Abstract
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 C3 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.
Highlights
Electrophilic Aromatic Substitution.2-aminothiophene (2-AT) moiety is widespread in FDA-approved drugs and is a privileged scaffold in medicinal chemistry that is known to confer many biological activities [1,2,3,4,5]
Compound 3 has been described as a hepatitis B virus replication inhibitor [7] and compound 4 showed antimicrobial activity against A. fumigatus, G. candidum, C. albicans and S. racemosum [8]. 2-AT derivatives are mostly synthesized using
Suzuki-Miyaura coupling conditions, ininour laborato trifluoromethyl hydroxyalkylation methodology we developed presence of va Scheme 1. 2-bromo-5-nitrothiophene
Summary
Gewald reaction [9,10] It involves condensation of a carbonyl derivative, a α-cyanoester in the presence of sulfur source. To this day, used methodologies often undergo to the generation of trisubstituted thiophene ring with an electron withdrawing group– negative mesomeric effect–on C3 atom (Figure 1a) [11,12,13,14,15]. Ullyot first reported hydroxyalkylation of aryl compounds with a carbonyl derivative under acidic conditions as new way to synthesize benzoins [20]. The methodologies described, respectively, by Schnakenburg [21], Ramanathan [22] and Chatti [23] are relevant examples of hydroxyalkylation on heteroaryls scaffolds (Figure 1b,c). We report the trifluoromethyl hydroxyalkylation methodology we developed in presence of various α-trifluoromethyl ketones (Figure 1d)
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