Aminothiolation of α-Bromocinnamaldehydes to Access Imidazo[2,1-b]thiazoles by Incorporation of Two Distinct Photoinduced Processes

Article abstract of DOI:10.1021/acs.orglett.0c02907

A visible-light-promoted metal-free catalytic system was developed to achieve the aminothiolation of α-bromocinnamaldehydes. This mechanistically novel approach allows the synthesis of diverse imidazo[2,1-b]thiazole derivatives in satisfactory yields at r

Full text of DOI:10.1021/acs.orglett.0c02907

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Letter
Aminothiolation of α‑Bromocinnamaldehydes to Access
Imidazo[2,1‑b]thiazoles by Incorporation of Two Distinct
Photoinduced Processes
Ziren Chen, Weiwei Jin, Yu Xia, Yonghong Zhang, Mengwei Xie, Shangchao Ma, and Chenjiang Liu*
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ABSTRACT: A visible-light-promoted metal-free catalytic system was developed to achieve the aminothiolation of α-
bromocinnamaldehydes. This mechanistically novel approach allows the synthesis of diverse imidazo[2,1-b]thiazole derivatives in
satisfactory yields at room temperature under visible-light irradiation by incorporation of two distinct photoinduced processes. The
reaction features readily accessible feedstocks, easy operation, mild reaction conditions, and wide reaction scope.
used nitrogen heterocycles1 and organic sulfur com-
pounds2 are key structural units, which are frequently
encountered in materials, natural products, agrochemicals, and
pharmaceutical drugs. Among them, imidazo[2,1-b]thiazoles
are valuable structural moieties (Figure 1) that are widely
properties. Typically, it has been reported that imidazo[2,1-
b]thiazole compounds could be synthesized through the
elemental sulfur or iron catalyzed annulation reactions of 2-
aminobenzothiazoles with ketones/chalcones or cyclic ketones
(Scheme 1a,b).11 In addition, imidazo[2,1-b]thiazole deriva-
tives could be synthesized via the copper-catalyzed cyclization
reactions of 2-mercaptobenzoimidazoles with alkynes,12 nitro-
alkenes,13 prefunctionalized olefins, and aromatics (Scheme
F
Scheme 1. Strategies Related the Construction of
Imidazo[2,1-b]thiazole Skeletons
Figure 1. Representative pharmaceuticals containing imidazo[2,1-
b]thiazoles.
present in biologically active compounds3 and functional
materials.4 For example, 11C-labeled molecule A was used for
PET imaging of Alzheimer’s patients’ brains and β-amyloid
plaques.5 Compounds B, C, and their derivatives are usually
present in antitumor drugs,6 antimicrobial drugs,7 antibacterial
agents,8 and antiallergic drugs.9 Moreover, the compound D
(tilomisole) has been utilized in the treatment of colon
cancer.10 In the past decades, imidazo[2,1-b]thiazoles have
attracted much attention, and various protocols for their
syntheses have been developed owing to their prominent
Received: August 30, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02907
© XXXX American Chemical Society
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1c).14 Recently, benzoimidazo[2,1-b]thiazoles were con-
structed via an DMSO/H2O2 promoted intermolecular
cyclization of 2-mercaptobenzoimidazoles and ketones
(Scheme 1d).15 Although significant achievements have been
demonstrated, these available methods have some limitations,
such as the requirement of heating and metal catalysts, which
are contrary to the concept of green chemistry. Furthermore,
due to the strong coordination between metals and
heteroatoms, trace transition metals are difficult to remove
from heteroaryl compounds.11a Therefore, from the perspec-
tive of green chemistry and pharmaceutical applications,
efficient synthetic methods for imidazo[2,1-b]thiazoles em-
ploying mild and metal-free conditions are highly desirable.
In recent years, visible-light-induced photoredox catalysis
has become a powerful strategy to achieve organic trans-
formations under very mild conditions.16,17 To date, photo-
redox catalysis has already been extensively used to construct
fused nitrogen heterocycles.18 In contrast, the preparation of
imidazo[2,1-b]thiazoles from 2-mercaptobenzimidazoles under
visible-light irradiation has not been reported. As part of our
continuing interest in the preparation of heterocyclic
compounds,19 herein we report a highly efficient intermolec-
ular cyclization of 2-mercaptobenzimidazoles and Z-α-
bromocinnamaldehydes for the convenient construction of
benzoimidazo[2,1-b]thiazole derivatives by incorporation of
two distinct visible-light-induced processes under metal-free
conditions (Scheme 1e), in which visible light combined with
base were found to be the key factors for the success of this
cyclization.
a
Table 1. Optimization of Reaction Conditions
b
entry
photocatalyst
eosin Y
eosin B
yield (%)
1
2
63
28
43
55
44
43
30
64
65
50
75
62
72
46
16
3
4
5
rhodamine B
rose bengal lactone
acid red
6
7
methylene blue
indigo
8
9
10
11
12
13
14
15
[Ru(bpy)3Cl2]·6H2O
Ru(bpy)3PF6
Ir(ppy)3
eosin Y
eosin Y
c
cd
,
ce
,
eosin Y
c
cf
,
eosin Y
a
Reaction conditions: 1a (0.25 mmol), 2a (0.3 mmol), photocatalyst
(10 mol %), K2CO3 (0.25 mmol), DMSO (1 mL), 10 W white LED,
rt, 12 h, air. Isolated yield. 5 mol % of eosin Y. 0.2 mmol of K2CO3.
b
c
d
e
f
0.3 mmol of K2CO3. Without visible-light irradiation, at 100 °C.
For our initial study, we chosen Z-α-bromocinnamaldehyde
(1a) and 2-mercaptobenzimidazole (2a) as the model
substrates, eosin Y as the photocatalyst, K2CO3 as the base,
and DMSO as the solvent for demonstrating the practicability
of aminothiolation under 10 W white LED irradiation.
Delightfully, the expected cyclization product 3a was obtained
in 63% yield after 12 h at room temperature (Table 1, entry 1).
The structure of 3a was further definitely determined by X-ray
diffraction. Encouraged by this result, various photocatalysts,
including organic dyes and ruthenium/iridium polypyridyl
complexes, were examined (Table 1, entries 2−10). However,
other organic dyes and Ir(ppy)3 led to lower yields, and
ruthenium polypyridyl complexes gave similar yields (Table 1,
entries 8 and 9). From the perspective of green and sustainable
chemistry, eosin Y was chosen as the best photocatalyst
because it is cheap, less toxic, and easier to handle. To our
delight, 3a was obtained in 75% yield by reducing the loading
of eosin Y to 5 mol % (Table 1, entry 11). Notably, neither
reducing nor increasing the amount of the K2CO3 can promote
the yield (Table 1, entries 12 and 13). Meanwhile, in the
absence of photocatalysts, 1a also reacted with 2a to afford 3a
in 46% yield (entry 14). Thus, we speculated that an electron
donor−acceptor (EDA) complex may be formed during this
novel cyclization reaction.17 Furthermore, to examine the
importance of visible light, the reaction was performed at 100
°C in the dark, providing 3a in lower yield (entry 15). These
results indicate that visible light is an important factor. After a
quick screen of other conditions such as visible-light sources,
bases, solvents, ratio of reactants, and time (see the Supporting
Information for details, Tables S1−S4), the reaction conditions
in entry 11 were selected as the optimal conditions.
Scheme 2. Substrate Scope of Z-α-
Bromocinnamaldehydes
a,b
a
Reaction conditions: 1 (0.25 mmol), 2a (0.3 mmol), K2CO3 (0.25
b
c
mmol), DMSO (1 mL), 10 W white LED, rt. Isolated yields. Z-α-
chlorocinnamaldehyde instead of 1a.
an electron-donating (CH3 and OCH3) or electron-with-
drawing (F, Cl, Br and CF3) group could react with 2-
mercaptobenzimidazole 2a smoothly to deliver cyclization
products in 60−67% yields (3b, 3c, 3e, 3f, 3g, and 3j).
Subsequently, to explore the effect of steric hindrance on this
With the optimized reaction conditions in hand, we started
to investigate the substrate scope (Scheme 2). Generally, a
variety of para-substituted Z-α-bromocinnamaldehydes bearing
B
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Letter
reaction, o-OCH3-, m-CF3-, m-Cl-, and o-Cl-substituted Z-α-
bromocinnamaldehydes were also performed under standard
conditions, rendering the corresponding imidazo[2,1-b]-
thiazoles in good yields (3d, 3h, 3i, and 3k, 67−82%). The
above results revealed that the reaction is not affected by
electronic and steric effects. It is worth noting that the target
compound 3l was also obtained with low yield (21%) when the
benzene ring was replaced by a furan ring. To our surprise, the
Z-α-chlorocinnamaldehyde was also an applicable substrate,
and the target product 3a could be isolated in 73% yield.
To further examine the scope of the visible-light-induced
cyclization reaction, various 2-mercaptobenzimidazole deriva-
tives were tested. As illustrated in Scheme 3, the effect of
containing heterocyclic compounds such as 1H-imidazole-2-
thiol, 4,5-diphenyl-1H-imidazole-2-thiol, and 2-mercaptoqui-
nazolin-4(3H)-one with 1a obtained corresponding products
(3t−3v, 31−81%). We delightedly found that 5-methoxy-3H-
imidazo[4,5-b]pyridine-2-thiol treated with 1a under standard
conditions could also afford the desired cyclized products (3w
+ 3w′, 76%). Unexpectedly, the reaction of pyrimidine-2-thiol
and 1a under standard conditions could not yield the cyclized
product but a substituted product (3x). Unfortunately, 2-
mercaptobenzothiazole and 2-mercaptobenzoxazole did not
give the target compounds under the standard conditions.
The benzoimidazo[2,1-b]thiazole 3a was delivered in 56%
yield in a gram-scale reaction (Scheme 4a). Meanwhile, we
a,b
Scheme 3. Substrate Scope of 2-mercaptobenzimidazoles
Scheme 4. Gram-Scale Reaction and Application of Present
Work
evaluated the transformation of 3a to 3aa and 3ab by the
derivatization reaction (Scheme 4b). When 3a was treated with
aniline and acetic acid in ethanol at 60 °C, the Schiff base
product with potential applications 3aa was obtained in 98%
yield. The Knoevenagel condensation reaction product 3ab
was synthesized in 95% yield when ethyl cyanoacetate was
used as the substrate with 3a. Because the solid of 3ab emits
strong fluorescence, it may have potential to be used as an
optoelectronic material.
To gain a preliminary understanding of the cyclization
reaction mechanism, several control experiments were carried
out. First, the reaction was conducted in the absence of K2CO3
or visible-light irradiation; expectedly, only a trace amount of
desired product 3a was observed (Figure 2a). The results
indicated that visible-light irradiation and base are all essential
to this transformation. The yield of 3a dropped sharply in the
presence of TEMPO, BHT, or 1,1-diphenylethylene (Figure
2b), and the TEMPO-trapped product was detected by ESI-
HRMS analysis (see the Supporting Information for details,
Figure S3). These results indicate that a radical pathway might
be involved. Meanwhile, EPR experiment further confirmed
the involvement of the free radical reaction pathway (see the
Supporting Information for details, Figure S4). The
elimination product 3-phenylprop-2-ynal (4) of 1a was not
observed when this reaction proceeded in the absence of 2a
(Figure 2c). Furthermore, the reaction of 4 and 2a under
standard conditions did not yield 3a (Figure 2d). These results
can rule out the way that 1a is first eliminated by base and then
subjected to free radical addition cyclization with 2a. To
further prove the effect of visible-light irradiation, “on/off”
experiments were performed, and the result clearly demon-
strates that the significant role of the visible-light in the
reaction system. (Figure 2e). To further explore the probable
a
Reaction condition: 1a (0.25 mmol), 2 (0.3 mmol), eosin Y (5 mol
%), K2CO3 (0.25 mmol), DMSO (1 mL), 10 W white LED, rt, 12 h,
air. Isolated yield. The isomeric ratio was determined by H NMR
analysis.
b
c
1
substituents on 2-mercaptobenzimidazoles was also inves-
tigated. 2-Mercaptobenzimidazoles with an electron-donating
substituent (such as Me, OMe, and OCHF2 with special
activity) or electron-withdrawing (Br) group on the 5 position
proceeded successfully, and the corresponding products as a
mixture of two isomers in modest to good yields were obtained
(3m + 3m′−3p + 3p′, 58−85%). Interestingly, double
substituted 2-mercaptobenzimidazoles also were efficiently
transformed into the desired products 3q, 3r, and 3s in 49%,
96% and 65% yields, respectively. Additionally, other nitrogen-
C
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Scheme 5. Proposed Mechanism
abstraction of an aryl hydrogen in intermediate I by base,
leading to the intermediate J. Finally, aromatization of J yields
the 3-phenylbenzoimidazo[2,1-b]thiazole-2-carbaldehyde 3a as
the final product, but other reaction paths cannot be
completely excluded.
In conclusion, we have successfully developed a novel
visible-light-promoted intermolecular cyclization reaction
between Z-α-bromocinnamaldehydes and 2-mercaptobenzoi-
midazoles, rendering a series of compounds containing an
imidazo[2,1-b]thiazole skeleton in satisfactory isolated yields
with one C(sp2)−S and one C(sp2)−N bonds formation and
one C(sp2)−Br bond cleavage in one pot. This novel approach
features metal-free, mild conditions, readily accessible raw
materials, inexpensive catalyst, easy operation, and excellent
functional group compatibility.
Figure 2. Mechanistic studies: (a) control experiments; (b) radical-
trapping experiments; (c) reaction of 1a under the standard reaction
conditions; (d) reaction of 4 and 2a under the standard reaction
conditions; (e) on/off LED irradiation experiments; (f) UV−vis
spectroscopic measurements on various combinations of 1a, 2a, and
K2CO3 in DMSO.
mechanism of this aminothiolation process, the UV−vis
spectroscopic measurements on various combinations of 1a,
2a, and K2CO3 in DMSO were conducted (Figure 2f). When
1a, 2a, and K2CO3 were combined, the solution showed a
distinct coloration and its absorption band showed a
bathochromic displacement in the visible region; the results
indicate that the EDA complex may be formed.17
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02907.
On the basis of the above control experiments and previous
reports,16,17 two possible reaction pathways were proposed in
Scheme 5. In path a (without eosin Y), first, an EDA complex
B17 was formed between 1a and thiolate anion A. Under
visible-light irradiation, this EDA complex B undergoes a
single-electron transfer (SET) to generate sulfur-centered
radical intermediate C and vinyl radical D. Then these free
radicals are coupled to obtain intermediate E. Next,
intermediate E undergoes intramolecular Michael addition to
form the intermediate J. In path b, initially, the intermediate F
is formed via the Michael addition of thiol tautomer of 2a to
1a.20 Under visible light irradiation, the photoredox catalyst
eosin Y goes to its excited state (eosin Y*), which undergoes a
SET with the intermediate F to produce an eosin Y radical
cation (eosin Y•+) and radical intermediate G. Subsequently,
intermediate G undergoes intramolecular cyclization to form
the intermediate H. Next, H reduces eosin Y•+ back to the
ground state, completing the oxidative quenching cycle and
generating a cationic intermediate I in the process. The
Experimental materials and procedures, NMR of
compounds (PDF)
Accession Codes
CCDC 2000586−2000587 and 2000589−2000591 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
■
Chenjiang Liu − Urumqi Key Laboratory of Green Catalysis
and Synthesis Technology, Key Laboratory of Energy Materials
Chemistry, Ministry of Education, Key Laboratory of Advanced
Functional Materials, Autonomous Region, College of Chemistry,
D
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Xinjiang University, Urumqi 830046, P.R. China;
pubs.acs.org/OrgLett
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Chem. 1966, 9, 545−551. (b) Budriesi, R.; Ioan, P.; Locatelli, A.;
Cosconati, S.; Leoni, A.; Ugenti, M. P.; Andreani, A.; Toro, R. D.;
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orcid.org/0000-0002-8241-0809; Email: pxylcj@126.com
Authors
Ziren Chen − Urumqi Key Laboratory of Green Catalysis and
Synthesis Technology, Key Laboratory of Energy Materials
Chemistry, Ministry of Education, Key Laboratory of Advanced
Functional Materials, Autonomous Region, College of
Chemistry, Xinjiang University, Urumqi 830046, P.R. China
Weiwei Jin − Urumqi Key Laboratory of Green Catalysis and
Synthesis Technology, Key Laboratory of Energy Materials
Chemistry, Ministry of Education, Key Laboratory of Advanced
Functional Materials, Autonomous Region, College of
Chemistry, Xinjiang University, Urumqi 830046, P.R. China;
orcid.org/0000-0002-5996-3229
Yu Xia − Urumqi Key Laboratory of Green Catalysis and
Synthesis Technology, Key Laboratory of Energy Materials
Chemistry, Ministry of Education, Key Laboratory of Advanced
Functional Materials, Autonomous Region, College of
Chemistry, Xinjiang University, Urumqi 830046, P.R. China
Yonghong Zhang − Urumqi Key Laboratory of Green Catalysis
and Synthesis Technology, Key Laboratory of Energy Materials
Chemistry, Ministry of Education, Key Laboratory of Advanced
Functional Materials, Autonomous Region, College of
Chemistry, Xinjiang University, Urumqi 830046, P.R. China;
orcid.org/0000-0002-7740-9408
Mengwei Xie − Urumqi Key Laboratory of Green Catalysis and
Synthesis Technology, Key Laboratory of Energy Materials
Chemistry, Ministry of Education, Key Laboratory of Advanced
Functional Materials, Autonomous Region, College of
Chemistry, Xinjiang University, Urumqi 830046, P.R. China
Shangchao Ma − Urumqi Key Laboratory of Green Catalysis
and Synthesis Technology, Key Laboratory of Energy Materials
Chemistry, Ministry of Education, Key Laboratory of Advanced
Functional Materials, Autonomous Region, College of
Chemistry, Xinjiang University, Urumqi 830046, P.R. China
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Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the National Natural Science
Foundation of China (Grant Nos. 21961037, 21702175, and
21572195) and the Graduate Innovation Project of Xinjiang
Uygur Autonomous Region (XJ2020G007). We thank Prof.
Dr. Guoquan Liu (Peking University) for his generous help
with the data processing of EPR.
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Organic Letters
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