Elsevier

Tetrahedron Letters

Volume 60, Issue 8, 21 February 2019, Pages 583-585
Tetrahedron Letters

Novel and efficient synthesis of triazolobenzodiazepine analogues through the sequential Ugi 4CR-click-N-arylation reactions

https://doi.org/10.1016/j.tetlet.2019.01.009Get rights and content

Highlights

  • A novel method for synthesis of triazolobenzodiazepine analogues was described.

  • Reactions were conducted with DMSO as solvent and CuI as catalyst.

  • A variety of isocyanides, aldehydes and benzoic acids was examined.

  • Simple starting material and excellent yield are the main advantage of this method.

Abstract

An efficient approach for the synthesis of N-alkyl-2-aryl-2-(6-oxo-4H-benzo[f][1,2,3]triazolo[1,5-a][1,4]diazepin-5(6H)-yl)acetamides is described. The protocol involves Ugi four-component reaction of 2-bromobenzoic acid, propargylamine, aldehydes and isocyanides followed by in situ sequential click reaction of azide ion with triple bond and N-arylation reaction to afford desired products in good to excellent yields.

Introduction

One of the major challenges in the field of synthetic chemistry is preparing complex chemical structures from simple methods and substrates. This is one of the most important characteristics of multi-component reactions (MCRs) [1]. The Ugi four-component reaction (Ugi-4CR) is useful isocyanide based MCRs that allow easy access to structurally varied and complex intermediates or scaffolds [2]. Such reactions have been extensively explored as combinational chemistry approaches for the synthesis of diversified target molecules from simple and readily available starting materials [3].

Fused triazolo-benzodiazepines scaffold are a key structural motif in numerous therapeutics that have sedative, muscle relaxant, and antitumor activities [4]. Alprazolam, adinazolam and estazolam are commercially available chemical drugs based on triazolo-benzodiazepine scaffold that widely used as anxiolytic and sedative agents (Fig. 1) [5]. Some triazolo-benzodiazepine derivatives have been reported to be weakly bound to the benzodiazepine receptor and prevent serine protease [6]. So, due to the therapeutic and biological applications of this class of compounds, the development of new methods for the preparation of these molecules is definitely of great importance.

Section snippets

Results and discussion

As a part of our efforts on development of novel synthetic methods for preparation of biologically active target molecules [7], herein, we have demonstrated an efficient approach for the synthesis of N-alkyl-2-aryl-2-(6-oxo-4H-benzo[f][1,2,3]triazolo[1,5-a][1,4]diazepin-5(6H)-yl)acetamides 6am via Ugi four-component reaction of 2-bromobenzoic acid 1a,b, propargylamine 2, aldehydes 3ah and isocyanides 4ac followed by sequential click reaction of sodium azide with triple bond and

Conclusion

In summary, we introduce a novel, and efficient approach for the preparation of N-alkyl-2-aryl-2-(6-oxo-4H-benzo[f][1,2,3]triazolo[1,5-a][1,4]diazepin-5(6H)-yl)acetamides through a sequential Ugi-4CR-click-intramolecular Csingle bondN arylation reactions of 2-bromobenzoic acid, propargylamine, aldehydes and isocyanides catalyzed CuI. The simplicity of the starting materials, high bond-forming efficiency and good chemical yields of the described transformation are the remarkable synthetic aspects of this

Acknowledgment

This research was supported by a grant from Iran National Science Foundation (INSF).

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