Photoinitiated Synthesis of Sulfides in Water

Article abstract of DOI:10.1071/CH15496

Herein, we report a synthetic route to obtain aryl sulfides using inexpensive and non-toxic reactants and water as solvent, that avoids the use of catalysts or heating. The photoinduced reaction between soluble substrates and a series of thiols in alkaline aqueous medium produces the corresponding sulfides in moderate to good yields.

Full text of DOI:10.1071/CH15496

CSIRO PUBLISHING
Aust. J. Chem.
Full Paper
http://dx.doi.org/10.1071/CH15496
Photoinitiated Synthesis of Sulfides in Water
A
B
B C
,
Sergio A. Rodriguez, Leandro D. Mena, and Maria T. Baumgartner
A
CITSE (CONICET), Instituto de Ciencias Qu´ımicas, UNSE, Av. Belgrano Sur 1912,
Santiago del Estero (4200), Argentina.
B
INFIQC- Dpto. Qca. Orga´nica, Fac. Cs. Qu´ımicas, Univ. Nac. Co´rdoba,
Ciudad Universitaria. Co´rdoba (5000), Argentina.
C
Corresponding author. Email: tere@fcq.unc.edu.ar
Herein, we report a synthetic route to obtain aryl sulfides using inexpensive and non-toxic reactants and water as solvent,
that avoids the use of catalysts or heating. The photoinduced reaction between soluble substrates and a series of thiols in
alkaline aqueous medium produces the corresponding sulfides in moderate to good yields.
Manuscript received: 13 August 2015.
Manuscript accepted: 16 March 2016.
Published online: 19 April 2016.
Introduction
1-bromo-2-naphthol) and a series of thiols in alkaline aqueous
medium.
Aryl sulfides are important structural motifs often found in
biologically and pharmaceutically active molecules.[1] For
instance, aryl sulfides are present in compounds that are
employed to treat Alzheimer’s, Parkinson’s, cancer, malaria,
and HIV diseases.[2] In the last few decades, a large number of
transition metal-catalyzed cross-coupling reactions involving
palladium,[3] nickel,[4] copper,[5] cobalt,[6] iron,[7] or indium[8]
have been developed for the synthesis of aryl sulfides in high
yields. However, these methods present some drawbacks such as
the use of expensive and toxic metal catalysts. Thus, the
development of new methodologies for the synthesis of these
compounds represents an interesting challenge.
In light of this, radical nucleophilic reactions have been
proposed as an attractive synthetic route to symmetrical and
unsymmetrical sulfides. These photoinduced reactions take
place between non-activated aryl halides and a variety of sulfur
anions, such as arene and alkanethiolates, MeCOSꢀ and H2N
(HN)CSꢀ.[9–11] Most of the reported methods involve the use of
liquid ammonia or DMSO as solvent. Thus, the replacement of
these commonly used solvents by an environmentally friendly
solvent could be of high value.
Considering that the design of sustainable protocols towards
useful industrial applications represents an important target in
chemistry nowadays, the use of a benign solvent such as water is
of great interest due to the advantages associated with its
intrinsic features (non-toxicity, low cost, safe handling, non-
flammability, and easy isolation of final products).[12,13]
Recently, the synthesis of diaryl sulfides from aryl halides and
potassium thiocyanate using water as the solvent and copper
salts as a catalyst has been reported.[14] However, these methods
require either phase-transfer agents or solid supports.
Result and Discussion
The photoinduced reactions of 1-bromo-2-naphthol (1) with
different aromatic thiols (2a–2d) were first studied, and the results
are summarized in Table 1. The reaction of 1-bromo-2-naphthol
(1) with thiophenol (2a) and equimolar amount of base in a
1 : 9: 9 ratio under nitrogen atmosphere formed 1-(phenylthio)-
2-naphthol (3a) in 68 % yield (Table 1, entry 1). An increase in
the yield was observed when the reaction was carried out with
excess base (Table 1, entry 2). Then, different synthesis condi-
tions were examined in order to optimize the product formation.
When the reaction time was reduced by half and the nitrogen
atmosphere was replaced by air, the product 3a was still formed
in good yields. Under these conditions, the reaction between 2a
and 1 at a ratio of 4 : 1 formed 3a in 67 % yield (Table 1, entry 3).
When the ratio was decreased to 2 : 1, the yield of the product
decreased by 10 % (Table 1, entry 4). Moreover, when KOtBu
was replaced by KOH (an inorganic and less expensive base),
the yield of 3a increased with respect to that observed in the
previous reaction (Table 1, entry 5). The reaction does not occur
in the absence of light (Table 1, entry 6), indicating that the
photostimulation is necessary for the progress of the reaction.
These results show that the product can be synthesized in good
yields under mild conditions.
The substitution product 1-(2-naphthylthio)-2-naphthol (3b)
was obtained in 77 % yield (Table 1, entry 7) through the
reaction of 1 with 2-naphthalenethiol (2b). When the base used
was KOH, the yield of 3b increased (Table 1, entry 8). This
increase was similar to that observed for the thiol 2a (Table 1,
entries 4 and 5).
We report, herein, a new metal-free synthetic route to obtain
aryl sulfides in moderate to good yields based on photoinduced
reactions between different water-soluble aryl halides (such as
Following this study, the C–S coupling reaction was exa-
mined with heterocyclic thiols. The photoinduced reaction of
the substrate 1 with 2-mercaptobenzoxazole (2c) in a 1 : 2 ratio
Journal compilation Ó CSIRO 2016
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B
S. A. Rodriguez, L. D. Mena, and M. T. Baumgartner
Table 1. Photoinduced reactions of thiols with 1-bromo-2-naphthol in waterA
Ar
Br
S
OH
OH
hn
ꢀ
Ar–SH
base, H2O
1
2
3
Entry
Thiol [equiv.]
Base [equiv.]
Substitution
product
Yield [%]B
1C,D
2C,D
3
9
9
4
2
2
9
9
12
8
68
82
67
57
65
SH
S
4
5
OH
5E
6F
16
9
2a
G
–
3a
7
8E
4
4
8
77
82
16
SH
S
OH
2b
3b
9
2
2
9
9
5
68
65
57
42
52
–
10D
O
11
1.5
1.5
1.5
4
O
N
N
S
SH
12
3.5
13E
14F
16
8
OH
2c
3c
15
16F
5
5
10
10
51H
S
Trace
S
N
S
SH
OH
N
2d
3d
AReactions were carried out using 1-bromo-2-naphthol (0.25 mmol), thiol, and base (KOtBu) in water (5 mL) for 3 h.
BDetermined by gas-liquid chromatography (GLC) using the internal standard method on the basis of the concentration of 1.
CReaction carried out under N2 atmosphere.
DReaction time: 6 h.
EBase: KOH.
FIn the dark at 308C.
GProduct not found.
HIsolated yield.
and in the presence of an excess of base afforded the product 3c
in 68 % yield (Table 1, entry 9). A 2-fold increase in reaction
time did not improve the yield (Table 1, entry 10). When the
concentration of 2c was decreased (Table 1, entry 11), there was
almost no change in the yield of the product. Also, a dependence
between the yield and the amount of base was observed (Table 1,
entry 12). Moreover, inthe reaction carried out withKOH as base,
the product 3c was obtained in moderate yield (Table 1, entry 13).
In the reaction performed using 2-mercaptobenzothiazole (2d),
the substitution product 3d was formed in 57 % yield. Again,
the reactions did not occur in the dark, as shown in Table 1,
entries 14 and 16. In summary, the photoinduced reaction of
1-bromo-2-naphthol with heterocyclic thiols 2c–2d afforded the
desired products in good yields, using water as the solvent.
Based on the promising results obtained with these thiols, we
studied the reaction of 1-bromo-2-naphthol with 4-chlorothio-
phenol (2e) in water (Table 2). In the reaction of 1 with 2e in a
1 : 3.5 ratio and with excess of base (Table 2, entry 1), the
product 3e was obtained in 18 % yield, and surprisingly, product
4 was also obtained in 40 % yield. This compound is the product
of a substitution on the chlorine atom of 3e. Considering that two
C–S bonds are formed in a single step, we can say that the
product 4 was obtained in very good yield. In addition, the
remaining chlorine atom in 4 can be potentially substituted.

Photoinitiated Synthesis of Sulfides in Water
C
Table 2. Photoinduced reactions of 4-chlorothiophenol with 1-bromo-2-naphthol in waterA
l
C
S
Br
SH
OH
ꢀ
S
S
hn
base, H2O
Cl
ꢀ
OH
OH
Cl
1
2e
4
3e
Entry
Thiol [equiv.]
Base [equiv.]
Substitution product
and yield [%]B
SH
1
3.5
3
7
6
3e, 18; 4, 40
3e, 12; 4, 50
3e, 25; 4, 53E
2C
3C,D
4F
Cl
10
14
13
2e
G
9
–
AReactions were carried out using 1-bromo-2-naphthol (0.25 mmol), thiol, and base (KOtBu) in water (5 mL) for 3 h.
BDetermined by GLC using the internal standard method on the basis of the concentration of 1.
CReaction time: 6 h.
DAmount of 1-bromo-2-naphthol: 1 mmol.
EIsolated yield.
FIn the dark at 308C.
GProduct not found.
Table 3. Thermal reactions of thiols with 1-bromo-2-naphthol (1) in waterA
Entry
Thiol [equiv.]
Base [equiv.]
Temperature [8C]
Time [h]
Substitution product
and yield [%]B
1
2b, 5
2b, 5
2b, 5
2b, 5
2b, 2.5
2b, 2.5
2c, 2
12
12
12
12
12
12
12
12
5
120
120
120
120
120
80
24
6
3b, 97
2
3b, 96
3
3
3b, 83
4
1
3b, 54
5
6
3b, 94
6
6
3b, 78
7C
8C
9C, D
10C
80
6
3c, –
2d, 2
2e, 3
80
4
3d, –
3e, 36; 5E, 18
3e, 25; 5E, 35
80
6
2e, 3
4
120
7
AThermal reactions conducted in closed system in the absence of N2 atmosphere using 0.5 mmol of 1 and KOH as base.
BDetermined by GLC using the internal standard method on the basis of the concentration of 1.
CAmount of 1-bromo-2-naphthol: 0.3 mmol.
DBase: KOtBu.
E5: 2-Naphthol.
In order to analyze the product distribution, the ratio of 1 : 2e
and the concentration were modified (Table 2, entries 3 and 4).
However, no change in the yield was observed. In all cases, 4 was
the major product. The reaction performed in the dark did not lead
tothe formation ofany products (Table 2, entry 4), suggesting that
the reaction requires photostimulation to proceed.
To evaluate the contribution of polar mechanism to our
results,[15] thermal reactions were performed (Table 3). At
temperatures below 508C, the reaction products were observed
in traces, demonstrating that there is no competition between
thermal and photoinduced reactions in water. At 1208C, product
3b is formed, and its yield depends on reaction time and the ratio
of 1/2b (Table 3, entries 1–5); at 808C, the yield of 3b decreased
(Table 3, entry 6). The products of the reactions involving
heterocyclic thiols were not observed under these conditions
(Table 3, entries 7 and 8).
The thermal reaction using thiol 2e gave product 3e only.
With an increase in the temperature, the yield of 3e did not
increase, but the amount of the substrate-decomposition product
(2-naphthol) increased (Table 3, entries 9 and 10). In both
reactions, product 4 was not observed.
In view of the results, we attempted to explore the mecha-
nism of the photoinduced reaction. For this purpose, the reaction
using product 3e as substrate and thiol 2e in the presence of base
and light irradiation was carried out. Under these conditions,
only product 4 was formed. This result, the lack of reaction in the
dark (Table 2, entry 4), and the results of the thermal reactions
(Table 3, entries 9 and 10) suggest a photoinduced electron
transfer mechanism, in which the radical anion 3eꢁ2 acts as an
intermediate (Scheme 1).[16]
Based on the good results mentioned above, and with the aim
of obtaining an aryl–alkyl sulfide, the one-pot, two-step method

D
S. A. Rodriguez, L. D. Mena, and M. T. Baumgartner
l
C
aryl–alkyl, and aryl–heteroaryl sulfides in good yields. The
current findings represent an improvement over previous
protocols, which require the presence of copper-containing
catalysts or a solid support in water.
Br
OH
hn
base
S
ꢀ
2e
OH
The method reported in this manuscript can generate unsym-
metrical sulfides under mild conditions. Experimental evidence
is in accordance with a photoinduced electron transfer mecha-
nism, and the results demonstrate that there is no competition
between this mechanism and polar mechanism under the
conditions investigated herein.
ꢁ
Clꢁ
·
3a ꢁ
S
S
2eꢁ
S
Cl
OH
OH
4
Experimental
3a
Materials and Methods
Scheme 1. Proposed mechanism.
All starting materials were purchased from Sigma-Aldrich.
They were used without further purification. DMSO was dried
1
and stored under molecular sieves (4 A). H NMR and 13C NMR
˚
wasstudied.[11] The photoinduced reaction of 1-bromo-2-naphthol
with thiourea in a 1: 10 ratio was carried out (Eqn 1). After
irradiation, the ArSꢀ ions obtained by the aromatic substitution
was quenched with methyl iodide, affording product ArSMe (3f)
in 67 % yield in a one-pot procedure. Different alkyl moieties can
be introduced trough this reaction if methyl iodide is replaced by
other primary alkyl halides. In order to improve the reaction
conditions, inexpensive reactants (sodium sulfide as nucleophile
and KOH as base) were used. Under these conditions, a 63 % yield
of 3f was obtained. These reactions did not occur in the dark.
spectra were recorded on 400 MHz nuclear magnetic resonance
spectrometers. Gas chromatography analyses were performed
on a chromatograph (Hewlett Packard 6890 series) equipped
with a flame ionization detector and an HP-5 capillary column
(30 m ꢂ 0.32 mm ꢂ 0.25 mm film thickness). Gas chromato-
graphy mass spectrometry analyses were carried out on a
Shimadzu GC-MS QP 5050 spectrometer, using a Vf-5 ms
30m ꢂ 0.25 mm ꢂ 0.25mm column. High-resolution mass spec-
trometry (HRMS) was conducted on a Bruker MicroTOF Q II,
operated with an electrospray ionization (ESI) or atmospheric
pressure photoionization source operated in positive or negative
mode, using nitrogen as nebulizing and drying gas and 10 mM
sodium formate as internal standard for calibration purposes.
Irradiation was conducted in a reactor equipped with two 400-W
lamps emittingat a maximum of 350nm (Philips Model HPT; air-
and water-refrigerated). Column chromatography was performed
on silica gel (70–270 mesh).
Sꢁ
S
S
OH
OH
hn, 3 h
ICH3
ꢀ
(1)
1
NH2
H2N
H2O,
base
2f
3f
Finally, in an attempt to expand the substrate scope, other
water-soluble halides were studied. The photoinduced reaction
of 5-bromouracil with thiophenol 2a was performed in water
under nitrogen atmosphere (Eqn 2), producing a 56 % yield of
the product 5.[17] The synthesis of this product using microwave
heating and different organic solvents has been reported with
comparable yield.[18]
General Procedure for Reactions of 1-Bromo-2-naphthol
and Thiols
The following procedure is representative of all the reactions of
1-bromo-2-naphthol with thiols. The reactions were carried out
in a 25-mL three-neck round-bottom flask equipped with
nitrogen inlet and magnetic stirrer. To degassed water (5 mL;
using a rotary evaporator), potassium t-butoxide (280 mg,
2.5 mmol) was added. After total dissolution of the base, thio-
phenol (275 mg, 2.5 mmol) was added and stirred for 5 min.
Then, 1-bromo-2-naphthol (111 mg, 0.5 mmol) was added. The
reaction mixture was irradiated for 3 h. After that, it was quen-
ched with an excess of ammonium nitrate and water (10 mL)
was added. It was then extracted with dichloromethane
(3 ꢂ 10 mL). The organic layer was dried over MgSO4, filtered,
and concentrated to give a residue, which after radial
chromatography on silica gel (petroleum ether/acetone) gave
1-phenylthio-2-naphthol (3a) as a white solid.
O
O
Br
SH
S
HN
hn, 3 h
HN
ꢀ
(2)
H2O, N2
base
N
H
O
N
H
O
2a
5 (56 %)
In the reaction of the substrate 2-iodo-N-methylbenzamide
with thiophenol 2a and base (1 : 9 : 9 ratio), the product 6 was
obtained in 88 % yield (Eqn 3). The yield of product was similar
to that obtained from the reaction carried out in nitrogen
atmosphere (80 %). As in the previous cases, products 5 and 6
were not obtained under dark conditions.
A similar procedure was used in the case of reactions in the
absence of nitrogen atmosphere. The system was closed but not
purged of atmospheric oxygen.
O
HN
SH
O
S
hn
N
H
ꢀ
(3)
H2O,
base
I
6 (88 %)
2a
Compound Characterization
Products were isolated by column or radial chromatography
(hexane/ethyl acetate: 1 : 1 or 1.5 : 1).
1-(Phenylthio)-2-naphthol (3a):[19] white solid, mp 61.5–
63.58C.
Conclusions
We have reported a simple and inexpensive method for the
metal-free formation of aryl–sulfur bonds at room temperature
using water as a solvent. The studied reactions afforded diaryl,
1-(2-Naphthylthio)-2-naphthol (3b):[20] white solid, mp
96–978C.

Photoinitiated Synthesis of Sulfides in Water
E
2-(2- Mercaptobenzoxazolyl)-2-naphthol (3c): dH (CDCl3,
400 MHz) 7.21–7.29 (2H, m), 7.34–7.44 (3H, m), 7.49–7.60
(3H, m), 7.82 (1H, d, J 8.1), 7.96 (1H, d, J 8.9), 8.33 (1H, d,
J 8.8). dC (CDCl3, 100.62 MHz) 111.70, 117.6, 120.9, 122.0,
124.1, 124.4, 124.6, 126.3, 127.2, 128.5, 128.7, 129.6, 134.4,
134.9, 135.6, 154.0, 157.6. m/z (EI, 70 eV) (%) 63 (11), 64 (7),
69 (9), 102 (27), 103 (10), 114 (12), 115 (18), 145 (13), 146(52),
147 (47), 158 (13), 232 (18), 233 (24), 252 (13), 260 (57), 261
(19), 276 (33), 293 (100), 294(19). HRMS (ESIꢀ) m/z 292.0442;
calcd for C17H10NO2S 292.0432.
2-(2-Mercaptobenzothiazolyl)-2-naphthol (3d): dH (CDCl3,
400 MHz) 7.32–7.49 (4H, m), 7.52–7.60 (2H, m), 7.86 (1H, d,
J 8.2), 7.90 (1H, d, J 8.2), 8.01 (1H, d, J 8.9), 8.33 (1H, d, J 8.5).
dC (CDCl3, 100.62 MHz) 111.70, 117.6, 120.9, 122.0, 124.1,
124.4, 124.6, 126.3, 127.2, 128.5, 128.7, 129.6, 134.4, 134.9,
135.6, 154.0, 157.6. m/z (EI, 70 eV) (%) 63 (20), 69 (16), 77 (11),
87 (11), 88 (11), 102 (27), 103 (16), 108 (22), 113 (13), 114 (22),
115 (32), 135 (14), 140 (18), 144 (10), 145 (20), 146 (33), 147
(29), 148 (10), 247 (10), 248 (26), 249 (21), 268 (11), 276 (100),
277 (46), 278 (18), 281 (10), 292 (74), 293 (20), 309 (49), 310
(17). HRMS (ESIꢀ) m/z 308.0216; calcd C17H10NOS2
308.0204.
1-(4-Chlorophenylthio)-2-naphthol (3e): [19] white solid, mp
105.0–106.08C. dH (CDCl3, 400 MHz) 6.85–6.88 (2H, d), 7.04–
7.07 (3H, m), 7.28–7.32 (1H, m), 7.40–7.44 (1H, m), 7.73–7.75
(1H, d), 7.83–7.85 (1H, d), 8.07–8.09 (1H, d). dC (CDCl3,
100.62 MHz) 107.64, 116.94, 124.03, 124.46, 127.65, 128.13,
128.69, 129.31, 129.55, 131.89, 133.13, 133.95, 135.21, 157.04.
m/z (EI, 70 eV) (%) 63 (13), 69 (12), 73 (8), 75 (10), 82 (7), 99
(15), 108 (67), 143 (100), 144 (15), 145 (44), 222 (9), 286 (66),
287 (9), 288 (50), 289 (6), 290 (11).
1-(4-(4-Chlorophenylthio)phenylthio)-2-naphthol (4): dH
(CDCl3, 400 MHz) 6.89–7.00 (2H, m), 7.10–7.15 (2H, m),
7.16–7.24 (4H, m), 7.31–7.35 (1H, m), 7.37–7.42 (1H, m),
7.47– 7.55 (1H, m), 7.82 (1H, d, J 8), 7.92 (1H, d, J 8.5), 8.18
(1H, d, J 8.5). dC (CDCl3, 100.62 MHz) 107.49, 116.93, 123.99,
124.51, 127.14, 128.09, 128.67, 128.90, 129.35, 129.52, 130.11,
131.99, 132.05, 132.71, 133.10, 134.27, 135.11, 135.30, 157.03.
HRMS (ESIꢀ) m/z 393.0192 (395.0158); calcd for
C22H14ClOS2 393.0175 (395.0145).
1-Methylthio-2-naphthol (3f ):[21] dH (ClCD3, 400 MHz)
2.20 (3H, s), 7.16–7.19 (2H, m), 7.47–7.51 (1H, m), 7.69–7.72
(2H, d), 8.24–8.27 (1H, d). dC (CDCl3, 100.62) 18.65, 112.56,
116.49, 123.52, 124.36, 127.61, 128.76, 129.41, 131.53, 134.88,
155.87. m/z (EI, 70 eV) (%) 69 (9), 73 (6), 77 (6), 95 (5), 102
(10), 103 (9), 115 (14), 145 (9), 147 (82), 148 (9), 175 (64), 176
(7), 190 (100), 191 (13).
5-(Phenylthio)uracil (5):[22] dH ((CD3)2SO, 400 MHz) 7.14–
7.29 (5H, m), 7.92 (1H, s), 11.40 (2H, s). dC ((CD3)2SO,
100.62 MHz) 102.41, 125.99, 126.74, 129.43, 137.21, 149.46,
151.76, 162.81.
N-Methyl-2-(phenylthio)benzamide (7):[23] dH ((CD3)2SO,
400 MHz) 2.84–2.89 (3H, m), 6.88–7.76 (9H, m). dC
((CD3)2SO, 100.62 MHz) 26.72, 126.43, 127.08, 127.97,
128.37, 128.51, 129.47, 130.57, 130.93, 132.62, 134.33,
135.57, 136.07, 168.86. m/z (EI, 70 eV) (%) 51 (8), 77 (8),
107 (39), 108 (7), 139 (9), 150 (31), 152 (16), 166 (7), 184 (71),
185 (18), 213 (100), 214 (16), 243 (89), 244 (14), 245 (5).
Acknowledgements
This work was supported by Consejo Nacional de Investigaciones Cient´ıficas
y Te´cnicas (CONICET) of Argentina, SECYT UNC, and CICYT-UNSE.
SAR acknowledges CONICET for his doctoral fellowship.
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