Olefin metathesis: what have we learned about homogeneous and heterogeneous catalysts from surface organometallic chemistry?

Since its early days, olefin metathesis has been in the focus of scientific discussions and technology development. While heterogeneous olefin metathesis catalysts based on supported group 6 metal oxides have been used for decades in the petrochemical industry, detailed mechanistic studies and the development of molecular organometallic chemistry have led to the development of robust and widely used homogeneous catalysts based on well-defined alkylidenes that have found applications for the synthesis of fine and bulk chemicals and are also used in the polymer industry. The development of the chemistry of high-oxidation group 5–7 alkylidenes and the use of surface organometallic chemistry (SOMC) principles unlocked the preparation of so-called well-defined supported olefin metathesis catalysts. The high activity and stability (often superior to their molecular analogues) and molecular-level characterisation of these systems, that were first reported in 2001, opened the possibility for the first direct structure–activity relationships for supported metathesis catalysts. This review describes first the history of SOMC in the field of olefin metathesis, and then focuses on what has happened since 2007, the date of our last comprehensive reviews in this field.

Surface organometallic chemistry bridges the gap between homogeneous and heterogeneous olefin metathesis catalysts.     

Access to substituted cyclobutenes by tandem [3,3]-sigmatropic rearrangement/[2 + 2] cycloaddition of dipropargylphosphonates under Ag/Co relay catalysis

We present herein an unconventional tandem [3,3]-sigmatropic rearrangement/[2 + 2] cycloaddition of simple dipropargylphosphonates to deliver a range of bicyclic polysubstituted cyclobutenes and cyclobutanes under Ag/Co relay catalysis. An interesting switch from allene–allene to allene–alkyne cycloaddition was observed based on the substitution of the substrates, which further diversified the range of compounds accessible from this practical method. Significantly, preliminary biological screening of these new compounds identified promising candidates as suppressors of cellular proliferation.

In situ generation of allenes through [3,3]-sigmatropic rearrangement of propargylphosphonates. Divergent allene–allene or allene–alkyne cycloaddition by Ag/Co relay catalysis. Products as promising suppressors of cellular proliferation.     

Acyclic nitronate olefin cycloaddition (ANOC): regio- and stereospecific synthesis of isoxazolines

We report the first demonstrations of intra- and intermolecular acyclic nitronate olefin cycloaddition (ANOC) reactions that enable the highly efficient syntheses of isoxazolines bearing various functional groups. This general approach to accessing γ-lactone fused isoxazolines was hitherto unprecedented. The room temperature transformations reported herein exhibit wide substrate scopes, as evidenced by more than 70 examples, including the generation of five tricyclic isoxazolines. The robustness of this methodology was confirmed by a series of trials that afforded highly functionalized isoxazolines. Both experimental results and density functional theory calculations indicate that these transformations proceed via the in situ formation of acyclic nitronates together with concerted [3+2] cycloaddition and tert-butyloxy group elimination processes to give regio- and stereospecificity.

A novel acyclic nitronate olefin cycloaddition (ANOC) reaction was successfully established, which enabled facile construction of various isoxazolines.     

Cu-catalyzed hydroxycyclopropanol ring-opening cyclization to tetrahydrofurans and tetrahydropyrans: short total syntheses of hyperiones

Tetrahydrofurans (THFs) and tetrahydropyrans (THPs) are important core scaffolds frequently found in many molecules of medicinal importance. Herein, we report a novel copper-catalyzed hydroxycyclopropanol ring-opening cyclization methodology to synthesize di- or tri-substituted THFs and THPs. In this reaction, a strained C–C bond was cleaved and a new Csp³–O bond was formed to produce the aforementioned O-heterocycles. The new THF synthesis features a broad substrate scope, scalability, and good functional-group tolerability. It enabled us to complete the shortest enantioselective syntheses of hyperiones A and B (3 and 4 steps, respectively), which is significantly shorter than the previously reported two total syntheses (≥10 steps).

A novel Cu-catalyzed hydroxycyclopropanol ring-opening cyclization was developed to synthesize substituted tetrahydrofuran/tetrahydropyran molecules including two norlignan natural products hyperiones A and B.     

Mechanistic insights into copper-catalyzed aerobic oxidative coupling of N–N bonds

Catalytic N–N coupling is a valuable transformation for chemical synthesis and energy conversion. Here, mechanistic studies are presented for two related copper-catalyzed oxidative aerobic N–N coupling reactions, one involving the synthesis of a pharmaceutically relevant triazole and the other relevant to the oxidative conversion of ammonia to hydrazine. Analysis of catalytic and stoichiometric N–N coupling reactions support an “oxidase”-type catalytic mechanism with two redox half-reactions: (1) aerobic oxidation of a Cu^I catalyst and (2) Cu^II-promoted N–N coupling. Both reactions feature turnover-limiting oxidation of Cu^I by O₂, and this step is inhibited by the N–H substrate(s). The results highlight the unexpected facility of the N–N coupling step and establish a foundation for development of improved catalysts for these transformations.

Mechanistic studies provide valuable insights into Cu-catalyzed N–N coupling reactions relevant to energy conversion and pharmaceutical synthesis.     

Diastereoselective synthesis of [1]rotaxanes via an active metal template strategy

Despite the impressive number of interlocked molecules described in the literature over the past 30 years, only a few stereoselective syntheses of mechanically chiral rotaxanes have been reported so far. In this study, we present the first diastereoselective synthesis of mechanically planar chiral [1]rotaxanes, that has been achieved using the active template Cu-mediated alkyne–azide cycloaddition reaction. This synthetic method has been applied to the preparation of a [1]rotaxane bearing a labile stopper that can then be substituted without disruption of the mechanical bond. This approach paves the way for the synthesis of a wide variety of mechanically planar chiral [1]rotaxanes, hence allowing the study of the properties and potential applications of this class of interlocked molecular architectures.

The first diastereoselective synthesis of mechanically planar chiral [1]rotaxanes has been achieved using the active template Cu-mediated alkyne–azide cycloaddition reaction.     

Decarbonylative ether dissection by iridium pincer complexes

A unique chain-rupturing transformation that converts an ether functionality into two hydrocarbyl units and carbon monoxide is reported, mediated by iridium(i) complexes supported by aminophenylphosphinite (NCOP) pincer ligands. The decarbonylation, which involves the cleavage of one C–C bond, one C–O bond, and two C–H bonds, along with formation of two new C–H bonds, was serendipitously discovered upon dehydrochlorination of an iridium(iii) complex containing an aza-18-crown-6 ether macrocycle. Intramolecular cleavage of macrocyclic and acyclic ethers was also found in analogous complexes featuring aza-15-crown-5 ether or bis(2-methoxyethyl)amino groups. Intermolecular decarbonylation of cyclic and linear ethers was observed when diethylaminophenylphosphinite iridium(i) dinitrogen or norbornene complexes were employed. Mechanistic studies reveal the nature of key intermediates along a pathway involving initial iridium(i)-mediated double C–H bond activation.

A unique chain-rupturing transformation that converts an ether functionality into two hydrocarbyl units and carbon monoxide is reported.     

Reversible metathesis of ammonia in an acyclic germylene–Ni0 complex

Carbenes, a class of low-valent group 14 ligand, have shifted the paradigm in our understanding of the effects of supporting ligands in transition-metal reactivity and catalysis. We now seek to move towards utilizing the heavier group 14 elements in effective ligand systems, which can potentially surpass carbon in their ability to operate via ‘non-innocent’ bond activation processes. Herein we describe our initial results towards the development of scalable acyclic chelating germylene ligands (viz.1a/b), and their utilization in the stabilization of Ni⁰ complexes (viz.4a/b), which can readily and reversibly undergo metathesis with ammonia with no net change of oxidation state at the Ge^II and Ni⁰ centres, through ammonia bonding at the germylene ligand as opposed to the Ni⁰ centre. The DFT-derived metathesis mechanism, which surprisingly demonstrates the need for three molecules of ammonia to achieve N–H bond activation, supports reversible ammonia binding at Ge^II, as well as the observed reversibility in the overall reaction.

Chelating single-centre ambiphile ligands based upon low-coordinate, acyclic germylenes have been developed, remaining highly Lewis acidic even when bound to Ni⁰, remarkably allowing for the reversible metathesis of the N–H bonds in ammonia at Ge^II.     

Rh(i)-catalyzed stereoselective desymmetrization of prochiral cyclohexadienones via highly exo-selective Huisgen-type [3 + 2] cycloaddition

A Rh(i)-catalyzed highly stereoselective desymmetrization of 2-alkynylbenzaldehyde-tethered cyclohexadienones triggered by intramolecular Huisgen-type [3 + 2] cycloaddition has been developed. This method enables convergent construction of complex epoxy-bridged polycyclic ring systems with five contiguous stereocenters with excellent exo-selectivity and broad substrate scope. The highly atom-economical process involves 6-endo-dig cyclization of carbonyl oxygen onto an activated alkyne resulting in a highly reactive metal–benzopyrylium intermediate, which readily undergoes intramolecular [3 + 2] annulation/hydration. Asymmetric induction is also achieved for the first time in Rh(i)-catalyzed 1,3-dipolar cycloaddition using an easily accessible chiral diene as the ligand.

A Rh(i)-catalyzed highly stereoselective desymmetrization of 2-alkynylbenzaldehyde-tethered cyclohexadienones triggered by intramolecular Huisgen-type [3 + 2] cycloaddition has been developed.     

TMTHSI,a superior 7-membered ring alkyne containing reagent for strain-promoted azide–alkyne cycloaddition reactions

We describe the development of TMTH-SulfoxImine (TMTHSI) as a superior click reagent. This reagent combines a great reactivity, with small size and low hydrophobicity and compares outstandingly with existing click reagents. TMTHSI can be conveniently functionalized with a variety of linkers allowing attachment of a diversity of small molecules and (peptide, nucleic acid) biologics.

TMTHSI was developed as new reagent for strain-promoted azide–alkyne cycloaddition reactions, enabling connection of a diversity of small to large molecular constructs.     

‘Sacrificial’ supramolecular assembly and pressure-induced polymerization: toward sequence-defined functionalized nanothreads

Limited supramolecular strategies have been utilized to synthesize sequence-defined polymers, despite the prominence of noncovalent interactions in materials design. Herein, we illustrate the utility of ‘sacrificial’ aryl-perfluoroaryl supramolecular synthons to synthesize sp³-hybridized nanothreads from sp²-enriched reactants. Our strategy features A–B reactant pairs in the form of a phenol:pentafluorophenol co-crystal that is preorganized for an electronically-biased and sequence-defined polymerization. The polymerization, initiated at 12 GPa, affords an alternating copolymer featuring exogenous –OH functionalities. The external substitution is confirmed through IR spectroscopy. Importantly, the inclusion of the functional unit provides the first experimental glimpse at reaction mechanism: keto–enol tautomerization that can only occur during cycloaddition is observed through IR spectroscopy. Our approach realizes the first example of a functionalized nanothread and attains sequence definition through sacrificial supramolecular preorganization and presents a further approach for de novo design of complex nanothreads.

Supramolecular synthons are exploited to synthesize –OH functionalized sp³-rich sequence-defined nanothreads using pressure-induced polymerization of a phenol:pentafluorophenol co-crystal.      

Tandem sequential catalytic enantioselective synthesis of highly-functionalised tetrahydroindolizine derivatives

An isothiourea-catalysed enantioselective synthesis of novel tetrahydroindolizine derivatives is reported through a one-pot tandem sequential process. The application of 2-(pyrrol-1-yl)acetic acid in combination with either a trifluoromethyl enone or an α-keto-β,γ-unsaturated ester in an enantioselective Michael addition–lactonisation process, followed by in situ ring-opening and cyclisation, led to a range of 24 tetrahydroindolizine derivatives containing three stereocentres in up to >95 : 5 dr and >99 : 1 er.

The isothiourea-catalysed enantioselective synthesis of tetrahydroindolizine derivatives containing three stereocentres is reported through a one-pot tandem sequential process.     

A direct route to six and seven membered lactones via γ-C(sp3)–H activation: a simple protocol to build molecular complexity

Lactones comprise a class of valuable compounds having biological as well as industrial importance. Development of a methodology to synthesize such molecules directly from readily available materials such as aliphatic carboxylic acid is highly desirable. Herein, we have reported synthesis of δ-lactones and ε-lactones via selective γ-C(sp³)–H activation. The γ-C–H bond containing aliphatic carboxylic acids provide six or seven membered lactones depending on the olefin partner in the presence of a palladium catalyst. A mechanistic investigation suggests that C–H activation is the rate-determining step. Further transformations of the lactones have been carried out to showcase the applicability of the present strategy.

Six and seven membered lactones have been synthesized directly from readily available aliphatic acids.     

Site-selective [2 + 2 + n] cycloadditions for rapid,scalable access to alkynylated polycyclic aromatic hydrocarbons

Polycyclic aromatic hydrocarbons (PAHs) are attractive synthetic building blocks for more complex conjugated nanocarbons, but their use for this purpose requires appreciable quantities of a PAH with reactive functional groups. Despite tremendous recent advances, most synthetic methods cannot satisfy these demands. Here we present a general and scalable [2 + 2 + n] (n = 1 or 2) cycloaddition strategy to access PAHs that are decorated with synthetically versatile alkynyl groups and its application to seven structurally diverse PAH ring systems (thirteen new alkynylated PAHs in total). The critical discovery is the site-selectivity of an Ir-catalyzed [2 + 2 + 2] cycloaddition, which preferentially cyclizes tethered diyne units with preservation of other (peripheral) alkynyl groups. The potential for generalization of the site-selectivity to other [2 + 2 + n] reactions is demonstrated by identification of a Cp₂Zr-mediated [2 + 2 + 1]/metallacycle transfer sequence for synthesis of an alkynylated, selenophene-annulated PAH. The new PAHs are excellent synthons for macrocyclic conjugated nanocarbons. As a proof of concept, four were subjected to alkyne metathesis catalysis to afford large, PAH-containing arylene ethylene macrocycles, which possess a range of cavity sizes reaching well into the nanometer regime. Notably, these high-yielding macrocyclizations establish that synthetically convenient pentynyl groups can be effective for metathesis since the 4-octyne byproduct is sequestered by 5 Å MS. Most importantly, this work is a demonstration of how site-selective reactions can be harnessed to rapidly build up structural complexity in a practical, scalable fashion.

An orthogonal [2 + 2 + n] cycloaddition/alkyne metathesis reaction sequence enables streamlined access to conjugated macrocyclic nanocarbons.     

Ti-catalyzed ring-opening oxidative amination of methylenecyclopropanes with diazenes

The ring-opening oxidative amination of methylenecyclopropanes (MCPs) with diazenes catalyzed by py₃TiCl₂(NR) complexes is reported. This reaction selectively generates branched α-methylene imines as opposed to linear α,β-unsaturated imines, which are difficult to access via other methods. Products can be isolated as the imine or hydrolyzed to the corresponding ketone in good yields. Mechanistic investigation via density functional theory suggests that the regioselectivity of these products results from a Curtin–Hammett kinetic scenario, where reversible β-carbon elimination of a spirocyclic [2 + 2] azatitanacyclobutene intermediate is followed by selectivity-determining β-hydrogen elimination of the resulting metallacycle. Further functionalizations of these branched α-methylene imine products are explored, demonstrating their utility as building blocks.

The ring-opening oxidative amination of methylenecyclopropanes (MCPs) with diazenes catalyzed by py₃TiCl₂(NR) complexes is reported.     

Redox-induced reversible [2 + 2] cycloaddition of an etheno-fused diporphyrin

3,5-Ethenoporphyrin is a π-extended porphyrin containing a fused ethene unit between the meso- and β-positions, exhibiting unique contribution of macrocyclic antiaromaticity. We have recently reported that its analogue, etheno-fused diporphyrin, underwent thermal [2 + 2] cycloaddition to furnish X-shaped cyclobutane-linked tetraporphyrins. Here we demonstrate that the cyclobutane-ring formation is dynamically redox-active. Namely, the tetraporphyrin underwent two-step four-electron oxidation to afford two etheno-fused diporphyrin dications. The reduction of the resulting dication regenerated the cyclobutane-linked tetraporphyrin. The dication was sufficiently stable to allow its isolation under ambient conditions. The structure of the dication has been confirmed by ¹H NMR spectroscopy and X-ray diffraction analysis. Importantly, the simultaneous double C–C bond cleavage in the cyclopropane ring in the tetraporphyrin is exceptional among dynamic redox (dyrex) systems to achieve large structural changes, thus offering new insights for the design of novel redox-active functional organic materials for electrochromic dyes, organic batteries, and organic memories.

A four-electron oxidation of an X-shaped tetraporphyrin affords stable etheno-fused diporphyrin dications through double C–C bond cleavage. The reduction of the dication recovers the tetraporphyrin via a thermal [2 + 2] cycloaddition.     

Fe-catalyzed Fukuyama-type indole synthesis triggered by hydrogen atom transfer

Fe, Co, and Mn hydride-initiated radical olefin additions have enjoyed great success in modern synthesis, yet the extension of other hydrogen radicalophiles instead of olefins remains largely elusive. Herein, we report an efficient Fe-catalyzed intramolecular isonitrile–olefin coupling reaction delivering 3-substituted indoles, in which isonitrile was firstly applied as the hydrogen atom acceptor in the radical generation step by MHAT. The protocol features low catalyst loading, mild reaction conditions, and excellent functional group tolerance.

A mild and efficient method has been developed to synthesize 3-substituted indoles via an Fe-catalyzed radical isonitrile–olefin coupling reaction initiated by MHAT to isonitriles.     

Tandem aza-Heck Suzuki and carbonylation reactions of O-phenyl hydroxamic ethers: complex lactams via carboamination

The palladium-catalysed tandem aza-Heck–Suzuki and aza-Heck–carbonylation reactions of O-phenyl hydroxamic ethers are reported. These formal alkene carboamination reactions provide highly versatile access to wide range complex, stereogenic secondary lactams and exhibit outstanding functional group tolerance and high diastereoselectivity.

The palladium-catalysed tandem aza-Heck–Suzuki and aza-Heck–carbonylation reactions of O-phenyl hydroxamic ethers are reported.     

Enantioselective transition metal catalysis directed by chiral cations

Enantioselective transition metal catalysis directed by chiral cations is the amalgamation of chiral cation catalysis and organometallic catalysis. Thus far, three strategies have been revealed: ligand scaffolds incorporated on chiral cations, chiral cations paired with transition metal ‘ate’-type complexes, and ligand scaffolds incorporated on achiral anions. Chiral cation ion-pair catalysis has been successfully applied to alkylation, cycloaddition, dihydroxylation, oxohydroxylation, sulfoxidation, epoxidation and C–H borylation. This development represents an effective approach to promote the cooperation between chiral cations and transition metals, increasing the versatility and capability of both these forms of catalysts. In this review, we present current examples of the three strategies and suggest possible inclusions for the future.

Enantioselective transition metal catalysis directed by chiral cations is the amalgamation of chiral cation catalysis and organometallic catalysis.     

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.