Phenylalanine to amphetamine or N-methylamphetamine

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Author Topic: Phenylalanine to amphetamine or N-methylamphetamine (Read 4475 times)
Assyl Fartrate
Re: Phenylalanine to amphetamine or N-methylamphetamine
« Reply #80 on: March 10, 2012, 08:34:18 AM »
Here's an idea:
Make an ester from phenylalanine.
Mannich reaction of the ester: formalin, ammonia, HCl.
Heat to deaminate.
Basify to break the ester and pull into xylene or mineral oil (if it'll be soluble in mineral oil) and heat to 300C to
decarboxylate. Alternatively, it could be done with spearmint oil catalyst under much milder conditions, but then you
have to worry about the Pictet Spengler reaction. Who knows if those products would be toxic.
Then, reduce with sodium dithionite (rust stain remover)... amphetamine.
Might be workable...
EDIT: Nevermind... obvious oversight... the center is not going to be able to deaminate with the carboxyl still there as
it'd result in a pentavalent carbon... and if the carboxyl group is gone, deamination wouldn't be possible.
« Last Edit: March 10, 2012, 06:15:34 PM by Assyl Fartrate »
Someone Who Is Me

atara
Re: Phenylalanine to amphetamine or N-methylamphetamine
« Reply #81 on: March 11, 2012, 12:33:08 AM »

Perhaps phenylalaninol would dehydrate and hydrolyze in acidic solution to form P2P in the same
manner that ephedrine does.

Probably, but the reaction will be slower than with ephedrine. Maybe with concentrated H2SO4. Of course, where
are you getting phenylalaninol is the real question.

wasabi
Re: Phenylalanine to amphetamine or N-methylamphetamine
« Reply #82 on: June 11, 2012, 12:27:19 AM »
I've seen talk elsewhere of going to benzyl cyanide and ultimately P2P.
I know it's a bit of a waste of the gift that is PA but I've searched and haven't seen the idea discussed here.

lugh
Re: Phenylalanine to amphetamine or N-methylamphetamine
« Reply #83 on: June 11, 2012, 01:33:46 AM »

I've seen talk elsewhere of going to benzyl cyanide and ultimately P2P.
I know it's a bit of a waste of the gift that is PA but I've searched and haven't seen the idea discussed
here.

You need to work some more on your search skills:
http://127.0.0.1/talk/index.php/topic,839.msg10047.html#msg10047

Chemistry is our Covalent Bond

wasabi
Re: Phenylalanine to amphetamine or N-methylamphetamine
« Reply #84 on: June 11, 2012, 09:10:18 AM »
Yes, I later found that thread, hiding away in "Other Chemistry" no less!
Regardless, should it really be omitted from the sticky just because it has been addressed to some extent
elsewhere?
Perhaps the first post of this thread could be tidied up to include an index of all routes discussed within.

wasabi
Re: Phenylalanine to amphetamine or N-methylamphetamine
« Reply #86 on: June 11, 2012, 04:57:22 PM »
Thank you.
I will now go into wasp hibernation (whether that exists or not) and will not be seen again until I can produce
something not "beaten to death"

phaseolus
Re: Phenylalanine to amphetamine or N-methylamphetamine
« Reply #87 on: February 16, 2013, 06:35:08 PM »
Kolbe electrolysis of Phe with acetic acid theoretically should give amphetamine (among tons of by products). Kolbe
is a pretty well known named reaction; I think this was even on the Hive. Or any kind of decarboxylative radical
coupling could do it, with a shitload of Phe-Phe dimerization. Might still be worth it given how cheap and innocent
Phe and AcOH are compared to amphetamine.

Assyl Fartrate
Re: Phenylalanine to amphetamine or N-methylamphetamine
« Reply #88 on: February 16, 2013, 09:44:53 PM »
The Kolbe decarboxylation doesn't work with alpha-amino acids.
Someone Who Is Me

phaseolus
Re: Phenylalanine to amphetamine or N-methylamphetamine
« Reply #89 on: February 17, 2013, 02:10:36 AM »

The Kolbe decarboxylation doesn't work with alpha-amino acids.

Didn't know that. Oh well.

Phe can be oxidized (this can be done electrolytically) into phenylacetonitrile. It doesn't take much imagination to
figure out what you could do with DOPA, the 3,4-dihydroxy derivative of Phe.

Sedit
Re: Phenylalanine to amphetamine or N-methylamphetamine
« Reply #90 on: February 17, 2013, 05:21:11 PM »

The Kolbe decarboxylation doesn't work with alpha-amino acids.

It does if the Amine is protected. There is also the possibility of it being converted to an electron Withdrawing group
which would cause yields to sky rocket.
There once were some bees and you took all there stuff!
You pissed off the wasp now enough is enough!!!

thepasta
Re: Phenylalanine to amphetamine or N-methylamphetamine
« Reply #91 on: February 19, 2013, 05:28:48 PM »
Welcome. I'm interested in the synthesis of nitriles by oxidation of primary amines (for research purposes), and I
have several article requests. I am seeking articles that build from techniques involved in this article:
Shono, T., Matsumura, Y., & Inoue, K. (1984). Electroorganic chemistry. 87. Indirect electrooxidation of amines to
nitriles using halogen ions as mediators. Journal of the American Chemical Society, 106(20), 6075-6076.
The above study reports, “In a typical procedure, a solution of octylamine (517 mg, 4 mmol) in methanol (30 mL)
containing NaBr (618 mg, 6 mmol) was placed in a cell equipped with a carbon rod cathode (8 mm phi) and a
platinum anode (2 x 2 cm). The distance between two electrodes was 3 mm and no diaphragm was used. A
constant current (0.3 A, 75 mA/cm^2, terminal voltage 5-7 V) was passed through the cell at about 10 degrees C
with external cooling. After 8.6 F/mol of electricity was passed, the yield (95%) of heptyl cyanide was determined by
GLC method. Then, solvent was evaporated in vacuo at room temperature, and the residue was poured into water.
The product, heptyl cyanide, was extracted with CH2Cl2 and isolated by bulb-to-bulb distillation (400 mg, 3.20
mmol, 80%)…The reaction of oxidized active species “Br+” with RCH2NH2 in the presence of bases formed by
cathodic reaction will yield bromoamines (RCH2NHBR) as the first intermediates, which are then converted to
imines (RCH=NH) through dehydrobromination. The intermediates (RCH=NH) will again react with (Base) to yield
nitriles (RCH2NHBr).” They also reported, “The electrooxidation of phenylalanine under our reaction conditions gave
phenylacetonitrile (80%).”
These are the articles I am looking for:
Yamazaki, S. (1997). A Simple and Convenient Method for the Synthesis of Nitriles by Oxidation of Primary Amines
with NaOCL in Ethanol. Synthetic Communications, 27(20), 3559-3564. DOI: 10.1080/00397919708007077

Rajender Reddy, K., Uma Maheswari, C., Venkateshwar, M. , Prashanthi, S., Lakshmi Kantam, M. (2009). Catalytic
oxidative conversion of alcohols, aldehydes and amines into nitriles using KI/I2-TBHP system. Tetrahedron Letters,
50(18), 2050-2053.
Okimoto, M., Takahashi, Y., Numata, N., Nagata, Y., & Sasaki, G. (2005). Electrochemical Oxidation of Benzylic
Amines into the Corresponding Imines in the Presence of Catalytic Amounts of KI. Synthetic Communications,
35(15), 1989-1995. DOI: 10.1081/SCC-200066648
Fleischmann, M., Korinek, K., Pletcher, D (1971). The oxidation of organic compounds at a nickel anode in alkaline
solution. Interfacial Electrochemistry, 31(1), 39-49.
Thanks in advance.

RoidRage
Re: Phenylalanine to amphetamine or N-methylamphetamine
« Reply #92 on: February 19, 2013, 08:45:52 PM »
Here are two of the papers you're requesting.
Electroorganic chemistry. 87. Indirect electrooxidation of amines to nitriles using halogen ions as
mediators.
Shono, T., Matsumura, Y., & Inoue, K. (1984).
Journal of the American Chemical Society, 106(20), 6075-6076.
DOI: 10.1021/ja00332a052
Catalytic oxidative conversion of alcohols, aldehydes and amines into nitriles using KI/I2-TBHP system
Rajender Reddy, K., Uma Maheswari, C., Venkateshwar, M. , Prashanthi, S., Lakshmi Kantam, M. (2009).
Tetrahedron Letters, 50(18), 2050-2053
DOI: 10.1016/j.tetlet.2009.02.057
I don't have access to the last one, and I'm not able to remove the institution name I'm downloading from in the
''Synthetic communications'' papers so I'm evidently not posting them. If nobody else ends up posting the papers, I'll
check to remove those infos from the publications. I just don't have the time to do it right now.

phaseolus
Re: Phenylalanine to amphetamine or N-methylamphetamine
« Reply #93 on: February 20, 2013, 12:03:54 AM »
Here are the other two papers. I exported the PDF to images and manually cropped out the institution name bullshit.
God knows what other identifying info is hidden in the PDF data. Greedy fucks want everyone to pay.
P.S. Look at page 3561 of the Yamazaki paper. Good to see that piperonyl amine [1-amino-3,4-(methylenedioxy)-1phenylmethane] can be oxidized to piperonyl cyanide [1-cyano-3,4-(methylenedioxy)-1-phenylmethane] in 95% yield
with grocery store reagents .

« Last Edit: February 20, 2013, 12:16:07 AM by phaseolus »

thepasta
Re: Phenylalanine to amphetamine or N-methylamphetamine
« Reply #94 on: February 24, 2013, 10:06:20 AM »
RoidRage, I was excited by the results reported by Rajender et al., until I realized that TBHP is an organic peroxide
(tert-Butyl hydroperoxide). TBHP has a flash point equal to its boiling point of 100 F, and it undergoes spontaneous
self-accelerating decomposition at 200 F. It's also genotoxic. That just sounds entirely like a bad idea. The
electrooxidation article (Shono et al.), however, still appears extremely useful. Sodium bromide, methanol, and the
carbon & platinum-plated titanium electrodes are inexpensive and readily available.
Phaseolus, thank you for finding those studies and extracting the images. I processed your images with optical
character recognition software and generated searchable PDFs from them. I noted that the Yamazaki paper
reported that "benzyl cyanide... is unstable under the reaction conditions due to the acidity of its benzylic protons." I
find this comment fascinating because Shono et al. reported conditions at least as basic if not more so; yet, Shono
reported no problems with stability or isolating the resulting phenylacetonitrile. Does anyone have any idea why
Yamazaki may have had a problem with stabilizing/isolating the final product? What side reaction is attacking the
benzyl cyanide?

zgoat65
Re: Phenylalanine to amphetamine or N-methylamphetamine
« Reply #95 on: February 24, 2013, 06:31:41 PM »
Here is a procedure that has worked for SWIz. From phenylalanine to PAA. This can bee scaled up to 500g
successfully in a 5gal bucket with 5kg of ice
Put 300g phenylalanine in a stainless steel bucket with ice bath and overhead stirring, add 1500ml DH2O and 50g
NaOH.
Once mixed together add Ice and 320g TCCA in 15g portions, make sure there is always ice present.
halfway into the TCCA addition add another 25g NaOH, when its all added let stir for 2 more hours.
Mix in 3-400ml 33% Hcl, add 1lt of DCM and stir for 20 mins.
If for some reason the hydrolysis cant be done instantly i'd recomend storing the dcm extraction in a HDPE bucket
with a couple of litres of water on top. This seems to lessen the tar formation.
collect DCM. DCM is washed 2x with 250ml 10% NaOH and 2x with 5lt water.
evap in a large open mouth vessel OUTSIDE. you really don't wan't to be breathing the fumes at this point.
take remaining brown liquid and add to 5lt RBF in water bath with rapid stirring, add 700ml 35% Hcl and set up for
reflux @ 55C for 1-1.5h
add 700ml DH2O and set temp to 85C for 4-5hours.
once cooled collect dirty PAA crystals and return to clean RBF.
add 500ml water and enough Na2CO3 until PAA dissolves, then add 200ml xylene and stir for 30 mins.
sep off xylene keep water and return to clean RBF, add Hcl and presto, instant fluffy white PAA ~120g

Credit goes to cactus for the actual write-up, but this procedure works as it is written.
If you build a man a fire, he'll be warm for a day.
If you set a man on fire, he'll be warm for the rest of his life

phaseolus
Re: Phenylalanine to amphetamine or N-methylamphetamine
« Reply #96 on: March 05, 2013, 05:12:39 AM »
Potentially novel approach. Warning: never actually performed.

Assyl Fartrate
Re: Phenylalanine to amphetamine or N-methylamphetamine
« Reply #97 on: March 05, 2013, 05:50:41 AM »
You have Br2 around an amine - it'll probably attack this. Seems unlikely to work. Was the idea to eliminate HX from
that product so you'd have an imine to hit with a Grignard? You'd lose a full equivalent of the Grignard to HX (HBr in
this case), and then it'd deprotonate the imine, costing you a second equivalent, and you'd be left with something a
lot less electrophilic and reactive, so it may not go at all.
« Last Edit: March 05, 2013, 05:56:30 AM by Assyl Fartrate »
Someone Who Is Me

phaseolus
Re: Phenylalanine to amphetamine or N-methylamphetamine
« Reply #98 on: March 05, 2013, 06:54:23 AM »
Okay, Grignard won't work; should have looked it up first. MeLi, MeCuLi, MeNa, MeK, and a couple other metalated
methanes will couple with alkyl halides. Plus it's intuitive seeing how electrophillic the terminal carbon is. How
exactly will bromine attack the amine?
Oh wow, just looked over the thread in the "topic summary" and saw someone else had the idea of Hunsdiecker on
phenylalanine. I wasn't trying to copy, I swear.

Assyl Fartrate
Re: Phenylalanine to amphetamine or N-methylamphetamine

« Reply #99 on: March 05, 2013, 08:07:06 AM »
Your alkyl bromide simply isn't a stable compound. It will undergo spontaneous elimination of HBr and give you an
imine.
Someone Who Is Me
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