Brominated thiophenes, formation

Introduction of a 3-bromosubstituent onto thiophene is accompHshed by initial tribromination, followed by reduction of the a-bromines by treatment with zinc/acetic acid, thereby utilizing only one of three bromines introduced. The so-called halogen dance sequence of reactions, whereby bromothiophenes are treated with base, causing proton abstraction and rearrangement of bromine to the produce the most-stable anion, has also been used to introduce a bromine atom at position 3. The formation of 3-bromotbiopbene [872-31-1] from this sequence of reactions (17) is an efficient use of bromine. Vapor-phase techniques have also been proposed to achieve this halogen migration (18), but with less specificity. Table 3 summarizes properties of some brominated thiophenes. 

Figure 18. Formation of lithiated thiophenes from brominated thiophenes.

A study of reactions of NBS in acetic acid and acetic anhydride with thiophenes substituted in the a-position by groups such as 4-thiazolyl or 2-quinolinyl demonstrated that after initial perbromide formation (at around 20°C), slow conversion into C-brominated products followed. Reactions carried out above 40°C with one molar equivalent of NBS gave 5-bromo products only, but introduction of electron-donating groups into the thia-zole substituent and excess brominating agent led to some thiazole bromi-nation. With a 2-aminothiazolyl substituent, bromination took place exclu-... 

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. 

The relative rates of bromination of some 2-substituted thiophenes (R = H, CH3, Cl, Br, I, C02H, C02Et) by molecular bromine in anhydrous acetic acid have been determined by the author,85 comparing the times necessary to achieve 10% reaction. All the thiophenes examined gave the 5-bromo derivative on substitution, without appreciable formation of any other isomer. Only 2-iodothiophene... 

The synthesis of 4-substituted products from 2-acylfurans and 2-acylselenophenes is difficult. Their predominant formation was observed on bromination of aluminum chloride complexes of furfural and to a lesser extent of 2-acetylfuran (731ZV2733). Bromination of complexes of selenophene-2-carbaldehyde and 2-acetylselenophene with AICI3 leads mainly to 4-substituted derivative (exceeded 70%) (95JHC53). In all cases a significant amount of 4,5-dibromo-substituted products was obtained (Scheme 21). Competing reactions show that the complex of selenophene-2-carbaldehyde with aluminum chloride is brominated more rapidly than its thiophene analogue (95JHC53). 

Using C02 as an electrophile, formation of 5-alkyl-2-thiophenecarbox-ylic acids (52) from the corresponding borates (51) can also be realized (86MI1) (Scheme 20). Analogously, 3-alkyl derivatives of furan and thiophene (54) are formed from the corresponding borates (53) and iodine or bromine (81BCJ1587) (Scheme 21). 

Reaction of 3-bromofuran and 3-bromothiophene with butyllithium does not lead to lithiation in the 2-position, but gives rise to bromine-lithium exchange with formation of 3-lithiofuran and its thiophene analogue [134, 135], With the weaker bases KNH2 in liquid ammonia, LDA in THF and PhLi in EtzO however, complete deprotonation of carbon atom 2 occurs under mild conditions [9, 136-138]. 

Thiophene undergoes electrophilic substitution much more readily than benzene. The initial substitution product is 2-bromothiophene, but the rate of further substitution in the 5-position is comparable to that for the mono-substitution. It is therefore not possible to prevent formation of 2,5-dibromothiophene. The addition of Br2 to the double bond, which leads to a decrease of the number of molecules (negative entropy) becomes more favourable at lower temperatures and we found that at —100 °C thiophene reacts very rapidly with two moles of bromine to gi ve the adduct. Cooling should therefore not be applied if electrophilic substitution is the intended reaction. 

From Other Sulphur Heterocycles. The reaction of (46) with 2 eq. of bromine in CHjC gave (47), except for, (46d), which directly gave (48a). Further bromination of (47a) gave (48b). The formation of (47) from (46) has been assumed to proceed via (49) to (53).15 The reaction of (54) with chloroacetone under basic conditions unexpectedly yielded (55) in 44% yield.16 Photolysis of (56) gave tetraphenylthiophen, tetraphenyl-1,4-dithiine, diphenyl-acetylene and sulphur. The products are assumed to be formed via the dimer (57) and (58), which were isolable under appropriate conditions. Photolysis of (56) in the presence of dimethyl acetylenedicarboxylate gave a 17% yield of dimethyl 2,5-dif)henyl-thiophen-3,4-dicarboxylate.17 The reaction of (59) with diphenyl-acetylene at 300°C gave tetraphenylthiophen.1 ... 

The benzene-fused analogue (189) has also been prepared in 14% yield by a Wittig reaction <72JA7087>. This could be oxidized to the sulfoxide and sulfone by H2O2 in acetic acid. Neither the sulfoxide nor the sulfone showed any tendency to dimerize by a Diels-Alder mode. This is in contrast to simple thiophene 5-oxides, and is probably because any such dimerization would result in the formation of a benzocyclobutadiene structure. Photolysis of the sulfone leads to a head-to-head dimer. The thiophene ring in (189) is very reactive. Bromination with pyridinium bromide... 

The oxidative formation of azulenoquinones from linearly fused azulenoheterocycles, on the other hand, exactly follows the rules of electrophilic substitution on azulenes (cf. Section 4.2.1). Thiophene 45a or furan 47a (Scheme 68) can be oxidized by bromine/aqueous acetic acid, phenyltrimethylammonium perbromide (PTAB) or pyridinium perbro-mide to yield mixtures of quinones 274a and 275a or 274b and 275b, respectively (96BCJ1149, 03H(61)271). 

---