Author Topic: 3-(1-naphthoyl)indole (Read 682 times)

pyramid · « **Reply #20 on:** May 31, 2012, 08:06:23 PM »

Well, you do not have to make naphthoyl-indoles, you can make benzoyl and phenylacetyl-indoles instead! However, 1-naphthaldehyde can be made from naphthalene by chloromethylation then sommelet, this has been done at Hyperlab. Oxidation of the aldehyde with KMnO4 gives the acid, the yields throughout are not the best but it is an easy way to make the acid.

Handling of SOCl2 is not too bad either, if you have a properly sealed apparatus and one gas trap you will be fine, just have ventilation when dismantling setup and handling the reagent, if you need it wear a respirator. The HCl/SO2 do not hang around for long. Dont use a water aspirator to remove the excess without a moisture trap between the setup of course, or use a membrane pump. Alternatively you can use a gas stream but this is wasteful and you must vent those gasses somewhere.

The preparation of 3-(1-naphthoyl)indole is not difficult, just be sure of the purity of the reagents. If you synthesize your own 1-naphthoyl chloride, you should distill it before use if the color is anything darker than yellow oil, but it will be fine if your starting acid is not colored and you have a reasonable quality SOCl2..
It is highly advisable to flash chromatograph the crude 1-pentyl-3-(1-naphthoyl)indole, you can just use EtOAc/hexane 1:1 and the product should come off in one fraction as a yellow oil. After this it is much easier to crystallize.

If you ever try making some of this class of compounds don't forget about the friedel-crafts which uses AlCl3, I showed an attempt above and the reference is there. Some compounds may have much better yield, and 3eq of AlCl3/acid chloride is not needed for everything.
Then all you have to do is make the respective alkyl indole (close to quant yield) and the acid chlorides (usually quant yield too).

BTW, an attempt was made to prepare 1-pentyl-3-(2-bromophenylacetyl)indole, first indole/2-bromophenylacetylchloride to give an intermediate which was alkylated in the standard fashion, giving a product of 4 spots TLC. This impure shit was smoked at 2mg and it was very active, but it is not pure and the yield was bad. If it is ever made properly it will be reported, it looks like a worthwhile product. Perhaps the FC is a better method, the phenylacetyl-indole was obtained in a bad yield.

carl_nnabis · « **Reply #21 on:** June 01, 2012, 12:10:29 AM »

The main reason for me to choose only one of the naphtoylindoles ever to make was their in comparison to the other indole-based cannabinoids prolonged effect. I have tried one of these phenylacetylindoles, jwh-250, and also rcs-4, one of those benzoylindoles.
But I dont know if it were only those two compounds or their whole categories, but they have only a really short effect, nothing worthwhile to even consider for me to make. Or do you know anything about longer lasting indolalkylamines than jwh018 does? I assume you have more experience in unusual ones maybe you stumbled upon one that is even longer acting? In my opinion that was by far the longest acting of them i ever had.

I have worked with SOCl2 before, and I even own a very small bottle nearly full, but even the imagination to open that bottle of nasty stuff gets me a shiver down the spine

The last times it was in use, was to chlorinate some alcohol and these times there were so small amounts in use, the alcohol and the thionyl chloride were both dissolved in chloroform and just poured together, then the solvent and fumes were distilled away until it was reduced to not more than 10% of the mother liquor, the received distillate was discarded, the edukt was then precipitated with addition of acetone. The chloroform that distilled of at the same time worked as I assume as some sort of trap for the gaseous byproducts as it dissolves most of them, because there was never that much gas around. Except precipitation everything was done outdoor off course. I had never problems with reactions that give off deadly fumes, cyanide salts were also prepared outdoor in a similiar manner, where HCN was bubbled through lye, and it is obvious that I havent died during this. But it sucks to know you got there lots of deadly fumes and if anything would broke, you would be dead or serious poisoned.

I have never really looked into carboxylic acid syntheses, in school i have done the kolbe schmitt rxn twice but havent considered as an option really.
I just wanted to make one of those classical ones, or some similiar compound (for example those CP ones) first, and that had to be a really strong one considered all the work and effort one has to put into synthesis of an olivetol-derivative.
But to see someone has done these indolalkylamines successfull a few times gave me the propulsion to put more effort into these cannabinoids too! The reaction you mentioned albeit looks interesting, and naphthalene is dirt-cheap too.. Isnt this some variation of a FC-reaction? Maybe it is an option for me if the acid can be obtained pure enough without fractioned distillation, i am going to have a look at it now^^

I dont have a serious vacuum pump, only aspirator setup, there is really no need for it for most purposes as euro-bee, because here you dont ever can get your hands on some safrole containing oil, except you distill it from dried bark powder (yeah maybe 5 gramms per kilo^^).
And only for some rarely needed other purposes is it nothing I can afford.
Membrane pump, yeah the cheapest I saw that are suitable for use with solvents start at 300-400 euros... would be pretty nice to have one off course! But I bet i can find some similiar process which avoids the need for (vacuum) distillation, so lesser trouble with pyrolysis and maybe pyrolysis-caused discoloration.

But anyway, this will only be considered to do when my chemicalsupplier says he wont get it, but this is very unlikely, it is possible that it is rather expensive, but better one avoids unsatisfying reactions with nasty reagents if possible. Otherwise if one does everything alone starting from naphthalene wont be the cheapest way either...

I know about the FC in their preparations, IIRC hadnt huffman himself used this reaction? I think he used some organic aluminiumchlorides, but i think he got a pretty low yield? This information was sourced from my poor memory, so I wouldnt give a fuck^^ Dry AlCl3 also has to be proper stored once the vial is broken open (and these are really expensive, if it gets wet and you could just use a tenth of an 100g vial before, that would be really a waste of money that will hurt.
A good grignard will always be my reaction of choice I think

I like those straight forward reaction, easy work-up, awesome yield, and at least this is a reaction I have done quite a few times and everytime it worked really proper for me.

What would be the better way in your opinion, to couple the alkylated indol and the acid chloride, or better to couple indol and the acid chloride and then one could afterwards clip that alkylchain on indoles aminegroup?

Edit: Oh chloromethylation using formalin! Ive read a few days ago about it on the hyperlab article about those napthalene stimulants! Was that maybe the article you meant? But that was really late at night, and reading on the hyperlab is always a pretty hard time for me with that crappy translator programs...
BTW it is 2:25 at morning on this side of the big pond now, everything from now on wont stick in my brain anyway

Edit2: Looked over your post once more, are you serious? Did you meant it in an ironic way, when you said use a moisture trap (filled with liquid nitrogen or what^^), flash-chromatography for purification and to evacuate using a membrane pump? That would be pretty hard to get even more expensive i guess

pyramid · « **Reply #22 on:** June 01, 2012, 04:16:54 PM »

First I will comment on your edits. Yes, a moisture trap between a water aspirator is needed, fill it with CaCl2. You don't need that if you use a membrane/diaphragm pump, nor if you use a gas stream. I gave you 3 ways to remove the SOCl2, do what fits you best. Alternatively, buy the acid chloride but knowing you can easily handle SOCl2 means you can prepare any acid chloride you ever want, you just have to make/buy the acid.

The longest lasting compound I have tried is the adamantoyl-indole shown previously, it lasts up to 6h for 30-40mg smoked. If you have a large cannabis tolerance then effects for all synthetics are diminished. Other thn that, they basically all fall in the general duration of cannabis itself, but different dose and intensity of effect.

It is very hard to purify the JWH-018 oil without flash chromatography, the stuff takes forever to crystallize and you get a lower yield. It is the easiest flash column you will run in your life, and if you are interested in any chemistry with these compounds or tryptamines, you should get used to silica usage as it is indispensable. It is not hard to buy silica gel for chromatography and it's not a suspicious item.

The chloromethyltion was done with paraformaldehyde/H3PO4/HCl, it is on the first page of the 1-naphthoic acid thread. The rest is there too, going to the aldehyde, and then oxidation with KMnO4/pyridine. You can do it without pyridine as I showed earlier in the thread. YOu do not need to distill the acid, it should precipitate as a white or beige solid if you do the work up I showed in the example earlier.. If it is dark, then recrystallize. You will only have to distill the acid chloride if it is obtained as a very dark oil and usually this won't be the case.

Also I have stored my AlCl3 for quite a few years now in standard reagent bottle with a Teflon cap. This is sealed in a bag, in turn another bag with a little CaCl2, then in vermiculite in a sealed can. It is fine and still free flowing even. Maybe there is much more humidity where you are.

If your target is JWH-018 then the best way is through the 3-acylindole then alkylation, for the others it is up to you to try either method. I think a reasonable yielding method can be had for using AlCl3 in the friedel crafts (on some substrates) but it is yet to be fully discovered, I only tried it on one thing a while back.

Also be aware during the syntheses of these compounds, the area will smell like fecal matter, it is not very nice. Labor of love...

carl_nnabis · « **Reply #23 on:** June 11, 2012, 02:03:02 PM »

Mhmm... I´ve compared this to the synthesis of the classical cannabinoids for an unusual aspect... The smell of their precursors

Both synthetic schemes are in general built around two "building blocks" in the end, here it is the napthoyl and indole part, the classical have that monoterpene and the olivetol counterpart.

I already knew that indole smells like shit but i was willing to work with it, but i will not bear such a project if the other building block does too!
Compared to classical cannabinoids which are build of one very pleasant floral or spicy smelling monoterpene (citral, verbenone, carveol and the like), and olivetol which i think correspondends a lot with the smell of oakmoss absolue (basically a olivetol and olivetoric acid enriched hexane extract), which has an earthy aromatic smell, also very pleasant, these two shit-smelling compounds dont look that worth aspiring to

Albeit i like to smoke these things, It seems better to let the chinese do their synthesis anyway

I´ll stick to the pleasant smelling precursors, you even made me think of them in a new light, jwh aint so sympathic to me no more

cft · « **Reply #24 on:** June 14, 2012, 09:42:13 AM »

Thank you for your research reports pyramid, these are very interesting results. We have done some work in this area, try making these two for instance

1-(cyclohexylmethyl)-3-(4-methoxy-1-naphthoyl)indole

1-(5-fluoropentyl)-3-(4-ethyl-1-naphthoyl)indole

First one is active at 2mg and long lasting for an indole, 4-5 hours. Second one is shorter lasting but very potent, active at 0.5mg.

I did not perform the synthesis, but I am told they are easily prepared in a similar way to the rest of these indoles.

pyramid · « **Reply #25 on:** July 21, 2012, 04:35:38 PM »

You need to acquire 1-bromo-5-fluoropentane which is the alkylation agent used. I'm not sure if the synthesis of these fluoro alkyl bromides is simple at all, it doesn't seem like it by first glance.

BTW... What is people's idea on 2-methyl-N-pentyl-3-(1-naphthoyl)indole? Should be standard methods from 2-methylindole.
Seems like it could be worthwhile.

pyramid · « **Reply #26 on:** July 21, 2012, 06:15:13 PM »

Bromo fluoro alkanes have been used to alkylate oxygen, sulfur and nitrogen. See the synthesis of some fluoroalkylthio phenethylamines to have greater confidence that it works how we need it to.

Skatole is 3-methylindole, and 2-methylindole has less of a bad odor than indole itself in my opinion. I do not like the smell of most of the intermediates, that's for sure! But I want to make the compounds so bad I deal with it.
I did try to make the above stated compound via FC (with AlCl3) with N-pentyl-2-methylindole and 1-naphtoyl chloride in 1,2-DCE. Unfortunately I had an idea to flash chromatograph the entire crude tar and the thing clogged and started to precipitate.. Bad idea. I don't know if the precipitate was the wanted product, it was dirty as hell.
Going through 2-methyl-3-(1-naphthoyl)indole is likely the better option. If anyone has some physical data on the final compound, such as melting point, it would be appreciated. I cannot find that data anywhere.

carl_nnabis · « **Reply #27 on:** July 21, 2012, 06:48:54 PM »

i happen to have some of huffmanns papers lying around in my data folder i will look trough them for you may i find it? just tell me how much of these papers do you have, all the ones from drugs-forums archive?
and btw, you may be interested in it, look over at science madness the user karlos³ which is me, made an cannabinoid ligand about its activity im not sure yet as ive never made it again yet, which is made from tryptophan via cyanate addition and acid catalysed ring closure to yield an imidazolidindionring, and then n-alkylated on this formerly made ring with use of the same reaction as in the last reaction of jwh synthesis. im not sure about its activity because there could be much placebo effect.
also it is very unpotent less than thc i think

carl_nnabis · « **Reply #28 on:** September 13, 2012, 05:40:12 PM »

I recently discovered how useful carbonate esters are, and i am amazed! IMO a nice and very safe method for addition of one carbon only, in some cases, can be hydrolysed straight or either reduced with an alkoxide to its alcohol.
Replaces dry ice or a lot more guesswork causing gaseous CO2 very well! Next time i do a one carbon addition maybe i will try a grignard to DMF like bouveault

Dimethylcarbonate and 1-Naphthylmagnesiumbromide in a grignard reaction,will form methylnaphthoate after an acid hydrolysis, which will on hydrolysis again in a basic milieu give the free naphthoic acid.

After 2,4g magnesium dust were charged and wetted with around 30ml of ether, a piece iodine and 20g 1-bromonaphthalene dissolved in 100ml of ether were added at once and the mixture heated a bit in a waterbath to initiate the reaction that slow proceeded visibly.
After a half hour it was cooled that caused maybe even complete precipitation of the grignard reagent, and then 15ml dimethyl carbonate dissolved in 150ml more ether were added, around a tenth initially then the rest dropped in over a half hour.
Dimethylcarbonate used was 0,15mol, other two reagents used 0,1mol here.
It was then heated again after addition was complete, around a half hour, then it was left to cool and react complete, for 10 hours.
Then it all was slowly poured on lots of ice and saltwater, 300ml, in a beaker, the organic layer decanted after it all was made acidic with 20% HCl, to hydrolyse to the ester.
The remaining solution was extracted again with some ether and both extracts combined washed with brine and dried over CaCl2 a few hours.
Then after the Et2O was destilled of nearly completely, to the remaining oil were added 50ml of a 20% NaOH solution, that caused the oil to dissolve slowly on heating, indicating the ester got hydrolysed to the free acid.
This aqueous portion was washed once with a bit Et2O, then made acidic slowly with concentrated HCl, until a ph of 3 was reached when nothing more precipitated even on cooling a few hours appeared.
This precipitate was filtered and washed few times to give 13,8g of crude naphthoic acid.
Didnt knew how useful dimethyl carbonate is before, that was amazing but the acid still has to be recrystallized so there will be some more loss.
I am a bit scared to check its melting point as i think the smell will show up once it is molten maybe? However the smell of the methylester wasnt noticed much.

references are
http://www.orgsyn.org/orgsyn/prep.asp?prep=cv2p0282
until note 3, i used brine to wash instead and hydrolysed the raw mixture consequently, and worked up as i would have the aqueous lye extract in:
http://www.orgsyn.org/orgsyn/prep.asp?prep=cv2p0425

But always get a lower yield than theirs, dont know if sloppy workup or sloppy synthesis work? I know a possible competing reaction can occur, forming the secondary alcohol 1,2 dinaphthylmethanol when leftover grignard reagent adds to already formed methylnaphthoate is that why?

carl_nnabis · « **Reply #29 on:** September 14, 2012, 05:02:39 PM »

I couldnt source dry ice so thats why i chosed this way.

cft · « **Reply #30 on:** September 16, 2012, 09:04:57 PM »

More results from research, try making this compound

Quinolin-8-yl 1-pentyl-1H-indole-3-carboxylate

Again this is potent, strongly active at 2.0mg. Effects like cannabinoid but with extra trippy feeling to it that is not like cannabinoid at all...good effect at low doses but take too much and it feels like you ate some bad mushrooms along with with smoking weed! The 1-cyclohexylmethyl version also works, and has similar activity. 1-(5-fluoropentyl) version is not made yet, but I would bet it will be very strong though perhaps with even more of the weird trippyness.

hippychikie · « **Reply #31 on:** October 10, 2012, 02:12:33 AM »

like the Pyramid name dropped a page back is that for high yields on small batches you best use Ionic liquids (seems the greenish (Bmim)PF4 is most liked candidate for the all nessesary steps in very high yields!:

144.206.159.178/ft/1010/64636/1102765.pdf

and

http://books.google.nl/books?id=genSumazO-IC&pg=PA167&lpg=PA167&dq=Pravadoline++ionic+liquids&source=bl&ots=VKffVDFpj5&sig=gRcDl_L9TdjRRamXlNaZ9fd4mnc&hl=nl&sa=X&ei=Qth0UIHkBseP0AXOxoCgAw&ved=0CDMQ6AEwAg#v=onepage&q=Pravadoline%20%20ionic%20liquids&f=false

Author Topic: 3-(1-naphthoyl)indole (Read 682 times)

pyramid

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carl_nnabis

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pyramid

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carl_nnabis

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cft

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pyramid

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pyramid

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carl_nnabis

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carl_nnabis

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carl_nnabis

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cft

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hippychikie

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