Studies on 2-Arylhydrazononitriles: Synthesis of 3-Aryl-2-arylhydrazopropanenitriles and Their Utility as Precursors to 2-Substituted Indoles, 2-Substituted-1,2,3-Triazoles, and 1-Substituted Pyrazolo[4,3-d]pyrimidines

Khaled D Khalil,Hamad M Al-Matar

doi:10.3390/molecules171012225

Khaled D Khalil, Hamad M Al-Matar

Open Access

https://doi.org/10.3390/molecules171012225

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Abstract

Coupling of 2-benzylmalononitrile with aromatic diazonium salts afforded 3-phenyl-2-arylhydrazonopropanenitriles 4a,b, which were rearranged into 2-cyanoindoles 5a,b upon heating with ZnCl2 in the presence of glacial acetic acid. The produced indole derivatives 5a,b can be successfully used as valuable precursors to synthesize 1,2,4-oxadiazolylindoles 8a,b. The reaction of arylhydrazononitriles 4a,b with hydroxylamine afforded an amidoximes 9a,b that could be cyclized into 1,2,3-triazole-4-amines 10a,b. In addition, 4a,b could be converted into 4-aminopyrazoles 12a,b via condensation with chloroacetonitrile in the presence of triethylamine as a basic catalyst. Finally, compounds 12a,b were refluxed with dimethylformamide dimethylacetal (DMFDMA) to afford amidines 13a,b that were readily cyclized to the corresponding pyrazolo[4,3-d]pyrimidines 14a,b when refluxed with ammonium acetate.

Highlights

5a,b upon heating with ZnCl2 in the presence of glacial acetic acid
In conjunction to that work we report an easy route to the title compounds and their utility as precursors for synthesis of various heterocycles. 1,2,3-Triazine derivatives are an important class of heterocyclic compounds that are considered useful precursors in organic synthesis and as pharmaceuticals [9,10,11]
Compounds 4a,b afforded the 2-cyanoindoles 5a,b upon treatment with zinc chloride and glacial acetic acid. This is an example of the utility of the Fisher indole synthesis in the synthesis of

Summary

Introduction

2-Arylhydrazononitriles 4a,b are versatile reagents and their chemistry has recently attracted considerable interest [1,2,3,4,5,6,7,8]. In previous recent work we have established the utility of these compounds as precursors for 1,2,4-triazoles [5], 1,2,3-triazoles [6], and pyrazolo[1,5-a]pyrimidines [7,8]. In conjunction to that work we report an easy route to the title compounds and their utility as precursors for synthesis of various heterocycles. 1,2,3-Triazine derivatives are an important class of heterocyclic compounds that are considered useful precursors in organic synthesis and as pharmaceuticals (e.g., as antimalarials) [9,10,11]. We enabled development of an easy approach to 1,2,4-oxadiazolylindole [12,13], and pyrazolo[4,3-d]pyrimidine derivatives of notable biological and pharmaceutical importance [14,15,16]

Results and Discussion

General Procedures

Synthesis of Pyrazolopyrimidine Derivatives

Conclusions