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Topic: Weinreb Amide Chemistry in the Presence of a γ-Lactam  (Read 1650 times)

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Offline mikeB

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Weinreb Amide Chemistry in the Presence of a γ-Lactam
« on: January 19, 2021, 02:01:32 AM »
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

Offline Babcock_Hall

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Re: Weinreb Amide Chemistry in the Presence of a γ-Lactam
« Reply #1 on: January 19, 2021, 10:35:43 AM »
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?

Offline mikeB

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Re: Weinreb Amide Chemistry in the Presence of a γ-Lactam
« Reply #2 on: January 19, 2021, 12:19:59 PM »
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
« Last Edit: January 19, 2021, 12:34:07 PM by mikeB »

Offline rolnor

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Re: Weinreb Amide Chemistry in the Presence of a γ-Lactam
« Reply #3 on: January 19, 2021, 12:49:43 PM »
I would try first just add the RLi, a lactam is very stable.

Offline mikeB

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Re: Weinreb Amide Chemistry in the Presence of a γ-Lactam
« Reply #4 on: January 19, 2021, 02:26:44 PM »
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

Offline Babcock_Hall

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Re: Weinreb Amide Chemistry in the Presence of a γ-Lactam
« Reply #5 on: January 19, 2021, 02:37:36 PM »
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.

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