Direct decarboxylative Giese reactions.

The quest to find milder and more sustainable methods to generate highly reactive, carbon-centred intermediates has led to a resurgence of interest in radical chemistry. In particular, carboxylic acids are seen as attractive radical precursors due their availability, low cost, diversity, and sustainability. Moreover, the corresponding nucleophilic carbon-radical can be easily accessed through a favourable radical decarboxylation process, extruding CO2 as a traceless by-product. This review summarizes the recent progress on using carboxylic acids directly as convenient radical precursors for the formation of carbon-carbon bonds via the 1,4-radical conjugate addition (Giese) reaction.

Direct C-H Functionalization of Phenanthrolines: Metal- and Light-Free Dicarbamoylations.

A direct method for C-H dicarbamoylations of phenanthrolines has been developed, which is capable of directly installing primary, secondary as well as tertiary amides. This is a significant improvement on the previous direct method, which was limited to primary amides. The metal-, light-, and catalyst-free Minisci-type reaction is cheap, operationally simple, and scalable. We demonstrate that the step efficiency toward dicarbamoylated phenanthroline targets can now be significantly improved.

Expanding the Tool Kit of Automated Flow Synthesis: Development of In-line Flash Chromatography Purification.

Recent advancements in in-line extraction and purification technology have enabled complex multistep synthesis in continuous flow reactor systems. However, for the large scope of chemical reactions that yield mixtures of products or residual starting materials, off-line purification is still required to isolate the desired compound. We present the in-line integration of a commercial automated flash chromatography system with a flow reactor for the continuous synthesis and isolation of product(s). A proof-of-principle study was performed to validate the system and test the durability of the column cartridges, performing an automated sequence of 100 runs over 2 days. Three diverse reaction systems that highlight the advantages of flow synthesis were successfully applied with in-line normal- or reversed-phase flash chromatography, continuously isolating products with 97-99% purity. Productivity of up to 9.9 mmol/h was achieved, isolating gram quantities of pure product from a feed of crude reaction mixture. Herein, we describe the development and optimization of the systems and suggest guidelines for selecting reactions well suited to in-line flash chromatography.

Heterogeneous photocatalysis in flow chemical reactors.

The synergy between photocatalysis and continuous flow chemical reactors has shifted the paradigms of photochemistry, opening new avenues of research with safer and scalable processes that can be readily implemented in academia and industry. Current state-of-the-art photocatalysts are homogeneous transition metal complexes that have favourable photophysical properties, wide electrochemical redox potentials, and photostability. However, these photocatalysts present serious drawbacks, such as toxicity, limited availability, and the overall cost of rare transition metal elements. This reduces their long-term viability, especially at an industrial scale. Heterogeneous photocatalysts (HPCats) are an attractive alternative, as the requirement for the separation and purification is largely removed, but typically at the cost of efficiency. Flow chemical reactors can, to a large extent, mitigate the loss in efficiency through reactor designs that enhance mass transport and irradiation. Herein, we review some important developments of heterogeneous photocatalytic materials and their application in flow reactors for sustainable organic synthesis. Further, the application of continuous flow heterogeneous photocatalysis in environmental remediation is briefly discussed to present some interesting reactor designs that could be implemented to enhance organic synthesis.

Synthesis and optoelectronic properties of benzoquinone-based donor-acceptor compounds.

Herein, we report a mild and efficient palladium-catalyzed C-H functionalization method to synthesize a series of benzoquinone (BQ)-based charge-transfer (CT) derivatives in good yields. The optoelectronic properties of these compounds were explored both theoretically and experimentally and correlations to their structures were identified as a function of the nature and position of the donor group (meta and para) attached to the benzoquinone acceptor. Compound 3, where benzoquinone is para-conjugated to the diphenylamine donor group, exhibited thermally activated delayed fluorescence (TADF) with a biexponential lifetime characterized by a prompt ns component and a delayed component of 353 µs.

Gold(I)-Catalysed Hydroarylation of 1,3-Disubstituted Allenes with Efficient Axial-to-Point Chirality Transfer.

Hydroarylation of enantioenriched 1,3-disubstituted allenes has the potential to proceed with axial-to-point chirality transfer to yield enantioenriched allylated (hetero)aryl compounds. However, the gold-catalysed intermolecular reaction was previously reported to occur with no chirality transfer owing to competing allene racemisation. Herein, we describe the development of the first intermolecular hydroarylations of allenes to proceed with efficient chirality transfer and summarise some of the key criteria for achieving high regio- and stereoselectivity.

Rapid Iododeboronation with and without Gold Catalysis: Application to Radiolabelling of Arenes.

Radiopharmaceuticals that incorporate radioactive iodine in combination with single-photon emission computed tomography imaging play a key role in nuclear medicine, with applications in drug development and disease diagnosis. Despite this importance, there are relatively few general methods for the incorporation of radioiodine into small molecules. This work reports a rapid air- and moisture-stable ipso-iododeboronation procedure that uses NIS in the non-toxic, green solvent dimethyl carbonate. The fast reaction and mild conditions of the gold-catalysed method led to the development of a highly efficient process for the radiolabelling of arenes, which constitutes the first example of an application of homogenous gold catalysis to selective radiosynthesis. This was exemplified by the efficient synthesis of radiolabelled meta-[125 I]iodobenzylguanidine, a radiopharmaceutical that is used for the imaging and therapy of human norepinephrine transporter-expressing tumours.

Auto-Tandem Catalysis: PdII -Catalysed Dehydrogenation/Oxidative Heck Reaction of Cyclopentane-1,3-diones.

A PdII catalyst system has been used to successfully catalyse two mechanistically distinct reactions in a one-pot procedure: dehydrogenation of 2,2-disubstituted cyclopentane-1,3-diones and the subsequent oxidative Heck coupling. This auto-tandem catalytic reaction is applicable to both batch and continuous flow processes, with the latter being the first example of a tandem aerobic dehydrogenation/oxidative Heck in flow. In addition, a telescoped reaction involving enantioselective desymmetrisation of the all-C quaternary centre was successfully achieved.

Chirality Transfer in Gold(I)-Catalysed Hydroalkoxylation of 1,3-Disubstituted Allenes.

Gold(I)-catalysed intermolecular hydroalkoxylation of enantioenriched 1,3-disubstituted allenes was previously reported to occur with poor chirality transfer due to rapid allene racemisation. The first intermolecular hydroalkoxylation of allenes with efficient chirality transfer is reported here, exploiting conditions that suppress allene racemisation. A full substrate scope study reveals that excellent regio- and stereoselectivities are achieved when a σ-withdrawing substituent is present.

Chirality Transfer in Gold(I)-Catalysed Direct Allylic Etherifications of Unactivated Alcohols: Experimental and Computational Study.

Gold(I)-catalysed direct allylic etherifications have been successfully carried out with chirality transfer to yield enantioenriched, γ-substituted secondary allylic ethers. Our investigations include a full substrate-scope screen to ascertain substituent effects on the regioselectivity, stereoselectivity and efficiency of chirality transfer, as well as control experiments to elucidate the mechanistic subtleties of the chirality-transfer process. Crucially, addition of molecular sieves was found to be necessary to ensure efficient and general chirality transfer. Computational studies suggest that the efficiency of chirality transfer is linked to the aggregation of the alcohol nucleophile around the reactive π-bound Au-allylic ether complex. With a single alcohol nucleophile, a high degree of chirality transfer is predicted. However, if three alcohols are present, alternative proton transfer chain mechanisms that erode the efficiency of chirality transfer become competitive.

Gold-Catalyzed Proto- and Deuterodeboronation.

A mild gold-catalyzed protodeboronation reaction, which does not require acid or base additives and can be carried out in "green" solvents, is described. As a result, the reaction is very functional-group-tolerant, even to acid- and base-sensitive functional groups, and should allow for the boronic acid group to be used as an effective traceless directing or blocking group. The reaction has also been extended to deuterodeboronations for regiospecific ipso-deuterations of aryls and heteroaryls from the corresponding organoboronic acid. Based on density functional theory calculations, a mechanism is proposed that involves nucleophilic attack of water at boron followed by rate-limiting B-C bond cleavage and facile protonolysis of a Au-σ-phenyl intermediate.

Gold(I)-catalysed direct thioetherifications using allylic alcohols: an experimental and computational study.

A gold(I)-catalysed direct thioetherification reaction between allylic alcohols and thiols is presented. The reaction is generally highly regioselective (S(N)2'). This dehydrative allylation procedure is very mild and atom economical, producing only water as the by-product and avoiding any unnecessary waste/steps associated with installing a leaving or activating group on the substrate. Computational studies are presented to gain insight into the mechanism of the reaction. Calculations indicate that the regioselectivity is under equilibrium control and is ultimately dictated by the thermodynamic stability of the products.

Palladium-catalyzed direct C-H functionalization of benzoquinone.

A direct Pd-catalyzed C-H functionalization of benzoquinone (BQ) can be controlled to give either mono- or disubstituted BQ, including the installation of two different groups in a one-pot procedure. BQ can now be directly functionalized with aryl, heteroaryl, cycloalkyl, and cycloalkene groups and, moreover, the reaction is conducted in environmentally benign water or acetone as solvents.

Direct C-H amidation of 1,3-azoles: light-mediated, photosensitiser-free vs. thermal.

We have developed one thermal and one light-mediated method for direct Minisci-type C-H amidation of 1,3-azoles, which are applicable to thiazoles, benzothiazoles, benzimidazoles, and for the first time, imidazoles. The new visible light-mediated approach can be rendered photosensitiser/photocatalyst-free and likely proceeds via an electron donor-acceptor (EDA) complex, the first direct Minisci-type amidation to do so.

Organocatalyzed carbonyl-olefin metathesis.

The heat is on: A new [3+2] cycloaddition/cycloreversion strategy allows for catalytic and thermally allowed carbonyl-olefin metathesis (see scheme). This strategy opens opportunities for new developments in the field of carbonyl-olefin metathesis, which traditionally relied on stoichiometric amounts of transition-metal reagents or photochemical promotion.

Gold(I)-catalysed one-pot synthesis of chromans using allylic alcohols and phenols.

A gold(I)-catalysed reaction of allylic alcohols and phenols produces chromans regioselectively via a one-pot Friedel-Crafts allylation/intramolecular hydroalkoxylation sequence. The reaction is mild, practical and tolerant of a wide variety of substituents on the phenol.

Direct decarboxylative Giese amidations: photocatalytic vs. metal- and light-free.

A direct intermolecular decarboxylative Giese amidation reaction from bench stable, non-toxic and environmentally benign oxamic acids has been developed, which allows for easy access to 1,4-difunctionalised compounds which are not otherwise readily accessible. Crucially, a more general acceptor substrate scope is now possible, which renders the Giese amidation applicable to more complex substrates such as natural products and chiral building blocks. Two different photocatalytic methods (one via oxidative and the other via reductive quenching cycles) and one metal- and light-free method were developed and the flexibility provided by different conditions proved to be crucial for enabling a more general substrate scope.

Gold(I)-catalyzed addition of thiols and thioacids to 3,3-disubstituted cyclopropenes.

Gold(I)-catalyzed reactions of thiols, thiophenols, and thioacids with 3,3-disubstituted cyclopropenes occur in a regioselective and chemoselective manner to produce either vinyl thioethers or primary allylic thioesters in good yields. A survey of commonly used gold(I) catalysts shows Echavarren's cationic gold(I) catalyst to be most tolerant of deactivation by sulfur. A novel digold with bridging thiolate complex is characterized by X-ray crystallography, shedding light on a possible deactivation pathway.

Computational studies on the mechanism of the gold(I)-catalysed rearrangement of cyclopropenes.

Density functional theory calculations have been employed to investigate the mechanism of gold(I)-catalysed rearrangements of cyclopropenes. Product formation is controlled by the initial ring-opening step which results in the formation of a gold-stabilised carbocation/gold carbene intermediate. With 3-phenylcyclopropene-3-methylcarboxylate, the preferred intermediate allows cyclisation via nucleophilic attack of the carbonyl group and hence butenolide formation. Further calculations on simple model systems show that substituent effects can be rationalised by the charge distribution in the ring-opening transition state and, in particular, a loss of negative charge at what becomes the ß-position of the intermediate. With 1-C(3)H(3)R cyclopropenes (R = Me, vinyl, Ph), ring-opening therefore places the substituent at the ß-position.

Direct Minisci-Type C-H Amidation of Purine Bases.

A method for the C-H carboxyamidation of purines has been developed that is capable of directly installing primary, secondary, and tertiary amides. Previous Minisci-type investigations on purines were limited to alkylations and arylations. Herein, we present the first method for the direct C-H amidation of a wide range of purines: xanthine, guanine, and adenine structures, including guanosine- and adenosine-type nucleosides. The Minisci-type reaction is also metal-free, cheap, operationally simple, scalable, and applicable to late-stage functionalizations of biologically important molecules.