2.3- Dihydrothiophene-3-carboxylate

Cyclobutanones are usually formed by the classical ketene-olefin [2 H- 2] cycloaddition method. Compound 77, which is related to the penam family, was readily obtained [55, 56] from ethyl 2,3-dihydrothiophene-3-carboxylate and dichloroketene (Scheme 28). The binding of this compound to the active site of R61 D,D-peptidase was proved by an X-ray crystallographic study [57]. 

A number of non-fused thiophene derivatives also show biological activity including thiophenes which are HTV-l strain MDR inhibitors (e.g., 129) <99BMCL3411>, protein kinase C inhibitors (e.g., 130) <99BMCL2279>, antidepressants (e.g., 131) <99BMC1349>, and a GAB A-AT inactivator (4-amino-4,5-dihydrothiophene-2-carboxylic acid) <99JA7751>. 

Several cycloaddition reactions of 2,5-dihydrothiophene derivatives have been reported. Compounds possessing an enamine system undergo [2 + 2] cycloaddition with acetylene-dicarboxylic ester (Scheme 215) (77AHC(2l)253). Diels-Alder addition of the 2,5-di-hydrothiophene-3-carboxylic ester (557) with butadiene, followed by desulfurization, leads to the trisubstituted cyclohexane (558) (B-74MI31404). 

Reaction of 711 with terminal alkynes occurs regioselectively living 3-thiahexa-l,5-dienyl radicals 715 which also undergo selective 1,5-ring closure to allylcarbinyl radicals 716. Depending on the substitution pattern, radicals 716 rearrange to cyclopropylcarbinyl radicals 717. From 716 and 717,2,3-dihydrothiophene-3-acetate 718 and 3-thiabicyclo[3.1.0]hexane-6-carboxylates 719 are formed, respectively. 

Rates of the reversible deprotonation of benzo[. ]-2,3-dihydrothiophene-2-one 200 by OH, primary aliphatic amines, secondary alicyclic amines, and carboxylate ions have been determined in water at 25 °C <2006JOC8203>. 

Dihydrothiophene 1,1-dioxide in the presence of l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) reacts with CO2 to give the carboxylic acid (Equation 69), which is a stable precursor to l,3-butadiene-2-carboxylic acid <2003SC3643>. The reaction proceeds through initial deprotonation at the 2a-position the resonance-stabilized carbanion thus generated reacts with CO2 to form the carboxylate. Abstraction of a proton from the 3-position by another molecule of the base generates a dianion, which isomerizes to the stable dianion as shown in Scheme 39. Final protonation produces 3-sulfolene-3-carboxylic acid. 

Methyl-4,5-dihydrothiophene-3-carboxylic acid yields the corresponding sulfoxide on treatment with peroxyphthalic acid and the sulfone on refluxing with hydrogen peroxide in acetic acid (equation 560) [16S. Neither oxidant affects the double bond under the conditions used. 

Thiophene is not reducible by direct electroreduction, but by indirect reduction (Chapter 29) in DMF using biphenyl radical anion as electron transfer agent it is possible to reduce thiophene to 2,5-dihydrothiophene and tetrahydrothiophene in high yield [192] thiophenes substituted at C-2 with carboxyl, however, may be reduced by direct electrolysis to the 2,5-dihydro derivatives [193]. 

Di- and Tetra-hydrothiophens.—Birch reduction of thiophen-2-carboxylic acid with three equivalents of lithium in liquid ammonia gave 2,5-dihydrothiophen-2-carboxylic acid and several other products. When the Birch reduction was carried out with five equivalents of lithium and with methanol as the proton source, a single product, c/s-5-mercaptopent-3-enoic acid, was obtained. Birch reduction of t-butyl 5-t-butylthiophen-2-carboxylate gave the 2,5-dihydro-derivative upon treatment with zinc dust and trimethylchlorosilane and then quenching with molar sodium hydroxide, this gave a mixture of (123) and (124) in the proportions 1 8. ... 

Birch reduction of thiophene-2-carboxylic acid did not afford a clean yield of standard Birch product even under modified conditions. Although 2,5-dihydrothiophene-2-carboxylic acid was the major product, the isolation of... 

Subsequently, it was found that the preparation of substituted 2,5-dihydrothiophenes can be conveniently realized by the lithium/ammonia reduction of the corresponding lithium thiophene carboxylate salts, instead of the acid [136]. As depicted in Scheme 118, the substituted thiophene-2-carboxylic acid was initially converted into the corresponding lithium salt by treatment with equivalent amount of lithium hydroxide, and then the reduction was accomplished with lithium/ammonia and ammonia chloride as the proton source. Through this procedure, the ultimate target products were obtained in yields of 75% and 50%, respectively, but as a mixture of approximately equal amoimts of 2,5-cis- and -frans-isomers. 

Birch reduction of more heavily substituted thiophene carboxylic acid salts proceeded readily to afford the corresponding substituted 2,5-dihydrothiophenes however, the ring-opened by-product (Z)-5-mercapto-3-pentenoic acid was still detectable. Reduction of dilithium 3,4-dimethylthiophene-2,5-dicarboxylate also... 

Birch reduction of 2-acyl- or 2-acetyl-5-alkylthiophenes and subsequent alkylation with an aUcyl halide gave 2-acyl-2-alkyl- or 2-acyl-2,5-dialkyl-2,5-dihydrothiophenes in moderate to good yields. As illustrated in Scheme 123, for a series of substrates, both 2-acylthiophenes and thiophene-2-carboxylic acid were tolerated in this process. The compounds 123 represent useful synthetic intermediates, which can be further converted into 1,3-dienes. Substituted dihydrothiophenes were subjected to m-CPBA, followed by thermolysis, and finally provided a series of 1,3-dienyl ketones [141]. 

Five- and Six-membered Ring Sulphur Systems.—It has previously been shown that 2,5-dihydrothiophens and dihydrothiopyrans are useful synthons for the preparation of specifically alkylated conjugated dienes. The general method has now been extended to the preparation of 3-carboxylated 2,5-dihydrothiophens/ which provides a method for the synthesis of 2-carboxybuta-l,3-dienes. The... 

Electrochemical Reactions.—An electrochemical method for the one-step preparation of 2,5-dihydrothiophen-2-carboxylic acid has been developed. A stable cation radical has been obtained from the electrochemical oxidation of 2-/7-nitrophenyl-3,4,5-triphenylthiophen. The reduction of 2-acetylthiophen, 2-benzoylthiophen, and 2,5-diformylthiophen by electrochemical methods on a mercury electrode has been investigated and compared in the latter case with chemical reductions. Electrochemical reactions have been carried out with some complex thiophens. " ... 

A soln. of a-ethoxalyl-5"thiolvalerolactone (prepn. s. 812) in coned. HGl kept 48 hrs. in a refrigerator5,6-dihydro-4H-thiopyran-2,3-dicarboxylic anhydride. Y 83%.—Similarly a-Acetyl-5-thiolvalerolactone after 1 hr. 2-methyl-5,6-dihydro-4H-thiopyran-3-carboxylic acid. Y 89%. F. e., also rearrangement to dihydrothiophene derivatives and limitations, s. F. Korte and K. H. Biichel, B. 93,1021 (1960). 

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