Photoredox Cleavage of a Csp3-Csp3 Bond in Aromatic Hydrocarbons.

Functionalizing molecules through the selective cleavage of carbon-carbon bonds is an attractive approach in synthetic chemistry. Despite recent advances in both transition-metal catalysis and radical chemistry, the selective cleavage of inert Csp3-Csp3 bonds in hydrocarbon feedstocks remains challenging. Examples reported in the literature typically involve substrates containing redox functional groups or highly strained molecules. In this article, we present a straightforward protocol for the cleavage and functionalization of Csp3-Csp3 bonds in alkylbenzenes using photoredox catalysis. Our method employs two distinct bond scission pathways. For substrates with tertiary benzylic substituents, a carbocation-coupled electron transfer mechanism is prevalent. For substrates with primary or secondary benzylic substituents, a triple single-electron oxidation cascade is applicable. Our strategy offers a practical means of cleaving inert Csp3-Csp3 bonds in molecules without any heteroatoms, resulting in primary, secondary, tertiary, and benzylic radical species.

Enantioselective Seleno-Michael Addition Reactions Catalyzed by a Chiral Bifunctional N-Heterocyclic Carbene with Noncovalent Activation.

The Michael reaction is a conjugate addition and is one of the most powerful methods with which to prepare functional molecules with a ß-stereogenic center. Despite its success in the formation of various asymmetric carbon-carbon and carbon-heteroatom bonds, enantioselective seleno-Michael addition remains essentially unexplored. We report here a highly enantioselective Michael addition reaction of alkyl selenols to enones. This method conveniently introduces a Se atom to an electron-deficient double bond asymmetrically. A chiral bifunctional N-heterocyclic carbene (NHC)/thiourea catalyst was developed as a key ingredient that delivers chiral ß-seleno ketones with remarkable selectivity. This new catalyst and its mode of action support broad applications in the catalytic activation of nucleophilic reactions.

A Thioether-Catalyzed Cross-Coupling Reaction of Allyl Halides and Arylboronic Acids.

C(sp3 )-C(sp2 ) cross-coupling reactions are an indispensable tool for organic synthesis. In these reactions transition metals have been extensively employed to promote the formation of valuable carbon-carbon bonds. Herein, we report our recent discovery of a designer thioether as a highly active organocatalyst for reactions between an allyl bromide and an arylboronic acid. The cross-coupling event occurred readily under mild condition in the presence of a weak inorganic base. Preliminary mechanistic studies suggested a sulfonium ylide mechanism.

Enantioselective Intramolecular [2,3]-Sigmatropic Rearrangement of Aldehydes via a Sulfonium Enamine Intermediate.

The rearrangement of sulfur-containing aldehydes by using a sulfonium enamine intermediate as a formylcarbene mimetic is reported. This is an enantioselective, organocatalytic [2,3]-sigmatropic rearrangement enabling chiral cyclic sulfides bearing an α-quaternary chiral center to be prepared in high optical purity. The enantioselectivity is controlled with a cooperative organocatalyst pair consisting of a chiral amine and a chiral phosphoric acid (CPA). The synthetic versatility of this method is demonstrated by its rapid access to structurally diverse chiral spiro S-heterocycles.

Enantio- and Diastereoselective Hydrofluorination of Enals by N-Heterocyclic Carbene Catalysis.

In contrast to well-established asymmetric hydrogenation reactions, enantioselective protonation is an orthogonal approach for creating highly valuable methine chiral centers under redox-neutral conditions. Reported here is the highly enantio- and diastereoselective hydrofluorination of enals by an asymmetric ß-protonation/α-fluorination cascade catalyzed by N-heterocyclic carbenes (NHCs). The two nucleophilic sites of a homoenolate intermediate, generated from enals and an NHC, are sequentially protonated and fluorinated. The results show that controlling the relative rates of protonation, fluorination, and esterification is crucial for this transformation, and can be accomplished using a dual shuttling strategy. Structurally diverse carboxylic acid derivatives with two contiguous chiral centers are prepared in a single step with excellent d.r. and ee values.

Aerobic Oxidation/Annulation Cascades through Synergistic Catalysis of RuCl3 and N-Heterocyclic Carbenes.

Cooperative catalysis combining a transition metal with an N-heterocyclic carbene is challenging due to strong binding of NHCs towards late transition metals. We report the first example of synergistic catalysis by a chiral NHC and a coordinatively unsaturated ruthenium compound. RuCl3 was found to mediate efficient aerobic oxidation of homoenolates generated from enals and the N-heterocyclic carbene. The resulting α,ß-unsaturated acylazolium intermediate reacts selectively with 1,3-dicarbonyl compounds or ketones at either the ß- or γ-carbon, yielding polysubstituted chiral lactones in high yield and with excellent enantioselectivity (up to 98 % yield, 94 % ee). This protocol can be applied to structurally sophisticated substrates.

Enantioselective Hydroamidation of Enals by Trapping of a Transient Acyl Species.

An enantioselective synthesis of ß-chiral amides through asymmetric and redox-neutral hydroamidation of enals is reported. In this reaction, a chiral N-heterocyclic carbene (NHC) catalyst reacts with enals to generate the homoenolate intermediate. Upon highly enantioselective ß-protonation through proton-shuttle catalysis, the resulting azolium intermediate reacts with imidazole to yield the key ß-chiral acyl species. This transient intermediate provides access to diversified ß-chiral carbonyl derivatives, such as amides, hydrazides, acids, esters, and thioesters. In particular, ß-chiral amides can be prepared in excellent yield and ee (40 chiral amides, up to 95 % yield and 99 % ee). This modular strategy overcomes the challenge of disruption of the highly selective proton-shuttling process by basic amines.

Direct Synthesis of Polysubstituted Aldehydes via Visible-Light Catalysis.

Aldehydes are among the most versatile functional groups for synthetic chemistry. However, access to polysubstituted alkyl aldehydes is very limited and requires lengthy synthetic routes that involve multiple-step functional-group conversion. This paper reports a one-step synthesis of polysubstituted aldehydes from readily available olefin substrates using visible-light photoredox catalysis. Despite a number of competing reaction pathways, commercial styrenes react with vinyl ethers selectively in the presence of an acridinium salt photooxidant and a disulfide hydrogen-atom-transfer catalyst under blue LED irradiation. Alkyl aldehydes with different substitution patterns are prepared in good yields. This strategy can be applied to structurally sophisticated substrates.

Enantioselective ß-Protonation of Enals via a Shuttling Strategy.

Remote asymmetric protonation is a longstanding challenge due to the small size of protons. Reactions involving electron-deficient olefins pose a further difficulty due to the electrophilic nature of these substrates. We report a shuttling system that delivers a proton in a highly enantioselective manner to the ß-carbon of enals using a chiral N-heterocyclic carbene (NHC) catalyst. Choices of a Brønsted base shuttle and a Brønsted acid cocatalyst are critical for highly stereoselective ß-protonation of the homoenolate intermediate and regeneration of the NHC catalyst results in functionalization of the carbonyl group. Thioesters with a ß-chiral center were prepared in a redox-neutral transformation with an excellent yield and ee.

Visible-Light-Mediated [4+2] Cycloaddition of Styrenes: Synthesis of Tetralin Derivatives.

We report a formal [4+2] cycloaddition reaction of styrenes under visible-light catalysis. Two styrene molecules with different electronic or steric properties were found to react with each other in good yield and excellent chemo- and regioselectivity. This reaction provides direct access to polysubstituted tetralin scaffolds from readily available styrenes. Sophisticated tricyclic and tetracyclic tetralin analogues were prepared in high yield and up to 20/1 diasteroselectivity from cyclic substrates.

Highly Enantioselective Aza-Michael Reaction between Alkyl Amines and ß-Trifluoromethyl ß-Aryl Nitroolefins.

The aza-Michael addition reaction is a vital transformation for the synthesis of functionalized chiral amines. Despite intensive research, enantioselective aza-Michael reactions with alkyl amines as the nitrogen donor have not been successful. We report the use of chiral N-heterocyclic carbenes (NHCs) as noncovalent organocatalysts to promote a highly selective aza-Michael reaction between primary alkyl amines and ß-trifluoromethyl ß-aryl nitroolefins. In contrast to classical conjugate-addition reactions, a strategy of HOMO-raising activation was used. Chiral trifluoromethylated amines were synthesized in high yield (up to 99 %) with excellent enantioselectivity (up to 98 % ee).

Photochemical three-component assembly of tri-substituted oxazoles through a carbenic phosphorus-nitrile hybrid ylide formation/trapping cascade.

Construction of complex molecular skeletons with ubiquitous chemical feedstocks in a single transformation is highly appealing in organic synthesis. We report a novel visible-light-induced three-component reaction for the construction of complex 2,4,5-trisubstituted oxazoles, which are valuable in medicinal chemistry, from simple and readily available iodonium-phosphonium hybrid ylides, carboxylic acids, and nitriles. This reaction features a carbenic phosphorus-nitrile hybrid ylide formation/trapping cascade, in which a photo-generated α-phosphonium carbene acts as a sequence trigger. This catalyst- and additive-free transformation exhibits high efficiency and broad substrate scope for synthesizing diverse oxazoles.

Water mediated redox-neutral cleavage of arylalkenes via photoredox catalysis.

Cleavage of carbon-carbon bonds remains a challenging task in organic synthesis. Traditional methods for splitting Csp2=Csp2 bonds into two halves typically involve non-redox (metathesis) or oxidative (ozonolysis) mechanisms, limiting their synthetic potential. Disproportionative deconstruction of alkenes, which yields one reduced and one oxidized fragment, remains an unexplored area. In this study, we introduce a redox-neutral approach for deleting a Csp2 carbon unit from substituted arylalkenes, resulting in the formation of an arene (reduction) and a carbonyl product (oxidation). This transformation is believed to proceed through a mechanistic sequence involving visible-light-promoted anti-Markovnikov hydration, followed by photoredox cleavage of Csp3-Csp3 bond in the alcohol intermediate. A crucial consideration in this design is addressing the compatibility between the highly reactive oxy radical species in the latter step and the required hydrogen-atom-transfer (HAT) reagent for both steps. We found that ethyl thioglycolate serves as the optimal hydrogen-atom shuttle, offering remarkable chemoselectivity among multiple potential HAT events in this transformation. By using D2O, we successfully prepared dideuteromethylated (-CD2H) arenes with good heavy atom enrichment. This work presents a redox-neutral alternative for alkene deconstruction, with considerable potential in late-stage modification of complex molecules.

N-Heterocyclic Carbene-Catalyzed Asymmetric SN2 Alkylation via Noncovalent Activation.

The field of asymmetric catalysis has been developed by exploring noncovalent interactions, particularly within N-heterocyclic carbene-mediated processes. Despite challenges due to the limited number of compatible electrophiles (predominantly π-acceptors), this study introduces the first asymmetric α-alkylation of 3-aryl oxindoles using Csp3 electrophiles. The innovative protocol integrates diverse oxindoles and alkyl, allyl, and propargyl electrophiles, achieving high yields and enantioselectivities. Preliminary mechanistic explorations support a noncovalent catalytic mechanism, enhancing the tool kit for constructing complex chiral molecules with potential applications.

Amide C-N bonds activation by A new variant of bifunctional N-heterocyclic carbene.

We report an organocatalyst that combines a triazolium N-heterocyclic carbene (NHC) with a squaramide as a hydrogen-bonding donor (HBD), which can effectively catalyze the atroposelective ring-opening of biaryl lactams via a unique amide C-N bond cleavage mode. The free carbene species attacks the amide carbonyl, forming an axially chiral acyl-azolium intermediate. Various axially chiral biaryl amines can be accessed by this methodology with up to 99% ee and 99% yield. By using mercaptan as a catalyst turnover agent, the resulting thioester synthon can be transformed into several interesting atropisomers. Both control experiments and theoretical calculations reveal the crucial role of the hybrid NHC-HBD skeleton, which activates the amide via H-bonding and brings it spatially close to the carbene centre. This discovery illustrates the potential of the NHC-HBD chimera and demonstrates a complementary strategy for amide bond activation and manipulation.

Enantioselective SN 2 Alkylation of Homoenolates by N-Heterocyclic Carbene Catalysis.

The functionalization of the ß-carbon of enals with electrophiles is a signature umpolung reactivity of N-heterocyclic carbene (NHC) derived homoenolates. However, only a limited number of electrophiles are shown to be compatible, with most of them being π-electrophiles. In this study, the successful enantioselective ß-alkylation of homoenolates is reported using Csp3 electrophiles through an SN 2 strategy. The protocol shows a broad scope regarding alkyl electrophiles, delivering good yields, and excellent enantioselectivities (up to 99% ee). It enables the installation of drug-like structural motifs in either enals or alkylating agents, demonstrating its potential as a valuable tool for late-stage modification. Furthermore, a concise synthetic route is presented to chiral pyrroloindoline-type skeletons. Preliminary mechanistic studies support a direct SN 2 mechanism.

Hydrogen co-production via nickel-gold electrocatalysis of water and formaldehyde.

Hydrogen is one of the most promising future energy sources due to its highly efficient energy storage and carbon-free features. However, the energy input required for a hydrogen production protocol is an essential factor affecting its widespread adoption. Water electrolysis for hydrogen production currently serves a vital role in the industrial field, but the high overpotential of the oxygen evolution reaction (OER) dramatically impedes its practical application. The formaldehyde oxidation reaction (FOR) has emerged as a more thermodynamically favorable alternative, and the innovation of compatible electrodes may steer the direction of technological evolution. We have designed Au-Vo-NiO/CC as a catalyst that triggers the electrocatalytic oxidation of formaldehyde, efficiently producing H2 at the ultra-low potential of 0.47 V (vs. RHE) and maintaining long-term stability. Integrated with the cathodic hydrogen evolution reaction (HER), this bipolar H2 production protocol achieves a nearly 100% Faraday efficiency (FE).

The thiol-sulfoxonium ylide photo-click reaction for bioconjugation.

Visible-light-mediated methods were heavily studied as a useful tool for cysteine-selective bio-conjugation; however, many current methods suffer from bio-incompatible reaction conditions and slow kinetics. To address these challenges, herein, we report a transition metal-free thiol-sulfoxonium ylide photo-click reaction that enables bioconjugation under bio-compatible conditions. The reaction is highly cysteine-selective and generally finished within minutes with naturally occurring riboflavin derivatives as organic photocatalysts. The catalysts and substrates are readily accessible and bench stable and have satisfactory water solubility. As a proof-of-concept study, the reaction was smoothly applied in chemo-proteomic analysis, which provides efficient tools to explore the druggable content of the human proteome.

Rhodium(III)-catalyzed C-H activation of arenes using a versatile and removable triazene directing group.

Diverse opportunities: A Rhodium(III)-catalyzed ortho-selective olefination of arenes using a novel triazene as a directing group is reported. This method exhibits substantial post-functionalization synthetic versatility, overcoming a vital limitation in C sp 2-H activation/functionalization products: restricted structural diversity.

An NHC-catalyzed [3+2] cyclization of ß-disubstituted enals with benzoyl cyanides.

The NHC-catalyzed asymmetric [3+2] cyclization of benzoyl cyanides to homoenolate generated in situ from enals was reported. This methodology leads to the efficient construction of a series of chiral cyclic compounds bearing vicinal quaternary stereocenters under mild reaction conditions. Additionally, the representative large-scale and derivatization reactions of the chiral cyclic products reveal the potential synthetic utility of this protocol.