2. Cycloaddition reactions of thiophene S-oxide prepared in situ in the presence of Lewis acids: thiophene S-oxides are isolated

Yields of cycloadducts have been found to be much higher, when oxidative cycloaddition reactions of thiophenes are carried out with meta-chloroperoxybenzoic acid (m-CPBA) or with H2O2 at lower temperatures such as at 20C in the presence of a Lewis acid catalyst such as BF3Et2O [11, 12, 25, 26] (Scheme 7) or of trifluoroacetic acid (CF3CO2H) [27]. Electron-poor dienophiles such as tetracyanoethylene, acetylene dicarboxylates, quinones, maleimides and maleic anhydride and mono-activated enes such as cyclopentenone and acrolein were used in these reactions.

Scheme 7. Oxidative cycloaddition of thiophene 36 to naphthoquinone (37) in the presence of BF3 . Et2O.

substituted cyclopentadienes [20]. Thiophene S,S-dioxides 2 are sterically more exacting than C5 non-substituted cyclopentadienes, with the lone electron pairs on the sulfone oxygens leading to adverse non-bonding interactions with potentially in-coming dienophiles of high π-electron density. Thus, thiophene S,S-dioxides 2 often require higher temperatures [21, 22] in cycloaddition reactions than identically substituted cyclopentadienes. Recent frontier molecular orbital calculations at the HF/6-311++G(d,p)//M06-2X/6-31+G(d) level theory have shown that both HOMO (by 0.5 eV) and LUMO (by 0.4 eV) in thiophene S-oxide (3) are slightly higher

Scheme 5. Cycloaddition of thiophene S-oxides prepared in situ—applications in the synthesis of functionalized

Oxidation of the thienyl-unit in 33 leads to an intramolecular cycloaddition, where indanones

in energy than in thiophene S,S-dioxide (2) [23].

Scheme 6. Intramolecular cycloaddition of in situ prepared thiophene S-oxide 34.

aminocarboxylic acids 25, crown ethers 29 and cyclophanes 32.

34 are obtained (Scheme 6) [24].

46 Chalcogen Chemistry

Scheme 8. Preparation of multifunctionalized cyclophane 41 by oxidative cycloaddition of thiophenophane 39 in the presence of BF3 . Et2O.

Scheme 9. Preparation of aethiosides A–C (44a–c) by oxidative cycloaddition of thienosteroidal sapogenin 42.

Scheme 10. Cycloaddition of 2,5-dimethylthiophene S-oxide (45), prepared in situ, to C60 (46).

prepared by double elimination from 3,4-dimesyloxy-2,3,4,5-tetrahydrothiophene S-oxide (53) and studied in solution. While subsequently the latter part of the assertion was thrown into doubt, the isolation of sesquioxides 7/8 from the reaction indicated at least the presence of

Scheme 11. Isolation of 2,5-bis-tert-butylthiophene S-oxide 51 by simple thiophene oxidation with meta-chloroperox-

The reaction of the cationic transitory ruthenium complex [Ru(C6R6)(C4R4S)]+ (57) with hydroxyl anion (OH) gives Ru(C6H6)(C4R4SO) (58) [35] (Scheme 14). Here, in contrast to the complex [Cp\*Rh(TMTO)] (56), the thiophene S-oxide ligand in Ru(C6H6)(C4R4SO) (58) is not






Thiophene *S*-Oxides

49

http://dx.doi.org/10.5772/intechopen.79080


thiophene S-oxide under these conditions [33] (Scheme 12).

rhodium complex [Cp\*Rh(η<sup>4</sup>

electrochemically to [Cp\*Rh(η<sup>4</sup>

Scheme 13. Oxidation of [Cp\*Rh(η<sup>4</sup>

[Cp\*Rh(TMTO)] (56). Reaction of [Cp\*Rh(η<sup>4</sup>

(56), which features a η<sup>4</sup>

ybenzoic acid (m-CPBA) [32].

Interestingly, a toluene solution of η5-ethyltetramethylcyclopentadienyl-η<sup>4</sup>

Scheme 12. In situ preparation of parent thiophene S-oxide (3) by an elimination reaction [33].


an X-ray crystal structure was carried out. Alternatively, [Cp\*Rh(η<sup>4</sup>

(KOSiMe3) leads back to [Cp\*Rh(TMTO)] (56) [34] (Scheme 13).

Figure 3. Orthothiophenophanes 48 and 49 do not allow for enough reaction volume and do not undergo oxidative cycloadditions with either alkynes or alkenes under the conditions (m-CPBA, BF3 . Et2O, CH2Cl2) [31].

Under the conditions m-CPBA/BF3Et2O, the cycloadditive transformation of thiophene Soxides, prepared in situ, was used in the synthesis of new cyclophanes such as 39 (Scheme 8) [25]. A series of 2,3-bis(hydroxyphenyl) substituted 7-thiabicyclo[2.2.1]hept-2-ene S-oxides as potential estrogen receptor ligands were prepared by oxidative cycloaddition of 3,4-bis (hydroxyphenyl)thiophenes in the presence of BF3Et2O [28]. Also the key step in Yu et al.'s [27] synthesis of steroidal saponins 44, closely related to the E-ring areno containing natural products aethiosides A–C, is a BF3Et2O catalyzed oxidative cycloaddition of the thienocontaining steroidal saponin 42 (Scheme 9) [26]. Furthermore, Zeng and Eguchi [29] were able to functionalize C60 (46) by cycloaddition with in-situ produced 2,5-dimethylthiophene Soxide (45) [29, 30] (Scheme 10). Nevertheless, sterically hindered thiophenes are more difficult to be subjected to the oxidative cycloaddition reactions (Figure 3).

### 3. Preparation and isolation of pure thiophene S-oxides

Thiophene S-oxides could be isolated in pure form as side-products in a number of oxidative cycloaddition reactions using alkylated thiophenes as substrates run with m-CPBA in the presence of BF3Et2O [11, 12]. Nevertheless, the first ascertained thiophene S-oxide (51) isolated in pure form came from the oxidation of the sterically exacting 2,5-bis-tert-butylthiophene (50) in absence of a Lewis acid or an added protic acid. 2,5-Bis-tert-butylthiophene S-oxide (51) could be isolated in 5% yield [32] (Scheme 11).

Previous to the isolation of thiophene S-oxides in pure form, based on UV-spectroscopic measurements, Procházka [33] had claimed that the parent thiophene S-oxide (3) could be

Scheme 11. Isolation of 2,5-bis-tert-butylthiophene S-oxide 51 by simple thiophene oxidation with meta-chloroperoxybenzoic acid (m-CPBA) [32].

prepared by double elimination from 3,4-dimesyloxy-2,3,4,5-tetrahydrothiophene S-oxide (53) and studied in solution. While subsequently the latter part of the assertion was thrown into doubt, the isolation of sesquioxides 7/8 from the reaction indicated at least the presence of thiophene S-oxide under these conditions [33] (Scheme 12).

Interestingly, a toluene solution of η5-ethyltetramethylcyclopentadienyl-η<sup>4</sup> -tetramethylthienyl rhodium complex [Cp\*Rh(η<sup>4</sup> -TMT)] (54) can be oxidized with dry oxygen to [Cp\*Rh(TMTO)] (56), which features a η<sup>4</sup> -coordinated thiophene S-oxide ligand. Complex 56 was isolated and an X-ray crystal structure was carried out. Alternatively, [Cp\*Rh(η<sup>4</sup> -TMT)] (54) can be oxidized electrochemically to [Cp\*Rh(η<sup>4</sup> -TMT)]2+ (55), which can also be obtained by protonation of [Cp\*Rh(TMTO)] (56). Reaction of [Cp\*Rh(η<sup>4</sup> -TMT)]2+ (55) with potassium methylsilanolate (KOSiMe3) leads back to [Cp\*Rh(TMTO)] (56) [34] (Scheme 13).

The reaction of the cationic transitory ruthenium complex [Ru(C6R6)(C4R4S)]+ (57) with hydroxyl anion (OH) gives Ru(C6H6)(C4R4SO) (58) [35] (Scheme 14). Here, in contrast to the complex [Cp\*Rh(TMTO)] (56), the thiophene S-oxide ligand in Ru(C6H6)(C4R4SO) (58) is not

Scheme 12. In situ preparation of parent thiophene S-oxide (3) by an elimination reaction [33].

Scheme 13. Oxidation of [Cp\*Rh(η<sup>4</sup> -TMT)] (54) to [Cp\*Rh(TMTO)] (56) [34].

Under the conditions m-CPBA/BF3Et2O, the cycloadditive transformation of thiophene Soxides, prepared in situ, was used in the synthesis of new cyclophanes such as 39 (Scheme 8) [25]. A series of 2,3-bis(hydroxyphenyl) substituted 7-thiabicyclo[2.2.1]hept-2-ene S-oxides as potential estrogen receptor ligands were prepared by oxidative cycloaddition of 3,4-bis (hydroxyphenyl)thiophenes in the presence of BF3Et2O [28]. Also the key step in Yu et al.'s [27] synthesis of steroidal saponins 44, closely related to the E-ring areno containing natural products aethiosides A–C, is a BF3Et2O catalyzed oxidative cycloaddition of the thienocontaining steroidal saponin 42 (Scheme 9) [26]. Furthermore, Zeng and Eguchi [29] were able to functionalize C60 (46) by cycloaddition with in-situ produced 2,5-dimethylthiophene Soxide (45) [29, 30] (Scheme 10). Nevertheless, sterically hindered thiophenes are more difficult

Figure 3. Orthothiophenophanes 48 and 49 do not allow for enough reaction volume and do not undergo oxidative

.

Et2O, CH2Cl2) [31].

Thiophene S-oxides could be isolated in pure form as side-products in a number of oxidative cycloaddition reactions using alkylated thiophenes as substrates run with m-CPBA in the presence of BF3Et2O [11, 12]. Nevertheless, the first ascertained thiophene S-oxide (51) isolated in pure form came from the oxidation of the sterically exacting 2,5-bis-tert-butylthiophene (50) in absence of a Lewis acid or an added protic acid. 2,5-Bis-tert-butylthiophene S-oxide (51)

Previous to the isolation of thiophene S-oxides in pure form, based on UV-spectroscopic measurements, Procházka [33] had claimed that the parent thiophene S-oxide (3) could be

to be subjected to the oxidative cycloaddition reactions (Figure 3).

cycloadditions with either alkynes or alkenes under the conditions (m-CPBA, BF3

Scheme 10. Cycloaddition of 2,5-dimethylthiophene S-oxide (45), prepared in situ, to C60 (46).

48 Chalcogen Chemistry

3. Preparation and isolation of pure thiophene S-oxides

could be isolated in 5% yield [32] (Scheme 11).

Scheme 14. Base hydrolysis of [Ru(C6R6)(C4R4S)]+ (57) [34].

stable, but opens to an acetylpropenethiolate. Stable osmium thiophene S-oxide complexes of type (cymene)Os(C4Me4S=O) have also been prepared [36]. In neither of the cases, was it tried to decomplex the thiophene S-oxide ligand.

In the 1990s, two main synthetic methodologies were developed to prepare thiophene S-oxides 63. The first involves the reaction of substituted zirconacyclopentadienes 62 with thionyl chloride (SOCl2), developed by Fagan et al. [37, 38] and by Meier-Brocks and Weiss [39]. Typically, tetraarylzirconacyclopentadienes 62a can be synthesized easily by reacting CpZrCl2 (59), n-BuLi and diarylethyne (61a) in one step (Scheme 15). This strategy was followed by Tilley et al. [40, 41] in their synthesis of substituted thiophene S-oxides. Miller et al. published results for a synthesis of 2,5-diarylthiophene S-oxides (63b) along the same lines, using ethynylarene (61b) [42].

peracid, but also coordinates to the oxygen in the formed thiophene S-oxide, thus reducing the electron-density on the sulfur of the thiophene S-oxide, making it less prone to undergo a

Scheme 16. Preparation of thiophene S-oxides 65 by oxidation of thiophenes 64 in the presence of a Lewis acid or a

Thiophene *S*-Oxides

51

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It has been shown that in a molecule, such as 66 or 67, with two thienyl cores, both can be oxidized to thienyl-S-oxides with m-CPBA, BF3Et2O CH2Cl2, 20C) [11, 17] . Under these conditions, the second thiophene unit can compete successfully with a thiophene S-oxide for

Even before thiophene S-oxides could be isolated in pure form, it was evident that thiophene Soxides are good dienes in cycloaddition reactions, as "trapping" by cycloaddition reaction was one of the standard techniques to gauge the presence of thiophene S-oxide intermediates and provided a versatile preparative entry to 7-thiabi-cyclo[2.2.1]heptene S-oxides 68. These in turn could be converted to substituted arenes 71 by either pyrolysis [15], photolysis [51], or PTCcatalyzed oxidative treatment with KMnO4 [15] or electrochemical oxidation [18] or 7-thiabicyclo-[2.2.1]heptenes (70) by reaction of 68 with PBr3 [52]. Reaction of 68 with tributyltin hydride gives cyclic dienes such as 72 [▬X▬X▬ = ▬(CO)N▬Ph(CO)▬]. Base catalyzed cleavage of the sulfoxy bridge of 1,4-dihalo-7-thiabicyclo[2.2.1]heptane S-oxides 68 (R<sup>1</sup> = Cl or

Br) leads to the generation of diaryl disulfides such as 69 (Scheme 17).

second oxidation to the thiophene S,S-dioxide.

Figure 4. Known bisthienyl-S-oxides 66 and 67.

4. Reactions of thiophene S-oxides

4.1. [4 + 2]-cycloaddition reactions

the oxidant (Figure 4).

protonic acid.

The other methodology involves an oxidation of a thiophene with either a peracid in the presence of a Lewis acid such as titanium tetrachloride (TiCl4) [43] or boron trifluoride etherate (BF3Et2O) [44, 45] or with hydrogen peroxide in the presence of a protonic acid such as trifluoroacetic acid [46, 47] (Scheme 16). Also, the use of the reaction system H2O2 in presence of NaFe(III) ethylenediaminetetraacetate/Al2O3 has been reported [48, 49] (Scheme 16) as has been the use of the reaction system [(C18H37)2(CH3)2N]3[SiO4H(WO5)3] [50]. The thiophene S-oxides 65, suitably substituted, can be isolated by column chromatography and can be held in substance for a number of weeks without appreciable degradation, when in crystallized form and when kept in the dark. It is supposed that the Lewis acid not only activates the

Scheme 15. Synthesis of tetraarylthiophene S-oxides 63a/b by reaction of tetraarylzirconacyclopentadienes 62a/b with SOCl2.

Scheme 16. Preparation of thiophene S-oxides 65 by oxidation of thiophenes 64 in the presence of a Lewis acid or a protonic acid.

Figure 4. Known bisthienyl-S-oxides 66 and 67.

stable, but opens to an acetylpropenethiolate. Stable osmium thiophene S-oxide complexes of type (cymene)Os(C4Me4S=O) have also been prepared [36]. In neither of the cases, was it tried

In the 1990s, two main synthetic methodologies were developed to prepare thiophene S-oxides 63. The first involves the reaction of substituted zirconacyclopentadienes 62 with thionyl chloride (SOCl2), developed by Fagan et al. [37, 38] and by Meier-Brocks and Weiss [39]. Typically, tetraarylzirconacyclopentadienes 62a can be synthesized easily by reacting CpZrCl2 (59), n-BuLi and diarylethyne (61a) in one step (Scheme 15). This strategy was followed by Tilley et al. [40, 41] in their synthesis of substituted thiophene S-oxides. Miller et al. published results for a synthesis of 2,5-diarylthiophene S-oxides (63b) along the same lines, using

The other methodology involves an oxidation of a thiophene with either a peracid in the presence of a Lewis acid such as titanium tetrachloride (TiCl4) [43] or boron trifluoride etherate (BF3Et2O) [44, 45] or with hydrogen peroxide in the presence of a protonic acid such as trifluoroacetic acid [46, 47] (Scheme 16). Also, the use of the reaction system H2O2 in presence of NaFe(III) ethylenediaminetetraacetate/Al2O3 has been reported [48, 49] (Scheme 16) as has been the use of the reaction system [(C18H37)2(CH3)2N]3[SiO4H(WO5)3] [50]. The thiophene S-oxides 65, suitably substituted, can be isolated by column chromatography and can be held in substance for a number of weeks without appreciable degradation, when in crystallized form and when kept in the dark. It is supposed that the Lewis acid not only activates the

Scheme 15. Synthesis of tetraarylthiophene S-oxides 63a/b by reaction of tetraarylzirconacyclopentadienes 62a/b with

to decomplex the thiophene S-oxide ligand.

Scheme 14. Base hydrolysis of [Ru(C6R6)(C4R4S)]+ (57) [34].

ethynylarene (61b) [42].

50 Chalcogen Chemistry

SOCl2.

peracid, but also coordinates to the oxygen in the formed thiophene S-oxide, thus reducing the electron-density on the sulfur of the thiophene S-oxide, making it less prone to undergo a second oxidation to the thiophene S,S-dioxide.

It has been shown that in a molecule, such as 66 or 67, with two thienyl cores, both can be oxidized to thienyl-S-oxides with m-CPBA, BF3Et2O CH2Cl2, 20C) [11, 17] . Under these conditions, the second thiophene unit can compete successfully with a thiophene S-oxide for the oxidant (Figure 4).
