Transition Metal-Catalyzed Transformations of Chalcones.

Chalcones are a class of naturally occurring flavonoid compounds associated to a variety of biological and pharmacological properties. Several reviews have been published describing the synthesis and biological properties of a vast array of analogues. However, overviews on the reactivity of chalcones has only been explored in a few accounts. To fill this gap, a systematic survey on the most recent developments in the transition metal-catalyzed transformation of chalcones was performed. The chemistry of copper, palladium, zinc, iron, manganese, nickel, ruthenium, cobalt, rhodium, iridium, silver, indium, gold, titanium, platinum, among others, as versatile catalysts will be highlighted, covering the literature from year 2000 to 2023, in more than 380 publications.

Recent Progress on NHC-Catalyzed 1,6-Conjugate Addition Reactions.

As a significant variant of the Michael reaction, the 1,6-addition reaction has undergone considerable development over the past decade. This effective strategy enables the synthesis of a variety of novel and potentially bioactive functional molecules. In this review, we summarize the recent progress in NHC-catalyzed 1,6-addition reactions, highlighting their efficiency in the rapid synthesis of complex functional molecules. We also provide our perspectives on the future development of this dynamic and highly active research area.

Stable and Durable Superhydrophobic Cotton Fabrics Prepared via a Simple 1,4-Conjugate Addition Reaction for Ultrahigh Efficient Oil-Water Separation.

Superhydrophobic materials used for oil-water separation have received wide attention. However, the simple and low-cost strategy for making durable superhydrophobic materials remains a major challenge. Here, this work reports that stable and durable superhydrophobic cotton fabrics can be prepared using a simple two-step impregnation process. Silica nanoparticles are surface modified by hydrolysis condensation of 3-aminopropyltrimethoxysilane (APTMS). 1,4-conjugate addition reaction between the acrylic group of cross-linking agent pentaerythritol triacrylate (PETA) and the amino group of octadecylamine (ODA) forms a covalent cross-linked rough network structure. The long hydrophobic chain of ODA makes the cotton fabric exhibit excellent superhydrophobic properties, and the water contact angle (WCA) of the fabric surface reaches 158°. The modified cotton fabric has good physical and chemical stability, self-cleaning, and anti-fouling. At the same time, the modified fabric shows excellent oil/water separation efficiency (98.16% after 20 cycles) and ultrahigh separation flux (15413.63 L m-2 h-1) due to its superhydrophobicity, superoleophilicity, and inherent porous structure. The method provides a broad prospect in the future diversification applications of oil/water separation and oil spill cleaning.

Copper-catalyzed C2-selective alkynylation of chromones via 1,4-conjugate addition.

Copper-catalyzed selective alkynylation with N-propargyl carboxamides as nucleophiles has been successfully developed for the synthesis of C2-functionalized chromanones. Under optimized reaction conditions, 21 examples were obtained in one-pot procedure through 1,4-conjugate addition. This protocol features readily available feedstocks, easy operations, and moderate to good yields, which provides viable access to pharmacologically active C2-functionalized chromanones.

Chiral Sodium Glycerophosphate Catalyst for Enantioselective Michael Reactions of Chalcones.

A chiral sodium glycerophosphate is successfully exploited as a catalyst in the Michael addition of methyl malonate to a number of chalcones. The reactions supplied the target adducts in satisfactory yields and good enantiomeric excesses. A tentative computational study is presented, aiming to understand the reaction mechanism.

Phosphine-Catalyzed γ'-Carbon 1,6-Conjugate Addition of α-Succinimide Substituted Allenoates with Para-Quinone Methides: Synthesis of 4-Diarylmethylated 3,4-Disubstituted Maleimides.

In this paper, an interesting γ'-carbon 1,6-conjugate addition for phosphine-catalyzed α-succinimide substituted allenoates has been disclosed. A wide array of substrates was found to participate in the reaction, resulting in the production of diverse 4-diarylmethylated 3,4-disubstituted maleimides with satisfactory to outstanding yields. Furthermore, a plausible mechanism for the reaction was proposed by the investigators.

Direct Catalytic Asymmetric Conjugate Addition of Benzofuran-3(2H)-ones to α,ß-Unsaturated Thioamides: Stereodivergent Synthesis of Rocaglaol.

Rocaglaol, a representative flavagline, has attracted significant attention because of its unique chemical structure and biological activities. This paper reports a mild and scalable copper-catalyzed enantioselective conjugate addition of benzofuran-3(2H)-one to α,ß-unsaturated thioamides. This method allows for the concise synthesis of all possible stereoisomers of a key intermediate of rocaglaol and its derivatives in a highly diastereo- and enantioselective manner using different chiral phosphine ligands. Theoretical insights into the reaction mechanism and the origin of ligand-dependent diastereodivergence were obtained using density functional theory calculations.

Bifunctional Iminophosphorane Catalyzed Amide Enolization for Enantioselective Cyclohexadienone Desymmetrization.

The organocatalytic enolization of 2-arylacetamides, followed by an enantioselective intramolecular conjugate addition to tethered 2,5-cyclohexadienones, yielding 3D fused N-heterocycles, is described. The transformation represents the first strong activating group-free activation of carboxamides via α-C-H deprotonation in a metal-free, catalytic, and enantioselective reaction, and is achieved by employing a bifunctional iminophosphorane (BIMP) superbase.

Combining Enantioselective Rh-Catalyzed Conjugate Addition and Ir-Catalyzed Allylic Alkylation in Stereodivergent, Multicomponent Coupling Reactions to Form Three Stereocenters.

Stereodivergent dual catalysis has emerged as a powerful tool to selectively prepare all four stereoisomers in molecules containing two chiral centers from common starting materials. Most processes involve the use of two substrates, and it remains challenging to use dual catalyst approaches to generate molecules having three newly formed stereocenters with high diastereo- and enantioselectivity. Here we report a multicomponent, stereodivergent method for the synthesis of targets containing three contiguous stereocenters by the combination of enantioselective Rh-catalyzed conjugate addition and Ir-catalyzed allylic alkylation methodologies. Both cyclic and acyclic α,ß-unsaturated ketones undergo ß-arylation using aryl boron reagents to form an enolate nucleophile that can be subsequently allylated at the α-position. The reactions proceed often with >95 % ee and with >90 : 10 dr. Epimerization at the α-carbonyl center enables the preparation of any of the eight possible stereoisomers from common starting materials, as demonstrated for cyclohexanone products.

Concise synthesis of amino acid component of amicoumacins via dihydrooxazine formation through intramolecular conjugate addition.

Amicoumacins are a family of antibiotics with a variety of important bioactivities. A concise and efficient method was developed for synthesizing the amino acid component of amicoumacins via the corresponding dihydrooxazine intermediate. The dihydrooxazine ring was formed with complete stereoselectivity through an intramolecular conjugate addition of a δ-trichloroacetimidoyloxy-α,ß-unsaturated ester, which was obtained from a known 4,6-O-p-methoxybenzylidene-protected d-glucose. The synthesis developed in this study can be used to synthesize the building blocks of amicoumacins and can likely be adapted for the synthesis of other types of molecules possessing dihydrooxazine rings or amino alcohol moieties.

Development of a New Methodology for Dearomative Borylation of Coumarins and Chromenes and Its Applications to Synthesize Boron-Containing Retinoids.

Dearomative borylation of coumarins and chromenes via conjugate addition represents a relatively unexplored and challenging task. To address this issue, herein, we report a new and general copper (I) catalyzed dearomative borylation process to synthesize boron-containing oxacycles. In this report, the borylation of coumarins, chromones, and chromenes comprising functional groups, such as esters, nitriles, carbonyls, and amides, has been achieved. In addition, the method generates different classes of potential boron-based retinoids, including the ones with oxadiazole and anthocyanin motifs. The borylated oxacycles can serve as suitable intermediates to generate a library of compounds.

Palladium Iodide Catalyzed Multicomponent Carbonylative Synthesis of 2-(4-Acylfuran-2-yl)acetamides.

2-Propargyl-1,3-dicarbonyl compounds have been carbonylated under oxidative conditions and with the catalysis of the PdI2/KI catalytic system to selectively afford previously unreported 2-(4-acylfuran-2-yl)acetamides in fair to good yields (54-81%) over 19 examples. The process takes place under relatively mild conditions and occurs via a mechanistic pathway involving Csp-H activation by oxidative monoamincarbonylation of the terminal triple bond of the substrates with formation of 2-ynamide intermediates, followed by 5-exo-dig O-cyclization (via intramolecular conjugate addition of the in situ formed enolate to the 2-ynamide moiety) and aromative isomerization.

Stereodivergent Construction of 1,3-Chiral Centers via Tandem Asymmetric Conjugate Addition and Allylic Substitution Reaction.

Herein, we report a synthesis of cyclohexanones bearing multi-continuous stereocenters by combining copper-catalyzed asymmetric conjugate addition of dialkylzinc reagents to cyclic enones with iridium-catalyzed asymmetric allylic substitution reaction. Good to excellent yields, diastereoselectivity and enantioselectivity can be obtained. Unlike the stereodivergent construction of adjacent stereocenters (1,2-position) reported in the literature, the current reaction can achieve the stereodivergent construction of nonadjacent stereocenters (1,3-position) by a proper combination of two chiral catalysts with different enantiomers.

Bifunctional Iminophosphorane-Catalyzed Enantioselective Nitroalkane Addition to Unactivated α,ß-Unsaturated Esters.

Herein we describe the enantioselective intermolecular conjugate addition of nitroalkanes to unactivated α,ß-unsaturated esters, catalyzed by a bifunctional iminophosphorane (BIMP) superbase. The transformation provides the most direct access to pharmaceutically relevant enantioenriched γ-nitroesters, utilizing feedstock chemicals, with unprecedented selectivity. The methodology exhibits a broad substrate scope, including ß-(fluoro)alkyl, aryl and heteroaryl substituted electrophiles, and was successfully applied on a gram scale with reduced catalyst loading, and, additionally, catalyst recovery was carried out. The formal synthesis of a range of drug molecules, and an enantioselective synthesis of (S)-rolipram were achieved. Additionally, computational studies revealed key reaction intermediates and transition state structures, and provided rationale for high enantioselectivities, in good agreement with experimental results.

Umpolung Asymmetric 1,5-Conjugate Addition via Palladium Hydride Catalysis.

Electronically matched nucleophilic 1,6-conjugate addition has been well studied and widely applied in synthetic areas. In contrast, nucleophilic 1,5-conjugate addition represents an electronically forbidden process and is considered unfeasible. Here, we describe modular protocols for 1,5-conjugate addition reactions via palladium hydride catalysis. Both palladium and synergistic Pd/organocatalyst systems are developed to catalyze 1,5-conjugate reaction, followed by inter- or intramolecular [3+2] cyclization. A migratory 1,5-addition protocol is established to corroborate the feasibility of this umpolung concept. The 1,5-addition products are conveniently transformed into a series of privileged enantioenriched motifs, including polysubstituted tetrahydrofuran, dihydrofuran, cyclopropane, cyclobutane, azetidine, oxetane, thietane, spirocycle and bridged rings. Preliminary mechanistic studies corroborate the involvement of palladium hydride catalysis.

First synthesis of acylated nitrocyclopropanes.

Although nitrocyclopropanedicarboxylic acid esters are widely used in organic syntheses, nitrocyclopropanes with an acyl group have not yet been synthesized. When adducts of ß-nitrostyrene and 1,3-dicarbonyl compounds are treated with (diacetoxyiodo)benzene and tetrabutylammonium iodide, iodination occurs at the α-position of the nitro group, and the subsequent O-attack of the enol moiety leads to 2,3-dihydrofuran. Cyclopropane was successfully synthesized through C-attack as the acyl group became bulkier. The obtained nitrocyclopropane was transformed into furan upon treatment with tin(II) chloride via a ring-opening/ring-closure process.

Enolates ambushed - asymmetric tandem conjugate addition and subsequent enolate trapping with conventional and less traditional electrophiles.

Metal enolates are useful intermediates and building blocks indispensable in many organic synthetic transformations. Chiral metal enolates obtained by asymmetric conjugate additions of organometallic reagents are structurally complex intermediates that can be employed in many transformations. In this review, we describe this burgeoning field that is reaching maturity after more than 25 years of development. The effort of our group to broaden possibilities to engage metal enolates in reactions with new electrophiles is described. The material is divided according to the organometallic reagent employed in the conjugate addition step, and thus to the particular metal enolate formed. Short information on applications in total synthesis is also given.

Asymmetric tandem conjugate addition and reaction with carbocations on acylimidazole Michael acceptors.

We present here a stereoselective tandem reaction based on the asymmetric conjugate addition of dialkylzinc reagents to unsaturated acylimidazoles followed by trapping of the intermediate zinc enolate with carbocations. The use of a chiral NHC ligand provides chiral zinc enolates in high enantiomeric purities. These enolates are reacted with highly electrophilic onium compounds to afford densely substituted acylimidazoles. DFT calculations helped to understand the reactivity of the zinc enolates derived from acylimidazoles and allowed their comparison with metal enolates obtained by other conjugate addition reactions.

Application of N-heterocyclic carbene-Cu(I) complexes as catalysts in organic synthesis: a review.

N-Heterocyclic carbenes (NHCs) are a special type of carbenes in which the carbene carbon atom is part of the nitrogen heterocyclic ring. Due to the simplicity of their synthesis and the modularity of their stereoelectronic properties, NHCs have unquestionably emerged as one of the most fascinating and well-known species in chemical science. The remarkable stability of NHCs can be attributed to both kinetic as well as thermodynamic effects caused by its structural features. NHCs constitute a well-established class of new ligands in organometallic chemistry. Although initially NHCs were regarded as pure σ-donor ligands, later experimental and theoretical studies established the presence of a significant back donation from the d-orbital of the metal to the π* orbital of the NHC. Over the last two decades, NHC-metal complexes have been extensively used as efficient catalysts in different types of organic reactions. Of these, NHC-Cu(I) complexes found prominence for various reasons, such as ease of preparation, possibility of structural diversity, low cost, and versatile applications. This article overviews applications of NHC-Cu(I) complexes as catalysts in organic synthesis over the last 12 years, which include hydrosilylation reactions, conjugate addition, [3 + 2] cycloaddition, A3 reaction, boration and hydroboration, N-H and C(sp2)-H carboxylation, C(sp2)-H alkenylation and allylation, C(sp2)-H arylation, C(sp2)-H amidation, and C(sp2)-H thiolation. Preceding the section of applications, a brief description of the structure of NHCs, nature of NHC-metal bond, and methods of preparation of NHC-Cu complexes is provided.

Asymmetric Alkylation of Cyclic Ketones with Dehydroalanine via H-Bond-Directing Enamine Catalysis: Straightforward Access to Enantiopure Unnatural α-Amino Acids.

The growing importance of structurally diverse and functionalized enantiomerically pure unnatural amino acids in the design of drugs, including peptides, has stimulated the development of new synthetic methods. This study reports the challenging direct asymmetric alkylation of cyclic ketones with dehydroalanine derivatives via a conjugate addition reaction for the synthesis of enantiopure ketone-based α-unnatural amino acids. The key to success was the design of a bifunctional primary amine-thiourea catalyst that combines H-bond-directing activation and enamine catalysis. The simultaneous dual activation of the two relatively unreactive partners, confirmed by mass spectrometry studies, results in high reactivity while securing high levels of stereocontrol. A broad substrate scope is accompanied by versatile downstream chemical modifications. The mild reaction conditions and consistently excellent enantioselectivities (>95 % ee in most cases) render this protocol highly practical for the rapid construction of valuable noncanonical enantiopure α-amino-acid building blocks.