Mitsunobu reaction

General Procedure:

To a solution of alcohol (1 eq.) in THF (10 Vol) is added triphenyl phosphine (TPP, 1.5 eq.), and NUCLEOPHILE. The mixture is cooled to 0 ^oC. DIAD (1.5 eq) is then added dropwise at 0 ^oC, and stirred at room temperature for 6 to 8 h. The reaction is monitored by TLC. (The formation of triphenylphosphine oxide, TPPO, as a solid is the indication of the progress of the reaction).

The reaction mixture is diluted with EtOAc or DCM (15 Vol) and filtered to remove the by-product triphenylphosphine oxide. The filtrate (i.e. organic layer) is successively washed with water (15 ml x 2), aq. NaHCO₃ solution (to remove unreacted acid) and brine solution (15 ml), dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product is purified by column chromatography.

• NUCLEOPHILE shall be alcohol, DPPA, carboxylic acid, Thiol, Phenol, Phthalimide. The key criteria of nucleophile (Nu-H) is that it should be acidic enough (pKa ≤ 15; refer to mechanism to understand more)

Note:

• 1^o and 2^o alcohols are generally used. 3^o alcohols do not react

• The most preferable solvent is THF. Other solvents such as DCM and Dioxane could also be used. The reaction is usually performed at RT

• The by-product namely triphenylphosphine oxide (TPPO) is usually removed by filtration

• The order of addition of reagents matters. Alcohol, Nucleophile and PPh₃ are dissolved in a suitable solvent and cooled to 0 ^oC. DIAD or DEAD is then added.

• When DPPA is used as a nucleophile, Mitsunobu reaction results in the formation of organic azides. Organic azides are known to be explosive. Safety studies are to be carried out before performing on large-scale. It is also better not to heat the reaction. It is always better to find an alternate synthetic approach to avoid azides

• DIAD is Diisopropyl azodicarboxylate. It comes as 40% in toluene. Azodicarboxylic esters are susceptible to explosion when subjected to heat, impact and friction. In order to reduce the risk, azodicarboxylic esters are available as a 40% solution in organic solvents.

For more details on reactions and reagents, 
refer to the tab "Reaction, Reagents and Mechanism"

Typical Procedure:

• Acid to Ester under Mitsunobu condition (OrgSyn) — Open access

• Mitsonobu condensation of N-hydroxyphthalimide and an alkanol (ChemSpider) — Open access

• Conversion of Polyethylene Glycol (PEG) to N-(3,6,9-Trioxadecyl)phthalimide (Mitsunobu Reaction) (ChemSpider) — Open access

• Mitsunobu Coupling between Tetrahydrophthalimide and 4-Pentyn-1-ol (ChemSpider) — Open access

• Mitsunobu coupling of an imide with an alcohol (ChemSpider) — Open access

• Mitsunobu Coupling between Tetrahydrophthalimide and 4-Pentyn-1-ol (ChemSpider) — Open access

• Alcohol to Azide using DPPA (TCI) — Please click the section ” Applications & Literature” — Open access

• The above reaction (Mitsunobu with DPPA) endangers the potential formation of the toxic and highly explosive hydrazoic acid as well as the stoichiometric formation of an organic azide intermediate. Hence, a detailed safety studies needs to be conducted before performing such reaction.

• It is always desirable to avoid azides and look for alternate methods of making the intermediate

• Mitsunobu Coupling between Tetrahydrophthalimide and 4-Pentyn-1-ol (ChemSpider) — Open access

• Diol to Epoxide (OrgSyn) – Intermolecular reaction between two alcohol groups under Mitsunobu — Open access

For more details on large-scale reactions and OPRD procedures, 
refer to the tab "Scale-up & Green Chem"

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