[Babcock_Hall]

Good Morning,

We are oxidizing a sulfide to a sulfone with a very slight excess of meta-chloroperoxybenzoic acid (mCPBA); the byproduct is presumably 3-chlorobenzoic acid.  The other functional groups present are a phosphonate ester and a tetraacetyl-protected glycoside.  In time points we observed a UV-active component ahead of the presumed product (either mCPBA or the corresponding aromatic acid).  The protocol we followed removed solids using a plug of alumina before chromatography, but we did not see any solid material; therefore, we moved on to chromatography and are in the process of characterizing the fractions.  We collected large amount of UV-active solid prior to the elution of the presumed product.

My two questions are whether or not people generally remove the byproduct of mCPBA oxidations before the silica column, and was it a good idea not to do so in this case.  I was thinking of sodium bicarbonate, followed by brine and drying the organic layer.  The only reason I can see for avoiding an aqueous wash is that one might observe hydrolysis of the acetyl protecting groups.  My guess is that bases stronger than bicarbonate should be avoided.

[wildfyr]

Usually you reduce any residual mcpba and extract the benzoic acid with basic wash.

Simply extracting with base won't work very well for MCPBA. I think sodium thiosulfate(?) or one of those sulfur salt reducing agents is what I used with good success.

https://www.chemicalforums.com/index.php?topic=78856.0

[Babcock_Hall]

That is an interesting thread; mCPBA chemistry is more complex than I realized.  I think that my protecting groups would tolerate a bicarbonate wash.

[rolnor]

Yes, per-acids are very much weaker acids than ordinary carboxylic acids. Thiosulfate is a good idea, followed by bicarbonate. I think you can use sodium meta periodate for the oxidation, maybe MeOH/H2O as solvent. Then you get only water-soluble by-products. Also, watch out, you have phosphonate and sulphonate in you molecule, these are very hydrophilic groups, you can loose material if you wash with water.

[Babcock_Hall]

Another reagent that oxidizes sulfides to sulfones in the presence of a protected glycoside is dimethyldioxirane.  The possibility of losing a sulfonyl phosphonate to the aqueous layer has long been on my mind; therefore, we usually do four extractions and have not yet observed a problem (knock on wood).  I sometimes avoid LiCl washes in the presence of phosphonates, but I don't have any data that bears on whether or not the lithium would pull a phosphonate into the aqueous layer.

[wildfyr]

There is also oxone.

[Babcock_Hall]

Oxone is acidic, and I worried about the glycoside linkage in this particular molecule.  But we have used Oxone for this transformation in other instances, and it is a fine reagent; sometimes a column is not even necessary after the oxidation.  If I had to use Oxone with acid-sensitive groups present, I would try buffering it, as Trost and a colleague did.

[rolnor]

Its mono-potassiumperoxysulfate I think? So you have a proton on there. Just sodium hydrogencarbonate as additive could work if worried about pH.

[rolnor]

Another reagent that oxidizes sulfides to sulfones in the presence of a protected glycoside is dimethyldioxirane.  The possibility of losing a sulfonyl phosphonate to the aqueous layer has long been on my mind; therefore, we usually do four extractions and have not yet observed a problem (knock on wood).  I sometimes avoid LiCl washes in the presence of phosphonates, but I don't have any data that bears on whether or not the lithium would pull a phosphonate into the aqueous layer.

Yes, but with only two or three extractions you might loose some. Ethyl acetate would be my choise of solvent fort the extraction.

[rolnor]

Have you tried NaIO4 for the oxidation? It would be very clean if it works, I think it would.

[Babcock_Hall]

We used Oxone to oxidize a sulfide bearing a 2-propyl group to a sulfone.  Although we have often used DCM in the extraction step, we tried ethyl acetate, and it worked well.  The yield was about 75%, and the product looks pure enough to be used without running a column.  The sulfide was made using 2-iodopropanol and a thiol (mercaptan).  I will try to follow up with a comment about the various oxidants.

[rolnor]

Nice! Its almost boring that you have no new problem...

[Babcock_Hall]

Review articles focused on sulfoxides and sulfone syntheses:
https://doi.org/10.1080/10426507.2019.1672691
"Selected methods for the synthesis of sulfoxides and sulfones with emphasis on
oxidative protocols". PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
2020, VOL. 195, NO. 3, 181–193.

Journal of Chemical Reviews, 2019, volume: 1, Issue: 2, pages: 99-113.
"A Concise Review on Synthesis of Sulfoxides and Sulfones with Special Reference to Oxidation of Sulfides"
DOI: 10.33945/SAMI/JCR.2019.1.99113

Some references that I have collected over the years follow.

Sodium periodate is good for oxidizing a sulfide to sulfoxide.
Griffith (1982) J. Biol. Chem., 257, 13704-13712.
Mikolajczyk and Zatorski (1973) Synthesis Communications, 669-671.

Sodium periodate/potassium permanganate is good for oxidizing a sulfide to a sulfone with some chemoselectivity.  Purrington used one equivalent each.  I think I have seen catalytic permanganate in the presence of sodium periodate also.
Purrington ST and Glenn AG Organic Preparations and Procedures International 1984 17(3):227-230.

Oxone is very good for oxidizing a sulfide to a sulfone as long as its pH (said to be between 2 and 3) can be tolerated.
Blumenkopf TA 1986 Synthetic Communications 16(2), 139-147.

Oxone buffered with borate is closer to neutral pH than Oxone itself is.  It has good chemoselectivity
Webb, K. S. (1994). A mild, inexpensive and practical oxidation of sulfides. Tetrahedron
Letters, 35(21), 3457-3460.
Trost BM, Curran DP Tet Lett 1981 22 1287

Hydrogen peroxide is useful for oxidations of water-soluble sulfides to sulfoxides (facile) or sulfones (in the presence of acetic acid and slightly elevated temperature).
Farrington et al., (1987) J. Med. Chem. 30, 2062-2072.

Hydrogen peroxide/sodium tungstate
Sato K 2012  Tetrahedron 57(13) 2469-2476.
Mauleon P et al., J Org Chem. 2007 9924-9935

N-methylmorpholine-N-Oxide/ruthenium catalyst
Alkenes are not oxidized.
Guertin KR, Kende AS (1993) Tetrahedron Lett 34:5369–5372

3-Chloroperbenzoic acid (mCPBA)
This is faster than Oxone, but removing the by-product might cause problems in some instances.

Dimethyldioxirane
This worked in the presence of a protected glycoside.
Chan 1993

Sodium perborate in acetic acid
Evans P et al., European Journal of Organic Chemistry, (7), 1740-1754; 2006
McKillop, A. and Sanderson, W.R. (1995) Tetrahedron 51, 6145-6166 (general review)

[rolnor]

OK, so you need a little KMnO4 together with NaIO4 then. Maybe its a matter of temperature, if you reflux MeOH and use only NaIO4, maybe you get Sulfone? Or hot DMF? m-CPBA is not ideal, its not 100%pure and can contaminate your product. Also explosive... Dimethyldioxirane you have to make yourself, you cant buy that, right? You use acetone+Oxone to make it, very volatile?

[rolnor]

Peracetic acid is a good option, easy to get rid of excess reagent. Cheap, I believe? If regular acetic acid with H2O2 works, peracetic acid should work.