Combined Experimental and Computational Investigations of Rhodium‐Catalysed CH Functionalisation of Pyrazoles with Alkenes

Detailed experimental and computational studies have been carried out on the oxidative coupling of the alkenes C₂H₃Y (Y=CO₂Me ( a ), Ph ( b ), C(O)Me ( c )) with 3‐aryl‐5‐R‐pyrazoles (R=Me ( 1 a ), Ph ( 1 b ), CF₃ ( 1 c )) using a [Rh(MeCN)₃Cp*][PF₆]₂/Cu(OAc)₂ ? H₂O catalyst system. In the reaction of methyl acrylate with 1 a , up to five products ( 2 aa – 6 aa ) were formed, including the trans monovinyl product, either complexed within a novel Cu^I dimer ( 2 aa ) or as the free species ( 3 aa ), and a divinyl species ( 6 aa ); both 3 aa and 6 aa underwent cyclisation by an aza‐Michael reaction to give fused heterocycles 4 aa and 5 aa , respectively. With styrene, only trans mono‐ and divinylation products were observed, whereas with methyl vinyl ketone, a stronger Michael acceptor, only cyclised oxidative coupling products were formed. Density functional theory calculations were performed to characterise the different migratory insertion and β‐H transfer steps implicated in the reactions of 1 a with methyl acrylate and styrene. The calculations showed a clear kinetic preference for 2,1‐insertion and the formation of trans vinyl products, consistent with the experimental results.     

Synthesis,Characterisation and Reactivity of Copper(I) Amide Complexes and Studies on Their Role in the Modified Ullmann Amination Reaction

A series of copper(I) alkylamide complexes have been synthesised; copper(I) dicyclohexylamide ( 1 ), copper(I) 2,2,6,6‐tetramethylpiperidide ( 2 ), copper(I) pyrrolidide ( 3 ), copper(I) piperidide ( 4 ), and copper(I) benzylamide ( 5 ). Their solid‐state structures and structures in [D₆]benzene solution are characterised, with the aggregation state in solution determined by a combination of DOSY NMR spectroscopy and DFT calculations. Complexes 1 , 2 and 4 are shown to exist as tetramers in the solid state by X‐ray crystallography. In [D₆]benzene solution, complexes 1 , 2 and 5 were found by using ¹H DOSY NMR to exist in rapid equilibrium between aggregates with average aggregation numbers of 2.5, 2.4 and 3.3, respectively, at 0.05 M concentration. Conversely, distinct trimeric, tetrameric and pentameric forms of 3 and 4 were distinguishable by one‐dimensional ¹H and ¹H DOSY NMR spectroscopy. Complexes 3 – 5 are found to react stoichiometrically with iodobenzene, in the presence or absence of 1,10‐phenanthroline as an ancillary ligand, to give arylamine products indicative of their role as potential intermediates in the modified Ullmann reaction. The role of phenanthroline has also been explored both in the stoichiometric reaction and in the catalytic Ullmann protocol.     

Divergent C?H Insertion–Cyclization Cascades of N‐Allyl Ynamides

Gold carbene reactivity patterns were accessed by ynamide insertion into a C(sp³) H bond. A substantial increase in molecular complexity occurred through the cascade polycyclization of N‐allyl ynamides to form fused nitrogen‐heterocycle scaffolds. Exquisite selectivity was observed despite several competing pathways in an efficient gold‐catalyzed synthesis of densely functionalized C(sp³)‐rich polycycles and a copper‐catalyzed synthesis of fused pyridine derivatives. The respective gold–keteniminium and ketenimine activation pathways have been explored through a structure–reactivity study, and isotopic labeling identified turnover‐limiting C H bond‐cleavage in both processes.     

A Novel Dual Drug Approach That Combines Ivermectin and Dihydromyricetin (DHM) to Reduce Alcohol Drinking and Preference in Mice

Alcohol use disorder (AUD) affects over 18 million people in the US. Unfortunately, pharmacotherapies available for AUD have limited clinical success and are under prescribed. Previously, we established that avermectin compounds (ivermectin [IVM] and moxidectin) reduce alcohol (ethanol/EtOH) consumption in mice, but these effects are limited by P-glycoprotein (Pgp/ABCB1) efflux. The current study tested the hypothesis that dihydromyricetin (DHM), a natural product suggested to inhibit Pgp, will enhance IVM potency as measured by changes in EtOH consumption. Using a within-subjects study design and two-bottle choice study, we tested the combination of DHM (10 mg/kg; i.p.) and IVM (0.5–2.5 mg/kg; i.p.) on EtOH intake and preference in male and female C57BL/6J mice. We also conducted molecular modeling studies of DHM with the nucleotide-binding domain of human Pgp that identified key binding residues associated with Pgp inhibition. We found that DHM increased the potency of IVM in reducing EtOH consumption, resulting in significant effects at the 1.0 mg/kg dose. This combination supports our hypothesis that inhibiting Pgp improves the potency of IVM in reducing EtOH consumption. Collectively, we demonstrate the feasibility of this novel combinatorial approach in reducing EtOH consumption and illustrate the utility of DHM in a novel combinatorial approach.     

Marfan syndrome in Europe

OBJECTIVES: Marfan syndrome (MFS) is a relatively frequent systemic connective tissue disorder with an important physical morbidity and mortality. The influences of MFS on physical problems, perception of severity, and impact on the quality of life and psychosocial well-being have been studied only limitedly. The aim of this study was to assess the association between the severity derived from the reported symptoms and subjectively experienced severity of MFS (expressed as a global judgment), with special emphasis regarding impact on relationships and pregnancies, psychosocial adjustment, and differences between the seven European countries. METHODS: A questionnaire designed specifically for this study and translated in each of the native languages was sent to 2,080 members of one of the patient support groups in Belgium, Denmark, France, Germany, The Netherlands, Switzerland, and the United Kingdom. 857 MFS patients of 13 years and older completed the questionnaire and were included in the data analysis. RESULTS: Physical impairments were scored by perception of severity of physical symptoms by the patients (physical severity perception score) and by their perception of the influence of MFS on their life (subjective severity score). Main discrepancy between physical severity perception and subjective severity score was the higher percentage of patients scoring in physical severity perception as severe (53.5%) compared to subjectively severe (26.5%). 61% of those who scored on the physical severity score as severely affected were designated as being mildly-moderately affected on subjective scoring. Both severity scores increased significantly with age. Two hundred-twenty women have carried 430 pregnancies (1.95 pregnancies/woman), with cardiovascular complications in 1.6%. Prenatal studies for MFS were rejected by 7.6% of MFS patients of 25 years and older, 33.6% were undecided, and 48.5% favored prenatal diagnosis for MFS if available. A positive general self-image was reported by 91.5% of patients. However, more than 90% stated that MFS had a negative influence on their sexual relationships, which they ascribed to negative perception of their body image. CONCLUSIONS: MFS has significant impact on daily life activities, but the majority of patients come to terms with their condition. Acceptance is mainly determined by subjective severity, and less by physical symptoms as reported by the patients themselves. It is important to stimulate a positive attitude towards MFS.     

Eigenfunction expansions for singular Schrodinger operators

We extend Ikebe's theory of eigenfunctions to a class of Schrodinger operators H = - + V on L ² (IR³), where the potential V is replaced by a measure which need not be absolutely continuous with respect to Lebesgue measure. Applications include the proof of the existence and completeness of the wave operators for a free particle which is partly reflected and partly transmitted by a compact 2-dimensional surface.     

Problems of non-uniqueness when interpreting the effect of fluid inertia on the complex viscosity function

A theoretical investigation is carried out into the interpretation of the effect of fluid inertia on the complex viscosity function as measured on a controlled stress rheometer. The problem of non-unique solutions to the governing equations is considered for the parallel plate geometry. The locations of these solutions are investigated by considering the critical points of the complex mapping associated with the linear viscoelastic equations of motion. It is shown that these critical points play an important role in determining where convergence problems are likely to occur when applying numerical methods of solution to the governing equations. Analytical approximations based on a series expansion about a critical point are developed as an alternative approach to a numerical solution in the neighbourhood of a critical point. In order to verify the theoretical predictions a numerical simulation of the behaviour of a single element Maxwell fluid on a controlled stress rheometer is carried out for a parallel plate geometry. Received: 27 July 1998 Accepted: 9 April 1999