Catalytic Allylic Alkylation Research Articles

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.

Dirhodium(II)/Xantphos-Catalyzed Relay Carbene Insertion and Allylic Alkylation Process: Reaction Development and Mechanistic Insights.

Although dirhodium-catalyzed multicomponent reactions of diazo compounds, nucleophiles and electrophiles have achieved great advance in organic synthesis, the introduction of allylic moiety as the third component via allylic metal intermediate remains a formidable challenge in this area. Herein, an attractive three-component reaction of readily accessible amines, diazo compounds, and allylic compounds enabled by a novel dirhodium(II)/Xantphos catalysis is disclosed, affording various architecturally complex and functionally diverse α-quaternary α-amino acid derivatives in good yields with high atom and step economy. Mechanistic studies indicate that the transformation is achieved through a relay dirhodium(II)-catalyzed carbene insertion and allylic alkylation process, in which the catalytic properties of dirhodium are effectively modified by the coordination with Xantphos, leading to good activity in the catalytic allylic alkylation process.

A borane-mediated palladium-catalyzed reductive allylic alkylation of α,β-unsaturated carbonyl compounds.

The development of the palladium-catalyzed allylic alkylation of in situ generated boron enolates via tandem 1,4-hydroboration is reported. Investigation of the reaction revealed insights into specific catalyst electronic features as well as a profound leaving group effect that proved crucial for achieving efficient allylic alkylation of ester enolates at room temperature and ultimately a highly preparatively useful synthesis of notoriously challenging acyclic all-carbon quaternary stereocenters. The method demonstrates boron enolates as viable pro-nucleophiles in transition-metal catalyzed allylic alkylation, potentially opening up further transformations outside their traditional use.

Indolyl-chalcone derivatives induce hepatocellular carcinoma cells apoptosis through oxidative stress related mitochondrial pathway in vitro and in vivo

A facile method of assembling oxindole and phthalide units through a Lewis based catalyzed allylic alkylation reaction of Morita–Baylis–Hillman carbonates of isatins and 3-cyanophthalides was recently developed. The method efficiently delivers a hybrid of 3,3′-disubstituted oxindole with a valuable phthalide pharmacophore. In the present study, we proved the deleterious effects of 5h2c, a screened synthesis compound, against hepatocellular carcinoma (HCC) in both in vitro and in vivo models. 5h2c strongly decreased cell viability, caused over-release of lactate dehydrogenase, inhibited cell migration, and enhanced the apoptosis rate in HepG2 and PLC/PRF/5 cells. 5h2c led to an increase in intracellular reactive oxygen species levels and a decrease in mitochondrial membrane potential. In HepG2-and PLC/PRF/5-xenograft tumor mouse models, treatment with 5h2c inhibited tumor growth without affecting the animals' bodyweight or organ functions. Proteome profiling of tumor tissues after 24-h exposure to 5h2c showed significantly enhanced expression levels of Bcl-2 associated X protein, cleaved caspase −3, −8, and −9, nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), heme oxygenase-2, paraoxonase 2, catalase, and factor associated suicide ligand, and reduced the expression levels of B-cell lymphoma-2, B-cell lymphoma-extra large, heat shock protein 27, heat shock protein 60, and heat shock protein 70 in HepG2 and PLC/PRF/5 cells. All of our data confirmed that oxidative stress-mediated mitochondrial apoptosis (especially the Nrf-2/HO-1 pathway) is responsible for 5h2c-induced HCC damage.

Palladium(0)-Catalyzed Allylic Alkylation of Difficult Substrates

Palladium(0)-Catalyzed Allylic Alkylation of Difficult Substrates

Highly Efficient Palladium‐Catalyzed Allylic Alkylation of Cyanoacetamides with Controllable and Chemoselective Mono‐ and Double Substitutions

AbstractThe front cover artwork for Issue 22/2016 is provided by Zi‐Wei Gao and Li‐Wen Xu's group of Shaanxi Normal University. The image shows a novel palladium catalyst system combined with a triazine‐modified new phosphine ligand that was developed successfully for the catalytic allylic alkylation of various cyanoacetamides. See the Full Paper itself at http://dx.doi.org/10.1002/cctc.201601021.

Rhodium-catalyzed chemo- and regioselective decarboxylative addition of β-ketoacids to alkynes.

A highly efficient rhodium-catalyzed chemo- and regioselective addition of β-ketoacids to alkynes is reported. Applying a Rh(i)/(S,S)-DIOP catalyst system, γ,δ-unsaturated ketones were prepared with exclusively branched selectivity under mild conditions. This demonstrates that readily available alkynes can be an alternative entry to allyl electrophiles in transition-metal catalyzed allylic alkylation reactions.

An Efficient Protocol for the Palladium-catalyzed Asymmetric Decarboxylative Allylic Alkylation Using Low Palladium Concentrations and a Palladium(II) Precatalyst.

Enantioselective catalytic allylic alkylation for the synthesis of 2-alkyl-2-allylcycloalkanones and 3,3-disubstituted pyrrolidinones, piperidinones and piperazinones has been previously reported by our laboratory. The efficient construction of chiral all-carbon quaternary centers by allylic alkylation was previously achieved with a catalyst derived in situ from zero valent palladium sources and chiral phosphinooxazoline (PHOX) ligands. We now report an improved reaction protocol with broad applicability among different substrate classes in industry-compatible reaction media using loadings of palladium(II) acetate as low as 0.075 mol % and the readily available chiral PHOX ligands. The novel and highly efficient procedure enables facile scale-up of the reaction in an economical and sustainable fashion.

Mechanism of Copper(I)‐Catalyzed Allylic Alkylation of Phosphorothioate Esters: Influence of the Leaving Group on α Regioselectivity

The mechanism of Cu(I) -catalyzed allylic alkylation and the influence of the leaving groups (OPiv, SPiv, Cl, SPO(OiPr)2 ; Piv: pivavloyl) on the regioselectivity of the reaction have been explored by using density functional theory (DFT). A comprehensive comparison of many possible reaction pathways shows that [(iPr)2 Cu](-) prefers to bind first oxidatively to the double bond of the allylic substrate at the anti position with respect to the leaving group, and this is followed by dissociation of the leaving group. If the leaving group is not taken into account, the reaction then undergoes an isomerization and a reductive elimination process to give the α- or γ-selective product. If OPiv, SPiv, Cl, or SPO(OiPr)2 groups are present, the optimal route for the formation of both α- and γ-substituted products changes from the stepwise elimination to the direct process, in which the leaving group plays a stabilizing role for the reactant and destabilizes the transition state. The differences to the energy barrier for the α- and γ-substituted products are 2.75 kcal mol(-1) with SPO(OiPr)2 , 2.44 kcal mol(-1) with SPiv, 2.33 kcal mol(-1) with OPiv, and 1.98 kcal mol(-1) with Cl, respectively; these values show that α regioselectivity in the allylic alkylation follows a SPO(OiPr)2 >SPiv>OPiv>Cl trend, which is in satisfactory agreement with the experimental findings. This trend mainly originates in the differences between the attractive electrostatic forces and the repelling steric interactions of the SPO(OiPr)2 , SPiv, OPiv, and Cl groups on the Cu group.

ChemInform Abstract: Triflimide‐Catalyzed Allyl—Allyl Cross‐Coupling: A Metal‐Free Allylic Alkylation.

AbstractA new simple and mild protocol for excellent regioselective direct catalytic allylic alkylation of acetates is presented by using a simple, cheap, and easily accessible catalyst.

Tandem Palladium(0) and Palladium(II)-Catalyzed Allylic Alkylation Through Complementary Redox Cycles

Tandem Palladium(0) and Palladium(II)-Catalyzed Allylic Alkylation Through Complementary Redox Cycles

Tandem Palladium(0) and Palladium(II)‐Catalyzed Allylic Alkylation Through Complementary Redox Cycles

Here it goes again: A tandem catalytic process effects sequential Pd0-catalyzed allylic alkylations through leaving group ionization and PdII-catalyzed allylic alkylations by CH activation. By employing an oxidative trigger to convert the catalytic species from Pd0 into PdII, both transformations can be conducted in a single reaction vessel using the same precatalyst. This allows for the selective introduction of otherwise indistinguishable allyl groups.

Dimethylcuprate-Catalyzed Decarboxylative Coupling of Allyl Acetate

Allylic alkylation of organocuprates represents an important class of C–C bond forming reactions. A drawback of these reactions is their stoichiometric nature. Although metal-catalyzed decarboxylative coupling reactions offer new opportunities for formation of C–C bonds, catalytic allylic alkylation reactions of organocuprates have not been previously reported. Here, multistage mass spectrometry experiments performed on ion trap mass spectrometers in conjunction with electronic structure calculations are used to demonstrate that the dimethylcuprate anion, [CH3CuCH3]−, can catalyze decarboxylative coupling of allyl acetate in the gas phase via a simple two-step catalytic cycle. In step 1, [CH3CuCH3]− undergoes a cross-coupling reaction with allyl acetate to yield [CH3CuO2CCH3]− as the major product ion. Step 2 involves subjecting the product ion to collision-induced decarboxylation to re-form [CH3CuCH3]−, thereby closing the catalytic cycle. Since the details of step 2 have been previously described (Rijs, N.; Khairallah, G. N.; Waters, T.; O’Hair, R. A. J. J. Am. Chem. Soc. 2008, 130,1069−1079), here the focus is on step 1. Comparison of the reactivity of dimethylcuprate toward allylic susbtrates reveals that while allyl acetate reacts around 70 times more slowly than allyl iodide, it is more selective for cross-coupling. This is rationalized by DFT calculations, which reveal that an increase in kinetic barrier is responsible for both reactivity trends. The lowest energy path was found to involve a stepwise π-oxidative addition proceeding via an η2-C3H5O2CCH3 intermediate and extrusion of a leaving group (LG) anion, followed by a reductive elimination where this LG is recomplexed to the copper center. Finally, DFT calculations were used to shed light on the role of leaving groups LG = CH3CO2–, I–, Br–, Cl– in the allylic alkylation. While selectivity is indeed achieved at the cost of reactivity, the LG effects were more complex than can be accounted for by a simple consideration of the anion proton affinity (APA) of the LG.

ChemInform Abstract: Palladium(0)‐Catalyzed Allylic Alkylation of Diketoester—Dioxinones with Allyl Acetates under Neutral Conditions: Synthesis of Hexasubstituted Benzene Derivatives.

Intermolecular palladium(0)-catalyzed allylic alkylation of diketoester–dioxinones was performed under neutral conditions with 2-alkenyl and 2-cycloalkenyl acetates. Subsequent aromatization using cesium carbonate gave rise to isopropylidene-protected hexasubstituted resorcylates.

ChemInform Abstract: Enantioselective Synthesis of Tertiary and Quaternary Stereogenic Centers: Copper/Phosphoramidite‐Catalyzed Allylic Alkylation with Organolithium Reagents.

ChemInform Abstract: Enantioselective Synthesis of Tertiary and Quaternary Stereogenic Centers: Copper/Phosphoramidite‐Catalyzed Allylic Alkylation with Organolithium Reagents.

Palladium(0)-Catalyzed Allylic Alkylation of Diketoester–Dioxinones with Allyl Acetates under Neutral Conditions: Synthesis of Hexasubstituted Benzene Derivatives

Intermolecular palladium(0)-catalyzed allylic alkylation of diketoester-dioxinones was performed under neutral conditions with 2-alkenyl and 2-cycloalkenyl acetates. Subsequent aromatization using cesium carbonate gave rise to isopropylidene-protected hexasubstituted resorcylates.

Enantioselective Synthesis of Tertiary and Quaternary Stereogenic Centers: Copper/Phosphoramidite‐Catalyzed Allylic Alkylation with Organolithium Reagents

Mit primären und sekundären Organolithiumreagentien und unter Einsatz von Phosphoramiditliganden gelingt eine effiziente und hoch enantioselektive kupferkatalysierte allylische Alkylierung von disubstituierten Allylhalogeniden. Ausgehend von trisubstituierten Allylbromiden können, erstmals mit diesen reaktiven Organometallreagentien, ausschließlich kohlenstoffsubstituierte quartäre Stereozentren enantioselektiv aufgebaut werden.

Enantioselective Synthesis of Tertiary and Quaternary Stereogenic Centers: Copper/Phosphoramidite‐Catalyzed Allylic Alkylation with Organolithium Reagents

Enantioselective Synthesis of Tertiary and Quaternary Stereogenic Centers: Copper/Phosphoramidite‐Catalyzed Allylic Alkylation with Organolithium Reagents

Retention of Regiochemistry and Chirality in the Ruthenium Catalyzed Allylic Alkylation of Disubstituted Allylic Esters

The regiospecific nucleophilic substitution during the ruthenium catalyzed allylic alkylation of 1,3-unsymmetrical disubstituted allylic esters was demonstrated. The nucleophile was selectively introduced at the position originally substituted with leaving group in the 2-DPPBA or ip-pybox ligated [RuCl(2)(p-cymene)](2) catalyzed allylic alkylation of 1,3-unsymmetrical disubstituted allylic esters. The chirality of the optically active allylic esters was also transferred to the alkylated products.

Artificial Metalloenzymes Based on the Biotin−Avidin Technology: Enantioselective Catalysis and Beyond

Artificial metalloenzymes are created by incorporating an organometallic catalyst within a host protein. The resulting hybrid can thus provide access to the best features of two distinct, and often complementary, systems: homogeneous and enzymatic catalysts. The coenzyme may be positioned with covalent, dative, or supramolecular anchoring strategies. Although initial reports date to the late 1970s, artificial metalloenzymes for enantioselective catalysis have gained significant momentum only in the past decade, with the aim of complementing homogeneous, enzymatic, heterogeneous, and organic catalysts. Inspired by a visionary report by Wilson and Whitesides in 1978, we have exploited the potential of biotin-avidin technology in creating artificial metalloenzymes. Owing to the remarkable affinity of biotin for either avidin or streptavidin, covalent linking of a biotin anchor to a catalyst precursor ensures that, upon stoichiometric addition of (strept)avidin, the metal moiety is quantitatively incorporated within the host protein. In this Account, we review our progress in preparing and optimizing these artificial metalloenzymes, beginning with catalytic hydrogenation as a model and expanding from there. These artificial metalloenzymes can be optimized by both chemical (variation of the biotin-spacer-ligand moiety) and genetic (mutation of avidin or streptavidin) means. Such chemogenetic optimization schemes were applied to various enantioselective transformations. The reactions implemented thus far include the following: (i) The rhodium-diphosphine catalyzed hydrogenation of N-protected dehydroaminoacids (ee up to 95%); (ii) the palladium-diphosphine catalyzed allylic alkylation of 1,3-diphenylallylacetate (ee up to 95%); (iii) the ruthenium pianostool-catalyzed transfer hydrogenation of prochiral ketones (ee up to 97% for aryl-alkyl ketones and ee up to 90% for dialkyl ketones); (iv) the vanadyl-catalyzed oxidation of prochiral sulfides (ee up to 93%). A number of noteworthy features are reminiscent of homogeneous catalysis, including straightforward access to both enantiomers of the product, the broad substrate scope, organic solvent tolerance, and an accessible range of reactions that are typical of homogeneous catalysts. Enzyme-like features include access to genetic optimization, an aqueous medium as the preferred solvent, Michaelis-Menten behavior, and single-substrate derivatization. The X-ray characterization of artificial metalloenzymes provides fascinating insight into possible enantioselection mechanisms involving a well-defined second coordination sphere environment. Thus, such artificial metalloenzymes combine attractive features of both homogeneous and enzymatic kingdoms. In the spirit of surface borrowing, that is, modulating ligand affinity by harnessing existing protein surfaces, this strategy can be extended to selectively binding streptavidin-incorporated biotinylated ruthenium pianostool complexes to telomeric DNA. This application paves the way for chemical biology applications of artificial metalloenzymes.