Allylic Alkylation Research Articles

Efficient and Sustainable One‐pot Synthesis of α‐Carbonyl Homoallylic Alcohols from Benzaldehyde and Allylic Alcohols Using both NHC and Nickel Catalysts

Abstractα‐carbonyl homoallylic alcohols have been synthesized in a one‐pot reaction from benzaldehyde and allylic alcohols. The nickel‐catalyzed allylation of α‐hydroxyketones has first been studied and allowed the identification of Ni(cod)2/dppf as the most suitable catalytic system. The tandem reaction that combines the benzoin condensation of aldehydes (synthesis of α‐hydroxyketones) promoted by the 1,3‐dimethylimidazolium chloride/DBU system and the nickel‐catalyzed allylic alkylation with allylic alcohol has been realized in EtOH as green solvent. The reaction is 100 % atom‐economical and water is formed as sole by‐product. A broad scope of different benzaldehyde derivatives as well as various allylic alcohols is also described.

COAP‐Palladium‐Catalyzed Asymmetric Linear Allylic Alkylation of Vinyl Benzoxazinanones for Multifunctional 3,3′‐Disubstituted Oxindole Derivatives

AbstractA Pd‐catalyzed enantioselective linear‐allylic alkylation of vinyl benzoxazinanones with a series of 3‐substituted oxindoles was reported in the presence of a chiral oxamide‐phosphine ligand (COAP−Bn) under mild reaction conditions. A series of optically active multifunctional 3,3′‐disubstituted oxindole derivatives bearing a quaternary stereogenic center and a linear aryl amino side chain were respectively obtained in 55–98% yields with 96–99% ee for 3‐(hetero)aryl substituted oxindoles. The developed protocol demonstrates that the COAP ligands could serve as a privileged chiral ligand to construct diverse chiral 3,3‐disubstituted oxindole compounds with various quaternary stereogenic centers, such as aza‐, thio‐ or all‐carbon quaternary stereogenic centers. The salient features of the method include broad substrate scope, N‐protecting group free, base‐free, and high regio‐ and enantioselectivity.magnified image

Asymmetric Formal Abnormal Claisen Rearrangement Enabled by Rh-Catalyzed Regio- and Enantioselective Allylic Alkylation

Asymmetric Formal Abnormal Claisen Rearrangement Enabled by Rh-Catalyzed Regio- and Enantioselective Allylic Alkylation

Palladium-catalyzed annulative allylic alkylation for regioselective construction of indole-fused medium-sized cyclic ethers

A new palladium-catalyzed annulative allylic alkylation (AAA) reaction of 2-(indol-2-yl)phenols with dual allylic electrophiles such as isobutylene dicarbonate and butene dicarbonate is described, leading to the regioselective synthesis of tetracyclic medium-sized cyclic ethers possessing a bridged aryl-indole scaffold, namely, benzo[2,3]oxocino[4,5-b]indoles and benzo[2,3]oxepino[4,5-b]indoles, in good to excellent yields. This protocol demonstrates a broad substrate scope, good compatibility with substituents and high regioselectivity, providing a catalytic and flexible method for creating bridged aryl-indole skeletons.

Enantioselective Synthesis of Skipped Dienes via Iridium-Catalyzed Allylic Alkylation of Phosphonates.

An enantioselective synthesis of skipped dienes has been developed based on an iridium-catalyzed allylic alkylation of phosphonates and Horner-Wadsworth-Emmons olefination. This two-step protocol uses easily accessible substrates and delivers C2-substituted skipped dienes bearing a C3 stereogenic center, generally with outstanding enantioselectivities (up to 99.5:0.5 er). This is the first catalytic enantioselective allylic alkylation of phosphonates, and the overall process represents a formal enantioselective α-C(sp2)-H allylic alkylation of α,β-unsaturated carbonyls and acrylonitrile.

Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers through a Convergent Petasis Borono-Mannich Reaction.

Strempeliopidine is a member of the monoterpenoid bisindole alkaloid family, a class of natural products that have been shown to elicit an array of biological responses including modulating protein-protein interactions in human cancer cells. Our synthesis of strempeliopidine leverages palladium-catalyzed decarboxylative asymmetric allylic alkylations to install the requisite all-carbon quaternary centers found in each of the two monomeric natural products, aspidospermidine and eburnamine. Initial studies employing Suzuki-Miyaura cross-coupling followed by diastereoselective hydrogenation provided evidence for a structural reassignment of the natural product. Our final synthetic sequence employs a diastereoselective Petasis borono-Mannich reaction to couple eburnamine to a trifluoroborate aspidospermidine derivative. These convergent approaches enabled the synthesis of eight diastereomers of this heterodimer and offer support for the reassignment of the absolute configuration of strempeliopidine.

Chiral Phosphine Catalyzed Allylic Alkylation of Benzylidene Succinimides with Morita–Baylis–Hillman Carbonates

Owing to their unique chemical properties, α-alkylidene succinimides generally act as versatile synthons in organic synthesis. Compared with well-established annulations, nucleophilic alkylations of α-alkylidene succinimides are very limited. Accordingly, an organocatalytic allylic alkylation of α-benzylidene succinimides with Morita-Baylis-Hillman (MBH) carbonates was established. In the presence of a chiral phosphine catalyst, α-benzylidene succinimides reacted smoothly with MBH carbonates under mild conditions to furnish a series of optical active succinimides in high yields and enantioselectivities. Different from the reported results, the organocatalytic enantioselective construction of pyrrolidine-2,5-dione frameworks bearing contiguous chiral tertiary carbon centers was achieved via this synthetic strategy. Scaling up the reaction indicated that it is a practical strategy for the organocatalytic enantioselective alkylation of α-alkylidene succinimides. A possible reaction mechanism was also proposed.

Palladium‐Catalyzed Asymmetric Hydrogenolysis of Aryl Triflates for Construction of Axially Chiral Biaryls

AbstractHere we report the first palladium‐catalyzed asymmetric hydrogenolysis of readily available aryl triflates via desymmetrization and kinetic resolution for facile construction of axially chiral biaryl scaffolds with excellent enantioselectivities and s selectivity factors. The axially chiral monophosphine ligands could be prepared from these chiral biaryl compounds and were further applied to palladium‐catalyzed asymmetric allylic alkylation with excellent ee values and high branched and linear ratio, which demonstrated the potential utility of this methodology.

Palladium-Catalyzed Asymmetric Hydrogenolysis of Aryl Triflates for Construction of Axially Chiral Biaryls.

Here we report the first palladium-catalyzed asymmetric hydrogenolysis of readily available aryl triflates via desymmetrization and kinetic resolution for facile construction of axially chiral biaryl scaffolds with excellent enantioselectivities and s selectivity factors. The axially chiral monophosphine ligands could be prepared from these chiral biaryl compounds and were further applied to palladium-catalyzed asymmetric allylic alkylation with excellent ee values and high branched and linear ratio, which demonstrated the potential utility of this methodology.

Enantioselective Allylation of Stereogenic Nitrogen Centers.

Most tertiary amines with a stereogenic nitrogen center undergo rapid racemization at room temperature. Consequently, the quaternization of amines under dynamic kinetic resolution seems feasible. N-Methyl tetrahydroisoquinolines are converted into configurationally stable ammonium ions by Pd-catalyzed allylic alkylation. The optimization of conditions and the evaluation of the substrate scope enabled high conversions and an enantiomeric ratio of up to 10:90. We report here the first examples for the enantioselective catalytic synthesis of chiral ammonium ions.

Atroposelective desymmetrization of 2-arylresorcinols via Tsuji-Trost allylation

Palladium-catalyzed asymmetric allylic alkylation has proven to be a powerful method for the preparation of a wide variety of chiral molecules. However, the catalytic and atroposelective allylic alkylation is still rare and challenging, especially for biaryl substrates. Herein, we report the palladium-catalyzed desymmetric and atroposelective allylation, in which the palladium complex with a chiral phosphoramidite ligand enables desymmetrization of nucleophilic 2-arylresorcinols in a highly enantioselective manner. With the aid of the secondary kinetic resolution effect, a wide variety of substrates containing a hydroxymethyl group at the bottom aromatic ring are able to provide O-allylated products up to 98:2 er. Computational studies show an accessible quadrant of the allylpalladium complex and provide three plausible transition states with intra- or intermolecular hydrogen bonding. The energetically favorable transition state is in good agreement with the observed enantioselectivity and suggests that the catalytic reaction would proceed with an intramolecular hydrogen bond.

Simultaneous Dual Cu/Ir Catalysis: Stereodivergent Synthesis of Chiral β-Lactams with Adjacent Tertiary/Quaternary/Tertiary Stereocenters

A stereodivergent synthesis of chiral β-lactams with contiguous tertiary/quaternary/tertiary stereocenters has been achieved by a Cu/Ir-catalyzed three-component interrupted Kinugasa allylic alkylation reaction. The two catalysts independently exert high local stereocontrol, providing access to four of the eight possible stereoisomers in high yields with >99% ee. The features of this strategy are the asymmetric simultaneous dual metal-catalyzed cascade reactions with stereoselective coupling of highly transient organometallic intermediates.

O- and N-Selective Electrophilic Activation of Allylic Alcohols and Amines in Pd-Catalyzed Direct Alkylation.

Catalytic control of chemoselectivity is crucial in the synthesis of highly functionalized compounds. Although there are reports of efficient chemoselective reactions of alcohols and amines as nucleophiles, there are no reports of the chemoselective activation of alcohols and amines as electrophiles. In this study, highly O- and N-selective electrophilic activation of allylic alcohols and amines was achieved in Pd-catalyzed direct allylic alkylation. Allylamines were inherently more reactive than allylic alcohols (N-selectivity). On the other hand, the addition of catalytic amounts of 9-phenanthreneboronic acid preferentially activated allylic alcohols over allylamines (O-selectivity). Density functional theory (DFT) calculations suggested that the N-selectivity is due to the selective activation of allylic amines with ammonium cations, and boronate formation accelerates the activation of allylic alcohols.

Palladium-Catalyzed Chemo- and Regioselective C-H Bond Functionalization of Phenols with 1,3-Dienes.

Chemo- and site-selective functionalization of phenols offers a rapid strategy for the synthesis of phenol derivatives with diverse structures. Herein, we report a Pd-catalyzed regioselective C-H bond allylic alkylation of phenols with 1,3-dienes, which has precision reactivity at the ortho C-H bond of 2-naphthols, 1-naphthols, and electron-rich phenols. The reaction is accelerated by a diphosphine ligand, does not need any other additive, and features broad substrate scope and good chemo- and regioselectivity. In addition, we have also investigated the asymmetric variant, and the product could be achieved in up to 55% ee.

Organocatalytic Regio- and Enantioselective Allylic Alkylation of Indolin-2-imines with MBH Carbonates toward 3-Allylindoles.

An organocatalytic asymmetric C3-allylic alkylation of indolone-2-imines with MBH carbonates has been developed for the first time. As opposed to previous reports, an "interrupted" annulation was achieved, affording 3-allylindoles in generally high yields with excellent stereoselectivities. The representative scale-up reaction and transformation of 3-allylindoles were examined. A possible mechanism was also proposed.

Nickel-Catalyzed Asymmetric Allylic Alkylation of β-Dicarbonyl Compounds via C–C Bond Activation of 2-Allylated Cyclic 1,3-Diketones

The asymmetric allylic alkylation (AAA) reaction using less reactive, stable allylic sources is challenging. We achieved a nickel(0)-catalyzed AAA reaction of β-dicarbonyl compounds under ambient conditions through unstrained C–C bond activation of 2-allylated 2-methylcyclohexane-1,3-dione derivatives to afford the corresponding quaternary chiral compounds in high yield with high enantioselectivity. The reaction proceeded almost irreversibly due to the low solubility of the side-product, 2-methylcyclohexane-1,3-dione. Control experiments and DFT calculations allowed for the elucidating the mechanism of the AAA reaction with the Ni(0)-(S)-tol-MeO-BIPHEP catalyst system; the turnover limiting step is C–C bond formation, and the reverse reaction requires 7.6 kcal mol–1 higher activation energy than the forward reaction.

Coupling Reactions on Secondary Allylic, Propargylic, and Alkyl Carbons Using Organoborates/Ni and RMgX/Cu Reagents

In the first part of this review, secondary carbon-carbon bond formation by using allylic coupling reactions with aryl and alkenyl borates is presented. Early investigations have revealed the suitability of a nickel catalyst and [RTB(OMe)3]Li (RT: transferable group). Due to their low reactivity, the borates were converted to more reactive congeners possessing an alkanediol ligand, such as 2,3-butanediol and 2,2-dimethyl-1,3-propanediol. Borates with such diol ligands were used to install aryl and alkenyl groups on the monoacetate of 4-cyclopentenyl-1,3-diol. Furthermore, alkenyl borates showed sufficient reactivity toward less reactive allylic alcohol derivatives with bromine atoms at the cis position, producing dieneyl alcohols. In the second part, copper-based and/or copper-catalyzed substitutions of secondary allylic picolinates, propargylic phosphonates, and alkyl (2-pyridine)sulfonates with RMgX are briefly summarized. The application of these reactions to the synthesis of biologically active compounds is also discussed.

Simple selenide-phosphoramidite as chiral ligand for Pd-catalyzed asymmetric allylic alkylation reactions

Simple selenide-phosphoramidite as chiral ligand for Pd-catalyzed asymmetric allylic alkylation reactions

Fungicide-inspired precursors of π-allylpalladium intermediates for palladium-catalyzed decarboxylative cycloadditions.

Inspired by a fungicide, we designed 5-vinyloxazolidine-2,4-diones as new precursors of π-allylpalladium zwitterionic intermediates and developed palladium-catalyzed asymmetric (5 + 3) cycloaddition with azomethine imines and (3 + 2) cycloaddition with 1,1-dicyanoalkenes. Both reactions proceeded smoothly under mild reaction conditions to produce various chiral heterocyclic compounds in high yields with excellent enantioselectivities. These results revealed that 5-vinyloxazolidine-2,4-diones were a type of suitable precursor for palladium catalysis and will find extensive applications in Pd-catalyzed reactions such as cycloaddition and allylic alkylation.

Evolution of a 'privileged' P-alkene ligand: added planar chirality beats BINOL axial chirality in catalytic asymmetric C-C bond formation.

Alkene planar chirality is introduced in the 'privileged' P-alkene phosphoramidite ligand 1. The resulting diastereomeric ligands (pR,R)-5 and (pS,R)-5 form optically pure complexes of Rh(I) and Pd(II), which catalyze conjugate additions of boron C-nucleophiles to enones and allylic alkylations, respectively. In the Rh-catalyzed reaction, the planar chirality of the alkene exerts absolute enantiocontrol over the potent BINOL auxiliary.