Iodine-mediated thiolation of phenol/phenylamine derivatives and sodium arylsulfinates in neat water

Article abstract of DOI:10.1039/c5ra24351c

An efficient and convenient protocol for iodine-mediated thiolation of phenols/phenylamines with sodium benzene-sulfinates in water has been achieved. In this transformation, environment-friendly conditions (including metal-free and water as solvent) are employed under air conditions, and a series of valuable thioethers are easily obtained in moderate to good yields.

Full text of DOI:10.1039/c5ra24351c

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Journal Name
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Iodine-Mediated Thiolation of Phenol/Phenylamine Derivatives
and Sodium Arylsulfinates in Neat Water
Received 00th January 20xx,
Accepted 00th January 20xx
Dingyi Wang, Rongxing Zhang, Sen Lin*, Zhaohua Yan and Shengmei Guo*
DOI: 10.1039/x0xx00000x
www.rsc.org/
An efficient and convenient protocol for iodine-mediated toxicity. Therefore, a new general and flexible approach under
thiolation of Phenols/Phenylamines with sodium benzene- metal-free conditions and with increased efficiency and decreased
sulfinates in water has been achieved. In this transformation, energy and cost is still required. Sodium sulfinates as desirable
environment-friendly conditions (including metal-free and water sulfur source have been extensively used to construct the C−S bond
as solvent) are employed under air condition, and a series of because they are readily accessible and environment-friendly. We
valuable thioethers are easily obtained in moderate to good envisaged that sodium sulfinates might serve as feasible thiolating
yields.
agents to couple with naphthols in the specified reaction conditions
due to sodium sulfinates can be reduced to disulphides, which are
classical sulfenylating agents. There is no doubt that many efficient
methods have also made great progress, which have been reported
by groups of Peddinti,11 Huang, 12 Wang, 13 and others.14 These urge
us to report our own discovery. Herein we present a range of
phenol/phenylamine derivatives readily experience thiolation with
sodium arylsulfinates mediated by I2–PPh3 in water.15
The reactions for the construction of C–C and C–X ( X = heteroatom )
bonds via C–H functionalization have emerged as important
research trend in organic synthesis.1 In decades past, a good deal of
novel and shortcut synthetic methods has been reported for the
construction of C-C and C-X via C–H functionalization between two
C–H/C–H and X–H centers. Among all C–H functionalization
reactions, the formation of C−S bond has aroused people’s concern
as an important field of research in contemporary synthetic organic Triphenylphosphine was often used as reducing agent in virtue of
chemistry.
its inexpensiveness, wide material sources and application.16
Inspired by this result, we began our investigation with the reaction
of sodium benzenesulfinate with 2-naphthalenol (2a) as a model
reaction to obtain the optimal reaction conditions and the results
are presented in Table 1. 2-naphthalenol was treated with
benzenesulfinic acid sodium salt (1a, 1.2 equiv.), iodine (1.0 equiv.)
and triphenylphosphine (1.2 equiv.) in 2 mL of toluene at 100 °C for
10 h in the opening system. In a preliminary attempt, we were
Aryl sulfides are important compounds because they often
appear in many natural products and are employed in total
synthesis, in functional materials science, and in medicinal
chemistry.2 It is noteworthy that the diaryl sulfide are applied in
numerous disease areas to cure HIV, allergies and cancer as well as
Alzheimer’s and Parkinson’s diseases.3 Compounds containing 2-
naphthalenol are still an important part in all sorts of
sulfocompounds because of their presence in many bioactive
relevant molecules, including glycine transporter-1 (GlyT-1)
inhibitions, and 4-hydroxy-3-(arylthio)-2H-chromen-2-ones exhibit-
ing antibacterial and analgesic activities.4 Over the past few
decades, there are plenty of C-S cross-coupling reactions of aryl
thiols and disulfides with aryl halides, boronic acids and triflates
involving various transition metals, such as Pd,5 Cu,6 Ni,7 In,8 Fe,9
Co10 and so on. Nevertheless, many of these sulfur sources are
often limited because of their expensiveness, instability and high-
particularly
pleased
that
the
target
product
1-
(phenylthio)naphthalen-2-ol (3a) was obtained in 71% yield (Table 1,
entry 1). Among the different solvents examined, water gave the
best efficiency in terms of product yield (82% yield) and as an
environment-friendly solvent (Table 1, entry 8). We further
investigated the effect of the stoichiometry of I2 and PPh3.
Unfortunately, obvious decreased yields of 3a were observed when
reducing the loads of iodine and triphenylphosphine (from 82%
yield to 17% yield) (Table 1, entries 9–12). Furthermore, when the
reaction was performed at lower temperature, the yield of 3a was
reduced as well (Table 1, entry 14). On the basis of the results
shown in Table 1, the I2/Ph3P system at 100 °C in water for 10 h
emerged as the optimized reaction conditions for follow-up studies.
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Table 2 C-1 Sulfenylation of 2-naphthalenol derivatives with sodium
sulfinates mediated by I2–PPh3 systema
Table 1 Optimization of reaction conditions for I2–PPh3 mediated C1
thiolation reaction of 2-naphthalenol (2a)a
Product, yieldb (%)
3a, 82
Entry
1
R1
R2
H
R3
H
C6H5
4-MeC6H4
2- MeC6H4
4-ClC6H4
4-BrC6H4
4-MeOC6H4
4-O2NC6H4
C6H5
H
H
3b, 89
2
Entry I2
PPh3
Solvent
temp
(°C)
100
100
100
100
100
100
100
100
100
100
100
100
80
Yieldb
(%)
71
H
H
3c, 83
3
(equiv.) (equiv.)
H
H
3d, 85
4
1
1
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.5
1
Toluene
CH2Cl2
THF
H
H
3e, 87
5
2
1
58
H
H
3f, 81
6
3
1
23
H
H
3g, trace
3h, 91
7
4
1
Dioxane
DMSO
DMF
EtOH
H2O
41
6-Br
7-OH
H
H
8
5
1
trace
42
9c
10d
11d
C6H5
H
3i, 88
6
1
C6H5
CH3
C2H5
3j, 71
7
1
18
C6H5
H
3k, 75
8
1
82
a Conditions: 1 (0.36 mmol), 2 (0.30 mmol), I2 (1.0 equiv.), and PPh3
(1.2 equiv.) in 2 mL of water reflux for 10 h in air. b Isolated yield
9
1
H2O
79
10
11
12
13
14
1
H2O
65
c
after column chromatography (SiO2). The reaction of 1a (0.30
0.5
1.5
1
1.2
1.2
1.2
1.2
H2O
17
d
mmol) with 2i (0.36 mmol) under the standard conditions. 2 equiv
H2O
80
of I2 and 1 equiv of PPh3 were added in water (2 mL) .
H2O
47
1
H2O
rt
trace
a Reaction conditions: 1a (0.36 mmol) and 2a (0.30 mmol) in 2
mL of solvent feflux for 10 h in air. b Yield of isolated product.
With the optimized conditions in hand, we next investigated the
substrate scope of the sulfanylation of 2-naphthalenol (2) with
various sulfinic acid sodium salts (1). The results were clarified in
Table 2. It was exhilarating to find that a range of substituted Scheme 1. Reaction of 2l with sodium benzenesulfinate.
sodium benzenesulfinates reacted with 2-naphthalenol to provide
entries 1-10). These compounds participated well to afford aryl
sulfides in good to excellent yields under the optimized conditions
(Table 3). Various sodium arylsulfinates having electron-
withdrawing and electron-donating halo-groups at the 4-position
were able to react with phenols/phenylates to give the desired
products 5aa-5eb in a few hours in moderate to high yields. Besides,
We further tested this protocol with the carbon nucleophile N,N-
dimethylaniline bearing an amino functionality providing the
corresponding aryl sulfides 5ac-5ec in good yields. In general, for
substituted sodium benzenesulfinates, the substrates containing
electron-donating groups showed higher reactivity than those with
electron- withdrawing groups.
the corresponding products in good to excellent yields. It was
important to note that both electron-withdrawing and electron-
donating groups were introduced into the thiolation products by
employing sodium benzenesulfinates bearing such groups on the
aromatic ring. However, it was found that the effect of sodium
benzenesulfinate with electron-withdrawing groups on the yield of
target products were higher than that of naphthalenols on it.
Obviously, when sodium 4-nitrobenzene sulfinate was employed
under the standard conditions, only a trace amount of 3g was
detected by TLC. What interesting is that 2-methoxynaphthalene
and 2-ethoxynaphthalene can be tolerated in this transformation,
but 2 equiv of I2 and 1 equiv of PPh3 were needed, and the
corresponding compounds were isolated in 71% and 75% yields,
respectively.
Inspired by these satisfactory results, we tried to probe the
synthetic adaptability of the present method. The gram-scale
reaction was completed between 1a and 2a, and the reaction
afforded 3a in 80% yield (Scheme 2). Consequently, this expedient
protocol could be served as an efficient method for the synthesis of
various thioether derivatives with hydroxy/amidogen/methoxyl
groups.
It's worth mentioning that when 5,6,7,8-tetrahydro-2-naphthol
(2l) was subjected to the transformation under the optimal reaction
conditions, the isolated yield of the corresponding product 3l can
reach 52%.
Then we explored the scope of the reaction with respect to a
variety of sodium sulfinates with other phenols/phenylates (Table 3,
2 | J. Name., 2012, 00, 1-3
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Table 3 C-4 Sulfenylation of Xa - Xc with sodium sulfinates mediated
by I2–PPh3 systema
Entry
1
R1
Xn
a
a
a
a
a
a
b
b
b
b
c
Time (h) Product yieldb (%)
C6H5
8
5aa, 80
5ba, 86
5ca, 82
5da, 80
5ea, 82
5fa, 78
5ab, 90
5bb, 92
5db, 88
5eb, 87
5ac, 83
5bc, 87
5dc, 84
5ec, 82
2
4-MeC6H4
4-ClC6H4
4-BrC6H4
4-OMeC6H4
4-O2NC6H4
C6H5
8
Scheme 3. Control experiments.
3
8
4
8
5
8
6
12
8
7
8
4-MeC6H4
4-BrC6H4
4-OMeC6H4
C6H5
8
9
8
10
11
12
13
14
8
10
10
10
10
4-MeC6H4
4-BrC6H4
4-OMeC6H4
c
c
c
a Conditions: 1 (0.3 mmol), 4 (0.36 mmol), I2 (1.0 equiv.), and PPh3
(1.2 equiv.) in 2 mL of water reflux for 10 h in air. b Isolated yield.
Scheme 4. The plausible mechanism.
Conclusions
In conclusion, a metal-free and convenient way for the synthesis of
diaryl sulfide derivatives via the I2–PPh3 system mediated thiolation
of substituted naphthols/phenylamines in water under air condition
Scheme 2. Synthesis of 3a on gram scale.
In order to gain further insight into the plausible reaction has been described. The thiolation of naphthols/phenylamines and
pathway of I2-mediated thiolation of substituted phenols, several sodium benzene-sulfinate undergoes S-S bond formation, S−S bond
control experiments were conducted under various reaction cleavage, and C-S bond formation. In this program, using a range of
conditions, as showed in Scheme 3. No reaction occurred upon arylsulfinic acid salts as sulfur source, structurally diversed
treatment of benzenesulfinic acid sodium salt 1a with 2-
naphthol/aniline thioethers can be smoothly produced in moderate
naphthalenol 2a in the absence of iodine (Scheme 3, a). Only phenyl to good yields. It is believed that this method would offer an
disulfide was produced in the standard conditions without 2- efficient approach to thioethers containing hydroxy /amino/alkoxy
naphthalenol (Scheme 3, b). In the optimized conditions, 2- groups.
naphthalenol 2a stably reacted with diphenyldisulfane 6 to give the
desired product 3a in 95% yield (Scheme 3, c).
Acknowledgements
On the basis of the experimental results described above and
together with previous relevant mechanistic studies,17 we proposed
a plausible reaction pathway depicted in Scheme 4. Initially, sodium
benzenesulfinate was reduced to diphenyldisulfane (6) in the
presence of I2 and PPh3. Then, 6 reacts with I2 to form 2 equiv of an
electrophilic species PhSI (7), which is attacked by 2 to yield the
desirable product 3 and HI.
We are grateful for the financial support from the National Natural
Science Foundation of China (21302084).
Notes and references
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4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C5RA24351C
Journal Name
COMMUNICATION
Iodine-Mediated Thiola1-9tion of
Phenol/Phenylamine Derivatives and
Sodium Arylsulfinates in Neat Water
Dingyi Wang, Rongxing Zhang, Sen Lin*, Zhaohua Yan
and Shengmei Guo*
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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