Tandem Pd/Au‐Catalyzed Route to α‐Sulfenylated Carbonyl Compounds from Terminal Propargylic Alcohols and Thiols

An efficient and highly atom‐economical tandem Pd/Au‐catalyzed route to α‐sulfenylated carbonyl compounds from terminal propargylic alcohols and thiols has been developed. This one‐step procedure has a wide substrate scope with respect to substituents at the α‐position of the alcohol. Both aromatic and aliphatic thiols generated the α‐sulfenylated carbonyl products in good to excellent yields. A mechanism is proposed in which the reaction proceeds through a Pd‐catalyzed regioselective hydrothiolation at the terminal triple bond of the propargyl alcohol followed by an Au‐catalyzed 1,2‐hydride migration.     

Gold‐ and Silver‐Catalyzed Reactions of Propargylic Alcohols in the Presence of Protic Additives

A wide range of primary, secondary and tertiary propargylic alcohols undergo a Meyer–Schuster rearrangement to give enones at room temperature in the presence of a gold(I) catalyst and small quantities of MeOH or 4‐methoxyphenylboronic acid. The syntheses of the enone natural products isoegomaketone and daphenone were achieved using this reaction as the key step. The rearrangement of primary propargylic alcohols can readily be combined in a one‐pot procedure with the addition of a nucleophile to the resulting terminal enone, to give β‐aryl, β‐alkoxy, β‐amino or β‐sulfido ketones. Propargylic alcohols bearing an adjacent electron‐rich aryl group can also undergo silver‐catalyzed substitution of the alcohol with oxygen, nitrogen and carbon nucleophiles. This latter reaction was initially observed with a batch of gold catalyst that was probably contaminated with small quantities of silver salt.     

Copper‐Catalyzed Cyanomethylation of Allylic Alcohols with Concomitant 1,2‐Aryl Migration: Efficient Synthesis of Functionalized Ketones Containing an α‐Quaternary Center

A copper‐catalyzed alkylation of allylic alcohols by alkyl nitriles with concomitant 1,2‐aryl migration was developed. Formation of the alkyl nitrile radical was followed by its intermolecular addition to alkenes and the migration of a vicinal aryl group with the concomitant generation of a carbonyl functionality to complete the domino sequence. Mechanistic studies suggested that 1,2‐aryl migration proceeded through a radical pathway (neophyl rearrangement). The protocol provided an efficient route to functionalized ketones containing an α‐quaternary center.     

One‐Pot Synthesis of 2,5‐Dihydropyrroles from Terminal Alkynes,Azides, and Propargylic Alcohols by Relay Actions of Copper,Rhodium, and Gold

Relay actions of copper, rhodium, and gold formulate a one‐pot multistep pathway, which directly gives 2,5‐dihydropyrroles starting from terminal alkynes, sulfonyl azides, and propargylic alcohols. Initially, copper‐catalyzed 1,3‐dipolar cycloaddition of terminal alkynes with sulfonyl azides affords 1‐sulfonyl‐1,2,3‐triazoles, which then react with propargylic alcohols under the catalysis of rhodium. The resulting alkenyl propargyl ethers subsequently undergo the thermal Claisen rearrangement to give α‐allenyl‐α‐amino ketones. Finally, a gold catalyst prompts 5‐endo cyclization to produce 2,5‐dihydropyrroles.     

Iridium‐Catalyzed Diastereoselective and Enantioselective Allylic Substitutions with Acyclic α‐Alkoxy Ketones

The asymmetric alkylation of acyclic ketones is a longstanding challenge in organic synthesis. Reported herein are diastereoselective and enantioselective allylic substitutions with acyclic α‐alkoxy ketones catalyzed by a metallacyclic iridium complex to form products with contiguous stereogenic centers derived from the nucleophile and electrophile. These reactions occur between allyl methyl carbonates and unstabilized copper(I) enolates generated in situ from acyclic α‐alkoxy ketones. The resulting products can be readily converted into enantioenriched tertiary alcohols and tetrahydrofuran derivatives without erosion of enantiomeric purity.     

Enantioselective Alkynylation of Ketones Promoted by β-Sulfonamide Alcohol-Titanium Complexes

A readily available β-sulfonamide alcohol-titanium complex was found to be effective on promoting the asymmetric addition reaction of an alkynylzinc reagent to unactivated simple ketones under very mild conditions. And the corresponding chiral tertiary propargylic alcohols were obtained with enantiomeric excesses of up to 86%, which provided a simple, practical and inexpensive method to generate chiral tertiary propargylic alcohols.     

Direct Zinc(II)‐Catalyzed Enantioconvergent Additions of Terminal Alkynes to α‐Keto Esters

The addition of terminal alkynes to racemic β‐stereogenic α‐keto esters was achieved in high levels of stereoselectivity, affording versatile tertiary propargylic alcohols containing two stereocenters. This environmentally benign enantioconvergent reaction proceeds with perfect atom economy, requires no solvent, and is catalyzed by a non‐toxic zinc salt. The alkyne moiety can be leveraged in downstream transformations including hydrogenation to the corresponding saturated tertiary alcohol, which represents the product of a formal enantioconvergent aliphatic nucleophile addition.     

Asymmetric Synthesis of Tertiary Alcohols and Thiols via Nonstabilized Tertiary α‐Oxy‐ and α‐Thio‐Substituted Organolithium Species

Nonstabilized α‐O‐substituted tertiary organolithium species are difficult to generate, and the α‐S‐substituted analogues are configurationally unstable. We now report that they can both be generated easily and trapped with a range of electrophiles with high enantioselectivity, providing ready access to a range of enantioenriched tertiary alcohols and thiols. The configurational stability of the α‐S‐organolithium species was enhanced by using a less coordinating solvent and short reaction times.     

Metal‐Free Oxidative Radical Addition of Carbonyl Compounds to α,α‐Diaryl Allylic Alcohols: Synthesis of Highly Functionalized Ketones

A metal‐free direct alkylation of simple carbonyl compounds (ketones, esters, and amides) with α,α‐diaryl allylic alcohols is described. The protocol provides facile access to highly functionalized dicarbonyl ketones by a radical addition/1,2‐aryl migration cascade. The regioselectivity of the reaction was precisely controlled by the nature of the carbonyl compound.     

Photosensitizer‐Free Visible‐Light‐Mediated Gold‐Catalyzed 1,2‐Difunctionalization of Alkynes

Under visible‐light irradiation, the gold‐catalyzed intermolecular difunctionalization of alkynes with aryl diazonium salts in methanol affords a variety of α‐aryl ketones in moderate to good yields. In contrast to previous reports on gold‐catalyzed reactions that involve redox cycles, no external oxidants or photosensitizers are required. The reaction proceeds smoothly under mild reaction conditions and shows broad functional‐group tolerance. Further applications of this method demonstrate the general applicability of the arylation of a vinyl gold intermediate instead of the commonly used protodemetalation step. This step provides facile access to functionalized products in one‐pot processes. With a P,N‐bidentate ligand, a stable aryl gold(III) species was obtained, which constitutes the first direct experimental evidence for the commonly postulated direct oxidative addition of an aryl diazonium salt to a pyridine phosphine gold(I) complex.     

Enantioselective NiH/Pmrox‐Catalyzed 1,2‐Reduction of α,β‐Unsaturated Ketones

The enantioselective 1,2‐reduction of α,β‐unsaturated ketones was achieved using a NiH catalyst in the presence of pinacolborane. This mild process represents a general method to access a wide variety of structurally diverse α‐chiral allylic alcohols in excellent yields and enantioselectivity, as well as very high levels of ambidoselectivity for 1,2‐ over 1,4‐reduction. Furthermore, for reactions on a 10 mmol scale, catalyst loadings as low as 0.5 mol % could be employed to deliver product without any detrimental effect on the yield, enantio‐, or ambidoselectivity.     

Stereodivergent Dual Catalytic α‐Allylation of Protected α‐Amino‐ and α‐Hydroxyacetaldehydes

Fully stereodivergent dual‐catalytic α‐allylation of protected α‐amino‐ and α‐hydroxyacetaldehydes is achieved through iridium‐ and amine‐catalyzed substitution of racemic allylic alcohols with chiral enamines generated in situ. The operationally simple method furnishes useful aldehyde building blocks in good yields, more than 99 % ee, and with d.r. values greater than 20:1 in some cases. Additionally, the γ,δ‐unsaturated products can be further functionalized in a stereodivergent fashion with high selectivity and with preservation of stereochemical integrity at the C_α position.     

The Regio‐ and Stereospecific Intermolecular Dehydrative Alkoxylation of Allylic Alcohols Catalyzed by a Gold(I) N‐Heterocyclic Carbene Complex

A 1:1 mixture of [AuCl(IPr)] (IPr=1,3‐bis(2,6‐diisopropylphenyl)imidazol‐2‐ylidine) and AgClO₄ catalyzes the intermolecular dehydrative alkoxylation of primary and secondary allylic alcohols with aliphatic primary and secondary alcohols to form allylic ethers. These transformations are regio‐ and stereospecific with preferential addition of the alcohol nucleophile at the γ‐position of the allylic alcohol syn to the departing hydroxyl group and with predominant formation of the E stereoisomer. The minor α regioisomer is formed predominantly through a secondary reaction manifold involving regioselective γ‐alkoxylation of the initially formed allylic ether rather than by the direct α‐alkoxylation of the allylic alcohol.     

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.     

Asymmetric Catalysis with CO2: The Direct α‐Allylation of Ketones

Quaternary stereocenters are found in numerous bioactive molecules. The Tsuji–Trost reaction has proven to be a powerful C?C bond forming process, and, at least in principle, should be well suited to access quaternary stereocenters via the α‐allylation of ketones. However, while indirect approaches are known, the direct, catalytic asymmetric α‐allylation of branched ketones has been elusive until today. By combining “enol catalysis” with the use of CO₂ as a formal catalyst for asymmetric catalysis, we have now developed a solution to this problem: we report a direct, highly enantioselective and highly atom‐economic Tsuji–Trost allylation of branched ketones with allylic alcohol. Our reaction delivers products bearing quaternary stereocenters with high enantioselectivity and water as the sole by‐product. We expect our methodology to be of utility in asymmetric catalysis and inspire the design of other highly atom‐economic transformations.     

Rh‐Catalyzed Reaction of Propargylic Alcohols with Aryl Boronic Acids–Switch from β‐OH Elimination to Protodemetalation

It is known that Rh‐catalyzed reaction of propargylic alcohols with aryl metallic reagents undergoes S_N2’‐type reaction affording allenes via a sequential arylmetalation and β‐OH elimination process. Here we report a Rh/Ag‐cocatalyzed reaction of propargylic alcohols with organoboronic acids affording stereo‐defined (E)‐3‐arylallylic alcohols via arylmetalation and protodemetalation with a high regio‐ and stereoselectivity under very mild conditions. The reaction exhibits a good substrate scope and the compatibility with synthetically useful functional groups with no racemization for optically active propargylic alcohols. Such a reaction may also be extended to homopropargylic alcohols with a remarkable regioselectivity and exclusive E‐stereoselectivity.     

Sulfilimines as Versatile Nitrene Transfer Reagents: Facile Access to Diverse Aza‐Heterocycles

We herein report the unprecedented synthesis of diverse biologically important aza‐heterocycles by employing sulfilimines as nitrene transfer reagents. This class of sulfur‐based aza‐ylides had not been successfully used for gold nitrene transfer before. This work contains an efficient generation of α‐imino gold carbenes by N?S cleavage of sulfilimines. These gold carbenes undergo C?H insertion, cyclopropanation, and nucleophilic attack to form indoles (44 examples), 3‐azabicyclo[3.1.0]hexan‐2‐imines (24 examples), and imidazoles (3 examples). Our study represents a unique gold‐catalyzed reaction between alkynes and sulfur ylides, and also includes the first aza‐heterocycle synthesis that proceeds by intermolecular nitrene transfer followed by cyclopropanation of the α‐imino gold carbenes. Moreover, an unexpected synthesis of 4‐acylquinolines (3 examples) from 2‐acylphenyl sulfilimines and propargylic silyl ether derivatives by a 1,2‐hydride shift onto the α‐imino gold carbene and a subsequent Mukaiyama aldol cyclization was discovered.     

One‐Pot Sequential Propargylation/Cycloisomerization: A Facile [4+2]‐Benzannulation Approach to Carbazoles

A novel one‐pot [4+2]‐benzannulation approach to substituted carbazoles is accomplished by acid‐catalyzed C3‐propargylation of 2‐alkenyl/aryl indoles with 1‐aryl propargylic alcohols, followed by cycloisomerization. A variety of 2‐alkenylated indoles and 2‐aryl/heteroaryl indoles successfully participated in this tandem reaction with 1‐aryl/heteroaryl propargylic alcohols to provide diversely substituted and annulated carbazoles, as well as an aza[5]helicene.     

CuCl‐Catalyzed Aerobic Oxidation of Allylic and Propargylic Alcohols to Aldehydes or Ketones with 1:1 Combination of Phenanthroline and Bipyridine as the Ligands

We developed a modified protocol for the oxidation of 2,3‐allenyl alcohols using CuCl with 1:1 combination of phenanthroline and bipyridine as the catalyst. To further investigate the applicability of this system, other types of alcohols such as allylic and propargylic alcohols have been tested: we found that both allylic and propargylic alcohols may be oxidized to the corresponding aldehydes or ketones using molecular oxygen in air as the oxidant with moderate to excellent yields.     

Highly Diastereoselective Synthesis of α‐Difluoromethyl Amines from N‐tert‐Butylsulfinyl Ketimines and Difluoromethyl Phenyl Sulfone

The first highly efficient and stereoselective difluoromethylation of structurally diverse N‐tert‐butylsulfinyl ketimines has been achieved with an in situ generated PhSO₂CF₂^? anion, which provides a powerful synthetic method for the preparation of a variety of structurally diverse homochiral α‐difluoromethyl tertiary carbinamines, including α‐difluoromethyl allylic amines and α‐difluoromethyl propargylamines. The stereocontrol mode of the present diastereoselective difluoromethylation of ketimines was found to be different from that of other known fluoroalkylations of N‐tert‐butylsulfinyl aldimines, which suggests that a cyclic six‐membered transition state may be involved in the reaction.