Selective acylation of 5-nitro- and 5-ethoxycarbonyl-4,6-diaryl-3,4- dihydropyrimidin-2(1H)-ones

Article abstract of DOI:10.1134/S1070428010110163

The acetylation and chloroacetylation of 5-nitro- and 5-ethoxycarbonyl- substituted 4,6-diaryl-3,4-dihydropyrimidin-2(1H)-ones proceeds regioselectively at the N³ atom of the heterocycle whereas the acetylation of the 5-aryloxy-substituted anal

Full text of DOI:10.1134/S1070428010110163

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 11, pp. 1695−1701. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © V.F. Sedova, O.P. Shkurko, 2010, published in Zhurnal Organicheskoi Khimii, 2010, Vol. 46, No. 11, pp. 1688−1693.
Selective Acylation of 5-Nitro- and 5-Ethoxycarbonyl-
4,6-diaryl-3,4-dihydropyrimidin-2(1Н)-ones
V. F. Sedova and O. P. Shkurko
Vorozhtsov Novosibirsk Institute of Organic Chemistry,
Siberian Branch, Russian Academy of Sciences, Novosibirsk, 630090 Russia
e-mail: oshk@nioch.nsc.ru
Received March 12, 2010
Abstract—The acetylation and chloroacetylation of 5-nitro- and 5-ethoxycarbonyl-substituted 4,6-diaryl-3,4-
dihydropyrimidin-2(1H)-ones proceeds regioselectively at the N3 atom of the heterocycle whereas the acetylation
of the 5-aryloxy-substituted analog results in a mixture of N1- and N3-acetylated regioisomers.
DOI: 10.1134/S1070428010110163
3,4-Dihydropyrimidin-2(1Н)-ones compose a special
structural group of heterocyclic compounds, whose func-
tional derivatives exhibit versatile biological activity, in
particular, antiviral, antitumor, antibacterial, and fungi-
cidal action and are modulators of calcium channels [1,
2]. The presence of substituents with a carbonyl group
at the endocyclic N3 atom often results in an increased
chemical resistance of the molecule with retaining the
character of the biological action [3]. For instance, among
the N3-acyl derivatives of 3,4-dihydropyrimidin-2(1Н)-
ones blockaders of the calcium channels of prolonged
action [3, 4], antagonists of adrenergic receptor α1а [5],
and antitumor agents [6] were found.
search we investigated the effect of structural factors in
the dihydropyrimidinones on the direction of the acylation
and formylation. 4-Aryl-6-phenyl-3,4-dihydropyrimidin-
2(1Н)-ones with a functional substituent in the position 5
of the heterocycle, namely, electron-withdrawing groups
NO2 (compounds Ia–Ic) or CO2Et (compounds IIa, IIb,
IId), or electron-donor substituent 4-O2NС6Н4O (com-
pound III) were acylated with acetic anhydride and chlo-
roacetyl chloride and formylated by Vilsmeier complex.
By long boiling of dihydropyrimidinones I and II with
acetic anhydride the monoacetylation occurred at the N3
atom of the heterocycle resulting in the formation of com-
pounds IV, V (Scheme 1), and the reaction products did
not contain even traces of impurities of N1-acetyl- (VI)
or N1,N3-diacetyl derivatives.
The main synthetic procedure for preparation of
these N-acyl derivatives is the acylation of appropriate
precursors. It was shown by an example of some 5-sub-
stituted (COOAlk, COAlk) dihydropyrimidinones that
the regioselectivity of the acylation depends both on the
character of the acylating agent and of the substituents
in the heterocycle [7]. As a rule the reaction occurs at the
more nucleophilic atom N3 at heating the initial neutral
compound with the acylating agent or by treating with
the agent the corresponding anion [8–10].
The IR spectra of these compounds lack the absorp-
tion bands in the region 3360–3450 and 3315 cm–1 cor-
responding to the stretching vibrations of the N3–Н bond
of the initial 5-nitro- and 5-ethoxycarbonylpyrimidinones.
From the 1Н NMR spectra of the products obtained the
signals of the protons Н3 disappeared, and the signals of
Н4 protons were observed as singlets whereas in the spec-
tra of initial compounds I, II they gave rise to doublets
[J(H3–H4) ~3 Hz] [11]. Owing to the anisotropic effect of
the carbonyl mgroup at the atom N3 the signal of proton
Н4 in the spectra of compounds IV, V shifted downfield
by 1.07–1.28 ppm. The signals of N1Н in the spectra of
We formerly obtained a series of 4,6-diaryl-3,4-
dihydropyrimidin-2(1Н)-ones containing a nitro group
in the position 5 of heterocycle I that showed a high
antiarrhythmic action [11, 12]. In extension of this re-
1695

SEDOVA, SHKURKO
1696
Scheme 1.
C6H4R1
NH
C6H4R1
C6H4R1
NAc
Ac2O or
R2
Ph
R2
R2
Ph
ClCH2COCl
NH
Ac2O
Ph
O
O
O
N
N
N
H
H
R3
VI
Iа_Ic, IIа, IIb, IId
IVа_IVc, Vа, Vb, Vd
10
ClCH2COCl
POCl3_DMF
Iа
11
9
12
8
7
4
C6H4R1
NCOCH2Cl
Ph
R2
Ph
O2N
Ph
O2N
NCH
3NCHO
NMe2
5
2
14
6
1
O
O
O
N
N
H
N
13
15
H
H
18
17
16
VIIа, VIIb, VIIIа, VIIIb
IX
X
I, IV, VII, R2 = NO2, R1 = H (a), 3-F (b), 3-NO2 (c); II, V, VIII, R2 = CO2Et, R1 = H (a), 3-F (b), 4-OCH3 (d); VI, R2 =
NO2, CO2Et; R3 = Ac, COCH2Cl.
these compounds were also observed in a weaker field
than in the spectra of initial dihydropyrimidines.
The acetylation of 5-(4-nitrophenoxy)derivative III
in contrast to dihydropyrimidinones I, II with electron-
withdrawing substituents in the heterocycle proceeded
less selectively with the formation of two acyl derivatives,
N3-acetylpyrimidinone and N1,N3-diacetyldihydropyrim-
idinones XI, XII in a ratio 3 : 1 according to the data of
1Н NMR (Scheme 2).
The chloroacetylation of dihydropyrimidines I, II was
carried out in dioxane in the presence of triethylamine or
sodium acetate. The reaction was slower than the acetyla-
tion with acetic anhydride and required longer boiling of
the reaction mixture. In both cases the reaction products
consisted exclusively of N3-chloroacetyl derivatives (VII,
VIII) whose spectral characteristics were similar to those
of N3-acetyl derivatives IV, V.
In the 13С NMR spectra of N3-acyldihydropyrim-
idinones IV, V, VII, VIII characteristic changes were
observed in the positions of the signals of the atoms С4,
С5 of the heterocycle and the ipso-atom С7 of the aryl
substituent С6Н4R: The signal of atom С5 shifted down-
field by ~2–3 ppm, whereas the signals of atom С4 and
linked to it С7 shifted upfield, and the strongest shift (up
to 4–5 ppm) occurred with С7.
The enhanced nucleophilicity of the endocyclic atom
N1 in compound III compared with compounds I, II is
governed by different character of the intramolecular
influence of the electron-donor nitrophenoxy group
and the acceptor nitro- or ester groups in the enamine
fragment of the initial molecules. However we failed to
isolate compound XII in a pure form apparently due to
the high lability of the N1-acetyl group. Similar N1,N3-
diacylpyrimidinones are known to be capable of the
deacylation to convert into N3-monoacyl derivatives [9].
Taking into consideration the importance of N-acyl-
dihydropyrimidinones as synthons in the preparation of
new bioactive compounds we analyzed the mass spectra
of the compounds synthesized to evaluate their relative
stability at the electron impact.
By an example of 5-nitrodihydropyrimidinone Iа the
high regiospecificity of formylation was also proved. The
treatment of the initial substrate with a mixture of POCl3
and DMF led to the formation of N3-formyl derivative
IX, whose 1Н NMR spectrum contained the characteristic
downfield signal of the atom Н4.
The peaks of molecular ions of compounds IV, V, VII,
VIII, XI are of low intensity (from 2 to 12%) showing
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 11 2010

SELECTIVE ACYLATION OF 5-NITRO- AND 5-ETHOXYCARBONYL
1697
Scheme 2.
Ph
Ph
Ph
4-O2NC6H4O
4-O2NC6H4O
Ph
4-O2NC6H4O
Ph
Ac2O
NH
NAc
O
NAc
O
+
Ph
O
N
H
N
H
N
Ac
III
XI
XII
SiO2
EXPERIMENTAL
their low stability. With respect to the effect on the stabil-
ity of the molecular ions of the compounds in question
the substituents in the position 5 of the heterocycle form
a series NO2 < CO2Et < OС6Н4NO2 in agreement with
their donor-acceptor properties. Therewith the stability
of the molecular ions of the chloroacetyl derivatives VII,
VIII is higher than that of their acetyl analogs IV, V.
IR spectra were recorded on a spectrophotometer
Bruker Vector 22 from pellets with KВr. UV absorption
spectra were taken on a spectrophotometer Specord
1
M-40 from solutions of compounds in ethanol. Н
and 13С NMR spectra were registered on spectrometer
Bruker AС-200 and AM-400, solvents DMSO-d6,
CDCl3, CF3COOH, the solvent signals served as internal
reference: DMSO (δH 2.50, δС 39.50 ppm), CHCl3
(δH .25 ppm), CH2Cl2 (δH 5.28 ppm). Mass spectra
were measured on an instrument Finnigan MAT 8200
(EI, 70 eV, direc admission of the sample into the ion
source). The homogeneity of compounds was checked
by TLC on Silufol UV-254 plates, eluent chloroform–
ethanol, 15 : 1. Compounds prepared by published
procedures: Ia–Ic [11], IIa [14], III [15].
The fragmentation of the molecular ions of the N-
acylpyrimidinones under the electron impact occurs with
the elimination of the acyl group fragments mainly by
two paths in agreement with the published data on the
fragmentation of aliphatic acids amides and acyl deriva-
tives of hydrogenated N-heterocycles [13]. The first path
is characterized by the elimination of ketene O=C=CHX
[X = H (IV, VII, XI), Cl (V, VIII)] from the N-acyl group
giving fragment cation-radicals. Along another path
the elimination of Н• radical from atom С4 [13] and the
ketene from the acyl substituent occurs resulting in the
formation of a cation of the corresponding substituted
pyrimidin-2(1Н)-one. The stability of these two fragment
ions (Irel 33–100%) and the direction of their further frag-
mentation is governed by the character of substituents R2
in the position 5 of the heterocycle.
6-Phenyl-4-(3-fluorophenyl)-5-ethoxycarbonyl-
3,4-dihydropyrimidin-2(1Н)-one (IIb). A mixture
of 18.6 g (0.15 mol) of 3-fluorobenzaldehyde, 28.8 g
(0.15 mol) of benzoylacetic ester, 22.8 g (0.38 mol)
of urea and 12 ml of concn. HCl in 150 ml of ethanol
was boiled for 14 h. The reaction mixture was cooled,
poured into 400 ml of water, the precipitate was filtered
off, washed in succession with the saturated solution of
NaHCO3, water, and ethanol. Yield 22.7 g (44%), mp
206–207°С (EtOH). UV spectrum, λmax, nm (log ε):
205 (4.42), 290 (4.00). IR spectrum, ν, cm–1: 3307 and
The data on the mass spectra of the N-acyldihydropy-
rimidinones may be useful in the structural research, in
particular, in the study on the regiodirection of reactions
of electrophilic substitution and oxidative aromatization
of dihydropyrimidinones.
1
3210 (NH), 1703 and 1663 (C=O), 1247 (С–О). Н
Thus the most reactive in the 5-substiuted 3,4-dihy-
dropyrimidin-2-ones I–III with respect to electrophilic
agents proved to be the N3 atom of the heterocycle.
The acetylation, chloroacetylation, and formylation of
compounds with electrom-withdrawing substituents
NO2 and CO2Et in the position 5 proceed regiospe-
cificaly, and with the donor substituent 4-O2NС6Н4O,
regioselectively.
NMR spectrum (200 MHz, DMSO-d6), δ, ppm: 0.73
3
t (3Н, СН3СН2O, J 7.2 Hz), 3.74 q (2Н, СН3СН2O,
3
3J 7.2 Hz), 5.28 d (1Н, Н4, JH–NH 3.4 Hz), 7.19 t (1Н,
H10, 3JH-Н ≈ 3JH–F ≈ 9 Hz), 7.27 d (1Н, Н8, 3JH–F 8 Hz),
7.30–7.52 m (7Н, Ph + Н11 + Н12), 7.95 d (1Н, N3H,
3JH–NH 3.4 Hz), 9.40 c (1Н, N1H). Mass spectrum, m/z
(Irel, %): 340 (29.9) [M]+, 311 (57.4), 295 (8.5), 294
(12.1), 267 (64.5), 245 (100), 217 (27.0), 122 (10.0), 104
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 11 2010

SEDOVA, SHKURKO
1698
3-Acetyl-5-nitro-6-phenyl-4-(3-fluorophenyl)-3,4-
dihydropyrimidin-2(1Н)-one (IVb). Yield 66%, mp
178–179°С (EtOH). UV spectrum, λmax, nm (log ε):
205 (4.40), 336 (3.80), 405 (3.64). IR spectrum, ν,
cm–1: 3239, 3138 (NH), 1721, 1697 (C=O), 1491, 1325
(40.8), 77 (20.9). Found, %: С 66.93; Н 4.94; F 5.78;
N 8.29. [M]+ 340.1223. C19H17FN2O3. Calculated, %:
С 67.05; Н 5.04; F 5.58; N 8.23. M 340.1223.
4-(4-Methoxyphenyl)-6-phenyl-5-ethoxy-
carbonyl-3,4-dihydropyrimidin-2(1H)-one
(IId)
1
(NO2). Н NMR spectrum (400 MHz, DMSO-d6), δ,
was similarly obtained. Yield 48%, mp 167–169°С
(EtOH). UV spectrum, λmax, nm (log ε): 206 (4.41),
283 (4.01). IR spectrum, ν, cm–1: 3315 and 3204 (NH),
1691 and 1678 (C=O), 1238 (С–О). 1Н NMR spectrum
(200 MHz, DMSO-d6), δ, ppm: 0.79 t (3Н, СН3СН2O,
3J 7.0 Hz), 3.76 c (3Н, CH3О), 3.79 q (2H, CH3CH2O,
3J 7.0 Hz), 5.35 d (1Н, Н4, 3JH–NH 2.8 Hz), 6.46 br.s (1Н,
ppm: 2.53 s (3Н, СН3СО), 6.89 s (1Н, Н4), 7.16 d.t (1Н,
Н10, JH–F ~10, JH-Н ~9, 4JH–H 2.0 Hz), 7.22 d.d (1Н, Н12,
3JH–Н 8.4, 4JH–H 2.0 Hz), 7.26 d (1Н, Н8, 3JH–F 8.0 Hz),
7.48–7.59 m (6Н, Ph + Н11), 10.92 s (1Н, N1H).
13С NMR spectrum (100 MHz, DMSO-d6), δ, ppm:
25.39 (СH3CO), 51.59 (С4), 113.08 d (С8, JC-F 22 Hz),
115.45 d (С10, JC-F 21 Hz), 122.03 d (С12, JC-F 3 Hz),
124.59 (С5), 128.37 (С14,18), 128.48 (С15,17), 130.65 (С13
+ С16), 131.20 d (С11, JC-F 9 Hz), 140.65 d (С7, JC-F 7 Hz),
148.06 (С6), 149.75 (С2), 162.27 d (С9, JC-F 244 Hz),
170.94 (СH3C=O). Mass spectrum, m/z (Irel, %): 355
(4.6) [M]+, 313 (100) [M–СН2=С=О]+, 312 (71.1)
[M–СН3СО]+. Found, %: С 61.35; Н 4.03; F 5.43;
N 11.72. [M]+ 355.0951. С18H14FN3O4. Calculated, %:
С 60.84; Н 3.97; F 5.35; N 11.83. M 355.0968.
3
N3Н), 6.84 d (2Н, Н9 + H11, J 6.8 Hz), 7.20–7.42 m
(7Н, Ph + Н8 + H12), 7.71 s (1Н, N1Н). Mass spectrum,
m/z (Irel, %): 352 (27.0) [M]+, 323 (75.9), 279 (100),
245 (32.6), 134 (7.1), 104 (20.1), 77 (11.7). Found, %:
С 68.38; Н 5.93; N 8.04. [M]+ 352.1427. C20H20N2O4.
Calculated, %: С 68.16; Н 5.72; N 7.95. M 352.1423.
General procedure for acetylation of compounds
Iа–Ic, IIа–IIc with acetic anhydride. A mixture of
1.5 mmol of dihydropyrimidinone and 5 ml of acetic
anhydride was boiled for 6.5 h (Iа, Ib, IIа, IId), 7.5 h
(IIb), 8.5 h (Ic). On cooling 25 ml of water was added,
the mixture was ground and left overnight. The water
layer was decanted, to the oily residue again was added
water, and the mixture was ground and left standing
at room temperature for 5–12 h, the precipitate was
filtered off and washed with water and ethanol. Thus
compounds IVа–IVc, Vа, Vb, Vd were obtained. When
necessary the compound was passed through a bed of
silica gel (3–5 cm), eluent chloroform–ethanol, 25 : 1, or
chloroform–ethyl acetate, 9 : 1, and recrystallized.
3-Acetyl-5-nitro-4-(3-nitrophenyl)-6-phenyl-3,4-
dihydropyrimidin-2(1Н)-one (IVc). Yield 89%, mp
196–198°С (EtOH). UV spectrum, λmax, nm (log ε):
202 (4.22), 251 (3.82), 334 (3.50). IR spectrum, ν, cm–1:
3216, 3120 (NH), 1714 (С=О), 1527, 1491, 1349, 1321
1
(NO2). Н NMR spectrum (400 MHz, DMSO-d6), δ,
ppm: 2.55 s (3Н, СН3СО), 6.93 s (1Н, Н4), 7.51–7.60 m
3
(5Н, Ph), 7.77 t (1Н, Н11, J 8.0 Hz), 7.90 d (1Н, Н10,
3J 8.0 Hz), 8.18 d.d (1Н, Н8, J 2.4, 1.9 Hz), 8.26 d.d (1Н,
Н12, J8.0, 2.4Hz), 11.11s(1Н, N1H). 13СNMRspectrum
(100 MHz, DMSO-d6), δ, ppm: 25.64 (СH3CO), 51.90
(С4), 121.11 (С8), 123.66 (С10), 124.11 (С5), 128.53
(С14,15,17,18), 130.62 (С13), 130.85 (С16), 130.98 (С11),
132.98 (С12), 140.08 (С7), 148.24 (С9), 148.53 (С6),
149.62 (С2), 171.29 (СH3C=O). Mass spectrum, m/z
(Irel, %): 382 (5.1) [M]+, 340 (93.1) [M– CH2=C=O]+,
339 (87.2) [M–CH3CO]+. Found, %: С 57.17; Н 4.22;
N 13.98. С18H14N4O6. Calculated, %: С 56.54; Н 3.69;
N 14.66.
3-Acetyl-5-nitro-4,6-diphenyl-3,4-dihydro-
pyrimidin-2(1Н)-one (IVа).Yield 85%, mp 217–219°С
(EtOH). UV spectrum, λmax, nm (log ε): 206 (4.38),
337 (3.87). IR spectrum, ν, cm–1: 3252 and 3142 (NH),
1719 and 1694 (С=О), 1493 and 1329 (NO2). 1Н NMR
spectrum (400 MHz, DMSO-d6), δ, ppm: 2.53 s (3Н,
СН3С=О), 6.93 s (1Н, Н4), 7.35–7.48 m (5Н, Ph), 7.49–
7.59 m (5Н, Ph), 10.92 s (1Н, N1Н). 13С NMR spectrum
(100 MHz, DMSO-d6), δ, ppm: 25.45 (СH3CO), 51.87
(С4), 125.11 (С5), 126.07 (С8,12), 128.40 (С9,11), 128.45
(С10 + С14,18), 129.02 (С15,17), 130.58 (С16), 130.83
(С13), 137.87 (С7), 147.85 (С6), 149.96 (С2), 170.88
(СH3C=O). Mass spectrum, m/z (Irel, %): 337 (1.8) [M]+,
295 (90.8) [M–СН2=С=О]+, 294 (65.5) [M–СН3СО]+.
Found, %: С 63.61; H 4.46; N 12.29. [M]+ 337.1058.
С18Н15N3О4. Calculated, %: С 64.09; Н 4.48; N 12.46.
M 337.1062.
3-Acetyl-4,6-diphenyl-5-ethoxycarbonyl-3,4-
dihydropyrimidin-2(1Н)-one (Va). Yield 95%, mp
156–157°С (70% EtOH). UV spectrum, λmax, nm (log ε):
205 (4.39), 289 (3.90). IR spectrum, ν, cm–1: 3226, 3133
(NH), 1708, 1680 (С=О), 1667, 1224 (С–О). 1Н NMR
spectrum (200 MHz, СDСl3), δ, ppm: 0.94 t (3Н,
CH3CH2O, 3J 7.2 Hz), 2.42 s (3Н, СН3СО), 3.94 q (2Н,
3
СН3СН2О, J 7.2 Hz), 6.70 с (1Н, Н4), 7.20–7.52 m
(10Н, 2Ph), 7.92 s (1Н, N1H). Mass spectrum, m/z (Irel,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 11 2010

SELECTIVE ACYLATION OF 5-NITRO- AND 5-ETHOXYCARBONYL
1699
%): 364 (8.8) [M]+, 321 (100) [M–CH3CO]+. Found, %:
С 69.24; H 5.76; N 7.76. [M]+ 364.1415. C21H20N2O4.
Calculated, %: С 69.21; Н 5.53; N 7.69. M 364.1423.
The obtained mixture of compounds XI, XII was
subjected to chromatography on a column packed
with SiO2, eluent chloroform–ethyl acetate, 9:1. After
passing of the initial fraction containing the mixture of
acetyl derivatives XI, XII the fraction was collected of
the individual N3-monoacetyl derivative XI. Yield 0.6 g
3-Acetyl-6-phenyl-4-(3-fluorophenyl)-5-
ethoxycarbonyl-3,4-dihydropyrimidin-2(1Н)-one
(Vb). Yield 88%, mp 146–148°С (70% EtOH). UV
spectrum, λmax, nm (log ε): 205 (4.46), 289 (3.95).
IR spectrum, ν, cm–1: 3268, 3174 (NH), 1721, 1707,
(66%), mp 204–209°С (ЕtОН). UV spectrum, λmax
,
nm (log ε): 207 (4.52), 225 sh (4.41), 292 (4.17). IR
spectrum, ν, cm–1: 3242, 3115 (NH), 1705, 1690 (C=O),
1
1668 (C=O), 1647, 1222 (С–О). Н NMR spectrum
1
1236 (С–О). Н NMR spectrum (200 MHz, CDCl3),
(200 MHz, СDСl3), δ, ppm: 0.93 t (3Н, СН3СН2О,
3J 7.0 Hz), 2.40 s (3Н, СН3СО), 3.94 q (2Н, СН3СН2О,
3J 7.0 Hz), 6.67 s (1Н, Н4), 6.90–7.03 m (1Н, Н10), 7.09–
7.32 m (3Н, Н8,11,12), 7.32–7.50 m (5Н, Ph), 8.15 s (1Н,
N1Н). Mass spectrum, m/z (Irel, %): 382 (9.1) [M]+, 340
(32.7) [M–СН2С=О]+, 339 (100) [M–СН3СО]+. Found,
%: С 66.02; Н 5.06; F 4.99; N 7.41. [M]+ 382.1325.
C21H19FN2O4. Calculated, %: С 65.96; Н 5.01; F 4.97;
N 7.33. M 382.1329.
δ, ppm: 2.61 s (3Н, СН3СО), 6.13 s (1Н, Н4), 6.95 d
(2Н, Нarom, J 9.0 Hz), 7.20–7.70 m (10Н, 2Ph), 8.11 d
(2Нarom, J 9.0 Hz), 8.26 s (1Н, N1H). Mass spectrum,
m/z (Irel, %): 429 (12) [M]+, 387 (54) [M–СН2С=О]+,
386 (100), [M–СН3СО]+. Found, %: С 67.07; Н 4.56;
N 9.72. [M]+ 429.1325. С24Н19N3О5. Calculated, %:
С 67.12; Н 4.46; N 9.79. M 429.1325.
General procedure for chloroacetylation of
compounds Iа, Ib IIа, IIb. A mixture of 2.0 mmol
of dihydropyrimidinone, 6.0 mmol of chloroacetyl
chloride, 4.0 mmol of triethylamine (for compound
IIa sodium acetate) was boiled in 8 ml of anhydrous
dioxane. On cooling 20 ml of water was added, and the
mixture was left overnight. The precipitate was filtered
off, washed with water and ethanol. The products were
subjected to chromatography on the column packed with
SiO2, eluent chloroform. Thus we obtained compounds
VIIа, VIIb and VIIIа, VIIIb.
3-Acetyl-4-(4-methoxyphenyl)-6-phenyl-5-
ethoxycarbonyl-3,4-dihydropyrimidin-2(1Н)-one
(Vd). Yield 90%, mp 173–174°С (70%-ный ЕtОН). UV
spectrum, λmax, nm (log ε): 205 (4.40), 223 (4.32), 283
(3.98). IR spectrum, ν, cm–1: 3233, 3138 (NH), 1707,
1679 (C=O), 1227 (С–О). 1Н NMR spectrum (200 MHz,
3
CDCl3), δ, ppm: 0.93 t (3Н, СН3СН2О, J 7.0 Hz),
2.42 s (3Н, СН3СО), 3.76 s (3Н, СН3О), 3.94 q (2Н,
СН3СН2О, J 7.0 Hz), 6.64 s (1Н, Н4), 6.83 d (2Н, Н9,11
,
J 8.8 Hz), 7.30–7.48 m (7Н, Ph + 2Нarom), 7.77 s (1Н,
N1H). Mass spectrum, m/z (Irel, %): 394 (8.2) [M]+, 351
(100) [M–СН3СО]+. Found, %: С 66.91; Н 5.67; N 7.09.
[M]+ 394.1522. С22Н22N2О5. Calculated, %: С 66.99;
Н 5.62; N 7.10. M 394.1529.
5-Nitro-4,6-diphenyl-3-chloroacetyl-3,4-dihydro-
pyrimidin-2(1Н)-one (VIIа). Reaction time 16.5 h,
yield 89%, mp 191–194°С (EtOH). UV spectrum,
λ
max, nm (log ε): 204 (4.42), 336 (3.83). IR spectrum,
3-Acetyl-5-(4-nitrophenoxy)-4,6-diphenyl-3,4-
dihydropyrimidin-2(1Н)-one (XI), 1,3-diacetyl-
5-(4-nitrophenoxy)-4,6-diphenyl-3,4-dihydro-
pyrimidin-2(1Н)-one (XII) were obtained from 0.8 g
(2.0 mmol) of pyrimidinone III and 8 ml of acetic
anhydride, reaction time 7 h. After the workup of the
reaction mixture as described above we obtained 0.9 g
of a mixture of pyrimidinones XI, XII in a ratio 3 : 1.
1Н NMR spectrum (200 MHz, CF3COOH), δ, ppm:
2.31 s (XII, N1COСН3), 2.91 s (XI, N3COСН3), 3.01 s
(XII, N3COСН3), 6.37 s (XI, H4), 6.55 s (XII, H4),
7.08 d (XI, 2Нarom, OС6Н4NO2, J 9.0 Hz), 7.19 d (XII,
ν, cm–1: 3226, 3144 (NH), 1742, 1704 (С=О), 1489
1
(NO2). Н NMR spectrum (400 MHz, DMSO-d6), δ,
ppm: 4.86 d (1Н, СНаНbCl, Jа–b 16.2 Hz), 5.07 d (1Н,
СНаНbCl, Jа–b 16.2 Hz), 6.90 с (1Н, Н4), 7.40–7.47 m
(5Н, Ph), 7.50–7.57 m (5Н, Ph), 11.09 s (1Н, N1Н).
13СNMRspectrum(100MHz, DMSO-d6), δ, ppm:45.49
(СH2Cl), 52.94 (С4), 125.11 (С5),126.16 (С8,12), 128.38
and 128.42 (С9,11 + С14,18 + С15,17), 128.64 (С10), 129.06
(С16), 130.65 (С13), 137.31 (С7), 147.52 (С6), 149.54
(С2), 167.71 (СH2C=O). Mass spectrum, m/z (Irel, %):
371 (7.8) [M]+, 295 (40.2) [M–СН2=С=О]+, 294 (83.2)
[M–СН3CО]+. Found, %: С 57.87; Н 3.95; Cl 9.70;
N 10.83. [M]+ 371.0655. С18Н14СlN3O4. Calculated, %:
С 58.15; Н 3.80; Сl 9.54; N 11.30. M 371.0673.
3
2Нarom, OС6Н4NO2, J 9.0 Hz), 7.30–7.80 m (10Н,
2Ph), 8.21 d (XI, 2Нarom, OС6Н4NO2, J 9.0 Hz), 8.32 d
(XII, 2Нarom, OС6Н4NO2, 3J 9.0 Hz), 8.68 с (XI, N1H).
Mass spectrum, m/z (Irel, %): 471 (0.7) [M]+ (XII), 429
(16) [M]+ dля (XI), 387 (29), 386 (100).
5-Nitro-6-phenyl-4-(3-fluorophenyl)-3-chloro-
acetyl-3,4-dihydropyrimidin-2(1Н)-one
(VIIb).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 11 2010

SEDOVA, SHKURKO
1700
5-Nitro-4,6-diphenyl-3-formyl-3,4-dihydro-
pyrimidin-2(1Н)-one (IX). To a solution of 1.00 g
(3.4 mmol) of dihydropyrimidinone Ia in 5 ml of
anhydrous DMF was added dropwise at stirring within
7 min 0.56 g (3.6 mmol) of POCl3. The reaction mixture
was heated at 70°С for 1 h, cooled to room temperature,
and poured on ice. The precipitate was filtered off,
washed with water and ethanol. Yield 0.8 g (73%), mp
214–219°С (EtOH). UV spectrum, λmax, nm (log ε): 206
(4.36), 334 (3.84). IR spectrum, ν, cm–1: 3237, 3134
(NH), 1726, 1691 (С=О), 1658, 1499, 1332 (NO2).
1Н NMR spectrum (200 MHz, CF3COOH), δ, ppm:
6.97 s (1Н, Н4), 7.40–8.00 m (10Н, 2Ph), 9.05 s (1Н,
N1H), 9.57 s (1Н, CHO). Mass spectrum, m/z (Irel, %):
323 (25) [M]+, 295 (20) [M–CO]+, 294 (20) [M–CHO]+,
278 (89) [M–CO – OH]+, 248 (81) [M–CHO– NO2]+, 47
(100) [M–CHO – HNO2]+, 218 (59) [M–CO – C6H5]+,
171 (52) [M–CHO – NO2 – C6H5]+, 104 (34), 77 (45)
[C6H5]+. Found, %: С 62.61; Н 4.10; N 12.99. [M]+
323.0909. С17Н13N3O4. Calculated, %: С 63.15; Н 4.05;
N 13.00. M 323.0906.
Reaction time 20.5 h, yield 92%, mp 187–189°С
(EtOH). UV spectrum, λmax, nm (log ε): 206 (4.38),
1
337 (3.58). Н NMR spectrum (200 MHz, DMSO-d6),
2
δ, ppm: 4.85 d (1Н, СНаНbCl, Jа–b 16.2 Hz), 5.09 d
2
(1Н, СНаНbCl, Jа–b 16.2 Hz), 6.89 s (1Н, Н4), 7.18–
7.35 m (2Н, Н10 + Н8), 7.45–7.60 m (7Н, Ph + Н11 +
Н12), 11.11 s (1Н, N1H). 13С NMR spectrum (50
MHz, DMSO-d6), δ, ppm: 46.04 (СH2Cl), 52.56 (С4),
113.23 d (С8, JC–F 22 Hz), 115.67 d (C10, JC–F 21 Hz),
122.21 (С12), 124.60 (С5), 128.49 (С14,15,17,18), 130.48
and 130.80 (С13 and С16), 131.25 d (С11, JC–F 8 Hz),
140.05 d (С7, JC–F 6.5 Hz), 147.86 (С6), 149.38 (С2),
162.31 d (С9, JC–F 244 Hz), 167.82 (СH2C=O). Mass
spectrum, m/z (Irel, %): 389 (6.3) [M]+, 313 (42.6) [M–
СlCH=C=O]+, 312 (84.0) [M–ClCH2CO]+. Found,
% : С 55.61; Н 3.43; Cl 9.30; F 5.00; N 10.81. [M]+
389.0582. C18H13ClFN3O4. Calculated, %: С 55.46;
Н 3.36; Cl 9.10; F 4.87; N 10.78. M 389.0579.
4,6-Diphenyl-3-chloroacetyl-5-ethoxycarbonyl-
3,4-dihydropyrimidin-2(1Н)-one(VIIIa)wasobtained
in the presence of sodium acetate, reaction time 12.5 h,
yield 63%, mp 184–186°С (EtOH). UV spectrum, λmax
,
ACKNOWLEDGMENTS
nm (log ε): 205 (4.39), 290 (3.85). IR spectrum, ν,
cm–1: 3228, 3133 (NH), 1730, 1709, 1683 (C=O), 1649,
The study was carried out in the framework of the
Integration program of the Siberian Division of the
RussianAcademy of Sciences (№ 146) “Development of
drugs and preventive health preparations for medicine.
Fundamentals and their implementation”.
1
1242 (C–O). Н NMR spectrum (200 MHz, CDCl3),
δ, ppm: 0.92 t (3Н, СН3СН2О, J 7.2 Hz), 3.93 q (2Н,
СН3СН2О, J 7.2 Hz), 4.45 s (2Н, CН2Сl), 6.65 s (1Н,
Н4), 7.25 – 7.55 m (10Н, 2Ph), 8.43 s (1Н, N1H). Mass
spectrum, m/z (Irel, %): 398 (10.0) [M]+, 321 (100)
[M–COCH2Cl]+. Found, %: С 63.38; Н 4.85; Cl 8.80;
N 7.26. [M]+ 398.1040. С21Н19ClN2O4. Calculated, %:
С 63.24; Н 4.80; Сl 8.89; N 7.03. M 398.1033.
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