Allylic Reactions Research Articles

Lewis Base Catalyzed Allylation Reaction of N-Aryl Amides with Morita–Baylis–Hillman Carbonates

Lewis Base Catalyzed Allylation Reaction of N-Aryl Amides with Morita–Baylis–Hillman Carbonates

Pd-Catalyzed Formal [3 + 3] Heteroannulation of Allylic gem-Diacetates: Synthesis of Chromene-Based Natural Products and Exploration of Photochromic Properties

Palladium-catalyzed allylic alkylation reactions of allylic gem-diacetates are rarely explored. This work unveils an unusual chemical reactivity pattern of allylic gem-diacetates and establishes them as new prototypes to synthesize complex benzo[f]chromene systems. Under the reaction conditions, the diacetates behave as 1,3-dicationic equivalents and undergo a [3 + 3] heteroannulation with 2-naphthols (and meta-substituted phenols) to produce novel polycyclic chromenes possessing spiro-, tri-, and tetrasubstituted carbon centers. The versatility of the method is demonstrated in the synthesis of several chromene-based bioactive natural products. Further, interesting photochromic properties of the new classes of benzo[f]chromenes are also discovered.

ProPhenol Derived Ligands to Simultaneously Coordinate a Main-Group Metal and a Transition Metal: Application to a Zn-Cu Catalyzed Reaction.

A new bifunctional ligand bearing chiral N-heterocyclic carbene (NHC) and prolinol moieties is presented. Utilizing the designed ligand, an in situ formed Cu/Zn hetero-bimetallic complex unlocks the asymmetric allylic alkylation reactions of allyl phosphates with zinc keto-homoenolates, leading to the formation of various γ-vinyl ketones with good regio- and enantio-selectivity. DF sT calculation supports that the chelation of allyl phosphates with catalyst promotes the SN 2' addition and the ligand-substrate steric interactions account for the stereoselective outcome.

Tris(4-bromophenyl)aminium Hexachloroantimonate-Mediated Intermolecular C(sp2)-C(sp3) Free Radical Coupling of Vindoline with β-Ketoesters and Related Compounds.

A powerful tris(4-bromophenyl)aminium hexachloroantimonate (BAHA) mediated regioselective intermolecular coupling reaction of vindoline with a wide range of substrates that include β-ketoesters, β-diketones, β-ketoaldehydes, β-ketonitriles, β-ketolactones, β-ketolactams, β-cyanoesters, and malononitriles is detailed. The BAHA-promoted intermolecular sp3/sp2 coupling, representing a special class of selective C-H functionalization reactions with direct carbon-carbon bond formation, proceeds with generation of a quaternary center bound to the aryl C15 center of vindoline capable of accommodating of the vinblastine C16' methyl ester and functionalized for subsequent divergent heterocycle introduction. A comprehensive examination of the reaction scope, optimization of subtle reaction parameters, and key insights into the reaction mechanism are described. Contrary to what might be prevailing expectations, studies suggest the plausible mechanism entails initial single-electron oxidation of the substrate enolate, not vindoline, and subsequent regiospecific addition of the resulting electrophilic radical to vindoline. As such and beyond the new arylation reaction with vindoline, the studies define a host of new, previously unrecognized, applications of BAHA and related triarylaminium radical cations that arises from their ability to generate stabilized electrophilic radicals from β-ketoesters and related substrates under nonreducing and metal-free conditions. Those exemplified herein include mediating stabilized enolate free radical arylation, dimerization, allylation, alkene addition, and α-oxidation reactions.

Nickel-Catalyzed Allylic Defluorinative Cross-Electrophile Coupling with Cycloalkyl Silyl Peroxides as the Alkyl Source.

Herein we demonstrate the first successful application of cycloalkyl silyl peroxides (CSP) as an electrophilic coupling partner in the cross-electrophile coupling reaction. Diverse CSP are efficiently cross-coupled with an array of α-trifluoromethyl alkenes under the catalysis of nickel with the assistance of zinc as the reducing agent. This method allows the use of unstrained CSP as the carbonyl-containing alkyl source in the allylic defluorinative reaction, to access a variety of gem-difluoroalkenes bearing a pendent ketone moiety with high functionality tolerance.

Insights into the Mechanism of an Allylic Arylation Reaction via Photoredox-Coupled Hydrogen Atom Transfer.

Despite widespread use as a synthetic method, the precise mechanism and kinetics of photoredox coupled hydrogen atom transfer (HAT) reactions remain poorly understood. This results from a lack of detailed kinetic information as well as the identification of side reactions and products. In this report, a mechanistic study of a prototypical tandem photoredox/HAT reaction coupling cyclohexene and 1,4-dicyanobenzene (DCB) using an Ir(ppy)3 photocatalyst and thiol HAT catalyst is reported. Through a combination of electrochemical, photochemical, and spectroscopic measurements, key unproductive pathways and side products are identified and rate constants for the main chemical steps are extracted. The reaction quantum yield was found to decline rapidly over the course of the reaction. An unreported cyanohydrin side product was identified and thought to play a key role as a proton acceptor in the reaction. Transient absorption spectroscopy (TAS) and quantum chemical calculations suggested a reaction mechanism that involves radical addition of the nucleophilic DCB radical anion to cyclohexene, with cooperative HAT occurring as the final step to regenerate the alkene. Kinetic modeling of the reaction, using rate constants derived from TAS, demonstrates that the efficiency of the reaction is limited by parasitic absorption and unproductive quenching between excited Ir(ppy)3 and the cyanohydrin photoproduct.

Nickel‐Catalyzed Allylic Substitution Reactions: An Evolving Alternative

AbstractTransition metal‐catalyzed allylic substitution reactions represent versatile transformations in organic synthesis forging C−C and C‐heteroatom bonds. Despite major contributions realized with precious transition metals, earth‐abundant nickel catalysis over the years has emerged as a relative sustainable and efficient alternative in the area of allylic substitution reactions. During the last two decades, the field has witnessed successful accomplishments of chemo‐, regio‐ and enantioselective conversions affording a plethora of products through the employment of Ni‐based methodologies. In this Minireview, the most imperative contributions will be discussed with special attention for the more sustainable character and unique reactivity of Ni, the overall process selectivity features and the functional group tolerance and product scope.

Imbuing an Old Heterocycle with the Power of Modern Catalysis: An Isoxazolidin-5-one Story.

Isoxazolidin-5-ones have been regarded as β-amino acid surrogates owing to their labile N-O bond. While many efforts have been devoted to the catalytic enantioselective synthesis of the core of this heterocycle, its further transformation has been less explored, especially in the context of catalysis. This review summarizes the author's research on the development of catalytic reactions using isoxazolidin-5-ones as substrates. Asymmetric catalysis has proven effective for C-C bond formation at the carbonyl α-carbon. Catalytic asymmetric allylation and direct Mannich-type reactions have been developed. Further, the resulting products have been readily converted into the corresponding quaternary β2,2-amino acids. Moreover, isoxazolidin-5-ones have been identified as alkyl nitrene precursors in the presence of a suitable metal catalyst. The generated metallonitrene undergoes either the electrophilic amination of the aromatic ring or aliphatic C-H insertion, affording a series of cyclic β-amino acids. A remarkable difference in chemoselectivity between rhodium and copper alkyl nitrenes has also been demonstrated, highlighting the unique nature of the underexplored reactive intermediates. The various linear and cyclic β-amino acids obtained through the study are likely to find great utility in a broad range of chemical sciences.

Steps toward Rationalization of the Enantiomeric Excess of the Sakurai-Hosomi-Denmark Allylation Catalyzed by Biisoquinoline N,N'-Dioxides Using Computations.

Allylation reactions of aldehydes are chemical transformations of fundamental interest, as they give direct access to chiral homoallylic alcohols. In this work, we focus on the full computational characterization of the catalytic activity of substituted biisoquinoline-N,N′-dioxides for the allylation of 2-naphthaldehyde. We characterized the structure of all transition states as well as identified the π stacking interactions that are responsible for their relative energies. Motivated by disagreement with the experimental results, we also performed an assessment of 34 different density functional methods, with the goal of assessing DFT as a general tool for understanding this chemistry. We found that the DFT results are generally consistent as long as functionals that correctly account for dispersion interactions are used. However, agreement with the experimental results is not always guaranteed. We suggest the need for a careful synergy between computations and experiments to correctly interpret the data and use them as a design tool for new and improved asymmetric catalysts.

Correction to “Kinetic Resolution of 2H-Azirines by Asymmetric Allylation Reactions”

Correction to “Kinetic Resolution of <i>2H</i>-Azirines by Asymmetric Allylation Reactions”

Kinetic Resolution of 2H-Azirines by Asymmetric Allylation Reactions

Kinetic Resolution of 2<i>H</i>-Azirines by Asymmetric Allylation Reactions

Insights into Organoamine-Catalyzed Asymmetric Synthesis of Axially Chiral Allenoates Using Morita-Baylis-Hillman Carbonates and Trisubstituted Allenoates: Mechanism and Origin of Stereoselectivity.

A computational study was performed to explore the possible mechanisms of β-isocinchonine-catalyzed asymmetric C(sp2)-H allylation of trisubstituted allenoates using Morita-Baylis-Hillman (MBH) carbonates for synthesis of axially chiral tetrasubstituted allenoates. The calculated results indicate that the most energetically favorable pathway includes (1) nucleophilic attack on MBH carbonate by β-isocinchonine, (2) BocO- dissociation, (3) stereoselective formation of the C-C bond, and (4) regeneration of the catalyst. By tracking the orbital overlap/interaction changes, the half shoulder-to-head orbital overlap mode can be smoothly switched to a head-to-head orbital overlap mode for the key C-C σ bond formation, which is also identified as the stereoselectivity-determining process. Further distortion/interaction, noncovalent interaction (NCI), and atom-in-molecule (AIM) analyses demonstrate that C-H···O and C-H···π interactions should be key for controlling the axial and central chirality. This work would be useful for rational design of organocatalytic allylic alkylation reactions for synthesis of axially chiral compounds in the future.

Palladium-Catalyzed Stereoselective C-F Bond Vinylation and Allylation of Tetrasubstituted gem-Difluoroalkenes via Stille Coupling: Synthesis of Monofluorinated 1,3- and 1,4-Dienes.

We herein describe a Pd-catalyzed stereoselective C-F bond vinylation and allylation reaction of tetrasubstituted gem-difluoroalkenes for the synthesis of valuable monofluorinated 1,3- and 1,4-dienes with excellent diastereoselectivities. Different from previously used Pd(PPh3)4, a catalytic system involving Pd(0) and dppe as the ligand was developed for Stille-type cross-coupling between gem-difluoroalkenes and vinyl- and allyltin reagents.

Pd-Catalyzed Enantioselective Dearomative Allylic Annulation to Access PPAPs Analogues.

Polycyclic polyprenylated acylphloroglucinols (PPAPs) share a common bicyclo[3.3.1]alkenone core structure and attract numerous attention from synthetic organic chemists due to their fascinating biological properties and associated synthetic challenges. We present herein that Pd-phosphoramidite catalysts promote the enantioselective dearomative allylic annulation reaction between allyl desoxyhumulones and allylic dicarbonates, affording PPAPs analogues in good yields and enantioselectivities. The reaction likely proceeds through two-step dearomative allylation by Pd, and the C-allylation pathway is the dominant mechanistic model.

Development of chiral bisphosphoric acid/boronic acid co-catalyst system for enantioselective SN2’ reaction

An enantioselective intramolecular SN2’ reaction of geometrically defined allylic substrates was developed by introducing a co-catalyst system composed of chiral bisphosphoric acid and phenylboronic acid. In the enantioselective nucleophilic substitution reaction using chiral phosphoric acids and derivatives (CPAs) as the catalyst, the formation of the corresponding CPA ester, which is afforded through the SN2 reaction of the substrate with the nucleophilic phosphate anion generated during the activation of a leaving group, has been a serious problem because of the catalyst deactivation. The developed co-catalyst system surmounted this fundamental problem by efficiently suppressing the catalyst deactivation process to afford enantioenriched vinyl epoxides in good yields with moderate to high enantioselectivities. Mechanistic elucidation of the present enantioselective intramolecular SN2’ reaction using the co-catalyst system revealed that the leaving group is involved in the enantio-determining transition states, and the anti-SN2’ pathway is considered to be the rational mechanism of the present allylic substitution reaction. In addition, the stereospecific Meinwald rearrangement of the thus-formed enantioenriched vinyl epoxide was aided by an equimolar amount of a Lewis acid, affording the corresponding all-carbon quaternary α-vinyl cyclohexanone without marked loss of enantiomeric purity.

Novel BIPHEN H2 based P,S-bidentate phosphoramidite ligand in palladium-catalyzed asymmetric allylation

The reaction of P,S-phosphoramidite bearing (Ra)-BIPHEN H2 core and exocyclic amino sulfide as the new ligand with [Pd(ppp-allyl)Cl]2 in the presence of AgBF4 yielded a cationic metallochelate [Pd(ppp-allyl)(L)]BF4. This new chiral inducer provided up to 90% ee in the Pd-mediated allylic substitution reaction of (E)-1,3-diphenylallyl acetate with various C- and N-nucleophiles. In the Pd-catalyzed amination of 2-diethoxyphosphoryl-1-phenylallyl acetate with aniline, ee values up to 57% were achieved.

Palladium-catalyzed asymmetric allylic alkylation of 3-amino-2-oxindoles: Synthesis of 3-allyl-3-amino-2-oxindoles

Tartrate derived bi(oxazoline) ligand with palladium (II) species catalyzed asymmetric allylic alkylation reaction to access highly valuable 3-allyl-3-amino-2-oxindoles with vicinal quaternary and tertiary stereocenters in very good yields (up to 91%) and excellent enantioselectivity (up to 98% ee) with moderate to good diastereoselectivity (up to 5:1). The synthetic utility of 3-allyl-3-amino-2-oxindole was further demonstrated to construct spiro(oxindole-3,2′-pyrrolidine) with consecutive one quaternary and three tertiary chiral centers in good stereoselectivity (dr = 8:1 and 80% ee) through metal-free intramolecular iodocyclization reaction.

Stereoselective Access to Spirooxindoles and Bisoxindoles Through Organocatalyzed Asymmetric Divergent Transformations of Isatin-derived MBH Carbonates.

An interesting β-isoquinidine catalyzed divergent reaction was developed to produce either spirocyclopentene oxindoles, spirocyclopentadiene oxindoles or bisoxindoles in a high enantioselective fashion. The utility of this protocol was demonstrated by the versatile transformations of the products. This work not only represents the first highly stereoselective intermolecular catalytic asymmetric allylic alkylation reaction between two isatin-derived MBH carbonate molecules but also constitutes a rare example of isatin-derived MBH carbonate-based enantioselective and α-regioselective [3+2] cycloaddition reactions.

Transition Metal Complexes of Heavier Vinylidenes: Allylic Coordination vs Vinylidene-Alkyne Rearrangement at Nickel.

Transition metal π-allyl complexes are key reagents/intermediates of various catalytic and stoichiometric allylation reactions. We now report the first transition metal complex of a heavier allylic π-system. The η3-Si2Ge allyl nickel complex is formally obtained by the oxidative addition of the Si-Cl bond of the heavier vinylidene [R2(Cl)Si-(R)Si═(NHC)Ge:] to [Ni(COD)2] (R = 2,4,6-triisopropylphenyl; NHC = 1,3-diisopropyl-4,5-dimethylimidazol-2-ylidene; COD = 1,5-cyclooctadiene). Due to geometric constraints, the coordination to the Ni(II) center occurs through the formal Si═Ge double bond instead of the residual lone pair of electrons at germanium. In contrast, the Si-N bond of the analogous vinylidene [R2(Me2N)Si-(R)Si═(NHC)Ge:] (obtained by nucleophilic substitution of Cl by NMe2) does not oxidatively add to Ni(0), and a hydridosilagermene-η2-nickel complex is obtained instead. The formation of this complex necessarily implies the isomerization of the heavier vinylidene to the corresponding heteroalkyne with the Si≡Ge triple bond in the coordination sphere of nickel followed by the activation of a C-H bond of one of the isopropyl groups of an N-heterocyclic carbene (NHC) ligand.

Synthesis of Morita–Baylis–Hillman-fluorides using 1,1,2,2-tetrafluoroethyl-N,N-dimethylamine

Morita–Baylis–Hillman (MBH)-fluorides are valuable platforms for asymmetric allylic substitution reactions. However, the preparation of MBH-fluorides requires the use of an explosive fluorinating reagent, namely (diethylamino)sulfur trifluoride (DAST). Thus, we herein report a safe, alternative method for the preparation of MBH-fluorides via the deoxyfluorination of MBH-alcohols using 1,1,2,2-tetrafluoroethyl-N,N-dimethylamine (TFEDMA). Accordingly, a variety of MBH-alcohols were smoothly converted to their corresponding MBH-fluorides in moderate to good yields without the requirement for an activator. This fluorination reaction was found to proceed via an SN1 process involving a stable allylic cation intermediate.