A Facile and Inexpensive Way to Synthesize N‐trifluoromethyl Compounds

Schaub, Stefan; Becker, Jonathan; Schindler, Siegfried

doi:10.1002/slct.202201803

Cited by 2 publications

(4 citation statements)

References 27 publications

(20 reference statements)

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“…It has been previously reported that alkyl N −CF 3 amines, particularly those without electron‐withdrawing groups attached, are susceptible to fluorine elimination;[ 2 , 5 ] furthermore, the groups of Schindler, Yi, and Xiao each reported independently that degradation can occur rapidly upon flash column chromatography purification. [ 5a , 10a , 10d ] To confirm that the aqueous conditions of the LCMS were the cause of the observed transformation, compound 2 f was subjected to the relevant aqueous ammonium bicarbonate conditions used in the LCMS analysis, which resulted in the formation of carbamoyl fluoride 6 a in 27 % isolated yield (Scheme 4 ).…”

Section: Resultsmentioning

confidence: 99%

“…Based on the pioneering work by Schoenebeck et. al ., [9] this approach has been used to synthesise a wide range of N −CF 3 amines in good yields under mild reaction conditions [5a,9,10] . Despite the Schoenebeck method employing the bench‐stable (Me 4 N)SCF 3 in a one‐pot protocol, the drawback of this method is the use, and associated relative expense, of super‐stoichiometric quantities of AgF [11] .…”

Section: Introductionmentioning

confidence: 99%

“…al ., [9] this approach has been used to synthesise a wide range of N −CF 3 amines in good yields under mild reaction conditions. [ 5a , 9 , 10 ] Despite the Schoenebeck method employing the bench‐stable (Me 4 N)SCF 3 in a one‐pot protocol, the drawback of this method is the use, and associated relative expense, of super‐stoichiometric quantities of AgF. [11] Alternatively, N −CF 3 amines may be synthesised by the direct trifluoromethylation of amines, using electrophilic reagents developed by Umemoto and Togni et al .…”

Section: Introductionmentioning

confidence: 99%

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Copper‐Mediated N‐Trifluoromethylation of O‐Benzoylhydroxylamines

Fleetwood,

Kerr,

Mason

2023

Chemistry A European J

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The use of trifluoromethyl containing compounds is well established within medicinal chemistry, with a range of approved drugs containing C−CF3 and O−CF3 moieties. However, the utilisation of the N−CF3 functional group remains relatively unexplored. This may be attributed to the challenging synthesis of this unit, with many current methods employing harsh conditions or less accessible reagents. A robust methodology for the N‐trifluoromethylation of secondary amines has been developed, which employs an umpolung strategy in the form of a copper‐catalysed electrophilic amination. The method is operationally simple, uses mild, inexpensive reagents, and has been used to synthesise a range of novel, structurally complex N−CF3 containing compounds.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Copper‐Mediated N‐Trifluoromethylation of O‐Benzoylhydroxylamines

Fleetwood,

Kerr,

Mason

2023

Chemistry A European J

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“…The reaction conditions were applicable to a wide range of disubstituted nitrogen, with substituents including phenyl, heteroaromatic or alkyl. Recently, Schindler et al applied chlorodithiophenylformiate as an electrophile and successfully obtained phenyl aminodithioate 30 [ 60 ]. Then trifluoromethylamines 31 were generated after the desulfurization and fluorination.…”

Section: Five-membered Heterocyclesmentioning

confidence: 99%

A Brief Review on the Synthesis of the N-CF3 Motif in Heterocycles

et al. 2023

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The trifluoromethyl group is widely recognized for its significant role in the fields of medicinal chemistry and material science due to its unique electronic and steric properties that can alter various physiochemical properties of the parent molecule, such as lipophilicity, acidity, and hydrogen bonding capabilities. Compared to the well-established C-trifluoromethylation, N-trifluoromethylation has received lesser attention. Considering the extensive contribution of nitrogen to drug molecules, it is predicted that constructing N-trifluoromethyl (N-CF3) motifs will be of great significance in pharmaceutical and agrochemical industries. This review is mainly concerned with the synthesis of heterocycles containing this motif. In three-membered heterocycles containing the N-CF3 motif, the existing literature mostly demonstrated the synthetic strategy, as it does for four- and larger-membered heterocycles. Certain structures, such as oxaziridines, could serve as an oxidant or building blocks in organic synthesis. In five-membered heterocycles, it has been reported that N-CF3 azoles showed a higher lipophilicity and a latent increased metabolic stability and Caco-2-permeability compared with their N-CH3 counterparts, illustrating the potential of the N-CF3 motif. Various N-CF3 analogues of drugs or bioactive molecules, such as sildenafil analogue, have been obtained. In general, the N-CF3 motif is developing and has great potential in bioactive molecules or materials. Give the recent development in this motif, it is foreseeable that its synthesis methods and applications will become more and more extensive. In this paper, we present an overview of the synthesis of N-CF3 heterocycles, categorized on the basis of the number of rings (three-, four-, five-, six- and larger-membered heterocycles), and focus on the five-membered heterocycles containing the N-CF3 group.

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A Facile and Inexpensive Way to Synthesize N‐trifluoromethyl Compounds

Cited by 2 publications

References 27 publications

Copper‐Mediated N‐Trifluoromethylation of O‐Benzoylhydroxylamines

Copper‐Mediated N‐Trifluoromethylation of O‐Benzoylhydroxylamines

A Brief Review on the Synthesis of the N-CF3 Motif in Heterocycles

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