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Topic: Use of sulfonyl fluorides to produce sulfonyl Phosphonates  (Read 2838 times)

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Offline Babcock_Hall

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Use of sulfonyl fluorides to produce sulfonyl Phosphonates
« on: June 24, 2022, 01:06:07 PM »
Won Bum Jang , Hyoung Joon Jeon & Dong Young Oh∗ (1998) Direct Sulfonylation of Lithiated Alkyl Phosphonates with Benzenesulfonyl Fluoride; Facile Method for Preparation of α-Sulfonyl Alkyl Phosphonates and Vinyl Sulfones, Synthetic Communications, 28:7,
1253-1256, DOI: 10.1080/00397919808005967

This paper uses lithium bis(trimethylsilyl)amide (lithium hexamethyldisilazane) to remove a proton from diethyl methylphosphonate (they are not far apart in pKa values).  The use of a sulfonyl fluoride, not chloride is critical.  This paper has not been followed up, except in two patents (at least based upon my searching).  How general is this method regarding the group bound to sulfur?  One potential problem I can see is that if there is an acidic proton on the sulfonyl fluoride, there could be a problem, and α-hydrogens relative to a sulfonyl have a broad range of pKa values, with the highest being about 31.  Cyclopropanesulfonyl fluoride is available, and cyclopropanyl would be one of the R groups of interest.  Biphenyl is another R group of interest.

Offline rolnor

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Re: Use of sulfonyl fluorides to produce sulfonyl Phosphonates
« Reply #1 on: June 24, 2022, 05:34:21 PM »
I have done a lot of chemistry on cyclopropanes. The method you have can be really good, it can be a problem with the acidic  proton on the sulphonylfluoride but you have to try, the reaction with the sulphonylfluoride can be very fast so maybe no problem. The product will have even more acidic protons with two activating groups.
If you can buy cyclopropane disulfide you can react this in a similar fascion to get the sulfide  and then you can oxidize this to the sulphone as you have shown. Thats a very generall method probably, also for the biphenyl I think. Disulfides are soft nice electrophiles with no acidic protons. I think you can buy a lot of them. They are also easy to make by alkaline iodine oxidation of sulfides. (Stench-warning, I used thiophenol…)
Here are some vendors: https://pubchem.ncbi.nlm.nih.gov/compound/Dicyclopropyldisulfide

Offline wildfyr

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Re: Use of sulfonyl fluorides to produce sulfonyl Phosphonates
« Reply #2 on: June 25, 2022, 02:07:24 PM »
Sulfonyl fluorides are very strong EWG, I think you want to try to go for a kinetically controlled reaction if possible, because that proton is quite acidic. But yeah the chances of making a mess are probably not small.

You very seldom see alkyl sulfonyl fluorides, much more common is aryl sulfonyl fluorides followed by unsaturated ones (like ethene sulfonyl fluoride), probably for this precise reason. If you look at SuFEx chemistry you can see a ton of example of the unsaturated ones.

Source: I made alkyl sulfonyl fluorides during my PhD.

Offline Babcock_Hall

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Re: Use of sulfonyl fluorides to produce sulfonyl Phosphonates
« Reply #3 on: June 27, 2022, 09:53:13 AM »
Thank you both very much.  Although S-cyclopropyl* is the first target that I have in mind, I would obviously like to be able to create as much structural diversity as possible. I don't see a problem with the S-biphenyl group.**  Two of the other sulfonyl fluorides that are commercially available are 2-pyramidinyl and 2-thiophenyl.  Do either of these look problematic for conversion into a sulfonyl phosphonate?

Regarding the S-CH2-P group in the product, its acidity is higher than the acidity of diethyl methylphosphonate, yet the method worked for phenylsulfonyl fluoride.  I take this as an encouraging sign.

*In another thread we discussed using S-cyclopropylsulfinate as the starting material for a sulfonyl phosphonate.  I still think that this idea has merit.
**EDT (added much later) I suspect that phenoxyphenyl would be OK, also.
« Last Edit: June 27, 2022, 11:24:57 AM by Babcock_Hall »

Offline rolnor

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Re: Use of sulfonyl fluorides to produce sulfonyl Phosphonates
« Reply #4 on: June 27, 2022, 10:12:13 AM »
It can be straightforward. If not the disulfide approach can be useful. You wright 2-thiophenyl, is that the free mercaptane? The 2-pyrimidanyl seems OK. Yes, I commented on the acidic protons in the product, the method does not seem to be so sensitive to this.

Offline Babcock_Hall

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Re: Use of sulfonyl fluorides to produce sulfonyl Phosphonates
« Reply #5 on: June 27, 2022, 11:19:52 AM »
By 2-thiophenyl, I mean a 5-membered heterocyclic structure with two double bonds and one sulfur.

Offline rolnor

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Re: Use of sulfonyl fluorides to produce sulfonyl Phosphonates
« Reply #6 on: June 27, 2022, 05:31:55 PM »
Ah, thiophene, OK. It should be OK, its very much like benzene. Its sensitive to oxidants and Raney-Ni will desulphurize it. Can be problematic if you want to hydrogenate, it poisons the catalyst. I made a thipophene-analouge of a 5HT-1a full agonist, it was similar in activity. Several biologicaly active compounds containing a thiophene instead of the phenyl-group has been studied, Salo Gronovits did many of these I think. Thiphene is a bio-isostere of the phenyl-group. It can be problematic in vivo in drugs because of S-oxidated metabolites sometimes, you get to fast metabolism.

Offline Babcock_Hall

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Re: Use of sulfonyl fluorides to produce sulfonyl Phosphonates
« Reply #7 on: June 27, 2022, 06:23:55 PM »
I probably should have written thiophene group or something equivalent.  Now that you mention it, I have seen S-oxidized metabolites show up in the forensic toxicological analysis of one or two pesticides (Aldicarb was one of them).  IIRC they come from the action of Cytochrome P450.  I will look into this a bit more before committing synthetic resources.

Offline rolnor

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Re: Use of sulfonyl fluorides to produce sulfonyl Phosphonates
« Reply #8 on: June 28, 2022, 12:45:53 AM »
Yes, its a good thing to avoid sulfides and sulphoxides in drugs, they tend to mess things up. Also, biologicaly, its probably no large gain going from phenyl to thiophene. Thiazol is more interesting, its much more polar. Pyridine is also interesting if you want to make a salt of the molecule for water solubility/oral bioavailability. Imidazole similar. But in your case the final target is an amino acid so you have less if these problems, rather the opposite.

Offline Babcock_Hall

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Re: Use of sulfonyl fluorides to produce sulfonyl Phosphonates
« Reply #9 on: June 29, 2022, 09:03:17 AM »
I have recently become interested in the furan and tetrahydrofuran rings for this project.
« Last Edit: June 29, 2022, 09:13:41 AM by Babcock_Hall »

Offline rolnor

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Re: Use of sulfonyl fluorides to produce sulfonyl Phosphonates
« Reply #10 on: June 29, 2022, 12:34:58 PM »
Ahh! Furane, I made some fluoro furanes. They are somewhat  acid labile, very unstable compared to thiophene. They are only partially aromatic. You can see this on NMR, the signals are closer to vinylethers than aromatic signals. But if you dont plan to boil in HCl they are fine. But maybe you should spread out the structures more, phenyl, thiophene, furane, biphenyl. They are all lipophilic. The pyrimidinyl you suggested is more different, hydrophilic. Sometimes you gain affinity to a receptor just by making the molecule more lipophilic just because the drug want to get away from the water surrounding the receptor if the drug is lipophilic, the drug-receptor complex gets stabilized. We had this effect on the PETT-nnRT-inhibitors in our HIV-project. So it could be good to make lipophilic things, thats for sure and in your case the rest of the molecule is polar so it could be even more important in your project. But you are digging in the same place with these molecules, maybe the thiophene+biphenyl is enough to start with, the furane is so similar? Just a thought.

Offline Babcock_Hall

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Re: Use of sulfonyl fluorides to produce sulfonyl Phosphonates
« Reply #11 on: July 05, 2022, 02:34:29 PM »
Sulfonyl fluorides are very strong EWG, I think you want to try to go for a kinetically controlled reaction if possible, because that proton is quite acidic. But yeah the chances of making a mess are probably not small.

You very seldom see alkyl sulfonyl fluorides, much more common is aryl sulfonyl fluorides followed by unsaturated ones (like ethene sulfonyl fluoride), probably for this precise reason. If you look at SuFEx chemistry you can see a ton of example of the unsaturated ones.

Source: I made alkyl sulfonyl fluorides during my PhD.

The compound CH2=CH-SO2F is commercially available.  It might be possible to do chemistry on the double bond after the sulfonyl phosphonate was formed.  On the other hand, the presence of an acidic proton between S and P might be problematic, and there might be attack on the ethyl carbon bound to oxygen under some circumstances.
« Last Edit: July 05, 2022, 03:18:10 PM by Babcock_Hall »

Offline rolnor

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Re: Use of sulfonyl fluorides to produce sulfonyl Phosphonates
« Reply #12 on: July 06, 2022, 09:08:14 AM »
This is a Michael acceptor so risc of attack on the double bond.

Offline Babcock_Hall

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Re: Use of sulfonyl fluorides to produce sulfonyl Phosphonates
« Reply #13 on: July 06, 2022, 09:25:38 AM »
I need to reread Phil Fuchs' reviews on vinyl sulfones, but I think that Michael chemistry could lead to some novel products, as long as the phosphonate portion doesn't mind.

Offline Babcock_Hall

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Re: Use of sulfonyl fluorides to produce sulfonyl Phosphonates
« Reply #14 on: July 13, 2022, 02:22:38 PM »
This is a Michael acceptor so risc of attack on the double bond.
Yes, the sulfonyl fluoride synthetic route will not work in this instance, but it looks promising for other R groups.  I will try a test reaction soon.

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