Limpet Chicken
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Indole ring position numbering system?
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Limpet Chicken
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I will expand on my idea a little now I understand the indole numbering system a little better.
Take norbaeocystin, indole ring structure with a dimethylamine group at the 2- position, and a phosphoryloxy group at the 4- position.
Prepare phospham, PN,H by passing dry NH3 over heated phosphorus and strongly heat the product.
Phospham produces secondary amines from the primary alcohol directly.
Condense indole with dimethylamine thus obtained (whilst holding ones nose due to the awful fishy reek
) (which would hopefully add CH2CH2-NH2 at the 2- position.
Add a phosphoryloxy group to the 4- position, I looked for psilocin/psilocybin in TIHKAL, thinking to use whatever method Shulgin used to add on a phosphoryloxy group at the 4- position of the molecule but I couldn't see psilocin in there for my life.
I am not sure what reagent woul be suitable for adding the phosphoryloxy in the correct position, I thought of perhaps phosphorus oxychloride, but then realised that might well cause a nucleophillic chlorination somewhere instead, producing some fucked-up chlorinated analogue of norbaeocystin (which might be interesting in its own right)
Would the dimethylamine group have to be protected first, to avoid attack by whatever reagent were to be used for the phosphorylation step? or perhaps conduct that latter reaction first, before introducing dimethylamine to the fray so to speak?
Take norbaeocystin, indole ring structure with a dimethylamine group at the 2- position, and a phosphoryloxy group at the 4- position.
Prepare phospham, PN,H by passing dry NH3 over heated phosphorus and strongly heat the product.
Phospham produces secondary amines from the primary alcohol directly.
Condense indole with dimethylamine thus obtained (whilst holding ones nose due to the awful fishy reek
) (which would hopefully add CH2CH2-NH2 at the 2- position.Add a phosphoryloxy group to the 4- position, I looked for psilocin/psilocybin in TIHKAL, thinking to use whatever method Shulgin used to add on a phosphoryloxy group at the 4- position of the molecule but I couldn't see psilocin in there for my life.
I am not sure what reagent woul be suitable for adding the phosphoryloxy in the correct position, I thought of perhaps phosphorus oxychloride, but then realised that might well cause a nucleophillic chlorination somewhere instead, producing some fucked-up chlorinated analogue of norbaeocystin (which might be interesting in its own right)
Would the dimethylamine group have to be protected first, to avoid attack by whatever reagent were to be used for the phosphorylation step? or perhaps conduct that latter reaction first, before introducing dimethylamine to the fray so to speak?
Limpet Chicken
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One thing I just dug up online, is that in psilocybin, chemically 4-phosphoryloxy-dimethyltryptamine immediately hydrolyses to psilocin on contact with gastric juices, hydrolysing the phosphoryloxy group to a hydroxyl- group.
What if the same were to happen with norbaeocystin, producing the 4-HO- analogue of norbaeocystin?
What if the same were to happen with norbaeocystin, producing the 4-HO- analogue of norbaeocystin?
fastandbulbous
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Chances are, the same happens with baeocystin and norbaeocystin, but you're a bit off on the rest. The indole nucleus has a dimethylaminoethyl group attached at the 3 position, and phenolic OH groups don't react in the same way as alcohol OH groups.
You need to look a little harder next time 
Also reacting anhydrous ammonia with phosphorus and heating the mixture?!?! That sounds like something chemists would do in the nineteenth century. In any case making any substituted tryptamine starting from indole is gonna be pretty damn difficult outside of a properly stocked lab.
Also reacting anhydrous ammonia with phosphorus and heating the mixture?!?! That sounds like something chemists would do in the nineteenth century. In any case making any substituted tryptamine starting from indole is gonna be pretty damn difficult outside of a properly stocked lab.
Limpet Chicken
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No, I wasn't thinking of mixing liquified anhydrous ammonia and phosphorus, more heating strong ammonia solution, passing the gas over a non-acidic drying agent, and then passing through a tube over heated phosphorus.
I suppose it would be better to start from tryptamine freebase, adding a hydroxyl group, perhaps with a peracid might work, as the phosphoryloxy group if present would most likely hydrolyse to a hydroxyl in vivo any way, as does psilocin.
I suppose it would be better to start from tryptamine freebase, adding a hydroxyl group, perhaps with a peracid might work, as the phosphoryloxy group if present would most likely hydrolyse to a hydroxyl in vivo any way, as does psilocin.
fastandbulbous
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About the only route to 4-substituted tryptamines is starting with 4-substituted indoles, and treatment with oxalyl chloride and dialkylamine. The 4-OH group is really sensitive to oxidation, so using strong oxidizers like peracids tends to take any such reaction way past the point where you want it to stop
I have seen reaction specifics for the phophorylation of phenols, but yields were somewhere around 18%, and your stomach acid will immediately dephosphorylate it anyway. Psilocin (4-OH-DMT) has been found to be just as active per mole than Psilocybin (4-PO4-DMT). 4-MeO substitution leads to a decrease in activity (see TiHKAL).
There are other, older (read easier) ways to synth psilocin and DMT than are listed in TiHKAL. A common plant hormone, 3-indole acetic acid, can be reduced to a primary alcohol which can then by halogenated and traded for dimethylamine via a nucleophilic substitution reaction.
This reaction is one of the oldest methods of producing synthetic DMT but appears in ancient, hard to find journals and thus making looking up reaction specifics and choice of solvents more like real work. If you are going to go to that much trouble, make some LSD from LSA (from the hydrolysis of any number of prescription migraine drugs of the ergoline family) and thionyl chloride and diethylamine (from the hydrolysis of the insect repellant DEET). Go to www.orgsyn.org and find all the reaction specifics for the conversion of a carboxylic acid to an N,N-diethylamide; one paper found there uses molecular sieves and strict anhydrous conditions to get about a 90% yield, stellar for the likes of LSD. However, the only FOAF who I have ever talked to who made LSD (1/2 gram) to pay for school did so at his place of work on a Saturday in the clean room. If you don't use lots of protective gear, then be prepared to trip harder than you probably ever have before. One gram of LSD tartrate equals 10,000 fairly strong hits.
Ibogaine really doesn't sound that great to me, and DMT crystals (crystallized from hexane with freebase DMT) can be obtained from the extraction and crystallization of DMT from the Mimosa hostilis tree roots and/or bark. Shrooms are also easily grown from kits; sterility is a must in this case. I have heard of fish tanks / aquariums and plenty of bateriocidal, non-toxic Clorox (sodium hypochlorite; NaOCl) being used to those ends.
As for the numbering system of indoles: look at a correct Kekule diagram of the structure of indole, with the 6-membered benzene ring on the left and the 5-membered ring with the amine on the right. Numbering of indole starts with that nitrogen being assigned number one and continues counterclockwise. Carbon numbers 2 and 3 are in the same ring as the nitrogen/amine. The reason the next carbon is skipped in the IUPAC numbering system is that that carbon already has 4 sigma bonds by necessity. Since no new functional group can bond to that carbon, there is no need to assign it a number. Continue numbering counterclockwise on the benzene ring. The last carbon you name should be #7. Excluding all hydrogens, indole contains 9 atoms (8 carbons and 1 nitrogen). Since two of the carbons that are members of both the 5 and the 6 membered ring have 4 sigma bonds already, can't bond to anything else and are left out of the numbering nomenclature, it is only correct that carbon #7 be the last to be numbered. 7 + 2 = 9.
As for norbaeocystin and baeocystin, their 4-phosphoryloxy groups are so fragile, besides being totally unnecessary for psychoactivity, as to hydrolyze in any process which would add the necessary N-methyl or N,N-dimethyl groups to your aliphatic nitrogen. However, norbaeocystin without the phosphate could be prepared from the formylation of 4-OH-indole, followed by condensation with nitromethane and reducing any number of ways. From there, N,N-dimethylation to psilocin can be accomplished with formaldehyde, methanol and sodium cyanoborohydride. There is no way you are going to get any
4-OH-tryptamine from tryptamine, but you could easily make DMT from tryptamine. Tryptamine can be had from the reflux of the amino acid L-tryptophan in a high boiling solvent such as turpentine (I think) via a decarboxylation mechanism.
Interestingly, amphetamine side chains have been added onto every available carbon that indole has got. Substitution at the 3-indole position leads to AMT, which is a kind of good / kind of crappy drug. The only other psychoactive product was found to be 5-(2-aminoisopropyl) indole. That is MDA with a 3,4-phenyl
-CH=CH-NH= ring instead of the usual 3,4-phenyl -O-CH2-O- group. It is reported to be a stimulant by Shulgin, the renegade master. I have no idea how to synthesize this final curiousity. All formylations of indole that I know of will naturally add to the #3 position rather before the #5 position, but I'm sure there are ways around that problem. Lastly, you could try 4-OH-MIPT if you know where to look. Hope that helps.
There are other, older (read easier) ways to synth psilocin and DMT than are listed in TiHKAL. A common plant hormone, 3-indole acetic acid, can be reduced to a primary alcohol which can then by halogenated and traded for dimethylamine via a nucleophilic substitution reaction.
This reaction is one of the oldest methods of producing synthetic DMT but appears in ancient, hard to find journals and thus making looking up reaction specifics and choice of solvents more like real work. If you are going to go to that much trouble, make some LSD from LSA (from the hydrolysis of any number of prescription migraine drugs of the ergoline family) and thionyl chloride and diethylamine (from the hydrolysis of the insect repellant DEET). Go to www.orgsyn.org and find all the reaction specifics for the conversion of a carboxylic acid to an N,N-diethylamide; one paper found there uses molecular sieves and strict anhydrous conditions to get about a 90% yield, stellar for the likes of LSD. However, the only FOAF who I have ever talked to who made LSD (1/2 gram) to pay for school did so at his place of work on a Saturday in the clean room. If you don't use lots of protective gear, then be prepared to trip harder than you probably ever have before. One gram of LSD tartrate equals 10,000 fairly strong hits.
Ibogaine really doesn't sound that great to me, and DMT crystals (crystallized from hexane with freebase DMT) can be obtained from the extraction and crystallization of DMT from the Mimosa hostilis tree roots and/or bark. Shrooms are also easily grown from kits; sterility is a must in this case. I have heard of fish tanks / aquariums and plenty of bateriocidal, non-toxic Clorox (sodium hypochlorite; NaOCl) being used to those ends.
As for the numbering system of indoles: look at a correct Kekule diagram of the structure of indole, with the 6-membered benzene ring on the left and the 5-membered ring with the amine on the right. Numbering of indole starts with that nitrogen being assigned number one and continues counterclockwise. Carbon numbers 2 and 3 are in the same ring as the nitrogen/amine. The reason the next carbon is skipped in the IUPAC numbering system is that that carbon already has 4 sigma bonds by necessity. Since no new functional group can bond to that carbon, there is no need to assign it a number. Continue numbering counterclockwise on the benzene ring. The last carbon you name should be #7. Excluding all hydrogens, indole contains 9 atoms (8 carbons and 1 nitrogen). Since two of the carbons that are members of both the 5 and the 6 membered ring have 4 sigma bonds already, can't bond to anything else and are left out of the numbering nomenclature, it is only correct that carbon #7 be the last to be numbered. 7 + 2 = 9.
As for norbaeocystin and baeocystin, their 4-phosphoryloxy groups are so fragile, besides being totally unnecessary for psychoactivity, as to hydrolyze in any process which would add the necessary N-methyl or N,N-dimethyl groups to your aliphatic nitrogen. However, norbaeocystin without the phosphate could be prepared from the formylation of 4-OH-indole, followed by condensation with nitromethane and reducing any number of ways. From there, N,N-dimethylation to psilocin can be accomplished with formaldehyde, methanol and sodium cyanoborohydride. There is no way you are going to get any
4-OH-tryptamine from tryptamine, but you could easily make DMT from tryptamine. Tryptamine can be had from the reflux of the amino acid L-tryptophan in a high boiling solvent such as turpentine (I think) via a decarboxylation mechanism.
Interestingly, amphetamine side chains have been added onto every available carbon that indole has got. Substitution at the 3-indole position leads to AMT, which is a kind of good / kind of crappy drug. The only other psychoactive product was found to be 5-(2-aminoisopropyl) indole. That is MDA with a 3,4-phenyl
-CH=CH-NH= ring instead of the usual 3,4-phenyl -O-CH2-O- group. It is reported to be a stimulant by Shulgin, the renegade master. I have no idea how to synthesize this final curiousity. All formylations of indole that I know of will naturally add to the #3 position rather before the #5 position, but I'm sure there are ways around that problem. Lastly, you could try 4-OH-MIPT if you know where to look. Hope that helps.
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Limpet Chicken
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Hot damn! I was actually looking into norbaeocystin and analogues, I guess if I hadn't realised, then DMT would have resulted, and oh BOY would I have been in for the shock of my life
Smyth
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I have done the Fischer Indole Synthesis and it really is not that hard at all. I suppose the real question is what to do with the tryptamines, ie which ones are going to be worth making.
That reminds me, this will come as being sort of off topic. But aromatic amino acids, Tyrosine, Phenylalanine, Tryptophan... are good psychoactives on total reduction of the carboxyl [I dont know what p-hydoxyl-amphetamine is like].
Well I was reading an article in Scientific American some months ago. Apparantly histamine is important wakefulness chemical. Maybe somebody should try making alpha-methyl-histamine. I guess someone probably has done this already but it is certainly not to my knowledge.
That reminds me, this will come as being sort of off topic. But aromatic amino acids, Tyrosine, Phenylalanine, Tryptophan... are good psychoactives on total reduction of the carboxyl [I dont know what p-hydoxyl-amphetamine is like].
Well I was reading an article in Scientific American some months ago. Apparantly histamine is important wakefulness chemical. Maybe somebody should try making alpha-methyl-histamine. I guess someone probably has done this already but it is certainly not to my knowledge.
Limpet Chicken
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Joystick, you mention cyanoborohydride, but is "ordinary" NaBH4 not selective enough, or would it work just as well/and/or/slightly lower yield?
Hmm...anyone know of something that could leave an -OH group in place of a methyl on the 4-position, as I have an idea involving skatole (4-methylindole)
Hmm...anyone know of something that could leave an -OH group in place of a methyl on the 4-position, as I have an idea involving skatole (4-methylindole)
It is just a fluke that NaBH4 in MeOH does not reduce the carbonyl functional group of MDP2P (methylenedioxyphenyl-2-propanone also sometimes referred to as PMK or piperonyl methyl ketone especially in Europe and East Asia); actually, it is most likely the added electron withdrawing properties of the two oxygen atoms on the already slightly electron withdrawing benzene ring that pull electron density away from MDP2P's carbonyl oxygen and thereby reduce the partial positive charge on the carbonyl's carbon atom. This has the effect of making the carbonyl harder to reduce / less reactive.
For most aldehydes and ketones, however, sodium borohydride reduces them to alcohols in short order. It is for that reason that sodium cyanoborohydride or borane amino pyridine (BAP) is used instead; however, changes in pH lead to large differences in the reactions catalyzed by sodium cyanoborohydride and care should always be taken when working with cyanide (i.e., a good fume hood).
Try the same methodology on P2P (known as BMK or benzyl methyl ketone in European circles) and you will get only about 30% at best usable product (meth, shards, glass, ice or shit) because most of the sodium borohydride reduces the ketone to P2Pol, phenyl-2-propanol. Likewise, if you try to N,N-dimethylate a primary amine such as tryptamine with formaldehyde and sodium borohydride, the formaldehyde will be chiefly reduced to useless methanol before reductive condensing with the amino residue occurs.
The use of sodium cyanoborohydride instead of plain, old sodium borohydride at the correct pH (7) avoids the reduction of sensitive carbonyl groups while not sparing the reduction of imines. Thus if the European 'base' manufacturers stopped using the Leuckart reaction with formamide and BMK/P2P and instead adapted their MeOH, NaBH4, PMK/MDP2P anhydrous reductive amination of large scale MDMA production a la LaBTop to P2P/BMK by substituting NaBH3CN for NaBH4, they would end up with methamphetamine versus the amphetamine that is currently produced by the Leuckart reaction of P2P/BMK with formamide or ammonium formate.
Apparently, N-methylformamide is as suspect in Europe as in America, or maybe the old timers would rather produce regular amphetamine than meth. I really don't know. At any rate, always keep in mind that a 3 to 4 molar excess of MeNH2 compared to ketone should always be used with the sodium cyanoborohydride method. Otherwise, some of your newly synthesized MDMA or methamphetamine molecules will nucleophilically attack an unreacted MDP2P or P2P molecule and you will get dimerized, psychoinactive crapola.
Skatole is actually 3-methylindole and comes from the same root word as 'shit' due to its offensive odor in high concentrations. In low concentrations, it smells like flowers. The only thing that I can think to do with skatole would be to convert the 3-methyl group to a carbonyl, which could then lead to AMT, AET or--with a little extra effort--DMT.
As for how to get something other than a hydrogen atom on indole's #4 position, I don't think it is easily done. If I run across a method, I'll try to let you know though. Rather, I think they actually synthesize the indole portion from a chemical molecule with something other than hydrogen already in the #4 position and then go from there.
I have seen 4-OH-indole for sale by the kilogram on the internet, but not lately. Then again, I'm not in the market for 4-OH-indole myself. [Mescalinic benzaldehyde (3,4,5-trimethoxybenzaldehyde) is also intermittently available from pseudolegitimate chemical sources, but that is another story as well.]
For most aldehydes and ketones, however, sodium borohydride reduces them to alcohols in short order. It is for that reason that sodium cyanoborohydride or borane amino pyridine (BAP) is used instead; however, changes in pH lead to large differences in the reactions catalyzed by sodium cyanoborohydride and care should always be taken when working with cyanide (i.e., a good fume hood).
Try the same methodology on P2P (known as BMK or benzyl methyl ketone in European circles) and you will get only about 30% at best usable product (meth, shards, glass, ice or shit) because most of the sodium borohydride reduces the ketone to P2Pol, phenyl-2-propanol. Likewise, if you try to N,N-dimethylate a primary amine such as tryptamine with formaldehyde and sodium borohydride, the formaldehyde will be chiefly reduced to useless methanol before reductive condensing with the amino residue occurs.
The use of sodium cyanoborohydride instead of plain, old sodium borohydride at the correct pH (7) avoids the reduction of sensitive carbonyl groups while not sparing the reduction of imines. Thus if the European 'base' manufacturers stopped using the Leuckart reaction with formamide and BMK/P2P and instead adapted their MeOH, NaBH4, PMK/MDP2P anhydrous reductive amination of large scale MDMA production a la LaBTop to P2P/BMK by substituting NaBH3CN for NaBH4, they would end up with methamphetamine versus the amphetamine that is currently produced by the Leuckart reaction of P2P/BMK with formamide or ammonium formate.
Apparently, N-methylformamide is as suspect in Europe as in America, or maybe the old timers would rather produce regular amphetamine than meth. I really don't know. At any rate, always keep in mind that a 3 to 4 molar excess of MeNH2 compared to ketone should always be used with the sodium cyanoborohydride method. Otherwise, some of your newly synthesized MDMA or methamphetamine molecules will nucleophilically attack an unreacted MDP2P or P2P molecule and you will get dimerized, psychoinactive crapola.
Skatole is actually 3-methylindole and comes from the same root word as 'shit' due to its offensive odor in high concentrations. In low concentrations, it smells like flowers. The only thing that I can think to do with skatole would be to convert the 3-methyl group to a carbonyl, which could then lead to AMT, AET or--with a little extra effort--DMT.
As for how to get something other than a hydrogen atom on indole's #4 position, I don't think it is easily done. If I run across a method, I'll try to let you know though. Rather, I think they actually synthesize the indole portion from a chemical molecule with something other than hydrogen already in the #4 position and then go from there.
I have seen 4-OH-indole for sale by the kilogram on the internet, but not lately. Then again, I'm not in the market for 4-OH-indole myself. [Mescalinic benzaldehyde (3,4,5-trimethoxybenzaldehyde) is also intermittently available from pseudolegitimate chemical sources, but that is another story as well.]
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