Regioselective Multi-component Synthesis of 7-Aryl-benzo[h][1,2,4]-triazolo[5,1-b]quinazoline-5,6-diones Catalyzed by n-Propylsulfonated γ-Al2O2

Abstract

Naphthoquinones constitute a major class of naturally occurring compounds, and interests in their chemistry continues unabated because of their wide range of biological and therapeutic properties such as antioxidant, antifungal, anti-inflammatory, antiallergic, antiviral, and anticancer activity. Triazoloquinazolines are ‘privileged medicinal scaffolds’ which are used for the development of pharmaceutical agents of various applications. Compounds with these motif show a wide range of pharmacological activities such as anticonvulsant, anti-inflammatory, antimicrobial, and antiviral. Considering the above reports, development of new and simple synthetic methods for efficient preparation of new ortho-naphthoquinones involving the “triazoloquinazoline” synthons are therefore an interesting challenge. In continuation of our efforts to develop novel reaction methodologies using nano n-propylsulfonated γ-Al2O3, 11 we now report herein a highly regioselective procedure for the preparation of 7-aryl-benzo[h][1,2,4]-triazolo[5,1-b]quinazoline-5,6-diones using nano n-propylsulfonated γ-Al2O3 as an efficient and versatile catalyst under solvent-free conditions (Scheme 1). First, to achieve suitable conditions for the synthesis of 7-arylbenzo[h][1,2,4]-triazolo[5,1-b]quinazoline-5,6-diones, we tested the three-component reaction of benzaldehyde, 2hydroxy-1,4-naphthoquinone, and 3-amino-1,2,4-triazole as a simple model system at 100 °C under solvent free conditions using various catalysts (Table 1). As shown in Table 1, the best result was obtained with 100 mg/mmol of nano npropylsulfonated γ-Al2O3 as the catalyst at 100 °C under solvent free conditions (Table 1, entry 3). Using less catalyst resulted in lower yields, whereas higher amounts of catalyst did not affect the reaction times and yields. When this reaction was carried out without nano n-propylsulfonated γAl2O3 or with other catalysts such as FeCl3, AlCl3, and nano γ-Al2O3, the yield of the expected product was much lower (< 30%). In the presence of p-TsOH, Fe(HSO4)3, or other nano n-propyl-sulfonated metal oxide such as nano npropyl-sulfonated SiO2, nano n-propylsulfonated ZnO the product was obtained still in lower yield (52-70%). After the successful preparation of 4a, we decided to introduce more diversity in the benzo[h][1,2,4]-triazolo[5,1b]quinazoline-5,6-dione scaffolds. With the optimized reaction conditions in hand we examined a variety of aldehydes and 2-hydroxy-1,4-naphthoquinone with 3-amino-1,2,4triazole and found that nano n-propylsulfonated γ-Al2O3 is an excellent catalyst system for the synthesis of a large spectrum of benzo[h][1,2,4]-triazolo[5,1-b] quinazoline-5,6diones (Table 2). Clearly, these reactions proceeded very cleanly under mild reaction conditions and no para-quinone isomeric systems were observed. It is worthwhile to mention that aromatic aldehydes with electron-donating and electronwithdrawing groups as well as heterocyclic aldehydes afforded the correspond products in excellent yields. The structure of the ortho-quinone structures 4 is in full agreement with H NMR, C NMR, MS and elemental analysis as illustrated below for a representative example (compound 4c). The Scheme 1. Synthesis of 7-aryl-benzo[h][1,2,4]-triazolo[5,1-b]quinazoline-5,6-diones using nano n-propylsulfonated γ-Al2O3. Table 1. Catalyst optimization for the synthesis 7-phenyl-benzo[h] [1,2,4]-triazolo[5,1-b]quinazoline-5,6-dionea