Metal-catalyzed Allylic Substitution Research Articles

Construction of Vicinal Quaternary Centers via Ru-Catalyzed Enantiospecific Allylic Substitution with Lithium Ester Enolates.

The installation of vicinal quaternary centers with absolute stereocontrol constitutes a considerable challenge in organic synthesis. Herein, we introduce a novel [Cp*Ru(MeCN)3]PF6/phenoxythiazoline catalyst system that achieves enantiospecific allylic substitution of tertiary carbonates with α,α-disubstituted lithium ester enolates to give products containing vicinal quaternary centers. Noteworthy features include the direct use of nonstabilized ester enolates, a class of nucleophiles which has rarely been used in transition metal-catalyzed allylic substitution reactions. The approach is demonstrated for a broad scope of tertiary electrophiles as well as ester enolates and accomplishes stereoretentive substitution with excellent conservation of ee (89-99%) and branched/linear regioselectivities (up to 40:1).

Pathway Bifurcations in the Activation of Allylic Halides by Palladium and Their Influence on the Dynamics of η1 and η3 Allyl Intermediates.

Transition-metal-catalyzed allylic substitution often exhibits complex product selectivity patterns, which have been primarily attributed to π ↔ σ ↔ π isomerization of the η1 and η3 allyl intermediates. Product selectivity may be even further complicated if η1- and η3-allyls share a single transition state (TS), leading to their formation resulting in a post-transition-state bifurcation (PTSB). In this work, density functional theory calculations using ab initio molecular dynamics (AIMD) have been carried out that support the presence of a PTSB in Pd-catalyzed allylic halide activation directly influencing product selectivity. The AIMD results initiated from the TS predict the η1-allyl to be favored in the gas phase and a low dielectric (ε < 2.5) for trialkylphosphines, while the selectivity shifts toward the η3-allyl in higher dielectrics. The minimum energy path is also predicted to shift in product preference, consistent with the dynamics predictions. The bifurcation in allylic chloride activation is predicted to largely favor the η3-allyl at any solvent polarity. A PTSB was also discovered to be present in Ni and Pt allylic activation but with less bifurcation. These results offer a unique view into the mechanism of metal-catalyzed allylic substitution.

Dynamic Kinetic Resolution of Alkenyl Cyanohydrins Derived from α,β-Unsaturated Aldehydes: Stereoselective Synthesis of E-Tetrasubstituted Olefins

A novel dynamic kinetic resolution (DKR) of tetrasubstituted alkenyl cyanohydrins prepared from the corresponding α,β-unsaturated aldehydes is described. The deprotonation of a geometrical mixture of tetrasubstituted alkenyl cyanohydrins with sodium diisopropylamide (NaDA) affords the allylic anions, which enables the equilibration of the E- and Z-olefins to permit the selective functionalization of the E-adduct. Theoretical studies indicate that the nature of the alkali metal cation is a critical component to lowering the barrier for interconversion between the two geometrical isomers, which provides the mechanistic basis for the DKR reaction. In addition, we demonstrate that the DKR reaction can be combined with a transition metal-catalyzed allylic substitution to generate a stereodefined E-tetrasubstituted olefin and quaternary center in a single cross-coupling reaction.

Asymmetric Rhodium-Catalyzed Allylic Substitution Reactions: Discovery, Development and Applications to Target-Directed Synthesis.

The transition metal-catalyzed allylic substitution reaction is a particularly versatile method for the construction of carbon-carbon and carbon-heteroatom bonds. In this regard, the rhodium-catalyzed variant has emerged as a powerful method for the regioselective and stereospecific allylic substitution of chiral nonracemic secondary and tertiary allylic carbonates with a variety of carbon- and heteroatom-based nucleophiles. In addition, recent developments have made the analogous enantioselective process possible using prochiral nucleophiles with achiral allylic electrophiles, which represents a significant advance in this area. In this Perspective, the discovery, development and applications of these conceptually orthogonal strategies to target-directed synthesis are discussed, with a particular emphasis given to those methods developed in our laboratory.

Copper(I)-Catalyzed Allylic Substitutions with a Hydride Nucleophile.

An easily accessible copper(I)/N-heterocyclic carbene (NHC) complex enables a regioselective hydride transfer to allylic bromides, an allylic reduction. The resulting aryl- and alkyl-substituted branched α-olefins, which are valuable building blocks for synthesis, are obtained in good yields and regioselectivity. A commercially available silane, (TMSO)2Si(Me)H, is employed as hydride source. This protocol offers a unified alternative to the established metal-catalyzed allylic substitutions with carbon nucleophiles, as no adaption of the catalyst to the nature of the nucleophile is required.

Transition metal-catalyzed allylic substitution reactions with unactivated allylic substrates.

The transition metal-catalyzed allylic substitution of unactivated allylic substrates (allylic alcohols, allylic ethers and allylic amines) is rapidly becoming an important area of research. There are several advantages to using these substrates in allylic substitution reactions: the use of unactivated alcohols minimizes the production of waste by-products and reaction steps; and allylic ethers and allylic amines are useful substrates because of their stability and their presence in numerous biologically active compounds. Research in this field has therefore gained widespread attention for promoting the development of efficient and environmentally benign procedures for the formation of C-C, C-N and C-O bonds.

ChemInform Abstract: Palladium‐Catalyzed Oxidative Heck‐Type Allylation of β,β‐Disubstituted Enones with Allyl Carbonates.

The palladium-catalyzed oxidative heck-type allylation of beta,beta-disubstitutedenones, i.e., alpha-oxoketene dithioacetals, was efficiently realized with allyl carbonates, providing a concise route to highly functionalized dienes. the present synthetic methodology utilizes the substrate activation strategy to activate the c-h bond of beta,beta-disubstituted enones by introduction of a 1,2-dithiolane functionality to make the enone substrate highly polarized and thus increase its reactivity, demonstrating rare examples for transition metal-catalyzed allylic substitution of beta,beta-disubstituted enones through a heck-type allylation process.

ChemInform Abstract: Carbon—Sulfur Bond Formation via Metal‐Catalyzed Allylations of Sulfur Nucleophiles

AbstractReview: 136 refs.

Application of pyranoside phosphite-pyridine ligands to enantioselective metal-catalyzed allylic substitutions and conjugate 1,4-additions

A series of glucopyranoside phosphite–pyridine ligands have been applied in the metal-catalyzed allylic substitution and conjugate 1,4-addition reactions of several substrate types. We have been able to identify ligands that provided promising enantioselectivities in the Pd-catalyzed intermolecular allylic substitution of cyclic substrates (ee’s up to 86%) and desymmetrization (ee’s up to 94%) and in the Cu-catalyzed conjugate addition of challenging aliphatic enones (ee’s up to 90%).

Carbon-Sulfur Bond Formation via Metal-Catalyzed Allylations of Sulfur Nucleophiles

The development of practical approaches for the construction of carbon–sulfur bonds is of interest to scientists. In particular, carbon–sulfur bond formation by transition-metal-catalyzed allylations has been attracting great attention. Allylic sulfides are important substances owing to their broad applications in synthetic and pharmaceutical areas. The alkene and sulfur moieties in allylic sulfides can lead to numerous transformations. This review details the development of carbon–sulfur bond formation through palladium-catalyzed rearrangements, palladium-catalyzed allylations, ­iridium-catalyzed regio- and enantioselective allylations and miscellaneous metal-catalyzed allylic substitutions. Carbon–selenium bond formations via metal-catalyzed allylic substitutions are also reviewed. 1 Introduction 2 Carbon–Sulfur Bond Formation via Palladium-Catalyzed Reactions 2.1 Rearrangements of Allylic Substrates 2.2 Allylations 2.3 Asymmetric Allylations 3 Carbon–Sulfur Bond Formation via Iridium-Catalyzed Regio­- and Enantioselective Allylations 4 Carbon–Sulfur Bond Formation via Miscellaneous Metal-Catalyzed Reactions 4.1 Nickel 4.2 Ruthenium 4.3 Gallium 4.4 Iron 5 Carbon–Selenium Bond Formation via Metal-Catalyzed Allylic­ Substitutions 6 Conclusions

Tandem Catalytic Allylic Amination and [2,3]-Stevens Rearrangement of Tertiary Amines

We have developed a catalytic allylic amination involving tertiary aminoesters and allylcarbonates, which is the first example of the use of tertiary amines as intermolecular nucleophiles in metal-catalyzed allylic substitution chemistry. This process is employed in a tandem ammonium ylide generation/[2,3]-rearrangement reaction, which formally represents a palladium-catalyzed Stevens rearrangement. Low catalyst loadings and mild reaction conditions are compatible with an unprecedented substrate scope for the ammonium ylide functionality, and products are generated in high yields and diastereoselectivities. Mechanistic studies suggested the reversible formation of an ammonium intermediate.

Palladium- or Iridium-Catalyzed Allylic Substitution of Guanidines: Convenient and Direct Modification of Guanidines

As a convenient and direct functionalization of guanidines, the transition metal-catalyzed allylic substitution of guanidines was studied. The guanidine derivatives bearing two electron-withdrawing substituents acted as reactive nucleophiles in the allylic substitution to give the monoallylated products. The double allylic substitution was achieved by using tri-Boc-guanidine bearing three electron-withdrawing substituents as a nucleophile to give the diallylated products. The regiocontrol in the allylic substitution of unsymmetrical allylic substrates has been investigated by employing the palladium or iridium catalysts. The iridium complex of chiral pybox ligand allowed the regio- and enantioselective allylic substitution. Asymmetric double allylic substitution of tri-Boc-guanidine with phosphate bearing the 1-naphthyl group gave the diallylated product with high diastereo-, regio-, and enantioselectivities.

Regio‐ and Stereocontrolled Palladium‐ or Iridium‐Catalyzed Allylation

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of E-vinylogous ( R)-amino acid derivatives via metal-catalyzed allylic substitutions on enzyme-derived substrates

Oxynitrilase-derived allylic ( R)-cyanohydrin carbonates 3 and allylic ( R)-α-hydroxy ester carbonates 6 were examined as substrates for a palladium(0)-catalyzed allylic azidation reaction. The enantioselectivities and cis/trans diastereoselectivities of the concomitant 1,3-chirality transposition step were studied. The cyano carbonates 3a– c were found to be unimpressive substrates producing γ-azido-α,β-unsaturated nitriles 4a– c with cis/trans ratios that approached unity and gave enantiomeric excesses that ranged from 57% to 85%. In contrast, ester carbonates 6a and b were excellent substrates for the reaction exclusively affording trans substitution products 7a and b in identical enantiomeric excesses of 95% ee.

Regio- and Stereocontrolled Palladium- or Iridium-Catalyzed Allylation

We studied palladium- or iridium-catalyzed allylation as an effective method for the asymmetric synthesis of α-amino acids, hydroxylamines, oximes, and amines. The stereochemistry of the palladium-catalyzed allylic alkylation of a prochiral diphenylimino glycinate was controlled by chiral PTC, and gave chiral amino acids. In contrast, iridium-catalyzed allylic substitution of diphenylimino glycinate proceeded with good enantio- and diastereoselectivities with a new bidentate chiral ligand to give a novel method for preparing two branched diastereoisomers by simply switching the base. For the synthesis of α,α-disubstituted amino acids, the palladium-catalyzed tandem reaction of dehydroamino acids was developed based on radical chemistry. Next, the viability of oximes and hydroxylamines as oxygen atom nucleophiles in transition metal-catalyzed allylic substitutions was examined. Regioand enantioselective allylic substitution of oximes and hydroxylamines was achieved by using the iridium complex of chiral pybox ligand. Sequential allylic amination gave a novel method for preparing azacycles. Finally, umpolung allylation with aldehyde or imine was studied by using palladium catalyst and indium iodide. The palladium-indium iodide-mediated reaction of chiral 2-vinylaziridines with aldehydride proceeded with excellent diastereoselectivity. The role of water in directing the diastereo- or regioselectivities was investigated in the allylation and propargylation of chiral oxime ether. The allylation of oxime ether with monosubstituted allylic reagents afforded either γ-adduct or α-adduct depending on the reaction conditions.

The fluorine-containing pi-allylmetal complex. The transition metal-catalyzed allylic substitution reaction of fluorinated allyl mesylates with various carbon nucleophiles.

The allylic substitution reaction of [small alpha]-fluoroalkylated allyl mesylates with various carbon nucleophiles in the presence of transition metal catalyst (Pd and Mo) proceeded with high regioselectivity to give the corresponding [gamma]-fluoroalkylated products in excellent yields.

Regio‐ and Enantiospecific Rhodium‐Catalyzed Arylation of Unsymmetrical Fluorinated Acyclic Allylic Carbonates: Inversion of Absolute Configuration.

The transition metal-catalyzed allylic substitution with unstabilized carbon nucleophiles represents an important cross-coupling reaction for the construction of ternary carbon stereogenic centers. We have developed a new regio- and enantiospecific rhodium-catalyzed allylic alkylation of acyclic unsymmetrical chiral nonracemic allylic alcohol derivatives with aryl zinc bromides. This study demonstrates that the hydrotris(pyrazolyl)borate rhodium catalyst and zinc(II) halide salt are crucial for efficiency, while the addition of lithium bromide to the catalyst is necessary for obtaining optimal regiospecificity. The stereochemical course of this reaction was established through the synthesis of (S)-ibuprofen, which demonstrated that the alkylation proceeds with net inversion of absolute configuration consistent with direct addition of the nucleophile to the metal center followed by reductive elimination.

Regio- and enantiospecific rhodium-catalyzed arylation of unsymmetrical fluorinated acyclic allylic carbonates: inversion of absolute configuration.

The transition metal-catalyzed allylic substitution with unstabilized carbon nucleophiles represents an important cross-coupling reaction for the construction of ternary carbon stereogenic centers. We have developed a new regio- and enantiospecific rhodium-catalyzed allylic alkylation of acyclic unsymmetrical chiral nonracemic allylic alcohol derivatives with aryl zinc bromides. This study demonstrates that the hydrotris(pyrazolyl)borate rhodium catalyst and zinc(II) halide salt are crucial for efficiency, while the addition of lithium bromide to the catalyst is necessary for obtaining optimal regiospecificity. The stereochemical course of this reaction was established through the synthesis of (S)-ibuprofen, which demonstrated that the alkylation proceeds with net inversion of absolute configuration consistent with direct addition of the nucleophile to the metal center followed by reductive elimination.

Effect of Adjacent Chiral Tertiary and Quaternary Centers on the Metal‐Catalyzed Allylic Substitution Reaction.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Effect of adjacent chiral tertiary and quaternary centers on the metal-catalyzed allylic substitution reaction.

The metal-catalyzed allylic substitution reaction of 5a,b and 6a was examined. Reaction with stabilized nucleophiles led to exclusive attack at the less-hindered allylic terminus, and the stereoselectivity varied with the bidentate ligand used but favored retention. The yields and reaction times were improved with the use of microwaves. Alkylation via transmetalation was only observed with phenyl- and vinylstannatranes and gave regio- and stereoselectivity opposite those observed with the stabilized anions. The epimeric carbonates 5a and 5b displayed very different reactivities. Catalysts containing metals other than palladium were completely unreactive and led to recovered starting material.