Aromatic compounds Vilsmeier-Haack reaction

The reaction of electron-rich aromatic compounds with yV,A -dimethylformamide 2 and phosphorus oxychloride to yield an aromatic aldehyde—e.g. 3 from the substituted benzene 1—is called the Vilsmeier reaction or sometimes the Vilsmeier-Haack reaction. It belongs to a class of formylation reactions that are each of limited scope (see also Gattermann reaction). 

There are several methods for the direct introduction of an aldehyde group into an aromatic compound. In the Vilsmeier-Haack reaction, activated aromatic systems such as aryl ethers and dialkylanilines are formylated by a mixture of dimethylformamide, HCONMe2, and phosphorus oxychloride, POCL, (Scheme 6.4). The process involves elec-trophilic attack by a chloroiminium ion, Me2N=CHCl, formed by interaction of dimethylformamide and phosphorus oxychloride. Hydrolysis of the dimethyl imine completes the synthesis. 

Vilsmeier-Haack reaction. Formulation of activated aromatic or heterocyclic compounds with disubstituted formamides and phosphorus oxychloride. 

The classical Vilsmeier-Haack reaction - involves electrophilic substitution of a suitable carbon nucleophile with a chloromethyleneiminium salt, for example salt (1). Suitable carbon nucleophiles are generally electron-rich aromatic compounds such as V,N-dimethylaniline (2), alkene derivatives such as styrene (3) or activated methyl or methylene compounds such as 2,4,6-trinitrotoluene (4 Scheme I). These compounds (2-4) react with salt (1) giving, after loss of hydrogen chloride, the corresponding im-inium salts (5-7). Hydrolysis of iminium salt (5) affords aldehyde derivative (8) and this transformation (Ar—H - Ar—CHO) is the well-known Vilsmeier-Haack formylation reaction. Hydrolysis of iminium... 

The Vilsmeier-Haack reaction of electron-rich carbocyclic aromatic compounds (Ar—H) with chloromethyleneiminium salt (1) gives aldehyde derivatives (Ar—CHO), generally in good yield. The intermediate iminium salt (cf. salt 5 Scheme 1) can be treated with hydroxylamine to obtain nitrile derivatives (Ar—CN). Benzene and naphthalene are not sufTiciently electron rich to participate in the Vilsmeier-Haack reaction, but polycyclic hydrocarbons, such as anthracene, do react. Benzene and naphthalene derivatives that possess an electron-releasing substituent (—OMe,—SMe,—NMe2, etc.) af-... 

A variation of the Vilsmeier-Haack reaction uses a formamide such as 211 with benzene (or another aromatic compound) to give the aromatic aldehyde (benzaldehyde) and the amine precursor to the formamide (N-methylaniline in this case). A solvent-free Vilsmeier reaction has been reported using microwave irradiation on silica gel. 39... 

In the Vilsmeier-Haack reaction, a reagent such as A(A-dimethylformamide (DMF) is the source of the formyl group. Reaction of DMF with phosphorus oxychloride (POCI3), creates an electrophilic iminium ion in situ that reacts with activated aromatic compounds. Hydrolysis of the resulting imininm ion results in a benzaldehyde derivative. 

The Vilsmeier-Haack reaction leads to the formation of aromatic aldehydes starting from reactive aromatic compounds. The usual reagent combination is phosphoryl chloride or phosgene together with V-methylformanilide (MFA) or VA -dimethyl-formamide (DMF) [139,140]. First, a V,V-dimethyliminium salt, e.g. 63, is formed which, after basic hydrolysis, gives carbaldehyde. 

The methylene carbon atom in a condensed 4-thiazolidinone flanked by a sulfur atom and a carbonyl group possesses enhanced nucleophilic activity and attacks an electrophilic center with ease. If the structure permits, the reaction product loses a molecule of water, and an unsaturated derivative is formed. The reaction is carried out in the presence of a base which abstracts a methylene proton. It is the anion thus formed that attacks the electrophilic center. Generally, the anion condenses with aromatic aldehydes, nitroso compounds, aryidiazonium salts, and ethyl orthoformate, as well as undergoing Vilsmeier-Haack and Mannich reactions. 

Electrophilic Aromatic Substitution Reactions. Friedel-Crafts alkylation, acylation, and the Vilsmeier-Haack formylation, shown below, are excellent reactions for the synthesis of substituted aromatic compounds. 

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