3- Methoxythiophene, reactions

Methoxythiophene and 3-cyanothiophene have been prepared from 3-bromothiophene by means of a cupric oxide-catalyzed Williamson synthesis and by reaction with cuprous cyanide in quinoline, respectively. 

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... 

The methoxy group of methoxythiophenes shows a reactivity which, in many respects, differs appreciably from the reactivity of the corresponding anisoles. Thus, in an attempted Hoesch synthesis with 5-methoxy-2-thenylcyanide (167) and phloroglucinol, the methoxy group reacted instead and 5-(2, 4, 6 -trihydroxyphenyl)-2-thenyl cyanide (168) was obtained. 2-Thenyl cyanide reacts normally in the Hoesch synthesis, Likewise, upon acid hydrolysis of the reaction product of 5-methoxy-2-thienyllithium with benzophenone, (169) was obtained instead of the expected substituted methoxythiophene. No defined products could be isolated from the attempted Claisen rear-... 

Furthermore, the preparation and reactions of 2-methoxythiophene were studied by Sice (70). This compound was obtained by a copper catalysed Williamson synthesis. It was also found that iodothiophene reacted readily with sodium alkoxides, whereas bromothiophene reacted slowly and chlorothiophene did not react at all. Sodium iodide accelerated the reaction of bromothiophene. The ortho, para orienting alkoxy group on carbon atom 2 increased the directive influence of the sulphur atom to the 5 position but competed with it to induce some attack on the 3 position by electrophilic reagents (nitration, acylation). The acylation of 2-methoxythiophene with stannic chloride at low temperatures furnished a mixture of two isomers. The 5-methoxy-2-acetothienone was obtained in higher yield and was identified by its ultraviolet absorption spectrum. 

Another electrophilic reagent which has been used to introduce an oxygen function is alkyl peroxybenzoate. Thus 5-methoxy-2-thienyllithium on reaction with r-butyl peroxy-benzoate gives 2-r-butoxy-5 -methoxythiophene in 72% yield (790R(26)1>. 

There have been several studies utilizing the ability of 4,6-dinitrobenzofuroxan (DNBF) to act as a super-electrophile. It has been shown that the initial product of its reaction with phenoxide ions is the O-bonded adduct (29), although this rearranges to give die C-bonded adduct.117 The reaction of DNBF with ethyl vinyl ether yields a dihydrooxazine A -oxidc cycloadduct as a mixture of two diastereoisomers, and in the presence of excess ether a di-adduct (30) is formed.118 Rate constants have been reported for the reaction of DNBF with 3-methoxythiophene in DMSO-water mixtures. The reaction results in a er-adduct which is the product of Se-At substitution in the thiophene, and the results were used to probe the carbon basicity of the thiophene derivative.119... 

With very reactive substrates, such as 2-methoxythiophene, step (2) is very fast and step (1) becomes rate-determining the reaction then follows second-order kinetics and the observed rate constant is equal to the rate constant Jc1 for the formation of the electrophilic adduct. 

However, Mannich reactions on the thiophene nucleus are rare 2- and 3-methoxythiophenes underwent this reaction in good yield to produce the Mannich bases (88) and (89) respectively (75SC59). 

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]. 

As in benzenoid chemistry, some nucleophilic displacement reactions can be copper catalyzed. Illustrative of these reactions is the displacement of bromide from 3-bromothiophene-2-carboxylic acid and 3-bromothiophene-4-carboxylic acid by active methylene compounds (e.g., AcCH2C02Et) in the presence of copper and sodium ethoxide (Scheme 136). Analogously, 2-methoxythiophene can be prepared in 83% yield by refluxing 2-bromothiophene in methanol containing excess sodium methoxide, along with copper(I) bromide as catalyst. For the analogous preparation of 3-methoxythiophene, addition of a polar cosolvent (e.g., l-methyl-2-pyrrolidone) is beneficial. In the case of halothiophenes, an SrnI mechanism is involved. 

Methoxy-5-(177-pyrrol-2-yl)-2-thienyl]-177-pyrrole 621 was also prepared by a cross-coupling reaction, Stille reaction in this case, between A -SEM-2-(trimethylstannyl)-l/7-pyrrole 620 and 2,5-dibromo-3-methoxythiophene in the presence of a Pd catalyst, followed by nitrogen deprotection (Scheme 126) <1997CM2876>. If Negishi coupling is applied, the main reaction product is, in this case, A -SEM-2,2 -dipyrrole, and the desired compound can be isolated only in trace amount. 

Thiophene itself undergoes Mannich reactions more sluggishly than furan or pyrrole. The Mannich reaction of 3-alkoxythiophenes and 3,4-dialkoxythiophenes has been investigated in detail <2001J(P1)2595>. The reaction of 3-methoxythiophene with secondary amines and formaldehyde in acetic acid at room temperature led to the... 

DNBF 205 is a powerful electrophile - even more powerful than the proton or/)-nitrobenzenediazonium cation. The reaction of 3-methoxythiophene with DNBF has been investigated <1997J(P2)2667>. The reaction leads to the formation of the formal product of SeAt substitution 206 in quantitative yield (Equation 96). The product could be isolated as a crystalline sodium salt. The kinetic data from this reaction provide strong support to the view that 3-methoxythiophene exhibits behavior characteristic of a vinyl ether. 

The reaction of 3-methoxythiophene is highly selective for C-2 and has been put to use for the synthesis of thiophene oligomers. The substitution of thiophenes, using aryl iodides, can also be carried out without interference from bromo substituents in the substrate. ... 

The halogen-metal exchange between 4-iodo-2-methoxythiophen and butyl-lithium, followed by reaction with dimethyl disulphide, carbon dioxide, or DMF, was used for the synthesis of various 4-substituted 2-methoxythio-phens. In connection with work on optically active 3-(cyclohexenyl)-thiophens, substituted 3-thienyl-lithium derivatives were allowed to react with cyclohexanones and cyclohexenones. The reaction of 3,4-dibromothiophen with two equivalents of butyl-Hthium and sulphur, followed by CS2, was used for the synthesis of (96), an intermediate for the synthesis of the organic metals (97). ... 

Partial reductive desulfurizations are also successful with 3-methoxythiophenes. This reaction was utilized for the synthesis of pheromones [29]. 

Aminomethylation of thiophene was reported long before the more common Mannich reaction - dimethylaminomethylation, which, although it can be achieved under routine conditions with methoxythiophenes," requires the use of Me2N =CH2 Cr ( Eschenmoser s salt is the iodide) for thiophene and alkylthiophenes." ... 

A second example is the competition between Diels-Alder cycloaddition and Michael addition during the reaction of 2-methoxythiophene III with DMAD under solvent-free conditions [73] (Fig. 4.12). 

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