synth of DOM from 2,5-dimethoxybenzyl alcohol?

[phenethyl_man]

I recently acquired some 2,5-dimethoxybenzyl alcohol and am trying to come up with a synth of DOM using this as a starting material..  Could anyone look over this reaction scheme and let me know if it is workable?  Any suggestions are welcome..

[psyloxy]

Advice can only come from experience so it's pretty hard for me to say anything definite. But when you're talking about DOM I cannot remain silent. What are your references for each step ?

Here are my thoughts on the issue:



Chloromethylation of the 2,5-dimethoxytoluene, followed by oxidation to 4-methyl-2,5-dimethoxybenzaldehyde is also a great possibility :

Post 415152

(Bandil: "Chloromethylation of 2,5-dimethoxytoluene", Novel Discourse)

[1]Tetrahedron, 47,3.1991;441-446
2g (74 mmol) Al powder, 2g (8.4 mmol) NiCl₂^.6H₂O and 20 mL EtOH were mixed at 60-65°C until the green colour disappeared (8-10 min). The slurry was cooled to 25°C, followed by the addition of 5 mL (49 mmol) benzyl alcohol and 20 mL  water. Then 18 mL (200 mmol) 36 wt% HCl was added dropwise and stirred for 1 h. After 0.5 h the slurry was filtered. Yield: 100%

[2] Reduction of benzyl alcohols with plain Ca(OH)₂ :

Patent US2401608

EDIT: won't work!

read the threads completely:
[3]

Post 207345 (missing)

(Antoncho: "Vilsmeier mechanism: the alternatives to POCl3", Chemistry Discourse)
[4]

Post 355321

(foxy2: "formylation by the "nitroso" method", Novel Discourse)
[5]

Post 333551

(Barium: "benzaldehydes to phenylacetones", Novel Discourse)

SOCl₂ from SO₂, S₂Cl₂ and Cl₂

Post 515659

(psyloxy: "thionyl chloride : finally, OTC!", Chemistry Discourse)
POCl₃ from P₂O₅

Post 513370

(psyloxy: "preparation of POCl3 / PCl5", Chemistry Discourse)
ethly chloropropionate from ethyl lactate and SOCl₂

Post 514668

(psyloxy: "skip the pyridine, use cat. DMF !", Novel Discourse)
alkali metal alkoxides

Post 512239 (missing)

(psyloxy: "some great alkali alkoxide patents", Chemistry Discourse)

--psyloxy--

[phenethyl_man]

I don't have references for every step; I am too lazy to compile them all.  The first reaction in the scheme, the chlorination of benzyl alcohol; I know that one works.. In fact, one only has to shake the benzyl alcohol with a large excess of hydrochloric acid for a couple minutes, at room temp, and the benzyl chloride is quickly formed.

The second reaction I am unsure about.. I just couldn't think of any other way to get that methyl group on there.  The procedure is located here:

https://www.thevespiary.org/rhodium/Rhodium/chemistry/5-methyl-vanillin.html

In the final step of this scheme, a 5-chloromethyl group located on vanillin is reduced to a methyl group using tin chloride in HCl and p-dioxane.  A problem could be that I don't have any p-dioxane, I wonder if any other solvents could be substituted here?

The reduction of the benzyl alcohol with Al/Ni sounds like it may be a better alternative here for forming 2,5-dimethoxytoluene.  However, I am confused by your second reference for the reduction using calcium hydroxide.  The patent you listed talks about methylation of phenols and doesn't even mention benzyl alcohols; are you sure this would work?..

As for the formylation of 2,5-dimethoxytoluene I would prefer to stick with a method that I know well; and I have never performed a vilsmeier..  I am debating between either, a) forming the mandelic acid w/glyoxylic acid and sulfuric acid, then this can be oxidized to the aldehyde with nitric acid or sodium hypochlorite, or, b) chloromethylation w/ HCl and paraformaldehyde, and subsequently refluxing this compound with 2-nitropropane, NaOH, and water, which also gives the aldehyde.  I have used both of these methods on other substituted benzenes; both involve two steps, however I think the mandelic acid route has a better yield.

I would also prefer sticking to the traditional methods of forming the nitrostyrene, etc.   I feel no real need to form the ketone since I don't plan on making any of the N-alkyl isomers of DOM, and I have a ton of nitroethane lying around.

I guess my main concern is getting from 2,5-dimethoxybenzyl alcohol to 2,5-dimethoxytoluene.. should be relatively easy from there.

Thanks for your input..

[moo]

Dioxane can be prepared from ethylene glycol with sulfuric acid in similar manner as diethyl ether is prepared from ethanol, this is mentioned at least in one post by late halfapint but I do not have more details at the moment.

The patent does discuss benzylic alcohols as benzyl alcohol is also called methylolbenzene, methylol group being -CH₂-OH. For example, 4-methylol-2-methylphenol from example 15 is actually 4-hydroxy-3-methylbenzyl alcohol. But I'm quite convinced that this interesting method is limited to phenolic benzyl alcohols only, after all, the phenols are acidic and calcium hydroxide is a base.

I think the method proposed by phenethyl_man looks ok. Alkaline hypochlorite shouldn't give ring-chlorination products. Still, the ring is quite activated and if the product isn't what it's supposed to be, this might have happened. Luckily there are plenty of other methods available.

[phenethyl_man]

Okay, I have modified the procedure somewhat so the synthesis is less lengthy..



The solvent-less oxidation of benzyl alcohol using alumina as a support should work well.. The reduction with tin chloride to the methyl group is now performed after the aldehyde is formed, since in my reference on rhodium it clearly states:

"We next considered the conversion of the dimethylaminomethyl group of 3 to a methyl group equivalent that can be reduced to a methyl group in the presence of a free aldehyde function. The chloromethyl group appeared to be such a group based on Sandin and Fieser's8 observation that the iodomethyl group of 9-methyl-10-iodomethyl-1,2-benzanthracene can be converted to a methyl group using SnCl2 in conc. HCl."

However, I am concerned that the ring might be too activated to perform a chloromethylation on 2,5-dimethoxybenzaldehyde.  I am surprised I can't find a synth anywhere for 4-methyl-2,5-dimethoxybenzaldehyde that stems from this aldehyde.  Every DOM synthesis I have seen starts with a compound that has the methyl group already on there.

I will have to synth the dioxane for the reduction thou.. Is antifreeze the only OTC source of ethylene glycol?  Merck states distillation of ethylene glycol with dilute sulfuric acid yields dioxane.  However, I can't perform a fractional distillation and this stuff is soluble in everything and forms azeotropes with everything.  I could just reflux dilute sulfuric acid with antifreeze but I am sure antifreeze is not pure ethylene glycol, and I am at a loss as to how I would clean this up afterwards.  Any thoughts?

Other than that, this should be money.  From the alcohol to the appropriate benzaldehyde in just three steps would be a dream.

[Nicodem]

Psyloxy: I’m sorry to say that the

Patent US2401608

“relates to the nuclear methylation of phenols” and not methoxy benzenes. To bad, it would be quite useful otherwise. (However, thanks for showing me the

Post 355321

(foxy2: "formylation by the "nitroso" method", Novel Discourse) which otherwise always escaped my enquiries.)

phenethyl_man: What do you mean by: “However, I am concerned that the ring might be too activated to perform a chloromethylation on 2,5-dimethoxybenzaldehyde.” You probably meant “not activated enough”?
Anyway, there was a discussion in a thread about whether it is possible to chloromethylate methoxybenzaldehydes or not. Somebee uploaded a French paper with such example (UTFSE) so it was concluded that maybe it might bee also possible to chloromethylate 2,5-diMeO-benzaldehyde. But I would not dare to speculate on which position the chloromethyl group would attach since there are too much anomalies here.
BTW, please add references to your propositions since it is very frustrating evaluating schemes without scientific value.

[psyloxy]

Nicodem: Yeah, right - I was a bit quick on implementing said patent, as I only concentrated on the methylol-sidechain.

phenethyl_man:

My gut-feeling tells me I wouldn't trust the 2^nd step. However, I'd be most grateful if you'd prove me wrong here.

What also comes to mind is:

1) reduce the benzyl alcohol (or the benzaldehyde) to the toluene with HCO₂NH₄ / Pd/C.

Tetrahedron Lett., 29,31.1988;3741-3744
Various methoxy substituted benzaldehydes are reduced in 10 to 25 min, yields are 57 to 70%.

You could just as well use the benzyl alcohol in that reduction, as it is an intermediate anyway.

A typical procedure for reduction of aldehydes and ketones is as follows: To a stirred suspension of an appropriate aldehyde or ketone (7.5 mmole) and 10% Pd-C (350 mg) in glacial acetic acid  (10 mL), the anhydrous ammonium formate (38 mmole) was added in a single portion under argon. The resulting reaction mixture was stirred at 110°C ⁺ 5°C for 10-30 min. The progress of reaction was monitored by TLC and GC. After completition of the reaction, 50 mL of CHCl₃ was added, and the catalyst was removed by filtration through a celite pad and washed with CHCl₃ (20mL). The combined organic filtrate was washed with water (2 x 20 mL), then with saturated NaHCO₃ solution (2 x 20 mL) and dried over anhydrous Na₂SO₄. The inorganic filtrate on evaporation, either under reduced pressure or at normal pressure, affored the desired product, which was further purified by column chromatography over silica gel using an ethyl acetate:hexane mixture as the mobile phase.

2) reduce the 2,5-dimehoxybenzaldehyde to 2,5-dimethoxytoluene with Zn/Hg, see

PiHKAL

(https://www.erowid.org/library/books_online/pihkal/pihkal036.shtml) EDIT: URL corrected.

Then go on as in one of the more well known (and known to work) procedures.

good luck,
--psyloxy--

Edit by Rhodium:

This reference is also available here:

Reduction of Aldehydes and Ketones to Methylene Derivatives Using Ammonium Formate as a Catalytic Hydrogen Transfer Agent
Siya Ram and Leonard D. Spicer

Tetrahedron Letters 29(31), 3741-3744 (1988)

(https://www.thevespiary.org/rhodium/Rhodium/chemistry/cth.carbonyl.deoxygenation.html)

Summary
Various aromatic aldehydes and ketones were reduced to the corresponding hydrocarbons using ammonium formate as the hydrogen source.

[Vitus_Verdegast]

reduce the 2,5-dimehoxybenzaldehyde to 2,5-dimethoxytoluene with Zn/Hg,

In the PiHKaL link you provided, there is only an example of the Wolff-Kishner reduction of 2,5-dimethoxyacetophenone.

I don't remember the details, but in the past I was also considering this, and from what I've heard a Clemmensen reduction of 2,5-DMBA will be low-yielding and messy. But I cannot provide a reference to back up this statement..

[psyloxy]

Sorry, I was so sure it was 2C-E that I didn't even look into the rxn details - turns out it is to be found under 2C-P.

Reduction of 2-hydroxy-5-methoxybenzaldehyde to 2-hydroxy-5-methoxytoluene w/ Zn/Hg, HCl:
Baciocchi, Enrico; Rol, Cesare; Sebastiani, Giovanni V.; GCITA9; Gazz.Chim.Ital.; EN; 112; 11/12; 1982; 513-518.

--psyloxy--

[Vitus_Verdegast]

Shulgin uses 150 gr Zn and 15 gr HgCl₂ for 20 g of the propiophenone, only to obtain 7,2 g 2,5-dimethoxypropylbenzene   .

Seriously, there must be something better then this.

[phenethyl_man]

Yes, that Zn/Hg reduction has quite an awful yield but at least the materials are available and I know it works (unlike my chloromethylation reaction.)  Perhaps the procedure can be tweaked and I can do it better than old shulgin

I am also suprised at the high quantities of reagents needed for this reduction.  150g of zinc and 15g of mercuric chloride for that kind of yield?  Perhaps I should try the Al/Ni reduction instead..

nicodem:  I know the chloromethylation reaction is sketchy at best.  Sorry for the lack of references, most all can be found on rhodium.

The oxidation of benzyl alcohols to aldehydes in solvent free conditions was on rhodium but now I can't find it and only have a printed copy.  I believe it's from Tetrahedron.  It involves the use of copper sulfate pentahydrate and alumina with KMnO4, however they don't use CuSO4 for the oxidation of benzyl alcohols.  KMnO4 is simply mixed with alumina and the alcohol is added and everything is stirred magnetically for 45 mins.  An organic solvent is then added and the product extracted.

I know this reaction works, I've performed it before to create piperonal from 3,4-methylenedioxybenzyl alcohol.

There is no reference for the chloromethylation of 2,5-dimethoxybenzaldehyde, I was just hoping it was going to work.   I cited the reduction of the benzyl chloride in another post.  I may just end up going that route, here is a reference for the chlorination of benzyl alcohol: 

https://www.thevespiary.org/rhodium/Rhodium/chemistry/pea.benzyloh.html

"p-Anisyl alcohol (100 g, 0.725 mole) was shaken with 500 ml of concd HCl for 2 min. The organic phase was washed with H20, 5% NaHCO3 and H2O"

The mandelic acid patents can easily be found by doing a search on this forum.

The formation of the aldehyde from benzyl chloride, NaOH/KOH, and 2-nitropropane can be found here:

https://www.thevespiary.org/rhodium/Rhodium/chemistry/halide.carbonyl.html

"In a 200-ml. two-necked flask fitted with a mechanical stirrer and a reflux condenser, 14 g. (0.25 mole) of potassium hydroxide was dissolved in 25 ml. of water. 2-Nitropropane (22.2 g., 0.25 mole) was added, and the hot mixture stirred to a clear yellow solution. Benzyl chloride (31.7 g., 0.25 mole) was added, and the mixture stirred and heated under reflux for two hours. After cooling, the mixture was filtered through a glass wool plug to remove precipitated potassium bromide, washing with 50 ml. of ether. The ether layer was separated, washed with 25 ml. of water, dried over magnesium sulfate, and distilled. A small amount of acetoxime crystallized in the condenser (b.p. 52°C (18 mm.)), m.p. and mixed m.p. 61-62°C. The benzaldehyde was collected at 62°C (1 mm.), 13 g. (49%); phenylhydrazone, m.p. 157-158°C.7"

The formation of the nitrostyrene with cyclohexylamine and nitroethane can be found under the MDMA synthesis in PiHKAL and the reduction he uses on the ketone is almost the same way to reduce a nitro compound, no amination is required though of course.

[phenethyl_man]

I should add a few things..

nicodem:  yes, that should say "I think the ring may be too deactivated."  my bad..

I have decided to move ahead with the first scheme I presented, since that chloromethylation of 2,5-dimethoxybenzaldehyde just does not seem feasible.. If I was going to work it that way I would just take it all the way to the amine and then chloromethylate that and try to reduce it.

The only modification I'm going to make to the referenced procedures is I am going to try using DMSO instead of dioxane (since I still have no source for the stuff) in the reduction of 2,5-dimethoxybenzyl chloride.  However, I am still debating between that and attempting to make the dioxane from antifreeze.  I am also going to perform the first two steps in one flask without isolation of the benzyl chloride, since the next reaction requires HCl anyways..

Anyone have any constructive criticism as to why or why not DMSO will work in this reduction?

In case anyone hasn't been following along, the reduction I am refering to is the following..

Koetschet, J. P., Helv. Chim. Acta, 1930, 13, 474-482:

4-Hydroxy-3-methoxy-5-methylbenzaldehyde

Enough p-dioxane (~400 mL) was added to ensure dissolution of the solid at 60-70°C. Then with efficient (mechanical) stirring 337.5 g (1.5 mol) of SnCl2·2 H2O was added and the mixture was refluxed for 30 min. After cooling to 25°C and dilution with 200 mL conc. HCl, the mixture was extracted with CHCl3 (5 x 150 mL). The combined organic layers were washed with 6 N HCl, water, 10% NaCl solution and then evaporated in vacuo to dryness. The crude residue was adsorbed on silica gel (63-200 mesh, 70 g) by adding silica gel to a solution of the crude in CHCl3 and then evaporating the solvent in vacuo. A slurry of the mixture in CHCl3 was then applied on a column of silica gel (100 g) and eluted with ether-hexane (2:1). Evaporation of eluents followed by sublimation (0.1 mm, 120°C) of the grey solid residue gave 70.6 g (85%) of 1 as a white granular solid: mp 99-101°C (lit.2 mp 99-100°C).


I appreciate everyone's comments and ideas so far..  Hopefully, I will be posting my yield of DOM in the not too distant future


- phenethylman -

[Rhodium]

That reference is incorrect - you have lifted that procedure from

Synth. Commun. 13, 677-683 (1983)

(https://www.thevespiary.org/rhodium/Rhodium/chemistry/5-methyl-vanillin.html)

[Nicodem]

I'm afraid DMSO oxidazes benzylchlorides to to benzaldehydes at elevated temperatures.
There are also examples of benzylalcohols being oxidazed to benzaldehydes in HCl/DMSO. I can look for some examples if you need that for your benzylalcohol oxidation. Besides, also SnCl2 would very probably reduce DMSO. I would rather try diglyme or something similar if you can't get dioxane.

[phenethyl_man]

rhodium:  my apologies, the reference I gave was actually the literature that they cite for the mp of 4-hydroxy-3-methoxy-5-methylbenzaldehyde in that very same article...

I was so exhausted when that was written that I shouldn't have been citating anything, I guess not sleeping at all can do that..