Oxidation of Organosulfides to Organosulfones with Trifluoromethyl 3-Oxo-1λ³,2-benziodoxole-1(3H)-carboxylate as an Oxidant

Abstract

An alternative approach is described for the oxidation of organosulfides to the corresponding organosulfones by using trifluoromethyl 3-oxo-1λ³,2-benziodoxole-1(3H)-carboxylate as an oxidant. The oxidation of the sulfides was performed by using 2.4 equivalents of the oxidant in refluxing acetonitrile. The oxidation products were isolated in good to excellent yields.

Key words

oxidation - sulfides - sulfones - hypervalent iodine - oxidizing agents

Organosulfones are important scaffolds in medicinal[1] and natural-product chemistry.[2] The presence of a sulfone functionality makes these compounds more suitable as synthetic intermediates and as chemical building blocks for many biologically active compounds, for example 1–6 (Figure [1]). Rofecoxib (Vioxx; 1) has been introduced as a COX-2 inhibitor and is a potent anti-inflammatory drug[3] and an analgesic.[4] Laropiprant (2) is a prostaglandin D₂ receptor antagonist.[5] Dapson (3) and sulfamethoxazole (4) have been developed as potent antibiotics for the treatment of leprosy and urinary infections, respectively.[6] [7] Glyburide (5) has been developed as a second-generation sulfonylurea, and is used in treating type 2 diabetes by enhancing insulin secretion.[8] Carbutamide (6) is classed as a first-generation sulfonylurea, and is also used as an antidiabetic agent.[9] In addition, various naturally occurring garlicnins isolated from Allium sativum L. have been shown to prevent cancer-cell growth.[2]

Figure 1Structures of biologically active compounds 1–6 possessing a sulfone moiety

Numerous procedures have been developed for the oxidation of sulfides to sulfoxides and sulfones by various oxidants.[10] [11] [12] In most of these approaches, oxidation of sulfides has been achieved by using various transition-metal derivatives, including Ti,[13] Sc,[10b] Ru,[14] Mn,[15] Zr,[16] Cu,[17] or Fe[18] complexes. In addition, several metal-free approaches have also been reported.[19] [20] Most oxidation approaches, however, involve the use of toxic metals or harsh reaction conditions. Recently, a synthesis of sulfones has been developed by using hypervalent iodine salts.[21]

In the past few decades, the chemistry of hypervalent iodine reagents has received attention due to their favorable safety profile and ease of handling.[22] [23] 1-Hydroxy-1λ³,2-benziodoxol-3(1H)-one 1-oxide (IBX) is one of the most common hypervalent iodine reagents, and it has been used in various oxidation reactions.[24] [25] Despite being a versatile oxidant, IBX has several drawbacks, such as poor solubility in common organic solvents[26] and a tendency to explode at elevated temperatures,[27] which limit its applications. We synthesized trifluoromethyl 3-oxo-1λ³,2-benziodoxole-1(3H)-carboxylate (8) by the oxidation of 2-iodobenzoic acid (7) with Oxone as oxidant in the presence of TFA (Scheme [1]).[28] The synthesis of compound 8 has been reported previously,[29] but its oxidative properties are still unexplored.

Scheme 1Synthesis of trifluoromethyl 3-oxo-1λ³,2-benziodoxole-1(3H)-carboxylate (8) by the oxidation of 2-iodobenzoic acid (7).

Herein, we report the selective oxidation of sulfides 9 to the corresponding sulfones 10 by using benziodoxole 8 as an oxidant. The precursors 9a–c were synthesized by the reaction of the corresponding thiophenols with t-butanol in the presence of an acid.[30a] Other starting materials 9d–h were synthesized by the reaction of thiophenols with alkyl bromides in the presence of sodium ethoxide.[30b]

Table 1Optimization of the Stoichiometry of the Iodine(III) Reagent 8 for the Oxidation of Sulfide 9a to Sulfone10a

Entry	Reagent 8 (equiv)	Temp	Time (h)	Yield (%)
1	1.0	r.t.	36	–
2	1.0	reflux	24	40
3	1.5	reflux	24	56
4	2.0	reflux	16	80
5	2.4	reflux	16	85
6	3.0	reflux	16	86

Initially, our efforts were directed at optimizing reaction conditions for the oxidation of tert-butyl phenyl sulfide (9a) as a model substrate. When the oxidation of sulfide 9a was performed with 1.0 equivalents of benziodoxole 8 in acetonitrile at room temperature for 36 hours, the oxidation product 10a was not obtained (Table [1], entry 1). When the same reaction was performed at the reflux temperature, conversion of the starting material was observed, and tert-butyl phenyl sulfide (10a) was obtained in 40% yield (entry 2). The oxidation product 10a was isolated in 56% yield when 1.5 equivalents of reagent 8 were used (entry 3). In this reaction, full conversion was not observed, and 40% of the starting material was recovered. When reactions were carried out by using 2.0 or 2.4 equivalents of 8, product 10a was obtained 80 and 85% yield, respectively (entries 4 and 5). When the reaction was performed with 3.0 equivalents of 8, no significant improvement was observed, and 10a was isolated in 86% yield (entry 6).

Next, our efforts were directed toward the optimization of the solvent. Various polar and nonpolar solvents were investigated for the oxidation of sulfide 9a (Table [2]). Initially, the oxidation was performed in MeCN, and oxidation product 10a was isolated in 85% yield (Table [2], entry 1). The oxidation proceeded well in the polar aprotic solvents DMSO and dichloromethane, giving 10a in 65 and 60% yield, respectively (entries 2 and 3). In the polar protic solvents methanol and ethanol, 10a was obtained in 50 and 52% yield, respectively (Table [2], entries 4 and 5). When the oxidation was performed in THF or 1,3-dioxane, 10a was obtained in 43 and 30% yield, respectively (entries 6 and 7). Therefore, the use of 2.4 equivalents of 8 in acetonitrile at the reflux for 16 hours was concluded to be optimal for the oxidation of sulfide 9a to the corresponding sulfone 10a.

Table 2The Optimization of Solvent for the Oxidation of Sulfide 9a to Sulfone 10a

Entry	Solvent	Time (h)	Yield (%)
1	MeCN	16	85
2a	DMSO	20	65
3	CH2Cl2	20	60
4	MeOH	20	50
5	EtOH	20	52
6	THF	20	43
7	1,3-dioxane	20	30

^a The reaction was performed at 100 °C.

A series of sulfides 9b–h was then successfully oxidized to the corresponding sulfones 10b–h in 68–91% yield under the optimized conditions (Table [3], entries 1–8).[31] All the oxidation reactions proceeded well, and both electron-withdrawing and electron-donating aromatic substituents were tolerated. The oxidation products were isolated in slightly better yields with substrates having electron-donating groups on the aromatic ring in comparison to substrates bearing electron-withdrawing groups.

Table 3Oxidation of Sulfides 9b–h

Entry	R1	R2	Time (h)	Product	Yield (%)
1	H	t-Bu	16	10a	85
2	4-Cl	t-Bu	20	10b	75
3	3-MeO	t-Bu	17	10c	89
4	H	Bn	16	10c	86
5	4-Cl	Bn	20	10e	81
6	3-MeO	Bn	16	10f	91
7	H	CH(Et)CO2Et	16	10g	75
8	4-Cl	CH(Et)CO2Et	18	10h	68

Next, we examined the selectivity of 8 towards the oxidation of sulfoxides and sulfides. To check the selectivity, a competitive reaction was performed between sulfide 9a and sulfoxide 11 in acetonitrile at the reflux temperature. Sulfoxide 11 was synthesized by the oxidation of sulfide 9c with m-CPBA at low temperature.[32] Sulfide 9a was oxidized to the corresponding sulfone 10a in 16 hours, whereas the oxidation of sulfoxide 11 to sulfone 10c was completed in eight hours. After the purification, sulfone 10a was isolated in 82% yield, and sulfone 10c was obtained in 89% yield (Scheme [2]). The results of the competitive reaction suggest that reagent 8 can be used for the oxidation of either sulfides or sulfoxides to sulfones, but the oxidation of sulfoxides is selective over that of sulfides.

Scheme 2Competitive oxidation of sulfide 9a and sulfoxide 11 by using reagent 8

In conclusion, we have developed an alternative approach for the oxidation of organosulfides to the corresponding organosulfones by using trifluoromethyl 3-oxo-1λ³,2-benziodoxole-1(3H)-carboxylate as an oxidant. This is the first report of the use of this compound as an oxidant.

Acknowledgements

Financial support by the DST, New Delhi, is gratefully acknowledged. We thank the SAIF Department, VIT Vellore, for the analytical data.

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• 31 Sulfones 10a–h; General Procedure A mixture of the appropriate sulfide 9 (0.5 mmol) and benziodoxole 8 (413 mg, 2.4 equiv) in MeCN (3 mL) was refluxed for 16–20 h. When the reaction was complete (TLC), sat. aq NaHCO₃ (5 mL) was added and the mixture was extracted with EtOAc (3 × 15 mL). The organic layers were combined, dried (Na₂SO₄), filtered, and concentrated under vacuum. The crude product was purified by column chromatography [silica gel, EtOAc–hexane (1:3)]. tert-Butyl Phenyl Sulfone (10a) ^22b White solid; yield: 84 mg (0.42 mmol, 85%); mp; 90–92 °C. IR (film): 697, 725, 749, 764, 802, 996, 1021, 1076, 1130, 1277, 1294, 1449, 1475 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.23 (s, 9 H, t-Bu), 7.46 (t, J = 7.6 Hz, 2 H, ArH), 7.56 (t, J = 7.6 Hz, 1 H, ArH), 7.77 (d, J = 7.6 Hz, 2 H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 23.5, 59.7, 128.7, 130.3, 133.6, 135.2. GC/MS: m/z (%) = 198(5), 143(25), 79(13), 77(50), 58(29), 57(100), 51(51), 41(50).
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