November 28, 2022, 11:22:12 PM
Forum Rules: Read This Before Posting


Topic: S- vs. O-alkylation using sodium sulfinates  (Read 4636 times)

0 Members and 1 Guest are viewing this topic.

Offline Babcock_Hall

  • Chemist
  • Sr. Member
  • *
  • Posts: 5335
  • Mole Snacks: +304/-22
S- vs. O-alkylation using sodium sulfinates
« 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.
« Last Edit: February 28, 2022, 11:44:02 AM by Babcock_Hall »

Offline rolnor

  • Chemist
  • Sr. Member
  • *
  • Posts: 1986
  • Mole Snacks: +135/-10
Re: S- vs. O-alkylation using sodium sulfinates
« Reply #1 on: March 01, 2022, 01:02:44 AM »
Can you use a sulfide instead and oxidize this after the coupling?

Offline Babcock_Hall

  • Chemist
  • Sr. Member
  • *
  • Posts: 5335
  • Mole Snacks: +304/-22
Re: S- vs. O-alkylation using sodium sulfinates
« Reply #2 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.
« Last Edit: March 01, 2022, 09:07:43 AM by Babcock_Hall »

Offline Babcock_Hall

  • Chemist
  • Sr. Member
  • *
  • Posts: 5335
  • Mole Snacks: +304/-22
Re: S- vs. O-alkylation using sodium sulfinates
« Reply #3 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.
« Last Edit: March 09, 2022, 12:55:58 PM by Babcock_Hall »

Offline Babcock_Hall

  • Chemist
  • Sr. Member
  • *
  • Posts: 5335
  • Mole Snacks: +304/-22
Re: S- vs. O-alkylation using sodium sulfinates
« Reply #4 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.

Offline Babcock_Hall

  • Chemist
  • Sr. Member
  • *
  • Posts: 5335
  • Mole Snacks: +304/-22
Re: S- vs. O-alkylation using sodium sulfinates
« Reply #5 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.

Offline rolnor

  • Chemist
  • Sr. Member
  • *
  • Posts: 1986
  • Mole Snacks: +135/-10
Re: S- vs. O-alkylation using sodium sulfinates
« Reply #6 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.

Offline rolnor

  • Chemist
  • Sr. Member
  • *
  • Posts: 1986
  • Mole Snacks: +135/-10
Re: S- vs. O-alkylation using sodium sulfinates
« Reply #7 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.

Offline rolnor

  • Chemist
  • Sr. Member
  • *
  • Posts: 1986
  • Mole Snacks: +135/-10
Re: S- vs. O-alkylation using sodium sulfinates
« Reply #8 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.

Offline hollytara

  • Chemist
  • Full Member
  • *
  • Posts: 316
  • Mole Snacks: +39/-0
Re: S- vs. O-alkylation using sodium sulfinates
« Reply #9 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


Offline Babcock_Hall

  • Chemist
  • Sr. Member
  • *
  • Posts: 5335
  • Mole Snacks: +304/-22
Re: S- vs. O-alkylation using sodium sulfinates
« Reply #10 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.

Offline rolnor

  • Chemist
  • Sr. Member
  • *
  • Posts: 1986
  • Mole Snacks: +135/-10
Re: S- vs. O-alkylation using sodium sulfinates
« Reply #11 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

Offline rolnor

  • Chemist
  • Sr. Member
  • *
  • Posts: 1986
  • Mole Snacks: +135/-10
Re: S- vs. O-alkylation using sodium sulfinates
« Reply #12 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

Offline Babcock_Hall

  • Chemist
  • Sr. Member
  • *
  • Posts: 5335
  • Mole Snacks: +304/-22
Re: S- vs. O-alkylation using sodium sulfinates
« Reply #13 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.
« Last Edit: March 14, 2022, 08:33:14 PM by Babcock_Hall »

Offline rolnor

  • Chemist
  • Sr. Member
  • *
  • Posts: 1986
  • Mole Snacks: +135/-10
Re: S- vs. O-alkylation using sodium sulfinates
« Reply #14 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?

Sponsored Links