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Author Topic: ether synthesis  (Read 2519 times)

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zarhym

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ether synthesis
« on: December 07, 2018, 06:53:08 PM »

I am trying to synthesis a ether bond in a dimethylmaleic anhydride derivatve.
This ether bond synthesis requires an oxygen nucleophile to selectively attack bromine in presence of a base without interupt the acid anhydride (see pic in the attachment).
We have done a couple experienments to vilidate this idea.
The first one uses NaH to make the oxygen nucleophile in THF, then attack the SM. This leads to complete disappear of starting material on TLC, leaving one spot with high polarity at the starting point.
The second one mixes SM, K2CO3, the alcohol in acetone at elevated temperature (50 to 60°C) for 6 hours. This leads to incomplete reaction, giving two new spots with higher Rf then SM and one spot with high polarity at the starting point on TLC plate. I tried a flash column seperation, but the reaction mixture was too messy. The HNMR may not provide suffcient infomation to tell whether I have the desired product.

Next week, I am going to try some weaker bases such as Na2CO3, Li2CO3 and even triethylamine.
I have digged the reaxys database. There is little information I can find on literatures.
Maybe this is an infeasible approach. But I'd like to try it several more times before giving up.
 
I'd like to have some opinions about this reaction.
Any suggestions will be appraciated.

Thanks a lot.
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zarhym

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Re: ether synthesis
« Reply #1 on: December 07, 2018, 07:20:40 PM »

BTW, there are similar approach using different nucleophile on literature. It looks like the acid anhydride should be stable enough for this kind nucleophile attack.
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rolnor

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Re: ether synthesis
« Reply #2 on: December 07, 2018, 11:39:41 PM »

I would try silver oxide as "base" maybe with sonication, the halide is allylic så this could be a SN1 type reaction. This reaction is slow and can take days.
Also you could try silvertriflate or silvertetrafluoroborate with a hindered base like 2,6-ditertbutylpyridine.
Triethyl amine is a better nucleophile then the alcohol so that will probably give a Q-salt.
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wildfyr

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Re: ether synthesis
« Reply #3 on: December 08, 2018, 03:03:21 AM »

Could you cite the sources? I gotta say, that is a pretty hot looking anhydride, I think you are getting the ring Opened product acid in both of those conditions. The stick polar spot is due to the carboxylic acid.

Not only is it an anhydride, the alkene is making it even more electron deficient.
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kriggy

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Re: ether synthesis
« Reply #4 on: December 08, 2018, 03:08:02 AM »

I think the higher rf spots are some esters being formed in the reaction while the low rf is definitely the opened acid. I think the opened acid derivative doesnt really matter because you can then convert it back into the anhydride

OrganicDan96

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Re: ether synthesis
« Reply #5 on: December 08, 2018, 04:37:56 AM »

depending on what you are doing next, could you take the diester, do the ether synthesis then hydrolyse the esters then form the anyhdrde, obviously this just adds steps to your synthesis
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zarhym

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Re: ether synthesis
« Reply #6 on: December 09, 2018, 02:11:20 PM »

The literature I am using is US2008/275057. This literature does have HNMR of the final target compound. But it requires successful synthesis of this compound which is not covered in this literature.

I agree that Ag2O looks like a promising way. Since it's a weak base, the anhydride ring should be more stable. I do find a reliable literature in which Ag2O is used to form ether bond between benzyl bromide and 4-hydroxy-2-butanone. (10.15227/orgsyn.060.0092)

I am ordering Ag2O. I'll post the results as soon as possilbe.
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zarhym

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Re: ether synthesis
« Reply #7 on: December 15, 2018, 04:06:27 PM »

Update

I tried Ag2O following a literature procedure (10.15227/orgsyn.060.0092).

All SM dissappeared after 12 hour stirring at R.T. (25°C). Everything binds with stationary phase at the starting point on TLC plate. I was thinking it could be the silver intermediate. Thus, I heated up to about 80°C. But on TLC, nothing happens. Maybe, Ag2O is still too strong as a base.

Since I have a very base sensitive acid anhydride ring in my starting material, I agree silver-mediated SN1 reaction is more promising then conventional SN2 nucleophilic attack.

I have ordered AgOTf and ditertbutylpyridine following another literature precedure(10.1016/0040-4039(94)88256-8). I'll give this up if this still does not work.

Thank you for all your suggestions.


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OrganicDan96

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Re: ether synthesis
« Reply #8 on: December 15, 2018, 11:36:15 PM »

maybe the stuff on the baseline is some carboxylic acid due to ring opening of the anhydride.
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hypervalent_iodine

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Re: ether synthesis
« Reply #9 on: December 16, 2018, 04:56:10 PM »

This might not be a good suggestion, but have you considered making the iodide via Finkelstein and using that instead of the bromide?
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zarhym

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Re: ether synthesis
« Reply #10 on: December 16, 2018, 09:01:06 PM »

This might not be a good suggestion, but have you considered making the iodide via Finkelstein and using that instead of the bromide?

It will be more reactive if the bromide is substituded by iodine. But I guess the reactive anhydride ring is still a problem in the SN2 reaction.

By using Ag2O or AgOTg, I am hoping it could switch the SN2 mechanism to SN1. Thus, the alcohol could react with carbon cation intermediate without nucleophilic attack on the anhydride ring.

I under there will be competiting reactions between SN1 and SN2 mechanisms. If this still does not work, I'll talk with my client and try convince them to change the synthetic route.

I guess I may have a mission impossible in my hand. But I am trying my best.
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rolnor

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Re: ether synthesis
« Reply #11 on: December 16, 2018, 11:44:34 PM »

Its clearly a difficult case, if you can have ester instead of anhydride it would be better. The anhydride does probably react with the alcohol even without base.
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zarhym

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Re: ether synthesis
« Reply #12 on: December 19, 2018, 07:40:45 PM »

update.

AgOTf method also failed. The reaction is messy and similar with previous conditions. 

The anhydride is simply too reactive for this kind of etherification. I am talking with my client to redesign the whole scheme.

But I do learned a lot from this.

Thank you again for all your suggestions.

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OrganicDan96

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Re: ether synthesis
« Reply #13 on: December 20, 2018, 06:43:50 AM »

update.

AgOTf method also failed. The reaction is messy and similar with previous conditions. 

The anhydride is simply too reactive for this kind of etherification. I am talking with my client to redesign the whole scheme.

But I do learned a lot from this.

Thank you again for all your suggestions.
as i said previously i would recommend having the carboxylic acids protected as esters then making then deprotecting and making the anhyfride in a later step
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zarhym

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Re: ether synthesis
« Reply #14 on: December 20, 2018, 03:45:22 PM »

as i said previously i would recommend having the carboxylic acids protected as esters then making then deprotecting and making the anhyfride in a later step

As a chemist, I completely agree with you.
However, in CRO business, the challenge is all in economics eventually.
We need find ways to lower the overall cost of our projects and increase the quality and efficiency.
This is perhaps the risk we have to take in order to survive.

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