Showing papers on "Alkylation published in 2021"
TL;DR: In this paper, the authors report the functionalization of numerous feedstock chemicals via the coupling of unactivated C(sp3)-H bonds with electron-deficient olefins.
Abstract: Utilizing catalytic CuCl2 we report the functionalization of numerous feedstock chemicals via the coupling of unactivated C(sp3)-H bonds with electron-deficient olefins The active cuprate catalyst undergoes Ligand-to-Metal Charge Transfer (LMCT) to enable the generation of a chlorine radical which acts as a powerful hydrogen atom transfer reagent capable of abstracting strong electron-rich C(sp3)-H bonds Of note is that the chlorocuprate catalyst is an exceedingly mild oxidant (05 V vs SCE) and that a proposed protodemetalation mechanism offers a broad scope of electron-deficient olefins, offering high diastereoselectivity in the case of endocyclic alkenes The coupling of chlorine radical generation with Cu reduction through LMCT enables the generation of a highly active HAT reagent in an operationally simple and atom economical protocol
123 citations
TL;DR: In this article, a mild and general nickel-catalysed asymmetric reductive hydroalkylation was proposed to convert enamides and enecarbamates into drug-like α-branched chiral amines and derivatives.
Abstract: To increase the reliability and success rate of drug discovery, efforts have been made to increase the C(sp3) fraction and avoid flat molecules. sp3-Rich enantiopure amines are most frequently encountered as chiral auxiliaries, synthetic intermediates for pharmaceutical agents and bioactive natural products. Streamlined construction of chiral aliphatic amines has long been regarded as a paramount challenge. Mainstream approaches, including hydrogenation of enamines and imines, C-H amination, and alkylation of imines, were applied for the synthesis of chiral amines with circumscribed skeleton structures; typically, the chiral carbon centre was adjacent to an auxiliary aryl or ester group. Herein, we report a mild and general nickel-catalysed asymmetric reductive hydroalkylation to effectively convert enamides and enecarbamates into drug-like α-branched chiral amines and derivatives. This reaction involves the regio- and stereoselective hydrometallation of an enamide or enecarbamate to generate a catalytic amount of enantioenriched alkylnickel intermediate, followed by C-C bond formation via alkyl electrophiles.
75 citations
TL;DR: In this paper, the first highly enantioselective catalytic synthesis of P-stereogenic secondary phosphine-boranes was realized by the asymmetric addition of primary phosphine to electron-deficient alkenes with a newly developed unsymmetric bisphosphine (PCP') pincer-nickel complex.
Abstract: The first highly enantioselective catalytic synthesis of P-stereogenic secondary phosphine-boranes was realized by the asymmetric addition of primary phosphine to electron-deficient alkenes with a newly developed unsymmetric bisphosphine (PCP') pincer-nickel complex Various P-stereogenic secondary phosphine-boranes were obtained in 57-92% yields with up to 99% ee and >20:1 dr The follow-up alkylation upon P-C bond formation with alkyl halides provided a practical way to access P-chiral compounds with diverse functional groups
60 citations
TL;DR: In this paper, a photochemically mediated method for the defluorinative alkylation of a commodity feedstock: ethyl trifluoroacetate was identified using a previously developed diaryl ketone HAT catalyst.
Abstract: The installation of gem-difluoromethylene groups into organic structures remains a daunting synthetic challenge despite their attractive structural, physical, and biochemical properties. A very efficient retrosynthetic approach would be the functionalization of a single C-F bond from a trifluoromethyl group. Recent advances in this line of attack have enabled the C-F activation of trifluoromethylarenes, but limit the accessible motifs to only benzylic gem-difluorinated scaffolds. In contrast, the C-F activation of trifluoroacetates would enable their use as a bifunctional gem-difluoromethylene synthon. Herein, we report a photochemically mediated method for the defluorinative alkylation of a commodity feedstock: ethyl trifluoroacetate. A novel mechanistic approach was identified using our previously developed diaryl ketone HAT catalyst to enable the hydroalkylation of a diverse suite of alkenes. Furthermore, electrochemical studies revealed that more challenging radical precursors, namely trifluoroacetamides, could also be functionalized via synergistic Lewis acid/photochemical activation. Finally, this method enabled a concise synthetic approach to novel gem-difluoro analogs of FDA-approved pharmaceutical compounds.
59 citations
TL;DR: In this article, the treatment of S-(alkyl) thianthrenium salts to generate non-stabilized alkyl radicals as key intermediates has been reported, with the controlled and selective outcome of the ensuing reactions under mild photoredox conditions.
Abstract: Sulfonium salts bearing a positively charged sulfur atom with three organic substituents have intrigued chemists for more than a century for their unusual structures and high chemical reactivity. These compounds are known to undergo facile single-electron reduction to emerge as a valuable and alternative source of aryl radicals for organic synthesis. However, the generation of non-stabilized alkyl radicals from sulfonium salts has been a challenge for several decades. Here we report the treatment of S-(alkyl) thianthrenium salts to generate non-stabilized alkyl radicals as key intermediates granting the controlled and selective outcome of the ensuing reactions under mild photoredox conditions. The value of these reagents has been demonstrated through the efficient construction of alkylboronates and other transformations, including heteroarylation, alkylation, alkenylation, and alkynylation. The developed method is practical, and provides the opportunity to convert C-OH bond to C-B and C-C bonds.
58 citations
TL;DR: A photo-induced and chemical oxidant-free cross-dehydrogenative coupling between alkanes and heteroarenes using catalytic chloride and cobalt catalyst was reported in this article.
Abstract: Hydrogen atom abstraction (HAT) from C(sp3)–H bonds of naturally abundant alkanes for alkyl radical generation represents a promising yet underexplored strategy in the alkylation reaction designs since involving stoichiometric oxidants, excessive alkane loading, and limited scope are common drawbacks. Here we report a photo-induced and chemical oxidant-free cross-dehydrogenative coupling (CDC) between alkanes and heteroarenes using catalytic chloride and cobalt catalyst. Couplings of strong C(sp3)–H bond-containing substrates and complex heteroarenes, have been achieved with satisfactory yields. This dual catalytic platform features the in situ engendered chlorine radical for alkyl radical generation and exploits the cobaloxime catalyst to enable the hydrogen evolution for catalytic turnover. The practical value of this protocol was demonstrated by the gram-scale synthesis of alkylated heteroarene with merely 3 equiv. alkane loading. Hydrogen atom abstraction from C(sp3)–H bonds of naturally abundant alkanes for alkyl radical generation represents a promising yet underexplored strategy in the alkylation reaction designs. Here the authors show a photo-induced and chemical oxidant-free cross-dehydrogenative coupling between alkanes and heteroarenes using catalytic chloride and cobalt catalyst.
54 citations
TL;DR: In this paper, a nickel-catalyzed, multicomponent regio-and enantioselective coupling via sequential hydroformylation and carbonylation from readily available starting materials has been developed.
Abstract: A nickel-catalyzed, multicomponent regio- and enantioselective coupling via sequential hydroformylation and carbonylation from readily available starting materials has been developed. This modular multicomponent hydrofunctionalization strategy enables the straightforward reductive hydrocarbonylation of a broad range of unactivated alkenes to produce a wide variety of unsymmetrical dialkyl ketones bearing a functionalized α-stereocenter, including enantioenriched chiral α-aryl ketones and α-amino ketones. It uses chiral bisoxazoline as a ligand, silane as a reductant, chloroformate as a safe CO source, and a racemic secondary benzyl chloride or an N-hydroxyphthalimide (NHP) ester of a protected α-amino acid as the alkylation reagent. The benign nature of this process renders this method suitable for late-stage functionalization of complex molecules.
54 citations
TL;DR: In this article, a carbene-catalyzed reductive coupling reaction of carboxylic esters and substituted Hantzsch esters is described, and the key steps of this reaction include one-electron reduction of a catalyzed carbene catalyst-bo...
Abstract: A carbene-catalyzed reductive coupling reaction of carboxylic esters and substituted Hantzsch esters is disclosed. Key steps of this reaction include one-electron reduction of a carbene catalyst-bo...
52 citations
TL;DR: In this paper, the authors summarize recent advances in Co(III, Rh(III) and Ir(III)-catalyzed direct C-H alkylation/alkenylation/arylation with carbene precursors and also discuss key synthetic intermediates within the catalytic cycles.
Abstract: Metal carbenes play a pivotal role in transition-metal-catalyzed synthetic transfer reactions. The metal carbene is generated either from a diazo compound through facile extrusion of N2 with a metal catalyst or in situ generated from other sources like triazoles, pyriodotriazoles, sulfoxonium ylides and iodonium-ylide. On the other hand, Co(III), Rh(III) & Ir(III)-catalyzed C-H functionalizations have been well established as a key synthetic step to enable the construction of various synthetic transformations. Interestingly, in recent years, merging of these two concepts C-H activation and carbene migratory insertion gained much attention, in particular group 9 metal-catalyzed arene C-H functionalizations with carbene precursors via carbene migratory insertion. In this review, we summarize recent advances in Co(III), Rh(III) & Ir(III)-catalyzed direct C-H alkylation/alkenylation/arylation with carbene precursors and also discuss key synthetic intermediates within the catalytic cycles.
50 citations
TL;DR: In this paper, an undirected para-selective two-step C-H alkylation of complex arenes is presented for late-stage functionalization using a siteselective thianthrenation with palladium-catalyzed reductive electrophile crosscoupling.
Abstract: Herein, we present an undirected para-selective two-step C-H alkylation of complex arenes useful for late-stage functionalization. The combination of a site-selective C-H thianthrenation with palladium-catalyzed reductive electrophile cross-coupling grants access to a diverse range of synthetically useful alkylated arenes which cannot be accessed otherwise with comparable selectivity, diversity, and practicality. The robustness of this transformation is further demonstrated by thianthrenium-based reductive coupling of two complex fragments.
47 citations
01 May 2021
TL;DR: In this article, the authors summarize recent progress of the radical-mediated decyanative alkylation reactions of cyano(hetero)arene via photo/electrochemistry via a radical pathway, in which C(sp3)-H, c(sp2)-H or C-hetero bonds are cleavaged and a new C-C bond is formed.
Abstract: Substituted pyridines are very important skeleton in natural products, agrochemicals and pharmaceuticals, which not only can be used to synthesis chiral ligands and functional materials but also as building blocks in the construction of new photo- or electrochemical properties. As a result, much efforts have been developed towards the synthesis of such compounds. Given the great influence of these synthesis methodologies in organic chemistry, we summarize recent progress of the radical-mediated decyanative alkylation reactions of cyano(hetero)arene via photo/electrochemistry via a radical pathway, in which C(sp3)-H, C(sp2)-H, C–C or C-hetero bonds are cleavaged and a new C–C bond is formed. We also discussed the mechanisms of these radical decyanative alkylation reactions.
TL;DR: In this article, the first enantioselective synthesis of N-N biaryl atropisomers via a Cu-bisoxazoline-catalyzed Friedel-Crafts alkylation reaction was described.
Abstract: Nitrogen-nitrogen bonds containing motifs are ubiquitous in natural products and bioactive compounds. However, the atropisomerism arising from a restricted rotation around an N-N bond is largely overlooked. Here, we describe a method to access the first enantioselective synthesis of N-N biaryl atropisomers via a Cu-bisoxazoline-catalyzed Friedel-Crafts alkylation reaction. A wide range of axially chiral N-N bisazaheterocycle compounds were efficiently prepared in high yields with excellent enantioselectivities via desymmetrization and kinetic resolution. Heating experiments showed that the axially chiral bisazaheterocycle products have high rotational barriers.
TL;DR: A mild electro-oxidative method for efficient C–H alkylation of quinoxalin-2(1H)-ones by means of radical addition reactions of alkyl boronic acids and esters and alkyL trifluoroborates to afford C–C coupled products is reported.
TL;DR: In this article, a cooperative strategy that can completely switch the reaction selectivity to give the alkylated α-fluoroalkene skeletons (branched selectivity) was proposed.
Abstract: Conventional approaches on Pd-catalyzed ring-opening cross-couplings of gem -difluorocyclopropanes with nucleophiles predominantly deliver the s-fluoroalkene scaffolds (linear selectivity). Herein, we report a cooperative strategy that can completely switch the reaction selectivity to give the alkylated α-fluoroalkene skeletons (branched selectivity). The unique reactivity of hydrazones that enabling analogous inner-sphere 3,3'-reductive elimination driven by denitrogenation, as well as the assistance of steric-embedded N -heterocyclic carbene ligand, are the key to the success tto switch the regioselectivity. A wide range of hydrazones that derived from naturally abundant aryl and alkyl aldehydes are well applicable, and various gem -difluorocyclopropanes, including those pharmaceutical and biological molecule-modified ones, can be efficiently functionalized with high value alkylated α-fluor inated alkene motifs under mild conditions.
TL;DR: In this paper, the development of a series of thianthrenium salts, which act as reliable alkylation reagents, are ready to engage in copper-catalyzed Sonogashira reaction to build C(sp 3 )-C(sp) bonds under mild photoinduced conditions.
Abstract: Alkyl constitutes one of the most widely used groups in organic synthesis. Here, the development of a series of thianthrenium salts, which act as reliable alkylation reagents, are ready to engage in copper-catalyzed Sonogashira reaction to build C(sp 3 )-C(sp) bonds under mild photoinduced conditions. Diverse alkyl thianthrenium salts, methyl and disubstituted thianthrenium salts are employed with great functional breadth, since sensitive Cl, Br and I are compatible and challenging to achieve by conventional approaches. The generality of the developed alkyl reagents has also been demonstrated in copper-catalyzed Kumada reactions.
TL;DR: Under blue light photoexcitation, copper(I)/carbazole-based bisoxazoline (CbzBox) catalytic system exhibits good reactivity and high stereoselectivity, thus offering an efficient strategy for constructing chiral alkyl azoles.
Abstract: A catalytic asymmetric alkylation of azoles with secondary 1-arylalkyl bromides through direct C-H functionalization is reported. Under blue-light photoexcitation, a copper(I)/carbazole-based bisoxazoline (CbzBox) catalytic system exhibits good reactivity and high stereoselectivity, thus offering an efficient strategy for the construction of chiral alkyl azoles. These reactions proceed at low temperature and are compatible with a wide range of azoles.
TL;DR: With this enzymatic system, pyrazole alkylation (methylation, ethylation, propylation) was achieved with unprecedented regioselectivity (>99 %), regiodivergence, and in a first example on preparative scale.
Abstract: Selective alkylation of pyrazoles could solve a challenge in chemistry and streamline synthesis of important molecules. Here we report catalyst-controlled pyrazole alkylation by a cyclic two-enzyme cascade. In this enzymatic system, a promiscuous enzyme uses haloalkanes as precursors to generate non-natural analogs of the common cosubstrate S-adenosyl-l-methionine. A second engineered enzyme transfers the alkyl group in highly selective C-N bond formations to the pyrazole substrate. The cosubstrate is recycled and only used in catalytic amounts. Key is a computational enzyme-library design tool that converted a promiscuous methyltransferase into a small enzyme family of pyrazole-alkylating enzymes in one round of mutagenesis and screening. With this enzymatic system, pyrazole alkylation (methylation, ethylation, propylation) was achieved with unprecedented regioselectivity (>99 %), regiodivergence, and in a first example on preparative scale.
TL;DR: Preliminary mechanistic experiments validate the dual catalytic, open-shell nature of this platform, which enables reactivity previously unattainable in traditional halide-based N-alkylation systems.
TL;DR: A copper(I)/cinchona-alkaloid-derived N, N, P -ligand catalytic system that enables oxidative addition with racemic alkyl bromides under mild conditions is reported, affording a number of potentially useful α-chiral alkylated azoles, such as 1,3,4-oxadiazoles, oxazoles, and benzo[ d ]oxazoles for drug discovery.
Abstract: The development of enantioconvergent cross-coupling of racemic alkyl halides directly with heteroarene C(sp2 )-H bonds has been impeded by the use of a base at elevated temperature that leads to racemization. We herein report a copper(I)/cinchona-alkaloid-derived N,N,P-ligand catalytic system that enables oxidative addition with racemic alkyl bromides under mild conditions. Thus, coupling with azole C(sp2 )-H bonds has been achieved in high enantioselectivity, affording a number of potentially useful α-chiral alkylated azoles, such as 1,3,4-oxadiazoles, oxazoles, and benzo[d]oxazoles as well as 1,3,4-triazoles, for drug discovery. Mechanistic experiments indicated facile deprotonation of an azole C(sp2 )-H bond and the involvement of alkyl radical species under the reaction conditions.
TL;DR: In this article, a copper-catalyzed asymmetric alkylation of HPAr1Ar2 with alkyl halides is uncovered, which provides an array of P-stereogenic phosphines in generally high yield and enantioselectivity.
Abstract: A copper(I)-catalyzed asymmetric alkylation of HPAr1Ar2 with alkyl halides is uncovered, which provides an array of P-stereogenic phosphines in generally high yield and enantioselectivity. The electrophilic alkyl halides enjoy a broad substrate scope, including allyl bromides, propargyl bromide, benzyl bromides, and alkyl iodides. Moreover, 11 unsymmetrical diarylphosphines (HPAr1Ar2) serve as competent pronucleophiles. The present methodology is also successfully applied to catalytic asymmetric double and triple alkylation, and the corresponding products were obtained in moderate diastereo- and excellent enantioselectivities. Some 31P NMR experiments indicate that bulky HPPhMes exhibits weak competitively coordinating ability to the Cu(I)-bisphosphine complex, and thus the presence of stoichiometric HPAr1Ar2 does not affect the enantioselectivity significantly. Therefore, the high enantioselectivity in this reaction is attributed to the high performance of the unique Cu(I)-(R,RP)-TANIAPHOS complex in asymmetric induction. Finally, one monophosphine and two bisphosphines prepared by the present reaction are employed as efficient chiral ligands to afford three structurally diversified Cu(I) complexes, which demonstrates the synthetic utility of the present methodology.
TL;DR: In this paper, an oxidant-free, electrocatalytic approach to achieve intramolecular oxidative allylic C-H amination and alkylation by employing tailored cobalt-salen complexes as catalysts is presented.
Abstract: Oxidative allylic C–H functionalization is a powerful tool to streamline organic synthesis as it minimizes the need for functional group activation and generates alkenyl-substituted products amenable to further chemical modifications. The intramolecular variants can be used to construct functionalized ring structures but remain limited in scope and by their frequent requirement for noble metal catalysts and stoichiometric chemical oxidants. Here we report an oxidant-free, electrocatalytic approach to achieve intramolecular oxidative allylic C–H amination and alkylation by employing tailored cobalt-salen complexes as catalysts. These reactions proceed through a radical mechanism and display broad tolerance of functional groups and alkene substitution patterns, allowing efficient coupling of di-, tri- and even tetrasubstituted alkenes with N- and C-nucleophiles to furnish high-value heterocyclic and carbocyclic structures. Oxidative allylic C–H functionalizations minimise the need for functional group activation and generate alkenyl-substituted products amenable to further chemical modifications. Here the authors report an oxidant-free, electrocatalytic approach to achieve intramolecular oxidative allylic C–H amination and alkylation by employing tailored cobalt-salen complexes as catalysts.
TL;DR: A review of catalytic enantioselective enolate alkylation methods for α-stereogenic carbonyl derivatives can be found in this paper, with a directed emphasis on the union of prochiral nucleophiles with carbon-centered electrophiles.
Abstract: The asymmetric alkylation of enolates is a particularly versatile method for the construction of α-stereogenic carbonyl motifs, which are ubiquitous in synthetic chemistry. Over the past several decades, the focus has shifted to the development of new catalytic methods that depart from classical stoichiometric stereoinduction strategies (e.g., chiral auxiliaries, chiral alkali metal amide bases, chiral electrophiles, etc.). In this way, the enantioselective alkylation of prochiral enolates greatly improves the step- and redox-economy of this process, in addition to enhancing the scope and selectivity of these reactions. In this review, we summarize the origin and advancement of catalytic enantioselective enolate alkylation methods, with a directed emphasis on the union of prochiral nucleophiles with carbon-centered electrophiles for the construction of α-stereogenic carbonyl derivatives. Hence, the transformative developments for each distinct class of nucleophile (e.g., ketone enolates, ester enolates, amide enolates, etc.) are presented in a modular format to highlight the state-of-the-art methods and current limitations in each area.
TL;DR: In this paper, a robust catalytic system was proposed for α-allenyl alcohols with tetrasubstituted silyl ketene acetals, which showed broad functional group tolerance for both reaction components and allowed efficient generation of β-allene ester products in good yield and with excellent enantioselectivity.
Abstract: Enantioselective bond formation between sterically hindered fragments to furnish acyclic products with vicinal quaternary centers is a formidable challenge. We report a solution that involves cocatalysis between a chiral Ir-(phosphoramidite,olefin) complex and La(OTf)3. This robust catalytic system effects highly enantioconvergent and regioselective alkylation of racemic tertiary α-allenyl alcohols with tetrasubstituted silyl ketene acetals. The transformation displays broad functional group tolerance for both reaction components and allows efficient generation of β-allenyl ester products in good yield and with excellent enantioselectivity. Furthermore, both the allene and ester functionalities were leveraged to upgrade the structural complexity of the products via a series of stereoselective metal-catalyzed functionalization reactions.
TL;DR: In this article, a phosphine-free pincer ruthenium(III) catalyzed β-alkylation of secondary alcohols with primary alcohols to α-alkyated ketones and two different secondary alphabets to β-branched ketones, which was extended to gram-scale reaction and for functionalization of complex vitamin E and cholesterol derivatives.
TL;DR: In this article, a double dehydrogenative cross-coupling of secondary and primary alcohols under nickel catalysis is reported, which provides an atom-and a step-economical method for the C-alkylation of secondary alcohols.
TL;DR: In this article, the direct C-H bond alkylation using unactivated H-H bonds was studied. And the authors proposed a method to develop privileged alkylated arenes and heteroarenes.
Abstract: Alkylation represents an important organic transformation in molecular science to develop privileged alkylated arenes and heteroarenes. Especially, the direct C–H bond alkylation using unactivated ...
29 Jun 2021
TL;DR: A stereodivergent Pd/Cu catalyst system for asymmetric desymmetric alkylation of allylic geminal dicarboxylates has been developed in this paper.
Abstract: A stereodivergent Pd/Cu catalyst system for asymmetric desymmetric alkylation of allylic geminal dicarboxylates has been developed, which was successfully applied to the asymmetric synthesis of β-h...
TL;DR: In this paper, the pyridinyl moiety was adopted as the coordinating group in the cobalt-catalysed asymmetric nucleophilic addition/alkylation of secondary phosphine oxides.
Abstract: The catalytic asymmetric synthesis of P-chiral phosphorus compounds is an important way to construct P-chiral ligands. Herein, we report a new strategy that adopts the pyridinyl moiety as the coordinating group in the cobalt-catalysed asymmetric nucleophilic addition/alkylation of secondary phosphine oxides. A series of tertiary phosphine oxides were generated with up to 99 % yield and 99.5 % ee, and with broad functional-group tolerance. Mechanistic studies reveal that (R)-secondary phosphine oxides preferentially interact with the cobalt catalysts to produce P-stereogenic compounds.
TL;DR: A visible light-induced palladium-catalyzed oxidative C-H alkylation of oximes has been developed, which allows for an efficient atom economical C-C bond construction of alkyl-substituted oximes.
Abstract: A visible light-induced palladium-catalyzed oxidative C–H alkylation of oximes has been developed. This mild protocol allows for an efficient atom economical C–C bond construction of alkyl-substitu...
TL;DR: In this article, the Wolff-Kishner reduction was used to couple various alcohols, aldehydes, and ketones with a broad range of both hard and soft carbon electrophiles in the presence of catalytic amounts of transition metals via the hydrazone derivatives.
Abstract: Construction of new carbon–carbon bonds is the cornerstone of organic chemistry. Organometallic reagents are amongst the most robust and versatile nucleophiles for this purpose. Polarization of the metal–carbon bonds in these reagents facilitates their reactions with a vast array of electrophiles to achieve chemical diversification. The dependence on stoichiometric quantities of metals and often organic halides as feedstock precursors, which in turn produces copious amounts of metal halide waste, is the key limitation of the classical organometallic reactions. Inspired by the classical Wolff–Kishner reduction converting carbonyl groups in aldehydes or ketones into methylene derivatives, our group has recently developed strategies to couple various alcohols, aldehydes, and ketones with a broad range of both hard and soft carbon electrophiles in the presence of catalytic amounts of transition metals, via the hydrazone derivatives: i.e., as organometallic reagent surrogates. This Tutorial Review describes the chronological development of this concept in our research group, detailing its creation in the context of a deoxygenation reaction and evolution to a more general carbon–carbon bond-forming strategy. The latter is demonstrated by the employment of carbonyl-derived alkyl carbanions in various transition-metal catalyzed chemical transformations, including 1,2-carbonyl/imine addition, conjugate addition, carboxylation, olefination, cross-coupling, allylation, alkylation and hydroalkylation.