Three-component condensation of α-nitroacetophenone, aromatic aldehydes, and methylurea

Article abstract of DOI:10.1007/s11172-007-0180-3

The three-component condensation of aromatic aldehydes, methylurea, and α-nitroacetophenone affords both N(1)-and N(3)-methyl-substituted 4,6-diaryl-5-nitro-3,4-dihydropyrimidin-2(1H)-ones depending on the structure of aldehyde. Intermediate 4,6-diaryl-4-hydroxy-3-methyl-5-nitrohexahydropyrimidin- 2-ones and trisubstituted urea, which is the transformation product of the 4-hydroxy-3-methyl derivative in an acidic medium (retro-Henry reaction), were identified in the reaction mixtures.

Full text of DOI:10.1007/s11172-007-0180-3

Russian Chemical Bulletin, International Edition, Vol. 56, No. 6, pp. 1184—1189, June, 2007
1184
Threeꢀcomponent condensation of
αꢀnitroacetophenone, aromatic aldehydes, and methylurea*
V. F. Sedova, V. P. Krivopalov, and O. P. Shkurkoꢀ
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences,
9 prosp. Akad. Lavrent´eva, 630090 Novosibirsk, Russian Federation.
Fax: +7 (383) 330 9752. Eꢀmail: oshk@nioch.nsc.ru
The threeꢀcomponent condensation of aromatic aldehydes, methylurea, and αꢀnitroꢀ
acetophenone affords both N(1)ꢀ and N(3)ꢀmethylꢀsubstituted 4,6ꢀdiarylꢀ5ꢀnitroꢀ3,4ꢀ
dihydropyrimidinꢀ2(1H )ꢀones depending on the structure of aldehyde. Intermediate 4,6ꢀdiarylꢀ
4ꢀhydroxyꢀ3ꢀmethylꢀ5ꢀnitrohexahydropyrimidinꢀ2ꢀones and trisubstituted urea, which is the
transformation product of the 4ꢀhydroxyꢀ3ꢀmethyl derivative in an acidic medium (retroꢀHenry
reaction), were identified in the reaction mixtures.
Key words: 3,4ꢀdihydropyrimidinꢀ2(1H )ꢀones, hexahydropyrimidinꢀ2ꢀones, methylurea,
aromatic aldehydes, αꢀnitroacetophenone, Biginelli reaction, retroꢀHenry reaction.
4ꢀArylꢀ3,4ꢀdihydropyrimidinone derivatives have a
broad spectrum of biological activities and are considered
as promising structures in the design of new drugs.1
Some of these compounds act as calcium channel
blockers, antihypertensive and antibacterial agents, or seꢀ
lective αꢀadrenoreceptor antagonists.2—4 NꢀSubstituted
dihydropyrimidinones, while having an equally broad
spectrum of biological activities,2,3,5 exhibit also properꢀ
ties of neutrophil elastase inhibitors,6 neuropeptide antaꢀ
gonists,6c and cancerostatics.7
3,4ꢀDihydropyrimidinꢀ2ꢀone derivatives can easily be
synthesized. One of procedures for their synthesis is based
on the threeꢀcomponent condensation of aldehydes, urea,
and CHꢀactive compounds (Biginelli reaction).2,3,8 It was
demonstrated8,9 that the use of alkylureas in the reactions
with nitroacetone, acetoacetic ester, and its derivatives
results in the regioselective formation of the correspondꢀ
ing N(1)ꢀalkyl derivatives of dihydropyrimidinone. The
synthesis of only one diarylꢀsubstituted N(3)ꢀmethylꢀ3,4ꢀ
dihydropyrimidinꢀ2ꢀone by the addition of methylurea to
the corresponding chalcone was documented.10 In addiꢀ
tion, the formation of a complex mixture of compounds
by the threeꢀcomponent condensation of acetylacetone,
aldehydes, and alkylureas was reported, although the reꢀ
action with urea proceeded in a usual way.11
agents of this structural type, we studied the behavior of
methylurea in the reaction with nitroacetophenone and
aromatic aldehydes. We used 3ꢀnitroꢀ (1), 4ꢀmethoxyꢀ (2),
and 3ꢀfluorobenzaldehydes (3) as aromatic aldehydes. This
allowed us to reveal the characteristic features of the indiꢀ
vidual steps of the threeꢀcomponent condensation and
estimate the influence of substituents in the aromatic ring
of the aldehyde component on the regioselectivity of the
reaction.
Aldehydes 1—3 were found to react with αꢀnitroꢀ
acetophenone and methylurea under acid catalysis to form
multicomponent mixtures of products (Scheme 1). Only
1ꢀmethylꢀ5ꢀnitroꢀ4ꢀ(3ꢀnitrophenyl)ꢀ6ꢀphenylꢀ3,4ꢀdiꢀ
hydropyrimidinꢀ2(1H )ꢀone (4) was isolated from the mixꢀ
ture obtained in the reaction with aldehyde 1.
4ꢀ(4ꢀMethoxyphenyl)ꢀ3ꢀmethylꢀ5ꢀnitroꢀ6ꢀphenylꢀ
3,4ꢀdihydropyrimidinꢀ2(1H )ꢀone (5) and 4ꢀhydroxyꢀ
6ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀmethylꢀ5ꢀnitroꢀ4ꢀphenylhexaꢀ
hydropyrimidinꢀ2ꢀone (6) were isolated from the mixture
obtained in the reaction involving aldehyde 2. The conꢀ
densation with the involvement of fluorobenzaldehyde 3
afforded a complex mixture of products, from which
1ꢀmethylꢀ and 3ꢀmethyldihydropyrimidinones (7 and 8,
respectively) and N1ꢀbenzoylꢀN3ꢀ[1ꢀ(3ꢀfluorophenyl)ꢀ2ꢀ
nitroethyl]ꢀN1ꢀmethylurea (9) were isolated. In addition,
4ꢀhydroxyꢀ3ꢀmethylhexahydropyrimidinone 10 was idenꢀ
tified in the mixtures with dihydropyrimidinones 7 and 8,
but we failed to isolate compound 10 in the individual
state. The structure of the latter compound was suggested
based on the analysis of the 1H and 13C NMR spectra, as
well as of the mass spectra of the aboveꢀmentioned mixꢀ
tures taking into account the spectroscopic characteristics
of structurally similar analog 6.
Earlier,4,12 we have synthesized a series of 4,6ꢀdiarylꢀ
5ꢀnitroꢀ3,4ꢀdihydropyrimidinꢀ2(1H )ꢀones exhibiting
high antiarrhythmic activity by condensation of αꢀnitroꢀ
acetophenone, aromatic aldehydes, and urea. With the
aim of extending the range of potential antiarrhythmic
* Dedicated to the memory of Academician N. N. Vorozhtsov
on the 100th anniversary of his birth.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1141—1145, June, 2007.
1066ꢀ5285/07/5606ꢀ1184 © 2007 Springer Science+Business Media, Inc.

NꢀMethylꢀ5ꢀnitrodihydropyrimidinꢀ2ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
1185
Scheme 1
Ar = 3ꢀO2NC6H4 (1), 4ꢀMeOC6H4 (2), 3ꢀFC6H4 (3)
The structures of the resulting compounds were estabꢀ
lished by spectroscopic methods. The UV spectra of comꢀ
pounds 4 and 7 and compounds 5 and 8 show a longꢀ
wavelength absorption band at ~348—350 nm characterꢀ
istic of 5ꢀnitroꢀ3,4ꢀdihydropyrimidinꢀ2ꢀones,12 whereas
the UV spectra of compounds 6, 9, and 10 have only a
shoulder at ~269 nm, which is indicative of the presence
of the unconjugated aromatic ring in the molecule.
spectrum. An additional spinꢀspin coupling constant
(J3,4 = 8.1 Hz) is observed for the signal of the H(4) atom,
which confirms the conclusion about the presence of
the N(1)—Me and N(3)—H fragments in this structure
(cf. lit. data14).
1
The H NMR spectra of Nꢀmethylꢀsubstituted hexaꢀ
hydropyrimidinones 6 and 10 show signals for the axial
H(5) and H(6) atoms as two doublets (J = 11 Hz) at δ 5—6.
The absence of additional splitting of the signal for the
H(6) atom (J1,6) apparently cannot be considered as an
indication of the presence of the methyl group at the N(1)
atom of the heterocycle, as evidenced from the published
data.15 Hence, we used mass spectrometric data to estabꢀ
lish the position of the methyl group in these compounds.
In the 13C NMR spectra, the resonances of the C(2),
C(4), C(5), and C(6) atoms are most informative for conꢀ
firming the structures of the resulting compounds. In the
spectra of dihydropyrimidinones 4 and 7 and compounds
5 and 8, these signals are in the ranges characteristic of
Nꢀunsubstituted 5ꢀnitrodihydropyrimidinones.12 The poꢀ
sitions of the signals for the C(2) and C(6) atoms in the
spectra of hexahydro derivatives 6 and 10 are only slightly
different from the positions of the analogous signals in the
spectra of dihydro derivatives 4 and 7 and compounds 5
and 8, whereas the signals for the C(4) and C(5) atoms are
shifted upfield (δ 85—95). In the spectrum of trisubstiꢀ
tuted urea 9, the signal for the C(6) atom of the benzoyl
group is observed at δ ~172.
The IR spectra of compounds 4 and 7 show the C=O
stretching band at 1700—1710 cm–1. In the IR spectra of
compounds 5 and 8, this band is observed in the range of
1650—1680 cm–1; in the spectra of 6 and 10, in the range
of 1639—1652 cm–1
.
The position of the methyl group in compounds 4, 5,
and 7—9 was established based on their 1H NMR spectra.
In the spectra of N(1)ꢀmethyldihydropyrimidinones 4
and 7, the —N(3)H—C(4)H— fragment is manifested as
two doublets of the H(3) and H(4) atoms (J ≈ 3—5 Hz),
whereas only a singlet of the H(4) atom is observed
in the spectra of N(3)ꢀmethyldihydropyrimidinones 5
and 8.9b,e,12,13 It is also noteworthy that there is a differꢀ
ence in chemical shifts for the protons of the NH groups
in the spectra of isomeric Nꢀmethyldihydropyrimidinones.
The signal for the proton H(1) is observed at δ > 10,
whereas the signal for the proton H(3) is observed at
higher field (δ 8.6—8.8) (cf. lit. data12). Compound 9 is
characterized by the presence of an ABX system of signals
1
for the H(4), H(5a), and H(5b) atoms in the H NMR

1186
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
Sedova et al.
The mass spectra of dihydropyrimidinones 4, 5, 7,
and 8 contain the following major ions: [M]+, [M – OH]+,
m/z 176 (90%) and [M – HNO2 – C6H5CONHCH3]+ at
m/z 175 (49%), whereas the ions at m/z 190 ([M –
NO2 – C6H5CONH2]+) and 189 ([M – HNO2
–
[M – HNO2 – H]+, [M – C6H4R]+, [M – HNO2
–
C6H4R]+, and [C6H5]+ (cf. lit. data12). The mass spectra
of compounds 4, 5, 7, and 8 differ in the intensities of the
fragment ions at m/z 118 ([C6H5C=NCH3]+) and 104
([C6H5C=NH]+), which characterize the presence or abꢀ
sence of substituents at the N(1) atom. For N(1)ꢀmethyl
derivatives 4 and 7, the relative intensities of the line at
m/z 118 are higher than 39%, whereas the intensities of
this line for N(3)ꢀmethyl derivatives 5 and 8 are <3%. The
intensity of the ion at m/z 104 in the mass spectra of
compounds 5 and 8 is >10%, whereas this ion is not
observed for N(1)ꢀmethyl derivatives 4 and 7.
Hexahydropyrimidine derivatives 6 and 10 and substiꢀ
tuted urea 9 are characterized by a similar topology and,
consequently, their massꢀspectrometric behavior is conꢀ
sidered jointly. The mass spectra of these compounds are
characterized by the presence of the line of [M]+ with
very low intensity (<1%). The line with the maximum
intensity at m/z 105 (100%) belongs to the [C6H5CO]+
ion. Based on these facts, we suggested that the electron
impact causes the opening of the heterocycle in unstable
βꢀnitro alcohols 6 and 10 accompanied by the C(4)—C(5)
bond cleavage and the formation of substituted urea by
analogy with the published data.14 The latter compounds
are characterized by the presence of the fragment ions
[M – NO2]+, [M – HNO2]+, [M – HNO2 – C6H5CO]+,
C6H5CONH2]+) are absent. An analogous pattern is obꢀ
served in the mass spectrum of compound 10. Based on
these facts, we assigned the structure of N(3)ꢀmethylꢀ
hexahydropyrimidinꢀ2ꢀones to compounds 6 and 10.
According to the classical scheme of the Biginelli reꢀ
action (condensation of acetoacetic ester, aromatic aldeꢀ
hyde, and urea) under acid catalysis, it can be hypoꢀ
thesized that aldehydes 1 and 3 react with urea to form the
reactive acyliminium cation (Scheme 2). The reaction of
the latter with αꢀnitroacetophenones at the CHꢀactive
fragment and the cyclization of the resulting ureido deꢀ
rivatives afford 4ꢀhydroxyhexahydropyrimidinꢀ2ꢀones,
which undergo dehydration to give dihydropyrimidinones
4 and 7.2,16 According to the published data,15,17 the deꢀ
hydration does not proceed only in the presence of an
electronꢀwithdrawing haloalkyl group at position 4 of the
heterocycle. The selective formation of N(1)ꢀsubstituted
dihydropyrimidinones through the path A is attributed
to the fact that the reaction of aldehyde with monoalkylꢀ
ureas proceeds only at the unsubstituted NH2 group
of urea2,8,9
.
An alternative pathway of the threeꢀcomponent conꢀ
densation (see Scheme 2, path B) involves the initial reꢀ
action of aldehyde with αꢀnitroacetophenones. As has
been shown earlier for other reactions, the resulting
carbocation reacts with monoalkylurea both at the alkylꢀ
amino group10 and the unsubstituted amino group9c,17—19
to give the corresponding N(1)ꢀ (4 and 7) or N(3)ꢀalkylꢀ
pyrimidinones (5 and 8) or their mixtures. Therefore,
depending on the reaction conditions and the structures
of the starting reagents, the reaction can follow predomiꢀ
[M – NO2 – C6H5CONHR]+, and [M – HNO2
–
C6H5CONHR]+ and ions at m/z 105 ([C6H5CO]+) and
77 ([C6H5]+).14 All these lines are observed also in the
spectrum of compound 9.
The spectrum of compound 6 shows lines of the
fragment ions [M – NO2 – C6H5CONHCH3]+ at
Scheme 2
Ar = 3ꢀO2NC6H4 (1, 4), 4ꢀMeOC6H4 (2, 5), 3ꢀFC6H4 (3, 7, 8)

NꢀMethylꢀ5ꢀnitrodihydropyrimidinꢀ2ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
1187
ν/cm–1: 3253, 3194 (NH), 2953 (Me), 1707 (C=O), 1525, 1348
(NO2). 1H NMR, δ: 2.73 (s, 3 H, Me); 5.87 (d, 1 H, H(4),
3J3,4 = 4.0 Hz); 7.40—7.62 (m, 5 H, Ph); 7.75 (t, 1 H, H(11),
nantly either the path A or path B.20 It cannot be ruled out
that the reaction products contain intermediates generꢀ
ated in the transformations involved in both pathways.
The condensation of αꢀnitroacetophenone, nitroꢀ
benzaldehyde 1, and methylurea follows predominantly
the path A to give N(1)ꢀmethylpyrimidinone 4 as the major
product. The reaction with methoxybenzaldehyde 2 folꢀ
lows predominantly the path B to form N(3)ꢀmethyl deꢀ
rivative 5.
3
3J = 8.0 Hz); 7.96 (d, 1 H, H(10), J = 8.0 Hz); 8.22 (dd, 1 H,
H(12), 3J = 8.0 Hz, 4J = 2.4 Hz); 8.31 (t, 1 H, H(8), 4J =
2.0 Hz); 8.78 (d, 1 H, H(3), 3J3,4 = 3.6 Hz). 13C NMR, δ: 32.49
(Me); 52.73 (C(4)); 121.51 (C(10)); 123.02 (C(8)); 124.09
(C(5)); 127.01, 127.23, 128.95, 129.04, 130.65, and 132.16
(all CPh); 129.53 (C(11)); 132.87 (C(12)); 143.72 (C(7)); 148.00
(C(9)); 150.88 (C(6)); 152.00 (C(2)).
4ꢀ(4ꢀMethoxyphenyl)ꢀ3ꢀmethylꢀ5ꢀnitroꢀ6ꢀphenylꢀ3,4ꢀdiꢀ
hydropyrimidinꢀ2(1H )ꢀone (5) and 4ꢀhydroxyꢀ6ꢀ(4ꢀmethoxyꢀ
phenyl)ꢀ3ꢀmethylꢀ5ꢀnitroꢀ4ꢀphenylhexahydropyrimidinꢀ2(1H )ꢀ
one (6). A mixture of αꢀnitroacetophenone (1.8 g, 11 mmol),
4ꢀmethoxybenzaldehyde (2) (1.2 g, 9 mmol), and methylurea
(1.3 g, 18 mmol) in ethanol (15 mL) containing concentrated
HCl (1.5 mL) was refluxed for 16 h and kept at ~4 °C for
15 days. The precipitate that formed was filtered off, succesꢀ
sively washed with ethanol, a saturated NaHCO3 solution, waꢀ
ter, and ethanol, and dried. Compound 5 was obtained in a yield
of 1.3 g (43%), m.p. 249—251 °C (from an ethanol—dioxane
mixture), Rf 0.75. Found (%): C, 63.30; H, 5.26; N, 12.28.
C18H17N3O4. Calculated (%): C, 63.71; H, 5.05; N, 12.38. MS,
m/z (Irel (%)): 339 [M]+ (14), 322 [M – OH]+ (81), 293
[M – NO2]+ (85), 291 [M – HNO2 – H]+ (100), 232
[M – C6H4OMe]+ (74), 185 [M – C6H4OMe – HNO2]+ (64),
118 (3), 104 [C6H5C=NH]+ (20), 77 [C6H5]+ (22). Highꢀresoꢀ
lution mass spectrum, found: m/z 339.1126 [M]+. C18H17N3O4.
Calculated: M = 339.1290. UV, λmax/nm (logε): 203 (4.50), 231
(4.28), 350 (3.89). IR, ν/cm–1: 3367, 3196 (NH), 2997, 2931
The reaction with fluorobenzaldehyde 3 as the aldeꢀ
hyde component takes apparently both paths (A and B),
resulting in the formation of isomeric N(1)ꢀ and
N(3)ꢀmethyldihydropyrimidinones 7 and 8, as well as
of 4ꢀhydroxyꢀ3ꢀmethylhexahydropyrimidinꢀ2ꢀone 10.
Evidently, the heterocycle in compound 10 is partially
cleaved under the reaction conditions (retroꢀHenry reacꢀ
tion) to form N(1)ꢀbenzoylꢀN(1)ꢀmethylurea 9 (cf. lit.
data14).
To summarize, we found that the threeꢀcomponent
acidꢀcatalyzed condensation of αꢀnitroacetophenone,
aromatic aldehydes, and methylurea produces both
N(1)ꢀ (4 and 7) and N(3)ꢀmethylꢀsubstituted dihydroꢀ
pyrimidinones (5 and 8). Intermediate 4ꢀhydroxyꢀ3ꢀ
methylhexahydropyrimidinꢀ2ꢀones 6 and 10 and trisubꢀ
stituted urea 9, which is generated in the retroꢀHenry
reaction of compound 10, were characterized for the
first time.
1
(Me), 1677 (C=O), 1492, 1328 (NO2), 1257. H NMR, δ: 2.79
(s, 3 H, NMe); 3.77 (s, 3 H, OMe); 5.65 (s, 1 H, H(4)); 6.99 (d,
2 H, H(9), H(11), 3J = 8.0 Hz); 7.35—7.65 (m, 7 H, H(8),
H(12), Ph); 10.22 (s, 1 H, H(1)). 13C NMR, δ: 32.32 (NMe);
55.03 (OMe); 60.15 (C(4)); 114.23 (C(9), C(11)); 122.52
(C(5)); 127.58, 128.24, 129.68, and 131.32 (all CPh); 128.24
(C(8), C(12)); 132.17 (C(7)); 148.22 (C(6)); 150.01 (C(2));
159.28 (C(10)).
Experimental
The IR spectra were measured on a Bruker Vector 22 specꢀ
trophotometer in KBr pellets. The UV spectra were recorded in
solution on a Specord Mꢀ40 spectrophotometer. The mass specꢀ
tra were obtained on a Finnigan MAT 8200 instrument (EI,
1
70 eV, direct inlet system). The H and 13C NMR spectra were
After separation of compound 5, the mother liquor was kept
at ~20 °C for 10 days. The white precipitate that formed was
filtered off, washed with ethanol, and dried on a filter. Hexaꢀ
hydropyrimidinone 6 was obtained in a yield of 0.13 g (4%),
m.p. 155—157 °C (from ethanol). Found (%): C, 60.35; H, 5.69;
N, 11.49. C18H19N3O5. Calculated (%): C, 60.49; H, 5.36;
N, 11.76. MS, m/z (Irel (%)): 357 [M]+ (0.5), 311 [M – NO2]+
(12), 310 [M – HNO2]+ (32), 205 [M – HNO2 – COC6H5]+
(33), 176 [M – NO2 – C6H5CONHMe]+ (90), 175 [M –
HNO2 – C6H5CONHMe]+ (49), 161 (35), 134 (40), 105
[COC6H5]+ (100), 77 [C6H5]+ (85). Highꢀresolution mass specꢀ
trum, found: m/z 357.1297 [M]+. C18H19N3O5. Calculated:
M = 357.1325. UV, λmax/nm (logε): 204 (4.43), 225 (4.31), 269
(3.81). IR, ν/cm–1: 3325, 3271, 3182 (OH, NH), 2936, 2840
recorded on a Bruker AMꢀ400 spectrometer in DMSOꢀd6 using
the signals of the solvent as the internal standard (δ 2.50 and
C 39.50). The purity of the compounds was monitored by TLC
on Silufol UVꢀ254 plates using a CHCl3—EtOH mixture (15 : 1)
as the eluent.
H
δ
1ꢀMethylꢀ5ꢀnitroꢀ4ꢀ(3ꢀnitrophenyl)ꢀ6ꢀphenylꢀ3,4ꢀdihydroꢀ
pyrimidinꢀ2(1H )ꢀone (4). A mixture of αꢀnitroacetophenone
(1.5 g, 9 mmol), 3ꢀnitrobenzaldehyde (1) (1.1 g, 7 mmol), and
methylurea (1.0 g, 13.5 mmol) in ethanol (10 mL) containing
concentrated HCl (1 mL) was refluxed for 15 h and kept at
~20 °C for 10 days. The precipitate that formed was filtered off,
successively washed with ethanol and a 1 : 1 ethanol—water
mixture (2×3 mL), and recrystallized from ethanol. Compound 4
was obtained in a yield of 0.85 g (34%), m.p. 241—243 °C,
Rf 0.56. Found (%): C, 57.23; H, 4.18; N, 15.67. C17H14N4O5.
Calculated (%): C, 57.62; H, 3.98; N, 15.81. MS, m/z (Irel (%)):
354 [M]+ (16), 337 [M – OH]+ (88), 310 (47), 306 [M –
HNO2 – H]+ (82), 232 [M – C6H4NO2]+ (100), 185
[M – C6H4NO2 – HNO2]+ (67), 118 [C6H5C=NCH3]+ (57),
77 [C6H5]+ (45). Highꢀresolution mass spectrum:
m/z 354.0983 [M]+. C17H14N4O5. Calculated: M = 354.0964.
UV, λmax/nm (logε): 205 (4.14), 249 (3.86), 350 (3.75). IR,
1
(Me), 1639 (C=O), 1559, 1372, 1329 (NO2). H NMR, δ: 2.48
3
(s, 3 H, NMe); 3.74 (s, 3 H, OMe); 5.17 (d, 1 H, H(5), J5,6
=
3
11.0 Hz); 5.33 (d, 1 H, H(6), J5,6 = 11.0 Hz); 6.92 (d, 2 H,
H(9), H(11), 3J = 8.8 Hz); 7.19 (br.s, 2 H, NH, OH); 7.33—7.50
(m, 5 H, Ph); 7.57 (d, 2 H, H(8), H(12), 3J = 8.8 Hz). 13C NMR,
δ: 29.75 (NMe); 52.85 (C(6)); 54.98 (OMe); 85.39 (C(5));
93.59 (C(4)); 113.69 (C(9), C(11)); 126.51, 128.11, 128.23,
128.63, 129.41 (C(8), C(12), CPh); 139.07 (C(7)); 154.71 (C(2));
159.42 (C(10)).

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Sedova et al.
Condensation of αꢀnitroacetophenone with 3ꢀfluorobenzꢀ
aldehyde (3) and methylurea. A mixture of αꢀnitroacetophenone
(1.5 g, 9 mmol), aldehyde 3 (0.9 g, 7 mmol), and methylurea
(1.0 g, 13.5 mmol) in ethanol (10 mL) containing concentrated
HCl (1.0 mL) was refluxed for 11 h and kept at ~4 °C for 7 days.
The precipitate that formed (1.25 g) was filtered off and succesꢀ
sively washed with ethanol, a saturated NaHCO3 solution, waꢀ
ter, and ethanol. N1ꢀBenzoylꢀN3ꢀ[1ꢀ(3ꢀfluorophenyl)ꢀ2ꢀnitroꢀ
ethyl]ꢀN1ꢀmethylurea (9) was obtained in a yield of 0.25 g (10%).
An analytically pure sample was obtained after threefold recrysꢀ
tallization from ethanol, m.p. 169—171 °C, Rf ~0.9. Found (%):
C, 59.34; H, 4.83; F, 5.63; N, 11.97. C17H16FN3O4. Calꢀ
culated (%): C, 59.12; H, 4.67; F, 5.50; N, 12.17. MS,
m/z (Irel (%)): 345 [M]+ (0.7), 299 [M – NO2]+ (31), 298
[M – HNO2]+ (43), 193 [M – HNO2 – COC6H5]+ (32), 164
spectrum, found: m/z 327.1018 [M]+. C17H14FN3O3. Calcuꢀ
lated: M = 327.1019. UV, λmax/nm (logε): 348 (3.68). IR,
ν/cm–1: 3371 (NH), 2954 (Me), 1706 (C=O), 1335 (NO2).
3
1H NMR, δ: 2.73 (s, 3 H, Me); 5.71 (d, 1 H, H(4), J3,4
=
=
3
4.0 Hz); 7.10—7.62 (m, 9 H, Ar); 8.65 (d, 1 H, H(3), J3,4
4.0 Hz). 13C NMR, δ: 32.32 (Me); 52.87 (C(4)); 113.36 (d,
C(10), JC,F = 21.8 Hz); 114.86 (d, C(8), JC,F = 20.9 Hz); 122.21
(d, C(12), JC,F = 2.7 Hz); 124.54 (C(5)); 126.87, 127.35, 129.36,
and 132.24 (all CPh); 130.84 (d, C(11), JC,F = 8.2 Hz); 144.37
(d, C(7), JC,F = 6.2 Hz); 150.95 (C(6)); 151.37 (C(2)); 162.23
(d, C(9), 1JC,F = 243 Hz).
4ꢀ(3ꢀFluorophenyl)ꢀ3ꢀmethylꢀ5ꢀnitroꢀ6ꢀphenylꢀ3,4ꢀdihydroꢀ
pyrimidinꢀ2(1H )ꢀone (8). The yield was 0.19 g (8%), m.p.
223—225 °C (from ethanol), Rf 0.74. Found (%): C, 62.46;
H, 4.29; F, 5.74; N, 12.59. C17H14FN3O3. Calculated (%):
C, 62.38; H, 4.31; F, 5.81; N, 12.84. MS, m/z (Irel (%)): 327 [M]+
(10), 310 [M – OH]+ (34), 279 [M – HNO2 – H]+ (26), 232
[M – C6H4F]+ (100), 185 [M – C6H4F – HNO2]+ (39), 104
[C6H5C=NH]+ (11), 77 [C6H5]+ (17). Highꢀresolution mass
spectrum, found: m/z 327.1021 [M]+. C17H14FN3O3. Calcuꢀ
lated: M = 327.1019. IR, ν/cm–1: 3194 (NH), 2924, 2810 (Me),
1652 (C=O), 1499, 1326 (NO2). 1H NMR, δ: 2.79 (s, 3 H, Me);
5.74 (s, 1 H, H(4)); 7.10—7.60 (m, 9 H, Ar); 10.28 (s, 1 H,
H(1)). 13C NMR, δ: 32.58 (Me); 60.21 (C(4)); 114.08 (d, C(10),
JC,F = 21.6 Hz); 115.38 (d, C(8), JC,F = 20.8 Hz); 121.83 (C(5));
122.90 (C(12)); 127.68, 128.32, 129.89, and 131.95 (all CPh);
131.12 (d, C(11), JC,F = 8.1 Hz); 142.16 (d, C(7), JC,F = 6.2 Hz);
149.01 (C(6)); 149.95 (C(2)); 162.20 (d, C(9), 1JC,F = 243 Hz).
[M – NO2 – C6H5CONHCH3]+ (12), 163 [M – HNO2
–
C6H5CONHCH3]+ (9), 105 [COC6H5]+ (100), 77 [C6H5]+ (35).
Highꢀresolution mass spectrum, found: m/z 345.1115 [M]+.
C17H16FN3O4. Calculated: M = 345.1125. UV, λmax/nm (logε):
203 (4.45), 269 (3.44). IR, ν/cm–1: 3270, 3184 (NH), 2912
1
(Me), 1640 (C=O), 1557, 1402, 1370 (NO2). H NMR, δ: 3.11
2
3
(s, 3 H, Me); 5.01 (dd, 1 H, HA(5), JA,B = 13.8 Hz, J4,5
=
5.7 Hz); 5.05 (dd, 1 H, HB(5), 2JA,B = 13.8 Hz, 3J4,5 = 7.9 Hz);
3
3
3
5.56 (dt, 1 H, H(4), J3,4 = 8.1 Hz, J4,5A = 7.9 Hz, J4,5B
=
=
3
5.7 Hz); 7.10—7.55 (m, 9 H, Ar); 9.33 (d, 1 H, H(3), J3,4
8.1 Hz). 13C NMR, δ: 34.10 (Me); 51.66 (C(4)); 77.73 (C(5));
113.67 (d, C(10), JC,F = 22.3 Hz); 114.75 (d, C(8), JC,F
=
20.9 Hz); 122.88 (C(12)); 126.93, 128.10, 130.63, and 135.72
(all CPh); 130.50 (d, C(11), JC,F = 8.2 Hz); 140.11 (d, C(7),
JC,F = 7.1 Hz); 154.99 (C(2)); 162.05 (d, C(9), 1JC,F = 242 Hz);
172.38 (C(6)).
References
The combined mother liquors were concentrated in vacuo to
dryness. Compounds 7 and 8 were isolated as analytically pure
samples by fractional crystallization of the residue (1.15 g) from
ethanol. Compound 10, which is better soluble in ethanol, was
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1
concentrated in tail fractions. According to the H NMR specꢀ
troscopic data, the total yield of 6ꢀ(3ꢀfluorophenyl)ꢀ4ꢀhydroxyꢀ3ꢀ
methylꢀ5ꢀnitroꢀ4ꢀphenylhexahydropyrimidinꢀ2ꢀone (10) was 15%.
The spectroscopic characteristics of this compound were obꢀ
tained by analyzing the spectra of a mixture of compounds 7
and 10 (3 : 1). MS, m/z (Irel (%)): 299 [M – NO2]+ (10), 298
[M – HNO2]+ (13), 193 [M – HNO2 – COC6H5]+ (9), 164
[M – NO2 – C6H5CONHCH3]+ (4), 163 [M – HNO2
–
C6H5CONHCH3]+ (3), 105 [COC6H5]+ (100), 77 [C6H5]+. IR,
ν/cm–1: 3371, 3240, 3187 (OH, NH), 1652 (C=O), 1557, 1376,
1326 (NO2). 1H NMR, δ: 2.48 (s, 3 H, Me); 5.27 (d, 1 H, H(5),
3J5,6 = 11.0 Hz); 5.49 (d, 1 H, H(6), 3J5,6 = 11.0 Hz); 7.10—7.65
(m, 11 H, Ar, NH, OH). 13C NMR, δ: 29.82 (Me); 53.12 (C(6));
85.51 (C(5)); 92.88 (C(4)); 115.07 (d, C(10), JC,F = 22.5 Hz);
115.57 (d, C(8), JC,F = 19.5 Hz); 124.74 (C(12)); 126.77, 128.14,
128.31, and 138.94 (all CPh); 130.21 (d, C(11), JC,F = 8.2 Hz);
139.70 (d, C(7), JC,F = 7.1 Hz); 154.61 (C(2)); 162.02 (d, C(9),
1JC,F = 242 Hz).
4ꢀ(3ꢀFluorophenyl)ꢀ1ꢀmethylꢀ5ꢀnitroꢀ6ꢀphenylꢀ3,4ꢀdihydroꢀ
pyrimidinꢀ2(1H )ꢀone (7). The yield was 0.37 g (16%), m.p.
185—188 °C (from ethanol), Rf 0.65. Found (%): C, 62.26;
H, 4.31; F, 5.72; N, 12.86. C17H14FN3O3. Calculated (%):
C, 62.38; H, 4.31; F, 5.81; N, 12.84. MS, m/z (Irel (%)): 327 [M]+
(18), 310 [M – OH]+ (75), 279 [M – HNO2 – H]+ (100), 232
[M – C6H4F]+ (97), 185 [M – C6H4F – HNO2]+ (69), 118
[C6H5C=NCH3]+ (39), 77 [C6H5]+ (48). Highꢀresolution mass
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Received February 13, 2007;
in revised form June 18, 2007