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Synthesis of N-(per)fluoroalkyl azoles by rhodium(II)-catalyzed transannulation of N-(per)fluoroalkyl-1,2,3-triazoles
Bakhanovich, Olga ; Beier, Petr (advisor) ; Kočovský, Pavel (referee) ; Kvíčala, Jaroslav (referee)
This Thesis deals with the synthesis of N-fluoroalkyl azoles via rhodium(II)-catalyzed transannulation of N-fluoroalkyl-1,2,3-triazoles obtained through copper(I)-catalyzed azide- alkyne cycloaddition (CuAAC) of N-fluoroalkyl azides and alkynes. The introductory chapter describes general approaches towards N-fluoroalkyl azoles, focusing on the synthesis of N-fluoroalkyl pyrroles and azoles. In the first part of the Thesis, rhodium(II)-catalyzed transannulation of N-fluoroalkyl-1,2,3- triazoles with terminal alkynes is described. The reaction provides access to N-fluoroalkyl pyrroles. The regioselectivity of the reaction is investigated and modifications of the primary product are suggested. In the second part of the Thesis, the reactivity of 4-cyclohexyl-N-fluoroalkyl-1,2,3-triazoles is investigated. A one-pot two-step reaction is presented, providing access to novel N- fluoroalkyl indoles. Several modification routes are suggested.
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Synthesis and applications of fluorophosphonates
Cherkupally, Prabhakar ; Beier, Petr (advisor) ; Hermann, Petr (referee) ; Kvíčala, Jan (referee)
In the Introduction part of this thesis, the chemistry of organo-fluorine compounds including the electronic properties that fluorine impacts onto organic molecules, steric effects, lipophilicity and other characteristics as well as applications and important features of organo-fluorine compounds are briefly discussed. Moreover, summary of the methods for their preparation, modern methods for fluorinations and enantioselective fluorinations, and fluoroalkylation methodologies in organic synthesis are described. Additionally, the chemistry of fluorinated phosphonates including their preparations, important applications and the chemistry of α,α-difluorophosphonates are discussed. The Results and discussion part describes nucleophilic trifluoromethylation of various electrophilic substrates using diethyl trifluoromethylphosphonate. Furthermore, efficient stereoselective synthesis of fluorovinylphosphonates by a base-induced HF elimination of α,α-difluorophosphonates is explained. In addition, synthesis of number of new, structurally diverse compounds, having a difluorophosphonate moiety using the reaction of diethyl difluoromethylphosphonate with various α,β-unsaturated carbonyl compounds, Michael acceptors and imines are reported. Also, preliminary experiments dealing with nucleophilic reactions of...
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Application of fluoroalkyl hypervalent iodine reagents in C-H functionalization of small molecules and aromatic amino acid residues
Rahimidashaghoul, Kheironnesae ; Beier, Petr (advisor) ; Kvíčala, Jaroslav (referee) ; Urban, Milan (referee)
The chemistry of fluorolkyl hypervalent iodine reagents has witnessed a great boast in recent years. These compounds are highly attractive as drug candidates, advanced materials and agrochemicals as described in detail in the Introduction. Despite this fact, applications of these reagents in biological studies are rather rare and under developed. The goal of this thesis is therefore the development of mild and metal-free methods in order to fill this gap. Two ways of application of fluoroalkyl hypervalent iodine reagents in labeling of biologically relevant compounds was explored. First, the applicability of previously reported parent Togni CF3 and their analogous tetrafluoroethyl reagents in radical fluoroalkylation of electron-rich substrates such as indole and pyrrole derivatives using sodium ascorbate as reductant was described. This afforded trifluoromethyl or 1,1,2,2-tetrafluoroethyl containing products in moderate to high yields. Next, same reagents were applied for labeling of several peptides and proteins bearing aromatic amino acids in their structure. This way, peptides and proteins containing electron-rich aromatics such as Trp, Phe, Tyr and His were reacted with fluoroalkyl groups with high selectivity toward Trp. In the second part of the work, a different approach of radical...
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Utilization of N-fluoroalkyl-1,2,3-triazoles in organic synthesis
Markos, Athanasios ; Beier, Petr (advisor) ; Veselý, Jan (referee) ; Hanusek, Jiří (referee)
Athanasios Markos Abstract This Thesis deals with denitrogenative transformations of N-fluoroalkyl-1,2,3-triazoles, easily available heterocycles via copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) of safe and stable N-fluoroalkyl azides and alkynes. The introductory chapter describes general approaches towards N1-substituted 1,2,3- triazoles, methods of N1-,-difluoroalkyl-1,2,3-triazoles preparation and both, transition metal-catalyzed and transition metal-free transformations of N1-substituted 1,2,3- triazoles. In the first part of the Thesis, rhodium-catalyzed reactions of N-fluoroalkyl-1,2,3-triazoles are described. Rhodium-catalyzed reactions of N-fluoroalkyl-1,2,3-triazoles in presence of suitable reagents provide access to five-membered N-fluoroalkyl heterocycles, 2- fluoroalkyl oxazoles and ketamides. In the second part of the Thesis, both Brønsted and Lewis acid-mediated transformations of N-fluoroalkyl-1,2,3-triazoles leading to stereodefined N-alkenyl compounds, such as enamides, enimines, amidines and other are discussed. The robustness of the method is showcased on gram scale syntheses and preparation of a drug analogue. At last, thermally-induced rearrangement of N-fluoroalkyl-1,2,3-triazoles to 3-fluoroalkyl-2H- azirines and the proposed mechanism of the reaction are described.
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Azidoperfluoroalkanes: Synthesis and Application
Blastik, Zsófia Eszter ; Beier, Petr (advisor) ; Církva, Vladimír (referee) ; Kvíčala, Jaroslav (referee)
The incorporation of the trifluoromethyl and perfluoroalkyl motifs into organic compounds has been a hot topic in synthetic organofluorine chemistry. There is a plethora of methods for the introduction of the CF3 moiety at carbon, oxygen and sulfur centers. In sharp contrast, methods for synthesizing N-trifluoromethyl and N-perfluoroalkyl compounds are very limited and new approaches are highly sought-after. The scarcity of these compounds prompted us to develop reagents capable of transferring the perfluoroalkyl unit to nitrogen atom. To fulfil this purpose, we have regarded azidoperfluoroalkanes as ideal reagents, therefore, this thesis is concerned with the synthesis and applications of these azides. The first part describes the preparation of azidoperfluoroalkanes. Upon activation by cesium fluoride, TMSCF3 transfers the trifluoromethyl group to an electrophilic azide to produce the desired azidotrifluoromethane. Longer carbon chain azidoperfluoroalkanes were prepared in a similar way, starting from the corresponding organosilane. A different synthetic strategy was applied for the preparation of azidopentafluoroethane where the perfluoroalkyl anion was generated from pentafluoroethane with n BuLi, followed by the addition of tosyl azide. The isolation of these fluorinated azides was...
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Synthesis and reactivity of hypervalent sulfur fluorides
Ajenjo, Javier ; Beier, Petr (advisor) ; Jahn, Ullrich (referee) ; Cibulka, Radek (referee)
The pentafluorosulfanyl (SF5) group displays remarkable and unique properties, including large dipole moment, high electronegativity, high thermal and chemical stability, as well as high lipophilicity. However, only a few synthetic methods for the preparation of aromatic pentafluorosulfanyl building blocks have been developed to date. This work aims at improving availability and accessibility of aryl sulfurpentafluoride building blocks. In the first part of the work, the synthesis of aryl sulfurpentafluorides by the direct fluorination of diaryl disulfides with elemental fluorine is described. Nowadays, this synthetic strategy is used by industry on a multi-kilogram scale. However, the scope of the reaction is only limited to 3- and 4- nitro-1-(pentafluorosulfanyl)benzenes. In this work, the synthesis of various para-, meta- and ortho-substituted-(pentafluorosulfanyl)benzenes following the same approach was carried out. In the second part, the derivatization of aryl sulfurpentafluoride building blocks was investigated. Direct fluorination of 3-nitro-1-(pentafluorosulfanyl)benzene afforded 3-fluoro-5-nitro-1- (pentafluorosulfanyl)benzene. The titled compound was derivatized by two different processes: nucleophilic aromatic substitution (SNAr) of fluorine and vicarious nucleophilic substitution of...
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Use of hypervalent ionide compounds and MBH carbonates in organocatalysis
Kamlar, Martin ; Veselý, Jan (advisor) ; Pour, Milan (referee) ; Beier, Petr (referee)
Beside transition-metal and enzymatic catalysis plays organocatalysis an important role in asymmetric organic sythesis. In the field of organocatalysis are amines group of compounds commonly used as organocatalysts. This thesis deals with the use of hypervalent iodine compounds in combination with amine catalysis and also with the use of Morita-Baylis-Hillman carbonates in organocatalytic allylic substitution reactions. In the first part an organocatalytic enantioselective α-selenylation reaction of saturated aldehydes using diphenyldiselenide and iodobenzene diacetate is described. Reaction is catalysed by commercially available first generation MacMillan catalyst. The products of the reaction were obtained in yields of 51-70 % and enantiomeric excess 95-99 %. Designed methodology was extended on the derivatives of β-ketoesters by catalysis of tertiary amines and quaternary ammonium salts. Apart from selenylation reactions we have also dealt with the possibility of formation C-C bond using hypervalent iodine compouds. Particularly, we focused on electrophillic alkynylation reactions of appropriate nucleophiles using acetylene-bearing hypervalent iodine compounds. Fluorinated sulfone derivatives and enolizable heterocycles such as pyrazolone derivatives, rhodanines, oxindoles and azlactones were...
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Sulfur-based reagents for nucleophilic and radical introduction of tetrafluoroethyl and tetrafluoroethylene groups
Chernykh, Yana ; Beier, Petr (advisor) ; Kvíčala, Jaroslav (referee) ; Církva, Vladimír (referee)
Charles University in Prague, Faculty of Science Department of Organic Chemistry Ing. Yana Chernykh Sulfur-Based Reagents for Nucleophilic and Radical Introduction of Tetrafluoroethyl and Tetrafluoroethylene Groups Ph.D. Thesis Prague 2014 ABSTRACT This project was aimed at developing new methodologies for selective introduction of tetrafluoroethyl and tetrafluoroethylene groups into organic molecules. The study was focused on reactivities of fluorinated sulfones and sulfides as tetrafluoroalkylation reagents. In the Introduction part of the thesis, main aspects of organofluorine chemistry are outlined, illustrating beneficial effects of fluorine atoms on physical, chemical and biological properties of organic compounds. General synthetic methods for the selective introduction of fluorine atoms and fluoroalkyl groups to organic molecules are described. Particular attention is given to reactivity and applications of CF2CF2-containing compounds, indicating challenges in synthetic approaches toward tetrafluoroalkylation. The Results and discussion part describes reactivities of four new fluorinated organosulfur reagents as tetrafluoroethyl and tetrafluoroethylene building blocks. The application of these reagents as various carbanionic or radical synthons proved to be effective for the incorporation of CF2CF2...
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Nucleophilic introduction of fluorinated functional groups using organophosphorus compounds.
Opekar, Stanislav ; Beier, Petr (advisor) ; Veselý, Jan (referee) ; Kvíčala, Jaroslav (referee)
In the Introduction part of this thesis, the chemistry of organofluorine compounds is discussed, particularly the methods for the preparation of organofluorine compounds mainly by fluoroalkylation methods. Furthermore, the chemistry of fluorinated phosphonates, methods of their preparation, reactivity and biological activity is discussed. Additionally, the reactivity of fluoromethane derivatives is briefly mentioned and especially, the reactivity of diethyl fluoromalonate and fluorobisfenylsulfonylmethane is described. The Results and discussion part is devoted to the reactivity of three fluorinated phosphonates: tetraethyl fluoromethylenbisphosphonate, diethyl fluorophenylsulfonylphosphonate and previously not described diethyl fluoronitromethylphosphonate. These fluorinated phosphonates belong to the family of nucleophilic monofluoroalkylation reagents, meaning that these compounds are convenient starting materials for the synthesis of complex organic molecules containing the fluorine atom. The results deal with the reactivity of above mentioned fluorinated phosphonates, mainly with alkylation reactions, Horner-Wadsworth-Emmons reactions and conjugated additions. Also, other synthetic methods such as the Mitsunobu reaction or the palladium catalyzed allylation reaction were investigated; however,...
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Synthesis and applications of fluorophosphonates
Cherkupally, Prabhakar ; Beier, Petr (advisor) ; Hermann, Petr (referee) ; Kvíčala, Jan (referee)
In the Introduction part of this thesis, the chemistry of organo-fluorine compounds including the electronic properties that fluorine impacts onto organic molecules, steric effects, lipophilicity and other characteristics as well as applications and important features of organo-fluorine compounds are briefly discussed. Moreover, summary of the methods for their preparation, modern methods for fluorinations and enantioselective fluorinations, and fluoroalkylation methodologies in organic synthesis are described. Additionally, the chemistry of fluorinated phosphonates including their preparations, important applications and the chemistry of α,α-difluorophosphonates are discussed. The Results and discussion part describes nucleophilic trifluoromethylation of various electrophilic substrates using diethyl trifluoromethylphosphonate. Furthermore, efficient stereoselective synthesis of fluorovinylphosphonates by a base-induced HF elimination of α,α-difluorophosphonates is explained. In addition, synthesis of number of new, structurally diverse compounds, having a difluorophosphonate moiety using the reaction of diethyl difluoromethylphosphonate with various α,β-unsaturated carbonyl compounds, Michael acceptors and imines are reported. Also, preliminary experiments dealing with nucleophilic reactions of...
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