Monofluorinated Nitrogen Containing Heterocycles: Synthesis, Characterization and Fluorine Effect

Abstract

A straight forward synthesis and efficient introduction of fluoromethyl group in nitrogen heterocycles is reported. Starting from the respective NH heterocycles fluoromethylation is performed with fluoroiodomethane and proceeds under mild reaction conditions. Structural information of monofluoromethylated nitrogen‐containing cyclic compounds containing the biologically active NCH2F moiety are reported. The particularly impressively change of physical and spectroscopic properties by the substitution of a methyl group by a monofluoromethyl group is discussed based on these examples.

Fluoroiodomethane: A CH2F‐Moiety‐Delivering Agent Suitable for Nucleophilic‐, Electrophilic‐, and Radical‐Harnessed Operations

“…This experiment further confirms the attitude of the CH 2 F to act as a competent manifold for nucleophilic substitutions. As later shown by Karaghiosoff, [71] the monofluoromethylation of nitrogen nucleophiles (phtalimide and 2-methylimidazole) with fluoroiodomethane could also be realized -albeit in lower yield -by forming the corresponding potassium salt (treatment with K 2 CO 3 in acetonitrile). Eventually, a second fluoromethylation could be run in the case of the imidazole analogue, providing the corresponding bis-fluoromethylated imidazolium salt.…”

Monofluoromethylation of N-Heterocyclic Compounds

“…N-Fluoromethylphthalimide was also obtained in the reaction of potassium phthalimide with fluoriodomethane in a MeCN medium. The yield is achieved at 71% by performing the reaction at 120 • C and increasing the pressure to 3.3 bar [66].…”

“…The reaction mixture was stirred overnight, and corresponding 1-fluoromethyl-2-methyl imidazole 22 was obtained with a yield of 63%. Adding another equivalent of iodofluoromethane leads to the formation of bisfluoromethyl-2-methylimidazolium iodide 23, with a yield of 73% [66] (Scheme 14). Monofluoromethyl(aryl)sulfonium bis(carbomethoxy)methylide 20 is a solid substance that can be stored at room temperature for more than a month, which is very convenient to use, unlike gaseous reagents [67].…”

“…The reaction mixture was stirred overnight, and corresponding 1-fluoromethyl-2-methyl imidazole 22 was obtained with a yield of 63%. Adding another equivalent of iodofluoromethane leads to the formation of bisfluoromethyl-2-methylimidazolium iodide 23, with a yield of 73% [66] (Scheme 14). The melting point of bisfluoromethyl-2-methylimidazolium iodide is 252 °C [66].…”

“…Adding another equivalent of iodofluoromethane leads to the formation of bisfluoromethyl-2-methylimidazolium iodide 23, with a yield of 73% [66] (Scheme 14). The melting point of bisfluoromethyl-2-methylimidazolium iodide is 252 °C [66]. Fluoriodomethane allows direct O-fluoromethylation of N-substituted 5-hydroxypyrazoles 24 in quantitative yields [65] (Scheme 15).…”