New tricyclic compounds with pyrimido[4,5-d]pyrimidine fragment, the 7,8-dihydro-1H-pyrimido[4,5,6-de]quinazoline derivatives

Article abstract of DOI:10.1007/s11172-011-0355-9

A reaction of 2-diaminomethylidenedimedone with aryl isocyanates leads to the formation of the corresponding ureas, which upon the action of sodium methoxide cyclize to 4-amino-7,8-dihydroquinazoline-2,5(1H,6H)-dione derivatives. The latter react with aryl isocyanates following the similar scheme to furnish 1,6-diaryl-8,8-dimethyl-7,8-dihydro-1H-pyrimido-[4,5,6-de] quinazoline-2,5(3H,6H)-diones, new tricyclic compounds containing pyrimidopyrimidine fragment.

Full text of DOI:10.1007/s11172-011-0355-9

Russian Chemical Bulletin, International Edition, Vol. 60, No. 11, pp. 2320—2324, November, 2011
2320
New tricyclic compounds with pyrimido[4,5ꢀd]pyrimidine fragment,
the 7,8ꢀdihydroꢀ1Hꢀpyrimido[4,5,6ꢀde]quinazoline derivatives*
V. A. Dorokhov, V. A. Voronkova, A. V. Komkov, and A. S. Shashkov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: vador@ioc.ac.ru
A reaction of 2ꢀdiaminomethylidenedimedone with aryl isocyanates leads to the formation
of the corresponding ureas, which upon the action of sodium methoxide cyclize to 4ꢀaminoꢀ
7,8ꢀdihydroquinazolineꢀ2,5(1H,6H)ꢀdione derivatives. The latter react with aryl isocyanates
following the similar scheme to furnish 1,6ꢀdiarylꢀ8,8ꢀdimethylꢀ7,8ꢀdihydroꢀ1Hꢀpyrimidoꢀ
[4,5,6ꢀde]quinazolineꢀ2,5(3H,6H)ꢀdiones, new tricyclic compounds containing pyrimidoꢀ
pyrimidine fragment.
Key words: 2ꢀdiaminomethylideneꢀ5,5ꢀdimethylcyclohexaneꢀ1,3ꢀdione, aryl isocyanates,
4ꢀaminoꢀ7,8ꢀdihydroquinazolineꢀ2,5(1H,6H)ꢀdiones, cyclization, 7,8ꢀdihydroꢀ1Hꢀpyrimidoꢀ
[4,5,6ꢀde]quinazolineꢀ2,5(3H,6H)ꢀdione derivatives, [1,5]ꢀhydride shift.
Pyrimido[4,5ꢀd]pyrimidines, close in the structure to
of MeONa in MeOH were converted to the 4ꢀaminoꢀ7,8ꢀ
dihydroquinazolineꢀ2,5(1H,6H)ꢀdione derivatives 4a,b
(Scheme 1). Thus, the enamine fragment is involved into
the heterocyclization, as in the case of the reaction of
βꢀoxoester diaminomethylidene derivatives.12
Earlier, it has been reported on the synthesis of
2ꢀureidomethylidenecyclohexaneꢀ1,3ꢀdiones by a threeꢀ
component reaction of 1,3ꢀcyclohexanediones, triethyl
orthoformate, and urea, however, these compounds were
not used in further processes of heterocyclization.15
Bicyclic compounds 4a,b are also able to react with
aryl isocyanates in boiling toluene with the formation of
ureas 5a,b in 87—89% yields. Cyclization of the latter in
the presence of MeONa in MeOH leads to 1,6ꢀdiarylꢀ8,8ꢀ
dimethylꢀ7,8ꢀdihydroꢀ1Hꢀpyrimido[4,5,6ꢀde]quinazolꢀ
ineꢀ2,5(3H,6H)ꢀdiones 6a,b, whose yields were 80 and
65%, respectively.
pteridines and purines, are a biologically interesting sysꢀ
tem and exhibit various kinds of pharmacological activity:
bronchodilatory,1 antibacterial,2,3 antiallergic,4 antihyperꢀ
tensive,5 as well as are inhibitors of phosphodiesterase1
and dihydrofolatreductase.6
In continuation of our studies on the synthesis of pyrꢀ
imido[4,5ꢀd]pyrimidines,7—12 in the present work we reꢀ
port on 7,8ꢀdihydropyrimido[4,5,6ꢀde]quinazolineꢀ2,5ꢀ
dione derivatives, tricyclic compounds containing a pyrꢀ
imidopyrimidine fragment.
One of the simple and efficient ways for the construcꢀ
tion of the pyrimido[4,5ꢀd]pyrimidine system is based on
the conversion of dioxoketene N,Nꢀacetals with isocyanꢀ
ates.8,11—13 Taking into account electronic and steric efꢀ
fects, it seems the most convenient to use ketene aminals
unsubstituted at the nitrogen atoms, like, for example, in
the scheme suggested by us for the synthesis of 3,6ꢀdiarylꢀ
5ꢀmethylpyrimido[4,5ꢀd]pyrimidineꢀ2,4,7(1H,3H,6H)ꢀ
triones.12
Recently, we have shown that ketene aminals of such a
type can be obtained from 1,3ꢀcyclohexanedione and
dimedone.14 In the present work, we consider heterocyꢀ
clization involving 2ꢀdiaminomethylideneꢀ5,5ꢀdimethylꢀ
cyclohexaneꢀ1,3ꢀdione (1) and aryl isocyanates. It was
found that ketene aminal 1 reacts with phenyl isocyanate
2a and 4ꢀchlorophenyl isocyanate 2b in boiling toluene
with the formation of ureas 3a,b, which do not react with
excess aryl isocyanate. Compounds 3a,b upon the action
The synthesized compounds 3—6 are well soluble in
chloroform. Their structures were confirmed by the IR
and 1H NMR spectroscopic data and mass spectrometric
data, whereas heterocycles 4 and 6 were additionally charꢀ
acterized by the 13C NMR spectroscopic data and 1H/13C
HSQC and HMBC twoꢀdimensional NMR spectra. Thus,
the mass spectra (EI) of compounds 3, 4, and 6 exhibit
peaks of molecular ions, whereas such peaks are absent in
the spectra of ureas 5, however, there are intensive peaks
of the [M – RNCO]+ and [RNCO]+ ions. The IR spectra
of compounds 3—6 are characterized by the presence of
the absorption bands of the CO, NH, and (or) NH2 group
1
(see Experimental). In the H NMR spectra (CDCl3) of
ureas 3, unlike in that of ketene aminal 1, the two CH2
groups have different chemical shifts (for example, for
* Dedicated to Academician of the Russian Academy of Sciences
O. M. Nefedov on the occasion of his 80th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2275—2279, November, 2011.
1066ꢀ5285/11/6011ꢀ2320 © 2011 Springer Science+Business Media, Inc.

7,8ꢀDihydropyrimido[4,5,6ꢀde]quinazolines
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 11, November, 2011 2321
Scheme 1
R = Ph (a), 4ꢀClC6H4 (b)
Reagents and conditions: i. toluene, Δ; ii. MeONa, MeOH, Δ; AcOH, 20 °C.
compound 3a they are at δ 2.30 and 2.37) and for dihydroꢀ
quinazolines 4 and ureas 5, the differences become more
pronounced (for example, for compound 4a: δ 2.28 and
2.40, for compound 5a: δ 2.35 and 2.47). In addition, if
ureas 3a,b have four broad singlets from the NH and (or)
NH2 groups, each of the compounds 4a,b and 5a,b have
only two broad singlets (nonequivalence of the protons of
the NH2 group in dihydroquinazolines 4a,b indicates forꢀ
mation of a hydrogen bond between the NH2 and CO
groups). The 1H NMR spectra (CDCl3) of dihydroꢀ
pyrimidoquinazolines 6 exhibit singlets for the CH2 group
at δ ~2.2 and for the proton H(9) at δ ~4.0. If the 13C NMR
spectrum (DMSOꢀd6) of dihydroquinazoline 4b has a signal
at δ 196.0 (C(5)), compounds 6 have the most lowꢀfield
tion upon the action of MeONa in MeOH led to the forꢀ
mation of isomeric compounds with the suggested strucꢀ
tures 6c,d (the yields were 67 and 80%, respectively).
1
The IR and mass spectral data, as well as H NMR
spectra (300 MHz) obtained for dihydropyrimidoquinazoꢀ
linediones resemble the spectral data for similar heteroꢀ
cycles 6a,b with the same substituents at the N(1) and
N(6) atoms. However, their 13C NMR spectra, as well as
1H NMR spectra (600 MHz) in both CDCl3 and DMSOꢀd6
exhibit a double set of closely placed signals (the 1H NMR
spectra in DMSOꢀd6 have two signals not only for the
aromatic protons and H(9) protons, but also for the proꢀ
1
tons of the CH2 group). Recording the H NMR spectra
in DMSOꢀd6 at 60 °C, as well as in the presence of
trifluoroacetic acid, produced no changes. These data inꢀ
dicate that the cyclization of both the urea 5c and the urea
5d leads to isomeric compounds 6c and 6d in virtually
1
signal at δ 156.6. The H/13C HMBC twoꢀdimensional
NMR spectra of dihydropyrimidoquinazolines 6 exhibit
the correlation peaks for the protons of the CH2 group
with the C(9b), C(9), C(8), C(6a) atoms and the methyl
groups, whereas the protons H(9), with the C(9a), C(9b),
C(8), C(7) atoms and the methyl groups. Attention should
be paid to considerable differences in the chemical shifts
for the C(9a) and C(6a) atoms in the 13C NMR spectra
(δ 130.7—130.9 and 154.8—155.0, respectively), which
confirms that the structures of pyrimidine rings in comꢀ
pounds 6 significantly differ.
Varying isocyanates in the steps of preparation of biꢀ
cyclic and tricyclic systems, one can obtain dihydropyꢀ
rimidoquinazolinediones with different substituents at poꢀ
sitions N(1) and N(6) (Scheme 2). By analogy with comꢀ
pounds 5a,b, ureas 5c,d were synthesized for this purpose
(the yields were 86—98%), whose intramolecular cyclizaꢀ
1
1
equal ratio. Recording the H/1H COSY, H/13C HSQC
and HMBC and H/15N HMBC twoꢀdimensional NMR
1
spectra allowed us to assign almost all the signals for comꢀ
1
pounds 6c and 6d in the H and 13C NMR spectra (see
Experimental). Heterocycles 6c and 6d do not differ in
their chromatographic lability.
It can be suggested that an equilibrium between the corꢀ
responding salts is reached upon the action of a base due to
the proton transfer over the cyclohexane ring, which disꢀ
appears after acidification with acetic acid. Apparently, this
process can be interpreted as a [1,5]ꢀhydride shift (see
review 16).
In conclusion, when pyrimidine ring is built as a part
of the biꢀ and tricyclic systems, 2ꢀdiaminomethylideneꢀ

2322
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 11, November, 2011
Dorokhov et al.
Scheme 2
Reagents and conditions: i. toluene, Δ; ii. MeONa, MeOH, Δ; iii. AcOH, 20 °C.
was added to ketene aminal 1 (0.2 g, 1.1 mmol) in anhydrous
toluene (3 mL), and the mixture was refluxed for 8 h, cooled to
20 °C, a precipitate that formed was filtered off, washed with
toluene and light petroleum, and recrystallized from MeOH to
obtain urea 3a (0.23 g, 71%), m.p. 219—220 °C. Found (%): C,
63.43; H, 6.10; N, 13.81. C16H19N3O3. Calculated (%): C, 63.77;
H, 6.36; N, 13.94. MS, m/z (Irel (%)): 301 [M]+ (6), 209
[M – PhNH]+ (24), 182 [M – PhNCO]+ (49), 119 [PhNCO]+
(70), 93 [PhNH2]+ (100). IR (CHCl3), ν/cm–1: 3336 (NH),
3030—2950 (NH, CH), 1708 (CO), 1644, 1532. 1H NMR
(CDCl3), δ: 0.99 (s, 6 H, 2 Me); 2.30 (s, 2 H, CH2); 2.37 (s, 2 H,
cyclohexaneꢀ1,3ꢀdiones can be used not only as N,Nꢀbiꢀ
nucleophiles (like amidines),14 but also as functionalized
enaminones.
Experimental
1
H NMR spectra were recorded on a Bruker AMꢀ300
spectrometer (300 MHz), 1H NMR spectra of tricyclic comꢀ
pounds 6, 13C NMR spectra, and 1H/1H COSY, 1H/13C HSQC
and HMBC, 1H/15N HMBC twoꢀdimensional NMR spectra
were recorded on a Bruker Avance 600 spectrometer (600, 150,
and 60.8 MHz for 1H, 13C, and 15N, respectively). Signals for
the residual protons of the deuterated solvents were used as
a reference in 1H NMR spectra (7.27 for CDCl3 and 2.50 for
DMSOꢀd6) and multiplet signals of the deuterated solvents, in
the 13C NMR spectra (39.50 for DMSOꢀd6 and 77.00 for CDCl3).
Chemical shifts of 15N were measured relatively to the external
standard MeNO2 (the highꢀfield chemical shifts are given with
the negative sign). IR spectra were recorded on a SpecordꢀM82
spectrometer, and mass spectra, on a Kratos MSꢀ30 instrument
(EI, 70 eV, temperature of the ionization chamber was 250 °C,
a direct injection of compounds). We used in the syntheses aryl
isocyanates purchased from Lancaster, anhydrous toluene was
obtained by distillation over sodium, methanol was purified by
fractional distillation. 2ꢀDiaminomethylideneꢀ5,5ꢀdimethylꢀ
cyclohexaneꢀ1,3ꢀdione 1 was synthesized according to the deꢀ
scribed by us procedure.14 Column chromatography was perꢀ
formed on Merck silica gel 60 (0.063—0.200 mm).
CH2); 7.16 (t, 1 H, pꢀHPh, J = 7.5 Hz); 7.35 (t, 2 H, mꢀHPh
,
J = 7.5 Hz); 7.41 (d, 2 H, oꢀHPh, J = 7.5 Hz); 8.32 (br.s, 1 H,
NHPh); 9.67 (br.s, 1 H, NH2); 11.43 (br.s, 1 H, NH2); 13.89
(br.s, 1 H, NH).
2ꢀ[Amino(N´ꢀ4ꢀchlorophenylureido)methylidene]ꢀ5,5ꢀdiꢀ
methylcyclohexaneꢀ1,3ꢀdione (3b) was synthesized similarly to
urea 3a from ketene aminal 1 and 4ꢀchlorophenyl isocyanate,
the yield was 77%, m.p. 239—240 °C (from methanol). Found (%):
C, 57.49; H, 5.02; Cl, 10.70; N, 12.48. C16H18ClN3O3. Calcuꢀ
lated (%): C, 57.23; H, 5.40; Cl, 10.56; N, 12.51. MS, m/z
(Irel (%)): 335 [M]+ (3), 209 [M – ClC6H4NH]+ (100), 166
[M – ClC6H4NCO – Me – H]+ (28), 153 [ClC6H4NCO]+ (27),
127 [ClC6H4NH2]+ (55). IR (KBr), ν/cm–1: 3296 (NH),
3210—2950 (NH, CH), 1700 (CO), 1636, 1528. 1H NMR
(CDCl3), δ: 1.01 (s, 6 H, 2 Me); 2.31 (s, 2 H, CH2); 2.38 (s, 2 H,
CH2); 7.31 (d, 2 H, C6H4, J = 7.5 Hz); 7.40 (d, 2 H, C6H4,
J = 7.5 Hz); 8.33 (br.s, 1 H, NHC6H4); 9.61 (br.s, 1 H, NH2);
11.47 (br.s, 1 H, NH2); 13.97 (br.s, 1 H, NH).
2ꢀ[Amino(N´ꢀphenylureido)methylidene]ꢀ5,5ꢀdimethylcycloꢀ
hexaneꢀ1,3ꢀdione (3a). Phenyl isocyanate (0.18 mL, 1.6 mmol)
4ꢀAminoꢀ7,7ꢀdimethylꢀ1ꢀphenylꢀ7,8ꢀdihydroquinazolineꢀ2,5ꢀ
(1H,6H)ꢀdione (4a). A solution of MeONa in MeOH (0.5 mL,

7,8ꢀDihydropyrimido[4,5,6ꢀde]quinazolines
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 11, November, 2011 2323
0.53 mmol) was added to urea 3a (0.16 g, 0.53 mmol) in MeOH
(5 mL), and the mixture was refluxed for 1 h, cooled to 20 °C,
acidified with AcOH, the solvent was evaporated in vacuo to
dryness. The residue was diluted with water, a precipitate was
filtered off, washed with diethyl ether to obtain dihydroquinazoꢀ
line 4a (0.12 g, 80%), m.p. 286—287 °C. Found (%): C, 67.95;
H, 5.67; N, 14.47. C16H17N3O2. Calculated (%): C, 67.83; H,
6.05; N, 14.83. MS, m/z (Irel (%)): 283 [M]+ (100), 268 [M – Me]+
(44), 241 [M – H2NCN]+ (23), 226 [M – Me – H2NCN]+ (24),
147 [M – Me – PhNCO – 2 H]+ (42), 117 [PhNCO – 2 H]+
(33). IR (CHCl3), ν/cm–1: 3480, 3320 (NH), 3010—2960 (NH,
(NH, CH), 1700 (CO), 1652, 1600, 1528. 1H NMR (CDCl3), δ:
1.06 (s, 6 H, 2 Me); 2.36 (s, 2 H, CH2); 2.48 (s, 2 H, CH2); 7.14
(d, 2 H, C6H4, J = 7.5 Hz); 7.28 (d, 2 H, C6H4, J = 7.5 Hz); 7.53
(d, 2 H, C6H4, J = 7.5 Hz); 7.58 (d, 2 H, C6H4, J = 7.5 Hz);
11.45 (br.s, 1 H, NH); 11.86 (br.s, 1 H, NH).
4ꢀ(N´ꢀ4ꢀChlorophenylureido)ꢀ7,7ꢀdimethylꢀ1ꢀphenylꢀ7,8ꢀdiꢀ
hydroquinazolineꢀ2,5(1H,6H)ꢀdione (5c) was synthesized simiꢀ
larly to urea 5a from dihydroquinazoline 4a and 4ꢀchlorophenyl
isocyanate, the yield was 98%, m.p. 255—256 °C (sublimes).
Found (%): C, 62.88; H, 4.75; Cl, 8.06; N, 12.69. C23H21ClN4O3.
Calculated (%): C, 63.23; H, 4.84; Cl, 8.11; N, 12.82. MS, m/z
(Irel (%)): 283 [M – ClC6H4NCO]+ (85), 282 [M – ClC6H4NCO –
– H]+ (97), 268 [M – ClC6H4NCO – Me]+ (69), 153
[ClC6H4NCO]+ (100), 127 [ClC6H4NH2]+ (34). IR (CHCl3),
ν/cm–1: 3175 (NH), 3020—2960 (NH, CH), 1700 (CO), 1652,
1604, 1528. 1H NMR (CDCl3), δ: 1.04 (s, 6 H, 2 Me); 2.36
(s, 2 H, CH2); 2.47 (s, 2 H, CH2); 7.21 (m, 2 H, Ph); 7.29 (m, 2 H,
C6H4); 7.58 (m, 5 H, C6H4, Ph); 11.46 (br.s, 1 H, NH); 11.94
(br.s, 1 H, NH).
1
CH), 1688 (CO), 1648, 1608, 1512. H NMR (CDCl3), δ: 1.02
(s, 6 H, 2 Me); 2.28 (s, 2 H, CH2); 2.40 (s, 2 H, CH2); 6.45 (br.s,
1 H, NH2); 7.18 (d, 2 H, Ph, J = 7.5 Hz); 7.52 (m, 3 H, Ph); 9.00
(br.s, 1 H, NH2).
4ꢀAminoꢀ1ꢀ(4ꢀchlorophenyl)ꢀ7,7ꢀdimethylꢀ7,8ꢀdihydroquinꢀ
azolineꢀ2,5(1H,6H)ꢀdione (4b) was synthesized similarly to diꢀ
hydroquinazoline 4a from urea 3b, the yield was 62%, m.p.
290—291 °C. Found (%): C, 60.17; H, 4.65; Cl, 11.19; N, 13.17.
C16H16ClN3O2. Calculated (%): C, 60.48; H, 5.08; Cl, 11.16;
N, 13.22. MS, m/z (Irel (%)): 317 [M]+ (55), 316 [M – H]+ (100),
302 [M – Me]+ (14), 127 [ClC6H4NH2]+ (17), 101 (62). IR
(CHCl3), ν/cm–1: 3480, 3320 (NH), 3030—2960 (NH, CH),
1680 (CO), 1648, 1608, 1512. 1H NMR (CDCl3), δ: 1.05 (s, 6 H,
2 Me); 2.29 (s, 2 H, CH2); 2.42 (s, 2 H, CH2); 6.35 (br.s, 1 H,
NH2); 7.15 (d, 2 H, C6H4, J = 8.0 Hz); 7.52 (d, 2 H, C6H4,
J = 8.0 Hz); 9.03 (br.s, 1 H, NH2). 1H NMR (DMSOꢀd6), δ: 0.93
(s, 6 H, 2 Me); 2.29 (s, 2 H, CH2); 2.36 (s, 2 H, CH2); 7.35 (d, 2 H,
oꢀHC H , J = 7.8 Hz); 7.59 (d, 2 H, mꢀHC H , J = 7.8 Hz); 8.01
1ꢀ(4ꢀChlorophenyl)ꢀ7,7ꢀdimethylꢀ4ꢀ(N´ꢀphenylureido)ꢀ7,8ꢀ
dihydroquinazolineꢀ2,5(1H,6H)ꢀdione (5d) was synthesized simiꢀ
larly to urea 5a from dihydroquinazoline 4b and phenyl isocyanꢀ
ate, the yield was 86%, m.p. 270—271 °C (sublimes). Found (%):
C, 63.07; H, 4.53; Cl, 8.16; N, 12.68. C23H21ClN4O3. Calculatꢀ
ed (%): C, 63.23; H, 4.84; Cl, 8.11; N, 12.82. MS, m/z (Irel (%)):
317 [M – PhNCO]+ (73), 316 [M – PhNCO – H]+ (100), 302
[M – PhNCO – Me]+ (15), 127 [ClC6H4NH2]+ (22); 119
[PhNCO]+ (46). IR (CHCl3), ν/cm–1: 3190 (NH), 3020—2960
(NH, CH), 1696 (CO), 1652, 1604, 1528. 1H NMR (CDCl3),
δ: 1.04 (s, 6 H, 2 Me); 2.34 (s, 2 H, CH2); 2.46 (s, 2 H, CH2);
7.16 (m, 3 H, oꢀHC H , pꢀHPh); 7.33 (m, 2 H, mꢀHPh); 7.57
4
6
4
(br.s,61 H, NH2); 8.69 (br.s, 1 H, NH2). 13C NMR (DMSOꢀd6),
δ: 27.39 (2 Me); 31.46 (C(7)); 41.71 (C(8)); 50.19 (C(6)); 99.62
(C(4a)); 129.48 (oꢀCC H ); 130.22 (mꢀCC H ); 133.25 (pꢀCC H );
6
4
(m, 4 H, mꢀHC H , oꢀHPh); 11.42 (br.s, 1 H, NH); 11.80 (br.s,
136.76 (ipsoꢀCC H );6 1453.44 (C(4)); 163.17 (C(2)); 1666.05
1 H, NH).
6
4
4
6
4
6
4
(C(8a)); 196.04 (C(5)). Assignment of the signals performed was
based on the 1H/13C HMBC twoꢀdimensional NMR.
8,8ꢀDimethylꢀ1,6ꢀdiphenylꢀ7,8ꢀdihydroꢀ1Hꢀpyrimido[4,5,6ꢀ
de]quinazolineꢀ2,5(3H,6H)ꢀdione (6a). A solution of MeONa in
MeOH (0.2 mL, 0.2 mmol) was added to urea 5a (0.08 g,
0.2 mmol) in MeOH (5 mL), and the mixture was refluxed for
10 min, cooled to 20 °C, acidified with AcOH, the solvent was
evaporated in vacuo to dryness. The residue was diluted with
water, a precipitate was filtered off and recrystallized from the
benzene—methanol mixture to obtain compound 6a (0.06 g,
80%), m.p. 308—309 °C. Found (%): C, 71.50; H, 5.19; N, 14.30.
C23H20N4O2. Calculated (%): C, 71.86; H, 5.24; N, 14.57.
MS, m/z (Irel (%)): 384 [M]+ (7), 369 [M – Me]+ (100), 326
[M – 2 Me – CO]+ (13), 250 [M – Me – PhNCO]+ (4), 119
[PhNCO]+ (17), 93 [PhNH2]+ (73). IR (CHCl3), ν/cm–1: 3392
7,7ꢀDimethylꢀ1ꢀphenylꢀ4ꢀ(N´ꢀphenylureido)ꢀ7,8ꢀdihydroꢀ
quinazolineꢀ2,5(1H,6H)ꢀdione (5a). Phenyl isocyanate (0.03 mL,
0.3 mmol) was added to dihydroquinazoline 4a (0.06 g, 0.2 mmol)
in anhydrous toluene (3 mL), and the mixture was refluxed for
6 h, cooled to 20 °C. A precipitate that formed was filtered off,
washed with toluene, dried in vacuo, and recrystallized from
MeOH to obtain urea 5a (0.07 g, 87%), m.p. > 300 °C. Found (%):
C, 68.78; H, 5.47; N, 13.77. C23H22N4O3. Calculated (%):
C, 68.64; H, 5.51; N, 13.92. MS, m/z (Irel (%)): 283 [M – PhNCO]+
(67), 282 [M – PhNCO – H]+ (100), 268 [M – PhNCO – Me]+
(12), 119 [PhNCO]+ (80), 93 [PhNH2]+ (81). IR (CHCl3),
ν/cm–1: 3184 (NH), 3030—2960 (NH, CH), 1696 (CO), 1648,
1596, 1528. 1H NMR (CDCl3), δ: 1.04 (s, 6 H, 2 Me); 2.35 (s, 2 H,
CH2); 2.47 (s, 2 H, CH2); 7.09 (t, 1 H, pꢀHPh, J = 7.5 Hz); 7.21
(d, 2 H, oꢀHPh, J = 7.5 Hz); 7.32 (m, 3 H, mꢀHPh, pꢀHPh); 7.59
(m, 4 H, oꢀHPh, mꢀHPh); 11.45 (br.s, 1 H, NH); 11.85 (br.s,
1 H, NH).
1ꢀ(4ꢀChlorophenyl)ꢀ4ꢀ(N´ꢀ4ꢀchlorophenylureido)ꢀ7,7ꢀdiꢀ
methylꢀ7,8ꢀdihydroquinazolineꢀ2,5(1H,6H)ꢀdione (5b) was synꢀ
thesized similarly to urea 5a from dihydroquinazoline 4b and
4ꢀchlorophenyl isocyanate, the yield was 89%, m.p. 290—291 °C
(sublimes). Found (%): C, 58.26; H, 4.14; Cl, 15.09; N, 11.72.
C23H20Cl2N4O3. Calculated (%): C, 58.61; H, 4.28; Cl, 15.04;
N, 11.89. MS, m/z (Irel (%)): 318 [M – ClC6H4NCO]+ (42), 317
[M – ClC6H4NCO – H]+ (57), 316 [M – ClC6H4NCO – 2H]+
(100), 153 [ClC6H4NCO]+ (58). IR (KBr), ν/cm–1: 3150—2950
1
(NH), 3024, 1712 (CO), 1652, 1632, 1560. H NMR (CDCl3),
δ: 0.93 (s, 6 H, 2 Me); 2.22 (s, 2 H, CH2); 3.99 (s, 1 H, H(9));
7.22 (d, 2 H, oꢀHPh, J = 8.0 Hz); 7.28 (d, 2 H, oꢀHPh, J = 8.0 Hz);
7.53 (m, 6 H, mꢀH, 2 Ph; pꢀH, 2 Ph); 7.97 (br.s, 1 H, NH).
13C NMR (CDCl3), δ: 28.62 (2 Me); 32.31 (C(8)); 40.16 (C(7));
95.12 (C(9b)); 106.95 (C(9)); 127.75 (oꢀCPh); 128.88 (oꢀCPh);
128.92 (pꢀCPh); 129.50 (pꢀCPh); 129.98 (mꢀCPh); 130.06 (mꢀCPh);
130.88 (C(9a)); 136.16 (ipsoꢀCPh); 136.68 (ipsoꢀCPh); 155.02
(C(6a)); 148.93, 156.02, 156.56 (C(2), C(3a), C(5)). Assignment
1
of the signals performed was based on the H/13C HMBC twoꢀ
dimensional NMR.
1,6ꢀDi(4ꢀchlorophenyl)ꢀ8,8ꢀdimethylꢀ7,8ꢀdihydroꢀ1Hꢀpyrꢀ
imido[4,5,6ꢀde]quinazolineꢀ2,5(3H,6H)ꢀdione (6b) was syntheꢀ
sized similarly to compound 6a from urea 5b, the yield was 65%, m.p.
295—296 °C (from the benzene—methanol mixture). Found (%):

2324
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 11, November, 2011
Dorokhov et al.
C, 60.92; H, 4.27; Cl, 15.62; N, 12.15. C23H18Cl2N4O2. Calcuꢀ
lated (%): C, 60.94; H, 4.00; Cl, 15.64; N, 12.36. MS, m/z
(Irel (%)): 453 [M]+ (1), 439 (72), 437 [M – Me – H]+ (100). IR
(CHCl3), ν/cm–1: 3400 (NH), 3020, 1712 (CO), 1652, 1628,
13C NMR spectra and to determine whether they belong to comꢀ
pound 6c or 6d.
This work was financially supported by the Russian
Academy of Sciences (Program for Basic Research of the
Presidium of RAS "Development of Methods for Preꢀ
paration of Chemical Compounds and Creation of New
Materials").
1
1560. H NMR (CDCl3), δ: 0.94 (s, 6 H, 2 Me); 2.21 (s, 2 H,
CH2); 4.00 (s, 1 H, H(9)); 7.17 (d, 2 H, oꢀHC H , J = 8.0 Hz);
6
4
7.22 (d, 2 H, oꢀHC H , J = 8.0 Hz); 7.50 (m, 4 H, mꢀH, 2 C6H4).
6
4
13C NMR (CDCl3), δ: 28.60 (2 Me); 32.33 (C(8)); 40.11 (C(7));
95.03 (C(9b)); 106.91 (C(9)); 129.26 (oꢀCC6H4); 130.28 (mꢀC,
2 C6H4); 130.37 (oꢀCC H ); 130.72 (C(9a)); 134.56 (ipsoꢀCC H );
6
6
4
134.86 (pꢀCC H ); 135.024(ipsoꢀCC H ); 135.58 (pꢀCC H ); 154.81
References
(C(6a)); 148.804, 155.53, 156.59 (C(24), C(3a), C(5)). Assignment
of the signals performed was based on the H/13C HMBC twoꢀ
6
6
6
4
1
1. Eur. Pat. Appl., EP 351058; Chem. Abstrs, 1990, 113, 40711r.
2. J. Cieplic, J. Pluta, O. Gubrynowicz, Acta Pol. Pharm., 2003,
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Soc., 2011, 32, 899.
4. Eur. Pat. Appl., EP 163599; Chem. Abstrs, 1986, 104,
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5. Ger. Offen., DE 3601731; Chem. Abstrs, 1988, 109, 54786y.
6. J. E. Gready, C. Mc Kinlay, M. G. Gebauer, Eur. J. Med.
Chem., 2003, 38, 719.
7. V. A. Dorokhov, M. F. Gordeev, A. V. Komkov, V. S. Bogꢀ
danov, Izv. Akad. Nauk SSSR, Ser. Khim., 1991, 159 [Bull.
Acad. Sci. USSR, Div. Chem. Sci. (Engl. Transl.), 1991, 40, 142].
8. V. A. Dorokhov, M. F. Gordeev, A. V. Komkov, V. S.
Bogdanov, Izv. Akad. Nauk SSSR, Ser. Khim., 1991, 2593
[Bull. Acad. Sci. USSR, Div. Chem. Sci. (Engl. Transl.), 1991,
40, 2267].
9. A. V. Komkov, A. M. Sakharov, V. S. Bogdanov, V. A. Doroꢀ
khov, Izv. Akad. Nauk, Ser. Khim., 1995, 1324 [Russ. Chem.
Bull. (Engl. Transl.), 1995, 44, 1278].
10. V. Dorokhov, A. Komkov, S. Baranin, ARKIVOC, 2003, 14,
178, www.arkatꢀusa.org, volume 2003, 14.
11. V. A. Voronkova, A. V. Komkov, V. A. Dorokhov, Izv. Akad.
Nauk, Ser. Khim., 2009, 347 [Russ. Chem. Bull., Int. Ed.,
2009, 58, 351].
dimensional NMR.
1ꢀ(4ꢀChlorophenyl)ꢀ8,8ꢀdimethylꢀ6ꢀphenylꢀ7,8ꢀdihydroꢀ1Hꢀ
pyrimido[4,5,6ꢀde]quinazolineꢀ2,5(3H,6H)ꢀdione (6c) and 6ꢀ(4ꢀ
chlorophenyl)ꢀ8,8ꢀdimethylꢀ1ꢀphenylꢀ7,8ꢀdihydroꢀ1Hꢀpyrimidoꢀ
[4,5,6ꢀde]quinazolineꢀ2,5(3H,6H)ꢀdione (6d) were synthesized
similarly to compound 6a from urea 5c and 5d. After concentraꢀ
tion, the residue was purified by column chromatography on
SiO2 (chloroform) to obtain a mixture of unseparable isomers 6c
and 6d (the ratio 1 : 1 according to the 1H NMR spectral data),
the yields were 67 and 80% from 5c and 5d, respectively, m.p.
284—285 °C. Found (%): C, 66.17; H, 4.62; Cl, 8.45; N, 13.00.
C23H19ClN4O2. Calculated (%): C, 65.95; H, 4.57; Cl, 8.46;
N, 13.38. MS, m/z (Irel (%)): 418 [M]+ (29), 403 [M – Me]+ (100),
148 (24). IR (CHCl3), ν/cm–1: 3400 (NH), 3020—2920 (NH,
1
CH), 1712 (CO), 1668, 1652, 1628, 1560. H NMR (600 MHz,
CDCl3), δ, isomer 6c/isomer 6d: 0.94/0.94 (s, 6 H, 2 Me);
2.22/2.22 (s, 2 H, CH2); 3.99/4.00 (s, 1 H, H(9)); 7.16—7.25/
7.16—7.25 (m, 4 H, oꢀHC H , oꢀHPh); 7.47—7.52/7.47—7.52
6
4
(m, 5 H, mꢀHC H , mꢀHPh, pꢀHPh); a signal for the proton from
4
NH is very bro6ad and resonates in the region ~8.70 1H NMR
(600 MHz, DMSOꢀd6), δ, isomer 6c/isomer 6d: 0.87/0.87 (s, 6 H,
2 Me); 2.20/2.22 (s, 2 H, CH2); 3.81/3.79 (s, 1 H, H(9)); 7.32/
7.27 (d, 2 H, oꢀHPh, J = 7.8 Hz); 7.32/7.39 (d, 2 H, oꢀHC H
,
6
4
J = 7.8 Hz); 7.49/7.44 (t, 1 H, pꢀHPh, J = 7.8 Hz); 7.55/7.53
(t, 2 H, mꢀHPh, J = 7.8 Hz); 7.57/7.59 (d, 2 H, mꢀHC H
,
12. V. A. Dorokhov, V. A. Voronkova, A. V. Komkov, S. V.
Baranin, L. S. Vasil´ev, Izv. Akad. Nauk, Ser. Khim., 2010,
1012 [Russ. Chem. Bull., Int. Ed., 2010, 59, 1035].
13. H. Wamhoff, W. Lamers, Synthesis, 1993, 111.
14. V. A. Voronkova, A. V. Komkov, A. S. Shashkov, V. A. Doroꢀ
khov, Izv. Akad. Nauk, Ser. Khim., 2011, 141 [Russ. Chem.
Bull., Int. Ed., 2011, 60, 148].
4
J = 7.8 Hz). 13C NMR (DMSOꢀd6), δ, isomer 6c/isomer 66d:
28.23/28.23 (2 Me); 31.40/31.40 (C(8)); 39.41/39.30 (C(7));
93.77/93.98 (C(9b)); 104.50/104.63 (C(9)); 127.88/128.84
(oꢀCPh); 128.54/128.02 (pꢀCPh); 129.16/129.21 (mꢀCPh); 129.43/
129.31 (mꢀCC H ); 130.87/129.93 (oꢀCC H ); 130.87/130.87
6
4
(C(9a)); 132.66/133.26 (pꢀCC H ); 135.53/61345.87 (ipsoꢀCC H ),
6
4
6
4
136.96/136.61 (ipsoꢀCPh); 154.34/154.19 (C(6a)); 148.96, 154.62,
154.70, 156.74, 156.91 (C(2), C(3a), C(5) from two isomers.
15N NMR based on the 1H/15N HMBC twoꢀdimensional NMR
spectrum (correlation on the orthoꢀprotons of the aryl groups,
the CH2 or CH protons, DMSOꢀd6), δ, isomer 6c/isomer 6d:
–250/–248 (N(1)); –205/–207 (N(6)). The 1H/1H COSY,
1H/13C HMBC and HSQC, and 1H/15N HMBC twoꢀdimenꢀ
sional NMR spectra were used to assign signals in the 1H and
15. I. Trummer, E. Ziegler, O. S. Wolfbeis, Synthesis, 1981, 225.
16. V. A. Mironov, A. D. Fedorovich, A. A. Akhrem, Usp. Khim.,
1981, 50, 1272 [Russ. Chem. Rev. (Engl. Transl.), 1981,
50, 666].
Received June 29, 2011;
in revised form September 28, 2011