1-bromo-4-fluoro-2-methylbenzene

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:0.00; pressure:0.00; stir:

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

Conditions: temp:100.01; pressure:0.00; stir:

Procedure: The general procedure A was followed using 1-bromo-4-fluoro-2-methylbenzene (61.5 uL, 0.5 mmol) and B2pin2 (126.9 mg, 0.5 mmol, 1.0 eq.) as starting material. The resulting mixture was allowed to stir 16 hours at 100 oC. 5o was obtained as white solid (158.0 mg, 100%) after purification by silica gel flash chromatography (EtOAc/PE=1:30 v/v). m.p.: 72-74 oC.

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

Procedure: A mixture of 2-bromo-5-fluorotoluene (2) (3.5 g, 18.5 mmol) and CuCN (2 g, 22 mmol) in DMF (100 mL) was refluxed for 24 hours. The reaction was diluted with water and extracted with hexane. The organics were dried over MgSO4 and the solvent removed to give product 3 (yield 60%). 1H-NMR (400 MHz, CDCl3): δ 7.60 (dd, J=5.6, 8.8 Hz, 1H), 6.93-7.06 (m, 2H), 2.55 (s, 3H). was refluxed for 24 hours extracted with hexane The organics were dried over MgSO4 the solvent removed

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

Procedure: To a solution of 2-bromo-5-fluorotoluene (20 g) in dry tetrahydrofuran (200 ml) was added dropwise lithium diisopropylamide (2.0 M, heptan-tetrohydrofuran-ethylbenzene solution, 52.9 ml) under argon atmosphere at −78° C. After stirring as such for 2 hours, a solution of DMF (41 ml) in dry tetrahydrofuran (50 ml) was added dropwise. The mixture was returned to room temperature and stirred for 1 hour. Then, water was added and the mixture was neutralized with 1N hydrochloric acid. After extraction with ethyl acetate, the extract was washed with saturated brine and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=24:1) and re-crystallized from hexane-ethyl acetate to give 5-bromo-2-fluoro-4-methylbenzaldehyde (9.39 g). was returned to room temperature stirred for 1 hour After extraction with ethyl acetate the extract was washed with saturated brine dried with magnesium sulfate The solvent was distilled off under reduced pressure the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=24:1) re-crystallized from hexane-ethyl acetate

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

Procedure: Combine 1-bromo-4-fluoro-2-methylbenzene (30.0 g, 159 mmol) in concentrated sulfuric acid (100 mL), cool to about −5° C., and treat dropwise with nitric acid (11.00 mL, 174 mmol) over 20 minutes. Allow reaction mixture to warm to RT and stir for 30 min. Pour onto crushed ice with stiffing and partition with tert-butyl methyl ether (MTBE) (200 mL). Separate the aqueous layer and extract with MTBE (2×50 mL). Combine organic layers, dry and concentrate under reduced pressure to provide 1-bromo-4-fluoro-2-methyl-5-nitrobenzene as an orange-colored viscous oil (39.0 g). Allow reaction mixture Pour onto crushed ice with stiffing partition with tert-butyl methyl ether (MTBE) (200 mL) Separate the aqueous layer extract with MTBE (2×50 mL) Combine organic layers, dry concentrate under reduced pressure