Bwiti (PVC-Analog Taste-Tester)
09-14-02 05:28
No 356168
      Alternative To P-Toluenesulfonic Acid In PCP-Synth  Bookmark   

  Lets say someone wants to make an imminium salt from cyclohexanone/butylamine(or a heavier amine), then add it to phenyl magnesium bromide to create a yummy PCP-analogue, but they can't get their hands on p-toluenesulfonic acid.mad Besides HBr, what else can form this imminium salt? Sulfamic acid? I remember seeing a patent that listed a few alternatives to p-toluenesulfonic acid(can't find the damn thing), but I also remember the bastards not showing one example of their use. Please help!

Love my country, fear my government.
 
 
 
 
    Aurelius
(Hive Bee)
09-14-02 06:17
No 356178
      Hey, the bears are out gathering again  Bookmark   

Hey Bwiti, you know those darn bears keep finding great stuff!  toluenesulfonyl chloride- not the acid, but not a far distance from it. 
 
 
 
 
    Ritter
(Master Whacker)
09-14-02 08:38
No 356213
      condensation catalyst  Bookmark   

Contrary to many published references, imine formation does not always require presence of an acid catalyst.  Simple reflux of equimolar quantities of the amine and ketone in toluene with a Dean-Stark water separator will provide a perfect yield of the imine in this case.
 
 
 
 
    Bwiti
(PVC-Analog Taste-Tester)
09-14-02 13:13
No 356237
      That's interesting because every ...  Bookmark   

  That's interesting because every phenylcyclohexylamine patent I've come across converts the cyclohexanone/amine(CA) to a nitrile or a salt of p-toluenesulfonic acid(not just as a catalyst, but equimolar portions added) before phenylmagnesium is added. With plain-old CA, phenyllithium is always used. Why is this? Normally I believe everything that a chem-buff such as yourself says, but patents like the following are causing me to have doubts:
GB758143
GB765902
GB766870
GB838748
GB853775
GB861350
US3192219
US3097207
GB836083
GB837747
US5969159
US3097136
  Is what you're saying a recent discovery?

Aurelius: Toluenesulfonyl chloride? To be honest, I wouldn't know where to begin; how would you go about converting it to the acid? I imagine that a hydroxide is involved somewhere. Maybe I should reside where those lucky bears live for a few months and copy everything they do!cool


Love my country, fear my government.
 
 
 
 
    Cyrax
(Hive Bee)
09-14-02 13:50
No 356243
      Bwiti, imines are formed by the reaction of an ...
(Rated as: excellent)
 Bookmark   

Bwiti, imines are formed by the reaction of an amine with a carbonyl compound with the simultaneous removal of water, for example
* by azeotropic distillation (what Ritter said, ref.: J. Chem. Soc. (1958), p 2209),
* by the addition of a drying agent such as
   - anhydrous sodium sulphate (ref.: J. Org. Chem. (1978) vol 43, p 2907)
   - anhydrous potassium carbonate (ref.: J. Org. Chem. (1974) vol 39, p 3104)
* by the addition of molecular sieves (ref.: Recl. Trav. Chim. Pays-Bas (1972) vol 91 p 605)
* by the use of titanium(IV)chloride (ref.: J. Org. Chem. (1967) vol 32, p 3246

If the amine and the carbonyl compound are both aliphatic, the imines tend to decompose or polimerise; in these cases their further reaction is carried out without delay.  When one or both of the reagents is aromatic, the imines are quite stable.

Check out:
../rhodium/chemistry /pcp/imine_synth.html#Examplepce
Here they use KOH as drying agent.

I suggest using a drying agent to condense cyclohexanone and n-butylamine, it seems to be more convenient / less suspicious.
Here 's the  J. Org. Chem. (1978) vol 43, p 2907 procedure:
2-methylpropanal (72 g, 1 mol) is added dropwise and with stirring during 2 hours to t-butylamine (73 g, 1 mol).  During the addition the temperature rises from 25 to 40 °C and an aqueous layer separates near the end of the addition.  The organic layer separates near the end of the addition.  The organic layer is treated with anhydrous potassium carbonate (15g), stirred at 25 °C for 17 hours, and then decanted on to barium oxide (12 g).  After the mixture has been stirred for 10 hours, it is filtered and the organic filtrate is distilled to separate the imine as a colourless liquid, b.p. 56 °C / 75 mm Hg, 88.3 g (70 %).

Use a good oil pump to distill under vacuum, so that the imine doesn't decompose.
 
 
 
 
    Bwiti
(PVC-Analog Taste-Tester)
09-15-02 07:21
No 356448
      Yes, but at http://www.rhodium.  Bookmark   

  Yes, but at../rhodium/chemistry /pcp/imine_synth.html#Examplepce the N-cyclohexylidenethylamine is added to phenyllithium. - I need to know if it can be done with phenylmagnesium.

Love my country, fear my government.
 
 
 
 
    Cyrax
(Hive Bee)
09-15-02 10:37
No 356488
      I don't know this for sure, but I am under the ...  Bookmark   

I don't know this for sure, but I am under the impression that only PhLi can be used in the synthesis of PCE and congeners.

I think to have read this somewere, but again I don't know it for sure ...
I 'll check my notes for you and give a more descent response later.
 
 
 
 
    Aurelius
(Hive Bee)
09-15-02 11:13
No 356503
      Bears  Bookmark   

Bears are a friendly sort when stoned.  and the seasons crop is in, so come on over to three bears house should you get the inclination.  aurelius is sure the bears would share their porrige with you. 
 
 
 
 
    Cyrax
(Hive Bee)
09-15-02 11:48
No 356511
      Sorry, I was a bit confused.  Bookmark   

Sorry, I was a bit confused.
It is in the Bruylants reaction (the displacement of the nitrile in PiperidinoCyclohexaneCarbonitrile with a phenyl group) that you have to use PhMgBr and you can't use PhLi.
If you use PhLi, this results in the addition to the nitrile rather than to its displacement.

I don't know if you can use PhMgBr for the reaction with N-alkylcyclohexylideneamine.  I only remark that in the US patent 3145229, examples 1, 2, 3, 4, 5, 6 and 7 they use PhLi instead of PhMgBr.  There has to be a reason for this, especially because PhLi is more expensive than PhMgBr.  It would be rather foolish if they wouldn't use the most economical procedure, I dare say.  Thus I think PhLi is more efficient.

Therefore, I advise to stick to the patent & use PhLi.

http://l2.espacenet.com/dips/bnsviewer?CY=gb&LG=en&DB=EPD&PN=US3145229&ID=US+++3145229A1+I+
In the second paragraph they say:" M represents an alkali metal, preferably lithium.  Does this exclude the use of PhMgBr?  I think the only way to find out is: run a small test reaction.

Bears are a friendly sort when stoned

Aurelius, this bear is even friendly when not stoned. winksmile
 
 
 
 
    Bwiti
(PVC-Analog Taste-Tester)
09-16-02 05:44
No 356811
      Slamming Ketamine With The Three Bears  Bookmark   

"I think the only way to find out is: run a small test reaction."

  Yes, you're right, because all I have to work with is strong assumptions. I wish I could find examples of an alternative to p-toluenesulfonic acid - Or, maybe I should once again start looking for a job as a janitor in a chemical supply building. I'll clean the place out more than they would like.wink

  Btw, what type(primary, secondary, etc.?) of amine is aniline(aminobenzene)? Seeing that it's easy to make and easy to work with, could it be used to synth an active product; phenylcyclohexylaniline?

"so come on over to three bears house"

  You tease!laugh

Love my country, fear my government.
 
 
 
 
    Cyrax
(Hive Bee)
09-16-02 13:20
No 356926
      What type(primary, secondary, etc.?  Bookmark   

What type(primary, secondary, etc.?) of amine is aniline(aminobenzene)? Seeing that it's easy to make and easy to work with, could it be used to synth an active product; phenylcyclohexylaniline?

Bwiti, I see the logic: you think about replacing the piperidine ring by aniline.  Well, aniline is neither a primary, secundary or tertiary amine.  This nomenclature is used for aliphatic amines.  It is a aromatic amine (the electron pair on the nitrogen is in conjugation with the electrons in the p orbitals of the benzene ring).  I never heard about phenylcyclohexylaniline, so I don't know if it will be active.  However, think about this twice: aniline is VERY toxic and carcinogenic.  Don't mess with it!!!
For inspiration about substituting the piperidine ring with something else, check out:
../rhodium/chemistry /pcp/sar.html#sarmods
I think using n-propylamine instead of piperidine is convenient, since ethylamine is rather volatile (b.p. 17 °C).

Your question about PCP inspired me to post Post 356567 (Cyrax: "PCP Patents, a compendium", Methods Discourse).  Now, you can validate your assumptions smile.  I 'm sure you have seen this already.

Or, maybe I should once again start looking for a job as a janitor in a chemical supply building. I'll clean the place out more than they would like.

LOL smilesmilesmile
 
 
 
 
    Osmium
(Stoni's sexual toy)
09-17-02 14:36
No 357278
      Addition of equimolar amounts of toluenesulfonic ...  Bookmark   

Addition of equimolar amounts of toluenesulfonic acid to the imine/enamine is necessary to direct the PhLi attack to the right carbon. If you omit the acid the PhLi will attach itself on the wrong position (other end of the enamine double bond, two carbons away from the nitrogen).

Toluenesulfonic acid can be prepared from toluene and H2SO4. Other sulfonic acids should work too.

I'm not fat just horizontally disproportionate.
 
 
 
 
    Bwiti
(PVC-Analog Taste-Tester)
09-18-02 07:01
No 357571
      Confused  Bookmark   

  I'm confused; Is the Schiff base of cyclohexanone and y-methoxypropylamine(or any other secondary/primary amine) an imine/enamine? I know of several synths that react a Schiff base with phenyllithium, which don't involve toluenesulfonic acid. Here's an example:
----------------------
GB861350
EXAMPLE 3.

A mixture composed of 52 ml. of cyclohexanone, 45 g. of y-methoxypropylamine and 200 ml. of benzene is subjected to azeotropic distillation until water ceases to be evolved.

The benzene is distilled from the reaction mixture and replaced with an equal volume of ether to obtain an ether solution of the
Schiff base of cyclohexanone and y-methoxypropylamine.

The ether solution prepared above is added dropwise to a solution of phenyl lithium (prepared from 18.2 g. of lithium, 125 ml. of bromobenzene and 800 ml. of ether) and the reaction mixture refluxed for 20 minutes. The
reaction mixture is decomposed by the addi
tion of water, the ether layer removed and
the aqueous phase extracted with ether. The
combined ether layer and extracts are dried,
the ether evaporated and the residue distilled
in vacuo to obtain the desired l-phenyl-cyclo hexyl-y-methoxypropylamine; b.p. 142--1460
C. at 2.5 mm.
---------------------
  Also, many patents say that phenyl-potassium or phenyl-sodium can be used in place of the phenyl-lithium. Someone told me that it wouldn't work; can't remember who. What's your take on this? Why do these patents mention phenyl-K and phenyl-Na if they're useless? Lets say I use phenyl-K in the above example instead of phenyl-lithium? What do I end up with? Will Lewis acids catalysts like Mg-bromide be needed? This is driving me fucking nuts!

  Btw, anyone here know of a synthesis for 2-phenylcyclohexanone? GB758143 uses this as a precursor for several phenylcyclohexylamines - unique synthesis. Peace!cool


Love my country, fear my government.
 
 
 
 
    Cyrax
(Hive Bee)
09-19-02 03:19
No 357900
      azeotropes
(Rated as: excellent)
 Bookmark   

Lets say someone wants to make an imminium salt from cyclohexanone/butylamine(or a heavier amine), then add it to phenyl magnesium bromide to create a yummy PCP-analogue, but they can't get their hands on p-toluenesulfonic acid.

It seems that British Patent 861,350 (example 7) deals with the requested synthesis of 1-phenylcyclohexyl-n-butylamine.
They use benzene (b.p. 80 °C) as a solvent & remove the water that is formed during the formation of cyclohexylidene-n-butylamine by azeotropical distillation. 
The benzene-water azeotrope (containing 9 % H2O) distills over at 69.3 °C, and the b.p. of n-butylamine is 77 °C.  Obviously, this drying technique cannot be used for amines with a b.p. < 69.3 °C.

Toluene forms also an azeotrope with water, with a b.p. of 85 °C & containing 20 % H2O.  Thus one can't use toluene in place of benzene in your synthesis.


I'm confused; Is the Schiff base of cyclohexanone and y-methoxypropylamine(or any other secondary/primary amine) an imine/enamine? I know of several synths that react a Schiff base with phenyllithium, which don't involve toluenesulfonic acid.

* Cyclohexanone + primary amine  --> imine
* Cyclohexanone + secundary amine --> enamine
* Cyclohexanone + secundary amine --> enamine
    enamine + p-toluene-sulphonic-acid or HBr --> iminium salt
 
 
 
 
    Bwiti
(PVC-Analog Taste-Tester)
09-19-02 04:54
No 357939
      Sweet!
(Rated as: excellent)
 Bookmark   

  Thanks for clearing that up for me! Much appreciated!

  Right now, the use of HBr doesn't sound that bad, because I just remembered this patent:

"US3199953
Process For Production Of Anhydrous Hydrogen Bromide From Lithium Bromide

  Into a turbomixer having approximately a 100ml capacity was charged 61g benzoic acid and 15g (approximately 0.15M) of lithium bromide. The mixture was heated to a temperature in the range 250-260*C with stirring, and nitrogen gas at a flow rate of 235ml per minute was passed through the heated mixture. After 1 hour at temperature, approximately 80% of the theoretical amount of hydrogen bromide had been evolved. At 2 hours, 89% of the theoretical hydrogen bromide had been evolved. The reaction is substantially complete after 4 hours of reaction time."


  Here's something from Rhodium's site:

”Step 2, method B. Use of HBr gas: The reaction mixture from step one(cyclohexenyl-piperidine) is diluted to 2 L with dry toluene and dry HBr gas was bubbled through until the solution is acidic. The resulting slurry is added at once to a cold (5 deg. C) stirrred solution of phenylmagnesium bromide”
../rhodium/chemistry /pcp/enam_synth.html#enamine

  How can one tell if the solution's acidic? Would litmus paper suffice? Toluene isn't good at absorbing HBr, or is it? It'll probably require large amounts of benzoic/lithium bromide to get the job done - and stirring.

”This method(HBr produces an intermediate imminium salt) is most applicable to cyclic secondary amine analogs such as piperidine, pyrrolidine, or morpholine, rather than an acyclic N-substituent such as ethyl or dimethyl”
-----------------  ../rhodium/chemistry /pcp/enam_synth.html#enamine

  If aminobutane's used, the yield will be lower than if piperidine's used? Oh well, a lower yield's better than no yield.

  Thanks all!cool



Love my country, fear my government.