3- thiophene, Vilsmeier-Haack

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. 

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). 

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). 

Methoxybenzo[J>]thiophene undergoes Friedel-Crafts acylation in the 7-position if this position is blocked, then substitution occurs exclusively in the 2-position.614 It undergoes Vilsmeier-Haack formylation to give its 7-formyl derivative.93... 

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... 

Dimethoxy- and 5,6-methylenedioxybenzo[6]thiophene undergo bromination, Vilsmeier-Haack formylation, and Friedel-Crafts acetylation in the 2-position (see Section VI, A).189 With nitric acid, however, 5,6-methylenedioxybenzo[6]thiophene affords an unidentified mononitro derivative, which is not the 2-nitro compound.548... 

When considering the synthesis of phospholes, one has to forget most of the classical and powerful methods employed for the preparation of thiophenes and pyrroles. For example, Paal-Knorr condensation, direct ortho-lithiation, halogenation with NBS or I2/Hg2+ and Vilsmeier-Haack formylation are not operative in phosphole chemistry. Likewise, no chemical or electrochemical oxidative polymerization... 

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-... 

Successive reduction of l,3-dimethyl-4,5,6,7-tetrahydrobenzo[c]-thiophen-4-one (Section III,C) with sodium borohydride and dehydration of the resulting alcohol with polyphosphoric acid gives the unstable 1,3-dimethyl derivative [(18) R = H] in excellent yield,35 and successive treatment of the same ketone with methylmagnesium iodide and acid gives the 1,3,7-trimethyl derivative [(18) R=Me] (Table IV) and a second compound which is reported to be a dimer. 36 When l,3-dimethyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one is treated with a mixture of phosphorus oxychloride and dimethyl-formamide (Vilsmeier-Haack formylation), it gives compound 19, which yields 20 on being treated successively with thioglycolic acid... 

VILSMEIER - HAACK - VIEHE Reagent 399 VOI6HT Alpha-amnoketone synthesis 400 VOLHARDT - ERDMANN Thiophene... 

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. 

---