Publications
99 results found
Higham J, Bull JA, 2020, Transient imine directing groups for the C–H functionalisation of aldehydes, ketones and amines: an update 2018-2020, Organic and Biomolecular Chemistry, Vol: 18, Pages: 7291-7315, ISSN: 1477-0520
The use of pre-installed directing groups has become a popular and powerful strategy to control site selectivity in transition metal catalysed C–H functionalisation reactions. However, the necessity for directing group installation and removal reduces the efficiency of a directed C–H functionalisation method. To overcome this limitation, taking inspiration from organocatalytic methodologies, the use of transient directing groups has arisen. These methods allow for a transient ligand to be used, potentially in catalytic quantities, without the need for discrete installation or removal steps, enabling the discovery of more efficient, and mechanistically intriguing, dual catalytic methods. This review summarises recent developments in this fast moving field covering >70 new methodologies, highlighting new directing group designs and advances in mechanistic understanding. It covers progress since 2018, providing an update to our previous review of the field.
Green SP, Wheelhouse KM, Payne AD, et al., 2020, On the Use of Differential Scanning Calorimetry for Thermal Hazard Assessment of New Chemistry: Avoiding Explosive Mistakes, Angewandte Chemie International Edition, Vol: 59, Pages: 15798-15802, ISSN: 1433-7851
<jats:title>Abstract</jats:title><jats:p>Differential scanning calorimetry (DSC) is increasingly used as evidence to support a favourable safety profile of novel chemistry, or to highlight the need for caution. DSC enables preliminary assessment of the thermal hazards of a potentially energetic compound. However, unlike other standard characterisation methods, which have well defined formats for reporting data, the current reporting of DSC results for thermal hazard assessment has shown concerning trends. Around half of all results in 2019 did not include experimental details required to replicate the procedure. Furthermore, analysis for thermal hazard assessment is often only conducted in unsealed crucibles, which could lead to misleading results and dangerously incorrect conclusions. We highlight the specific issues with DSC analysis of hazardous compounds currently in the organic chemistry literature and provide simple “best practice” guidelines which will give chemists confidence in reported DSC results and the conclusions drawn from them.</jats:p>
Dubois MAJ, Smith MA, White AJP, et al., 2020, Short Synthesis of Oxetane and Azetidine 3-Aryl-3-carboxylic Acid Derivatives by Selective Furan Oxidative Cleavage, Organic Letters, Vol: 22, Pages: 5279-5283, ISSN: 1523-7060
Coleman JA, Navratna V, Antermite D, et al., 2020, Chemical and structural investigation of the paroxetine-human serotonin transporter complex, eLife, Vol: 9, ISSN: 2050-084X
Antidepressants target the serotonin transporter (SERT) by inhibiting serotonin reuptake. Structural and biochemical studies aiming to understand binding of small-molecules to conformationally dynamic transporters like SERT often require thermostabilizing mutations and antibodies to stabilize a specific conformation, leading to questions about relationships of these structures to the bonafide conformation and inhibitor binding poses of wild-type transporter. To address these concerns, we determined the structures of ∆N72/∆C13 and ts2-inactive SERT bound to paroxetine analogues using single-particle cryo-EM and x-ray crystallography, respectively. We synthesized enantiopure analogues of paroxetine containing either bromine or iodine instead of fluorine. We exploited the anomalous scattering of bromine and iodine to define the pose of these inhibitors and investigated inhibitor binding to Asn177 mutants of ts2-active SERT. These studies provide mutually consistent insights into how paroxetine and its analogues bind to the central substrate-binding site of SERT, stabilize the outward-open conformation, and inhibit serotonin transport.
Tota A, Carlucci C, Pisano L, et al., 2020, Synthesis of glycosyl sulfoximines by a highly chemo- and stereoselective NH- and O-transfer to thioglycosides, Organic & Biomolecular Chemistry, Vol: 18, Pages: 3893-3897, ISSN: 1477-0520
<p>The first highly stereoselective sulfoximine formation directly from sulfides is achieved in the preparation of unprecedented glycosyl sulfoximines. X-ray analysis and a computational model establish the configuration at sulfur.</p>
Higham J, Bull JA, 2020, Copper catalysed oxidative α-sulfonylation of branched aldehydes using the acid enhanced reactivity of manganese(IV) oxide, Chemical Communications, Vol: 56, Pages: 4587-4590, ISSN: 1359-7345
The oxidative coupling of secondary aldehydes and sulfinate salts is achieved using copper catalysis to form a-sulfonyl aldehydes. The use of an acidic co-solvent is important to adjust the oxidation potential of MnO2 as oxidant. A broad range of sulfonylated aldehydes is prepared, and their further functionalisation is demonstrated. A dual ionic/radical pathway mechanism is proposed.
St John-Campbell S, White AJP, Bull JA, 2020, Methylene C(sp<sup>3</sup>)–H β,β′-Diarylation of Cyclohexanecarbaldehydes Promoted by a Transient Directing Group and Pyridone Ligand, Organic Letters, Vol: 22, Pages: 1807-1812, ISSN: 1523-7060
Green S, Wheelhouse K, Payne A, et al., 2020, Thermal stability and explosive hazard assessment of diazo compounds and diazo transfer reagents, Organic Process Research and Development, Vol: 24, Pages: 67-84, ISSN: 1083-6160
Despite their wide use in academia as metal-carbene precursors, diazo compounds are often avoided in industry owing to concerns over their instability, exothermic decomposition and potential explosive behaviour. The stability of sulfonyl azides and other diazo-transfer reagents is relatively well understood, but there is little reliable data available for diazo compounds. This work firstly collates available sensitivity and thermal analysis data for diazo-transfer reagents and diazo compounds to act as an accessible reference resource. Thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and accelerating rate calorimetry (ARC) data for the model donor/acceptor diazo compound ethyl (phenyl)diazoacetate is presented. We also present a rigorous DSC dataset with 43 other diazo compounds, enabling direct comparison to other energetic materials to provide a clear reference work to the academic and industrial chemistry communities. Interestingly, there is a wide range of onset temperatures (Tonset) for this series of compounds which varied between 75 and 160 °C. The thermal stability variation depends on the electronic effect of substituents and the amount of charge delocalisation. A statistical model is demonstrated to predict the thermal stability of differently substituted phenyl diazoacetates. A maximum recommended process temperature (TD24) to avoid decomposition is estimated for selected diazo compounds. Average enthalpy of decomposition (∆HD) for diazo compounds without other energetic functional groups is −102 kJ mol−1. Several diazo transfer reagents are analyzed using the same DSC protocol and found to have higher thermal stability, which is in general agreement with reported values. For sulfonyl azide reagents an average ∆HD of −201 kJ mol−1 is observed. High quality thermal data from ARC experiments shows the initiation of decomposition for ethyl (phenyl)diazoacetate to be 60 °C , compared to 100 °C for t
Brown P, Tan A-C, El-Esawi MA, et al., 2019, Large expert-curated database for benchmarking document similarity detection in biomedical literature search, Database: the journal of biological databases and curation, Vol: 2019, Pages: 1-66, ISSN: 1758-0463
Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency–Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.
Briggs EL, Tota A, Colella M, et al., 2019, Synthesis of Sulfonimidamides from Sulfenamides via an Alkoxy-amino-λ<SUP>6</SUP>-sulfanenitrile Intermediate, ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, Vol: 58, Pages: 14303-14310, ISSN: 1433-7851
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- Citations: 53
Croft RA, Dubois MAJ, Boddy AJ, et al., 2019, Catalytic Friedel-Crafts Reactions on Saturated Heterocycles and Small Rings for sp<sup>3</sup>-sp<sup>2</sup> Coupling of Medicinally Relevant Fragments, European Journal of Organic Chemistry, Vol: 2019, Pages: 5385-5395, ISSN: 1434-193X
gem-Diarylheterocycles display a wide range of biological activity. Here we present a systematic study into the formation of 4- to 6-membered O- and N-heterocycles and cyclobutanes bearing the diaryl motif through a catalytic Friedel–Crafts reaction from the corresponding benzylic alcohols. 3,3-Diaryltetrahydrofurans, 4,4-diaryltetrahydropyrans, 3,3-diarylpyrrolidines, 4,4-diaryl-piperidines, as well as diarylcyclobutanes are examined, with results for 3,3-diaryloxetanes and 3,3-diarylazetidines presented for comparison. Three catalytic systems are investigated for each substrate [Ca(II), Li(I) and Fe(III)], across preinstalled aromatic groups of differing electronic character. In most cases examined, the diaryl product is obtained directly from the alcohol with good yields using the most appropriate catalyst system. In the absence of a nucleophile, the olefins from the 5- and 6-membered substrates by elimination of water are obtained under the same reaction conditions.
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- Citations: 13
Antermite D, Bull JA, 2019, Transition Metal-Catalyzed Directed C(sp<SUP>3</SUP>)-H Functionalization of Saturated Heterocycles, SYNTHESIS-STUTTGART, Vol: 51, Pages: 3171-3204, ISSN: 0039-7881
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- Citations: 39
St John-Campbell S, Bull JA, 2019, Base Metal Catalysis in Directed C(sp<sup>3</sup>)−H Functionalisation, Advanced Synthesis and Catalysis, Vol: 361, Pages: 3662-3682, ISSN: 1615-4150
Directed C(sp3)−H functionalisation has made enormous progress in recent years, but has largely been restricted to catalysis using noble metals, particularly palladium. However, since 2013, there have been prominent advances that exploit the reactivity of abundant first row transition metals for a multitude of new bond formations. The use of base metal catalysis for C−H functionalisation can provide huge advantages in terms of cost and sustainability compared to methods using noble metals. This review covers all examples, to the end 2018, of auxiliary-assisted, base metal-catalysed C(sp3)−H functionalisation reactions. Successful examples are reported for Fe, Co, Ni and Cu catalysis with monodentate or bidentate directing groups for C−N, C−O, C−S and C−C bond forming reactions. This review aims to highlight the current state of this field and potential for expansion and so scope and limitations are highlighted. Notably, examples to date have required sterically activated α-disubstituted substrates, particularly propanamide derivatives with bidentate directing groups, such as 8-aminoquinoline amides. Monodentate quinoline and thioamide directing groups have also been used with Co catalysis for C−N and C−C bond formations. Mechanistic details are provided to outline the nature of the proposed organometallic intermediates and potential reaction pathways. We hope this review will stimulate further developments in this growing and important field. (Figure presented.).
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- Citations: 21
St John-Campbell S, Bull JA, 2019, Intramolecular palladium(ii)/(iv) catalysed C(sp3)-H arylation of tertiary aldehydes using a transient imine directing group., Chem Commun (Camb), Vol: 55, Pages: 9172-9175
Palladium catalysed β-C(sp3)-H activation of tertiary aldehydes using a transient imine directing group enables intramolecular arylation to form substituted indane-aldehydes. A simple amine bearing a methyl ether (2-methoxyethan-1-amine) is the optimal TDG to promote C-H activation and reaction with an unactivated proximal C-Br bond. Substituent effects are studied in the preparation of various derivatives. Preliminary mechanistic studies identify a reversible C-H activation, product inhibition and suggest that oxidative addition is the turnover limiting step.
Dubois MAJ, Lazaridou A, Choi C, et al., 2019, Synthesis of 3-Aryl-3-Sulfanyl Azetidines by Iron-Catalyzed Thiol Alkylation with N-Cbz Azetidinols, Journal of Organic Chemistry, Vol: 84, Pages: 5943-5956, ISSN: 0022-3263
New small-ring derivatives can provide valuable motifs in new chemical space for drug design. 3-Aryl-3-sulfanyl azetidines are synthesized directly from azetidine-3-ols in excellent yield by a mild Fe-catalyzed thiol alkylation. A broad range of thiols and azetidinols bearing electron-donating aromatics are successful, proceeding via an azetidine carbocation. The N-carboxybenzyl group is a requirement for good reactivity and enables the NH-azetidine to be revealed. Further reactions of the azetidine sulfides demonstrate their potential for incorporation in drug discovery programs.
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- Citations: 16
Green SP, Payne AD, Wheelhouse KM, et al., 2019, Diazo-Transfer Reagent 2-Azido-4,6-dimethoxy-1,3,5-triazine Displays Highly Exothermic Decomposition Comparable to Tosyl Azide, JOURNAL OF ORGANIC CHEMISTRY, Vol: 84, Pages: 5893-5898, ISSN: 0022-3263
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- Citations: 9
Boddy AJ, Cordier C, Goldberg K, et al., 2019, Acid-mediated ring-expansion of 2,2-disubstituted azetidine carbamates to 6,6-disubstituted 1,3-oxazinan-2-ones, Organic Letters, Vol: 21, Pages: 1818-1822, ISSN: 1523-7052
The ring expansion of 2-ester-2-aryl-azetidine carbamates can be achieved using Brønsted acids to form 6,6-disubstituted 1,3-oxazinan-2-ones. The reaction is rapid at room temperature with Boc or Cbz derivatives, and proceeds with excellent yield (up to 96%) and broad substrate scope. Derivatives of drug compounds and natural products are incorporated. The combina-tion of this ring expansion in a 3-step N–H insertion/cyclization/expansion (NICE) sequence is applied to directly access medicinally relevant scaffolds from acyclic precursors.
Boultwood T, Bull J, 2019, Synthesis of selenoaziridines: a study on stereochemical outcomes of the reaction of aziridine radicals and anions generated from iodoaziridines, ACS Omega, Vol: 4, Pages: 870-879, ISSN: 2470-1343
The synthesis of a new functional group in the form of selenyl-substituted aziridines is described. Selenoaziridines are stereoselectively prepared by functionalization of intact aziridine precursors involving radical and anionic intermediates. Radicals are generated from cis-N-Ts iodoaziridines by activation of the C–I bond using alkoxides as a source of single electrons. These form predominantly trans-substituted seleno-aziridines dependent on the size of the diselenide. cis-Aziridinyllithiums generated by Li–I exchange also react with diselenides stereospecifically to form a range of cis-selenoaziridines. Proposals for the stereochemical outcome are presented.
Boddy AJ, Affron DP, Cordier CJ, et al., 2019, Rapid Assembly of Saturated Nitrogen Heterocycles in One-Pot: Diazo-Heterocycle "Stitching" by N-H Insertion and Cyclization, ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, Vol: 58, Pages: 1458-1462, ISSN: 1433-7851
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- Citations: 45
Denis C, Dubois MAJ, Voisin-Chiret AS, et al., 2019, Synthesis of 3,3-Diarylazetidines by Calcium(II)-Catalyzed Friedel-Crafts Reaction of Azetidinols with Unexpected Cbz Enhanced Reactivity, ORGANIC LETTERS, Vol: 21, Pages: 300-304, ISSN: 1523-7060
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- Citations: 17
St John-Campbell S, Ou AK, Bull JA, 2018, Palladium-Catalyzed C(sp<SUP>3</SUP>)-H Arylation of Primary Amines Using a Catalytic Alkyl Acetal to Form a Transient Directing Group, CHEMISTRY-A EUROPEAN JOURNAL, Vol: 24, Pages: 17838-17843, ISSN: 0947-6539
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- Citations: 42
Croft RA, Bull J, 2018, Oxetanes and Oxetan-3-ones (37.3), Science of Synthesis Knowledge Updates, Vol: 4, Pages: 379-434
Croft RA, Mousseau JJ, Choi C, et al., 2018, Oxetane ethers are formed reversibly in the lithium-catalyzed Friedel-Crafts alkylation of phenols with oxetanols: synthesis of dihydrobenzofurans, diaryloxetanes, and oxetane ethers, Tetrahedron, Vol: 74, Pages: 5427-5435, ISSN: 0040-4020
Studies on the mechanism and intermediate products in the Friedel–Crafts reaction between oxetanols and phenols are presented. Formation of O-alkylated intermediates is identified using 1H NMR spectroscopy, in a reversible formation of the kinetic oxetane ether products. An interesting relationship between the electronic nature of the nucleophile and the degree of O-alkylation is uncovered. For phenols substituted with an electron withdrawing group such as CN, oxetane ethers are the only products isolated regardless of reaction time. Increasing the electron rich nature of the phenol leads to an increased proportion of the thermodynamic C-alkylated Friedel–Crafts products after just one hour and as the sole product/s after extended reaction times. These studies have enabled a more complete catalytic cycle to be proposed. Using the same lithium catalyst and carefully selected reaction times, several examples of oxetane ethers are successfully isolated as novel bioisosteres for ester groups.
St John-Campbell S, Bull JA, 2018, Transient imines as ‘next generation’ directing groups for the catalytic functionalisation of C–H bonds in a single operation, Organic and Biomolecular Chemistry, Vol: 16, Pages: 4582-4595, ISSN: 1472-7781
C–H Functionalisation promises a paradigm shift in synthetic planning. However, the additional steps often required to install and remove directing groups currently detracts from the efficiency. The strategy of reversible installation of a directing group via an imine linkage has recently emerged, with the imine formed and hydrolysed in situ. Such transient directing groups can promote transition metal catalysed functionalisation of unactivated C–H bonds of aldehydes, ketones and amines. This approach removes additional steps usually required for covalent directing groups and can use catalytic quantities of the imine forming component. This review updates the rapidly developing field of transient directing groups for C–H functionalisation on sp2 and sp3 carbon centres, to form new C–C and C–X bonds. We focus on the structures of the transient directing groups as mono or bidentate coordinating groups for various metal catalysts.
Antermite D, Affron DP, Bull JA, 2018, Regio- and Stereoselective Palladium-Catalyzed C(sp<SUP>3</SUP>)-H Arylation of Pyrrolidines and Piperidines with C(3) Directing Groups, ORGANIC LETTERS, Vol: 20, Pages: 3948-3952, ISSN: 1523-7060
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- Citations: 42
Tota A, St John-Campbell S, Briggs E, et al., 2018, Highly chemoselective NH- and O-transfer to thiols using hypervalent iodine reagents: synthesis of sulfonimidates and sulfonamides, Organic Letters, Vol: 20, Pages: 2599-2602, ISSN: 1523-7052
Aryl thiols can be selectively converted to sulfonimidates or sulfonamides with 3 new S–X connections being made selectively in one-pot. Using hypervalent iodine reagents in the presence of ammonium carbamate, NH- and O-groups are transferred under mild and practical conditions. Reducing the loading of ammonium carbamate changed the product distribution, converting the sulfonimidate to the sulfonamide. Studies into the possible intermediate species are presented, suggesting that multiple pathways may be possible via sulfinate esters, or related intermediates, with each species forming the same products.
Vysniauskas A, Lopez Duarte I, Thompson AJ, et al., 2018, Surface functionalisation with viscosity-sensitive BODIPY molecular rotor, Methods and Applications in Fluorescence, Vol: 6, ISSN: 2050-6120
Surface functionalisation with viscosity sensitive dyes termed ‘molecular rotors’ can potentially open up new opportunities in sensing, for example for non-invasive biological viscosity imaging, in studying the effect of shear stress on lipid membranes and in cells, and in imaging contacts between surfaces upon applied pressure. We have functionalised microscope slides with BODIPY-based molecular rotor capable of viscosity sensing via its fluorescence lifetime. We have optimised functionalisation conditions and prepared the slides with the BODIPY rotor attached directly to the surface of glass slides and through polymer linkers of 5 kDa and 40 kDa in mass. The slides were characterised for their sensitivity to viscosity, and used to measure viscosity of supported lipid bilayers during photooxidation, and of giant unilamellar vesicles lying on the surface of the slide. We conclude that our functionalised slides show promise for a variety of viscosity sensing applications.
Croft RA, Mousseau JJ, Choi C, et al., 2018, Lithium-Catalyzed Thiol Alkylation with Tertiary and Secondary Alcohols: Synthesis of 3-Sulfanyl-Oxetanes as Bioisosteres, CHEMISTRY-A EUROPEAN JOURNAL, Vol: 24, Pages: 818-821, ISSN: 0947-6539
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- Citations: 23
Bull JA, Degennaro L, Luisi R, 2017, Straightforward Strategies for the Preparation of NH-Sulfox-imines: A Serendipitous Story, Synlett, Vol: 28, Pages: 2525-2538, ISSN: 0936-5214
Sulfoximines are emerging as valuable new isosteres for use in medicinal chemistry, with the potential to modulate physicochemical properties. Recent developments in synthetic strategies have made the unprotected 'free' NH-sulfoximine group more readily available, facilitating further study. This account reviews approaches to NH-sulfoximines, with a focus on our contribution to the field. Starting from the development of catalytic strategies involving transition metals, more sustainable metal-free processes have been discovered. In particular, the use of hypervalent iodine reagents to mediate NH-transfer to sulfoxides is described, along with an assessment of the substrate scope. Furthermore, a one-pot strategy to convert sulfides directly into NH-sulfoximines is discussed, with N- and O-transfer occurring under the reaction conditions. Mechanistic evidence for the new procedures is included as well as relevant synthetic applications that further exemplify the potential of these approaches. 1 Introduction 2 Strategies to Form NH-Sulfoximines Involving Transition-Metal Catalysts 3 Metal-Free Strategies to Prepare NH-Sulfoximines 4 Mechanistic Evidence for the Direct Synthesis of NH-Sulfoximines from Sulfoxides and Sulfides 5 Further Applications 6 Conclusion.
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Chawner SJ, Cases-Thomas MJ, Bull JA, 2017, Divergent Synthesis of Cyclopropane-Containing Lead-like Compounds, Fragments and Building Blocks via a Cobalt Catalyzed Cyclopropanation of Phenyl Vinyl Sulfide, European Journal of Organic Chemistry, Vol: 2017, Pages: 5015-5024, ISSN: 1434-193X
Cyclopropanes provide important design elements in medicinal chemistry and are widely present in drug compounds. Here we describe a strategy and extensive synthetic studies for the preparation of a diverse collection of cyclopropane-containing fragments, lead-like compounds and building blocks exploiting a single precursor. The bifunctional cyclopropane (E/Z)-ethyl 2-(phenylsulfanyl)-cyclopropane-1-carboxylate was designed to allow derivatization through the ester and sulfide functionalities to topologically varied compounds designed to fit in desirable chemical space for drug discovery. A cobalt-catalyzed cyclopropanation of phenyl vinyl sulfide affords these scaffolds on multigram scale. Divergent, orthogonal derivatization is achieved through hydrolysis, reduction, amidation and oxidation reactions as well as sulfoxide–magnesium exchange/functionalization. The cyclopropyl Grignard reagent formed from sulfoxide exchange is stable at 0 C for >2 h, enabling trapping with various electrophiles and Pd-catalyzed Negishi cross-coupling reactions. The library prepared, as well as a further virtual elaboration, is analyzed against parameters of lipophilicity (ALogP), MW, and molecular shape using the LLAMA (Lead-Likeness and Molecular Analysis) software, to illustrate the success in generating lead-like compounds and fragments.
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