Monofluoromethylation of N-Heterocyclic Compounds

Abstract

The review focuses on recent advances in the methodologies for the formation or introduction of the CH₂F moiety in N-heterocyclic substrates over the past 5 years. The monofluoromethyl group is one of the most versatile fluorinated groups used to modify the properties of molecules in synthetic medical chemistry. The review summarizes two strategies for the monofluoromethylation of N-containing heterocycles: direct monofluoromethylation with simple XCH₂F sources (for example, ICH₂F) and the assembly of N-heterocyclic structures from CH₂F-containing substrates. The review describes the monofluoromethylation of pharmaceutically important three-, five- and six-membered N-heterocycles: pyrrolidines, pyrroles, indoles, imidazoles, triazoles, benzothiazoles, carbazoles, indazoles, pyrazoles, oxazoles, piperidines, morpholines, pyridines, quinolines and pyridazines. Assembling of 6-fluoromethylphenanthridine, 5-fluoromethyl-2-oxazolines, C5-monofluorinated isoxazoline N-oxides, and α-fluoromethyl-α-trifluoromethylaziridines is also shown. Fluoriodo-, fluorchloro- and fluorbromomethane, FCH₂SO₂Cl, monofluoromethyl(aryl)sulfoniummethylides, monofluoromethyl sulfides, (fluoromethyl)triphenylphosphonium iodide and 2-fluoroacetic acid are the main fluoromethylating reagents in recent works. The replacement of atoms and entire functional groups with a fluorine atom(s) leads to a change and often improvement in activity, chemical or biostability, and pharmacokinetic properties. The monofluoromethyl group is a bioisoster of -CH₃, -CH₂OH, -CH₂NH₂, -CH₂CH₃, -CH₂NO₂ and -CH₂SH moieties. Bioisosteric replacement with the CH₂F group is both an interesting task for organic synthesis and a pathway to modify drugs, agrochemicals and useful intermediates.

Keywords: fluorination; fluorine; fluoromethylation; imidazoles; indoles; nitrogen heterocyles; pyridazines; pyridines; pyrrolidines; quinalines.

Scheme 1

The synthesis of α-fluoromethyl-α-trifluoromethylaziridines 4 via the reaction of trifluoroactimidoyl chloride (TFAIC) 1 and lithium monohalocarbenoids.

Scheme 2

Synthesis of α-fluoroaziridine from N-tosyl-substituted diphenyl ketimine and ICH₂F.

Scheme 3

Hydrofluoromethylation of N-Benzylmaleimide using ICH₂F and (TMS)₃SiH.

Scheme 4

Formation of 3-fluoromethylated N-benzylpyrrolidine.

Scheme 5

Hydrofluoromethylation of pyrrolidines in the presence of 2-phenylacetaldehyde.

Scheme 6

Synthesis of 3-fluoromethylated indolines with nucleophilic ring-opening of oxirane ring in spiro-epoxyoxindoles.

Scheme 7

N-Methyl-N-phenylmethacrylamide cyclization using CH₂FSO₂Cl.

Scheme 8

The proposed mechanism for N-Methyl-N-phenylmethacrylamide cyclization in the presence of CH₂FSO₂Cl.

Scheme 9

N-Fluoromethoxymethylation of aromatic heterocycles using ICH₂F in the presence of KOH.

Scheme 10

The proposed mechanism of N-fluoromethoxymethylation of aromatic heterocycles using ICH₂F in the presence of KOH.

Scheme 11

N-Fluoromethylation of N-heterocycles using ICH₂F in the presence of Cs₂CO_3.

Scheme 12

Electrophilic N-Fluoromethylation of heteroarenes using monofluoromethyl(aryl)sulfonium bis(carbomethoxy)methylide.

Scheme 13

Synthesis of monofluoromethyl(aryl)sulfonium bis(carbomethoxy)methylide.

Scheme 14

Bisfluoromethylation of 2-methylimidazolole.

Scheme 15

O-Fluoromethylation of N-substituted 5-hydroxypyrazoles 24 using ICH₂F in the presence of Cs₂CO₃.

Scheme 16

S-Fluoromethylation of 2-thio-benzo[d]oxazole and 2-thio-benzo[d]thiazole using ICH₂F in the presence of Cs₂CO₃.

Scheme 17

Synthesis of monofluoromethyl selenoethers using 2-(amimo)benzooxazole and 2-(amimo)benzothiazole.

Scheme 18

The proposed mechanism for the selenomonofluoromethylation of 2-(amimo)benzooxazole and 2-(amimo)benzothiazole.

Scheme 19

Synthesis of azidofluoromethane and 4-substituted 1,2,3-triazoles.

Scheme 20

4,5-Disubstituted triazole formation through the reaction of azidofluoromethane using β-ketoesters or 1,3-diones.

Scheme 21

Electrochemical synthesis of 5-fluoromethyl-2-oxazolines.

Scheme 22

The proposed mechanism for the electrochemical synthesis of 5-fluoromethyl-2-oxazolines.

Scheme 23

Synthesis of C5-monofluorinated isoxazoline N-oxides.

Scheme 24

[3 + 2]-Dipolar cycloaddition of isoxazoline-N-oxides with phenylacrylate.

Scheme 25

N-Monofluoromethylation of saturated N-containing heterocycles using aldehydes and fluoroiodomethane.

Scheme 26

4-Monofluoromethylation of 1-benzylpiperidin-4-one with lithium fluorocarbenoid.

Scheme 27

The synthesis of (fluoromethyl)triphenylphosphonium iodide.

Scheme 28

2-Fluoromethylation of pyridine-N-oxides.

Scheme 29

The proposed mechanism for the 2-fluoromethylation of pyridine-N-oxides.

Scheme 30

N-Fluoromethylation of 4(1H)-cinnolinone with ICH₂F in the presence of Cs₂CO_3.

Scheme 31

Synthesis of ortho-fluoromethylated pyridines in the presence of arylboronates.

Scheme 32

NiI₂-Catalyzed CH–monofluoroalkylation of pyridine and quinoline.

Scheme 33

The synthesis of 6-fluoromethylphenanthridine through the reaction of 2-((fluoromethyl)sulfonyl)-6-nitrobenzothiazole with 2-isocyano(1,1′-diphenyl).

Scheme 34

Proposed mechanism of the assembling of 6-fluoromethylphenanthridine.

Scheme 35

C–H–monofluoromethylation of pyridines, pyrazines and quinoxaline.

Scheme 36

C–H–bis(monofluoro)methylation of pyridines, pyrazines and quinoxalines.

Scheme 37

Fluoromethylation of tRNA guanine N37 using FMeTeSAM.

Scheme 38

Synthesis of FMeTeSAM.

Scheme 39

Synthesis of monofluoromethyl selenoesters from quinoline-3-amine.