Copper catalyzed direct tert-butyl sulfonylation of alkynes with t-butylsulfinamide leading to (E)-vinyl sulfones

Abstract

The first copper-catalyzed tert-butyl sulfonylation reaction of alkynes with t-butylsulfinamide for the construction of (E)-vinyl sulfones has been developed. The cleavage of the N–S bond of t-butylsulfinamide, which was catalyzed by CuSO₄·5H₂O, is the key step for this transformation.

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Vinyl sulfones have attracted considerable attention for applications in organic synthesis and medicinal chemistry.¹ Very recently, some investigations have also shown that vinyl sulfone derivatives are potent antiparasitic drugs² and neuroprotective agents.³ To date, various methodologies have been developed to synthesize vinyl sulfones. Traditional methodologies generally involve (1) the Knoevenagel condensation of aldehydes with sulfonylacetic acids (Scheme 1-a),⁴ (2) wittig reactions,⁵ and (3) elimination from α- or β-substituted sulfones.⁶ However, these methods suffer from some limitations such as tedious procedures, poor selectivity or inaccessible raw materials. In recent years, a number of studies targeting the synthesis of vinyl sulfones have been accomplished such as the direct oxidation of the corresponding vinyl sulfides with oxidants (Scheme 1-b);⁷ the cross-coupling reactions of sulfinate salts with alkynes,⁸ alkenes⁹ (Scheme 1-c)^9a and their derivative vinyl halides¹⁰ and arylboronic acids;¹¹ and the addition of sodium sulfinates or 1,2-bis-(phenylsulfonyl)ethane to alkynes.¹² Only recently, the palladium-catalyzed or iodine-catalyzed sulfonylation of alkenes with sulfonyl hydrazides, gold-catalyzed sulfonylation of alkynes with sulfinic acids and copper-catalyzed aerobic decarboxylative sulfonylation of cinnamic acids with sodium sulfinates were developed by Jiang,¹³ Lei,¹⁴ Shi,¹⁵ and Guo,¹⁶ respectively. In addition, a novel sulfone source, DMSO, has also been discovered for the synthesis of vinyl sulfones. For example, Loh's group described the alternative Cu(I)-catalyzed methyl sulfonylation of alkynes using DMSO as a methyl sulfone source (Scheme 1-d).¹⁷ Yuan's group published the iodide-induced sulfonylation of alkenes using DMSO as a methyl sulfone source.¹⁸ Our group has also developed the CuSO₄·5H₂O–H-phosphonate catalyzed synthesis of vinyl alkylsulfones from alkynes and the widely available solvent, DMSO.¹⁹ Despite the remarkable improvement in vinyl sulfone synthesis, the discovery of diverse sulfone sources is still highly desired. Herein, we disclose an efficient method for the synthesis of (E)-vinyl sulfones from alkynes and t-butylsulfinamide using a CuSO₄-phosphorous acid catalytic system to catalyze the formation of the vinyl–S bond. To the best of our knowledge, this is the first example of the use of t-butylsulfinamide as a sulfur source to prepare vinyl sulfones.

Scheme 1 Comparison of previous work with this work.

We initiated this study by establishing optimal experimental conditions using the model reaction of phenylacetylene (1a) with t-butylsulfinamide 2 in the presence of CuSO₄·5H₂O, phosphorous acid and trifluoroacetic acid (TFA) in DMF under open-air conditions for 12 h at 100 °C, as summarized in Table 1. Initially, the reaction of phenylacetylene (1a) with t-butylsulfinamide (2) was performed in DMF to examine the catalytic activities of several relatively inexpensive transition-metal salts, including Cu, Ag, Pd, Ni and Fe salts (Table 1, entries 1–8). Among the above-mentioned metal salts, copper salts, especially CuSO₄·5H₂O, turned out to be the most effective catalyst, which afforded a yield of 65%. (Table 1, entry 1). Metal salts, such as AgNO₃, Pd(OAc)₂, NiCl₂·6H₂O and FeCl₃·6H₂O, failed to deliver the product, 3a (Table 1, entries 5–8). The model reaction did not proceed in the absence of a metal, H₃PO₃ or TFA (Table 1, entries 9–11). The ideal amounts of CuSO₄·5H₂O, H₃PO₃ and TFA were also explored (Table 1, entries 1 and 12, 13, 16–19). The amounts shown in entry 12 afforded the highest yield. Besides TFA, other acids, such as HNO₃ and H₂SO₄, were also examined. The result showed that these acids failed to produce the product, 3a (Table 1, entries 14–15). Further screening of solvents showed that DMF was the best choice among the tested solvents. The reaction in toluene and 1,4-dioxane failed to generate the product, 3a (Table 1, entries 21–22), while the reaction conducted in DMSO obtained a yield of 32% 3a and 43% vinyl methyl sulfones (Table 1, entry 20). Therefore, the optimal reaction conditions are 2.0 equiv. H₃PO₃, 20 mol% CuSO₄·5H₂O and 2.0 equiv. TFA in DMF at 100 °C for 12 h.

Table 1 Optimization of reaction conditions^a,b

Entry	Cat (mol%)	H3PO3 (equiv.)	Acid (equiv.)	Solvent	T (°C)	Yield^b (%) (E)
a Reaction conditions: 1a (0.5 mmol), 2 (0.6 mmol), catalyst (0–30 mol%) H3PO3 (0–3.0 equiv.) and acid (0–3.0 equiv.) at 100 °C for 12 h.b Isolated yields.
1	CuSO4·5H2O(20)	H3PO3(2.0)	TFA(1)	DMF	100	65
2	Cu(OAc)2·H2O(20)	H3PO3(2.0)	TFA(1)	DMF	100	48
3	Cul(20)	H3PO3(2.0)	TFA(1)	DMF	100	Trace
4	Cu2O(20)	H3PO3(2.0)	TFA(1)	DMF	100	Trace
5	AgNO3	H3PO3(2.0)	TFA(1)	DMF	100	NR
6	Pd(OAc)2	H3PO3(2.0)	TFA(1)	DMF	100	NR
7	NiCl26H2O(25)	H3PO3(2.0)	TFA(1)	DMF	100	NR
8	FeCl3·6H2O	H3PO3(2.0)	TFA(1)	DMF	100	NR
9	—	H3PO3(2.0)	TFA(1)	DMF	100	NR
10	CuSO4·5H2O(20)	—	TFA(1)	DMF	100	NR
11	CuSO4·5H2O(20)	H3PO3(2.0)	—	DMF	100	Trace
12	CuSO4·5H2O(20)	H3PO3(2.0)	TFA(2)	DMF	100	81
13	CuSO4·5H2O(20)	H3PO3(2.0)	TFA(3)	DMF	100	76
14	CuSO4·5H2O(20)	H3PO3(2.0)	HNO3(2)	DMF	100	Trace
15	CuSO4·5H2O(20)	H3PO3(2.0)	H2SO4(2)	DMF	100	Trace
16	CuSO4·5H2O(20)	H3PO3(2.0)	TFA(2)	DMF	100	52
17	CuSO4·5H2O(20)	H3PO3(2.0)	TFA(2)	DMF	100	80
18	CuSO4·5H2O(20)	H3PO3(1.0)	TFA(2)	DMF	100	60
19	CuSO4·5H2O(20)	H3PO3(3.0)	TFA(2)	DMF	100	76
20	CuSO4·5H2O(20)	H3PO3(2.0)	TFA(2)	DMSO	100	32
21	CuSO4·5H2O(20)	H3PO3(2.0)	TFA(2)	Toluene	100	Trace
22	CuSO4·5H2O(20)	H3PO3(2.0)	TFA(2)	1,4-Dioxane	100	Trace
23	CuSO4·5H2O(20)	H3PO3(2.0)	TFA(2)	DMF	80	35
24	CuSO4·5H2O(20)	H3PO3(2.0)	TFA(2)	DMF	120	78

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The substrate scope of alkynes and t-butylsulfinamide under the optimized conditions was then explored, as demonstrated in Table 2. Various vinyl sulfones were efficiently obtained via the new reaction. It can be seen that both the electron-donating (OCH₃, CH₃, C₂H₅, n-C₃H₇) and electron-withdrawing groups (F, Cl, Br) of aryl terminal alkynes were suitable for this protocol, and the corresponding vinyl sulfones were obtained in good to excellent yields (3a–o). Common functionalities, which include halogen, methoxy, acetamide and cyano groups, were well tolerated. In addition, the reaction of 1-ethynylcyclohexene with t-butylsulfinamide efficiently afforded the conjugated sulfone, 3p (70%). To our delight, heteroaromatic alkynes also gave the corresponding 3q–s in moderate to good yields, which range from 51% to 69%. 1,3-Diethynylbenzene produced the expected product 3t (53%) in moderate yield. However, the reaction with 1-phenylpropyne did not progress well, and only a trace amount of product was obtained (3u).

Table 2 Scope of hydrosulfonylation^a,b

a Reaction conditions: 1 (1.0 mmol), 2 (1.2 mmol), H₃PO₃ (2.0 mmol), CuSO₄·5H₂O (20 mol%), TFA (2.0 mmol) at 100 °C for 12 h.b Isolated yields.

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To further probe the reaction mechanism, some experiments were subsequently carried out (Scheme 2). When the reaction was carried out under a nitrogen atmosphere, the corresponding vinyl sulfone, 3a, was not obtained (Scheme 2-a), which indicates that the copper-catalyzed hydrosulfonylation of alkynes requires the presence of oxygen. When TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy), a widely used radical scavenger, was added into the reaction system, the reaction was completely suppressed (Scheme 2-b), which suggests that these reactions undergo a radical mechanism. Moreover, an isotopic labeling experiment was performed. The reaction of phenylacetylene with t-butylsulfinamide in the presence of 10 equiv. H₂¹⁸O afforded ¹⁸O-labeled 3a (Scheme 2-c), which clearly demonstrates that the additional oxygen atom of 3a originated from H₂O instead of O₂ in air.

Scheme 2 Experiments investigating the reaction mechanism. (a) 1a (1.0 mmol), 2 (1.2 mmol), H₃PO₃ (2.0 mmol), CuSO₄·5H₂O (20 mol%), TFA (2.0 mmol) at 100 °C under nitrogen atmosphere for 12 h; (b) 1a (1.0 mmol), 2 (1.2 mmol), H₃PO₃ (2.0 mmol), CuSO₄·5H₂O (20 mol%), TFA (2.0 mmol), TEMPO (3 equiv.) at 100 °C for 12 h. (c) 1a (1.0 mmol), 2 (1.2 mmol), H₂¹⁸O (10 equiv.), H₃PO₃ (2.0 mmol), CuSO₄ (20 mol%), TFA (2.0 mmol), at 100 °C for 12 h.

Although the reaction mechanism is not fully understood, a plausible mechanism for the reaction is proposed in Scheme 3. Herein, the cheap and easily available phosphorous acid 4 (tetracoordinated form) existed with its tautomer 5 (tricoordinated form). 5 and t-butylsulfinamide 2 initially coordinated with Cu²⁺ to form complex 6. Moreover, a six-membered ring was generated inside 6 through an intramolecular hydrogen bond (O–H⋯O=S), and subsequently a proton transfer from the OH group to the oxygen of the S=O group occurs, thus giving copper complex 7. It can be noted that complex 7 could resonate with 8. The two positive charges at the sulfur atom of the resonance structure 8 implies the high sensitivity of the protonated sulfinyl group to nucleophilic attack. Subsequently, a molecule of water attacked the protonated sulfinyl group of 7 to afford the pentavalent intermediate 9. Then, intermediate 9 immediately lost an amino group, to yield copper complex 10. Copper complex 10 then homolytically cleaved to complex 11, Cu⁺ and tert-butyl sulfonyl radical 12. Cu⁺ was oxidized back to Cu²⁺ by oxygen in air, and phosphonate ion 11 was protonated to form phosphorous acid 4. Herein, the selective addition of radical 12 to the terminal alkyne 1 led to the formation of vinyl radical 13. Then, vinyl radical 13 interacted with water to yield the final vinyl sulfone 3 and the hydroxyl radical. Moreover, the vinyl radical 13 could react with another phosphorous acid 4 molecule to produce the final product 3 together with phosphite radical 14. Then, phosphoric acid 15 might possibly be formed via the termination reaction of the phosphite radical 14 and hydroxyl radical in a related reaction process.

Scheme 3 Plausible mechanism.

Conclusions

In conclusion, the practical CuSO₄·5H₂O catalyzed synthesis of (E)-vinyl sulfones from alkynes and t-butylsulfinamide was developed. The cleavage of the N–S bond of t-butylsulfinamide, which was catalyzed by an inexpensive and easily available CuSO₄·5H₂O-phosphorous acid catalytic system, was the key step for this transformation. The method described in this study opens a new door to the construction of vinyl sulfones. Studies of the detailed mechanism of this process and its application are currently underway in our laboratory.

Acknowledgements

This study was financially supported by the NSFC (no. 21072178), the Innovation Specialist Projects of Henan Province (no. 114200510023), and the Technology and Science talent Cultivation Project in Zhengzhou City (no. 112PLJRC359). The Special Fund for the Doctoral Program of Higher Education (no. 20124101110003) and Foundational and Frontier Technology Research Foundation of Henan Province are acknowledged for their financial support (no. 132300410027).

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra13474a

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