The development of a palladium-catalysed C–H carbonylation of hindered secondary amines is described. Central to this strategy is the temporary conversion of simple ketones into hindered secondary amines that facilitates a sterically promoted palladium-catalysed C–H activation. A range of functional groups are shown to be compatible with this catalytic process, and with exclusive regioselectivity for the terminal ethyl sp 3 C–H in most cases. This method allows an overall incorporation of a carboxyl group to the b-position of terminal ketones, generating 1,4- dicarbonyl moieties which are important synthetic building blocks. The sterically promoted C–H functionalisation strategy has been employed as the key step in the synthesis of a functionalised analogue of astemizole, a pharmaceutical agent which suffers from undesired hERG activity. The increased steric bulk around the tertiary amine, coupled with introduction of a polar hydroxyl group via the C–H acetoxylation reaction, is proposed to reduce binding to the hERG channel. The hERG profile of this analogue is not yet established.

by Fuk Yee Kwong. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2000. / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

Since the discovery that diazomethane, CH2N2, can effect the cyclopropanation of alkenes under palladium catalysis in the 1960s, this reaction has been used to great effect in synthesis. However, the necessity of preparing and handling diazomethane, a toxic and explosive reagent, is unappealing. The substitution of diazomethane for a commercially-available and thermally-stable silylated congener, namely trimethylsilyldiazomethane (TMSDAM), has been investigated. Under optimised conditions, designed to promote protodesilylation, use of this reagent affords the same products as would be obtained with the more hazardous diazomethane, with no trace of the corresponding silylated cyclopropanes. NMR spectroscopy has revealed that the protodesilylating agent employed in the reaction, tetrabutylammonium bifluoride (n-Bu4N+ HF2 -, TBABF), reacts cleanly with TMSDAM to generate diazomethane. Under catalytic conditions, the consumption of the desilylated diazo reagent by palladium is sufficiently rapid to prevent the accumulation of this hazardous reagent in solution. Spectroscopic titration studies also revealed a “hidden” mode of TBABF catalysis, whereby adventitious water drives the regeneration of the bifluoride salt. This observation was exploited by the development of an EtOH-driven reaction variant in which catalytic amounts (20 mol%) of TBABF could be employed. The ability to effect the in situ generation of diazomethane has allowed for mechanistic studies into the course of the cyclopropanation reaction to be undertaken. These reveal a partitioning in the consumption of nascent diazomethane between the desired cyclopropanation reaction and a side reaction. The product of the side reaction was identified as cyclopropane (C3H6), the product of formal methylene cyclotrimerisation, by employing EtOD in TBABF-catalysed deuterodesilylative cyclopropanation. The partitioning between the two pathways is dependent on the nature of the substrate, with efficient cyclopropanation dominating with electrondeficient alkenes. For an electronically-varied range of styrenes, the relative rate of productive diazomethane consumption correlates well with the energy of the frontier molecular orbitals (as determined by DFT calculations). These results are consistent with an initial, substrate-dependent partitioning of the palladium pre-catalyst between species able to effect alkene cyclopropanation, and those (likely higher-order) species which promote only the cyclotrimerisation of diazomethane.

Some interesting, biologically active natural products have been found to contain poly-azole fragments within their core. These fragments are linked through the 2- position of one azole and the 4-position of its neighbour. Decarboxylative cross-coupling methodology may provide a route to these desired linked azoles through cross-coupling of azole-4-carboxylic acids with azole-2- halides or with azoles containing no substitution at the 2-position. Investigations into the silver-mediated decarboxylation, and subsequent coupling potential, of thiazole and oxazole-4-carboxylic acids are reported. Methods towards the synthesis of novel chlorinated thiazole and oxazole acids and their precursors are also described. A method to successfully couple these acids to aryl iodides has been developed and the scope of this reaction extended to a variety of functionalised azole-4-carboxylic acids. Attempts to extend this methodology and combine the decarboxylative coupling with CH activation of a second azole are also described.

The palladium-catalysed asymmetric allylic alkylation is a mild and versatile bond forming reaction between a nucleophile and allylic electrophile. The wide scope of nucleophiles used, and the high regio- and stereoselectivity obtainable renders this transformation an important technique in enantioselective synthesis. The mechanism is known to go via a key palladium π-allyl intermediate, followed by nucleophilic addition occurring at the terminal allylic carbon. Both the formation of the palladium π-allyl, and the nucleophilic addition to generate the alkylated product and palladium(0) proceed with high levels of inversion of stereochemistry, and both provide an opportunity for the induction of stereochemistry. However in the case of ligand controlled nucleophilic addition memory effects have been observed. The epimerisation of the palladium π-allyl before nucleophilic attack is key to achieving high levels of selectivity when racemic starting materials and chiral ligands are employed. Previous work in the Lloyd-Jones group has determined that prolonging the lifetime of the palladium π-allyl species, either by the use of weakly coordinating counter ions or slow addition of the nucleophile reduces this memory effect, however increasing the rate of epimerisation would have a result in a similar effect. One of the mechanisms resulting in the epimerisation of the palladium π-allyl species is mediated by palladium(0), however the details of the mechanism are not well understood. We describe the synthesis of a diastereotopic palladium cyclohexenyl ester and labelled the complex with 108palladium and d3 at the cyclohexenyl ester. Using simultaneous 31P NMR and mass spectrometry, we have acquired strong evidence against mechanisms involving a single electron transfer, as proposed by Stille, of formation of a dinuclear palladium(I) species followed by an inversion event, and we have gained evidence supporting the direct nucleophilic addition of the palladium(0), resulting in inversion of stereochemistry. The differences in rates of nucleophilic attack involving monodentate and bidentate phosphine ligands on both the palladium I-cyclohexenyl ester have also been explored. Throughout the mechanistic investigation, it was noted that the 31P NMR spectroscopy experiment used gave non-quantitative results, and in fact the differences in quantification of the species varied with the spectrometer used. We also describe our investigations into where these differences arise from and an optimum set of parameters for quantitative 31P NMR spectroscopy. The conclusions are also applicable to other heternuclear NMR spectroscopic experiments.

Ces travaux de thèse traitent de l’activation/fonctionnalisation de liaisons C-H pour la formation de dérivés d’hétéroaryles. Nous nous sommes ainsi intéressés à la réactivité de dérivés du 4-formylpyrazole pour les couplages pallado-catalysés via l’activation de liaisons C-H. La fonction formyle en C4 permet de contrôler la régiosélectivité de l’arylation. Par la suite, nous avons étudié la réactivité de 2-bromofluorènes dans ces mêmes réactions de couplage. La troisième partie se focalise sur la synthèse d’aminothiophènes et de pyrrolyl-thiophènes. L’originalité de notre approche est l’utilisation de ces composés comme précurseur dans des réactions pallado-catalysés. Enfin, la dernière partie est consacré à la réactivité du 3-bromobenzothiophène dans des réactions pallado-catalysées sans clivage de la liaison C-Br en C3 du benzothiophène. / This thesis work dealing with the activation / functionalization of CH bonds for the formation of derivatives of heteroaryl. We sum so interested in the reactivity of derivatives of 4-formylpyrazole for pallado-catalyzed via CH bond activation couplings. The formyl C4 is used to control the regioselectivity of the arylation. Subsequently, we investigated the reactivity of 2-bromofluorènes in these coupling reactions. The third part focuses on the synthesis of aminothiophenes and pyrrolyl-thiophene. The originality of our approach is the use of these compounds as a precursor in pallado-catalyzed reactions. Finally, the last part is devoted to the reactivity of 3-bromobenzothiophene in pallado-catalysed reactions without cleavage of the C-Br bond C3 benzothiophene.

Since its discovery in 1979, the Suzuki-Miyaura (SM) reaction has become one of the most widely utilised tools for carbon-carbon bond formation. The palladium catalysed coupling of an organoboron and organohalide compounds proceeds through a three-stage mechanism of oxidative addition, transmetalation and reductive elimination. The transmetalation of boronic acids to a palladium(II) complex has been widely studied. However, very little is known about the transmetalation of boronic esters, which are commonly used as an alternative to unstable boronic acids. Whether these species undergo direct transmetalation or prior hydrolysis to the boronic acid under SM conditions remains unknown. This research aimed to elucidate the mechanism of this cross-coupling process. Initial results under typical SM conditions created a biphasic reaction, promoted by the inorganic base and solvent composition, and showed that the boronic esters and corresponding boronic acid couple at the same absolute rate. This is thought to be a consequence of the formation of a biphasic mixture, rendering phase transfer the turnover-limiting step. The conditions were thus adapted to maintain a monophasic system using an organic soluble base, 2-tert-butyl-1,1,3,3-tetramethylguanidine, enabling the focus to be transmetalation as the turnover-limiting step. These new conditions show a significant difference in both reaction rate and induction period when using a boronic ester compared to the corresponding boronic acid. The use of guanidine was also shown to have an interesting effect on the boronic acid/ester species by 19F and 11B NMR. Further studies found the use of guanidine to create a boronate species, with this species being an aryl trihydroxyboronate or the hydroxyl"ate"-complex of the boronic ester, depending on the presence of diol in the system. Formation of a boronate species was found to be crucial for efficient cross-coupling. When testing weaker bases, unable to form a boronate species, poor SM cross-coupling conversion was found using the newly developed phosphine-free guanidine conditions, showing the importance of the boronate species under these conditions. The results suggest that depending on the strength of base used, the pathway of transmetalation pathway can be switched, between the boronate pathway and the oxo-palladium pathway, under the specific conditions developed.

O presente trabalho visa o estudo da eletrossíntese de H2O2 a partir da reação de redução de oxigênio (RRO) utilizando carbono Printex 6L modificado com óxidos binários compostos de nióbio, molibdênio e paládio, síntetizados pelo método dos precursores poliméricos. A análise dos materiais preparados foi feita a partir de experimentos de análise termogravimétrica (do inglês, TGA), fluorescência de raios X (FRX) e também de difração de raios X (DRX). As temperaturas de síntese foram escolhidas a partir dos resultados de TGA e tendo como temperatura máxima de 400 °C. As análises dos espectros de emissão de FRX mostraram a eficiência na incorporação dos materiais na matriz de carbono. Experimentos de DRX mostraram a presença de fases cristalinas de MoO2 e Nb2 O5 e PdO, e em comparação aos resultados da técnica de voltametria cíclica, existem pares redox que podem ser associados as transições dos metais nos estados de oxidação de +4 e +5, para molibdênio e nióbio, respectivamente e do estado +2 para o paládio. Nos experimentos de voltametria de varredura linear pode-se observar a tendência de maior geração de H2O2 pelo material com teor de 1% NbMo quando comparado com o carbono Printex 6L, de modo que foram calculadas as eficiências de geração de H2O2 , obtendo um resultado de 55,5% para o modificador de 1% NbMo comparado com 47,4% para o Printex 6L, e também de número de elétrons envolvidos na reação com um valor de 2,9 para o material de 1% e 3,1 para o carbono Printex. As análises das curvas de Koutechy-Levich confirmam os resultados anteriores. Análises em condições reduzidas na síntese orgânica corroboraram a melhor eficiência do material de 1% para o material com nióbio e molibdênio e revelaram a também a melhora eletrocatalítica do carbono quando incorporado com óxidos mistos de nióbio e paládio, sendo o melhor resultado expresso no material contendo 5% de nióbio e paládio, na proporção molar de 95 para 5% de cada elemento, respectivamente. / The present work aim the electrosynthesis study of H2O2 from the reduction reaction of oxygen (RRO) using carbon Printex 6L modified with binary oxides composed of niobium, molybdenum and palladium, synthetized by precursors method. The analyses of prepared compounds were made from thermogravimetric analyses (TGA) as well as x-ray fluorescence (XRF) and x-ray diffraction (XRD). The synthesis temperature was chosen by TGA results and having a maximum temperature of 400oC. The emission spectrum analysis from XRF showed the efficiency of materials incorporation in carbon matrix. DRX experiments showed the presence of crystalline phases of MoO2, Nb2O5 and PdO, and in comparison to the cyclic voltammetry technique results, there are redox pairs which can be associated to the transition of the metals in oxidation states of +4 and +5, to molybdenum and niobium, respectively, and state of +2 for palladium. In the experiments linear sweep voltammetry, it can be observed that the tendency of higher H2O2 generation by the material with 1% of NbMo content when it is compared to the Printex 6L carbon, so that were calculated the efficiency of H2O2 generation, obtaining a result of 55,5% for the 1% modifier in comparison with 47,4% for the Printex carbon, as well as the number of electrons involved in the reaction with a value of 2,9 to the 1% material and 3,1 to the Printex carbon. The analysis of Koutechy-Levich curves, confirm the previous results. Analysis under reduced conditions in the organic synthesis corroborates to greater efficiency of 1% material to the material with niobium and molybdenum and they also revealed the electrocatalytic improvement of carbon when it is incorporated with mixed oxide of niobium and palladium, being the best result expressed in the material containing 5% of niobium and palladium, in the molar proportion of 95 to 5% of each element, respectively

This study gives the details about several experiments done in Eugene Mallove Laboratory for New Energy Research. Three experiments are presented and discussed in detail with different type of microscopes and mass spectrometry techniques. Also inspired by work done by Rolison and O'Grady [1], the other part of this study presents the variation of isotopic abundance after experiments on palladium cathode immersed in a heavy water electrolyte. This original inspiring paper has been published through proceedings of the first edition of International Conference on Cold Fusion held in Washington D.C. in 1989. In other words, both works provides similar evidence of an isotopic variation before and after low energy nuclear experiments. By measuring the variation in isotopic concentration, before and after electrolysis, these measurements provide insight for how the low energy nuclear phenomenon occurs. Scanning electron microscopes are used in the first part to provide high resolution, high magnification images of the electrodes. They show the morphology the topology of the cathode after experiment. An energy dispersive mass spectrometer is used to provide elemental composition of the cathode and provide a second independent measurement of elemental composition of the cathode. The presented isotopic measurements are made with a secondary ion mass spectrometer. [1]: D. Rolison & W. O'Grady - Mass/Charge Anomalies in Pd after electrochemical loading with deuterium - Section 10 in Proceedings: EPRI-NSF Workshop on Anomalous Effects in Deuterided Metals - (October 16-18, 1989) Washington, D.C.

Palladium-catalyzed carbon-carbon cross-coupling reactions have emerged a broadly useful, selective and widely applicable method to synthesize pharmaceutical active ingredients. As currently practiced in the pharmaceutical industry, homogeneous Pd catalysts are typically used in cross-coupling reactions. The rational development of heterogeneous catalysts for cross-coupling reactions is critical for overcoming the major drawbacks of homogeneous catalysis including difficulties in the separation, purification, and quality control process in drug production. In order to apply heterogeneous catalysis to flow reactors that may overcome this limitation, the catalyst must be strongly bound to a support, highly stable with respect to leaching, and highly active. While the primary role of supports in catalysis has been to anchor metal particles to prevent sintering and leaching, supports can also activate catalytic processes. In this study, by using a xi combined theoretical and experimental method, we probed the effect of graphene as support in the complex reaction cycle of Suzuki reactions. The density functional theory study provides a fundamental understanding of how a graphene support strongly binds the Pd nanoparticles and act as both an efficient charge donor and acceptor in oxidation and reduction reaction steps. Theoretical investigations prove that the Pd-graphene interaction promotes electron flow between the metal cluster and the defected graphene to reduce reaction barrier. The ability for graphene to both accept and donate charge makes graphene an unusually suitable support for multi-step catalytic processes that involve both oxidation and reduction steps. The computer-aided catalyst design with the atomic precise accuracy demonstrates the Pd/graphene catalyst can be further optimized and the first-row transition metal nanoparticles have great potential to replace Pd to catalyze the Suzuki reaction. The corresponding experimental study shows that the method to immobilize the Pd nanoparticles on the graphene is crucial to increasing the reactivity and stability of the resulted catalyst. A comparison of the activation energy and turn over frequency for a series of supported and homogeneous catalysts indicates that exposing palladium-graphene to defect inducing microwave radiation results in dramatically lower activation energies and higher turnover frequencies. Furthermore, the heterogeneity tests demonstrate the Suzuki reactions are carried out on the surface of the immobilized Pd nanoparticle agreeing with the theoretical results. A method to engineer the 2-D graphene support to a 3-D structure to minimize the re-stacking and agglomeration of the graphene lattice will also be introduced in this study.