Activated Nitriles in Heterocyclic Synthesis: A Novel Synthesis of Pyridazine, Pyrimidine, Pyridine and Pyrano[4,3-b]pyridine Derivatives

R. M. Mohareb and S. M. Fahmy* Chemistry Depar tment , Faculty of Science, Cairo University, Giza, Egypt

Z. Naturforsch. 40b, 664-668 (1985); received December 5, 1984

Activated Nitriles, Heterocycles, Pyridazine Derivatives

Diethyl-3-amino-2-cyano-2-pentendioate (1) reacts with aromatic amines and aminohetero-cyclic compounds to yield amide derivatives (2 c—h). The latter derivatives were utilised in syn-thesis of pyridazines (4a, b), pyrimidine (6), pyridone (9) and pyrano[4,3-b]pyridine (16a, b) derivatives via reaction with aryldiazonium chloride, trichloroacetonitrile, sodiummethoxide and cinnamonitrile derivatives, respectively.

The chemistry of diethyl-3-amino-2-cyano-2-pen-tendioate (1) has received considerable attention in the recent time [1—4]. In a previous article, we re-ported that 1 reacts with hydrazines to yield a mono-hydrazide derivatives of which structures 2a, b were established [5]. The work presented here reports the results obtained on reaction of equimolecular amounts of 1 with different primary aromatic amines and aminoheterocyclic compounds to yield the amide derivatives 2 c—h. The structure of 2 c—h were estab-lished based on analytical and spectral data. The lat-ter derivatives were utilised in synthesis of several new, otherwise difficulty accessible, heterocyclic de-rivatives of potential biological and synthetic inter-est. Thus 2 c, d found to couple with aryldiazonium chloride only in presence of 5% sodium hydroxide to yield the pyridazine derivatives 4 a, b; in which the alkaline coupling medium favours the immediate cyclisation of the non isolable intermediate 3 via loss of ethanol.

2 c reacts readily with trichloroacetonitrile to yield a product of molecular formula C15H1403N4. Struc-ture 6 was assigned for the reaction product based on analytical and spectral data. It seems that 6 was formed via cyclisation of the non isolable inter-mediate 5 via elimination of chloroform and enolisa-tion of the keto pyrimidine formed. 6 reacts with hydrazine hydrate and benzenediazonium chloride to give the hydrazide 7 and the phenylazo derivative 8, respectively.

2 c cyclises via loss of ethanol into 4-amino-3-cy-ano-5-hydroxy-l-phenyl-2-pyridone (9) on refluxing

* Reprint requests to Dr. S. M. Fahmy. Verlag der Zeitschrift für Naturforschung, D-7400 Tübingen 0340 - 5087/85/0500 - 0664/$ 01.00/0

with sodium methoxide. 9 couples with ben-zenediazonium chloride in presence of sodium hy-droxide to afford the phenylazo derivative [10].

2 c condensed with salicylaldehyde to give the aryl-idine derivative 11. Attempts to cyclisation of 11 under different reaction conditions were unsuc-cessful.

2 c reacts with benzylidinemalononitrile and benzyl-idineethylcyanoacetate (12a, b) to yield the expected pyridine derivatives [6] 13a, b, respectively; the struc-tures of 13 a, b were furtherly confirmed by elemental and spectral data. Trials to cyclise the pyridine deriva-tives 13 a, b on refluxing with sodium methoxide did not afford the expected pyrido[4,3-b]pyridine deriva-tives 14a, b; instead, a pyrano[4.3-b]pyridine deriva-tives 16a, b were obtained. The latter structures were confirmed via inspection of elemental and spectral data. The NMR spectrum of 16a re-vealed a singlet broad band for OH at ö 7.0 ppm, a multiplet at d 7.30 ppm corresponds for one phenyl group, in the mean time it revealed the absence of the characteristic signals for the protons of the ethyl-carboxylate group. This result was confirmed by in-spection of 'H NMR of 16b. 16a, b assumed to be logically formed via hydrolysis of the anilide moiety in 13 a, b to give the non isolable intermediate 15, followed by cyclisation via elimination of ethanol.

Experimental Melting points are uncorrected. IR spectra were

recorded (KBr) on a Pye Unicam SP-1000. ! H NMR spectra were obtained on an EM-90 MHZ spectro-meter in DMSO using TMS as internal standard and chemical shifts are expressed as d ppm. Analytical

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665 R . M . M o h a r e b —S. M . F a h m y • A c t i v a t e d N i t r i l e s in H e t e r o c y c l i c S y n t h e s i s

H 2N CN

EtOOC -CH 2 COOEt

1

H 2 N S ,CN 0 , c . c x

R - N - C - C H 2 COOEt

2 a - h e : R = P h - p - N H 2

F: R=N V ON

H

a : R = N H 2

b : R= NHPh

c : R=Ph

d : R= P h - p - c i

® e R-N = NCL H,N CN

CCU-CN

H 0 C = C ii / \

Ph -N -C -C COOEt II

N s NH i R 3

H2N C l 3 C - C = N CN J \ /

0 C=C

Ph M Ä -N -C

) NH2

: A r C N

9 : R H O V N H

I R

Aa: R= Ph A b : R= P h - p - c i

H,N NH,NH,

H Ph -N -C -CH 2

5 COOEt

H,N.

P h - N

HO

> = N CN

COOEt

P h - N

HO

> = N

Ph-N=N-Cl

H,N

H 0 C = C CH,ONa

INH2 CN © e Ph-N = N. CN

Ph-N=NCl T ^ Y

P h N - C - C H 2 COOEt

2c

II I HO N O

CN

C-NHNH, II 1

0

7 H2N

> = N CN PH-N W '

> = < COOEt HO N=N

i Ph

8

12a: X=CN Etooc 12b:x=cooEt

CN

13 a : X=CN 13 b: x=cooEt

o ' " N " ' CN

16 a: X = CN 16 b: x = cooEt

666 R. M. Mohareb —S. M. Fahmy • Activated Nitriles in Heterocyclic Synthesis

data were performed by the microanalytical data Unit at Cairo University.

Preparation of anilides 2 c—f

A mixture of equimolecular amounts of each of compound 1 and the appropriate amino aromatic compound were fused together at 140 °C for 2 h then left to cool. The solid product so formed is washed with dilute hydrochloric acid then collected by filtra-tion (cf. Tables I and II for data).

Preparation of anilides 2g—h The same procedure described for anilides 2 c—f

but carried out on refluxing with dimethylformamide instead of fusion (cf. Table I).

Reaction of compound 2 c with aryldiazonium chloride to give pyridazine derivatives 4 a, b

A solution of aryldiazonium chloride (prepared by adding sodium nitrite (0.01 mol) to the appropriate quantity of aryl amine in hydrochloric acid) is added to a stirred solution of 2c (0.01 mol) in ethanol (50 ml) and 5 ml (5%) sodium hydroxide solution. The mixture is left at room temperature for 15 min. The solid obtained is collected by filtration (cf. Tables I and II).

Reaction of compound 2 c with trichloroacetonitrile to give pyrimidine derivative 6

To a solution of compound 2c (0.01 mol) in dioxan (40 ml) containing triethylamine (1 ml) trichloro-acetonitrile (0.01 mol) is added. The reaction mix-

ture refluxed for 3 h then evapourated in vacuo. The solid product formed is triturated with ethanol and collected by filtration (cf. Tables I and II).

Reaction of compound 6 with hydrazine hydrate to give hydrazide derivative 7

An equimolecular amounts of each of compound 6 and hydrazine hydrate is heated in a boiling water bath for Vi h then left to cool. The solid product, so formed, is washed with ethanol and collected by fil-tration (cf. Tables I and II).

Coupling of compounds 6 with benzenediazonium chloride to give phenylazo derivative 8

A solution of benzenediazonium chloride (pre-pared as mentioned above) is added to a stirred solu-tion of compound 6 (0.01 mol) in ethanol (40 ml) containing sodium hydroxide 5 ml (5%). The reac-tion mixture is left at room temperature for 30 min the resultant solid is collected by filtration (cf. Tables I and II).

Cyclisation of compound 2 c to give pyridine derivative 9

Compound 2c (0.01 mol) is dissolved in ethanol (50 ml) containing sodium methoxide (0.03 mol) then the whole mixture is refluxed in a boiling water bath for 14 h. The solid product, so formed during boiling is dissolved in water and neutralised with hydrochloric acid till pH 6. The precipitated product is collected by filtration (cf. Tables I and II).

Compound Colour Solvent of crystals

M.p. [°C]

Yield [%] Molecular formula

2c colourless ethanol 230-•232 92 C1 4H1 5O3N3 2d colourless dioxan 240-•242 94 C14H14O3N3CI 2e grey dioxan >300 91 C1 4H1 6O3N4 2f colourless D M F 125 65 C12H13O3N5

2g colourless DMF-water 220-•222 81 C„H 1 3 O 4 N 5 2h pale-yellow DMF-water 170 73 C17H16O3N4S 4a pale-yellow DMF-water 250-•253 70 C18H13O2N5 4b yellow dioxan 296-•298 82 C18H12O2N5CI 6 colourless dioxan 155 66 C1 5H1 4O3N4 7 colourless D M F 185-•187 60 C1 3H1 2O2N6 8 yellow DMF-water >300 90 C2 1H1 8O3N6 9 light-brown DMF-water >300 95 C1 2H9O2N3

10 red DMF-water 288-•290 84 C1 8H1 3O2N5 11 yellow DMF-water 170 60 C2 1H1 9O4N3 13 a pale-yellow DMF-water 211-•213 75 C24H19O3N5 13 b colourless dioxan 180-•182 62 C26H24O5N4 16 a brown dioxan 270-•272 70 C1 6H8O3N4 16 b light-brown dioxan 235-•237 68 C18H13O5N3

Table I. Synthetic data for com-pounds prepared.

Satisfactory elemental analysis of all the synthesized com-pounds were obtained.

667 R. M. Mohareb —S. M. Fahmy • Activated Nitriles in Heterocyclic Synthesis

Coupling of compound 9 with benzenediazonium chloride to give phenylazo derivatives 10

The same experimental procedure described for synthesis of compound 8 is carried out (cf. Tables I and II).

Reaction of compound 2 c with salicylaldehyde to give arylidene derivative 1 1

To a solution of compound 2c (0.01 mol) in ethanol (30 ml) containing Vi ml of piperidine

(0.01 mol) of salicylaldehyde is added. The reaction mixture is refluxed for 2 h the evapourated in vacuo. The solid product so formed on adding dilute hydro-chloric acid is collected by filtration (cf. Tables I and II).

Reaction of compound 2 c with cinnamonitrile derivatives 12 a, b to give pyridine derivatives 13 a, b, respectively

To a solution of compound 2c (O.Olmol) in etha-nol (40 ml) containing (V4 ml) of triethylamine

Table II. IR and 'H NMR data of compounds prepared.

Compound IR [cm '] selected bands 'H N M R [ppm]

2c

2d

4a

4b

6

7

8

9

10

13 a

13 b

16 a

16 b

3450-3320 (NH 2 and NH); 3050 (CH aromatic); 2980 (CH2); 2220 (CN); 1710, 1680 (two CO groups) and 1635 ( C = C )

3500-3320 (NH 2 and NH); 3050 (CH aromatic); 2980 (CH2); 2220 (CN); 1705, 1680 (two CO groups) and 1635 (NH2 deformation)

3400-3320 (NH 2 and NH); 3045 (CH aromatic); 2220 (CN); 1700, 1680 (two CO groups) and 1640 ( C = N )

3400-3320 (NH 2 and NH); 3050 (CH aromatic); 2220 (CN); 1710, 1680 (two CO groups) and 1650 ( C = N )

3490 (OH); 3450-3400 (NH3); 3050 (CH aromatic); 2980 (CH2 , CH3); 2210 cm"1 (CN) and 1650-1630 (NH2 de-formation and C = C )

3490 (OH); 3450-3400 (NH, and NH) ; 3050 (CH aroma-tic); 2220 cm"1 (CN) and 1650 (NH2 deformation)

3490 (OH); 3450-3400 (NH2 and NH) ; 3050 (CH aroma-tic); 2980 (CH 2 , CH3) ; 2220 (CN) and 1650-1630 (NH 2 deformation and N = N )

3480 (OH); 3450-3330 (NH2); 3050 (CH aromatic); 2210 (CN); 1680 (CO); 1650 (NH2 deformation)

3490 (OH); 3450-3320 (NH2); 3040 (CH aromatic); 2220 (CN); 1690 (CO) and 1650-1630 (NH2 deformation)

3450-3320 (NH 2 and NH); 3050 (CH aromatic); 2980 (CH2 , CH3); 2220, 2210 (two CN groups); 1700, 1680 (two CO groups) and 1650-1620 (NH2 deformation and C = C )

3500-3320 (NH 2 and NH); 3045 (CH aromatic); 2980 (CH2 and CH 3) ; 2220 (CN); 1710-1680 (three CO); 1650-1635 (NH 2 deformation and C = C )

3490 (OH); 3450-3320 (NH2); 3050 (CH aromatic); 2220, 2210 (two CN groups); 1680 (CO); 1650 (NH2 de-formation)

3490 (OH); 3450-3320 (NH2); 3050 (CH aromatic); 2980 (CH2 , CH3); 2220 (CN); 1700, 1680 (two CO) and 1650 (NH2 deformation)

1.16 (t, 3 H , CH 3) ; 3.27 (s, 2 H , H2); 4.21 (q, 2 H , CH2) ; 3.54 (br, 2 H , NH 2) ; 7.35 (s, 5 H , C6H5) and 10 (s, br , 1H, NH)

1.16 (t, 3 H , CH3) ; 3.28 (s, 2 H , CH2); 3.54 (s, 2 H , NH 2 ) ; 4.1 (q, 2 H , CH2); 7.44 (m, 4 H , C6H4) and 10.36 (s, br, 1H, NH)

5.43 (br, 2 H , NH 2) ; 7 .30 -7 .67 (m, 10H, 2C6H5) and 9.78 (br, s, 1H, NH)

1.16 (t, 3 H , CH3) ; 3.78 (s, 1H, pyrimidine CH); 5.33 (s, br, 2 H , NH 2) ; 7.35 (s, 5 H , C6H5) and 10.0 (br, 1H, O H )

3.87 (br, 2 H , NH 2 ) ; 7 . 1 - 7 . 5 5 (m, 6 H , pyri-dine C5 and C6H5) and 8.47 (br, 1H, O H )

1.37 (m, 4 H , CH 3 , pyridine H-3); 4.25 (m, 4 H , C H , and NH 2 ) ; 6.22 (s, 1H, NH) ; 7 .43 -7 .64 (2s, 10, 2C 6H 5 )

1.32 (m, 7 H , 2CH 3 , pyridine H-3); 4.23 (m, 6 H , 2CH 2 , NH 2 ) ; 6.22 (s, 1H, NH) ; 7 .40 -7 .64 (2s, 10H, 2C 6H 5 )

5.45 (NH2) ; 7.0 (br, 1H, O H ) ; 7.35 (s, 5 H , C6H5)

1.17 (t, 3 H , CH3) ; 4.34 (q, 2 H , CH2) ; 5.45 (br, 2 H , NH 2) ; 7.0 (br, 1H, OH) ; 7.35 (m, 5 H , C6H5)

Mass spectral data for compounds 2d and 16a: Compound mle

2d 308 16a 305

668 R. M. Moha reb —S. M. Fahmy • Activated Nitriles in Heterocyclic Synthesis

(0.01 mol) of each of compounds 12a or 12b is ad-ded. The reaction mixture is refluxed for 4 h then evapourated in vacuo. The solid product, so formed on dilution with water is collected by filtration (c/. Table I and II).

Cyclisation of compounds 13 a, b to give pyrano[4,3-b]pyridine derivatives 16a, b, respectively

The same experimental procedure described for preparation of compound 9 is carried out (c/. Tab-les I and II).

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