Cheap and efficient protocol for the synthesis of tetrahydroquinazolinone, dihydropyrimidinone, and pyrimidinone derivatives

Article abstract of DOI:10.1080/00397910902883736

The article reports a practical, simple, and inexpensive procedure for the synthesis of tetrahydroquinazolinone and dihydropyrimidinone derivatives from aldehydes, cyclic ketones, and urea using a catalytic amount of ammonium chloride or lithium perchlorate. The protocol provides good yields and simple workup procedure for the products. By this method, we have prepared and characterized the 4-aryl-3,4,5,6-tetrahydrobenzo[h]quinazolin-2(1H)-one (3a, c, d, f, g, j, k), 4-aryl-3,4-dihydro-1H-indeno[1,2-d]pyrimidin-2(5H)-one (3b, e, h, i), 4-aryl-5,6-dihydrobenzo[h]quinazolin-2(3H)-one (3j', k', l'), and 4-aryl-3,5-dihydro-2H-indeno[1,2-d]pyrimidin-2-one (3i', m', n', o', p') derivatives. Furthermore, we have synthesized the pyrimidinone derivatives (6a'-e') using a catalytic amount of cupric chloride from aldehydes, acyclic ketones and urea. The tautomeric interconversion of pyrimidinone derivatives 6a'-e'6a''-e'' has been observed.

Full text of DOI:10.1080/00397910902883736

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Cheap and Efficient Protocol for the
Synthesis of Tetrahydroquinazolinone,
Dihydropyrimidinone, and Pyrimidinone
Derivatives
Maryam Mirza-Aghayan a , Alireza Moradi a , Mohammad Bolourtchian
a & Rabah Boukherroub b
a Chemistry and Chemical Engineering Research Center of Iran
(CCERCI), Tehran, Iran
b Institut de Recherche Interdisciplinaire (IRI, USR 3078) and Institut
d'Electronique, de Microélectronique et de Nanotechnologie (IEMN,
UMR 8520) Cité Scientifique, Villeneuve d'Ascq, France
Published online: 09 Dec 2009.
To cite this article: Maryam Mirza-Aghayan , Alireza Moradi , Mohammad Bolourtchian & Rabah
Boukherroub (2009) Cheap and Efficient Protocol for the Synthesis of Tetrahydroquinazolinone,
Dihydropyrimidinone, and Pyrimidinone Derivatives, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 40:1, 8-20, DOI:
10.1080/00397910902883736
To link to this article: http://dx.doi.org/10.1080/00397910902883736
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Synthetic Communications1, 40: 8–20, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902883736
CHEAP AND EFFICIENT PROTOCOL FOR THE
SYNTHESIS OF TETRAHYDROQUINAZOLINONE,
DIHYDROPYRIMIDINONE, AND PYRIMIDINONE
DERIVATIVES
Maryam Mirza-Aghayan,1 Alireza Moradi,1 Mohammad
Bolourtchian,1 and Rabah Boukherroub2
1Chemistry and Chemical Engineering Research Center of Iran (CCERCI),
Tehran, Iran
2Institut de Recherche Interdisciplinaire (IRI, USR 3078) and Institut
´
d’Electronique, de Microelectronique et de Nanotechnologie (IEMN, UMR
8520) Cite Scientifique, Villeneuve d’Ascq, France
´
The article reports a practical, simple, and inexpensive procedure for the synthesis of
tetrahydroquinazolinone and dihydropyrimidinone derivatives from aldehydes, cyclic
ketones, and urea using a catalytic amount of ammonium chloride or lithium perchlorate.
The protocol provides good yields and simple workup procedure for the products. By this
method, we have prepared and characterized the 4-aryl-3,4,5,6-tetrahydrobenzo[h]
quinazolin-2(1H)-one (3a, c, d, f, g, j, k), 4-aryl-3,4-dihydro-1H-indeno[1,2-d]pyrimidin-
2(5H)-one (3b, e, h, i), 4-aryl-5,6-dihydrobenzo[h]quinazolin-2(3H)-one (3j0, k0, l0), and
4-aryl-3,5-dihydro-2H-indeno[1,2-d]pyrimidin-2-one (3i0, m0, n0, o0, p0) derivatives.
Furthermore, we have synthesized the pyrimidinone derivatives (6a0–e0) using a catalytic
amount of cupric chloride from aldehydes, acyclic ketones and urea. The tautomeric
interconversion of pyrimidinone derivatives 6a0–e0 $ 6a00–e00 has been observed.
Keywords: Ammonium chloride; cupric chloride; dihydropyrimidinone derivatives; lithium perchlorate;
pyrimidinone derivatives; tetrahydroquinazolinone derivatives
Octahydroquinazolinone derivatives have attracted considerable attention in
the recent years because of their potential antibacterial activity against Staphylo-
coccus aureus, Escherichia coli, and pseudomonas aeruginosa[1] and their activity as
a calcium antagonist.[2] Dihydropyrimidin-2(1H)-ones (DHPMs) possess significant
therapeutic and pharmacological properties.[2a–3] Certain DHPMs act as calcium
channel blockers,[4] a-1a-adrenergic receptor antagonists,[5] mitotic kinesin inhibi-
tors, antihypertensive agents, neuropeptide Y (NPY) antagonists, and antiviral
and antibacterial agents.[6]
Received August 19, 2008.
Address correspondence to Maryam Mirza-Aghayan, Chemistry and Chemical Engineering
Research Center of Iran (CCERCI), P. O. BOX 14335-186, Tehran, Iran. E-mail: m.mirzaaghayan@
ccerci.ac.ir
8

TETRAHYDROQUINAZOLINONE DERIVATIVES
9
Octahydroquinazolinone derivatives are commonly synthesized using the
Biginelli reaction. The classical Biginelli reaction involves one-pot condensation of
an aldehyde, a b-ketoester, and urea under strongly acidic conditions. In recent
years, interest in this reaction has increased rapidly, and several modified procedures
aimed at improving the efficiency of the Biginelli dihydropyrimidine synthesis have
been reported.[7] The Biginelli reaction was enlarged by the variation of the 1,3-dicar-
bonyl compound building blocks, including the use of b-ketoesters and cyclic
b-diketones. For example, Zhu et al. have reported the preparation of spiro-
heterotricyclic adducts and pyrimidinone scaffold compounds by the condensation
of cycloalkanones, urea, and aldehydes.[8] In addition, the Biginelli-type reaction
using acetophenones instead of 1,3-dicarbonyl compounds was recently investi-
gated.[9] Sedova et al. have described the synthesis of hexahydropyrimido[4,5-
d]pyrimidine-2,7-diones using acetophenones, urea, and aldehydes as starting
materials, and they have shown that acetophenones behave differently during
condensation with 4-bromobenzaldehyde and urea.[9a] In addition, Wang et al. have
found that the products obtained from acyclic ketones, urea, and aldehydes were
contaminated with their isomeric adducts and it is necessary to purify them with
additional workup.[9b]
In continuation of our investigations in organic synthesis,[10] herein we describe
a simple and efficient protocol for the three-component cyclocondensation reaction
of aldehydes, cyclic ketones, and urea for the synthesis of tetrahydroquinazolinone
and dihydropyrimidinone derivatives using NH4Cl or LiClO4 as catalyst and the
preparation of 4,6-bisaryl-pyrimidinone derivatives using CuCl2 catalyst via three-
component cyclocondensation reaction of aldehydes, acyclic ketones, and urea.
At an earlier stage of our work, we have examined the catalytic efficiency of
NH4Cl and LiClO4. In a typical experiment, an equimolar quantity of aldehyde,
cyclic ketone, 1.5 equivalents of urea, and NH4Cl (50 mol%) or LiClO4 (20 w=w%)
catalyst in acetonitrile were mixed and heated at reflux in solvent for 10 h
(Scheme 1). The crude products were poured onto crushed ice after stirring, directly
filtered through a sintered funnel, and washed with ethylacetate–hexane (1:3). For
further purification, the product was recrystallized from ethanol. For example, yields
of 40% and 19% were obtained for the reaction of 4-nitrobenzaldehyde with
a-tetralone using NH4Cl or LiClO4 catalysts, respectively.
Scheme 1. NH4Cl or LiClO4 catalyzed the preparation of fused-ring quinazolinone and pyrimidinone
derivatives.

10
M. MIRZA-AGHAYAN ET AL.
In the next step, we have used trimethylchlorosilane (TMSCl) for chemical acti-
vation of the ketones. As previously, 1 equimolar of TMSCl was added to a stirred
mixture of aldehyde, ketone, urea, and NH4Cl (50 mol %) or LiClO4 (20% w=w) in
acetonitrile, and the mixture was heated at reflux in solvent. Using TMSCl, the reac-
tion time decreased from 10 to 6 h, and the yields were better. For example, the yield
of the reaction increased to 65 and 70% using NH4Cl or LiClO4 catalysts in the
presence of TMSCl, respectively, as compared to 40 and 19% in the absence of
TMSCl for the reaction of 4-nitrobenzaldehyde with a-tetralone. The results are
summarized in Table 1.
The obtained yields are good: 50–91% and 45–98% using NH4Cl (50 mol%) or
LiClO4 (20% w=w aldehyde), respectively. All compounds were characterized on
the basis of their spectroscopic data such as 1H NMR, mass spectroscopy,
infrared (IR) spectra, and elemental analysis. The products, 4-aryl-3,4,5,6-
tetrahydrobenzo[h]quinazolin-2(1H)-one (3a, c, d, f, g, j, k) and 4-aryl-3,4-dihydro-1-
H-indeno[1,2-d]pyrimidin-2(5H)-one (3b, e, h, i), were fully characterized with the
structure proposed in Scheme 1. The products (3i–k) and (3i0–k0) were obtained as
a mixture. The structure of 4-(3-hydroxyphenyl)-5,6-dihydrobenzo[h]quinazolin-2(3-
H)-one (3 l0) and 4-aryl-3,5-dihydro-2H-indeno[1,2-d]pyrimidin-2-one (3 m0–p0) is
1
proposed in Scheme 2. H NMR spectra of the products 3 l0–p0 do not show the
signal of CH of C4 and NH at 5–6 and 6–7 ppm, respectively. The absence of these
signatures may be due to subsequent oxidation during the workup of the products.
1H NMR and elemental analyses have also confirmed the structure of the products
3 l0–p0 (Scheme 2).
Table 1. NH4Cl or LiClO4 catalyzed the preparation of fused-ring quinazolinone and pyrimidinone
derivativesa in the presence of TMSCl
Entry
Ar
Ketone
Productb
Yieldc (%)
Mp (ꢀC)
1
2
C6H5
C6H5
4-(Br)-C6H4
a-Tetralone
1-Indanone
a-Tetralone
a-Tetralone
1-Indanone
a-Tetralone
a-Tetralone
1-Indanone
1-Indanone
a-Tetralone
a-Tetralone
a-Tetralone
1-Indanone
1-Indanone
1-Indanone
1-Indanone
3a
3b
70 (65)
70 (70)
85 (80)
(75)
275–277[11]
276–278[11a]
258–260
257–259
249–251
219–221
239–241
271–273
—
3
3c
3d
4
3-(NO2)-C6H4
3-(NO2)-C6H4
4-(NO2)-C6H4
2-(OCH3)-C6H4
2-(OCH3)-C6H4
4-(Br)-C6H4
5
3e
(98)
6
3f
3g
65 (70)
50 (45)
54 (54)
91 (80)
80 (80)
65 (63)
70 (76)
61 (59)
50 (60)
65 (60)
55 (53)
7
8
3h
3i, i0 (3.0=1.0)
3j, j0 (1.5=1.0)
3k, k0 (1.2=1.0)
9
10
11
12
13
14
15
16
3-(OCH3)-C6H4
4-(CH3)-C6H4
3-(OH)-C6H4
3-(OH)-C6H4
2-(OH)-1-naphthyl
3-(OCH3)-C6H4
4-(CH3)-C6H4
—
—
3 l0
3 m0
3n0
3o0
3p0
>355
>355
298–300
291–293
286–288
aReaction conditions: aldehyde 2 mmol, a-tetralone or 1-indanone 2 mmol, urea 3 mmol, TMSCl
2 mmol, NH4Cl 50 mol% or LiClO4 20% w=w aldehyde, 10 mL CH3CN, reflux 6h.
bThe number between the parentheses shows the ratio of the nonoxidized to oxidized products.
cIsolated yield using NH4Cl catalyst; the number between the parentheses shows the yield using LiClO4
catalyst.

TETRAHYDROQUINAZOLINONE DERIVATIVES
11
Scheme 2. The proposed structure for 3 l0–p and their possible tautomery.
It should be noted that there is a possible tautomery for this structure as shown
in Scheme 2. The adducts 3 l0–p0 typically exist also as hydrogen-bonded dimers, and
significant amounts of dimers can also be present in solution. Interconversion of
these species is rapid in solution, and only averaged signals for this compound
1
and its dimer can be observed in H NMR spectra.[12]
Scheme 3. CuCl2 catalyzed the synthesis of 5-unsubstituted pyrimidin-2(1H)-ones derivatives.

12
M. MIRZA-AGHAYAN ET AL.
Table 2. CuCl2 catalyzed the synthesis of 5-unsubstituted pyrimidin-2(1H)-ones derivativesa in the
presence of TMSCl
Entry
R1
R2
Product
Yielda,b
Mp (ꢀC)
1
2
3
4
5
4-OCH3
4-CH3
H
H
H
6a0
6b0
6c0
6d0
6e0
68
84
43
73
63
255–257
303–305
264–266
320–322
313–315
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-CH3
aReaction conditions: aldehyde 2 mmol, acetophenone or 4-methoxy acetophenone 2 mmol, urea
3 mmol, TMSCl 2 mmol, CuCl2 10 mol%, 10 mL CH3CN, reflux 8 h.
bIsolated yield.
We have also synthesized 5-unsubstituted pyrimidin-2(1H)-one derivatives in
good yields by the reaction of acyclic ketones with aldehydes and urea using CuCl2
catalyst in the presence of TMSCl (Scheme 3). The results are summarized in Table 2.
The products 6a0–e0 have been isolated, and their structure is shown in Scheme 3. 1H
NMR spectra of the products 6a0–e0 do not exhibit the signal of CH of C4 at
5–6 ppm, in agreement with the proposed structure. The elemental analyses of the
obtained products have also confirmed this structure.
Scheme 4. The possible tautomery for 6a0 and 6c0.

TETRAHYDROQUINAZOLINONE DERIVATIVES
13
We have observed a similar tautomery for 6a0–e0 $ 6a00–e00 as shown in
Scheme 3. The products 6a0 and 6c0 display melting points of 255–257 and
264–266ꢀC, respectively. The result is consistent with a difference in the structure
1
of 6a0 and 6c0 in solid state. However, H NMR spectra of 6a0 and 6c0 are similar,
which indicates that they have similar structures in solution and they are in equilib-
rium with their tautomer and or their dimer. As shown in Scheme 4, it is clear that
the structures of 6a00 and 6c00 are identical.
In conclusion, we have synthesized fused-ring tetrahydroquinazolin-2(1H)-one
and dihydroindenopyrimidin-2(5H)-one derivatives by three-component cyclocon-
densation reactions of aldehydes, cyclic ketones, and urea in the presence of TMSCl
using NH4Cl or LiClO4 as available and inexpensive catalysts. By this method, we
have obtained dihydroquinazolin-2(3H)-one and indenopyrimidin-2-one fused ring
products that are fully characterized. We have also prepared pyrimidin-2(1H)-one
derivatives in good yields by the reaction of the acyclic ketones with aldehydes
and urea using CuCl2 catalyst in the presence of TMSCl. The results showed that
there is a potential tautomery for these products.
EXPERIMENTAL
Melting points were determined in evacuated capillaries with a Buchi B-545
apparatus. Gas chromatography=mass spectrometry (GC=MS) analysis was
performed on a Fison GC 8000 series Trio 1000 gas chromatograph equipped with
a capillary column (CP Sil.5 CB, 60 M ꢁ 0.25 mm i.d.). 1H NMR spectra were
recorded on a Bruker 500 spectrometer using tetramethylsilane (TMS) as internal
standard. Infrared (IR) spectra were recorded from KBr disks with a Bruker Vector
22 fourier transform (FT)–IR spectrometer. Elemental analyses were performed on a
ThermoFinigan Flash EA 1112 series elemental analyzer.
Typical Procedure for Fused Ring 3a–k and 3i0–p0
TMSCl (2 mmol), a-tetralone, or 1-indanone (2 mmol) and NH4Cl (50 mol%)
or LiClO4 (20% w=waldehyde) were added to a solution of aldehyde 1 (2 mmol) and
urea (3 mmol) in CH3CN (10 mL). The reaction mixture was heated at reflux of
solvent for 6 h. After completion of the reaction, the mixture was poured into
crushed ice, directly filtered through a sintered funnel after stirring, and washed
by ethylacetate–hexane (1:3). For further purification, the product was purified by
recrystallization from ethanol.
Data
1
Entry 1, Table 1, 3a. Mp: 275–277ꢀC. H NMR (DMSO-d6, 500 MHz): d ¼
1.77 (m, 1H, CH2), 2.13 (m, 1H, CH2), 2.58 (m, 1H, CH2), 2.71 (m, 1H, CH2),
4.93 (s, 1H, CH), 7.14–7.38 (m, 8H, CH arom. & 1H, NH), 7.58 (d, J ¼ 7.3 Hz,
1H, CH arom.), 8.53 (s, 1H, NH). 13C NMR (DMSO-d6, 125 MHz): d ¼ 24.38,
28.47, 59.97, 108.91, 122.08, 127.17, 127.74, 128.29, 128.31, 128.43, 128.54, 129.42,
129.66, 136.26, 145.02, 154.20. IR (KBr): n ¼ 3331, 3232, 3088, 2939, 2362, 1681,
1487, 1429, 1340, 1290, 763 cmꢂ1. MS (70 eV), m=z (%): 276 (45) (Mþ), 260 (3),

14
M. MIRZA-AGHAYAN ET AL.
248 (5), 232 (11), 199 (100), 181 (11), 114 (21), 89 (10), 77 (27). Anal. calcd. for
C18H16N2O: C, 78.24; H, 5.84; N, 10.14%. Found: C, 77.47; H, 5.82; N, 10.05%.
Entry 2, Table 1, 3b. Mp: 276–278ꢀC. 1H NMR (DMSO-d6, 500 MHz):
d ¼ 2.80 (d, J ¼ 22.6 Hz, 1H, CH2), 3.27 (d, J ¼ 22.6 Hz, 1H, CH2), 5.46 (d,
J ¼ 0.7 Hz, 1H, CH), 7.14–7.17 (m, 1H, CH arom.), 7.19 (br s, 1H, NH),
7.25–7.39 (m, 7H, CH arom.), 7.62 (d, J ¼ 7.5 Hz, 1H, CH arom.), 9.34 (s, 1H,
NH).13C NMR (DMSO-d6, 125 MHz): d ¼ 35.50, 58.04, 113.08, 119.02, 124.77,
125.94, 127.05, 127.23, 128.24, 129.44, 135.69, 138.35, 143.60, 145.28, 154.24. IR
(KBr): n ¼ 3402, 3329, 3205, 3088, 2999, 2958, 2366, 1678, 1460, 1355, 773,
744 cmꢁ1. MS (70 eV), m=z (%): 261 (50) (Mþ), 243 (3), 231 (4), 216 (17), 185
(100), 115 (22), 89 (7), 77 (28). Anal. calcd. for C17H14N2O: C, 77.84; H, 5.38; N,
10.68%. Found: C, 77.46; H, 5.38; N, 10.60%.
Entry 3, Table 1, 3c. Mp: 258–260ꢀC. 1H NMR (DMSO-d6, 500 MHz):
d ¼ 1.76 (m, 1H, CH2), 2.11 (m, 1H, CH2), 2.59 (m, 1H, CH2), 2.70 (m, 1H, CH2),
4.95 (s, 1H, CH), 7.14–7.22 (m, 3H, CH arom.), 7.29 (m, 2H, CH arom. & 1H,
NH), 7.54–7.74 (m, 3H, CH arom.), 8.58 (s, 1H, NH).13C NMR (DMSO-d6,
125 MHz): d ¼ 24.27, 28.46, 59.31, 108.36, 121.53, 122.15, 127.19, 128.35, 128.40,
128.82, 129.54, 130.01, 132.34, 136.29, 144.29, 154.26. IR (KBr): n ¼ 3334, 3221,
3086, 2933, 2362, 1682, 1483, 1286, 769, 731 cmꢁ1. MS (70 eV), m=z (%): 355 (25)
(Mþ), 353 (27), 340 (3), 327 (4), 312 (4), 199 (100), 181 (12), 115 (21), 89 (9), 76
(6). Anal. calcd. for C18H15BrN2O: C, 60.86; H, 4.26; N, 7.89%. Found: C, 60.48;
H, 4.22; N, 7.97%.
Entry 4, Table 1, 3d. Mp: 257–259ꢀC. 1H NMR (DMSO-d6, 500 MHz):
d ¼ 1.80 (m, 1H, CH2), 2.20 (m, 1H, CH2), 2.63 (m, 1H, CH2), 2.73 (m, 1H, CH2),
5.18 (d, J ¼ 1.9 Hz, 1H, CH), 7.17–7.22 (m, 3H, CH arom.), 7.36 (br s, 1H, NH),
7.61 (d, J ¼ 7.8 Hz, 1H, CH arom.), 7.69 (t, J ¼ 7.8 Hz, 1H, CH arom.), 7.81 (d,
J ¼ 7.8 Hz, 1H, CH arom.), 8.15–8.19 (m, 2H, CH arom.), 8.60 (s, 1H, NH). 13C
NMR (DMSO-d6, 125 MHz): d ¼ 24.12, 28.40, 59.05, 107.83, 122.27, 122.32,
123.49, 127.21, 128.40, 128.56, 129.30, 129.39, 131.19, 134.49, 136.35, 147.20,
148.82, 153.99. IR (KBr): n ¼ 3238, 3086, 2943, 2364, 1686, 1527, 1483, 1431,
1346, 1273, 773, 734 cmꢁ1. MS (70 eV), m=z (%): 321 (9) (Mþ), 292 (4), 274 (3),
246 (3), 230 (6), 217 (4), 199 (100), 181 (50), 154 (11), 140 (13), 127 (34), 115 (45),
89 (36), 76 (97). Anal. calcd. for C18H15N3O3: C, 67.28; H, 4.71; N, 13.08%: Found:
C, 66.28; H, 4.51; N, 12.72%.
Entry 5, Table 1, 3e. Mp: 249–251ꢀC. 1H NMR (DMSO-d6, 500 MHz):
d ¼ 2.85 (d, J ¼ 22.7 Hz, 1H, CH2), 3.33 (d, J ¼ 22.7 Hz, 1H, CH2), 5.69 (s, 1H,
CH), 7.18 (t, J ¼ 7.5 Hz, 1H, CH arom.), 7.28 (t, J ¼ 7.5 Hz, 1H, CH arom.), 7.35
(d, J ¼ 7.4 Hz, 1H, CH arom.), 7.38 (br s, 1H, NH), 7.65 (d, J ¼ 7.5 Hz, 1H, CH
arom), 7.69 (t, J ¼ 7.7 Hz, 1H, CH arom), 7.80 (d, J ¼ 7.7 Hz, 1H, CH arom),
8.14–8.16 (m, 2H, CH arom), 9.50 (s, 1H, NH). 13C NMR (DMSO-d6, 125 MHz):
d ¼ 35.38, 57.32, 111.89, 119.23, 121.79, 123.26, 124.85, 126.20, 127.11, 131.17,
134.04, 136.29, 138.06, 143.69, 147.40, 148.86, 154.12. IR (KBr): n ¼ 3255, 2872,
2362, 1686, 1527, 1465, 1431, 1344, 1269, 1095, 819, 767 cmꢁ1. MS (70 eV), m=z
(%): 307 (17) (Mþ), 278 (4), 260 (9), 248 (3), 231 (5), 217 (16), 185 (100), 167 (13),

TETRAHYDROQUINAZOLINONE DERIVATIVES
15
155 (22), 139 (21), 129 (30), 115 (50), 89 (22), 76 (94). Anal. calcd. for C17H13N3O3:
C, 66.44; H, 4.26; N, 13.67%. Found: C, 66.05; H, 4.16; N, 13.37%.
Entry 6, Table 1, 3f. Mp: 219–221ꢀC. 1H NMR (DMSO-d6, 500 MHz):
d ¼ 1.76 (m, 1H, CH2), 2.17 (m, 1H, CH2), 2.59 (m, 1H, CH2), 2.73 (m, 1H, CH2),
5.14 (s, 1H, CH), 7.15–7.23 (m, 3H, CH arom.), 7.43 (s, 1H, NH), 7.60–7.62 (m,
3H, CH arom.), 8.25 (d, J ¼ 8.7 Hz, 2H, CH arom.), 8.67 (s, 1H, NH). IR (KBr):
n ¼ 3404, 3334, 3242, 3107, 2927, 2360, 1670, 1598, 1517, 1467, 1344, 1269, 826,
812, 763, 731 cmꢁ1. MS (70 eV), m=z (%): 321 (31) (Mþ), 320 (12), 274 (14), 305
(3), 293 (4), 277 (5), 199 (100), 181 (18), 115 (33), 89 (9), 76 (6). Anal. calcd. for
C18H15N3O3: C, 67.28; H, 4.71; N, 13.08%. Found: C, 67.19; H, 4.55; N, 12.80%.
Entry 7, Table 1, 3g. Mp: 239–241ꢀC. 1H NMR (DMSO-d6, 500 MHz):
d ¼ 1.83 (m, 1H, CH2), 2.14 (m, 1H, CH2), 2.60 (m, 1H, CH2), 2.70 (m, 1H, CH2),
3.82 (s, 3H, CH3), 5.35 (d, J ¼ 1.8 Hz, 1H, CH), 6.83 (br s, 1H, NH), 6.96 (t,
J ¼ 7.9 Hz, 1H, CH arom.), 7.02 (d, J ¼ 7.8 Hz, 1H, CH arom.), 7.15–7.28 (m, 5H,
CH Arom.), 7.57 (d, J ¼ 7.9 Hz, 1H, CH arom.), 8.41 (br, s, 1H, NH). IR (KBr):
n ¼ 3236, 3101, 2924, 2889, 2833, 2360, 1642, 1593, 1475, 1026, 761 cmꢁ1. MS
(70 eV), m=z (%): 306 (45) (Mþ), 305 (35), 291 (4), 289 (10), 277 (4), 246 (11), 230
(9), 202 (3), 199 (100), 181 (4), 154 (4), 140 (6), 127 (14), 114 (15), 77 (27). Anal.
calcd. for C19H18N2O2: C, 74.49; H, 5.92; N, 9.14%. Found: C, 73.78; H, 5.83; N,
9.14%.
Entry 8, Table 1, 3h. Mp: 271–273ꢀC. 1H NMR (DMSO-d6, 500 MHz):
d ¼ 2.88 (d, J ¼ 22.9 Hz, 1H, CH2), 3.29 (d, J ¼ 22.3 Hz, 1H, CH2), 3.87 (s, 3H,
CH3), 5.79 (s, 1H, CH), 6.92 (br s, 1H, NH), 6.96 (t, J ¼ 7.2 Hz, 1H, CH arom.),
7.03 (d, J ¼ 8.1 Hz, 1H, CH arom), 7.15 (t, J ¼ 7.2 Hz, 1H, CH arom), 7.25 (m,
3H, CH arom), 7.34 (d, J ¼ 7.4 Hz, 1H, CH arom), 7.59 (d, J ¼ 7.4 Hz, 1H, CH
arom), 9.29 (s, 1H, NH).13C NMR (DMSO-d6, 125 MHz): d ¼ 35.78, 51.70, 56.35,
111.81, 112.91, 118.78, 121.58, 124.70, 125.82, 126.98, 127.71, 129.25, 133.19,
135.76, 138.36, 143.51, 154.77, 156.39. IR (KBr): n ¼ 3385, 3319, 3197, 3086, 2954,
2870, 2385, 1670, 1591, 1462, 1404, 1357, 1276, 1242, 1186, 1155, 1107, 1020, 833,
758, 719 cmꢁ1. MS (70 eV), m=z (%): 292 (75) (Mþ), 276 (15), 263 (11), 248 (4),
233 (25), 217 (15), 189 (6), 185 (100), 167 (60), 155 (13), 140 (16), 127 (18), 115
(36), 89 (11), 77 (32). Anal. calcd. for C18H16N2O2: C, 73.95; H, 5.52; N, 9.58%.
Found: C, 73.31; H, 5.51; N, 9.55%.
Entry 9, Table 1, 3 i, i0. 1H NMR (DMSO-d6, 500 MHz): d ¼ 2.81 (d,
0
J ¼ 22.6 Hz, 1Hi, CH2), 3.26 (d, J ¼ 23.1 Hz, 1Hi, CH2), 4.07 (s, 2Hi , CH2), 5.47
0
(s, 1Hi, CH), 7.16–7.79 (m, 8Hi, CH arom. & 5Hi , CH arom. & 1Hi, NH), 7.94
0
0
(d, J ¼ 7.6 Hz, 2Hi , CH arom.), 8.04 (d, J ¼ 7.3 Hz, 1Hi , CH arom.), 9.38 (s, 1Hi,
0
NH), 12.02 (s, 1Hi , NH). IR (KBr): n ¼ 3394, 3209, 3095, 2960, 2868, 2364, 1677,
1560, 1426, 1402, 1361, 829, 779, 746 cmꢁ1. MS (70 eV), m=z (%) 343 (16)
ðM þ 2Þþi , 341 (26) ðMþi Þ & ðM þ 2Þiþ0 , 339 (24) ðMiþ0 Þ, 185 (100), 155 (23), 115
(15), 89 (8), 77 (10).
Entry 10, Table 1, 3 j, j0. 1H NMR (DMSO-d6, 500 MHz): d ¼ 1.81 (m, 1Hj,
0
CH2), 2.13 (m, 1Hj, CH2), 2.58 (m, 1Hj, CH2), 2.71 (m, 1Hj, CH2 & 2Hj , CH2), 2.82
0
(m, 2Hj , CH2), 3.74 (s, 3Hj, OCH3), 3.83 (s, 3Hj , OCH3), 4.90 (s, 1Hj, CH),
0

16
M. MIRZA-AGHAYAN ET AL.
0
6.85–7.58 (m, 8Hj, CH arom. & 7Hj , CH arom. & 1Hj, NH), 8.18 (d, J ¼ 7.7 Hz,
0
0
1Hj , CH arom.), 8.51 (s, 1Hj, NH), 11.81 (br s, 1Hj , NH). IR (KBr): n ¼ 3226,
3084, 2933, 2831, 2364, 1640, 1637, 1583, 1485, 1429, 1369, 1246, 1145, 1041, 875,
769, 731 cmꢁ1. MS (70 eV): m=z (%) 306 (33) ðMþÞ, 304 (100) ðMjþ0 Þ, 289 (4), 260
j
(4), 245 (3), 217 (4), 199 (55), 181 (6), 167 (3), 152 (50), 140 (8), 114 (8), 77 (6).
Entry 11, Table 1, 3k, k0. 1H NMR (DMSO-d6, 500 MHz): d ¼ 1.17 (m, 1Hk,
CH2), 2.10 (m, 1Hk, CH2), 2.28 (s, 3Hk, CH3), 2.39 (s, 3Hk’, CH3), 2.57 (m, 1Hk,
0
CH2), 2.70 (m, 1Hk, CH2 & 2Hk , CH2), 2.80 (m, 2Hk , CH2), 4.88 (s, 1Hk, CH),
0
0
0
7.13–7.58 (m, 15Hk, k , CH Arom. & 1Hk, NH), 8.18 (d, J ¼ 7.6 Hz, 1Hk or k , CH
0
arom.), 8.50 (s, 1Hk, NH), 11.81 (br s, 1Hk , NH). IR (KBr): n ¼ 3454, 3221, 2906,
2362, 1630, 1506, 1463, 1425, 1373, 827, 769 cmꢁ1. MS (70 eV): m=z (%) 290 (8)
ðMþk Þ, 289 (36), 287 (100), 274 (3), 273 (6), 199 (27), 114 (15), 89 (14), 77 (5).
Entry 12, Table 1, 3 l0. Mp: >355ꢀC. 1H NMR (DMSO-d6, 500 MHz):
d ¼ 2.67 (m, 2H, CH2), 2.82 (m, 2H, CH2), 6.92–6.94 (m, 2H, CH arom.), 6.96 (d,
J ¼ 7.5 Hz, 1H, CH arom.), 7.31–7.34 (m, 2H, CH arom.), 7.40 (t, J ¼ 7.4 Hz, 1H,
CH arom.), 7.48 (t, J ¼ 7.3 Hz, 1H, CH arom.), 8.19 (d, J ¼ 7.6 Hz, 1H, CH arom.),
9.70 (s, 1H, OH), 11.76 (br s, 1H, NH).13C NMR (DMSO-d6, 125 MHz): d ¼ 22.81,
27.37, 115.45, 116.81, 119.26, 125.82, 126.85, 128.00, 129.46, 131.50, 140.31, 157.18.
IR (KBr): n ¼ 3277, 3190, 3124, 2927, 2837, 2368, 1634, 1573, 1477, 1431, 1379, 1338,
1321, 1240, 1203, 769, 731 cmꢁ1. MS (70 eV), m=z (%): 290 (56) (Mþ), 289 (100), 273
(4), 271 (7), 261 (5), 246 (6), 199 (4), 114 (10), 93 (6), 88 (5), 76 (4). Anal. calcd. for
C18H14N2O2: C, 74.47; H, 4.86; N, 9.65%. Found: C, 72.44; H, 4.89; N, 9.32%.
Entry 13, Table 1, 3 m0. Mp: >355ꢀC. 1H NMR (DMSO-d6, 500 MHz):
d ¼ 4.02 (s, 2H, CH2), 6.98 (m, 1H, CH arom.), 7.33 (m, 1H, CH arom.),
7.37–7.38 (m, 2H, CH arom.), 7.52 (t, J ¼ 7.4 Hz, 1H, CH arom.), 7.61 (t, J ¼ 7.4 Hz,
Hz, 1H, CH arom.), 7.68 (d, J ¼ 7.5 Hz, 1H, CH arom.), 8.01 (d, J ¼ 7.3 Hz, 1H, CH
arom.), 9.76 (s, 1H, OH), 11.88 (br s, 1H, NH). IR (KBr): n ¼ 3037, 3022, 2929, 2852,
2362, 1640, 1610, 1560, 1483, 1373, 1344, 1292, 1224, 1147, 779, 732 cmꢁ1. MS
(70 eV), m=z (%): 276 (45) (Mþ), 259 (4), 247 (8), 231 (6), 203 (7), 185 (100), 115
(18), 89 (10), 77 (15).
1
Entry 14, Table 1, 3n0. Mp: 298–300ꢀC. H NMR (DMSO-d6, 500 MHz):
d ¼ 3.38 (d, J ¼ 21.4 Hz, 1H, CH2), 3.50 (d, J ¼ 21.0 Hz, 1H, CH2), 7.33 (d,
J ¼ 8.9 Hz, 1H, CH arom.), 7.37 (m, 1H, CH arom.), 7.46 (m, 2H, CH arom.),
7.56 (m, 3H, CH arom.), 7.91 (d, J ¼ 8.1 Hz, 1H, CH arom.), 8.00 (m, 2H, CH
arom.), 10.36 (br s, 1H, OH), 11.80 (br s, 1H, NH). IR (KBr): n ¼ 2931, 2366,
1638, 1544, 1510, 1473, 1435, 1373, 1280, 785, 746 cmꢁ1. MS (70 eV), m=z (%): 326
(84) (Mþ), 325 (100), 309 (7), 295 (5), 282 (49), 267 (4), 254 (12), 226 (7), 214 (2),
184 (2), 163 (10), 140 (14), 127 (25), 113 (32), 77 (7). Anal. calcd. for C21H14N2O2:
C, 77.29; H, 4.32; N, 8.58%. Found: C, 79.36; H, 4.35; N, 8.23%.
1
Entry 15, Table 1, 3o0. Mp: 291–293ꢀC. H NMR (DMSO-d6, 500 MHz):
d ¼ 3.87 (s, 3H, OCH3), 4.05 (s, 2H, CH2), 7.15 (d, J ¼ 8.0 Hz, 1H, CH arom.),
7.48–7.54 (m, 4H, CH arom.), 7.61 (t, J ¼ 7.4 Hz, 1H, CH arom.), 7.68 (d, J ¼ 7.5 Hz,
Hz, 1H, CH arom.), 8.01 (d, J ¼ 7.6 Hz, 1H, CH arom.), 11.93 (br s, 1H, NH). 13C
NMR (DMSO-d6, 125 MHz): d ¼ 33.92, 56.23, 114.37, 117.73, 121.69, 123.26,

TETRAHYDROQUINAZOLINONE DERIVATIVES
17
126.62, 128.39, 130.77, 132.67, 147.23, 160.23. IR (KBr): n ¼ 3010, 2927, 2843, 2366,
1636, 1485 1373, 1240, 785, 734 cmꢁ1. MS (70 eV), m=z (%): 290 (100) (Mþ), 275 (4),
260 (17), 246 (10), 231 (18), 219 (14), 203 (15), 190 (7), 176 (12), 140 (10), 134 (40),
129 (17), 101 (18), 91 (14), 77 (16). Anal. Calcd. for C18H14N2O2: C, 74.47; H, 4.86;
N, 9.65%. Found: C, 73.58; H, 4.84; N, 9.45%.
1
Entry 16, Table 1, 3p0. Mp: 286–288ꢀC. H NMR (DMSO-d6, 500 MHz):
d ¼ 2.41 (s, 3H, CH3), 4.05 (s, 2H, CH2), 7.39 (d, J ¼ 8.2 Hz, 2H, CH arom.),
7.52 (t, J ¼ 7.4 Hz, 1H, CH arom.), 7.61 (t, J ¼ 7.4 Hz, 1H, CH arom.), 7.68 (d,
J ¼ 7.5 Hz, 1H, CH arom.), 7.85 (d, J ¼ 7.3 Hz, 2H, CH arom.), 8.00 (d, J ¼ 7.3 Hz,
Hz, 1H, CH arom.), 11.94 (br s, 1H, NH). IR (KBr): n ¼ 3412, 3128, 2918, 2854,
2374, 1640, 1612, 1560, 1512, 1469, 1371, 819, 783, 732 cmꢁ1. MS (70 eV), m=z
(%): 274 (100) (Mþ), 259 (5), 245 (12), 231 (20), 202 (6), 156 (30), 118 (90), 89
(34), 77 (17). Anal. calcd. for C18H14N2O: C, 78.81; H, 5.14; N, 10.21%. Found:
C, 77.24; H, 5.38; N, 10.06%.
Typical Procedure for 5-Unsubstituted Pyrimidin-2(1H)-one
Derivatives (6a0–e0)
CuCl2 (10 mol %), TMSCl (2 mmol), and acetophenone or 4-methoxy aceto-
phenone (2 mmol) were added to a solution of aldehyde 4 (2 mmol) and urea
(3 mmol) in CH3CN (10 mL). The reaction mixture was heated at reflux of solvent
for 8 h. After completion of the reaction, the mixture was poured into crushed
ice, and after stirring, it directly filtered through a sintered funnel and washed with
ethylacetate.
Entry 1, Table 2, 6a0. Mp: 255–257ꢀC.1H NMR (DMSO-d6, 500 MHz):
d ¼ 3.86 (s, 3H, OCH3), 7.10 (d, J ¼ 8.7 Hz, 2H, CH arom.), 7.49 (br s, 1H, CH),
7.54–7.59 (m, 3H, CH arom.), 8.14 (d, J ¼ 7.0 Hz, 2H, CH arom.), 8.17 (d,
J ¼ 8.6 Hz, 2H, CH arom.), 11.92 (br s, 1H, NH).13C NMR (DMSO-d6,
125 MHz): d ¼ 56.29, 100.02, 114.47, 115.05, 127.64, 128.39, 129.19, 129.64,
130.25, 132.22, 133.65, 135.49, 158.93, 160.40, 162.95. IR (KBr): n ¼ 2926, 2360,
1610, 1508, 1456, 1425, 1394, 1301, 1255, 1176, 1026, 821, 775, 696, 586 cmꢁ1
.
MS, m=z (%): 278 (61) (Mþ), 277 (100), 263 (7), 234 (13), 220 (2), 193 (4), 179 (6),
158 (3), 136 (15), 89 (8), 77 (18). Anal. calcd. for C17H14N2O2: C, 73.37; H, 5.07;
N, 10.07%. Found: C, 72.09; H, 5.05; N, 9.92%.
Entry 2, Table 2, 6b0. Mp: 303–305ꢀC. 1H NMR (DMSO-d6, 500 MHz):
d ¼ 2.40 (s, 3H, CH3), 7.37 (d, J ¼ 8.0 Hz, 2H, CH arom.), 7.54–7.61 (m, 3H, CH
arom.& 1H, CH), 8.08 (d, J ¼ 7.8 Hz, 2H, CH arom.), 8.16 (d, J ¼ 6.9 Hz, 2H, CH
arom.), 11.98 (br s, 1H, NH). IR (KBr): n ¼ 2900, 1620, 1508, 1456, 1419, 1336,
1246, 1180, 989, 808, 773, 592 cmꢁ1. MS (70 eV), m=z (%): 262 (19) (Mþ), 261
(57), 247 (18), 233 (9), 217 (6), 204 (17), 190 (5), 165 (6), 141 (23), 128 (29), 115
(43), 102 (43), 91(25), 89 (65), 77 (100). Anal. calcd. for C17H14N2O: C, 77.84; H,
5.38; N, 10.68%. Found: C, 77.17; H, 5.37; N, 10.90%.
Entry 3, Table 2, 6c0. Mp: 264–266ꢀC. 1H NMR (DMSO-d6, 500 MHz):
d ¼ 3.86 (s, 3H, OCH3), 7.10 (d, J ¼ 8.7 Hz, 2H, CH arom.), 7.49 (br s, 1H, CH),
7.54–7.60 (m, 3H, CH arom.), 8.14 (d, J ¼ 7.0 Hz, 2H, CH arom.), 8.17 (d,

18
M. MIRZA-AGHAYAN ET AL.
J ¼ 8.6 Hz, 2H, CH arom.), 11.92 (br s, 1H, NH).13C NMR (DMSO-d6, 125 MHz): d
¼55.38, 99.16, 114.14, 126.23, 126.76, 127.43, 128.70, 129.29, 131.26, 135.30, 159.54,
162.02, 163.20. IR (KBr): n ¼ 2926, 2358, 1610, 1510, 1456, 1425, 1394, 1338, 1255,
1176, 1028, 823, 775 cmꢁ1. MS (70 eV), m=z (%): 278 (61) (Mþ), 277 (100), 263 (7),
234 (13), 136 (15), 89 (8), 77 (18). Anal. calcd. for C17H14N2O2: C, 73.37; H, 5.07; N,
10.07%. Found: C, 72.27; H, 5.01; N, 9.93%.
Entry 4, Table 2, 6d0. Mp: 320–322ꢀC. 1H NMR (DMSO-d6, 500 MHz):
d ¼ 3.86 (s, 6H, OCH3), 7.09 (d, J ¼ 8.4 Hz, 4H, CH arom.), 7.41 (br s, 1H, CH),
8.14 (d, J ¼ 7.1 Hz, 4H, CH arom.), 11.80 (br s, 1H, NH).13C NMR (DMSO-d6,
125 MHz): d ¼ 55.43, 114.18, 128.35, 129.22, 161.95. IR (KBr): n ¼ 2904, 2835,
1610, 1508, 1438, 1394, 1338, 1303, 1250, 1176, 817, 570 cmꢁ1. MS (70 eV) m=z
(%): 308 (53) (Mþ), 307 (100), 293 (8), 292 (10), 277 (4), 262 (2), 89 (13), 69 (64).
Anal. calcd. for C18H16N2O3: C, 70.12; H, 5.23; N, 9.09%. Found: C, 68.74; H,
5.14; N, 8.80%.
Entry 5, Table 2, 6e0. Mp: 313–315ꢀC. 1H NMR (DMSO-d6, 500 MHz):
d ¼ 2.40 (s, 3H, CH3), 3.86 (s, 3H, OCH3), 7.09 (d, J ¼ 8.9 Hz, 2H, CH arom.),
7.36 (d, J ¼ 8.1 Hz, 2H, CH arom.), 7.45 (br s, 1H, CH), 8.05 (d, J ¼ 7.0 Hz, 2H,
CH arom.), 8.16 (d, J ¼ 8.2 Hz, 2H, CH arom.), 11.86 (br s, 1H. NH). IR (KBr):
n ¼ 2912, 2360, 1610, 1510, 1444, 1396, 1338, 1305, 1251, 1178, 808 cmꢁ1. MS
(70 eV), m=z (%): 291 (100) (Mþ), 276 (13), 261 (4), 248 (28), 146 (18), 89 (22), 77
(6). Anal. calcd. for C18H16N2O2: C, 73.95; H, 5.52; N, 9.58%. Found: C, 73.85;
H, 5.62; N, 9.56%.
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