N N HN CF3 NH2 1 ArCH C(CN)2 2a–g N N N CF3 NH2 CN Ar CN 3 HN N N CF3 NH Ar CN NC 5 N NH N N Ar CN NH2 CF3 N NH N N NH2 CN Ar CF3 4a–g 6a–g NH N N N Ar CF3 8a–g CH2(CN)2 1 ArCHO 7a–g N NH N N NH2 CO2Et Ar CF3 10a–e N NH N N O CN Ar CF3 11a–e CN CH2CO2Et ArCH C(CN)CO2Et Ar Ph C6H4Me- p C6H4F- p C6H4NO2- p C6H4OMe- p S 2-10 a b c d e f g C6H4Cl- p 9a–e 392 J. CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 392–393 J. Chem. Research (M), 1997, 2378–2394 Reactions with 3-Amino-5-trifluoromethyl-1,2,4-triazole: a Simple Route to Fluorinated Poly-substituted Triazolo[1,5-a]pyrimidine and Triazolo[5,1-c]triazine Derivatives Hussein F.Zohdi* Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt 3-Amino-5-trifluoromethyl-1,2,4-triazole has been utilized for the syntheses of poly-substituted 2-trifluoromethyl- [1,2,4]triazolo[1,5-a]pyrimidine derivatives, via its reactions with acrylonitrile derivatives and various 1,3-dicarbonyl compounds, and of trifluoromethyl[1,2,4]triazolo[5,1-c]triazine derivatives, via its diazotization and coupling with active methylene reagents.Fluorine-containing heterocyclic compounds have received considerable interest owing to their potent pharmacological activity.1,2 In continuation of our interest in the synthesis of azoles and their fused derivatives bearing a trifluoromethyl group,6–8 we report herein the utility of 3-amino-5-trifluoromethyl- 1,2,4-triazole9 for the synthesis of several new polysubstituted 2-trifluoromethyl[1,2,4]triazolo[1,5-a]pyrimidine and 7-trifluoromethyl[1,2,4]triazolo[5,1-c][1,2,4]triazine derivatives required for a medicinal chemistry programme.The reaction of 3-amino-5-trifluoromethyl-1,2,4-triazole (1) with various b-aryl-a-cyanoacrylonitrile derivatives 2a–g afforded in each case a single product, as evidenced by TLC. Based on analytical data, two isomeric structures are possible, 5-amino-7-aryl-6-cyano-4,7-dihydro-2-trifluoromethyl- [1,2,4]triazolo[1,5-a]pyrimidine 4 or its regioisomer 7-amino- 5 - a r y l - 6 - c y a n o - 4 , 5 - d i h y d r o - 2 - t r i f l u o r o m e t h y l [ 1 , 2 , 4 ] t r i a z o l o- [1,5-a]pyrimidine 6 (Scheme 1).Spectrosocpic data could not distinguish between these two, and therefore further evidence for the correct structure was sought by approaching the product through another route. Thus, treatment of the Schiff’s bases 8a–g with malononitrile afforded products identical in all respects with those obtained from the reaction of 1 with 2a–g.The formation of compounds 6a–g is, therefore, assumed to proceed via initial attack of the exocyclic amino group of 1 on the activated double bond of 2 to form the non-isolable Michael adduct 5, which alternatively can be formed via the addition of the active methylene of malononitrile to the double bond of the Schiff’s base 8. This Michael adduct then undergoes intramolecular cyclization to afford compounds 6a–g (Scheme 1).Compound 1 reacted with ethyl b-aryl-a-cyanoacrylate derivatives 9a–e to yield in each case a single product which may be formulated as ethyl 7-amino-5-aryl-4,5-dihydro-2-trif l u o r o m e t h y l [ 1 , 2 , 4 ] t r i a z o l o [ 1 , 5 - a] p y r i m i d i n e - 6 - c a r b o x y l a t e 10 or 5-aryl-6-cyano-4,5,6,7-tetrahydro-2-trifluoromethyl- [1,2,4]triazolo[1,5-a]pyrimidin-7-one derivatives 11 (Scheme 1). Structure 11 was readily ruled out for the reaction products on the basis of analytical and spectroscopic data, and support for structure 10 was provided by independent syntheses of compounds 10a–e from the reaction of the appropriate Schiff’s base 8a–e with ethyl cyanoacetate.It is worth noting that the reaction of ethyl cyanoacetate with each of 8f,g gave ethyl b-(p-methoxyphenyl)-a-cyanoacrylate (9f) and ethyl b-thienyl-a-cyanoacrylate (9g), respectively, along with compound 1. The reaction of compound 1 with several b-diketones, b-keto esters and their a-substituted derivatives was carried out by heating either in acetic acid or, preferably, in toluene.*E-mail: ZOHDI@FRCU.EUN.EG Scheme 1N NH N N CF3 O R2 R1 N NH N N CF3 R1 R2 O 12 a b c d e R1 CF3 Me Me Me Me H H Cl N N Ph N N C6 H4Me- p R2 12a–e 13 R1COCH(R2)CO2Et 1 N N N N CF3 Me X Me N N N N CF3 R2 R1 a X = H b X = Cl 15 14a–c R1 R2 a Me Ph b CF3 Me c CF3 S 14 MeCOCH(X)COMe R1COCH2COR2 N NH N N CF3 O O N NH N N CF3 O N O 16 17a,b 1 N N N N N CF3 NH2 CO2Et N N N N N CF3 NH2 19 20 NCCH2CO2Et CH2(CN)2 NH Ar CH2(CO2Et)2 a Ar = C6H4NO2- p b Ar = C6H4Me- p ArN2 +Cl– CN HN N N CF3 N2 + 18 HONO p-NO2C6H4NHN C(CO2Et)2 J.CHEM. RESEARCH (S), 1997 393 Thus, the reaction of 1 with ethyl 4,4,4-trifluoroacetoacetate, ethyl acetoacetate, ethyl 2-chloroacetoacetate and ethyl 2-arylazoacetoacetate produced in each case in a single product, as evidenced by TLC. The reaction products can be represented as [1,2,4]triazolo[1,5-a]pyrimidin-7-one derivatives, 12a–e (Scheme 2), evidence for the assigned structures being provided by analytical and spectroscopic data.Although one may argue that the reaction of 1 with b-ketoesters may lead to the other possible regioisomer (the [1,2,4]triazolo[1,5-a]pyrimidin-5-one, 13) the regioselectivity of such reactions is well established.10,11 The reaction of compound 1 with benzoylacetone, 1,1,1-trifluoropentane-2,4-dione and thenoyltrifluoroacetone produced in each case a mixture of two regioisomers, as evidenced by TLC of the crude products.The major products, 14a–c (Scheme 2), were obtained in good yield after recrystallization. The assigned regiochemistry is in agreement with literature reports12–14 regarding the reactions of aminoazoles with asymmetric 1,3-diketones. Similarly, the reaction of compund 1 with acetylacetone and 3-chloroacetylacetone afforded 5,7-dimethyl-2-trifluoromethyl- [1,2,4]triazolo[1,5-a]pyrimidine and its 6-chloro derivative, 15a,b, respectively.Compound 1 reacted with diethyl malonate in refluxing toluene to produce 4,6-dihydro-5,7-dioxo-2-trifluoromethyl- [1,2,4]triazolo[1,5-a]pyrimidine (16). Compound 16 underwent electrophilic substitution upon coupling with arenediazonium chloride at the active methylene to afford the corresponding aryl hydrazone derivatives 17a,b. Compound 17a was alternatively prepared by heating compound 1 with diethyl p-nitrophenylazomalonate in toluene at reflux (Scheme 3).The reactions of 5-trifluoromethyl[1,2,4]triazole-3-diazonium sulfate (18) with ethyl cyanoacetate, and with malononitrile, in pyridine afforded ethyl 4-amino-7-trifluoromethyl[ 1,2,4]triazolo[5,1-c]triazine-3-carboxylate (19) and 4-amino-3-cyano-7-trifluoromethyl[1,2,4]triazolo[5,1-c][1,2,4]- triazine (20), respectively (Scheme 3). Techniques used: IR, 1H NMR, 13C NMR, mass spectrometry References: 15 Received, 17th February 1997; Accepted, 28th July 1997 Paper E/7/01093A References cited in this synopsis 1 J.W. Welch and S. Eswarakrishnan, in Fluorine in Bioorganic Chemistry, Wiley, New York, 1991. 2 R. Filler and S. M. Naqui, in Biomedical Aspects of Fluorine Chemistry, Elsevier Biomedical, Amsterdam, 1982, p. 1. 6 H. F. Zohdi, J. Chem. Res. (S), 1992, 82. 7 H. F. Zohdi, A. H. H. Elghandour, N. M. Rateb and M. M. M. Sallam, J. Chem. Res., 1992, (S) 396; (M) 3015. 8 H. F. Zohdi, H. Y. Afeefy and A. O. Abdelhamid, J. Chem. Res. (S), 1993, 76. 9 V. A. Lopyrev and T. N. Rakhmatulina, Zh. Obshch. Khim., 1983, 53, 1684 (Chem. Abstr., 1983, 99, 139865y). 10 G. Maury, in Special Topics in Heterocyclic Chemistry, ed. A. Weissberger and E. C. Taylor, Wiley–Interscience, New York, 1977, p. 196. 11 J. S. Bajwa and P. J. Sykes, J. Chem. Soc., Perkin Trans. 1, 1979, 3085. 12 R. Balicki, Polish J. Chem., 1981, 55, 1985. 13 A. Kreutzberger and L. Manfred, Arch. Pharm. (Weinheim), 1982, 315, 438. 14 W. A. Kleschick and J. Bordner, J. Heterocycl. Chem., 1989, 26, 1489. Scheme 2 Scheme 3