Reactions of thiophenes

The halogen-metal exchange technique has also been used during preparation of the thiophene-based phosphaquinomethanes 35, which were obtained in excellent overall yields by lithiation of the precursor 36, followed by dehydration of the intermediate carbinols 05JA8926 . 

It has been established that thiophenes undergo regiospecific oxidative cyanation at C-2 with TMSCN, as illustrated by the general transformation of 41 into 42 05OL537 . Conversion of 3-bromobenzo[6]thiophene to benzo[6]thiophene-3-carbonitrile has been accomplished by treatment of the substrate with Zn(CN)2 in the presence of a catalytic system consisting of Pd/C, Zn dust, Br2, and PPhs in A/jA -dimetliylacetamide 05TL 1849 . 

It has been shown that C-H bond activation in bromothiophenes may be readily achieved by palladium catalysis in the presence of the reagent combination AgNOa/KF, for instance as illustrated by the synthesis of the 2,2 -bithiophene 45 from 2-bromothiophene 46, providing access to a variety of brominated thiophene derivatives suitable for further functionalization 050L5083 . 

Oxidation of the 5-hydroxybenzo[h]thiophenes 55 with IBX gave the rmstable intermediate o-quinones 56, which were not isolated, but subjected directly to Diels-Alder reactions with the dienes 57, producing the tricyclic systems 58 05T9097 . 

In a different approach to fused benzo[h]thiophenes, taking advantage of the thermal decomposition of DMSO as a source of formaldehyde, the starting material 59 was converted to the product 60, along with minor amounts of the dehydrogenated system 61 by means of a modified Pictet-Spengler reaction 05TL2465 . 

The most common way of accessing new thiophene derivatives is by modification of existing thiophene rings. Metalation reactions, including halogen-metal exchange, are particularly important in this context, allowing introduction of a wide variety of substituents. 

A novel approach to a sexithiophene relying on metalation of the terthiophene 30 has been reported, wherein treatment of its lithio-derivative with dppfPtCL gave the complex 31, which could in turn be converted to the target molecule 32 by an oxidative homocoupling 

Lithiation of the alcohol 33 with ter/-butyllithium in THF/DMPU is accompanied by a silyl migration. Subsequent introduction of an electrophile takes place at C-2, giving for instance the product 34. Substrates bearing other silyl groups (TES, TBS) behaved in a similar manner 07OL4655 . 

Treatment of the sulfone 35 with three equivalents of butyllithium gave an intermediate selectively dimetalated at C-2 and the adjacent methyl group. Subsequent reactions of this species with aromatic or heteroaromatic esters, such as methyl thiophene-2-carboxylate, and final acid induced elimination of water, gave a series of thieno[ 3,2 -6] thiophene 1,1-dioxide systems, for example 36 07S1827 . On the other hand, 3-methylthiophene undergoes selective deprotonation at C-5 upon treatment with lithium 2,2,6,6-tetramethylpiperidide (LiTMP), giving access to a 2,4-disubstituted thiophene derivatives 07JOC 1031 . 

Aryl or diaryl substituted 3,4-(ethylenedioxy)thiophenes have been prepared by palladium-catalyzed direct C-H arylation of 3,4-(ethylenedioxy)thiophene itself with ary 1/he ternary 1 iodides/bromides 07TL539, 07T10363 , and direct coupling of 

An interesting example of trilithiation has been reported, wherein 3-(methylthio)thiophene 36 was exposed to the powerful base system LICKOR (t-BuOK/BuLi), giving direct access to the products 37 after quenching of the intermediate 38 with suitable electrophiles. Reactions involving 2-(methylthio)thiophene gave 2,5-disubstituted products resulting from a dilithiated intermediate 06S3855 . 

A tandem palladium catalyzed multi-component approach has been devised providing direct access to for instance trisubstituted thiophenes from the simple starting material 3-iodothiophene 41. In a representative experiment, the substrate 41 was converted to the product 42 by treatment with ethyl acrylate and iodobutane in the presence of a catalytic system consisting of Pd(OAc)2, tri(2-furyl)phosphine (TFP), norbomene, and a base. A mechanistic rationale accounting for this outcome was also proposed 06OL3939 . 

Bui (10 equiv.), methyl acrylate (2 equiv.) norbornene (6 equiv.), CS2CO3, CH3CN, 80 C, 1 d 

Exposure of the benzo[b]thiophene derivative 44 to a palladium catalyst in the presence of tri(2-furyl)phosphine (TFP) as the ligand led to the product 45, which incorporated two heterocyclic units from the starting material. The mechanistic aspects of this transformation were also discussed, which appears to involve palladacycle intermediates 06JA722 . 

The dithienyldienyne 46, which was prepared by sequential palladium catalyzed couplings, underwent intramolecular annulation to compound 47 in excellent yield. Similar cyclizations involving closely related substrates were also studied 06OLl 197 . 

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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. 

Side-Chain Derivatization. Reaction of thiophene with aqueous formaldehyde solution in concentrated hydrochloric acid gives 2-chloromethylthiophene [765-50-4]. This relatively unstable, lachrymatory material has been used as a commercial source of further derivatives such as 2-thiopheneacetonitrile [20893-30-5] and 2-thiopheneacetic acid [1918-77-0] (24). Similar derivatives can be obtained by peroxide, or light-catalyzed (25) halogenation of methylthiophenes, eg, Ai-bromosuccinimide/benzoylperoxide on 2-, and 3-methylthiophenes gives the corresponding bromomethylthiophenes. 

Halothiophenes. The biomothiophenes, coimneicially the most impoitant of the halothiophenes, are readily made and can be further derivatized. Manufacture of 2-bromothiophene involves the reaction of thiophene with a solution of sodium bromide/sodium bromate in acid solution. 

Manufacture of 2-acetylthiophenes involves direct reaction of thiophene or alkylthiophene with acetic anhydride or acetyl chloride. Preferred systems use acetic anhydride and have involved iodine or orthophosphoric acid as catalysts. The former catalyst leads to simpler workup, but has the disadvantage of leading to a higher level of 3-isomer in the product. Processes claiming very low levels of 3-isomer operate with catalysts that are proprietary, though levels of less than 0.5% are not easily attained. 

An important extension of these reactions is the Mannich reaction, in which aminomethyl-ation is achieved by the combination of formaldehyde, a secondary amine and acetic acid (Scheme 24). The intermediate immonium ion generated from formaldehyde, dimethyl-amine and acetic acid is not sufficiently reactive to aminomethylate furan, but it will form substitution products with alkylfurans. The Mannich reaction appears to be still more limited in its application to thiophene chemistry, although 2-aminomethylthiophene has been prepared by reaction of thiophene with formaldehyde and ammonium chloride. The use of A,iV-dimethyf (methylene) ammonium chloride (Me2N=CH2 CF) has been recommended for the iV,iV-dimethylaminomethylation of thiophenes (83S73). 

In the earlier sections, the reactions of thiophenes as typical aromatic compounds, always reverting to type, have been discussed. Now the reactions leading to the destruction of the aromatic system will be treated. 

Using these assumptions and conventions, Imoto and co-workers have correlated a number of series of reactions of thiophenes and furans. The reactions studied are the acid-base equilibria pK values) and the acid catalyzed methylations (thiophenes only) of thiophene-and furan-carboxylic acids and the alkaline hydrolyses of their ethyl esters the side-chain bromination of the a-acetylthiophenes, and the a-mercuration of thiophenes and the polarographic half-wave potentials of the methyl esters of thiophene- and furan-carboxylic acids and of nitrothiophenes. The pK values were determined and the ester hydrolyses studied for all three substitution orientations in the thiophene series. For the 4-R-2-Y and 5-R-2-Y series, the p-values do not appear significantly different and the data could probably be combined into a single series unfortunately, however, no limits of accuracy are reported for the p-values, and some of the raw data are not readily available so recalculation is not easily possible. For the 5-R-3-Y series the p-values deviate considerably from the other values however, whereas they are higher for the pK values, they are lower for the ester hydrolyses, and it is possible that the differences are neither systematic nor significant. 

The cycloaddition reactions of thiophene oxides and dioxides (290 and 291280,281) have already been discussed (Section V.A). 

TT-Facial selectivity in the Diels-Alder reactions of thiophen 1-oxides has recently attracted keen attention (Scheme 49). Fallis and coworkers reported in situ generated 2,5-dimethylthiophene 1-oxide 98 reacted with various electron-deficient dienophiles exclusively at the syn face with respect to sulfoxide oxygen [57],... 

Scheme 50 Diels-Alder reactions of thiophen 1-oxide 111 with dienophiles...

The reaction of tetrafluorobenzyne with iV-methylpyrrole leads to a good yield of the adduct (106), and with thiophen to tetrafluoro-naphtha-ene 56>. That this latter reaction was the first example of a Diels-Alder reaction of thiophen was shown by following the reaction by XH n.m.r. spectroscopy. Evidence for the intermediacy of the episulphide (107) was obtained. 

A similar reaction of thiophene analogues of Troger s base with formaldehyde was carried out by Kobayashi et al. <2002J (P1)1963>. 

Organic sulfur compounds are present in gasoline and diesel. With the increased emphasis on the requirement for more environmentally friendly transportation fuels [1], oxidative desulfurization, using H202 and redox-molecular sieves [2,5,6,7], has been studied and shown to significantly reduce the sulfur content of gasoline and diesel. The reaction of thiophene and its derivatives were successfully converted to oxidized compounds, but the identification of oxidized compounds was not simple because the concentrations of individual sulfur compounds were low. Most of the previous literature has reported sulfone formation. 

Additional studies featuring reactions of thiophene derivatives detail biohydrolysis of (S)-3-(thiophen-2-ylthio)butanenitrile <06TL8119>, lipase catalyzed resolution of thiotetronic acids <06TL7163>, enzymatic kinetic resolution of l,l-dioxo-2,3-dihydrothiophen-3-ol <06TL5273>, and efficient synthesis of 6-methyl-2,3-dihydrothieno[2,3-c]furan 55, a coffee... 

Reaction of Thiophene-2-acetonitrile 57 and Thiophene-3-acetonitrile 59 with 6 (Type IV, 4a and Type-V, 5a Model) An Efficient New General Synthesis of Highly Substituted Benzo[A thiophenes... 

The aqueous-biphase hydrogenation reactions of thiophenes to the corresponding cyclic thioethers have been shown to be mechanistically similar to those in truly homogenous phase. 

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