An expeditious synthesis of 1,2,4-triazolo[1,5- a ]pyrimidine

: A simple, efficient, and diversity oriented synthesis of library of 1,2,4-triazolo[1,5-a ]pyrimidine was undertaken using 5-amino,1,2,4-triazole as a building block. The synthesized analogues were fully characterized by known spectroscopic techniques like FT-IR, 1 H NMR, 13 C NMR, and mass spectroscopy.


INTRODUCTION
One-pot multi-component reactions (MCRs) have been exploited as a powerful tool for the assembly of large libraries of biologically active compounds. Among heterocycles, triazolopyrimidines have attracted a great deal of attention due to their therapeutic and pharmacological properties [1,2] such as antitumor potency [3,4], inhibition of KDR kinase [5], antifungal effect [6] and macrophage activation [7]. They have proved to be promising anticancer agents with dual mechanisms of tubulin polymerization promotion [8,9] as well as cyclin dependent kinases 2 inhibition [10]. Some examples of published derivatives of 1,2,4-triazolo[1,5-a]pyrimidine with their biological activities are depicted in figure 1.

Antimalarial Activity
Thus in view of finding novel analogues of triazole[1,5-a]pyrimidine with potential biological activities, we set upon a synthetic program involving 5-amino,1,2,4-triazole as building block. Although different strategies have been employed for the synthesis of these compounds, [11][12][13][14][15] these methods suffer from drawbacks such as long reaction times, cumbersome isolation of the products and harsh reaction conditions. Herein, we report a facile and efficient multi-component synthesis of 1,2,4-triazolo[1,5-a]pyrimidine in excellent yields from 3-amino-1,2,4-triazole, aldehydes and ethyl 3-oxo hexanoate respectively by simple fusion followed by adding catalytic amount of dimethylformamide (Scheme 1). Synthesis of fifteen novel analogues of 1,2,4triazolo[1,5-a]pyrimidines containing an appropriate 1,3-bifunctional synthon has been undertaken. The structures of all the newly synthesized compounds were elucidated by FT-IR, mass spectra, 1 H NMR, 13 C NMR and elemental analysis.

EXPERIMENTAL
Melting points were determined in open capillary tubes and are uncorrected. Formation of the compounds was routinely checked by TLC on silica gel-G plates of 0.5 mm thickness and spots were located by iodine. IR spectra were recorded Shimadzu FT-IR-8400 instrument using KBr pellet method. Mass spectra were recorded on Shimadzu GC-MS-QP-2010 model using Direct Injection Probe technique. 1 H NMR and 13 C NMR was determined in DMSO-d 6 solution on a Bruker Ac 400 MHz spectrometer. Elemental analysis of the all the synthesized compounds was carried out on Elemental Vario EL III Carlo Erba 1108 model and the results are in agreements with the structures assigned.

-a]pyrimidine-6-carboxamides
A mixture of the aminoazole (0.01 mol), ethyl 3-oxohaxenoate (0.01 mol) and an appropriate aromatic aldehyde (0.01 mol) was fused in 0.4 mL of DMF for 10-12 min. After cooling, methanol (~10 mL) was added. The reaction mixture was allowed to stand overnight and then filtered to give the solid triazolopyrimidine products, which were crystallized from ethanol and subsequently dried in air.

RESULTS AND DISCUSSION
The reaction mechanism of this three-component condensation is probably similar to the described [16] mechanism for the "classical" Biginelli reaction (Pathway 1). The first step is a nucleophilic addition of N 2 of the aminoazole to a carbonyl carbon of aldehyde, followed by subsequent cyclization with respective 1,3-carbonyl compound to form the dihydropyrimidine ring. An alternate sequence is also possible and cannot be excluded [17] (Pathway 2), which is the initial formation of an enamine by reaction of aminoazole with respective 1,3-carbonyl followed by cyclocondensation. The third alternative involving the formation of arylidene derivatives as intermediates requires the presence of a strong base [18] and is most likely not possible for the case described herein.