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Developing more efficient catalytic processes using abundant and low toxicity transition metals is key to enable their mainstream use in synthetic chemistry. We have rationally designed a new Mn(I)-catalyst for hydroarylation reactions that displays much improved catalytic activity over the commonly used MnBr(CO)5. Our new catalyst, MnBr(CO)3(MeCN)2, avoids the formation of the off-cycle manganacycle-(CO)4 species responsible for low catalyst activity, allowing near room temperature hydroarylation of alkenes and alkynes with broad functional group tolerance including late stage functionalization and diversification of bioactive molecules.

Summary The C–H alkylation of arenes with N-based directing groups typically requires high temperatures and/or harsh reaction conditions, which has traditionally reduced its functional group compatibility and applicability for late-stage functionalization. We report that a cyclometallated Ru complex is able to perform the C–H alkylation of arenes bearing a variety of N-directing groups with primary alkyl bromides at room temperature and under mild reaction conditions. We demonstrate this with an extended substrate scope, which includes several examples of late-stage alkylation of drug molecules, thus showcasing the “real-world” capabilities of this method. Mechanistic studies show that, in contrast to previous mechanistic proposals, the reaction proceeds via a bis-cyclometallated Ru intermediate, followed by an SN2-type oxidative addition.

The UbiD family of reversible (de)carboxylases depends on the recently discovered prenylated-FMN (prFMN) cofactor for activity. The model enzyme ferulic acid decarboxylase (Fdc1) decarboxylates unsaturated aliphatic acids via a reversible 1,3-cycloaddition process. Protein engineering has extended the Fdc1 substrate range to include (hetero)aromatic acids, although catalytic rates remain poor. This raises the question how efficient decarboxylation of (hetero)aromatic acids is achieved by other UbiD family members. Here, we show that the Pseudomonas aeruginosa virulence attenuation factor PA0254/HudA is a pyrrole-2-carboxylic acid decarboxylase. The crystal structure of the enzyme in the presence of the reversible inhibitor imidazole reveals a covalent prFMN-imidazole adduct is formed. Substrate screening reveals HudA and selected active site variants can accept a modest range of heteroaromatic compounds, including thiophene-2-carboxylic acid. Together with computational studies, our data suggests prFMN covalent catalysis occurs via electrophilic aromatic substitution and links HudA activity with the inhibitory effects of pyrrole-2-carboxylic acid on P. aeruginosa quorum sensing.

Summary Although Ru-catalyzed meta-selective sp2 C–H alkylation with secondary alkyl halides is well established, ortho selectivity has never been achieved. We demonstrate that the use of a cyclometalated Ru-complex, RuBnN, as the catalyst results in a complete switch of the inherent meta-selectivity to ortho selectivity in the Ru-catalyzed sp2 C–H alkylation reaction with unactivated secondary alkyl halides. The high catalytic activity of RuBnN allows mild reaction conditions that result in a transformation of broad scope and versatility. Preliminary mechanistic studies suggest that a bis-cycloruthenated species is the key intermediate undergoing oxidative addition with the alkyl bromides, thus avoiding the more common SET pathway associated with meta-selectivity.

The UbiD family of reversible (de)carboxylases depends on the recently discovered prenylated-FMN (prFMN) cofactor for activity. The model enzyme ferulic acid decarboxylase (Fdc1) decarboxylates unsaturated aliphatic acids via a reversible 1,3-cycloaddition process. Protein engineering has extended the Fdc1 substrate range to include (hetero)aromatic acids, although catalytic rates remain poor. This raises the question how efficient decarboxylation of (hetero)aromatic acids is achieved by other UbiD family members. Here, we show that the Pseudomonas aeruginosa virulence attenuation factor PA0254/HudA is a pyrrole-2-carboxylic acid decarboxylase. The crystal structure of the enzyme in the presence of the reversible inhibitor imidazole reveals a covalent prFMN–imidazole adduct is formed. Substrate screening reveals HudA and selected active site variants can accept a modest range of heteroaromatic compounds, including thiophene-2-carboxylic acid. Together with computational studies, our data suggests prFMN covalent catalysis occurs via electrophilic aromatic substitution and links HudA activity with the inhibitory effects of pyrrole-2-carboxylic acid on P. aeruginosa quorum sensing.

Biaryls are ubiquitous core structures in drugs, agrochemicals and organic materials that have profoundly improved many aspects of our society. Although traditional cross-couplings have made practical the synthesis of many biaryls, C–H arylation represents a more attractive and cost-effective strategy for building these structural motifs. Furthermore, the ability to install biaryl units in complex molecules via late-stage C–H arylation would allow access to valuable structural diversity, novel chemical space and intellectual property in only one step. However, known C–H arylation protocols are not suitable for substrates decorated with polar and delicate functionalities, which are commonly found in molecules that possess biological activity. Here we introduce a class of ruthenium catalysts that display a unique efficacy towards late-stage arylation of heavily functionalized substrates. The design and development of this class of catalysts was enabled by a mechanistic breakthrough on the Ru(ii)-catalysed C–H arylation of N–chelating substrates with aryl (pseudo)halides, which has remained poorly understood for nearly two decades. Nearly two decades after its discovery, the Ru(II)-catalysed C–H arylation of N-chelating aromatics with aryl halides was reinvestigated and a new key reaction intermediate was uncovered. A thorough mechanistic elucidation has now led to the development of a new class of catalysts with unique efficacy towards late-stage arylation of ‘real-world’ compounds.

Methods for the conversion of aliphatic acids to alkyl halides have progressed significantly over the past century, however, the analogous decarboxylative bromination of aromatic acids has remained a longstanding challenge. The development of efficient methods for the synthesis of aryl bromides is of great importance as they are versatile reagents in synthesis and are present in many functional molecules. Herein we report a transition metal-free decarboxylative bromination of aromatic acids. The reaction is applicable to many electron-rich aromatic and heteroaromatic acids which have previously proved poor substrates for Hunsdiecker-type reactions. In addition, our preliminary mechanistic study suggests that radical intermediates are not involved in this reaction, which is in contrast to classical Hunsdiecker-type reactivity. Overall, the process demonstrates a useful method for producing valuable reagents from inexpensive and abundant starting materials.

The biaryl unit is a recurrent building block in numerous compounds that have profoundly changed many aspects of the modern era. As a structural component in drugs, agrochemicals, and materials, the biaryl moiety is a highly desirable synthetic target for both industry and academia. In recent years, transition metal-catalyzed C–H arylation methodologies for the construction of the biaryl skeleton have been acknowledged as a sustainable alternative to traditional cross-coupling reactions. The aim of this review is to offer a general overview on the most successful strategies for the formation of CAr–CAr bonds in this rapidly evolving field. Particular emphasis on the mechanistic implications governing both selectivity and reactivity will be provided, where appropriate.

Herein we report the first Ru‐catalyzed C−H arylation of benzoic acids with readily available aryl (pseudo)halides. The reaction, which does not require the use of silver salt additives, allows the arylation of previously challenging hindered benzoic acids and the use of generally unreactive ortho‐substituted halorarenes. Furthermore, our new protocol can efficiently be applied to indole carboxylic acids, thus allowing access to C7‐, C6‐, C5‐ and C4‐arylated indole compounds, a departure from the classical enhanced reactivity of the C2 and C3 positions of indole.

[Image: see text] The biological production of FDCA is of considerable value as a potential replacement for petrochemical-derived monomers such as terephthalate, used in polyethylene terephthalate (PET) plastics. HmfF belongs to an uncharacterized branch of the prenylated flavin (prFMN) dependent UbiD family of reversible (de)carboxylases and is proposed to convert 2,5-furandicarboxylic acid (FDCA) to furoic acid in vivo. We present a detailed characterization of HmfF and demonstrate that HmfF can catalyze furoic acid carboxylation at elevated CO(2) levels in vitro. We report the crystal structure of a thermophilic HmfF from Pelotomaculum thermopropionicum, revealing that the active site located above the prFMN cofactor contains a furoic acid/FDCA binding site composed of residues H296-R304-R331 specific to the HmfF branch of UbiD enzymes. Variants of the latter are compromised in activity, while H296N alters the substrate preference to pyrrole compounds. Solution studies and crystal structure determination of an engineered dimeric form of the enzyme revealed an unexpected key role for a UbiD family wide conserved Leu residue in activity. The structural insights into substrate and cofactor binding provide a template for further exploitation of HmfF in the production of FDCA plastic precursors and improve our understanding of catalysis by members of the UbiD enzyme family.