Synthesis of 1-aryl-substituted-4-chloroimidazo[1,2-a]quinoxalines catalyzed by PdCl2 in water

Article abstract of DOI:10.1016/j.tetlet.2012.01.028

The reaction of 2-chloro-3-propargylaminoquinoxaline with various aryl iodides and bromides catalyzed by Pd-Cu in the presence of potassium carbonate as the base in water leads to the one-pot formation of 1-aryl-substituted-4- chloroimidazo[1,2-a]quinoxal

Full text of DOI:10.1016/j.tetlet.2012.01.028

Tetrahedron Letters 53 (2012) 1447–1449
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Synthesis of 1-aryl-substituted-4-chloroimidazo[1,2-a]quinoxalines
catalyzed by PdCl2 in water
⇑
Mohammad Bakherad , Ali Keivanloo, Shahrzad Samangooei
School of Chemistry, Shahrood University of Technology, Shahrood, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of 2-chloro-3-propargylaminoquinoxaline with various aryl iodides and bromides catalyzed
by Pd–Cu in the presence of potassium carbonate as the base in water leads to the one-pot formation of 1-
aryl-substituted-4-chloroimidazo[1,2-a]quinoxalines in moderate-to-high yields.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 9 October 2011
Revised 19 December 2011
Accepted 6 January 2012
Available online 21 January 2012
Keywords:
Pd–cu catalyzed
Sonogashira reaction
Aryl halides
Imidazo[1,2-a]quinoxaline
The quinoxaline nucleus is present in many pharmaceutical
agents exhibiting a broad spectrum of biological activities such as
antitumor,1 antiviral,2 antiglaucoma,3 antituberculosis,4 antiinflam-
matory,5 and anticancer.6 Furthermore, imidazo[1,2-a]quinoxaline
derivatives have been shown to have antitumor activity7 and act as
adenosine A1 receptor antagonists.8 Although several procedures
have been developed for the synthesis of imidazo[1,2-a]quinoxa-
lines,9 no examples involving the arylation of imidazoquinoxaline
via Pd–Cu catalyzed (Sonogashira coupling) reactions have been
reported in the literature.
The Sonogashira reaction catalyzed by palladium and copper is a
powerful and straightforward method for the construction of arylat-
ed internal alkynes.10 These are important intermediates in organic
synthesis, and for the preparation of natural products,11 biologically
active molecules,12 molecular electronics,13 and polymers.14
The original Sonogashira reaction was generally performed in
the presence of palladium and copper(I) iodide as a co-catalyst in or-
ganic solvents, which are harmful to the environment. In most
catalytic processes, organic solvents are usually employed as the
reaction media, often creating safety, health, and environmental is-
sues due to their flammability, toxicity, and volatility. From an
economic and environmental standpoint, it is desirable to avoid
the use of hazardous and expensive organic solvents. The use of
water as a reaction medium demonstrates useful benefits since this
solvent is highly polar and therefore immiscible with most organic
compounds. Thus water-soluble by-products remain and separa-
tion of the organic materials is simple. Several examples of Pd-cat-
alyzed Sonogashira reactions in aqueous medium have been
reported.15
Continuing our efforts directed toward the straightforward prep-
aration of biologically active target molecules through Sonogashira
coupling reactions,16 we performed the synthesis of new derivatives
of imidazo[1,2-a]quinoxaline via Pd–Cu catalyzed Sonogashira
coupling in water.
Treatment of 2,3-dichloroquinoxaline (1) with propargylamine
in refluxing 1,4-dioxane gave 2-chloro-3-propargylamino quinoxa-
line (2) in an 88% yield. The 1H NMR spectrum of 2 showed the
presence of a CH proton at 2.15 ppm, CH2 protons at 4.25 ppm,
and a single resonance for the NH group at 7.50 ppm that
disappeared on deuteration.
When compound 2 was treated with aryl halides 3a–g and
K2CO3 in water in the presence of palladium chloride, triphenyl-
phosphine, and copper iodide at 70 °C, 1-aryl-substituted-4-chlo-
roimidazo[1,2-a]quinoxalines 4a–g were obtained in moderate-
to-high yields (Scheme 1, Table 1). The reactions were carried
out under an argon atmosphere, and the water was degassed prior
to use.
The 1H NMR spectrum of product 4a exhibited an aromatic sin-
glet at 8.02 ppm, which is characteristic of a fused imidazole ring.
The other eight aromatic protons appeared at 7.15–8.12 ppm. In
the aliphatic region, the singlet proton at 5.10 ppm was due to
the benzylic protons.
As shown in Table 1, compound 2 reacted with various aryl io-
dides such as p-nitroiodobenzene, 4-chloro-2-nitroiodobenzene,
and 2-chloro-4-nitroiodobenzene delivering the corresponding
products in high yields (entries 2–4). Unsurprisingly, 4-chloro-2-
nitroiodobenzene (entry 3) was found to be the most reactive
⇑
Corresponding author.
E-mail address: m.bakherad@yahoo.com (M. Bakherad).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.028

1448
M. Bakherad et al. / Tetrahedron Letters 53 (2012) 1447–1449
N
N
Cl
Cl
N
N
Cl
ArX
PdCl2, PPh3, CuI
NH2CH2
1,4-dioxane
3a-g
K2CO3, H2O, 70 ºC
NH
1
2
N
N
Cl
N
N
Cl
N
N
Cl
Pd(II)
K2CO3
NH
N
N
ArCH
ArCH2
4a-g
Ar
Scheme 1. A plausible mechanism for the formation of 1-aryl-substituted-4-chloroimidazo[1,2-a]quinoxalines 4.
Table 1
groups to give the desired products in high yields. The presence
of electron-withdrawing groups such as –NO2, –CN, –CHO, and –
Cl on the aryl halides was essential for a successful reaction. When
p-iodoanisole or iodobenzene was used as the aryl halide, only a
small amount of product was isolated after column
chromatography.
Melting points and yields of 1-aryl-substituted-4-chloroimidazo[1,2-a]quinoxalines
4a–ga
Entry
1
X
I
Ar
Product
Mp (°C)
Yieldb (%)
87
NO2
4a
220–222
It was found that while Pd/C, PdCl2(PPh3)2, PdCl2/PPh3, and
PdCl2 all catalyzed the reaction without the aid of any surfactant,
PdCl2/PPh3 proved to be the best catalyst in terms of yields.
Although PdCl2/PPh3 was the catalyst of choice, the addition of
copper(I) iodide as a co-catalyst was essential. The reactions car-
ried out with PdCl2 alone led to poor yields of mixtures of products.
Among the bases tested, potassium carbonate was found to be the
most suitable giving cleaner products and better yields. Unsatisfac-
tory results were obtained with organic bases such as Et3N, DIEA,
pyridine and piperidine.
A plausible two-step mechanism is suggested for the reaction
(Scheme 1). First a standard Sonogashira coupling takes place
followed by Pd(II)-catalyzed intermolecular cyclization of the
nucleophilic nitrogen on the triple bond, and finally base-induced
aromatization to afford the product 4.17
2
3
4
I
I
I
4b
4c
4d
211–213
250–252
240–242
91
95
92
NO2
NO2
Cl
Cl
NO2
5
6
7
I
4e
4a
4b
216–218
220–222
211–213
82
66
68
In conclusion, we have described a successful synthesis of 1-
aryl-substituted-4-chloroimidazo[1,2-a]quinoxalines via a PdCl2-
mediated Sonogashira coupling reaction in water. Since
water-based syntheses are safer and environmentally friendly, the
method described may hold promise in organic synthesis.
COCH3
NO2
Br
Br
2-Chloro-3-propargylaminoquinoxaline (2)
NO2
CHO
CN
A mixture of 1,2-dichloroquinoxaline (1.99 g, 10 mmol) and
propargylamine (1.2 mL, 20 mmol) in 1,4-dioxane (10 mL) was
heated under reflux for 4 h. The resulting precipitate was filtered
and recrystallized from EtOH to afford the title compound in an
88% yield, mp 80–82 °C; 1H NMR (400 MHz, DMSO-d6): d = 2.15
(t, J = 4.0 Hz, 1H), 4.25 (d, J = 4.0 Hz, 2H), 7.50 (s, 1H), 7.70–7.85
(m, 4H), 13C NMR (100 MHz, DMSO-d6): d = 29.23, 70.12, 75.23,
8
9
Br
Br
4f
230–232
228–230
75
72
4g
125.14, 129.89, 134.48, 140.56, 160.78; IR,
t (KBr): 3300, 3100,
2230 cmÀ1; HRMS (ESI): 216.0361.
a
Reaction and conditions: 2 (1.20 mmol), 3a–g (1.0 mmol), K2CO3 (2 mmol),
PdCl2 (0.05 mmol), PPh3 (0.1 mmol), CuI (0.1 mmol), H2O (5 mL), 70 °C, 12 h.
b
1-Aryl-substituted-4-chloroimidazo[1,2-a]quinoxalines (4a–g)
Isolated yield.
A mixture of aryl halide (1.0 mmol), PdCl2 (0.05 mmol), PPh3
(0.10 mmol), CuI (0.1 mmol) and K2CO3 (2.0 mmol) was stirred in
H2O (5 mL) at room temperature under an argon atmosphere. 2-
Chloro-3-propargylaminoquinoxaline (2) (1.20 mmol) was added,
and the mixture stirred at 70 °C for 12 h. After completion of the
reaction, the resulting solution was concentrated in vacuo, and
the crude residue subjected to column chromatography (silica
among the aryl halides studied. The reaction of aryl bromides such
as o-nitrobromobenzene, p-nitrobromobenzene, p-bromobenzal-
dehyde, and p-bromobenzonitrile with compound 2 gave the corre-
sponding products in moderate yields (entries 6–9). As expected,
aryl iodides with electron-withdrawing groups reacted more effi-
ciently than the aryl bromides possessing electron-withdrawing

M. Bakherad et al. / Tetrahedron Letters 53 (2012) 1447–1449
1449
gel) using CHCl3–CH3OH (98:2) as an eluent to afford the pure
References and notes
product (Table 1).
4a: 1H NMR (400 MHz, DMSO-d6): d = 5.10 (s, 2H, CH2), 7.15–
7.21 (m, 2H), 7.42 (s, 1H), 7.45–7.53 (m, 3H), 8.02 (s, 1H), 8.05–
8.12 (m, 2H); 13C NMR (100 MHz, DMSO-d6): d = 31.20, 115.29,
125.76, 127.04, 128.57, 128.93, 130.36, 131.13, 131.44, 134.11,
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135.32, 135.74, 137.38, 143.68, 148.61; IR,
t (KBr): 1540,
1350 cmÀ1; HRMS (ESI): 338.0542.
4b: 1H NMR (400 MHz, DMSO-d6): d = 5.05 (s, 2H), 7.20–7.32
(m, 4H), 7.42–7.50 (m, 3H), 7.62–7.65 (m, 1H), 8.10 (s, 1H); 13C
NMR (100 MHz, DMSO-d6): d = 31.75, 115.74, 120.08, 125.82,
127.32, 128.43, 128.92, 130.10, 131.25, 131.85, 134.15, 135.05,
135.60, 137.28, 143.60, 148.52; IR,
HRMS (ESI): 338.0538.
t ;
(KBr): 1520, 1340 cmÀ1
4c: 1H NMR (400 MHz, DMSO-d6): d = 5.10 (s, 2H), 7.10–7.20 (m,
3H), 7.42–7.52 (m, 3H), 7.95–7.98 (m, 1H), 8.15 (s, 1H); 13C NMR
(100 MHz, DMSO-d6): d = 30.75, 115.07, 125.90, 127.13, 128.16,
128.49, 129.01, 129.96, 130.47, 132.26, 134.16, 134.81, 135.40,
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137.54, 143.83, 148.84; IR,
(ESI): 372.0205.
t
(KBr): 1520, 1330 cmÀ1; HRMS
4d: 1H NMR (400 MHz, DMSO-d6): d = 5.03 (s, 2H), 7.40 (d,
J = 8.4, 1H), 7.46–7.53 (m, 2H), 7.65–7.73 (m, 3H), 8.40–8.46 (m,
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126.92, 127.88, 128.23, 129.22, 129.69, 130.32, 132.42, 134.16,
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134.72, 135.30, 137.45, 143.90, 148.73; IR,
t (KBr): 1550,
1330 cmÀ1; HRMS (ESI): 372.0152.
4e: 1H NMR (400 MHz, DMSO-d6): d = 2.65 (s, 3H), 4.89 (s, 2H),
7.11–7.17 (m, 2H), 7.64–7.74 (m, 4H), 8.04–8.10 (m, 2H), 8.20 (s,
1H); 13C NMR (100 MHz, DMSO-d6): d = 27.52, 31.28, 115.30,
125.95, 126.80, 127.35, 128.35, 129.42, 129.75, 130.23, 131.55,
132.27, 134.56, 140.74, 143.65, 148.37, 198.34; IR,
t (KBr):
1690 cmÀ1; HRMS (ESI): 335.0852.
4f: 1H NMR (400 MHz, DMSO-d6): d = 5.27 (s, 2H), 7.35–7.42 (m,
3H), 7.52–7.58 (m, 2H), 7.75–7.78 (m, 1H), 7.80–7.87 (m, 2H), 8.20
(s, 1H), 10.20 (s, 1H); 13C NMR (100 MHz, DMSO-d6): d = 31.69,
115.12, 125.26, 127.35, 128.21, 128.38, 129.13, 129.54, 130.27,
130.79, 132.48, 137.65, 143.25, 148.42, 190.85; IR,
t (KBr):
1710 cmÀ1; HRMS (ESI): 321.0635.
4g: 1H NMR (400 MHz, DMSO-d6): d = 5.25 (s, 2H), 7.40–7.50
(m, 3H), 7.57–7.63 (m, 2H), 7.76–7.85 (m, 3H), 8.15 (s, 1H); 13C
NMR (100 MHz, DMSO-d6): d = 31.87, 108.25, 115.25, 115.95,
128.26, 128.83, 129.16, 129.47, 130.68, 131.26, 132.20, 133.35,
133.58, 143.84, 145.28; IR,
318.0698.
t
(KBr): 2200 cmÀ1; HRMS (ESI):
Acknowledgment
17. Bates, D. K.; Xia, M. D.; Aho, M.; Mueller, H.; Raghavan, R. R. Heterocycles 1999,
51, 475.
We are grateful to the Research Council of Shahrood University
of Technology for the financial support of this work.