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Topic: Grignard Addition to Anhydride  (Read 1191 times)

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Offline AlphaScent

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Grignard Addition to Anhydride
« on: February 22, 2019, 10:47:46 AM »
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?
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Offline spirochete

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Re: Grignard Addition to Anhydride
« Reply #1 on: February 22, 2019, 01:18:10 PM »
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.
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Offline AlphaScent

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Re: Grignard Addition to Anhydride
« Reply #2 on: February 22, 2019, 03:41:08 PM »
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.
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Offline AlphaScent

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Re: Grignard Addition to Anhydride
« Reply #3 on: February 22, 2019, 04:00:58 PM »
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.
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Offline spirochete

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Re: Grignard Addition to Anhydride
« Reply #4 on: February 22, 2019, 05:58:53 PM »
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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Offline spirochete

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Re: Grignard Addition to Anhydride
« Reply #5 on: February 23, 2019, 02:26:35 AM »
Except my last idea would be a waste of time because then you'd just have one equivalent of water that would burn up your grignard anyway...unless you removed water from it somehow. So it would probably be better and/or easier to just waste one equivalent of grignard like you said originally.
I'm an online organic chemistry tutor and teacher. I have a Master's in organic chemistry, and have years of experience as a TA and teacher. Visit my website http://www.organicchemistrysolutions.com for more information.

Offline OrganicDan96

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Re: Grignard Addition to Anhydride
« Reply #6 on: February 23, 2019, 05:49:06 AM »
I once did a grignard in the presence of CeCl2 which is supposed to only give 1,2 addition, this might be an idea.

Offline rolnor

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Re: Grignard Addition to Anhydride
« Reply #7 on: February 23, 2019, 09:38:26 AM »
The lactone you want, can you show the structure?

Offline AlphaScent

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Re: Grignard Addition to Anhydride
« Reply #8 on: February 23, 2019, 10:28:28 AM »
Spirochete,

Yeah wasting an equivalent of Grignard is then best, and easiest way.  I do wonder though if this solves my problem of 1,4-addition.  We know the intermediate complex after one addition of an organometallic mitigates a second equivalent of organometallic to add but does it attenuate 1,4-addition?  It is an odd reaction, because one would think an anhydride to begin with is more reactive than a Weinreb amide, so why is it not adding to that faster in the first place?  These are just my thoughts that I honestly do not have a concrete answer to.  The PNG attachment shows the intermediate complex. 

Of course if this route works you deserve some acknowledgment, it was not my idea after all.  I am a firm believer of giving credit where credit is due.  Too much bulls*** in this world.

rolnor,

Attached is the scheme I propose to my lactone.  Do you mean you did the reaction in the presence of CeCl3?  Like Leuche conditions for sodium borohydride reductions?
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Offline OrganicDan96

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Re: Grignard Addition to Anhydride
« Reply #9 on: February 23, 2019, 01:23:29 PM »
  Do you mean you did the reaction in the presence of CeCl3?  Like Leuche conditions for sodium borohydride reductions?

could have been, cannot exactly remember

Offline AlphaScent

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Re: Grignard Addition to Anhydride
« Reply #10 on: March 12, 2019, 05:19:26 PM »
Just an update here.  Still waiting on the Weinreb salt to come in.  Stay patient!
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Offline spirochete

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Re: Grignard Addition to Anhydride
« Reply #11 on: March 12, 2019, 08:44:40 PM »
I do wonder though if this solves my problem of 1,4-addition.  We know the intermediate complex after one addition of an organometallic mitigates a second equivalent of organometallic to add but does it attenuate 1,4-addition?  It is an odd reaction, because one would think an anhydride to begin with is more reactive than a Weinreb amide, so why is it not adding to that faster in the first place?  These are just my thoughts that I honestly do not have a concrete answer to.  The PNG attachment shows the intermediate complex. 

Regarding this, I think the Weinreb amide does solve the problem of 1,4 addition, as long as you add two equivalents of the grignard (one to be base, the other to be nucleophile, like you said). Or even if you did add too much grignard, you break down the special tetrahedral intermediate with water anyway, so that should quench additional grignard before it does much conjugate addition.

Also thank you for update!
I'm an online organic chemistry tutor and teacher. I have a Master's in organic chemistry, and have years of experience as a TA and teacher. Visit my website http://www.organicchemistrysolutions.com for more information.

Offline AlphaScent

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Re: Grignard Addition to Anhydride
« Reply #12 on: March 13, 2019, 02:28:39 PM »
Weinreb salt is in!! Will be making the Weinreb amide tomorrow!  Ill let you know how the alkylation goes.

Cheers!
If you're not part of the solution, then you're part of the precipitate

Offline rolnor

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Re: Grignard Addition to Anhydride
« Reply #13 on: March 13, 2019, 06:05:43 PM »
If you can make the aldehyde to the left you can get the lactone in one step.

Offline AlphaScent

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Re: Grignard Addition to Anhydride
« Reply #14 on: March 14, 2019, 01:11:11 PM »
rolnor,

I have been down this road before.  It is not that simple to make that aldehyde.  The Weinreb amide has the most chemo and regioselectivity.  Once I hydrolyze it should lactonize as well.

I will keep in touch.  Just did the reaction outlined in Tetrahedron 42,23,1987 p. 5475.

Will keep in touch!

Cheers!
If you're not part of the solution, then you're part of the precipitate

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