Author Topic: Subst. P2Ps via acetonylation?  (Read 15415 times)

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Subst. P2Ps via acetonylation?
« on: March 20, 2002, 08:20:00 AM »
I was reading M. V. Smith's book and stumbled upon this:

Amphetamines from Bromobenzenes JACS 63,602(1941)
0.2 M p-methoxy (or other group)-Br-benzene (see this paper for preparation) and 4.6 g Mg. Rapidly add 18.5 g chloroacetone in 50 ml ether. Evaporate the ether by heating in oil bath and then at about 135ø for one hour. Cool and add ice and dilute HCl; extract the oil with ether and dry, evaporate in vacuum to get about 11 g product (can distill 106/18). 0.057 M of the ketone product in 16 g formamide in 100 ml round bottom flask, with an air condenser. Heat twelve hours at boiling and then reflux with 35 ml 30% NaOH eleven hours and separate the amine layer and dry, evaporate in vacuum to get the amphetamine.

Now, this was somewhat discussed a long time ago - see

Post 108627 (missing)

(dormouse: "P2P  -niteflier", Novel Discourse)
But nothing particularly conclusive was voiced.

What is completely confusing about this synth is - is this a Grignar or it's just as simple as that - mixing chloroacetone, Ph-Br and some magnesium?

Sounds way too easy to bee true.

Maybee, someone can say smth informative about this? Any input will bee very appreciated.

Another similar possibility is to react a subst. benzene w/haloacetone in friedel-Crafts-like fashion.
However, i've never seen a proc. like that for a substituted ring (i thought i have but it turned out to bee a mistake so i edited it out). Has anyone?

Disclaimer: i have read absolutely everything concerning haloacetones that is on this site, so don't bother telling me it's too dangerous to work with.

Well, that's true, but someone i know did that quite easily with a help of an ordinary gas mask. OTOH, such rxns, should someone make them applicaple to subst'ted rings, would bee a revolutionary breakthrough, IMHO.

I also have an excellent bromoacetone preparation procedure (which actually inspired my looking into these routes), submitted onto HyperLab by Zealot, which i will post soon. Zealot says it can bee made w/out a gas mask, but not washed or transferred.



  • Guest
« Reply #1 on: March 20, 2002, 03:17:00 PM »
Here is a rough procedure for bromoacetone, sounds easy.
cough... cough...

Post 198346

(foxy2: "Bromoacetone", Chemistry Discourse)

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


  • Guest
P2Ps via acetonylation - some scepticism
« Reply #2 on: March 20, 2002, 06:40:00 PM »
It is really interesting, but :(
- Bromoacetone with Mg as Grignar reagent can react with another molecule of bromoacetone (C=O group). This is a way to produce polymers aka black liquid tar :(
- Bromoacetone is really easy autodestructed, particularly with acids. AlCl3 with benzene and bromoacetone will produce black liquid tar :(

With best regards,
Dennis Prochko aka Wolf


  • Guest
Practice, not theory
« Reply #3 on: March 20, 2002, 07:00:00 PM »
The referenced article says it works, and I believe this is worth a try - could somebody type up that article verbatim?

Wasn't it Assholium who said that epichlorohydrin (3-chloro-1,2-epoxypropane) could be used as a chloroacetone equivalent, the PhMgBr attacking the epoxide, forming the MgBr salt of 3-Phenyl-1-chloro-2-propanol, which immediately undergoes an intramolecular etherification forming 3-phenyl-1,2-epoxypropane (and MgBrCl), which is then isomerized to the ketone?


  • Guest
Necessary actions :)
« Reply #4 on: March 21, 2002, 04:20:00 AM »
Yep, Dennis, i heard that too ;( However. can't it bee used with milder Lewis acids like FeCl3? I believe, in case of subst'd rings that could bee quite appropriate.

and - Rhodium - should we then put this article into the Wanted Refs section?



  • Guest
Library visit
« Reply #5 on: March 21, 2002, 05:12:00 AM »
Nah, I'll just swirl by the library later today, JACS is available anywhere.


  • Guest
« Reply #6 on: March 21, 2002, 05:33:00 AM »
The most exquisite search thru HyperLab's archives didn't reveal any mention of the epichlorohydrine route you spoke of. However, here's a quotation from a discussion between Assholium and C_Nemo which i - to my greatest surprize - discovered while searching:

"C_Nemo: i wonder what if one tried to attach bromoacetone to benzodioxole?

Assholium: well, if done with cooling and a mild FC-catalyst - no obstacles! However, if the product is not very thoroughly washed from traces of the catalyst it polymerizes into black crap in 10 hours. Such is the nature of the fucken methylendioxy bridge.

However, there are much more interesting things..."

- and then he goes at length to describe in detail his synthesis of alpha-oxo-indametamine.

P.P.S. I wrote a couple of paragraphs more after that, but then it beecame evident to me that they were much better in the cathinone thread - so see

Post 285853 (missing)

(Antoncho: "Cathinones and related", Novel Discourse)
for continuation.

P.P.P.S. I will bee looking forward to see that article!


  • Guest
Bromoacetone Synthesis
« Reply #7 on: March 21, 2002, 09:38:00 AM »
Here's the promised bromoacetone synth.

As you all know, the problem w/halogenating acetone is that it tends to polyhalogenate, the dihaloacetone being difficult to remove by distillation (like someone could consider fractionally distilling bromoacetone ::)  :)  ;D )


... Bromination with dioxanedibromide is applied in cases when bromination w/straight bromine doesn't give good results.

1. In a 100 ml flask there is added 20 ml (20,6 g) dioxane and w/slight cooling there is added thru an addition funnel 12 ml (37,4 g) Br2. That causes the flask contents to crystallize completely.

2. To thus obtained dioxane*Br2 (DDB) there is added at RT 17 ml (14 g) acetone, which 1st causes dissolution of DDB and then complete discoloration of the mixture. To the obtained soln (here's the part when you 1st need a gas mask) add 30 mls aqua, stir well and neutralize generated HBr (which is mostly bound by dioxane) w/conc. Na2CO3 soln. (if water isn't added 1st, addition of carbonate will cause instant polymerization of Br-acetone). Then the rxn is washed 3-4 times w/small amt's of water to remove dioxane, the last washing is done w/distilled water (! important if you don't use it immediately). Bromoacetone is obtained as heavy colorless oil. It's immiscible w/water and always forms lower layer during washings. It can bee dried exclusively w/MgSO4, as any carbonate will cause it to polymerize at once (but what of Na2SO4???) It has a very poor storage capacity and even stabilized w/small q't'ties of H2O turns completely black in a week. Upon more prolonged storage it turns very viscous and   is very difficult to extract even w/chloroform. It is best to use it immediately.

Density = 1,6 g/ml
bp = 136,5 decomp.

So... as you can see it's not particularly easy, but quite doable. Much more importantly, all the procedures don't require almost any equipment so they can (and should) bee performed outdoors.

May i attract your attention to the fact that in this reaction they use a stoichometric amt of reagents, instead of a large xcess of acetone? The bromination is indeed very selective. The source of the procedure is an old Russian chem. textbook, it is not only fully valid, but also practically tested by Zealot, whom i want to thank again for his contribution - not the only one, BTW - a coupla more are still in store.

I wonder though how one can dry Br-acetone to the extent that it can bee used in a Grignar... Wait, to quench a Grignar one doesn't need a totally unhydrous reagent, does he?

And - the hottest of all - Friedel-Crafts - if there only was a single example present! Maybee, some devoted bee w/an access to a good electronic database could do a search on 'bromoacetone'?

Well... i hope, time will clarify this issue.

Sincerely Yours,



  • Guest
« Reply #8 on: March 21, 2002, 10:05:00 AM »
Suppose you have axs to a glovebox when working with Br-acetone? Or whats the trick? Br-acetone is one of the single most nasty things i've ever done! Once above the waterphase it's time to leave the house pronto. It seconds to dropping POCl3 on a hotplate though....


  • Guest
Dear Sonson!
« Reply #9 on: March 21, 2002, 10:18:00 AM »
Yep, i read that earlier post of yours when you described that sad occurrence. Actually, i considered posting a compilation of Post No.'s in this thread , which describe in detail all the horrors of dealing w/BrAcMe - but then just changed my mind :)  - wrote the disclaimer instead.

Now, i personally have some xperiense chlorinating acetone, so, believe me, i imagine what it's gonna bee like - but despite i have an axs to a glovebox, albeit self-made :) , i never considered ever doing it indoors, neither for SWIMself, nor for anyone else.

I still am firmly certain that this route could bee very worthwhile - if we figured out a precise way to do that.

Making a research on (Br-/Cl-)-acetonylation is certainly not a dream of my life, but having a good solid proc... Could bee substituted P2Ps in one step ...

BTW, am very happy to see you around! :)



  • Guest
« Reply #10 on: March 23, 2002, 01:05:00 AM »
JACS 63, 602-604 (1941)

A Grignard reagent was prepared from 35g (0.2 mole) p-fluorobromobenzene and 4.6g (0.19 mole) of magnesium in diethyl ether. To this was added 18.5g (0.2 mole) chloroacetone in 50ml diethyl ether as rapidly as the refluxing of the reaction mixture would allow. The ether was removed by heating the reaction flask in an oil bath and at 100°C the residue foamed with the formation of a gel from which ether was removed slowly by heating at 135-140°C for 45 min. The flask was cooled, ice and dilute sulfuric acid was added, the heavy oil which separated was removed with ether and the ether solution dried and fractionately distilled. There was obtained 11.2g (37%) of practically pure p-Fluorophenyl-2-propanone distilling at 106-107°C/18mmHg.

The introduction in the text says that the ketone was obtained by "rearrangement of the addition product between chloroacetone and p-fluorobromobenzene Grignard". Could it be so that at first the MgBr salt of the alpha-methylstyrene halohydrin forms the alpha-methylstyrene epoxide, which is then rearranged to the ketone? Theoretically possible, but is it actual fact?


  • Guest
Oh, Rhodium!
« Reply #11 on: March 23, 2002, 07:09:00 AM »
Hey, Rhodium, excellent! Thanx a lot.

Now, i wonder, where Michael Smith got these refs from :):):) It's not the 1st mistake he has in his writings.

Well, my limited knowledge of chemistry doesn't allow me to judge about the rxn mechanism, but i don't think it proceeds thru epoxide. What i do know that =O group in haloacetone is more acidic than Cl- , so addition of Grignar is bound to prefer the ketogroup. That's also the reason, i beelieve, for low yields in Friedel-Crafts acetonylations.

Note also that smth similar happens in Mn3+-catalyzed acetonylations - 1st addition takes place at ketogroup, then the complex rearranges and is reduced w/another Mn3+ ion.

But, please, don't overestimate my thoretical skills, i'm just rambling mostly, really ::) .

Another issue: isn't it true that the more electron-rich the ring is, the harder it is to make a Grignar from it (like, the bromine atom gets less electrophyllic)? IIRC, Bwiti had a great difficulty making one from bromoanisole. Although, C_Nemo didn't seem to have any making one from p-DMB - see the proc. posted by Tricky (about straight addition of ethylenamine). In any case, i wonder if the rxn will go the same w/electron-rich rings.....

In any case, it seems to me that bromoacetone would work better. What do you say?



  • Guest
aryl grignards
« Reply #12 on: March 23, 2002, 11:28:00 AM »
hi antoncho,

concerning aryl grignard compounds otto has opened a new thread.