Amino acid-catalyzed cascade [3+2]-cycloaddition/hydrolysis reactions based on the push-pull dienamine platform: synthesis of highly functionalized NH-1,2,3-triazoles.

1,2,3-Triazoles are an important class of heterocycles, which display very large spectrum of biological activities and are widely used as pharmaceuticals and agrochemicals. Compounds containing 1,2,3-triazoles have also found industrial applications as corrosion inhibitors, lubricants, dyes, and photostabilizers. As such, the development of new and more general methods for their preparation is of significant interest. The conventional method to triazoles is the Huisgen 1,3-dipolar cycloaddition of alkynes with azides. Recent discovery of the novel technology of Cu-catalyzed [3+2]cycloaddition reactions of terminal alkynes with organic azides provided a general route to a variety of 1,4-disubstituted 1,2,3-triazoles in good yields, and it has become a paradigm of a “click chemistry” reaction. The advent of click reaction technology triggered a burst of activity in the synthesis of a huge variety of differently substituted 1,2,3-triazoles as in vitro and in vivo conditions. Recently, the copper-catalyzed azide–alkyne click reaction has proven extremely valuable for attaching small molecular probes to various biomolecules in a test tube or on immobilized cells. However, its use in the labeling of biomolecule in living cells or organisms is not feasible because the reaction conditions require a cytotoxic copper catalyst. As part of our program to engineer direct organocatalytic cascade reactions, herein we have report the discovery of a copper-free, novel and green technology for the synthesis of highly substituted a-diazo compounds and NH-1,2,3-triazoles using organocatalytic cascade enamine amination/elimination (EA/E) and [3+2]-cycloaddition/hydrolysis ([3+2]CA/H) reactions from commercially available activated enones, azides and amines/amino acid [Eq. (1)]. In this communication, we report to the best of knowledge for the first time an organocatalytic approach for the synthesis of NH1,2,3-triazole products. Over the last few years, we have been interested in amine-mediated in situ generation and application of novel push–pull dienamines/push–pull dienols [A and B, see Eq. (2)] in cascade reactions from Hagemann3s esters with nitrogen-containing species for the formation of C N bonds. During our search for new coupling species for such processes, we decided to explore the potential ability of organic azides to participate in an amine/amino acid-catalyzed coupling reaction. We expected that the coupling of an organic azide with in situ generated push–pull dienamines would lead to protected 1,2,3-triazoles. However, protected 1,2,3-triazoles were not detected, but instead NH1,2,3-triazoles were obtained under the standard reaction conditions. This unexpected result of the cascade reaction represents a novel methodology for the preparation of NH1,2,3-triazoles and a new reactivity for amino acid catalysts. Herein, we report our findings regarding these new amino acid-catalyzed cascade reactions. We initiated our preliminary studies of the cascade EA/E or [3+2]-CA/H reactions by screening a number of both [a] Prof. Dr. D. B. Ramachary, K. Ramakumar, V. V. Narayana School of Chemistry University of Hyderabad Hyderabad-500046 (India) Fax: (+91)40-23012460 E-mail : [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.200801325.