Methylated PEA benzaldehyde precursors

[Manichi]

High bees!  

I want to share with you this part of the experimental of the article J.Med.Chem. 39(16) 1996, 3148-3157. (hosted by Pharmacist here:

http://pharmacist.the-hive.tripod.com/juno.pdf

, Thanx Ph!   )

They synthetise from 2,5-dimethoxy-3,6-dimethylbenzaldehyde (precursor to JUNO) another methylated benzaldehyde: the 2,4,5-trimethoxy-3,6-dimethylbenzaldehyde (precursor to 3,6-dimethyl-TMA-2), through 4-Hydroxy-2,5-dimethoxy-3,6-dimethylbenzaldehyde (precursor to 3,6-dimethyl-MEM analogs). The synthesis has good yield and the final products are highly interesting for the PEA-SAR fanatics.  

Also the route can bee followed to achieve other strange and atypical PEAs, like some 2,3,5- and 2,3,6-  analogs, lets make 'em and taste 'em too!  

Here we go:

General Procedure for the Synthesis of the Aldehydes 10, 14, and 17: Representative Route to the Aldehyde 10a.

2,5-Dimethoxy-3,6-dimethylphenol (8a).

m-Chloro-perbenzoic acid (70%, 130 g, 0.53 mol) was added portionwise to a solution of 2,5-dimethoxy-3,6-dimethylbenzaldehyde (7a) (94 g, 0.48 mol) in dichloromethane (660 mL) with stirring at room temperature. The mixture was heated to reflux for 30 min, then ice (Z00 g) and a saturated solution of sodium thiosulfate (200 mL) were added. The resulting solid were filtered off and washed with a small amount of dichloromethane. The combined organic layer was washed successively with 1 N sodium hydroxide and brine, dried, and evaporated. The residue was dissolved in methanol (250 mL). To the solution was added 28% sodium methoxide in methanol (120 mL, 0.59 mol), and the mixture was stirred at room temperature for 30 min. Ice-water (300 mL) was added to the reaction mixture, and then the mixture was neutralized with 2 N hydrochloric acid affording white precipitate. The solid was collected by filtration, washed with water, and dried to afford crude 8a (75 g, 0.41 mol, 81%) as a white solid, which was used for the next step without further purification: 1H NMR (400 MHz, CDCl3) S 2.13 (s, 3H), 2.27 (s, 3H), 3.75 (s, 3H), 3.77 (s, 3H), 5.73 (br s, 1H), 6.29 (s, 1H).

4-Hydroxy-2,5-dimethoxy-3,6-dimethylbenzaldehyde (9a).
 
To the solution of 2,5-dimethoxy-3,6-dimethylphenol (8a) (31 g, 0.28 mol) in dichloromethane (330 mL) was added titanium(IV) chloride (40 mL, 0.36 mol) under 10 °C, and the resulting deep purple solution was stirred for an additional 15 min at 0 °C. a,a-Dichloromethyl methyl ether (39 mL, 0.43 mol) was added to the solution under 15 °C, and the mixture was stirred at room temperature for 2.5 h. The reaction was quenched carefully with 300 mL of ice-water and the mixture extracted with ethyl acetate twice. The organic layer was washed successively with saturated sodium hydrogen carbonate and brine, dried, and evaporated. The residue was treated with ether, and the resulting solid was collected by filtration and washed with a small amount of ethanol and n-hexane (1:1) to afford 9a (38 g, 0.18 mol, 65%) as a white solid, which was used for the next step without further purification: mp 168-169 °C (EtOH-n-hexane); 1H NMR (400 MHz, CDCl3) d 2.20 (s, 3H), 2.52 (s, 3H), 3.75 (s, 3H), 3.81 (s, 3H), 6.40 (s, 1H), 10.39 (s, 1H).

2,4,5-Trimethoxy-3,6-dimethylbenzaldehyde (10a).

To the solution of 4-hydroxy-2,5-dimethoxy-3,6-dimethylbenzaldehyde (9a) (38 g, 0.18 mol) in N,N-dimethylformamide (300 mL) was added sodium hydride (60% oil suspension, 8.0 g, 0.20 mol) with stirring in an ice bath. After 15 min, iodomethane (12.5 mL, 0.20 mol) was added dropwise to the reaction mixture at room temperature. The mixture was stirred for an additional 3 h, the reaction was quenched with water, and the mixture was extracted with ethyl acetate twice. The organic layer was washed with brine, dried, and evaporated. The crude residue was purified by flash column chromatography on silica gel (solvent: ethyl acetate-n-hexane = 1:9) to afford l0a (41 g, 0.18 mol, >99%) as a yellow solid: mp 29-30 °C (ethyl acetate-n-hexane); 1H NMR (400 MHz, CDCl3) d 2.20 (s, H3), 2.48 (s, 3H), 3.75 (s, 3H), 3.79 (s, 3H), 3.92 (s, 3H), 10.43 (s, 1H).

[Rhodium]

They aren't telling where they got the starting benzaldehyde from, and the only literature prep in Beilstein was through Gattermann formylation of para-Xyloquinone, found in J. Org. Chem. 6, 427-431 (1941) and J. Amer. Chem. Soc. 59, 673-678 (1937).

The starting material, para-Xyloquinone, is commercially available but pretty expensive, as it is relatively hard to make [sad]

[ning]

ning appologizes in advance if this is out of place, but since ning has been studying quinones so much of late, a thought came to the fingers...

p-xyloquinone is quinone of p-xylene, right?

assuming you had p-xylene, ning can't see why it would bee so hard too:

mononitrate p-xylene (can't miss on this one...only one place to go!)

reduce to 2-amino p-xylene with zinc or iron powder

oxidize thru to quinone using one of the many methods in posession of the hive, preferably something involving bleach.

Now that doesn't sound like such an expensive route to ning...hope it's not too obvious to all you master chemists

[Rhodium]

I made a literature search once on that (hydro)quinone and it seemed like most of the usual routes were very low-yielding  

[Chimimanie]

The above mentioned hydroquinone (2,6-dimethyl-hydroquinone) can bee made with reasonable yield (20-30%) through Elbs-persulfate oxydation of 2,6-Xylenol, I have the paper somewhere, IIRC it is J. Chem. Soc. 2303 1948W. Baker, N. C. Brown found from this old thread

Post 122784

(dormouse: "Bromo-benzodifuranyl-isopropylamine  -Lilienthal", Serious Chemistry).

I agree with what you said in this thread Rhodium:

Still, making 2,5-dimethoxy-4,6-methyl-amphetamine (6-Me-DOM) from 2,6-dimethyl-p-hydroquinone would be very interesting. The compound should be really active.

as, AFAIK the 6-methyl group push the side chain downward in a good conformation, contrary to the 2-methyl group which push it upward in a less good conformation (also 2-ethoxy tweetios are less potent too). I remember this from somewhere i dont remember, I think it was from some paper on ring-methylated MDA analogs, and I also think the 3-methyl didnt have such a strong steric effect (as it is located further from the side chain).

In conclusion AFAIK:

- 2-methyl-DOM (if it existed, but only the tweetio (methoxy replaced by ethoxy) can exist, it is called Florence in Pihkal and has not been bioassayed yet) should be less potent than DOM:

Quote from Pihkal,

2C-D entry:

(http://www.erowid.org/library/books_online/pihkal/pihkal023.shtml)

In every compound to be found in the 2C-X family, there are two methoxy groups, one at the 2-position and one at the 5-position. There are thus three possible tweetio compounds, a 2-EtO-, a 5-EtO- and a 2,5-di-EtO-. Those that have been evaluated in man are included after each of the 2C-X's that has served as the prototype. In general, the 2-EtO- compounds have a shorter duration and a lower potency, the 5-EtO- compounds have a relatively unchanged potency and a longer time duration; the 2,5-di-EtO- homologues are very weak, if active at all.

The 2-EtO-homologue of 2C-D is 2-ethoxy-5-methoxy-4-methylphenethylamine, or 2CD-2ETO. The benzaldehyde (2-ethoxy-5-methoxy-4-tolualdehyde) had a melting point of 60.5-61 °C, the nitrostyrene intermediate a melting point of 110.5-111.5 °C, and the final hydrochloride a melting point of 207-208 °C. The hydrobromide salt had a melting point of 171-173 °C. At levels of 60 milligrams, there was the feeling of closeness between couples, without an appreciable state of intoxication. The duration was about 4 hours.

2CD-2ETO is the 2C, phenethylamine homologue of Florence (3C, amphetamine homologue)


- 3-methyl-DOM exist, it is

Ganesha

(http://www.erowid.org/library/books_online/pihkal/pihkal085.shtml) in Pihkal.

Its potency is a bit lowered, but not too much vs DOM (DOM: 3-10mg vs Ganesha: 20-32mg), and is a bit more long lived (DOM: 14-20h vs Ganesha: 18-24h).

So, I conclude the 3-methyl change slightly the duration and require 2 or 3x the same dosage, which is still quite good IMHO.


- 6-methyl-DOM exist, it is Juno in Pihkal, but sadly it is untested:

Quote from Pihkal,

Ariadne entry

(http://www.erowid.org/library/books_online/pihkal/pihkal008.shtml)

And, finally, JUNO (3,6-dimethoxy-2,4-dimethylamphetamine) has been made (from 2,5-dimethoxy-m-xylene, which was reacted with POCl3 and N-methylformanilide to the benzaldehyde, mp 53-54 °C, and to the nitrostyrene with nitroethane, mp 73-74 °C from cyclohexane, and to the final amine hydrochloride with LAH in THF). Rather amazingly, I have had JUNO on the shelf for almost 14 years and have not yet gotten around to tasting it.

Personally I think Juno will bee, by extrapolation of the work on side chain configuration of methylated MDA analogs:

    -Slighty more potent or at least equal potency than DOM.
    -Slighty more long lived (wild guess from Ganesha).
    -Of course very interesting.

Also, I have in this ref: Journal of Organic Chemistry, 48(17), 2932-3, 1983

the preparation of the above mentioned quinone (2,6-dimethyl-quinone) from 2,6-xylenol, by bichromate oxydation, easily, in good yield and big scale.

The abstract of this paper is:

Jones oxidn. of alkylphenols was a simple effective method for the large scale (30-60 g) prepn. of p-quinones, which usually gave quinones of reasonably high purity without chromatog. purifn.  Six quinones thus prepd. included I-III.

And they claim the reaction 2,6-dimethyl-phenol ---Na2Cr2O7, H2SO4---> 2,6-dimethyl-quinone in 84% yield.

(in general alkylated quinones are easier to prepare than non alkylated ones btw)

This quinone can be reduced to the hydroquinone easily by shaking with sodium dithionite aqueous solution. Trimethylphosphate or any other methylating agent can then alkyl both phenols. For DMS check this ref, it could be interesting: Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry (1997), 36B(11), 1044-1046.

The real problem is in the formylation, as i have found no refs for this except the one from Pihkal.    Further research is needed, it must exist a preparation somewhere!

As a side note, an alternative attractive procedure someone has to try is to use the beautiful reactivity of the quinone to our advantage. With a bit of luck, the 2,6-dimethyl-quinone will react with allyl-oxalate in the presence of AgNO3/Persulfate, to yield the allyl quinone in one step! (see

Post 471656

(Chimimanie: "Why i prefer p-Meo-phenol?", Novel Discourse) and Chem. lett. 1992 7 1299)

2,6-xylenol --Jones Oxydation--> 2,6-dimethyl-quinone --allyl-oxalate, AgNO3/persulfate--> the allyl-quinone --1.dithionite, 2.methylation--> 2,5-dimethoxy-4,6-dimethyl-allylbenzene --> to Juno

...will obviate the need to use POCl3 which is a watched chem.

Please someone find some formylation refs for the 2,5-dimethoxy-m-xylene! Rhodium: your refs seems interesting, I will check them, thx!  

[Rhodium]

Simple, inexpensive procedure for the large-scale production of alkyl quinones
Dennis Liotta, Jack Arbiser, James W. Short, Manohar Saindane

J. Org. Chem.; 1983; 48(17); 2932-2933 (1983)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/alkylphenol2alkylquinone.pdf)

[moo]

Process for the preparation of quinones

Patent EP0249289

Phenols are oxidated to quinones with hydrogen peroxide in the presence of catalytic amounts of bromine, iodine, hydrogen bromide and hydrogen iodide.

2,6-dimethylbenzoquinone from 2,6-dimethoxyphenol, yield 85%.

[Rhodium]

Checking out Gattermann formylations, I found that 2,5-dimethoxybenzaldehyde is prepared with that method in the following articles:

· Justus Liebigs Ann. Chem. 357, 373 (1907)
· Chem.Ber. 40, 840 (1907)
· Chem.Ber. 40, 2357 (1907)
· J.Chem.Soc. 1482 (1928)

A superior method seems to be the one used in

Patent FR1415670

but as I cannot read french, I could only see some bragging about "rendement supériurs à 90.5% et souvent quantitatif" which sounds nice, regardless of what language it was written in. Maybe someone can decrypt and post the essential improvements they made to the method?

[Antoncho]

i can't read French either , but what i managed to read witnesses the fact that they use liquid HCN , which isn't the nicest of all alternatives, definitely


A-cho

[ning]

To convert that hydroquinone to an allylbenzene? Use the allyl chloride, and then heat. As far as I know, when the claisen rearrangement is blocked, it moves to the next available position. Though whether that includes the meta position, not sure.

[Rhodium]

It doesn't - only ortho/para.

[ning]

[Rhodium]

Even if we pretend that no side reactions occur in that wild soup, the methyl groups would add in 2,5-orientation as the position para to the first introduced methyl group would be the most activated one after the first was introduced.

[Vitus_Verdegast]

ning, I really admire your enthusiasm and commitment towards chemistry, but I have to ask you...


...are you sponsored by a company that produces acetaminophen?  

You seem to have quite some affection towards using acetaminophen as a precursor for just about anything. A query on TFSE showed that you already made 23 posts on the subject.

If you keep this trend going, one day you'll probably earn the title 'acetaminophen'.  

[ning]

Shh! Don't let the word get out, or all the tylenol codeine people will lynch me! Looks like somebody on high thought your suggestion was a good idea...
Seriously, with 50 grams of the stuff, almost pure, off the shelf, so close to quinone and who knows what else, just begging to bee experimented with, who couldn't resist? Unless you're not enough of an acetaminophanatic...

Rhodium, I have a paper that might make you reconsider that "misinforming" rating...Admittedly, they use a catalyst, but they do just what we want.
aniline --> 2,6 dimethyl aniline with MeI and Pd(OAc)2.
[mol]c1ccccc1NC(=O)C>>c1cc(C)c(NC(=O)C)c(C)c1[/mol]
Turns out the palladium acetate will selectively ortho-alkylate all manner of things in high yields. Pretty cool.

And of course, you're right, the activation will change, I know. But there must bee a way to make this xyloquinone, without catalysts...I will keep searching.

The paper will bee posted shortly.

[Rhodium]

Turns out the palladium acetate will selectively ortho-alkylate all manner of things in high yields.

And if you have both an OH and a NH₂ on the ring, which will it ortho-alkylate?

I have a paper that might make you reconsider that "misinforming" rating...

Even if you have a palladium-catalyzed aromatic alkylation procedure up your sleeve it still doesn't change the fact that you incorrectly stated that FC alkylation of acetaminophen would give 4-hydroxy-2,6-dimethylaniline. As an aromatic OH group is more activated (and a lot less sterically hindered) than an aromatic NHAc, the first alkylation would very likely end up ortho to the phenol, even... As backwards as can be.

You will continue to recieve misinforming ratings if you in the future don't check the literature more closely before posting long ranting essays about "possibilities". It is a lot more useful to people if you post one single well-researched synthesis than if you post 20 "possible" syntheses which haven't been tried in any lab ever...

A bird in the hand is worth ten in the bush, or what they say...

[Chimimanie]

If you keep this trend going, one day you'll probably earn the title 'acetaminophen'.

Hahaha    it is not acetaminophen but acetaminophanatic !

   

Ning: cannot you get xylenol? please stop propagandising for the big pharm houses in this thread...

What do you think is easier to get? Pd-diacetate or xylenol??? Really do you think xylenol or acetaminophen is more suitable here, to make xyloquinone?  

 btw i find it astounding nobody still posted the Chem. lett. 1992 7 1299 article, which ref I gave one month ago. Finally as noone seemed interested, I decided to post it there

Post 477519

(Chimimanie: "convenient procedure for allylation of quinone", Novel Discourse), as a valuable article for a possible route, that might bee very useful in this case, as we have to pass trough the quinone nonetheless, better to exploit the chemistry at its best here I think...


Please Ning, restrain your posting.... You dont have to bee in such a rush you known, you should photocopy plenty ref, keep them for yourself, think about them, compare with other, rethink about the former, then, if they finally seem worthy, you can post them... literature is huge, dont clutter the hive with useless rambling, stim bee have a hard time enough to follow, so keep it clean and simple.  

hahaha acetaminophanatic!    suit you well  

[Nicodem]

Ning: Congratulations for your new title, he, he...

But, I don't really get the point of all this theoretisizing about (alkyl)quinones synth. What is the purpose? If you would want to make DOM, Ganesha and all the other DOM positional isomers, what could be easier than electroanodic oxidation of toluene. This has already been covered a few times, check

Post 473897 (missing)

(Lego: "2,5-Dimethoxyprecursors from benzene or anisole", Chemistry Discourse). I know everybody gets scared away when they hear about electrochemistry, don't know why.
Well, instead of seeing these p-benzoquinone-bis-dimethylketals just as precursors to the p-dimetoksibenzenes try thinking of them as a beutiful substrates for 1,4-additions of carboanions that can lead directly to x-methyl-2,5-dimethoxy-P2P (where x=3, 4 or 6).
Nobody ever heard about the Nenitzescu reaction? It is used to make 5-hydroxy-indoles and 5-hydroxy-benzofuranes. The key point in its mechanism is the 1,4-addition of ethylacetoacetate (or its imine or similar) carboanion and then the cyclisation to the aforementioned cmpnds. Now if you react the ethylacetoacetate carboanion with a p-benzoquinone-bis-dimethylketal, the last step - cyclisation, is impossible and you get a product that after hydrolysis/decarboxylation gives a 2,5-dimethoxy-P2P. To all those Bees that have troubles visualizing structures (draw the other two positional isomers by yourself):

Molecule:

what do you think of this? ("C/1=C/C(\C(=C/C\1(OC)OC)C)(OC)OC.C(C(=O)C)C(=O)OCC>>c1(cc(c(cc1OC)C)OC)C(C(=O)C)C(=O)OCC")



I really don’t know why nobody posted this before? I don’t believe nobody envisioned this. Maybe some egoism at work, or everybody except me knows it does not work, or I just don’t know how to UTFSE? Ideas are made to be shared, aren’t they? Almost everything is in Lego’s post, including the examples of nucleophilic additions to these weird ketales in the Synthesis articles and all the necessary patents in the link to Bottleneck’s and PolytheneSam’s posts.
OK, if anybody knows an easier and more OTC way to DOM and its isomers, I’ll shut up and beg for forgiveness   .

Thanks to prof. Nenitzescu for the idea...

http://www.arkat-usa.org/ark/journal/2002/Nenitzescu/CN-461T/CN-461T.pdf

[ning]

First, I think the MeI would methylate the OH group.
It seems to only alkylate ortho to the acetylamino group.
This has something to do with the metal complex it forms, which has limited "reach", and also something to do with the acetate on the palladium. Or maybe not. See for yourself:

JACS 1984, 5759

And Rhodium, I said you were right and I was wrong. Did you miss that?

They also used this process to cyclize acetaniline with allyl iodide to give an indole derivative, which might be of some interest.

Here is the reactions of interest:

Molecule:

will it alkylate twice? Yes. ("CC(=O)Nc1ccccc1>>CC(=O)Nc1c(C)cccc1C")


81% yield. 15x excess MeI, 1.5x excess Pd(OAc)2 (yuck), 100 C

Molecule:

what about phenol group? ("CC(=O)Nc1c(OC)cccc1>>CC(=O)Nc1c(OC)cccc1C")


79.7% yield.

I would bee posting more "real world" results if I was in a position to do so right now. But I'm not. Sometimes it's a time for theory, sometimes it's a time for experiment, and now is my time for theory. I hope that is understandable.

[Vitus_Verdegast]

A couple of posts back Chimimanie stated in this thread:

The real problem is in the formylation, as i have found no refs for this except the one from Pihkal.  Further research is needed, it must exist a preparation somewhere!

So we learned that we can easily oxidize 2,6-xylenol to 2,6-dimethyl-1,4-benzoquinone in high yields using either dichromate (

Post 472971

(Rhodium: "alkyl quinones from alkyl phenols", Novel Discourse)) or H₂O₂ with a catalytic amount of halogen (the

Patent EP0249289

moo provided), and reducing this compound to the corresponding hydroquinone is pretty straightforward, as pointed out by Chimimanie in the abovementioned post.

What I would suggest is, instead of fully methylating the substituted hydroquinone, why not monomethylate it?
I found only 1 reference on this matter (I will dig it up after the weekend):

2,6-dimethylhydroquinone  --(MeOH, H₂SO₄)--> 4-methoxy-2,6-dimethylphenol
Chem. Ber. 36 (1903), 2033

Considering that it is similar to the preparation of p-methoxyphenol from hydroquinone/benzoquinone via the hemiketal as described in:

Post 267698

(Antoncho: "P-MeO-phenol from hydroquinone: part II", Novel Discourse)

Patent GB1557237

it would not be so unreasonable to assume that this procedure could give acceptable yields for 2,6-dimethylhydroquinone too, as it does for unsubstituted hydroquinone.


However, if this proposed procedure would turn out to be not viable, the 2,6-dimethylhydroquinone can still be monomethylated with Me₂SO₄ using one of these procedures:

Post 268898

(foxy2: "Re: P-MeO-phenol from hydroquinone: part II", Novel Discourse)

Post 267779

(moo: "Re: P-MeO-phenol from hydroquinone: part II", Novel Discourse)


When we have obtained the 4-methoxy-2,6-dimethylphenol my next suggestion would be to perform a Reimer-Tiemann formylation on it. As there is only the ortho- position that can be formylated, a Reimer-Tiemann on this phenol should give decent yields of 2-hydroxy-5-methoxy-4,6-dimethylbenzaldehyde, analogueous to what is done on p-MeO-phenol:

Post 454518

(Rhodium: "Two Syntheses of 2,5-Dimethoxybenzaldehyde", Chemistry Discourse)

Post 330714

(Antoncho: "A patented improvement", Chemistry Discourse)


Alternatively, the phenol could also be formylated with Mg(OCH₃)₂ or paraformaldehyde/amine/SnCl₂, methods that have been discussed before here.
References can be found here:

Post 273718

(Osmium: "Re: P-MeO-phenol from hydroquinone: part II", Novel Discourse)

(Ah yes, and if one is really desperate, there is always the Duff formylation to try too   , or if you happen to have some trifluoroacetic acid around..)


2-Hydroxy-5-methoxy-4,6-dimethylbenzaldehyde can then be methylated with either dimethyl sulfate and K₂CO₃ in acetone or methyl iodide and silver oxide in chloroform.

Post 475637

(Rhodium: "Synthesis of 2C-B from Anise Oil (Anethole)", Novel Discourse)

Post 425432

(Vitus_Verdegast: "J. Chem. Soc. (1923) 123, page 1587 and 1588", Methods Discourse)


I really hope that the more OTC approach, the monomethylation with MeOH/H₂SO₄ followed by a Reimer-Tiemann, will work, as this will facilitate the route to JUNO alot.  

Comments, thoughts, suggestions... ?