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 (https://www.thevespiary.org/talk/index.php?topic=12506.msg48663500#msg48663500)
(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 here (https://www.thevespiary.org/rhodium/Rhodium/pdf/domcl-domom.pdf)
(https://www.thevespiary.org/rhodium/Rhodium/pdf/domcl-domom.pdf) 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 (https://www.thevespiary.org/talk/index.php?topic=11892.msg47510900#msg47510900)
(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?
Regards
Bandil
References
[1]
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.
[2]
Reviews: Pizey Synthetic Reagents, vol. 1; Wiley: New York, 1974, vol 1, 1974, pp. 101-294.
[3]
Masamune; Rossy; Bates J. Am. Chem. Soc. 1973, 95, 6452.
Masamune; Bates; Georghiou J. Am. Chem. Soc., 1974, 96, 3686.
[4]
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.
[5]
Hutchins; Bertsch; Hoke J. Org. Chem. 1971, 36, 1568.
[6]
March Advanced Organic Chemistry, Fourth ed. pp. 438-439.
Bandil, you sure were faster, but I had it writen offline so sorry if I posted it anyway:
Post 487534 (https://www.thevespiary.org/talk/index.php?topic=12506.msg48753400#msg48753400)
(Nicodem: "Azole, that's a nice and ingenious synth", Serious Chemistry)
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 (https://www.thevespiary.org/talk/index.php?topic=11818.msg46802100#msg46802100)
(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 (https://www.thevespiary.org/talk/index.php?topic=7698.msg43562000#msg43562000)
(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.
Very nice idea indeed, but the choice of reducing agent must be something else than the NaBH4 - as mentioned in Post 487534 (https://www.thevespiary.org/talk/index.php?topic=12506.msg48753400#msg48753400)
(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 (https://www.thevespiary.org/talk/index.php?topic=11797.msg48661100#msg48661100)
(Rhodium: "Reference #5: C-Methylation of Vanillin", Novel Discourse))."
The article by Fuson et al from Organic Reactions 1 63-90 (1942):
(https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_imgs/djvu.gif)
A link for downloading Deja Vu Solo can bee found in Post 218955 (https://www.thevespiary.org/talk/index.php?topic=12952.msg21895500#msg21895500)
(Antoncho: "All DejaVu programs may now bee downloaded", Tryptamine Chemistry)
:)
Chloromethylation of anisaldehyde - 90% yield
----------------------------------------------
ref: Quelet and Allard, Compt. rend. 205, pg. 238 (1937)
Here it is!
(https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_imgs/djvu.gif)
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 (https://www.thevespiary.org/talk/index.php?topic=9808.msg37371500#msg37371500)
(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 (https://www.thevespiary.org/talk/index.php?topic=9808.msg38489700#msg38489700)
(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. ;)
No, he is referring to the bromination of 2,5-DMBA:
https://www.thevespiary.org/rhodium/Rhodium/chemistry/25-dmb.halogenation.html (https://www.thevespiary.org/rhodium/Rhodium/chemistry/25-dmb.halogenation.html)
https://www.thevespiary.org/rhodium/Rhodium/chemistry/bromodimethoxybenzaldehyde.html (https://www.thevespiary.org/rhodium/Rhodium/chemistry/bromodimethoxybenzaldehyde.html)
4-chloromethyl-2,5-dimethoxybenzaldehyde is an unknown compound, at least according to Beilstein.