The Synthesis of 8-Hydroxyquinazoline Derivatives and Their Acid-Base Interactions

Article abstract of DOI:10.1002/jhet.5570410215

The reaction of N-(2-R¹-oxyphenyl)benzimidoyl chlorides with cyanamide derivatives in the presence of titanium tetrachloride as a catalyst has yielded some new 4-amino-8-R¹-oxy-2-phenylquinazolines. pK _a values have been determined for these compounds and the influence of substituents at the basicity of the parent system has been discussed. Some investigations on the methyl-quinazolinyl ether cleavage in different medium have been done yielding the appropriate hydroxyquinazoline derivatives. In those cases when the deprotection of 4-amino-8-methoxy-2-phenylquinazoline was carried in aqueous acidic solutions, the formation of the hydrolysis products 3,4-dihydro-2-phenyl-4-quinazolone derivatives was observed as well.

Full text of DOI:10.1002/jhet.5570410215

Mar-Apr 2004
247
The Synthesis of 8-Hydroxyquinazoline Derivatives and Their
Acid–Base Interactions
Agnieszka Kudelko and Wojciech Zielin´ski*
Department of Organic Technology and Petrochemistry
Silesian University of Technology
Ul. Krzywoustego 4, PL-44101 Gliwice, Poland
Received November 20, 2003
1
The reaction of N-(2-R -oxyphenyl)benzimidoyl chlorides with cyanamide derivatives in the presence of
1
titanium tetrachloride as a catalyst has yielded some new 4-amino-8-R -oxy-2-phenylquinazolines. pK val-
a
ues have been determined for these compounds and the influence of substituents at the basicity of the parent
system has been discussed. Some investigations on the methyl-quinazolinyl ether cleavage in different
medium have been done yielding the appropriate hydroxyquinazoline derivatives. In those cases when the
deprotection of 4-amino-8-methoxy-2-phenylquinazoline was carried in aqueous acidic solutions, the for-
mation of the hydrolysis products 3,4-dihydro-2-phenyl-4-quinazolone derivatives was observed as well.
J. Heterocyclic Chem., 41, 247 (2004).
Quinazolines have been attracting attention for a few
methoxyphenyl)benzamide (Scheme 1). The synthesis
involves conversion of N-(2-R1-oxyphenyl)benzamide
derivatives (1) to the appropriate benzimidoyl chlorides
(2) in the reaction with PCl5. Such chlorides obtained in
almost quantitative yields react at room temperature with
cyanamide derivatives (R2 = H, Me, Et) yielding probably
linear products [3] (4), which undergo cyclization to final
8-R1-oxyquinazolines (5) with the use of a Lewis acid cat-
alyst Ti C l4. After several hours of heating in toluene a
highly stable quinazoline-TiCl4 complex was isolated. The
compound was broken up using concentrated acid solution
(20% HCl), however, difficulties with the separation of the
quinazoline from the post-reaction mixture adversely
affect product yield (42-86%). Although the number of the
obtained quinazolines is relatively small, one could
observe a relationship between the basicity of the quinazo-
line and its yield. The stronger the acidity of the compound
is, the lower yield is achieved during the acidic cleavage of
the quinazoline-TiCl4 complex.
decades due to their wide range of biological activity [1].
Particular attention has been focused on amino, methoxy
and hydroxy derivatives which display anti-malaria and
anticance properties and are used to work in drugs against
hypertension and to fight infections involving AIDS [2].
The topic of this study is the synthesis and basicity of
8-hydroxyquinazoline derivatives. Only a few 4-amino-
and 2,4-diaminoquinazoline derivatives have been synthe-
sized earlier from the original substituted benzamides or
ureas using cyanamide derivatives and TiCl4 in a several-
step reactions [3-7]. We have tried to apply a similar pro-
cedure to the synthesis of 8-hydroxyquinazolines. Apart
from all the aspects connected with the biological activity,
such quinazolines have been the subject of detailed studies
because they are analogues of 8-hydroxyquinoline. They
form complexes with many cations (Cu+2, Ni+2, Zn+2
,
Fe+2, Mg+2, Li+ and others), which are used in the spectro-
photometric determinations of the metals [8-10].
A group of 4-amino-8-hydroxy-2-phenylquinazoline
derivatives (5) has been synthesized from well-known
compounds: N-(2-hydroxyphenyl)benzamide and N-( 2 -
Unfortunately, the unsubstituted N-(2-hydroxyphenyl)-
benzamide (R1 = H) reacts with PCl5 in anhydrous
toluene yielding mainly 2-phenyl-1,3-benzoxazole [11]
Scheme 1

248
A. Kudelko and W. Zielin´ski
Vol. 41
(3, Scheme 1). It was necessary to protect the hydroxy
group in amide using trityl chloride [12] Ph3CCl to avoid
such side reaction and then transfer the protected amide
into the benzimidoyl chloride and finally to quinazoline.
We have not obtained the quinazoline with triphenyl-
methoxy group in the position 8 because the deprotection
of such ether occurs during the cleavage of the quinazo-
line-catalyst complex in the acidic medium (Scheme 2).
HBr/CH3COOH solution, thus forming 6b quinazolone
when the reaction time was adequately prolonged.
The structures of the new quinazolines (5a-5d) and
quinazolones (6 a - 6 b) were confirmed by means of ele-
mental analyses and typical spectroscopic methods (MS,
UV, 1H-, 13C-NMR).
Considering the fact that the biological activity of com-
pounds is also greatly dependent on their acid-base charac-
Scheme 2
Studies of the methyl-quinazolinyl ether cleavage have
been also carried out using some typical reagents suggested
in those cases where the leaving group is methyl, CH3. A
selective cleavage of 5b ether to the appropriate hydroxy
derivative 5d took place during heating with NaBH4 in
methanol (Scheme 3). We did not succeed with a more reac-
tive system than the former one – LiAlH4 in benzene [13].
Two 3,4-dihydro-2-phenyl-4-quinazolones (6 a, 6 b) have
been also obtained during the refluxing of 5b compound
with other suggested reagents such as aqueous HCl [14] or
HBr in glacial acetic acid [15]. 4-N , N-Dimethylamino-8-
methoxyquinazoline derivative 5b, when heated both in a
boiling aqueous HCl or HBr in glacial CH3COOH under-
goes mainly the hydrolysis [7,16,17] to the corresponding
quinazolone 6a without disturbing the methoxy group. This
group was replaced by the hydroxy group in boiling
teristics, the pKa values of the synthesized compounds
have been determined. The determination of the pKa disso-
ciation constants was performed according to the spec-
trophotometric method of Albert and Serjeant [18] in 50%
aqueous-methanol solution (10-5M, room temperature).
Our results show that the strongest base among the three
derivatives of 8-methoxy-2-phenylquinazoline (5 a, 5 b, 5 c)
is the quinazoline 5b with a strongly electron-donating
dimethylamino group NMe2 in the position 4 (Scheme 4).
We have observed a lowering of the pKa value in the case
of 5c with diethylamino group NEt2. According to our ear-
lier investigation [19] protonated quinazolines with
strongly electron-donating substituents in the 4 position are
stabilized by the resonance effect and a prevailing contribu-
tion in the resonance hybride has a para-quinoid form
(5 c-1, Scheme 5).
Scheme 3

Mar-Apr 2004
Synthesis of 8-Hydroxyquinazoline Derivatives and Their Acid–Base Interactions
249
Scheme 4
That is why a bulky diethylamino group NEt2 remains
untwisted in the ring plane and its steric hindrance toward
the addition of the proton increases. It is also worthwhile to
considerably from the pKa of 8-methoxyquinazoline deriv-
atives. The formation of the very stable para-quinoid form
is limited here because of the hydrogen bonding [21]
(5 d-1, Scheme 5) which involves the N1 nitrogen atom
and decreases the basicity.
Scheme 5
EXPERIMENTAL
UV spectra were recorded on a Shimadzu UV-2102 spec-
trophotometer; basic medium: 0.05 M NaOH in 50% aqueous
methanol solution, acidic medium: 0.05 M HCl in 50% aqueous
methanol solution. Elemental analyses were carried out with a
1
13
Perkin Elmer 240c analyser. The H and C nmr spectra were
recorded on a Varian Inova 300 spectrometer in DMSO solution
using TMS as internal standard. MS spectra were obtained with a
Shimadzu QP-200 mass spectrometer. Thin layer chromatogra-
phy was carried out on silica gel 60 F (Merck) thin layer chro-
254
matography plates using a benzene-ethyl acetate-diethylamine
mixture (6:2:1 v/v/v) as the mobile phase.
consider the basicity of 4-(N, N-dimethylamino)-2-phenyl-
quinazoline substituted differently with the methoxy group
in the benzene fragment in different positions (6-methoxy-,
7-methoxy- and 8-methoxy isomers, Scheme 4). A steric
e ffect of the untwisted bulky dimethylamino group in the 4
position causes a weakening of the C4-C4a bond and the
electronic effects of the substituents in the benzene ring are
mostly transfered via C8a-N1 bond [20]. Thus, the electron
transfer in such quinazolines occurs in the same fashion as
in substituted aniline. The strongest base in this group is
6-methoxy-4-(N,N-dimethylamino)-2-phenylquinazoline
(para arrangement) which is attributed to the possibility of
the electron coupling with the protonation centre (endo-
cyclic nitrogen atoms N1, N3) [4]. No such coupling is
observed in the case of the 7-methoxy derivative (meta
arrangement). The 8-methoxy derivative 5c has the lowest
pKa value. It should be noted that we have here the ortho
arrangement where the equilibrium achieved between
induction, resonance and steric effect is complex [20].
A replacement of the methoxy group in the 8 position of
the quinazoline with the hydroxy group drastically
changes the character of the compound and leads to
amphoteric properties. Such a quinazoline base 5d is also a
phenol and that is why its dissociation constant diff e r s
N-(2-Hydroxyphenyl)benzamide (1a).
A solution of 2-aminophenol (6.55 g, 0.06 mole) in pyridine
(25 mL) and benzoic anhydride (15 g, 0.065 mol) was heated
under reflux for about 1 hour. After cooling it was poured into ice
water. The resulting precipitate was collected by filtration and
crystallized from ethanol giving white crystals of 1a; yield: 86%;
mp: 169-171°C; lit. [22]: 173 °C, R : 0.17.
f
N-(2-Methoxyphenyl)benzamide (1b).
Benzoyl chloride (12.5 mL, 0.09 mole) was added dropwise
with stirring to 2-methoxyaniline (10 g, 0.08 mol) in aqueous
10% NaOH solution (70 ml). After the addition of chloride was
completed, the stirring was continued for about 1 hour. The crude
product was collected by filtration and crystallized from ethanol
giving yellow crystals of 1b; yield: 71%; mp: 64-66°C; lit. [23]:
68-69 °C; R : 0.64.
f
N-[2-(Triphenylmethoxy)phenyl]benzamide (1c).
A solution of 1a (7.1 g, 0.034 mole) in pyridine (50 mL)
and trityl chloride (10.2 g, 0.037 mole) was gently heated at
about 50 °C for 48 hours. Then it was left for crystallization

250
A. Kudelko and W. Zielin´ski
Vol. 41
giving white crystals of 1c; yield: 54%; mp: 77-80 °C; R :
f
), 8.48
4-(N,N-Dimethylamino)-8-methoxy-2-phenylquinazoline (5b).
1
0.61; H nmr (CDCl , Me Si): δ 7.24-7.30 (m, 24 H
3
4
(s, 1 H, NH) ppm; uv: λ
arom
(ε·10 ) MeOH: 256.4 (8.31),
This compound was obtained as a pink solid; yield: 86%; mp:
1
147-148 °C; R : 0.38; H nmr (CDCl , Me Si): δ 3.39 (s, 6 H,
-3
max
f
3
4
N(CH ) ), 4.06 (s, 3 H, OCH ), 7.06 (d, J = 7.5, 1 H, H-7), 7.27
215.0 (28.43) nm.
Anal. Calcd. for C
3 2
(dd, J = 7.5 and 8.1, 1 H, H-6), 7.42-7.50 (m, 3 H, H-3', H-4', H-
3
H NO : C, 84.36; H, 5.54; N, 3.07.
32 25 2
Found: C, 84.02; H, 5.40; N, 2.98.
5'), 7.63 (d, J = 8.1, 1 H, H-5), 8.60 (d, J = 8.1, 2 H, H-2', H-6')
13
ppm; C nmr: δ 37.3 (N(CH ) ), 51.7 (OCH ), 106.0 (C-4a),
1
General Procedure for the Preparation of N-(2-R -oxyphenyl)-
benzimidoyl Chlorides (2).
3 2
111.1 (C-5), 112.7 (C-6), 119.3 (C-8), 123.6 (C-3', C-5'), 124.0
3
(C-2', C-6'), 125.4 (C-4'), 134.3 (C-7), 140.4 (C-1'), 150.7 (C-8a),
154.1 (C-2), 159.6 (C-4) ppm; uv: λ
1
N-(2-R -oxyphenyl)benzamide (1) (0.05 mole), anhydrous
toluene (100 mL) and PCl ( 11.5 g, 0.055 mole) were heated
-3
(ε· 1 0 ) acidic: 335.4
max
(10.10), 271.0 (36.84), 203.2 (29.01), basic: 331.8 (15.48), 257.6
(38.28), 214.8 (15.27) nm; ms: m/z (%) 77 (11), 205 (13), 235
5
under reflux until the disappearance of the benzamide (TLC) was
completed. Then the toluene and POCl were removed using
1
3
a rotary evaporator. The crude N-(2-R -oxyphenyl)benzimidoyl
+
(20), 249 (26), 250 (29), 278 (M , 100), 279 (94), 280 (18); pK
a
= 5.93 ± 0.12 (λ = 332.6 nm).
anal
A n a l. Calcd. for C H N O: C, 73.09; H, 6.14; N, 15.03.
chloride (2) was pure enough to be used in the next step.
N-[2-(Triphenylmethoxy)phenyl]benzimidoyl Chloride (2c).
17 17
Found: C, 72.90; H, 6.12; N, 14.96.
3
This compound was obtained as a brown-yellowish solid;
yield: 64%; mp: 112-114 °C; R : 0.57; uv: λ
4-(N,N-Diethylamino)-8-methoxy-2-phenylquinazoline (5c).
-3
(ε·10 ) MeOH:
f
max
This compound was obtained in 77% yield; mp: 142-145 °C;
1
R : 0.42; H nmr (CDCl , Me Si): δ 1.44 (t, J = 7.8, 6 H,
255.0 (12.81) nm.
A n a l. Calcd. for C H NOCl: C, 81.59; H, 5.11; N, 2.95.
f
N(CH CH ) ), 3.70 (q, J = 7.8, 4 H, N(CH CH ) ), 4.05 (3 H, s,
3
4
32 24
Found: C, 81.32; H, 5.21; N, 2.99.
2
3 2
2
3 2
OCH ), 7.05 (d, J = 7.8, 1 H, H-7), 7.28 (m, 1 H, H-6), 7.38-7.50
3
(m, 3 H, H-3', H-4', H-5'), 7.55 (d, J = 9.0, 1 H, H-5), 8.58 (d, J =
7.5, 2 H, H-2', H-6') ppm; uv: λ
212.6 (21.18), basic: 232.4 (11.23) nm; ms: m/z (%) 72 (10), 77
+
(28), 105 (41), 178 (12), 195 (18), 210 (M , 100), 211 (17), 278
2-Phenyl-1,3-benzoxazole (3).
-3
(ε·10 ) acidic: 271.8 (8.96),
max
This compound was obtained as a yellowish solid; yield: 78%;
1
mp: 100-101 °C; lit. [11]: 102 °C; R : 0.62; H nmr (DMSO-d ,
f
Me Si): δ 7.43 (d, J = 8.4, 1H, H-7), 7.45 (d, J = 8.4, 1H, H-4),
6
4
7.62-7.65 (m, 3H, H-3', H-4', H-5'), 7.81 (t, J = 8.4, 2H, H-5, H-
(15), 306 (13), 307 (32), 308 (12); pK = 5.81 ± 0.10 (λ
a
=
anal
230.8 nm).
A n a l. Calcd. for C H N O: C, 74.23; H, 6.89; N, 13.66.
-3
(ε·10 ) acidic:
6), 8.22 (d, J = 6.9, 2 H, H-2', H-6') ppm; uv: λ
max
19 21 3
Found: C, 74.28; H, 6.80; N, 13.61.
297.5 (19.70), 291.3 (20.70), 202.5 (2.86), basic: 300.2 (18.63),
292.5 (18.72), 238.8 (6.94) nm.
4-(N,N-Dimethylamino)-8-hydroxy-2-phenylquinazoline (5d).
This compound was obtained in 42% yield; mp: 165-167 °C;
General Procedure for the Preparation of 4-Amino-8-hydroxy-2-
phenylquinazoline Derivatives (5a-5d).
1
R : 0.38; H nmr (CDCl , Me Si): δ 3.26 (s, 6 H, N(CH ) ), 7.01
1
The crude N-(2-R -oxyphenyl)benzimidoyl chloride (2) (0.05
f
(d, J = 7.8, 1H, H-7), 7.15 (d, J = 7.8, 1H, H-5), 7.24-7.32 (m, 3
3
4
3 2
1
mole), prepared from the appropriate N-(2-R -oxyphenyl)benza-
mide (1) was dissolved in the portion of anhydrous toluene (70
H, H-3', H-4', H-5'), 7.66 (dd, J = 7.8 and 7.8, 1 H, H-6), 8.75 (d,
J = 7.8, 2H, H-2', H-6') 11.30 (s, 1H, OH) ppm; uv: λ
-3
(ε·10 )
2
mL). Then cyanamide derivative (R = H, Me, Et) (0.05 mole) in
max
acidic: 348 (5.00), 294.8 (4.33), 275.0 (10.09), 265.4 (9.70),
213.1 (14.65), basic: 338 (3.33), 264.8 (13.92), 239.2 (17.72) nm;
ms: m/z (%) 51 (23), 72 (23), 78 (83), 79 (13), 93 (36), 94 (15),
anhydrous diethyl ether (5 mL) was added there. The mixture
was left for 1 hour, and then, TiCl (5 mL, 0.05 mole) in anhy-
4
drous toluene (20 mL) was gradually added. The stirring was
continued at 50 °C for about 3 hours. Solvents were removed
using a rotary evaporator and the resulting gluey solid was
washed with toluene and 20% aqueous HCl (100 mL) was added.
After a rapid decomposition the mixture was extracted with chlo-
roform. Purified and dried (calcium chloride) compounds (5)
were crystallized from methanol or 2-propanol.
119 (49), 120 (22), 121 (23), 146 (17), 148 (18), 161 (21), 164
+
(40), 175 (10), 190 (M , 100), 191 (19), 265 (36); pK = 8.34 ±
a
0.05 (λ = 267.4 nm).
anal
A n a l. Calcd. for C H N O: C, 72.43; H, 5.71; N, 15.83.
16 15 3
Found: C, 72.25; H, 5.57; N, 15.91.
Quinazoline 5d was also Obtained by Another Method.
4-Amino-8-methoxy-2-phenylquinazoline (5a).
8-Methoxy-4-( N, N-dimethylamino)-2-phenyl-quinazoline
(5b) (0.5 g, 1.79 mmole) was dissolved in methanol (20 mL) and
NaBH (0.139 g, 3.67 mmole) was added there. The mixture was
stirred at 40 °C for 12 hours. Then it was cooled down and acidi-
fied with 5% aqueous HCl solution. A white precipitate was crys-
tallized from ethanol giving quinazoline 5d (yield: 84%).
This compound was obtained as a white solid; yield: 54%; mp:
1
155-157 °C; R : 0.56; H nmr (CDCl , Me Si): δ 3.75 (s, 2 H,
4
f
3
4
NH ), 3.84 (s, 3 H, OCH ), 7.16 (d, J = 7.8, 1H, H-7), 7.24 (m,
2
1H, H-6), 7.40-7.50 (m, 3 H, H-3', H-4', H-5'), 7.64 (d, J = 8.4, 1
3
-3
(ε·10 )
H, H-5), 8.29 (d, J = 7.8, 2 H, H-2', H-6') ppm; uv : λ
max
acidic: 300.0 (17.30), 248.8 (14.33), 210.0 (26.67), basic: 289.0
(19.4), 235.4 (19.85) nm; ms: m/z (%) 51 (12), 63 (13), 77 (40),
Preparation of 3,4-Dihydro-8-methoxy-2-phenyl-4-quinazolone
(6a).
+
92 (13), 104 (12), 105 (41), 167 (15), 195 (87), 210 (M , 100),
Method A.
211 (19), 227 (12), 250 (15), 251 (25); pK = 5.16 ± 0.09 (λ
a
anal
= 230.0 nm).
A n a l. Calcd. for C H N O: C, 71.69; H, 5.22; N, 16.71.
Found: C, 71.80; H, 5.31; N, 16.65.
8-Methoxy-4-(N , N-dimethylamino)-2-phenylquinazoline (5 b)
(0.45 g, 1.61 mmole) was dissolved in the 20% aqueous HCl (10
mL). The mixture was kept under reflux for 20 hours until the
15 13
3

Mar-Apr 2004
Synthesis of 8-Hydroxyquinazoline Derivatives and Their Acid–Base Interactions
251
disappearance of starting quinazoline was complete. Then it was
cooled down yielding a white precipitate 6a that was was crystal-
lized from acetone (yield: 74%).
(23.85), 203.4 (26.84), basic: 341.6 (9.53), 238.6 (28.77), 214.2
(38.60), 205.2 (16.18) nm; ms: m/z (%) 63 (16), 77 (12), 104
+
(21), 105 (11), 107 (39), 135 (12), 238 (M , 100), 239 (18).
A n a l. Calcd. for C H N O : C, 70.57; H, 4.24; N, 11.75.
14 10
2 2
Found: C, 70.80; H, 4.32; N, 11.68.
Method B.
8-Methoxy-4-(N,N -dimethylamino)-2-phenylquinazoline (5 b)
(0.45 g, 1.61 mmole) was dissolved in a mixture of glacial
CH COOH (7 mL) and 45% HBr (10 mL). The solution was kept
3
REFERENCES AND NOTES
under reflux for 3 hours until the disappearance of starting quina-
zoline was complete. Then it was cooled down and alkalized with
20% aqueous NaOH solution yielding a white precipitate 6a
which was crystallized from acetone (yield: 82%); mp: 260-262
[1] W. L. F. Armarego, Fused Pyrimidines: Part I-Quinazolines,
Interscience Publishers, New York-London-Sydney, 1967.
[2] R. O. Dempcy and E. B. Skibo, Biochemistry, 30, 8480
(1991).
[3] W. Zielin´ski and M. Mazik, Polish J. Chem., 68, 489 (1994).
[4] W. Zielin´ski, A. Kudelko and E. M. Holt, Heterocycles, 31,
1201 (1996).
[5] W. Zielin´ski, A. Kudelko and E. M. Holt, Heterocycles, 48,
319 (1998).
[6] W. Zielin´ski and A. Kudelko, Monatsh. Chem., 131 , 895
(2000).
[7] W. Zielin´ski and A. Kudelko, J. Heterocyclic Chem., 39, 1289
(2002).
[8] A. Albert and A. Hampton, J. Chem. Soc., 505 (1954).
[9] H. Irving and H. S. Rossotti, J. Chem. Soc., 2910 (1954).
[10] W. R. J. Simpson, German Patent 2,338,669 (1974); Chem.
Abstr., 80, 120986z (1974).
[11] Z. Seha and C. D.Weis, Helv. Chim. Acta, 63, 917 (1980).
[12] B. Helferich, L. Moog and A. Jugler, Chem. Ber., 7 4, 559
(1925).
[13] J. F. Carroll, S. Kulkowit and M. A. McKervey, J. Chem. Soc.
Chem. Comm., 11, 507 (1980).
1
°C; R : 0.07; H nmr (DMSO-d , Me Si): δ 3.96 (s, 3 H, OCH ),
f
4.20 (br, 1 H, NH), 7.39 (d, J = 7.8, 1 H, H-7), 7.46 (dd, J = 7.8
6
4
3
and 7.8, 1 H, H-6), 7.52-7.60 (m, 3 H, H-3', H-4', H-5'), 7.71 (d,
13
J = 7.8, 1 H, H-5), 8.16 (d, J = 7.5, 2 H, H-2', H-6') ppm; C
nmr: δ 56.0 (OCH ), 115.2 (C-4a), 116.8 (C-8), 121.8 (C-5),
3
126.9 (C-6), 127.7 (C-2', C-6'), 128.4 (C-3', C-5'), 131.2 (C-4'),
132.5 (C-7), 138.6 (C-1'), 151.2 (C-8a), 154.3 (C-2), 161.9 (C-4)
ppm; uv: λ
-3
(ε·10 ) acidic: 327.0 (10.15), 251.0 (23.00), 202.4
max
(27.88), basic: 316.0 (12.70), 249.0 (32.92), 212.8 (44.55) nm;
ms: m/z (%) 77 (17), 104 (12), 194 (11), 222 (34), 223 (43), 251
+
(100), 252 (M , 86), 253 (16).
A n a l. Calcd. for C H N O : C, 71.41; H, 4.80; N, 11.10.
15 12
Found: C, 71.37; H, 4.75; N, 11.15.
2 2
Preparation of 3,4-Dihydro-8-hydroxy-2-phenyl-4-quinazolone
(6b).
4-(N,N-Dimethylamino)-8-methoxy-2-phenylquinazoline (5b)
(0.40 g, 1.43 mmole) was dissolved in a mixture of glacial acetic
acid (10 mL) and 45% HBr (10 mL). The solution was kept under
reflux for 48 hours until the disappearance of starting quinazoline
was complete. Then it was cooled down, poured into water (150
mL) and alkalized with 20% aqueous NaOH solution yielding
a white precipitate 6b (yield: 97%).
[14] E. J. Corey and J. Das, J. Am. Chem. Soc., 104, 5551 (1982).
[15] K. M. Doxsee, M. Feigel, K. D. Stewart, J. W. Canary, C. B.
Knobler and D. J. Cram, J. Am. Chem. Soc., 109, 3089 (1987).
[16] J. R. Keneford, J. S. Morley, J. C. Simpson and P. H. Wright,
J. Chem. Soc., 1104 (1950).
[17] B. E. Christensen and A. J. Tomisek, J. Am. Chem. Soc., 68,
1306 (1946).
Such derivative was also obtained by heating of 3,4-dihydro-8-
methoxy-2-phenyl-4-quinazolone (6a) ( 0.4 g, 1.58 mmole) with
the mixture of glacial acetic acid (10 mL) and 45% HBr (10 mL)
[18] A. Albert and E. P. Serjeant, Ionization Constants of Acids
and Bases, London: Methuen&Co Ltd, New York: J. Willey&Sons, 1962,
p 69.
[19] W. Zielin´ski and A. Kudelko, Monatsh. Chem., 131 , 733
(2000).
[20] J. Shorter, Correlation Analysis in Organic Chemistry,
Clarendon Press, Oxford, 1973.
[21] W. L. F. Armarego, J. Chem. Soc., 561 (1962).
[22] A. L. Le Rosen and E. D. Smith, J. Am. Chem. Soc., 70, 2705
(1948).
1
in the similar manner (yield: 95%); mp: 295-297°C; R : 0.02; H
f
nmr (DMSO-d , Me Si): δ 4.65 (br, 1 H, NH), 7.23 (d, J = 7.8,
6
4
1H, H-7), 7.34 (dd, J = 7.8 and 7.8, 1 H, H-6), 7.50-7.62 (m, 4 H,
H-3', H-4', H-5', H-5), 8.42 (d, J = 7.8, 2H, H-2', H-6'), 11.50 (s,
13
1 H, OH) ppm; C nmr: δ 115.7 (C-4a), 118.2 (C-8), 121.7
(C-5), 127.0 (C-6), 128.0 (C-2', C-6'), 128.4 (C-3', C-5'), 131.2
(C-4'), 132.7 (C-7), 137.7 (C-1'), 150.6 (C-8a), 153.0 (C-2),
[23] F. Hibbert, J. F. Mills, S. C. Nyburg and A. W. Parkins, J.
Chem. Soc. Perkin Trans. 2, 3, 629 (1998).
-3
(ε·10 ) acidic: 328.2 (9.42), 252.0
162.5 (C-4) ppm; uv: λ
max