1. Early history of oxidation reactions of thiophenes: cycloaddition reactions of thiophene S-oxides prepared in situ in absence of Lewis acids

In the first half of the 20th century, considerable effort was devoted to the oxidation of the heteroaromatic thiophene (1) with the understanding that the oxidation of thiophene to thiophene S,S-dioxide (2) (Figure 1) would be accompanied by the loss of aromaticity [1, 2]. The non-substituted thiophene S,S-dioxide (1) is not very stable in the pure state [3], but undergoes a slow dimerization with concurrent extrusion of SO2 from the primary cycloadduct (4) [4], leading to 5 (Scheme 1). Only much later were the properties and reactivity of pure, isolated non-substituted thiophene S,S-dioxide (2) described [5].

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and eproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Figure 1. Structure of thiophene (1) and oxygenated thiophenes 2 and 3.

Scheme 1. Dimerisation of unsubstituted thiophene S,S-dioxide (2).

Much of the early work on the oxidation of thiophenes to thiophene S,S-dioxides involved hydrogen peroxide (H2O2) as oxidant, later meta-chloroperoxybenzoic acid (m-CPBA). That thiophene S-oxide was an intermediate in such oxidation reactions [6–8] was evident from the isolation of so-called sesquioxides as dimerization products of thiophene S-oxides [9–12]. Here, the thiophene S-oxide acted as diene with either another molecule of thiophene S-oxide or thiophene S,S-dioxide acting as ene [9–12] to give cycloadducts 6–8 (Figure 2). Thiophene S-monoxide (3) as an intermediate in the oxidation process of thiophene (1) to thiophene S,Sdioxide (2) could not be isolated under the conditions.

Nevertheless, the idea that a thiophene S-oxide intermediate could be reacted with an alkene of choice led Torssell [13] oxidize methylated thiophenes with m-CPBA in the presence of quinones such as p-benzoquinone (12). This gave cycloadducts 13 and 14 (Scheme 2) [13]. Further groups [11, 12, 14–19] used this strategy to react thiophene S-oxides such as 11, prepared in-situ with alkenes and alkynes in [4 + 2]-cycloadditions (Schemes 3 and 4). In the reaction with alkenes, 7-thiabicyclo[2.2.1]heptene S-oxides such as 13 were obtained, while the reaction of thiophene S-oxides with alkynes led to cyclohexadienes and/or to aromatic products, where the initially formed, instable 7-thiabicyclo[2.2.1]hepta-2,5-diene S-oxide system 21 extrudes its SO bridge spontaneously (Scheme 4). A number of synthetic routes to multifunctionalized cyclophanes 32 [17], aryl amino acids 25 [16] and to crown ethers 29 [15] (Scheme 5)

have used the cycloaddition of thiophene S-oxides 19, created in-situ, as a key step. The formation of the 7-thiabicyclo[2.2.1]heptene S-oxides (such as 13, 18) proceeds with stereocontrol. The cycloadditions yield predominantly endo-cycloadducts, with the oxygen of the sulfoxy bridge directed towards the incoming dienophile, exhibiting the syn-π-facial stereoselective nature of the reaction (see below for further discussion of the stereochemistry of the cycloadducts). Thiophene S,S-dioxides 2 possess an electron-withdrawing sulfone group, which leads both to a polarization and to a reduction of the electron density in the diene [20]. This results in a decrease of the energy of the HOMO as compared to identically

Scheme 2. Thiophene S-oxide (11), created in situ, reacts in Diels-Alder type fashion with p-benzoquinone (12).

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Scheme 3. Cycloaddition of thiophene S-oxides, prepared in situ, with alkenes.

Scheme 4. Cycloaddition of thiophene S-oxides (19), prepared in situ, with alkynes.

Figure 2. Sesquioxides obtained by dimerization of elusive thiophene S-oxide and by cycloaddition of thiophene S-oxide to thiophene S,S-dioxide.

Thiophene *S*-Oxides http://dx.doi.org/10.5772/intechopen.79080 45

Scheme 2. Thiophene S-oxide (11), created in situ, reacts in Diels-Alder type fashion with p-benzoquinone (12).

Scheme 3. Cycloaddition of thiophene S-oxides, prepared in situ, with alkenes.

Much of the early work on the oxidation of thiophenes to thiophene S,S-dioxides involved hydrogen peroxide (H2O2) as oxidant, later meta-chloroperoxybenzoic acid (m-CPBA). That thiophene S-oxide was an intermediate in such oxidation reactions [6–8] was evident from the isolation of so-called sesquioxides as dimerization products of thiophene S-oxides [9–12]. Here, the thiophene S-oxide acted as diene with either another molecule of thiophene S-oxide or thiophene S,S-dioxide acting as ene [9–12] to give cycloadducts 6–8 (Figure 2). Thiophene S-monoxide (3) as an intermediate in the oxidation process of thiophene (1) to thiophene S,S-

Nevertheless, the idea that a thiophene S-oxide intermediate could be reacted with an alkene of choice led Torssell [13] oxidize methylated thiophenes with m-CPBA in the presence of quinones such as p-benzoquinone (12). This gave cycloadducts 13 and 14 (Scheme 2) [13]. Further groups [11, 12, 14–19] used this strategy to react thiophene S-oxides such as 11, prepared in-situ with alkenes and alkynes in [4 + 2]-cycloadditions (Schemes 3 and 4). In the reaction with alkenes, 7-thiabicyclo[2.2.1]heptene S-oxides such as 13 were obtained, while the reaction of thiophene S-oxides with alkynes led to cyclohexadienes and/or to aromatic products, where the initially formed, instable 7-thiabicyclo[2.2.1]hepta-2,5-diene S-oxide system 21 extrudes its SO bridge spontaneously (Scheme 4). A number of synthetic routes to multifunctionalized cyclophanes 32 [17], aryl amino acids 25 [16] and to crown ethers 29 [15] (Scheme 5)

Figure 2. Sesquioxides obtained by dimerization of elusive thiophene S-oxide and by cycloaddition of thiophene S-oxide

dioxide (2) could not be isolated under the conditions.

to thiophene S,S-dioxide.

Scheme 1. Dimerisation of unsubstituted thiophene S,S-dioxide (2).

Figure 1. Structure of thiophene (1) and oxygenated thiophenes 2 and 3.

44 Chalcogen Chemistry

Scheme 4. Cycloaddition of thiophene S-oxides (19), prepared in situ, with alkynes.

have used the cycloaddition of thiophene S-oxides 19, created in-situ, as a key step. The formation of the 7-thiabicyclo[2.2.1]heptene S-oxides (such as 13, 18) proceeds with stereocontrol. The cycloadditions yield predominantly endo-cycloadducts, with the oxygen of the sulfoxy bridge directed towards the incoming dienophile, exhibiting the syn-π-facial stereoselective nature of the reaction (see below for further discussion of the stereochemistry of the cycloadducts). Thiophene S,S-dioxides 2 possess an electron-withdrawing sulfone group, which leads both to a polarization and to a reduction of the electron density in the diene [20]. This results in a decrease of the energy of the HOMO as compared to identically

2. Cycloaddition reactions of thiophene S-oxide prepared in situ in the

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

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

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

. Et2O.

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presence of Lewis acids: thiophene S-oxides are isolated

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

these reactions.

presence of BF3

. Et2O.

Scheme 5. Cycloaddition of thiophene S-oxides prepared in situ—applications in the synthesis of functionalized aminocarboxylic acids 25, crown ethers 29 and cyclophanes 32.

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

Oxidation of the thienyl-unit in 33 leads to an intramolecular cycloaddition, where indanones 34 are obtained (Scheme 6) [24].

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