Orientador: Carlos Roque Duarte Correia / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-22T19:40:59Z (GMT). No. of bitstreams: 1 Biajoli_AndreFranciscoPivato_D.pdf: 15667381 bytes, checksum: c96d7fd628b3e5359cce9f6bbe7c724c (MD5) Previous issue date: 2013 / Resumo: Tetrafluoroboratos de arenodiazônio são compostos estáveis e de fácil preparo que têm sido largamente empregados na reação de Heck-Matsuda, permitindo o desenvolvimento de métodos rápidos, brandos e livres de fosfinas. No tocante à arilação direta de compostos (hetero)aromáticos, uma metodologia que emergiu na década de 2000 e que dispensa a necessidade de pré-funcionalização de ambos os parceiros de acoplamento, sais de arenodiazônio foram empregados com sucesso como fontes de radicais arílicos. Por outro lado, a arilação direta de (hetero)aromáticos com sais de arenodiazônio através da catálise por metais de transição havia sido relatada, até há pouco, em apenas um trabalho na literatura (de 1999), com os rendimentos obtidos sendo, na melhor das hipóteses, modestos. Isto posto, resta claro que o desenvolvimento de uma metodologia que explore sais de arenodiazônio em arilações diretas catalisadas por metais de transição seria um avanço importante na química destes sais. Com isso, no presente trabalho foi desenvolvida uma metodologia rápida e em condições brandas para a arilação de indóis, benzofurano e benzotiofeno empregando-se paládio como catalisador. A alta nucleofilicidade dos indóis, que tendem a reagir com sais de arenodiazônio formando compostos azo (corantes), pôde ser contornada, com os produtos monoarilados desejados sendo obtidos com altas regiosseletividades e bons rendimentos. Também foi estudado o comportamento de outros heteroaromáticos, como furanos e o tiofeno, em arilações diretas com sais de arenodiazônio via paládio. Estudos mecanísticos forneceram evidências de que as reações apresentadas operam a partir de uma espécie altamente eletrofílica de arilpaládio catiônico que vem a ser atacada pelos compostos heteroaromáticos eletronicamente ricos / Abstract: Aryldiazonium tetrafluoroborates are stable, easy-to-prepare compounds that have been largely employed in Heck-Matsuda reactions, allowing the development of fast, mild and phosphine-free methods. Regarding direct arylations of (hetero)aromatic compounds, an area of research that emerged at the beginning of the current century, arildiazonium salts have been employed mainly as radical sources; on the other side, only one example in the literature (dating from 1999) presented arylations of heteroaromatic compounds with aryldiazonium salts in a non-radicalar, transition metal-catalyzed process, with poor yields being observed. With that in mind, it is clear that a methodology exploiting the full potential of aryldiazonium salts in a non-radicalar fashion is highly desirable. Therefore, in the present work a methodology for the direct arylation of indoles, benzofuran and benzothiophene employing palladium as catalyst is presented. The high nucleophilicity of indoles, that are prone to react with these salts to furnish azocompounds (dyes), could be surpassed, with the desired monoarylated products being obtained with both high yields and regioselectivity. The behaviour of 2-methylfuran and thiophene was also investigated. Mechanistically, evidences pointing to the formation of a highly electrophilic cationic arylpalladium species that is attacked by the electronrich heterocycles are presented / Doutorado / Quimica Organica / Doutor em Ciências

L’incorporation de groupements pharmacologiquement intéressants pendant la dernière étape de synthese d’une cible thérapeutique potentielle permet une exploration rapide et efficace de son espace chimique. En particulier, les cycles hétéroaromatiques sont des structures clefs en chimie médicinale et agrochimie et un grand nombre d’études ont porté sur leur modification tardive. La chimie radicalaire des xanthates est apparue comme étant particulièrement adaptée à cette stratégie, grâce à sa grande tolérance de groupements fonctionnels. La fonctionnalisation d’hétéroaryles par l’intermédiaire des xanthates a permis l’introduction de groupements tertiaires et secondaires sur des motifs hétéroaromatiques simples, ainsi que sur des composes plus complexes telles que des principes actifs de médicaments et produits phytosanitaires commerciaux. / The late introduction of pharmacologically relevant groups before evaluating the biological properties of potent targets enables a faster and efficient exploration of their chemical space. This has been particularly studied and applied on heteroaromatic rings which are key scaffolds in medicinal and agrochemical research. In this context, the radical chemistry of xanthates has emerged as an useful tool, thanks to its high functional group compatibility. The xanthate-mediated addition of tertiary and secondary alkyl radicals to heteroarenes enables the easy functionalization of heteroaromatic rings as well as more decorated structures, such as marketed drugs or agrochemicals.

Au cours de cette thèse, nous nous sommes intéressés à l'activation de liaisons sp² et sp³ C-H catalysée par le palladium pour la préparation d'(hétéro)aryl-aryles et de biaryles. Cette méthode est considérée comme attractive pour l'environnement par rapport aux méthodes classiques, tels que Suzuki, Heck, ou Negishi. Tout d'abord, nous avons décrit que la C2-arylation directe de benzothiophènes peut être effectuée par un catalyseur du palladium en l'absence de ligand phosphine avec une grande sélectivité. Nous avons également démontré qu'il est possible d'activer les positions C2 et C5 de pyrroles pour accéder en une seule étape a des 2,5-diarylpyrroles. Des 2,5-diarylpyrroles non-symétriques ont été formés par arylation séquentielle en C2 suivie par une arylation en C5. Nous avons également étudié la réactivité de polychlorobenzenes pour l'activation de liaisons C-H catalysé au palladium. Nous avons finalement étudié l'activation sp² et sp³ sélective catalysé au palladium de liaisons C-H du guaiazulene. La sélectivité de la réaction dépend du solvant et de la base : C2-arylation (KOAc en éthylbenzène), C3-arylation (KOAc dans le DMAc) et C4-Me arylation (CsOAc/K₂CO₃ dans le DMAc). Grâce à cette méthode, une liaison sp³ C-H peu réactive a été activée. / During this thesis, we were interested in the sp² and sp³ C-H bond activation catalyzed by palladium catalysts for the preparation of (hetero)aryl-aryls and biaryls. This method is considered as cost effective and environmentally attractive compared to the classical couplings such as Suzuki, Heck, or Negishi. First we described the palladium-catalyzed direct C2-arylation of benzothiophene in the absence of phosphine ligand with high selectivity. We also demonstrated that it is possible to active both C2 and C5 C-H bonds for access to 2,5-diarylated compounds in one step, and also to non-symmetrically substituted 2,5-diarylpyrroles via sequential C2 arylation followed by C5 arylation. We also studied the reactivity of polychlorobenzenes via palladium-catalyzed C-H activation. We finally examined the palladium-catalysed selective sp² and sp³ C-H bond activation of guaiazulene. The selectivity depends on the solvent and base: sp² C2-arylation (KOAc in ethylbenzene), sp² C3-arylation (KOAc in DMAc) and sp³ C4-Me arylation (CsOAc/K₂CO₃ in DMAc). Through this method, a challenging sp³ C-H bond was activated.

This thesis describes novel reaction protocols for the synthesis of diaryliodonium salts and also provides an insight to the mechanism of α-arylation of carbonyl compounds with diaryliodonium salts.  The first chapter gives a general introduction to the field of hypervalent iodine chemistry, mainly focusing on recent developments and applications of diaryliodonium salts. Chapter two describes the synthesis of electron-rich to electron-poor diaryliodonium triflates, in moderate to excellent yields from a range of arenes and iodoarenes. In chapter three, it is described that molecular iodine can be used together with arenes in a direct one-pot, three-step synthesis of symmetric diaryliodonium triflates. A large scale synthesis of bis(4-tert-butylphenyl)iodonium triflate is also described, controlled and verified by an external research group, further demonstrating the reliability of this methodology. The fourth chapter describes the development of a sequential one-pot synthesis of diaryliodonium salts from aryl iodides and boronic acids, furnishing symmetric and unsymmetric, electron-rich to electron-poor diaryliodonium tetrafluoroborates in moderate to excellent yields. This method was developed to overcome the regiochemical limitations imposed by the reaction mechanism in the protocols described in the preceding chapters. Chapter five describes a one-pot synthesis of heteroaromatic iodonium salts under similar conditions described in chapter two. The final chapter describes the reaction of enolates with chiral diaryliodonium salts or together with a phase transfer catalyst yielding racemic products. DFT calculations were performed, which revealed a low lying energy transition state (TS) between intermediates, which is believed to be responsible for the lack of selectivity observed in the experimental work. It is also proposed that a [2,3] rearrangement is preferred over a [1,2] rearrangement in the α-arylation of carbonyl compounds. The synthetic methodology described in this thesis is the most generally applicable, efficient and high-yielding to date for the synthesis of diaryliodonium salts, making these reagents readily available for various applications in synthesis.

Au cours de cette thèse, nous nous sommes intéressés à l'activation de liaisons C-H catalysée par des catalyseurs au palladium pour la préparation de biaryles portant un groupement SO₂R. De très nombreux composés biologiques possèdent une fonction SO₂R. Nous avons donc choisi d'étudier activation de liaisons C-H de ce type de substrat. L'activation de liaisons C-H est considérée comme attractive pour l'environnement par rapport à d'autres types de couplages tels que Suzuki, Stille, ou Negishi. D'abord, nous avons démontré qu'il est possible d'appliquer la méthode d'activation de liaisons C-H pour l'arylation directe de thiophènes portant un substituant SO₂R. Nous avons ensuite établi un système catalysé au palladium pour l'arylation sélective en C2 de dérivés N-tosylpyrrole. Nous avons constaté que le N-tosylpyrrole est plus réactif comparé au pyrrole non protégé. Nous avons également étudié l'arylation directe d'hétéroarènes par des bromobenzènes possédant un substituant SO₂R soit en C2 ou C4 par catalyse au palladium. Cette méthode fournit un accès simple à des dérivés de ArSO₂R. Enfin, nous avons développé la première méthode de déshydrogénation de liaisons sp³ C-H catalysée au palladium de N-alkyl-benzènesulfonamides pour produire des N-alcényle benzènesulfonamides. / During this Ph.D. period, we were interested in the C-H bonds activation catalysed by palladium catalysts for the preparation of biaryls units bearing SO₂R group. Many biological compounds present a SO₂R function and thus we chose to activate this family of substrates. This method is considered as cost effective and environmentally attractive compared to other types of couplings such as Suzuki, Stille, or Negishi. First, we demonstrated that it is possible to apply C-H bond activation method for the direct arylation of thiophene derivatives bearing a SO₂R substituent. We then established palladium-catalysed system for the selective C2 arylation of N-tosylpyrrole derivatives. We found that N-tosylpyrrole is more reactive than free NH-pyrrole. We also studied the direct arylation of heteroarenes using bromobenzenes bearing SO₂R substituents either at C2 or C4 via palladium-catalysed C-H activation. This method provides a simpler access to substituted SO₂R derivatives. Finally we developed the first palladium-catalysed dehydrogenative sp³ C-H bond functionalization/activation of N-alkyl-benzenesulfonamides to produce N-alkenyl-benzenesulfonamides. The reaction proceeds with easily accessible ligand-free Pd(OAc)₂ catalyst for aryl bromides bearing electron-withdrawing groups or PdCl(C₃H₅)(dppb) catalyst for aryl bromides with electron-donating substituents. We found that the reaction tolerates a variety of substituents both on nitrogen and on the bromobenzene moiety.