Inorganic chemistry, theMannich reaction is a three-componentorganic reaction that involves theamino alkylation of the α-position of a ketone or aldehyde with an aldehyde and anullary, primary, or secondaryamine (−NH2).[1] The final product is a β-amino-carbonyl compound also known as aMannich base. The reaction is named afterCarl Mannich.[2][3]
An acid-catalyzed three component reaction with amine, ketone or aldehyde, and an enolizable carbonyl to yield a β-amino carbonyl.
If the enolizable ketone or aldehyde has a substituent at the α-position, proline and similar-amino acidorganocatalysts may be used to achieve the Mannich reaction stereoselectively (in regard to the relative stereochemistry of α-substituent and the resulting amino functionality at the β-position of the product).
An(S)-prolinecatalyzed Mannich reaction favors the formation of the product in which the substituent and amino functionalities aresyn relative to one another.[5] A modified proline catalyst, such as a methylated pyrrolidinecarboxylic acid, can be used to favor the formation of the product with the substituentsanti to one another.[6]In both cases, the organocatalyst transforms the enolizable aldehyde or ketone to an (E)-enamine. The facial selectivity of the nucleophilic attack is dictated by the preferred conformation adopted by the enamine (e.g., s-cis vs. s-trans) and the relative orientations of the enamine and imine such that the carboxylic acid functionality can protonate the imine nitrogen.
^abcCarey, Francis A.; Sundberg, Richard J. (2007).Advanced Organic Chemistry: Part B: Reactions and Synthesis (5th ed.). New York: Springer. pp. 140–142.ISBN978-0-387-68354-6.
