Hydrodeoxygenation of isocyanates : snapshots of a magnesium-mediated C=O bond cleavage

Organic isocyanates are readily converted to methyl amine products through their hydroboration with HBpin in the presence of a β-diketiminato magnesium catalyst. Although borylated amide and N-,O-bis(boryl)hemiaminal species have been identified as intermediates during the reductive catalysis, the overall reduction and C–O activation is metal-mediated and proposed to occur through the further intermediacy of well-defined magnesium formamidato, formamidatoborate and magnesium boryloxide derivatives. Examples of all these species have been identified and fully characterised through stoichiometric reactivity studies and the stability of the borate species leads us to suggest that, under catalytic conditions, the onward progress of the deoxygenation reaction is crucially dependent on the further activation provided by the Lewis acidic HBpin substrate. These deductions have been explored and ratified through a DFT study

Magnesium-catalysed nitrile hydroboration

A β-diketiminato n-butylmagnesium complex is presented as a selective precatalyst for the reductive hydroboration of organic nitriles with pinacolborane (HBpin). Stoichiometric reactivity studies indicate that catalytic turnover ensues through the generation of magnesium aldimido, aldimidoborate and borylamido intermediates, which are formed in a sequence of intramolecular nitrile insertion and inter- and intramolecular B–H metathesis events. Kinetic studies highlight variations in mechanism for the catalytic dihydroboration of alkyl nitriles, aryl nitriles bearing electron withdrawing (Ar(EWG)CN) and aryl nitriles bearing electron donating (Ar(EDG)CN) substitution patterns. Kinetic isotope effects (KIEs) for catalysis performed with DBpin indicate that B–H bond breaking and C–H bond forming reactions are involved in the rate determining processes during the dihydroboration of alkyl nitriles and Ar(EDG)CN substrates, which display divergent first and second order rate dependences on [HBpin] respectively. In contrast, the hydroboration of Ar(EWG)CN substrates provides no KIE and HBpin is not implicated in the rate determining process during catalysis. Irrespective of these differences, a common mechanism is proposed in which the rate determining steps are deduced to vary through the establishment of several pre-equilibria, the relative positions of which are determined by the respective stabilities of the dimeric and monomeric magnesium aldimide and magnesium aldimidoborate intermediates as a result of adjustments to the basicity of the nitrile substrate. More generally, these observations indicate that homogeneous processes performed under heavier alkaline earth catalysis are likely to demonstrate previously unappreciated mechanistic diversity

The significance of secondary interactions during alkaline earth-promoted dehydrogenation of dialkylamine-boranes

Reactions of anilidoimine magnesium n-butyl and calcium bis(trimethylsilyl)amide derivatives with Me2NH·BH3 at 25 °C resulted in the isolation of complexes containing [NMe2BH2NMe2BH3]− and [NMe2BH3]− anions respectively.</p

Alkaline Earth-Centered CO Homologation, Reduction, and Amine Carbonylation

Reactions of β-diketiminato magnesium and calcium hydrides with 1 atm of CO result in a reductive coupling process to produce the corresponding derivatives of the <i>cis</i>-ethenediolate dianion. Computational (DFT) analysis of this process mediated by Ca, Sr, and Ba highlights a common mechanism and a facility for the reaction that is enhanced by increasing alkaline earth atomic weight. Reaction of CO with PhSiH₃ in the presence of the magnesium or calcium hydrides results in catalytic reduction to methylsilane and methylene silyl ether products, respectively. These reactions are proposed to ensue via the interception of initially formed group 2 formyl intermediates, an inference which is confirmed by a DFT analysis of the magnesium-centered reaction. The computational results identify the rate-determining process, requiring traversal of a 33.9 kcal mol^–1 barrier, as a Mg–H/C–O σ-bond metathesis reaction, associated with the ultimate cleavage of the C–O bond. The carbonylation reactivity is extended to a variety of magnesium and calcium amides. With primary amido complexes, which for calcium include a derivative of the parent [NH₂]⁻ anion, CO insertion is facile and ensues with subsequent nitrogen-to-carbon migration of hydrogen to yield a variety of dinuclear and, in one case, trinuclear formamidate species. The generation of initial carbenic carbamoyl intermediates is strongly implicated through the isolation of the CO insertion product of a magnesium <i>N</i>-methylanilide derivative. These observations are reinforced by a DFT analysis of the calcium-centered reaction with aniline, which confirms the exothermicity of the formamidate formation (Δ<i>H</i> = −67.7 kcal mol^–1). Stoichiometric reduction of the resultant magnesium and calcium formamidates with pinacolborane results in the synthesis of the corresponding <i>N</i>-borylated methylamines. This takes place via a sequence of reactions initiated through the generation of amidato­hydridoborate intermediates and a cascade of reactivity that is analogous to that previously reported for the deoxygenative hydroboration of organic isocyanates catalyzed by the same magnesium hydride precatalyst. Although a sequence of amine formylation and deoxygenation may be readily envisaged for the catalytic utilization of CO as a C₁ source in the production of methylamines, our observations demonstrate that competitive amine–borane dehydrocoupling is too facile under the conditions of 1 atm of CO employed

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Ytterbium (II) Hydride as a Powerful Multielectron Reductant

International audienceA dimeric beta-diketiminato ytterbium(II) hydride affects both the two-electron aromatization of 1,3,5,7-cyclooctatetraene (COT) and the more challenging two-electron reduction of polyaromatic hydrocarbons, including naphthalene (E-0=-2.60 V). Confirmed by Density Functional Theory calculations, these reactions proceed via consecutive polarized Yb-H/C=C insertion and deprotonation steps to provide the respective ytterbium (II) inverse sandwich complexes and hydrogen gas. These observations highlight the ability of a simple ytterbium(II) hydride to act as a powerful two-electron reductant at room temperature without the necessity of an external electron to initiate the reaction and avoiding radicaloid intermediates

Coordination of arenes and phosphines by charge separated alkaline earth cations

International audienceGeneration of beta-diketiminato group 2 cations, [((BDI)-B-Me)Ae](+) and [(t-BuBDI)Ae](+) ((BDI)-B-Me = HC{(Me)CN-2,6-i-Pr2C6H3}(2); t-BuBDI = HC{(t-Bu)CN-2,6-i-Pr2C6H3}(2); Ae = Mg or Ca), in conjunction with the weakly coordinating anion, [Al{OC(CF3)(3)}(4)](-), allows the characterisation of charge separated alkaline earth eta(6)-pi adducts to toluene or benzene when crystallised from the arene solvents. Addition of 1,4-difluorobenzene to [((BDI)-B-Me)Mg](+) results in the isolation of [((BDI)-B-Me)Mg(1,4-F2C6H4)(3)](+) in which the fluorobenzene molecules coordinate via kappa(1)-F-M interactions. Although DFT analysis indicates that the polyhapto arene binding to Mg is effectively electrostatic in origin, the interactions with Ca (Sr and Ba) are observed to invoke small but significant pi overlap of the arene HOMOs with the alkaline earth valence nd orbitals. Reaction of triphenylphosphine with [((BDI)-B-Me)Mg](+) and [(t-BuBDI)Mg](+) in toluene solvent allows the isolation of the respective terminally coordinated magnesium-phosphine adducts. The resultant Mg-P bond lengths [2.5972(13), 2.6805(12) angstrom] are comparable to those previously observed in magnesium derivatives of terminal but formally anionic phosphide ligands, while the effectively electrostatic nature of the bonding is supported by DFT calculations

Hydroarylation of olefins catalysed by a dimeric ytterbium(II) alkyl

International audienceAlthough the nucleophilic alkylation of aromatics has recently been achieved with a variety of potent main group reagents, all of this reactivity is limited to a stoichiometric regime. We now report that the ytterbium(II) hydride, [(BDIYbH)-Yb-Dipp](2) (BDIDipp=CH[C(CH3)NDipp](2), Dipp = 2,6-diisopropylphenyl), reacts with ethene and propene to provide the ytterbium(II) n-alkyls, [(BDIYbR)-Yb-Dipp](2) (R=Et or Pr), both of which alkylate benzene at room temperature. Density functional theory (DFT) calculations indicate that this latter process operates through the nucleophilic (S(N)2) displacement of hydride, while the resultant regeneration of [(BDIYbH)-Yb-Dipp](2) facilitates further reaction with ethene or propene and enables the direct catalytic (anti-Markovnikov) hydroarylation of both alkenes with a benzene C-H bond. Nucleophilic alkylation of aromatics with main group reagents was achieved, but it is limited to a stoichiometric regime. Here, the authors report that the ytterbium(II) hydride reacts with ethene and propene to afford ytterbium(II) n-alkyls, both of which can facilitate the catalytic alkylation of benzene at room temperature via an S(N)2 mechanism

Alane-Centered Ring Expansion of <i>N</i>‑Heterocyclic Carbenes

The β-diketiminato aluminum dihydrides, [HC­{(Me)­CNAr}₂AlH₂] [<b>4</b>: Ar = 2,6-di-<i>iso</i>propylphenyl (Dipp), <b>5</b>: 2,4,6-trimethyl­phenyl (Mes)] react directly with <i>N</i>-aryl-substituted <i>N</i>-heterocyclic carbenes (NHCs) by C–N bond activation to afford aluminum amido-alkyl derivatives of the form [HC­{(Me)­CNAr}₂AlCH₂(N­(Ar′)­CH)₂]. The more sterically congested alane (<b>4</b>), bearing <i>N</i>-Dipp substitution, does not react with either 1,3-bis­(2,6-di-<i>iso</i>propylphenyl)­imidazol-2-ylidene (IPr) or 1,3-bis­(2,4,6-trimethyl­phenyl)­imidazol-2-ylidene (IMes), even under forcing conditions. In contrast, <i>in situ</i> generation of 1,3-bis­(phenyl)­imidazol-2-ylidene through deprotonation of the corresponding imidazolium tetrafluoroborate by KN­(SiMe₃)₂ in the presence of compound <b>4</b> provides facile ring opening of the NHC at room temperature to yield [HC­{(Me)­CNDipp}₂AlCH₂(N­(Ph)­CH)₂]. Although compound <b>5</b> also does not react with IPr, relaxation of the steric demands of the supporting β-diketiminate ligand to <i>N-</i>mesityl substitution enables analogous ring opening of IMes, with the formation of [HC­{(Me)­CNMes}₂AlCH₂(N­(Mes)­CH)₂] (<b>7</b>), when the reaction is heated to 80 °C. DFT calculations performed on model systems suggest that in comparison to the parent alane (AlH₃) the enhanced propensity of these systems to induce NHC ring cleavage is a consequence of the relative stability of the initially formed five- and four-coordinate adducts as well as the augmented hydridic character of the Al–H bonds within the β-diketiminate-supported molecules