Chiral Allylic Amines Research Articles

Enantioselective 1,2-Carboamination of 1,3-Dienes with N-Hydroxyphthalimide (NHP) Esters Enabled by a Photoinduced Pd Catalysis.

Herein, a photoinduced, Pd-catalyzed direct 1,2-carboamination of conjugated 1,3-dienes has been successfully achieved. Sequential regioselective C-C bond and enantioselective C-N bond formation allows rapid assembly of a wide range of value-added chiral allylic amines from readily available N-hydroxyphthalimide (NHP) esters and 1,3-dienes under mild conditions. This developed protocol further demonstrates the versatility and potency of the photoexcited Pd catalytic system with a bifunctional reagent in the streamlined difunctionalization of C═C bonds.

Regio‐ and enantioselective nickel-alkyl catalyzed hydroalkylation of alkynes

The migratory insertion of metal-hydride into alkene has allowed regioselective access to organometallics, readily participating in subsequent functionalization as one conventional pathway of hydroalkylation, whereas analogous process with feedstock alkyne is drastically less explored. Among few examples, the regioselectivity of metal-hydride insertion is mostly governed by electronic bias of alkynes. To alter the regioselectivity and drastically expand the intermediate pools that we can access, one aspirational design is through alternative nickel-alkyl insertion, providing opposite regioselectivity induced by steric demand. Leveraging in situ formed nickel-alkyl species, we herein report the regio- and enantioselective hydroalkylation of alkynes with broad functional group tolerance, excellent regio- and enantioselectivity, enabling efficient route to diverse valuable chiral allylic amines motifs. Preliminary mechanistic studies indicate the aminoalkyl radical species can participate in metal-capture and lead to formation of nickel-alkyl, of which the migratory insertion is key to reverse regioselectivity observed in metal-hydride insertion.

Nickel Catalyzed Enantioselective 1,4-Hydroamination of 1,3-Dienes.

Transition metal-catalyzed enantioselective hydroamination of 1,3-dienes provides a direct methodology for the construction of chiral allylamines. So far, all of the reported examples used nucleophilic amines and proceeded with 3,4-regioselectivity. Herein, we describe the first example of nickel-catalyzed enantioselective 1,4-hydroamination of 1,3-dienes using trimethoxysilane and hydroxylamines with a structurally adaptable aromatic spiroketal based chiral diphosphine (SKP) as the ligand, affording a wide array of α-substituted chiral allylamines in high yields with excellent regio- and enantioselectivities. This operationally simple protocol demonstrated a broad substrate scope and excellent functional group compatibility, significantly expanding the chemical space for chiral allylamines. Experimental and DFT studies were performed to elucidate the mechanism and to rationalize the regio- and enantioselectivities of the reaction.

Asymmetric synthesis of allylic sulfonamides with axially and central chirality via palladium-catalyzed of atroposelective N-allylic alkylation

Axially chiral anilide compounds are an emerging but scarcely investigated class of stereogenic molecules with potential applications as chiral catalysts, biologically active scaffolds and functional materials. Compared to the C–C axially chiral molecules, the synthesis of axially chiral anilide compounds is a challenge owing to the lower rotation barriers. Herein, the construction of chiral allylic amine bearing axial chirality and central chirality via Pd-catalyzed atroposelective N-allylic alkylation reaction of cyclic vinyl carbonates and sulfonamides is reported. A diverse range of chiral sulfonamides bearing axial chirality and central chirality were synthesized in high yields and excellent enantioselectivities (up to 92 ​% yield and 99 ​% ee). In addition, the practical application of this protocol was also demonstrated by gram-scale synthesis and derivatives of the compound.

Photoinduced Pd-Catalyzed Enantioselective Carboamination of Dienes via Aliphatic C-H Bond Elaboration.

Three-component diene carboaminations offer a potent means to access synthetically valuable allylic amines with rapid molecular complexity escalation. The existing literature primarily discloses racemic examples, necessitating the use of halides/pseudohalides as substrates. This paper introduces a photoinduced Pd-catalyzed enantioselective three-component carboamination of aryl-substituted 1,3-dienes, leveraging aliphatic C-H bonds for rapid synthesis. The reaction employs 10 mol % of chiral palladium catalyst and an excess aryl bromide as the HAT reagent. This approach yields diverse chiral allylamines with moderate to excellent enantioselectivities. Notably, it stands as the first instance of an asymmetric three-component diene carboamination reaction, directly utilizing abundant C(sp3)-H bearing partners, such as toluene-type substrates, ethers, amines, esters, and ketones. The protocol exhibits versatility across amines, encompassing aliphatic, aromatic, primary, and secondary derivatives. This method could serve as a versatile platform for stereoselective incorporation of various nucleophiles, dienes, and C(sp3)-H bearing partners.

Nickel-Catalyzed Chemo- and Enantioselective Hydrogenation and Deuteration of α,β-Unsaturated Ketimines Using Alcohols: Synthesis of Deuterated Chiral Allylic Amines.

A nickel-catalyzed chemoselective asymmetric transfer hydrogenation of α,β-unsaturated ketimines using ethanol as a hydrogen donor under mild conditions that avoid using high-pressure hydrogen gas was developed. With this catalyst, C1-selective deuterated chiral allylic amines were efficiently synthesized using only stoichiometric 2-propanol-d8. Mechanism studies demonstrated the formation of a nickel hydride intermediate.

Catalytic Asymmetric Synthesis of Zinc Metallacycles.

Transition-metal-catalyzed reductive coupling reactions of alkynes and imines are attractive methods for the synthesis of chiral allylic amines. Mechanistically, these reactions involve oxidative cyclization of the alkyne and the imine to generate a metallacyclic intermediate, which then reacts with H2 or a H2 surrogate to form the product. As an alternative to this hydrogenolysis pathway, here we show that transmetalation to zinc can occur, forming a zinc metallacycle product. This organozinc product serves as a versatile nucleophile for carbon-carbon and carbon-heteroatom coupling reactions. Mechanistic studies based on isotopic labeling experiments and DFT calculations suggest that the key transmetalation step occurs between a Co(II) species and ZnCl2.

Enantioselective Synthesis of Chiral 2-Nitroallylic Amines via Cooperative Cation-Binding Catalysis.

Chiral allylic amines are valuable building blocks for biologically important compounds and natural products. In this study, we present the use of cooperative cation-binding catalysis as an efficient method for synthesizing chiral allylic amines. By utilizing a chiral oligoEG and potassium fluoride as a cation-binding catalyst and base, respectively, a wide range of biologically relevant chiral 2-nitroallylic amines are obtained with excellent enantioselectivities (up to >99 % ee) through the organocatalytic asymmetric aza-Henry-like reaction of β-monosubstituted and β,β-disubstituted nitroalkenes with α-amidosulfones as imine precursors. Extensive experimental studies are presented to illustrate plausible mechanisms. Preliminary use of a chiral 2-nitroallylic amine as a Michael acceptor demonstrated its potential application for diversity-oriented synthesis of bioactive compounds.

Synthesis of α,γ-Chiral Trifluoromethylated Amines through the Stereospecific Isomerization of α-Chiral Allylic Amines.

Chiral γ-branched aliphatic amines are present in a large number of pharmaceuticals and natural products. However, enantioselective methods to access these compounds are scarce and mainly rely on the use of designed chiral transition-metal complexes. Herein, we combined an organocatalytic method for the stereospecific isomerization of chiral allylic amines with a diastereoselective reduction of the chiral imine/enamine intermediates, leading to γ-trifluoromethylated aliphatic amines with two noncontiguous stereogenic centers, in excellent yields and high diastereo- and enantioselectivities. This approach has been used with primary amine substrates. This approach also provides a new synthetic pathway to chiral trifluoromethylated scaffolds, of importance in medicinal chemistry. Additionally, a gram-scale reaction demonstrates the applicability of this synthetic procedure.

A Diastereoselective Catalytic Approach to Pentasubstituted Pyrrolidines by Tandem Anionic‐Radical Cross‐Over Reactions

AbstractPentasubstituted pyrrolidines are ubiquitous constituents of natural products and drugs, however the access options to them especially with respect to absolute and relative stereochemistry are not well developed. We report an asymmetric synthesis of N,2,3,4,5‐pentasubstituted pyrrolidines by oxidative single‐electron transfer‐catalyzed tandem aza‐Michael addition/radical 5‐exo cyclization/oxygenation reactions. The absolute stereochemistry is set by applying readily accessible chiral allylamines in asymmetric conjugate additions to various β‐substituted‐α,β‐unsaturated esters, which dependent on the substituent R2 sets the configuration of the two stereocenters next to the amine function, whereas two more are diastereoselectively generated by the radical 5‐exo cyclization step. This allows the diastereodivergent single‐step synthesis of pyrrolidines with four contiguous stereogenic centers. The stereoselectivity is rationalized by a predictive model.magnified image

Chiral Allylic Amine Synthesis Enabled by the Enantioselective CpXRh(III)-Catalyzed Carboaminations of 1,3-Dienes

Considering the importance of the chiral allylic amine structural motif and the rarity of synthetic methods toward their construction, herein, we report a CpXRh(III)-catalyzed enantioselective inte...

Nickel-Catalyzed Chemoselective Asymmetric Hydrogenation of α,β-Unsaturated Ketoimines: An Efficient Approach to Chiral Allylic Amines.

An efficient synthetic route to chiral allylic amines has been developed by nickel/(S,S)-Ph-BPE complex catalyzed chemoselective asymmetric hydrogenation of α,β-unsaturated ketoimines. Varieties of α,β-unsaturated ketoimines have been well tolerated in this transformation to give chiral allylic amines with high yields and excellent ee values (up to 99% yield, up to 99% ee). A gram-scale reaction with 0.2 mol % catalyst loading has also been achieved.

Ni-Catalyzed Enantioselective Intermolecular Hydroamination of Branched 1,3-Dienes Using Primary Aliphatic Amines.

A Ni-catalyzed intermolecular enantioselective hydroamination of branched 1,3-dienes is reported. The method is broadly applicable, highly regio-, chemo-, and enantioselective, and provides direct access to valuable chiral allylic amines starting from linear or α-branched aliphatic primary amines or secondary amines. Mechanistic studies have been conducted using 31P NMR spectroscopy for reaction progress monitoring, isotopic labeling experiments (2H), and kinetic analysis. The resting state of the catalyst is a Ni-π-allyl complex, and the outer-sphere nucleophilic attack of H-bonded amine aggregates is proposed to be the rate-determining step. This hypothesis guided the identification of an improved set of reaction conditions for the enantioselective hydroamination of branched 1,3-dienes.

Organocatalytic Allylic Amination of Morita–Baylis–Hillman Carbonates­

An organocatalytic asymmetric allylic amination of Morita–Baylis–Hillman carbonates with aromatic amines in the presence of β-isocupreidine is described. Chiral allylic amines were obtained in almost quantitative yields (90–96%) with moderate enantioselectivity. Recrystallization afforded products in good yields (45–73%) and high optical purity (82–99% ee). This method provides a facile and efficient route to obtain optically active β-lactams, including the building block of the cholesterol-lowering drug Ezetimibe.

Decarboxylative Organocatalytic Allylic Amination of Morita-Baylis-Hillman Carbamates.

The present study reports the organocatalytic enantioselective allylic amination of Morita-Baylis-Hillman carbamates efficiently catalyzed by a chiral amine in the presence of a Brønsted acid. Chiral allylic amines were produced in high yields (up to 98 %) and enantioselectivities (up to 97 % ee). This method provides an efficient and easily performed route to prepare α-methylene-β-lactams, and other optically active β-lactams, such as the cholesterol-lowering drug Ezetimibe.

Ni(II)-catalyzed asymmetric alkenylations of ketimines

Chiral allylic amines are not only present in many bioactive compounds, but can also be readily transformed to other chiral amines. Therefore, the asymmetric synthesis of chiral allylic amines is highly desired. Herein, we report two types of Ni(II)-catalyzed asymmetric alkenylation of cyclic ketimines for the preparation of chiral allylic amines. When ketimines bear alkyl or alkoxycarbonyl groups, the alkenylation gives five- and six-membered cyclic α-tertiary allylic amine products with excellent yields and enantioselectivities under mild reaction conditions. A variety of ketimines can be used and the method tolerates some variation in alkenylboronic acid scope. Furthermore, with alkenyl five-membered ketimine substrates, an alkenylation/rearrangement reaction occurs, providing seven-membered chiral sulfamide products bearing a conjugated diene skeleton with excellent yields and enantioselectivities. Mechanistic studies reveal that the ring expansion step is a stereospecific site-selective process, which can be catalyzed by acid (Lewis acid or Brønsted acid).

Rhodium-Catalyzed Enantioselective Alkenylation of Cyclic Ketimines: Synthesis of Multifunctional Chiral α,α-Disubstituted Allylic Amine Derivatives.

By employing a simple open-chain chiral phosphite-olefin ligand, a highly enantioselective rhodium-catalyzed alkenylation of 1,2,5-thiadiazole 1,1-dioxide-type cyclic ketimines with diverse vinylboronic acids was achieved under mild conditions at room temperature. This protocol provides an efficient and practical access to multifunctional α,α-disubstituted chiral allylic amines bearing quaternary stereocenters in high yields (up to 99%) with good to excellent ee's (up to 99%).

Catalytic Diastereo- and Enantioselective Fluoroamination of Alkenes.

The stereoselective synthesis of syn-β-fluoroaziridine building blocks via chiral aryl iodide-catalyzed fluorination of allylic amines is reported. The method employs HF-pyridine as a nucleophilic fluoride source together with mCPBA as a stoichiometric oxidant, and affords access to arylethylamine derivatives featuring fluorine-containing stereocenters in high diastereo- and enantioselectivity. Catalyst-controlled diastereoselectivity in the fluorination of chiral allylic amines enabled the preparation of highly enantioenriched 1,3-difluoro-2-amines bearing three contiguous stereocenters. The enantioselective catalytic method was applied successfully to other classes of multifunctional alkene substrates to afford anti-β-fluoropyrrolidines, as well as a variety of 1,2-oxyfluorinated products.

Ligand-Controlled Rhodium-Catalyzed Site-Selective Asymmetric Addition of Arylboronic Acids to α,β-Unsaturated Cyclic N-Sulfonyl Ketimines.

A site-selective rhodium-catalyzed asymmetric 1,4-/1,2-addition of arylboronic acids to challenging α,β-unsaturated cyclic ketimines was realized through a ligand-controlled strategy. By employing different chiral olefin ligands, a ligand-controlled switch in the reaction regioselectivity was attained for the first time. The reactions allow the synthesis of highly valuable α,α-disubstituted chiral allylic amines and enantioenriched 1,4-adducts. Further product transformation provided easy access to various quaternary carbon-containing chiral amines and amino acid derivatives bearing multifunctional groups.

Ni(II)/mono-RuPHOX-catalyzed asymmetric addition of alkenylboronic acids to cyclic aldimines

A Ni(II)-catalyzed asymmetric addition of alkenylboronic acids to aldimines has been developed employing a mono-RuPHOX ligand. A series of cyclic aldimines and alkenylboronic acids are tolerated under our catalytic system, giving various chiral allylamines in good yields and ees.