K₂CO₃-promoted aerobic oxidative cross-coupling of trialkyl phosphites with thiophenols

Abstract

Convenient, practical and economical phosphorylation of thiols has been achieved via halogen- and metal-free K₂CO₃-promoted aerobic oxidative cross-coupling of trialkyl phosphites, dimethyl phenylphosphonite, or methyl diphenylphosphinite with thiophenols using air as the oxidant at room temperature. This transformation provides a straightforward route to the construction of phosphorus–sulfur bonds with wide functional group compatibility, which affords phosphorothioates in up to 94% yield.

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In recent years, the development of new methods to construct phosphorus–sulfur bonds has been of particular interest due to the wide applications of organophosphorus–sulfur compounds in biological chemistry, organic synthesis, and agrochemistry.¹ A variety of useful synthetic methods have been well documented. The traditional preparation of this class of compounds mainly relies on the use of toxic and moisture sensitive reagents or pre-functionalized substrates (e.g., R₂P(O)X, RSX and RSSR).² On the other hand, the cross-dehydrogenative coupling (CDC) between P(O)H compounds and commercially available thiols is gradually developed (Fig. 1, eqn (1)).^3–7 In 2013, Kaboudin reported a copper-catalyzed coupling of H-phosphonates with thiols in the presence of Et₃N.³ In 2015, Pan reported a TBPB-promoted oxidative coupling of secondary phosphine oxides or H-phosphonates with thiols.⁴ In 2016, Li and Zhang reported a visible-light-mediated oxidative coupling of P(O)H compounds with thiols in the presence of a photocatalyst.⁵ Interestingly, Chen and Han recently reported an oxidant-free Pd-catalyzed dehydrogenative phosphorylation of thiols.⁶ Most recently, Song and Jiao reported a Cs₂CO₃-catalyzed aerobic oxidative CDC reaction of phosphonates with thiols.⁷ The possible mechanism showed that disulfides are reaction intermediates generated via the oxidative coupling of thiols in the presence of Cs₂CO₃ and O₂.⁷ Undoubtedly, this strategy represents more straightforward, efficient, and atom-economic to construct phosphorus–sulfur bonds. However, the CDC reactions suffered from limitations with regard to high cost and less availability of P(O)H compounds. Thus, the development of a convenient, practical and economical protocol for the synthesis of phosphorothioates is still a significant issue.

Fig. 1 Current developments in the synthesis of phosphorothioates from phosphites and thiols.

With our recent studies on the construction of carbon–sulfur, phosphorus–aryl, phosphorus–fluorine, and phosphorus–oxygen bonds,⁸ we have been interested in studying the construction of phosphorus–sulfur bonds based on an economical approach. In comparison with P(O)H compounds, trialkyl phosphites are relatively inexpensive and readily available as phosphorus nucleophiles, which have also been widely used for the synthesis of various organophosphorus compounds.⁹ In consideration of searching phosphorus nucleophiles instead of P(O)H compounds, we envision that the interaction between trialkyl phosphites and thiols might produce phosphorothioates via the elimination of an alcohol. Herein, we report an alternative approach to the synthesis of phosphorothioates based on K₂CO₃-promoted aerobic oxidative cross-coupling of trialkyl phosphites with thiophenols using air as the oxidant at room temperature.

According to the reaction conditions of the CDC reactions between dialkyl phosphites and thiols developed by Song and Jiao,⁷ our hypothesis was tested by using a model reaction of triethyl phosphite 1a with p-toluenethiol 2a in solvents under air atmosphere at 40 °C, and the results were shown in Table 1. Initially, the reaction of 1a with 2a in CH₃CN under air in the absence of bases gave only trace amounts of the desired coupling product 3aa (entry 1). When Cs₂CO₃ (1 equiv.) was added, the reaction proceeded smoothly to afford 3aa in 68% yield, while the oxidation product 4a was also obtained in 24% yield (entry 2). When the reaction was carried out under N₂, only trace amounts of 3aa were detected (entry 3). This result demonstrates that this reaction involved an aerobic oxidative cross-coupling. Switching the solvent from CH₃CN to THF, dioxane, or DMSO decreased the yield of 3aa (entries 4–6). We then turned to screen other bases (entries 7–10). To our delight, the use of cheaper base K₂CO₃ gave 3aa in excellent yield (98%, entry 7), while the yield of the side product 4a was significantly decreased. We then carried out the reaction at room temperature, the yield of 3aa was only slightly decreased (97%, entry 11). The catalytic efficiency of K₂CO₃ was then tested. When 0.5 or 0.1 equiv. of K₂CO₃ was introduced, 3aa was still obtained in 87% or 81% yield (entries 12 and 13). It is noteworthy that disulfide 5a, which was generated via an aerobic oxidative homocoupling of thiol 2a,¹⁰ was observed in all cases (in the presence of bases and air). Finally, we concluded that the optimized combination for the cross-coupling reaction of trialkyl phosphites with thiols was to use 1 equiv. of K₂CO₃ as the base, CH₃CN as the solvent, and the reaction was set at room temperature under air atmosphere (entry 11).

Table 1 Optimization of reaction conditions^a,b

Entry	Base (equiv.)	Solvent	T (°C)	Yield 3aa (%)	Yield 4a (%)
a Reaction conditions: 1a (0.20 mmol), 2a (0.46 mmol), base, solvent (1 mL), open air, 5 h.b Yield based on 1a was determined by ^31P NMR analysis of crude products using an internal standard.c The reaction was carried out under N2.
1		CH3CN	40	Trace	Trace
2	Cs2CO3 (1)	CH3CN	40	68	24
3^c	Cs2CO3 (1)	CH3CN	40	Trace	Trace
4	Cs2CO3 (1)	THF	40	18	3
5	Cs2CO3 (1)	Dioxane	40	28	4
6	Cs2CO3 (1)	DMSO	40	Trace	Trace
7	K2CO3 (1)	CH3CN	40	98	1
8	Na2CO3 (1)	CH3CN	40	71	16
9	K3PO4 (1)	CH3CN	40	55	14
10	Et3N (1)	CH3CN	40	82	8
11	K2CO3 (1)	CH3CN	rt	97	1
12	K2CO3 (0.5)	CH3CN	rt	87	8
13	K2CO3 (0.1)	CH3CN	rt	81	12

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We then set out to explore the generality of the cross-coupling of trialkyl phosphites with thiols. We first applied the optimized conditions to the coupling of triethyl phosphite 1a with a variety of thiols 2, and the results are illustrated in Table 2. The results showed that thiophenol substrates bearing different groups such as alkyl groups, OMe, NH₂, Br, Cl, F, CF₃, and NO₂ at para, ortho or meta or at both positions of aromatic rings, as well as 2-naphthalenethiol and thiophene-2-thiol, were all well tolerated. The corresponding products 3aa–3ax were isolated in moderate to high yields, indicating that the electronic and steric effects were not evident in this reaction. However, the phosphorylation of aliphatic thiols such as benzylthiol and cyclohexylthiol failed to give the desired 3ay or 3az. The scale-up of the reaction of 1a with 2a was also attempted. When we increased the scale of the reaction from 0.4 to 4 mmol, 3aa was also isolated in good yield (65%).

Table 2 Scope of thiols^a,b

a Reaction conditions: 1a (0.40 mmol), 2 (0.92 mmol), and K₂CO₃ (0.40 mmol) in CH₃CN (2 mL) stirring at room temperature under air for 5–12 h.b Isolated yield based on 1a.c The reaction was performed in a 4 mmol scale.

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We then turned to explore the generality of the cross-coupling of trialkyl phosphites and their derivatives with p-toluenethiol 2a and/or p-chlorobenzenethiol 2g under the optimized conditions, and the results were shown in Table 3. Trimethyl phosphite 1b afforded the desired 3ba and 3bg in low yields probably due to its relatively weak nucleophilicity, while triisopropyl phosphite 1c and tributyl phosphite 1d smoothly gave the desired 3ca, 3cg, 3da, and 3dg in high yields. However, triphenyl phosphite 1e failed to give the coupling product 3ea. In addition, the cross-coupling of P(III) compounds bearing one or two methoxy substituents were also attempted. Pleasingly, the protocol was found to work well when dimethyl phenylphosphonite 1f or methyl diphenylphosphinite 1g was employed as the phosphorus nucleophile. The corresponding coupling products 3fa and 3ga were isolated in 45% and 55% yields, respectively. Notably, the side products 4 and disulfides 5 were detected in most cases of Tables 2 and 3.

Table 3 Scope of P(III) compounds^a,b

1	3
a Reaction conditions: 1 (0.40 mmol), 2 (0.92 mmol), and K2CO3 (0.40 mmol) in CH3CN (2 mL) stirring at room temperature under air for 5–12 h.b Isolated yield based on 1.

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The above experimental results (Table 1, entries 1 and 3) showed that both bases and air are indispensable for the cross-coupling reaction. To gain more insight into the mechanism of this reaction, a couple of control experiments were then conducted (Scheme 1). In consideration of the generation of disulfides in all cases, the reaction of thiol 2a with K₂CO₃ under air was carried out, leading to the formation of disulfide 5a in quantitative yield (eqn (1)), which suggests that K₂CO₃ might increase the oxidation rate of thiols with dioxygen.^11,12 In addition, the reaction of 1a with disulfide 5a under air or N₂ in the absence of K₂CO₃ also gave 3aa in high yield (eqn (2) and (3)). The above results suggest that disulfide might be an intermediate in the cross-coupling reaction.

Scheme 1 Mechanistic studies.

According to the literatures and our observations, together with the generation of side products 4, a plausible reaction mechanism is outlined in Scheme 2. Initially, thiyl radical is generated from a single electron oxidation of thiol 2 in the presence of dioxygen, followed by the loss of the proton with the assistance of K₂CO₃. Thiyl radical could undergo homocoupling to produce disulfide 5.^7,11–13 Then the nucleophilic attack of P(III) compound 1 on disulfide 5 affords phosphonium cation 6, which reacts with water to form the unstable intermediate 7. Subsequent alcohol elimination of 7 gives the desired phosphorothioate 3 (path a), whereas the thiophenol elimination affords the oxidation product 4 (path b).

Scheme 2 Proposed mechanism.

Conclusions

In conclusion, we have developed the K₂CO₃-promoted aerobic oxidative cross-coupling of trialkyl phosphites, dimethyl phenylphosphonite, or methyl diphenylphosphinite with thiophenols, which provides a convenient, practical and economical protocol for the synthesis of phosphorothioates with wide functional group compatibility. We envision that the reaction mode outlined here will have potential applications in organic synthesis. Further studies on the transformations of thiols with electrophiles are ongoing and will be reported in due course.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by the Science and Technology Planning Project of Guangdong Province (No. 2015A020211026 and 2017A010103044), 100 Young Talents Programme of Guangdong University of Technology (220413506), and the Open Fund of the Key Laboratory of Functional Molecular Engineering of Guangdong Province (2016kf07, South China University of Technology).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: General information and copies of ¹H, ¹³C, and ³¹P NMR spectra. See DOI: 10.1039/c7ra09057a

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