Water-accelerated synthesis of novel bis-2,3-dihydroquinazolin-4(1H)-one derivatives

Article abstract of DOI:10.1055/s-2005-924766

Bisdihydroquinazolinones were synthesized for the first time by a novel pseudo five-component condensation of isatoic anhydride, a primary amine, and a dialdehyde in water. Several solvents were examined for this reaction; however, in terms of reaction yield and time, water was found to be the optimum solvent. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-924766

344
PAPER
Water-Accelerated Synthesis of Novel Bis-2,3-dihydroquinazolin-4(1H)-one
Derivatives
N
ovel Bis-2,3-dihydro
o
s
(1
H
)
-one
D
t
erivat
a
ives fa Baghbanzadeh,a Peyman Salehi,*b Minoo Dabiri,a Gholamreza Kozehgarya
a
Department of Chemistry, Faculty of Sciences, Shahid Beheshti University, Evin, Tehran, Iran
b
Department of Phytochemistry, Medicinal Plants and Drugs Research Institute, Shahid Beheshti University, P.O.Box 19835-389, Evin,
Tehran, Iran
Fax +98(21)22418679; E-mail: p-salehi@cc.sbu.ac.ir
Received 28 June 2005; revised 22 July 2005
Furthermore, the study of bis-heterocyclic systems has at-
tracted interest, owing to their potential biological activi-
ties.6 To the best of our knowledge, there are no reports on
the synthesis of bis-dihydroquinazolinone compounds 2
and 3 in the literature (Figure 1).
Abstract: Bisdihydroquinazolinones were synthesized for the first
time by a novel pseudo five-component condensation of isatoic an-
hydride, a primary amine, and a dialdehyde in water. Several sol-
vents were examined for this reaction; however, in terms of reaction
yield and time, water was found to be the optimum solvent.
Key words: multicomponent reactions, heterocycles, catalysis, bis-
dihydroquinazolinones, water
Very recently we reported a novel method for the synthe-
sis of 2,3-dihydroquinazolin-4(3H)-ones by the condensa-
tion of isatoic anhydride, primary amines, and aromatic
aldehydes in the presence of silica sulfuric acid.7 To fur-
ther improve the utility and user-friendliness of this pro-
cess we have developed its practical pseudo five-
component variant, which is described herein.
The ever-increasing demand for novel medicinally active
compounds and the laborious process of lead discovery
and optimization have resulted in the continuous search
for simple and efficient methods for the generation of li-
braries for biological screening.1 Heterocycles are an im-
portant class of substrates that are found in natural
products and pharmaceuticals. The rigidity of the hetero-
cyclic core, which results from the substitution of the
core, limits the conformational freedom especially when
compared with the corresponding acyclic structure. 2,3-
Dihydroquinazolin-4(3H)-ones 1 are a class of heterocy-
cles which exhibit biological and pharmaceutical activity
as anti-tumor, diuretic, and herbicidal agents, as well as
plant growth regulators, and anti-cancer drugs.2 Also
these compounds can be easily oxidized to their quinazo-
lin-4(3H)-one analogues,3 which are among the most im-
portant biologically active heterocyclic compounds,4 and
can be found in some natural products.5
For the preparation of our potential target compounds 2
and 3, isatoic anhydride was treated with primary amine
and terphtaldehyde (4) or glyoxal (5) in the presence of p-
toluenesulfonic acid (Scheme 1). Different organic sol-
vents were examined for the reaction and we found that
ethanol was the solvent of choice (Table 1).
Currently the use of non-toxic and environmentally
friendly organic solvents is of much interest. Room tem-
perature ionic liquids are novel solvents with outstanding
environmental and technical features.8 Tetra-n-butylam-
monium bromide (TBAB) and 1-butyl-3-methylimidazo-
lium bromide ([bmim]Br) were investigated as solvents
for the above reaction. Ionic liquids proved to be almost
Table 1 Solvent Effectsa
Solvent
CH2Cl2
CH3C6H5
CH3CN
CH3OH
CH3CH2OH
TBAB
Yield (%)b
Time (h)
–
–
10
25
38
70
58
60
64
48
24
14
5.5
5
Figure 1
[bmim]Br
H2O
5
3
a Reaction of EtNH2, isatoic anhydride, and terephthaldehyde in the
presence of p-TsOH.
b Isolated yield based on isatoic anhydride.
SYNTHESIS 2006, No. 2, pp 0344–0348
x
x
.
x
x
.2
0
0
5
Advanced online publication: 21.12.2005
DOI: 10.1055/s-2005-924766; Art ID: Z12305SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Novel Bis-2,3-dihydroquinazolin-4(1H)-one Derivatives
345
O
R1
CHO
O
N
HN
PTSA
O
R1 NH2
+
+
NH
N
solvent
R1
O
N
H
O
2a–f
CHO
4
O
R1
O
N
HN
O
H
H
PTSA
O
R1 NH2
+
+
solvent
NH
N
R1
O
N
H
O
O
5
3a
Scheme 1
as good as ethanol, with 1-butyl-3-methylimidazolium under reflux conditions to afford the expected products
bromide giving a slightly better yield than tetra-n-butyl- (Scheme 2).
ammonium bromide.
O
O
The use of water as a solvent for organic transformations
R3
PTSA
N
offers several environmental benefits. In many reactions,
significant rate enhancements are observed in water com-
pared to organic solvents. This acceleration has been at-
tributed to many factors, including the hydrophobic
effect, enhanced hydrogen bonding in the transition state,
and the cohesive energy density of water.9
O
R2 CHO
R3 NH2
+
+
N
H
R2
H2O or EtOH
N
H
O
1a–o
Scheme 2
When the reactions were conducted in water, the expected
products were obtained in good yields and with better re-
action times compared to organic solvents or ionic liquids
(Table 2).
Monosubstituted 2,3-dihydroquinazolin-4(1H)-ones were
also synthesized successfully using ammonium acetate as
an ammonia source (Scheme 3).
O
All bis-dihydroquinazolinones synthesized by this pseudo
five-component reaction were reported for the first time
and could be considered as potentially biologically active
compounds with a quinazolinone core.
O
H
N
PTSA
O
R2 CHO
NH4OAc
+
+
R2
H2O or EtOH
N
H
N
H
O
1p–v
We also synthesized mono- and disubstituted 2,3-dihyd-
roquinazolin-4(1H)-ones. Water as solvent resulted in
shorter reaction times than ethanol (Table 3). For the syn-
thesis of disubstituted derivatives, isatoic anhydride, a pri-
mary amine, and an aromatic aldehyde in the presence of
p-toluenesulfonic acid were reacted in ethanol or water
Scheme 3
In addition to the above-mentioned advantages are the
simple work-up procedure, that makes this process envi-
ronmentally friendly, and the easy purification, that re-
Table 2 Synthesis of Bis-2,3-dihydroquinazolin-4(1H)-onesa
Product
Aldehyde
R1
H2O
EtOH
[bmim]Br
Yield (%)
Time (h)
Yield (%)a
Time (h)
Yield (%)
Time (h)
2a
2b
2c
2d
2e
2f
5
5
5
5
5
5
6
4-CH3C6H4
4-ClC6H4
H
3.5
4
60
59
62
64
50
66
66
12
8
62
57
66
70
54
71
64
12
8
62
57
66
70
54
71
64
3
6
6
CH3CH2
2-Thiazolyl
C6H5CH2
H
3
5.5
10
6.5
5
5.5
10
6.5
5
5
3.5
3
3a
a Reaction of isatoic anhydride, dialdehyde, and a primary amine or ammonium acetate in the presence of p-TsOH.
a Isolated yields based on isatoic anhydride.
Synthesis 2006, No. 2, 344–348 © Thieme Stuttgart · New York

346
M. Baghbanzadeh et al.
PAPER
Table 3 Synthesis of 2,3-Dihydroquinazolin-4(1H)-onesa
Productb
R2
R3
H2O
EtOH
Mp (°C)
Time (h)
Yield (%)c
85
Time (h)
Yield (%)
73
Found7
1a
1b
1c
1d
1e
1f
Ph
Me
Me
Me
Et
1.5
2
3
165
4-ClC6H4
4-CH3OC6H4
Ph
83
3.5
3
74
190
1.5
1.5
1
82
70
146
86
3.5
3.5
3
75
136–137
134–137
157–160
175–178
125–128
205–206
196–199
216–217
187–190
216–218
120–121
180–182
218–220
198–200
178–180
165–167
233–234
210–213
166–167
4-ClC6H4
4-NO2C6H4
3-NO2C6H4
4-CH3OC6H4
Ph
Et
84
74
Et
1
86
80
1g
1h
1i
Et
1
90
3
82
Et
2
86
4
74
Ph
Ph
Ph
Ph
4-ClC6H4
Pr
2.5
2
79
6.5
7
65
1j
4-NO2C6H4
4-ClC6H4
3-NO2C6H4
Ph
80
68
1k
1l
2
78
6
70
2
80
5.5
7
73
1m
1n
1o
1p
1q
1r
1s
1.5
1
75
63
4-NO2C6H4
4-HOC6H4
Ph
86
4
77
Et
1.5
1
80
6
70
H
84
4
75
4-ClC6H4
4-CH3OC6H4
2-CH3OC6H4
4-CH3C6H4
3,4-(CH3O)2C6H3
2-Furyl
H
1.5
2
85
5
85
H
88
7
75
H
2
81
4
67
1t
H
2
80
5
70
1u
1v
H
2
78
5
70
H
2.5
75
4
75
a Reaction of isatoic anhydride, a primary amine or ammonium acetate and aromatic aldehyde in the presence of p-TsOH.
b The products were characterized by comparison of their spectroscopic and physical data with authentic samples synthesized by the reported
procedure.7
c Isolated yield based on isatoic anhydride.
quires only filtration of the products followed by able candidate for combinatorial and parallel synthesis in
recrystallization from ethanol.
drug discovery.
In conclusion, a simple and environmentally friendly
method for the synthesis of a novel class of quinazolin-
ones is described. In this pseudo five-component proce-
dure six C–N bonds are formed in a tandem one-pot
process, which is comparable with other important reac-
tions in multicomponent chemistry.10 Also the work-up
procedure is very simple, and chromatography is not re-
quired. Starting materials are inexpensive and commer-
Products 1a–m and 1p–v are known compounds and their physical
data, IR and 1H NMR spectra were essentially identical with those
of authentic samples. Other products, which are new, were charac-
1
terized by IR, H, and 13C NMR spectroscopy, MS, and elemental
analysis. MPs were obtained in open capillary tubes and were mea-
sured on an electrothermal 9100 apparatus and are uncorrected.
Mass spectra were recorded on a Shimadzu QP 1100 BX mass spec-
trometer. Elemental analysis was performed using a Heracus CHN-
cially available. By the reaction of a range of amines and O-Rapid analyzer. IR spectra were recorded on KBr pellets on a
Shimadzu IR-470 spectrophotometer. 1H and 13C NMR spectra
dialdehydes, novel libraries of bisdihydroquinazolinones
were determined on a Bruker 300 DRX Avance instrument at 300
could be obtained, which would make this method a suit-
and 75 MHz, respectively.
Synthesis 2006, No. 2, 344–348 © Thieme Stuttgart · New York

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Novel Bis-2,3-dihydroquinazolin-4(1H)-one Derivatives
347
Bis-2,3-dihydroquinazolin-4(1H)-ones; General Procedure
(H2O or EtOH)
2,3-Dihydro-2-[4-(1,2,3,4-tetrahydro-4-oxoquinazolin-2-
yl)phenyl]quinazolin-4(1H)-one (2c)
White solid; mp 243–245 °C.
Isatoic anhydride (1 mmol, 0.163 g), terephthaldehyde or glyoxal
(0.5 mmol), and primary amine or ammonium acetate (1.2 mmol)
were placed in a round-bottomed flask. Solvent (5 mL) was added,
followed by p-TsOH (0.6 mmol), and the mixture was heated to re-
flux. When the reaction was complete (TLC; n-hexane–EtOAc, 2:1)
the mixture was cooled to r.t. and the precipitate was filtered.
IR (KBr): 3265 (NH), 3187 (NH), 1640 (C=O) cm–1.
1H NMR (DMSO-d6): d = 5.73 (d, J = 2.0 Hz, 2 H, CH), 6.62–8.19
(m, 16 H, 12 × ArH, 4 × NH).
13C NMR (DMSO-d6): d = 66.4 (2 C, CH), 114.9, 115.4, 117.6,
127.1, 127.8, 133.8, 142.4, 148.1, 164.0 (2 C, C=O).
Bis-2,3-dihydroquinazolin-4(1H)-ones; General Procedure
(Ionic Liquid)
MS (EI, 70 eV): m/z (%) = 366 (20) [M+], 136 (10), 119 (100).
Anal. Calcd for C22H18N4O2: C, 71.3; H, 4.9; N, 15.1. Found: C,
71.2; H, 4.9; N, 14.9.
A mixture of isatoic anhydride (1 mmol, 0.163 g), dialdehyde (1
mmol), amine or ammonium acetate (1.2 mmol), and p-TsOH (0.6
mmol) were added to an ionic liquid (0.3 g) and stirred at 100 °C for
the time indicated in Table 2. When the reaction was complete
(TLC) the mixture was cooled to r.t. and EtOH (5 mL) was added.
The precipitate was filtered and washed with cold EtOH.
3-Ethyl-2-[4-(3-ethyl-1,2,3,4-tetrahydro-4-oxoquiazolin-2-
yl]phenyl)-2,3-dihydroquinazolin-4(1H)-one (2d)
White solid; mp 235 °C (dec.).
IR (KBr): 3305 (NH), 2978 (CH), 1627 (C=O) cm–1.
Mono- and Disubstituted-2,3-dihydroquinazolin-4(1H)-ones;
General Procedure (Water)
1H NMR (DMSO-d6): d = 1.02 (t, J = 7.0 Hz, 6 H, CH3), 2.79 (dt,
J = 13.6, 7.0 Hz, 2 H, CH), 3.80 (dt, J = 13.6, 7.0 Hz, 2 H, CH), 5.84
(s, 2 H, CH), 6.57–7.31 (m, 14 H, 12 × ArH, 2 × NH).
To a round-bottomed flask containing H2O (5 mL) was added isato-
ic anhydride (1 mmol, 0.163 g), aldehyde (1 mmol), amine or am-
monium acetate (1.2 mmol), and p-TsOH (0.5 mmol). The mixture
was heated under reflux for the time indicated in Table 3. The pre-
cipitate was filtered and recrystallized (EtOH).
13C NMR (DMSO-d6): d = 13.6 (2 C, CH3), 69.9 (2 C, CH), 114.6,
115.3, 117.6, 126.8, 127.8, 133.6, 142.0, 146.7, 162.3 (2 C, C=O).
MS (EI, 70 eV): m/z (%) = 426 (22) [M+], 252 (70), 175 (100), 119
(30).
Mono- and Disubstituted-2,3-dihydroquinazolin-4(1H)-ones;
General Procedure (Ethanol)
Anal. Calcd for C22H26N4O2: C, 73.2; H, 6.1; N, 13.1. Found: C,
73.0; H, 6.1; N, 13.0.
p-TsOH (0.5 mmol) was added to a mixture of isatoic anhydride (1
mmol, 0.163 g), amine or ammonium acetate (1.2 mmol), and alde-
hyde (1 mmol) and heated under reflux for the time indicated in
Table 3. When the reaction was complete (TLC; n-hexane–EtOAc,
2:1), the solvent was evaporated under reduced pressure and H2O
(10 mL) was added. The precipitate was filtered and recrystallized
(EtOH).
2,3-Dihydro-2-{4-[1,2,3,4-tetrahydro-4-oxo-3-(thiazol-2-
yl)quinazolin-2-yl]phenyl}-3-(thiazol-2-yl)quinazolin-4(1H)-
one (2e)
Light brown solid; mp >260 °C (dec.).
IR (KBr): 3320 (NH), 1615 (C=O) cm–1.
1H NMR (DMSO-d6): d = 6.71–8.00 (m, 20 H).
2,3-Dihydro-2-[4(1,2,3,4-tetrahydro-4-oxo-3-p-tolylquinazolin-
2-yl)phenyl]-3-p-tolylquinazolin-4(1H)-one (2a)
White solid; mp 254–256 °C.
13C NMR (DMSO-d6): d = 68.2 (2 C, CH), 114.0, 116.2, 118.8,
125.9, 126.3, 128.6, 128.7, 135.6, 137.9, 139.0, 145.2, 160.8 (2 C,
C=O).
IR (KBr): 3290 (NH), 1640 (C=O) cm–1.
MS (EI, 70 eV): m/z (%) = 536 (0.5) [M+], 263 (20), 219 (25), 120
(100), 119 (47).
1H NMR (DMSO-d6): d = 2.24 (s, 6 H, CH3), 6.15 (d, J = 1.8 Hz, 2
H, CH), 6.66–7.67 (m, 20 H, ArH), 7.53 (d, J = 1.8 Hz, 2 H, NH).
Anal. Calcd for C28H20N6O2S2: C, 62.7, H, 3.8; N, 15.6. Found: C,
62.7; H, 4.0; N, 15.3.
13C NMR (DMSO-d6): d = 20.5 (2 C, CH3), 72.5 (2 C, CH), 114.6,
115.1, 117.4, 126.4, 126.6, 127.9, 129.0, 133.6, 135.3, 138.0, 140.8,
146.5, 162.0 (2 C, C=O).
3-Benzyl-2-[4-(3-benzyl-1,2,3,4-tetrahydro-4-oxoquinazolin-2-
yl)phenyl]-2,3-dihydroquinazolin-4(1H)-one (2f)
White solid; mp >270 °C (dec.).
MS (EI, 70 eV): m/z (%) = 550 (50) [M+], 442 (45), 237 (75), 120
(100), 91 (60), 77 (76).
IR (KBr): 3290 (NH), 1640 (C=O) cm–1.
Anal. Calcd for C36H30N4O2: C, 78.5; H, 5.5; N, 10.1. Found: C,
78.4; H, 5.5; N, 9.7.
1H NMR (DMSO-d6): d = 3.79 (d, J = 15.4 Hz, 2 H, CH), 5.29 (d,
J = 15.4 Hz, 2 H, CH), 5.72 (d, J = 2.3 Hz, 2 H, CH), 6.61–7.68 (m,
22 H, ArH), 7.39 (2 H, d, J = 2.3 Hz, D2O exchange, NH).
3-(4-Chlorophenyl)-2-{4-[3-(4-chlorophenyl)-1,2,3,4-tetrahy-
dro-4-oxoquinazolin-2-yl]phenyl}-2,3-dihydroquinazolin-
4(1H)-one (2b)
13C NMR (DMSO-d6): d = 45.98 (2 C, CH2), 68.2 (2 C, CH), 113.2,
113.4, 116.1, 125.1, 125.9, 126.2, 126.4, 127.2, 132.3, 136.3, 139.7,
145.0, 161.1 (2 C, C=O).
White solid; mp 258 °C (dec.).
IR (KBr): 3320 (NH), 1615 (C=O) cm–1.
MS (EI, 70 eV): m/z (%) = 550 (20) [M+], 237 (37), 119 (20), 91
(100).
1H NMR (DMSO-d6): d = 6.17 (s, 2 H, CH), 6.65–7.64 (m, 22 H,
20 × ArH, 2 × NH).
Anal. Calcd for C36H30N4O2: C, 78.5; H, 5.5; N, 10.1. Found: C,
78.4; H, 5.5; N, 9.9.
13C NMR (DMSO-d6): d = 70.8 (2 C, CH), 113.3, 113.4, 116.1,
125.4, 126.5, 126.7, 128.9, 132.5, 137.9, 139.0, 145.2, 160.8 (2 C,
C=O).
2,3-Dihydro-2-(1,2,3,4-tetrahydro-4-oxoquinazolin-2-
yl)quinazoline-4(1H)-one (3a)
White solid; mp 238 °C (dec.).
MS (EI, 70 eV): m/z (%) = 246 (3), 172 (21), 120 (100), 119 (47).
Anal. Calcd for C34H24Cl2N4O2: C, 69.0; H, 4.0; N, 9.4. Found C,
68.5; H, 4.3; N, 8.9.
IR (KBr): 3354 (NH), 3300 (NH), 1635 (C=O) cm–1.
Synthesis 2006, No. 2, 344–348 © Thieme Stuttgart · New York

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M. Baghbanzadeh et al.
PAPER
1H NMR (DMSO-d6): d = 4.81–4.85 (m, 2 H, CH), 6.63–7.76 (m,
10 H, 8 × ArH, 2 × NH), 8.43 (2 H, d, J = 5.3 Hz, D2O exchange,
NH).
(2) (a) Hamel, E.; Lin, C. M.; Plowman, J.; Wang, H.; Lee, K.;
Paull, K. D. Biochem. Pharmacol. 1996, 51, 53. (b) Biressi,
M. G.; Cantarelli, G.; Carissimi, M.; Cattaneo, A.; Ravenna,
F. Farmaco, Ed. Sci. 1969, 24, 199. (c) Bhalla, P. R.;
Walworth, B. L. American Cyanamid Co. Eur. Pat. Appl.
Ep58.822, 1982; Chem. Abstr. 1983, 98, 1669. (d) Bhalla,
P. R.; Walworth, B. L. American Cyanamid Co., US Patent
4.431.440, 1984; Chem. Abstr. 1984, 100, 174857.
(e) Hour, M.; Huang, L.; Kuo, S.; Xia, Y.; Bastow, K.;
Nakanishi, Y.; Hamel, E.; Lee, K. J. Med. Chem. 2000, 43,
4479.
13C NMR (DMSO-d6): d = 67.2 (2 C, CH), 117, 117.5, 118.4, 126.3,
127.3, 132.4, 132.5, 144.8, 167.4 (2 C, C=O).
MS (EI, 70 eV): m/z (%) = 294 (1) [M+], 277 (60), 172 (50), 119
(22), 91 (100).
Anal. Calcd for C16H14N4O2: C, 65.3; H, 4.8; N, 19.0. Found: C,
65.3; H, 4.7; N, 18.8.
(3) (a) Rao, V. B.; Hanumanthu, P.; Ratnam, C. V. Indian J.
Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1979, 18, 493.
(b) Lopez, S. E.; Rosales, M. E.; Urdaneta, N.; Godoy, M.
V.; Charris, J. E. J. Chem. Res., Synop. 2000, 258.
(c) Abdel-Jalil, R. J.; Volter, W.; Saeed, M. Tetrahedron
Lett. 2004, 45, 3475.
2,3-Dihydro-2-(4-nitrophenyl)-3-propylquinazolin-4(1H)-one
(1n)
Yellow solid; mp 120–121 °C.
IR (KBr): 3420, 1680 (C=O) cm–1.
1H NMR (500 MHz, CDCl3): d = 0.94 (t, J = 7.3 Hz, 3 H, CH3),
1.64 (m, 2 H, CH2), 2.77 (ddd, J = 14.1, 8.6, 5.8 Hz, 1 H, CH), 4.05
(ddd, J = 13.9, 8.7, 6.6 Hz, 1 H, CH), 5.82 (s, 1 H, CH), 6.50–8.20
(m, 8 H, ArH).
(4) (a) Wolf, J. F.; Rathman, T. L.; Sleevi, M. C.; Campbell, J.
A.; Greenwood, T. D. J. Med. Chem. 1990, 33, 161.
(b) Padia, J. K.; Field, M.; Hinton, J.; Meecham, K.; Pablo,
J.; Pinnock, R.; Roth, B. D.; Singh, L.; Suman-Chauhan, N.;
Trivedi, B. K.; Webdale, L. J. Med. Chem. 1998, 41, 1042.
(c) Kung, P.-P.; Casper, M. D.; Cook, K. L.; Wilson-
Lingard, L.; Risen, L. M.; Vickers, T. A.; Ranken, R.; Blyn,
L. B.; Wyatt, R.; Cook, P. D.; Ecker, D. J. J. Med. Chem.
1999, 42, 4705. (d) Tsou, H.-R.; Mamuya, N.; Johnson, B.
D.; Reich, M. F.; Gruber, B. C.; Ye, F.; Nilakantan, R.; Shen,
R.; Discafani, C.; Deblanc, R.; Davis, R.; Kohen, F. E.;
Greenberger, L. M.; Wang, Y.-F.; Wissner, A. J. Med.
Chem. 2001, 44, 2719. (e) Matsuno, K.; Ichimura, M.;
Nakajima, T.; Tahara, K.; Fujiwara, S.; Kase, H.; Vishiki, J.;
Giese, N. A.; Pandey, A.; Scarborough, R. M.; Lokker, N.
A.; Yu, J.-C.; Irie, J.; Tsukuda, E.; Ide, S.-I.; Oda, S.;
Nomoto, Y. J. Med. Chem. 2002, 45, 3057.
13C NMR (CDCl3): d = 12.5 (CH3), 22.3 (CH2), 48.1 (NCH2), 71.9
(CH), 116.0, 117.4, 120.9, 125.3, 128.3, 129.5, 134.9, 145.4, 148.3,
149.2, 164.1 (C=O).
MS (EI, 70eV): m/z (%) = 311 (64) [M+], 174 (47.6), 119 (45.2), 105
(44.3), 77 (51.6).
Anal. Calcd for C17H17N3O3: C, 65.6; H, 5.5; N, 13.5. Found: C,
65.5; H, 5.5; N, 13.2.
3-Ethyl-2,3-dihydro-2-(4-hydroxyphenyl)quinazolin-4(1H)-one
(1o)
White solid; mp 180–182 °C.
IR (KBr): 3440, 1680 (C=O) cm–1.
1H NMR (DMSO-d6): d = 1.00 (t, J = 7.1 Hz, 3 H, CH3), 2.83 (dq,
J = 13.6, 7.0 Hz, 1 H, CH), 3.71 (dq, J = 13.6, 7.2 Hz, 1 H, CH),
5.73 (d, J = 1.9 Hz, 1 H, CH), 6.60–6.70 (m, 4 H, ArH), 7.11–7.18
(m, 3 H, ArH), 7.20 (d, J = 1.9 Hz, 1 H, NH), 7.62 (dd, J = 7.6, 1.4
Hz, 1 H, ArH), 9.48 (s, 1 H, OH).
(5) Maskey, R. P.; Shaaban, M.; Grun-Wollny, I.; Laatsch, H. J.
Nat. Prod. 2004, 67, 1131.
(6) Reddy, G. M.; Bhavani, A. K. D.; Reddy, P. P.; Reddy, P. S.
N. Synthesis 2002, 1311; and references sited therein.
(7) Salehi, P.; Dabiri, M.; Zolfigol, M. A.; Baghbanzadeh, M.
Synlett 2005, 1155.
(8) (a) Holbrey, J. D.; Seddon, K. R. Clean Prod. Proc. 1999, 1,
223. (b) Elare, M. J.; Seddon, K. R. Pure Appl. Chem. 2000,
72, 1391. (c) Welton, T. Chem. Rev. 1999, 99, 2071.
(d) Wasserschied, P.; Kiem, M. Angew. Chem. Int. Ed. 2000,
39, 3772. (e) Sheldon, R. Chem. Commun. 2001, 2399.
(f) Olivier-Bourbigou, H.; Magna, L. J. Mol. Catal. A:
Chem. 2002, 182, 419. (g) Wilks, J. S. J. Mol. Catal. A:
Chem. 2004, 214, 11. (h) Jain, N.; Kumar, A.; Chauhan, S.;
Chauhan, S. M. S. Tetrahedron 2005, 61, 1015.
13C NMR (DMSO-d6): d = 14.6 (CH3), 71.6 (CH), 115.6, 116.3,
116.7, 118.5, 128.9, 129.3, 133.0, 134.4, 148.1, 159.2, 163.3 (C=O).
MS (EI, 70eV): m/z (%) = 268 (60) [M+], 174 (67.1), 105 (53.5), 77
(40.5).
Anal. Calcd for C16H16N2O2: C, 71.6; H, 6.0; N, 10.4. Found: C,
71.6; H, 5.9; N, 10.2.
Acknowledgment
(9) (a) Breslow, R. Acc. Chem. Res. 1991, 24, 159.
(b) Gajewski, J. J. Acc. Chem. Res. 1997, 30, 219. (c) Otto,
S.; Engberts, J. B. F. N. Org. Biomol. Chem. 2003, 1, 2809.
(d) Pratt, L. R.; Pohrille, A. Chem. Rev. 2002, 102, 2671.
(e) Ludwig, R. Angew. Chem. Int. Ed. 2001, 40, 1808.
(10) (a) Pandey, G.; Singh, R. P.; Gary, A.; Singh, V. K.
Tetrahedron Lett. 2005, 46, 2137. (b) Werner, B.; Domling,
A. Molecules 2003, 8, 53. (c) Domling, A.; Ugi, I. Angew.
Chem. Int. Ed. 2000, 39, 3169. (d) Kappe, C. O. Acc. Chem.
Res. 2000, 33, 879. (e) Terret, N. K.; Gardner, M.; Gordon,
D. W.; Kobylecki, R. J.; Steele, J. Tetrahedron 1995, 51,
8135.
We gratefully acknowledge financial support from the Research
Council of Shahid Beheshti University.
References
(1) (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem.
Int. Ed. 2001, 40, 2004. (b) Kolb, H. C.; Sharpless, K. B.
Drug Discov. Today 2003, 8, 1128.
Synthesis 2006, No. 2, 344–348 © Thieme Stuttgart · New York