Synthesis and Reactivity of Aryl- and Heteroaryl-Magnesium Reagents Bearing Keto Groups

Abstract

The reaction of iodophenyl ketones with neo-pentylmagnesium bromide in THF or THF:NMP or THF:DMAC mixtures allows the first preparation of aryl- and heteroarylmagnesium species bearing a ketone. Under appropriate conditions, these new reagents react with a range of electrophiles, leading to polyfunctional products.

Key words

functionalised organomagnesium reagents - iodine-magnesium exchange - cross-coupling - palladium catalysis

References

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• Typical procedures:
• 9a

  Preparation of 2-[2-(2,2-dimethylpropionyl)-benzyl]-acrylic acid ethyl ester (3d) using Method A (entry 4 of Table [1] ):
  A dry and argon flushed 50 mL Schlenk tube, equipped with a septum and a magnetic stirrer was charged with 1-(2-iodophenyl)-2,2-dimethylpropan-1-one(1b) (288 mg, 1.0 mmol) in dry THF (0.5 mL). The solution was cooled to -50 °C and NpMgBr (3.6 mL, 0.6 M in THF, 2.25 mmol) was slowly added. The pale yellow mixture was stirred for 3 d at -40 °C until GC-analysis of a reaction aliquot indicated complete iodine-magnesium exchange. Then CuCN·2LiCl [8] (2.3 mL, 1.0 M in THF, 2.3 mmol) was slowly added. After 15 min, ethyl (2-bromomethyl)acrylate [4] (500 mg, 0.35 mL, 2.5 mmol) was added and the reaction mixture was allowed to warm up to room temperature overnight. After quenching with sat. aq NH₄Cl (5 mL), the aqueous phase was extracted with dichloromethane (3 × 30 mL) and the combined organic phases were dried with sat. aq. NaCl and concentrated in vacuo. The residue was purified by flash chromatography (95:5 pentane/ether) yielding 2-[2-(2,2-dimethylpropionyl)-benzyl]acrylic acid ethyl ester (3d) as a clear oil (215 mg, 81%).

• 9b

  Preparation of 2,2-dimethyl-1-(2-phenylthio-phenyl)-propan-1-one (3f) using Method B (entry 6 of Table [1] ):
  A dry and argon flushed 10 mL Schlenk flask, equipped with a septum and a magnetic stirrer, was charged with 1-(2-iodophenyl)-2,2-dimethylpropan-1-one (1b) (145 mg, 0.5 mmol) in dry THF (0.5 mL). The solution was cooled to
  -45 °C and NpMgBr (1.0 mL, 0.6 M in THF, 0.6 mmol), then NMP (0.5 mL) were slowly added. The yellow mixture was rapidly stirred and warmed up to -25 °C within 15 min, with formation of a sticky, brownish precipitate. At this temperature, GC-analysis of a reaction aliquot indicated complete iodine-magnesium exchange. Diphenyl disulphide (220 mg, 1.0 mmol) was added. The reaction mixture was stirred for 8 h and slowly warmed up to room temperature. GC-analysis indicated complete conversion. After quenching with sat. aq NH₄Cl (3 mL), the aqueous phase was extracted with dichloromethane (3 × 20 mL) and the combined organic phases were dried with sat. aq. NaCl and concentrated in vacuo. The residue was purified by flash chromatography (95:5 pentane/ether), yielding 2,2-dimethyl-1-(2-phenylthiophenyl)-propan-1-one (3f) as a clear oil (99 mg, 74%).

• 9c

  Preparation of 1-(5-trimethylstannylthiophen-2-yl)-butan-1-one (13) using Method B (entry 8 of Table [1] ):
  A dry and argon flushed 50 mL Schlenk tube, equipped with a septum and a magnetic stirrer, was charged with 2-butyryl-5-iodothiophene (9) (280 mg, 1.0 mmol) in dry THF (5 mL) and DMAC (1.0 mL). The reaction mixture was cooled to
  -90 °C and NpMgBr (2.0 mL, 0.6 M in THF, 1.2 mmol) was slowly added. The mixture was rapidly stirred for 1 h at -78 °C with formation of a white precipitate. Chlorotrimethylstannane (2.0 mL, 1.0 M in THF, 2.0 mmol) was slowly added and the reaction mixture was allowed to warm up to room temperature over 12 h. The reaction mixture was quenched by the addition of sat. aq. NH₄Cl (5 mL). The aqueous phase was extracted with dichloromethane (3 × 30 mL) and the combined organic phases were dried with sat. aq NaCl and concentrated in vacuo. The residue was purified by flash chromatography (95:5 pentane/ethyl acetate), yielding 1-(5-trimethylstannyl-thiophen-2-yl)-butan-1-one (13) as a clear liquid (190 mg, 60%).