Trifluoromethyl nitrogen heterocycles: synthetic aspects and potential biological targets

Abstract

Recent advances regarding the synthetic chemistry of fluorinated aziridines, azetidines, pyrrolidines and their lactam/amino acid counterparts are presented. These heterocycles are of high importance both as building blocks for more complex structures and as active parts of medicinal chemistry-oriented compounds.

Experimental and Theoretical Study on the Cycloreversion of a Nucleobase‐Derived Azetidine by Photoinduced Electron Transfer

“…They are interesting pharmacological units, in part due to the rigidity of their strained ring, which offers an added value in the search for new compact scaffolds, but also in connection with their presence in natural products and their application as peptidomimetics . From a synthetic point of view, their facile ring opening by nucleophiles makes them valuable building blocks in the construction of complex nitrogen‐containing molecules . Moreover, azetidines have found application as chiral auxiliaries or ligands in metal‐catalyzed reactions …”

Synthesis of Substituted α-Trifluoromethyl Piperidinic Derivatives

“…In this context, the trifluoromethyl group is often used as a bioisostere of a chloride or a methyl group to modulate the steric and electronic properties of a lead compound or to protect a reactive methyl group from metabolic oxidation. This substituent can also increase the lipophilicity of molecules [8]. …”

Strategies for the Efficient Synthesis of Biheterocyclic 5-[2-(Trifluoromethylheteroaryl)-ethyl]-1,3,4-oxadiazoles from Levulinic Acid

“…It has attracted interest in medicinal chemistry as a bioisostere for carboxylic acids, esters, and carboxamides. 4 The ability of 1,3,4-oxadiazole heterocyclic compounds to undergo various chemical reactions has made them important for molecule planning, which has enormous biological potential. [6][7][8][9][10][11][12][13] Recently we have reported the synthesis of methyl 1,1,1-trifluoro-4-methoxy-6-oxo-4-heptenoate as a building block for trifluoromethyl containing heterocyclic systems.…”

“…It is well known that adding a fluorinated group to certain compounds will modify their physicochemical profiles, increasing their lipophilicity and metabolic stability. 4,5 Among heterocyclic compounds, 1,3,4-oxadiazole has become an important construction template for the development of new drugs. It has attracted interest in medicinal chemistry as a bioisostere for carboxylic acids, esters, and carboxamides.…”

“…This substrate has three electrophilic centers allowing its use in [4 + 1], [3 + 2], and [3 + 3] cyclocondensation processes, as shown in Scheme 1. [14][15][16][17][18] Our ongoing interest in producing and understanding the biological activities of halogenated heterocyclic systems led us to study strategies for synthesizing a diversity of biheterocyclic systems, such as 5-[2-(trifluoromethylheteroaryl)-ethyl]-1,3,4-oxadiazoles (4)(5)(6)(7), with an ethylene spacer between heterocyclic nuclei, from methyl 3-(trifluoromethylheteroaryl)propanoates, where trifluoromethylheteroaryl is 5(3)-trifluoromethyl-1H-pyrazol-3(5)-yl, 2-phenyl-6-trifluoromethyl pyrimidin-4-yl, Vol. 28, No.…”