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S- vs. O-alkylation using sodium sulfinates

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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.

Can you use a sulfide instead and oxidize this after the coupling?

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.

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.
Kielbasinski R...Mikolajczyk M. Tetrahedron 1988 44 6687-6692.

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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