Multi-component Synthesis of 1,2,3-Triazoles from Carboxylic Acids, 3-Bromoprop-1-yne and Azides Using Click Chemistry

In 2001, Sharpless and co-workers invented the concept of click chemistry. A very powerful example of a click chemistry reaction is the 1,3-dipolar cycloaddition of azides and terminal acetylenic compounds to produce 1,2,3-triazoles. These highly-sought compounds are extensively used in medicines, agrochemicals, pigments, photographic materials, and in corrosion-inhibitory compositions. It is known that 1,2,3-triazoles possess anti-HIV properties, antimicrobial activities, and selective b-3 adrenergic receptor agonism. Synthesis of 1,2,3-triazoles in the absence of a transition-metal catalyst is not regioselective, producing a mixture of 1,4and 1,5-regioisomers, and high temperatures are essential for the reaction to progress. In 2002, Meldal and co-workers noted that the use of catalytic quantities of a copper(I) salt will lead to fast, highly efficient, and regioselective formation of 1,2,3-triazoles at room temperature. At the same time, Sharpless and co-workers also reported the synthesis of 1,2,3-triazoles using a copper(I) catalyst with an excellent 1,4-regioselectivity and high reaction yields. Multi-component reactions (MCRs) are powerful and popular chemical methods for the synthesis of organic compounds. MCRs provide such notable benefits as high atom economy, short reaction times, energy-savings, facile extraction, simple work-ups, and convenient purification processes. In furtherance of our investigations aimed at the expansion of methods for organic synthesis, herein we report a highly efficient multi-component reaction for the preparation of (1-aryl-1H-1,2,3-triazol-4-yl)methyl esters. This report builds on our earlier work for the preparation of new 1,2,3-triazoles through 1,3-dipolar cycloaddition. The novel (1-aryl-1H-1,2,3-triazol-4-yl)methyl esters (4a-j) were formed from the reaction of several carboxylic acids (1a-f), 3-bromoprop-1-yne (2) and aromatic azides (3a-c) in the presence of a copper catalyst at room temperature (Scheme 1). We selected the synthesis of 4a as a model reaction for the optimization of the reaction conditions. As listed in Table 1, the best conditions were sought for the reaction of benzoic acid (1a), 3-bromoprop-1-yne (2) and 1-azido-4-nitrobenzene (3a). Optimal results were represented by entry 7 in the table, including 10mol% loading of CuSO4, in dimethylformamide (DMF) as the solvent, with K2CO3 as the base, at room temperature.