Mustard Carbonate Analogues as Sustainable Reagents for the Aminoalkylation of Phenols

• Published in: European journal of organic chemistry 2021-06, Vol.2021 (24), p.3459-3464
• Main Authors: Annatelli, Mattia, Trapasso, Giacomo, Salaris, Claudio, Salata, Cristiano, Castellano, Sabrina, Aricò, Fabio
• Format: Article
• Language: English
• Subjects: Chlorine; Chlorine-free; Dialkyl carbonate; Direct alcohol substitution; Green chemistry; Macromolecules; Mustard gas; Neighboring group participation; Nitrogen; Phenols; Reagents; Scaffolds; Substrates; Toxicity
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.202100328

N,N‐dialkyl ethylamine moiety can be found in numerous scaffolds of macromolecules, catalysts, and especially pharmaceuticals. Common synthetic procedures for its incorporation in a substrate relies on the use of a nitrogen mustard gas or on multistep syntheses featuring chlorine hazardous/toxic chemistry. Reported herein is a one‐pot synthetic approach for the easy introduction of aminoalkyl chain into different phenolic substrates through dialkyl carbonate (β‐aminocarbonate) chemistry. This new direct alcohol substitution avoids the use of chlorine chemistry, and it is efficient on numerous pharmacophore scaffolds with good to quantitative yield. The cytotoxicity via MTT of the β‐aminocarbonate, key intermediate of this synthetic approach, was also evaluated and compared with its alcohol precursor. The nitrogen mustard gas moiety is present as a basic, amine‐containing side chain in numerous pharmacophore scaffolds engaging in crucial interactions with targeted biological macromolecules. Herein, a one‐pot synthetic approach for the easy introduction of nitrogen mustard‐like moieties through dialkyl carbonate chemistry into different phenolic substrates is reported. The scope and limitations of this reaction as a chlorine‐free direct substitution of the phenolic −OH group have been investigated.