(Official Hive Translator)
A cool PCP synthesis
(Rated as: excellent)
Well, guys, certain pieces of this synth have been previously known, but it is soo cooool that i couldn't resist putting it here in one piece, and save our beeloved Rhodium some time.
The funny thing about it is that virtually all required precursors are pyridine and benzoyl chloride.
These procedures (the 1st three) have been found and scanned by The Renowned Bibliophyl of Hyperlab, Garin - may his brilliant head bee blessed 4ever. You can read the originals in Russian at http://chembook.narod.ru/Others/Piperidi
1. Reduction of pyridine to piperidine.
Into a 5-liter flask w/a powerful RC (Note1: recommended 180 cm in length, w/the inner tube diameter >=2 cm - smaller size doesn't allow the rxn to bee carried out as fast as is necessary to obtain a good result) there are placed 130 g (131ml, 1,64 mole) (Note2: if the purity of pyridine is unknown, it should bee dried w/NaOH and distilled, collecting the fraction 112-117 C) and 3 l absolute EtOH.
During 40-50 min gradually add 450 g (19,6 mole) sodium. It's added in as large chunks as the flask's mouth will allow. Then add 1,5 l abs. EtOH and heat the rxn on an oilbath for 2-3 h until Na fully dissolves. It is desirable that the mixtr doesn't chill (Note3: leads to freezing of the soln, which is difficult to melt again. Add water if you desire to stop the process at this point) and piperidine doesn't separate immediately. For this sake the RC is replaced w/DC, the 2nd neck is fitted w/a sepfunnel and remove EtOH on an oilbath (Note4: do not heat it directly - alkali will dissolve glass). Addition of a piece of Zn provides for smooth distillation.
As the dist'n proceeds, 1700-1800 ml water is added thru the sepfunnel, at 1st slowly, then (after 200 ml is added - the mixtr thickens) as fast as possible. Dist'n is cont'd for 3-4 hrs, until almost all EtOh is removed. At this time in the rxn flask there's left ~1500 ml goo, it's discarded. The distillate (~5 l) is mixed w/200ml conc HCl (dens=1,19) and transferred into dist'n flask. EtOH is removed until 600-800ml is left in the flask (2-3 hrs).
(one more sodium/EtOH reduction popped up all coincidentally)
2. Benzoyl piperidine.
This mixture is transferred into 2 l RBF w/add'n funnel & mech. stirrer and treat w/stirring with 170 g NaOH in 300 ml water. Then w/constant stirring there's added 235 g (1,67mol) benzoyl chloride, constantly chilling the flask w/cold water. The flask is then cooled, amide is separated (Note5: sometimes during benzoylation forms an emulsion, it can bee broken w/adding more strong alkali, or, if that fails, xtract the product w/C6H6), wash w/a little water (Note6: NaOH causes destruction of the amide, so wash it thoroughly, w/a small qtty of H2O) and distill in vacuo (Note7: it is very prone to overheating, which complicates dist'n), bp 180-184 C/ 20 mmHg, 191-194 / 27 mmHg, 240-244 / 130 mmHg. It is a straw-yellow viscous oil, on standing or seeding crystallizes as needles w/mp 44 C (lit. 48 C).
Yield 240-250 g (77-81%)
If one takes 180 g pyridine instead of 130 and scales up accordingly everything xcept Na and EtOH, one gets 300-326 g (70-75%), but the factual yield compensates the excess of taken pyridine (Note8: describes the identical prep'n of benzoylpiperidine from piperidine, yield 87-91%)
In a 500ml Claisen flask there's placed 80 g (0,42mole) benzoylpiperidine and to it is slowly w/stirring and cooling added 115 g (0,43mole) PBr3. To thus obtained weakly colored homogenous liquid, w/good stirring and cooling, there's added 65 g (20,8ml; 0,405 mole) bromine. The flask is connected w/a vac. distillation setup and evacuated. When the pressure settles, the flask is cautiously heated - at 1st a vigorous effervescence of gas occurs, then at approx. 70C/20mmHg the mixture of dibromopentamethylene, POBr3 and PhCN starts coming over; a yellow precipitate appears in the condenser. Distillation is continued until the rxn mixtr starts to decompose, which is indicated by its blackening. Distillate is poured onto ice to decompose POBr3 - if this is done in a flask equipped w/a RC and mech. stirrer, that takes ~1 hour.
The heavy oily layer is sep'd and mixed with 125 ml 40% HBr; the mixtr is refluxed w/energetic stirring for 3 hours to fully break down PhCN. Then the mixtr is steam-distilled, thru an air Liebig condenser, the receiving flask being connected to a RC - such design is necessary to prevent plugging of the condenser w/benzoic acid.
The product is washed w/aq. NaHCO3, dried w/CaCl2 and vac distilled - bp 108-110 / 20 mmHg.
Yield 63-70 g (65-72%)
Note: there have been data in the literature that so obtained dibromopentamethlene contains significant amounts of PhCN. For its complete removal it is recommended to do the following:
The crude product, after decompos'n of POBr3, is washed w/water and vac distilled, collecting the fraction boiling up to 105 C / 10 mmHg. The distillate is dissolved in twice its volume petroleum ether and 7 times xtracted w/conc. H2SO4 - 3ml for each 10 ml distillate. The petroleum phase is washed w/dilute NaOH, filtered in case of emulsion forming, dried w/CaCl2 and distilled.
OTOH, there are indications that PhCN is completely removed using the method of Braun and Schteindorf (spelling?) : the crude distillate (containing POBr3, benzonitrile and 1,5-DBP) is carefully poured (stirring and cooling) into 85-95 mlwater, and the mixtr is refluxed for 8-10 hrs, occasionally adding 3-4 ml EtOH to minimize tarring. The product is xtrcted w/ether, washed w/NaHCO3, steam-distilled and vac distilled.
When shaking 1,5-DBP w/conc. H2SO4, an emulsion always forms. Usage of solv'ts,such as pet ether, allows to circumvent that problem, but in such cases the yield is always somewhat less.
Pentamethylene bromide can bee obtained by following methods (the list of refs - can type'em, if interested): by action of fuming HBr on pentamethyleneglycol of 1,5-dipheoxypentane, by action of HBr on 1,5-diisoamyloxypentane in GAA, by action of PBr5 on benzoylpiperidine.
(taken from Rhodium's)
A Grignard reagent is prepared from 56 g of magnesium turnings and 230 g of 1,5-dibromopentane in 2 liters of ether, and the mixture stirred and refluxed for 3 hrs. 151 g of N-benzoyl piperidine is added, and the ether is removed by distilling until the temperature in reaction vessel reaches about 83 C. The reaction mixture is then stirred at this temperature for sixteen hours, cooled and treated with sufficient ammonium hydroxide and a saturated solution of NH4Cl until the precipitate dissolves. The solution was diluted with 2 L of ether, and the ether layer removed by decantation. The ether layer is then washed, dried over sodium hydroxide, and the ether distilled off. The residue is distilled in vacuo to obtain PCP (bp 128-134 C/0.8 mm).