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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
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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.
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Can you use a sulfide instead and oxidize this after the coupling?
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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.
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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.
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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.
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"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.
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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.
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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.
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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.
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Take a look at this paper: they did a lot of variations.
DOI: 10.1021/bk-1995-0614.ch009
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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.
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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
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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
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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.
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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?
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If you mix the cyclopropylGrignard with 1eqv. sulphur and evaporate you have the magnesium salt of the thiol.
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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.
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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.
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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.
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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.
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Have you tried the triflate vs the iodo? Maybe that gives non-wanted O-alkylation?
It would be much faster.
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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.
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Its easy to make the diethyl directly? The alcohol is commersially available I think.
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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
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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.
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Yes, its a fairly stable triflate. The method I mentioned gives NMR-pure material, you dont need purufication.
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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.
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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.
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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.
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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.
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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.
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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?
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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.
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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.
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Excellent! I move my fingers like Mr Burns in "Simpsons".
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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.
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One of my previous model reactions used TsOCH2P(O)(Out)2. It produced a mixture with the desired product PhSO2CH2P(O)(OEt)2 as the most abundant form. I hope to see a greater percentage of the desired product by switching from a harder to a softer electrophile. I found a reaction in the patent literature (WO 2021/263278) between sodium cyclopropanylsulfinate and BrCH2P(O)(OiPr)2 in DMF with tetrabutylammonium iodide as a catalyst. The mole ratio of the sodium sulfinate to phosphonate to TBAI was 1.5:1.0:0.1. They worked at 100 °C and ran overnight. I did not see a yield.
I decided to try a model reaction with sodium phenylsulfinate and ICH2P(O)(Out)2 in DMF but without TBAI. One difference between this reaction and previous reactions is that I used fresher DMF. After about 16 hours at 77 °C the reaction had proceeded to about 25% completion, as judged by P-31 NMR. I raised the bath temperature to 109 °C and I will take another time point. I am not sure of of how much rate enhancement to expect by adding a catalyst. The catalyst may be helping to make the sodium phenylsulfinate more soluble, but in warm DMF, I did not think that it would make a big difference. I thought that the reaction in the patent literature primarily used TBAI to obtain a catalytic halogen exchange. I plan to set up a second model reaction which includes TBAI, but I am unsure about the best choice of temperature.
The cyclopropane derivative is one of my targets, but the 2-propane derivative is also on my list, and I have both of the appropriate sodium sulfinates in hand. I just need to optimize my conditions.
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TBAI is not logic to use when you have a alkyliodide, I dont see the point. But a iodide should be more soft than a tosylate?.How about my suggestion, use a sulfide and get 100% S-alkylation, then oxidise this to sulphone with one of many possible oxidizers. You can make the sulfide if you pick a proton from the corresponding methylphosphonate with LDA and the add sulphur, then add the alkylhalide to the so formed lithiosulphide in one pot. Foolproof.
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Sorry I did not see the post with thiopyridine. You should be aware that pyridine can be oxidized to the N-oxide with some oxidizers. Thiophenolate is a good nucleophile so it should work fine if you want to go that way. But thiophenol stinks, you can use bleach to remove the smell.
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I tried this route again for two reasons. One is that I used fresher DMF and the other is that I had additional support from the literature in the form of a similar reaction. I imagined that the TBAI also functioned as a phase transfer catalyst, but at 80-100 °C, maybe not.
I can imagine using HSCH2P(O)(OEt)2 and the tosylate derivative of cyclopropyl alcohol as a viable route (we made a small portion of this thiol recently). The opposite disconnection is not a viable route.
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Increasing the temperature to about 107 °C did not bring about completion of the reaction with diethyl iodomethylphosphonate. I am thinking of picking up some diisopropyl bromomethylphosphonate, which is the exact compound used in the patent.
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Sorry I did not see the post with thiopyridine. You should be aware that pyridine can be oxidized to the N-oxide with some oxidizers. Thiophenolate is a good nucleophile so it should work fine if you want to go that way. But thiophenol stinks, you can use bleach to remove the smell.
We made the sulfonyl phosphonate starting with 2-thiopyridine twice, in a two-step synthesis. Both times we had to run a column after the oxidation, something that we do not have to do when we oxidized the corresponding S-methyl sulfide to its sulfone. We are not sure about the identities of the side-products yet, but we may know more next week.
I decided to buy diisopropyl bromomethylphosphonate, and when it comes in, I will try a small test reaction along the lines of the protocol in the patent before committing more expensive starting materials.
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The bromo would be much less reactive then the iodo, but thiolates will probably displace bromo quick anyway.
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In this case the nucleophile is a sodium alkylsulfinate, and there will be tetrabutylammonium iodide as the catalyst. No yield was given in this patent. "A mixture of diisopropyl (bromomethyl)phosphonate (0.5 g, 1.93 mmol), sodium cyclopropanesulfinate (0.37 g, 2.895 mmol) and TBAI (0.071 g, 0.19 mmol) in DMF (4 mL) was heated overnight in a IOO0C oil bath. The mixture was cooled to it and diluted with EtOAc and water. The layers were separated, and the organic layer was washed with saturated NaHC03, brine, dried (Na2S04) and filtered. The solvent was removed and the crude was purified by silica gel to obtain the title compound."
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Yes, the sulfinate is much weaker nucleophile than sulfide so it could be useful with TBAI. Cesium iodide would be easier to remove after the reaction.
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Yields in patents can be lower than 1% in some cases.
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When diisopropyl bromomethylphosphonate comes in, I will test it using sodium phenylsulfinate, because I have the product that I can use as a standard. At some point, I will also test the corresponding diethyl toluenesulfonate. I did this once before, and I had some product formation, but not quite as much as I had hoped for.