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600 CHEMICAL PROBLEMS 2019 no. 4 (17) ISSN 2221-8688
UDC 547.327
SYNTHESIS OF SOME FUNCTIONALIZED PYRIDONES DERIVATIVES
F.N. Naghiyev
Baku State University AZ-1148 Baku, Z.Khalilov 23, e-mail: farid.orgchemist@gmail.com
Received 15.07.2019
It was establishedformation of new substituted pyridone derivativesin terms of addition reaction according to Michael with the participation of 2-cyano-3-(4-pyridul) acrylamide and benzoylacetone or ethyl alcohol in ether of acatecetic acid in the presence (MP) in methanol medium. The boiling of ethyl 5-cyano-2-hydroxy-2-methyl-6-oxo-4-phenylpiperidine-3-carboxylate in ethanole during 4 hours followed by dehydration and dehydrogenation (by air oxidation) generated 5-cyano-2-methyl -6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic acid. Under similar conditions there were synthesized appropriate products of substituted pyridone according to Michael' addition reaction through interacting of 4-bromobenzoylacetonitrile with 2-cyano-3-(2-fluorophenyl)acrylamide. Structures of all synthesized compounds were proven by NMR spectroscopy.
Keywords: 2-cyano-3-(4-pyridyl)acrylamide, fluorobenzylidenecyanoacetamide, 4-chloroacetoacetate, 4-
bromobenzoylacetonitrile
DOI: 10.32737/2221-8688-2019-4-600-606
Introduction
2-Pyridone, hydroxypyridine, is heteroaromatic rings bioactive molecules
tatomer of 2-one of the major in natural products, and pharmaceutical
ingredients. Ciclopirox, milrinone, campto-thecin, (-)-citisin, fredericamycin, perampanel, bioactive molecules and pharmaceutical ingre-
dients contain valuable pyridone fragments in their composition. Also, synthesis methods of these compounds are different from in reaction conditions in literature [1-12]. Some articles [13-17] research into antimicrobial activity of pyridone derivatives.
Results and discussion
In the presence of methylpiperazine acetoacetate, 2-cyano-3-(pyridine-4-yl)
and methanol medium according to Michael acrylamide at a room temperature was addition reaction of benzoilacetone or ethyl hydroxysubsituted pyridone derivatives.
Scheme 1
CN C-CH3
/ \—ch=/ + h2c/
:—nh2
:—r
3 damci MP CH3OH, o.t. * R.
R = OEt, Ph
R = a) OEt, b) Ph
Scheme 1. Reaction of 2-cyano-3-(4-pyridyl)acrylamide with benzoylacetone and ethyl acetoacetate.
N
O
In our view, in the initial step of reaction the nucleophilic attack methylpiperazine to me-thylene-active compound results in the formation of corresponding anion
(nucleophilic particle), which, in turn, drew to the CH-electrophilic center of the activated double bound to form intermediate A (according to Michael adduct). In the final
CHEMICAL PROBLEMS 2019 no. 4 (17)
www.chemprob.org
step, in the intermediate A, the amide nitrogen desired ring closure product - pyridione attacked the carbonyl group to generate a (Scheme 2).
¿^CHX
C—CH3 —CH3 + H2C/
V—R
O
R = OEt, Ph
C—CH3
+ H/ . C—NH2 \c—R
C O
R = OEt, Ph
C—CH3
H^ + H:
V—R
Scheme 2
—CH3
R = OEt, Ph
# Wc^H/
CN
NH,
CN
CH3
OH
1
R = a) OEt, b) Ph
Boiling of ethyl 5-cyano-2-hydroxy-2-methyl- oxidation) to provide 5-cyano-2-methyl -6-
6-oxo-4-phenylpiperidine-3-carboxylate in oxo-4-phenyl-1,6-dihydropyridine-3-
ethanole for 4 hours was followed by carboxylic acid. dehydration and dehydrogenation (by air
oh 1a 2
Scheme 2. Synthesis of ethyl 5-cyano-2-methyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-
carboxylat
Scheme 4 NO2
O2N
CN
O
C_C
_ CH2Cl
\-CH=/ + H,^ 3 dame1 MP
' 2 \ EtO-
2 t—OEt
NH2
CN
ClH2C
OH
Scheme 3. Reaction of 2-cyano-3-(4-nitrophenyl)acrylamide with ethyl 4-chloroacetoacetate.
O
O
N
O
R
A
O
O
3
Scheme 5
CN
CN
+ H2
—NH2
Nc
3 damci MP
CH3OH, o.t.
\ /
Br
Scheme 4. Reaction of 2-cyano-3-(2-fluorophenyl)acrylamide with 4-bromobenzoylacetonitrile.
F
Br
Under the same reaction condition, the acrylamide led to the formation of appropriate Michael addition of 4-bromobenzoyl- hydroxy substituted pyridone derivatives. acetonitrile to 2-cyano-3-(2-fluorophenyl)
Fig. 1. 1H NMR spectrum of 2-(4-bromophenyl)-4-(2-fluorophenyl)-2-hydroxy-6-oxopiperidine-3,5-dicarbonitrile (4)
13
Fig. 2. C NMR spectrum of 2-(4-bromophenyl)-4-(2-fluorophenyl)-2-hydroxy-6-oxopiperidine-3,5-dicarbonitrile (4)
Experimental part.
All commercially available chemicals were obtained from Merck and Fluka (Sigma -Aldrich) companies and used without further purification. Melting points were measured by Stuart SMP30 apparatus without correction. 1H, 13 C NMR spectra (Fig. 1) were recorded on BrukerAvance 300-MHz spectrometer at 300 and 75 MHz, respectively. Thin-layer chromatography (TLC) on commercial aluminum-backed plates of silica gel (60 F254) was used to monitor the reaction course.
Experimental procedures: Ethyl 5-cyano-2-hydroxy-2-methyl-6-oxo-4-(pyridin-4-yl)piperidine-3-carboxylate (1a): 2-Cyano-3-(4-pyridyl)acrylamide (5.1 mmol) and ethyl acetoacetate (5.2 mmol) was stirrered in 35 ml of methyl alcohol. Then 3-4 drops of
1-methylpiperazine were added to reaction mixture and stirrered for 5 minutes. Then reaction mixture was held out at a room temperature for 48 h. Reaction course was monitored by TLC (EtOAc/n-hexane, 3:1). Crystals were precipitated after evaporation of solvent, filtered, recrystallized from ethanol-water mixture and obtained in pure form (yield 1.27 g, 82.47%). Tmp. = 173°C.
rH NMR (300 MHz, DMSO-d6): 0.84 (t, 3H, CH3, Vh-h = 7); 1.47 (s, 3H, CH3); 3.44 (d, 1H, CH, 3Jh-h = 12.4); 3.82 (k, 2H, CH2O, 3Jh-h = 6.9); 3.92 (t, 1H, CH-Ar, 3Jh-h = 12.3); 4.31 (d, 1H, CH, 3Jh-h = 12.6); 6.27 (s, 1H, OH); 7.39 (d, 2H, 2CHpynd., 3Jh-h = 5.1); 8.55 (d, 2H, 2CHpyrid., 3Jh-h = 5.1); 8.97 (s, 1H, NH). 13C NMR (75 MHz, DMSO-dfc): 14.02 (CH3CH2), 28.34 (CH3), 40.41 (CH-CN), 41.44 (CH-Ar), 54.24 (CH-CO2), 60.64 (CH2O), 80.72 (O-Cdordlu), 117.29 (CN), 123.85 (2CHpyrid.), 148.63 (Cpyid.), 150.33 (2CHpynd.), 162.56 (N-C=O), 168.58 (O-C=O).
Found, %: 59.35 C; 5.67 H; 13.81 N. C15H17N3O4. Calculated, %: 59.40 C; 5.61 H; 13.86 N.
5-Benzoyl-6-hydroxy-6-methyl-2-oxo-4-(pyridin-4-yl)piperidine-3-carbonitrile (1b):
2-Cyano-3-(4-pyridyl)acrylamide (5.1 mmol) and benzoylacetone (5.2 mmol) was stirrered in 35 ml of methyl alcohol. After 3-4 drops of 1-methylpiperazine added to reaction mixture and stirrered for 5 minutes. Then reaction
General remarks
mixture was held out at a room temperature for 48 h. Reaction course was monitored by TLC (EtOAc/n-hexane, 3:1). Crystals were precipitated after evaporation of solvent, filtered, recrystallized from ethanol-water mixture and obtained in pure form (yield 1.32 g, 77.65%). Tmp. = 192°C.
1H NMR (300 MHz, DMSO-J6): 1.35 (s, 3H, CH3); 3.86 (t, 1H, CH-Ar, Vh-h = 11.4); 4.60 (d, 1H, CH, Vh-h = 12.3); 4.68 (d, 1H, CH, Vh-h = 11.1); 6.46 (s, 1H, OH); 7.44-8.44 (m, 9H, 5Ar-H+4CHpyrid); 8.84 (s, 1H, NH). 13C NMR (75 MHz, DMSO-öfc): 27.01 (CH3), 40.78 (CH-CN), 42.98 (CH-Ar), 55.15 (CH-C=O), 82.86 (O-Cdördlü), 117.26 (CN), 123.83 (2CHarom), 129.04 (2CHpMd.), 129.14 (2CHarom.), 134.09 (CHarom.), 138.17 (Car.), 148.52 (Cpyrid.), 150.25 (2CH„ynd.), 162.43 (N-C=O), 199.23 (C=O).
Found, %: 68.00 C; 5.02 H; 12.60 N. C19H17N3O3. Calculated, %: 68.06 C; 5.07 H; 12.54 N.
Ethyl 5-cyano-2-methyl-6-oxo-1,6-dihydro-[4,4'-bipyridine]-3-carboxylate (2):
Ethyl 5-cyano-2-hydroxy-2-methyl-6-oxo-4-(pyridin-4-yl)piperidine-3-carboxylate (5.1 mmol) was dissolved in 35 ml of ethyl alcohol and 5 h refluxed. Then the resulting reaction mixture was placed in a glass. Crystals were precipitated after evaporation of solvent, filtered, recrystallized from ethanol-water mixture and obtained in pure form (yield 1.07 g, 74.30%). Tmp. = 147°C.
1H NMR (300 MHz, DMSO-J6): 0.70 (t, 3H, CH3, Vh-h = 7.2); 2.45 (s, 3H, CH3); 3.83 (k, 2H, CH2O, Vh-h = 7); 7.36 (d, 2H, 2CHpynd., Vh-h = 5.1); 8.71 (d, 2H, 2CHpynd., Vh-h = 5.1); 12.82 (s, 1H, NH). 13C NMR (75 MHz, DMSO-^6): 13.37 (CH3CH2), 19.13 (CH3-C=), 61.43 (CH2O), 101.07 (=Cdördlü), 111.09 (=Cdördlü), 115.42 (CN), 122.35 (2CHpyrid.), 144.51 (Cpyrid.), 150.25 (2CHpynd.), 155.45 (=Cdördlü), 157.53 (=Cdördlü), 160.00 (N-C=O), 164.64 (O-C=O).
Found, %: 63.55 C; 4.65 H; 14.89 N. C15H13N3O3. Calculated, %: 63.60 C; 4.59 H; 14.84 N.
Ethyl 2-(chloromethyl)-5-cyano-2-hydroxy-4-(4-nitrophenyl)-6-oxopiperidine-3-carbo-
xylate (3): 2-Cyano-3-(4-
nitrophenyl)acrylamide (5.1 mmol) and ethyl 4-chloroacetoacetate (5.2 mmol) stirrered in 35 ml of methyl alcohol. After 3-4 drops of 1-methylpiperazine added to reaction mixture and stirrered for 5 minutes. Then reaction mixture hold out at room temperature for 48 h. Reaction course was monitored by TLC (EtOAc/n-hexane, 3:1). Crystals were precipitated after evaporation of solvent, filtered, recrystallized from ethanol-water mixture and obtained in pure form (yield 1.57 g, 80.51%). Tmp. = 209°C.
fH NMR (300 MHz, DMSO-d6): 0.86 (t, 3H, CH3, Vh-h = 6.9); 3.68 (d, 1H, CH, 3Jh-h = 12.3); 3.69 (s, 3H, CH2CO; 3.85 (k, 2H, CH2O, 3Jh-h = 7); 4.10 (t, 1H, CH-Ar, 3Jh-h = 12.3); 4.63 (d, 1H, CH, 3Jh-h = 12); 7.12 (s,
IH, OH); 7.70 (d, 2H, 2CHarom., 3Jh-h = 8.4); 8.24 (d, 2H, 2CHarom., 3Jh-h = 8.4); 9.10 (s, 1H, NH). 13C NMR (75 MHz, DMSO-öfc): 13.97 (CH3CH2), 40.13 (CH-CN), 41.31 (CH-Ar), 48.16 (CH?Cl), 49.80 (CH-COO), 61.06 (CH2O), 83.03 (O-Cdördlü), 117.01 (CN), 124.13 (3 CHarom.), 130.21 (CHarom.), 147.10 (Car.), 147.47 (Car.), 163.30 (N-C=O), 167.71 (O-C=O).
Found, %: 50.39 C; 4.14 H; 11.07 N. C16H16N3O6CL Calculated, %: 50.33 C; 4.19 H;
II.02 N.
2-(4-Bromophenyl)-4-(2-fluorophenyl)-2-hydroxy-6-oxopiperidine-3,5-dicarbonitrile (4): 2-Cyano-3-(2-fluorophenyl)prop-2-
enamide (5.1 mmol) and 4-bromobenzoylace-tonitrile (5.2 mmol) stirrered in 35 ml of methyl alcohol. After 3-4 drops of 1-methylpiperazine were added to reaction mixture and stirrered for 5 minutes. Then reaction mixture were held out at a room temperature for 48 h. Reaction course was monitored by TLC (EtOAc/n-hexane, 3:1). Crystals were precipitated after evaporation of solvent, filtered, recrystallized from ethanol-water mixture and obtained in pure form (yield 1.77 g, 84.28%). Tmp. = 121°C.
1H NMR (300 MHz, DMSO-^6): 3.98 (d,
IH, CH, Vh-h = 11.4); 4.56 (t, 1H, CH, 3Jh-h =
II.5); 4.66 (d, 1H, CH, 3Jh-h = 11.7); 7.287.72 (m, 8H, 8Ar-H+OH); 9.42 (s, 1H, NH). 13C NMR (75 MHz, DMSO-^6): 39.90 (CH-CN), 41.07 (CH-Ar), 46.08 (CH-CN), 82.34 (O-Cdordlu), 116.13 (CHarom), 116.43 (CHarom), 116.88 (CN), 117.03 (CN), 122.66 (Br-Car.), 124.45-124.67 (Car.), 125.88 (CHarom), 129.21 (2CHarom), 131.10-131.19 (CHarom), 131.42 (2CHarom), 141.11 (Car), 159.02-162.25 (F-Car), 163.12 (N-C=O).
Found, %: 55.01 C; 3.20 H; 10.09 N. C19H13NsFBrO2. Calculated, %: 55.07 C; 3.14 H; 10.14 N.
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BdZi FUNKSiONALLA§MI§ PiRIDON TÖROMdLdRiMN SiNTEZi
F.N. Nagiyev
Baki Dövldt Universiteti AZ 1148 Baki, Z.Xdlilov küg., 23; e-mail: farid.orgchemist@gmail.com
Metanol mühitindd, metilpiperazinin (MP) i§tirakinda vd otaq temperaturunda 2-siano-3-(4-piri-dil)akrilamid ild benzoilasetonun vd ya asetosirkd tur§usunun etil efirinin Mixael birld§md reaksiyasindan müvafiq yeni dvdzldnmi§ piridon tördmdldrinin dmdld gdldiyi müdyydn edilmi§dir. 5-Siano-2-hidroksi-2-metil-6-okso-4-fenilpiperidin-3-karboksil tur§usunun etil efirinin 4 saat etil spirtindd qaynadilmasindan 5-siano-2-metil-6-okso-4-fenil-1,6-dihidropiridin-3-karboksil
turgusunun etil efiri этэ1э galmigdir. Eyni reaksiya garaitinda 4-brombenzoilasetonitrilin 2-siano-3-(2-flüorfenil)akrilamida Mixael birlagma reaksiyasindan müvafiq piridon töramasi al-inmigdir. Hamginin, eyni reaksiya garaitinda 2-siano-3-(4-nitrofenil)akrilamid ila 4-xlorasetoase-tat turgusunun etil efirinin qargiliqli tasir reaksiyasindan uygun piridon töramasi sintez edilmigdir. Sintez edilmig bütün birlagmalarin quruluglari NMR spektroskopiyasinin kömayila tasdiq edilmigdir.
Agar sözldr: 2-siano-3-(4-piridil)akrilamid, flüorbenzilidensianoasetamid, 4-xlorasetoasetat efiri, 4-brombenzoilasetonitril
СИНТЕЗ ПРОИЗВОДНЫХ НЕКОТОРЫХ ФУНКЦИОНАЛИЗИРОВАННЫХ
ПИРИДОНОВ
Ф.Н. Нагиев
Бакинский государственный университет AZ1148 Баку, ул. З.Халилова, 23; e-mail: farid.orgchemist@gmail.com
Выявлено образование новых производных замещенных пиридонов в условиях реакции присоединения по Михаэлю при участии 2-циано-3-(4-пиридил)акриламида и бензоилацето-на или этилового эфира ацетоуксусной кислоты в присутствии метилпиперазина (MP) в среде метанола. При кипячении в этиловом спирте этилового эфира 5-циано-2-гидрокси-2-метил-6-оксо-4-фенилпиперидин-3-карбоновой кислоты в течение 4 часов образуется этиловый эфир 5-циано-2-метил-6-оксо-4-фенил-1,6-дигидропирид-3-карбоновой кислоты. В аналогичных условиях были синтезированы соответствующие продукты замещенных пиридонов по реакции присоединения Михаэля взаимодействием 4-бромбензоилацетонитрила с 2-циано-3-(2-фторфенил)акриламидом и 2-циано-3-(4-нит-рофенил)акриламида с этилового эфира 4-хлорацетоуксусной кислоты. Структуры всех синтезированных соединений доказаны методом ЯМР-спектроскопии. Ключевые слова: 2-циано-3-(4-пиридил)акриламид, фторбензилиденцианоацетамид, 4-хлорацетоуксусный эфир, 4-бромбензоилацетонитрил
