Bismuth(V)-Mediated C–H Arylation of Phenols and Naphthols

We recently reported a general and practical strategy for the Bi(V)-mediated C–H arylation of phenols and naphthols. Our telescoped protocol proceeds via transmetallation from readily available arylboronic acids to a stable Bi(III) precursor, oxidation to a reactive Bi(V) intermediate, and subsequent ortho-selective phenol arylation. The process exhibits broad scope with respect to both components and tolerates functionality that is incompatible with conventional cross-coupling methods. Preliminary investigations provide insight into the mechanism of each key reaction step

Global 30–240 keV proton precipitation in the 17–18 April 2002 geomagnetic storms: 3. Impact on the ionosphere and thermosphere

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94894/1/jgra18704.pd

ICAR: endoscopic skull‐base surgery

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The PREDICTS database: a global database of how local terrestrial biodiversity responds to human impacts

Biodiversity continues to decline in the face of increasing anthropogenic pressures such as habitat destruction, exploitation, pollution and introduction of alien species. Existing global databases of species’ threat status or population time series are dominated by charismatic species. The collation of datasets with broad taxonomic and biogeographic extents, and that support computation of a range of biodiversity indicators, is necessary to enable better understanding of historical declines and to project – and avert – future declines. We describe and assess a new database of more than 1.6 million samples from 78 countries representing over 28,000 species, collated from existing spatial comparisons of local-scale biodiversity exposed to different intensities and types of anthropogenic pressures, from terrestrial sites around the world. The database contains measurements taken in 208 (of 814) ecoregions, 13 (of 14) biomes, 25 (of 35) biodiversity hotspots and 16 (of 17) megadiverse countries. The database contains more than 1% of the total number of all species described, and more than 1% of the described species within many taxonomic groups – including flowering plants, gymnosperms, birds, mammals, reptiles, amphibians, beetles, lepidopterans and hymenopterans. The dataset, which is still being added to, is therefore already considerably larger and more representative than those used by previous quantitative models of biodiversity trends and responses. The database is being assembled as part of the PREDICTS project (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems – www.predicts.org.uk). We make site-level summary data available alongside this article. The full database will be publicly available in 2015

Bismuth(V) mediated meta-arylation

Despite offering many options for functionalisation, unattractive synthetic routes have left 2,4-cyclohexadienones relatively unexplored. Reported methods to make these substrates are marred by poor regio- and chemoselectivity, toxic reagents, and inefficient processes. The work detailed in this thesis aims to remove barriers to implementation by presenting a synthetic method for their preparation that is selective and predictive, uses benign reagents, and offers excellent yields. To showcase their applicability in synthetic organic chemistry, they will be used as intermediates in the synthesis of meta-substituted phenols and anilines. A three-step process was developed to access the elusive meta-position of phenols and is described in Chapter 2. Here, a straightforward procedure was developed to access a 6,6-disubstituted 2,4-cyclohexadienone from a single, universal bismuth precursor and a phenol. Following the isolation and full characterisation of the 2,4-cyclohexadienone, a Lewis acid mediated 1,2-aryl migration was optimised to provide the meta-arylated phenol. An extensive substrate scope showed that this methodology is applicable to phenols and arylboronic acids bearing a range of electronic descriptors and is permitting of highly functionalised handles poised for subsequent diversification chemistry. In addition to this, the selectivity of the arylation step was assessed and found to be influenced more by electronics than sterics, occurring ipso to the most electron rich position. A comprehensive mechanistic study was undertaken on the 1,2-aryl migration step: passing through a phenonium ion intermediate. Using this chemistry to access meta-substituted phenols, analogues of mexiletine, lidocaine, and dimethachlor were synthesised in excellent yield to showcase how this chemistry can be applied to the targeted synthesis of important biologically active molecules. Chapter 3 builds on this work, developing a route to meta-arylated anilines. Using Bi(V) mediated synthesis of 2,4-cyclohexadienones developed in Chapter 2, a deoxyamination reaction step was implemented to deliver a 2,4-cyclohexadienimine. This was found to be competent in a similar 1,2-aryl migration step, yielding the meta-arylated aniline. This method not only describes a means to access these contra-electronic products, but also a formal phenol to aniline conversion – a highly sought-after transformation

Bismuth(V) mediated meta-arylation

Despite offering many options for functionalisation, unattractive synthetic routes have left 2,4-cyclohexadienones relatively unexplored. Reported methods to make these substrates are marred by poor regio- and chemoselectivity, toxic reagents, and inefficient processes. The work detailed in this thesis aims to remove barriers to implementation by presenting a synthetic method for their preparation that is selective and predictive, uses benign reagents, and offers excellent yields. To showcase their applicability in synthetic organic chemistry, they will be used as intermediates in the synthesis of meta-substituted phenols and anilines. A three-step process was developed to access the elusive meta-position of phenols and is described in Chapter 2. Here, a straightforward procedure was developed to access a 6,6-disubstituted 2,4-cyclohexadienone from a single, universal bismuth precursor and a phenol. Following the isolation and full characterisation of the 2,4-cyclohexadienone, a Lewis acid mediated 1,2-aryl migration was optimised to provide the meta-arylated phenol. An extensive substrate scope showed that this methodology is applicable to phenols and arylboronic acids bearing a range of electronic descriptors and is permitting of highly functionalised handles poised for subsequent diversification chemistry. In addition to this, the selectivity of the arylation step was assessed and found to be influenced more by electronics than sterics, occurring ipso to the most electron rich position. A comprehensive mechanistic study was undertaken on the 1,2-aryl migration step: passing through a phenonium ion intermediate. Using this chemistry to access meta-substituted phenols, analogues of mexiletine, lidocaine, and dimethachlor were synthesised in excellent yield to showcase how this chemistry can be applied to the targeted synthesis of important biologically active molecules. Chapter 3 builds on this work, developing a route to meta-arylated anilines. Using Bi(V) mediated synthesis of 2,4-cyclohexadienones developed in Chapter 2, a deoxyamination reaction step was implemented to deliver a 2,4-cyclohexadienimine. This was found to be competent in a similar 1,2-aryl migration step, yielding the meta-arylated aniline. This method not only describes a means to access these contra-electronic products, but also a formal phenol to aniline conversion – a highly sought-after transformation

meta-Selective C–H arylation of phenols via regiodiversion of electrophilic aromatic substitution

Electrophilic aromatic substitution is among the most widely used mechanistic manifolds in organic chemistry. Access to certain substitution patterns is, however, precluded by intrinsic and immutable substituent effects that ultimately restrict the diversity of the benzenoid chemical space. Here we demonstrate that the established regioselectivity of electrophilic aromatic substitution can be overcome simply by diverting the key σ-complex intermediate towards otherwise inaccessible substitution products. This ‘regiodiversion’ strategy is realized through the development of a general and concise method for the meta-selective C–H arylation of sterically congested phenols. Consisting of a Bi(V)-mediated electrophilic arylation and a subsequent aryl migration/rearomatization, our process is orthogonal to conventional C–H activation and cross-coupling approaches, and does not require prefunctionalization of the substrate. Mechanistically informed applications in synthesis showcase its utility as a versatile and enabling route to highly functionalized, contiguously substituted aromatic building blocks that defy synthesis via existing methods