Organolithium bases in flow chemistry: a review

Flow chemistry is a continually emerging and ever-growing area of synthetic organic chemistry. It provides an orthogonal approach to traditional batch chemistry, oftentimes allowing for more efficient routes to desired target molecules. It is generally accepted that flow chemistry offers a valuable change to the process landscape. From a process perspective, there are many advantages associated with flow chemistry over traditional batch chemistry, the most prominent of which is an increased safety profile with the use of highly reactive chemical species, such as organolithiums. These reagents are highly valuable species for the efficient synthesis of pharmaceutical intermediates. Disadvantageously, use of these reagents on commercial scale is severely hindered by the highly energetic nature of the reaction intermediates and their concomitant safety risk. Flow chemistry provides a viable platform for use of these reagents, offering a high degree of control over reaction parameters. In this review, we present a comprehensive account of the published literature implementing the use of organolithium reagents as strong bases for deprotonation reactions in flow systems

The emergence of Pd-mediated reversible oxidative addition in cross coupling, carbohalogenation and carbonylation reactions

Exploiting the reversibility of chemical processes is a long-standing tactic of organic chemists, and permeates most areas of the discipline. The notion that oxidative addition of Pd(0) to Ar–X bonds can be considered an irreversible process has been challenged, periodically, over the last 30 years. Recent examples of methodologies that harness the reversibility of oxidative addition reactions in catalytic processes have enabled access to challenging carbocyclic and heterocyclic scaffolds. This Perspective seeks to describe the development of these processes from the early proof-of-principle findings, and highlight key challenges that remain in this avenue of research. In particular, we draw attention to significant deficiencies that remain in the choice of suitable ligands and additives for these transformations. We conclude by describing how the concept of reversible oxidative addition has recently been exploited in the development of novel carbonylation reactions

Recent advances in manganese-catalysed C–H activation: scope and mechanism

As a synthetic methodology, C–H activation represents a complimentary protocol to traditional cross-couplings such as the Suzuki–Miyaura and Stille reactions, by avoiding the extra synthetic steps required to install activating groups. C–H activation also often avoids the production of waste associated with B, Sn, halide etc. Pd-catalysed transformations have been most prominent in the C–H activation realm. However, as a society we are over-reliant on transitional metals, cost is increasing, and the accessible supply is dwindling. One potential solution is to develop chemistry using Earth Abundant Metals (EAMs). Manganese (Mn), in particular, demonstrates great promise. Since the publication of an excellent review by Ackermann in 2016 (ACS Catal. 2016, 6, 3743–3652), there has been a flurry of reports on Mn-catalysed C–H activation. We report here an overview of approximately 30 new papers, which include a number of notable advances since April 2016

Enhanced catalytic activity of high index faceted palladium nanoparticles in Suzuki-Miyaura coupling due to efficient leaching mechanism

The structure-property relationship of palladium (Pd) catalysts in Suzuki-Miyaura cross-coupling reactions was investigated using Pd nanocrystals of uniform size and shape. Superior catalytic reactivity was observed for Pd nanoparticles with high-index {730} surface facets compared to low-index {100} facets. Although the nanocrystal morphologies were maintained during the reaction, the presence of Pd clusters, identified by high-resolution transmission electron microscopy (TEM), indicates a leaching mechanism. The nature of the surface facets on the nanoparticles was observed to influence the rate of Pd leaching during the Suzuki coupling reaction. The enhanced reactivity observed for the high-index facet catalysts stems from the greater number of leachable atoms of low abstraction energy available on high-index planes

The origin of shape sensitivity in palladium-catalyzed Suzuki–Miyaura cross coupling reactions

The shape sensitivity of Pd catalysts in Suzuki–Miyaura coupling reactions is studied using nanocrystals enclosed by well-defined surface facets. The catalytic performance of Pd nanocrystals with cubic, cuboctahedral and octahedral morphologies are compared. Superior catalytic reactivity is observed for Pd NCs with {100} surface facets compared to {111} facets. The origin of the enhanced reactivity associated with a cubic morphology is related to the leaching susceptibility of the nanocrystals. Molecular oxygen plays a key role in facilitating the leaching of Pd atoms from the surface of the nanocrystals. The interaction of O2 with Pd is itself facet-dependent, which in turn gives rise to more efficient leaching from {100} facets, compared to {111} facets under the reaction conditions

Monolayer doping of Si with improved oxidation resistance

In this article, the functionalization of planar silicon with arsenic- and phosphorus-based azides was investigated. Covalently bonded and well-ordered alkyne-terminated monolayers were prepared from a range of commercially available dialkyne precursors using a well-known thermal hydrosilylation mechanism to form an acetylene-terminated monolayer. The terminal acetylene moieties were further functionalized through the application of copper-catalyzed azide–alkyne cycloaddition (CuAAC) reactions between dopant-containing azides and the terminal acetylene groups. The introduction of dopant molecules via this method does not require harsh conditions typically employed in traditional monolayer doping approaches, enabling greater surface coverage with improved resistance toward reoxidation. X-ray photoelectron spectroscopy studies showed successful dialkyne incorporation with minimal Si surface oxidation, and monitoring of the C 1s and N 1s core-level spectra showed successful azide–alkyne cycloaddition. Electrochemical capacitance–voltage measurements showed effective diffusion of the activated dopant atoms into the Si substrates

Palladium(II) oxide impregnated on magnetite as a catalyst for the synthesis of 4-arylcoumarins via a Heck-arylation/cyclization process

Heck-arylation/cyclization was achieved using heterogeneous palladium(II) oxide impregnated on magnetite catalyst (2.5 mol%) with a lower catalyst loading than that reported for similar processes. Ethanol was used as a non-toxic and bio-renewable solvent. Good yields were afforded using a broad range of substrates (40–98%). The catalyst could be partially recycled, and analyses confirmed the almost total reduction of palladium(II) oxide to palladium(0) as well as the iodine poissoning effect, which is the main barrier to complete recyclability.The authors thank the Spanish Ministerio de Economía y Competitividad (MICINN; CTQ2011-24151), University of Alicante, Irish Research Council (RC) and Science Foundation Ireland (SFI/12/IP/1315 and SFI/12/RC/2275). J. M. P. thanks the MICINN (FPI program) for her fellowship

Quinolones modulate ghrelin receptor signaling: potential for a novel small molecule scaffold in the treatment of cachexia

Cachexia is a metabolic wasting disorder characterized by progressive weight loss, muscle atrophy, fatigue, weakness, and appetite loss. Cachexia is associated with almost all major chronic illnesses including cancer, heart failure, obstructive pulmonary disease, and kidney disease and significantly impedes treatment outcome and therapy tolerance, reducing physical function and increasing mortality. Current cachexia treatments are limited and new pharmacological strategies are needed. Agonists for the growth hormone secretagogue (GHS-R1a), or ghrelin receptor, prospectively regulate the central regulation of appetite and growth hormone secretion, and therefore have tremendous potential as cachexia therapeutics. Non-peptide GHS-R1a agonists are of particular interest, especially given the high gastrointestinal degradation of peptide-based structures, including that of the endogenous ligand, ghrelin, which has a half-life of only 30 min. However, few compounds have been reported in the literature as non-peptide GHS-R1a agonists. In this paper, we investigate the in vitro potential of quinolone compounds to modulate the GHS-R1a in both transfected human cells and mouse hypothalamic cells. These chemically synthesized compounds demonstrate a promising potential as GHS-R1a agonists, shown by an increased intracellular calcium influx. Further studies are now warranted to substantiate and exploit the potential of these novel quinolone-based compounds as orexigenic therapeutics in conditions of cachexia and other metabolic and eating disorders.Irish Research Council for Science and Technology (IRCSET)Science Foundation Ireland (SFI/12/IP/1315)Science Foundation Ireland (SFI/12/RC/2275)Science Foundation Ireland (SFI/12/RC/2273)Universidad de Sevill

Access to Some C5-Cyclised 2-Pyrones and 2-Pyridones via Direct Arylation; Retention of Chloride as a Synthetic Handle

The synthetic effort towards the functionalisation of C–H bonds on 2-pyrones and 2-pyridones has been enabled by the preferential reactivity of the C-3 position. Herein, we report a direct arylation protocol for the intramolecular coupling of 2-pyrones and 2-pyridones, allowing access to a previously unavailable class of C-5 cyclised products with an unstudied biological profile. A C–Cl bond was retained at C-3 during the direct arylation process allowing further derivatisation at C-3, using a Suzuki–Miyaura cross-coupling reaction

Impregnated palladium on magnetite as catalyst for direct arylation of heterocycles

Palladium impregnated on magnetite is an efficient, cheap and easy to prepare catalyst for the direct arylation of heterocycles. Good yields are afforded under relatively mild conditions and a broad substrate scope is evident. The catalyst is regioselective in many cases, affording arylated products, at the C2- or C3-position (depending of the heterocycle used). The methodology can be extended to prepare chromenes through an intramolecular direct arylation reaction. Some evidence is provided for two catalyst deactivation pathways, which prevents efficient recycling.The authors thank the Irish Research Council (RC), Science Foundation Ireland (SFI/12/IP/1315 and SFI/12/RC/2275), Spanish Ministerio de Economía y Competitividad (MICINN; CTQ2011-24151, University of Alicante and MICINN FPI program (JMP)