HETEROCYCLES

Paper | Regular issue | Vol. 89, No. 3, 2014, pp. 641-651
Received, 10th December, 2013, Accepted, 16th January, 2014, Published online, 24th January, 2014.
DOI: 10.3987/COM-13-12910

■ Synthesis of Pyrazoles Based on Functionalized Allenoates

Ilshat M. Sakhautdinov,* Aynur M. Gumerov, Ilnur R. Batyrshin, Akhnaf A. Fatykhov, Kyrill Yu. Suponitsky, and Marat S. Yunusov

Institute of Organic Chemistry, Bioorganic Chemistry, Ufa Research Centre, Russian Academy of Sciences, Prospect Oktyabrya, 71, 450054, Ufa, Russia

Abstract

Regiospecific synthesis of pyrazole-3-carboxylate derivatives by 1,3-dipolar cycloaddition of diazomethane with allenoates in presence of triethylamine is demonstrated. Reaction of allenoates with stearic acid moiety containing diazoketone is explored under ultrasonic conditions. Novel derivatives of pyrazole were achieved in excellent yields.

INTRODUCTION
Among compounds containing nitrogen heterocyclic frameworks, pyrazole is one of most useful building blocks for various biologically active molecules. The biological activities of these compounds have been widely used as antidiabetic, antiviral, antimicrobial, antibacterial, anticancer agents. In addition to their biological importance, pyrazoles play important role as catalysts, molecular magnetic devices and sensors.1-3 1,3-Dipolar cycloaddition reactions of diazo compounds to double and triple bonds are well known and documented.4 In contrast, studies including this methodology with regard to allenes have received much less attention.5 In consideration of biological activity of compounds bearing the pyrazole moiety we planned the synthesis of series of pyrazole derivatives from functionalized allenoates.

RESULTS AND DISCUSSION
Allenoates 2a-f were obtained from N-phthalyl amino acids 1a-c and fatty acids 1d-f. Thionyl chloride was used to convert acids 1a-f to their corresponding acid chlorides. The reaction of acid chlorides with triethylamine produced ketenes, followed by treatment with methyl (triphenylphosphoranylidene)acetate afforded allenoates 2a-f6 (Table 1).

The allenoates 2a-c were treated by excess diazomethane in the presence of equimolar quantity of triethylamine, what lead to formation of isomeric N-methylpyrazoles 4a-с, 5a-с (Table 2). Formation of N-methylpyrazoles observed even in a small excess of diazomethane but the best results were achieved in a six-fold excess.

When the reaction of allene 2a with diazomethane was carried out in equimolar quantities, we obtained 3a in 20% yield. The structure of pyrazole 3a was confirmed by X-ray crystallographic analysis (Figure 1). Molecular structure of 3a has some similarities and differences to 4a that we characterized recently.7

Regioisomeric compounds 4a-c and 5a-c were individually isolated by column chromatography on silica gel. The structure of 4a was determined by X-ray crystallography, and the structure of compound 5a was elucidated by a comparative analysis of the NMR spectra of compounds 4a and 5a using homo- and heteronuclear 2D correlations COSY, NOESY, HSQC, HMBС and 1H-15N-HMBC.7
1,3-Dipolar cycloaddition reaction of diazoketone, obtained from stearic acid, with allenoates 2a-c was carried out under ultrasonic irradiation in benzene at 65 °С during 20 h. The reaction proceeded regioselectively to provide pyrazole derivatives 6a-c (Scheme 1).

However, without ultrasonic treatment in benzene at reflux for 40 h, reaction did not proceed at all. Formation of the N-H insertion products were not observed when obtained pyrazoles 6a-c were treated with excess of diazomethane or diazoketone from stearic acid, that is evidenced by the lack of consumption of the starting materials. It was found that the pyrazoles 7a-c, obtained from allenes 2d-f including stearic, palmitic and caproic acids moieties, behave similarly (Scheme 2).

1,3-Dipolar cycloaddition reaction of diazomethane with allenoates in the presence of triethylamine lead to regiospecific formation of pyrazoles, in case of absence of triethylamine we got the mixture of products that we couldn't isolate and identify. Apparently triethylamine forms complex with diazomethane,8 which regioselectively attacks electrophilic sp-hybridized central carbon atom with the closure into cycle by the nucleophilic carbon that is in α-position to an ester group. The mechanism is shown in Figure 2.

Formation of two N-methylpyrazoles from allenoates 2a-c is explained by the isomerization of pyrazoline into pyrazole derivative that can exist in two tautomeric forms.9,10 Due to formation of hydrogen bond similar to carboxylic acids11 pyrazoles produce dimers, which tend to prototropic tautomerism (Figure 3).

Polarization of N←H+ bond, in the presence of electron acceptor group next to nitrogen atom, promotes N-H insertion of diazomethane similar to known reaction of the О-Н insertion of diazomethane in carboxylic acids. In case of stearic, palmitic and caproic acids moieties containing pyrazoles 7a-c, formation of N-methyl derivatives hindered due to steric factor and, on the other hand, being electron donor substituents, fatty acid moieties reduce N←H+ polarization.
In conclusion, we have demonstrated that the treatment of 1,2-dienoates with diazomethane in the presence of triethylamine gives pyrazole-3-carboxylate derivatives with good regioselectivity. We have succeeded in developing the 1, 3-dipolar cycloaddition reaction of stearic acid moiety containing diazoketone with allenoates under ultrasonic condition, and a series of novel derivatives of pyrazole were obtained.

EXPERIMENTAL
The IR spectra were measured on a Spekord M-80 spectrometer from thin films or suspensions in mineral oil. The 1H and 13C NMR spectra were recorded on a Bruker AM-500 spectrometer at 500.13 and 125.76 MHz, respectively, using tetramethylsilane as internal standard. Correct assignment of signals in the NMR spectra of compounds was achieved using homo- and heteronuclear 2-D correlation techniques: COSY, NOESY, HSQC, HMBС, 1H-15N-HMBC. The progress of reactions was monitored by thin-layer chromatography on Sorbfil PTSKh-AF-A plates; spots were detected by UV irradiation, treatment with iodine vapor, or spraying with a solution of ninhydrin or p-methoxybenzaldehyde with subsequent heating to 100–120 °C. The mass spectra were obtained on a Shimadzu LCMS-2010EV instrument. Elemental analysis was carried out using a EURO EA-3000 CHN element analyzer. Ultrasound was generated using a UZDN-2T setup with an operating frequency of 22 kHz. X-Ray diffraction measurements were carried out with Bruker APEX-II CCD diffractometer at 100K. Melting points were measured with a Buetius apparatus. The products were isolated by column chromatography on silica gel (40–100 and 100–160 μm; Chemapol).
General procedure for the synthesis of the allenoates 2a-f by Wittig reaction 1 g of an acid was dispersed in 10 mL of anhydrous benzene, five-fold excess of thionyl chloride was added, and the mixture was heated for 3 h under reflux. The solvent and excess thionyl chloride was distilled off on a rotary evaporator, and the residue (phthalimidoacetyl chloride) was used without additional purification. An equimolar amount of triethylamine was added to a solution of methyl (triphenyl-λ5- phosphanylidene)acetate in THF, the mixture was cooled to -10 °C, and a cold solution of phthalimidoacetyl chloride was slowly added dropwise. The mixture was stirred for 0.5 h and kept at 0 °C for 6 h, the precipitate was filtered off, the solvent was distilled off from the filtrate, and the residue was subjected to column chromatography on silica gel using petroleum ether–EtOAc (4 : 1) as eluent.
Methyl 4-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)buta-2,3-dienoate (2a). Yield 0.75 g (63%), white crystals, mp 95–97 °C. IR spectrum, ν cm–1: 1782, 1763. 1H NMR spectrum (CDCl3), δ ppm: 3.72 s (3H, CH3), 6.21 d (1H, CH, J = 5.1 Hz), 7.25 d (1H, CH, J = 5.1 Hz), 7.74–7.83 m (4H, C6H4). 13C NMR spectrum (CDCl3), δ ppm: 52.62 (CH3), 91.77 (CH), 96.71 (CH), 123.77 (CHarom), 131.76 (Carom), 134.67 (CHarom), 164.49 (C=O), 164.74 (C=O), 210.03 (=C=); MS: m/z 244 [MH]+, 243 [M]-. Anal. Calcd for C13H9NO4 (243.21): C 64.20; H 3.73; N 5.76; O 26.31. Found: C 64.21; H 3.74; N 5.73.
Methyl 5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)penta-2,3-dienoate (2b). Yield 0.88 g (75%), white crystals, mp 87-88 °C. IR spectrum, ν сm-1: 1709, 1771, 1964. 1H NMR (CDCl3), δ ppm: 3.63 s (3Н, СН3); 4.36 m. (2H, CH2), 5.64 d.d. (1H, CH, J = 6.2, 2.9, 2.6 Hz), 5.74 m (1H, CH), 7.66-7.81 m (4Н, С6Н4). 13C NMR (CDCl3), δ ppm: 35.09 (CH2), 52.11 (СH3), 90.43 (СНallene.), 91.40 (СНallene.), 123.39 (СНarom.), 131.91 (Сarom.), 134.15 (СНarom.), 165.36 (С=O), 167.39 (С=О), 212.37 (=С=). MS: m/z 258 [MH]+, 257 [M]-. Anal. Calcd for С14Н11NO4 (257.07): С 65.37; Н 4.31; N 5.44; O 24.88. Found: С 65.35; Н 4.29; N 5.44.
Methyl 6-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)hexa-2,3-dienoate (2c). Yield 1.01 g (87%), white crystals, mp 102-104 °C. IR, ν сm-1: 1701, 1765, 1952. 1H NMR (CDCl3), δ ppm: 2.59 m (2H, CH2), 3.54 s (3Н, СН3); 3.87 t (2H, CH2, J = 7 Hz), 5.52 m (1H, CH), 5.65 m (1H, CH), 7.68-7.83 m (4Н, С6Н4). 13C NMR (CDCl3), δ ppm: 26.70 (CH2), 36.77 (CH2), 51.76 (СH3), 88.39 (СНallene.), 91.69 (СНallene.), 123.21 (СНarom.), 131.97 (Сarom.), 133.93 (СНarom.), 165.96 (С=O), 168.11 (С=О), 212.44 (=С=). MS: m/z 272 [MH]+, 271 [M]-. Anal. Calcd for С15Н13NO4 (271.27): С 66.41; Н 4.83; N 5.16; O 23.59. Found: С 66.39; Н 4.81; N 5.16.
Methyl icosa-2,3-dienoate (2d). Yield 0.88 g (77%), yellow oil. IR, ν сm-1: 1724, 1961, 2852, 2922. 1H NMR (CDCl3), δ ppm: 0.88 t (3Н, СН3, J = 7.2); 1.25 m (26Н, 13СН2), 1.63 m (2Н, СН2), 3.73 s (3Н, СН3), 4.45 m (2H, CH2), 5.57 m (1Н, =СН, J = 7.0), 5.63 d (1Н, =СН, J = 7.0). 13C NMR (CDCl3), δ ppm: 14.07 (СH3), 22.66 (СН2), 27.43 (СН2), 28.7 (СН2), 28.95 (СН2), 29.33 (СН2), 29.67 (9СН2), 31.91 (СН2), 51.83 (СН3), 87.7 (=СНallene), 95.44 (=СНallene), 167.2 (С=О), 212.41 (=С=). MS: m/z 323 [MH]+, 322 [M]-. Anal. Calcd for С21Н38O2 (322.53): С 78.2; Н 11.88; O 9.92. Found: С 78.2; Н 11.88.
Methyl octadeca-2,3-dienoate (2e). Yield 0.98 g (85%), yellow oil. IR, ν сm-1: 1961, 61. 1H NMR (CDCl3), δ ppm: 0.85 t (3Н, СН3, J = 6.7); 1.14-1.23 m (22Н, 2СН2), 1.38-1.46 m (2Н, СН2), 2.08-2.14 m (2Н, СН2), 3.59 s (3Н, СН3), 5.53 s (1Н, =СН), 5.58 s (1H, =СН). 13C NMR (CDCl3), δ ppm: 14.8 (СH3), 22.62 (СН2), 25.74 (СН2), 28,64 (СН2), 28,79 (СН2), 28,91 (СН2), 29.09 (СН2), 29.3 (СН2), 29.48 (5СН2), 31.88 (СН2), 51,8 (OСН3), 87.85 (=СНalk), 95.45 (СН), 166.58 (С=О), 212.32 (=С=). MS: m/z 295 [MH]+, 294 [M]-. Anal. Calcd for С19Н34O2 (294.47): С 77.5; Н 11.64; O 10.87. Found: С 77.51; Н 11.65; O 10.84.
Methyl octa-2,3-dienoate (2f). Yield 0.88 g (66%), yellow oil. IR, ν сm-1: 1961, 61. 1H NMR (CDCl3), δ ppm: 0.87 t (3Н, СН3, J = 6,5); 1.21-1.48 m (4Н, 2СН2), 2.15 m (2Н, СН2), 3.74 s (3Н, СН3), 5.64 s (1Н, =СН), 6.55 s (1H, =СН). 13C NMR (CDCl3), δ ppm: 13.64 (СH3), 21.82 (СН2), 25.74 (СН2), 30.67 (СН2), 51.86 (OСН3), 87.78 (=СНalk), 95.36 (СН), 167.8 (С=О), 211.8 (=С=). MS: m/z 155 [MH]+, 154 [M]-. Anal. Calcd for С9Н14O2 (154,21): C 70.10; Н 9.15; O 20.75. Found: С 70.12; Н 9.15.
General procedure for the synthesis of the pyrazoles 3a, 4a-c, 5a-c, 7a-c from allenoates 2a-f A cold solution (0 °C) of 0.5 g of allenoates 2a-f in 20 mL of CH2Cl2 was combined with an equimolar amount of triethylamine, and a six-fold excess of a freshly prepared solution of diazomethane in CH2Cl2 was added dropwise. The reaction mixture was stirred on a magnetic stirrer for 6 h at room temperature. The precipitate formed was separated by filtration, the solvent was removed, and the reaction products were separated by column chromatography on silica gel (eluent: petroleum ether/EtOAc 4/1).
Methyl 4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1H-pyrazole-3-carboxylate (3a). Yield 0.12 g (20%), mp 196-198 °C. IR, ν сm-1: 1107, 1362, 1377, 1457, 1694. 1H NMR (d6-DMSO), δ ppm: 3.86 s (3Н, CH3O); 4.90 s (2H, CH2), 7.87 s (1H, =CHN), 7.85-7.89 m (2H, C6H2), 7.91-7.94 m (2H, C6H2), 13.43 s (1H, NH). 13C NMR (CDCl3), δ ppm: 33.24 (СH2), 51.92 (CH3O), 119.75 (С), 123.57 (СHarom.), 129.69 (=CHN), 132.27 (Сarom.), 134.80 (СHarom.), 139.41(С=N), 163.35 (O=СO), 168.05 (O=СN). 15N NMR (CDCl3), δ ppm: 121 (N), 164 (NC=O), 213 (NH). MS: m/z 286 [MH]+, 285 [M]-. Anal. Calcd for С14Н11N3O4 (285.25): С 58.95; Н 3.89; N 14.73; O 22.44. Found: С 58.95; Н 3.89; N 14.73.
X-Ray diffraction data of 3a. Monoclinic, space group P21/c: a = 12.9491(13)Å, b = 12.6702(13)Å, c = 7.9024(8)Å, β = 90.524(2)°, V = 1296.5(2)Å3, Z = 4, M = 285.26, dcalc = 1.461 g cm-3, wR2 = 0.1087 calculated on F2hkl for all 3435 independent reflections with 2θ<58°, (GOF = 1.019 R = 0.0427 calculated on Fhkl for 2711 reflections with I>2σ(I)). Crystallographic data (excluding structure factors) for the structure have been deposited at the Cambridge Crystallographic Data Centre (CCDC) as supplementary publication No. CCDC 858681.
Methyl 4-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-methyl-1H-pyrazole-5-carboxylate (4b). Yield 0.31 g (51%), mp 110-112 °C. IR, ν сm-1: 1125, 1286, 1396, 1466, 1713. 1H NMR (CDCl3), δ ppm: 3.02 t (2H, CH2, J = 7.6, 7.4 Hz), 3.85 t (2H, CH2N, J = 7.6, 7.4 Hz), 3.91 s (3Н, CH3O), 4.08 s (3H, CH3N), 7.29 s (1H, CH=N), 7.71-7.75 m (2H, C6H2), 7.76-7.79 m (2H, C6H2). 13C NMR (CDCl3), δ ppm: 24.40 (СH2), 38.22 (СH2N), 40.29 (СH3N), 51.89 (CH3O), 122.83 (С), 123.16 (СHarom.), 129.76 (=СN), 131.97 (Сarom.), 133.92 (СHarom.), 138.62 (CH=N), 160.60 (O=СO), 168.10 (O=СN). 15N NMR (CDCl3), δ ppm: 19 (N), 163 (Nphtalyl.), 207 (NCH3). MS: m/z 314 [MH]+, 213 [M]-. Anal. Calcd for С16Н15N3O4 (313.31): С 61.34; Н 4.83; N 13.41; O 20.43. Found: С 61. 33; Н 4.83; N 13.41.
Methyl 4-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-methyl-1H-pyrazole-3-carboxylate (5b). Yield 0.15 g (24%), mp 153-154 °C. IR, ν сm-1: 1119, 1273, 1385, 1466, 1705. 1H NMR (CDCl3), δ ppm: 3.14 t (2H, CH2, J = 7.6, 7.1 Hz), 3.89 s (3Н, CH3O); 3.91 s (3H, CH3N), 3.95 t (2H, CH2N, J = 7.6, 7.1 Hz), 7.33 s (1H, CHN), 7.70-7.73 m (2H, C6H2), 7.75-7.78 m (2H, C6H2). 13C NMR (CDCl3), δ ppm: 23.38 (СH2), 38.10 (СH2N), 39.64 (СH3N), 51.77 (CH3O), 121.71 (С), 123.17 (СHarom.), 131.00 (СHN), 131.85 (Сarom.), 133.88 (СHarom), 140.47 (C=N), 162.81 (O=СO), 168.16 (O=СN). 15N NMR (CDCl3), δ ppm: 18 (N), 163 (Nphtalyl.), 205 (NCH3). MS: m/z 314 [MH]+, 213 [M]-. Anal. Calcd for С16Н15N3O4 (313.31): С 61.34; Н 4.83; N 13.41; O 20.43. Found: С 61. 34; Н 4.83; N 13.41.
Methyl 4-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]-1-methyl-1H-pyrazole-5-carboxylate (4c). Yield 0.16 g (27%), mp 74-75 °C. IR, ν сm-1: 1119, 1293, 1614, 1721, 1765. 1H NMR (CDCl3), δ ppm: 1.95-1.97 m (2H, CH2), 2.73 t (2H, CH2, J = 8.0, 7.3 Hz), 3.73 t (2H, CH2, J = 6.6, 4.7 Hz), 3.85 s (3Н, CH3O); 4.09 s (3H, CH3N), 7.37 s (1H, CHN), 7.70-7.72 m (2H, C6H2), 7.83-7.85 m (2H, C6H2). 13C NMR (CDCl3), δ ppm: 22.63 (СH2), 29.10 (СH2), 37.73 (СH2N), 40.27 (СH3N), 51.66 (CH3O), 123.16 (СHarom.), 127.31 (С), 132.09 (Сarom.), 133.15 (=СN), 133.97 (СHarom.), 138.02 (CHN), 160.82 (O=СO), 168.33 (O=СN). MS: m/z 328 [MH]+, 227 [M]-. Anal. Calcd for С17Н17N3O4 (327.33): С 62.38; Н 5.23; N 12.84; O 19.55. Found: С 62.39; Н 5.20; N 12.81.
Methyl 4-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]-1-methyl-1H-pyrazole-3-carboxylate (5c). Yield 0.13 g (21%), white powder, mp 87-88 °C. IR, ν сm-1: 1125, 1279, 1655, 1726, 1765. 1H NMR (CDCl3), δ ppm: 2.12-2.14 m (2H, CH2), 3.22 t (2H, CH2, J = 7.6, 7.3 Hz), 3.96 s (3Н, CH3O), 4.02 s (3H, CH3N), 4.07 t (2H, CH2, J = 6.4, 3.9 Hz), 7.69-7.72 m (2H, C6H2), 7.76 s (1H, CHN), 7.81-7.83 m (2H, C6H2). 13C NMR (CDCl3), δ ppm: 29.69 (СH2), 33.23 (СH2), 39.24 (СH3N), 39.73 (СH2N), 53.09 (CH3O), 123.29 (СHarom.), 124.24 (С), 132.06 (Сarom.), 134.07 (СHN), 134.09 (СHarom.), 139.13 (C=N), 160.56 (O=СO), 168.09 (O=СN). MS: m/z 328 [MH]+, 227 [M]-. Anal. Calcd for С17Н17N3O4 (327.33): С 62.38; Н 5.23; N 12.84; O 19.55. Found: С 62.40; Н 5.22; N 12.84.
Methyl 4-heptadecyl-1H-pyrazole-3-carboxylate (7a). Yield 0.34 g (60%), white oil. IR, ν сm-1: 1697.36, 2868, 2936, 3238. 1H NMR (CDCl3), δ ppm: 0.9 t (3Н, СН3, J = 6,7); 1.27-1.38 m (28Н, 14СН2), 1.61 m (2Н, СН2), 2.77 m (2Н,СН2), 3.97 s (3H, CH3), 7.59 s (1Н, =СН), 12.87 s (1Н, = N Н). 13C NMR (CDCl3), δ ppm: 14.11 (СH3), 22.69 (СН2), 24,44 (СН2), 29.36 (СН2), 29.43 (СН2), 29.47 (СН2), 29.65 (СН2), 29.69 (8СН2), 30.42 (СН2), 31.92 (СН2), 51.65 (OСН3), 125.43 (=СНalk), 130.5 (=СН), 133.26 (С= N), 162.73 (С=О). MS: m/z 365 [MH]+, 364 [M]-. Anal. Calcd for С22Н40N2O2 (364.57): С 72.48; Н 11.06; N 7.68; O 8.78. Found: С 72.46; Н 10.05; N 7.65.
Methyl 4-pentadecyl-1H-pyrazole-3-carboxylate (7b). Yield 0.33 g (58%), white oil. IR, ν сm-1: 1697, 2868, 2936, 3238. 1H NMR (CDCl3), δ ppm: 0.7 t (3Н, СН3, J = 7.2); 1.25-1.31 m (24Н, 12СН2), 1.60 m (2Н, СН2), 2.75 m (2Н, СН2), 3.97 s (3H, ОCH3), 7.55 s (1Н, =СН), 12.85 s (1Н, N Н). 13C NMR (CDCl3), δ ppm: 14.11 (СH3), 22.69 (СН2), 24.05 (СН2), 29.35 (СН2), 29.42 (СН2), 29.60 (СН2), 29.65 (СН2), 29.68 (СН2.), 30.26 (СН2), 31.92 (СН2), 51.93 (OСН3), 125 (=СНalk), 129.88 (=СН), 133.61 (С= N), 162.073 (С=О). MS: m/z 337 [MH]+, 336 [M]-. Anal. Calcd for С20Н36N2O2 (336.51): С 71.38; Н 10.78; N 8.32 О 9.51. Found: С 71.38; Н 10.75; N 8.32.
Methyl 4-pentyl-1H-pyrazole-3-carboxylate (7c). Yield 0.13 g (20%), yellow oil. IR, ν сm-1: 1961, 61. 1H NMR (CDCl3), δ ppm: 0.93 t (3Н, СН3, J = 7.5); 1.46 m (4Н, 2СН2), 1.63 m (2Н, СН2), 2.77 m (2Н, СН2), 3.18 s (3Н, ОСН3), 7.57 s (1H, =СН), 9.02 s (1Н, NH). 13C NMR (CDCl3), δ ppm: 14.01 (СH3), 22.42 (СН2), 24.07 (СН2), 29.9967 (СН2), 31.52 (СН2), 51.78 (OСН3), 125.1 (=СНalk), 133.85 (=СН), 135.77 (С=N), 162.1 (С=О). MS: m/z 197 [MH]+, 196 [M]- Anal. Calcd for С10Н16N2O2 (196.25): С 61.20; Н 8.22; N 14.27; О 16.31. Found: С 61.22; Н 8.21; N 14.23.
1-Diazononadecan-2-one. 1 g (3.5 mmol) of stearic acid , was dispersed in 10 mL of anhydrous benzene, five-fold excess of thionyl chloride was added, and the mixture was heated for 3 h under reflux. The solvent and excess thionyl chloride were removed under vacuum. The stearoyl chloride was dissolved in THF (15 mL), solution was stirred at 0 °C and diazomethane, obtained from nitrosomethylurea (26 mmol) in CH2Cl2 (26 mL), was slowly added dropwise. The mixture was stirred until gas no longer evolved. The solvent was removed under vacuum. The resulting crude products were purified by column chromatography using CH2Cl2 as eluent. Yield 0.89 g (82%), mp 52–53 °C. IR, ν сm-1: 1620, 2122, 2849, 2918, 2955. 1H NMR (CDCl3), δ ppm: 0.88 t (3H, CH3, 3J = 5.7 Hz), 1.15-1.41 m (28H, 14CH2), 1.59-1.74 m (2H, CH2), 2.25-2.42 m (2H, CH2), 5.23 s (1Н, СНN2). 13C NMR (CDCl3), δ ppm: 14.06 (CH3), 22.65 (СH2), 25.19 (СH2), 29.20 (СH2), 29.33 (СH2), 29.43 (СH2), 29.65 (СH2), 31.90 (СH2), 41.10 (СH2), 54.07 (СHN2), 195.23 (C=O). Anal. Calcd for С19Н36N2O: С 73.97; Н 11.76; N 9.08. Found: С 74.15; Н 11.71; N 9.12.
General procedure for the synthesis of the pyrazoles 6a-c from allenoates 2a-c. Dry 50 ml flask was charged with allene (1mmol), 1-diazononadecan-2-one (1 mmol) and benzene (10 mL). The mixture was sonicated at 68 °C for 20 h (monitored by TLC). After completion of the reaction, the solvent was removed under vacuum. The resulting crude products were purified by column chromatography using petroleum ether – EtOAc (7:3) as eluent.
Methyl 4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-5-stearoyl-1H-pyrazole-3-carboxylate (6a). Yield 0.28 g (51%), mp 98-99 °C, IR, ν, сm-1: 1686, 1709, 2918. 1H NMR (CDCl3), δ ppm: 0.92 t (3H, CH3, 3J = 6.9 Hz), 1.19-1.40 m (28H, 14CH2), 1.71-1.79 m (2H, CH2), 3.09 t (2H, CH2, 3J = 7.7 Hz), 3.90 с (3Н, СН3), 5.40 s (2Н, СН2N), 7.73-7.74 m (2H, C6H2), 7.83-7.85 m (2H, C6H2), 11.82 s (1H, NH). 13C NMR (CDCl3), δ ppm: 14.13 (CH3), 22.69 (СH2), 23.59 (СH2), 29.29 (СH2), 29.36 (СH2), 29.50 (СH2), 29.52 (СH2), 29.66 (СH2), 31.70 (СH2), 31.92 (СH2), 39.88 (СH2), 52.63 (СH2N), 120.05 (CCH2), 123.17 (СHarom.), 132.01 (Сarom.), 132.02 (CCOOCH3), 133.83 (СHarom.), 149.56 (C-C=O), 159.61 (O=СO), 167.84(O=СN), 197.43 (С=O). MS: m/z 552 [MH]+, 551 [M]-. Anal. Calcd for С32Н45N3O5 (551.72): С 69.66; Н 8.22; N 7.62; О 14.50. Found: С 69.68; Н 8.20; N 7.62.
Methyl 4-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-stearoyl-1H-pyrazole-3-carboxylate (6b). Yield 0.38 g (67%), mp 66-67 °C. IR, ν, сm-1: 1672, 1715, 2851. 1H NMR (CDCl3), δ ppm: 0.86 t (3H, CH3, 3J = 6.5 Hz), 1.12-1.32 m (28H, 14CH2), 1.53-1.61 m (2H, CH2), 2.96 t (2H, CH2, 3J = 7.5 Hz), 3.44 t (2H, CH2, 3J = 7.5 Hz), 3.74 s (3Н, СН3), 4.00 t (2Н, СН2N, 3J = 6.5 Hz), 7.64-7.66 m (2H, C6H2), 7.71-7.73 m (2H, C6H2), 11.78 s (1H, NH). 13C NMR (CDCl3), δ ppm: 14.12 (CH3), 22.68 (СH2), 22.90 (СH2), 23.88 (СH2), 29.28 (СH2), 29.35 (СH2), 29.52 (СH2), 29.69 (СH2), 31.90 (СН2), 35.12 (СH2), 37.82 (СН2N), 39.58 (СH2СO), 52.25 (CH3), 123.04 (CHarom.), 124.06 (CCH2), 132.03 (Сarom.), 132.95 (CCOOCH3), 133.73 (СHarom.), 148.85 (CC=O), 160.03 (O=СO), 168.19 (O=СN), 197.49 (С=O). MS: m/z 566 [MH]+ 565 [M]-. Anal. Calcd for С33Н47N3O5 (565.74): С 70.06; Н 8.37; N 7.43; О 14.14. Found: С 69.98; Н 8.35; N 7.42.
Methyl 4-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]-5-stearoyl-1H-pyrazole-3-carboxylate (6c). Yield 0.25 g (43%), mp 60-61 °C. IR, ν сm-1: 1689, 1724, 2925. 1H NMR (CDCl3), δ ppm: 0.90 t (3H, CH3, 3J = 6.9 Hz), 1.18-1.40 m (28H, 14CH2), 1.68-1.74 m (2H, CH2), 2.01-2.03 m (2H, CH2), 3.04 t (2H, CH2, 3J = 7.5 Hz), 3.16 t (2H, CH2, 3J = 7.7 Hz), 3.81 t (2H, CH2, 3J = 7.0 Hz), 3.89 s (3Н, СН3), 7.74-7.76 m (2H, C6H2), 7.88-7.89 m (2H, C6H2), 11.77 s (1H, NH). 13C NMR (CDCl3), δ ppm: 14.13 (CH3), 21.02 (СH2), 22.70 (СH2), 23.91 (СH2), 28.99 (СH2), 29.31 (СH2), 29.36 (СH2), 29.54 (СH2), 29.71 (СH2), 31.92 (СH2), 37.83 (СН2N), 39.67 (СH2СO), 52.25 (CH3), 123.17 (CHarom.), 123.21 (Carom.), 123.54 (CCOOCH3), 127.05 (ССН2), 133.80 (СHarom.), 148.43 (CC=O), 160.14 (O=СO), 168.46 (O=СN), 197.09 (С=O). MS: m/z 580 [MH]+ 579 [M]-. Anal. Calcd for С33Н47N3O5 (579.77): С 70.44; Н 8.52; N 7.25; О 13.80. Found: С 70.42; Н 8.55; N 7.25.

ACKNOWLEDGEMENTS
This study was performed under financial support by the President of the Russian Federation (program for support of leading scientific schools, project no. NSh-7014.2012.3) and by the Russian Foundation for Basic Research Competition «a» 14-03-00180.

References

1. J. Elguero, P. Goya, N. Jagerovic, and A. M. S. Silva, Targets in Heterocyclic Systems, ed. by O. A. Attanasi and D. Spinelli, Italian Society of Chemistry, Rome, 2002, 6, 52.
2. A. A. Bekhit, H. M. Ashour, and A. A. Guemei, Arch. Pharm., 2005, 338, 167. CrossRef
3. A. Ramadan, A. Eltaib, and U. Kamal, Tetrahedron, 2012, 68, 1637. CrossRef
4. (a) G. Maas, In Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry toward Heterocycles and Natural Products; Wiley: Hoboken, NJ, 2003; (b) M. Kissane, S. E. Lawrence, and A. R. Maguire, Org. Biomol. Chem., 2010, 8, 2735; CrossRef (c) J. L. Ruano, M. T. Peromingo, M. Alonso, A. Fraile, M. R. Martin, and A. Tito, J. Org. Chem., 2005, 70, 8942; CrossRef (d) M. Yu. Ovchinnikov, T. A. Yangirov, A. N. Lobov, R. M. Sultanova, and S. L. Khursan, Int. J. of Chem. Kinet., 2013, 45, 499. CrossRef
5. N. Krause and A. S. K. Hashmi, Modern Allene Chemistry, WILEY-VCH Verlag GmbH & Co. KGaA: Weinheim, 2004, 675.
6. (a) R. W. Lang and H. J. Hansen, Helv. Chim. Acta, 1979, 62, 1025; CrossRef (b) R. W. Lang and H. J. Hansen, Helv. Chim. Acta, 1980, 63, 438; CrossRef (c) R. W. Lang and H. J. Hansen, Org. Synth., 1984, 62, 202.
7. I. M. Sakhautdinov, I. R. Batyrshin, A. A. Fatykhov, V. M. Yumabaeva, K. Yu. Suponitsky, M. Yu. Antipin, and M. S. Yunusov, J. Struct. Chem., 2013, 54, 383. CrossRef
8. R. K. Palakodety, R. S. Empati, and M. Florence, Tetrahedron Lett., 2008, 49, 6768. CrossRef
9. E. Consuelo, B. Mercedes, M. Rosa, S. Dionisia, and E. José, The Open Org. Chem. J., 2008, 2, 10.
10. G. Bekker, An Introduction to the Electronic Theory of Organic Reactions, Moscow, 1977, 164.
11. J. Steed and J. Atwood, Supramolecular Chemistry, J. Wiley & Sons: Chichester, 2009, 29. CrossRef