Catalytic Access to Functionalized Allylic gem‐Difluorides via Fluorinative Meyer–Schuster‐Like Rearrangement

An unprecedented approach for efficient synthesis of functionalized allylic gem‐difluorides via catalytic fluorinative Meyer–Schuster‐like rearrangement is disclosed. This transformation proceeded with readily accessible propargylic fluorides, and low‐cost B–F reagents and electrophilic reagents by sulfide catalysis. A series of iodinated, brominated, and trifluoromethylthiolated allylic gem‐difluorides that were difficult to access by other methods were facilely produced with a wide range of functional groups. Importantly, the obtained iodinated products could be incorporated into different drugs and natural products, and could be expediently converted into many other valuable gem‐difluoroalkyl molecules as well. Mechanistic studies revealed that this reaction went through a regioselective fluorination of alkynes followed by a formal 1,3‐fluorine migration under the assistance of the B–F reagents to give the desired products.     

Enantioselective Synthesis of Tertiary Allylic Fluorides by Iridium‐Catalyzed Allylic Fluoroalkylation

Few allylic electrophiles containing two different substituents at a single allyl terminus and none in which one of the two substituents is a heteroatom, have been shown previously to react with iridium catalysts to form substitution products. We report that iridium‐catalysts are uniquely suited to form tertiary allylic fluorides enantioselectively by the addition of a diverse range of carbon‐centered nucleophiles at the fluorine‐containing terminus of 3‐fluoro‐substituted allylic esters. The products contain tertiary stereogenic centers bearing a single fluorine, which are isosteric with common tertiary stereocenters containing a single hydrogen. Computational studies reveal the principal steric interactions influencing the stability of endo and exo π‐allyl intermediates formed from 3,3‐disubstituted allylic electrophiles.     

Enantioselective Synthesis of Vicinal All‐Carbon Quaternary Centers via Iridium‐Catalyzed Allylic Alkylation

The development of the first enantioselective transition‐metal‐catalyzed allylic alkylation providing access to acyclic products bearing vicinal all‐carbon quaternary centers is disclosed. The iridium‐catalyzed allylic alkylation reaction proceeds with excellent yields and selectivities for a range of malononitrile‐derived nucleophiles and trisubstituted allylic electrophiles. The utility of these sterically congested products is explored through a series of diverse chemo‐ and diastereoselective product transformations to afford a number of highly valuable, densely functionalized building blocks, including those containing vicinal all‐carbon quaternary stereocenters.     

Ligand‐Controlled Copper‐Catalyzed Highly Regioselective Difluoromethylation of Allylic Chlorides/Bromides and Propargyl Bromides

Highly regiodivergent copper‐catalyzed allylic/propargylic difluoromethylation reactions by employing different ligands are described. When 5,6‐dimethyl‐1,10‐phenanthroline was used as the ligand, exclusively α‐difluoromethylated products were obtained, while γ‐selective difluoromethylated products were generated when N‐heterocyclic carbene‐SIPr was used as the ligand. Likewise, high α‐ vs. γ‐selectivities were achieved in the presence of similar copper catalysts for the reactions of propargyl bromides. Moreover, a copper‐catalyzed asymmetric allylic difluoromethylation reaction with moderate to good enantioselectivity by the use of chiral ligands was developed.     

Iridium‐Catalyzed Enantioselective Allylic Substitution of Unstabilized Enolates Derived from α,β‐Unsaturated Ketones

We report Ir‐catalyzed, enantioselective allylic substitution reactions of unstabilized silyl enolates derived from α,β‐unsaturated ketones. Asymmetric allylic substitution of a variety of allylic carbonates with silyl enolates gave allylated products in 62–94 % yield with 90–98 % ee and >20:1 branched‐to‐linear selectivity. The synthetic utility of this method was illustrated by the short synthesis of an anticancer agent, TEI‐9826.     

Allylic Functionalization of Unactivated Olefins with Grignard Reagents

New advances in the functionalization of unactivated olefins with carbon nucleophiles have provided more efficient and practical approaches to convert inexpensive starting materials into valuable products. Recent examples have been reported with stabilized carbon nucleophiles, tethered carbon nucleophiles, diazoesters, and trifluoromethane donors. A general method for functionalizing olefins with aromatic, aliphatic, and vinyl Grignard reagents was developed. In a one‐pot process, olefins are oxidized by a commercially available reagent to allylic electrophiles, which undergo selective copper‐catalyzed allylic alkylation with Grignard reagents. Products are formed in high yield and with high regioselectivity. This was utilized to synthesize a series of skipped dienes, a class of compounds that are prevalent in natural products and are difficult to synthesize by known allylic alkylation methods.     

Regioselective Transition‐Metal‐Free Allyl–Allyl Cross‐Couplings

Readily prepared allylic zinc halides undergo S_N2‐type substitutions with allylic bromides in a 1:1 mixture of THF and DMPU providing 1,5‐dienes regioselectively. The allylic zinc species reacts at the most branched end (γ‐position) of the allylic system furnishing exclusively γ,α′‐allyl–allyl cross‐coupling products. Remarkably, the double bond stereochemistry of the allylic halide is maintained during the cross‐coupling process. Also several functional groups (ester, nitrile) are tolerated. This cross‐coupling of allylic zinc reagents can be extended to propargylic and benzylic halides. DFT calculations show the importance of lithium chloride in this substitution.     

Enantioselective Synthesis of Acyclic α‐Quaternary Carboxylic Acid Derivatives through Iridium‐Catalyzed Allylic Alkylation

The first highly enantioselective iridium‐catalyzed allylic alkylation that provides access to products bearing an allylic all‐carbon quaternary stereogenic center has been developed. The reaction utilizes a masked acyl cyanide (MAC) reagent, which enables the one‐pot preparation of α‐quaternary carboxylic acids, esters, and amides with a high degree of enantioselectivity. The utility of these products is further explored through a series of diverse product transformations.     

Asymmetric Allylic Alkylation of β‐Ketoesters with Allylic Alcohols by a Nickel/Diphosphine Catalyst

Asymmetric allylic alkylation of β‐ketoesters with allylic alcohols catalyzed by [Ni(cod)₂]/(S)‐H₈‐BINAP was found to be a superior synthetic protocol for constructing quaternary chiral centers at the α‐position of β‐ketoesters. The reaction proceeded in high yield and with high enantioselectivity using various β‐ketoesters and allylic alcohols, without any additional activators. The versatility of this methodology for accessing useful and enantioenriched products was demonstrated.     

Rh‐Catalyzed Aldehyde?Aldehyde Cross‐Aldol Reaction under Base‐Free Conditions: In Situ Aldehyde‐Derived Enolate Formation through Orthogonal Activation

The chemoselective generation of aldehyde‐derived enolates to realize an aldehyde? aldehyde cross‐aldol reaction is described. A combined Rh/dippf system efficiently promoted the isomerization/aldol sequence by using primary allylic, homoallylic, and bishomoallylic alcohols; secondary allylic and homoallylic alcohols; and trialkoxyboranes that were derived from primary allylic and homoallylic alcohols. The reaction proceeded at ambient temperature under base‐free conditions, thus giving cross‐aldol products with high chemoselectivity. Mechanistic studies, as well as its application to double‐aldol processes under protecting‐group‐free conditions, are also described.     

Tandem Thorpe Reaction/Palladium Catalyzed Asymmetric Allylic Alkylation: Access to Chiral β‐enaminonitriles with Excellent Enantioselectivity

A new type of nucleophile, a 3‐imino nitrile carbanion generated in situ by Thorpe reaction of acetonitrile with a base, was developed successfully and applied in a Pd‐catalyzed asymmetric allylic alkylation with mono‐substituted allyl reagents under Pd/SIOCPhox catalysis, affording β‐enaminonitrile products in high yields with excellent regio‐ and enantioselectivities.     

Applications of Transition‐Metal‐Catalyzed Asymmetric Allylic Substitution in Total Synthesis of Natural Products: An Update

Metal‐catalyzed asymmetric allylic substitution (AAS) reaction is one of the most synthetically useful reactions catalyzed by metal complexes for the formation of carbon‐carbon and carbon‐heteroatom bonds. It comprises the substitution of allylic substrates with a wide range of nucleophiles or S_N2′‐type allylic substitution, which results in the formation of the above‐mentioned bonds with high levels of enantioselective induction. AAS reaction tolerates a broad range of functional groups, thus has been successfully applied in the asymmetric synthesis of a wide range of optically pure compounds. This reaction has been extensively used in the total synthesis of several complex molecules, especially natural products. In this review, we try to highlight the applications of metal (Pd, Ir, Mo, or Cu)‐catalyzed AAS reaction in the total synthesis of the biologically active natural products, as a key step, updating the subject from 2003 till date.     

Pd‐Catalyzed Allylic Substitution with Enantiomerically Pure Catalysts and Chiral Non‐Racemic Substrates: A New Approach to Catalyst‐Based Regiocontrol,Preliminary Communication

Chiral, enantiomerically pure Pd‐catalysts were used to control the regioselectivity of nucleophilic attack in allylic substitutions with optically active 1,3‐disubstituted allyl acetates (Schemes 4 – 6). In contrast to reactions with achiral catalysts, where the regioselectivity is determined by the steric and electronic effects of the allylic substituents, chiral catalysts allow selective preparation of either one of the two regioisomeric products, depending on which enantiomer of the catalyst is employed. It is not necessary to start from an enantiomerically pure substrate, because the major and minor enantiomers are converted to different regioisomers (not to enantiomeric products; see Scheme 3), resulting in products of very high ee, even when the starting material is only of moderate enantiomer purity.     

Access to 1,3‐Dinitriles by Enantioselective Auto‐tandem Catalysis: Merging Allylic Cyanation with Asymmetric Hydrocyanation

Enantioselective auto‐tandem catalysis represents a challenging yet highlight attractive topic in the field of asymmetric catalysis. In this context, we describe a dual catalytic cycle that merges allylic cyanation and asymmetric hydrocyanation. The one‐pot conversion of a broad array of allylic alcohols into their corresponding 1,3‐dinitriles proceeds in good yield with high enantioselectivity. The products are densely functionalized and can be easily transformed to chiral diamines, dinitriles, diesters, and piperidines. Mechanistic studies clearly support a novel sequential cyanation/hydrocyanation pathway.     

Iridium‐Catalyzed Stereoselective Allylic Alkylation Reactions with Crotyl Chloride

The development of the first enantio‐, diastereo‐, and regioselective iridium‐catalyzed allylic alkylation reaction of prochiral enolates to form an all‐carbon quaternary stereogenic center with an aliphatic‐substituted allylic electrophile is disclosed. The reaction proceeds with good to excellent selectivity with a range of substituted tetralone‐derived nucleophiles furnishing products bearing a newly formed vicinal tertiary and all‐carbon quaternary stereodyad. The utility of this protocol is further demonstrated via a number of synthetically diverse product transformations.     

Isoxazole‐Embedded Allylic Zinc Reagent for the Diastereoselective Preparation of Highly Functionalized Aldol‐Type Derivatives Bearing a Stereocontrolled Quaternary Center

Highly functionalized aldol‐type products bearing a β‐quaternary center and a stereoselectively controlled γ‐hydroxy function are readily prepared by the diastereoselective addition of an allylic zinc reagent embedded in an isoxazole ring to various aromatic and heteroaromatic aldehydes, in the presence of Lewis acids, such as MgCl₂ or LaCl₃?2 LiCl. After reductive cleavage of the N?O bond by using Fe, NH₄Cl, aldol‐type products bearing a stereocontrolled β‐quaternary center and a γ‐hydroxy group were observed. The benzylic reactivity of the isoxazolylmethylzinc reagent towards other electrophiles, such as acid chlorides, aryl and allylic halides, as well as aldehydes in the presence of BF₃?OEt₂ are also described.     

Palladium‐Catalyzed Asymmetric Allylic Alkylations with Toluene Derivatives as Pronucleophiles

The first two highly enantioselective palladium‐catalyzed allylic alkylations with benzylic nucleophiles, activated with Cr(CO)₃, have been developed. These methods enable the enantioselective synthesis of α‐2‐propenyl benzyl motifs, which are important scaffolds in natural products and pharmaceuticals. A variety of cyclic and acyclic allylic carbonates are competent electrophilic partners furnishing the products in excellent enantioselectivity (up to 99 % ee and 92 % yield). This approach was employed to prepare a nonsteroidal anti‐inflammatory drug analogue.     

Adaptive Organic Nanoparticles of a Teflon‐Coated Iron (III) Porphyrin Catalytically Activate Dioxygen for Cyclohexene Oxidation

Self‐organized organic nanoparticles (ONP) are adaptive to the environmental reaction conditions. ONP of fluorous alkyl iron(III) porphyrin catalytically oxidize cyclohexene to the allylic oxidation products. In contrast, the solvated metalloporphyrin yields both allylic oxidation and epoxidation products. The ONP system facilitates a greener reaction because about 89% reaction medium is water, molecular oxygen is used in place of synthetic oxidants, and the ambient reaction conditions used require less energy. The enhanced catalytic activity of these ONP is unexpected because the metalloporphyrins in the nanoaggregates are in the close proximity and the TON should diminish by self‐oxidative degradation. The fluorous alkyl chain stabilizes the ONP toward self‐oxidative degradation.     

Sequential catalytic isomerization and allylic substitution. Conversion of racemic branched allylic carbonates to enantioenriched allylic substitution products

A catalytic protocol for the conversion of readily accessible racemic, branched aromatic allylic esters to branched allylic amines, ethers, and alkyls has been developed. Palladium-catalyzed isomerization of branched allylic esters to terminal allylic esters, followed by sequential iridium-catalyzed allylic substitution, gave the branched allylic products in good yield with high regioisomeric and enantiomeric selectivity. Both electron-rich and electron-poor branched allylic esters gave products in >90% ee. High enantiomeric excesses were also observed for the products from the reactions of 2-thienyl acetates and dienyl carbonates.     

Phosphine-Catalyzed Annulations between Modified Allylic Derivatives and Polar Dienes and Substituent Effect on the Annulation Mode

in this work, the phosphine-catalyzed annulation reactions between modified allylic derivatives and polar 1,1-dicyano-1,3-dienes have been studied. In the catalysis of PPh3 （20 mol%）, a [4 ＋ 1 ] annulation reaction is realized between a series of l,l-dicyano-2,4-diaryl-1,3-dienes and ethoxycarbonyl-activated allylic acetate, producing polysubstituted cyclopentenes in modest to excellent yields. It is also observed that the substituents of both 1,3-dienes and allylic derivatives have a significant influence on the annulation mode： under the catalysis of PPh3 or PBu3 （20 mol%）, regioselective [3 ＋ 2] annulation products are formed from differently substituted substratcs.