Formylation of aromatics

Formylation of aromatic hydrocarbons to aldehydes with dichloromethyl ether 47, 2... 

Reactions 11-15-11-18 are direct formylations of the ring. Reaction 11-14 has not been used for formylation, since neither formic anhydride nor formyl chloride is stable at ordinary temperatures. Formyl chloride has been shown to be stable in chloroform solution for 1 h at -60°C, but it is not useful for formylating aromatic rings under these conditions. Formic anhydride has been prepared in solution, but has not been isolated.Mixed anhydrides of formic and other acids are known and can be used to formylate amines (see 10-56) and alcohols, but no formylation takes place when they are applied to aromatic rings. See 13-15 for a nucleophilic method for the formylation of aromatic rings. 

The reaction with disubstituted formamides and phosphorus oxychloride, called the Vilsmeier or the Vilsmeier-Haack reaction,is the most common method for the formylation of aromatic rings. However, it is applicable only to active substrates, such as amines and phenols. An intramolecular version is also known.Aromatic hydrocarbons and heterocycles can also be formylated, but only if they are much more active than benzene (e.g., azulenes, ferrocenes). Though A-phenyl-A-methyl-formamide is a common reagent, other arylalkyl amides and dialkyl amides are also used. Phosgene (COCI2) has been used in place of POCI3. The reaction has also been carried out with other amides to give ketones (actually an example of 11-14),... 

Formylation of aromatic rings with formamides and POCI3... 

Friedel-Crafts acylation reactions of aromatics are promoted by Tilv complexes.104 In some cases, a catalytic amount of the titanium compound works well (Scheme 28). In addition to acyl halides or acid anhydrides, aldehydes, ketones, and acetals can serve as electrophile equivalents for this reaction.105 The formylation of aromatic substrates in the presence of TiCl4 is known as the Rieche-Gross formylation metalated aromatics or olefins are also formylated under these conditions.106... 

Formylation of aromatic substrates with the dimethylformamide-car-bonyl chloride complex in chloroform68 demonstrates simple kinetics.69... 

The only formic acid derivative that allows the direct formylation of aromatics is formyl fluoride1617 since others (halides and the anhydride) that could be used in Friedel-Crafts-type acylations are quite unstable. Other related methods, however, are available to transform aromatic hydrocarbons to the corresponding aldehydes. The most frequently used such formylations are the Gattermann-Koch reaction16 17 and the Gattermann synthesis.10 16 17... 

Other methods which are variously suitable for the formylation of aromatic hydrocarbons, phenols, phenolic ethers and heterocyclic systems, employ a range of alternative formaldehyde equivalents. These latter include the species 0... 

The Vilsmeier-Haack reaction (herein, Vilsmeier reaction ) provides an effective method for the formylation of aromatic systems. The combination of phosphoryl chloride with V-methylaniline or dimethylformamide generates an iminium phosphorus derivative or chloro-iminium cation that is the active electrophile in an electrophilic substitution reaction. The resulting substitution product is an iminium salt 1, which is hydrolyzed on workup with alkali to give the carbaldehyde product 2 (Scheme l).1,2 The method is particularly useful with activated arenes or electron-rich heterocycles, such as pyrroles, furans, thiophenes, and indoles. We had a special interest in the preparation of indole-7-carbal-dehydes, namely, their properties as isosteres of salicylaldehyde. Thus, we became involved in a wide-ranging investigation of 4,6-dimethoxy-... 

Titanium(rV) Lewis Acids 731 Table 17. Formylation of aromatic compounds with (MeO)CHCl2 and TiC. ... 

Reimer-Tiemann reaction The formylation of aromatic rings using CHC13 and OH-. Useful only for phenol, and a few heterocyclic compounds. 

PPA has been used for the formylation of aromatic compounds with hexamethylenetetramine yields are not high, but the method is simple. ... 

Duff reaction. The ortho-formylation of phenols or para-formylation of aromatic amines with hexamethylenetetramine in the presence of an acidic catalyst. 

More recently, Feng and coworkers [62] realized that the enantioselective cyano-formylation of aromatic aldehydes with ethyl cyanoformate, using a chiral quaternary ammonium salt and triethylamine. However, despite their optimization studies on the catalyst structure and reaction conditions, only moderate ee values (up to 72% ee) were obtained. 

Carbon monoxide and formic derivatives can also be used to make formylations of aromatic compounds (ref. 4) in acidic or superacidic medium. 

Formylation of aromatic rings with carbon monoxide requires the use of superacidics to activate carbon monoxide by protonation and to protonate the formed aldehyde which is the thermodynamic driving force of the reaction. 

In conclusion, formylation of aromatic rings can be obtained in HF-BF3 medium using methyl formate, a stable and cheap material. 

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