An N‐Trifluoromethylation/Cyclization Strategy for Accessing Diverse N‐Trifluoromethyl Azoles from Nitriles and 1,3‐Dipoles

Abstract

N‐Trifluoromethyl azoles are valuable targets in medicinal chemistry, but their synthesis is challenging. Classical preparation of N‐CF3 azoles relies on the functional group interconversions but suffers from tedious N‐pre‐functionalization and unfriendly agents. Introduction of the CF3 onto the nitrogen of heterocycles provides a direct route to such motifs, but the N‐trifluoromethylation remains underdeveloped. Reported here is an alternative and scalable cyclization strategy based on NCF3‐containing synthons for constructing N‐CF3 azoles. The approach involves the N‐trifluoromethylation of nitriles followed by a [3+2] cyclization between resulting N‐CF3 nitrilium derivatives and 1,3‐dipoles. PhICF3Cl was an effective CF3 source for the transformation. As a result, a generic platform is established to divergently synthesize N‐trifluoromethylated tetrazoles, imidazoles, and 1,2,3‐triazoles by using sodium azide, activated methylene isocyanides, and diazo compounds as dipoles.

Synthesis of N-CF3 Amidines/Imidates/Thioimidates via N-CF3 Nitrilium Ions

“…These results indicated that the catalysis with DMAP was crucial to the success of this process. As for Et 3 N, according to our previous work, there are at least two roles: assistance with in situ generation of the N -CF 3 benzonitrilium ion from the DMAP-stabilized N -CF 3 benzonitrilium ion ( s-6 ) and activation of the nucleophile. No better yield was observed when the loading of the DMAP catalyst was increased (entry 5 vs entry 1).…”

“…They have been readily diversified to N -CF 3 amides, carbamates, and ureas as well as to N -CF 3 -decorated indoles, hydrazines, amides, quinolones, and so on. Besides, DMAP-stabilized N -CF 3 nitrilium ions ( s-6 ) were synthesized by us recently and well used as N -CF 3 synthons in 1,3-dipolar cyclizations to construct diverse N -CF 3 azoles . It can be seen that the development of N -CF 3 synthons brings out a new opportunity to unlock numerous N -CF 3 compounds.…”

“…The involvement of an in situ -formed N -CF 3 nitrilium ion in a Ritter-type reaction was proposed by Togni’s group in 2011 . In our recent work as described in Scheme - IIa , by treatment of DMAP-stabilized N -CF 3 nitrilium salts s-6 with Et 3 N, the in situ -generated N -CF 3 nitrilium ions could be also used to construct N -CF 3 azoles . Salts s-6 were usually required to be prepared first via N -trifluoromethylation of nitriles followed by DMAP trapping.…”

General Access to N−CF3 Secondary Amines and Their Transformation to N−CF3 Sulfonamides

“…Introducing CF 3 into organic molecules often significantly changes the physical and chemical properties, [1–7] metabolic stability, [8] and bioavailability [9] of these molecules. Over the past decade, the N ‐trifluoromethylation reaction has made appreciable progress, [10–16] including recent remarkable advances in the work of N −CF 3 amides [17–23] . However, access to N −CF 3 compounds simply from N −CF 3 secondary amines is still challenging.…”

General Synthesis of N-Trifluoromethyl Compounds with N-Trifluoromethyl Hydroxylamine Reagents

“…On the other hand, thanks to the development of new trifluoromethylating reagents, Umemoto and Togni first accomplished the trifluoromethylation of amines and nitriles using their reagents, respectively (Scheme , b). Following their pioneering work, new trifluoromethylation reactions, including electrophilic, nucleophilic, radical, and oxidative trifluoromethylation of other N-containing compounds, such as azoles, ketimines, azodicarboxylates, p -toluenesulfonyl azide, nitrosoarenes, sulfoximines, or amides, have been reported by different groups to access the corresponding N -CF 3 compounds.…”