyl ester (0.094 g, 0.5 mmol), benzylamine (0.076 mL, 0.7 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-benzyl-6-fluoro-2,3-dihydro-isoindol-1-one (0.085 g, 70.7%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.24 (s, 2H), 4.79 (s, 2H), 7.18-7.39 (m, 7H), 7.55 (m, 1H). GC-MS: m/z 241 (M)+, 164 (M−77)+. was heated

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

Procedure: A mixture of methyl 2-(bromomethyl)-5-fluorobenzoate (0.750 g, 3.04 mmol) and calcium carbonate (1.823 g, 18.21 mmol) in 1,4-dioxane (30 mL) and water (30.0 mL) was heated at reflux for 2.5 hr. The insoluble material was removed by filtration. The filtrate was concentrated under vacuum and then extracted with CH2Cl2 (4×30 mL). The combined extract was dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (0.423 g, 2.78 mmol, 92% yield) as a white solid. was heated at reflux for 2.5 hr The insoluble material was removed by filtration The filtrate was concentrated under vacuum extracted with CH2Cl2 (4×30 mL) The combined extract was dried over anhydrous MgSO4 Removal of solvent under vacuum

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

Procedure: In a dry flask under nitrogen, di-tert-butyl iminodicarboxylate (Aldrich, 3.86 g, 17.8 mmol) was dissolved in dry DMF (5 mL) and treated with NaH (60% dispersion in oil, 0.71 g, 17.8 mmol). After the evolution of gas had ceased, Methyl 2-(bromomethyl)-5-fluorobenzoate (4 g, 16.2 mmole) dissolved in DMF (5 mL) was added. An additional 5 mL of DMF was added to aid stirring. The reaction was stirred for 2 hrs, then partitioned between water and EtOAc. The organic layer was dried with Na2SO4, filtered and concentrated and the residue was purified on silica eluting first with toluene, then with a gradient of 0-5% MeOH(CHCl3. The impure product thus obtained was re-chromatographed on silica eluting with a gradient of 0-30% EtOAc/Hexanes. The product was obtained as a clear oil. was added The reaction was stirred for 2 hrs partitioned between water and EtOAc The organic layer was dried with Na2SO4 filtered concentrated the residue was purified on silica eluting first with toluene The impure product thus obtained was re-chromatographed on silica eluting with a gradient of 0-30% EtOAc/Hexanes The product was obtained as a clear oil

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

Procedure: With no precautions to maintain a dry atmosphere, methyl 5-fluoro-2-methylbenzoate (Maybridge, 5 g, 29.7 mmole) was dissolved in CCl4 (50 mL). N-bromosuccinimide (5.82 g, 32.7 mmol) and benzoyl peroxide (0.36 g, 1.48 mmole) were added and the reaction brought to reflux overnight. An additional 0.3 eq of NBS and 0.01 eq of benzoyl peroxide was added and the reaction refluxed for 4 hrs, then cooled, filtered and concentrated. The residue was chromatographed on silica eluting with a gradient of 0-10% EtOAc/Hexanes. The fractions were collected to give the product, which was a mixture of mono and bis-brominated materials, as a clear oil. to reflux overnight the reaction refluxed for 4 hrs cooled filtered concentrated The residue was chromatographed on silica eluting with a gradient of 0-10% EtOAc/Hexanes The fractions were collected to give the product, which a mixture of mono and bis-brominated materials

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

Procedure: In a dry flask under nitrogen, di-tert-butyl iminodicarboxylate (Aldrich, 3.86 g, 17.8 mmol) was dissolved in dry DMF (5 mL) and treated with NaH (60% dispersion in oil, 0.71 g, 17.8 mmol). After the evolution of gas had ceased, Methyl 2-(bromomethyl)-5-fluorobenzoate (4 g, 16.2 mmole) dissolved in DMF (5 mL) was added. An additional 5 mL of DMF was added to aid stirring. The reaction was stirred for 2 hrs, then partitioned between water and EtOAc. The organic layer was dried with Na2SO4, filtered and concentrated and the residue was purified on silica eluting first with toluene, then with a gradient of 0-5% MeOH/CHCl3. The impure product thus obtained was re-chromatographed on silica eluting with a gradient of 0-30% EtOAc/Hexanes. The product was obtained as a clear oil. was added The reaction was stirred for 2 hrs partitioned between water and EtOAc The organic layer was dried with Na2SO4 filtered concentrated the residue was purified on silica eluting first with toluene The impure product thus obtained was re-chromatographed on silica eluting with a gradient of 0-30% EtOAc/Hexanes The product was obtained as a clear oil

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

Procedure: With no precautions to maintain a dry atmosphere, methyl 5-fluoro-2-methylbenzoate (Maybridge, 5 g, 29.7 mmole) was dissolved in CCl4 (50 mL). N-bromosuccinimide (5.82 g, 32.7 mmol) and benzoyl peroxide (0.36 g, 1.48 mmole) were added and the reaction brought to reflux overnight. An additional 0.3 eq of NBS and 0.01 eq of benzoyl peroxide was added and the reaction refluxed for 4 hrs, then cooled, filtered and concentrated. The residue was chromatographed on silica eluting with a gradient of 0-10% EtOAc/Hexanes. The fractions were collected to give the product, which was a mixture of mono and bis-brominated materials, as a clear oil. to reflux overnight the reaction refluxed for 4 hrs cooled filtered concentrated The residue was chromatographed on silica eluting with a gradient of 0-10% EtOAc/Hexanes The fractions were collected to give the product, which a mixture of mono and bis-brominated materials