Stereoselective rhodium-catalyzed 2-C–H 1,3-dienylation of indoles: dual functions of the directing group

A rhodium-catalyzed intermolecular highly stereoselective 1,3-dienylation at the 2-position of indoles with non-terminal allenyl carbonates has been developed by using 2-pyrimidinyl or pyridinyl as the directing group. The reaction tolerates many functional groups affording the products in decent yields under mild conditions. In addition to C–H bond activation, the directing group also played a vital role in the determination of Z-stereoselectivity for the C–H functionalization reaction with 4-aryl-2,3-allenyl carbonates, which is confirmed by the E-selectivity observed with 4-alkyl-2,3-allenyl carbonates. DFT calculations have been conducted to reveal that π–π stacking involving the directing 2-pyrimidinyl or pyridinyl group is the origin of the observed stereoselectivity. Various synthetic transformations have also been demonstrated.

A rhodium-catalyzed intermolecular highly stereoselective 1,3-dienylation at the 2-position of indoles with non-terminal allenyl carbonates has been developed by using 2-pyrimidinyl or pyridinyl as the directing group.     

Visible-light-driven palladium-catalyzed Dowd–Beckwith ring expansion/C–C bond formation cascade

A visible-light-induced palladium-catalyzed Dowd–Beckwith ring expansion/C–C bond formation cascade is described. A range of six to nine-membered β-alkenylated cyclic ketones possessing a quaternary carbon center were accessed under mild conditions. Besides styrenes, the electron-rich alkenes such as silyl enol ethers and enamides were also compatible, providing the desired β-alkylated cyclic ketones in moderate to good yields.

An intermolecular Dowd–Beckwith ring expansion/C–C bond formation is achieved through light-induced palladium catalysis. Not only styrenes but also the electron-rich alkenes such as silyl enol ethers and enamides were also compatible in this reaction.     

Torsional strain inversed chemoselectivity in a Pd-catalyzed atroposelective carbonylation reaction of dibenzothiophenium

A palladium-catalyzed enantioselective ring-opening/carbonylation of cyclic diarylsulfonium salts is reported. In comparison to thioethers, the sulfonium salts displayed high reactivity and enabled the reaction to be performed under mild conditions (room temperature). The steric repulsion of the two non-hydrogen substituents adjacent to the axis led cyclic diarylsulfonium salts to be distorted, which enabled the ring-opening reaction to proceed with significant preference for breaking the exocyclic C–S bond.

Torsional strain inversed chemoselectivity: from bond a to bond b.     

RhodiumIII-catalyzed remote difunctionalization of arenes assisted by a relay directing group

Rhodium-catalyzed diverse tandem twofold C–H bond activation reactions of para-olefin-tethered arenes have been realized, with unsaturated reagents such as internal alkynes, dioxazolones, and isocyanates being the coupling partner as well as a relay directing group which triggers cyclization of the para-olefin group under oxidative or redox-neutral conditions. The reaction proceeded via initial ortho-C–H activation assisted by a built-in directing group in the arene, and the ortho-incorporation of the unsaturated coupling partner simultaneously generated a relay directing group that allows sequential C–H activation at the meta-position and subsequent cyclization of the para-olefins. The overall reaction represents C–C or N–C difunctionalization of the arene with the generation of diverse 2,3-dihydrobenzofuran platforms. The catalytic system proceeded with good efficiency, simple reaction conditions, and broad substrate scope. The diverse transformations of the products demonstrated the synthetic utility of this tandem reaction.

Rhodium-catalyzed twofold C–H bond activation of para-olefin-tethered arenes has been realized using diverse unsaturated reagents. The overall reaction represents C–C or N–C difunctionalization of arenes with the generation of diverse 2,3-dihydrobenzofurans.     

Enantioselective palladium-catalyzed C(sp2)–C(sp2) σ bond activation of cyclopropenones by merging desymmetrization and (3 + 2) spiroannulation with cyclic 1,3-diketones

Catalytic asymmetric variants for functional group transformations based on carbon–carbon bond activation still remain elusive. Herein we present an unprecedented palladium-catalyzed (3 + 2) spiro-annulation merging C(sp²)–C(sp²) σ bond activation and click desymmetrization to form synthetically versatile and value-added oxaspiro products. The operationally straightforward and enantioselective palladium-catalyzed atom-economic annulation process exploits a TADDOL-derived bulky P-ligand bearing a large cavity to control enantioselective spiro-annulation that converts cyclopropenones and cyclic 1,3-diketones into chiral oxaspiro cyclopentenone–lactone scaffolds with good diastereo- and enantio-selectivity. The click-like reaction is a successful methodology with a facile construction of two vicinal carbon quaternary stereocenters and can be used to deliver additional stereocenters during late-state functionalization for the synthesis of highly functionalized or more complex molecules.

An unprecedented palladium-catalyzed (3 + 2) spiro-annulation merging C–C bond activation and desymmetrization was developed for the enantioselective construction of synthetically versatile and value-added oxaspiro products with up to 95% ee.     

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.     

Direct visible-light-induced synthesis of P-stereogenic phosphine oxides under air conditions

Over the past two decades, visible-light-induced transformations have been regarded as being among the most environmentally benign and powerful strategies for constructing complex molecules and diverse synthetic building blocks in organic synthesis. However, the development of efficient photochemical processes for assembling enantiomerically pure molecules remains a significant challenge. Herein, we describe a simple and efficient visible-light-induced C–P bond forming reaction for the synthesis of P-chiral heteroaryl phosphine oxides in moderate to high yields with excellent ee values (97–99% ee). Even in the absence of transition metal or photoredox catalysts, a variety of P-chiral heteroaryl phosphine oxides, including chiral diphosphine oxide 41, have been directly obtained under air conditions. Density functional theory (DFT) calculations have shown that the reaction involves intersystem crossing and single electron transfer to give a diradical intermediate under visible light irradiation.

We describe a simple and efficient visible-light-induced C–P bond forming reaction for the synthesis of P-chiral heteroaryl phosphine oxides in moderate to high yields with excellent ee values (97–99% ee).     

Atroposelective synthesis of N-aryl peptoid atropisomers via a palladium(ii)-catalyzed asymmetric C–H alkynylation strategy

The introduction of chirality into peptoids is an important strategy to determine a discrete and robust secondary structure. However, the lack of an efficient strategy for the synthesis of structurally diverse chiral peptoids has hampered the studies. Herein, we report the efficient synthesis of a wide variety of N-aryl peptoid atropisomers in good yields with excellent enantioselectivities (up to 99% yield and 99% ee) by palladium-catalyzed asymmetric C–H alkynylation. The inexpensive and commercially available l-pyroglutamic acid was used as an efficient chiral ligand. The exceptional compatibility of the C–H alkynylation with various peptoid oligomers renders this procedure valuable for peptoid modifications. Computational studies suggested that the amino acid ligand distortion controls the enantioselectivity in the Pd/l-pGlu-catalyzed C–H bond activation step.

The introduction of chirality into peptoids is an important strategy to determine a discrete and robust secondary structure.     

An economical approach for peptide synthesis via regioselective C–N bond cleavage of lactams

An economical, solvent-free, and metal-free method for peptide synthesis via C–N bond cleavage using lactams has been developed. The method not only eliminates the need for condensation agents and their auxiliaries, which are essential for conventional peptide synthesis, but also exhibits high atom economy. The reaction is versatile because it can tolerate side chains bearing a range of functional groups, affording up to >99% yields of the corresponding peptides without racemisation or polymerisation. Moreover, the developed strategy enables peptide segment coupling, providing access to a hexapeptide that occurs as a repeat sequence in spider silk proteins.

An economical, solvent-free, and metal-free method for peptide synthesis via C–N bond cleavage using lactams has been developed.     

Photoinduced metal-free borylation of aryl halides catalysed by an in situ formed donor–acceptor complex

Organoboron compounds are very important building blocks which can be applied in medicinal, biological and industrial fields. However, direct borylation in a metal free manner has been very rarely reported. Herein, we described the successful direct borylation of haloarenes under mild, operationally simple, catalyst-free conditions, promoted by irradiation with visible light. Mechanistic experiments and computational investigations indicate the formation of an excited donor–acceptor complex with a −3.12 V reduction potential, which is a highly active reductant and can facilitate single-electron-transfer (SET) with aryl halides to produce aryl radical intermediates. A two-step one-pot method was developed for site selective aromatic C–H bond borylation. The protocol''s good functional group tolerance enables the functionalization of a variety of biologically relevant compounds, representing a new application of aryl radicals merged with photochemistry.

We reported a facile metal-free conversion of aryl halides to the corresponding boronic esters catalysed by an in situ formed donor–acceptor complex. A two-step one-pot method was also developed for site selective aromatic C–H bond borylation.     

Palladium-catalyzed direct asymmetric C–H bond functionalization enabled by the directing group strategy

In the past decade, selective C–C and C-heteroatom bond construction through palladium-catalyzed direct C–H bond functionalization has been extensively studied by employing a variety of directing groups. Within this category, direct asymmetric C(sp²)–H and C(sp³)–H activation for the construction of highly enantiomerically enriched skeletons still progressed at a slow pace. This minireview briefly introduces the major advances in the field for palladium-catalyzed direct asymmetric C–H bond functionalization via the directing group strategy.

This minireview introduces Pd-catalyzed direct asymmetric C–H functionalization reactions using a directing group strategy.     

Palladium-catalyzed C–H glycosylation and retro Diels–Alder tandem reaction via structurally modified norbornadienes (smNBDs)

This report describes palladium-catalyzed C–H glycosylation and retro Diels–Alder tandem reaction via structurally modified norbornadienes (smNBDs). smNBDs were proposed to regulate the reactivity of the aryl-norbornadiene-palladacycle (ANP), including its high chemoselectivity and regioselectivity, which were the key to constructing C2 and C3 unsubstituted C4-glycosidic indoles. The scope of this substrate is extensive; the halogenated six-membered and five-membered glycosides were applied to the reaction smoothly, and N-alkyl (primary, secondary and tertiary) C4-glycosidic indoles can also be obtained by this method. In terms of mechanism, the key ANP intermediates characterized by X-ray single-crystal diffraction and further controlled experiments proved that the migration-insertion of smNBDs with phenylpalladium intermediate endows them with high chemo- and regioselectivity. Finally, density functional theory (DFT) calculation further verified the rationality of the mechanism.

This report describes palladium-catalyzed C–H glycosylation and retro Diels–Alder tandem reaction via structurally modified norbornadienes (smNBDs).     

Annulative coupling of vinylboronic esters: aryne-triggered 1,2-metallate rearrangement

A stereoselective annulative coupling of a vinylboronic ester ate-complex with arynes producing cyclic borinic esters has been developed. An annulation reaction that proceeded through the formation of two C–C bonds and a C–B bond was realized by exploiting a 1,2-metallate rearrangement of boronate triggered by the addition of a vinyl group to the strained triple bond of an aryne. The generated aryl anion would then cyclize to a boron atom to complete the annulation cascade. The annulated borinic ester could be converted to boronic acids and their derivatives by oxidation, halogenation, and cross-coupling. Particularly, halogenation and Suzuki–Miyaura coupling proceeded in a site-selective fashion and produced highly substituted alkylboronic acid derivatives.

A stereoselective annulative coupling of a vinylboronic ester ate-complex with arynes producing cyclic borinic esters has been developed.     

Palladium-catalyzed hydroalkylation of methylenecyclopropanes with simple hydrazones

A palladium-catalyzed hydroalkylation reaction of methylenecyclopropanes via highly selective C–C σ-bond scission was achieved under mild conditions, in which simple hydrazones served as carbanion equivalents. This method featured good functional group compatibility, affording high yields of C-alkylated terminal alkenes.

A palladium-catalyzed hydroalkylation of methylenecyclopropanes via selective C–C σ-bond scission was achieved, in which simple hydrazones served as carbanion equivalents. This method affords high yields of C-alkylated terminal alkenes with good functional group compatibility.     

Ruthenaelectro-catalyzed C–H acyloxylation for late-stage tyrosine and oligopeptide diversification

Ruthenaelectro(ii/iv)-catalyzed intermolecular C–H acyloxylations of phenols have been developed by guidance of experimental, CV and computational insights. The use of electricity bypassed the need for stoichiometric chemical oxidants. The sustainable electrocatalysis strategy was characterized by ample scope, and its unique robustness enabled the late-stage C–H diversification of tyrosine-derived peptides.

Ruthenaelectro(ii/iv)-catalyzed intermolecular C–H acyloxylations of oligopeptides have been developed by the guidance of key experimental, CV and computational insights.     

A directing group switch in copper-catalyzed electrophilic C–H amination/migratory annulation cascade: divergent access to benzimidazolone/benzimidazole

We present here a copper-catalyzed electrophilic ortho C–H amination of protected naphthylamines with N-(benzoyloxy)amines, cyclization with the pendant amide, and carbon to nitrogen 1,2-directing group migration cascade to access N,N-disubstituted 2-benzimidazolinones. Remarkably, this highly atom-economic tandem reaction proceeds through a C–H and C–C bond cleavage and three new C–N bond formations in a single operation. Intriguingly, the reaction cascade was altered by the subtle tuning of the directing group from picolinamide to thiopicolinamide furnishing 2-heteroaryl-imidazoles via the extrusion of hydrogen sulfide. This strategy provided a series of benzimidazolones and benzimidazoles in moderate to high yields with low catalyst loading (66 substrates with yields up to 99%). From the control experiments, it was observed that after the C–H amination an incipient tetrahedral oxyanion or thiolate intermediate is formed via an intramolecular attack of the primary amine to the amide/thioamide carbonyl. It undergoes either a 1,2-pyridyl shift with the retention of the carbonyl moiety or H₂S elimination for scaffold diversification. Remarkably, inspite of a positive influence of copper in the reaction outcome, from our preliminary investigations, the benzimidazolone product was obtained in good to moderate yields in two steps under metal-free conditions. The N-pyridyl moiety of the benzimidazolone was removed for further manipulation of the free NH group.

A novel directing group switch strategy is explored in a copper-catalyzed divergent synthesis of benzimidazolone via electrophilic C–H amination/cyclization/1,2-C → N directing group migration cascade and benzimidazole through the extrusion of H₂S.     

Nickel-catalyzed C–O/N–H,C–S/N–H,and C–CN/N–H annulation of aromatic amides with alkynes: C–O,C–S,and C–CN activation

The Ni-catalyzed reaction of ortho-phenoxy-substituted aromatic amides with alkynes in the presence of LiO^tBu as a base results in C–O/N–H annulation with the formation of 1(2H)-isoquinolinones. The use of a base is essential for the reaction to proceed. The reaction proceeds, even in the absence of a ligand, and under mild reaction conditions (40 °C). An electron-donating group on the aromatic ring facilitates the reaction. The reaction was also applicable to carbamate (C–O bond activation), methylthio (C–S bond activation), and cyano (C–CN bond activation) groups as leaving groups.

The Ni-catalyzed reaction of ortho-phenoxy-substituted aromatic amides with alkynes in the presence of LiO^tBu as a base results in C–O/N–H annulation with the formation of 1(2H)-isoquinolinones.     

Highly effective and chemoselective hydrodeoxygenation of aromatic alcohols

Effective hydrodeoxygenation (HDO) of aromatic alcohols is very attractive in both conventional organic synthesis and upgrading of biomass-derived molecules, but the selectivity of this reaction is usually low because of the competitive hydrogenation of the unsaturated aromatic ring and the hydroxyl group. The high activity of noble metal-based catalysts often leads to undesired side reactions (e.g., saturation of the aromatic ring) and excessive hydrogen consumption. Non-noble metal-based catalysts suffer from unsatisfied activity and selectivity and often require harsh reaction conditions. Herein, for the first time, we report chemoselective HDO of various aromatic alcohols with excellent selectivity, using porous carbon–nitrogen hybrid material-supported Co catalysts. The C–OH bonds were selectively cleaved while leaving the aromatic moiety intact, and in most cases the yields of targeted compounds reached above 99% and the catalyst could be readily recycled. Nitrogen doping on the carbon skeleton of the catalyst support (C–N matrix) significantly improved the yield of the targeted product. The presence of large pores and a high surface area also improved the catalyst efficiency. This work opens the way for efficient and selective HDO reactions of aromatic alcohols using non-noble metal catalysts.

Porous carbon–nitrogen hybrid material-supported Co catalysts can effectively promote the chemoselective hydrodeoxygenation reaction of a various of aromatic alcohols in ethanol and hydrogen atmosphere, under relatively mild conditions.     

Rh(iii)-Catalyzed [5 + 1] annulation of 2-alkenylanilides and 2-alkenylphenols with allenyl acetates

Herein, we report a mild and highly regioselective Rh(iii)-catalyzed non-oxidative [5 + 1] vinylic C–H annulation of 2-alkenylanilides with allenyl acetates, which has been elusive so far. The reaction proceeds via vinylic C–H activation, regioselective 2,3-migratory insertion, β-oxy elimination followed by nucleophilic cyclization to get direct access to 1,2-dihydroquinoline derivatives. The strategy was also successfully extended to C–H activation of 2-alkenylphenols for constructing chromene derivatives. In the overall [5 + 1] annulation, the allene serves as a one carbon unit. The acetate group on the allene is found to be crucial both for controlling the regio- and chemoselectivity of the reaction and also for facilitating β-oxy elimination. The methodology was scalable and also further extended towards late stage functionalization of various natural products.

A highly regioselective Rh(iii)-catalyzed non-oxidative [5 + 1] vinylic C–H annulation of 2-alkenylanilides and 2-alkenylphenols with allenyl acetates was described for accessing dihyroquinoline and chromene derivatives.     

Stereoretentive and regioselective selenium-catalyzed intermolecular propargylic C–H amination of alkynes

Herein we report an intermolecular propargylic C–H amination of alkynes. This reaction is operationally convenient and requires no transition metal catalysts or additives. Terminal, silyl, and internal alkynes bearing a wide range of functional groups can be aminated in high yields. The regioselectivity of amination for unsymmetrical internal alkynes is strongly influenced by substitution pattern (tertiary > secondary > primary) and by relatively remote heteroatomic substituents. We demonstrate that amination of alkynes bearing α-stereocenters occurs with retention of configuration at the newly-formed C–N bond. Competition experiments between alkynes, kinetic isotope effects, and DFT calculations are performed to confirm the mechanistic hypothesis that initial ene reaction of a selenium bis(imide) species is the rate- and product-determining step. This ene reaction has a transition state that results in substantial partial positive charge development at the carbon atom closer to the amination position. Inductive and/or hyperconjugative stabilization or destabilization of this positive charge explains the observed regioselectivities.

Selenium catalysis enables a general intermolecular propargylic C–H amination of alkynes. The concerted mechanism gives rise to high regioselectivity for the more electron-rich end of the alkyne and retention of the C–H propargylic stereocenter.