Ultrasound irradiation promotes the synthesis of new 1,2,4-triazolo[1,5-a]pyrimidine

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Highlights

  • A series of 7-trifluoromethyl[aryl]-triazolo[1,5-a]pyrimidines under ultrasound irradiation was synthesized.

  • Ultrasound irradiation method was more efficient than conventional thermal heating.

  • Products were obtained with excellent yields.

Abstract

Ultrasonic irradiation was used in the synthesis of a series of novel 1,2,4-triazolo[1,5-a]pyrimidines. The products were synthetized from the cyclocondensation reaction of 1,1,1-trifluoro-4-metoxy-3-alken-2-one [CF3C(O)CHdouble bondC(R)OMe, where R = Ph, 4-F-C6H4, 4-Br-C6H4, 4-I-C6H4, 4-CH3-C6H4, 4-CH3O-C6H4, Thien-2-yl, Biphen-4-yl] or β-enaminones [RC(O)CHdouble bondCHNMe2, where R = Ph, 4-F-C6H4, 4-Br-C6H4, 4-I-C6H4, 4-CH3-C6H4, 4-CH3O-C6H4, 4-NO2-C6H4, Thien-2-yl, Biphen-4-yl, Naphth-2-yl, Pyrrol-2-yl, CCl3] with 5-amino-1,2,4-triazole in acetic acid at 99 °C with 5–17 min of ultrasound irradiation. This methodology has shown several advantages, such as shorter reaction times, mild conditions, high regioselectivity, and excellent yields, when compared with conventional thermal heating (oil bath).

Introduction

Triazolo [1,5-a]pyrimidine derivatives have attracted a lot of attention in the medical field due to their broad-spectrum biological activities as cardiovascular vasodilators [1] and human A2a adenosine and A3 receptor ligands [2]. Additionally, substituted triazolopyrimidine-2-sulfonamides, such as flumetsulam [3], florasulam [4], and metosulam [5], have shown excellent herbicidal and plant growth regulation [6]. Consequently, various derivatives of 1,2,4-triazolo[1,5-a]pyrimidine have found applications in pharmaceutics, agriculture, and other areas [7]. The synthesis of triazolopyridines from the heterocyclization of aminotriazole and 1,3-dieletrophiles such as enaminones, chalcones, dicarbonyl and substituted vinyl ketones is conventionally performed in the reflux of acetic acid, acetonitrile, ethanol, or pyridine/HCl; however, significant variations in yields and reaction times limit the choice of substrates that can be utilized. The synthesis of trifluoromethylated triazolo[1,5-a]pyrimidine from trifluoromethylated substrates is limited [8]. The incorporation of fluorine into a drug allows simultaneous modulation of electronic, lipophilic and steric parameters, all of which can critically influence both the pharmacodynamic and pharmacokinetic properties of drugs. The small size, very low polarizability, and the strong inductive effect are responsible for biophysical and chemical properties such as hydrophobicity, acidity/basicity, reactivity, as well as the conformation of compounds where fluorine atoms or the trifluoromethyl group is present [9].

Additionally, the development in the last few years of synthetic protocols employing ultrasound irradiation has led to an important change in organic reactions and has permitted the activation of poorly reactive substrates [10]. Notable features of the ultrasonic irradiation method include enhanced reaction rates, the formation of purer products at high yields, easier manipulation, and improved energy conservation, when compared with the conventional thermal heating method (oil bath) [11]. These characteristics for using ultrasound irradiation are demonstrated in the synthesis of various heterocycles described in the literature [12]. Our research group has published about the synthesis of azolopyrimidines, both under ultrasound irradiation and with the conventional method. The results showed that the use of ultrasound furnishes shorter reaction times than the microwave method and higher yields [13], [14].

Over the past 20 years, our research group has been studying the synthesis of 4-alkoxy-1,1,1-trihalo-3-alken-2-ones and their effectiveness in heterocyclic preparations [15]. During this time we have supported the importance of these halogen-containing building blocks in heterocyclic synthesis and more recently we have been focusing our attention on minimizing waste generation, reducing reaction time, and improving yields, by using ionic liquid [16], solvent-free solutions [17], microwave [16](d), [16](e), [18], and ultrasound irradiation [8](a), [13] to promote the reactions. Therefore, in the continuation of our work, and considering the importance of triazolo[1,5-a]pyrimidine and the restrictions to its synthesis, we will describe an efficient and mild approach to the synthesis of regiospecific 1,2,4-triazolo[1,5-a]pyrimidines under ultrasonic irradiation and compare the results with those from conventional thermal heating.

Section snippets

Results and Discussion

We started our investigation by examining the cyclocondensation reaction of 1,1,1-trifluoro-4-methoxy-4-phenyl-3-alken-2-one (1a) with aminotriazole (2), under ultrasound irradiation. The ultrasound amplitude was established based on the relation between temperature reached by theses solvents during 5 min of irradiation. Solvents such as AcOH, EtOH, and CH3CN reached the highest temperature when an amplitude of 20% was tested to optimize the reaction. According to Table 1, the reactions in AcOH

Materials

The reagents and solvents used were obtained from commercial suppliers without further purification. The reactions in ultrasound were done with a tapered microtip probe (6 mm) connected to a Sonics Vibra-Cell™ (500 W) ultrasonic processor equipped with an integrated temperature control probe. The device operates at 20 kHz of frequency and the amplitude was set to 20% of the maximum power output. The equipment can operate at a maximum temperature of 99 °C. 1H and 13C NMR spectra were recorded on a

Conclusion

We have developed a fast, new, practical and simple method for the preparation of 1,2,4-triazolo[1,5-a]pyrimidine. New trifluoromethylated 1,2,4-triazolo[1,5-a]pyrimidines were synthesized with high regioselectivity in short reaction times and at excellent yields. These compounds, especially those having the trifluoromethyl group in their structure, are excellent models for studies on the biological activities.

Acknowledgments

The authors are grateful for the financial support from the National Council for Scientific and Technological Development (CNPq – Universal Proc. No. 578426/2008-0; 471519/2009-0), the Rio Grande do Sul Research Support Foundation (FAPERGS/CNPq-PRONEX Edital No. 008/2009, Proc. No. 10/0037-8), and the Coordination for Improvement of Higher Education Personnel (CAPES/PROEX). The fellowships from CNPq (M.A.P.M., T.S.M., M.R.B.M., N.Z., H.G.B.), and CAPES (L.B.) are also acknowledged.

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