One-pot NBS-promoted synthesis of imidazoles and thiazoles from ethylarenes in water

Article abstract of DOI:10.3390/molecules24050893

A facile and eco-friendly method has been developed for the synthesis of imidazoles and thiazoles from ethylarenes in water. The reaction proceeds via in situ formation of α-bromoketone using NBS as a bromine source as well as an oxidant, followed by trapping with suitable nucleophiles to provide the corresponding products in good yields under metal-free conditions.

Full text of DOI:10.3390/molecules24050893

molecules
Article
One-Pot NBS-Promoted Synthesis of Imidazoles and
Thiazoles from Ethylarenes in Water
Liang Chen 1,2, Huajian Zhu 1,2, Jiang Wang 2,* and Hong Liu 1,2,
*
1
School of Pharmacy, China Pharmaceutical University, Nanjing 210009, Jiangsu, China;
zhulinfengcl@163.com (L.C.); cpuzhj@163.com (H.Z.)
State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of
Materia Medica, Chinese Academy of Sciences, Shanghai 201203, Shanghai, China
Correspondence: jwang@simm.ac.cn (J.W.); hliu@simm.ac.cn (H.L.); Tel.: +86-50807042 (H.L.)
2
*
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 2 January 2019; Accepted: 26 February 2019; Published: 4 March 2019
Abstract: A facile and eco-friendly method has been developed for the synthesis of imidazoles and
thiazoles from ethylarenes in water. The reaction proceeds via in situ formation of α-bromoketone
using NBS as a bromine source as well as an oxidant, followed by trapping with suitable nucleophiles
to provide the corresponding products in good yields under metal-free conditions.
Keywords: NBS; nitrogen-containing heterocycle; water; one-pot
1. Introduction
Nitrogen-containing heterocycles are found in many biologically active synthetic targets,
including natural products and designed pharmaceuticals [1–3]. Therefore, the construction and
functionalization of nitrogen-containing heterocycles has attracted considerable attention from
synthetic chemists. Imidazoles and thiazoles are of particular interest, as these building blocks
have been incorporated into a number of bioactive compounds including zolpidem, miroprofen,
amiphenazole, zolimidine, YM-11124, and CICTO (Figure 1) [
plethora of biological properties displayed over a broad range of therapeutic classes, including
antibacterial, antifungal, antiviral, antiulcer, anti-inflammatory, -amyloid formation inhibitory,
immunosuppressive, GABA receptor agonist, cardiotonic agent, and nonpeptide B2 receptor antagonist
effects [17 21]. Various synthetic methods have been reported for the construction of these motifs
such as C-H amination, oxidative cyclization, multi-component reaction, hydroamination, and tandem
processes from various starting materials [22 26]. Traditionally, procedures for these reactions required
4–16]. These compounds exhibit a
β
–
–
the use of metals and catalysts in various organic solvents, which makes the sequence longer and
increases waste production. For example, Toste et al. reported a dichloro(2-pyridinecarboxylato)-gold
[PicAuCl2]-catalyzed reaction of 2-aminopyridine N-oxide and alkynes in dichloromethane for
the synthesis of imidazo[1,2-a]pyridines. The reaction needs an expensive gold catalyst and an
acid additive, which increases costs and creates pollution [27]. Hence, the development of new
methodologies for the synthesis of these compounds continues to attract the interest of academic and
industrial researchers.
As a direct and efficient approach to the synthesis of these imidazoles and thiazoles,
α
-halo-ketones have reacted with suitable nitrogen nucleophiles and bases in various organic solvents
(Scheme 1a) [28 29]. Although this method is suitable for certain synthetic conditions, sometimes,
,
however, these procedures have one or more disadvantages such as the use of hazardous organic
solvents, long reaction times, use of stoichiometric and even excess amounts of reagents, etc.
To overcome these limitations, Mahesh and co-workers recently reported a two-step approach to
synthesize these heterocycles from alkenes, which involves preparing α-bromoketones by reaction
Molecules 2019, 24, 893; doi:10.3390/molecules24050893
www.mdpi.com/journal/molecules

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of olefins with NBS in water, and these
α
-bromoketones were treated with suitable nucleophiles to
give a diverse range of imidazoles and thiazoles (Scheme 1b) [30]. This method is only applied in
synthesis of some specific nitrogen-containing heterocycles, but, other heterocycles are not mentioned.
α
-Bromoacetophenone was also reported by Shimokawa et al. to be the important intermediate dealing
with ethylarenes with NBS in a mixture of ethyl acetate and water [31]. In this report, a variety of
ethylarenes were converted into the corresponding primary aromatic amides. Inspired by this work,
we envisaged the possibility to synthesize various imidazoles and thiazoles from ethylarenes.
Figure 1. Biologically active compounds based on imidazoles and thiazoles.
a) Traditional method
R2
O
N
H2N
Base
X
Y
R2
+
R1
Organic Solvent
Heating
Y
R1
[X=Br,Cl,I]
[Y=N,S,]
b) Recent method
R2
H2N
R2
Y
N
Y
NBS (2 equiv.)
R1
R1
H2O, 80 oC, 1.2 h
80 oC, 2 h
[Y=N,S]
R2
1st step
2nd step
c) This work
H2N
R2
NBS (3.5 equiv.)
AIBN (10 mol %)
Y
N
Y
R1
EA:H2O (5:1)
65 oC, 1.5 h
1st step
H2O, 80oC,
Na2CO3, 2-8 h
2nd step
R1
[Y=N,S]
Scheme 1. Approach for the synthesis of imidazoles and thiazoles.

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Here, we report an NBS-promoted, one-pot method for the construction of various imidazoles
and thiazoles from ethylarenes in water as a solvent (Scheme 1c).
NBS plays a dual role of both a safe bromine source and an oxidant, and the reaction was carried
out with water, which also acts as the oxygen source for the in situ preparation of
Water is an economical, safe, and environmentally benign solvent, and, therefore, its use as a solvent
for organic reactions is a very attractive option [32 33]. This protocol presents an operationally simple,
α-bromoketones.
,
rapid, and environmentally friendly strategy for enriching a complex nitrogen heterocycle library.
2. Results and Discussion
2.1. Optimization of Reaction Conditions for Synthesis of Imi-azo[1,2-a]pyridine 3a
Our study was initiated by treating ethylbenzene (1a, 1 mmol) as model substrate with NBS (3.5
equiv.) in the presence of AIBN (10 mol %) in a mixture of ethyl acetate:water (5:1, 6 mL) at 65 ◦C for
◦
1.5 h, followed by addition of 2-aminopyridine (2a) at 80 C to give the desired imidazo[1,2-a]pyridine
(3a) in 38% yield (Table 1, entry 1). Interestingly, when NBS was replaced with N-chlorosuccinimide
(NCS) or N-iodosuccinimide (NIS), formation of 3a was not observed (Table 1, entries 2 and 3), whereas
with N-bromophthalimide (BrNPhth), compound 3a was obtained in 34% yield (Table 1, entry 4).
Table 1. Optimization of reaction conditions a.
N
2-Aminopyridine
2a
Oxidant
AIBN (10 mol%)
N
Solvent, 65oC
Solvent, Base
Temp.
1a
1st step
2nd step
3a
First Step
Solvent
Second Step
Temp.
Yield b
(%)
Entry
Base
(Equiv.)
Oxidant
Solvent
◦
( C)
1
2
3
4
5
6
7
8
9
NBS
NCS
NIS
BrNPhth
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
EA/H2O (5:1)
EA/H2O (5:1)
EA/H2O (5:1)
EA/H2O (5:1)
EA/H2O (5:1)
EA/H2O (5:1)
EA/H2O (5:1)
MeCN/H2O (5:1)
Acetone/H2O (5:1)
1,4-Dioxane/H2O (5:1)
H2O
80
80
80
80
75
50
95
80
70
50
80
80
reflux
none
none
none
none
none
none
none
none
none
none
38
0
0
EA/H2O (2:1)
34
33
28
trace
67
65
62
72
78
77
MeCN/H2O (5:1)
Acetone/H2O (5:1)
1,4-Dioxane/H2O (5:1)
EA/H2O (5:1)
EA/H2O (5:1)
EA/H2O (5:1)
EA/H2O (5:1)
EA/H2O (5:1)
EtOH
Acetone
H2O
H2O
10
11
12
13
a
Na2CO3 (2)
Na2CO3 (5)
Na2CO3 (5)
EA/H2O (5:1)
H2O
Reactions were run with ethylbenzene 1a (1 mmol) of with oxidant in the presence of AIBN (10 mol %) in 6 mL of
solvent at 65 ◦C for 1.5 h, followed by reaction with 2-aminopyridine 2a (1.2 mmol) and base if needed heated for 2
b
h. Isolated yields.
No improvement in the yield was observed by using acetonitrile, acetone, and 1,4-dioxane instead
of ethyl acetate (Table 1, entries 5–7). A series of screening reactions to optimize the amount of oxidant,
solvent system and reaction temperature was also performed, which had no good effect (Tables S1
and S2, see the Supplementary Information for details). After extensive experimentation, it was found
that the presence of ethyl acetate in the reaction mixture was detrimental to the second reaction step.
Hence, the solvent of second reaction step was replaced with water, ethanol, and acetone [34,35]. Water
was found to be the best solvent, furnishing imidazo[1,2-a]pyridine (3a) in 67% yield (Table 1, entries
8–10). Further optimization of the reaction conditions was made by adding sodium carbonate (Table 1,

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entries 11 and 12). In these cases, the yield of target product was improved to 78%. It is presumed that
the sodium carbonate neutralizes the acid formed in the reaction, which accelerates the intramolecular
cyclization of the second step. Bringing the temperature to reflux did not have any noteworthy effect
on the yield of 3a (Table 1, entry 13).
2.2. Substrate Scope for the Imidazo[1,2-a]pyridines
With optimized conditions in hand, the reactions of different 2-aminopyridines with various
ethylarenes were investigated to explore the scope and generality of this method for the synthesis
of different imidazo[1,2-a]pyridines (Table 2). The reaction of 2-aminopyridine (2a) with ethylarenes
containing electron-withdrawing groups on the aromatic ring such as halogen, trifluoromethyl,
methylsulfonyl, and cyano, provided the corresponding products 3b–3h smoothly in medium to
good yields (32% and 65%). Ethylbenzenes with electron-rich groups, such as methyl and methoxy,
also afforded the corresponding imidazo[1,2-a]pyridines 3i and 3j in very good yield (68% and
59%). The same treatment of 1-ethylnaphthalene gave the desired product 3k in good yield (65%).
Furthermore, electron-rich and electron-withdrawing groups in the 2-aminopyridines were well
tolerated. The results revealed that electron-rich groups such as methyl and methoxyl afforded the
corresponding products in very good yield (yields 75–80%, 3l–3p). However, introduction of the
electron-withdrawing groups such as halogen, trifluoromethyl, and cyano afforded the corresponding
products in lower yields (yields 56–71%, 3q–3u).
2.3. Substrate Scope for Diverse Imidazoles and Thiazoles
Encouraged by the results above, we shifted to investigate the scope of other nucleophiles.
As shown in Figure 2, a range of nucleophiles were suitable for this reaction. These substrates
4a–4g were effective to give corresponding products 5a–5g in moderate to high yields (60–91%).
It is worth noting that valuable and more-complex substrates were also suitable for this reaction to
afford corresponding products, which is extremely useful for enriching a complex nitrogen-containing
heterocycle library.
Figure 2. Substrate scope for diverse imidazoles and thiazoles.

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Table 2. Substrate scope for the imidazo[1,2-a]pyridines a.
a
Reactions were run with 1 (1 mmol) of with NBS (3.5 equiv.) in the presence of AIBN (10 mol %) in EA:H2O (5:1,
6 mL) at 65 ◦C for 1.5 h, followed by reaction with
monitored by TLC. b Isolated yields.
2
(1.2 mmol) and Na2CO3 (5 equiv.) at 80 ◦C in water for 2–8 h,
2.4. Gram-Scale Preparation and Practice Application
To evaluate the efficiency and potential for practical applications of our method, a scale-up
experiment was carried out under the standard conditions (Scheme 2a). As a result, preparation
of 3a on a gram scale (2.95 g) was carried out, giving 76% yield. The compatibility of this reaction
encouraged us to start the study of large-scale synthesis of zolimidine, which is a gastroprotective
drug previously used for peptic ulcers and gastroesophageal reflux disease [36–38]. Starting with

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1-bromo-4-ethylbenzene (1c) the intermediate product 1h was obtained on the basis of a literature
procedure [39]. Then, according to the standard conditions, the target product 3h was obtained in 40%
yield in total (Scheme 2b).
Scheme 2. Gram-scale preparation of 3a and synthesis of the gastroprotective drug zolimidine.
2.5. Mechanism
A series of mechanistic experiments were performed to shed more light on the reaction mechanism,
as shown in Scheme 3.
Scheme 3. Mechanism experiments.

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When ethylbenzene (1a) was treated with NBS (3.5 equiv.) in the presence of AIBN (10 mol%) in a
◦
mixture of ethyl acetate and water (5:1) at 65 C for 1.5 h, 2-bromoacetophenone (1aa) was obtained in
86% yield. At the same time, α,α-dibromoethybenzene (1ab) and acetophenone (1ac) were formed in
7% and 3% yields, respectively (Scheme 3b). 2-Phenylimidazo[1,2-a]pyridine (3a) was obtained in 95%
◦
yield when 2-bromoacetophenone (1aa) was directly treated with pyridin-2-amine (2a) at 80 C for 2 h
(Scheme 3c).
α
,
α
-Dibromoethybenzene (1ab) was treated with NBS (1.5 equiv.) in the presence of AIBN
◦
(10 mol %) in a mixture of ethyl acetate and water (5:1) at 65 C for 1.5 h, followed by the reaction with
◦
2a at 80 C for 2 h to give◦3a in 71% yields (Scheme 3d). Besides, when acetophenone (1ac) was treated
◦
with NBS (1 equiv.) at 60 C for 1 h, followed by the reaction with 2a at 80 C for 2 h, 3a was obtained in
86% yield (Scheme 3e). As a result,
be converted into 3a using the present reaction procedure and conditions, which contributes to improve
the yield of this reaction. On the basis of mechanistic experiments and a literature survey [24 40],
α,α-dibromoethybenzene (1ab) and acetophenone (1ac) could also
,
a plausible pathway for the reaction has been proposed, as shown in Scheme 4, taking the reaction
of ethylbenzene (1a) and 2-aminopyridine (2a) for the synthesis of imidazo[1,2-a]pyridine (3a) as an
example.
formed from NBS (Wohl-Ziegler reaction) [41].
the second Wohl-Ziegler reaction of -bromoethylarene. The hydrolysis of
1ab) in a mixture of ethyl acetate and water under warming conditions proceeds to give acetophenone
1ac). Meanwhile, the hydrolysis of -bromoethybenzene may occur to form -hydroxyethybenzene
-hydroxyethybenzene
α
-Bromoethybenzene is formed in the reaction of ethylbenzene (1a) with bromine atoms
-Dibromoethybenzene (1ab) is the main product of
-dibromoethybenzene
α,α
α
α,α
(
(
α
α
as a minor product. Acetophenone (1ac) can also be easily obtained from
α
oxidized by NBS. Once acetophenone (1ac) is formed, it smoothly reacts with NBS to form the
important intermediate 2-bromo-acetophenone (1aa) which is isolated by column chromatography
and confirmed by comparison of NMR with literature. Finally, treatment of 2-bromoacetophenone
(1aa) with 2a afforded the desired product 3a by cyclization.
Scheme 4. Plausible reaction mechanism.
3. Materials and Methods
3.1. General Information
The reagents (chemicals) were purchased from commercial sources, and used without further
purification. Analytical thin layer chromatography (TLC) was performed on HSGF 254 (0.15–0.2 mm
thickness) plates. All products were characterized by their NMR and MS spectra. The 1H- (500 MHz)
and 13C-NMR (125 MHz) spectra were recorded in deuterochloroform (CDCl3) on Bruker Avance
III spectrometer (Billerica, MA, USA). Chemical shifts were reported in parts per million (ppm, δ)

Molecules 2019, 24, 893
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downfield from tetramethylsilane. Proton coupling patterns are described as singlet (s), doublet (d),
triplet (t), quartet (q), multiplet (m). Low- and high-resolution mass spectra (LRMS and HRMS) were
measured on Agilent 1260 Infinity II and Agilent 1290-6545 UHPLC-QTOF respectively (Palo Alto,
CA, USA).
3.2. Experimental Part Method
3.2.1. General Procedure for the Synthesis of Nitrogen-Containing Heterocycles
Synthesis of 3a is representative. To a solution of ethylbenzene (1a, 1 mmol, 107 mg) in ethyl
acetate:water (5:1, 6 mL) were added NBS (3.5 mmol, 628 mg) and AIBN (0.1 mmol, 16.5 mg) at room
temperature, and the mixture was stirred at 65 ◦C for 1.5 h. The mixture was concentrated to dryness
and then dissolved in water (5 mL), followed by reaction with 2-aminopyridine (2a, 1.2 mmol, 114 mg)
◦
and sodium carbonate (5 mmol, 534 mg) for 2 h at 80 C. After completion of the reaction (as indicated
by TLC), the crude product was extracted with ethyl acetate (3
was dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by
×
10 mL). The combined organic layer
silica gel column chromatography (PE/EA = 8/1–4/1, v/v) to give 3a (78% yield) as a white solid.
3.2.2. Procedure for the Synthesis of 1-Ethyl-4-(methylsulfonyl)benzene (1h)
1-Bromo-4-ethylbenzene (1c, 10 mmol), DMSO (50 mL), acetyl acetone (10 mmol), Cu2O (1 mmol),
and t-BuOK (45 mmol) were added into the reactor in turn. The reaction was carried out at reflux
(100 ◦C) under an air atmosphere for 20 h. After the reaction was finished, the mixture was diluted
with the saturated NaCl aqueous solution and extracted with ethyl acetate (3
layers were combined, and then dried with anhydrous Na2SO4. After the solvent was removed by
×
40 mL). The organic
rotovapor, the product was purified by column chromatograph (PE/EA = 5/1, v/v).
3.3. Product Characterization
2-Bromo-1-phenylethan-1-one (1aa) [42]: white solid, 1H-NMR (CDCl3)
δ 8.04–7.95 (m, 2H), 7.65–7.59 (m,
1H), 7.53–7.47 (m, 2H), 4.46 (s, 2H). 13C-NMR (CDCl3) δ 191.0, 133.7, 133.7, 128.7, 128.6, 30.7.
1
2-Phenylimidazo[1,2-a]pyridine (3a): white solid, H-NMR (CDCl3)
δ 8.11 (dt, J = 6.8, 1.3 Hz, 1H),
8.00–7.91 (m, 2H), 7.85 (s, 1H), 7.64 (d, J = 9.1 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.37–7.30 (m, 1H), 7.17
(ddd, J = 9.1, 6.7, 1.3 Hz, 1H), 6.77 (td, J = 6.8, 1.2 Hz, 1H). 13C-NMR (CDCl3)
δ 145.7, 145.6, 133.7, 128.7,
128.0, 126.0, 125.6, 124.7, 117.5, 112.4, 108.1. LRMS (ESI) m/z: [M + H]+ found 195.1, HRMS (ESI) m/z:
[M + H]+ Calcd. for C13H10N2 195.0917; found 195.0914.
2-(4-Fluorophenyl)imidazo[1,2-a]pyridine (3b): white solid, 1H-NMR (CDCl3)
1H), 7.97–7.87 (m, 2H), 7.80 (s, 1H), 7.69–7.54 (m, 1H), 7.22–7.03 (m, 3H), 6.78 (td, J = 6.7, 1.2 Hz, 1H).
δ 8.11 (dd, J = 6.8, 1.3 Hz,
13C-NMR (CDCl3)
δ 163.7, 161.7, 145.7, 144.9, 129.9, 127.7, 125.6, 124.8, 117.4, 115.7, 115.5, 112.5, 107.7.
LRMS (ESI) m/z: [M + H]+ found 213.1, HRMS (ESI) m/z: [M + H]+ Calcd. for C13H9FN2 213.0823;
found 213.0822.
2-(4-Bromophenyl)imidazo[1,2-a]pyridine (3c): white solid, 1H-NMR (CDCl3)
1H), 7.92–7.76 (m, 3H), 7.69–7.58 (m, 1H), 7.59–7.47 (m, 2H), 7.23–7.08 (m, 1H), 6.79 (td, J = 6.8, 1.2 Hz,
δ 8.10 (dt, J = 6.8, 1.2 Hz,
1H). 13C-NMR (CDCl3)
δ 145.8, 144.8, 132.8, 132.0, 131.9, 127.7, 125.7, 125.0, 122.0, 117.7, 112.7, 108.3.
LRMS (ESI) m/z: [M + H]+ found 273.1, HRMS (ESI) m/z: [M + H]+ Calcd. for C13H10BrN2 273.0022;
found 273.0017.
2-(4-Chlorophenyl)imidazo[1,2-a]pyridine (3d): white solid, 1H-NMR (CDCl3)
8.07 (s, 1H), 8.03–7.92 (m, 3H), 7.53–7.46 (m, 1H), 7.43–7.37 (m, 2H), 7.10 (t, J = 6.8 Hz, 1H). 13C-NMR
(CDCl3)
142.7, 135.5, 131.5, 129.3, 129.1, 128.2, 127.7, 126.5, 115.3, 108.8. LRMS (ESI) m/z: [M + H]+
found 229.0, HRMS (ESI) m/z: [M + H]+ Calcd. for C13H9ClN2 229.0527; found 229.0527.
δ 8.36 (d, J = 6.7 Hz, 1H),
δ

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2-(3,5-Difluorophenyl)imidazo[1,2-a]pyridine (3e): white solid, 1H-NMR (CDCl3)
δ
8.67 (s, 1H), 8.43 (s,
1H), 8.25 (d, J = 9.1 Hz, 1H), 7.70 (qt, J = 7.6, 4.5 Hz, 3H), 7.30 (d, J = 6.6 Hz, 1H), 6.86 (tt, J = 8.7, 2.3 Hz,
1H). 13C-NMR (CDCl3)
δ 164.4, 164.3, 162.4, 162.3, 127.4, 116.8, 114.5, 110.0, 109.8, 105.8, 105.6, 105.4.
LRMS (ESI) m/z: [M + H]+ found 231.0, HRMS (ESI) m/z: [M + H]+ Calcd. for C13H8F2N2 231.0728
found 231.0725.
4-(Imidazo[1,2-a]pyridin-2-yl)benzonitrile (3f): white solid, 1H-NMR (CDCl3)
1H), 8.11–8.07 (m, 2H), 7.99–7.96 (m, 1H), 7.77–7.68 (m, 3H), 7.29–7.23 (m, 1H), 6.88 (td, J = 6.8, 1.1 Hz,
δ 8.18 (dt, J = 6.7, 1.2 Hz,
1H). 13C-NMR (CDCl3)
δ 145.7, 143.3, 137.9, 132.6, 126.4, 125.8, 125.8, 118.9, 117.7, 113.2, 111.2, 109.5.
LRMS (ESI) m/z: [M + H]+ found 220.1, HRMS (ESI) m/z: [M + H]+ Calcd. for C14H9N3 220.0869; found
220.0872.
2-(4-(Trifluoromethyl)phenyl)imidazo[1,2-a]pyridine (3g): white solid, 1H-NMR (CDCl3)
1.3 Hz, 1H), 8.11 (d, J = 8.1 Hz, 2H), 7.97 (s, 1H), 7.76 (d, J = 9.1 Hz, 1H), 7.72 (d, J = 8.2 Hz, 2H),
δ 8.20 (dt, J = 6.8,
7.33–7.29 (m, 1H), 6.90 (td, J = 6.8, 1.1 Hz, 1H). 13C-NMR (CDCl3)
δ 145.2, 143.3, 130.1, 129.9, 126.2,
126.0, 125.8, 125.8, 125.7, 125.2, 123.0, 117.4, 113.4, 109.0. LRMS (ESI) m/z: [M + H]+ found 263.0, HRMS
(ESI) m/z: [M + H]+ Calcd. for C14H9F3N2 263.0791; found 263.0791.
2-(4-(Methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (3h): white solid, 1H-NMR (CDCl3)
δ 8.19–8.11 (m,
3H), 8.04–7.94 (m, 3H), 7.64 (dd, J = 9.0, 1.1 Hz, 1H), 7.22 (ddd, J = 9.1, 6.7, 1.3 Hz, 1H), 6.83 (td, J = 6.8,
1.2 Hz, 1H), 3.08 (s, 3H). 13C-NMR (CDCl3) δ 145.7, 143.3, 139.0, 127.6, 126.3, 125.5, 125.2, 117.6, 112.8,
109.4, 44.3. LRMS (ESI) m/z: [M + H]+ found 272.9, HRMS (ESI) m/z: [M + H]+ Calcd. for C14H12N2O2S
273.0692; found 273.0694.
1
2-(p-Tolyl)imidazo[1,2-a]pyridine (3i): white solid, H-NMR (CDCl3)
δ 8.23 (dt, J = 6.8, 1.2 Hz, 1H),
7.93–7.83 (m, 4H), 7.34–7.30 (m, 1H), 7.26 (d, J = 7.9 Hz, 2H), 6.96–6.88 (m, 1H), 2.40 (s, 3H). 13C-NMR
(CDCl3)
144.1, 143.4, 138.8, 129.6, 126.61, 126.2, 125.9, 116.4, 113.7, 107.9, 21.3. LRMS (ESI) m/z: [M + H]+
found 209.1, HRMS (ESI) m/z: [M + H]+ Calcd. for C14H12N2 209.1073; found 209.1072.
δ
2-(4-Methoxyphenyl)imidazo[1,2-a]pyridine (3j): white solid, 1H-NMR (CDCl3)
8.15 (dt, J = 6.7, 1.2 Hz,
1H), 7.95–7.90 (m, 2H), 7.81 (d, J = 0.7 Hz, 1H), 7.74 (d, J = 9.0 Hz, 1H), 7.24 (ddd, J = 9.1, 6.8, 1.3 Hz,
δ
1H), 7.02–6.97 (m, 2H), 6.84 (td, J = 6.8, 1.1 Hz, 1H), 3.87 (s, 3H). 13C-NMR (CDCl3)
δ 159.9, 144.8, 144.5,
127.4, 125.6, 125.4, 125.2, 116.8, 114.2, 112.9, 107.2, 55.3. LRMS (ESI) m/z: [M + H]+ found 225.1, HRMS
(ESI) m/z: [M + H]+ Calcd. for C14H12N2O 225.1022; found 225.1025.
2-(Naphthalen-1-yl)imidazo[1,2-a]pyridine (3k): white solid, 1H-NMR (CDCl3)
δ 8.59–8.49 (m, 1H), 8.15
(dt, J = 6.7, 1.2 Hz, 1H), 8.01 (dd, J = 8.5, 1.7 Hz, 1H), 7.99 (d, J = 0.7 Hz, 1H), 7.96–7.88 (m, 2H), 7.86–7.82
(m, 1H), 7.69 (dd, J = 9.0, 1.2 Hz, 1H), 7.53–7.44 (m, 2H), 7.21 (ddd, J = 9.1, 6.7, 1.3 Hz, 1H), 6.81 (td,
J = 6.7, 1.1 Hz, 1H). 13C-NMR (CDCl3)
δ 145.7, 145.5, 140.7, 140.6, 132.7, 128.7, 127.4, 127.3, 126.9, 126.4,
125.5, 124.6, 117.5, 112.4, 108.2. LRMS (ESI) m/z: [M + H]+ found 244.9, HRMS (ESI) m/z: [M + H]+
Calcd. for C17H12N2 245.1073; found 245.1072.
8-Methyl-2-phenylimidazo[1,2-a]pyridine (3l): white solid, 1H-NMR (CDCl3)
(m, 1H), 7.76 (s, 1H), 7.54 (d, J = 9.2 Hz, 1H), 7.42 (t, J = 7.7 Hz, 2H), 7.32 (d, J = 7.4 Hz, 1H), 7.01 (dd,
δ 7.98–7.91 (m, 2H), 7.91–7.85
J = 9.2, 1.7 Hz, 1H), 2.37–2.27 (m, 3H). 13C-NMR (CDCl3)
δ 145.7, 145.1, 135.1, 133.5, 128.2, 127.4, 125.7,
124.3, 115.5, 114.6, 107.1, 21.0. LRMS (ESI) m/z: [M + H]+ found 209.2, HRMS (ESI) m/z: [M + H]+ Calcd.
for C14H12N2 209.1073; found 209.1075.
7-Methyl-2-phenylimidazo[1,2-a]pyridine (3m): white solid, 1H-NMR (CDCl3)
δ 8.02–7.87 (m, 3H), 7.76 (s,
1H), 7.50–7.36 (m, 3H), 7.32 (d, J = 7.3 Hz, 1H), 6.59 (dd, J = 6.9, 1.7 Hz, 1H), 2.39 (d, J = 1.1 Hz, 3H).
13C-NMR (CDCl3) δ 145.7, 145.1, 135.2, 133.5, 128.2, 127.4, 125.6, 124.3, 115.5, 114.6, 107.1, 21.0. LRMS
(ESI) m/z: [M + H]+ found 209.2, HRMS (ESI) m/z: [M + H]+ Calcd. for C14H12N2 209.1073; found
209.1075.

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6-Methyl-2-phenylimidazo[1,2-a]pyridine (3n): white solid, 1H-NMR (CDCl3)
δ
8.00–7.86 (m, 3H), 7.77 (s,
1H), 7.54 (d, J = 9.2 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.36–7.29 (m, 1H), 7.01 (dd, J = 9.2, 1.7 Hz, 1H),
2.34–2.28 (m, 3H). 13C-NMR (CDCl3)
δ 134.0, 128.8, 127.9, 127.9, 126.0, 123.4, 122.1, 116.9, 107.9, 18.1.
LRMS (ESI) m/z: [M + H]+ found 209.2, HRMS (ESI) m/z: [M + H]+ Calcd. for C14H12N2 209.1073;
found 209.1075.
6-Methoxy-2-phenylimidazo[1,2-a]pyridine (3o): white solid, 1H-NMR (CDCl3)
(s, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.53 (d, J = 9.7 Hz, 1H), 7.42 (t, J = 7.7 Hz, 2H), 7.32 (d, J = 7.3 Hz, 1H),
δ 7.95–7.87 (m, 2H), 7.79
6.97 (dd, J = 9.7, 2.4 Hz, 1H), 3.82 (s, 3H). 13C-NMR (CDCl3)
δ 148.9, 145.2, 142.4, 133.5, 128.3, 127.3,
125.4, 119.4, 117.3, 108.8, 107.1, 55.8. LRMS (ESI) m/z: [M + H]+ found 225.1, HRMS (ESI) m/z: [M + H]+
Calcd. for C14H12N2O 225.1022; found 225.1018.
5-Methoxy-2-phenylimidazo[1,2-a]pyridine (3p): white solid, 1H-NMR (CDCl3)
(s, 1H), 7.68 (d, J = 2.4 Hz, 1H), 7.57 (d, J = 9.7 Hz, 1H), 7.45 (t, J = 7.8 Hz, 2H), 7.34 (td, J = 7.2, 1.3
δ 7.97–7.92 (m, 2H), 7.83
Hz, 1H), 7.00 (dd, J = 9.7, 2.3 Hz, 1H), 3.86 (s, 3H). 13C-NMR (CDCl3)
δ 149.4, 146.8, 145.1, 133.9, 128.6,
127.8, 126.0, 125.9, 109.4, 103.6, 87.7, 56.3. LRMS (ESI) m/z: [M + H]+ found 225.1, HRMS (ESI) m/z:
[M + H]+ Calcd. for C14H12N2O 225.1022; found 225.1018
6-Fluoro-2-phenylimidazo[1,2-a]pyridine (3q): white solid, 1H-NMR (CDCl3)
1H), 7.99–7.94 (m, 2H), 7.86 (d, J = 0.7 Hz, 1H), 7.62 (d, J = 9.5 Hz, 1H), 7.47 (dd, J = 8.4, 7.0 Hz,
δ 8.20 (dd, J = 2.0, 0.9 Hz,
2H), 7.41–7.35 (m, 1H), 7.18 (dd, J = 9.5, 2.0 Hz, 1H). 13C-NMR (CDCl3)
δ 146.6, 144.0, 133.1, 128.8,
128.3, 128.1, 126.1, 125.5, 118.1, 108.2, 107.0. LRMS (ESI) m/z: [M + H]+ found 213.2, HRMS (ESI) m/z:
[M + H]+ Calcd. for C13H9FN2 213.0823; found 213.0822.
6-Chloro-2-phenylimidazo[1,2-a]pyridine (3r): white solid, 1H-NMR (CDCl3)
1H), 8.03–7.88 (m, 2H), 7.84 (s, 1H), 7.60 (d, J = 9.5 Hz, 1H), 7.45 (t, J = 7.5 Hz, 2H), 7.36 (d, J = 7.3 Hz,
δ 8.18 (dd, J = 2.0, 0.9 Hz,
1H), 7.15 (dd, J = 9.5, 2.0 Hz, 1H). 13C-NMR (CDCl3)
δ 147.1, 144.3, 133.6, 129.1, 128.6, 126.4, 126.4,
123.7, 120.9, 118.2, 108.8. LRMS (ESI) m/z: [M + H]+ found 229.1, HRMS (ESI) m/z: [M + H]+ Calcd. for
C13H9ClN2 229.0527; found 229.0526.
6-Bromo-2-phenylimidazo[1,2-a]pyridine (3s): white solid, 1H-NMR (CDCl3)
(m, 2H), 7.82 (s, 1H), 7.53 (d, J = 9.5 Hz, 1H), 7.44 (dd, J = 8.3, 6.8 Hz, 2H), 7.39–7.30 (m, 1H), 7.23
δ 8.33–8.21 (m, 1H), 8.00–7.89
(dd, J = 9.5, 1.9 Hz, 1H). 13C-NMR (CDCl3)
δ 147.0, 144.4, 133.5, 129.1, 128.6, 128.4, 126.4, 125.9, 118.5,
108.6, 107.3. LRMS (ESI) m/z: [M + H]+ found 273.1, HRMS (ESI) m/z: [M + H]+ Calcd. for C13H10BrN2
273.0022; found 273.0017.
2-Phenyl-6-(trifluoromethyl)imidazo[1,2-a]pyridine (3t): white solid, 1H-NMR (CDCl3)
Hz, 1H), 8.02–7.96 (m, 4H), 7.49 (t, J = 7.7 Hz, 2H), 7.43–7.37 (m, 1H), 6.99 (dd, J = 7.1, 1.8 Hz, 1H).
δ 8.25 (d, J = 7.0
13C-NMR (CDCl3)
δ 147.8, 145.3, 132.9, 128.9, 128.6, 126.2, 124.6, 120.6, 118.1, 109.2. LRMS (ESI) m/z:
[M + H]+ found 263.1, HRMS (ESI) m/z: [M + H]+ Calcd. for C14H10 F3N2 263.0791; found 263.0794.
1
2-Phenylimidazo[1,2-a]pyridine-6-carbonitrile (3u): white solid, H-NMR (CDCl3)
δ 8.20 (dd, J = 7.0,
1.0 Hz, 1H), 8.08–7.90 (m, 4H), 7.46 (d, J = 7.8 Hz, 2H), 7.40 (d, J = 7.3 Hz, 1H), 6.94 (dd, J = 7.0, 1.6
Hz, 1H). 13C-NMR (CDCl3)
δ 149.0, 143.5, 132.6, 129.0, 126.3, 126.2, 123.7, 117.7, 112.8, 110.3, 107.2.
LRMS (ESI) m/z: [M + H]+ found 220.1, HRMS (ESI) m/z: [M + H]+ Calcd. for C14H9N3 220.0869; found
220.0862.
1
2-Phenylbenzo[d]imidazo[2,1-b]thiazole (5a): white solid, H-NMR (CDCl3)
δ 7.95 (d, J = 2.1 Hz, 1H),
7.91–7.82 (m, 2H), 7.72–7.63 (m, 1H), 7.63–7.55 (m, 1H), 7.45–7.38 (m, 3H), 7.36–7.29 (m, 2H). 13C-NMR
(CDCl3) δ 148.1, 147.7, 133.8, 132.2, 130.3, 128.7, 127.5, 126.2, 125.2, 124.9, 124.4, 112.6, 106.8. LRMS (ESI)
m/z: [M + H]+ found 251.1, HRMS (ESI) m/z: [M + H]+ Calcd. for C15H10N2S 251.0637; found 251.0632.
1
6-Phenylimidazo[2,1-b]thiazole (5b): white solid, H-NMR (CDCl3)
δ
7.88–7.82 (m, 2H), 7.77 (s, 1H),
150.2, 147.9, 134.1,
7.47–7.39 (m, 3H), 7.34–7.28 (m, 1H), 6.85 (d, J = 4.5 Hz, 1H). 13C-NMR (CDCl3)
δ

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128.6, 127.3, 125.2, 118.4, 112.4, 107.9. LRMS (ESI) m/z: [M + H]+ found 201.1, HRMS (ESI) m/z: [M +
H]+ Calcd. for C11H9N2S 201.0481; found 201.0482.
N,4-Diphenylthiazol-2-amine (5c): white solid, 1H-NMR (CDCl3)
δ 7.88 (dd, J = 8.2, 1.4 Hz, 2H), 7.49–7.30
(m, 7H), 7.09 (tt, J = 6.9, 1.5 Hz, 1H), 6.84 (s, 1H). 13C-NMR (CDCl3)
δ 164.3, 139.7, 133.9, 129.0, 128.2,
127.5, 125.7, 122.6, 117.8, 101.2. LRMS (ESI) m/z: [M + H]+ found 253.0, HRMS (ESI) m/z: [M + H]+
Calcd. for C15H12N2S 253.0794; found 253.0797.
4-Phenylthiazol-2-amine (5d): white solid, 1H-NMR (CDCl3)
δ 7.86–7.67 (m, 2H), 7.38 (t, J = 7.5 Hz, 2H),
7.30 (d, J = 7.4 Hz, 1H), 6.72 (s, 1H), 5.26 (s, 2H). 13C-NMR (CDCl3)
δ 167.3, 151.3, 134.7, 128.5, 127.7,
126.0, 102.8. LRMS (ESI) m/z: [M + H]+ found 177.1, HRMS (ESI) m/z: [M + H]+ Calcd. for C9H8N2S
177.0481; found 177.0486.
2-Methyl-4-phenylthiazole (5e): white solid, 1H-NMR (CDCl3)
δ
δ
7.93–7.88 (m, 2H), 7.44 (dd, J = 8.3, 7.0
165.9, 155.1, 134.5, 128.7, 128.0, 126.3,
Hz, 2H), 7.38–7.31 (m, 2H), 2.81 (s, 3H). 13C-NMR (CDCl3)
112.2, 19.3. LRMS (ESI) m/z: [M + H]+ found 176.0, HRMS (ESI) m/z: [M + H]+ Calcd. for C10H9NS
176.0534; found 176.0530.
2,4-Diphenylthiazole (5f): white solid, 1H-NMR (CDCl3)
δ 8.09 (dd, J = 7.8, 1.7 Hz, 2H), 8.06–8.01 (m,
2H), 7.56–7.44 (m, 6H), 7.43–7.34 (m, 1H). 13C-NMR (CDCl3)
δ 168.0, 133.6, 130.1, 128.9, 128.8, 128.2,
126.7, 126.5, 112.6. LRMS (ESI) m/z: [M + H]+ found 238.0, HRMS (ESI) m/z: [M + H]+ Calcd. for
C15H11NS 238.0612; found 238.0614.
2-Phenylimidazo[2,1-a]isoquinoline (5g): white solid, 1H-NMR (CDCl3)
δ 8.77 (d, J = 8.0 Hz, 1H), 8.12–8.01
(m, 2H), 7.90 (d, J = 7.2 Hz, 1H), 7.83 (s, 1H), 7.73–7.70 (m, 1H), 7.67 (ddd, J = 8.2, 7.1, 1.2 Hz, 1H),
7.59 (ddd, J = 8.2, 7.2, 1.3 Hz, 1H), 7.48 (t, J = 7.7 Hz, 2H), 7.40–7.33 (m, 1H), 7.05 (d, J = 7.2 Hz, 1H).
13C-NMR (CDCl3)
δ 144.0, 143.3, 134.0, 129.4, 128.7, 128.1, 127.5, 126.9, 125.8, 123.8, 123.5, 122.9, 113.0,
109.8. LRMS (ESI) m/z: [M + H]+ found 244.9, HRMS (ESI) m/z: [M + H]+ Calcd. for C17H12N2 245.1073;
found 245.1072.
4. Conclusions
In summary, we demonstrated a one-pot approach for the synthesis of various imidazoles and
thiazoles. The process involves the reaction of different ethylarenes with different suitable nucleophiles
via treatment with NBS and a catalytic amount of AIBN in a mixture of ethyl acetate and water, to give
corresponding products. It is notable that all reactions were carried out in water as the solvent and
were metal-free, with NBS playing a dual role as both a bromine source and oxidant.
Supplementary Materials: The supplementary materials are available online.
Author Contributions: Conceptualization, L.C. and H.Z.; Experiments and analyses, L.C.; Writing—Original
Draft Preparation, J.W. and H.L.; Writing—Review & Editing.
Funding: We gratefully acknowledge financial support from the National Natural Science Foundation of China
(81620108027, 21632008, and 21672231), the Major Project of Chinese National Programs for Fundamental Research
and Development (2015CB910304).
Conflicts of Interest: The authors declare no conflict of interest.
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