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Chemistry Forums for Students => Organic Chemistry Forum => Organic Chemistry Forum for Graduate Students and Professionals => Topic started by: Babcock_Hall on February 28, 2022, 11:32:32 AM

Title: S- vs. O-alkylation using sodium sulfinates
Post by: Babcock_Hall on February 28, 2022, 11:32:32 AM
When sodium sulfinates are used as nucleophiles, one sometimes observes both alkylation at sulfur and at oxygen (reference available upon request).  I would like to use diethyl phosphonate with a tosyl group or iodine atom at the alpha position as the leaving group.  To make a long story short, there are β-sulfonyl phosphonate derivatives that would be difficult or expensive to make in other ways.  I have only found one such reaction in the literature (Liu et al., Synthetic Communications 2007 37:119-127.  DOI: 10.1080/00397910600978515), and the sulfinate was supported on a polymer.  The solvent was THF/DMF, and the temperature was 80 °C with a 12-hour reaction time.  There was a two-fold excess of phosphonate.

We plan to work in solution.  What are some possible pitfalls in adapting this reaction to the solution phase?  Are there any general tactics to favor S-alkylation that one might apply in this situation?  I have thought about trying various solvents and possibly switching the counter-ion to lithium via Dowex-50.
Title: Re: S- vs. O-alkylation using sodium sulfinates
Post by: rolnor on March 01, 2022, 01:02:44 AM
Can you use a sulfide instead and oxidize this after the coupling?
Title: Re: S- vs. O-alkylation using sodium sulfinates
Post by: Babcock_Hall on March 01, 2022, 08:42:54 AM
We have used the two step synthesis you suggested (alkylation, then oxidation of the sulfide with Oxone or mCPBA) before, and we are doing so again this week.  Oxone is easy to handle, and the oxidation reaction can be followed by P-31 NMR, as well as using TLC.  In one case the sulfide is prohibitively expensive.  In another, the thiol might be a bit volatile.  In a third instance, I would like to make HOCH2S(O)R.  Rongalite, the starting sodium sulfinate can be protected as the TBDMS ether, although the synthesis looks a bit inelegant, for lack of a better word.
Title: Re: S- vs. O-alkylation using sodium sulfinates
Post by: Babcock_Hall on March 09, 2022, 10:27:10 AM
I am rereading Nigel S. Simpkins' 1993 book Sulphones in Organic Synthesis.  There are at least two sections that deal with sodium sulfinates as nucleophiles to make sulfones.  One section (starting on p. 11) discusses the S vs. O alkylation issue (the other section is on p. 60).  This section mentioned that replacing methanol with polyethylene glycol as the solvent was advantageous.  It also indicated that the product of O-alkylation, a sulfinate ester, could sometimes rearrange to make the sulfone.  Another work-around is to run the reaction under conditions where the sulfinate ester hydrolyzes back to starting material.  Eventually the sulfone is produced.  The use of an ion-exchange resin to make the counter-ion a quaternary ammonium salt is also discussed.  This section also discussed ultrasound as a method to speed up the reaction.  In addition to an alkyl halide and TolSO2Na, one paper used DBU and acetonitrile.  I am not sure what the DBU is doing, but I will try to obtain this paper and see (possibly the authors started with a sulfinic acid, as opposed to a sodium salt).
"A Simple Synthesis of Sulfones" Biswas G and Mal D, J. Chem. Res. (S) 1988 308.

The discussion that I am having the most trouble understanding concerns hard vs. soft electrophiles.  The reaction of TolSO2Na with dimethyl sulfate gave almost entirely the sulfinate ester, but the use of methyl iodide gave predominantly the sulfone.  It is surprising to me that the leaving group makes such a big difference, but the authors of the 1968 paper invoke hard and soft acid-base theory to explain it.  It makes me think that there may be a difference between ICH2P(O)(OEt)2 and the corresponding tosylate in the reaction I am planning.
Meek JS and Fowler JS, J. Org. Chem. 1968 33 3422.  https://pubs.acs.org/doi/pdf/10.1021/jo01273a014
Kielbasinski R...Mikolajczyk M. Tetrahedron 1988 44 6687-6692.
Title: Re: S- vs. O-alkylation using sodium sulfinates
Post by: Babcock_Hall on March 10, 2022, 12:37:37 PM
In the 1968 JOC paper by Meek and Fowler, dimethyl sulfate gave 88% sulfinate ester (from O-alkylation) and 12% sulfone (from S-alkylation), methyl tosylate gave 77% sulfinate ester, and iodomethane gave 7% sulfinate ester.  All three of these reactions were performed in DMF, but the paper gives data on other solvents.
Title: Re: S- vs. O-alkylation using sodium sulfinates
Post by: Babcock_Hall on March 10, 2022, 09:17:27 PM
"A Simple Synthesis of Sulfones" Biswas G and Mal D, J. Chem. Res. (S) 1988 308.
Regarding this paper (which I mentioned in a previous comment), the authors used a sulfinic acid and deprotonated with DBU in acetonitrile.  Yields were good.
Title: Re: S- vs. O-alkylation using sodium sulfinates
Post by: rolnor on March 11, 2022, 12:02:38 AM
In the 1968 JOC paper by Meek and Fowler, dimethyl sulfate gave 88% sulfinate ester (from O-alkylation) and 12% sulfone (from S-alkylation), methyl tosylate gave 77% sulfinate ester, and iodomethane gave 7% sulfinate ester.  All three of these reactions were performed in DMF, but the paper gives data on other solvents.

A alkyl sulphate is a hard electrophile so it goes for O-alkylation. A alkyl iodide is softer and will give more S-alkylation I think. O is a harder nucleophile than S.
Title: Re: S- vs. O-alkylation using sodium sulfinates
Post by: rolnor on March 11, 2022, 12:04:55 AM
I am rereading Nigel S. Simpkins' 1993 book Sulphones in Organic Synthesis.  There are at least two sections that deal with sodium sulfinates as nucleophiles to make sulfones.  One section (starting on p. 11) discusses the S vs. O alkylation issue (the other section is on p. 60).  This section mentioned that replacing methanol with polyethylene glycol as the solvent was advantageous.  It also indicated that the product of O-alkylation, a sulfinate ester, could sometimes rearrange to make the sulfone.  Another work-around is to run the reaction under conditions where the sulfinate ester hydrolyzes back to starting material.  Eventually the sulfone is produced.  The use of an ion-exchange resin to make the counter-ion a quaternary ammonium salt is also discussed.  This section also discussed ultrasound as a method to speed up the reaction.  In addition to an alkyl halide and TolSO2Na, one paper used DBU and acetonitrile.  I am not sure what the DBU is doing, but I will try to obtain this paper and see (possibly the authors started with a sulfinic acid, as opposed to a sodium salt).
"A Simple Synthesis of Sulfones" Biswas G and Mal D, J. Chem. Res. (S) 1988 308.

The discussion that I am having the most trouble understanding concerns hard vs. soft electrophiles.  The reaction of TolSO2Na with dimethyl sulfate gave almost entirely the sulfinate ester, but the use of methyl iodide gave predominantly the sulfone.  It is surprising to me that the leaving group makes such a big difference, but the authors of the 1968 paper invoke hard and soft acid-base theory to explain it.  It makes me think that there may be a difference between ICH2P(O)(OEt)2 and the corresponding tosylate in the reaction I am planning.
Meek JS and Fowler JS, J. Org. Chem. 1968 33 3422.  https://pubs.acs.org/doi/pdf/10.1021/jo01273a014
Kielbasinski R...Mikolajczyk M. Tetrahedron 1988 44 6687-6692.

You should know that ICH2P(O) etc. is a poor electrophile, much less reactive than ordinary alkyliodides.
Title: Re: S- vs. O-alkylation using sodium sulfinates
Post by: rolnor on March 11, 2022, 12:08:13 AM
We have used the two step synthesis you suggested (alkylation, then oxidation of the sulfide with Oxone or mCPBA) before, and we are doing so again this week.  Oxone is easy to handle, and the oxidation reaction can be followed by P-31 NMR, as well as using TLC.  In one case the sulfide is prohibitively expensive.  In another, the thiol might be a bit volatile.  In a third instance, I would like to make HOCH2S(O)R.  Rongalite, the starting sodium sulfinate can be protected as the TBDMS ether, although the synthesis looks a bit inelegant, for lack of a better word.

In the end you gain by using this strategy, you can make the thiol yourself if expensive and if volatile just use a tight cap on the reaction flask.
Title: Re: S- vs. O-alkylation using sodium sulfinates
Post by: hollytara on March 14, 2022, 02:38:10 AM
Take a look at this paper: they did a lot of variations.

DOI: 10.1021/bk-1995-0614.ch009

Title: Re: S- vs. O-alkylation using sodium sulfinates
Post by: Babcock_Hall on March 14, 2022, 02:47:40 PM
biphenyl-SO2Cl was reduced to its corresponding thiol using TCEP or PPh3 in refluxing water/dioxane in 16 hours.  However, cyclopropylthiol has a boiling point of 60-72 °C, from what I can gather.
Title: Re: S- vs. O-alkylation using sodium sulfinates
Post by: rolnor on March 14, 2022, 04:55:13 PM
Just close the flask with a stopper, also you may not need reflux. You could also distill of the product and collect it.

Or buy it:

https://www.sigmaaldrich.com/SE/en/product/enamine/ena457511885?context=bbe

https://chemtronica.com/sv/chemicals?cas_number=6863-32-7&

Here is some reading, maybe good https://link.springer.com/article/10.1007/BF00954373
Title: Re: S- vs. O-alkylation using sodium sulfinates
Post by: rolnor on March 14, 2022, 05:06:48 PM
You can make it from cyclopropyllithium and sulphur, you can isolate it as lithium salt.

Or use the Grignard+sulphur:

https://www.sigmaaldrich.com/SE/en/product/aldrich/526797
Title: Re: S- vs. O-alkylation using sodium sulfinates
Post by: Babcock_Hall on March 14, 2022, 08:11:55 PM
Isolating it as the lithium salt sounds like a good idea; thank you.  I will do some reading as you suggested.  I have a little experience with free iodomethylphosphonic acid, and it is a terrible electrophile, as you implied.  I switched to trifluoromethanesulfonate as the leaving group and had much better results in one project.  With respect to diesters, we have been able to get both iodide and tosylate to work as leaving groups in the presence of primary thiols.  We did have one reaction which did not go well recently (it was a pyridylthiol), and we are still looking into the reasons for that.
Title: Re: S- vs. O-alkylation using sodium sulfinates
Post by: rolnor on March 14, 2022, 11:44:34 PM
Yes, the thiol is a very good nucleophile so it works even with a week electrophile.
It seems as if you are doing a lot if chemistry on these compounds, are they interesting biologicaly?
Title: Re: S- vs. O-alkylation using sodium sulfinates
Post by: rolnor on March 15, 2022, 06:42:58 AM
If you mix the cyclopropylGrignard with 1eqv. sulphur and evaporate you have the magnesium salt of the thiol.
Title: Re: S- vs. O-alkylation using sodium sulfinates
Post by: Babcock_Hall on March 15, 2022, 09:13:07 AM
In one class our best inhibitor has a value of kinact/Ki near 5000 M-1 sec-1 against the target enzyme.  In a different class the value is about 40,000.  A few of the compounds show activity in disk diffusion assays, but I was hoping for a bit more.
Title: Re: S- vs. O-alkylation using sodium sulfinates
Post by: Babcock_Hall on July 04, 2022, 12:25:34 PM
I set up a test reaction with diethyl phoshonomethyltoluenesulfonate and PhSO2Na, which was in 20% excess.  I used DMF and the reaction temperature was 80-90 °C.  I took a time point of the reaction after about 14 hours. There are four spots by TLC and three peaks by P-31 NMR. One signal (at 15.2 ppm) and one TLC spot are consistent with diethyl phosphonomethyltosylate standard, and one signal (about 11.5 ppm) and one TLC spot are consistent to authentic product. I think that the reaction is roughly 65% complete. By TLC the starting material and the product elute with fairly close R(f) values in ethyl acetate/hexanes, but I have not searched exhaustively for a solvent system. I would predict that the O-alkylated product would have a more downfield shift than the S-alkylated product, and the unassigned signal is near 24 ppm, but have not yet checked whether or not this is a known compound.
Title: Re: S- vs. O-alkylation using sodium sulfinates
Post by: Babcock_Hall on July 05, 2022, 11:46:24 AM
To my surprise the second time point (24 hours later) looked essentially the same as the first time point, both by TLC and by P-31 NMR.  Therefore there are probably three products, with just under 50% being the product of interest.  I plan to do a similar, small-scale synthesis with diethyl iodomethylphosphonate next.  If the iodomethyl test reaction worked better but I had to use the tosylate for some reason, I might be tempted to add tetrabutylammonium iodide as a catalyst.
Title: Re: S- vs. O-alkylation using sodium sulfinates
Post by: Babcock_Hall on July 06, 2022, 09:29:37 AM
The reaction of sodium phenylsulfinate with diethyl iodomethylphosphonate was about 20% complete after four hours at about 90 °C.  I have been performing microextractions using 5% aqueous LiCl versus ethyl acetate fo the TLC time points, with the hope of removing most of the DMF.
Title: Re: S- vs. O-alkylation using sodium sulfinates
Post by: rolnor on July 06, 2022, 12:18:50 PM
Have you tried the triflate vs the iodo? Maybe that gives non-wanted O-alkylation?
It would be much faster.
Title: Re: S- vs. O-alkylation using sodium sulfinates
Post by: Babcock_Hall on July 06, 2022, 01:44:47 PM
I have not tried the diethyl triflate yet (I used to make the di-tert-butyl version and then remove the protecting groups).  I agree that it will be faster, and I also agree that it may give less-than-ideal S versus O-alkylation.  The other thing that could be tried is a microwave-based reaction, but I have no personal experience with it.
Title: Re: S- vs. O-alkylation using sodium sulfinates
Post by: rolnor on July 06, 2022, 06:36:17 PM
Its easy to make the diethyl directly? The alcohol is commersially available I think.
Title: Re: S- vs. O-alkylation using sodium sulfinates
Post by: rolnor on July 07, 2022, 01:09:29 AM
You can easily make it from parafirmaldehyde+diethylphosphite. The triflate is obtained by treting the alcohol with tfmsaa+DIPEA in Et2O at -78°, then just dekant the solution to remove the DIPE-Triflate salt and evaporate. You dont need to wash with H2O.

https://www.sigmaaldrich.com/SE/en/product/aldrich/392626
Title: Re: S- vs. O-alkylation using sodium sulfinates
Post by: Babcock_Hall on July 07, 2022, 10:13:00 AM
We have diethyl hydroxymethylphosphonate on hand.  The addition of paraformadehyde to a phosphite can be little finicky, but basically it can be done.  The triflate can be purified via flash chromatography if need be.
Title: Re: S- vs. O-alkylation using sodium sulfinates
Post by: rolnor on July 07, 2022, 09:28:31 PM
Yes, its a fairly stable triflate. The method I mentioned gives NMR-pure material, you dont need purufication.
Title: Re: S- vs. O-alkylation using sodium sulfinates
Post by: Babcock_Hall on July 08, 2022, 09:19:37 AM
The second time point (about 16 hours of reaction) of the iodomethylphosphonate indicated that the product peak was smaller and a new, broad peak was seen.  This is surprising, in that a similar reaction worked in the solid phase.  Perhaps the conditions could be improved (fresher solvent, less light, etc.). However, I might try a preliminary reaction with a sulfonyl fluoride instead.
Title: Re: S- vs. O-alkylation using sodium sulfinates
Post by: rolnor on July 09, 2022, 02:01:13 AM
Is there a risc of error in the analysis of the mixture? It seems strange that the product breaks down? How do you work-up samples? Is is TLC, in that case, how do you dry the spots before developing? Do you have DMF as solvent? You should get iodide-ions as by-product, these can sometimes interfere.
Title: Re: S- vs. O-alkylation using sodium sulfinates
Post by: Babcock_Hall on July 09, 2022, 10:13:40 AM
For the P-31 NMR samples I simply sampled about 10 µL and dissolved in CDCl3.  For the TLC, I took 20 µL and extracted with about 50 µL each of 5% aqueous LiCl and ethyl acetate.  The percentage of the peak area at 11.2 ppm went down from the first time point to the second.  Two new, broad peaks are visible that were not visible before, but they both have very low signal-to-noise.  The reaction picked up a brown color with time.  I am not sure what any degradation product might be.

I also spiked the first time point for the TsOCH2P(O)(OEt)2 reaction with an internal standard of diethyl phosponomethyltoluenesulfonate, and the peak near 15.2 ppm increased in intensity, confirming its assignment.  What is odd about this reaction is that the first and second second time points had similar ratios of peak areas to each other.  It is also odd that there was still diethyl phosphonomethyltoluenesulfonate left at time point 2; I set up the reaction to have PhSO2Na in 20% excess.  Perhaps there is water present in this salt, or perhaps my technique was not good.  I have not yet performed an internal standard experiment with authentic product, but I am fairly confident that the peak near 11.2 is the product, based on similar molecules.
Title: Re: S- vs. O-alkylation using sodium sulfinates
Post by: Babcock_Hall on July 09, 2022, 06:06:07 PM
Post script, One thing that surprised me a little is that I was able to detect diethyl iodomethylphosphonate by UV quenching in TLC.  I am giving some thought to either looking to improve the toluenesulfonate reaction slightly or to trying a microwave-promoted reaction with either leaving group.
Title: Re: S- vs. O-alkylation using sodium sulfina
Post by: rolnor on July 10, 2022, 02:18:04 AM
You are very dedicated, good. Still it would be nice to se a chromatogram, preferably a LC-MS. You dont learn so much from this NMR-study, its mostly confusing.
Yes, why do you see the iodide? Thats key, it should be consumed. If you used the sulfide as nuchleophile and then oxidised to sulphone you would get fast and more clear result I think. You could even do this one-pot.
Title: Re: S- vs. O-alkylation using sodium sulfinates
Post by: Babcock_Hall on July 10, 2022, 09:58:42 AM
The TLC results and the P-31 NMR results were consistent with each other regarding both leaving groups.  With P-31 one might be able to learn what the side-product is when I used toluenesulfonate as the leaving group.  I am consulting with someone with much greater expertise in P-31 NMR than I have, although MS could also identify it.

The sulfonyl fluoride reaction followed by a Horner reaction can be done in one pot, but I am not sure that I want to go that route.  Do you mean sulfide, disulfide, or thiol?
Title: Re: S- vs. O-alkylation using sodium sulfinates
Post by: rolnor on July 10, 2022, 01:33:25 PM
If you alkylate a sulfide-Na salt  with the tosylate or iodide you get the sulfide, then oxidize this one-pot with Oxone to the desired sulphone. What you need is mercapto ethanol sodium salt I think?
Its probably so, that you dont get the product you want now, just as your NMR shows, but you dont know why, if you run LC-MS you can maybe see what goes wrong.
Title: Re: S- vs. O-alkylation using sodium sulfinates
Post by: Babcock_Hall on July 11, 2022, 04:19:15 PM
We performed the reaction between 3-mercapto-1-propanol and diethyl phosphonomethyltoluenesulfonate at least twice, once with potassium carbonate as the base and IIRC once with cesium carbonate as the base.  Although the yield has been variable in our hands, it is a satisfactory reaction overall.  The oxidation to the sulfone went smoothly.  It would make sense to use 2-mercaptoethanol in a similar reaction; it is inexpensive and not that volatile.  However, the corresponding sulfonyl phosphonate is not presently one of our targets.  The high cost of many of the sodium sulfinates makes this route (EDT, meaning sulfinate as the nucleophile) less attractive to me than it was before, but I already have sodium cyclopropanesulfinate in hand.
Title: Re: S- vs. O-alkylation using sodium sulfinates
Post by: rolnor on July 11, 2022, 05:25:50 PM
Excellent! I move my fingers like Mr Burns in "Simpsons".
Title: Re: S- vs. O-alkylation using sodium sulfinates
Post by: Babcock_Hall on July 12, 2022, 09:52:36 AM
A year ago we alkylated benzyl mercaptan and then oxidized the product sulfide.  This spring we alkylated 2-thiopyridine and then oxidized the product.  I suspect that these reactions are slower owing to steric problems associated with the quaternary phosphorus atom, but they are otherwise OK.