Petasis Reaction

What Is Petasis Reaction?

The Petasis reaction (also called the Petasis borono–Mannich reaction) is a three-component coupling that combines a carbonyl compound (usually an aldehyde), an amine, and an organoboron reagent (typically a boronic acid or boronate) to give substituted amines in a single step. It is a mild, operationally simple alternative to classical Mannich and organometallic addition methods: metal-free or metal-minimal, tolerant of water and many functional groups, and particularly well suited to syntheses of α-amino acids, β-amino alcohols, allylic/benzylic amines, and diverse building blocks for medicinal chemistry.

• Solvents/Additives: protic solvents (MeOH, EtOH, MeOH/H₂O) often beneficial; catalytic Brønsted or Lewis acids used in special cases.
• Reactants:
  a) Aldehyde (most common; glyoxylic acid/glyoxylates for α-amino acids).
  b) Amine (primary or secondary; includes amino acids, amino alcohols).
  c) Organoboron reagent (aryl, heteroaryl, alkenyl, allyl, benzyl types).
• Products: Substituted amine derivatives, most notably: α-Amino acids (when glyoxylic acid is used); Allylic amines (with α,β-unsaturated carbonyls); 1,2-Amino alcohols or benzoxazines (with salicylaldehydes); Structurally diverse amines with new C–C bonds.
• Reaction Type: Multicomponent reaction.
• Related Reactions: Classical Mannich reaction, Suzuki–Miyaura cross-coupling, Passerini reaction and Ugi reaction.
• Experimental Tips:
  a) The reaction typically benefits from a mixed aqueous-organic solvent system (e.g., THF/water, DCM/water, or sometimes neat). Mild heating (40-60°C) can accelerate slower reactions, but many proceed at room temperature over 12-48 hours.
  b) The most common variants involve: 1) Aldehydes + amines + aryl/alkenyl boronic acids: to yield substituted amines. 2) Glyoxylic acid + amines + boronic acids: to directly synthesize α-aryl/alkenyl glycine derivatives. 3) Salicylaldehydes: these are particularly reactive, often leading to cyclic products like 1,2-amino alcohols or benzoxazines.

Fig 1. Petasis reaction and its mechanism. [1]

Mechanism of Petasis Reaction

1. Imine / iminium formation. The amine and aldehyde condense to form an imine (or in presence of acid, an iminium ion). With glyoxylic derivatives the equilibria favor reactive intermediates that can be attacked readily.
2. Activation of organoboron. The boronic acid can form a tetra-coordinate boronate in the presence of a Lewis base (solvent, alcohol) or coordinate to the oxygen/nitrogen centre of the intermediate, increasing nucleophilicity of the attached organic group.
3. Carbon–carbon bond formation. Transfer (formal transmetalation) of the organic group from boron to the electrophilic carbon of the iminium/iminium-like species gives the new C–C bond and the substituted amine. A boron-containing byproduct (boric acid/boronate) is expelled.

This is mechanistically analogous to a Mannich-type addition where the nucleophile is provided by the organoboron species rather than an enol/enolate.

Application Examples of Petasis Reaction

• Example 1: Yao Jiang et al. achieved enantioselective synthesis of allenes using a catalytic traceless Petasis reaction. Specifically, they developed two enantioselective synthetic methods: the addition of alkynyl boronic esters to glycolaldehyde imine to generate allylic hydroxyl allenes, and the addition of allyl boronic esters to alkynyl imines to generate 1,3-alkenyl allenes. Both reactions yielded products with high yields and high enantioselectivity. [2]
• Example 2: Jun Yi et al. reported a photoredox-catalyzed multicomponent Petasis reaction. Unlike the traditional two-electron Petasis reaction, which is only applicable to unsaturated boronic acids, various primary, secondary, and tertiary alkyl trifluoroborates can effectively participate in this reaction via a single-electron transfer mechanism. This method is highly suitable for the diversification of benzyl-type and glyoxylate-derived aldehydes, anilines, and alkyl trifluoroborates, thus constructing a library of highly complex compounds with significant importance in the pharmaceutical and agrochemical fields. [3]

Fig 2. Synthetic examples via Petasis reaction.

Related Products

CAS No.	Structure	Product
154230-29-2		TRANS-2-(4-CHLOROPHENYL)VINYLBORONIC ACID
352525-91-8		TRANS-2-(4-(TRIFLUOROMETHYL)PHENYL)-
480425-29-4		e-(4-Butylphenyl)ethenylboronic acid
72316-18-8		TRANS-2-(4-METHOXYPHENYL)-
849062-22-2		trans-2-(3-Fluorophenyl)vinylboronic acid
214907-24-1		trans-2-(4-Fluorophenyl)vinylboronic acid

References

1. Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 436-439.
2. Jiang, Yao, et al. Journal of the American Chemical Society 139.5 (2017): 1998-2005.
3. Yi, Jun, et al. Organic letters 21.12 (2019): 4853-4858.

Please kindly note that our products are for research use only.