Enantioselective Alkylation of N‐Arylhydrazones Derived from α‐Keto Esters and Isatin Derivatives through Asymmetric Phase‐Transfer Catalysis

The phase‐transfer‐catalyzed asymmetric alkylation reactions of N‐arylhydrazones derived from α‐keto‐esters and isatin derivatives afford enantioenriched azo compounds that bear a tetra‐substituted carbon stereocenter in good yields with high chemo‐ and enantioselectivity. The alkylation products can be readily converted into chiral amino esters, hydrazine derivatives, and aza‐β‐lactams without loss of enantiopurity.     

Copper‐Complex‐Catalyzed Asymmetric Aerobic Oxidative Cross‐Coupling of 2‐Naphthols: Enantioselective Synthesis of 3,3′‐Substituted C1‐Symmetric BINOLs

A novel chiral 1,5‐N,N‐bidentate ligand based on a spirocyclic pyrrolidine oxazoline backbone was designed and prepared, and it coordinates CuBr in situ to form an unprecedented catalyst that enables efficient oxidative cross‐coupling of 2‐naphthols. Air serves as an external oxidant and generates a series of C₁‐symmetric chiral BINOL derivatives with high enantioselectivity (up to 99 % ee) and good yield (up to 87 %). This approach is tolerant of a broader substrates scope, particularly substrates bearing various 3‐ and 3′‐substituents. A preliminary investigation using one of the obtained C₁‐symmetric BINOL products was used as an organocatalyst, exhibiting better enantioselectivity than the previously reported organocatalyst, for the asymmetric α‐alkylation of amino esters.     

Enantioselective Rhodium‐Catalyzed Allylic Alkylation of β,γ‐Unsaturated α‐Amino Nitriles: Synthetic Homoenolate Equivalents

An enantioselective rhodium‐catalyzed allylic alkylation of β,γ‐unsaturated α‐amino nitriles is described. This protocol provides a novel approach for the construction of β‐stereogenic carbonyl derivatives via the catalytic asymmetric alkylation of a homoenolate equivalent. The particularly challenging nature of this transformation is highlighted by the fact that three modes of selectivity must be manipulated, namely regio‐ and enantioselectivity, in addition to geometrical control. The γ‐stereogenic cyanoenamine products can be readily hydrolyzed in situ to afford the β‐substituted carboxylic acids, which in turn provide expedient access to a number of related carbonyl derivatives. Additionally, control experiments indicate that the chiral rhodium‐allyl intermediate facilitates the selective formation of the E‐cyanoenamine products, which is critical since the Z‐isomer affords significantly lower enantiocontrol.     

Catalytic,Enantioselective α‐Alkylation of Azlactones with Nonconjugated Alkenes by Directed Nucleopalladation

A palladium(II)‐catalyzed enantioselective α‐alkylation of azlactones with nonconjugated alkenes is described. The reaction employs a chiral BINOL‐derived phosphoric acid as the source of stereoinduction, and a cleavable bidentate directing group appended to the alkene to control the regioselectivity and stabilize the nucleopalladated alkylpalladium(II) intermediate in the catalytic cycle. A wide range of azlactones were found to be compatible under the optimal reaction conditions to afford products bearing α,α‐disubstituted α‐amino‐acid derivatives with high yields and high enantioselectivity.     

Catalytic,Enantioselective α‐Alkylation of Azlactones with Nonconjugated Alkenes by Directed Nucleopalladation

A palladium(II)‐catalyzed enantioselective α‐alkylation of azlactones with nonconjugated alkenes is described. The reaction employs a chiral BINOL‐derived phosphoric acid as the source of stereoinduction, and a cleavable bidentate directing group appended to the alkene to control the regioselectivity and stabilize the nucleopalladated alkylpalladium(II) intermediate in the catalytic cycle. A wide range of azlactones were found to be compatible under the optimal reaction conditions to afford products bearing α,α‐disubstituted α‐amino‐acid derivatives with high yields and high enantioselectivity.     

PPh3‐catalyzed knoevenagel condensation: A facile synthesis of 5‐(1H‐indol‐3‐yl)Meth‐ ylene)‐2, 2‐Dimethyl‐1, 3‐Dioxane‐4, 6‐dione,and their N‐alkyl derivatives by using peg‐600 as the reaction medium

Triphenylphosphine (TPP) has been utilized as a novel and efficient catalyst for the Knoevenagel condensation of indole‐3‐carboxaldehydes 1(a–e) , 1‐methyl‐1H‐indole‐3‐carboxaldehydes 4(a–e) , and 1‐ethyl‐1H‐indole‐3‐carboxaldehydes 6(a–e) with the active methylene compound, that is, meldrum's acid ( 2 ), to afford substituted derivatives 5‐((1H‐indol‐3‐yl) methylene)‐2,2‐dimethyl‐1,3‐dioxane‐4,6‐dione 3(a–e) , 2,2‐dimethyl‐5‐((1‐methyl‐1H‐indol‐3‐yl)methylene)‐1,3‐dioxane‐4,6‐dione 5(a–e) , and 2,2‐dimethyl‐5‐((1‐ethyl‐1H‐indol‐3‐yl)methylene)‐1,3‐dioxane‐4,6‐dione 7(a–e) , respectively, in ethanol medium at RT just within 1 h in excellent yields. The products 3(a–e) were reacted independently with alkylating agents, that is, DMS and DES in the presence of PEG‐600 as an efficient and green solvent, to afford the corresponding N‐substituted methyl and ethyl derivatives 5(a–e) and 7(a–e) , respectively. © 2011 Wiley Periodicals, Inc. Heteroatom Chem 23:41–48, 2012; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.20750     

Catalytic Asymmetric N‐Alkylation of Indoles and Carbazoles through 1,6‐Conjugate Addition of Aza‐para‐quinone Methides

Catalytic asymmetric N‐alkylation of indoles and carbazoles represents a family of important but underdeveloped reactions. Herein, we describe a new organocatalytic strategy in which in situ generated aza‐para ‐quinone methides are employed as the alkylating reagent. With the proper choice of a chiral phosphoric acid and an N‐protective group, the intermolecular C−N bond formation with various indole and carbazole nucleophiles proceeded efficiently under mild conditions with excellent enantioselectivity and functional‐group compatibility. Control experiments and kinetic studies provided important insight into the reaction mechanism.     

Transition‐Metal‐Free Hydrogen Autotransfer: Diastereoselective N‐Alkylation of Amines with Racemic Alcohols

A practical method for the synthesis of α‐chiral amines by alkylation of amines with alcohols in the absence of any transition‐metal catalysts has been developed. Under the co‐catalysis of a ketone and NaOH, racemic secondary alcohols reacted with Ellman's chiral tert‐butanesulfinamide by a hydrogen autotransfer process to afford chiral amines with high diastereoselectivities (up to >99:1). Broad substrate scope and up to a 10 gram scale production of chiral amines were demonstrated. The method was applied to the synthesis of chiral deuterium‐labelled amines with high deuterium incorporation and optical purity, including examples of chiral deuterated drugs. The configuration of amine products is found to be determined solely by the configuration of the chiral tert‐butanesulfinamide regardless of that of alcohols, and this is corroborated by DFT calculations. Further mechanistic studies showed that the reaction is initiated by the ketone catalyst and involves a transition state similar to that proposed for the Meerwein–Ponndorf–Verley (MPV) reduction, and importantly, it is the interaction of the sodium cation of the base with both the nitrogen and oxygen atoms of the sulfinamide moiety that makes feasible, and determines the diastereoselectivity of, the reaction.     

Chiral N‐Heterocyclic Carbene Ligands Bearing a Pyridine Moiety for the Copper‐Catalyzed Alkylation of N‐Sulfonylimines with Dialkylzinc Reagents

Amino acid‐derived chiral imidazolium salts, each bearing a pyridine ring, were developed as N‐heterocyclic carbene ligands. The copper‐catalyzed asymmetric alkylation of various N‐sulfonylimines with dialkylzinc reagents in the presence of these chiral imidazolium salts afforded the corresponding alkylated products with high enantioselectivity (up to 99 % ee). The addition of HMPA to the reaction mixture as a co‐solvent is critical in terms of chemical yield and enantioselectivity. A wide range of N‐sulfonylimines and dialkylzinc reagents were found to be applicable to this reaction.     

Chemoselective N‐Alkylation of Indoles in Aqueous Microdroplets

Many reactions show much faster kinetics in microdroplets than in the bulk phase. Most reported reactions in microdroplets mirror the products found in bulk reactions. However, the unique environment of microdroplets allows different chemistry to occur. In this work, we present the first chemoselective N‐alkylation of indoles in aqueous microdroplets via a three‐component Mannich‐type reaction without using any catalyst. In sharp contrast, bulk reactions using the same reagents with a catalyst yield exclusively C‐alkylation products. The N‐alkylation yield is moderate in microdroplets, up to 53 %. We extended the scope of the microdroplet reaction and obtained a series of new functionalized indole aminals, which are likely to have biological activities. This work clearly indicates that microdroplet reactions can show reactivity quite different from that of bulk‐phase reactions, which holds great potential for developing novel reactivities in microdroplets.     

Catalytic Reaction of Aryldiazoacetates with Indole and Its Derivatives:Profound Effect of N‐1 Substitutent on the Reaction Pathways

The reaction of indole and its derivatives with aryldiazoacetates has been studied in the presence of copper and rhodium catalysts. The electronic property of N-1 substitutent showed significant effect on the reaction pathways. The electron-donating group favored the formation of the β-alkylation products, while the electron-withdrawing group favored the formation of the cyclopropane products. A reaction mechanism was proposed based on the experimental data and previous research results. The structure of aryl group in diazo compounds also affected the yield of the β-alkylation products or the cyclopropane products.     

Highly Enantioselective Synthesis of β‐Heteroaryl‐Substituted Dihydrochalcones Through Friedel–Crafts Alkylation of Indoles and Pyrrole

A highly enantioselective Friedel–Crafts (F–C) alkylation of indoles and pyrrole with chalcone derivatives catalyzed by a chiral N,N′‐dioxide–Sc(OTf)₃ complex has been developed that tolerates a wide range of substrates. The reaction proceeds in moderate to excellent yields and high enantioselectivities (85–92 % enantiomeric excess) using 2 mol % (for indole) or 0.5 mol % (for pyrrole) catalyst loading, which showed the potential value of the catalyst system. Meanwhile, a strong positive nonlinear effect was observed. On the basis of the experimental results and previous reports, a possible working model is proposed to explain the origin of the activation and asymmetric induction.     

Iron‐Catalyzed Asymmetric Hydrosilylation of 1,1‐Disubstituted Alkenes

The highly regio‐ and enantioselective iron‐catalyzed anti‐Markovnikov hydrosilylation of 1,1‐disubstituted aryl alkenes was developed using iminopyridine oxazoline ligands to afford chiral organosilanes. Additional derivatization of these products lead to chiral organosilanols, cyclic silanes, phenol derivatives, and 3‐substituted 2,3‐dihydrobenzofurans.     

Direct α‐Alkylation of Aldehydes by Brønsted‐Acid Catalysis

A Brønsted acid catalyzed direct alkylation reaction of aldehydes was described. The 3,5‐dinitrobenzoic acid promoted the reaction between aldehydes and diarylmethanols to afford the corresponding alkylation products with middle to high yields (up to 91% yield).     

Cobalt‐Catalyzed Enantioselective Hydroboration/Cyclization of 1,7‐Enynes: Asymmetric Synthesis of Chiral Quinolinones Containing Quaternary Stereogenic Centers

An asymmetric cobalt‐catalyzed hydroboration/cyclization of 1,7‐enynes to synthesize chiral six‐membered N‐heterocyclic compounds was developed. A variety of aniline‐tethered 1,7‐enynes react with pinacolborane to afford the corresponding chiral boryl‐functionalized quinoline derivatives in high yields with high enantioselectivity. This cobalt‐catalyzed asymmetric cyclization of 1,7‐enyens provides a general approach to access a series of chiral quinoline derivatives containing quaternary stereocenters.     

Asymmetric Friedel–Crafts Alkylation of Electron‐Rich N‐Heterocycles with Nitroalkenes Catalyzed by Diphenylamine‐Tethered Bis(oxazoline) and Bis(thiazoline) ZnII Complexes

The asymmetric Friedel–Crafts alkylation of electron‐rich N‐containing heterocycles with nitroalkenes under catalysis of diphenylamine‐tethered bis(oxazoline) and bis(thiazoline)‐Zn^II complexes was investigated. In the reaction of indole derivatives, the complex of ligand 4 f with trans‐diphenyl substitutions afforded better results than previously published ligand 4 e with cis‐diphenyl substitutions. Excellent yields (up to greater than 99 %) and enantioselectivities (up to 97 %) were achieved in most cases. The complex of ligand 4 d bearing tert‐butyl groups gave the best results in the reactions of pyrrole. Moderate to good yields (up to 91 %) and enantioselectivities (up to 91 %) were achieved in most cases. The origin of the enantioselectivity was attributed to the NH–π interaction between the catalyst and the incoming aromatic system in the transition state. Such an interaction was confirmed through comparison of the enantioselectivity and the absolute configuration of the products in the reactions catalyzed by designed ligands.     

Chiral Carboxylic Acid Enabled Achiral Rhodium(III)‐Catalyzed Enantioselective C−H Functionalization

Reported is an achiral Cp^xRh^III/chiral carboxylic acid catalyzed asymmetric C?H alkylation of diarylmethanamines with a diazomalonate, followed by cyclization and decarboxylation to afford 1,4‐dihydroisoquinolin‐3(2H)‐one. Secondary alkylamines as well as nonprotected primary alkylamines underwent the transformation with high enantioselectivities (up to 98.5:1.5 e.r.) by using a newly developed chiral carboxylic acid as the sole source of chirality to achieve enantioselective C?H cleavage by a concerted metalation‐deprotonation mechanism.     

Molecular Iodine Catalyzed One‐pot Aza‐Diels‐Alder Reaction under Solvent‐free Conditions

Catalyzed by molecular iodine at room temperature, under solvent‐free conditions, a two component aza‐Diels‐Alder cyclization of N‐vinyl‐2‐pyrrolidinone with N‐arylimine gave tetrahydroquinoline derivatives in good yields and high stereo‐selectivity. And three components aza‐Diels‐Alder reaction of N‐vinyl‐2‐pyrrolidinone, anilines and indole‐3‐carbaldehydes under the same condition afford only cis‐product in good yields.     

Gold‐Catalyzed CH Annulation of Anthranils with Alkynes: A Facile,Flexible, and Atom‐Economical Synthesis of Unprotected 7‐Acylindoles

The gold‐catalyzed C? H annulation of anthranil derivatives with alkynes offers a facile, flexible, and atom‐economical one‐step route to unprotected 7‐acylindoles. An intermediate α‐imino gold carbene, generated by an intermolecular reaction, promotes ortho‐aryl C? H functionalization to afford the target products. The transformation proceeds with a broad range of substrates under mild conditions. Moreover, the obtained functionalized indole products represent a versatile platform for the construction of diverse indolyl frameworks.     

Enantioselective Copper‐Catalyzed Alkylation of Quinoline N‐Oxides with Vinylarenes

An asymmetric copper‐catalyzed alkylation of quinoline N ‐oxides with chiral Cu–alkyl species, generated by migratory insertion of a vinylarene into a chiral Cu−H complex, is reported. A variety of quinoline N ‐oxides and vinylarenes underwent this Cu‐catalyzed enantioselective alkylation reaction, affording the corresponding chiral alkylated N‐heteroarenes in high yield with high‐to‐excellent enantioselectivity. This enantioselective protocol represents the first general and practical approach to access a wide range of chiral alkylated quinolines.