Copper-catalyzed reductive coupling of aryl sulfonyl chlorides with H-phosphonates leading to S-aryl phosphorothioates

Article abstract of DOI:10.1039/c4cc02693d

An efficient protocol for copper-catalyzed reductive cross-coupling of aryl sulfonyl chlorides with H-phosphonates has been developed. The various S-aryl phosphorothioates were afforded in up to 86% yield for 20 examples. This protocol features high effic

Full text of DOI:10.1039/c4cc02693d

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Copper-catalyzed reductive coupling of aryl
sulfonyl chlorides with H-phosphonates leading
to S-aryl phosphorothioates†
Jie Bai,a Xiuling Cui,*ab Hui Wanga and Yangjie Wu*a
Cite this: Chem. Commun., 2014,
50, 8860
Received 11th April 2014,
Accepted 18th June 2014
DOI: 10.1039/c4cc02693d
www.rsc.org/chemcomm
An efficient protocol for copper-catalyzed reductive cross-coupling
of aryl sulfonyl chlorides with H-phosphonates has been developed.
The various S-aryl phosphorothioates were afforded in up to 86%
yield for 20 examples. This protocol features high efficiency, wide
functional group tolerance, commercially available aryl sulfonyl
chlorides as starting materials and base-free conditions.
Phosphorothioate has proven to be a useful skeleton in organic
synthesis as a valuable building block, in pharmaceuticals and
pesticides due to its biological and physical properties.1–4 In
particular, S-aryl phosphorothioate represents an important
structural element in antiproliferative agents (A),5 pesticides
(B),6 antibacterials (C),7 curing accelerators (D),8 antistatic
agents (E),9 and anticholinesterases (F)10 (Scheme 1). However,
the investigation on building such a structure has lagged
behind. Hence, a rapid, efficient and practical access to S-aryl
phosphorothioates is highly desired.
Traditional procedures to synthesize S-aryl phosphorothioates
involved the reaction of trialkyl phosphites with sulfenyl chlorides
by chlorinating the mercaptan or disulfide with sulfuryl chloride,11
and the coupling of H-phosphonates with disulfides by compli-
cated electrosynthetic processes.12 Witt’s group obtained phos-
phorothioates by the treatment of (5,5-dimethyl-2-thioxo-1,3,
2-dioxaphosphorin-2-yl) disulfanyl derivatives with trimethyl phos-
phate, in which the substrate was limited to trimethyl phosphate.13
Very recently, Liu and co-workers reported a two-step process to
synthesize phosphorothioates from thiols and phosphonates pro-
moted by N-chlorosuccinimide.14 Transition-metal-catalyzed direct
Scheme 1 Several examples illustrating the importance of S-aryl
phosphorothioates.
coupling reactions of dialkyl phosphonates with organic disulfides
(or benzenethiols) have provided an alternative protocol to synthe-
size S-aryl phosphorothioates, in which a base is required.15,16 In
summary, some problems exist with these procedures, such as: (1)
requirement of complicated or foul-smelling starting materials,
which are not commercially available and (2) a narrow scope of
substrates. The remaining challenge is to develop a general and
applicable strategy for a variety of S-aryl phosphorothioates. There-
fore, we focus our current research interests on building such a
structure. Herein, we disclose a simple and practical procedure to
synthesize various S-aryl phosphorothioates via copper-catalyzed
reductive cross-coupling reactions of commercially available aryl
sulfonyl chlorides with dialkyl phosphonates under an air atmo-
sphere and base-free conditions (Scheme 2).
We initiated our investigation with the reaction of tosyl
chloride (1a) with dimethyl phosphonate (2a) as a model reac-
tion to identify the optimal reaction conditions. Several para-
meters, such as catalyst sources, solvents and reaction temperature
a Department of Chemistry, Henan Key Laboratory of Chemical Biology and Organic
Chemistry, Key Laboratory of Applied Chemistry of Henan Universities,
Zhengzhou University, Zhengzhou, 450052, P. R. China. E-mail: cuixl@zzu.edu.cn,
wyj@zzu.edu.cn; Tel: +86-371-67767753
b Xiamen Key Laboratory of Ocean and Gene Drugs, School of Biomedical Sciences
and Institute of Molecular Medicine of Huaqiao University, Huaqiao University,
Engineering Research Center of Molecular Medicine of Chinese Education
Ministry, Xiamen, 361021, P. R. China. E-mail: cuixl@hqu.edu.cn
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc02693d
Scheme 2 Synthesis of S-aryl phosphorothioates.
8860 | Chem. Commun., 2014, 50, 8860--8863
This journal is ©The Royal Society of Chemistry 2014

View Article Online
Communication
ChemComm
Table 1 Screening the reaction parameters for the copper-catalyzed
coupling reaction of tosyl chloride (1a) with dimethyl phosphonate (2a)a
Entry
Catalyst
Solvent
T (1C)
Yieldg (%)
1
2
3
4
5
6
7
8
—
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DCE
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
120
140
150
0
0
Pd(OAc)2
CuI
CuBr
Scheme 3 The corresponding product and byproducts under the optimal
reaction conditions.
37
45
35
Trace
60
58
33
33
0
63
65
66
70
67
72
76
74
CuBr2
Cu(OTf)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
dibutyl phosphonate, diisopropyl phosphonate and di-sec-butyl
phosphonate could be coupled well with tosyl chloride (1a), afford-
ing the corresponding products in 66–76% yields (Table 2, 3a–3f).
The steric hindrance of H-phosphonates did not significantly affect
this transformation. Diisopropyl phosphonate and di-sec-butyl phos-
phonate gave similar results as dipropyl phosphonate and dibutyl
phosphonate (Table 2, 3c vs. 3e, 3d vs. 3f). Then aryl sulfonyl
chlorides substituted by electron-withdrawing and electron-
donating groups were tested (Table 2, 3a, 3g–3s). The significant
influence of the electron density in aryl sulfonyl chloride on this
transformation was not observed. All of the electron-rich (3a, 3g–3i),
electron-neutral (3m) and electron-deficient (3n–3r) aryl sulfonyl
chlorides could give the corresponding products in good yields.
Moreover, the halo groups remained intact in the products, which
would provide the possibility for the further useful transformation.
4-Fluoro, 4-chloro, and 4-bromo benzenesulfonyl chlorides were
9
Dioxane
Toluene
DMSO
10
11
12b
13c
14d
15e
16f
17e
18e
19e
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
a
Reaction conditions: 1a (0.4 mmol), 2a (0.8 mmol), catalyst (15 mol%),
b
solvent (2.5 mL), under air, 24 h. Reaction conditions: 2a (3 equiv.).
c
e
g
d
Reaction conditions: 2a (5 equiv.). Reaction conditions: 2a (6 equiv.).
f
Reaction conditions: 2a (7 equiv.). Reaction conditions: 2a (8 equiv.).
Reaction conditions: isolated yields based on 1a.
were screened. The results are listed in Table 1. The absence of any suitable and reacted smoothly with dimethyl H-phosphonate (2a),
metal and the presence of Pd(OAc)2 (15 mol%) led to disappointing leading to the S-aryl phosphorothioates in 86%, 78%, and 76%
results at 100 1C under an air atmosphere (Table 1, entries 1 and 2). yields, respectively (Table 2, 3p–3r). It is worthy of note that these
Among the copper salts investigated (Table 1, entries 3–7), Cu(OAc)2 standard reaction conditions were applied to 2-naphthalenesulfonyl
proved to be an ideal choice, and gave the desired product in chloride and 2-thiophenesulfonyl chloride, affording the corre-
a promising yield of 60% (Table 1, entry 7). A variety of solvents sponding products 3s and 3t in 72% and 63% yields, respec-
(e.g. DCE, dioxane, toluene, and DMSO) were tested (Table 1, tively. Sterically hindered aryl sulfonyl chlorides, such as
entries 7–11). CH3CN was clearly the best choice for this catalytic 2,4-dimethylphenyl sulfonyl chloride, 2,4,6-trimethylphenyl
system (Table 1, entry 7). To our delight, the yield improved to 70% sulfonyl chloride, and 2-methyl-3-chloro-phenyl sulfonyl chlor-
when the ratio of 1a and 2a was changed to 1 : 7, which indicated ide, were also suitable substrates and successfully afforded the
that the ratio of substrates played an important role in this reaction desired products in 65%, 54% and 69% yields, respectively
(Table 1, entries 12–15). The yield improved to 76% when the (Table 2, 3j, 3k and 3l). In summary, donating, withdrawing and
temperature was increased to 140 1C (Table 1, entry 17). The large bulky groups in aryl sulfonyl chlorides were compatible in
optimized reaction conditions were eventually identified as follows: this catalytic system.
the ratio of 1a and 2a was 1:7 in the presence of Cu(OAc)2
To clarify the role of air in the reaction mechanism, some
(15 mol%) in CH3CN at 140 1C for 24 h in the absence of any controlled experiments were performed (Scheme 4). When the
base, oxidant, or ligand and under an air atmosphere (Table 1, reaction of tosyl chloride (1a) with dimethyl phosphonate (2a)
entry 17). With the optimal reaction conditions in hand, remaining was carried out under a nitrogen atmosphere, the desired
tosyl chloride was not detected after the model reaction was product 3a was obtained in 17% yield (Scheme 4, eqn (1)).
complete. 4a and 4b as byproducts were generated in 7% and While an air atmosphere could afford 76% yield. These results
4% isolated yields, respectively (Scheme 3).
indicate that the oxygen molecule in air was necessary.
With the optimal reaction conditions in hand, the scope of When 2 equivalents of BHT were added to the reaction
the substrates was examined. It was gratifying to find that a mixture of 1a and 2a, the yield of the desired product was
variety of H-phosphonates could couple with diverse sulfonyl reduced dramatically (Scheme 4, eqn (2)). The reaction of BHT
chlorides in satisfactory yields. The results are shown in with 1a gave product 5a in 15% yield (Scheme 4, eqn (3)).
Table 2. Firstly, various H-phosphonates were tested. Dimethyl These results indicated that the reaction might proceed via a
phosphonate, diethyl phosphonate, dipropyl phosphonate, radical pathway.
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 8860--8863 | 8861

View Article Online
ChemComm
Communication
Table 2 Synthesis of S-aryl phosphorothioates from sulfonyl chlorides
and H-phosphonatesa
Scheme 4 Controlled experiments.
Scheme 5 Proposed reaction mechanism.
intermediate D provided S-aryl phosphorothioates and generated
Cu(I). Cu(I) E was oxidized by oxygen to Cu(II) for the next cycle.
In conclusion, a novel, simple and efficient protocol for the
synthesis of S-aryl phosphorothioates via copper-catalyzed direct
coupling of commercially available aryl sulfonyl chlorides with
H-phosphonates under an air atmosphere and base-free condi-
tions has been developed. Various S-aryl phosphorothioates were
obtained in moderate to good yields for 20 examples. Electronic
a
Reaction conditions: 0.4 mmol aryl sulfonyl chlorides, 2.8 mmol
phosphite esters, 15 mol% Cu(OAc)2, 140 1C, air, 24 h. Isolated yields
in parentheses.
A proposed reaction mechanism is outlined in Scheme 5 and steric effects from both sulfonyl chloride and H-phosphonate
based on the results obtained and reported literature.17,18 Tosyl had no significant influence on this reaction.
chloride (1a) underwent single-electron transfer (SET) with
This work was supported by the NSF of China (21102133,
Cu(OAc)2 to produce the tosyl radical and Cu(III) intermediate A. 21172200), and the NSF of Henan (082300423201).
The homo-coupling phosphorus compound P(O)–P(O) in the
reaction system was detected by Q-TOF LC/MS. The ligand-
exchange reaction between Cu(OAc)2 and 2a could occur to
Notes and references
1 (a) S. W. Rhee, R. P. Iyer, J. E. Coughlin, S. Padmanabhan and J. P.
afford intermediate B and release HOAc. Intermediate B was
attacked by the tosyl radical to obtain the Cu(III) intermediate C.
Then, intermediate C was reduced by H-phosphonate, affording
the Cu(III) intermediate D. Finally, reductive elimination of
Malerich, J. Labelled Compd. Radiopharm., 2012, 55, 197; (b) A. Leisvuoria,
Z. Ahmeda, M. Ora, L. Beigelmanb, L. Blattb and L. Harri, Helv.
Chim. Acta, 2012, 95, 1512; (c) M. Noro, S. Fujita and T. Wada, Org. Lett.,
2013, 15, 5948; (d) R. Xie, Q. Zhao, T. Zhang, J. Fang, X. Mei, J. Ning and
Y. Tang, Bioorg. Med. Chem., 2013, 21, 278; (e) T. S. Kumar, T. Yang,
8862 | Chem. Commun., 2014, 50, 8860--8863
This journal is ©The Royal Society of Chemistry 2014

View Article Online
Communication
ChemComm
S. Mishra, C. Cronin, S. Chakraborty, J. B. Shen, B. T. Liang and 16 Y. J. Ouyang, Y. Y. Li, N. B. Li and X. H. Xu, Chin. Chem. Lett., 2013,
K. A. Jacobson, J. Med. Chem., 2013, 56, 902. 24, 1103.
2 (a) M. Fukuoka, S. Shuto, N. Minakawa, Y. Ueno and A. Matsuda, 17 (a) W. Zhou, L. Zhang and N. Jiao, Angew. Chem., Int. Ed., 2009,
J. Org. Chem., 2000, 65, 5238; (b) P. Jhajharia, M. K. Samota and
G. Seth, Heteroat. Chem., 2010, 21, 84; (c) A. M. Lauer, F. Mahmud
and J. Wu, J. Am. Chem. Soc., 2011, 133, 9119; (d) F. Robertson and
J. Wu, Org. Lett., 2010, 12, 2668; (e) A. M. Lauer and J. Wu, Org. Lett.,
2012, 14, 5138; ( f ) K. A. Mazzio, K. Okamoto, Z. Li, S. Gutmann,
E. Strein, D. S. Ginger, R. Schlaf and C. K. Luscombe, Chem.
Commun., 2013, 49, 1321.
3 S. T. Crooke and C. F. Bennett, Annu. Rev. Pharmacol. Toxicol., 1996,
36, 107.
4 (a) P. Guga, M. Boczkowska, M. Janicka, A. Maciaszek, B. Nawrot,
S. Antoszczyk and W. J. Stec, Pure Appl. Chem., 2006, 78, 993;
48, 7094; (b) J. E. M. N. Klein, A. Perry, D. S. Pugh and R. J. K. Taylor,
Org. Lett., 2010, 12, 3446; (c) C. Gou, J. Song, S. W. Luo and
L. Z. Gong, Angew. Chem., Int. Ed., 2010, 49, 5558; (d) S. Chiba,
L. Zhang and J. Y. Lee, J. Am. Chem. Soc., 2010, 132, 7266;
(e) L. Zhang, G. Y. Ang and S. Chiba, Org. Lett., 2011, 13, 1622;
( f ) K. K. Toh, Y. F. Wang, E. P. J. Ng and S. Chiba, J. Am. Chem. Soc.,
2011, 133, 13942; (g) C. Yu, Y. Zhang, S. Zhang, H. Li and W. Wang,
Chem. Commun., 2011, 47, 1036; (h) G. S. Kumar, C. U. Maheswari,
R. A. Kumar, M. L. Kantam and K. R. Reddy, Angew. Chem., Int. Ed.,
2011, 50, 11748; (i) S. P. Simonovich, J. F. V. Humbeck and
D. W. C. MacMillan, Chem. Sci., 2012, 3, 58.
(b) H. Yan, X. Wanga, R. KuoLee and W. Chen, Bioorg. Med. Chem. 18 (a) A. Amine, Z. Atmani, A. E. Hallaoui, M. Giorgi, M. Pierrot and
´
Lett., 2008, 18, 5631.
M. Reglier, Bioorg. Med. Chem. Lett., 2002, 12, 57; (b) S. H. Bertz,
5 E. P. Reddy, M. V. R. Reddy and S. C. Bell, PCT Int. Appl.,
WO 2005089269 A2 20050929, 2005.
6 S. Tadao, K. Hiroshi, S. Tadashi and T. Akira, Jpn. Kokai Tokkyo
Koho., JP 49069836 A 19740705, 1974.
S. Cope, D. Dorton, M. Murphy and C. A. Ogle, Angew. Chem., Int.
Ed., 2007, 46, 7082; (c) S. H. Bertz, S. Cope, M. Murphy, C. A. Ogle
and B. J. Taylor, J. Am. Chem. Soc., 2007, 129, 7208; (d) H. P. Hu and
¨
J. P. Snyder, J. Am. Chem. Soc., 2007, 129, 7210; (e) T. Gartner,
7 H. Kazuo, S. Katsuki, H. Mitsuo, N. Masaru, T. Kenji and Y. Masaaki,
Jpn. Tokkyo Koho., JP 48018461 B 19730606, 1973.
8 M. Yasuhiko, K. Yasuyuki, T. Harumi and Y. Takashi, Jpn. Kokai
Tokkyo Koho., JP 51033200 A 19760322, 1976.
9 K. Hiroshi, Jpn. Tokkyo Koho., JP 45026974 B4 19700904, 1970.
10 L. L. Murdock and T. L. Hopkins, J. Agric. Food Chem., 1968, 16, 954.
11 D. C. Morrison, J. Am. Chem. Soc., 1955, 77, 181.
12 S. Torii, H. Tanaka and N. Sayo, J. Org. Chem., 1979, 44, 2938.
13 S. Lach and D. Witt, Synthesis, 2011, 3975.
14 Y. C. Liu and C. F. Lee, Green Chem., 2014, 16, 357.
15 (a) Y. X. Gao, G. Tang, Y. Cao and Y. F. Zhao, Synthesis, 2009, 1081;
(b) B. Kaboubin, Y. Abedi, J. Kato and T. Yokomatsu, Synthesis, 2013, 2323.
W. Henze and R. M. Gschwind, J. Am. Chem. Soc., 2007, 129, 11362;
( f ) R. J. Phipps, N. P. Grimster and M. J. Gaunt, J. Am. Chem. Soc.,
2008, 130, 8172; (g) A. E. King, T. C. Brunold and S. S. Stahl, J. Am.
Chem. Soc., 2009, 131, 5044; (h) A. E. King, L. M. Huffman,
A. Casitas, M. Costas, X. Ribas and S. S. Stahl, J. Am. Chem. Soc.,
2010, 132, 12068; (i) X. M. Zeng, L. Ilies and E. Nakamura, J. Am.
Chem. Soc., 2011, 133, 17638; ( j) S. H. Bertz, R. A. Hardin,
M. D. Murphy, C. A. Ogle, J. D. Richter and A. A. Thomas, J. Am.
Chem. Soc., 2012, 134, 9557; (k) L. Zhang, C. Peng, D. Zhao, Y. Wang,
H. J. Fu, Q. Shen and J. X. Li, Chem. Commun., 2012, 48, 5928;
(l) D. K. Li, M. Wang, J. Liu, Q. Zhao and L. Wang, Chem. Commun.,
2013, 49, 3640.
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 8860--8863 | 8863