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Reactions with the Arylhydrazones of some a-Cyanoketones

Ezzat Mohemed Kandeel*, Kamal Usef Sadek, and Mohamed Hilmy Elnagdi Chemistry Department; Mansoura University at Elmansoura and Faculty of Science Cairo University, Giza, A. R. Egypt

Z. Naturforsch. Bob, 91-94 (1980); received May 10, 1979

Arylhydrazones, a-Cyanoketones

The N-methylarylhydrazones of mesoxalodinitrile (3) and of ethyl cyanoglyoxalate (7) could be prepared via methylation of the corresponding phenylhydrazones 4 and 6 respectively. The hydrazones 3 and 8 reacted with hydrazine hydrate to yield the amidra-zone 1 and the hydrazide 2 b. The behavior of compounds 1 and 2 a, b towards a variety of reagents is reported. A variety of new a-arylhydrazononitriles were synthesised.

The considerable biological and medicinal activ-ities of the arylhydrazones of a-cyanoketones as antituberculoses [1-3] and oxidative phosphoryla-tion inhibitors [4-7] have stimulated recent interest in the chemistry of this class of compounds [8-11]. As a part of our programe dealing with the synthesis [12] and chemistry [13] of a-cyanoarylhydrazones we report here the synthesis and chemistry of the a-cyanoarylhydrazones 1 and 2 a, b.

the hydrazide obtained was usually contaminated with 3-amino-4-phenylazo-2-pyrazolin-5-one (7) re-sulting from base catalysed cyclization of 6 by the action of traces of excess hydrazine.

NC CN

N. \ N-CHj

\ H 5

NC CN Y \ NH I c6Hs

NH, I 2 C. V CONH-NH,

^ N-R

"NJI-CH, C6HS

c8h5 2a : R = H 1 2b : R = CHJ

Compound 1 could be obtained via the action of hydrazine hydrate on methylphenylhydrazono-mesoxalonitrile (3) the latter could be synthesised via the action of methyl iodide on phenylhydrazono-mesoxalonitrile (4). Although this product was previously prepared by Elnagdi and Abdoula [14] via the action of diazomethane on 4, the methylation procedure appeared to us more convienient as it afforded better yield of 3 with almost no side reaction products as those always formed in the reaction of 4 with diazomethane. Compound 2a was synthesised for the present investigation via coupling of cyanoacethydrazide (5) with benzene diazonium chloride. Again this procedure proved also to be better than the previously reported [15] synthesis of 2 a from ethyl phenylazocyanoacetate (6) and hydrazine hydrate as in the last procedure

* Reprint requests to Prof. Dr. E. M. Kandeel. 0340-5087/80/0100-91/$ 01.00/0

The hydrazide 2 b could be synthesised via the action of hydrazine hydrate on 8 now obtained via methylation of 6 by methyl iodide.

NC-CH2-CO-NH-NH2 P H - N ° N C I . 2A . H I " -™R H » ° C2HSO-! CN Y

PH-N-N „ NH2 J N\ H I i f ^ ^ NH"Ph

o^f1 6 H

C2H5O

2b H2N-NH2 C H 3 - Y

1 Ph

Compound 1 reacted with benzoyl isothiocyanate, in re fluxing acetone to yield the 1-aminotriazine derivative 9. Attempted cyclization of 1 into a 3,5-diaminopyrazole derivative by reflux in acetic acid has afforded a product for which structure 10 was suggested based on the available data. Further work to establish this structure is now undertaken. When 1 was refluxed in pyridine or in acetone for long period it was converted, almost quantitatively into 3. Under a variety of other conditions com-pound 1 could not be cyclised into 3,5-diamino-pyrazole derivative. This is incontrast to the well

92 E. M. Kandeel et al. • Reactions with the Arylhydrazones of some a-Cyanoketones

established ready formation of 4-arylazo-3,5-di-aminopyrazoles (11) from reaction of 4 with hydrazine hydrate via intermediate, highly unstable amidrazones [14].

3 p y r i d i n e 1 P h C O N C S ^ N C

o r a c e t o n e * AcOH H CHj-N

S A N N 1 I

NC

CH3\ /N N

P h

CN P h

10

CH3-N

C6H5

i N = N ^ N H

Compound 2 a reacted with hydroxylamine hydrochloride on cold in the presence of sodium acetate to afford 3-amino-4-phenylhydrazono-2-isoxazolin-5-one (12). The structure of this product was established by identity with an authentic speciment [8]. On the other hand, treatment of 2 a with neutralized hydroxylamine has afforded the isomeric isoxazolone derivative 13. In contrast to the behaviour of 2 a compound 2 b reacted with hydroxylamine hydrochloride in the presence of little excess of sodium carbonate to yield the amidoxime 14.

HjN CH

CONH•NH2

N

H2N 0

13

OH P h H - N NH2QH 2 A NH2QH-HCI

N a O A C

CHJ(CN),

r V " " '

0' N̂ H

-N-N H

I H

CN

15

hydrazono-2-pyrazolin-5-one (17) by reflux in acetic acid.

The procedures described here were found all satisfactory. Good yields of interesting reaction products could be synthesised.

CH,

N C . .CONH • N H C S N H R • Y 2b- N NH,

> N ' N

\ / N I P h

14

The cyano group of 2 a could be condensed with malononitrile in refluxing DMF to yield a product the analytical and spectral data of which indicate structure 15. The formation of 14 in this reaction might be assumed to proceed as shown below.

The behavior of 2 a, b toward the action of benzoyl and of ethoxycarbonyl isothiocyanates has also been investigated. Whereas 2 a afforded a mixture of products in these reactions which could not be identified, 2 b reacted smoothly with both reagents to yield the thiourea derivatives 16a, b.

Finally in contrast to 1 compound 2 b could be readily cyclised into 3-amino-4-methylphenyl-

16a: R = CO2C2H5

1 6 b : R = C O P h

Experimental All melting points are uncorrected. IR spectra

were recorded (KBr) with a Pye Unicam IR 20. !H NMR Spectra were obtained on EM-390-90MHz spectrophotometer using TMS as internal indicator and chemical shifts are expressed as d ppm.

N-Methyl-phenylazomalononitrile (3) To a solution of 1.7 g (0.01 mole) of phenylazo

malononitrile in 50 ml acetone; was added 1.4 g (0.01 mole) methyl iodide and 2 g of anhydrous potassium carbonate. The reaction mixture was refluxed for 90 min, then evaporated in vacuo. The solid product so formed was collected by filtration and crystallised from methanol.

Compound 3 formed yellow crystals, m.p. 100 °C; yield 80%. IR : 2200 and 2220cm-1 {v two CN), 1590 cm-i (vC=N). C10H8N4

Calcd C 65.2 H 4.3, Found C 65.1 H 4.6.

93 E. M. Kandeel et al. • Reactions with the Arylhydrazones of some a-Cyanoketones

This compound was found identical with authentic speciment [14].

N-Methylphenylazocyanoacetamidrazone (1) A solution of 1.8 g (0.01 mole) of 3, in 50 ml

ethanol, was treated with 0.5 g (0.01 mole) of hydrazine hydrate (98%). The reaction mixture was refluxed for 90 min, then evaporated in vacuo. The solid product so formed Avas collected by filtration and crystallised from ethanol.

Compound 1 formed yellow needles, m.p. 140 °C, yield 75%. m NMR: 3.83 (S, 3H, CH3); 5.36, 5.53 (two singuletts, 4H, lost afters D 2 0 exchange. "NH 2 protons); 7 .00 -7 .45 (m. 5H, phenyl pro-tons). I R : 3440 and 3340 cm"1 (vNH2 and NH). 2200 cm-i (vCN), 1650 cm-1 (<5C=N), and 1600 cm-1

(<5NH2). CloHloN Q

Found C 55.0 H 5.0 N 38.7, Calcd C 55.5 H 5.5 N 38.8.

Phenylazo cyanoacethydrazide (2 a) A solution of 1.4 g (0.01 mole) of benzene di-

azoniumchloride was added to a solution of 0.09 g (0.01 mole) of cyanoacethydrazide in ethanol, containing 2 g of sodium acetate. The solid product, formed on standing, was collected by filtration and crystallised from methanol.

Compound 2a formed yellow needles m.p. 140 °C. This compound was found identical with authentic speciment.

N-Methyl phenylazoethylcyanoacetate (8)

To a solution of 2.17 g (0.01 mole) of 6 in 50 ml acetone, was added 1.4 g (0.01 mole) methyl iodide and 2 g of anhydrous potassium carbonate. The reaction mixture was refluxed for 90 min then evaporated in vacuo. The product was triturated with water, collected by filtration and crystallised from methanol-water mixture.

Compound 8 formed yellow crystalls, m.p. 60 °C; yield 80%, IR 1630-1640 cm-1 (conjugated ester CO), 2240 cm-1 (vCN).

N-M ethylphenylazo-cyanoacethydrazide (2 b) A solution of 2.3 g (0.01 mole) of 8 in 50 ml

absolute ethanol was treated with 1.5 g (0.01 mole) of hydrazine hydrate (98%). The reaction mixture was refluxed for 90 min, then evaporated in vacuo. The solid product so formed was collected by filtra-tion and crystallised from methanol.

Compound 2b formed yellow needles, m. p. 166 °C; yield 80%. I R : 3320 and 3240cm"1 (vNH2), 1660 to 1670 cm-1 (vCO), 1600 cm-1 (vC=N); 2200 cm"1

(vCN). CxoHnNsO

Calcd C 55.3 H 5.2 N 32.2, Found C 55.0 H 5.1 N 32.3.

Reaction of 1 with benzoyl isothiocyanate To a solution of 0.01 mole of benzoyl isothio-

cyanate (prepared as has been previously described) [16] in 100 ml of acetone, 1.7 g (0.01 mole) of 1 was added. The reaction mixture was refluxed for 2 h, then eATaborated in vacuo. The remaining product Avas triturated with water and the solid product, so formed, Avas collected by filtration and crystallised from DMF-water mixture.

Compound 9 formed yellow crystalls, m.p. above 280 °C, vield 60%, I R : 3095 and 3190 cm-1 (vNH); 2200 cm-1 (vCN) and 1670 cm-1 (<5NH2). Cv&HmN 7S

Calcd C 59.8 H4 .1 S 8.8, Found C 60.1 H 4.0 S 8.8.

Reaction of 1 with acetic acid A solution of 1.7 g (0.01 mole) of 1 in 50 ml

acetic acid was refluxed for 30 min. The solvent was then evaporated in vacuo. The remaining product AAras triturated with water and the solid product so formed, was collected by filtration. Repeated crystallisation from methanol afforded analytically pure sample.

Compound 10 formed greenish yellow crystals, m.p. 115 °C,yield70%, I R : broad band at 3450cm-1

(j>NH), 2200 cm-1 (vCN), 1600 cm-1 (<5C = N). CioHnN §

Calcd C 62.6 H 4.4 N 32.8, Found C 62.8 H 4.5 N 32.5.

3-Amino-4-phenylazo-2-isoxazolin-5-one (12) To a solution of 0.01 mole of 2 a in 50 ml ethanol,

was added 0.07 g (0.01 mole) of hydroxylamine hydrochloride and 2 g of sodium acetate. The reaction mixture was stirred for 4 h, then evap-orated in vacuo. The solid product, so formed, was crystallised from methanol.

Compound 12 formed yellow crystals, m.p. 196°C, I R : 3060, 3140, 3360 and 3480 cm-1 (vNH), 1700 cm-1 (vCO), 1600 cm-1 (<5NH). CsHs02N4

Calcd C 52.9 H 3.9 N 27.4, Found C 52.6 H 4.0 N 27.2.

4-Phenylazo-5-amino-3-isoxazolone (13) A solution of 1.9 g (0.01 mole) of 2a in 50 ml

ethanol was treated with 0.07 g (0.01 mole) of hydroxylamin (prepared as has previously de-scribed). The reaction mixture, was stirred for 4 h, then evaporated in vacuo. The solid product so formed Avas collected by filtration and crystallised from DMF-water mixture.

Compound 13 formed yellow crystals, m. p. 238 °C, yield 75%, I R : 3060, 3240 and 3490 cm-1 (vNH), 1700 cm-1 (vCO), 1600 cm-1 (<5NH).

94 E. M. Kandeel et al. • Reactions with the Arylhydrazones of some a-Cyanoketones

C9HA02N4

Calcd C 52.9 H 3.9, Found C 52.4 H 4.0.

Reaction of 2 b with hydroxylamine A solution of 2 g (0.01 mole) of 2b in 50 ml

ethanol was treated with 0.7 g (0.01 mole) hydroxyl-amine hydrochloride and 2 g of sodium carbonate. The reaction mixture was refluxed for 2 h, and evaporated in vacuo. The remaining product was triturated with water, collected by filtration and crystallised from water.

Compound 14 formed yellow crystals, m. p. 220 °C, yield 70%. IR broad band from 3350-3050 cm"1

(vNH and OH), 1680 cm-1 (vC=N). C\qH.\\02N 6

Calcd C 48.0 H 5.6, Found C 48.4 H 5.0.

4-Phenylazo-5-oxo-2-pyrazolin-3-yl-malononitrile(lb) A solution of 1.9 g (0.01 mole) of 2 a in 50 ml

DMF was treated with 0.33 g (0.01 mole) malono-nitrile. The reaction mixture was refluxed for 30 min and evaporated in vacuo. The remaining product was triturated with water, collected by filtration and crystallised from methanol-water mixture.

Compound 15 formed brown crystals, m.p. 280 °C, yield 60%. IR : 3240, 3360 and 3480 cm"1 (vNHa and NH), 2190, 2220 cm-1 (vCN bands), 1720 cm"1

(vCO), 1640 cm-1 (<3NH). C12HSON6

Calcd C 57.1 H 3.2, Found C 57.1 H 3.4.

Reaction of 2 b with isothiocyanates To a solution of 0.1 mole of benzoyl or ethoxy-

carbonyl isothiocyanate (prepared as has been

previously described) in 50 ml of acetone, 0.01 mole of 2 b was added. The reaction mixture was refluxed for 90 min, then evaporated in vacuo. The solid product was collected by filtration and crystallised from the appropriate solvent.

Compound 16 a formed yellow crystals from ethanol, m.p. 222 °C yield '75%. XH NMR. 1.23 (t, 3H, CHs), 4.00 (S, 3H, N-CH3) ; 4.22 (2H, CH2), 7.2, 7.66 (m, 5H; C6H5); 10.20 (NH), 10.77 (S, 1H. NH) and 12.00 (S, 1H, NH). IR : 3040 and 3340cm-1

(vNH), 2200 cm-1 (vCN), 1725 (vCO), 1670 cm-1

(<5NH). CuHieNeOaS

Calcd C 48.3 H 4.6 S 9.2, Found C 48.6 H 5.0 S 9.8.

Compound 16 b formed yellow needles from acetone, m.p. 212 °C yield 75%. XH NMR: 4.00 (S, 3H, NCH3); 7.2, 8.0 (m, 10H, 2C6H5), 10.3 (S, 1H, NH); 11.1 (S, 1H, NH) and 12.0 (S, 1 H. NH). IR : 3080, 3340 cm-1 (vNH), 2200 cm-1

(vCN), 1620 cm-1 (i>C0), 1600 cm-1 (<5NH). CisHieN q02S

Calcd C 56.8 H 4.2 N22.1, Found C 56.5 H 4.0 N21.8.

3-Amino-4-N-methylphenylazo-2-pyrazolin-5-one A solution of 2 g (0.01 mole) of 2 b in 50 ml acetic

acid was refluxed for 30 min, then evaporated in vacuo. The remaining product was triturated with water, collected by filtration and crystallised from methanol-water mixture.

Compound 17 formed brown crystals, m.p. 250°C, yield 60%, IR broad band at 3370 cm-1 (vNH), 1630 cm-1 (i'CO). CxoHuON5

Calcd C 55.3 H5.1, Found C 55.3 H 5.2.

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