Iodination thiophenes

Acylation. To achieve acylation of thiophenes, acid anhydrides with phosphoric acid, iodine, or other catalysts have been widely used. Acid chlorides with AlCl, SnCl, ZnCl2, and BF also give 2-thienylketones. AH reactions give between 0.5 and 2.0% of the 3-isomer. There has been much striving to find catalyst systems that minimize the 3-isomer content attempting to meet to customer specifications. The standard procedure for formylation is via the Vil smeier-H a ack reaction, using phosphoms o xycbl o ri de / /V, / V- dim e tb yl fo rm a m i de (POCl /DMF) or /V-m ethyl form an i1 i de. 

Manufacture of 2-acetylthiophenes involves direct reaction of thiophene or alkylthiophene with acetic anhydride or acetyl chloride. Preferred systems use acetic anhydride and have involved iodine or orthophosphoric acid as catalysts. The former catalyst leads to simpler workup, but has the disadvantage of leading to a higher level of 3-isomer in the product. Processes claiming very low levels of 3-isomer operate with catalysts that are proprietary, though levels of less than 0.5% are not easily attained. 

Halogens react with benzo[6]furan by an addition-elimination mechanism to give 2- and 3-substituted products (76JCS(P2)266). Treatment of benzo[6]thiophene with chlorine or bromine in acetic acid gives predominantly 3-substituted products (71JCS(B)79). 2,2,3,3,4,5,6,7-Octachloro-2,3-dihydrobenzothiophene is obtained when benzo[6]thio-phene is treated with chlorine in the presence of 1 mole of iodine (80JOC2l5l). 

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. 

Catalytic reduction of thiophenes over cobalt catalysts leads to thiolane derivatives, or hydrocarbons. " Noncatalytic reductions of thiophenes by sodium or lithium in liquid ammonia leads, via the isomeric dihydrothiophenes, to complete destructions of the ring system, ultimately giving butenethiols and olefins. " Exhaustive chlorination of thiophene in the presence of iodine yields 2,2,3,4,5,5,-hexachloro-3-thiolene, Pyrolysis of thiophene at 850°C gives a... 

D) Preparation of 4-[1 -Methyl-Piperidyl-(4 )]-9,10-Dihydro-4H-Benzol4,5]Cyciohepta[1,2-b] Thiophen-(4)-ol 0.94 g of magnesium filings which have been activated with iodine are covered with a layer of absolute tetrahydrofuran and etched with a few drops of ethylene bromide. A solution of 5.0 g of 1-methyl-4-chloropiperidine in 5 ml of tetrahydrofuran is then added dropwise and boiling then effected for a further hour under reflux. After cooling to room temperature, the solution of 4.5 g of 9,lO-dihydro-4H-benzo[4,5] cyclohepta[1,2-b] thio-phen-(4)-one in 5 ml of tetrahydrofuran is added dropwise. 

Iodination of 4 with molecular iodine in the presence of mercuric oxide formed the 3-iodo derivative (52JA4951 66CJC2283). Iodine in tetrahydro-furan oxidatively cyclized /3-(3-benzo[b]thienyl)-a-mercaptoacrylic acids rather than iodinating the thiophene ring [70JCS(C)2431]. 

This applies to what may be called dilute solid solutions and has been confirmed by Bijlert (1891) for iodine, and for thiophene, dissolved in benzene, and by Bruni for iodoform in bromoform. 

In the context of preparing benzothienyloxy phenylpropanamines as inhibitors of serotonin and norepinephrine uptake, a group from Eli Lilly and Company has developed a two-step synthesis of benzo[fo]thiophenes (Scheme 6.193) [354]. Thus, a 2-mercapto-3-phenylpropenoic acid derivative was cyclized with iodine in 1,2-dimethoxyethane at 120 °C to give 5-fluoro-4-methoxybenzothiophene-2-carboxylic acid in 67% yield. Decarboxylation under strongly basic conditions involving 1,8-di-azabicyclo[5.4.0]undec-7-ene (DBU) as base in N,N-dimethylacetamide (DMA) as... 

Iodobenzothiophene 15 was prepared by iodination of 2-trifluoroacetylamino-benzo[6]thiophene (14), although the same reaction with the regioisomeric 3-trifluoroacetylammobenzo[b]thiophene gave only unidentified polymeric material [13]. In another case, thienylpyridine 16 could be either brominated [14], or iodinated to give 17 [15,16]. 

Lithiothiophene, arising from lithiation of thiophene with n-BuLi, was treated with iodine to give 2-iodothiophene, which was allowed to react with sodium malononitrile in the presence of catalytic PdCl2(Ph3P)2 to afford thienylmalononitrile 18. Interestingly, a-metalation of ethyl 3-... 

Sonogashira reactions of both a-halothiophenes [117] and P-halothiophenes [118] proceed smoothly even for fairly complicated molecules as illustrated by the transformation of brotizolam (134) to alkyne 135 [119]. Interestingly, 3,4-bis(trimethylsilyl)thiophene (137), derived from the intermolecular cyclization of 4-phenylthiazole (136) and bis(trimethylsilyl)acetylene, underwent consecutive iodination and Sonogashira reaction to make 3,4-bisalkynylthiophenes [120], Therefore, a regiospecific mono-i/wo-iodination of 137 gave iodothiophene 138, which was coupled with phenylacetylene to afford alkynylthiophene 139. A second iodination and a Sonogashira reaction then provided the unsymmetrically substituted 3,4-bisalkynylthiophene 140. 

SCHEME 2.62 Synthesis of alkylthiophenes 397-399 through oxidative iodination of the thiophene followed by Ni-catalyzed polymerization. (From Bolognesi, A., Botta, C., Geng, Z., Flores, C., and Denti, L., Synth. Met., 71, 2191, 1995 Bolognesi, A., Porzio, W., Bajo, G., Zannoni, G., and Fanning, L., Acta Polym., 50, 151, 1999.)... 

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 the four monocarboxylic acids of dibenzothiophene has been recorded in the previous review. However, several modified preparations have since been described. Ethyl 1-dibenzothiophene-carboxylate has been synthesized from 2-allylbenzo[6]thiophene (Section IV,B, 1) hydrolysis afforded the 1-acid (57% overall). In a similar manner, 3-methyl-1-dibenzothiophenecarboxylic acid was obtained from the appropriately substituted allyl compound. This method is now the preferred way of introducing a carbon-containing substituent into the 1-position of dibenzothiophene. 2-Dibenzothiophenecarboxylic acid has been prepared by oxidation of the corresponding aldehyde or by sodium hypoiodite oxidation of the corresponding acetyl compound. Reaction of 2-acetyldibenzothiophene with anhydrous pyridine and iodine yields the acetyl pyridinium salt (132) (92%), hydrolysis of which yields the 2-acid (85%). The same sequence has been carried out on 2-acetyldibenzothiophene 5,5-dioxide. The most efficient method of preparing the 2-acid is via carbonation of 2-lithio-... 

A limited number of hypervalent iodine-mediated synthesis of thiophenes and benzothiophenes have been reported. An indirect approach for the synthesis of thiophenes involves formation of 1,4-butanediones [85JC-S(CC)420 87JCS(P1)559 88TL3703 89JOC2605], followed by treatment with phosphorus pentasulfide. This approach is especially useful for the synthesis of 3,2 5, 3"-terthiophene (134) starting from 1,4-diketone 65 (85SC789). 

Propionylation (EtCOCl/SnCl4/CS2) of thienothiophene 2 readily gives (in 88% yield) 2-propionylthieno[3,2-i]thiophene. With acetic anhydride and traces of iodine, 2 yields 2-acetylthieno[3,2-6]thiophene (50%). The latter was also prepared by acetyl chloride treatment of the monomercury compound produced by mercuration (HgClj) of thienothiophene 2. ... 

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