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Topic: success with the test reaction and failure with the desired reaction  (Read 3406 times)

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Offline Babcock_Hall

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We are making sulfonyl phosphonates of the form RSO2CH2P(O)(OR')2.  Previous test reactions using diethyl iodomethylphosphonate and sodium phenylsulfinate have failed.  A previous attempt using TsOCH2P(O)(OEt)2 gave a mixture of products but had some promise.  We found a patent that used diisopropyl bromomethylphosphonate and TBAI as a catalyst.  The protocol used sodium cyclopropylsulfinate as the nucleophile. 

For the purposes of testing the procedure, I used 1.5 equivalents of sodium phenylsulfinate (inexpensive) to one equivalent of diisopropyl bromomethylphosphonate to 0.1 equivalents of TBAI.  I ran for 10.5 hours at 87 °C vs. overnight at 100 °C in the patent procedure we are following.  The starting material has a P-31 chemical shift of about 16.4 ppm.  My test reaction showed a small amount of starting material and a new peak at 9 ppm.  I have diethyl phenylsulfonylmethylphosphonate (which shows up near 11 ppm--I can check my records if anyone is interested) on hand.  I do not have diisopropyl phenylsulfonylmethylphosphonate as a standard.  However 9 ppm is qualitatively in range for the product of S-alkylation.  We did not isolate this product.

Encouraged by these results we set up a reaction with sodium 2-propylsulfinate (moderately pricey) and the other two starting materials.  After about 18 hours at 102 °C, we saw a large peak near 16.45 ppm and a very small peak a little downfield, but nothing in the correct range for a sulfonyl phosphonate.  We have not done anything to the reaction mixture beyond letting it cool.  This is obviously a disappointing and puzzling result.

I have two questions.  One is what might have gone wrong?  Two is whether there is any way to push the present reaction forward?  The only thing I can think of is to add more TBAI and heat again.
« Last Edit: April 11, 2023, 04:42:09 PM by Babcock_Hall »

Offline Babcock_Hall

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Re: success with the test reaction and failure with the desired reaction
« Reply #1 on: April 11, 2023, 08:09:56 PM »
It has occurred to me that the starting material, sodium 2-propanesulfinate, might not be what it claims to be.  That is all that I can come up with so far.

Offline Babcock_Hall

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Re: success with the test reaction and failure with the desired reaction
« Reply #2 on: April 12, 2023, 09:16:25 AM »
DOI: 10.1080/00397910600978515. I forgot to mention one report of a polymer-supported arylsulfinate reacting with slightly less than a twofold excess of the electrophile. "Either diethyl iodomethylphosphonate (4.0 mmol) or diisopropyl iodomethylphosphonate (4.0 mmol) was added, and the reaction mixture was stirred at 80 °C for 12 h."

Regarding the failure of sodium 2-propanesulfinate vs other alkyl or aryl groups, it might be related to greater stability of the 2-propyl radical.  In other words there may be a decomposition of one starting material that is not as much of an issue for the other starting materials.
« Last Edit: April 12, 2023, 09:45:20 AM by Babcock_Hall »

Offline phth

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Re: success with the test reaction and failure with the desired reaction
« Reply #3 on: April 25, 2023, 06:36:38 PM »
We are making sulfonyl phosphonates of the form RSO2CH2P(O)(OR')2.  Previous test reactions using diethyl iodomethylphosphonate and sodium phenylsulfinate have failed.  A previous attempt using TsOCH2P(O)(OEt)2 gave a mixture of products but had some promise.  We found a patent that used diisopropyl bromomethylphosphonate and TBAI as a catalyst.  The protocol used sodium cyclopropylsulfinate as the nucleophile. 

For the purposes of testing the procedure, I used 1.5 equivalents of sodium phenylsulfinate (inexpensive) to one equivalent of diisopropyl bromomethylphosphonate to 0.1 equivalents of TBAI.  I ran for 10.5 hours at 87 °C vs. overnight at 100 °C in the patent procedure we are following.  The starting material has a P-31 chemical shift of about 16.4 ppm.  My test reaction showed a small amount of starting material and a new peak at 9 ppm.  I have diethyl phenylsulfonylmethylphosphonate (which shows up near 11 ppm--I can check my records if anyone is interested) on hand.  I do not have diisopropyl phenylsulfonylmethylphosphonate as a standard.  However 9 ppm is qualitatively in range for the product of S-alkylation.  We did not isolate this product.

Encouraged by these results we set up a reaction with sodium 2-propylsulfinate (moderately pricey) and the other two starting materials.  After about 18 hours at 102 °C, we saw a large peak near 16.45 ppm and a very small peak a little downfield, but nothing in the correct range for a sulfonyl phosphonate.  We have not done anything to the reaction mixture beyond letting it cool.  This is obviously a disappointing and puzzling result.

I have two questions.  One is what might have gone wrong?  Two is whether there is any way to push the present reaction forward?  The only thing I can think of is to add more TBAI and heat again.

Don't they react differently? 2-propyl is not the same as phenyl. Are you sure that the phosphorus NMR is correct; what about carbon NMR or another secondary line of evidence?

Offline Babcock_Hall

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Re: success with the test reaction and failure with the desired reaction
« Reply #4 on: April 25, 2023, 06:54:33 PM »
When you say react differently, what do you mean?  We have not attempted a purification on the mixture.

Offline rolnor

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Re: success with the test reaction and failure with the desired reaction
« Reply #5 on: April 26, 2023, 02:59:25 PM »
You will probably puke on me now, but use the sulfide-method, skip the sulfinate-method.

Offline Babcock_Hall

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Re: success with the test reaction and failure with the desired reaction
« Reply #6 on: April 26, 2023, 03:56:50 PM »
Actually the thiol to sulfide to sulfone route is what we were planning to do next (and the electrophile just came in), except with the thiol on the phosphonate portion of the molecule, not on the 2-propyl portion.  There are two potential problems with thiol-to-sulfide approach.  One is the cost of the thiol, and the other is volatility of the thiol.  Diethyl mercaptomethylphosphonate is not as volatile as the thiol in the opposite disconnection.  We have a little of this thiol on hand, and we also have its S-protected precursor.

As an aside, we used diethyl mercaptomethylphosphonate with calcium carbonate and an electrophile having a primary bromine last fall, and this past week we oxidized the product (a sulfide) with mCPBA and followed the reaction with P-31 NMR.  In the past we used Oxone, but mCPBA was the better choice based on the other functional groups that were present, one of which I believe to be acid-sensitive.

The scope of the sulfinate reaction may be limited to aromatic sulfinates, but I am only speculating.
« Last Edit: April 26, 2023, 07:48:32 PM by Babcock_Hall »

Offline Babcock_Hall

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I tried a mini-scale reaction using cyclopropylsulfinate, and the P-31 NMR time point was promising.  I tried an extraction and a purification, and the H-1 and P-31 NMR are consistent with the desired product, a sulfonyl phosphonate.  The yield was modest, perhaps because I lack experience working at a small scale.  I scaled up and both the P-31 time points and the mass after the extraction are better than the mini-scale.  The next step will be to purify the larger scale synthesis over silica.  I do not have an explanation for why this reaction worked for cyclopropyl and probably phenyl but not 2-propyl as the R group.  I can speculate that decomposition of 2-propylsulfinate was the problem.  Someone who is more accomplished in method development than I am might be in a better position to explore the scope and limitations of this reaction.

I will use a different disconnection for the S-2-propyl compound.  I will start with a thiol and 2-propyliodide.  If the alkylation goes well, I will oxidize with oxone or mCPBA.
« Last Edit: May 06, 2023, 01:46:26 PM by Babcock_Hall »

Offline rolnor

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I tried a mini-scale reaction using cyclopropylsulfinate, and the P-31 NMR time point was promising.  I tried an extraction and a purification, and the H-1 and P-31 NMR are consistent with the desired product, a sulfonyl phosphonate.  The yield was modest, perhaps because I lack experience working at a small scale.  I scaled up and both the P-31 time points and the mass after the extraction are better than the mini-scale.  The next step will be to purify the larger scale synthesis over silica.  I do not have an explanation for why this reaction worked for cyclopropyl and probably phenyl but not 2-propyl as the R group.  I can speculate that decomposition of 2-propylsulfinate was the problem.  Someone who is more accomplished in method development than I am might be in a better position to explore the scope and limitations of this reaction.

I will use a different disconnection for the S-2-propyl compound.  I will start with a thiol and 2-propyliodide.  If the alkylation goes well, I will oxidize with oxone or mCPBA.

Great!

Offline rolnor

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Actually the thiol to sulfide to sulfone route is what we were planning to do next (and the electrophile just came in), except with the thiol on the phosphonate portion of the molecule, not on the 2-propyl portion.  There are two potential problems with thiol-to-sulfide approach.  One is the cost of the thiol, and the other is volatility of the thiol.  Diethyl mercaptomethylphosphonate is not as volatile as the thiol in the opposite disconnection.  We have a little of this thiol on hand, and we also have its S-protected precursor.

As an aside, we used diethyl mercaptomethylphosphonate with calcium carbonate and an electrophile having a primary bromine last fall, and this past week we oxidized the product (a sulfide) with mCPBA and followed the reaction with P-31 NMR.  In the past we used Oxone, but mCPBA was the better choice based on the other functional groups that were present, one of which I believe to be acid-sensitive.

The scope of the sulfinate reaction may be limited to aromatic sulfinates, but I am only speculating.

Nice! You have some compounds coming out now so the bio-people have something to test, thats an exciting part of a project. Banging your head against failed chemistry is not nice in the long run. Really good news Babcock!

Offline Babcock_Hall

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Re: success with the test reaction and failure with the desired reaction
« Reply #10 on: June 22, 2023, 05:53:31 PM »
I will use a different disconnection for the S-2-propyl compound.  I will start with a thiol and 2-propyliodide.  If the alkylation goes well, I will oxidize with oxone or mCPBA.
The alkylation of the thiol with 2-iodopropane to make the S-2-propyl sulfide (thioether) bearing a phosphonate was successful.  In the next few days, I will use Oxone to make the sulfone.  We have previously oxidized diethyl S-methylthiomethylphosphonate on several occasions with this reagent.

Offline rolnor

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Re: success with the test reaction and failure with the desired reaction
« Reply #11 on: June 23, 2023, 03:21:55 AM »
Great news! Oxone is easy to get rid of the excess and by-products. Better than m-CPBA.

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