Synthesis of 1-arylcytosine-5-carboxylic acid esters

Article abstract of DOI:10.1007/s11172-010-0201-5

A reaction of alkyl 2-(diaminomethylidene)-3-oxoalkanoates with arylisocyanates leads to the formation of the corresponding ureas, which upon the action of Na alkoxides cyclize to 1-aryl-6-R-cytosine-5-carboxylates. The latter reacting with arylisocyanates according to the similar scheme give rise to 3,6-diaryl-5-methylpyrimido[4,5-d]pyrimidine-2,4,7(1H,3H,6H)-triones.

Full text of DOI:10.1007/s11172-010-0201-5

Russian Chemical Bulletin, International Edition, Vol. 59, No. 5, pp. 1035—1040, May, 2010
1035
Synthesis of 1ꢀarylcytosineꢀ5ꢀcarboxylic acid esters
V. A. Dorokhov, V. A. Voronkova, A. V. Komkov, S. V. Baranin, and L. S. Vasil´ev
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 alkyl 2ꢀ(diaminomethylidene)ꢀ3ꢀoxoalkanoates with arylisocyanates leads
to the formation of the corresponding ureas, which upon the action of Na alkoxides cyclize to
1ꢀarylꢀ6ꢀRꢀcytosineꢀ5ꢀcarboxylates. The latter reacting with arylisocyanates according
to the similar scheme give rise to 3,6ꢀdiarylꢀ5ꢀmethylpyrimido[4,5ꢀd]pyrimidineꢀ
2,4,7(1H,3H,6H)ꢀtriones.
Key words: 2ꢀ(diaminomethylidene)ꢀ3ꢀoxobutanoic and 2ꢀ(diaminomethylidene)ꢀ3ꢀoxoꢀ
3ꢀphenylpropanoic acid esters, arylisocyanates, 1ꢀarylcytosineꢀ5ꢀcarboxylic acid esters, pyriꢀ
midoꢀ[4,5ꢀd]pyrimidineꢀ2,4,7(1H,3H,6H)ꢀtriones, baseꢀcatalyzed intramolecular cyclization.
Among cytosine derivatives, which is one of the most
important nucleic bases, there are known medicines of
antitumor, antiviral, antibacterial, antifungal, and antiꢀ
HIV action (see, for example, review1). At present, comꢀ
pounds of the cytosine series containing substituents at
position 5 of the pyrimidine ring are of particular interest,
for example, recently published works on the synthesis of
5ꢀaryloxyꢀ,2 5ꢀfluoroꢀ6ꢀfluoromethylꢀ,2 5ꢀaminomethylꢀ,3
5ꢀaminoꢀ,4 and 5ꢀphenylthiocytosines4 can be mentioned.
Earlier,5 we have suggested a convenient method for
the preparation of 5ꢀacetylcytosines 1 monoꢀ and disubꢀ
stituted at the exocyclic nitrogen atom from the correꢀ
sponding diacetyl ketene N,Nꢀacetals 2 and arylisoꢀ
cyanates (Scheme 1). The heterocyclization was carried
out upon reflux of the equimolar mixture of reagents
in toluene in the absence of catalysts. It is obvious that
ureas 3 are the intermediates in this process, though their
formation has not been registered.
Scheme 1
In continuation of our works on the synthesis of funcꢀ
tionally substituted pyrimidines,5—10 we studied the
action of arylisocyanates on 2ꢀ(diaminomethylidene)ꢀ
3ꢀoxoalkanoic esters, i.e., acyl alkoxycarbonyl ketene
aminals unsubstituted at the nitrogen atoms. In the preꢀ
ceding report,11 it was shown that cyclocondensation of
ketene aminals of this type with trichloroacetonitrile
results in obtaining 2ꢀtrichloromethylpyrimidines with
vicinal arrangement of the amino and alkoxycarbonyl
groups. Therefore, one could expect that heterocyclization
with arylisocyanates would lead (similarly to Scheme 1)
to the formation of 1ꢀarylcytosineꢀ5ꢀcarboxylic acid esters.
Ethyl cytosineꢀ5ꢀcarboxylate unsubstituted at the N(1)
atom is usually obtained from urea, cyanoacetic ester,
and ethyl orthoformate.12,13 Thiourea can be used instead
of urea, in this case the corresponding 2ꢀthiocytosine
derivative is isolated, which is further hydrolyzed.14 Anaꢀ
logous transformations involving Nꢀalkylureas lead to
3ꢀalkylcytosineꢀ5ꢀcarboxylic acid esters15,16 and, thereꢀ
fore, such an approach can not be used for the synthesis of
1ꢀsubstituted cytosines.
We found that reflux of aminals 4a—c with arylisoꢀ
cyanates in toluene afforded the corresponding ureas
5a—d precipitating on cooling the reaction mixtures
(Scheme 2). No intramolecular cyclization takes place
under these conditions. However, upon treatment with
sodium alkoxides compounds 5a—d eliminate water to be
transformed to 1ꢀarylcytosineꢀ5ꢀcarboxylic acid esters
6a—d. A solution of MeONa in MeOH is necessary to use
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 1012—1016, May, 2010.
1066ꢀ5285/10/5905ꢀ1035 © 2010 Springer Science+Business Media, Inc.

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Dorokhov et al.
for the synthesis of methyl esters, whereas for obtaining
ethyl esters, a solution of EtONa in EtOH. If, for example,
urea 5a is treated with MeONa in MeOH, methyl ester 6b
is smoothly formed instead of ethyl ester 6a as a result of
transesterification.
of signals. However, as it has been shown earlier, ketene
aminals 8 form intramolecular hydrogen bonds (IHB)
...
N—H O in neutral solvents, which promote the rotaꢀ
tion to slow down. In fact, their spectra in CDCl3 contain
a double set of signals, which indicates the presence of
E,Zꢀisomers existing in the dynamic equilibrium (Scheme 3).
Scheme 2
Scheme 3
i. Toluene, Δ
R1
Me
Me
Ph
R2
Et
Me
Et
Ar
Ph
Ph
a
b
c
d
Similar picture is observed in the spectra of compounds
5a—d in CDCl3 (the ratio of isomers ~3.5 : 1). The most
lowꢀfield of the NH signals belongs to a predominant
isomer. Apparently, it should be assigned to the proton
involved into the formation of the IHB with participation
of the most acidic (carbamide) and most basic (acyl) fragꢀ
ments. Thus, in the spectrum of compound 5a this signal
has chemical shift δ 14.67, whereas chemical shift of the
most lowꢀfield signal of the minor isomer is equal to
δ 12.60 (cf. with the corresponding values11 in the specꢀ
trum of compound 8 (R = Me) in CDCl3: for the preꢀ
dominant Eꢀisomer, δ 15.70; for the minor Zꢀisomer,
δ 13.79). The twoꢀdimensional NMR spectrum {1H—1H}
COSY of urea 5b in CDCl3 exhibits correlation between
the protons of the NH groups with chemical shifts δ 9.66
and 9.89 for the major isomer and with chemical shifts
δ 9.58 and 11.77 for the minor isomer, which should be
assigned to the protons of the NH2 group.
Pyrimidines 6a—d are colorless crystalline compounds,
which are well soluble in DMF, chloroform, and acetone,
but insoluble in hexane and benzene. Their mass spectra
contain the molecular ion peaks, whereas the IR spectra
(KBr) are characterized by the presence of the absorpꢀ
tion band for C=O in the region 1670—1675 cm–1. The
1H NMR spectra exhibit signals for the COOR2 groups,
whereas NH2 protons resonate as two singlets, one of
Ph
Me
Et
4ꢀMeC6H4
Thus, the acyl groups of compounds 5a—d participate
in the heterocyclization, though, elimination of alcohol
from the alkoxycarbonyl fragment can, in principle, lead
to the pyrimidine ring closure as well. Thus, for example
6ꢀaminoꢀ3ꢀRꢀuracils were obtained from ethyl 3,3ꢀdiꢀ
aminopropenoate and isocyanates.17 However, no formaꢀ
tion of the corresponding alternative
products, viz., uracils of the type 7,
was observed. It should be noted that
in the case of the reaction of ketene
aminals 4 with trichloroacetonitrile,
only the acyl group is involved into
the formation of the pyrimidine ring.11
Crystalline adducts 5a—d are well
soluble in DMSO, chloroform, and acetone, but insoluble
in hexane. Their mass spectra are characterized by the
presence of the molecular ion peaks and the absence of
[M – H2O]+ peaks. Compounds of the type 5 are close in
their structures to acetyl alkoxycarbonyl ketene aminal
Nꢀbenzoyl derivatives 8 studied by us earlier.18 A barrier
to rotation around the C=C bond for such pushꢀpull sysꢀ
tems is very low and the 1H NMR spectra of compounds 5
in DMSOꢀd6, like in the case of aminals 8, exhibit one set

Alkyl 1ꢀarylcytosineꢀ5ꢀcarboxylates synthesis
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 5, May, 2010
1037
which is in significantly lower field (see Experimental),
that, apparently, is explained by the formation of the
N—H O IHB.
Experimental
1H NMR spectra were recorded on a Bruker AMꢀ300
spectrometer (300 MHz), 13C and twoꢀdimensional NMR
spectra {1H—1H} COSY, {1H—13C} HSQC, and HMBC were
recorded on a Bruker Avance 600 spectrometer (600 MHz
(1H) and 150 MHz (13C), respectively). Residual signals of the
deuterated solvents (7.27 for CDCl3 and 2.50 for DMSOꢀd6 in
...
The presence of vicinal amino and alkoxycarbonyl
groups at positions 4 and 5 of the pyrimidine ring is favorable
for the annulation of the second pyrimidine ring. Earlier, a
series of pyrimido[4,5ꢀd]pyrimidineꢀ2,4(1H,3H)ꢀdione
derivatives has been obtained by the heterocyclization of
the such type pyrimidines with isocyanates.7,11,19
We have shown that cytosineꢀ5ꢀcarboxylic acid esters
can be also used for the synthesis of pyrimidopyrimidines.
Reflux of esters 6a,b,d with arylisocyanates in toluene
furnished the corresponding pyrimidinꢀ4ꢀylureas 9a—c,
which upon the action of MeONa in MeOH were conꢀ
verted to 3,6ꢀdiarylꢀ5ꢀmethylpyrimido[4,5ꢀd]pyrimidineꢀ
2,4,7(1H,3H,6H)ꢀtriones 10a—c (Scheme 4).
the H NMR spectra and 39.50 for DMSOꢀd6 in the 13C NMR
1
spectrum) were used as a reference. IR spectra were recorded on
a SpecordꢀM82 spectrometer, mass spectra, on a Kratos MSꢀ30
instrument (EI, 70 eV, temperature of the ionization chamber
was 250 °C, direct injection of compounds). Ketene aminals
4a—c were synthesized according to the known procedures.11,23
Arylisocyanates were purchased from Lancaster, anhydrous
toluene was obtained by distillation over Na, commercial
anhydrous ethanol and methanol were used after fractional
distillation.
2ꢀ[Amino(N´ꢀarylureido)methylidene]ꢀ3ꢀoxobutanoic and
2ꢀ[amino(N´ꢀphenylureido)methylidene]ꢀ3ꢀoxoꢀ3ꢀphenylꢀ
propanoic acid esters (5a—d). A mixture of the corresponding
ketene aminal 4a—c (8.0 mmol) and phenylꢀ or 4ꢀtolylisocyanate
(12 mmol) in anhydrous toluene (6 mL) was refluxed for 6 h,
cooled to 20 °C, a precipitate formed was filtered off (for 5c,
toluene was evaporated in vacuo, the residue was recrystallized
from the benzene—hexane solvent mixture), washed with
toluene, recrystallized from the corresponding solvent to obtain
colorless crystalline compounds 5a—d.
Scheme 4
Ethyl
2ꢀ[amino(N´ꢀphenylureido)methylidene]ꢀ3ꢀoxo
butanoate (5a). The yield was 69%, m.p. 160—162 °C (from
benzene). Found (%): C, 58.03; H, 6.11; N, 14.38. C14H17N3O4.
Calculated (%): C, 57.72; H, 5.88; N, 14.42. MS, m/z (Irel (%)):
291 [M]+ (36), 246 [M – EtO]+ (13), 213 [M – Ph – H]+
(63), 199 [M – PhNH]+ (35), 172 [M – PhNCO]+ (20), 152
[M – PhNH2 – EtOH]+ (63), 119 [PhNCO]+ (71), 93 [PhNH2]+
(100). IR (CHCl3), ν/cm–1: 3420, 3365, 3250—2820 (NH, CH),
1710 (CO), 1660 (CO), 1620. 1H NMR (DMSOꢀd6), δ: 1.29
(t, 3 H, MeCH2, J = 7.0 Hz); 2.35 (s, 3 H, Me); 4.20 (q, 2 H,
CH2, J = 7.0 Hz); 7.05 (t, 1 H, pꢀPh, J = 7.8 Hz); 7.31 (t, 2 H,
mꢀPh, J = 7.8 Hz); 7.51 (d, 2 H, oꢀPh, J = 7.8 Hz); 9.54 (br.s,
1 H, NH); 10.30 (br.s, 2 H, 2 NH); 13.11 (br.s, 1 H, NH).
1H NMR (CDCl3), δ, Eꢀisomer: 1.34 (t, 3 H, MeCH2, J = 7.0 Hz);
2.41 (s, 3 H, Me); 4.26 (q, 2 H, CH2, J = 7.0 Hz); 7.15 (t, 1 H,
pꢀPh, J = 7.8 Hz); 7.41 (m, 4 H, Ph); 7.88 (br.s, 1 H, NHPh);
9.61, 9.87 (both br.s, 2 H, NH2); 14.67 (br.s, 1 H, NH). The
spectrum also exhibits signals for the minor Zꢀisomer (19%):
11.71 (br.s, 1 H, NH from NH2); 12.60 (br.s, 1 H, NH), the rest
of signals overlap with the signals for the major isomer.
Methyl 2ꢀ[amino(N´ꢀphenylureido)methylidene]ꢀ3ꢀoxoꢀ
butanoate (5b). The yield was 90%, m.p. 170—172 °C (from
benzene—ethanol). Found (%): C, 56.13; H, 5.38; N, 15.04.
C13H15N3O4. Calculated (%): C, 56.31; H, 5.45; N, 15.15.
MS, m/z (Irel (%)): 277 [M]+ (54), 245 [M – MeOH]+ (10), 185
[M – PhNH]+ (35), 158 [M – PhNCO]+ (38), 152 [M – PhNH2 –
– MeOH]+ (71), 143 [M – PhNCO – Me]+ (56), 119 [PhNCO]+
(86), 93 [PhNH2]+ (100). IR (KBr), ν/cm–1: 3340, 3250, 3200
(NH, CH), 1710 (CO), 1660 (CO), 1620, 1600, 1540. 1H NMR
(CDCl3), δ, Eꢀisomer: 2.38 (s, 3 H, Me); 3.78 (s, 3 H, OMe);
7.12 (t, 1 H, pꢀPh, J = 7.8 Hz); 7.38 (m, 4 H, mꢀPh, oꢀPh); 8.02
(br.s, 1 H, NHPh); 9.66, 9.82 (both br.s, 2 H, NH2); 14.61 (br.s,
1 H, NH). The spectrum also exhibits signals for the minor
Ar1
Ph
Ph
Ar2
Ph
4ꢀClC6H4
Ph
R
Me
Et
a
b
c
4ꢀMeC6H4
Et
Pyrimidinylureas 9a—c and bicyclic compounds
10a—c were obtained as white crystalline compounds.
Their structures were confirmed by spectral methods
(1H and 13C NMR and IR spectroscopy, mass specꢀ
trometry). In particular, the mass spectra of pyrimidoꢀ
pyrimidine derivatives 10 are characterized by the presꢀ
ence of intensive peaks of molecular ions. In the 1H NMR
spectra (DMSOꢀd6) of these compounds, in contrast to
ureas 9a—c, there are no signals for the protons of the
COOR groups and one broad singlet for the NH at
δ 12.10—12.13 is observed.
Pyrimido[4,5ꢀd]pyrimidineꢀ2,4,7(1H,3H,6H)ꢀtriones
are poorly studied. Separate representatives of this type of
compounds have been synthesized earlier from uracil
derivatives.20—22

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Dorokhov et al.
Zꢀisomer (21%): 9.58, 11.71 (both br.s, 2 H, NH2); 12.48 (br.s,
1 H, NH), the rest of signals overlap with the signals for the
major isomer.
[M – EtOH]+ (21), 119 [PhNCO]+ (37), 118 [PhNCO – H]+
(46), 101 (100), 93 [PhNH2]+ (88). IR (KBr), ν/cm–1: 3400,
1
3130, 3075 (NH, CH), 1672 (CO), 1620, 1594, 1560. H NMR
Ethyl
2ꢀ[amino(N´ꢀphenylureido)methylidene]ꢀ3ꢀoxoꢀ
(CDCl3), δ: 1.35 (t, 3 H, MeCH2, J = 7.0 Hz); 2.25 (s, 3 H, Me);
4.33 (q, 2 H, CH2, J = 7.0 Hz); 7.05, 7.80 (both br.s, 2 H, NH2);
7.20 (d, 2 H, oꢀPh, J = 7.8 Hz); 7.50 (m, 3 H, mꢀPh, pꢀPh).
Methyl 4ꢀaminoꢀ6ꢀmethylꢀ2ꢀoxoꢀ1ꢀphenylꢀ1,2ꢀdihydroꢀ
pyrimidineꢀ5ꢀcarboxylate (6b). The yields from ureas 5a and 5b
were 61 and 70%, respectively, m.p. 247—249 °C (from methanol).
Found (%): C, 60.09; H, 5.08; N, 16.00. C13H13N3O3. Calculꢀ
ated (%): C, 60.23; H, 5.05; N, 16.21. MS, m/z (Irel (%)): 259
[M]+ (100), 244 [M – Me]+ (22), 231 [M – CO]+ (22), 226
[M – MeOH – H]+ (89), 199 [M – CO2 – Me – H]+ (78).
IR (KBr), ν/cm–1: 3400, 3072 (NH, CH), 1672 (CO), 1592,
1560, 1492. 1H NMR (CDCl3), δ: 2.27 (s, 3 H, Me); 3.87 (s,
3 H, OMe); 6.93, 7.78 (both br.s, 2 H, NH2); 7.19 (d, 2 H, oꢀPh,
J = 7.8 Hz); 7.50 (m, 3 H, mꢀPh, pꢀPh).
Ethyl 4ꢀaminoꢀ2ꢀoxoꢀ1,6ꢀdiphenylꢀ1,2ꢀdihydropyrimidineꢀ
5ꢀcarboxylate (6c). The yield was 65%, m.p. 268—270 °C (from
ethanol). Found (%): C, 67.83; H, 5.17; N, 12.71. C19H17N3O3.
Calculated (%): C, 68.05; H, 5.11; N, 12.53. IR (CHCl3),
ν/cm–1: 3500, 3280 (NH, CH), 1675 (CO), 1615. 1H NMR
(CDCl3), δ: 0.60 (t, 3 H, MeCH2, J = 7.0 Hz); 3.80 (q, 2 H,
CH2, J = 7.0 Hz); 6.56, 7.95 (both br.s, 2 H, NH2); 6.97—7.22
(m, 10 H, 2 Ph).
3ꢀphenylpropanoate (5c). The yield was 81%, m.p. 163—165 °C
(from benzene—hexane). Found (%): C, 64.58; H, 5.11; N,
11.84. C19H19N3O4. Calculated (%): C, 64.58; H, 5.42; N, 11.89.
MS, m/z (Irel (%)): 353 [M]+ (5), 261 [M – PhNH]+ (4), 234
[M – PhNCO]+ (7), 105 [PhCO]+ (100), 93 [PhNH2]+ (78).
IR (CHCl3), ν/cm–1: 3415, 3380, 3320—2840 (NH, CH), 1715
1
(CO), 1660 (CO), 1630. H NMR (DMSOꢀd6), δ: 0.54 (t, 3 H,
Me, J = 7.0 Hz); 3.71 (q, 2 H, CH2, J = 7.0 Hz); 7.09 (t, 1 H,
pꢀPh, J = 7.8 Hz); 7.31—7.43 (m, 7 H, 2 Ph); 7.51 (d, 2 H,
oꢀPh, J = 7.8 Hz); 9.52 (br.s, 1 H, NH); 9.82 (br.s, 1 H, NH);
10.48 (br.s, 1 H, NH); 12.29 (br.s, 1 H, NH). 1H NMR (CDCl3),
δ, Eꢀisomer: 0.64 (t, 3 H, MeCH2, J = 7.0 Hz); 3.80 (q, 2 H,
CH2, J = 7.0 Hz); 7.05—7.45 (m, 10 H, 2 Ph); 8.10 (br.s, 1 H,
NHPh); 9.48, 9.58 (both br.s, 2 H, NH2); 13.68 (br.s, 1 H, NH).
The spectrum also exhibits signals for the minor Zꢀisomer
(23.5%): 10.80 (br.s, 1 H, NH from NH2); 12.02 (br.s, 1 H, NH),
the rest of signals overlap with the signals for the major isomer.
Ethyl
2ꢀ[amino(N´ꢀ4ꢀtolylureido)methylidene]ꢀ3ꢀoxoꢀ
butanoate (5d). The yield was 79%, m.p. 165—167 °C (from
benzene). Found (%): C, 59.00; H, 6.42; N, 13.47. C15H19N3O4.
Calculated (%): C, 59.01; H, 6.27; N, 13.76. MS, m/z
(Irel (%)): 305 [M]+ (7), 172 [M – MeC6H4NCO]+ (17), 157
[M – MeC6H4NCO – Me]+ (29), 133 [MeC6H4NCO]+ (85),
107 [MeC6H4NH2]+ (100). IR (KBr), ν/cm–1: 3312, 3192, 2984
(NH, CH), 1704 (CO), 1656 (CO), 1612, 1544, 1512. 1H NMR
(DMSOꢀd6), δ: 1.26 (t, 3 H, MeCH2, J = 7.0 Hz); 2.26 (s, 3 H,
Me); 2.35 (s, 3 H, Me); 4.19 (q, 2 H, CH2, J = 7.0 Hz); 7.11 (d,
2 H, mꢀC6H4, J = 7.8 Hz)*; 7.39 (d, 2 H, oꢀC6H4, J = 7.8 Hz);
9.58 (br.s, 1 H, NH); 10.26 (br.s, 1 H, NH); 10.31, 13.10 (both
Ethyl 4ꢀaminoꢀ6ꢀmethylꢀ2ꢀoxoꢀ1ꢀ(4ꢀtolyl)ꢀ1,2ꢀdihydropyriꢀ
midineꢀ5ꢀcarboxylate (6d). The yield was 58%, m.p. 217—219 °C
(from ethanol). Found (%): C, 62.78; H, 5.72; N, 14.77.
C15H17N3O3. Calculated (%): C, 62.71; H, 5.96; N, 14.62.
MS, m/z (Irel (%)): 287 [M]+ (58), 240 [M – C2H5OH – H]+
(26), 213 [M – CO2 – C2H5 – H]+ (20), 91 [MeC6H4]+ (100).
IR (KBr), ν/cm–1: 3400, 3080 (NH, CH), 1668 (CO), 1568,
1
1496. H NMR (CDCl3), δ: 1.35 (t, 3 H, MeCH2, J = 7.0 Hz);
1
br.s, 2 H, NH2). H NMR (CDCl3), δ, Eꢀisomer: 1.34 (t, 3 H,
2.26 (s, 3 H, Me); 2.40 (s, 3 H, Me); 4.35 (q, 2 H, CH2, J = 7.0 Hz);
6.69, 7.80 (both br.s, 2 H, NH2); 7.07 (d, 2 H, oꢀC6H4, J = 7.8 Hz);
7.31 (d, 2 H, mꢀC6H4, J = 7.8 Hz).
MeCH2, J = 7.0 Hz); 2.33 (s, 3 H, Me); 2.42 (s, 3 H, Me); 4.25
(q, 2 H, CH2, J = 7.0 Hz); 7.15 (d, 2 H, mꢀC6H4, J = 7.8 Hz);
7.29 (d, 2 H, oꢀC6H4, J = 7.8 Hz); 7.94 (br.s, 1 H, NHC6H4);
9.64, 9.86 (both br.s, 2 H, NH2); 14.56 (br.s, 1 H, NH). The
spectrum also exhibits signals for the minor Zꢀisomer (22%):
9.60, 11.69 (both br.s, 2 H, NH2), 12.50 (br.s, 1 H, NH), the
rest of signals overlap with the signals for the major isomer.
4ꢀAminoꢀ1ꢀarylꢀ6ꢀmethyl(phenyl)ꢀ2ꢀoxoꢀ1,2ꢀdihydroꢀ
pyrimidineꢀ5ꢀcarboxylic esters (6a—d). A mixture of urea 5a—d
(2 mmol) and solution of the corresponding R2ONa (1 mmol) in
anhydrous R2OH (10 mL) was stirred for 15—30 min at 20 °C
until a precipitate was completely dissolved (for the synthesis of
pyrimidine 6b from urea 5a, 2 mmol of MeONa in anhydrous
MeOH (10 mL) was used and the reaction time was increased to
1 h for accomplishing transesterification of the ester group). The
solvent was evaporated dry in vacuo at 20 °C, the residue was
washed with water, dried, and washed with diethyl ether
(10 mL) to obtain white crystalline compounds 6a—d.
Methyl 6ꢀmethylꢀ2ꢀoxoꢀ1ꢀphenylꢀ4ꢀ(N´ꢀphenylureido)ꢀ
1,2ꢀdihydropyrimidineꢀ5ꢀcarboxylate (9a). A mixture of pyriꢀ
midine 6b (0.23 g, 0.9 mmol) and phenylisocyanate (0.14 mL,
1.3 mmol) in anhydrous toluene (3 mL) was refluxed for 6 h,
cooled to 20 °C, a precipitate formed was filtered off, washed
with toluene and light petroleum to obtain white crystals
of compound 9a (0.27 g, 79%), m.p. 250—252 °C (from
benzene—methanol). Found (%): C, 63.66; H, 4.91; N, 15.02.
C20H18N4O4. Calculated (%): C, 63.49; H, 4.79; N, 14.81.
MS, m/z (Irel (%)): 378 [M]+ (1), 259 [M – PhNCO]+ (55), 144
(28), 119 [PhNCO]+ (100). IR (KBr), ν/cm–1: 3424, 3184
(NH, CH), 1696 (CO), 1672 (CO), 1584, 1524. 1H NMR
(CDCl3), δ: 2.33 (s, 3 H, Me); 3.97 (s, 3 H, OMe); 7.11 (t, 1 H,
pꢀPhNH, J = 7.8 Hz); 7.22 (d, 2 H, oꢀPhN, J = 7.8 Hz); 7.33
(t, 2 H, mꢀPhNH, J = 7.8 Hz); 7.60 (m, 5 H, 2 Ph); 10.09 (br.s,
1 H, NH); 11.99 (br.s, 1 H, NH).
Ethyl 4ꢀaminoꢀ6ꢀmethylꢀ2ꢀoxoꢀ1ꢀphenylꢀ1,2ꢀdihydropyriꢀ
midineꢀ5ꢀcarboxylate (6a). The yield was 65%, m.p. 196—198 °C
(from ethanol). Found (%): C, 61.49; H, 5.64; N, 15.14.
C14H15N3O3. Calculated (%): C, 61.53; H, 5.53; N, 15.38.
MS, m/z (Irel (%)): 273 [M]+ (56), 245 [M – CO]+ (13), 227
Ethyl 4ꢀ[N´ꢀ(4ꢀchlorophenyl)ureido]ꢀ6ꢀmethylꢀ2ꢀoxoꢀ
1ꢀphenylꢀ1,2ꢀdihydropyrimidineꢀ5ꢀcarboxylate (9b). A mixture
of pyrimidine 6a (0.1 g, 0.4 mmol) and 4ꢀchlorophenylisocyanate
(0.1 g, 0.6 mmol) in anhydrous toluene (3 mL) was refluxed
for 10 h. The solvent was evaporated in vacuo, the residue
was recrystallized from the benzene—hexane solvent mixture
to obtain white crystals of compound 9b (0.14 g, 87%),
m.p. 186—188 °C. Found (%): C, 59.35; H, 4.68; N, 12.76;
Cl, 8.47. C21H19ClN4O4. Calculated (%): C, 59.09; H, 4.49;
1
* Here and in the H NMR spectra that follow, positions of the
protons in the disubstituted benzene ring is given with respect to
the carbon atom bound to the nitrogen atom.

Alkyl 1ꢀarylcytosineꢀ5ꢀcarboxylates synthesis
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 5, May, 2010
1039
N, 13.13; Cl, 8.31. MS, m/z (Irel (%)): 273 [M – ClC6H4NCO]+
(9), 152 [ClC6H4NCO – H]+ (100). IR (CHCl3), ν/cm–1: 3380,
3180 (NH, CH), 1704 (CO), 1680 (CO), 1604, 1592, 1524.
1H NMR (CDCl3), δ: 1.40 (t, 3 H, MeCH2, J = 7.0 Hz); 2.31 (s,
3 H, Me); 4.42 (q, 2 H, CH2, J = 7.0 Hz); 7.22 (m, 4 H, oꢀPh,
mꢀC6H4); 7.58 (m, 5 H, mꢀPh, pꢀPh, oꢀC6H4); 10.19 (br.s, 1 H,
NH); 12.08 (br.s, 1 H, NH).
Found (%): C, 66.48; H, 4.25; N, 15.15. C20H16N4O3. Calculꢀ
ated (%): C, 66.66; H, 4.48; N, 15.55. MS, m/z (Irel (%)): 360
[M]+ (100), 332 [M – CO]+ (69), 240 [M – PhNCO – H]+ (51),
226 [M – MeC6H4NCO – H]+ (53), 213 [M – PhNCO – CO]+
(89), 132 [MeC6H4NCO – H]+ (86), 91 [MeC6H4]+ (93).
IR (KBr), ν/cm–1: 3440, 3176 (NH, CH), 1740 (CO), 1684
(CO), 1616, 1536, 1508. 1H NMR (DMSOꢀd6), δ: 2.38 (s, 3 H,
Me); 2.46 (s, 3 H, Me); 7.22 (d, 2 H, oꢀPh, J = 7.8 Hz); 7.29 (d,
2 H, oꢀC6H4, J = 7.8 Hz); 7.38 (d, 2 H, mꢀC6H4, J = 7.8 Hz);
7.48 (m, 3 H, Ph); 12.10 (br.s, 1 H, NH).
Ethyl 6ꢀmethylꢀ2ꢀoxoꢀ1ꢀ(4ꢀtolyl)ꢀ4ꢀ(N´ꢀphenylureido)ꢀ
1,2ꢀdihydropyrimidineꢀ5ꢀcarboxylate (9c) was synthesized
similarly to urea 9a from pyrimidine 6d and PhNCO. The yield
was 76%, m.p. 178—180 °C. Found (%): C, 65.18; H, 5.39; N,
13.49. C22H22N4O4. Calculated (%): C, 65.01; H, 5.46; N, 13.78.
MS, m/z (Irel (%)): 406 [M]+ (2), 287 [M – PhNCO]+ (88), 286
[M – PhNCO – H]+ (100), 258 [M – MeC6H4NCO – Me]+
(32), 240 (73), 213 [M – MeC6H4NCO – Me – OEt]+ (75), 119
[PhNCO]+ (69). IR (KBr), ν/cm–1: 3408—3000 (NH, CH),
The authors are grateful to A. S. Shashkov (IOCh
RAS) for the recording of twoꢀdimensional NMR spectra.
This work was financially supported by the Russian
Academy of Sciences (Program for Basic Research of
the Presidium of RAS “Development of Methods for the
Preparation of Chemical Compounds and Creation of
New Materials”).
1
1710 (CO), 1680 (CO), 1596, 1532. H NMR (CDCl3), δ: 1.40
(t, 3 H, MeCH2, J = 7.0 Hz); 2.35 (s, 3 H, Me); 2.43 (s, 3 H,
Me); 4.42 (q, 2 H, CH2, J = 7.0 Hz); 7.08 (d, 2 H, oꢀC6H4,
J = 7.8 Hz); 7.19 (t, 1 H, pꢀPh, J = 7.8 Hz); 7.31 (m, 4 H, mꢀPh,
mꢀC6H4); 7.61 (d, 2 H, oꢀPh, J = 7.8 Hz); 10.12 (br.s, 1 H,
NH); 11.97 (br.s, 1 H, NH).
References
5ꢀMethylꢀ3,6ꢀdiphenylpyrimido[4,5ꢀd]pyrimidineꢀ2,4,7ꢀ
(1H,3H,6H)ꢀtrione (10a). A mixture of urea 9a (0.1 g, 0.3 mmol)
and MeONa (0.3 mmol) in MeOH (5 mL) was stirred for 10 min
at 20 °C until urea was completely dissolved. The reaction
mixture was acidified with AcOH to pH 6, the solvent was
evaporated dry in vacuo, the residue was washed with water,
dried, and washed with diethyl ether to obtain bicycle 10a
(0.065 g, 72%), m.p. > 300 °C. Found (%): C, 65.48; H, 3.88;
N, 16.03. C19H14N4O3. Calculated (%): C, 65.89; H, 4.07;
N, 16.18. MS, m/z (Irel (%)): 346 [M]+ (100), 318 [M – CO]+
(41), 226 [M – PhNCO – H]+ (22), 212 [M – PhNCO – Me]+
(17), 199 [M – PhNCO – CO]+ (33), 77 [Ph]+ (46). IR (KBr),
ν/cm–1: 3496, 3176, 3056 (NH, CH), 1736 (CO), 1708 (CO),
1. K. S. Jain, T. S. Chitre, P. B. Miniyar, M. K. Kathiravan,
V. S. Bendre, V. S. Veer, S. R. Shahane, C. J. Shishoo,
Current Science, 2006, 90, 793.
2. J. L. Barkin, M. D. Faust Jr, W. C. Trenkle, Org. Lett., 2003,
5, 3333.
3. D. Prukala, Tetrahedron Lett., 2006, 47, 9045.
4. L.ꢀK. Huang, Y.ꢀC. Cherng, Y.ꢀR. Cheng, J.ꢀP. Jang,
Y.ꢀL. Chao, Y.ꢀJ. Cherng, Tetrahedron, 2007, 63, 5323.
5. V. A. Dorokhov, M. F. Gordeev, A. V. Komkov, V. S.
Bogdanov, Izv. Akad. Nauk, Ser. Khim., 1991, 2593 [Bull.
Acad. Sci. USSR, Div. Chem. Sci. (Engl. Transl.), 1991, 40,
2267].
6. V. A. Dorokhov, M. F. Gordeev, A. V. Komkov, V. S.
Bogdanov, Izv. Akad. Nauk, Ser. Khim., 1990, 145 [Bull.
Acad. Sci. USSR, Div. Chem. Sci. (Engl. Transl.), 1990, 39,
130].
7. V. A. Dorokhov, M. F. Gordeev, A. V. Komkov, V. S.
Bogdanov, Izv. Akad. Nauk, Ser. Khim., 1991, 159 [Bull.
Acad. Sci. USSR, Div. Chem. Sci. (Engl. Transl.), 1991, 40,
142].
8. A. V. Komkov, A. M. Sakharov, V. S. Bogdanov, V. A.
Dorokhov, Izv. Akad. Nauk, Ser. Khim., 1995, 1324 [Russ.
Chem. Bull. (Engl. Transl.), 1995, 44, 1278].
1
1668, 1612, 1536. H NMR (DMSOꢀd6), δ: 2.46 (s, 3 H, Me);
7.28 (d, 2 H, oꢀPh, J = 7.8 Hz); 7.38 (d, 2 H, oꢀPh, J = 7.8 Hz);
7.49 (m, 3 H, Ph); 7.59 (m, 3 H, Ph); 12.12 (br.s, 1 H, NH).
3ꢀ(4ꢀChlorophenyl)ꢀ5ꢀmethylꢀ6ꢀphenylpyrimido[4,5ꢀd]ꢀ
pyrimidineꢀ2,4,7(1H,3H,6H)ꢀtrione (10b) was synthesized
similarly to compound 10a from urea 9b. The yield was 51%,
m.p. > 300 °C (from benzene—methanol). Found (%): C, 59.53;
H, 3.60; Cl, 9.51; N, 14.44. C19H13ClN4O3. Calculated (%):
C, 59.93; H, 3.44; Cl, 9.31; N, 14.71. MS, m/z (Irel (%)): 380
[M]+ (100), 352 [M – CO]+ (57), 199 [M – ClC6H4NCO – CO]+
(43), 118 [PhNCO – H]+ (58), 76 [C6H4]+ (95). IR (KBr),
ν/cm–1: 3430, 3064, 2924 (NH, CH), 1740 (CO), 1688 (CO),
1612, 1592, 1540. 1H NMR (DMSOꢀd6), δ: 2.45 (s, 3 H, Me); 7.34
(d, 2 H, oꢀC6H4, J = 8.4 Hz); 7.36 (d, 2 H, oꢀPh, J = 7.8 Hz);
7.52 (t, 1 H, pꢀPh, J = 7.8 Hz); 7.55 (d, 2 H, mꢀC6H4, J = 8.4 Hz);
7.58 (t, 2 H, mꢀPh, J = 7.8 Hz); 12.13 (br.s, 1 H, NH). 13C NMR
(DMSOꢀd6), δ: 19.56 (Me); 95.35 (C(4a)); 127.72 (oꢀPh); 128.87
(mꢀC6H4); 129.10 (pꢀPh); 129.69 (mꢀPh); 131.02 (oꢀC6H4);
132.89 (pꢀC6H4); 134.08 (ipsoꢀC6H4); 137.52 (ipsoꢀPh); 149.80,
159.54, 160.74 (C(2), C(4), C(7), C(8a)); 167.39 (C(5)).
Assignment of signals in the 1H and 13C NMR spectra was
performed based on the twoꢀdimensional spectra {1H—1H}
COSY, {1H—13C} HSQC, and HMBC.
9. V. Dorokhov, A. Komkov, S. Baranin, ARKIVOC, 2003, XIV,
178, www.arkatꢀusa.org.
10. A. V. Komkov, V. A. Dorokhov, Izv. Akad. Nauk, Ser. Khim.,
2007, 2212 [Russ. Chem. Bull., Int. Ed., 2007, 56, 2290].
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].
12. C. W. Whitehead, J. Am. Chem. Soc., 1953, 75, 671.
13. R. S. Vardanyan, V. J. Hruby, G. G. Danagulyan, A. D.
Mkrtchyan, J. Heterocycl. Chem., 2005, 42, 557.
14. T. L. V. Ulbricht, Ch. C. Price, J. Org. Chem., 1956, 21, 567.
15. C. W. Whitehead, J. J. Traverso, J. Am. Chem. Soc., 1955,
77, 5867.
5ꢀMethylꢀ3ꢀphenylꢀ6ꢀ(4ꢀtolyl)ꢀpyrimido[4,5ꢀd]pyrimidineꢀ
2,4,7(1H,3H,6H)ꢀtrione (10c) was synthesized similarly to comꢀ
pound 10a from urea 9c. The yield was 55%, m.p. 283—285 °C.
16. M. Deshmukh, M. Mittelbach, H. Junek, Monatsh. Chem.,
1995, 126, 91.

1040
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 5, May, 2010
Dorokhov et al.
17. P. B. Sulay, I. C. Ivanov, Liebigs Ann. Chem., 1987, 1101.
18. V. A. Dorokhov, M. F. Gordeev, Z. K. Dem´yanets, M. N.
Bochkareva, V. S. Bogdanov, Izv. Akad. Nauk, Ser. Khim.,
1989, 1806 [Bull. Acad. Sci. USSR, Div. Chem. Sci. (Engl.
Transl.), 1989, 38, 1654].
22. W. K. Chung, S. K. Kim, M. W. Chun, D. Kim, Yakhak
Hoechi, 1984, 28, 97; Chem. Abstrs, 1984, 101, 171197c.
23. V. A. Dorokhov, Z. K. Dem´yanets, Izv. Akad. Nauk, Ser.
Khim., 1993, 419 [Russ. Chem. Bull. (Engl. Transl.), 1993,
42, 384].
19. N. Graveleau, T. Masquelin, Synthesis, 2003, 1739.
20. H. Bredereck, G. Simchen, R. Wahl, F. Effenberger, Chem.
Ber., 1968, 101, 512.
Received January 26, 2010;
in revised form March 19, 2010
21. I. Devi, H. N. Borah, P. J. Bhuyan, Tetrahedron Lett., 2004,
45, 2405.