nb198 - 22-7-2015 at 17:59
I am trying to carry out a Fischer indole synthesis to make skatole. I plan to use phenylhydrazine and propanal. I have about 2g phenylhydrazine and
20g propanal, so I dont have TOO much to work with (phenylhydrazine wise)
I understand that the formation of the hydrazone is pretty simple. Mix the hydrazine + propanal with ethanol. Heat off the ethanol and be left with
decent yield of hydrazone. The next step is the cyclization and this is where my question is.
Most syntheses call for the use of ZnCl2. Does it have to be anhydrous? Generally, what solvents are used? What is the workup like?
I was also looking into not using ZnCl2 and instead using something like H2SO4 or AcOH. However, I can't really seem to find any decent procedure
regarding the use of either of those for indole synthesis. What are the reaction conditions? What is the general workup?
Any information would be appreciated.
Nevermind I think I found what I was looking for.
[Edited on 23-7-2015 by nb198]
byko3y - 22-7-2015 at 23:48
http://pubs.acs.org/doi/abs/10.1021/ja01135a515 - example with polyphosphoric acid
http://pubs.rsc.org/en/Content/ArticleLanding/1945/JR/JR9450... - Example with dillute sulfuric acid for tetrahydrocarbazole preparation.
http://pubs.acs.org/doi/abs/10.1021/cr60224a003 - Extensive review
AvBaeyer - 24-7-2015 at 19:48
The synthesis of 3-substituted indoles from aldehyde phenylhydrazones is difficult in general. Most things just do not work well unless one spends
considerable time optimizing. Skatole is usually prepared from indole using a Vilsmeier-Haack reaction (DMF+POCl3) to get indole-3-aldehyde followed
by reduction with LiAlH4 to 3-methylindole.
If you manage to get skatole and you get any on you, you will smell like a turd for days. I speak from sad experience years ago as an undergraduate
research assistant to a grad student who assigned me a prep starting with skatole. Long story short, my girlfriend would not come near me for days.
AvB
careysub - 24-7-2015 at 22:29
Slightly off-topic, but I am curious about the specification of "polyphosphoric acid", which I have seem referenced in other syntheses. This would
seem to be a mixture of indeterminate composition. Would plain orthophosphoric acid not suffice?
zed - 25-7-2015 at 15:05
Polyphosphoric Acid is a syrup/paste that's use was on the rise some decades back.
I've used it in the Fischer synthesis, and it works. That being said, it also produced a fair amount of highly colored crud as a bye-product.
It isn't exactly OTC, and last time I checked, it was spendy in small quantities. Like $100 a liter, or more.
ZnCl works pretty well. It is cheap and available.
Since I was just reading on this subject a few days ago, I have a handy reference. There is claim of an 80% yield, via the path you wish to follow.
https://books.google.com/books?id=2NH-cagtLSoC&pg=PA4&am...
Follow the Yellow Brick Road.
[Edited on 25-7-2015 by zed]