Direct C(sp3)-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(sp3)-H bonds. Over the past few years, we have worked on developing effective and versatile approaches for directly acylating activated hydrocarbons to forge ketones.Initially, thioesters were explored as the acyl source to achieve the direct acylation of ethers, but an unexpected thioesterification reaction was observed instead. To gain insights into this reactivity, we conducted the optimization of reaction conditions, substrate scope evaluation, and mechanistic studies. Drawing from our understanding of Ni/Ir photocatalysis obtained in this study, we subsequently developed a method for the direct acylation of simple hydrocarbons. The use of less-reactive amides as the acyl electrophiles was found to be critical for suppressing undesired pathways. This seemingly counterintuitive reactivity was carefully studied, revealing a substrate-assisted reaction mechanism in which the suppressed oxidative addition leads to early-stage nickel oxidation and C-H activation.To address the drawbacks of this method, which primarily arose from decarbonylative and transmetallative side pathways, we employed N-acyllutidiniums as the acyl electrophile. This prevented undesired decomposition pathways, enabling the use of α-chiral acyl substrates with the retention of their stereochemistry, particularly those derived from α-amino acids. The developed versatile methodology allowed us to access a diverse range of α-amino ketones and their homologues.Despite the elegant utility of Ni/photoredox catalysis in developing new synthetic methodologies, the precise behavior of nickel catalysts under redox conditions is incompletely understood. To gain insight into this behavior and develop new chemical reactions, we used a combination of experimental and computational methods. Our investigations revealed that devised adjustments to the reaction conditions in nickel/photoredox catalysis can result in significant differences in the reaction outcomes, providing chemists with opportunities to tailor reactions through carefully designed mechanistic strategies. We believe that continued efforts to study and apply nickel redox modulation will lead to the discovery of additional organic transformations.

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. Various functional groups were compatible, providing efficient one-step access to diversely functionalized α-aminoacetals, which provides a promising platform for further research.

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(sp3)-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. In-depth mechanistic analysis reveals that the strategic generation of an N-acyllutidinium intermediate is critical for the success of this reaction. The barrierless reduction of the N-acyllutidinium intermediate facilitates the delivery of chiral amino ketones with retention of stereochemistry. This pathway avoids the formation of a detrimental nickel intermediate, which could be responsible for undesirable decarbonylation and transmetalation reactions that limit the utility of previously reported methods.

Direct C(sp3)-H Cyanation Enabled by a Highly Active Decatungstate Photocatalyst.

A highly efficient, direct C(sp3)-H cyanation was developed under mild photocatalytic conditions. The method enabled the direct cyanation of various C(sp3)-H substrates with excellent functional group tolerance. Notably, complex natural products and bioactive compounds were efficiently cyanated.

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. Electronic modulation of the cobalt complexes led to the enhanced amidation efficiency, and these effects were theoretically rationalized by the FMO analysis of presupposed cobalt nitrenoid species. Under the current cobalt protocol, a secondary C-H bond selectivity was observed in various nonactivated alkanes to reverse the intrinsic tertiary preference, which is attributed to the steric demands of the cobalt system that imposes difficulties in accessing tertiary C-H bonds. Experimental and computational studies suggested that the putative triplet Co nitrenoids are transferred to the C-H bonds of alkanes via a radical-like hydrogen abstraction pathway.

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 ß-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. The reaction is applied to late-stage functionalizations of diverse biologically significant scaffolds and iterative double Mizoroki-Heck annulations, affording high molecular complexity in a single step. Notably, studies on the kinetic isotope effects in combination with density functional theory (DFT)-computations completely exclude the involvement of a previously proposed ß-hydride elimination in the catalytic cycle, revealing that the chlorine atom transfer process is the key catalytic turnover step. This distinctive single-electron transfer mediated reaction pathway resolves a longstanding challenge in traditional two-electron based Pd-catalyzed Mizoroki-Heck cross-coupling with alkyl electrophiles, wherein the ß-hydride elimination is involved in the formation of both the desired product and undesired by-products.

Direct C(sp3 )-H Trifluoromethylation of Unactivated Alkanes Enabled by Multifunctional Trifluoromethyl Copper Complexes.

A mild and operationally simple C(sp3 )-H trifluoromethylation method was developed for unactivated alkanes by utilizing a bench-stable CuIII complex, bpyCu(CF3 )3 , 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 CF3 radical through photoinduced homolytic cleavage of bpyCu(CF3 )3 , followed by hydrogen abstraction from an unactivated C(sp3 )-H bond. Comprehensive mechanistic investigations based on a combination of experimental and computational methods suggested that C-CF3 bond formation was enabled by radical-polar crossover and ionic coupling between the resulting carbocation intermediate and the anionic CF3 source. The methylene-selective reaction can be applied to the direct, late-stage trifluoromethylation of natural products and bioactive molecules.

Author Correction: Direct C(sp2)-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(sp2)-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(sp2)-H alkylation of unactivated arenes with a readily available alkyl halide remains elusive. Here, we report the catalytic C(sp2)-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. The direct syntheses of structurally diverse linear and branched alkylarenes, including the late-stage phenylation of biologically active molecules and an orthogonal one-pot sequential Pd-catalyzed C-C bond-forming reaction, are achieved with exclusive chemoselectivity and exceptional functional group tolerance. Comprehensive mechanistic investigations through a combination of experimental and computational methods reveal a distinguishable Pd(0)/Pd(I) redox catalytic cycle and the origin of the counter-intuitive reactivity differences among alkyl halides.

Synergistic Activation of Amides and Hydrocarbons for Direct C(sp3 )-H Acylation Enabled by Metallaphotoredox Catalysis.

The utilizations of omnipresent, thermodynamically stable amides and aliphatic C(sp3 )-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(sp3 )-H, via metallaphotoredox catalysis to directly acylate aliphatic C-H bonds utilizing amides as stable and readily accessible acyl surrogates. N-acylsuccinimides served as efficient acyl reagents for the streamlined synthesis of synthetically useful ketones from simple C(sp3 )-H substrates. Detailed mechanistic investigations using both computational and experimental mechanistic studies were performed to construct a detailed and complete catalytic cycle. The origin of the superior reactivity of the N-acylsuccinimides over other more reactive acyl sources such as acyl chlorides was found to be an uncommon reaction pathway which commences with C-H activation prior to oxidative addition of the acyl substrate.

The site-selectivity and mechanism of Pd-catalyzed C(sp2)-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(sp2)-H arylation of simple arenes via 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. Counterintuitively, electron-rich arenes preferably undergo meta-arylation without the need for a specifically designed directing group, whereas electron-deficient arenes bearing fluoro or cyano groups exhibit high ortho-selectivity and electron-deficient arenes bearing bulky electron-withdrawing groups favor the meta-product. Comprehensive mechanistic investigations through a combination of kinetic measurements and stoichiometric experiments using arylpalladium complexes have revealed that the Pd-based catalytic system works via a cooperative bimetallic mechanism, not the originally proposed monometallic CMD mechanism, regardless of the presence of a strongly coordinating L-type ligand. Notably, the transmetalation step, which is influenced by a potassium cation, is suggested as the selectivity-determining step.

Synthesis of N-aryl amines enabled by photocatalytic dehydrogenation.

Catalytic dehydrogenation (CD) via visible-light photoredox catalysis provides an efficient route for the synthesis of aromatic compounds. However, access to N-aryl amines, which are widely utilized synthetic moieties, via 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 N-aryl amines was achieved by the CD of allylic amines. The unusual strategy using C6F5I as an hydrogen-atom acceptor enables the mild and controlled CD of amines bearing various functional groups and activated C-H bonds, suppressing side-reaction of the reactive N-aryl amine products. Thorough mechanistic studies suggest the involvement of single-electron and hydrogen-atom transfers in a well-defined order to provide a synergistic effect in the control of the reactivity. Notably, the back-electron transfer process prevents the desired product from further reacting under oxidative conditions.

Synthesis of Conjugated Polyenynes with Alternating Six- and Five-Membered Rings via ß-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 ß-addition using a Ru carbene containing a dithiolate ligand, and thus, synthesized unique conjugated polyenynes having alternating cyclohexene and cyclopentene units in the backbone. Furthermore, detailed in situ NMR studies revealed an interesting phenomenon that the adjacent triple bond strongly chelates to the propagating Ru carbene during the polymerization.

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. Trifluoromethanesulfonamide-based catalysts initiated ultrarapidly even at temperatures as low as -60 °C and continuously propagated rapidly, enabling the enthalpically and entropically less-favored ring-opening metathesis polymerizations of low-strained functionalized cyclopentene derivatives, some of which are not accessible with previous olefin-metathesis catalysts. To our surprise, the developed catalysts facilitated the polymerization of cyclopentadiene (CPD), a feedstock that is easily and commonly obtainable through the steam cracking of naphtha, which has, to the best of our knowledge, not been previously achieved due to its low ring strain and facile dimerization even at low temperatures (below 0 °C).

Formal Giese addition of C(sp3)-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(sp3)-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. This reaction provides complementary access to traditional 1,4-addition reactions of enones, with a future perspective to develop triplet diradical-based transition metal catalysis.

Highly Regioselective and E/ Z-Selective Hydroalkylation of Ynone, Ynoate, and Ynamide via Photoredox Mediated Ni/Ir Dual Catalysis.

Exclusively α- and highly E/ Z-selective hydroalkylation of ynone, ynoate, and ynamide was achieved via photoredox mediated Ni/Ir dual catalysis with high atom and step economy, producing trisubstituted enones, which are versatile synthetic building blocks. The developed reaction selectively delivered the α/ Z isomer, which is complementary to the previously reported ß-alkylation processes. The trisubstituted enones could be transformed to more valuable compounds via post-functionalization.

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 C1 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. Kinetic control of the aliphatic amine monomethylation was achieved by using a readily available ruthenium catalyst at an adequate temperature under hydrogen pressure. Various substrates including bio-related molecules and pharmaceuticals were selectively monomethylated, demonstrating the general utility of the developed method.

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. The electronic demands of the ruthenium-based Fischer carbenes are found to innately prefer to form five-membered rings. Reducing the electrophilicity of the carbene by enforcing a trigonal-bipyramidal structure for the ruthenium, where stronger π-backdonation increases the electron density on the carbene, is predicted to invert the regioselectivity. Subsequent experiments provide strong support for the new concept, and it is possible to completely switch the regioselectivity to a ratio of <1:99.

Photoredox mediated nickel catalyzed C(sp3)-H thiocarbonylation of ethers.

The first direct C(sp3)-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 via 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. A nickel complex binds to the thiolate and induces the decarbonylation of the acyl radical to form an aryl radical, which abstracts hydrogen from the α-oxy carbon of the ether. The resulting α-oxy C(sp3) centered radical re-binds to the (RS)(CO)Ni complex, which undergoes CO migratory insertion and reductive elimination to give the desired thioester product.