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Chemistry Forums for Students => Organic Chemistry Forum => Organic Chemistry Forum for Graduate Students and Professionals => Topic started by: matman27 on August 16, 2012, 12:52:00 PM

Title: Mitsunobu Reaction with Methanol - Repeated Failure
Post by: matman27 on August 16, 2012, 12:52:00 PM

Hello Everyone,

I am working on methylation of a succinimide.  I have other sites for alkylation on my substrate, so my advisor suggested a Mitsunobu reaction.  I have been failing at this reaction, and there is not much in the literature about the Mitsunobu reaction using succinimide as the pronucleophile.  Mitsunobu did report it in one of his reviews as an unpublished result though.   There are plenty examples regarding phthalimide.

Can anyone suggest any tips or reaction conditions that my help me get this reaction to proceed.  I have dried the methanol over 4AMS, tried DIAD, DEAD, ADDP, and even refluxed the reaction overnight.  It seems my succinimide just will not react.

Thanks,

-Matt

Title: Re: Mitsunobu Reaction with Methanol - Repeated Failure
Post by: zoork34 on August 23, 2012, 04:31:42 PM

What order are you adding the reactants in?  Do you get any reaction at all, or just starting material back?  what solvent are you using? 

Title: Re: Mitsunobu Reaction with Methanol - Repeated Failure
Post by: matman27 on August 28, 2012, 10:52:19 AM

Hello,

I have been running the reaction in THF.  I have tried adding the DIAD to a solution of other reagents drop-wise in THF at 0.  I have also tried adding the methanol in THF to a solution of the other regents.  Does this seem reasonable?  I am recovering the imide from the reaction.

Thanks!

Title: Re: Mitsunobu Reaction with Methanol - Repeated Failure
Post by: zoork34 on August 29, 2012, 04:47:14 PM

This reaction from a J Med Chem paper adds them in a different order at 0 C, so you might try that.  The only mitsunobu reaction I ever tried in grad school failed miserably, so unfortunately I dont have any great advice. good luck.

http://syntheticfocus.com/synthesis-and-preparation-of-amines/alcohols-to-amines/conversion-of-alcohols-to-amines-via-the-mitsunobu-reaction-using-triphenylphosphine-and-dead/