Copper catalyzed synthesis of unsymmetrical diaryl sulfones from an arenediazonium salt and sodium p-toluenesulfinate

Abstract

Aryl sulfones have been for the first time synthesized by the reaction of sodium p-toluenesulfinate and arenediazonium salts using a CuI catalyzed homogeneous system. The developed protocol is a simple and efficient new route for the synthesis of diaryl sulfones with excellent product yields. The mild reaction conditions tolerate a range of functional groups. The best results were obtained with CuI, N,N′-dimethylethylenediamine, TBAI and K₂CO₃ in dimethyl sulfoxide at 100 °C under an inert atmosphere.

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1 Introduction

Carbon–sulphur (C–S) bond forming reactions have gained importance in organic synthesis, as these reactions are the key steps in the formation of various biologically valuable compounds.¹ Aryl sulfones are an important class of sulfur containing moieties which are found in many pharmaceuticals, agrochemicals and polymeric compounds (Fig. 1).² Particularly, the bioactivity of aryl sulfones has immense importance in medicinal chemistry. Aryl sulfones show various pharmacological properties such as anti-tumour, anti-inflammatory, and anti-fungal activities, and also inhibit HIV-1 reverse transcriptase.³ Sulfone derivatives were found in cyclooxygenase-2 (COX-2) inhibitors⁴ which exhibit high antifungal and antibacterial activities.⁵ They also exhibit interesting chemical properties⁶ and are useful as intermediates in organic synthesis.⁷

Fig. 1 Aryl sulfones containing molecules.

This broad utility has prompted significant efforts toward the synthesis of sulfone containing compounds. As a result of this, various methods have been developed for the synthesis of aryl sulfones such as nucleophilic substitution reaction of halide with thiol, followed by oxidation of the corresponding sulphide,⁸ sulfonylation of heterocycles with aryl sulfonyl chlorides via metal-catalyzed C–H bonds activation,⁹ Pd- or Cu-catalyzed coupling reactions between sodium sulfinates and aryl halides or aryl boronic acids¹⁰ and vinyl sulfones from terminal epoxides and sodium sulfinates.¹¹ Various catalysts have been developed for the synthesis of sulfones.¹² However, these methods have some drawbacks such as use of toxic or expensive transition metals, multi-step synthesis, low functional group tolerance, limited availability of substrates, low yields, use of expensive aryl halides, longer reaction times, and dry reaction conditions. Recently B. T. V. Srinivas et al. reported synthesis of diaryl sulfones from various boronic acids using Cu-catalyst.¹³ Fig. S1† depicts the various reported methods for the synthesis of aryl sulfones.

An arenediazonium salt is currently attracting much attention because of the ready availability of these compounds and the ease with which they can be synthesized. They are more reactive than aryl halides or boronic acids, making them good choice as arylating agents. Arenediazonium salts can be used in a range of various reactions, such as Suzuki–Miyaura,¹⁴ Stille,¹⁵ Sonogashira,¹⁶ or Mizoroki–Heck reactions.¹⁷ Here we report the synthesis of aryl sulfones using arenediazonium salts with CuI and N,N′-dimethylethylenediamine ligand in DMSO at 100 °C under inert atmosphere (Scheme 1).¹⁹

Scheme 1 Model reaction between sodium p-toluenesulfinate and arenediazonium salt.

2 Results and discussion

Initially, various reaction conditions were optimized step by step for the model reaction between sodium p-toluenesulfinate and arenediazonium salt. Ligand plays a very crucial role in homogeneous catalysis with respect to product yield. Therefore, we carried out the model reaction with CuI as a catalyst in DMSO using various ligands. Here we screened four ligands such as N,N′-dimethylethylenediamine (L₁), N,N,N′,N′-tetramethylethylenediamine (L₂), bipyridine (L₃) and 1,10-phenanthroline (L₄) for model reaction along with CuI catalyst (Fig. S2†). The obtained results are represented in Fig. S3.† This clearly shows that L₁ is a superior ligand than others giving excellent product yield along with CuI. We examined various Cu sources such as CuI, CuBr, Cu₂O, Cu(OAc)₂, CuSO₄, Cu(Phen)(PPh₃)₂NO₃ and Cu(acac)₂ for the model reaction of sodium p-toluenesulfinate and arenediazonium salt and found that CuI is the best source of Cu as catalyst (Table 1, entries 1–7). Furthermore, we studied model reaction by using various solvents such as DMSO, DMF, toluene and H₂O. DMSO solvent gave maximum yield of desired product (Table 1, entries 1, 8–10). We also studied the reaction in various bases and found K₂CO₃ as the most suitable base amongst the other bases such as NaHCO₃, Na₂CO₃, K₃PO₄, Cs₂CO₃ and ^tBuONa (Table 1, entries 1, 11–15). The solvation of K⁺ ion is greater than that of Na⁺ ion due to the ionic size, which consequently increases the rate of reaction. In this reaction we used TBAI (tetrabutylammonium iodide), TBAB (tetrabutylammonium bromide), KI (potassium iodide) and KBr (potassium bromide) additives as halogen source to form halobenzene in situ.¹⁸ The arylation reaction was more efficient with the halogen source TBAI (Table 1, entries 1, 16–18). The optimum temperature was found to be 100 °C for the model reaction. Increase in temperature to 120 °C, did not improve the product yield. Significant decrease in the product yield was observed when the temperature was decreased to 80 °C (Table 1, entries 1, 19 and 20).

Table 1 Optimization of reaction parameters^a

Entry	Catalyst	Solvent	Base	Additive	Temperature (°C)	Yield^b (%)
a Reaction conditions: sodium p-toluenesulfinate (1 mmol), arenediazonium salts (1.3 mol), Cu source (15 mol%), ligand (15 mol%), additive (1.3 mmol), base (3 mmol), solvent (2 mL), under N2.b Isolated yield.c Without ligand.
1	CuI	DMSO	K2CO3	TBAI	100	91
2	CuBr	DMSO	K2CO3	TBAI	100	72
3	Cu2O	DMSO	K2CO3	TBAI	100	59
4	Cu(OAc)2	DMSO	K2CO3	TBAI	100	75
5	CuSO4	DMSO	K2CO3	TBAI	100	68
6	Cu(Phen)(PPh3)2NO3	DMSO	K2CO3	TBAI	100	56^c
7	Cu(acac)2	DMSO	K2CO3	TBAI	100	67
8	CuI	DMF	K2CO3	TBAI	100	26
9	CuI	Toluene	K2CO3	TBAI	100	20
10	CuI	H2O	K2CO3	TBAI	100	Trace
11	CuI	DMSO	NaHCO3	TBAI	100	56
12	CuI	DMSO	Na2CO3	TBAI	100	74
13	CuI	DMSO	K3PO4	TBAI	100	69
14	CuI	DMSO	Cs2CO3	TBAI	100	47
15	CuI	DMSO	^tBuONa	TBAI	100	Trace
16	CuI	DMSO	K2CO3	KBr	100	Trace
17	CuI	DMSO	K2CO3	TBAB	100	10
18	CuI	DMSO	K2CO3	KI	100	82
19	CuI	DMSO	K2CO3	TBAI	120	92
20	CuI	DMSO	K2CO3	TBAI	80	83

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We also examined the effect of the catalytic amount and ligand concentration on the product yield of the model reaction by varying the amount of catalyst and ligand from 10 to 20 mol% (Fig. S4†). Fig. S4† shows that increase in the catalyst and ligand concentration from 10 to 15 mol% increases the yield of the desired product. However increase in the catalyst and ligand concentration up to 20 mol% did not increase the product yield significantly. The amount of tetrabutylammonium iodide additive was also optimized by varying its concentration from 1.2 to 1.4 mmol. It was clear from the results depicted in Fig. S5† that the concentration of additive also plays an important role in the reaction, and the optimal concentration of tetrabutylammonium iodide for the model reaction was found to be 1.3 mmol. We also evaluated the exact required time for the model arylation reaction and the graph plotted in Fig. S6† clearly indicates that 24 h is the required time for the completion of reaction. All above experiments reveal that the optimised reaction conditions are sodium p-toluenesulfinate (1 mmol), arenediazonium salt (1.3 mol), CuI (15 mol%), L₁ (15 mol%), TBAI (1.3 mmol), K₂CO₃ (3 mmol), DMSO (2 mL), 100 °C and 24 h under inert atmosphere.

After optimizing parameters such as catalyst, ligand, solvent, base, additive, concentration of catalyst, reaction temperature and time, we further investigated the catalytic activity for the coupling of structurally different arenediazonium salts and sodium p-toluenesulfinate and the results are summarized in Table 2. Arenediazonium salts with many valuable functional groups present on aromatic ring such as –OCH₃, –Cl, –F, –CH₃, and –NO₂ groups were screened and it was found that substrates containing electron donating group deliver excellent products as compared to substrates containing withdrawing groups (Table 2, entries 2–10). The substituents at p-position exhibit greater reactivity than o- or m-position. We also carried out the reaction of disubstituted arenediazonium salts such as 3,5-dimethoxy, 3,5-dichloro, 3,4-dichloro and 2,4-dimethyl arenediazonium salts with sodium p-toluenesulfinate and obtained excellent yield of corresponding products (Table 2, entries 11–14). The substrate 4-phenyl arenediazonium salt smoothly coupled giving 74% yield of product (Table 2, entry 15).

Table 2 Reaction between sodium p-toluenesulfinate and arenediazonium salts^a

Entry	Arenediazonium salts	Products	Yield^b (%)
a Reaction conditions: sodium p-toluenesulfinate (1 mmol), arenediazonium salts (1.3 mol), CuI (15 mol%), L1 (15 mol%), TBAI (1.3 mmol), K2CO3 (3 mmol), DMSO (2 mL), 100 °C, 24 h under N2.b Isolated yield.
1			91
2			89
3			88
4			79
5			87
6			83
7			87
8			76
9			84
10			81
11			86
12			84
13			85
14			72
15			74

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The plausible reaction mechanism for arylation of sulfones is illustrated in Fig. 2.

Fig. 2 The plausible mechanism for the arylation of sulfones.

3 Conclusions

In summary, here we report the arylation of sulfones with arenediazonium salts using homogeneous copper catalysed system. Arenediazonium salts are the best alternatives to other environmentally hazardous or costly arylating agents and are used for the first time for arylation of sulfones. The methodology can tolerate many important substituted arenediazonium salts giving good to excellent yield of product.

Acknowledgements

The authors are thankful to the UGC-SAP, New Delhi, India for the award of fellowship.

Notes and references

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19. Synthesis of diaryl sulfones: a mixture of sodium p-toluenesulfinate (1 mmol), arenediazonium salt (1.3 mmol), copper iodide (15 mol%), N,N′-dimethylethylenediamine (L₁) (15 mol%), additive TBAI (1.3 mmol), K₂CO₃ (3 mmol) and 2 mL of DMSO in a sealed tube was heated to 100 °C under inert atmosphere for 24 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and filtered through a plug of Celite. The filtrate was washed sequentially with H₂O and brine the organic layer was separated, dried (Na₂SO₄), and concentrated under vacuum. The crude product was purified by column chromatography (silica gel; PE–EtOAc, 90 : 10). The products were analyzed by GC-MS, ¹H NMR, and ¹³C NMR which are found consistent with those reported in the literature.

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, mass, ¹H NMR and ¹³C NMR spectra of synthesized compound. See DOI: 10.1039/c5ra10291j

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