Chemical Forums
Chemistry Forums for Students => Organic Chemistry Forum => Organic Chemistry Forum for Graduate Students and Professionals => Topic started by: mikeB on January 19, 2021, 02:01:32 AM
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Hi,
Does anyone have experience in reducing and adding organolithium/magnesium reagents to a Weinreb amide in the presence of a γ-lactam group? That is, can this be done without protecting the lactam NH? I was thinking about deprotonating the lactam NH first with NaH and then do business as usual at the Weinreb amide site. Any thoughts or suggestions?
--Mike
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I don't have experience in the presence of a γ-lactam. Are you following a published protocol, or has this not been done before?
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No, I have not found examples of this done before. For the reduction I will be using Lithium diisobutyl-tert-butoxyaluminum hydride (LDBBA), which was actually mentioned on this forum in a topic on ester reduction. It's a very mild reducing reagent, but highly reactive toward Weinreb amides. Not sure how much more Weinreb amides are susceptible to nucleophilic additions then regular amides. Based on electronics I expect them to be more reactive, but I wasn't able to find literature to corroborate that.
--Mike
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I would try first just add the RLi, a lactam is very stable.
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I would try first just add the RLi, a lactam is very stable.
I would think the RLi would be quenched by the lactam unless the addition to the Weinreb amide is faster than protonation by the lactam NH.
--Mike
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When I used one equivalent of LDBBA, the reduction of the Weinreb was unsuccessful. My tentative interpretation is that the reagent abstracted a proton from a BOC-NH group on another portion of my molecule. I should have added a second equivalent, but I did not think of it at the time.