Reaction of 2-chloro-1-alkyl-1H-indole-3-carbaldehydes with barbituric acids and 5-methyl-2-phenyl-2,4-dihydropyrazol-3-one. Formation of compound with extremely short intramolecular hydrogen bond in eight-membered pseudocycle

Article abstract of DOI:10.3987/COM-14-13135

New indolin-2-one derivatives, containing in its molecules eight-membered pseudo-cycle with unusually short intramolecular hydrogen bond in OHO-bridge have been synthesized by reaction of 2-chloro-1-alkyl-1H-indole-3-carbaldehyde with barbituric acids or 5-methyl-2-phenyl-2,4-dihydropyrazol-3-one. Under the action of amines they undergo fragmentation to 5-aminomethylenebarbituric acids or 4-aminomethylenepyrazolones and 1-alkyl-1,3-dihydroindol-2-ones.

Full text of DOI:10.3987/COM-14-13135

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HETEROCYCLES, Vol. 91, No. 1, 2015
HETEROCYCLES, Vol. 91, No. 1, 2015, pp. 64 - 75. © 2015 The Japan Institute of Heterocyclic Chemistry
Received, 22nd November, 2014, Accepted, 17th December, 2014, Published online, 25th December, 2014
DOI: 10.3987/COM-14-13135
REACTION
CARBALDEHYDES WITH BARBITURIC ACIDS AND 5-METHYL-2-
PHENYL-2,4-DIHYDROPYRAZOL-3-ONE. FORMATION OF
OF
2-CHLORO-1-ALKYL-1H-INDOLE-3-
COMPOUND WITH EXTREMELY SHORT INTRAMOLECULAR
HYDROGEN BOND IN EIGHT-MEMBERED PSEUDOCYCLE
Konstantin F. Suzdalev,a,* Maria N. Babakova,a Victor G. Kartsev,b and
Konstantin A. Krasnovc
aChemical Department of Southern Federal University, Zorge Street 7, 344090
Rostov-on-Don, Russia, E-mail: konsuz@gmail.com
bInterBioScreen Ltd., PO Box 218, Moscow, 119019 Russia, E-mail:
screen@ibscreen.chg.ru
cInstitute of Toxicology FMBA of Russia, Bekhterev str., 1, St-Petersburg, 192019,
Russia, E-mail: krasnov_tox@mail.ru
Abstract – New indolin-2-one derivatives, containing in its molecules
eight-membered pseudo-cycle with unusually short intramolecular hydrogen bond
in
OHO-bridge
have
been
synthesized
with
by
reaction
acids
of
or
2-chloro-1-alkyl-1H-indole-3-carbaldehyde
barbituric
5-methyl-2-phenyl-2,4-dihydropyrazol-3-one. Under the action of amines they
undergo fragmentation to 5-aminomethylenebarbituric acids or
4-aminomethylenepyrazolones and 1-alkyl-1,3-dihydroindol-2-ones.
INTRODUCTION
It is known, that 2-chloroindole-3-carbaldehydes react with CH-acids, such as malononitrile1 and
1,3-dihydroindol-2-ones2 to give Knoevenagel condensation products with retention of chlorine atom in a
molecule. The products of the second reaction are of interest as anticancer drugs.2
To obtain such derivatives we have investigated reactions of 2-chloroindole-3-carbaldehydes 1a,b with
barbituric acids 2a,b and 5-methyl-2-phenyl-2,4-dihydropyrazol-3-one 7. We have surprisingly found that
unlike the reactions described in the literature1,2 products of other species were prepared. Elemental
1
analysis, mass spectra, IR and NMR H data have shown that these products include indole nucleus and

HETEROCYCLES, Vol. 91, No. 1, 2015
65
fragments of active methylene compounds but do not contain a chlorine atom. X-Ray analysis of the
crystals, obtained by reacting of aldehyde 1b with 1,3-dimethylbarbituric acid has sown this product (3c)
contain a specific eight-membered heterocyclic ring system. The purpose of this paper is to describe the
synthesis, structural features and some chemical properties of the compounds obtained.
RESULTS AND DISCUSSION
The heating of starting materials 1a,b with barbituric acids 2a,b in butanol gave a 1,3-dihydroindol-2-ones
3a-d. It is apparent, that the Knoevenagel products A formed at the initial stage underwent the conjugate
addition of water followed by the elimination of HCl and formation of substances 3a-d (Scheme 1).
R1
R1
N
O
N
O
O
O
O
R1
R1
O
N
N
N
O
R1
O
Cl
N
O
N
R1
N
O
O...
R
H
Cl
R
H
O
N
R
1
2
3
H
3a R = R1 = Me
2a R1 = Me
1a R = Me
1b R = Et
A
1
1
3b
3c
2b
R =Me, R = H
R = H
2
1
HC(OEt)3
+ R2NH2
'
R NH2 /
R = Et, R = Me
R2NH2 / rt
3d R = Et, R1 = H
R1
N
R2
R1
O
O
R2
O
R1
N
NH
H
N
HN
O
O
O
O
N
R1
N
R1
N
N
N
N
OH HO
O
R1
R
O
R
6
5
O
R
NH3R2
6a R1 = Me, R2 = C H -
B
n
7
3
4
1
2
5a R = Me
5b R = Et
6b
6c
R = Me, R = CH2Ph
1
2
1
2
4a
4b
R = R = Me, R = C H -
n
3
7
R = Me, R = NH2
1
2
6d R1 = H, R2 = C H -
R = R = Me, R = CH2Ph
n
7
3
Scheme 1
1
Barbituric acid moiety of compounds 3a-d exists in the enol form. H-NMR spectra in CDCl3 of
compounds 3a-d include the signals of strongly unshielded protons of OH groups (17.75-17.80 ppm),
connected by a hydrogen bond to the carbonyl group in the 2-position of the indole ring. The presence of
hydrogen bonding has also been proven by two narrow singlets of N-methyl groups of barbituric acid
fragments in products 3a and 3c. This demonstrates the fixation of the fragments by a hydrogen bond. The
1H-NMR spectrum of compound 3a, in DMSO-d6 essentially differs from its spectrum in CDCl3. The broad
singlet of 6 protons of two NCH3 groups of barbituric acid moiety, located at δ 3.32 ppm, may be explained

66
HETEROCYCLES, Vol. 91, No. 1, 2015
by the hindered rotation of this part of a molecule at room temperature in this solvent. It corresponds to the
break of the H-bond, due to intermolecular association with DMSO.
Figure 1. ORTEP view of structure 3c
Figure 2. Ball and stick view of structure 3c. Planes C8-C1-O1 and C12-C15-O4

HETEROCYCLES, Vol. 91, No. 1, 2015
67
The X-ray analysis of compound 3c (Figure 1) shows the presence of asymmetrical intramolecular
hydrogen bond in a crystalline state. The distance between atoms O4 and H4 is 1.088 Å, while O1···H4 –
1.310 Å, which is considerably less than the sum of Van-der-Waals radii and indicates the presence of a
"strong OHO bridge".3 The formation of hydrogen bridge makes the molecule almost flat, the dihedral
angle between the planes C1-C8-O1 and C12-C15-O4 is 8.41°, as shown in Figure 2. Since the hydrogen
atom is located between O1 and O4, the angle C8-C11-C12 significantly deviates from its standard value
(120 °) and is of 141.14°. Values of the remaining angles of the ring with a hydrogen bond vary between
109.81° - 133.57°, except for the angle O1-H4-O4 which is 173.49°.
We have undertaken a literature search of substances similar in structure to our compound. According to
database CCDC,4 few structures having a conjugate system of carbonyl group, two double bonds and
OH-function have been described.5 They can be divided into three groups. The first includes compounds in
which intramolecular hydrogen bonding is not occurring, and hence an eight-membered cycle does not
form.5a In the second group two kinds of molecules with different interatomic distances O···O coexist in the
crystal.5b In the third group the intramolecular hydrogen bond of the same type is formed in all molecules of
the crystal.5c-g Our substance 3c represents a third type of compounds. In this group only the one compound
with two symmetrically placed pyrazolone rings is practically flat: the dihedral angle between planes
analogous to shown in Figure 2 makes 0.13°.5c Most of compounds reported to be considerably twisted: the
dihedral angle varies from 28.21° 5b to 59.98°.5g
The shortest H-bond OHO in eight-membered pseudocycle among described molecules is 2.408 Å.5c In our
compound 3c distance between atoms O1 and O4 is 2.394 Å, indicating its unique structure.
We have investigated the reaction of derivatives 3a-d with primary amines and hydrazine hydrate. Under
mild conditions (at room temperature) compounds 4a,b were obtained. They are ammonium salts of
barbituric acid derivatives (Scheme 1). The structure of salts 4a,b is confirmed by IR and 1H-NMR spectra.
+
In its IR spectra peaks at a long-wave part between 2527 and 3380 cm- 1 correspond to NH3 group
vibrations. The 1H-NMR spectrum of compound 4a contains a broad singlet at δ 7.60 ppm, corresponding
+
to the three protons of NH3 group. In the 1H-NMR spectrum of the product 4b the similar signal is at 8.05
ppm. We have not determine a geometry of the exo-cyclic double bond attached at the 3-position of the
indolin-2-one in products 4a,b, because of their instability. It seems plausible negative charge distribution
between the two oxygen atoms of the pyrimidine ring and the carbonyl group of the indole moiety. Heating
of compounds 4a,b in n-BuOH leads to their destruction up to 1,3-dihydroindol-2-ones 5a,b and
5-aminomethylenebarbiturates 6a,b. Compounds 6a-d may be obtained at once from substances 3a-d by
their boiling with amines in n-BuOH (Scheme 1). Structure of compounds 6a,b was proved using the
oncoming synthesis – ternary condensation of barbituric acid 2a, triethylorthoformate and the appropriate
amine according to a known method.6 Melting points and spectroscopic data of 1,3-dihydroindol-2-ones
5a,b and the deliberately obtained samples7 are the same.

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HETEROCYCLES, Vol. 91, No. 1, 2015
Reaction of aldehyde 1a with 5-methyl-2-phenyl-2,4-dihydropyrazol-3-one 7 passes through the same
pathway (as in the case of barbituric acids 2a,b) to give the product 8 (Scheme 2). 1H-NMR spectrum of
compound 8 in CDCl3 contains a signal of strongly unshielded enol proton at G 16.10 ppm that confirms the
presence of intramolecular hydrogen bond in this solvent. The signals of methyl protons at the indole
nitrogen atom and pyrazolone cycle appear at δ 3.40 and 2.40 ppm, respectively. In contrast to compound
3a, the product 8 in DMSO-d6 partly retains the intramolecular hydrogen bond; duplication of the signals in
1H-NMR spectrum indicates the presence of non-chelated conformer of this compound. So, in DMSO-d6
NCH3 group is characterized by singlets at G 3.40 and 3.78 ppm, and CCH3 group of pyrazolone cycle – by
singlets at G 2.25 and 2.40 ppm.
Reaction of compound 8 with tryptamine 9 proceeds as described above reacting compounds 3a,с with
amines and produces decomposition products 5a and 10 (Scheme 2).
Scheme 2
Reaction of the compound 3a with 5-methyl-2-phenyl-2,4-dihydropyrazol-3-one 7 led to formation of
products 8 and 11 (Scheme 3).
Scheme 3

HETEROCYCLES, Vol. 91, No. 1, 2015
69
First, as in the case of reaction with amines, Michael addition to the double bond occurs. Elimination of
dimethylbarbituric acid fragment 2a from intermediate B gives compound 8 in 10% yield. Alongside with
the product 8, a substance 11 was obtained. Presumably, an anion, derived from pyrazolone 7 existing in a
reaction mixture, attacks the double bond of the product 8. A subsequent elimination of
1-methyl-1,3-dyhidroindol-2-one 5a leads to the formation of substance 11 with yield of 9.5%. The melting
point of the compound 11 is the same as described in the literature.8 This reaction shows that the anion
formed from pyrazolone 7 consistently displaces barbiturate and indolin-2-one fragments from the parent
molecule 3a to form the symmetrical thermodynamically stable product 11.
In conclusion, the observed reactions may be used as a method for the synthesis of
1,3-dihydro-2H-indol-2-ones (oxindoles) containing heterocyclic moieties. A large number of such
compounds exhibit useful pharmaceutical properties,9 including anticancer,10 analgesic,11
anti-inflammatory,12 and serotonergic.13 Recently oxindoles have been actively investigated as
antiglycation agents – preparations for the prevention of late diabetic complications.14 As regards the
compounds 3a-d, they are derivatives of barbituric acid. The importance of such compounds for drug
design is well known: they can be used as hypnotics, sedatives, anticonvulsants and anesthetics.15 Recently,
much attention is paid to the use of barbituric acid derivatives in coordination and supramolecular
chemistries.16 The metal complexes of barbituric acids possess antitumor activities.17 When the substances
3a-d will be used as ligands, they may be employed in this field.
EXPERIMENTAL
IR spectra were taken on Varian 3100 FT-IR, Excalibur Series instrument by means of Attenuated Total
Reflectance (ATR) method. NMR spectra were recorded on Varian Unity 300 spectrometer (300 MHz).
2-Chloro-1-methyl-1H-indole-3-carbaldehyde (1а). To
a
solution of 2-chloro-1H-indole-3-
carbaldehyde18 (12.56 g, 70 mmol) in DMSO (40 mL) was added a solution of sodium hydroxide (3.5 g,
87.5 mmol) in water (3.5 mL). Hereupon the temperature of a mixture rose up to 43 °С. After 10 min the
temperature started to fall and the mixture became to darken. Through 30 min after addition of alkali a
mixture was cooled up to 10 °С and dimethyl sulfate (8.46 mL, 87.5 mmol) was added dropwise for
maintaining temperature not above 20 °С. A mixture was stirred at rt during 1 h, then warmed up to
55-60 °С. To a warm solution cold water (70 mL) was added dropwise. A precipitated product of light-pink
color was filtered. Recrystallization from benzene and washing with petroleum ether (bp 40-70 °С) gave
compound 1a (11.52 g, 85%) as colorless crystals; mp 105 °С (lit. 89-91 °С18) IR 1645 (С=О), 1590
(С-СAr) cm-1; 1Н-NMR (CDCl3) δ: 3.82 (3Н, s, NСН3), 7.24-7.37 (3Н, m, НAr), 8.23-8.35 (1Н, m, Н-4Ind),
10.10 (1Н, s, СНО). Anal. Calcd for C10H8ClNO: C, 62.03; H, 4.16; Cl, 18.31; N, 7.23. Found: C, 62.00; Н,
4.2; Сl, 18.30; N, 7.25.

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HETEROCYCLES, Vol. 91, No. 1, 2015
2-Chloro-1-ethyl-1H-indole-3-carbaldehyde (1b). 2-Chloro-1H-indole-3-carbaldehyde18 (15.72 g, 90
mmol) was treated with diethyl sulfate (14.8 mL, 110 mmol) in the described above manner to give 1b.
Recrystallization from i-PrOH gave pale beige crystals (14.3 g, 76%); mp 107 °С; IR 1645 (С=О), 1600,
1
1580 (C-СAr) cm-1; Н-NMR (CDCl3) δ: 1.43 (t, J = 7.4 Hz, 3Н, СН2СН3), 4.30 (q, J = 7.4 Hz, 2Н,
СН2СН3), 7.25-7.37 (m, 3Н, НAr.), 8.30 (m, 1Н, H-4Ind), 10.15 (s, 1Н, СНО). Anal. Calcd for C11H10NClO:
C, 63.62; H, 4.85; N, 6.75; Cl, 17.07. Found: C, 63.40; Н, 4.80; N, 6.80; Cl, 17.00.
6-Hydroxy-1,3-dimethyl-5-(1-methyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrimidine-2,4-
dione (3a). A mixture of 2-chloro-1-methyl-1H-indol-3-carbaldehyde (1а) (1.94 g, 10 mmol) and
1,3-dimethylbarbituric acid 2a (1.56 g, 10 mmol) was refluxed in n-BuOH (15 mL) for 30 min. The yellow
residue began to precipitate from hot solution. Recrystallization from benzene gave 3a (2.1 g, 68%); mp
243-245 °С; IR 1700, 1633(C=O), 1600 (C-СAr) cm-1; 1Н-NMR (CDCl3) δ: 3.40 (s, 3H, CH3), 3.50 (s, 3H,
CH3), 3.56 (s, 3H, CH3), 7.08-7.40 (m, 3H, HAr), 7.80 (d, J = 7.0 Hz, 1H, H-4Ind), 8.6 (s, 1H, =CH-), 17.63
(s, 1H, OH). 1Н-NMR (DMSO-d6) δ: 3.32 (br s, 6Н, 2СН3), 3.55 (s, 3Н, NInd-CH3), 7.20 (m, 3Н, НAr), 7.60
(d, 1Н, Н-4Ind), 8.40 (s, 1Н, =CH-), 17.55 (br s, 1Н, OH). МS m/z: 313 (M). Anal. Calcd for C16H15N3O4: C,
61.34; H, 4.83; N, 13.41. Found: C, 61.30; H, 4.80; N, 13.40.
6-Hydroxy-5-(1-methyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrimidine-2,4-dione (3b). The
compound 1a (0.29 g, 1.5 mmol) was refluxed in n-BuOH (2 mL) with barbituric acid 2b (0.19 g, 1.5
mmol) in the described above manner to give 3b (0.374 g, 87%) as a yellow residue, which was
recrystallized from DMF. The crystals were refluxed in CCl4 (15 mL) during 5 h for removal of DMF to
give 3b, mp 320 °С. IR 3200, 3290 (NH); 1700, 1660 (C=O), 1580 (C-CAr) cm-1; 1Н-NMR (DMSO-d6) δ:
3.5 (s, 3H, NCH3), 7.10-7.28 (m, 3Н, НAr), 7.60 (d, J = 7.1 Hz, 1Н, Н-4Ind), 8.28 (s, 1H, =CH-), 11.10 (br s,
1Н, NH), 11.60 (br s, 1Н, NH), 17.78 (br s, 1H, OH). Anal. Calcd for С14H11N3O4: C, 58.95; H, 3.89; N,
14.73. Found: C, 58.83; H 3.97; N, 14.85.
6-Hydroxy-1,3-dimethyl-5-(1-ethyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrimidine-2,4-
dione (3с). The compound 1b (0.415 g, 2 mmol) was heated with 1,3-dimethylbarbituric acid 2a (0.312 g,
2 mmol) in n-BuOH (3 mL) in the described above manner (preparation of 3a) to give compound 3c.
Recrystallization from i-PrOH gave yellow crystals (0.584 g, 80%), mp 250 °С; IR 1700, 1640 (С=О),
1600, 1590 (С–СAr) cm-1; 1Н-NMR (CDCl3) δ: 1.40 (t, J = 7.4 Hz, 3Н, СН3СН2), 3.45 (s, 3Н, NCH3), 3.55
(s, 3Н, NCH3), 4.10 (q, J = 7.4 Hz, 2Н, СН3СН2), 7.10 – 7.35 (m, 3Н, НAr), 7.70 (d, J = 7.0 Hz, 1Н, Н-4Ind),
8.60 (s, 1Н, =CH-), 17.68 (s, 1H, OH). Anal. Calcd for C17H17N3O4: C, 62.38; Н, 5.23; N, 12.84. Found: С,
62.30; Н, 5.30; N, 12.70. Crystal data: FW = 327.34, monoclinic, space group P2(1)/n a = 9.2686(8) Å, b =
6.9221(6) Å, c = 24.256(2) Å, α = 90°, β = 91.022(2)°, γ = 90°, V= 1556.0(2) Å3, Z = 4, Dx = 1.397 Mg/m3.
T = 293(2) K, wavelength 0.71073 Å. Absorption coefficient 0.102 mm-1, F (000) = 688. Crystal size: 0.40
x 0.05 x 0.05 mm. R (int) = 0.0406. Final R indices [I>2 sigma (I)] R1 = 0.0481, Rw2 = 0.1232. R indices (all

HETEROCYCLES, Vol. 91, No. 1, 2015
71
data) R1 = 0.0742, Rw2 = 0.1372. Extinction coefficient - 0.11 (2). Largest diff. peak and hole 0.216 and
-0.193 e/ Å3. Refinement method - full-matrix least-squares on F2. Goodness-of-fit on F2 1.014. Deposition
number CCDC-1031039 for compound No. 3с. Free copies of the data can be obtained via
http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge, CB2 1EZ, UK; Fax: +44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk).
6-Hydroxy-5-(1-ethyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrimidine-2,4-dione (3d). The
compound 1b (0.387 g, 2 mmol) was refluxed with barbituric acid 2b (0.256 g, 2 mmol) in the described
above manner (preparation of 3a) to give 3d. Residue was recrystallized from DMF and then refluxed in
CCl4 (15 mL) during 5 h for removal of DMF. Yield 0.42 g (70%), mp 320 °С. IR 3280, 3200, 3050 (NH,
OH), 1700, 1660 (С=О), 1590, 1610, 1600 (С – СAr) cm-1; 1Н-NMR (DMSO-d6) δ: 1.35 (t, J = 7.4 Hz, 3Н,
СН3СН2), 4.05 (q, J = 7.4 Hz, 2Н, СН3СН2), 7.10–7.30 (m, 3Н, НAr), 7.60 (d, J = 7.2 Hz, 1Н, Н-4Ind), 8.30
(s, 1Н, =CH-), 11.10 (s, 1Н, NH), 11.60 (s, 1Н, NH), 17.78 (br s, 1Н, ОН). Anal. Calcd for C15H13N3O4: С,
60.20; Н, 4.38; N, 14.04. Found: С, 60.10; Н, 4.40; N, 14.10.
1,3-Dimethyl-5-(1-methyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,6-dioxohexahydropyrimi-
din-4-ol 1-propylammonium salt (4a). To a solution of compound 3а (0.94 g, 3 mmol) in CHCl3 (10 mL)
was added 1-propylamine (0.3 mL, 3.6 mmol) and reaction mixture was left over night at rt. Yellow crystals
+
of 4a were collected by filtration. Yield - 0.96 g (89%), mp 245-248 °С. IR 3100, 2527 (NН3 ), 1670, 1660,
1650 (С=О), 1550 (С-СAr) cm-1; 1Н-NMR (DMSO-d6) δ: 0.90 (t, J = 7.3 Hz, 3H, CH3CH2CH2NH3 ), 1.55
+
+
+
(m, 2H, CH3CH2CH2NH3 ), 2.70 (t, J = 7.5 Hz, 2H, CH3CH2CH2NH3 ), 3.20 (s, 6Н, 2NСН3), 3.22 (s, 3H,
+
NIndCH3), 6.70-7.00 (m, 4Н, НInd), 7.60 (br s, 3Н, NH3 ), 7.80 (s, 1Н, =СН-). Anal. Calcd for C19H24N4O4:
С, 61.28; Н, 6.50; N, 15.04. Found: С, 61.37; Н, 6.62; N, 15.72.
1,3-Dimethyl-5-(1-methyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,6-dioxohexahydropyrimi-
din-4-ol benzylammonium salt (4b). The compound 3a (0.31 g, 1 mmol) was reacted with benzylamine
(0.11 mL, 1 mmol) in the described above manner to give 4b. Yield - 0.348 g (87%), mp 243-245 °С. IR
3380, 3170, 2648 (NН3 ), 1660, 1610 (C=O), 1600, 1580 (C-CAr) cm-1; 1Н-NMR (DMSO-d6) δ: 3.20 (s, 6Н,
+
2NСН3), 3.23 (s, 3H, NIndCH3), 3.96 (s, 2Н, СН2Рh), 6.70-7.00 (m, 4Н, НInd), 7.30-7.45 (m, 5Н, HAr), 7.80
+
(s, 1H, =CH-), 8.05 (br s, 3H, -NH3 ). Anal. Calcd for C23H24N4O4: С, 65.70; Н, 5.75; N, 13.33. Found: С,
65.62; Н, 5.81; N, 13.43.
1-Methyl-1,3-dihydroindol-2-one (5a), 1,3-dimethyl-5-propylaminomethylenepyrimidine-2,4,6-
trione (6a) (Method A). The mixture of compound 3a (0.31 g, 1 mmol) and 1-propylamine (0.1 mL, 1.2
mmol) in n-BuOH (3 mL) was refluxed for 1 h. White powder was filtered and recrystallized from i-PrOH
1
to give 6a. Yield - 0.12 g (53%), mp 145 °С. IR 3170 (NH), 1630, 1650, 1670 (С=О) cm-1; Н-NMR
(CDCl3) δ: 1.00 (t, J = 7.3 Hz, 3H, CH3CH2CH2), 1.70 (m, 2H, CH3CH2CH2), 3.33 (s, 6H, 2NCH3), 3.42 (m,
2H, CH3CH2CH2), 8.20 (d, J = 10.3 Hz, 1Н, =СН-), 10.31 (br s, 1H, NH). МS m/z: 225 (М+). Anal. Calcd

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HETEROCYCLES, Vol. 91, No. 1, 2015
for C10H15N3O3: C, 53.32; H, 6.71; N, 18.66. Found: C, 53.20; H, 6.7; N, 18.70. Mother liquor was
evaporated in vacuo up to dryness. The residue was purified by column chromatography on Al2O3 (eluent –
CHCl3, column - d=2 cm, l=20 cm, Rf = 0.79). The first fraction was collected and the solvent evaporated.
The residue of 5a was recrystallized from i-PrOH to give colorless needles (0.062 g, 46%); mp 86 °С (lit.
mp 86 °С).7
1,3-Dimethyl-5-propylaminomethylenepyrimidine-2,4,6-trione (6a) (Method B) The mixture of
1-propylamine (0.17 mL, 2 mmol), 1,3-dimethylbarbituric acid 2a (0.312 g, 2 mmol) and triethyl
orthoformate (0.4 mL, 2.5 mmol) was refluxed for 15 min in EtOH (2.5 mL). Filtered residue of 6a was
recrystallized from EtOH, to give 6a as colorless crystals 0.315 g (70%), mp 145 ºС; Spectral data for
compound 6a, obtained by both methods are the same.
1-Ethyl-1,3-dihydroindol-2-one (5b), 5-hydrazinomethylene-1,3-dimethylpyrimidine-2,4,6-trione
(6c). The mixture of compound 3c (0.655 g, 2 mmol) and hydrazine hydrate (0.1 mL, 2 mmol) in CHCl3 (10
mL) was left for 24 h at rt. Precipitated residue of crude product 6c was filtered and purified by column
chromatography on Al2O3 [eluent – CHCl3 /MeOH (8 : 2), column - d=2 cm, l=20 cm, Rf = 0.65]. The first
colorless fraction was collected and the solvent was evaporated. Recrystallization from EtOH gave
compound 6c ( 0.05 g, 13%), mp 135 °С. Anal. Calcd for C7H10N4O3: C, 42.42; H, 5.09; N, 28.27. Found: С,
1
42.30; H, 5.10; N, 28.40. IR 3310, 3250 (NH2), 3200 (NH), 1680, 1650, 1610 (С=О) cm-1; Н-NMR
(DMSO-d6) δ: 2.90 (s, 6Н, 2NСН3), 5.50 (s, 2Н, NH2), 8.10 (s, 1H, -СН=), 11.15 (br d, J = 10.2 Hz, 1Н,
NH). МS m/z: 198 (М). Filtrate was evaporated in vacuo and residue was recrystallized from
benzene/petroleum ether (bp 40-70 °С) (5:1) to give colorless needles of compound 5b (0.05g, 17%); mp
96 °С (lit. mp 96 ºС).7
5-(Benzylaminomethylene)-1,3-dimethylpyrimidine-2,4,6-trione (6b) Method A: The mixture of
compound 3a (0.31 g, 1 mmol) and benzylamine (0.11 mL, 1 mmol) was refluxed in n-BuOH in the manner
used for preparation of compound 6a (Method A) to give 6b. Yield - 0.238 g (87%).
Method B: The mixture of benzylamine (0.22 mL, 2mmol), 1,3-dimethylpyrimidine-2,4,6-trione (0.312 g, 2
mmol) and triethyl orthoformate (0.4 mL, 2.5 mmol) was refluxed in EtOH in the manner used for
preparation of compound 6a (Method B) to give 6b. Yield - 0.437 g (80%), mp 160 °С. IR 3170 (NH), 1600,
1590 (С-СAr), 1650, 1680 (С=О) cm-1; 1Н-NMR (CDCl3) δ: 3.28 (s, 3H, NCH3), 3.32 (s, 3H, NCH3), 4.63
(d, J = 11.3 Hz, 2H, CH2Ph), 7.20-7.45 (m, 5H, HAr), 8.30 (1H, d, J = 10.2 Hz, =CH-), 10.54 (br s, 1H, NH).
Anal. Calcd for C14H15N3O3: C 61.53; H 5.53; N 15.38. Found: C, 61.59; H, 5.40; N, 15.40.
5-Propylaminomethylenepyrimidine-2,4,6-trione (6d). The mixture of compound 3b (0.29 g, 1 mmol)
and 1-propylamine (0.12 mL, 1.5 mmol) was refluxed in n-BuOH in the manner used for preparation of 6a
(Method A). Filtered residue was recrystallized from DMF to give 6d. Yield - 0.084 g (43%), mp 260 °С. IR
3300, 3260, 3060, 3000 (NH3 ), 1700, 1640, 1610 (С=О), 1590 (С-СAr) cm-1; 1Н-NMR (DMSO-d6) δ: 0.90
+

HETEROCYCLES, Vol. 91, No. 1, 2015
73
(t, J = 7.3 Hz, 3H, CH3CH2CH2), 1.64 (m, 2H, CH3CH2CH2), 3.45 (m, 2H, CH3CH2CH2), 8.10 (d, 1H, J =
10.1 Hz, -CH=), 10.15 (m, 1H, NHCH2CH2CH3), 10.32 (d, 1H, NH), 10.45 (s, 1H, NH). Anal. Calcd for
C8H11N3O3: C, 48.73; H, 5.62; N, 21.31. Found: C, 48.65; H, 5.56; N, 21.44.
3-(5-Hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-ylmethylene-1-methyl-1,3-dihydroindol-2-one (8).
The mixture of compound 1а (1.93g, 10 mmol) and 5-methyl-2-phenyl-2H-pyrazol-3-one 7 (1.74 g, 10
mmol) was refluxed in n-ВuOH (15 mL) for 2 h and then cooled. Yellow crystals were collected by
filtration and recrystallized from benzene, washing by petroleum ether (bp 40-70 °C) to give compound 8 (1
1
g, 30%), mp 150-152 °С. IR 1640 (C=O), 1605, 1550 (C-CAr) cm-1; Н-NMR (CDCl3) δ: 2.40 (s, 3H,
C-CH3), 3.40 (s, 3H, N-CH3), 6.90-7.95 (m, 10H, НAr), 16.10 (s, 1Н, OH). 1Н-NMR (DMSO-d6) δ: 2.15 and
2.40 (s + s, together 3H, C-CH3), 3.40 and 3.75 (s + s, together 3H, N-CH3), 7.00-7.90 (m, 10H, HAr), 16.20
(s, 1H, OH). MS m/z: 331 (M). Anal. Calcd for C20H17N3O2: C, 72.49; H, 5.17; N, 12.68. Found: C, 72.58;
H, 5.18; N, 12.59.
4-{[2-(1H-Indol-3-yl)ethylamino]-methylene}-5-methyl-2-phenyl-2,4-dihydropyrazol-3-one (10).
The mixture of compound 8 (0.33 g, 1 mmol) and tryptamine 9 (0.16 g, 1 mmol) was refluxed in n-BuOH (3
mL) for 3 h. Formed residue was filtered. Recrystallization from n-BuOH with charcoal gave 10 as
colorless crystals. Yield - 0.146 g (42%), mp 198 °С. IR 3373 (NH), 1633(С=О), 1584, 1567 (С-СAr) cm-1;
1Н-NMR (CDCl3) δ: 2.05 (s, 3Н, СН3), 3.15 (t, J = 7.4 Hz, 2Н, NHCH2CH2Ind), 3.70 (m, 2Н, NHCH2CH2
Ind), 7.02-7.28 (m, 5Н, НAr), 7.32-7.43 (m, 4Н, НAr), 7.60 (d, 1Н, Н-4Ind), 7.96 (d, J = 10.1 Hz, 1Н, -CH=),
7.98 (d, J = 9.0 Hz, 1Н, Н-4Ind), 8.15 (s, 1Н, NHInd), 9.90 (br s, 1Н, NH). Anal. Calcd for C21H20N4O: C,
73.23; H, 5.85; N, 16.27. Found: C, 73.36; H, 5.77; N, 16.35.
5-Methyl-4-[(5-methyl-3-oxo-2-phenyl-2,4-dihydro-3H-pyrazol-4-yl)methylene]-2-phenyl-2,4-dihyd-
ro-3H-pyrazol-3-one (11), 3-(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-ylmethylene-1-methyl-
1,3-dihydroindol-2-one (8). The mixture of compound 3а (0.31 g, 1 mmol) and 5-methyl-2-phenyl-
2H-pyrazol-3-one 7 (0.17 g, 1 mmol) was refluxed in chlorobenzene (3 mL) for 4 h and left overnight.
Yellow residue was filtered off and divided by column chromatography on Al2O3 (eluent – CHCl3, column -
d=2 cm, l=70 cm) First fraction (Rf = 0.73) was separated and the solvent was removed in vacuo. Residue
was recrystallized from benzene/petroleum ether (bp 40-70 °C) (1/2) to give compound 11 (0.034 g, 9.5%),
mp 178-180 °C (lit. mp 178-180 °С).8 1Н-NMR (CDCl3) δ: 2.29-2.45 (s, 6Н, 2СН3), 7.20-8.00 (m, 11Н,
10НAr, -СН=), 17.95 (s, 1Н, ОН). MS m/z: 358 (M). The second yellow fraction (Rf = 0.23) was collected
and the solvent was evaporated. The residue was recrystallized from benzene to give compound 8. Yield -
0.032 g (10%); mp 150-152 °C; spectral data are the same as in the described above protocol.

74
HETEROCYCLES, Vol. 91, No. 1, 2015
ACKNOWLEDGEMENTS
Research was carried out according the state task of the Ministry of Education and Science of the Russian
Federation № 4.129.2014/K.
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