Formylation of Thiophene

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. 

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The introduction of the cheap and commercially available N,N-dimethylformamide, instead of A-methylformanilide in the POCI3 catalyzed Vilsmeier formylation of thiophene, has made 2-thio-... 

Thiophene-2-carbaldehyde has become extremely cheap and easily available through the Vilsmeier formylation of thiophene. The reactions of thiophene substrates with several iminium salts have been investigated (B-76MI31400). 3-Phenylthiophene gives 4-phenylthiophene-2-carbaldehyde with chloromethylene iminium ion. In the case of 2-methoxy-5-methylthiophene, a dealkylation takes place above 50-70 °C. If the intermediate iminium salt (91) is formed at 20 °C and then hydrolyzed, the aldehyde (92) is obtained. 

A kinetic study of the Vilsmeier-Haak formylation of thiophene derivatives in dichloroethane solution has been recently reported.156 Reactions of thiophene and 2-methylthiophene follow third-order kinetics, first-order in substrate, dimethylformamide (DMF), and phosphorus oxychloride. These results are in agreement with a mechanism involving a rapid preequilibrium step leading to an... 

V-Methyl-/V-phenylformamide has been used as an alternative amide in determination of the relative reactivities toward formylation of thiophene and selenophene (73JGU871). 

Kinetic investigation of the formylation of thiophene and of 2- and 3-methylthiophene in 1,2-dichloroethane showed the reactions to be first order in each of aromatic, DMF, and POC1,. However, for the much more reactive 2-methoxythiophene, the reaction is second order overall, and zeroth order in aromatic. This is consistent with a slow pre-equilibrium to form the electrophile [(Me2NC+HCl)P02Cl2-], which reacts with the aromatic to give the Wheland intermediate in a step which is ratedetermining except when the aromatic is very reactive, whereupon this step becomes relatively fast. Finally, the intermediate decomposes to products in a fast step [72JCS(P2)2070]. 

Linda, P., Marino, G., Santini, S. Electrophilic substitutions in five-membered heteroaromatic systems. XIII. Kinetics and mechanism of the Vilsmeier formylation of thiophene derivatives. Tetrahedron Lett. 1970,4223-4224. 

Organic Syntheses procedures utilizing DMF-POC Is I ciigcnt iillonJ p-dimethyl-aminobenzuldehyde in 80-84% yield and 2-pyrroleuldehydc in 78-79% yield." Formylation of thiophene derivatives with the reagent is reported."... 

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. 

Acylation. To achieve acylation of thiophenes, acid anhydrides with phosphoric acid, iodine, or other catalysts have been widely used. Acid chlorides with AlCl, SnCl, ZnCl2, and BF also give 2-thienylketones. AH reactions give between 0.5 and 2.0% of the 3-isomer. There has been much striving to find catalyst systems that minimize the 3-isomer content attempting to meet to customer specifications. The standard procedure for formylation is via the Vil smeier-H a ack reaction, using phosphoms o xycbl o ri de / /V, / V- dim e tb yl fo rm a m i de (POCl /DMF) or /V-m ethyl form an i1 i de. 

It is thus apparent that the selectivity of a reagent toward thiophene and benzene can differ appreciably, and this difference in selectivity is also strongly noticeable in the proportions of 2- and 3-isomers formed. Although in certain reactions no 3-isomer has been detected, appreciable amounts have been found in other reactions. Thus 0.3% of the 3-isomer has been found in the chlorination of thiophene.- Earlier results indicated that 5-10% 3-nitrothiophene is formed in the nitration of thiophene and a recent gas-chromatographic analysis by Ostman shows that the mononitrothiophene fraction contains as much as 16% of the 3-isomer. It appears that gas-chromatographic analysis should be very useful for the detection of small amounts of 3-isomers in other substitution reactions. However, from routine analyses of IR spectra, it appears to the present author that the amount of 3-isomers formed in acylation, formylation, and bromina-tion of thiophene are certainly less than a few per cent. 

The authors of this review have developed a straightforward procedure for the synthesis of unsubstituted and alkyl-substituted thieno-thiophenes 1, 2, and 3 the method involves intramolecular condensation of ortho-bifunctional thiophene derivatives. Vilsmeier formylation of an alkyl (5-ethyl-2-thienylthio)acetate (53) furnishes the (5-ethyl-3-formyl-. 2-thienylthio)acetate (54) which when heated with alcoholic sodium... 

Gol dfarb and Litvinov first formylated a thienothiophene. In Vilsmeier formylation of 2-ethylthieno[2,3- ]thiophene (20) the formyl group enters the vacant a-position, producing 5-ethyl-2-formylthieno-[2,3- ]thiophene 16%). Oxidation of the latter with silver oxide gives 5-ethylthieno[2,3-6]thiophene-2-carboxylic acid (55) identical with that formed by cydizing the ester of (5-ethyl-3-formyl-2-thienylthio)acetic... 

When a-positions in thienothiophenes 1 and 2 are both blocked, the formyl group enters a -position. Thus, formylation of 5-ethyl-2-ethylthiothieno[2,3-h]thiophene and 5-ethyl-2- ylthiothieno[3,2-hj-thiophene afforded high yields of the 3-formyl derivatives lEqs. (64) and (65)]. 2-Ethylthiobenzo[ ]thiophene reacts analogously. 

More vigorous conditions were required for the formylation of thienothiophene 3 with an electron acceptor group in the molecule. Thus, refluxing methyl thieno[3,4-6]thiophene-2-carboxylate, iV-methyl-formanilide and phosphorus oxychloride for 1 hour gave a mixture (1 1)... 

Viismeier reaction Formylation of pyrrole, furan or thiophene is carried out using a combination of phosphorus oxychloride (POCI3) and... 

Most work, however, has been done on systems with several substitution sites. Formylation of the thieno[2,3-6]pyrroles (389) and (390) showed that in the former case, formylation takes place predominantly (90%) at C-5, and 10% at C-4. An electron-attracting substituent at C-5, as in 390, orients substitution into the thiophene ring (95% at C-2).407... 

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-... 

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