Halogenation of thiophenes

The halogenation of thiophene follows a similar pattern in that (a) chlorination is the most difficult to control and (b) substitution occurs preferentially in the a-positions. With... 

Direct halogenation of thiophenes is undoubtedly the most commonly used method for making... 

Halogenation of thiophene occnrs very readily at room temperatnre and is rapid even at -30 °C in the dark tetrasubstitntion occnrs easily. The rate of halogenation of thiophene at 25 °C is abont 10 times that of benzene. 2-Bromo-, 2-chloro- and 2-iodothiophenes and 2,5-dibromo- and 2,5-dichlorothiophenes can be prodnced cleanly nnder varions controlled conditions. Controlled bromination of 3-bromothiophene produces 2,3-dibromothiophene. ... 

Halogenation of thiophene occurs very readily at room temperature and is rapid even at -30°C in the dark tetrasubstitution occurs easily. The rate of halogenation of... 

The halogenation of thiophene and substituted thiophenes has been dealt with adequately in CHEC-I <84CHEC-i(4)74l>. Subsequently, an exhaustive account of all aspects of halogenation of thiophenes was published <86HC(44/2)159>. A more recent review of the halogenation of five-mem-bered heterocycles has made an extensive survey of the literature on halogenation of thiophenes... 

Direct mono-halogenation of thiophene gives only 2-halothiophene. The preparation of 3-halothiophenes involves quite a few steps. In a significant new development, it has been shown that the best way to obtain these 3-halothiophenes is by zeolite-catalyzed isomerization of the 2-halo isomers (Dettmeier et al., 1987). The zeolite used is the strongly acidic silicon-rich HZSM-5. 

Halogenation of thiophene occurs very readily at room temperature and is rapid even at — 30°C in the dark higher temperatures give rise to polysubstitution and even addition products. The rate of halogenation of thiophene, at 25°C, is about 10 times that of benzene. 2-Bromo- and 2-iodothiophene can be produced cleanly under various controlled conditions, free from 2,5-disubstituted product which is always present in chlorinations. 

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. 

The halogens of halothiophenes are more labile than those of the corresponding benzenes in accordance with theoretical considera-tions which indicate that thiophenes should also undergo nucleophilic substitutions more rapidly than benzenes. Hurd and Kreuz" found that in qualitative experiments 3,5-dinitro-2-chlorothiophene was more reactive toward piperidine and methanolic potassium hydroxide than 2,4-dinitrochlorobenzene. A quantitative study on the reaction of the six isomeric bromonitrothiophenes with piperidine (Table V) shows that the thiophenes react about one thousand times... 

Two different sets of experimental conditions have been used. Buu-Hoi et al. and Hansen have employed the method introduced by Papa et using Raney nickel alloy directly for the desulfurization in an alkaline medium. Under these conditions most functional groups are removed and this method is most convenient for the preparation of aliphatic acids. The other method uses Raney nickel catalysts of different reactivity in various solvents such as aqueous ammonia, alcohol, ether, or acetone. The solvent and activity of the catalyst can have an appreciable influence on yields and types of compounds formed, but have not yet been investigated in detail. In acetic anhydride, for instance, desulfurization of thiophenes does not occur and these reaction conditions have been employed for reductive acetylation of nitrothiophenes. Even under the mildest conditions, all double bonds are hydrogenated and all halogens removed. Nitro and oxime groups are reduced to amines. 

Oxidation of thiophene with Fenton-like reagents produces 2-hydroxythiophene of which the 2(570 One isomer is the most stable (Eq. 1) <96JCR(S)242>. In contrast, methyltrioxorhenium (Vn) catalyzed hydrogen peroxide oxidation of thiophene and its derivatives forms first the sulfoxide and ultimately the sulfone derivatives <96107211>. Anodic oxidation of aminated dibenzothiophene produces stable radical cation salts <96BSF597>. Reduction of dihalothiophene at carbon cathodes produces the first example of an electrochemical halogen dance reaction (Eq. 2) <96JOC8074>. 

Halogenation can be run under milder conditions using more active quaternary ammonium polyhalides such as pyridinium tribromide. The reaction between thiophene and benzyltrimethylammonium tribromide in acetic acid-ZnCl2 provided 2,5-dibromothiophene [6]. Chloro- and iodo-substituted thiophene derivatives may be prepared in the same manner. In comparison, bromination of thiophene employing 2 equivalents of NBS in chloroform gave 2,5-dibromothiophene in 56% yield [7]. 

Although chlorination, bromination and iodination of thiophenes by polyhalide salts require forcing conditions with the addition of zinc chloride [52], halogenation of acridine and acridone has been recorded to yield both 3-halo and 3,7-dihalo derivatives under relatively mild reaction conditions [53], However, whereas chloro-, bromo- and iodo-compounds are readily obtained from acridone, acridine only forms the bromo derivatives, as it produces stable complexes with the dichloroiodate and tetrachloroiodate salts [53]. 

Thienyliodomium salts (e.g., 28, 29) can be made by direct oxidation of thiophene with iodine in either the +5 or the +3 oxidation states (58JA4279), or by iodination of thienyl-lithium species (77JHC281 80CS(15)135). Such compounds are, however, of limited use only for the synthesis of halogenated thiophenes (Scheme 11). 

The reaction of heterocyclic lithium derivatives with organic halides to form a C-C bond has been discussed in Section 3.3.3.8.2. This cannot, however, be extended to aryl, alkenyl or heteroaryl halides in which the halogen is attached to an sp2 carbon. Such cross-coupling can be successfully achieved by nickel or palladium-catalyzed reaction of the unsaturated organohalide with a suitable heterocyclic metal derivative. The metal is usually zinc, magnesium, boron or tin occasionally lithium, mercury, copper, and silicon derivatives of thiophene have also found application in such reactions. In addition to this type, the Pd-catalyzed reaction of halogenated heterocycles with suitable alkenes and alkynes, usually referred to as the Heck reaction, is also discussed in this section. 

Halogens attached to the thiophene nucleus can be removed by reagents such as Zn/Hg, Na/Hg, Al/Hg, LAH, etc. Zn/HOAc is one of the most useful systems for selective removal of a-halogens. Some examples are shown in Scheme 170 (63AHC(l)l>. In a one-pot procedure for polybromination-debromination (81SC25) of thiophenes, bromination is effected by... 

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