Alkylation Of Imines Research Articles

Synthesis of the Indolizidine Core of Virosinine A via a Microwave-Promoted Cascade Cyclization Involving Iminyl Radicals.

The indolizidine core of virosinine A was synthesized by means of a microwave-promoted cascade reaction featuring 5-exo-trig iminyl radical cyclization, thiyl radical elimination, and intramolecular imine alkylation. The resulting bicyclic iminium ion underwent stereoselective reduction by Red-Al to deliver the target compound. DFT calculations suggested that both the radical cyclization and thiyl radical elimination steps are reversible at high reaction temperatures.

Visible-light-driven photocatalyst-free deoxygenative alkylation of imines with alcohols

In this report, we developed a photocatalyst-free visible-light-promoted deoxygenative alkylation of imines with alcohols assisted by carbon disulfide and tricyclohexylphosphine. The key to success of this method is the activation of alcohols upon the formation and direct photoexcitation of xanthate anions. This one-pot protocol enables the selective C-O bond homolysis of diverse primary, secondary and tertiary alcohols to react with a variety of N-sulfonyl and N-aryl imines, providing a general and efficient platform for α-branched amine synthesis from alcohols.

Excited-state palladium-catalysed reductive alkylation of imines: scope and mechanism.

Palladium catalysis induced by visible-light irradiation is a promising tool for promoting unusual chemical transformations. We describe the development of excited-state palladium-catalyzed reductive alkylation of imines with alkyl bromides. The new methodology shows broad functional group tolerance and can additionally be applied in the direct three-component reaction of aldehydes, anilines, and alkyl bromides to give the alkyl amines under mild reaction conditions. Time-resolved photoluminescence experiments allowed the determination of the excited-state reaction kinetics and indicate that the reaction is proceeding via the inner-sphere electron transfer mechanism.

Cobalt-Catalyzed Umpolung Alkylation of Imines To Generate α-Branched Aliphatic Amines.

Here we report a general and mild approach to prepare α-branched aliphatic amines from imines. This method capitalizes on a cobalt-catalyzed umpolung alkylation of imines, employs easily available reaction partners, and demonstrates a broad substrate scope. Mechanistic studies suggest this transformation occurs by a radical pathway.

Catalytic asymmetric reductive hydroalkylation of enamides and enecarbamates to chiral aliphatic amines

To increase the reliability and success rate of drug discovery, efforts have been made to increase the C(sp3) fraction and avoid flat molecules. sp3-Rich enantiopure amines are most frequently encountered as chiral auxiliaries, synthetic intermediates for pharmaceutical agents and bioactive natural products. Streamlined construction of chiral aliphatic amines has long been regarded as a paramount challenge. Mainstream approaches, including hydrogenation of enamines and imines, C–H amination, and alkylation of imines, were applied for the synthesis of chiral amines with circumscribed skeleton structures; typically, the chiral carbon centre was adjacent to an auxiliary aryl or ester group. Herein, we report a mild and general nickel-catalysed asymmetric reductive hydroalkylation to effectively convert enamides and enecarbamates into drug-like α-branched chiral amines and derivatives. This reaction involves the regio- and stereoselective hydrometallation of an enamide or enecarbamate to generate a catalytic amount of enantioenriched alkylnickel intermediate, followed by C–C bond formation via alkyl electrophiles.

Tackling N‐Alkyl Imines with 3d Metal Catalysis: Highly Enantioselective Iron‐Catalyzed Synthesis of α‐Chiral Amines

AbstractA readily activated iron alkyl precatalyst effectively catalyzes the highly enantioselective hydroboration of N‐alkyl imines. Employing a chiral bis(oxazolinylmethylidene)isoindoline pincer ligand, the asymmetric reduction of various acyclic N‐alkyl imines provided the corresponding α‐chiral amines in excellent yields and with up to >99 % ee. The applicability of this base metal catalytic system was further demonstrated with the synthesis of the pharmaceuticals Fendiline and Tecalcet.

Synthesis of C2 Hybrid Amide‐Based PTC Catalysts and Their Comparison with Saturated Analogues

AbstractWe investigated the synthesis and catalytic efficiency of four new C2 hybrid PTC catalysts and their saturated analogues with reduced double bond. These eight novel hybrid catalysts can be straightforwardly synthesized with good yields and high structural design diversity (with various linkers). The catalytic efficiency of our catalysts was systematically investigated using a glycine imine alkylation reaction, carried out under PTC conditions. It was found that saturated catalysts show both higher reaction yield (up to 98%) and enantioselectivity (up to 94% ee).

Reductive coupling of imines with redox-active esters by visible light photoredox organocatalysis

The direct alkylation of imines with redox-active esters by visible light photoorganocatalysis provides a direct way for accessing α-branched secondary amines which are found in numerous bioactive molecules.

Reductive alkylation of imines via asymmetric Cu-catalyzed addition of organozirconium reagents

Chiral amines are important as medicines or agrochemicals. They are often assembled by nucleophilic addition to corresponding compounds featuring CN bond. Pre-made organometallics are typical nucleophiles in this reaction. In this work, we describe asymmetric reductive alkylation of imines with alkenes. Hydrozirconation of these alkenes generated organozirconium species in situ. The transformation is catalyzed by Cu-Segphos complex and affords chiral amines in enantioselectivities up to 93% ee.

Enantioselective Alkylation of Imines via Copper-Catalyzed Asymmetric Photoredox

Enantioselective Alkylation of Imines via Copper-Catalyzed Asymmetric Photoredox

Copper(II)-Catalyzed Asymmetric Photoredox Reactions: Enantioselective Alkylation of Imines Driven by Visible Light

Asymmetric photoredox catalysis offers exciting opportunities to develop new synthetic approaches to chiral molecules through novel reaction pathways. Employing the first-row transition metal complexes as the chiral photoredox catalysts remains, however, a formidable challenge, although these complexes are economic, environmentally friendly, and often exhibit special reactivities. We report in this Article the development of one class of highly efficient asymmetric/photoredox bifunctional catalysts based on the copper(II) bisoxazoline complexes (CuII-BOX) for the light-induced enantioselective alkylation of imines. The reactions proceed under very mild conditions and without a need for any other photosensitizer. The simple catalytic system and readily tunable chiral ligands enable a significantly high level of enantioselectivity for the formation of chiral amine products bearing a tetrasubstituted carbon stereocenter (36 examples, up to 98% ee). Overall, the CuII-BOX catalysts initiate the radical generation, and also govern the subsequent stereoselective transformations. This strategy utilizing chiral complexes comprised of a first-row transition metal and a flexible chiral ligand as the asymmetric photoredox catalysts provides an effective platform for the development of green asymmetric synthetic methods.

Visible light-promoted alkylation of imines using potassium organotrifluoroborates.

A mild, redox-neutral, alkylation of imines with potassium alkyltrifluoroborates is described. The reaction proceeds under photoredox conditions at ∼30 °C with primary, secondary, and tertiary alkyltrifluoroborates, leading to alkylation products in moderate to good yield in most cases. Aryl-, vinyl-, and cyclopropyltrifluoroborates failed to react under the reported conditions.

Asymmetric Imine Hydroboration Catalyzed by Chiral Diazaphospholenes

AbstractThe first use of diazaphospholenes as chiral catalysts has been demonstrated with enantioselective imine hydroboration. A chiral diazaphospholene prepared in a simple three‐step synthesis from commercial materials has been shown to achieve the highest enantioselectivity for the hydroboration of alkyl imines with pinacolborane reported to date. Enantiomer ratios of up to 88:12 were obtained with low (2 mol %) catalyst loadings. Twenty examples of asymmetric reduction employing this main‐group catalysis protocol, including the synthesis of the pharmaceuticals ent‐rasagiline and fendiline, are shown.

Asymmetric Imine Hydroboration Catalyzed by Chiral Diazaphospholenes.

The first use of diazaphospholenes as chiral catalysts has been demonstrated with enantioselective imine hydroboration. A chiral diazaphospholene prepared in a simple three-step synthesis from commercial materials has been shown to achieve the highest enantioselectivity for the hydroboration of alkyl imines with pinacolborane reported to date. Enantiomer ratios of up to 88:12 were obtained with low (2 mol %) catalyst loadings. Twenty examples of asymmetric reduction employing this main-group catalysis protocol, including the synthesis of the pharmaceuticals ent-rasagiline and fendiline, are shown.

Radical Alkylation of Imines with 4-Alkyl-1,4-dihydropyridines Enabled by Photoredox/Brønsted Acid Cocatalysis.

Radical alkylation of imines with 4-alkyl-1,4-dihydropyridines cocatalyzed by iridium/ruthenium complex and Brønsted acid under visible light irradiation has been achieved. Both aldimines and ketimines can undergo this transformation. Common functional groups, such as hydroxyl groups, ester, amide, ether, cyanide, and heterocycles, can be tolerated in this reaction. A variety of structurally diverse amines (57 examples) have been produced with up to 98% isolated yields using this method.

Redox-Neutral Alkylation of Imines through Organic Photocatalysis

Redox-Neutral Alkylation of Imines through Organic Photocatalysis

Mild, Redox-Neutral Alkylation of Imines Enabled by an Organic Photocatalyst.

An operationally simple, mild, redox-neutral method for the photoredox alkylation of imines is reported. Utilizing an inexpensive organic photoredox catalyst, alkyl radicals are readily generated from the single-electron oxidation of ammonium alkyl bis(catecholato)silicates and are subsequently engaged in a C–C bond-forming reaction with imines. The process is highly selective, metal-free, and does not require a large excess of the alkylating reagent or the use of acidic additives.

Polarity‐Reversed Allylations of Aldehydes, Ketones, and Imines Enabled by Hantzsch Ester in Photoredox Catalysis

AbstractThe polarity reversal (umpolung) reaction is an invaluable tool for reversing the chemical reactivity of carbonyl and iminyl groups, which subsequent cross‐coupling reactions to form C−C bonds offers a unique perspective in synthetic planning and implementation. Reported herein is the first visible‐light‐induced polarity‐reversed allylation and intermolecular Michael addition reaction of aldehydes, ketones, and imines. This chemoselective reaction has broad substrate scope and the engagement of alkyl imines is reported for the first time. The mechanistic investigations indicate the formation of ketyl (or α‐aminoalkyl) radicals from single‐electron reduction, where the Hantzsch ester is crucial as the electron/proton donor and the activator.

Polarity-Reversed Allylations of Aldehydes, Ketones, and Imines Enabled by Hantzsch Ester in Photoredox Catalysis.

The polarity reversal (umpolung) reaction is an invaluable tool for reversing the chemical reactivity of carbonyl and iminyl groups, which subsequent cross-coupling reactions to form C-C bonds offers a unique perspective in synthetic planning and implementation. Reported herein is the first visible-light-induced polarity-reversed allylation and intermolecular Michael addition reaction of aldehydes, ketones, and imines. This chemoselective reaction has broad substrate scope and the engagement of alkyl imines is reported for the first time. The mechanistic investigations indicate the formation of ketyl (or α-aminoalkyl) radicals from single-electron reduction, where the Hantzsch ester is crucial as the electron/proton donor and the activator.

Stereoselective Alkylation of Imines and its Application towards the Synthesis of β‐Lactams

Abstract(S)‐4‐Isopropyl‐1‐[(R)‐1‐phenylethyl]imidazolidin‐2‐one was evaluated as a chiral auxiliary for asymmetric acetate and propionate Mannich‐type reactions, by generation of the titanium enolates, affording excellent yields and stereoselectivities. The application of the auxiliary was exemplified in the stereoselective synthesis of the β‐lactam antihyperlipidemic drug ezetimibe.