Cu-catalyzed three-component synthesis of substituted benzothiazoles in water

Article abstract of DOI:10.1002/chem.201103525

Three in one: Copper-catalyzed three-component reactions, involving 2-iodoanilines, aldehydes, and sulfur powder, afford 2-phenylbenzothiazoles in water. A variety of 2-substituted benzothiazoles can be obtained in good to excellent yields of up to 96% (see scheme). Copyright

Full text of DOI:10.1002/chem.201103525

DOI: 10.1002/chem.201103525
Cu-Catalyzed Three-Component Synthesis of Substituted Benzothiazoles in
Water
Hang Deng,[a] Zhengkai Li,[a] Fang Ke,[a] and Xiangge Zhou*[a, b]
Multicomponent reactions (MCRs), by virtue of high se-
lectivity, atom economy, and convergence,[1] have gained
considerable and steadily increasing interest recently. Com-
pared with the classical step-by-step formation of individual
bonds for a given target molecule, the utmost attribute of
MCRs is the inherent formation of several bonds in one op-
eration, without isolating the intermediates, changing the re-
action conditions, or adding further reagents.[2] Consequent-
ly, multicomponent reactions have served as a powerful tool
in synthetic chemistry.
During our studies of copper-catalyzed reactions in water,
we found that iodobenzene (1) reacted with an excess
amount of elemental sulfur (2) to form diphenyldisulfide 3
or in the presence of a different molar ratio between iodo-
benzene and sulfur formed diphenylsulfide 4 (Scheme 1).[10]
Substituted benzothiazoles have been widely known as
prominent agents with a broad spectrum of pharmaceutical
activities, namely as antitumor agents,[3] orexin receptor an-
tagonists,[3,4] and as Gram-positive selective antibacterials.[5]
Normally, the classical strategies to synthesize the benzo-
thiazole framework are based on the condensation reaction
of 2-aminothiophenols with carboxylic acids, nitriles, or al-
dehydes, which is limited by the difficulty to obtain the un-
stable 2-aminothiophenol substrates.[6] To overcome this
drawback, some more sustainable cross-coupling reactions
to prepare the target heterocycles under comparatively
milder reaction conditions have recently been developed.
For example, 2-substituted benzothiazoles was obtained by
copper- or palladium-catalyzed intramolecular cross-cou-
pling reactions starting from an amine.[7] In most cases such
processes require the Lawesson reagent to convert the
amides into the corresponding thioamides, which is general-
ly not feasible for substrates containing functional groups
such as ketone, ester, and amide moieties. Recently, Itoh
and Ma et al. developed a novel and practical synthesis of
benzothiazoles by using a cross-coupling reaction between
2-haloanilides and metal sulfides[8] and 2-ethylhexyl-3-mer-
captopropionate.[9]
Scheme 1. Reaction of iodobenzene with sulfur powder.
Moreover, diphenyldisulfide 3, when treated with excess io-
dobenzene, formed the stable product 4. In addition, Ma
and Jiang have already reported that sulfur powder could be
used as a coupling partner for copper-catalyzed arylation.[11c]
On the basis of these results, we assumed that the nucleo-
philic reagent 3 could react with another component, lead-
ing to the formation of new compounds. Indeed, three-com-
ponent reactions involving 2-iodoaniline, aldehydes, and
sulfur powder work well to afford benzothiazoles in water
and the results are reported herein.
Our initial efforts focused on searching for an efficient
catalytic system based on 2-iodoaniline, benzaldehyde, and
sulfur powder as model substrates. As shown in Table 1,
among the different ligands examined, L1 (1,10-phenanthro-
line) exhibited the highest catalytic activity in 81% yield
(Table 1, entries 1–5). Control experiments indicated that
the use of metal and ligand was essential, only 13% or trace
amounts of product were obtained in the absence of
a ligand or catalyst (Table 1, entries 6 and 7). Comparison of
different copper sources indicated that CuCl2 was superior
[a] H. Deng, Z. Li, Dr. F. Ke, Prof. Dr. X. Zhou
Institute of Homogeneous Catalysis
College of Chemistry, Sichuan University
Chengdu 610064 (P.R. China)
Fax : (+86)28-8541-2904
E-mail: zhouxiangge@scu.edu.cn
to other sources, including CuACTHNUTRGNEU(NG OAc)2, CuSO4, CuI, and
[b] Prof. Dr. X. Zhou
Cu2O (Table 1, entries 8–11). The base screening suggested
that K2CO3 was optimal (Table 1, entries 12–15). Reaction
time was another important factor to affect the results.
When the reaction time was decreased to 12 h, the yield of
the desired product dropped to 80% (Table 1, entry 16).
State Key Laboratory of Physical Chemistry of Solid Surface
Xiamen University
Xiamen 361005 (P.R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103525.
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Chem. Eur. J. 2012, 18, 4840 – 4843

COMMUNICATION
Table 1. Screening of catalysts and reaction conditions for the catalytic
three-component reaction.[a]
Table 2. Catalytic three-component reaction by using different
aldehydes.[a]
Entry
Aldehyde
Product
Yield
[%][b]
1
2
a
92
84
b
Entry
[Cu]
Ligand
Base
Yield [%][b]
3
4
c
82
85
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
–
CuSO4·5H2O
CuCl2·2H2O
Cu2O
L1
L2
L3
L4
L5
–
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Na2CO3
K3PO4
NaOH
K2CO3
K2CO3
81
58
20
19
72
13
trace
84
92
72
82
75
88
87
77
80
42
d
5
6
7
8
e
f
92
86
96
89
–
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
9
10
11
12
13
14
15
16[c]
17[d]
g
h
CuACHTUNGTRENNUNG(OAc)2·H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
9
i
94
90
93
[a] All reactions were carried out using 2-iodoaniline (0.3 mmol), benz-
ACHTUNGTRENNUNGaldehyde (0.4 mmol), sulfur powder (0.9 mmol), Cu source and ligand
(0.03 mmol), and base (0.6 mmol) in water (3 mL) at 1008C for 24 h.
[b] Isolated yield. [c] The reaction time was 12 h. [d] The reaction tem-
perature was 808C.
10
11
j
k
12
l
83
Furthermore, lower temperatures resulted in lower yields,
and only a 42% yield was obtained at 808C (Table 1,
entry 17). Thus, the optimal catalytic conditions consist of
CuCl2·2H2O (10 mol%), L1 (10 mol%), and K2CO3
(2 equiv) in water at 1008C for 24 h.
13
14
m
n
72
63
Then, a variety of aldehydes were examined under the op-
timized reaction conditions to explore the scope of the sub-
strates. As shown in Table 2, benzaldehydes containing elec-
tron-donating and withdrawing groups were employed to
afford the corresponding benzothiazoles in good to excellent
yields ranging from 82 to 94%. No significant substituent
effect was observed (Table 2, entries 2–12). Furthermore,
some heterocyclic aldehydes such as pyrrole-2-carboxalde-
hyde, furfuraldehyde, and aliphatic aldehydes such as acetal-
dehyde and pentaldehyde were also investigated and found
to form the desired products in moderate yields ranging
from 52 to 72% (Table 2, entries 13–16).
To expand the scope of this the methodology, we also ex-
amined a series of substituted 2-iodoanilines. As summar-
ized in Table 3, several functional groups, such as fluoro,
chloro, bromo, ketone, and ester groups, are well-tolerated
under the reaction conditions and give the corresponding
benzothiazoles in moderate to excellent yields (Table 3).
Furthermore, substitution at the 4-position showed more in-
fluence than substitution at the 5-position. For example,
15
16
o
p
52
63
[a] All reactions were carried out using o-iodoaniline (0.3 mmol), alde-
hyde (0.4 mmol), sulfur powder(0.9 mmol), Cu source and ligand
(0.03 mmol) and base(0.6 mmol) in water (3 mL). [b] Isolated yield.
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
when 2-iodo-4-fluoroaniline or 2-iodo-4-methylaniline were
used in place of 2-iodoaniline, the yields changed dramati-
cally from 92 to 60 or 91%, respectively, which indicated
that electron-donating groups that were para to the amino
group benefited the catalysis (Table 2, entry 1 and Table 3,
entries 5 and 6). Furthermore, electron-withdrawing groups
in the 4-position promote the intermolecular coupling reac-
tion of 2-iodoaniline, which forms the main side product of
this reaction, phenazines (Table 3, entries 3–5). Meanwhile,
when 2-iodo-5-fluoroaniline was used in place of 2-iodoani-
Chem. Eur. J. 2012, 18, 4840 – 4843
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4841

X. Zhou et al.
Table 3. Catalytic three-component reaction by using different 2-iodo-
ACHTUNGTRENNUNG
anilines.[a]
(5) in 76% yield (Scheme 3A), whereas only a small
amount of 5 was observed in the absence of the Cu source
and ligand (Scheme 3B). This experiment demonstrates the
essential role of the copper catalyst for this reaction. Next,
the reaction of 5 with benzaldehyde afforded the desired
product in a lower yield of 22% (Scheme 4A). Whereas, in
Entry
2-Iodoaniline
Product
Yield
[%][b]
1
2
3
4
5
6
7
q
r
86
90
64
51
60
91
90
s
t
u
v
w
Scheme 4. Reaction of diaryl disulfides with benzaldehyde.
the presence of sulfur powder (2 equiv), a significant in-
crease in yield was observed (Scheme 4B). This result sug-
gested that the sulfur powder serves as both the sulfur
source and reaction promoter. Astoundingly, the reaction
can proceed well in the absence of catalyst (Scheme 4C).
Thus, the copper catalyst only promotes the coupling reac-
tion of 2-iodoaniline with sulfur powder. Ultimately, a con-
trol experiment was performed as shown in Scheme 5, the
8
x
91
[a] All reactions were carried out using o-iodoaniline (0.3 mmol), benz-
ACHTUNGTRENNUNGaldehyde (0.4 mmol), sulfur powder (0.9 mmol), Cu source and ligand
(0.03 mmol), and base (0.6 mmol) in water (3 mL). [b] Isolated yield.
line, the yields remained quite stable at around 90%
(Table 2, entry 1 and Table 3, entry 2). These phenomena
might be caused by the fact that the 4-substituted electron-
donating groups could stabilize the intermediate radical III
in Scheme 6 to form benzothiazole products.
Finally, PMX 610, which is a potential antitumor agent,
could also be prepared by this method starting from 5-
fluoro-2-iodobenzenamine and 3,4-dimethoxybenzaldehyde
in a good yield of 84% (Scheme 2).[3] It was formerly ob-
tained by a more complicated multiple step procedure.[6g,j]
To explore the catalytic mechanism, the following experi-
ments were performed as shown in Scheme 3. 2-Iodoaniline
reacted well with sulfur powder to provide diaryl disulfide
Scheme 5. Reaction of sulfur powder with N-benzylidene-2-iodoaniline 8.
reaction of imine 8 with sulfur powder provided hydrolyzed
product as the main product and a small amount of the de-
sired product 2-phenylbenzothiazole after 24 h. This experi-
ment proved that the three-component reaction of 2-iodo-
AHCTUNGTREGaNNUN niline, aldehydes, and sulfur powder proceeds mainly
through compound 5, not imine 8.
Scheme 2. Synthesis of PMX 610 in water.
According to the above observations, a tentative mecha-
nism for the formation of 2-arylbenzothiazoles was proposed
based on previous reports in the literature.[11] As shown in
Scheme 6, the copper-catalyzed coupling of 2-iodoaniline
with sulfur powder first provides a diaryl disulfide product I.
Then, a nucleophilic addition–elimination reaction of I with
an aldehyde affords intermediate II, and intramolecular nu-
cleophilic addition of the disulfides to the C=N bond in II
gives III. Finally, further oxidation of III provides the target
product.
Scheme 3. Reaction of 2-iodoaniline with sulfur powder.
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Cu-Catalyzed Synthesis of Benzothiazoles in Water
COMMUNICATION
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In summary, we have developed an efficient, simple, and
environmentally friendly three-component reaction of o-
iodoaniline, aldehydes, and sulfur powder to form benzo-
ACHTUNGTRENNUNGthiazoles in a simple one-pot procedure. In this catalytic
system, neat water is used as the solvent. The tolerance of
diverse functional groups makes the present system attrac-
tive. To the best of our knowledge, this is the first example
to use sulfur powder as the sulfur source in the synthesis of
substituted benzothiazoles in water. Considering the inex-
pensive catalytic system, and the readily available starting
materials, this strategy would thus be highly useful in the
synthesis of biologically important compounds containing
a benzoACHTUNGTRENNUNGthiazole framework.
Experimental Section
General procedure: 2-Iodoaniline (0.3 mmol), benzaldehyde (0.4 mmol),
sulfur powder (0.9 mmol), CuCl2·2H2O (0.03 mmol), 1,10-Phen L1
(0.03 mmol), and K2CO3 (0.6 mmol) in water (3 mL) were put into
a Teflon septum screw-capped tube. The reaction mixture was stirred at
1008C for 24 h without an inert gas atmosphere and then cooled to room
temperature and extracted with ethyl acetate. The organic layer was
dried over Na2SO4 and the solvent was removed under reduced pressure.
The residue was purified by silica-gel column chromatography to afford
the corresponding product.
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Acknowledgements
We are grateful to the Natural Science Foundation of China (Nos.
21072132), the Sichuan Provincial Foundation (08ZQ026–041) and the
Ministry of Education (NCET-10–0581) for financial support, and the
Analytical & Testing Centre of Sichuan University for NMR analysis.
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Keywords: catalysis
multicomponent reactions · sulfur
·
copper
·
heterocycles
·
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Received: November 9, 2011
Revised: February 7, 2012
Published online: March 19, 2012
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4843