Author Topic: benzaldehydes to phenylacetones  (Read 32801 times)

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Barium

  • Guest
benzaldehydes to phenylacetones
« on: July 17, 2002, 02:14:00 AM »
To a 500ml rb three-neck flask with a thermometer and a stir bar was added 16,6g (100 mmol) 2,5-dimethoxybenzaldehyde and 18,3g (150mmol) methyl 2-chloropropionate. 100ml MeOH was added to get the benzaldehyde into solution. While keeping the reaction mixture at 15 deg C, 8,1g (150 mmol) sodium methoxide in 50ml MeOH was added dropwise during 40min. When all alkoxide was added the reaction mixture was allowed to come to room temp and stir for another hour. The reaction mixture was then added to 10g (250 mmol) NaOH in 40ml water while keeping the temp at 20 deg C, then all was stirred at room temp over night. The next morning there was a thick white precipitate in the solution. To this 15% aq HCl was added until pH 3,5 was reached. This caused a clear yellow oil to fall out. The solution was heated on a waterbath at 65 deg C for two hours to complete the decarboxylation. The methanol was removed by distillation in a rotovap and the ketone was isolated by steam distillation. The distillate was extracted with 3x75ml toluene and the collected toluene phases dried over MgSO4. The toluene was removed by distillation in a rotovap leaving a clear yellow oil.

Yield: 14.94g (76,9 mmol) 2,5-dimethoxyphenylacetone
Purity: 96% by HPLC


Now where did I put the hydroxylamine and iodine?..... 8)

Rhodium

  • Guest
Great Barium! I put this synthesis at http://www.
« Reply #1 on: July 17, 2002, 07:54:00 AM »
Great Barium! I put this synthesis at

https://www.thevespiary.org/rhodium/Rhodium/chemistry/25dmp2p.html



But what are you going to do with the iodine?

Barium

  • Guest
Hmm
« Reply #2 on: July 17, 2002, 08:12:00 AM »
Guess I´ll be needing some silver sulphate also.

I´m also right now trying another way of generating that carbanion. It does so far look very good. If this works one can forget about alkoxides and use 50% aq. NaOH instead.
More news tomorrow.

foxy2

  • Guest
Nice, One more in the quiver
« Reply #3 on: July 17, 2002, 08:13:00 AM »
But what are you going to do with the iodine?

DOI, I presume.

Those who give up essential liberties for temporary safety deserve neither liberty nor safety

Barium

  • Guest
Holy cow!!!
« Reply #4 on: July 17, 2002, 08:41:00 AM »
This can and will be improved, but it was just a first trial.

Aq. NaOH/Aliquat 336 instead of NaOCH3

16,6g (100 mmol) 2,5-dimethoxybenzaldehyde was added to 50ml toluene and 2g (approx 5 mol%)Aliquat 336 in a 250ml rb flask with a thermometer and a stirbar, then 5,6g (140 mmol) NaOH was dissolved in 7ml water and added to the flask. To this two-phase system 14,7g (120 mmol) methyl 2-chloropropionate was added dropwise during 30 minutes. The temperature was maintained at 20 deg C using a icebath. When the addition was complete the reaction mixture was stirred for another 30 minutes at roomtemp. 10g (250 mmol) NaOH dissolved in 50ml water was then added and the mixture was stirred for another hour at room temp. The phases was then separated and the aqueous layer saved. The toluene layer was extracted with another 50ml water and then discarged. The combined aqueous phaes was then acidified with dilute HCl until pH 3 was reached.

The lovely yellow oil comes once again....

I do not have time to work it up properly today but I will do that first thing tomorrow.

Rhodium

  • Guest
Wow, if this is tested on several benzaldehydes, ...
« Reply #5 on: July 17, 2002, 08:55:00 AM »
Wow, if this is tested on several benzaldehydes, it could become one of the preferred methods of synthesizing P2P's. It is a wonderful way around the use of nitroethane (which incidently also can be made from 2-halopropionic acid).

Antoncho

  • Guest
Ah! Ah! Ah!
« Reply #6 on: July 17, 2002, 09:17:00 AM »
Barium, you did this!

Ah, how amazing!

Congratulations, congratulations!!







Yours,


Antoncho

GC_MS

  • Guest
1- or 2- propanones ?
« Reply #7 on: July 17, 2002, 12:07:00 PM »
Congrats Barium with your discovery  8) . SWIM has some questions though, mainly because he doesn't see the mechanism behind the reaction. When he tries to "solve" the problem, he finds a reaction like this:



Note that the charges symbolize partially charged atoms (SWIM didn't find the delta+/- in his editor  ::) ). He thinks that the chloropropionate reacts with the aldehyde by splitting HCl. As you see, he ends up with the C=O as 1-propanone, and not 2-propanone. On Rhodium's site, there is a pic with the formation of an epoxide, but SWIM fails to understand that epoxide formation reaction...  :( .
If this works as you advertised, then SWIM certainly wants to test this thing on other benzaldehyde derivatives. But maybe the ortho positioned MeO- is very important (to increase the partially positive charge on the alfa carbon relative to the phenyl), and you will need proper substituents on the phenyl to get equally high yields.
Just SWIM's thought... he could be very wrong  ::) .

-[ A Friend With W33D Is A Friend Indeed ]-

Rhodium

  • Guest
The base grabs the halogen from the alpha-halo ...
« Reply #8 on: July 17, 2002, 05:24:00 PM »
The base grabs the halogen from the alpha-halo ester, forming a carbanion, which adds to the carbonyl, forming the epoxide. The reaction is a Darzen Condensation, and you should be able to look up the detailed mechanism either online or at the library.

The epoxy ester is then hydrolyzed and the formed acid decarboxylated. During the decarboxylation, the epoxide also rearranges to the ketone.

Barium

  • Guest
The yield from the trial yesterday was 5,4g ...
« Reply #9 on: July 18, 2002, 03:39:00 AM »
The yield from the trial yesterday was 5,4g ketone. Not too shabby considering the very short reaction time and overall impatience. I just wanted to see if this twist actually could give something useful. I will now try to perform this reraction properly and see what I get.

By the way I´m currently running a batch of 2,4-dimethoxybenzaldehyde. This time I used NaOH dissolved in MeOH with aliquat 336. Just want too see if it behaves diffrent.

I´ll keep you informed

Soo many things to do, so little time.... :P

Barium

  • Guest
Not optimized but pretty good.
« Reply #10 on: July 18, 2002, 07:09:00 AM »
Not optimized but pretty good.

100mmol 2,4-dimethoxybenzaldehyde, 120mmol NaOH, 2g aliquat 336, 50ml MeOH and 50ml toluene was stirred together in a 500ml rb flask. 120mmol methyl 2-chloropropionate was added dropwise over 20 min while the temp was kept at 20 deg C. When addition was complete stirring was maintained for another 30 min. 150mmol NaOH in 15ml water was then added and stirring was continued for 30 min.
Workup was done as before but without steam distillation leaving 6,7g 2,4-dimethoxyphenylacetone as a bright yellow oil.

Reaction times should be longer to give optimum yields.
But the method works!! ;D

Barium

  • Guest
A 500mmol batch of 2,5-dimethoxybenzaldehyde was ...
« Reply #11 on: July 19, 2002, 08:48:00 AM »
A 500mmol batch of 2,5-dimethoxybenzaldehyde was started yesterday. Procedure was exactly like the first one in this thread. Anhydrous conditions with sodium methoxide as the base.

Yield: 91,5g (94,2%) 2,5-dimethoxyphenylacetone as a yellow oil which becomes slightly orange over a couple of hours in contact with air.


This morning I decided to try a few different benzaldehydes just to see if they would give the corresponding phenylacetones as well. The reactions were not allowed to run full time.

100mmol 2-fluorobenzaldehyde 34% ketone 
100mmol 4-fluorobenzaldehyde 38% ketone 
100mmol 2,4-dimethoxybenzaldehyde 31% ketone 
100mmol 3,4-ethylenedioxybenzaldehyde 42% ketone 

Reaction conditions used were:
100mmol aldehyde, 2g aliquat 336, 120mmol NaOH as a 50% aq. soln. and 50ml toluene was stirred at 20 deg C. 105mmol methyl 2-chloropropionate added dropwise during 30 min while temp was kept at 20 deg C. Stirring was continued for 30 min then 150mmol NaOH in 50ml water was added and stirring continued for 1 hour. Phases separated and toulene phase extracted once with 50 ml water. The combined aqueous extracts was acidified to pH 3,5 with diluted HCl, heated to 45 deg C for 20 min, then extracted with 2x 30ml DCM. The combined DCM extractions was dried over MgSO4 and the solvent removed in a rotovap, leaving the ketone as a yellow oil.

I guess we have a winner..... ;)


Aurelius

  • Guest
novel compounds
« Reply #12 on: July 19, 2002, 04:09:00 PM »
Hey Barium, the last P2P you mention is  "3,4-ETHYLENEdioxy" compound.  did you mean METHYLENEDIOXY?  in either case, maybe this is a novel compound that could be explored with no more difficulty than regular MDMA compounds.

Rhodium

  • Guest
3,4-Ethylenedioxyamphetamine has already been ...
« Reply #13 on: July 19, 2002, 05:57:00 PM »
3,4-Ethylenedioxyamphetamine has already been evaluated in Pihkal and found to be inactive.

Aurelius

  • Guest
activity
« Reply #14 on: July 19, 2002, 06:19:00 PM »
Completely inactive?  that surprising- to aurelius anyway.   thanks Rhodium.  and Barium, aurelius thinks you meant methylenedioxy?

Rhodium

  • Guest
3,4-Ethylenedioxy-N-Methyl-Amphetamine: DOSAGE: ...
« Reply #15 on: July 19, 2002, 06:27:00 PM »
3,4-Ethylenedioxy-N-Methyl-Amphetamine:

DOSAGE: 200mg or more

DURATION: 3 - 5 h.

QUALITATIVE COMMENTS:

(with 150 mg) A flood of paresthesia at the 30 minute point, and then nothing. There was the development of a plus one-and-a half effect over the next hour with the tendency to drift into a dozing state with hypnogogic imagery. There were colored letters in the periphery of my visual field. There was no appetite loss nor was there any blood pressure rise. And no eye jiggle or teeth clenching. I was out of the experience in 4 to 5 hours. A repeat of this level a few days later gave a bare possible threshold with no other effects.

(with 200 mg) There was something unmistakable at 45 minutes, with hints of nystagmus. Possibly MDMA-like, with no indicators of anything psychedelic. Subtle return to baseline, and there were no after-effects.

(with 250 mg) Alert at 40 minutes, and to a clear ++ at an hour. Slight something in the eye muscles. Dropping thirty minutes later, and baseline at three hours.

(with 250 mg) I am at a bare threshold at best.

Barium

  • Guest
Aurelius: I really mean 3,4- ethylene ...
« Reply #16 on: July 21, 2002, 01:33:00 AM »
Aurelius: I really mean 3,4-ethylenedioxybenzaldehyde. I do not touch anything controlled without proper licences.  :P

Antibody2

  • Guest
nice peice of work Barium, hats off
« Reply #17 on: July 21, 2002, 09:28:00 AM »
nice peice of work Barium, hats off

Beaker

  • Guest
NaOH conditions
« Reply #18 on: July 23, 2002, 03:01:00 PM »
Very cool.

With regards to the trials you ran using NaOH/aliquat 336, I would suspect that the lower yields you are seeing are due to the hydroxide saponifying some of the methyl ester on either the starting alpha-halo ester or the epoxy ester, such that there is not enough of the carbanion(due to either a lack of methyl 2-chloropropionate or NaOH) around to react with all of the aldehyde.

Did you check the toluene extracts for starting material?

You may be able to get the higher yields you are seeing with the NaOMe conditions by simply raising the amount of methyl 2-chloropropionate and/or NaOH in the first step until all of the aldehyde gets consumed.

Also, given the result you had with the NaOH/Aliquat 336 in MeOH/toluene, the PTC may not be neccesary. Just add the methyl 2-chloropropionate to the aldehyde/NaOH in MeOH.

Of course, I have no way of knowing whether you have already checked to see that the aldehyde is being completely consumed and the lower yields are due to some other reason.

Anyways, excellent work!

Barium

  • Guest
2,5-DMMA
« Reply #19 on: July 24, 2002, 05:36:00 AM »
To verify the identidy of the 2,5-dimethoxyphenylacetone I decided to N-alkylate it with methylamine.


2,5-dimethoxyphenylacetone 30mmol
methylamine 40mmol
sodium borohydride 50mmol

Methylamine as a 25% aqueous solution was allowed to react with the ketone dissolved in 25ml toluene for 1 hour under violent stirring at room temp. The layers were separated and the toluene layer washed once with 25ml water. The toluene phase was added in one portion to a stabilised aqueous solution of sodium borohydride (the borohydride dissolved in 15ml water containing two drops of 50% aq. NaOH) and the mixture stirred violently for 1.5 hours at room temp. 20% aq HCl added dropwise until pH 2 was reached and the phases separated, the organic phase extractd twice more with 25ml water. The combined aqueous extractions were baified until pH 13 was reached and extracted with 2x30ml toluene. Drying, solvent removal and crystallisation yielded 4.1g (55%) 2,5-dimethoxy-N-methylamphetamine hydrochloride (2,5-DMMA) as bright white crystals. Crystallisation was performed in EtOAc which is a great solvent for this purpose.