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Mannich Reaction
Multicomponent Reactions

Petasis Reaction

The Petasis Reaction is a multicomponent reaction (MCR) that enables the preparation of amines and their derivatives such as α-amino acids.

The reaction is also referred to as the Boronic Acid Mannich Reaction, since it proceeds via an imine with the organic ligand of the boronic acid acting as the nucleophile, similar to the role of the enolizable ketone component in the original Mannich Reaction.

Mechanism of the Petasis Reaction

As in the classical reaction that it resembles, the Petasis Reaction also involves a large number of interdependent equilibrium steps, some of them identical to those in the Mannich Reaction.

Little is known with certainty in connection with the key step that involves the nucleophilic addition of the organic ligand from the boronate to the imine. One proposal is that the transfer is actually intramolecular, and takes place via the adduct pictured above:

Regardless of how it does take place, the fact that this addition is irreversible certainly imparts a clear advantage. In the classical Mannich, the reversibility of the final step limits the number of cases where the yields are synthetically useful. By comparison, the Boronic Acid Mannich Reaction permits a much broader scope of conversions to be carried out.

The direct reaction with glyoxylic acid merits particular mention, since it leads to interesting, unnatural α-amino acids in a single step, while avoiding the appearance of toxic byproducts such as seen with the Strecker Synthesis.

This reaction can be carried out with secondary amines, sterically hindered primary amines, hydrazines or anilines in dichloromethane at room temperature. The range of potential nucleophilic partners includes alkenylboronic acids, and electroneutral as well as electron-rich (hetero-)arylboronic acids. The conversion of electron-poor boronic acids can be effected at elevated temperatures (MW) in suitable solvents (M. Follmann et al. Synlett 2005, 1009. DOI).

Recent Literature

Petasis Boronic Mannich Reactions of Electron-Poor Aromatic Amines under Microwave Conditions
M. Follmann, F. Gaul, T Schäfer, S. Kopec, P. Hamley, Synlett, 2005, 1009-1011.

A Copper-Catalyzed Petasis Reaction for the Synthesis of Tertiary Amines and Amino Esters
R. Frauenlob, C. Carcía, G. A. Bradshaw, H. M. Burke, E. Bergin, J. Org. Chem., 2012, 77, 4445-4449.

A Palladium-Catalyzed Three-Component Synthesis of Arylmethylsulfonamides
T. Beisel, G. Manolikakes, Synthesis, 2016, 48, 379-386.

Component-Selective and Stereocontrolled One-Step Three-Component Reaction among Aldehydes, Amines, and Allenyl Boronic Acids or Allenyl Pinacolboronates
F. Liepouri, G. Bernasconi, N. A. Petasis, Org. Lett., 2015, 17, 1628-1631.

Mild and Catalyst-Free Petasis/Decarboxylative Domino Reaction: Chemoselective Synthesis of N-Benzyl Propargylamines
H. Feng, H. Jia, Z. Sun, J. Org. Chem., 2014, 79, 11812-11818.

Microwave-Assisted Neat Procedure for the Petasis Reaction
P. Nun, J. Martinez, F. Lamaty, Synthesis, 2010, 2063-2068.

Copper-Catalyzed Petasis-Type Reaction: A General Route to α-Substituted Amides From Imines, Acid Chlorides, and Organoboron Reagents
M. S. T. Morin, Y. Lu, D. A. Black, B. A. Arndtsen, J. Org. Chem., 2012, 77, 2013-2017.

Regioselective and Diastereoselective Borono-Mannich Reactions with Pinacol Allenylboronate
T. Thaima, S. G. Pyne, Org. Lett., 2015, 17, 778-781.

A Direct Synthesis of Allenes by a Traceless Petasis Reaction
D. A. Mundal, K. E. Lutz, R. J. Thomson, J. Am. Chem. Soc., 2012, 134, 5782-5785.

Organic Chemistry Highlights

Selected Articles

The Petasis Reaction of Boronic Acids, Oxo Components and Amines (Pt-3CR)