Microwave irradiation for accelerating synthesis of diarylimidizo[1,5-a] pyrimidine based on isoflavones

Article abstract of DOI:10.1002/cjoc.201100405

Microwave irradiation was used to accelerate the cyclocondensation of isoflavones and 5-amino-1H-imidazole-4-carboxamide in the presence of sodium hydroxide to produce 3,4-diphenyl-imidazo[1,5-a]pyrimidines in good to moderate yields. Microwave irradiatio

Full text of DOI:10.1002/cjoc.201100405

NOTE
DOI: 10.1002/cjoc.201100405
Microwave Irradiation for Accelerating Synthesis of Di-
arylimidizo[1,5-a]pyrimidine Based on Isoflavones
Zhang, Zunting*,a(张尊听)
Zhang, Pengfeia(张鹏飞)
Zhu, Mulina(祝木林)
Kang, Taoyinga,b(康桃英)
a Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry,
National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China,
and School of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi'an, Shaanxi 710062, China
b College of Chemical Engineering, Qinghai University, Xining, Qinghai 710062, China
Microwave irradiation was used to accelerate the cyclocondensation of isoflavones and 5-amino-1H-imidazole-
4-carboxamide in the presence of sodium hydroxide to produce 3,4-diphenyl-imidazo[1,5-a]pyrimidines in good to
moderate yields.
Keywords isoflavone, imidazo[1,5-a]pyrimidine, 5-amino-1H-imidazole-4-carboxamide, cyclocondensation
Introduction
Scheme 1 Chemical structure of an imidazo[1,5-a]pyrimi-
dines pharmaceutical target
Fused heteroaromatic compounds containing ring-
junction nitrogen atoms are important for the prepara-
tion of biologically active molecules.[1,2] Imidazo[1,5-
a]pyrimidine is an important pharmaceutical target
(Scheme 1). Imidazo[1,5-a]pyrimidine exhibited bio-
logical activities, such as treatment and prevention of
diseases mediated by GABAA receptor α-1 and α-2 sub-
nuits;[3] and metabotropic glutamate receptor antago-
nist.[4]
R3
N
N
N
R1
N
R2
Numerous methods for the synthesis of imidazo-
[1,5-a]pyrimidine have been reported in the last decades,
which involved the reaction between aminoimidazos
and 1,3-biselectrophilic compounds, such as α,β-unsatu-
rated carbonyl,[3] β-dicarbonyl,[4] α-cyano acrylonitrile
with β-thioalkoxy, β-alkoxy, or β-chloro leaving group
compounds.[5] It was reported that the chromone frag-
ment present in isoflavones can generate a 1,3-diketone
equivalent in the presence of alkali, which readily reacts
with amidines,[6] guanidine,[7] hydrazine,[8] to form the
corresponding 2-substituted pyrimidines and diarylpyra-
zoles. Recently we have reported the 2-aminobenzimi-
dazole,[9] triazole,[10] and 3-amino-5-hydroxypyrazole,[11]
condensed with isoflavones to get pyrimido[1,2-a]benz-
imidazoles, triazolopyrimidines, pyrazolo[3,4-b]pridines,
respectively. To the best of our knowledge, there is no
report on the synthesis of 3,4-diphenylimidazo[1,5-a]-
pyrimidine. Herein, we report a new strategy for the
preparation of the unknown class of 3,4-diphenyl-
imidazo[1,5-a]pyrimidines from isoflavones.
Experimental
Microwave irradiation was carried out using the
commercial microwave oven MCR-3 (Zhengzhuo China).
Melting points were measured on X-5 micro melting
point apparatus, which are uncorrected. IR spectra were
1
recorded on Fourier transform Infrared Spectrometer. H
NMR spectra were recorded at 300 MHz on Bruker
DRX-300 Advance spectrometer; chemical shifts (δ scale)
are reported downfield from Me4Si which was used as the
1
internal standard for all NMR spectra. H NMR spectra
are reported in order: multiplicity and approximate cou-
pling constant (J value) in hertz (Hz), number of protons;
signals were characterized as s (singlet), d (doublet), t
(triplet), m (multiplet), and br (broad signal). The 13C
NMR spectra were recorded at 75 MHz. The elemental
analyses were performed with an Elementar Analysen-
syteme GmbH Vario EL III. All the products are new
1
compounds, which were characterized by IR, H NMR,
and 13C NMR spectra. All other commercially obtained
reagents were used as received. Thin layer chromatogra-
*
E-mail: zhangzt@snnu.edu.cn; Tel.: 0086-029-85303940; Fax: 0086-029-85303940
Received September 26, 2011; accepted November 27, 2011.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201100405 or from the author.
Chin. J. Chem. 2012, 30, 997—1000
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
997

Zhang et al.
NOTE
phy (TLC): silica gel 60 GF254 plate; and the eluant of
column chromatography was the mixture of petroleum
ether and ethyl acetate at volume ratio of 1∶1.
calcd for C21H18N4O4: C 64.72, H 4.72, N 14.45; found
C 64.61, H 4.65, N 14.35.
8-Carbomoyl-4-(2-hydroxy-4,6-dimethoxyphenyl)-
3-(4-methoxyphenyl)imidazo[1,5-a]pyrimidine (3e)
m.p. 304—305 ℃. IR (KBr) ν: 3455, 1642, 1504, 1350,
General procedure for the synthesis of diarylimi-
dazo[1,5-a]pyrimidine 3
－
1
993, 857, 542 cm ; 1H NMR (DMSO-d6, 300 MHz) δ:
3.54 (s, 3H), 3.75 (s, 6H), 6.15 (d, J＝6.0 Hz, 2H), 6.90
(d, J＝6.0 Hz, 2H), 7.20—7.35 (m, 3H), 7.58 (s, 1H),
7.74 (s, 1H), 8.58 (s, 1H), 10.1 (s, 1H); 13C NMR
(DMSO-d6, 75 MHz) δ: 55.6, 56.2, 56.5, 90.9, 94.4,
98.8, 114.3, 122.8, 123.8, 125.3, 127.4, 130.3, 135.4,
138.2, 152.2, 157.5, 159.3, 159.4, 163.4, 163.5. Anal.
calcd for C22H20N4O5: C 62.97, H 4.89, N 13.52; found
C 62.85, H 4.79, N 13.33.
The isoflavone 1a—1i (1.5 mmol), 5-amino-1H-imi-
dazole-4-carboxamide 2 (2.4 mmol), and sodium hydro-
oxide (4.5, 6.0 and 7.5 mmol were used for 0, 1 and 2
free hydroxyl group of 1) were refluxed in DMF (8 mL)
by microwave irradiation for 12—30 min at 100 ℃
with microwave output 240 W. All reactions were
monitored by TLC, which showed the disappearance of
the starting materials. The reaction mixture was poured
into water (100 mL) and acidified with 10% HCl/H2O to
the neutral pH and a light yellow precipitate formed.
The precipitated yellow solid was filtered off and was
purified on silica gel column (chloroform/methanol,
40∶1) to give the corresponding product 3.
8-Carbomoyl-4-(2,4-dihydroxyphenyl)-3-(4-meth-
oxyphenyl)imidazo[1,5-a]pyrimidine (3f) m.p. 305
—306 ℃. IR (KBr) ν: 3409, 1613, 1506, 1423, 1377,
－
1
1
1251, 987, 858,542 cm ; H NMR (DMSO-d6, 300
MHz) δ: 3.74 (s, 3H), 6.23 (s, 1H), 6.48 (s, 1H), 6.82—
7.35 (m, 6H), 7.60 (s, 1H), 7.74 (s, 1H), 8.58 (s, 1H),
9.89 (s, 1H), 10.15 (s, 1H); 13C NMR (DMSO-d6, 75
MHz) δ: 55.6, 103.3, 107.9, 108.1, 114.4, 122.3, 122.7,
125.6, 127.0, 131.1, 132.2, 138.1, 138.8, 152.5, 157.4,
159.2, 161.0, 163.5. Anal. calcd for C20H16N4O4: C
63.89, H 4.35, N 14.92; found C 63.82, H 4.28, N 14.89.
8-Carbomoyl-4-(2,4-dihydroxyphenyl)-3-phenyl-
imidazo[1,5-a]pyrimidine (3g) m.p. 306—307 ℃.
8-Carbomoyl-4-(2-hydroxy-4-isopropoxyphenyl)-
3-phenylimidazo[1,5-a]pyrimidine (3a) m.p. 305—
307 ℃. IR (KBr) ν: 3428, 1665, 1609, 1501, 1379, 993,
－
1
858, 542 cm ; 1H NMR (DMSO-d6, 300 MHz) δ: 1.27
(s, 6H), 4.56 (s, 1H), 6.39 (s, 1H), 6.53 (s, 1H), 6.93 (s,
1H), 7.32 (s, 6H), 7.62 (s, 1H), 7.79 (s, 1H), 8.60 (s, 1H),
10.33 (s, 1H); 13C NMR (DMSO-d6, 75 MHz) δ: 22.2,
70.0, 103.3, 107.6, 109.0, 122.5, 122.9, 125.8, 128.3,
128.9, 129.8, 132.4, 134.8, 138.2, 138.9, 152.5, 157.3,
161.0, 163.6. Anal. calcd for C22H20N4O3: C 68.29, H
5.22, N 12.56; found C 68.03, H 5.19, N 12.60.
－
1
IR (KBr) ν: 3367, 3187, 1651, 1053, 1012, 833, 541 cm ;
1H NMR (DMSO-d6, 300 MHz) δ: 6.19 (s, 1H), 6.46 (s,
1H), 6.82 (d, J＝9.0 Hz, 1H), 7.30 (d, J＝9.0 Hz, 6H),
7.58 (s, 1H), 7.77 (s, 1H), 8.60 (s, 1H), 9.77 (s, 1H),
10.87 (s, 1H) ; 13C NMR (DMSO-d6, 75 MHz) δ: 103.3,
107.8, 108.0, 122.7, 125.8, 127.9, 128.0, 128.9,129.9,
132.2, 135.1, 138.2, 139.3, 152.3, 157.5, 161.1, 163.5.
Anal. calcd for C19H14N4O3: C 65.93, H 4.15, N 16.24;
found C 65.89, H 4.07, N 16.18.
8-Carbomoyl-4-(2-hydroxy-4-methoxy-6-methyl-
phenyl)-3-phenylimidazo[1,5-a]pyrimidine (3b) m.p.
303—305 ℃. IR (KBr) ν: 3486, 2959, 1652, 1501,
－
1
1
1350, 1206, 979, 856, 542 cm ; H NMR (DMSO-d6,
300 MHz) δ: 1.72 (s, 3H), 3.73 (s, 3H), 6.33 (s, 1H),
6.45 (s, 1H), 7.34—7.68 (m, 8H), 8.65 (s, 1H), 10.2 (s,
1H); 13C NMR (DMSO-d6, 75 MHz) δ: 19.4, 55.5, 99.5,
107.5, 109.4, 123.1, 123.5, 125.2, 128.5, 128.9, 129.2,
134.8, 137.9, 138.2, 138.7, 152.2, 157.6, 162.1, 163.5.
Anal. calcd for C21H18N4O3: C 67.50, H 5.02, N 15.11;
found C 67.37, H 4.85, N 14.96.
8-Carbomoyl-4-(2,4-dihydroxyphenyl)-3-(4-hydro-
xyphenyl)imidazo[1,5-a]pyrimidine (3h) m.p. 306—
307 ℃. IR (KBr) ν: 3578, 1568, 1539, 1542, 1388, 980,
－
1
852, 536 cm ; 1H NMR (DMSO-d6, 300 MHz) δ: 6.23
(d, J＝9.0 Hz, 1H), 6.55 (s, 1H), 6.71—6.81 (m, 3H),
7.06 (d, J＝9.0Hz, 2H), 7.39 (s, 1H), 7.63—7.72 (m,
2H), 8.57 (s, 1H), 9.75 (s, 1H), 10.82 (s, 1H), 11.73 (s,
1H); 13C NMR (DMSO-d6, 75 MHz) δ: 103.4, 105.8,
108.0, 115.8, 122.4, 122.7, 125.2, 125.6, 131.0, 132.1,
138.1, 138.7, 152.8, 157.5, 157.6, 161.1, 163.8. Anal.
calcd for C19H14N4O4: C 63.05, H 4.02, N 15.54; found
C 62.98, H 3.89, N 15.46.
8-Carbomoyl-4-(2-hydroxy-4-methoxyphenyl)-3-
phenylimidazo[1,5-a]pyrimidine (3c) m.p. 301—302
℃. IR (KBr) ν: 3418, 1668, 1610, 1503, 1443, 1380, 944,
－
1
1
856, 543 cm ; H NMR (DMSO-d6, 300 MHz) δ: 3.70
(s, 3H), 6.41—7.77 (m, 11H), 8.62 (s, 1H), 10.38 (s, 1H);
13C NMR (DMSO-d6, 75 MHz) δ: 55.6, 102.0, 106.3,
122.8, 125.2, 128.9, 132.3, 134.6, 138.6, 148.6, 152.3,
157.5, 162.6, 163.5. Anal. calcd for C20H16N4O3: C 66.82,
H 4.52, N 15.62; found C 66.66, H 4.48, N 15.55.
8-Carbomoyl-4-(2-hydroxyphenyl)-3-phenylimid-
azo[1,5-a]pyrimidine (3i) m.p. 310—311 ℃. IR
(KBr) ν: 3428, 1668, 1602, 1504, 1379, 997, 858, 527
8-Carbomoyl-4-(2-hydroxy-4-methoxyphenyl)-3-
－
1
cm ; 1H NMR (DMSO-d6, 300 MHz) δ: 6.80—6.85 (m,
1H), 7.03—7.11 (m, 2H), 7.31—7.40 (m, 8H), 7.72 (s,
1H), 8.65 (s, 1H), 10.32 (s, 1H) ; 13C NMR (DMSO-d6,
75 MHz) δ: 116.7, 116.9, 120.1, 122.8, 122.9, 125.5,
128.4, 128.9, 129.8, 131.3, 132.7, 134.6, 138.1, 138.7,
152.3, 156.1, 163.4. Anal. calcd for C19H14N4O2: C
69.13, H 4.32, N 17.02; found C 69.08, H 4.27, N 16.96.
(4-methoxyphenyl)imidazo[1,5-a]pyrimidine
(3d)
m.p. 318—319 ℃. IR (KBr) ν: 3438, 1665, 1609, 1501,
－
1
1
1379, 993, 858, 542 cm ; H NMR (DMSO-d6, 300
MHz) δ: 3.75 (s, 6H), 6.43—7.74 (m, 10H), 8.59 (s, 1H),
10.35 (s, 1H); 13C NMR (DMSO-d6, 75 MHz) δ: 55.7,
102.1, 106.4, 109.7, 114.4, 122.5, 122.8, 125.5, 126.9,
131.0, 132.3, 138.2, 152.5, 157.4, 162.5, 163.5. Anal.
998
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 997—1000

Microwave Irradiation for Accelerating Synthesis of Diarylimidizo[1,5-a]pyrimidine
Results and Discussion
showed that NaOH was the most effective (Entry 3).
Further studies using variable amount of NaOH re-
vealed that highest product yield could be obtained with
3 equivalents of base (Entry 10). The ratio of 1a and 2
was also evaluated. With a ratio of 1a/2 (1∶1.6), the
yield of 3a was the highest (Entry 14). Our optimized
conditions were suitable for the condensation of a vari-
ety of structurally divergent isoflavones 1a—1i with
5 - a m i n o - 1 H - i m i d a z o l e - 4 - c a r b o x a m i d e 2
[1∶2∶NaOH (1∶1.6∶3)/DMF/10—30 min/microwave]
affording the corresponding 3,4-diphenylimidazo[1,5-
a]pyrimidines 3a—3i in moderate to good yields (58%
—88%, Table 2). The yields were lower when the hy-
droxyl group was present in ring A (58%—82%, Table
2 Entries 6, 7, 8). It seems possible that the hydroxyl
groups of the isoflavones can generate phenolates under
basic reaction conditions, increasing the electron-
donating ability of the hydroxyl-isoflavones more than
the corresponding alkoxyiso-flavones. All products
were characterized by spectroscopic techniques and
elemental analysis.
Treatment of ipriflavone (1a) with 5-amino-1H-
imidazole-4-carboxamide 2 (1∶1 equiv.) in refluxing
ethanol in the presence of NaOH (1 equiv.) for 20 h af-
forded 8-carbomoyl-4-(2-hydroxy-4-isopropoxyphe-
nyl)-3-phenylimidazo[1,5-a]pyrimidine (3a) in 25%
yield. On the other hand, treatment of 1a with 2 (1∶1
equiv.) in ethanol in the presence of NaOH (1 equiv.)
under microwave irradiation for 10 min afforded 3a in
better yield (34%) (Table 1, Entry 1). Then we started to
optimize the conditions by using 1a and 2 as model re-
action (Table 1). First, NaOH was used as a base in dif-
ferent solvents such as MeOH, EtOH, DMF, glycol, and
DMSO, and DMF was found to give the highest product
yield (Entry 3). A comparative study of different bases
Table 1 Optimization of cyclocondensation of isoflavone 1a
with 5-amino-1H-imidazole-4-carboxamide 2a
H
O
O
O
N
NH2
NH2
Base/Solvent
Microwave
+
N
Table 2 Synthesis of 3,4-diphenyl-imidazo[1,5-a]pyrimidine by
the cyclocondensation of various isoflavones with 5-amino-1H-
imidazole-4-carboxamide a
O
1a
2
NH2
N
R1
O
C
H
O
N
NH2
Base/DMF
Microwave
N
A
B
R3
+
N
N
NH2
R2
O
1a
O
2
HO
NH2
O
N
O
N
N
B
3a
R3
HO
R2
Molar ratios (1a∶ Yield
A
EntrySolvent
Base
2∶base)
1∶1∶1
1∶1∶1
1∶1∶1
1∶1∶1
1:1∶1
(3a)b/%
R1
3
1
2
3
4
5
6
7
8
9
EtOH
MeOH
DMF
NaOH
NaOH
NaOH
34
23
65
41
50
trace
15
30
71
75
70
79
84
89
85
EntryCompd.R1
R2
R3
Product 3
b
Yield /% Time/min
HOCH2CH2OH NaOH
1
2
3
4
5
6
7
8
9
i-OPr
H
H
H
H
88
79
65
86
61
82
58
62
76
10
10
20
15
20
10
25
30
10
1a
1b
1c
1d
1e
1f
3a
3b
3c
3d
3e
3f
DMSO
DMF
DMF
DMF
DMF
NaOH
Et3N
1∶1∶1
OMe Me
CH3ONa 1∶1∶1
OMe
OMe
H
H
K2CO3
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
1∶1∶1
1∶1∶2
OMe
OMe OMe OMe
10 DMF
11 DMF
12 DMF
13 DMF
14 DMF
15 DMF
1∶1∶3
1∶1∶4
OH
OH
OH
H
H
H
H
H
OMe
H
1∶1.2∶3
1∶1.4∶3
1∶1.6∶3
1∶1.7∶3
1g
1h
1i
3g
3h
3i
OH
H
a All reactions were carried out in the appropriate solvent (8 mL)
using 1a (1.5 mmol), 2 and base until complete disappearance of
1a (microwave irradiation for 10—20 min). Reaction temperature:
MeOH, EtOH at boiling; DMF, glycol, DMSO at 100 ℃. Micro-
a Isoflavones 1 (1.5 mmol), 2 (2.4 mmol), NaOH (4.5, 6.0 and 7.5
mmol are used for 0, 1 and 2 free hydroxyl groups in 1 respec-
tively), 100 ℃. Microwave output＝240 W. b Isolated yield after
silica chromatography.
b
wave output＝240 W. Isolated yield after silica chromatogra-
phy.
Further experimentation and mechanistic studies are
Chin. J. Chem. 2012, 30, 997—1000
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
999

Zhang et al.
NOTE
required to fully understand the regioselectivity of the
cyclocondensation of isoflavone 1 with imidazo 2. It
was reported that isoflavone may undergo ring opening
reaction when refluxing in the presence of alkali form-
ing a 1,3-diketo intermediate 4 (Scheme 2).[12] The pri-
mary amine of 2 attacked the β-carbon in 4. Ring-clo-
sure reaction between nitrogen atom at position 1 of 2
and the carbonyl carbon then afforded product 3.
vone in DMF and the presence of sodium hydroxide by
microwave irradiation. It is an efficient and regioselec-
tive approach toward the synthesis of 3,4-diphenylimid-
azo[1,5-a]pyrimidines.
Acknowledgement
This research was supported by the National Natural
Science Foundation of China (No. 20772076), and the
Fundamental Funds Research for the Central Universi-
ties (No. Gk200901010).
Scheme 2 Proposed mechanism for the formation of 3
OH
R1
R1
O
OH
O
References
R2
O
R2
O
R3
R3
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Conclusions
In summary, we have developed a useful method
for the construction of fused 3,4-diphenylimidazo-
[1,5-a]pyrimidines derivatives by the cyclocondensation
of 5-amino-1H-imidazole-4-carboxamide with isofla-
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(Cheng, F.)
1000
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 997—1000