Allylic Electrophiles Research Articles

Direct Catalytic Enantioselective Benzylation from Aryl Acetic Acids.

We demonstrate that metal-catalyzed enantioselective benzylation reactions of allylic electrophiles can occur directly from aryl acetic acids. The reaction proceeds via a pathway in which decarboxylation is the terminal event, occurring after stereoselective carbon-carbon bond formation. This mechanistic feature enables enantioselective benzylation without the generation of a highly basic nucleophile. Thus, the process has broad functional group compatibility that would not be possible employing established protocols.

Umpolung of Carbonyl Groups as Alkyl Organometallic Reagent Surrogates for Palladium‐Catalyzed Allylic Alkylation

AbstractPalladium‐catalyzed allylic alkylation of nonstabilized carbon nucleophiles is difficult and remains a major challenge. Reported here is a highly chemo‐ and regioselective direct palladium‐catalyzed C‐allylation of hydrazones, generated from carbonyls, as a source of umpolung unstabilized alkyl carbanions and surrogates of alkyl organometallic reagents. Contrary to classical allylation techniques, this umpolung reaction utilizes hydrazones prepared not only from aryl aldehydes but also from alkyl aldehydes and ketones as renewable feedstocks. This strategy complements the palladium‐catalyzed coupling of unstabilized nucleophiles with allylic electrophiles by providing an efficient and selective catalytic alternative to the traditional use of highly reactive alkyl organometallic reagents.

Umpolung of Carbonyl Groups as Alkyl Organometallic Reagent Surrogates for Palladium-Catalyzed Allylic Alkylation.

Palladium-catalyzed allylic alkylation of nonstabilized carbon nucleophiles is difficult and remains a major challenge. Reported here is a highly chemo- and regioselective direct palladium-catalyzed C-allylation of hydrazones, generated from carbonyls, as a source of umpolung unstabilized alkyl carbanions and surrogates of alkyl organometallic reagents. Contrary to classical allylation techniques, this umpolung reaction utilizes hydrazones prepared not only from aryl aldehydes but also from alkyl aldehydes and ketones as renewable feedstocks. This strategy complements the palladium-catalyzed coupling of unstabilized nucleophiles with allylic electrophiles by providing an efficient and selective catalytic alternative to the traditional use of highly reactive alkyl organometallic reagents.

Silicon Grignard Reagents as Nucleophiles in Transition-Metal-Catalyzed Allylic Substitution

A broad range of transition-metal catalysts is shown to promote allylic substitution reactions of allylic electrophiles with silicon Grignard reagents. The procedure was further elaborated for CuI as catalyst. The regioselectively is independent of the leaving group for primary allylic precursors, favoring α over γ. The stereochemical course of this allylic transposition was probed with a cyclic system, and anti-dia­stereoselectivity was obtained.

Stereoselective Allylic Alkylation of 1-Pyrroline-5-carboxylic Esters via a Pd/Cu Dual Catalysis.

The asymmetric allylation of 1-pyrroline-5-carboxylic esters has been accomplished through a synergistic Pd/Cu catalyst system under mild reaction conditions. The mechanistic studies suggested that (1) nucleophilic attack is the enantiodiscriminating step; (2) the cooperative action of two chiral reactive species, N-metalated azomethine ylides and π-allylpalladium, is most likely responsible for its high reactivity and excellent enantioselectivity (up to >99% ee); and (3) the steric hindrance and electronic factors of the allylic electrophiles and imino ester substrates are crucial for the formation of the linear products. A series of 3,4-2 H-pyrrole derivatives bearing a quaternary stereogenic center were easily synthesized in high yields and with high to excellent regioselectivity and enantioselectivity.

Asymmetric Cα-Alkylation of Proline via Chirality Transfers of Conformationally Restricted Proline Derivative: Application to the Total Synthesis of (-)-Amathaspiramide F.

An efficient strategy for the asymmetric synthesis of Cα-tetrasubstituted proline derivatives from proline has been established. A nitrogen-fused bicyclic system was devised to control the stereodynamics of proline. Through N-quaternizations with allylic electrophiles followed by [2,3]-rearrangements, the bicyclic proline system delivered enantioenriched Cα-tetrasubstituted prolines. This strategy was applied to the concise total synthesis of (-)-amathaspiramide F.

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

AbstractFew 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 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.

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.

Pd(0)-Catalyzed Chemoselective Deacylative Alkylations (DaA) of N-Acyl 2-Oxindoles: Total Syntheses of Pyrrolidino[2,3- b]indoline Alkaloids, (±)-Deoxyeseroline, and (±)-Esermethole.

We report an efficient Pd(0)-catalyzed deacylative allylation of N-acyl 3-substituted 2-oxindoles via the coupling of in situ generated nucleophiles (3 and 4) with allyl electrophiles for the synthesis of a variety of 2-oxindoles with C3-quaternary centers. Gratifyingly, this alkylation process is found to be highly chemoselective in nature, where a C-C bond formation is completely predominant over a C-N bond formation. A variety of key intermediates were synthesized utilizing an aforementioned methodology.

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.

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

AbstractThe 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.

Traversing Steric Limitations by Cooperative Lewis Base/Palladium Catalysis: An Enantioselective Synthesis of α‐Branched Esters Using 2‐Substituted Allyl Electrophiles

AbstractCooperative catalysis enables the direct enantioselective α‐allylation of linear prochiral esters with 2‐substituted allyl electrophiles. Critical to the successful development of the method was the recognition that metal‐centered reactivity and the source of enantiocontrol are independent. This feature is unique to simultaneous catalysis events and permits logical tuning of the supporting ligands without compromising enantioselectivity.

Traversing Steric Limitations by Cooperative Lewis Base/Palladium Catalysis: An Enantioselective Synthesis of α-Branched Esters Using 2-Substituted Allyl Electrophiles.

Cooperative catalysis enables the direct enantioselective α-allylation of linear prochiral esters with 2-substituted allyl electrophiles. Critical to the successful development of the method was the recognition that metal-centered reactivity and the source of enantiocontrol are independent. This feature is unique to simultaneous catalysis events and permits logical tuning of the supporting ligands without compromising enantioselectivity.

Si-directed regiocontrol in asymmetric Pd-catalyzed allylic alkylations using C1-ammonium enolate nucleophiles

Cooperative catalysis enables the direct enantioselective α-allylation of linear prochiral esters using Si-substituted allyl electrophiles. The Si-substituent directs the regioselectivity of enantioselective bond formation and provides products containing synthetically versatile pentafluorophenyl ester and vinylsilane moieties. Critical to the efficacy of this process was the recognition that the ancillary ligand on palladium could be altered to prevent formation of a deleterious ether by-product, whilst retaining enantioselectivity through the Lewis base catalyst. Flexibility such as this is unique to cooperative catalysis events and provides efficient access to an array of enantioenriched products that are orthogonally functionalized and easily modified.

Enantiospecific Brook Rearrangement of Tertiary Benzylic α‐Hydroxysilanes

The Brook rearrangement of simple, chiral tertiary benzylic α‐hydroxysilanes is presented. The rearrangement followed by proton trapping is enantiospecific and proceeds with inversion of the configuration at the carbon center. Importantly, the [1,2]‐Brook rearrangement can be followed by trapping of methyl or allyl electrophiles even in the protic environment, although with minimal retention of chirality.

Transient [3,3] Cope rearrangement of 3,3-dicyano-1,5-dienes: computational analysis and 2-step synthesis of arylcycloheptanes.

A simple and modular route to arylcycloheptene scaffolds is reported. The two-step route from Knoevenagel adducts and allylic electrophiles is made possible through the design of a Cope rearrangement that utilizes a "traceless" activating group to promote an otherwise thermodynamically unfavorable transformation. Experimentally, the [3,3] rearrangement occurrs transiently at room temperature with a computed barrier of 19.5 kcal mol-1, which ultimately allows for three-component bis-allylation. Ring-closing metathesis delivers the arylcycloheptane and removes the activating group. This report describes the design and optimization of the methodology, scope and mechanistic studies, and computational analysis.

Iridium-catalyzed enantioselective direct vinylogous allylic alkylation of coumarins.

The first iridium-catalyzed enantioselective vinylogous allylic alkylation of coumarins is presented. Using easily accessible linear allylic carbonates as the allylic electrophile, this reaction installs unfunctionalized allyl groups at the γ-position of 4-methylcoumarins in an exclusively branched-selective manner generally in high yields with an excellent level of enantioselectivity (up to 99 : 1 er).

Diastereo- and enantioselective copper catalyzed hydroallylation of disubstituted cyclopropenes.

A highly diastereo- and enantioselective protocol for the hydroallylation of 1,1- and 1,2-disubstituted cyclopropenes has been developed utilizing an in situ formed copper hydride. A variety of allyl electrophiles could be utilized yielding a diverse range of trisubstituted cyclopropanes. Finally a preliminary enantioselective variant could be established employing a recently described P-stereogenic xantphos derivative as ligand.

Mechanistic Insights into Solvent and Ligand Dependency in Cu(I)-Catalyzed Allylic Alkylation with gem-Diborylalkanes.

The recent Cu-catalyzed allylic substitution reaction between gem-diboryalkane and allyl electrophiles shows intriguing solvent and ligand-controlled regioselectivity. The α-alkylation product was obtained in DMF solvent, while γ-alkylation product was obtained in dioxane solvent and the dioxane and NHC ligand situation. In the present study, density functional theory calculations have been used to investigate the reaction mechanism and origin of the regioselectivity. For both dioxane and DMF, γ-alkylation undergoes successive oxidative addition (CH2Bpin trans to leaving group) and direct Cγ-C reductive elimination. The α-alkylation is found to undergo oxidative addition (CH2Bpin trans to leaving group), isomerization, and Cα-C reductive elimination rather than the previously proposed oxidative addition (-CH2Bpin cis to the leaving group) and Cα-C reductive elimination. The γ-alkylation and α-alkylation is, respectively, favorable for dioxane and DMF solvent, which is consistent with the γ- and α-selectivity in experiment. The solvent interferes the isomerization step, thereby affects the relative facility of the α- and γ-alkylation. Further investigation shows that η1-intermediate formation promoted by solvent is the rate-determining step of the isomerization. The stronger electron-donating ability of DMF than dioxane facilitates the η1-intermediate formation and finally results in the easier isomerization in DMF. For dioxane and NHC situation, in the presence of neutral NHC ligand, the -PO4Et2 group tightly coordinates with the Cu center after the oxidative addition, preventing the isomerization process. The regioselectivity is determined by the relative facility of the oxidative addition step. Therefore, the favorable oxidative addition (in which -CH2Bpin trans to the leaving group) results in the facility of γ-alkylation.