Ning thinks anyone who can make Mandrax should be able to make tryptamines. Is the reissert synth popular amongst denizens of the hive?
It is attractive to ning for several reasons. First, OTC.
oxalic acid --> diethyl oxalate, easy.
toluene --> o-nitrotoluene, annoying but easy.
Now, how about the base?
Ning has refs where they use everything from NaNH2 to NaOMe to condense the ethyl/methyl oxalate with the nitrotoluene. What's up with that?
Helv. Chim. Acta 2001, pg 1456 suggests that the reason may bee that there is a tautomerism between the nitro and aci- forms of the nitrotoluene, and that while the nitro form has a pKa of 20.6, the aci form is only 3.6! I guess this means that once it is deprotonated, it would tautomerize to the aci-form and get stuck there, much like a nitroalkane.
(the paper also says nitromethane nitro=10.2, aci=3.25; nitroethane nitro=8.44, aci=4.41)
I have a lot of papers on this sort of thing, but to begin with, here's the pitch: Could the strong base bee replaced with PTC? NaOMe is not much stronger than hydroxide. Honestly, ning thinks the only reason hydroxide isn't used is because it would hydrolyze the oxalate ester. But, with carbonate or phosphate ion and solid-liquid PTC, this is not a problem. So why not PTC this?
It goes deeper than that, though. Ning has not seen ANY examples ANYWHERE of PTC claisen condensations. WTF not? It's just a carbanion reacting with an ester, right? Is ning missing anything? If not, then this should work.
The innovation (i.e. why are you making your own indole when you could buy it, dum dum) is that the intermediate form in the reissert synth is very convenient for another step that would greatly simplify the whole thing.
Molecule:
First, alkylate like this ("c1(N(=O)=O)ccccc1[C-]C(=O)C(=O)OCC.ClCCN(CC)CC>>c1(N(=O)=O)ccccc1C(C(=O)C(=O)OCC)CCN(CC)CC")
Molecule:
and then close the ring with Fe/HCl ("c1(n2)ccccc1c(c2C(=O)OCC)CCN(CC)CC")
Lastly, hydrolyze/decarboxylate.
See what ning's getting at? After the Claisen condensation, that benzylic methylene group becomes REALLY acidic, with all those electron-withdrawing groups nearby. To alkylate it would be so simple. And if you do that now, you don't have to worry about protecting the indole's amine group, because it isn't formed yet.
See JMC 1994, 1625 on page 1626 and 1628, where they alkylate such an indole precursor with methyl iodide.
Yield's not so hot, but there's many possible reasons for that.
Also, alkylation of ethyl phenylacetate and benzyl cyanide under PTC conditions with a number of various nucleophiles has been done. Particularly benzyl cyanide, I guess because it's an important industrial precursor.
pKa of benzyl cyanide (calculated) = 22.1
pKa of ethyl phenylacetate (calculated) = 19.4
pKa of ethyl benzylglyoxylate (calc'd) =
11<
http://ibmlc2.chem.uga.edu/sparc/pka/singlepka.cfm