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Nucleophilic addition of Grignard to acid chloride in the presence of N-Methyl pyrrolidine; p-fluoro-4'-chlorobutyrophenone

SyntheticPage 533
DOI: 10.1039/SP533
Submitted Jan 31, 2012, published Feb 03, 2012
Ramesha Ramakrishna (

			Reaction Scheme: Nucleophilic addition of <em></em>Grignard to acid chloride in the presence of N-Methyl pyrrolidine

Chemicals Used

4-chlorobutyrylchloride - commercial -purity min 98%
4-fluorobromobenzene - Commercial, purity min. 98%
magnesium freshly cut , 99%
Tetrahydrofuran - commercial, predried over sodium before use 
Toluene- commercial , 99% pure
Dichloromethane -commercial, 99% pure
Ammonium chloride -commercial, 98% pure 
N-Methylpyrrolidine -commercial, purity min 98% 


Part A: p-fluorophenylmagnesium bromide:

Dry THF (20 mL) was charged to a three necked 100 mL flask under nitrogen atmosphere. Magnesium turnings (0.65 g, 27 mmol, initiation works better if it is dried at 70-80 oC for 2 h and used immediately). To this about 1 mL of a solution of p-bromofluorobenzene (3.37 g, 25 mmol) in 10 mL dry toluene is added and the Grignard reaction initiated. Once the reaction is initiated (if the initiation does not start, a drop of dibromo ethane is added), the exotherm is further continued by the addition of above solution. After complete addition, the reaction mixture is refluxed for 2 h and cooled under nitrogen atmosphere to get para fluoro phenyl magnesium bromide in THF-toluene solution.

Part B: Reaction of para-fluorophenylmagnesium bromide with 4-chlorobutyryl chloride :

To a well-stirred solution of N-methylpyrrolidine (2.5 g, 25.3 mmol) in dry toluene (10 mL) under nitrogen, was added 4-chlorobutyrylchloride (3.52g, 25.0 mmol) in toluene (10 mL) at 0 oC during 15 mins and the reaction mixture was stirred for 15 mins at the same temperature. To this PART A solution ( freshly prepared para-fluorophenyl magnesium bromide solution) was added at 0 to -5 ºC during 15 mins. The mixture was further stirred at 0 to -5 oC for 4 hrs and quenched the reaction mixture with aqueous ammonium chloride solution (10 g solution in 30 mL water, exothermic- care should be taken while adding initial 25% of ammonium chloride solution). The organic layer was seperated and the aqueous layer was extracted with CH2Cl2 (3 × 50 mL ). The combined organic layer was washed with dil HCl (20%, 100mL), saturated sodium bicarbonate solution (100mL) and with water (2 × 50 mL). The combined organic layer was dried over sodium sulfate and the solvent was removed completely under reduced pressure. The residue was purified by column chromatography on silica gel to obtain the para fluoro -4‘-chloro butyrophenone (6.017 g, 88%).

Author's Comments

1. THF should be dried before use.
2. Toluene is dried by the way of distilling 20% and cooling under nitrogen.
3. N-Methyl pyrrolidine with moisture content <0.2% used for the reaction.
4. During the initial part of reaction if the temperature goes above 5 degree, THF-acid chloride opened product is observed as side product.
5. This reaction scaled up to 500 g batch with out any problem. 


Colorless liquid; IR (Neat, cm-1): 2964, 1687,

 1H NMR (CDCl3, 400 MHz); δ 7.90 - 8.00 (m, 2H), 7.0 - 7.10 (m, 2H,), 3.68 (t, 2H, J = 6.2 Hz), 3.16 (t,2H, J = 6.9 Hz), 2.22 (quintet, 2H, J = 6.4 Hz).

13C NMR (CDCl3, 75 MHz): δ 197.2, 166.9, 164.4, 133.0, 130.5, 130.4, 115.7, 115.5, 35.0, 31.0, 26.5;

MS (EI) m/z 201(M+).

Lead Reference

M. S. Gowda, S. S. Pandey, Ramesha A. Ramakrishna, Prabhu, K. R Org. Biomol. Chem., 2011, 9, 5365.

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Keywords: acid chloride, aromatics/arenes, electrophilic, Grignard reaction, ketones, N-methylpyrrolidine, nucleophilic, transition metal catalysed

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