Author Topic: PCP via enamine intermediate [pictures]  (Read 5448 times)

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Xicori

  • Guest
PCP via enamine intermediate [pictures]
« on: August 03, 2003, 09:20:00 AM »
High Bees!

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. ~ 108°C@good aspirator vacuum)


Apparatus for azeotropic removal of water


reaction mixture


water in the dean stark receiver


Apparatus for vacuum distillation of the reaction contents


distilled, nearly pure enamine in the recveiver

Note:
Piperidine is corrossive, toxic, and has a very unpleasent amine smell – avoid spilling it -> use a syringe!


Step 2: Removal of water from p-Toluene sulfonic acid Monohydrate

0,1mole (19g) of p-Toluene sulfonic acid Monohydrate were added to 40ml of Toluene, and heated under a Dean stark trap, until no more water seperated, and the distillate was completely clear. Theoretically water amount: 1,8ml


apparatus


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-Toluene-Sulfonic 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 iodine-colour, 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


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!!


closeup

Notes:

The mixture turns a bit brown during grignard reagent formation. That’s 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 5°C. 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).


addition of the anhydrous p-Toluene Sulfonic Acid


a thick white slurry is formed

Note: use a big stirrbar to allow stirring even if the flask contents get a bit sticky.

Step 4: PCP

Now cool your Phenylmagnesium-bromide solution in an ice bath, and transfer the etheral solution into a dropping funnel. All apparatus must be absolutely dry! – Do this as quick as possible to avoid reacting of the Grignard-reagent with humidity/CO2 in the air.

Now add your Grignard-Solution to the slurry produces in Step 4. Cool with ice, and add the solution dropwise! The temp should not go above 5°C. Now the slurry gets easy stirrable again. After everything is added remove the ice bath and stir for additional 30-45min.


Phenyl Magnesium Bromide Solution transferred into dropping funnel.


addition of the grignard reagent.




after finished addition

Now pour the reaction mixture onto 200ml of crushed ice, 20g of NH4Cl and 20ml of concentratet ammonia solution. Let the ice melt and stir well. Everything should go into solution, and 2 layers form.

Transfer the Solution into a seperatory funnel and separate the organic (top) phase.



Extract the water phase once more with 50ml of Ether, and add the extract to the organic phase from above.

Now wash your combined organic phases once with 200ml of water, and dry the organic phase with Na2SO4.


washing with water


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.


gassing apparatus (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!


crystals spring to live


some product drying in an crystallisation dish

Bioassay (~5mg) was used to confirm identity of the substance. – swim had a very dissiociative night, yesterday ;)

So bee safe, have fun!

LG
xicori

flipper

  • Guest
Great work. Beautiful pic's.
« Reply #1 on: August 04, 2003, 03:30:00 AM »
Great work. Beautiful pic's. Thanks.

Aurelius

  • Guest
BWITI!!!!
« Reply #2 on: August 04, 2003, 12:21:00 PM »
Bwiti absolutely has to see this!   That is a beautiful work!  Extra karma on that one!

Hey Rhodium, Please, Please Include this on your site! 

(sorry, I got a little excited- PCP is a good thing :P  yummy.)


anarae

  • Guest
fucking brilliant writeup!
« Reply #3 on: August 04, 2003, 08:28:00 PM »
fucking brilliant writeup! nice clean workspace

talk to Rh about putting this on his site?????

raffike

  • Guest
Very nice pics,what cam do you use?
« Reply #4 on: August 04, 2003, 10:51:00 PM »
Very nice pics,what cam do you use?
Raf has had plans for PCP dream(raf likes DXM,he thinks PCP might be nice too) too but getting precursours(especially piperidine) some seems to be moderately difficult.Glad that posting pics is becoming trend at Hive...


Xicori

  • Guest
the cam used was a simple digital camera with...
« Reply #5 on: August 05, 2003, 12:51:00 AM »
the cam used was a simple digital camera with settings for 640X480 pixels,with some special feature for close-up pictures...

...if you cant get piperidine substitute it with pyrrolidine/morpholine/dimethylamine... especially dimethylamine should produce a very nice compound :)

would be nice to see the writeup on rhodiums page ;)

lg
xicori

Chimimanie

  • Guest
Yep, good work
« Reply #6 on: August 05, 2003, 01:21:00 AM »
I like it... :)

...and if i was Rhodium i would put it on my page Xicori :) , but hell i am not him. ;)

Nice pics BTW. Do you synth in your bathroom or so?

Aurelius

  • Guest
Ethoxyethyl analogue
« Reply #7 on: August 05, 2003, 11:41:00 AM »
PCEE (ethoxyethyl analog) is very delicious also.

15-30mg is a good start dose.  40mg is wow. and 50-80mg is mind-blowing.


Bwiti

  • Guest
Nice!
« Reply #8 on: August 05, 2003, 05:54:00 PM »
I must say that I'm enjoying this thread. 8)


Rhodium

  • Guest
Soon...
« Reply #9 on: August 05, 2003, 07:20:00 PM »
The pictures are actually hosted from my page, the only thing which is lacking at the moment is a nice HTML doc which links most pictures and shows the 3-4 most interesting ones, along the lines of the docs below:

https://www.thevespiary.org/rhodium/Rhodium/clandestine/nano/


https://www.thevespiary.org/rhodium/Rhodium/clandestine/nasa/


Aurelius

  • Guest
HTML
« Reply #10 on: August 05, 2003, 11:14:00 PM »
I'm working on getting to that stage. I'm not good enough with HTML yet.

Still learning.


Xicori

  • Guest
HTMLizing would be no problem....
« Reply #11 on: August 06, 2003, 03:13:00 AM »
HTMLizing would be no problem....

ill send u the document, when finished, rhodium ;)

Barium

  • Guest
Wow!
« Reply #12 on: August 06, 2003, 05:22:00 AM »
Great post, just great!


edg3

  • Guest
Awesome!
« Reply #13 on: August 07, 2003, 11:28:00 AM »
That was a great write up Xicori, brilliant.


CSIdet

  • Guest
Very nice, great equipment
« Reply #14 on: August 16, 2003, 09:48:00 PM »
What a pro I have a lot of newbee envey. it's a goal to work toward 8)


dioulasso

  • Guest
Great!!!
« Reply #15 on: August 18, 2003, 06:12:00 AM »
Really  8)  writeup!

It should work w/ PhMgCl too, right?

Xicori

  • Guest
yeah, PhMhCl would also work, but bromobenzene
« Reply #16 on: August 18, 2003, 07:16:00 AM »
yeah, PhMhCl would also work, but bromobenzene is much more common than chlorobenzene.

goods luck ;)

Bwiti

  • Guest
Secondary Amines??
« Reply #17 on: August 19, 2003, 10:13:00 PM »
"if you cant get piperidine substitute it with pyrrolidine/morpholine/dimethylamine... especially dimethylamine should produce a very nice compound"

  In my dreams, I've used diethylamine, and it was a failure. I did the same as you; diethylamine/cyclohexanone  --> p-Tosic acid --> Phenyl Grignard. I assumed it was because this method didn't work with diethylamine, but now I'm thinking it was a failure because of my sloppy technique. Am I right? Does the p-tosic method work with all primary and secondary amines? Peace! 8)


hypo

  • Guest
hummm...
« Reply #18 on: August 19, 2003, 11:58:00 PM »
> Does the p-tosic method work with all primary and secondary amines?

i think the Mg-grignard only works withg secondary amines, who form
an enamine intermediate. primary amines, forming an imine intermediate
might need an Li-grignard. phenyl grignards are pretty weak.

but this is from the top of my head, so take with some rock salt.


synthon

  • Guest
On Xicori's old post...
« Reply #19 on: June 11, 2004, 08:11:00 PM »
Hi Xicori!

I red one of your earlier posts; it is impossible to reply to it, so I post the reply here, incredibly, there were no replies to it;

Post 391039

(Xicori: "New route to PCP´s?", Novel Discourse)
. You wanted to transform 1-Phenylcyclohexanol to (1-bromocyclohexyl)-benzene. (1-iodocyclohexyl)-benzene would work as well in the synthesis. It could be prepared using the notorious iodine/red phosphorous method. Aluminium and iodine might be adequate for this purpose as well. It works well with the simple alcohols (MeOH, EtOH…), giving generally lower (than rP/I2) but still excellent yields, see: Jones; Green; J.Chem.Soc.; 1926; 2760; J.Chem.Soc.; 1927; 928. Tosylation/mesylation of the 1-Phenylcyclohexanol is maybe yet another option?

Another more OTC and hence interesting approach would be to simply gas the alcohol with HCl in DCM, see: H.; Tsushima,T.; J.Amer.Chem.Soc.; 92; 1970; 3397-3403. and Arumugam,N. et al.; Indian J.Chem.Sect.B; 16; 1978; 917-920 - both describe the synthesis of (1-chloroyclohexyl)-benzene using conc. HCl (or gas?). Finally, there is a paper where they react (I) with various amines, amides...: Baiocchi,L. et al.; Gazz.Chim.Ital.; 103; 1973; 61-69.. Might be worth checking it out for the yields/chemistry as many different nucleophiles were used, unfortunately I can't get it...


Nicodem

  • Guest
tertiary halides give elimination products
« Reply #20 on: June 12, 2004, 02:24:00 AM »
You can't use nucleophylic substitution on tertiary halides (or pseudohalides) because they give mostly just the elimination product. The classical example thought in the school books is t-butyl-chloride which gives mostly isobutene while tBu-OH is the minor product of the solvolysis. I guess it would bee possible to use very mild conditions to give some PCP but it would always bee the in low yields.


synthon

  • Guest
J. Am. Chem. Soc.; 1988; 110(20); 6818-6825:
« Reply #21 on: June 12, 2004, 07:14:00 AM »
2-Phenyl-2-bromopropane: A solution of 33 g of PBr3 (0.12 mol) in 55 mL of chloroform was added dropwise at 40 C to a stirred solution of 50 g of a,a-dimethylbenzyl alcohol (0.36 mol) in 700 mL of chloroform.The reaction mixture was stirred for 2 h at 40 C. The chloroform layer was separated from the viscous inorganic layer and poured into 500 mL of ice water. The organic layer was separated, washed twice with a saturated aqueous Na2CO3 solution and once with water, and dried over MgSO4. The chloroform was removed under reduced pressure. After distillation a colorless liquid was obtained; boiling region 57-80 C (0.05 mmHg). The product contained 31% of the elimination product a-methylstyrene. The product was used without further purification for the synthesis of lf. The yield of 2-phenyl-2-bromopropane was 57%

a,a-Dimethylbenzylamine: This amine was obtained by treatment of 2-phenyl-2-bromopropane with liquid ammonia.* After evaporation of the ammonia, the product was dissolved in 1 M aqueous HCl and the a-methylstyrene was extracted with diethyl ether. The water layer was brought to pH 14, and the free amine was extracted with ether. The ether layer was dried over MgSO4, and the ether removed under reduced pressure. The yield was 53%

*: Brander, M. M. Red. Trm. Chim. Puys-Bus Belg. 1918,37,76-87.

I agree, the yields are not the best..

Alcohols/Alkenes to chlorides:

A Convenient Procedure for the Quantitative Conversion of Reactive Alcohols and Olefins into the Corresponding Chlorides
Herbert C. Brown, Min-Hon Rei;
J. Org. Chem.; 1966; 31(4); 1090-1093.



..and refs in there.

Nicodem

  • Guest
That is not a bad yield
« Reply #22 on: June 12, 2004, 09:05:00 AM »
Actually a yield of 53% is about two times better than I thought it is :) . That is quite a decent yield. But you have to consider the very low temperature used (-33°C) and the ammonia being a weaker base than piperidine. I guess piperidine in a non-polar solvent like CH2Cl2 that would inhibit carbocation formation and working at <-10°C temperature would still give about a 30% yield. And you could even recycle the 1-phenyl-cyclohexene side product.
The other bad thing is that converting the alcohol to the halide causes the same problem of H2O elimination. However, there are conditions that should give a good yield even when using conc. HCl. One is by adding a PTC catalyst because you would then have the same conditions needed for the benzylic –OH substitution as well as double bond hydrochlorination of any 1-phenyl-cyclohexene that would form from the elimination pathway.

But you still need a phenyl Grignard to prepare 1-phenyl-cyclohexanol so why should this bee any better than preparing PCP directly with the usual method?

( If you find a paper where the preparation of 1-phenyl-cyclohexene is described by the condensation of benzene and cyclohexanone then this method would prove to bee an excellent alternative. )


ning

  • Guest
Urea?
« Reply #23 on: June 12, 2004, 09:25:00 AM »
Can't urea convert directly tertiary alcohols to amines in acidic conditions, by SN1 reaction, followed by hydrolysis? Yields were supposed to be good.

In this case, one would have to alkylate the amine later. I think a reductive amination with actone or methyl ethyl ketone sounds nice and attractive. Perhaps even direct alkylation with alkyl halide would work, due to steric hinderance preventing overalkylation.

Perhaps pyrolysis of PCA with pyran would give PCP directly-- if I remember correctly, one way piperazine is made is by pyrolysis of morpholine with ammonia.


synthon

  • Guest
Oh, what a great idea, Ning...
« Reply #24 on: June 13, 2004, 10:22:00 AM »
Many thanks to Nicodem on the Ritter-type of reactions and their use for this purpose. At the espacenet a patent was found based on Ning's idea that tert. alcohols can be treated with urea and conc. H2SO4 to give condensation products, which upon hydrolysis give amines.

PCA intermediate is very interesting as simple reductive amination with various ketones/aldehydes can give a spectrum of extreamly potent analogues.

Tertiary Alkyl Urea and Process for Preparing Same:

Patent US2247495




acx01b

  • Guest
in the patent, with the urea way they get...
« Reply #25 on: October 12, 2004, 12:39:00 AM »
in the patent, with the urea way they get seventy percent of MONO tertiary butyl urea...

but (tert-butyl)-NH-CO-NH-(tert-butyl) can exist too :-)
(why would it not exist??)
so maybe the total yield of pca from pcoh is not far from 90+ %...