Mannich Reaction

This multi-component condensation of a nonenolizable aldehyde, a primary or secondary amine and an enolizable carbonyl compound affords aminomethylated products. The iminium derivative of the aldehyde is the acceptor in the reaction.

The involvement of the Mannich Reaction has been proposed in many biosynthetic pathways, especially for alkaloids.

---

Mechanism of the Mannich Reaction

Recent Literature

Transition Metal Salt-Catalyzed Direct Three-Component Mannich Reactions of Aldehydes, Ketones, and Carbamates: Efficient Synthesis of N-Protected β-Aryl-β-Amino Ketone Compounds
L.-W. Xu, C.-G. Xia, L. Li, J. Org. Chem., 2004, 69, 8482-8484.

Catalytic Silicon-Mediated Carbon-Carbon Bond-Forming Reactions of Unactivated Amides
S. Kobayashi, H. Kiyohara, M. Yamaguchi, J. Am. Chem. Soc., 2011, 133, 708-711.

Ag-Catalyzed Asymmetric Mannich Reactions of Enol Ethers with Aryl, Alkyl, Alkenyl, and Alkynyl Imines
N. S. Josephsohn, M. L. Snapper, A. H. Hoveyda, J. Am. Chem. Soc., 2004, 126, 3734-3735.

The Direct and Enantioselective, One-Pot, Three-Component, Cross-Mannich Reaction of Aldehydes
Y. Hayashi, W. Tsuboi, I. Ashimine, T. Urushima, M. Shoji, K. Sakai, Angew. Chem. Int. Ed., 2003, 42, 3677-3680.

Organocatalysis with proline derivatives: improved catalysts for the asymmetric Mannich, nitro-Michael and aldol reactions
A. J. A. Cobb, D. M. Shaw, D. A. Longbottom, J. B. Gold, S. V. Ley, Org. Biomol. Chem., 2005, 3, 84-96.

Catalysis of 3-Pyrrolidinecarboxylic Acid and Related Pyrrolidine Derivatives in Enantioselective anti-Mannich-Type Reactions: Importance of the 3-Acid Group on Pyrrolidine for Stereocontrol
H. Zhang, S. Mitsumori, N. Utsumi, M. Imia, N. Garcia-Delgado, M. Mifsud, K. Albertshofer, P. H.-Y. Cheong, K. N. Houk, F. Tanaka, C. F. Barbas, III, J. Am. Chem. Soc., 2008, 130, 875-886.

Diarylborinic Acid Derivatives as a Catalytic Iminium Ion Generator in the Mannich-Type Reaction Using Secondary Amines, Aldehydes, and Ketene Silyl Acetals
Y. Tanaka, T. Hasui, M. Suginome, Synlett, 2008, 1239-1241.

Stereoselective Synthesis of β-Amino Ketones via Direct Mannich-Type Reactions, Catalyzed with ZrOCl₂ · 8 H₂O under Solvent-Free Conditions
B. Eftekhari-Sis, A. Abdollahifar, M. M. Hashemi, M. Zirak, Eur. J. Org. Chem., 2006, 5152-5157.

In a highly enantioselective direct Mannich-type reaction of aldimines with dialkyl malonates, an inexpensive Mg(II)-BINOLate salt can activate both aldimines and malonates as a cooperative acid-base catalyst. Various β-aminoesters and α-halo-β-aminoesters could be synthesized in high yields and with high enantioselectivities even in gram-scale.
M. Hatano, T. Horibe, K. Ishihara, Org. Lett., 2010, 12, 3502-3505.

Diastereoselectively Switchable Enantioselective Trapping of Carbamate Ammonium Ylides with Imines
J. Jiang, H.-D. Xu, J.-B. Xi, B.-Y. Ren, F.-P. Lv, X. Guo, L.-Q. Jiang, Z.-Y. Zhang, W.-H. Hu, J. Am. Chem. Soc., 2011, 133, 8428-8431.

Chiral Lithium(I) Binaphtholate Salts for the Enantioselective Direct Mannich-Type Reaction with a Change of Syn/Anti and Absolute Stereochemistry
M. Hatano, T. Horibe, K. Ishihara, J. Am. Chem. Soc., 2010, 132, 56-57.

Oxidative Mannich Reaction of N-Carbobenzyloxy Amines with 1,3-Dicarbonyl Compounds
J-I. Matsuo, Y. Tanaki, H. Ishibashi, Org. Lett., 2006, 8, 4371-4374.

Organocatalytic and Highly Stereoselective Direct Vinylogous Mannich Reaction
T.-Y. Liu, H.-L. Cui, J. Long, B.-J. Li, Y. Wu, L.-S. Ding, Y.-C. Chen, J. Am. Chem. Soc., 2007, 129, 1878-1879.

Pyridinium 1,1'-Binaphthyl-2,2'-disulfonates as Highly Effective Chiral Brønsted Acid-Base Combined Salt Catalysts for Enantioselective Mannich-Type Reaction
M. Hatano, T. Maki, K. Moriyama, M. Arinobe, K. Ishihara, J. Am. Chem. Soc., 2008, 130, 16858-16860.

Asymmetric Mannich Reactions with in Situ Generation of Carbamate-Protected Imines by an Organic Catalyst
J. Song, H.-W. Shih, L. Deng, Org. Lett., 2007, 9, 603-606.

Direct-Type Catalytic Three-Component Mannich Reactions Leading to an Efficient Synthesis of α,β-Diamino Acid Derivatives
M. M. Salter, J. Kobayashi, Y. Shimizu, S. Kobayashi, Org. Lett., 2006, 8, 3533-3536.