Pyrimidine Derivatives and Related Compounds, VII Synthesis of Some New Pyrazolo[l,5-a]-S-triazines, Pyrazolo [3,4-c] -as-triazines, Pyrazolo [1,5-a] pyrimidines and Pyrazolo [3,4-b]pyrones M o h a m e d H il m y E l n a g d i *, E z z a t M o h a m e d Z a y e d , E z z a t M o h a m e d K a n d e e l , a n d S h e r i f M a h m o u d F a h m y Department of Chemistry, Faculty of Science, Cairo University, Giza and Mansoura University at Elmansoura, A. R. Egypt (Z. Naturforsch. 32b, 430-433 [1977]; received October 26, 1976) Pyrimidine Derivatives, Pyrazolylthiourea Derivatives 3-Amino-4-phenylhydrazono-2-pyrazolin-5-one (1) reacts with isothiocyanate to yield the corresponding pyrazolylthiourea derivatives (2a-c). W hereas 2a reacted with hydra­ zines to yield the pyrazolylamino-l,2,4-triazoles (3a, b), it cyclised into the pyrazolo- [3,4-e]-as-triazine derivative (4) upon treatment with concentrated sulphuric acid. On the other hand, the pyrazolo[l,5-c]-S-triazine derivative (5) was formed from reaction of 2a with ethanolic sodium ethoxide. 3-Amino-2-pyrazolin-5-one (8) reacted with ethyl acrylate to yield a mixture of the 4-dialkylated derivative (9) and the pyrazolo[3,4-b]pyrone (11). Compound 11 could be converted into the corresponding pyrazolo[3,4-b]pyrones (12) and (13) by the action of acetic acid hydrochloric acid mixture and of concentrated sulphuric acid, respectively. The chemistry of fused pyrazoles has received We have been particularly interested to see if considerable recent attention1-5. Many fused pyra- reactions of this type might be extended to include zole derivatives proved to be active antiinflam­ more general synthesis of other substituted matory and antitumur agents6-8. In previous work pyrazolo[3,4-e]-as-triazines. It has been found that we have reported a variety of new routes for the 4-phenylhydrazones-3-amino-2-pyrazolin-5-one (1) synthesis of fused pyrazole derivatives9-14, from react with benzoyl isothiocyanate, ethoxycarbonyl readily obtainable 5-aminopyrazoles. In continua­ isothiocyanate and with phenyl isothiocyanate to tion of this work we report here the results of our afford the corresponding pyrazolylthiourea deriva­ investigations directed for the development of new tives (2a,c). That the reaction of 1 with isothio­ synthetic procedures for the synthesis of fused cyanates has involved the exocyclic aminonitrogen pyrazole derivatives. rather than pyrazole ring NH groups was assumed on the basis of analogy to the well established Synthesis of Pyrazolo [1,5-a]-S-triazines behaviour of 3(5)-aminopyrazoles toward the same and Pyrazolo [1,5-c] -as-triazines reagents. However, this is incontrast to the recently Recently15 it has been shown that 5-amino- reported formation of 1-thiocarbamoylpyrazoles on 4-aryl-hydrazono-3-substituted-pyrazoles react treatment of 3,5-diamino-4-arylazopyrazoles with with benzoylisothiocyanate to yield the correspond­ isothiocyanates16. ing pyrazolylthioureas which could be readily cyclized into the corresponding pyrazolo[3,4-e]-as- /N . ___ /NH2 .hL NHC-MHR Phlf I----if triazine derivatives. Phf F I T RN-C-X H o ' V -------- u H 2a: R = COPh, X =S, Requests for reprints should be sent to Dr. M. H. 2b: R = C02C7H5, X = S, E l n a g d i , Chemistry Department, Faculty of Science, 2c: R = Ph; X =S, Cairo University, Giza, A. R. Egypt. 2d: R = Ph; X =0. M. H . Elnagdi et al. • Pyrimidine Derivatives and Related Compounds 431 Compound 2 a could be cyclised under different product on basis of elimental data and analogy to conditions to form different poly cyclic compounds. the well established behaviour of 3-amino-4-aryl- Thus, when 2 a was treated with hydrazine hydrate azopyrazoles toward the same reagent12. or with phenylhydrazine it was converted into the corresponding 2-(pyrazol-5-yl)amino-l,2,4-triazole Synthesis of Pyrazolo[3,4-b]pyrones derivatives (3a,b). On the other hand the pyrazolo- In previous work the behaviour of 1 toward acti­ [3,4-c]-as-triazine derivative (4) was formed upon vated double bond systems has been reported17. treatment of 2a with concentrated sulphuric acid. Also the reaction of 3-amino-l-phenyl-2-pyrazolin- However, when 2 a was treated with ethanolic 5-ones toward the same reagents was investigated17. sodium ethoxide the pyrazolo[l,5-c]-S-triazine In the present work the behaviour of 3-amino-2- derivative (5) was formed. The structures proposed pyrazolin-5-one (8) toward acrylonitrile and ethyl- for compounds 3-5 were based on analytical and acrylate was investigated. We have found that the IR data. reaction of 8 with acrylonitrile under a variety of 7*? experimental conditions results in the formation of V ~ \ an oily mixture of several products. These could not be isolated in pure state. On the other hand, from the reaction of 8 with ethyl acrylate two products of m.p. 168 and 300 °C were formed and separated by fractional crystallisation. The molecular formula H2S04 N— NR /N of the former was found to be C13 H2 1O5N 3 via its PhNH I J, .1, NaOC2H5 RNH.NH2 Ph^ f analytical and molecular weight determination. h T --------- ------------ - 0 H This formula corresponds to an adduct formed from 3 a : R=H two molecules of ethyl acrylate and one molecule 3 b : R = Ph of 8. Structure 9 was assumed for this adduct based In contrast to the behaviour of 2 a, attempted on analogy to the well established behaviour of cyclization of 2 b under the same experimental 3-amino-l-phenyl-2-pyrazolin-5-one17 toward the conditions has resulted in its decomposition quanti­ same reagent and on the fact that the IR spectra of tatively into 1. On the other hand, attempted this product revealed the presence of a free NH 2 cyclization of 3 C by the action of ethanolic sodium band. ethoxide has resulted in the formation of the Molecular weight determinations and analytical pyrazolylurea derivative (2d). Compound 2d was data for the latter (m.p. 300 °C) indicated a also obtained by the action of phenyl isocyanate molecular formula of C 15H 16O5N 6. Two structures on 1. seemed probable for this compound (cf. formulae 10 Synthesis of 3-Phenylhydrazono-2-oxo-2,3- and 11). NMR of this product revealed a compli­ dihydropyrazolo[l,5-a] pyrimidines cated pattern and it seemed difficult to utilise it for the discrimination between both structures. The IR For continuing investigation of the biological spectra of this compound showed the presence of d activity of 3-arylhydrazonopyrazolo-l,5-a-pyrimi- lactone CO group at 1730 cm-1, amide CO band at dine derivatives samples of some 3-phenylhydra- 1680 cm-1 and revealed absence of absorption for zono - 2 - oxo - 2,3 - dihydropyrazolo -1,5 - a - pyrimidine NH 2 group. The absence of NH 2 absorption in the derivatives were required. The reaction of 1 with a IR spectrum of this product might eliminate the variety of ^-bifunctional reagents was performed. possible structure 10. Thus, it seems most likely Thus, 1 reacted with acetyl acetone to yield the that this product have structure 11. 5,6-dimethylpyrazolo[l ,5-a]pyrimidine derivative When compound 11 was refluxed in acetic acid- (6). Similarly, treatment of 1 with ethyl acetoacetate hydrochloric acid mixture, the carboxylic acid (12) has afforded the 2,7-dioxopyrazolo[l,5-a]pyrimidine was formed. On the other hand, when 11 was derivative (7). Structure 7 was established for this treated with concentrated sulphuric acid it was Ph-N^ PhN' converted into the pyrazolo[3,4-b]pyrone derivative ACCH2CO2C2H5 * o r V (13). 13 was also obtained when 12 was treated with concentrated sulphuric acid. Structures 12 and 13 432 M. H . Elnagdi et al. • Pyrimidine Derivatives and Related Compounds were inferred from analytical and IR data. The product wras collected by filtration and crystallised readily elimination of acrylic acid from 12 to yield 13 from acetic acid. 2c; orange crystals; m.p. 250 °C; yield 90%. is similar to the reported ready dealkylation N- cyanoethylated and N-/?-carboxyethylamines. Ci 6H14ON6S Found C 56.76 H 4.21 N 25.00 S 9.50, __ ^NH2 C5H5O2CCH2CH2 __ .NH2 Calcd C 56.80 H 4.17 N 24.84 S 9.46. Hfccscoas. c2%o,cch2ch2^ J 3-(4-Phenylazo-5-oxo-2-pyrazolin-5-yl)- c 15h 1 6 °5 n 6 amino-5-phenyl-l,2,4-triazoles (3a, b) CH2-CHCN A mixture of 2 a (2.0 g) and hydrazine hydrate unidentifiable products (2.0 ml; 98%) or phenylhydrazine (2.0 ml) was heated on a boiling water bath for three hours. The NH2 reaction mixture w^as then dissolved in ethanol, .Kl-CH2CH2CON. diluted with wrater and acidified with hydrochloric acid. The resulting solid product was collected by filtration and crystallised. 3a: red crvstals from acetic acid m.p. 286 °C; ^ ^NHCH2CH2CONr yield 70%. 0A 0^N 'N Ci 7H14ON8 11 Found C 58.50 H 4.32 N 32.66, AcOH.HCl Calcd C 58.98 H 4.04 N 32.37. NHCH2CH2C02H 3b: yellow crystals form ethanol; m.p. 241 °C; yield 75%. C23H 18ON8 Experimental Found C 65.70 H 4.00 N 26.35, All melting points are uncorrected. The IR spectra Calcd C 65.40 H 4.26 N 26.54.