Efficient synthesis of novel imidazo[1,2-a]pyrimidine derivatives via one-pot three-component procedure

Article abstract of DOI:10.1007/s13738-014-0564-x

Abstract Synthesis of novel derivatives of imidazo[1,2-a]pyrimidine from one-pot three-component reaction of aldehydes, 2-amino-benzimidazole, and α-tetralone in the presence of catalytic amount of p-toluene sulfonic acid under reflux condition in EtOH has been presented. The simplicity and safety of the process, high yields and short reaction times were the main advantages of this protocol.

Full text of DOI:10.1007/s13738-014-0564-x

J IRAN CHEM SOC
DOI 10.1007/s13738-014-0564-x
ORIGINAL PAPER
Efficient synthesis of novel imidazo[1,2‑a]pyrimidine derivatives
via one‑pot three‑component procedure
Samahe Sadjadi · Fatemeh Nahavandi · Majid Heravi
Received: 2 July 2014 / Accepted: 22 November 2014
© Iranian Chemical Society 2014
Abstract Synthesis of novel derivatives of imidazo[1,2-a]
pyrimidine from one-pot three-component reaction of alde-
hydes, 2-amino-benzimidazole, and α-tetralone in the pres-
ence of catalytic amount of p-toluene sulfonic acid under
reflux condition in EtOH has been presented. The simplic-
ity and safety of the process, high yields and short reaction
times were the main advantages of this protocol.
To date, the synthesis of various derivatives of these
compounds has been reported [13–18]. The most com-
mon synthetic methods reported for the preparation of
imidazo[1,2-a]pyrimidine ring systems involve closure of
the imidazole ring by the condensation of 2-aminopyrimi-
dine and closure of the pyrimidine ring by the condensa-
tion of 2-aminoimidazole with appropriate electrophilic
compounds.
Keywords Imidazo[12-a]pyrimidines · One-pot reaction ·
Multi-component reaction
Synthesis of imidazo[1,2-a]pyrimidines via condensa-
tion of 2-aminopyrimidine with α-halocarbonyl compounds
has also been developed. The drawback of this method is
difficulty in preparation, purification, toxicity, and lachry-
matory property of α-halocarbonyl compounds which limit
its reliability. Taking this fact into account, developing an
efficient and simple route for synthesis of imidazo[1,2-a]
pyrimidines is of great interest [19–24].
In our efforts to use MCRs in the synthesis of hetero-
cycles [25–27], herein we present a multi-component and
efficient route for the synthesis of novel imidazo[1,2-a]
pyrimidines from the reaction of aldehydes, 2-amino-ben-
zimidazole, and α-tetralone in the presence of catalytic
amount of p-toluene sulfonic acid (Scheme 1).
Introduction
Multi-component reactions (MCRs) involving at least three
starting materials in a one-pot reaction have gained much
attention in modern organic chemistry. MCRs’ outstanding
features such as atom economy, efficiency, simplicity, envi-
ronmental amiability, and cost-effectiveness in comparison
to multi-step processes have made it a convenient tool for
synthesis of various organic compounds [1–7].
Imidazo[1,2-a]pyrimidines have received much attention
due to their physiological, anti-inflammatory [8], analgesic
[9], antipyretic [10], bronchodilator, anxiolytic, and anti-
fungal [11, 12] activities.
Experimental procedures
A mixture of aldehydes (10 mmol), 2-amino-benzimida-
zole (10 mmol), and α-tetralone (10 mmol) with catalytic
amount of p-toluene sulfonic acid (0.5 mol%) was refluxed
in EtOH in appropriate reaction time. The progress of the
reaction was monitored by TLC. At the end of reaction, the
precipitated products were filtered and recrystallized from
n-hexane: chloroform mixture (1.5:2).
S. Sadjadi (*)
Iranian Polymer and Petrochemical Institute, Tehran, Iran
e-mail: samahesadjadi@yahoo.com
F. Nahavandi · M. Heravi
Department of Chemistry, School of Science, Azzahra University,
P.O.Box 1993891176, Tehran, Iran
Characterization was performed using 1H and 13C NMR,
FTRI, and GC techniques.
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J IRAN CHEM SOC
(s, 1H, NH), 6.98–8.72 (m, 12H, CH), 6.15 (s, 1H, CH),
3.01 (t, 2H, CH2), 2.80 (t, 2H, CH2); 13C NMR (100 MHz,
DMSO-d6): 24.00, 27.90, 67.40, 109.10, 113.10, 115.40,
120.30, 121.50, 124.20, 125.70, 125.80, 127.40, 127.70,
128.00, 131.40, 131.90, 132.60, 135.20, 139.80, 141.50,
149.10, 158.40; FT-IR: 3,444 (NH), 1,626 (C=N); MS: m/z
394[M+].
N
O
HN
N
N
Catalyst
EtOH
R
+
RCHO +
NH2
N
H
1
2
3
4
Scheme 1 Synthesis of imidazo[1,2-a]pyrimidines derivatives via
one-pot three-component reaction of aldehydes, 2-amino-benzimida-
zole, and α-tetralone
7‑(3‑Nitro‑phenyl)‑5,6,7,13‑tetrahydro‑7a,12,13‑tri‑
aza‑indeno[1,2‑b]phenanthrenes
(Entry
5) m.p.:
1
Physical and spectral data
316 °C, H NMR (500 MHz, DMSO-d6, δ ppm): 8.72
(s, 1H, NH), 7.00–8.72 (m, 12H, CH), 6.17 (s, 1H, CH),
3.00 (t, 2H, CH2), 2.80 (t, 2H, CH2); 13C NMR (100 MHz,
DMSO-d6): 23.80, 28.00, 67.30, 109.10, 113.70, 119.50,
122.20, 125.50, 126.80, 126.40, 126.80, 127.80, 128.30,
128.50, 128.50, 129.60, 131.40, 131.70, 132.40, 135.50,
140.20, 143.00, 148.80, 158.50; FT-IR: 3,442 (NH), 1,625
(C=N); MS: m/z 394[M+].
7‑Phenyl‑5, 6, 7, 13‑tetrahydro‑7a, 12, 13‑tri‑
aza‑indeno[1,2‑b]phenanthrenes
(Entry
1) m.p.:
1
282 °C, H NMR (500 MHz, DMSO-d6, δ ppm): 8.72
(s, 1H, NH), 6.87–8.70 (m, 13H, CH), 5.62 (s, 1H, CH),
2.97 (t, 2H, CH2), 2.81 (t, 2H, CH2); 13C NMR (100 MHz,
DMSO-d6): 21.40, 28.1, 66.60, 109.00, 114.00, 121.00,
123.30, 125.50, 126.80, 127.30, 127.60, 128.00, 128.40,
129.10, 129.00, 130.70, 131.60, 132.30, 140.00, 142.60,
145.00, 158.40; FT-IR: 3,426 (NH), 1,629 (C=N); MS: m/z
349[M+].
7‑p‑Tolyl‑5, 6, 7, 13‑tetrahydro‑7a, 12, 13‑tri‑
aza‑indeno[1,2‑b]phenanthrenes
(Entry
6) m.p.:
1
251 °C, H NMR (500 MHz, DMSO-d6, δ ppm): 8.74 (s,
1H, NH), 6.99–8.723 (m, 12H, CH), 6.32 (s, 1H, CH), 2.98
(t, 2H, CH2), 2.82 (t, 2H, CH2), 2.40 (s, 3H, CH3); 13C
NMR (100 MHz, DMSO-d6): 21.70, 24.30, 28.00, 64.40,
109.10, 114.20, 115.40, 120.10, 121.30, 124.00, 125.50,
125.40, 126.40, 127.70, 127.80, 129.40, 130.90, 131.60,
134.20, 138.80, 140.50, 148.10, 157.40; FT-IR: 3,421
(NH), 1,622 (C=N); MS: m/z 363[M+].
7‑(4‑Chloro‑phenyl)‑5,6,7,13‑tetrahydro‑7a,12,13‑tri‑
aza‑indeno[1,2b]phenanthrenes (Entry 2) m.p.: 260 °C,
1H NMR (500 MHz, DMSO-d6, δ ppm): 8.73 (s, 1H, NH),
7.10–8.75 (m, 12H, CH), 6.31 (s, 1H, CH), 2.98 (t, 2H,
CH2), 2.83 (t, 2H, CH2); 13C NMR (100 MHz, DMSO-d6):
23.80, 33.00, 67.40, 109.10, 115.10, 122.50, 125.50, 126.80,
127.10, 127.40, 127.70, 128.00, 129.30, 129.50, 129.00,
131.60, 132.80, 136.90, 140.00, 143.40, 144.90, 158.20;
FT-IR: 3,421 (NH), 1,624 (C=N); MS: m/z 383[M+].
7‑(4‑Methoxy‑phenyl)‑5,6,7,13‑tetrahydro‑7a,12,13‑tri‑
aza‑indeno[1,2‑b]phenanthrenes
(Entry
7) m.p.:
1
270 °C, H NMR (500 MHz, DMSO-d6, δ ppm): 8.71 (s,
1H, NH), 6.96–8.70 (m, 12H, CH), 6.35 (s, 1H, CH), 4.02
(s, 3H, CH3), 2.95 (t, 2H, CH2), 2.80 (t, 2H, CH2); 13C
NMR (100 MHz, DMSO-d6): 23.80, 28.1, 55.5, 66.60,
109.00, 114.00, 120.80, 123.30, 125.30, 127.20, 127.40,
127.90, 129.30, 129.30, 128.40, 128.90, 130.10, 131.40,
133.00, 140.00, 144.70, 145.10, 158.420; FT-IR: 3,420
(NH), 1,600 (C=N); MS: m/z 379[M+].
7‑(3‑Chloro‑phenyl)‑5,6,7,13‑tetrahydro‑7a,12,13‑tri‑
aza‑indeno[1,2b]phenanthrenes
(Entry
3) m.p.:
1
306 °C, H NMR (500 MHz, DMSO-d6, δ ppm): 8.73
(s, 1H, NH), 7.03–8.72 (m, 12H, CH), 6.33 (s, 1H, CH),
2.98 (t, 2H, CH2), 2.79 (t, 2H, CH2); 13C NMR (100 MHz,
DMSO-d6): 23.70, 27.70, 67.40, 109.10, 113.70, 119.50,
121.10,125.50, 125.40, 126.80, 126.80, 127.00, 127.30,
127.50, 128.10, 128.60, 131.00, 131.60, 132.60, 135.60,
140.10, 143.00, 144.80, 158.10; FT-IR: 3,422 (NH), 1,627
(C=N); MS: m/z 383[M+].
5,6,7,13‑Tetrahydro‑7a,12,13‑triaza‑indeno[1,2‑b]phen‑
1
anthrenes (Entry 8) m.p.: 185 °C, H NMR (500 MHz,
DMSO-d6, δ ppm): 8.60 (s, 1H, NH), 7.93–7.70 (m, 8H,
CH), 4.42 (s, 2H, CH2), 2.25 (t, 2H, CH2), 2.20 (t, 2H,
CH2); 13C NMR (100 MHz, DMSO-d6): 23.80, 28.1,
55.50, 109.00, 114.10, 115.15, 121.80, 123.21, 123.30,
126.80, 127.00, 127.30, 128.40, 128.90, 134.40, 138.30,
7‑(4‑Nitro‑phenyl)‑5,6,7,13‑tetrahydro‑7a,12,13‑tri‑
aza‑indeno[1,2‑b]phenanthrenes
309 °C, H NMR (500 MHz, DMSO-d6, δ ppm): 8.73
(Entry
4) m.p.:
1
1 3

J IRAN CHEM SOC
Table 1 Synthesis of imidazo[1,2-a]pyrimidines using p-toluene sul-
fonic acid under reflux condition in EtOH
141.20, 152.80; FT-IR: 3,430 (NH), 1,610 (C=N); MS: m/z
273[M+].
Entry
R
Time (min)
Yielda (%)
1
Ph
10
15
20
35
25
30
35
20
35
40
45
95
98
97
94
96
94
95
92
88
85
82
7‑ Methyl‑ 5,6,7,13‑tetrahydro‑7a,12,13‑triaza‑indeno
[1,2‑b]phenanthrenes (Entry 9) m.p.: 199 °C, H NMR
2
4-Cl C6H4
3-Cl C6H4
4-NO2 C6H4
3-NO2 C6H4
4-Me C6H4
4-OMe C6H4
H
1
3
(500 MHz, DMSO-d6, δ ppm): 8.70 (s, 1H, NH), 7.97–7.73
(m, 8H, CH), 4.43 (s, 1H, CH), 2.26 (t, 2H, CH2), 2.21 (t,
1H, CH), 2.20 (d, 3H, CH3); 13C NMR (100 MHz, DMSO-
d6): 22.50, 23.80, 28.10, 45.50, 119.00, 114.10, 115.00,
121.83, 123.15, 123.30, 126.80, 127.20, 127.30, 128.40,
128.90, 134.40, 138.30, 141.20, 152.80; FT-IR: 3,440
(NH), 1,615 (C=N); MS: m/z 287[M+].
4
5
6
7
8
9
CH3
10
11
CH3CH2
CH3CH2CH2
7‑ Ethyl‑ 5,6,7,13‑tetrahydro‑7a,12,13‑triaza‑indeno
[1,2‑b]phenanthrenes (Entry 10) m.p.: 210 °C, 1H
NMR (500 MHz, DMSO-d6, δ ppm): 8.80 (s, 1H, NH),
7.97–7.73 (m, 8H, CH), 4.43 (s, 1H, CH), 2.26 (t, 2H,
CH2), 2.21 (t, 2H, CH2), 1.65 (m, 2H, CH2),1.00 (t, 3H,
CH3); 13C NMR (100 MHz, DMSO-d6): 12.50, 23.80,
24.1, 28.00, 53.50, 119.00, 114.10, 115.00, 121.80, 123.01,
123.30, 126.80, 127.12, 127.30, 128.40, 128.90, 134.40,
138.30, 141.20, 152.80; FT-IR: 3,440 (NH), 1,600 (C=N);
MS: m/z 301[M+].
a
Isolated yields
115.00, 121.80, 122.80, 123.30, 126.80, 127.30, 128.40,
128.90, 134.40, 138.30, 141.20, 152.80; FT-IR: 3,448
(NH), 1,614 (C=N); MS: m/z 315[M+].
Results and discussion
Imidazo[1,2-a]pyrimidines derivatives have been success-
fully obtained from the reaction of aldehydes, 2-amino-
benzimidazole, and α-tetralone in the presence of catalytic
amount of p-toluene sulfonic acid. The reliability of the
process has been investigated by using various aliphatic
and aromatic aldehydes and ketones (Table 1). The results
showed that this reaction did not proceed in the presence of
ketones. This observation was attributed to lower activities
of ketones in comparison to aldehydes.
7‑ Propyl‑ 5,6,7,13‑tetrahydro‑7a,12,13‑triaza‑indeno
[1,2‑b]phenanthrenes (Entry 11) m.p.: 225 °C, 1H
NMR (500 MHz, DMSO-d6, δ ppm): 8.78 (s, 1H, NH),
7.97–7.73 (m, 8H, CH), 4.43 (s, 1H, CH), 2.26 (t, 2H,
CH2), 2.21 (t, 2H, CH2), 1.80 (t, 2H, CH2), 1.40 (m, 2H,
CH2),1.00 (t, 3H, CH3); 13C NMR (100 MHz, DMSO-
d6): 14.20, 18.20, 22.50, 28.1, 36, 51.50, 119.00, 114.10,
H
N
H
Scheme 2 The proposed
mechanism of imidazo [1,2-a]
pyrimidine derivatives forma-
tion
H
N
O
N
N
N
N
NH2
OH
+
NH2
NH
OH
NH
H
R
N
N
H
R
R
A
O
OH
N
N
N
N
NH2
NH2
O
+
R
N
OH
R
B
N
N
N
HN
N
R
R
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J IRAN CHEM SOC
Table 2 Synthesis of compound 4 using various amounts of p-tolu-
ene sulfonic acid under reflux condition in EtOH
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Entry
Amount of catalyst
Time (min)
Yielda (%)
1
2
3
4
2
30
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95
95
94
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1
0.5
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a
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It is worth mentioning that this procedure cannot be gen-
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presence.
Regarding the reaction mechanism, it has been pro-
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zimidazole produced intermediates A which successively
reacted with α-tetralone and formed B. The cyclization of
B gave the desired imidazo[1,2-a]pyrimidine derivatives
(Scheme 2) [28].
To study and optimize the reaction condition, synthesis
of derivative 4 (Table 1) was selected as the model reaction.
This reaction was performed under solvent-free and stir-
ring condition in the presence and absence of catalyst.
The results showed that under both conditions, no prod-
uct was obtained in the absence of catalyst even after a long
reaction time of 12 h. Also, reflux condition was better than
stirring, and higher yield and shorter reaction time were
obtained under this condition. Therefore, all derivatives
were synthesized using this protocol.
The optimum amount of catalyst was obtained by per-
forming the model reaction in the presence of various
amounts of catalyst (2, 1, 0.5, 0. 25 mol%). The results are
summarized in Table 2. As shown in this table, the opti-
mum amount of catalyst is 0.5 mol%.
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Conclusion
In summary, we have developed a facile and efficient
method for the synthesis of new derivatives of imidazo[1,2-
a]pyrimidine from one-pot three-component reaction of
aldehydes, 2-amino-benzimidazole, and α-tetralone in the
presence of catalytic amount of p-toluene sulfonic acid
under reflux condition in EtOH.
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1 3