Thiophenes Friedel-Crafts reaction

A/-sulfonated ayiridines have also been used in Friedel-Crafts reactions (qv) (63). The successful C-alkylation of the heteroaromatic compounds indole (qv) [120-72-9] (64—66) and thiophene [110-02-1] (67) with a2itidines has also been reported ... 

This activation of the ortho position is most strikingly illustrated in the reactivity of 2,5-dimethylthiophene, which competitive experiments have shown to undergo the SnCb-catalyzed Friedel-Crafts reaction more rapidly than thiophene and even 2-methylthiophene. The influence of the reagent on the isomer distribution is evident from the fact that 2-methoxythiophene is formylated and bromi-nated (with A -bromosuccinimide) only in the 5-position. Similarly, although 3-bromo-2-methylthiophene has been detected in the bromi-nation of 2-methylthiophene with bromine, only the 5-isomer (besides some side-chain bromination) is obtained in the bromination of alkylthiophenes with A -bromosuccinimide. ° However, the mechanism of the latter type of bromination is not established. No lines attributable to 2-methyl-3-thiocyanothiophene or 2-methyl-3-chIoro-thiophene could be detected in the NMR spectra of the substitution products (5-isomers) obtained upon thiocyanation with thiocyanogen or chlorination with sulfuryl chloride. 2-Methyl- and 2-ethyl-thiophene give, somewhat unexpectedly, upon alkylation with t-butyl chloride in the presence of Feds, only 5-t-butyl monosubstituted and... 

Such eliminations do not occur with chloro compounds. 2,5-Dichlorothiophene undergoes AlCU-catalyzed sulfonylation with ben-zenesulfonyl chloride. Attempts to extend this reaction to thiophene, 2,5-dimethylthiophene, and 2-chloro-5-iodothiophene resulted in the formation of intractable tars even with other catalysts. Sul-fones of this type are often prepared in much better yields by using thiophenesulfonyl chlorides and benzenes in the Friedel-Crafts reaction. ... 

Thiophenethiols are prepared by reduction of the sulfonyl chlorides or, more conveniently, by the reaction of Grignard rea-gents or thienyllithium compounds with sulfur. They have also been obtained by cleavage or thienyl alkyl sulfides with sodium in liquid ammonia. 3-Thiophenethiol is a by-product in the commercial thiophene synthesis. Thiophenethiols have recently also been prepared by a synthesis involving Friedel-Crafts reaction of 2,4-dinitrobenzenesulfenyl chloride with thiophenes, followed by basic cleavage of the resulting sulfide. ... 

Proton acids can be used as catalysts when the reagent is a carboxylic acid. The mixed carboxylic sulfonic anhydrides RCOOSO2CF3 are extremely reactive acylating agents and can smoothly acylate benzene without a catalyst.265 With active substrates (e.g., aryl ethers, fused-ring systems, thiophenes), Friedel-Crafts acylation can be carried out with very small amounts of catalyst, often just a trace, or even sometimes with no catalyst at all. Ferric chloride, iodine, zinc chloride, and iron are the most common catalysts when the reactions is carried out in this manner.266... 

Disulfides were shown to be intermediates in the iodine oxidation of 1,3-butadiene-l-thiols and related compounds to form thiophenes (56JOC39). Several simple disulfides were converted to thiophene derivatives under these same conditions (64JOC2372). For example, bis(2-biphenyl) disulfide (13) produced dibenzothiophene (14) in 64% yield when heated with iodine in ethylene glycol for one hour. Treatment of (13) in benzene with aluminum bromide gave (14) in 76% theoretical yield, with an equivalent amount of the thiol, 2-biphenylthiol (62JOC4111). Thus the iodine reagent is more efficient, since it oxidizes the mercaptan, formed by the Friedel-Crafts reaction of disulfide on the adjacent aromatic ring, to disulfide for further reaction, and also serves as a catalyst for the initial reaction. 

The use of modern physical methods (NMR, UV, and IR spectroscopy, mass spectrometry, and gas-liquid (GLC) and thin-layer (TLC) chromatography is becoming increasingly noticeable. By 19522 few systematic studies of the preparation of derivatives of benzo [6]thiophene had been undertaken, no attempt had been made to alkylate benzo[6]thiophene by means of the Friedel-Crafts reaction, and Friedel-Crafts acylation had been little studied. Halogenation of benzo[6]thiophene had only been superficially investigated and... 

Tetrahydrobenzo[ ]thiophene behaves like thiophene in electrophilic substitution reactions. Thus, it is formylated with a mixture of vV-methylformanilide and phosphorus oxychloride,436 iodinated in the presence of mercuric oxide,193 and brominated by V-bromosuccinimide,193 all in the 2-position in Friedel-Crafts reactions with acetyl chloride,194-436 propionyl chloride,436 succinic... 

Benzylbenzo[i>]thiophene13z and 2-p-methoxybenzylbenzo[i>]-thiophene and its 3-ethyl derivative 464 may be prepared by treating 2-benzo[6]thienyllithium or its 3-ethyl derivative with benzyl chloride or anisyl chloride, respectively. Various p-methoxybenzyl-benzo [6]thiophenes may be prepared by Friedel-Crafts reactions between the appropriate benzo[6]thiophene and anisyl chloride.464... 

Cope and Burrows414 have prepared a number of aminoalkylbenzo-[6]thiophenes with the general formula (195) by Friedel-Crafts reaction between benzo[6]thiophene and various amino tertiary alcohols. On treatment with formamide in formic acid, (3-benzo[6]-thienyl)acetone affords 3-(2-aminopropyl)benzo[6]thiophene [Eq. (11)].557 Recent patents535,570 describe how isocyanates with the... 

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... 

Friedel-Crafts reaction of benzo[6]thiophene with ester chlorides of the type Et02C(CH2) C0Cl (w = 4-8) gives a mixture of the corresponding 2- and 3-keto ester.135 The 3-isomers may also be obtained by reaction of di(3-benzo[6]thienyl)cadmium with the above ester chlorides.135... 

Acetylthiophene reacts with synthesis gas to give 2-ethylthiophene. If the reaction is carried to completion, 2-ethylthiacyclopentane is secured. Acylated thiophenes are readily secured by the Friedel-Crafts reaction and their hydrogenation by hydrogen-carbon monoxide mixtures opens up a new synthetic route to the alkylthiophenes. and their tetra-hydro analogs. The evidence seems to indicate that the conversion of a substituted thiophene to the reduced thiacyclopentane is a stepwise process which with 2-thiophenecarboxyaldehyde may be represented as follows ... 

If the reduction follows two Friedel-Crafts reactions on thiophene the product is a 1,6-diketone instead of the 1,4-diketones from furan. Thiophene is well behaved in Friedel-Crafts acylations, and reaction occurs at the 2- and 5-positions unless these are blocked. 

Much more work was done on extended quinones. Syntheses of six parent compounds (159-164) has been accomplished by two methods. In the first approach, a Friedel-Crafts reaction between thiophene-3,4-dicarboxylic acid and benzene or thiophenes was used, and in the second one chromium trioxide oxidation of the corresponding acetoxy derivatives was applied (72JOC1712). These systems behave differently in the presence of excess lithium aluminum hydride and aluminum hydride. Compounds 161 and 162 were reduced to hydroquinones, compounds 160 and 163 were deoxygenated... 

Commercial benzene (bp 80°) and toluene (bp 111°) contain thiophene and methylthiophene as the main impurities. These impurities are more reactive than benzene or toluene in aromatic substitution reactions and therefore should be removed before using the material for reactions such as the Friedel-Crafts reaction. The thiophenes may be removed by shaking or stirring the hydrocarbon with one-tenth its volume of concentrated sulfuric acid for one-half hour. Because of the reactivity of toluene, the temperature should be maintained under 35° by occasional cooling. This treatment is, however, rarely necessary since thiophene-free benzene and toluene are commercially available at a reasonable cost. 

Friedel-Crafts reaction of phosgene with heterocyclic aromatic compounds is also difficult to stop at the acid chloride stage. However, under selected conditions, heteroaromatics such as thiophene can be directly acylated to give thiophenecarbonyl chloride [Scheme T9] (Ref. 15) ... 

You may be surprised that thiophene is the least reactive of the three but this is because the p orbital of the lone pair of electrons on sulfur that conjugates with the ring is a 3p orbital rather than the 2p orbital of N or O, so overlap with the 2p orbitals on carbon is less good. Both furan and thiophene undergo more or less normal Friedel-Crafts reactions though the less reactive anhydrides are used instead of acid chlorides, and weaker Lewis acids than AICI3 are preferred. 

J. W. Cook introduced the method of cyclizing an o-aroylbenzoic acid to an anthraquinone by heating the keto acid with phosphorus pentoxide in nitrobenzene at 150-165 . For example, the isomeric acids (3) and (4) resulting from the Friedel-Crafts reaction of 1,2-naphthalic anhydride with thiophene are cyclized to the same quinone (5). ... 

As a catalyst for the Friedel-Crafts reaction, stannic chloride is milder than aluminum chloride. Thiophene is so reactive that it can be acylated with stannic... 

If one considers that in the modifications, in place of the hydrocarbons, ethers, mono- and poly-add phenols, naphthalene, thiophene, diphenyl,naphthol-ethers, and many other compounds can be used, the great value of the Friedel-Crafts reaction will be readily understood. 

Thiophen Analogues of Polycyclic Aromatic Hydrocarbons Analogues of Anthracene and Phenanthrene. - Keto-enol tautomerism in a naphtho- and several anthra-thiophen systems [such as (241) (242)] has been studied. The system (241) (242) was obtained via the Friedel-Crafts reaction of thiophen with naphthalene-2,3-dicarboxylic anhydride followed by ring-closure. A [c] -fused system was similarly obtained by starting from... 

---