[Babcock_Hall]

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.

[wildfyr]

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?

[Babcock_Hall]

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.

[crawlingmcedge]

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.

[pgk]

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.

[wildfyr]

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

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.

[Babcock_Hall]

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.

[wildfyr]

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

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

[Babcock_Hall]

When I was a graduate student, I had to remove the methyl groups from a labile compound, sym-monothiopyrophosphate.  This compound hydrolyzed roughly 10,000,000-fold more quickly than pyrophosphate under similar conditions.  A previous synthesis had used iodotrimethylsilane to transesterify, followed by removal of the four Me₃Si- groups using isopropanol and diisopropylethylamine.  However, in my hands the results were sometimes good but were inconsistent.  Often the major products were phosphate and CH₃SPO₃.  I tried distilling TMSI onto copper shot, and it would still start to turn pink as soon as the distillation was over.  Perhaps a more sophisticated handling technique would have produced better results with this reagent.  My approach was modeled after the idea of using chlorotrimethylsilane/NaI, but I wanted to remove the methyl groups at lower temperatures (-30 to -60 °C); therefore, I used TMS-trifluoromethanesulfonate (TMSOTf)/tetrabutylammonium iodide in DCM (see attached document).  The results I obtained were more consistent in terms of how much cleavage of the P-S bond I obtained.  Some of the cleavage must have happened after the removal of iodomethane, because thiophosphate was a common side product.

My question is whether or not an approach based on TMSCl, TMSoTf, or some other silylating agent should be something we consider to remove methyl, ethyl, or benzyl groups with respect to our vinylsulfones.

[Babcock_Hall]

pgk,

Thank you.  The authors of the 2007 Tetrahedron Letters article state, "It is, also, of interest that the saponification of β,γ-unsaturated esters (entries 10 and 11) was accomplished without any isomerization to the corresponding α,β-unsaturated acids..."  This is obviously good to know from our perspective.  We will try this reaction with a model 3-carbon vinyl sulfone to see whether or not the vinyl sulfone group stays intact.

[pgk]

You are welcome.
I wish the best.

[Babcock_Hall]

DOI 10.1002/ardp.201600307
WAng J, et al., Arch. Pharm. Chem. Life Sci. 2017, 350, e1600307
We made the 3-phenylvinylsufone derivative of ethyl acrylate as a model compound for deprotection studies that will start later this week.  My student recently found a paper in which they deprotected this very compound with lithium hydroxide, THF/ H₂O, at room temperature for one hour.  This is step iii of Scheme 2 of their paper. 

I think that there might be an error in the reagent of step i in their scheme 2 (I don't see how the thiol can form a bond to an unactivated carbon; maybe they used ethyl propynoic acid, but I am just guessing).  Their written explanation of step iii has an unfamiliar use of the term hydraulic:  "To a solution of an appropriate intermediate 18a–d (7.1 mmol) dissolved in THF/H₂O (25 mL, 3:2) was added 2 eq of lithium hydroxide monohydrate, and the resulting suspension was stirred for 1 h at room temperature. Then, most of the solvent was evaporated, and the residue was poured into water (5mL). The aqueous layer was acidified by addition of 6 N hydrochloric acid solutions until pH 3, and then separated out from hydraulic. The mixture was filtered to collected substituted acids (19a–d)."

It may be that upon acidification, that the product precipitates from aqueous solution.  Possibly "hydraulic" was a spelling error of some kind.  Despite these nitpicks, I think that there paper is very encouraging news, in that a mild alkaline hydrolysis is not enough to destroy the vinyl sulfone group.

[wildfyr]

Shoot the author an email and ask for clarifications, its from 2017. Hopefully the language barrier isn't too bad.

[pgk]

“…The aqueous layer was acidified by addition of 6 N hydrochloric acid solutions until pH 3, and then separated out from the pasty (= hydraulic) precipitate. The mixture was filtered to collected substituted acids (19a–d).
Which means:
The aqueous layer was acidified by addition of 6 N hydrochloric acid solutions until pH = 3, and then a pasty precipitate separated out. The mixture of the aqueous layer and the formed, pasty precipitate was filtered, in order to collect the substituted acids (19a–d).
PS: Hydraulic material is a mineral or organic powder that forms a paste when absorbing water, e.g. hydraulic cement, paper pulp, etc.

[Babcock_Hall]

Thank you; that makes sense.  We sent an email a few days ago, but we have not heard back.  Should we expect that it will be difficult to handle because of its pasty consistency?