Copper-Mediated N-Trifluoromethylation of O-Benzoylhydroxylamines.

The use of trifluoromethyl containing compounds is well established within medicinal chemistry, with a range of approved drugs containing C-CF3 and O-CF3 moieties. However, the utilisation of the N-CF3 functional group remains relatively unexplored. This may be attributed to the challenging synthesis of this unit, with many current methods employing harsh conditions or less accessible reagents. A robust methodology for the N-trifluoromethylation of secondary amines has been developed, which employs an umpolung strategy in the form of a copper-catalysed electrophilic amination. The method is operationally simple, uses mild, inexpensive reagents, and has been used to synthesise a range of novel, structurally complex N-CF3 containing compounds.

An Umpolung Approach to Acyclic 1,4-Dicarbonyl Amides via Photoredox-Generated Carbamoyl Radicals.

A method for the generation and reaction of carbamoyl radicals from oxamate salts, followed by reaction with electron-poor olefins, is described. The oxamate salt acts as a reductive quencher in the photoredox catalytic cycle, allowing mild and mass-efficient formation of 1,4-dicarbonyl products; a challenging transformation in the context of functionalized amide formation. Increased understanding has been obtained by the use of ab initio calculations, in support of experimental observations. Furthermore, steps have been taken towards an environmentally-friendly protocol, by utilizing sodium as a cheap and low mass counterion, and demonstrating successful reactions using a metal-free photocatalyst and a sustainable, non-toxic solvent system.

Recent advances in iridium(I) catalysis towards directed hydrogen isotope exchange.

The initial discovery and establishment of a family of novel iridium catalysts possessing N-heterocyclic carbene units alongside bulky phosphine ligands allowed selected substrates to be labelled using deuterium or tritium gas at desirably low catalyst loadings via an ortho-directed C-H insertion process. Such a method has broad applicability and offers distinct advantages within the pharmaceutical industry, directly facilitating the ability to carefully monitor a potential drug molecule's biological fate. Over the past decade since these initial protocols were divulged, many additional advances have been made in terms of catalyst design and substrate scope. This review describes the broadened array of new iridium catalysts and associated protocols for direct and selective C-H activation and hydrogen isotope insertion within a number of new chemical entities of direct relevance to the pharmaceutical industry.

Synthesis of [3 H] and [14 C]genipin.

[3 H]Genipin was synthesized in a single step by Ir(I) catalyzed hydrogen isotope exchange. Conditions for selective exchange of the sp2 CH bond ortho to the methyl ester functionality were developed through deuterium modeling studies through a catalyst screen. Optimized conditions so obtained were then utilized with tritium gas to generate [3 H]genipin at a specific activity of 18.5 Ci/mmol. Racemic [14 C]genipin was prepared in eight steps in overall 5.4% radiochemical yield from potassium [14 C]cyanide.

Design, synthesis and antibacterial properties of pyrimido[4,5-b]indol-8-amine inhibitors of DNA gyrase.

According to the World Health Organization (WHO), approximately 1.7 million deaths per year are caused by tuberculosis infections. Furthermore, it has been predicted that, by 2050, antibacterial resistance will be the cause of approximately 10 million deaths annually if the issue is not tackled. As a result, novel approaches to treating broad-spectrum bacterial infections are of vital importance. During the course of our wider efforts to discover unique methods of targeting multidrug-resistant (MDR) pathogens, we identified a novel series of amide-linked pyrimido[4,5-b]indol-8-amine inhibitors of bacterial type II topoisomerases. Compounds from the series were highly potent against gram-positive bacteria and mycobacteria, with excellent potency being retained against a panel of relevant Mycobacterium tuberculosis drug-resistant clinical isolates.

Deuterium- and Tritium-Labelled Compounds: Applications in the Life Sciences.

Hydrogen isotopes are unique tools for identifying and understanding biological and chemical processes. Hydrogen isotope labelling allows for the traceless and direct incorporation of an additional mass or radioactive tag into an organic molecule with almost no changes in its chemical structure, physical properties, or biological activity. Using deuterium-labelled isotopologues to study the unique mass-spectrometric patterns generated from mixtures of biologically relevant molecules drastically simplifies analysis. Such methods are now providing unprecedented levels of insight in a wide and continuously growing range of applications in the life sciences and beyond. Tritium (3 H), in particular, has seen an increase in utilization, especially in pharmaceutical drug discovery. The efforts and costs associated with the synthesis of labelled compounds are more than compensated for by the enhanced molecular sensitivity during analysis and the high reliability of the data obtained. In this Review, advances in the application of hydrogen isotopes in the life sciences are described.

C-H Functionalisation for Hydrogen Isotope Exchange.

The various applications of hydrogen isotopes (deuterium, D, and tritium, T) in the physical and life sciences demand a range of methods for their installation in an array of molecular architectures. In this Review, we describe recent advances in synthetic C-H functionalisation for hydrogen isotope exchange.

A Practical and General Amidation Method from Isocyanates Enabled by Flow Technology.

The addition of carbon nucleophiles to isocyanates represents a conceptually flexible and efficient approach to the preparation of amides. This general synthetic strategy has, however, been relatively underutilized owing to narrow substrate tolerance and the requirement for less favourable reaction conditions. Herein, we disclose a high-yielding, mass-efficient, and scalable method with appreciable functional group tolerance for the formation of amides by reaction of Grignard reagents with isocyanates. Through the application of flow chemistry and the use of substoichiometric amounts of CuBr2 , this process has been developed to encompass a broad range of substrates, including reactants found to be incompatible with previously published procedures.

Iridium-Catalyzed Formyl-Selective Deuteration of Aldehydes.

We report the first direct catalytic method for formyl-selective deuterium labeling of aromatic aldehydes under mild conditions, using an iridium-based catalyst designed to favor formyl over aromatic C-H activation. A good range of aromatic aldehydes is selectively labeled, and a one-pot labeling/olefination method is also described. Computational studies support kinetic product control over competing aromatic labeling and decarbonylation pathways.

Iridium(I) N-Heterocyclic Carbene (NHC)/Phosphine Catalysts for Mild and Chemoselective Hydrogenation Processes.

The directed chemoselective hydrogenation of olefins has been established by using iridium(I) catalysts, which feature a tuned NHC/phosphine ligand combination. This selective reduction process has been demonstrated in a wide array of solvents, including more environmentally acceptable media, also allowing further refinement of hydrogenation selectivity.

Hydrogen isotope exchange with highly active iridium(I) NHC/phosphine complexes: a comparative counterion study.

Herein, we present a range of substrates that undergo hydrogen isotope exchange with an iridium(I) N-heterocyclic carbene/phosphine complex bearing the less coordinating tetrakis[3,5-bis(trifluoromethyl)phenyl]borate counterion and compare these with labelling using the equivalent, more established hexafluorophosphate complex. The changes in reactivity and selectivity of these complexes in a series of solvents are examined. Copyright © 2016 John Wiley & Sons, Ltd.

Efficient methods for enol phosphate synthesis using carbon-centred magnesium bases.

Efficient conversion of ketones into kinetic enol phosphates under mild and accessible conditions has been realised using the developed methods with di-tert-butylmagnesium and bismesitylmagnesium. Optimisation of the quench protocol resulted in high yields of enol phosphates from a range of cyclohexanones and aryl methyl ketones, with tolerance of a range of additional functional units.

Iridium-Catalysed ortho-Directed Deuterium Labelling of Aromatic Esters--An Experimental and Theoretical Study on Directing Group Chemoselectivity.

Herein we report a combined experimental and theoretical study on the deuterium labelling of benzoate ester derivatives, utilizing our developed iridium N-heterocyclic carbene/phosphine catalysts. A range of benzoate esters were screened, including derivatives with electron-donating and -withdrawing groups in the para- position. The substrate scope, in terms of the alkoxy group, was studied and the nature of the catalyst counter-ion was shown to have a profound effect on the efficiency of isotope exchange. Finally, the observed chemoselectivity was rationalized by rate studies and theoretical calculations, and this insight was applied to the selective labelling of benzoate esters bearing a second directing group.

Discovery of novel irreversible inhibitors of interleukin (IL)-2-inducible tyrosine kinase (Itk) by targeting cysteine 442 in the ATP pocket.

IL-2-inducible tyrosine kinase (Itk) plays a key role in antigen receptor signaling in T cells and is considered an important target for anti-inflammatory drug discovery. In order to generate inhibitors with the necessary potency and selectivity, a compound that targeted cysteine 442 in the ATP binding pocket and with an envisaged irreversible mode of action was designed. We incorporated a high degree of molecular recognition and specific design features making the compound suitable for inhaled delivery. This study confirms the irreversible covalent binding of the inhibitor to the kinase by x-ray crystallography and enzymology while demonstrating potency, selectivity, and prolonged duration of action in in vitro biological assays. The biosynthetic turnover of the kinase was also examined as a critical factor when designing irreversible inhibitors for extended duration of action. The exemplified Itk inhibitor demonstrated inhibition of both TH1 and TH2 cytokines, was additive with fluticasone propionate, and inhibited cytokine release from human lung fragments. Finally, we describe an in vivo pharmacodynamic assay that allows rapid preclinical development without animal efficacy models.

Iridium(I)-catalyzed regioselective C-H activation and hydrogen-isotope exchange of non-aromatic unsaturated functionality.

Isotopic labelling is a key technology of increasing importance for the investigation of new CH activation and functionalization techniques, as well as in the construction of labelled molecules for use within both organic synthesis and drug discovery. Herein, we report for the first time selective iridium-catalyzed CH activation and hydrogen-isotope exchange at the ß-position of unsaturated organic compounds. The use of our highly active [Ir(cod)(IMes)(PPh3 )][PF6 ] (cod=1,5-cyclooctadiene) catalyst, under mild reaction conditions, allows the regioselective ß-activation and labelling of a range of α,ß-unsaturated compounds with differing steric and electronic properties. This new process delivers high levels of isotope incorporation over short reaction times by using low levels of catalyst loading.

Anion effects to deliver enhanced iridium catalysts for hydrogen isotope exchange processes.

Synthesis of a series of iridium(I) complexes of the type [(COD)Ir(IMes)(PPh3)]X (X = BF4, OTf, and BArF) has been established. Application of these species in mild hydrogen isotope exchange processes revealed more efficient catalysis and, further, a wider solvent scope when employing larger, more weakly coordinating counterions.

Influence of precursor solvent extraction on stable isotope signatures of methylamphetamine prepared from over-the-counter medicines using the Moscow and Hypophosphorous routes.

A number of methods of clandestine manufacture of methylamphetamine involve the extraction and subsequent reaction of pseudoephedrine hydrochloride with other essential chemicals. The precursor can be easily extracted from over-the-counter medication widely available in the UK and elsewhere. Essential chemicals such as iodine and red phosphorous are also readily available and can be extracted from iodine tinctures and matchboxes, respectively. This work reports the repetitive preparation of methylamphetamine using two popular routes (the Moscow and Hypophosphorous synthesis). The focus was on the extraction solvent used for isolation of the precursor chemical and any consequential isotopic variation which may arise in the final product. Six batches of methylamphetamine were prepared under precisely controlled conditions for each synthetic route and for each of three different precursor extraction solvents. Synthesis of the final product from laboratory grade precursor using the synthetic methods described was used as a template for comparison. The resultant IRMS data from all 48 prepared samples suggests some underlying trends in the identification of the synthetic route which may aid in the interpretation of IRMS data derived from clandestine samples.

Application of neutral iridium(I) N-heterocyclic carbene complexes in ortho-directed hydrogen isotope exchange.

Bench-stable complexes of the type [Ir(COD)(NHC)Cl] (NHC = N-heterocyclic carbene) have been investigated within the field of hydrogen isotope exchange. By employing a sterically encumbered NHC within such complexes and catalyst loadings of only 5 mol%, moderate to high deuterium incorporations were achieved across a range of aromatic ketones and nitrogen-based heterocycles. The simple and synthetically accessible catalysts reported herein present alternatives to phosphine-based species and increase the available labelling systems with respect to established iridium-based isotope exchange methodologies.

Elemental profiling using ICPMS of methylamphetamine hydrochloride prepared from proprietary medication using the Moscow and hypophosphorous synthesis.

Illicit drugs manufactured from clandestine laboratories are often impure due to poor laboratory conditions, variations in synthesis and impure starting materials extracted either from common household products or pharmaceutical grade chemicals. Inductively coupled plasma mass spectrometry (ICPMS) can be utilised as a multi-element analytical tool to elicit the inorganic impurities which may be present in such samples, however the interpretation of the resultant data can be problematic and complex. This is particularly true when dealing with seized samples of unknown provenance. In this work, we have presented and interpreted inorganic profiles as a means to explore within and between batch variations in known provenance samples produced via two different popular synthetic routes. Samples were prepared from essential chemicals recovered from household materials and pharmaceutical medication available in the UK and extracted using different solvents. The presence or absence of elements in the final synthesised products could be linked to the synthesis route, salting out method and potentially the solvent used in the precursor extraction process.

Experimental and computational insights into the mechanism of the copper(i)-catalysed sulfonylative Suzuki-Miyaura reaction.

A mechanistic study into the copper(i)-catalysed sulfonylative Suzuki-Miyaura reaction, incorporating sulfur dioxide, is described. Utilising spectroscopic and computational techniques, an exploration into the individual components of the competing catalytic cycles is delineated, including identification of the resting state catalyst, transmetalation of arylboronic acid onto copper(i), the sulfur dioxide insertion process, and the oxidative addition of aryl halide to CuI. Studies also investigated prominent side-reactions which were uncovered, including a competing copper(ii)-catalysed mechanism. This led to an additional proposed and connected CuI/CuII/CuIII catalytic cycle to account for by-product formation.