Org Prep Daily

June 5, 2007

Bartoli Does Not Like You

Filed under: mechanisms — milkshake @ 2:38 pm


Following a close literature precedent in Bioorg. Med. Chem. Lett. 15, 2005, 4867-71, I was trying to make an intermediate piece from a substituted nitroaniline using Bartoli indole synthesis [J. Chem. Soc. Perkin 2, 1991, 657-663]. I got some indole alright. The yields are average of two runs at one gram scale, workup was done with sat NH4Cl. I think this qualifies in the “Look what happened to me doc – it’s all black” category. 


  1. Wow! You’ve metallated the piperidine? Interesting.

    Comment by Greg The Chemist — June 5, 2007 @ 4:14 pm

  2. Looks like someone activated a C-H bond. Get that JACS communication written up ASAP!

    Comment by bad wolf — June 5, 2007 @ 8:12 pm

  3. There is no C-H metallation, only intramolecular redox. We could argue about the role of Grinard, if the proces is radical-like (SET). Bartoli goes by reduction of nitro to nitroso (Vinyl Grignard would add to NO to make vinylarylhydroxylamine that cyclizes). With the otho aniline substituent present, the nitroso can tautomerise to quinoid zwiterionic structure, the double bond shift in these systems to iminium is known – and you are there, modifying alpha on the piperidine. This kind of intramolecular redox stuff was seen before, on antraquinones with piperidine attached ortho to C=O.
    (But I found all this after the fact, you can imagine my puzzlement when looking at the NMR, LC/MS signals)

    I think this is not very useful synthetically nor general – I think this is probably a special case, very much derived from the crammed 1,2,3 substitution pattern and the tertiary amine ortho to nitro. I could probably write a short note about this curious complication but I think Tet Lett has too many issues even without my help.
    If Cordova or Kahn is reading this blog: You can probably use isopropyl Grignard to get more of the benzimidazole and probably do the inverse addition, of the nitro into the excess of vinyl Grignard if you wish to obtain more 2-vinylpiperidine. So here you go

    Comment by milkshake — June 5, 2007 @ 11:22 pm

  4. The scheme reminded me of the graphical abstract from a semi-recent publication:

    Selective and Catalytic Arylation of N-Phenylpyrrolidine: sp3 C-H Bond Functionalization in the Absence of a Directing Group
    Bengü Sezen and Dalibor Sames
    J. Am. Chem. Soc.; 2005; 127(15) pp 5284 – 5285; (Communication) DOI: 10.1021/ja050269o

    Comment by bad wolf — June 6, 2007 @ 9:53 am

  5. Now with Bengu gone maybe I should ask Dali if he would take me in, as his student…

    Comment by milkshake — June 6, 2007 @ 5:14 pm

  6. Are the results the same if you use the bromo-Grignard?

    Comment by TWYI — June 6, 2007 @ 5:33 pm

  7. never tried

    Comment by milkshake — June 6, 2007 @ 5:40 pm

  8. We’ve been using a similar prep into order to get an appropriate substitution on the 7-position of the indole. We’ve been using the bromo Grignard (as TWYI suggested) and I believe we’re getting mostly the indole. I’m looking into the same synthesis for my own stuff, as I’m wanting to cut out 1) an expensive and not-easy-to-find starting material and 2) using DMFDMA/DMF on my very first step, thus causing me to waste several days as I “dry” the stuff down in the vac oven.

    Comment by Matt J. — June 14, 2007 @ 10:44 am

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