(5<i>S</i>)‐5‐(Trifluoromethyl)pyrrolidin‐2‐one as a Promising Building Block for Fluoroorganic Chemistry

Anopheles darlingi is the main vector of malaria in Brazil, characterized by a high level of anthropophilia and endophagy. Imidacloprid, thiacloprid, and acetamiprid are the most widespread insecticides of the neonicotinoid group. However, they produce adverse effects on the non-target insects. Flupyradifurone has been marketed as an alternative to non-fluorinated neonicotinoids. Neonicotinoids containing trifluoroacethyl substituent reveal increased insecticidal activity due to higher hydrophobicity and metabolic stability. We synthesized novel neonicotinoid insecticides containing fluorinated acceptor groups and their interactions were estimated with the nicotinic acetylcholine receptor (nAChR) binding site by molecular docking studies, to evaluate their larvicidal activity against A. darlingi, and to assess their outdoor photodegradation behavior. New neonicotinoid analogues were prepared and characterized by NMR and mass-spectrometry. The synthesized molecules were modelled by time-dependent density functional theory and analyzed, their interaction with nAChR was investigated by molecular docking. Their insecticide activity was tested on Anopheles larvae collected in suburban area of Manaus, Brazil. Four new fluorinated neonicotinoid analogs were prepared and tested against 3 rd instars larvae of A. darlingi showing high larvicidal activity. Docking studies reveal binding modes of the synthesized compounds and suggest that their insecticidal potency is governed by specific interactions with the receptor binding site and enhanced lipophilicity. 2-Chloro-5-(2-trifluoromethyl-pyrrolidin-1ylmethyl)pyridine 5 showed fast degradation in water maintaining high larvicidal activity. All obtained substances possessed high larvicidal activity in low concentrations in 48 hours of exposure, compared to commercial flupyradifurone. Such activity is connected to a unique binding pattern of the synthesized compounds to insect's nAChR and to their enhanced bioavailability owing to introduction of fluorinated amino-moieties. Therefore, the compounds in question have a high potential for application as control agents for insects transmitting tropical diseases, and they will be less persistent in the environment.

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“…2-(trifluoromethyl)pyrrolidine was obtained according to our previously described procedure [52]. b) synthesis of neonicotinoids.…”

Section: General Synthetic Proceduresmentioning

confidence: 99%

“…During last few years we have developed synthetic approaches to generate novel low-molecular weight fluorinated amines and investigated their properties [52][53][54]. Substances of that kind have never been used as neonicotinoid building blocks.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, molecular docking studies, and larvicidal activity evaluation of new fluorinated neonicotinoids against Anopheles darlingi larvae

et al. 2020

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“…The preparation of 2-(trifluoromethyl)pyrrolidine can be realized from CF 3 CO 2 Et, 25 or by conversion of carboxylic acids with SF 4 /HF mixture (Scheme 14). 26 These two approaches start from pyrrolidinone 45 or (S)-pyroglutamic acid (48), and include in the last step a reduction reaction.…”

Section: Figure 5 Coagulation Factor X Inhibitormentioning

confidence: 99%

Synthesis of Fluoropyrrolidines and (Fluoroalkyl)pyrrolidines

Pfund

Lequeux

2017

Synthesis

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Pyrrolidines and their derivatives are of great interest in medicinal chemistry and organic synthesis. Fluoropyrrolidines and (fluoroalkyl)pyrrolidines have been utilized in the preparation of medicinal drugs and also as organocatalysts. The synthesis of such compounds is achieved through the fluorination of pyrrolidine derivatives or by multistep synthesis from already containing fluoroalkyl precursors.1 Introduction1.1 General Interest of Fluorine-Containing Pyrrolidines1.2 Fluoroalkylpyrrolidines and the Gauche Effect2 Fluoropyrrolidines2.1 3-Fluoropyrrolidines2.2 3,3- and 3,4-Difluoropyrrolidines2.3 3,3,4-Trifluoropyrrolidines2.4 3,3,4,4-Tetrafluoropyrrolidines3 (Difluoromethyl)- and (Trifluoromethyl)pyrrolidines3.1 2-(Trifluoromethyl)pyrrolidines3.2 3- and 4-(Trifluoromethyl)pyrrolidines3.3 2-(Difluoromethyl)pyrrolidines3.4 3- and 4-(Difluoromethyl)pyrrolidines4 (Monofluoroalkyl)pyrrolidines4.1 2-(Monofluoromethyl)pyrrolidines4.2 2-(Monofluoroalkyl)pyrrolidines4.3 2-(Monofluoroalkenyl)pyrrolidines5 Conclusion

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“…The corresponding cycloadduct 199 was obtained in 92% yield with an ee of 499%. 120 Fluorinated five membered rings 200 were also prepared by reaction of imine 24 bearing Bn or phenyl glycinol methyl ether group with ethyl 2-(bromomethyl)acrylate and Zn under Barbier conditions in up to 60% yields 121 (Fig. 36).…”

Section: F Meyermentioning

confidence: 99%

Trifluoromethyl nitrogen heterocycles: synthetic aspects and potential biological targets

Meyer

2016

Chem. Commun.

143

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(5S)‐5‐(Trifluoromethyl)pyrrolidin‐2‐one as a Promising Building Block for Fluoroorganic Chemistry

Abstract: Pyroglutamic acid smoothly reacts with sulfur tetrafluoride at room temperature to afford enantiomerically pure (5S)-5-(trifluoromethyl)pyrrolidin-2-one (92 % yield, Ͼ99 % ee).

Cited by 13 publications

References 32 publications

Synthesis, molecular docking studies, and larvicidal activity evaluation of new fluorinated neonicotinoids against Anopheles darlingi larvae

Synthesis, molecular docking studies, and larvicidal activity evaluation of new fluorinated neonicotinoids against Anopheles darlingi larvae

Synthesis of Fluoropyrrolidines and (Fluoroalkyl)pyrrolidines

Trifluoromethyl nitrogen heterocycles: synthetic aspects and potential biological targets

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