Thiophene sulfoxide

The principal electrophiles to attack ring sulfur are either oxidants or alkylating reagents. Thiophene sulfoxide and sulfone formation is discussed in Section 3.02.2.6. Alkylating agents capable of forming thiophenium salts include trimethyloxonium tetrafluoroborate (MeaO BF ) and alkyl fluorosulfonates (ROSO2F). The salts e.g. 87) are conveniently isolated as hexafluorophosphates (88). 

Oxidation of thiophene with peracid under carefully controlled conditions gives a mixture of thiophene sulfoxide and 2-hydroxythiophene sulfoxide. These compounds are trapped by addition to benzoquinone to give ultimately naphthoquinone (225) and its 5-hydroxy derivative (226) (76ACS(B)353). The further oxidation of the sulfoxide yields the sulfone, which may function as a diene or dienophile in the Diels-Alder reaction (Scheme 88). An azulene synthesis involves the addition of 6-(A,A-dimethylamino)fulvene (227) to a thiophene sulfone (77TL639, 77JA4199). 

Melles and Backer " found, from a study of the oxidation of substituted thiophenes with perbenzoic or peracetic acid, that sulfones could be obtained from polysubstituted methyl- and phenyl-thiophenes and that the presence of electron-attracting groups, such as nitro, hindered the oxidation. Oxidation of thiophene - led to a product which was formed through a Diels-Alder reaction between the intermediate thiophene sulfoxide (211) and thiophene sulfone (212) and for which two alternative structures, (213) or (214), were suggested. Similar sesquioxides were also obtained from 2- and 3-methylthiophene and 3-phenylthiophene. The structures were not proved. Bailey and Cummins synthesized thiophene-1,1-dioxide... 

The benzo[fc]thiophene sulfoxides, such as (142), generated from the parent benzo-thiophene on the H202-TFA-mediated oxidation, undergoes Michael-type nucleophilic addition of oxygen and sulfur nucleophiles in acidic media to produce 3-substituted benzo[fc]thiophenes (143). This method provides an easy two-step functionalization of 2-acylbenzo[fc]thiophene derivatives. ... 

Unsubstituted thieno[3,4-6]thiophene (3) (see Litvinov and Fraenkel ), was prepared by Cava and Pollack s method for benzo[c]-thiophene i.e., thermal decomposition of H, 3 -benzo[c]thiophene sulfoxide. By refluxing 4/f,6/f-thieno[3,4-ft]thiophene-2-carboxylic acid 5-oxide (91) with acetic anhydride (the synthesis of dihydrothieno-thiophenes will be described below), Wynberg et a/." obtained the mixed anhydride 92 in 95% yield. Hydrolysis gave thieno[3,4-6]-thiophene-2-carboxylic acid (93) (88%). Decarboxylation of the acid (93) gave thienothiophene 3, unstable at room temperature [Eq. (29)]. 

In 1973 Cava et al. reported the synthesis of 4,6-dimethyl-l/f,3if-thieno[3,4-c]thiophene (142) and l,3,4,6-tetraphenylthieno[3,4-cl-thiophene (149) ° as well as data on some chemicaJ conversions of the latter and the dehydration of 4,6-dimethoxycarbonyl-l/f,3H-thieno-[3,4-c]thiophene sulfoxide. Thienothiophene (149) was also obtained (42%) by Potts and McKeough by condensation of anhydro-4-hydroxy-2,3,5-triphenylthiazolium hydroxide with dibenzoylacetylene followed by reaction of the product with P S,. 

The question of aromaticity arises. Neither thiophenium salts nor thiophene sulfoxides are especially stable, making the classical reactivity test of electrophilic aromatic substitution difficult. The former dealkylate readily and the latter, at least for the case of thiophene sulfoxide, readily undergo self-dimerization (65CCC1158) (the bulky substituents of (57) impede this reaction). Aromaticity requires that the lone pair on sulfur participate in the aromatic sextet. If the lone pair, because of sp3 hybridization and improper symmetry, is not delocalized into the butadiene segment, the system will be antiaromatic. 

Thiophene sulfoxides and thiophene sulfones can be prepared by direct oxidation of the corresponding sulfides (Section 3.15.9.5.1) with hydrogen peroxide. 2-Thiophene sulfones are also prepared by reaction of arylsulfonyl chlorides with thiophene under mild Friedel-Crafts conditions, or by condensation of 2-thiophenesulfonyl chlorides with aromatic compounds (Section 3.14.2.4). 

Sulfoxides O II R-S-R DMSO, diethyl-sulfoxide, thiophene sulfoxide ls-tt 2477.0-2478.0a-b-d-e -hJ... 

Figure 10. Simplification of the proposed pathways from dibenzothiophene co-metabolism by pure cultures of aerobic bacteria. (I) dibenzo-thiophene-sulfoxide, (II) 1,2-dihydroxydibenzothiophene, (III) 3-hydroxy-2-formylbenzothiophene.

An ab initio computational study on thiophene sulfoxide 25, benzo[/ ]thiophene sulfoxide 26, and dibenzothio-phene sulfoxide 27 have been reported <1996JOC1275>. 

Jenks et al. studied the effects of conjugation and aromaticity on the sulfoxide bond by means of ab initio computation <1996JOC1275>. They calculated S-O bond dissociation energies (BDEs) and found that, in a formally aromatic system such as thiophene sulfoxide, the SO BDE is decreased by as much as 25kcalmoP relative to the BDE of DMSO. Although the BDE of the formally antiaromatic thiirene sulfoxide increased by about 15 kcal moP the authors concluded, on the basis of calculated geometries and isodesmic reactions with pure hydrocarbons, that cyclic unsaturated sulfoxides are neither significantly aromatic nor antiaromatic. 

FIGURE 16.8 Oxidation of tienilic acid by CYP2C9 to an unstable electrophilic thiophene sulfoxide, which binds specifically with CYP2C9 to form a liaptenic conjugate or reacts with water to form 5-hydroxy tienilic acid. 

The structural similarities between S-alkylthiophenium salts and thiophene sulfoxides have prompted the suggestion that both classes are antiaromatic (70JA7610, 70JCS(C)1764). Thiophene sulfoxides are exceptionally reactive, undergoing spontaneous Diels-Alder dimerization unless stabilized by bulky substituents at the 2- and 5-positions. This type of reactivity is reminiscent of cyclobutadiene. In stark contrast to the sulfoxides, S-alkylthiophenium salts show no tendency to take part in Diels-Alder reactions either in an intra- or intermolecular sense. Pentamethylthiophenium hexafluorophosphate (11, X = PFg ) was shown to be completely unreactive toward both electron-rich and electron-deficient dienophiles under conditions where thiophene sulfoxides undergo efficient cycloaddition reactions. 

On the other hand, Lemal and his coworkers prepared Dewar thiophene sulfoxide. A study of the NMR spectrum reveals that the sulfoxide group migrates around the cyclobutene ring 130). They called this migration a pseudopericyclic reaction. An investigation of the temperature-dependent NMR spectrum shows that this migration... 

Valadon, P, Dansette, P. M., Girault, J. P, Amar, C., Mansuy, D. Thiophene sulfoxides as reactive metaboUtes formation upon microsomal oxidation of a 3-aroylthiophene and fate in the presence of nucleophiles in vitro and in vivo. ChettL Res. Toxicol. 1996, 9, 1403-1413. 

In humans, the bioactivation of tienilic acid as its reactive intermediate depends on cytochrome P-450 2C9. This isoform is one of the major forms of cytochrome P-450 in the human liver. It has recently been demonstrated that in the presence of cytochrome P-450 thiophene is oxidized in vivo to yield thiophene sulfoxide (Fig. 32.12). This unusual function is a very electrophilic species capable of reacting with thiol group nucleophiles such as glutathione (detoxication) or proteins. This interaction with free proteins that contain thiol groups may give rise to an adduct and the potential associated toxicity. 

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