New strategies for molecular diversification of 2-[Aminoalkyl-(1H-1,2,3-Triazol-1- yl)]-1,4-naphthoquinones using click chemistry

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.