Mannich Reaction
Scheme:
The Mannich Reaction is an important carbon-carbon-bond forming reaction that is commonly employed in the synthesis of alkaloid natural products and is involved in a number of biosynthetic pathways. The reaction uses three components: an amine, a non-enolizable aldehyde or ketone, and a compound containing an enolizable carbonyl moiety. The final product of the reaction is a β-amino-carbonyl compound.
Mechanism:
The amine and non-enolizable aldehyde or ketone react to form an iminium ion or “Schiff base”. The second carbonyl compound tautomerizes to the enol form and attacks the iminium ion at the electrophilic carbon atom. The reaction typically requires long reaction times and elevated temperature under acidic conditions.
The reaction has continued to enjoy frequent use by synthetic chemists and has been employed in a several of the most important accomplishments in organic synthesis including strychnine, quinine, and atropine. The reaction has been extended by the discovery that a catalytic amount of (S)-proline, an inexpensive and naturally occurring amino acid, can be used to control the stereoselectivity of the reaction and provide products with high ee (enantiomeric excess).
Experimental Procedure:
For an example of the laboratory procedure for the Mannich reaction, see the synthesis of 4-(diethylamino)butan-2-one.
References:
Cordova, A.; Watanabe, S.; Tanaka, F.; Notz, W.; Barbas, C. F., III (2002). “A Highly Enantioselective Route to Either Enantiomer of Both α- and β-Amino Acid Derivatives”. Journal of the American Chemical Society 124 (9): 1866–1867. doi:10.1021/ja017833p.
Mannich, C.; Krosche, W. (1912). “Ueber ein Kondensationsprodukt aus Formaldehyd, Ammoniak und Antipyrin”. Archiv der Pharmazie 250: 647–667. doi:10.1002/ardp.19122500151.
Mitsumori S., Zhang H., Ha-Yeon Cheong P., Houk K. N.,Tanaka F., Barbas III C. F. (2006). “Direct Asymmetric anti-Mannich-Type Reactions Catalyzed by a Designed Amino Acid”. Journal of the American Chemical Society 128 (4): 1040–1041. doi:10.1021/ja056984f.