Novel heterometallic complexes for C-F and C-H bond activation

The interest in bimetallic systems stems from the principle that ‘two metals are better than one’. In other words, cooperation between two metals can enable in some cases modes of reactivity that are inaccessible for the individual monometallic species. Furthermore, the presence of two (or more) metals in close proximity gives rise to unusual coordination modes and bonding configurations. In this thesis, new transition metal – main group heterometallic systems have been prepared. Highly unusual structural motifs have been identified and studied carefully. For instance, the reaction coordinate for the addition of Mg–H and Zn–H bonds to Pd and Pt has been analysed, by generating structural snapshots along the reaction coordinates and computationally interrogating their bonding. One of the first simple, molecular transition metal complexes possessing a hexagonal planar geometry around the metal has been disclosed. The reactivity of these novel complexes has also been explored, with a focus on the activation and functionalisation of C–F and C–H bonds. Detailed mechanistic studies have revealed the intimate role of heterometallic intermediates in the processes of bond breaking and bond formation. This allowed for the development of novel approaches to bond functionalisation, such as Pd catalysed C–H bond magnesiation or zincation reactions.Open Acces

Palladium–mediated organofluorine chemistry

Producción CientíficaThe substitution of fluorine for hydrogen in a molecule may result in profound changes in its properties and behaviour. Fluorine does not introduce special steric constraints since the F atom has a small size. However, the changes in bond polarity and the possibility of forming hydrogen bonds with other hydrogen donor fragments in the same or other molecules, may change the solubility and physical properties of the fluorinated compound when compared to the non-fluorinated one. Fluorine forms strong bonds to other elements and this ensures a good chemical stability. Altogether, fluorinated compounds are very attractive in materials chemistry and in medicinal chemistry, where many biologically active molecules and pharmaceuticals do contain fluorine in their structure and this has been shown to be essential for their activityJunta de Castilla y León (programa de apoyo a proyectos de investigación – Ref. VA302U13)Junta de Castilla y León (programa de apoyo a proyectos de investigación – Ref. VA256U13

The transmetalation step in Pd-catalyzed processes: understanding the role of the classical nucleophile, the ligands and the synthetic potential of a third metal

The transmetalation step of Pd-catalyzed reactions is studied in-depth in this Doctoral Thesis. New bimetallic systems based on the Au/Pd and the Cu/Pd couple have been developed in the context of the Stille reaction and the Hiyama reaction that are very efficient for the coupling of bulky groups. This type of couplings are very challenging with other methodologies and provide excellent results under a synthetic point of view with our bimetallic approach. The bimetallic systems have been examined under a mechanistic point of view. The role of the cocatalyst, the auxiliary ligands and the tin and silicon organometallics have been understood, providing relevant information for the improvement of these systems and the development of new others. The secondary transmetalations that lead to undesired byproducts in the Negishi reaction have been studied in detail by experimental and computational techniques. The information obtained in our study provides important information that will contribute to develop more efficient Negishi reactions. A ligand designed in our group to promote challenging reductive eliminations has been tested for the Pd-catalyzed fluorination and trifluoromethylation of aryl halides. The ligand is not effective for this reaction due to the existence of a migratory insertion process that prevents the desired reductive elimination. This process has been studied by DFT calculations. The mechanisms of the N-H activation of anilines by Ir(PCP) complexes has been carried out by experimental and computational techniques. The information obtained will be used to design more efficient reactions based on this activation.Departamento de Química Física y Química InorgánicaDoctorado en Química: Química de Síntesis, Catálisis y Materiales Avanzado

Kitamura Electrophilic Fluorination Using HF as a Source of Fluorine

This review article focused on the innovative procedure for electrophilic fluorination using HF and in situ generation of the required electrophilic species derived from hypervalent iodine compounds. The areas of synthetic application of this approach include fluorination of 1,3-dicarbonyl compounds, aryl-alkyl ketones, styrene derivatives, α,β-unsaturated ketones and alcohols, homoallyl amine and homoallyl alcohol derivatives, 3-butenoic acids and alkynes.This research was funded by the National Natural Science Foundation of China (No. 21761132021), and IKERBASQUE, Basque Foundation for Science

Enantioselective and Enantiospecific Transition-Metal-Catalyzed Cross-Coupling Reactions of Organometallic Reagents To Construct C–C Bonds

The stereocontrolled construction of C−C bonds remains one of the foremost challenges in organic synthesis. At the heart of any chemical synthesis of a natural product or designed small molecule is the need to orchestrate a series of chemical reactions to prepare and functionalize a carbon framework. The advent of transition-metal catalysis has provided chemists with a broad range of new tools to forge C−C bonds and has resulted in a paradigm shift in synthetic strategy planning. The impact of these methods was recognized with the awarding of the 2010 Nobel Prize in Chemistry to Richard Heck, Ei-ichi Negishi, and Akira Suzuki for their seminal contributions to the development of Pd-catalyzed cross-coupling

Interconversion and Interception of Reactive Intermediates Using H2

This dissertation describes the advances in hydrogen transfer catalysis with nitrogen-based substrates using ruthenium pincer catalysts. Compared to C–O bonds, amines, imines, and nitriles are difficult substrates for (de)hydrogenation reactions. The high Lewis basicity of nitrogen often encourages the deactivation or inhibition of a transition-metal catalyst and can promote undesirable side reactions between the organic intermediates. Because of these challenges, the mechanistic details and catalyst requirements for hydrogen transfer across C–N bonds are not well-understood. The ruthenium-pincer catalyst, HRu(bMepi)(PPh3)2 (1, bMepi = 1,3-bis(6’-methyl-2’-pyridylimino)isoindoline) provides critical details needed for developing new synthetic strategies based on nitrogen-containing substrates by capturing snapshots of amine, imine, and nitrile intermediates during hydrogen transfer. Primary amines undergo dehydrogenation catalyzed by 1 to selectively form nitriles with the release of 2 equivalents of H2. Computational, kinetic, and spectroscopic experiments elucidate an inner-sphere dehydrogenation mechanism with a high kinetic barrier to form a Ru–(2-H2) intermediate via H+ transfer between a Ru–NH2 to Ru–H unit (ΔG‡ = 35(2) kcal/mol for octylamine). The unusual selectivity for nitrile products, rather than secondary amines or imines, depends on a fast second dehydrogenation event and a high binding affinity of imino groups to Ru. Additionally, bulky ortho-pyridyl substituents on the pincer ligand are required to stabilize high energy 5-coordinate Ru-amido intermediates. This mechanism is compared to analogous hydrogen transfer reactions of alcohols, revealing the fundamental differences between substrate classes despite similar elementary steps. The new chemical knowledge gained from our mechanistic analysis was further applied to develop new hydrogen transfer methodologies for amines and nitriles. The reversibility of hydrogen transfer and high binding affinity of nitrogen was exploited in a new protocol for the stereoretentive H/D exchange of primary amines using D2O. While 1 promotes the H/D exchange of (S)-1-phenylethylamine with 90% ee, the cationic derivative, [Ru(bMepiMe)(PPh3)OTf]OTf, facilitates H/D exchange with complete stereoretention. The binding affinity of a prochiral imino intermediate increases with the increased positive charge on Ru. In addition to the high binding affinity of a Ru-imino intermediate, stereospecific coordination of the chiral amine to Ru and a fast H/D exchange from Ru–H are hypothesized to promote stereoretentive H/D exchange. These studies led to the successful labeling of primary amines with high deuterium content (70-99% D) and complete stereoretention (99% ee) at the α-CH position. Finally, α,β-unsaturated nitriles are intercepted through hydride insertion to produce novel Ru-ketenimine intermediates. X-ray crystallography of a Ru-ketenimine derived from α-phenylcinnamonitrile reveals a highly unusual bent geometry with Ru–N–C of 141°. Spectroscopic and computational analysis suggest that subsequent reactivity is dictated by the electronic environment of the α,β-unsaturated nitrile, which influence the nucleophilic and electrophilic character of the –C2=C1=N heterocumulene group. To regenerate the Ru–H intermediate and enable catalytic reactivity, electrophilic and nucleophilic additions were performed under an H2 atmosphere. Under these conditions, the hydrogenation, hydroboration, hydroacylation, and hydrosilylation of α,β-unsaturated nitriles via ketenimine intermediates are explored.PHDChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/147591/1/lilhale_1.pd

Reactions of 4,5-difluoro-1,2-dinitrobenzene with amines in dimethylformamide or EtOH

Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.Peer reviewedPublisher PD

C–F bond functionalisation using main group reagents

Fluorinated compounds have greatly increased our quality of life. They have found application in nearly every industry. Among their many uses they find applications as aerosols, in polymeric materials, as solvents and surfactants whilst they are particularly relied upon for refrigeration purposes. However, the fluorine industry is not currently sustainable. Most organofluorine compounds can be considered ‘single-use’ and the majority are lost into the atmosphere as fluorinated gases such as hydrofluorocarbons. The desirable characteristics of organofluorine compounds are also their detriment. They are particularly inert to decomposition and are therefore persistent in the environment. The emission of fluorocarbons into the atmosphere is a significant contributor to climate change and environmental pollution. The recycling of fluorinated compounds therefore represents a timely challenge to synthetic chemists. Due to the increasing incorporation of fluorine into complex molecules such as pharmaceuticals and agrochemicals, the upgrading of fluorine-dense hydrofluorocarbons and hydrofluoroolefins (HFOs and HFCs) to fluorine containing reactive building blocks is an attractive method to close the fluorine cycle. In this context, we demonstrate methods to selectively activate sp2 and sp3C–F bonds in fluorocarbons using main group compounds. We have developed efficient methods to chemically upgrade industrially relevant HFOs and HFCs to simple-bench stable silicon compounds. Furthermore, we have advanced the understanding of how to activate strong C–F bonds, by interrogating the reaction mechanisms using computational calculations (DFT).Open Acces

PALLADIUM-CATALYZED DECARBOXYLATIVE ALLYLATIONS OF ESTER ENOLATE EQUIVALENTS AND PALLADIUM-CATALYZED CYCLIZATIONS VIA CO2 AND SILYL ACTIVATION

Palladium-catalyzed decarboxylative allylation (DcA) has received much attention as an alternative C-C bond formation method to traditional metal-catalyzed cross-coupling reactions. Among various nucleophilic partners that undergo DcA, ester enolates are reported to be difficult to allylate and often demand harsher conditions. Herein we report the development of a mild and fast method that provides access to various types of α-allylated amides and esters via decarboxylative allylation of ester enolate equivalents. These amide and ester products undergo further transformations such as hydrolysis, reduction and nucleophilic addition reactions without pre-functionalization. Also enantioselective DcA and diastereoselective DcA of α,α-disubstituted amide enolates are extensively studied and reported. Rapid and efficient synthesis of complex molecules via multicomponent reactions (MCR) is a viable alternative method to time- and resource-consuming stepwise synthesis. In general, multicomponent reactions assemble three or more different reactive components into a multisubstituted product in a one-pot, batch-wise process. Also, this process allows the formation of multiple new bonds in a single operation. Herein we report the development of one-pot, three-component and four-component double decarboxylative allylation reactions to produce α- and γ-allylated amides. In these MCRs, benzylic amide enolates exhibited remarkable success over alkyl amide enolates due to stability differences between two nucleophiles. In the progress of transition metal-catalyzed allylation reactions, it is of great interest to activate allylic alcohols in situ to obtain π-allyl intermediates instead of using pre-activated allyl sources. Due to the inherently poor leaving ability of the hydroxyl group several attempts to activate allyl alcohols have been made using Lewis acids such as Ti(OPri)4, BEt3, BPh3, and SnCl2. Compared to these methods, activation of allyl alcohol using CO2, an inexpensive and readily available gas, is an economical choice. CO2 activates the allylic alcohol in 2-(1-hydroxyallyl)phenol substrate allowing formation of π-allyl palladium intermediate followed by intramolecular etherification to synthesize benzopyrans. Furthermore, we report a successful attempt to activate allyl alcohols by an adjacent silyl group to obtain benzopyrans