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Molecules
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Tri- and Di-Fluoromethylation and Tri- and Di-Fluoromethylchalcogenation Reactions
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Tri- and Di-Fluoromethylation and Tri- and Di-Fluoromethylchalcogenation Reactions

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Organic Chemistry".

Deadline for manuscript submissions: closed (30 April 2017) | Viewed by 33631

Special Issue Editor

Prof. Dr. Thierry Billard

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Guest Editor
Institute of Chemistry and Biochemistry (ICBMS - UMR CNRS 5246), Univ Lyon, Université Claude Bernard-Lyon 1, CNRS, Villeurbanne, France CERMEP - in vivo imaging, Groupement Hospitalier Est, Lyon, France
Interests: fluorine chemistry; fluoroalkylchalcogenation; medicinal chemistry; radiochemistry; Fluorine-18; carbon-11; medical imaging

Special Issue Information

Dear Colleagues,

Because of the unique properties of fluorine atom, fluorinated compounds have shown growing interest in various fields of application. Among the fluorinated substituents, the CF3 and HCF2 groups have been particularly studied in recent years; in particular because of their potential benefits in life science. Furthermore, the association of these fluorinated parts with heteroatoms, and mainly chalcogens, have shown a particular interest due the obtained specific physico-chemical properties. Therefore, molecules bearing CF3O, CF3S, CF3Se, HCF2O, HCF2S and HCF2Se groups have been recently synthesized and studied. Such chemistry requires the development of new reagents and new methodologies to propose larger molecular diversity and complexity. The aim of this Special Issue is to gather research articles or reviews concerning, not only the development of new synthetic strategies to obtain these fluorinated molecules, but also the study of the properties and potential applications of these new compounds.

Prof. Dr. Thierry Billard
Guest Editor

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Keywords

  • trifluoromethylation
  • difluoromethylation
  • trifluoromethylthiolation
  • difluoromethylthiolation
  • trifluoromethylselenolation
  • difluoromethylselenolation
  • trifluoromethoxylation
  • difluoromethoxylation

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Published Papers (5 papers)

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Research

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891 KiB  
Article
Trifluoroethoxy-Coated Phthalocyanine Catalyzes Perfluoroalkylation of Alkenes under Visible-Light Irradiation
by Kohei Matsuzaki, Tomoya Hiromura, Hideki Amii and Norio Shibata
Molecules 2017, 22(7), 1130; https://doi.org/10.3390/molecules22071130 - 7 Jul 2017
Cited by 18 | Viewed by 5440
Abstract
We disclose herein the perfluoroalkylation of alkenes catalyzed by trifluoroethoxy-coated zinc phthalocyanine under irradiation of visible light. Perfluoroalkyl iodides were nicely incorporated into unsaturated substrates, including alkyne, to provide perfluoroalkyl and iodide adducts in moderate to good yields. Trifluoromethylation is also possible by [...] Read more.
We disclose herein the perfluoroalkylation of alkenes catalyzed by trifluoroethoxy-coated zinc phthalocyanine under irradiation of visible light. Perfluoroalkyl iodides were nicely incorporated into unsaturated substrates, including alkyne, to provide perfluoroalkyl and iodide adducts in moderate to good yields. Trifluoromethylation is also possible by trifluoromethyl iodide under the same reaction conditions. The mechanistic study is discussed. Full article
(This article belongs to the Special Issue Tri- and Di-Fluoromethylation and Tri- and Di-Fluoromethylchalcogenation Reactions)
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Graphical abstract

Graphical abstract
Full article ">Figure 1
<p>Perfluoroalkylation reaction of <b>1</b> with TFEO-ZnPc under visible light irradiation. The reaction of <b>1</b> (0.25 mmol) with perfluoroalkyliodide (0.375 mmol) was carried out in the presence of TFEO-ZnPc (0.0025 mmol) and Na ascorbate (0.0875 mmol) in MeCN (1.0 mL) and MeOH (0.75 mL) at room temperature under irradiation with white LED (10 W). Yields are shown as isolated yield. <b>2ad</b>: The reaction was carried out for 5 h with an excess amount of CF<sub>3</sub>I. <b>2g</b>: 3.7:1 dr. <b>2j</b>: 1.8:1 dr. R<sub>F</sub>I: perfluoroalkyliodide.</p> Full article ">Figure 2
<p>The time profile and light/dark experiment on trifluoromethylation of <b>1a</b> with TFEO-ZnPc under visible light irradiation: (<b>a</b>) Trifluoromethylation of <b>1a</b> with TFEO-ZnPc under optimized conditions for a reaction time of 1 h and 5 h; (<b>b</b>) Time profile and light/dark experiment on trifluoromethylation of <b>1a</b> with TFEO-ZnPc.</p> Full article ">Scheme 1
<p>Plausible reaction mechanism of trifluoromethylation of alkenes with TFEO-ZnPc.</p> Full article ">
720 KiB  
Article
Dichlorotrifluoromethoxyacetic Acid: Preparation and Reactivity
by Riadh Zriba, Alaric Desmarchelier, Frédéric Cadoret, Sébastien Bouvet, Anne-Laure Barthelemy, Bruce Pégot, Patrick Diter, Guillaume Dagousset, Jean-Claude Blazejewski, Elsa Anselmi, Yurii Yagupolskii and Emmanuel Magnier
Molecules 2017, 22(6), 966; https://doi.org/10.3390/molecules22060966 - 9 Jun 2017
Cited by 1 | Viewed by 4527
Abstract
We describe the first gram scale preparation of the reagent dichlorotrifluoromethoxyacetic acid. This stable compound is obtained in five steps starting from the cheap diethylene glycol. The reactivity of the sodium salt of this fluorinated acid was also tested and allowed the preparation [...] Read more.
We describe the first gram scale preparation of the reagent dichlorotrifluoromethoxyacetic acid. This stable compound is obtained in five steps starting from the cheap diethylene glycol. The reactivity of the sodium salt of this fluorinated acid was also tested and allowed the preparation of new amides. Full article
(This article belongs to the Special Issue Tri- and Di-Fluoromethylation and Tri- and Di-Fluoromethylchalcogenation Reactions)
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Scheme 1

Scheme 1
<p>First preparation of dichlorotrifluoromethoxyacetic acid <b>3</b>.</p> Full article ">Scheme 2
<p>Attempts at carbene generation.</p> Full article ">Scheme 3
<p>Preparation of various dichlorotrifluoromethoxy acetamides.</p> Full article ">
1497 KiB  
Article
Electrophilic Trifluoromethylselenolation of Boronic Acids
by Clément Ghiazza, Anis Tlili and Thierry Billard
Molecules 2017, 22(5), 833; https://doi.org/10.3390/molecules22050833 - 19 May 2017
Cited by 27 | Viewed by 7467
Abstract
Trifluoromethylselenylated compounds are emergent compounds with interesting physicochemical properties that still suffer from a lack of efficient synthetic methods. We recently developed an efficient one-pot strategy to generate in situ CF3SeCl and use it in various reactions. Herein, we continue our [...] Read more.
Trifluoromethylselenylated compounds are emergent compounds with interesting physicochemical properties that still suffer from a lack of efficient synthetic methods. We recently developed an efficient one-pot strategy to generate in situ CF3SeCl and use it in various reactions. Herein, we continue our study of the reactivity scope of this preformed reagent. Cross-coupling reactions with aromatic and heteroaromatic boronic acids have been investigated. The expected products have been obtained, using a stoichiometric amount of copper, with moderate yields. Full article
(This article belongs to the Special Issue Tri- and Di-Fluoromethylation and Tri- and Di-Fluoromethylchalcogenation Reactions)
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Graphical abstract

Graphical abstract
Full article ">Figure 1
<p>Ligands used in <a href="#molecules-22-00833-t001" class="html-table">Table 1</a>.</p> Full article ">Scheme 1
<p>Trifluoromethylselenolation of aromatic boronic acids. Yields shown are those of the isolated products.</p> Full article ">
5022 KiB  
Article
Evaluation of Efficient and Practical Methods for the Preparation of Functionalized Aliphatic Trifluoromethyl Ethers
by Taras M. Sokolenko, Maya I. Dronkina, Emmanuel Magnier, Lev M. Yagupolskii and Yurii L. Yagupolskii
Molecules 2017, 22(5), 804; https://doi.org/10.3390/molecules22050804 - 14 May 2017
Cited by 8 | Viewed by 5963
Abstract
The “chlorination/fluorination” technique for aliphatic trifluoromethyl ether synthesis was investigated and a range of products with various functional groups was prepared. The results were compared with oxidative desulfurization-fluorination of xanthates with the same structure. Full article
(This article belongs to the Special Issue Tri- and Di-Fluoromethylation and Tri- and Di-Fluoromethylchalcogenation Reactions)
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Scheme 1

Scheme 1
<p>Synthesis and structures of methylxanthates.</p> Full article ">Scheme 2
<p>Syntheses of trifluoromethoxiderivatives.</p> Full article ">

Review

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6044 KiB  
Review
Fluoroalkyl Amino Reagents (FARs): A General Approach towards the Synthesis of Heterocyclic Compounds Bearing Emergent Fluorinated Substituents
by Bruno Commare, Etienne Schmitt, Fallia Aribi, Armen Panossian, Jean-Pierre Vors, Sergiy Pazenok and Frédéric R. Leroux
Molecules 2017, 22(6), 977; https://doi.org/10.3390/molecules22060977 - 12 Jun 2017
Cited by 15 | Viewed by 9398
Abstract
Fluorinated heterocycles are important building blocks in pharmaceutical, agrochemical and material sciences. Therefore, organofluorine chemistry has witnessed high interest in the development of efficient methods for the introduction of emergent fluorinated substituents (EFS) onto heterocycles. In this context, fluoroalkyl amino reagents (FARs)—a class [...] Read more.
Fluorinated heterocycles are important building blocks in pharmaceutical, agrochemical and material sciences. Therefore, organofluorine chemistry has witnessed high interest in the development of efficient methods for the introduction of emergent fluorinated substituents (EFS) onto heterocycles. In this context, fluoroalkyl amino reagents (FARs)—a class of chemicals that was slightly forgotten over the last decades—has emerged again recently and proved to be a powerful tool for the introduction of various fluorinated groups onto (hetero)aromatic derivatives. Full article
(This article belongs to the Special Issue Tri- and Di-Fluoromethylation and Tri- and Di-Fluoromethylchalcogenation Reactions)
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Graphical abstract

Graphical abstract
Full article ">Figure 1
<p>Launched succinate dehydrogenase inhibitors (SDHIs) based on fluorinated pyrazolecarboxamides.</p> Full article ">Scheme 1
<p>Preparation of fluoroalkyl amino reagents (FARs)—hydroamination of polyfluoroalkenes.</p> Full article ">Scheme 2
<p>Lewis acid-mediated activation of FARs. TFEDMA, 1,1,2,2-tetrafluoro-<span class="html-italic">N</span>,<span class="html-italic">N</span>-dimethylethan-1-amine.</p> Full article ">Scheme 3
<p>Activation of FARs with BF<sub>3</sub>·OEt<sub>2</sub>.</p> Full article ">Scheme 4
<p>Overview of the diverse reactivity modes and applications of FARs.</p> Full article ">Scheme 5
<p>Dehydroxyfluorination— mechanism proposed by Petrov et al. [<a href="#B19-molecules-22-00977" class="html-bibr">19</a>].</p> Full article ">Scheme 6
<p>Beckmann rearrangement initiated by the Yarovenko reagent.</p> Full article ">Scheme 7
<p>Acylation of electron-rich aromatics with FARs by Wakselman et al. [<a href="#B66-molecules-22-00977" class="html-bibr">66</a>].</p> Full article ">Scheme 8
<p>Difluoroacylation of electron-rich heterocycles with TFEDMA.</p> Full article ">Scheme 9
<p>Difluoroacylation of electron-rich arenes under microwave heating. EDG, electron-donating group; MW, microwave.</p> Full article ">Scheme 10
<p>Difluoroacylation of electron-rich arenes with non-S<sub>E</sub>Ar (electrophilic aromatic substitution) regioselectivity by Br/Li exchange followed by trapping with a difluoroacetamide.</p> Full article ">Scheme 11
<p>Synthesis of fluoroalkylated benzo-fused heterocycles without activation of FARs by Ishikawa et al. [<a href="#B71-molecules-22-00977" class="html-bibr">71</a>].</p> Full article ">Scheme 12
<p>Use of FARs ((<b>A</b>) Reaction of TFEDMA with methoxy acrylate; (<b>B</b>) with dimethylamino acrylate; (<b>C</b>) with a methylhydrazone) and acrylates to prepare ethyl 3-(difluoromethyl)-1-methyl-1<span class="html-italic">H</span>-pyrazole-4-carboxylate (DFMMP) with full regioselectivity.</p> Full article ">Scheme 13
<p>Reaction of activated TFEDMA <b>3a</b> with vinyl ethers.</p> Full article ">Scheme 14
<p>Reaction of <b>3a</b> with silyl enol ethers of cyclopentanone and cyclohexanone.</p> Full article ">Scheme 15
<p>Reaction of <b>3a</b> with silyl enol ethers of acetophenone and acetylacetone.</p> Full article ">Scheme 16
<p>Preparation of difluoromethyl 5-aminopyrazoles- and isoxazoles. <sup>a 19</sup>F-NMR yield using PhF as internal standard. <sup>b</sup> isolated yield. <sup>c</sup> 40 °C, 18 h. DIPEA, <span class="html-italic">N</span>,<span class="html-italic">N</span>-diisopropylethylamine.</p> Full article ">Scheme 17
<p>First preparation of 3,5-bis(fluoroalkyl)pyrazolecarboxylates and -carboxylic acids and their decarboxylation to afford 3,5-bis(fluoroalkyl)-NH-pyrazoles. TFA, trifluoroacetic acid; NMP, <span class="html-italic">N</span>-methyl-2-pyrrolidone.</p> Full article ">Scheme 18
<p>First preparation of 3,5-bis(fluoroalkyl)isoxazolecarboxylates and carboxylic acids.</p> Full article ">Scheme 19
<p>The fluorinated azine-based strategy to access 3,5-bis(fluoroalkyl)-NH-pyrazoles.</p> Full article ">Scheme 20
<p>Preparation of fluoroacetone-derived azines from benzophenone hydrazine.</p> Full article ">Scheme 21
<p>Synthesis of novel 3,5-bis(fluoroalkyl)-NH-pyrazoles. Pathway <b>A</b>: from in situ formed vinamidiniums; Pathway <b>B</b>: from isolated vinamides.</p> Full article ">Scheme 22
<p>Supposed mechanism for the intramolecular cyclization from vinamidinums. (Pathway <b>A</b>) or vinamides (Pathway <b>B</b>).</p> Full article ">Scheme 23
<p>Synthesis of unprecedented 3-(CHF<sub>2</sub>)-5-(fluoroaryl)-NH-pyrazoles.</p> Full article ">Scheme 24
<p>Synthesis of 3,5-bis(fluoroalkyl)-NH-pyrazoles from fluorinated ketimines and hydrazine hydrate.</p> Full article ">Scheme 25
<p>Synthesis of 3,5-bis(fluoroaryl)-<span class="html-italic">N</span>Me-pyrazoles. Pathway <b>A</b>: from in situ formed vinamidiniums; Pathway <b>B</b>: from isolated vinamides.</p> Full article ">Scheme 26
<p>Synthesis of various N-substituted pyrazoles from vinamidiniums and vinamides. <b>Method 1</b>: hydrazine/conc. H<sub>2</sub>SO<sub>4</sub>, or hydrazine·HCl/NEt<sub>3</sub>, MeCN, 25–50 °C, 1 h.; <b>Method 2</b>: hydrazine, conc. H<sub>2</sub>SO<sub>4</sub>, toluene/MeCN, 120–140 °C, MW, 0.5–2 h.</p> Full article ">Scheme 27
<p>Observed side-reaction product with 2,4-dinitrophenylhydrazine.</p> Full article ">Scheme 28
<p>Regioselective preparation of 5-<span class="html-italic">N</span>-benzylamino- and 5-hydroxypyrazolines and isoxazolines. <b>Method 1</b>: hydrazine, conc. H<sub>2</sub>SO<sub>4</sub>, MeCN, 25–50 °C, 1 h. <b>Method 2</b>: hydrazine, toluene/MeCN, 120–140 °C, MW, 0.5–2 h. <b>Method 3</b>: hydrazine, HFIP (hexafluoropropan-2-ol), 100–140 °C, 0.5–5 h. <sup>a 19</sup>F NMR yield with PhF as internal standard. <sup>b</sup> R group cleaved between 120 °C and 150 °C. bis(CHF<sub>2</sub>)-NH-pyrazole <b>71</b> formed. <sup>c</sup> R group cleaved between 80 °C and 120 °C. bis(CHF<sub>2</sub>)-NH-pyrazole <b>71</b> formed. <sup>d</sup> prepared from a mixture of semicarbazide hydrochloride and NEt<sub>3</sub>, with no acid added. <sup>e</sup> Pyrazole <b>103</b> was isolated directly. <sup>f</sup> No conc. H<sub>2</sub>SO<sub>4</sub> used. <sup>g</sup> <span class="html-italic">N</span>-(<span class="html-italic">p</span>Tolyl)-pyrazole (<b>104</b>) was separated by chromatography from pyrazoline <b>96e</b> (29% isolated). <sup>h</sup> Pyrazolines <b>97h</b> and <b>97’h</b> were prepared from a 65/35 mixture of vinamides <b>91d</b> and <b>91’d</b> and separated by chromatography. <sup>i</sup> Hydroxylamine (50 wt. % aq.) used instead of hydrazine. <sup>j</sup> Hydroxylamine·HCl used instead hydrazine.</p> Full article ">Scheme 29
<p>Dehydration of several pyrazolines in basic conditions; <sup>a</sup> Yield of isolated product. <sup>b 19</sup>F NMR yield with PhF as internal standard. <sup>c</sup> bis(CHF<sub>2</sub>)-NH-pyrazole <b>73</b> formed after BOC (<span class="html-italic">tert</span>-butoxycarbonyle) cleavage.</p> Full article ">Scheme 30
<p>Preparation of 2,4-bis(fluoroalkyl)quinolines from aryl fluoroketimines.</p> Full article ">Scheme 31
<p>Reaction between the Ishikawa reagent and allylic or propargylic alcohols.</p> Full article ">Scheme 32
<p>Synthesis of fluorinated heterocycles from the hydrolyzed Ishikawa reagent [<a href="#B106-molecules-22-00977" class="html-bibr">106</a>].</p> Full article ">
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