What is the order of addition and concentration?  Both of these can have large effects on your rate of reagent consumption and speed of reaction.

I found that  using a mixture of toluene and THF, in this case 3:2 at 0.3 M concentration with respect to substrate made the reaction very fast, even at 0 C. This Mitsunobu, when in THF only, took 2 days, but with toluene too it took 2 hours.

Hi Luke,

Thank you for the response Sir. I dissolved triphenyl phosphine, N-hydroxyphthalimide and 3-butynol in anhy. THF first. And then I added DIAD drop wisely in an ice bath. Even after two days I can see lot of N-hydroxyphthalimide (TLC/UV) but I cant see any triphenyl phosphine. I think it reacted completely and what I can see is triphenyl phosphine oxide.

Hi  Brennan,

Thank you for the suggestion. Let me try with toluene as well.

Are you sure its not the unwanted sidereaction you are observing? Where your DIAD has reacted as the nucleophile, that would explain your loss of the triphenylphosphine and formation of triphenylphosphine oxide.

What does the NMR say? TLC in these systems can be horrible due to O=PPh3's promiscuity on TLC.

It is also worth considering here that the N-OH isn't a typical alpha hetero-nucleophile as it has a deactivated nitrogen (the lone pair is delocalised into 2 carbonyls).  Anyway, what is the likely hood of the butynol forming the dimer and getting the corresponding ether out?  Would explain the consumption of the reagents while the phthalimide gets left behind.  If the NMR is ambiguous, to a click with 1 eq of azide to desymmetrise.

Perhaps the better way is to go with BocNHOH, deprotect then dehydrate the corresponding anhydride.  Granted that the amine is still deactivated slighly but should be better than the phthalimide.

You may find some additional useful data by reading:

http://www.chem.wisc.edu/areas/organic/studsemin/jantzi/jantzi-abs.pdf

The best way to perform a Mitsunobu reaction is to first form the complex between PPh3 and DIAD (or DEAD) at 0 °C in THF; separately you mix the nucleophile and the substrate in the right solvent and once the complex PPh3-DIAD is formed (pale yellow milky colored suspension) you pour it into the other solution. I prefer to pour the Nu-sbstrate mix into the PPh3-DIAD complex, at 0 °C and then slowly warm up till RT. After 2/3 hours you can monitor the reaction by TLC and, if u will see just a poor or none product formation, you can heat till 40/50 °C.

Thank you everyone ! Really appreciate your suggestions. 

I would expect your proposed reaction to be quite facile as the N-hydroxy phthalimide is an established nucleophile. Preforming the activated DIAD/PPh3 complex would be the first port of call, initially using an ice salt bath then allowing it to reach room temperature. Try adding the alkynol last.

Failing that, use DEAD instead of DIAD as the reagent is orders of magnitude faster, you may need to run the reactions at -20 to avoid decomposition. Use of a smaller phosphine nucleophile also helps with the reaction rate, consider PBu3 or P(OEt)3.

Use a stain to visualise the products by TLC, KMnO4 should be reliable and ought to stain any alkyne containing spots rapidly, potentially without heating.

As Eric already answered, DEAD and a large excess of Triphenylphosphine, but you can try also PPh3 and iron phtalocianine.

use good quality reagents of DIED AND PPh3 and reaction must be in anhydrous and inert conditions. 

Sometimes adding Sodium benzoate helps

Using anhydrous THF and fresh DIAD is important to speed up the reaction.

I have found that a mixture THF/toluene 1:1is also a nice trick to reduce your reaction time

Regards

Today I made Mitsunobu with N-hydroxyphthalimide-Diphenylmethanol, and N-Hydroxyphthalimide-Geraniol. I used sonication (no stirring) and heating at 30-40C and reaction was completed at 3h and 2h respectively. Still have not isolated the products so I dont know about the yields. I saw that in other procedures using only stirring the reaction takes longer... so try sonication and let us know how it goes

Regards!

hi there, for the reaction u can use dcad ( p-dichlorbenzyl derivative) which is stable at room temperature, the reaction can be performed at 10-15C initially, monitor the reaction with TLC, the addition for alkynol occur at last.

this method offer simplicity of isolation by filtering only.

solvent used is DCM.

Article Simplification of the Mitsunobu Reaction. Di-p-chlorobenzyl ...