3-aryl(alkyl)quinazoline-2,4(1H,3H)-diones and their alkyl derivatives

Article abstract of DOI:10.1134/S1070428009110190

Two-stage reaction of methyl anthranilate with aryl(alkyl) isocyanates in keeping with the quantumchemical calculations and XRD analysis resulted in 3-aryl(alkyl)quinazoline-2,4(1H,3H)-diones that by treatment with alkyl halides, phenacyl bromides, esters

Full text of DOI:10.1134/S1070428009110190

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 11, pp. 1691−1696. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © A.S. Shestakov, O.E. Sidorenko, I.S. Bushmarinov, Kh.S. Shikhaliev, M.Yu. Antipin, 2009, published in Zhurnal Organicheskoi
Khimii, 2009, Vol. 45, No. 11, pp. 1697−1702.
3-Aryl(alkyl)quinazoline-2,4(1H,3H)-diones
and Their Alkyl Derivatives
A. S. Shestakova, O. E. Sidorenkoa, I. S. Bushmarinovb, Kh. S. Shikhalieva, and M. Yu.Antipinb
aVoronezh State University, Voronezh, 394006 Russia
e-mail: chocd261@chem.vsu.ru
bNesmeyanov Institute of Organoelemental Compounds, Russian Academy of Sciences
Received April 6, 2009
Abstract—Two-stage reaction of methyl anthranilate with aryl(alkyl) isocyanates in keeping with the quantum-
chemical calculations and XRD analysis resulted in 3-aryl(alkyl)quinazoline-2,4(1H,3H)-diones that by treatment
with alkyl halides, phenacyl bromides, esters and amides of chloroacetic acid were converted into the corresponding
1-alkyl derivatives.
DOI: 10.1134/S1070428009110190
Compounds containing a fragment of a quinazoline-
2,4(1H,3H)-dione may be regarded as analogs of methyl-
xanthines and purine nucleotides and therefore they might
exhibit high biological activity. Some among them are
under investigation as antidiabetic [1] and antitumor drugs
[1–3]. The target of the present study was the develop-
ment of synthesis methods for preparation of combina-
torial library with the use of quinazolinediones. Formerly
a building up was described of analogous library of sulf-
amides containing a fragment of 1,3-dimethyl-1H-quin-
azoline-2,4-dione [1].
One of the preparation procedures for 3-R-
quinazoline-2,4(1H,3H)-diones V is underlain by the
application of isocyanates II and anthranilic acid (Ia),
and also its ester Ib, amide Ic, or nitrile (Scheme 1) [2–
7]. In the first stage carbamide III is formed whose
further cyclization is catalyzed both by acids and bases.
The acid catalysis under mild conditions leads to the
formation of isomeric 2-(R-amino)-4H-benzo[d][1,3]-
oxazin-4-ones IV that under more stringent conditions
Scheme 1.
O
O
O
O
R2
R2
O
O
N
H
N
N
N
H
H+
IV
IV'
R1
R1
HN R2
N
H+, Δ
R2
C
+
OH_
O
N
H
NH2
Ià_Ic
O
O
O
IIIa_IIIc
II
R2
O
R2
N
N
N
H
V
N
OH
V'
R1 = OH (a), OMe (b), NH2 (c); R2 = 4-ClC6H4
1691

SHESTAKOV et al.
1692
are converted into target compounds V. Under the basic
catalysis or the hard acid treatment 3-R-quinazoline-
2,4(1H,3H)-diones V formed from the carbamides.
In keeping with Scheme 1 we prepared a number of
quinazolinediones V with diverse substituents in positions
3, 6, and 7 (Scheme 2). The heating of anthranilates with
the isocyanate resulted in the formation of carbamides
III that after isolation were subjected to cyclization into
the corresponding quinazolinediones by boiling in alcohol
solution of KOH. The potassium hydroxide (sodium
hydroxide and alcoholate are also suitable) operates as a
catalyst that reacting with the intermediate carbamide
causes of the deprotonation of the nitrogen atoms thus
in-creasing their nucleophilicity. At the use of aryl iso-
cyanates N,N'-di-arylcarbamides are formed where the
proton elimination from any of the two nitrogen atoms is
equally probable. With alkyl isocyanates N-aryl-, N'-
alkylcarbamides are formed. In these compounds the
nitrogen linked to the alkyl substituent and playing the
part of the nucleophilic site during the cyclization is less
“acidic”, and this apparently is the reason of lower yields
in the synthesis of 3-alkylquinazoline-2,4(1H,3H)-diones.
We performed quantum-chemical calculations of
geometrical parameters and electronic structure of
compounds IV and V employing program package
GAUSSIAN 03 [8]. The calculations were carried out
by the density functional method B3LYP. The full
optimization of the molecules geometry and the calculation
of the electronic structure were performed in the basis
6-31G**.
The comparison of energy of isolated molecules of
regioisomers IV and V and their tautomers IV' and V'
shows that the lowest energy corresponds to compound
V. The energy difference between compounds IV and V
amounts to 54.4 kJ mol−1. The tautomeric forms IV and
V are more feasible than IV'and V' (energy difference
equals 26.0 and 54.4 kJ mol−1 respectively). Thus
compound V is thermodynamically more stable in
agreement with the published data [2, 4–6].
The quantum-chemical calculation of the electronic
structure of compound III shows that the energy
difference between the lowest unoccupied molecular
orbital (LUMO) and the highest occupied molecular
orbital (HOMO) is small and equals 0.1617 eV. In the
anionic form of carbamide III where the attacking
nitrogen atom (Scheme 1) is negatively charged this
difference is even smaller and amounts to 0.0317 eV
thus suggesting the orbital control of the reaction. The
form of the frontier orbitals in compound III both in the
neutral molecule and anion is favorable for the formation
just of compound V.
The structure of compounds V is not planar according
to the calculations. The torsion angle between the planes
of the benzene ring and the heterocycle is 63 deg. The
rotation of the aromatic ring into the plane of the
heterocyclic fragment requires 38.9 kJ mol−1 that is
considerably more than the insurmountable barrier to the
rotation around the carbon-carbon bond (~12 kJ mol−1).
The proof that the cyclization of carbamides III resulted
just in 3-R-quinazoline-2,4(1H,3H)-diones V and not in
their isomers, 2-(R-amino)-4H-benzo[d][1,3]oxazin-4-
ones IV, was obtained by XRD analysis of compound Vc
(see the figure).
Compound Vc crystallizes with one molecule of
dimethylacetamide and exists in the amide tautomeric
form in full agreement with the calculated and published
data (see the figure). The plane of the ring of the para-
chlorophenyl substituent is orthogonal to the plane of the
heterocycle with the angle of rotation of 81.2(2)°. The
bond distances and bond angles in molecule Vc are close
to the respective values in the 3-phenylquinazoline-
2,4(1H,3H)-dione [9]. The analysis of intermolecular
interactions showed that the amide hydrogen formed a
strong hydrogen bond with the oxygen atom of the solvent
General appearance of the molecule of 3-(4-chlorophenyl)-
quinazoline-2,4(1H,3H)-dione Vc with atoms represented by
thermal ellipsoids. The solvent is disordered by two positions
with the ratio of occupancy 0.65 : 0.35, the position with
...
...
...
N1–H1N O1S (distance N O 2.757(2) , angle NH O
166°). The other intermolecular contacts in the crystal
lesser occupancy is not shown in the figure.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 11 2009

3-ARYL(ALKYL)QUINAZOLINE-2,4(1H,3H)-DIONESAND THEIR ALKYL DERIVATIVES
1693
Scheme 2.
O
O
O
R1
R2
R1
R2
R3
O
R1
R2
R3
O
OMe
R4X
N
N
N
+
R3
C
O
NH2
N
H
N
R4
IIa_IIf
Va_Vk
VIa_VIk
II, R3 = Ph (a), 3-ClC6H4 (b), 4-ClC6H4 (c), 3,4-Cl2C6H3 (d), Et (e), cyclohexyl (f); V, R1 = R2 = H, R3 = Ph (a), 3-ClC6H4 (b), 4-
ClC6H4 (c), 3,4-Cl2C6H3 (d), Et (e), cyclohexyl (f); R1 = Br, R2 = H, R3 = Ph (g), Et (h), cyclohexyl (i); R1 = R2 = MeO, R3 = Et
(j), cyclohexyl (k); VI, R1 = R2 = H: R3 = Ph, R4 = 2,5-(MeO)2C6H3NHCOCH2 (a); R3 = 3-ClC6H4, R4 = MeAc (b); R3 =
4-ClC6H4, R4 = 3,4-(MeO)2C6H3COCH2 (c); R3 = 3,4-Cl2C6H3, R4 = 3-ClBn (d); R3 = Et, R4 = 4-TolNHCOCH2 (e); R3 =
cyclohexyl, R4 = 4-TolCOCH2 (f); R1 = Br, R2 = H: R3 = Ph, R4 = 4-ClBn (g); R3 = Et, R4 = Me (h); R3 = cyclohexyl, R4 =All (i);
R1 = R2 = MeO: R3= R4 = Et (j), R3 = cyclohexyl, R4 = 4-MeOC6H4COCH2 (k); X = Cl, Br, I.
The structure was solved by the direct method and by
successive syntheses of the electron density. Positions
of hydrogen atoms were revealed from the difference
Fourier syntheses. The refinement was performed for
F2hkl in anisotropic approximation for nonhydrogen atoms
except for C1S' (see below). The hydrogen atoms were
refined in isotropic approximation in the rider model. The
solvent molecule in the crystal is disordered by two
positions with the common O1S atom. The refinement of
the occupancy of the positions at fixed thermal parameters
gave 0.65 : 0.35 ratio. The atom C1S' of the minor
component is located at a distance 0.36 from the atom
C1S of the main component, and it is refined in the isotropic
approximation for solving the problem of instability of the
least squares method.
correspond to the common van der Waals interactions.
As follows from the XRD findings, in quinazolinediones
V a mobile amide hydrogen atom is present in the position
1. These compounds are relatively strong acids (pKa ≈
10 [10, 11]) which easily form the correspondins salts.
This fact provides a possibility to involve compound V
into alkylation reactions. By treating with 1M solution of
sodium methylate compound V was converted into the
sodium salt. On removing methanol the salt was dissolved
in DMF and treated with the alkyl halide solution.Ashort
heating resulted in the formation of the alkyl derivative.
The developed procedure makes it possible to prepare
quickly and is good yields a number of 1-alkyl-3-aryl-
(alkyl)quinazoline-2,4(1H,3H)-diones.
EXPERIMENTAL
The final values of divergence factors: R1 0.0518
[calculated for Fhkl of 3935 reflections with I > 2σ(I)],
wR2 0.1464 (calculated for F2hkl of all 5162 reflections),
the number of refined parameters 266, GOF 1.001. The
calculations were carried out using program package
SHELXTL 5.10 [12].
The monitoring of reaction progress and checking of
homogeneity of compounds obtained was performed by
TLC on Merck UV-254 plates, eluent chloroform–
1
methanol, 20:1. H NMR spectra were registered on a
spectrometer Bruker AC-300 (300 MHz), internal
reference TMS.
3-Phenylquinazoline-2,4(1H,3H)-dione (Va). In
anhydrous dioxane 1.51 g (10 mmol) of ester Ib and
1.19 g (10 mmol) of isocyanate IIa was heated at 70°C
for 5 h, the reaction mixture was poured into 100 ml of
water, the precipitate was filtered off, washed with
2-propanol and placed into a solution of 0.5 g (9 mmol)
of potassium hydroxide in 20 ml of methanol. The solution
obtained was boiled for 4 h. The reaction mixture was
poured into 100 ml of water and acidified till weak acid
reaction. The precipitate was filtered off, washed with
water, and recrystallized from a mixture 2-propanol–
DMF. Yield 2.32 g (85%), mp 281–282°C (280–282 [4],
Colorless crystals of compound Vc (C18H18ClN3O3)
were grown from a solution in dimethylacetamide. Crys-
tals monoclinic, space group P21/n, a 9.1792(6),
b 14.5533(9), c 13.3453(8) , β 93.5898(13)°,
V 1779.27(19) 3, Z 4 (Z' 1), dcalc 1.343 g/cm–3, μ(MoKα)
0.237 cm–1, F(000) 752. The intensities of 20334
reflections were measured at 120 K on a diffractometer
Bruker SMART1000 CCD [λ(MoKα) 0.71073 , ù-scan-
ning, 2θ < 60°], 5162 independent reflections (Rint 0.0247)
were used in further refining.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 11 2009

SHESTAKOV et al.
1694
1
281 [5], 272 [3], 274–275°C [13]). H NMR spectrum
6-Bromo-3-phenylquinazoline-2,4(1H,3H)-dione
(Vg). Yield 2.21 g (87%), mp 254–255°C. H NMR
1
(DMSO-d6 + CCl4), δ, ppm: 7.18–7.29 m (4Harom), 7.40–
7.52 m (3Harom), 7.66 t (1Harom, J 7 Hz), 7.95 d (1Harom
J 8 Hz), 11.51 s (1H, NH). Found, %: C 70.39; H 4.17;
N 11.86. C14H10N2O2. Calculated, % C 70.58; H 4.23;
N 11.76.
,
spectrum (DMSO-d6 + CCl4), δ, ppm: 7.07–7.21 m
(3Harom), 7.39–7.50 m (2Harom), 7.78 d (1Harom, J 8 Hz),
8.10 d (1Harom, J 8 Hz), 8.18 s (1Harom), 11.47 s (1H,
NH). Found, %: C 52.94; H 2.91; N 8.77. C14H9BrN2O2.
Calculated, %: C 53.02; H 2.86; N 8.83.
Quinazolinediones Vb–Vk were similarly prepared.
6-Bromo-3-ethylquinazoline-2,4(1H,3H)-dione
(Vh). Yield 1.40 g (52%), mp 218–219°C. H NMR
3-(3-Chlorophenyl)quinazoline-2,4(1H,3H)-dione
(Vb). Yield 2.26 g (83%), mp 261–262°C. H NMR
1
1
spectrum (DMSO-d6), δ, ppm: 1.20 t (3H, CH2CH3,
spectrum (DMSO-d6 + CCl4), δ, ppm: 7.30 d (1Harom
J 7 Hz), 7.38 t (1Harom, J 7 Hz), 7.45 s (1Harom), 7.54 d
(1Harom, J 7 Hz), 7.62–7.78 m (2Harom), 7.81 t (1Harom
,
J 8 Hz), 3.84 q (2H, CH2CH3, J 7 Hz), 7.82 d (1Harom
,
J 8 Hz), 8.06 d (1Harom, J 8 Hz), 8.14 s (1Harom), 11.52 s
(1H, NH). Found, %: C 44.69; H 3.30; N 10.36.
C10H9BrN2O2. Calculated, %: C 44.63; H 3.37; N 10.41.
,
J 8 Hz), 8.19 d (1Harom, J 7 Hz) 11.34 s (1H, NH). Found,
%: C 61.69; H 3.21; N 10.16. C14H9ClN2O2. Calculated,
%: C 61.66; H 3.33; N 10.27.
6-Bromo-3-cyclohexylquinazoline-2,4(1H,3H)-
1
dione (Vi). Yield 1.81 g (56%), mp 230–231°C. H NMR
3-(4-Chlorophenyl)quinazoline-2,4(1H,3H)-
dione (Vc). Yield 2.24 g (82%), mp 281–282°C (295°C
[3]). 1H NMR spectrum (DMSO-d6 + CCl4), δ, ppm:
7.22 t (1Harom, J 7 Hz), 7.39 d (1Harom, J 7 Hz), 7.55 d
spectrum (DMSO-d6 + CCl4), δ, ppm: 1.15–1.40 m
(3Haliph), 1.54–1.76 m (3Haliph), 1.85–1.96 m (2Haliph),
2.28–2.37 m (2Haliph), 4.70–4.79 m (1Haliph), 7.76 d
(1Harom, J 8 Hz), 8.00 d (1Harom, J 8 Hz), 8.12 s (1Harom),
11.34 s (1H, NH). Found, %: C 57.59; H 5.53; N 11.28.
C14H15BrN2O2. Calculated, %: C 52.03; H 4.68; N 8.67.
2Harom, J 8 Hz), 7.69 t (1Harom, J 8 Hz), 7.86 d (2Harom
,
J 8 Hz), 8.08 d (1Harom, J 7 Hz), 11.28 s (1H, NH). Found,
%: C 61.57; H 3.30; N 10.32. C14H9ClN2O2. Calculated,
%: C 61.66; H 3.33; N 10.27.
6,7-Dimethoxy-3-ethylquinazoline-2,4(1H,3H)-
dione (Vj). Yield 1.60 g (64%), mp 287–288°C. 1H NMR
spectrum (DMSO-d6 + CCl4), δ, ppm: 1.26 t (3H,
CH2CH3, J 8 Hz), 3.79 s (3H, OCH3), 3.86 s (3H, OCH3),
4.07 q (2H, CH2CH3, J 7 Hz), 6.56 s (1Harom), 7.26 s
(1Harom), 10.97 s (1H, NH). Found, %: C 57.59; H 5.53;
N 11.28. C12H14N2O4. Calculated, %: C 57.59; H 5.64;
N 11.19.
3-(3,4-Dichlorophenyl)quinazoline-2,4(1H,3H)-
dione (Vd). Yield 2.64 g (86%), mp 282–283°C. 1H NMR
spectrum (DMSO-d6 + CCl4), δ, ppm: 7.29–7.36 m
(2Harom), 7.58 d (1Harom, J 8 Hz), 7.74 t (1Harom, J 7 Hz),
7.95 d (1Harom, J 8 Hz), 8.10 d (1Harom, J 7 Hz), 8.26 s
(1Harom), 11.37 s (1H, NH). Found, %: C 54.68; H 2.61;
N 9.16. C14H8Cl2N2O2. Calculated, %: C 54.75; H 2.63;
N 9.12.
6,7-Dimethoxy-3-cyclohexylquinazoline-
3-Ethylquinazoline-2,4(1H,3H)-dione (Ve). Yield
2,4(1H,3H)-dione (Vk). Yield 1.70 g (56%), mp 288–
290°C. H NMR spectrum (DMSO-d6), δ, ppm: 1.28–
1
1.05 g (55%), mp 196–197°C (198°C [14], 194–196°C
1
[15]). H NMR spectrum (DMSO-d6 + CCl4), δ, ppm:
1.51 m (3Haliph), 1.61–1.74 m (3Haliph), 1.80–1.97 m
(2Haliph), 2.29–2.41 m (2Haliph), 3.80 s (3H, OCH3),
3.88 s (3H, OCH3), 4.70–4.80 m (1Haliph), 6.62 s (1Harom),
7.28 s (1Harom), 11.09 sC (1H, NH). Found, %: C 63.09;
H 6.60; N 9.11. C16H20N2O4. Calculated, %: C 63.14;
H 6.62; N 9.20.
1.19 t (3H, CH2CH3, J 8 Hz), 3.98 q (2H, CH2CH3,
J 7 Hz), 7.14–7.19 m (2Harom), 7.59 t (1Harom, J 7 Hz),
7.93 d (1Harom, J 8 Hz), 11.28 s (1H, NH). Found, %:
C 61.69; H 3.21; N 10.16. C10H10N2O2. Calculated, %:
C 63.15; H 5.30; N 14.73.
3-Cyclohexylquinazoline-2,4(1H,3H)-dione (Vf).
Yield 1.25 g (51%), mp 271–272°C (270–271°C [4, 14]).
1H NMR spectrum (DMSO-d6), δ, ppm: 1.21–1.46 m
(3Haliph), 1.57–1.72 m (3Haliph), 1.80–1.96 m (2Haliph),
2.36–2.45 m (2Haliph), 4.67–4.75 m (1Haliph), 7.30 t
N-(2,5-Dimethoxyphenyl)-2-[2,4-dioxo-3-phenyl-
3,4-dihydroquinazolin-1(2H)-yl]acetamide (VIa). In
5 ml of 1M solution of sodium methylate in methanol (that
was prepared by dissolving sodium in methanol with
subsequent checking of the concentration by titration)
was dissolved 1.19 g (5 mmol) of reagent Va. The solution
was evaporated on a rotary evaporator, the residue was
dissolved in anhydrous DMF, and a solution of 1.15 g
(5 mmol) of 2-chloro-N-(2,5-dimethoxy-phenyl)acetamide
(1Harom, J 7 Hz), 7.39 d (1Harom, J 7 Hz), 7.72 t (1Harom
,
J 7 Hz), 8.06 d (1Harom, J 8 Hz), 11.16 s (1H, NH). Found,
%: C 68.78; H 6.61; N 11.46. C14H16N2O2. Calculated,
%: C 68.83; H 6.60; N 11.47.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 11 2009

3-ARYL(ALKYL)QUINAZOLINE-2,4(1H,3H)-DIONESAND THEIR ALKYL DERIVATIVES
1695
(DMSO-d6 + CCl4), δ, ppm: 1.19 t (3H, CH2CH3,
J 7 Hz), 2.22 s (3H, CH3), 4.01 q (2H, CH2CH3, J 7 Hz),
in anhydrous DMF was added. The solution obtained was
heated for 10 min at 100°C and on cooling was poured
into 50 ml of water. The precipitate was filtered off and
recrystallized from a mixture 2-propanol–DMF. Yield
4.95 s (2H, CH2), 7.11 d (2Harom, J 7 Hz), 7.32 t (1Harom
,
J 7 Hz), 7.36 d (1Harom, J 7 Hz), 7.42 d (2Harom, J 7 Hz),
7.74 t (1Harom, J 8 Hz), 8.10 d (1Harom, J 7 Hz), 10.23 s
(1H, NH). Found, %: C 67.60; H 5.60; N 12.33.
C19H19N3O3. Calculated, %: C 67.64; H 5.68; N 12.45.
1
1.92 g (89%), mp 228–230°C. H NMR spectrum
(DMSO-d6), δ, ppm: 3.66 s (3H, OCH3), 3.82 s (3H,
OCH3), 5.21 s (2H, CH2), 6.64 d (1Harom, J 10 Hz),
6.99 d (1Harom, J 10 Hz), 7.63–7.74 m (3Harom), 7.43 d
3-Cyclohexyl-1-[2-oxo-2-(p-tolyl)ethyl]quin-
azoline-2,4(1H,3H)-dione (VIf). To ensure dissolution
of 3-cyclohexylquinazoline-2,4(1H,3H)-dione (Vf) to
5 ml of 1M sodium methylate solution was added 1 ml of
anhydrous DMF. Yield 1.38 g (79%), mp 147–148°C.
1H NMR spectrum (DMSO-d6), δ, ppm: 1.19–1.49 m
(3Haliph), 1.60–1.73 m (3Haliph), 1.82–1.93 m (2Haliph),
2.41–2.52 m (2Haliph), 4.73–4.89 m (1Haliph), 5.61 s (2H,
CH2), 7.09 d (1Harom, J 7 Hz), 7.21 t (1Harom, J 7 Hz),
7.38 d (2Harom, J 8 Hz), 7.57 t (1Harom, J 7 Hz), 7.99 d
(2Harom, J 8 Hz), 8.10 d (1Harom, J 7 Hz). Found, %:
C 75.74; H 6.86; N 7.97. C22H24N2O2. Calculated, %:
C 75.83; H 6.94; N 8.04.
(1Harom, J 7 Hz), 7.48 d (1Harom, J 7 Hz), 7.53 t (2Harom
,
J 7 Hz), 7.39 s (1Harom), 7.62 t (1Harom, J 8 Hz), 8.21 d
(1Harom, J 8 Hz), 9.69 s (1H, NH). Found, %: C 66.74;
H 4.88; N 9.71. C24H21N3O5. Calculated, %: C 66.81;
H 4.91; N 9.74.
The alkylated derivatives of quinazolinediones VIb–
VIk were obtained in a similar way.
Methyl 2-[2,4-dioxo-3-(3-chlorophenyl)-3,4-di-
hydroquinazolin-1(2H)-yl]acetate (VIb). Into a solu-
tion of 5 mmol of sodium salt Vb in anhydrous DMF
was added 0.88 ml (10 mmol) of methyl 2-chloroacetate,
the precipitate was recrystallized from 2-propanol. Yield
1
6-Bromo-3-phenyl-1-(4-chlorobenzyl)quin-
0.85 g (49%), mp 157–158°C. H NMR spectrum
azoline-2,4(1H,3H)-dione (VIg). Yield 1.24 g (56%),
mp 169–171°C. H NMR spectrum (DMSO-d6 + CCl4),
(DMSO-d6 + CCl4), δ, ppm: 3.76 s (3H, OCH3), 5.00 s
1
(2H, CH2), 7.28 d (1Harom, J 6 Hz), 7.34 t (1Harom
,
δ, ppm: 4.80 s (2H, CH2), 7.05–7.20 m (3Harom), 7.26 d
J 7 Hz), 7.41 s (1Harom), 7.43 d (1Harom, J 7 Hz), 7.47–
7.53 m (2Harom), 7.77 t (1Harom, J 8 Hz), 8.11 d (1Harom
(2Harom, J 8 Hz), 7.39–7.50 m (2Harom), 7.67 d (2Harom
,
,
J 8 Hz), 7.81 d (1Harom, J 8 Hz), 8.11 d (1Harom, J 8 Hz),
8.18 s (1Harom). Found, %: C 57.02; H 3.24; N 6.28.
C21H14BrClN2O2. Calculated, %: C 57.10; H 3.19; N 6.34.
J 7 Hz). Found, %: C 59.28; H 3.72; N 8.22.
C17H13ClN2O4. Calculated, %: C 59.23; H 3.80; N 8.13.
1-[2-(3,4-Dimethoxyphenyl)-2-oxoethyl]-3-(4-
chlorophenyl)quinazoline-2,4(1H,3H)-dione (VIc).
Yield 1.31 g (58%), mp 160–162°C. 1H NMR spectrum
(DMSO-d6 + CCl4), δ, ppm: 3.76 s (3H, OCH3), 3.81 s
(3H, OCH3), 5.34 s (2H, CH2), 6.63 d (1Harom, J 8 Hz),
6-Bromo-1-methyl-3-ethylquinazoline-
2,4(1H,3H)-dione (VIh). To a solution of sodium salt
Vh in anhydrous DMF was added 0.94 ml (15 mmol) of
methyl iodide. Yield 1.08 g (76%), mp 140–142°C
1
7.08 s (1Harom), 7.16–7.28 m (2Harom), 7.46 d (1Harom
,
(2-propanol). H NMR spectrum (DMSO-d6), δ, ppm:
J 8 Hz), 7.58 d (1Harom, J 8 Hz), 7.86 d (2Harom, J 8 Hz),
7.91 t (2Harom, J 7 Hz), 8.08 d (1Harom, J 7 Hz). Found,
%: C 63.99; H 4.26; N 6.17. C24H19ClN2O5. Calculated,
%: C 63.93; H 4.25; N 6.21.
1.20 t (3H, CH2CH3, J 8 Hz), 3.57 s (3H, CH3), 3.84 q
(2H, CH2CH3, J 7 Hz), 7.82 d (1Harom, J 8 Hz), 8.06 d
(1Harom, J 8 Hz), 8.14 s (1Harom). Found, %: C 46.67;
H 3.84; N 9.93. C11H11BrN2O2. Calculated, %: C 46.67;
H 3.92; N 9.89.
3-(3,4-Dichlorophenyl)-1-(3-chlorobenzyl)-quin-
azoline-2,4(1H,3H)-dione (VId). Yield 1.96 g (91%),
mp 183–185°C. 1H NMR spectrum (DMSO-d6 + CCl4),
δ, ppm: 4.82 s (2H, CH2), 7.12–7.23 m (3Harom), 7.30–
1-Allyl-6-bromo-3-cyclohexylquinazoline-
2,4(2H,3H)-dione (VIi). To ensure dissolution of dione
VI to 5 ml of 1M sodium methylate solution was added
1 ml of anhydrous DMF. Into a solution of 5 mmol of
sodium salt in DMF obtained by evaporation of methanol
was added 0.82 ml (10 mmol) of allyl chloride. Yield
7.39 m (3Harom), 7.60 d (1Harom, J 8 Hz), 7.79 t (1Harom
,
J 7 Hz), 7.94 d (1Harom, J 8 Hz), 8.08 d (1Harom, J 7 Hz),
8.25 s (1Harom). Found, %: C 58.35; H 2.98; N 6.58.
C21H13Cl3N2O2. Calculated, %: C 58.43; H 3.04; N 6.49.
1
1.62 g (89%), mp 90–91°C (2-propanol). H NMR
spectrum (DMSO-d6 + CCl4), δ, ppm: 1.15–1.40 m
(3Haliph), 1.54–1.76 m (3Haliph), 1.85–1.96 m (2Haliph),
2.28–2.37 m (2Haliph), 4.48 d.d (2H, CH2, 2J 3, 3J 8 Hz),
N-p-Tolyl-2-[(2,4-dioxo-3-ethyl-3,4-dihydroquin-
azolin-1(2H)-yl]acetamide (VIe). Yield 1.33 g (79%),
mp 232–233°C (2-propanol). H NMR spectrum
1
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 11 2009

SHESTAKOV et al.
1696
4.70–4.79 m (1Haliph), 5.38 d.d (1H, =CH2, 2J 3, 3J 9 Hz),
5.66 d.d (1H, =CH2, 2J 4, 3J 18 Hz), 6.48–6.56 m (1H, –
CH=CH2), 7.76 d (1Harom, J 8 Hz), 8.00 d (1Harom, J 8
Hz), 8.12 s (1Harom), 11.34 s (1H, NH). Found, %: C
56.14; H 5.27; N 7.74. C17H19BrN2O2. Calculated, %: C
56.21; H 5.27; N 7.71.
andYatluk, Yu.G., Khim. Geterotsikl. Soedin., 2007, p. 440.
4. Taub, B. and Hino, J.B., J. Org. Chem., 1961, vol. 26, p.
5238.
5. Kurihara, M. andYoda, N., Tetrahedron Lett., 1965, p. 2597.
6. Papadopoulos, E.P., J. Heterocycl. Chem., 1980, vol. 17, p.
1553; Papadopoulos, E.P. and Torres, C.D., J. Heterocycl.
Chem., 1982, vol. 19, p. 269.
7. Chern, J-W., Shish, F.-J., Chan, C.-H., and Liu, K.-C., J.
Heterocycl. Chem., 1988, vol. 25, p. 1103; Shiau, C.-Y., Chern,
J-W., Liu, K.-C., and Cheng, M.-C., J. Heterocycl. Chem.,
1990, vol. 27, p. 1467.
8. Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E.,
Robb, M.A., Cheeseman, J.R., Montgomery, J.A., Vreven,
T. Jr., Burant, J.C., Millam, J.M., Iyengar, S.S., Tomasi, J.,
Barone, V., Men-nucci, B., Cossi, M., Scalmani, G., Rega,
N., Petersson, G.A., Nakatsuji, H., Hada, M., Ehara, M.,
Toyota, K., Fukuda, R., Hasegawa, J., Ishida, M., Nakajima,
T., Honda, Y., Kitao, O., Nakai, H., Klene, M., Li, X., Knox,
J.E., Hratchian, H.P., Cros, J.B., Adamo, C., Jaramillo, J.,
Gomperts, R., Stratmann, R.E., Yazyev, O., Austin, A.J.,
Cammi, R., Pomelli, C., Ochterski, J.W., Ayala, P.Y.,
Morokuma, K., Voth, G.A., Salvador, P., Dannen-berg, J.J.,
Zakrzewski, V.G., Dapprich, S., Daniels,A.D., Strain, M.C.,
Farkas, O., Malick, D.K., Rabuck,A.D., Paghavachari, K.,
Foresman, J.B., Ortiz, J.V., Cui, Q., Baboul,A.G., Clifford, S.,
Cioslowski, J., Stefanov, B.B., Liu, G., Liashenko, A.,
Piskorz, P., Komafomi, I., Martin, R.L., Fox, D.J., Keith, T.,
Al-Laham, M.A., Peng, C.Y., Faanayakkara, A., Challa-
combe, M., Gill, P.M.W., Johnson, B., Chen, W.,
Wong, M.W., Gonzalez, C., Pople, J.A., Gaussian, 03. Rev.
C.02, Gaussian, Inc., Wallingford, CT, 2004.
6,7-Dimethoxy-1,3-diethylquinazoline-
2,4(1H,3H)-dione (VIj). To a solution of 5 mmol of
sodium salt of dione Vj in anhydrous DMF was added
0.75 ml (10 mmol) of ethyl bromide. Yield 1.07 g (77%),
mp 149–151°C. 1H NMR spectrum (DMSO-d6 + CCl4),
δ, ppm: 1.11 t (3H, CH2CH3, J 8 Hz), 1.24 t (3H, CH2CH3,
J 8 Hz), 3.80 s (3H, OCH3), 3.89 s (3H, OCH3), 4.07 q
(2H, CH2CH3, J 7 Hz), 4.19 q (2H, CH2CH3, J 7 Hz),
6.62 s (1Harom), 7.24 s (1Harom). Found, %: C 60.42;
H 6.60; N 10.10. C14H18N2O4. Calculated, %: C 60.42;
H 6.52; N 10.07.
6,7-Dimethoxy-1-[2-(4-methoxyphenyl)-2-
oxoethyl)-3-cyclohexylquinazoline-2,4(1H,3H)-
dione (VIk). To ensure dissolution of dione Vk to 5 ml
of 1M sodium methylate solution was added 2 ml of
anhydrous DMF. Yield 1.11 g (49%), mp 185–186°C.
1H NMR spectrum (DMSO-d6 + CCl4), δ, ppm: 1.16–
1.48 m (3Haliph), 1.53–1.72 m (3Haliph), 1.80–1.91 m
(2Haliph), 2.36–2.50 m (2Haliph), 3.77 s (3H., OCH3),
3.84 s (3H, OCH3), 3.91 s (3H, OCH3), 4.69–4.85 m
(1Haliph), 5.60 s (2H, CH2), 6.70 s (1Harom), 7.03 d
(2Harom, J 8 Hz), 7.41 s (1Harom), 8.08 d (2Harom, J 8 Hz).
Found, %: C 66.42; H 6.28; N 6.17. C25H28N2O6.
Calculated, %: C 66.36; H 6.24; N 6.19.
9. Kitano, Y., Kashiwagi, M., and Kinoshita, Y., Acta Cryst.,
1972, vol. B28, p. 1223.
REFERENCES
10. Brown, D.J., Comp. Heterocycl. Chem. 1984, vol. 3, p. 60.
11. Dawson, R.M.C., Elliott, D.C., Elliott, W.H., and
Jones, K.M., Data for Biochemical Research, Oxford
University Press, 1989.
12. Sheldrick, G.M., Acta Cryst., 2008, vol.A64, p. 112.
13. Iwakura, Y., Uno, H., and Kang, S., J. Org. Chem., 1966,
vol. 31, p. 142.
14. Staiger, R.P. and Wagner, E.C., J. Org. Chem., 1953, vol. 18,
p. 1427.
15. Sheehan, J.C. and Daves, G.D. Jr., J. Org. Chem., 1964,
vol. 29, p. 3599.
1. Khakhina, M.Yu., Korsakov, M.K., Balakin, K.V., Skorenko,
A.V., Kravchenko, D.V., Solov’ev, M.Yu., Proskurina, I.K.,
and Dorogov, M.V., Izv. Vuzov Khim. & Khim. Tekhnol.,
2003, vol. 46, no. 8, p. 12; Khakhina, M.Yu., Proskuri-
na, I.K., Balakin, K.V., Dorogov, M.V., Solov’ev, M.Yu.,
and Yakovleva, Yu.N., Izv. Vuzov Khim. & Khim. Tekhnol.,
2004, vol. 47, no. 4, p. 101.
2. Kakuta, H., Koiso, Y., Takahashi, H., Nagasawa, K., and
Hashimoto, Y., Heterocycles, 2001, vol. 55, p. 1433.
3. Azev, Yu.A., Golomolzin, B.V., Dyul’ks, T., Klyuev, N.A.,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 11 2009