Vilsmeier-Haack Reaction
The Vilsmeier-Haack reaction is the formylation reaction of an electron-rich arene using a Vilsmeier reagent. The reagent is prepared from a N,N-disubstituted formamide (such as DMF) and POCl3.
General features:
1. The Vilsmeier reagent is a weak electrophile that can react with electron-rich aromatic or heteroaromatic compounds, electron-rich alkenes, and 1,3-dienes. 2. The transformation is regioselective. Substitution takes place at the less sterically hindered position (para position on a benzene ring); additionally, electronic effects can also influence the product distribution. 3. Common solvents for this transformation are DCM, DMF, and POCl3.
Vilsmeier-Haack Reaction
Reaction Mechanism
1. Formation of the Vilsmeier reagent: a substituted amide reacts with phosphorus oxychloride to afford a substituted chloroiminium ion. 2. Electrophilic Aromatic Substitution: the electron-rich aromatic ring attacks the iminium ion. 3. Release of a chloride ion generates an iminium intermediate. 4. Final hydrolysis affords the corresponding ketone or aldehyde.
Example
Experimental Procedure
To a solution of the substrate (44.5 mmol, 1.0 equiv) in DMF (440 mL) was added (Chloromethylene)dimethyliminium Chloride (1.5 equiv) at 0 °C. After stirring for 6.5 h at room temperature, a solution of NaOAc (5.6 equiv) in water (200 mL) was added at 0 °C and stirred for 10 min. at 0 °C. The reaction mixture was diluted with water and extracted with Et2O. The organic layer was washed with brine and dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the aldehyde (yield 77%).
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