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Grignard Addition to Anhydride
AlphaScent:
It always works on paper..
I took 3-methylglutaric anhydride and treated it with 1 eq of isopropenylmagnesium bromide at -78 (ref ACIE 41(6) 2002 p. 1057, they use PhMgBr). I expected the conjugated ketone, but found a mixture (3:2) of the 1,4-addition product to the conjugated ketone. There was also hydrolyzed starting material (diacid). So I decided to try the reaction using 0.5 eq of Grignard to see if I could mitigate 1,4-addition.
Nope. A mixture still. This time 1:1. All products were confirmed with 2D NMR experiments (HSQC, HMBC, and COSY)
My question is does anyone have any ideas as to why this is happening without copper? Also, does anyone have any ideas on how to possibly get the product I want?
I think the 1,4-addition is happening due to sterics. The 1,2-addition of a second Grignard is too crowded, so 1,4-predominates. Still doesn't make sense to have 1,4 over addition to an anhydride though. I think there may be some Lewis acid activation of the carbonyl from magnesium and is activating the conjugate product to afford 1,4 addition. My idea is to change to isopropenyl lithium.
What y'all think?
spirochete:
I'm not an expert, but I have read it's very common for grignard to do 1,4 addition over 1,2 addition or give a mixture. I think it's somewhere in March's Advanced Organic. I am more surprised about the 1,4 addition being faster than substitution at the anhydride, just like you.
To get a better yield maybe you could try using a excess of the anhydride to favor only the anhydride reacting and not the product, if the anhydride is cheap. Or you could open it up to make a Weinreb's amide first. I think this would avoid ever having to deal with the organometallic ever being in contact with the enone.
AlphaScent:
Spirochete,
I tried to use excess anhydride and it still gave a mixture. 1:1. I think your idea about the Weinreb amide is a good one. Do you have precedent for making Weinreb amides from anhydrides?
I would get the carboxylic acid on one end and the Weinreb amide on the other, Correct? Then possibly protect the acid as methyl or isopropyl ester and then react with Grignard? I want the lactone in the end.
AlphaScent:
Bioorganic and Medicinal Chemistry Letters 26(2), 662, 2016. Claim 98% yield on my exact substrate.
This is a good idea Spirochete. I dont like having to waste an equivalent of my Grignard on deprotonation but such is life.
I think I may try this. If this works I will be messaging you for acknowledgment when I write the paper. Havent thought about Weinreb Amides since second semester of grad school!! Thank you for your help.
spirochete:
That's awesome. That would make my day if you acknowledged me. I don't even have easy access to the literature any more. I think you could use 1 equiv of simple base like NaOH if you don't want to waste grignard.
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