[mdma]

Hi

I need to do a coupling between a phenol and an alcohol using mitsunobu conditions. Attached is the reaction scheme, including the desired target and isolated side-product. I was mixing the alcohol, phenol, PPh3 and adding DIAD slowly last.

What i know is this: the phenol para position reacts with the DIAD probably at the same rate as the PPh3, so i end up with the DIAD-alkylated target, confirmed by HNMR and MS.

I then modify the order of addition, by mixing the PPh3 with DIAD, then adding the alcohol, and last adding the phenol. It increased the ratio target / side product slightly (5 %).

The way i see it is the phenol probably attack the DIAD before the mitsunobu coupling takes place, otherwise there isnt suppose to be any DIAD left in the reaction...

Anyone has any idea how to avoid such side reaction?

[phth]

I'd try a more reactiv4e phosphine such as PEt₃ and cool down. 

[kriggy]

It might be good good idea to mix PPh3, DIAD and alcohol and then let it be for some time (15-30 mins) and then add it to the phenol. The order of addition plays quite a important role in mitsunobu.

[mdma]

So i pre-mix the DIAD and the PPh3 in THF at OC for 30 min, then added the alcool slowly at OC, after 45 min added the phenol at rt.

I end up with no side-product AT ALL! Also the yield went from 20 % to 60 %.

I think the trick was to use slight excess of PPh3 vs DIAD, so there is no way thet the nucleophile sees any DIAD.