Heterocyclization of functionalized heterocumulenes with C,N-, C,O-, and C,S-binucleophiles: XI.* synthesis of dialkyl 2-oxo-3,6-diaryl-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylates by cyclocondensation of 1-Chlorobenzyl isocyanates with dial

Article abstract of DOI:10.1134/S1070428010050209

1-Chlorobenzyl isocyanates react with N-arylfumarates with the formation of dialkyl 2-oxo-3,6-diaryl-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylates that on alkaline hydrolysis are converted into 6-alkoxycarbonyl-1,4-diaryl-2-oxo-1,2, 3,4-tetrahydropyrimi

Full text of DOI:10.1134/S1070428010050209

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 5, pp. 709−715. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © M.V. Vovk, O.V. Kushnir, V.A. Sukach, I.F. Tsymbal, 2010, published in Zhurnal Organicheskoi Khimii, 2010, Vol. 46,
No. 5, pp. 716−722.
Heterocyclization of Functionalized Heterocumulenes
with C,N-, C,O- , and C,S-Binucleophiles: XI.* Synthesis
of Dialkyl 2-Oxo-3,6-diaryl-1,2,3,6-tetrahydropyrimidine-4,5-
dicarboxylates by Cyclocondensation of 1-Chlorobenzyl
Isocyanates with Dialkyl Anilinofumarates
M. V. Vovka, O. V. Kushnirb, V. A. Sukacha, and I. F. Tsymbala
aInstitute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev, 02094 Ukraine
e-mail: mvovk@i.com.ua
bFed’kovich Chernovtsy National University, Chernovtsy, Ukraine
Received May 19, 2009
Abstract—1-Chlorobenzyl isocyanates react with N-arylfumarates with the formation of dialkyl 2-oxo-3,6-diaryl-
1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylates that on alkaline hydrolysis are converted into 6-alkoxycarbonyl-
1,4-diaryl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acids. The condensation of 1-chloro-1-phenyl-2,2,2-
trifluoroethyl isocyanate with N-arylfumarates results in dialkyl 6-oxo-2,3-diaryl-2-trifluoromethyl-1,2,3,6-
tetrahydropyrimidine-4,5-dicarboxylates.
DOI: 10.1134/S1070428010050209
tetrahydropyrimidine-4,5-dicarboxylic acid esters
proceeding from the diethyl N-phenylfumarate.
The cyclization of 1-chlorobenzyl isocyanates with
deactivated enamines that we have formerly found is a
convenient way of preparation of 3,4-dihydropyrimidine
systems [2]. In particular, the employment as the C,N-
binucleophilic component 2-aroyl(nitro)-S,N-ketenacetals
[1, 3] made it possible to obtain previously unknown
Biginelli compounds, 5,6-bifunctionally substituted 3,4-
dihydropyrimidin-2(1H)-ones. In extension of the
research on the design of the polyfunctional partially
hydrogenated pyrimidines we report here on the new
reaction involving deactivated enamines, dialkyl
anilinofumarates. The latter are used in the syntheses of
versatile heterocyclic compounds. For instance, their
thermal intramolecular cyclization provides quinoline-2-
carboxylic acids derivatives [4–7], the condensation with
amines gives pyrrole-2,5-diones [8, 9]. The reactions with
electrophilic reagents where the N-arylfumarates act as
1,3-binucleophiles, do not go beyond the examples of
reactions with oxalyl chloride [10] and chloroc-
arbonylsulfophenyl chloride [11]. Quite recently [12] a
publication appeared on the Mannich synthesis of 1,2,3,6-
We found that the reaction of 1-chlorobenzyl
isocyanates Ia–If with dialkyl N-arylaminofumarates IIa–
IIf in toluene at 15–20°C led to the formation of dialkyl
2-oxo-3,6-diaryl-1,2,3,6-tetrahydro-4,5-dicarboxylates
IIIa–IIIo in 41–79% yields (Scheme 1). Apparently
similarly to the cyclocondensation involving the S,N-
ketenacetals [1, 3] the more nucleophilic carbon atom of
the aminofumarate II attacks the activated C=N bond
of the N-chloroformyl imine form of isocyanate I [13]
resulting in the formation of intermediate A. Its structure
originating from the prototropy in the triade N–C=C
permits under relatively mild conditions the formation of
the pyrimidine ring by the attack of the imine nitrogen on
the chlorocarbamoyl group.
The structure of compounds IIIa–IIIo was confirmed
by the combination of physicochemical investigations.
Their 1H NMR spectra are characterized by the doublets
of the proton H6 at 5.27–5.55 ppm and of the NH proton
at 8.31–8.62 ppm with the coupling constant 3.0–3.5 Hz.
The methoxy groups of diesters IIIa–IIIh appear as
* For Communication X, see [1].
709

VOVK et al.
710
We formerly showed [1] that the regiodirection of the
cyclocondensation changed in the reaction of S,N-
ketenacetals with 1-aryl-1-chloro-2,2,2-trifluoroethyl
isocyanates. We demonstrated by examples of reactions
of 1-chloro-1-phenyl-2,2,2-trifluoroethyl isocyanate (IV)
with anilinofumarates IIb and IIf that unlike the process
involving 1-chlorobenzyl isocyanates I at the room
temperature products B formed from C-carbamoylation
which was detected by the presence in the 19F NMR
spectra of the reaction mixture of signals in the region
–69...–70 ppm. Intermediates B only at heating for 12 h
in the boiling toluene were converted into dialkyl 6-oxo-
2,3-diaryl-2-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-
4,5-dicarboxylates Va and Vb in 20–22% yield that
evidently was caused by the low nucleophilicity of the
secondary amino group insufficient for the easy
intramolecular cyclization (Scheme 2).
singlets at 3.36–3.47 and 3.54–3.62 ppm, and the ethoxy
groups of diesters ²²²i–IIIo give rise to triplets at 0.92–
0.97 and 1.08–1.13 ppm and quartets at 3.87–3.93 and
4.00–4.06 ppm. In the 13C NMR spectra the signals of
the carbon atoms of the partially hydrogenated pyrimidine
ring are observed in the regions 49–53 (C6), 100–103
(C5), 142–143 (C4), and 150–151 (C2) ppm.
The IR spectra of compounds IIIa–IIIo recorded in
KBr pellets contain strong absorption bands of the C=O
groups of the pyrimidine ring at 1700–1705 cm–1 and of
alkoxycarbonyl moieties at 1735–1745 cm–1; the same
bands are observed in the spectra of CH2Cl2 solutions.
In the absorption range of the stretching vibrations of
N–H bond in the spectra taken in KBr two broad bands
are observed in the region 3120–3140 and 3235–3245
cm–1 indicating that the compounds exist as dimers. In
the CH2Cl2 solutions instead of these bands a single
absorption band appears at 3420–3425 cm–1 showing the
decomposition of the intermolecular associates involving
the NH groups.
The most compelling proves of the structure of
compounds Va and Vb are the 19F NMR spectra where
the signals at –75...–74 ppm correspond to the CF3 group
Scheme 1.
O
AlkO
HN
Ar2
IIa_IIf
OAlk
O
O
Ar1
NH
O
O
Ar'
N
H
O
O
Ar1
N
NH
Ar1
N C O
AlkO
AlkO
AlkO
AlkO
_HCl
O
N
O
Cl
Cl
Ia_If
Cl
Ar2
Ar2
IIIa_IIIo
A
I,Ar1 = Ph (a), 2-FC6H4 (b), 3-BrC6H4 (c), 3-NO2C6H4 (d), 4-NO2C6H4 (e), 3,4-Cl2C6H3 (f); II,Alk = Me,Ar2 = Ph (a), 4-MeC6H4
(b), 4-ClC6H4 (c), 4-BrC6H4 (d); Alk = Et, Ar2 = 4-ClC6H4 (e), 4-BrC6H4 (f); III, Alk = Me: Ar1 = Ar2 = Ph (a); Ar1 = Ph,
Ar2 = 4-BrC6H4 (b);Ar1 = 2-FC6H4,Ar2 = 4-ClC6H4 (c);Ar1 = 3-BrC6H4,Ar2 = 4-MeC6H4 (d);Ar1 = 4-NO2C6H4,Ar2 = Ph (e),
4-ClC6H4 (f), 4-BrC6H4 (g), 4-MeC6H4 (h);Alk = Et:Ar1 = Ph,Ar2 = 4-ClC6H4 (i);Ar1 = 2-FC6H4,Ar2 = 4-ClC6H4 (j), 4-BrC6H4
(k);Ar1 = 3-BrC6H4,Ar2 = 4-ClC6H4 (l);Ar1 = 3-NO2C6H4,Ar2 = 4-BrC6H4 (m);Ar1 = 4-NO2C6H4,Ar2 = 4-ClC6H4 (n);Ar1 =
3,4-Cl2C6H4,Ar2 = 4-ClC6H4 (o).
Scheme 2.
O
O
O
O
CF3
N C O
N
IIb, IIf
_HCl
AlkO
AlkO
NH
CF3
AlkO
AlkO
CF3
Ph
N
NH
Ar
Cl
Ph
Ph
O
Ar
O
Va, Vb
B
IV
V,Alk = Me,Ar = 4-MeC6H4 (a);Alk = Et,Ar = 4-BrC6H4 (b).
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HETEROCYCLIZATION OF FUNCTIONALIZED HETEROCUMULENES...: XI.
711
in the aminal fragment NC(CF3)PhNH, and the 13C
NMR spectra containing a characteristic quartet of atom
C2 in the region 79–80 ppm [14]. In the IR spectra of
these compounds recorded in the KBr pellets the C=O
bond of the lactam fragment gives rise to two bands at
1670 and 1690–1695 cm–1, and of the exocyclic ester
groups, to the band at 1742–1745 cm–1. The vibrations
of the N–H bond are characterized by the bands at 3095
and 3190 cm–1, which in the CH2Cl2 solution transform
into the band of the monomer structure at 3400 cm–1.
from protons. In this spectrum of compound VIc the most
downfield signal appears at 165.17 ppm as a doublet, 3JC–
3.0 Hz, and corresponds to the carbon atom of the
H
carboxy group coupled with the proton in the position 4
of the heterocycle, whereas the triplet with 3JC–H 3.7 Hz
at 162.00 ppm corresponds to the carbonyl carbon of the
ester group.
The longer heating at the alkaline hydrolysis according
to the data of GC-MS analysis provided a complex mixture
of mono- and diacids and their decarboxylation products.
1
The observed recently high interest directed on the
polyfunctional 3,4-dihydropyrimidin-2(1H)-ones is due in
a large measure to the pharmacological properties of this
unique structure [15–17]. Among the common initial
compounds for the synthesis of these derivatives 4-aryl-
2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acids
should be mentioned [18–21] that as a rule are obtained
from the corresponding esters by hydrogenolysis or
alkaline hydrolysis [22]. Therefore we deemed useful to
investigate the behavior of diesters IIIh, IIIk, IIIl, and
IIIo under the conditions of alkaline hydrolysis.
The H NMR spectra of acids VIa–VId alongside
the signals of the alkoxy substituents [3.39 (s), 0.94–0.99
(t), 3.85–3.89 ppm (q)] contain doublets of the proton H4
of the hydrogenated pyrimidine ring with the coupling
constant 1.0–1.8 Hz. In the 13C NMR spectra of
compounds VIa and VId the corresponding atom C4 gives
rise to the signal at 49–53 ppm. The IR spectra in the
absorption region of C=O bonds are characterized by a
strong wide band with weakly pronounced maxima at
1650, 1680–1685, 1705–1710, and 1730–1735 cm–1, in
the absorption range of the OH bond a wide band is
present at 2400–2650 cm–1, the vibrations of the NH bond
appear as two bands at 3085 and 3235 cm–1.
It was established that the presence in the structure
of compounds III of two ester groups and an N-aryl
substituent makes them relatively inert to the treatment
with water-alcoholic alkali solution. For instance, the
mentioned compounds were not hydrolyzed by boiling over
7 h with an equimolar amount of KOH in a water-alcohol
mixture. A selective hydrolysis of a single ester group
was achieved by boiling for 3 h with the double excess
of alkali in a mixture ethanol–water, 5:1. As a result
6-alkoxycarbonyl-1,4-diaryl-2-oxo-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylic acids VIa–VId were obtained
(Scheme 3). Analysis of their 1H NMR spectra lacking
the downfield signals of alkoxy groups indicated that the
ester group in the position 5 of the pyrimidine ring
underwent the hydrolysis. This conclusion was confirmed
by the 13C NMR spectra recorded without decoupling
EXPERIMENTAL
IR spectra compounds in KBr pellets were recorded
on a spectrophotometer UR-20. 1H and 13C NMR spectra
were registered on a spectrometer Bruker Avance DRX-
500 (500.13, 125.75 MHz respectively), internal reference
TMS. GC-MS analysis was performed on an instrument
Aligent 1100/DAD/HSD/VLG 119562. 1-Chlorobenzyl
isocyanates ²a–If and 1-aryl-2,2,2-trifluoro-1-chloroethyl
isocyanate (²V) were prepared by procedures [2] and
[15] respectively.
Dialkyl 3,6-diaryl-2-oxo-1,2,3,6-tetrahydro-
pyrimidine-4,5-dicarboxylates IIIa–IIIo. To a solution
of 5 mmol of N-arylaminofumarate IIa–IIf in 20 ml of
anhydrous toluene was added 5 mmol of isocyanate Ia–
If, and the mixture was left standing at room temperature
for 24 h. The separated precipitate was filtered off, dried,
and recrystallized from ethanol.
Scheme 3.
O
Ar1
NH
KOH
HO
IIIh, IIIk, IIIl, IIIo
EtOH H2O
AlkO
N
Ar2
O
Dimethyl 2-oxo-3,6-diphenyl-1,2,3,6-tetra-
hydropyrimidine-4,5-dicarboxylate (IIIa). Yield 46%,
mp 239–241°C. IR spectrum, ν, cm–1: 3240, 3120 (NH),
O
VIà_VId
1
1740, 1702 (C=O). H NMR spectrum, δ, ppm: 3.36 s
VI, Alk = Me, Ar1 = 4-NO2C6H4, Ar2 = 4-MeC6H4 (a);
Alk = Et: Ar1 = 2-FC6H4, Ar2 = 4-BrC6H4 (b); Ar1 =
3-BrC6H4, Ar2 = 4-ClC6H4 (c);Ar1 = 3,4-Cl2C6H3, Ar2 =
4-ClC6H4 (d).
(3H, CH3O), 3.59 s (3H, CH3O), 5.28 d (1H, H6, J 3.0
Hz), 7.18–7.41 m (10Harom), 8.35 d (1H, NH, J 3.0 Hz).
13C NMR spectrum, δ, ppm: 51.98 (CH3O), 52.41
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VOVK et al.
712
(CH3O), 53.07 (C6), 102.79 (C5), 126.26, 128.05, 128.66,
128.73, 128.93, 129.67, 136.13, 142.76 (Carom), 143.03
(C4), 150.98 (C2), 162.14 (C=O), 163.88 (C=O). Found,
%: C 65.83; H 5.07; N 7.41. [M + 1]+ 367. C20H18N2O5.
Calculated, %: C 65.57; H 4.95; N 7.65. M 366.
1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate
(IIIe). Yield 58%, mp 242–244°C. IR spectrum, ν, cm–
1: 3240, 3125 (NH), 1735, 1705 (C=O). H NMR
1
spectrum, δ, ppm: 3.38 s (3H, CH3O), 3.60 s (3H, CH3O),
5.44 d (1H, H6, J 3.3 Hz), 7.21 m (2Harom), 7.42 m
(3Harom), 7.68 d (2Harom, J 8.7 Hz), 8.30 d (2Harom
,
Dimethyl 3-(4-bromophenyl)-2-oxo-6-phenyl-
1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate
(²²Ib). Yield 49%, mp 191–193°C. IR spectrum, ν, cm–1:
J 8.7 Hz), 8.51 d (1H, NH, J 3.3 Hz). 13C NMR spectrum,
δ, ppm: 52.08 (CH3O), 52.48 (CH3O), 52.74 (C6), 101.74
(C5), 124.27, 127.78, 128.64, 128.86, 129.76, 135.90,
143.56, 147.21, 149.73 (Carom), 143.56 (C4), 150.64 (C2),
161.85 (C=O), 163.61 (C=O). Found, %: C 58.18; H
4.04; N 10.37. [M + 1]+ 412. C20H17N3O7. Calculated,
%: C 58.39; H 4.17; N 10.21. M 411.
1
3235, 3130 (NH), 1737, 1700 (C=O). H NMR spectrum,
δ, ppm: 3.47 s (3H, CH3O), 3.62 s (3H, CH3O), 5.31 d
(1H, H6, J 3.3 Hz), 7.17 d (2Harom, J 8.5 Hz), 7.35–7.44 m
(5Harom), 7.60 d (2Harom, J 8.5 Hz), 8.41 d (1H, NH,
13
J 3.3 Hz). C NMR spectrum, δ, ppm: 52.04 (CH3O),
52.64 (CH3O), 53.12 (C6), 103.24 (C5), 121.95, 126.29,
128.08, 128.93, 131.74, 131.80, 135.48, 142.43 (Carom),
142.59 (C4), 150.64 (C2), 162.08 (C=O), 163.79 (C=O).
Found, %: C 53.73; H 3.97; N 6.48. [M + 1]+ 446.
C20H17BrN2O5. Calculated, %: C 53.95; H 3.85; N 6.29.
M 445.
Dimethyl 6-(4-nitrophenyl)-2-oxo-3-(4-chloro-
phenyl)-1,2,3,6-tetrahydropyrimidine-4,5-dicarb-
oxylate (IIIf). Yield 71%, mp 218–220°C. IR spectrum,
ν, cm–1: 3235, 3130 (NH), 1745, 1705 (C=O). 1H NMR
spectrum, δ, ppm: 3.45 s (3H, CH3O), 3.60 s (3H, CH3O),
5.47 d (1H, H6, J 3.5 Hz), 7.28 d (2Harom, J 8.7 Hz),
7.48 d (2Harom, J 8.7 Hz), 7.67 d (2Harom, J 8.7 Hz),
8.29 d (2Harom, J 8.7 Hz), 8.59 d (1H, NH, J 3.5 Hz).
13C NMR spectrum, δ, ppm: 52.12 (CH3O), 52.69
(CH3O), 52.80 (C6), 102.18 (C5), 124.24, 127.85, 128.75,
131.62, 133.56, 134.82, 147.23, 149.56 (Carom), 143.07
(C4), 150.39 (C2), 161.81 (C=O), 163.53 (C=O). Found,
%: C 54.06; H 3.57; N 9.31. [M + 1]+ 446.
C20H16ClN3O7. Calculated, %: C 53.88; H 3.62; N 9.43.
M 445.
Dimethyl 2-oxo-6-(2-fluorophenyl)-3-(4-chloro-
phenyl)-1,2,3,6-tetrahydropyrimidine-4,5-dicarb-
oxylate (IIIc). Yield 41%, mp 255–257°C. IR spectrum,
ν, cm–1: 3245, 3135 (NH), 1740, 1705 (C=O). 1H NMR
spectrum, δ, ppm: 3.43 s (3H, CH3O), 3.54 s (3H, CH3O),
5.51 d (1H, H6, J 3.0 Hz), 7.21–7.47 m (8Harom), 8.33 d
(1H, NH, J 3.0 Hz). 13C NMR spectrum, δ, ppm: 49.48
(C6), 51.92 (CH3O), 52.58 (CH3O), 100.83 (C5), 115.95 d
(JC–F 21.2 Hz), 124.76, 128.75, 129.31, 129.55 d
(JC–F 19.4 Hz), 130.30, 131.60, 133.40, 135.12, 160.26 d
(Carom, JC–F 245.0 Hz), 142.90 (C4), 150.19 (C2), 162.01
(C=O), 163.61 (C=O). Found, %: C 57.61; H 3.72;
N 6.47. [M + 1]+ 419.6. C20H16ClFN2O5. Calculated, %:
C 57.36; H 3.85; N 6.69. M 418.6.
Dimethyl 3-(4-bromophenyl)-6-(4-nitrophenyl)-2-
oxo-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate
(IIIg). Yield 76%, mp 224–226°C. IR spectrum, ν, cm–1:
3245, 3130 (NH), 1740, 1703 (C=O). 1H NMR spectrum,
δ, ppm: 3.46 s (3H, CH3O), 3.61 s (3H, CH3O), 5.55 d
(1H, H6, J 3.0 Hz), 7.27 d (2Harom, J 8.5 Hz), 7.64 d
Dimethyl 6-(3-bromophenyl)-2-oxo-3-(4-tolyl)-
1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate
(IIId). Yield 67%, mp 199–200°C. IR spectrum, ν,
(2Harom, J 8.5 Hz), 7.71 d (2Harom, J 8.5 Hz), 8.32 d (2Harom
,
J 8.5 Hz), 8.62 d (1H, NH, J 3.0 Hz). 13C NMR spectrum,
δ, ppm: 52.11 (CH3O), 52.67 (CH3O), 52.80 (C6), 102.17
(C5), 122.08, 124.20, 127.83, 131.69, 131.87, 135.26,
147.19, 149.53 (Carom), 142.97 (C4), 150.31 (C2), 161.79
(C=O), 163.50 (C=O). Found, %: C 49.18; H 3.41;
N 8.40. [M]+ 490. C20H16BrN3O7. Calculated, %:
C 49.00; H 3.29; N 8.57. M 490.
1
cm–1: 3235, 3125 (NH), 1739, 1703 (C=O). H NMR
spectrum, δ, ppm: 2.35 s (3H, CH3), 3.41 Cs(3H, CH3O),
3.61 s (3H, CH3O), 5.27 d (1H, H6, J 3.3 Hz), 7.03 d
(2Harom, J 8.4 Hz), 7.30 d (2Harom, J 8.4 Hz), 7.39 d (2Harom
,
J 8.4 Hz), 7.49–7.55 m (2Harom), 8.36 d (1H, NH,
J 3.3 Hz). 13C NMR spectrum, δ, ppm: 20.66 (CH3),
52.05 (CH3O), 52.46 (CH3O), 52.50 (C6), 101.91 (C5),
121.90, 125.12, 129.15, 129.25, 129.40, 130.91, 131.33,
133.32, 138.35, 143.52 (Carom), 145.26 (C4), 150.81 (C2),
161.95 (C=O), 163.69 (C=O). Found, %: C 55.24; H 4.03;
N 6.25. [M + 1]+ 460. C21H19BrN2O5. Calculated, %: C
54.92; H 4.17; N 6.10. M 459.
Dimethyl 6-(4-nitrophenyl)-2-oxo-3-(4-tolyl)-
1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate
(IIIh). Yield 62%, mp 275–277°C. IR spectrum, ν, cm–1:
1
3230, 3130 (NH), 1730, 1705 (C=O). H NMR spectrum,
δ, ppm: 2.35 s (3H, CH3), 3.40 s (3H, CH3O), 3.59 s
(3H, CH3O), 5.43 d (1H, H6, J 3.3 Hz), 7.09 d (2Harom
J 8.1 Hz), 7.20 d (2Harom, J 8.1 Hz), 7.66 d (2Harom
,
,
Dimethyl 6-(4-nitrophenyl)-2-oxo-3-phenyl-
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(CH2O), 100.75 (C5), 115.79 d (JC–F 21.3 Hz), 121.92,
124.66, 129.50 (JC–F 12.5 Hz), 129.70, 130.15, 131.63,
132.20, 135.54, 160.25 d (Carom, JC–F 245.0 Hz), 142.71
(C4), 150.21 (C2), 161.37 (C=O), 163.06 (C=O). Found,
%: C 54.05; H 4.22; N 5.89. [M + 1]+ 492.
C22H20BrFN2O5. Calculated, %: C 53.78; H 4.10; N 5.70.
M 491.
J 8.4 Hz), 8.29 d (2Harom, J 8.4 Hz), 8.47 d (1H, NH, J
3.3 Hz). 13C NMR spectrum, δ, ppm: 20.64 (CH3), 52.05
(CH3O), 52.50 (C6), 52.73 (CH3O), 101.51 (C5), 124.24,
127.76, 129.11, 129.46, 133.30, 138.39, 147.19, 149.78
(Carom), 143.76 (C4), 150.73 (C2), 161.87 (C=O), 163.62
(C=O). Found, %: C 59.53; H 4.27; N 9.99. [M + 1]+
426. C21H19N3O7. Calculated, %: C 59.29; H 4.50; N
9.88. M 425.
Diethyl
6-(3-bromophenyl)-2-oxo-3-(4-
chlorophenyl)-1,2,3,6-tetrahydropyrimidine-4,5-
dicarboxylate (²²Il). Yield 79%, mp 202–204°C. IR
spectrum, ν, cm–1: 3238, 3125 (NH), 1738, 1703 (C=O).
1H NMR spectrum, δ, ppm: 0.93 t (3H, CH3, J 7.5 Hz),
1.13 t (3H, CH3, J 7.5 Hz), 3.87 q (2H, CH2O, J 7.5 Hz),
4.04 q (2H, CH2O, J 7.5 Hz), 5.31 d (1H, H6, J 3.0 Hz),
7.22 d (2Harom, J 8.4 Hz), 7.39–7.54 m (6Harom), 8.44 d
(1H, NH, J 3.0 Hz). 13C NMR spectrum, δ, ppm: 13.09
(CH3), 13.70 (CH3), 52.81 (C6), 60.77 (CH2O), 61.81
(CH2O), 102.50 (C5), 121.77, 125.26, 128.73, 129.54,
130.89, 131.37, 131.78, 133.54, 134.85, 145.34 (Carom),
142.63 (C4), 150.57 (C2), 161.29 (C=O), 163.10 (C=O).
Found, %: C 52.36; H 4.12; N 5.37. [M + 1]+ 509.
C22H20BrClN2O5. Calculated, %: C 52.04; H 3.97; N
5.52. M 508.
Diethyl 2-oxo-6-phenyl-3-(4-chlorophenyl)-
1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate
(²²Ii). Yield 44%, mp 185–186°C. IR spectrum, ν, cm–1:
1
3235, 3140 (NH), 1730, 1700 (C=O). H NMR spectrum,
δ, ppm: 0.92 t (3H, CH3, J 7.5 Hz), 1.10 t (3H, CH3, J 7.2
Hz), 3.87 q (2H, CH2O, J 7.5 Hz), 4.02 q (2H, CH2O, J
7.2 Hz), 5.28 d (1H, H6, J 3.3 Hz), 7.23 d (2Harom, J 8.7
Hz), 7.32–7.46 m (7Harom), 8.38 d (1H, NH, J 3.3 Hz).
13C NMR spectrum, δ, ppm: 13.10 (CH3), 13.71 (CH3),
53.26 (C6), 60.66 (CH2O), 61.73 (CH2O), 103.22 (C5),
126.36, 128.03, 128.69, 128.85, 131.83, 133.45, 135.02,
142.30 (Carom), 142.80 (C4), 150.83 (C2), 161.47 (C=O),
163.27 (C=O). Found, %: C 61.35; H 5.07; N 6.69. [M]+
429.2. C22H21ClN2O5. Calculated, %: C 61.61; H 4.94;
N 6.53. M 428.9.
Diethyl 3-(4-bromophenyl)-6-(3-nitrophenyl)-2-
oxo-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate
(²²Im). Yield 69%, mp 229–231°C. IR spectrum, ν, cm–
1: 3240, 3130 (NH), 1730, 1705 (C=O). 1H NMR
spectrum, δ, ppm: 0.97 t (3H, CH3, J 7.0 Hz), 1.15 t (3H,
CH3, J 7.0 Hz), 3.93 q (2H, CH2O, J 7.0 Hz), 4.07 q (2H,
Diethyl
2-oxo-6-(2-fluorophenyl)-3-(4-
chlorophenyl)-1,2,3,6-tetrahydropyrimidine-4,5-
dicarboxylate (²²Ij). Yield 51%, mp 184–186°C. IR
spectrum, ν, cm–1: 3240, 3135 (NH), 1735, 1704 (C=O).
1H NMR spectrum, δ, ppm: 0.92 t (3H, CH3, J 7.5 Hz),
1.08 t (3H, CH3, J 8.0 Hz), 3.89 q (2H, CH2O, J 7.5 Hz),
4.00 q (2H, CH2O, J 8.0 Hz), 5.51 d (1H, H6, J 3.0 Hz),
7.27–7.55 m (8Harom), 8.31 d (1H, NH, J 3.0 Hz). 13C
NMR spectrum, δ, ppm: 13.06 (CH3), 13.57 (CH3), 49.56
(C6), 60.50 (CH2O), 61.65 (CH2O), 100.74 (C5), 115.86
d (JC–F 21.3 Hz), 124.64, 128.65, 129.48, 129.68 d (JC–F
CH2O, J 7.0 Hz), 5.49 d (1H, H6, J 3.0 Hz), 7.21 d (2Harom
,
J 8.0 Hz), 7.61 d (2Harom, J 8.0 Hz), 7.76 t (1Harom, J 6.5
Hz), 7.87 d (1Harom, J 7.5 Hz), 8.22 d (1Harom, J 8.0 Hz),
8.28 C (1Harom), 8.56 d (1H, NH, J 3.0 Hz). 13C NMR
spectrum, δ, ppm: 13.05 (CH3), 13.63 (CH3), 52.72 (C6),
60.82 (CH2O), 61.83 (CH2O), 102.24 (C5), 121.26, 122.08,
122.98, 130.74, 131.68, 132.10, 133.03, 135.21, 144.80,
147.86 (Carom), 142.86 (C4), 150.42 (C2), 161.16 (C=O),
163.01 (C=O). Found, %: C 51.26; H 3.75; N 8.22. [M +
1]+ 519. C22H20BrN3O7. Calculated, %: C 50.98; H 3.89;
N 8.11. M 518.
12.6 Hz), 130.14, 131.91, 133.44, 135.09, 160.18 d (Carom
,
JC–F 245.0 Hz), 142.79 (C4), 150.27 (C2), 161.39 (C=O),
163.07 (C=O). Found, %: C 58.88; H 4.64; N 6.39. [M +
1]+ 447. C22H20ClFN2O5. Calculated, %: C 59.13; H 4.51;
N 6.27. M 446.
Diethyl
3-(4-bromophenyl)-2-oxo-6-(2-
Diethyl
6-(4-nitrophenyl)-2-oxo-3-(4-
fluorophenyl)-1,2,3,6-tetrahydropyrimidine-4,5-
dicarboxylate (²²Ik). Yield 47%, mp 195–196°C. IR
spectrum, ν, cm–1: 3245, 3128 (NH), 1735, 1700 (C=O).
1H NMR spectrum, δ, ppm: 0.97 t (3H, CH3, J 7.0 Hz),
1.11 t (3H, CH3, J 7.5 Hz), 3.91 q (2H, CH2O, J 7.0 Hz),
4.01 q (2H, CH2O, J 7.5 Hz), 5.54 d (1H, H6, J 3.0 Hz),
7.22–7.45 m (6Harom), 7.62 d (2Harom, J 8.5 Hz), 8.30 d
(1H, NH, J 3.0 Hz). 13C NMR spectrum, δ, ppm: 13.05
(CH3), 13.57 (CH3), 49.55 (C6), 60.50 (CH2O), 61.66
chlorophenyl)-1,2,3,6-tetrahydropyrimidine-4,5-
dicarboxylate (²²In). Yield 47%, mp 229–231°C. IR
spectrum, ν, cm–1: 3240, 3135 (NH), 1743, 1702 (C=O).
1H NMR spectrum, δ, ppm: 0.94 t (3H, CH3, J 7.5 Hz),
1.12 t (3H, CH3, J 7.5 Hz), 3.88 t (2H, CH2O, J 7.5 Hz),
4.05 t (2H, CH2O, J 7.5 Hz), 5.45 d (1H, H6, J 3.3 Hz),
7.28 d (2Harom, J 8.4 Hz), 7.45 d (2Harom, J 8.4 Hz), 7.68
d (2Harom, J 8.7 Hz), 8.29 d (2Harom, J 8.7 Hz), 8.55 d
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 5 2010

VOVK et al.
714
(1H, NH, J 3.3 Hz). 13C NMR spectrum, δ, ppm: 13.08
(CH3), 13.68 (CH3), 52.93 (C6), 60.84 (CH2O), 61.83
(CH2O), 102.05 (C5), 124.18, 127.92, 128.66, 131.95,
133.59, 134.78, 147.17, 149.77 (Carom), 142.91 (C4),
150.48 (C2), 161.18 (C=O), 163.01 (C=O). Found, %:
C 55.57; H 3.36; N 8.98. [M]+ 474. C22H20ClN3O7.
Calculated, %: C 55.76; H 4.25; N 8.87. M 474.
163.88 (C=O). 19F NMR spectrum, δ, ppm: –74.09.
Found, %: C 59.16; H 2.17; N 6.42. [M + 1]+ 449.
C22H19F3N2O5. Calculated, %: C 58.93; H 4.27; N 6.25.
M 448.
Diethyl 3-(4-bromophenyl)-6-oxo-2-phenyl-2-
trifluoromethyl-1,2,3,6-tetrahydropyrimidine-4,5-
dicarboxylate (Vb). Yield 20%, mp 169–170°C. IR
spectrum, ν, cm–1: 3190, 3095 (NH), 1745, 1695, 1670
(C=O). 1H NMR spectrum, δ, ppm: 0.92 t (3H, CH3,
J 7.2 Hz), 1.13 t (3H, CH3, J 7.2 Hz), 3.83 q (2H, CH2O,
Diethyl 2-oxo-6-(3,4-dichlorophenyl)-3-(4-
chlorophenyl)-1,2,3,6-tetrahydropyrimidine-4,5-
dicarboxylate (²²Io). Yield 53%, mp 199–201°C. IR
spectrum, ν, cm–1: 3240, 3120 (NH), 1735, 1700 (C=O).
1H NMR spectrum, δ, ppm: 0.94 t (3H, CH3, J 7.2 Hz),
1.13 t (3H, CH3, J 7.2 Hz), 3.87 q (2H, CH2O, J 7.2 Hz),
4.06 q (2H, CH2O, J 7.2 Hz), 5.32 d (1H, H6, J 3.3 Hz),
7.24 d (2Harom, J 8.7 Hz), 7.38 d (1Harom, J 8.4 Hz),
J 7.2 Hz), 3.98 q (2H, CH2O, J 7.2 Hz), 7.26 d (2Harom
J 8.4 Hz), 7.38–7.44 m (3Harom), 7.56 d (2Harom
,
,
J 8.4 Hz), 7.61–7.63 m (2Harom), 9.03 s (1H, NH).
13C NMR spectrum,δ, ppm: 13.29 C (CH3), 13.43 C (CH3),
61.18 (CH2O), 62.57 (CH2O), 79.64 q (C2, JC–F 29.0 Hz),
102.81 (C5), 124.40 q (CF3, JC–F 280.4 Hz), 123.54,
127.45, 128.51, 129.00, 131.27, 132.15, 134.45, 137.33
(Carom), 150.8 (C4), 156.74 (C6), 161.41 (C=O), 162.76
(C=O). 19F NMR spectrum, δ, ppm: –74.45. Found, %:
C 50.76; H 3.89; N 5.24. [M]+ 541. C23H20BrF3N2O5.
Calculated, %: C 51.03; H 3.72; N 5.17. M 541.
7.45 d (2Harom, J 8.7 Hz), 7.55 C (1Harom), 7.65 d (1Harom
,
J 8.4 Hz), 8.46 d (1H, NH, J 3.3 Hz). 13C NMR spectrum,
δ, ppm: 13.04 (CH3), 13.65 (CH3), 52.43 (C6), 60.76
(CH2O), 61.80 (CH2O), 102.05 (C5), 126.56, 128.66,
128.80, 130.64, 131.19, 131.30, 131.81, 133.55, 134.79,
143.64 (Carom), 142.79 (C4), 150.42 (C2), 161.18 (C=O),
163.03 (C=O). Found, %: C 53.39; H 3.96; N 5.50. [M]+
498. C22H19Cl3N2O5. Calculated, %: C 53.09; H 3.85;
N 5.63. M 498.
6-Alkoxycarbonyl-1,4-diaryl-2-oxo-1,2,3,4-tetra-
hydropyrimidine-5-carboxylic acids VIa–VId. To
a solution of 1 mmol of diester IIIh, IIIk, IIIl, IIIo in
25 ml of ethanol was added 0.12 g (2.2 mmol) of KOH in
5 ml of water, and the mixture was boiled for 3 h. On
cooling the reaction mixture was poured into 50 ml of
water and neutralized with dilute hydrochloric acid. The
separated precipitate was filtered off, dried, and
recrystallized from acetonitrile.
Dialkyl 2,3-diaryl-6-oxo-2-trifluoromethyl-
1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylates Va
and Vb. To a solution of 5 mmol of N-arylaminofumarate
IIb or IIf in 20 ml of anhydrous toluene was added
dropwise at stirring 0.7 ml (5 mmol) of triethylamine, and
then over 30 min, 5 mmol (1.2 g) of isocyanate IV. The
reaction mixture was stirred for 8 h and the precipitate
of the triethylamine hydrochloride was filtered off. In the
19F NMR spectrum containing compound Va or Vb
a signal was observed in the region –70...–69 ppm. The
filtrate was boiled for 12 h, the solvent was evaporated,
the residue was subjected to column chromatography on
silica gel, eluent ethyl acetate–hexane, 1:1.
1-(4-Methylphenyl)-6-methoxycarbonyl-4-(4-
nitrophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-
carboxylic acid (V²a). Yield 80%, mp 282–284°C. IR
spectrum, ν, cm–1: 3235, 3085 (NH), 2420–2630 (OH),
1
1735, 1705, 1680, 1650 (C=O). H NMR spectrum, δ,
ppm: 2.37 s (3H, CH3), 3.39 s (3H, CH3O), 5.42 d (1H,
H6, J 1.2 Hz), 7.09 d (2HapOm, J 7.0 Hz), 7.20 d (2Harom
,
J 7.0 Hz), 7.70 d (2Harom, J 8.5 Hz), 8.14 br.s (1H, NH),
8.31 d (2Harom, J 8.5 Hz), 12.63 br.s (1H, COOH). Found,
%: C 58.63; H 4.27; N 10.01. [M]+ 411. C20H17N3O7.
Calculated, %: C 58.39; H 4.17; N 10.21. M 411.
Dimethyl 3-(4-methylphenyl)-6-oxo-2-phenyl-2-
trifluoromethyl-1,2,3,6-tetrahydropyrimidine-4,5-
dicarboxylate (Va). Yield 22%, mp 181–183°C. IR
spectrum, ν, cm–1: 3190, 3095 (NH), 1742, 1690, 1670
1
(C=O). H NMR spectrum, δ, ppm: 2.16 s (3H, CH3),
1-(4-Bromophenyl)-2-oxo-4-(2-fluorophenyl)-6-
ethoxycarbonyl-1,2,3,4-tetrahydropyrimidine-5-
carboxylic acid (VIb). Yield 88%, mp 203–205°C. IR
spectrum, ν, cm–1: 3235, 3085 (NH), 2400–2650 (OH),
3.32 s (3H, CH3O), 3.64 s (3H, CH3O), 7.01 d (2Harom
,
J 8.2 Hz), 7.26–7.44 m (5Harom), 7.44–7.51 m (2Harom),
9.13 s (1H, NH). 13C NMR spectrum, δ, ppm: 20.40
(CH3), 51.62 (CH3O), 52.57 (CH3O), 79.32 q (C2,
JC–F 29.1 Hz), 99.34 (C5), 123.79 q (CF3, JC–F 278.5 Hz),
128.15, 128.87, 129.53, 130.01, 130.95, 132,38, 135.21,
138.44 (Carom), 153.11 (C4), 159.83 (C6), 162.04 (C=O),
1
1730, 1710, 1685, 1650 (C=O). H NMR spectrum, δ,
ppm: 0.99 t (3H, CH3, J 6.8 Hz), 3.89 q (2H, CH2O,
J 6.8 Hz), 5.50 d (1H, H6, J 1.0 Hz), 7.23–7.60 m (8Harom
,
7Harom, NH), 8.20 s (1Harom), 12.67 br.s (1H, COOH).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 5 2010

HETEROCYCLIZATION OF FUNCTIONALIZED HETEROCUMULENES...: XI.
715
13C NMR spectrum, δ, ppm: 13.10 (CH3), 49.57 (C6),
61.50 (CH2O), 100.79 (C5), 115.85 d (JC–F 21.2 Hz),
121.82, 124.69, 129.24 (JC–F 12.6 Hz), 130.09, 131.33,
131.62, 132.23, 135.71, 159.28 d (Carom, JC–F 242.2 Hz),
142.40 (C4), 150.45 (C2), 161.63 (C=O), 164.63 (C=O).
Found, %: C 52.07; H 3.28; N 6.26. [M]+ 463.
C20H16BrFN2O5. Calculated, %: C 51.85; H 3.48; N 6.05.
M 463.
4. Corling, R.W., Leeson, P.D., Moseley,A.M., Baker, R., and
Foster,A.C., J. Med. Chem., 1992, vol. 35, p. 1942.
5. Jaen, J.C., Laborde, E., Bush, R.A., Caprathe, B.W., and
Sorenson, R.I., J. Med. Chem., 1995, vol. 38, p. 4439.
6. Edmondt, D., Rocher, R., Plisson, C., and Chenoult, J.,
Bioorg. Med. Chem. Lett., 2000, vol. 10, p. 1831.
7. Borza, I., Kolok, S., Galgoczy, K., Gere, A., Horvath, C.,
Farkas, S., Grewer, J., and Domany, G., Bioorg. Med. Chem.
Lett., 2007, vol. 17, p. 406.
8. Chepyshev, S.V., Mazurkevich, Yu.N., Lebed’, O.S., and
Prosyanik,A.V., Khim. Geterotsikl. Soedin., 2007, p. 1001.
9. Bergman, J., Janosi, K.T., Koch, E., and Polcman, B.,
J. Chem. Soc., Perkin Trans. 1, 2000, p. 2615.
10. Makri, K., Kawie, A., Horigushi, Y., and Isobe, K.,
Heterocycles, 1999, vol. 51, p. 2377.
11. Grohe, K. and Heitzer, H., Lieb. Ann., 1973, p. 1018.
12. Zhang, H., Jiang, H., Liu, H., and Zhi, Q., Org. Lett., 2007,
vol. 9, p. 4111.
13. Gorbatenko, V.I. and Samarai, L.I., Synthesis, 1980, p. 85.
14. Vovk, M.V. and Pirozhenko, V.V., Khim. Geterotsikl. Soedin.,
1994, p. 85.
15. Fetyukhin, V.N., Koretskii, A.S., Gorbatenko, V.I., and
Samarai, L.I., Zh. Org. Khim., 1977, vol. 13, p. 271.
16. Kappe, C.O., Eur. J. Med. Chem., 2000, vol. 35, p. 1043.
17. Kappe, C.O., QSAR Comb. Sci., 2003, vol. 22, p. 630.
18. Pesai, B., Dallinger, D., and Kappe, C.O., Tetrahedron, 2006,
vol. 62, p. 4651.
4-(3-Bromophenyl)-2-oxo-1-(4-chlorophenyl)-6-
ethoxycarbonyl-1,2,3,4-tetrahydropyrimidine-5-
carboxylic acid (V²c). Yield 90%, mp 206–207°C. IR
spectrum, ν, cm–1: 3235, 3085 (NH), 2420–2650 (OH),
1
1735, 1705, 1685, 1650 (C=O). H NMR spectrum, δ,
ppm: 0.94 t (3H, CH3, J 7.0 Hz), 3.85 q (2H, CH2O, J 7.0
Hz), 5.26 d (1H, H6, J 1.8 Hz), 7.20 d (2Harom, J 8.7 Hz),
7.41–7.54 m (6Harom, 5Harom, NH), 8.36 d (1Harom
,
J 3.6 Hz), 12.74 br.s (1H, COOH). Found, %: C 50.35;
H 3.32; N 5.97. [M]+ 480. C20H16BrClN2O5. Calculated,
%: C 50.07; H 3.36; N 5.84. M 480.
2-Oxo-4-(3,4-dichlorophenyl)-1-(4-chloro-
phenyl)-6-ethoxycarbonyl-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylic acid (VId). Yield 92%, mp
204–206°C. IR spectrum, ν, cm–1: 3235, 3085 (NH),
2470–2640 (OH), 1730, 1705, 1680, 1650 (C=O).
1H NMR spectrum, δ, ppm: 0.99 t (3H, CH3, J 6.4 Hz),
3.89 q (2H, CH2O, J 6.4 Hz), 5.31 d (1H, H6, J 1.5 Hz),
19. Matthews, J.M., Liotta, F., Hageman, W., Rivero, R.A.,
Westover, L., Yang, M., Xu, J., and Demarest, K., Bioorg.
Med. Chem. Lett., 2004, vol. 14, p. 1155.
20. Blackburn, C., Guan, B., Brown, J., Cullis, C., Condon, S.M.,
Jenkins, T.J., Peluso, S., Ye, Y., Gimeno, R.E., Purreddy, S.,
Sun, Y., Wu, H., Hubbard, B., Kaushik, V., Tummino, P.,
Sanchetti, P., Sun, D.Y., Daniels, T., Tozzo, E., Balan, S.K.,
and Raman, P., Bioorg. Med. Chem. Lett., 2006, vol. 16,
p. 3504.
7.22 d (2Harom, J 8.5 Hz), 7.41–7.67 m (5Harom, 4Harom
,
NH), 8.32 s (1Harom), 12.75 br.s (1H, COOH). 13C NMR
spectrum, δ, ppm: 13.25 (CH3), 52.93 (C6), 61.76 (CH2O),
103.66 (C5), 125.40, 128.85, 129.51, 130.85, 131.45,
131.91, 132.01, 133.55, 135.15, 145.56 (Carom), 142.48
(C4), 150.98 (C2), 163.01 (C=O), 165.09 (C=O). Found,
%: C 51.43; H 3.17; N 6.08. [M]+ 469. C20H15Cl3N2O5.
Calculated, %: C 51.14; H 3.22; N 5.96. M 469.
21. Barrow, J.C., Nantermet, P.G., Selnick, H., Glass, K.L.,
Rittle, K.E., Gilbert, K.F., Steele, T.G., Homnick, C.F., Freidin-
ger, R.M., Ranson, R.W., Klig, P., Reiss, D., Broten, T.P.,
Shoun, T.W., Chang, R.S.L., O’Malley, S.S., Olah, T.V.,
Ellis, J.D., Burrish, A., Kossahan, K., Leppert, P.,
Nagarathnam, O., and Forrey, C., J. Med. Chem., 2000,
vol. 43, p. 2703.
REFERENCES
1. Kushnir, O.V., Sukach, V.A, andVovk, M.V., Zh. Org. Khim.,
2009, vol. 45, p. 767.
2. Sukach, V.A., Bol’but,A.V., Sinitsa,A.D., and Vovk, M.V.,
Synlett., 2006, p. 375.
3. Sukach, V.A., Bol’but,A.V., Petin, A.Yu., and Vovk, M.V.,
Synthesis, 2007, p. 835.
22. Zegeuner, G., Knopp, C., and Blaschke, H., Monatsh.
Chem., 1976, vol. 107, p. 587.
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