The fast-moving fields of photoredox and photocatalysis have recently provided fresh opportunities to expand the potential of synthetic organic chemistry. Advances in light-mediated processes have mainly been guided so far by empirical findings and the quest for reaction invention. The general perception, however, is that photocatalysis is entering a more mature phase where the combination of experimental and mechanistic studies will play a dominant role in sustaining further innovation. This Review outlines the key mechanistic studies to consider when developing a photochemical process, and the best techniques available for acquiring relevant information. The discussion will use selected case studies to highlight how mechanistic investigations can be instrumental in guiding the invention and development of synthetically useful photocatalytic transformations.

Mechanistic Studies in Photocatalysis

This review describes the development of enantioselective methods for the ring opening of cyclopropanes. Both approaches based on the reaction of nonchiral cyclopropanes and (dynamic) kinetic resolutions and asymmetric transformations of chiral substrates are presented. The review is organized according to substrate classes, starting by the more mature field of donor-acceptor cyclopropanes. Emerging methods for enantioselective ring opening of acceptor- or donor-only cyclopropanes are then presented. The last part of the review describes the ring opening of more reactive three-membered rings substituted with unsaturations with a particular focus on vinylcyclopropanes, alkylidenecyclopropanes, and vinylidenecyclopropanes. In the last two decades, the field has grown from a proof of concept stage to a broad range of methods for accessing enantioenriched building blocks, and further extensive developments can be expected in the future.

/pdf/catalytic-enantioselective-ring-opening-reactions-of-2bjvxhx1y2.pdf

Catalytic Enantioselective Ring-Opening Reactions of Cyclopropanes.

Radical cascade reactions are an attractive tool for the rapid construction of complex molecular architectures. Although a large number of powerful radical cascades have been developed, stoichiometric amounts of reagents and/or additives are often required to mediate these processes. Radical relay strategies, in which radical character is recycled, require only a catalytic amount of reagent and are particularly attractive as they promise cascades that are high in atom economy. This tutorial review highlights recent advances in this rapidly developing area by setting out and dissecting the reaction designs underpinning state-of-the-art processes involving radical relays. Advances in the field of radical relay cascades will open the door to more efficient synthesis with far-reaching benefits for the makers and end-users of complex molecules.

Catalytic cascade reactions by radical relay

Low-valent early transition metals are often intrinsically highly reactive as a result of their strong propensity toward oxidation to more stable high-valent states. Harnessing these highly reducing complexes for productive reactivity is potentially powerful for C–C bond construction, organic reductions, small-molecule activation and many other reactions that offer orthogonal chemoselectivity and/or regioselectivity patterns to processes promoted by late transition metals. Recent years have seen many exciting new applications of low-valent metals through building new catalytic and/or multicomponent reaction manifolds out of classical reactivity patterns. In this Review, we survey new methods that employ early transition metals and invoke low-valent precursors or intermediates in order to identify common themes and strategies in synthesis and catalysis. Low-valent early transition metals are experiencing a renaissance in synthesis and catalysis, finding applications in unusual C–C bond forming reactions, oxidative group-transfer catalysis, proton-coupled electron transfer, photoredox catalysis and more.

/pdf/modern-applications-of-low-valent-early-transition-metals-in-2q7hvm8obg.pdf

Modern applications of low-valent early transition metals in synthesis and catalysis

Transition metal catalyzed cross-electrophile coupling of alkyl electrophiles has evolved into a privileged strategy that permits the facile construction of valuable C(sp3)-C bonds. Numerous elegant Ni-catalyzed coupling methods, for example, arylation, allylation, acylation, and vinylation of primary and secondary alkyl halides have been developed. This prior work has provided important mechanistic insights into the selectivity and reactivity of the coupling partners, which are largely dictated by both the catalysts and the reactants. In spite of the advances made to date, a number of challenging issues remain, including (1) achieving stereoselective syntheses of C-C bonds that rely primarily on functionalized or activated alkyl precursors, (2) diversifying the electrophiles, and (3) gaining insights into the underlying reaction mechanisms.In this Account, we summarize a number of Ni- and Fe-catalyzed reductive C-C bond forming methods developed in our laboratory, which have allowed us to couple activated, sterically hindered tertiary alkyl and C(sp3)-O bond electrophiles and to access methylated and trifluoromethylated products, esters, C-glycosides, and quaternary carbon centers. We will begin with a brief discussion of Ni-catalyzed chemoselective construction of unactivated alkyl-alkyl bonds, with focus on the effects of ligands and reductants, along with leaving group-directed reactivities of alkyl halides, and the role they play in promoting the reductive coupling of activated electrophiles, including methyl, trifluoromethyl, and glycosyl electrophiles, and chloroformates. Matching the reactivities of these electrophiles with suitable coupling partners is considered essential for success; this is something that can be tuned by means of appropriate Ni catalysts. Second, we will detail how tuning the steric and electronic effects of nickel catalysts with labile pyridine-type ligands and additives (primarily MgCl2) permits effective creation of arylated all-carbon quaternary centers through the coupling of aryl halides with sterically encumbered tertiary alkyl halides. In contrast, the use of bulkier bipyridine and terpyridine ligands permits the incorporation of relative small-sized acyl and allyl groups into acylated and allylated all-carbon quaternary centers. Finally, we will show how the knowledge gained with halide electrophiles enabled us to develop methods that permit the coupling of tertiary alkyl oxalates with allyl, aryl, and vinyl electrophiles, wherein Barton C-O bond radical fragmentation is mediated by Zn and MgCl2 and promoted by Ni catalysts. The same protocol is applicable to the arylation of secondary alkyl oxalates derived from α-hydroxyl carbonyl substrates, which involves the formation of relatively stable α-carbonyl carbon centered radicals. Thus, this Account not only summarizes synthetic methods that allow formation of valuable C-C bonds using challenging electrophiles but also provides insight into the relationship between the structure and reactivity of the substrates and catalysts, as well as the effects of additives.

Cross-Electrophile Couplings of Activated and Sterically Hindered Halides and Alcohol Derivatives.

We report Ti-catalyzed radical formal [3+2] cycloadditions of N-acylaziridines and alkenes. This method provides an efficient approach to the synthesis of pyrrolidines, structural units prevalent in bioactive compounds and organocatalysts, from readily available starting materials. The overall redox-neutral reaction was achieved via a redox-relay mechanism, which harnesses radical intermediates for selective C—N bond cleavage and formation.

Radical Redox-Relay Catalysis: Formal [3+2] Cycloaddition of N-Acylaziridines and Alkenes

We report a stereoselective formal [3 + 2] cycloaddition of cyclopropyl ketones and radical-acceptor alkenes to form polysubstituted cyclopentane derivatives. Catalyzed by a chiral Ti(salen) complex, the cycloaddition occurs via a radical redox-relay mechanism and constructs two C-C bonds and two contiguous stereogenic centers with generally excellent diastereo- and enantioselectivity.

Diastereo- and Enantioselective Formal [3 + 2] Cycloaddition of Cyclopropyl Ketones and Alkenes via Ti-Catalyzed Radical Redox Relay

Alkyl chlorides are common functional groups in synthetic organic chemistry. However, the engagement of unactivated alkyl chlorides, especially tertiary alkyl chlorides, in transition-metal-catalyzed C–C bond formation remains challenging. Herein, we describe the development of a TiIII-catalyzed radical addition of 2° and 3° alkyl chlorides to electron-deficient alkenes. Mechanistic data are consistent with inner-sphere activation of the C–Cl bond featuring TiIII-mediated Cl atom abstraction. Evidence suggests that the active TiIII catalyst is generated from the TiIV precursor in a Lewis-acid-assisted electron transfer process.

/pdf/ti-catalyzed-radical-alkylation-of-secondary-and-tertiary-2gdcxvjpkj.pdf

Ti-Catalyzed Radical Alkylation of Secondary and Tertiary Alkyl Chlorides Using Michael Acceptors.

New catalytic strategies that leverage single-electron redox events have provided chemists with useful tools for solving synthetic problems. In this context, Ti offers opportunities that are comple...

Recent Advances in Titanium Radical Redox Catalysis

Ti(salen) complexes catalyze the asymmetric [3 + 2] cycloaddition of cyclopropyl ketones with alkenes. While high enantioselectivities are achieved with electron-rich alkenes, electron-deficient alkenes are less selective. Herein, we describe mechanistic studies to understand the origins of catalyst and substrate trends in an effort to identify a more general catalyst. Density functional theory (DFT) calculations of the selectivity determining transition state revealed the origin of stereochemical control to be catalyst distortion, which is largely influenced by the chiral backbone and adamantyl groups on the salicylaldehyde moieties. While substitution of the adamantyl groups was detrimental to the enantioselectivity, mechanistic information guided the development of a set of eight new Ti(salen) catalysts with modified diamine backbones. These catalysts were evaluated with four electron-deficient alkenes to develop a three-parameter statistical model relating enantioselectivity to physical organic parameters. This statistical model is capable of quantitative prediction of enantioselectivity with structurally diverse alkenes. These mechanistic insights assisted the discovery of a new Ti(salen) catalyst, which substantially expanded the reaction scope and significantly improved the enantioselectivity of synthetically interesting building blocks.

Xiangyu Wu

Papers

Radical Redox-Relay Catalysis: Formal [3+2] Cycloaddition of N-Acylaziridines and Alkenes

Diastereo- and Enantioselective Formal [3 + 2] Cycloaddition of Cyclopropyl Ketones and Alkenes via Ti-Catalyzed Radical Redox Relay

Ti-Catalyzed Radical Alkylation of Secondary and Tertiary Alkyl Chlorides Using Michael Acceptors.

Recent Advances in Titanium Radical Redox Catalysis

Mechanistic Studies Inform Design of Improved Ti(salen) Catalysts for Enantioselective [3 + 2] Cycloaddition.