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AZERBAIJAN CHEMICAL JOURNAL № 2 2019
35
UDC 547.327+547.326
THE INVESTIGATION OF MICHAEL ADDITION OF ACETOACETANILIDE AND METHYL ACETOPYRUVATE TO SOME YLIDENECYANOACETAMIDES
F.N.Naghiyev
Baku State University [email protected] Received 08.01.2019
It was established that by the Michael addition of substituted ylidenecyanoacetamides with acetoacetanilide in methanol media and in the presence of methyl piperazine at room temperature, various new substituted pyridone derivatives were formed. Also, by the interaction of 2-fluorobenzylidenecyanoacetamide and methyl acetopyruvate in the methanol media, in the presence of methyl piperazine corresponding pyridone derivative was synthesized. Structures of all synthesized compounds confirmed by NMR spectroscopy.
Keywords: ylidenecyanoacetamides, fluorobenzylidenecyanoacetamide, acetoacetanilide, methyl acetopyruvate.
https://doi.org/10.32737/0005-2531-2019-2-35-39
Introduction
By the multicomponent interaction of car-bonyl compounds of cyanoacetamides and aldehydes in the presence of various catalytic systems [1-7] biologically active compounds containing quinazoline, pyridine, pyrimidine, indole, imi-dazole pyrane fragments has been synthesized.
Antibacterial, spazmolitical, diuretic, anti-coagulyant, antidiabetic, anticancer va antiana-philactic and other various pharmacological properties of quinazolines, 3,4-dihydropyrdine-
2-one and 2-amino-4H-pyrane derivatives were investigated [8-10].
Results and discussions
We carried out Michael addition reaction of various ylidenecyanoacetamides with aceto-acetanilide in methanol solution and in the presence of catalytic amount of methyl piperazine (MP), at room temperature, for 2448 hours and obtained new substituted pyridon derivatives (Scheme 1).
CN
O
O
R-CH-
/
C \
,Ph
3—4 drop methylpiperazine (MP), CH3OH, r.t., 48 h.
PhHN
NH
NH
CN
0
1
R = a) C6H5, b) 4-CH3C6H4,
c) 4-(CH3OC6H4, d) thiophenyl, e) 4-pyridyl.
NH O OH
3
a) C6H5, b) 4-CH3C6H4, c) 4-CH3OC6H4, d) thiophenyl, e) 4-pyridyl.
Scheme 1. Reaction of substituted ylidenecyanoacetamides (1a-e) with acetoacetanilide.
Also by Michael addition of 2-fluoroben-zylidenecyanoacetamide and methyl acetopyruva-te in methanol solution and in the presence of ca-
talytic amount of methyl piperazine (MP) at 65-700C for 5 min was synthesized new tetrahydro-pyridone derivatives with high yield (Scheme 2).
F
O O
qqjj 3-4 drop methylpiperazine (MP),
3 CH3OH, 65-75°C, 5 min, then 48 h, r.t.
H3CO. r
F
CN .
H3C NH O
Scheme 2. Reaction of substituted 2-fluorobenzylidenecyanoacetamide (4) with methyl acetopyruvate.
O
R
+
2
R
+
2
O
O
5
4
6
Experimental part. General remarks
All commercially available chemicals were obtained from Merck and Fluka (Sigma-Aldrich) companies and used without further purification. Melting points were measured on an Stuart SMP30 apparatus without correction. 1H,
13
C NMR spectra (Figures 1, 2) were recorded on BrukerAvance 300-MHz spectrometer at 300 and 75 MHz, respectively. Thin-layer chroma-tography (TLC) on commercial aluminum-backed plates of silica gel (60 F254) was used to monitor the progress of reactions.
Fig. 1. 13C NMR spectrum of methyl 2-(5-cyano-4-(2-fluorophenyl)-2-methyl-6-oxo-1,4,5,6-tetrahyd-ropyridin-3-yl)-2-oxoacetate (6) (see experimental part).
Fig.2. C NMR spectrum of methyl 2-(5-cyano-4-(2-fluorophenyl)-2-methyl-6-oxo-1,4,5,6-tetrahyd-ropyridin-3-yl)-2-oxoacetate (6) (see experimental part).
General experimental procedure
5-Cyano-2-hydroxy-2-methyl-4-oxo-N,6-diphenylcyclohexane-1-carboxamide (3a). Yli-denecyanoacetamide (4 mmol) and acetoacet-anilide (4.1 mmol) stirrered in 35 ml of methyl alcohol. 3-4 drops of 1-methyl piperazine added to reaction mixture and stirrered for 4-5 min. Then reaction mixture hold out at room temperature for 48 h. The progress of the reaction was monitored by TLC (EtOAc/«-hexane, 3:1). Crystals were precipitated after evaporation of solvent, filtered, recrystallized from etha-nol-water mixture and obtained in pure form (yield - 1.23 g, 87.86%). Tmp = 1720C.
1H NMR (300 MHz, DMSO-^6): 1.51 (s, 3H, CH3), 3.21 (d, 1H, CH, Vh-h = 12), 4.04 (d, 1H, CH, 3Jh-h = 12.1), 4.48 (d, 1H, CH, Vh-h = 12), 6.20 (s, 1H, OH), 6.96-7.48 (m, 10H, 10Ar-H), 8.94 (s, 1H, NH), 9.78 (s, 1H, NH). 13C NMR (75 MHz, DMSO-^6): 28.14 (CH3), 41.63 (CH), 42.42 (CH), 56.11 (CH), 80.88 (Cquat), 118.00 (CN), 120.30 (CHarom), 124.12 (CHarom), 128.02 (CHarom), 128.79 (2CHarom), 128.98 (CHarom), 138.63 (Car), 139.27 (Car), 163.91 (N-C=O), 167.61 (N-C=O).
Found, %: 68.72 C, 5.38 H, 11.98 N. C20H19N3O3. Calculated, %: 68.77 C, 5.44 H, 12.03 N.
5-Cyano-2-hydroxy-2-methyl-6-oxo-N-phenyl-4-(p-tolyl)piperidine-3-carboxamide (3b)
was synthesized in the same reaction condition (yield - 1.28 g, 88.89%). Tmp = 1680C.
1H NMR (300 MHz, DMSO-d6): 1.47 (s, 3H, CH3), 2.22 (s, 3H, CH3), 3.16 (d, 1H, CH, 3Jh-h = 12); 3.96 (d, 1H, CH, Vh-h = 12), 4.37 (d, 1H, CH, 3Jh-h = 12), 6.16 (s, 1H, OH), 6.957.35 (m, 9H, 9Ar-H), 8.89 (s, 1H, NH), 9.77 (s,
IH, NH). 13C NMR (75 MHz, DMSO-d6): 21.11 (CH3), 28.10 (CH3), 41.14 (CH), 42.58 (CH), 56.12 (CH), 80.84 (Cquat), 118.01 (CN), 120.14 (2CHarom), 124.05 (CHarom), 128.59 (CHarom), 128.99 (3CHarom), 129.39 (2CHarom), 136.31 (Car), 137.05 (Car), 138.72 (Car), 163.91 (N-C=O), 167.59 (N-C=O).
Found, %: 69.48 C, 5.83 H, 11.52 N. C21H21N3O3. Calculated, %: 69.42 C, 5.78 H,
II.57 N.
5-Cyano-2-hydroxy-4-(4-methoxyphe-nyl)-2-methyl-6-oxo-N-phenylpiperidine-3-car-boxamide (3c) was synthesized in the same condition (yield 1.22 g, 80.26%). Tmp = 1700C.
1H NMR (300 MHz, DMSO-^6): 148 (s, 3H, CH3), 3.14 (d, 1H, CH, 3Jh-h = 12.6), 3.67 (s, 3H, CH3O), 3.95 (d, 1H, CH, 3Jh-h = 12), 4.35 (d, 1H, CH, 3Jh-h = 12), 6.18 (s, 1H, Oh), 6.83-7.37 (m, 9H, 9Ar-H), 8.89 (s, 1H, Nh), 9.79 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): 28.08 (CH3), 40.83 (CH), 42.68 (CH), 55.36 (CH3O), 56.24 (CH), 80.82 (Cquat), 114.15 (2CHarom), 118.05 (CN), 120.26 (2CHarom), 124.16 (CHarom), 129.01 (3CHarom), 129.83 (CHarom), 131.10 (Car), 138.62 (Car), 158.90 (O-Car), 164.01 (N-C=O), 167.76 (N-C=O).
Found, %: 66.44 C, 5.48 H, 11.14 N. C21H21N3O4. Calculated, %: 66.49 C, 5.54 H, 11.08 N.
5-Cyano-2-hydroxy-2-methyl-6-oxo-N-phenyl-4-(thiophen-2-yl)piperidine-3-carbox-amide (3d) was synthesized in the same condition (yield - 1.16 g, 81.69%). Tmp = 1370C.
1H NMR (300 MHz, DMSO-d6): 1.49 (s, 3H, CH3), 3.17 (d, 1H, CH, 3Jh-h = 12), 4.35 (d,
IH, CH, 3Jh-h = 12.3), 4.51 (d, 1H, CH, Vh-h = 12), 6.18 (s, 1H, OH), 6.83-7.37 (m, 9H, 9Ar-H), 8.89 (s, 1H, NH); 9.79 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): 28.00 (CH3), 36.89 (CH), 43.36 (CH), 57.42 (CH), 80.79 (Cquat), 117.92 (CN), 120.23 (2CHarom), 124.13 (CHarom), 125.61 (CHarom), 126.59 (CHarom), 127.33 (CHarom), 129.05 (2CHarom), 138.76 (Car), 142.11 (Cthioph), 163.46 (N-C=O), 167.22 (N-C=O).
Found, %: 60.90 C, 4.84 H, 11.88 N. C18H17N3O3S. Calculated, %: 60.84 C, 4.79 H,
II.83 N.
5-Cyano-2-hydroxy-2-methyl-6-oxo-N-phenyl-4-(pyridin-4-yl)piperidine-3-carbox-amide (3e) was synthesized in the same condition (yield - 1.19 g, 85.61%). Tmp = 1960C.
1H NMR (300 MHz, DMSO-d6): 1.50 (s, 3H, CH3), 3.19 (d, 1H, CH, 3Jh-h = 12), 4.09 (d, 1H, CH, 3Jh-h = 12), 4.57 (d, 1H, CH, Vh-h =
12); 6.29 (s, 1H, OH); 6.96-7.33 (m, 5H, 5Ar-H), 7.47 (d, 2H, 2CHpyrd.3JH-H = 4.2), 8.52 (d, 2H, 2CHpyrd.VH-H = 4.5), 8.99 (s, 1H, NH), 9.84 (s, 1H, NH). 13C NMR (75 MHz, DMSO-^): 28.02 (CH3), 40.97 (CH), 41.36 (CH), 55.59 (CH), 80.89 (Cquat), 117.62 (CN), 120.25 (2CHarom), 124.09 (CHarom), 124.25 (CHarom), 129.04 (3CHarom), 138.48 (Car), 148.19 (Car), 150.14 (2CHarom), 163.34 (N-C=O), 166.96 (N-C=O).
Found, %: 65.09 C, 5.08 H, 16.05 N. C19H18N4O3. Calculated, %: 65.14 C, 5.14 H, 16 N.
Methyl 2-(5-cyano-4-(2-fluorophenyl)-
2-methyl-6-oxo-1,4,5,6-tetrahydropyridine-3-yl)-2-oxoacetate (6). 2-Fluorine-benzylidency-anoacetamide (4 mmol) and acetoacetanilide (4.1 mmol) stirrered in 35 ml of methyl alcohol,
3-4 drops of 1-methyl piperazine added to reaction mixture and stirrered for 4-5 minutes. Then reaction mixture heated for 60-650C for 5-6 minutes and hold out at room temperature. The progress of the reaction was monitored by TLC (EtOAc/«-hexane, 3:1). Crystals were precipitated after evaporation of solvent, filtered by paper, recrystallized from ethanol-water mixture and obtained in pure form (yield - 0.98 g, 77.78%). Tm = 157bC.
1H NMR (300 MHz, DMSO-4,): 1.81 (s, 3H, CH3), 3.70 (s, 3H, CH3O), 4.43 (d, 1H, CH, Vh-h = 12.3), 4.54 (d, 1H, CH, Vr-h = 12.3), 7.19-7.59 (m, 4H, 4Ar-H); 9.41 (s, 1H, NH). 13C NMR (75 MHz, DMSO-4,): 29.87 (CH3), 41.86 (CH), 53.43 (CH3O), 58.34 (CH), 82.73 (2=Cquat), 115.96-116.26 (CHarom), 116.99 (CN), 125.62 (CHarom), 125.80 (Car), 129.28 (CHarom), 130.47130.58 (CHarom), 158.84-162.10 (F-Car), 162.88 (N-C=O), 169.65 (O-C=O), 204.06 (C=O).
Found, %: 60.81 C, 4.17 H, 8.81 N. C16H13N2O4F. Calculated, %: 60.76 C, 4.11 H, 8.86 N.
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ASETOASETANiLiD УЭ PiRUVAT TUR§USUNUN METiL EFiRlNiN BOZi iLiDENSiANOAMiDLORO MiXAEL BiRLO§MO REAKSiYASININ TODQiQi
F.N.Nagiyev
Ovazlanmi§ ilidensianoasetamidlar ila asetoasetanilidin Mixael birla§ma reaksiyasi metanol muhitinda, metilpiperazin i§tirakinda, otaq temperaturunda aparilmi§ va reaksiyadan yeni avazlanmi§ piridon toramalarinin amala galdiyi muayyan edilmi§dir. Elaca da metanol muhitinda, metilpiperazin i§tirakinda, piridilidensianoasetamid, 2-fluor-benzilidensianoasetamidin methyl acetopiruvate ila qar§iliqli tasir reaksiyasindan uygun avazlanmi§ piridon toramasi sintez edilmi§dir. Structures of all synthesized compounds confirmed by NMR spectroscopy.
Agar sozfar: ilidensianoasetamidlar, 2-fluorbenzilidensianoasetamid, asetoasetanilid, metil asetopiruvat.
ИССЛЕДОВАНИЕ ПРИСОЕДИНЕНИЯ ПО МИХАЭЛЮ НЕКОТОРЫХ ИЛИДЕНЦИАНО-АЦЕТАМИДОВ К АЦЕТОАЦЕТАНИЛИДУ И МЕТИЛАЦЕТОПИРУВАТУ
Ф.Н.Нагиев
Установлено, что реакцией присоединения по Михаэлю илиденцианоацетамидов к ацетоацетанилиду в среде метанола в присутствии метилпиперазина при комнатной температуре образуются различные новые замещенные производные пиридона. Также взаимодействием 2-фторбензилиденцианоацетамида и метилацетопирувата в среде метанола и в присутствии метилпиперазина синтезировано соответствующее замещенное производное. Структуры всех синтезированных соединения подтверждены методом :H и 13C ЯМР.
Keywords: илиденцианоацетамиды, 2-фторбензилиденцианоацетамид, ацетоацетанилид, метилацетопируват.
