With the recent soaring production of natural gas, the use of methane and other light hydrocarbon feedstocks as starting materials in synthetic transformations is becoming increasingly economically ...attractive, although it remains chemically challenging. We report the development of photocatalytic C-H amination, alkylation, and arylation of methane, ethane, and higher alkanes under visible light irradiation at ambient temperature. High catalytic efficiency (turnover numbers up to 2900 for methane and 9700 for ethane) and selectivity were achieved using abundant, inexpensive cerium salts as photocatalysts. Ligand-to-metal charge transfer excitation generated alkoxy radicals from simple alcohols that in turn acted as hydrogen atom transfer catalysts. The mixed-phase gas/liquid reaction was adapted to continuous flow, enabling the efficient use of gaseous feedstocks in scalable photocatalytic transformations.
Alkoxy radicals are highly reactive species that have long been recognized as versatile intermediates in organic synthesis. However, their development has long been impeded due to a lack of ...convenient methods for their generation. Thanks to advances in photoredox catalysis, enabling facile access to alkoxy radicals from bench-stable precursors and free alcohols under mild conditions, research interest in this field has been renewed. This review comprehensively summarizes the recent progress in alkoxy radical-mediated transformations under visible light irradiation. Elementary steps for alkoxy radical generation from either radical precursors or free alcohols are central to reaction development; thus, each section is categorized and discussed accordingly. Throughout this review, we have focused on the different mechanisms of alkoxy radical generation as well as their impact on synthetic utilizations. Notably, the catalytic generation of alkoxy radicals from abundant alcohols is still in the early stage, providing intriguing opportunities to exploit alkoxy radicals for diverse synthetic paradigms.
Conspectus Indole alkaloids, one of the largest classes of alkaloids, serve as an important and rich source of pharmaceuticals and have inspired synthetic chemists to develop novel chemical ...transformations and synthetic strategies. Many biologically active natural products contain challenging indoline scaffolds, which feature a C3 all-carbon quaternary stereocenter that is often surrounded by a complicated polycyclic ring system. The creation of this quaternary stereocenter creates an inherent synthetic challenge because the substituents on the carbon center cause high steric repulsion. In addition, the presence of nitrogen atoms within the surrounding polycyclic rings can lead to synthetic difficulties. Oxidative coupling between two sp3-hybridized carbon anions provides a unique and powerful method for building C–C single bonds, especially for generating a C–C bond that joins one or two vicinal quaternary stereocenters. Although chemists have known of this transformation for a long time, they have only applied this reaction in total synthesis of complex natural products during the past decade. The progress of this class of reaction depends on the use of indole moieties as coupling partners. In this Account, we summarize our recent efforts to develop iodine-mediated intramolecular dearomative oxidative coupling (IDOC) reactions of indoles as part of a unified strategy for the total synthesis of three classes of indoline alkaloids. We categorized these IDOC reactions into three types based on their mode of connection to the indole moiety. In type I, the carboanion nucleophile was tethered to the indole at the C3 position. This reaction enabled the assembly of skeleton A, which features a spiro ring at the C3 position of the indole. We demonstrated the efficiency of this method by quickly assembling two classes of tetracyclic compounds and completing the total synthesis of (−)-communesins F, A, and B. For the type II IDOC reactions, the carboanion nucleophile residing at the C2 position of the indole formed a quaternary center at the C3 position of indole to produce skeleton B. We applied this IDOC reaction to synthesize two akuammiline alkaloids, vincorine and aspidophylline A. Type III IDOC reactions employed substrates with a preinstalled ring at the C2 and C3 positions of the indole. These transformations proceeded smoothly to afford polycyclic ring system C, which we used in the first enantioselective total synthesis of Kopsia alkaloid methyl N-decarbomethoxychanofruticosinate. These results further demonstrate how new chemical strategies and reactions facilitate both the first total syntheses of natural products and the discovery of more efficient synthetic routes.
Under mild reaction conditions with inexpensive cerium and nickel catalysts, easily accessible free alcohols can now be utilized as operationally simple and robust carbon pronucleophiles in selective ...C(sp3)–C(sp2) cross-couplings. Facilitated by automated high-throughput experimentation, sterically encumbered benzoate ligands have been identified for robust cerium complexes, enabling the synergistic cooperation of cerium catalysis in the emerging metallaphotoredox catalysis. A broad range of free alcohols and aromatic halides can be facilely employed in this transformation, representing a new paradigm for the C(sp3)–C(sp2) bond construction between free alcohols and aryl halides with the extrusion of formaldehyde. Moreover, mechanistic investigations have been conducted, leading to the identification of a tribenzoate cerium(III) complex as a viable intermediate.
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•Photocatalytic alkoxy radical-mediated reactions.•Alkoxy radicals mediated CH functionalizations.•CC bond cleavage and functionalizations of alcohols.
Alkoxy radicals have been ...intensively studied as versatile synthetic intermediates with well-established reactivity and selectivity. Due to the difficulties associated with the generation of these transient and high-energy radicals, the utilization of the unique reactivity of alkoxy radicals in catalytic platforms has become a rather challenging task. Recent studies on the alkoxy radical-mediated transformations have benefited tremendously from advances in modern photoredox catalysis. In this digest, we aim to highlight reported transformations that utilize alkoxy radicals in a photocatalytic fashion, in particular, underline novel catalytic platforms which we anticipate will find broad application in the near future.
Modern photoredox catalysis has traditionally relied upon metal-to-ligand charge-transfer (MLCT) excitation of metal polypyridyl complexes for the utilization of light energy for the activation of ...organic substrates. Here, we demonstrate the catalytic application of ligand-to-metal charge-transfer (LMCT) excitation of cerium alkoxide complexes for the facile activation of alkanes utilizing abundant and inexpensive cerium trichloride as the catalyst. As demonstrated by cerium-catalyzed C–H amination and the alkylation of hydrocarbons, this reaction manifold has enabled the facile use of abundant alcohols as practical and selective hydrogen atom transfer (HAT) agents via the direct access of energetically challenging alkoxy radicals. Furthermore, the LMCT excitation event has been investigated through a series of spectroscopic experiments, revealing a rapid bond homolysis process and an effective production of alkoxy radicals, collectively ruling out the LMCT/homolysis event as the rate-determining step of this C–H functionalization.
The direct application of carboxylic acids as a traceless activation group for radical Michael additions has been accomplished via visible light-mediated photoredox catalysis. Photon-induced ...oxidation of a broad series of carboxylic acids, including hydrocarbon-substituted, α-oxy, and α-amino acids, provides a versatile CO2-extrusion platform to generate Michael donors without the requirement for organometallic activation or propagation. A diverse array of Michael acceptors is amenable to this new conjugate addition strategy. An application of this technology to a three-step synthesis of the medicinal agent pregabalin (commercialized by Pfizer under the trade name Lyrica) is also presented.
A general strategy for the cleavage and amination of C−C bonds of cycloalkanols has been achieved through visible‐light‐induced photoredox catalysis utilizing a cerium(III) chloride complex. This ...operationally simple methodology has been successfully applied to a wide array of unstrained cyclic alcohols, and represents the first example of catalytic C−C bond cleavage and functionalization of unstrained secondary cycloalkanols.
Breaking (D)BAD: A general strategy for the cleavage and amination of C−C bonds of cycloalkanols has been achieved through visible‐light‐induced photoredox catalysis utilizing a cerium(III) chloride complex. This method represents the first example of catalytic C−C bond cleavage and functionalization of unstrained secondary cycloalkanols. DBAD=di‐tert‐butyl azodicarboxylate, Boc=tert‐butoxycarbonyl.
Here, we report a general catalytic manifold for the selective C–C bond scission of ketones via the exploitation of the ligand-to-metal charge transfer (LMCT) excitation mode. Through a cooperative ...utilization of Lewis acid catalysis and LMCT catalysis, the C–C bond of ketones could be selectively and effectively cleaved, enabling the installation of different functionalities at each carbon of the cleaved C–C bond through a sequential and orthogonal manner. This reaction manifold serves as a photocatalytic alternative to the Norrish type I reaction with the combination of visible light and inexpensive cerium salts. Under operationally simple conditions, a wide range of acyclic and cyclic ketones, from simple strained cyclobutanones to complex androsterone with less strained cyclopentanone moiety, could be successfully transformed into versatile chemical building blocks.
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•Development of a photocatalyzed C–C bond scission of ketones•Ligand-to-metal charge transfer catalysis•Cooperative utilization of cerium and titanium catalysts
In the endeavor to search for innovative catalysis, the synthetic chemists face ever-increasing financial and environmental demands in chemical production. The development of catalytic modes employing abundant and inexpensive metal catalysts has drawn significant research attention in the chemical community with regard to addressing the current challenges in the sustainable development of chemical synthesis. The selective C–C bond cleavage and functionalizations have recently emerged as an unconventional yet advantageous synthetic strategy, nevertheless, currently predominated by transition metals such as Rh, Ir, etc. The utilization of cost-effective and abundant metal catalysts would undoubtedly expedite the synthetic application of C–C bond cleavage transformations while addressing economic and ecological concerns; more importantly, the use of metal catalysts would potentially prompt the development of new catalytic paradigms.
The Norrish type I reaction represents a powerful approach to cleave C–C bonds of ketones, yet the synthetic application has been limited because of selectivity and practicality problems. Through the catalytic utilization of the ligand-to-metal charge transfer excitation, Chen and colleagues describe a photocatalytic transformation, in which C–C bonds of ketones are exploited as unconventional handles for selective functionalizations. This protocol, with its utilization of blue LED and inexpensive cerium catalyst, has been successfully employed to cleave a broad range of ketones, regardless of cyclic or acyclic, from simple dibenzyl ketone to complex androsterone.
A concise asymmetric total synthesis of (−)-communesin F (∼6% overall yield in the longest linear sequence of 19 steps) is described. It features an unprecedented intramolecular oxidative coupling ...strategy for the elaboration of the requisite spiro-fused indoline moiety. Other notable elements are the use of TBS-protected (S)-phenylglycinol as a chiral auxiliary to induce the asymmetric formation of the spiro-fused indoline part, the mesylate-mediated formation of its G ring, and the introduction of the A ring at the final stage via intramolecular Staudinger reaction. This intramolecular Staudinger reaction proceeded smoothly at 80 °C, providing an additional example illustrating that twisted amides are more reactive than simple amides. Along with the total synthesis, we were able to assign the absolute configuration of natural communesin F as 6R,7R,8R,9S,11R.
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