Hydrolytic opening of the quinazoline ring in 3-furfuryl-4-oxo-3,4- dihydroquinazoline derivatives

Article abstract of DOI:10.1134/S1070428010080208

Ethyl 3-furfuryl-4-oxo-3,4-dihydroquinazoline-2-carboxylate extremely readily undergoes hydrolysis in acid, alkaline, or neutral medium with formation of 2-(2-ethoxy-1,2-dioxoethylamino)-N-furfurylbenzamide. The reaction of ethyl 3-furfuryl-4-oxo-3,4-dihy

Full text of DOI:10.1134/S1070428010080208

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 8, pp. 1243–1245. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © L.A. Shemchuk, V.P. Chernykh, D.V. Levashov, K.M. Sytnik, 2010, published in Zhurnal Organicheskoi Khimii, 2010, Vol. 46,
No. 8, pp. 1241–1243.
Hydrolytic Opening of the Quinazoline Ring in 3-Furfuryl-4-oxo-
3,4-dihydroquinazoline Derivatives
L. A. Shemchuk, V. P. Chernykh, D. V. Levashov, and K. M. Sytnik
National Pharmaceutical University of Ukraine, ul. Pushkinskaya 53, Khar’kov, 61002 Ukraine
e-mail: elmitro_dv@mail.ru
Received May 19, 2009
Abstract—Ethyl 3-furfuryl-4-oxo-3,4-dihydroquinazoline-2-carboxylate extremely readily undergoes hydrol-
ysis in acid, alkaline, or neutral medium with formation of 2-(2-ethoxy-1,2-dioxoethylamino)-N-furfurylbenz-
amide. The reaction of ethyl 3-furfuryl-4-oxo-3,4-dihydroquinazoline-2-carboxylate with phenylmagnesium
bromide yields N-furfuryl-2-(2-hydroxy-2,2-diphenyl-1-oxoethylamino)benzamide as a result of hydrolytic
cleavage of the quinazoline ring.
DOI: 10.1134/S1070428010080208
With a view to obtain new biologically active com-
pounds we planned to synthesize a series of 4-oxo-3,4-
dihydroquinazoline derivatives containing as pharma-
cophoric fragment a benzilic [hydroxy(diphenyl)ace-
tic] acid residue built in the quinazoline ring. Benzilic
acid derivatives are widely used in medical practice;
examples are phenytoin, dimenoxadol, and platyphyl-
line [1, 2]. Some widely used medical agents of syn-
thetic (prazozin, doxazozin) and natural origin (deoxy-
peganine hydrochloride) are derivatives of quinazo-
linone [3, 4].
We intended to synthesize ethyl 3-furfuryl-4-oxo-
3,4-dihydroquinazoline-2-carboxylate (III) and exam-
ine its reaction with Grignard compounds. As starting
compound we used 2-amino-N-furfurylbenzamide (II)
which was prepared by reaction of isatoic anhydride
[I, 4H-3,1-benzoxazine-2,4(1H)-dione] with 2-furyl-
methanamine. Quinazolinone III was obtained by
heating amide II with diethyl oxalate or by reaction of
II with ethoxalyl chloride in acetic acid. We failed to
stop the reaction at the stage of formation of amido
ester IV and isolate the latter under the above condi-
tions. Compound IV was synthesized by carrying out
the reaction with ethoxalyl chloride in acetone; on
heating in acetic anhydride, compound IV underwent
cyclization to quinazolinone III (Scheme 1).
in the dihydropyrimidine ring. 4-Oxo-3,4-dihydroquin-
azoline derivatives having a substituent in the 2-posi-
tion react with Grignard compounds at the carbonyl
group, and the process may be accompanied by open-
ing of the heteroring [5] or not [6, 7]. The formation of
1,3-benzoxazinones is also possible [8]. Quinazolinone
derivatives having no substituent on C2 react with
organomagnesium compounds just at that position, and
the reaction involves opening of the heteroring [9, 10].
In the reaction of quinazolinone III with phenyl-
magnesium bromide, instead of expected 3-furfuryl-2-
[hydroxy(diphenyl)methyl]-3,4-dihydroquinazolin-4-
one (VI), we isolated N-furfuryl-2-(2-hydroxy-2,2-di-
phenyl-1-oxoethylamino)benzamide (V) (Scheme 1).
This result may be rationalized assuming that the reac-
tion of the Grignard compound at the ester group is ac-
companied by cleavage of the dihydropyrimidine ring.
In keeping with published data [11], unsubstituted
3,4-dihydroquinazolin-4-one is very stable to hydrol-
ysis [11]. Alkaline hydrolysis of its substituted deriva-
tives was reported to produce anthranilic acid deriva-
tives [12–14]. There are no published data on the
hydrolysis of such compounds in other media. In our
case, hydrolytic cleavage of the dihydropyrimidine
ring could be related to the presence of excess phenyl-
magnesium bromide and subsequent addition of dilute
hydrochloric acid. However, compound V was also
formed in the reaction with an equimolar amount of
phenylmagnesium bromide, as well as upon replace-
ment of hydrochloric acid by ammonium chloride.
Addition of dilute hydrochloric acid to a solution of
Published data on reactions of 4-oxo-3,4-dihydro-
quinazoline derivatives with Grignard compounds are
few in number, and they are ambiguous. The results of
searching over Beilstein Database showed that the
direction of these reactions depends on the substituents
1243

SHEMCHUK et al.
1244
Scheme 1.
O
O
O
N
(COOEt)2 (a) or
ClC(O)COOEt
Et3N, AcOH (b)
O
N
H
N
NH2
+
O
O
O
N
H
O
NH2
COOEt
I
II
III
O
H2O, H+
or H2O, OH–
or H2O, EtOH
N
H
ClC(O)COOEt, Et3N, Me2CO
O
II
NH
Ac2O
O
COOEt
IV
O
(1) PhMgBr
(2) H2O, NH4Cl
N
O
Ph
O
N
Ph
HO
VI
(1) PhMgBr
(2) H2O, NH4Cl
N
H
O
NH
Ph
Ph
O
OH
V
quinazolinone III in tetrahydrofuran led to the forma-
tion of 2-(2-ethoxy-1,2-dioxoethylamino)-N-furfuryl-
benzamide (IV) as a result of nucleophilic opening of
the quinazoline ring. Further examination of the hy-
drolysis conditions of compound III showed that the
dihydropyrimidine ring therein undergoes opening not
only in weakly acidic but also in weakly alkaline medi-
um. In the latter case, amido ester IV was also isolated.
Conservation of the ester group suggests high sensi-
tivity of the quinazoline ring in III to hydrolysis.
Hydrolytic opening of the heteroring also occurred in
neutral medium, when compound III was heated for
a short time in aqueous alcohol. We failed to effect
cyclization of amide V to compound VI, presumably
for steric reasons. Compound V was also synthesized
by reaction of amido ester IV with phenylmagnesium
bromide.
the mixture was heated until carbon dioxide no longer
evolved. The mixture was cooled, and the product was
recrystallized from ethanol. Yield 85%, mp 92°C.
1H NMR spectrum, δ, ppm: 4.30 d (2H, CH2), 6.20 d
(1H, 3′-H), 6.40 m (4H, 4′-H, 5-H, NH2), 6.70 d (1H,
3-H), 7.20 t (1H, 4-H), 7.50 m (2H, 5′-H, 6-H), 8.60 t
(1H, NH). Found, %: C 66.62; H 5.61; N 12.93.
C12H12N2O2. Calculated, %: C 66.64; H 5.60; N 12.96.
Ethyl 3-(furan-2-ylmethyl)-4-oxo-3,4-dihydro-
quinazoline-2-carboxylate (III). a. A mixture of
2.16 g (0.01 mol) of amide II and 4.2 ml (0.03 mol) of
diethyl oxalate was heated for 30 min. The mixture
was cooled, 5 ml of ethanol was added, and the precip-
itate was filtered off, dried, and recrystallized from
ethanol. Yield 80%, mp 105°C.
b. Compound II, 2.16 g (0.01 mol), was dissolved
in glacial acetic acid on heating. After cooling, 1.4 ml
(0.01 mol) of triethylamine and 1.2 ml (0.01 mol) of
ethyl 2-chloro-2-oxoacetate were added in succession,
and the mixture was heated for 1 h. The precipitate
was filtered off, dried, and recrystallized from ethanol.
Yield 40%, mp 105°C.
EXPERIMENTAL
The 1H NMR spectra were measured from solutions
in DMSO-d6 on a Varian M-200 spectrometer
(200 MHz) using tetramethylsilane as internal refer-
ence. The elemental compositions were determined on
a Carlo Erba CHNS-O EA 1108 analyzer.
2-Amino-N-(furan-2-ylmethyl)benzamide (II).
Furan-2-ylmethanamine, 0.92 ml (0.01 mol), was
added to 1.63 g (0.01 mol) of isatoic anhydride (I), and
c. A mixture of 3.14 g (0.01 mol) of amido ester IV
and 10 ml of acetic anhydride was heated for 20 min.
The precipitate was filtered off, dried, and recrystal-
1
lized from ethanol. Yield 65%, mp 105°C. H NMR
spectrum, δ, ppm: 1.40 t (3H, CH3), 4.40 q (2H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 8 2010

HYDROLYTIC OPENING OF THE QUINAZOLINE RING
1245
OCH2), 5.40 s (2H, NCH2), 6.40 m (2H, 3-H, 4′-H),
7.60–7.70 m (3H, 5′-H, 6-H, 8-H), 7.90 t (1H, 7-H),
8.30 d (1H, 5-H). Found, %: C 66.39; H 4.75; N 9.40.
C16H14N2O4. Calculated, %: C 66.41; H 4.74; N 9.39.
on cooling (or a saturated solution of ammonium
chloride was added), the organic layer was separated,
and the solvent was distilled off. The precipitate of
compound IV was filtered off, dried, and recrystallized
from ethanol. Yield 80%, mp 120°C.
b. Compound III, 2.96 g (0.01 mol), was mixed
with 100 ml of distilled water, a few drops of
a 1% solution of sodium hydroxide were added to
pH 8.0–9.0, and the mixture was stirred until complete
dissolution and left to stand for 2 h. The precipitate
was filtered off, dried, and recrystallized from ethanol.
Yield 80%, mp 120°C.
Ethyl 2-[2-(furan-2-ylmethylcarbamoyl)phenyl-
amino]-2-oxoacetate (IV). Compound II, 2.16 g
(0.01 mol), was dissolved in a minimal amount of
acetone, 1.4 ml (0.01 mol) of triethylamine and 1.2 ml
(0.01 mol) of ethyl 2-chloro-2-oxoacetate were added
in succession, and the mixture was left to stand for
12 h. The precipitate was filtered off, dried, and recrys-
1
tallized from ethanol. Yield 70%, mp 120°C. H NMR
spectrum, δ, ppm: 1.10 t (3H, CH3), 4.20 d (2H,
NHCH2), 4.40 q (2H, OCH2), 6.20 d (1H, 3′-H),
6.40 m (1H, 4′-H), 7.10 t (1H, 5-H), 7.50 m (2H, 5′-H,
4-H), 7.80 d (1H, 3-H), 8.50 d (1H, 6-H), 9.20 t (1H,
NHCH2), 12.80 s (1H, NHCO). Found, %: C 60.75;
H 5.13; N 8.84. C16H16N2O5. Calculated, %: C 60.74;
H 5.11; N 8.86.
c. Compound III, 2.96 g (0.01 mol), was dissolved
in 30 ml of ethanol, 15 ml of water was added, and the
mixture was stirred at 35–40°C until a solid separated.
The precipitate was filtered off, dried, and recrystal-
lized from ethanol. Yield 85%, mp 120°C.
REFERENCES
N-(Furan-2-ylmethyl)-2-[(2-hydroxy-2,2-diphen-
ylethanoyl)amino]benzamide (V). a. A solution of
2.96 g (0.01 mol) of compound III in freshly distilled
tetrahydrofuran was added dropwise to a solution of
phenylmagnesium bromide prepared from 0.53 g
(0.02 mol) of magnesium and 2.02 ml (0.02 mol) of
phenyl bromide in THF [15]. The mixture turned dark
brown. It was stirred for 1 h and treated with a satu-
rated solution of ammonium chloride, the organic layer
was separated, the solvent was distilled off, and the
residue was recrystallized from anhydrous methanol.
Yield 70%, mp 180–185°C.
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1
methanol. Yield 75%, mp 180–185°C. H NMR spec-
trum, ppm: 4.40 d (2H, CH2), 6.20 d (1H, 3′-H),
6.30 m (1H, 4′-H), 7.10 m (2H, 5-H, OH), 7.30–7.40 m
(11H, C6H5, 4-H), 7.45 d (1H, 3-H), 7.60 d (1H, 5′-H),
8.50 d (1H, 6-H), 9.10 t (1H, NHCH2), 12.10 s (1H,
NHCO). Found, %: C 73.20; H 5.19; N 6.57.
C26H22N2O5. Calculated, %: C 73.21; H 5.21; N 6.57.
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concentrated hydrochloric acid with water was added
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