Palladium-Catalyzed Branch- and Z-Selective Allylic C-H Amination with Aromatic Amines.

Allylamines are important building blocks in the synthesis of bioactive compounds. The direct coupling of allylic C-H bonds and commonly available amines is a major synthetic challenge. An allylic C-H amination of 1,4-dienes has been accomplished by palladium catalysis. With aromatic amines, branch-selective allylic aminations are favored to generate thermodynamically unstable Z-allylamines. In addition, more basic aliphatic cyclic amines can also engage in the reaction, but linear dienyl allylic amines are the major products.

Enantioconvergent Palladium-Catalyzed Alkylation of Tertiary Allylic C-H Bonds.

Enantioconvergent catalysis enables the conversion of racemic molecules into a single enantiomer in perfect yield and is considered an ideal approach for asymmetric synthesis. Despite remarkable advances in this field, enantioconvergent transformations of inert tertiary C-H bonds remain largely unexplored due to the high bond dissociation energy and the surrounding steric repulsion that pose unparalleled constraints on bond cleavage and formation. Here, we report an enantioconvergent Pd-catalyzed alkylation of racemic tertiary allylic C-H bonds of α-alkenes, providing a unique approach to access a broad range of enantioenriched γ,δ-unsaturated carbonyl compounds featuring quaternary carbon stereocenters. Mechanistic studies reveal that a stereoablative event occurs through the rate-limiting cleavage of tertiary allylic C-H bonds to generate σ-allyl-Pd species, and the achieved E/Z-selectivity of σ-allyl-Pd species effectively regulates the diastereoselectivity via a nucleophile coordination-enabled SN 2'-allylation pathway.

Palladium-Catalyzed Enantioselective C(sp3)-H/C(sp3)-H Umpolung Coupling of N-Allylimine and α-Aryl Ketones.

Asymmetric functionalization of the C(sp3)-H bond is an attractive yet challenging strategy to achieve versatile bond-forming events, enabling the precise assembly of molecular complexity with minimal manipulation of functional groups. Here, we report an asymmetric C(sp3)-H/C(sp3)-H umpolung coupling of N-allylimine and coordinating α-aryl carbonyls by using chiral phosphoramidite-palladium catalysis. A wide variety of α-heteroaryl ketones and 2-acylimidazoles are nicely tolerated to open a convenient and tunable avenue for efficient synthesis of enantioenriched ß-amino-γ,δ-unsaturated carbonyl derivatives with high levels of regio- and stereoselectivities, capable of providing a key intermediate for asymmetric synthesis of Focalin. This protocol showcases an umpolung reactivity of the N-allylimines through a concerted proton and two-electron transfer process to cleave the allylic C-H bond, effectively complementing established methodology for allylic C-H functionalization. An inner-sphere allylation pathway for both α-heteroaryl carbonyls and 2-acylimidazoles to attack the π-allylpalladium species is suggested by computational studies and experimental facts, wherein the nitrogen coordination to the palladium center enables the preference of branched regioselectivity.

Palladium-Catalyzed Asymmetric Allylic C-H Functionalization: Mechanism, Stereo- and Regioselectivities, and Synthetic Applications.

Asymmetric functionalization of inert C-H bonds is undoubtedly a synthetically significant yet challenging bond-forming process, allowing for the preparation of densely functionalized molecules from abundantly available feedstocks. In the past decade, our group and others have found that trivalent phosphorus ligands are capable of facilitating Pd-catalyzed allylic C-H functionalization of α-alkenes upon using p-quinone as an oxidant. In these reactions, a 16-electron Pd(0) complex bearing a monodentate phosphorus ligand, a p-quinone, and an α-alkene has been identified as a key intermediate. Through a concerted proton and two-electron transfer process, electrophilic π-allylpalladium is subsequently generated and can be leveraged to forge versatile chemical bonds with a wide range of nucleophiles. This Account focuses on describing the origin, evolution, and synthetic applications of Pd-catalyzed asymmetric allylic C-H functionalization reactions, with an emphasis on the fundamental mechanism of the concerted proton and two-electron transfer process in allylic C-H activation.Enabled by the cooperative catalysis of the palladium complex of triarylphosphine, a primary amine, and a chiral phosphoric acid, an enantioselective α-allylation of aldehydes with α-alkenes is established. The combination of chiral phosphoric acid and a palladium complex of a chiral phosphoramidite ligand allows the allylic C-H alkylation of α-alkenes with pyrazol-5-ones to give excellent enantioselectivities, wherein the chiral ligand and chiral phosphoric acid synergistically control the stereoselectivity. Notably, the palladium-phosphoramidite complexes are also efficient catalysts for allylic C-H alkylation, with a wide scope of nucleophiles. In the case of 1,4-dienes, the geometry and coordination pattern of the nucleophile are able to vary the transition states of bond-forming events and thereby determine the Z/E-, regio-, and stereoselectivities.These enantioselective allylic C-H functionalization reactions are tolerant of a wide range of nucleophiles and α-alkenes, providing a large library of optically active building blocks. Based on enantioselective intramolecular allylic C-H oxidation, the formal synthesis of (+)-diversonol is accomplished, and enantioselective intramolecular allylic C-H amination can enable concise access to letermovir. In particular, the asymmetric allylic C-H alkylation of 1,4-dienes with azlactones offers highly enantioenriched α,α-disubstituted α-amino acid derivatives that are capable of serving as key building blocks for the enantioselective synthesis of lepadiformine alkaloids. In addition, a tachykinin receptor antagonist and (-)-tanikolide are also synthesized with chiral molecules generated from the corresponding allylic C-H alkylation reactions.

Asymmetric Allylic C-H Alkylation of Allyl Ethers with 2-Acylimidazoles.

An asymmetric allylic C-H alkylation of allyl ethers has been established by chiral phosphoramidite-palladium catalysis, affording a wide variety of functionalized chiral 2-acylimidazoles in moderate to high yields and with high levels of enantioselectivity. Moreover, this protocol could be applied to a concise asymmetric synthesis of a tachykinin receptor antagonist.

Nucleophile-Dependent Z/ E- and Regioselectivity in the Palladium-Catalyzed Asymmetric Allylic C-H Alkylation of 1,4-Dienes.

The asymmetric allylic alkylation (AAA), which features employing active allylic substrates, has historical significance in organic synthesis. The allylic C-H alkylation is principally more atom- and step-economic than the classical allylic functionalizations and thus can be considered a transformative variant. However, asymmetric allylic C-H alkylation reactions are still scarce and yet underdeveloped. Herein, we have found that Z/ E- and regioselectivities in the Pd-catalyzed asymmetric allylic C-H alkylation of 1,4-dienes are highly dependent on the type of nucleophiles. A highly stereoselective allylic C-H alkylation of 1,4-dienes with azlactones has been established by palladium-chiral phosphoramidite catalysis. The protocol proceeds under mild conditions and can accommodate a wide scope of substrates, delivering structurally divergent α,α-disubstituted α-amino acid surrogates in high yields and excellent levels of diastereo-, Z/ E-, regio-, and enantioselectivities. Notably, this method provides key chiral intermediates for an efficient synthesis of lepadiformine marine alkaloids. Experimental and computational studies on the reaction mechanism suggest a novel concerted proton and two-electron transfer process for the allylic C-H cleavage and reveal that the Z/ E- and regioselectivities are governed by the geometry and coordination pattern of nucleophiles.

Nucleophile Coordination Enabled Regioselectivity in Palladium-Catalyzed Asymmetric Allylic C-H Alkylation.

Branched selectivity in asymmetric allylic C-H alkylation is enabled by using 2-acylimidazoles as nucleophiles in the presence of a chiral phosphoramidite-palladium catalyst. A wide range of terminal alkenes, including 1,4-dienes and allylarenes, are nicely tolerated and provide chiral 2-acylimidazoles in moderate to high yields and with high levels of regio-, and enantio-, and E/Z-selectivities. Mechanistic studies using density-functional theory calculations suggest a nucleophile-coordination-enabled inner-sphere attack mode for the enantioselective carbon-carbon bond-forming event.

Palladium(II)-Catalyzed Deacylative Allylic C-H Alkylation.

The first deacylative allylic C-H alkylation has been established by employing the palladium-catalyzed allylic C-H activation and decarboxylative nucleophile generation. A wide scope of nucleophiles are tolerated and densely functionalized alkylation products turn out to be furnished in moderate to good yield. More importantly, this strategy provides an alternative method for the allylic C-H alkylation with less stabilized carbon nucleophiles, and can be further expanded to the synthesis of unconjugated enynes.

Access to Chiral Hydropyrimidines through Palladium-Catalyzed Asymmetric Allylic C-H Amination.

A palladium-catalyzed asymmetric intramolecular allylic C-H amination controlled by a chiral phosphoramidite ligand was established for the preparation of various substituted chiral hydropyrimidinones, the precursors of hydropyrimidines, in high yields with high enantioselectivities. In particular, dienyl sodium N-sulfonyl amides bearing an arylethene-1-sulfonyl group underwent a sequential allylic C-H amination and intramolecular Diels-Alder (IMDA) reaction to produce chiral fused tricyclic tetrahydropyrimidinone frameworks in high yields and with high levels of stereoselectivity. Significantly, this method was used as the key step in an asymmetric synthesis of letermovir.

Highly Enantioselective Allylic C-H Alkylation of Terminal Olefins with Pyrazol-5-ones Enabled by Cooperative Catalysis of Palladium Complex and Brønsted Acid.

A highly enantioselective allylic C-H alkylation reaction of allylarenes with pyrazol-5-ones has been established by the cooperative catalysis of a chiral palladium complex and chiral Brønsted acid to afford a wide spectrum of functionalized chiral N-heterocycles with an all-carbon quaternary stereogenic center in high yields and with high levels of enantioselectivity (up to 96% ee), wherein the chiral ligand and phosphoric acid showed synergistic effect on the control of stereoselectivity. In addition, a palladium-catalyzed asymmetric allylic C-H alkylation of 1,4-pentadienes with pyrazol-5-ones has been realized to furnish highly functionalized pyrazol-5-ones in high enantioselectivities. In this case, the chiral ligand controls the stereoselectivity while the achiral Bronsted acid, 2-fluorobenzoic acid, turns out to be a better cocatalyst than the chiral phosphoric acid. The installation of electron-deficient substituents at 3,3'-positions of binaphthyl backbone of chiral phosphoramidites is actually beneficial to the allylic C-H oxidation due to their survival in the presence of quinone derivative oxidants. These allylic C-H alkylation reactions undergo smoothly under mild conditions and tolerate a wide range of substrates. The resultant highly functionalized chiral pyrazol-5-ones have been applied to the preparation of more structurally diverse heterocycles by classical transformations.

Asymmetric Allylic C-H Oxidation for the Synthesis of Chromans.

An enantioselective intramolecular allylic C-H oxidation to generate optically active chromans has been accomplished under the cooperative catalysis of a palladium complex of chiral phosphoramidite ligand and 2-fluorobenzoic acid. Mechanistic studies suggest that this reaction commences with a Pd-catalyzed allylic C-H activation event and then undergoes asymmetric allylic alkoxylation. The synthetic significance of the method has been embodied by concisely building up a key chiral intermediate to access (+)-diversonol.

Hybrid gold/chiral Brønsted acid relay catalysis allows an enantioselective synthesis of (-)-5-epi-eupomatilone-6.

An enantioselective synthesis of (-)-5-epi-eupomatilone-6 has been accomplished by using relay catalytic cascade intramolecular hydrosiloxylation and Mukaiyama aldol reaction of 2,3,4-trimethoxy-6-(phenylethynyl)phenyl dimethylsilanol with fluorenylglyoxylate.

Chiral counteranion strategy for asymmetric oxidative C(sp³)-H/C(sp³)-H coupling: enantioselective α-allylation of aldehydes with terminal alkenes.

The first enantioselective α-allylation of aldehydes with terminal alkenes has been realized by combining asymmetric counteranion catalysis and palladium-catalyzed allylic C-H activation. This method can tolerate a wide scope of α-branched aromatic aldehydes and terminal alkenes, thus affording allylation products in high yields and with good to excellent levels of enantioselectivity. Importantly, the findings suggest a new strategy for the future creation of enantioselective C-H/C-H coupling reactions.

Enantioselective relay catalytic cascade intramolecular hydrosiloxylation and Mukaiyama aldol reaction.

Cascading chemistry! The first practical relay catalytic cascade intramolecular hydrosiloxylation of arylacetylene and asymmetric Mukaiyama aldol reaction has been established to give synthetically useful products in high yields and with excellent ee (see scheme).

Redox-Neutral 1,4-Dicarbonfunctionalization of 1,3-Butadiene by Merging Photoredox and Nickel Catalysis.

The diverse functionalization of 1,3-butadiene provides wide applicability toward the synthesis of abundant and useful allylic compounds. Here, we describe a three-component and redox-neutral assembly of readily available C═X compounds, 1,3-butadiene, and various nucleophiles by merging photoredox and nickel catalysis, enabling the rapid synthesis of structurally diverse homoallyl amines and homoallylic alcohols.

Hybrid metal/organo relay catalysis enables enynes to be latent dienes for asymmetric Diels-Alder reaction.

The hybrid Au(I)/Brønsted acid binary catalyst system enables enynes to serve as latent 1,3-silyloxydienes capable of participating in the first cascade hydrosiloxylation of an enynyl silanol/asymmetric Diels-Alder reaction. A variety of polycyclic compounds bearing multistereogenic centers were obtained in high yields and excellent enantioselectivities from the relay catalytic cascade reaction between (2-(but-3-en-1-ynyl)phenyl) silanols and quinones catalyzed by the combined achiral gold complex and chiral N-triflyl phosphoramide.

Access to chiral γ-butenolides via palladium-catalyzed asymmetric allylic C-H alkylation of 1,4-dienes.

Asymmetric allylic C-H alkylation of 1,4-pentadienes with α-angelica lactones has been developed by tri-axial phosphoramidite-palladium catalysis. This reaction can tolerate a range of functional groups under mild conditions, furnishing versatile chiral γ,γ-disubstituted butenolides in high yields with good to high levels of stereoselectivity.

Asymmetric Photocatalytic C(sp3)-H Bond Addition to α-Substituted Acrylates.

Asymmetric functionalization of inert C(sp3)-H bonds is a straightforward approach to realize versatile bond-forming events, allowing the precise assembly of molecular complexity with minimal functional manipulations. Here, we describe an asymmetric photocatalytic C(sp3)-H bond addition to α-substituted acrylates by using tetrabutylammonium decatungstate (TBADT) as a hydrogen atom transfer (HAT) photocatalyst and chiral phosphoric acid as a chiral proton-transfer shuttle. This protocol is supposed to occur via a radical/ionic relay process, including a TBADT-mediated HAT to cleave the inert C(sp3)-H bond, a 1,4-radical addition, a back hydrogen abstraction, and an enantioselective protonation. A variety of inert C-H bond patterns and α-substituted acrylates are well tolerated to enable the rapid synthesis of enantioenriched α-stereogenic esters from simple raw materials.

Recent Progress in Asymmetric Relay Catalysis of Metal Complex with Chiral Phosphoric Acid.

Asymmetric metal/organo relay catalysis, utilizing a metal complex and a chiral organocatalyst in a one-pot cascade reaction, is aimed to sequentially impart activation on multiple steps by distinct catalysts. Such a catalysis merges the advantages of both metal catalysis and organocatalysis, providing step-economy, and, more importantly, the potential to achieve inaccessible reactivity by a single catalyst. Chiral phosphoric acids are among the most robust organocatalysts, rendering a broad range of enantioselective bond-forming reactions. The combination of metal complexes and chiral phosphoric acids in a single vessel has been well documented. In particular, the asymmetric relay catalysis of metal complex with chiral phosphoric acid has grown rapidly since 2008. Several excellent reviews have been published to cover almost all examples in this area from 2008 to early 2014; therefore, in this chapter, we will mainly highlight progress from 2014 to mid-2019.