Synthesis of 1-hetaryl-2,2-difluorocyclopropane-derived building blocks: The case of pyrazoles

Nosik, Pavel S.; Ryabukhin, Sergey V.; Pashko, Mykola O.; Grabchuk, G. P.; Grygorenko, Oleksandr O.; Volochnyuk, Dmitriy M.

doi:10.1016/j.jfluchem.2018.11.006

Cited by 22 publications

(11 citation statements)

References 32 publications

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“…0.8–1.2 equivalents of CF 3 SiMe 3 ; an induction period was observed. This is yet another fact showing that the reaction cannot be described simply as difluorocarbene cycloaddition;, in particular, some type of radical mechanism might be involved.…”

Section: Resultsmentioning

confidence: 99%

“…While a number of papers describe synthetic approaches to the compounds having a gem ‐difluorocyclopropyl group attached to the carbon atom, as well as their chemical transformations,, the corresponding N ‐substituted analogues are much less studied. Most of them referred to the parent gem ‐difluorocyclopropylamine ( 5 ) or its derivatives (Scheme );, it should be noted that similar aliphatic amines (e.g.…”

Section: Introductionmentioning

confidence: 99%

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N‐Difluorocyclopropyl‐Substituted Pyrazoles: Synthesis and Reactivity

et al. 2019

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Difluorocyclopropanation of N‐vinylazoles with the CF3SiMe3–NaI system was studied. It was found that N‐vinylpyrazoles could be transformed into the corresponding N‐difluorocyclopropyl‐substituted derivatives. The method was efficient on a 100 g scale and could be applied for the preparation of various functionalized regioisomeric pyrazole derivatives bearing a gem‐difluorocyclopropane moiety, such as amines, carboxylic acids, aldehydes, bromides, and boronic esters. It was found that N‐difluorocyclopropylpyrazole moiety tolerated many common reagents including nitrating mixture, bromine, aqueous acids and alkali, KMnO4, LiBH4, and Pd0 complexes; it was unstable towards AlCl3, catalytic hydrogenation and lithiation conditions. The products obtained are advanced building blocks which of potential importance to medicinal and agrochemistry.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

N‐Difluorocyclopropyl‐Substituted Pyrazoles: Synthesis and Reactivity

et al. 2019

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“…Ester 2 a was treated with (MeO)MeNH⋅HCl in the presence of Me 3 Al, (toluene, 70 °C) to afford the trans ‐difluorocyclopropyl Weinreb amide 7 (65 %). Subsequent addition of phenylethynyllithium and condensation of the resulting ynone with N 2 H 4 ⋅H 2 O delivered the ( gem ‐difluoro‐ cyclopropyl)pyrazole 8 (42 %) (Scheme ).…”

Section: Figurementioning

confidence: 99%

Asymmetric Transfer Hydrogenation of gem‐Difluorocyclopropenyl Esters: Access to Enantioenriched gem‐Difluorocyclopropanes

et al. 2020

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Catalytic enantioselective access to disubstituted functionalized gem-difluorocyclopropanes, which are emerging fluorinated motifs of interest in medicinal chemistry, was achieved through asymmetric transfer hydrogenation of gemdifluorocyclopropenyl esters, catalyzed by a Noyori-Ikariya (p-cymene)-ruthenium(II) complex, with (N-tosyl-1,2-diphenylethylenediamine) as the chiral ligand and isopropanol as the hydrogen donor. The resulting cis-gem-difluorocyclopropyl esters were obtained with moderate to high enantioselectivity (ee = 66-99 %), and post-functionalization reactions enable access to valuable building blocks incorporating a cis-or transgem-difluorocyclopropyl motif.

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“…Because application of these reaction conditions to functionalized substrates is limited by their thermal stability and their susceptibility to side reactions at elevated temperatures, a selection of a TMSCF 3 –NaI system as a difluorocarbene equivalent was envisaged. The usage of TMSCF 3 , which is also referred as Ruppert–Prakash reagent, for gem ‐difluoromethylation reaction was first developed by Hu, Prakash and co‐workers, and was further adapted for preparation of gem ‐difluorocyclopropanes bearing diverse functional groups . Nonetheless, the addition of difluorocarbene equivalent derived from TMSCF 3 to alkenylboronic derivatives was unknown until the present study.…”

Section: Introductionmentioning

confidence: 96%

gem‐Difluorocyclopropanation of Alkenyl Trifluoroborates with the CF₃SiMe₃–NaI System

et al. 2020

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Difluorocyclopropanation of alkenyl trifluoroborates using TMSCF 3 -NaI system was reported for the first time. The developed method allowed preparation of monocyclic, spiroand fused-bicyclic gem-difluorocyclopropanes bearing addi-groups. [20][21][22][23][24] Nonetheless, the addition of difluorocarbene equivalent derived from TMSCF 3 to alkenylboronic derivatives was unknown until the present study. Scheme 1. Difluorocyclopropanation of alkenylboronic derivatives.In this work, application of TMSCF 3 -NaI system in refluxing THF (66°C) for the synthesis of gem-difluorocyclopropyl boronic derivatives and its effectiveness for multigram scale synthesis is reported (Scheme 1). It is shown that alkenyl trifluoroborates are optimal substrates for the preparation of aliphatic derivatives which facilitate isolation of the target products. The studied reaction scope included substrates bearing secondary N-Boc protected amine, ester, ether, phenyl and cyclopropyl moieties and provided products with spiro-and fused-bicyclic molecular topologies. Results and DiscussionOur study commenced with testing TMSCF 3 -NaI system in reaction with substrate 5a (Scheme 2), for which the difluorocyclopropanation using XCF 2 CO 2 Na (X = Cl, Br) at 180°C and 150°C, Scheme 2. Attempted difluorocyclopropanation of alkenyl boronic derivatives using the TMSCF 3 -NaI system. 2218Scheme 3. Preparation of trifluoroborate salts 7 from pinacolboronates 9.Scheme 4. Synthesis of pinacolboronates 9e (A) and 9p (B).

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Synthesis of 1-hetaryl-2,2-difluorocyclopropane-derived building blocks: The case of pyrazoles

Cited by 22 publications

References 32 publications

N‐Difluorocyclopropyl‐Substituted Pyrazoles: Synthesis and Reactivity

N‐Difluorocyclopropyl‐Substituted Pyrazoles: Synthesis and Reactivity

Asymmetric Transfer Hydrogenation of gem‐Difluorocyclopropenyl Esters: Access to Enantioenriched gem‐Difluorocyclopropanes

gem‐Difluorocyclopropanation of Alkenyl Trifluoroborates with the CF₃SiMe₃–NaI System

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Synthesis of 1-hetaryl-2,2-difluorocyclopropane-derived building blocks: The case of pyrazoles

Cited by 22 publications

References 32 publications

N‐Difluorocyclopropyl‐Substituted Pyrazoles: Synthesis and Reactivity

N‐Difluorocyclopropyl‐Substituted Pyrazoles: Synthesis and Reactivity

Asymmetric Transfer Hydrogenation of gem‐Difluorocyclopropenyl Esters: Access to Enantioenriched gem‐Difluorocyclopropanes

gem‐Difluorocyclopropanation of Alkenyl Trifluoroborates with the CF3SiMe3–NaI System

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gem‐Difluorocyclopropanation of Alkenyl Trifluoroborates with the CF₃SiMe₃–NaI System