Author Topic: Yet another PCA reaction idea  (Read 949 times)

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  • Guest
Yet another PCA reaction idea
« on: June 13, 2004, 06:29:00 PM »
This one is a small modification of the well-known methods.

It avoids the need for either cyclohexanone or halobenzene.

Basically, one first produces benzonitrile by baking the crap out of benzoic acid and urea (~160 C). Then, the grignard (or possibly zinc alkyl) of dibromopentane is formed, and reacted with benzonitrile. I believe the following steps will occur.

First, an imine will be formed. Then, the imine will be attacked to yield an amine.


one-step to PCA?? ("c1ccccc1C#N.BrCCCCCBr>>c1ccccc1C2(N)CCCCC2")

I'm not sure if the imine's conjugation with the aromatic ring will make the reaction untenable, or if some other effect would make this not work. In any case, grignard addition to imines is well known.

The advantage of this path is that it avoids the need for Hofmann rearrangement that the normal alkylative path to PCA requires, as well as the strong bases normally required to deprotonate benzyl cyanide (although PTC technology is very good at this too)

The oxalic acid eschweiler-clarke reaction would be excellent to make the dimethyl derivative (PCDM)

One interesting point is that if one does use the hoffman rearrangement in the normal PCA synthesis, they can perform it in alcohol instead of water, and rather than hydrolyzing the thus formed carbamate, it can be alkylated with an alkyl halide and fairly strong base, perhaps even in-situ. This means PCA-carbamate + EtBr ---NaOH/PTC---> PCE-carbamate, hydrolyze--> PCE. Also, since isopropyl bromide or chloride is easily formed from isopropyl alcohol, this offers a very convenient route to PCiP.


  • Guest
« Reply #1 on: June 13, 2004, 10:11:00 PM »
You could have posted this in Xicori's thread to keep the discussion going?

Basically, one first produces benzonitrile by baking the crap out of benzoic acid and urea (~160 C).

What do you meen by baking? How would you make benzonitrile from benzoic acid an urea?

Then, the grignard (or possibly zinc alkyl) of dibromopentane is formed, and reacted with benzonitrile. I believe the following steps will occur.

First, an imine will be formed. Then, the imine will be attacked to yield an amine.

I can't see why that wouldn't work with alkyl-lithium/Grignard as you say, maybe someone else can. I still have a negative feeling about it in practice. However, there are proven Grignard reactions that do work, so what is the advantage of this one? Your proposal still dosen't avoid the application of organo-metallic chemistry.

It avoids the need for either cyclohexanone or halobenzene.

Why would these compounds be harder to get than those in your synthesis?

Well, I still liked your urea-idea (in Xicori's thread) for PCA very much. Once you've past the Grignard and got the tert. alcohol the amine is not a problem. You only need urea (instead of NaCN as traditionally done). The patent I found claims 70% yeild for the preparation of tert. alkyl (mono) ureas. They used tert. butyl alcohol, if I recall correctly. The only thing that I can think of would cause trouble in case of 1-phenylcyclohexanol as substrate is the presence of the benzene ring, since it contributes more than an simple alkyl group to stabilize the carbocation. We want the carbocation to be as reactive (unstable) as possible since urea is a lowsy nucleophile, but I don't think this matters that much yield-wise, just let it run longer. It was a great idea.


  • Guest
Phenylcyclohexane as starting material for PCA
« Reply #2 on: June 14, 2004, 08:29:00 AM »
Ning, your Grignard addition to benzonitrile is described in

Patent GB853775

(see line 35 + example 12 and 13) which, by the way, contains a lot of cool chemistry. Apparently the patent indicates that PCA is orally active as it also describes the preparation of pills and capsules containing from 2.5 to 25mg of PCA each.

I will here present some possible routes to PCA and PCP-like dissociatives starting from phenylcyclohexane. Producing phenylcyclohexane is very easy, check

Patent US3412165

. No, no, I’m just joking, that is just for the industry. Phenylcyclohexane is a cheap chemical available from most chemical suppliers and as far as I know it is not watched anywhere. Using phenylcyclohexane was alredy proposed in

Post 281087 (missing)

(PrimoPyro: "PCP Analog Precursors From Phenyl-Cyclohexane", Chemistry Discourse)
but for some reason there was no interest shown.

From phenylcyclohexane

1.) Oxidation to 1-phenyl-cyclohexanol with oxygen:

Patent GB980272

Example 1 [general procedure]: The runs […] were carried out with cumene in resin pot equipped with a motor driven stirrer, gas inlet tube, thermometer and reflux condenser at a temperature of 100°C, air being bubbled through the liquid at a rate of about 50 liters per hour per litre of organic liquid.[…]
Example 2: The runs tabulated in Table II were carried out essentially as in Example 1 using 50 grams of 40% aqueous NaOH per 100 ml of each of the hydrocarbons specified and using the temperatures and times specified. Practically no ketone was formed in any run. The carbinol made up 19% of the organic layer, aldehydes and ketones formed at most 0.1% of the organic layer.

From the Table II: 21% of phenylcyclohexane reacted in 14h/125°C giving a mixture of 4 : 6 of the phenyl-cyclohexanol : 1-peroxy-phenyl-cyclohexan.
Obviously it should bee possible to recycle the unreacted phenyl-cyclohexane, but the patent gives no details on the separation of the product. Furthermore it should bee also possible and advisable to transform the peroxide to the alcohol by washing the mixture with a reducent (sulphite, iodide etc.) therefore boosting the total yield to about 20%. I also suspect the yield would substantially increase if a PTC catalyst would bee used: it would carry the hydroxide anions into the organic phase and would allow for the peroxy radicals to form there instead in the water-alkali phase. If this still does not work it might bee also wise to use a surfactant to make the substrate more soluble in the water-alkali phase. I’m sure there are ways to improve it. Maybe hydrogen peroxide instead of air can be more useful?

2.) Side chain halogenation to a 1-phenyl-cyclohexylhalide:
This should bee quite easy with either chlorine or bromine due to the stability of the tertiary radical formed from the phenylcyclohexane. Given that even the oxidation with elemental oxygen is possible, I would assume that the conditions for this reaction should bee much milder than the chlorination of toluene to benzylchloride which requires quite high temperature (reflux at 110-160°C). Probably a temperature of 60 to 100°C should do, but don’t forget the irradiation with light (a mercury lamp or sunlight) which is necessary to produce the initial chlorine or bromine radicals which are needed to start the radical chain reaction (a peroxide radical initiator like (PhCOO)2 can also bee used).
Anyway, I’m quite sure that this particular preparation is described somewhere in the literature, but I did not search for it.

1-phenyl-cyclohexylhalide from 1-phenyl-cyclohexanol

3.) Hydroxy to halide: I don’t see any special need to go here, however…
- see the method exemplified by alpha,alpha-dimethylbenzyl alcohol

Post 512970

(synthon: "J. Am. Chem. Soc.; 1988; 110(20); 6818-6825:", Methods Discourse)

- In principle concentrated HCl or HBr can be used for the transformation of benzylalcohols to benzylhalides. But not just any method can bee used here since 1-phenyl-cyclohexanol readily dehydrate to the alkene. Therefore only such methods can bee used that work on both, benzyl alcohols and alkenes. We need the same method that would also work for 1-phenyl-cyclohexene. I don’t know if it would work but for such cases this one is my favorite:
Addition of hydrohalogenic acids to alkenes in aqueous-organic, two phase systems in the presence of catalytic amounts of onium salts. J. Org. Chem. 45 (1980) 3527-3529.

Getting 1-phenyl-cyclohexene

4.) Elimination of HX: If you came up to a 1-phenyl-cyclohexylhalide you might want to transform it into a more useful 1-phenyl-cyclohexene. This should not bee a problem at all. Stirring in a hot ethanol/water solution of NaOH for an hour should do.

5.) Dehydration of 1-phenyl-cyclohexenol: This does not seem to bee very useful as all the Ritter reactions described probably work just as well with 1-phenyl-cyclohexene as with 1-phenyl-cyclohexanol. But in case somebee has any use of it I’m quite confident that 1-phenyl-cyclohexanol dehydrates by simply letting it stir with 70 to 90% sulphuric acid for a while.

Getting close to PCA from 1-phenyl-cyclohexanol

7a.) Ritter reaction with cianide:

8a.) Ritter reaction with acetonitrile: The use of cyanides can usually be avoided by using acetonitrile instead, though this might lower the yields.

9a.) Ritter-like reaction with urea: It seems that urea nicely adds to the carbocation formed from tertiary alcohols in sulphuric acid. See the method described in

Post 513173

(synthon: "Oh, what a great idea, Ning...", Methods Discourse)

- another route from 1-phenyl-cyclohexanol trough the azide:

Getting close to PCA from 1-phenyl-cyclohexene

7b, 8b and 9b.) Essentially Ritter reactions on the alkene which is known to proceed in the same way as with the equivalent tertiary alcohols. Therefore, the same as for 7a, 8a and 9a.

The last steps

10.) Hydrolysis:
- of N-formyl-PCA is described in:

- of N-acetyl-PCA should be straightforward and similar to the above
- of N-aminocarbamoil-PCA is briefly mentioned in

Patent GB853775

Another method for the preparation of 1-phenylcyclohexylamine and its acid addition salts consists in subjecting to hydrolysis a 1-phenylcyclohexane compound of the formula: [see patent] where R is an isocyanate, isothiocyanate, acylamino, urea or N-carboalkoxyamino group, which upon hydrolysis yields a primary amine group. In general, the hydrolysis is preferably carried out using a mineral acid such, as hydrochloric acid, sulfuric acid phosphoric acid which results in; the production of the corresponding addition salt. Alkaline hydrolytic agents such as sodium hydroxide and potassium hydroxide yield, when used, the free base of l-phenylcyclohexylamine.

6. and 11.) Alkylation of amines with 1-phenyl-cyclohexylhalide: Alkylating amines or other good nucleophyles with tertiary halides is low yielding due to the HX elimination as I already explained in

Post 512938

(Nicodem: "tertiary halides give elimination products", Methods Discourse)
. However see again the post

Post 512970

(synthon: "J. Am. Chem. Soc.; 1988; 110(20); 6818-6825:", Methods Discourse)
, for an example and my comment on it

Post 512992

(Nicodem: "That is not a bad yield", Methods Discourse)

12.) Alkylation of PCA:
- there are many methods, but you can UTFSE and see the examples described in some pages linked from


Patent GB837747

      Example 5, 6, 7: methylation/ethylation by reduction of the formamide/acetamide with LiAlH4
      Example 8, 10, 11: methylation with the Leuckart reaction
      Example 9: reductive butylation with H2/Pd
      Example 12, 13, 15: alkylation with alkyl(pseudo)halides

From the Hive history:
Also, interestingly nobody realized that 1-phenyl-cyclohexene can bee used instead 1-phenyl-cyclohexanol for the Ritter reactions:

Post 241745 (missing)

(wandering101: "Phenylcyclohexanol / Phenylcyclohexene", Chemicals & Equipment)
. See also:

Post 190310 (missing)

(Bwiti: "1-Phenylcyclohexanol Patents", General Discourse)

Post 70003 (missing)

(Bwiti: "PCP & Analogues", Chemistry Discourse)

Post 391039

(Xicori: "New route to PCP´s?", Novel Discourse)

Post 475464

(ning: "phencyclidine sans cyclohexanone", Novel Discourse)
and others. The PCP patents compilation is a very useful source of literature:

Post 356567

(Cyrax: "PCP Patents, a compendium", Methods Discourse)
. And of course:

Post 506789

(Aurelius: "PCP and Relatives: A Synthetic View", Methods Discourse)
where you can also find all the patents referred here (except

Patent GB980272



  • Guest
« Reply #3 on: June 14, 2004, 09:41:00 AM »
Nicodem, that's quite a megapost. Why don't you make a digest of "Known cyclohexylamine methods", with that chart?

If one wants a singly-alkylated cyclohexylamine, they can perform a PTC basic alkylation on the N-formyl or N-acetyl PCA with an alkyl halide, then hydrolyze, I think.

Synthon, cyclohexanone and halobenzenes are both watched. That's one big advantage.

I don't know the exact conditions, but basically the carboxylic acid --> nitrile reaction occurs like this:

H2N-CO-NH2 + R-COOH ---heat---> R-CONH2 + NH3 + CO2 (Transamidation/decarboxylation)
R-CONH2 ---heat---> R-CN + H2O (dehydration)

By performing the reaction at > 100 C, the water is continuously removed, driving equilibrium forward.

If you read zealot's ketamine synthesis, I believe he alludes to this, but there isn't more info. In any case, I have an old british patent that talks about making acetonitrile from ammonium acetate by a similar method.

benzoic acid boils at 249 C
benzamide boils at 288 C
benzonitrile boils at 188 C

The quote I heard was for this reaction to work well around 160 C. It is supposed to be catalyzed by stainless steel (nickel, iron, copper?)


  • Guest
The power of Friedel-Crafts...
« Reply #4 on: June 14, 2004, 02:43:00 PM »
Thanks for putting that great review together, it sure helps a lot.

Another possibility for phenylcyclohexene could be the Friedel-Crafts. But of course substituting the hexanedioic acid with heptanedioic acid in the acylation step:


  • Guest
« Reply #5 on: June 14, 2004, 06:00:00 PM »
"Apparently the patent indicates that PCA is orally active"

  Just wanted to confirm that PCA is definately active, and will give a full-blown dissociative effect at about twice the amount that you'd take of PCP. ;)  8)


  • Guest
So is norketamine, apparently
« Reply #6 on: June 15, 2004, 08:06:00 AM »
these cyclohexylamines are very flexible in their SAR, it would appear.


  • Guest
can i ask here what would happen when reacting
« Reply #7 on: October 28, 2004, 12:56:00 AM »
can i ask here what would happen when reacting H2S2O8 with phenylcyclohexane ? (and by the way this product looks like reacting with many organics tfse is so poor on this compound... let's discover the wonderful powers of this coumpound : D )