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β-Amino acids are frequently found as important components in numerous biologically active molecules, drugs and natural products. In particular, they are broadly utilized in the construction of bioactive peptides and peptidomimetics, thanks to their increased metabolic stability. Despite the number of methodologies established for the preparation of β-amino acid derivatives, the majority of these methods require metal-mediated multistep manipulations of prefunctionalized substrates. Here we disclose a metal-free, energy-transfer enabled highly regioselective intermolecular aminocarboxylation reaction for the single-step installation of both amine and ester functionalities into alkenes or (hetero)arenes. A bifunctional oxime oxalate ester was developed to simultaneously generate C-centred ester and N-centred iminyl radicals. This mild method features a remarkably broad substrate scope (up to 140 examples) and excellent tolerance of sensitive functional groups, and substrates that range from the simplest ethylene to complex (hetero)arenes can participate in the reaction, thus offering a general and practical access to β-amino acid derivatives.

Hybrid fused two-dimensional/three-dimensional (2D/3D) rings are important pharmacophores in drugs owing to their unique structural and physicochemical properties. Preparation of these strained ring systems often requires elaborate synthetic effort and exhibits low efficiency, thus representing a limiting factor in drug discovery. Here, we report two types of energy-transfer-mediated cascade dearomative [2 + 2] cycloaddition/rearrangement reactions of quinoline derivatives with alkenes, which provide a straightforward avenue to 2D/3D pyridine-fused 6−5−4−3- and 6−4−6-membered ring systems. Notably, this energy-transfer-mediated strategy features excellent diastereoselectivity that bypasses the general reactivity and selectivity issues of photochemical [2 + 2] cycloaddition of various other aromatics. Tuning the aza-arene substitutions enabled selective diversion of the iridium photocatalysed energy transfer manifold towards either cyclopropanation or cyclobutane-rearrangement products. Density functional theory calculations revealed a cascade energy transfer scenario to be operative.

The carbonyl group stands as a fundamental scaffold and plays a ubiquitous role in synthetically important chemical reactions in both academic and industrial contexts. Venerable transformations, including the aldol reaction, Grignard reaction, Wittig reaction, and Nozaki-Hiyama-Kishi reaction, constitute a vast and empowering synthetic arsenal. Notwithstanding, two-electron mechanisms inherently confine the breadth of accessible reactivity and topological patterns.Fostered by the rapid development of photoredox catalysis, combing well-entrenched carbonyl addition and radicals can harness several unique and increasingly sustainable transformations. In particular, unusual carbon-carbon and carbon-heteroatom disconnections, which are out of reach of two-electron carbonyl chemistry, can be conceived. To meet this end, a novel strategy toward the utilization of simple carbonyl compounds as intermolecular radical acceptors was developed. The reaction is enabled by visible-light photoredox-initiated hole catalysis. In situ Brønsted acid activation of the carbonyl moiety prevents β-scission from occurring. Furthermore, this regioselective alkyl radical addition reaction obviates the use of metals, ligands, or additives, thus offering a high degree of atom economy under mild conditions. On the basis of the same concept and the work of Schindler and co-workers, carbonyl-olefin cross-metathesis, induced by visible light, has also been achieved, leveraging a radical Prins-elimination sequence.Recently, dual chromium and photoredox catalysis has been developed by us and Kanai, offering a complementary approach to the revered Nozaki-Hiyama-Kishi reaction. Leveraging the intertwined synergy between light and metal, several radical-to-polar crossover transformations toward eminent molecular motifs have been developed. Reactions such as the redox-neutral allylation of aldehydes and radical carbonyl alkylation can harvest the power of light and enable the use of catalytic chromium metal. Overall, exquisite levels of diastereoselectivity can be enforced via highly compact transition states. Other examples, such as the dialkylation of 1,3-dienes and radical carbonyl propargylation portray the versatile combination of radicals and carbonyl addition in multicomponent coupling endeavors. Highly valuable motifs, which commonly occur in complex drug and natural product architectures, can now be accessed in a single operational step. Going beyond carbonyl addition, seminal contributions from Fagnoni and MacMillan preconized photocatalytic HAT-based acyl radical formation as a key aldehyde valorization strategy. Our group articulated this concept, leveraging carboxy radicals as hydrogen atom abstractors in high regio- and chemoselective carbonyl alkynylation and aldehyde trifluoromethylthiolation.This Account, in addition to the narrative of our group and others' contributions at the interface between carbonyl addition and radical-based photochemistry, aims to provide core guiding foundations toward novel disruptive synthetic developments. We envisage that extending radical-to-polar crossovers beyond Nozaki-Hiyama-Kishi manifolds, taming less-activated carbonyls, leveraging multicomponent processes, and merging single electron steps with energy-transfer events will propel eminent breakthroughs in the near future.

The formation of carbon-carbon bonds lies at the heart of synthetic organic chemistry and is widely applied to construct complex drugs, polymers, and materials. Despite its importance, catalytic carbonyl arylation remains comparatively underdeveloped, due to limited scope and functional group tolerance. Herein we disclose an umpolung strategy to achieve radical carbonyl arylation via dual catalysis. This redox-neutral approach provides a complementary method to construct Grignard-type products from (hetero)aryl bromides and aliphatic aldehydes, without the need for pre-functionalization. A sequential activation, hydrogen-atom transfer, and halogen atom transfer process could directly convert aldehydes to the corresponding ketyl-type radicals, which further react with aryl-nickel intermediates in an overall polarity-reversal process. This radical strategy tolerates─among others─acidic functional groups, heteroaryl motifs, and sterically hindered substrates and has been applied in the late-stage modification of drugs and natural products.

Ketyl-olefin coupling reactions stand as one of the fundamental chemical transformations in synthetic chemistry and have been widely employed in the generation of complex molecular architectures and natural product synthesis. However, catalytic ketyl-olefin coupling, until the recent development of photoredox chemistry and electrosynthesis through single-electron transfer mechanisms, has remained largely undeveloped. Herein, we describe a new approach to achieve catalytic ketyl-olefin coupling reactions by a halogen-atom transfer mechanism, which provides innovative and efficient access to various

Summary Control of selectivity is a pivotal challenge in radical chemistry owing to the high reactivity and instability of radical species. Herein, a switchable, base-controlled strategy toward the reincorporation/release of SO2 in photocatalyzed radical difunctionalization of alkenes has been described. By this chemodivergent strategy, a variety of valuable, otherwise difficult-to-access γ-trifluoromethylated ketones and trifluoromethylated sulfonyl ketones can be selectively furnished from the same starting materials. This method features high chemoselectivity, a broad substrate scope, excellent functional group tolerance, and facile scale-up and was applied in a one-pot synthetic procedure. Evaluation of the reaction conditions and mechanistic studies indicate that the choice of base can invert the chemoselectivity of the reaction, demonstrating control over a challenging radical selectivity pattern.

Summary The development of a catalytic strategy for one-carbon homologation is of foundational importance in organic synthesis enabling quick elaboration of useful molecules. Herein, we report a dual nickel/photoredox catalytic strategy for transforming a range of α-amino acids into β-amino aldehydes in a simple one-step operation. This method provides a new catalytic blueprint for one-carbon homologation of α-amino acids without requiring any pre-functionalization step and could be strategically important for streamlining the preparation of value-added β-amino aldehydes, versatile building blocks applied in a variety of synthetic transformations. More broadly, mechanistic studies demonstrated here show how a radical generated in situ can be captured for rapid access of aldehydes, which would promote the applications of numerous other molecules for valuable aldehyde synthesis.

N-Heterocyclic carbenes, despite being isolated and characterized three decades ago, still capture scientists’ interest as versatile, modular and strongly coordinating moieties. In the last decade, driven by the increasingly refined fundamental understanding of their behaviour, the emergence of new carbene frameworks and cogent sustainability issues, N-heterocyclic carbenes have experienced a tremendous increase in utilization across several disparate fields. In this Review, a concise overview of N-heterocyclic carbenes encompassing their history, properties and applications in transition metal catalysis, on-surface chemistry, main group chemistry and organocatalysis is provided. Emphasis is placed on developments emerging in the last seven years and on envisaging future directions. N-Heterocyclic carbenes continue to mesmerize scientists and open up new research avenues for academia and industry. Here, we provide a concise and up-to-date overview of N-heterocyclic carbenes, encompassing their history, properties and applications in transition metal catalysis, main group chemistry, on-surface chemistry and organocatalysis.

Photochemical dearomative cycloaddition has emerged as a useful strategy to rapidly generate molecular complexity. Within this context, stereo- and regiocontrolled intermolecular

Cycloaddition reactions─epitomized by the Diels-Alder reaction─offer an arguably unmatched springboard for achieving chemical complexity, often with excellent selectivity, in a modular single step. We report the synthesis of aza-acenaphthenes in a single step by an unprecedented formal

We report the synthesis of β-lactams from α-ketoacylsilanes and imines, which proceeds via a formal [2+2] photochemical cycloaddition with in situ generation of siloxyketene. This mild and operationally simple reaction proceeds in an atom-economic fashion with broad substrate scope, including aldimines, ketimines, hydrazones, and fused nitrogen heterocycles, affording a variety of important β-lactams with satisfactory diastereoselectivities in most cases. This reaction also features good functional-group tolerance, facile scalability and product diversification. Experimental and computational studies suggest that α-ketoacylsilanes can serve as photochemical precursors by engaging in a 1,3 silicon shift to the distal carbonyl group.

Heterogeneous catalysts represent the backbone of many industrial processes and thus have a considerable societal impact. The active sites of these heterogeneous catalysts are often metal surfaces, which consist of a large ensemble of metal atoms, and their properties differ significantly from metal complexes bearing highly developed ligands typically used in homogeneous catalysis. A highly interesting approach is the combination of these sophisticated ligand systems from homogeneous catalysis with metal surfaces to improve parameters such as stability, reactivity and selectivity. One class of these advanced ligands is N-heterocyclic carbenes (NHCs), which have been increasingly applied as molecular modifiers for metal surfaces. This review summarizes developments in this area, covering fundamental properties, preparation methods, important analytical techniques and reactions of NHC-modified metal surfaces. Emerging strategies for NHC design are categorized and future directions are outlined. N-Heterocyclic carbenes are versatile ligands that can be used to modulate the properties of metallic surfaces. This Review focuses on efforts to tune the reactivity of metal-based heterogeneous catalysts by such molecular species, providing an overview of the techniques to study carbene–surface interaction and examples of successful catalytic reactions based on this approach.

Developments in synthetic chemistry are increasingly driven by improvements in the selectivity and sustainability of transformations. Bifunctional reagents, either as dual coupling partners or as a coupling partner in combination with an activating species, offer an atom-economic approach to chemical complexity, while suppressing the formation of waste. These reagents are employed in organic synthesis thanks to their ability to form complex organic architectures and empower novel reaction pathways. This Review describes several key bifunctional reagents by showcasing selected cornerstone research areas and examples, including radical reactions, C–H functionalization, cross-coupling, organocatalysis and cyclization reactions. Developments in synthetic chemistry are increasingly driven by attempts to improve both selectivity and sustainability. This Review highlights the versatility of bifunctional reagents in generating chemical complexity with enhanced atom-economy-leveraging radical reactions, C–H functionalizations, cross-couplings, organocatalysed processes and cyclizations.

A highly modular radical cascade strategy based upon radical cyclisation/allylic substitution sequence between alkyl/aryl bromides, 1,3-dienes and nucleophiles ranging from sulfinates to amines, phenols and 1,3-dicarbonyls is described (>80 examples). Palladium phosphine complexes – which merge properties of photo- and cross coupling-catalysts – allow to forge three bonds with complete 1,4-selectivity and stereocontrol, delivering highly value added carbocyclic and heterocyclic motifs that can feature – inter alia – vicinal quaternary centers, free protic groups, gem-difluoro motifs and strained rings. Furthermore, a flow chemistry approach was for the first time applied in palladium–photocatalysed endeavors involving radicals.

Carbonyl propargylation has been established as a valuable tool in the realm of carbon-carbon bond forming reactions. The 1,3-enyne moiety has been recognized as an alternative pronucleophile in the above transformation through an ionic mechanism. Herein, we report for the first time, the radical carbonyl propargylation through dual chromium/photoredox catalysis. A library of valuable homopropargylic alcohols bearing all-carbon quaternary centers could be obtained by a catalytic radical three-component coupling of 1,3-enynes, aldehydes and suitable radical precursors (41 examples). This redox-neutral multi-component reaction occurs under very mild conditions and shows high functional group tolerance. Remarkably, bench-stable, non-toxic, and inexpensive CrCl3 could be employed as a chromium source. Preliminary mechanistic investigations suggest a radical-polar crossover mechanism, which offers a complementary and novel approach towards the preparation of valuable synthetic architectures from simple chemicals.

Self-assembly of cyclohexyl cyclic (alkyl)(amino)carbenes (cyCAAC) can be realized and reversibly switched from a close-packed trimer phase to a chainlike dimer phase, enabled by the ring-flip of the cyclohexyl wingtip. Multiple methods including scanning tunneling microscopy (STM), X-ray photoelectron spectroscopy (XPS) and density functional theory (DFT) calculations identified a distinct isomer (axial or equatorial chair conformer) in each phase, and consequently support the conclusion regarding the determination of molecular surface geometry on the self-assembly of cyCAAC. Moreover, various substrates such as Ag (111) and Cu (111) are tested to elucidate the importance of cyCAAC-surface interactions on cyCAAC based nanopatterns. These investigations of patterned surfaces prompted a deep understanding of cyCAAC binding mode, surface geometry and reversible self-assembly, which are of paramount significance in the areas of catalysis, biosensor design and surface functionalization.

The structural properties and binding motif of a strongly σ‐electron‐donating N‐heterocyclic carbene have been investigated on different transition‐metal surfaces. The examined cyclic (alkyl)(amino)carbene (CAAC) was found to be mobile on surfaces, and molecular islands with short‐range order could be found at high coverage. A combination of scanning tunneling microscopy (STM), X‐ray photoelectron spectroscopy (XPS), and density functional theory (DFT) calculations highlights how CAACs bind to the surface, which is of tremendous importance to gain an understanding of heterogeneous catalysts bearing CAACs as ligands., Served on a (golden) tray! A highly reactive and electron‐rich (alkyl)(amino)carbene (CAAC) derivative was deposited on a surface, and its binding mode and ordering were investigated for the first time. Mobile CAAC‐Au species were found that form islands on the surface. These results open the door for more on‐surface studies of the highly relevant class of CAACs.

An intermolecular, two‐component vicinal carboimination of alkenes has been accomplished by energy transfer catalysis. Oxime esters of alkyl carboxylic acids were used as bifunctional reagents to generate both alkyl and iminyl radicals. Subsequently, addition of the alkyl radical to an alkene generates a transient radical for selective radical–radical cross‐coupling with the persistent iminyl radical. Furthermore, this process provides direct access to aliphatic primary amines and α‐amino acids by simple hydrolysis., Two birds, one stone: Oxime esters of aliphatic carboxylic acids were used as a bifunctional source of both C‐ and N‐radicals. The persistency of the N‐radicals enables highly selective intermolecular radical carboaminations of alkenes.

Selective C-F bond functionalization of perfluoalkyl units has huge potential towards accessing functionalized organofluorinated compounds, but remains challenging due to the high C-F bond strength and inherent selectivity challenges. We report a new catalytic approach to the selective functionalization of strong C-F bonds in polyfluorinated aliphatic esters and amides. This simple reaction proceeds in mild and operational fashion with divergent conversions, including hydrodefluorination, defluoroalkylation, and defluoroalkenylation, affording a diverse array of important partially fluorinated motifs. Straightforward downstream chemistry towards fluorinated alcohols, amines and drug derivatives highlights the potential of the protocol.

Adsorption of chiral molecules on heterogeneous catalysts is a simple approach for inducing an asymmetric environment to enable enantioselective reactivity. Although the concept of chiral induction is straightforward, its practical utilization is far from simple, and only a few examples toward the successful chiral induction by surface anchoring of asymmetric modifiers have been demonstrated so far. Elucidating the factors that lead to successful chiral induction is therefore a crucial step for understanding the mechanism by which chirality is transferred. Herein, we identify the adsorption geometry of OH-functionalized N-heterocyclic carbenes (NHCs), which are chemical analogues to chiral modifiers that successfully promoted α-arylation reactions once anchored on Pd nanoparticles. Polarized near-edge X-ray absorption fine structure (NEXAFS) measurements on Pd(111) revealed that NHCs that were associated with low enantioselectivity were characterized with a well-ordered structure, in which the imidazole ring was vertically positioned and the OH-functionalized side arms were flat-lying. OH-functionalized NHCs that were associated with high enantioselectivity revealed a disordered/flexible adsorption geometry, which potentially enabled better interaction between the OH group and the prochiral reactant.

A highly modular radical cascade strategy based upon radical cyclisation/allylic substitution sequence between alkyl/aryl bromides, 1,3-dienes and nucleophiles ranging from sulfinates to amines, phenols and 1,3-dicarbonyls is described (>80 examples). Palladium phosphine complexes – which merge properties of photo- and cross coupling-catalysts – allow to forge three bonds with complete 1,4-selectivity and stereocontrol, delivering highly value added carbocyclic and heterocyclic motifs that can feature – inter alia – vicinal quaternary centers, free protic groups, gem-difluoro motifs and strained rings. Furthermore, a flow chemistry approach was for the first time applied in palladium–photocatalysed endeavors involving radicals., Highly modular three-bond three-component cascade featuring palladium as dual photoredox/cross coupling catalyst.

No more substrate restrictions! Cerium photocatalytic decarboxylative hydrazination of carboxylic acids yields synthetically useful hydrazine derivatives under mild reaction conditions., We report the cerium photocatalyzed radical decarboxylative hydrazination of carboxylic acids with di-tert-butylazodicarboxylate (DBAD). The operationally simple protocol provides rapid access to synthetically useful hydrazine derivatives and overcomes current scope limitations in the photoredox-catalyzed decarboxylation of carboxylic acids.

Heteroaromatics lured into cycloadditions The Diels-Alder reaction is widely used to produce six-membered carbon rings from alkenes and dienes. Heteroaromatics such as quinolines resemble dienes in principle, but in practice their pairs of double bonds are inert toward cycloadditions because of aromatic stabilization. Ma et al. report that by using an iridium photosensitizer, they could excite quinolines and related azaarenes to triplet states, thereby disrupting the aromaticity and enabling intermolecular, Diels-Alder–like reactivity toward alkenes (see the Perspective by Schmidt). The reactions proceeded exclusively at the flanking carbons outside the nitrogen-containing ring. Science , this issue p. 1338 ; see also p. 1313

Phenyl rings are one of the most prevalent structural moieties in active pharmaceutical ingredients, even if they often contribute to poor physico-chemical properties. Herein, we propose the use of a bridged piperidine (BP) moiety as a phenyl bioisostere, which could also be seen as a superior phenyl alternative as it led to strongly improved drug like properties, in terms of solubility and lipophilicity. Additionally, this BP moiety compares favorably to the recently reported saturated phenyl bioisosteres. We applied this concept to our γ-secretase modulator (GSM) project for the potential treatment of Alzheimer's disease delivering clinical candidates.

Transition metal-catalysed allylic functionalization reactions have been established as a central synthetic transformation to enable the construction of carbon-carbon and carbon-heteroatom bonds. Although they have been widely investigated by numerous research groups all over the world, frequently applied in drug discovery and natural product synthesis, most research endeavours focus on ionic mechanisms. Transition metal-catalysed allylic functionalization reactions involving radicals are comparatively underexplored, but provide a powerful alternative strategy to current approaches, considerably extending the amenable coupling partners. This tutorial review highlights the recent advances in this rapidly expanding area, which experienced an unprecedented momentum thanks to the rapid development of radical chemistry. The rationalization of the main scenarios in the generation of allylic intermediates, radical species as formal nucleophiles, and activated transition metals as well as the utilization of allylic radical intermediates in β-functionalization of carbonyls will highlight the common mechanistic threads. In addition the extension of amenable substrates and the new product motifs that can be generated will be summarized.

Developing efficient and selective strategies to approach complex architectures containing (multi)stereogenic centers has been a long-standing synthetic challenge in both academia and industry. Catalytic cascade reactions represent a powerful means of rapidly leveraging molecular complexity from simple feedstocks. Unfortunately, carrying out cascade Heck-type reactions involving unactivated (tertiary) alkyl halides remains an unmet challenge owing to unavoidable β-hydride elimination. Herein, we show that a modular, practical, and general palladium-catalyzed, radical three-component coupling can indeed overcome the aforementioned limitations through an interrupted Heck/allylic substitution sequence mediated by visible light. Selective 1,4-difunctionalization of unactivated 1,3-dienes, such as butadiene, has been achieved by employing different commercially available nitrogen-, oxygen-, sulfur-, or carbon-based nucleophiles and unactivated alkyl bromides (130 examples, mostly95:5

The redox-neutral dicarbofunctionalization of tri- and tetrasubstituted olefins to form a variety of (hetero)cyclic compounds under photoinduced palladium catalysis is described. This cascade reaction process was used to couple styrenes or acryl amides with a broad range of highly decorated olefins tethered to aryl or alkyl bromides (>50 examples). This procedure enables one or two contiguous all-carbon quaternary centers to be formed in a single step. The products could be readily diversified and applied in the synthesis of a bioactive oxindole analogue.

A photoinduced carboxylation of alkyl halides with CO2 at remote sp3 C@H sites enabled by the merger of photoredox and Ni catalysis is described. This protocol features a predictable reactivity and site selectivity that can be modulated by the ligand backbone. Preliminary studies reinforce a rationale based on a dynamic displacement of the catalyst throughout the alkyl side chain.

Visible light catalysis allows the regioselective synthesis of oxazolines in high yields. The mild photosensitized manifold leverages the intermolecular formation of oxazolines with a wide functional group tolerance on both benzoyl azides and alkenes partners. Mechanistic investigations suggest the sensitization of the azide moiety as the key activation step.

A new class of saturated boron-incorporated cyclic molecules has been synthesized employing an arene-hydrogenation methodology. cis-Selective hydrogenation of easily accessible, and biologically important molecules comprising benzoxaborole, benzoxaborinin, and benzoxaboripin derivatives is reported. Among the various catalysts tested, rhodium cyclic(alkyl)(amino)carbene [Rh-CAAC] (1) pre-catalyst revealed the best hydrogenation activity confirming turnover number up to 1400 with good to high diastereoselectivity. A broad range of functional groups was tolerated including sensitive substituents such as -F, -CF