Author Topic: Novel DOM synthesis  (Read 2533 times)

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  • Guest
Novel DOM synthesis
« on: February 09, 2004, 10:37:00 PM »
Easy DOM (2,5-dimethoxy-4-methylamphetamine) from DMA theory.

My dear fellow bees!

I have searched thoroughly on the search engine, but have not found anything that corresponds to my idea, so i truly hope it is a novel idea and not a sleazy knock off  :) .

Brief overview

DMA.HCl is bromomethylated, and the resulting DOMBr is subsequently isolated. DOMBr is then dehalogenated using rather simple and non toxic chemicals to DOM.

          Paraformaldehyde, KBr, H2SO4
DMA.HCl ---------------------------> DOMBr
               NaBH4, DMSO
DOMBr  ----------------------------> DOM

Description of the idea

DOM has always been notoriously difficult to prepare because of the somewhat odd precursors required and the formylation step needed to make the benzaldehyde. After the discussion in the serious chemistry forum about the two new active compounds DOMCl and DOMOM (

Post 486635

(Rhodium: "Two new DOM analogs made and evaluated", Serious Chemistry)
), the idea for the new DOM synthesis spawned.

The starting material is DMA.HCl In the article


( they chloromethylate this in very high yields(70.8%). As debated earlier chloromethylation is not a very nice procedure, because of the complicated set up, noxious and toxic gasses involved. Bromomethylation ala Lego looks much nicer(see

Post 475109

(Lego: "Amphetamines/PEAs w/o benzaldehyde or nitroethane", Novel Discourse)
, as no gassing is required. I suppose the same yields can be expected from the bromomethylation as the chloromethylation. After the isolation of the -most likely nasty/toxic- DOMCl the next step can commence.

As the whole DOM molecule is quite stable there are many ways of dehalogenate this. Many reducing agents will do the job[1]. The most common being lithium aluminium hydride[2]. Another powerful reagent, which reduces primary, secondary, tertiary, allylic, vinylic, aryl and neopentyl halides, is a complex formed from lithium trimethoxyaluminium hydride LiAlH(OMe)3 and CuI[3]. A milder reducing agent is Sodium Borohydride, NaBH4, in a dipolar aprotic solvent such as Me2SO (DMSO), DMF or sulfolane[4], which at room temperature or above reduces primary, secondary, and some tertiary[5] halides in good yield without affecting other functional groups that would be reduced by LiAlH4.

There are also many other ways of dehalogenating alkylhalides, but many of these seem quite exotic compared to the ones i have mentioned. See [6] for further reading.

For bees the route with borohydride in DMSO / DMF is probably the best way to go. The yields are supposed to be high, and the reaction conditions are mild. An obstacle could be the large aromatic ring connected to the same carbon as the halogen, which could cause some sterical hinderance. However, [4] and [5] states that secondary and even some tertiary halogens are reduceable using this method. I would guess that it ought to work even though it might be a bit hindered with this in mind. I don't have the reference on the specific reaction conditions on this one, but perhaps a friendly bee can dig it up somewhere? After a successfull dehalogenation, we all know what wonderfull molecule awaits us  8) . So if it really is a feasible route i would think that the synthesis of DOM has become quite alot easier. But i suppose there is only one way of finding out if it works nicely  ;)

Anyone have some feedback on the idea?



Reviews: Hudlický Reductions in Organic Chemistry; Ellis Horwood: Chichester, 1984, pp 62-67, 181.
Pinder Synthesis 1980, pp. 425-452.
For a list of reagents see Larock Comprehensive Organic Transformations; VCH New York, 1989, pp. 18-24.

Reviews: Pizey Synthetic Reagents
, vol. 1; Wiley: New York, 1974, vol 1, 1974, pp. 101-294.

Masamune; Rossy; Bates J. Am. Chem. Soc. 1973, 95, 6452.
Masamune; Bates; Georghiou J. Am. Chem. Soc., 1974, 96, 3686.

Bell; Vanerslice; Spehar J. Org. Chem. 1969, 34, 3923.
Hutchins; Hoke; Keogh; Koharski Tetrahedron Lett. 1969, 3495.
Vol'pin; Dvolaitzky; Levitin Bull. Soc. Chim. Fr. 1970, 1526.
Hutchins; Kandasamy; Dux; Maryanoff; Rotstein; Goldsmith; Burgoyne; Cistone; Dalessandro; Puglis J. Org. Chem. 1978, 43, 2259.

Hutchins; Bertsch; Hoke J. Org. Chem. 1971, 36, 1568.

March Advanced Organic Chemistry, Fourth ed. pp. 438-439.


  • Guest
Bandil, you were faster
« Reply #1 on: February 09, 2004, 11:47:00 PM »
Bandil, you sure were faster, but I had it writen offline so sorry if I posted it anyway:

Post 487534

(Nicodem: "Azole, that's a nice and ingenious synth", Serious Chemistry)


  • Guest
That is a very nice idea indeed.
« Reply #2 on: February 10, 2004, 05:43:00 AM »
That is a very nice idea indeed. :)  And do not forget DOET and such - it is also possible to alpha-chloroalkylate the aromatic ring by using different aldehydes(

Post 468021

(Rhodium: "Styrene Derivatives by Aromatic Chloroalkylation", Novel Discourse)
), might well work with the H2SO4/KBr variation too. Edit: Well, after translating the first reference a bit, it appears that the starting point of the article is the fact that when an aromatic is condensed with acetaldehyde in presence of hydrochloric and sulfuric acids, the product is the corresponding alpha-diphenylethane, not the alpha-chloroethylbenzene.

Concerning the dehalogenation, it occurred to me that the Zn/Ni couple reduction patent (

Post 435620

(moo: "Reduction of phenylacetonitriles w/ Zn/Ni couple", Chemistry Discourse)
) also discussed dehalogenation, but the halogen there was aromatic. I guess there isn't much difference compared to traditional catalytic dehalogenations with hydrogen, as nickel is a hydrogenation calalyst like platinum and palladium which are used in those reactions, but of course it is obvious that the benzylic carbon can make a great difference along with the lower activity of the nickel catalyst. And maybe something else as the source of hydrogen just to avoid messy workups. The literature could have something to say about this subject I haven't had a reason to concentrate on yet.


  • Guest
Acidic reducing agent needed
« Reply #3 on: February 10, 2004, 06:50:00 AM »
Very nice idea indeed, but the choice of reducing agent must be something else than the NaBH4 - as mentioned in

Post 487534

(Nicodem: "Azole, that's a nice and ingenious synth", Serious Chemistry)
: "However, Bandil forgot that the DOMBr just like DOMCl must not be free-based and to choose the reducing agent appropriately to this.".
Nicodem instead suggests tin(II)chloride: "Could the reaction they used for DOMCl be used for the synthesis of DOM, maybe even without isolating the DOMCl intermediate, simply by adding SnCl2×2H2O at the end of the chloromethylation (see

Post 486611

(Rhodium: "Reference #5: C-Methylation of Vanillin", Novel Discourse)


  • Guest
Damn monday posts
« Reply #4 on: February 10, 2004, 09:59:00 AM »
God dammit! Why is it so hard to read and understand an article on mondays - sorry about that. Should have read it more carefully before blabbering about.

But of course you are right, acidic reduction it is. If the bromomethylation is done in GAA with sulfuric acid and KBr, the resulting mixture should be quite acidic. Will this environment be adequate for reduction with Stannic(II)Chloride hydrate?

In the reference you gave Rhodium, they use dioxane / HCl as the solvent for the reduction. Perhaps GAA / H2SO4 will work aswell? It could be one sweet reaction if so!

Oh well, i suppse theres really only one way to find out  8)



  • Guest
« Reply #5 on: February 10, 2004, 10:50:00 AM »
I think there is a point in using conc. HCl rather than H2SO4 (as SnCl2 is used). The dioxane is probably there for the sake of solubilizing the organics while still being water soluble, THF might do the trick too with good stirring. I don't know if HOAc will interfer with the reduction.


  • Guest
I see your point! When bromomethylating ...
« Reply #6 on: February 10, 2004, 10:59:00 AM »
I see your point!

When bromomethylating benzene, it is quite easy to purify it, as they simply add lots of water and extract with something non-polar. This is not possible in the case of 4-bromomethyl-2,5-dimethoxyamphetamine, as it will be in its acidic form after the reaction. As basification was not an option, it seems rather hard to isolate it.

Any bright ideas on how to solve this problem, without turning to chloromethylation?



  • Guest
Why not make the aldehyde?
« Reply #7 on: February 10, 2004, 11:13:00 AM »
Is there any oint in not performing bromomethylation at the aldehyde stage rather than on DMA?

It really seems to me that it would save the chemist a lot of problems.



  • Guest
benzaldehydes cannot be halomethylated
« Reply #8 on: February 10, 2004, 11:26:00 AM »


  • Guest
Not true
« Reply #9 on: February 10, 2004, 11:56:00 AM »
benzaldehydes cannot be halomethylated

That is not true. The first article I can grab (E Profft et al. Ueber das Aethylvanillin. Arch Pharm 297(5) (1964) 292) describes the chloromethylation of ethylvanillin.

30 g Aethylvanillin werden in 300 mL konz. Salzsaeure geloest. Nach Zugabe von 7 mL Phophoroxychlorid und 10.3 mL "Chlormethylalkohol" wird vorsichting durchgeschuettelt und 2 Tage stehengelassen. Sodann wird mit viel Wasser verduennt. Der ausfallende schwarze, koernige Koerper wird filtriert und miet 100 mL kalter 5proz. Sodaloesung gewaschen, sodann mit 50 mL Wasser nachgespuelt. Nach Trocknen wird mehrmals mit 750 mL sidendem Petrolaether (Sdp 100-120°C) ausgezogen und abgekuehlt. Nach mehrmaligem Umkristallisieren aus Petrolaether werden 18.3 g (47% d. Th.) erhalten; Schmp. 121°C.

Also, check out the early volumes of Organic Reactions. I remember one containing a chapter on chloromethylations, and several references to the chloromethylation of benzaldehydes are given there. I do know for sure there is a reference given for the chloromethylation of anisaldehyde with a 90% yield.


  • Guest
Organic Reactions Article
« Reply #10 on: February 10, 2004, 11:59:00 PM »
The article by Fuson et al from Organic Reactions 1 63-90 (1942):

A link for downloading Deja Vu Solo can bee found in

Post 218955

(Antoncho: "All DejaVu programs may now bee downloaded", Tryptamine Chemistry)



  • Guest
I dont have the reference here, but i read in...
« Reply #11 on: February 11, 2004, 09:51:00 AM »
I dont have the reference here, but i read in March - Advanced organic chemistry under the section "dehalogenation", that primary and secondary alkylhalogens are easily reduced/dehalogenated using Zinc in basically any acidic medium. Anyone have the reference handy? I dont have the book here, so i cannot post it before tomorrow...

Any trick to reading that article of yours? I just get a "" file for download or something like that...



  • Guest
« Reply #12 on: February 11, 2004, 02:14:00 PM »
I noticed that in this thread there has been a misunderstanding of an essential part of the DOMOM-DOMCl paper. The chloromethylation works only because the conditions and particularly the solvent (chlorobenzene) were such as to avoid the Pictet-Spengler reaction:
"In order to synthesize a dimethoxyamphetamine with a chloromethyl group in position 4, it is necessary to avoid reactions with the highly reactive amino function."

The authors rationalize their choice, but they do it in such a way that it was impossible for me to understand it completely. So please, if there is somebee out there better skilled in English language he could make me slightly happier by decoding this:
"The problems mentioned can be avoided using the Blanc reaction, if it is possible to find a dissolver for 2,5-dimethoxyamphetamine [17], which forms a hydrochloride salt under these working conditions, and is therefore insoluble in the known solvents for this reaction. A solvent
which is polar enough to dissolve the educt as hydrochloride is unsuitable in this Blanc reaction."

[17] A.Shulgin in Pihkal (Ed.:D.Joy),TransformPress, Barkley 1991, p. 53.
Could someone with the printed version of PIHKAL please check what did they reffer to.

Maybe chlorobenzene can be easily substituted with toluene even though toluene can be also chloromethylated. But I think this side reaction would not be of great extent because the temperature "should not exceed 20°C" and the preparation done in 30 minutes. Furtermore the 2,5-Dimethoxyamphetamine is much more reactive than toluene. But I'm highly skeptic about using acetic acid as a solvent as proposed (even if it is for the bromomethylation). I think this would favor the Pictet-Spengler reaction yielding mostly the dimethoxy-methyl-tetrahidroisoquinoline (formic acid is the usual solvent for these Pictet-Spengler condensations!).

primary and secondary alkylhalogens are easily reduced/dehalogenated using Zinc in basically any acidic medium

When I proposed this Zn/AcOH system for the reduction of their "haloephedrines" in the Stimulants forum there was no response at all. It is funny how fanatically they stick with their red phosphorus/iodine  :P .


  • Guest
Reduction Procedures
« Reply #13 on: March 04, 2004, 08:26:00 AM »
From JOC 1960, Vol 25, pp.1714...

General Reduction Procedure: The chloromethyl derivative (0.5g) in acetic acid (8 ml.) and water (2 ml.) was treated during 0.5 hr. with zinc dust (0.5 g.) and the reaction mixture heated on a steam bath for 2 hr. in all. The reaction mixture was then filtered and poured into cold water. The methyl derivative which separated was crystallized from dilute acetic acid. It was necessary to add hydrochloric acid (0.5 ml.) in the case of 7-methoxy-3,6-dichloromethyl-4-methylcoumarin to prevent the formation of the diacetoxymethyl derivative, and in the case of 7-hydroxy-2,8-dichloromethylcoumarin and 7-methoxy-3-chloromethyl-4-methylcoumarin-6-carboxylic acid to precipiatate the product.

-No yields given. But, SWIM has A LOT of other refs all stating that Zn/AcOH is a standard way of reducing benzylic chloromethyl compounds and offers good yields.

Reduction of Iodomethyl derivatives using SnCl2/HCl in dioxane
JACS vol , pp3098 (1940)...

A solution of 1.05 g. of 9-methyl-10-iodomethyl-1,2-benzanthracene in 60 cc. of dioxane containing 3 cc. of hydrochloric acid was added a solution of 10 g. of stannous chloride crystals in 50 cc. of dioxane and 30 cc. of concentrated hydrochloric acid. It is necessary to use a very strongly acidic medium in order to avoid the formation of tar. After being refluxed gently for 5 minutes, the originally dark yellow solution became pale yellow; the solution was allowed to stand for one-half hour and then diluted with 500 cc. of water. After standing overnight to allow the precipitate hydrocarbon to coagulate, there was collected 0.71 g. (99%) of only faintly colored 9,10-dimethyl-1,2-benzanthracene.

JACS vol 80, pp1405 (1958)...

10-iodomethyl-9-anthranyl-propionic acid was dissolved in a boiling solution of 224g. of stannous chloride, 675ml concentrated hydrochloric acid and 1125 ml. of dioxane. The clear, light yellow solution was cooled and poured into 2250 ml. of water. The precipitated solid was collected and washed successively with 15% hydrochloric acid and water. Crystallization of the crude acid from ethyl acetate afforded 45.1g (85%) of the methyl derivative.

*Note that this same reduction technique is used to reduce 5-chloromethylvanillin in the synthesis of 5-Me-MDA on Rhodium's.

Reduction using Zinc in two-phase system of benzene and 2N NaOH

SWIM will type it up if anybody is interested. Many chloromethyl compounds will be fine under basic conditions, but this obviously won't work for 2,5-DMA.HCl.


  • Guest
Chloromethylation of Benzaldehydes
« Reply #14 on: March 04, 2004, 08:38:00 AM »
Chloromethylation of anisaldehyde - 90% yield
ref: Quelet and Allard, Compt. rend. 205, pg. 238 (1937)

Coming soon...

(SWIM has to order this ref.. If anyone can get it sooner please do so, SWIM will avoid a headache.)

Other Chloromethylations....

ref: Ber., 34, 2455 (1901)

SWIM likes the idea of halomethylating 2,5-DMB. Reaction will occur at the activated 4-position, and the SnCl2/HCl reduction in dioxane would seem to be the most sure-fire method (the procedure having been used successfully on a benzaldehyde... see 5-Me-MDA).

To moo: SWIM read the Quelet paper too. Not sure why you say the main product is the diphenylalkane compound - diphenylalkanes only formed when a lack of HCl(aq & g) and not enough cooling were applied. Otherwise, Quelet was able to chloroethylate and propylate anisole in decent yields. Although he mentions chloropropylation is much more difficult to effect than chloroethylation. A simple method to DOET would be amazing.

Also iodomethylation is quite easy to effect as well. HI/paraformaldehyde will usually do the trick, or you can take the chloromethyl derivative, dissolve in some GAA and add HI... the iodomethyl derivative is much less soluble and will precipitate out. SWIM can provide literature if anyone is interested.


  • Guest
Imp, thanks for providing the examples of...
« Reply #15 on: March 04, 2004, 09:41:00 AM »
Imp, thanks for providing the examples of Zn/AcOH reductions. It was already time for somebody to do that. :)

SWIM likes the idea of halomethylating 2,5-DMB. Reaction will occur at the activated 4-position

The position 4 is deactivated by the -CHO group. The most probable position for an electrophilic attack on 2,5-diMeO-benzaldehide is the position 3 as it is activated by MeO- (ortho to it) and the less deactivated by -CHO (meta to it; the other meta position is ocupied by the 5-MeO).


  • Guest
« Reply #16 on: March 04, 2004, 10:21:00 AM »
Chloromethylation of anisaldehyde - 90% yield
ref: Quelet and Allard, Compt. rend. 205, pg. 238 (1937)

Here it is!


  • Guest
« Reply #17 on: March 04, 2004, 09:10:00 PM »
With the danger of sound like an old man.
Take care when you chlorometylate something. One of the biproduct (dichloromethylether) is extreamly caracinogenic. Not like HMPA, ect. but real dangererous.


  • Guest
: I was thinking along the lines of a H SO...
« Reply #18 on: March 04, 2004, 11:38:00 PM »
Imp: I was thinking along the lines of a H2SO4/KBr reaction with acetaldehyde and  the aromatic. According to that article the diphenylmethane would be the product. But you are right about the actual reaction in that paper. The second article in that series suggests that using chloroethylation with dimethoxybenzenes might not be that easy, though, as they say that even the reaction products obtained from cresol methyl ethers are very labile and side reactions are unavoidable. On the other hand they also say that ortho-methoxy compounds are much more stabile than para-methoxy compounds. If it could be get to work somehow, it would be nice indeed!  :)

One way to overcome the formation of diphenylmethanes would be the addition of the aromatic substrate to the reaction mixture (eg.

Post 373715

(Chimimanie: "Synthesis of 2-Chloromethyl-5-alkyl-DMB", Methods Discourse)
), but depending on the substrate it might give rise to a disubstituted product, the reason why p-dimethoxybenzene is chloromethylated the other way around (

Post 384897

(Rhodium: "Chloromethylation of p-dimethoxybenzene - 61%!", Methods Discourse)

Nicodem: According to those rules 2,5-dimethoxybenzaldehyde would get brominated in the position 3 instead of the experimentally verified positions 4 and 6. It appears that sometimes those rules do not apply. ;)


  • Guest
Does that mean that there is a paper with the...
« Reply #19 on: March 05, 2004, 10:22:00 AM »
...the experimentally verified positions 4 and 6...

Does that mean that there is a paper with the chloromethylation of 2,5-dimethoxybenzaldehyde? Can you please give a reference to it or better yet post it?