Research into one-step three component reaction of some ylidenecyanoacetamides (or ylidenemalononitriles), malononitrile and 1,3-diaminopropane Текст научной статьи по специальности «Химические науки»

CHEMICAL PROBLEMS 2019 no. 2 (17) ISSN 2221-8688

275

UOT 547.97+535.37

RESEARCH INTO ONE-STEP THREE COMPONENT REACTION OF SOME YLIDENECYANOACETAMIDES (OR YLIDENEMALONONITRILES), MALONONITRILE AND 1,3-DIAMINOPROPANE

F.N. Naghiyev

Baku State University, Chemical Faculty Z. Khalilov 23, Baku, Azerbaijan, e-mail: [email protected]

Received 21.04.2019

Abstract: The one-step interaction of substituted ylidenecyanoacetamides (or ylidenema-lononitriles), malononitrile and 1,3-diaminopropane was carried out in methanol environment at room temperature and it established the formation of new substituted dihydropyridopyrimidine derivatives. It also revealed that under the same conditions through the use of one-step three-component reaction of pyridylidenecyanoacetamide (or pyridylidenemalononitrile), 2-chloro-5-nitrobenzylidenecyanoacetamide (or 2-chloro-5-nitrobenzylidenemalononitrile), 2,6-dichlorobenzylidenecyanoacetamide (or 2,6-dichlorobenzylidenemalononitrile), malononitrile and 1,3-diaminopropane there formed substituted derivatives not of dihydropyridopyrimidine but tetrahydropyridopyrimidine. Structures of all synthesized compounds were verified by NMR and X-Ray spectroscopy.

Keywords: ylidenecyanoacetamides, pyridylidenecyanoacetamide, malononitrile,

1,3-diaminopropane, NMR

DOI: 10.32737/2221-8688-2019-2-275-281

Introduction

The literature refers to new methods of theirv ibhibiting properties in respect of production of pyrimidine derivatives and various disease-producing factors [1-12].

Results and discussion

We carried out the one-step three component interaction of various ylidenecyanoacetamides (or ylidenema-lononitriles), malononitrile and 1,3-diaminopropane in methanol environment and

at room temperature, for 24-28 hours and established the possibility of production of substituted new dihydropyrido[1,2-a]pyrimidines (4a-j) irrespective of the nature of polarized double bond.

CN CN R-CH=^ + / +

\

h2n"

vnh2

CH3OH r.t., 48 h

= a) C6H5, b) 4-CH,C6H4, c) 4-CH,OC6H4, d) 4-F-C6H„, e) 3-Cl-CH f) 4-Br-C6H„, g) 4-CF3C6H4, h) 3-CH3O-4-OH-C6H3, j) thiophenyl

X = CONH,, CN

3

1

R

A plausible mechanism of the reaction is presented below:

(NC)2CH2 + H2N(CH2)3NH2

(NC)2CH + H3N(CH2)3NH2

NC

CN

NC

+ NH3(CH2)3NH2 ^

^^^ " NH2(CH2)3NH2 -

CN

//

^ V

N NH2

R = a) C6H4, b) 4-CH3C6H„, c) 4-CH3OC6H4, d) 4-F-C6H4, e) 3-Cl-C6H4, f) 4-Br-C6H4, g) 4-CF3C6H4, h) 3-CH3O-4-OH-C6H3,

CN NC

H^

CN

H2N

\

NH2

j) thiophenyl

NC

CN

NH2

Through the use of similar one-step three-component reaction of pyridylidene cyano acetamide (or pyridylidenemalononitrile) as compound with polarized double-bond,2,6-dichlorobenzylidenecyanoacetamide (or 2,6-dichlorobenzylidene malononitrile),

malononitrile and 1,3-diaminopropane at the same conditions, it became possible to establish the formation of corresponding substituted tetrahydropyrido[1,2-a]pyrimidine derivatives (6, 8, 10), not dihydropyrido[1,2-a]pyrimidines.

CN CN

R1-CH=^ + / +

^ CN

NC

NH

1 2 r t 48 h. ^^^^

3 ' HN ^N^ NH2

CN

R1 = pyridyl (5), 2-Cl-5-NO2-C6H3 (6), 2,6-Cl-C6H3 (7)

8, 9, 10

X = CONH CN

A plausible reaction mechanism and 13C NMR spectra (fig.1, fig.2) of compound 4e is presented below.

(nc)2CH2 + H2n(ch2)3NH2

r,

(nc)2CH + H3n(ch2)3NH2

cn

nc

+ NH3(CH2>NH2

cn

h,n

nh,

R1 = pyridyl, 2-Cl-5-NO2-C6H,, 2,6-Cl-C6H3

r.

cn

nc

nh2

cn nc

-NH3*

h2n h

nc

CNch Ov ^ - "H«™"3NH- c

c ^ c^nh c#

# ......"

cn

nh2

cn

nh2 ^n^ ^nh-

8, 9, 10

R

R

R

R

NH

R

R

R

H

R

CHOH

H2N

r

r

r

r

Fig. 1. NMR spectrum of 6-amino-8-(3-chlorophenyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidi-ne-7,9-dicarbonitrile (4e).

Fig. 2. 13C NMR spectrum of 6-amino-8-(3-chlorophenyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidi-ne-7,9-dicarbonitrile (4e).

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 Stuart SMP30 apparatus without correction.

13C NMR spectra were recorded on Bruker Avance 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 mo

nitor the course of reactions.

General experimental procedure

6-Amino-8-phenyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidine-7,9-dicarbonitrile (4a): Benzylidenecyanoacetamide, (4 mmol) malononitril (4.1 mmol) and 1,3-diaminopropane (4.1 mmol) stirrered in 35 ml of methyl alcohol. Then the reaction mixture is maintained at room temperature for 2 days. The course of the reaction was monitored by

TLC (EtOAc/n-hexane, 3:2). Crystals were precipitated after evaporation of solvent, filtered by paper, recrystallized from ethanol-water mixture and obtained in pure form (yield 0.81 g, 72.97%). Tmp.=234°C.

1H NMR (300 MHz, DMSO-J6): 1.94 (t, 2H, CH2, 3Jh-h = 6,6); 3.38 (t, 2H, CH2, 3Jh-h = 6,3);3.86 (t, 2H, CH2, 3Jh-h = 5,7); 7.417.52 (m, 5H, 5Ar-H); 7.84 (s, 2H, NH2). 13C NMR spektr (DMSO-J6), 5, m.h.: 19.39 (CH2), 40.72 (2=Cquat), 42.99 (CH2), 43.04 (CH2), 117.25 (CN), 117.85 (CN),128.39 (2CHarom), 128.99 (2CHarom), 130.30 (CHarom), 135.67 (Car), 155.81 (=Cquat.), 156.27 (2=Cquat.).

Found, %: 69.76 C; 4.68 H, 25.50 N. C16H13N5. Calculated, %: 69.82 C; 4.73 H, 25.45 N.

6-Amino-8-(p-tolyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidine-7,9-dicarbonitrile (4b): Synthesized by the same way(yield 0.88 g, 75.86%). Tmp. = 250°C.

1H NMR (300 MHz, DMSO-J6): 1.93 (t, 2H, CH2, 3Jh-h = 6,7); 2.37 (s, 3H, CHs-Ar); 3.37 (t, 2H, CH2, 3Jh-h = 6,3); 3.85 (t, 2H, CH2, 3Jh-h = 6,9); 7.31 (m, 4H, 4Ar-H); 7.82 (s, 2H, NH2). 13C NMR spektr (DMSO-J6), 5, m.h.: 19.37 (CH2), 21.37 (Ar-CH2), 40.54 (CH2), 40.66 (2=Cquat), 42.99 (CH2), 117.33 (CN), 117.96 (CN), 128.35 (2CHarom), 129.52 (2CHarom), 132.72 (Car), 140.08 (Car), 155.85 (=Cquat.), 156.31 (2=Cquat.).

Found, %: 70.64 C; 5.25 H, 24.16 N. C17H15N5. Calculated, %: 70.59 C; 5.19 H, 24.22 N.

6-Amino-8-(4-methoxyphenyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidine-7,9-di-carbonitrile (4c): Synthesized by the same way (yield 0.9 g, 73.17%). Tmp. = 231°C.

1H NMR (300 MHz, DMSO-J6): 1.93 (s, 2H, CH2); 3.37 (s, 2H, CH2); 3.81 (s, 3H, CHO-Ar); 3.85 (s, 2H, CH2); 7.05 (d, 2H, 2Ar-H, 3Jh-h = 8,1); 7.39 (d, 2H, 2Ar-H, 3Jh-h = 7,8); 7.80 (s, 2H, NH2). 13C NMR spektr (DMSO-J6), 5, m.h.: 19.40 (CH2), 38.91 (2=Cquat.), 40.52 (CH2), 42.99 (CH2), 55.73 (CH3O), 114.28 (2CHarom), 117.50 (CN), 118.13 (CN), 127.58 (Car), 127.59 (=Cquat.), 130.12 (2CHarom), 155.88 (=Cquat.), 155.94 (=Cquat), 160.85 (O-Car).

Found, %: 66.82 C; 4.87 H, 23.01 N. C17H15N5O. Calculated, %: 66.88 C; 4.92 H, 22.95 N.

6-Amino-8-(4-fluorophenyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidine-7,9-dicarbonitrile (4d): Synthesized by the same way (yield 0.79 g, 67.52%). Tmp. = 238°C.

1H NMR (300 MHz, DMSO-J6): 1.93 (s, 2H, CH2); 3.38 (s, 2H, CH2); 3.85 (s, 2H, CH2); 7.12-7.52 (m, 4H, 4Ar-H); 7.96 (s, 2H, NH2). 13C NMR spektr (DMSO-J6), 5, m.h.: 19.37 (CH2), 39.02 (2=Cquat), 40.68 (CH2), 43.06 (CH2), 115.91-116.20 (2CHarom), 117.22 (CN), 117.78 (CN), 130.89-131.00 (2CHarom), 132.02 (Car), 155.33 (2=Cquat.), 155.75 (=Cquat), 161.66-164.92 (F-Car).

Found, %: 65.59 C; 4.14 H, 23.84 N. C16H12N5F. Calculated, %: 65.53 C; 4.09 H, 23.89 N.

6-Amino-8-(3-chlorophenyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidine-7,9-dicarbonitrile (4e): Synthesized by the same way (yield 0.91 g, 73.39%). Tmp. = 254°C.

1H NMR (300 MHz, DMSO-J6): 1.93 (s, 2H, CH2); 3.38 (s, 2H, CH2); 3.84 (s, 2H, CH2); 7.38-7.60 (m, 4H, 4Ar-H); 7.90 (s, 2H, NH2). 13C NMR spektr (DMSO-J6), 5, m.h.: 19.39 (CH2), 40.72 (CH2), 40.79 (2=CqUat.), 43.14 (CH2), 117.05 (CN), 117.60 (CN), 127.25 (CHarom), 128.17 (CH^m), 130.23 (CHarom), 131.06 (CHarom), 133.56 (Car), 137.66 (Car), 154.68 (2=Cquat.), 155.68

(=Cquat.).

Found, %: 62.09 C; 3.93 H, 22.56 N. C16H12N5CL Calculated, %: 62.03 C; 3.88 H, 22.62 N.

6-Amino-8-(4-bromophenyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidine-7,9-di-carbonitrile (4f): Synthesized by the same way (yield 0.89 g, 62.68%). Tmp. = 278°C.

1H NMR (300 MHz, DMSO-J6): 1.93 (s, 2H, CH2); 3.37 (s, 2H, CH2); 3.83 (s, 2H, CH2); 7.38 (d, 2H, 2Ar-H, 3Jh-h = 8,1); 7.73 (d, 2H, 2Ar-H, 3Jh-h = 8,1); 7.93 (s, 2H, NH2). 13C NMR spektr (DMSO-J6), 5, m.h.: 19.37 (CH2), 40.69 (CH2), 40.72 (2=Cquat.), 43.15 (CH2), 117.15 (CN), 117.69 (CN), 123.85 (Br-Car), 130.60 (2CHarom), 132.09 (2CHarom), 134.87 (Car), 155.15 (2=Cquat.), 155.67

(=Cquat.).

Found, %: 54.19 C; 3.33 H, 19.82 N. Ci6Hi2N5Br. Calculated, %: 54.24 C; 3.39 H, 19.77 N.

6-Amino-8-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidine-7,9-dicarbonitrile (4g): Synthesized by the same way (yield 0.9 g, 65.69%). Tmp. = 331°C.

1H NMR (300 MHz, DMSO-d6): 1.94 (s, 2H, CH2); 3.38 (s, 2H, CH2); 3.84 (s, 2H, CH2); 7.66 (d, 2H, 2Ar-H, Vh-h = 7,8); 7.90 (d, 2H, 2Ar-H, 3Jh-h = 7,8); 7.96 (s, 2H, NH2). 13C NMR spektr (DMSO-d6), 5, m.h.: 19.35 (CH2), 40.62 (CH2), 40.75 (2=CqUat), 43.19 (CH2), 117.02 (CN), 117.54 (CN), 126.03126.17 (2CHarom), 129.50 (2CHarom), 130.28 (CF3-Car), 130.70 (CF3), 139.80 (Car), 154.93 (2=Cquat.), 155.66 (=Cquat.).

Found, %: 59.41 C; 3.45 H, 20.47 N. C17H12N5F3. Calculated, %: 59.47 C; 3.50 H,

20.41 N.

6-Amino-8-(4-hydroxy-3-methoxyphenyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidine-7,9-dicarbonitrile (4h): Synthesized by the same way (yield 0.93 g, 72.66%). Tmp. = 181°C.

1H NMR (300 MHz, DMSO-d6): 1.93 (s, 2H, CH2); 3.36 (s, 2H, CH2); 3.78 (s, 3H, CH3O); 3.85 (s, 2H, CH2); 6.86-7.61 (m, 6H, 3Ar-H+Ar-OH+NH2). 13C NMR spektr (DMSO-d6), 5, m.h.: 19.53 (CH2), 40.62 (CH2), 42.85 (CH2), 56.13 (CH3O), 76.70 (=Cquat.),

80.42 (=Cquat), 112.88 (CHarom), 115.80 (CHarom), 117.80 (CN), 118.52 (CN), 121.81 (CHarom), 125.67 (Car), 147.70 (=Cquat.), 149.42 (=Cquat.), 151.57 (=Cquat.), 156.14 (O-Car), 156.24 (O-Car).

Found, %: 63.60 C; 4.73 H, 21.76 N. C17H15N5O2. Calculated, %: 63.55 C; 4.67 H, 21.81 N.

6-Amino-8-(thiophen-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidine-7,9-dicarbonitrile (4j): Synthesized by the same way (yield 0.76 g, 67.86%). Tmp. = 227°C.

1H NMR (300 MHz, DMSO-d6): 1.93 (m, 2H, CH2); 3.37 (s, 2H, CH2); 3.84 (s, 2H, CH2); 7.21 (t, 1H, Thioph-H, 3Jh-h = 4,2); 7.41 (d, 1H, Thioph-H, 3Jh-h = 3); 7.76 (s, 2H, NH2); 7.83 (d, 1H, Thioph-H, 3Jh-h = 4.8). 13C NMR spektr (DMSO-d6), 5, m.h.: 19.34 (CH2), 40.68 (2=Cquat), 40.72 (CH2), 43.18

(CH2),117.27 (CN), 117.89 (CN),127.93 (CHthioph), 129.79 (CHthioph), 130.47 (CHthioph), 134.67 (Cthioph), 148.41 (=Cquat.), 155.70 (=Cquat.), 162.35 (=Cquat.).

Found, %: 59.74 C; 3.85 H, 24.96 N. C14H11N5S. Calculated, %: 59.79 C; 3.91 H, 24.91N.

6-Amino-8-(pyridin-4-yl)-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrimidine-7,9-dicarbonitrile (6): Synthesized by the same way (yield 0.85 g, 76.57%). Tmp. = 242°C.

1H NMR (300 MHz, DMSO-d6): 1.88 (m, 2H, CH2); 3.13 (m, 2H, CH2); 3.60 (m, 2H, CH2); 4.06 (s, 1H, CH-Ar); 6.27 (s, 2H, NH2); 6.90 (s, 1H, NH); 7.18 (m, 2H, 2Ar-H); 8.51 (m, 2H, 2Ar-H).13C NMR spektr (DMSO-d6), 5, m.h.: 22.01 (CH2), 38.61 (CH2), 38.94 (Ar-CH), 43.07 (CH2), 54.05 (=Cquat), 57.64 (=Cquat.), 121.90 (2CN), 122.28 (2CHarom), 150.31 (2CHarom), 151.26 (Car), 153.21 (=Cquat.), 155.15 (=Cquat.).

Found, %: 64.69 C; 4.98 H, 30.26 N. C15H14N6. Calculated, %: 64.75 C; 5.03 H, 30.21 N.

6-Amino-8-(2-chloro-5-nitrophenyl)-1,3,4,8-tetrahydro-2H-pyrido[1,2-a] pyrimi-dine-7,9-dicarbonitrile (8): Synthesized by the same way (yield 1 g, 69.93%). Tmp. = 243°C.

1H NMR (300 MHz, DMSO-d6): 1.90 (m, 2H, CH2); 3.18 (m, 2H, CH2); 3.64 (s, 2H, CH2); 4.73 (s, 1H, CH-Ar); 6.36 (s, 2H, NH2); 7.00 (s, 1H, NH); 7.71 (d, 1H, Ar-H); 8.07 (d, 2H, 2Ar-H) 13C NMR spektr (DMSO-d6), 5, m.h.: 22.12 (CH2), 37.14 (Ar-CH), 38.64 (CH2), 43.20 (CH2), 53.64 (=Cquat), 57.02 (=Cquat.), 121.48 (CN), 121.89 (CN), 123.65 (CHarom), 124.58 (CHarom), 131.64 (CHarom), 138.68 (Car), 145.56 (Car), 147.37 (Car), 151.69 (=Cquat.), 153.70 (=Cquat.).

Found, %: 53.91 C; 3.71 H, 23.50 N. C^bNACI. Calculated, %: 53.86 C; 3.65 H, 23.56 N.

6-Amino-8-(2,6-dichlorophenyl)-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrimidine-7,9-dicarbonitrile (10): Synthesized by the same way (yield 1.07 g, 77.54%). Tmp. = 268°C.

1H NMR (300 MHz, DMSO-d6): 1.89 (m, 2H, CH2);3.13 (m, 2H, CH2);3.67 (s, 2H,

CH2);5.31 (s, 1H, CH-Ar); 6.14 (s, 2H, NH2); 6.78 (s, 1H, NH);7.25 (t, 1H, Ar-H, Vh-h = 8,1);7.42 (d, 2H, 2Ar-H, Vh-h = 7,8). 13C NMR spektr (DMSO-J6), S, m.h.: 22.30 (CH2), 36.32 (Ar-CH), 38.62 (CH2), 42.92 (CH2), 51.70 (=Cquat.), 55.06 (=Cquat.), 121.61

(CN), 122.04 (CN), 129.56 (3CHarom), 138.25 (Car), 152.11 (Cl-Car), 152.12 (=CqUat.), 154.16 (=Cquat.), 154.17 (Cl-Cr).

Found, %: 55.43 C; 3.71 H, 20.28 N. C16H13N5CI2. Calculated, %: 55.49 C; 3.76 H, 20.23 N.

This study was performed under financial support by the Baku State University (grant 50+50).

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BdZi iLiDENSiANOASETAMiDLdRIN (VB YA HtDENMALONOMTRiLLBRiN) MALONONiTRiL VB 1,3-DiAMiNOPROPANiLB BiRMBRHBLBLi, üQKOMPONENTLI

REAKSiYASININ TBDQiQi

F.N. Nagiyev

Baki Dövldt Universiteti AZ1148 Baki, Z.Xdlilov кйд., 23; e-mail: [email protected]

9vdzldnmi§ ilidensianoasetamidldr (vd ya ilidenmalononitrilldrin) malononitril vd 1,3-diaminopropan ild birmdrhdldli, ügkomponentli reaksiyasi metanol mühitindd, otaq temperaturunda aparilmi§ vd dvdzldnmi§ yeni dihydropyridopirimidin tördmdldrinin dmdld gdldiyi müdyydn edilmi§dir. Eyni reaksiya §draitindd pi-ridilidensianoasetamid (vd ya piridilidenmalononitril), 2-xlor-5-nitrobenzylidensianoasetamid (vd ya 2-xlor-5-nitrobenzylidenmalononitril), 2,6-dixlorbenzylidensianoasetamidin (vd ya 2,6-dixlorbenzyliden-malononitrilin)malononitril vd 1,3-diaminpropan ild bir-mdrhdldli, ügkomponentli reaksiyasindan uygun dvdzldnmi§ dihydropyridopirimidinldr deyil, tetrahydropyridopirimidin tördmdldrinin dmdld gdlmdsi müdyydnld§dirilmi§dir. Bütün sintez edilmi§ birld§mdldrin qurulu§u NMR spektroskopiyasi ild tdsdiq edilmi§dir.

Keywords: ilidensianoasetamidldr, piridilidensianoasetamid, malononitril, 1,3-diaminopropan, NMR

ИССЛЕДОВАНИЕ ОДНОСТАДИЙНОЙ ТРЕХКОМПОНЕНТНОЙ РЕАКЦИИ НЕКОТОРЫХ ИЛИДЕНЦИАНОАЦЕТОАМИДОВ (ИЛИ ИЛИДЕНМАЛОНОНИТРИЛОВ), МАЛОНОНИТРИЛА И 1,3-ДИАМИНОПРОПАНА

Ф.Н. Нагиев

Бакинский государственный университет AZ1148 Баку, ул. З.Халилова, 23; e-mail: [email protected]

Осуществлено одностадийное взаимодействие замещенных илиденцианоацетамидов (или илиденмалононитрилов), малононитрила и 1.3-диаминопропана в среде метанола при комнатной температуре, и установлено образование новых замещенных производных дигидропиридопиримидина. Показано, что в тех же условиях путем одностадийной трехкомпо-нентной реакции пиридилиденцианоацетамида (или пиридилиденмалононитрила), 2-хлор-5-нитро-бензилиденцианоацетамида (или 2-хлор-5-нитробензилиден малоно- нитрила), 2,6-дихлор-бензилиденцианоацетамида (или 2,6-дихлорбензилиденмалоно- нитрила), малононитрила и 1,3-диаминопропана образуются замещенные производные не дигидропиридопиримидина, а тетрагидропиридопиримидина. Структуры синтезированных соединений подтверждены методом ЯМР-спектроскопии.

Ключевые слова: илиденцианоацетамиды, пиридилиденцианоацетамид, малононитрил, 1,3-ди-аминопропан, ЯМР