Direct Asymmetric Mannich Reaction Research Articles

Cu-Catalyzed Direct Asymmetric Mannich Reaction of 2-Alkylazaarenes and Isatin-Derived Ketimines.

The first direct catalytic asymmetric Mannich reaction of 2-alkylazaarenes and ketimines was realized with a chiral Cu-bis(oxazoline) complex as the catalyst. The asymmetric addition of 2-alkylpyridines to isatin-derived ketimines proceeded smoothly to afford α,β-functionalized 2-substituted pyridines bearing 3-amino-3,3-disubstituted oxindole motifs with excellent results (≤99% yield, 99:1 dr, and 98% ee). The catalytic system was also extended to 2-alkylbenzothiazoles as nucleophiles for the asymmetric Mannich reaction of ketimines.

Copper-Catalyzed Direct Asymmetric Vinylogous Mannich Reaction between β,γ-Alkynyl-α-ketimino Esters and β,γ-Unsaturated N-Acylpyrazoles.

We report a Cu(I)-Ph-BPE-catalyzed asymmetric vinylogous Mannich reaction of β,γ-alkynyl-α-ketimino esters with β,γ-unsaturated N-acylpyrazoles. In this process, the Cu(I)-Ph-BPE catalyst activates the β,γ-alkynyl-α-ketimino ester through N,O-coordination, enabling the subsequent nucleophilic addition of a dienolate generated from the β,γ-unsaturated N-acylpyrazole via α-position deprotonation with a catalytic amount of tertiary amine. The reactions gave useful products with very high enantioselectivities. A broad range of substrates with various substituents are tolerated in this reaction. The versatility of this method was demonstrated by a gram-scale reaction, and subsequent elaboration of the Mannich adducts was also provided.

Design of Bifunctional Amino Tf-Amide Organocatalysts and Application in Various Asymmetric Transformations.

In this personal account, we describe our recent developments on the four types of amino Tf-amide catalysts in asymmetric transformations. Firstly, axially chiral biaryl-based secondary-amino Tf-amide catalyzed various stereoselective reactions via enamine intermediates. Secondly, pyrrolidine-based secondary-amino aliphatic Tf-amide catalyzed asymmetric direct Mannich reaction. Thirdly, chiral primary-amino aliphatic Tf-amide catalyzed asymmetric direct aldol reaction and conjugate addition. Finally, modified chiral amino aromatic Tf-amide catalyzed asymmetric transformations. These four different strategies are illustrated by using various organocatalyzed asymmetric transformations.

Borane-Catalyzed Direct Asymmetric Vinylogous Mannich Reactions of Acyclic α,β-Unsaturated Ketones.

Herein, we report that, by using chiral bicyclic bisborane catalysts, we have achieved the first highly regio-, diastereo-, and enantioselective direct asymmetric vinylogous Mannich reactions of acyclic α,β-unsaturated ketones. The strong Lewis acidity and steric bulk of the bisborane catalysts were essential for the observed high yields and selectivities.

Direct Asymmetric Vinylogous Mannich Reactions of Acyclic α,β-Unsaturated Ketones Catalyzed by Chiral Boranes

Direct Asymmetric Vinylogous Mannich Reactions of Acyclic <i>α</i>,<i>β</i>-Unsaturated Ketones Catalyzed by Chiral Boranes

Direct Asymmetric Three-Component Mannich Reaction Catalyzed by Chiral Counteranion-Assisted Silver

Direct asymmetric three-component Mannich reaction involving simple ketones (such as cyclohexanone, acetone, and acetophenone) as donors and catalyzing by silver tartaric acid-derived phosphate was realized to afford a series of optically active β-amino-ketone derivatives in high yields (up to 96%) and good-to-high enantioselectivities (up to 97%) with moderate-to-good diastereoselectivities. This is the first example of direct catalytic asymmetric three-component Mannich reaction via a chiral counteranion-directed strategy.

Acyclic Branched α-Fluoro Ketones for the Direct Asymmetric Mannich Reaction Leading to the Synthesis of β-Tetrasubstituted β-Fluoro Amines.

The preparation of acyclic β-fluoro amines bearing tetrasubstituted fluorine stereocenters is described via a direct Zn/ProPhenol-catalyzed Mannich reaction. The reaction utilizes branched vinyl or alkynyl α-fluoro ketones that can be coupled with a range of aryl, heteroaryl, vinyl, or cyclopropyl aldimines in high yield and with excellent diastereo- (up to >20:1) and enantioselectivity (up to 99 %). The use of readily cleaved tert-butoxycarbonyl (Boc) or carboxybenzyl (Cbz) imine protecting groups adds utility to the reaction by allowing for easy access to the free amine products under mild and chemoselective reaction conditions.

Acyclic Branched α‐Fluoro Ketones for the Direct Asymmetric Mannich Reaction Leading to the Synthesis of β‐Tetrasubstituted β‐Fluoro Amines

AbstractThe preparation of acyclic β‐fluoro amines bearing tetrasubstituted fluorine stereocenters is described via a direct Zn/ProPhenol‐catalyzed Mannich reaction. The reaction utilizes branched vinyl or alkynyl α‐fluoro ketones that can be coupled with a range of aryl, heteroaryl, vinyl, or cyclopropyl aldimines in high yield and with excellent diastereo‐ (up to &gt;20:1) and enantioselectivity (up to 99 %). The use of readily cleaved tert‐butoxycarbonyl (Boc) or carboxybenzyl (Cbz) imine protecting groups adds utility to the reaction by allowing for easy access to the free amine products under mild and chemoselective reaction conditions.

Enantioselective Mannich Reaction Promoted by Chiral Phosphinoyl-Aziridines

In this study, a set of enantiomerically pure aziridines bearing a phosphine oxide moiety were prepared in high yields and tested as chiral catalysts in the direct asymmetric Mannich reaction of hydroxyacetone, an amine (p-anisidine), and various aromatic aldehydes. The appropriate Mannich adducts were formed in chemical yields from moderate to good with a high level of enantio- and diastereoselectivity. The best results were obtained using the catalysts bearing a free NH-aziridine subunit.

Anti-selective direct asymmetric Mannich reaction catalyzed by protease

The anti-selective direct asymmetric Mannich reaction of (hetero) aromatic aldehydes, 4-anisidine and O-protected hydroxyacetones for the synthesis of stereodefined anti-β-amino-α-hydroxycarbonyl compounds was developed. Protease type XIV from Streptomyces griseus (SGP) was used as a biocatalyst in 1,4-dioxane/phosphate buffer under mild reaction conditions. The excellent diastereoselectivities of up to >99:1 (anti/syn) and good enantioselectivities of up to 90% ee were achieved. This method provides a more sustainable complement to chemically catalyzed anti-selective direct asymmetric Mannich reactions.

Direct Asymmetric Mannich Reaction Catalyzed by a d-Glucosamine-Derived Organocatalyst

Sugar-based primary amines have been employed as organocatalysts for the direct asymmetric Mannich reaction. By catalyst-screening experiments, we observed that catalysts bearing a hydroxy function at C-3 actively participated in the reaction, possibly through hydrogen bonding with the imine generated in situ, to provide β-amino carbonyl compounds with better diastereoselectivity and enantioselectivity. All the products were obtained in good to excellent enantiomeric excess.

Chiral phosphoric acid-catalyzed direct asymmetric mannich reaction of cyclic C-acylimines with simple ketones: facile access to C2-quaternary indolin-3-ones.

A chiral Brønsted acid-catalyzed direct asymmetric Mannich reaction of simple ketones with cyclic C-acylimines has been established for the synthesis of C2-quaternary indolin-3-ones. In the presence of 5-10 mol% chiral phosphoric acid, a series of 2-(2-oxo-2-phenylethyl)-2-arylindolin-3-ones were obtained in good to high yield with up to 99% ee. The adducts obtained could be readily converted into indolines, tricyclic indolin-3-ones, and tetracyclic tetrahydro-indolo[1,2-a]quinolines by simple modifications.

Three-Component Asymmetric Mannich Reaction Catalyzed by a Lewis Acid with Rhodium-Centered Chirality.

A highly efficient direct asymmetric three-component Mannich reaction of an N-acylpyrazole, an aldehyde and a primary or secondary amine, was enabled by a rhodium-based Lewis-acid catalyst with metal-centered chirality. Excellent enantioselectivities were achieved for a variety of substrates at a typical catalyst loading of merely 0.5 mol % (23 examples, up to 98 % ee).

Asymmetric Aziridination of N-Sulphonyl Ketimines with Unfunctionalized Ketones: A One-pot Approach to Multisubstituted Fused Aziridines.

A highly diastereo- and enantioselective aziridination of N-sulphonyl ketimines with unfunctionalized ketones was reported. In this efficient method, a sequential direct asymmetric Mannich reaction and oxidative C-H amination were involved, which enabled a straightforward route to multisubstituted-fused aziridines in one pot. More importantly, two different products could be selectively obtained in the reaction by adding or removing a metal additive.

Direct Asymmetric Aza-Vinylogous Mannich Reaction of Nitrones from Isatins and Ketimines

Direct Asymmetric Aza-Vinylogous Mannich Reaction of Nitrones from Isatins and Ketimines

A novel homobimetallic nickel complex for the asymmetric direct Mannich reaction of imines: a practical method on a multi-gram scale.

A novel dinuclear Ni complex has been developed for the direct Mannich reaction of malonates with N-tosyl aryl imines with a low catalyst loading (0.1-0.05 mol%) on a preparative scale (5-50 mmol). The structure of the active species was verified via control experiments, ESI-HRMS, and DFT calculations.

First example of an organocatalytic asymmetric Mannich reaction between aldimines of glycinates and sulphonyl imines

The catalytic enantioselective Mannich-type reaction between glycinate Schiff base and imines has been one of the most efficient routes for accessing α,β-diamino acids. However, the glycinate Schiff bases used in the references were almost ketimines. Only several examples of aldimines were used in the presence of metal catalyst. We developed the first example of an asymmetric direct Mannich reaction using aldimines of glycinates instead of ketimines of glycinates. The reaction was well catalyzed by chiral guanidine with high yield (up to 92%) and moderate stereoselectivity (up to 65%).

ChemInform Abstract: Direct Catalytic Asymmetric Mannich Reactions for the Construction of Quaternary Carbon Stereocenters.

AbstractThe first direct asymmetric Mannich reaction by using α‐branched ketones as nucleophilic partners is presented and gives an enantio‐ and diastereoselective access to various β‐amino ketones.

ChemInform Abstract: Bifunctional Amino Sulfonohydrazide Catalyzed Direct Asymmetric Mannich Reaction of Cyclic Ketimines with Ketones: Highly Diastereo‐ and Enantioselective Construction of Quaternary Carbon Stereocenters.

AbstractA bifunctional amino sulfonohydrazide is shown to enhance reactivity and enantioselectivity in the direct asymmetric Mannich reaction of N‐sulfonyl cyclic ketimines with ketones.

ChemInform Abstract: Primary Amino Acid Catalyzed Asymmetric Intramolecular Mannich Reaction for the Synthesis of 2‐Aryl‐2,3‐dihydro‐4‐quinolones.

AbstractPrimary amino acids are found to be efficient catalysts for the direct asymmetric Mannich reaction of 2‐aminoacetoacetophenones with aldehydes furnishing 2‐aryldihydroguinolones (III) (25 examples) in moderate to good yield and good to high enantioselectivities.