Vilsmeier-Haack formylation, activation

Activation Parameters for Vilsmeier-Haack Formylation in CHC1,... 

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. 

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... 

Synthesis of left-hand segment began with 7-benzyloxyindole 197. A Vilsmeier-Haack formylation followed by condensation afforded nitroalkene 198. Reduction, acylation with succinic anhydride, and subsequent Bischler-Napieralski cyclization provided dihydro-p-carboline 199. Noyori asymmetric reduction of 199, further treatment with A-iodosuccinimide, followed by activation with silver triflate in the presence of dimethoxy-N,N-diallylaniline furnished the desired coupling product 200. Subsequent saponification and cyclization via a ketene intermediate gave the rearrangement precursor 201. Oxidative skeletal rearrangement initiated by m-CPBA followed by removal of the Fmoc group and conversion of the aniline to the hydrazine furnished Fischer indole precursor 202 (Scheme 35). 

VILSMEIER - HAACK - VIEHE Reagent Formylation of aremalics, alkenes, activated H compounds by MeaN -CHCI Cl (Vilsmeier-... 

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),... 

Scheme 11.5 gives some examples of these acylation reactions. Entry 1 is an example of a chloromethylation reaction. Entry 2 is a formylation using carbon monoxide. Entry 3 is an example of formylation via to-chloromethyl ether. A cautionary note on this procedure is the potent carcinogenicity of this reagent. Entries 4 and 5 are examples of formylation and acetylation, using HCN and acetonitrile, respectively. Entries 6 to 8 are examples of Vilsmeier-Haack reactions, all of which are conducted on strongly activated aromatics. 

In miscellaneous oxidative processes of indoles, two methods for the preparation of 3-hydroxyindoles have been reported. The first approach involves initial Vilsmeier-Haack reaction of indole-2-carboxylates 176 to afford the corresponding 3-formyl analogs 177. Activation of the aldehyde with p-toluenesulfonic acid (PTSA) and Baeyer-Villiger oxidation with m-chloroperoxybenzoic acid (wi-CPBA) then affords high yields of the 3-hydroxy compounds 178 <00TL8217>... 

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-... 

Formylation of aromatics, alkenes, activated H compounds by Me2N+=CHCICI (Vilsmeier-Haack) or Me2N+=CCI2CI (Viehe) reagent (see 1st edition). 

Treatment of DMF with Tf20 results in the formation of an imminium triflate, which formylates less active aromatics. It is a convenient variation of the Vilsmeier-Haack reaction (eq 30). ... 

Another useful method for introducing formyl and acyl groups onto aromatic nuclei involves the use of N,N-dialkylamides and phosphorus oxychloride this is the Vilsmeier-Haack reaction. The active electrophile shown in the mechanistic outline is a product of phosphorylation of the amide at oxygen ... 

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. 

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