Megatherium
(Hive Bee)
02-19-03 16:30
No 409923
      Prodine, the old way
(Rated as: excellent)
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This is the classic way to make prodine.  Although this is rather old stuff [JACS (1947), p 911 - 914], the article is very good (nice descriptive procedure):

Synthesis of 1,3-dimethyl-4-phenyl-4-hydroxypiperidine

One liter of dry ether and 15 g of Li wire cut in to small pieces were placed in a 3-liter RB flask provided with a condenser, stirrer, and dropping-funnel.  Bromobenzene (172 g) was placed in the dropping-funnel and 10 ml added at one time to the flask.  Gentle warming was employed until the reaction started and then the bromobenzene was added from the dropping-funnel at such a rate that the ether refluxed vigorously.  At the end of the reaction the dropping-funnel was rinsed with 100 ml of ether and the flask cooled to -5 C.  One hundred twenty-seven grams of 1,3-dimethyl-4-piperidone was added slowly from the funnel, maintaining the temperature at -5 C.  After the addition, the contents were stirred for 1 hour at room temperature.  The flask was cooled in an ice-bath and 200 ml of water was added slowly from the funnel with continued stirring.  The ether layer was separated and dried over K2CO3
After the removal of the ether the residue was distilled in vacuo and the fraction boiling at 130 C / 2 mm Hg was collected.  This product was dissolved in 300 ml of n-hexane (Skellysolve B), and on standing in the ice-box the product crystallized, yielding 150 g of colorless crystals, m.p. 72 - 85 C.  This is a mixture of diastereomeric alcohols.


Synthesis of 1,3-dimethyl-4-phenyl-4-propionoxypiperidine

1,3-dimethyl-4-phenyl-4-hydroxypiperidine (229 g) was dissolved in a mixture of 350 ml of pyridine and 350 ml of propionic anhydride.  The solution was refluxed for 3 hours and the solvents were distilled of in vacuo from a steam-bath using a water-pump.  The residue, after cooling, was mixed with 200 ml of water and basified with 20 % NaOH solution to bring the pH to 9 - 10.  The separated oil was extracted with ether, the ether solution dried over K2CO3, filtered, and hydrogen chloride gas bubbled in until no more hydrochloride separated.  The solid, after drying in a vacuum dessicator ofer NaOH, was crystallized from about 600 ml of acetone containing a little methanol.  One hundred forthy-five grams of colorless crystals, m.p. 212 - 214 C, was obtained in the first crop.  This fraction is dl-alpha-1,3-dimethyl-4-phenyl-4-propionoxypiperidine hydrochloride.  The filtrate was concentrated to 250 ml and allowed to stand in the ice-box overnight.  A second crop of crystals was obtained which on recrystallization three times from acetone melted at 190 - 192 C, yield: 107 g.  This is dl-beta-1,3-dimethyl-4-phenyl-4-propionoxypiperidine. hydrochloride.



Just One Fix
 
 
 
 
    pHarmacist
(Hive Addict)
02-20-03 05:10
No 410113
      Good find!  Bookmark   

With all due respect I still think that the one-step procedure described in Patent US2765315 (Patented Oct. 2, 1956.) kicks ass. But it's always nice with more and more possibilities. Good work Megatherium!

Accept No Imitations, There Can Only Bee One; www.the-hive.ws
 
 
 
 
    Megatherium
(Hive Bee)
02-20-03 07:12
No 410142
      You 're quite right: the method in US patent...  Bookmark   

You 're quite right: the method in US patent 2,765,315 is a synthetic beauty, but the yield is rather low and the alpha ethylstyrene synthesis can be cumbersome.  I thought about the Tebbe reaction to make it, but this is rather exotic.  A similar reaction as the one in US patent 2,765,315 can be found in Post 404354 (Megatherium: "1-(2-phenethyl)-4-phenyl-4-acetoxypiperidine synth", Chemistry Discourse).

Speaking of patents, the 'old method' is also described in US patent 2498433.  The yield of esterification of the tertiary alcohol can be crancked up by using the acylcloride in chloroform instead of the anhydride, and the use of DMAP as a catalist will give even better results.
A more convenient method for the acylation is the application of one of those funny coupling reagents used in peptide chemistry such as dicyclohexylcarbodiimide.  I 've got an interesting looking ref. for that:
 big molecule with secundary alcohol + acid  --DCC/DMAP--> ester  (yield: 97 % !!!)
 ref.: JACS (1984) vol 106 p 3811
So, one doesn't have to go through the trouble making the acid chloride (yukk!).  I 'll check that ref. out, results will follow.
 
 
 
 
    Rhodium
(Chief Bee)
02-20-03 08:43
No 410162
      The above article  Bookmark   

../rhodium/pdf /archive/jacs.1984.106.3811-3814.pdf
 
 
 
 
    Megatherium
(Hive Bee)
02-20-03 09:33
No 410171
      Thanks Rhodium. That procedure for the ...  Bookmark   

Thanks Rhodium.

That procedure for the synthesis of (+)-dihydrocompactin (3) [prodine in our case] seems to be a very convenient one (especially if it is compared to the above anhydride / pyridine acylation): equimolar amounts, room temperature, and no need to prepare that nasty propionyl chloride smile.  Probably, no (or not much) MPTP contaminant will be formed in this reaction since the conditions are mild.
 
 
 
 
    SPISSHAK
(Hive Addict)
02-21-03 13:00
No 410526
      RE: alpha-ethyl styrene  Bookmark   

you mentioned a teebe reaction but I think it would be a lot easier to perform a wittig-horner reaction on propiophenone using triethylphosphite/methylhalide/and excess Potassium tert-butoxide as a base.
BTW, this stuff is ridiculosly potent (8 times that of morphine) and I hear it makes you nodd out real easy, what's LD-50 of that stuff in mice? it sounds like it could be deadly if it is not titurated properly, hell I knew doctors who thought they knew what they were doing die from opiods, and opiates, it's not hard to kill yourself if your not careful.
BTW I was scratching my head over the cyclization mechanism in a reaction between alykl-styrenes, trimethyltriazine,and an acid. howis this ring formed? The only thing I know about it which may help is that the major product is a oxazine, the minor product is of course the phenyl dimethyl piperidinate ester. Does anyone who doe'snt suck at reaction mechanisms know?
 
 
 
 
    Megatherium
(Hive Bee)
02-22-03 04:05
No 410731
      This are some interesting issues you brought...
(Rated as: excellent)
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This are some interesting issues you brought up, SPISSHAK.

You mentioned a Tebbe reaction but I think it would be a lot easier to perform a wittig-horner reaction on propiophenone using triethylphosphite/methylhalide/and excess Potassium tert-butoxide as a base.

You 're quite right.  I rejected the Wittig reaction because it required n-BuLi to deprotonate the phosphonium salt.  The Wittig-Horner reaction is indeed more convenient, since less stong bases such as NaH, EtONa, t-BuOK can be used to generate the phosphonate carbanion.  I was tempted by the Tebbe reaction, because the yield is usually very high.

It sounds like it could be deadly if it is not titurated properly, hell I knew doctors who thought they knew what they were doing die from opiods, and opiates, it's not hard to kill yourself if your not careful.

I am more concerned with MPTP formation than with overdose (which can be easily circumvented if one dillutes the product efficiently, just as you said).

BTW I was scratching my head over the cyclization mechanism in a reaction between alykl-styrenes, trimethyltriazine,and an acid. howis this ring formed?

A better starting point to elucidate the reaction mechanism is the procedure in post Post 404354 (Megatherium: "1-(2-phenethyl)-4-phenyl-4-acetoxypiperidine synth", Chemistry Discourse) (which is, as far as I am concerned, functionally equivalent).
This is what I think will happen:
* R-NH2 + CH20   --HCl--> [R-NH=CH2]+Cl-

* [R-NH=CH2]+Cl- + Ph-C(=CH2)-CH3 --> R-NH-CH2-CH2-C(=CH2)-Ph

* R-NH-CH2-CH2-C(=CH2)-Ph + CH20   --HCl-->  [R-N(=CH2)-CH2-CH2-C(=CH2)-Ph]+Cl-

Now, water initiates a intramolecular olefin - iminium ion cyclization:
* [R-N(=CH2)-CH2-CH2-C(=CH2)-Ph]+Cl- + H2O  --> piperidinol end product

The anhydride in the one-pot reaction just acylates the piperidinol.

Now that I think of it, this is a nice way to make 4-methylpiperidine:

Use benzylamine & isobutene in the Post 404354 (Megatherium: "1-(2-phenethyl)-4-phenyl-4-acetoxypiperidine synth", Chemistry Discourse) reaction + remove the benzyl protecting group & the alcohol by hydrogenation.

How active is PhenylCyclohexyl-4-methylPiperidine?
 
 
 
 
    SPISSHAK
(Hive Addict)
02-22-03 12:35
No 410837
      Megatherium  Bookmark   

Thank you for providing a viable postulated mechanism,sometimes it's hard to visualize and it leaves one scratchinghis nogginin frustration patiently trying to understand what is happening in a system. As for Methyl phenyltetrahydro pyridine formation with this 1,3,4 substitued piperidine I read the original article on Rhodium's page and they mention this by-product in thier patent, in which they state that it does'nt share the deleterious nature of it's 1,4 substitued counter part.
I'm sure more testing would be in order, you mention that an acid anhydride is of use in acylating the tertiary alcohol, well if you look at the above referenced patent they say it's purpose is only to remove water from the phosphoric acid catalyst, which in all probability is why they prefer the polymerized forms like orthophosphoric, etc. due to it's lack of water content. I think the only thing nessecary to acylate this compound in-situ is the prescence of acylating acid (and preferrably a catylist like H3PO4, etc.) the reason being that an intermediate formof the piperidinol is acylated and not the tertiary alcohol which would be impossible to acylate with just an acid due to steric hinderance.
And yes the phosphonate carbanion is considerbly easier to generate and with a diethyl alkyl phosphonate (wittig-horner reagent) than it is is with a straight wittig reagent such as a triphenyl phosphonium alkane reagent, ancillirilly it is also much more nucleophilic and more enthusiastically attacks your ketone function than the later, I hear the trick to this reaction is anhydrous conditions, and the use of an excess of base (2-1 molar ratio) to genrate the phosphonium carbanion,in addition you have the added benifit of ease of seperation of the by-products from the product due to thier polar characteristics (water solubility).
 
 
 
 
    Megatherium
(Hive Bee)
02-22-03 14:13
No 410862
      Very interesting. Then, in US patent 2765315 a  Bookmark   

Very interesting. Then, in Patent US2765315  propionic acid (instead of water) attacks C* and thereby the formation of MPTP is mechanistically impossible (which is rather important IMHO):

* [CH3-N(=CH2)-CH2-CH(CH3)-C*(=CH2)-Ph]+Cl- + EtCOOH  --> prodine

The more I think about this reaction, the better I like it.
 
 
 
 
    SPISSHAK
(Hive Addict)
02-22-03 18:57
No 410941
      I seem to notice that too.  Bookmark   

yeah if you look at the first example it's only trimethyl triazine, alpha-methyl styrene, and a carboxylic acid which implies that the carboxylic acid reacts with the intermediate, this is a synthetic marvel indeed.
I rememer that alpha methyl-styrenes a lot easier to get too, I don't know what it's use is for in commerce (I suspect in polymer chemistry). So if it is mechanistically impossible to get MPTP formation using this simple method then one can safely substitute the methyl-styrene for the ethylstyrene (which is impossible to find). That being the case who cares about yeild.

Another question, in the proposed mechanism in the above post I see, that the aldimine attacks the carbon ajacent to the alkene group, and in the case of ethylstyrene the carbon ajacent tothe alkene gets attacked too giving the 3-methyl substitued product. Well looking at that mechanism (still a little fuzzy) I see that in order to generate the aldimine species you need formaldehyde, and methylamine.
In the case where trimethyl triazine is used would'nt some water in the form of it's hydronium ion (H3O+) be nessecary to generate the aldimine, or would the prescence of acid do the trick? Maybe that reaction procedds by a different mechanism?
 
 
 
 
    Megatherium
(Hive Bee)
02-26-03 16:40
No 412095
      Refs. for this kind of reaction
(Rated as: excellent)
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The reaction of iminium ions with olefins (e.g. alpha-methylstyrene, beta-pinene) has been reported to give rise to aminomethylated products in poor yield:
a) Hennion G.F., JACS (1955) vol 77, p 4633
b) Schmidle C.J., JACS (1955) vol 77, p 4636, 5698, 5754
c) Bohme H., W. Arch. Pharm. (Weinheim, Ger.) (1972) p 305, 601, 610
d) Manninen K., Acta Chem. Scand., Ser. B (1974) B28, p 433

For examples of intramolecular olefin - iminium ion cyclizations:
a) Grewe V., Liebigs. Ann. Chem. (1953) vol 581, p 85
b) Bohlmann F., Chem. ber. (1960) vol 93, p 1956
c) Cope A., JOC (1966) vol 31, p 3099
d) Wilcock J.D., Chem. Ber. (1974) vol 107, p 975
 
 
 
 
    SPISSHAK
(Hive Addict)
02-26-03 17:37
No 412113
      Thanks a million  Bookmark   

I do appreciate your contributution, did you find this in chem abs. by searching according to subject matter?
 
 
 
 
    Megatherium
(Hive Bee)
02-26-03 18:21
No 412126
      No, I stumbled on this while reading some...  Bookmark   

No, I stumbled on this while reading some articles about the synthesis of heterocycles (my favorite topic).
 
 
 
 
    pHarmacist
(Hive Addict)
02-26-03 23:40
No 412192
      Wow Megatherium  Bookmark   

Thanks a bunch... You are one promising bee!!! Have fun and Keep it real! wink

Accept No Imitations, There Can Only Bee One; www.the-hive.ws