Reaction of unsymmetrical allylic electrophiles with amines gives rise to regioisomeric allylamines. It was found that linear products result from the thermodynamically controlled isomerization of the corresponding branched products, which form initially. The isomerization was found to be promoted by the presence of acid and active palladium catalyst. The use of base shut down the isomerization pathway and allowed for the preparation and isolation of branched allylamines. This methodology provides a powerful control element, which allows for the installation of quaternary and chiral centres next to nitrogen. Later, the isomerization was combined with ring-closing metathesis to afford the synthesis of exocyclic allylamines from their thermodynamically less-stable endocyclic precursors. This rearrangement became feasible as a result of the electrophilic nature of a C – N bond in allylamines. When compared to the conventional intramolecular allylic amination, such approach escapes chemoselectivity issues, which makes it attractive attractive for late-stage synthetic modifications.

The review of this thesis describes palladium catalysed allylic amination in the context of the mechanism and synthetic utility. Examples of alkene geometry, regioselectivity and net retention have been illustrated as a consequence of the amination mechanism. The synthetic aspects of palladium catalysed allylic amination consists of other examples of the formation of enantiomerically enriched allylic amines and amino acids.

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Conventional ligand design in transition metal catalysis capitalizes on the ability of phosphorous, nitrogen, carbon, oxygen, and sulfur-based donors to modify the steric and electronic properties of a reactive metal center. Heterobimetallic transition metal complexes that contain a dative metal-metal bond provide a unique approach to ligand design where the reactivity of the metal center can be modified by metal-metal electronic communication. Our laboratory is interested in using the unique properties of heterobimetallic complexes to address significant limitations in current transition metal catalysis. My PhD work has focused on the ability of early/late transition metal heterobimetallic complexes to facilitate catalysis by speeding up reductive processes that occur at the late transition metal center. My initial studies were aimed at understanding the importance of the metal-metal interaction to catalysis in allylic amination reactions catalyzed by Pd–Ti heterobimetallic complexes and the potential of these catalysts to enable reactivity with challenging nitrogen nucleophiles. We also explored the substrate scope of the allylic amination with a variety of hindered amines and allylic chloride substrates under mild conditions. Aminations of this type have previously been shown to require harsh reaction conditions and tend to give low yields. A variety of sterically hindered secondary amine nucleophiles were able to readily undergo allylic substitution. Many of these aminations were complete within ten minutes. A series of allylic electrophiles were also shown to undergo the reaction. We have also looked at the ability of hindered amines to undergo intramolecular cyclizations to produce pyrrolidine and piperidine products. My continuing efforts in the laboratory are focused on developing chiral titanium-phosphinoamide ligands for enantioselective heterobimetallic catalysis. We have synthesized a series of chiral diamine-based phosphinoamide-titanium ligands in order to investigate enantioselective intramolecular aminations. Importantly, each of these new Ti-ligands enables room temperature catalysis in intramolecular aminations with hindered amines, suggesting contributions by the Ti center. Similar reactivity has not been achieved with monometallic chiral Pd catalysts in our lab. Importantly, many of these ligands enable modest enantioselectivity in the allylic aminations.

The use of small molecule building blocks in, for example, pharmaceutical research and new material development, creates a need for new and improved organic synthesis methods. The use of transition metals as mediators and catalysts opens up new reaction pathways that have made the synthesis of completely new compounds possible as well as greatly improved the synthetic routes to known compounds. Herein, the development of new metal-mediated and catalyzed reactions for construction of vinylic and allylic carbon-carbon and carbon-heteroatom bonds is described.  The use of iodonium salts as coupling partners in Pd-catalyzed Heck type reactions with alkenes is shown to improve the current substrate scope. Results from a mechanistic study indicate that the reaction proceeds via high oxidation state palladium intermediates. The use of IIII reagents is also believed to facilitate a PdII/PdIV catalytic cycle in allylic silylation of alkenes using (SiMe3)2, which, to the best of our knowledge, is the first method developed for metal-catalyzed allylic C-H silylation. The same silyl-source, (SiMe3)2, has previously been used in a Pd-catalyzed allylic substitution reaction in which allylic silanes are formed from allylic alcohols. A detailed mechanistic investigation of this reaction is described in which by-products as well as intermediates, including the resting state of the catalyst, are identified using 1H, 11B, 19F and 29Si NMR spectroscopy. Kinetic experiments are performed that give information about the turn-over limiting step and the mechanism of the analogous borylation using B2pin2 is also investigated. Insights from this study further made it possible to improve the stereoselectivity of this reaction. Additionally, a new method for Cu-mediated trifluoromethylation of allylic halides is presented in which linear products are formed exclusively from both linear and branched allylic substrates at room temperature.  Identification of allylic fluorides as by-products during the reaction also led to the development of a similar Cu-mediated reaction for the fluorination of allylic halides. / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.</p>

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.

Heterobimetallic complexes present a unique approach to catalyzing challenging reactions. By having two metals in close proximity to each other, the metals are able to interact and alter their electronics in a way that simple organic ligands (carbon, nitrogen, sulfur etc.) cannot. Our studies of heterobimetallic complexes focus on a Pd–Ti complex. The complex features a dative interaction between the palladium and the titanium held together by a phosphonamide scaffold. This interaction increases the electrophilicity of the palladium and makes it a very suitable catalyst for allylic amination reactions. We have conducted extensive studies of this catalyst in allylic aminations, the results of which will be discussed. Our first studies with heterobimetallic Pd–Ti complexes focused on their potential to catalyze challenging allylic amination reactions. These studies showed that the Pd–Ti complex was effective at catalyzing allylic aminations with sterically hindered secondary amines, a reaction which had heretofore proved challenging. We then developed a method for synthesizing the catalyst in situ, greatly simplifying the procedure by which the catalyst is used and making it that much more accessible. We also tested the substrate scope and varied the structure of both the amine and chloride substrates. Our results demonstrated the high catalytic activity of heterobimetallic catalysts with most substrates, in spite of steric hindrance of notoriously challenging substrates. Next, investigated the origin of the fast catalysis we had observed with heterobimetallic Pd–Ti complexes. We confirmed the catalytic cycle and determined the activation barrier for the rate-determining step. We computationally investigated the reactivity of various control catalysts in which the Pd–Ti interaction was severed. These results were compared with the reactivity of the heterobimetallic catalyst. We found that the activation barrier for turnover-limiting reductive amine addition was lowered with the bimetallic complex because of an increased electrophilicity at palladium. We further supported our claim by synthesizing a phosphinoamide palladium complex lacking a titanium atom and testing it in the allylic amination reaction. Our findings in the lab corroborated our calculations. We also ensured that the Pd–Ti catalyst was not transformed prior to catalysts by examining various decomposition pathways and determining that they all resulted in higher energy pathways. We discovered that the Pd–Ti interaction is made possible only by the steric interaction provided by N-tert-butyl groups on the amines which sterically reinforce the Pd–Ti interaction. Lastly, we tested the catalytic activity of the complex with allylic acetates and found them to be ineffective due to catalyst decomposition. It is our hope that these findings can serve as guiding principles when designing heterobimetallic complexes for future catalytic applications.

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No description available.