Sur la base des travaux antérieurs du laboratoire, nous avons développé une nouvelle approche synthétique énantiosélective, en deux étapes, pour l’accès à des glutarimides fonctionnalisés à partir de cyclobutanones facilement accessibles, selon deux directions: une stratégie impliquant une extension de cycle à deux atomes et une stratégie basée sur une contraction de cycle à deux atomes. En parallèle, nous avons démontré que les arynes porteurs de la chiralité axiale en position ortho de la triple liaison réactive peuvent être générés à partir des précurseurs iodo/triflate de type Suzuki et réagissent in situ avec divers substrats. Leur stabilité configurationnelle et leur grande réactivité nous ont permis de proposer une nouvelle méthode de synthèse pour introduire un fragment biaryle à chiralité axiale au sein de pratiquement toutes molécules organiques réactives vis-à-vis des arynes / Based on the previous work in our laboratory, we have developed a new enantioselective two-step synthetic approach to access functionalized glutarimide derivatives using readily available cyclobutanones following two directions: a two-atom ring expansion strategy and a two-atom ring contraction strategy. Meanwhile, we have demonstrated that arynes bearing axial chirality ortho to their reactive triple bond can be generated from the corresponding iodo/triflate Suzuki-type precursors and trapped in situ by various substrates. Their configurational stability and high reactivity allow us to propose a new synthetic method for the facile introduction of an axially chiral biaryl unit onto virtually any organic molecule reacting with arynes

The arylation of readily accessible N-tosyl hydrazones has been achieved using arynes generated in situ under mild conditions. The resulting N-tosyl-N-aryl hydrazones undergo a one-pot Fischer indole reaction on the addition of acid, giving a synthesis of protected indoles that avoids handling unstable intermediates and arylhydrazines. A new route to functionalised 2-(trimethylsilyl)phenyl triflate aryne precursors via Suzuki cross-coupling has been developed. The method allows the incorporation of a wide range of aryl and heteroaryl groups and reactions of arynes generated from these novel precursors have been demonstrated, including a cyclotrimerisation and a fluorenone synthesis. Work was also undertaken on aryne σ-insertion reactions. The addition of benzyne to ynamides was found to result in its net insertion between the nitrogen and acetylene species. The reaction proceeds from attack at the terminal carbon in an analogous manner to C(sp)–O insertions.

This thesis investigated whether or not it is possible to generate and capture arynes under mechanochemical conditions. The investigation covered mechanochemical parameters, as well as parameters known to influence aryne generation in solution such as crown ether and CsF loading. Experiments were performed in steel vessels, each equipped with a single free moving steel ball in a shaker type mill. Different reactivities were probed, including nucleophilic addition, [4+2] Diels-Alder cycloaddition, [3+2] cycloaddition and Pd-catalyzed cyclotrimerization. Acquired crude product mixtures were analysed with NMR spectroscopy, and spectra were compared to reported spectra of reactants and expected products. The results showed generation and capturing of arynes to be possible under mechanochemical conditions with borylated, as well as non-borylated aryne precursors in moderate to good yields. Regioselectivity did not appear to differ from solvent conditions since only single regioisomers were observed. / Detta kandidatarbete undersökte möjligheten att generera och reagera aryner under mekanokemiska förhållanden. Undersökningen täcker mekanokemiska parametrar likaså parametrar som, sen tidigare, är kända för att påverka generering av aryner i lösning, exempelvis mängden tillsatt kron-eter och CsF. Experimenten utfördes i stålbehållare innehållandes en stålkula vardera som skakades med hjälp av en kvarn av skaktyp. Olika reaktiviteter utforskades, däribland nukleofil addition, [4+2] Diels-Alder cykloaddition, [3+2] cykloaddition och Pd-katalyserad cyklotrimerisering. Erhållna rå-lösningar analyserades med NMR-spektroskopi och erhållna spektran jämfördes därefter med tidigare rapporterade spektran av reaktanterna och de förväntade produkterna. Resultaten visade att generering av och reaktion med aryner är möjligt med både borylerade och icke-borylerade aryn-föregångare under mekanokemiska förhållanden. Regioselektiviteten hos reaktionerna under mekanokemiska förhållanden skilde sig inte från den regioselektivitet som tidigare observerats i lösning.

The first project in this thesis describes our research reacting arynes with tertiary allyl amines to generate functionalised anilines via a benzyne induced aza-Claisen reaction. This process works in good to excellent yields and the methodology can be further applied to make benzannulated medium sized ring amine systems. The second project covered in this thesis details our studies in the generation of benzyne from benzoic acid. This process utilises palladium catalysis involving an ortho C-H activation of benzoic acid which generates a 5 membered palladacycle. This palladacycle then spontaneously decomposes with heat to generate palladium bound benzyne and carbon dioxide. The yield of benzyne was monitored by observing the amount of triphenylene formed in the process. Further synthetic applications in this process were limited, but it was shown that the benzyne could be reacted with alkynes to generate phenanthrene and naphthalene products. The third project in this thesis details our work on the insertion of benzyne into the C–S bond of thioesters. Using palladium catalysis and an o-trimethylsilylphenyl triflate benzyne precursor, a variety of thioethers were produced. The yields for this reaction were moderate to good but it was found that only aromatic substituents were tolerated on the thioester.

This work can be separated into two parts; the first will encompass chapters one and two, which discuss the use of the Catellani reaction to access different heterocycles. The second part will encompass the remaining chapters and deals with stereoselective reactions of arynes. Chapter one outlines the development of a general and high yielding synthesis of the phenanthridine nucleus via a palladium-catalyzed domino reaction of aryl iodides with N-H or N-trimethylsilyl imines. This strategy was applied in a succinct synthesis of benzo[c]phenanthridine alkaloids nitidine and NK109. Chapter two details the development of a Catellani-type reaction of aryl iodides with 2H-azirines. Conditions were found to selectively provide access to either the indole nucleus or unusual dihydroimidazoles. The yields of the products ranged from moderate to good, however, the success of the reaction is highly dependent on the structure of the 2H-azirine. A mechanism was proposed involving oxidative addition of the azirine to generate an azaalyl intermediate. In Chapter three the foray into the area of aryne chemistry begins. A stereoselective nickel- catalyzed [2+2+2] cycloaddition of 1,6-enynes with aryne intermediates was developed. Attempts were made at the development of an asymmetric variant of the reaction, however, only low enantiomeric excess was observed. Good diastereoselectivity could be obtained when an allylic substituent was present. The yields of the products ranged from moderate to excellent. However, the yields vary greatly and in a number of cases the reactions were unsuccessful. Finally, in chapter four the development of a general and high yielding annulation strategy for the synthesis of various carbo- and heterocycles, based on an intramolecular aryne ene reaction is described. It was found that the geometry of the olefin is crucial to the success of the reaction and it that regioselective hydrogen migration occurs. Furthermore, the electronic nature of the aryne was found to be important to the success of the reaction. Deuterium labeling studies and DFT calculations provided insight into the reaction mechanism. The data suggested a concerted asynchronous transition state, resembling a nucleophilic attack on the aryne. This strategy was successfully applied to the formal synthesis of the ethanophenanthridine alkaloid (±)-crinine. In a similar vein, preliminary results demonstrating an intramolecular, formal [2+2] cycloaddition of an aryne with an S, O-ketene acetal to give interesting tricyclic benzocyclobutene products are disclosed.

This work can be separated into two parts; the first will encompass chapters one and two, which discuss the use of the Catellani reaction to access different heterocycles. The second part will encompass the remaining chapters and deals with stereoselective reactions of arynes. Chapter one outlines the development of a general and high yielding synthesis of the phenanthridine nucleus via a palladium-catalyzed domino reaction of aryl iodides with N-H or N-trimethylsilyl imines. This strategy was applied in a succinct synthesis of benzo[c]phenanthridine alkaloids nitidine and NK109. Chapter two details the development of a Catellani-type reaction of aryl iodides with 2H-azirines. Conditions were found to selectively provide access to either the indole nucleus or unusual dihydroimidazoles. The yields of the products ranged from moderate to good, however, the success of the reaction is highly dependent on the structure of the 2H-azirine. A mechanism was proposed involving oxidative addition of the azirine to generate an azaalyl intermediate. In Chapter three the foray into the area of aryne chemistry begins. A stereoselective nickel- catalyzed [2+2+2] cycloaddition of 1,6-enynes with aryne intermediates was developed. Attempts were made at the development of an asymmetric variant of the reaction, however, only low enantiomeric excess was observed. Good diastereoselectivity could be obtained when an allylic substituent was present. The yields of the products ranged from moderate to excellent. However, the yields vary greatly and in a number of cases the reactions were unsuccessful. Finally, in chapter four the development of a general and high yielding annulation strategy for the synthesis of various carbo- and heterocycles, based on an intramolecular aryne ene reaction is described. It was found that the geometry of the olefin is crucial to the success of the reaction and it that regioselective hydrogen migration occurs. Furthermore, the electronic nature of the aryne was found to be important to the success of the reaction. Deuterium labeling studies and DFT calculations provided insight into the reaction mechanism. The data suggested a concerted asynchronous transition state, resembling a nucleophilic attack on the aryne. This strategy was successfully applied to the formal synthesis of the ethanophenanthridine alkaloid (±)-crinine. In a similar vein, preliminary results demonstrating an intramolecular, formal [2+2] cycloaddition of an aryne with an S, O-ketene acetal to give interesting tricyclic benzocyclobutene products are disclosed.

Nesta tese foram desenvolvidas metodologias sintéticas para a abertura de N-tosilaziridinas, provenientes de aminoácidos, via arilcianocupratos de ordem superior, os quais foram gerados pela reação de troca telúrio/cobre entre teluretos arílicos e cianocupratos; tais aberturas levam à formação de estruturas análogas a fenetilaminas em bons rendimentos, as quais possuem atividades farmacológicas interessantes. Adicionalmente, um conjunto de amino teluretos contendo diferentes grupos protetores foram preparados a partir dos respectivos aminoálcoois, em bons rendimentos (72 a 83%), e avaliados como potenciais espécies nucleofílicas. Os teluretos, que contêm como grupo protetor benzoíla, foram utilizados em reações de troca telúrio/lítio, gerando as espécies dilitiadas, as quais foram capturadas com diversos eletrófilos, levando à formação de aminoálcoois de cadeia maior e também à formação de análogos de fenetilaminas em bons rendimentos. Nesta tese também foram estudadas reações que envolvem química de arinos, os quais podem ser gerados de várias maneiras. Dentre essas formas para produzir os arinos, destacamos o uso de 2-(trimetilsilil)fenil triflato, o qual, na presença de fontes de íons fluoreto em solvente polar aprótico, gera a espécie reativa. Empregamos essa metodologia para geração de benzinos na reação de inserção em ligações do tipo σ de disselenetos de diarila. Tendo visto o sucesso da metodologia desenvolvida, decidimos sintetizar outros arinos derivados do 2-(trimetilsilil)fenil triflato e empregá-los em outro tipo de reação de inserção em ligações do tipo σ, desta vez em ligações entre selênio/estanho de tributil(fenilselanil)estanana, levando a uma difuncionalização nas posições 1 e 2 do anel aromático. / In this PhD thesis we developed a synthetical methodology for the ring opening reaction of N-tosyl aziridines by high order arylcyanocuprates that have been generated by tellurium/copper exchange reaction between aryl tellurides and cyanocuprates. These ring opening reactions lead to an interesting class of phenethylamines in good yields. Additionally, a set of tellurium amines containing different protecting groups were conveniently prepared in good yields (72 - 83%) from aminoalcohols and evaluated as potencial nucleophilic species. The corresponding tellurium amines have been evaluated in the tellurium/lithium exchange reaction. The nitrogen-containing organolithium compounds were efficiently prepared by using N-Bz tellurium amines and a mixture of n-butyllithium and lithium naphthalenide (LiNp) to performe the exchange reaction. The dianion intermediates were trapped with a wide range of electrophiles, resulting in this corresponding products in good to excellent yields. The reaction was also employed in the synthesis of phenethylamines. In this work we also studied reactions involving aryne chemistry, that are reactive species. A number of methods for benzyne formation have been reported in the literature. Among them we pay particular attention to the use of 2-(trimethylsilyl)aryl triflates in the presence of fluoride ion sources and aprotic polar solvents that generate this reactive species. We employed this methodology for generation of benzyne in the insertion reaction of diaryl diselenide σ bond. In view of the success of the developed methodology, we decided to synthesize other ayne derivatives from 2-(trimethylsilyl)phenyl triflate and use them on another type of σ bond insertion reaction. The insertion reaction of arynes into Se-Sn sigma bond of tributyl(phenylselanyl)stannane, leading a double functionality in the aromatic system.

Nesta tese foram desenvolvidas metodologias sintéticas para a abertura de N-tosilaziridinas, provenientes de aminoácidos, via arilcianocupratos de ordem superior, os quais foram gerados pela reação de troca telúrio/cobre entre teluretos arílicos e cianocupratos; tais aberturas levam à formação de estruturas análogas a fenetilaminas em bons rendimentos, as quais possuem atividades farmacológicas interessantes. Adicionalmente, um conjunto de amino teluretos contendo diferentes grupos protetores foram preparados a partir dos respectivos aminoálcoois, em bons rendimentos (72 a 83%), e avaliados como potenciais espécies nucleofílicas. Os teluretos, que contêm como grupo protetor benzoíla, foram utilizados em reações de troca telúrio/lítio, gerando as espécies dilitiadas, as quais foram capturadas com diversos eletrófilos, levando à formação de aminoálcoois de cadeia maior e também à formação de análogos de fenetilaminas em bons rendimentos. Nesta tese também foram estudadas reações que envolvem química de arinos, os quais podem ser gerados de várias maneiras. Dentre essas formas para produzir os arinos, destacamos o uso de 2-(trimetilsilil)fenil triflato, o qual, na presença de fontes de íons fluoreto em solvente polar aprótico, gera a espécie reativa. Empregamos essa metodologia para geração de benzinos na reação de inserção em ligações do tipo σ de disselenetos de diarila. Tendo visto o sucesso da metodologia desenvolvida, decidimos sintetizar outros arinos derivados do 2-(trimetilsilil)fenil triflato e empregá-los em outro tipo de reação de inserção em ligações do tipo σ, desta vez em ligações entre selênio/estanho de tributil(fenilselanil)estanana, levando a uma difuncionalização nas posições 1 e 2 do anel aromático. / In this PhD thesis we developed a synthetical methodology for the ring opening reaction of N-tosyl aziridines by high order arylcyanocuprates that have been generated by tellurium/copper exchange reaction between aryl tellurides and cyanocuprates. These ring opening reactions lead to an interesting class of phenethylamines in good yields. Additionally, a set of tellurium amines containing different protecting groups were conveniently prepared in good yields (72 - 83%) from aminoalcohols and evaluated as potencial nucleophilic species. The corresponding tellurium amines have been evaluated in the tellurium/lithium exchange reaction. The nitrogen-containing organolithium compounds were efficiently prepared by using N-Bz tellurium amines and a mixture of n-butyllithium and lithium naphthalenide (LiNp) to performe the exchange reaction. The dianion intermediates were trapped with a wide range of electrophiles, resulting in this corresponding products in good to excellent yields. The reaction was also employed in the synthesis of phenethylamines. In this work we also studied reactions involving aryne chemistry, that are reactive species. A number of methods for benzyne formation have been reported in the literature. Among them we pay particular attention to the use of 2-(trimethylsilyl)aryl triflates in the presence of fluoride ion sources and aprotic polar solvents that generate this reactive species. We employed this methodology for generation of benzyne in the insertion reaction of diaryl diselenide σ bond. In view of the success of the developed methodology, we decided to synthesize other ayne derivatives from 2-(trimethylsilyl)phenyl triflate and use them on another type of σ bond insertion reaction. The insertion reaction of arynes into Se-Sn sigma bond of tributyl(phenylselanyl)stannane, leading a double functionality in the aromatic system.