3- thiophene, Vilsmeier-Haack reaction

Acylthiophenes. Manufacturing methods introducing the carboxaldehyde group into the 2- or 5-positions of thiophene and alkylthiophenes utilise the Vilsmeier-Haack reaction. To synthesize 2-thiophenecarboxaldehyde (Table 5), a controlled addition of phosphoms oxychloride to thiophene in /V, /V- dim ethyl form am i de is carried out, causing the temperature to rise. Completion of the reaction is followed by an aqueous quench, neutralization, and solvent extraction to isolate the product. 

The Vilsmeier-Haack reaction of ketones forms chlorovinyl aldehydes, which can add thiols readily. The reaction with a-tetralone gave the chlorovinyl aldehyde (230), and reaction with ethyl thioglycolate in ethanolic ethoxide solution formed the dihydro derivative (231), easily dehydrogenated to naphtho[l,2-6]thiophene-2-carboxylate (73JCS(P1)2956). 

Thenaldehyde (thiophene-2-carbaldehyde) is readily available via the Vilsmeier-Haack reaction of DMF with thiophene catalyzed by phosphorus oxychloride. The Sommelet reaction with 2-chloromethylthiophene also gives reasonable yields (63AHC(l)l). Likewise, thiophene is readily acylated with acyl anhydrides or acid chlorides (equation 14), using mild Friedel-Crafts catalysts, such as tin(IV) chloride, zinc chloride, boron trifluoride, titanium tetrachloride, mercury(II) chloride, iodine and even silica-alumina gels or low-calcium-content montmorillonite clays (52HC(3)l). 

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-... 

The synthesis of 5- and 6-(N,N-di- -propyl)amino-4,5,6,7-tetrahydrobenzo[ ]thiophene (34 and 35) has been described previously (Chapter 2). Using a Vilsmeier-Haack reaction, a formyl moiety was introduced on the 2-position of the thiophene ring.240 An excess of N-methylformanilide was used which could be easily removed by column chromatography. Reduction of the formaldehydes 65 and 68 with NaBFC yielded the hydroxymethyl compounds 66 and 69. From compound 65, the aldoxime 67 was synthesised, using hydroxylamine.HCl in ethanol and 5N NaOH-solution. 

The Vilsmeier-Haack reaction has been used in die synthesis of thiophenes with potential anti-inflammatory properties. The electron-rich ring of the thiophene system makes it an ideal nucleophile for the Vilsmeier-Haack... 

Usually formylation of thiophenes is possible through a direct Vilsmeier-Haack reaction [208, 209]. Alternatively, thiophene-carbaldehydes, for example, 78 and 80, can be prepared by the reaction of thienyllithiums with iV,iV-dimethylformamide (Scheme 33, Table 20) [210, 212, 213, 215-219]. Notably, thiophene-3-carbaldehyde derivatives are easily accessible using this formylation methodology. 

Thiophene is also readily acylated under both Friedel-Crafts and Vilsmeier-Haack conditions and similarly to pyrrole and furan gives 2-acylated products. An almost quantitative conversion of thiophene into its 2-benzoyl derivative is obtained by reaction with 2-benzoyloxypyridine and trifluoroacetic acid. The attempted preparation of 2-benzoylthiophene under standard Friedel-Crafts conditions, however, failed (80S139). 

Alkoxybenzo[6]thiophenes undergo electrophilic substitution in the 2-position. Thus, 6-ethoxybenzo[6]thiophene affords its 2-bromo, 2-formyl, and 2-acetyl derivatives on bromination, Vilsmeier-Haack formylation, and Friedel-Crafts acetylation, respectively,424 and 6-methoxybenzo[6]thiophene undergoes Friedel-Crafts reaction with /3-carbomethoxypropionyl chloride in the 2-position.618... 

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