Convenient synthesis of some 2-substituted 4(3H)-quinazolinone derivatives

Article abstract of DOI:10.1002/jhet.5570430436

A series of 2-substituted-4(3H)-quinazolinones 13-20 has been synthesized in good yields using the reaction of double lithiated 2-methylquinazolinone-4 with a variety of aromatic aldehydes. They have been easily transformed in high yields into the corresp

Full text of DOI:10.1002/jhet.5570430436

Jul-Aug 2006
Convenient Synthesis of Some
1057
2-Substituted 4(3H)-Quinazolinone Derivatives
I. Philipova*, G. Dobrikov, K. Krumova, J. Kaneti.
Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences,
Acad. G. Bonchev str., Block 9, 1113 Sofia, Bulgaria, e-mail: irena@orgchm.bas.bg
Received November 16, 2005
O
N
O
O
1. LDA
F3CCOOH
CH3OH
NH
NH OH
NH
2. RCHO
N
R
N
R
13-20
21-28
A series of 2-substituted-4(3H)-quinazolinones 13-20 has been synthesized in good yields using the
reaction of double lithiated 2-methylquinazolinone-4 with a variety of aromatic aldehydes. They have been
easily transformed in high yields into the corresponding 2-substituted conjugated derivatives 21-28 bearing
terminal aryl groups by F3CCOOH mediated dehydration.
J. Heterocyclic Chem., 43, 1057 (2006).
Introduction.
prepared since 1910 [24] and are active against certain
types of cancer [4]. Pyridylvinyl-4(3H)-quinazolinones 8
showed anticonvulsant, hypnotic, tranquilizing and muscle
relaxant activity. Their preparation occurs in two steps –
condensation of 2-methyl-3,1-benzoxazin-4-one with 3-
pyridine carboxaldehyde, followed by reaction with o-
toluidine [26]. The atropisomers, 2-(2-heteroarylvinyl)-3-
aryl-6-fluoro-4(3H)-quinazolinone 9, known as AMPA
(ꢀ-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)
receptor antagonists [9], have been prepared using
different synthetic procedures [27-31]. 2,6-Disubstituted
4(3H)-quinazolinones 10 are known as transmembrane
receptor antagonists and their activity has been subjected
to extensive molecular modeling [32]. Recent modeling
and Quantitative Structure-Activity Relationships (QSAR)
studies include quinazolinone inhibitors of poly(ADP-
ribose) polymerase [33,34], indicating that quinazolinone
drug design is rapidly approaching pre-clinical stage.
4(3H)-Quinazolinones 1 are known for more than a
century [1]. Molecules based on quinazoline and quinazo-
linone exhibit a multitude of interesting pharmacological
activities [2], including anticonvulsant, antibacterial and
antidiabetic activity [3,4]. The important natural and
synthetic 4(3H)-quinazolinones include l-vasicinone 2 [5],
chrysogine 3 [6], methaquinalon 4 [7] – a sedative,
piriqualone 5 [8,9] – an anticonvulsant, although the latter
type of activity does not seem confined to pyridine
derivatives of 4(3H)-quinazolinone [10]. Febrifugine 6
and isofebrifugine 7 were known as potent but toxic
antimalarial agents long before their initial isolation [11]
and recent chemical studies [12-15].
O
O
O
O
R3
R2
N
NH
N
N
R
OH
N
N
N
N
OH
1
2
3
4
Cl
O
O
F
O
N
N
O
N
H
O
N
H
N
N
N
N
N
N
N
N
N
O
O
HO
N
N
N
HO
8
9
5
6
7
N
HN
HN
The most common synthetic approach to 2-substituted
3H-quinazolin-4-ones is based on acylation of anthranilic
acid (or derivatives, e.g. 2-aminobenzonitrile) followed by
cyclization and usually proceeds via an o-amidobenzamide
intermediate [16-20]. Although there are numerous
methods for the construction of the quinazolinone skeleton
[21], only a few procedures for the synthesis of 2-vinyl
derivatives of 3H-quinazolin-4-ones have been reported
[22-24]. Several 2-styrylquinazolin-4(3H)-ones have been
HN CH2CH=CH
N
O
n
X =
X
Y
NH
HN
COOH
N
HN CH2
n
H
10
R
R
SO2
CO
Y =

1058
I. Philipova, G. Dobrikov, K. Krumova, J. Kaneti
Vol 43
reagent 12, with no nucleophilic attack of LDA at either
the carbonyl group or the imine group of the
quinazolinone ring. The addition of LDA yielded a deep
red solution, presumably due to formation of the anion of
12. The mixture was allowed to stir at -78 °C for 1 h to
ensure complete reaction.
Derivatives of quinazoline and quinazolin-4-one are
among the relatively less known dyes and pigments [35]
and apparently no interest has been shown in their
potential application in the nonlinear optics. As a part of
our search program for suitable quinazolinone derivatives
with promising classical and nonlinear optical properties
like fluorescence and high (hyper) polarizabilities, we
synthesized a series of 2-substituted 4(3H)-quinazoli-
nones, experimentally registered their fluorescence
spectra, and calculated theoretically the corresponding
electrooptical properties [36].
The reaction of the anion 12 with a range of electrophiles,
such as 4-methoxybenzaldehyde, 4-(dimethylamino)benz-
aldehyde, (E)-3-(4'-dimethylaminophenyl)acrylaldehyde, 3-
pyridinecarboxldehyde, 4-pyridinecarboxaldehyde, biphenyl-
4-carbaldehyde, 2-naphthaldehyde, 1-naphthaldehyde,
Table 1
Preparation of alcohols 13-20 according to Scheme 1.
Aldehyde RCHO,
Yield,
%
Entry
1
Product
R =
3"
2"
1"
OCH3
13
14
15
58
56
50
4"
6"
5"
N(CH3)2
2
3
2"
3"
1"
4'
N(CH3)2
4"
6" 5"
1"
3'
4
16
55
N
3"
1"
4"
N
5
6
7
17
18
19
64
81
73
8
20
72
In the present paper we describe a convenient route for
the preparation of several 2-substituted 4(3H)-quinazo-
linones from 2-methyl-4(3H)-quinazolin-4-one, as
mentioned earlier [36].
resulted in the formation of the corresponding 2-substituted-
4(3H)-quinazolinones 13–20 (Scheme 1) in good yields
within 2 h reaction time (Table 1).
Scheme 1
Results and Discussion.
OLi
O
O
Previously it has been shown that double lithiation of 3-
unsubstituted 2-alkyl-4(3H)-quinazolinone is an useful
method for side chain modification providing access to a
broad variety of 2-substituted derivatives [37,38]. A series
of 2-(2-hydroxy-2-arylethyl)-4-(3H)-quinazolinones (13–
20) has been synthesized starting from 2-methyl-4(3H)-
quinazolinone 11 (Scheme 1). As a lithiation agent LDA
was chosen. Lithiation of 11 was achieved with 3
equivalents of LDA in THF at -78 °C to give a dilithio
LDA
N
RCHO
-78°C
NH
CH3
NH OH
2'
THF
-78°C, 1h
CH2Li
N
N
N
R
1'
11
12
13 - 20
O
N
CF3COOH
NH
2'
MeOH
-H2O
R
1'
21 - 28

Jul-Aug 2006
Convenient synthesis of some 2-substituted 4(3H)-quinazolinone derivatives
1059
In all cases the obtained secondary alcohols were
isolated in pure form by recrystallization from methanol.
The structures of the compounds were confirmed by 1D
and 2D NMR spectra and mass spectra as well as by
elemental analysis. The synthesis of compound 13 by
reaction of 2-methyl-4(3H)-quinazolinone 11 with p-
methoxybenzaldehyde was reported previously but no
NMR data were presented for this compound [37].
With the aim to obtain interesting quinazolinone
derivatives with promising classical and nonlinear optical
properties, a practical procedure has been optimized for
the preparation of a series of 2-arylethylene and 2-aryl-
butadienyl substituted 4-(3H)-quinazolinones [36].
some of the obtained products as a solvent for recording
of NMR spectra a combination of CDCl3 / CD3OD/
CF3COOD has been used. The dehydration of the
secondary alcohols 13–20 in all cases led to the formation
of the trans-isomers only. Preparation of compounds 21
and 22 has been reported recently by reaction of 2-
methylquinazolinone-4 with the corresponding aromatic
aldehydes in the presence of sodium acetate in acetic acid
[24] but no NMR data for these products have been
presented.
Conclusions.
We have demonstrated a practical method for the
preparation of 2-substituted-4(3H)-quinazolinones (13–
20), which can easily be transformed into 2-substituted
conjugated derivatives (21–28) bearing terminal aryl
groups. These compounds, 13-20, as well as 21-28, may
possess biological activity, while the latter group indicates
promising applications in nonlinear optics [36].
The dehydration of the secondary alcohols 13–20 was
carried out in methanol under reflux using trifluoroacetic
acid as a dehydration agent (Scheme 1). The corre-
sponding 2-substituted aminoquinazolinone derivatives
21–28 were formed in high yields (Table 2). The reactions
were relatively slow in the case of alcohols 13, 16-20 (3h
- 16h), whereas the dehydration of alcohols 14 and 15
Table 2
Preparation of compounds 21-28 according to Scheme 1.
Starting
alcohol
Reaction
time
Entry
1
R
Product
Yield, %
95
3"
2"
6"
1"
OCH3
13
14
15
21
3 h
4"
5"
N(CH3)2
2
3
22
23
15 min
15 min
92
94
2"
3"
1"
4'
N(CH3)2
4"
6" 5"
1"
3'
4
16
24
16 h
75
N
3"
1"
4"
N
5
6
7
17
18
19
25
26
27
16 h
16 h
6 h
72
96
88
8
20
28
6 h
87
Acknowledgement.
(entries 2, 3) was completed within 15 min, as monitored
by TLC. In all cases the corresponding 2-substituted 4-
(3H)-quinazolinones have been isolated in pure form and
their structures were identified by spectroscopic methods
and elemental analysis. Because of the low solubility of
We wish to thank D.Sc. S. Simova and Dr. N. Vassilev
from the Laboratory of Nuclear Magnetic Resonance for
their assistance and helpful discussion.

1060
I. Philipova, G. Dobrikov, K. Krumova, J. Kaneti
Vol 43
EXPERIMENTAL
2-(2-(4-(Dimethylamino)phenyl)-2-hydroxyethyl)quinazolin-
4(3H)-one (14).
The reactions with organolithiums were carried out in
Schlenk flasks under an argon atmosphere. THF was distilled
over Na/benzophenone. Thin layer chromatography (TLC):
aluminum sheets pre-coated with silica gel 60 F254 (Merck).
Melting points of the compounds were determined using
"Electrothermal" MEL-TEMP apparatus (uncorrected). The
NMR spectra were recorded at ambient temperature (300 K)
in DMSO-d6 solutions, unless otherwise stated, on a Bruker
Avance DRX-250 spectrometer, operating at 250.13 and
62.90 MHz for 1H NMR and 13C NMR respectively, with
TMS as internal standard for chemical shifts (ꢀ, ppm). Mass
spectra (MS) were recorded on a Hewlett-Packard 5973A
spectrometer at 70 eV EI and are reported as fragmentation
in m/z with relative intensities (%) in parentheses. Elemental
analyses were performed by the Microanalytical service
Laboratory of the Institute of Organic Chemistry, Bulgarian
Academy of Science.
The compound was obtained as pale yellow crystals, m.p.
285-287°C; H-NMR: ꢀ 2.85-2.89 (m, 2H, 1'-H), 2.85 (s, 6H,
1
(CH3)2N), 5.07 (t, 1H, 2'-H, J = 7.5 Hz), 6.69 (d, 2H, 2"-H, 6"-H,
J = 8.8 Hz), 7.23 (d, 2H, 3"-H, 5"-H, J = 8.8 Hz), 7.42-7.49 (m,
1H, 6-H), 7.62 (d, 1H, 8-H, J = 7.8 Hz), 7.74-7.81 (m, 1H, 7-H),
8.08 (dd, 1H, 5-H, J = 1.5, 7.8 Hz); 13C-NMR: ꢀ 40.3 (q,
(CH3)2N), 44.9 (t, 1'-C), 70.6 (d, 2'-C), 112.2 (d, 3"-C, 5"-C),
120.9 (s, 4a-C), 125.7 (d, 8-C), 125.9 (d, 5-C), 126.5 (d, 2"-C,
6"-C), 126.7 (d, 6-C), 132.6 (s, 1"-C), 134.3 (d, 7-C), 148.9 (s,
8a-C), 149.7 (s, (2-C), 155.7 (s, 4"-C), 161.8 (s, 4-C); ms: m/z
309 (M+, 4), 291 (M+-H2O, 100), 276 (26), 262 (19), 160 (M+-
(CH3)2NC6H5CHO, 69), 148 (64), 120 (18), 92 (14), 77 (16).
Anal. Calcd. for C18H19N3O2 (309.36): C 69.88, H 6.19, N
13.58. Found: C 69.55, H 6.38, N 13.28.
2-(4-(4-(Dimethylamino)phenyl)-2-hydroxybut-3-enyl)quinazolin-
4(3H)-one (15).
The following commercially available starting materials
The compound was obtained as a pale yellow crystals, m.p.
172 °C; 1H-NMR: ꢀ 2.79-2.87 (m, 8H, N(CH3)2, 1'-H), 4.67 (dd,
1H, 2'-H, J = 6.4, 12.72 Hz), 6.36 (dd, 1H, 3'-H, J = 6.4, 15.9
Hz), 6.43 (d, 1H, 4'-H, J = 15.7 Hz), 6.64 (d, 2H, 2"-H, 6"-H, J =
8.8 Hz), 7.21 (d, 2H, 3"-H, 5"-H, J = 8.8 Hz), 7.41-7.47 (m, 1H,
6-H), 7.60 (d, 1H, 8-H, J = 8.3 Hz), 7.76 (ddd, 1H, 7-H, J = 1.5,
7.1, 8.1 Hz), 8.07 (dd, 1H, 5-H, J = 1.2, 7.8 Hz); 13C-NMR: ꢀ
40.2 (q, N(CH3)2), 43.3 (t, 1'-C), 70.3 (d, 2'-C), 112.5 (d, 3"-C,
5"-C), 121.1 (s, 4a-C), 124.8 (s, 1"-C), 125.9 (d, 8-C), 126.3 (d,
3'-C), 126.9 (d, 5-C), 127.5 (d, 2"-C, 6"-C), 127.9 (d, 6-C),
129.5 (d, 4'-C), 134.6 (d, 7-C), 149.1 (s, 8a-H), 150.2 (s, 4"-C),
155.8 (s, 2-C), 162.1 (s, 4-C); ms: m/z 335 (M+, 6), 317 (M+-
H2O, 100), 197 (68), 171 (24), 146 (6), 134 (60), 121 (16), 90
(6), 77 (6).
were
used:
2-Methyl-4(3H)-quinazolinone
hydrate
(Aldrich), LDA 2M solution in THF/heptane/ethyl benzene
(Fluka), 4-methoxybenzaldehyde (Aldrich), 4-(dimethyl-
amino)benzaldehyde (Aldrich), (E)-3-(4'-dimethylamino-
phenyl)acrylaldehyde
(Merck),
3-pyridinecarbaldehyde
(Aldrich), 4-pyridinecarbaldehyde (Aldrich), biphenyl-4-
carbaldehyde (Aldrich), 2-naphthaldehyde (Aldrich), 1-
naphthaldehyde (Aldrich).
General Procedure for the Synthesis of 2-Substituted 4(3H)-
Quinazolinone Derivatives 13-20.
A 2 M solution of LDA (3.75 ml, 7.5 mmol) was added
dropwise to a stirred solution of 11 (2.5 mmol) in anhydrous
THF (25 ml) at -78 °C under argon atmosphere. Formation of
the dianion was observed as a very deep red solution. The
mixture was stirred at -78 °C for 1 h, after which an aldehyde
(2.5 mmol) was added. The mixture was stirred for 2 h, then
removed from the cooling bath and allowed to warm to room
temperature and neutralized with aqueous saturated ammonium
chloride solution and then with dilute HCl (2 M solution) till pH
6.5 – 7.0. The obtained precipitated solid was collected by
filtration and recrystallized from methanol.
Anal. Calcd. for C20H21N3O2 (335.40): C 71.62, H 6.31, N
12.53. Found: C 71.36, H 6.45, N 12.46.
2-(2-Hydroxy-2-(pyridin-3-yl)ethyl)quinazolin-4(3H)-one (16).
The compound was obtained as colorless crystals, m.p. 185-
186 °C; 1H-NMR: ꢀ 2.89-3.04 (m, 2H, 1'-H), 5.24 (dd, 1H, 2'-H,
J = 6.12, 7.83 Hz), 5.74 (s, br., OH), 7.37 (dd, 1H, 3"-H, J = 4.6,
7.8 Hz), 7.43-7.50 (m, 1H, 6-H), 7.62 (d, 1H, 8-H, J = 7.8 Hz),
7.75-7.83 (m, 2H, 7-H, 4"-H), 8.08 (dd, 1H, 5-H, J = 1.5, 7.8
Hz), 8.46 (dd, 1H, 2"-H, J = 1.7, 4.6 Hz), 8.60 (d, 1H, 6"-H, J =
2.0 Hz), 12.19 (s, 1H, -NH); 13C-NMR: ꢀ 44.5 (t, 1'-C), 68.9 (d,
2'-C), 123.5 (d, 4"-C), 125.8 (d, 8-C), 126.2 (d, 5-C), 126.9 (d,
6-C), 133.7 (d, 3"-C), 134.5 (d, 7-C), 140.1 (s, 5"-C), 147.7 (d,
2"-C), 148.5 (d, 6"-C), 148.9 (s, 8a-C), 155.0 (s, 2-C), 161.9 (s,
4-C); ms: m/z 267 (M+, 31), 248 (38), 160 (M+-C5H3NCHO,
100), 145 (6), 132 (14), 120 (16), 108 (24), 92 (14), 77 (17).
Anal. Calcd. for C15H13N3O2 (267.28): C 67.40, H 4.90, N
15.72. Found: C 67.94, H 5.20, N 15.42.
2-(2-Hydroxy-2-(4-methoxyphenyl)ethyl)quinazolin-4(3H)-one
(13).
The compound was obtained as a colorless crystals, m.p. 180-
181 °C (lit., [37] 177.5-179°C); 1H-NMR: ꢀ 2.89 (d, 2H, 1'-H, J
= 6.6 Hz), 3.72 (s, 3H, H3CO), 5.13 (dd, 1H, 2'-H, J = 6.6, 7.09
Hz), 6.89 (d, 2H, 3"-H, 5"-H, J = 8.8 Hz), 7.34 (d, 2H, 2"-H, 6"-
H, J = 8.6 Hz), 7.43-7.49 (m, 1H, 6-H), 7.62 (d, 1H, 8-H, J = 7.6
Hz), 7.74-7.81 (m, 1H, 7-H), 8.08 (dd, 1H, 5-H, J = 0.9, 7.8 Hz),
12.17 (s, 1H, NH); 13C-NMR: ꢀ 44.9 (t, 1'-C), 55.0 (q, CH3O),
70.4 (d, 2'-C), 113.5 (s, 3"-C, 5"-C), 120.9 (s, 4a-C), 125.7 (d, 8-
C), 125.9 (d, 5-C), 126.8 (d, 6-C), 126.9 (d, 2"-C, 6"-C), 134.3
(d, 7-C), 137.0 (s, 1"-C), 148.9 (s, 8a-C), 155.5 (s, 2-C), 158.3
(s, 4"-C), 161.8 (s, 4-C); ms: m/z 296 (M+, 4), 160 (M+-
CH3OC6H5CHO, 100), 145 (12), 135 (82), 119 (17), 107 (14), 92
(26), 77 (27).
2-(2-Hydroxy-2-(pyridin-4-yl)ethyl)quinazolin-4(3H)-one (17).
The compound was obtained as colorless crystals, m.p. 215-
217 °C; 1H-NMR: ꢀ 2.84 (dd, 1H, 2'-Hb, J = 9.5, 13.9 Hz), 3.00
(dd, 1H, 2'-Ha, J = 4.2, 13.9 Hz), 2.89-3.04 (m, 2H, 1'-H), 5.19–
5.22 (m, 1H, 2'-H), 5.82 (s, br., OH), 7.42 (d, 2H, 3"-H, 5"-H, J
= 5.6 Hz), 7.44–7.50 (m, 1H, 6-H), 7.62 (d, 1H, 8-H, J = 8.1
Hz), 7.79 (ddd, 1H, 7-H, J = 1.2, 7.3, 8.1 Hz), 8.09 (d, 1H, 5-H,
J = 7.1 Hz), 8.53 (d, 2H, 2"-H, 6"-H, J = 5.6 Hz), 12.24 (s, 1H,
Anal. Calcd. for C17H16N2O3 (296.32): C 68.91, H 5.44, N
9.45. Found: C 68.67, H 5.46, N 9.34.

Jul-Aug 2006
Convenient synthesis of some 2-substituted 4(3H)-quinazolinone derivatives
1061
-NH); 13C-NMR: ꢀ 44.0 (t, 1'-C), 69.4 (d, 2'-C), 120.8 (d, 3"-C,
5"-C), 125.6 (d, 8-C), 126.0 (d, 5-C), 126.7 (d, 6-C), 134.3 (d, 7-
C), 148.7 (s, 4"-C), 149.4 (d, 6"-C, 2"-C), 153.4 (s, 8a-C), 154.7
(s, 2-C), 161.7 (s, 4-C); ms: m/z 267 (M+, 38), 249 (50), 248
(45), 221 (8), 161 (19), 160 (100), 145 (10), 132 (14), 120 (20),
119 (25), 118 (15), 117 (10), 108 (12), 107 (31), 106 (13), 92
(19), 90 (19), 80 (13), 78 (18), 64 (10), 63 (11), 52 (11), 51 (19),
50 (13).
123.3 (s, 1 arom. C), 123.6 (d, 1 arom. C), 125.6 (d, 1 arom. C),
125.7 (d, 1 arom. C), 125.8 (d, 2 arom. C), 126.1 (d, 1 arom. C),
127.0 (d, 1 arom. C), 127.8 (d, 1 arom. C), 128.8 (d, 1 arom. C),
130.0 (s, 1 arom. C), 133.4 (s, 1 arom. C), 134.4 (d, 1 arom. C),
140.7 (s, 1 arom.C), 149.0 (s, 8a-C), 155.8 (s, 2-C), 162.0 (s, 4-
C); ms: m/z 316 (M+, 25), 297 (13), 161 (19), 160 (100), 157
(15), 156 (57), 155 (38), 145 (10), 132 (10), 129 (24), 128 (62),
127 (55), 126 (16), 120 (13), 119 (16), 118 (15), 102 (9), 92
(16), 90 (15), 77 (15), 76 (10), 75 (11), 64 (10), 63 (14), 51 (8),
50 (8).
Anal. Calcd. for C15H13N3O2 (267.28): C 67.40, H 4.90, N
15.72. Found: C 67.15, H 4.93, N 15.48.
Anal. Calcd. for C20H16N2O2 (316.35): C 75.93, H 5.10, N
8.86. Found: C 75.71, H 5.14, N 8.40.
2-(2-(Biphenyl-4-yl)-2-hydroxyethyl)quinazolin-4(3H)-one (18).
The compound was obtained as colorless crystals, m.p. 201-
202 °C; 1H-NMR: ꢀ 2.87–3.04 (m, 2H, 1'-H), 5.25 (dd, 1H, 2'-H,
J = 4.6, 8.8 Hz), 7.31–7.37 (m, 1H, arom. proton), 7.42–7.54 (m,
5H, 6-H, 4 arom. protons), 7.63–7.66 (m, 5H, 7-H, 4 arom.
protons), 7.79 (ddd, 1H, 7-H, J = 1.2, 7.1, 8.1 Hz), 8.11 (dd, 1H,
5-H, J = 1.2, 7.8 Hz); 13C-NMR: ꢀ 44.8 (t, 1'-C), 70.6 (d, 2"-C),
70.6 (d, 2"-C), 121.0 (s, 1 arom. C), 125.8 (d, 1 arom. C), 126.1,
(d, 1 arom. C), 126.4, (d, 2 arom. C), 126.5 (d, 2 arom. C), 126.7
(d, 2 arom. C), 126.8 (d, 1arom. C), 127.4 (d, 1 arom. C), 129.0
(d, 2 arom. C), 134.4 (d, 1 arom. C), 139.0 (s, 1 arom.C), 140.0
(s, 1 arom.C), 144.2 (s, 1 arom.C), 148.9 (s, 8a-C), 155.5 (s, 2-
C), 161.9 (s, 4-C); ms: m/z 342 (M+, 10), 323 (19), 182 (100),
181 (97), 161 (14), 160 (95), 154 (16), 153 (51), 152 (67), 151
(22), 145 (12), 131 (9), 127 (9), 120 (13), 119 (19), 18 (17), 102
(7), 92 (17), 90 (17), 77 (19), 76 (23), 75 (10), 64 (10), 63 (15),
51 (9), 50 (10).
General Procedure for the Synthesis of 2-Substituted-4(3H)-
Quinazolinone Derivatives 21–28.
To a solution of the corresponding alcohol (13 – 20) (0.5
mmol) in methanol (20 ml) trifluoroacetic acid (5 ml) was added
and the reaction mixture was stirred under reflux. The reaction
was monitored by TLC until completion of the reaction. The
reaction mixture was neutralized with aqueous saturated sodium
bicarbonate solution and the obtained precipitated solid was
collected by filtration and recrystallized from methanol.
(E)-2-(4-Methoxystyryl)quinazolin-4(3H)-one (21).
The compound was obtained as a pale yellow crystals, m.p.
1
269-270 °C (lit., [24] 295-298 °C); H-NMR (CDCl3/CD3OD/
CF3COOD): ꢀ 3.82 (s, 3H, CH3O), 6.86–6.95 (m, 3H, 1'-H, 3"-
H, 5"-H), 7.58 (d, 2H, 2"-H, 6"-H, J = 8.8 Hz), 7.65 (t, 1H, 6-H,
J = 7.6 Hz), 7.75 (d, 1H, 8-H, J= 8.1 Hz), 7.94 (t, 1H, 7-H, J =
7.3 Hz), 8.09 (d, 1H, CH=CH, J = 15.9 Hz), 8.25 (d, 1H, 5-H, J
= 7.3 Hz), 13C-NMR: ꢀ 55.8 (q, (CH3O), 106.1 (d, C=C), 115.5
(d, 3"-C, 5"-C), 117.3 (s, 4a-C), 119.8 (d, 8-C), 125.4 (s, C=C),
128.1 (d, 5-C), 130.0 (d, 6-C), 132.6 (d, 2"-C, 6"-C), 137.9 (s,
8a-C), 138.7 (d, 7-C), 150.9 (d, 1'-C), 153.9 (s, 4"-C), 160.2 (s,
2-C), 164.9 (s, 4-C); ms: m/z 278 (M+, 64), 277 (100), 263 (M+-
CH3, 17), 234 (14), 145 (3), 119 (8), 90 (7), 77 (3).
Anal. Calcd. for C22H18N2O2 (342.39): C 77.17, H 5.30, N
8.18. Found: C 77.08, H 5.42, N 8.12.
2-(2-Hydroxy-2-(naphthalen-2-yl)ethyl)quinazolin-4(3H)-one
(19).
The compound was obtained as colorless crystals, m.p. 207-
209 °C; 1H-NMR: ꢀ 2.91–3.08 (m, 2H, 1'-H), 5.33–5.38 (m, 1H,
2'-H), 5.72 (s, br., OH), 7.42–7.48 (m, 3H, 6-H, 2 arom.
protons), 7.57–7.64 (m, 2H, 8-H, 1 arom. proton), 7.74–7.92 (m,
5H, 7-H, 4 arom. protons), 8.08 (d, 1H, 5-H, J = 7.6 Hz), 12.22
(s, 1H, -NH); 13C-NMR: ꢀ 44.8 (t, 1'-C), 70.9 (d, 2"-C), 120.9
(s, 1 arom. C), 124.1 (d, 1 arom. C), 124.4 (d, 1 arom. C), 125.7
(d, 2 arom. C), 126.1 (d, 1 arom. C), 126.2 (d, 1 arom. C), 126.8
(d, 1 arom. C), 127.6 (d, 1 arom. C), 127.7 (d, 1 arom. C), 127.8
(d, 1 arom. C), 132.4 (s, 1 arom. C), 132.9 (s, 1 arom. C), 134.4
(d, 1 arom. C), 142.5 (s, 1 arom.C), 148.9 (s, 8a-C), 155.4 (s, 2-
C), 161.8 (s, 4-C); ms: m/z 316 (M+, 48), 297 (10), 161 (21),
160 (100), 157 (17), 156 (52), 155 (45), 147 (11), 132 (11), 129
(33), 128 (38), 127 (57), 126 (13), 120 (12), 119 (14), 102 (7),
92 (13), 90 (13), 77 (15), 63 (11), 51 (6), 50 (60).
Anal. Calcd. for C17H14N2O2 (278.31): C 73.37, H 5.07, N
10.07. Found: C 73.22, H 5.20, N 10.18.
(E)-2-(4-(Dimethylamino)styryl)quinazolin-4(3H)-one (22).
The compound was obtained as yellow crystals, m.p. >260 °C
1
(lit., [24] >300 °C); H-NMR (CDCl3/CD3OD/CF3COOD): ꢀ
3.02 (s, 6H, CH3O), 6.56 (d, 1H, CH=CH, J = 16.0 Hz), 6.67 (d,
2H, 2"-H, 6"-H, J = 9.1 Hz), 7.46-7.55 (m, 3H ,6-H, 3"-H, 5"-
H), 7.65 (d, 1H, 8-H, J = 8.0 Hz), 7.77-7.84 (m, 1H, 7-H), 8.06
(d, 1H, CH=CH, J = 16.0 Hz), 8.14 (dd, 1H, 5-H, J = 1.3, 8.0
Hz), 13C-NMR: ꢀ 38.9 (q, N(CH3)2), 103.8 (d, C=C), 111.4 (d,
3"-C, 5"-C), 118.2 (s, 4a-C), 119.2 (d, 8-C), 120.67 (s, 1"-C),
126.6 (d, 5-C), 127.0 (d, 6-C), 131.1 (d, 2"-C, 6"-C), 135.6 (d,
7-C), 139.7 (s, 8a-C), 147.8 (d, C=C), 153.1 (s, 4"-C), 154.1 (s,
2-C), 159.5 (s, 4-C); ms: m/z 291 (M+, 100), 276 (26), 262 (19),
247 (14), 171 (11), 145 (11), 120 (4), 90 (5), 77 (4).
Anal. Calcd. for C20H16N2O2 (316.35): C 75.93, H 5.10, N
8.86. Found: C 76.17, H 5.23, N 9.12.
2-(2-Hydroxy-2-(naphthalen-1-yl)ethyl)quinazolin-4(3H)-one
(20).
Anal. Calcd. for C18H17N3O (291.35): C 74.29, H 5.88, N
14.42. Found: C 74.03, H 5.98, N 14.37.
The compound was obtained as colorless crystals, m.p. 198-
200 °C; 1H-NMR: ꢀ 2.00 (dd, 1H, 2'-Hb, J = 9.8, 14.3 Hz), 3.15
(dd, 1H, 2'-Ha, J = 3.2, 14.2 Hz), 5.77 (s, br., OH), 5.96–5.99 (m,
1H, 2'-H), 7.45–7.61 (m, 4H, 6-H, 3 arom. protons), 7.66-7.70
(m, 1H, 8-H), 7.75–7.86 (m, 3H, 7-H, 2 arom. protons), 7.93-
7.96 (d, 1H, arom. proton, J = 7.6 Hz), 8.12 (d, 1H, 5-H, J = 7.6
Hz), 8.40 (d, 1H, arom. proton, J = 8.07 Hz), 12.33 (s, 1H, -NH);
13C-NMR: ꢀ 44.1 (t, 1'-C), 68.1 (d, 2"-C), 121.1 (d, 1 arom. C),
2-((1E,3E)-4-(4-(Dimethylamino)phenyl)buta-1,3-dienyl)-
quinazolin-4(3H)-one (23).
The compound was obtained as a orange crystals, m.p. 257
°C; 1H-NMR (CDCl3/CD3OD/CF3COOD): ꢀ 2.95 (s, 6H,
N(CH3)2), 6.42 (d, 1H, CH=CH, J = 15.3 Hz), 6.72 (d, 2H, 3"-H,
5"-H, J = 8.3 Hz), 6.92 (dd, 1H, 2'/3'-H, J= 10,8, 15.2 Hz), 7.16

1062
I. Philipova, G. Dobrikov, K. Krumova, J. Kaneti
Vol 43
(M+, 90), 323 (100), 295 (15), 247 (27), 204 (11), 178 (10), 162
(9), 152 (9), 120 (13), 119 (12), 92 (9), 90 (7), 77 (6).
Anal. Calcd. for C22H16N2O (324.38): C 81.46, H 4.97, N
8.64. Found: C 81.42, H 4.91, N 8.59.
(d, 1H, CH=CH, J = 15.3 Hz), 7.39 (d, 2H, 2"-H, 6"-H, J = 8.8
Hz), 7.48 (ddd, 1H, 6-H, J = 1.0, 7.2, 8.1 Hz), 7.79 (ddd, 1H, 7-
H, J = 1.5, 7.2, 8.1 Hz), 7.91 (d, 1H, 8-H, J = 8.1 Hz), 8.04 (dd,
1H, 5-H, J = 1.3, 8.1 Hz), 8.17 (dd, 1H, 2'/3'-H, J = 10.9, 15.3
Hz), 13C-NMR: ꢀ 40.7 (q, N(CH3)2), 109.8 (d, C=C), 113.2 (d,
3"-C, 5"-C), 118.2 (s, 4a-C), 119.3 (d, 8-C), 122.7 (d, 2'/3'-C),
125.3 (s, 1"-C), 127.0 (d, 5-C), 127.7 (d, 6-C), 130.3 (d, 2"-C,
6"-C), 136.1 (d, 7-C), 138.4 (s, 8a-C), 148.1 (d, C=C), 150.2 (s,
4"-C), 151.1 (d, 2'/3'-C), 153.9 (s, 2-C), 157.4 (s, 4-C); ms: m/z
317 (M+, 86), 303 (31), 197 (100), 171 (25), 144 (6), 134 (59),
120 (19), 91 (8), 77 (8).
(E)-2-(2-(Naphthalen-2-yl)vinyl)quinazolin-4(3H)-one (27).
The compound was obtained as colorless crystals, m.p. 273-
1
275 °C; H-NMR (CDCl3/CD3OD/CF3COOD): ꢀ 7.16 (d, 1H,
CH=CH, J = 16.4 Hz), 7.43–7.46 (m, 2H, arom. protons), 7.60
(ddd, 1H, 6-H, J = 1.0, 7.1, 8.1 Hz), 7.72–7.93 (m, 6H, 7-H, 8-
H, 4 arom. protons), 8.13 (s, 1H, arom. proton), 8.18 (d, 1H, 5-
H, J = 8.1, 1.0 Hz), 8.37 (d, 1H, CH=CH, J = 16.4 Hz). 13C-
NMR: ꢀ 111.1 (d, 1 arom. C), 118.8 (s, 1 arom. C), 119.2 (d, 1
arom. C), 122.5 (d, 1 arom. C), 126.9 (d, 1 arom. C), 127.2 (d, 1
arom. C), 127.5 (d, 1 arom. C), 128.4 (d, 1 arom. C), 128.7 (d, 1
arom. C), 128.9 (d, 1 arom. C), 129.1 (d, 1 arom. C), 130.5 (s, 1
arom. C), 132.7 (d, 1 arom. C), 133.0 (s, 1 arom. C), 135.1 (s, 1
arom. C), 136.6 (d, 1 arom. C), 137.8 (s, 1 arom. C), 149.0 (d, 1
arom. C), 155.0 (s, 2-C), 159.3 (s, 4-C); ms: m/z 299 (13), 298
(68), 297 (M+, 100), 269 (12), 178 (4), 149 (5), 152 (11), 151
(6), 149 (5), 120 (8), 119 (6), 92 (5), 90 (4).
Anal. Calcd. for C20H19N3O (317.38): C 75.69, H 6.05, N
13.24. Found: C 75.40, H 6.19, N 13.38.
(E)-2-(2-(Pyridin-3-yl)vinyl)quinazolin-4(3H)-one (24).
The compound was obtained as colorless crystals, m.p. 240-
1
241 °C; H-NMR (CDCl3/CD3OD) ꢀ 6.98 (d, 1H, CH=CH, J =
16.4), 7.38–7.47 (m, 2H, 6-H, 3"-H), 7.65–7.78 (m, 2H, 8-H, 7-
H), 7.86 (d, 1H, CH=CH, J = 16.4 Hz), 8.00 (dt, 1H, 4"-H, J =
1.7, 8.1 Hz), 8.16–8.20 (m, 1H, 5-H), 8.49 (dd, 1H, 4"-H, J =
1.5, 4.9 Hz), 8.71 (d, 1H, 6"-H, J = 2.2 Hz), 13C-NMR: ꢀ 121.5
(s, 4a-C), 123.5(d, 1 arom. C), 124.9 (d, 1 arom. C), 126.7 (d, 1
arom. C), 127.5 (d, 2 arom. C), 132.0 (s, 5"-C), 135.2 (d, 1
arom. C), 135.5 (d, 1 arom. C), 135.7 (d, 1 arom. C), 149.2 (d,
C=C), 149.3 (s, 8a-C), 150.15 (d, C=C), 151.5 (s, 2-H), 163.8
(s, 4-C); ms: m/z 250 (21), 249 (M+, 88), 248 (100), 222 (10),
221 (29), 220 (37), 205 (5), 196 (13), 168 (6), 129 (6), 120 (15),
119 (17), 110 (7), 104 (9), 92 (12), 90 (14), 77 (10), 76 (10), 64
(7), 63 (8), 51 (10), 50 (7).
Anal. Calcd. for C20H14N2O (298.34): C 80.52, H 4.73, N
9.39. Found: C 80.36, H 4.51, N 9.19.
(E)-2-(2-(Naphthalen-1-yl)vinyl)quinazolin-4(3H)-one (28).
The compound was obtained as colorless crystals, m.p. >260
°C; 1H-NMR (CDCl3/CD3OD/CF3COOD): ꢀ 7.25 (d, 1H,
CH=CH, J = 16.2 Hz), 7.54–7.75 (m, 4H, 6-H, 8-H, 2arom.
protons), 7.80–7.90 (m, 2H, arom. protons), 7.95–8.09 (m, 3H,
7-H, 2arom. protons), 8.31 (d, 1H, 5-H, J = 8.1, 1.2 Hz), 8.40 (d,
1H, arom. proton, J = 8.4 Hz), 9.21 (d, 1H, CH=CH, J = 16.2
Hz). 13C-NMR: ꢀ 114.0 (d, 1 arom. C), 120.2 (d, 1 arom. C),
123.3 (s, 1 arom. C), 123.5 (d, 1 arom. C), 126.3 (d, 1 arom. C),
127.1 (d, 1 arom. C), 127.5 (d, 1 arom. C), 128.3 (d, 1 arom. C),
128.6 (d, 1 arom. C), 129.8 (d, 1 arom. C), 129.9 (s, 1 arom. C),
132.6 (s, 1 arom. C), 134.0 (s, 1 arom. C), 134.2 (s, 1 arom. C),
134.7 (d, 1 arom. C), 137.7 (d, 1 arom. C), 146.3 (s, 1 arom. C),
146.4 (d, 1 arom. C), 146.6 (d, 1 arom. C), 155.8 (s, 4-C); ms:
m/z 299 (15), 298 (73), 297 (M+, 100), 269 (7), 178 (6), 152
(18), 151 (10), 120 (9), 119 (7), 92 (6), 90 (4).
Anal. Calcd. for C15H11N3O (249.27): C 72.28, H 4.45, N
16.86. Found: C 72.30, H 4.50, N 16.72.
(E)-2-(2-(Pyridin-4-yl)vinyl)quinazolin-4(3H)-one (25).
The compound was obtained as colorless crystals, m.p.
1
>260°C; H-NMR (CDCl3/CD3OD) ꢀ 7.11 (d, 1H, CH=CH, J =
16.4 Hz), 7.44–7.54 (m, 3 H, 6-H, 3"-H, 5"-H), 7.68–7.72 (m,
1H, 8-H), 7.72–7.81 (m, 1H, 7-H), 7.81 (d, 1H, CH=CH, J =
16.4), 8.21 (dd, 1H, 5-H, J = 1.5, 7.9 Hz), 8.54–8.57 (m, 2H, 2"-
H, 6"-H). 13C-NMR: ꢀ 121.6 (s, 4a-C), 122.5 (d, 2 arom. C),
126.1 (d, 1 arom. C), 126.7 (d, 1 arom. C), 127.6 (d, 1 arom. C),
127.7 (d, 1 arom. C), 135.5 (d, 1 arom. C), 136.4 (d, 1 arom. C),
143.8 (s, 4"-C), 149.1 (s, 8a-C), 150.0 (d, C=C), 151.0 (s, 2-C),
163.6 (s, 4-C); ms: m/z 250 (17), 249 (M+, 100), 248 (88), 221
(14), 220 (11), 196 (6), 120 (11), 119 (17), 104 (8), 92 (7), 90
(10), 77 (7), 76 (7), 63 (6), 51 (7).
Anal. Calcd. for C20H14N2O (298.34): C 80.52, H 4.73, N
9.39. Found: C 80.25, H 4.82, N 9.14.
REFERENCES
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Jul-Aug 2006
Convenient synthesis of some 2-substituted 4(3H)-quinazolinone derivatives
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