1-(3-bromophenyl)-1-methylhydrazine

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

Procedure: 1-(3-Bromophenyl)-1-methylhydrazine (0.50 g, 2.5 mmol) and 1-azabicyclo[3.2.2]nonan-4-one (0.38 g, 2.7 mmol) were dissolved in isopropanol (4 mL), and concentrated aqueous HCl (0.8 mL) was added. The reaction mixture was heated to reflux for 18 h, concentrated and basified using 2 N NaOH. The aqueous layer was extracted with methylene chloride (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash column chromatography (silica gel, 0%-100% solvent mixture B in methylene chloride; solvent mixture B=80:18:2 methylene chloride/methanol/concentrated ammonium hydroxide) to give the title compound (438 mg, 58%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 7.40 (d, J=2.0 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 7.16 (d, J=1.6 Hz, 1H), 4.25 (s, 2H), 3.61 (s, 3H), 3.30-3.24 (m, 3H), 3.14-3.08 (m, 2H), 2.02-1.99 (m, 4H). The reaction mixture was heated to reflux for 18 h concentrated The aqueous layer was extracted with methylene chloride (3×) The combined organic extracts were dried over Na2SO4 filtered concentrated to dryness The residue was purified by flash column chromatography (silica gel, 0%-100% solvent mixture B in methylene chloride; solvent mixture B=80:18:2 methylene chloride/methanol/concentrated ammonium hydroxide)

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

Procedure: 1-(3-Bromophenyl)-1-methylhydrazine (0.48 g, 2.3 mmol) and 1-azabicyclo[3.2.1]octan-4-one (0.33 g, 2.6 mmol) were dissolved in isopropanol (3 mL), and concentrated aqueous HCl (0.75 mL) was added. The reaction mixture was heated to reflux for 18 h, concentrated and basified using 2 N NaOH. The aqueous layer was extracted with methylene chloride (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash column chromatography (silica gel, 10%-100% solvent mixture B in ethyl acetate; solvent mixture B=80:18:2 ethyl acetate/methanol/concentrated ammonium hydroxide) to give the title compound (634 mg, 95%) as a yellow semisolid: 1H NMR (300 MHz, CDCl3) δ 7.42 (d, J=2.5 Hz, 1H), 7.20 (d, J=13.5 Hz, 1H), 7.14 (d, J=13.5 Hz, 1H), 4.40 (d, J=26.5 Hz, 1H), 3.72 (d, J=26.0 Hz, 1H), 3.63 (s, 3H), 3.34-3.25 (m, 1H), 3.20-3.17 (m, 2H), 3.17-3.13 (m, 1H), 2.97-2.92 (m, 1H), 2.87-2.76 (m, 2H). The reaction mixture was heated to reflux for 18 h concentrated The aqueous layer was extracted with methylene chloride (3×) The combined organic extracts were dried over Na2SO4 filtered concentrated to dryness The residue was purified by flash column chromatography (silica gel, 10%-100% solvent mixture B in ethyl acetate; solvent mixture B=80:18:2 ethyl acetate/methanol/concentrated ammonium hydroxide)

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

Procedure: To a solution of 3-bromophenylhydrazine hydrochloride (15 g, 67 mmol) in anhydrous THF (360 mL) was added LiHMDS (1.0 M solution in THF, 127 mL, 127 mmol) dropwise over a period of 1 h at 0° C. The reaction mixture was stirred for 30 min while warming to room temperature. The flask was recooled to −78° C., and MeI (4.1 mL, 67 mmol) was added. The reaction mixture was stirred for 2 h at 0° C. and then was quenched with water (600 mL). The aqueous layer was extracted with methylene chloride (3×200 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, hexanes/EtOAc, 60:40) gave the title compound (10.2 g, 76%) as yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.18 (t, J=3.5 Hz, 1H), 7.08 (t, J=13.5 Hz, 1H), 6.91-6.86 (m, 2H), 3.69 (br s, 2H), 3.11 (s, 3H). was recooled to −78° C. The reaction mixture was stirred for 2 h at 0° C. was quenched with water (600 mL) The aqueous layer was extracted with methylene chloride (3×200 mL) the combined organic layers were dried over sodium sulfate filtered concentrated under reduced pressure Purification by flash column chromatography (silica gel, hexanes/EtOAc, 60:40)