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Chemistry Forums for Students => Organic Chemistry Forum => Organic Chemistry Forum for Graduate Students and Professionals => Topic started by: synthon on February 07, 2014, 10:20:07 AM

Title: Phthalimide deprotection - continued
Post by: synthon on February 07, 2014, 10:20:07 AM

So, I fear I've boned myself somewhat, by using a phthalimide PG in an intermediate with another amide group.  Clearly I didn't think this through, and efforts to deprotect the intended primary amines through hydrazine or base, followed by heating with inorganic acid hydrolyze the amide as well. 

So, as Dr. Nick would say, a 2-part question, 1) Am I boned?  Or might there somehow, be a phthalimide deprotection protocol which is sensitive to amides.  And 2) if boned, any recommendations for a primary amine PG for which the deprotection is sensitive to amides?

I assume boned, as a key part to phthalimide deprotection is an amide hydrolysis, but will keep looking. :-[

Title: Re: Phthalimide deprotection - continued
Post by: discodermolide on February 07, 2014, 10:25:35 AM

You probably are *"+"ed.
The only thing I can think of is try and silylate the amide with a bulky silyl group, triphenyl or the like, using a silyl-triflate.
Then give the hydrazine another shot. You maybe able to O-silylate, or at best N-silylate.

Title: Re: Phthalimide deprotection - continued
Post by: Dan on February 07, 2014, 10:33:07 AM

Try this one:

Tetreahedron Lett. 1984, 25, 2093 (http://www.sciencedirect.com/science/article/pii/S0040403901811692)

I have never used it myself but the authors report phthalimide cleavage from a dipeptide in 95% yield without hydrolysing peptide linkage.

Title: Re: Phthalimide deprotection - continued
Post by: synthon on February 07, 2014, 10:50:34 AM

Dan, that method is the one I based this synthesis on, and heating in AcOH @ 80C rips the amide apart as well.  From my notes, it doesn't look like I followed the rxn too closely so I'm trying to see if heating less or not at all will move the rxn forward with a small sample.  This is work that I haven't actively pursued in months, so I'm having some pains wading through old mistakes. :)

The nice thing is that the previous step in the synthesis isn't the protection, but the amide coupling, so I'm really just getting my starting material back, and can try again with an alternately protected carboxyllic acid.  Perhaps as a benzylidene amine, which looks much more labile?