N-Trifluoromethyl Amines and Azoles: An Underexplored Functional Group in the Medicinal Chemist’s Toolbox

Abstract

Introducing trifluoromethyl groups is a common strategy to improve the properties of biologically active compounds. However, N-trifluoromethyl moieties on amines and azoles are very rarely used. To evaluate their suitability in drug design, we synthesized a series of N-trifluoromethyl amines and azoles, determined their stability in aqueous media, and investigated their properties. We show that N-trifluoromethyl amines are prone to hydrolysis, whereas N-trifluoromethyl azoles have excellent aqueous stability. Compared to their N-methyl analogues, N-trifluoromethyl azoles have a higher lipophilicity and can show increased metabolic stability and Caco-2 permeability. Furthermore, N-trifluoromethyl azoles can serve as bioisosteres of N-iso-propyl and N-tert-butyl azoles. Consequently, we suggest that N-trifluoromethyl azoles are valuable substructures to be considered in medicinal chemistry.

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

“…As it was mentioned in the Introduction, these include, for example, sulfoximines, [39,527,528] sulfonimidamides [529,530] and their analogs, [531] dialkyl phospine oxides [40,145] -unusual isosteres of amides, sulfonamides, sulfones, and related compounds (Figure 13), as well as deuterated analogues, [41] silicon-containing isosteres, [42] or Ntrifluoromethylated azoles. [43] It is interesting to note that nearly all these examples, as well as most of those discussed in this review, originate from organosulfur, -boron, -phosphorus, -silicon, or -fluorine chemistry. We believe that early drug discovery will continue to benefit from these and related areas of organo-element chemistry, and more neglected chemotypes will be uncovered in the nearest future.…”

“…Such emerging motifs are represented by boronic acids as the covalent warheads, [36] unusual fluorinecontaining aliphatic substituents, [37,38] sulfoximines, [39] phosphine oxides, [40] deuterated substituents, [41] silicon-containing isosteres, [42] or N-trifluoromethylated azoles. [43] Evolution of all three types of emerging building blocks for medicinal chemistry can be schematically represented by "the building block triangle" (visually similar to high-throughput screening (HTS) triangle [44] or principal moment of inertia (PMI) plots [45] ) (Figure 2). The vertices of this triangle correspond to the building blocks with functional groups for novel synthetic methodologies, novel sp 3 -enriched carbo-and heteroaliphatic cores, and emerging medicinal chemistry motifs, respectively.…”

The Powerful Symbiosis Between Synthetic and Medicinal Chemistry

“…For the first time, this functional group has become readily accessible using mild conditions, without the need for hazardous reagents or elaborate prefunctionalization. We set out to investigate the aqueous stability and in vitro properties of this compound class to judge its suitability for application in medicinal chemistry [6]. We found that tertiary N-trifluoromethyl N-alkyl amines, including benzyl amines and anilines, rapidly hydrolyze in aqueous media.…”

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

“…Azoles earn an important place in the fields of biology, pharmaceuticals, functional materials, and organic synthesis [1] . Because the incorporation of a trifluoromethyl (CF 3 ) group onto the nitrogen can largely decrease the basicity, thereby improving the metabolic stability, lipophilicity or bioavailability of lead compounds, [2] N ‐CF 3 azole cores have become highly pursued targets, especially in the medicinal chemist's toolbox [3, 4] . By contrast to the most prevalence of N ‐methyl azoles, N ‐trifluoromethyl azoles are not yet routinely used in drug discovery though studies have shown that the replacement of the N ‐methyl by the N ‐trifluoromethyl could lead to significantly increased bioactivities of azole derivatives (Figure 1).…”

“…This type of fluorination‐based strategy has been used for accessing N ‐CF 3 azoles (Scheme 1 A). [3, 5, 6b–d] However, limited examples are available because the methodology shares the fundamental limitations of unavoidably requiring both tedious N ‐pre‐functionalization and unfriendly reagents. By comparison, direct introduction of the CF 3 onto the heterocyclic nitrogen allows for economic and convenient entry to N ‐CF 3 azoles.…”