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

Article abstract of DOI:10.1039/c7ra09057a

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.

Full text of DOI:10.1039/c7ra09057a

RSC Advances
View Article Online
View Journal | View Issue
PAPER
K2CO3-promoted aerobic oxidative cross-coupling
of trialkyl phosphites with thiophenols†
Cite this: RSC Adv., 2017, 7, 45416
ab
Chunxiao Wen,a Qian Chen,
Yulin Huang,a Xiaofeng Wang,a Xinxing Yan,a
*
a
a
Jiekun Zeng,a Yanping Huo
and Kun Zhang
*
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.
Received 16th August 2017
Accepted 18th September 2017
DOI: 10.1039/c7ra09057a
rsc.li/rsc-advances
In recent years, the development of new methods to construct a convenient, practical and economical protocol for the
phosphorus–sulfur bonds has been of particular interest due to synthesis of phosphorothioates is still a signicant issue.
the wide applications of organophosphorus–sulfur compounds
With our recent studies on the construction of carbon–
in biological chemistry, organic synthesis, and agrochemistry.1 sulfur, phosphorus–aryl, phosphorus–uorine, and phos-
A variety of useful synthetic methods have been well docu- phorus–oxygen bonds,8 we have been interested in studying the
mented. The traditional preparation of this class of compounds construction of phosphorus–sulfur bonds based on an
mainly relies on the use of toxic and moisture sensitive reagents economical approach. In comparison with P(O)H compounds,
or pre-functionalized substrates (e.g., R2P(O)X, RSX and RSSR).2 trialkyl phosphites are relatively inexpensive and readily avail-
On the other hand, the cross-dehydrogenative coupling (CDC) able as phosphorus nucleophiles, which have also been widely
between P(O)H compounds and commercially available thiols is used for the synthesis of various organophosphorus
gradually developed (Fig. 1, eqn (1)).3–7 In 2013, Kaboudin re- compounds.9 In consideration of searching phosphorus nucle-
ported a copper-catalyzed coupling of H-phosphonates with ophiles instead of P(O)H compounds, we envision that the
thiols in the presence of Et3N.3 In 2015, Pan reported a TBPB- interaction between trialkyl phosphites and thiols might
promoted oxidative coupling of secondary phosphine oxides produce phosphorothioates via the elimination of an alcohol.
or H-phosphonates with thiols.4 In 2016, Li and Zhang reported Herein, we report an alternative approach to the synthesis of
a
visible-light-mediated oxidative coupling of P(O)H phosphorothioates based on K2CO3-promoted aerobic oxidative
compounds with thiols in the presence of a photocatalyst.5 cross-coupling of trialkyl phosphites with thiophenols using air
Interestingly, Chen and Han recently reported an oxidant-free as the oxidant at room temperature.
Pd-catalyzed dehydrogenative phosphorylation of thiols.6 Most
According to the reaction conditions of the CDC reactions
recently, Song and Jiao reported a Cs2CO3-catalyzed aerobic between dialkyl phosphites and thiols developed by Song and
oxidative CDC reaction of phosphonates with thiols.7 The Jiao,7 our hypothesis was tested by using a model reaction of
possible mechanism showed that disuldes are reaction inter- triethyl phosphite 1a with p-toluenethiol 2a in solvents under
mediates generated via the oxidative coupling of thiols in the
presence of Cs2CO3 and O2.7 Undoubtedly, this strategy repre-
sents more straightforward, efficient, and atom-economic to
construct phosphorus–sulfur bonds. However, the CDC reac-
tions suffered from limitations with regard to high cost and less
availability of P(O)H compounds. Thus, the development of
aSchool of Chemical Engineering and Light Industry, Guangdong University of
Technology, Guangzhou 510006, China. E-mail: qianchen@gdut.edu.cn; kzhang@
gdut.edu.cn; Fax: +86 20 3932 2235; Tel: +86 20 3932 2231
bKey Laboratory of Functional Molecular Engineering of Guangdong Province, South
China University of Technology, Guangzhou 510640, China
Fig. 1 Current developments in the synthesis of phosphorothioates
† Electronic supplementary information (ESI) available: General information and
copies of 1H, 13C, and 31P NMR spectra. See DOI: 10.1039/c7ra09057a
from phosphites and thiols.
45416 | RSC Adv., 2017, 7, 45416–45419
This journal is © The Royal Society of Chemistry 2017

View Article Online
Paper
RSC Advances
Table 1 Optimization of reaction conditionsa,b
Table 2 Scope of thiolsa,b
T
(ꢀC)
Yield 3aa
(%)
Yield 4a
(%)
Entry
Base (equiv.)
Solvent
1
CH3CN
CH3CN
CH3CN
THF
Dioxane
DMSO
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
40
40
40
40
40
40
40
40
40
40
rt
Trace
68
Trace
18
28
Trace
98
71
55
82
97
Trace
24
Trace
3
2
Cs2CO3 (1)
Cs2CO3 (1)
Cs2CO3 (1)
Cs2CO3 (1)
Cs2CO3 (1)
K2CO3 (1)
Na2CO3 (1)
K3PO4 (1)
Et3N (1)
3c
4
5
6
7
8
4
Trace
1
16
14
8
1
8
12
9
10
11
12
13
K2CO3 (1)
K2CO3 (0.5)
K2CO3 (0.1)
rt
rt
87
81
a
Reaction conditions: 1a (0.20 mmol), 2a (0.46 mmol), base, solvent
a
(1 mL), open air, 5 h. Yield based on 1a was determined by 31P NMR
analysis of crude products using an internal standard. The reaction
b
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–
c
b
c
12 h. Isolated yield based on 1a. The reaction was performed in
was carried out under N2.
a 4 mmol scale.
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 signicantly
decreased. We then carried out the reaction at room tempera-
ture, 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
disulde 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 tri-
alkyl 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 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 elec-
tronic and steric effects were not evident in this reaction.
However, the phosphorylation of aliphatic thiols such as ben-
zylthiol 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%).
We then turned to explore the generality of the cross-
coupling of trialkyl phosphites and their derivatives with p-tol-
uenethiol 2a and/or p-chlorobenzenethiol 2g under the opti-
mized 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 phenyl-
phosphonite 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 disuldes 5
were detected in most cases of Tables 2 and 3.
We then set out to explore the generality of the cross-
coupling of trialkyl phosphites with thiols. We rst applied
the optimized conditions to the coupling of triethyl phosphite
1a with a variety of thiols 2, and the results are illustrated in
This journal is © The Royal Society of Chemistry 2017
RSC Adv., 2017, 7, 45416–45419 | 45417

View Article Online
RSC Advances
Paper
Table 3 Scope of P(III) compoundsa,b
1
3
Scheme 2 Proposed mechanism.
addition, the reaction of 1a with disulde 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 disulde might be an
intermediate in the cross-coupling reaction.
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 disulde 5.7,11–13 Then the nucleophilic attack of P(III)
compound 1 on disulde 5 affords phosphonium cation 6,
which reacts with water to form the unstable intermediate 7.
Subsequent alcohol elimination of 7 gives the desired phos-
phorothioate 3 (path a), whereas the thiophenol elimination
affords the oxidation product 4 (path b).
Conclusions
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.
In conclusion, we have developed the K2CO3-promoted aerobic
oxidative cross-coupling of trialkyl phosphites, dimethyl phe-
nylphosphonite, or methyl diphenylphosphinite with thio-
phenols, 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.
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 con-
ducted (Scheme 1). In consideration of the generation of
disuldes in all cases, the reaction of thiol 2a with K2CO3 under
air was carried out, leading to the formation of disulde 5a in
quantitative yield (eqn (1)), which suggests that K2CO3 might
increase the oxidation rate of thiols with dioxygen.11,12 In
Conflicts of interest
There are no conicts to declare.
Acknowledgements
This work was supported by the Science and Technology Plan-
ning Project of Guangdong Province (No. 2015A020211026 and
2017A010103044), 100 Young Talents Programme of Guang-
dong 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).
Scheme 1 Mechanistic studies.
45418 | RSC Adv., 2017, 7, 45416–45419
This journal is © The Royal Society of Chemistry 2017

View Article Online
Paper
RSC Advances
2014, 356, 2591; (m) D. S. Panmand, A. D. Tiwari,
S. S. Panda, J.-C. M. Monbaliu, L. K. Beagle, A. M. Asiri,
C. V. Stevens, P. J. Steel, C. D. Hall and A. R. Katritzky,
Tetrahedron Lett., 2014, 55, 5898; (n) J. Bai, X. Cui, H. Wang
and Y. Wu, Chem. Commun., 2014, 50, 8860; (o) S. Li,
T. Chen, Y. Saga and L.-B. Han, RSC Adv., 2015, 5, 71544;
(p) X. Bi, J. Li, F. Meng, H. Wang and J. Xiao, Tetrahedron,
2016, 72, 706; (q) M. Xia and J. Cheng, Tetrahedron Lett.,
2016, 57, 4702; (r) Y.-m. Lin, G.-p. Lu, G.-x. Wang and
W.-b. Yi, J. Org. Chem., 2017, 82, 382; (s) Y. Moon, Y. Moon,
H. Choi and S. Hong, Green Chem., 2017, 19, 1005.
3 B. Kaboudin, Y. Abedi, J.-y. Kato and T. Yokomatsu,
Synthesis, 2013, 45, 2323.
Notes and references
1 (a) N. N. Melnikov, Chemistry of Pesticides, Springer-Verlag,
New York, 1971; (b) L. D. Quin,
A
Guide to
Organophosphorus Chemistry, Wiley Interscience, New York,
2000; (c) P. J. Murphy, Organophosphorus Reagents, Oxford
University Press, Oxford, UK, 2004; (d) N.-S. Li,
J. K. Frederiksen and J. A. Piccirilli, Acc. Chem. Res., 2011,
44, 1257; (e) J. F. Milligan and O. C. Uhlenbeck,
Biochemistry, 1989, 28, 2849; (f) S. H. Vollmer,
M. B. Walner, K. V. Tarbell and R. F. Colman, J. Biol.
Chem., 1994, 269, 8082; (g) S. Cogoi, V. Rapozzi,
F. Quadrifoglio and L. Xodo, Biochemistry, 2001, 40, 1135;
(h) G. G. Durgam, T. Virag, M. D. Walker, R. Tsukahara,
S. Yasuda, K. Liliom, L. A. van Meeteren, W. H. Moolenaar,
N. Wilke, W. Siess, G. Tigyi and D. D. Miller, J. Med. Chem.,
2005, 48, 4919; (i) P. Carta, N. Puljic, C. Robert,
4 J. Wang, X. Huang, Z. Ni, S. Wang, J. Wu and Y. Pan, Green
Chem., 2015, 17, 314.
5 J.-G. Sun, H. Yang, P. Li and B. Zhang, Org. Lett., 2016, 18,
5114.
ˆ
6 Y. Zhu, T. Chen, S. Li, S. Shimada and L.-B. Han, J. Am. Chem.
Soc., 2016, 138, 5825.
7 S. Song, Y. Zhang, A. Yeerlan, B. Zhu, J. Liu and N. Jiao,
Angew. Chem., Int. Ed., 2017, 56, 2487.
A.-L. Dhimane, L. Fensterbank, E. Lacote and M. Malacria,
Org. Lett., 2007, 9, 1061; (j) M. Piekutowska and
Z. Pakulski, Carbohydr. Res., 2008, 343, 785; (k)
V. K. Pandey, A. Dwivedi, O. P. Pandey and S. K. Sengupta,
J. Agric. Food Chem., 2008, 56, 10779; (l) T. Ruman,
K. Długopolska, A. Jurkiewicz, D. Rut, T. Fr˛aczyk, J. Ciesla,
A. Les, Z. Szewczuk and W. Rode, Bioorg. Chem., 2010, 38,
8 (a) Q. Chen, X. Wang, C. Wen, Y. Huang, X. Yan and J. Zeng,
RSC Adv., 2017, 7, 39758; (b) Q. Chen, X. Yan, Z. Du, K. Zhang
and C. Wen, J. Org. Chem., 2016, 81, 276; (c) Q. Chen, X. Yan,
C. Wen, J. Zeng, Y. Huang, X. Liu and K. Zhang, J. Org. Chem.,
2016, 81, 9476; (d) Q. Chen, J. Zeng, X. Yan, Y. Huang,
C. Wen, X. Liu and K. Zhang, J. Org. Chem., 2016, 81,
10043; (e) Q. Chen, J. Zeng, X. Yan, Y. Huang, Z. Du,
K. Zhang and C. Wen, Tetrahedron Lett., 2016, 57, 3379.
9 For selected examples, see: (a) R. A. Dhokale and
S. B. Mhaske, Org. Lett., 2013, 15, 2218; (b) J. Ballester,
J. Gatignol, G. Schmidt, C. Alayrac, A.-C. Gaumont and
M. Taillefer, ChemCatChem, 2014, 6, 1549; (c) T. Balalas,
C. Peperidou, D. J. Hadjipavlou-Litina and K. E. Litinas,
Synthesis, 2016, 48, 281; (d) N. A. Dangroo, A. A. Dar,
R. Shankar, M. A. Khuroo and P. L. Sangwan, Tetrahedron
´
´
74; (m) A. M. Lauer, F. Mahmud and J. Wu, J. Am. Chem.
Soc., 2011, 133, 9119; (n) A. M. Lauer and J. Wu, Org. Lett.,
2012, 14, 5138; (o) M. W. Loranger, S. A. Beaton,
K. L. Lines and D. L. Jakeman, Carbohydr. Res., 2013, 379,
43; (p) T. S. Kumar, T. Yang, S. Mishra, C. Cronin,
S. Chakraborty, J.-B. Shen, B. T. Liang and K. A. Jacobson,
J. Med. Chem., 2013, 56, 902; (q) Y. Qiu, J. C. Worch,
D. N. Chirdon, A. Kaur, A. B. Maurer, S. Amsterdam,
C. R. Collins, T. Pintauer, D. Yaron, S. Bernhard and
K. J. T. Noonan, Chem.–Eur. J., 2014, 20, 7746.
2 (a) F. R. Atherton and A. R. Todd, J. Chem. Soc., 1947, 674; (b)
J. Michalski and J. Wasiak, J. Chem. Soc., 1962, 5056; (c)
R. G. Harvey, H. I. Jacobson and E. V. Jensen, J. Am. Chem.
Soc., 1963, 85, 1618; (d) P.-Y. Renard, H. Schwebel,
P. Vayron, L. Josien, A. Valleix and C. Mioskowski, Chem.–
Eur. J., 2002, 8, 2910; (e) B. Kaboudin, Tetrahedron Lett.,
2002, 43, 8713; (f) J.-D. Ye, C. D. Barth, P. S. R. Anjaneyulu,
T. Tuschl and J. A. Piccirilli, Org. Biomol. Chem., 2007, 5,
2491; (g) Y.-X. Gao, G. Tang, Y. Cao and Y.-F. Zhao,
Synthesis, 2009, 1081; (h) G. Wang, R. Shen, Q. Xu,
M. Goto, Y. Zhao and L.-B. Han, J. Org. Chem., 2010, 75,
3890; (i) Y.-J. Ouyang, Y.-Y. Li, N.-B. Li and X.-H. Xu, Chin.
Chem. Lett., 2013, 24, 1103; (j) B. Xiong, Y. Zhou, C. Zhao,
M. Goto, S.-F. Yin and L.-B. Han, Tetrahedron, 2013, 69,
9373; (k) Y.-C. Liu and C.-F. Lee, Green Chem., 2014, 16,
357; (l) G. Kumaraswamy and R. Raju, Adv. Synth. Catal.,
¨
Lett., 2016, 57, 2717; (e) R. S. Shaikh, S. J. S. Dusel and
¨
B. Konig, ACS Catal., 2016, 6, 8410; (f) P. Huang and J. Xu,
RSC Adv., 2016, 6, 63736; (g) M.-T. Chen, X. You, L.-G. Bai
and Q.-L. Luo, Org. Biomol. Chem., 2017, 15, 3165.
´
10 J. L. G. Ruano, A. Parra and J. Aleman, Green Chem., 2008, 10,
706 and references cited therein.
11 W.-L. Dong, G.-Y. Huang, Z.-M. Li and W.-G. Zhao,
Phosphorus, Sulfur Silicon Relat. Elem., 2009, 184, 2058.
12 (a) T. J. Wallance and A. Schriesheim, J. Org. Chem., 1962, 27,
1514; (b) T. J. Wallance, A. Schriesheim and W. Bartok, J. Org.
Chem., 1963, 28, 1311.
13 H. Wang, Q. Lu, C. Qian, C. Liu, W. Liu, K. Chen and A. Lei,
Angew. Chem., Int. Ed., 2016, 55, 1094.
This journal is © The Royal Society of Chemistry 2017
RSC Adv., 2017, 7, 45416–45419 | 45419