Syntheses of 2-benzylsubstituted imidazo[1,2-a]pyrimidines via coupling-cyclization under Pd-Cu catalysis

Article abstract of DOI:10.2174/157017811796064368

The reaction of 1-(prop-2-yn-1yl)pyrimidin-2(1H)-imin with various halobenzenes in the presence of a palladium catalyst leads to the production of 2-benzylsubstituted imidazo[1,2-a]pyrimidines. 2011 Bentham Science Publishers Ltd.

Full text of DOI:10.2174/157017811796064368

Letters in Organic Chemistry, 2011, 8, 401-405
401
Syntheses of 2-benzylsubstituted Imidazo[1,2-a]pyrimidines Via Coupling–
Cyclization Under Pd-Cu Catalysis
Mohammad Bakherad*, Ali Keivanloo, Marzieh Mohammadi and Saeideh Jajarmi
School of Chemistry, Shahrood University of Technology, Shahrood, Iran
Received July 15, 2010: Revised October 13, 2010: Accepted January 31, 2011
Abstract: The reaction of 1-(prop-2-yn-1yl)pyrimidin-2(1H)-imin with various halobenzenes in the presence of a
palladium catalyst leads to the production of 2-benzylsubstituted imidazo[1,2-a]pyrimidines.
Keywords: Sonogashira coupling, aryl iodide, imidazo[1,2-a]pyrimidines, Pd-catalyzed.
The Sonogashira reaction (i.e., the palladium and copper
cocatalyzed coupling of terminal alkynes with aryl and vinyl
halides) is one of the most widely used C-C bond formation
reactions [1]. It provides an efficient route to aryl alkynes,
which are interesting intermediates for the preparation of a
variety of target compounds with applications ranging from
natural products [2] and pharmaceuticals [3] to molecular
organic materials [4]. Because of the utility of the products,
the development of new catalyst systems has received
considerable attention. Palladium-catalyzed reactions have
been immensely practical for both carboannulation [5] and
heteroannulation [6] processes.
catalytic amount of the PdCl2(PPh3)2. As shown in Table 1,
the reaction is significantly influenced by the base employed.
It works very well when a base such as Et3N, DIEA, K2CO3,
and Na2CO3 is used (entries 1, 2, 5, and 7), with the best
result obtained in the case of K2CO3 as the inorganic base
(entry 5). Among the solvents used, DMF was the best
choice (entry 5). Increasing the amount of the palladium
catalyst reduced the reaction time but did not increase the
yield (entry 23). A low palladium concentration prolonged
the reaction time and decreased the yield (entry 24).
Using the optimized reaction conditions (0.03 mmol of
PdCl2(PPh3)2, 0.06 mmol of CuI, 2.0 mmol of K2CO3),
compound 2 was treated in DMF with the aryl iodides and
aryl bromides 3a-i at 70 ºC to obtain 2-benzylsubstituted
imidazo[1,2-a]pyrimidines 4a-i in moderate to good yields
(Scheme 1, Table 2). The reactions had to be carried out
under an argon atmosphere, and the mixture of DMF had to
be degassed prior to use.
Imidazo[1,2-a]pyrimidines possess diverse biological
activities, and this structural motif is present in analgesics,
inflammatory inhibitors [7], and benzodiazepine receptor
ligands [8] as well as insecticidal, acaricidal and nematocidal
agents [9]. Considering the potent bioactivities of
compounds possessing an imidazopyrimidine core, the
development of a new strategy to synthesize 2- arylsubs-
tituted imidazo[1,2-a]pyrimidines efficiently attracted our
attention.
Mechanistically, the formation of 2-benzylsubstituted
imidazo[1,2-a]pyrimidines involves the following steps (as
shown in Scheme 1): (a) formation of ArPdX (II) through
oxidative addition of Pd(0) (I) to ArX; [11] (b)
transmetallation of ArPdX with the Cu salt of (III),
generating the alkynyl palladium species (IV); (c) reductive
elimination to yield (V); and (d) isomerization to the allenic
intermediates [12] (VI) which then cyclize to products 4a-i.
In continuation of our recent studies [10] on the synthesis
of fused heterocycles and the Pd-catalyzed reaction of
acetylenes leading to heterocyclic compounds of biological
significance, we became interested in developing a synthetic
route to 2-arylsubstituted imidazo[1,2-a]pyrimidines.
In this communication, we report that treatment of 2-
aminopyrimidine 1 with propargyl bromide in refluxing
acetonitrile afforded 1-(prop-2-yn-1yl)pyrimidin-2(1H)-imin 2 in
Compound 2 reacted with aryl halides such as p-
nitrobromobenzene, p-nitroiodobenzene, and 1-iodo-2-
methyl-4-nitrobenzene, delivering the corresponding
products in good to excellent yields (Table 2).
Unsurprisingly, 1-iodo-2-methyl-4-nitrobenzene, (entry 3)
was found to be the most reactive amongst the aryl halides
studied (entries 1, 3, and 10). As expected, aryl iodides with
electron-withdrawing groups reacted better than aryl
bromides possessing electron-donating groups to give the
desired products in high yields. The presence of electron-
withdrawing groups such as –NO2, or –Cl on the aryl halides
was essential for successful reaction. When p-iodoanisole or
iodobenzene were used as the aryl halide, only a small
amount of product was isolated by column chromatography.
1
good yield. The H-NMR spectrum of 2 shows a CH proton
at 3.08 ppm, CH2 protons at 4.90 ppm and a single resonance
for the NH group at 8.80 ppm, this signal was removed on
deuteration (Scheme 1).
For optimization of the reaction conditions, we chose the
reaction of compound 2 with p-iodonitrobenzene as the
model reaction, and the effects of the base, solvent, and
catalyst were examined (Table 1). First, several bases and
solvents were screened for the reaction in the presence of a
*Address correspondence to this author at the Faculty of Chemistry,
Shahrood University of Technology, Shahrood, Post Code: 3619995161,
Iran; Tel/Fax: +982733395441; E-mail: m.bakherad@yahoo.com
In conclusion, we have developed
palladium-catalyzed reaction for the synthesis of 2-benzyl-
a
successful
1570-1786/11 $58.00+.00
© 2011 Bentham Science Publishers Ltd.

402 Letters in Organic Chemistry, 2011, Vol. 8, No. 6
Bakherad et al.
Pd (PPh3)2Cl2
a
ArI
3a-i
Pd (0)
ArPdI
(I)
(II)
N
N
N
BrH2C
C
CH
b
N
NH2
N
NH
CH3CN
N
NH
CuI
CCu
1
2
(III)
N
N
N
C
N
c
d
N
NH
N
NH
N
C
NH
N
N
CPdAr
CAr
Pd(0)
CH2Ar
CHAr
4a-i
(VI)
(V)
(IV)
Scheme 1. Proposed mechanism for the formation of 2-arylsubstituted imidazo[1,2-a]pyrimidines at 70 ºC. Reagents and conditions: (a)
Reduction of Pd(II) to Pd(0) with alkyne and K2CO3; (b) CuI, K2CO3; (c) isomerization to an allene with CuI, K2CO3; (d) nucleophilic attack
on the allene (VI) to generate the 2-benzylsubstituted imidazo[1,2-a]pyrimidines 4a-i.
Table 1. The Reaction of Compound 2 with p-iodonitrobenzene in the Presence of Several Bases and Solventsa
Entry
Solvent
Base
PdCl2(PPh3)2 (mol%)
Time (h)
Yieldb (%)
1
2
DMF
DMF
Et3N
DIEA
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
10
10
12
10
12
8
90
90
85
85
92
87
90
88
80
82
75
70
75
57
55
70
85
80
40
85
3
DMF
Pyrrolidine
Morpholine
K2CO3
4
DMF
5
DMF
6
DMF
Cs2CO3
Na2CO3
KOH
7
DMF
9
8
DMF
10
15
15
13
17
12
10
15
15
12
12
15
10
9
CH3CN
CH3CN
CH3CN
CH3CN
NMP
Et3N
10
11
12
13
14
15
16
17
18
19
20
DIEA
Pyrrolidine
Morpholine
Et3N
NMP
DIEA
NMP
Pyrrolidine
Morpholine
Et3N
NMP
DMAC
DMAC
DMAC
DMAC
DIEA
Pyrrolidine
Morpholine
21
22
23
24
Morpholine
Pyrrolidine
DMF
Morpholine
Pyrrolidine
K2CO3
3.0
3.0
5.0
1.0
20
18
8
35
78
92
70
DMF
K2CO3
15
aReaction conditions: compound 2 (1.2 mmol), p-iodonitrobenzene (1.0 mmol), base (2.0 mmol), PdCl2(PPh3)2 (3 mol%), CuI (6 mol %), solvent (5 mL) at 70 ºC.
bIsolated yield.

Syntheses of 2-benzylsubstituted Imidazo[1,2-a]pyrimidines
Letters in Organic Chemistry, 2011, Vol. 8, No. 6
403
Table 2. Yields of 2-benzylsubstituted Imidazo[1,2-a]pyrimidines 4a-ia
Ar
Entry
X
Product
Yield(%)
1
I
4a
92
NO2
2
3
I
I
4b
4c
70
95
NO2
CH3
NO2
NO2
4
5
I
I
4d
4e
68
75
Cl
NO2
Cl
Cl
6
7
I
I
4f
70
65
NO2
4g
COCH3
NO2
8
9
Br
Br
4h
4i
60
56
Cl

404 Letters in Organic Chemistry, 2011, Vol. 8, No. 6
Bakherad et al.
(Table 2). Contd…..
Ar
Entry
X
Product
Yield(%)
10
Br
4a
70
62
NO2
11
Br
4b
NO2
aReaction conditions: 2 (1.20 mmol), 3a-i (1.0 mmol), K2CO3 (2 mmol), PdCl2(PPh3)2(0.03 mmol), CuI (0.06 mmol), DMF (5 mL), at 70 ºC for 12 h.
substituted imidazo[1,2-a]pyrimidines from readily available
starting materials. To our knowledge, this is the first reported
general procedure for the palladium-copper catalyzed
synthesis of 2-2-benzylsubstituted imidazopyrimidines.
2-(3-Nitrobenzyl)imidazo[1,2-a]pyrimidine 4b
MP 118-119 °C; 1H NMR (500 MHz, DMSO-d6 ꢀ ppm):
4.22 (s, 2H, CH2), 6.97 -7.10 (m, 1H, CH), 7.55 (s, 1H, CH),
7.70-,7.87 ( m, 2H, CH), 8.01-8.20 (m, 2H, CH); 8.40-8.55
(m, 1H, CH), 8.80-8.90 (m, 1H, CH); 13C NMR ꢀ (125 MHz,
DMSO-d6): 34.50, 108.05, 109.38, 121.94, 128,08, 128.55,
132.54, 133.78, 138.91, 146.10, 146.68, 147.89, 150.32; IR,
ꢁ (KBr): 1500, 1335 cm-1; Anal. Calcd for C13H10N4O2: C,
61.41; H, 3.96; N, 22.04. Found: C, 61.65; H, 4.05; N, 22.26.
Synthesis of 2-imino-1-(2-propynyl)pyrimidine 2
A mixture of 2-aminopyrimidine (1.9 g, 20 mmol) and
propargyl bromide (2 mL, 24 mmol) in acetonitrile (10 mL)
was heated under reflux for 2 h. The precipitate formed was
filtered off and recrystallized from ethanol to afford the title
compound. yield, 80%; MP 220-222 °C; 1H NMR (500
MHz, DMSO-d6 ꢀ ppm): 3.08 (t, J=3.0 Hz, 1H, CH), 4.90 (d,
J=3.0 Hz, 2H, CH2), 7.15 (dd, J=8.0 Hz, J=5.5 Hz, 1H, CH),
8.75 (dd, J=8.5 Hz, J=2.5 Hz, 1H, CH), 8.90 (dd, J=5.3 Hz,
J=2.5 Hz, 1H, CH), 8.80 (s, 1H, NH); 13C NMR ꢀ (125 MHz,
DMSO-d6): 44.21, 74.71, 81.18, 111.24, 149.37, 155.43,
167.07; IR, ꢁ (KBr): 3300, 2100, 1650 cm-1; Anal. Calcd. for
C7H8N3: C, 63.14; H, 5.30; N, 31.56%. Found: C, 63.43; H,
5.45; N, 31.36%.
2-(2-Methyl-4-nitrobenzyl)imidazo[1,2-a]pyrimidine 4c
MP 246-247 °C; 1H NMR (500 MHz, DMSO-d6 ꢀ ppm):
2.30 (s, 3H, CH3), 4.22 (s, 2H, CH2), 6.92-7.10 (m, 1H, CH);
7.45 (d, J=10.5, 1H, CH), 7.62 ( s, 1H, CH), 8.02 (dd, J=10.4
Hz, J=3.0 Hz, 1H, CH), 8.08 (d, J=3.0 Hz, 1H, CH), 8.40-
8.50 (m, 1H, CH), 8.77 (dd, J=8.5 Hz, J=2.5 Hz, 1H, CH);
13C NMR ꢀ (125 MHz, DMSO-d6): 19.61, 33.02, 108.91,
109.44, 121.37, 124.86, 131.27, 135.27, 139.03, 145.92,
146.49, 146.75, 148.11, 150.24; IR, ꢁ (KBr): 1520, 1340 cm-1;
Anal. Calcd for C14H12N4O2: C, 62.68; H, 4.51; N, 20.88.
Found: C, 62.89; H, 4.64; N, 20.68.
Syntheses of 2-arylsubstituted imidazo [1,2-a]pyrimidines
4a-i
A mixture of the aryl halide (1.0 mmol), (PPh3)2PdCl2
(0.03 mmol), CuI (0.06 mmol) and K2CO3 (2 mmol) was
stirred in DMF (5 mL) at room temperature under an argon
atmosphere. 2-Imino-1-(2-propynyl)pyrimidine (1.20 mmol)
was then added and the mixture was stirred at 70 ºC for 12 h.
After completion of the reaction, the resulting solution was
concentrated in vacuo and the crude product was subjected to
silica gel column chromatography using CHCl3–CH3OH
(98:2) as eluent to afford the pure product (Table 2).
2-(4-Chloro-2-nitrobenzyl)imidazo[1,2-a]pyrimidine 4d
MP 235-236 °C; 1H NMR (500 MHz, DMSO-d6 ꢀ ppm):
4.30 (s, 2H, 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 ꢀ (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; IR, ꢁ (KBr): 1510,
1350 cm-1 Anal. Calcd. for C13H9ClN4O2: C, 54.09; H, 3.14;
N, 19.41. Found: C, 54.32; H, 3.23; N, 19.58.
2-(4-Nitrobenzyl)imidazo[1,2-a]pyrimidine 4a
2-(4-Chloro-3-nitrobenzyl)imidazo[1,2-a]pyrimidine 4e
MP 154-155 °C; 1H NMR (500 MHz, DMSO-d6 ꢀ ppm):
4.35 (s, 2H, CH2), 6.90-7.00 (m, 1H, CH), 7.50 (s, 1H, CH),
7.60-7.75 ( m, 2H, CH), 8.20-8.38 (m, 2H, CH), 8.50 (dd,
J=5.2 Hz, J=2.5 Hz, 1H, CH), 8.65 (dd, J=8.3 Hz, J=2.5 Hz,
1H, CH); 13C NMR ꢀ (125 MHz, DMSO-d6): 34.25, 108.55,
109.42, 122.90, 124.86, 127.82, 133.20, 134.63, 139.33,
146.65, 147.24, 148.16, 150.04; IR, ꢁ (KBr): 1525, 1350 cm-1;
Anal. Calcd for C13H10N4O2: C, 61.41; H, 3.96; N, 22.04.
Found: C, 61.26; H, 3.84; N, 21.88.
MP 250-251 °C; 1H NMR (500 MHz, DMSO-d6 ꢀ ppm):
4.20 (s, 2H, CH2), 6.95-7.20 (m, 2H, CH), 7.60-7.88 (m, 2H,
CH); 8.10 ( s, 1H, CH), 8.40-8.51 (m, 1H, CH), 8.85-9.02
(m, 1H, CH); 13C NMR ꢀ (125 MHz, DMSO-d6): 34.06,
108.60, 109.08, 126.80, 127.95, 129.45, 134.90, 135.33,
139.47, 146.88, 147.67, 148.56, 149.94; IR, ꢁ (KBr): 1525,
1320 cm-1; Anal. Calcd for C13H9ClN4O2: C, 54.09; H, 3.14;
N, 19.41. Found: C, 54.38; H, 3.20; N, 19.25.

Syntheses of 2-benzylsubstituted Imidazo[1,2-a]pyrimidines
Letters in Organic Chemistry, 2011, Vol. 8, No. 6
405
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2-(2-Chloro-4-nitrobenzyl)imidazo[1,2-a]pyrimidine 4f
MP 270-271 °C; 1H NMR (500 MHz, DMSO-d6 ꢀ ppm):
4.45 (s, 2H, CH2), 6.90-7.01 (m, 1H, CH), 7.50-8.00 (m, 3H,
CH), 8.30 (s, 1H, CH), 8.55-8.70 (m, 1H, CH), 8.94-9.15 (m,
1H, CH); 13C NMR ꢀ (125 MHz, DMSO-d6): 34.41, 108.75,
109.55, 122.90, 123.43, 128.87, 132.06, 134.20, 139.30,
146.52, 147.62, 149.54, 150.28; IR, ꢁ (KBr): 1510, 1340 cm-
1; Anal. Calcd. for C13H9ClN4O2: C, 54.09; H, 3.14; N,
19.41. Found: C, 53.84; H, 3.02; N, 19.62.
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2-(4-Acetobenzyl)imidazo[1,2-a]pyrimidine 4g
MP 136-137 °C; 1H NMR (500 MHz, DMSO-d6 ꢀ ppm):
2.55 (s, 3H, CH3), 4.16 (s, 2H, CH2), 7.01-7.20 (m, 1H, CH),
7.47 (d, J=8.0 Hz, 2H, CH), 7.65 ( s, 1H, CH), 7.90 (d, J=8.1
Hz, 2H, CH), 8.47 (dd, J=4.0 Hz, J=1.9 Hz, 1H, CH), 8.90
(dd, J=6.6 Hz, J=1.8 Hz, 1H, CH); 13C NMR ꢀ (125 MHz,
DMSO-d6): 27.50, 34.15, 108.27, 108.95, 127.12, 128.50,
128.87, 132.73, 138.17, 139.66, 146.42, 147.17, 148.25,
150.22, 197.83; IR, ꢁ (KBr): 1695 cm-1; Anal. Calcd. for
C15H13N3O: C, 71.70; H, 5.21; N, 16.72. Found: C, 71.45; H,
5.05; N, 16.55.
[5]
[6]
2-(2-Nitrobenzyl)imidazo[1,2-a]pyrimidine 4h
MP 128-129 °C; 1H NMR (500 MHz, DMSO-d6 ꢀ ppm):
4.20 (s, 2H, CH2), 7.02 -7.10 (m, 1H, CH), 7.15-7.27 (m, 1H,
CH), 7.45-7.60 (m, 2H, CH), 7.88-8.06 (m, 2H, CH), 8.50-
8.68 (m, 2H, CH); 13C NMR ꢀ (125 MHz, DMSO-d6): 34.20,
108.34, 109.76, 123.10, 124.34, 128.05, 133.43, 134.35,
139.40, 146.24, 147.54, 147.90, 149.85; IR, ꢁ (KBr): 1520,
1345 cm-1; Anal. Calcd for C13H10N4O2: C, 61.41; H, 3.96;
N, 22.04. Found: C, 61.54; H, 4.10; N, 21.90.
[7]
[8]
2-(4-Chlorobenzyl)imidazo[1,2-a]pyrimidine 4i
mp 146-147 °C; 1H NMR (500 MHz, DMSO-d6 ꢀ ppm):
4.25 (s, 2H, CH2), 6.950-7.04 (m, 1H, CH), 7.57 (s, 1H, CH),
7.72-7.90 ( m, 2H, CH), 8.22-8.43 (m, 2H, CH), 8.65 (d,
J=8.2 Hz, 1H, CH), 8.75 (d, J=8.0 Hz, 1H, CH); 13C NMR ꢀ
(125 MHz, DMSO-d6): 34.46, 108.72, 109.24, 119.56,
131.42, 131.94, 134.80, 139.35, 147.63, 147.92, 149.86; IR,
ꢁ (KBr): 1090 cm-1; Anal. Calcd for C13H10ClN3: C, 64.07;
H, 4.14; N, 17.24. Found: C, 64.32; H, 4.25; N, 17.02.
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ACKNOWLEDGEMENT
benzylimidazo[2,1-b][1,3]benzothiazoles
through
palladium-
We are grateful to the Research Council of Shahrood
University of Technology for the financial support of this
work.
catalyzed heteroannulation of acetylenic compounds. Tetrahedron
Lett., 2008, 49, 6188-6191; (c) Kamali,T. A.; Bakherad, M.;
Nasrollahzadeh, M.; Farhangi, S.; Habibi, D. Synthesis of 6-
substituted
imidazo[2,1-b]thiazoles
via
Pd/Cu-mediated
Sonogashira coupling in water. Tetrahedron Lett., 2009, 50, 5459-
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Sonogashira, K.; Tohda, Y.; Hagihara, N. A convenient synthesis
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