Visible-Light-Mediated Synthesis of Unsymmetrical Diaryl Sulfides via Oxidative Coupling of Arylhydrazine with Thiol

Article abstract of DOI:10.1021/acs.orglett.8b03549

A metal-free visible-light-promoted oxidative coupling between thiols and arylhydrazines has been developed to afford diaryl sulfides using a catalytic amount of rose bengal as photocatalyst under aerobic conditions. A library of unsymmetrical diaryl sulfides with broad functionalities was synthesized in good yields at room temperature. The present methodology is also applicable to benzo[d]thiazole-2-thiols, benzo[d]oxazole-2-thiol, 1H-benzo[d]imidazole-2-thiols, and 1H-imidazole-2-thiol.

Full text of DOI:10.1021/acs.orglett.8b03549

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Visible-Light-Mediated Synthesis of Unsymmetrical Diaryl Sulfides
via Oxidative Coupling of Arylhydrazine with Thiol
Golam Kibriya, Susmita Mondal, and Alakananda Hajra*
Department of Chemistry, Visva-Bharati (A Central University), Santiniketan 731235, India
S
* Supporting Information
ABSTRACT: A metal-free visible-light-promoted oxidative coupling between thiols and arylhydrazines has been developed to
afford diaryl sulfides using a catalytic amount of rose bengal as photocatalyst under aerobic conditions. A library of
unsymmetrical diaryl sulfides with broad functionalities was synthesized in good yields at room temperature. The present
methodology is also applicable to benzo[d]thiazole-2-thiols, benzo[d]oxazole-2-thiol, 1H-benzo[d]imidazole-2-thiols, and 1H-
imidazole-2-thiol.
ulfur-containing organic scaffolds, particularly diaryl
sulfides, have a valuable impact in the biological as well
al. reported a Pd(II)-catalyzed oxidative cross-coupling
between phenylhydrazine and thioarenes for the synthesis of
diaryl sulfides at 100 °C.7 However, synthesis of unsymmetrical
diayl sulfides via oxidative coupling at room temperature as
well as in water is rare. Therefore, development of a simple and
environmentally benign method for the formation of unsym-
metrical diaryl sulfides is highly desirable in organic synthesis.
In recent years, visible-light-mediated photoredox catalysis
becomes a powerful synthetic tool in organic synthesis.8
Organic dyes are considered as alternatives of photoredox
transition metal catalysts due to their inexpensiveness,
synthetic versatility, nontoxicity, and better environmental
perspective.9 In continuation of our research interest in visible-
light-promoted C−C and C−heteroatom bond forming
reactions,10 herein we report a visible-light-promoted C−S
bond forming reaction for the synthesis of unsymmetrical
diaryl sulfides using rose bengal as a photocatalyst under
ambient air at room temperature in water (Scheme 1B).
We commenced our study using 4-methoxybenzenethiol
(1a) and phenylhydrazine hydrochloride (2a) as model
substrates employing Na2CO3 (2 equiv) as the base and rose
bengal (2 mol %) as the photocatalyst in CH3CN under 34 W
blue LED at room temperature. Gratifyingly, the oxidative
cross-coupling product (3aa) was obtained with a 58% yield
within 8 h under aerobic conditions (Table 1, entry 1).
Inspired by the initial result, we carried out the reaction under
different conditions to optimize the yield and the results are
summarized in Table 1. We first screened the effect of different
solvents such as 1,2-DCE, DCM, THF, toluene, DMSO, DMF,
EtOH, and H2O (Table 1, entries 2−9). Among them, a high
yield was obtained in H2O (Table 1, entry 9). The effect of
other organic dyes such as eosin Y, eosin B, and rhodamine 6G
S
as pharmaceutical field because of their immense response
against cancer, malarial, Alzheimer’s, Parkinson’s, HIV, etc.
diseases.1 They serve as the building block of several natural
products.2 Besides, diaryl sulfides show various applications in
material sciences.3 Moreover, ipso-substitution reactions via
C−S bond cleavage enhance the utility of aryl sulfides as
synthetic intermediates.4
Over the past few decades, synthesis of organic sulfides has
received considerable attention from synthetic organic
chemists. The conventional methods for the synthesis of
diaryl sulfides involve the cross-coupling reaction between
prefunctionalized arenes with a suitable arylsulfur reagent
(Scheme 1A).5 Most of the reported methods require toxic and
Scheme 1. Synthesis of Unsymmetrical Diaryl Sulfides
expensive transition metal (Pd, Cu, Ru, Ir, etc.) catalysts in the
presence of ligands under harsh reaction conditions. Recently,
arylhydrazine has emerged as an effective coupling partner in
various carbon−carbon and carbon−heteroatom bond-forming
cross-coupling reactions.6 It is considered as an environ-
mentally benign arylating agent for oxidative cross-coupling
reactions, as it releases only nitrogen gas and water as
byproducts during C−N bond cleavage. Very recently Zhao et
Received: November 6, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03549
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Substrate Scope of Arylhydrazines
entry
photocatalyst
base (equiv)
solvent
yield (%)
1
2
3
4
5
6
7
8
rose bengal
rose bengal
rose bengal
rose bengal
rose bengal
rose bengal
rose bengal
rose bengal
rose bengal
eosin Y
Na2CO3 (2)
Na2CO3 (2)
Na2CO3 (2)
Na2CO3 (2)
Na2CO3 (2)
Na2CO3 (2)
Na2CO3 (2)
Na2CO3 (2)
Na2CO3 (2)
Na2CO3 (2)
Na2CO3 (2)
Na2CO3 (2)
K2CO3 (2)
Et3N (2)
CH3CN
1,2-DCE
DCM
THF
toluene
DMSO
DMF
EtOH
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
58
45
28
47
35
65
58
78
85
72
69
53
81
64
71
9
10
11
12
13
14
15
16
17
18
19
20
21
eosin B
rhodamine 6G
rose bengal
rose bengal
rose bengal
rose bengal
rose bengal
rose bengal
−
a
Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), Na2CO3 (0.4
b
mmol), rose bengal (2 mol %) in 3 mL of H2O, 34 W blue LED. 6
mmol scale.
DBU (2)
b
Na2CO3 (3)
Na2CO3 (1)
−
Na2CO3 (2)
Na2CO3 (2)
Na2CO3 (2)
84
c
52, 45
trace
products without any difficulties (3bh, 3ai, and 3aj). 2-
Hydrazinopyridine also participated in this coupling reaction
to afford the desired product in good yield (3ak).
Diphenyldiselenide also reacted with 4-methoxy phenyl-
hydrazine hydrochloride to give the coupling product (4-
methoxyphenyl)(phenyl)selane (3b′l) in good yield. The
gram-scale reaction of the present methodology was also
performed in the usual laboratory setup by taking 4-
methoxybenzenethiol (1a) and phenylhydrazine hydro-
choloride (2a) on 6 mmol scale. The desired diaryl sulfide
product (3aa) was obtained without a significant decrease in
yield which implies the practical applicability of the present
methodology.
d
nr
e
rose bengal
rose bengal
nr
f
g
nr, 37
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), photocatalyst
b
(2 mol %), base, solvent (3 mL), 34 W blue LED for 8 h. 3 mol %
photocatalyst used. 1.5 mol % photocatalyst and 2 equiv of Na2CO3
c
d
e
f
were used. No reaction. In the dark. Under an argon atmosphere.
g
5 W blue LED for 20 h.
were also studied (Table 1, entries 10−12). But all of them
gave lower yields of the desired product. Then the reaction was
carried out with different bases, but no improvement of yield
was observed (Table 1, entries 13−15). No further improve-
ment of the yield was observed with increasing the amount of
both rose bengal (3 mol %) and Na2CO3 but decreased
significantly with decreasing the loading of both photocatalyst
(1.5 mol %) and base (Table 1, entries 16−17). Only a trace
amount of product was obtained in the absence of base (Table
1, entry 18). No formation of product was observed in the
absence of any photocatalyst (Table 1, entry 19). However, the
reaction did not proceed in dark conditions and as well as
under an argon atmosphere (Table 1, entries 20 and 21). A
lower yield of the coupling product was obtained under
irradiation with a 5 W blue LED for 20 h (Table 1, entry 21).
Thus, the optimized yield was obtained using 2 mol % rose
bengal and 2 equiv of Na2CO3 in H2O under irradiation with a
34 W blue LED for 8 h in air (Table 1, entry 9).
Next, to further expand the substrate scope, we carried out
this coupling reaction with a variety of thiols and the results are
summarized in Scheme 3. Arenethiols containing electron-
donating groups, such as −Me and −NH2, successfully
a
Scheme 3. Substrate Scope of Thiols
After obtaining the optimized conditions, next we
investigated the scope of this cross-coupling reaction exploring
various arylhydrazines (Scheme 2). Arylhydrazines with an
electron-donating substituent such as −CH3 at the ortho- and
para- position afforded the corresponding products with
excellent yields (3aa and 3ab). Halogen substituted arylhy-
drazines also successfully coupled with 4-methoxybenzenethiol
to give the desired products in high yields (3ad−3ag). Strong
electron-withdrawing groups (−NO2, −CF3, and −CN)
substituted onto arylhydrazines also furnished the coupling
a
Reaction conditions: 1 (0.2 mmol), 2j (0.4 mmol), Na2CO3 (0.4
mmol), rose bengal (2 mol %) in 3 mL of H2O, 34 W blue LED.
B
DOI: 10.1021/acs.orglett.8b03549
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
afforded the diaryl sulfide with excellent yields (3cj and 3dj).
Moreover, the halogen substituted (−F and −Cl) arenethiols
also furnished the desired products in good yields (3ej and
3fj). To our delight, naphthalene-2-thiol and pyridine-2-thiol
were also well tolerable for such transformation (3gj and 3ha).
Benzyl mercaptan and butane-1-thiol also reacted well to afford
the desired products in good yields (3ij and 3jj).
reaction was carried out in the presence of a singlet oxygen
quencher such as 1,4-diazabicyclo[2.2.2]octane (DABCO),11
the reaction proceeded with equal ease (Scheme 5, eq B). This
result indicates that the singlet oxygen is not involved in this
cross-coupling reaction. Disulfide (6a) was obtained from 4-
methoxybenzenethiol (1a) in the absence of phenylhydazine
hydrochloride under the standard reaction conditions (Scheme
5, eq C). In addition, 1,2-bis(4-methoxyphenyl)disulfane (6a)
produced the desired coupling product 3aa with phenyl-
hydrazine hydrochloride in 56% yield under the optimized
reaction conditions. These results indicate that the present
reaction might proceed through the formation of disulfide
(Scheme 5, eq D).
The present protocol is also applicable to various heteroaryl
thiols (Scheme 4). Benzo[d]thiazole-2-thiols, benzo[d]-
a
Scheme 4. Substrate Scope of Other Heteroarylthiols
On the basis of control experiments and literature
reports,6f,g,9h a plausible mechanistic pathway has been
proposed in Scheme 6. First, the ground state of RB (rose
Scheme 6. Plausible Mechanistic Pathway
a
Reaction conditions: 4 (0.2 mmol), 2 (0.4 mmol), Na2CO3 (0.4
mmol), rose bengal (2 mol %) in 3 mL of H2O, 34 W blue LED.
oxazole-2-thiol, 1H-benzo[d]imidazole-2-thiols, and 1H-imida-
zole-2-thiol reacted with phenyl hydrazine derivatives to
provide the diaryl sulfide products in high yields (5aa−5fa).
To understand the mechanistic pathway of this cross-
coupling reaction, few control experiments were performed as
shown in Scheme 5. The reaction was carried out in the
presence of different radical scavengers such as 2,2,6,6-
tetramethylpiperidine-1-oxyl (TEMPO) (Scheme 5, eq A,
(i)) and 2,6-di-tert-butyl-4-methylphenol (BHT) (Scheme 5,
eq A (ii)). However, in both cases, only a trace amount of the
product was obtained. These results suggest that the reaction
possibly proceeds through a radical pathway. When the
bengal) is converted to its excited state RB* upon irradiation
with blue LED light. RB* reacts with thiol to afford thiol
radical cation A and RB•− via single electron transfer (SET).
Subsequently RB is regenerated through the reduction of O2 to
•−
O2 which abstracts a proton from A to produce thiyl radical
B. Next thiyl radical B undergoes a homocoupling reaction to
generate diaryl disulfide (6). On the other hand arylhydrazine
C is oxidized by RB* to afford radical cation D. Upon
deprotonation, radical cation D is converted to radical
intermediate E. Radical intermediate G is formed from E
through sequential SET and deprotonation. An aryl radical is
generated from G by the elimination of nitrogen. Finally, the
aryl radical is coupled with diaryl disulfide (6) to afford the
desired coupling product (3) and thiyl radical B which again
dimerizes to regenerate 6.
Scheme 5. Control Experiments
In summary, we have developed a visible-light-promoted
oxidative C−S cross-coupling reaction between arylhydrazine
and thiol to synthesize unsymmetrical diaryl sulfides under
organophotoredox catalysis. A library of diaryl sulfides with
broad functionalities was synthesized at ambient temperature
under aerobic conditions. Scalability, metal-free conditions, use
of water as a green solvent, and ambient air as the oxidant
make this method more practicable in organic synthesis. To
the best of our knowledge, this is the first report of a visible-
light-promoted synthesis of unsymmetrical diaryl sulfides in
water at room temperature. We believe our present method-
ology becomes more interesting in organic synthesis as well as
in medicinal chemistry.
C
DOI: 10.1021/acs.orglett.8b03549
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(7) Wang, C.; Zhang, Z.; Tu, Y.; Li, Y.; Wu, J.; Zhao, J. J. Org. Chem.
2018, 83, 2389.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03549.
■
S
(8) (a) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev.
2013, 113, 5322. (b) Narayanam, J. M. R.; Stephenson, C. R. J. Chem.
Soc. Rev. 2011, 40, 102. (c) Shaw, M. H.; Twilton, J.; MacMillan, D.
W. C. J. Org. Chem. 2016, 81, 6898. (d) Sun, M.-J.; Liu, Y.; Yan, Y.; Li,
R.; Shi, Q.; Zhao, Y. S.; Zhong, Y.-W.; Yao, J. J. Am. Chem. Soc. 2018,
140, 4269. (e) Zhou, Q.-Q.; Zou, Y.-Q.; Lu, L.-Q.; Xiao, W.-J. Angew.
Chem., Int. Ed. 2018, DOI: 10.1002/anie.201803102. (f) Kundu, D.;
Ahammed, S.; Ranu, B. C. Org. Lett. 2014, 16, 1814.
Experimental procedures and spectral data (PDF)
AUTHOR INFORMATION
■
(9) (a) Pan, Y.; Kee, C. W.; Chen, L.; Tan, C.-H. Green Chem. 2011,
13, 2682. (b) Ravelli, D.; Fagnoni, M. ChemCatChem 2012, 4, 169.
(c) Fukuzumi, S.; Ohkubo, K. Chem. Sci. 2013, 4, 561. (d) Hari, D. P.;
Corresponding Author
*E-mail: alakananda.hajra@visva-bharati.ac.in.
ORCID
̈
Konig, B. Chem. Commun. 2014, 50, 6688. (e) Sun, P.; Yang, D.; Wei,
W.; Jiang, M.; Wang, Z.; Zhang, L.; Zhang, H.; Zhang, Z.; Wang, Y.;
Wang, H. Green Chem. 2017, 19, 4785. Wei, W.; Wang, L.; Bao, P.;
Shao, Y.; Yue, H.; Yang, D.; Yang, X.; Zhao, X.; Wang, H. Org. Lett.
2018, 20, 7125. (g) Romero, N. A.; Nicewicz, D. A. Chem. Rev. 2016,
116, 10075. (h) Hong, B.; Lee, J.; Lee, A. Tetrahedron Lett. 2017, 58,
2809.
Susmita Mondal: 0000-0002-8795-942X
Alakananda Hajra: 0000-0001-6141-0343
Notes
The authors declare no competing financial interest.
(10) (a) Singsardar, M.; Dey, A.; Sarkar, R.; Hajra, A. J. Org. Chem.
2018, 83, 12694. (b) Kibriya, G.; Bagdi, A. K.; Hajra, A. J. Org. Chem.
2018, 83, 10619. (c) Kibriya, G.; Bagdi, A. K.; Hajra, A. Org. Biomol.
Chem. 2018, 16, 3473. (d) Kibriya, G.; Samanta, S.; Jana, S.; Mondal,
S.; Hajra, A. J. Org. Chem. 2017, 82, 13722. (e) Mitra, S.; Ghosh, M.;
Mishra, S.; Hajra, A. J. Org. Chem. 2015, 80, 8275.
ACKNOWLEDGMENTS
■
A.H. acknowledges the financial support from CSIR, New
Delhi (Grant No. 02(0307)/17/EMR-II). S.M. thanks CSIR-
New Delhi (CSIR-SRF) for her fellowship.
(11) Keshari, T.; Yadav, V. K.; Srivastava, V. P.; Yadav, L. D. S.
Green Chem. 2014, 16, 3986.
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