Thiophene acylation reactions

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. 

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). 

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 most direct synthesis of 2-acylbenzo[6]thiophenes involves reaction of the readily available 2-lithio derivative with acylating agents, such as nitriles, acid anhydrides, etc. (equation 19). Benzo[f>]thiophene-2-carboxylic acids are available by a variety of cyclization reactions (Section 3.15.9.2.4) and the acid chlorides or esters can be used to synthesize 2-acyl derivatives by conventional means. 

Kinetic studies of acylation reactions are somewhat limited by the insolubility of the acyl halide-Lewis acid complexes in many of the solvent systems that are used. However, useful results have been obtained and, as far as we are concerned, relative rates of reactions are of greater importance than absolute values. In any case it is not possible to distinguish between the two mechanistic extremes on the basis of the observed kinetics." Friedel-Crafts acylations are generally characterized by high substrate selectivity and frequently by high positional selectivity. Relative rate data show, as expected, that toluene is more reactive than benzene and that /n-xylene is the most reactive of the dimethylbenzenes. Values, relative to benzene, for benzoylation catalyzed by aluminum chloride were r-butylbenzene (72), toluene (1.1 X 10 ), p-xylene (1.4 x 10 ), o-xylene (1.12 x 10 ), and m-xylene (3.94 x 10- ). Competition data for the trifluoroacetylation of a number of heterocycles using trifluoroacetic anhydride at 75 "C gave the relative rates thiophene (1.0), furan (1.4 x lO ), 2-methylfuran (1.2 x 10 ) and pyrrole (5.3 x 10 ). ... 

The use of acidic heterogeneous catalysts for the acylation reaction has rarely been studied until recently. Nevertheless some interesting results were obtained in 1947 [6] for the acylation of the very reactive thiophene with acetyl chloride (Eq. 2)... 

Isaev, Y. and Fripiat, J. J. 1999. A Lewis acid site-activated reaction in zeolites thiophene acylation by butyryl chloride. /. Catal. 182 257-263. 

The relative reactivities of the five-membered-ring heterocycles are reflected in the Lewis acid required to catalyze a Friedel-Crafts acylation reaction (Section 15.13). Benzene requires AICI3, a relatively strong Lewis acid. Thiophene is more reactive than benzene, so it can undergo a Friedel-Crafts reaction using SnCl4, a weaker Lewis acid. An even weaker Lewis acid, BF3, can be used when the substrate is furan. Pyrrole is so reactive that an anhydride is used instead of a more reactive acyl chloride, and no catalyst is necessary. 

As shown in Exp. 14, methyl phenyl sulfide can be successfully converted into LiCH2SPh with one mol equivalent of the BuLiTMEDA reagent. Very recently Cabiddu et al. [1] reported that the mono-lithium compound can be specifically lithiated at the ortho-carbon atom in the ring by prolonged treatment with a second equivalent or butyllithium. A useful synthetic application is the preparation of benzo[b]thiophenes by reaction of the dilithio compounds with acyl chlorides [2]. 

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. ... 

Both NbCls and AgClOa can catalyse FC acylation reactions, but the yields are rather low. The combination of these salts is much more effective, and 2-benzoyl thiophene was obtained with 86% yield using only 1 mol% of NbCls and 3 mol% of AgClOa (Scheme 7) [27]. 

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. 

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