Mitsunobu Reaction

Invented by Professor Oyo Mitsunobu in 1967

Here is a video explaining the Mechanism of Mitsunobu Reaction!

Recently DEAD has been replaced with less harmful DIAD 

Scalable Solvent free sillylation of alcohols

Procedure

1. Charged 100g of staring alcohol (liquid or solid) to a 1L 4 neck RBF under nitogen atmosphere.
2. Added 2.5 Meq. of imidazole at RT.
3. Stirred at RT for 30 minutes if alcohol liquid and if alcohol is solid, heated the mass to melting point of alcohol or imidazole whichever is higher and stirred for 30 minutes.
4. Set the temperature 50-60 degree and added 1.5Meq. of TBDMSCl in lots.
5. Stirred the reaction mass for 5h and checked TLC/ HPLC analysis.
6. If completed, forward to step 9.
7. If incomplete, added 0.2Meq of TBDMSCl and stirred for 1h more at 50-60 degree.
8. Generally reaction completes as per TLC.
9. Cooled the reaction mixture to RT.
10. 1volume = 100mL MeOH is added to the reaction mass and cooled to 0-5 degree.
11. Stirred the mass at 0-5 degree for 1-2h (thick free salt is observed).
12. Filtered the reaction mass under nitrogen atmosphere and washed the solid (filter) with 0.5Volume = 50mL X2 chilled MeOH.
13. Suck dried under nitrogen.
14. Concentrated the reaction mass under vacuum and dissolved it in 15volume = 1.5L EtOAc.
15. Transferred the organic mass to a 3L 4 neck RBF and added 2volume = 200mL water and cooled to 15-20 degree.
16. Adjusted pH of mixture to 5.8-6.3 with 1N HCl.
17. Stirred, settled and separeted layers.
18. Repeated the above pH treatment once more.
19. Now further added 1volume = 100mL water to the organic layer and adjusted it's pH = 8.5-9.0 with saturated sodium bicarbonate solution.
20. Stirred, settled and separeted layers.
21. Repeated the above pH treatment once more.
22. Concentrated the organic mass.
23. The obtained silylated product can be forwarded to the next step as such or can be purified using recrystallization/ coloumn chromatography.

Esterification of a diversly functionalized molecule

One of our colleagues has to perform an esterfication reaction to prepare ester derivative of a carboxylic acid function bearing compound. The compound has a secondary OH and N-Ac functions in addition to the carboxyl group. Use of oxalyl chloride was suggested by one of us to prepare the acid chloride and covert it into the ester. 

This reaction however resulted in the formation of one exclusive compound which was other than required ester. Careful investigation of 1H-NMR & MS data revealed that reaction occurred at another site too along with at the desired site.
Later, he tried the carbodiimide coupling procedure for the same reaction, this resulted in observation of two spots of almost similar intensity well separated to each other and at desired Rf value.
Next,

Acetonide protection in presence of acid sensitive O-Protection

Acetonide protection in presence of acid sensitive O-protective group is very critical. You have to be very careful during this reaction. Usually acetonide protection has been carried out in presence of catalytic amount of p-TSA in acetone.

But when you have acid sensitive protective group such as TBDMS, TBDPS etc, donot use p-TSA more than 0.001 equivalent otherwise acid sensitive protective group does not stand any more. The best procedure is the use of 2,2'-dimethoxy propane with 0.001 equivalent p-TSA in anhydrous THF. In this procedure your acid labile protective group will be intact in excellent yield and this is the beauty of this procedure.

Reference: Organic Syntheses, Vol. 82, p. 75 (2005); Coll. Vol. 11, p.88 (2009).

Acetonide protection in presence of acid labile O-Protection

Dr RR and Dr US have performed such a reaction few times and they have interesting observations to share, I hope these observations would be useful to many new Chemists and Grad Students in Chemistry:

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Welcome to Reaction Tips & Tricks WebSite!