Sciencemadness Discussion Board

Amphetamine from Cinnamaldehyde

Filemon - 4-8-2006 at 12:18

I was thinking to make amphetamine from Cinnamaldehyde:

1. - Cinnamaldehyde + HCl--> 3-Phenyl-2-chloropropanal. But may it self-condenser?

2. - 3-Phenyl-2-chloropropanal + ammonia--> 3-Phenyl-2-amino-propanal

3. - reduction of the ketone.

Vitus_Verdegast - 4-8-2006 at 12:28

You will make a mess

Quote:
1. - Cinnamaldehyde + HCl--> 3-Phenyl-2-chloropropanal. But may it self-condenser?


it will polymerize.

Your second proposed reaction would not work either; at the very least your amino-aldehyde would self-condense.

Your third suggestion, "reduction of the ketone": propanal is an aldehyde.

Cinnamaldehyde can best be cleaved w base to yield benzaldehyde.

From there you can go w acidic MEK aldol condensation, followed by Baeyer-Villager oxidation and subsequent hydrolysis to obtain P2P.

Details you can find here and on other websites more dedicated to the subject.

Be aware that in most countries it is a felony to produce and/or possess amphetamine without a license.





[Edited on 4-8-2006 by Vitus_Verdegast]

Organikum - 4-8-2006 at 13:40

It is a pity that one has to cleave the cinnamaldehyde just to go through serious hassles to attach this carbon again.

Isn´t there another way? Through the epoxide maybe? If I am not mistaken then there are two different epoxides possible depending on the conditions of the epoxidation, base or acid catalysed.

Just musings, I had no closer look into this I admit.

Addon:
Cinnamaldehyde -> cinnamic alcohol -> reduction followed by bromination -> amine

Step 1 by yeast almost quantitative IIRC
Step 2 by HI in excellent yields
Step 3 oh now I forgot what we get in 1, either HBr or Br, yields depend
Step 4 methylamine, good yields

or

Step 1+2 Clemmensen or catalytic hydrogenation

Something wrong with this? Sorry I am tired....

/ORG

[Edited on 4-8-2006 by Organikum]

hinz - 4-8-2006 at 14:28

I would first reduce the Cinnamaldehyde to Phenyl-1-propen-3-ol with NaAlH4/NaBH4. Then I would chlorinate the alkohole with thionyl chloride to form Phenyl-1-propen-3-chloride. Now form the grignard with Mg to get Phenyl-1-propen-3-magnesium chloride(Ph-CH=CH-CH2-Mg-Cl). Now add an acid like HCl or whatever, this will protonate your negative charged organic rest. I hope the double bond doesn't konjugate, forming Phenyl-2-propen (Ph-CH2-CH=CH2) but since a primary carboanion is more stable, this should be the minor product. Now you could electrophilic add HI, HBr or maybe HCl to the double bond, yielding Phenyl-2-halopropan (Ph-CH2-CH(X)-CH3) by the majority (makovnikow). The rest is clear I think, hope this works. Maybe you could reduce the Phenyl-1-propen-3-ol also by nascent hydrogen, but then I can't guarante the existence of the double bond afterwards.

Vitus_Verdegast - 4-8-2006 at 15:05

I think I have a better idea.... :D

I had a look at the possibilities to reduce both the double bond and the aldehyde in one step, obtaining hydrocinnamylalcohol.

Of course sodium aluminium hydride in THF does this job quantitatively in 5 minutes but we are looking for some more OTC solutions. Nevertheless some more or less promising references were found:

using lithium amalgam in EtOH/AcOH:
Yakugaku Zasshi 74 (1954) 1037; Chem.Abstr. (1955) 11593.

using fermenting yeast (nod to Organikum ;) ):
Justus Liebigs Ann. Chem. 529 (1937) 87, 100.
Justus Liebigs Ann. Chem. 513 (1934) 266,276
Justus Liebigs Ann. Chem. 522 (1936) 2,10.

using NiAl alloy in aqueous ethanolic NaOH at 90°C:
J. Org. Chem. 7 (1942) 587, 589.

using palladium in AcOH:
J. Am. Chem. Soc. 63 (1941) 3268.

using CuCl2.2H2O and Mg in H2O/THF (70% yield):
Tetrahedron Lett. 36, 39 (1995) 7119-7122.

and this one looks especially promising to me:

using electrolytic reduction in neutral solution at a lead cathode:
J. Chem. Soc. 101 (1912) 1017
J. Chem. Soc. 101 (1912) 1550.
------------------------------------------------------------------------------

Second step, once hydrocinnamyl alcohol is obtained, it can be passed over Kieselguhr at 400-500°C in a tube furnace, to obtain propenylbenzene:

C. R. Hebd. Seances Acad. Sci. 188 (1929) 638
The article, kindly provided by solo:
http://rapidshare.de/files/25876073/allybenzene_article___fr...

A quick translation of the article:

1. When allylbenzene vapours are passed through a column of infusorial earth heated at 400-500°C isomerisation to propenylbenzene occurs. Until the same conditions estragole and safrole are isomerised into anethole and isosafrole respectively.

2. At room temperature dehydration of 3-phenyl-1-propanol yields allylbenzene as the main product. For example, treatment of allylbenzene with SOCl2 yields chiefly allylbenzene and a small amount of propenylbenzene.
ref: Compt. Rend. 186 (1928) p. 1301, 1626, 1848

3. At elevated temperatures next to dehydration isomeration also occurs. When 3-phenyl-1-propanol vapours are passed over infusorial earth at 400-500°C propenylbenzene was the chief product, accompagnied with a small amount of allylbenzene.


From propenylbenzene, of course, standard route to the end product peracid oxidation etc...


Hydrocinnamyl alcohol is also available cheaply from the fragnance industry BTW. It is commonly used and not watched as far as I know.

Nicodem - 5-8-2006 at 00:18

Quote:
1. - Cinnamaldehyde + HCl--> 3-Phenyl-2-chloropropanal. But may it self-condenser?

Of course you can't do a Michael addition on such an aldehyde due to reasons already stated. But in case aldehyde polymerisation would not be a problem one would get the 1,4-addition product, hence 3-chloro-3-phenylpropanal.
Quote:
Now you could electrophilic add HI, HBr or maybe HCl to the double bond, yielding Phenyl-2-halopropan (Ph-CH2-CH(X)-CH3) by the majority (makovnikow).

According to those rules (the nucleophile adds on the position where the most stable carbocation can form) you would obviously get 1-halo-1-phenylpropane by hydrohalogenating 1-phenylpropene.

I would say the reduction to cynamyl alcohol (or its aquisition given that it's pretty cheap), substitution with conc. HCl to yield cynamyl chloride, reduction with Zn/AcOH to yield 1-phenylpropene from which the route proceeds by well known reactions.

Filemon - 5-8-2006 at 10:51

Quote:
Originally posted by Vitus_Verdegast


Be aware that in most countries it is a felony to produce and/or possess amphetamine without a license.





[Edited on 4-8-2006 by Vitus_Verdegast]


Of course, they allow me microsynthesis but it should be immediately destroyed.

Filemon - 5-8-2006 at 11:16

I have in mind to use the Wolff-Kisher Reduction:

ph-CH=CH-CH=O + NH2-NH2 => PH-CH=CH-CH=N-NH2

PH-CH=CH-CH=N-NH2 + NaOH + head => ph-CH=CH-CH3

Nicodem - 5-8-2006 at 12:13

You got any reference for that?

I highly doubt that is possible. In your fiirst post you seam to have been aware that cynamaldehyde is a Michael acceptor. Thus the nucleophiles can react with the double bond as well. In the conditions for the Wolf-Kishner reduction the hydrazide get on and off the carbonyl and thus adds to the double bond as well. I doubt that the reduction would go smooth.

[Edited on 5-8-2006 by Nicodem]

Filemon - 5-8-2006 at 13:10

here => http://www.chem.harvard.edu/groups/myers/handouts/1_Reductio...

pg.7

http://en.wikipedia.org/wiki/Wolff-Kishner_reduction

[Edited on 5-8-2006 by Filemon]

Sandmeyer - 5-8-2006 at 15:47

Filemon, those links as provided do not prove your point. However, yield of propenylbenzene by the reduction of cinnamic aldehyde is 70% using Huang-Minlon variant of Wolff-Kishner:

http://rapidshare.de/files/28334409/huang.pdf.html

I meen you can't go from that aldehyde for the sake of going from there, even if it involves hydrazine reduction, hinz even suggests Grignard. If this starting material is to be used then I like Nicodems idea of making alcohol, then chloride, then OTC reduction. But to get to propenylbenzene you could go from propiophenone (cheap, IMO probably the best single precursor if you're interested in simple stimulants [including phenmetrazine, which at least Swedish speedfreaks prefer over methamphetamine according to Wikipedia, and one such person did report it better than amph on bluelight]
and have no regard for the law), reduce and dehydrate with tosic or sulfuric. Hell, there are other smoother ways of doing this, but amphetamine dosen't interest me, so you find out..



[Edited on 6-8-2006 by Sandmeyer]

ergoamide - 5-8-2006 at 16:09

Whoops this post wasnt really needed, i didnt read sandmeyer's post correctly i though he was sayin it wouldnt work. But here's the post from the hive who discussed this method a while ago.

moo
(Hive Addict)
07-29-04 22:56
No 522534
Propenylbenzene from cinnamaldehyde
(Rated as: excellent)

There are two references discussing the Wolff-Kishner reduction of cinnamaldehyde to propenylbenzene.


--------------------------------------------------------------------------------


Reduction of Steroid Ketones and other Carbonyl Compounds by Modified Wolff--Kishner Method
Huang-Minlon
J. Am. Chem. Soc. 71, 3302 (1949)



General procedure

The reduction has been carried out by procedures similar to those described in previous papers1,2. Thus a mixture of the starting material, diethylene or triethylene glycol (Note 1), alkali hydroxide and 85% hydrazine hydrate (Notes 2 and 3) was refluxed for about half an hour and the condenser was then removed to allow the aqueous liquor to evaporate and the temperature of the reaction mixture to rise to about 200°. In cases where either the starting material or the reduced product is volatile a takeoff adapter was used instead of removing the condenser to evaporate aqueous liquor. After refluxing at this temperature for about two hours the reaction mixture was cooled, diluted with water (Note 4) and the separated reaction product was filtered or extracted with ether (Note 5).

NOTE 1. The amount of diethylene glycol or triethylene glycol used can be varied according to the solubility of the carbonyl compound or its hydrazone formed during the reaction so that a clear or nearly clear reaction mixture is obtained during the heating period. Sometimes it is advisable to dissolve the carbonyl compound in alcohol before addition of glycol and other reagents, e.g., in the case of cholestanone and cholestenone.
NOTE 2. The amount of alkali hydroxide used is about 10% to the volume of the glycol used and the amount of 85% hydrazine hydrate used is always in excess (3 moles or more).
NOTE 3. In reduction of alkali sensitive compounds such as aldehydes, ±,²-unsaturated ketones and those carbonyl compounds in which the carbonyl group is adjacent to an asymmetric center it is advisable to reflux the glycol solution of starting material with hydrazine hydrate for about half an hour and then add a concentrated aqueous solution of alkali hydroxide slowly as described previously.
NOTE 4. If the reduced product is acidic, it is obtained by acidifying the cooled reaction mixture with dilute hydrochloric acid.
NOTE 5. In cases where the starting material contains methoxy group the crude reduced product was remethylated with dimethyl sulfate.
NOTE 6. Most of the technical steroid ketones were recrystallized before reduction, since otherwise the yield is sometimes unsatisfactory. The yields of reduced products given in Table I are on the basis of pure products for which the melting points are given.
NOTE 7. In cases where the carbonyl compound is unstable and difficult to purify such as a-naphthaldehyde the hydrazone or semicarbazone can be taken as starting material for reduction.

(I took the liberty to omit all the steroid ketones from the table and leave the ones bees might be more interested in)

Table 1.
Compound Product B. p. °C. Yield,
% n25D
Vanillin 3,4-Dimethoxy-1-methylbenzenea 133-135 (50 mm.) 77.3 1.5257
Veratraldehyde 3,4-Dimethoxy-1-methylbenzene 122-124 (27 mm.) 81 1.5259
Cinnamic aldehyde Propenylbenzene 176-178 (755 mm.) 70 1.5464
aOn methylation of the crude reduced product with dimethyl sulfate.

1 Huang-Minlon, J. Am. Chem. Soc. 68, 2487 (1946)
2 Huang-Minlon, J. Am. Chem. Soc. 70, 2802 (1948)


--------------------------------------------------------------------------------


The other ref is Helv. Chim. Acta 35, 780 (1949) where the hydrazone of cinnamaldehyde is first formed separately and then decomposed with alcoholic alkali by heating in a pressure tube.



[Edited on 6-8-2006 by ergoamide]

[Edited on 6-8-2006 by ergoamide]

Organikum - 6-8-2006 at 07:49

Quote:

Hell, there are other smoother ways of doing this
Well Herr Sandmeyer thats called teasing. What about a hint?

And wouldn´t acetophenone or mandelic acid be the starting materials of choice for phenmetrazine?

;)

/ORG

[Edited on 6-8-2006 by Organikum]

turd - 6-8-2006 at 11:31

Quote:
Originally posted by Organikum
Cinnamaldehyde -> cinnamic alcohol -> reduction followed by bromination -> amine
[...]
Step 2 by HI in excellent yields

Really? Would that work for phenylalanine or tryptophan?

Quote:
Originally posted by Sandmeyer
including phenmetrazine

Interesting compound. What about the aminoethanol derivate (2-phenylmorpholine), is it pharmacologically active?

Sandmeyer - 6-8-2006 at 11:40

Quote:

And wouldn´t acetophenone or mandelic acid be the starting materials of choice for phenmetrazine?
;)


A quick scifinder litt search revealed that the existing methods to that compound are not too good IMO, if I was to make it from propiophenone I'd take propiophenone alpha brominate it, swap the bromine with ethanolamine, reduce the keto function with NaBH4 and treat the diol with HCl to construct the morpholino moity. But since I will never brake the law it's up to someone with the propper license to test the route in practice.

[Edited on 6-8-2006 by Sandmeyer]

[Edited on 6-8-2006 by Sandmeyer]

Organikum - 6-8-2006 at 11:41

Quote:
Originally posted by turd
Quote:
Originally posted by Organikum
Cinnamaldehyde -> cinnamic alcohol -> reduction followed by bromination -> amine
[...]
Step 2 by HI in excellent yields

Really? Would that work for phenylalanine or tryptophan?
Huh? Thats both aminoacids and cinnamaldehyde is an aldehyde, thats a bit a difference isn´t it?

confused
/ORG

turd - 6-8-2006 at 11:55

Excuse me for being unclear.

I was talking about reducing the acids to alcohols with LiAlH4 or NaBH4 and using HI to reduce the alcohol. Usually this second reduction is done in multiple steps by protecting the amine, tosylating the alcohol, cleaving the ester and finally deprotecting the amine. I always assumed it is done this way because rP/I reductions don't work on primary alcohols, but maybe there are different reasons...

Organikum - 6-8-2006 at 12:58

At least phenylalaninol is commercially available without problems AFAIK.

About the possibilty to reduce phenylalaninol with HI are conflicting reports, on the Hive it was claimed possible but others were not able to reproduce it. By theory HI is able to do this. Protecting the amine by methylation with formaldehyde might be a good idea though - to preserve the amine under the harsh conditions necessary and resulting in a more active product.

/ORG

Sandmeyer - 6-8-2006 at 13:21

Phenylalaninol (or the HCl salt) could be reacted with SOCl2 and the hydrochloride salt of the formed chloride reduced with Zn/acetic...

Organikum - 6-8-2006 at 18:09

obsolete.

[Edited on 7-8-2006 by Organikum]

Nicodem - 7-8-2006 at 03:29

Quote:
Originally posted by turd
Quote:
Originally posted by Sandmeyer
including phenmetrazine

Interesting compound. What about the aminoethanol derivate (2-phenylmorpholine), is it pharmacologically active?


Interestingly there is nothing on its pharmacology in the literature. That’s kind of weird given that its 3-methyl analogue is such a strong stimulant. The pharmaceutical companies trafficking phenmetrazine surely tested 2-phenylmorpholine on animals as well, but these companies rarely release much about their development research.

However, a certain somebody prepared 2-phenylmorpholine hydrochloride and tested it at 80mg. This somebody said it was one of the most annoying drugs he ever tried. It was psychoactive to some mild degree, but the most pronounced effect was of an extreme feeling of tiredness, kind of like due to a drop of blood pressure. So if the psychoactivity mechanism included any catecholamines release, its consequences were not noted because the subject was sedated from tiredness. The subject said its unpleasantness can only compare to drugs like opiates or benzodiazepins and these would even leave a better impression as it is always better to be put down due to psychological and not physiological activity.
At least it is ridiculously easy to prepare from styrene in a couple of steps, but what a stupid poison!

Nicodem - 7-8-2006 at 03:45

Quote:
Originally posted by Sandmeyer
A quick scifinder litt search revealed that the existing methods to that compound are not too good IMO, if I was to make it from propiophenone I'd take propiophenone alpha brominate it, swap the bromine with ethanolamine, reduce the keto function with NaBH4 and treat the diol with HCl to construct the morpholino moity. But since I will never brake the law it's up to someone with the propper license to test the route in practice.


Actually, there already exist a couple of patents describing this route to phenmetrazine with the only difference in that H2SO4 is used in the cyclisation step. I hope anybody isn't going to bother asking for numbers as I believe those who are not motivated enough to do their own literature search should stay away from stimulants. To imagine that some irresponsible hillbilly who never made a single step inside a library can nowadays sell homemade meth! :mad: Lazy bastards should end up on opiates instead, thus contributing to the human evolution. :P

Sandmeyer - 7-8-2006 at 06:08

Quote:
Originally posted by Nicodem

Actually, there already exist a couple of patents describing this route to phenmetrazine with the only difference in that H2SO4 is used in the cyclisation step.


Strange, when I did a scifi search I got some crappy method from a Bulgarian? group, I might have had the patents-off filter on...

jon - 3-10-2006 at 21:10

the phemetazine process orginally was from 2-hydroxylethylnor-ephedrine however that was prepared, probably exactly the way you describe with bromopropiophenone and ethanolamine. . the other processes involve the reaction of nor-ephedrine with oxalyl chloride then reduction with LiAlH4 then cyclization with H2SO4, or reaction with chloracetyl chloride treatment with a base, reduction and then cyclization with H2SO4. I was wondering if a simpler route to the intermediate would be treatment with 2-iodoethanol of norephedrine. of couse you would have multiple substitution by-products in this case you would use a stochiometric excess of amine to suppress the formation of tertiary and quaternary amines, but distillation would deal with this.
that's how phendimetrazine is made by reaction with 2-iodo ethanol on ephedrine then cyclization, phendimetrazine isn't as euphorogenic as phenmetrizine the old BI-62s
a method I think organikum might be interested in is the reaction of ethanolamine with phenylacetylcarbinol to get the shiff's base (this can also be isolated as a cyclic intermediate by dehydrating over silica and extaction) this can be reduced to the 2-hydroxynorephedrine and cyclized to some prized goods.


[Edited on 4-10-2006 by jon]

[Edited on 4-10-2006 by jon]

[Edited on 5-10-2006 by jon]

[Edited on 5-10-2006 by jon]

swip2 - 10-8-2008 at 23:04

Was any of these methods ever confermed ?

Ergo's write up dose look good tho.

stoichiometric_steve - 11-8-2008 at 00:20

Quote:
Originally posted by Vitus_Verdegast
2. At room temperature dehydration of 3-phenyl-1-propanol yields allylbenzene as the main product. For example, treatment of allylbenzene with SOCl2 yields chiefly allylbenzene and a small amount of propenylbenzene.
ref: Compt. Rend. 186 (1928) p. 1301, 1626, 1848


i couldn't find any experimental part in that reference.

refs

swip2 - 11-8-2008 at 16:31

Could those refs be posted

solo - 11-8-2008 at 19:05

Quote:
Originally posted by stoichiometric_steve
Quote:
Originally posted by Vitus_Verdegast
2. At room temperature dehydration of 3-phenyl-1-propanol yields allylbenzene as the main product. For example, treatment of allylbenzene with SOCl2 yields chiefly allylbenzene and a small amount of propenylbenzene.
ref: Compt. Rend. 186 (1928) p. 1301, 1626, 1848


i couldn't find any experimental part in that reference.


Attachment: Franch journal allylbenzene synthesis info.pdf (403kB)
This file has been downloaded 1795 times


S.C. Wack - 12-8-2008 at 01:07

Quote:
Originally posted by swip2
Could those refs be posted

Mood: Fuck all ya"ll....


Right backatcha. Perhaps you could download it yourself from Gallica like stoichiometric_steve did.

Related some to some posts in this thread...there is another dehydration of hydrocinnamyl alcohol in the literature that I'm aware of.

But it is as an ester and the product was allylbenzene.

Hydrocinnamyl acetate, b.p. 133° (18 mm.) (61 g., 0.34 mole) was passed over glass wool heated at 460-485°. The pyrolysis product was washed with aqueous sodium carbonate solution, dried and distilled at atmospheric pressure. The yield of allylbenzene, b.p 150-160°, was 31 g. (76%).
-JACS 78, 584 (1956)

swip2 - 15-8-2008 at 18:41

Well the link is all good and everything but Its In French ffs :o..

Is it possible for anyone to translate it, Or provide a link to an english version...

Dose stoichiometric_steve have it in english.

And could S.C. Wack please provide a refrence to the hydrocinnamyl alcohol comment please.

stoichiometric_steve - 16-8-2008 at 00:45

i can read french pretty well but it has NO experimental section.

no1uno - 19-8-2008 at 12:37

There is at least one reference to researchers having a-brominated cinnamaldehyde to the 2-bromo, which was reduced with yeast to the wanted a-bromophenylpropan-3-ol. The researchers in question claim seriously high enantio-ratios, in using this process for making phenylalaninol/phenylalaninal (I think Solo will know the reference I refer to*). Yeast reduction seems to be a useful route to enantiospecificity, which in the case of such chiral compounds might make it worth a look.

Once you have n-methylphenylalaninol then a number of options open up, the scientific interest would be in the economical production of anti-retroviral agents (which is what the paper deals with). It would be nice if someone could come up with a synthesis for pirating such agents, given that the pharm. companies continue to charge incredible prices (well beyond the means of most sufferers).

* IIRC the part-title makes reference to 'Yeast reduction of cinnamaldehyde derivatives...'?

WizardX - 19-8-2008 at 16:49

http://wizardx.t35.com/achive/cinnamic.html

The site in question was violating our TOS and was removed.

I'll upload it again soon.

[Edited on 20-8-2008 by WizardX]

zgoat65 - 6-3-2012 at 11:51

Quote: Originally posted by Nicodem  
Quote:


I would say the reduction to cynamyl alcohol (or its aquisition given that it's pretty cheap), substitution with conc. HCl to yield cynamyl chloride, reduction with Zn/AcOH to yield 1-phenylpropene from which the route proceeds by well known reactions.


Would this be a valid route to (ref attached) cynnamyl chloride? This seems like the Holy Grail of OTC routes

Attachment: THE_REACTION_BETWEEN_ALCOHOLS_AND_AQUEOUS_SOLUTIONS_OF_HYDROCHLORIC_AND_HYDROBROMIC_ACIDS..pdf (671kB)
This file has been downloaded 1333 times

[Edited on 6-3-2012 by zgoat65]

[Edited on 6-3-2012 by zgoat65]

zgoat65 - 6-3-2012 at 17:39

"There is a reference to the bromination of cinnamyl alcohol in Organic Synthesis (http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv5...).

The authors cite a 1918 German paper where it is claimed that cinnamyl bromide can been prepared from cinnamyl alcohol by the action of hydrogen bromide in cold acetic acid. I'm don't know why these conditions wouldn't also brominate the alkene double bond. I don't have access to the paper so I'm afraid I can't help more. You might be able to brominate the alcohol and the halide in one step. If you could selectively dehalogenate the primary, you should be able to from the 2-Bromo-1-phenylpropane. You can then convert the halide to the iodide with the Finkelstein reaction in acetone. (http://en.wikipedia.org/wiki/Finkelstein_reaction). Finally you should be able to aminate the iodide with methylamine in dry IPA as ++++ has shown with iodosafrole."w

Taken from a thread elsewhere

[Edited on 7-3-2012 by zgoat65]

cinnamyl_alchohol_to_MA-1.gif - 20kB

[Edited on 7-3-2012 by zgoat65]

cal - 9-3-2012 at 07:23

Quote: Originally posted by Sandmeyer  
Filemon, those links as provided do not prove your point. However, yield of propenylbenzene by the reduction of cinnamic aldehyde is 70% using Huang-Minlon variant of Wolff-Kishner:

http://rapidshare.de/files/28334409/huang.pdf.html

I meen you can't go from that aldehyde for the sake of going from there, even if it involves hydrazine reduction, hinz even suggests Grignard. If this starting material is to be used then I like Nicodems idea of making alcohol, then chloride, then OTC reduction. But to get to propenylbenzene you could go from propiophenone (cheap, IMO probably the best single precursor if you're interested in simple stimulants [including phenmetrazine, which at least Swedish speedfreaks prefer over methamphetamine according to Wikipedia, and one such person did report it better than amph on bluelight]
and have no regard for the law), reduce and dehydrate with tosic or sulfuric. Hell, there are other smoother ways of doing this, but amphetamine dosen't interest me, so you find out..

That link does not exist anymore so if you have a copy, then post it and do not reference it.

[Edited on 6-8-2006 by Sandmeyer]

solo - 10-3-2012 at 07:56

"The authors cite a 1918 German paper where it is claimed that cinnamyl bromide can been prepared from cinnamyl alcohol by the action of hydrogen bromide in cold acetic acid. I'm don't know why these conditions wouldn't also brominate the alkene double bond. I don't have access to the paper so I'm afraid I can't help more. You might be able to brominate the alcohol and the halide in one step. If you could selectively dehalogenate the primary, you should be able to from the 2-Bromo-1-phenylpropane. You can then convert the halide to the iodide with the Finkelstein reaction in acetone. (http://en.wikipedia.org/wiki/Finkelstein_reaction). Finally you should be able to aminate the iodide with methylamine in dry IPA as ++++ has shown with iodosafrole."w"

........in your last sentence...."Finally you should be able to aminate the iodide with methylamine in dry IPA as ++++ has shown with iodosafrole."w"......do you have a reference for that statement?.......solo

zgoat65 - 21-3-2012 at 10:24

OR...........how bout this ref? Forget halogenation/dehalogenation, and go from alcohol to olefin using amalgamated zinc?

http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv6...

License

cal - 25-3-2012 at 10:03

Quote: Originally posted by Filemon  
Quote:
Originally posted by Vitus_Verdegast


Be aware that in most countries it is a felony to produce and/or possess amphetamine without a license.





[Edited on 4-8-2006 by Vitus_Verdegast]


Of course, they allow me microsynthesis but it should be immediately destroyed.

Along with most all chemicals we want to buy now. That does not stop us from making what we need.

Link

cal - 25-3-2012 at 10:07

Quote: Originally posted by cal  
Quote: Originally posted by Sandmeyer  
Filemon, those links as provided do not prove your point. However, yield of propenylbenzene by the reduction of cinnamic aldehyde is 70% using Huang-Minlon variant of Wolff-Kishner:

http://rapidshare.de/files/28334409/huang.pdf.html

I meen you can't go from that aldehyde for the sake of going from there, even if it involves hydrazine reduction, hinz even suggests Grignard. If this starting material is to be used then I like Nicodems idea of making alcohol, then chloride, then OTC reduction. But to get to propenylbenzene you could go from propiophenone (cheap, IMO probably the best single precursor if you're interested in simple stimulants [including phenmetrazine, which at least Swedish speedfreaks prefer over methamphetamine according to Wikipedia, and one such person did report it better than amph on bluelight]
and have no regard for the law), reduce and dehydrate with tosic or sulfuric. Hell, there are other smoother ways of doing this, but amphetamine dosen't interest me, so you find out..

That link does not exist anymore so if you have a copy, then post it and do not reference it.

[Edited on 6-8-2006 by Sandmeyer]

Do you have this document as the download link is no longer available.

chemrox - 8-4-2012 at 21:21

Quote: Originally posted by Sandmeyer  

http://rapidshare.de/files/28334409/huang.pdf.html





[Edited on 6-8-2006 by Sandmeyer]

Could you repost without using rapidshare? It's really volatile. That link was dead within a few days and I missed it.

S.C. Wack - 9-4-2012 at 11:43

It's in any arcHive, with Huang-Minlon_propenylbenzene in the file title. Not convenient to quote from.

Dihydrocinnamyl alcohol dehydration

cmos6667 - 10-5-2015 at 13:44

I read up on this and apparently you need either KHSO4 or conc. H2SO4 and high heat.
However, the product doesn't boil out, even being way past water's BP.

As far as I know, you should remove water but if you go beyond 80C, you get loads of side-reaction product.

Is it possible that (PhCH2CH2CH2)2O is formed and that's why you don't dehydrate?
In that case: can I take say 3 equiv EtOH and 1 equiv PhCH2CH2CH2OH to form the ethyl ether of dihydrocinnamyl alcohol (along with Et2O), then use KHSO4 at 80C to eliminate EtOH while removing it and leaving behind allylbenzene?

Chemosynthesis - 10-5-2015 at 14:47

Why don't you post what you have read, as this section generally requires references?

cmos6667 - 11-5-2015 at 00:30

Apologies, here: http://chemistry.mdma.ch/hiveboard/chemistrydiscourse/000204...
Before you get any wrong idea: the alkene is at the end position, so wacker or performic or whatever won't work, you need a catalyst under inert atmosphere to rearrange it to the middle ;)

Mesa - 11-5-2015 at 02:12

You should probably add in that the beckmann will also not work on this substrate...

cmos6667 - 11-5-2015 at 04:01

No carbonyl, no beckmann ;)

cmos6667 - 11-5-2015 at 06:34

seriously though, any help here please?

byko3y - 11-5-2015 at 15:41

My experience with acrolein tells, that you will get some solid gummy tar as a product, unless you distill your dehydrated product as fast as it is formed.
Allylbenzene has b.p. 156-157°C, so this procedure can be performed pretty easily, until you condense the product back to where it will polimerize.
Those compounds are usually processed in gas phase via heterogenous catalyst, thus ensuring a short contact time.
PS: the problem is called "acid catalyzed alkene polimerization".

[Edited on 11-5-2015 by byko3y]

cmos6667 - 12-5-2015 at 04:53

fair, solid input, thank you :)

CuReUS - 20-5-2015 at 08:49

Quote: Originally posted by cmos6667  

Before you get any wrong idea: the alkene is at the end position, so wacker or performic or whatever won't work, you need a catalyst under inert atmosphere to rearrange it to the middle ;)

actually,wacker oxidation will convert terminal olefins to methyl ketones,so it will work very well.And you don't need any special catalyst or inert atmosphere,conc KOH with heat will do the job

for the dehydration,why can't phosphoric acid be used?
85% phosphoric acid is available as rust remover

also,instead of using cinnamaldehyde,why can't cinnamic acid be used? one could cyclopropanate the double bond(if choroform is used,then you will get dichlorocarbene instead of methylene group which won't make much of a difference, I think,and if diazomethane is used,then the COOH should be esterified first),reduce it (catalytic hydrogenation or maybe even Zn/AcOH)to get 2-methyl-3-phenylpropanoic acid and then do schimdt reaction to get the amphetamine.

[Edited on 20-5-2015 by CuReUS]

cyclo.jpg.bmp - 616kB

cmos6667 - 24-5-2015 at 13:39

That's a rather tedious process, no?
Use nitric acid and iron wool and put cinnamaldehyde on acidic alumina --> get carboxylic acid nitrostyrene, then use P + I2 followed by lots of NaBH4, and again P + I2 followed by Mg

chemrox - 8-4-2016 at 10:17

Will the HI (P + I2, [ as cited in March]) reduction work on reduction of beta nitrostyrene to the corresponding ketone? I doubt it but maybe I'm (as often) wrong.

Chemi Pharma - 7-5-2016 at 10:48

Alcohols and aldehydes like cinnamyl alcohol and cinnamaldehyde going into reductions to alkanes (or alkenes) with Clemensen reduction (Zn/Hg + HCL) using diethyl ether as a solvent, gassing HCL trought it at a temperature of - 15 º C, like zgoat65 said:

http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv6...

Both are sold as perfumery flagrancies, at least here, in Latin America.

It will produce a mix of propenyl benzene and allyl benzene, and the last can be isomerised to the first by heating with KOH. Propenyl benzene trated with performic acid leads to 2 phenyl propanone as you can see in the attachment below.

Phenyl Propanone forms amphetamine or methamphetamine by Leuckart Reaction with formic acid and ammonia or methylamine (formamide or n-methyl formamide as well), reaction which were already discussed in another topics here in this forum.

Here is an interesting Methamphetamine You tube Leuckart reaction video:

https://www.youtube.com/watch?v=nAIlFwaBju0

Attachment: performic-oxidation-of-safrole and phenyl propene (further isomerization).pdf (1MB)
This file has been downloaded 598 times

[Edited on 8-5-2016 by Chemi Pharma]

clearly_not_atara - 7-5-2016 at 11:46

I'm pretty sure that any dissolving metal reduction, including Zn/HCl, will saturate the C=C bond in cinnamaldehyde, giving phenylpropanol or phenylpropane.

Hydrazine on the other hand may be selective enough to work.

Chemi Pharma - 7-5-2016 at 15:42

It seems that the double bond presented in cinnamyl alcohol and cinnamaldehyde is quite resistent to reduction. I reproduce below a text published at rhodium pages, where a guy called "Psychokitty" experiments this kind of reduction with cinnamyl alcohol affording 60% yield of allylbenzene (4 parts) and propenylbenzene (1 part). He broght as reference Tetrahedron 27, 5081 (1971).

Another guy called "Rev Drone" claims even LIALH4 can't break the double bond afther chlorination with mesyl choride and further reduction, giving a lot of references and discussing others routes.


Here's the text:

"Psychokitty:

This appears optional. According to the review, commercial Zn dust worked just fine when used in procedure A.
Commercial zinc dust (16 g., 325 mesh) was activated by stirring for 3-4 minutes with 100 ml of 2% hydrochloric acid. The zinc was immediately filtered under suction, washed to neutrality with water, and then washed with 50 ml of ethanol, 100 ml of acetone, and diethyl ether. The resulting powder was dried at 90°C under vacuum (10 minutes) and was used within 10 hours of preparation.

Procedure A:

Cinnamyl alcohol (1.30 mm) was dissolved in 75 ml of dry ether saturated with hydrogen chloride at 0°C. Activated zinc dust (5.0 g; 0.076 mol) was slowly added to the cooled mixture with vigorous stirring at a rate such that the temperature maintained below 5°C. The reaction was exothermic and considerable hydrogen evolution occurred. The reaction mixture was stirred for 1 hour at 0°C and then filtered. The filtrate was shaken with 500 ml of ice water and then washed to neutrality with aqueous sodium carbonate. The aqueous washings were dried over sodium sulfate and evaporated under vacuum. Chromotography of the residual oil over silica gel (Mallinckrodt, 100 mesh, 25 g) using benzene as eluant afforded 60% yield of allylbenzene (4 parts) and propenylbenzene (1 part).
The above ratios seems a little steep for the average bee with the volume of solvent too great. A more practical method that is on a preparative scale can be found in Tetrahedron 27, 5081 (1971).

Rev Drone:

I know nobody likes it, but how about going from cinnamyl alcohol to allyl benzene using LAH? Yeah, its overkill, and yeah its water sensitivity is a pain-in-the-ass, but you know it'll get the job done. The work-up should be particularily easy, as far as LAH reduction work-ups go around here. A little esterification with mesyl chloride wouldn't hurt things either (but isn't necessary unless you're really worried about maximizing your yield.)

Ref's:
• Indian J. Chem. Sect. B 23(4), 303-306 (1984)
• Carbohydr. Res. 141, 49-56 (1985)
• Liebigs Ann. Chem. 12, 1249-1255 (1990)
• Liebigs Ann. Chem. 1, 87-94 (1992)
• J. Org. Chem. 60, 872-882 (1995)

Also, you could go this route:

cinnamyl alcohol + HI/RP -> propenyl benzene
( "" -> phenylacetone)
Ref = Chem.Ber. 11, 671 (1878)

Just to add onto Rhodium's idea of cinnamyl alcohol -> 3-phenyl-1-pronanol -> allyl benzene:
aryl propenyl alcohol + H2 + (Cat.) -> 3-aryl-1-propanol

• (Cat.) = Pd/SrCO3
• J. Chem. Soc. 618, 619 (1953)

• (Cat.) = Pd
• Justus Liebigs Ann. Chem. 401, 151 (1913) [Anm.]
• J. Org. Chem. 24, 736, 740 (1959)
• Phytochemistry 20(6), 1543-1546 (1981)

• (Cat.) = nickel
• Chem. Zentralbl. 95(I), 1878 (1924)
• Zh. Obshch. Khim. 20, 1199, 1206 (1950)
• Acta Chem. Scand. 15, 357-369 (1961)

• (Cat.) = Ni2B (nickel boride)
• Chem. Pharm. Bull. 38(6), 1720-1723 (1990)

There are actually dozens more ref's on this, but I'm getting tired of listing them, so I think you get the general idea... Anyways, the next question is: what about the ref's for the dehydration? The "cinnamyl alcohol + -> allyl benzene" step? Well,

3-Phenyl-1-Propanol --[Reagent]--> Allyl benzene
• SOCl2
• C.R.Hebd.Seances Acad. Sci. 188, 638 (1929)

• Ac2O
• JACS 78, 584, 589 (1956)
• Helv. Chim. Acta 62, 135-139 (1979)

• H3PO4
• JACS 57, 151, 155 (1935)

• Mol. Sieves
• J. Chem. Soc. Faraday Trans. 1, 78, 2017-2022 (1982)


Cinnamyl alcohol to propenylbenzene

This contradictory response was started last night, before it became contradictory.

There are numerous literature references for the SN2 substitution of the OH in cinnamyl alcohol for chloride, bromide and iodide, using HCl, HBr and HI respectively. In fact, HI can go on to reduce the alkyl iodide to give the ever-usable propenylbenzene in one-pot.

The substitution works probably because of the conjugation of the molecule, which gives a greatly stabilised transition state for the SN2 displacement (much like the rate enhancing effects when a leaving group is alpha- to a ketone). The addition across the double bond happens at its usual (slower) rate; addition across the double bond also disrupts the favourable conjugation. Because of these effects, the -OH of cinnamyl alcohol behaves effectively like the reactive -OH of benzyl alcohol.

I would suggest adding HBr to cinnamyl alcohol to give cinnamyl bromide, followed by reduction to propenylbenzene with borohydride/PTC. Many reductions give a mixture of products (e.g. allylbenzene/propenylbenzene/propylbenzene) but with a suitable hydride nucleophile you can selectively displace the bromide with hydride (again, this may be made easier because of the conjugation stabilising the transition state).

Here are some references (some of which are available online for free). Some of them look very interesting:


Cinnamyl chloride from cinnamyl alcohol with HCl

J.Amer.Chem.Soc. 107 (7), 1985, 2033-2046
Chem.Ber., 39, 1906, 2553
Arch.Pharm.(Weinheim Ger.), 247, 1909, 349
J.Org.Chem., 42, 1977, 871-875
Justus Liebigs Ann. Chem., 479, 1930, 211, 248
J.Chem.Soc., 1941, 507, 510.


Cinnamyl chloride from cinnamyl alcohol using other sources of chloride

SOCl2, 94% yield: Org.Lett., 5 (8), 2003, 1167-1170
PPh3/trichlorocyanuric acid: Synth.Commun., 32 (17) 2002, 2691-2694
Trichlorocyanuric acid/DMF/DCM, 92% yield: Org.Lett. 4 (4), 2002, 553-556
SOCl2/benzotriazole, 100% yield: Syn.Lett., 11, 1999, 1763-1765
Potassium carbonate/chlorotrimethylsilane, 91% yield: Synthesis, 4, 1983, 314-315 [Article in German].


Cinnamyl bromide from cinnamyl alcohol with HBr

J.Amer.Chem.Soc. 38, 1916, 1076
Chem.Ber., 58, 1925, 280
J.Org.Chem., 25, 1960, 1719-1722
J.Chem.Soc., 97, 1910, 426
Chem.Ber. 39, 1906, 2553.


Cinnamyl bromide from cinnamyl alcohol using other sources of bromide

PBr3: Chem.Ber. 43, 1910, 178
NaBr/BF3/acetonitrile (79% yield): Tetrahedron Lett., 26 (32), 1985, 3863-3866
Hexamethyldisilane/pyridinium bromide perbromide (100% yield): J.Org.Chem. 45 (9), 1980, 1638-1639
Chlorotrimethylsilane/lithium bromide (93% yield): J.Org.Chem., 45 (9), 1980, 1638-1639.


Cinnamyl iodide from cinnamyl alcohol with HI

Justus Liebigs Ann. Chem. 479, 1930, 211, 248.


Cinnamyl alcohol to propenylbenzene with HI

Chem.Ber., 11, 1878, 671.


Reduction of cinnamyl bromide to propenylbenzene

NaBH4/PTC, 80% yield: J.Org.Chem., 46 (19), 1981, 3909-3911
Lithium tri-sec butyl borohydride, 99% yield: Bull.Chem.Soc.Jpn., 58 (2), 1985, 789-790
Zn(BH4)2, 60% yield: Angew.Chem., 95 (7), 1983, 568-569 [Article in German]
LiAlH(i-Bu)2(n-Bu), 95% yield: J.Org.Chem. 49 (10), 1984, 1717-1724.



clearly_not_atara - 7-5-2016 at 15:50

Generalizing the reactivity of cinnamyl alcohol to cinnamaldehyde is a fool's errand. Most reductions of an alpha,beta-unsaturated aldehyde will attack the C=C bond before the C=O bond. This is because the reaction is really a 1,4 conjugate reduction.

If cinnamaldehyde were reduced to allylbenzene by Zn/HCl -- the cheapest reducing agent around -- someone would have noticed.

Chemi Pharma - 7-5-2016 at 16:26

Clearly, in organic chemistry reactions not ever the products follow what to be expected. Read the article linked below and you will see that cinnamaldehyde reduced with LAH can give propenyl benzene, or propyl benzene, according the manner you conduct the reaction. "add LAH to cinnamaldehyde and you get just reduction of the carbonyl group; invert the order of addition and you additionally get reduction of the double bond", the researcher claims:

http://www.ch.imperial.ac.uk/rzepa/blog/?p=13688

CuReUS - 7-5-2016 at 21:55

I remember reading somewhere that if a phenyl ring was attached to the b-carbon of an a,b unsaturated carbonyl compound(like cinnamaldehyde),there would be reduction of the double bond along with reduction of the carbonyl group to alcohol using LiAlH4

[Edited on 8-5-2016 by CuReUS]

Chemi Pharma - 8-5-2016 at 03:25

I apologize. Cinamaldehyde reduction with LAH gives hydrocinnamyl alcohol or phenylpropyl alcohol, nor propenyl benzene or propyl benzene like i wrote. See:

F.A. Hochstein, and W.G. Brown, "Addition of Lithium Aluminum Hydride to Double Bonds", J. Am. Chem. Soc., vol. 70, pp. 3484-3486, 1948. http://dx.doi.org/10.1021/ja01190a082

But the question is: Why some experiments, like Psychokitty did (as posted above) with activated zinc and HCL reduces the C=O group to alkane, and don't touch the C=C bond ???

Do Clemensen reduction works with cinnamaldehyde reducing the C=O group to CH2 preserving the C=C bond affording propenyl benzene and allyl benzene like Cinnamyl alcohol does ???

My Lab is still under construction and i enjoy if someone could test this and post the results here.

NitreRat - 9-5-2016 at 11:06

Whilst I don't think this thread deserves as much attention as it has, I stumbled upon this paper earlier which deals with the exact problem you're discussing and almost completely OTC: http://www.organic-chemistry.org/abstracts/lit2/441.shtm

Turn your fruity flavored Ethyl cinnamte into Diydrocinnamyl alcohol in just 24 hours.

Chemi Pharma - 10-5-2016 at 08:07

Sorry Nitrerat but i don't see any relationship between what you have posted and what we are discussing here.

Cinnamyl esther to cinnamyl alcohol could be afforded by too many routes.

What is on discussion here is why cinnamyl alcohol suffers clemensen reduction to propenyl benzene and allyl benzene and cinnamaldehyde doesn't. I claim that it works, but other members think the C=C bond will be reduced as well, affording propylbenzene.

I wonder if you think about this matter and bring references, pratical results or a solid study that validates or refute this theory.

NitreRat - 10-5-2016 at 09:26

You're right Chemi Pharma, my apologies.

But perhaps I can offer a little help. I imagine the differences in the reductions is because the of all the resonant forms cinnamaldehyde can take on.

NHjHjZ3.jpg - 14kB

I don't know if a Clemmensen reduction is completely selective of just reducing carbonyls to hydrocarbons. I don't remember the reference but I'm sure in some cases it can reduce carbonyls to alkenes.

[Edited on 5/10/2016 by NitreRat]

NitreRat - 10-5-2016 at 10:19

According to this paper I found in the Rhodium archives A Modified Clemmensen Reduction Procedure for Conversion of Aryl Ketones Into Aryl Alkenes

Quote:

...While this procedure was successful with many compounds, variations were devised in order to widen the applicability of the reduction.2-4 In some instances the formation of alkenes was observed...


I don't have access to any of the papers it references though so this might be completely useless

[Edited on 5/10/2016 by NitreRat]