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 stille reaction, 38 years later

Producción CientíficaThe first now named Stille reaction was published 38 years ago, and the last comprehensive revision of this catalysis was in 2004. Since then the knowledge of the different steps of the three possible (and sometimes competing) reaction pathways (cyclic, open, and ionic) has been almost completed by synergistic experimental and theoretical studies: the Stille reaction is perhaps the best characterized catalytic process if we consider the number of intermediates that have been detected. This review concentrates on the mechanistic new knowledge, and on important aspects as the revolution with the use of bulky phosphines, the bimetallic alternative of the Stille reaction, the enantioselectivity in Stille and palladium free Stille processes, the meaning of copper effect, or the possible approaches to make Stille coupling a greener process.Junta de Castilla y León (programa de apoyo a proyectos de investigación – Ref. GR 169 and VA256U13)Ministerio de Economía, Industria y Competitividad (CTQ2013-48406-P

Oxidant-Free Au(I)-Catalyzed Halide Exchange and Csp2–O Bond Forming Reactions

Au has been demonstrated to mediate a number of organic transformations through the utilization of its π Lewis acid character, Au(I)/Au(III) redox properties or a combination of both. As a result of the high oxidation potential of the Au(I)/Au(III) couple, redox catalysis involving Au typically requires the use of a strong external oxidant. This study demonstrates unusual external oxidant-free Au(I)-catalyzed halide exchange (including fluorination) and Csp2–O bond formation reactions utilizing a model aryl halide macrocyclic substrate. Additionally, the halide exchange and Csp2–O coupling reactivity could also be extrapolated to substrates bearing a single chelating group, providing further insight into the reaction mechanism. This work provides the first examples of external oxidant-free Au(I)-catalyzed carbon–heteroatom cross-coupling reactions

Experimental study of the [ZnCl2(THF)2] catalyzed cis/trans-isomerization of [Pd(C6Cl2F3)Me(PPh3)2] and of the transmetalation of trans-[PdCl(C6Cl2F3)(PPh3)2] with [ZnMeCl(THF)2]

Producción CientíficaThe kinetics of the transmetalation reaction between trans-[PdCl(C6Cl2F3)(PPh3)2] and [ZnMeCl(THF)2] shows a complex dependence on [PPh3] for the rate of formation of different reaction products: cis and trans-[Pd(C6Cl2F3)Me(PPh3)2], trans-[PdClMe(PPh3)] (which further reacts with [ZnClMe(THF)2]), and [Zn(C6Cl2F3)Cl(THF)2]. To better understand the system the reactions between cis and trans-[Pd(C6Cl2F3)Me(PPh3)2] and [ZnCl2(THF)2] (the retro-transmetalation reactions) and their kinetic dependence on [PPh3] were studied. These reactions lead to the formation of trans-[PdClMe(PPh3)] and [Zn(C6Cl2F3)Cl(THF)2] as main products. Additionally, the experiments show that the isomerization of cis to trans-[Pd(C6Cl2F3)Me(PPh3)2] is catalyzed by [ZnCl2(THF)2]. In this catalyzed isomerization the concentration of PPh3 is involved in two ways: It modulates the concentration of the organozinc [Zn(C6Cl2F3)Cl(THF)2], and also it shifts a ligand substitution equilibrium in the palladium complex, producing an anomalous dependence of the reaction rate on the concentration of triphenylphosphine.Ministerio de Economía, Industria y Competitividad (project CTQ2016-80913-P)Ministerio de Ciencia e Innovación (project PID2019-111406GB-100)Junta de Castilla y León (projects VA051P17 and VA062G18

1,3-Dien-5-ynes: Versatile Building Blocks for the Synthesis of Carbo- and Heterocycles

1,3-Dien-5-ynes have been extensively used as starting materials for the synthesis of a wide number of different carbo- and heterocycles. The aim of this review is to give an overview of their utility in organic synthesis, highlighting the variety of compounds that can be directly accessed from single reactions over these systems. Thus, cycloaromatization processes are initially commented, followed by reactions directed toward the syntheses of five-membered rings, other carbocycles and, finally, heterocycles. The diverse methodologies that have been developed for the synthesis of each of these types of compounds from 1,3-dien-5-ynes are presented, emphasizing the influence of the reaction conditions and the use of additional reagents in the outcome of the transformations.Ministerio de Economía y Competitividad (MINECO) and FEDER (CTQ2013-41336-P, CTQ2013- 48937-C2-1-P, and CTQ2014-52488-R), Universidad de Alcalá (CCG2015/EXP-003) and Junta de Castilla y León (BU237U13

Comparative analysis of palladium, nickel and copper phosphane/carbene catalysts in Suzuki–Miyaura couplings: Mechanistic insights and reactivity trends

Suzuki–Miyaura coupling is a useful synthetic method of the formation of new car- bon–carbon bonds between an organic halide and a boronic acid (or boronate ester), generally catalyzed by palladium compounds in the presence of an external base. In the search of more sustainable and green chemistry processes, precious metals such as palladium are currently being replaced by base metal analogues, which produce more affordable and accessible catalytic platforms. In this work, the catalytic cycle of the Suzuki–Miyaura coupling reaction between phenyl bromide and phenylboronate has been studied by computational means for different combinations of metal/ligand systems. Three transition metals: palladium, nickel, and copper, and four monodentate ligands, including two phosphanes (PMe3 and P(CF3)3) and two N-heterocyclic carbenes (1,3-bis(methyl)imidazol-2-ylidene and 1,3-bis(trifluoromethyl)limidazol-2-ylidene), have been used to construct and explore the reaction for monoligated catalytic species. Overall, the palladium systems display the lowest activation barriers for the Suzuki–Miyaura reaction, with nickel producing the second-best catalysts. On the other hand, copper seems to produce slightly worse systems, with reaction barriers over 25 kcal mol−1 for all the ligands

Exploring New Reaction Pathways Mediated by Palladium(IV) Complexes

Carbon-carbon bond-forming processes featuring palladium catalysts play an important role in the synthesis of biologically active organic compounds. In the early 2000s, Canty, Sanford, Ritter and others have focused on studying palladium complexes in the oxidation state Palladium(IV). The PdII-PdIV transformations possess distinct advantages over the traditional catalytic process mediated by palladium in the oxidation states Palladium(0) and Palladium(II). In these transformations, reductive elimination to form new C-C bonds from the PdIV intermediate is expected to occur at a faster rate than &beta-hydride elimination. Overall, the C(sp3)-C(sp3) bond coupling is expected to be favorable. In the past decade, the Malinakova group has been studying the synthesis of unique pallada(II)cycles and exploring their reactivity with different electrophilic organic oxidants. These studies established that allyl halides as well as vinyl and alkynyl iodonium salts are capable of producing PdIV complexes possessing three Pd-C bonds. A stable PdIV complex was isolated, characterized and shown to mediate the formation of a heterocycle. In this Dissertation, the synthesis of various PdIV complexes and studies aimed at explaining the range of fundamental transformations at the PdIV-center beyond reductive elimination are presented. Chapter One discusses a general introduction into Palladium(IV) chemistry which includes a comparison between Pd0-PdII and PdII-PdIV catalytic cycles. This introduction also documents the observed and the proposed advantages of Palladium(IV) complexes in the applications to organic synthesis. Chapter Two constitutes a review of Palladium(IV) complexes in organometallic chemistry with particular emphases on the following themes in Palladium(IV) chemistry: (1) the use of strong oxidants to create various Pd-carbon or Pd-heteroatom bonds; (2) the presence of stabilizing ligands to aid in isolating the PdIV complexes; (3) the overview of known organometallic transformations being mediated by the PdIV-center Chapter Three provides the preliminary studies into the use of diazonium salt oxidants to generate PdIV complexes at low temperatures. The PdIV complexes feature the tripodal tris(pyrazol-1-yl)borate (Tp) ligand as well as two Pd-C(sp3) bonds and the oxidant generates a new Pd-C(sp2) bond. Detailed 1H NMR spectroscopic studies at low temperature provided the evidence of the formation for the (Tp)PdII intermediate via ligand exchange and the formation of the desired PdIV complexes in solution. Chapter Four describes the study of PdIV-mediated C-H activation in an organic oxidant yielding PdIV complexes with multiple Pd-C(sp2/sp3) bonds. Reductive elimination generates a complex heterocycle featuring two new C(sp2)-C(sp3) bonds. Detailed low temperature 1H NMR spectroscopic studies monitor the formation of the PdIV intermediates, give insight into the oxidative addition and C-H activation pathway during the reaction sequence and confirm carbon-carbon bond-formation by establishing the structure of the final organic product. Chapter Five details the synthesis of stable PdIV complexes featuring different auxiliary ligands. These PdIV complexes, which also possess the stabilizing tripodal Tp ligand, are generated in the presence of iodonium salts. The chapter reports our studies on the effect of the electronic properties of auxiliary ligands on the reactivity of the PdIV complex. The studies detailed in the chapter were aimed at exploring the C-H activation in organic substrates induced by the PdIV complexes. However, initial work indicated a limited scope of ligand substitution reactions, which prevented us from realizing the desired C-H activation on the organic substrate. Detailed ligand exchange studies with nucleophiles/additives are described in this chapter

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