Carbon-carbon Bond-forming Reactions Research Articles

Lactone Enolates of Isochroman-3-ones and 2-Coumaranones: Quantification of Their Nucleophilicity in DMSO and Conjugate Additions to Chalcones.

Owing to stereoelectronic effects, lactones often deviate in reactivity from their open-chain ester analogues as demonstrated by the CH acidity (in DMSO) of 3-isochromanone (pKa = 18.8) and 2-coumaranone (pKa = 13.5), which is higher than that of ethyl phenylacetate (pKa = 22.6). We have now characterized the reactivity of the lactone enolates derived from 3-isochromanone and 2-coumaranone by following the kinetics of their Michael reactions with p-quinone methides and arylidenemalonates (reference electrophiles) in DMSO at 20 °C. Evaluation of the experimentally determined second-order rate constants k2 by the Mayr-Patz equation, lg k2 = sN(N + E), furnished the nucleophilicity parameters N (and sN) of the lactone enolates. By localizing their position on the Mayr nucleophilicity scale, the scope of their electrophilic reaction partners becomes predictable, and we demonstrate a novel catalytic methodology for a series of carbon-carbon bond-forming reactions of lactone enolates with chalcones under phase transfer conditions in toluene.

Efficient Radical-Mediated Intermolecular α-Alkylation Reactions of Carbonyl Compounds with Nonactivated Alkenes.

Alkylation reactions are fundamental carbon-carbon bond-forming reactions in synthetic organic chemistry. Among them, intermolecular α-alkylation reactions of carbonyl compounds with alkenes are important because they are more atom-economical than the equivalent processes using alkyl halides. However, intermolecular reactions with nonactivated alkenes such as 1-hexene, which can allow the use of a wide range of valuable substrates, have been considered to be very challenging for a long time. In this review, radical-mediated intermolecular α-alkylation reactions of carbonyl compounds with nonactivated alkenes are discussed. The examples are grouped into three types of reactions: peroxide-mediated reactions, metal-oxidant-mediated reactions, and photoactivated reactions. Photoredox-catalyzed alkylation reactions under visible-light irradiation are discussed as a particularly promising recent hot topic. This review provides brief history and new prospects on the α-alkylation process with nonactivated alkenes using α-carbonyl radical species.

Pathway-divergent coupling of 1,3-enynes with acrylates through cascade cobalt catalysis

Catalytic cascade transformations of simple starting materials into highly functionalized molecules bearing a stereochemically defined multisubstituted alkene, which are important in medicinal chemistry, natural product synthesis, and material science, are in high demand for organic synthesis. The development of multiple reaction pathways accurately controlled by catalysts derived from different ligands is a critical goal in the field of catalysis. Here we report a cobalt-catalyzed strategy for the direct coupling of inexpensive 1,3-enynes with two molecules of acrylates to construct a high diversity of functionalized 1,3-dienes containing a trisubstituted or tetrasubstituted olefin. Such cascade reactions can proceed through three different pathways initiated by oxidative cyclization to achieve multiple bond formation in high chemo-, regio- and stereoselectivity precisely controlled by ligands, providing a platform for the development of tandem carbon-carbon bond-forming reactions.

Alcohol-alcohol cross-coupling enabled by SH2 radical sorting.

Alcohols represent a functional group class with unparalleled abundance and structural diversity. In an era of chemical synthesis that prioritizes reducing time to target and maximizing exploration of chemical space, harnessing these building blocks for carbon-carbon bond-forming reactions is a key goal in organic chemistry. In particular, leveraging a single activation mode to form a new C(sp3)-C(sp3) bond from two alcohol subunits would enable access to an extraordinary level of structural diversity. In this work, we report a nickel radical sorting-mediated cross-alcohol coupling wherein two alcohol fragments are deoxygenated and coupled in one reaction vessel, open to air.

Vinyl and Alkynyl Substituted Heterocycles as Privileged Scaffolds in Transition Metal Promoted Stereoselective Synthesis.

ConspectusBiologically active compounds and pharmaceutically relevant intermediates often feature sterically congested stereogenic centers, in particular, carbon stereocenters that are either tertiary tetrasubstituted ones or quaternary in nature. Synthons that comprise such bulky and often structurally complex core units are of high synthetic value and represent important incentives for communities connected to drug discovery and development. Streamlined approaches that give access to a diverse set of compounds incorporating acyclic bulky stereocenters are relatively limited, though vital. They enable further exploration of three-dimensional entities that can be designed and implemented in discovery programs, thereby extending the pool of molecular properties that is inaccessible for flat molecules. However, the lack of modular substrates in particular areas of chemical space inspired us to consider functionalized heterocycles known as cyclic carbonates and carbamates as a productive way to create sterically crowded alkenes and stereocenters.In this Account, we describe the major approximations we followed over the course of 8 years using transition metal (TM) catalysis as an instrument to control the stereochemical course of various allylic and propargylic substitution processes and related transformations. Allylic substitution reactions empowered by Pd-catalysis utilizing a variety of nucleophiles are discussed, with amination being the seed of all of this combined work. These procedures build on vinyl-substituted cyclic carbonates (VCCs) that are simple and easy-to-access precursors and highly modular in nature compared to synthetically limited vinyl oxiranes. Overall these decarboxylative conversions take place with either "linear" or "branched" regioselectivities that are ligand controlled and offer access to a wide scope of functional allylic scaffolds. Alternative approaches, including dual TM/photocatalyzed transformations, allowed us to expand the repertoire of challenging stereoselective conversions. This was achieved through key single-electron pathways and via formal umpolung of intermediates, resulting in new types of carbon-carbon bond formation reactions significantly expanding the scope of allylic substitution reactions.Heterocyclic substrate variants that have triple bond functional groups were also designed by us to enable difficult-to-promote stereoselective propargylic substitution reactions through TM catalysis. In these processes, inspired by the Nishibayashi laboratory and their seminal findings in the area, we discovered various new reactivity patterns. This provided access to a range of different stereodefined building blocks such as 1,2-diborylated 1,3-dienes and tetrasubstituted α-allenols under Cu- or Ni-catalysis. In this realm, the use of lactone-derived substrates gives access to elusive chiral γ-amino acids and lactams with high stereofidelity and good structural diversity.Apart from the synthetic efforts, we have elucidated some of the pertinent mechanistic manifolds operative in these transformations to better understand the limitations and opportunities with these specifically functionalized heterocycles that allowed us to create complex synthons. We combined both theoretical and experimental investigations that lead to several unexpected outcomes in terms of enantioinduction models, catalyst preactivation, and intermediates that are intimately connected to rationales for the observed selectivity profiles. The combined work we have communicated over the years offers insight into the unique reactivity of cyclic carbonates/carbamates acting as privileged precursors. It may inspire other members of the synthetic communities to widen the scope of precursors toward novel stereoselective transformations with added value in drug discovery and development in both academic and commercial settings.

Chloromethylation of Lignin as a Route to Functional Material with Catalytic Properties in Cross-Coupling and Click Reactions.

We present a novel, greener chloromethylation procedure for organosolv aspen lignin under mild reaction conditions without Lewis acid as a catalyst and in acetic acid as a solvent. This synthetic protocol provides a reliable approach to chloromethylated lignin (CML) and means to obtain valuable lignin derivatives. The resulted CML was subsequently transformed into 1-methylimidazolium lignin (ImL), which effectively serves as a stabilizing agent for Pd/CuO nanoparticles (Pd/CuO-NPs). To evaluate the versatility of developed lignin-based catalyst, we investigate its performance in a series of carbon-carbon bond formation reactions, including Suzuki-Miyaura, Sonogashira, Heck reactions, and azide-alkyne cycloaddition (click) reaction. Remarkably, this catalyst exhibited a high degree of catalytic efficiency, resulting in reactions with yields ranging from average to excellent. The heterogeneous catalyst demonstrated outstanding recyclability, enabling its reuse for at least 10 consecutive reaction cycles, with yields consistently falling within the range of 42 % to 84 %. A continuous flow reactor cartridge prototype employing Lignin@Pd/CuO-NPs was developed, yielding results comparable to those achieved in batch reactions. The utilization of Lignin@Pd/CuO-NPs as a catalyst showcases its potential to facilitate diverse carbon-carbon bond formation reactions and underscores its promising recyclability, aligning with the green chemistry metrics and principles of sustainability in chemical processes.

Photochemical Deoxygenative Hydroalkylation of Unactivated Alkenes Promoted by a Nucleophilic Organocatalyst.

The direct utilization of simple and abundant feedstocks in carbon-carbon bond-forming reactions to embellish sp3 -enriched chemical space is highly desirable. Herein, we report a novel photochemical deoxygenative hydroalkylation of unactivated alkenes with readily available carboxylic acid derivatives. The reaction displays broad functional group tolerance, accommodating carboxylic acid-, alcohol-, ester-, ketone-, amide-, silane-, and boronic ester groups, as well as nitrile-containing substrates. The reaction is operationally simple, mild, and water-tolerant, and can be carried out on multigram-scale, which highlights the utility of the method to prepare value-added compounds in a practical and scalable manner. The synthetic application of the developed method is further exemplified through the synthesis of suberanilic acid, a precursor of vorinostat, a drug used for the treatment of cutaneous T-cell lymphoma. A novel mechanistic approach was identified using thiol as a nucleophilic catalyst, which forms a key intermediate for this transformation. Furthermore, electrochemical studies, quantum yield, and mechanistic experiments were conducted to support a proposed catalytic cycle for the transformation.

Synthesis and study of antibiofilm and antivirulence properties of flavonol analogues generated by palladium catalyzed ligand free Suzuki-Miyaura coupling against Pseudomonas aeruginosa PAO1.

The Suzuki-Miyaura coupling is one of the ubiquitous method for the carbon-carbon bond-forming reactions in organic chemistry. Its popularity is due to its ability to undergo extensive coupling reactions to generate a broad range of biaryl motifs in a straightforward manner displaying a high level of functional group tolerance. A convenient and efficient synthetic route to arylate different substituted flavonols through the Suzuki-Miyaura cross-coupling reaction has been explained in this study. The arylated products were acquired by the coupling of a variety of aryl boronic acids with flavonols under Pd(OAc)2 catalyzed reaction conditions in a ligand-free reaction strategy. Subsequently, the antibiofilm and antivirulence properties of the arylated flavonols against Pseudomonas aeruginosa PAO1 were studied thoroughly. The best ligands for quorum sensing proteins LasR, RhlR, and PqsR were identified using molecular docking study. These best fitting ligands were then studied for their impact on gene expression level of P. aeruginosa by RT-PCR towards quorum sensing genes lasB, rhlA, and pqsE. The downregulation in the gene expression with the effect of synthesized flavonols endorse the antibiofilm efficiency of the compounds.

N-Boc-Amino Acid Mediated Morita-Baylis Hillman reaction of methylphenyl glyoxylate

The organocatalyzed Morita-Baylis Hillman (MBH) reaction of α-keto esters is a challenging carbon-carbon bond-forming reaction. We developed a catalytic system for the MBH reaction of methylphenyl glyoxylate with methyl vinyl ketone in a polar aprotic solvent. We used N-Boc-L-pipecolinic acid as a proton transfer mediator and 4-dimethylaminopyridine as the tertiary amine catalyst. We obtained the MBH adduct with a 66% yield in 48h. We proposed a detailed reaction mechanism involving a transition state that includes the hydrogen transfer by the acid functional group of N-Boc-L-pipecolinic acid.

Narrow-Pore Engineering of Vinylene-Linked Covalent Organic Frameworks with Weak Interaction-Triggered Multiple Responses.

Vinylene-linked covalent organic frameworks (COFs) are emerging as promising crystalline materials, but their narrow pore engineering is severely impeded by the weak reversibility of the carbon-carbon double bond formation reaction, which has led to less exploration of their ultramicroporous structures and properties. Herein, we developed a single aromatic ring-based tetratopic monomer, tetramethylpyrazine, which undergoes a smooth Knoevenegal condensation at its four arylmethly carbon atoms with linear aromatic dialdehyde monomers upon the self-catalyzed activation of pyridine nitrogen-containing monomers in the presence of an organic anhydride. This has resulted in the formation of two vinylene-linked COFs, which both crystallized in orthorhombic lattices, and layered in AA stacking fashions along the vertical directions. They exhibit high surface areas and well-tailored ultramicropore sizes up to 0.5 nm. The unique cross-linking mode at two pairs of para-positions of each pyrazine unit through carbon-carbon double bonds afford them with π-extended conjugation over the in-plane backbones and substantial semiconducting characters. The resultant COFs can be well-dispersed in water to form stable sub-microparticles with negative charges (zeta potentials: ca. -30 mV), and exhibiting tunable aggregation behaviors through protonation/deprotonation. As a consequence, they exhibit pore-size-dependent colorimetric responses to various anions with different pKa values in high selectivity.

Excited-state tris(pentafluorophenyl)borane as a strong single-electron oxidant: Photophysical properties and catalysis

The photophysical properties and photocatalysis of tris(pentafluorophenyl)borane [B(C6F5)3], known as a strong Lewis acid, were revealed. The excited-state B(C6F5)3 exerts single-electron oxidation capability with an oxidation potential (Ered* = 2.02 V vs SCE) close to those of electronically unbiased toluene derivatives (Eox = 2.01 to 2.29 V). This property was experimentally proven by the direct observation of the radical cation of the toluene dimer by the transient absorption spectroscopy of a mixture of B(C6F5)3 and toluene. In cooperation with a suitable Brønsted base catalyst, B(C6F5)3 catalytically generated benzylic radicals from toluene derivatives under photoirradiation for subsequent carbon-carbon bond-forming reactions.

Advancements in N-heterocyclic carbenes (NHCs) catalysis for benzoin reactions: A comprehensive review from past to present

N-heterocyclic carbenes (NHCs) catalyze benzoin condensation, which is a unique carbon-carbon bond-forming reaction. It entails a coupling reaction between two aldehydes catalyzed by NHCs that produce a-hydroxycarbonyl compounds (acyloins). NHCs have emerged as a potent class of organocatalysts, catalyzing numerous benzoin and benzoin-type reactions. This review provides an overview of the historical development of NHCs and their application in benzoin reactions. Additionally, recent advancements in NHC catalysis, including the use of chiral NHCs, are discussed. This review aims to provide a comprehensive understanding of the current state of NHC catalysis for benzoin reactions and its potential for future developments in synthetic chemistry.

Diverse Synthetic Transformations Using 4-Bromo-3,3,4,4-tetrafluorobut-1-ene and Its Applications in the Preparation of CF2 CF2 -Containing Sugars, Liquid Crystals, and Light-Emitting Materials.

Organic molecules with fluoroalkylene scaffolds, especially a tetrafluoroethylene (CF2 CF2 ) moiety, in their molecular structures exhibit unique biological activities, or can be applied to functional materials such as liquid crystals and light-emitting materials. Although several methods for the syntheses of CF2 CF2 -containing organic molecules have been reported to date, they have been limited to methods using explosives and fluorinating agents. Therefore, there is an urgent need to develop simple and efficient approaches to synthesize CF2 CF2 -containing organic molecules from readily available fluorinated substrates using carbon-carbon bond formation reactions. This personal account summarizes the simple and efficient transformation of functional groups at both ends of 4-bromo-3,3,4,4-tetrafluorobut-1-ene and discusses its synthetic applications to biologically active fluorinated sugars and functional materials, such as liquid crystals and light-emitting molecules.

Cu-Mediated Thianthrenation and Phenoxathiination of Arylborons.

Great success in synthetic chemistry is motivated by the development of novel and reactive linchpins for carbon-carbon and carbon-heteroatom bond formation reactions, which has dramatically altered chemists' approach to building molecules. Herein, we report the ready synthesis of aryl sulfonium salts, a versatile electrophilic linchpin, via a novel Cu-mediated thianthrenation and phenoxathiination of commercially available arylborons with thianthrene and phenoxathiine, providing a series of aryl sulfonium salts in high efficiency. More importantly, by leveraging the sequential Ir-catalyzed C-H borylation and Cu-mediated thianthrenation of arylborons, the formal thianthrenation of arenes is also achieved. The Ir-catalyzed C-H borylation with undirected arenes normally occurred at the less steric hindrance position, thus providing a complementary method for thianthrenation of arenes in comparison with electrophilic thianthrenation. This process is capable of late-stage functionalization of a series of pharmaceuticals, which might find wide synthetic applications in both industry and academic sectors.

Engineering C-C Bond Cleavage Activity into a P450 Monooxygenase Enzyme.

The cytochrome P450 (CYP) superfamily of heme monooxygenases has demonstrated ability to facilitate hydroxylation, desaturation, sulfoxidation, epoxidation, heteroatom dealkylation, and carbon-carbon bond formation and cleavage (lyase) reactions. Seeking to study the carbon-carbon cleavage reaction of α-hydroxy ketones in mechanistic detail using a microbial P450, we synthesized α-hydroxy ketone probes based on the physiological substrate for a well-characterized benzoic acid metabolizing P450, CYP199A4. After observing low activity with wild-type CYP199A4, subsequent assays with an F182L mutant demonstrated enzyme-dependent C-C bond cleavage toward one of the α-hydroxy ketones. This C-C cleavage reaction was subject to an inverse kinetic solvent isotope effect analogous to that observed in the lyase activity of the human P450 CYP17A1, suggesting the involvement of a species earlier than Compound I in the catalytic cycle. Co-crystallization of F182L-CYP199A4 with this α-hydroxy ketone showed that the substrate bound in the active site with a preference for the (S)-enantiomer in a position which could mimic the topology of the lyase reaction in CYP17A1. Molecular dynamics simulations with an oxy-ferrous model of CYP199A4 revealed a displacement of the substrate to allow for oxygen binding and the formation of the lyase transition state proposed for CYP17A1. This demonstration that a correctly positioned α-hydroxy ketone substrate can realize lyase activity with an unusual inverse solvent isotope effect in an engineered microbial system opens the door for further detailed biophysical and structural characterization of CYP catalytic intermediates.

Exploring Guanidinium Organocatalysts for Hypoiodite-Mediated Reactions.

This account describes our recent work on developing guanidinium hypoiodite- catalysts for oxidative carbon-nitrogen and carbon-carbon bond-forming reactions. These reactions proceeded smoothly using guanidinium hypoiodite generated in situ by treating 1,3,4,6,7-hexahydro-2H-pyrimido[1,2-a]pyrimidine hydroiodide salts with an oxidant. In this approach, the ionic interaction and hydrogen bonding ability of the guanidinium cations enable bond-forming reactions that have been difficult with conventional methods. Enantioselective oxidative carbon-carbon bond-forming reaction was also achieved by using a chiral guanidinium organocatalyst.

Carbotrifluoromethylations of C-C Multiple Bonds (Excluding Aryl- and Alkynyltrifluoromethylations).

Organofluorine chemistry has become an expanding area of research in organic chemistry and drug design. The synthesis of fluorine-containing molecules has received high significance in synthetic chemistry. Trifluoromethylative difunctionalizations of carbon-carbon multiple bonds with the simultaneous introduction of a CF3 group and another function have considerable relevance. Because of the high importance of carbon-carbon bond-forming reactions in organic synthesis, carbotrifluoromethylations are considered to be a field of synthetic chemistry of increasing importance. Our current goal in this review is to summarize recent developments of various trifluoromethylation reactions (excluding aryl- and alkynyl-trifluoromethylations) taking into consideration several main approaches, such as alkenyltrifluoromethylation, alkyltrifluoromethylation, carbonyltrifluoromethylation, and cyanotrifluoromethylation reactions.

Cobalt-Catalyzed Diastereo- and Enantioselective Carbon-Carbon Bond Forming Reactions of Cyclobutenes.

Catalytic enantioselective functionalization of cyclobutenes constitutes a general and modular strategy for construction of enantioenriched complex cyclobutanes bearing multiple stereogenic centers, as chiral four-membered rings are common motifs in biologically active molecules and versatile intermediates in organic synthesis. However, enantioselective synthesis of cyclobutanes through such a strategy remained significantly limited. Herein, we report a series of unprecedented cobalt-catalyzed carbon-carbon bond forming reactions of cyclobutenes that are initiated through enantioselective carbometalation. The protocols feature diastereo- and enantioselective introduction of allyl, alkynyl, and functionalized alkyl groups. Mechanistic studies indicated an unusual 1,3-cobalt migration and subsequent β-carbon elimination cascade process occurred in the allyl addition. These new discoveries established a new elementary process for cobalt catalysis and an extension of diversity of nucleophiles for enantioselective transformations of cyclobutenes.

Protected syn-Aldol Compounds from Direct, Catalytic, and Enantioselective Reactions of N-Acyl-1,3-oxazinane-2-thiones with Aromatic Acetals.

A direct and asymmetric syn-aldol reaction of N-acyl-1,3-oxazinane-2-thiones with dialkyl acetals from aromatic acetals in the presence of 2-5 mol % [DTBM-SEGPHOS]NiCl2, TMSOTf, and lutidine has been developed. It has been established that the oxazinanethione heterocycle, used for the first time as a scaffold in asymmetric carbon-carbon bond-forming reactions, can be smoothly removed to give access to a variety of enantiomerically pure compounds with high synthetic value.

Guanidinium Hypoiodite-Catalyzed Intramolecular Oxidative Coupling Reaction of Oxindoles with β-Dicarbonyls.

Spiro[indoline-3,4'-piperidine] is a fundamental motif present in various biologically active compounds. Here, we report an intramolecular oxidative coupling reaction of oxindoles with β-dicarbonyls in the presence of a guanidinium hypoiodite catalyst, providing spiro-coupling products in moderate to excellent yields. Furthermore, a chiral hypoiodite catalyst derived from the chiral guanidinium organocatalyst is effective for the challenging asymmetric carbon-carbon bond-forming reaction, affording optically active spiro[indoline-3,4'-piperidines].