Org Prep Daily

February 14, 2010

Fisher indole synthesis

Filed under: procedures — milkshake @ 6:27 pm

5-chloro-2-hydroxyacetophenone 5.655g (33.15 mmol) and 10 drops of acetic acid in a 0.5L round flask was combined with absolute EtOH 20mL and phenylhydrazine 3.60mL (4.031g; 37.3 mmol) was added. The mixture was stirred on a 80C bath for 75 min and the resulting slurry was evaporated to dryness on rotovap. The solid hydrazone intermediate was dried briefly on highvac, then neat methanesulfonic acid 20mL was added and the mix was stirred on 80C bath until complete dissolution. The bath temperature was then raised to 120C and the mix was stirred at 120C for 1 hour, then cooled to ambient temperature. A large excess of ice-cold water (about 400mL) was added to the mix, the resulting sticky slurry was cooled on ice bath (30 min), the solids were collected by filtration and washed with ice-cold water.  The crude product was dissolved in methanol 50mL at reflux, the solution was gradually diluted with water (450mL) and the mix was stirred for about 20 min, the precipitate was collected by filtration, washed with water and dried by suction. Y=7.706g (95.5% th) of a light-brown crystalline solid, pure by 1H-NMR and HPLC.

Note 1: Phenylhydrazine is exceptionally unhealthy – avoid skin contact.

Note 2: This condensation can be done in one operation as well: 5-fluoro-2-hydroxyacetophenone 5.462g (35.43 mmol) was combined with neat phenylhydrazine 4.334g (40mmol) in a 0.5L round flask and neat methanesulfonic acid 22mL was carefully added. The mixture was stirred on a 80 C bath until the mix became homogennous (15 min) and then at 120 C for one hour, then cooled to ambient temperature.  The rest of the workup is the same as above. The crude product was re-precipitated from a mixture of methanol 150mL and water 300mL as above, to provide 6.130g (76%) of the pure product as a off-white fluffy crystalline solid

2 Comments »

  1. I apologize for the lack of NMR in this case – my NMR folder got left behind with my previous employer. Indoles have lovely proton spectra, I suppose you take my word for it.

    Comment by milkshake — February 14, 2010 @ 6:30 pm

  2. This synthesis has been updated to ChemSPider here: http://www.chemspider.com/Chemical-Structure.15267079.html

    Comment by ChemSpiderman — February 14, 2010 @ 9:01 pm


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