Regioselective Preparation of 3-Alkoxy-4,5-difluoroanilines by SNAr

• Published in: European journal of organic chemistry Vol. 2012; no. 36; pp. 7048 - 7052
• Main Authors: Van Brandt, Sven, Rombouts, Frederik J. R., Martínez-Lamenca, Carolina, Leenaerts, Jos, Rauws, Tom R. M., Trabanco, Andrés A.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01.12.2012; WILEY‐VCH Verlag; Wiley; Wiley Subscription Services, Inc
• Subjects: Arenes; Aromatic substitution; Chemistry; Chemistry, Organic; Fluorine; Nucleophilic substitution; Physical Sciences; Science & Technology; SUBSTITUTION; ALKOXIDES; Fluorine; Arenes; DISPLACEMENT; Nucleophilic substitution; Aromatic substitution; DERIVATIVES; SOLVENT
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.201201228

A simple and scalable procedure to introduce alcohols selectively at the 3‐position of 3,4,5‐trifluoroaniline is described. The procedure uses powdered NaOH as base and catalytic 15‐crown‐5 in refluxing toluene with a Dean–Stark trap. A short exploration of other nucleophiles and fluoroaryl electrophiles is also described. Nucleophilic aromatic meta‐substitution of 3,4,5‐trifluoroaniline was optimized and exemplified with a diverse set of alcohols. The conditions are cheap, simple, and highly scalable. Variation of both the nucleophile and the electrophile was explored.