Org Prep Daily

June 6, 2007

Spiroindoline from Fischer indole synthesis

Filed under: mechanisms — milkshake @ 12:19 am

There is a rather helpful paper from Merck Process group from 1997:


I repeated the procedure with Alloc -protected piperidine carboxaldehyde. Without the final mesylation, I got the NH indoline in the incredible yield 37% after some tedious workup (acidic extraction of the product into water etc., then a big column) and the product then crystallized nicely. The final compound was completely inactive in our project. But the joy of spiroannelation – priceless. 


  1. This is off topic but I’d like to throw it out anyway. As a replacement for triflic anhydride partly due to its high costs, perfluorobutane sulfonyl fluoride can be used. We are trying to use it to activate an alcohol and subsequently do a SN2 in DCM with TEA to trap HF (tosylate won’t work). Any suggestions or comments in dealing with this, mainly regarding the safety issue, considering HF is involved (The reaction will eventually be run on kilo scale)? I initially tried to ask this on ChemBark when I saw its May 24th entry ( but I guess it’s too late.

    Comment by pc — June 7, 2007 @ 11:34 am

  2. I am not a safety expert but I suppose you should have the Ca-gluconate-in-glycerine gelly available, to treat any skin contact, full facial shields when handling the stuff and wearing double disposable gloves and probably having a special safety training class about dangers of HF (delayed effects, etc). Maybe you could also notify a nearby hospital poison center/burn unit that you are working with this material so that they would be up to speed and know how to treat HF burn emergencies.

    Frankly I don’t think you will have too much HF generated (1 kilo of the sulfonyl fluoride is about 3 moles which produces is about 60g of HF) and you will have it diluted and neutralized with the amine. I would be more concerned about the direct tissue-corrosive action of the starting sulfonyl fluoride – and there of course it can produce fluoride poisoning within, apart from the normal chemical burn.
    Generally it is better to be more safety concious than the opposite extreme. I know from my own unfortunate experiences that exotherms, spils and other hazzards increase with scale.

    Comment by milkshake — June 7, 2007 @ 1:02 pm

  3. Splitting hairs…but it’s Fischer

    Comment by Wavefunction — June 12, 2007 @ 1:30 pm

  4. thank you – corrected the typo

    Comment by milkshake — June 12, 2007 @ 3:59 pm

  5. Hi MS,

    Bit off topic. I am trying to synthesize 2,4 dimethoxy benzyl chloride/bromide from the benzyl alcohol. But the literature conditions (SOCl2/Oxalyl chloride etc) are unsuccessful with low yield. Could you please suggest me any mild conditions to make this compound at lower temp or else I can generate in situ for the next stage.
    Your suggestions would be very much appreciated.



    Comment by marto — August 25, 2012 @ 6:16 am

    • First, the conditions that you are using are maybe good for normal benzyl alcohols but they are too harsh for p-methoxybenzyl alcohol – and you are turning the material into a dark tar polymer. p-MeOBn(+) cation is even more easily formed than tert-butyl cation, that means it can be produced under quite mild conditions i.e. with aqueous HCl, and o,p-dimethoxybenzyl cation is even more stabilized. The correct way of making these benzyl chlorides is here:

      Click to access CV4P0576.pdf

      When you make these chlorides, store them in the fridge over a small amount of solid NaHCO3 – they hydrolyze easily and even a small amount of dissolved anhydrous HCl (if stored improperly at room temperature) can cause quite violent runaway decomposition. Do not make bromides – they are unstable. If you need to increase the reactivity of pMeOBn-Cl, add a catalytic amount of Bu4N(+) I(-) or NaI to the alkylation reaction

      Comment by milkshake — August 25, 2012 @ 9:58 pm

      • Hi MS,

        Thanks very much for the suggestions and procedure.


        Comment by marto — August 26, 2012 @ 2:23 am

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