Palladium-catalyzed microwave-assisted direct arylation of imidazo[2,1-b]thiazoles with aryl bromides: Synthesis and mechanistic study

Article abstract of DOI:10.1039/c4ob00600c

A palladium-catalyzed direct C-H arylation of various imidazo[2,1-b] thiazoles with a range of aryl bromides under microwave irradiation is described. 6-Phenyl substituted imidazo[2,1-b]thiazoles could be regioselectively C-5 arylated using the developed protocol. The utility of this method enables the representative coupling product to be achieved by a sequential one-pot reaction. Density functional theory (DFT) calculations show that this arylation proceeds via a concerted metalation-deprotonation (CMD) pathway, which is in agreement with our experimental results. This work provides a convenient access to a variety of biologically active imidazo[2,1-b]thiazole derivatives. Also, it enriches the mechanism study of site-selective C-H arylation in fused heterocycles, and offers a valuable guide to design highly efficient catalytic systems for the preparation of similar compounds. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00600c

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Graphical and Textual Abstract
site-selective C-H arylation under CMD process
R2
H
R2
Ar
Pd(OAc)2, PPh3, K2CO3
N
MW, 130 °C, 90 min
S
N
R1
Ph
R1
Ph
Br Ar
S
N
N
R1 = H, R2 = H, CH3;
R1 R2 = (CH)4, (CH2)4
26 examples
CMD TS
A palladium-catalyzed regioselective C–H arylation of imidazo[2,1-b]thiazoles under microwave
irradiation via concerted metalation deprotonation (CMD) pathway was developed.

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Palladium-catalyzed
microwave-assisted
direct
arylation
of
imidazo[2,1-b]thiazoles with aryl bromides: synthesis and mechanistic
study
Yis-huo Zhu, Benyi Shi, Ran Fang, Xiaoxuan Wang, Huanwang Jing*
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou
University, Lanzhou 730000, P. R. China
hw-jing@163.com
A palladium-catalyzed direct C−H arylation of various imidazo[2,1-b]thiazoles with a range of aryl
bromides under microwave irradiation is described. 6-Phenyl substituted imidazo[2,1-b]thiazoles
could be regioselectively C-5 arylated using the developed protocol. The utility of this method enables
the representative coupling product to be achieved by a sequential one-pot reaction. Density functional
theory (DFT) calculations show that this arylation proceeds via a concerted metalation–deprotonation
(CMD) pathway, which is agreement with our experimental results. This work provides a convenient
access to a variety of biologically active imidazo[2,1-b]thiazole derivatives. Also, it enriches the
mechanism study of site-selective C−H arylation in fused heterocycles, and offers a valuable guide to
design highly efficient catalytic systems for the preparation of similar compounds.
Introduction
Imidazo[2,1-b]thiazoles represent an important class of heteroaromatic compounds that are key
structural motifs of numerous bioactive molecules and functional materials,1 such as tetramisole (i),2
pifithrin-β
(ii),3
4-imidazo[2,1-b]thiazole-1,4-dihydropyridines
(iii),4
5,6-di(hetero)-arylimidazo[2,1-b]thiazoles (iv),5 3-methyl-5,6-diarylimidazo[2,1-b]thiazoles (v),6
2,3-diarylbenzo[d]-imidazo[2,1-b]thiazoles (vi)1b (Fig. 1). Although a variety of methods have been
reported for the synthesis of di(hetero)arylimidazo[2,1-b]thiazoles,5, 7 they have the restrictions of

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particular substitution patterns,7b low overall yields and long experimental periods,7c as well as
stoichiometric organoboron reagents and extra synthetic manipulations in Pd-mediated Suzuki-type
cross-coupling.7d
Fig. 1 Structure of bioactive imidazo[2,1-b]thiazoles.
In recent years, transition metal catalyzed direct C–H arylation8 has emerged as a promising
strategy for the formation of biaryl compounds without prior functionalization to metalated or
halogenated substrates. This new approach avoids availability problems, metal waste, and additional
synthetic steps for arylmetals. In this context, a broad range of useful heterocyclic compounds have
been depicted to construct heteroarenes by metal-catalyzed direct arylations.9 However, regioselective
C–H arylation towards specific location of heterocycles bearing multiple C–H bonds is still
problematic. It is widely believed, on one hand, for electron-rich heterocyclic molecules such as
imidazole, thiazole, oxazole, pyrrole, and indole, C–H arylation is prone to suffer from electrophilic
aromatic substitution (SEAr) pathway10 owing to their high nucleophilicity, though Heck-like,11
oxidative C−H insertion12 and stepwise 1,2-migratory insertion13 process also can occur in rare
circumstances. On the other hand, as for electron-poor heterocycles such as pyridine, diazine, and
azine N-oxides, C–H arylation often takes place through a concerted metalation−deprotonation (CMD)
mechanism.14 Besides, several direct arylations of electron-rich heterocyclic compounds also have
been demonstrated via a CMD process.15 Nevertheless, the mechanism study on condensed
heterocyclic ring systems containing two or more π-excessive heterocycles are less explored. In view

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of illustrated importance of 5,5-fused imidazo[2,1-b]thiazoles, we set out to retrieve the reported
direct C-H arylations of these compounds. Surprisingly, few examples have been disclosed to arylate
at C-4 position of imidazole moiety of the fused ring under palladium catalysis,5, 7a and in these
reports the scope defined for the imidazo[2,1-b]thiazole scaffold was very narrow, although direct C-5
arylation of 4-methyl substituted thiazole ring of the parent heterocycle have been achieved by copper
catalysts.16 So far, a general synthetic route to accomplish regioselective C-4 arylation of the
imidazole
ring
of
6-arylimidazo[2,1-b]thiazoles
(or
called:
C5-arylation
of
6-arylimidazo[2,1-b]thiazoles) haven’t been established yet. Hence, we attempt to develop a practical
and efficient protocol to access these molecules from readily available aryl bromides, and further
investigate the relevant reaction mechanism.
Results and Discussion
1
Prior to investigatation of the arylation, various imidazo[2,1-b]thiazoles were evaluated by H NMR
for the selection of model substrate. (Fig. 2, 1a-d). It’s revealed that each C−H bond of different
imidazo[2,1-b]thiazoles exhibits unequal acidity, even in the identical substrate such as 1a or 1d,
multiple C−H bonds are rather divergent, thereby furnishing possibilities of site-selective arylation.
Fig. 2 δC-H of 1H NMR (300 MHz, CDCl3) in various imidazo[2,1-b]thiazoles cores.
Since more attention in medicinal chemistry and synthetic chemistry was focused on
6-arylimidazo[2,1-b]thiazole, 1a was chosen as model substrate to couple with

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1-bromo-4-nitrobenzene (2a)10b in our initial exploration of this Pd-catalyzed arylation. It’s pleasing
that 1a and 2a led to the coupling product 3aa in 15% yield and a trace of byproduct from which no
C-2 arylated product could be isolated utilizing PdCl2/PPh3. Unambiguously, the structure of
C-5-arylated product 3aa was in concordance with all the spectral data and further independently
confirmed by an X-ray crystal structure (CCDC 942540).17 Then, 1a and 2a were selected for model
substrates to optimize the reaction conditions (Table 1). A number of palladium catalysts in
conjunction with different ligands, bases and solvents were screened. Some palladium catalysts, such
as PdCl2, Pd(PPh3)4 and Pd(PPh3)2Cl2, resulted in moderate yields of 35-59% (Table 1, entry 1-3). To
our delight, the desired product 3aa was obtained in 72% yield, when the reaction was performed in
the presence of K2CO3 using Pd(OAc)2/PPh3 as catalytic system in DMF (Table 1, entry 4). No
improvement was observed by increasing the reaction time or temperature. In contrast, conventional
heating led to lower yield (45%) within 13 h. This demonstrates the green microwave heating could
greatly accelerate the arylation, not only in reduced reaction time, but also in enhanced yield. In the
absence of palladium catalyst, no arylated product was found. In an attempt to increase the yield of
reaction, various ligands such as PBu3, PCy3, Phen (1,10-Phenanthroline) and PhenꢀH2O
(1,10-Phenanthroline monohydrate) were tested, and none showed better activities than PPh3 (Table 1,
entry 5-8). Increasing the amount of PPh3 from 10 mol % to 25 mol % seemed to be detrimental to
reactivity (Table 1, entry 9), while a decrease was observed in the absence of ligand (Table 1, entry
10). Next the effects of different bases were also investigated. Compared with Cs2CO3, K3PO4, KOAc,
t-BuOK, AgOAc, Cs2CO3 were found to be as effective as K2CO3 and a maximum yield of 72% was
achieved (Table 1, entry 11-15). Subsequently, variations in solvent were examined. Polar solvents
generally gave a better reaction performance but less effective than DMF, while apolar solvents led to
significantly low yields of 3aa (Table 1, entry 16-21). Additional use of PivOH (pivalic acid) as

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proton shuttle precursor proved to be deleterious to the reaction (Table 1, entry 22). Furthermore, aryl
iodide was found to be inferior to aryl bromide possibly due to poisoning of the catalyst by
accumulated iodide in DMF (Table 1, entry 23).15c, 18 Therefore, the optimum reaction conditions were
described as follows: using K2CO3 (3 equiv) as a base in the presence of Pd(OAc)2 (5 mol %) and
PPh3 (10 mol %) in DMF at 130 °C for 90 min under microwave irradiation. It is worth mentioning
that the poisoning effect of sulfur19 wasn’t found in the arylation of this S-containing heterocycle.
Table 1 Optimization of direct arylation of 1aa
Entry
1
Catalyst
Ligand
PPh3
-
Base
Solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Yield(%)
PdCl2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
35
2
Pd(PPh3)4
Pd(PPh3)2Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
57
3
-
59
4
PPh3
PBu3
PCy3
Phen
PhenꢀH2O
PPh3
-
72 (45)b
39
5
6
36
7c
8
5
19
9d
10
11
46
48
PPh3
72

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12
13
14
15e
16
17
18
19
20
21
22f
23g
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
K3PO4
KOAc
t-BuOK
AgOAc
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMF
59
62
9
DMF
DMF
DMF
n.r.
64
66
59
14
11
37
49
59
DMSO
DMA
NMP
Toluene
Dioxane
CH3CN
DMF
DMF
a General conditions: 1a (0.25 mmol), 2a (0.30 mmol), Pd-catalyst (5 mol %), ligand (10 mol %), base (3.0 equiv) in
o
solvent (1 ml), MW, 130 C, 90 min. Isolated yields were given. Under air atmosphere, oil bath, 130 C, 13 h.
b
o
c
Phen = 1,10-phenanthroline; d PPh3 (25 mol %). e n.r. = no reaction. f PivOH (30 mol %) was used as an additive. g
2a was 1-iodo-4-nitrobenzene.
With the optimized conditions in hand, we next evaluate the substrate scope of the reaction employing
various aryl bromides and imidazo[2,1-b]thiazoles. These results are summarized in Table 2. It was found that a
variety of aryl bromides containing important functional groups such as p-NO2, m-NO2, o-NO2, p-CN, p-CF3,
p-COMe and p-COOMe were compatible under this transformation (3aa-g). In all cases, C5 arylated products
were successfully formed in moderate to good yields without any modification of the reaction conditions.
Moreover, modestly electron-rich aryl bromide was also tolerated in the presence of small amount of pivalic
acid while comparatively low yield was detected (3ah). It’s demonstrated that both electron-deficient and

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moderately electron-rich aryl bromides could couple with 1a, and electron-deficient aryl bromides generally
resulted in higher yields which might be attributed to lower oxidative addition barriers for electron-deficient
aryl bromides.20 This can be understood since the black Pd(0) was precipitated from the solution regardless of
the addition of pivalic acid when 1a was used to arylate with 4-bromotoluene, while the phenomenon was not
observed utilizing electron-depleted aryl bromides. Besides, some poly-substituted aryl bromides were then
proved to be applicable, providing the expected products 3ai and 3aj in 44% and 54% yields, respectively.
Furthermore,
other
different
substituted
imidazo[2,1-b]thiazoles,
such
as
2-phenylbenzo[d]imidazo[2,1-b]thiazole (1b), 2-phenyl-5,6,7,8-tetrahydrobenzo[d]imidazo[2,1-b]thiazole (1c)
and 3-methyl-6-phenylimidazo[2,1-b]thiazole (1d) were probed. When 1b possessing a well conjugated system
was applied to the arylation, a maximum yield of 98% (3ba) was observed using 2a as coupling partner. With
an array of aryl bromides, 1b proceeded smoothly in 61%-85% yields (3bb-f). Subsequently, the use of
pifithrin-β derivatives 1c and 2a resulted in 91% yield of 3ca. Actually, 1c was tolerant of different aryl
bromides and gave the coupling products in moderate to good yields (3cb-f). Then, electron-rich
imidazo[2,1-b]thiazoles 1d was also found to be amenable to the reaction conditions and arylated with aryl
bromides in moderate to satisfactory yields (3da-d). Among them, it was interesting that 2,5-diarylated
products of 1d were achieved in 86% yield (3dd).
Table 2 Substrate scope of the Pd-catalyzed direct arylation of imidazo[2,1-b]thiazoles with aryl bromidesa

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a
General conditions: 1 (0.25 mmol), 2 (0.30 mmol), Pd(OAc)2 (5 mol %), PPh3 (10 mol %), K2CO3 (3.0 equiv) in
o
DMF (1 ml), MW, 130 C, 90 min. All reported reaction yields were isolated yields. Pivalic acid (30 mol %) was
b
added. c The present yield was given on the basis of relatively insufficient amount of aryl bromide.
To further minimize the synthetic steps and wastes, this method was extended to a one-pot reaction
for the construction of diarylimidazo[2,1-b]thiazoles starting from 2-aminothiazol and
2-bromoacetophenone. Delightfully, a typical product of 3aa was attained by a sequential reaction
sequence in overall 58% yield within 95 min under microwave irradiation (Scheme 1).

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Scheme 1 Sequential one-pot synthesis of 3aa.a
a Condition 1: 2–aminothiazol (0.50 mmol), 2-bromoacetophenone (0.50 mmol), Na2CO3 (0.30 mmol, 0.60 equiv) in
o
DMF (1 ml), MW, 120 C, 5 min; condition 2: 2a (0.60 mmol, 1.2 equiv), Pd(OAc)2 (5 mol %), PPh3 (10 mol %),
K2CO3 (3.0 equiv), MW, 130 oC, 90 min. Reported reaction yields were isolated yields.
Although the participation of AgOAc was demonstrated to efficiently catalyze C–H arylation under
electrophilic palladation process,21 it has been proved to be unreactive in this reaction (Table 1, entry
15), indicating the authentic arylation mechanism is likely to conflict with the SEAr pathway. In
addition, since exclusively regioselective arylation of 1a at C-4 position of less π-electrons rich
imidazole ring rather than C-5/4 position of more π-electrons rich thiazole ring was observed, it
suggests that the preferential regiochemistry for the reactive sites, to some extent, depends on C−H
acidity of 1a, not on heterocyclic nucleophilicity. For these reasons, the SEAr process could be
excluded. On the contrary, CMD mechanism seems to be hopeful. Moreover, 1b with a much more
acidic sp2 C−H bond (Fig. 2) was used to couple with 2a in higher yield compared to other substrate
such as 1a, 1c, and 1d (Table 2, 3aa vs 3ba vs 3ca vs 3da). In this regard, the C−H acidity also exerts
an effect on the reactivity of the arylation. All of these above imply that the C−H bond
functionalization may undergo a CMD pathway (Scheme 2). The process is consisted of oxidative
addition of aryl bromide to Pd(0) to generate ArPdBr (A), a nucleophilic attack of KOAc on A to form
ArPd(OAc) complex (B), substrate 1 in reaction with B to produce C as a transition-state, as well as
reductive elimination of D to give the coupling product 3 and regenerate of Pd(0). As delineated by us,

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the generation of ArPdBr (A) is susceptible to the nature of aryl bromides due to oxidative addition
barrier. As a result, the performances of pivalic acid in the arylation (3ah of Table 2 vs entry 22 of
Table 1) were distinct. For modest electron-rich aryl bromide 4-bromotoluene which is difficult to
accomplish oxidative addition, the effect of pivalic acid was found to be positive (Table 2, 3ah), since
KOPiv produced by the added PivOH and K2CO3 is more alkaline than KOAc generated from HOAc
and K2CO3 and thus considered to be helpful for the crucial dehydrogenation process; as for
electron-deficient aryl bromide 2a, the effect of pivalic acid was found to be negative (Table 1, entry
22). Since oxidative addition is effortless for 2a, KOPiv might be alkaline excessively and result in
partial homocoupling of 2a,14e, 22 thus hampered the catalytic activity. For the same reason, the slight
decrease in yield resulted from the addition of KOAc could be understood (Table 1, entry 13).
Scheme 2 Possible mechanism.
To gain some insight into the mechanism, density functional theory (DFT) analysis with the B3LYP
exchange correlation functional23 was performed to examine this pathway (for details, see Supporting
Information). Computational studies reveal that the predominance of regioselective arylation at C-5
position in our experimental observations resulted from the lowest C−H activation energy of CMD
transition state (TS) in comparison to other sites (C2, C3). As shown in Scheme 3, when 1a and 2a
were used to calculate the barriers of the CMD TS, C5-TS was found to require the lowest energy
barrier (TS-1a, 33.2 kcal mol−1), followed by C2-TS (TS-2a, 35.8 kcal mol−1), and the highest

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reaction barrier (TS-3a, 37.0 kcal mol−1) was required for C3-TS. These calculated results are well in
agreement with available experimental results. Similar computational results were found when 1d and
para/meta substituted aryl bromide 2a/2b (Scheme 4/5) were employed to calculate the barriers of the
CMD TS, the lowest energy barriers still were C5 transition states (33.9 kcal mol−1 of TS-1da and
33.1 kcal mol−1 of TS-1db). It is worth noting that energy barrier gaps between C5-TS and C2-TS of
1d (2.3 kcal mol−1 for 2a and 1.8 kcal mol−1 for 2b) decreased relative to 1a (2.6 kcal mol−1 for 2a).
This indicates the formation of double-arylated products 3dd (Table 2) was probably due to the
smaller energy barrier differences (1.8 kcal mol−1).
Scheme 3 Free energy diagram (ꢁGrel‡) for CMD TS of 1a.

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Scheme 4 Free energy diagram (ꢁGrel‡) for CMD TS of 1d (with 2a).
Scheme 5 Free energy diagram (ꢁGrel‡) for CMD TS of 1d (with 2b).
Conclusion
In summary, we have developed a new strategy to access diarylimidazo[2,1-b]thiazole derivatives via
Pd-catalyzed direct arylation as a key step. With MW irradiation, the coupling reaction for the
synthesis of title compounds can proceed smoothly under non-inert conditions. This method is
atom-economic, convenient, regioselective and tolerant to a series of functional groups on the aryl
bromide. Electron-deficient aryl bromides commonly exhibit better performance in yield than

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moderately electron-rich one due to easier oxidative addition. DFT studies towards the mechanism
demonstrate this regioselective C-5 arylation of imidazo[2,1-b]thiazoles undergoes a CMD pathway
that is consistent with our experimental results. Briefly, this work not only offers a straightforward
route to a number of novel imidazo[2,1-b]thiazoles which enrich the heterocyclic library, but also
provides a better mechanism understanding on site-selectivity of C−H arylation in fused heterocycles
which would be a valuable guide for the synthesis of similar molecules. We believe this work should
be profitable in synthetic and pharmaceutical chemistry.
Experimental section
1
General Information. H and 13C NMR spectra were recorded on a Varian Mercury plus 300 MHz
spectrometer (75 MHz for carbon). Chemical shifts (δ) are reported in ppm relative to
tetramethylsilane (δ = 0.0 ppm) with the solvent resonance as an internal reference (CDCl3: δH = 7.26
ppm, δC = 77.0 ppm, DMSO-d6: δH = 2.50 ppm), 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 (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 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 0-300 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

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Application program. Reaction times refer to the hold time at the desired set temperature. Control
experiment employing conventional oil bath heating was run under air atmosphere in an oven-dried
round-bottom flask equipped with magnetic stir bar.
General procedure for the arylation of substituted imidazo[2,1-b]thiazoles (Table 2, 3aa-dd).
To a 10 ml oven dried microwave vessel capped with a Teflon septum was sequentially added 1 (0.25
mmol), 2 (0.30 mmol, 1.2 equiv), Pd(OAc)2 (2.8 mg, 5 mol%), PPh3 (6.6 mg, 10 mol%), K2CO3 (104
mg, 0.75 mmol, 3.0 equiv) and DMF (1 ml). Then the reaction tube was placed in the microwave
cavity. The reaction mixture in the vessel was continuously stirred and irradiated with microwaves at
o
130 C for 90 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, gravity filtered, and concentrated on 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 3.
Typical procedure for sequential one-pot synthesis of 3aa (Scheme 1). An oven-dried
microwave vial (10mL) was charged with phenacyl bromide (100 mg, 0.50 mmol), 2-aminothiazol (50
mg, 0.50 mmol), Na2CO3 (32 mg, 0.30 mmol, 0.60 equiv) and DMF (1ml). The reaction tube was
sealed with a Teflon septum and placed in the microwave cavity. The reaction mixture in the vial was
o
continuously stirred and irradiated with microwaves at 120 C for 5 min. After cooled to ambient
temperature, 1-bromo-4-nitrobenzene (2a, 121 mg, 0.60 mmol, 1.2 equiv), Pd(OAc)2 (5.6 mg, 5
mol%), PPh3 (13.2 mg, 10 mol%), K2CO3 (208 mg, 1.50 mmol, 3.0 equiv) were added to the reaction
o
mixture and subjected to microwave irradiation at 130 C for 90 min. After cooling to room
temperature, poured in water (15 ml) and extracted with ethyl acetate (3 × 15 ml). The combined
organic layer was washed with brine, dried over Na2SO4, gravity filtered, and concentrated on rotatory

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evaporator under vacuum. The crude residue was purified by column chromatography over silica gel
using 25% EtOAc in petroleum ether as eluent to afford 3aa.
Acknowledgements
We thank the National Natural Science Foundation of China (NSFC 21173106, 21203080) for
financial support.
Notes and references
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