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PCP Via Enamine Intermediate
PCP Via Enamine Intermediate
by Xicori
After a few trials on PCP-Synthesis via the N-Benzoylpiperidine route (they have all failed, if someone wants details, let me know),
Swim has performed a PCP synthesis via the enamine route. The whole synthesis was illustrated with pictures, so that other bees get a
easy to follow writeup
Here we go:
Step 1: N-piperidin-cyclohexene
Into a 250ml RBF with a Dean Stark water-trap, a Dimroth reflux condensor and some boiling stones there were added 39,6ml of
Piperidine, 34,5ml of cyclohexanone, 500mg of p-Toluene-sulfonic-acid and 100ml Toluene as solvent.
The mixture was heated with a heating mantle until all water had seperated (~5,4ml). Heating was stopped, and after the contents had
cooled down the reaction mixture was washed with ~30ml of water to remove the catalyst acid. The organic phase was seperated,
dried over Na2SO4 and distilled under aspirator vacuum to yield 45g of colourless, nearly smellless enamine. (b.p. ~ 108C@good
aspirator vacuum)
2) Reaction Mixture
6) Apparatus
7) boiling mixture
Notes: At first 2 Layers are formed I think the top layer consists of Toluene, and the bottom layer consists of melted P-TolueneSulfonic Acid Monohydrate. -> Use a magnetic stirrer to mix the two phases well. During the seperation of water the bottom layer
dissappears -> anhydrous Acid dissolves into the toluene.
Step 3: Preparing of a Phenyl Magnesium Bromide-Solution in Et2O (Grignard-Rnx)
All glassware for this step should be dried in an oven. Anhydrous solvents are absolutely necessary! (use molecular sieves or Na to
dry Et2O)
Into a 250ml 3-necked RBF were added 2,4g (01,1 mole) of Mg turnings, 1 small iodine xtal, and 30ml of ether. Now there were
slowly added 0,1mole of bromobenzene in 15ml of Et2O. The start of the reaction is noticed by disappearing of the purple iodinecolour, and the ether beginning to boil.
Add the residual Bromobenzene at a rate that keeps the ether refluxing. When all the bromobenzene has been added reflux the mixture
for additional 3 hours to finish the reaction.
reaction just started let bromobenzene drip into the mix slowly
8) apparatus for grignard rnx note the drying tubes on condensor and dropping funnel an effective reflux condensor is also
necessary. A liebig-condensor will not work!!
9) Closeup
Notes:
The mixture turns a bit brown during grignard reagent formation. Thats no reason to worry.
When the reaction goes to fast use a cold water bath to slow things down.
Always use magnetic stirring!
Use CaCl2-Drying tubes and an efficient reflux condensor!
Read Organikum, Vogel, etc. about grignard reactions!
Step 4: Salting your enamine from step 1 with your anhydrous acid from step 2
In a 500ml 2-Necked RBF add 16,5g of Cyclohexenyl-Piperidine (from step 1), and add 50ml of anhydrous ether. Add a stirbar, a
condensor, a dropping funnel, and attach drying tubes!
Immerse the flask into an ice bath to keep temp below 5C. Now add your anhydrous P-ToSufoAcid in Toluene, prepared in step 2.
the addition has to be done dropwise.
The enamine forms a salt with the acid (the salt isnt soluble in ether/toluene, so a white slurry is formed).
Now wash your combined organic phases once with 200ml of water, and dry the organic phase with Na2SO4.
16) washing with water
17) freebase in Et2O/Toluene with drying agent added.
After 30min of drying (swirl the flask sometimes) the liquid was decanted and the Na2SO4 was washed with a bit of fresh, dry Et2O.
The wash was combined with the etheral solution, and a HCl-Gas generator was set together.
18) assembled HCl-gas-generator (gas is dried by a washing bottle filled with CaCl2)
Now the freebase solution is diluted with additional 150ml of anhydrous Et2O, and gassed for ~30sek. Move your gassing tube
around to avoid clogging.
when the xtals have settled down gassing is continued until no more crystals appear.
Now the solution was vacuum filtered to leave slight yellow, sticky crystals. The crystals were washed with acetone to leave ~8g of
finely white PCP hydrochloride.
Notes: Maybe a acid/base extraction would avoid the stickiness of the xtals.
Be careful with HCl-gas! Its toxic, and highly corrossive!
19) crystals spring to live
20) some product drying in an crystallisation dish
Bioassay (~5mg) was used to confirm identity of the substance. swim had a very dissiociative night ;)
So bee safe, have fun!
LG
xicori