Научная статья на тему 'The investigation of convertion of benzylidenemalononitriles with acetoacetanilide'

The investigation of convertion of benzylidenemalononitriles with acetoacetanilide Текст научной статьи по специальности «Химические науки»

CC BY
137
70
i Надоели баннеры? Вы всегда можете отключить рекламу.
Журнал
Azerbaijan Chemical Journal
Область наук
Ключевые слова
P-TRIFLUOROBENZYLIDENEMALONONITRILE / 2-CHLORO-5-NITROBENZYLIDENEMALONONITRILE / ACETOACETANILIDE / NMR

Аннотация научной статьи по химическим наукам, автор научной работы — Maharramov A.M., Naghiyev F.N., Asgerova A.R., Guseynov E.Z., Mamedov I.G.

By the Michael addition reaction of p -methyl, p -nitro substituted benzylidenemalononitriles and thiophenylidenemalononitrile 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 -trifluorobenzylidenemalononitrile and 2-chloro-5-nitrobenzylidenemalononitrile with acetoacetanilide has been investigated

i Надоели баннеры? Вы всегда можете отключить рекламу.
iНе можете найти то, что вам нужно? Попробуйте сервис подбора литературы.
i Надоели баннеры? Вы всегда можете отключить рекламу.

Текст научной работы на тему «The investigation of convertion of benzylidenemalononitriles with acetoacetanilide»

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 [email protected] 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.

iНе можете найти то, что вам нужно? Попробуйте сервис подбора литературы.
i Надоели баннеры? Вы всегда можете отключить рекламу.