Three-component condensation of diethyl isophthaloyldiacetate, aromatic aldehyde, and urea as a new method for the synthesis of 1,3-bis(2-oxo-1,2,3,4- tetrahydropyrimidin-6-yl)benzenes

Article abstract of DOI:10.1007/s11172-008-0161-1

Condensation of diethyl isophthaloyldiacetate, aromatic aldehyde, and urea in the presence of Me₃SiCl proceeds efficiently and faster than in the absence of the latter to form 1,3-bis(2-oxo-1,2,3,4-tetrahydropyrimidin-6- yl)benzene derivatives capable to give inclusion complexes with DMF.

Full text of DOI:10.1007/s11172-008-0161-1

Russian Chemical Bulletin, International Edition, Vol. 57, No. 6, pp. 1257—1263, June, 2008
1257
Threeꢀcomponent condensation of diethyl isophthaloyldiacetate,
aromatic aldehyde, and urea as a new method for the synthesis
of 1,3ꢀbis(2ꢀoxoꢀ1,2,3,4ꢀtetrahydropyrimidinꢀ6ꢀyl)benzenes
V. A. Mamedov, S. V. Vdovina, E. I. Vorkunova, L. V. Mustakimova,
A. F. Saifina, A. T. Gubaidullin, I. Kh. Rizvanov, Ya. A. Levin, and I. A. Litvinov
A. E. Arbuzov Institute of Organic and Physical Chemistry,
Kazan Scientific Center of the Russian Academy of Sciences,
8 ul. Akad. Arbuzova, 420088 Kazan, Russian Federation.
Fax: +7 (843) 273 2253. Eꢀmail: mamedov@iopc.knc.ru
Condensation of diethyl isophthaloyldiacetate, aromatic aldehyde, and urea in the presence
of Me3SiCl proceeds efficiently and faster than in the absence of the latter to form 1,3ꢀbis(2ꢀoxoꢀ
1,2,3,4ꢀtetrahydropyrimidinꢀ6ꢀyl)benzene derivatives capable to give inclusion complexes with DMF.
Key words: diethyl isophthaloyldiacetate, the Biginelli reaction, 2ꢀoxoꢀ1,2,3,4ꢀtetraꢀ
hydropyrimidines, trimethylsilyl chloride, NMR spectra, Xꢀray analysis.
Special interest to 2ꢀoxoꢀ1,2,3,4ꢀtetrahydropyrimꢀ
idines (the "Biginelli compounds") is caused in the last
years by the finding among their derivatives compounds
with important pharmacological properties,1 including
blocators of calcium channels,2 antiꢀhypertonic meꢀ
dicins,3—5 alphaꢀ1aꢀantagonists, and antagonists of neuꢀ
ropeptide Y (NPY).7 It was also found that the marine
alkaloids containing dihydropyrimidineꢀ5ꢀcarboxylate
fragment8,9 are inhibitors of the HIV gpꢀ120ꢀCD4.10,11
Nowadays, a plenty of methods for the modification
of the Biginelli synthesis of 2ꢀoxoꢀ1,2,3,4ꢀtetrahydropyꢀ
rimidines is developed, among them are methods, which
include a classic cyclocondensation of βꢀketoester, aldeꢀ
hyde, and urea,12 methods with the use of microwave and
ultrasonic irradiation,13 with the use of Lewis acids
and protonꢀdonor acids such as ZrCl4,14 InBr3,15
Ce(NH4)2(NO3)6,16 Mn(OAc)3•2H2O,17 In(OTf)3,18
InCl3,19 LaCl3,20 H2SO4,21 AcOH,22 KSF montmorilloꢀ
nite,23 polyphosphate esters,24 BF3—OEt2/CuCl/
AcOH,25 HCl (see Refs 26—28), and ionic liquids such
as 1ꢀnꢀbutylꢀ3ꢀmethylimidazolium tetrafluoroborate or
1ꢀnꢀbutylꢀ3ꢀmethylimidazolium hexafluorophosphate.29
However, the attempts to synthesize various pyrimiꢀ
dine derivatives by this reaction so far were generally
limited to the variations in aldehydes or ketones and very
rarely in ketoesters, the sources of a twoꢀcarbon fragꢀ
ment.1—29
synthesis of podands with dihydropyrimidine and dihyꢀ
droazolopyrimidine terminal fragments with the use of
1,7ꢀbis(2ꢀformylphenyl)ꢀ1,4,7ꢀtrioxaheptane and poꢀ
dands with dihydropyrimidine and dihydropyrimidinethꢀ
ione fragments with the use of 1,5ꢀbis(ureido)ꢀ3ꢀoxaꢀ
pentane30 were presented. In the second work, another
oneꢀstep synthesis of the rigidly oriented 1,3ꢀ and
1,4ꢀbis(pyrimidinyl)benzenes with the use of isoꢀ and
terephthalic aldehydes is described.31
Compounds with two ketoester groups, suppliers of
a twoꢀcarbon fragment for the construction of pyrimidine
ring, so far were not used in the Biginelli reaction. We
found that if diethyl isophthaloyldiacetate (1) is used in
this reaction as the synthetic equivalent of the twoꢀcarbon
synthons instead of usual ketoester, then the earlier unꢀ
known 1,3ꢀbis(2ꢀoxoꢀ1,2,3,4ꢀtetrahydropyrimidinꢀ6ꢀ
yl)benzene derivatives 2 can be obtained. The keeping of
the reaction mixture composed of diester 1, urea, and
the corresponding aldehyde in acetic acid at room temꢀ
perature for 30 days leads to the final products in low
yield (Scheme 1).
An increase in the reaction time and temperature, as
well as a change in the concentrations of reagents did not
lead to substantial increase in the yields of the target
products. When a classic version of the Biginelli reacꢀ
tion (ethanol + catalytic amount of hydrochloric acid,
the reaction time of 18—25 h, heating)26 was used,
the yields of the target products were only 3—6%. Atꢀ
tempts to carry out the reaction of diketoester 1 in soluꢀ
tion of acetic acid and methanol were not successful at all
in the isolation of the desired products, though, earlier
As to the use in this reaction of bisꢀreagents, viz.,
compounds containing two identical functional groups
necessary for the Biginelli reaction, only two papers are
published on this subject.30,31 In one of them, a oneꢀstep
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1233—1239, June, 2008.
1066ꢀ5285/08/5706ꢀ01257 © 2008 Springer Science+Business Media, Inc.

1258
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 6, June, 2008
Mamedov et al.
Scheme 1
R =
(a),
(b),
(c),
(d),
(e),
(f),
(g)
we successfully conducted the Biginelli reaction with parꢀ
ticipation of dichloroacetylaroylmethanes in this solution,
which allowed us to reach high yields of perhydropyrimꢀ
idines.
We found that if the reaction under consideration (see
Scheme 1) is carried out in a mixture of DMF and acetoꢀ
nitrile (1 : 2) in the presence of trimethylchlorosilane,
the reaction time decreases (to 1 day) and the target
1,3ꢀbis(2ꢀoxoꢀ1,2,3,4ꢀtetrahydropyrimidinꢀ6ꢀyl)benꢀ
zene derivatives 2а—g are obtained in higher yields
(Scheme 2).
autocatalysis with HCl, which is eliminated during interꢀ
action of Me3SiCl with the product of this reaction, i.e.,
water, could have been another cause for the acceleration
of the reaction under consideration by trimethylchlorosiꢀ
lane. Though, the carrying out of the process in the flow
of dry hydrogen chloride leads to its considerable accelꢀ
eration neither in МеОН nor in DMF—MeCN, the posꢀ
sibility of catalysis by hydrogen chloride, apparently, can
exist since in the course of the reaction, it is formed
gradually, which, probably, creates a possibility for
the selective course of the process.
It could have been suggested that the order of addition
of reagents, as it was observed in Ref. 35, will favor
an increase in the yield of final products. However,
the condensation of diethyl isophthaloyldiacetate, benzꢀ
aldehyde, and urea according to the earlier published
procedure,35 when the high yields were obtained by addiꢀ
tion of urea into the reaction mixture formed after
the keeping of βꢀdicarbоnyl compounds with aldehydes
in the system ClSiMe3—DMF for 12 h, did not give the
expected result. Variations in the time and temperature of
the keeping of diethyl isophthaloyldiacetate and benzꢀ
aldehyde in the system ClSiMe3—DMF also did not lead
to the expected results: the yield of the desired product
did not exceed 7%.
Scheme 2
This result can be explained by the "activation by
silicon"32 of reactions with participation of Nꢀnucleoꢀ
philes. Nucleophilic addition of the intermediately
formed Nꢀsilylated acyliminium cation А (see Refs 33
and 34) to the enol (most likely, predominant) tautomer
of βꢀdicarbоnyl compound 1 leads to the intermediate B,
the cyclization of which with elimination of Me3SiOH
provides the formation of the final product (Scheme 3).
This sequence of transformations occurs faster than
the reaction in the absence of trimethylchlorosilane. An
The presence of the signals for the protons of the
phenyl and phenylene fragments, the singlet signals for
Scheme 3

Synthesis of 1,3ꢀbispyrimidinyl benzenes
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 6, June, 2008
1259
the four equivalent in pairs NH groups in the regions
δ 7.71—7.99 and 8.84—8.96 (the former signals being
always broadened), as well as the doublet signals with
3JNH—CH = 3.1—4.3 Hz for the atoms H(4´) in the region
δ 4.88—5.78, along with signals for the methyl and meꢀ
thylene protons of the ethoxy groups, is characteristic of
1,2,3,4ꢀtetrahydropyrimidinꢀ6ꢀyl)benzene derivatives
2a,f,g, that completely agrees with the chemical shift and
spinꢀspin coupling constant (JC,H) values for 2ꢀoxoꢀ
1,2,3,4ꢀtetrahydropyrimidine36—41 and 1,3ꢀbis(hetaryl)ꢀ
benzene derivatives.42 In addition to the mentioned sigꢀ
nals, there are also less intensive singlet signals at δ 31.0,
36.2, and 162.8 in the 13C NMR spectra of compounds
2a,f,g, which confirms the formation of inclusion comꢀ
plexes of 1,3ꢀbis(2ꢀoxoꢀ1,2,3,4ꢀtetrahydropyrimidinꢀ6ꢀ
yl)benzene derivatives with DMF.
1
the Н NMR spectra of 1,3ꢀbis(2ꢀoxoꢀ1,2,3,4ꢀtetrahyꢀ
dropyrimidinꢀ6ꢀyl)benzenes 2а—g.
The presence of two asymmetric carbon atoms with
identical substituents in compounds 2а—g suggested forꢀ
mation of one racemic form (S,Sꢀ and R,Rꢀenantiomers)
and one meso form (S,Rꢀform = R,Sꢀform). However, as
Xꢀray analysis for one of these compounds, namely,
for 2e, also confirms this.
1
it could be seen from the Н NMR spectra of crude
According to the Xꢀray data, compound 2e crystallizꢀ
es with the molecule of DMF in ratio 1 : 1. The DMF
molecule is disordered over two positions with populaꢀ
tions of 0.76 and 0.24. In the molecule of compound
under study, the methyl group of С(9В) ethoxy fragment
is also disordered over two positions with populations of
0.72 and 0.28. Despite of the fact that according to
the structural formula, the compound can posses the plane
of symmetry or the axis of the second order, the molecule
during crystallization loses the symmetry and is located
in the crystal in general position (Fig. 1).
The nonequivalence of the structurally identical parts
of the molecule is attested by the differences in the
torsional angles formed by the pyrimidine rings and
the ethoxy group: С(6B)—C(5B)—C(7B)—O(8B) is
170.8(6)° and С(6A)—C(5A)—C(7A)—O(8A) is
158.1(6)°. The positions of the dichloroꢀsubstituted benꢀ
zene rings (С(10А)—С(15А) and C(10B)—C(15B)) relꢀ
atively to the meanꢀsquare planes of the corresponding
pyrimidine rings (N(1A)—C(6A) and N(1B)—C(6B))
also somewhat differ: the dihedral angles are equal to
87.3(4) and 83.4(5)°, respectively. The pyrimidine rings
themselves (N(1A)—C(6A) and N(1B)—C(6B)) form
with the plane of the central benzene ring dihedral angles
equal to 70.0(4) and 66.1(5)°, respectively.
products and products obtained after recrystallization,
no broadening or doubling of the signals is observed in
none of the regions in none of the cases, which attests
either a selective formation of a single form mentioned
above or the formation of both forms, but with identical
chemical shifts and spinꢀspin coupling constants for
the protons, which is unlikely.
Another characteristic feature inherent in the 1Н NMR
spectra of compounds 2а—g is the presence of three sinꢀ
glet signals at δ 2.75, 2.90, and 7.97, which correspond to
the signals for the protons of DMF used as the solvent not
only to carry out of the reaction, but also for the recrystalꢀ
1
lization. As the Н NMR spectra show, depending on
the compound and method of purification, DMF is
present in various quantities in the solutions under conꢀ
sideration (from 9.0—12.0 to 2.0—3.0%), which correꢀ
sponds to complexes composed of the compound under
study and DMF in the ratios 1 : 1 and 4 : 1. These data are
confirmed by the elemental analysis data for the samples
obtained after recrystallization from the corresponding
mixtures of solvents and keeping the samples in vacuo
(1—2 Torr) at ~200 °С for 1 h. The analytically pure
samples of compounds 2а—g are obtained only after thorꢀ
ough removal of DMF in vacuo (1—2 Torr) at 250—300 °С
for 0.5 h.
In the crystal, the DMF molecule is located in the
"chelaꢀlike" cavity of the 1,3ꢀbis(2ꢀoxoꢀ1,2,3,4ꢀtetrahyꢀ
dropyrimidinꢀ6ꢀyl)benzene 2e molecule. And the DMF
molecule does not participate in any noticeable intermoꢀ
lecular interactions with the molecule of the compound,
in the cavity of which it is located, and it is kept in it,
apparently, exclusively by the van der Waals contacts.
At the same time, the DMF molecule located in the
cavity participates in the hydrogen bonding with the neighꢀ
boring molecule of tetrahydropyrimidinylbenzene, which
is symmetrically bonded to the molecule, in the caviꢀ
ty of which DMF is located. Parameters of the hydꢀ
rogen bond N(3A´)—H(3A´)...O(50A) are as folꢀ
lows: d(H(3A´)...O(50A)) is 1.73 Å, the angle
N(3A´)—H(3A´)...O(50A) is 166°, (1/2 – x, 1/2 + y,
3/2 – z). Owing to the formation of eight classic hydroꢀ
gen bonds N—H...O, the Hꢀassociates consisting of two
DMF molecules and two 1,3ꢀbis(2ꢀoxoꢀ1,2,3,4ꢀtetrahyꢀ
Note that 1,3ꢀbis(2ꢀoxoꢀ1,2,3,4ꢀtetrahydropyrimiꢀ
dinꢀ6ꢀyl)benzenes 2а—g form inclusion complexes with
DMF even if recrystallization of these compounds
is carried out with the use of a mixture of solvents
(MeOH—DMF, MeCN—DMF, DMF—CHCl3, etc.),
which is attested by the presence of characteristic singlet
signals of DMF in the 1Н NMR spectra recorded
in DMSO.
The presence of two doublet (δ ~53.5 (J = 145 Hz),
~153.2 (J = 6.6 Hz)) and two singlet (δ ~100.0, ~149.0)
signals for two pyrimidine rings and two doublet (δ ~127.0
(J = 157 Hz), ~135.0 (J = 7.5 Hz)), doublet of doublets
of doublets (δ ~128.1 (J = 160, 6, 6 Hz)), and doublet of
multiplets (δ ~131.5 (J = 160 Hz)) signals for the central
benzene ring along with other signals for the carbon atꢀ
oms of the ester groups and substituents in positions 4´ is
characteristic of the 13C NMR spectra of 1,3ꢀbis(2ꢀoxoꢀ

1260
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 6, June, 2008
Mamedov et al.
C(5)
O(7A)
C(7A)
C(6A)
C(8A)
C(8B)
C(4)
C(6)
C(1)
O(7B)
C(7B)
C(9A)
O(8A)
C(9B)
O(8B)
C(7B)
C(5A)
C(3)
C(6B)
N(1B)
C(2)
C(5B)
C(4B)
C(4A)
N(3A)
C(2A)
N(3B)
Cl(1)
N(1A)
Cl(3)
C(11A)
C(12A)
C(15B)
C(14B)
C(15A)
C(11B)
O(2A)
O(2B)
C(13A)
Cl(4)
C(14A)
C(12B)
C(13B)
Cl(2)
Fig. 1. Geometry of the molecule of compound 2e in the crystal and the scheme of numeration; the methyl group with greater population is
shown, the solvate molecule of DMF is not shown.
dropyrimidinꢀ6ꢀyl)benzene 2e molecules appear in the
crystal (Fig. 2). Parameters of the hydrogen bonds are as folꢀ
lows: for N(1A)—H(1A)...O(1В″), d(H(1A)...O(2В″))
is 1.86 Å, d(N(1A)...O(2В″)) is 2.85 Å,
the angle N(1A)—H(1A)...O(2В″) is 176°; for
N(1B)—H(1B)...O(2В″), d(H(1B)...O(2В″)) is 2.01 Å,
The DMF molecules, located on the ends of the
Hꢀassociates, enter the cavities of the tetrahydropyrimidꢀ
inylbenzene molecules from the neighboring symmetriꢀ
cally bonded associates. The compound also form nonꢀ
classic hydrogen bonds of the types C—H...O and
C—H...Cl, the cumulative influence of which leads to
the formation of chains of the molecules along the crysꢀ
tallographic axis 0у. Though the compound forms hydroꢀ
gen bonds of various types, the density of packing of
the molecules in a crystal is not high. The packing coefꢀ
ficient is equal to 64.1%, which is lower than values
characteristic of the crystals of organic compounds
(65—75%). Apparently, the formation of inclusion
compound by the molecules of 1,3ꢀbis[2ꢀoxoꢀ4ꢀ(2,4ꢀ
dichloro)phenylꢀ5ꢀethoxycarbonylꢀ1,2,3,4ꢀtetrahydroꢀ
pyrimidinꢀ6ꢀyl]benzene and DMF, as well as its stability
can be explained in the first place by complementarity
of the DMF molecules and the cavity of the "host" moꢀ
lecules.
d(N(1B)...O(2В″))
is
2.98
Å,
the
angle
N(1B)—H(1B)...O(2В″)
is
165°;
for
N(3B)—H(3B)...O(2A″), d(H(3B)...O(2A″)) is 1.91 Å,
the angle N(3B)—H(3B)...O(2A″) is 166° (operation
of symmetry 1/2 – х, 1/2 – y, 1 – z).
H(3B)
H(3A)
H(1B)
H(1A)
In conclusion, it can be stated that 1,3ꢀbis(oxoꢀ
tetrahydropyrimidinꢀ6ꢀyl)benzene derivatives 2а—g obꢀ
tained by us can be used as the selective receptors
for DMF.
Experimental
Melting points were determined on a Boetius apparatus. Mass
spectra (electron ionization) were recorded on a ThermoQuest/Finꢀ
nigan TRACE MS quadrupole mass spectrometer, inlet of the sample
was performed through the system of the direct injection with water
cooling. IR spectra were recorded on a Vectorꢀ22 (Bruker) Fourier
spectrometer (Nujol mulls for compounds 2a,c,e,g and KBr pellets
Fig. 2. Fragment formed by two molecules of compound 2e and two
molecules of DMF owing to the hydrogen bond N—H...O
(the dotted line). Only hydrogen atoms participating in the hydrogen
bonds are shown.

Synthesis of 1,3ꢀbispyrimidinyl benzenes
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 6, June, 2008
1261
for compounds 2b,d,f) in the range of frequencies 400—3600 cm–1
1H NMR spectra for compounds 2a—g and 13C{H} NMR spectra
for compounds 2a,f,g were recorded on a Avanceꢀ600 spectrometer
(Bruker) (600.00 MHz (1Н) and 150.864 MHz (13C)). Chemical
shifts are given in δ scale. A residual signal of the nondeuterated
solvents СH3CN (δН 1.96) for compound 1 and DMSO (δН 2.52)
for compounds 2a—g were used as the internal standard.
.
J = 6.1 Hz, J = 6.0 Hz); 128.17 (ddd, 2 С, 2 С(4″), J = 161.6 Hz, J =
7.8 Hz, J = 7.8 Hz); 129.25 (dd, 4 С, 2 С(2″) + 2 С(6″), J = 160.0 Hz,
J = 7.2 Hz); 131.36 (dm, 2 С, 1 С(4) + 1 С(6), J = 156.8 Hz); 134.78
(d, 2 С, 1 С(1) + 1 С(3), J = 7.8 Hz); 144.94 (br.s, 2 С, 2 С(1″));
148.27 (br.s, 2 С, 2 С(6´)); 153.02 (d, 2 С, 2 С(2´), J = 6.6 Hz);
165.79 (s, 2 С, 2 CO2CH2CH3).
B. Trimethylsilyl chloride (0.71 g, 6.53 mmol) was added
dropwise to a mixture of ester 1 (0.50 g, 1.63 mmol), urea (3)
(0.39 g, 6.53 mmol), benzaldehyde (4а) (0.34 g, 3.26 mmol),
MeCN (6 mL), and DMF (3 mL). The reaction mixture was heated
for 25 h at 80 °С. The solvent was evaporated in vacuo, ether and
methanol (4 : 1) were added to the crystalꢀlike mixture, the crystals
formed were filtered off and dried in air. The yield was 0.52 g
(56.0%), white crystals, m.p. 298—299 °C.
C. Dry gaseous hydrogen chloride (obtained according to the
procedure described earlier43 from NaCl (0.95 g, 16.30 mmol) and
98% H2SO4 (1.48 mL, 27.71 mmol)) was passed through a stirred
solution of ester 1 (0.50 g, 1.63 mmol), urea (3) (0.29 g, 4.89 mmol),
and benzaldehyde (4а) (0.34 g, 3.26 mmol) in methanol (30 mL) at
~15 °С for 1 h. The reaction mixture was refluxed for 10 h.
The solvent was evaporated in vacuo, ether was added to the crystalꢀ
like mixture, the crystals formed were filtered off and dried in air.
The yield was 0.05 g (5.4%), white crystals, m.p. 298—299 °C.
D. Dry gaseous hydrogen chloride (obtained according to
the procedure described earlier43 from NaCl (0.95 g, 16.30 mmol)
and 98% H2SO4 (1.48 mL, 27.71 mmol)) was passed through
a stirred solution of ester 1 (0.50 g, 1.63 mmol), urea (3) (0.29 g,
4.89 mmol), and benzaldehyde (4а) (0.34 g, 3.26 mmol) in
DMF—acetonitrile (6 + 12 mL) at 23 °С for 1 h. The reaction
mixture was heated for 15 h at 75 °С. The solvent was evaporated
in vacuo, ether and methanol (5 : 2) were added to the crystalꢀlike
mixture, the crystals formed were filtered off and dried in air.
The yield was 0.04 g (4.3%), white crystals, m.p. 298—299 °C.
Spectral characteristics of compounds obtained by the methods
A—D are identical.
Diethyl isophthaloyldiacetate (1). A mixture of acetoacetic ester
(14.6 g, 56.15 mmol), isopropyl ether (40 mL), and water (38 mL)
was cooled to 5 °С and a 33% aqueous NaOH (4.8 mL) was added
to it. The temperature was kept below 7 °С and рН ~11, isophthaꢀ
loyl chloride (12.33 g, 60.73 mmol) and 33% aq. NaOH (20 mL)
were added simultaneously for 1 h. Then the reaction mixture was
kept for 1 h at 40 °С. The organic layer was separated and can be
used in the subsequent experiments as the solvent without additional
purification, ammonium chloride (6.5 g, 121.60 mmol) was added
to the aqueous layer. The mixture was stirred for 18 h followed by
the extraction with toluene (3×100 mL). The combined organic
layer was dried with MgSO4, the solvent was evaporated in vacuo.
The product formed was recrystallized from ether. The yield was
8.56 g (46%), yellow crystals, m.p. 43—45 °C. Found (%):
C, 62.70; H, 5.93. C16H18O6. Calculated (%): C, 62.74; H, 5.92.
IR, ν/cm–1: 1748, 1683, 1629, 1418, 1360, 1347, 1320, 1290, 1261,
1248, 1176, 1146, 1081, 1025, 812, 798, 677, 595. 1H NMR
(CD3CN), δ: keto form, 1.28 (t, 6 Н, 2 CH3CH2O, J = 7.3 Hz);
4.18 (s, 4 Н, 2 С(О)СН2СО2Et); 4.25 (q, 4 Н, 2 CH3CH2O,
J = 7.3 Hz); 7.72 (dd, 1 Н, 1 Н(5), J = 8.1 Hz, J = 8.1 Hz); 8.28
(d, 2 Н, 1 Н(4) + 1 Н(6), J = 8.1 Hz); 8.55 (s, 1 Н, 1 Н(2)); enol
form, 1.38 (t, 6 Н, 2 CH3CH2O, J = 7.3 Hz); 4.36 (q, 4 Н,
2 CH3CH2O, J = 7.3 Hz); 5.96 (s, 2 Н, 2 С(ОН)=СН); 7.70
(dd, 1 Н, 1 Н(5), J = 8.1 Hz, J = 8.1 Hz); 8.15 (d, 2 Н, 1 Н(4) + 1 Н(6),
J = 8.1 Hz); 8.45 (s, 1 Н, 1 Н(2)); 12.72 (br.s, 2 Н, 2 ОН).
1
Ratio of tautomers, which is calculated from the Н NMR
spectrum recorded in СD3CN, is 8 : 1, whereas, in DMSOꢀd6 it
is 5 : 1 (in both cases, in favor of the keto form).
1,3ꢀBis(5ꢀethoxycarbonylꢀ2ꢀoxoꢀ4ꢀphenylꢀ1,2,3,4ꢀtetrahyꢀ
dropyrimidinꢀ6ꢀyl)benzene (2a). А. A mixture of ester 1 (0.50 g,
1.63 mmol), urea (3) (0.29 g, 4.89 mmol), benzaldehyde (4а)
(0.34 g, 3.26 mmol), and acetic acid (30 mL) was stirred for 1 h until
complete dissolution and kept for 30 days at ~20 °C. The solvent
was evaporated in vacuo, methanol was added to the crystalꢀlike
mixture, the crystals formed were filtered off, dried in air, and
recrystallized from ethyl acetate—DMF (5 : 1). The yield was 0.43 g
(47.0%), white crystals, m.p. 298—299 °C. Found (%): C, 67.80;
H, 5.35; N, 9.92. C32H30N4O6. Calculated (%): C, 67.83; H, 5.34;
N, 9.89. MS, m/z (Irel (%)): 566 [М]+ (3), 520 (37), 494 (26), 474
(28), 448 (32), 447 (100), 443 (63), 404 (40), 354 (27), 224 (22),
210 (28), 206 (18), 194 (38), 178 (20), 132 (51), 131 (45), 104 (24),
103 (33), 77 (18). IR, ν/cm–1: 3338, 3224, 3105, 1704, 1667, 1343,
1302, 1270, 1251, 1204, 1095, 827, 812, 781, 753, 709, 699, 654,
472. 1H NMR (DMSOꢀd6), δ: 0.89 (t, 6 Н, 2 CH3CH2O,
J = 7.0 Hz); 3.82—3.88 (m, 4 Н, 2 CH3CH2O); 5.31 (d, 2 Н,
2 Н(4´), J = 3.4 Hz); 7.31 (dd, 2 Н, 2 Н(4″), J = 7.0 Hz, J = 7.0
Hz); 7.37 (dd, 1 Н, 1 Н(5), J = 7.7 Hz, J = 7.7 Hz); 7.38—7.46
(m, 11 Н, 1 Н(2) + 1 Н(4) + 1 Н(6) + 2 Н(2″) + 2 Н(3″) + 2 Н(5″)
+ 2 Н(6″)); 7.95 (br.s, 2 H, 2 N(3´)H); 8.92 (s, 2 H, 2 N(1´)H).
13С NMR (DMSOꢀd6), δ: 14.30 (q, 2 С, 2 CH3CH2O, J =
126.8 Hz); 53.22 (d, 2 С, 2 С(4´), J = 146.6 Hz); 60.12 (tq, 2 С,
2 CH3CH2O, J = 147.5 Hz, J = 4.2 Hz); 101.28 (br.s, 2 С, 2 С(5´));
127.12 (dm, 4 С, 2 С(3″) + 2 С(5″), J = 158.9 Hz); 127.49 (d, 1 С,
1 С(2), J = 162.8 Hz); 128.08 (ddd, 1 С, 1 С(5), J = 160.4 Hz,
1,3ꢀBis[4ꢀ(4ꢀchlorophenyl)ꢀ5ꢀethoxycarbonylꢀ2ꢀoxoꢀ
1,2,3,4ꢀtetrahydropyrimidinꢀ6ꢀyl]benzene (2b) was obtained simiꢀ
larly from ester 1 (0.50 g, 1.63 mmol), urea (3) (0.29 g, 4.89 mmol),
and 4ꢀchlorobenzaldehyde (4b) (0.46 g, 3.26 mmol). The yield was
0.59 g (56.8%, method А), 0.68 g (66.0%, method B), m.p.
304—306 °C (ethyl acetate—DMF, 5 : 1). Found (%): C, 60.42;
H, 4.49; Сl, 11.13; N, 8.82. C32H28Cl2N4O6. Calculated (%):
C, 60.48; H, 4.44; Сl, 11.16; N, 8.82. MS, m/z (Irel (%)): 636
[М (35Cl37Cl)]+ (2), 635 (1), 634 [М (35Cl)2]+ (2), 588 (22), 542
(24), 518 (21), 517 (69), 516 (38), 515 (100), 477 (51), 472 (38),
388 (34), 308 (19), 292 (22), 266 (25), 245 (43), 244 (64), 224
(59), 168 (37), 44 (80). IR, ν/cm–1: 3228, 3103, 1704, 1681, 1645,
1490, 1412, 1338, 1293, 1262, 1243, 1198, 1092, 1014, 839, 798,
772, 702, 649, 465. 1H NMR (DMSOꢀd6), δ: 0.88 (t, 6 Н,
2 CH3CH2O, J = 7.0 Hz); 3.84 (q, 4 Н, 2 CH3CH2O, J = 7.0 Hz);
5.31 (d, 2 Н, 2 Н(4´), J = 3.1 Hz); 7.37 (dd, 1 Н, 1 Н(5),
J = 7.7 Hz, J = 7.7 Hz); 7.43—7.47 (m, 11 Н, 1 Н(2) + 1 Н(4) +
1 Н(6) + 2 рꢀClC6H4); 7.98 (br.s, 2 H, 2 N(3´)H); 8.95 (br.s, 2 H,
2 N(1´)H).
1,3ꢀBis[4ꢀ(4ꢀbromophenyl)ꢀ5ꢀethoxycarbonylꢀ2ꢀoxoꢀ
1,2,3,4ꢀtetrahydropyrimidinꢀ6ꢀyl]benzene (2c) was obtained simiꢀ
larly from ester 1 (0.50 g, 1.63 mmol), urea (3) (0.29 g, 4.89 mmol),
and 4ꢀbromobenzaldehyde (4c) (0.60 g, 3.26 mmol). The yield was
0.53 g (45.0%, method А), 0.63 g (53.0%, method B), white
crystals, m.p. 286—288 °C (ethyl acetate—DMF, 5 : 1). Found (%):
C, 53.00; H, 3.93; Br, 22.10; N, 7.70. C32H28Br2N4O6. Calculatꢀ

1262
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 6, June, 2008
Mamedov et al.
53.06; H, 3.90; Br, 22.06; N, 7.73. MS, m/z (Irel (%)): 726 [М
(81Br)2]+ (0.2), 724 [М (79Br81Br)]+ (0.3), 722 [М (79Br)2]+ (0.3),
604 (17), 212 (12), 117 (51), 103 (21), 59 (100). IR, ν/cm–1: 3335,
3226, 3104, 1703, 1703, 1486, 1411, 1342, 1294, 1265, 1249, 1204,
1096, 1010, 801, 707, 655, 473. 1H NMR (DMSOꢀd6), δ: 0.89 (t, 6
(d, 2 Н, 2 Н(4´), J = 3.1 Hz); 6.74 (d, 4 Н, 2 Н(3″) + 2 Н(5″),
J = 8.5 Hz); 7.22 (d, 4 Н, 2 Н(2″) + 2 Н(6″), J = 8.5 Hz); 7.36
(dd, 1 Н, 1 Н(5), J = 7.6 Hz, J = 7.6 Hz); 7.40—7.42 (m, 3 Н,
1 Н(2) + 1 Н(4) + 1 Н(6)); 7.81 (br.s, 2 H, 2 N(3´)H); 8.84 (br.s,
2 H, 2 N(1´)H). 13С NMR (DMSOꢀd6), δ: 14.48 (q, 2 С,
2 CH3CH2O, J = 127.4 Hz); 41.11 (br.s, 4 С, 2 N(CH3)2); 54.67
(d, 2 С, 2 С(4´), J = 143.6 Hz); 60.16 (tq, 2 С, 2 CH3CH2O,
J = 147.2 Hz, J = 4.2 Hz); 101.14 (br.s, 2 С, 2 С(5´)); 113.34
(dm, 4 С, 2 С(3″) + 2 С(5″), J = 156.8 Hz); 127.54 (d, 1 С, 1 С(2),
J = 163.4 Hz); 127.93 (dm, 4 С, 2 С(2″) + 2 С(6″), J = 155.6 Hz);
128.12 (ddd, 1 С, 1 С(5), J = 160.4 Hz, J = 6.1 Hz, J = 6.0 Hz);
131.51 (dm, 2 С, 1 С(4) + 1 С(6), J = 164.0 Hz); 132.90 (br.s, 2 С,
2 С(4″)); 134.97 (d, 2 С, 1 С(1) + 1 С(3), J = 7.2 Hz); 147.83 (br.s,
2 С, 2 С(1″)); 150.68 (br.s, 2 С, 2 С(6´)); 153.28 (d, 2 С, 2 С(2´),
J = 6.6 Hz); 165.99 (s, 2 С, 2 CO2CH2CH3).
1,3ꢀBis[5ꢀethoxycarbonylꢀ2ꢀoxoꢀ4ꢀstyrylꢀ1,2,3,4ꢀtetrahyꢀ
dropyrimidinꢀ6ꢀyl]benzene (2g) was obtained similarly from ester 1
(0.50 g, 1.63 mmol), urea (3) (0.29 g, 4.89 mmol), and cinnamaldeꢀ
hyde 4g (0.43 g, 3.26 mmol). The yield was 0.49 g (49.0%, methꢀ
od А), 0.60 g (58.7%, method B), white crystals, m.p. 275—278 °C
(ethyl acetate—DMF, 5 : 1). Found (%): C, 69.82; H, 5.57; N, 9.00.
C36H34N4O6. Calculated (%): C, 69.89; H, 5.54; N, 9.06. MS, m/z
(Irel (%)): 619 (3), 618 [М]+ (7), 500 (29), 499 (50), 456 (16), 452
(26), 395 (24), 394 (42), 302 (25), 258 (21), 228 (29), 207 (32),
198 (24), 197 (25), 158 (49), 131 (21), 130 (80), 115 (100), 91 (92),
77 (20), 44 (20), 28 (25). IR, ν/cm–1: 3229, 3099, 1727, 1680,
1645, 1491, 1338, 1292, 1248, 1199, 1096, 963, 781, 750, 692, 651.
1H NMR (DMSOꢀd6), δ: 0.98 (t, 6 Н, 2 CH3CH2O, J = 7.0 Hz);
3.93—3.95 (m, 4 Н, 2 CH3CH2O); 4.88 (dd, 2 Н, 2 Н(4´),
J = 6.0 Hz, J = 4.3 Hz); 6.38 (dd, 2 Н, 2 СН=СН—Ph, J = 15.8
Hz, J = 6.0 Hz); 6.52 (d, 2 Н, 2 СН=СН—Ph, J = 15.8 Hz); 7.27
(dd, 2 Н, 2 Н(4″), J = 7.3 Hz, J = 7.3 Hz); 7.34 (dd, 1 Н, 1 Н(5),
J = 7.2 Hz, J = 7.2 Hz); 7.35 (dd, 4 Н, 2 Н(3″) + 4 Н(5″),
J = 7.6 Hz, J = 7.3 Hz); 7.39 (dd, 1 Н, 1 Н(2), J = 1.2 Hz,
J = 1.2 Hz); 7.44 (dd, 2 Н, 1 Н(4) +1 Н(6), J = 7.2 Hz, J = 1.2 Hz);
7.47 (d, 4 Н, 2 Н(2″) + 2 Н(6″), J = 7.6 Hz); 7.71 (br.s, 2 H,
2 N(3´)H); 8.86 (br.s, 2 H, 2 N(1´)H). 13С NMR (DMSOꢀd6), δ:
14.36 (q, 2 С, 2 CH3CH2O, J = 126.8 Hz); 53.14 (d, 2 С, 2 С(4´),
J = 144.8 Hz); 60.04 (tq, 2 С, 2 CH3CH2O, J = 147.2 Hz,
J = 4.2 Hz); 99.83 (br.s, 2 С, 2 С(5´)); 127.10 (dm, 4 С, 2 С(3″) +
2 С(5″), J = 158.6 Hz); 127.28 (d, 1 С, 1 С(2), J = 163.4 Hz);
128.09 (ddd, 1 С, 1 С(5), J = 159.2 Hz, J = 6.6 Hz, J = 6.6 Hz);
128.28 (ddd, 2 С, 2 С(4″), J = 161.6 Hz, J = 8.4 Hz, J = 8.4 Hz);
129.29 (dd, 4 С, 2 С(2″) + 2 С(6″), J = 161.6 Hz, J = 7.5 Hz);
129.40 (d.br.d, 2 С, 2 СН=СН—Ph, J = 150.8 Hz, J ≈ 4.0 Hz);
130.41 (dd, 2 С, 2 СН=СН—Ph, J = 153.2 Hz, 4.8 Hz); 131.46
(dm, 2 С, 1 С(4) + 1 С(6), J = 162.8 Hz); 134.01 (d, 2 С, 1 С(1) +
1 С(3), J = 7.8 Hz); 137.09 (br.s, 2 С, 2 С(1″)); 148.29 (br.s, 2 С,
2 С(6´)); 153.36 (d, 2 С, 2 С(2´), J = 7.2 Hz); 165.56 (s, 2 С,
2 CO2CH2CH3).
Н,
2
CH3CH2O,
J
=
7.0
Hz);
3.83—3.88
(m, 4 Н, 2 CH3CH2O); 5.29 (d, 2 Н, 2 Н(4´), J = 3.7 Hz); 7.37—7.61
(m, 12 Н, 1 Н(2) + 1 Н(4) + 1 Н(5) + 1 Н(6) + 2 рꢀBrC6H4); 7.99
(br.s, 2 H, 2 N(3´)H); 8.96 (s, 2 H, 2 N(1´)H).
1,3ꢀBis[5ꢀethoxycarbonylꢀ4ꢀ(4ꢀiodophenyl)ꢀ2ꢀoxoꢀ1,2,3,4ꢀ
tetrahydropyrimidinꢀ6ꢀyl]benzene (2d) was obtained similarly from
ester 1 (0.50 g, 1.63 mmol), urea (3) (0.29 g, 4.89 mmol), and
4ꢀiodobenzaldehyde (4d) (0.76 g, 3.26 mmol). The yield was 0.61 g
(45.7%, method А), 0.70 g (52.0%, method B), white crystals, m.p.
294—296 °C (ethyl acetate—DMF, 5 : 1). Found (%): C, 46.91;
H, 3.46; I, 31.08; N, 6.82. C32H28I2N4O6. Calculated (%):
C, 46.96; H, 3.45; I, 31.01; N, 6.85. MS, m/z (Irel (%)): 818 [М]+
(2), 775 (40), 774 (60), 729 (42), 728 (46), 727 (16), 726 (27),
357 (17), 272 (18), 258 (44), 257 (45), 230 (42), 224 (22), 183
(18), 155 (100), 130 (47), 103 (25), 102 (28), 29 (45). IR, ν/cm–1
:
3336, 3223, 3105, 1702, 1668, 1600, 1444, 1341, 1247, 1202,
1
1095, 1005, 805, 762, 705, 653, 471. H NMR (DMSOꢀd6), δ:
0.89 (t, 6 Н, 2 CH3CH2O, J = 7.0 Hz); 3.81—3.89 (m, 4 Н,
2 CH3CH2O); 5.26 (d, 2 Н, 2 Н(4´), J = 3.4 Hz); 7.23 (d, 4 Н,
2 Н(3″) + 2 Н(5″), J = 8.4 Hz); 7.36 (dd, 1 Н, 1 Н(5), J = 7.6 Hz,
J = 7.6 Hz); 7.42—7.45 (m, 3 Н, 1 Н(2) + 1 Н(4) + 1 Н(6)); 7.77
(d, 4 Н, 2 Н(2″) + 2 Н(6″), J = 8.4 Hz); 7.98 (br.s, 2 H, 2 N(3´)H);
8.95 (br.s, 2 H, 2 N(1´)H).
1,3ꢀBis[4ꢀ(2,4ꢀdichlorophenyl)ꢀ5ꢀethoxycarbonylꢀ2ꢀoxoꢀ
1,2,3,4ꢀtetrahydropyrimidinꢀ6ꢀyl]benzene (2e) was obtained simiꢀ
larly from ester 1 (0.50 g, 1.63 mmol), urea (3) (0.29 g, 4.89 mmol),
and 2,4ꢀdichlorobenzaldehyde (4e) (0.57 g, 3.26 mmol). The yield
was 0.47 g (41.3%, method А), 0.57 g (49.6%, method B), white
crystals, m.p. 301—303 °C (acetonitrile—DMF, 8 : 1). Found (%):
C, 54.08; H, 4.28; Cl, 20.24; N, 8.00. C32H26Cl4N4O6. Calculatꢀ
ed (%): C, 54.56; H, 3.72; Cl, 20.13; N, 7.95. MS, m/z (Irel (%)):
704 [М ((35Cl)337Cl)]+ (0.5), 702 [М (2 (35Cl)2)]+ (0.4), 658
(15), 587 (21), 585 (43), 583 (30), 513 (18), 511 (25), 386 (24),
301 (20), 293 (28), 292 (17), 291 (18), 279 (36), 242 (40), 228
(41), 223 (33), 202 (15), 200 51), 36 (18), 32 (22), 28 (100). IR,
ν/cm–1: 3231, 3089, 1716, 1646, 1586, 1443, 1369, 1338, 1289,
1257, 1206, 1098, 1043, 800, 748, 702, 659, 474. 1H NMR
(DMSOꢀd6), δ: 0.86 (t, 6 Н, 2 CH3CH2O, J = 7.0 Hz); 3.80
(q, 4 Н, 2 CH3CH2O, J = 7.0 Hz); 5.78 (d, 2 Н, 2 Н(4´), J = 3.0 Hz);
7.40 (dd, 1 Н, 1 Н(5), J = 7.5 Hz, J = 7.5 Hz); 7.48—7.65 (m, 9 Н,
1 Н(2) + 1 Н(4) + 1 Н(6) + 2 рꢀCl2C6H3); 7.95 (br.s, 2 H,
2 N(3´)H); 8.96 (br.s, 2 H, 2 N(1´)H).
1,3ꢀBis[5ꢀethoxycarbonylꢀ4ꢀ(4ꢀdimethylaminophenyl)ꢀ2ꢀoxoꢀ
1,2,3,4ꢀtetrahydropyrimidinꢀ6ꢀyl]benzene (2f) was obtained simiꢀ
larly from ester 1 (0.50 g, 1.63 mmol), urea (3) (0.29 g, 4.89 mmol),
and 4ꢀdimethylaminobenzaldehyde (4f) (0.49 g, 3.26 mmol). The
yield was 0.56 g (53.0%, method А), 0.64 g (59.5%, method B),
white crystals, m.p. 282—284 °C (ethyl acetate—DMF, 5 : 1).
Found (%): C, 66.20; H, 6.21; N, 12.85. C36H40N6O6. Calculatꢀ
ed (%): C, 66.24; H, 6.18; N, 12.87. MS, m/z (Irel (%)): 653 (5),
652 [М]+ (11), 532 (26), 531 (84), 458 (18), 274 (21), 230 (22),
175 (43), 174 (31), 145 (30), 128 (38), 120 (54), 104 (100), 91 (48),
78 (38), 77 (53). IR, ν/cm–1: 3232, 1700, 1617, 1525, 1445, 1343,
1278, 1244, 1199, 1167, 1093, 1012, 798, 782, 704, 651, 465.
1H NMR (DMSOꢀd6), δ: 0.90 (t, 6 Н, 2 CH3CH2O, J = 7.0 Hz);
2.89 (s, 12 Н, 2 N(CH3)2); 3.81—3.88 (m, 4 Н, 2 CH3CH2O); 5.19
Xꢀray
analysis
of
compound
2e.
Crystals
C32H26Cl4N4O6•C3H7NO, suitable for the Xꢀray study were obꢀ
tained from DMF—MeCN.
The experiment was carried out at 20 °С on a Enraf—Nonius
CADꢀ4 automatic diffractometer with the use of monochromatꢀ
ic CuꢀKαꢀradiation (λ = 1.54184 Å). The unit parameters:
а = 31.673(3) Å, b = 14.190(1) Å, c = 21.224(2) Å, β = 127.28(7)°,
V = 7590(11) Å3, Z = 8, М = 777.46, dcalc = 1.36 g cm–3
,
μ(Cu) = 32.80 cm–1, space group C2/c. Intensities of 8371 reflecꢀ
tions were measured (ωꢀscanning, 2θ < 57.4°), 1868 reflections
from them were with I > 2σ. The structure was decoded by the direct

Synthesis of 1,3ꢀbispyrimidinyl benzenes
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 6, June, 2008
1263
method by the SIR program44 and refined first in isotropic, then in
anisotropic approximation with the use of the SHELXL45 and
WinGX46 programs. Coordinates of hydrogen atoms of the NH
group were revealed from the differential series of electron density,
coordinates of the rest of hydrogen atoms were calculated on the
basis of stereochemical criteria and refined by the riding model.
The final values of divergence factors are as follows: R = 0.0597,
Rw = 0.1316 on 1868 independent reflections with F 2 ≥ 2σ.
Preliminary data processing was carried out with the use of
the MolEN program.47 Analysis of the molecular and crystal strucꢀ
tures and intermolecular interactions was performed with the use of
the PLATON program.48 Coordinates of atoms and their temperaꢀ
ture parameters for compound 2e were deposited with the Camꢀ
bridge Structural Database (CCDC 639961).
17. K. A. Kumar, M. Kasthuraiah, C. S. Reddy, C. D. Reddy,
Tetrahedron Lett., 2001, 42, 7873.
18. Y. Ma, C. Qian, L. Wang, M. Yang, J. Org. Chem., 2000,
65, 3864.
19. B. C. Ranu, A. Hajra, U. Jana, J. Org. Chem., 2000, 65, 6270.
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This work was financially supported by the Russian
Foundation for Basic Research (Project Nos 07ꢀ03ꢀ
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Received June 14, 2007;
in revised form January 11, 2008