Synthesis of Thiophene and Benzothiophene

The classic example of a Fiesselman thiophene synthesis is the reaction involving a methylthioglycolate and an a,p-acetylenic ester in the presence of a base. 

The mechanism involves the formation of a thioacetal followed by a Dieckman condensation to produce the requisite five-membered ring. The reaction is completed with elimination and tautomerization to form the desired product. 

One widely used variation of the Fiesselman reaction is the use of cyanoalkynes in the presence of a thioglycolate under basic conditions to produce 3-aminothiophenes. This strategy was used in the production of 2-aminothiopehene-based p38 kinase inhibitors. 

An interesting example of the Fiesselman thiophene synthesis was reported during the investigation of the susceptibility of golfomycin A toward nucleophilic attack. Treatment of TBS-protected golfomycin A with methyl thioglycolate in the presence of base produced the strained thiophene product in 20% yield.  

The Fiesselmaim thiophene synthesis has also been used to produce various 2,3-diarylthiophenes to investigate their potential anti-inflammatory properties. The thiophene intermediate synthesized via the Fiesselman 

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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). 

I, 1-dioxides, and thiophene 1-oxides, in Science of synthesis, knowledge updates 2011/2 (A. Fuerstner, Ed.). Thieme Chemistry, Stuttgart, Germany, 2011, Vol. 9, pp. 371-444. (d) E. R. Biehl, Top. Heterocycl. Chem. 2012,29,347-380. Recent advances in the synthesis of thiophenes and benzothiophenes. (e)A.El-Mekabaty,5y fA Commun. 2014,44,1-31. Chemistry of 2-amino-3-carbethoxythiophene and related compounds. 

Diels-Alder reactivity of thiophene and benzothiophene remains poorly understood. AMI semiempirical studies examining the activation of thiophene for this thermally allowed [4+2] cycloaddition process have shown that the usual synthesis approaches (use of highly reactive dienophiles, substitution on thiophene, increased reaction pressures) have only small effects on rate enhancement. However, use of the corresponding S-methylthiophenium salts, which have little aromaticity, should provide excellent activation for Diels-Alder reactions of thiophenes even with poor dienophiles such as ethylene <95JHC483>. This AMI approach has been applied to examine Diels-Alder reactions of benzo[6] and benzo[c]thiophenes the theoretical data agree with experimental results <95JCS(P1)1217>. 

The synthetic methods will be arranged in order of bond formation, beginning with the formation of one bond, between sulfur and carbon-2 of thiophene, and proceeding around the ring, then two bonds, etc. This method is outlined in the chapter by Meth-Cohn (B-79MI31500) who has calculated that there are 19 different ways that thiophenes can be formed by different bond formations. Of these only 11 are of practical value currently. We have treated benzothiophenes and other polycyclic thiophenes as derivatives of thiophene, and discussed their synthesis in the specific bond formation sections. Likewise since methods... 

Chloro-2,3-diethyl-2-cyclobutenone (611) undergoes a palladium-catalyzed cross-coupling with 2-(tri- -butyl)stannyl-5-trimethylsilylthiophene (612) to give the intermediate compound (614) (Equation (110)). Without isolation, (614) is converted to the benzothiophene (613) on thermolysis at 100°C followed by acetylation. Although this procedure seems not to be generally applicable to benzo[6]thiophene synthesis, it provides a general synthesis of dibenzothiophenes, and thus a series... 

Benzothiophenes may be accessed by a variety of methods including variations of the Fiesselmann and Gewald thiophenes synthesis. In addition, acid-catalyzed and electrophilic (iodo) cyclizations have been used to create valuable synthetic thiophene and benzothiophene intermediates with varied substitution patterns. 

Abstract The review considers the synthesis and structures of photochromic products, in which hetaryl substituents are separated by the centtal 1,2-perfluorocyclopentene moiety. It was also briefly presented main methods for synthesis of octafluorocyclopentene and its reactivity. Among methods used for the synthesis of the photochromes, the reactions of hthium derivatives of thiophene, benzothiophene, and other heterocyclic compounds with octafluorocyclopentene, 1,2-dichlorohexafluorocyclopentene, and their analogues are described. Another general method for the synthesis of dihetarylethenes, considered in the review, is based on the McMurry reaction involving the initial... 

Larocket fl/. in 2000 developed the fluoren-9-one synthesis by the cyclocarbonyla-tion of ort/zo-halobiarys with a commercially available Pd(PCy3)2 catalyst [17] This procedure was initiated by the palladium(0) and could be utilized to the synthesis of polycyclic and heterocyclic fluorenones containing the fused isoquinoline, indole, pyrrole, thiophene, benzothiophene, and benzofuran rings (Table 15.12). 

Benzothiophenes have always been of interest for medicinal chemistry and can be found in a number of marketed drugs such as Sertaconazole (Gineder-mofix), Zileuton (Leutrol) and Raloxifene (Evista). The classical synthesis of benzo thiophenes starts from thiophenols, reacting with bromoacetaldehyde dimethyl acetal, followed by cycUzation using strong acid. An alternative and more convenient route was also described starting from benzaldehydes which... 

The versatility of Jl-heteroaromatic annulation has been further established by its application to the synthesis of isomeric benzo[b]thiophenes 58 and 60 <00T8153>. Both 2-cyanomethyl- (57) and 3-cyanomethyl- (59) thiophenes isomers have been reacted with various oxoketene dithioacetals 6 to obtain wide range of 4,5- (58) and 6,7- (60) substituted and condensed benzothiophenes <81AHC171 90JCSP(I)2909> in excellent... 

The synthesis of photochromic compounds containing combinations of benzothiophene and thiophene 70 (04JPP(A)97, 09JMS100), indene 71 (06TL1267), or benzofuran rings 72 and 73 (06BCJ1100, 08BCSJ644) was documented (Scheme 22). 

Reports detailing the chemistry and syntheses of thiophenes, benzothiophenes, and related ring systems that have appeared during the past year are the primary focus of this review. The synthesis of heterocycles including thiophenes has been reviewed <99JCS(P1)2849, 99JH1469>. As always, the author apologizes in advance for all errors and omissions. 

The last step in the synthesis of the sulfur- and selenium-containing psoralen analogues (174) (7/7-thieno[3,2- ][l]benzothiopyran-7-one, 7//-seleno[3,2-/][l]benzothiophen-7-one, 2//-selenolo [3,2- ][l]benzothiopyran-2-one, and 7//-selenolo[3,2-g][ 1 ]benzoselenopyran-7-one) was the poly-phosphoric acid silyl ether (PPSE)-mediated cyclization of benzol-thiophenes or selenophenes shown in Equation (76) <92H(34)lli9>. 

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