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Author Topic: Possible vinylsulfone to allylsulfone isomerization  (Read 311 times)

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Babcock_Hall

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Possible vinylsulfone to allylsulfone isomerization
« on: April 16, 2018, 10:48:45 AM »

We are trying to make a vinylsulfone, in order to test it as a possible enzyme inhibitor.  We have made or purchased diethyl esters of vicinyl dibromides.  In some cases we have converted them to the corresponding vinylsulfone.  We need to deprotect any esters.  Recently we looked into base-promoted transesterification to tert-butylesters (because we can remove the tert-butyl group with TFA), and we can practice this tactic with a 3-carbon ester.  However, I have become concerned about possibly isomerizing from a vinylsulfone to an allylsulfone or to a different vinylsulfone.

In Nigel Simpkins’ book Sulfones in Organic Synthesis, he treats this subject on pages 39 (Scheme 61), 64 (Scheme 115), 81 (Scheme 151), 219, and 313 (Scheme 39).  On page 39 he says that there is a report (147) which says that the allylsulfone is more stable than the vinylsulfone, but then he points out that isomerizations have been reported in both directions (148, 149) and mentions relative stability (150).  In one tert-butoxide-catalyzed case the vinyl was favored, but it is more substituted.  On page 64 in Scheme 115 there is a base-catalyzed isomerization: compound 134 converts into 135 (88).  It is unclear to me what the driving force is.  On p. 81 in Scheme 151, compound 183 isomerizes into 184 under base-catalyzed conditions (314).  On page 219 he discusses rearrangements of allylsulfones with additional sulfur groups.  Pd might catalyze some of these reactions.  On page 313 in Scheme 39 is shown an allyl to vinylsulfone isomerization (66).  It looks as if a mixture is created at first.  NaH is the base, and the reaction happens at -4 °C.

Could we use molecular mechanics to predict the relative stabilities of the allylsulfones vs. vinylsulfones?  We can tolerate a minor amount of a different isomer for preliminary experiments.  Should we be looking at another deprotection strategy?  We can probably protect the vinyl sulfone as a methyl ester and look into TMS esters, for example.
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wildfyr

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Re: Possible vinylsulfone to allylsulfone isomerization
« Reply #1 on: April 16, 2018, 12:49:59 PM »

I've been following your research on this for a while and still struggle with the transformation, care to chemdraw this out a bit for us with some generic structures?
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Babcock_Hall

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Re: Possible vinylsulfone to allylsulfone isomerization
« Reply #2 on: April 16, 2018, 01:15:12 PM »

With respect to the derivative of diethyl propionate, we were able to purchase the dibrominated compound; with others we have to start back at the unsaturated carboxylic acid.  We attempted the synthesis with propionate so that we could try out different deprotection strategies on a relatively simple compound first.
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crawlingmcedge

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Re: Possible vinylsulfone to allylsulfone isomerization
« Reply #3 on: April 17, 2018, 12:48:25 AM »

I'm not sure MM calculations would be good enough for determining whether your compound will isomerize to try and roadmap your reactions. MM modelling is good enough for conformational analysis (in some cases as that) but electronic and solvation effects are generally pretty off. You could try using DFT/QM methods and add in solvation models, but this quickly becomes time and resource consuming.

It'd just be faster to lob some base into a nmr tube.
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pgk

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Re: Possible vinylsulfone to allylsulfone isomerization
« Reply #4 on: April 17, 2018, 08:01:25 AM »

1). Vinyl sulfone is more thermodynamically stable than allyl sulfone, due to the conjugation of the double bond with the sulfone group. Thus, it is unlike that basic catalysis can favor this kind of isomerization.
2). Except if, isomerization can lead to another (and stronger) conjugation like in the schemes 115 and 151. But even so, you need to adequately heat it.
3). So check if, your molecule's isomerization could lead to another conjugation:
a). If not (like in your attached example: <Vinylsulfone_ester_deprotection_v1.pdf>) then, there is no problem.
b). If yes (e.g. methacrylate phenylsulfone, instead of acrylate phenylsulfone of the above example), you saponify the ester at low temperature:
i). Facile Hydrolysis of Esters with KOH-Methanol at Ambient Temperature,  Monatshefte für Chemie-Chemical Monthly, (2004), 135(1), 83-87
https://link.springer.com/article/10.1007%2Fs00706-003-0114-1
ii). A simple method for the alkaline hydrolysis of esters, Tetrahedron Letters, (2007), 48(46), 8230-8233
https://www.sciencedirect.com/science/article/pii/S0040403907018539
That way, you work at low temperature that does not favor isomerizations and on the other hand, the so formed carboxyl salt will not favor the isomerization via the alkaline α-carboxyl dehydrogenation.
4). You can also check it by using NaOD/CDCl3 in an 1H-NMR tube, as Crawlingmcedge suggests.

« Last Edit: April 17, 2018, 08:25:02 AM by pgk »
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wildfyr

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Re: Possible vinylsulfone to allylsulfone isomerization
« Reply #5 on: April 17, 2018, 08:43:55 AM »

What is your reluctance to use acidic hydrolysis to cut the ethyl ester?

If you are willing to get to the methyl ester (easily obtained at any step from the ethyl ester by dissolving in dry methanol and a tiny amount of catalytic sulfuric acid and stirring overnight), there is a well known and nifty trick for very mild anhydrous deprotection of methyl esters: DMF/LiCl. I even found a two year old chemical forums thread you commented on where this procedure is mentioned :P

I can't get access to it right now but here is a microwave version:
https://www.tandfonline.com/doi/abs/10.1080/00397910902778001
I'm sure it has non-microwave procedure for this cited somewhere. PM me if you can't get access or find another lit procedure for DMF/LiCl ester hydrolysis.
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Babcock_Hall

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Re: Possible vinylsulfone to allylsulfone isomerization
« Reply #6 on: April 17, 2018, 09:36:50 AM »

Two of the vinylsulfones we are making or contemplate making are capable of cis-trans isomerization, which is generally acid-catalyzed.  I don't think that this is a deal-breaker, however, because I don't see having a small amount of a second isomer as a problem.  Your memory is better than mine, but now that you mention it, the use of LiCl rings a bell.  We'll move forward searching for these other methods as quickly as possible.

I just reread an earlier message.  I meant derivative of ethyl propionate, not diethyl.  We are also doing or planning the syntheses of one dicarboxylic acid, and one tricarboxylic acid, each of which will have the vinylsulfone warhead.
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wildfyr

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Re: Possible vinylsulfone to allylsulfone isomerization
« Reply #7 on: April 17, 2018, 10:10:20 AM »

Not memory, google. I think this predates my time here by a couple months

http://www.chemicalforums.com/index.php?topic=87120.0
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