Full text of DOI:10.1134/S1070428018090208

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2018, Vol. 54, No. 9, pp. 1389–1394. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © T.V. Anis’kova, A.Yu. Egorova, 2018, published in Zhurnal Organicheskoi Khimii, 2018, Vol. 54, No. 9, pp. 1374–1379.
Synthesis of Substituted Pyridazin-3-ones, 1,2-Oxazin-3-ones,
and Furopyrimidines from (Arylmethylidene)furan-2(3H)-ones
a
a
T. V. Anis’kova * and A. Yu. Egorova
a
Institute of Chemistry, Chernyshevskii Saratov National Research State University,
ul. Astrakhanskaya 83, bld. 1, Saratov, 410012 Russia
*
e-mail: aniskovatv@mail.ru
Received August 30, 2017
Abstract—Reactions of 5-substituted 3-(arylmethylidene)furan-2(3H)-ones with hydrazine hydrate, hydroxyl-
amine, and guanidine involved opening of the furanone ring. Their hydrazinolysis under mild conditions
afforded acyclic 4-oxoalkanoic acid hydrazides which underwent heterocyclization to substituted pyridazinones
in boiling ethanol. The presence of an alkyl substituent in the 5-position of the initial furanone favored
heterocyclization with the formation of pyrazolidinone derivatives. The reactions of 3-(arylmethylidene)furan-
2
3
(3H)-ones with hydroxylamine and guanidine also produced new six-membered heterocycles, 2H-1,2-oxazin-
(4H)-ones and 4,6-disubstituted 3,4-dihydrofuro[2,3-d]pyrimidin-2-amines, respectively.
DOI: 10.1134/S1070428018090208
Heterocyclic compounds containing a pyrimidine,
pyridazine, or oxazine fragment attract considerable
interest due to their potential diverse biological ac-
tivity. These structural fragments are present in mole-
cules of natural compounds and synthetic drugs
exhibiting antitumor, antiviral, antibacterial, and other
kinds of activity [1–9].
pyridine and pyridazine fragments is a promising
research line. In the present work we studied reactions
of 5-substituted 3-arylmethylidenefuran-2(3H)-ones
with hydrazine, hydroxylamine, and guanidine.
Furanones 1a–1d reacted with an equimolar
amount of hydrazine hydrate in ethanol at room tem-
perature to give 4-oxoalkanoic acid hydrazides 2a–2d
1
Six-membered heterocycles are most often syn-
thesized on the basis of binucleophiles containing
(Scheme 1). The H NMR spectra of 2a–2d showed
singlets due to CH
7.15 ppm), NH (δ 7.85–8.03 ppm), and NH
(δ 3.13–3.21 ppm), C=CH (δ 7.08–
protons
2
an HNNH, C=N, or CNH moiety, such as guanidine,
2
2
hydrazine, and hydroxylamine. These nitrogen nu-
cleophiles are characterized by high reactivity and are
widely used to construct new nitrogen-containing
heterocyclic systems with various combinations of
heteroatoms. Readily obtainable 3-arylmethylidene-
furan-2(3H)-ones are convenient and accessible sub-
strates for the synthesis of various difficultly acces-
sible heterocyclic, spirocyclic, and polycyclic com-
pounds [10–18]. 3-Arylmethylidenefuran-2(3H)-ones
possess a combination of properties typical of cyclic
esters and α,β-unsaturated carbonyl compounds, and
they are capable of reacting with compounds having
labile hydrogen atoms. In this respect, arylmethylidene
derivatives of furan-2(3H)-ones can be regarded as
suitable building blocks for the synthesis of various
heterocyclic compounds with pyrimidine and pyrida-
zine fragments.
(δ 5.18–5.23 ppm), as well as aromatic proton signals
at δ 7.03–7.98 ppm. The structure of previously un-
known compounds 2a–2d was additionally proved by
1
3
C NMR spectra which contained an upfield signal
at δ 41.5–47.1 ppm due to methylene carbon atom,
downfield signals from two carbonyl carbon atoms at
C
δ 164.3–169.4 and 193.1–197.5 ppm, and a number of
C
2
signals of sp -hybridized carbons.
Compounds 2a–2d were formed as a result of
2
opening of the lactone ring of 1a–1d at the C –O bond,
Scheme 1.
Ar
Ar
O
N H ·H O
2
4
2
H
N
R
NH
2
R
O
O
O
1a–1d
2a–2d
In view of the above stated, development of
methods for the synthesis of compounds containing
R = Ph, Ar = 2-ClC
6
H
4
(a), R = 4-MeC , Ar = 2-ClC
6
H
4
6 4
H (b),
4-MeOC
6
H
4
(c); 3-O NC H (d).
2
6 4
1
389

1
390
ANIS’KOVA, EGOROVA
Scheme 2.
Ar
O
NH
R
R
N
3
a–3d
Ar
Ar
O
H
N
N H ·H O, 60–70°C
2
4
2
1
a–1d
O
R
NH2
N
O
NH2
R
O
O
HN
Ar
N
H
R = Ph, Ar = 2-ClC
6
H
4
(a), R = 4-MeC
6
H
4
, Ar = 2-ClC
6
H
4
(b), 4-MeOC
6
H
4
(c); 3-O
2
NC
6
H
4
(d).
and no further heterocyclization occurred under the
given conditions.
When the reaction of 1a–1d with hydrazine hydrate
was carried out in boiling ethanol, the products
intramolecular cyclization to pyridazinone derivative
via attack by the primary amino group on the ketone
carbonyl carbon atom and elimination of water mole-
cule. No alternative reaction paths leading to five-
membered heterocycles (dihydropyrrole or pyrazoli-
dine) were observed.
were substituted dihydropyridazin-3(2H)-ones 3a–3d
1
(
Scheme 2). The H NMR spectra of 3a–3d displayed
5
singlets of methylene protons on C of the pyridazine
ring (δ 2.15–2.22 ppm), proton on the exocyclic double
bond (δ 6.89–7.01 ppm), NH proton (δ 7.02–7.12 ppm),
and aromatic protons (δ 7.19–8.05 ppm). In the
C NMR spectra of 3a–3d, the C signal was observed
at δ 35.7–41.2 ppm, sp -hybridized carbons resonated
The presence of an alkyl (pentyl) group in the
5
-position of initial 3-arylmethylidenefuran-2(3H)-
ones 1e–1g changed the reactivity, and the reaction of
e–1g with hydrazine hydrate afforded 68–72% of
1
1
3
5
substituted pyrazolidin-3-ones 4a–4c (Scheme 3). The
structure of 4a–4c was proved by spectral methods. In
2
C
1
in the region δ 118.6–153.6 ppm, and the carbonyl
C
the H NMR spectra of 4a–4c we observed a multiplet
carbon signal was located at δ 166.2–169.4 ppm.
C
signal of the alkyl substituent at δ 0.96–2.48 ppm,
doublets of doublets of exocyclic methylene protons at
δ 2.67–2.74 and 3.42–3.49 ppm, a multiplet of 4-H at
δ 3.63–3.77 ppm, a doublet of 3-H at δ 4.22–4.31 ppm,
Unlike the reaction at room temperature which
stops at the stage of formation of acyclic hydrazide, in
boiling ethanol intermediate hydrazide undergoes
Scheme 3.
Ar
O
O
H
N
O
C H
NH2
5
11
Ar
Ar
N H ·H O
C H
5 11
2
4
2
A
NH
C H
O
O
5
11
O
Ar
N
H
1
e–1g
4a–4c
C H
NH
5
11
O
HO
N
H
B
1
2 6 4 6 4
e, 4a, Ar = Ph; 1f, 4b, Ar = 3-O NC H ; 1g, 4c, Ar = 4-MeOC H .
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 9 2018

SYNTHESIS OF SUBSTITUTED PYRIDAZIN-3-ONES
1391
Scheme 4.
Ar
Ar
Ar
O
O
NH OH
2
H
N
4
-MeC H
OH
NH
6
4
4
-MeC H
O
6
4
O
4-MeC
6
H
4
O
O
1
b–1d
5a–5c
1
6 4 6 4 2 6 4
b, 5a, Ar = 2-ClC H ; 1c, 5b, Ar = 4-MeOC H ; 1d, 5c, Ar = 3-O NC H .
2
two broadened NH singlets at δ 6.12–6.16 and 8.31–
.37 ppm, and a set of aromatic proton signals in the
(δ 7.23–8.13 ppm). A series of signals of sp -carbon
1
3
8
atoms were observed in the C NMR spectra of 5a–5c
in the region δ 103.6–147.2 ppm, and the carbonyl
carbon signal was located at δ 168.5–174.9 ppm,
which provided an additional support to the proposed
structure.
1
3
region δ 6.76–7.43 ppm. The C NMR spectra of
a–4c contained a series of upfield signals due to
C
4
C
3
sp -carbons and two downfield carbonyl carbon
signals, as well as other signals.
In this case, the reaction path is determined mainly
by the activity of different reaction centers in the inter-
mediate. The latter may be either hydrazide A or bi-
cyclic structure B. Due to the presence of alkyl substit-
uent, the positive charge on the neighboring carbonyl
carbon atom of intermediate hydrazide A is reduced,
so that cyclization to six-membered pyridazinones can
be ruled out; on the other hand, the carbon atom of the
arylmethylidene fragment remains electron-deficient,
which favors formation of pyrazolidine system.
Another reaction sequence is also possible, namely the
formation of bicyclic system B and subsequent open-
ing of the furanone ring to give compounds 4a–4c.
Hydroxylamine molecule possesses two nonequiv-
alent nucleophilic centers, among which the nitrogen
atom is more nucleophilic. Attack of hydroxylamine on
2
C of the furan ring of 1b–1d gives intermediate
hydroxamic acid which undergoes intramolecular
cyclization via attack of the NHOH oxygen atom on
the ketone carbonyl carbon atom. The cyclization is
4
favored by deficit of electron density on C and high
nucleophilicity of the OH oxygen atom. Furthermore,
flexibility of the C–N–OH fragment in the hydroxamic
acid molecule favors appropriate spatial arrangement
of the reaction centers for oxazine ring closure.
The reactions of 5-substituted 3-arylmethylidene-
furan-2(3H)-ones 1a, 1b, and 1h with guanidine car-
bonate were carried out by heating the reactants for 5 h
in boiling ethanol in the presence of sodium ethoxide.
The mixtures were then neutralized with concentrated
aqueous HCl. The products were identified as dihydro-
furo[2,3-d]pyrimidin-2-amines 6a–6c (Scheme 5).
Treatment of furan-2(3H)-ones 1b–1d with excess
hydroxylamine hydrochloride in the presence of a cata-
lytic amount of pyridine in boiling ethanol for 6–8 h
led to the formation of 1,2-oxazin-3(4H)-ones 5a–5c
1
(
Scheme 4). The H NMR spectra of 5a–5c contained
singlets of proton on the exocyclic double bond
1
(
(
δ 7.44–7.58 ppm) and 5-H of the oxazine ring
δ 7.20–7.25 ppm) and downfield signals of the NH
Their H NMR spectra displayed singlets of 5-H
(δ 6.54–6.82 ppm), 4-H (δ 5.13–5.45 ppm), 3-H
proton (δ 8.39–8.51 ppm) and aromatic protons
(δ 3.10–3.18 ppm), and NH group (δ 0.97–1.13 ppm)
2
Scheme 5.
C H Cl-2
6
4
C H Cl-2
6
4
O
NH
EtONa, EtOH
H
N
+
NH2
R
H N
NH2
R
O
2
O
O
NH
1
a, 1b, 1h
C H Cl-2
C H Cl-2
C H Cl-2
6
4
6
4
6
4
R
HCl
R
NH
NH
NH
–
H O
2
R
O
OH
HO
O
O
N
NH2
N
NH2
N
NH2
6
a–6c
6
, R = Ph (a), 4-MeC
6
H
4
(b), 4-MeOC
6
H
4
(c).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 9 2018

1
392
ANIS’KOVA, EGOROVA
1
and a set of aromatic proton signals in the region
mp 131–133°C. H NMR spectrum, δ, ppm: 2.45 s
1
3
δ 7.06–7.51 ppm. In the C NMR spectra of 6a–6c,
(3H, CH ), 3.17 s (2H, CH ), 5.23 s (2H, NH ), 7.08 s
(1H, =CH), 7.18 d and 7.32 d (2H each, MeC H , J =
3
2
2
4
2
the C nucleus resonated at δ 49.8–52.1 ppm, sp -car-
C
6 4
bon signals were located at δ 103.9–146.2 ppm, and
8.1 Hz), 7.39–7.68 m (4H, Harom), 8.03 s (1H, NH).
C
2
13
the C signal was observed at δ 157.4–159.9 ppm.
C NMR spectrum, δ , ppm: 25.8, 45.4, 121.5, 122.8,
C
C
1
1
23.2, 125.2, 126.4, 127.7, 126.7, 128.9, 133.2,
33.2, 134.1, 137.1, 164.3, 193.1. Found %: C 66.03;
Taking into account high reactivity of guanidine
and the presence of several electrophilic centers in
arylmethylidenefuranones 1, some alternative reaction
paths could be expected. However, the product struc-
ture suggests the following transformation sequence:
initial attack of the amino group of guanidine on the
lactone fragment of furan-2-one with opening of the
lactone ring, closure of pyrimidine ring via intramolec-
ular attack of the imino group on the C=C double
bond, and subsequent enolization and intramolecular
dehydration (Scheme 5).
H 4.91; N 8.72. C H ClN O . Calculated %: C 65.75;
H 5.21; N 8.52.
1
8
17
2
2
2-[(4-Methoxyphenyl)methylidene]-4-(4-methyl-
phenyl)-4-oxobutanehydrazide (2c). Yield 76%,
mp 123–125°C. H NMR spectrum, δ, ppm: 2.43 s
(3H, CH
(2H, NH
8.1 Hz), 7.46 d (2H, Harom, J = 8.1 Hz), 7.28 d and
7.56 d (2H each, MeC , J = 8.1 Hz), 7.96 s (1H,
NH). C NMR spectrum, δ , ppm: 22.1, 42.9,
1
), 3.45 s (OCH
), 3.21 s (2H, CH
), 5.21 s
3
3
2
), 7.11 s (1H, =CH), 7.03 d (2H, Harom, J =
2
H
4
6
1
3
C
EXPERIMENTAL
53.2, 118.4, 120.3, 122.2, 124.7, 128.2, 129.1, 130.4,
1
31.7, 133.8, 158.2, 166.2, 197.5. Found, %: C 70.38;
1
13
The H and C NMR spectra were recorded at 20–
5°C on a Varian 400 spectrometer (operating fre-
H 6.42; N 9.04. C H N O . Calculated, %: C 70.35;
H 6.21; N 8.64.
-(4-Methylphenyl)-2-[(3-nitrophenyl)methyli-
dene]-4-oxobutanehydrazide (2d). Yield 86%,
mp 143–145°C. H NMR spectrum, δ, ppm: 2.52 s
19
20
2
3
2
quencies 400 and 100 MHz, respectively) using CDCl3
as solvent and tetramethylsilane as internal standard.
Analytical thin-layer chromatography was performed
on DC-Fertigfolien ALUGRAM Xtra SIL G/UV-254
plates using hexane–ethyl acetate–chloroform (2:2:1)
as eluent; spots were visualized under UV light. The
melting points were measured in open capillaries. The
elemental analyses were obtained with a Vario Micro
cube Elementar CHNS analyzer.
4
1
(
(
3H, CH ), 3.19 s (2H, CH ), 5.20 s (2H, NH ), 7.14 s
1H, =CH), 7.23 d and 7.65 d (2H each, MeC H ,
3 2 2
6
4
J = 8.1 Hz), 7.74–7.98 m (4H, Harom), 8.01 s (1H, NH).
13
C NMR spectrum, δ , ppm: 27.4, 41.5, 119.3,
C
1
1
20.2, 121.9, 122.8, 124.1, 125.3, 126.1, 127.4, 128.3,
30.5, 133.5, 137.5, 165.6, 197.3. Found, %: C 64.04;
Initial 5-substituted 3-arylmethylidenefuran-2(3H)-
ones 1a–1h were synthesized according to the proce-
dure described in [19].
H 5.49; N 12.65. C H N O . Calculated, %: C 63.71;
H 5.05; N 12.38.
1
8
17
3
4
Compounds 3a–3d and 4a–4c (general proce-
dure). A mixture of 0.02 mol of compound 1a–1g and
0.06 mol of hydrazine hydrate in 20 mL of ethanol was
refluxed with stirring for 50–60 min. After cooling,
the precipitate was filtered off, washed with water, and
recrystallized from propan-2-ol.
4
-Oxobutanoic acid hydrazides 2a–2d (general
procedure). A mixture of 0.02 mol of compound 1a–1d
and 0.02 mol of hydrazine hydrate in 12 mL of ethanol
was stirred for 30–50 min at 20–25°C. The precipitate
was filtered off, washed with water, and recrystallized
from ethanol.
4
-[(2-Chlorophenyl)methylidene]-6-phenyl-
2
-[(2-Chlorophenyl)methylidene]-4-oxo-
4,5-dihydropyridazin-3(2H)-one (3a). Yield 69%,
mp 192–194°C. H NMR spectrum, δ, ppm: 2.15 s
1
4
1
5
-phenylbutanehydrazide (2a). Yield 84%, mp 129–
31°C. H NMR spectrum, δ, ppm: 3.13 s (2H, CH ),
.18 s (2H, NH ), 7.15 s (1H, =CH), 7.34–7.79 m
9H, Harom), 7.85 s (1H, NH). C NMR spectrum, δ ,
ppm: 47.1, 119.1, 121.3, 122.8, 124.3, 125.9, 127.9,
29.5, 130.5, 131.7, 132.3, 134.6, 135.9, 136.4, 138.5,
69.4, 194.7. Found, %: C 65.15; H 5.21; N 9.24.
1
2
(2H, CH ), 7.01 s (1H, =CH), 7.08 s (1H, NH), 7.19–
2
1
3
2
7.68 m (9H, Harom). C NMR spectrum, δ , ppm: 38.3,
C
1
3
(
116.2, 117.4, 118.3, 119.1, 121.9, 122.7, 124.5, 126.1,
127.9, 128.4, 130.2, 131.5, 133.3, 139.3, 142.1, 164.2.
Found, %: C 69.11; H 4.73; N 9.76. C H ClN O.
C
1
1
1
7
13
2
Calculated, %: C 68.81; H 4.42; N 9.44.
C H ClN O . Calculated, %: C 64.87; H 4.80; N 8.90.
1
7
15
2
2
4
-[(2-Chlorophenyl)methylidene]-6-(4-methyl-
2
-[(2-Chlorophenyl)methylidene]-4-(4-methyl-
phenyl)-4,5-dihydropyridazin-3(2H)-one (3b). Yield
73%, mp 201–203°C. H NMR spectrum, δ, ppm:
1
phenyl)-4-oxobutanehydrazide (2b). Yield 81%,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 9 2018

SYNTHESIS OF SUBSTITUTED PYRIDAZIN-3-ONES
1393
2
7
.20 s (2H, CH ), 2.48 s (3H, CH ), 6.93 s (1H, =CH),
5-(4-Methoxyphenyl)-4-(2-oxoheptyl)pyrazoli-
din-3-one (4c). Yield 72%, mp 92–93°C. H NMR
2
3
1
.02 s (1H, NH), 7.03 d and 7.46 d (2H each, MeC H ,
6
4
1
3
J = 8.1 Hz), 7.67–7.95 m (4H, Harom). C NMR spec-
spectrum, δ, ppm: 1.04–2.48 m (11H, C H ), 2.74 d.d
5
11
trum, δ , ppm: 24.6, 40.1, 119.8, 120.6, 121.3, 123.7,
(2H, J = 13.2, 4 Hz), 3.49 d.d (2H, CH , J = 13.2,
C
2
1
1
25.1, 126.3, 127.5, 129.5, 131.5, 133.1, 134.6, 138.2,
40.3, 162.3. Found, %: C 69.76; H 5.12; N 8.68.
7 Hz), 3.71–3.77 m (1H, 4-H), 3.75 s (3H, OCH3),
4.22 d (1H, 5-H, J = 8.1 Hz), 6.16 s (1H, NH), 8.35 s
13
C H ClN O. Calculated, %: C 69.57; H 4.86; N 9.01.
(1H, NH), 7.00–7.28 m (4H, Harom). C NMR spec-
trum, δ , ppm: 14.7, 22.3, 26.1, 30.4, 36.2, 42.9, 45.9,
1
8
15
2
4
-[(4-Methoxyphenyl)methylidene]-6-(4-methyl-
C
7
2
5.2, 126.2, 127.3, 129.1, 132.5, 133.6, 135.3, 184.2,
10.5. Found, %: C 67.15; H 8.13; N 9.34.
phenyl)-4,5-dihydropyridazin-3(2H)-one (3c). Yield
1
7
2
6
6%, mp 209–211°C. H NMR spectrum, δ, ppm:
.16 s (2H, CH ), 2.45 s (3H, CH ), 3.53 s (OCH ),
C
17
H
24
N
2
O
3
. Calculated, %: C 67.08; H 7.95; N 9.20.
2
3
3
.89 s (1H, =CH), 7.05 s (1H, NH), 7.07 d (2H, Harom
,
Compounds 5a–5c (general procedure). A mixture
J = 8.1 Hz), 7.49 d (2H, Harom, J = 8.1 Hz), 7.21 d and
7
trum, δ , ppm: 25.9, 39.5, 54.7, 116.2, 121.4, 122.7,
1
1
of 0.01 mol of compound 1b–1d, 0.03 mol of hy-
droxylamine hydrochloride, and 0.03 mol of pyridine
in 30 mL of ethanol was refluxed with stirring for 6–
1
3
.68 d (2H each, MeC H , J = 8.1 Hz). C NMR spec-
6 4
C
23.3, 125.6, 128.2, 129.8, 133.2, 135.1, 142.1, 159.3,
63.9. Found, %: C 74.62; H 6.21; N 9.54.
8
h. The mixture was cooled and poured into cold
water, and the precipitate was filtered off, washed with
water, and recrystallized from propan-2-ol.
C H N O . Calculated, %: C 74.49; H 5.92; N 9.14.
1
9
18
2
2
6
-(4-Methylphenyl)-4-[(3-nitrophenyl)methyli-
4
-[(2-Chlorophenyl)methylidene]-6-(4-methyl-
dene]-4,5-dihydropyridazin-3(2H)-one (3d). Yield
8%, mp 210–212°C. H NMR spectrum, δ, ppm:
.22 s (2H, CH ), 2.51 s (3H, CH ), 6.94 s (1H, =CH),
.12 s (1H, NH), 7.25 d and 7.71 d (2H each, MeC H ,
J = 8.1 Hz), 7.87–8.05 m (4H, Harom). C NMR spec-
trum, δ , ppm: 25.2, 38.9, 118.8, 124.7, 125.1, 125.9,
26.3, 127.7, 128.1, 128.9, 129.4, 130.2, 132.1, 133.9,
43.3, 161.2. Found, %: C 66.97; H 5.03; N 13.42.
phenyl)-2H-1,2-oxazin-3(4H)-one (5a). Yield 72%,
mp 117–119°C. H NMR spectrum, δ, ppm: 2.45 s
3H, CH ), 7.20 s (1H, 5-H), 7.44 s (1H, =CH), 7.23 d
and 7.39 d (2H each, MeC H , J = 8.1 Hz), 7.85–
.13 m (4H, Harom), 8.47 s (1H, NH). C NMR spec-
trum, δ , ppm: 23.9, 103.6, 125.1, 125.8, 126.2, 127.8,
28.3, 132.6, 133.4, 137.6, 157.4, 168.5. Found, %:
C 69.69; H 4.87; N 4.87. C H ClNO . Calculated, %:
1
6
2
7
1
2
3
(
3
6
4
1
3
6
4
13
8
C
C
1
1
1
1
8
14
2
C H N O . Calculated, %: C 67.28; H 4.71; N 13.08.
1
8
15
3
3
C 69.35; H 4.53; N 4.49.
4
-(2-Oxoheptyl)-5-phenylpyrazolidin-3-one (4a).
1
4-[(4-Methoxyphenyl)methylidene]-6-(4-methyl-
phenyl)-2H-1,2-oxazin-3(4H)-one (5b). Yield 69%,
mp 115–117°C. H NMR spectrum, δ, ppm: 2.41 s
3H, CH ), 3.58 s (3H, OCH ), 7.25 s (1H, 5-H), 7.53 s
1H, =CH), 7.02 d (2H, Harom, J = 8.1 Hz), 7.35 d (2H,
Harom, J = 8.1 Hz), 7.12 d and 7.41 d (2H each,
MeC H , J = 8.1 Hz), 8.39 s (1H, NH). C NMR spec-
trum, δ , ppm: 25.3, 54.8, 107.5, 117.6, 126.6, 128.3,
Yield 71%, mp 97–99°C. H NMR spectrum, δ, ppm:
.96–2.35 m (11H, C H ), 2.69 d.d (2H, J = 13.2,
Hz), 3.46 d.d (2H, CH , J = 13.2, 7 Hz), 3.63–3.69 m
1H, 4-H), 4.27 d (1H, 5-H, J = 8.1 Hz), 6.12 s (1H,
NH), 8.37 s (1H, NH), 6.76–7.05 m (5H, Harom).
C NMR spectrum, δ , ppm: 12.2, 21.5, 24.9, 29.7,
7.8, 41.4, 46.7, 74.7, 123.8, 124.7, 127.8, 129.1,
32.1, 133.8, 182.9, 209.7. Found, %: C 70.47;
H 7.70; N 10.67. C H N O . Calculated, %: C 70.04;
0
4
(
5 11
1
2
(
(
3 3
1
3
C
1
3
6
4
3
1
C
1
1
27.7, 128.9, 130.4, 132.4, 134.5, 136.2, 159.1, 163.6,
69.8. Found, %: C 73.88; H 5.76; N 4.78. C H NO .
Calculated, %: C 74.25; H 5.58; N 4.56.
1
6
22
2
2
1
9
17
3
H 8.08; N 10.21.
5
-(3-Nitrophenyl)-4-(2-oxoheptyl)pyrazolidin-
1
6
-(4-Methylphenyl)-4-[(3-nitrophenyl)methyli-
3
-one (4b). Yield 79%, mp 112–113°C. H NMR spec-
trum, δ, ppm: 0.99–2.43 m (11H, C H ), 2.67 d.d (2H,
J = 13.2, 4 Hz), 3.42 d.d (2H, CH , J = 13.2, 7 Hz),
.68–3.72 m (1H, 4-H), 4.31 d (1H, 5-H, J = 8.1 Hz),
.14 s (1H, NH), 8.31 s (1H, NH), 7.17–7.43 m (4H,
Harom). C NMR spectrum, δ , ppm: 14.7, 22.3, 26.1,
0.4, 36.2, 42.9, 45.9, 75.2, 126.2, 127.3, 129.1, 132.5,
33.6, 135.3, 184.2, 210.5. Found, %: C 60.42;
H 6.95; N 12.98. C H N O . Calculated, %: C 60.17;
dene]-2H-1,2-oxazin-3(4H)-one (5c). Yield 67%,
mp 92–94°C. H NMR spectrum, δ, ppm: 2.43 s (3H,
5
11
1
2
CH ), 7.23 s (1H, 5-H), 7.58 s (1H, =CH), 7.15 d and
3
6
3
7.38 d (2H each, MeC
(4H, Harom), 8.51 s (1H, NH). C NMR spectrum,
, ppm: 26.7, 108.4, 116.5, 123.8, 125.1, 127.3,
128.7, 129.3, 131.6, 132.4, 135.3, 136.1, 138.4, 147.2,
158.5, 174.9. Found, %: C 66.78; H 4.85; N 8.61.
H , J = 8.1 Hz), 7.78–8.07 m
6 4
1
3
13
C
3
1
δ
C
1
6
21
3
4
H 6.63; N 13.16.
C H N O . Calculated, %: C 67.07; H 4.38; N 8.69.
18 14 2 4
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 9 2018

1
394
ANIS’KOVA, EGOROVA
Compounds 6a–6c (general procedure). A mixture
of 0.01 mol of compound 1a, 1b, or 1h and 0.01 mol
of guanidine carbonate in 15 mL of ethanol containing
.001 mol of sodium ethoxide was refluxed with stir-
ring for 5 h. The mixture was cooled and neutralized
with concentrated aqueous HCl, and the precipitate
was filtered off, washed with water, and recrystallized
from propan-2-ol.
2. Sagong, H.Y., Bauman, J.D., Patel, D., Das, K.,
Arnold, E., and LaVoie, E.J., J. Med. Chem., 2014,
vol. 57, p. 8086.
3
. Zuniga, E.S., Korkegian, A., Mullen, S., Hembre, E.J.,
Ornstein, P.L., Cortez, G., Biswas, K., Naresh, K.,
Cramer, J., Masquelin, T., Hipskind, P.A., Odingo, J.,
and Parish, T., Bioorg. Med. Chem., 2017, vol. 25,
p. 3922.
0
4
. Pretorius, S.I., Breytenbach, W.J., de Kock, C.,
Smith, P.J., and N’Da, D.D., Bioorg. Med. Chem., 2013,
vol. 21, p. 269.
4
-(2-Chlorophenyl)-6-phenyl-3,4-dihydrofuro-
[
2,3-d]pyrimidin-2-amine (6a). Yield 67%, mp 176–
1
1
3
7
1
1
78°C. H NMR spectrum, δ, ppm: 1.13 s (2H, NH ),
2
5. Sams, A.G., Hentzer, M., Mikkelsen, G.K., Larsen, K.,
Bundgaard, C., Plath, N., Christoffersen, C.T., and
Bang-Andersen, V., J. Med. Chem., 2010, vol. 53,
p. 6386.
.13 s (1H, NH), 5.45 s (1H, 4-H), 6.54 s (1H), 7.21–
1
3
.43 m (9H, Harom). C NMR spectrum, δ , ppm: 52.1,
C
05.1, 119.1, 124.3, 124.9, 125.1, 127.2, 128.1, 128.9,
30.2, 131.8, 132.4, 135.9, 137.3, 143.1, 159.6. Found,
6. Dave, C.D. and Shah, R.D., Molecules, 2002, vol. 7,
%
: C 66.35; H 4.13; N 13.34. C H ClN O . Calculat-
p. 554.
1
8
14
3
4
ed, %: C 66.77; H 4.36; N 12.98.
7. Madhavan,
G.R.,
Chakrabarti,
R.,
Vikrama-
dithyan, R.K., Mamidi, R.N.V.S., Balraju, V.,
Rajesh, B.M., Misra, P., Kumar, S.K.B., Lohray, B.B.,
Lohray, V.B., and Rajagopalan, R., Bioorg. Med. Chem.,
4
-(2-Chlorophenyl)-6-(4-methylphenyl)-3,4-dihy-
drofuro[2,3-d]pyrimidin-2-amine (6b). Yield 73%,
1
mp 196–198°C. H NMR spectrum, δ, ppm: 1.05 s
2
002, vol. 10, p. 2671.
(
(
2H, NH ), 2.67 s (3H, CH ), 3.18 s (1H, NH), 5.13 s
1H, 4-H), 6.68 s (1H), 7.21 d and 7.43 d (2H each,
2 3
8
. Gangiee, A., Adaira, O., and Queener, S.F., Bioorg.
Med. Chem., 2001, vol. 9, p. 2929.
MeC H , J = 8.1 Hz), 7.25–7.38 m (4H, Harom).
6
4
1
3
9. Saladino, R., Ciambecchini, U., Maga, G., Mastro-
marino, P., Conti, C., and Botta, M., Bioorg. Med.
Chem., 2002, vol. 10, p. 2143.
0. Aniskova, T., Kamneva, I., and Egorova, A., Lett. Org.
Chem., 2016, vol. 13, p. 699.
C NMR spectrum, δ , ppm: 25.3, 49.8, 103.9, 121.8,
C
1
1
22.5, 124.5, 125.7, 127.5, 128.1, 128.9, 129.3, 131.6,
33.6, 134.5, 135.2, 145.3, 157.4. Found, %: C 67.87;
1
H 4.93; N 12.82. C H ClN O. Calculated, %:
1
9
16
3
C 67.56; H 4.77; N 12.44.
1
1. Anis’kova, T.V., Yegorova, A.Yu., and Chadina, V.V.,
4
-(2-Chlorophenyl)-6-(4-methoxyphenyl)-3,4-di-
Mendeleev Commun., 2008, vol. 18, p. 167.
hydrofuro[2,3-d]pyrimidin-2-amine (6c). Yield 65%,
mp 188–190°C. H NMR spectrum, δ, ppm: 0.97 s
1
2. Aniskova, T.V., Chadina, V.V., and Yegorova, A.Yu.,
1
Synth. Commun., 2011, vol. 41, p. 2315.
(
(
7
2H, NH ), 3.10 s (1H, NH), 3.65 s (3H, OCH ), 5.28 s
2
3
13. Anis’kova, T.V., Kamneva, I.E., and Egorova, A.Yu.,
1H, 4-H), 6.82 s (1H), 7.06 d (2H, Harom, J = 8.1 Hz),
.51 d (2H, Harom, J = 8.1 Hz), 7.18–7.31 m (4H,
Rev. J. Chem., 2014, vol. 4, p. 204.
14. Anis’kova, T.V. and Egorova, A.Yu., Russ. J. Org.
Chem., 2013, vol. 49, p. 1514.
1
3
Harom). C NMR spectrum, δ , ppm: 50.2, 54.8, 107.7,
C
1
1
19.6, 122.7, 124.2, 124.9, 125.1, 126.2, 127.8, 128.1,
29.1, 130.2, 131.2, 132.5, 146.2, 159.9. Found, %:
C 64.79; H 4.24; N 12.05. C H ClN O . Calculated,
15. Anis’kova, T.V. and Yegorova, A.Yu., Chem. Hetero-
cycl. Compd., 2011, vol. 47, p. 514.
16. Anis’kova, T.V. and Egorova, A.Yu., Russ. J. Org.
Chem., 2012, vol. 48, p. 1578.
1
9
16
3
2
%
: C 64.50; H 4.56; N 11.88.
1
7. Aniskova, T., Grinev, V., and Yegorova, A., Molecules,
017, vol. 22, p. 1251.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 16-03-00530).
2
1
8. Anis’kov, A.A., Kamneva, I.Ye., Zheleznova, M.A., and
Yegorova, A.Yu., Chem. Heterocycl. Compd., 2015,
vol. 51, p. 709.
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. Coates, W.J., Prain, H.D., Reeves, M.L., and Warring-
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 9 2018