Tertiary Allylic Research Articles

Merging Photoredox and Nickel Catalysis: A Ligand-Free Cross-Coupling of Vinyl Halides and α-Silylamines toward Tertiary Allylic Alkylamines

Merging Photoredox and Nickel Catalysis: A Ligand-Free Cross-Coupling of Vinyl Halides and α-Silylamines toward Tertiary Allylic Alkylamines

Experimental and Computational Studies on Cobalt(I)‐Catalyzed Regioselective Allylic Alkylation Reactions

AbstractHere, we report the development of cobalt(I)‐catalyzed regioselective allylic alkylation reactions of tertiary allyl carbonates with 1,3‐dicarbonyl compounds. A family of well‐defined tetrahedral cobalt(I) complexes bearing commercially available bidentate bis(phosphine) ligands [(P,P)Co(PPh3)Cl] are synthesized and explored as catalysts in allylic alkylation reactions. The catalyst [(dppp)Co(PPh3)Cl] (dppp=1,3‐Bis(diphenylphosphino)propane) enables the alkylation of a large variety of tertiary allyl carbonates with high yields and excellent regioselectivity for the branched product. Remarkably, this methodology is selective for the activation of tertiary allyl carbonates even in the presence of secondary allyl carbonates. This contrasts with the selectivity observed in cobalt‐catalyzed allylic alkylations enabled by visible light photocatalysis. Mechanistic insights by means of experimental and computational investigations support a Co(I)/Co(III) catalytic cycle.

Experimental and Computational Studies on Cobalt(I)-Catalyzed Regioselective Allylic Alkylation Reactions.

Here, we report the development of cobalt(I)-catalyzed regioselective allylic alkylation reactions of tertiary allyl carbonates with 1,3-dicarbonyl compounds. A family of well-defined tetrahedral cobalt(I) complexes bearing commercially available bidentate bis(phosphine) ligands [(P,P)Co(PPh3 )Cl] are synthesized and explored as catalysts in allylic alkylation reactions. The catalyst [(dppp)Co(PPh3 )Cl] (dppp=1,3-Bis(diphenylphosphino)propane) enables the alkylation of a large variety of tertiary allyl carbonates with high yields and excellent regioselectivity for the branched product. Remarkably, this methodology is selective for the activation of tertiary allyl carbonates even in the presence of secondary allyl carbonates. This contrasts with the selectivity observed in cobalt-catalyzed allylic alkylations enabled by visible light photocatalysis. Mechanistic insights by means of experimental and computational investigations support a Co(I)/Co(III) catalytic cycle.

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.

Measurement of MAO Enzymatic Activity by Spectrophotometric Direct Assays.

MAO activity measurement can be monitored by direct peroxidase-free assays following different spectroscopy methods. Typically, these are assays that follow the conversion of different MAO substrates into its corresponding products monitored in either absorbance or fluorescence. Herein, we describe the assays for enzyme activity assessment with MAO B and particularly the MAO A substrate kynuramine, as well as the MAO B substrate benzylamine. Moreover, we also describe MAO activity determination using the tertiary amine substrate allyl amine 1-methyl-4-(1-methyl-1 H-pyrrol-2-yl)-1,2,3,6-tetrahydropyridine (MMTP). These are very useful methods for the investigation of MAO inhibitory activity by molecules known to be HRP-interfering. In the present chapter we demonstrate the application of these methods in MAO activity and Michaelis-Menten curve determinations as well as inhibitory activity experiments.

Stereodefined Skipped Dienes through Iridium‐Catalyzed Formal Addition of Tertiary Allylic C−H Bonds to Alkynes

Preparation of skipped dienes with a quaternary carbon center at the C-3 position remains a synthetic challenge. We report here an iridium-catalyzed formal addition of tertiary sp3 C-H bond to alkyne for the facile preparation of skipped dienes. The tertiary allylic C-H bond is cleaved regioselectively, at the site of which a new C-C bond is formed. Enantioselective construction of acyclic quaternary carbon stereocenters is also demonstrated.

Stereodefined Skipped Dienes through Iridium‐Catalyzed Formal Addition of Tertiary Allylic C−H Bonds to Alkynes

AbstractPreparation of skipped dienes with a quaternary carbon center at the C‐3 position remains a synthetic challenge. We report here an iridium‐catalyzed formal addition of tertiary sp3C−H bond to alkyne for the facile preparation of skipped dienes. The tertiary allylic C−H bond is cleaved regioselectively, at the site of which a new C−C bond is formed. Enantioselective construction of acyclic quaternary carbon stereocenters is also demonstrated.

Stereoselective Synthesis of Tertiary Allylic Amines by Titanium-Catalyzed Hydroaminoalkylation of Alkynes with Tertiary Amines.

Intermolecular hydroaminoalkylation reactions of symmetrical and unsymmetrical alkynes with tertiary amines take place in the presence of catalytic amounts of TiBn4, Ph3C[B(C6F5)4], and a sterically demanding aminopyridinato ligand precursor. The resulting products, synthetically and pharmaceutically useful tertiary β,γ‐disubstituted allylic amines, are formed in convincing yields and with excellent stereoselectivity. Particularly promising for future applications is the fact that even the industrial side product trimethylamine can be used as a substrate.

Facile Synthesis of Skipped Dienes through Iridium-Catalyzed Formal Addition of Tertiary Allylic C—H Bonds to Alkynes

Facile Synthesis of Skipped Dienes through Iridium-Catalyzed Formal Addition of Tertiary Allylic C—H Bonds to Alkynes

Asymmetric Enamide-Imine Tautomerism in the Kinetic Resolution of Tertiary Alcohols.

An efficient protocol for kinetic resolution of tertiary alcohols has been developed through an unprecedented asymmetric enamide-imine tautomerism process enabled by chiral phosphoric acid catalysis. A broad range of racemic 2-arylsulfonamido tertiary allyl alcohols could be kinetically resolved with excellent kinetic resolution performances (with s-factor up to >200). This method is particularly effective for a series of 1,1-dialkyl substituted allyl alcohols, which produced chiral tertiary alcohols that would be difficult to access via other asymmetric methods. Facile and versatile transformations of the chiral α-hydroxy imine and enamide products, especially the efficient stereodivergent synthesis of all four stereoisomers of β-amino tertiary alcohols using one enantiomer of the catalyst, demonstrated the value of this kinetic resolution method.

Asymmetric Enamide–Imine Tautomerism in the Kinetic Resolution of Tertiary Alcohols

AbstractAn efficient protocol for kinetic resolution of tertiary alcohols has been developed through an unprecedented asymmetric enamide‐imine tautomerism process enabled by chiral phosphoric acid catalysis. A broad range of racemic 2‐arylsulfonamido tertiary allyl alcohols could be kinetically resolved with excellent kinetic resolution performances (with s‐factor up to >200). This method is particularly effective for a series of 1,1‐dialkyl substituted allyl alcohols, which produced chiral tertiary alcohols that would be difficult to access via other asymmetric methods. Facile and versatile transformations of the chiral α‐hydroxy imine and enamide products, especially the efficient stereodivergent synthesis of all four stereoisomers of β‐amino tertiary alcohols using one enantiomer of the catalyst, demonstrated the value of this kinetic resolution method.

Kinetic Resolution of 2‐N‐Acylamido Tertiary Allylic Alcohols: Asymmetric Synthesis of Oxazolines

AbstractA series of cyclohexyl‐fused SPINOL‐derived phosphoric acids (Cy‐SPA) have been developed to catalyze the kinetic resolution of 2‐N‐acylamido tertiary allylic alcohols, providing access to chiral oxazolines bearing C‐2 alkyl substituents with high enantioselectivities (with s‐factors up to 153). Gram‐scale reaction with 1 mol% catalyst loading and transformations of the chiral products demonstrates the value of these methods.magnified image

Synthesis of α-Tertiary Amines by the Ruthenium-catalyzed Regioselective Allylic Amination of Tertiary Allylic Esters

We demonstrated a ruthenium-catalyzed regioselective allylic amination of tertiary allylic esters with various amines using [Cp*Ru(CH3CN)3][PF6]/5,5′-dimethyl-2,2′-bipyridine (5,5′-diMe-2,2′-bpy) a...

Stereospecific Asymmetric Synthesis of Tertiary Allylic Alcohol Derivatives by Catalytic [2,3]-Meisenheimer Rearrangements.

Chiral acyclic tertiary allylic alcohols are very important synthetic building blocks, but their enantioselective synthesis is often challenging. A major limitation in catalytic asymmetric 1,2‐addition approaches to ketones is the enantioface differentiation by steric distinction of both ketone residues. Herein we report the development of a catalytic asymmetric Meisenheimer rearrangement to overcome this problem, as it proceeds in a stereospecific manner. This allows for high enantioselectivity also for the formation of products in which the residues at the generated tetrasubstituted stereocenter display a similar steric demand. Low catalyst loadings were found to be sufficient and the reaction conditions were mild enough to tolerate even highly reactive functional groups, such as an enolizable aldehyde, a primary tosylate, or an epoxide. Our investigations suggest an intramolecular rearrangement pathway.

Selective Aerobic Oxygenation of Tertiary Allylic Alcohols with Molecular Oxygen

AbstractAerobic epoxidation of tertiary allylic alcohols remains a significant challenge. Reported here is an efficient and highly chemoselective copper‐catalyzed epoxidation and semipinacol rearrangement reaction of tertiary allylic alcohols with molecular oxygen. The solvent 1,4‐dioxane activates dioxygen, thereby precluding the addition of a sacrificial reductant.

Selective Aerobic Oxygenation of Tertiary Allylic Alcohols with Molecular Oxygen.

Aerobic epoxidation of tertiary allylic alcohols remains a significant challenge. Reported here is an efficient and highly chemoselective copper-catalyzed epoxidation and semipinacol rearrangement reaction of tertiary allylic alcohols with molecular oxygen. The solvent 1,4-dioxane activates dioxygen, thereby precluding the addition of a sacrificial reductant.

Influence of n-Butanol Addition on C3H3 Formation in n-Butane Combustion

The effects of different n-butanol blending ratios (Rb) on the formation of propargyl radical (C3H3), an important benzene precursor, during the combustion of n-butanol/n-butane blends are studied. A detailed kinetic combustion model of n-butanol/n-butane is developed and the premixed n-butanol/n-butane flames are calculated at an equivalence ratio of 1.5, an initial pressure of 1.0 atm, and a temperature range from 800 to 2000 K in a perfectly stirred reactor (PSR), with Rb varying from 0 to 1.0. The results show that under the investigated conditions, the peak value of the mole fraction of C3H3 decreases non-linearly with the increase of Rb. Due to the interaction between combustion products of n-butane and n-butanol during the combustion process, the actual peak mole fraction of C3H3 is higher than the theoretical value. A rate of production (ROP) analysis reveals that the number of β-carbon atoms in the molecule of n-butane and n-butanol affects the efficiency of H-abstraction reactions in generating 2-butyl (sC4H9) and C4H8OH-3 (CH3–*CH–CH2–CH2–OH), which are the two major original sources of C3H3. For both n-butane and n-butanol, the main pathway of forming C3H3 from propene (C3H6) is basically the same, which is C3H6 → C3H5-a (symmetric allyl radical) → C3H4-a (allene) → C3H4-p (propyne) → C3H3. When Rb ranges from 0.4 to 0.6, the deviation degrees of the peak mole fraction of the involved C3 species reach a maximum, indicating that the interaction between the two fuels is the most significant. The non-linear decrease in the mole fraction of C3H3 can attribute to three reasons: (a) the increase of Rb promotes the increase of the conversion ratios of n-butane to sC4H9 and n-butanol to C4H8OH-3; (b) the contribution ratios of the reactions involved in the C3H5-a → C3H4-a → C3H4-p → C3H3 pathway decrease with increasing Rb; (c) C3H5-t (tertiary allyl radical) → C3H4-p → C3H3 is the secondary pathway for the formation of C3H3. With the increase of Rb, the dependence of C3H4-p on C3H5-t increases and the conversion ratio of C3H5-t to C3H4-p increases. This study investigates the non-linear decrease of the mole fraction of C3H3 by revealing the interactions between n-butanol and n-butane during the combustion, which can help better understand the effect of n-butanol on the formation of benzene.

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.

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.

Intermolecular Stereoselective Iridium-Catalyzed Allylic Alkylation: An Evolutionary Account.

Our lab has long been interested in the development of methods for the creation of enantioenriched all-carbon quaternary stereocenters. Historically, our interest has centered on palladium-catalyzed allylic alkylation, though recent efforts have moved to include the study of iridium catalysts. Whereas palladium catalysts enable the preparation of isolated stereocenters, the use of iridium catalysts allows for the direct construction of vicinal stereocenters via an enantio-, diastereo-, and regioselective allylic alkylation. This account details the evolution of our research program from inception, which focused on the first iridium-catalyzed allylic alkylation to prepare stereodyads containing a single quaternary center, to our most recent discovery that allows for the synthesis of vicinal quaternary centers.