Author Topic: Alcohols to Amines w/ a 60-63% theoretical yield .  (Read 10953 times)

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  • Guest
Alcohols to Amines w/ a 60-63% theoretical yield .
« on: September 20, 2004, 11:24:00 PM »
This post would be dear to Strike's heart if he ever sees it.  If you recall, he was very interested in the conversion of MDP2Pol to honey, but his ideas never seemed to make it off the ground or resonate with anyone else really. 

That is, until now. 

Now, for a quick synthetic overview followed by the groundbreaking, reportedly well-established reaction specifics and then finally some references and closing remarks: 

In this reaction, compounds containing a secondary alcohol functional group are converted to secondary amines with stereochemical inversion. 

The example given is the conversion of trans-2-(2-propenyl)cyclopentanol to cis-2-(2-propenyl)cylcopentylamine, but soon the bees will be busy applying it to
1-(3,4-methylendioxyphenyl)-2-propanol, 1-(2,4,5-trimethoxyphenyl)-2-propanol, 1-(3,4,5-trimethoxyphenyl)-2-propanol, 1-(3-methoxy-4,5-methylenedioxyphenyl)-2-propanol and maybe even some good 'ole 1-phenyl-2-propanol. 

All of these chemicals, save for the last one, can be prepared from their respective essential oils via hyroxylation using age old the Hg(OAc)2 oxymercuration/demercuration reaction to add a hydroxyl group to the Markonikov carbon of the oils' respective allylic or propenylic alkyl side chains. 

Best of all, this method has nothing to do with the perpetually failing, but tenacious, almost epic HBr and NH3 "pipe bomb" method so prevalent on the net during the mid 1990s.


B.  cis-2-(2-propenyl)cyclopentylamine:  A 1000 mL, 3 necked, RB flask equipped with a magnetic stirring bar, 2 addition funnels, and a stopcock is charged with 41.5 g (158 mmol) of triphenylphosphine (see Note 9) and 23.3 g (158 mmol) of phthalimide (see Note 10).  The system is evacuated and placed under an argon atmosphere.  To one of the addition funnels is added 20.0 g (158 mmol) of trans-2-(2-propenyl)cyclopentanol; 27.5 g (158 mmol) of diethyl azodicarboxylate (see Note 11) is added to the other one.  500 mL of tetrahydrofuran (see Note 12) is added to the flask via a cannula, and stirring is begun.  The substrate and diethyl azodicarboxylate are simultaneously and slowly added dropwise over the course of about 30 minutes (see Note 13), with stirring; the solution turns clear and yellow (see Note 14).  The reaction is then allowed to proceed for 2 days at room temperature; then the solution is transferred to a 1000 mL, one-necked, round bottomed flask, and the solvent is removed under reduced pressure to leave a white-yellow semisolid.  A magnetic stirring bar is added to the flask and the semisolid is taken up in 250 mL of reagent grade methanol to which 10.1 g (316 mmol) of hydrazine (Note 15) is added.  A reflux condenser is attached to the flask, stirring is begun, and the system is brought up to its reflux level (see Note 16).  A large amount of clumpy white solid forms in a yellow-to-orange solution.  After 4 hours of refluxing, the solution is allowed to cool to room temperature; a mixture of 20 mL of hydrochloric acid (see Note 17) and 65 mL of methanol, and the system is refluxed overnight.  The resulting reaction mixture is filtered to remove the precipitate, and the solvent is removed under reduced pressure to yield a white to pink solid, which is taken up in 800 mL of water and 28 mL of hydrochloric acid.  The solution is then filtered, and the solid washed with water (2 x 200 mL) and 20 mL of hydrochloric acid.  The liquids are combined, placed in a 2000 mL separatory funnel, and washed with chloroform (3 x 250 mL), and ethyl ether (1 x 250 mL).  The aqueous layer is transferred to a 2000 mL Erlenmeyer flask and cooled in an ice-water bath.  A saturated aqueous sodium hydroxide is used to make the solution basic, to a pH level of approximately 14, whereupon the solution turns dark olive green.  The basic solution is extracted with ethyl ether (10 x 250 mL or by continous extraction overnight) and the combined organic layers are dried over a mixture of anhydrous sodium sulfate and anhydrous potassium carbonate.  Filtration and solvent removal at atmospheric pressure yields a green-yellow oil.  Distillation (52 to 58 C, 8 to 11 mm Hg) gives cis-2-(2-propenyl)cyclopentylamine (11.8 to 12.5 g, 60 to 63% yield) as a clear, colorless oil (see Note 18).

Notes 9 through 18:

9.  Anhydrous triphenylphosphine is purchased from CENSORED and is used without further purification.

10.  Phthalimide, 98%, is also purchased from CENSORED and used without further purification.

11.  Diethyl azodicarboxylate is purchased from CENSORED and is also used without further purification.

12.  THF is freshly distilled from sodium/benzophenone ketyl at atmospheric pressure under nitrogen gas.

13.  Too rapid a rate of addition may cause the solution to boil over.

14.  The solution does not become homogenous until it is warmed by the heat of the reaction.

15.  Anhydrous hydrazine, greater than or equal to 97% purity, is purchased from CENSORED and is also used without further purification.

16.  ACHTUNG! Because of the dangerous nature of hydrazine, a safety shield should always be in place during this reaction.

17.  ACS reagent hydrochloric acid is purchased from CENSORED and is used without further purification.

18.  The spectral properties of this compound are as follows.........

Overall this compound is, in general, symbolically rendered by the following equation.

R-OH + phthalimide + EtO2CN=NCO2Et + Ph3P --> N2H4 -->
R-NH2, where R is a secondary carbon and an inversion of chirality occurs.  In our cases, racemates--the desired form of MDMA et al--will end up being produced.

Submitted by Louis S. Hegedus, Michael S. Holden, and James M. McKearin.  Checked by Christoph Nubling and Ian  Fleming.

Only the parts of this paper, about a fourth of it, which was deemed to be germane to the production of amphetamines from phenyl-2-propanols has been reproduced here for your delight and has been taken from the following source:

_Organic Synthesis_, CV 7, 501, "cis-N-tosyl-3-methyl-2-azabicyclo[3.3.0]oct-3-ene."

The Discussion section affirms that the "conversion of an alcohol to an amine with inversion" (see Mitsunobu, O.; Wada, M.; Sano, T. _J. Am. Chem. Soc._, 1972, 94, 679) is by now "a standard synthetic process."

I really hope this is the first time you guys have seen this reaction.  I'm sure you'll let me know either way though.


  • Guest
DEAD in the water
« Reply #1 on: September 20, 2004, 11:46:00 PM »
I seem to have started a lot of my recent posts with the word 'unfortunately', so I will try to refrain here.

Have you seen the price of DEAD (diethyl azodicarboxylate)? This is why the idea is not of any practical use for us, I am sorry to say. The transformation of alcohols to amines (and other functional groups using the same conditions; see

Merck Index #264. Mitsunobu Reaction

( for a very brief outline, and some references) is the Mitsunobu reaction, which has been discussed here before.

Fortunately, :)  there are related and better alternatives. See

Post 407575

(Chimimanie: "Well chief if you ask me", Novel Discourse)
for a start, and read the rest of the thread for some more insight.

Edit: I will take a look at the Merck Index references tomorrow: if any of them are of interest, I will post the articles.


  • Guest
Alcohols to Amines References......
« Reply #2 on: September 21, 2004, 12:14:00 AM »
Part of the references quoted on cattleproder post

Submitted by: Louis S. Hegedus, Michael S. Holden, and James M. McKearin
Published in Collective Volume 7 p. 501, Annual Volume 62 p. 48

Annual Volume 62

Stereospecific and Stereoselective Reactions :Preparation of Amines from Alcohol

OyoMitsunobu, Makoto Qada, Takashi Sano

Journal of the American Chemical Society Vol.94, No.2. , 679, 1972

(not available still looking..if you have it , post it)


  • Guest
Mitsunobu reaction - JACS article
« Reply #3 on: September 21, 2004, 01:26:00 AM »
Here is the JACS 1972 article mentioned by Cattleprodder and not found/requested by Java.

Stereospecific and stereoselective reactions. I. preparation of amines from alcohols
(Oyo Mitsunobu, Makoto Wada, Takashi Sano)
J. Am. Chem. Soc. 1972, 94(2) p. 679-680



  • Guest
Various Refs on DEAD & Mitsunobu Chemistry
« Reply #4 on: September 21, 2004, 02:00:00 AM »
Mitsunobu Reagent [Triphenyl-phosphine(TPP) and Diethyl Azodi-carboxylate (DEAD)/Diisopropyl azodicarboxylate(DIAD)]
Satish Kumar Nune, Synlett 1221-1222 (2003)


(Free access!)
____ ___ __ _

Recently Modified Mitsunobu Reactions
Takashi Onozawa, Tokyo Kasei Chemicals Note #104

____ ___ __ _


____ ___ __ _

Preparation of Diethyl Azodicarboxylate (DEAD):

Organic Syntheses, CV 4, 411


Organic Syntheses, CV 3, 375

____ ___ __ _

Mitsunobu Reaction Bibliography:
Mitsunobu, O.; Wada, M.; Sano, T. J. Am. Chem. Soc., 1972, 94, 679.
R. F. C. Brown et al., Tetrahedron, 1994, 50, 5469.  (Methodology Development)
M. A. Poelert et al., Rec. Trav. Chim., 1994, 113, 355. (Usage)
H. Schedel et al., Tetrahedron Asymmetry, 2000, 11, 2125 . (Usage)
T. Watanabe et al., Chirality, 2000, 12, 346. (Mechanism)
O. Mitsunobu, Synthesis, 1981, 1-28. (Overview)
Hughes, D. L. Org. Reac. 1992, 42, 335-656. (Overview)


  • Guest
The price of DEAD.
« Reply #5 on: September 21, 2004, 10:02:00 AM »

I saw 100 g of DEAD listed for $173.80.  That's really not all that expensive; you could get at least on oz of honey from it.  Plus, the ability to have pure, certified MDA, 3,4-DMA, MMDA or TMA would justify throwing away 200 bucks in my opinion.  Many drugs are very expensive; for example, a bottle of thirty 20 mg Zyprexa tablets costs around $550 even at Super Wal-Mart.  To recoup your investment on buying the DEAD, all you would have to do is sell 10 caps at $20 each, which is only a gram of product.


  • Guest
A caveat regarding the Mitsunobu
« Reply #6 on: September 22, 2004, 02:31:00 AM »
Having had personal experience with the Mitsunobu reaction, I feel I should say a couple of things regarding its proposed use here.

First, it can be a touchy reaction to run. Anhydrous conditions are pretty much necessary for decent yields. Also, it doesn't necessarily work with all substrates; only experimentation would say for sure if it'd work in this case. Some fine-tuning is possible however. For example, DEAD isn't the only azodicarboxylate that will work here; there's DBAD (di-tert-butyl) as well as others.

Second, I don't think this reaction is well-suited for the average clandestine lab. I say this because the triphenylphosphine oxide formed in the reaction can be a real bitch to get rid of. In my experience, chromatography is always necessary to rid the product of the triphenylphosphine oxide, as well as the reduced azodicarboxylate by-product.

This isn't to say it might not be a very nice procedure if it works out. :) Could also consider making a mesylate from the MDP2Pol and displacing that with a suitable nitrogen nucleophile.