Bromothiophene reaction

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. 

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. 

Rates of debromination of bromonitro-thiophenes and -selenophenes with sodium thio-phenoxide and sodium selenophenoxide have been studied. Selenophene compounds were about four times more reactive than the corresponding thiophene derivatives. The rate ratio was not significantly different whether attack was occurring at the a- or /3-position. As in benzenoid chemistry, numerous nucleophilic displacement reactions are found to 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 77) (75JCS(P1)1390). 

Procedures have been worked out which increased the yield of 2-bromothiophene to 78% on direct bromination in acetic acid-ether mixtures and to 67% in carbon tetraehlorided With the mild brominating agent, dioxane dibromide, quantitative yields of 2-bromothiophene are obtained. A very convenient procedure for the iodination of thiophenes consists of the acid-catalyzed (HzSOi) reaction with iodine and HIO3, giving 2-iodothiophene in 75% yieldd In contrast to the HgO method, all the iodine is utilized. 

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. 

In the reactions of 2,5-disubstituted thiophenes elimination of an a-substituent occurs to a much greater extent than in the benzene series. The Friedel-Crafts acetylation of 5-bromo-2-ethylthiophene in the presence of SnCE gives 2-ethyl-5-acetyIthiophene. Elimination of an a-bromine occurs also in the chloromethylation of 2,5-di-bromothiophene, leading to a mixture of 2-bromo-5-chloromethyIthio-phene and 2,5-dibromo-3-chloromethyIthiophene. Bromine atoms at both the and -position are exchanged for chlorine in the... 

Halothiophenes, which are not activated through the presence of —I—M-substituents, undergo substitution smoothly under more forcing conditions with copper salts in pyridine or quinoline. Hence 3-cyanothiophene and 5-methyl-2-cyanothiophene have been obtained from the corresponding bromo compounds. 2-Bromothiophene reacts readily with aliphatic cuprous mercaptides in quinoline at 200°C to give thioethers in high yields. The use of the copper-catalyzed Williamson synthesis of alkoxythiophenes from iodo- or bromo-thiophenes and alcoholate has been mentioned before. The reaction of 2-bromothiophene with acetanilide in nitrobenzene in... 

Recently, nitration of organolithiums and Gngnards v/iih has been developed for the preparation of certain kmds of nitro compounds fEqs. 2.14 and 2.15. The success of this process depends on the reaction conthdons (low remperanirei and the stnicnire of substrates. For example, 3-nitrothiophene can be obtained in 70% overall yield from 3-bromothiophene this is far superior to the older method. 3-Nitroveratrole cannot be prepared usefully by classical electrophilic nitradonof veratrole, but it can now be prepared by direct orr/io-lithiadon followed The mechanism is believed to proceed by dirutrogen rathcal, followed by the rathcal s combinadon. 

To a solution of thienyl magnesium bromide prepared from 21.4 g of magnesium and 144 g of 2-bromothiophene are added 39.B g of ethyl 4-dimethylaminocyclohexylcarboxylate. The mixture is ailowed to warm to room temperature and stirred for an additional six hours. The reaction mixture is then decomposed with dilute ammonium chloride solution and extracted with ether. The combined ether extracts are extracted thoroughiy with 10% hydrochloric acid and the acid solution made alkaline with ammonium hydroxide. The aqueous solution is extracted with chloroform which is then washed with water, dried and evaporated to a residue in vacuo. Recrystallization of the residue from hexane yields Oi.O -dithienyl-4-dimethyl-aminocyclohexyl carbinol, melting point 156°C to 157°C after recrystallization from benzene. 

Remarkably, one year later Leadbeater described that biaryls can be synthesized via a Suzuki-type coupling under transition-metal free conditions [51, 52]. The reaction conditions were almost identical to those reported for the ligand-free process, with the difference being that a larger amoimt of Na2C03 and arylboronic acid were used. Only one successful example of a heteroaryl haUde substrate is shown namely, the coupling of 2-bromopyridine with phenylboronic acid (Scheme 32). 3-Bromothiophene did not couple under the same reaction conditions. Unfortimately, attempts to use heteroarylboronic acids such as 3-pyridinylboronic acid, 3-thienylboronic acid, and lH-indol-5-ylboronic acid on 4-bromoacetophenone completely failed. 

The synthesis of (hetero)aryl cyanides from (hetero)aryl halides via transition-metal catalysis is a very valuable reaction since a nitrile can be easily transformed into several other functional groups. Not until 2000 were the first examples on microwave-assisted cyanation reported in the literature. Alter-man and Hallberg found that 3-bromopyridine and 3-bromothiophene were... 

The efficient synthesis of dithicno[2,3-A 32 -r/ thiophenes 12 has been achieved from 3-bromothiophene 298 <2006JOC3264>. The sequence of a-connection and [l-annelation afford annulated [1-trithiophene 12 (Scheme 54). Optimization of reaction conditions (solvent and temperature) for the a-connection step provides significantly improved yields compared to earlier report. 

In addition, complexes of P(/-Bu)3 have been shown to catalyze the formation of diaryl heteroarylamines from bromothiophenes.224 Aminations of five-membered heterocyclic halides such as furans and thiophenes are limited because their electron-rich character makes oxidative addition of the heteroaryl halide and reductive elimination of amine slower than it is for simple aryl halides. Reactions of diarylamines with 3-bromothiophenes occurred in higher yields than did reactions of 2-bromothiophene, but reactions of substituted bromothiophenes occurred in more variable yields. The yields for reactions of these substrates in the presence of catalysts bearing P(/-Bu)3 as ligand were much higher than those in the presence of catalysts ligated by arylphosphines. 

Dibromobistriphenylphosphinepalladium(II) is an effective carbonylation catalyst in the reaction of 2-bromothiophene with aniline145 (Scheme 80) acylpalladium species are presumably intermediates in this type of reaction, which can also be used to prepare pyridine derivatives. 2-Bromothiophene... 

The allylic germanes and stannanes obtained are useful synthons. The hydrogermylation of acetylenes can also be performed with dimethyl(2-thiophenyl)germane58. This compound can be prepared quantitatively by the Grignard reaction of Cl2GeMe2 with 2-bromothiophene (Scheme 8). 

Xu et al. have further expanded the scope of such Pd-catalyzed Csp2—P bond formation reactions [84, 85]. In one instance, they coupled 2-bromothiophene with n-butyl phenylphosphite to form n-butyl arylphosphinate 83. They also prepared alkyl arylphenylphosphine oxides, functionalized alkyl arylphenylphosphinates, alkenyl arylphenylphosphinates, alkenylbenzyl-phosphophine oxide, as well as chiral, nonracemic isopropyl arylmethylphosphinates in the same fashion [86]. Intramolecular Pd-catalyzed Csp2—P bond formation has also been reported [86]. 

The mechanism for the Pd-catalyzed Csp2—P bond formation proposed by Xu et al. is virtually the same as Hirao s with a slight variation. Oxidative addition of 2-bromothiophene to Pd(0) results in Pd(II) intermediate 84, which then undergoes a ligand exchange to give intermediate 85 with the aid of triethylamine. Triethylamine here serves as a base to neutralize HBr so that the reaction is driven forward. Finally, reductive elimination of 85 furnishes unsymmetrical alkyl arylphosphinate 83, regenerating Pd(0). 

In addition, arylthiophene 70 was obtained by a one-pot Suzuki coupling of p-methoxyiodobenzene and 3-bromothiophene via an in situ boronate formation using one equivalent of the thermally stable diborane 69 [55], This method avoids the isolation of boronic acids and is advantageous when base-sensitive groups such as aldehyde, nitriles and esters are present. However, the cross-coupling yields are low when both aryl halides are electron-poor because of competitive homocoupling during the reaction. 

The Suzuki coupling of soluble polyethylene glycol (PEG)-bound bromothiophene 71 and p-formylphenylboronic acid provided biaryl 72 [56]. Due to the high solubilizing power of PEG, the reaction was conducted as a liquid-phase synthesis. Treatment of 72 with o-pyridinediaminc resulted in a two-step-one-pot heterocyclization through an imine intermediate. Nitrobenzene served as an oxidant in the ring closure step. Finally, transesterification with NaOMe in MeOH resulted in l//-imidazole[4,5-e]pyridine 73. 

Most functional groups will tolerate Pd-catalyzed reactions between a halothiophene and hexaalkylditin for the preparation of stannylthiophenes [71, 72]. In practice, however, this method often suffers from consumption of large quantities of hexaalkylditin because of its disproportionation reaction. When bromothiophene 84 was refluxed with hexamethylditin under the agency of Pd(Pli3P)4 catalysis, stannane 85 was obtained in good yield [73]. 

Both 2-bromothiophene and 3-bromothiophene have been coupled with allyl alcohols to make thienylated a, 3-unsaturated ketones [124], Iodothiophenes were more reactive than the corresponding bromides, whereas the chlorothiophenes were unreactive. As expected, 2-bromothiophene was two to three times more reactive than 3-bromothiophene. In addition to the expected Heck adduct 149, the reaction of 2-bromothiophene 148 with l-methylprop-2-en-l-ol also resulted in the regiosmer 150. 

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