[nox]

I'm trying to tosylate an indole derivative, the reaction works just fine, the issue is my final product runs right into tosyl chloride, so separation is near impossible. Somehow I just can't get hydrolyze tosyl chloride from my crude for whatever reason.

I run the tosylations either in DCM or benzene, with 3-5 equiv KOH, 1.2 equiv TsCl, and 10 mol% of a phase transfer catalyst (usually tetrabuylammonium hydrogensulfate). Eventually I found out that the PTC isn't really needed and the reaction works just fine with 3 equiv of KOH (finely powerded) in DCM.

I always get full conversion and the reaction is clean (spot to spot pretty much), but I always see excess TsCl. I quench my reactions with water, wash with 1M NaOH, water, and a final rinse with brine. You'd think with excess KOH and a phase transfer reagent in there, the TsCl would get hydrolyzed just like that, but no that never happens! I always, always see TsCl left in my crude. And I know it's not coming from my product, because I see only 2 spots -- product + TsCl.

Anyone have any ideas for why TsCl is so damn stable in my system? I guess one easy and quick fix is to use less TsCl, maybe 1.05 equiv or even just 1 equiv -- I'd much rather have 90% conversion than get TsCl in all my fractions...

[opsomath]

I also noticed that TsCl is relatively slow to hydrolyze. I only ever used a slight xs of TsCl though, and therefore never really had a terrible problem with that.

[408]

I use it 1:1 in DMF with Et3N as base.  Pouring into water after filtration of triethylammonium chloride leads to precipitation of the tosylated stuff. 

[nox]

I should give an update. Thanks to a colleague of mine who had similar problems with benzoyl chloride, the issue has now been resolved. The trick is to quench the reaction with saturated NH₄Cl rather than water, as ammonia is much more nucleophilic and rapidly converts any remaining tosyl chloride to the sulfonamide. I haven't tried this personally, but I presume the sulfonamide can be extracted away by washing with 1M NaOH, since sulfonamides are quite acidic (pKa ~10-12).

In any case, after the NH[₄Cl quench, all the tosyl chloride is gone, and I get a baseline spot, which I presume to be the sulfonamide. Separation is now much more trivial.

[Nosterius]

I like to use benzenesulfonyl chloride instead of tosyl chloride.

It is easier to handle on large scale since it is a liquid (controlled-rate addition), and benzenesulfonic acid is slightly more soluble in water than p-toluenesulfonic acid, which can help during work-up.

Your collegue gave a nice piece of advice though... I'll have to keep that in mind!