Now I was wandering about the internet the other day and was thinking about something entirely different (Morphine synthesis from two adjacent 6-membered rings, ala "Pummerer's Ketone", strangely enough thinking about that is what led to the biomimetic synthesis of morphine) and for some strange reason had a look at limonene & THC...

That caused me to have a look at Cannibidiol (which apparently has the fortunate habit of cyclizing to THC in acid media), which essentially limonene attached via the ring to 3,5-Dihydroxy-1-pentylbenzene (at the p-position of the benzene ring).

Ok - so how to get to there? The wiki article on Terpineol may well provide the answer (provided the Pummerer-type route is open & I can't see why it shouldn't be).

The two oxygens - the one from the a-Terpineol and either of the phenolic hydroxyl's (look at the molecule - whichever one it binds to will give the same product) ala Pummerer ie. limonene + the 3,5-dihydroxy-1-pentylbenzene should react, in acid media, to give the ketone (given that the cannibidiol & limonene both give the wanted a-terpineol derivative in acid kinda supports that for mine). Once the -O- bond is formed then the rest should be relatively simple (if not exactly OTC or kitchen chemistry), as with morphine & Pummerer's ketone, once that -O- bridge is formed, oxidative cyclization (per Szantay, et al) or cyclization with strong acid (per Rice, et al) should give an effective (and hell shorter) route to THC. That would obviate the clunky as fuck technical synthesis that I've seen floating around online (erowid type).

Wouldn't that be interesting? Actual THC in a short-synthesis that is easier than that of the cannabinoid-receptor-ligands.

Have a peek at one of the cheapest essential oil terpines - Eucalyptol which has the double=bonded oxygen ether in the center of the reduced-limonene structure already - this would cleave readily enough to give the quaternary OH at the top and the other quaternary OH at the bottom - ie. it will bond via the hydroxyls with the phenolic hydroxyls of the olivetol. Dehydration of the top one gives us the ability to add the unsaturation in the correct spot.

Actually, Razdan (in his review of Cannabinoid's, attached) describes the synthesis from the cleaved "epoxide" (aka p-meth-2-ene-1,8-diol) on pages 197-198 (pp.12-13 of the attached paper), which gives the best yields with ZnCl₂/CH₂Cl₂.

Just looking around at the various routes to olivetol, I'll attach a couple of the better routes soon - surely there is an FC route? Although there are several that look do-able. Nearly all of them proceed from 3,5-dihydroxybenzoic acid (a-resorcylic acid) which you will see isn't that far removed from benzoic acid itself.

I have two papers on the subject - they both go via the reduction of the acid, then a Grignard from that... One is for labeling purposes and seems to have shit yields overall, but the relevant part of the synthesis (they add a labeled methyl group to the end of the chain - so we can disregard that fuck around) is the use of n-butyl halides.

I have requested a couple more on the synthesis of the Olevitol, obviously it was a sticking point to the researchers as well, so there are some big names involved in the synthesis of the intermediate.

Nitration of benzoic acid gives 3,5-dinitrobenzoic acid and supposedly the 3,5-dihydroxycompound from the 3,5-diaminobenzoic acid when reacted with ammonium hydrogen sulfate (according to this patent).

Interesting, the nitration does not need fuming sulfuric acid (always a hassle), but does reportedly need fuming nitric acid, to give the 3,5-dinitrobenzoic acid. But at least that way there is no need for alkali fusion and shitloads of solvents (the sulfuric acid route does NOT appeal).

Fuming nitric acid may or may not be necessary, there are several papers on the preparation of 3/m-nitrobenzoic acid (even in the MW) in much less arduous conditions. Further nitration may or may not need harsher conditions, I'm searching everywhere I can think of to find out. I have found at least one paper (Russian IIRC) that claims the best route to the 3,5-dinitrobenzoic acid is from the 3/m-nitrobenzoic acid.

Harder than that is working out a workable source of n-butyl alcohol, or n-pentanoic acid to react with the benzaldehyde/benzyl halide.

One step at a time, although the last paper seems to hold the key to a nice, short and more to the point, fairly simple route to the 3,5-dinitrobenzoic acid (excerpt pp.370-371, pp.3-4 of the attached paper):

3:5-Dinitrobenzoic acid

Benzoic acid (50 g.) was dissolved in conc. H₂SO₄ (230 ml.) in a litre flask which was then fitted with a ground-in condenser. Nitric acid (73 ml., sp.gr. 1.5) was then added, a few ml. at a time, the flask being well shaken and cooled in ice-water during the addition. Much heat was evolved and a clear yellow solution was obtained. After adding porous pot, the mixture was heated gradually in a water bath up to 100° during 45 min. At 70-80° the reaction tended to become vigorous and was moderated, when necessary, by  immersing the flask in cold water. The mixture was maintained at 100° for 15 min., with occasional shaking, and then transferred to an oil bath at 100° and the temperature raised to 130° over 30 min. and then kept between 130 and 140° for 1 hr. (The total period of heating was thus 2- hr.) The flask was allowed to cool and at about 90°, crystals began to separate, the process of crystallization being accelerated by shaking. When cold, the contents of the flask were poured into 3-4 L. of ice-water and the crystals filtered off. After washing with water and drying they had M.P. 204° and were sufficiently pure, without recrystallization, for most purposes. (Found: C: 39.6; H: 2.04. Calc. for C₇H₄0₆N₂: C: 39.6; H: 1.90 %). After recrystallization from water, the acid was obtained in characteristic rhombs. M.P. 204°.

That looks easy enough, especially given that to proceed ANY further a Grignard/Alkyllithium is needed (ie. if the procedure above scares you, don't proceed).

PS Just added another synthetic route to Olivetol

PPS If we could only access the 3,5-dihydroxybenzaldehyde, it would under Claisen-Schmidt Condensation with 2-butanone (MEK), with basic catalyst, to give the 3,5-dihydroxy-1-phenylpentan-3-one, which upon reduction gives the 3,5-dihydroxy-1-pentylbenzene (aka olivetol). It is just reducing that fucking benzoic acid to the benzaldehyde...

Very little of what you posted in your last post is reasonable, particularly "di-THC", I mean what the fuck man? Look at the link you gave to the paper, the authors retracted their findings. I suggest you read up on the decarboxylation of substituted benzoic acids or perhaps a way of cleaving that alkene on resveratrol (though many have tried). Sorry to be a dick but I don't have time on my hands, this is interesting and your aldol route to the oxidized olivetol is very good, but you should do more reading first.

Has everyone/anyone seen this? I find it a fascinating prospect, since d-limonene is so easily available:

LAC 674,93 (1964) cf. BSC 3961 (1971), JOC 38,1684 (1973)

136g (+)limonene in 2 liters methanol; 2g bengal rose dye. Illuminate with a high voltage Hg lamp (e.g., HgH 5000) for fourteen hours or until about 1M of O2 is taken up. Evaporate the methanol at 0-10øC to about 500 ml and then stir with ice cooling and add this solution dropwise to solution of 250g Na2CO3 in 1.5 liters water and continue stirring for twelve hours. Heat two hours at 70øC and extract with ether and dry, evaporate in vacuum (can distill with addition of Na2CO3 at 40-70/0.2) to get about 100g mixture containing about 40% product which can be purified by fractional distillation.
==============================================

The only part that really confuses me is where it says "evaporate the methanol at 0-10C", unless they mean under really strong vac.

Here is one of the referances if anyone wants to check it, I'll work on getting the rest:

(+)-Limonene oxidation with selenium dioxide-hydrogen peroxide
Charles W. Wilson III, Philip E. Shaw
J. Org. Chem., 1973, 38 (9), pp 1684–1687
DOI: 10.1021/jo00949a014

Quote from: Methyl Man on April 22, 2011, 05:14:07 PM

Has everyone/anyone seen this? I find it a fascinating prospect, since d-limonene is so easily available:

LAC 674,93 (1964) cf. BSC 3961 (1971), JOC 38,1684 (1973)

136g (+)limonene in 2 liters methanol; 2g bengal rose dye. Illuminate with a high voltage Hg lamp (e.g., HgH 5000) for fourteen hours or until about 1M of O2 is taken up. Evaporate the methanol at 0-10øC to about 500 ml and then stir with ice cooling and add this solution dropwise to solution of 250g Na2CO3 in 1.5 liters water and continue stirring for twelve hours. Heat two hours at 70øC and extract with ether and dry, evaporate in vacuum (can distill with addition of Na2CO3 at 40-70/0.2) to get about 100g mixture containing about 40% product which can be purified by fractional distillation.
==============================================

The only part that really confuses me is where it says "evaporate the methanol at 0-10C", unless they mean under really strong vac.

Yes, it means under strong vacuum. You excerpted that quote from the Rhodium THC chemistry page where it occurs, right? That same page says that the low-temperature evaporation is to work safely with the potentially explosive hydroperoxide mixture.

No, actually it's an excerpt from the Smith book Psychedelic Chemistry, but maybe we're talking about the same thing if it appears at Rhodium too.

Thanks for the warning if that is the case, I had no idea. That'll teach me to ask a knowledgable friend about any and all scenarios I might consider participating in regarding hidden dangers such as that one. Explosive peroxides are without doubt over the top for me. None for me, thanks.

I don't even get how you can distill MeOH at less than room temp even with a really powerful vac, I'm sorry. 10C being 50F... how is it done, you cool it and yet distill it at the same time? The vac being so strong that it pulls the cold MeOH vapor over? My vac pump is surely not in that league.

You know, I think this synth, as slick as it is, still just gives the one isomer (Delta 9 I assume?) and I hear that it is not really that much fun at all when isolated. Maybe the product would have to be mixed with High-CBD oil from an extraction to be something that feels good. It would be weird to be high on THC that originated from orange rind instead of cannabis plants.

Thanks RR. You know what, I went on lookchem.com today and posted a request for info on bengal rose dye and woah, in about 10 minutes 40 Chinese suppliers had emailed me and given a wide range of prices for it. Gawd, these Chinese chem sellers so reek of desperation. I love it

I'm really wondering whether this synth would be worth trying because I already have limonene and after the bengal rose stuff, everything else is dirt cheap (only MeOH and sodium carbonate, wasn't it)?

I mean even if I screwed it up, it is such a novel synth that it would be worth doing it for the sheer novelty of it, especially if it were photo-documented.

That reminds me---why are there no photos attached to posts here? I've seen small diagrams of course, but no actual pics... is there a rule (forgive me mods if it's in a FAQ or something, I'll look now...)?

Quote from: Methyl Man on April 25, 2011, 06:47:46 AM

That reminds me---why are there no photos attached to posts here? I've seen small diagrams of course, but no actual pics... is there a rule (forgive me mods if it's in a FAQ or something, I'll look now...)?

I don't think there is a rule about posting pictures as far as I know...Member Palladium posted some lovely ones when he was working on Jon's Bromosafrole route. I like pictures I would post some too if I would be running something novel, which I'm not at the moment. Maybe later this summer

Pictures are wanted, and to be attached - not embedded! The idea here is that it prevents it from being lost as easily.
Just make sure the picture is "safe" for you to post.
 

Double=post time - anyone else think that Resveratrol would be an interesting project to make THC analogues from? I mean, Resveratrol and Eucalyptol are both OTC, and there is at least one paper which says that Resveratrol already binds to the CB₁ Cannabinoid Receptor (only to be expected, same base structure as THC & the other cannabinoids based thereon, different side chain, but the length looks about right (anyone want to superimpose them?). Analogue wise, I think it might even scrape through, there is a whole-nother ring is a big argument even judges can understand.

There are a metric fuck-ton of resorcinols which can in theory be condensed with terpenes to yield cannabinoids. Resveratrol is just the tip of a big iceberg. Unfortunately most of them are flavonoids and I don't know if those will give anything useful.