The chemistry of thiophene S -oxides 1 and related compounds

The synthesis and reactivity of thiophene S -oxides is discussed, with special emphasis on the use of thiophene S -oxides as dienes in Diels-Alder type reactions, on the photochemistry and on the electrochemistry of the molecules. Where useful, the reactivity is compared to that of benzo[ b ]thiophene S -oxides, dibenzothiophene S-oxides, and tetracyclones


Introduction
While thiophene S,S-dioxides 1 are well-known compounds, thiophene S-oxides 2 (Figure 1) have remained an elusive species until fairly recent times.As the methods of preparation and derivatization of thiophenes 3 are inherently different from those of all-carbon arenes, thiophene S-oxides 2 were viewed as interesting building blocks with the proviso that they could be synthesized from thiophenes directly and would prove be suitable cyclic dienes for cycloaddition reactions that would lead to multi-functionalized arenes, thus complementing existing routes to these compounds.This has been shown to be the case.Furthermore, thiophene S-oxides 2 have been found to exhibit a wealth of interesting reactivity.In the following, some of the chemistry of thiophene S-oxides 2 is detailed with an emphasis on reactions carried out in our laboratory.

Preparation and Structure
Thiophenes 3 can be oxidized to thiophene S-oxides 2, 2 a route taken in the oxidation of thiophenes 3 with hydrogen peroxide or with peracids to yield the normally very stable thiophene S,S-dioxides 1 3 of cyclic diene character.In fact, a long time before their actual isolation and characterization, thiophene S-oxides 2 were considered as intermediates in the oxidation of thiophenes 3 to thiophene S,S-dioxides 1.This was due to the fact that dimeric cycloadducts, the so-called sesquioxides 7 -9 (Figure 2), 4,5 can be found as side-products in these reactions.These stem from the cycloaddition of thiophene S-oxide to thiophene S-oxide (for 7 and 8) or to thiophene S,S-dioxide (for 9).Interestingly, sesquioxides can also be found in oxidatively treated, thiophene-containing fuel. 6hat the oxidation of thiophenes can be stopped at the monoxide stage is a matter of adding a Lewis acid such as boron trifluoride etherate in the case of the peracid oxidants 5,7 and of a proton acid such as trifluoroacetic acid in the case of hydrogen peroxide (Scheme 1). 8The same holds true for the oxidation of benzothiophenes 10 to benzothiophene S-oxides 4, 9,10 the acid most likely having a dual function, namely to activate the peroxide/peracid and to complex to the monoxide once it is formed, hindering by the withdrawal of electron density from sulfur a further oxidation to the corresponding thiophene-or benzothiophene-S,S-dioxide.
Figure 3 The oxidation of thiophenes is not the only path to thiophene S-oxides.The second, versatile approach to aryl substituted thiophene S-oxides is via reaction of thionyl chloride with zirconacyclopentadienes 13, 11 themselves prepared from diarylacetylenes 11 and dicyclopentadienylzirconium dichloride (12) (Scheme 1).Interestingly, the first preparation of a thiophene S-oxide, namely of 15, if only as a transient, detected species, utilized neither of the two routes, but rather took advantage of a bis-dehydromesylation of the tetrahydrothiophene S-oxide 14 (Scheme 1). 12n contrast, the all-carbon analogs of thiophene S-oxides, the tetra-arylcyclopentadienones (tetracyclones) 6 are routinely prepared by the Weiss reaction. 13A similar preparation of thiophene S-oxides via dibenzyl sulfoxide (16) has not been reported thus far.
Thiophene S-oxides 2 and also benzothiophene S-oxides 4 are much more sensitive than their dioxide counterparts.Depending on their substitution pattern, some of them cannot be kept in substance at room temperature.The thiophene S-oxides have been discussed as having an aromatic, anti-aromatic, and purely cycloalkadiene-like character. 14What has been found, also from X-ray crystal structures (Figure 3), 7b,8,15 is that they are in fact dienes, where the lone pair of the sulfur does not interact with the cyclic diene moiety, the heterocyclic ring being puckered, this in contrast to the much better studied tetracyclones, which are planar molecules. 16Tetraaryl-substituted thiophene S-oxides are pale yellow, while tetra-arylcyclopentadienones are dark purple.Thiophene S-oxides, however, do invert at the sulfur with different substituents at the C2/C5 positions leading to different barriers of inversion. 2,17cheme 2 Thiophene S-oxides are useful dienes and add stereoselectively to a row of dienophiles (Scheme 2). 18,19With acetylenes 20 as the ene components, the substituted arenes 22 form directly.The sulfoxide bridge in 7-thiabicyclo[2.2.1]heptadiene S-oxides 21 is extruded spontaneously.With alkenes 18 as ene component, 7-thiabicyclo[2.2.1]heptene S-oxides 19 are formed.The stereochemistry at sulfur is controlled in the cycloaddition, stereoselectivity stemming from the 'Cieplak'-effect (23 vs. 24, Scheme 2). 20Often, these cycloaddition reactions occur at room temperature.A competitive experiment at room temperature between tetracyclone 6 and tetraphenylthiophene S-oxide (2) and N-phenylmaleimide (25) leads to exclusive formation of 7-thiabicyclo[2.2.1]heptene S-oxide 26 (Scheme 3).Tetra-arylthiophene S-oxides are thermally stable for limited periods of time, so that they can be reacted with substrates under microwave irradiation, successfully.While thiophene S-oxides are useful dienes in Diels Alder reactions, it is much more difficult to react them as the ene component as either self-dimerization occurs with the less substituted thiophene-S-oxides or the molecules are too sluggish to react in case of heavily substituted thiophene-S-oxides.The extrusion can be accomplished thermally, 23 electrochemically, 23 photochemically 24 or by using KMnO 4 as oxidant 25 under phase transfer conditions (Scheme 6).The last three reactions are run at room temperature.As the reaction of thiophenes to thiophene S-oxides also proceeds at room temperature or below, the above represents a two-step procedure of transforming substituted thiophenes to substituted arenes at room temperature.This transformation, also run as a one-pot oxidation -cycloaddition reaction, 26 has been used to prepare multi-functionalized cyclophanes such as 41 and 43 (Scheme 7), 27 crown ethers such as 45 (Scheme 8) 25 and phenyl-substituted amino acids 49 (Scheme 8) 28 from their thienyl precursors.Furthermore, 7thiabicyclo[2.2.1]heptene S-oxides 19 can be transformed to 7-thiabicyclo[2.2.1]heptenes 37 by action of PBr 3 , 24 to substituted cyclohexadienes 38 with Bu 3 SnH 24 and to diphenyl disulfides 36, 29 when halo substituted 7-thiabicyclo[2.2.1]heptene S-oxides are reacted with base (Scheme 6).

Photochemistry of Thiophene S-Oxides
When thiophene S-oxides are left in solution exposed to daylight, most revert slowly to the corresponding thiophenes, where a number of other products can be in evidence.This deoxygenation occurs in the dark, too, but much more slowly.Thiophene S-oxides exhibit a certain cytotoxicity. 30Typical examples are shown in Fig. 4. Studies on the interaction between 3,4-dibenzyl-2,5-dimethylthiophene S-oxide (2b) and isolated dsDNA have been carried out electroanalytically. 31 As 2b shows very low solubility in polar solvents, a mixture of dsDNA and compound in pH 7.4 phosphate buffer was placed on the glassy carbon electrode surface and dried for 24h.It was found that 2b does not damage dsDNA directly.Only after an initial reductive step of 2b at -1.6V vs. SCE was damage to dsDNA observed due to the appearance of an oxidation peak corresponding to 8-oxoguanine in the differential pulse voltammogram.The preparation of water-soluble thiophene S-oxides in form of carbohydrate-substituted thiophene-S-oxides for studies in polar aqueous or alcoholic solvents has been unsuccessful thus far. 32Nevertheless, the possibility that the cytotoxicity of the molecules is also linked to their deoxygenation has been considered. 33

Scheme 9
As light accelerates the deoxygenation of the thiophene S-oxides 2, photochemical investigations of thiophene S-oxides were initiated, although the authors were aware of the fact that the mechanisms leading to deoxygenation and operating in the light-reaction and in the dark-reaction might well be different.It was found that the molecules exhibit a rich photochemistry, 34 which depends on the substitution pattern of the thiophene S-oxides.Photoirradiation of 2-or 5-alkylated thiophene-S-oxides such as 2b with a proton in a position alpha to the heterocyclic ring leads to hydroxylated thiophenes such as to 50 and 51 (Scheme 9).The presence of a reductant in the reaction mixture, such as of an amine, leads to exclusive deoxygenation to the parent thiophene compound 53 (Scheme 11).In the presence of thiophenol 54, again exclusive photodeoxygenation is found.Here, diphenyl disulfide 55 is obtained as the oxidized product (Scheme 11).It is believed that water is formed concomitantly.The nature of the initially liberated oxygen species has been a matter of discussion.

Scheme 10
When dibenzothiophene S-oxides are photo-irradiated, deoxygenation also occurs. 35It is this transformation that has initiated the discussion on the nature of such a photo-extruded oxygen.A mono-molecular process has been considered. 36In such a case, the liberated oxygen species may be monoatomic oxygen O( 3 P).This mechanism has been supported by trapping experiments. 36,37ew work by Jenks and his co-workers indicates that in the case of dibenzothiophene S-oxides the photochemical active state is the lowest singlet, not the lowest triplet. 37Previously, the possibility of release of singlet oxygen via an excited benzothiophene S-oxide dimer has been put forward. 38Attempts to substitute dibenzothiophene S-oxides in such a way that formation of an excited dimer would be sterically unfavorable, led to the observation that while 4,6trimethylsilyldibenzothiophene S-oxide deoxygenates less effectively than non-substituted dibenzothiophene S-oxide or 4,6-dimethyldibenzothiophene S-oxide, the equally bulky 4,6-bis-(2,5-dimethylphenyl)dibenzothiophene S-oxide deoxygenates very efficiently. 39This seems to indicate that steric requirements do not influence the rate of deoxygenation but rather that the nature of the substituent (substituent effect) influences the outcome of the photoreaction.

Scheme 11
In thiophene-S-oxides that do not possess a substituent at C2 or C5 with a proton alpha to the heterocyclic ring system the photo-irradiation leads to a different reaction outcome.Thus, both 2,5-diphenylthiophene S-oxide and 2,5-bis-(t-butyl)thiophene S-oxide (2e) (Scheme 10) give significant amounts of furans.Small quantities of difuryl disulfides can be isolated as side products.The authors have postulated oxathiin (Scheme 10) as a possible intermediate.Important, though, is that this transformation represents a photo-induced extrusion of sulfur from thiophene derivatives.

Electrochemistry of Thiophene S-Oxides
Thiophene S-oxides exhibit interesting electrochemistry, which differs from that of the corresponding C-analogs, the tetracyclones.In the reductive electrochemistry, the main reaction is a reduction of thiophene S-oxide 2 to the thiophene 3, 40 in the case of the tetracyclone 6 it is the formation of its stable radical anion followed by further reduction.

Scheme 12
The oxidative electrochemistry of the classes of molecules also differs -under forced electro-oxidative conditions thiophene S-oxides 2 form diphenacylstilbenes under extrusion of sulfur, 42 while the tetracyclones 6 form α-pyrones 58.Ultrasonication of the substrates at 40 and 850 kHz during the electro-oxidation enhanced the current for both tetraphenylthiophene S-oxide and tetracyclone, 43 but did not mitigate 23 the fouling processes that are often associated with the oxidative processes.Indications that 2-substituted benzothiophene-S-oxides ring-open oxidatively have been obtained. 44The electro-oxidative extrusion of sulfur may find some future application in an electro-oxidative desulfurization of benzo-and dibenzothiophene containing fuels.

Scheme 3 22 ISSN
Scheme 3 Scheme 8 Figure 4 Photochemical reactions of thiophene S-oxides: Pathway 1 Scheme 13 Photochemical reactions of thiophene S-oxides: Pathway 2Insertion of the oxygen into the heterocyclic ring and extrusion of sulfur Photochemical reactions of thiophene S-oxides: Pathway 3 Exclusive deoxygenation, of ten found in the presence of an additive that can be oxidized 41