HETEROCYCLES

Paper | Regular issue | Vol. 91, No. 1, 2015, pp. 64-75
Received, 22nd November, 2014, Accepted, 17th December, 2014, Published online, 25th December, 2014.
DOI: 10.3987/COM-14-13135

■ Reaction of 2-Chloro-1-alkyl-1H-Indol-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

Konstantin F. Suzdalev,* Maria N. Babakova, Victor G. Kartsev, and Konstantin A. Krasnov

Department of Chemistry, Southern Federal University, Zorge Street 7, Rostov-on-Don, 344090, Russia

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 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.

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 analysis, mass spectra, IR and NMR 1H data have shown that these products include indole nucleus and 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).

Barbituric acid moiety of compounds 3a-d exists in the enol form. 1H-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 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.

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.
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 δ 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 δ 3.40 and 3.78 ppm, and CCH3 group of pyrazolone cycle – by singlets at δ 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).

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).

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.
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, 1580 (C-СAr) cm-1; 1Н-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 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 to give 6a. Yield - 0.12 g (53%), mp 145 °С. IR 3170 (NH), 1630, 1650, 1670 (С=О) cm-1; 1Н-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 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, 42.30; H, 5.10; N, 28.40. IR 3310, 3250 (NH2), 3200 (NH), 1680, 1650, 1610 (С=О) cm-1; 1Н-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 (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 g, 30%), mp 150-152 °С. IR 1640 (C=O), 1605, 1550 (C-CAr) cm-1; 1Н-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.

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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