Approach for 2-(arylthio)imidazoles and imidazo[2,1-b]thiazoles from imidazo[2,1-b][1,3,4]thiadiazoles by ring-opening and -reconstruction

Article abstract of DOI:10.1039/c6ob00102e

A highly efficient one-pot synthesis of imidazo[2,1-b]thiazole derivatives has been developed and proceeds via a ring-opening and ring-closing reconstruction of imidazo[2,1-b][1,3,4]thiadiazoles with phenylacetylene in the presence of potassium tert-butox

Full text of DOI:10.1039/c6ob00102e

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Approach to 2-(arylthio)imidazoles and imidazo[2,1-b]thiazoles
from imidazo[2,1-b][1,3,4]thiadiazoles by ring-opening and -
reconstruction
Received 00th January 20xx,
Accepted 00th January 20xx
Benyi Shi,a Zhouhe Zhu,a Yi-Shuo Zhu,a Dagang Zhou,a Jinyuan Wang,a Panpan Zhoua and
DOI: 10.1039/x0xx00000x
Huanwang Jing*a,b
www.rsc.org/
Abstract: Highly efficient one-pot synthesis of imidazo[2,1-b]thiazole derivatives has been developed by a ring-opening
and ring-closing reconstruction of imidazo[2,1-b][1,3,4]thiadiazoles with phenylacetylene in the presence of potassium
tert-butoxide (t-BuOK) under very mild reaction conditions. Proposed mechanism is computerized by using a DFT method
at B3LYP/6-31+G(d, p) level. The imidazo[2,1-b][1,3,4]thiadiazoles are also successfully converted to a series of 2-(arylthio)-
1H-imidazoles by using aryl halide as reactant, copper (II) acetylacetonate (Cu(acac)2) as catalyst under microwave
irradiation conditions. The key features of these reactions can be readily available reagents, simple operations, convenient
utilization of new heterocyclic synthons, and a great variety of substrates with functional group compatibility.
endurance.7 As important frameworks, diaryl thioethers are
discovered widely in natural products, material chemicals,8
Introduction
Imidazo[2,1-b]thiazole,
heteroaromatic compounds, has been found in numerous
bioactive molecules (Fig. 1). 3-Methyl-5,6-diarylimidazo[2,1-
pharmaceuticals,9 and medicinal reagents (Fig. 1, iv vi).10
-
one
important
scaffold
of
Recently, such compounds have been also utilized as ligands in
constituting metal organic frameworks (MOFs).11 Even so, their
synthetic routes are very limited due to the poisoning of
b]thiazoles (
i
) exhibit anti-coccidia behaviour.1 Imidazo[2,1- metallic catalysts by sulfur atom toward oxidative
decomposition or oligomerization.12 Therefore, new strategies
b]benzothiazoles (ii) show to be a good antibacterial and a
superb fluoroprobe in the positron emission tomography (PET)
imaging analysis of Alzheimer’s disease.2 5,6-Diarylimidazo[2,1-
b][1,3]thiazoles (iii) display excellent antibacterial property.3
Although current methodologies for the preparation of
imidazo[2,1-b]thiazoles are focused on the construction of
fused rings from the substitution of heterocycles at oriented
positions,4 they suffer some drawbacks of restrictions of
particular substitution patterns,5a low yields and long
experimental periods,5b or extra synthetic manipulations in Pd-
mediated Suzuki-type cross-coupling.5c,d
to approach these sulfur-containing heterocyclic compounds
are extremely desired at present.
In the last decades, the C-X construction has emerged as a
promising methodology to build organic compounds including
various heterocycles without functionalization.6 Alternative to
traditional palladium catalysed coupling reactions, copper
catalysed coupling reactions have been developed increasingly
in terms of their economy, convenience and environmental
Fig. 1 Bioactive imidazo[2,1-b]thiazoles and thioethers.
Herein, we describe an unprecedented protocol to an array
of 2-(arylthio)-1H-imidazoles under microwave irradiation via a
ring-openning and reformation of imidazo[2,1-b][1,3,4]
thiadiazoles in the presence of aryl halide, which is quite
unproductive by conventional oil-bath heating. Moreover, the
easily obtained imidazo[2,1-b][1,3,4]thiadiazoles are applied as
heterocyclic synthons to establish a series of imidazo[2,1-b]
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Table
1
The ring-open and thioetherification of imidazo[2,1-b][1,3,4]
View Article Online
thiadiazole in various reaction conditions.a
DOI: 10.1039/C6OB00102E
Entry
Catalyst
Base
Additive
Solvent
Yield(%)b
1
CuI
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
DMF
54
57
63
50
67
52
47
55
50
58
61
66
56
49
40
43
47
60
trace
67
54
85c
80d
65e
0f
2
CuCl
3
CuCN
Fig. 2 Reconstruction of imidazo[2,1-b][1,3,4]thiadiazoles to imidazo[2,1-
b]thiazoles or thioethers.
4
CuBr2
5
Cu(acac)2
Cu(OAc)2
6
thiazoles through a tandem reaction with arylacetylene
initiated by t-BuOK (Fig. 2).
7
Cu(OAc)2H2O t-BuOK
8
Cu(OTf)2
CuSO4
t-BuOK
t-BuOK
t-BuOLi
Na2CO3
K2CO3
9
10
11
12
13
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Results and discussion
Pursuant to our previous research on imidazo[2,1-
b]thiazoles,13 we tried to achieve arylation of imidazo[2,1-
CsCO3
b][1,3,4] thiadiazole (
1
) to compound
6
under similar reaction 14
K3PO43H2O
DIPEA
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
a
conditions (Scheme 1). Initially, Pd(OAc)2, PdCl2 and Pd(PPh3)4
were used as catalysts in microwave-assisted coupling reaction
TEMED
DMEDA
K2CO3
of compound
1 and bromobenzene. After screening typical
bases, ligands, additives, such as K2CO3, Cs2CO3, t-BuOK, PPh3,
pyridine, 1,10-phenanthroline (Phen), and pivalic acid (PivOH)
K2CO3
DMSO
DMA
DMF:Xylene=1:1
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
K2CO3
at appropriate temperature, the goal product
6 was not
K2CO3
detected at all. Surprisingly, when CuI was introduced into this
microwave-assisted reaction utilizing t-BuOK as base in DMF,
an unexpected ring-open and thioetherification product of 2-
K2CO3
K2CO3
K2CO3
(phenylthio)-1H-imidazole (3) was only identified.
K2CO3
To further optimize reaction conditions, 6-phenylimidazo
[2,1-b][1,3,4]thiadiazole (1a), bromobenzene (2a) as model
substrates, CuI as catalyst and t-BuOK as base were mixed in 1
mL NMP and carried out under microwave irradiation at
proper temperature for 90 min. The product 3aa was detected
when the temperature was arisen to 110 oC. It could be
isolated in 54% yield when the temperature was sequentially
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
PPh3
63
61
54
54
48
68
Py
Phen
TMEDA
PivOH
Al2O3
General conditions: 1a (0.5 mmol), 2a (0.75 mmol, Cat. 0.25 mmol, base 1.0 mmol,
o
arisen up to 140 C (Table 1, entry 1). To further screen
solvent 1 mL, reaction time 90 min. b isolated yield after column chromatography of the
catalysts, CuCl, CuCN, CuBr2, Cu(acac)2,
Cu(OAc)2,
c
d
e
crude product. reaction time 120 min. reaction time 150 min. reaction time 180
min. f heating with oil bath, 140 oC 12 h.
o
Cu(OAc)2 H2O, Cu(OTf)2 and CuSO4 were examined at 140 C

for 90 min under microwave irradiation (Table 1, entries 2-9).
Cu(acac)2 was found to be a good catalyst in this ring-openning
and thioetherification reaction resulting 3aa in 67% yield
(Table 1, entry 5). Considering the important role of base, eight
bases were used in this reaction (Table 1, entries 5, 10-17). The
results exhibited that K2CO3 could be the best base. Solvents
were also screened in this microwave-assisted reaction (Table
1, entries 12, 18−21). Even though the common used solvent
DMF was found to be a good solvent for this reaction, NMP
was finally chosen as the optimal solvent for this reaction
owing to its better stability. Meanwhile, DMA could result
slightly higher yield than that of NMP (67% vs 66%, entries 20
vs 12). When the reaction time was extended from 90 to 120
min, the highest yield (85%) of 3aa was gained under optimal
conditions (Table 1, entry 22). Further extension of reaction
time resulted in a decrease of yield (Table 1 entry 23-24) due
Scheme
1 Formation of thioethers or arylation of imidazo [2,1-b][1,3,4]
to
a decomposition of product. In contrast, a control
thiadiazole.
experiment was also carried out with conventional oil-bath
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heating at 140 oC for 12 h without any thioetherification Table 2. The scope of products for the ring-open and thioetherification of
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DOI: 10.1039/C6OB00102E
products (Table 1 entry 25). These phenomena demonstrated imidazo[2,1-b][1,3,4] thiadiazoleswith aryl halide.a,b
that the microwave irradiation was really requisite to this
transformation. Subsequently, the activities of ligands and
additives such as PPh3, pyridine, Phen, PivOH, MEDA and Al2O3
were also investigated and revealed negativity to this reaction
(Table 1, entries 26-31).
When bromobenzene was replaced by iodobenzene, 4-
phenyl-2-(phenylthio)-1H-imidazole 3aa could be obtained in
80% yield (Table 2). When chlorobenzene was used, 3aa could
not be detected at all due to its low activity. To further extend
the scope of reaction under optimized reaction conditions, a
series of bromobenzenes were applied to this
thioetherification reaction. As shown in Table 2,
bromobenzenes tolerated modestly electron-rich or electron-
withdrawing groups on the phenyl ring such as p-CH3, m-CH3,
o-CH3, p-OCH3, p-CF3, p-COCH3, p-CN, o-CN, p-F and p-Cl were
compatible in this transformation. Reversely, bromobenzenes
bearing a strong electron-withdrawing group of o-NO2 or o-
COCH3 could not generate target molecules due to their higher
activity of C-Br bond. Otherwise, disubstituted bromobenzenes
had moderate activities due to their steric effect (Table 2, 3al
-
3am). Furthermore, other different substituted imidazo[2,1-b]
[1,3,4] thiadiazoles, such as 6-(p-tolyl)imidazo[2,1-b][1,3,4]
thiadiazole
(
1b),
6-(4-chlorophenyl)imidazo[2,1-b][1,3,4]
thiadiazole (1c) and 6-(naphthalen-2-yl)imidazo[2,1-b][1,3,4]
thiadiazole (1d) were examined to yield considerable products
(Table 2, 3ba-3db).
These results clearly indicate that this protocol is general
and applicable to the imidazo[2,1-b][1,3,4]thiadiazoles
suffering aryl group with electron-rich or electron-withdrawing
groups. Naturally, we attempt to understand the mechanism
for this thioetherification reaction. After great efforts putting
on the experiments, a ring-openning product intermediate
9 is
successfully isolated at room temperature. The proposed
mechanism is depicted in Scheme 2 that is consistent with
previous studies on the arylation of heterocycles.14 Firstly,
a
b
General conditions: 1 (0.5 mmol), solvent 1 mL. isolated yield after column
chromatography of the crude product.
intermediate
A is generated by adding t-BuOK onto an
imidazo[2,1-b][1,3,4]thiadiazole (1a). ArCuBr generated from
an oxidative addition of copper with bromobenzene is
infra). The leaving of cyano group can be also confirmed by a
attacked by sulfur atom of
A to produce intermediate B
verification experiment (vide infra). Finally, the intermediate
B
accompanying with a leaving of cyano group.15 The ring-
openning of substrate can be proved by DFT calculation (vide
undergoes reductive elimination to yield product 3aa and
release Cu(I) catalyst synchronously. For confirming this
proposed mechanism, the separated intermediate
9 reacts
with bromobenzene to generate 3aa in 87 % yield.
With the novel intermediate
9 in hand, we originally tried to
reconstruct a 6-heterocycle ring by using benzaldehyde or
cinnamaldehyde. Disappointedly, expected products had not
been found at room temperature or under optimal reaction
conditions. When a more active phenylacetylene was chosen
as reactant, to our delight, the desired ring-closing product
was isolated in 77% yield in the presence of t-BuOK and
characterized to be 3,6-diphenylimidazo[2,1-b]thiazole.
To optimize reaction condition, the base, solvent, temperature,
and the ratio of substrates for this transformation were
carefully investigated (Table 3). DMF was a better solvent than
Scheme 2 Proposed mechanism for copper catalyzed ring-open and
thioetherification of imidazo[2,1-b][1,3,4] thiadiazoles.
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Table 3 The screening of reaction conditionsa
Table 4 The products for the ring-reconstruction of imidazo[2,1-b][1,3,4]thiadiazoles
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with various arylacetylenesa,b
DOI: 10.1039/C6OB00102E
Entrya
1a:4a (mmol)
Base
Solvent
Yield(%)b
1
1.0:1.0
1.0:1.0
1.0:1.0
1.0:1.0
1.0:1.0
1.0:1.0
1.0:1.0
1.0:1.0
1.0:1.0
1.0:1.0
1.0:1.0
1.0:1.0
1.0:1.1
1.0:1.2
1.0:1.5
1.0:2.0
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOLi
LDA
DMF
1,4-Dioxane
DMSO
THF
77
10
75
30
70
40
12
9
2
3
4
5
DMA
NMP
EtOAc
EtOH
MeOH
DMF
DMF
DMF
DMF
DMF
DMF
DMF
b
6
7
8
9
74
35
trace
no
79
87
82
84
10
11
12
13
14
15
16
a
n-Butyllithium
t-BuOK
t-BuOK
t-BuOK
t-BuOK
Reaction conditions: 1a (0.5 mmol), solvent 1 mL. isolated yield after column
chromatography.
others (Table 3, entries 1-9). t-BuOK provided better result
than t-BuOLi (Table 3, entry 1 vs 10). But LDA and n-
butyllithium gave worse results (Table 3, entries 11, 12). We
must emphasize that these ring-opening and ring-closing
reactions are very sensitive to reaction temperature. When it
o
was increased from room temperature to 35 C, intermediate
9
was decomposed without any products monitored by TLC.
Furthermore, increasing the ratio of phenylacetylene 4a to 1a
from 1:1 to 2:1, prominent enhancement of yield had obtained
(Table 3, entries 1, 13-16). The best yield of 5aa (87%) was
obtained with the ratio of 1:1.2 (Table 3, entry 14).
Under optimal reaction conditions, the scope and limitation of
this new ring-reconstruction reaction were investigated. A
variety of substituted arylacetylenes bearing both the
electron-donating or electron-withdrawing groups such as Me,
OMe, F, Cl, Br and CF3 were utilized in this reaction. All
reactions could be well carried out to generate target
compounds. As expectation, the corresponding imidazo[2,1-
b]thiazole derivatives were gained in excellent yields (Table 4
a
b
Reaction conditions:
chromatography.
1 (0.5 mmol), solvent 1 mL. isolated yield after column
In the preparation of this paper, Grubbs’s work about the
silylation of C–H bonds in aromatic heterocycles was reported
and really interested,16 in which, the common base of t-BuOK
plays a key role in those C–Si formation. Inspiring by his work,
a proposed mechanism for this ring-reconstruction was
illustrated in Scheme 3 and calculated by DFT method using
Gaussian 09 software at the B3LYP/6-31+G(d,p) level using
polarized continuum model (IEFPCM).17 The solvation effect
(DMF) was simulated by utilizing the Gaussian 09 suite of
programs.18 Firstly, the substrate 1a reacts with t-BuOK (R1 =
1a + t-BuO) to produce an intermediate IM1 via H-shift
transition state (TS1). Then, a ring-opening reaction (TS2)
makes IM1 into an intermediate IM2 that convert easily to an
5ab, 5ac, 5ad, 5ae, 5af, and 5ai). Furthermore, this
transformation was less sensitive to steric effect and gave
excellent yield using ortho-, para- and meta- substituted
arylacetylene (5ab
phenylacetylene and m-methylphenylacetylene provided
nearly quantity products (98%, 5ae 5ag). Moreover, to enlarge
the scope of heterocyclic substrates, 6-(p-tolyl)imidazo[2,1-b]
[1,3,4]thiadiazole(1b), 6-(4-chlorophenyl) imidazo[2,1-b]
, 5ad, 5ag, 5ah, 5aj). Especially, p-chloro-
,
intermediate
9 (IM3). However, in the presence of
[1,3,4]thiadiazole (1c) and 6-(naphthalen-2-yl)imidazo[2,1-b]
[1,3,4]thiadiazole (1d) were also reacted with substituted
arylacetylene to give the relative molecules in good yields.
phenylacetylene, the acquired negative ion attacks the
intermediate
9
forming a TS4 led to IM4 that is deprotonated
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Scheme 3 Proposed mechanism for ring-reconstruction
to generate an intermediate IM5. The IM5 is converted to IM6
via a ring-closing TS5. IM6 captures the proton from t-BuOH to
Conclusions
In summary, we have discovered a novel strategy to realize the
syntheses of useful 3,6-diarylimidazo[2,1-b]thiazoles in high
yields via a ring-opening and ring-closing of arylimidazo[2,1-
b][1,3,4]thiadiazoles. The reaction conditions are extremely
mild in the presence of arylacetylene and t-BuOK without
metal catalyst. This method bypasses the costly and tedious
transition-metal-catalyzed pattern and makes a new family of
imidazo[2,1-b]thiazoles easily available. A simple mechanism
for ring-reconstruction of arylimidazo[2,1-b][1,3,4]thiadiazole
is also proposed and verified by a DFT calculation at the
B3LYP/6-31+G(d, p) level. Furthermore, we can reason that
unstable arylimidazothiadiazoles can be synthons for new
synthetic methodologies of heterocycles in the near future.
Besides, the arylimidazo[2,1-b][1,3,4]thiadiazoles can also
react with aryl halide in the presence of copper salt yielding a
wide variety of bioactive 2-(arylthio)-1H-imidazoles under
microwave irradiation.
produce the target product 5aa (P) via a TS6. An alternative
mechanism via a TS3 (IM2 + phenylacetylene) with a short
path is also described in supporting information. The relative
energies of species and coordinates are illustrated in Scheme 4.
These new routes not only provide useful heterocyclic
synthons to achieve biologically active heteroaromatic
compounds, but also furnish a new protocol to approach C–S
construction in the presence of copper salt catalysis under
microwave irradiation.
Scheme 4 Relative energy of reaction species versus reaction coordinates
In order to verify this proposed mechanism (Scheme 3), a
verification experiment had been designed and achieved using
Experimental section
a benzyl thiocyanate instead of intermediate
9 under the same
Material and methods
reaction conditions (Scheme 5). Coupling compound
8 was
1H and 13C NMR spectra were recorded on a Varian Mercury
plus 300 MHz spectrometer (75 MHz for carbon). Chemical
triumphantly obtained that implied reasonable mechanism.19
shifts (
0.0 ppm) with the solvent resonance as an internal reference
(CDCl3: H = 7.26 ppm, C = 77.0 ppm, DMSO-d6: H = 2.50 ppm),
) are reported in ppm relative to tetramethylsilane ( =



and coupling constants (J) are given in hertz (Hz). Multiplicity is
indicated by one or more of the following abbreviations: s
(singlet); d (doublet); t (triplet); q (quartet); m (multiplet); br
Scheme 5 Verification experiment
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Typical procedure for synthesis of 3,6-diphenylimidazo [2,1-
(broad). Melting points (mp) were determined on a XT-4
melting point apparatus and are uncorrected. Infrared spectra
(IR) were obtained from a NEXUS670 FT-IR spectrometer and
reported in cm−1 (%T). Mass spectra (EI) were recorded on a
Thermo TRACE DSQ spectrometer. ESI-MS were measured
with Bruker ESQ6000 instruments. High resolution mass
spectra (HRMS) were carried out on an LTQ Orbitrap Elite
(Thermo) mass spectrometer with ESI mode unless otherwise
stated. Microwave irradiation experiments were performed in
a dedicated CEM-Discover monomode microwave reactor,
operating at a frequency of 2.45 GHz with continuous
irradiation power from 0 to 300 W. The reaction temperature
was measured with an IR sensor on the outer surface of the
process vessel and monitored using the associated ChemDriver
Discover Application program. Reaction times refer to the hold
time at the desired set temperature. Control experiment
employing conventional oil bath heating was run under an air
atmosphere in an oven-dried round-bottom flask equipped
with a magnetic stir bar.
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b]thiazole (5aa)
DOI: 10.1039/C6OB00102E
To a 10 mL oven-dried round-bottom flask, 1a (0.5 mmol), t-
BuOK (112.2mg, 1.0 mmol, 2.0 equiv.) and DMF (1 mL) was
sequentially charged. After stirring for 2 minutes at room
temperature, 4a (0.6 mmol, 1.2 equiv.), and t-BuOK (56 mg,
0.5 mmol, 1.0 equiv.) was added and then stirred for 3 minutes.
The reaction mixture was filtered by a stratum of silica gel and
then washed with 50 mL of EtOAc. The combined organic
solution was concentrated on a rotatory evaporator under
vacuum and the silica gel was immersed to eliminate KCN. The
crude residue was purified by column chromatography over
silica gel using 25% EtOAc in petroleum ether as eluent to
afford pure 5aa
.
Acknowledgements
This work was funded by the National Natural Science
Foundation of China (NSFC 21173106) and by the Foundation
of State Key Laboratory of Coal Conversion (Grant No. J16-17-
913).
Synthetic procedures
Typical procedure for synthesis of arylimidazo[2,1-b][1,3,4]
thiadiazole
Notes and references
An oven-dried microwave vial (10 mL) was charged with 2-
bromoacetophenone (100 mg, 0.50 mmol), 1,3,4-thiadiazol-2-
amine (51 mg, 0.50 mmol), Na2CO3 (32 mg, 0.30 mmol, 0.60
equiv.) and DMF (1 mL). The reaction tube was sealed with a
Teflon septum and placed in the microwave cavity. The
reaction mixture in the vial was continuously stirred and
irradiated with microwaves at 100 °C for 10 min. After cooling
to ambient temperature, the mixture was poured into water
(15 mL) and extracted with ethyl acetate (3 × 15 mL). The
combined organic layer was washed with brine, dried over
Na2SO4, filtered, and concentrated on a rotatory evaporator
under vacuum. The crude residue was purified by column
chromatography over silica gel using 25% EtOAc in petroleum
ether as eluent to afford 1a in 80% yield.
1
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To a 10 mL oven-dried microwave vessel capped with a Teflon
septum was sequentially added 1a (0.5 mmol), 2a (0.75 mmol,
1.5 equiv.), Cu(acac)2 (66.5 mg, 20 mol %), K2CO3 (138.2 mg,
1.0 mmol, 2.0 equiv.) and NMP (1 mL). Then the reaction tube
was placed into the microwave cavity. The reaction mixture in
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vessel was continuously stirred and irradiated with
microwaves at 140 °C for 120 min. After cooling to ambient
temperature, the reaction mixture was filtered by a stratum of
silica gel and then washed with 50 mL of EtOAc, concentrated
on a rotatory evaporator under vacuum and the silica gel was
immersed into a ferrous sulfate solution to eliminate KCN
leading a nontoxic complex of K4Fe(CN)6. The crude residue
was purified by a column chromatography over silica gel using
25% EtOAc in petroleum ether as the eluent to afford 3aa
.
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