Iron-catalyzed S-arylation of benzothiazole with aryl iodides under aqueous medium: Facile synthesis of aryl(2-aminoaryl) sulfides

Article abstract of DOI:10.1055/s-0034-1379484

A simple route for facile access of aryl(2-aminoaryl) sulfide was reported. With the aid of iron(III) chloride catalyst and diamine ligand, benzothiazole was efficiently S-arylated with various aryl iodides (19 examples) in water under air atmosphere. This operationally simple protocol provides aryl(2-aminoaryl) sulfides in moderate to good yields.

Full text of DOI:10.1055/s-0034-1379484

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▌2743
cIlrusotenr -Catalyzed S-Arylation of Benzothiazole with Aryl Iodides under Aqueous
Medium: Facile Synthesis of Aryl(2-aminoaryl) Sulfides
Aryl(2-aminoaryl) Sulfides
Hang Wai Lee, Ka Fu Yung,* Fuk Yee Kwong*
State Key Laboratory of Chirosciences and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University,
Hung Hom, Kowloon, Hong Kong
Fax +85223649932; E-mail: kf.yung@polyu.edu.hk; E-mail: fuk-yee.kwong@polyu.edu.hk
Received: 13.09.2014; Accepted after revision: 28.09.2014
exploration of another user-friendly method that especial-
Abstract: A simple route for facile access of aryl(2-aminoaryl) sul-
ly allows the S-arylation reaction to be conducted under
fide was reported. With the aid of iron(III) chloride catalyst and di-
air would be highly favorable.
amine ligand, benzothiazole was efficiently S-arylated with various
aryl iodides (19 examples) in water under air atmosphere. This op-
erationally simple protocol provides aryl(2-aminoaryl) sulfides in
moderate to good yields.
F
O
N
OEt
O
S
Key words: S-arylation, iron, catalysis, benzothiazole, water
O
Me
N
Me
Diaryl thioethers is a versatile building block for numer-
ous pharmaceutical and biologically active compounds.1
In particular, aryl(2-aminophenyl) sulfide motif consti-
tutes as bioactive subunit such as G protein coupled recep-
tor,2 antiviral compounds for treatment of HCV
infection,3 Topoisonmerase I inhibitor (TopoI),4 and Sero-
tonin transporter imaging agent (Figure 1),5 in which they
have attracted considerable interest. Traditional organic
synthesis for preparing aryl(2-aminophenyl) sulfides is
the reaction of aryl azide with sulfides.6 This protocol suf-
fers from regioselectivity as both 2- and 4-amino-substi-
tuted products were often resulted. To achieve a better
selectivity, an alternative synthesis of nitroaryl sulfides
followed by subsequent reduction of the nitro group was
reported.7 In recent decades, transition-metal-catalyzed
carbon–sulfur bond formation has emerged as an attrac-
tive tool for convergent and modular synthesis.8 Of the
catalytic processes reported, the low-cost and toxic cop-
per-catalyzed9 C–S bond coupling is one of the most at-
tractive methods. These protocols often employ ArSH and
Ar′X as the starting materials.10 In addition to arylthiols,
aryldisulfides have been shown as alternative ArS cou-
pling partner with either specific tris(fluorophenyl)borox-
ins,11 general aryltrimethoxysilane,12 or arylboronic
acids13 to access an array of aryl(2-aminoaryl) sulfides.
Yet, polar organic solvents such as DMSO11 and expen-
sive phosphine ligands (e.g., JohnPhos) were necessary in
these reactions.12 Recently, a thiol surrogate of potassium
ethyl xanthogenate was reported.14 Aryl thiols were gen-
erated in situ through the reaction between xanthate and
aryl iodides.15 In fact, 2-aminothiophenols16 are the more
straightforward coupling partners, however, they are eas-
ily oxidized under air17 and thus reaction conditions of un-
der inert atmosphere are generally required. Therefore, an
F
S
S
NH2
NH2
G protein coupled
receptor
serotonin transporter
imaging agent (SERT)
Br
H2N
S
O
HN
O
N
H2N
S
NH
O
N
O
Cl3
topoisomerase I inhibitor
(TopoI)
antiviral compounds for
treatment of HCV infection
Figure 1 Pharmaceutical and biologically active compounds bearing
an aryl(2-aminoaryl) sulfide skeleton
Benzothiazole can be potentially used as a more econom-
ical and stable substitute to 2-aminothiolphenol.18 Indeed,
2-aminothiophenol would be generated in situ through a
ring-opening process of benzothiazole under basic condi-
tions.19 This intermediate allows the subsequent metal-
catalyzed C–S bond formation. Nevertheless, recent re-
ports showed that nitrogen or argon environment with the
uses of specific base (n-Bu4NOH)19f and solvent (PEG-
600)19g were required. To date, it is still a challenge to de-
velop a simple and environmentally benign catalysis for
the synthesis of aryl(2-aminoaryl) sulfides. Iron catalysts
have become successful in C–S bond-forming reactions
over the past few years.20 In continuing our efforts in iron-
catalyzed N-arylation of pyrazoles,21 we herein report
SYNLETT 2014, 25, 2743–2747
Advanced online publication: 21.10.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0034-1379484; Art ID: st-2014-w0764-c
© Georg Thieme Verlag Stuttgart · New York

2744
H. W. Lee et al.
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iron(III) chloride associated diamine ligand that facilitate addition of base did not improve the product yield (Table
the synthesis of aryl(2-aminoaryl) sulfides.
1, entry 9). Interestingly, solvent screening showed that
water gave the best yield for the S-arylation process. Di-
oxane, DMF, and neat conditions did not promote the re-
action (Table 1, entries 10–14). Lower product yield was
observed when the reaction was run at 130 °C (Table 1,
entry 15).
Benzothiazole and electronically neutral iodobenzene
were chosen as the model substrates in our initial investi-
gation (Table 1). A survey of commercially available di-
amine
ligands
revealed
that
trans-1,2-
diaminocyclohexane (L1) was the best ligand while
DMEDA and 1,10-Phen provided slightly lower product With our optimized reaction conditions in hand, we next
yields (Table 1, entries 1–3). Control experiment showed examined the substrate scope of this S-arylation reaction
that no S-arylation product was afforded in the absence of (Table 2). A range of aryl iodides were tested and they
either ligand or metal (Table 1, entries 4–6). Of the com- proceeded smoothly to give the corresponding products in
monly used bases examined, NaOH gave superior perfor- good yields. Functional groups such as bromo, chloro, and
mance whereas NaOt-Bu and KOH provided slightly enolizable keto and nitro groups were compatible under
lower conversions (Table 1, entries 1, 7, and 8). Further these reaction conditions (Table 2, entries 4–9). In partic-
ular, the intact chloro and bromo group is beneficial for
further functionalization at a later stage using other cross-
coupling protocols.
Table 1 Initial Screenings on the Feasibility of Aqueous Iron-Cata-
lyzed S-Arylation of Benzothiazolea
The nitro group was tolerated during the course of reac-
tion (55% yield), thus providing a complementary method
NH2
I
to the reported copper catalyst system,22 which gave the
FeCl3
ligand
N
S
desired product in only 35% yield (Table 2, entry 5). Par-
ticularly noteworthy is that this S-arylated product can un-
dergo further reduction and acylation to form potential
antiviral compounds.23 Moreover, (2-aminophenyl)-3-ni-
trophenylsulfide is a useful substructure of the nitroqui-
noxalinedone core, which can be used as neuronal death
inhibitors for treatment of HCV infection.24 ortho-Substi-
tuted aryl iodides were applicable substrates for the S-ary-
lation (Table 2, entries 10–14). More sterically hindered
2-iodocumene furnished the product with comparable
yield to that of 2-iodotoluene (Table 2, entry 12 vs. 14).
+
NaOH, H2O
110 °C, 24 h
S
Me
NH
Me
N
H
H2N
NH2
N
N
L1
L2
L3
Entry
Catalyst
Base
Solvent
Yield (%)b
1
2
FeCl3/L1
FeCl3/L2
FeCl3/L3
FeCl3/–
–/L1
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOH
H2O
58
Table 2 Iron-Catalyzed S-Arylation of Benzothiazole with Aryl Io-
H2O
42
didesa
3
H2O
56
NH2
4
H2O
n.r.
n.r.
n.r.
60
I
FeCl3, L1
S
N
S
5
H2O
+
NaOH, H2O
110 °C, 24 h
H2N
NH2
6
–
H2O
L1
R
R
7
FeCl3/L1
FeCl3/L1
FeCl3/L1
FeCl3/L1
FeCl3/L1
FeCl3/L1
FeCl3/L1
FeCl3/L1
FeCl3/L1
H2O
Entry
ArI
Product
Yield
(%)b
8
KOH
H2O
54
9c
10
11
12
13
14
15d
NaOH
H2O
58
S
1
2
60
61
I
NaOH
dioxane
dioxane
DMF
t-BuOH
neat
n.r.
n.r.
n.r.
trace
trace
54
NH2
S
NaOt-Bu
NaOt-Bu
NaOH
Me
Me
I
Me
NH2
S
Me
NaOH
I
3
4
54
53
NaOH
H2O
NH2
a Reaction conditions: benzothiazole (1.0 mmol), iodobenzene (1.5
mmol), iron catalyst (20 mol%), diamine ligand (40 mol%), base (3.0
mmol), and solvent (1 mL) were stirred at 110 °C for 24 h under air.
b Calibrated GC yields using dodecane as internal standard.
c Conditions: 5.0 mmol of NaOH were used.
Me
Me
S
OMe
I
NH2
MeO
d The reaction was performed at 130 °C.
Synlett 2014, 25, 2743–2747
© Georg Thieme Verlag Stuttgart · New York

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Aryl(2-aminoaryl) Sulfides
2745
Table 2 Iron-Catalyzed S-Arylation of Benzothiazole with Aryl Io-
To further evaluate the efficacy of this catalyst system, we
continued to examine the S-arylation with heteroaryl
iodides (Table 3). Moderate to good yields of the corre-
sponding products were obtained. 2-Chloro-6-iodo-
pyridine was found to be a feasible substrate for the
reaction (Table 3, entry 3). This product gives opportunity
for further structural modification using established cross-
coupling of aryl chlorides. Thienyl substrate furnished the
desired product smoothly (Table 3, entry 5).
didesa (continued)
NH2
I
FeCl3, L1
S
N
+
NaOH, H2O
110 °C, 24 h
H2N
NH2
S
L1
R
R
Entry
5
ArI
Product
Yield
(%)b
Table 3 Iron-Catalyzed S-Arylation with Heteroaryl Iodidesa
S
NO2
NH2
I
55
35c
I
FeCl3, L1
S
Z
N
S
NH2
S
O2N
Br
Z
+
NaOH, H2O
110 °C, 24 h
H2N
NH2
L1
R
I
I
R
6
7
64
62
Br
Cl
NH2
S
Entry
1
ArI
Product
Yield (%)b
Cl
S
N
N
NH2
S
58
I
I
NH2
S
OMe
OMe
I
N
N
8
9
50
43
53
51
MeO
2
3
4
5
43
50
42
60
NH2
S
OMe
NH2
S
O
N
Cl
I
I
O
NH2
N
Cl
NH2
S
Me
Me
N
N
Br
I
I
S
Br
N
NH2
S
N
S
10
11
NH2
S
I
I
NH2
NH2
NH2
NH2
S
S
S
a Reaction conditions: benzothiazole (1.0 mmol), heteroaryl iodide
(1.5 mmol), FeCl3 (20 mol%), trans-1,2-diaminocyclohexane (40
mol%), NaOH (3.0 mmol), and H2O (1 mL) were stirred at 110 °C for
24 h under air.
Me
I
b Isolated yield.
Me
12
13
52
64
In summary, we have developed a simple protocol for fac-
ile preparation of aryl(2-aminophenyl) sulfides. This in-
expensive, air-stable, and green reaction system is found
to promote the S-arylation in an open-to-air vessel. Mod-
erate to good functional group compatibility was found
under the stated reaction conditions. This protocol poten-
tially provides a more complementary access to the S-con-
taining pharmaceutically useful intermediates. Further
investigation is currently underway.
I
OMe
MeO
Me
S
Me
Me
I
NH2
Me
14
60
a Reaction conditions: benzothiazole (1.0 mmol), aryl iodide (1.5
mmol), FeCl3 (20 mol%), trans-1,2-diaminocyclohexane (40 mol%),
NaOH (3.0 mmol), and H2O (1 mL) were stirred at 110 °C for 24 h
under air.
Acknowledgment
We thank the Research Grants Council of Hong Kong (CERG: Po-
lyU5010/13P) and PSKL for financial support. F. Y. K. thanks the
Croucher Foundation for the Croucher Senior Research Fellowship
2013. We thank Dr. Pui Ying Choy for assistance in NMR analysis
and graphical abstract design. We are grateful to Prof. Albert S. C.
b Isolated yield.
c Benzothiazole (0.5 mmol), aryl iodide (1.0 mmol), copper powder
(10 mol%), Cs2CO3 (1.0 mmol), and ethylene glycol (2 mL) were
stirred at 140 °C for 6 h under N2.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2743–2747

2746
H. W. Lee et al.
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Synlett 2014, 25, 2743–2747
© Georg Thieme Verlag Stuttgart · New York

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Chem. Ber. Recl. 1997, 130, 1213. (b) Zhuravlev, F. A.
Tetrahedron Lett. 2006, 47, 2929. (c) Sánchez, R. S.;
Zhuravlev, F. A. J. Am. Chem. Soc. 2007, 129, 5824.
(d) Zhang, W.; Zeng, Q.; Zhang, X.; Tian, Y.; Yue, Y.; Guo,
Y.; Wang, Z. J. Org. Chem. 2011, 76, 4741. (e) Yang, Z.;
Chen, X.; Wang, S.; Liu, J.; Xie, K.; Wang, A.; Tan, Z.
J. Org. Chem. 2012, 77, 7086. (f) Feng, Y.-S.; Qi, H.-X.;
Wang, W.-C.; Liang, Y.-F.; Xu, H.-J. Tetrahedron Lett.
2012, 53, 2914. (g) Yao, L.; Zhou, Q.; Han, W.; Wei, S. Eur.
J. Org. Chem. 2012, 6856. (h) Gao, Q.; Wu, X.; Jia, F.; Liu,
M.; Zhu, Y.; Cai, Q.; Wu, A. J. Org. Chem. 2013, 78, 2792.
(i) Yang, Z.; Wang, A.; Chen, X.; Gui, Q.; Liu, J.; Tan, Z.;
Wang, H.; Shi, J.-C. Synlett 2013, 24, 1549.
(20) For a review on iron-catalyzed C–S coupling reactions, see:
(a) Correa, A.; Macheño, O. G.; Bolm, C. Chem. Soc. Rev.
2008, 37, 1108. For a highlight about the controversial Cu-
or Fe-catalyzed couplings, see: (b) Buchwald, S. L.; Bolm,
C. Angew. Chem. Int. Ed. 2009, 48, 5586. For selected
examples of iron-catalyzed C–S cross-coupling reactions,
see: (c) Correa, A.; Carril, M.; Bolm, C. Angew. Chem. Int.
Ed. 2008, 47, 2880. (d) Wu, J.-R.; Lin, C.-H.; Lee, C.-F.
Chem. Commun. 2009, 4450. (e) Wu, W. Y.; Wang, J. C.;
Tsai, F. Y. Green Chem. 2009, 11, 326. (f) Ku, X.; Huang,
H.; Jiang, H.; Liu, H. J. Comb. Chem. 2009, 11, 338. (g) Qiu,
J.-W.; Zhang, X.-G.; Tang, R.-Y.; Zhong, P.; Lia, J.-H. Adv.
Synth. Catal. 2009, 351, 2319. (h) Kovács, S.; Novák, Z.
Org. Biomol. Chem. 2011, 9, 711. (i) Wang, H.; Wang, L.;
Shang, J.; Li, X.; Wang, H.; Gui, J.; Lei, A. Chem. Commun.
2012, 48, 76. (j) Lin, Y.-Y.; Wang, Y.-J.; Lin, C.-H.; Chen,
C.-H.; Lee, C.-F. J. Org. Chem. 2012, 77, 6100.
FeCl3 (32 mg, 20 mol%), trans-1,2-diaminocyclohexane
(48 μL, 40 mol%), benzothiazole (108 μL, 1.0 mmol),
(hetero)aryl iodide (1.5 mmol), NaOH (0.12 g, 3.0 mmol),
and H2O (1.0 mL) were loaded into a reaction tube equipped
with a septum in the presence of Teflon-coated magnetic
stirrer bar on bench-top under air. The tube was then placed
into a preheated oil bath (110 °C) and stirred for 24 h. After
completion of reaction as judged by GC analysis, the
reaction tube was allowed to cool to r.t. EtOAc was added
for product extraction. The organic layer was separated, and
the aqueous layer was further washed with EtOAc (3× ca. 10
mL). The organic part was concentrated under reduced
pressure. The crude products were purified by flash column
chromatography on silica gel (230–400 mesh) to afford the
desired product (see Supporting Information for details).
2-Aminophenyl Phenyl Sulfide (Table 2, Entry 1)
Yellow liquid; Rf = 0.6 (EtOAc–hexane, 1:9). 1H NMR (400
MHz, CDCl3): δ = 4.18 (br s, 2 H), 6.81–6.85 (m, 2 H), 7.18
(t, J = 7.6 Hz, 3 H), 7.27–7.32 (m, 3 H), 7.52–7.55 (dd,
J = 6.8, 1.2 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ =
114.39, 115.44, 118.8, 125.5, 126.5, 129.0, 131.2, 136.9,
137.5, 148.9 (see Supporting Information for details).
(2-Aminophenyl) 3-Pyridyl Sulfide (Table 3, Entry 1)
Brown solid; Rf = 0.5 (EtOAc–hexane, 1:1). 1H NMR (400
MHz, CDCl3): δ = 4.39 (br s, 2 H), 6.71–6.77 (m, 2 H), 7.06–
7.09 (q, J = 4.8 Hz, 1 H), 7.20–7.24 (td, J = 8.0, 1.6 Hz, 1 H),
7.27–7.29 (dt, J = 6.4, 1.6 Hz, 1 H), 7.42–7.44 (dd, J = 7.6,
1.2 Hz, 1 H), 8.30–8.32 (dd, J = 4.8, 1.6 Hz, 1 H), 8.38 (d,
J = 1.6 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ = 112.4,
115.5, 118.8, 123.7, 131.6, 133.8, 134.2, 137.4, 146.4,
147.5, 149.0 (see Supporting Information for details).
(21) Lee, H. W.; Chan, A. S. C.; Kwong, F. Y. Tetrahedron Lett.
2009, 50, 5868.
(22) Using 10 mol% Cu with 2 equiv Cs2CO3 in 2.0 mL ethylene
glycol catalytic system (ref. 19g), 35% GC yield was
obtained for reaction of benzothiazole and 3-nitroiodobenzene.
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Synlett 2014, 25, 2743–2747

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