The ketimine Mannich reaction is an asymmetric synthetic technique using differences in starting material to push a Mannich reaction to create an enantiomeric product with steric and electronic effects, through the creation of a ketimine group. Typically, this is done with a reaction with proline or another nitrogen-containing heterocycle, which control chirality with that of the catalyst. This has been theorized to be caused by the restriction of undesired (E)-isomer by preventing the ketone from accessing non-reactive tautomers. Generally, a Mannich reaction is the combination of an amine, a ketone with a β-acidic proton and aldehyde to create a condensed product in a β-addition to the ketone. This occurs through an attack on the ketone with a suitable catalytic-amine unto its electron-starved carbon, from which an imine is created. This then undergoes electrophilic addition with a compound containing an acidic proton (which is an enol). It is theoretically possible for either of the carbonyl-containing molecules to create diastereomers, but with the addition of catalysts which restrict addition as of the enamine creation, it is possible to extract a single product with limited purification steps and in some cases as reported by List et al.; practical one-pot syntheses are possible. The process of selecting a carbonyl-group gives the reaction a direct versus indirect distinction, wherein the latter case represents pre-formed products restricting the reaction's pathway and the other does not. Ketimines selects a reaction group, and circumvent a requirement for indirect pathways.
Theory It is well-known that Lewis acids and bases can influence carbonyl activity by either protonation of the oxygen or de-protonation of a beta-site to influence electrophilicity at the carbon. In the former case, there is a stabilization effect and priming for a potential leaving group by providing an equilibrium between a formal positive charge and an alcohol group. In either case, the carbon sees enhanced reactivity as the bonds are strained to equalize charge by seeking a nucleophile to which the building charge will equalize into in the subsequent reaction. Potentiation in such reactions is therefore generally driven by how well a material can produce and stabilize a charge gradient through resonance or inductive effects in substituents. The surfaces of acids can catalyze these effects by stabilizing the distortion of the carbonyl's electron cloud, leading to sensitivity in the reaction to acid-base conditions, with acidic conditions typically favoring reaction by enhancing carbonyl leavability. Mannich reactions are named after their pioneer, Carl Mannich. After the discovery of Mannich reaction in 1912, he found that combination of a ketone, aldehyde and amine consistently produced an addition of the aldehyde unto the site originally containing an acidic β-proton in the ketone. He theorized the mechanism to be one of mixed-aldol; featuring the dehydration of an alcohol and Michael-Addition of the complex. The reaction suffered from a lack of specificity, and this problem persisted until 1997, in which an asymmetrical method was discovered independently by several researchers. Kobayashi et al. used Brønsted-acid to demonstrate that the organic reaction could occur in an aqueous medium, and also found an enantiomeric excess of nearly 55%. It was hypothesized that one of the reactants must be using the acid surface to change its electronic structure since otherwise the mixture would be immiscible, though the study used chiral Lewis acid as catalyst. Prior, Hajos et al. demonstrated a method by which L-proline could be used in an aldol-cyclization. Subsequent studies have focused on improving the catalyst or materials through substituent effects, from which controls using sterics or restriction of charge sites are expected to improve catalytic yields. Alternatives to the catalyst are not readily explored due to the ubiquity of L-proline, its low cost, and its high selectivity; cementing its proliferation as a catalytic standard. L-proline restricted reactions through its five-membered ring which favours the addition of another reactant in a fixed direction. List et al. theorize in their study that this restriction is primarily in the carboxylic-acid group next to the enamine attachment, which can stabilize the imine product. List also expands upon the role of the imine by listing its ratio with the aldehyde to be 1 using 1H-NMR methods, indicating that the Michael Addition is rate-determining and not the proline-complexation or, obviously, aldehyde activation. This is further confirmed in a Hammett study on para-substituted aromatic aldehydes, in which List confirmed positive correlation between withdrawing effect and increasing imine reactivity, a sign that Michael addition had to be happening with the former aldehyde as an electrophile.
Substituent studies Substituent studies have focused on increasing or decreasing steric or electronic influences on material to favor product. In 2012, the first non-aromatic ketiminoester was produced with the capability of reduction into either syn- or anti- lactones with NaBH4 reduction. Kano et al. demonstrated a 20:1 excess of desired product, electrophilic enhancement of the ketone by different flanking esters.
Endocyclic ketimines without electron-withdrawing substituents BINOL phosphoric acid-catalyzed Mannich reaction (2019) Reddy and coworkers proposed the method to produce endocyclic N-acyl ketimines from a stable precursor, 3-aryl-3-hydroxyisoindolin-1-ones in 2019. The reaction yields a high stereoselectivity under high temperature as the adjacent quaternary and stereogenic centers creating chirality. Meanwhile, if 3-hydroxy-3-pentylisoindoline-1-one is used, 95% enamide would be generated instead of Mannich product under the same mechanism.
Proline-catalyzed direct asymmetric Mannich reaction of 3-substituted-2H-1,4-benzoxazines (2013) In 2013, Wang and coworkers studied using 3,4-dihydro-2H-1,4-benzoxazines to produce N-heterocyclic products. This reaction was the first catalytic asymmetric Mannich reaction of 3,4-dihydro-2H-1,4-benzoxazines. The aromatic ring strain in 3,4-dihydro-2H-1,4-benzoxazines helps increase reactivity of the C=N double bond and gives the considerable yield with no electron withdrawing substituents. Similar mechanism also occurred in the reaction catalyzed by wheat germ lipase in 2016 provided by Guan, He and coworkers.
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