Efficient Synthesis of Phenoxathiines via the Cascade C–H Hydroxylation–C–S Coupling–C–O Cyclization Reaction

Article abstract of DOI:10.1134/S1070363219120351

The ligand-free and simple cascade C–H hydroxylation–C–S coupling–C–O cyclization reaction has been used as the synthetic approach to disulfides and o-chloro-iodobenzenes using CuI as a catalyst. This approach provides an easy and convenient method of synthesis of phenoxathiin derivatives.

Full text of DOI:10.1134/S1070363219120351

ISSN 1070-3632, Russian Journal of General Chemistry, 2019, Vol. 89, No. 12, pp. 2558–2561. © Pleiades Publishing, Ltd., 2019.
Efficient Synthesis of Phenoxathiines via the Cascade C–H
Hydroxylation–C–S Coupling–C–O Cyclization Reaction
Fei Chaoa, Wen-Heng Xua, Zhi-Lin Renb, and Long Wanga,c*
a Key Laboratory of Inorganic Nonmetallic Crystalline and Energy Conversion Materials, College of Materials and Chemical
Engineering, China Three Gorges University, Yichang, Hubei, 443002 China
b College of Chemical Engineering, Hubei University of Arts and Science, Xiangyang, Hubei, 441053 China
c Material Analysis and Testing Center, China Three Gorges University, Yichang, Hubei, 443002 China
*e-mail: wanglongchem@ctgu.edu.cn
Received September 15, 2019; revised December 15, 2019; accepted December 18, 2019
Abstract—The ligand-free and simple cascade C–H hydroxylation–C–S coupling–C–O cyclization reaction has
been used as the synthetic approach to disulfides and o-chloro-iodobenzenes using CuI as a catalyst. This approach
provides an easy and convenient method of synthesis of phenoxathiin derivatives.
Keywords: ligand-free, disulfides, C–H hydroxylation, cascade reaction, phenoxathiines
DOI: 10.1134/S1070363219120351
INTRODUCTION
was synthesized by the facile tandem coupling reaction
using 2-hydroxyphenol and o-difluorobenzene with
strong electron withdrawing groups [3]. Later synthesis
of phenoxathiin derivatives by the cross coupling reac-
tion of 1-halo-2-nitroarenes and 2-sulfanylphenol was
developed [4].
Phenoxathiin derivatives are structural blocks of a
broad number of heterocyclic compounds that demon-
strate some potential as pharmaceuticals and sensors
[1,2]. Therefore, development of highly efficient synthetic
approach to phenoxathiin derivatives could be of consid-
erable importance. A series of phenoxathiin derivatives
The C–H hydroxylation with S atom as the directing
group, remains a challenging issue, because of the strong
Scheme 1. One-pot synthesis of phenoxathiin derivatives.
Previous work:
S
X
Y
SH
[M], Ligand
+
R
X = I or Br
ꢀ
O
OH
X = I, NO2
ꢀ ꢀ
ꢀ ꢀ
H hydroxylation
This work: disulfide-directed C S coupling C
C O cyclization stragegy
S
18
R
I
S
ꢀ
DMSO
O
S
18
O
H
Cl
C
2-H hydroxylation
In situ
Cascade reaction stragegy
ligand-free
sp
one-pot synthetic
[Cat.] CuI; (DG) Disulfide; (Oxidant) DMSO; (Solvent) DMSO.
2558

EFFICIENT SYNTHESIS OF PHENOXATHIINES
Table 1. Screening of reaction conditionsa
2559
S
Ph-p-Cl
I
S
S
+
H
Cl
Cl
Cl
O
1a
2a
3a
Entry
Catalyst
CuI
Base
Sovlent
Yield, %b
Entry
7
Catalyst
PdCl2
Pd(OAc)2
CuI
Base
Sovlent
DMSO
DMSO
DMF
Yield, %b
1
2
3
4
5
6
NaOH
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
<5
13
62
22
28
0
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
0
0
CuI
Na2CO3
Cs2CO3
K2CO3
Cs2CO3
Cs2CO3
8
CuI
9
<5
0
CuI
10
11
12
CuI
THF
CuCl
FeCl3
CuI
Toluene
DMSO
0
CuI
23c
a Conditions: 1a (0.5 mmol), 2a (0.6 mmol), catalyst (10 mol %), base (3 equiv), solvent (5 mL), 9 h, 120°C, N2. b Isolated yields. c 90°C.
coordination between sulfur and metal cations. The cop-
per-catalyzed Csp2-H hydroxylation involving arylthiols
and aryl iodides or arylboronic acids was reported [5–9].
Our group also described the disulfide-directed Csp2-H
hydroxylation reaction of disulfides and arylboronic acids
or aryl iodides [10].
RESULTS AND DISCUSSION
Initially, the reaction conditions were optimized using
disulfide (1a) and o-chloro-iodobenzene (2a) as model
substrates (Table 1) in the presence of different bases,
including KOH, Na2CO3, K2CO3 and Cs2CO3 (1.8 mmol).
Heating of the reaction mixture in DMSO (5 mL) at 120°C
for 9 h under the atmosphere of N2 (entries 1–4), gave the
desired product 3a. The highest yield 62% was achieved
by using Cs2CO3 as a base. That result initiated further
attempts in catalyst optimization. CuCl catalyst led to a
significantly lower yield (Table 1, entry 5). Upon applica-
The presented here study is a further development
of our prior research [11–20]. Here, the highly efficient
cascade C–H activation–C–S coupling–C–O cyclization
reaction catalyzed by CuI provided an easy and efficient
method of synthesis of phenoxathiin derivatives.
Table 2. Expansion of cascade C–H hydroxylation–C–S coupling–C–O cyclization reaction substratea
R1
S
S
I
CuI, 120o
C, N2
S
R1
R2
+
R1
R2
9 h
,
DMSO, Cs2CO3
H
O
Cl
1
2
3
Comp. no.
R1
R2
H
H
H
H
H
Yield, %b
Comp. no.
R1
R2
Yield, %b
3a
3b
3c
3d
3e
4-Cl
62
58
59
41
43
3f
3g
3h
3i
4-Cl
4-Cl
4-Cl
59
52
58
53
55
4-CH3
4-OCH3
2-Cl
5-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-Cl
2-CH3
3j
4-OCH3
a Conditions: 1 (0.5 mmol), 1 (0.5 mmol), 2 (0.6 mmol), CuI (10 mol %),Cs2CO3 (3 equiv), DMSO (5 mL), 9 h, 120°C, N2. b Isolated yields.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 12 2019

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FEI CHAO et al.
tion of FeCl3, PdCl2 or Pd(OAc)2 no desired product was
detected (Table 1, entries 6–8). The effect of solvents,
such as DMF, THF and toluene, was also tested, though
with no improvement of the yields (Table 1, entries 6–8).
Upon heating at temperature below 120 the reaction did
not occur (Table 1, entry 12). Based on the above screen-
ing, the optimized reaction conditions were determined to
be 10% CuI as a catalyst, 3 equiv of Cs2CO3 as an alkaline
reagent, DMSO as a solvent, 120°C, atmosphere of N2,
and the process time 9 h.
The compounds 3b–3j were synthesized according
to the above method from the appropriate compounds
(Table 2).
3-Methylphenoxathiine (3b). 1H NMR spectrum, δ,
ppm: 7.10–6.95 m (2H), 6.99–6.86 m (3H), 6.78–6.71 m
(2H), 2.22 s (3H).
3-Methoxyphenoxathiine (3c). 1H NMR spectrum,
δ, ppm: 7.10–7.00 m (2H), 6.98–6.85 m (3H), 6.55–6.47
m (2H), 3.72 s (3H).
1-Chlorophenoxathiine (3d). 1H NMR spectrum, δ,
ppm: 7.09–7.02 m (2H), 6.99–6.91 m (3H), 6.89 d (1H,
J = 8.0 Hz), 6.79 d (1H, J = 7.6 Hz).
1-Methylphenoxathiine (3e). 1H NMR spectrum, δ,
ppm: 7.03–6.98 m (2H), 6.97–6.89 m (3H), 6.81–6.75 m
(2H), 2.22 s (3H).
3,7-Dichlorophenoxathiine (3f). 1H NMR spectrum,
δ, ppm: 7.07–7.07 m (2H), 7.05–7.01 m (3H), 6.91 d
(2H, J = 8.4Hz).
The optimal conditions were applied for the CuI
catalyzed cascade C–H hydroxylation–C–S coupling–
C–O cyclization of disulfides and o-chloroiodobenzenes.
Generally, the cascade reactions proceeded well, and
various phenoxathiin derivatives were separated with
moderate to good yields. However, it was observed that
ortho-substituted disulfides lowered the yield because
formation of the C-S bond was retarded by the steric
hindrance (3d and 3e).
In summary, the ligand-free and simple cascade C–H
hydroxylation–C–S coupling–C–O cyclization synthetic
approach to disulfides and o-chloroiodobenzenes has
been developed by using CuI as the catalyst. The simple
process leads to the synthesis of phenoxathiin derivatives.
1
7-Chloro-2-methylphenoxathiine (3g). H NMR
spectrum, δ, ppm: 6.99–6.93 m (3H), 6.95–6.83 m (3H),
2.26 s (3H).
3,7-Dimethylphenoxathiine (3h). 1H NMR spectrum,
δ, ppm: 6.97 d (2H, J = 7.6Hz), 6.82 d (4H J = 8.4Hz),
2.29 s (6H).
EXPERIMENTAL
1
3-Chloro-7-methylphenoxathiine (3i). H NMR
All solvents were dried and purified by the known
procedures and freshly distilled under the atmosphere
of nitrogen prior to use. The products were isolated by
column chromatography on silica gel (200–300 mesh)
by using ethyl acetate and petroleum ether as the eluents.
All yields are presented for the compounds isolated by
column chromatography. Reactions progress and products
purity were monitored by TLC using SiO2 plates, and the
spots were visualized under UV light. 1H NMR spectra
were measured in CDCl3 on a Varian Mercury 400 spec-
trometer using TMS as the internal standard.
spectrum, δ, ppm: 7.05–6.90 m (4H), 6.84 d (2H), 2.30
s (3H).
1
3-Methoxy-7-methylphenoxathiine (3j). H NMR
spectrum, δ, ppm: 6.98 d (2H J = 8.4Hz), 6.83 d (2H,
J = 9.6Hz), 6.65–6.55 m (2H), 3.78 s (3H), 2.30 s (3H).
FUNDING
We gratefully acknowledge financial support of this work by
the National Natural Science Foundation of China(21602123)
and the 111 Project of Hubei Province (grant no. 2018-19-1).
Synthesis of 3-chlorophenoxathiine (3a). CuI
(10 mol %) Was added at room temperature to a mixture
of disulfide 1a (0.5 mmol) with o-chloro-iodobenzene 2a
(0.6 mmol) and Cs2CO3 (1.8 mmol) in DMSO (5 mL). The
reaction mixture was stirred at 120°C for 9 h under the
atmosphere of nitrogen. Upon completion of the process,
the solvent was distilled off, and the residue was purified
by column chromatography on silica gel (ethyl acetate–
petroleum ether = 1 : 30, v:v) to give the product 3a.
CONFLICT OF INTEREST
No conflict of interest was declared by the authors.
REFERENCES
1. Zhang, Q., Li, B., Huang, S., Nomura, H., Tanaka, H., and
Adachi, C., Nat. Photonics, 2014, vol. 8, p. 326.
https://doi.org/10.1038/nphoton.2014.12
2. Oana, M., Tintaru, A., Gavriliu, D., Maior, O., and Hille-
brand, M., J. Phys. Chem. B., 2002, vol. 106, p. 257.
https://doi.org/10.1021/jp012198v
1H NMR spectrum, δ, ppm: 7.06 t (1H, J = 7.2 Hz),
7.01 d (1H, J = 7.6 Hz), 6.99–6.83 m (5H).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 12 2019

EFFICIENT SYNTHESIS OF PHENOXATHIINES
2561
3. Eastmond, G.C., Gilchrist, T.L., Paprotny, J., and Stein-
er, A., New. J. Chem., 2001, vol. 25, p. 385.
https://doi.org/10.1039/B008503K
12. Liu, M.G., Liu, N., Xu, W.H., and Wang, L., Tetrahedron,
2019, vol. 75, p. 2748.
https://doi.org/10.1016/j.tet.2019.03.057
13. Wang, L., Xie, Y.B., Huang, N.Y., Yan, J.Y., Hu, W.M.,
Liu, M.G., and Ding, M.W., ACS Catal., 2016, vol. 6,
p. 4010.
4. Hu, F., Zhao, X., Li, Y., Feng, L., and Ma, C., Synthesis,
2013, vol. 45, p. 966.
https://doi.org/10.1055/s-0032-1316863
https://doi.org/10.1021/acscatal.6b00165
5. Wang, D.W., Yu, X., Yao, W., Hu, W.K., Ge, C.Y., and
Shi, X.D., Chem. Eur. J., 2016, vol. 22, p. 5543.
https://doi.org/10.1002/chem.201600597
14. Xie, Y.B., Ye, S.P., Chen, W.F., Hu, Y.L., Li, D.J., and
Wang, L., Asian. J. Org. Chem., 2017, vol. 6, p. 746.
https://doi.org/10.1002/ajoc.201700127
15. Wang, L., Xie, Y.B., Yang, Q.L., Liu, M.G., Zheng, K.B.,
Hu, Y.L., Huang, N.Y., J. Iran. Chem. Soc., 2016,
vol. 13, p. 1797.
6. Wang, D.W., Yu, X.L., Wang, L.K., Yao, W., Xu, Z.J.,
and Wan, H.D., Tetrahedron Lett., 2016, vol. 57,
p. 5211.
https://doi.org/10.1016/j.tetlet.2016.10.028
https://doi.org/10.1007/s13738-016-0897-8
16. Liu, Y.W., Xie, Y.B., Li, D.J., and Wang, L., Russ.
J. Gen. Chem., 2015, vol. 85, p. 2163.
7. Ye, D.D., Huang, R.H., Zhu, H.Y., Zou, L.H., and
Wang, D.W., Org. Chem. Front., 2019, vol. 6, p. 62.
https://doi.org/10.1039/c8qo00941d
https://doi.org/10.1134/S1070363215090212
17. Wang. L., Sun, M., and Ding, M.W., Eur. J. Org.
Chem., 2017, p. 2568.
8. Ge, C.Y., Sang, X.X.,Yao, W., Zhang, L., andWang, D.W.,
Green Chem., 2018, vol. 20, p.1805.
https://doi.org/10.1039/c7gc02892j
https://doi.org/10.1002/ejoc.201601628
18. He, X.K., Cai, B.G., Yang, Q.Q., Wang, L., and Xuan, J.,
Chem. Asian. J., 2019, vol. 14, p. 3269.
9. Ye, D.D., Pan, L., Zhu, H.Y., Jin, L., Miao, H.Y., and
Wang, D.W., Mater. Chem. Front., 2019, vol. 3, p. 216.
https://doi.org/10.1039/c8qm00510a
https//doi.org/10.1002/asia.201901078
10. Wang, L., Xie, Y.B., Huang, N.Y., Zhang, N.N., Li, D.J.,
Hu, Y.L., Liu, M.G., and Li, D.S., Adv. Synth. Catal.,
2017, vol. 359, p. 779.
19. Yao, W., Ge, C., Zhang, Y., Xia, X.-F., Wang, L., and
Wang, D., Chem. Eur. J., 2019, vol. 25, p. 16099.
https//doi.org/10.1002/chem.201904095
https://doi.org/10.1002/adsc.201600861
20. Yang, Q.Q., Liu, N., Yan, J.Y., Ren, Z.L., and Wang, L.,
Asian. J. Org. Chem. (2019) (in press).
11. Liu, N., Chao, F., Liu, M.G., Huang, N.Y., Zou, K.,
and Wang, L., J. Org. Chem., 2019, vol. 84, p. 2366.
https://doi.org/10.1021/acs.joc.8b03242
https://doi.org/10.1002/ajoc.201900666
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