Organocatalyzed Asymmetric Mannich Reaction: An Update

Abstract

The Mannich reaction is a multicomponent reaction resulting in aminoalkylation of an acidic proton placed next to a carbonyl functional group. It involves an appropriate carbonyl compound, such as formaldehyde and a primary or secondary amine or ammonia. The final product is a β‐amino‐carbonyl compound known as a Mannich base. Reactions between aldimines and α‐methylene carbonyls are also considered as Mannich reaction since these imines are generated from the reaction of amines and aldehydes. It comprises the reaction of primary or secondary amines or ammonia, formaldehyde and appropriate α‐CH‐acidic compounds (nucleophiles) such as carbonyl compounds having α‐CH‐acidic, nitriles, acetylenes, aliphatic nitro compounds, α‐alkyl‐pyridines or imines. Owing to the development of asymmetric organocatalysis, reports on asymmetric Mannich reaction have been drastically increased. The asymmetric Mannich reaction offers access to enantioenriched β‐amino ketones or β‐amino aldehydes, which are present as a scaffold in several natural products. Organocatalysts have been developed not only as a supplement to metal‐catalyzed reactions or to biocatalysis, but nowadays, they are extensively used for the synthesis of various optically pure compounds that could not be achieved via metal‐ or biocatalyzed reactions. In this review, we try to update the advances in organocatalyzed asymmetric Mannich reactions, covering the recent advances of the subject from 2008 to date.

A Data-Driven Workflow for Assigning and Predicting Generality in Asymmetric Catalysis

“…In this first stage of developing an unsupervised learning platform, we sought to identify a “privileged” reaction type in catalysis wherein many different catalyst chemotypes had been employed. As imine electrophiles and carbonyl nucleophiles are amenable to a variety of catalytic modes of activation, we identified the organocatalytic Mannich reaction as the unifying reaction platform (Figure A). − This reaction type provides a wide range of both substrate and catalyst structures from published sources. We curated a data set consisting of 3003 reactions from 106 publications wherein diverse chiral H-bonding (1418 reactions), Brønsted acid (256 reactions), covalent catalysts (1182 reactions), and miscellaneous catalysts (147 reactions) had been employed (Figure ).…”

Enantio- and Diastereoselective Mannich Reactions of ß-Dicarbonyls by Second Stage Diastereoconvergent Crystallization

“…We began our studies with the reaction of ethyl acetoacetate 1a and the benzyl carbamate (Cbz) protected imine 2a using Takemoto’s chiral nonracemic tertiary amine catalyst I (Figure b) . In agreement with the prior art, when the reaction was performed in homogeneous conditions (e.g., solvent = DCM), no diastereoselectivity was observed. ,, Ethereal solvents proved crucial to the selective crystallization of one diastereomer directly from the reaction mixture (see Supporting Information for reaction optimization) . Fine-tuning the carbamate solubility properties by using a mixture of diethyl ether and pentanes (3:1) resulted in good isolated yield while retaining excellent stereoselectivity after a single filtration of the reaction mixture (68% yield, >20:1 dr, 90:10 er).…”

Asymmetric oxidative Mannich reactions promoted by photocatalysis and electrochemistry

“…2 Asymmetric catalytic Mannich reactions have emerged as a direct strategy for constructing chiral nitrogenous molecules with important biological activities. 3…”

“…2 Asymmetric catalytic Mannich reactions have emerged as a direct strategy for constructing chiral nitrogenous molecules with important biological activities. 3 The traditional Mannich reaction is a three-component condensation of an aldehyde (or ketone) and an amine with a compound containing an active hydrogen compound (such as aldehyde or ketone), which affords aminoalkylated derivatives. This process is also generally referred to as the direct Mannich reaction (Scheme 1), in which the critical element is the imine intermediate formed by an aldehyde (or ketone) and an amine.…”