Synthesis and Characterization of a Novel Biheterocyclic -amino Acid Precursor of the Triazole-Tetrazole Type, via the Copper (I) Catalyzed Alkyne-Azide Cycloaddition Reaction (CuAAC)

Abstract

In this paper, we describe the regioselective synthesis of a novel tri-heterocyclic compound, a biheterocyclic amino acid precursor, derived from both triazole and tetrazole. The key step of our synthesis approach was the Huigsen 1,3-dipolar cycloaddition reaction, catalyzed by the copper (I) formed in situ by reduction of Cu(II) salts (CuSO4), 5H2O) by sodium ascorbate, and using as dipole the oxazoline azide derivative 4-(azidomethyl)-4-ethyl-2-phenyl-4,5-dihydrooxazole (4) and as dipolarophile 5-(4-methoxyphenyl)-2-(prop-2-yn-1-yl)-2H-tetrazole (3). The Cu(I) catalysis allowed us to carry out the cycloaddition at room temperature during a reaction time of only 8 hours and also to selectively obtain the 1,4-regioisomer; one of the two possible isomers, with a yield of 90% after chromatography on a silica gel column (ether/hexane: 1/2), and recrystallization in an ether/acetone mixture. The desired compound, 4-ethyl-4-((4-((5-(4-methoxyphenyl)-2H-tetrazol-2-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl)-2-phenyl-4,5-dihydrooxazole (5) was analyzed by 1D magnetic resonance spectroscopy (1H, 13C), and characterized physico-chemically by mass spectrometry and elemental analysis.

Naphthalen-2-yl 1-(benzamido(diethoxyphosphoryl)methyl)-1H-1,2,3-triazole-4-carboxylate

“…In direct connection with the principles of green chemistry and drawing on the reactions found in nature, Sharpless introduced in 2001 the concept of a "chemistry click" [32], which proposes the development and promotion of the use of the most effective and selective reactions possible, in particular those that do not generate by-products. The latter, initiated by Sharpless [33] and his collaborators, has given rise to various applications in the fields of organic synthesis [34][35][36], functionalization [37] of biomaterials in cell biology [38,39], and the synthesis of biopolymers involved in encapsulation processes [40]. In terms of our study, we prepared diethyl (-azido(benzamido)methyl)phosphonate (1), which is obtained under dehydrating operating conditions of neutral pH, with an overall yield of 85%, by adopting the strategy of Elachqar et al [19].…”