Научная статья на тему 'SYNTHESIS OF PYRAZOLES BASED ON α, β-UNSATURATED KETONES'

SYNTHESIS OF PYRAZOLES BASED ON α, β-UNSATURATED KETONES Текст научной статьи по специальности «Химические науки»

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Ключевые слова
pyrazole / ketone / hydrazines / chalcone / piperidine / acid catalysis. / пиразол / кетон / гидразины / халкон / пиперидин / кислотный катализ.

Аннотация научной статьи по химическим наукам, автор научной работы — Ibraev M. K., Nurkenov O.A., Rakhimberlinova Zh.B ., Takibayeva A.T., Isabayeva M.B.

The article presents a method for obtaining pyrazoles based on α,β-unsaturated ketones. The structure of the compounds was confirmed by IR, NMR, and two-dimensional spectroscopy NMR HMQC (1H-13C)

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СИНТЕЗ ПИРАЗОЛОВ НА ОСНОВЕ α, β-НЕНАСЫЩЕННЫХ КЕТОНОВ

В статье представлена методика получения пиразолов на основе α,β-ненасыщенных кетонов. Структура соединений подтверждена методами ИК, ЯМР, а также методом двумерной спектроскопии ЯМР HMQC (1H-13C)

Текст научной работы на тему «SYNTHESIS OF PYRAZOLES BASED ON α, β-UNSATURATED KETONES»

«етуушшим-шишаи» #щ1©ш, жш / chemical sciences

65

UDK 547 (075.8)

Ибраев М.К.

Д.х.н., профессор Карагандинского технического университета им. А.С. Сагинова

г. Караганда Нуркенов О.А.

Д.х.н., профессор ТОО «Институт органического синтеза иуглехимии РК»

Рахимберлинова Ж.Б.

к.х.н. Карагандинского технического университета им. А.С. Сагинова

Такибаева А. Т.

к.х.н. Карагандинского технического университета им. А.С. Сагинова

Исабаева М.Б.

к.х.н., доцент Карагандинского медицинского университета DOI: 10.24412/2520-6990-2022-15138-65-69 СИНТЕЗ ПИРАЗОЛОВ НА ОСНОВЕ а, Р-НЕНАСЫЩЕННЫХ КЕТОНОВ

Ibraev M. K.

Doctor of Chemical Sciences, Professor of the Karaganda Technical University named after A.S. Saginov,

Karaganda Nurkenov O.A.

Doctor of Chemical Sciences, Professor ofLLP "Institute of Organic Synthesis and Carbon Chemistry of the КК"

Rakhimberlinova Zh.B. Ph.D. of Karaganda Technical University named after A.S. Saginov

Takibayeva A. T.

Candidate of Chemical Sciences of Karaganda Technical University named after A.S. Saginov

Isabayeva M.B.

PhD, Associate Professor of Karaganda Medical University SYNTHESIS OF PYRAZOLES BASED ON а, P-UNSATURATED KETONES Аннотация

В статье представлена методика получения пиразолов на основе а,в-ненасъщенных кетонов. Структура соединений подтверждена методами ИК, ЯМР, а также методом двумерной спектроскопии ЯМР HMQC ('H-13C) Abstract

The article presents a method for obtaining pyrazoles based on afl-unsaturated ketones. The structure of the compounds was confirmed by IR, NMR, and two-dimensional spectroscopy NMR HMQC (1H-13C)

Ключевые слова: пиразол, кетон, гидразины, халкон, пиперидин, кислотный катализ. Key words: pyrazole, ketone, hydrazines, chalcone, piperidine, acid catalysis.

The cyclocondensation reaction of hydrazines to a,p-unsaturated ketones is an important method for the synthesis of 1,2-azoles.Pyrazoles that attract attention as biologically active substances. they exhibit the properties of analgesics and inhibitors of platelet aggregation, have a strong antibacterial and anesthetic effect [1,2]. N-substituted pyrazoles are used as nonsteroidal anti-inflammatory agents (lonazolac drug), and are also used in the treatment of rheumatoid arthritis (pirazolac drug).

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The presence of unsaturated compounds of the electron acceptor carbonyl group in the molecules greatly facilitates the attack of nucleophilic reagents. Conjugation with carbonyl manifests itself in cases when the substituent standing next to it has n-bonds, filled, vacant or semi-vacant p-orbitals located at the carbon atom in the state of sp2- or sp-hybridization. Electron displacement is carried out for both double and triple bonds, however, in the second case, due to the greater mobility of the electrons of acetylene carbon atoms, there is a greater polarization [3, 4].

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It is known that hydrazines are stronger nucleophiles compared to primary and secondary amines. Depending on the conditions of the reaction, the reagent attack can proceed both by the carbonyl group (1,2-addition) and by the double or triple bond (3,4-addition) of unsaturated ketones. The different

regional orientation of the interaction of 1,3-disubstituted propenones with hydrazines of organic acids was noted in the monograph by S. L. Desenko and V. D. Orlov [4]. It has been shown that under conditions of acid catalysis, the addition of acylhydrazines to chalcone proceeds exclusively along the carbonyl

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CHEMICAL SCIENCES / «COLyOMUM-JMTMaL» 2022

group 2, and the reaction in piperidine leads to the formation of adducts along the double bond 1.

The resulting hydrazones 1 can easily be isomerized into pyrazoles 8. This was observed by the authors of, in the reaction of chalcons with a small

excess of arylhydrazines under the action of catalytic

amounts of acetic acid in ethyl alcohol. The yield of 3-aryl-1 -R- 5-phenyl-4,5 -dihydro - lH-pyrazo les 3

products in this case was 72-85% [5, 6].

In [5-6], the interaction of halcones 4-6 with hydrazine hydrate was studied. It was found that when boiling halcones with hydrazine hydrate in ethanol, in-

tramolecular cyclocondensation of the intermediate hydrazone occurs with the formation of corresponding py-razole derivatives 7-9.

The structure of compounds 7-9 was confirmed by IR and NMR spectroscopy. Thus, in the IR spectra of pyrazolines 7-9, the medium intensity band of the C=N group of the pyrazolone core in the region of 1601-1605 cm -1 is clearly manifested.

In the NMR1H spectrum of 4-(5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazole-3-yl)-benz-1,3-diol (9), signals of methylene (5(Ha)=2,84 m.d., 5(№)=3,43 m.d.) and methine (4,68 m.d.) groups of the five-membered nitrogen cycle.

A three-proton signal with a chemical shift of 3.70 m.d. can be attributed to protons of the methoxy substituent of the benzene ring. In the low-field part of the spectrum (6.27-7.32 m.d.), the resonance of CH -groups of aromatic systems was noted.

In the NMR 13C spectrum of compound 9, the secondary and tertiary carbon atoms of the diazo cyclic system give signals at 41,59 and 61,86 ppm, respectively. The signal of the methoxy group is observed at 55,62 m.d.

Equivalent carbon atoms of the methoxyphenyl radical resonate at 114,35 and 128,39 m.d. signals with chemical shifts of 102,92, 107,50 and 129,40 m.d. can be attributed to the methine groups of the aromatic ring. Quaternary atoms give signals at 109,44, 134,76, 153,87, 159,09, 159,74 and 162,10 m.d.

Continuing research on the synthesis of pyrazolone compounds, the interaction of N-cinnamoyl derivatives of anabazine and cytisine 10, 11 with hydrazine hydrate was carried out. It was found that the

«<g©yl©(mum~joy©mal» 2022 / CHEMICAL sciences

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interaction of acrylamide derivatives 10, 11 with hydrazine hydrate in ethanol leads to the formation of corresponding pyrazole compounds 12, 13, possibly formed as a result of intramolecular cyclocondensation of hydrazones of N-cinnamoyl derivatives 10 and 11.

NMR spectroscopic study of the obtained pyrazole derivatives 12 and 13 showed that anabazine and cytisine fragments mainly retain their regions of chemical shifts in the and 13C NMR spectra during the transition from cinnamoyl derivatives to pyrazole.

Thus, in the 1H NMR spectrum of compound (13), cytisine protons H-18 appeared in the strongest-field

region of the spectrum at 1,87-1,99 m.d. with a two-proton multiplet. In the broadband multiplet at 2,253,33 m.d., cytisine protons H-8, H-16 and H-7 and pyrazole protons H-4 resonated with a six-proton multiplet.

The next five-proton multiplet at 3.58-4.63 m.d. housed cytisine protons H-17 and H-9 and another pyrazole proton H-5. At 6.11-6.20 m.d., protons of the H-12 and H-14 pyrazole cycle resonated with a two-proton multiplet. The seven-proton multiplet at 6.977.64 m.d. housed cytisine proton H-13, protons of the amino group H-1 and aromatic protons H-20-24.

In the 13C NMR spectrum of compound (13), the signals of carbon atoms of cytisine rings are observed at 25.80 (C-18), 27.52 (C-8), 33.76 (C-16), 48.75 (C-9), 49.18 (C-7), 51.21 (C-17), 105.27 (C-14), 116.31 (C-12), 139.30 (C-13), 150.19 (C-15) and 170.85 (C-11) m.d. Signals with chemical shifts at 34.79, 52.82 and 162.64 m.d. correspond to carbon atoms C-4, C-5 and C-3, respectively. Aromatic ring carbon appeared at 126.32 (C-22), 128.51 (C-21, 23), 129.25 (C-20, 24) and 141.62 (C-19) m.d.

The structure of compound (13) was also confirmed by two-dimensional NMR spectroscopy

HMBC (!H-13C), which allows to establish spin-spin interactions of heteronuclear nature. The observed correlations in the molecule are shown in figures 1 and 2.

Heteronuclear interactions of protons with carbon atoms through a single bond were established for pairs: H18-C18 (1.88, 26.44), H8-C8 (2.44, 28.40), H16-C16 (2.52, 34.62), H7-C7 (2.74, 48.79), H4-C4 (3.10, 34.89), H5-C5 (4.22, 53.55), H17-C17 (4.43, 51.92), H9-C9 (4.53, 48.45), H14-C14 (6.15, 105.77), H12-C12 (6.21, 117.00), H2123-C2123 (7.09, 129.08), H22-C22 (7.12, 126.67), H2024-C2024 (7.32, 129.32) h H13-C13 (7.28, 139.80).

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CHEMICAL SCIENCES / <«g©LL©(MUM~JOy©MaL» #W№®1 2022

Figure 1 - HMQC connection correlation diagram (13)

Figure 2 - HMQC survey of the connection spectrum (13) in DMSO

General procedure for obtaining substituted pyrazolines 7-9, 12, 13: 0,02 mol of hydrazine hydrate was added to 0,002 mol of substituted chalcone in 10 ml of ethanol. The mixture was heated at a temperature of 70-80° C for 4 hours, then cooled and diluted in 50 ml of water. The precipitate was filtered out, washed with water and recrystallized from ethanol [7, 8].

4-[5-(4-Methoxyphenyl)-4,5-dihydro-1H-pyrazole-3-yl]phenyl (7). The yield of product 7 was 53%, the melting point was 119-120oC. NMR spectrum 1H, 5, m.d.: 2.68 dd (1H, H4ax, 2J 16.3 Hz, 3J 11.0 Hz), 3.27 dd (1H, H4eq, 2J 16.5 Hz , 3J 10.5 Hz ), 3.67 c (1H, H20), 4.68 t (1H, H5, 3J 10.1 Hz), 6.72 d (2H, H810, 3J 8.7 Hz), 6.84 d (2H, H1416, 3J 8.7 Hz), 7.21 d (2H, H1317, 3J 8.7 Hz), 7.40 d (2H, H711, 3J 8.2 Hz), 9.67 ym. c (1H, OH). NMR 13C spectrum, 5, m.d: 41.42 (C4), 55.55 (C5), 63.51 (C20), 114.22 (C1416), 115.84 (C810), 124.92 (C6), 127.52 (C13,17), 128.28 (C7,11), 135.51 (C12), 149.71 (C3), 158.16 (C15), 158.86 (C9).

2,2'-(4,5-Dihydro-1H-pyrazole-3,5-diyl)phenol (8). The yield of product 8 was 72%, the melting point

was 124-125oC. NMR spectrum 1H, 5, m.d:2.88 dd (1H, CH4ax, 2J 16.5 Hz, 3J 10.1 Hz), 3.53 dd (1H, CH4eq, 2J 16.7 Hz, 3J 10.7 Hz), 5.00 t (1H, CH5, 3J 10.5 Hz), 6.72-6.87 m (4H, CH8101416arom), 7.03-7.07 m (1H, CH11arom), 7.15-7.18 m (1H, CH17arom), 7.25 t (2H, CH915arom, 3J 7.8 Hz), 7.50 ym. c. (1H, NH). NMR 13C, 5, m.d.:40.01 (C4), 57.67 (C5), 115.63 (C8), 115.91 (C14), 116.41 (C10), 117.45 (C16), 119.50 (C612), 127.38 (C17), 128.06 (C15), 128.54 (C9), 130.00 (C11), 153.46 (C3), 155.33 (C13), 157.28 (C7).

4-[5- (4-Methoxyphenyl)-4,5-dihydro-1H-pyrazole-3-yl]benzo-1,3-diol (9). The yield of product 9 was 37%, the melting point was 149-150 °C. NMR spectrum !H, 5, m.d.:2.84 dd (1H, H4ax, 2J 11.0 Hz, 3J 11.0 Hz), 3.43 dd (1H, H4eq, 2J 5.3 Hz, 3J 10.5 Hz), 3.70 c (3H, H21),4.68 t (1H, H5, 3J 10.5 Hz), 6.27 m (2H, H810), 6.87 g (2H, H1416, 3J 8.7 Hz), 7.05 d (1H, H11, 3J 8.7 Hz), 7.27 d (2H, H1317, 3J 8.7 Hz), 11.22 ym. c. (1H, NH). NMR 13C,5, m.d.: 41.59 (C4), 55.62 (CH3), 61.86 (C5), 102.92 (C8), 107.50 (C10), 109.44 (C6), 114.35

«етуушшим-шишаи» жш / chemical sciences

(CH16), 128.39 (C13,17), 129.40 (C11), 134.76 (C12), 153.87 (C3), 159.09 (C9), 159.74 (C15), 162.10 (C7).

3-((2S)-1-(5-Phenyl-4,5-dihydro-1H-pyrazole-3-yl)piperidine-2-yl)pyridine (12). 2.33g (7.97 mol) of N-cinnamoylanabazine (10) was dissolved in 100 ml of ethanol and 1.9 ml (39.85 mol) of hydrazine hydrate was added drop by drop. The reaction mixture was stirred for 1 hour at 25 ° C and an additional 7 hours at 70-75° C, cooled and evaporated. The resulting mass was dissolved in CHCl3 (300 ml), washed with water (3x 60 ml) and dried over MgSO4. The desiccant was filtered out, the solvent was evaporated at reduced pressure, the residue was chromatographed on a column with aluminum oxide (eluent: benzene, benzene-chloroform, 100:1). 2.028 g (87.03%), 3-((2S)-1 -(5-phenyl-4,5 -dihydro -1H-pyrazo le-3-yl)piperidine-2-yl)pyridine 12 was isolated in the form of a yellow-green thick oil. NMR spectrum 1H, 5, m.d. (J, Hz): 1.31-1.52 m (1H. H9ax), 1.53-1.61 m (3H, H8ax,i0ax,9eq), 1.70-1.88 m (1H, H8eq), 2.18-2.40 m (1H, H10eq), 2.76-2.84 m (2H, H4ax,7ax), 2.96-2.98 m (1H, H7eq), 3.58-3.65 m (2H, H4eqH-11), 4.58 ym. c (1H, H1), 5.12-5.21 m (1H, H5), 7.18-7.22 m (3H, H141516), 7.257.37 m (4H, H13172223), 8.40-8.50 (2H, H1921). NMR spectrum 13C, 5c, md.: 19.43 (C9), 25.93 (C8), 26.96 (C10), 42.12 (C11), 42.14 (C4), 49.01 (C7), 70.49 (C5), 126.29 (C14,15,16), 127.58 (C15,21), 128.61 (C13,17,19,23), 134.60 (C13172223), 141.20 (C18), 141.22 (C12), 148.61 (C1921). Cross-peaks of the COSY (!H-!H) NMR spectra, m.d.:H4ax-H5 (2.76, 5.16 h 5.16, 2.75), H1317-H1416 (7.34, 7.16 h 7.16, 7.34), H2123-H22 (8.39, 7.34 h 7.34, 8.39). Cross-peaks of HMBC NMR spectra (1H-13C), m.d.: H4ax-C4 (2.75, 42.19), H4eq-C4 (3.64, 42.19), H5-C5 (5.20, 70.38), H8ax-C8 (1.53, 25.86), H8eq-C8 (1.73, 25.86), H9ax-C9 (1.37, 19.54), H9eq-C9 (1.61, 19.54), H10eq-C10 (2.25, 26.85), H11-C11 (3.58, 42.12), H22-C22 (7.34, 134.83).

3-(5-Phenyl-4,5-dihydro-1H-pyrazole-3-yl)-3,4,5,6-tetrahydro- 1H-1,5-methanopyride-1,2-a][1,5] -diazocin -8(2H)- she (13).

0.33 g (1.03 mmol) of N-cine-moylcitizine 11 was dissolved in a minimum amount of ethanol (~15 ml) and 0.50 ml (10.28 mmol) of hydrazine hydrate was added drop by drop. The reaction mixture was stirred for 2 hours at 25 ° C and an additional 6 hours at 70-75 ° C, cooled and evaporated. The resulting mass was dissolved in CHCls (100 ml), washed with water (3x20 ml) and dried over MgSO4. The desiccant was filtered out, the solvent was evaporated at reduced pressure, the residue was chromatographed on a column with aluminum oxide (eluent: petroleum ether, petroleum ether-benzene, 100:1).

Allocated 0.283g (85.75 %), 3-(5- phenyl - 4,5 -dihydro- 1H- pyrazol -3 -il) - 3,4,5,6-

tetrahydro-1H-1,5-methanopyrido[1,2-a][1,5]diazocin-8(2H)-he (13) in the form of yellow needle crystals with a melting temperature of 122-125° C. NMR spectrum !H, 5, m.d. (J, Hz): 1.87-1.99 m (2H, H1818), 2.25-3.33 m (6H. H4,477,8,16), 3.58-4.63 m (5H, H5991717), 6.11-6.20 m (2H, H1214), 6.97-7.64 m (7H, H1 1320-24). NMR spectrum 13C, 5C, m.d: 25.80 (C18),

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27.52 (С8), 33.76 (С16), 34.79 (С4), 48.75 (С9), 49.18 (С7), 51.21 (С17), 52.82 (С5), 105.27 (С14), 116.31 (С12), 126.32 (С22), 128.51 (С21-23), 129.25 (С20,24), 139.30 (С13), 141.62 (С19), 150.19 (С15), 162.64 (С3), 170.85 (С11). Cross-peaks of HMBC NMR spectra (1H-13C), m.d.:H18-C18 (1.88, 26.44), Н8-С8 (2.44, 28.40), Н16-С16 (2.52, 34.62), Н7-С7 (2.74, 48.79), Н4-С4 (3.10, 34.89), Н5-С5 (4.22, 53.55), Н17-С17 (4.43, 51.92), Н9-С9 (4.53, 48.45), Н14-С14 (6.15, 105.77), Н12-С12 (6.21, 117.00), Н2123-С2123 (7.09, 129.08), Н22-С22 (7.12, 126.67), н20,24-С20,24 (7.32, 129.32), Н13-С13 (7.28, 139.80).

Thus, the creation of highly effective components of medicines is an urgent task for modern medicine. All over the world, there is a search and research of compounds with potential biological activity. Recently, heterocyclic nitrogen-containing aliphatic compounds, in particular, pyrazole derivatives, have attracted particular interest of synthetic chemists. Based on the above, it becomes clear that the synthesis of new pyrazole derivatives is an urgent direction in synthetic organic chemistry.

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7. Ибраев М.К., Нуркенов О.А., Такибаева А.Т., Сейлханов Т.М., Рахимберлинова Ж.Б., Исабаева М.Б. Синтез, строение и антиоксидантная активность (4S, 5S) -2-(1'-,бром-2'-фенилвинил)-3,4-диметил-5-фенил-1,3-оксазолидина. Вестник Тверского госуд. унив-та. Серия: Химия №3(45), 2021. Вып.4.стр 144-149.

8. Нуркенов О.А., Ибраев М.К., Рахимберлинова Ж.Б., Сейлханов Т.М., Такибаева А.Т.,Исабаева М.Б. Синтез, строение и антимикробная активность 2-[3,4-диметил-5-фенилоксазолидин-2-ил] бензойной кислоты. Вестник Воронежского государственного университета, 2021. №4. Стр.33-39

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