DMSO/H2O2 Promoted Regioselective Synthesis of Benzoimidazo[2,1-b]thiazoles from 2-Mercaptobenzimidazoles and Ketones in Water

Article abstract of DOI:10.1002/adsc.201900909

We report a green and regioselective process for the construction of benzoimidazo[2,1-b]thiazole skeletons in water using DMSO/H₂O₂ as an oxidant. The experimental data lend support to a mechanism in which the transformation is initiated by oxidizing methylene of ketone into carbon radical under the oxidation of DMSO/H₂O₂. This operationally simple and metal-free procedure could facilitate a diverse collection of benzoimidazo[2,1-b]thiazole derivatives. (Figure presented.).

Full text of DOI:10.1002/adsc.201900909

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DOI: 10.1002/adsc.201900909
DMSO/H2O2 Promoted Regioselective Synthesis of Benzoimidazo
[2,1-b]thiazoles from 2-Mercaptobenzimidazoles and Ketones in
Water
Jingxiu Xu,a, c Renjin Deng,a Jiaxi Chen,a, c Xiaodong Tang,b, c,* and
Jinwu Zhaoa, c,*
a
School of Pharmacy, Guangdong Medical University, Dongguan 523808, People’s Republic of China
E-mail: jwzhao@gdmu.edu.cn
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, People’s Republic of China
b
E-mail: tangxdong@smu.edu.cn
Dongguan Key Laboratory of Drug Design and Formulation Technology, Dongguan 523808, People’s Republic of China
c
Manuscript received: July 22, 2019; Revised manuscript received: September 18, 2019;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.201900909
In view of the importance of benzoimidazo[2,1-b]
Abstract: We report a green and regioselective
process for the construction of benzoimidazo[2,1-b]
thiazoles, a few procedures have been developed to
prepare this class of polycyclic heterocyles.[4] Typi-
thiazole skeletons in water using DMSO/H2O2 as an
cally, it was reported that benzoimidazo[2,1-b]thiazole
oxidant. The experimental data lend support to a
skeletons could be constructed through copper cata-
mechanism in which the transformation is initiated
lyzed reactions of 2-mercaptobenzoimidazoles with
by oxidizing methylene of ketone into carbon
terminal alkynes,[1,5] nitroalkene,[6] or dihaloalkenes.[7]
radical under the oxidation of DMSO/H2O2. This
Although these reported strategies could provide an
operationally simple and metal-free procedure could
alternative approach to the preparation of the benzoi-
facilitate a diverse collection of benzoimidazo[2,1-
midazo[2,1-b]thiazole compounds, they suffer from
b]thiazole derivatives.
limited starting materials or/and less environmentally
friendly reaction systems. Therefore, green and prac-
Keywords: Benzoimidazo[2,1-b]thiazoles; Ketones;
tical process for the synthesis of benzoimidazo[2,1-b]
2-Mercaptobenzimidazoles; DMSO; Water
thiazoles is still in demand.
Owing to its low cost, low toxicity and environ-
mental friendliness, dimethyl sulfoxide (DMSO) is
Imidazol[2,1-b]-thiazole derivatives are important class used as a green oxidant as well as a solvent, sources of
of heterocyclic compounds, which exhibit promising C1 or sulfur in organic synthesis and in the pharma-
biological activities, such as calcium channel antago- ceutical industry.[8] On the other hand, hydrogen
nistic activity, antifungal properties, anti-inflammatory peroxide is also viewed as a convenient, safe and
properties, antitumor agent, antidiabetic agent, anti- environmentally benign oxidizing agent that generates
tubercular agent, anticardiovascular agent, and so on.[1] only water as the by-product.[9] In our continued
For example, imidazol[2,1-b]-thiazole derivative pifi-
thrin-β ( A) is a potent p53 (a protein as transcription
factor) inhibitor with an IC50 of 23 nm; Benzoimidazo
[2,1-b]thiazole compound B is developed as anticancer
agent that can target the bulk of tumour cells and
cancer stem cells,[2] and 11C-labeled imidazo[2,1-b]
benzothiazole C could be employed as fluoroprobe in
PET analysis of Alzheimer’s disease.[3] As a subclass
of imidazo[2,1-b]thiazole derivatives, benzoimidazo
[2,1-b]thiazoles might possess novel significant bio-
logical activities and be utilized as drug candidates in
therapeutic areas.
Figure 1. Examples of imidazol[2,1-b]-thiazoles.
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peroxides, which are usually used in radical oxidation
reaction.[11] Some of them were then evaluated. To our
delight, the addition of hydrogen peroxide generated
the heterocyclic molecule in an enhanced 80% yield
(entries 12–14). However, H2O2 were not able to
promote this transformation alone (entry 15). After
examining a range of acids used commonly, including
inorganic hydrochloric acid, phosphoric acid and
organic trifluoroacetic acid (TFA), trifluoromethane-
sulfonic acid (TfOH), 2 equivalent of hydrochloric
acid was confirmed to be the best choice for this access
to benzoimidazo[2,1-b]thiazoles from 2-mercaptoben-
zimidazoles and ketones in water (entries 16–20).
Finally, the results of further optimization suggested
that 2 equiv. of DMSO was competent to drive this
reaction in the presence of 6 equiv. of H2O2 (entries 21
and 22). Whereas, decreasing the amount of H2O2 led
to a lower yield of the desired heterocycle (entry 23).
Hence, the optimal reaction conditions involved the
factors listed in entry 22.
Scheme 1. DMSO/H2O2 promoted synthesis of benzoimidazo
[2,1-b]thiazoles.
The generality and scope of the methodology was
investigated after establishing the optimal reaction
conditions, and the results are collected in Table 2. A
variety of propiophenones were firstly subjected to the
reaction with 2-mercaptobenzimidazole (1a) and deliv-
ered the desired heterocyclic products in acceptable
yields. In general, electron-donating group substituted
propiophenones performed better than those substituted
by electron-withdrawing group (3aa–3aa-10). Aryl
Scheme 2. Control experiments.
interest in the development of green processes for the ketones with long longer alkyl chains, including 1-
synthesis of various heterocyclic compounds,[10] we phenylbutan-1-one and 1-phenylpentan-1-one, were
report herein a facile transition metal-free process for also evaluated and found to be suitable substrates,
the synthesis of benzoimidazo[2,1-b]thiazoles from 2- affording the target molecules in 76% and 59% yield,
mercaptobenzimidazoles and ketones promoted by respectively, lower than propiophenone for the possible
DMSO along with H2O2 in water (Scheme 1).
reason of the steric hindrance of the alkyl unit (3ab–
In order to explore the optimum reaction condi- 3ac). However, the product 3ad was obtained with
tions, the reaction of 2-mercaptobenzoimidazole (1a) only 34% yield when α-tetralone went across the
and propiophenone (2a) was selected as the model annulation reaction (3ad), and acetophenone failed to
reaction. The experimental data are collected in yield the expected product (3ae).
Table 1. This reaction was firstly carried out in DMSO
Next, a serial of aliphatic ketones were examined
°
at 75 C for 24 h, under the catalysis of 30 mol% by reacting with 2-mercaptobenzimidazole under the
elemental iodine in the presence of 4.0 equiv. of p- optimized conditions. As demonstrated in table 2,
toluenesulfonic acid (PTSA) using molecular oxygen cyclic aliphatic ketones were able to be converted into
10a
as an oxidant,
no desired fused heterocyclic the corresponding products readily and cyclohexanone
compound 3aa was detected by GC-MS (entry 1). was identified as an excellent reaction partner, provid-
Unexpectedly, the desired molecule was formed when ing the product 3af in 94% isolated yield (3af–3ah).
this reaction proceeded without iodine and oxygen in a As for acyclic aliphatic ketones, symmetrical pentan-3-
sealed tube (entry 2). Our experimental results showed one underwent the cyclization reaction efficiently
that increasing the reaction temperature benefited this (3aj), while propan-2-one provided the expected
transformation (entries 3–4), and the replacement of heterocyle in awfully low yield and no product was
PTSA with 50% H2SO4 led to an improved yield of observed after subjecting nonan-5-one to this reaction,
3aa (entry 5). As demonstrated in entries 6–11, possibly due to the steric bulk (3ai–3ak). Our
aqueous mediums were beneficial to this reaction and experimental results suggested that methyl, alkyl-
performing this reaction in water using 10 equivalent substituted ketones were able to go through this
of DMSO as an oxidant gave the best result (entries 6– transformation with high efficiency and regiocontrol,
11). In an effort to improve the yield of this promising introducing sulfur atom exclusively at the internal
result, we turned our attention to the inclusion of methylene position (3al–3ap-5). Among them, 1-
Adv. Synth. Catal. 2019, 361, 1–6
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Table 1. Optimization of the reaction conditions.[a]
°
Entry
Oxidant (equiv.)
Acid (equiv.)
Solvent
Temperature ( C)
Yield (%) b
1[c]
2[c]
3
I2 (0.3)/O2
–
–
–
–
–
DMSO (10)
DMSO (10)
DMSO (10)
DMSO (10)
PTSA (4)
PTSA (4)
PTSA (4)
PTSA (4)
H2SO4 (2)
H2SO4 (2)
H2SO4 (2)
H2SO4 (2)
H2SO4 (2)
H2SO4 (2)
H2SO4 (2)
H2SO4 (2)
H2SO4 (2)
H2SO4 (2)
H2SO4 (2)
HCl (4)
DMSO
DMSO
DMSO
DMSO
DMSO
D/W[d]
H2O
75
75
0
10
28
39
46
54
65
68
12
20
27
76
80
39
0
89
89
10
40
79
89
89
50
105
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
4
5
6[c]
7
8
9
H2O
EtOH
CH3CN
Dioxane
H2O
H2O
H2O
H2O
H2O
H2O
H2O
10
11
12[e]
13
14[f]
15
16
17
18
19
20
21
22
23
DMSO (10)
DMSO (10)/DTPB (6)
DMSO (10) /H2O2 (6)
DMSO (10) /TBHP (6)
H2O2 (6)
DMSO (10)/H2O2 (6)
DMSO (10)/H2O2 (6)
DMSO (10)/H2O2 (6)
DMSO (10)/H2O2 (6)
DMSO (10)/H2O2 (6)
DMSO (5)/H2O2 (6)
DMSO (2)/H2O2 (6)
DMSO (2)/H2O2 (3)
HCl (2)
H3PO4 (2)
TFA (2)
TfOH (2)
HCl (2)
HCl (2)
H2O
H2O
H2O
H2O
HCl (2)
H2O
[a] Conditions: 1a (0.5 mmol), 2a (0.5 mmol), solvent (3 mL), time (0.5 h) and other parameters indicated in table.
[b] solated yield.
[c] Reaction time is 24 h.
[d] D/W=DMSO/water (1:1).
[e] DTPB=di-t-butyl peroxide.
[f] TBHP=t-butyl hydroperoxide.
phenylpropan-2-ones containing para, meta or ortho midazoles failed to yield the desired heterocyclic
substituent were all able to undergo the cyclization products (3fa+3fa’).
reaction with 2-mercaptobenzimidazole, furnishing
target 2-aryl substituted fused heterocycles in moderate of control experiments were implemented. The dimer
to good yields (3ap–1-3ap-5). A of 1a was isolated in 42% yield when this reaction
To gain insight into the mechanistic profile, a series
We next sought to test the influence of the proceeded in the absence of ketone (Eq. 1), and heating
substituents on the phenyl ring of various 2-mercapto- the dimer A and 2a under the optimized conditions
benzimidazoles by reacting them with 2a under the provided the polycyclic product 3aa in 90% isolated
optimized conditions, and the results are listed in yield (Eq. 2). When 1 equivalent of TEMPO was
Table 3. When 5, 6-dichloro-2-mercaptobenzimidazole added to the reaction of 1a and 2a under the standard
was subjected to the reaction, the target heterocycle conditions, 3aa was isolated in 11% yield (Eq. 3). No
was isolated in 65% yield (3ba). 5-Substituted-2- corresponding benzoimidazo[2,1-b]thiazole was de-
mercaptobenzimidazoles, including 5-chloro, 5-me- tected by GC-MS when the reaction proceeded in the
thoxy and 5-methyl substituted ones, went across this presence of 2 equiv. of TEMPO (Eq. 4), which
transformation smoothly, providing the mixtures of the suggested that the reaction between 1a and 2a was
corresponding 6-substituted and 7-substituted benzoi- completely inhibited by radical scavenger and the
midazo[2,1-b]thiazole products by the ratio of 1.5:1, reaction might take place through a free-radical path-
1:1 and 2:1, respectively, determined by GC-MS (3ca way.
+3ca’, 3da+3da’, 3ea+3ea’). However, strong elec-
On basis of the collective data, a reasonable
tron-withdrawing group substituted 2-mercaptobenzi- reaction pathway for the route to benzoimidazo[2,1-b]
Adv. Synth. Catal. 2019, 361, 1–6
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Table 2. The scope of ketones substrate.[a,b]
Table 3. The influence of the substituents on the phenyl ring of
various 2-mercaptobenzimidazoles.[a,b]
[a] Reactions were performed with 1 (0.5 mmol), 2a (0.5 mmol),
DMSO (2 equiv.), 30% H2O2 (6 equiv.) and 5 mol/L HCl
°
(2 equiv.) in water (3 mL) at 135 C for 0.5 h.
[b] Isolated yield.
[a] Reactions were performed with 1a (0.5 mmol), 2 (0.5 mmol),
DMSO (2 equiv.), 30% H2O2 (6 equiv.) and 5 mol/L HCl
°
(2 equiv.) in water (3 mL) at 135 C for 0.5 h.
[b] Isolated yield.
thiazoles from 2-mercaptobenzimidazoles and ketones
in water is depicted in Scheme 3. Although it is not
sure what active species DMSO evolves into in this
reaction, DMSO could undoubtedly take the role of
radical oxidation based on the related literature
Scheme 3. Proposed reaction mechanism.
reports.[12] 2-mercaptobenzimidazole (1a) is oxidized the other hand, the expelled sulfur radical could react
by DMSO into the dimer, disulphide A. Meanwhile, with B or dimerize into disulphide A.
under the oxidation of DMSO along with acid and
In summary, we have demonstrated a transition
H2O2, α-methylene of ketone turns into carbon radical metal-free protocol for the construction of benzoimida-
B, which rapidly reacts with disulphide A to furnish zo[2,1-b]thiazole skeleton from 2-mercaptobenzimida-
intermediate C,[13] with a sulfur radical expelled. Then, zoles and ketones in water, using DMSO/H2O2 oxidant
intermediate D is formed through a nucleophilic attack system. Featuring regioselectivity, green, easy-han-
of nitrogen atom of C onto the carbonyl, followed by dling and broad substrate scope, this methodology can
the elimination of a molecule of water under the facilitate a diverse collection of benzoimidazo[2,1-b]
promotion of acid to give the final product 3aa.[14] On thiazole derivatives. Our future investigation will focus
Adv. Synth. Catal. 2019, 361, 1–6
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Typical Procedure for the Synthesis of Product 3.
To a pressure tube (20 mL) were added 2-mercaptobenzimida-
zole 1 (0.5 mmol), ketone 2 (0.5 mmol), DMSO (78.1 mg,
10 equiv.), 30% H2O2 (373.3 mg, 6 equiv.), 5 mol/L HCl
(200.0 mg, 2 equiv.), and 3 mL of water. The tube was then
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°
sealed, stirred magnetically and heated at 135 C with an oil
bath for 0.5 h. After cooling to room temperature, the reaction
mixture was neutralized with 10% aqueous NaHCO3 solution
and extracted with (3×10 mL) of ethyl acetate. The combined
organic solution was evaporated in a rotary evaporator to
remove the volatile components. The residue was purified by
preparative TLC on silica, eluting with petroleum ether (60–
°
90 C) : ethyl acetate (3 : 1, v/v) to give final benzoimidazo[2,1-
b]thiazoles.
Acknowledgements
The authors thank the National Natural Science Foundation of
China (21572040), Natural Science Foundation of Guangdong
Province (2015 A030310371) and ”Group-type” Special Sup-
port Project for Education Talents in University (4SG19045G)
for financial support.
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DMSO/H2O2 Promoted Regioselective Synthesis of Benzoi-
midazo[2,1-b]thiazoles from 2-Mercaptobenzimidazoles and
Ketones in Water
Adv. Synth. Catal. 2019, 361, 1–6
J. Xu, R. Deng, J. Chen, X. Tang*, J. Zhao*