<p>The Heck reaction is one of the most appreciated methods for carbon-carbon bond formation. Due to its mildness and ability to be tuned by additives, it often leaves few alternative competitive reactions. It has also proven easy to develop the reaction conditions in an environmentally benign direction. Through the introduction of palladium chelating groups in olefinic precursors for the Heck reaction, it has been possible to direct the substitution in the following Heck arylation in favor of the terminal position with good regioselectivity. In this thesis, the concept has been utilized to produce a small array of drug-like compounds at useful yields under fast microwave-enhanced conditions utilizing the thermostable Herrmanns palladacycle. During the last decade, this, together with other palladacycles has become commonly employed as precatalyst for the Heck reaction. However, there have been conflicting opinions regarding the mechanisms governing its catalytic effect. A Pd^II-Pd^IV catalytic cycle has been suggested to be operative, in contrast to the classical Pd⁰-Pd^II cycle. In order to clarify the presence of such a mechanism, a set of Heck reactions was performed with the advent of different palladium precatalysts (classical and palladacycles), which revealed that the regiochemicαal substitution pattern is highly conserved, regardless of which precatalyst was employed, and thus, the same mechanism seems to be operative. This is also supported by data from ESI-MS investigations where all the reactions investigated gave rise to the same set of oxidative addition complexes. A crafted route to 3-aryl-1,2-cyclohexandiones has been developed in which 1,2-cyclohexandione is produced <i>is situ</i> from 2,3-epoxycyclohexanone, followed by Heck arylation. A diverse array of aryl bromides encompassing electron-rich, electron-poor, neutral and sterically hindered repressentatives has been successfully utilized to produce the corresponding products at useful yields.The intramolecular Heck reaction offers a route to quaternary carbonic centersand is being increasingly exploited in synthetic endeavors. However, the use of electron-rich olefinic precursors is only reported in a few cases. The implementation of one capto-dative and five electron-rich olefins has therefore been successfully subjected to Heck reaction conditions rendering the corresponding spiro compounds.</p>

The Heck reaction is one of the most appreciated methods for carbon-carbon bond formation. Due to its mildness and ability to be tuned by additives, it often leaves few alternative competitive reactions. It has also proven easy to develop the reaction conditions in an environmentally benign direction. Through the introduction of palladium chelating groups in olefinic precursors for the Heck reaction, it has been possible to direct the substitution in the following Heck arylation in favor of the terminal position with good regioselectivity. In this thesis, the concept has been utilized to produce a small array of drug-like compounds at useful yields under fast microwave-enhanced conditions utilizing the thermostable Herrmanns palladacycle. During the last decade, this, together with other palladacycles has become commonly employed as precatalyst for the Heck reaction. However, there have been conflicting opinions regarding the mechanisms governing its catalytic effect. A PdII-PdIV catalytic cycle has been suggested to be operative, in contrast to the classical Pd0-PdII cycle. In order to clarify the presence of such a mechanism, a set of Heck reactions was performed with the advent of different palladium precatalysts (classical and palladacycles), which revealed that the regiochemicαal substitution pattern is highly conserved, regardless of which precatalyst was employed, and thus, the same mechanism seems to be operative. This is also supported by data from ESI-MS investigations where all the reactions investigated gave rise to the same set of oxidative addition complexes. A crafted route to 3-aryl-1,2-cyclohexandiones has been developed in which 1,2-cyclohexandione is produced is situ from 2,3-epoxycyclohexanone, followed by Heck arylation. A diverse array of aryl bromides encompassing electron-rich, electron-poor, neutral and sterically hindered repressentatives has been successfully utilized to produce the corresponding products at useful yields.The intramolecular Heck reaction offers a route to quaternary carbonic centersand is being increasingly exploited in synthetic endeavors. However, the use of electron-rich olefinic precursors is only reported in a few cases. The implementation of one capto-dative and five electron-rich olefins has therefore been successfully subjected to Heck reaction conditions rendering the corresponding spiro compounds.

<p>Homogeneous palladium-catalyzed Heck vinylation of aryl chlorides was investigated under air using Herrmann’s palladacycle and the P(<i>t</i>-Bu)₃-liberating salt [(<i>t</i>-Bu)₃PH]BF₄. Based on the results, controlled microwave heating was utilized to accelerate model Heck reactions with aryl chlorides down to 30 min employing an electron-poor olefin and a mixture of an ionic liquid and 1,4-dioxane as solvent.</p><p>For the first time, a highly regioselective general protocol has been developed for palladium-catalyzed terminal (β-) arylation of acyclic vinyl ethers using inexpensive aryl chlorides as starting materials and the preligand [(<i>t</i>-Bu)₃PH]BF₄ as the key additive. This swift and straightforward protocol exploits non-inert conditions and controlled microwave heating to reduce handling and processing times, and aqueous DMF or environmentally friendly PEG-200 as the reaction medium. Somewhat higher selectivity for the linear β-product was observed in PEG-200. DFT calculations were performed at the B3LYP level of theory for the regioselectivity-determining insertion step in the Heck reaction following the neutral pathway. A series of <i>para</i>-substituted phenylpalladium(II) complexes was investigated in the computational study. The calculations support a ligand-driven selectivity rationale, where the electronic and steric influence of the bulky P(<i>t</i>-Bu)₃ ligand provides improved β-selectivity. The preparative methodology was used to synthesize the β-adrenergic blocking agent Betaxolol.</p><p>Highly stereoselective Pd(0)-catalyzed β-arylation and β-vinylation of a tetra-substituted cyclopentenyl ether have been accomplished using a chiral, pyrrolidine-based and substrate-bound palladium(II)-directing group under neutral reaction conditions. To the best of the author’s knowledge, this P(<i>t</i>-Bu)₃-mediated method represents the first examples of the successful utilization of aryl and vinyl chlorides in asymmetric Heck reactions. The Heck arylation products formed were hydrolyzed and isolated as the corresponding quaternary 2-aryl-2-methyl cyclopentanones in good to moderate two-step yields with excellent stereoselectivity (90-96% ee). Inclusion of vinyl triflates under neutral reaction conditions and one aryl triflate equipped with a strongly electron-withdrawing <i>para</i>-cyano substituent under cationic conditions increased the preparative usefulness of the methodology.</p><p>Furthermore, diastereoselective Heck arylation of both five- and six-membered cyclic vinyl ethers with aryl bromides, using the identical chiral auxiliary and suitable Pd sources, was performed. Arylated products from the tetra-substituted cyclopentenyl ether were also in this case hydrolyzed to the corresponding 2-aryl-2-methyl cyclopentanones with high to excellent enantioselectivity (85-94% ee). Despite low reaction rates and relatively modest yields, arylation reactions with the tri-substituted cyclohexenyl ether were found to be highly diastereoselective (94-98% de).</p><p>Thus, an attractive supplement to direct Pd(0)-catalyzed α-arylation protocols, particularly when the use of organic chlorides, aryl bromides, and milder reaction conditions are of great importance, have been developed.</p>

Homogeneous palladium-catalyzed Heck vinylation of aryl chlorides was investigated under air using Herrmann’s palladacycle and the P(t-Bu)3-liberating salt [(t-Bu)3PH]BF4. Based on the results, controlled microwave heating was utilized to accelerate model Heck reactions with aryl chlorides down to 30 min employing an electron-poor olefin and a mixture of an ionic liquid and 1,4-dioxane as solvent. For the first time, a highly regioselective general protocol has been developed for palladium-catalyzed terminal (β-) arylation of acyclic vinyl ethers using inexpensive aryl chlorides as starting materials and the preligand [(t-Bu)3PH]BF4 as the key additive. This swift and straightforward protocol exploits non-inert conditions and controlled microwave heating to reduce handling and processing times, and aqueous DMF or environmentally friendly PEG-200 as the reaction medium. Somewhat higher selectivity for the linear β-product was observed in PEG-200. DFT calculations were performed at the B3LYP level of theory for the regioselectivity-determining insertion step in the Heck reaction following the neutral pathway. A series of para-substituted phenylpalladium(II) complexes was investigated in the computational study. The calculations support a ligand-driven selectivity rationale, where the electronic and steric influence of the bulky P(t-Bu)3 ligand provides improved β-selectivity. The preparative methodology was used to synthesize the β-adrenergic blocking agent Betaxolol. Highly stereoselective Pd(0)-catalyzed β-arylation and β-vinylation of a tetra-substituted cyclopentenyl ether have been accomplished using a chiral, pyrrolidine-based and substrate-bound palladium(II)-directing group under neutral reaction conditions. To the best of the author’s knowledge, this P(t-Bu)3-mediated method represents the first examples of the successful utilization of aryl and vinyl chlorides in asymmetric Heck reactions. The Heck arylation products formed were hydrolyzed and isolated as the corresponding quaternary 2-aryl-2-methyl cyclopentanones in good to moderate two-step yields with excellent stereoselectivity (90-96% ee). Inclusion of vinyl triflates under neutral reaction conditions and one aryl triflate equipped with a strongly electron-withdrawing para-cyano substituent under cationic conditions increased the preparative usefulness of the methodology. Furthermore, diastereoselective Heck arylation of both five- and six-membered cyclic vinyl ethers with aryl bromides, using the identical chiral auxiliary and suitable Pd sources, was performed. Arylated products from the tetra-substituted cyclopentenyl ether were also in this case hydrolyzed to the corresponding 2-aryl-2-methyl cyclopentanones with high to excellent enantioselectivity (85-94% ee). Despite low reaction rates and relatively modest yields, arylation reactions with the tri-substituted cyclohexenyl ether were found to be highly diastereoselective (94-98% de). Thus, an attractive supplement to direct Pd(0)-catalyzed α-arylation protocols, particularly when the use of organic chlorides, aryl bromides, and milder reaction conditions are of great importance, have been developed.

Palladium-catalysed coupling reactions have been embraced by synthetic chemists as one of the preferred means for smooth formation of new carbon-carbon bonds: a truly ubiquitous methodology of synthesizing complex molecules. This thesis describes the study of a series of palladium(0)-catalysed C2-arylations of a 1-cyclopentenyl ether, equipped with a chiral (S)-N-methyl-pyrrolidine auxiliary. The investigated olefin was demonstrated to undergo Si-face insertion, providing (R)-configuration of the arylated C2-carbon. In addition, the mild and novel palladium(II)-catalysed dominoHeck/Suzuki β,α-diarylation-reduction of a dimethylaminoethyl-substituted chelating vinyl ether was developed using arylboronic acids as arylating agents in combination with 1,4-benzoquinone (BQ). Further, highly regioselective palladium(II)-catalysed α-and β-monoarylation of the chelating vinyl ether was achieved using either a bidentate ligand or by employing ligand-less conditions. These studies demonstrate that the choice of ligands has a profound effect on the reaction outcome, as productive β,α-diarylation could only be obtained by suppressing the competing β-hydride elimination using BQ as the stabilising ligand and terminal reoxidant. The pivotal role of BQ in the reaction was studied using computer-aided density functional theory calculations. The calculations highlight the crucial role of BQ as a Pd(II)-ligand. In addition of serving as an oxidant of palladium, the calculations support the view that the coordination of BQ to the Pd(II)-centre in the key σ-alkyl complex leads to a low-energy pathway, aided by a strong η2 Pd-BQ donation-back-donation interaction. Furthermore, an investigation of the scope and limitations of novel stereoselective and BQ-mediated palladium(II)-catalysed domino Heck/Suzuki β,α-diarylation reactions, involving metal coordinating cyclic methylamino vinyl ethers and a number of electronically diverse arylboronic acids, conducted. In addition, a set of 4-quinolone-3-carboxylic acids, structurally related to elvitegravir and bearing different substituents on the condensed benzene ring, was designed and synthesized as potential HIV-1 integrase inhibitors. Finally, in an effort to identify a new class of HIV-1 protease inhibitors, four different stereopure β-hydroxy γ-lactam-containing inhibitors were synthesized, biologically evaluated, and co-crystallized with the enzyme. / The time 12:05 for the public defense mentioned in the thesis is incorrect. It will take place at 09:15, 2012-06-08.