Access to a new class of synthetic building blocks via trifluoromethoxylation of pyridines and pyrimidines

Abstract

Since the first synthesis of trifluoromethyl ethers in 1935, the trifluoromethoxy (OCF3) group has made a remarkable impact in medicinal, agrochemical, and materials science research. However, our inability to facilely incorporate the OCF3 group into molecules, especially heteroaromatics, has limited its potential across a broad spectrum of technological applications. Herein, we report a scalable and operationally simple protocol for regioselective trifluoromethoxylation of a wide range of functionalized pyridines and pyrimidines under mild reaction conditions. The trifluoromethoxylated products are useful scaffolds that can be further elaborated by amidation and palladium-catalysed cross coupling reactions. Mechanistic studies suggest that a radical O-trifluoromethylation followed by the OCF3-migration reaction pathway is operable. Given the unique properties of the OCF3 group and the ubiquity of pyridine and pyrimidine in biologically active molecules and functional materials, trifluoromethoxylated pyridines and pyrimidines could serve as valuable building blocks for the discovery and development of new drugs, agrochemicals, and materials.

Mechanistic studies on intramolecular C–H trifluoromethoxylation of (hetero)arenes via OCF3-migration

“…2). 19 Our approach is operationally simple and amenable to one pot as well as gram-scale synthesis, features a broad substrate scope and high functional group compatibility, and provides a wide range of valuable ortho -trifluoromethoxylated (hetero)arylamine scaffolds that would otherwise be difficult to synthesize. In view of its potential synthetic utility, an in-depth understanding of its mechanism is desirable.…”

Radical Trifluoromethoxylation of Arenes Triggered by a Visible‐Light‐Mediated N−O Bond Redox Fragmentation

“…[14] This method is simpler to carry out than existing trifluoromethylation strategies and has been adopted, for example,b yN gai and co-workers for the trifluoromethylation of N-hydroxyanilines. [7,15] In this regard, oxyphthalimide 1 seemed particularly predestined for redox-neutral fragmentation of the N À O bond, akin to an umber of reports for the scission of NÀOAlkyl [16] and NÀSCF 3 [17] bonds.Avery recent publication from Ngai and co-workers invoking as imilar hypothesis prompted us to disclose our own results in this area. [18] Phthalimide 1 and derivatives thereof were prepared in good yields using our previously reported method.…”

Radikalische Trifluormethoxylierung aromatischer Verbindungen durch photochemische N‐O‐Bindungsaktivierung

“…[ Bereits 2014 berichteten wir über eine allgemeine Methode fürd ie Trifluormethylierung von Hydroxylaminen, welche die potenziellen Reagenzien dieses Ty ps liefert, insbesondere N-Trifluormethoxyphthalimid (1). [7,15] In dieser Hinsicht erscheint das Oxyphthalimid 1 füre ine redoxneutrale Fragmentierung der N-O-Bindung geeignet, ähnlich wie im Falle von N-OAlkyl- [16] und N-SCF 3 -Spaltungen. B. von Ngai fürd ie Tr ifluormethylierung von N-Hydroxyanilinen.…”

“…Die entsprechenden Produkte kçnnen durch Hofmann-Martius-Umlagerung in Tr ifluormethoxy(hetero)arene umgewandelt werden. [7,15] In dieser Hinsicht erscheint das Oxyphthalimid 1 füre ine redoxneutrale Fragmentierung der N-O-Bindung geeignet, ähnlich wie im Falle von N-OAlkyl- [16] und N-SCF 3 -Spaltungen. [17] Eine erst kürzlich publizierte und durch eine ähnliche Hypothese gestützte Arbeit von Ngai veranlasste uns,u nsere Ergebnisse ebenfalls zu verçffentlichen.…”