What Is Mitsunobu Reaction?
In the presence of diethyl azodicarbonate (DEAD) or diisopropyl azodicarbonate (DIAD) and triphenylphosphine, alcohols and carboxylic acids and other compounds containing active hydrogen go through substitution reactions into C-O, C-N, C-S, C-C bonds and so on, which is the Mitsunobu reaction. Because it is the reaction of chiral alcohols, the structure of the carbon atom that the alcohol hydroxyl group is attached to will typically be reversed. Mitsunobu et al. in 1967 and is generally carried out under mild neutral conditions. This is why Mitsunobu reaction is widely employed in total synthesis of natural products or functional group transformation of molecules. It is a reaction with a wide range of applications.
Many other nucleophiles can replace conventional carboxylic acids for the reaction, but the nucleophiles should be acidic because one of the reagents (DEAD) must be protonated during the reaction to prevent side reactions.
- Reagents: Triphenylphosphine (PPh3), dialkyl azodicarboxylate (DEAD or DIAD)
- Reactants: Alcohols, Nucleophile (e.g., carboxylic acids, amines, thiol).
- Products: Compounds containing C-O, C-N, C-S, and C-C bonds.
- Reaction type: Nucleophilic substitution with inversion of configuration.
- Experimental tips: For the Mitsunobu reaction, feeding order matters. The carboxylic acid, alcohol and triphenylphosphine are to be first dissolved in a suitable solvent like tetrahydrofuran or ether etc., tipped down to zero, then DEAD is added dropwise, and finally stirred at room temperature. When the reaction is not finished, it can be heated to room temperature or continuous heating. There is another feeding protocol of pouring triphenylphosphine and DEAD in the solvent and stirring then the alcohol and acid in the solvent in turn.
Fig 1. Mitsunobu reaction and its mechanism. [1]
Mechanism of Mitsunobu Reaction
- In the first step, triphenylphosphine reacts with azocarboxylate to form a zwitterionic adduct, which then extracts a proton from the nucleophile to form a nucleophilic anion.
- Then the alcohol combines with phosphorus to form a phosphorus oxide compound, while releasing hydrogenated azocarboxylate.
- Finally, the nucleophilic anion attacks from the back of the alcohol to obtain a configuration flip product.
Application Examples of Mitsunobu Reaction
- Example 1 - C-O bond formation: Teruaki Mukaiyama et al. used in situ formed alkoxydiphenylphosphine, 2,6-dimethyl-1,4-benzoquinone and carboxylic acid for redox condensation reaction, providing an effective method for preparing trans-tertiary alkyl carboxylates from various chiral tertiary alcohols. The Mitsunobu reaction played a role in the configuration-inverting step. [2]
- Example 2 - C-N bond formation: Tianwen Hu et al. synthesized three pramipexole dihydrochloride impurities and constructed the desired configuration at C7 of product 3 through Mitsunobu reaction. Specifically, 3-10 was prepared from intermediates 4 and 3-11 under standard Mitsunobu reaction conditions. The configuration of C7 in 3-11 was reversed in the Mitsunobu reaction to produce 3-10. [3]
Fig 2. Synthetic examples via Mitsunobu reaction.
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References
- Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 358-361.
- Mukaiyama, Teruaki, et al. Journal of the American Chemical Society, 2003, 125(35), 10538-10539.
- Hu, Tianwen, et al. Organic Process Research & Development, 2016, 20(11), 1899-1905.
