Reactions of Disulfides with Silyl Phosphites to Generate Thiophosphates Under Neat Conditions

Article abstract of DOI:10.1002/cssc.201800236

An efficient procedure for the synthesis of thiophosphates is described. Without using any metallic catalyst or base, the direct sulfur–phosphorus coupling reaction of disulfides and dialkyl trimethylsilyl phosphite (DTSP) was carried out under solvent-fr

Full text of DOI:10.1002/cssc.201800236

Accepted Article
Title: Clean and green reactions of disulfides with DTSP generating
thiophosphates under neat reaction condition
Authors: Zhen Zhan, Zhongzhen Yang, Dena Ma, Hao Zhang, Yuesen
Shi, Qiantao Wang, Yong Deng, Li Hai, and Yong Wu
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10.1002/cssc.201800236
ChemSusChem
COMMUNICATION
Clean and green reactions of disulfides with DTSP generating
thiophosphates under neat reaction condition
Zhen Zhan+, Zhongzhen Yang+, Dena Ma, Hao Zhang, Yuesen Shi, Qiantao Wang, Yong Deng, Li Hai*
and Yong Wu*
Abstract: An efficient protocol for the synthesis of thiophosphates is
described. Without using any metallic catalyst, base and solvent, the
direct sulfur-phosphorus bond coupling reaction of disulfides and
dialkyl trimethylsilyl phosphite (DTSP) was promoted under neat
reaction condition in moderate to excellent yields with good
functional group compatibility. The reaction condition is superior to
other methods not only in predigesting process but also in
shortening the reaction time apparently. Notably, these
transformations are easy to conduct and can be readily applied to
gram-scale preparation.
transition metal catalysts, unstable carbene organocatalysts,
oxidants, and/or longer reaction time, an alternative strategy to
generate thiophosphates via a simple and environmentally
benign protocol is still in great demand.
The S-P bond forming reaction is immensely valuable and has
always been the unremitting pursuit in the field of medicine
synthesis due to the widely application of thiophosphates in
many therapeutic agents.[1] Apart from these applications,
thiophosphates are also known as pesticides in agrochemistry
(Scheme 1A).[2]
Consequently, thiophosphates are of enormous interests and
numerous methodologies have been developed to construct the
S-P(O) frameworks. Traditional methods for the preparation of
thiophosphates are often based on nucleophilic substitution
using RSX or R2P(O)X, which suffers drawbacks such as
tedious procedures, low yields and lack of functionality
tolerance.[3,5e] In 2013, Kaboudin and co-workers have found
that copper(I) iodide catalyzed coupling of H-phosphine
oxides/H-phosphonates with thiols proceeds effectively in the
presence of triethylamine (Scheme 1B).[4] Afterwards, N-
chlorosuccinimide or peroxide-mediated reactions have been
successfully applied to activate thiols for S-P(O) bond formation,
but these approaches are only suitable for highly active
diphenylphosphine oxides (Scheme 1C).[5] Recently, Han and
co-workers reported an efficient Pd-catalyzed dehydrogenative
phosphorylation of the readily available P(O)H compounds with
thiols to produce phosphorothioates in high yields while
stoichiometric amounts of styrene and high reaction temperature
were required for this coupling reaction (Scheme 1D).[6] In 2017,
Jiao and co-workers presented the first example of direct
oxidative cross-coupling of thiols with P(O)H compounds for the
construction of S-P(O) bonds via Cs2CO3 catalysis to produce
phosphorothioate derivatives at 30oC under O2 atmosphere
(Scheme 1E).[7] Furthermore, impressive results were obtained
by using N-heterocyclic carbenes (NHCs) as organocatalyst to
promote the challenging reactions in dry toluene (Scheme 1F).[8]
As these strategies for S-P(O) bond formation require expensive
Scheme 1. Application and strategies for the preparation of phosphinothioates.
Key Laboratory of Drug-Targeting of Education Ministry and Department of
Medicinal Chemistry, West China School of Pharmacy
Sichuan University
Chengdu 610041 (P. R. China)
E-mail: smile@scu.edu.cn; wyong@scu.edu.cn
In this context, we are interested in developing a convenient
and “greener” protocol for S-P(O) bond formation. This new
strategy, without using any catalyst, oxidants and even solvents
in the reaction, has excellent yields. It is superior to other
traditional approaches not only in its green and predigesting
process but also in its much shortened reaction time.
Supporting information for this article is given via a link at the end of the
document
[+] These authors contributed equally to this work.
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As we all know, disulfides are important sulfur source in
building P-S bonds, which have been proved to be more stable
and have less odor in comparison with thiols. Under this
background, we conducted a coupling reaction of 1,2-di-p-
chlorodisulfide 1a with diethyl trimethylsilyl phosphite 2a. To our
delight, the initial investigations revealed that 1a and 2a reacted
smoothly to afford the desired product 3a in MeCN at room
temperature without using any oxidants or metals or bases
under an air atmosphere for 20 min (Table 1, entries 1-3). A very
high yield (92%) of thiophosphinate 3a was produced when 2.0
equiv of 2a was employed (Table 1, entry 4). The use of
1:2.0
1:1.0
1:1.2
1:1.5
1:2.0
1:2.0
1:2.0
1:2.0
1:2.0
MeOH
THF
60
40
30
60
40
60
20
2
trace
80
8
9
DMF
90
10
11
12
13
14
15
16
toluene
DMSO
dioxane
NR
81
66
Diethyl
ether
87
dichloromethane,
acetone,
ethyl
acetate,
N,N-
/
95
dimethylformamide and diethyl ether as a solvent was similarly
effective (87-90%, Table 1, entries 5-7, 10 and 14). The S-P(O)
bond coupling reaction also proceeded in THF, DMSO and 1,4-
dioxane (Table 1, entries 9, 12-13). However, the reaction did
not proceed well in toluene even the reaction time was
prolonged (Table 1, entry 11).
/
5
96
[a] Reaction conditions: 0.5 mmol 1,2-di-p-chlorodisulfide (1a), 1.0 mmol
diethyl trimethylsilyl phosphite (2a), [b] 31P NMR yield using
triphenylphosphine as an internal standard. NR = no reaction.
Green chemistry is a set of principles and practices that aim to
reduce the use of hazardous materials in chemical products and
processes. The concept of neat reaction is now widely adopted
to meet the scientific challenges of protecting environment while
simultaneously achieving commercial viability. The trend in the
field is oriented to explore alternative reaction conditions and
reaction media to accomplish the desired chemical
transformations with minimum waste generation, as well as to
eliminate the use of conventional organic solvents.[9] Much to our
delight, the targeted product 3a was obtained in 95% yield
without any solvent under neat reaction conditions (Table 1,
entry 15). The yield of 3a did not improve significantly when the
reaction was run for 5 min (Table 1, entry 16). The result shows
that the neat reaction condition is superior to other different
solvents not only in predigesting process but also in shortening
the reaction time apparently (Fig. 1). Herein, we demonstrate the
first example of a neat reaction of disulfides with dialkyl
trimethylsilyl phosphite to produce thiophosphinates. Without
using any metals or bases or oxidants, thiophosphates can be
obtained in excellent yields.
Figure 1. Variation of isolated yield of thiophosphates with change in neat
condition and different solvents. Conditions: 0.5 mmol 1,2-di-p-chlorodisulfide
(1a), 1.0 mmol diethyl trimethylsilyl phosphite (2a).
After optimizing the reaction conditions with disulfides (1a)
and commercially available diethyl trimethylsilyl phosphite (2a)
as model system. We also explored several other substituted
silylphosphites in this reaction. These reagents were either
commercially available or readily synthesized in one step by the
Table 1. Optimization of the reaction conditions.[a]
silylation of the corresponding phosphonates with TMSCl
12]
(trimethylsilyl chloride) in the presence of Et3N.[10,
Efficient
product formation was also observed by applying dimethoxyl
(trimethyl)silyl phosphite (Table 2, entry 1) and chloromethyl-
substitutde silyl phosphite (Table 2, entry 2), furnishing the
corresponding thiophosphate 3x in an excellent yield.
Substituents on the phosphite nucleophiles did not lead to an
obvious difference in reactivity. Other alkyl like triethyl-
triisopropyl, and chloromethyl-substituted phosphites (2d-2g)
also survived, facilitating further functionalization of the products
Entry
1a:2a (equiv.)
1:1.0
Solvent
MeCN
Time (min)
Yield (%)b
60
30
20
20
20
20
20
80
85
89
92
90
87
90
1
2
3
4
5
6
7
1:1.2
MeCN
MeCN
MeCN
DCM
1:1.5
1:2.0
(3a). Strikingly,
a
benzene ring derivative was also
1:2.0
phosphorylated in 95% yield under the optimized reaction con
ditions (2h). Isopropyl-substituted phosphite 2i was also proved
to be a good substrate (Table 2, entry 8). Interestingly,
silylphosphites bearing two nonidentical alkoxy and phenyl sub-
1:2.0
acetone
EA
1:2.0
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COMMUNICATION
Table 2. Phosphite scope of the coupling reaction.[a]
Scheme 2. Scope of the coupling reactions.[a]
Entry
1
Phosphite
Product
Yield (%)b
81
2b
2c
2
3
95
94
3x
2d
4
5
6
2e
2f
93
90
96
3a
2g
7
8
2h
95
85
2i
3y
9
2l
81
83
3aa
[a] Reaction conditions: 0.5 mmol disulfides (1), 1.0 mmol diethyl trimethylsilyl
phosphite (2a). Yields of isolated products are given. [b] time = 10 min, [c] time
= 5 min.
10
2m
3ab
[a] Reaction conditions: 0.5 mmol 1,2-di-p-chlorodisulfide (1a), 1.0 mmol
silylphosphites (2), [b] Yields of isolated products are given.
With the optimized reaction conditions in hand, the scope of
the reaction was studied, various disulfides (1) were first tested
with diethyl trimethylsilyl phosphite (2a) as the reaction partner
to produce the corresponding thiophosphates (3) in good to
excellent yields (Scheme 2). Electronic effects on the aryl thiols
did lead to a less obvious difference in reactivity, diaryl disulfides
with methyl, methoxyl and tert-butyl substituent at the para-,
meta- and ortho- position of the aromatic ring all furnished the
stituents were also investigated (Table 2, entries 9). Notably,
dialkyl(trimethyl)silyl phosphite furnished the desired product in
good yields (Table 2, entries 10).
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10.1002/cssc.201800236
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desired thiophosphates in good yields (see 3c, 3d, 3g, 3r and
3w), but the substrates with electron-withdrawing groups like
cyano coupled less readily with diethyl trimethylsilyl phosphite,
generating the coupling products in reduced yield (3k). Halogens
like chloro-, fluoro- and bromo- groups were well tolerated (see
3a, 3e-f and 3u). To our delight, sensitive groups, such as free
amine and hydroxyl, were well persevered under oxidative
conditions and gave good yields (see 3l and 3m). Besides,
functionalities including amide, ester, ketone, olefin and sulfonyl
groups also gave excellent yields (see 3i-3j, 3n, 3p, 3s and 3t).
However, naphthalene-2-disulfide and benzyl disulfide were
proved to have lower yields (see 3h and 3v). Meanwhile, the
ortho- substituted substituent (3t) revealed less reactivity when
compared with their para- analogs (3j). Strikingly, a benzyloxy-
group derivative was also phosphorylated in 90% yield under the
optimized reaction conditions (3q). In addition, the disulfide
scope of the coupling reactions was not limited to the phenyl
disulfides with same substituents (Scheme 2A), instead, the
heteroaryl disulfides (see 3ac, 3ad and 3ae) and different
substituents (see 3af and 3ag) could also be coupled with
diethyl trimethylsilyl phosphite to afford the corresponding
thiophosphates in moderate to excellent yields (Scheme 2B).
functionalized thiophosphates. Without using any oxidants,
metals or bases, thiophosphates, which are widely present in
agrochemicals and therapeutic molecules, can be obtained in
good to excellent yields under mild conditions and much shorter
reaction time. The transformation is easy to conduct and can be
scaled-up with good functional group tolerability. This strategy
would therefore of great interest in medicinal chemistry and
organic chemistry. Further investigation of this method will focus
on the detailed mechanism and applications in organic synthesis.
Experimental Section
General information
Unless otherwise indicated, all reactions were performed under air
atmosphere in glass tube equipped with a magnetic stir bar. Solvents
were purified and dried according to standard methods prior to use. All
the reactions were monitored by thin-layer chromatography (TLC) and
visualization was accomplished with UV light. The products were purified
by flash column chromatography on silica gel (100-200 meshes). All new
compounds were characterized by NMR spectroscopy, high resolution
mass spectroscopy (HRMS), and melting point (if solids). Proton and
carbon nuclear magnetic resonance spectra (1H NMR and 13C NMR)
were recorded on a Varian INOVA-400/54, Agilent DD2-600/54 in CDCl3
with TMS as the internal standard (1H NMR: TMS at 0.00ppm, CHCl3 at
7.260 ppm; 13C NMR: CDCl3 at 77.16 ppm) and 31P NMR spectra were
obtained by using the same NMR spectrometers and data were relative
to H3PO4 (85% solution in D2O, 0 ppm). Coupling constants are given in
Hz. Chemical shifts (δ) were reported as parts per million (ppm)
downfield from tetramethylsilane and the following abbreviations were
used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet, br = broad and all combinations thereof can be
explained by their integral parts. HRMS spectra were recorded on a
Waters Q-TOF Premier. Melting points (m.p.) were recorded on an
INESA SGW X-4 melting point apparatus. Commercial reagents from
Adamas Reagent Co., Ltd., Best Reagent, Astatech Chemical
Technology Co., Ltd. and etc were used without further purification. High-
resolution mass spectra were recorded using the EI method with a
double focusing magnetic mass analyzer. Unless otherwise noted, the
yields of products reported were all isolated yields.
Scheme 4. Gram-scale reaction.
Subsequently, to illustrate the practical synthetic utility of our
methodology, a scale-up reaction was conducted to demonstrate
the utility of ultrasound promoted P-S bonds coupling reaction.
As shown in Scheme 4, under the standard conditions, 2.80 g
(10.0 mmol) of 1a could be converted to 3a in 90% yield.
General procedure for the coupling of disulfides with silyl phosphites
An oven-dried sealed tube equipped with a magnetic stir bar was
charged with 1,2-bis(4-chlorophenyl)disulfane (0.5 mmol, 1.0 equiv.) and
diethyl (trimethylsilyl) phosphite (1.0mmol, 2.0 equiv.) under an air
atmosphere. The resulting mixture was vigorously stirred at room
temperature for 2 min. After this time, the crude product was further
purified by column chromatography on silica gel to afford desired product.
Scheme 5. Proposed mechanism.
Based on the experimental results and previously reported
works,[13] the proposed mechanism of the synthesis of
thiophosphates derivatives was outlined in Scheme 5. Initially,
the dialkyl trimethylsilyl phosphite (2) was coordinated to the
disulfide (1) to generate S-P intermediate 2’. Subsequently, 2’
was attacked by the nucleophile formed by disulfide to provide
the corresponding thiophosphate 3.
In summary, we have established a very green and simple
methodology for coupling reactions between disulfides and
diethyl trimethylsilyl phosphite under neat reaction condition.
Different substituted silylphosphites and disulfides have been
utilized in this study, providing a clean and effective access to
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (NSFC) (grant numbers 81373259,
81573286 and 81602954).
Conflicts of interest
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[4]
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There are no conflicts to declare.
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Keywords: S-P bond coupling • neat reaction • thiophosphates •
disulfides • dialkyl trimethylsilyl phosphite
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COMMUNICATION
Zhen Zhan+, Zhongzhen Yang+, Dena
Ma, Hao Zhang, Yuesen Shi, Qiantao
Wang, Yong Deng, Li Hai* and Yong
Wu*
Page No. – Page No.
Clean and green reactions of
disulfides with DTSP generating
thiophosphates under neat reaction
condition
Text for Table of Contents
An efficient protocol for the synthesis of thiophosphates is described. Without using any metallic catalyst, base and solvent, the direct
sulfur-phosphorus bond coupling reaction of disulfides and dialkyl trimethylsilyl phosphite (DTSP) was promoted under neat reaction
condition in moderate to excellent yields with good functional group compatibility. The reaction condition is superior to other methods
not only in predigesting process but also in shortening the reaction time apparently. Notably, these transformations are easy to
conduct and can be readily applied to gram-scale preparation.
This article is protected by copyright. All rights reserved.