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New Methodologies in Transition Metal Catalysis. Organofluorine Chemistry As the Benchmark Application

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New Methodologies in Transition Metal Catalysis. Organofluorine Chemistry As the Benchmark Application Facultad de Química Departamento de Química Orgánica Programa de Doctorado en Química (3056) con Mención de Excelencia New methodologies in transition metal catalysis. Organofluorine chemistry as the benchmark application. Tesis Doctoral Javier Miró Arenas Dirigida por: Prof. Santos Fustero Lardiés Valencia Dr. Carlos del Pozo Losada Febrero 2017 D. Santos Fustero Lardiés, Catedrático de Química Orgánica de la Universidad de Valencia y D. Carlos del Pozo Losada, Profesor Titular de la Universidad de Valencia CERTIFICAN: Que la presente Tesis Doctoral, titulada “New methodologies in transition metal catalysis. Organofluorine chemistry as the benchmark application”, ha sido realizada bajo su dirección en el Departamento de Química Orgánica de la Universidad de Valencia, por el licenciado en Química D. Javier Miró Arenas, y autorizan su presentación para que sea calificada como Tesis Doctoral. Valencia, Febrero 2017 Fdo. Santos Fustero Lardiés Fdo. Carlos del Pozo Losada A mi familia List of abbreviations [M] metal complex dtbbpy di-tert-butylbipyridine [N-F] electrophilic N-fluorine source E electrophile [O] oxidant e.g. for example Å armstrongs ECP effective core potential Ac acetyl ee enantiomeric excess aq aqueous EI electronic impact Ar aryl equiv equivalents atm atmospheres er enantiomeric ratio B2(pin)2 bis(pinacolato)diboron ESI electrospray ionization BEMP 2-tert-butylimino-2-diethyl- Et ethyl amino-1,3-dimethylperhydro-1,3,2-diazaphos- EWG electron-withdrawing group phorine EYM enyne metathesis Bn benzyl FDA food and drug administration Boc tert-butoxycarbonyl FG functional group BOX bisoxazoline g grams br broad GC-MS gass chromatography-mass Bu butyl spectrometry Bz benzoyl gem geminal CAN cerium ammonium nitrate Glc glucosyl CAPT chiral anion phase-transfer h hours cat catalytic amount HMBC heteronuclear multiple bond Cbz carboxybenzyl correlation CEYM cross enyne metathesis HOMO highest occupied molecular or- CM cross metathesis bital Cy cyclohexyl HPLC high-performance liquid chro- d doublet matography dan 1,8-diaminenaphtalene HRMS high-resolution mass spectro- DAR Diels Alder reaction metry dba dibenzylideneacetone Hz Hertzs DCE 1,2-dichloroethane i.e. that is DCM dichloromethane IMDAR intramolecular Diels Alder re- DFT density-functional theory action DIBAL-H diisobutyl aluminium hydride iPr isopropyl DMAP 4-dimethylaminopyridine LG leaving group DMF N,N-dimethyl formamide Ln ligand DOS diversity-oriented synthesis Ln* chiral ligand dr diastereomeric ratio LRMS low-resolution mass spectro- RF fluorine-containing substituent metry rt room temperature m meta s singlet M molar sat saturated m multiplet SM starting material MALDI matrix-assisted laser desorpti- t triplet on TBS tert-butyl dimethyl silyl Me methyl tBu tert-butyl min minutes TCB 1,2,4,5-tetracyanobenzene mp melting point Tf triflyl, trifluoromethanesulfo- Ms mesyl, methanesulfonyl nyl MS molecular sieves TFA trifluoroacetic acid MTBE methyl tert-butyl ether THF tetrahydrofuran N normal TIPS triisopropyl silyl NCE new chemical entity TLC thin-layer chromatography nd not determined Tmajor retention time of major enan- NFSI N-fluorobenzenesulfonimide tiomer NMR nuclear magnetic resonance Tminor retention time of minor enan- no not observed tiomer Ns nosyl, nitrobenzenesulfonyl TMS trimethyl silyl Nu nucleophile TOF time of flight o ortho Tol tolyl ºC degrees Celsius Ts tosyl, toluenefulfonyl ORTEP oak ridge thermal ellipsoid TS transition state plot UV ultraviolet p para w/o without PA phosphoric acid δ chemical shift PET positron emission tomography µW microwave irradiation Piv pivaloyl, trimethylacetyl PMP para-methoxyphenyl ppm parts per million PTC phase-transfer catalyst Py pyridine PyrOX pyridine-oxazoline q quartet RCEYM ring-closing enyne metathesis RCM ring-closing metathesis Abstract Organofluorine compounds have found increasing applications in medicinal, agrochemical and materials sciences. Due to its singularity, fluorine is able to induce significant alterations on key physicochemical properties, such as lipophilicity, electron-density distribution, acid-base properties, hydrogen-bonding capability, and even on conformational equilibria. Nevertheless, fluorine is scarcely found in naturally occurring organic molecules, and the vast majority of fluorine-containing molecules are synthetic. Therefore, the development of new practical methodologies for the generation of fluorine-containing organic frameworks, either by site selective fluorination reactions or yielding them from simple fluorinated building blocks, is of great interest to the synthetic community. On this basis, the present thesis discloses a novel series of synthetic methodologies based on transition metal catalysis, ultimately establishing organofluorine chemistry as their top benchmark application. Herein, we disclose the discovery of the beneficial effect of 1,7-octadiene on assisting enyne metathesis reactions, the generation of a new family of fluorinated α-amino acid derivatives by means of gold- catalysis and the development of two new methodologies for the enantioselective palladium-catalyzed 1,1-difunctionalization of terminal alkenes, including a selective electrophilic fluorination reaction. Resumen A lo largo de las últimas décadas, los compuestos organofluorados han encontrado numerosas aplicaciones dentro del campo de las industrias farmacéutica y agroquímica, así como en ciencias de los materiales. Dadas las singulares propiedades del átomo de flúor, éste es capaz de inducir alteraciones significativas en propiedades físico-químicas de las moléculas como lipofilia, distribución de cargas, acidez-basicidad, capacidad de formar enlaces de hidrógeno e incluso, equilibrios conformacionales. Sin embargo, la presencia de flúor en productos naturales es escasa. De hecho, la gran mayoría de las moléculas orgánicas que contienen flúor son sintéticas. De ahí el gran interés por parte de la comunidad sintética en el desarrollo de nuevas metodologías para la introducción de flúor en moléculas orgánicas, bien sea mediante reacciones de fluoración selectivas sobre posiciones específicas de la molécula, o bien mediante el empleo de building blocks fluorados, y así construir la nueva molécula alrededor de estos sillares. En este contexto, en la presente tesis doctoral se describe el desarrollo de nuevas metodologías sintéticas catalizadas por complejos de metales de transición, estableciendo la química de flúor como el principal marco de aplicación de dichas metodologías. El descubrimiento del efecto beneficioso del empleo de 1,7-octadieno en reacciones de metátesis de eninos, la generación de una nueva familia de derivados fluorados de α-aminoácidos mediante catálisis con complejos de oro, así como el desarrollo de dos nuevas metodologías sintéticas para la 1,1-difuncionalización enantioselectiva de alquenos terminales, incluyendo una nueva reacción de fluoración electrofílica selectiva, serán objeto de discusión en la presente memoria. Index General introduction, overview and objectives 1 Chapter 1. 1,7-Octadiene-assisted tandem multicomponent cross enyne metathesis-Diels Alder reaction. A useful alternative to Mori’s conditions 7 1.1. Introduction and current state-of-the-art 7 1.2. 1,7-Octadiene-assisted tandem multicomponent cross enyne metathesis-Diels Alder reaction 19 1.3. Results and discussion 20 1.4. Conclusions 27 1.5. Experimental section 28 1.5.1. General procedure for the multicomponent tandem protocol 28 1.5.2. Validation of 1,7-octadiene-assisted tandem protocol versus Mori’s conditions 35 Chapter 2. Differential reactivity of fluorinated homopropargyl-α-amino esters versus Au(I) complexes. The role of nitrogen protecting group 41 2.1. Introduction and current state-of-the-art 41 2.1.1. A brief on gold catalysis 41 2.1.2. Fluorinated building blocks in gold-catalyzed processes 45 2.2. Gold-promoted differential reactivity of fluorinated homopropargyl-α-amino esters 52 2.3. Results and discussion 55 2.3.1. Gold-catalyzed tandem hydroamination-formal aza-Diels Alder reaction 55 2.3.2. Gold-catalyzed synthesis of fluorinated 1,2-dihydroquinoline derivatives 67 2.3.3. Gold-catalyzed O-addition with concomitant loss of isobutene 70 2.3.4. Tandem gold self-relay catalysis for the synthesis of dihydropyridinones. Combining σ and π Lewis acid properties of gold species 73 2.4. Conclusions 86 2.5. Experimental section 87 2.5.1. Gold-catalyzed tandem hydroamination-formal aza-Diels Alder reaction 87 2.5.1.1. Preparation of N-aryl-α-imino esters 87 2.5.1.2. General procedure for the preparation of N-aryl propargyl-α-amino esters 90 2.5.1.3. General procedure for the gold-catalyzed tandem hydroamination-formal aza-Diels Alder reaction 93 2.5.1.4. HPLC data 97 2.5.1.5. Computational study 98 2.5.2. Gold-catalyzed synthesis of fluorinated 1,2-dihydroquinoline derivatives 103 2.5.2.1. General procedure for the alkylation of propargyl-α-amino esters 103 2.5.2.2. General procedure for the tandem hydroarylation-isomerization reaction 105 2.5.3. Gold-catalyzed O-addition with concomitant loss of isobutene 107 2.5.3.1. General procedure for the preparation of N-Boc-propargyl-α-amino esters 107 2.5.3.2. General procedure for the synthesis of the fluorinated alkylidene oxazinones 111 2.5.4. Tandem gold self-relay catalysis for the synthesis of dihydropyridinones 113 2.5.4.1. General procedure for the preparation of homopropargyl amides 113 2.5.4.2. General procedure for the isolation of oxazines 117 2.5.4.3. General procedure for the hydrolysis of oxazines 120 2.5.4.4. General
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