Direct C(sp)-H Acylation by Mechanistically Controlled Ni/Ir Photoredox Catalysis.

ConspectusSynthetic chemists have consistently aimed to develop efficient methods for synthesizing ketones, which are essential building blocks in organic chemistry and play significant roles in bioactive molecules. Recent efforts have focused on using photoredox catalysis, which enables previously inaccessible activation modes, to synthesize ketones through the cross-coupling of an acyl electrophile and simple C(sp)-H bonds. Over the past few years, we have worked on developing effective and versatile approaches for directly acylating activated hydrocarbons to forge ketones.

Synthesis of α-Aminoacetals via Decarboxylative Coupling of Imine and 2,2,-Diethoxyacetic Acid.

Atom-economical C-C coupling between imines and a C1 source could provide α-aminoaldehyde derivatives. Nevertheless, such a coupling has rarely been achieved owing to the lack of appropriate nucleophilic C1 sources. In this study, photocatalytic synthesis of α-aminoacetals was achieved via decarboxylative coupling of imine and 2,2-diethoxyacetic acid using a nonstoichiometric amount of a radical initiator.

Stereoretentive cross-coupling of chiral amino acid chlorides and hydrocarbons through mechanistically controlled Ni/Ir photoredox catalysis.

The direct modification of naturally occurring chiral amino acids to their amino ketone analogs is a significant synthetic challenge. Here, an efficient and robust cross-coupling reaction between chiral amino acid chlorides and unactivated C(sp)-H hydrocarbons is achieved by a mechanistically designed Ni/Ir photoredox catalysis. This reaction, which proceeds under mild conditions, enables modular access to a wide variety of chiral amino ketones that retain the stereochemistry of the starting amino acids.

Direct C(sp)-H Cyanation Enabled by a Highly Active Decatungstate Photocatalyst.

A highly efficient, direct C(sp)-H cyanation was developed under mild photocatalytic conditions. The method enabled the direct cyanation of various C(sp)-H substrates with excellent functional group tolerance. Notably, complex natural products and bioactive compounds were efficiently cyanated.

Synthesis of -aryl amines enabled by photocatalytic dehydrogenation.

Catalytic dehydrogenation (CD) visible-light photoredox catalysis provides an efficient route for the synthesis of aromatic compounds. However, access to -aryl amines, which are widely utilized synthetic moieties, visible-light-induced CD remains a significant challenge, because of the difficulty in controlling the reactivity of amines under photocatalytic conditions. Here, the visible-light-induced photocatalytic synthesis of -aryl amines was achieved by the CD of allylic amines.

The site-selectivity and mechanism of Pd-catalyzed C(sp)-H arylation of simple arenes.

Control over site-selectivity is a critical challenge for practical application of catalytic C-H functionalization reactions in organic synthesis. Despite the seminal breakthrough of the Pd-catalyzed C(sp)-H arylation of simple arenes a concerted metalation-deprotonation (CMD) pathway in 2006, understanding the site-selectivity of the reaction still remains elusive. Here, we have comprehensively investigated the scope, site-selectivity, and mechanism of the Pd-catalyzed direct C-H arylation reaction of simple arenes.

Cobalt-Catalyzed Intermolecular C-H Amidation of Unactivated Alkanes.

Alkanes are an abundant and inexpensive source of hydrocarbons; thus, development of new methods to convert the hydrocarbon feedstocks to value-added chemicals is of high interest. However, it is challenging to achieve such transformation in a direct and selective manner mainly due to the intrinsic inertness of their C-H bonds. We herein report a tailored Cp*Co(III)(LX)-catalyzed efficient and site-selective intermolecular amidation of unactivated hydrocarbons including light alkanes.

Pd-catalyzed formal Mizoroki-Heck coupling of unactivated alkyl chlorides.

The use of alkyl chlorides in Pd-catalyzed Mizoroki-Heck coupling reactions remains an unsolved problem despite their significant potential for synthetic utility and applicability. The combination of the high thermodynamic barrier of alkyl chloride activation and kinetic propensity of alkylpalladium complexes to undergo undesired β-hydride elimination provides significant challenges. Herein, a variety of alkyl chlorides, even tertiary chlorides, are shown to efficiently participate in Mizoroki-Heck cross-coupling reactions with excellent functional group compatibility under mild reaction conditions via photoinduced Pd catalysis.

Direct C(sp )-H Trifluoromethylation of Unactivated Alkanes Enabled by Multifunctional Trifluoromethyl Copper Complexes.

A mild and operationally simple C(sp )-H trifluoromethylation method was developed for unactivated alkanes by utilizing a bench-stable Cu complex, bpyCu(CF ) , as the initiator of the visible-light photoinduced reaction, the source of a trifluoromethyl radical as a hydrogen atom transfer reagent, and the source of a trifluoromethyl anion for functionalization. The reaction was initiated by the generation of reactive electrophilic carbon-centered CF radical through photoinduced homolytic cleavage of bpyCu(CF ) , followed by hydrogen abstraction from an unactivated C(sp )-H bond. Comprehensive mechanistic investigations based on a combination of experimental and computational methods suggested that C-CF bond formation was enabled by radical-polar crossover and ionic coupling between the resulting carbocation intermediate and the anionic CF source.

Author Correction: Direct C(sp)-H alkylation of unactivated arenes enabled by photoinduced Pd catalysis.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-020-19812-8 .

Direct C(sp)-H alkylation of unactivated arenes enabled by photoinduced Pd catalysis.

Despite the fundamental importance of efficient and selective synthesis of widely useful alkylarenes, the direct catalytic C(sp)-H alkylation of unactivated arenes with a readily available alkyl halide remains elusive. Here, we report the catalytic C(sp)-H alkylation reactions of unactivated arenes with alkyl bromides via visible-light induced Pd catalysis. The reaction proceeds smoothly under mild conditions without any skeletal rearrangement of the alkyl groups.

Synergistic Activation of Amides and Hydrocarbons for Direct C(sp )-H Acylation Enabled by Metallaphotoredox Catalysis.

The utilizations of omnipresent, thermodynamically stable amides and aliphatic C(sp )-H bonds for various functionalizations are ongoing challenges in catalysis. In particular, the direct coupling between the two functional groups has not been realized. Here, we report the synergistic activation of the two challenging bonds, the amide C-N and unactivated aliphatic C(sp )-H, via metallaphotoredox catalysis to directly acylate aliphatic C-H bonds utilizing amides as stable and readily accessible acyl surrogates.

Synthesis of Conjugated Polyenynes with Alternating Six- and Five-Membered Rings via β-Selective Cascade Metathesis and Metallotropy Polymerization.

Cascade metathesis and metallotropy (M&M) polymerization, which involves sequential olefin metathesis and metallotropic 1,3-shift reactions specifically from multiyne monomers, is the only method reported so far to prepare conjugated polyenynes via the chain-growth mechanism. Using this method, various conjugated polyenynes containing cyclopentene units in the backbone could be synthesized via exclusive α-addition by using the third-generation Grubbs catalyst. Herein, we demonstrate the complete switch of regioselectivity toward β-addition using a Ru carbene containing a dithiolate ligand, and thus, synthesized unique conjugated polyenynes having alternating cyclohexene and cyclopentene units in the backbone.

Highly active ruthenium metathesis catalysts enabling ring-opening metathesis polymerization of cyclopentadiene at low temperatures.

Development of versatile ruthenium olefin-metathesis catalysts with high activity, stability, and selectivity is a continuous challenge. Here we report highly controllable ruthenium catalysts using readily accessible and versatile N-vinylsulfonamides as carbene precursors. Catalyst initiation rates were controlled in a straightforward manner, from latent to fast initiating, through the facile modulation of the N-vinylsulfonamide ligands.

Formal Giese addition of C(sp)-H nucleophiles enabled by visible light mediated Ni catalysis of triplet enone diradicals.

An unprecedented utilization of triplet excited enones in Ni-catalysis enabled a formal Giese addition of C(sp)-H nucleophiles. This mechanism-based approach has greatly widened the reaction scope, allowing the synthesis of previously inaccessible structures. In this process, the enone diradical acted as two distinct reaction centers, participating in both metalation and hydrogen atom transfer, ultimately furnishing a range of formal Giese addition products in a highly general context.

Hydrogenation of silyl formates: sustainable production of silanol and methanol from hydrosilane and carbon dioxide.

A new process for simultaneously obtaining two chemical building blocks, methanol and silanol, was realized starting from silyl formates which can be derived from silane and carbon dioxide. Understanding the reaction mechanism enabled us to improve the reaction efficiency by the addition of a small amount of methanol.

Selective Monomethylation of Amines with Methanol as the C Source.

The N-monomethyl functionality is a common motif in a variety of synthetic and natural compounds. However, facile access to such compounds remains a fundamental challenge in organic synthesis owing to selectivity issues caused by overmethylation. To address this issue, we have developed a method for the selective, catalytic monomethylation of various structurally and functionally diverse amines, including typically problematic primary aliphatic amines, using methanol as the methylating agent, which is a sustainable chemical feedstock.

Understanding the Origin of the Regioselectivity in Cyclopolymerizations of Diynes and How to Completely Switch It.

Grubbs-type olefin metathesis catalysts are known to cyclopolymerize 1,6-heptadiynes to afford conjugated polyenes containing five- or six-membered carbocycles. Although high levels of regioselectivity up to >99:1 were observed previously for the formation of five-membered rings, it was neither possible to deliberately obtain six-membered rings at similar levels of selectivity nor understood why certain catalysts showed this selectively. Combining experimental and computational methods, a novel and general theory for what controls the regiochemistry of these cyclopolymerizations is presented.

Photoredox mediated nickel catalyzed C(sp)-H thiocarbonylation of ethers.

The first direct C(sp)-H thiocarbonylation reaction is achieved by visible light photoredox/Ni dual catalysis. The thioester group of thiobenzoate is transferred to the α-oxy carbon of various cyclic/acyclic ethers, which is the opposite to the commonly expected chemical reactivity involving acyl group transfer the weaker C(acyl)-S activation. Through mechanistic studies, we proposed that the reaction is initiated by photocatalytic reduction and fragmentation of the thioester into an acyl radical and a thiolate.

Gold(I)/Gold(III)-Catalyzed Selective Synthesis of N-Sulfonyl Enaminone Isomers from Sulfonamides and Ynones via Two Distinct Reaction Pathways.

Au-catalyzed chemoselective methods for synthesizing N-sulfonyl enaminones are developed. Two different isomers are obtained in a chemocontrolled manner by employing the different properties of Au(I) and Au(III) catalysts. Hydroamidation and proton-assisted carbonyl activation followed by Meyer-Schuster rearrangement are proposed as the working mechanisms for the reactions.

Dual Activation of Nucleophiles and Electrophiles by N-Heterocyclic Carbene Organocatalysis: Chemoselective N-Imination of Indoles with Isocyanides.

The first chemoselective N-imination of indoles with isocyanides by using an N-heterocyclic carbene (NHC) as an organocatalyst was achieved. A concurrent activation of nucleophile (indole) and electrophile (isocyanide) took place facilitated by the novel NHC organocatalysis via initial activation of isocyanide. The in situ generated indole anion and imine-azolium species performed a coupling reaction, producing several new indole-based formamidines in high yields under mild conditions, which was not feasible via previously reported strategies.

Organocatalytic activation of isocyanides: N-heterocyclic carbene-catalyzed enaminone synthesis from ketones.

The first example of the use of an N-heterocyclic carbene (NHC) as an organocatalyst for the activation of isocyanides was demonstrated. On the basis of previous reports on the interaction between NHCs and isocyanides, we developed a catalytic cycle involving transient imidoyl intermediate. The reaction of ketones with isocyanides produced the corresponding enaminones with high efficiency.

Cyanuric Acid-Based Organocatalyst for Utilization of Carbon Dioxide at Atmospheric Pressure.

A organocatalytic system based on economical and readily available cyanuric acid has been developed for the synthesis of 2-oxazolidinones and quinazoline-2,4(1H,3H)-diones from propargylamines and 2-aminobenzonitriles under atmospheric pressure carbon dioxide. Notably, a low concentration of carbon dioxide in air was directly converted into 2-oxazolidinone in excellent yields without an external base. Through mechanistic investigation by in situ FTIR spectroscopy, cyanuric acid was demonstrated to be an efficient catalyst for carbon dioxide fixation.

Ruthenium-Catalyzed Urea Synthesis Using Methanol as the C1 Source.

An unprecedented protocol for urea synthesis directly from methanol and amine was accomplished. The reaction is highly atom-economical, producing hydrogen as the sole byproduct. Commercially available ruthenium pincer complexes were used as catalysts.