Metal-Free Synthesis of Imidazo[2,1-b]thiazoles from Thioimidazoles and Ketones Mediated by Selectfluor

Article abstract of DOI:10.1002/ejoc.202000815

This paper presents a practical and efficient strategy for the preparation of imidazol[2,1-b]-thiazoles from thioimidazoles and ketones mediated by Selectfluor. The proposed mechanism suggests that this transformation took place through electrophilic thiolation at an α-carbon of ketones by sulfur cation, which is produced by the oxidation of thioimidazole by Selectfluor. This metal-free protocol tolerated various ketones, including methyl ketones or non-methyl ketones, aryl ketones or aliphatic ketones. The experimental results indicated that steric hindrance of the substituents at the α-position of ketones or on the aromatic ring of aryl ketones had significant influence on the yields of imidazol[2,1-b]-thiazoles. Thioimidazole and benzothioimidazoles were well tolerated while 5-substituted benzothioimidazoles provided the mixture of the corresponding 6-substituted and 7-substituted benzoimidazo[2,1-b]thiazole products.

Full text of DOI:10.1002/ejoc.202000815

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Metal-free Synthesis of Imidazo[2,1-b]thiazoles from
Thioimidazoles and Ketones Mediated by Selectfluor
Authors: Jinwu Zhao, Qiannan Xiao, Jiaxi Chen, and Jingxiu Xu
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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to this Accepted Article as a result of editing. Readers should obtain
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000815
Link to VoR: https://doi.org/10.1002/ejoc.202000815
01/2020

10.1002/ejoc.202000815
European Journal of Organic Chemistry
FULL PAPER
Metal-free Synthesis of Imidazo[2,1-b]thiazoles from
Thioimidazoles and Ketones Mediated by Selectfluor
Jinwu Zhao,*[a, b] Qiannan Xiao,[a, b] Jiaxi Chen [a] and Jingxiu Xu*[a, b]
[a]
Dr. Jinwu Zhao, * Qiannan Xiao, Jiaxi Chen, Jingxiu Xu
School of Pharmacy
Guangdong Medical University
No.1 Xincheng Blvd, Songshan Lake National High-tech Industrial Development Zone,Dongguan, 523808, China
E-mail: jwzhao@gdmu.edu.cn
jingxiuxu@sohu.com
[b]
Key Laboratory of Big Data Mining and Precision Drug Design
Guangdong Medical University
No.1 Xincheng Blvd, Songshan Lake National High-tech Industrial Development Zone,Dongguan, 523808, China
Supporting information for this article is given via a link at the end of the document.
Abstract: This paper presents a pratical and efficient strategy for the
preparation of imidazol[2,1-b]-thiazoles from thioimidazoles and
ketones mediated by Selectfluor. Regarding the mechanism, it was
proposed that this transformation took place through electrophilic
thiolation at an -carbon of ketones by sulfur cation, which is
produced by the oxidation of thioimidazole by Selectfluor. This
metal-free protocol tolerated various ketones, including methyl
ketones or non-methyl ketones, aryl ketones or aliphatic ketones.
The experimental results indicated that steric hindrance of the
substituents at a-position of ketones or on the aromatic ring of aryl
ketones had significant influence on the yields of imidazol[2,1-b]-
thiazoles. Thioimidazole and benzothioimidazoles were well
tolerated while 5-substituted benzothioimidazoles provided the
mixture of the corresponding 6-substituted and 7-substituted
benzoimidazo[2,1-b]thiazole products.
According to literature reports, 2-aminobenzothiazoles could
yield imidazo[2,1-b]thiazole molecules via the heterocyclization
[6]
reaction with traditional -bromoketone,
aryl methyl ketones,
chalcones, [7] cyclic ketones, [8] 2-phenoxyacetophenones, [9] aryl
[10]
aldehydes coupled with alkynes,
aryl aldehydes coupled with
On the other hand, 2-
[11]
[12]
isocyanides,
and so on.
mercaptobenzoimidazoles were also able to afford this class of
heterocyclic compounds through the annulation reactions with
[13]
[14]
[15]
terminal alkynes,
dihalobenzenes,
Nitroalkenes,
dihaloalkenes.
ortho-
[16]
[17]
or ortho-halonitrobenzenes.
Moreover, it
was disclosed that
a few samples of benzoimidazo[2,1-
b]thiazoles were obtained through the reflux of 2-
mercaptobenzoimidazoles and acetophenones in acetic acid
containing concentrated sulfuric acid followed by the addition of
acetic anhydride. [18] However, this multi-step procedure led an
annoying work-up due to the use of a large amount of base, and
those protocols mentioned above suffer from limited starting
materials or/and less environmentally friendly reaction systems,
although they could provide alternative approaches to
imidazo[2,1-b]thiazole compounds. Therefore, green and
practical process for the synthesis of imidazo[2,1-b]thiazoles is
still in demand.
Introduction
Imidazo[2,1-b]thiazole derivatives constitute an important class
of fused heterobicyclic compounds, and have a wide range of
applications in medicinal chemistry because of their broad
spectrum of biological activities, such as antitumor, antifungal,
Selectfluor is a commercially available solid reagent. Due to its
high safety, exceptional stability, non-toxicity and unique
antidiabetic, anthelmintic, cardiodepressant, antitubercular
[1]
activities, and so on.
For example, as an imidazol[2,1-b]-
reactive activities, Selectfluor is employed as not only
a
thiazole derivative, pifithrin-β (Figure 1. A) is a potent p53
“fluorine-free” functional reagent in organic transformations at
[2]
inhibitor with an IC50 of 23 nm;
a
11C-labeled imidazo[2,1-
both the laboratory and industrial levels, but also an oxidant or
b]benzothiazole B was reported to serve as fluoroprobe in PET
[19]
Lewis acid in a variety of organic reactions.
In the aspect of
[3]
analysis of Alzheimer's disease, and a patented imidazol[2,1-
heterocyles synthesis, a variety of functionalized heterocyclic
molecules has been realized successfully using Selectfluor as a
mild oxidant. [20]
b]-thiazole compound C was developed as sirtuin modulator. [4]
In our previous work, we demonstrated that non-methyl ketones
could
react
with
2-mercaptobenzimidazoles
to
give
benzoimidazo[2,1-b]thiazoles promoted by DMSO/H2O2 in water,
[21] which was deemed to proceed through a free-radical pathway.
Unfortunately but expectedly, aryl methyl ketones are not
applicable to this protocol. Herein, we disclose that imidazol[2,1-
b]-thiazole heterocyclic compounds could be prepared under the
promotion of Selectfluor from 2-mercaptobenzoimidazoles and
various ketones, including aryl methyl ketones (Scheme 1)
Figure 1. Representative drug or drug candidates containing imidazo[2,1-
b]thiazole moieties
In view of the importance of imidazo[2,1-b]thiazole derivatives, a
[5]
number of procedures have been developed to prepare them.
1
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10.1002/ejoc.202000815
European Journal of Organic Chemistry
FULL PAPER
an oxidant. We then turned our attention to other oxidants and
found that Selectfluor was a superior oxidant for the electrophilic
thiolation reaction (entries 4-7). As expected, the results of
screening reaction solvents indicated that polar solvent favored
this reaction more, and sulfolane was found to be the most
beneficial medium (entries 8-12). We next evaluated the
influence of various acids on this cyclization reaction. This
transformation took place likewise smoothly in the presence of
1.2 equivalent of methanesulfonic acid together with 2.0
equivalent of Ac2O (entry 13). As shown in entries 14-18,
methanesulfonic acid proved to be the best choice with
comparable promotion against p-toluenesulfonic acid, while non-
protic acids, BF3.OEt2 and Sc(OTf)3, performed inefficiently
(entries 14-18). We finally found that the yield of the target
hetercycle was slightly improved when sulfolane solvent was
decreased from 3 mL to 1 mL (entry 19).
Scheme 1. Synthesis of imidazo[2,1-b]thiazoles from thioimidazoles and
Ketones.
Results and Discussion
We initiated our investigations by examining the cyclization of 2-
mercaptobenzoimidazole (1a) with acetophenone (2a), and the
results are tabulated in table 1.
Having identified optimal conditions, we next evaluated the
generality and scope of the methodology for the synthesis of
benzoimidazo[2,1-b]thiazoles via the oxidative cyclization of
ketones and 2-mercaptobenzimidazoles (table 2).
Table 1. Optimization of the reaction conditions. [a]
Table 2. The scope of ketones substrate. [a, b]
entry
Acid (equiv)
oxidant
Solvent
Yield
(%) [b]
0
1
con.H2SO4 (2.5)
--
AcOH
2
con.H2SO4 (2.5)/Ac2O
CH3SO3H (5.0)/Ac2O
CH3SO3H (5.0)/Ac2O
CH3SO3H (5.0)/Ac2O
CH3SO3H (5.0)/Ac2O
CH3SO3H (5.0)/Ac2O
CH3SO3H (5.0)/Ac2O
CH3SO3H (5.0)/Ac2O
CH3SO3H (5.0)/Ac2O
CH3SO3H (5.0)/Ac2O
CH3SO3H (5.0)/Ac2O
CH3SO3H (1.2)/Ac2O
TsOH (1.2)/Ac2O
--
AcOH
23
0
3
--
AcOH
4
K2S2O8
AcOH
26
11
61
59
51
36
19
8
5
Br2
AcOH
6
selectfluor
NFSI
AcOH
7 [c]
8
AcOH
selectfluor
selectfluor
selectfluor
selectfluor
selectfluor
selectfluor
selectfluor
selectfluor
selectfluor
selectfluor
selectfluor
selectfluor
CH3CN
Dioxane
DCE
9
10
11
12
13
14
15
16
17
18
Toluene
Sulfolane
Sulfolane
Sulfolane
Sulfolane
Sulfolane
Sulfolane
Sulfolane
Sulfolane
74
74
75
60
33
10
0
TfOH (1.2)/Ac2O
CF3COOH (1.2)/Ac2O
BF3.OEt2 (1.2)/Ac2O
Sc(OTf)3 (1.2/Ac2O
CH3SO3H (1.2)/Ac2O
19 [d]
77
[a]
Reaction Conditions: 1a (0.5 mmol), 2a (0.5 mmol), oxidant (1.0 equiv),
Ac2O (2.0 equiv), time (2h) and other parameters indicated in table. [b] Isolated
yield. [c] NFSI = N-Fluorobenzenesulfonimide.[d] 1 mL of Sulfolane was used
When this reaction proceeded in the presence of 2.5 equivalent
of concentrated H2SO4 in acetic acid at 120 oC for 2h, no desired
hetercyclic compound was obtained (entry 1). [18] The addition of
2 equivalent acetic anhydride to the reaction led to the formation
of 3aa in 23% yield (entry 2). However, replacing concentrated
H2SO4 with methanesulfonic acid resulted in no dectectable
product formation (entry 3). These results suggested that
concentrated H2SO4 acted as not only a proton source but also
[a]
Reactions were performed with 1a (0.5 mmol), 2 (0.5 mmol), CH3SO3H (1.2
equiv) and Ac2O (2.0 equiv) in sulfolane (1mL) at 120 oC for 2h.
Isolated
[b]
yield.
2
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10.1002/ejoc.202000815
European Journal of Organic Chemistry
FULL PAPER
2-Mercaptobenzimidazole was firstly treated with a variety of
ketones under the optimal reaction conditions. In comparison
with acetophenone, para-alkyl substituted acetophenones could
go through this transformation with similar high efficiency (3aa-
3ad), while para-substituted acetophenones with non-alkyl,
whether electron donating groups or electron withdrawing
groups, delivered the desired polycyclic S, N-heterocycles in
lower yields (3ae-3ai). Unexpectedly, meta-substituted
acetophenones provided higher yields than para-substituted
ones (3aj-3al). 3’, 4’-(Methylenedioxy)acetophenone and 2’-
methylacetophenon could also undergo this reaction, and
produced the target S,N-containing molecules in inferior yields
compared with the standard substrate (3am-3an). As indicated
in table 2, other aryl ethanones, including 1-(naphthalen-2-
Additionally, 2-thioimidazole could also go across this oxidative
cyclization reaction and the desired product was isolated in 68%
yield (3fa).
In order to verify whether this transformation takes place through
a free-radical pathway, 1 equivalent of butylated hydroxytoluene
（BHT） was added to the reaction of 1a and 2a under the
standard conditions and 3aa was isolated in 76% yield (scheme
2). The control experiment showed that radical scavenger had
no influence on this transformation and the reaction occurs in a
way different from our previous work. [21]
yl)ethan-1-one,
1-(thiophen-3-yl)ethan-1-one
and
1-
Scheme 2. Control experiment
(benzo[b]thiophen-2-yl)ethan-1-one, could react with 1a
efficiently and provided the target heterocyclic compounds in
yields of 70%, 62% and 53%, respectively (3ao-3aq). Aryl
ketones with longer alkyl chains, such as propiophenone and 1-
phenylpentan-1-one, were then evaluated and found to be
suitable substrates, yielding the target products in 70% and 60%
yield, respectively, lower than acetophenone for the possible
reason of the steric hindrance of the alkyl unit (3ar-3as). As a
cyclic aryl ketone, 7-Br-α-tetralone was found to be a great
reaction partner, giving the expected products in excellent yields
(3at). Aliphatic ketones were finally examined and the
experimental results showed that they were all able to react with
thioimidazole with lower efficiency than aryl ketones (3au-3aw).
Based on the above experimental results and the related
[22]
literature report,
a reasonable reaction pathway for this
oxidative cyclization reaction of ketones and thioimidazoles is
proposed in Scheme 3. Electrophilic thionic intermediate A is
firstly produced through the oxidation of thioimidazole by
Selectfluor. Promoted by protonation, ketone can enolize into B,
which then attacks sulfur of intermediate A to furnish the -sulfur
substituted ketone C. A nitrogen atom of imidazole launches an
intramolecular nucleophilic attack on the carbonyl to facilitate D.
Hydroxyl of D reacts with acetic anhydride to form acetic ester E,
which eliminates a molecule of acetic acid to give the final
imidazo[2,1-b]thiazole product.
Next, various thioimidazoles were treated with acetophenone
under the optimized reaction conditions (table 3).
Table 3. The scope of thioimidazoles substrate. [a, b]
Scheme 3. Proposed mechanism
Conclusion
In summary, we have disclosed an oxidative cyclization reaction
for the preparation of imidazol[2,1-b]-thiazoles from
thioimidazoles and ketones mediated by Selectfluor. This metal-
free protocol demonstrates broad substrate scope and
comparatively simple operation. Additionally, this process will
also enable the construction of exotic heterocyclic motifs for
important biological studies.
[a]
Reactions were performed with 1 (0.5 mmol), 2a (0.5 mmol), CH3SO3H (1.2
equiv) and Ac2O (2.0 equiv) in sulfolane (1mL) at 120 oC for 2h.
Isolated
[b]
yield.
As shown in table 3, 5, 6-dichloro-2-mercaptobenzimidazole
reacted with acetophenone smoothly, facilitating the desired
heterocyclic compound in 69% isolated yield (3ba). When 5-
substituted-2-mercaptobenzimidazoles were subjected to the
reaction, similar outcomes to our previous work were observed
due to the alternative nitrogen atom in the benzimidazole ring
capable of nucleophilic additions (3ca-3da). Whereas, strong
electron-withdrawing nitro substituted 2-mercaptobenzimidazole
was not able to afford the expected S, N-heterocyclic product
(3ea), possibly owing to the poor nucleophilicity of the nitrogen
atom caused by the strong electron-withdrawing group.
Experimental Section
General information
All reagents were of analytical grade and obtained from commercial
suppliers and used without further purification. 1H and 13C NMR spectra
were obtained on a Bruker AVANCE III HD 400 at 400 MHz and 100
3
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10.1002/ejoc.202000815
European Journal of Organic Chemistry
FULL PAPER
MHz respectively, using CDCl3 as the solvent with tetramethylsilane
(TMS) as an internal standard at room temperature. High-resolution
mass spectra were obtained on Agilent 6545 Q-TOF LC/MS system
using electrospray ionisation. GC-MS were performed on Thermo Trace
DSQ.
7.31 (m, 3H), 7.29 – 7.23 (m, 1H), 7.11 (ddd, J = 8.3, 7.2, 1.1 Hz, 1H), 6.64 (s, 1H), 2.40 (s,
3H). 13C NMR (101 MHz, CDCl3) δ 169.1, 157.0, 151.9, 148.6, 133.2, 129.9, 129.9, 126.8,
123.4, 122.3, 120.5, 119.2, 111.5, 107.5, 21.1. HRMS calcd for C17H12N2O2S [M+H]+:
309.0692. Found: 309.0698
3-(4-(trifluoromethyl)phenyl)benzo[4,5]imidazo[2,1-b]thiazole (3ai) white solid, mp
173−174 °C. 1H NMR (400 MHz, CDCl3) δ 7.73 (t, J = 9.7 Hz, 5H), 7.33 – 6.94 (m, 3H),
6.61 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 157.1, 148.1, 132.7 (q, J = 248.6 Hz), 130.3,
129.7, 129.1, 126.1 (q, J = 3.8 Hz), 125.0 (q, J = 22.3 Hz), 123.9, 122.4, 120.9, 119.2,
111.6, 109.3. HRMS calcd for C16H9F3N2S [M+H]+: 319.0511. Found: 319.0515
3-(m-tolyl)benzo[4,5]imidazo[2,1-b]thiazole (3aj) white solid, mp 83−84 °C. 1H NMR (400
MHz, CDCl3) δ 7.78 (d, J = 8.2 Hz, 1H), 7.52 – 7.42 (m, 3H), 7.38 (td, J = 4.8, 1.8 Hz, 1H),
7.34 – 7.28 (m, 1H), 7.23 (d, J = 8.3 Hz, 1H), 7.06 (t, J = 7.7 Hz, 1H), 6.57 (s, 1H), 2.46 (s,
3H). 13C NMR (101 MHz, CDCl3) δ 138.9, 134.4, 130.9, 129.4, 129.3, 128.8, 125.9, 123.3,
120.4, 119.1, 111.7, 106.9, 22.8. HRMS calcd for C16H12N2S [M+H]+: 265.0794. Found:
265.0806
Typical procedure for the synthesis of product 3.
To a test tube (25 mL) were added thioimidazole 1 (0.5 mmol), ketone 2
(0.5 mmol), CH3SO3H (57.7mg, 1.2 equiv), Ac2O (76.6mg, 1.5 equiv) and
o
1 mL of sulfolane. The tube was heated at 120 C with an oil bath under
magnetic stirring for 2 h. 10 mL of water was then added after cooling.
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 oC) : ethyl acetate (4 : 1, v/v)
to give final imidazo[2,1-b]thiazoles.
3-(3-methoxyphenyl)benzo[4,5]imidazo[2,1-b]thiazole (3ak) white solid, mp 134−135 °C.
1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.3 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 7.38 – 6.96
(m, 6H), 6.59 (s, 1H), 3.85 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 159.9, 134.1, 130.5, 130.1,
123.4, 121.1, 120.5, 119.2, 115.9, 114.2, 111.9, 107.3, 55.5. HRMS calcd for C16H12N2OS
[M+H]+: 281.3525. Found: 281.3523.
Analytic data of the obtained compounds.
3-phenylbenzo[4,5]imidazo[2,1-b]thiazole (3aa) 12b white solid, mp 136−137 °C. 1H NMR
(400 MHz, CDCl3) δ 7.81 (d, J = 8.2 Hz, 1H), 7.65 (dd, J = 4.9, 2.5 Hz, 2H), 7.58 (m, 3H),
7.33 (ddd, J = 8.3, 7.1, 1.3 Hz, 1H), 7.24 (d, J = 8.2 Hz, 1H), 7.07 (ddd, J = 8.4, 7.0, 1.3 Hz,
1H), 6.59 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 157.1, 148.6, 134.2, 130.1, 130.0, 129.3,
128.9, 128.7, 123.3, 120.4, 119.1, 111.7, 107.1.
3-(3-fluorophenyl)benzo[4,5]imidazo[2,1-b]thiazole (3al) white solid, mp 193−194 °C. 1
H
NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.2 Hz, 1H), 7.59 (td, J = 8.0, 5.7 Hz, 1H), 7.49 (dt, J
= 7.7, 1.3 Hz, 1H), 7.45 – 7.24 (m, 4H), 7.13 (t, J = 7.7 Hz, 1H), 6.69 (s, 1H). 13C NMR (101
MHz, CDCl3) δ 162.7 (d, J = 248.9 Hz), 157.0, 148.6, 132.8 (d, J = 2.1 Hz), 131.2 (d, J = 8.2
Hz), 130.7 (d, J = 8.5 Hz), 129.9, 124.5 (d, J = 3.2 Hz), 123.5, 120.6, 119.3, 117.1 (d, J =
21.0 Hz), 115.9 (d, J = 22.7 Hz), 111.5, 108.1. HRMS calcd for C15H9FN2S [M+H]+:
269.0543. Found: 269.0537
3-(p-tolyl)benzo[4,5]imidazo[2,1-b]thiazole (3ab) 12b white solid, mp 115−116 °C. 1
H
NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.3 Hz, 1H), 7.57 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 7.8
Hz, 2H), 7.35 (ddd, J = 8.2, 7.2, 1.1 Hz, 1H), 7.28 (d, J = 4.5 Hz, 1H), 7.15 – 7.04 (m, 1H),
6.60 (s, 1H), 2.52 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 157.2, 148.7, 140.3, 134.3, 130.1,
129.6, 128.7, 126.4, 123.3, 120.4, 119.1, 111.8, 106.7, 21.5.
3-(benzo[d][1,3]dioxol-5-yl)benzo[4,5]imidazo[2,1-b]thiazole (3am) white solid, mp
158−159 °C. 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.2 Hz, 1H), 7.33 (dt, J = 9.3, 7.6 Hz,
2H), 7.20 – 7.06 (m, 3H), 6.99 (d, J = 7.8 Hz, 1H), 6.56 (s, 1H), 6.11 (s, 2H). 13C NMR (101
MHz, CDCl3) δ 157.0, 149.1, 148.5, 148.1, 133.8, 130.0, 123.3, 123.0, 120.4, 119.1, 111.6,
109.1, 108.7, 106.8, 101.7. HRMS calcd for C16H10N2O2S [M+H]+: 295.0536. Found:
295.0534
3-(4-isobutylphenyl)benzo[4,5]imidazo[2,1-b]thiazole (3ac) white solid, mp 86−87 °C. 1
NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.2 Hz, 1H), 7.52 (d, J = 7.6 Hz, 2H), 7.27 (dd, J =
31.9, 8.1 Hz, 4H), 7.10 – 6.99 (m, 1H), 6.52 (s, 1H), 2.59 (d, J = 7.4 Hz, 2H), 1.96 (dt, J =
14.0, 6.8 Hz, 1H), 0.97 (d, J = 7.0 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 157.3, 148.6,
144.1, 134.4, 130.1, 129.7, 128.6, 126.7, 123.3, 120.4, 119.1, 111.8, 106.7, 45.3, 30.2, 22.5.
HRMS calcd for C19H18N2S [M+H]+: 307.1263. Found: 307.1265.
H
3-(o-tolyl)benzo[4,5]imidazo[2,1-b]thiazole (3an) white solid, mp 53−54 °C. 1H NMR (400
MHz, CDCl3) δ 7.77 (d, J = 8.2 Hz, 1H), 7.38 (ddt, J = 52.2, 27.5, 7.3 Hz, 5H), 6.98 (t, J =
7.5 Hz, 1H), 6.70 (d, J = 8.3 Hz, 1H), 6.55 (s, 1H), 2.17 (s, 3H). 13C NMR (101 MHz, CDCl3)
δ 156.7, 148.5, 138.3, 132.9, 130.7, 130.7, 130.6, 130.0, 128.9, 126.4, 123.4, 120.8, 119.1,
110.6, 107.1, 19.7. HRMS calcd for C16H12N2S [M+H]+: 265.0794. Found: 265.0802.
3-(naphthalen-1-yl)benzo[4,5]imidazo[2,1-b]thiazole (3ao) white solid, mp 149−150 °C.
1H NMR (400 MHz, CDCl3) δ 7.98 (dd, J = 38.6, 8.4 Hz, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.63
– 7.42 (m, 2H), 7.24 (dt, J = 60.1, 8.2 Hz, 1H), 6.77 – 6.59 (m, 1H), 6.27 (d, J = 8.7 Hz, 1H).
13C NMR (101 MHz, CDCl3) δ 156.8, 148.6, 133.5, 132.0, 131.9, 130.9, 130.0, 129.0, 128.7,
127.6, 126.9, 126.7, 125.4, 125.1, 123.3, 120.6, 119.0, 111.4, 108.7. HRMS calcd for
C19H12N2S [M+H]+: 301.0794. Found: 301.0806
3-([1,1'-biphenyl]-4-yl)benzo[4,5]imidazo[2,1-b]thiazole (3ad) white solid, mp
131−132 °C. 1H NMR (400 MHz, CDCl3) δ 7.85 – 7.59 (m, 7H), 7.55 – 7.19 (m, 5H), 7.07 (t,
J = 7.9 Hz, 1H), 6.58 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 157.3, 148.7, 143.0, 139.9,
134.1, 130.1, 129.2, 129.1, 128.2, 128.1, 127.6, 127.2, 123.5, 120.5, 119.2, 111.9, 107.4.
HRMS calcd for C21H14N2S [M+H]+: 327.0950. Found: 327.0954.
3-(4-(methylthio)phenyl)benzo[4,5]imidazo[2,1-b]thiazole (3ae) white solid, mp
152−153 °C. 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.3 Hz, 1H), 7.57 – 7.48 (m, 2H),
7.42 – 7.22 (m, 4H), 7.05 (t, J = 7.3 Hz, 1H), 6.53 (s, 1H), 2.56 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 157.2, 148.7, 141.7, 133.8, 129.0, 126.0, 125.5, 123.4, 120.5, 119.2, 111.8, 107.0,
15.3. HRMS calcd for C16H12N2S2 [M+H]+: 297.0515. Found: 297.0513.
3-(thiophen-3-yl)benzo[4,5]imidazo[2,1-b]thiazole (3ap) 12b white solid, mp 93−94 °C. 1
NMR (400 MHz, CDCl3) δ 7.78 – 7.43 (m, 3H), 7.26 (dd, J = 22.3, 7.0 Hz, 3H), 7.02 (t, J =
H
3-(4-methoxyphenyl)benzo[4,5]imidazo[2,1-b]thiazole (3af) 12b white solid, mp
146−147 °C. 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.3 Hz, 1H), 7.59 – 7.43 (m, 2H),
7.37 – 7.18 (m, 2H), 7.12 – 6.97 (m, 3H), 6.48 (s, 1H), 3.89 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 161.0, 157.2, 148.6, 134.1, 130.3, 130.1, 123.3, 121.5, 120.4, 119.1, 114.3, 111.7,
106.4, 55.5.
7.8 Hz, 1H), 6.54 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 156.9, 148.5, 130.1, 129.5, 129.3,
127.7, 127.1, 126.5, 123.5, 120.6, 119.2, 111.5, 107.5.
3-(benzo[b]thiophen-2-yl)benzo[4,5]imidazo[2,1-b]thiazole (3aq) white solid, mp
126−127 °C. 1H NMR (400 MHz, CDCl3) δ 7.96 – 7.89 (m, 2H), 7.81 (d, J = 8.3 Hz, 1H),
7.67 (s, 1H), 7.51 (dd, J = 23.0, 7.6 Hz, 3H), 7.35 (t, J = 7.9 Hz, 1H), 7.11 (t, J = 8.0 Hz, 1H),
6.83 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 156.6, 148.4, 140.3, 139.1, 130.1, 129.3, 127.4,
126.3, 125.9, 125.3, 124.5, 123.7, 122.5, 120.9, 119.3, 111.9, 110.5. HRMS calcd for
C17H10N2S2 [M+H]+: 307.0358. Found: 307.0358.
3-(4-(benzyloxy)phenyl)benzo[4,5]imidazo[2,1-b]thiazole (3ag) white solid, mp
122−123 °C. 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.4 Hz, 1H), 7.57 – 7.18 (m, 9H),
7.09 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 8.3 Hz, 1H), 6.42 (s, 1H), 5.11 (s, 2H). 13C NMR (101
MHz, CDCl3) δ 160.2, 157.2, 148.7, 136.4, 134.0, 130.3, 130.1, 128.8, 128.3, 127.6, 123.4,
121.8, 120.4, 119.2, 115.3, 111.8, 106.5, 70.2. HRMS calcd for C22H16N2OS [M+H]+:
357.1056. Found: 357.1057
2-methyl-3-phenylbenzo[4,5]imidazo[2,1-b]thiazole (3ar) [21] white solid, mp 168−169 °C.
1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.2 Hz, 1H), 7.65 – 7.57 (m, 5H), 7.57 – 7.45 (m,
3H), 7.30 – 7.21 (m, 2H), 6.98 (ddd, J = 8.3, 7.2, 1.1 Hz, 2H), 6.88 – 6.78 (m, 1H), 2.32 (s,
4-(benzo[4,5]imidazo[2,1-b]thiazol-3-yl)phenyl acetate (3ah) white solid, mp 165−166 °C.
1H NMR (400 MHz, CDCl3) δ 7.83 (dt, J = 8.3, 0.9 Hz, 1H), 7.71 (d, J = 8.6 Hz, 2H), 7.42 –
4
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10.1002/ejoc.202000815
European Journal of Organic Chemistry
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3H). 13C NMR (101 MHz, CDCl3) δ 154.9, 147.8, 130.1, 130.0, 129.9, 129.0, 128.7, 128.4,
122.8, 120.2, 119.5, 118.9, 111.1, 13.1.
Keywords: Selectfluor • ketones • thioimidazoles • imidazo[2,1-
b]thiazoles • metal-free
3-phenyl-2-propylbenzo[4,5]imidazo[2,1-b]thiazole (3as) [21] yellow solid, mp 94−95 °C.
1H NMR (400 MHz, CDCl3) δ 7.76 (dd, J = 8.2, 0.9 Hz, 1H), 7.61 (dd, J = 4.9, 2.0 Hz, 3H),
7.56 – 7.49 (m, 2H), 7.30 – 7.22 (m, 1H), 6.97 (ddd, J = 8.2, 7.2, 1.0 Hz, 1H), 6.75 (dd, J =
8.3, 1.0 Hz, 1H), 2.65 (t, J = 7.5 Hz, 2H), 1.69 (h, J = 7.4 Hz, 2H), 0.96 (t, J = 7.3 Hz, 3H).
13C NMR (101 MHz, CDCl3) δ 155.1, 147.8, 130.2, 130.0, 129.9, 129.0, 128.8, 128.4, 125.6,
122.9, 120.2, 118.8, 111.0, 29.3, 24.1, 13.4.
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J = 8.3 Hz, 1H), 7.41 (t, J = 8.1 Hz, 2H), 7.26 (dt, J = 25.7, 8.3 Hz, 2H), 3.00 (t, J = 7.8 Hz,
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130.5, 130.0, 128.3, 128.2, 125.7, 125.3, 123.4, 120.9, 120.5, 119.6, 112.6, 29.1, 24.0.
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148−149 °C. 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.3 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H),
7.32 (ddd, J = 8.3, 7.3, 1.2 Hz, 1H), 7.19 (ddd, J = 8.3, 7.2, 1.1 Hz, 1H), 3.04 (ddt, J = 6.2,
4.4, 2.2 Hz, 3H), 2.71 (tt, J = 5.9, 2.2 Hz, 3H), 2.11 – 1.83 (m, 5H). 13C NMR (101 MHz,
CDCl3) δ 147.6, 127.2, 122.7, 120.4, 119.3, 118.9, 110.4, 24.3, 23.2, 22.6, 21.7.
3-methylbenzo[4,5]imidazo[2,1-b]thiazole (3av) [21] white solid, mp 169−170 °C. 1H NMR
(400 MHz, CDCl3) δ 7.77 (dd, J = 11.8, 8.3 Hz, 2H), 7.36 (dd, J = 8.3, 7.1 Hz, 1H), 7.26 –
7.12 (m, 1H), 6.32 (s, 1H), 2.70 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 157.2, 148.3, 130.2,
129.8, 123.2, 120.6, 119.0, 110.4, 104.6, 14.4.
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3-ethyl-2-methylbenzo[4,5]imidazo[2,1-b]thiazole (3aw) [21] white solid, mp 114−115 °C.
1H NMR (400 MHz, CDCl3) δ 7.77 (t, J = 7.7 Hz, 1H), 7.67 (t, J = 7.5 Hz, 1H), 7.33 (q, J =
7.5 Hz, 1H), 7.22 (q, J = 7.7 Hz, 1H), 3.00 (dq, J = 15.5, 7.7 Hz, 2H), 2.36 (s, 2H), 1.36 (dt,
J = 15.1, 7.6 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 155.4, 147.8, 130.4, 129.8, 122.8,
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6,7-dichloro-3-phenylbenzo[4,5]imidazo[2,1-b]thiazole (3ba) white solid, mp
211−212 °C. 1H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.71 – 7.49 (m, 5H), 7.30 (s, 1H),
6.66 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 159.0, 147.6, 134.1, 130.7, 129.3, 128.8, 128.7,
127.7, 124.4, 120.1, 112.9, 108.2. HRMS calcd for C15H8Cl2N2S [M+H]+: 318.9858. Found:
318.9860.
6-(difluoromethoxy)-3-phenylbenzo[4,5]imidazo[2,1-b]thiazole and 7-
(difluoromethoxy)-3-phenylbenzo[4,5]imidazo[2,1-b]thiazole (3ca + 3ca’)
1H NMR (400 MHz, CDCl3) δ 7.85 – 7.42 (m, 6H), 7.21 – 6.78 (m, 2H), 6.76 – 6.08 (m, 2H).
13C NMR (101 MHz, CDCl3) δ 158.3 (d, J = 66.8 Hz), 148.3 (d, J = 163.6 Hz), 134.1 (d, J =
17.1 Hz), 130.4 (d, J = 10.3 Hz), 129.2, 128.7 (d, J = 3.7 Hz), 119.7, 116.4, 113.3, 112.2,
110.0, 107.7, 107.6, 104.1. HRMS calcd for C16H10F2N2OS [M+H]+: 317.0555. Found:
217.0569.
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phenylbenzo[4,5]imidazo[2,1-b]thiazole (3da + 3da’)
1H NMR (400 MHz, CDCl3) δ 7.73 – 7.39 (m, 6H), 7.18 – 6.92 (m, 1H), 6.85 (d, J = 8.6 Hz,
1H), 6.50 (s, 1H), 2.45 (s, 2H), 2.33 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 157.1, 156.6,
149.0, 146.8, 134.2, 134.2, 133.2, 130.3, 130.2, 130.1, 130.1, 129.5, 129.5, 129.0, 128.9,
128.8, 128.7, 128.2, 124.9, 121.9, 119.0, 118.7, 111.8, 111.2, 107.1, 106.8, 21.8, 21.7.
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12b
3-phenylimidazo[2,1-b]thiazole (3fa)
white solid, mp 70−71 °C. 1H NMR (400 MHz,
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Acknowledgements
The authors thank the National Natural Science Foundation of
China (21572040) for financial support.
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Entry for the Table of Contents
Imidazo[2,1-b]thiazoles could be prepared from thioimidazoles and Ketones promoted by Selectfluor. This metal-free protocol was
applicable to various ketones, including strong electron-withdrawing substituted aryl ketones, methyl ketones or non-methyl ketones.
Moreover, this procedure featured simple operation and easy work-up.
7
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