Electrochemically driven synthesis of phosphorothioates from trialkyl phosphites and aryl thiols

Article abstract of DOI:10.1016/j.electacta.2021.138748

A facile and elegant protocol for synthesis of phosphorothioates from trialkyl phosphites and aryl thiols via indirect electrochemical oxidation mediated by KI has been successfully developed. KI as a redox mediator, enabled the reaction of trialkyl phosp

Full text of DOI:10.1016/j.electacta.2021.138748

Electrochimica Acta 389 (2021) 138748
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Electrochimica Acta
journal homepage: www.elsevier.com/locate/electacta
Electrochemically driven synthesis of phosphorothioates from trialkyl
phosphites and aryl thiols
Lingmin Zhao, Xin Liu, Shuxian Shi, Zengzhi Wu, Xiaqun Guo, Zhenlu Shen∗, Meichao Li∗
College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile and elegant protocol for synthesis of phosphorothioates from trialkyl phosphites and aryl thiols
via indirect electrochemical oxidation mediated by KI has been successfully developed. KI as a redox
mediator, enabled the reaction of trialkyl phosphites and aryl thiols effectively at low potential. Cyclic
voltammetry and in situ FTIR were applied to investigate the electrocatalytic activity of KI for the cross-
coupling of trialkyl phosphites with aryl thiols. A variety of phosphorothioates were obtained in good
to excellent yields under the optimal conditions. This strategy provided an expedient access to construct
P–S bond with good functional group compatibility and a broad substrate scope.
Received 7 May 2021
Revised 2 June 2021
Accepted 3 June 2021
Available online 8 June 2021
Keywords:
Electrochemical oxidation
Trialkyl phosphites
Aryl thiols
© 2021 Elsevier Ltd. All rights reserved.
Phosphorothioates
KI
1. Introduction
With the development of modern organic synthesis chemistry,
oxidative cross-coupling reactions without transition metals be-
Phosphorothioates with P–S bond motifs have a wide range
of application in agricultural chemistry, organic synthesis and
medicinal chemistry [1–3]. Most of them possess notable bioac-
tivities, such as suppression of HIV expression [4], inhibition of
cholinesterases [5], and inhibitory activity to AChE [6]. In light
of the significance of phosphorothioates, numerous methodolo-
gies have been explored to prepare them. Timperley’s team de-
scribed an approach to synthesize phosphorothioates through
cross-coupling reactions of thiols with phosphorochloridates or
phosphorobromidates [7]. Nevertheless, it was necessary to pre-
pare the reactants phosphorochloridates or phosphorobromidates
before the synthesis, which often involved the toxic halogen such
as chlorine or bromine. Recently, cross-coupling reactions of H-
phosphonates with thiols have been reported using transition-
metals, such as Pd [8], Fe [9], Cu [10] and Ni [11]. An efficient ap-
proach for synthesis of phosphorothioates via Pd-catalyzed dehy-
drogenative coupling of H-phosphonates with thiols has been re-
alized in high yields, but the reactions were carried out at about
100 °C for 20 h [8]. A Fe(Pc)-catalyzed oxidative coupling reaction
of H-phosphonates and thiols was achieved in the presence of base
for 24 h [9]. It could effectively improve the selectivity and yield
for the synthesis reactions, but the use of transition-metal catalysts
would result in metal residue [12].
come more desirable to synthesize phosphorothioates [13–18]. P–
S formation reaction to obtain phosphorothioates was performed
with 2.0 equiv. di-tert-butyl peroxide (DTBP) as the oxidant from
H-phosphonates with thiophenols/disulfides at 80 °C for 20 h [14].
Such coupling reaction would also be realized with the oxidant
1,3-dichloro-5,5-dimethylhydantotin in excellent yields [15]. Great
progress has been made in this field, but most of these methods
should be associated with stoichiometric oxidants.
Over the past decade, electrochemical anodic oxidation pro-
vided a mild tool for various organic transformations, which was
a green and sustainable synthesis method [19–22]. Instead of the
traditional methods, P–Se [23], P–O [24,25], P–C [26–28], P–S [29–
31] bonds were successfully constructed by electrochemical oxida-
tion. Zheng et al disclosed a direct electrochemical dehydrogena-
tive cross-coupling of H-phosphine oxide with thiols to construct
P–S bond, and put forward a mechanism of free radical pathway
[30]. Lee’s team reported a method for preparing phosphoroth-
ioates from thiols and H-phosphonates through electrochemical re-
action, which was carried out under argon atmosphere for 7 h [31].
Their work was very interesting and valuable.
Very recently we reported a simple and convenient method for
synthesis of phosphorothioates by the reaction of trialkyl phos-
phites and thiols with trichloroisocyanuric acid as the oxidant [32].
Inspired by the aforementioned works, and continuation of our
work on mercaptan chemistry [33–35], we attempted to build P–S
bond to obtain phosphorothioates from trialkyl phosphites and aryl
thiols via electrochemical method. The redox properties of reaction
∗
Corresponding authors.
E-mail addresses: zhenlushen@zjut.edu.cn (Z. Shen), limc@zjut.edu.cn (M. Li).
https://doi.org/10.1016/j.electacta.2021.138748
0013-4686/© 2021 Elsevier Ltd. All rights reserved.

L. Zhao, X. Liu, S. Shi et al.
Electrochimica Acta 389 (2021) 138748
were investigated by cyclic voltammetry, in suit FTIR, control ex-
periment and electrosynthsis. In addition, a plausible mechanism
was proposed on the basis of all the experiments.
2.4.2. O,O-Diethyl S-(o-tolyl) phosphorothioate (3ab)
Colorless oil (104.9 mg, 0.40 mmol, 81% yield). 1H NMR (500
MHz, CDCl3) δ 7.62-7.61 (m, 1H), 7.28-7.27 (m, 2H), 7.20-7.16 (m,
1H), 4.21-4.11 (m, 4H), 2.53 (d, J = 1.2 Hz, 3H), 1.31-1.28 (m, 6H);
13C NMR (125 MHz, CDCl3) δ 141.9 (d, J = 5.0 Hz), 135.8 (d, J = 3.8
Hz), 130.5 (d, J = 2.5 Hz), 129.0 (d, J = 2.5 Hz), 126.4 (d, J = 3.8
Hz), 125.4 (d, J = 7.5 Hz), 63.8 (d, J = 7.5 Hz), 21.0, 15.7 (d, J = 6.3
Hz). MS(EI), m/z 260.13 [M+, 41%], 91.18 (100%).
2. Experimental section
2.1. General information
The solvent and other chemical materials were acquired from
commercial suppliers and used directly without further purifica-
tion. Gas chromatography (GC) analysis was recorded at Agilent
GC6890 system equipped with a SH-Rtx-Was capillary column and
a flame ionization detector (FID). GC-MS analysis was performed
on Thermo Trace ISQ instrument with TG 5 MS capillary column.
13C NMR and 1H NMR spectra for 125 MHz and 500 MHz were
measured on a Bruker Avance Ⅲ spectrometer. Tetramethylsilane
was used as the interal standard and CDCl3 as the solvent.
2.4.3. O,O-Diethyl S-(m-tolyl) phosphorothioate (3ac)
Colorless oil (107.5 mg, 0.41 mmol, 83% yield). 1H NMR (500
MHz, CDCl3) δ 7.38 (d, J = 12.1 Hz, 2H), 7.28-7.23 (m, 1H), 7.17 (d,
J = 7.6 Hz, 1H), 4.27-4.14 (m, 4H), 2.36 (s, 3H), 1.34-1.26 (m, 6H);
13C NMR (125 MHz, CDCl3) δ 139.2, 135.2 (d, J = 5.0 Hz), 131.6 (d,
J = 5.0 Hz), 129.9, 129.1 (d, J = 2.5 Hz), 126.2 (d, J = 8.8 Hz), 64.0
(d, J = 6.3 Hz), 21.3, 16.0 (d, J = 7.5 Hz). MS(EI), m/z 259.99 [M+,
35%], 124.13 (100%).
2.4.4. O,O-Diethyl S-(4-methoxyphenyl) phosphorothioate (3ad)
Colorless oil (114.7 mg, 0.46 mmol, 83% yield). 1H NMR (500
MHz, CDCl3) δ 7.48-7.46 (m, 2H), 6.89 (d, J = 8.7 Hz, 2H), 4.23-4.12
(m, 4H), 3.81 (s, 3H), 1.33-1.30 (m, 6H). 13C NMR (125 MHz, CDCl3)
δ 160.5 (d, J = 2.5 Hz), 136.3 (d, J = 5.0 Hz), 116.6 (d, J = 7.5 Hz),
115.0 (d, J = 1.3 Hz), 64.0 (d, J = 6.3 Hz), 55.3, 16.0 (d, J=7.5 Hz).
MS(EI), m/z 276.05 [M+, 62%], 139.95 (100%).
2.2. Electrochemical characterization
Cyclic voltammetry measurements were carried out on CHI600e
electrochemical workstation (CH Instrument Inc. Austin, TX, USA).
The experiments were measured with an L-type Pt electrode (3
mm diameter) as the working electrode in a 25 mL undivided cell
with acetonitrile (CH3CN) as the solvent and sodium tetrafluorobo-
rate (NaBF4) as the supporting electrolyte. Another Pt electrode (1.5
cm × 1.5 cm) was employed as the counter electrode and Ag/Ag+
electrode (0.1 mol/L AgNO3 in CH3CN) was as the reference elec-
trode.
2.4.5. O,O-Diethyl S-(4-isopropylphenyl) phosphorothioate (3ae)
Colorless oil (125.3 mg, 0.44 mmol, 87% yield).1H NMR (500
MHz, CDCl3) δ 7.49-7.47 (m, 2H), 7.21 (d, J = 8.3 Hz, 2H), 4.25-
4.15 (m, 4H), 2.93-2.88 (m, 1H), 1.33-1.30 (m, 6H), 1.24 (d, J = 7.0
Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 150.1 (d, J = 3.8 Hz), 134.7
(d, J = 3.8 Hz), 127.6 (d, J = 2.5 Hz), 123.0 (d, J = 6.3 Hz), 64.0,
33.8, 23.8, 16.0 (d, J = 6.3 Hz). MS(EI), m/z 288.05 [M+, 8%], 91.00
(100%).
In situ FTIR spectroscopy experiments were measured on Nico-
let 670 FTIR spectrometer, which was equipped with liquid-
nitrogen-cooled MCT-A detector. The working electrode was a Pt
disk (6 mm in diameter). A three-electrode spectro-electrochemical
cell with CaF2 window at the bottom was used. The reference po-
tential was selected at -600 mV. Each spectrum was collected at 8
cm−1 resolution at different potential.
2.4.6. S-(4-(tert-Butyl)phenyl) O,O-diethyl phosphorothioate (3af)
Colorless oil (105.0 mg, 0.36 mmol, 70% yield).1H NMR (500
MHz, CDCl3) δ 7.50-7.47 (m, 2H), 7.37 (d, J = 8.4 Hz, 2H), 4.25-4.15
(m, 4H), 1.33-1.30 (m, 15H); 13C NMR (125 MHz, CDCl3) δ 152.4 (d,
J = 3.8 Hz), 134.3 (d, J = 5.0 Hz), 126.5 (d, J = 1.3 Hz), 122.8 (d,
J = 6.3 Hz), 64.0 (d, J = 5.0 Hz), 34.7, 31.2, 16.0 (d, J = 7.5 Hz).
MS(EI), m/z 301.81 [M+, 8%], 70.08 (100%).
2.3. Typical electrolysis experiments
Electrolysis experiments were performed in a 25 mL undi-
vided cell using Vertex Potentiostat/Galvanostat. Two Pt elec-
trodes (1.5 cm × 1.5 cm) were employed as the working elec-
trode and the counter electrode, respectively. The Ag/Ag+ elec-
trode (0.1 mol/L AgNO3 in CH3CN) was used as the reference elec-
trode. NaBF4/CH3CN solution (0.1 mol/L, 15 mL), triethyl phosphite
(1a, 0.5 mmol), 4-methylbenzenethiol (2a, 0.9 mmol) and KI (0.08
mmol) were added into the cell. Then the electrolysis reaction was
carried out at the potential of 0.2 V at 40 °C with stirring. When
the reaction was finished (monitored by GC or TLC), the result-
ing mixture was concentrated under reduced pressure. Finally, the
residue was purified by column chromatography on silica gel us-
ing petroleum ether : ethyl acetate (8 : 1) as eluent to afford O,O-
diethyl S-(p-tolyl) phosphorothioate (3aa) as colorless oil in 85%
yield.
2.4.7. O,O-Diethyl S-(4-fluorophenyl) phosphorothioate (3ag)
Colorless oil (108.6 mg, 0.41 mmol, 82% yield). 1H NMR (500
MHz, CDCl3) δ 7.57-7.54 (m, 2H), 7.07-7.04 (m, 2H), 4.25-4.12 (m,
4H), 1.33-1.30 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 163.4 (dd,
J = 249, 2.5 Hz), 136.7 (dd, J = 13.8, 5.0 Hz), 121.7 (dd, J = 11.3,
3.8 Hz), 116.5 (dd, J = 25, 1.3 Hz), 64.2 (d, J = 6.3 Hz), 16.0 (d,
J = 6.3 Hz). MS(EI), m/z 263.86 [M+, 10%], 82.93 (100%).
2.4.8. S-(4-Chlorophenyl) O,O-diethyl phosphorothioate (3ah)
Colorless oil (126.0 mg, 0.45 mmol, 90% yield). 1H NMR (500
MHz, CDCl3) δ 7.51-7.49 (m, 2H), 7.32 (d, J = 8.5 Hz, 2H), 4.24-4.14
(m, 4H), 1.33-1.25 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 135.8 (d,
J = 6.3 Hz), 135.5 (d, J = 2.5 Hz), 129.5 (d, J = 1.3 Hz), 125.1 (d,
J = 7.5 Hz), 64.2 (d, J = 6.3 Hz), 16.0 (d, J = 7.5 Hz). m/z 279.90
[M+, 10%], 108.93 (100%).
2.4. Characterization data of products
2.4.1. O,O-Diethyl S-(p-tolyl) phosphorothioate (3aa)
2.4.9. S-(4-Bromophenyl) O,O-diethyl phosphorothioate (3ai)
Colorless oil (138.0 mg, 0.42 mmol, 85% yield). 1H NMR (500
MHz, CDCl3) δ 7.47 (d, J = 8.6 Hz, 2H), 7.44-7.42 (m, 2H), 4.24-4.12
(m, 4H), 1.33-1.30 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 135.9 (d,
J = 5.0 Hz), 132.5 (d, J = 2.5 Hz), 125.8 (d, J = 7.5 Hz), 123.6 (d,
J = 3.8 Hz), 64.2 (d, J = 6.3 Hz), 16.0 (d, J = 6.3 Hz). MS(EI), m/z
323.80 [M+, 8%], 109.06 (100%).
Colorless oil (110.5 mg, 0.43 mmol, 85% yield). 1H NMR (500
MHz, CDCl3) δ 7.46-7.44 (m, 2H), 7.15 (d, J = 8.0 Hz, 2H), 4.24-4.13
(m, 4H), 2.35 (d, J = 1.8 Hz, 3H), 1.33-1.30 (m, 6H); 13C NMR (125
MHz, CDCl3) δ 139.2 (d, J = 3.8 Hz), 134.5 (d, J = 5 Hz), 130.1 (d,
J = 2.5 Hz), 122.8 (d, J = 7.5 Hz), 63.91 (d, J = 6.3 Hz), 21.1, 15.9
(d, J = 5 Hz). MS(EI), m/z 260.11 [M+, 35%], 124.02 (100%).
2

L. Zhao, X. Liu, S. Shi et al.
Electrochimica Acta 389 (2021) 138748
2.4.10. S-(2,4-Dimethylphenyl) O,O-diethyl phosphorothioate (3aj)
Colorless oil (104.7 mg, 0.38 mmol, 76% yield). 1H NMR (500
MHz, CDCl3) δ 7.49-7.47 (m, 1H), 7.08 (s, 1H), 7.00-6.98 (m, 1H),
4.23-4.10 (m, 4H), 2.49 (s, 3H), 2.31 (d, J = 2.1 Hz, 3H), 1.32-1.29
(m, 6H); 13C NMR (125 MHz, CDCl3) δ 142.1 (d, J = 5.0 Hz), 139.7
(d, J = 3.8 Hz), 136.2 (d, J = 5.0 Hz), 131.7 (d, J = 1.3 Hz), 127.6 (d,
J = 2.5 Hz), 122.0 (d, J = 6.3 Hz), 64.0 (d, J = 6.3 Hz), 21.3, 21.1,
16.0 (d, J = 7.5 Hz), MS(EI), m/z 273.97 [M+, 10%], 105.12 (100%).
2I−3 − 2e− ꢀ 3I2
(2)
The oxidation of I− began at about -0.25 V and the first oxida-
tion peak at -0.07 V might be assigned to the formation of triiodine
−
anion I3 (Eq. (1)). The second oxidation peak at 0.32 V might be
−
−
related to the oxidation of I3 to I2 (Eq. (2)). Therefore, I3 and
I2 were always believed to be the key species in iodine-catalyzed
electrochemical reactions and participated in the catalytic cycle to
promote the reaction continuously [38–40].
2.4.11. O,O-Diethyl S-(naphthalen-2-yl) phosphorothioate (3ak)
Colorless oil (123.8 mg, 0.42 mmol, 84% yield). 1H NMR (500
MHz, CDCl3) δ 8.10 (s, 1H), 7.86-7.80 (m, 3H), 7.63 (d, J = 8.6 Hz,
1H), 7.54-7.51 (m, 2H), 4.29-4.17 (m, 4H), 1.34-1.31 (m, 6H); 13C
NMR (125 MHz, CDCl3) δ 134.4 (d, J = 6.8 Hz), 133.6 (d, J = 1.3
Hz), 133.0, 130.9 (d, J = 3.8 Hz), 129.0, 127.7 (d, J = 5.0 Hz), 127.0,
126.7, 123.8 (d, J = 7.8 Hz), 64.1 (d, J = 6.3 Hz), 16.0 (d, J = 6.3 Hz).
MS(EI), m/z 296.02 [M+, 12%], 115.10 (100%).
When both of 1a and KI were added in NaBF4/CH3CN solution,
the oxidation current for 1a increased sharply (curve a Fig. 1(A))
by comparison of curve b. In addition, the second peak current re-
lated to Eq. (2) disappeared. It was most likely that the oxidation
of 1a was promoted by I3−. However, without KI under the sim-
iliar conditions, almost no voltametric response for the oxidation
of 1a in NaBF4/CH3CN solution was observed (curve c). Therefore,
1a was difficult to be oxidized at low potential directly and its
oxidation could be effectively catalyzed by the presence of KI in
NaBF4/CH3CN solution. Only at high potential, electrochemical oxi-
dation of 1a could take place in the absence of KI, which could be
proved by the cyclic voltammogram shown in curve d Fig 1(B).
Subsequently, the reaction of 2a and KI has been investigated
by cyclic voltammetry. As shown in Fig. 2 (A), there was no obvi-
ous oxidation peak when 2a was added in NaBF4/CH3CN solution
without KI (curve f), but the oxidation peak current rose sharply
with the addition of KI at the potential higher than 0.05 V (curve
e). Thus KI played an important role for the oxidation of 2a [41,42].
In situ time-resolved FTIR spectra were applied to analyze the
reaction of 2a and KI in NaBF4/CH3CN solution and collected dur-
ing reaction of 2a (1.8 mmol) and KI (0.32 mmol) in 0.1 mol/L
NaBF4/CH3CN solution at the potential of 50 mV. The positive-
going and negative-going peaks represent material consumption
and product generation respectively [43]. As shown in Fig. 2(B), the
positive bands at 2562 and 1495 cm−1 were attributed to stretch-
ing vibration of S–H band and benzene ring vibration of 2a, re-
spectively [44]. At the same time, the negative-going peaks at 1485
cm−1 represented skeleton vibration of the benzene ring of 1,2-di-
p-tolyldisulfane which was generated from 2a. Combined with the
results of cyclic voltammetry and in situ FTIR, it could be found
that 1,2-di-p-tolyldisulfane was formed at about 0.05 V.
2.4.12. O,O-Diethyl S-(thiophen-2-yl) phosphorothioate (3al)
Colorless oil (94.5 mg, 0.38 mmol, 75% yield). 1H NMR (500
MHz, CDCl3) δ 7.45-7.43 (m, 1H), 7.28-7.24 (m, 1H), 7.05-7.03 (m,
1H), 4.28-4.20 (m, 4H), 1.37-1.34 (m, 6H); 13C NMR (125 MHz,
CDCl3) δ 136.1 (d, J = 7.5 Hz), 131.0 (d, J = 3.8 Hz), 127.8 (d, J = 2.5
Hz), 123.2 (d, J = 8.8 Hz), 64.4 (d, J = 6.3 Hz), 16.0 (d, J = 7.5 Hz).
MS(EI), m/z 251.96 [M+, 31%], 115.9 (100%).
2.4.13. O,O-Diethyl S-(benzyl) phosphorothioate (3am)
Colorless oil (62.4 mg, 0.24 mmol, 48% yield). 1H NMR (500
MHz, CDCl3) δ 7.39-7.28 (m, 5H), 4.16-4.12 (m, 2H), 4.07-4.02 (m,
4H), 1.32-1.28 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 137.5 (d,
J = 5.0 Hz), 128.9, 128.7, 127.6, 63.5 (d, J = 5.0 Hz), 29.7 (d, J = 5.0
Hz), 16.0 (d, J = 6.3 Hz), MS(EI), m/z 260.08 [M+, 30%], 91.03
(100%).
2.4.14. O,O-Disopropyl S-(p-tolyl) phosphorothioate (3ba)
Colorless oil (128.2 mg, 0.45 mmol, 89% yield). 1H NMR (500
MHz, CDCl3) δ 7.48-7.46 (m, 2H), 7.13 (d, J = 7.95 Hz, 2H), 4.79-
4.72 (m, 2H), 2.32 (d, J = 1.2 Hz, 3H), 1.32 (d, J = 6.2 Hz, 6H), 1.25
(d, J = 6.2 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 138.8 (d, J = 2.5
Hz), 134.3 (d, J = 6.3 Hz), 129.9 (d, J = 2.5 Hz), 123.5 (d, J = 7.5
Hz), 73.1 (d, J = 6.3 Hz), 23.8 (d, J = 3.8 Hz), 23.5 (d, J = 6.3 Hz),
21.1. MS(EI), m/z 288.09 [M+, 52%], 153.94 (100%).
With the addition of 1a and 2a in the NaBF4/CH3CN solution
in the presence of KI, the current started to rise at about -0.2 V
(curve h Fig. 3(A)). Moreover, two oxidation peaks were clearly ob-
served at around 0 V and 0.67 V. The obvious peak at around 0 V
might be caused by the reaction of 1a and 2a mediated by I3−. The
oxidation peak at about 0.67 V might be related to the reaction
of 1,2-di-p-tolyldisulfane and 1a. For comparison, cyclic voltam-
mogram was also collected in NaBF4/CH3CN without KI under the
similar conditions. It showed that current for electrochemical oxi-
dation of 1a and 2a was small at low potential (curve g), illustrat-
ing that electro-oxidation reaction of them was quite slow. In or-
der to better understand the electrochemical reaction of 1a and 2a,
high potential scanning was applied and the result was presented
in Fig. 3(B). High anodic current was clearly observed at about 1.90
V (curve i), and it indicated that only high potential helped to re-
alize the high conversion of the reaction without KI.
2.4.15. O,O-Dibutyl S-(p-tolyl) phosphorothioate (3ca)
Colorless oil (121.4 mg, 0.38 mmol, 77% yield). 1H NMR (500
MHz, CDCl3) δ
7.46-7.43 (m, 2H), 7.15 (d, J = 8.0 Hz, 2H), 4.17-4.05 (m, 4H),
2.34 (d, J = 1.8 Hz, 3H), 1.65-1.60 (m, 4H), 1.38-1.34 (m, 4H), 0.92-
0.89 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 139.2 (d, J = 3.8 Hz),
134.6 (d, J = 5.0 Hz), 130.1 (d, J = 2.5 Hz), 122.9 (d, J = 7.5 Hz),
67.7 (d, J = 7.5 Hz), 32.1 (d, J = 6.3 Hz), 21.1, 18.6, 13.5. MS(EI), m/z
316.04 [M+, 7%], 91.09 (100%).
3. Results and discussion
3.1. Electrochemical analysis
The electrochemical cross-coupling reaction of triethyl phos-
phite (1a, 0.5 mmol) with 4-methylbenzenethiol (2a, 0.9 mmol)
catalyzed by KI (0.08 mmol) was carried out in 0.1 mol/L
NaBF4/CH3CN solution by cyclic voltammetry between -0.6 V and
0.8 V at the scan rate of 50 mV/s. Cyclic voltammogram of KI in
NaBF4/CH3CN solution was collected and shown in curve b Fig. 1
(A). The specific reaction process of KI on the electrode surface
might consist of the following steps [36,37]:
In addition, the cross-coupling reaction between 1a and 2a was
also investigated with in situ FTIR technique, which was carried
out in 0.1 mol/L NaBF4/CH3CN solution in the presence of 1a (2.0
mmol), 2a (2.0 mmol) and KI (0.32 mmol) at potentials varied from
-600 mV to 300 mV. As shown in Fig. 3(C), four important posi-
tive bands at 2562, 1495, 1025 and 926 cm−1 and three negative
bands at 1258, 1062 and 977 cm−1 could be observed. Two impor-
tant positive-going peaks at 2562 and 1495 cm−1 associated with
2a were observed. The positive bands at 1025 and 926 cm−1 were
3I− − 2e− ꢀ I−3
(1)
3

L. Zhao, X. Liu, S. Shi et al.
Electrochimica Acta 389 (2021) 138748
0.16
0.12
0.08
0.04
0.00
-0.04
(B)
(A)
0.24
0.18
0.12
0.06
0.00
a:1a+KI
b:KI
c:1a
d
d: 1a
a
b
c
-0.6 -0.4 -0.2 0.0 0.2 0.4 0.6 0.8
0.0
0.4
0.8
1.2
1.6
2.0
2.4
ꢀ
ꢀ
E/V vs. Ag/Ag
E/V vs. Ag/Ag
Fig. 1.. (A) Cyclic voltammograms recorded in 0.1 mol/L NaBF4/CH3CN from -0.6 V to 0.8 V at the scan rate of 50 mV/s in the presence of (a) 1a (0.5 mmol) and KI (0.08
mmol); (b) KI (0.08 mmol); (c) 1a (0.5 mmol). (B) Cyclic voltammogram recorded in 0.1 mol/L NaBF4/CH3CN from 0 V to 2.4 V at the scan rate of 50 mV/s with (d) 1a (0.5
mmol).
1.0
(A)
e
0.8
e: 2a+KI
f: 2a
0.6
b: KI
0.4
f
0.2
b
0.0
-0.6 -0.4 -0.2 0.0 0.2 0.4 0.6 0.8
ꢀ
E/V vs. Ag/Ag
Fig. 2. (A) Cyclic voltammograms recorded in 0.1 mol/L NaBF4/CH3CN between -0.6 ~ 0.8 V at the scan rate of 50 mV/s in the presence of (b) KI (0.08 mmol); (e) 2a (0.9
mmol) and KI (0.08 mmol); (f) 2a (0.9 mmol). (B) In situ time-resolved FTIR spectra collected during reaction of 2a (1.8 mmol) and KI (0.32 mmol) in 0.1 mol/L NaBF4/CH3CN
solution at the potential of 50 mV.
attributed to stretching vibrations C–O(P) and P–O(C) of 1a, respec-
tively [45]. The four positive bands were related to the consump-
tion of 1a and 2a.
4 h (Table 1, entry 1). When the amount of 2a was decreased to
1.6 equiv., the selectivity to 3aa declined to 76% (Table 1, entry 2),
indicating that the ratio of reactants was an important factor for
the reaction. Therefore, the following two reactions were carried
out. The reaction with equal equivalent of 1a and 2a failed to pro-
vide satisfactory result (Table 1, entry 3). A 100% conversion of 2a
with 56% selectivity to 3aa was obtained by treatment of 1.0 equiv.
2a with 1.6 equiv. of 1a (Table 1, entry 4). It showed that excess
of 2a was conducive to the reaction, which might be due to two
reasons. On the one hand, excessive 2a was beneficial to inhibit
hydrolysis reactions of 1a and intermediate, which could improve
the selectivity to 3aa [48]. On the other hand, when 1a was
converted into the target product, the released ethyl radical could
react with 2a to generate the by-product ethyl(p-tolyl)sulfane
which was detected by GC-MS. Thus, 1.8 equiv. of 2a was used
in the following experiments. Decreasing the loading of KI to 8
mol% gave a lower conversion and selectivity (Table 1, entry 5).
An improvement for the selectivity to 3aa (89%) was obtained
when the loading of KI was increased to 12 mol% (Table 1, entry
6). These results encouraged us to further screen the loading of KI
(Table 1, entries 7 and 8). It was found that 100% converison of
1a with 92% selectivity to 3aa was achieved in the presence of 16
The negative band at 1062 cm−1 was attributed to the stretch-
ing vibration C–O(P). When the valence of phosphorus changes
from 3 to 5, the absorption peak of P–O shifted to a high wave
number value [45,46]. Thus the negative peak at 977 cm−1 was
assigned to the stretching vibration of P–O single bond of 3aa. In
addition, the P=O bond formed at 1258 cm−1 was increased with
the depletion of 1a [45,47]. Based on the above infrared analysis,
the corresponding product 3aa has been generated. So synthesis of
3aa could be carried out sucessfully from 1a and 2a at low poten-
tial in the present of KI.
3.2. Optimization of electrolysis experiment conditions
As an initial attempt, triethyl phosphite (1a) and 4-
methylbenzenethiol (2a) were selected as the model substrates to
ensure the optimal conditions and the results were summarized
in Table 1. It was found that a good selectivity to 3aa (84%) was
attained when 1a reacted with 1.8 equiv. of 2a in the 0.1 mol/L
NaBF4/CH3CN solution at the potential of 0.4 V with 10 mol% KI in
4

L. Zhao, X. Liu, S. Shi et al.
Electrochimica Acta 389 (2021) 138748
0.20
0.15
0.10
0.05
0.00
1.6
1.2
0.8
0.4
0.0
(A)
(B)
i: 1a+2a
h
h:1a+2a+KI
b: KI
g:1a+2a
i
0.030
0.015
0.000
b
0.4
0.8
ꢀ
E/V vs. Ag/Ag
g
-0.6 -0.4 -0.2 0.0 0.2 0.4 0.6 0.8
0.0
0.4
0.8
1.2
1.6
2.0
2.4
ꢀ
ꢀ
E/V vs. Ag/Ag
E/V vs. Ag/Ag
Fig. 3. (A) Cyclic voltammograms recorded in 0.1 mol/L NaBF4/CH3CN between -0.6 ~ 0.8 V at the scan rate of 50 mV/s in the presence of (g) 1a (0.5 mmol) and 2a (0.9
mmol); (b) KI (0.08 mmol); (h) 1a (0.5 mmol), 2a (0.9 mmol) and KI (0.08 mmol). (B) Cyclic voltammogram recorded in 0.1 mol/L NaBF4/CH3CN between 0 ~ 2.4 V at the
scan rate of 50 mV/s in the presence of (i) 1a (0.5 mmol) and 2a (0.9 mmol). (C) In situ FTIR spectra collected during the reaction of 1a (2.0 mmol), 2a (2.0 mmol) and KI
(0.32 mmol) in 0.1 mol/L NaBF4/CH3CN solution at potentials varied from -600 mV to 300 mV.
mol% of KI. Thus 16 mol% of KI was appropriate for the following
experiments. As a comparison, we carried out the reaction under
N2 atmosphere, and the result was the same as that under air
atmosphere (Table 1, entry 9).
3.3. Control experiments and plausible mechanism
To gain insight into the reaction mechanism, a series of control
experiments were conducted (Scheme 1). When the reaction of 1a
and 2a performed under the standard conditions (1a (0.5 mmol),
2a (0.9 mmol), KI (0.08 mmol), NaBF4/CH3CN (0.1 mol/L), 0.2 V,
40 °C, 4 h.), the isolated yield of 3aa was 85% (Scheme 1, Eq. (3)).
However, no expected product was observed without electric cur-
rent (Scheme 1, Eq. (4)), and only trace amount of 3aa could be
detected in the absence of KI (Scheme 1, Eq. (5)). These results
revealed that KI and electricity played important roles in this elec-
trochemical reaction. Treatment of 2a to the standard conditions,
1,2-di-p-tolyldisulfane (4) could be obtained in excellent isolated
yield (Scheme 1, Eq. (6)). Then, 78% isolated yield of 3aa could
be achieved in the reaction of 4 and 1a (Scheme 1, Eq. (7)). In
addition, when TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) was
added as the radical scavenger, the isolated yield of 3aa was de-
creased sharply to 37% (Scheme 1, Eq. (8)). This result showed that
a radical pathway might be involved in this reaction. According
to Fig. 2(A), 2a could hardly be oxidized at the potential of -0.1
V. Decreasing the potential to -0.1 V, 26% isolated yield of 3aa
Decreasing the reaction temperature from 40 to 25 °C, the con-
version of 1a was 92% even if the reaction time was prolonged
to 6 h (Table 1, entry 10). Thus, 40 °C was chosen for the fol-
lowing experiments. Next, the potential was investigated. When
the potential was set at 0.2 V, the conversion of 1a and selectiv-
ity to 3aa were high as that at 0.4 V (Table 1, entry 11). There-
fore, 0.2 V might be high enough for this reaction. In addition,
an 81% conversion of 1a with 90% selectivity to 3aa was achieved
by the use of carbon rod as the anode instead of platinum plate
(Table 1, entry 12). Platinum as the anode was slightly better for
this reaction. When the reaction of 1a and 2a was carried out in
nBu4NBF4/CH3CN, the conversion of 1a was 100% and the selec-
tivity to 3aa was 88% (Table 1, entry 13). Electrolyte might have
little effect on this reaction. Taking into the comprehensive con-
sideration, the optimized conditions for this reaction were per-
formed at 0.2 V under air atmosphere with 16 mol% KI for 4 h in
NaBF4/CH3CN solution using platinum as the anode and cathode.
5

L. Zhao, X. Liu, S. Shi et al.
Electrochimica Acta 389 (2021) 138748
Table 1.
Optimization of electrolysis experiment conditionsa.
Entry
1a (equiv.)
2a (equiv.)
Potential (V)
T (°C)
KI (mol%)
Conv.b,c
Select.c,d
1
2
3
4
5
6
7
8
1
1.8
1.6
1
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.2
0.2
0.2
40
40
40
40
40
40
40
40
40
25
40
40
40
10
10
10
10
8
98
98
67
84
76
64
56
82
89
92
93
92
92
92
90
88
1
1
e
1.6
1
1
100
1.8
1.8
1.8
1.8
1.8
1.8
1.8
1.8
1.8
84
1
12
16
20
16
16
16
16
16
98
1
100
100
100
92
1
f
9
1
g
10
1
11
1
100
81
h
12
1
i
13
1
100
a
Electrolytic conditions: 1a (0.5 mmol), Pt anode, Pt cathode, 0.1 mol/L NaBF4/CH3CN solution (15
mL), 4 h.
b
c
d
e
f
Conversion of 1a.
Determined by GC with peak area normalization method.
Selectivity to 3aa.
Conversion of 2a.
Under N2 atmosphere.
g
h
i
Reaction time: 6 h.
C anode, Pt cathode.
0.1 mol/L nBu4NBF4/CH3CN solution (15 mL).
Scheme 1. Control experiments. Standard conditions: 1a (0.5 mmol), 2a (0.9 mmol), KI (0.08 mmol), NaBF4/CH3CN (0.1 mol/L), 0.2 V, 40 °C, 4 h.
was obtained by the reaction of 1a and 2a in the presence of KI
(Scheme 1, Eq. (9)). It indicated that 2a could be involved directly
in this reaction without previous oxidation.
[51,52]. After radical 6 was captured by P(OEt)3, radical intermedi-
ate 7 was formed. Then the product 3aa was produced via β scis-
sion of ethoxyl group [53–55]. Finally, radical 6 reacted with ethyl
radical to produce the side product ethyl(p-tolyl)sulfane (8) which
could be detected in the reaction mixture.
Based on control experiment results and literatures, a plausible
mechanism was proposed in Scheme 2. Initially, I− was oxidized
−
to I3 at the anode, and then iodophosphate 5 was formed from
1a and I3−. Iodophosphate 5 would easily react with 2a by nucle-
ophilic substitution, giving the desired product 3aa [49,50].
In addition, another pathway might be involved in this reac-
tion. Disulfide 4 was formed from 2a in the presence of I2. Radi-
cal 6 would be generated by homolytically cleavage of disulfide 4
3.4. Coupling of aryl thiols with trialkyl phosphites by indirect
electro-oxidation
With the optimized conditions in hand, we applied this elec-
trochemical system for the cross-coupling of aryl thiols with tri-
6

L. Zhao, X. Liu, S. Shi et al.
Electrochimica Acta 389 (2021) 138748
Scheme 2. Plausible mechanism.
alkyl phosphites. Firstly, the coupling of triethyl phosphite (1a)
with a variety of thiophenols (2a–m) was investigated, and the
results were shown in the Table 2. The reactions of p, o, m-
methylbenzenethiols with 1a gave the corresponding phosphoroth-
ioates 3aa, 3ab and 3ac in 85%, 81% and 83% isolated yields re-
spectivily, which could be inferred that steric hindrance had lit-
tle effect on the reaction. Benzenethiols bearing electron-rich or
electron-neutral substituents such as p-OCH3, p-iPr and p-nBu un-
derwent coupling with 1a smoothly to provide the desired phos-
phorothioates 3ad–af in 70%–87% isolated yields. Furthermore, aryl
thiols with electron withdrawing groups (p-F, p-Cl and p-Br) could
successfully couple with 1a to afford the corresponding products
(3ag–ai) in high isolated yields. When 2,4-dimethylbenzenethiol
was subjected to the reaction, S-(2,4-dimethylphenyl) O,O-
diethyl phosphorothioate (3aj) could be obtained in 76% isolated
yield.
3.5. Coupling of aryl thiols with trialkyl phosphites by galvanostatic
electrolysis
Potentiostatic electrolysis and galvanostatic electrolysis have
their own unique advantages, and have a wide range of applica-
tions in electrochemical synthesis. Therefore, galvanostatic electrol-
ysis experiments have also been performed and the results were
shown in Table 3. According to Faraday’s law, the required elec-
trolysis time were 965 s, 2412 s and 9648 s, respectiviely, when
the electrolysis current were 50 mA, 20 mA and 5 mA. However,
only 40% conversion of 1a with 70% selectivity to 3aa was obtained
at 50 mA for 965 s (Table 3, entry 1). Conducting this reaction at
20 mA for 2412 s gave 56% conversion of 1a and 83% selectivity to
3aa (Table 3, entry 2). When the reaction was performed at 5 mA
for 9648 s, the conversion of 1a and the selectivity to 3aa were in-
creased to 69% and 86% respectively (Table 3, entry 3). Prolonging
the reaction time to 14400 s, 1a could be completely converted
with 82% selectivity to 3aa (Table 3, entry 4). These results indi-
cated that more electrolysis time was needed at a low current, but
product selectivity was increased.
In addition to these benzenethiols, naphthalene-2-thiol worked
well with 1a under the standard conditions to gave the product
3ak in 85% isolated yield. Pleasingly, the scope of the aryl thi-
ols could be extended to heteroaromatic benzenethiol. For exam-
ple, when thiophene-2-thiol was used as the substrate, the iso-
lated yield of 3al was 75%. Besides, benzyl mercaptan (2m) could
react with 1a to form the desired product in 48% isolated yield.
Relevant attempts about aliphatic compounds have also been car-
ried out. It was a pity that only trace amount of target prod-
ucts could be detected. The scope of trialkyl phosphites was also
investigated. Both triisopropyl phosphite (1b) and tributyl phos-
phite (1c) could react with 4-methylbenzenethiol smoothly, and
the desired products 3ba and 3ca were achieved in good isolated
yields.
3.6. Coupling of aryl thiols with trialkyl phosphites by direct
electrochemical oxidation
According to Fig. 3(B), the peak current at about 1.90 V for oxi-
dation of 1a and 2a in NaBF4/CH3CN solution without KI was quite
high. Thus, the electrolysis experiments without KI have also been
carried out. As shown in Table 4, almost no target product was ob-
tained at the potential of 0.2 V (Table 4, entry 1). Although the se-
lectivity to 3aa was increased to 56% at the potential of 0.4 V, the
7

L. Zhao, X. Liu, S. Shi et al.
Electrochimica Acta 389 (2021) 138748
Table 2
Electrochemical coupling of trialkyl phosphites with aryl thiolsa.
a
Electrolytic conditions: 1 (0.5 mmol), 2 (0.9 mmol), KI (0.08 mmol), Pt anode, Pt cathode, 0.1 mol/L NaBF4/CH3CN solution (15 mL),
0.2 V, 40 °C, 4 h. Isolated yields.
conversion of 1a was only 17% (Table 4, entry 2). Increasing the po-
tential to 0.9 V, an 89% conversion of 1a with 30% selectivity to 3aa
was achieved (Table 4, entry 3). Using the potential of 1.4 V gave
98% conversion of 1a and 17% selectivity to 3aa (Table 4, entry 4).
When the potential was further increased to 1.6 V, the conversion
was up to 100%, but the selectivity to 3aa was decreased to 14%
(Table 4, entry 5). A lower selectivity to 3aa (12%) was obtained at
the potential of 1.8 V (Table 4, entry 6). These results indicated that
over-oxidation occurred and more by-products would be produced
at high potential.
What’s more, the reaction of different aryl thiols and 1a were
performed by direct electrochemical oxidation at 0.9 V. It was
8

L. Zhao, X. Liu, S. Shi et al.
Electrochimica Acta 389 (2021) 138748
Table 3.
Acknowledgments
Galvanostatic electrolysis experiments for 1a and 2aa.
Entry
Time (s)
Current (mA)
Conv.b,c
Select.c,d
This work was financially supported by National Natural Science
Foundations of China (21773211 and 21776260) and Key Research
and Development Project of Zhejiang Province (No. 2021C01079).
1
2
3
4
965
50
20
5
40
70
83
86
82
2412
9648
14400
56
69
5
100
a
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