Synthesis of Alkyl Aryl Sulfones via Reaction of N-Arylsulfonyl Hydroxyamines with Electron-Deficient Alkenes

Abstract

Alkyl aryl sulfones were prepared in high yields via the reaction of N-arylsulfonyl hydroxylamines with electron-deficient alkenes. These reactions have the advantages of simplicity, easily available starting materials and mild reaction conditions.

1. Introduction

Sulfones are important starting compounds in the synthesis of different sulfur-containing compounds and natural products [1]. Sulfones also exist in a wide range of biologically active molecules, such as oxycarboxin (a highly efficient agricultural fungicide) [2], fipronil (a pesticide) [3], and benzobicyclon (a herbicide) [4]. In addition, the structures of alkyl aryl sulfones are well known as the core structural unit in pharmaceutical molecules. For instance, eletriptan is an efficient drug for early migraine [5], and bicalutamide is used for the treatment of advanced prostate cancer [6] (Figure 1). Therefore, a variety of synthetic approaches have been developed for the synthesis of alkyl aryl sulfones, including the Zn/CuI-mediated coupling reaction of alkyl halides with vinyl arylsulfones [7], FeCl₃/TMSCl-catalyzed β-sulfonation of α,β-unsaturated carbonyl compounds with p-toluenesulfinates [8], the aerobic oxysulfonylation of alkenes with various sulfinic acids [9], Cu(OAc)₂-catalyzed direct oxysulfonylation of alkenes with dioxygen and sulfonylhydrazides [10], the reaction of alkenes with sodium arylsulfinates catalyzed by molecular iodine under aerobic oxidative conditions [11], sulfonylation of activated alkenes with sulfonylhydrazides [12], the direct sulfonylation of 2-methylquinolines with sodium aryl sulfinates mediated by KI in the presence of oxidant [13], nickel-catalyzed hydroxysulfonylation of alkenes using sodium sulfinates [14], and oxygen-mediated reaction of diethyl 1-arylvinyl phosphates with arylsulfinic acid [15]. Recently, He and co-workers reported the preparation of α-sulfonylethanone oximes from the reaction of styrenes with substituted N-arylsulfonyl hydroxylamines in the presence of tetrabutylammonium periodate as oxidant (n-Bu₄NIO₄) (Scheme 1) [16]. In this paper, we report the reaction of N-arylsulfonyl hydroxylamines with electron-deficient alkenes to provide an alternative procedure for the synthesis of alkyl aryl sulfones under mild conditions (Scheme 1).

2. Results and Discussion

We initiated our study on the reaction of N-phenylsulfonyl hydroxylamine (1a) with methyl acrylate (2a) to optimize the reaction conditions. As summarized in

Table 1. Optimizing the reaction conditions ^a.

Entry	R	Solvent	Base (Equiv.)	Yield (%) b
1	COOMe	CH3CN	--	0
2		CH3CN	NaOAc (1)	39
3		CH3OH	NaOAc (1)	98(93)
4	CN	toluene	NaOAc (1)	45
5		CH3CN	NaOAc (1)	53
6		CH3OH	NaOAc (1)	85(80)
7		CH3OH	NaOAc (2)	84
8		CH3OH	NaOAc (0.5)	67
9		CH3OH	Na2CO3	44
10		CH3OH	DABCO (1)	0
11		CH3OH	DBU (1)	0
12		CH3OH	pyridine	0
13		CH3OH	--	0

^a Reactions were carried out using 1.0 mmol of 1a, 2.0 mmol of 2a or 2f, and base in 10.0 mL of solvent in a sealed tube. ^b GC yield based on the amount of 1a used. Number in parenthesis is isolated yield.

, when a mixture of 1a and 2a (2.0 equiv.) in CH₃CN was heated with stirring at 60 °C for 18 h, not any product was formed by the analyses of the reaction mixture by GC-MS, and both 1a and 2a were recovered (entry 1). However, in the presence of NaOAc (1.0 equiv.), repeating the same reaction gave the desired compounds 3aa in 39% GC yield (entry 2) [17], indicating that the presence of base is crucial for the formation of 3aa. In addition, when CH₃OH was used as solvent to replace CH₃CN, 3aa was formed in 98% GC yield (entry 3). In the case of acrylonitrile employed, the yield of the corresponding product 3af is also greatly depending on the solvents used, and CH₃OH is the best choice (entries 4–6). Increasing the amount of NaOAc (from 1.0 equiv. to 2.0 equiv.) afforded 3af in the same yield (entry 7), but the decreasing amount of NaOAc (from 1.0 equiv. to 0.5 equiv.) resulted in the considerable decrease of the yield of 3af (entry 8). Moreover, the use of Na₂CO₃ as base led to 44% of 3af (entry 9), and the use of 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU) and pyridine as base, or without the use of base led to no formation of 3af at all (entries 10–13).

Under the optimized reaction conditions shown in entries 3 and 6 in Table 1, the generality for the formation of alkyl aryl sulfones was investigated by using a variety of N-arylsulfonyl hydroxylamines and alkenes, and the obtained results are summarized in

Table 2. Synthesis of alkyl aryl sulfones ^a.

^a Reactions were carried out using 1.0 mmol of 1, 2.0 mmol of 2, and 1.0 mmol of NaOAc in 10.0 mL of MeOH at 60 °C for 18 h. All the yields are isolated yields.

and

Table 3. Synthesis of alkyl aryl sulfones ^a.

Entry	1	2	3	Yield (%) b
1	1a			75
2	1c	2g		76

^a Reactions were carried out using 1.0 mmol of 1, 2.0 mmol of 2, and 1.0 mmol of NaOAc in 10.0 mL of MeOH at 60 °C for 18 h. ^b Isolated yields.

. As shown in Table 2, 1a reacted with acrylates 2b–e to give the expected alkyl aryl sulfones 3ab–3ae in high yields. No significant electron effect was observed, and when R are both electron-donating and electron-withdrawing groups, N-arylsulfonyl hydroxylamines underwent the present reaction smoothly to afford the corresponding alkyl aryl sulfones 3ba, 3bb, 3ca, and 3da–fa in good yields.

In addition, it is also interesting to prepare the multi-sulfur atom-bearing compounds, thus we performed the reactions of 1a and 1c with phenyl vinyl sulfone (2g). As shown in Table 3, the desired products 3ag and 3cg were isolated in good yields.

On the basis of the known decomposition of N-arylsulfonyl hydroxyamines under basic conditions to nitrosyl hydride and arylsulfinate [18], a proposed mechanism for the formation of alkyl aryl sulfones is shown in Scheme 2. It involves the formation of an arylsulfinate anion/arylsulfonyl anion intermediate [12], and its Michael addition with an electron-deficient alkene to afford alkyl aryl sulfone 3.

3. Materials and Methods

3.1. General Methods

All organic starting materials and solvents are analytically pure and used without further purification. Nuclear magnetic resonance (NMR) spectra were recorded on a JEOL ECA-300 spectrometer (JEOL, Tokyo, Japan) using CDCl₃ as a solvent at 298 K. ¹H-NMR (300 MHz) chemical shifts (δ) were referenced to internal standard TMS (for ¹H, δ = 0.00 ppm). ¹³C-NMR (75 MHz) chemical shifts were referenced to internal solvent CDCl₃ (for ¹³C, δ = 77.16 ppm). The ¹H- and ¹³C-NMR charts of products are reported as supplementary materials. The high-resolution mass spectra (ESI) were obtained with a micrOTOF-Q 10142 spectrometer (Agilent, California, CA, USA).

3.2. Typical Experiment Procedure for the Reaction of N-Phenylsulfonyl Hydroxylamine (1a) with Methyl Acrylate (2a) Affording Methyl 3-(Phenylsulfonyl)propanoate (3aa) (Table 1, Entry 3)

A mixture of N-phenylsulfonyl hydroxylamine (1a, 173.0 mg, 1.0 mmol), methyl acrylate (2a) (172.0 mg, 2.0 mmol) and NaOAc (82.0 mg, 1.0 mmol) was heated in CH₃OH (10.0 mL) at 60 °C (oil bath temperature) with stirring for 18 h in a screw-capped thick-walled Pyrex tube under an air atmosphere. After the reaction mixture was cooled to room temperature, it was directly subjected to a short silica column chromatography (2~3 cm, eluted with CH₂Cl₂) to remove the insoluble materials. To the collected solution, n-octadecane (25.5 mg, 0.1 mmol as internal standard for GC analysis) was then added with stirring. After GC and GC-MS analyses of the mixture, volatiles were then removed under reduced pressure, and the residue was subjected to silica gel column chromatography, eluted with a mixture of solvents of petroleum ether/acetone (from 100:0~100:2 in volume). 3aa was obtained in 212.0 mg (0.93 mmol, 93%) as yellow oil. The GC analysis of reaction mixture revealed the formation of 3aa [19] in 98% GC yield. ¹H-NMR (CDCl₃) δ 7.85 (m, 2H), 7.56 (m, 3H), 3.56 (s, 3H), 3.39 (t, 2H, J = 7.8 Hz), 2.70 (t, 2H, J = 7.8 Hz); ¹³C-NMR (CDCl₃) δ 170.3, 138.6, 134.1, 129.4, 128.1, 52.2, 51.4, 27.6; HRMS (ESI): Calcd. for: C₁₀H₁₃O₄S [M + H]⁺: 229.0529; found: 229.0528.

The following compounds were similar prepared:

Ethyl 3-(phenylsulfonyl)propanoate (3ab) [20]: ¹H-NMR: δ 7.80 (m, 2H), 7.57 (m, 3H), 4.04 (dd, 2H, J = 7.2 Hz), 3.40 (t, 2H, J = 7.8 Hz), 2.70 (t, 2H, J = 7.8 Hz),1.18 (t, 3H, J = 7.2 Hz); ¹³C-NMR: δ 170.0, 138.4, 134.0, 129.4, 128.1,61.3, 51.4, 27.8, 14.0; HRMS (ESI): Calcd. for: C₁₁H₁₂NO₄S [M + H]⁺: 254.0482; found: 254.0486.

n-Butyl 3-(phenylsulfonyl)propanoate (3ac): pale yellow oil; ¹H-NMR: δ 7.89 (m, 2H), 7.63 (m, 3H), 4.03 (m, 2H), 3.45 (t, 2H, J = 7.5 Hz), 2.73 (t, 2H, J = 7.5 Hz), 1.56 (m, 2H), 1.33 (m, 2H), 0.90 (m, 3H); ¹³C-NMR: δ 169.7, 138.3, 133.8, 129.2, 127.9, 64.9, 51.2, 30.2, 27.6, 18.8, 13.4; HRMS (ESI): Calcd. for: C₁₃H₁₉O₄S [M + H]⁺: 271.0999; found: 271.0998.

t-Butyl 3-(phenylsulfonyl)propanoate (3ad): yellow solid, m.p. 46~48 °C; ¹H-NMR: δ 7.91 (m, 2H),7.62 (m, 3H), 3.37 (t, 2H, J = 7.8 Hz), 2.65 (t, 2H, J = 7.8 Hz), 1.38 (s, 9H); ¹³C-NMR: δ 169.2, 138.7, 134.0, 129.5, 128.2, 82.0, 51.7, 29.0, 28.1; HRMS (ESI): Calcd. for: C₁₃H₁₉O₄S [M + Na]⁺: 293.0818; found: 293.0819.

Benzyl 3-(phenylsulfonyl)propanoate (3ae): pale yellow solid, m.p. 61~63 °C; ¹H-NMR: δ 7.89 (m, 2H), 7.59 (m, 3H), 7.32 (m, 5H), 5.05 (s, 2H), 3.43 (t, 2H, J = 7.8 Hz), 2.73 (t, 2H, J = 7.8 Hz); ¹³C-NMR: δ 169.7, 138.3, 135.1, 134.0, 139.4, 128.6, 128.4, 128.3, 128.1, 67.0, 51.3, 27.8; HRMS (ESI): Calcd. for: C₁₆H₁₆NaO₄S [M + Na]⁺: 327.0662; found: 327.0666.

3-(Phenylsulfonyl)propanenitrile (3af) [19]: ¹H-NMR: δ 7.94 (m, 2H), 7.69 (m, 3H), 7.32 (m, 5H), 3.40 (t, 2H, J = 7.6 Hz), 2.82 (t, 2H, J = 7.6 Hz); ¹³C-NMR: δ 137.5, 134.8, 129.8, 128.3, 116.1, 51.1, 12.1; HRMS (ESI): Calcd. for: C₉H₉NNaO₂S [M + Na]⁺: 218.0246; found: 218.0249.

Methyl 3-tosylpropanoate (3ba) [20]: ¹H-NMR: δ 7.72 (d, 2H, J = 8.2 Hz), 7.31 (d, 2H, J = 8.2 Hz), 3.57 (s, 3H), 3.35 (t, 2H, J = 7.5 Hz), 2.67 (t, 2H, J = 7.5 Hz), 2.39 (s, 3H); ¹³C-NMR: δ 170.4, 145, 135.4, 129.9, 128.1, 52.1, 51.4, 27.6, 21.5; HRMS (ESI): Calcd. for: C₁₁H₁₅O₄S [M + H]⁺: 243.0686; found: 243.0690.

Ethyl 3-tosylpropanoate (3bb) [20]: ¹H-NMR: δ 7.74 (d, 2H, J = 7.8 Hz), 7.32 (d, 2H, J = 7.8 Hz), 4.03 (q, 2H, J = 7.1 Hz), 3.36 (t, 2H, J = 7.6 Hz), 2.66 (t, 2H, J = 7.6 Hz), 2.40 (s, 3H), 1.17 (t, 2H, J = 7.1 Hz), 0.90 (m, 3H); ¹³C-NMR: δ 170.0, 145.0, 135.5, 130.0, 128.1, 61.3, 51.5, 27.9, 21.6, 14.0; HRMS (ESI): Calcd. for: C₁₂H₁₇O₄S [M + H]⁺: 257.0842; found: 257.0844.

Methyl 3-((4-methoxyphenyl)sulfonyl)propanoate (3ca) [20]: ¹H-NMR: δ 7.83 (d, 2H, J = 9.0 Hz), 7.04 (d, 2H, J = 9.0 Hz), 3.89 (s, 3H), 3.64 (s, 3H), 3.41 (t, 2H, J = 7.1 Hz), 2.74 (t, 2H, J = 7.1 Hz); ¹³C-NMR: δ 170.4, 163.9, 130.3, 129.8, 114.5, 55.7, 52.2, 51.6, 27.7; HRMS (ESI): Calcd. for: C₁₁H₁₅O₅S [M + H]⁺: 259.0635; found: 259.0637.

Methyl 3-((4-chlorophenyl)sulfonyl)propanoate (3da) [21]: ¹H-NMR: δ 7.78 (d, 2H, J = 8.5 Hz), 7.49 (d, 2H, J = 8.5 Hz), 3.55 (s, 3H), 3.38 (t, 2H, J = 7.6 Hz), 2.67 (t, 2H, J = 7.6 Hz); ¹³C-NMR: δ 170.1, 140.5, 136.8, 129.6, 52.2, 51.3, 27.4; HRMS (ESI): Calcd. for: C₁₀H₁₁ClNaO₄S [M + Na]⁺: 284.9959; found: 284.9962.

Methyl 3-((4-(trifluoromethyl)phenyl)sulfonyl)propanoate (3ea): white solid, m.p. 120~122 °C; ¹H-NMR: δ 8.06 (d, 2H, J = 8.2 Hz), 7.85 (d, 2H, J = 8.6 Hz), 3.64 (s, 3H), 3.47 (t, 2H, J = 7.5 Hz), 2.77 (t, 2H, J = 7.5 Hz); ¹³C-NMR: δ 170.2, 142.0, 135.7, 128.9, 127.0, 126.6, 52.4, 51.4, 27.4; HRMS (ESI): Calcd. for: C₁₁H₁₁F₃NaO₄S [M + Na]⁺: 319.0222; found: 319.0226.

Methyl 3-((4-cyanophenyl)sulfonyl)propanoate (3fa): pale yellow solid, m.p. 119~122 °C; ¹H-NMR: δ 8.03 (m, 2H), 7.87 (m, 2H), 3.64 (s, 3H), 3.46 (t, 2H, J = 7.5 Hz), 2.77 (t, 2H, J = 7.5 Hz); ¹³C-NMR: δ 17.02, 142.8, 133.3, 129.1, 118.0, 117.1, 52.6, 51.5, 27.4; HRMS (ESI): Calcd. for: C₁₁H₁₂NO₄S [M + H]⁺: 254.0482; found: 254.0486.

1,2-Bis(phenylsulfonyl)ethane (3ag) [22]: ¹H-NMR: δ 7.88 (m, 4H), 7.70 (m, 2H), 7.60 (m, 6H), 3.45 (s, 4H); ¹³C-NMR: δ 138.0, 134.6, 129.7, 128.1, 49.5.

1-Methoxy-4-((2-(phenylsulfonyl)ethyl)sulfonyl)benzene (3cg): white solid, m.p. 150~152 °C; ¹H-NMR: δ 7.87 (d, 2H, J = 7.6 Hz), 7.78 (d, 2H, J = 8.8 Hz, 7.70 (t, 1H, J = 7.4 Hz ), 7.58 (t, 2H, J = 7.7 Hz ), 3.88 (s, 3H), 3.42 (m, 4H); ¹³C-NMR: δ 164.4, 138.1, 134.6, 130.4, 129.8, 129.4, 128.1, 114.5, 55.9, 49.8; HRMS (ESI): Calcd. for: C₁₅H₁₇O₅S₂ [M + H]⁺: 341.0512; found: 341.0515.

4. Conclusions

In summary, we have studied the reaction of N-arylsulfonyl hydroxylamines with electron-deficient alkenes to provide an alternative efficient synthetic method for the formation of alkyl aryl sulfones in good yields. The present method has the advantages with simple and easily available starting materials, under mild conditions, with high atom-utilization.