Decarboxylative sulfoximination of benzoic acids enabled by photoinduced ligand-to-copper charge transfer

Sulfoximines are synthetically important scaffolds and serve important roles in drug discovery. Currently, there is no solution to decarboxylative sulfoximination of benzoic acids; although thoroughly investigated, limited substrate scope and harsh reaction conditions still hold back traditional thermal aromatic decarboxylative functionalization. Herein, we realize the first decarboxylative sulfoximination of benzoic acids via photo-induced ligand to copper charge transfer (copper-LMCT)-enabled decarboxylative carbometalation. The transformation proceeds under mild reaction conditions, has a broad substrate scope, and can be applied to late-stage functionalization of complex small molecules.

We report the first decarboxylative sulfoximination of benzoic acids via photoinduced ligand-to-copper charge transfer. The transformation proceeds at ambient reaction temperature and demonstrates broad substrate scope.     

Sequential C–O decarboxylative vinylation/C–H arylation of cyclic oxalates via a nickel-catalyzed multicomponent radical cascade

A selective, sequential C–O decarboxylative vinylation/C–H arylation of cyclic alcohol derivatives enabled by visible-light photoredox/nickel dual catalysis is described. This protocol utilizes a multicomponent radical cascade process, i.e. decarboxylative vinylation/1,5-HAT/aryl cross-coupling, to achieve efficient, site-selective dual-functionalization of saturated cyclic hydrocarbons in one single operation. This synergistic protocol provides straightforward access to sp³-enriched scaffolds and an alternative retrosynthetic disconnection to diversely functionalized saturated ring systems from the simple starting materials.

A selective, sequential C–O decarboxylative vinylation/C–H arylation of cyclic alcohol derivatives enabled by visible-light photoredox/nickel dual catalysis has been described.     

Phosphite mediated asymmetric N to C migration for the synthesis of chiral heterocycles from primary amines

A phosphite mediated stereoretentive C–H alkylation of N-alkylpyridinium salts derived from chiral primary amines was achieved. The reaction proceeds through the activation of the N-alkylpyridinium salt substrate with a nucleophilic phosphite catalyst, followed by a base mediated [1,2] aza-Wittig rearrangement and subsequent catalyst dissociation for an overall N to C-2 alkyl migration. The scope and degree of stereoretention were studied, and both experimental and theoretical investigations were performed to support an unprecedented aza-Wittig rearrangement–rearomatization sequence. A catalytic enantioselective version starting with racemic starting material and chiral phosphite catalyst was also established following our understanding of the stereoretentive process. This method provides efficient access to tertiary and quaternary stereogenic centers in pyridine systems, which are prevalent in drugs, bioactive natural products, chiral ligands, and catalysts.

N-Alkylpyridinium salt of chiral amines undergoes phosphite mediated stereoretentive migrations to generate chiral alkylpyridines. The role of phosphite on reactivity and stereoselectivity were examined to achieve a catalytic asymmetric version.     

Merging Grubbs second-generation catalyst with photocatalysis enables Z-selective metathesis of olefins: scope,limitations, and mechanism

Olefin cross-metathesis is a cornerstone reaction in organic synthesis where stereoselectivity is typically governed by the structure of the catalyst. In this work, we show that merging Grubbs second generation catalyst, a classical E-selective catalyst, with a readily available photocatalyst, enables the exclusive formation of the contra-thermodynamic Z-isomer. The scope and limitations of this unprecedented approach are discussed based on both computational and experimental mechanistic data.

Light is magic! The combination of Grubbs second generation catalyst, a well-known catalyst for E-selective olefin metathesis, with a photosensitizer enables efficient access to the contra-thermodynamic Z-isomers.     

Excited-state palladium-catalysed reductive alkylation of imines: scope and mechanism

Palladium catalysis induced by visible-light irradiation is a promising tool for promoting unusual chemical transformations. We describe the development of excited-state palladium-catalyzed reductive alkylation of imines with alkyl bromides. The new methodology shows broad functional group tolerance and can additionally be applied in the direct three-component reaction of aldehydes, anilines, and alkyl bromides to give the alkyl amines under mild reaction conditions. Time-resolved photoluminescence experiments allowed the determination of the excited-state reaction kinetics and indicate that the reaction is proceeding via the inner-sphere electron transfer mechanism.

Palladium catalysis induced by visible-light irradiation is a promising tool for promoting unusual chemical reactivity. Here, the hybrid alkyl radical/Pd(i) species generated is used to promote the reductive alkylation of imines.     

Regiodivergent sulfonylarylation of 1,3-enynes via nickel/photoredox dual catalysis

Catalytic difunctionalization of 1,3-enynes represents an efficient and versatile approach to rapidly assemble multifunctional propargylic compounds, allenes and 1,3-dienes. Controlling selectivity in such addition reactions has been a long-standing challenging task due to multiple reactive centers resulting from the conjugated structure of 1,3-enynes. Herein, we present a straightforward method for regiodivergent sulfonylarylation of 1,3-enynes via dual nickel and photoredox catalysis. Hinging on the nature of 1,3-enynes, diverse reaction pathways are feasible: synthesis of α-allenyl sulfones via 1,4-sulfonylarylation, or preparation of (E)-1,3-dienyl sulfones with high chemo-, regio- and stereoselectivity through 3,4-sulfonylarylation. Notably, this is the first example that nickel and photoredox catalysis are merged to achieve efficient and versatile difunctionalization of 1,3-enynes.

A mild reaction protocol for regiodivergent sulfonylarylation of 1,3-enynes via dual nickel and photoredox catalysis has been developed, which led to efficient synthesis of α-allenyl sulfones or 1,3-dienyl sulfones.     

Stereoselective peptide catalysis in complex environments – from river water to cell lysates

Many stereoselective peptide catalysts have been established. They consist, like nature''s catalysts, of amino acids but have significantly lower molecular weights than enzymes. Whereas enzymes operate with exquisite chemoselectivity in complex biological environments, peptide catalysts are used in pure organic solvents and at higher concentrations. Can a peptide catalyst exhibit chemoselectivity reminiscent of enzymes? Here, we investigated the properties of tripeptide catalysts in complex mixtures in hydrophobic and aqueous solvents. We challenged the catalysts with biomolecules bearing functional groups that could interfere by coordination or reaction with the peptide, the substrates, or intermediates. H-dPro-αMePro-Glu-NHC₁₂H₁₅ emerged through tailoring of the trans/cis ratio of the tertiary amide as a conformationally well-defined tripeptide that catalyzes C–C bond formations with high reactivity and stereoselectivity – regardless of the solvent and compound composition. The chemoselectivity of the tripeptide is so high that it even catalyzes reactions in cell lysates. The findings provoke the question of the potential role of peptide catalysis in nature and during the evolution of enzymes.

The reactivity, stereo-, and chemoselectivity of a tripeptide are so high that it catalyzes conjugate addition reactions with high stereoselectivity in complex compound mixtures—even in cell lysates.     

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.

The synergy of SET, HAT, and BET enables a visible-light induced catalytic dehydrogenation for the synthesis of N-aryl amines.     

Acid-catalysed liquid-to-solid transitioning of arylazoisoxazole photoswitches

Molecular photoswitches play a vital role in the development of responsive materials. These molecular building blocks are particularly attractive when multiple stimuli can be combined to bring about physical changes, sometimes leading to unexpected properties and functions. The arylazoisoxazole molecular switch was recently shown to be capable of efficient photoreversible solid-to-liquid phase transitions with application in photoswitchable surface adhesion. Here, we show that the arylazoisoxazole forms thermally stable and photoisomerisable protonated Z- and E-isomers in an apolar aprotic solvent when the pK_a of the applied acid is sufficiently low. The tuning of isomerisation kinetics from days to seconds by the pK_a of the acid not only opens up new reactivity in solution, but also the solid-state photoswitching of azoisoxazoles can be efficiently reversed with selected acid vapours, enabling acid-gated photoswitchable surface adhesion.

Molecular photoswitches are versatile components for materials with bistable and photoreversible properties. Here, we enrich the functionality of the arylazoisoxazole molecular switch by analyzing its photoresponsive protonated Z- and E-isomers.     

Stereodivergent synthesis of β-iodoenol carbamates with CO2via photocatalysis

Photocatalytic conversion of carbon dioxide (CO₂) into value-added chemicals is of great significance from the viewpoint of green chemistry and sustainable development. Here, we report a stereodivergent synthesis of β-iodoenol carbamates through a photocatalytic three-component coupling of ethynylbenziodoxolones, CO₂ and amines. By choosing appropriate photocatalysts, both Z- and E-isomers of β-iodoenol carbamates, which are difficult to prepare using existing methods, can be obtained stereoselectively. This transformation featured mild conditions, excellent functional group compatibility and broad substrate scope. The potential synthetic utility of this protocol was demonstrated by late-stage modification of bioactive molecules and pharmaceuticals as well as by elaborating the products to access a wide range of valuable compounds. More importantly, this strategy could provide a general and practical method for stereodivergent construction of trisubstituted alkenes such as triarylalkenes, which represents a fascinating challenge in the field of organic chemistry research. A series of mechanism investigations revealed that the transformation might proceed through a charge-transfer complex which might be formed through a halogen bond.

Stereodivergent synthesis of β-iodoenol carbamates was achieved via a photocatalytic three-component coupling reaction of ethynylbenziodoxolones, CO₂ and amines.     

A Ni-catalyzed asymmetric C(sp)–P cross-coupling reaction for the synthesis of P-stereogenic alkynylphosphines

Due to the high reactivity of the triple bond, P-stereogenic alkynylphosphines could be easily derivatized, serving as universal building blocks for structurally diverse phosphine compounds. However, the synthesis of alkynylphosphines via direct P–C bond formation was unprecedented. Here, we report an efficient method for the synthesis of P-stereogenic alkynylphosphines with high enantioselectivity via a Ni-catalyzed asymmetric cross-coupling reaction. The reaction could tolerate a variety of functional groups, affording products that can be converted into useful phosphine derivatives.

A catalytic asymmetric C(sp)–P cross coupling reaction for the synthesis of P-stereogenic alkynylphosphines was realized. A series of alkynylphosphines which could be derivatized to useful phosphine compounds was synthesized with excellent enantioselectivities.     

Three-component carboformylation: α-quaternary aldehyde synthesis via Co(iii)-catalysed sequential C–H bond addition to dienes and acetic formic anhydride

All carbon α-quaternary aldehydes are prepared via Co(iii)-catalysed sequential C–H bond addition to dienes and acetic formic anhydride, representing a rare example of intermolecular carboformylation. A wide range of internally substituted dienes containing diverse functionality can be employed in this reaction, affording complex α-quaternary aldehydes that would not be accessible via hydroformylation approaches. Mechanistic investigations, including control reactions and deuterium labeling studies, establish a catalytic cycle that accounts for formyl group introduction with an uncommon 1,3-addition selectivity to the conjugated diene. Investigations into the role of the uniquely effective additive Proton Sponge® were also conducted, leading to the observation of a putative, intermediate Co(i) tetramethylfulvene complex at low temperatures via NMR spectroscopy. The synthetic utility of the aldehyde products is demonstrated by various transformations, including proline-catalysed asymmetric aldol addition, reductive amination, and the asymmetric synthesis of amines using tert-butanesulfinamide technology.

Co(iii)-catalysed sequential C–H bond addition to dienes and acetic formic anhydride results in a rare example of intermolecular carboformylation, generating versatile α-quaternary aldehyde products that are inaccessible via hydroformylation methods.     

Alkene insertion reactivity of a o-carboranyl-substituted 9-borafluorene

The synthesis of 9-borafluorene with an electron-withdrawing o-carboranyl substituent and its reactions with a series of alkenes are described. The o-carboranyl substituent is bonded via one of the cluster carbon atoms to the boron atom of the 9-borafluorene moiety. In all cases, the reactions afford partly saturated analogs of borepins (i.e. 6,7-dihydroborepins) by unprecedented alkene insertion into the endocyclic B–C bond of the borole ring. Comparative studies with 9-bromo-9-borafluorene illustrate the superior insertion reactivity of the carboranyl-substituted derivative. A suite of experimental and computational techniques disclose the unique properties of the 9-borafluorene and provide insight into how the 9-carboranyl substituent affects its chemical reactivity.

A 9-carboranyl-substituted 9-borafluorene is reported, which is capable of undergoing efficient ring expansion to 6,7-dihydroborepins by a previously unknown alkene insertion.     

Reusable Co-nanoparticles for general and selective N-alkylation of amines and ammonia with alcohols

A general cobalt-catalyzed N-alkylation of amines with alcohols by borrowing hydrogen methodology to prepare different kinds of amines is reported. The optimal catalyst for this transformation is prepared by pyrolysis of a specific templated material, which is generated in situ by mixing cobalt salts, nitrogen ligands and colloidal silica, and subsequent removal of silica. Applying this novel Co-nanoparticle-based material, >100 primary, secondary, and tertiary amines including N-methylamines and selected drug molecules were conveniently prepared starting from inexpensive and easily accessible alcohols and amines or ammonia.

A general cobalt-catalyzed N-alkylation of amines with alcohols by borrowing hydrogen methodology to prepare different kinds of amines is reported.     

Ni-catalyzed arylation of alkynes with organoboronic acids and aldehydes to access stereodefined allylic alcohols

A new, efficient and practical method for the three-component arylative coupling of aldehydes, alkynes and arylboronic acids has been developed through nickel catalysis. This transformation provides diverse Z-selective tetrasubstituted allylic alcohols without the use of any aggressive oragnometallic nucleophiles or reductants. Moreover, benzylalcohols are viable coupling partners via oxidation state manipulation and arylative coupling in one single catalytic cycle. This reaction features a direct and flexible approach for the preparation of stereodefined arylated allylic alcohols with broad substrate scope under mild conditions. The utility of this protocol is demonstrated through the synthesis of diverse biologically active molecular derivatives.

A direct, efficient and practical method for the three-component arylative coupling of aldehydes (or the corresponding alcohols), alkynes and arylboronic acids has been developed through nickel catalysis.     

Enzymology of standalone elongating ketosynthases

The β-ketoacyl-acyl carrier protein synthase, or ketosynthase (KS), catalyses carbon–carbon bond formation in fatty acid and polyketide biosynthesis via a decarboxylative Claisen-like condensation. In prokaryotes, standalone elongating KSs interact with the acyl carrier protein (ACP) which shuttles substrates to each partner enzyme in the elongation cycle for catalysis. Despite ongoing research for more than 50 years since KS was first identified in E. coli, the complex mechanism of KSs continues to be unravelled, including recent understanding of gating motifs, KS–ACP interactions, substrate recognition and delivery, and roles in unsaturated fatty acid biosynthesis. In this review, we summarize the latest studies, primarily conducted through structural biology and molecular probe design, that shed light on the emerging enzymology of standalone elongating KSs.

Ketosynthases (KSs) accept substrates from the acyl carrier protein (ACP) to catalyse carbon–carbon bond formation in fatty acid and polyketide biosynthesis. In this review, we delineate the enzymology of standalone elongating ketosynthases with a focus on the enzyme gates.     

Diastereodivergent cis- and trans-fused [4 + 2] annulations of cyclic 1,3-dienes and 1-azadienes via ligand-controlled palladium catalysis

Despite the blossoming of reports of diastereodivergent synthesis over the past years, switchable control of the stereochemistry of the bridgehead atoms of the fused frameworks has been significantly underdeveloped. Here we disclose the ability of Pd⁰-π-Lewis base catalysis to finely reverse the concerted inverse-electron-demand aza-Diels–Alder cycloaddition reaction between cyclic 1,3-dienes and aurone-derived 1-azadienes. In contrast, the in situ-formed HOMO-energy-increased Pd⁰-η²-complexes of cyclic 1,3-dienes underwent a cascade vinylogous Michael addition/allylic amination process with 1-azadienes. Moreover, judicious selection of chiral ligands allowed for switchable diastereodivergent [4 + 2] annulations to be accomplished, resulting in the construction of both cis- and trans-fused tetrahydropyridine architectures in high yields with moderate to excellent stereoselectivity levels. A variety of acyclic 1,3-dienes and 1-heterodienes were also applied, and furnished a structural diversity of enantioenriched frameworks.

Diastereodivergent and asymmetric [4 + 2] annulations between cyclic 1,3-dienes and 1-azadienes via ligand-controlled Pd catalysis have been realized, furnishing both cis- and trans-fused tetrahydropyridines in good yields and stereoselectivity levels.     

Spatiotemporal dynamics of supramolecular polymers by in situ quantitative catalyst-free hydroamination

Implementing chemical reactivity into synthetic supramolecular polymers based on π-conjugated molecules has been of great interest to create functional materials with spatiotemporal dynamic properties. However, the development of an in situ chemical reaction within supramolecular polymers is still in its infancy, because one needs to design optimal π-conjugated monomers having excellent reactivity under mild conditions possibly without byproducts or a catalyst. Herein we report the synthesis of a supramolecular polymer based on ethynyl core-substituted naphthalenediimide (S-NDI2) molecules that react with various amines quantitatively in a nonpolar solvent, without a catalyst, at 298 K. Most interestingly, the in situ reaction of the S-NDI2 supramolecular polymer with a linear aliphatic diamine proceeded much faster than the homogeneous reaction of a monomeric naphthalenediimide with the same diamine, affording diamine-linked S-NDI2 oligomers and polymers. The acceleration of in situ hydroamination was presumably due to rapid intra-supramolecular cross-linking between ethynyl and amino groups fixed in close proximity within the supramolecular polymer. Such intra-supramolecular cross-linking did not occur efficiently with an incompatible diamine. The systematic kinetic studies of in situ catalyst-free hydroamination within supramolecular polymers provide us with a useful, facile and versatile tool kit for designing dynamic supramolecular polymeric materials based on electron-deficient π-conjugated monomers.

A supramolecular polymer based on ethynyl core-substituted naphthalenediimides reacted with various amines quantitatively without a catalyst, exhibiting unconventional reaction kinetics and products.     

Copper catalyzed borocarbonylation of benzylidenecyclopropanes through selective proximal C–C bond cleavage: synthesis of γ-boryl-γ,δ-unsaturated carbonyl compounds

A copper catalyzed borocarbonylation of BCPs via proximal C–C bond cleavage for the synthesis of γ-boryl-γ,δ-unsaturated carbonyl compounds has been developed. Using substituted benzylidenecyclopropanes (BCPs) and chloroformates as starting material, a broad range of γ-boryl-γ,δ-unsaturated esters were prepared in moderate to excellent yields with excellent regio- and stereoselectivity. Besides, when aliphatic acid chlorides were used in this reaction, γ-boryl-γ,δ-unsaturated ketones could be produced in excellent yields. When substituted BCPs were used as substrates, the borocarbonylation occurred predominantly at the proximal C–C bond trans to the phenyl group in a regio- and stereoselective manner, which leads to the Z-isomers as the products. This efficient methodology involves the cleavage of a C–C bond and the formation of a C–C bond as well as a C–B bond, and provides a new method for the proximal C–C bond difunctionalization of BCPs.

A copper catalyzed borocarbonylation of benzylidenecyclopropanes (BCPs) via proximal C–C bond cleavage for the synthesis of γ-boryl-γ,δ-unsaturated carbonyl compounds has been developed.     

Electrooxidative dearomatization of biaryls: synthesis of tri- and difluoromethylated spiro[5.5]trienones

Radical spirocyclization via dearomatization has emerged as an attractive strategy for the rapid synthesis of structurally diverse spiro molecules. We report the use of electrochemistry to perform an oxidative dearomatization of biaryls leading to tri- and difluoromethylated spiro[5.5]trienones in a user friendly undivided cell set-up and a constant current mode. The catalyst- and chemical oxidant-free dearomatization procedure features ample scope, and employs electricity as the green and sole oxidant.

Radical spirocyclization via dearomatization has emerged as an attractive strategy for the rapid synthesis of structurally diverse spiro molecules.