Thiophenes Dihydrothiophenes

Reaction of various aldehydes with hydrogen sulfide leads to substituted thiophenes, dihydrothiophenes, dithiolanes and trithiolane, as well as to six-membered ring thiopyran derivatives and dithiins. Ledl (33) obtained 2,4-dimethylthiophene (1, R Me) as a product of the reaction of propionaldehyde with hydrogen sulfide in the presence of ammonia. Sultan (29) reported the formation of 2,4-diethylthiophene (1, R - Et), 2,4-dibutyl-thiophene (1, R - Bu), and their dehydro derivatives from the reaction of ammonium sulfide with butyraldehyde and caproaldehyde (hexanal), respectively. The mechanism suggested for their formation is depicted in Scheme 1. Space limitations do not allow us to discuss the mechanism here in detail (for additional information, see ref. 29). 

Reduction and Hydrodesulfurization. Reduction of thiophene to 2,3- and 2,5-dihydrothiophene and ultimately tetrahydrothiophene can be achieved by treatment with sodium metal—alcohol or ammonia. Hydrogen with Pd, Co, Mo, and Rh catalysts also reduces thiophene to tetrahydrothiophene [110-01-0] a malodorous material used as a gas odorant. 

Does the fact that thiophene reacts similarly to benzene mean that it is aromatic One way to tell is to calculate first and second hydrogenation energies of thiophene, leading to dihydrothiophene and tetrahydrothiophene, respectively. (The energy of hydrogen is provided at right.)... 

Dichlorothiophene has become easily available through chlorination and dehydrochlorination of tetrahydrothiophened Another example of the aromatization of tetrahydrothiophene derivatives is the preparation of 3-substituted thiophenes by the reaction of 3-ketotetrahydrothiophene with Grignard reagents followed by the aromatization of the intermediate dihydrothiophene. Recent gas chromatographic analysis showed, however, that 2,3-dichlorothio-phene is the main product from the dehydrochlorination of tetra-chlorotetrahydrothiophene. 

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... 

Methyl-2,5-dihydrothiophene was converted into the corresponding S-oxide 4 in 57% yield after treatment with 30% excess of hydrogen peroxide for 60 h. By the same procedure the sulphoxides 5 derived from thiophene and its a-substituted analogues were also prepared18. 

Dimethylene-2,3-dihydrothiophene (37, Figure 2.3) is the thiophene analog [38] of o-quinodimethanes and has been used to develop a Diels-Alder-based synthetic approach to benzothiophene derivatives. Generated in situ by treating the trimethylsylyl ammonium derivatives 38 or 39 with Bu4N F , it... 

In contrast, synthesis of 3,4-diphosphorylthiophenes requires more elaboration because of low reactivity of 3,4-positions of thiophene and unavailability of 3,4-dihalo or dimetallated thiophenes. Minami et al. synthesized 3,4-diphosphoryl thiophenes 16 as shown in Scheme 24 [46], Bis(phosphoryl)butadiene 17 was synthesized from 2-butyne-l,4-diol. Double addition of sodium sulfide to 17 gave tetrahydrothiophene 18. Oxidation of 18 to the corresponding sulfoxide 19 followed by dehydration gave dihydrothiophene 20. Final oxidation of 20 afforded 3,4-diphosphorylthiophene 16. 3,4-Diphosphorylthiophene derivative 21 was also synthesized by Pd catalyzed phosphorylation of 2,5-disubstituted-3,4-dihalothiophene and converted to diphosphine ligand for Rh catalysts for asymmetric hydrogenation (Scheme 25) [47],... 

Additional studies featuring reactions of thiophene derivatives detail biohydrolysis of (S)-3-(thiophen-2-ylthio)butanenitrile <06TL8119>, lipase catalyzed resolution of thiotetronic acids <06TL7163>, enzymatic kinetic resolution of l,l-dioxo-2,3-dihydrothiophen-3-ol <06TL5273>, and efficient synthesis of 6-methyl-2,3-dihydrothieno[2,3-c]furan 55, a coffee... 

Tetracyanoethylene (TCNE)175,176 reacts with thiobenzophenones to yield 2,3-dihydrothiophene, thiophene, and 1,2-dithiin derivatives, thus depending on temperature. Okuma suggested a mechanism176 for the formation of 2,3-dihydrothiophenes through [2+2] and [4+2] sequential cycloadditions. 

The thiophene ring system can be utilized as a synthetic scaffold for the preparation of nonthiophene materials as the sulfur moiety can be removed by reduction (desulfurization) or extrusion (loss of SO2). The extrusion of sulfur dioxide from 3-sulfolenes (2,5-dihydrothiophene 1,1-dioxides) give dienes (butadienes or o-quinodimethanes) that can be utilized to prepare six-membered rings by cycloaddition chemistry. For example, thermolysis of 3-sulfolene 120 provided tricyclic pyrazole 122 via an intramolecular cycloaddition of the o-quinodimethane 121 that results by extrusion of sulfur dioxide <00JOC5760>. Syntheses of 3-sulfolenes 123 and 124 <00S507> have recently been reported. 

Figure 33 shows the UPS spectra of 2,5-bis(diphenylmethy-lene)-2,5-dihydrothiophene and di-hydroselenophene, as compared with that of 2,5-bis(dithienyl methy-lene)-2,5-dihydrothiophene, together with the spectra of benezene and thiophene for references, irrespective of the central ring with sulphur or selenium the UPS spectra are found to be almost same. However, the spectra were significantly different with changing the substituent rings at the exocyclic double bonds from the phenyl to the thienyl groups. In both the phenyl and the thienyl substituents, the spectra are very similar to those of benzene and thiophene... 

Figure 33. UPS spectra of 2,5-bis(diphenyl-methylene)-2,5-dihydrothiophene, dihydro-selenophene and 2,5-bis(dithienylmethy-lene)-2,5-dihydrothiophene, as compared with those of benzene and thiophene.

Recently the non-catalytic reduction of thiophene and its homologs was thoroughly investigated (5), (6). The preparation of both 2- and 3-thiolenes (dihydrothiophenes) was studied and reported to occur in accordance with the following scheme ... 

Studies on heterogeneous catalysts seem to invoke partial hydrogenation of thiophene prior to desulfurization [42] the catalysts are also active hydrogenation catalysts. Recently evidence for a facile and selective desulfurisation of partly hydrogenated thiophene has been reported, the reaction of 2,5-dihydrothiophene on (110) molybdenum surfaces (Figure 2.41) [43]. 

Cycloadditions with other symmetrical acetylenes were carried out by using thiocarbonyl (5)-methylide (69) (159). Interestingly, no reaction was observed when acetylene dicarboxamide was used. The reaction of 69 with cyclooctyne resulted in the formation of cycloadduct 103 (Scheme 5.38). Interestingly, the spirocyclic 2,5-dihydrothiophenes of type 103 or 104 undergo acid-catalyzed ring opening upon treatment with silica gel or trifluoroacetic acid to give thiophenes 105 and 106, respectively. 

A novel route to 2,3-dihydrothiophenes involved a titanocene-promoted carbene formation and subsequenct intramolecular cyclization onto a thiol ester <99SL1029>. Treatment of thioacetal 9 with the low-valent titanium complex 10 gave 2,3-dihydrothiophene 12 by intramolecular olefination of the thiol ester of titanium-carbene intermediate 11. Another metal-mediated cyclization onto the thiophene ring system involved the palladium-catalyzed cyclization of 1,6-diynes <99T485>. For example, treatment of thioether 1,6-diyne 13 with Pdlj in the presence of CO and Oj in methanol followed by treatment with base gave 14. 

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>. 

The product from the fluorination of thiophene over potassium tetrafluorocobaltate(III) varied, not surprisingly, with temperature.108 At 120 C, virtually the sole product was the dihydrothiophene 5, albeit in low yield (14%) this compound is obviously analogous to 2,2.5,5-tetra-fluoro-2,5-dihydrofuran from tetrahydrofuran and potassium tetrafluorocobaltate(IIl). At 350-370 °C, 5 is still a major product, but now seven others are also present, the main ones being 6-8 and the sulfur extruded product perfluorobutane. 

Dehydrogenation of 2,5- and 4,5-dihydrothiophenes. Lederle chemists1 have converted the 2,5-dihydrothiophene derivative 1 into the thiophene 2 with S02C12. 

Reaction with acetylenic dipolarophiles represents an efficient method for the preparation of 2,5-dihydrothiophenes. These products can be either isolated or directly converted to thiophene derivatives by dehydration procedures. The most frequently used dipolarophile is dimethyl acetylenedicarboxylate (DMAD), which easily combines with thiocarbonyl ylides generated by the extrusion of nitrogen from 2,5-dihydro-1,3,4-thiadiazoles (8,25,28,36,41,92,94,152). Other methods involve the desilylation (31,53,129) protocol as well as the reaction with 1,3-dithiolium-4-olates and l,3-thiazolium-4-olates (153-158). Cycloaddition of (S)-methylides formed by the N2-extrusion or desilylation method leads to stable 2,5-dihydrothiophenes of type 98 and 99. In contrast, bicyclic cycloadducts of type 100 usually decompose to give thiophene (101) or pyridine derivatives (102) (Scheme 5.37). 

The relative importance of through-bond (hyperconjugative) and through-space (homoconjugative) interactions between the heteroatom and the double bond in 2,5-dihydro-furan, -thiophene and -pyrrole has been the subject of a CNDO/S study (76ZN(A)215). This analysis concluded that the proportion of through-space interaction increased from 19% in the dihydrofuran and 20% for dihydrothiophene to 83% for the dihydropyrrole (cf. Section 2.3.3.9). 

NMR has been widely invoked in assessing aromaticity. Comparison of the chemical shifts of furan, H-2 7.46 and H-3 6.41, with those observed for 4,5-dihydrofuran, H-2 6.31 and H-3 4.95 (66JCS(B)127), indicates there is ca. 1-1.5 ppm downfield shift attributable to the presence of an aromatic ring current in furan. The same effect is observed for thiophene, H-2 7.35 and H-3 7.13, and 4,5-dihydrothiophene, H-2 6.17 and H-3 5.63 ppm. The similar range of chemical shifts observed for all of the parent heterocycles may be compared with that for benzene, 7.27 8, and further attests to their possessing appreciable ring currents. 

Chlorine and bromine react with thiophene to give successively the halogenation products shown (70-73). The bromination can be interrupted at the intermediate stages monochloro and dichloro derivatives have been obtained preparatively by chlorination with MeCONHCl. Addition products are also formed during chlorination prolonged action (with Cl2-I2) gives the dihydrothiophene derivative (74 Z = S). Iodination (I2-HgO) results in mono- and di-iodothiophenes (70) and (71) (X = I) only. Substituted compounds are halogenated as expected, e.g. (75). 

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