Bromination of thiophene derivatives

Fig. 13. Bromination of arenes with BTMA Bt3 Bromination of thiophene derivatives...

Bromination of thiophene derivatives by A-bromosuccinimide (NBS) in 50 50 (v/v) chloroform-acetic acid proceeds by an electrophilic rather than a radical mechanism.91 Many experimental facts favor such a hypothesis (i) only ring-substituted products are formed, with exclusion of addition or side-chain substitution (ii) the reaction is very selective, only a-substituted products are formed and (in) the... 

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]. 

The bromination of annotated thiophene derivatives appears to quite substrate-specific. While bromination of 3,4-dimethylthiophene (54) leads to substitution, the bromination of cyclobutathicqthene derivatives (54-56, Figure 7) leads exclusively to addition products. It has been speculated that annelation induces localiza-... 

Two excellent reviews <71AHC(13)235, 72IJS(C)(7)6l) have dealt with quantitative aspects of electrophilic substitution on thiophenes. Electrophilic substitution in the thiophene ring appears to proceed in most cases by a mechanism similar to that for the homocyclic benzene substrates. The first step involves the formation of a cr-complex, which is rate determining in most reactions in a few cases the decomposition of this intermediate may be rate determining. Evidence for the similarity of mechanism in the thiophene and benzene series stems from detailed kinetic studies. Thus in protodetritiation of thiophene derivatives in aqueous sulfuric and perchloric acids, a linear correlation between log k and —Ho has been established the slopes are very close to those reported for hydrogen exchanges in benzene derivatives. Likewise, the kinetic profile of the reaction of thiophene derivatives with bromine in acetic acid in the dark is the same as for bromination of benzene derivatives. The activation enthalpies and entropies for bromination of thiophene and mesitylene are very similar. 

Methyl 4,5,6,7-tetrafiuorobenzo[h](hiophene-2-carboxylate is oxidized by trifluoroperacetic acid or m-CPBA to form a 2,3-epoxysulfbne reaction with chlorine or sulfuryl chloride produces a 2,3-dichIoride derivative <94JFCS1>. HOF MeCN is a novel oxidant which oxidizes a variety of thiophene derivatives to 3,5-dioxides <94CC1959>. Bromination of thieno[c]fused l,S-n hthyridines occurs with tetrabutylammonium perbromide <94H331> or with dibromoisocyanuric acid/sulfuric acid <94JHCS21>. 

The reactivity sequence furan > tellurophene > selenophene > thiophene is thus the same for all three reactions and is in the reverse order of the aromaticities of the ring systems assessed by a number of different criteria. The relative rate for the trifluoroacetylation of pyrrole is 5.3 x lo . It is interesting to note that AT-methylpyrrole is approximately twice as reactive to trifluoroacetylation as pyrrole itself. The enhanced reactivity of pyrrole compared with the other monocyclic systems is also demonstrated by the relative rates of bromination of the 2-methoxycarbonyl derivatives, which gave the reactivity sequence pyrrole>furan > selenophene > thiophene, and by the rate data on the reaction of the iron tricarbonyl-complexed carbocation [C6H7Fe(CO)3] (35) with a further selection of heteroaromatic substrates (Scheme 5). The comparative rates of reaction from this substitution were 2-methylindole == AT-methylindole>indole > pyrrole > furan > thiophene (73CC540). 

Since thiophene derivatives, heterocyclic aromatic compounds, are sensitive toward electrophilic substitution reactions, the bromination of these compounds generally gives a mixture of mono-, di-, and other poly-substituted bromination products (ref. 19). However, we have recently found that BTMA Br3 is a useful... 

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]. 

The synthesis of alkylated thieno[3,2-h]thiophenes (2) via a similar procedure was also studied. As stated above, existing methods for the preparation of a-alkyl-substituted thienothiophene 2 derivatives and thienothiophene 2 itself are inefficient. The reduction of 4-bromo-2-acetothienone (56) (prepared by bromination of 2-acetothienone )... 

Biedermann and Jacobson, who first prepared thieno[2,3-6]-thiophene (1) in 1886, characterized it as a 2,3,4,5-tetrabromo derivative with m.p. 172°. Later Capelle reported the isolation of a dibromo derivative of thienothiophene 1 with m.p. 122.5°, which was shown by Challenger and Harrison to be 2,3,5-tribromothieno[2,3-6]thiophene (m.p. 123°-124°). Capelle also obtained a tetrabromide, m.p. 223°, by bromination of the product of reaction of acetylene with sulfur. The tetrabromide seems to be identical with that prepared from the product of reaction of methane, acetylene, and hydrogen sulfide, m.p. 229°-230°, and is evidently 2,3,5,6-tetrabromothieno[3,2-6j-thiophene. ... 

IR spectroscopy has shown that thienothiophenes 1 and 2 are brominated with iV-bromosuccinimide to furnish dibromo along with monobromo derivatives. An unpurified bromination product of thienothiophene 1 contained 8% of the initial thienothiophene 1,83% of 2-bromothieno[2,3-fe]thiophene, and 9% of 2,5-dibromothieno[2,3-fc]-thiophene 15% of the initial thienothiophene 2, 70% of 2-bromothieno-[3,2-6]thiophene and 15% of 2,5-dibromothieno[3,2-6]thiophene were detected on bromination of thienothiophene 2. ... 

Compounds 38 and 40, prepared by the method shown in Scheme 7 (Section 10.09.6), undergo ready bromocycliza-tion to give oxazolo-fused derivatives 39 and 41 (Equations 8 and 9) <2005JHC755>. In this case, bromination of the thiophene 2-position precedes bromocyclization. Further elaborations are then possible by displacement of the alkyl bromide <2005JHC763>. 

Treatment of 2-methoxy-5-methylthiophene with NBS gave a 4 1 mixture of 3- and 4-bromo products, with some 3,4-dibromination also evident. The dibromination became more significant when 2 mol of NBS were used. Similarly 2-methoxythiophene gave the 3,5-dibromo derivative (84BAU1447). Bromination of 2-(2 -thienyl)-thiophenes (21) and 2-(3 -thienyl)-thiophenes gave the 5- and 2-bromo products in high yield [79CS157 91H(32)1805]. With four molar equivalents of bromine in acetic acid the tetrabromo derivative (22) was obtained in 97% yield. Reduction removed the 5,5 -bromines preferentially [91H(32)1805] (Scheme 9). This... 

Bromination The five-membered aromatic heterocycles are all more reactive toward electrophiles than benzene is, and the reactivity is similar to that of phenol. These compounds undergo electrophilic bromination. However, reaction rates vary considerably, and for pyrrole, furan and thiophene the rates are 5.6 x 10, 1.2 x 10 and 1.00, respectively. While unsubstituted five-membered aromatic heterocycles produce a mixture of bromo-derivatives, e.g. bromothiphenes, substituted heterocycles produce a single product. 

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