Org Prep Daily

September 29, 2010

Oxindole-5-carboxylic acid

Filed under: procedures — milkshake @ 12:42 pm


Indole-5-carboxylic acid 5.00g [Combiblocks] (31.0 mmol) solution in ethanol 99% 120mL and tert-butanol 180mL in a 1L RB flask was cooled on ice bath to +5 C. Meanwhile, a solution of lithium bromide 9.0g (103.6 mmol) in neat acetic acid 60mL was placed into an addition funnel. Neat bromine 5.0mL (16.0g; 100.1 mmol) was then charged to this LiBr solution and the addition funnel was briefly swirled by hand to mix the reagents. The resulting bromine+LiBr solution was dropwise added into the vigorously stirred indolecarboxylic acid solution at +5 C over a 90 min period. (After a complete addition the addition funnel was then washed with EtOH 2 x 5 mL and the washings were added to the reaction mix). At the end of the bromine addition the cooling bath was let to expire and the reaction mix was stirred at +5 to +15 C bath for 1 hour and at 15 C for additional 15 min. The reaction mixture was then diluted with additional acetic acid 100mL. Zn dust 20g [Aldrich; <10 micron] (306 mmol) was added in one portion (gas evolution!) and the mixture was stirred in an open flask on ambient water bath overnight (16 hours).

The next day, the precipitated solids were collected by filtration, washed with ethanol and dried by suction. The solid (containing a mix of the product, unreacted Zn metal and Zn salts) was transferred into a large beaker on a hotplate, suspended in boiling methanol (300mL) and filtered. The extraction with boiling methanol was repeated  twice more, to separate the unreacted Zn metal from the product. The combined methanolic filtrates were evaporated to dryness. Separately, the acetic acid+LiBr – containing filtrates from the reaction mix were concentrated to a small volume on rotovap and the produced salt-rich residue was diluted with water 0.6L and acidified with 6M HCl to about pH= 1.5. This mixture was then combined with the evaporation residue obtained from the methanolic filtrates. The solids in the flask were re-suspended by a brief sonication (5 min) and the slurry was cooled down on ice bath, then placed into a freezer (-20C) for 4 hours. The precipitated product was collected by filtration, washed with ice-cold water, dried by suction and on highvac. Y=5.23g (95%) of a light tan solid.

1H(d6-DMSO, 400MHz): 12.58 (br s, 1H), 10.72(s, 1H), 7.82 (dd, 8.3Hz, 1.6Hz, 1H), 7.75 (s, 1H), 6.88 (d, 8.3Hz, 1H), 3.54 (s, 2H)

Note: Skin contact with bromine produces excruciating burns: Heavy duty protective gloves with extended sleeves are required. Make sure that the used syringe does not leak, work in the hood, do not wash bromine-contaminated glassware with acetone (use water or alcohol).


  1. First step goes through the acetal?

    Comment by subnaught — September 29, 2010 @ 2:42 pm

    • there is one clearly identifiable intermediate, 3-bromoindole, with nearly quantitative conversion at a stage when only 1 equiv of Br2 is added. I suppose the next intermediate is 3,3-dibromoindolenine but whatever the dibrominated product is, it does not hang around for long – it gets further oxidized to 3,3-dibromooxindole, maybe through the 2,3,3-tribromoindolenine.

      Comment by milkshake — September 29, 2010 @ 2:52 pm

  2. I wonder what is the purpose of LiBr here, do you have any idea? Just a mild Lewis acid?

    Comment by JH — September 29, 2010 @ 6:14 pm

    • Makes me wonder, too, for AcOH + Br2 is accepted to produce AcO- Br+, a nice, mild, yet electrophilic, bromine cation source. So, would LiBr + Br2 make Li+ (Br3)- ?

      Thanks to Milkshake’s employers, making him scale up some early intermediate with worthwhile chemistry, so that we can discuss, and, like we say in French, “shovel up a few clouds”, i.e. discuss…. 😉

      Comment by HPCC — September 29, 2010 @ 6:50 pm

    • I’m also wondering about the blend of two alcohols as the solvent – why not use one or the other?

      Comment by Ron — September 29, 2010 @ 7:14 pm

  3. tBuOH is there as a scavenger of HBr ; strongly acidic media would mess up the indole. The produced tBu-Br is volatile so it is removed on rotovap. I suppose one could use tBuOH alone (instead of tBuOH+EtOH mix) but the reaction mixture would freeze upon cooling on ice.

    LiBr is there as a organic-soluble source of bromide. Br(-) with Br2 produces a Br3(-) solution, which is a somewhat milder brominating agent than Br2 alone. The bromination works without it but is messier – when you leave LiBr out the overall yield of this procedure drops down to 75% th.

    The original procedure for making oxindoles from indoles actually calls for using commercially-available pyridine.HBr.Br2 complex which is on molar basis far more expensive then Br2. This complex is a brown solid with a low vapor tension and one can conveniently run the bromination with it just in a beaker and spoon the pyridinium tribromide complex in. But the bromination needs to be done at room temp as the complex has some solubility issues at +5C and one ends up with lots of pyridine-Zn stuff in the reaction mix which I suppose keeps a part on the product in the supernatants, even after acidification. I never got over 85% Y with the pyridinium tribromide reagent at room temperature – and I figured that using a more soluble analog of it (for example from LiBr and bromine) adding it dropwise and cooling the reaction mixture should improve the yield a little.

    Comment by milkshake — September 30, 2010 @ 1:19 pm

    • That’s interesting. In a way it is the same kind of ideas as in this bromination method in Org. Syn. I ran across a few days ago. What a coincidence.

      Comment by JH — October 4, 2010 @ 11:06 pm

      • yeah, the trimethylanilinium tribromide reagent is commercial – I actually have a Aldrich bottle of this stuff under the hood. I found it in our chem inventory but I did not get to use it. It is supposed to work even better than py.HBr.Br2 for some selective bromination (according to Paquette monograph on organic reagents). I was reluctant to use trimethylanilinium quat salt reagent because my product has a free carboxyl and I worried that I could get screwed if my product would not precipitate out of the reaction mix.

        Comment by milkshake — October 5, 2010 @ 1:04 am

  4. Why is it a bad idea to wash out bromine-contaminated glassware with acetone? Does it give bromoacetone which is a strong lachrymator?

    Comment by UG4 — October 1, 2010 @ 11:46 pm

    • Pretty much. Along with HBr, which is nasty corrosive. I personally just squirt out the last drops at the back of the hood and take the (disposable) syringe apart for trace Br2 vapours to vapourise. A friend of mine would rinse his syringe with 1M sodium thiosulfate solution. That’s even better – it turns Br+ into innocuous Br-.

      Comment by HPCC — October 2, 2010 @ 3:41 am

    • bromoacetone is a tear gas – it has almost no odor but it is very irritating

      Comment by milkshake — October 2, 2010 @ 3:02 pm

  5. An old co-worker was transferring Br2 with a fat syringe, and it somehow “burped” several droplets onto his arm…. truly horrific lesions that took months and months to heal….

    Comment by Jose — October 4, 2010 @ 7:38 am

    • I only saw a color picture in a lab safety manual… The caption explained that Br2 damage is comparable to effects of mustard gas.

      Comment by milkshake — October 4, 2010 @ 8:46 am

  6. I made 3-methyl oxindole from skatole (mmmmmmh) using DMSO and c. HCl. 80%+ yield and in 0.25h. Can’t see why this would not work with your substrate?? It’s a sort of like a Swern type oxidation I guess – protonate at C3, trap an C2 on oxygen of DMSO, then eliminate DMS Swern-fashion.

    S. Takase, I. Uchida, H. Tanaka and H. Aoki, Tetrahedron, 1986, 42, 5879

    Comment by anon — October 6, 2010 @ 6:23 am

    • thank you for the reference – I was not aware of this simple method for making oxindoles. Please does this work also for indoles that lack the substituent in the 3 position?
      Also, my symphaties for working with skatole. Indole is already bad enough but skatole smell is unbelievable. We had a kilo-sized bottle of skatole at my first company and I though I could use it as a scavenger for a solid phase cleavage/deprotection. And I found the bottle still packed in the original drum – with tight lid, vermiculite all around, and wrapped in three plastic bags. I only opened the first plastic bag and then I reconsidered and closed the drum. I chose thioanisole-ethylenedithiol mix instead, as a less revolting scavenger alternative.

      Comment by milkshake — October 6, 2010 @ 8:48 am

      • Actually I have never done it with 3-unsubstituted indoles, hence the comment “Can’t see why this would not work…..”

        But I guess it is possible that the +I 3-methyl group promotes C3 protonation to an extent that the reaction works, but if the 3-substitutent is missing, or -I, then it may not be so good or fail completely….

        Comment by anon — October 7, 2010 @ 7:32 am

  7. Careful with how you do those Swern-type of indole oxidations. A British postdoc once used this reference for a mechanism problem during group meeting:

    Bailey et al. Tetrahedron Lett. 1999, 40(24), 4593-4596.

    Comment by AnotherChemist — October 8, 2010 @ 3:19 pm

  8. how we can product the oxindole (the reactivities of oxindole)?

    Comment by boubou — December 28, 2010 @ 8:04 am

  9. I am finding diifculty in synthesizing derivatives with CH2SiR3 on indole nitrogen and also CH2B(OH)2 derivatives. These derivatives seems very labile and I see the displacement of B(OH)2 group by OH and also the displacement of Silyl groups in the other derivative. I dont understand why that happens..Please suggest me what could be the reason for its unstability.



    Comment by marto — February 1, 2011 @ 2:19 pm

    • well I don’t have any experience with this type of compounds but perhaps switching to more bulky groups, for example CH2Si(iPr)3 and CH2-BBN, would make things slightly more stable

      Comment by milkshake — February 1, 2011 @ 3:37 pm

  10. Hi MS,

    I am getting low yield of allylic bromination of a non heteroaromatic compound under radical conditions (NBS/AIBN, CCl4 reflux). I need to convert CH3 to to CH2LG (LG- Br, Cl or any other group). Please suggest me any other reactions I can try. Thanks for the help.


    Comment by marto — March 21, 2011 @ 7:33 am

    • I don’t know any alternative system for allylic bromination that is substantially different.
      It is impossible for me to guess what is going on since I don’t know the structure of your compound…

      So why is your yield low – is the rest of the reaction mix a starting material or do you get some other products too?
      Is NBS being consumed in your reaction? (This is easy to tell because NBS is poorly soluble and heavier than CCl4 so it sits at the bottom. Succinimide sideproduct is also poorly soluble in CCl4 but lighter so it floats up in the reaction mix when NBS is consumed.)

      These radical brominations are greatly accelerated by visible light – typically one would use a back-mirrored floodlight lightbulb or halogen lightbulb, few hundred watts, the kind that one would use for illuminating stage, and shine the bright white light on the flask. Go to a home improvement/hardware store and buy the strongest light source that they sell and shine it on your reaction.

      Also, the other radical initiator catalyst that was traditionally used for this reaction is benzoyl peroxide…

      Comment by milkshake — March 21, 2011 @ 6:32 pm

  11. i want to synthesised oxindole 5-carboxylic acid from oxindole.. any idea??

    Comment by kakadiya dipesh — January 27, 2015 @ 9:00 am

    • don’t even try. It is horrible. It involves Friedels-Craft on oxindole, into 5 position – this step works – with chloroacetyl choride and AlCl3, followed by degradation of chloroacetyl into carboxyl (use of pyridine to displace chlorine to make N-subst pyridinium quaternary salt, followed by hydrolysis with NaOH). This last step is exceptionally dirty and the product is very difficult to purify because of its poor solubility. My unhappiness with the published oxindole-5-carboxylic acid preparation from oxindole led me to look into alternative of making it from indole-5-carboxylic acid. And it was so much nicer.

      Comment by milkshake — January 27, 2015 @ 1:37 pm

      • Wouldn’t it be possible to do the Friedel-Crafts with trichloroacetyl chloride, followed by hydrolysis with NaOH to give desired carboxylic acid (I am unsure whether the -CCl3 is directly eliminated a la haloform reaction, or whether it is hydrolysed to -COOH first).

        Comment by Daniel — June 25, 2015 @ 4:39 am

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