New Strategies for Molecular Diversification of 2-[Aminoalkyl-(1H-1,2,3-triazol-1- yl)]-1,4-naphthoquinones Using Click Chemistry

Ronaldo De Oliveira,Mauro Da Silva,Josinete Da Paz,Wagner Valença,Celso Camara,Moara Da Silva,Valentina Melo

doi:10.21577/0103-5053.20160207

Abstract

Click chemistry-based strategies for the synthesis of 2-amino-alkyl-1,2,3-triazole-1,4-naphthoquinone derivatives make it possible to obtain desired products from 1,4-naphthoquinone (1,4-NQ), and bio-based lawsone, nor-lapachol and lapachol. The first route (Strategy A) starting from 1,4-NQ and amino alcohols, then 2-amino-alkyl-1,4-NQ alcohols, were tosylated. The azide ion displaced the tosylate group to afford 2-azide-alkyl-1,4-NQ, which was submitted to a copper-catalyzed azide alkyne cycloaddition (CuAAC) condition. The triazole-naphthoquinones were obtained in an overall yield of roughly 47%. Another pathway (Strategy B) substituted bromo-alkyl-phthalimides using NaN3 as the nucleophile, sequential CuAAC and deprotection of phthalimide group with hydrazine producing amino-triazoles. The subsequent reaction with 1,4-NQ produced 2-amino-alkyl-1,2,3-triazole-1,4-NQ derivatives in an overall yield of 45-76% in four steps. After we developed these two strategies, linear synthesis (Strategy A) was chosen to prepare 2-[(2-(1H-1,2,3-triazol-1-yl)ethylamino)]-3-(3-methylpropenyl)-1,4-naphthoquinones from lawsone with an overall yield of approximately 27% in six steps. On the other hand, convergent synthesis (Strategy B) was employed for the synthesis of 2-[(4-phenyl-1H-1,2,3-triazol-1-yl)alkyl-amino)]-3-(3-methylbut-2-en-1-yl)-1,4-naphthoquinones from the reaction between 2-methoxy-lapachol with amino-triazoles with a global yield of about 21%. These synthetic strategies might lead us to new opportunities to build small-molecule libraries for future biological exploration.

Highlights

The synthesis of New Chemical Entities (NCE) remains unaffected by changes in the focus of chemical science.[1]
We report on the synthesis of novel 2-amino-alkyl-(1H-1,2,3-triazol-1-yl)-1,4naphthoquinones employing the copper-catalyzed Huisgen reaction between azide-alkyl-amino-1,4-naphthoquinones with terminal alkynes
Our investigation began with the reaction between naphthoquinone 1 (1,4-NQ) with aminoalcohols to furnish 2-hydroxyalkyl-amino-1,4-NQs 2-3 using CH3CN at room temperature for 3 h in yields of 73 and 67%, respectively (Scheme 1)

Summary

Introduction

The synthesis of New Chemical Entities (NCE) remains unaffected by changes in the focus of chemical science.[1]. Our investigation began with the reaction between naphthoquinone 1 (1,4-NQ) with aminoalcohols to furnish 2-hydroxyalkyl-amino-1,4-NQs 2-3 using CH3CN at room temperature for 3 h in yields of 73 and 67%, respectively (Scheme 1). The tosylated compounds 4-5 were carried out as substrates for the SN2 displacement reaction with NaN3 in DMSO to provide the azide 6 and 7 in almost quantitative yields.

Results

Conclusion