Chemical Forums
Chemistry Forums for Students => Organic Chemistry Forum => Organic Chemistry Forum for Graduate Students and Professionals => Topic started by: Babcock_Hall on June 24, 2022, 01:06:07 PM
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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.
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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
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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.
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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.
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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.
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By 2-thiophenyl, I mean a 5-membered heterocyclic structure with two double bonds and one sulfur.
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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.
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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.
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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.
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I have recently become interested in the furan and tetrahydrofuran rings for this project.
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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.
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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.
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This is a Michael acceptor so risc of attack on the double bond.
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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.
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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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Yes, the double bond would be nice if possible, cleave to aldehyde, then wittig. Or metathesis reaction. The acidic proton in the sulphone-phosphonate makes som limitation, you easily get polymer if you have an electrophile present in the other end of the molecule and use basic conditions. Or ringclosure.
You could make the first step with sodium sulfide, to get the phosphonate-sulfide, then you can put on different alkyl groups, sulfur being a powerfull nucleophile, then oxidize with oxone. But it will be a smelly business. You can also use LDA+the methyl phosphonate , then add elemental sulfur, then one-pot add the alkyl halide to the formed lithium sulfide to form the sulfide of your choice. Then oxidize with oxone, three one-pot steps.
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I tried the reaction of diethyl methylphosphonate, LiHMDS, and PhSO2F twice. The first time did not go well, and there were several things that might have contributed. Yet the second time gave me a crude yield of 72% and what looks like almost a pure compound by P-31 and H-1 NMR.
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Fantastic! Nice! You really need some success after so much hard work.
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Using sulfonyl fluorides is an attractive route to sulfonyl phosphonates, yet at least one of the sulfonyl fluorides that we would like to use is on backorder. Another one is expensive and is also on backorder. It has been suggested to me that potassium bifluoride could be used to convert a sulfonyl chloride into a sulfonyl fluoride. Does such a reaction require special glassware or present any unique problems of execution?
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Ive done this dozens of times! Literally my area of grad school expertise, to make SuFEx substrates.
Works like a charm. Do it in polypropylene bisphaic with MeCN/water. Treat it with the respect of aqueous HF.
Use my supplementary information
https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.201506253
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Nice wildfyr! Its supplied as a hydrate, or? Yes, hydrogen fluoride is nasty, causes neuropathy?
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KFHF is just a white salt, but you use a large excess and its in water/MeCN anyways so hydrate hardly matters.
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Thank you. We will purchase a sulfamyl fluoride which can be the precursor to one of our targets. The 1998 article (upon which I based a test reaction) used a sulfonyl fluoride, and I cannot find an example of the same chemistry with a sulfamyl fluoride in the literature yet. I imagine that the reaction will be slower, but I don't see a problem. There are other targets on our to-do list that will need fluoride exchange, and we will pursue them as we move forward.
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Look up Barry Sharpless' recent work, he has pursued a lot of things around SOx-F cores lately and their corresponding reactivity.
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https://doi.org/10.1021/acssuschemeng.8b00489
This paper has a synthesis of 2-propanesulfonyl fluoride from the corresponding chloride in the presence of Bu4NCl and potassium bifluoride in water. This sounds similar. I am not familiar with "bisphaic."
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Zhang L et al., Chinese Journal of Chemistry (2022), 40(14), 1687-1692. https://doi.org/10.1002/cjoc.202200112.
"The Et3N-3HF complex is a liquid HF with improve safety. In this work, we report electrochemical synthesis of a series of sulfonyl fluoride with Et3N-3HF as fluoride source." The method is electrochemical. One of the sulfonyl fluorides that they make is cyclopropanesulfonylfluoride, in 18% isolated yield.
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"2-propanesulfonyl fluoride (9.58 g; 75.9 mmol; 76%) collected at 48–52 °C/35 mbar as a colorless liquid". Should I be worried about losing a little product in the prior rotary evaporation of DCM. I am interested in both 2-propyl and cyclopropy, and I am looking for the boiling point of cyclopropanesulfonyl fluoride. Wildfyr, should I have read bisphaic as biphasic?
EDT
My last few comments were either written late at night or very early in the morning, before the coffee kicked in. I apologize for any lack of clarity.
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Yes, its bisphasic. Also known as "on water." You just stir the organic and aqueous phases very aggressively with a magnetic stir bar in a plastic bottle for a few hours or overnight. Never failed.
I think the Et3N-3HF probably acts like a bit of a phase transfer agent, but I never found that to be necessary. Just MeCN and water with KFHF. Dilute in ether or DCM and take the organic phase. Don't overthink it. The swap of chloride for fluoride is just much more favored than hydrolysis. You can flash the material through a plug of silica or do a weakly basic wash to remove any sulfonic acid from hydrolysis of sulfonyl chloride.
Something that low boiling maybe you could lose some. I would be more concerned with not inhaling it than the yield for the 2-propyl, since starting material 2-propyl sulfonyl chloride is pretty cheap.
https://www.sigmaaldrich.com/US/en/product/aldrich/242705
The cyclopropyl is a whole different can of worms, sigma selling cyclopropane sulfonyl chloride for $300/500mg. Maybe sulfonic acid/sulfonate salt is cheaper and you can make it with thionyl chloride. Couldn't find it quickly.
FYI it is pretty difficult to tell the SO2-F from the SO2Cl by NMR, so pay close attention if you suspect there is leftover SO2Cl.