Sciencemadness Discussion Board

Synthesis of Hexahydrocannabinol

stoichiometric_steve - 7-5-2021 at 06:02

Efficient one-pot synthetic approaches for cannabinoid analogues and their application to biologically interesting (-)-hexahydrocannabinol and (+)-hexahydrocannabinol

Tetrahedron Letters 49 (2008) 3283–3287


In this publication, the author presents a synthesis of Hexahydrocannabinols from Olivetol and Citronellal catalyzed by Ethylenediamine diacetate (EDDA) and Triethylamine (TEA) in refluxing Xylene (no volume given :mad: ).

The problem i see here is that EDDA isn't soluble in non-polar solvents while TEA (used in HUGE amounts here, ~14 eq. wrt. Olivetol - so basically as a solvent) doesn't help with the solubility of EDDA either.

Heating the mix of Xylene, EDDA and TEA also surely doesn't reach the bp. of Xylene with that considerable amount of TEA present.

Additionally, heating to close to 100°C will make diamides from EDDA with the elimination of water, so the "catalyst" is being consumed.

So this obviously can't work...now the question is, what information is the dude withholding or is this just another bullshit paper to boost his position in scientific 8==D measuring contest databases?

Xylene might in theory be a good fit in terms of its high bp., but i'm thinking a similarly high boiling alcohol like 1-Hexanol might work (although i'd assume it's already not polar enough with that long alkyl chain to be reasonably miscible with EDDA.



[Edited on 7-5-2021 by stoichiometric_steve]

DraconicAcid - 7-5-2021 at 09:04

Quote: Originally posted by stoichiometric_steve  
Efficient one-pot synthetic approaches for cannabinoid .....


Huh. I thought all cannibiniods came from a one-pot synthesis.

symboom - 7-5-2021 at 14:07

Interesting I've heard of Delta 8 thc and Delta 10 thc from cbd never heard of this one. It would be interesting if salvia divatorum (as a kappa agonist) would have this many compounds.

HeYBrO - 7-5-2021 at 19:21

I definitely see your concerns, but why not give it a shot? as far as I know these reagents are pretty cheap. 2-5 ml of xylenes per 1 mmol of SM is probably a good ball park amount of solvent. Reaction monitoring should be easy enough with TLC as long as you remove the xylenes. Experiment will tell if this is bs or not

stoichiometric_steve - 13-5-2021 at 01:19

I've tried it different ways, there is still formation of some insoluble sludge (presumably EDDA) and the reflux temp never even gets above 100degC for obvious reasons, even when using only a fifth the amount of TEA.

Dr.Bob - 13-5-2021 at 05:10

None of the products are going to convert into CBD or THC easily, and the starting materials are not that readily available. So not sure what utility this would have when CBD is readily available for cheap now, both synthetically and from natural product extraction. Lots of people want to make synthetic compounds, but given how much CBD is now available, that is the obvious SM for most cannabinoids now.

chemist1243 - 13-5-2021 at 07:57

This is Neat, but I’m highly skeptical as THC of any kind is almost never made in a lab by synthesis, for a good reason too: its really difficult. Maybe there is a pathway to the desired compound through more easy to obtain precursors, like delta 8 THC. I have no clue how you would achieve that or what reducing agent you would need, but it’s probably easier to get than most of the stuff needed for the preperation you describe here.

Old Method

MadHatter - 13-5-2021 at 09:30

I remember this from some years ago but can't remember the source:

Citral + olivetol with boron trifluoride etherate as the catalyst.

C10H16O + C11H16O2 --> C21H30O2 + H2O

chemist1243 - 13-5-2021 at 11:36

https://www.designer-drug.com/pte/12.162.180.114/dcd/chemist...

This sort of mentions it but the yields are pathetic

karlos³ - 13-5-2021 at 11:41

If you have the olivetol already, you're much better off choosing a different approach.
Pulegone and POCl3 for example.

stoichiometric_steve - 14-5-2021 at 01:39

Quote: Originally posted by karlos³  
If you have the olivetol already, you're much better off choosing a different approach.
Pulegone and POCl3 for example.


Except
Quote:

The condensation between olivetol and pulegone under acid catalysis for the preparation of Δ6a,10a-THC in its racemic form was investigated in the early 1940s


Reference

Pinnick - 14-5-2021 at 07:50

I hope this helps, its in German but I think this reaction is somewhat similar since I also used Citronellal and EDDA. Worked fine for me. Your required temperature could be a Problem. It says that there will be side reactions with the Methanol but thats only because the prep uses Meldrum's Acid.
Good Luck!

Attachment: Tietze, Eicher - Reaktionen und Synthesen - 1991 P-3b.pdf (126kB)
This file has been downloaded 257 times

stoichiometric_steve - 14-5-2021 at 12:00

Quote: Originally posted by Pinnick  
Worked fine for me.


This type of reaction is what the dude from the paper i posted based his method on, he substituted the 1,3-dicarbonyl compound for Olivetol.

What i'm not sure about is if he even tried measuring the reflux temperature, since basically any amount of TEA mixed in with Xylene will reflux at around 95degC.

Opylation - 19-5-2021 at 00:59

Quote: Originally posted by DraconicAcid  
Quote: Originally posted by stoichiometric_steve  
Efficient one-pot synthetic approaches for cannabinoid .....


Huh. I thought all cannibiniods came from a one-pot synthesis.


Your joke was not lost on me hahahaha

Pinnick - 19-5-2021 at 10:11

Quote: Originally posted by stoichiometric_steve  
I've tried it different ways, there is still formation of some insoluble sludge (presumably EDDA) and the reflux temp never even gets above 100degC for obvious reasons, even when using only a fifth the amount of TEA.


but the pkb of TEA is lower then the pkb of Ethylenediamine and it is in excess so you should get free Ethylenediamine right?(Sludge maybe is TEA acetate?) Have you tried the hexanol yet? And have you tried the other reaction conditions with only EDDA in table 1? Maybe using EDDA:TEA 1:1 will do the trick.

stoichiometric_steve - 21-5-2021 at 05:29

Quote: Originally posted by Pinnick  
the pkb of TEA is lower then the pkb of Ethylenediamine and it is in excess so you should get free Ethylenediamine right


That was my reasoning as well. I don't see how acetic acid does anything here at all if it only goes on to protonate TEA which is in drastic excess anyways.

Maybe separately preparing the Imine of Citronellal with EDDA in a suitable solvent, then combining it with the TEA-diphenolate salt of Olivetol would make sense.
Quote: Originally posted by Pinnick  
Have you tried the hexanol yet?


not yet
Quote: Originally posted by Pinnick  
have you tried the other reaction conditions with only EDDA in table 1?


no, and that doesn't seem like a good idea to me with the quoted product distribution. using TEA alone looke like a better idea, albeit with much worse conversion but (probably) better selectivity.
Quote: Originally posted by Pinnick  
Maybe using EDDA:TEA 1:1 will do the trick.


I don't really see how, TEA is surely used to deprotonate Olivetol into the diphenolate, while ED would form an imine with Citronellal. Increasing the amount of ED (not EDDA) might actually do something.