A Simple, Convenient, One-Pot Synthesis of Dihydro-azolopyrimidines, DFT Calculation, and NMR Determination by Using H-Ferrierite Zeolite as Catalyst

Article abstract of DOI:10.1002/jhet.2152

The multicomponent reaction of acetophenone derivatives with heterocyclic amines and benzaldehyde derivatives in water in the presence of H-ferrierite zeolite for short time 8-15 min afforded new series of [1,2,4]triazolo[1,5-a]pyrimidines and pyrimido[1,

Full text of DOI:10.1002/jhet.2152

Month 2014
A Simple, Convenient, One-Pot Synthesis of Dihydro-azolopyrimidines,
DFT Calculation, and NMR Determination by Using H-Ferrierite Zeolite
as Catalyst
*
H. M. E. Hassaneen and T. A. Farghaly
Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
*
E-mail:thoraya-f@hotmail.com
Received August 29, 2013
DOI 10.1002/jhet.2152
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
The multicomponent reaction of acetophenone derivatives with heterocyclic amines and benzaldehyde
derivatives in water in the presence of H-ferrierite zeolite for short time 8–15 min afforded new series of
[1,2,4]triazolo[1,5-a]pyrimidines and pyrimido[1,2-a]benzimidazole derivatives. The structure of the actual
tutomeric product was established on the bases of spectral data [IR, NMR (1H and 13C), and nuclear
Overhauser effect] and density functional theory calculations.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
zeolite beta [11]. Many reports [12] indicated that 1,4-dihyd
ro-azolopyrimidine were synthesized via cyclocondensation
of amino azoles with α,β-unsaturated ketones (chalcones)
[12,13] in DMF under reflux for 2–35 h. But this reaction
has disadvantages such as isolation of mixture of products
[14]. In addition, azolopyrimidine systems showed many
pharmacological activities [15–17]. Among all of the afore-
mentioned findings and as a part of our program that aimed
at achieving simple and environmentally compatible synthetic
methodologies in search of important heterocycles [18–20],
we are interested in the synthesis of a new series of 1,4-di
hydro-azolopyrimidine derivatives through MCR of heterocy-
clic amine, acetophenone derivatives, and substituted
benzaldehydes by using catalytic amount of zeolite ferrierite,
in its acidic form H-ferrierite (H-FER), in water. Moreover,
we conducted an investigation of the actual tutomeric
structure of the product through IR, NMR (1H and 13C),
nuclear Overhauser effect (NOE), and density functional
theory (DFT) calculations.
Multicomponent reactions (MCRs) have been proven to
be a very important and rapid way to access heterocyclic ring
compounds in a single synthetic operation from simple
building blocks and show high selectivity [1–3]. There
remains the necessity to develop a more effective and
convenient synthetic procedure as the reported methods have
many disadvantages such as the use of a high-boiling solvent
[e.g., dimethylformamide (DMF)] that is difficult to recover,
excess amounts of acid or base, special apparatus,
corrosive (e.g., HCl gas and trifluoroacetic acid) and hazard-
ous (e.g., pyridine and piperidine,) reagents/solvents and spe-
cial efforts to prepare the catalysts and adsorb the reactants
on a solid support. RE exchanged Y zeolites are reported as
effective catalyst in organic chemistry, petroleum industry,
agriculture, and domestic water treatment, and their specific-
ity in gas phase transformations is widely used in such indus-
try [4]. Many organic reactions such as cyclization,
alkylation, polymerization [5], or preparation of nitroalkane
[6] occurred in gas phase or with reactants adsorbed within
zeolite. Lately, there have been sundry reports on the utiliza-
tion of acidic zeolites (HY) in macro-lactonization [7,8],
acetylation [9], and gem-diacetalization [10], as well as in
the synthesis and application of the organic-functionalized
RESULTS AND DISCUSSION
Multicomponent reaction of 3-amino-1,2,4-triazole 1
with substituted benzaldehyde derivatives and acetophenone
© 2014 HeteroCorporation

H. M. E. Hassaneen and T. A. Farghaly
Vol 000
Scheme 1
Table 1
derivatives 2 were examined. When such reactions were
carried out in refluxing water in the presence of 2 g of
H-FER zeolite for 8–15 min, they yielded, in each case,
one product (as evidenced by thin-layer chromatography)
of the six isomers, 3A, 3B, 4, 5A, 5B, and 6 (Scheme 1).
All spectral data of the products are consistent with struc-
ture of 5B rather than that of the other isomers, 3A, 3B, 4,
5A, and 6 (Scheme 1). For example, the IR spectra of
the products revealed strong absorption bands for the
NH–C═C– fragment in the region 1612–1658 cmÀ1[14].
Synthesis of 4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidines (5a–f) by using
H-FER zeolite.
Time Yield
Entry
Ar/Ar′
Product
(min)
(%)
1
2
3
4
5
6
4-FC6H4/4-FC6H4
4-BrC6H4/4-FC6H4
4-MeC6H4/4-FC6H4
4-MeOC6H4/4-FC6H4
4-FC6H4/3,4-MeOC6H3
4-FC6H4/3,4,5-MeOC6H2
5a
5b
5c
5d
5e
5f
9.0
10.0
8.0
8.0
10.0
9.0
85
85
88
87
81
80
1
In H NMR, the protons of the NH group, the aromatic
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
A Simple, Convenient, One-Pot Synthesis of Dihydro-azolopyrimidines, DFT
Calculation, and NMR Determination by Using H-Ferrierite Zeolite
nuclei, and the dihydropyrimidine ring always appear, and
these eliminate 3A, 4, 5A, and 6. Moreover, NOE
difference experiments indicated that triazole proton and
protons of aromatic substituent (Ar′) and proton of C7-H
do not show mutual signal in triazolo[1,5-a]pyrimidine
ring, which is consistent with the structure of 5B. All the
triazolo[1,5-a]pyrimidine derivatives were obtained in
excellent yields with good purity and in very short time
(Table 1).
In order to explore the generality of the reaction, we
extended our study using 2-aminobenzimidazole 8 as
amino source, reacting with acetophenone derivatives 2,
H-FER zeolite as catalyst in presence of water with differ-
ent substituted benzaldehydes to prepare a series of
pyrimidobenzimidazole derivatives. The isolated product
may be formulated as 9A, 9B, or 10 (Scheme 2, Table 2).
The structure of 9B could be readily established for this
product based on IR and NMR (1H and 13C) spectra as well
as on results of NOE difference experiments. Thus, the
irradiation at the NH group resonance has not enhanced the
C4-H signal in the pyrimido[1,2-a]benzimidazole ring, which
is consistent with the structure of 9B (see Experimental part).
Thus, the presence or absence of a NOE between specific
protons allowed the structures for these compounds to be
established.
This can suggest that the acid sites on zeolite work as
active sites for this reaction and accelerate the reactions.
We have proposed the plausible mechanism for the forma-
tion of [1,2,4]triazolo[1,5-a]pyrimidines 5a–f or pyrimido
[1,2-a]benzimidazole derivatives 9a–f in the presence of
H-FER zeolite (Scheme 3). The hypothesis supported the
fact that initially the reaction was initiated by H-FER
zeolite, which reacts with benzaldehydes and forms a
complex I. Then complex I reacts with acetophenone de-
rivatives to give the intermediate II. The latter intermediate
II reacts with, for example, 3-amino-[1,2,4]triazole, giving
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

H. M. E. Hassaneen and T. A. Farghaly
Vol 000
Table 2
is less than that of 1B by 13.5 kcal. As the energy gap
decreases, the reactivity of compound increases; this means
that compound 1A is more reactive than compound 1B in
the reaction mechanism. The computed dipole moment that
measures the polarity of compound showed that 1B is more
polar than 1A by about 1.5 D. Therefore, compound 1B is
stabilized in aprotic solvent, whereas 1A is stabilized in
protic solvent. Also, the data predicted that 3B is more
stable than 3A by about 4 kcal, that is, a statistical mixture
of 3A and 3B is formed in the reaction medium, and 3B is
the predominant structure. The formation of 4 could be
ruled out because it is less stable than 3A by about 10 kcal.
The products’ reactivity, measured by the energy gap
(ELUMO À EHOMO), indicated that 3B is more reactive than
3A by about 4 kcal (Table 3). For the MO calculations, a
statistical mixture of 5A and 5B is formed where 5B is
more stable than 5A by 2.2 kcal. Moreover, the energy gap
(ELUMO À EHOMO) of 5B is less than that of 5A by about
10 kcal; this means that 5B is more reactive than 5A. In
addition, compound 6 was ruled out because it was shown
to be energetically less stable than 5A and 5B by 5.6 and
7.5 kcal, respectively. In summary, compound 5B is
energetically more stable than 3A, 3B, 4, 5A, or 6, and it
seemed to be the predominant isomer in the gas phase as
Synthesis of 1,4-dihydro-pyrimido[1,2-a]benzimidazole (9a–f) by using
H-FER zeolite.
Time Yield
Entry
Ar/Ar′
Product
(min)
(%)
1
2
3
4
5
6
4-FC6H4/4-FC6H4
4-BrC6H4/4-FC6H4
4-MeC6H4/4-FC6H4
4-MeOC6H4/4-FC6H4
4-FC6H4/3,4-MeOC6H3
4-FC6H4/3,4,5-MeOC6H2
9a
9b
9c
5d
9e
9f
10.0
10.0
12.0
13.0
15.0
15.0
87
88
90
90
81
80
rise to complex III and, upon loss of two water molecules,
gives the target products 5B (Scheme 3).
Molecular orbital calculations. The results of molecular
orbital (MO) calculations using B3LYP/6-31G* [21] for
compounds 1A, 1B, 3A, 3B, 5A, 5B, 6, 9A, 9B, and 10
are depicted in Tables 3 and 4. 3-Amino-1,2,4-triazole is
considered to exist in two forms, 1A and 1B (Scheme 1).
Inspection of data in Table 3 revealed the following: the
3-amino-1,2,4-triazole 1A form is more stable than 1B by
about 7.6 kcal and seemed to be the predominant form in
the gas phase. The energy gap (ELUMO À EHOMO) of 1A
Scheme 3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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A Simple, Convenient, One-Pot Synthesis of Dihydro-azolopyrimidines, DFT
Calculation, and NMR Determination by Using H-Ferrierite Zeolite
Table 3
Total energy (a.u.), energy of HOMO (a.u.), energy of LUMO (a.u.), energy gap (eV), and dipole moment (D) for compounds 1 and 3–6.
Parameter
1A
1B
3A
3B
4
5A
5B
6
ET, a.u.
À297.6188
À0.2171
0.0171
À297.6005
À0.2274
0.0279
À875.2154
À0.1989
À0.0349
4.460
À875.2217
0.2187
À875.2059
À0.1977
À0.0466
4.109
À875.2292
À0.2041
À0.0374
4.530
À875.2327
À0.2241
À0.0739
4.080
À875.2202
À0.2053
À0.0431
4.410
EHOMO, a.u.
ELUMO, a.u.
ΔE, eV
À0.0683
6.372
6.948
4.090
Dipole moment μ, D
3.909
5.426
6.193
8.117
6.4808
4.072
5.254
3.649
HOMO, highest occupied molecular orbital; LOMO, lowest unoccupied molecular orbital.
using a PyeUnicam SP-1000 spectrophotometer (Pye-Unicam, Ltd.,
Cambridge, UK). 1H NMR spectra were obtained on a Varian
EM-300MHz spectrometer (1H NMR 300MHz) using DMSO-d6,
solvent with TMS as internal standard. 13C NMR spectra were
measured on a Varian EM-300MHz spectrometer (75 MHz). Mass
spectra were recorded on an AEI MS 30 mass spectrometer operat-
ing at 70 eV. Elemental analyses were carried out by the Microana-
lytical Center of Cairo University, Giza, Egypt.
Reaction of acetophenone derivatives 2a–d with heterocyclic
amines and benzaldehydes. A mixture of 3-amino-1,2,4-triazole 1
Table 4
Total energy (a.u.), energy of HOMO (a.u.), energy of LUMO (a.u.), energy
gap (eV), and dipole moment (D) for compounds 9A, 9B, and 10.
Parameter
9A
9B
10
ET, a.u.
À1012.8308 À1012.8503 À1012.8203
EHOMO, a.u.
ELUMO, a.u.
ΔE, eV
À0.1911
0.0342
4.267
À0.2057
0.0704
3.678
0.1909
À0.0360
4.213
Dipole moment
5.231
4.245
4.185
or benzimidazole
8 (1.0mmol), benzaldehyde derivatives
μ, D
(1.0mmol), acetophenone derivatives 2 (1.0 mmol), and water
(5 mL) was taken in a round-bottom flask, H-FER zeolite (10 mol%)
was added, and the mixture was stirred at 80 °C for 10–15 min.
After completion of the reaction, as monitored by thin-layer
chromatography, the zeolite catalyst was filtered first, and the reaction
mass was cooled to room temperature; and the solid separated was
filtered and washed with water, dried, and crystallized from the
proper solvent to afford the corresponding 1,2,4-triazolo[1,5-a]
pyrimidines 5a–f or pyrimido[1,2-a]benzimidazole 9a–f .
5,7-Di-(4-fluorophenyl)-4,7-dihydro-1,2,4-triazolo[1,5-a]
pyrimidine (5a). Yellow solid, mp 180–182 °C (ethanol). 1H NMR
(DMSO-d6) δ 5.20 (d, J= 4 Hz, 1H, CH), 6.12 (d, J=4Hz, 1H, CH),
7.09–7.75 (m, 8H, Ar-H), 8.23 (s, 1H, triazole-H), 10.11 (s, 1H, NH);
IR (KBr) νmax 3250, 1612 cmÀ1. MS m/z (%) 312 (M+ +2, 34), 311
(M+ +1, 96), 310 (M+, 100), 118 (43), 106 (12), 91 (40), 77 (72).
Anal. Calcd for C17H12F2N4 (310.31): C, 65.80; H, 3.90; N, 18.06.
HOMO, highest occupied molecular orbital; LOMO, lowest unoccupied
molecular orbital.
1
indicated from H and 13C NMR in liquid phase. Also, the
MO calculation predicted that the 9B that formed in the
reaction medium was fully optimized at the B3LYP/6-31G*
level (Table 4), and the calculation indicated that 9B was
more stable than isomers 9A and 10 by 12.2 and 18.9 kcal,
respectively. Also, the reactivity of 9B was greater than that
of 9A by 13.6 kcal and that of 10 by 12.3 kcal.
Because of the wide range of pharmacological activity of
the oxidized form of [1,2,4]triazolo[1,5-a]pyrimidines and
pyrimido[1,2-a]benzimidazoles [15–17], we cyclized com-
pounds 5B and 9B with bromine in acetic acid to 7 and 11,
respectively (Schemes 1 and 2). The structure of compounds
7 and 11 was confirmed on the bases of spectral data and
elemental analyses (see Experimental part).
Found: C, 65.74; H, 3.98; N, 18.15%.
5-(4-Bromophenyl)-7-(4-fluorophenyl)-4,7-dihydro-1,2,4-tria
zolo[1,5-a]pyrimidine (5b). Yellow solid, mp 220–222 °C (DMF).
1H NMR (DMSO-d6) δ 5.23 (d, J = 3.6 Hz, 1H, CH), 6.24 (d,
J = 3.6 Hz, 1H, CH), 7.17–7.83 (m, 8H, ArH), 8.74 (s, 1H,
triazole-H), 10.09 (s, 1H, NH); IR (KBr) νmax 3200, 1624 cmÀ1
.
CONCLUSIONS
MS m/z (%) 373 (M+ +2, 11), 372 (M+ +1, 5), 371 (M+, 58), 155
(15), 106 (32), 91 (67), 76 (100). Anal. Calcd for C17H12BrFN4
(371.21): C, 55.01; H, 3.26; N, 15.09. Found: C, 55.23; H, 3.09;
N, 15.01%.
In this context, we have developed an efficient and facile
method for the synthesis of new series of [1,2,4]triazolo
[1,5-a]pyrimidines and pyrimido[1,2-a]benzimidazoles by
MCR using H-FER zeolite catalysts in water. The mild reac-
tion conditions are reduced pollution, reusability, high selec-
tivity, low cost, and short reaction time. Also, the structure
of these products was established on the bases of spectral data
[IR, NMR (1H and 13C), and NOE] and DFT calculations.
7-(4-Fluoophenyl)-5-(4-methylphenyl)-4,7-dihydro-1,2,4-tria
zolo[1,5-a]pyrimidine (5c). Orange solid, mp 199–201 °C
(DMF). 1H NMR (DMSO-d6) δ 2.32 (s, 3H, CH3), 5.14 (d,
J = 3.6 Hz, 1H, CH), 6.23 (d, J = 3.6 Hz, 1H, CH), 7.17–7.53
(m, 8H, Ar-H), 7.66 (s, 1H, triazole-H), 10.03 (s, 1H, NH); 13C
NMR (DMSO-d6) δ 20.96, 58.81, 95.99, 106.45, 115.25, 125.71,
128.74, 128.95, 131.24, 135.21, 138.28, 138.31, 149.36, 149.69.
IR (KBr) νmax 3310, 1626 cmÀ1. MS m/z (%) 308 (M+ +2, 1), 307
(M+ +1, 7), 306 (M+, 37), 305 (45), 211 (100), 118 (11), 91 (11).
Anal. Calcd for C18H15FN4 (306.13): C, 70.57; H, 4.94; N, 18.29.
Found: C, 70.31; H, 4.69; N, 18.10%.
EXPERIMENTAL
Melting points were determined on an electrothermal Gallenkamp
apparatus and are uncorrected. The IR spectra were recorded in KBr
Journal of Heterocyclic Chemistry
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H. M. E. Hassaneen and T. A. Farghaly
Vol 000
7-(4-Fluorophenyl)-5-(4-methoxyphenyl)-4,7-dihydro-1,2,4-
triazolo[1,5-a]pyrimidine (5d). Pale yellow solid, mp
230–232 °C (DMF). 1H NMR (DMSO-d6) δ 3.79 (s, 3H,
OCH3), 5.10 (d, J = 4 Hz, 1H, CH), 6.22 (d, J = 4 Hz, 1H, CH),
7.17–7.53 (m, 8H, Ar-H), 7.64 (s, 1H, triazole-H), 9.95 (s, 1H,
NH); IR (KBr) νmax 3195, 1632 cmÀ1. MS m/z (%) 324 (M+ +2,
6), 323 (M+ +1, 11), 322 (M+, 19), 118 (45), 91 (18). Anal.
Calcd for C18H15FN4O (322.34): C, 67.07; H, 4.69; N, 17.38.
Found: C, 66.92; H, 4.44; N, 17.21%.
5-(4-Fluorophenyl)-7-(3,4-dimethoxyphenyl)-4,7-dihydro-
1,2,4-triazolo[1,5-a]pyrimidine (5e). Yellow solid, mp
72–74 °C (ethanol). 1H NMR (DMSO-d6) δ 3.72, 3.82 (2 s,
6H, 2OCH3), 5.15 (d, J = 3.2 Hz, 1H, CH), 6.14 (d, J = 3.2 Hz,
1H, CH), 6.91 (d, J = 8 Hz, 1H, Ar-H), 7.0 (d, J = 8 Hz, 1H,
Ar-H), 7.32 (d, J = 8 Hz, 2H, Ar-H), 7.55 (s, 1H, Ar-H), 7.67
(d, J = 8 Hz, 2H, Ar-H), 7.93 (s, 1H, triazole-H), 10.0 (s, 1H,
NH); IR (KBr) νmax 3194, 1658 cmÀ1. MS m/z (%) 353 (M+
+1, 22), 352 (M+, 91), 324 (24), 257 (21), 215 (100), 173
(16), 138 (23), 121 (21), 91 (13), 77 (25). Anal. Calcd for
C19H17FN4O2 (352.37): C, 64.76; H, 4.86; N, 15.90. Found:
C, 64.56; H, 4.70; N, 15.82%.
4-(4-Fluorophenyl)-2-(4-methoxyphenyl)-1,4-dihydro-pyrimido
[1,2-a]bezimidazole (9d). Dark yellow solid, mp 240–242 °C
(DMF). 1H NMR (DMSO-d6) δ 3.79 (s, 3H, OCH3), 5.60 (d,
J = 4 Hz, 1H, CH), 6.16 (d, J= 4 Hz, 1H, CH), 6.85–8.41 (m, 12H,
Ar-H), 10.01 (s, 1H, NH); IR (KBr) νmax 3100, 1638 cmÀ1. MS m/
z (%) 373 (M+ +2, 14), 372 (M+ +1, 25), 371 (M+, 39), 369 (100),
326 (12), 276 (11), 148 (8). Anal. Calcd for C23H18FN3O
(371.42): C, 74.38; H, 4.88; N, 11.31. Found: C, 74.20; H, 4.64;
N, 11.09%.
2-(4-Fluorophenyl)-4-(3,4-dimethoxyphenyl)-1,4-dihydro-
pyrimido[1,2-a]benzimidazole (9e). Orange solid, mp 220–222°C
1
(ethanol). H NMR (DMSO-d6) δ 3.69, 3.72 (2s, 6H, 2OCH3),
5.23 (d, J = 3.6 Hz, 1H, CH), 6.25 (d, J = 3.6 Hz, 1H, CH),
6.79–8.25 (m, 11H, Ar-H), 10.12 (s, 1H, NH); 13C NMR
(DMSO-d6) δ 55.46, 55.51, 56.38, 97.77, 109.74, 110.41,
112.0, 115.29, 115.90, 118.75, 119.29, 121.38, 128.1, 130.33,
131.05, 133.35, 134.26, 142.41, 148.05, 148.38, 148.80,
161.13. IR (KBr) νmax 3147, 1624 cmÀ1. MS m/z (%) 402 (M+
+1, 18), 401 (M+, 54), 400 (51), 399 (37), 264 (100), 200 (11),
133 (12), 90 (12), 76 (8). Anal. Calcd for C24H20FN3O2
(401.44): C, 71.81; H, 5.02; N, 10.47. Found: C, 71.65; H,
5-(4-Fluorophenyl)-7-(3,4,5-trimethoxyphenyl)-4,7-dihydro-
1,2,4-triazolo[1,5-a]pyrimidine (5f). Orange solid, mp
5.14; N, 10.28%.
2-(4-Fluorophenyl)-4-(3,4,5-trimethoxyphenyl)-1,4-dihydro-
1
132–134 °C (ethanol). H NMR (DMSO-d6) δ 3.75, 3.80, 3.87
pyrimido[1,2-a]benzimidazole (9f). Yellow solid, mp 202–204°C
(ethanol). 1H NMR (DMSO-d6) δ 3.69, 3.78, 3.81 (3s, 9H,
3OCH3), 5.25 (d, J = 3.6Hz, 1H, CH), 5.87 (d, J = 3.6 Hz, 1H,
CH), 6.55 (s, 2H, Ar-H), 6.68–8.49 (m, 8H, Ar-H), 10.18 (s, 1H,
NH); 13C NMR (DMSO-d6) δ 55.88, 56.23, 56.83, 59.96, 97.41,
103.85, 107.20, 109.75, 115.29, 115.50, 115.96, 119.40, 121.48,
128.25, 130.26, 132.15, 137.01, 137.54, 142.39, 148.0, 153.18.
IR (KBr) νmax 3159, 1635 cmÀ1. MS m/z (%) 433 (M+ +2, 5),
432 (M+ +1, 21), 431 (M+, 74), 264 (100), 236 (15), 111 (12),
97 (27), 83 (33), 72 (42), 57 (46). Anal. Calcd for C25H22FN3O3
(431.47): C, 69.59; H, 5.14; N, 9.74. Found: C, 69.40; H, 5.02;
N, 9.58%.
Oxidation of compounds 5a–f and 9a–f. Bromine (0.052 g,
1 mmol) in acetic acid (5 mL) was added dropwise to a stirred
solution of the appropriate compounds 5a–f or 9a–f (1 mmol of
each) in acetic acid (10 mL) and sodium acetate (0.5 g). The
reaction mixture was stirred overnight and then poured onto ice-
cold water, and the solid that precipitated was filtered off,
washed with sodium bicarbonate solution and then with water,
dried, and crystallized from the appropriate solvent to give the
respective compounds, 7a–f or 11a–f.
(3 s, 9H, 3OCH3), 5.23 (d, J = 3.4 Hz, 1H, CH), 6.26 (d,
J = 3.4 Hz, 1H, CH), 6.89 (d, J = 8 Hz, 2H, Ar-H), 7.18 (d,
J = 8 Hz, 2H, Ar-H), 7.41 (s, 2H, Ar-H), 7.99 (s, 1H, triazole-
H), 10.18 (s, 1H, NH); IR (KBr) νmax 3311, 1615 cmÀ1. MS m/z
(%) 484 (M+ +2, 10), 483 (M+ +1, 15), 482 (M+, 37), 105
(100), 91 (24), 76 (38). Anal. Calcd for C20H19FN4O3 (382.40):
C, 62.82; H, 5.01; N, 14.65. Found: C, 62.65; H, 5.14; N, 14.49%.
2,4-Di-(4-fluorophenyl)-1,4-dihydro-pyrimido[1,2-a]benzimi
dazole (9a). Orange solid, mp 250–252°C (ethanol/dioxane). 1H
NMR (DMSO-d6) δ 5.24 (d, J = 3 Hz, 1H, CH), 6.37 (d, J = 3 Hz,
1H, CH), 6.86–7.71 (m, 12H, ArH), 10.21 (s, 1H, NH); IR (KBr)
ν
max 3301, 1640 cmÀ1. MS m/z (%) 361 (M+ +2, 2), 360 (M+ +1,
10), 359 (M+, 50), 358 (28), 357 (30), 264 (100), 90 (13). Anal.
Calcd for C22H15F2N3 (359.38): C, 73.53; H, 4.21; N, 11.69.
Found: C, 73.28; H, 4.06; N, 11.52%.
2-(4-Bromophenyl)-4-(4-fluorophenyl)-1,4-dihydro-pyrimido
[1,2-a]benzimidazole (9b). Dark yellow solid, mp 260–262 °C
(DMF). 1H NMR (DMSO-d6) δ 5.27 (d, J = 3.6 Hz, 1H, CH),
6.34 (d, J = 3.6 Hz, 1H, CH), 6.85–8.32 (m, 12H, Ar-H), 10.20
(s, 1H, NH); 13C NMR (DMSO-d6) δ 55.86, 97.81, 109.42,
114.31, 115.93, 119.37, 121.44, 127.04, 127.97, 128.16,
131.24, 131.76, 133.64, 137.87, 142.26, 147.87, 148.84,
151.25. IR (KBr) νmax 3305, 1663 cmÀ1. MS m/z (%) 422
(M+ +2, 6), 421 (M+ +1, 10), 420 (M+, 45), 419 (100), 338
(10), 324 (47), 244 (10), 90 (6). Anal. Calcd for C22H15BrFN3
(420.29): C, 62.87; H, 3.60; N, 10.00. Found: C, 62.66; H,
5,7-Di-(4-fluorophenyl)-1,2,4-triazolo[1,5-a]pyrimidine
(7a). Orange solid, mp 234–236 °C (ethanol). 1H NMR (DMSO-d6)
δ 7.22–7.83 (m, 8H, Ar-H), 8.17 (s, 1H, pyrimidine-H), 8.27
(s, 1H, triazole-H); MS m/z (%) 310 (M+ +2, 47), 309 (M+ +1, 29),
308 (M+, 100), 307 (95), 95 (28), 91 (64), 77 (39), 76 (57). Anal.
Calcd for C17H10F2N4 (308.29): C, 66.23; H, 3.27; N, 18.17.
3.51; N, 10.12%.
4-(4-Fluorophenyl)-2-(4-methylphenyl)-1,4-dihydro-pyrimido
Found: C, 66.15; H, 3.08; N, 18.07%.
5-(4-Bromophenyl)-7-(4-fluorophenyl)-1,2,4-triazolo[1,5-a]
[1,2-a]benzimidazole (9c). Orange solid, mp 270–272 °C (DMF).
1H NMR (DMSO-d6) δ 2.32 (s, 3H, CH3), 5.21 (d, J = 4 Hz, 1H,
CH), 6.35 (d, J = 4 Hz, 1H, CH), 6.85–7.55 (m, 12H, Ar-H),
10.21 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.70, 55.85, 96.57,
109.39, 114.22, 115.43, 116.22, 120.54, 121.99, 125.72, 126.56,
127.99, 128.55, 131.35, 134.01, 142.42, 142.65, 148.07, 151.15.
IR (KBr) νmax 3150, 1648 cmÀ1. MS m/z (%) 357 (M+ +2, 5),
356 (M+ +1, 15), 355 (M+, 70), 260 (100), 223 (6), 91 (6). Anal.
Calcd for C23H18FN3 (355.41): C, 77.73; H, 5.10; N, 11.82.
Found: C, 77.56; H, 5.31; N, 11.62%.
pyrimidine (7b). Yellow solid, mp 270–272 °C (DMF). 1H
NMR (DMSO-d6) δ 7.50–7.82 and 8.35–8.42 (m, 8H, ArH),
8.19 (s, 1H, pyrimidine-H), 8.73 (s, 1H, triazole-H); 13C NMR
(DMSO-d6) δ 106.58, 115.55, 115.77, 125.29, 126.22, 129.83,
131.99, 132.56, 135.29, 146.65, 155.73, 156.14, 159.45. MS
m/z (%) 370 (M+ +1, 92), 369 (M+, 100), 368 (71), 343 (38),
342 (75), 131 (79), 116 (50), 84 (58), 76 (67). Anal. Calcd for
C17H10BrFN4 (369.20): C, 55.31; H, 2.73; N, 15.18. Found:
C, 55.20; H, 2.85; N, 15.09%.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
A Simple, Convenient, One-Pot Synthesis of Dihydro-azolopyrimidines, DFT
Calculation, and NMR Determination by Using H-Ferrierite Zeolite
7-(4-Fluorophenyl)-5-(4-methylphenyl)-1,2,4-triazolo[1,5-a]
pyrimidine (7c). Dark yellow solid, mp 220–222 °C (DMF). 1H
NMR (DMSO-d6) δ 2.41 (s, 3H, CH3), 7.37–7.82 and 8.31–8.40
(m, 8H, ArH), 8.18 (s, 1H, pyrimidine-H), 8.61 (s, 1H, triazole-
H); MS m/z (%) 306 (M+ +2, 32), 305 (M+ +1, 21), 304 (M+, 75),
211 (27), 118 (54), 94 (31), 91 (46), 76 (100). Anal. Calcd for
C18H13FN4 (304.11): C, 71.04; H, 4.31; N, 18.41. Found: C,
368 (77), 342 (59), 341 (96), 220 (36), 169 (27), 133 (59), 105
(82), 90 (32), 77 (96). Anal. Calcd for C23H16FN3O (369.39): C,
74.78; H, 4.37; N, 11.38. Found: C, 74.65; H, 4.24; N, 11.18%.
2-(4-Fluorophenyl)-4-(3,4-dimethoxyphenyl)-pyrimido[1,2-a]
benzidazole (11e). Dark orange solid, mp 288–290 °C (ethanol).
1H NMR (DMSO-d6) δ 3.66, 3.75 (2s, 6H, 2OCH3), 6.79–8.25
(m, 11H, Ar-H), 8.27 (s, 1H, pyrimidine-H); MS m/z (%) 401
(M+ +2, 5), 400 (M+ +1, 26), 399 (M+, 38), 106 (45), 90 (25),
76 (58). Anal. Calcd for C24H18FN3O2 (399.14): C, 72.17; H,
71.11; H, 4.20; N, 18.24%.
7-(4-Fluorophenyl)-5-(4-methoxyphenyl)-1,2,4-triazolo[1,5-
a]pyrimidine (7d). Orange solid, mp 248–250 °C (DMF). 1H
NMR (DMSO-d6) δ 3.87 (s, 3H, OCH3), 7.10–7.52 and
8.07–8.38 (m, 8H, Ar-H), 8.07 (s, 1H, pyrimidine-H), 8.65
(s, 1H, triazole-H); 13C NMR (DMSO-d6) δ 55.45, 106.11,
114.35, 115.52, 115.74, 126.40, 128.39, 129.59, 132.47,
132.56, 146.14, 155.78, 160.25, 161.98. MS m/z (%) 322
(M+ +2, 6), 321 (M+ +1, 15), 320 (M+, 100), 292 (19), 90 (3),
76 (6). Anal. Calcd for C18H13FN4O (320.33): C, 67.49; H,
4.54; N, 10.52. Found: C, 72.03; H, 4.34; N, 10.34%.
2-(4-Fluorophenyl)-4-(3,4,5-trimethoxyphenyl)-pyrimido
[1,2-a]benzimidazole (11f). Orange solid, mp 236–2328 °C
(ethanol/dioxane). 1H NMR (DMSO-d6) δ 3.72, 3.87 (2s,
9H, 3OCH3), 7.25 (s, 2H, Ar-H, pyrimidine-H), 7.42–7.44
and 8.27–8.27 (m, 5H, Ar-H), 7.73 (d, J = 9 Hz, 2H, Ar-H),
7.89 (d, J = 9 Hz, 2H, Ar-H); MS m/z (%) 431 (M+ +2, 14),
430 (M+ +1, 33), 429 (M+, 100), 428 (78), 105 (16), 90
(10), 75 (14). Anal. Calcd for C25H20FN3O3 (429.44): C,
69.92; H, 4.42; N, 9.78. Found: C, 69.68; H, 4.20; N, 9.61%.
4.09; N, 17.49. Found: C, 67.23; H, 4.25; N, 17.19%.
5-(4-Fluorophenyl)-7-(3,4-dimethoxyphenyl)-1,2,4-triazolo
[1,5-a]yrimidine (7e). Orange solid, mp 138–140 °C (ethanol).
1H NMR (DMSO-d6) δ 3.72, 3.87 (2s, 6H, 2OCH3), 7.25
(s, 2H, pyrimidine-hand triazole-H), 7.40–7.44 and 8.25–8.29
(m, 3H, Ar-H), 7.69 (d, J = 9 Hz, 2H, ArH), 7.89 (d,
J = 9 Hz, 2H, ArH); MS m/z (%) 352 (M+ +2, 15), 351 (M+
+1, 11), 350 (M+, 36), 349 (42 ),155 (13), 138 (56), 105
(15), 91 (24), 77 (100). Anal. Calcd for C19H15FN4O2
(350.36): C, 65.14; H, 4.32; N, 15.99. Found: C, 64.94; H,
4.24; N, 15.79%.
Acknowledgment. The authors thank Prof. Dr. Hussein Mustafa,
Department of Chemistry, Faculty of Science, Cairo University,
for his help in the molecular orbital calculations.
REFERENCES AND NOTES
5-(4-Fluorophenyl)-7-(3,4,5-trimethoxyphenyl)-1,2,4-triazolo
[1,5-a]pyrimidine (7f). Orange solid, mp 260–262 °C (ethanol/
dioxane). H NMR (DMSO-d6) δ 3.39, 3.96 (2s, 9H, 3OCH3),
6.14 (d, J = 7 Hz, 2H, ArH), 6.82 (d, J = 7 Hz, 2H, ArH), 7.51,
8.37 (2s, 2H, Ar-H), 7.62 (s, 2H, pyrimidine-H and triazole-H);
MS m/z (%) 382 (M+ +2, 4), 381 (M+ +1, 2), 380 (M+, 12), 379
(19), 212 (42), 94 (26),76 (100). Anal. Calcd for C20H17FN4O3
(380.38): C, 63.15; H, 4.50; N, 14.73. Found: C, 63.0; H, 4.32;
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1
N, 14.50%.
2,4-Di-(4-fluorophenyl)-pyrimido[1,2-a]benzimidazole (11a).
Orange solid, mp > 300 °C (dioxane). 1H NMR (DMSO-d6) δ
6.86–7.71 (m, 12H, ArH), 8.32 (s, 1H, pyrimidine-H); MS m/z
(%) 359 (M+ +2, 24), 358 (M+ +1, 18), 357 (M+, 58), 356 (48),
262 (26), 167 (10), 95 (32), 76 (100). Anal. Calcd for
C22H13F2N3 (357.36): C, 73.94; H, 3.67; N, 11.76. Found: C,
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73.68; H, 3.48; N, 11.55%.
2-(4-Bromophenyl)-4-(4-fluorophenyl)-pyrimido[1,2-a]benzi
midazole (11b). Yellow solid, mp 300–302 °C (DMF). 1H NMR
(DMSO-d6)
δ 6.73–7.97 (m, 12H, Ar-H), 8.32 (s, 1H,
pyrimidine-H); MS m/z (%) 420 (M+ +2, 14), 419 (M+ +1, 36),
418 (M+, 100), 105 (25), 91 (20), 77 (37). Anal. Calcd for
C22H13BrFN3 (418.26): C, 63.17; H, 3.13; N, 10.05. Found: C,
63.0; H, 3.41; N, 10.22%.
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Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.;
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4-(4-Fluorophenyl)-2-(4-methylphenyl)-pyrimido[1,2-a]benzi
1
midazole (11c). Orange solid, mp 309–311 °C (DMFDMF). H
NMR (DMSO-d6) δ 2.46 (s, 3H, CH3), 6.72–7.95 (m, 12H, Ar-
H), 8.36 (s, 1H, pyrimidine-H); MS m/z (%) 354 (M+ +1, 26),
353 (M+, 100), 352 (93), 351 (44), 177 (22), 176 (39), 162
(20), 106 (17), 91 (15), 77 (19). Anal. Calcd for C23H16FN3
(353.39): C, 78.17; H, 4.56; N, 11.89. Found: C, 78.05; H,
4.29; N, 11.87%.
4-(4-Fluorophenyl)-2-(4-methoxyphenyl)-pyrimido[1,2-a]ben
zimidazole (11d). Yellow solid, mp 290–292 °C (DMF). 1H
NMR (DMSO-d6) δ 3.93 (s, 3H, OCH3), 6.67–7.93 (m, 12H,
Ar-H), 8.29 (s, 1H, pyrimidine-H); MS m/z (%) 369 (M+, 100),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

H. M. E. Hassaneen and T. A. Farghaly
Vol 000
Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.;
Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.;
Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.;
Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith,
T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.;
Gill, P. M. W., Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.;
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet