Palladium‐Catalyzed 2,2,2‐Trifluoroethoxylation of Aromatic and Heteroaromatic Chlorides Utilizing Borate Salt and the Synthesis of a Trifluoro Analogue of Sildenafil

• Published in: Chemistry : a European journal Vol. 23; no. 62; pp. 15628 - 15632
• Main Authors: Pethő, Bálint, Zwillinger, Márton, Csenki, János T., Káncz, Anna E., Krámos, Balázs, Müller, Judit, Balogh, György T., Novák, Zoltán
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 07.11.2017; Wiley Subscription Services, Inc
• Subjects: Animals; Blood-Brain Barrier - metabolism; borates; Borates - chemistry; Catalysis; Chemical reactions; Chemical synthesis; Chemistry; Chemistry, Multidisciplinary; Chlorides; Chlorides - chemistry; Cross coupling; Fluorine - chemistry; Half-Life; heterocycles; homogeneous catalysis; Humans; Male; Palladium; Palladium - chemistry; Physical Sciences; Rats; Salts; Science & Technology; Sildenafil; Sildenafil Citrate - analogs & derivatives; Sildenafil Citrate - chemical synthesis; Sildenafil Citrate - pharmacokinetics; Substrates; trifluoroethoxylation; TRIFLUOROETHYLATION; borates; EFFICIENT SYNTHESIS; O BOND FORMATION; ALCOHOLS; MEDIATED OXIDATIVE TRIFLUOROMETHYLATION; homogeneous catalysis; heterocycles; trifluoroethoxylation; POLYFLUOROALKOXYLATION; cross-coupling; palladium; FLUORINE; FLUOROALKOXYLATION; ARYL; IONIC LIQUIDS
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201704205

A simple and convenient method was developed for the introduction of a 2,2,2‐trifluoroethoxy group to various aromatic and heteroaromatic systems. The novel process utilizes aromatic chlorides as substrates, and tetrakis(2,2,2‐trifluoroethoxy) borate salt as an inexpensive and readily available fluoroalkoxy source in a palladium‐catalyzed cross‐coupling reaction. The power of the developed methodology was demonstrated in the synthesis of a fluorous derivative of Sildenafil. Fluorine Blue: A novel palladium‐catalyzed trifluorethyoxylation of aryl chlorides was developed with the aid of a new type of borate‐based trifluoroethoxylating reagent. Beyond the functionalization of various aromatic and heteroaromatic systems, the synthesis of the trifluoro analogue of Sidenafil (Viagra) was achieved together with the determination of its physicochemical properties.