Author Topic: A really wet reductive alkylation  (Read 8658 times)

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XrLeap

  • Guest
hi Bandil, SWIM used 99+% IPA(reagent grade)...
« Reply #60 on: August 13, 2004, 05:11:00 AM »
hi Bandil,

SWIM used 99+% IPA(reagent grade) for his previous 5 aminations, all yielded 0% or extremely low yield(>10%). SWIM thought that it might be the NaBH4 and NaOH/methylamine salt were too "salty"(too concentrated), some white crystals often deposited at the bottom of the flask.

SWIM is now keen to find out what was the percentage of IPA used in those successful aminations(yielded more than 40%).

SWIM will give it another go, using aliquat 336, toluene as solvent method.


XrLeap

  • Guest
Re: Username: Barium Title: Hive Addict ...
« Reply #61 on: September 10, 2004, 10:02:00 PM »

Username:  Barium
Title:  Hive Addict
Subject:  PTC - imine reduction
Post:
It seems like there is no great benefit from anhydrous conditions anymore, unless one wants to squeeze out the highest possible yield.


1-(2,4-dimethoxyphenyl)-2-propanone, 250 mmol
Methylamine HCl, 375 mmol
NaOH, 375 mmol
Sodium borohydride, 290 mmol
Aliquat 336, 5 mol%
Toluene
Water


To a solution of the ketone in 100 ml toluene was added a solution of 25,3 g methylamine hydrochloride in 30 ml water followed by dropwise addition of 15 g NaOH dissolved in 40 ml water while stirring the mixture violently. The addition of NaOH was allowed to take five minutes so the liberated methylamine had time to react with the ketone instead of being pushed out of solution. When the addition was complete the mixture was stirred for another hour at room temperature. The aqueous layer was then separated and discharged.

To the toluene solution of the imine was added 4,8 g (12 mmol, roughly 5 mol%) Aliquat 336 followed by a solution of 11 g sodium borohydride in 35 ml water containing 25 mg NaOH1 in one portion. The mixture was violently stirred2 for one hour at 35?by slight warming. The residual borohydride was destroyed by addition of diluted acetic acid until gas evolution ceased and the aqeous layer separated and discharged. The toluene solution was extracted with 3x100 ml 10% HCl and the extracts combined, washed with 50 ml toluene and saturated with NaCl.
The aqueous solution was then made alkaline with NaOH until pH 14 was reached and extracted with 2x50 ml toluene. The combined toluene extractions was washed once with water and once with brine, and then dried over MgSO4. The solvent was removed at 40?@ 80 mbar leaving a slightly yellow oil weighing 48 g (92%). The hydrochloride was made by dissolving the free base in 250 ml EtOAc and adding 5N HCl/IPA until pH 4 was reached. Sparkly crystals formed immediately and was removed by filtration and dried to constant weight. Yield 45g 2,4-dimethoxy-N-methylamphetamine hydrochloride (2,4-DMMA)


1. NaOH is added to avoid the decomposition of sodium borohydride in water.
2. The stirring should powerful enough to create a emulsion. This allows the surface area of the two phases to be as large as possible, which means better contact and short reaction time.


Comments
I'm sure about 0,5 molar equivalents sodium borohydride is sufficient. The large amount used here was actually due to a miscalculation on my side.
My firm belief is that the in situ liberation of methylamine is more effective than using a premade 40% aqueous solution. The addition of NaOH to MeAm HCl, using the concentrations above, makes a nearly saturated solution of NaCl at the same time. This kicks out the methylamine from the aqueous phase and forces it into contact with the ketone. If a premade 40% solution is used the amine is much more prone to stay in where it is, thus less of the target imine is formed.





For this method, can tetra-n-butylammonium bromide, TBAB be used instead of the Aliquat 336?




hest

  • Guest
yes
« Reply #62 on: September 12, 2004, 07:53:00 PM »
I'm sure it will work as well.
Actual I'm quite sure that Bandil have a post where he don't use anye PTC, red he's post's first.

XrLeap

  • Guest
Hi Hest, Thanks for the comment.
« Reply #63 on: September 16, 2004, 04:45:00 PM »
Hi Hest,

Thanks for the comment.

SWIM has read it many times, during SWIM's meals too. SWIM will try bandil's mol sieves method once he gets the methylamine solution. :-[

As for the method outlined, without PTC, the amount of each chemical used is very sensitive towards the resulting yield. Eg, the amount of H20 used is the major thing, if the solution is not salty(concentrated) enough, not enough methylamine gas is pushed to the IPA, thus affecting yield. If the NaBH4 used is slightly more, the water is not able to dissolve all. SWIM has got extreme low yield(range from 0% to 10% m/m if you wanna know) when using a mechinical weighing machine which is not very sensitive to weighing things at 10g scale. SWIM purchased a digital weighing machine, with 0.1g increment. All followed to the letter outlined in the post. Yield was around less than 15%. SWIM was very happy and that was some improvement. SWIM tried to use IPA 91%(all previous used was 99.7% claimed by manufacturer), highest yield was about 40%. SWIM has tried to vary the method to give optimum output but failed. Oops, SWIM is not going to declare it fail yet. SWIM will try until he gets good result, with repeatability.

Now, SWIM has planned to use other solvent, toluene is in the list, ethanol, DCM, DMF are some others. SWIM has no experience with PTC at all, thus the previous post.

Please forgive SWIM's lack of knowledge and asking a lot of stupid quetions.

By the way, did you(hest, hive addickt) produce the same result using aq. solvent? If yes, can you please be kind enough to share what are the tips in achieving the mentioned yield. SWIM firmly believe that it is achievable, thus has performed so many aminations.

Anyway, SWIM has replaced the IPA method using methanol as solvent, generating methylamine gas in situ. Has got his yield shoot up.