Thesis (Ph.D.)--University of Ottawa, 2008. / Includes bibliographies. Also available via the World Wide Web.

Thesis (Ph.D.)--University of Ottawa, 2008. / Includes bibliographies.

This thesis describes the work carried out on the lithiation and rearrangement of N-aryl- and N-vinyl allylic thiocarbamates, with the aim of preparing a wide range of versatile tertiary thiols. The synthesis of the racemic allylic starting materials has been achieved through in situ [3,3]-sigmatropic rearrangement of O-allylthiocarbamates to their S-counterparts (II.A). The enantioselective version relies either on asymmetric metal catalysis (achiral substrates) or stereospecificity (enantiopure substrates) in the [3,3]-sigmatropic rearrangement. Lithiation followed by N to C aryl migration proceeds in generally good to excellent yields, with both electron-poor and electron-rich rings. The scope and the influence of various substituents at Cα or on the allylic double bond are presented in Section II.B.1. Section II.B.2 proposes a mechanistic pathway and details NMR studies carried out to get structural data in the α-thioallyllithium intermediates. Investigations of the stereospecificity of the rearrangement show that most rings migrate without loss of enantioenrichment in substrates bearing an unsubstituted allylic double bond (II.B.3.a). Complete enantiospecificity with all rings has been achieved in thiocarbamates bearing a cyclohexyl-substituted double bond (II.B.3.b). Section II.C reports the results obtained in the N to C transfer of non-aromatic groups. Excellent enantiospecificities have been achieved in the migration of a vinyl substituent, although yields remain moderate. Higher yields can be obtained but they come along with lower enantiomeric ratios. Section II.D details the transformations undertaken in the rearranged tertiary allylic thiocarbamates. A wide range of tertiary thiols has been obtained with good to excellent yields. Functionalisation of the allylic double bond in these hindered substrates was not straightforward. Eventually, ring-closing metathesis in S-allyl sulfides allows the preparation of biologically interesting 2,5-dihydrothiophenes bearing a highly enantioenriched quaternary centre. Finally, evidence for retentive aryl migration in allylic thiocarbamates is outlined in Section II.E. Circular dichroism experiments were carried out in the derivatised 2,5-dihydrothiophenes and compared with predictions obtained via DFT calculations for both enantiomers of a model compound. The absolute configuration of the 2,5-dihydrothiophenes and their tertiary thiocarbamate precursors has been unambiguously established, confirming a retentive pathway in both aryl and vinyl migrations.

The synthesis of amines bearing an adjacent quaternary stereocentre is challenging. Work within our group has demonstrated that the intramolecular transfer of an aryl group within a lithiated benzylic urea is possible. Subsequent cleavage of this urea moiety allows the synthesis of chiral aryl amines bearing quaternary stereocentres. This thesis details investigations into the lithiation of allylic and vinylic ureas. A sequential transformation of allyl ureas into diarylallyl ureas has been developed, a reaction that can be carried out enantioselectively using chiral lithium amides. Deprotection of the urea allows for the isolation of amines bearing highly substituted centres. It has been shown that the use of the acid-labile vinylic protecting groups allows the corresponding Cbz protected diarylallyl amines to be synthesised. Investigations have demonstrated that these analogues can be converted into otherwise synthetically challenging diarylglycine derivatives. During these investigations it has also been shown that carbolithiation of vinyl ureas is possible. The ureas formed from this tandem β-alkylation/α-arylation sequence can then be converted to their highly substituted amine counterparts in good yields. A range of allylic ureas has been investigated; their synthesis and reactivity upon lithiation are discussed within this thesis.

The regioselectivity in Pd(0)-catalyzed direct arylation of pyrrole, thiophene, and indole can be improved by blocking some of the reactive sites with a chloride group, leading to increased yields of the desired regioisomers. Competition experiments and computational studies show that the blocking group also activates the substrates toward arylation. Due to the activated nature of chlorinated heteroaromatics, rare and sought after regioisomers, such as 3-arylthiophenes, can be obtained under mild conditions in good yields. Chlorine-bearing thiophenes arylated at C3 and C4 have the potential to undergo controlled regioregular polymerization under conditions developed in the field of polythiophene chemistry. Mechanistic studies support the hypothesis that the arylation of the substrates under investigation likely proceeds via the CMD transition state.

Post-functionalization of 3,5-bis(2-pyridyl)-4-hydro-1,2,4,6-thiatriazine (Py2TTAH) and its synthetic precursors have been explored through alkylation, arylation, and coordination. While alkylation was initially pursued at the central nitrogen atom of Py2TTAH, functionalization instead occurred on the sulfur atom. Consequently, the proclivity of the sulfur towards alkylation and arylation was studied. Neutral 3,5-bis(2-pyridyl)-S-methyl-1,2,4,6-thiatriazine (S-Me-Py2TTA) and 3,5-bis(2-pyridyl)-S-ethyl-1,2,4,6-thiatriazine were achieved via either anionic or cationic intermediates, and all isolable species were fully characterized. In addition, an aromatic derivative, 3,5-bis(2-pyridyl)-S-phenyl-1,2,4,6-thiatriazine was obtained through reactions using hypervalent iodide as an electrophile. Functionalization of Py2TTAH and S-Me-Py2TTA was also explored through coordination with iron. The synthesis and crystal structures of two different iron complexes are described. The incorporation of boron with Py2TTAH and its precursor, N-2-pyridylimidoyl-2-pyridylamidine was also considered. Both compounds afforded the same boratriazine ring. Overall, this thesis describes the groundwork for future functionalization of the Py2TTA framework, and its potential for molecular materials applications.

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.

京都大学 / 0048 / 新制・課程博士 / 博士(理学) / 甲第22267号 / 理博第4581号 / 新制||理||1658(附属図書館) / 京都大学大学院理学研究科化学専攻 / (主査)准教授 加納 太一, 教授 依光 英樹, 教授 大須賀 篤弘 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

En comparaison avec d’autres techniques de couplage-croisé adaptées à la synthèse de polymères conjugués, la polymérisation par (hétéro)arylation directe (PHAD) s’avère avantageuse d’une perspective industrielle et environnementale. En effet, elle permet d’éviter l’utilisation d’agents de transmétallation nécessaires aux méthodes classiques de polymérisation. La réaction de PHAD exploite l’activation de liens aromatiques carbone-hydrogène (C–H) pour une synthèse efficace de polymères conjugués avec une excellente économie d’atomes. La réaction d’(hétéro)arylation directe permet la formation d’un lien entre deux atomes de carbone d’hybridation sp2 à partir d’un lien C–H via l’état de transition de la métallation-déprotonation concertée (CMD). La majorité des polymères conjugués utilisés en électronique organique contient des unités de répétition à base de thiophène. Cet hétérocycle, possédant des propriétés électroniques et stériques désirables, sont fonctionnalisés avec des groupes donneurs ou accepteurs d’électrons, ainsi qu’avec des chaînes aliphatiques à des fins de solubilité. Cependant, l’utilisation du motif thiophène peut mener à des défauts structuraux dans la chaîne polymère puisqu’elle comporte plusieurs liens C–H activables en PHAD. Si un lien C-H non-désiré (en position β du motif thiophène) est activé plutôt que le lien en position α, un défaut en β peut alors être incorporé de manière covalente dans la structure polymérique résultante. La présence de défauts en β mène à une perturbation de la conjugaison du polymère et de l’organisation du matériau à l’état solide, des facteurs qui peuvent réduire les performances en dispositifs d’électronique organique. Étant donné l’omniprésence du motif thiophène au sein des polymères conjugués et sa sélectivité parfois problématique, une étude computationnelle du mécanisme de l’arylation directe sur des unités thiophènes modèles a été entreprise dans le cadre de ce projet. En utilisant la théorie de la fonctionnelle de la densité et le cluster couplé, les barrières d’activation pour l’état de transition de la CMD de plusieurs substrats modèles ont été calculées et analysées par la méthode de la distorsion-interaction. L’effet activant d’un halogène sur les liens C–H adjacents à celui-ci a été étudié. Les résultats permettront de guider la conception de monomères pour la réalisation de matériaux régioréguliers par PHAD. / The direct (hetero)arylation polymerization (DHAP) reaction harnesses the single-step activation and arylation of aromatic carbon-hydrogen bonds for the efficient synthesis of conjugated polymers. By avoiding the need for transmetalating agents used in other polymerization techniques, the number of synthesis steps is reduced, the need for expensive and often unstable reagents is minimized and the production of toxic organometallic by-products is eliminated. These factors contribute to a reaction which is more favourable than traditional methods for the preparation of conjugated polymers from an industrial and an environmental perspective. Most high-performing conjugated polymers for organic electronic applications contain thiophene-based repeating units. These heterocycles possess desirable electronic features and are easily functionalized with electron-accepting or -donating substituents or solubilizing side-chains to tune their electronic and physical properties. However, the issue has arisen over the selectivity of the concerted metalation-deprotonation (CMD) transition state, the key step of the direct arylation mechanism which determines the selectivity of C–H bond activation. There are multiple reactive C–H bonds on thiophene monomers, and if the undesired bond (the “Cβ–H” bond) were to be activated, it would generate a β-defect in the resulting polymer. This may lead to a disruption in both the π-conjugation of the polymer and the supramolecular organization of the material in the solid state, factors which can contribute to reduced performance in organic electronic devices. Given the ubiquity of thiophene-based units in conjugated polymers and the assumed issues regarding selectivity, we used computational techniques to study the direct arylation mechanism on model thiophene substrates possessing various electronic features. Using density functional theory and coupled-cluster methods, activation barriers for the CMD transition states of various C–H bonds were calculated and analyzed using the distortion/interaction model. The activating effect of a halide on thiophene was also studied. The results suggest that there are inherent features of selectivity for electron-rich or electron-poor thiophenes, and that the location of the halogen greatly influences coupling selectivity by activating the undesirable Cβ–H bond. These findings could guide the design of monomers amenable to high-selectivity DHAP protocols.

京都大学 / 0048 / 新制・課程博士 / 博士(理学) / 甲第18097号 / 理博第3975号 / 新制||理||1573(附属図書館) / 30955 / 京都大学大学院理学研究科化学専攻 / (主査)准教授 依光 英樹, 教授 丸岡 啓二, 教授 大須賀 篤弘 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM