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.     

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.     

Ruthenium-catalyzed formal sp3 C–H activation of allylsilanes/esters with olefins: efficient access to functionalized 1,3-dienes

Ru-catalysed oxidative coupling of allylsilanes and allyl esters with activated olefins has been developed via isomerization followed by C(allyl)–H activation providing efficient access to stereodefined 1,3-dienes in excellent yields. Mild reaction conditions, less expensive catalysts, and excellent regio- and diastereoselectivity ensure universality of the reaction. In addition, the unique power of this reaction was illustrated by performing the Diels–Alder reaction, and enantioselective synthesis of highly functionalized cyclohexenone and piperidine and finally synthetic utility was further demonstrated by the efficient synthesis of norpyrenophorin, an antifungal agent.

Ru-catalysed oxidative coupling of allylsilanes and allyl esters with activated olefins has been developed via isomerization followed by C(allyl)–H activation providing efficient access to stereodefined 1,3-dienes in excellent yields.

1,3-Dienes not only are widespread structural motifs in biologically pertinent molecules but also feature as a foundation for a broad range of chemical transformations.^1–14 Indeed, these conjugated dienes serve as substrates in many fundamental synthetic methodologies such as cycloaddition, metathesis, ene reactions, oxidoreduction, or reductive aldolization. It is well-understood that the geometry of olefins often influences the stereochemical outcome and the reactivity of reactions involving 1,3-dienes.¹⁵ Hence, a plethora of synthetic methods have been developed for the stereoselective construction of substituted 1,3-dienes.^16–24 The past decade has witnessed a huge advancement in the field of metal-catalyzed C–H activation/functionalization.^25–27 Although, a significant amount of work in the field of C(alkyl)–H and C(aryl)–H activation has been reported; C(alkenyl)–H activation has not been explored conspicuously, probably due to the complications caused by competitive reactivity of the alkene moiety, which can make chemoselectivity a significant challenge. Over the past few years, several different palladium-based protocols have been developed for C(alkenyl)–H functionalization, but the reactions are generally limited to employing conjugated alkenes, such as styrenes,^28–31 acrylates/acrylamides,^32–36 enamides,³⁷ and enol esters/ethers.^38,39 To date, only a few reports have appeared in the literature for expanding this reactivity towards non-conjugated olefins, which can be exemplified by camphene dimerization,⁴⁰ and carboxylate-directed C(alkenyl)–H alkenylation of 1,4-cyclohexadienes.⁴¹ In 2009, Trost et al. reported a ruthenium-catalyzed stereoselective alkene–alkyne coupling method for the synthesis of 1,3-dienes.⁴² The same group also reported alkene–alkyne coupling for the stereoselective synthesis of trisubstituted ene carbamates.⁴³ A palladium catalyzed chelation control method for the synthesis of dienes via alkenyl sp² C–H bond functionalization was described by Loh et al.⁴⁴ Recently, Engle and coworkers reported an elegant approach for synthesis of highly substituted 1,3-dienes from two different alkenes using an 8-aminoquinoline directed, palladium(ii)-mediated C(alkenyl)–H activation strategy.⁴⁵ Allyl and vinyl silanes are known as indispensable nucleophiles in synthetic chemistry.⁴⁶ Alder ene reactions of allyl silanes with alkynes are reported for the synthesis of 1,4-dienes.⁴⁷ Innumerable methods are known for the preparation of both allyl and vinyl silanes^48–52 but limitations are associated with many of the current protocols, which impedes the synthesis of unsaturated organosilanes in an efficient manner. Silicon-functionalized building blocks are used as coupling partners in the Hiyama reaction⁵³ and are easily converted into iodo-functionalized derivatives (precursor for the Suzuki cross-coupling reaction), but there is little attention given for the synthesis of functionalized vinyl silanes. Herein, we report a general approach for the stereoselective synthesis of trisubstituted 1,3-dienes by the Ru-catalyzed C(sp³)–H functionalization reaction of allylsilanes (Scheme 1).Open in a separate windowScheme 1Highly stereoselective construction of 1,3-dienes.In 1993, Trost and coworkers reported an elegant method for highly chemoselective ruthenium-catalyzed redox isomerization of allyl alcohols without affecting the primary and secondary alcohols and isolated double bonds.^54,55 Inspired by the potential of ruthenium for such isomerization of double bonds in allyl alcohols, we sought to identify a ruthenium-based catalytic system that can promote isomerization of olefins in allylsilanes followed by in situ oxidative coupling with an activated olefin to form substituted 1,3-dienes. We initiated our studies by choosing trimethylallylsilane 1a and acrylate 2a by using a commercially available [RuCl₂(p-cymene)]₂ catalyst in the presence of AgSbF₆ as an additive and co-oxidant Cu(OAc)₂ in 1,2-DCE at 100 °C. Interestingly, it resulted into direct formation of (2E,4Z)-1,3-diene 3aa as a single isomer in 55% yield. It is likely that this reaction occurs by C(allyl)–H activation of the π-allyl ruthenium complex followed by oxidative coupling with the acrylate and leaving the silyl group intact (Table 1). π-Allyl ruthenium complex formation may be highly favorable due to the α-silyl effect which stabilizes the carbanion forming in situ in the reaction.⁵⁶ Next, the regioselective C–H insertion of vinyl silanes could be controlled by stabilization of the carbon–metal (C–M) bond in the α-position to silicon. This stability arises due to the overlapping of the filled carbon–metal orbital with the d orbitals on silicon or the antibonding orbitals of the methyl–silicon (Me–Si) bond.⁵⁷ The stereochemistry of the diene was established by 1D and 2D spectroscopic analysis of the compound 3aa. To quantify the C–H activation mediated coupling efficiency, an extensive optimization study was conducted (allylsilanes followed by in situ oxidative coupling with an activated olefin to form substituted 1,3-dienes). The change of solvents from 1,2-DCE to t-AmOH, DMF, dioxane, THF or MeCN did not give any satisfactory result, rather a very sluggish reaction rate or decomposition of starting materials was observed in each case (entry 2–6).Optimization of reaction conditions^a

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.     

Pd-catalyzed cross-electrophile Coupling/C–H alkylation reaction enabled by a mediator generated via C(sp3)–H activation

Transition-metal-catalyzed cross-electrophile C(sp²)–(sp³) coupling and C–H alkylation reactions represent two efficient methods for the incorporation of an alkyl group into aromatic rings. Herein, we report a Pd-catalyzed cascade cross-electrophile coupling and C–H alkylation reaction of 2-iodo-alkoxylarenes with alkyl chlorides. Methoxy and benzyloxy groups, which are ubiquitous functional groups and common protecting groups, were utilized as crucial mediators via primary or secondary C(sp³)–H activation. The reaction provides an innovative and convenient access for the synthesis of alkylated phenol derivatives, which are widely found in bioactive compounds and organic functional materials.

A cascade Pd-catalyzed cross-electrophile coupling and C–H alkylation reaction of 2-iodo-alkoxylarenes with alkyl chlorides has been developed by using an ortho-methoxy or benzyloxy group as a mediator via C(sp³)–H activation.     

Renewable resources for sustainable metallaelectro-catalysed C–H activation

The necessity for more sustainable industrial chemical processes has internationally been agreed upon. During the last decade, the scientific community has responded to this urgent need by developing novel sustainable methodologies targeted at molecular transformations that not only produce reduced amounts of byproducts, but also by the use of cleaner and renewable energy sources. A prime example is the electrochemical functionalization of organic molecules, by which toxic and costly chemicals can be replaced by renewable electricity. Unrivalled levels of resource economy can thereby be achieved via the merger of metal-catalyzed C–H activation with electrosynthesis. This perspective aims at highlighting the most relevant advances in metallaelectro-catalysed C–H activations, with a particular focus on the use of green solvents and sustainable wind power and solar energy until June 2020.

The merger of C–H activation with electrosynthesis, powered by renewable energies and resources, will guide towards a sustainable future.     

Functionalisation of ethereal-based saturated heterocycles with concomitant aerobic C–H activation and C–C bond formation

With an ever-growing emphasis on sustainable synthesis, aerobic C–H activation (the use of oxygen in air to activate C–H bonds) represents a highly attractive conduit for the development of novel synthetic methodologies. Herein, we report the air mediated functionalisation of various saturated heterocycles and ethers via aerobically generated radical intermediates to form new C–C bonds using acetylenic and vinyl triflones as radical acceptors. This enables access to a variety of acetylenic and vinyl substituted saturated heterocycles that are rich in synthetic value. Mechanistic studies and control reactions support an aerobic radical-based C–H activation mechanism.

Herein we disclose a novel method for the aerobic C–H activation of ethereal-based heterocycles to generate various α-functionalised building blocks.     

Hexafluoroisopropanol: the magical solvent for Pd-catalyzed C–H activation

Among numerous solvents available for chemical transformations, 1,1,1,3,3,3-hexafluoro-2-propanol (popularly known as HFIP) has attracted enough attention of the scientific community in recent years. Several unique features of HFIP compared to its non-fluoro analogue isopropanol have helped this solvent to make a difference in various subdomains of organic chemistry. One such area is transition metal-catalyzed C–H bond functionalization reactions. While, on one side, HFIP is emerging as a green and sustainable deep eutectic solvent (DES), on the other side, a major proportion of Pd-catalyzed C–H functionalization is heavily relying on this solvent. In particular, for distal aromatic C–H functionalizations, the exceptional impact of HFIP to elevate the yield and selectivity has made this solvent irreplaceable. Recent research studies have also highlighted the H-bond-donating ability of HFIP to enhance the chiral induction in Pd-catalyzed atroposelective C–H activation. This perspective aims to portray different shades of HFIP as a magical solvent in Pd-catalyzed C–H functionalization reactions.

Among numerous solvents available for chemical transformations, 1,1,1,3,3,3-hexafluoro-2-propanol (popularly known as HFIP) has attracted enough attention of the scientific community in recent years.     

Ortho C–H arylation of arenes at room temperature using visible light ruthenium C–H activation

A ruthenium-catalyzed ortho C–H arylation process is described using visible light. Using the readily available catalyst [RuCl₂(p-cymene)]₂, visible light irradiation was found to enable arylation of 2-aryl-pyridines at room temperature for a range of aryl bromides and iodides.

A ruthenium-catalyzed ortho C–H arylation process is described using visible light.     

Recent development in transition metal-catalysed C–H olefination

Transition metal-catalysed functionalizations of inert C–H bonds to construct C–C bonds represent an ideal route in the synthesis of valuable organic molecules. Fine tuning of directing groups, catalysts and ligands has played a crucial role in selective C–H bond (sp² or sp³) activation. Recent developments in these areas have assured a high level of regioselectivity in C–H olefination reactions. In this review, we have summarized the recent progress in the oxidative olefination of sp² and sp³ C–H bonds with special emphasis on distal, atroposelective, non-directed sp² and directed sp³ C–H olefination. The scope, limitation, and mechanism of various transition metal-catalysed olefination reactions have been described briefly.

Transition metal-catalysed functionalizations of inert C–H bonds to construct C–C bonds represent an ideal route in the synthesis of valuable organic molecules.     

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.     

Site-selective functionalization of remote aliphatic C–H bonds via C–H metallation

Directing group assistance provided a paradigm for controlling site-selectivity in transition metal-catalyzed C–H functionalization reactions. However, the kinetically and thermodynamically favored formation of 5-membered metallacycles has greatly hampered the selective activation of remote C(sp³)–H bonds via larger-membered metallacycles. Recent development to achieve remote C(sp³)–H functionalization via the C–H metallation process largely relies on employing specific substrates without accessible proximal C–H bonds. Encouragingly, recent advances in this field have enabled the selective functionalization of remote aliphatic C–H bonds in the presence of equally accessible proximal ones by taking advantage of the switch of the regiodetermining step, ring strain of metallacycles, multiple non-covalent interactions, and favourable reductive elimination from larger-membered metallacycles. In this review, we summarize these advancements according to the strategies used, hoping to facilitate further efforts to achieve site- and even enantioselective functionalization of remote C(sp³)–H bonds.

Recent advances in site-selective functionalization of remote aliphatic C–H bonds in organometallic pathways are summarized.     

Magnesium-mediated sp3 C–H activation in cascade cyclization of 1-arylethynyl-2-alkyl-o-carboranes: efficient synthesis of carborane-fused cyclopentanes

This work reports an unprecedented cascade cyclization of 1-arylethynyl-2-alkyl-o-carboranes promoted by magnesium-mediated sp³ C–H activation. Treatment of 1-arylethynyl-2-alkyl-o-carboranes with MeMgBr gives a series of carborane-fused cyclopentanes in very good yields. Deuterium labelling and control experiments suggest that HMgBr, resulting in situ from the nucleophilic substitution of cage B–H bonds with Grignard reagent, initiates the reaction, in which magnesium-promoted intramolecular sp³ C–H activation serves as a key step. This work not only offers a new route for the synthesis of carborane-fused cyclopentanes, but also sheds some light on Mg-mediated C–H activation and functionalization.

An unprecedented cascade cyclization of 1-arylethynyl-2-alkyl-o-carboranes with Grignard reagent for synthesizing carborane-fused cyclopentanes has been disclosed, in which magnesium-mediated intramolecular sp³ C–H activation serves as a key step.     

Selective cleavage of unactivated arene ring C–C bonds by iridium: key roles of benzylic C–H activation and metal–metal cooperativity

The cleavage of aromatic C–C bonds is central for conversion of fossil fuels into industrial chemicals and designing novel arene functionalisations through ring opening, expansion and contraction. However, the current progress is hampered by both the lack of experimental examples of selective oxidative addition of aromatic C–C bonds and limited understanding of the factors that favour insertion into the C–C rather than the C–H bonds. Here, we describe the comprehensive mechanism of the only reported chemo- and regioselective insertion of a transition metal into a range of substituted arene rings in simple iridium(i) complexes. The experimental and computational data reveal that this ring cleavage requires both reversible scission of a benzylic C–H bond and cooperativity of two Ir centres sandwiching the arene in the product-determining intermediate. The mechanism explains the chemoselectivity and scope of this unique C–C activation in industrially important methylarenes and provides a general insight into the role of metal–metal cooperativity in the cleavage of unsaturated C–C bonds.

The detailed mechanism of iridium-mediated C–C cleavage in unactivated arenes reveals the key factors enabling the process and helps predict the scope of the cleavage reaction.     

Borane-catalyzed selective dihydrosilylation of terminal alkynes: reaction development and mechanistic insight

Here, we describe simple B(C₆F₅)₃-catalyzed mono- and dihydrosilylation reactions of terminal alkynes by using a silane-tuned chemoselectivity strategy, affording vinylsilanes and unsymmetrical geminal bis(silanes). This strategy is applicable to the dihydrosilylation of both aliphatic and aryl terminal alkynes with different silane combinations. Gram-scale synthesis and conducting the reaction without the exclusion of air and moisture demonstrate the practicality of this methodology. The synthetic utility of the resulting products was further highlighted by the structural diversification of geminal bis(silanes) through transforming the secondary silane into other silyl groups. Comprehensive theoretical calculations combined with kinetical isotope labeling studies have shown that a prominent kinetic differentiation between the hydrosilylation of alkynes and vinylsilane is responsible for the chemoselective construction of unsymmetrical 1,1-bis(silanes).

A B(C₆F₅)₃/silane-based system enables the chemoselective dihydrosilylation of terminal alkynes. Using a combination of different types of hydrosilanes, a series of unsymmetrical or symmetrical 1,1-bis(silanes) could be constructed.     

Ruthenium-catalyzed intermolecular coupling reactions of arylamines with ethylene and 1,3-dienes: mechanistic insight on hydroamination vs ortho-C-H bond activation

[reaction: see text]. The cationic ruthenium complex [(PCy3)2(CO)(Cl)Ru=CHCH=C(CH3)2]+BF4- was found to be an effective catalyst for the coupling reaction of aniline and ethylene to form a approximately 1:1 ratio of N-ethylaniline and 2-methylquinoline products. The analogous reaction with 1,3-dienes resulted in the preferential formation of Markovnikov addition products. The normal isotope effect of k(NH)/k(ND) = 2.2 (aniline and aniline-d7 at 80 degrees C) and the Hammett rho = -0.43 (correlation of para-substituted p-X-C6H4NH2) suggest an N-H bond activation rate-limiting step for the catalytic reaction.     

Thioether-enabled palladium-catalyzed atroposelective C–H olefination for N–C and C–C axial chirality

Thioethers allowed for highly atroposelective C–H olefinations by a palladium/chiral phosphoric acid catalytic system under ambient air. Both N–C and C–C axial chiral (hetero)biaryls were successfully constructed, leading to a broad range of axially chiral N-aryl indoles and biaryls with excellent enantioselectivities up to 99% ee. Experimental and computational studies were conducted to unravel the walking mode for the atroposelective C–H olefination. A plausible chiral induction model for the enantioselectivity-determining step was established by detailed DFT calculations.

Thioethers allowed for highly atroposelective C–H olefinations by a palladium/chiral phosphoric acid catalytic system under ambient air.     

Counterintuitive solvation effect of ionic-liquid/DMSO solvents on acidic C–H dissociation and insight into respective solvation

How would acidic bond dissociation be affected by adding a small quantity of a weakly polar ionic liquid IL (the “apparent” or “measured” dielectric constant ε of the IL is around 10–15) into a strongly polar molecular solvent (e.g., ε of DMSO: 46.5), or vice versa? The answer is blurred, because no previous investigation was reported in this regard. Toward this, we, taking various IL/DMSO mixtures as representatives, have thoroughly investigated the effects of the respective solvent in ionic–molecular binary systems on self-dissociation of C–H acid phenylmalononitrile PhCH(CN)₂via pK_a determination. As disclosed, in this category of binary media, (1) no linear correspondence exists between pK_a and molar fractions of the respective solvent components; (2) only ∼1–2 mol% of weakly polar ILs in strongly polar DMSO make C–H bonds even more dissociative than in neat DMSO; (3) a small fraction of DMSO in ILs (<10 mol%) can dramatically ease acidic C–H-dissociation; and (4) while the DMSO fraction further increases, its acidifying effect becomes much attenuated. These findings, though maybe counterintuitive, have been rationalized on the basis of the precise pK_a measurement of this work in relation to the respective roles of each solvent component in solvation.

The dependence of PhCH(CN)₂ pK_a on the molar fraction of ionic liquids in ionic–molecular binary mixtures showed a nonlinear three-fragment plot, which was rationalized for the first time by the respective roles of each solvent component for solvation.     

Substrate-controlled C–H or C–C alkynylation of cyclopropanes: generation of aryl radical cations by direct light activation of hypervalent iodine reagents

We report the first oxidative C–H alkynylation of arylcyclopropanes. Irradiation of ethynylbenziodoxolone (EBX) reagents with visible light at 440 nm promoted the reaction. By the choice of the aryl group on the cyclopropane, it was possible to completely switch the outcome of the reaction from the alkynylation of the C–H bond to the oxyalkynylation of the C–C bond, which proceeded without the need for a catalyst, in contrast to previous works. The oxyalkynylation could also be extended to aminocyclopropanes as well as styrenes. Computations indicated that the C–H activation became a favoured nearly barrierless process in the presence of two ortho methyl groups on the benzene ring.

C–C or C–H alkynylation of aryl cyclopropanes was realized by direct activation of EBX reagents with visible light. With ortho methyl groups on the benzene, C–H functionalization became favoured.