Pd/C-catalyzed heterocyclization during copper-free Sonogashira coupling: Synthesis of 2-benzylimidazo[1,2-a]pyrimidines in water

Article abstract of DOI:10.1016/j.tetlet.2010.10.168

An efficient synthesis of 2-benzylimidazo[1,2-a]pyrimidines in water is accomplished via Pd/C-catalyzed reaction of 2-imino-1-(2-propynyl)pyrimidine with various aryl iodides in the presence of K₂CO₃ as the base.

Full text of DOI:10.1016/j.tetlet.2010.10.168

Tetrahedron Letters 52 (2011) 228–230
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Tetrahedron Letters
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Pd/C-catalyzed heterocyclization during copper-free Sonogashira coupling:
synthesis of 2-benzylimidazo[1,2-a]pyrimidines in water
⇑
Mohammad Bakherad , Ali Keivanloo, Zahra Kalantar, Saeideh Jajarmi
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:
An efficient synthesis of 2-benzylimidazo[1,2-a]pyrimidines in water is accomplished via Pd/C-catalyzed
Received 12 August 2010
Revised 21 October 2010
Accepted 29 October 2010
Available online 4 November 2010
reaction of 2-imino-1-(2-propynyl)pyrimidine with various aryl iodides in the presence of K2CO3 as the
base.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Pd/C-catalyzed
Sonogashira reaction
Aryl iodide
Imidazopyrimidine
1. Introduction
been reported.9 Compared to frequently used expensive palladium
catalysts [e.g., Pd(PPh3)4, (PPh3)2PdCl2, etc.], Pd/C-based methods
Imidazo[1,2-a]pyrimidines possess diverse biological activities
and this structural motif is present in analgesics, inflammatory
inhibitors,1 and benzodiazepine receptor ligands2 as well as in
insecticidal, acaricidal, and nematocidal agents.3 The structure of
the imidazo[1,2-a]pyrimidine nucleus is related to the purine ring
system and, therefore, we were interested in the synthesis of
various 2-benzylimidazo[1,2-a]pyrimidines. Although several
methods are reported4 for the synthesis of 2-substituted imi-
dazo[1,2-a]pyrimidines, a literature survey revealed no references
concerning a Pd-catalyzed preparation of this system.
Transition metal mediated cross-coupling reactions have pro-
ven to be powerful tools for mild, highly efficient carbon–carbon
bond formation.5 Among these processes, palladium-catalyzed alk-
ynylation of aryl or heteroaryl rings, the Sonogashira reaction,6 is a
powerful tool for C–C bond formation.7 However, a one-pot process
involving a Sonogashira-type coupling followed by electrophilic or
transition metal mediated cyclization of the resulting alkynes, pos-
sessing a suitable nucleophilic moiety in proximity of the triple
bond, has now emerged as a versatile and efficient route to various
substituted heterocyclic systems.8
have an economic advantage, and hence remain attractive for large
or industrial scale preparations.
In recent years, a variety of modifications have been reported
for this reaction and significant progress has been made.10 The
most important modification is the elimination of the copper salt,11
since it can induce Glaser-type homocoupling of terminal alkynes
in the presence of oxidants or air.12 Furthermore, in most of the
catalytic processes, organic solvents are employed as the reaction
media, often creating safety, health, and environmental problems
due to their flammability, toxicity, and volatility. From an eco-
nomic and environmental standpoint, it is desirable to avoid the
use of hazardous and expensive organic solvents. The use of water
or aqueous solutions represents economically and environmentally
viable alternatives to organic solvents for metal-catalyzed reac-
tions.13 Several examples of Pd-catalyzed Sonogashira reactions
in aqueous media have been reported.14
In continuation of our interest in palladium-catalyzed reac-
tions,15 we report a novel and efficient method for the synthesis
of 2-benzylimidazo[1,2-a]pyrimidines via Pd/C-mediated copper-
free Sonogashira coupling in water.
Typically, these coupling-cyclization reactions were carried out
using a palladium catalyst [e.g., Pd(PPh3)4, (PPh3)2PdCl2, etc.], and a
copper salt as the co-catalyst in the presence of an amine base.
The use of Pd/C–CuI–PPh3 as a catalytic system for the efficient
Sonogashira coupling of aryl halides with terminal alkynes has also
We first prepared 2-imino-1-(2-propynyl)pyrimidine (2) by
reaction of 2-aminopyrimidine (1) with propargyl bromide in
refluxing acetonitrile. The 1H NMR spectrum of 2 showed a CH
alkyne proton at 3.08 ppm, CH2 protons at 4.90 ppm, and a
resonance for the NH group at 9.60 ppm that disappeared on
deuteration (Scheme 1).
For optimization of the reaction conditions, we studied the
effect of various reaction parameters including the palladium
⇑
Corresponding author. Fax: +98 2733395441.
E-mail address: m.bakherad@yahoo.com (M. Bakherad).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.168

M. Bakherad et al. / Tetrahedron Letters 52 (2011) 228–230
229
Table 2
ArI, Pd/C, PPh3
K2CO3, H2O
N
C
N
Melting points and yields of 2-arylimidazo[1,2-a]pyrimidines 4a–j
BrH2C
CH3CN
NH2
C
CH
N
NH
CH
Entry
Ar
Product
Mp (°C)
Yield (%)
Sonogashira coupling
N
1
2
1
4a
154–156
90
65
78
N
NO
2
N
N
K2CO3
Pd(II)
N
NH
N
N
2
3
4b
4c
118–120
138–140
N
N
C
NO
C
2
Ar
CH2Ar
CHAr
4a-j
Scheme 1.
Cl
Br
Table 1
4
5
6
7
8
9
4d
4e
4f
145–147
246–248
235–237
270–272
250–252
135–137
70
94
77
84
65
85
Effect of base, catalyst, and temperature on the heterocyclization during the copper-
free Sonogashira coupling of compound 2 with 4-nitroiodobenzene (3a)a
Entry
Catalyst (mol %)
Base
Temp
(°C)
Yield
(%)
CH
NO
Cl
3
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
PdCl2 (5)/PPh3 (20)
PdCl2(PPh3)2 (5)
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
KOH
Et3N
DIEA
Pyrrolidine
2-Methoxyethylamine
Ethanolamine
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
95
95
95
95
95
95
95
95
95
95
95
95
95
95
95
80
25
70
78
82
42
90
85
75
55
82
60
42
65
52
90
90
65
40
Pd2(dba)3ÁCHCl3 (5)
NO
Cl
2
Pd(PhCN)2Cl2 (5)
2
10%Pd/C (5)/PPh3 (20)
10%Pd/C (5)/PPh3 (20)
10%Pd/C (5)/PPh3 (20)
10%Pd/C (5)/PPh3 (20)
10%Pd/C (5)/PPh3 (20)
10%Pd/C (5)/PPh3 (20)
10%Pd/C (5)/PPh3 (20)
10%Pd/C (3)/PPh3 (12)
10%Pd/C (1)/PPh3 (4)
10%Pd/C (7)/PPh3 (25)
10%Pd/C (10)/PPh3 (30)
10%Pd/C (5)/PPh3 (20)
10%Pd/C (5)/PPh3 (20)
4g
4h
4i
NO2
a
NO
Reaction conditions: 2 (1.2 mmol), 3a (1 mmol), base (2 mmol), degassed H2O
2
(5 mL), 10 h.
Cl
catalyst, the base, and temperature on the outcome of the copper-
free reaction of 2 with 4-nitroiodobenzene (3a) (Table 1). Among
the catalysts tested, Pd/C proved to be the most efficient (entry
5). Other parameters, such as the base, catalyst loading, and reac-
tion temperature were also examined. The reaction was influenced
significantly by the base employed. It worked very well when inor-
ganic bases such as K2CO3 and KOH were used (entries 5 and 6),
with the best result obtained in the case of potassium carbonate
(entry 5). Two of the organic bases used, triethylamine and pyrrol-
idine, also gave good yields (entries 7 and 9).
When the catalyst loading was decreased to 3 mol % and
1 mol %, the yields of 2-(4-nitrobenzyl)imidazo[1,2-a]pyrimidine
(4a) were 65% and 52%, respectively (entries 12 and 13). Increasing
the amount of palladium catalyst did not improve the yield (entries
14 and 15). Over the temperatures evaluated (25, 80 and 95 °C), the
highest temperature (95 °C) gave the best result (entry 5), whereas
decreasing the temperature to 25 °C caused the yield to decrease to
40% (entry 17). This indicated that the reaction temperature had an
important effect upon the yield of the reaction, and excellent re-
sults were obtained when the reactions were carried out with
5 mol % of Pd/C and 20 mol % of PPh3 at 95 °C in the presence of
K2CO3 as base.
COMe
10
11
4j
179–181
130–132
90
5
COOMe
OMe
4k
yields (Scheme 1, Table 2). The reactions were carried out under
an argon atmosphere, and water was degassed prior to use.
A possible two-step mechanism is suggested for the reaction
(Scheme 1). First a standard Sonogashira coupling takes place
followed by a known Pd(II)-catalyzed intermolecular cyclization
of the nucleophilic nitrogen on the triple bond, and finally base-
induced aromatization affords the product 4.16
In order to examine the scope of this reaction, compound 2 was
reacted with various aryl iodides 3a–j, in water at 95 °C to afford
2-benzylimidazo[1,2-a]pyrimidines 4a–j in moderate to good
The presence of electron-withdrawing groups such as NO2, Cl,
COMe, and COOMe on the aryl iodide seems to be essential. When
iodobenzene or p-iodoanisole (Table 2, entry 11) were used, only a

230
M. Bakherad et al. / Tetrahedron Letters 52 (2011) 228–230
small amount of product was isolated after work-up and column
chromatography.
Supplementary data
In conclusion, we have described a successful synthesis of
2-arylimidazo[1,2-a]pyrimidines via a Pd/C-mediated copper-free
Sonogashira coupling reaction in water. Since water-based synthe-
ses are safer and environmentally friendly, the method described
here holds promise in organic synthesis.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.10.168.
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CH), 8.20–8.38 (m, 2H, CH), 8.50 (dd, J = 4.0 Hz, J = 1.3 Hz, 1H,
CH), 8.65 (dd, J = 6.9 Hz, J = 2.1 Hz, 1H, CH); 13C NMR d (125 MHz,
DMSO-d6): 34.25, 108.55, 109.42, 122.90, 124.86, 127.82, 133.20,
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134.63, 139.33, 146.65, 147.24, 148.16, 150.04; IR,
m (KBr): 1525,
1350 cmÀ1; Anal. Calcd for C13H10N4O2: C, 61.41; H, 3.96; N,
22.04. Found: C, 61.26; H, 3.84; N, 21.88.
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CH2), 7.02–7.20 (m, 2H, CH), 7.50–8.10 (m, 2H, CH), 8.20 (s, 1H,
CH), 8.50–8.60 (m, 1H, CH), 8.75–8.90 (m, 1H, CH); 13C NMR d
(125 MHz, DMSO-d6): 34.40, 108.26, 108.88, 123.24, 128.20,
131.31, 132.72, 134.43, 139.14, 146.67, 147.54, 149.20, 150.32;
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IR,
m
(KBr): 1510, 1350 cmÀ1; Anal. Calcd for C13H9ClN4O2: C,
54.09; H, 3.14; N, 19.41. Found: C, 54.32; H, 3.23; N, 19.58.
Compound 4j: 1H NMR (500 MHz, DMSO-d6): d = 3.82 (s, 3H,
CH3), 4.15 (s, 2H, CH2), 6.98–7.20 (m, 1H, CH), 7.44 (d, J = 3.4 Hz,
2H, CH), 7.66 (s, 1H, CH), 7.92 (d, J = 3.5 Hz, 2H, CH), 8.46–8.48
(m, 1H, CH), 8.90 (d, J = 3.7 Hz, 1H, CH); 13C NMR d (125 MHz,
DMSO-d6): 34.86, 51.23, 108.76, 109.23, 128.12, 128.87, 129.27,
132.78, 133.02, 137.92, 139.67, 147.29, 147.91, 150.60, 167.15;
IR,
m
(KBr): 1720 cmÀ1; Anal. Calcd for C15H13N3O2: C, 67.41; H,
4.90; N, 15.72. Found: C, 67.22; H, 4.67; N, 15.90.
Acknowledgment
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We are grateful for the financial support from the Research
Council of Shahrood University of Technology.