No description available.

This thesis describes research carried out on the synthesis of tertiary alcohols or derivatives by N to C aryl/vinyl migration in lithiated carbamates. Section II.1 describes the first enantioselective synthesis of the antihistamine agent clemastine, as its (S,S)-stereoisomer as an illustration of the methodology. It has been achieved by ether formation between a proline-derived chloroethylpyrrolidine and an enantiomerically enriched tertiary alcohol. The tertiary alcohol was formed from the carbamate derivative of alpha-methyl-p-chlorobenzyl alcohol by invertive aryl migration on lithiation. The (S,S)-stereochemistry of the product confirms the invertive nature of the rearrangement in contrast with related ureas. Modelling work to establish the origin of this stereodivergent behaviour is reported in Section II.2. This also reports in-situ IR experiments providing evidence of the mechanistic pathway of the rearrangement of an O-benzyl-N-aryl carbamate. The scope of the N to C aryl migration in other stabilised organolithiums is shown in section II.3. The rearrangement is now addressed in more systematic manner, thus allowing the alpha-arylation of O-allyl and O-propargylcarbamates (by alpha-deprotonation) and O-vinylcarbamates (by alpha-deprotonation) to be achieved in good yields but with poor stereoselectivity. Section II.4 goes on to show that enol carbamates derived from aromatic or alpha,beta-unsaturated compounds and bearing an N-aryl substituent undergo carbolithiation by nucleophilic attack at the alpha position of the enol double bond. The resulting carbamate-stabilised allylic, propargylic or benzylic organolithium rearranges with N to C migration of the N-aryl substitutent, creating a quaternary carbon alpha to O. The products may be easily hydrolysed to generate multiply branched tertiary alcohols in good to moderate yields in a one-pot tandem reaction. Finally, Section II.5 proves that the rearrangement in lithiated carbamates can be extended to N to C vinyl transfer.

No description available.

This thesis describes the use of 2H-azirines, three-membered unsaturatednitrogen-containing heterocycles, as reactive intermediates ina number of Lewis acid promoted alkylations and Diels-Alderreactions providing synthetically useful aziridines. In order to carry out this investigation a new generalprocedure for the ring closure of vinyl azides, forming theresultant 3-substituted-2H-azirines, was developed applying low boiling solventsin closed reaction vessels at elevated temperatures. The addition of organolithium reagents in the presence ofcommercially available chiral ligands, to the 3-(2-naphthyl)-2H-azirine was studied, which gave the correspondingaziridines. Several Lewis acids were shown to catalyze the normalelectron-demand Diels-Alder reaction between 3-alkyl-,3-aromatic-, and 3-ester-substituted 2H-azirines and various dienes. These reactions gave theexpected cycloadducts in moderate yields. Using a chiral auxiliary high diastereoselectivity wasobtained in the addition of alkyl radicals to a8-phenylmenthyl-substituted 2H-azirine-3-carboxylate. The alkyl radicals weregenerated from the corresponding trialkyl borane and molecularoxygen. Hydroborations and transmetallations were used toprepare these trialkylboranes. Catalytic amounts of CuClincreased the diastereoselectivity in the radical additionreactions. Attempts were made to explain how the coordination of aLewis acid to the azirine nitrogen atom affects thereactivity/stability of the azirine. DFT calculations and NMRexperiments involving Lewis acid-azirine complexes wereperformed. Keywords:Enantioselective, diastereoselective, vinylazide, 2H-azirines, aziridines, Lewis acid, chiral ligand,chiral auxiliary, organolithiums, Diels-Alder reaction, alkylradicals, triethylborane.

<p>This thesis describes the use of 2<i>H</i>-azirines, three-membered unsaturatednitrogen-containing heterocycles, as reactive intermediates ina number of Lewis acid promoted alkylations and Diels-Alderreactions providing synthetically useful aziridines.</p><p>In order to carry out this investigation a new generalprocedure for the ring closure of vinyl azides, forming theresultant 3-substituted-2<i>H</i>-azirines, was developed applying low boiling solventsin closed reaction vessels at elevated temperatures.</p><p>The addition of organolithium reagents in the presence ofcommercially available chiral ligands, to the 3-(2-naphthyl)-2<i>H</i>-azirine was studied, which gave the correspondingaziridines.</p><p>Several Lewis acids were shown to catalyze the normalelectron-demand Diels-Alder reaction between 3-alkyl-,3-aromatic-, and 3-ester-substituted 2<i>H</i>-azirines and various dienes. These reactions gave theexpected cycloadducts in moderate yields.</p><p>Using a chiral auxiliary high diastereoselectivity wasobtained in the addition of alkyl radicals to a8-phenylmenthyl-substituted 2<i>H</i>-azirine-3-carboxylate. The alkyl radicals weregenerated from the corresponding trialkyl borane and molecularoxygen. Hydroborations and transmetallations were used toprepare these trialkylboranes. Catalytic amounts of CuClincreased the diastereoselectivity in the radical additionreactions.</p><p>Attempts were made to explain how the coordination of aLewis acid to the azirine nitrogen atom affects thereactivity/stability of the azirine. DFT calculations and NMRexperiments involving Lewis acid-azirine complexes wereperformed.</p><p><b>Keywords:</b>Enantioselective, diastereoselective, vinylazide, 2<i>H</i>-azirines, aziridines, Lewis acid, chiral ligand,chiral auxiliary, organolithiums, Diels-Alder reaction, alkylradicals, triethylborane.</p>

Dans ce travail, il est montré que les alkyl/vinyl/aryl lithiens et magnésiens réagissentavec les acides C-1(F/OMe) naphtoïques en l'absence de catalyseur métallique. Cette nouvelleréaction de substitution nucléophile aromatique permet potentiellement de préparer n’importequel biaryle tout en s'affranchissant des étapes de protection et de déprotection de la fonctionacide (CO2H). Les alkyllithiens linéaires et ramifiés réagissent avec la même efficacité que lesalkylmagnésiens même à basse température (–78 °C). Le déplacement d'un fluor ou d'unméthoxy s'effectue avec la même facilité. L'absence d'ortho-lithiation est confirmée par lepiégeage du milieu réactionnel en fin de réaction par l'iodométhane (après addition de n-BuLi,s-BuLi et t-BuLi). Le bromure de vinylmagnésium requiert un chauffage au reflux du THF.La méthode étudiée permet de préparer extrêmement facilement des 1- et 2-phénylnaphtalènes, 1,1’-binaphtalènes et 2,2’-binaphtalènes. Dans les exemples où lesaryllithiens donnent des rendements moyens-faibles en produits de couplage, les réactifs deGrignard sont beaucoup plus efficaces. Le o-tolyllithium, le bromure de o-tolylmagnésium, lebromure de (4-méthoxyphényl)magnésium, le bromure de (2,5-diméthylphényl)magnésium etle bromure de benzo[d][1,3]dioxol-5-ylmagnésium déplacent facilement le groupefluoro/méthoxy en ortho du groupe CO2M pour donner les produits de substitutioncorrespondants alors que la réaction du bromure de (2,6-diméthoxyphényl)magnésium estmoins efficace sans doute en raison de l'encombrement stérique causé par les deux groupesortho-méthoxy. L'acide 1-(2-méthoxyphényl)-2-naphtoïque est un produit particulièrementintéressant. La déprotection du groupe méthoxy suivie d'une cyclisation est réalisée par BBr3pour donner la 6H-naphtho[2,1-c]chromén-6-one qui est isolée avec un rendement de 97 %.Cette lactone est utile pour la préparation de composés atropoisomères optiquement actifsaprès ouverture énantiosélective du cycle lactone selon la technique mise au point parBringmann. / Alkyl as well as aryl substitution can be readily accomplished in generally excellentyields via a nucleophilic mode by displacement of an ortho-fluoro or methoxy group inunprotected naphthoic acids with lithium and Grignard reagents in the absence of a metalcatalyst.Alkyllithium reagents typically gave good-to-excellent yields, whether primary,secondary, or tertiary at –78 °C. Displacement of a fluoro or a methoxy group occurs withequal efficacy. The absence of ortho-lithiation was confirmed by quenching the reactionproduct with MeI after addition of n-BuLi, s-BuLi and t-BuLi. Alkyl Grignard reagentsEtMgBr and n-BuMgBr proved to be very reactive at –78 °C while vinyl magnesium bromiderequired refluxing in THF.The method provides excellent latitude with respect to the synthesis of 1- and 2-phenylnaphthalenes, 1,1’-binaphthalenes, and 2,2’-binaphthalenes. In those instances wherethe aryllithium reagents gave poor yields of coupling products, the corresponding Grignardreagents proved to be much more effective. o-Tolyllithium, o-tolylmagnesium bromide, (4-methoxyphenyl)magnesium bromide, (2,5-dimethylphenyl)magnesium bromide andbenzo[d][1,3]dioxol-5-ylmagnesium bromide smoothly displaced the fluoro/methoxy grouportho to the CO2M group to give the corresponding substitution products while reaction of(2,6-dimethoxyphenyl)magnesium bromide proceeded with less efficiency presumably due tosteric effects imparted by the two ortho-methoxy groups. Particularly useful is 1-(2-methoxyphenyl)-2-naphthoic acid which allows for further elaboration after the coupling isperformed. Deprotection of the methoxy group followed by cyclization was realized withBBr3 to afford 6H-naphtho[2,1-c]chromen-6-one which was isolated in 97% yield. Thislactone is the starting building block for the preparation of optically active atropisomers byenantioselective ring opening.