Iodide-Catalyzed Phosphorothiolation of Heteroarenes Using P(O)H Compounds and Elemental Sulfur

Article abstract of DOI:10.1002/adsc.201900291

Organothiophosphates have found widespread application as biologically active compounds and synthetic intermediates in medicinal chemistry. The first transition-metal-free one-pot direct synthesis of heterocyclic phosphorothioates involving indole or imidazo[1,2-a]pyridine derivatives, elemental sulfur, and P(O)H compounds is presented. The use of NaI or KI as a catalyst, tert-butyl hydroperoxide as an oxidant, various indole and imidazo[1,2-a]pyridine derivatives are tolerant in this transformation, affording the corresponding products in good to excellent yields. Moreover, this method can be easily adapted to large-scale preparation. O,O-Diethyl S-(1-phenyl-1H-indol-3-yl) phosphorothioate presents potent anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated RAW264.7 cells in a dose-dependent manner. (Figure presented.).

Full text of DOI:10.1002/adsc.201900291

Title: Iodide-Catalyzed Phosphorothiolation of Heteroarenes Using
P(O)H Compounds and Elemental Sulfur
Authors: Shanshan Shi, Jun Chen, Shaohua Zhuo, Zi’ang Wu, Meijuan
Fang, Guo Tang, and Yufen Zhao
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900291
Link to VoR: http://dx.doi.org/10.1002/adsc.201900291

Advanced Synthesis & Catalysis
10.1002/adsc.201900291
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Iodide-Catalyzed Phosphorothiolation of Heteroarenes Using
P(O)H Compounds and Elemental Sulfur
a
b
a
a
b,
Shanshan Shi, Jun Chen, Shaohua Zhuo, Zi’ang Wu, Meijuan Fang, * Guo
a,
a
Tang, *and Yufen Zhao
a
Department of Chemistry, College of Chemistry and Chemical Engineering, and the Key Laboratory for Chemical
Biology of Fujian Province, Xiamen University, Xiamen, Fujian 361005, China
Fax: (+86)-592-218-5610; e-mail: t12g21@xmu.edu.cn
b
School of Pharmaceutical Sciences and Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen
University, Xiamen, Fujian 361005, China
E-mail: fangmj@xmu.edu.cn; t12g21@xmu.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201######.((Please delete if not appropriate))
Abstract. Organothiophosphates have found widespread application as biologically active compounds and
synthetic intermediates in medicinal chemistry. The first transition-metal-free one-pot direct synthesis of
heterocyclic phosphorothioates involving indole or imidazo[1,2-a]pyridine derivatives, elemental sulfur, and
P(O)H compounds is presented. The use of NaI or KI as a catalyst, tert-butyl hydroperoxide as an oxidant,
various indole and imidazo[1,2-a]pyridine derivatives are tolerant in this transformation, affording the
corresponding products in good to excellent yields. Moreover, this method can be easily adapted to large-scale
preparation. O,O-Diethyl S-(1-phenyl-1H-indol-3-yl) phosphorothioate presents potent anti-inflammatory activity
in lipopolysaccharide (LPS)-stimulated RAW264.7 cells in a dose-dependent manner.
Keywords: phosphorothiolation; heteroarenes; elemental sulfur; tert-butyl hydroperoxide
moisture sensitive RSX or P(O)-X,[5a] or by the
condensation reaction between phosphorylation
Introduction
Organophosphorus compounds bearing C-S-P(O)
bonds have received increasing attention for more
than 60 years due to their well-documented biological
properties in the fields of pharmaceuticals and
agrochemicals, such as kitazin, vamidothion,
fosthiazate,
azamethiphos,
edifenphos
and
ethoprophos.[
1]
Recently,
S,S,S-tris(4-
fluorophenyl)phosphorotrithioate was found potent
anti-inflammatory activity and lower cytotoxicity
(
Figure
1).[
2]
In
antisense
drugtherapy,
phosphorothionate subunit imparts greater metabolic
[3]
stability to the oligonucleotides than phosphate unit.
Additionally, phosphorothioates are also the
important synthetic intermediates for a variety of
complex molecules in organic synthesis.
Generally, S-aryl phosphorothioates are prepared
either by the nucleophilic substitution of the toxic and
Figure 1. Selected agrochemicals of phosphorothioates.
[4]
reagents and thiols.[5b-d] In recent two years, Han and
Jiao reported the direct dehydrogenative coupling of
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201900291
P(O)H groups with thiols.[6] Wu, Cui, Hong and
Kumaraswamy developed the sulfenylation of H-
As one of the most important heterocyclic
compounds, indole represents an important structural
component of a vast number of biologically active
compounds, such as almotriptan and frovatriptanetc.
On the other hand, the imidazo[1,2-a]pyridine
scaffold constitutes the fundamental structure of
various drug molecules such as zolpidem, olprinone
and zolimidine. Therefore, the demand for indole and
imidazo[1,2-a]pyridine derivatives has stimulated
extensive studies of the structural modifications of
these two scaffolds to discover and develop novel
[7]
phosphonates with arylsulfonyl derivatives. In
009, our group reported the direct coupling of
P(O)H compounds with diaryl disulfides in the
2
[8a]
presence of catalytic amounts of copper iodide.
016, we successfully reported the preparation of S-
aryl phosphorothioates via Cu-catalyzed
phosphorothiolations of arylboronic acids,
diazonium, or -iodonium salts with R P(O)H
In 2018, the
In
2
-
2
[9a-b]
compounds and sulfur powder.
[13]
Gooßen group developed a phosphorothiolation
reagent, O,O-dimethyl-S-(N-phthalimido)phosphoro-
thioate, which enabled the phosphorothiolation of
therapeutic agents.
Among them, direct carbon–
hydrogen bond functionalization is a more convenient
method for the formation of carbon–heteroatom bond
[14]
diversely
functionalized
alkyl [
halides,
on indole and imidazo[1,2-a]pyridine rings. We
10]
arenediazonium salts, arylboronic acids. However,
these aryl precursors and phosphorothiolation reagent
are usually prepared through complicated multistep
reactions. Futhermore, additional procedures have to
be used to reduce the amount of residual transition
metals in order for the final products to qualify as
pharmaceutical ingredients.
speculated that, if both a (RO) P(O)S group and a
2
heteroarene structural motif can be simultaneously
introduced into novel organic compounds, efficient
synthesis of phosphorothioheteroarenes might be
expected. Further it would provide an opportunity to
introduce a phosphorothioate group into the original
lead compounds to adjust their bioactivities. The
synthesis and application of indoylphosphonates have
been studied deeply, however, the efficient synthesis
of indole or imidazo[1,2-a]pyridine bearing a
In recent years, the atom efficient cross
dehydrogenative coupling (CDC) has been widely
investigated for the formation of C-X bonds as it
[
11]
[10,14a-d]
eliminates the preparation of functional groups.
phosphorothioate group is quite rare.
The concept has also been explored regarding P-X
As a continuation of our endeavour to develop
bond formation.[ With regard to sulfur sources,
12]
step-economical syntheses of S-aryl phosphoro-
[2,8a,9a-b]
disulfides, thiols, sulfonyl
chlorides, sulfonyl
thioates,
we decided to investigate one-pot
hydrazines and sulfinic acids were well developed to
multi-component coupling of indoles or imidazo[1,2-
a]pyridines, elemental sulfur (S ), and P(O)H
compounds via transition-metal-free cross
dehydrogenative coupling reaction (Scheme 1).
construct C–S–P bonds. In comparison with those
8
aforementioned sulfur species, sulfur powder (S
8
) is
a
cheap and more abundant in nature. Utilization of
sulfur powder and involvement of CDC formation of
C(aryl)–S–P bond via a transition-metal-free system
should make this multicomponent reaction (MCR) Results and Discussion
much more attractive both fundamentally and
synthetically.
[
a]
Table 1. Reaction conditions optimization .
Entry Catalyst
Oxidant
air
TBHP
TBHP
TBHP
TBHP
Solvent
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
Yield (%)
1
2
3
4
5
6
7
8
9
1
I
I
KI
2
0
42
82
47
95
75
55
20
2
Bu
4
NI
NaI
NaI
NaI
--
NaI
NaI
H
O
2
O
2
2
(balloon) EtOH
TBHP
TBHP
TBHP
EtOH
Solvent
MeCN
[
b]
21-77
[
c]
0
a]
92, 0
[
TBHP: tert-butyl hydroperoxide (70% in water).
Isolated yield.
[
[
b]
c]
Solvent: CHCl
3
, toluene, THF, DMF.
Without CF COOH.
3
Scheme 1. Synthesis of organothiophosphates.
Initially, this idea was first examined by using
indole (1a), (EtO)
2
P(O)H (2a) and elemental sulfur as
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201900291
reaction partners (Table 1). An ethanol solution of
diisopropyl (2c), dibutyl (2d), and dibenzyl (2e) H-
phosphates all could be used as the substrates,
indole 1a, P(O)H 2a (1.2 equiv), and S (1.2
8
equiv)was successively treated with 1.2 molar
generating
the
corresponding
S-3-indolyl
o
equivalents of triethylamine (1.2 equiv, 60 C, 10 min)
phosphorothioindoles (3r-3u) in 82-95% yields.
and a catalytic oxidation process (a mixture of
3
Indoles having a reactive triple bond and a C(sp )-Br
CF
3
COOH, catalyst and an oxidizing agent). In the
could also be used in the reaction to give the desired
beginning, I
2
was tested as the catalyst under
S-3-indolyl phosphorothioates selectively without
aerobic conditions (entry 1), but no desired product
3
damaging the triple bond and C(sp )-Br (3v and 3w).
was observed. When tert-butyl hydroperoxide (TBHP,
2
equiv) was used as the oxidant at 60 °C for 8 h, the
The reaction of 1H-pyrrolo[2,3-b]pyridine did not
proceed at all (3x), and 1H-pyrrolo[2,3-b]pyridine
was recovered quantitatively. Diphenyl phosphine
oxide was also examined. Unfortunately, only trace
amounts of the desired product (3y) was detected by
desired product 3a was obtained in 42% yield (entry
). We were delighted to find that the C−H
phosphorothiolation in the presence of KI and Bu NI
provided 3a in 82% and 47% yields, respectively
entries 3 and 4). Gratifyingly, NaI as a catalyst could
further improve the reaction, giving 3a in 95% yield
entry 5). Hydrogen peroxide and O are also
2
4
(
31
P NMR.
(
2
Table 2. Synthesis of S-3-indolyl phosphorothioates
effective oxidants, producing 3a in 75% and 55%
yields (entries 6 and 7). Performing the reaction in
the absence of NaI resulted in the formation of
product 3a in low yield (entry 8). A brief survey of
some other solvents such as CHCl
DMF and CH CN, indicated that EtOH and CH
3
, toluene, THF,
CN
3
3
are both suitable solvents (entries 5, 9 and 10). No S-
indolyl phosphorothioate was obtained without any
acids (entry 10).
With the optimal conditions in hand (Table 1, entry
), the generality of the method was explored, and the
5
results were summarized in Table 2. Indoles with
electron-donating groups, such as 5-methyl, 7-methyl,
5
-methoxy and 4-benzyloxy on the benzene ring,
reacted with (EtO) P(O)H (2a) and elemental sulfur
2
efficiently and gave the desired products 3b-3e in
good to excellent yields (81%−90%). The electron-
withdrawing acyl groups led to the formation of
products 3f-3h in slightly lower yields (60%−86%).
Halogen atoms such as F, Cl, Br and I on the benzene
ring had no impact on the reaction which produced
the corresponding products 3i-3l in high yields
(
85%−90%), thus providing ample opportunity for
further elaboration by the transition-metal catalyzed
cross-coupling reactions. Then, we turned our
attention to examining the effect of N-substituents in
this reaction. No obvious differences in yield of 3
were observed (3m–3o, 3v). For example, product
3
m with N-methyl group was obtained in 92% yield;
and 3n with N-phenyl group was obtained in 91%
yield (3m and 3n vs 3a). The structure of 3n was
unambiguously confirmed by X-ray crystal structure
analysis (see Table 2 and the Supporting Information)
[16]
.
The indoles with N-methyl (3o), N-hydrogen (3g)
afforded the desired products in the same yields
under the standard conditions. These results indicated
that the species of substituents at the nitrogen atom of
indole had a low negative influence on the reaction.
Furthermore, both 2-methyl indole and more bulky
2
-phenyl indole could also react smoothly with 2a to
afford the expected products in high yields (3p 86%;
q 95%), indicating the steric effect of ortho
3
substituents exhibited slightly negative effects on the
thiophosphorylation reaction. In regard to the H-
phosphonates, in addition to 2a, dimethyl (2b),
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201900291
Encouraged by the findings described above, we
continued to explore the synthesis of S-aryl
hydrogen phosphorothioate (A) was used under the
standard conditions, phosphorylpersulfide B was
obtained quantitatively (eq. 2). Carrying out the
reaction of diethyl phosphorylpersulfide B and indole
[17]
phosphorothioates from imidazo[1,2-a]pyridines
.
To our delight, when imidazo[1,2-a]pyridines were
employed, the reaction took place under slightly
modified conditions. The optimal reaction conditions
are i) imidazo[1,2-a]pyridine (4a, 0.2 mmol), P(O)H
(
1a) generated phosphorotrithioate 3a in 50% or 98%
yield depending on the equivalents of B (0.5 equiv or
equiv, eq. 3). These results suggest that
1
phosphorylpersulfide B was the key intermediate.
(
2, 0.24 mmol), triethylamine (0.24 mmol),
potassium iodide (0.02 mmol) in acetonitrile (2 mL)
at 60 °C for 10 min; ii) CF COOH (0.5 mmol) and
This idea was examined by using indole (1a) and
(EtO) P(O)SH (A) as reaction partners. We were
2
3
delighted to find that the C−H phosphorothiolation in
the presence of NaI and TBHP provided 3a in 95%
yield (eq. 4). It was found that the reaction was
TBHP (0.4 mmol) at 60 °C for 2 h. It was found that
a wide range of imidazo[1,2-a]pyridines proceeded
efficiently (Table 3, 5a-5q). The steric hindrance has
no influence on the formation of 3-phosphorothio-
imidazo[1,2-a]pyridines (5b and 5d). Imidazo[1,2-
a]pyridine was also examined. Unfortunately, no
product (5r) was detected.
partially suppressed when I
2
was used instead of NaI
(
Table 1, entry 2). This result suggested that either
+
-
+
-
sodium hypoiodite (Na [IO] ) or iodite (Na [IO ] )
2
[15]
might be the catalytic species.
Based on the above experiments and previous
[9a-b]
research,
a plausible catalytic cycle is presented
in Scheme 3. Initially, the reaction between NaI and
TBHP would give the active intermediate sodium
Table 3. Scope of imidazo[1,2-a]pyridines
[15]
hypoiodite or iodite.
iodite promoted (EtO)
Then sodium hypoiodite or
P(O)SH (A) to form
2
phosphorylpersulfide B which would further react
with indole to afford the desired product 3a while
releasing (EtO) P(O)SH (A).
2
Scheme 2. Control experiments.
To gain insights into the mechanistic pathway,
several control experiments were performed (Scheme
Scheme 3. Tentative mechanistic pathway.
2
). When (EtO)
2
P(O)H (2a) was treated with
O,O-diethyl S-hydrogen
The inflammatory response is a very common and
essential pathological process in combating infection,
but can also induce tissue injury that may lead to
elemental sulfur,
phosphorothioate (A) was isolated in almost
quantitative yield (eq. 1). When O,O-diethyl S-
4
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Advanced Synthesis & Catalysis
10.1002/adsc.201900291
many diseases such as cardiovascular diseases,
[18]
rheumatoid arthritis, bronchitis, and cancers. The
pro-inflammatory cytokines such as interleukin 1 beta
(
IL-1), interleukin-6 (IL-6), and tumor necrosis
factor alpha (TNF-) are involved in the
inflammatory response as important inflammatory
mediators.[ Therefore, we evaluated the inhibitory
effects of S-3-indolyl phosphorothioates on the
mRNA expressions of IL-1, IL-6, and TNF- in
LPS-treated macrophage RAW264.7 cells by using
Real-time Quantitative PCR (qPCR) assay. Our data
indicated that compounds 3a, 3f, 3i, 3m, 3n, 3v, 5d,
19]
Figure 3. Compounds 3n inhibited the inflammatory genes
expression induced by LPS in mouse RAW 264.7 cells:
(
A) IL-1, (B) IL-6, and (C) TNF-. Data are the
mean±SD of each group of cells from three independent
experiments; *: 0.01 < p < 0.05, **: 0.001 < p < 0.01, ***:
p < 0.001 compared with LPS group.
5
i, and 5m showed potent anti-inflammatory activity
at a dose of 20 μmol/L (Figure 2(A)~2(C)). Among
active compounds, compound 3n showed the
strongest inhibitory effect on LPS-induced cytokine
expression and low toxicity with the cell viability of
Conclusion
In summary, we have successfully developed the first
example of the construction of S-3-indolyl
phosphorothioates and S-3-imidazo[1,2-a]pyridinyl
phosphorothioates via phosphorothiolation of indoles
and imidazo[1,2-a]pyridines with P(O)H compounds
and sulfur powder. The significance and advantages
of the method are: 1) the method is general,
producing a variety of products in high yields; 2) the
TBHP oxidant system is a transition-metal-free, cost-
effective, and environmentally benign system; 3) this
method can be easily adapted to large-scale
preparations; 4) the use of non-prefunctional
heteroarenes, P(O)H compounds and inorganic sulfur
8
2
0.89% at 20 μmol/L in RAW264.7 cells (Figure
(D)). Thus, we examined the effect of 3n at different
concentrations on LPS induced IL-1, IL-6, and
TNF- production in RAW264.7 cells. The effects of
compounds 3n on pro-inflammatory cytokine
production are shown in Figure 3. Treatment with 3n
at 2.5~20 μmol/L diminished the mRNA expressions
of IL-1, IL-6, and TNF- in RAW 264.7 cells in a
dose-dependent manner. Compound 3n displayed
inhibition toward IL-1, IL-6, and TNF- with IC50
values of 4.57±0.52 μmol/L, 9.95±0.68 μmol/L, and
13.03±1.70 μmol/L, respectively.
powder (S ) means that this facile protocol will be
8
attractive for academia and industry. Moreover, the
anti-inflammatory activities of the synthesized S-3-
indolyl phosphorothioates were evaluated using
qPCR assay in a LPS-stimulated inflammation model,
and compound 3n showed the most potent anti-
inflammatory activity.
Experimental Section
General procedure for the phosphorothiolation of
indoles
To an ethanol solution (2.0 mL) containing NaI (0.02
mmol, 3.0 mg), indole (0.2 mmol), R
and elemental sulfur (0.24 mmol, 7.68 mg) was added
NEt (0.24 mmol, 24.2 mg). The reaction mixture was
stirred at 60 °C for 10 minutes. Then, CF COOH (0.5
2
P(O)H (0.24 mmol),
3
3
Figure 2. The anti-inflammatory activities and
toxicity of active compounds: RAW264.7 cells were
stimulated in triplicate with 1 μg/mL LPS in the presence
or absence of individual compounds at 20 μmol/L for 12 h,
and the levels of (A) IL-1, (B) IL-6, and (C) TNF- in
the supernatants of each group of cells were determined by
qRT-PCR. The effect of compounds for cell viability of
RAW 264.7 cells is displayed in (D). Data are the
mean±SD of each group of cells from three independent
experiments; *: 0.01 < p < 0.05, **: 0.001 < p < 0.01, ***:
p < 0.001 compared with LPS group.
mmol) and tert-butyl hydroperoxide (70% in water, 0.4
mmol) were added to the system. The resulting mixture
o
was stirred at 60 C for 8 h. After completion, the crude
reaction mixture was purified by flash chromatography
using petroleum−AcOEt (3:1, v/v) as the eluent to give S-
3
-indolyl phosphorothioates 3.
General procedure for the phosphorothiolation of
imidazo[1,2-a]pyridines
To a CH
.3 mg), imidazo[1,2-a]pyridine(0.2 mmol), R
0.24 mmol), and elemental sulfur (0.24 mmol, 7.68 mg)
was added NEt (0.24 mmol, 24.2 mg). The reaction
mixture was stirred at 60 C for 10 minutes. Then,
CF COOH (0.5 mmol) and tert-butyl hydroperoxide
3
CN solution (2.0 mL) containing KI (0.02 mmol,
3
2
P(O)H
(
3
o
3
(
70% in water, 0.4 mmol) were added to the system. The
5
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Advanced Synthesis & Catalysis
10.1002/adsc.201900291
resulting mixture was stirred at 60 °C for 2 h. The crude
product was purified by column chromatography on
silica gel to obtain 3-phosphorothio-imidazo[1,2-
[8] a) Y. Gao, G. Tang, Y. Cao, Y. Zhao, Synthesis 2009,
1081; b) S. Mitra, S. Mukherjee, S. K. Sen, A. Hajra,
Bioorg. Med. Chem. Lett. 2014, 24, 2198; c) Y.-J.
Ouyang, Y. -Y. Li, N.-B. Li, X.-H. Xu, Chin. Chem. Lett.
a]pyridines 5.
2
013, 24, 1103.
[
9] a) L. Zhang, P. Zhang, X. Li, J. Xu, G. Tang, Y. Zhao,
J. Org. Chem. 2016, 81, 5588; b) J. Xu, L. Zhang, X.
Li, Y. Gao, G. Tang, Y. Zhao, Org. Lett. 2016, 18,
Acknowledgements
We thank NSFC (21772163, 21778042), Natural Science
1
266; c) X. Zhang, Z. Shi, C. Shao, J. Zhao, D. Wang,
Foundation
of
Fujian
Province
of
China
G. Zhang, L. Li, Eur. J. Org. Chem. 2017, 2017, 1884.
(
2018J01132), NFFTBS (J1310024), and the Fundamental
Research Funds for the Central Universities
20720180051).
[10]S. Kovács, B. Bayarmagnai, A. Aillerie, L. J. Gooßen,
(
Adv. Synth. Catal. 2018, 360, 1913.
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