Author Topic: The most interesting CTH reaction ever documented?  (Read 24827 times)

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  • Guest
Another way to methaephetamine
« Reply #80 on: May 03, 2004, 10:07:00 PM »
Before attempting a simultaneous reduction of both the azido and acetoxy functions of 1-acetoxy-1-(5-indanyl)-2-azidopropane, I decided to test the reduction of 1-acetoxy-2-methylamino-1-phenylbutane to see if the patent worked as described.

This was my first CTH reduction, which may in part explain the yields. But the point is: it works.

It would be great if someone more experienced could give this a try to see how far we can push the yields. The procedure works beautifully and should tolerate far more functional groups (e.g. aryl ethers) than the over-zealous HI/P reduction.


1-acetoxy-2-methylamino-1-phenylbutane HCl

9.7g (45mmol) 2-methylamino-1-phenyl-1-butanol HCl1
5.3ml (56mmol) acetic anhydride
Acetic acid

The aminoalcohol HCl was stirred in 20ml acetic acid at 50oC to create a uniform slurry. Acetic anhydride was added in one portion and the temperature was increased to 80oC, by which point the salt had fully dissolved. Stirring was continued at 80-85o for 2 hours then the still hot solution was diluted with 60ml THF,2 causing a heavy precipitate to fall out of solution almost immediately. The flask was allowed to cool to room temperature then left in the freezer overnight. The precipitate was isolated by filtration, rinsed with THF and dried under vacuum.

Yield: 9.2g (35.6mmol, 79%)3


9.2g (35.6mmol) 1-acetoxy-2-methylamino-1-phenylbutane HCl
9.0g (107mmol) potassium formate
250mg 10% Pd/C

The O-acetoxy compound from the previous step was stirred with 25ml water at 50oC until all had dissolved. The catalyst was added and the temperature was increased to 70oC. A solution of HCOOK in 10ml water was then added over 5 minutes. Gas evolution was noted almost immediately. The reaction was stirred at 70-75oC for 2 hours then allowed to cool. The solution was basic at this point so concentrated HCl was added to bring the pH down to 1. A small amount of celite was added with stirring, then the slurry was filtered and the filtrate washed with 2x50ml DCM. The filtrate was then made strongly basic with NaOH solution and the liberated freebase taken up in 2x50ml ether. The extracts were washed with 2x50ml brine and dried over magnesium sulfate. Removal of the solvent afforded the title product as a clear, colourless oil.4

Yield: 2.9g (18mmol, 51%)5

Comments and references

1 This was the remaining intermediate from

Post 475219

(Kinetic: "Benzene -> methaephetamine", Novel Discourse)
2 The precipitate was very fine and difficult to filter. Heptane is recommended in the patent as the precipitate is granular, making this process easier.
3 Some of the product may well still be in solution at this point. It should be possible to remove the acetic acid and excess acetic anhydride under vacuum instead of adding a further solvent to cause precipitation. Unreacted, N-acetylated, or N,O-diacetylated products should not interfere in the CTH reduction and will be removed during the final workup.
4 100mg of which was bioassayed 1 1/2 hours ago. Warm and fuzzy feelings all round.
5 Migration of the acetyl group to the nitrogen is probably the most significant factor in the low yield for the reduction step. According to

the migration will happen more readily with the threo- (pseudo) isomer. The starting aminoalcohol in my case appears to be mainly this isomer, whereas the patent deals with the erythro- isomer, which is less prone to migration.


  • Guest
Someone retrieve those acetic acid papers...
« Reply #81 on: May 26, 2004, 03:00:00 AM »
What can I say, Kinetic, you are a great researcher doing such an interesting work, always making routes so simple and brilliant, what an example...

Can someone be kind to get the papers mentioned in

Post 499517

(Kinetic: "Catalytic Transfer Information", Novel Discourse)

Cu(NO3)2*3H2O/AcOH in 90% yield after 2 hours: Synth.Commun.; 28; 11; 1998; 1923-1934.

SiO2/AcOH in DCM giving an 88% yield after 4 hours: Synth.Commun.; 26; 14; 1996; 2715-2722.

Sodium borohydride/AcOH at 85oC - 90oC for 3 hours (unspecified yield): Indian J.Chem.Sect.B; 19; 9; 1980; 822-823.

Don't even have to mention that acid chlorides should work as good as anhydrides in this prep. However, H2SO4 is a nice idea for catalyst, polyphosphoric and tosic should also be given a chance.

I really like this route for getting rid of benzylic -OH, esp for possibilty of use on alkyloxylated ring due to mildness. Good work and well written write-up Kinetic!  ;)


  • Guest
most weird acylation reagent
« Reply #82 on: May 26, 2004, 04:55:00 PM »
For Ganesha:

Sodium Borohydride - Carboxylic Acid Systems - A new Method of Acylation of Alcohols, Phenols & Thiophenols
M. Prashad, V. B. Jigajinni, and P. N. Sharma
Ind. J. Chem.
, 19B, 822-823 (1980).

   A number of alcohols was acylated by heating in a solution of NaBH4 in AcOH or EtCOOH at 85-90 °C. Yields of acylated derivatives were invariably better with primary alcohols in comparison to secondary alcohols. Attempts to acylate tertiary alcohols were unsuccessful. Acylation of phenols and thiophenols was observed at the reflux temperature. A plausible mechanism of this acylation includes the formation of a dehydrating agent (B(OCOR)3) from NaBH4and RCOOH.


  • Guest
More acetylation papers
« Reply #83 on: June 11, 2004, 09:06:00 PM »
What can I say, Ganesha; you are a master of the art of flattery. Here are the remaining papers I now feel obliged to provide:

Selective Acetylation of Primary Alcohols: Acetyl and Formyl Transfer Reactions With Copper (II) Salts
N. Iranpoor, H. Firouzabadi and M. A. Zolfigol
Synthetic Communications
, 28 (11), 1923-1934 (1998)

Carboxylic Acids Supported on Silica: A Smooth Acylating Agent for Alcohols
Maria da Graca Nascimento, Sandra Patricia Zanotto, Marivania Scremin and Marcos Caroli Rezende
Synthetic Communications
, 28 (14), 2715-2721 (1996)


  • Guest
O-acetylation with anhydrides and MgBr2
« Reply #84 on: August 01, 2004, 07:48:00 PM »
The following paper confirms that acetylation of aryl nitroalcohols is indeed possible, and details the acetylation of 1-phenyl-2-nitroethanol to give its O-acetyl ester in 95% yield. The key seems to be the use of acidic catalysis (5-10% MgBr2) which reduces the chance of dehydration:

Magnesium Bromide Catalysed Acylation of Alcohols
Sunil V. Pansare,* Mahesh G. Malusare and Anand N. Rai
Synthetic Communications
, 30(14), 2587-2592 (2000)

Magnesium bromide is an efficient cataylst for the acetylation and benzoylation of a variety of primary and secondary alcohols with the respective acid anhydrides at ambient temperature. Acetylation of tertiary alcohols requires subambient temperature to suppress competing dehydration. Coordinating solvents retard the acylation process.


  • Guest
O-Acetylation of Nitroalcohols with AcOH & KF
« Reply #85 on: August 08, 2004, 08:37:00 PM »
Potassium Fluoride Assisted Selective Acetylation of Alcohols with Acetic Acid
J. W. John Bosco, B. Rama Raju, Anil K. Saikia, Synth. Commun. 34(15), 2849-2855 (2004)


Potassium fluoride promotes the acetylation of primary and secondary alcohols with acetic acid in excellent yield. Phenols are not affected under this reaction conditions. The groups like double bond, chloro, methoxy, benzyloxy, thiol, and nitro remain unaffected.

It was observed that primary and secondary alcohols can be acetylated readily with a very high yield and neither fluorinated nor eliminated products were identified. This is due to the fact that the hydrogen bonding between fluoride ion and hydroxyl group of acetic acid reduces nucleophilicity and basicity of the fluoride ion. In the case of tertiary alcohol, the reaction becomes sluggish and takes longer time with the formation of elimination products and the reaction ends up with a low yield. However, phenols are not affected and alcoholic group can be selectively acetylated. More importantly, hydroxyl groups residing in chiral center could be acetylated with retention of configuration. The groups like double bond, chloro, nitro, methoxy, benzyloxy, thiol, etc. remain unaffected. Moreover, the reaction does not require any dry glassware and inert atmosphere. The operation is quite simple, because the dehydrating systems like Dean–Stark apparatus or agent like molecular sieve is not necessary. The purification process is very simple, as both potassium fluoride and acetic acid are water-soluble and final product does not require any tedious purification procedures.


  • Guest
Acylation of Amino Alcohols
« Reply #86 on: August 08, 2004, 09:18:00 PM »
Kinetic  Hoping not to be off topic , my question is on a particular Amino alcohol, Phenylalaninol,  once acylated with any of the great methods listed on this thread , many posted by you, the reduction to a hydrocarbon could be ......?  I posted some time ago

Post 516488

(java: "Removal of Acyl protecting Groups....", Newbee Forum)
on de-acylation which may or may not apply here , however I don't know if the reduced product would be the respective hydrocarbon.

Another question would any of this acylation methods acylate the amine group as well as the -OH  of the before mentioned alcohol,  so that when the reduction occurs the amine would be alkylated and the alcohol reduced to the hydrocarbon?

Maybe the answer is here but just looking too hard...that happens


  • Guest
Deprotection of acetyl alcohols=hydrolisys
« Reply #87 on: August 08, 2004, 10:07:00 PM »
Java, before Kinetic answers your question on the reduction, I just want to warn you that the paper you mention in

Post 516488

(java: "Removal of Acyl protecting Groups....", Newbee Forum)
is about hydrolisys and not about reduction like you seam to imply. That means that you would get your phenylalaninol back from O-acetyl-phenylalaninol and not amphetamine.

BTW, to reduce the OH in phenylalaninol you have to esterify it with an acid that forms a much better leaving group than acetyl (tosyl, halides, mesityl, triflate etc).


  • Guest
Clarification of de-acylation of Amino Alcohols
« Reply #88 on: August 08, 2004, 11:44:00 PM »

I posted some time ago 

Post 516488

(java: "Removal of Acyl protecting Groups....", Newbee Forum) ....", Newbee Forum) on de-acylation which may or may not apply here , however I don't know if the reduced product would be the respective hydrocarbon.

Nicodem're correct ,sorry if I caused some confusion...

is about hydrolisys and not about reduction like you seam to imply

but pehaps my wishful thinking implied more than just "may or may not apply here".

As to acylating the OH  maybe perhaps it would be an easier leaving group that can be hydrogenated with Pd and get the respective hydrocarbon as Kinetic speculated in the application of acylating amino alcohols . I guess I will go back and read the whole thread again to clear this point.

By the way there is a method of removing the acetyl group in Phenyalanine as mentioned in...

Post 523004

(java: "Hydrogenolysis of Phenylalaninol.....", Serious Chemistry)

and methylating the amine