Copper(I) iodide catalyzed synthesis of thiophosphates by coupling of H -phosphonates with benzenethiols

Article abstract of DOI:10.1055/s-0033-1339186

A simple, efficient, and new method has been developed for the preparation of thiophosphates from benzenethiols. The method involves copper(I) iodide catalyzed coupling of thiols with H-phosphonates in the presence of triethylamine. The reaction proceeds effectively to afford the corresponding thiophosphates in moderate to good yields via an aerobic dehydrogenative coupling of H-phosphonates with benzenethiols. This method is easy, rapid, and good-yielding for the synthesis of thiophosphates from benzenethiols. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1339186

PAPER
▌2323
paper
Copper(I) Iodide Catalyzed Synthesis of Thiophosphates by Coupling of
H-Phosphonates with Benzenethiols
Coupling of H-Phosphonates with Benzenethiols
Babak Kaboudin,*a Yaghoub Abedi,a Jun-ya Kato,b Tsutomu Yokomatsub
a
Department of Chemistry, Institute for Advanced Studies in Basic Sciences (IASBS), Zanjan 45137-66731, Iran
Fax +98(241)4214949; E-mail: kaboudin@iasbs.ac.ir
b
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received: 27.03.2013; Accepted after revision: 15.05.2013
To the best of our knowledge, there is no general and ef-
ficient method for the synthesis of thiophosphates.
Abstract: A simple, efficient, and new method has been developed
for the preparation of thiophosphates from benzenethiols. The
method involves copper(I) iodide catalyzed coupling of thiols with
H-phosphonates in the presence of triethylamine. The reaction pro-
ceeds effectively to afford the corresponding thiophosphates in
moderate to good yields via an aerobic dehydrogenative coupling of
H-phosphonates with benzenethiols. This method is easy, rapid, and
good-yielding for the synthesis of thiophosphates from benzenethi-
ols.
Copper is an important metal, available in the earth’s
crust. From an industrial viewpoint, simple and inexpen-
sive copper catalysts play an important role in numerous
organic reactions. As part of our efforts to use copper cat-
alysts in organic transformations and to develop novel
methods for the synthesis of organophosphorus com-
pounds,14 herein we report a new method for the synthesis
of phosphorothioates via an aerobic dehydrogenative cou-
pling of H-phosphonates with benzenethiols. We have
found that copper(I) iodide catalyzed coupling of thiols
with H-phosphonates proceeds effectively in the presence
of triethylamine.
Key words: thiophosphates, copper iodide, thiols, H-phospho-
nates, coupling
Phosphate esters are valuable intermediates in organic
synthesis.1 Among the phosphate esters, thiophosphate
derivatives are of interest as effective pesticides.2 A num-
ber of dialkyl aryl thiophosphates have been studied as
nerve gases, insecticides, and enzyme modifiers.3 S-Aryl
phosphorothioates can be also used to construct an intra-
molecular pyrophosphate linkage4 and for the thiophos-
phorylation of terminal alkynes.5 In recent years a number
of thiophosphates have been introduced as potential HIV-
1 and ACHE inhibitors.6 The synthesis of thiophosphates
is an important objective in organic synthesis, since they
have found use in the preparation of biologically active
molecules, and are also versatile intermediate in organic
synthesis. Despite the wide range of industrial and syn-
thetic applications, the synthesis of thiophosphates has re-
ceived little attention. Synthetic routes to thiophosphates,
not generally applicable, involve the reactions of dialkyl
phosphonates with sulfenyl chlorides,7 sulfenyl cyanides,8
thiosulfonates,9 disulfides,10 and sulfur,11 and condensa-
tion of phosphorochloridates with thiols.12 However, most
of the methodologies for the synthesis of S-aryl phospho-
rothioates have involved special reagents sensitive to air
or moisture, thus they must be performed under special re-
action conditions and this limits their application. The tra-
ditional method for the preparation of S-aryl
phosphorothioates is through the nucleophilic substitution
reaction of dialkyl phosphorochloridates (RO)2P(O)Cl
with alkali metal salts such as sodium arenethiolates
ArSNa, which suffer from drawbacks such as low yields,
tedious procedures, and lack of functionality tolerance.13
Initially, the H-phosphonate coupling of diethyl phospho-
nate (2a) with p-toluenethiol (1a) was chosen as the mod-
el reaction and the experimental data for screening
conditions are listed in Table 1. A mixture of diethyl phos-
phonate (2a; 1 equiv), p-toluenethiol (1a; 1.2 equiv), and
triethylamine (2.5 equiv) as base was stirred in the pres-
ence of copper(I) chloride (5 mol%) as the catalyst in N,N-
dimethylformamide (1 mL) at room temperature for five
hours under air to give 3a in 63% yield (entry 1). Even if
copper(I) bromide salt was used instead of copper(I) chlo-
ride, the yield was not significantly improved (entry 2).
Addition of ligands such as 1,10-phenanthroline or
N,N,N′,N′-tetramethylethylenediamine was found to en-
hance the copper(I) chloride catalyzed coupling reaction
(entries 3 and 4). When the reaction was carried out in the
presence of copper(I) iodide for five hours at room tem-
perature with 1,10-phenanthroline or N,N,N′,N′-tetra-
methylethylenediamine as a ligand, the reaction yield was
increased to 93 and 94%, respectively (entries 5 and 6).
In the presence of the ligands, the dehydrogenative homo-
coupling product of H-phosphonates was also detected by
31P NMR.15 The ligand-free coupling reaction of 1a with
diethyl phosphonate (2a) when using copper(I) iodide
gave 3a in 96% yield (entry 7). Screening of various cop-
per(II) salts showed that use of copper(II) chloride and
copper(II) sulfate resulted in lower yields compared with
that of copper(I) iodide (entries 8 and 9). Solvent screen-
ing indicated that N,N-dimethylformamide was still the
best solvent for this reaction (entries 10–12). It should be
noted that the reaction failed to give thiophosphate 3a un-
der an atmosphere of argon instead of air or without cop-
per catalyst under air at room temperature.
SYNTHESIS 2013, 45, 2323–2327
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DOI: 10.1055/s-0033-1339186; Art ID: SS-2013-Z0240-OP
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B. Kaboudin et al.
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Table 1 Coupling of Diethyl Phosphonate (2a) with p-Toluenethiol
(1a) under Different Reaction Conditionsa
Table 2 Coupling of H-Phosphonates with Benzenethiols
O
O
SH
S
P(OR)2
S
P(OEt)2
SH
O
CuI (5 mol%), Et3N
DMF, air, r.t., 5 h
O
+
H
P(OR)2
copper salts
air, r.t., 5 h
+
H
P(OEt)2
X
X
1
2
3
Entry
1
X
R
Product
3a
Yield (%)b
1a
2a
3a
Entry Copper salt Solvent Ligand
Yield (%)b
O
4-Me Et
3a 91
3b 88
S
P(OEt)2
1
CuCl
CuBr
CuCl
CuCl
CuI
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
EtOH
EtOH
CH2Cl2
–
–
63
65
O
2
2
3
4
5
H
Et
Et
Et
S
P(OEt)2
3
1,10-phenanthrolinec,d 76
TMEDAc,d
76
1,10-phenanthrolinec,d 93
O
4
4-Br
4-F
3c
92
Br
S
P(OEt)2
5
O
6
CuI
TMEDAc,d
94
3d 87
F
S
P(OEt)2
7
CuI
–
–
–
–
–
–
96 (91)e
73
O
8
CuCl2
CuSO4
CuSO4
CuI
4-NH2 Et
2-Me Et
3e
3f
92
83
H2N
S
P(OEt)2
9
70
O
10
11
12
63
6
S
S
P(OEt)2
77
O
CuI
55
7
H
i-Pr
3g 90
3h 93
P(Oi-Pr)2
a Reaction conditions: 2a (1 mmol), 1a (1.2 equiv), Et3N (2.5 equiv),
copper salt (5 mol%), solvent (1 mL), air, r.t., 5 h.
b Yields are based on 2a and determined by 31P NMR by comparison
to an internal standard.
O
8
4-Me i-Pr
S
P(Oi-Pr)2
c Ligand (10 mol%) was used.
O
d In the presence of the ligand, the homocoupling product of the
H-phosphonate was also detected by 31P NMR as a byproduct.
e Isolated yield.
9
4-Br
4-F
i-Pr
i-Pr
3i
3j
92
85
91
Br
S
P(Oi-Pr)2
O
10
11
F
S
P(Oi-Pr)2
With the optimal conditions established above, we then
examined the general applicability of the aerobic dehy-
drogenative coupling of H-phosphonates with benzeneth-
iols, and the results are summarized in Table 2. Diethyl
phosphonate offered excellent yields and diisopropyl
phosphonate was also employed with high efficiency un-
der the same reaction conditions (Table 2). The unstable
diphenyl phosphonate afforded a mixture of unknown
products. The reaction of 4-fluorobenzenethiol with di-
phenyl phosphonate and copper(I) iodide (5 mol%) as the
catalyst in N,N-dimethylformamide (1 mL) at room tem-
perature for five hours under air gave only pyrophosphate
4 in 80% isolated yield (Scheme 1 and entry 13).
O
4-NH2 i-Pr
H2N
S
P(Oi-Pr)2 3k
12
13
4-Me Ph
–
–
–
O
O
4-F
Ph
4
80
(PhO)2P
O
P(OPh)2
a Conversions were monitored by TLC.
b Yields refer to those of isolated, pure products.
SH
Subsequently, our investigations were focused on the use
of various benzenethiols. As illustrated in Table 2, the use
of substituted benzenethiols bearing electron-withdraw-
ing and -donating groups had no influence on the yields of
the products. Benzenethiols bearing a coordinating group
such as the amino group could also be used to obtain the
O
O
O
CuI, Et3N, DMF
+
H
P(OPh)2
(PhO)2P
O
P(OPh)2
air, r.t., 5 h, 80%
2a
4
F
Scheme 1 Reaction of p-fluorobenzenethiol with diphenyl phospho-
nate
Synthesis 2013, 45, 2323–2327
© Georg Thieme Verlag Stuttgart · New York

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Coupling of H-Phosphonates with Benzenethiols
2325
mixture was stirred for 5 h at r.t. The resulting soln was diluted with
H2O (30 mL) and extracted with CH2Cl2 (2 × 25 mL). The organic
layer was washed with brine (50 mL) and dried (Na2SO4). The pure
product was obtained after column chromatography (silica gel, n-
hexane–EtOAc, 9:1 to 6:4). All products gave satisfactory spectral
data in accord with the assigned structures and literature reports.
desired coupling product in excellent yield (entries 5 and
11).
It was also possible to carry out this reaction for phenyl-
methylthiol. The reaction gave the corresponding thio-
phosphate adduct in a moderate yield (61%), which was
possibly due to the lower acidity of phenylmethylthiol
compared to that of benzenethiol (Scheme 2).
O,O′-Diethyl S-4-Tolyl Phosphorothioate (3a)10d
Yield: 237 mg (91%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.55 (dd, J = 6.4, 2.4 Hz, 2 H),
7.30–7.31 (m, 3 H), 4.08–4.20 (m, 4 H), 1.25 (t, J = 6.8 Hz, 6 H).
O
CH2SH
CH2S P(OEt)2
13C NMR (100 MHz, CDCl3): δ = 139.3 (d, J = 3 Hz), 134.6 (d, J =
5 Hz), 130.2 (d, J = 3 Hz), 122.8 (d, J = 7 Hz), 64.0 (d, J = 6 Hz),
21.2, 16.0 (d, J = 8 Hz).
O
CuI (5 mol%), Et3N
+
H
P(OEt)2
DMF, air, r.t., 5 h, 61%
31P NMR (400 MHz, CDCl3): δ = 23.4.
2a
5
O,O′-Diethyl S-Phenyl Phosphorothioate (3b)10d
Yield: 216 mg (88%); colorless oil.
Scheme 2 Reaction of phenylmethylthiol with diethyl phosphonate
1H NMR (400 MHz, CDCl3): δ = 7.55 (dd, J = 6.4, 2.4 Hz, 2 H),
7.30–7.31 (m, 3 H), 4.08–4.20 (m, 4 H), 1.25 (t, J = 6.8 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 134.5 (d, J = 6 Hz), 129.3 (d, J =
3 Hz), 129.0 (d, J = 3 Hz), 126.5 (d, J = 7 Hz), 64.0 (d, J = 6 Hz),
15.9 (d, J = 7 Hz).
Finally the coupling reaction of disulfides with diethyl
phosphonate was studied. The reaction of bis-p-tolyl di-
sulfide with diethyl phosphonate in the presence of five
mol% of copper(I) iodide and triethylamine in N,N-di-
methylformamide at room temperature for 12 hours gave
only 8% of the corresponding thiophosphate 3a (Scheme
3). The same reaction proceeded smoothly at 40 °C for 24
hours, giving 3a in 50% yield. Gao et al. reported that di-
ethylamine as a base has a crucial role in the copper-
catalyzed coupling reaction of diphenyl disulfide with di-
isopropyl phosphonate in dimethyl sulfoxide.10d
31P NMR (400 MHz, CDCl3): δ = 22.8.
O,O′-Diethyl S-4-Bromophenyl Phosphorothioate (3c)16
Yield: 298 mg (92%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.42–7.49 (m, 4 H), 4.13–4.25 (m,
4 H), 1.30 (t, J = 7.6 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 135.9 (d, J = 5 Hz), 132.3 (d, J =
2 Hz), 125.7 (d, J = 7 Hz), 123.6 (d, J = 6 Hz), 64.2 (d, J = 7 Hz),
16.0 (d, J = 7 Hz).
O
31P NMR (400 MHz, CDCl3): δ = 22.0.
S
P(OEt)2
S
O,O′-Diethyl S-4-Fluorophenyl Phosphorothioate (3d)16
O
CuI (5 mol%), Et3N
+
H
P(OEt)2
Yield: 230 mg (87%); colorless oil.
DMF, air, r.t., 12 h, 8%
1H NMR (400 MHz, CDCl3): δ = 7.55 (m, 2 H), 7.06 (t, J = 7.6, 2
H), 4.13–4.25 (m, 4 H), 1.32 (t, J = 7.6 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 163.3 (dd, J = 248, 3 Hz), 136.7
(dd, J = 10, 5 Hz), 121.6 (d, J = 4 Hz), 116.5 (dd, J = 22, 2 Hz), 64.1
(d, J = 7 Hz), 16.0 (d, J = 7 Hz).
2
2a
3a
Scheme 3 Reaction of bis-p-tolyl disulfide with diethyl phosphonate
31P NMR (400 MHz, CDCl3): δ = 22.7 (d, J = 4 Hz).
We reported here a copper-catalyzed synthesis of thio-
phosphates by coupling of benzenethiols with dialkyl
phosphonates in N,N-dimethylformamide at room tem-
perature in air. Copper(I) iodide, which is easily available,
was found to be an effective catalyst for this transforma-
tion. Simple workup, mild reaction conditions, good to
excellent yields, and clean reactions make this method an
attractive and useful contribution to present methodolo-
gies.
O,O′-Diethyl S-4-Aminophenyl Phosphorothioate (3e)
Yield: 240 mg (92%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.32 (dd, J = 8, 2 Hz, 2 H), 6.64
(d, J = 8 Hz, 2 H), 4.13–4.24 (m, 4 H), 4.13–4.13 (br, 2 H), 1.32 (t,
J = 6.8 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 147.3, 137.3 (d, J = 4 H), 115.9
(d, J = 2 Hz), 113.2 (d, J = 7 Hz), 63.9 (d, J = 6 Hz), 16.0 (d, J = 7
Hz).
31P NMR (400 MHz, CDCl3): δ = 24.1.
HRMS: m/z [MH+] calcd for C10H17NO3SP: 262.0667; found:
262.0663.
All chemicals were commercial products and distilled or recrystal-
lized before use. NMR spectra were obtained on a 400 MHz Bruker
Avance instrument. Column chromatography was carried out over
silica gel 100 (Merck No. 10184). Merck silica-gel 60 F254 plates
(No. 5744) were used for preparative TLC. Mass spectra were mea-
sured on a LCMASS micromass LCT and Micromass Autospec in-
strument. Melting points are uncorrected.
O,O′-Diethyl S-2-Tolyl Phosphorothioate (3f)17
Yield: 234 mg (83%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.21 (d, J = 8 Hz, 2 H), 6.86 (d,
J = 8 Hz, 2 H), 6.77 (m, 2 H), 3.80–3.69 (m, 4 H), 2.12 (s, 3 H), 0.88
(t, J = 7.2 Hz, 6 H).
Phosphorothioates 3; General Procedure
13C NMR (100 MHz, CDCl3): δ = 141.8 (d, J = 3 Hz), 135.8 (d, J =
4 Hz), 130.5 (d, J = 2 Hz), 129.1 (d, J = 3 Hz), 126.3 (d, J = 3 Hz),
125.2 (d, J = 7 Hz), 63.7 (d, J = 7 Hz), 20.9, 15.6 (d, J = 7 Hz).
The dialkyl phosphonate 2 (1 mmol) was added to a stirred mixture
of CuI (0.05 mmol, 5 mol%) and Et3N (2.5 mmol) in DMF (1 mL).
The thiol 1 (1.2 mmol) was added to the reaction mixture and the
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2323–2327

2326
B. Kaboudin et al.
PAPER
31P NMR (400 MHz, CDCl3): δ = 22.1.
31P NMR (400 MHz, CDCl3): δ = –17.6 (reported: δ = –25.5 in the
reaction mixture).
O,O′-Diisopropyl S-Phenyl Phosphorothioate (3g)10d
Yield: 247 mg (90%); colorless oil.
O,O′-Diethyl S-Benzyl Phosphorothioate (5)19
Yield: 158 mg (61%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.30–7.39 (m, 5 H), 4.11–4.15 (m,
2 H), 4.04–4.07 (m, 4 H), 1.31 (t, J = 7.2 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 137.5 (d, J = 5 Hz), 128.9, 128.6,
127.6, 63.5 (d, J = 6 Hz), 34.9 (d, 4.0 Hz), 15.9 (d, J = 7.0 Hz).
1H NMR (400 MHz, CDCl3): δ = 7.57 (m, 2 H), 7.31 (m, 3 H), 4.71–
4.77 (m, 2 H), 1.30 (d, J = 2 Hz, 6 H), 1.23 (d, J = 1.6 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 134.2 (d, J = 6 Hz), 129.2 (d, J =
3 Hz), 128.6 (d, J = 3 Hz), 127.3 (d, J = 3 Hz), 73.3 (d, J = 7 Hz),
23.8 (d, J = 4 Hz), 23.5 (d, J = 6 Hz).
31P NMR (400 MHz, CDCl3): δ = 20.43.
31P NMR (400 MHz, CDCl3): δ = 26.7.
O,O′-Diisopropyl S-4-Tolyl Phosphorothioate (3h)10d
Yield: 268 mg (93%); colorless oil.
Acknowledgment
1H NMR (400 MHz, CDCl3): δ = 7.50 (dd, J = 8, 1.6 Hz, 2 H), 7.16
(d, J = 8 Hz, 2 H), 4.75–4.80 (m, 4 H), 2.35 (s, 3 H), 1.35 (d, J = 6
Hz, 6 H), 1.28 (d, J = 6.4 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 138.9 (d, J = 3 Hz), 134.3 (d, J =
5 Hz), 130.0 (d, J = 2 Hz), 123.5 (d, J = 7 Hz), 73.2 (d, J = 7 Hz),
23.8 (d, 5 Hz), 23.5 (d, J = 5 Hz), 21.1.
The authors gratefully acknowledge support by the Institute for Ad-
vanced Studies in Basic Sciences (IASBS) Research Council under
grant No. G2010IASBS120.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
31P NMR (400 MHz, CDCl3): δ = 20.9.
O,O′-Diisopropyl S-4-Bromophenyl Phosphorothioate (3i)
Yield: 324 mg (92%); colorless oil.
References
1H NMR (400 MHz, CDCl3): δ = 7.48 (s, 4 H), 4.74–4.80 (m, 2 H),
1.35 (d, J = 6.4 Hz, 6 H), 1.29 (d, J = 6 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 135.6 (d, J = 8 Hz), 132.3 (d, 2
Hz), 126.6 (d, J = 7 Hz), 123.2 (d, J = 3 Hz), 73.7 (d, J = 7 Hz), 23.8
(d, J = 6 Hz), 23.5 (d, J = 5 Hz).
31P NMR (400 MHz, CDCl3): δ = 19.5.
HRMS: m/z [MH+] calcd for C12H19O3SBrP: 352.9976; found:
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O,O′-Diisopropyl S-4-Fluorophenyl Phosphorothioate (3j)
Yield: 248 mg (85%); colorless oil.
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1H NMR (400 MHz, CDCl3): δ = 7.58 (m, 2 H), 7.05 (t, J = 7.6 Hz,
2 H), 4.74–4.79 (m, 2 H), 1.33 (d, J = 6.4 Hz, 6 H), 1.28 (d, J = 6.4
Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ =163.2 (dd, J = 248, 3 Hz), 136.4
(dd, J = 8, 5 Hz), 121.6 (dd, J = 8, 4 Hz), 116.4 (dd, J = 22, 2 Hz),
73.5 (d, J = 6 Hz), 23.8 (d, J = 4 Hz), 23.5 (d, J = 6 Hz).
31P NMR (400 MHz, CDCl3): δ = 20.3 (d, J = 4 Hz).
HRMS: m/z [MH+] calcd for C12H19O3FSP: 293.0777; found:
293.0768.
O,O′-Diisopropyl S-4-Aminophenyl Phosphorothioate (3k)
Yield: 263 mg (91%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.36 (dd, J = 8, 2 Hz, 2 H), 6.64
(d, J = 8 Hz, 2 H), 4.73–4.78 (m, 2 H), 4.69 (br, 2 H), 1.34 (d, J = 6
Hz, 6 H), 1.29 (d, J = 6.4 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 147.4 (d, J = 2 Hz), 136.2 (d, J =
5 Hz), 115.6 (d, J = 2 Hz), 113.6, 73.0 (d, J = 7 Hz), 23.9 (d, J = 4
Hz), 23.6 (d, J = 6 Hz).
31P NMR (400 MHz, CDCl3): δ = 21.8.
HRMS: m/z [MH+] calcd for C12H21NO3SP: 290.0980; found:
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Tetraphenyl Pyrophosphate (4)18
Yield: 131 mg (80%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.38 (t, J = 8 Hz, 2 H), 7.22–7.29
(m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 150.4 (d, J = 7 Hz), 129.9, 125.6,
120.1 (d, J = 5 Hz).
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Coupling of H-Phosphonates with Benzenethiols
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2323–2327