Construction of 2-Arylbenzo[4,5]thieno[2,3-d]thiazole Skeleton via CuCl/S-Mediated Three-Component Reaction

Article abstract of DOI:10.1021/acs.orglett.9b04206

An exclusive thiophene-fused polycyclic I-conjugated 2-arylbenzo[4,5]thieno[2,3-d]thiazole skeleton was constructed via a one-pot CuCl-mediated three-component reaction, using 2-(2-bromophenyl)acetonitrile and aromatic aldehydes as substrates and elementa

Full text of DOI:10.1021/acs.orglett.9b04206

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Construction of 2‑Arylbenzo[4,5]thieno[2,3‑d]thiazole
Skeleton via CuCl/S-Mediated Three-Component
Reaction
Wei Zhang,† Shanqing Tao,† Huaibin Ge,† Qiao Li,† Zhenkang Ai,† Xiaoxian Li,† Beibei Zhang,†
Fengxia Sun,‡ Xiaqing Xu,§ and Yunfei Du*,†
†Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin
University, Tianjin 300072, China
‡College of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang 050018, China
§Department of Chemistry and Biochemistry, Suffolk University, Boston, Massachusetts 02108, United States
S
* Supporting Information
ABSTRACT: An exclusive thiophene-fused polycyclic π-con-
jugated 2-arylbenzo[4,5]thieno[2,3-d]thiazole skeleton was con-
structed via a one-pot CuCl-mediated three-component reaction,
using 2-(2-bromophenyl)acetonitrile and aromatic aldehydes as
substrates and elemental sulfur as sulfur source in the presence of
K2CO3 and 1,10-phen in DMSO. A plausible reaction mechanism
was proposed, which involved formation of benzo[b]thiophen-2-
amines through cyclization of 2-bromophenyl acetonitrile and sulfur, and subsequent intramolecular condensation/
dehydrogenation with aromatic aldehydes.
Scheme 1. Synthetic Strategies for the Construction of
Benzothienothiazole Skeleton
oth thiophene and thiazole frameworks are ubiquitous in
1−6
pharmaceuticals,7−13 organic materi-
Bnatural products,
als,14−18 dyes,19−21 and particularly in biologically active
molecules.22−25 Accordingly, many synthetic methods have
been reported for the construction of thiophene26−32 and
thiazole33 skeletons, respectively. However, to the best of our
knowledge, there has been less study on the construction of the
fused heterocyclic ring systems containing both thiophene and
thiazole moieties. Specifically, benzo[4,5]thieno[2,3-d]thiazole,
being an exclusive S-containing fused heterocyclic ring system,
has received attention from both synthetic and medicinal
chemists. Accordingly, several synthetic methods have been
reported for the assemblage of this unique heterocyclic
skeleton. For example, Heikel and co-workers reported an
intramolecular cyclization of 3-thiocyanatobenzo[b]thiophen-
2-amines forming the corresponding benzo[4,5]thieno[2,3-
d]thiazol-2-amines under acidic conditions (Scheme 1, method
a).34 In 1942, Middleton et al. realized the construction of the
same skeleton from the reaction of 3-bromo-2-nitrobenzo[b]-
thiophene with Na2S·9H2O/S followed by reduction of the
formed thioether intermediate with zinc (Scheme 1, method
b).35 Zhiryakov reported that the framework could also be
built by treating N-(3-bromobenzo[b]thiophen-2-yl)acetamide
with P2S5 (Scheme 1, method c).36 Each of these methods has
respective merits in preparing the substituted benzo[4,5]-
thieno[2,3-d]thiazole compounds. However, one obvious
drawback of these methods is that all of the substituted
benzo[4,5]thieno[2,3-d]thiazole products had to be derived
from the preformed benzothiophenes skeleton in the starting
material. Furthermore, nearly all the aforementioned methods
Received: November 23, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04206
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
were restricted to the synthesis of methyl or amino substituted
benzo[4,5]thieno[2,3-d]thiazole. Our literature search revealed
that no method was available for the construction of 2-aryl
substituted benzo[4,5]thieno[2,3-d]thiazole to date. It is
worthy to note that Deng and co-workers developed a facile
copper-catalyzed system for the construction of a similar
skeleton, a fused thieno[3,2-d]thiazole motif, through a bis-
heteroannulation of methyl aromatic ketoximes with aromatic
aldehydes and elemental sulfur (Scheme 1, method d).37
Recently, Jiang also reported the synthesis of benzo[4,5]-
thieno[3,2-d]thiazole from a three-component system, i.e.,
oxime esters/alkenyl azide, phenylacetylene/benzaldehyde,
and S8 via a copper-catalyzed tandem cyclization (Scheme 1,
method e).38
Table 1. Optimization of the Reaction Conditions
temp
yield
b
entry
catalyst
CuCl2
CuI
ligand
base
solvent
(°C)
(%)
1
2
3
4
5
6
7
8
A
A
A
A
A
B
C
A
A
A
A
A
A
A
A
A
A
A
A
A
A
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DBU
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
toluene
CH3CN
pyridine
DMF
100
100
100
100
100
100
100
100
100
100
100
100
80
120
140
120
120
120
120
120
120
22
46
18
25
60
0
0
0
9
30
28
41
28
72
66
62
47
17
28
33
69
Cu(OAc)2
CuBr
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
As shown above, the construction of the S-containing
polyheterocyclic ring systems often relied on the introduction
of sulfur atom by a variety of sulfur sources including
potassium thiosulfate, potassium sulfide, DMSO, potassium
ethylxanthate,39−42 the use of elemental sulfur as sulfur source
is undoubtedly highly desirable owing to its inexpensive,
nontoxic, inodorous, and stable characteristics.43−51 In this
communication, we report a one-pot protocol for a convenient
assemblage of the 2-arylbenzo[4,5]thieno[2,3-d]thiazole
framework using elemental sulfur as sulfur source. To the
best of our knowledge, this could represent the first synthesis
of aryl substituted benzo[4,5]thieno[2,3-d]thiazole up to date.
Furthermore, it is worthy to note that the current benzo[4,5]-
thieno[2,3-d]thiazole skeleton is different from the ones
reported by Deng and Jiang, as the positions of the sulfur
and nitrogen atoms in the thiazole ring are not the same.
During our study on the synthesis of S-containing
heterocycles, we serendipitously found that 6,7-dimethoxy-2-
phenylbenzo[4,5]thieno[2,3-d]thiazole 4a could be obtained
in 22% yield from the reaction of 2-(2-bromo-4,5-
dimethoxyphenyl)acetonitrile 1a, benzaldehyde 2a and S4 3
in the presence of copper catalyst. Further condition screening
was carried out to establish the most optimal conditions using
2-(2-bromo-4,5-dimethoxyphenyl)acetonitrile 1a and benzal-
dehyde 2a as model substrates, elemental sulfur 3 as sulfur
source, and 1,10-phenanthroline A as ligand. Initially, several
copper catalysts including CuCl2, CuI, Cu(OAc)2, CuBr, and
CuCl were screened, and the results showed that CuCl was the
most effective additive (Table 1, entries 1−5). The use of
copper combining with other ligands, namely, L-proline or
picolinic acid, were also attempted. However, no desired
product was observed in each case (Table 1, entries 6−7). We
found that 1,10-phenanthroline, which was frequently used as a
high efficient ligand to achieve C−S bond formation,52−57
proved to be the optimal ligand for this three-component
reaction (Table 1, entry 5). Other solvents including toluene,
CH3CN, pyridine, H2O, DMF, and DMSO were also tested,
and DMSO was found to be the most effective solvent, while
the others afforded inferior results (Table 1 entries 8−12).
Reaction temperature screening revealed that the best yield
could be achieved if the reaction was carried out at 120 °C
(Table 1, entries 13−15). It is worthy to note that running this
reaction in a sealed tube did not make obvious improvement
on the reaction outcome (Table 1, entry 16). Other additives
including DBU, Et3N, and Cs2CO3 were also introduced to the
system; however, K2CO3 still showed the highest efficiency,
and its most suitable dosage was confirmed to be 1 mmol
(Table 1, entries 17−20). In the absence of the catalyst and
ligand, the yield of the reaction significantly decreased to 6%,
9
10
11
12
13
14
15
H2O
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
c
16
17
18
19
Et3N
Cs2CO3
K2CO3
K2CO3
d
20
e
21
a
Reaction conditions: 1 (1 mmol), 2 (2 mmol), sulfur powder 3 (1.5
mmol), catalyst (20 mol %), ligand (20 mol %), base (1 mmol),
b
c
d
solvent (25 mL), 24 h. Isolated yield. In a sealed tube. Base (2
e
mmol). S8 instead of S4 (1.5 mmol).
which indicated that both the catalyst and the ligand were
indispensable for this reaction. It is worthy to note that S4
could also be replaced with S8, as the reaction delivered the
target product 4a in 69% yield (Table 1, entry 21). Finally, the
best reaction conditions were determined to be 2-(bromo-
methyl)-4,5-dimethoxybenzonitrile 1 (1 mmol), benzaldehyde
2 (2 mmol), sulfur powder 3 (1.5 mmol) with CuCl (20 mol
%), 10-phenanthroline (20 mol %) and K2CO3 (1 mmol) in
DMSO (25 mL) for 24 h.
With the optimal conditions in hand, we came to investigate
the scope and limitations of this newly established method.
First, a series of substrates bearing various R1 substituents were
studied. The results showed that 2-(2-bromophenyl)-
acetonitriles bearing either electron-donating or electron-
withdrawing groups smoothly gave the corresponding 2-
arylbenzo[4,5]thieno[2,3-d]thiazole products (Scheme 2,
4a−h), and the former gave slightly better results. It is worthy
to note that the reaction of 1f also gave a mixture of many
byproducts, in addition to the desired product 4f. The most
obvious byproduct (by TLC analysis) has been confirmed, by
X-ray crystal analysis, to be dibenzo[b,f ]thiepine-10,11-
dicarbonitrile (see SI for details). Disappointingly, when 2-
(2-bromophenyl)acetonitrile 1i bearing an electron-withdraw-
ing trifluoromethyl group was applied, the reaction failed to
provide the desired product 4i. Regarding the R2 groups, both
B
DOI: 10.1021/acs.orglett.9b04206
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Organic Letters
Letter
analogous selenazole, as the reaction using elemental selenium
with the other conditions unchanged did not afford the
expected Se-containing heterocyclic compound (not shown).
The structures of the products were confirmed by detailed
study of their spectroscopic data. Furthermore, the structure of
4f was unambiguously confirmed by X-ray crystallographic
analysis (Figure 1). To our delight, all the 2-arylbenzo[4,5]-
Scheme 2. Scope Studies of 2-(2-
Bromophenyl)acetonitriles
a b
,
Figure 1. X-ray crystal structure of 4f.
thieno[2,3-d]thiazole compounds listed in Scheme 2 were
found to possess striking fluorescent features due to their
existing polycyclic π-conjugated systems. According to the X-
ray crystal structure of compound 4f, we believe that the
compound is basically planar and can serve as a novel
fluorophore, since the rigidity and π-conjugation are
commonly recognized as positive structural factors in
enhancing the fluorophore brightness because of the reduction
of the energy consumption from rotation and vibration. As
shown in Table 2, compound 4f exhibited maximum
a
Reaction conditions: 1 (1 mmol), 2a (2 mmol), sulfur powder 3 (1.5
mmol), CuCl (20 mol %), 1,10-phenanthroline (20 mol %), K2CO3
(1.0 mmol), DMSO (25 mL), 120 °C, 24 h. Isolated yield.
b
electron-rich and electron-deficient aryl substituents were well
tolerated during the process. The substrate carrying electron-
withdrawing F group provided the lowest yield (Scheme 3, 4j−
Table 2. Optical Data of Representative Products
a b
,
Scheme 3. Scope Studies of Aromatic Aldehydes
λ
abs a
εmax
λ
Stokes shift
(nm)
b
em a
c
product
(nm)
(M−1 cm−1
)
(nm)
φ
4j
349
354
353
351
350
359
24 880
22 520
22 660
22 000
23 570
28 960
410
424
420
420
412
446
60
69
65
70
62
86
0.89
0.82
0.88
0.80
0.62
0.62
4t
4r
4p
4l
4b
a
Wavelengths of maximum absorbance (λabs) or emission intensity
b
c
(λem). Extinction coefficient. Quantum yield.
absorption at 348 nm with a moderate extinction coefficient
(2.24 × 104 M−1 cm−1) and maximum emission at 412 nm
with a high quantum yield (φ = 0.89) in DMSO. All those
compounds exhibited very strong blue fluorescence when
excited at around 365 nm. In general, the alkoxy substitution
on the α-phenyl ring led to red shifts of the maximum
absorbance and improvements in the Stokes shift (Figure 2).
a
Reaction conditions: 1f (1 mmol), 2 (2 mmol), sulfur powder 3 (1.5
mmol), CuCl (20 mol %), 1,10-phenanthroline (20 mol %), K2CO3
b
(1.0 mmol), DMSO (25 mL), 120 °C (oil bath), 24 h. Isolated yield.
s). It is worthy to note that the method was also applicable to
the substrates with the phenyl R2 group being replaced with a
pyridinyl or naphthyl ring (Scheme 3, 4t−u). Other aliphatic
aldehydes including n-butylaldehyde, pentanal, 2-chloroacetal-
dehyde, and paraformaldehyde were also investigated under
the standard conditions; however, no desired product was
obtained in each case (not shown). Despite this result, the
method is complementary to the existing methods, which are
only applicable to the synthesis of 2-methyl substituted
benzo[4,5]thieno[2,3-d]thiazole.35,36 To our disappointment,
the method was not applicable to the synthesis of the
Figure 2. Absorption spectra (solid line) and fluorescence spectra
(dashed line) in DMSO.
C
DOI: 10.1021/acs.orglett.9b04206
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Substitution with the electron-donating group and halide in the
β-phenyl ring at 4-position did not lead to the substantial
change of the quantum yield. As shown in the SI, compound
4u was poorly fluorescent, exhibiting larger Stokes shift (94
nm) and lower fluorescence quantum yield (11%). This may
due to the increasing of the π conjugation at the β-phenyl ring,
which is a well-known phenomenon between Stokes shift and
emission efficiency.
Scheme 5. Control Experiments
On the basis of results from the previous literature
research,58−62 a plausible mechanism (Scheme 4) is proposed
Scheme 4. Proposed Mechanistic Pathway
mediate for this three-component reaction, but was impractical
to be detected and isolated due to its high reactivity under the
conditions. Besides, we found that upon the introduction of 3
equiv of BHT or TEMPO to the reaction of 1f under standard
conditions, the yield of 4f was not significantly decreased
(Scheme 5c and 5d). This result might indicate that the
reaction did not undergo a radical mechanistic pathway.
In summary, a copper-based catalytic annulation has been
developed and applied to a one-pot synthesis of the exclusive
2-arylbenzo[4,5]thieno[2,3-d]thiazoles from 2-(2-
bromophenyl)acetonitrile, aromatic aldehydes, and sulfur
powder. To our knowledge, this could represent the first
three-component construction of benzothienothiazole skeleton
via the successive formation of the thiophene and thiazole
rings. Further studies on the reaction mechanism as well as its
application are in progress in our lab.
for this newly discovered three-component one-pot reaction.
First, in the presence of the copper catalyst, 2-(2-
bromophenyl)acetonitrile 1f was converted to intermediate A
via an oxidative insertion. Then intermediate A reacted with
sulfur, H2O, and K2CO3 to afford intermediate B. It is worthy
2−
to note that sulfur might be converted to Sn species, as
elemental sulfur undergoes disproportionation to give an
oligosulfide anion and sulfite under basic conditions.61,62 Next,
reductive elimination of intermediate B delivered intermediate
C, which was converted to intermediate D63 through the
removal of three-membered sulfur ring. Intramolecular
cyclization followed by proton shift in D gave intermediate
E, which furnished intermediate G via a nucleophilic attack to
the electrophilic S4. Next, the condensation of G with aromatic
aldehyde afforded intermediate J, via intermediate H. Finally,
the automatic air-oxidation of K delivered the target
compound.
Control experiments (Scheme 5) were carried out to further
corroborate the postulated mechanistic pathway. First, 2-(2-
bromophenyl)acetonitrile and S4 were subjected to the
standard reaction conditions, and the benzo[b]thiophen-2-
amine was expected to be detected and characterized under the
conditions without the involvement of aromatic aldehyde.
However, to our disappointment, no desired benzo[b]-
thiophen-2-amine 5a could be observed.32,64 We also changed
the temperature to 60, 80, 100, 140 °C, respectively, or
switched the solvent to DMF/glycol (20:1).32 However, no
desired product could be observed in each case. Second, when
benzo[b]thiophen-2-amine, prepared via the reaction of 2-(2-
bromophenyl)acetonitrile with Pd(dppf)Cl2, dppf, Na2S2O3,
and Cs2CO3,32 reacted with benzaldehyde and S4 under the
conditions, the title 2-arylbenzo[4,5]thieno[2,3-d]thiazole
could be achieved in 35% yield. These results might indicate
that benzo[b]thiophen-2-amine serves as the crucial inter-
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04206.
■
S
Experimental procedures, data of compounds character-
ization (PDF)
Accession Codes
CCDC 1951852 and 1972173 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
*Tel: +86-22-27406121. E-mail: duyunfeier@tju.edu.cn.
ORCID
Yunfei Du: 0000-0002-0213-2854
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We acknowledge the National Natural Science Foundation of
China (#21472136) for financial support.
■
D
DOI: 10.1021/acs.orglett.9b04206
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Organic Letters
Letter
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DOI: 10.1021/acs.orglett.9b04206
Org. Lett. XXXX, XXX, XXX−XXX