Photocatalytic Late-Stage C-H Functionalization.

The emergence of modern photocatalysis, characterized by mildness and selectivity, has significantly spurred innovative late-stage C-H functionalization approaches that make use of low energy photons as a controllable energy source. Compared to traditional late-stage functionalization strategies, photocatalysis paves the way toward complementary and/or previously unattainable regio- and chemoselectivities. Merging the compelling benefits of photocatalysis with the late-stage functionalization workflow offers a potentially unmatched arsenal to tackle drug development campaigns and beyond. This Review highlights the photocatalytic late-stage C-H functionalization strategies of small-molecule drugs, agrochemicals, and natural products, classified according to the targeted C-H bond and the newly formed one. Emphasis is devoted to identifying, describing, and comparing the main mechanistic scenarios. The Review draws a critical comparison between established ionic chemistry and photocatalyzed radical-based manifolds. The Review aims to establish the current state-of-the-art and illustrate the key unsolved challenges to be addressed in the future. The authors aim to introduce the general readership to the main approaches toward photocatalytic late-stage C-H functionalization, and specialist practitioners to the critical evaluation of the current methodologies, potential for improvement, and future uncharted directions.

Strain-Release Photocatalysis.

The concept of strain in organic compounds is as old as modern organic chemistry and was initially introduced to justify the synthetic setbacks along the synthesis of small ring systems (pars construens of strain). In the last decades, chemists have developed an arsenal of strain-release reactions (pars destruens of strain) which can generate─with significant driving force─rigid aliphatic systems that can act as three-dimensional alternatives to (hetero)arenes. Photocatalysis added an additional dimension to strain-release processes by leveraging the energy of photons to create chemical complexity under mild conditions. This perspective presents the latest advancements in strain-release photocatalysis─with emphases on mechanisms, catalytic cycles, and current limitations─the unique chemical architectures that can be produced, and possible future directions.

Merging Carbonyl Addition with Photocatalysis.

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 ß-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.

Radical Carbonyl Umpolung Arylation via Dual Nickel Catalysis.

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.

Visible-Light Photocatalyzed peri-(3 + 2) Cycloadditions of Quinolines.

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 peri-(3 + 2) cycloaddition of simple quinolines with alkynes. A commercially available iridium complex exerts a dual role of photosensitizer and photoredox catalyst, fostering a cyclization/rearomatization cascade. The initial energy-transfer phase leads to the acenaphthene skeleton, while the ensuing redox shuttling step leads to aromatization. We applied this technology to 8-substituted quinolines and phenanthrolines, which smoothly reacted with both terminal and internal alkynes with excellent levels of regio- and diastereoselectivity. Density functional theory calculations revealed the intertwined EnT/SET nature of the process and offered guiding design principles for the synthesis of new aza-acenaphthenes.

Photochemical Dearomative Cycloadditions of Quinolines and Alkenes: Scope and Mechanism Studies.

Photochemical dearomative cycloaddition has emerged as a useful strategy to rapidly generate molecular complexity. Within this context, stereo- and regiocontrolled intermolecular para-cycloadditions are rare. Herein, a method to achieve photochemical cycloaddition of quinolines and alkenes is shown. Emphasis is placed on generating sterically congested products and reaction of highly substituted alkenes and allenes. In addition, the mechanistic details of the process are studied, which revealed a reversible radical addition and a selectivity-determining radical recombination. The regio- and stereochemical outcome of the reaction is also rationalized.

Access to Unexplored 3D Chemical Space: cis-Selective Arene Hydrogenation for the Synthesis of Saturated Cyclic Boronic Acids.

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, -CF3 , and -silyl groups. The utility of the synthesized products was demonstrated by the recognition of diols and sugars under physiological conditions. These motifs can have a substantial importance in medicinal chemistry as they possess a three-dimensional structure, are highly stable, soluble in water, form hydrogen bonds, and interact with diols and sugars.

Photoredox-Catalyzed Defluorinative Functionalizations of Polyfluorinated Aliphatic Amides and Esters.

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.

Reversible Self-Assembly of an N-Heterocyclic Carbene on Metal Surfaces.

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.

Influence of N-Substituents on the Adsorption Geometry of OH-Functionalized Chiral N-Heterocyclic Carbenes.

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.

Transition metal-catalysed allylic functionalization reactions involving radicals.

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 ß-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.

Radical Carbonyl Propargylation by Dual Catalysis.

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.

Visible-Light-Induced Cycloaddition of α-Ketoacylsilanes with Imines: Facile Access to ß-Lactams.

We report the synthesis of ß-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 ß-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.

Three-Component, Interrupted Radical Heck/Allylic Substitution Cascade Involving Unactivated Alkyl Bromides.

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 ß-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, mostly >95:5 E/Z, >20:1 rr). Sequential C(sp3)-C(sp3) and C-X (N, O, S) bonds have been constructed efficiently with a broad scope and high functional group tolerance. The flexibility and versatility of the strategy have been illustrated in a gram-scale reaction and streamlined syntheses of complex ether, sulfone, and tertiary amine products, some of which would be difficult to access via currently established methods.

Synthesis of All-Carbon Quaternary Centers by Palladium-Catalyzed Olefin Dicarbofunctionalization.

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.

Photosensitized Intermolecular Carboimination of Alkenes through the Persistent Radical Effect.

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.

An Electron-Rich Cyclic (Alkyl)(Amino)Carbene on Au(111), Ag(111), and Cu(111) Surfaces.

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.

Site-Selective, Remote sp3 C-H Carboxylation Enabled by the Merger of Photoredox and Nickel Catalysis.

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-Induced Regioselective Cycloaddition of Benzoyl Azides and Alkenes To Yield Oxazolines.

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.

Catalytic defluorinative ketyl-olefin coupling by halogen-atom transfer.

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 gem-difluorohomoallylic alcohols under mild conditions with broad substrate scope. Preliminary mechanistic experimental and computational studies demonstrate that this radical-to-polar crossover transformation could be achieved by sequentially orchestrated Lewis acid activation, halogen-atom transfer, radical addition, single-electron reduction and ß-fluoro elimination.