Direct Mannich Reaction Research Articles

Enantioselective synthesis of α-(3-pyrrolyl)methanamines with an aza-tetrasubstituted center under metal-free conditions.

Construction of a chiral methanamine unit at the C3 position of pyrrole is highly desirable; nevertheless, it remains challenging due to its intrinsic electronic properties. Herein, we present an operationally straightforward and direct asymmetric approach for accessing α-(3-pyrrolyl)methanamines under benign organocatalytic conditions for the first time. The one-pot transformation proceeds smoothly through an amine-catalyzed direct Mannich reaction of succinaldehyde with various endo-cyclic imines, followed by a Paal-Knorr cyclization with a primary amine. Several N-H/alkyl/Ar α-(3-pyrrolyl)methanamines with an aza-tetrasubstituted center have been synthesized with good yields and excellent enantioselectivity.

Organo‐Catalyzed Enantioselective [4+2] Annulation of Glutaraldehyde and C3‐Indolyl‐imines To Access Indol‐3‐yl‐piperidines

AbstractA simple and straightforward method is developed for the enantioselective synthesis of indol‐3‐yl‐piperidine. The reaction proceeds through a proline‐catalyzed direct Mannich reaction between glutaraldehyde and C3‐indolyl‐imines, followed by intramolecular reductive cyclization as an overall [4+2] annulation in one‐pot fashion. A series of indol‐3‐yl‐piperidine have been accessed with good yields up to 71 % and high enantioselectivity up to >99 % ee.

Stereoselective Mannich reaction catalyzed by tetrahydroindolo[3,2-b]indole under solvent-free conditions

A series of indole-based organocatalysts (4b,9b-aryl-4b,5,9b,10-tetrahydroindolo[3,2-b]indole derivatives) (2a-2f) have been designed and synthesized for the three-component direct Mannich reaction of aromatic aldehydes and aromatic amines with ketones. Significantly, the organocatalyst 2a delivered excellent catalytic stereoselectivity (up to >99:1) with good yields (up to 88 %) for above reaction process under the solvent-free conditions at room temperature. X-ray diffraction analysis reveals that organocatalyst 2a is of eight-membered central ring structure with interesting strained quadricyclic ring connectivity. The characteristic rigid V-shape indole ring structure contained in 2a and the formed hydrogen-bonding interaction between 2a and intermediate prefer to the anti-stereoselective product.

Deployment of Sulfinimines in Charge-Accelerated Sulfonium Rearrangement Enables a Surrogate Asymmetric Mannich Reaction.

β-Amino acid derivatives are key structural elements in synthetic and biological chemistry. Despite being a hallmark method for their preparation, the direct Mannich reaction encounters significant challenges when carboxylic acid derivatives are employed. Indeed, not only is chemoselective enolate formation a pitfall (particularly with carboxamides), but most importantly the inability to reliably access α-tertiary amines through an enolate/ketimine coupling is an unsolved problem of this century-old reaction. Herein, we report a strategy enabling the first direct coupling of carboxamides with ketimines for the diastereo- and enantioselective synthesis of β-amino amides. This conceptually novel approach hinges on the innovative deployment of enantiopure sulfinimines in sulfonium rearrangements, and at once solves the problems of chemoselectivity, reactivity, and (relative and absolute) stereoselectivity of the Mannich process. In-depth computational studies explain the observed, unexpected (dia)stereoselectivity and showcase the key role of intramolecular interactions, including London dispersion, for the accurate description of the reaction mechanism.

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.

Synthesis and structure of the bimetallic organoantimony catalyst and its application in diastereoselective direct Mannich reaction as facile separation catalytic system

A bimetallic organoantimony catalyst with four Lewis/Brønsted acidic/basic sites assembled orderly was successfully synthesized and showed high catalytic efficiency. It has been applied in diastereoselective direct Mannich reaction by adding 0.1 mol% catalyst. This reaction presented unexpected facile separation ability from homogenous solution to heterogeneous solution.

Direct Asymmetric α‐Selective Mannich Reaction of β,γ‐Unsaturated Ketones with Cyclic α‐Imino Ester: Divergent Synthesis of Cyclocanaline and Tetrahydro Pyridazinone Derivatives

The first regio-, diastereo-, and enantioselective direct Mannich reaction of β,γ,-unsaturated ketones with benzoxazinone cyclic imines was enabled by Lewis acid/Brønsted base cooperative catalysis. The dinuclear zinc complex catalyzed the reaction of a broad range of β,γ-unsaturated ketones to proceed at the α-site exclusively, leading to corresponding adducts with two consecutive tertiary carbon stereocenters in diastereomeric ratios of up to >20:1 and enantioselectivities generally in the 90-99 % ee range. These products were used as general intermediates in the synthesis of multisubstituted cyclocanalines, tetrahydro pyridazinones, and 4H-furo[2,3-b][1,4]benzoxazine derivatives.

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 Amine-Catalyzed Enantioselective Synthesis of Pentacyclic Dibenzo[b,f][1,4]oxazepine/Thiazepine-Fused Isoquinuclidines along with DFT Calculations.

A direct protocol for the asymmetric synthesis of dibenzoxazepine/thiazepine-fused [2.2.2] isoquinuclidines is developed. The reaction proceeds through a proline-catalyzed direct Mannich reaction followed by an intramolecular aza-Michael cascade sequence between 2-cyclohexene-1-one and various tricyclic imines, like dibenzoxazepines/thiazepines, as an overall [4 + 2] aza-Diels-Alder reaction. A series of pentacyclic isoquinuclidines have been prepared, with complete endo-selectivity, in good to high yields and excellent enantioselectivity (>99:1). Density functional theory (DFT) calculations further support the observed high stereochemical outcome of the reaction.

Enantioselective direct Mannich reactions of 3-substituted oxindoles catalyzed by chiral phosphine via dual-reagent catalysis

A combination of an amino acid-derived chiral phosphine catalyst and methyl acrylate to catalyze the direct Mannich reaction of 3-substituted oxindoles and imines has been reported to afford 3-tetrasubstituted oxindole derivatives which are key structures for biological activities. The products are formed with a quaternary carbon and featured with two adjacent chiral centers. Various N-EDG(electron-donating group) and N-EWG(electron-withdrawing group) protected oxindoles, including 3-aryl and 3-alkyl substituted ones, have been evaluated with aromatic and aliphatic imines under this catalytic system, smoothly giving desired products in good yields as well as excellent diastereo- and enantioselectivities.

Asymmetric organocatalytic direct Mannich reaction of acetylacetone and isatin derived ketimines: Low catalyst loading in chiral cinchona-squaramides

A highly enantioselective synthesis of 3-amino-2-oxindoles by direct Mannich reaction between acetylacetone and N-carbamoyl isatin ketimine has been described herein. Corresponding chiral adducts were obtained in high yields (up to 98%) and with excellent enantioselectivities (up to >99% ee) by very low (1 mol%) catalyst loading of 2-adamantyl substituted bifunctional cinchona-squaramide.

Mannich Reaction of Indole with Cyclic Imines in Water

An efficient MsOH promoted direct Mannich reaction of indoles with α-nonsubstituted aliphatic cyclic imines has been developed. The reactions were performed in water and the obtained piperidin-2-yl-indoles act as a useful precursor for the synthesis of various alkaloid-like derivatives.

Asymmetric Synthesis of α-Fluoro-β-Amino-oxindoles with Tetrasubstituted C-F Stereogenic Centers via Cooperative Cation-Binding Catalysis.

Biologically relevant chiral 3,3-disubstituted oxindole products containing a β-fluoroamine unit are obtained in high yields and with excellent stereoselectivity (up to 99% ee, dr >20:1 for syn) through the organocatalytic direct Mannich reaction of 3-fluoro-oxindoles as fluoroenolate precursors and α-amidosulfones as the bench-stable precursors of sensitive imines by using a chiral oligoethylene glycol and KF as a cation-binding catalyst and base, respectively. This protocol can be easily scaled without compromising the asymmetric induction. Furthermore, this protocol was also successfully extended to generate tetrasubstituted C-Cl and C-Br stereogenic centers.

Dual-reagent organophosphine catalyzed asymmetric Mannich reactions of isocyanoacetates with N-Boc-aldimines

A combination of an amino-acid derived chiral phosphine catalyst and methyl acrylate has been employed to catalyze the direct Mannich reaction of α-aryl isocyanoacetate and N-Boc-aldimines efficiently. The loading of the catalyst could be as low as 0.5 mol% without compromise on the yield and enantioselectivity and the corresponding chiral adducts were obtained in excellent yields (up to 98%) and good enantioselectivities (up to 95%).

Enantioselective direct Mannich reaction of functionalized acetonitrile to N-Boc imines catalyzed by quaternary phosphonium catalysis

Quaternary phosphonium ion-pair or a salt derived from amino acid has been developed to catalyze the Mannich-type reaction of α-substituted ethyl cyanoacetates and 2-(2-nitrophenyl) acetonitrile to N-Boc imines. Experiments shown that more active cyanoacetates could be catalyzed by the gentle phosphonium ion-pair catalysis, while 2-(2-nitrophenyl) acetonitrile as the substrate has to be activated by quaternary phosphonium salts and strong base. All the reactions gave the corresponding highly functionalized chiral β-amino nitriles products with good yields, high diastereo- and enantioselectivities in mild conditions.

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.

ChemInform Abstract: Direct Carbon—Carbon Bond Formation via Reductive Soft Enolization: A syn‐Selective Mannich Addition of α‐Iodo Thioesters.

The β-amino carboxylic acid moiety is a key feature of numerous important biologically active compounds. We describe a syn-selective direct Mannich addition reaction that uses α-iodo thioesters and sulfonyl imines and produces β-amino thioesters. Enolate formation is achieved by reductive soft enolization. The products of the reaction provide straightforward access to biologically important β-lactams through a variety of known reactions.

Asymmetric Mannich Reaction of Aryl Methyl Ketones with Cyclic Imines Benzo[e][1,2,3]oxathiazine 2,2-Dioxides Catalyzed by Cinchona Alkaloid-based Primary Amines.

Aryl ketones represent problematic substrates for asymmetric Mannich reactions due to a large steric hindrance exhibited by such compound species. A highly enantioselective direct Mannich reaction of aryl methyl ketones with cyclic imine benzo[e][1,2,3]oxathiazine 2,2-dioxides could be successfully carried out utilizing a combination of cinchona alkaloid-derived primary amines with trifluoroacetic acid (TFA); the primary amines feature a superior catalytic efficacy over secondary amines with a variety of sterically hindered carbonyl compounds as substrates. The reaction proceeded well with various cyclic imines in 89-97 % ee and with various aryl methyl ketones in 85-98 % ee. Moreover, the aryl carbonyl of a Mannich product could be transformed to ketoxime, which further undergoes a Beckmann rearrangement to produce an amide compound while maintaining enantioselectivity.

ChemInform Abstract: Enantioselective Construction of Imidazolines Having Vicinal Tetra‐Substituted Stereocenters by Direct Mannich Reaction of α‐Substituted α‐Isocyanoacetates with Ketimines.

The catalytic Mannich reaction of α-substituted α-isocyanoacetates with ketimines has been investigated. A variety of imidazolines containing congested vicinal tetra-substituted stereocenters were obtained in excellent yields with high diastereo- and enantioselectivity using cinchona alkaloid amide/Ni(II) and base catalysts.

ChemInform Abstract: Organocatalyzed Enantioselective Direct Mannich Reaction of α‐Styrylacetates.

An organocatalyzed direct Mannich reaction of unactivated α-styrylacetates was realized for the first time. By using a quinidine-derived C6′-urea catalyst, the direct Mannich reaction of α-styrylacetates and N-tosylimines gave the desired β-amino esters in high yields, diastereoselectivities, and ee values. The reaction provides a highly stereoselective (up to 96:4 dr and 97% ee) and the most straightforward synthesis of functionalized N-tosylated β-amino esters. The products can be used as precursors for the highly selective synthesis of tetrahydrofuran derivatives.