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ISSN 2522-1841 (Online) az9rbaycan kimya jurnali № 4 2018 ISSN 0005-2531 (Print)
UDC 547.97+535.37
THE INVESTIGATION OF CONVERTION OF BENZYLIDENEMALONONITRILES
WITH ACETOACETANILIDE
A.M.Maharramov, F.N.Naghiyev, A.R.Asgerova, E.Z.Guseynov, I.G.Mamedov
Baku State University farid.orgchemist@gmail.com Received 08.06.2018
By the Michael addition reaction of p-methyl, p-nitro substituted benzylidenemalononitriles and thiophe-nylidenemalononitrile with acetoacetanilide pyridine derivatives were synthesized. Michael addition reaction was carried out for 2,6-dichlorobenzylidenemalononitrile with acetoacetanilide and (E)-2-amino-4-(2,6-dichlorophenyl)-5-(1-hydroxyethylidene)-6-oxo-1-phenyl-1,4,5,6-tetrahydropyridine-3-carbonitrile that is corresponding derivative of pyridine was obtained. Unlike V, VI and VII in this reaction the main product of this reaction is mainly in enol-form. Also the Michael addition reaction of p-trifluorobenzylide-nemalononitrile and 2-chloro-5-nitrobenzylidenemalononitrile with acetoacetanilide has been investigated.
Keywords: p-trifluorobenzylidenemalononitrile, 2-chloro-5-nitrobenzylidenemalononitrile, acetoacetanilide, nMr.
Introduction
Benzylidenemalononitriles been Knoeve-nagel adducts are very important synthones in synthesis of such functionally-substituted compounds as 4#-pyranes, substituted pyridines, pyrazoles etc. Pyridine ring demonstrates fungicidal and bacterial activity. 2-Amino-5-substitu-ted pyridine derivatives were synthesized, their antimicrob properties against fitopatogen candidas, bacterias were investigated and conformation analysis was carried out [1, 2]. In other paper [3] various 3,6-diamino-l#-pyrazolo[3,4-é]pyridine derivatives were synthesized and their biological activity was presented. Also researches investigated several new 2-amino-3,4,5, 6-tetrahydropyridine derivatives that can show muscarinic agonist activity in rats brain [4].
Authors carried out the reaction between a-cyano- and a-benzoylcinnamonitrile dervatives with acetoacetanilide for getting hexasubstituted pyridine derivatives. But from the reaction of a-carboxamide and a-thiocarboxamidocinnamonit-rile derivatives with acetoasetanilide pyridines penta-substituted derivatives were synthesized [5].
In next work corresponding pyrane derivatives were obtained on the basis of benzylidene-malononitrile and benzylideneacetophenone [6]. In presented paper by three-component condensation of acetoacetanilide, benzaldehyde and ma-lononitrile in water and at room temperature by using K2CO3 the 4#-pyranes were obtained [7]. By the same reaction, but by using of MgVCO3 catalyst and ethanol as solvent the corresponding
pyridin derivatives were synthesized [8]. In some works in three-component condensation of acetoacetanilide with various aldehydes and malononitrile, three-ethylamine used as catalyst [9], but in [10] using of NaOH has been shown.
Results and discussions
In present work, by Michael addition reaction of p-methyl, p-nitro substituted benzylide-nemalononitriles and thiophenylidenemalono-nitrile with acetoacetanilide in methanol, at 60-650C and for 4-6 minutes the corresponding ace-tyl substituted pyridine derivatives were synthesized. The NMR investigations confirmed the presence of keto-enol tautomerism in reaction mixture. On the basis of 1H NMR spectra we assumed that the keto-form was dominant in reaction mixture (Figure 1).
As well at Michael addition reaction carried out for 2,6-dichlorobenzylidenemalononitrile with acetoacetanilide in methanol media, at 60-650C temperature, for 4-6 minutes the corresponding substituted pyridine derivative - (E)-2-amino-4-(2,6-dichlorophenyl)-5-(1-hydroxyethylidene)-6-oxo-1 -phenyl-1,4,5,6-tetrahydropyridine-3 -carbo-nitrile was obtained.
Unlike V, VI and VII, in this reaction product the dominant is enol-form. According to our investigation, the reason of domination of enol-form is connected with formation of intramolecular hydrogen bonds between hydrogen atom of hydroxyl group and chlorine atom of aromatic ring (Scheme 2, Figure 2).
r
o
cn
/
r-ch=c
\ cn
R = 4-CH3C6H4 (I), 4-NO2C6H4 (П), tiofenil (III)
oo
3-4 drop pyperidine CH3OH, 60-650C, 4-6 min
ch2 nh
iv
nc
hn
ch
R = 4-CH3C6H4 (V), 4-NO2C6H (VI), tiofenil (VII)
Scheme 1. Reaction of ^-methyl, ^-nitro substituted benzylidenemalononitriles (I), (II) and thiopheny-lidenemalononitrile (III) with acetoacetanilide.
R = 4-CH3C5H4 (V), 4-N02C6H4 (VI), tiofenil (VII) R = ^CHjCjft, (VHI), 4-N02C6H4 (IX), tiofenil (X)
+
Fig. 1. JH NMR spectrum of 5-acetyl-2-amino-6-oxo-1-phenyl-4-[(4-(thiophen-2-yl)phenyl)]-1,4,5,6-tetrahydropyridine-3-carbonitrile (VII).
CN O O I,
\ // \ H3C CH2 NH - CN
IV
3—4 drops pyperidine CH3OH. 60-65°C. 4-6 mt^
Scheme 2. Reaction of 2,6-dichlorobenzylidenemalononitrile (XI) with acetoacetanilide.
Fig. 2. 1H NMR spectrum of (E)-2-amino-4-(2,6-dichlorophenyl)-5-(1 -hydroxyethylidene)-6-oxo-1 -phenyl-1,4,5,6-tetrahydropyridine-3-carbonitrile (XII).
\ /
O O
\ H3C CH2 NH
CN
3—4 drops pyperidine NC
CH3OH. 60-65°C. 4-6 min_
H2N N O
Scheme 3. Reaction of ^-trifluorobenzylidenemalononitrile (XIII) with acetoacetanilide.
3
FC
F3C
+
By Michael addition reaction of ^-triflu-orobenzylidenemalononitrile with acetoacetanilide under the same conditions, 2-amino-6-oxo-1-phenyl-4-(4-(trifluoromethyl)phenyl)-1,4,5,6-tetrahydropyridine-3-carbonitrile was synthesized. The investigations proved the elimination of acethyl-group (Scheme 3).
By Michael addition reaction of 2-chloro-
5-nitrobenzylidenemalononitrile and acetoacetanilide in the same conditions for 15 min at room temperature two reaction products were obtained: 5-acetyl-2-amino-4-(2-chloro-5-nitrophenyl)-
6-oxo-1 -phenyl-1,6-dihydropyridine-3 -carbonitrile (XVI) and 5-acetyl-2-amino-4-(2-chloro-5-nitro-phenyl)-6-oxo-1-phenyl-1,4,5,6-tetrahydropyri-dine-3-carbonitrile (XVII, Scheme 4).
XVII
Scheme 4. Reaction of 2-chloro-5-nitrobenzylidenemalononitrile (XV) with acetoacetanilide.
Experimental part. General remarks
All commercially available chemicals were obtained from Merck and Fluka (sigmaal-drich) companies and used without further purification. Melting points were measured on Stuart SMP30 apparatus without correction. 1H and 13C NMR spectra were recorded on Bruker Avance 300-MHz spectrometer at 300 and 75 MHz, respectively. X-ray analyses were performed on Bruker APEX X-ray equipment. Thin-layer chromatography (TLC) on commercial aluminum-backed plates of silica gel (60 F254) was used to monitor the progress of reactions.
General experimental procedure
5-Acetyl-2-amino-6-oxo-1-phenyl-4-(p-to-lyl)-1,4,5,6-tetrahydropyridine-3-carbonitrile (V). 4-Methylbenzylidenemalononitrile (4.56 mmol) and acetoacetanilide (4.6 mmol) stirred in 35 ml of methyl alcohol. 3-4 drops of pyper-idine added to obtained reaction mixture and stirred 2-3 min. Then reaction mixture was heated at 60-650C for 4-6 min and held 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, re-crystallized from ethanol-water mixture and obtained in pure form
(yield - 1.25 g, 79.62%).
White powder; m.p.2080C; 1H NMR (300 MHz, DMSO-J6): 2.28 (s, 3H, CH3-Ar); 2.30 (s, 3H, CH3); 4.04 (d, 1H, CH, 3Jh-h = 4.5); 4.23 (d, 1H, CH, 3Jh-h = 4.5); 5.87 (s, 2H, NH2); 7.17-7.53 (m, 9H, 9Ar-H). 13C NMR (75 MHz, DMSO-J6): 21.04 (CH3-Ar), 28.95 (CH3), 38.41 (CH-Ar), 57.85 (=Cquat), 63.25 (ch), 121.03 (CN), 127.41 (2CHarom), 129.42 (CHarom), 129.61 (2CHarom), 129.94 (2CHarom), 130.31 (2CHarom), 135.09 (Car), 137.13 (Car), 137.53 (Car), 154.63 (=Cquat), 167.16 (N-C=O), 203.13 (C=O).
5-Acetyl-2-amino-4-(4-nitrophenyl)-6-oxo-1-phenyl-1,4,5,6-tetrahydropyridine-3-car-bonitrile (VI) was synthesized by the same methods. Crystals were filtered by the paper and recrystallized from ethanol-water mixture. Yield - 1.18 g, 69%.
White powder with; m.p.2590C; 1H NMR (300 MHz, DMSO-J6): 2.34 (s, 3H, CH3); 4.12 (d, 1H, CH, 3Jh-h = 4.2); 4.32 (d, 1H, CH, 3Jh-h = 4.2); 5.96 (s, 2H, NH2); 7.20-7.51 (m, 9H, 9Ar-H). 13C NMR (75 MHz, DMSO-^6) 28.95 (CH3), 43.29 (CH-Ar), 57.72 (=Cquat), 63.20 (CH), 121.09 (CN), 127.85 (2CHarom), 128.11 (CHarom), 129.02 (2CHarom), 129.39 (2CHarom), 130.09 (2CHarom), 135.13 (Car), 140.79 (Car),
154.72 (=Cquat), 165.34 (Car), 167.08 (N-C=O), 202.96 (C=O).
5-Acetyl-2-amino-6-oxo-1-phenyl-4-(thi-ophen-2-yl)-1,4,5,6-tetrahydropyridine-3-car-bonitrile (VII) was synthesized by the same methods. Crystals were filtered by the paper and recrystallized from ethanol-water mixture. Yield - 1.34 g, 87.01%.
White powder; m.p.2270C; 1H NMR (300 MHz, DMSO-d6): 2.35 (s, 3H, CH3); 4.13 (d, 1H, CH, Vh-h = 2.7); 4.56 (d, 1H, CH, Vh-h = 2.7); 6.02 (s, 2H, NH2); 6.99-7.54 (m, 8H, 5Ar-H+3CHthioph). 13C NMR (75 MHz, DMSO-d6): 28.71 (CH3), 34.60 (CH-Ar), 59.07 (=Cquat), 63.86 (CH), 120.80 (CN), 125.46 (CHarom), 125.51 (CHthioph), 128.12 (CHthioph), 129.54 (CHthioph), 130.09 (4CHarom), 135.06 (Car), 145.91 (Cthioph), 154.64 (=Cquat), 166.67 (N-C=O), 202.21 (C=O).
(E)-2-Amino-4-(2,6-dichlorophenyl)-5-(1-hydroxyethylidene)-6-oxo-1-phenyl-1,4,5,6-tetrahydropyridine-3-carbonitrile (XII) was synthesized by the same methods. Crystals were filtered by the paper and recrystallized from ethanole-water mixture. Yield: 1.45 g, 79.23%.
White powder; m.p.2650C; 1H NMR (300 MHz, DMSO-d6): 1.77 (s, 3H, CH3); 5.49 (s, 3H, NH2+CH-Ar); 7.18-7.57 (m, 9H, 9Ar-H); 14.49 (s, 1H, OHenol). 13C NMR (75 MHz, DMSO-d6): 19.66 (CH3), 35.85 (CH-Ar), 55.80 (=Cquat), 96.44 (=Cquat), 120.10 (CN), 129.06 (CHarom), 129.78 (CHarom), 130.01 (2CHarom), 130.10 (2CHarom), 131.36 (CHarom), 134.14 (CHarom), 134.96 (Car), 135.21 (2Car), 137.96 (Car), 151.97 (=Cquat), 169.53(=Cquat-O), 176.43 (N-C=O).
2-Amino-6-oxo-1-phenyl-4-(4-(trifluoro-methyl)phenyl)-1,4,5,6-tetrahydropyridine-3-carbonitrile (XIV) was synthesized by the same methods. Crystals were filtered by the paper and recrystallized from ethanole-water mixture. Yield: 1.41 g, 86.50%.
White powder; m.p.2230C; 1H NMR (300 MHz, DMSO-d6): 2.82 (dd, 1H, CH2, 3Jh-h = 10.5); 3.22 (dd, 1H, CH2, Vh-h = 9); 4.07 (t, 1H, CH, 3Jh-h = 5.7); 5.93 (s, 2H, NH2); 7.23-7.80 (m, 9H, 9Ar-H). 13C NMR (75 MHz, DMSO-d6): 36.29 (CH-Ar), 40.13 (CH2), 58.59 (=Cquat), 121.26 (CN), 126.14 (CHarom), 126.19 (CHarom), 126.24 (CHarom), 126.28 (CHarom), 128.04 (CHarom),
128.32 (Car), 128.47 (Car), 129.35 (CHarom), 129.83 (CHarom), 129.94 (CHarom), 135.44 (Car), 147.59 (=Cquat), 155.42 (CF3), 168.88 (N-C=O).
5-Acetyl-2-amino-4-(2-chloro-5-nitrophe-nyl)-6-oxo-1-phenyl-1,6-dihydropyridine-3-car-bonitrile (XVI). 2-Chloro-5-nitrobenzylidene-malononitrile (4.56 mmol) and acetoacetanilide (4.6 mmol) were stirred in 35 ml of methanol. Then 3-4 drops of pyperidine were added to reaction mixture and stirred again for 2-3 min. The progress of the reaction was monitored by TLC (EtOAc/n-hexane, 3:1). Crystals were precipitated after evaporation of solvent, filtered by paper, recrystallized from ethanol-water mixture and obtained in pure form (yield - 0.7 g, 37.63%).
White powder; m.p.2090C; 1H NMR (300 MHz, DMSO-d6): 2.29 (s, 3H, CH3); 7.33-8.27 (m, 10H, 8Ar-H+NH2). 13C NMR (75 MHz, DMSO-d6): 31.50 (CH3), 75.34 (=Cquat), 115.05 (=Cquat), 115.91 (CN), 123.97 (CHarom), 124.91 (CHarom), 128.75 (CHarom), 130.43 (CHarom), 130.97 (CHarom), 131.06 (3 CHarom), 134.42 (Car), 138.51 (Car), 139.27 (Car), 146.62 (=Cquat), 153.23 (NO2-Car), 156.89 (=Cquat), 160.71 (N-C=O), 196.81 (C=O).
5-Acetyl-2-amino-4-(2-chloro-5-nitrophe-nyl)-6-oxo-1-phenyl-1,4,5,6-tetrahydropyridine-3-carbonitrile (XVII) was synthesized by the same methods. Crystals were filtered by the paper and recrystallized from ethanol-water mixture. Yield: 1 g, 53.76%.
White powder with m.p.2240C; 1H NMR (300 MHz, DMSO-d6): 2.41 (CH3), 4.14 (d, 1H, CH, 3Jh-h = 3.6); 4.23 (d, 1H, CH, Vh-h = 3.6); 6.35 (s, 2H, NH2); 7.26-7.63 (m, 8H, 8Ar-H). 13C NMR (75 MHz, DMSO-d6): 28.98 (CH3), 36.43 (CH-Ar), 55.24 (=Cquat), 60.72 (CH), 120.33 (CN), 123.26 (CHarom), 124.90 (CHarom), 129.50 (CHarom), 129.81 (CHarom), 129.91 (CHarom), 130.23 (CHarom), 132.36 (2CHarom), 134.83 (Car), 139.54 (Car), 140.23 (Car), 147.38 (NO^Car), 155.84 (=CqUat), 166.26 (N-C=O), 201.63 (C=O).
References
1. Saad R.El-Z. Antimicrobial activity of some 2-amino-5-subsituted pyridine derivatives // Journal Archives of Phytopathology and Plant Protection. 2011. V. 44. Iss. 4. P. 381-389.
2. Fatma E.G., Alaa A.-M.Abdel-Aziz, Omer A.A. Synthesis, antimicrobial activity and confor-
mational analysis of novel substituted pyridines: BF3-promoted reaction of hydrazine with 2-alkoxy pyridines // Bioorganic & Medicinal Chem. 2004. V. 12. iss. 8. P. 1845-1852.
3. Mourad Ch., Abdelouahid S., Elena S., Olivier L., Laurent M., José Marco-C. Synthesis and biological evaluation of 3,6-diamino-1H-pyrazolo[3,4-b]pyridine derivatives as protein kinase inhibitors // Bioorganic & Med. Chem. Letters. 2009. V. 19. iss. 16. P. 4566-4569.
4. Messer W.S.Jr., Abuh Y.F., Liu Y., Periyasamy S., Ngur D O., Edgar M.A., El-Assadi A.A., Sbeih S., Dunbar P.G., Roknich S., Rho T., Fang Z., Ojo B., Zhang H., Huzl J.J., Nagy P.I. Synthesis and biological characterization of 1,4,5,6-tetrahyd-ropyrimidine and 2-amino-3,4,5,6-tetrahydropyri-dine derivatives as selective m1 agonists // J. Med. Chem. 1997. V. 40. No 8. P. 1230-1246.
5. Hamdy A.H., Ahmed, M.El-Reedy and Sohair M.H. Reactions with a-substituted cinnamonitri-les. A novel synthesis of Aexa-substituted pyridines // J. Heterocycl. Chem. 1986. V. 23. Iss. 4. P. 1203-1206.
6. Mohamed Sh., Mohamed A., Nabil Y., Mohamed G. Studies on heterocyclization of acetoacetanilide // J. Iran Chem. Soc. 2013. V. 10. P. 85-91.
7. Ramakanth P., Suresh M., and Sreekanth B.J. Mild and Efficient Synthesis of Polyfunctionalized 4H-Pyran-3-carboxamide Derivatives // Org. Prep. Proced. Int. 2014. V. 46. Iss. 3 . P. 261-266.
8. Suresh M., Ramakanth P., Surjyakantha R., Shravankumar K., Sreekantha B.J. Mg-V/CO3 hydrotalcite: an efficient and reusable catalyst for one-pot synthesis of multisubstituted pyridines // Res. Chem. Intermed. 2015. V. 41. Iss. 11. P. 8269-8278.
9. Rasha A.A., Rafat M.M. Multicomponent Reactions of Acetoacetanilide Derivatives with Aromatic Aldehydes and Cyanomethylene Reagents to Produce 4H-Pyran and 1,4-Dihydropyridine Derivatives with Antitumor Activities // Chem. Pharm. Bull. 2015. V. 63. Iss. 12. P. 1055-1064.
10. Xin X., Yan W., Santosh K., Xu L., Yingjie L., and Dewen D. Efficient one-pot synthesis of substituted pyridines through multicomponent reaction. Org. Biomol. Chem. 2010. V. 8. Iss. 13. P. 3078-3082.
BOZi BENZiLiDENMALONONiTRlLLORlN ASETOASETANiLiD iLO CEVRiLMOSiNiN TODQiQi
A.M.M3h3rramov, F.N.Nagiyev, A.R.Osg3rova, E.Z.Hüseynov, LQ.Mammadov
p-Metil-, p-nitroavazli benzilidenmalononitrillarin va tiofenilidenmalononitrilin asetoasetanilidla Mixael birla§ma reak-siyasindan uygun avazlanmi§ piridin töramalari sintez edilmi§dir 2,6-Dixlorbenzilidenmalononitrilin asetoasetanilidla Mixael birla§ma reaksiyasi apanlmi§ va uygun avazlanmi§ piridin töramasi olan (£)-2-amin-4-(2,6-dixlorfenyl)-5-(1-hidroksiethiliden)-6-okso-1-fenil-1,4,5,6-tetrahidropiridin-3-karbonitril birla§masi alinmi§dir. V, VI va VII birla§ma-larindan farqli olaraq bu reaksiyada enol formasinda olan reaksiya mahsulunun üstünlük ta§kil etdiyi müayyan edilmi§dir. Hamginin p-triflüorbenzilidenmalononitril va 2-xlor-5-nitrobenzilidenmalononitrilin asetoasetanilidla Mixael birla§ma reaksiyasi tadqiq edilmi§dir.
Keywords: p-triflüorbenzilidenmalononitril, 2-xlor-5-nitrobenzilidenmalononitril, asetoasetanilid, NMR.
ИССЛЕДОВАНИЕ ПРЕВРАЩЕНИЙ НЕКОТОРЫХ БЕНЗИЛИДЕНМАЛОНОНИТРИЛОВ С
АЦЕТОАЦЕТАНИЛИДОМ
А.М.Магеррамов, Ф.Н.Нагиев, А.Р.Аскерова, Е.З.Гусейнов, И.Г.Мамедов
Реакцией присоединения Михаеля w-метил-, w-нитрозамещенных бензилиденмалононитрилов и тиофени-лиденмалононитрила с ацетоацетанилидом синтезированы замещенные пиридиновые производные. Реакция присоединения Михаеля была также проведена между 2,6-дихлорбензилиденмалононитрилом и ацетоацетанилидом с получением соответствующего пиридинового производного (£)-2-амино-4-(2,6-дихлорофенил)-5-(1-гидроксиетилиден)-6-оксо-1-фенил-1,4,5,6-тетрагидропиридин-3-карбонитрила. В отличие от соединений V, VI и VII, в данной реакции продукты находятся преимущественно в енольной форме. Кроме того, была изучена реакция присоединения Михаеля w-трифторобензилиденмалононитрила и 2-хлор-5-нитробензилиденмалоно-нитрила с ацетоацетанилидом.
Ключевые слова: п-трифторобензилиденмалононитрил, 2-хлор-5-нитробензилиденмалононитрил, ацетоацет-анилид, ЯМР.
