Sciencemadness Discussion Board

Hemetsberger indole synthesis with ortho-vanillin

KissC001 - 4-1-2016 at 12:10

Hi ! I came across a paper about Hemetsberger indole synthesis :https://smartech.gatech.edu/bitstream/handle/1853/52171/HEANER-DISSERTATION-2013.pdf
So, I thought maybe by replacing benzaldehyde with o-vanillin (with HO protected) would it be possible to obtain 4-HO-5-MeO-Indole 2 carboxylate ?
They have a 53% overall yield with 4-MeO-Indole by starting with 4-MeO-benzaldehyde and reacting it with ethyl azidoacetate, wich was made with NaN3 and ethyl bromoacetate.

Etaoin Shrdlu - 4-1-2016 at 16:05

I see no reason the condensation with the azidoacetate wouldn't happen. As for the cyclization who knows. It appears to work on all different substrates, most relevant to you o- and m- methoxybenzaldehyde. Will adding an -OH and/or your protecting group of choice send everything to hell? Why not find out?

http://chemistry.mdma.ch/hiveboard/tryptamine/000531852.html

KissC001 - 4-1-2016 at 16:53

So, you think it really worse to give a try ? I think it's really wishable to find a convinient way to synthesis 4,5-substituted indoles. Do you think as protecting group acetyl will do the job ? Or, I thought maybe the ortho vanillin can be demethylated to be used as precursor for 2,3-MDO-benzaldehyde.

Etaoin Shrdlu - 4-1-2016 at 18:47

This is convenient? I thought it was unstable and tricky.

Yes I think it would be worth trying, why not? Do you have the capability?

The alkoxide would take your acetyl protecting group back off.

KissC001 - 4-1-2016 at 19:55

I have the capability to try at least but it will take me some time and ressources. I already have the glassware and some of reagents. The more problematic for me will be the analytical part but I can maybe have access to a GC-MS this summer. Yes, it's a little unstable and tricky but it doesn't require fancy reagents or material, as others, and eliminate the probleme of regioselectivity during cyclization.

byko3y - 5-1-2016 at 06:08

The answer is... Synthesis of chromeno[3,4-b]indoles as Lamellarin D analogues : A novel DYRK1A inhibitor class

clearly_not_atara - 6-1-2016 at 14:43

I suggest benzyl as the protecting group. Aryl esters are too labile and more complex approaches are unnecessary. Debenzylation can be accomplished with magnesium in methanol:

http://www.sciencedirect.com/science/article/pii/S0040403905...

careysub - 6-1-2016 at 14:59

There is also this using trifluoroacetic acid, which is also a reagent required in the improved Hemetsberger synthesis in the above OP's reference:
http://www.sciencedirect.com/science/article/pii/S0040403908...

(However TFA is not a panacea. The referenced paper contains a situation where this fails.)

BTW, check out this excellent survey of the subject of indole synthesis:
http://medchem.rutgers.edu/mc506/pdfs/indole_synthesis.pdf

[Edited on 7-1-2016 by careysub]

careysub - 7-1-2016 at 05:20

There is also a good Hemetsberger procedure on the Hyperlab site:
Post=556542, Jun 17 2012, 00:09.

byko3y - 7-1-2016 at 11:48

clearly_not_atara, it's 2-nitro and 2-carboxylate-benzyl protecting group, not just an unsubstituted benzyl. Also, i'm not sure whether it is stable in highly basic conditions of knoevenagel condensation (benzaldehyde + azidocarboxylate).
IN fact, the article contains some comparision of debenzylation methods, and I'm impressed with FeCl3 procedure. Notice they have failed with TFA, because there's not ortho-deactivating group. Just like in the indole ring, which has deactivating group (amine) meta to phenolic ether at 4-th position, as far as I understand.
Debenzylation.png - 57kB

clearly_not_atara - 8-1-2016 at 09:19

Basic conditions present no hazard for an ethereal protecting group (in the absence of oxidants). Ethers can even be deprotonated without decomposition. Electrophiles, on the other hand, can attack the ring, but likely won't, if the conditions are right. Benzyl groups are always removed by reduction. Strong nucleophiles such as alkyllithiums can also attack the ether.

o-nitrobenzyl is a difficult protecting group however. Maybe best to stick with a deprotection that works on unsubstituted benzyls.

[Edited on 8-1-2016 by clearly_not_atara]

[Edited on 8-1-2016 by clearly_not_atara]

careysub - 10-1-2016 at 18:41

Quote: Originally posted by byko3y  
...IN fact, the article contains some comparision of debenzylation methods...


Has the complete article ever been posted here?

byko3y - 11-1-2016 at 15:16

If you wish.

Attachment: New selective O-debenzylation of phenol with Mg-MeOH - 10.1016@j.tetlet.2005.06.046.pdf (102kB)
This file has been downloaded 2150 times

careysub - 11-1-2016 at 20:11

Thanks! Upon reading the paper I find the following comment:
"In the case of FeCl3/CH2Cl2, the debenzylation products 9h–j were given,
respectively, while clean benzyl was solely debenzylated." and as you pointed out from the table the FeCl3 procedure is very interesting.

Unfortunately the conditions for this are not given in any further detail, but they do cite the following paper for this:
3. Rodebaugh, R.; Debenham, J. S.; Fraser-Reid, B. Tetrahedron
Lett. 1996, 37, 5477–5478.

It would be interesting to see this paper also.

byko3y - 11-1-2016 at 20:15

This article is about oligosacharides, not about benzyl phenyl ether debenzylation.
Quote:
Typical Procedure: The substrate (10 - 150 mg) was dissolved in distilled CH2Cl2 under argon and anhydrous FeCl3
added (see Table I for equiv.). Note, the reaction must be kept extremely dry for optimal yield. The reaction was quenched
with H20 (0.5 mL), and diluted with CHCl3 (30 mL). The organic layer was extracted with brine (10 mL), and the
aqueous layer was reextracted with CHCl3:EtOAc (1 : 1, 2 x 10 mL). The organic layers were combined, dried over
Na2SO4, filtered, concentrated, and flash chromatographed on a silica column to give the desired product.