Synthesis and Characterization of Silica@Copper Core–Shell Nanoparticles: Application for Conjugate Addition Reactions

Silica@copper (SiO₂@Cu) core–shell nanoparticles were synthesized and well characterized by XRD, TEM, AFM, XPS, UV/Vis, TGA–MS, and ICP–AES techniques. The synthesized SiO₂@Cu core–shell nanoparticles were employed as catalysts for the conjugate addition of amines to α,β‐unsaturated compounds in water to obtain β‐amino carbonyl compounds in excellent yields in shorter reaction times. Furthermore, the catalyst works well for hetero‐Michael addition reactions of heteroatom nucleophiles such as thiols to α,β‐unsaturated compounds. As the reaction is performed in water, it allows for easy recycling of the catalyst with consistent activity.     

Racemic Vinylallenes in Catalytic Enantioselective Multicomponent Processes: Rapid Generation of Complexity through 1,6‐Conjugate Additions

Racemic vinylallenes are shown to be effective substrates for catalytic multicomponent diastereo‐ and enantioselective 1,6‐conjugate addition of multifunctional allyl moieties to easily accessible α,β,γ,δ‐unsaturated diesters. Reactions may be catalyzed by 5.0 mol % of a readily accessible NHC‐Cu complex at ambient temperature, and other than a vinylallene, involve B₂(pin)₂ and an α,β,γ,δ‐unsaturated diester. A variety of vinylallenes were converted to products bearing a Z‐trisubstituted alkenyl‐B(pin) moiety, a vinyl group, a β,γ‐unsaturated diester unit, and vicinal stereogenic centers in up to 67 % yield, 87:13 Z/E ratio, >98:2 d.r., and 98:2 e.r. Chemoselective modifications involving the alkenyl‐B(pin), the vinyl, or the 1,2‐disubstituted olefin moieties were carried out to demonstrate versatility and utility. Stereochemical models, based on mechanistic and DFT studies, demonstrate the dynamic behavior of intermediated Cu‐allyl species and account for various selectivity profiles.     

Asymmetric Conjugate Alkynylation of Cyclic α,β‐Unsaturated Carbonyl Compounds with a Chiral Diene Rhodium Catalyst

Asymmetric conjugate alkynylation of cyclic α,β‐unsaturated carbonyl compounds (ketones, esters, and amides) was realized by use of diphenyl[(triisopropylsilyl)ethynyl]methanol as an alkynylating reagent in the presence of a rhodium catalyst coordinated with a new chiral diene ligand (Fc‐bod; bod=bicyclo[2.2.2]octa‐2,5‐diene, Fc=ferrocenyl) to give high yields of the corresponding β‐alkynyl‐substituted carbonyl compounds with 95–98 % ee.     

Highly Chemo‐, Enantio‐, and Regioselective Synthesis of α,α‐Disubstituted Furanones by Cu‐Catalyzed Conjugate Addition

A highly chemo‐, enantio‐, and regioselective synthesis of furanones bearing an α,α‐disubstituted quaternary stereogenic center is reported. The Cu‐catalyzed enantioselective conjugate addition of organoaluminum reagents to unsaturated ketoesters at room temperature and subsequent lactonization took place. Synthetic transformations of furanones represent facile approaches to various cyclic or acyclic compounds bearing a quaternary stereogenic center.     

Direct Conjugate Addition of Alkynes with α,β‐Unsaturated Carbonyl Compounds Catalyzed by NCN‐Pincer Ru Complexes

NCN‐pincer Ru‐complexes containing bis(oxazolinyl)phenyl ligands serve as suitable catalysts in the direct conjugate additions of α,β‐unsaturated carbonyl compounds, including ketones, esters, and amides, as well as vinylphosphonates, giving various β‐alkynyl carbonyl and phosphonate compounds. A bis(oxazolinyl)phenyl (phebox)–Ru complex also catalyzes the asymmetric conjugate addition of an alkyne with a β‐substituted, α,β‐unsaturated ketone to produce a chiral β‐alkynyl ketone.     

Phase‐Transfer‐Catalyzed Asymmetric SNAr Reaction of α‐Amino Acid Derivatives with Arene Chromium Complexes

Although phase‐transfer‐catalyzed asymmetric S_NAr reactions provide unique contribution to the catalytic asymmetric α‐arylations of carbonyl compounds to produce biologically active α‐aryl carbonyl compounds, the electrophiles were limited to arenes bearing strong electron‐withdrawing groups, such as a nitro group. To overcome this limitation, we examined the asymmetric S_NAr reactions of α‐amino acid derivatives with arene chromium complexes derived from fluoroarenes, including those containing electron‐donating substituents. The arylation was efficiently promoted by binaphthyl‐modified chiral phase‐transfer catalysts to give the corresponding α,α‐disubstituted α‐amino acids containing various aromatic substituents with high enantioselectivities.     

Rhodium(I)-catalyzed enantioselective 1,4-addition of nucleophilic silicon

A rhodium(I)-catalyzed activation of a silicon-boron linkage, that is, the transmetalation of silicon from boron to rhodium(I) by means of an Rh^I-OH complex, enables the conjugate transfer of nucleophilic silicon onto α,β-unsaturated acceptors. Pre- or in situ formed cationic rhodium(I)-binap complexes catalyze this novel carbon-silicon bond formation with exceptional enantiocontrol, 92 to >99% ee for cyclic carbonyl and carboxyl compounds as well as >99% ee for acyclic carboxyl compounds.     

Electrophilic Activation of α,β‐Unsaturated Amides: Catalytic Asymmetric Vinylogous Conjugate Addition of Unsaturated γ‐Butyrolactones

Although catalytic asymmetric conjugate addition reactions have remarkably advanced over the last two decades, the application of less electrophilic α,β‐unsaturated carboxylic acid derivatives in this useful reaction manifold remains challenging. Herein, we report that α,β‐unsaturated 7‐azaindoline amides act as reactive electrophiles to participate in catalytic diastereo‐ and enantioselective vinylogous conjugate addition of γ‐butyrolactones in the presence of a cooperative catalyst comprising of a soft Lewis acid and a Brønsted base. Reactions mostly reached completion with as little as 1 mol % of catalyst loading to give the desired conjugate adducts in a highly stereoselective manner.     

Halogen‐Bonding‐Induced Conjugate Addition of Thiophenes to Enones and Enals

Herein, we report the conjugate addition of α,β‐unsaturated carbonyl compounds to thiophene derivatives. We used a 2‐iodoimidazolinium triflate salt as a halogen‐bonding donor, which afforded moderate‐to‐excellent yields of the corresponding alkylated thiophenes. Insight into the catalytic process was obtained from ¹H NMR spectroscopy studies and DFT calculations, which indicated a halogen‐bonding‐supported mechanism with limited Brønsted acid catalysis.     

Diarylprolinol‐Mediated Asymmetric Direct Cross‐Aldol Reaction of α,β‐Unsaturated Aldehyde as an Electrophilic Aldehyde

The diarylprolinol‐mediated asymmetric direct cross‐aldol reaction of α,β‐unsaturated aldehyde as an electrophilic aldehyde was developed. The reaction becomes accelerated by an acid when a carbonyl group is introduced at the γ‐position of the α,β‐unsaturated aldehyde. Synthetically useful γ,δ‐unsaturated β‐hydroxy aldehydes were obtained with high anti‐selectivity and excellent enantioselectivity.     

Copper‐Catalyzed Asymmetric Conjugate Addition of Dimethylzinc to Acyl‐N‐methylimidazole Michael Acceptors: a Powerful Synthetic Platform

An efficient copper‐catalyzed enantioselective conjugate addition of dimethylzinc to α,β‐ and α,β,γ,δ‐unsaturated 2‐acyl‐N‐methylimidazoles has been achieved using a chiral bidentate hydroxyalkyl‐NHC ligand. The reactions proceeded with both excellent regio‐ and enantioselectivity (14 examples, 87–95 % ee) to afford the desired 1,4‐adducts, which were easily transformed to the corresponding aldehydes, esters, and ketones. Subsequently, this powerful methodology was therefore successfully applied in the synthesis of natural products. Furthermore, an iterative process was also disclosed leading to highly desirable 1,3‐desoxypropionate skeletons (up to 94 % d.e.).     

Chemoselective Synthesis of Substituted Imines,Secondary Amines,and β‐Amino Carbonyl Compounds from Nitroaromatics through Cascade Reactions on Gold Catalysts

Substituted imines, α,β‐unsaturated imines, substituted secondary amines, and β‐amino carbonyl compounds have been synthesized by means of new cascade reactions with mono‐ or bifunctional gold‐based solid catalysts under mild reaction conditions. The related synthetic route involves the hydrogenation of a nitroaromatic compound in the presence of a second reactant such as an aldehyde, α,β‐unsaturated carbonyl compound, or alkyne, which circumvents an ex situ reduction process for producing the aromatic amine. The process is shown to be highly selective towards other competing groups, such as double bonds, carbonyls, halogens, nitriles, or cinnamates, and thereby allows the synthesis of different substituted nitrogenated compounds. For the preparation of imines, substituted anilines are formed and condensed in situ with aldehydes to provide the final product through two tandem reactions. High chemoselectivity is observed, for instance, when double bonds or halides are present within the reactants. In addition, we show that the Au/TiO₂ system is also able to catalyze the chemoselective hydrogenation of imines, so that secondary amines can be prepared directly through a three‐step cascade reaction by starting from nitroaromatic compounds and aldehydes. On the other hand, Au/TiO₂ can also be used as a bifunctional catalyst to obtain substituted β‐amino carbonyl compounds from nitroaromatics and α,β‐unsaturated carbonyl compounds. Whereas gold sites promote the in situ formation of anilines, the intrinsic acidity of Ti species on the support surface accelerates the subsequent Michael addition. Finally, two gold‐catalyzed reactions, that is, the hydrogenation of nitro groups and a hydroamination, have been coupled to synthesize additional substituted imines from nitroaromatic compounds and alkynes.     

Chiral Nanoparticles/Lewis Acids as Cooperative Catalysts for Asymmetric 1,4‐Addition of Arylboronic Acids to α,β‐Unsaturated Amides

Cooperative catalysts consisting of chiral Rh/Ag nanoparticles and Sc(OTf)₃ have been developed that catalyze asymmetric 1,4‐addition reactions of arylboronic acids with α,β‐unsaturated amides efficiently. The reaction has been considered one of the most challenging reactions because of the low reactivity of the amide substrates. The new catalysts provide the desired products with outstanding enantioselectivities (>98 % ee) in the presence of low loadings (<0.5 mol %) of the catalyst.     

Rhodium/Chiral Diene‐Catalyzed Asymmetric 1,4‐Addition of Arylboronic Acids to Chromones: A Highly Enantioselective Pathway for Accessing Chiral Flavanones

Chromone has been noted to be one of the most challenging substrates in the asymmetric 1,4‐addition of α,β‐unsaturated carbonyl compounds. By employing the rhodium complex associated with a chiral diene ligand, (R,R)‐Ph‐bod*, the 1,4‐addition of a variety of arylboronic acids was realized to give high yields of the corresponding flavanones with excellent enantioselectivities (≥97 % ee, 99 % ee for most substrates). Ring‐opening side products, which would lead to erosion of product enantioselectivity, were not observed under the stated reaction conditions.     

Catalytic Asymmetric Epoxidation of α,β‐Unsaturated Esters with Chiral Yttrium–Biaryldiol Complexes

The full details of the asymmetric epoxidation of α,β‐unsaturated esters catalyzed by yttrium complexes with biaryldiol ligands are described. An yttrium–biphenyldiol catalyst, generated from Y(OiPr)₃–biphenyldiol ligand–triphenylarsine oxide (1:1:1), is suitable for the epoxidation of various α,β‐unsaturated esters. With this catalyst, β‐aryl α,β‐unsaturated esters gave high enantioselectivities and good yields (≤99 % ee). The reactivity of this catalyst is good, and the catalyst loading could be decreased to as little as 0.5–2 mol % (the turnover number was up to 116), while high enantiomeric excesses were maintained. For β‐alkyl α,β‐unsaturated esters, an yttrium–binol catalyst, generated from Y(OiPr)₃–binol ligand–triphenylphosphine oxide (1:1:2), gave the best enantioselectivities (≤97 % ee). The utility of the epoxidation reaction was demonstrated in an efficient synthesis of (?)‐ragaglitazar, a potential antidiabetes agent.     

Catalytic Asymmetric Formation of δ‐Lactones from Unsaturated Acyl Halides

Previously unexplored enantiopure zwitterionic ammonium dienolates have been utilized in this work as reactive intermediates that act as diene components in hetero‐Diels–Alder reactions (HDAs) with aldehydes to produce optically active δ‐lactones, subunits of numerous bioactive products. The dienolates were generated in situ from E/Z mixtures of α,β‐unsaturated acid chlorides by use of a nucleophilic quinidine derivative and Sn(OTf)₂ as co‐catalyst. The latter component was not directly involved in the cycloaddition step with aldehydes and simply facilitated the formation of the reactive dienolate species. The scope of the cycloaddition was considerably improved by use of a complex formed from Er(OTf)₃ and a simple commercially available norephedrine‐derived ligand that tolerated a broad range of aromatic and heteroaromatic aldehydes for a cooperative bifunctional Lewis‐acid‐/Lewis‐base‐catalyzed reaction, providing α,β‐unsaturated δ‐lactones with excellent enantioselectivities. Mechanistic studies confirmed the formation of the dienolate intermediates for both catalytic systems. The active Er^III complex is most likely a monomeric species. Interestingly, all lanthanides can catalyze the title reaction, but the efficiency in terms of yield and enantioselectivity depends directly on the radius of the Ln^III ion. Similarly, use of the pseudolanthanides Sc^III and Y^III also resulted in product formation, whereas the larger La^III and other transition metal salts, as well as main group metal salts, proved to be inefficient. In addition, various synthetic transformations of 6‐CCl₃‐ or 4‐silyl‐substituted α,β‐unsaturated δ‐lactones, giving access to a number of valuable δ‐lactone building blocks, were investigated.     

Octahedral Chiral‐at‐Metal Iridium Catalysts: Versatile Chiral Lewis Acids for Asymmetric Conjugate Additions

Octahedral iridium(III) complexes containing two bidentate cyclometalating 5‐tert‐butyl‐2‐phenylbenzoxazole ( IrO ) or 5‐tert‐butyl‐2‐phenylbenzothiazole ( IrS ) ligands in addition to two labile acetonitrile ligands are demonstrated to constitute a highly versatile class of asymmetric Lewis acid catalysts. These complexes feature the metal center as the exclusive source of chirality and serve as effective asymmetric catalysts (0.5–5.0 mol % catalyst loading) for a variety of reactions with α,β‐unsaturated carbonyl compounds, namely Friedel–Crafts alkylations (94–99 % ee), Michael additions with CH‐acidic compounds (81–97 % ee), and a variety of cycloadditions (92–99 % ee with high d.r.). Mechanistic investigations and crystal structures of an iridium‐coordinated substrates and iridium‐coordinated products are consistent with a mechanistic picture in which the α,β‐unsaturated carbonyl compounds are activated by two‐point binding (bidentate coordination) to the chiral Lewis acid.     

Combined Transition‐Metal‐ and Organocatalysis: An Atom Economic C3 Homologation of Alkenes to Carbonyl and Carboxylic Compounds

A combination of regioselective room‐temperature/ambient‐pressure hydroformylation (transition‐metal catalysis) and decarboxylative Knoevenagel reactions (organocatalysis) allowed for the development of an efficient, one‐pot C3 homologation of terminal alkenes to (E)‐α,β‐unsaturated acids and esters, (E)‐β,γ‐unsaturated acids, (E)‐α‐cyano acrylic acids, and α,β‐unsaturated nitriles. All reactions proceed under mild conditions, tolerate a variety of functional groups, and furnish unsaturated carbonyl compounds in good yields and with excellent regio‐ and stereocontrol. Further, an iterative C2 homologation of (E)‐α,β‐unsaturated carboxylic acids is possible through a combination of decarboxylative hydroformylation employing a supramolecular catalyst followed by decarboxylative Knoevenagel condensation with an organocatalyst.     

A Novel Method for the Synthesis of α,β‐Unsaturated Amides Mediated by Samarium Diiodide

Promoted by Samarium diiodide (SmI₂), α,β‐unsaturated amides were formed from nitrogen anions (formed in situ by the reduction of nitro compounds) and α,β‐unsaturated esters. This reaction contrasts with the conjugate addition between amines and α,β‐unsaturated esters promoted by samarium triiodide (SmI₃) and provides an alternative attractive way to obtain α,β‐unsaturated amides using SmI₂.     

Asymmetric Hydrogenation of α,β‐Unsaturated Nitriles with Base‐Activated Iridium N,P Ligand Complexes

Although many chiral catalysts are known that allow highly enantioselective hydrogenation of a wide range of olefins, no suitable catalysts for the asymmetric hydrogenation of α,β‐unsaturated nitriles have been reported so far. We have found that Ir N,P ligand complexes, which under normal conditions do not show any reactivity towards α,β‐unsaturated nitriles, become highly active catalysts upon addition of N,N‐diisopropylethylamine. The base‐activated catalysts enable conjugate reduction of α,β‐unsaturated nitriles with H₂ at low catalyst loadings, affording the corresponding saturated nitriles with high conversion and excellent enantioselectivity. In contrast, alkenes lacking a conjugated cyano group do not react under these conditions, making it possible to selectively reduce the conjugated C?C bond of an α,β‐unsaturated nitrile, while leaving other types of C?C bonds in the molecule intact.