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Reactions with Heterocyclic Diazonium Salts, II Synthesis of Some New Pyrazolo[l,5-c]-as-triazines and l,2,4-Triazolo[l,5-c] -as-triazines

Mohamed Hilmy Elnagdi, Mohamed Rifaat Hamza Elmoghayar, Shereif Mahmoud Fahmy, Mohamed Kamal Ahmed Ibraheim, and Hikmat Hussein Alnima

Department of Chemistry, Faculty of Science, Cairo University, Giza, A. R. Egypt

Z. Naturforsch. 88b, 216-219 (1978); received July 29/November 22, 1977

Heterocyclic Diazonium Salts, Pyrazolo[l,5-c]-as-triazines

3-Phenylpvrazole-5-diazonium chloride (2) couples with benzoylacetonitrile and with phenacylthiocyanate to yield the corresponding hydrazone derivatives 3 a, b. Whereas 3 a cyclised into the pyrazolo[l,5-c]-as-triazine derivative (4a) upon treatment with concen-trated sulphuric acid via elimination of water, treatment of 3 b with the same reagent under the same conditions has resulted in elimination of thiocyanic acid and the formation of the pyrazolo[l,5-c]-as-triazine derivative (4b).

Treatment of 2 with aqueous sodium acetate has afforded the corresponding 3-phenyl-5-diazopyrazole (6). The latter reacted readily with dipolarophiles to yield pyrazolo-[l,5-c]-as-triazine derivatives. Pyrazolo[l,5-c]-as-triazines has also been formed upon treatment of 6 with active methylene compounds. The mechanism of reaction of 2 and 6 with active methylene compounds is discussed.

Diazotization of 5-amino-3-ethyl-l,2,4-triazole nitrate (7) has afforded the correspond-ing diazonium derivative which coupled with benzoylacetonitrile and with acetoacet-anilide to yield the corresponding hydrazones 9 a, b. The latter could be cyclised into l,2,4-triazolo[l,5-c]-as-triazines by the action of concentrated sulphuric acid.

Diazotized 1 H-aminoazoles are versatile reagents and their synthetic potentialities has received con-siderable recent attention [1-5]. As a part of our program directed for development of new procedures for the synthesis of bridge-head azoles [6-12] we have previously [6, 11] reported the synthesis of a variety of pyrazolo[l,5-c]-as-triazines and pyrazolo-[l,5-c]-l,2,4-triazoles based on the coupling reaction of 3-phenylpyrazole-5-diazonium chloride with active methylene compounds. In continuation of this work we report here the results of our further investigation on the reaction of diazotized 1H-aminoazoles. The work has resulted, in addition to synthesis of several new pyrazolo[l,5-c]-as-triazines in clarification of the mechanistic pathways for reaction of diazotized 5-aminopyrazoles with active methylene compounds. Thus, diazotization of 5-amino-3-phenylpyrazole (1) has afforded 3-phenyl -pyrazole-5-diazonium chloride (2) which coupled with benzoylacetonitrile and with phenacylthio-cyanate to yield the corresponding hydrazon derivatives 3 a, b, respectively. The isolation of 3 b from reaction of 2 and phenacylthiocyanate is incontrast to the recently reported spontaneous

Requests for reprints should be sent to Dr. M. H. Elnagdi, Department of Chemistry Faculty of Science, Cairo University, Giza, A. R. Egypt.

cyclization of the coupling products of aryl-diazonium salts with phenacylthiocyanate [13].

Compound 3 a readily cyclised into the pyrazolo-[l,5-a]-as-triazine derivative (4a) upon treatment with concentrated sulphuric acid. On the other hand, when 3 b was similarly treated, compound 4 b, the structure of which was inferred from analytical and spectral data, was formed. The formation of 4b from 3 b and concentrated sulphuric acid might be assumed to proceed via initial elimination of thio-cyanic acid leading to the formation of a resonance stablised nitrile imine intermediate which cyclises then to afford the final reaction products (c/. Chart 1).

Previously we have reported [11] that 2 reacts with acrylonitrile, ethyl acrylate and with dimethyl acetylene-dicarboxylate to yield the pyrazolo[l,5-c]-as-triazine derivatives 5a, b and 4c, respectively. Intermediacy of 3-phenyl-5-diazopyrazole (6) has been suggested to account for the formation of these products. Now, we would like to report the isolation of 6 as well as its reactions with dipolaro-philes [13]. Thus, when 2 was treated with aqueous sodium acetate solution it was converted almost quantitatively into the diazobetaien 6. The latter was stable at room temperature but exploded when heated at 145 °C. Compound 6 decomposed on

M. H. Elnagdi et al. • Reactions with Heterocyclic Diazonium Salts 217

boiling in ethanol or in benzene. The nature of the decomposition products will be a subject for a separate comunication. When compound 6 was treated with acrylonitrile ethyl acrylate or with dimethyl acetylenedicarboxylate, products identical in all aspects with those previously formed on treatment of 2 with the same reagents were formed in excellent yields. Compound 6 readily added less reactive dipolarophiles namely chalcone and methyl cinnamate to yield the pyrazolo[l,5-c]-as-triazine derivatives 5 c, d, respectively.

Compound 6 reacted with benzoylacetonitrile, ethyl acetoacetate, 3-iminobutyronitrile, ethyl cyanoacetate and with malononitrile to yield the pyrazolo[l,5-c]-as-triazine derivatives 4a, d-g. Un-der similar conditions compound 6 failed to react with phenacylthiocyanate.

RF NH2 ^ NaN02

HCl PTV

N=N Cl"

,NH PhC0CH2X

Ph V N H

* NH.N=C

CO Ph

RCH=CHX

R = H , X = CN R =H , X = C02C2H5 R = Ph, X = COPh R=Ph, X = C02CH3

Ph'

Ph

| NaN02

sQt-

3 a : X = CN 3 b : X = SCN

4 a , d - g

Ph

4 a : R=Ph , X=CN

N=N

C-C02C2H5

C-CO2C2H5

4 c

4 b 4 c 4 d

R= Ph , X= H R = X = C02CH3

R = CH3,X= CO2C2H5

4 e R= CH3, X= CN 4 f ; R = NH2, x = C02C2H5

4 g • R = NH2,X = CN

In an attempt to prepare authentic speciment of 4f via cyclization of the hydrazone 7, recently synthesised via coupling of 2 with ethyl cyano-acetate, it has been found that the latter (7) is only formed when the coupling is performed in presence of an excess of acetic acid as has been described for its synthesis. Coupling of 2 and ethyl cyanoacetate in less acidic media using the experimental procedure recently reported by us [11] has resulted in the

direct formation of 4f. This result clearly indicate that the accepted assumption [15] that the acid eliminated during the coupling reaction is respon-sible, by catalysing cyclisation of a hypothetically formed hydrazones, for the inability of several authors to isolate acyclic intermediates for the coupling reaction of diazotized 1 H-aminoazoles with certain active methylene compounds. It seems to us most probable that the formation of cyclic or acyclic products from the coupling reaction with active methylene compounds with diazotized aminoazoles is determined by the mechanistic pathway for the reaction. Thus, reagents affording directly cyclic products react, most likely, with the diazonium compound, which under the coupling condition is expected to exist in equilibrium with the diazobetaiene, via a 1,3-dipolarcyclo addition. On the other hand, the formation of hydrazones results from a usual coupling reaction.

In order to gain further information of the mechanism of coupling of diazotized 5-amino-pyrazoles with active methylene compounds a re-investigation of the behavior of 2 toward a variety of active methylene compounds was undertaken. It has been found that 2 reacts with ethyl acetoacetate and with 3-iminobutyronitrile under a variety of basic, neutral and acidic conditions to yield pyrazolo[l,5-c]-as-triazine derivatives (4d, e). The same products were obtained on treatment of 6 with the same reagents in ethanolic solutions. On the other hand, benzoylacetonitrile, ethyl cyano-acetate and malononitrile afforded the respective hydrazones when the coupling reaction was per-formed in faintly acidic medium. In neutral and in basic media the cyclic pyrazolo[l,5-c]-as-triazines (4 a, f, g) were the only isolable reaction products. Compounds 4 a, f, g were also formed from the reaction of 6 with the same reagents in ethanolic solutions. Phenacylthiocyanate did not react with 2 in basic or in neutral media. However in acidic solutions the acyclic hydrazones 3 b was the only obtainable product. These results are in good agreement with the suggested mechanism of reac-tion of 2 with active methylene compounds.

As an extention of our work an investigation of the behavior of 5-amino-3-ethyl-l,2,4-triazole (8) on diazotization was undertaken. Similar to literature attempted diazotization of 8 in the presence of hydrochloric acid resulted in the formation of the corresponding chloro derivative 9. On the other

218 M. H. Elnagdi et al. • Reactions with Heterocyclic Diazonium Salts 218

hand, diazotization of 8 in the presence of nitric acid has generated the corresponding diazonium salt in solution. Although attempted isolation of the latter has resulted in its decomposition, evidence for the formation of the diazonium salt was obtained via coupling with benzoylacetonitrile and with acetoacetanilide to yield the corresponding hydra-zones 10 a, b. Attempted coupling of ethylaceto-acetate, ethyl cyanoacetate or with 3-iminobutyro-nitrile under similar conditions were unsuccessful.

K HN^

NH2

,C2H5 NaN02/HCl

NaNÜ2/HNO3

P2H5

C2H5 K

11

H

NyN^R

12

r .c2H5

t N . N?N N03*

K C 2 H S HN̂ N

T / NH.N=C

\C

COR

!o <!H2

10a. R = C6H5 , X=CN 10b: R= CH3, X=C0NHPh

1 1 , 1 2 a : R = C5H5 , X = CN 1 1 , 1 2 b : R = CH3 , X = CONHPh

Compounds 10 a, b were readily cyclised by the action of concentrated sulphuric acid to yield products that can be formulated as the 1,2,4-triazolo[l,5-c]-as-triazines (11a, b) or the isomeric l,2,4-triazolo[3,4-c]-as-triazines (12a, b). Although we have not now evidence in favour of any of the two isomeric structures, structure 11 seems most likely based on analogy to the behaviour of tri-azolylhydrazones on cyclisation [1].

Experimental All melting points are uncorrected. IR spectra

were recorded on a Perkin-Elmer model 337 spectro-photometer.

2- ( 3-Phenylpyrazol-5-yl )hydrazono-3-oxo-3-phenylpropionitrile (3 a)

A solution of benzoylacetonitrile (0.1 mol) in ethanol (100 ml) was treated with a suspension of sodium acetate (10.0 g in 50 ml of water). A suspension of 3-phenylpyrazol-5-diazonium chloride (2) (prepared by diazotization of 0.1 mol of 1 in the presence of hydrochloric acid-acetic acid mixture as has been recently described [6]) was added with

stirring to this solution. The reaction mixture was kept at room temperature for two hours and the solid product, so formed, was collected by filtration. Recrystallisazion from ethanol afforded analytically pure sample of 3a as brown crystals, m.p. 235 °C, yield 80%. I R : 1640 cm-1 (conjugated CO), 2220 cm-1 (conjugated CN) and3300-3380 cm - 1 (NH). Ci8H13ON3

Found C 68.69 H 4 . l l N 22.29, Calcd C 68.56 H 4.16 N 22.21.

l-Phenyl-2-thiocyanatoglyoxalate-2-(3-phenylpyrazol-5-ylJhydrazone (3b)

Phenacylthiocyanate (0.1 mol) was coupled with 2 using the experimental procedure described above for the preparation of 3 a. The reaction product was crystallised from ethanol.

Compound 3b, brown crystals, m.p. 185 °C, yield 75%. IR : 1650 cm"1 (conjugated CO) and 3300-3420 cm-1 (NH). Ci8HI30N5S

Found C 62.40 H 3.70 N 19.85 S 9.00, Calcd C 62.24 H 3.74 N 20.17 S 9.22.

Cyclisation of 3 a, b by concentrated sulphuric acid A mixture of each of 3a,b (3.0 g) and concentrated

sulphuric acid (2.0 ml) was warmed on water-bath for 30 minutes then left to stand overnight at room temperature. The mixture was then diluted with water, neutralised by addition of ammonia and the resulting product was collected by filtration and crystallised from ethanol.

Compound 4a formed colourless crystals, m.p. 206 °C, yield 55%. I R : 1640 cm-1 ( N = N ) and 2220 cm-1 (conjugated CN). CisHuNs

Found C 72.69 H 3.61 N 23.29, Calcd C 72.72 H 3.70 N 23.56.

Compound 4b formed colourless crystals, m.p. 110 °C, yield 48%. C 1 7 H 1 2 N 4

Found C 74.98 H 4.43 N 20.49, Calcd C 75.00 H 4.47 N 20.58.

3-Phenyl-5-diazopyrazole (6) A suspension of 2 (2.0 g) in water (50 ml) was

treated with sodium acetate solution (prepared by dissolving 3 g of anhydrous sodium acetate in 100 ml of water). The reaction mixture was stirred at room temperature for four hours. The solid product, so formed, was collected by filtration and washed several times with cold water (till the washing were free from chloride ions). The product so obtained afforded correct analytical and XHNMR data.

Compound 6, buff powder, explodes at 145 °C, I R : 2175 cm-1 (diazo band), XHNMR: 7.0 (s, 1H, pyrazole CH) and 7.4-7 .8 (m, 5H, C6H5).

M. H. Elnagdi et al. • Reactions with Heterocyclic Diazonium Salts 219

C9H6N4

Found C 63.55 H 3 . l l N 33.09, Calcd C 63.52 H 3.55 N 32.93.

Reaction of 6 with activated double bond systems A suspension of 6 (0.1 mol) in ethanol (100 ml)

was treated with the appropriate activated double bond reagent (0.12 mol). The reaction mixture was left to stand in a refrigerator for 24 hours, then poured onto water. The solid product, so formed, was collected by filtration and crystallised.

The product obtained from reaction of 6 with acrylonitrile, ethyl acrylate and dimethyl acetylene dicarboxylate proved to be identical in all aspects with the recently prepared 5 a, b and 4 c [11] respectively.

Compound 5 c, formed colourless crystals from ethanol, m.p. 135 °C, yield 60%. C24Hi8ON4

Found C 76.47 H 4.50 N 15.00, Calcd C 76.17 H 4.75 N 14.81.

Compound 5d formed colourless crystals from methanol, m.p. 164 °C, yield 62%. C2OHI 8 0 2 N4

Found C 69.50 H 5.00 N 16.00, Calcd C 69.35 H 5.24 N 16.18.

The reaction of 6 with active methylene compounds A suspension of 6 (0.1 mol) in ethanol (100 ml)

was treated with the appropriate active methylene compound (0.1 mol). The reaction mixture was stirred for six hours then evaporated in vacuo. The remaining product was triturated with water and the resulting solid was collected by filtration and crystallised. The reaction products with activated methylene compounds were identified (m.p. and mixed m.p.) as 4a,d-g, respectively.

a,ß-DioxO'2-ethyl-l,2,4-triazole-5-yl-a-hydrazono-hydrocinnamonitrile (10 a, b)

A solution of 8 (0.01 mol) in concentrated nitric acid (5 ml, 65%) and water (10 ml) was treated with continual stirring by a solution of sodium

[1] E. J. Gray, M. F. G. Stevens, G. Tennant, and R. J. S. Vevers, J. Chem. Soc. Perkin 11976, 1496.

[2] G. Tennant and R. J. S. Vevers, J. Chem. Soc. Perkin I 1976, 421.

[3] J. Slouka, V. Bekarek, and J. Kubata, Monatsh. Chem. 105, 535 (1974).

[4] H. Majie and G. Tennant, Tetrahedron Lett. 1972, 4719.

[5] W. L. Magee and H. Shechter, J. Am. Chem. Soc. 1977, 633.

[6] M. H. Elnagdi, M. R. H. Elmoghayar, D. H. Fleita, E. A. Hafez, and S. M. Fahmy, J. Org. Chem. 41, 3781 (1976).

[7] M. H. Elnagdi, Tetrahedron 30, 2791 (1974). [8] M. H. Elnagdi, D. H. Fleita, and M. R. H. Elmog-

hayar, Tetrahedron 31, 63 (1975). [9] M. H. Elnagdi, S. M. Fahmy, E. M. Zayed, and

M. A. M. Illias, Z. Naturforsch. 31b, 795 (1976).

nitrite (0.7 g dissolved in the least ammount of water). The resulting solution was then added to a solution of the appropriate active methylene com-pound (0.01 mol) in ethanol-water mixture (50 ml, 75%) saturated with sodium acetate. The mixture was then left in a refrigerator for six hours. The solid product, so obtained was collected by filtration and crystallised.

Compound 10 a formed orange crystals, from ethanol, m.p. 197 °C, yield 62%. C13H12ON6

Found C 57.90 H 4.80 N 31.00, Calcd C 58.20 H 4.51 N 31.33.

Compound 10 b formed yellow crystals from ethanol, m.p. 149 °C, yield 55%. Ci4H 1 3 0 2 N 6

Found C 56.00 H 5.55 N 28.27, Calcd C 55.90 H 5.37 N 27.99.

Cyclisation of 10 a, b A mixture of each of 10a, b (2.0 g) and concen-

trated sulphuric acid (2.0 ml) was left at room temperature for six hours then diluted with water and neutralised by concentrated ammonia. The solid product, so formed, was collected by filtration and crystallised from ethanol.

Compound 11a formed yellow crystals from ethanol, m.p. 165 °C, yield 73%. C13Hi0N6

Found C 62.72 H 4.10 N 33.75, Calcd C 62.39 H 4.03 N 33.58.

Compound l i b formed yellow crystals from ethanol, m.p. 162 °C, yield 68%. Ci4Hi4ON6

Found C 59.20 H 5.46 N 30.00, Calcd C 59.56 H 5.00 N 29.77.

The authors acknowledge the receipt of a research grant from the Royal Norweigian Council for Scien-tific and Industrial Research which helped in completing this work.

[10] M. H. Elnagdi, M. M. M. Sallam, and M. A. M. Illias, Helv. Chim. Acta 58, 1944 (1975).

[11] M. H. Elnagdi, M. R. H. Elmoghayar, E. M. Zayed, and M. K. A. Ibraheim, J. Heterocycl. Chem. 14, 227 (1977).

[12] M. H. Elnagdi, E. M. Kandeel, E. M. Zayed, and Z. A. Kandil, J. Heterocycl. Chem. 14, 155 (1977).

[13] A. S. Shawalli and A." O. Abdelhamid, Tetra-hedron Lett. 1975, 163.

[14] Up to our knowledge, with the exception of our earlier report (ref. [11]), only one report has dealt with the reactivity of 5-diazopyrazoles as di-polarophiles (ref. [5]).

[15] M. Kocever, D. Kolman, H. Krajne, S. Polanc, B. Porovne, B. Stanovnik, and M. Tisler, Tetra-hedron 32, 725 (1976).