Visible-light-induced transition metal and photosensitizer free decarbonylative addition of amino-arylaldehydes to ketones

The decarbonylative-coupling reaction is generally promoted by transition metals (via organometallic complexes) or peroxides (via radical intermediates), often at high temperatures to facilitate the CO release. Herein, a visible-light-induced, transition metal and external photosensitizer free decarbonylative addition of benzaldehydes to ketones/aldehydes at room temperature is reported. Tertiary/secondary alcohols were obtained in moderate to excellent yields promoted by using CsF under mild conditions. The detailed mechanistic investigation showed that the reaction proceeded through photoexcitation–decarbonylation of the aldehyde to generate an aromatic anion, followed by its addition to ketones/aldehydes. The reaction mechanism was verified by the density functional theory (DFT) calculations.

A visible-light-induced, transition-metal and external photosensitizer free decarbonylative addition of benzaldehydes to ketones/aldehydes via anion intermediates at room temperature is developed.     

Activation of Si–H and B–H bonds by Lewis acidic transition metals and p-block elements: same,but different

In this Perspective we discuss the ability of transition metal complexes to activate and cleave the Si–H and B–H bonds of hydrosilanes and hydroboranes (tri- and tetra-coordinated) in an electrophilic manner, avoiding the need for the metal centre to undergo two-electron processes (oxidative addition/reductive elimination). A formal polarization of E–H bonds (E = Si, B) upon their coordination to the metal centre to form σ-EH complexes (with coordination modes η¹ or η²) favors this type of bond activation that can lead to reactivities involving the formation of transient silylium and borenium/boronium cations similar to those proposed in silylation and borylation processes catalysed by boron and aluminium Lewis acids. We compare the reactivity of transition metal complexes and boron/aluminium Lewis acids through a series of catalytic reactions in which pieces of evidence suggest mechanisms involving electrophilic reaction pathways.

In this Perspective we compare the ability of transition metals and p-block Lewis acids to activate electrophilically hydrosilanes and hydroboranes. The mechanistic similarities and dissimilarities in different catalytic transformations are analyzed.     

Docking rings in a solid: reversible assembling of pseudorotaxanes inside a zirconium metal–organic framework

An unprecedented zirconium metal–organic framework featuring a T-shaped benzimidazole strut was constructed and employed as a sponge-like material for selective absorption of macrocyclic guests. The neutral benzimidazole domain of the as-synthesized framework can be readily protonated and fully converted to benzimidazolium. Mechanical threading of [24]crown-8 ether wheels onto recognition sites to form pseudorotaxanes was evidenced by solution nuclear magnetic resonance, solid-state fluorescence, and infrared spectroscopy. Selective absorption of [24]crown-8 ether rather than its dibenzo counterpart was also observed. Further study reveals that this binding process is reversible and acid–base switchable. The success of docking macrocyclic guests in crystals via host–guest interactions provides an alternative route to complex functional materials with interpenetrated structures.

A T-shaped ligand was designed as struts for building a zirconium metal–organic framework. Acid–base switchable docking and releasing a 24-membered crown ether inside crystals was successfully accomplished via post-synthetic modification.     

Visible-light-induced cross-coupling of aryl iodides with hydrazones via an EDA-complex

A visible-light-induced, transition-metal and photosensitizer-free cross-coupling of aryl iodides with hydrazones was developed. In this strategy, hydrazones were used as alternatives to organometallic reagents, in the absence of a transition metal or an external photosensitizer, making this cross-coupling mild and green. The protocol was compatible with a variety of functionalities, including methyl, methoxy, trifluoromethyl, halogen, and heteroaromatic rings. Mechanistic investigations showed that the association of the hydrazone anion with aryl halides formed an electron donor–acceptor complex, which when excited with visible light generated an aryl radical via single-electron transfer.

Visible-light-induced catalyst-free cross-coupling of aryl iodides with hydrazones via single-electron-transfer was reported. The mechanistic investigations showed that the association of hydrazone anion with aryl iodides formed an EDA complex.     

Me3SiSiMe2(OnBu): a disilane reagent for the synthesis of diverse silacycles via Brook- and retro-Brook-type rearrangement

Herein, a readily available disilane Me₃SiSiMe₂(OⁿBu) has been developed for the synthesis of diverse silacycles via Brook- and retro-Brook-type rearrangement. This protocol enables the incorporation of a silylene into different starting materials, including acrylamides, alkene-tethered 2-(2-iodophenyl)-1H-indoles, and 2-iodobiaryls, via the cleavage of Si–Si, Si–C, and Si–O bonds, leading to the formation of spirobenzosiloles, fused benzosiloles, and π-conjugated dibenzosiloles in moderate to good yields. Preliminary mechanistic studies indicate that this transformation is realized by successive palladium-catalyzed bis-silylation and Brook- and retro-Brook-type rearrangement of silane-tethered silanols.

A readily available disilane Me₃SiSiMe₂(OⁿBu) as a silylene source has been developed for the synthesis of diverse silacycles via Brook- and retro-Brook-type rearrangement.     

Regiodivergent synthesis of pyrazino-indolines vs. triazocines via α-imino carbenes addition to imidazolidines

Hexahydropyrazinoindoles were prepared in a single step from N-sulfonyl triazoles and imidazolidines. Under dirhodium catalysis, α-imino carbenes were generated and formed nitrogen ylide intermediates that, after subsequent aminal opening, afforded the pyrazinoindoles predominantly via formal [1,2]-Stevens and tandem Friedel–Crafts cyclizations. Of mechanistic importance, a regiodivergent reactivity was engineered through the use of a specific unsymmetrically substituted imidazolidine that promoted the exclusive formation of 8-membered ring 1,3,6-triazocines. Based on DFT calculations, an original Curtin–Hammett-like situation was demonstrated for the mechanism. Further derivatizations led to functionalized tetrahydropyrazinoindoles in high yields.

Hexahydropyrazinoindoles are prepared in a single step from N-sulfonyl triazoles and imidazolidines. Of mechanistic importance, a regiodivergent reactivity can be engineered towards the exclusive formation of 8-membered ring 1,3,6-triazocines.     

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.     

Rhodium-catalysed ortho-alkynylation of nitroarenes

The ortho-alkynylation of nitro-(hetero)arenes takes place in the presence of a Rh(iii) catalyst to deliver a wide variety of alkynylated nitroarenes regioselectively. These interesting products could be further derivatized by selective reduction of the nitro group or palladium-catalysed couplings. Experimental and computational mechanistic studies demonstrate that the reaction proceeds via a turnover-limiting electrophilic C–H metalation ortho to the strongly electron-withdrawing nitro group.

Rh(iii)-catalyzed ortho-alkynylation of nitro-(hetero)arenes leads to a wide variety of alkynylated nitroarenes via a turnover-limiting electrophilic C–H ortho-metalation.     

Understanding the mechanism of direct visible-light-activated [2 + 2] cycloadditions mediated by Rh and Ir photocatalysts: combined computational and spectroscopic studies

The mechanism of [2 + 2] cycloadditions activated by visible light and catalyzed by bis-cyclometalated Rh(iii) and Ir(iii) photocatalysts was investigated, combining density functional theory calculations and spectroscopic techniques. Experimental observations show that the Rh-based photocatalyst produces excellent yield and enantioselectivity whereas the Ir-photocatalyst yields racemates. Two different mechanistic features were found to compete with each other, namely the direct photoactivation of the catalyst–substrate complex and outer-sphere triplet energy transfer. Our integrated analysis suggests that the direct photocatalysis is the inner working of the Rh-catalyzed reaction, whereas the Ir catalyst serves as a triplet sensitizer that activates cycloaddition via an outer-sphere triplet excited state energy transfer mechanism.

The mechanism of [2 + 2] cycloadditions activated by visible light and catalyzed by bis-cyclometalated Rh(iii) and Ir(iii) photocatalysts was investigated, combining density functional theory calculations and spectroscopic techniques.     

Diboramacrocycles: reversible borole dimerisation–dissociation systems

We report that the outcome of the tin–boron exchange reaction of a mixed thiophene-benzo-fused stannole with aryldibromoboranes is associated with the steric bulk of the aryl substituent of the borane reagent, leading to either boroles or large diboracycles as products. NMR spectroscopic studies indicate that the two products can reversibly interconvert in solution, and mechanistic density functional theory (DFT) calculations reveal boroles to be intermediates in the formation of the diboracyclic products. The addition of Lewis bases to the diboracycles leads to the corresponding borole adducts, demonstrating that they react as “masked” boroles. Additionally, the reaction of the title compounds with a series of organic azides affords complex heteropropellanes, formally 2 : 1 borole-azide adducts, that deviate from the usual BN aromatic compounds formed via nitrogen atom insertion into the boroles.

Diboramacrocycles are a new form of borole dimers, participating in various addition reactions as “masked” boroles. The reaction of a less crowded diboramacrocycle with organic azides affords unprecedented complex heteropropellanes.     

Synthesis of tryptophan-containing 2,5-diketopiperazines via sequential C–H activation: total syntheses of tryprostatin A,maremycins A and B

Indole 2,5-diketopiperazines (DKPs) are an important type of metabolic cyclic dipeptides containing a tryptophan (Trp) unit possessing a range of interesting biological activities. The intriguing structural features and divergent activities have stimulated tremendous efforts towards their efficient synthesis. Herein, we report the development of a unified strategy for the synthesis of three Trp-containing DKPs, namely tryprostatin A, and maremycins A and B, via a sequential C–H activation strategy. The key Trp skeletons were synthesized from the inexpensive, readily available alanine via a Pd(ii)-catalyzed β-methyl C(sp³)–H monoarylation. A subsequent C2-selective prenylation of the resulting 6-OMe-Trp by Pd/norbornene-promoted C–H activation led to the total synthesis of tryprostatin A in 12 linear steps from alanine with 25% overall yield. Meanwhile, total syntheses of maremycins A and B were successfully accomplished using a sequential Pd-catalyzed methylene C(sp³)–H methylation as the key step in 15 linear steps from alanine.

Indole 2,5-diketopiperazines (DKPs) are an important type of metabolic cyclic dipeptides containing a tryptophan (Trp) unit possessing a range of interesting biological activities.     

Rapid one-pot iterative diselenide–selenoester ligation using a novel coumarin-based photolabile protecting group

The development of an iterative one-pot peptide ligation strategy is described that capitalises on the rapid and efficient nature of the diselenide–selenoester ligation reaction, together with photodeselenisation chemistry. This ligation strategy hinged on the development of a novel photolabile protecting group for the side chain of selenocysteine, namely the 7-diethylamino-3-methyl coumarin (DEAMC) moiety. Deprotection of this DEAMC group can be effected in a mild, reagent-free manner using visible light (λ = 450 nm) without deleterious deselenisation of selenocysteine residues, thus enabling a subsequent ligation reaction without purification. The use of this DEAMC-protected selenocysteine in iterative DSL chemistry is highlighted through the efficient one-pot syntheses of 60- and 80-residue fragments of mucin-1 as well as apolipoprotein CIII in just 2–4 hours.

A method for the rapid one-pot iterative assembly of proteins via diselenide–selenoester ligation (DSL) chemistry is described that capitalises on a novel coumarin-based photolabile protecting group for selenocysteine.     

Stereoregular functionalized polysaccharides via cationic ring-opening polymerization of biomass-derived levoglucosan

We report the facile synthesis and characterization of 1,6-α linked functional stereoregular polysaccharides from biomass-derived levoglucosan via cationic ring-opening polymerization (cROP). Levoglucosan is a bicyclic acetal with rich hydroxyl functionality, which can be synthetically modified to install a variety of pendant groups for tailored properties. We have employed biocompatible and recyclable metal triflate catalysts – scandium and bismuth triflate – for green cROP of levoglucosan derivatives, even at very low catalyst loadings of 0.5 mol%. Combined experimental and computational studies provided key kinetic, thermodynamic, and mechanistic insights into the cROP of these derivatives with metal triflates. Computational studies reveal that ring-opening of levoglucosan derivatives is preferred at the 1,6 anhydro linkage and cROP proceeds in a regio- and stereo-specific manner to form 1,6-α glycosidic linkages. DFT calculations also show that biocompatible metal triflates efficiently coordinate with levoglucosan derivatives as compared to the highly toxic PF₅ used previously. Post-polymerization modification of levoglucosan-based polysaccharides is readily performed via UV-initiated thiol–ene click reactions. The reported levoglucosan based polymers exhibit good thermal stability (T_d > 250 °C) and a wide glass transition temperature (T_g) window (<−150 °C to 32 °C) that is accessible with thioglycerol and lauryl mercaptan pendant groups. This work demonstrates the utility of levoglucosan as a renewably-derived scaffold, enabling facile access to tailored polysaccharides that could be important in many applications ranging from sustainable materials to biologically active polymers.

We demonstrate the facile synthesis and characterization of stereoregular polysaccharides from the biomass-derived platform molecule levoglucosan via metal-triflate mediated cationic-ring opening polymerization.     

The Morita–Baylis–Hillman reaction for non-electron-deficient olefins enabled by photoredox catalysis

A strategy for overcoming the limitation of the Morita–Baylis–Hillman (MBH) reaction, which is only applicable to electron-deficient olefins, has been achieved via visible-light induced photoredox catalysis in this report. A series of non-electron-deficient olefins underwent the MBH reaction smoothly via a novel photoredox-quinuclidine dual catalysis. The in situ formed key β-quinuclidinium radical intermediates, derived from the addition of olefins with quinuclidinium radical cations, are used to enable the MBH reaction of non-electron-deficient olefins. On the basis of previous reports, a plausible mechanism is suggested. Mechanistic studies, such as radical probe experiments and density functional theory (DFT) calculations, were also conducted to support our proposed reaction pathways.

A strategy for overcoming the limitation of the Morita–Baylis–Hillman (MBH) reaction, which is only applicable to electron-deficient olefins, has been achieved via visible-light induced photoredox catalysis in this report.     

Cobalt-catalyzed chemoselective dehydrogenation through radical translocation under visible light

The transformations that allow the direct removal of hydrogen from their corresponding saturated counterparts by the dehydrogenative strategy are a dream reaction that has remained largely underexplored. In this report, a straightforward and robust cobaloxime-catalyzed photochemical dehydrogenation strategy via intramolecular HAT is described for the first time. The reaction proceeds through an intramolecular radical translocation followed by the cobalt assisted dehydrogenation without needing any other external photosensitizers, noble-metals or oxidants. With this approach, a series of valuable unsaturated compounds such as α,β-unsaturated amides, enamides and allylic and homoallylic sulfonamides were obtained in moderate to excellent yields with good chemo- and regioselectivities, and the synthetic versatility was demonstrated by a range of transformations. And mechanistic studies of the method are discussed.

The dehydrogenative reactions proceeded through selective 1,n-hydrogen atom transfer (n = 5–7) for remote C–H activation by cobaloxime catalysis.     

Asymmetric hydrogenation for the synthesis of 2-substituted chiral morpholines

Asymmetric hydrogenation of unsaturated morpholines has been developed by using a bisphosphine-rhodium catalyst bearing a large bite angle. With this approach, a variety of 2-substituted chiral morpholines could be obtained in quantitative yields and with excellent enantioselectivities (up to 99% ee). The hydrogenated products could be transformed into key intermediates for bioactive compounds.

2-Substituted chiral morpholines were synthesized via a newly developed asymmetric hydrogenation of dehydromorpholines catalyzed by a bisphosphine–rhodium complex bearing a large bite angle.     

Machine learning and semi-empirical calculations: a synergistic approach to rapid,accurate, and mechanism-based reaction barrier prediction

Modern QM modelling methods, such as DFT, have provided detailed mechanistic insights into countless reactions. However, their computational cost inhibits their ability to rapidly screen large numbers of substrates and catalysts in reaction discovery. For a C–C bond forming nitro-Michael addition, we introduce a synergistic semi-empirical quantum mechanical (SQM) and machine learning (ML) approach that allows the prediction of DFT-quality reaction barriers in minutes, even on a standard laptop using widely available modelling software. Mean absolute errors (MAEs) are obtained that are below the accepted chemical accuracy threshold of 1 kcal mol⁻¹ and substantially better than SQM methods without ML correction (5.71 kcal mol⁻¹). Predictive power is shown to hold when the ML models are applied to an unseen set of compounds from the toxicology literature. Mechanistic insight is also achieved via the generation of full SQM transition state (TS) structures which are found to be very good approximations for the DFT-level geometries, revealing important steric interactions in some TSs. This combination of speed, accuracy, and mechanistic insight is unprecedented; current ML barrier models compromise on at least one of these important criteria.

A synergistic approach that combines machine learning with semi-empirical methods enables the fast and accurate prediction of DFT-quality reaction barriers, with mechanistic insights available from semi-empirical transition state geometries.     

Ring-opening fluorination of bicyclic azaarenes

We have discovered a ring-opening fluorination of bicyclic azaarenes. Upon treatment of bicyclic azaarenes such as pyrazolo[1,5-a]pyridines with electrophilic fluorinating agents, fluorination of the aromatic ring is followed by a ring-opening reaction. Although this overall transformation can be classified as an electrophilic fluorination of an aromatic ring, it is a novel type of fluorination that results in construction of tertiary carbon–fluorine bonds. The present protocol can be applied to a range of bicyclic azaarenes, tolerating azines and a variety of functional groups. Additionally, mechanistic studies and enantioselective fluorination have been examined.

A ring-opening fluorination of bicyclic azaarenes was developed. Although this overall transformation can be classified as an electrophilic fluorination of aromatics, it is a novel type of fluorination that results in construction of tert-C–F bonds.     

Direct metal–carbon bonding in symmetric bis(C–H) agostic nickel(i) complexes

Agostic interactions are examples of σ-type interactions, typically resulting from interactions between C–H σ-bonds with empty transition metal d orbitals. Such interactions often reflect the first step in transition metal-catalysed C–H activation processes and thus are of critical importance in understanding and controlling σ bond activation chemistries. Herein, we report on the unusual electronic structure of linear electron-rich d⁹ Ni(i) complexes with symmetric bis(C–H) agostic interactions. A combination of Ni K edge and L edge XAS with supporting TD-DFT/DFT calculations reveals an unconventional covalent agostic interaction with limited contributions from the valence Ni 3d orbitals. The agostic interaction is driven via the empty Ni 4p orbitals. The surprisingly strong Ni 4p-derived agostic interaction is dominated by σ contributions with minor π contributions. The resulting ligand–metal donation occurs directly along the C–Ni bond axis, reflecting a novel mode of bis-agostic bonding.

Symmetric Ni(i) agostic complexes reveal an unusual mode of bonding that is dominated by direct carbon-to-metal charge transfer.