Fluorination methods in drug discovery

Fluorination reactions of medicinal and biologically-active compounds will be discussed. Late stage fluorination strategies of medicinal targets have recently attracted considerable attention on account of the influence that the fluorine atom can impart to targets of medicinal importance, such as a modulation of lipophilicity, electronegativity, basicity and bioavailability, this latter as a consequence of membrane permeability. Therefore, the recourse to late-stage fluorine substitution on compounds with already known and relevant biological activity can provide the pharmaceutical industry with new leads with improved medicinal properties. The fluorination strategies will take into account different fluorinating reagents, nucleophilic, electrophilic and of radical nature. Diverse families of organic compounds such as (hetero)aromatic rings, and aliphatic substrates (sp3 , sp 2 , and sp carbon atoms) will be studied in late-stage fluorination reaction strategies.Fil: Yerien, Damián Emilio. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Orgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bonesi, Sergio Mauricio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Centro de Investigaciones en Hidratos de Carbono. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Centro de Investigaciones en Hidratos de Carbono; ArgentinaFil: Postigo, Jose Alberto. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Orgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

New approaches to aromatic fluorinations

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Palladium–mediated organofluorine chemistry

Producción CientíficaThe substitution of fluorine for hydrogen in a molecule may result in profound changes in its properties and behaviour. Fluorine does not introduce special steric constraints since the F atom has a small size. However, the changes in bond polarity and the possibility of forming hydrogen bonds with other hydrogen donor fragments in the same or other molecules, may change the solubility and physical properties of the fluorinated compound when compared to the non-fluorinated one. Fluorine forms strong bonds to other elements and this ensures a good chemical stability. Altogether, fluorinated compounds are very attractive in materials chemistry and in medicinal chemistry, where many biologically active molecules and pharmaceuticals do contain fluorine in their structure and this has been shown to be essential for their activityJunta de Castilla y León (programa de apoyo a proyectos de investigación – Ref. VA302U13)Junta de Castilla y León (programa de apoyo a proyectos de investigación – Ref. VA256U13

Asymmetric Preparation of α-Quaternary Fluorinated β-keto Esters. Review

In this review, recent advances over the past decade in the preparation of fluorinated stereogenic quaternary centers on β-keto esters compounds are analyzed. Since the incorporation of fluorine and fluorinated groups is of special interest in pharmaceutical chemistry, a range of metal-catalyzed and organocatalyzed methods have been developed. Herein, we review the enantioselective fluorination, trifluoromethylation and trifluoromethylthiolation of 3-oxo esters. The scope, the induction of enantioselectivity and mechanistic investigations are presented

Next Generation Shilov Catalysis: Ligand Design and Computational Analysis for Improved Catalysis in C-H Activation and Functionalization Chemistry.

The activation and functionalization of C-H bonds has been a long standing goal in organometallic chemistry. The catalytic cycle involves three main catalytic steps: C-H activation, oxidation, and bond-forming reductive elimination. This work describes the combined use of computational analysis, ligand design, high-throughput screening, stoichiometric studies, and catalytic assays in an effort to achieve rational catalyst design. With recent advances in the field illustrating the use of in situ generated and decomposition susceptible cationic nitrogen based ligands, 2nd and 3rd generation stable and isolable bipyridine and pyridine-based ligands containing pyridinium substituents have been synthesized and fully characterized. With these ligands, catalysts based upon Pt, Pd, Rh, and Ir have been tested for C-H activation activity and compared against their neutral bipyridine and pyridine analogs. In all of these systems, the pyridinium substituent was found to have beneficial effects in catalyst activity for C-H activation through an H/D exchange assay with arene substrates. The Pd-based systems have also been utilized to achieve the catalytic C–H acetoxylation of aromatic substrates. The efficient use of potassium persulfate as a cheap stoichiometric oxidant has been achieved in these reactions (up to 73 turnovers), with the newly designed ligands key for achieving this reactivity. Computational studies have been employed to study the reductive elimination of coupling components which are traditionally difficult to achieve, Aryl-F and Aryl-CF3. Through these calculations, a novel mechanism for Aryl-carboxylate reductive elimination was discovered.Ph.D.ChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/91598/1/jbgary_1.pd

C–H activation through late transition metal cyclometallation. Addressing selectivity and reactivity problems.

The ligand-directed C—H activation relies on a coordinating donor atom being in proximity to the C—H bond activated. Cyclometallation of 2-(1-naphthyl)-pyridine – a substrate containing both γ- and δ-positions in proximity to the directing nitrogen atom – was studied. Cycloruthenation and cyclopalladation result in γ-substitution and formation of the corresponding 5-membered metallacycles, which is in agreement with published regioselectivities of the corresponding catalytic reactions. Simultaneously, cycloauration and cycloborylation result in δ-substitution and formation of the corresponding 6-membered metallacycles. X-ray structures of all the metallacycles are presented. Deuterium labelling studies show that the cyclopalladation and cycloauration are irreversible, while the cycloruthenation is reversible and happens in both γ- and δ-positions. Attempts to synthesise bimetallic palladium complexes, consisting of two (2-phenyl-pyridine) palladium fragments connected via bridging ligands, resulted predominantly in the formation of monometallic species. While 1,8-naphthyridine and 7-aza-indole bind to palladium in an L-fashion with only one of the two nitrogen atoms, N-piperidine dithiocarbamic acid binds with both sulfur atoms in a chelating, rather than a bridging fashion. 3,3-Dimethylglutaric acid acts as a bridging ligand. X-ray structures of naphthyridine and dithiocarbamate complexes are presented. No increase in the reactivity is observed, when 1,8-naphthyridine, 7-aza-indole and N-piperidine dithiocarbamic acid were used as additives in palladium-catalysed acetoxylation and bromination of 2-phenyl-pyridine. Oxidative anion metathesis was employed as a method of synthesis of organic salts. Trimethylsulfoxonium iodide salts can be converted to tetrafluoroborate, hexafluorophosphate, trifluoroacetate, tosylate and bis-triflimide salts in the presence of hydrogen peroxide and the corresponding acids. The scope of cations, suitable for this reaction also includes N-alkylpyridinium and quaternary phosphonium salts. N-acetoxypyridinium chloride was employed as an oxidant in the palladium-catalysed C—H functionalisation of 2-aryl-pyridine resulting in the formation of the corresponding chloro-derivative. Trimethylsulfoxonium tetrafluoroborate, hexafluorophosphate and tosylate are unreactive as oxidants towards 2-(phenyl)-pyridine palladium acetate. Cyclopalladation of PCP pincer ligands with aromatic and aliphatic backbones by (PhCN)2PdCl2 was shown to proceed at temperatures as low as -62⁰C. The initial interaction results in the formation of a mixture of coordinated species, only some of which react further to form metallacyclic pincer compounds. The formation of pre-cyclometallation intermediates is kinetically disfavoured. However, C—H activation is fast and not rate-limiting in case of neither sp2 nor sp3 C—H bonds

Radiosynthesis and use of [18F]F2 derivatives [18F]Selectfluor bis(triflate) and [18F]ClF

Positroniemissiotomografia (PET) on kajoamaton kuvantamismenetelmä, jolla voidaan tutkia biologisia ja farmakologisia prosesseja elävissä ihmisissä ja eläimissä. PET käyttää biologisesti aktiivisia yhdisteitä, joihin on liitetty lyhytikäinen positroni (β+) säteilijä, kuten 18F. Lääketieteellinen fluorikemia perustuu luonnonyhdisteiden tai niiden johdosten fluoraukseen, vaikka luonnonyhdisteissä fluori onkin harvinainen. Fluorin hapetuskyky on korkea, mikä johtaa helposti lämpöä vapauttaviin radikaaliketjureaktioihin ja epätoivottujen sivutuotteiden muodostumiseen. Alkuaine fluorin voimakkaasta reaktiivisuudesta johtuen elektrofiilisessa radiofluorauksessa saavutetaan usein huono paikkaselektiivisyys ja matala saanto. Tästä johtuen elektrofiilisessa radiofluorauksessa on tavoitteena kehittää helpommin käsiteltäviä ja vähemmän reaktiivisia elektrofiilisen fluorin lähteitä, joilla saavutetaan myös parempi paikkaselektiivisyys radiofluorauksessa. [18F]F2:n johdokset, [18F]Selectfluor bis(triflaatti) ([18F]SF) ja [18F]ClF, tehtiin korkealla ominaisaktiivisuudella ja niitä käytettiin malliyhdisteiden elektrofiilisessa synteesissä. Kaksi 6-[18F]FDOPA:n lähtöainetta, tina- ja booriesteriyhdiste, leimattiin käyttäen [18F]SF:a. [18F]NS12137, norepinefriinin kuljettajaproteiini (NET) -selektiivinen PET-merkkiaine, fluorattiin käyttäen kahta elektrofiilista fluorauslähtöainetta, [18F]SF ja [18F]F2, sekä nukleofiilista synteesimenetelmää. [18F]ClF:lleSiirretty Doriast

Radical Aromatic Substitutions Mediated by Weak Bases

The aim of this thesis was the development of transition metal-free radical aromatic substitutions mediated by weak, inexpensive, and non-toxic inorganic bases. In the beginning, the general preparation and properties of arenediazonium salts were given. An overview of existing reaction types of arenediazonium compounds from the old ones to the most modern was given. The major focus laid on the transformations of arenediazonium salts in the presence of weak bases. The key mechanistic steps were highlighted, where authors could propose a mechanism. Chapters 3 and 4 dealt with the generation of aryl radicals from arenediazonium tetrafluoroborates by very weak bases. This strategy was applied to the preparation of aromatic sulfides, selenides, tellurides, as well as diverse tert-butyl, alkyl, and i-propyl benzoates. Unexpected heterocyclic products were synthesized from arenediazonium salts using this method. In order to prove the proposed mechanisms, mechanistic investigations were made, involving spectroscopic and computational techniques and deuterium labeling. The postulated mechanisms involved homolysis of the initially formed diazoacetate or diazoformate. Mechanistic studies in thiolation reactions indicated the operation of a radical aromatic substitution mechanism via aryl, acetyloxyl, thiyl, and dimsyl radicals. In the alkoxycarbonylation reactions the aryl radical reacted with carbon monoxide to provide the acyl radical, which was confirmed by trapping experiments. Chapter 5 aimed to compare photoredox catalysis and base mediation in a radical aromatic trifluoromethylthiolation reaction. Three related synthetic protocols (two photocatalytic and one base-mediated) utilizing arenediazonium tetrafluoroborates as starting compounds were developed. Diverse aromatic trifluoromethyl sulfides were synthesized employing a photo-catalyzed protocol which afforded significantly higher yields