Detailed Synthesis of JWH-018!!

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Disclaimer: The Following is for educational purposes ONLY. It was posted on a well-known forum, and I cannot confirm or disprove that it is accurate, but it appears to be. I am not responsible for any foolhardy attempts to replicate this exercise. Any attempt to replicate this should be done only be qualified professionals in a licensed lab. I make no guarantees as to the accuracy of this experiment. For all we know, this may be the irresponsible recipe responsible for hospitalizations and making it illegal in various jurisdictions. 

Originally Posted by pyramid

Here is an example of alkylation to JWH-018, 1-pentyl-3-(1-naphthoyl)indole, MW 341.4

To a 250ml 3 neck RBF fitted with thermometer, condenser and a stir bar there is added 3-(1-naphthoyl)indole (3g, 11mmol) followed by dry DMF 50ml. Potassium hydroxide flakes (1.5g, 27.5mmol 1.5eq.) were added in one portion and the setup purged with butane. The flask was heated to 60-70 degrees C on a water bath for 20 minutes with stirring. A green solution with ppt is obtained. After this time, 1-bromopentane (4.3g, 28.6mmol) was added in one portion via glass syringe. There is an immediate color change to red and the flask is heated at an internal temp of 60-65 C for 3 hours. KBr ppts in the first few minutes after addition of the alkyl halide. It is then cooled to RT and diluted with 150ml H2O, and extracted with DCM 3x 40ml. The organics are washed with water 3 times then the solvent is evaporated. There is excess bromopentane as noticed by the smell so it is removed under vacuum in a hot water bath. 3g of amber oil was obtained (8.8mmol, 80% yield) The amber oil that remains is the product. It is a pain to get it to crystallize. Only after 1 month in the refrigerator did crystals begin to form. By covering them with a small amount of IPA cleaned them up and caused all of the oil to crystallize. Once you have a seed crystal the oil can be directly crystallized after alkylation, but I have had no luck getting it to crystallize right after without the seed or with ethanol. The obtained material is completely melted by 61 C, lit Mp is 60-62 C.

The product is fucking active and is obtained as beige to yellow slightly gummy crystals. It would be best to straight chromotograph the oil but not everyone can do that. :P

Huffman JW, Mabon R, Wu MJ, Lu J, Hart R, Hurst DP, Reggio PH, Wiley JL, Martin BR.
“3-Indolyl-1-naphthylmethanes: new cannabimimetic indoles provide evidence for aromatic stacking interactions with the CB(1) cannabinoid receptor”.
Bioorg Med Chem. 2003 Feb 22;11(4):539-49.

Originally Posted by meme

Shouldn't alkylation be done first? If only to eliminate the (mildly) acid pyrrole nitrogen from the Grignard? While it is not needed (indole grignards are routine chemistry), is there any advantage to doing that step last?

Also, all of the JWH compounds that the DEA has issued intent to control contain the napthoyl moiety, perhaps that would be best to "leave off." The naphthoyl group can be replaced with a LARGE variety of functionals, much more than the 1-position of the indole can withstand and retain psycho-activity.

Originally Posted by pyramid

I do not know how it would effect the reaction by alkylating first, but the main reason for making the naphthoyl indole first was it opens up a few compounds that can be made directly from it. Now of course if alkylation first resulted in the product we want then I'd probably want to do it first, and this would not make a difference in the order of alkylation. It is worth a shot though, however I won't be attempting that soon.

Yes indeed most of these compounds are scheduled or soon will be so analogs containing other groups would be an excellent thing to research. A wide variety of analogs can be made with alkoxy-naphthoyl chlorides and finding synthesis options for many of the starting acids would be useful. What ideas do you have for replacement of the naphthoyl? I'm not super knowledgable in pharmacology affecting groups so not sure what to start thinking of in that regard. Keep in mind, this is purely at home chemical curiosity for me and I do not have EXTENSIVE knowledge yet.

Originally Posted by meme

2-substituted phenylacetic acid compounds seem quite worthwhile (i.e. JWH 250).

Anthracene is another homolog of naphthalene which fits into this discussion.

Originally Posted by pyramid

250 is definitely on my to do list. I'M also thinking of 4-methoxybenzoyl chloride, which following the same steps would give RCS-4. Am I right in assuming 4-methoxybenzoic acid can be simply turned into the acid chloride with the usual method? Then the main issue is acquiring the acids, but its not too hard.

Originally Posted by Intergalactic Captain

A thread was posted under my SN on SMDB a year or two ago regarding a couple of potential ideas - Which were, for the most part, seen as either unfeasible or stupidly circuitous. The concensus, IIRC, was that huffmann's original and later routes were the quickest, cleanest, and cheapest; alkylate indole, then react with the naphthoyl (or whatever) chloride; indole + acid chloride, then alkylate...

3 reagents, 2 synthetic steps - How could it be easier? Well, try aquiring indole, napthoyl chloride, phenylacetyl chloride (substituted, etc), napthoylindole, etc... Or any common acid a-halogenation reagents for that matter, in quantities over 1-5 grams, as an individual... The quantity qualifier is important, as these reagents CAN be found, but at one hell of a "price of convenience" premium. Alkyl halides are a piece of cake, provided you can find the parent alcohol (and don't bother looking for n-pentanol or n-pentyl esters - Unless you get a COA, you've probably got iso or sec-amyl... I've found one source, expensive, but it's a cornucopia that doesn't operate on the quasi-legal side of the fence...Not gonna mass-publicize them)...

The goal here should be finding a way to AVOID huffman's routes - They're nothing special, nothing novel, just sophomore-level o-chem hoisted to infamy for the end result. Given an academic lab, anyone could do it - However, without that type of stockroom, where are we left?

...In summation, here's an idea, or a few that I've been tossing around... Phenylacetic halides are ripe for exploration and "relative" ease of preparation... Many substitution patterns are readily availabe as their benzaldehydes, acetophenones, and benzoic acids - These are all simple starting blocks for homologation to the phenylacetic acids and, (the caveat), the phenacyl halides... A few reactions to look up - Stephen reduction, and (Don't think there's a name for it, but it's patented) and one-pot from a benzoic acid to a benzonitrile via NaHSO4/Urea/Sulfamic Acid ... And the reaction of a benzyl halide with a cyanide... And probably countless others...

So, long story short, we should be focusing on the precursors (as it used to be?)... Short and sweet (minus the chromatographic separation), but that's only when one has the napthoyl or phenacyl halide - Perhaps those interested should be focusing instead on the preparation of acid-halide reagents, or a new route altogether (and forget grignards - I haven't explored EVERYTHING, but that nitrogen, alkylated or not, seems to fuck with just about any grignard or grignard-style organometalic couplings)...