Acylation reactions of thiophenes

All lation. Thiophenes can be alkylated in the 2-position using alkyl halides, alcohols, and olefins. Choice of catalyst is important the weaker Friedel-Crafts catalysts, eg, ZnCl2 and SnCl, are preferred. It is often preferable to use the more readily accompHshed acylation reactions of thiophene to give the required alkyl derivatives on reduction. Alternatively, metalation or Grignard reactions, on halothiophenes or halomethylthiophenes, can be utilized. 

The kinetic study of the acylation reaction of thiophene with acyl chlorides over dealuminated HY zeolites, in chlorobenzene as solvent, has been shown to follow a Langmuir-Hinshelwood type kinetic law. In liquid phase conditions, thiophene is slightly more adsorbed than the acyl chloride. Moreover, the study of the reaction with various substituted benzoyl chlorides X-CgH4-COCl shows that the nature of the substituent has very little influence on the initial rate. 

The high reactivity of thiophene towards electrophilic substitution has been reported for a long time, and acylation reaction of thiophene has been widely studied. Lewis acids, mainly AICI3 and ZnCl2 [5], and more recently SnCU [6, 7] or FeCla [8], have been mostly used as catalysts. 

Acylation reactions of thiophene have been also investigated under heterogeneous conditions a montmorillonite clay and silica-alumina [9] and Nafion-H [10] have been shown to be efficient catalysts of the acylation of thiophene with acetyl chloride. 

The acylation reaction of thiophene with various para substituted benzoylchlorides has been studied, over HY (Si/Al =15) zeolite, in the same conditions as described above. 

Dealuminated HY zeolites have been shown to be efficient catalysts for the selective preparation of 2-acyl thiophenes in the reaction nf thiophene with various acyl chlorides. The acylation reaction of thiophene with butyroyl chloride over HY (Si/Al =15) zeolite, in chlorobenzene as solvent, follows a Langmuir-Hinshelwood kinetic law, which involves the adsorption of the two reactants on identical sites of the catalyst surface. ... 

Effect of Tempbratubb on a /3 Ratio in Acylation Reactions of Thiophene"... 

The following acylation reactions of thiophenes are regioselective (C2) and high yielding. Both reactions are key C-C bond forming reactions that have been used in the synthesis of duloxetine. ... 

Acylation of heterocyclics, such as thiophene, seems to require a lower acid strength of the catalyst which is best met by B-ZSM-5. The reaction of thiophene with acetic anhydride to 2-acetylthiophene proceeds with 99% selectivity at 24% conversion and the conversion of pyrrole with acetic anhydride to 2-acetylpyrrole with 98% selectivity at 41% conversion [115]. 

We have shown that HY zeolites are convenient catalysts for the highly selective preparation of 2-acylthiophenes in the reaction of thiophene with various aliphatic acyl chlorides (C H2n+i COCl with n=l,3,5,7). 

Ch. 3 Formyl and Acyl Derivatives of Thiophenes and Their Reactions... 

The first three reactions are all electrophilic substitutions a bromination of a pyrrole, the nitration of quinoline, and a Friedel-Crafts reaction of thiophene. Bromination of the pyrrole occurs at the only remaining site. Nitration of quinoline occurs on the benzene rather than the pyridine ring (actually giving a mixture of 5- and 8-nitroquinolines) and the acylation occurs next to sulfur. 

Carboxylic acids are more convenient as acylating reagents in comparison to acid chlorides or anhydrides [30]. The formation of ketones in the reaction of thiophene with acetic or benzoic acid in the presence of triflic anhydride, without involving a metallic catalyst, was complete at room temperature in only minutes with high yields. Acetylatitm with acetic acid proceeded in solvent-free conditions, but benzoic acid needed nitromethane as the solvent. The reaction mechanism is believed to involve the formation of a mixed anhydride between the carboxylic acid and triflic anhydride which then reacts with thiophene. Triflic acid is formed as a side product (Scheme 10) [30]. 

Reaction of thiophene with 2,2-difluorocyclopropanecarbonyl chloride tmder Friedel-Crafts conditions gave the expected acylation product 10 along with a small amount of ring-opened product 11 in an overall 86% yield (Scheme 16) [36]. This case demonstrates the high reactivity of thiophene in electrophilic substitution reactions since less reactive benzene and alkylated benzenes gave mostly the ring-opened products [36]. 

Sulfonated styrene—divinylbensene cross-linked polymers have been appHed in many of the previously mentioned reactions and also in the acylation of thiophene with acetic anhydride and acetyl chloride (209). Resins of this type (Dowex 50, Amherljte IR-112, and Permutit Q) are particularly effective catalysts in the alkylation of phenols with olefins (such as propylene, isobutylene, diisobutylene), alkyl haUdes, and alcohols (210) (see Ion exchange). Superacids. 

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. 

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). 

Interesting results have been obtained in intramolecular acylation reactions involving pyrrole and thiophene derivatives. A muscone synthesis involves selective intramolecular acylation at a vacant a-position (Scheme 18) (80JOC1906). In attempts to prepare 5,5-fused systems via intramolecular acylation reactions on to a jS-position of a thiophene or a pyrrole, in some cases ipso substitution occurs with the result that rearranged products are formed (Scheme 19) (82TH30200). 

An interesting application of the Paal thiophene synthesis was documented for the synthesis of a polystyrene-oligothiophene-polystyrene copolymer. In the Stetter reaction of aldehyde 13 and P-dimethylaminoketone 14, in situ generation of the a,p-unsaturated ketone preceded nucleophilic 1,4-conjugate addition by the acyl anion... 

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 thenyl cyanides are of great importance for the preparation of thiophene derivatives. Because of the acidifying effects of both the thienyl and of the cyano groups, carbanions are easily obtained through the reaction with sodamide or sodium ethoxide, which can be alkylated with halides, carbethoxylated with ethyl carbonate, or acylated by Claisen condensation with ethyl... 

Additional acylation studies were also reported (24), (26). In the first case it is claimed that acylation of thiophene is achieved by means of HC104 and acetic anhydride affording a 65 % yield of 2-acetylthiophene. In the second paper Levine and coworkers reported that while 2,5-dimethylthiophene could be readily acetylated, 2,5-dichlorothiophene acetylated sluggishly. This is, however, readily explained, since the presence of chlorine atoms on the thiophene ring decreased its reactivity in electrophilic substitution reactions. In the case of methyl substitution, however, the 3 and 4 positions of the ring are activated toward electrophilic substitution by the inductive and hyperconjugative effects. Thus 2,5-dimethylthiophene was successfully acylated by the boron fluoride etherate method in high yield with three aliphatic anhydrides. 

Nevertheless, we can interpret the reactions of furan and thiophene by logical consideration as we did for pyrrole. In electrophilic substitutions, there is again a preference for 2- rather than 3-substitution, and typical electrophilic reactions carried out under acidic conditions are difficult to control. However, because of lower reactivity compared with pyrrole, it is possible to exploit Friedel-Crafts acylations, though using less-reactive anhydrides rather than... 

The electron-rich thiophene ring system can be annelated by intramolecular Friedel-Crafts acylation reactions to give fused thiophenes <99IJC648, 99JMC2774>. The synthesis of a thiophene isostere of ninhydrin involved an intramolecular Friedel-Crafts acylation <99SL1450>. Specifically, treatment of thiophene 86 with thionyl chloride followed by aluminum chloride gave annelated thiophene 87. The synthesis of isothianinhydrin 88 was then accomplished in six steps from 87. 

The acylation of thiophenes has been reviewed (86HC(44/3)309). The best catalyst for the Friedel-Crafts acylation of thiophene, using free carboxylic acids, appears to be 2-(trifhioromethylsulfonyloxy)pyridine (84) in conjunction with TFA. 2-Acylthiophene is formed in quantitative yield, without any evidence of the thiophene dimerizing. The reaction might be mediated by the mixed anhydride (85) (Scheme 15) (88BCJ455) (cf. (84CHEC-(4)74l)). 

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