Palladium Bisphosphine Monoxide Complexes: Synthesis, Scope, Mechanism, and Catalytic Relevance.

Recent studies in transition metal catalysis employing chelating phosphines have suggested a role for partial ligand oxidation in formation of the catalytically active species, with potentially widespread relevance in a number of catalytic systems. We examine the internal redox reaction of Pd(bisphosphine)X (X = Cl, OAc, ) complexes to reveal previously underexplored aspects of bisphosphine monoxides (BPMOs), including evaluation of ligand structure and development of general reaction conditions to access a collection of structurally diverse BPMO precatalysts based on organopalladium oxidative addition complexes. In particular, a series of Pd(BPMO)(R)(X) (R = aryl, alkyl; X = I, Br) oxidative addition complexes bearing 24 different BPMO ligands were characterized by NMR and X-ray crystallography.

Post-ROSC Atrial fibrillation is not associated with rearrest but is associated with stroke and mortality following out of hospital cardiac arrest.

Background: Atrial fibrillation (AF) in patients resuscitated from cardiac arrest (CA) is associated with increased short-term mortality. However, whether this is because AF adversely affects early resuscitation success, causes post-resuscitation morbidity, or because it is a marker for patient co-morbidities, remains unclear. We aimed to determine the prevalence of AF in patients with ROSC to test the hypothesis that AF is associated with increased risk of rearrest and to determine its impact on mortality and stroke risk.

A survey of preferences and expectations for surgical interventions targeting atonic seizures in Lennox-Gastaut syndrome.

Purpose: To assess preferences and outcome expectations for vagus nerve stimulation (VNS) and corpus callosotomy (CC) surgeries in the treatment of atonic seizure in Lennox-Gastaut syndrome (LGS).

Methods: A total of 260 surveys were collected from patients are caregivers of LGS patients via Research Electronic Data Capture (REDCap).

Results: Respondents reported an average acceptable atonic seizure reduction rate of 55.

(Phenoxyimine)nickel-Catalyzed C(sp)-C(sp) Suzuki-Miyaura Cross-Coupling: Evidence for a Recovering Radical Chain Mechanism.

Phenoxyimine (FI)-nickel(II)(2-tolyl)(DMAP) compounds were synthesized and evaluated as precatalysts for the C(sp)-C(sp) Suzuki-Miyaura cross coupling of (hetero)arylboronic acids with alkyl bromides. With 5 mol % of the optimal (MeFI)Ni(Aryl)(DMAP) precatalyst, the scope of the cross-coupling reaction was established and included a variety of (hetero)arylboronic acids and alkyl bromides (>50 examples, 33-97% yield). A β-hydride elimination-reductive elimination sequence from reaction with potassium isopropoxide base, yielding a potassium (FI)nickel(0)ate, was identified as a catalyst activation pathway that is responsible for halogen atom abstraction from the alkyl bromide.

Benchtop Nickel Catalysis Invigorated by Electron-Deficient Diene Ligands.

ConspectusDue to the rarity of precious metals like palladium, nickel catalysis is becoming an increasingly important player in organic synthesis, especially for the formation of bonds with sp-hybridized carbon centers. Traditionally, catalytic processes involving active Ni(0) species have relied on Ni(COD) or in situ reduction of Ni(II) salts. However, Ni(COD) is an air- and temperature-sensitive material that requires use in an inert-atmosphere glovebox, and in situ reduction protocols of Ni(II) salts using metallic or organometallic reductants add additional complications to reaction development.

Electroreductive Synthesis of Nickel(0) Complexes.

Over the last fifty years, the use of nickel catalysts for facilitating organic transformations has skyrocketed. Nickel(0) sources act as useful precatalysts because they can enter a catalytic cycle through ligand exchange, without needing to undergo additional elementary steps. However, most Ni(0) precatalysts are synthesized with stoichiometric aluminum-hydride reductants, pyrophoric reagents that are not atom-economical and must be used at cryogenic temperatures.

Ligand-Enabled Carboamidation of Unactivated Alkenes through Enhanced Organonickel Electrophilicity.

Catalytic carboamination of alkenes is a powerful synthetic tool to access valuable amine scaffolds from abundant and readily available alkenes. Although a number of synthetic approaches have been developed to achieve the rapid buildup of molecular complexity in this realm, the installation of diverse carbon and nitrogen functionalities onto unactivated alkenes remains underdeveloped. Here we present a ligand design approach to enable nickel-catalyzed three-component carboamidation that is applicable to a wide range of alkenyl amine derivatives via a tandem process involving alkyl migratory insertion and inner-sphere metal-nitrenoid transfer.

Phenoxythiazoline (FTz)-Cobalt(II) Precatalysts Enable C(sp )-C(sp ) Bond-Formation for Key Intermediates in the Synthesis of Toll-like Receptor 7/8 Antagonists.

Evaluation of the relative rates of the cobalt-catalyzed C(sp )-C(sp ) Suzuki-Miyaura cross-coupling between the neopentylglycol ester of 4-fluorophenylboronic acid and N-Boc-4-bromopiperidine established that smaller N-alkyl substituents on the phenoxyimine (FI) supporting ligand accelerated the overall rate of the reaction. This trend inspired the design of optimal cobalt catalysts with phenoxyoxazoline (FOx) and phenoxythiazoline (FTz) ligands. An air-stable cobalt(II) precatalyst, (FTz)CoBr(py) was synthesized and applied to the cross-coupling of an indole-5-boronic ester nucleophile with a piperidine-4-bromide electrophile that is relevant to the synthesis of reported toll-like receptor (TLR) 7/8 antagonist molecules including afimetoran.

Development of a Crystallization-Induced Diastereomer Transformation of Oxime Isomers for the Asymmetric Synthesis of (1,6)-3,9-Diazabicyclo[4.2.1]nonane.

Herein we report a practical crystallization-induced diastereomer transformation (CIDT) of oxime isomers for the scalable asymmetric synthesis of the bicyclic diamine (1,6)-3,9-diazabicyclo[4.2.1]nonane derivative that serves as a valuable building block in medicinal chemistry.

Mechanistic Investigations of Phenoxyimine-Cobalt(II)-Catalyzed C(sp)-C(sp) Suzuki-Miyaura Cross-Coupling.

The mechanism of phenoxyimine (FI)-cobalt-catalyzed C(sp)-C(sp) Suzuki-Miyaura cross-coupling was studied using a combination of kinetic measurements and catalytic and stoichiometric experiments. A series of dimeric (FI)cobalt(II) bromide complexes, [(4-CFPhFI)CoBr], [(4-OMePhFI)CoBr], and [(2,6-diPrPhFI)CoBr], were isolated and characterized by H and F NMR spectroscopies, solution and solid-state magnetic susceptibility, electron paramagnetic resonance (EPR) spectroscopy, X-ray crystallography, and diffusion-ordered NMR spectroscopy (DOSY). One complex, [(4-CFPhFI)CoBr], was explored as a single-component precatalyst for C(sp)-C(sp) Suzuki-Miyaura cross-coupling.

Structurally Diverse Bench-Stable Nickel(0) Pre-Catalysts: A Practical Toolkit for In Situ Ligation Protocols.

A flurry of recent research has centered on harnessing the power of nickel catalysis in organic synthesis. These efforts have been bolstered by contemporaneous development of well-defined nickel (pre)catalysts with diverse structure and reactivity. In this report, we present ten different bench-stable, 18-electron, formally zero-valent nickel-olefin complexes that are competent pre-catalysts in various reactions.

Three-Component Asymmetric Ni-Catalyzed 1,2-Dicarbofunctionalization of Unactivated Alkenes via Stereoselective Migratory Insertion.

An asymmetric 1,2-dicarbofunctionalization of unactivated alkenes with aryl iodides and aryl/alkenylboronic esters under nickel/bioxazoline catalysis is disclosed. A wide array of aryl and alkenyl nucleophiles are tolerated, furnishing the products in good yield and with high enantioselectivity. In addition to terminal alkenes, 1,2-disubstituted internal alkenes participate in the reaction, establishing two contiguous stereocenters with high diastereoselectivity and moderate enantioselectivity.

Cobalt-Catalyzed C(sp)-C(sp) Suzuki-Miyaura Cross-Coupling Enabled by Well-Defined Precatalysts with L,X-Type Ligands.

Cobalt(II) halides in combination with phenoxy-imine (FI) ligands generated efficient precatalysts for the C(sp)-C(sp) Suzuki-Miyaura cross coupling between alkyl bromides and neopentylglycol (hetero)arylboronic esters. The protocol enabled efficient C-C bond formation with a host of nucleophiles and electrophiles (36 examples, 34-95%) with precatalyst loadings of 5 mol%. Studies with alkyl halide electrophiles that function as radical clocks support the intermediacy of alkyl radicals during the course of the catalytic reaction.

Selectivity in the Elaboration of Bicyclic Borazarenes.

Among aromatic compounds, borazarenes represent a significant class of isosteres in which carbon-carbon bonds have been replaced by B-N bonds. Described herein is a summary of the selective reactions that have been developed for known systems, as well as a summary of computationally-based predictions of selectivities that might be anticipated in reactions of yet unrealized substructures.

A Process Chemistry Benchmark for sp-sp Cross Couplings.

As sp-sp disconnections gain acceptance in the medicinal chemist's toolbox, an increasing number of potential drug candidates containing this motif are moving into the pharmaceutical development pipeline. This raises a new set of questions and challenges around the novel, direct methodologies available for forging these bonds. These questions gain further importance in the context of process chemistry, where the focus is the development of scalable processes that enable the large-scale delivery of clinical supplies.

Ni-Catalyzed 1,2-Diarylation of Alkenyl Ketones: A Comparative Study of Carbonyl-Directed Reaction Systems.

A nickel-catalyzed 1,2-diarylation of alkenyl ketones with aryl iodides and arylboronic esters is reported. Ketones with a variety of substituents serve as effective directing groups, offering high levels of regiocontrol. A representative product is diversified into a wide range of useful products that are not readily accessible via existing 1,2-diarylation reactions.

Transcriptomics of bronchoalveolar lavage cells identifies new molecular endotypes of sarcoidosis.

Background: Sarcoidosis is a multisystem granulomatous disease of unknown origin with a variable and often unpredictable course and pattern of organ involvement. In this study we sought to identify specific bronchoalveolar lavage (BAL) cell gene expression patterns indicative of distinct disease phenotypic traits.

Methods: RNA sequencing by Ion Torrent Proton was performed on BAL cells obtained from 215 well-characterised patients with pulmonary sarcoidosis enrolled in the multicentre Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study.

Defining the optimal disease duration of early diffuse systemic sclerosis for clinical trial design.

Objectives: Clinical trials in early diffuse cutaneous systemic sclerosis (SSc) using the modified Rodnan skin score (mRSS) as the primary outcome measure have most often been negative. We wanted to assess how the definition of disease onset (first SSc manifestation vs first non-Raynaud manifestation) and varying lengths of disease duration at trial entry as an inclusion criteria functioned. Our objective was to optimize trial inclusion criteria.

Cobalt-Catalyzed C(sp)-C(sp) Suzuki-Miyaura Cross Coupling.

A cobalt-catalyzed method for the C(sp)-C(sp) Suzuki-Miyaura cross coupling of aryl boronic esters and alkyl bromides is described. Cobalt-ligand combinations were assayed with high-throughput experimentation, and cobalt(II) sources with -,'-dimethylcyclohexane-1,2-diamine (DMCyDA, L) produced optimal yield and selectivity. The scope of this transformation encompassed steric and electronic diversity on the aryl boronate nucleophile as well as various levels of branching and synthetically valuable functionality on the electrophile.

Pd- and Ni-Based Systems for the Catalytic Borylation of Aryl (Pseudo)halides with B(OH).

Despite recent advancements in metal-catalyzed borylations of aryl (pseudo)halides, there is a continuing need to develop robust methods to access both early-stage and late-stage organoboron intermediates amendable for further functionalization. In particular, the development of general catalytic systems that operate under mild reaction conditions across a broad range of electrophilic partners remains elusive. Herein, we report the development and application of three catalytic systems (two Pd-based and one Ni-based) for the direct borylation of aryl (pseudo)halides using tetrahydroxydiboron (B(OH)).

Palladium-Catalyzed Reductive Heck Coupling of Alkenes.

The Mizoroki-Heck reaction is one of the most studied palladium-catalyzed cross-coupling reactions, representing a powerful method for forming C-C bonds between diverse substrates with broad functional group compatibility. However, the reductive variant has received considerably less attention. In this Review, we summarize distinct mechanistic aspects of the reductive Heck reaction, highlight recent contributions to the field, and discuss potential applications of the reductive Heck reaction in the pharmaceutical industry.

Ligand-Enabled Pd(II)-Catalyzed C(sp)-H Lactonization Using Molecular Oxygen as Oxidant.

Pd(II)-catalyzed C-H lactonization of -methyl benzoic acid substrates has been achieved using molecular oxygen as the oxidant. This finding provides a rare example of C-H oxygenation through Pd(II)/Pd(0) catalysis as well as a method to construct biologically important benzolactone scaffolds. The use of a gas mixture of 5% oxygen in nitrogen demonstrated the possibility for its application in pharmaceutical manufacturing.

Ni(COD)(DQ): An Air-Stable 18-Electron Nickel(0)-Olefin Precatalyst.

We report that Ni(COD)(DQ) (COD=1,5-cyclooctadiene, DQ=duroquinone), an air-stable 18-electron complex originally described by Schrauzer in 1962, is a competent precatalyst for a variety of nickel-catalyzed synthetic methods from the literature. Due to its apparent stability, use of Ni(COD)(DQ) as a precatalyst allows reactions to be conveniently performed without use of an inert-atmosphere glovebox, as demonstrated across several case studies.

Nickel-Catalyzed 1,2-Diarylation of Alkenyl Carboxylates: A Gateway to 1,2,3-Trifunctionalized Building Blocks.

A nickel-catalyzed conjunctive cross-coupling of alkenyl carboxylic acids, aryl iodides, and aryl/alkenyl boronic esters is reported. The reaction delivers the desired 1,2-diarylated and 1,2-arylalkenylated products with excellent regiocontrol. To demonstrate the synthetic utility of the method, a representative product is prepared on gram scale and then diversified to eight 1,2,3-trifunctionalized building blocks using two-electron and one-electron logic.

Utilizing Native Directing Groups: Mechanistic Understanding of a Direct Arylation Leads to Formation of Tetracyclic Heterocycles via Tandem Intermolecular, Intramolecular C-H Activation.

A mechanistic study on a direct arylation using a native picolylamine directing group is reported. Kinetic studies determined the concentration dependence of substrates and catalysts, as well as catalyst degradation, which led to the development of a new set of reaction conditions capable of affording a robust kinetic profile. During reaction optimization, a small impurity was observed, which was determined to be a dual C-H activation product.