Electrochemical Dehydrogenative Phosphorylation of Thiols

Article abstract of DOI:10.1021/acs.orglett.9b02825

We report herein a new approach for the synthesis of organothiophosphates from phosphonates and thiols through electrochemical reaction. The reactions were conducted without the addition of oxidant, transition-metal base, or base at room temperature. This

Full text of DOI:10.1021/acs.orglett.9b02825

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Electrochemical Dehydrogenative Phosphorylation of Thiols
Chung-Yen Li,† You-Chen Liu,† Yi-Xuan Li,† Daggula Mallikarjuna Reddy,† and Chin-Fa Lee*,†,‡,§
†Department of Chemistry, National Chung Hsing University, Taichung City 402, Taiwan, R.O.C.
‡Research Center for Sustainable Energy and Nanotechnology (RCSEN), National Chung Hsing University, Taichung City 402,
Taiwan, R.O.C.
§Innovation and Development Center of Sustainable Agriculture (IDCSA), National Chung Hsing University, Taichung City 402
Taiwan, R.O.C.
S
* Supporting Information
ABSTRACT: We report herein a new approach for the
synthesis of organothiophosphates from phosphonates and
thiols through electrochemical reaction. The reactions were
conducted without the addition of oxidant, transition-metal
base, or base at room temperature. This system has a good
substrate scope and functional group tolerance. Aryl and alkyl
thiols worked well with phosphonates to afford the
corresponding organothiophosphates in good yields.
Scheme 1. Methods for P(O)−S Bond Formation
rganothiophosphates are ubiquitous structural motifs
that have crucial biological and chemical properties and,
O
furthermore, are employed in many fields such as pharma-
ceutical industry, organic synthesis, and pesticide chemistry.1
Structure−activity relationship studies also revealed that many
organothiophosphates display notable biological activities.1j,k
Consequently, the development of novel strategies for
synthesizing organothiophosphates is highly desirable. Con-
ventionally, the synthesis of organothiophosphates has often
been achieved through substitution reaction of R2P(O)X or
RSX; this always results in limitations, for example, low
functional group tolerance and tedious procedures.2 Bearing in
mind the importance of organothiophosphates as therapeutics
and agrochemicals, considerable advancements have been
achieved in their preparation.3−7 In 2014, we have developed a
method for preparing thiophosphates through N-chlorosucci-
nimide-promoted P(O)−S bond formations (Scheme 1a).2l
Among the methods developed thus far for the formation of
P(O)−S bonds, the oxidative cross-dehydrogenative coupling
(CDC) reactions from the P(O)−H bond and S−H bond have
become the most attractive path due to issues of atom
economy and increasing the reaction efficiency.3−6
In 2016, Han et al. developed a palladium-catalyzed CDC
reaction to prepare organothiophosphates from thiols and
phosphonates at 100 °C (Scheme 1b).4 Visible-light-mediated
oxidative cross-coupling reaction of thiols with phosphonates is
known for the synthesis of organothiophosphates (Scheme
1c,d).5,6
Over the past decade, organic electrosynthesis has been
acknowledged as an environmentally benign and mild synthetic
tool for various organic transformations.7,8 Furthermore,
various simple and elegant electrochemical CDC reactions
for making carbon−carbon and carbon−heteroatom bonds
have been extensively studied.9−11 However, a P(O)−S bond
formation by electrochemical CDC reaction is not well-
established. Herein, we report the first electrochemical
oxidative CDC of thiols with phosphonates in an undivided
cell under remarkably mild reaction conditions (Scheme 1e).
To investigate the optimized electrochemical conditions for
P(O)−S bond formation, we first selected di-n-butyl phosphite
(1a) and 4-methoxythiophenol (2a) as substrates. Experiments
Received: August 9, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02825
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
to optimize of the electrochemical CDC reaction indicated that
With optimized reaction conditions in hand, we next
investigated the scope of substrates in this electrochemical
coupling reaction (Scheme 2). Thiophenols bearing electron-
the highest yield (72%) of thiophosphate 3a was obtained by
n
conducting electrolysis in an electrolyte solution of Bu4NI in
CH3CN by using a platinum anode and a platinum cathode
with 12 mA at room temperature for 7 h (Table 1, entry 1).
a
Scheme 2. Scope of the Electrochemical CDC Reaction
Table 1. Screening of Electrochemical CDC Reaction of
a
P(O)−S Bond Formation
entry
variation from the standard conditions
none
yield (%)
1
2
3
4
72
n
NH4I instead of Bu4NI
ND
ND
25
n
LiClO4 instead of Bu4NI
n
nBu4NBF4 instead of Bu4NI
n
5
nBu4NBr instead of Bu4NI
41
n
6
7
8
9
without Bu4NI
ND
54
61
trace
19
23
68
63
68
72
CH3OH instead of CH3CN
DMF instead of CH3CN
CH2Cl2 instead of CH3CN
9 mA instead of 12 mA
15 mA instead of 12 mA
under N2
under air
6 h of reaction time
8 h of reaction time
1.8 equiv of thiol instead of 2.0 equiv
graphite rod as anode
diphenyl disulfide (1.0) instead of 2a
with TEMPO (2 equiv)
10
11
12
13
14
15
16
17
18
19
a
Reaction conditions: platinum plate anode (0.5 mm × 0.5 mm × 10
cm), platinum plate cathode (0.5 mm × 0.5 mm × 10 cm), 1 (1.0
mmol), 2 (2.0 mmol), nBu4NI (1.0 mmol), acetonitrile (4 mL), room
temperature, argon atmosphere, 7 h.
69
61
72
52
withdrawing and electron-donating groups at different
positions on the phenyl ring proceeded to give the
thiophosphates 3a−p in good yields (35−79%). For example,
when methyl and methoxy groups were present at the ortho-,
meta-, and para-positions of the arylthiol, the corresponding
thiophosphates (3a−3f) were obtained in moderate to good
yields. Furthermore, thiophenol coupled well with di-n-butyl
phosphite under the reaction conditions and produced
thiophosphate (3g) in a moderate yield. The use of thiols
containing electron-withdrawing groups for this electro-
chemical CDC reaction provided the products in lower yields
(3h and 3i). Bulky alkyl substituents on the aryl group of thiol
did not considerably affect the yield of the product, obtaining it
in moderate to good yields (3j−3l). In addition to these thiols,
disubstituted arylthiols worked well with di-n-butyl phosphite
under the reaction conditions, producing the corresponding
thiophosphates (3m−3p) in good yields. In addition to the use
of di-n-butyl phosphite, we also used diethyl phosphite (1b) to
couple with aryl thiols, affording the corresponding thiophos-
phates in moderate yields (3q−3s).
After successful coupling of arylthiols with di-n-butyl
phosphite (1a) and diethyl phosphite (2a) under electro-
chemical CDC conditions, we also used alkylthiols to couple
with di-n-butyl phosphite and obtained the corresponding
thiophosphates (5a−5d) in good yields. When we used
diphenyl phosphite (1c) as a coupling partner to react with n-
hexylmercaptan (4c), the corresponding product (5e) was
obtained in lower yield (Scheme 3).
Successful development of the electrochemical dehydrogen-
ative phosphorylation of thiols encouraged us to perform cyclic
voltammogram (CV) experiments to know the redox behavior
of the reactions (Figure 1). In curve b (in the absence of
a
Standard conditions: platinum plate anode (0.5 mm × 0.5 mm × 10
cm), platinum plate cathode (0.5 mm × 0.5 mm × 10 cm), 1a (1.0
mmol), 2a (2.0 mmol), Bu4NI (1.0 mmol), solvent (4 mL), room
temperature, argon atmosphere, 7 h. Isolated yields. ND = not
detected.
n
n
No product was detected when Bu4NI was replaced with
other electrolytes such as NH4I and LiClO4, whereas in the
n
n
presence of Bu4NBF4 or Bu4NBr it was isolated in lower
yields (Table 1, entries 2−5). No product was formed in the
absence of nBu4NI during the reaction (Table 1, entry 6). The
use of CH3OH or DMF as solvent in place of acetonitrile
produced inferior results compared with acetonitrile (Table 1,
entries 7 and 8). When CH2Cl2 was used as the solvent, only a
trace amount of 3a was detected (Table 1, entry 9). Both a
decrease and an increased in current provided lower product
yields (Table 1, entries 10 and 11, respectively). Moreover,
when the reaction was performed under a nitrogen
atmosphere, a decrease in the product yield was observed,
and under an air atmosphere, a lower yield was obtained
(Table 1, entries 12 and 13, respectively). Decreasing or
increasing the reaction times lowered the formation of product
(Table 1, entries 14 and 15, respectively). A slightly lower yield
was observed when thiol was loaded with decreased
equivalents (Table 1, entry 16). The choice of electrode
material proved critical; only 61% of the product was isolated
when we used a graphite rod as the anode (Table 1, entry 17).
When diphenyl disulfide was used, 3a was obtained with 72%
yield (Table 1, entry 18). The product was formed with 52%
yield in the presence of 2 equiv of TEMPO (Table 1, entry
19). This result might rule out the radical mechanism.
B
DOI: 10.1021/acs.orglett.9b02825
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Scope of the Alkylthiols in the Electrochemical
CDC Reaction
Scheme 4. Proposed Mechanism for P−S Bond Formation
a
a
Reaction conditions: platinum plate anode (0.5 mm × 0.5 mm × 10
cm), platinum plate cathode (0.5 mm × 0.5 mm × 10 cm), 1 (1.0
mmol), 4 (2.0 mmol), nBu4NI (1.0 mmol), acetonitrile (4 mL), room
temperature, argon atmosphere, 7 h.
thiolate anion and thiyl radical, and thiolate anion would react
with the iodophosphate to afford the product.
In summary, we have developed an efficient and green
electrochemical dehydrogenative P−H/S−H cross coupling
for synthesis of thiophosphates. This reaction protocol avoids
the use of external chemical oxidants; H2 is the only byproduct.
Under undivided electrolytic conditions, a series of thiophos-
phates can be obtained in moderate to good yields. In this
reaction case, electrochemical external oxidant-free dehydro-
genative cross-coupling demonstrated a green approach
compared to the traditional oxidative cross-coupling protocol,
which may inspire people to use electrochemical methods in
more oxidative cross-coupling reactions.
Figure 1. Cyclic voltammograms of reactants and the mixtures in 0.1
M LiClO4/CH3CN using a glassy carbon-disk working electrode
(diameter, 3 mm). Pt disk as counter; Ag/AgCl as reference electrode,
at 100 mV/s scan rate: (a) background, (b) 1a (10 mmol/L), (c)
nBu4NI (2 mmol/L), (d) 1a (10 mmol/L) + nBu4NI (2 mmol/L), (e)
1a (10 mmol/L) + 2a (10 mmol/L), and (f) 1a (10 mmol/L) + 2a
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02825.
n
(10 mmol/L) + Bu4NI (2 mmol/L).
Experimental procedures, spectroscopic data, copies of
NMR and crystallographic data (PDF)
nBu4NI), 1a shows no oxidation peak (0.0−1.0 V versus Ag/
n
n
AgCl) without Bu4NI. The CV of Bu4NI had two oxidation
peaks at 0.53 and 0.83 V (curve c), which correspond to the
oxidation of I− to I3− and I3− to I2, respectively. A similar curve
AUTHOR INFORMATION
■
n
Corresponding Author
*E-mail: cfalee@dragon.nchu.edu.tw.
ORCID
was displayed when 1a and Bu4NI were combined (curve d).
Thus, 1a cannot be oxidized to its corresponding radical.
Interestingly, we found that the CV of the mixture of 1a and 2a
presented an oxidation peak at 1.38 V, and we thought 2a went
through oxidation and formed disulfide without addition of
electrolyte (curve e). The CV of the mixture of 1a, 2a, and
nBu4NI demonstrated an apparent oxidation peak at 1.01 V
(curve f), which illustrated there had been a chemical
interaction between the three compounds.
Chin-Fa Lee: 0000-0003-0735-5691
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
On the basis of the above observations and literature
reports,11b a proposed mechanism of electro-oxidative P−H/
S−H cross coupling is depicted in Scheme 4. First, I2 will be
This work was financially supported by the Ministry of Science
and Technology, Taiwan (MOST 107-2113-M-005-019-
MY3), National Chung Hsing University, Research Center
for Sustainable Energy and Nanotechnology, and the
“Innovation and Development Center of Sustainable Agricul-
ture” from The Featured Areas Research Center Program
within the framework of the Higher Education Sprout Project
by the Ministry of Education (MOE) in Taiwan. We also thank
n
generated from Bu4NI in the reaction mixture, and I2 can
oxidize phosphonate and thiol to iodophosphate and sulfenyl
iodide, respectively.12 Disulfide is well-known to occur from
thiol through an electrochemical approach.11b Cathodic
reduction of the disulfide would generate the corresponding
C
DOI: 10.1021/acs.orglett.9b02825
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Organic Letters
Letter
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voltammogram instruments.
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