Catalyst-Free Site Selective Hydroxyalkylation of 5-Phenylthiophen-2-amine with α-Trifluoromethyl Ketones through Electrophilic Aromatic Substitution

• Published in: Molecules (Basel, Switzerland) Vol. 27; no. 3; p. 925
• Main Authors: Duvauchelle, Valentin, Bénimélis, David, Meffre, Patrick, Benfodda, Zohra
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 29.01.2022; MDPI
• Subjects: Carbonyl compounds; Carbonyls; catalyst-free; Catalysts; Chemical Sciences; chemoselective; Communication; hydroxyalkylation; Imines; Indoles; Ketones; Lewis acid; Medicinal Chemistry; Organic chemistry; Reagents; site selective; Substitution reactions; Thiophenes; trifluoromethyl hydroxyalkylation; trifluoromethyl ketone; 5-phenylthiophen-2-amine; trifluoromethyl hydroxyalkylation; hydroxyalkylation; catalyst-free; 2-aminothiophene; chemoselective; site selective; trifluoromethyl ketone; trifluoromethyl hdroxyalkylation; Site selective; trifluoromethyl ketones; catalyst free
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules27030925

An original and effective approach for achieving trifluoromethyl hydroxyalkylation of 5-phenylthiophen-2-amine using α-trifluoromethyl ketones is described. In the last few years, reaction of Friedel-Crafts had been widely used to realize hydroxyalkylation on heterocycles such as indoles or thiophenes by means of Lewis acid as catalyst. Additionally, amine functions are rarely free when carbonyl reagents are used because of their tendency to form imines. This is the first time that a site-selective electrophilic aromatic substitution on C atom of an unprotected 5-phenylthiophen-2-amine moiety is reported. The liberty to allow reaction in neutral conditions between free amine is valuable in a synthesis pathway. The reaction proceeds smoothly using an atom-economical metal-and catalyst-free methodology in good to excellent yields. A mechanism similar to an electrophilic aromatic substitution has been proposed.