Synergistic Relay Reactions To Achieve Redox-Neutral α-Alkylations of Olefinic Alcohols with Ruthenium(II) Catalysis

Herein, we report a ruthenium-catalyzed redox-neutral α-alkylation of unsaturated alcohols based on a synergistic relay process involving olefin isomerization (chain walking) and umpolung hydrazone addition, which takes advantage of the interaction between the two rather inefficient individual reaction steps to enable an efficient overall process. This transformation shows the compatibility of hydrazone-type “carbanions” and active protons in a one-pot reaction, and at the same time achieves the first Grignard-type nucleophilic addition using olefinic alcohols as latent carbonyl groups, providing a higher yield of the corresponding secondary alcohol than the classical hydrazone addition to aldehydes does. A broad scope of unsaturated alcohols and hydrazones, including some complex structures, can be successfully employed in this reaction, which shows the versatility of this approach and its suitability as an alternative, efficient means for the generation of secondary and tertiary alcohols.     

Tandem Three‐Component Synthesis of syn‐1,2‐ and syn‐1,3‐Diol Derivatives

The development of efficient methods for stereocontrolled synthesis of polyol derivatives has been of continuing interest for the synthetic community. We describe herein tandem olefin cross‐metathesis/hemiacetalization/intramolecular oxa‐Michael addition of allylic/homoallylic alcohols, α,β‐unsaturated ketones, and aldehydes, which enabled the synthesis of syn‐1,2‐ and syn‐1,3‐diol derivatives in a step‐economical manner. A series of differentially protected polyol derivatives could be obtained in subsequent transformations via chemoselective/regioselective cleavage of the acetal moiety of the tandem reaction products.     

Iron‐catalyzed one‐pot oxidation/Knoevenagel condensation reaction using air as an oxidant

A green and highly efficient iron‐catalyzed one‐pot oxidation/Knoevenagel tandem reaction for the synthesis of α, β‐unsaturated nitriles from secondary alcohols and malononitrile has been achieved. The reaction performed under mild conditions with air as an oxidant, and provided the corresponding oxidation/Knoevenagel prudocts in good to excellent yields within short times avoiding the use of noble metal catalysts and bases. Remarkably, water is the only byproduct in this methodology. The reaction could be performed on a gram scale under the standard reaction conditions.     

New Types of Reactivity of α,β‐Unsaturated N,N‐Dimethylhydrazones: Chemodivergent Diastereoselective Synthesis of Functionalized Tetrahydroquinolines and Hexahydropyrrolo[3,2‐b]indoles

The indium trichloride‐catalyzed reaction between aromatic imines and α,β‐unsaturated N,N‐dimethylhydrazones in acetonitrile afforded 1,2,3,4‐tetrahydroquinolines bearing a hydrazone function at C4 through a one‐pot diastereoselective domino process that involves the formation of two C? C bonds and the controlled generation of two stereocenters, one of which is quaternary. This reaction constitutes the first example of an α,β‐unsaturated dimethylhydrazone that behaves as a dienophile in a hetero Diels–Alder reaction. The related reaction between anilines, aromatic aldehydes, and methacrolein dimethylhydrazone in CHCl₃ with BF₃?Et₂O as catalyst afforded polysubstituted 1,2,3,3a,4,8b‐hexahydropyrrolo[3,2‐b]indoles as major products through a fully diastereoselective ABB′C four‐component domino process that generates two cycles, three stereocenters, two C? C bonds, and two C? N bonds in a single operation.     

TBAF‐Mediated Dimerization Reaction of β,γ‐Unsaturated Arylketones

A simple and high‐yield method for the synthesis of several 1,5‐diaryl‐1,5‐dicarbonyl compounds has been established starting from TBAF‐mediated isomerization and dimerization reaction of β,γ‐unsaturated arylketones (allyl arylketones) with mono‐, di‐, and tri‐methoxy groups, which is derived from allylation of commercially available different benzaldehydes and followed by oxidation of the resulting secondary alcohols.     

Room‐Temperature Guerbet Reaction with Unprecedented Catalytic Efficiency and Enantioselectivity

We report herein an unprecedented highly efficient Guerbet‐type reaction at room temperature (catalytic TON up to >6000). This β‐alkylation of secondary methyl carbinols with primary alcohols has significant advantage of delivering higher‐order secondary alcohols in an economical, redox‐neutral fashion. In addition, the first enantioselective Guerbet reaction has also been achieved using a commercially available chiral ruthenium complex to deliver secondary alcohols with moderate yield and up to 92 % ee. In both reactions, the use of a traceless ketone promoter proved to be beneficial for the catalytic efficiency.     

Efficient Organocatalytic Construction of C4‐Alkyl Substituted Piperidines and Their Application to the Synthesis of (+)‐α‐Skytanthine

Chiral piperidines which contain an alkyl group at C4 positions are one of the important architectures because it is appeared in several natural products. An efficient protocol for the preparation of C4‐alkyl substituted chiral piperidines using secondary amine catalyzed formal aza [3+3] cycloaddition reaction with aliphatic α,β‐unsaturated aldehydes and thiomalonamate derivatives is reported. In our reaction system, thiomalonamate is an excellent nucleophile and the addition of suitable acid and its amount is an important factor for the acceleration effect in organocatalytic reaction. Furthermore, water and MeOH also have an acceleration effect. These efforts lead to only 0.1 mol % catalyst loading in multigram scale synthesis for suitable reaction time. In addition, the efficient enantioselective total synthesis of (+)‐α‐skytanthine by using our developed reaction as key step was achieved in total 15 % yield. All carbon and nitrogen units were introduced by one step with high enantioselectivity.     

Synthesis of Quinolines via a Metal‐Catalyzed Dehydrogenative N‐Heterocyclization

Efficient ruthenium‐, rhodium‐, palladium‐, copper‐ and iridium‐catalysed methodologies have been recently developed for the synthesis of quinolines by the reaction of 2‐aminobenzyl alcohols with carbonyl compounds (aldehydes and ketones) or the related alcohols. The reaction is assumed to proceed via a sequence involving initial metal‐catalysed oxidation of 2‐aminobenzyl alcohols to the related 2‐aminobenzaldehydes, followed by cross aldol reaction with a carbonyl compound under basic conditions to afford α,β‐unsaturated carbonyl compounds. These aldehydes or ketones can be also generated in situ via dehydrogenation of the related primary and secondary alcohols. In the final step cyclodehydration of the α,β‐unsaturated carbonyl compound intermediates gives quinolines. Good yields of quinolines were also obtained by reacting 2‐nitrobenzyl alcohols and secondary alcohols in the presence of a ruthenium catalyst. Finally, aniline derivatives afforded also a useful access to quinolines by the reaction with 1,3‐propanediol or 3‐amino‐1‐propanol, or in a three‐component reaction with benzyl alcohol and aliphatic alcohols.     

Amidation of Aldehydes and Alcohols through α‐Iminonitriles and a Sequential Oxidative Three‐Component Strecker Reaction/Thio‐Michael Addition/Alumina‐Promoted Hydrolysis Process to Access β‐Mercaptoamides from Aldehydes,Amines, and Thiols

Mild and general alumina‐promoted hydrolysis conditions for converting α‐iminonitriles into carboxamides have been developed. In combination with the oxidative three‐component Strecker reaction, the one‐pot direct amidation of aldehydes and alcohols is reported. Subsequently, an Yb(OTf)₃‐catalyzed Michael addition of thiols to α,β‐unsaturated α‐iminonitriles is reported for the synthesis of β‐mercapto‐α‐iminonitriles. The successful integration of an oxidative Strecker reaction, thio‐Michael addition, and neutral‐alumina‐promoted hydrolysis of β‐mercapto‐α‐iminonitriles into a three‐component one‐pot process allowed us to develop the direct conversion of amines, aldehydes, and thiols into β‐mercaptoamides. All of these procedures were applicable to aromatic and aliphatic amines and aldehydes.     

One‐Pot Alkoxylation of Phenols with Urea and 1,2‐Glycols

A one‐pot epoxide‐free alkoxylation process has been developed for phenolic compounds. The process involves heating phenols and urea in 1,2‐glycols at 170‐190 °C using Na₂CO₃/ZnO as co‐catalysts under atmospheric conditions. During the course of this new alkoxylation reaction, a five‐membered ring cyclic carbonate intermediate, ethylene carbonate (EC) or propylene carbonate (PPC), was produced in‐transit as the key intermediate and was subsequently consumed by phenols to form alkoxylated ether alcohols as final products in excellent yields. For instance, phenol, bisphenol A (BPA), hydroquinone and resorcinol were converted into their respective mono‐alkoxylated ether alcohols on each of their phenolic groups in 80‐95% isolated yields. In propoxylation of phenols, this approach shows great product selectivity favoring production of high secondary alcohols over primary alcohols in isomeric ratios of nearing 95/5. Since ammonia (NH₃) and carbon dioxide (CO₂) evolving from the reaction can be re‐combined in theory into urea for re‐use, the overall net‐alkoxylation by this approach can be regarded as a simple condensation reaction of phenols with 1,2‐glycols giving off water as its by‐product. This one‐pot process is simple, safe and environmentally friendlier than the conventional alkoxylated processes based on ethylene oxide (EO) or propylene oxide (PO). Moreover, this process is particularly well‐suited for making short chain‐length alkoxyether alcohols of phenols.     

Chiral Phosphoric Acid Catalyzed Kinetic Resolution of 2‐Amido Benzyl Alcohols: Asymmetric Synthesis of 4H‐3,1‐Benzoxazines

An efficient method for the asymmetric synthesis of 4H‐3,1‐benzoxazines was developed by kinetic resolution of 2‐amido benzyl alcohols using chiral phosphoric acid catalyzed intramolecular cyclizations. A broad range of benzyl alcohols (both secondary and tertiary alcohols) were kinetically resolved with high selectivities, with an s factor of up to 94. Mechanistic studies were performed to elucidate the mechanism of these reactions, wherein the amide moieties reacted as the electrophiles. Gram‐scale reaction and facile transformations of the chiral products demonstrate the potential of this method in asymmetric synthesis of biologically active chiral heterocycles.     

Light‐Driven Enantioselective Organocatalytic β‐Benzylation of Enals

A photochemical organocatalytic strategy for the direct enantioselective β‐benzylation of α,β‐unsaturated aldehydes is reported. The chemistry capitalizes upon the light‐triggered enolization of 2‐alkyl‐benzophenones to afford hydroxy‐o ‐quinodinomethanes. These fleeting intermediates are stereoselectively intercepted by chiral iminium ions, transiently formed upon condensation of a secondary amine catalyst with enals. Density functional theory (DFT) studies provided an explanation for why the reaction proceeds through an unconventional Michael‐type addition manifold, instead of a classical cycloaddition mechanism and subsequent ring‐opening.     

A Free‐Radical‐Promoted Stereospecific Decarboxylative Silylation of α,β‐Unsaturated Acids with Silanes

A stereospecific decarboxylative silylation of acrylic and propiolic acids with silanes was developed. This reaction represents the first example of decarboxylative C? Si bond formation and provides an efficient and convenient approach to various synthetically useful alkenyl and alkynyl organosilicon compounds through the reaction of α,β‐unsaturated acids with silanes. Spin‐trapping and EPR experiments support a radical addition/elimination process.     

InI3‐ or ZnI2‐Catalyzed Reaction of Hydroxylated 1,5‐Allenynes with Thiols: A New Access to 3,5‐Disubstituted Toluene Derivatives

Transition‐metal‐activated alkynes or allenes can accept nucleophilic attack and undergo direct addition of the nucleophiles to the unsaturated bonds or trigger subsequent rearrangement reactions. This chemistry has witnessed increasing development in recent years. In this report, we have focused on the metal‐catalyzed reactions of a variety of substituted propargyl allenic alcohols and thiophenols using indium(III) and zinc(II) catalysts, which can activate both the alcohol and alkyne. In this reaction, thio groups play the role of a nucleophile and trigger subsequent rearrangements to give benzene derivatives. The products can be further transformed into various 1,3,5‐trisubstituted aromatic compounds by nickel‐catalyzed coupling reactions through the cleavage of the C? S bonds.     

Palladium‐Catalyzed Stereoselective Intramolecular Oxidative Amidation of Alkenes in the Synthesis of 1,3‐ and 1,4‐Amino Alcohols and 1,3‐Diamines

An efficient and practical Pd‐catalyzed intramolecular oxidative allylic amidation provides facile access to derivatives of 1,3‐ and 1,4‐amino alcohols and 1,3‐diamines. The method operates under mild reaction conditions (RT) with molecular oxygen (1 atm) as the sole reoxidant of Pd. Excellent diastereoselectivities were attained with substrates bearing a secondary stereogenic center     

Fe(OTf)3‐Catalyzed α‐Benzylation of Aryl Methyl Ketones with Electrophilic Secondary and Aryl Alcohols

Acid‐catalyzed Friedel–Crafts alkylation of 1,3‐dicarbonyl compounds with electrophilic alcohols, is known to be an effective C? C bond forming reaction. However, until now, this reaction has not been amenable for α‐alkylation of aryl methyl ketones because of the notoriously low nucleophilicities of these compounds. Therefore, α‐alkylation of aryl methyl ketone relies on precious metal catalysts and also, the use of primary alcohols is mandatory. In this study, we found that a system composed of a Fe(OTf)₃ catalyst and chlorobenzene solvent is sufficient to promote the title Friedel–Crafts reaction by using benzhydrols as electrophiles. 3,4‐Dihydro‐9‐(2‐hydroxy‐4,4‐dimethyl‐6‐oxo‐1‐cyclohexen‐1‐yl)‐3,3‐dimethyl‐xanthen‐1(2 H)‐one was also applicable as an electrophile in this type of benzylation reaction. On the basis of this result, a three‐component reaction of salicylaldehyde, dimedone, and aryl methyl ketone was also developed, and this provided an efficient way for the synthesis of densely substituted 4H‐chromene derivatives.     

Copper(I)‐Catalyzed Three‐Component Reaction of Terminal Propargyl Alcohols,Aldehydes, and Amines: Synthesis of 3‐Amino‐2‐pyrones and 2,5‐Dihydrofurans

A novel copper(I)‐catalyzed three‐component reaction for the efficient synthesis of 3‐amino‐2‐pyrones and 2,5‐dihydrofurans from propargyl alcohols, aldehydes, and amines has been developed. The starting materials are easily available and the scope of this method is broad. Through mechanistic studies, it is believed that the three‐component reaction consists of an A³‐coupling to propargylic amine, alkyne–allene isomerization, and intramolecular cyclization of the allenol to form a furan. In case of using ethyl glyoxalate as the aldehyde, a ring‐opening, lactonization, and isomerization process affords the 3‐amino‐2‐pyrones.     

Copper(I)‐Catalyzed Three‐Component Reaction of Terminal Propargyl Alcohols,Aldehydes, and Amines: Synthesis of 3‐Amino‐2‐pyrones and 2,5‐Dihydrofurans

A novel copper(I)‐catalyzed three‐component reaction for the efficient synthesis of 3‐amino‐2‐pyrones and 2,5‐dihydrofurans from propargyl alcohols, aldehydes, and amines has been developed. The starting materials are easily available and the scope of this method is broad. Through mechanistic studies, it is believed that the three‐component reaction consists of an A³‐coupling to propargylic amine, alkyne–allene isomerization, and intramolecular cyclization of the allenol to form a furan. In case of using ethyl glyoxalate as the aldehyde, a ring‐opening, lactonization, and isomerization process affords the 3‐amino‐2‐pyrones.     

Catalytic Asymmetric Inverse‐Electron‐Demand Oxa‐Diels–Alder Reaction of In Situ Generated ortho‐Quinone Methides with 3‐Methyl‐2‐Vinylindoles

The first catalytic asymmetric inverse‐electron‐demand (IED) oxa‐Diels–Alder reaction of ortho‐quinone methides, generated in situ from ortho‐hydroxybenzyl alcohols, has been established. By selecting 3‐methyl‐2‐vinylindoles as a class of competent dienophiles, this approach provides an efficient strategy to construct an enantioenriched chroman framework with three adjacent stereogenic centers in high yields and excellent stereoselectivities (up to 99 % yield, >95:5 d.r., 99.5:0.5 e.r.). The utilization of ortho‐hydroxybenzyl alcohols as precursors of dienes and 3‐methyl‐2‐vinylindoles as dienophiles, as well as the hydrogen‐bonding activation mode of the substrates met the challenges of a catalytic asymmetric IED oxa‐Diels–Alder reaction.     

Microwave‐Assisted Oxidation of Alcohols with N,N,N′,N′‐Tetrabromobenzene‐1,3‐Disulfonamide and Poly(N‐Bromobenzene‐1,3‐Disulfonamide) under Solvent‐Free Conditions

An efficient and mild methodology for the oxidation of primary and secondary alcohols to the corresponding carbonyl functions is described with N,N,N′,N′‐tetrabromobenzene‐1,3‐disulfonamide and poly(N‐bromobenzene‐1,3‐disulfonamide) using microwave irradiation under solvent‐free conditions. Aliphatic, benzylic and allylic alcohols are rapidly oxidized without over‐oxidation to carboxylic acids. Secondary carbinols are slowly oxidized so that the reaction is highly chemoselective.