Thiophene chloromethylation

Thiophene and selenophene can be chloromethylated by treatment with formaldehyde and hydrochloric acid. Depending on the conditions, 2-chloromethyl or 2,5-bis(chloromethyl) derivatives are obtained. The chloromethylation of benzo[6]thiophene gives the 3-chloromethyl derivative and that of benzo[6]furan the 2-chloromethyl compound (71AHC(13)235). 

Benzo[6]thiophene, 2-(aryloxymethyl)-3-chloromethyl-synthesis, 4, 872 Benzo[6]thiophene, 2-arylthio-synthesis, 4, 931 Benzo[6]thiophene, 2-bromo-reaction with potassamide, 4, 829-830 synthesis, 4, 934 Benzo[6]thiophene, 3-bromo-Grignard reagents, 4, 831 reactions, 4, 830 synthesis, 4, 934 Benzo[6]thiophene, 4-bromo-synthesis, 4, 878, 934 Benzo[6]thiophene, 5-bromo-electrophilic substitution, 4, 797 Benzo[6]thiophene, 6-bromo-synthesis, 4, 878, 934 Benzo[6]thiophene, 5-t-buty 1-3-methyl-synthesis, 4, 880... 

Substituted thiophenes, such as 2-iodo-, 2-bromo-, 2 chloromethyl-, and 2-acetyl-thiophene have been obtained by reacting crude, coal-tar benzene with the appropriate reagents. ... 

The chloromethylation of thiophene has come somewhat into discredit, partly because of the lachrymatory nature of 2-thenyl chloride, partly because this reaction is highly dependent on the conditions used. Formalin in concentrated hydrochloric acid has been used for chloromethylation, as has the anhydrous system, formaldehyde and hydrogen chloride." The use of a-chloromethyl methylether has also been recommended. The sensitivity of chloromethylation to the experimental conditions is illustrated by the fact that addition of zinc chloride gives di-(2-thienyl)methane as the main product and... 

The position of substitution in disubstituted thiophenes can, in most cases, easily be deduced from the directing effect of each substituent. Thus with a - -M-substituent in the 2-position and a —M-substituent in the 5-position, both substituents direct the entering group to the 3-position as is exemplified by the nitration of methyl 2-bromo-5-thiophenecarboxylate to methyl 2-bromo-3-nitro-5-thio-phenecarboxylate (109) or in the chlororaethylation of methyl 2-methyl-5-thiophenecarboxylate to methyl 2-methyl-3-chloromethyl-5-thiophenecarboxylate (110). °... 

Further substitution of 2,4-disubstituted and most 2,3-disubstituted thiophenes occurs in the free a-position, except when a - -M-substituent in the 3-position strengthens the 4-directing power of a —1—M-sub-stituent in the 2-position. Thus methyl 3-methyl-2-thiophenecar-boxylate is brominated in the 4-position and 3-brorao-2-thiophene-aldehyde is nitrated in the 4-position. Recent investigations on the chloromethylation, sulfonation, mercuration, and nitration of 2,4-di-chlorothiophene, which without proof are assumed to occur in the 5-position serves as examples of the reactivity of a 2,4-disubstituted thiophene. Formylation with iV,A-dimethylformamide and... 

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... 

The chloromethylation of 2,6-dimethyl- and 2,5-diethyl-thiophene both with chlorodimethyl ether and formaldehyde and hydrochloric acid gives a mixture of mono- and di-chloromethylated product. " The former reagent gives the larger proportion of monochloromethyl-ated product. " If the chloromethylation is carried out in the presence of zinc chloride, (120) and (121) are obtained. ... 

Thieno-o-quinodimethanes 46 and 48, generated in situ by iodide-induced 1,4-elimination from the respective 2,3-bis(chloromethyl)thiophene 45 and 2,3-bis(bromomethyl)benzo[b]thiophene 47 precursors, undergo Diels Alder... 

The great instability of 2-bromomethyl- and 2-chloromethyl-furans, often manifest as violent or explosive decomposition on attempted distillation, is reviewed. The furan nucleus is sensitive to traces of halogen acids, and decomposition becomes autocatalytic. Individually indexed compounds are 2,5-Bis(chloromethyl)thiophene, 2305 2-Bromomethylfuran, 1840 2-Bromomethyl-5-methylfuran, 2346... 

Dihydrothieno[3,4-Z ]thiophene (131) was prepared by two methods. In the first (Scheme 8), chloromethylation of methyl thiophene-2-carboxylate (132) forms methyl 2,3-bischloromethyl-thiophene-5-carboxylate (133) (85%) cyclization of 133 with sodium sulfide in methanol yields (66%) methyl 4,6-dihydrothieno[3,4-i]-thiophene-2-carboxylate (134). Peroxide oxidation of 134 gives 2-methoxycarbonyl-4,6-dihydrothieno[3,4-h]thiophene 5,5-dioxide (135) and hydrolysis of 134 followed by metaperiodate oxidation furnishes the sulfoxide (91). Thienothiophene (131) was produced by hydrolysis and decarboxylation of 134. As indicated above, the sulfoxide (91) was used for the synthesis of thieno[3,4-6]thiophene (3). 

The preparation and reactivity of many chloromethyl thiophenes have been described. Paraformaldehyde and HCl at 50 produces... 

Acid-catalyzed reaction of the thienylethanol (86) with carbonyl compounds gave fused pyrans (87) (75JHC591). The chloromethylation of thiophene can give 2-thenyl chloride and 2,5-bis(chloromethyl)thiophene, depending on the reaction conditions (52HC(3)187). 

The 5-(aminomethyl)thiophene-2-acetic acid isomer 76 was prepared by chloromethylation in position 2 of thiophene followed by nucleophilic displacement with phthalimide to afford 81, and a second chloromethylation in position 5 to give 82 (Scheme 23). Subsequent reaction with cyanide gave 83, the hydolysis of which afforded the phthalide-protected amino acid 84 which was coupled to H-Ala-Ile-Gly-OMe using propanephosphoric anhydride, followed by hydrazine N-deprotection)110 ... 

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