Alkylating the 4- position of 2,5-dimethoxybenzaldehyde

[Rabidreject]

Hey everyone,

I’ve been looking into an alternative route to 2,5-dimethoxy-4-alkylbenzaldehydes, which are key intermediates in certain syntheses. Instead of going through the usual P2P-style alkylation of the ketone, I’m considering an electrophilic aromatic substitution (EAS) + Grignard approach.


Proposed Route:

1. Brominate 2,5-DMOBA (2,5-dimethoxybenzaldehyde) at the 4-position

• This should be straightforward via Br₂/AcOH or NBS.

2. Form the Grignard reagent by reacting the 4-bromo-2,5-DMOBA with Mg in dry ether (or THF).

3. React with an alkyl halide (e.g., ethyl bromide or methyl iodide) to replace Br with the desired alkyl group.



Questions:

• Has anyone here successfully alkylated the 4-position this way?

• Are there any major complications or side reactions I should watch out for?

• Would iodination instead of bromination work better, or would it introduce stability/reactivity issues?

• Could a lithium-halogen exchange (n-BuLi) method work better than a Grignard?



I’ve mostly seen people buy the pre-alkylated ketone rather than alkylate the aldehyde directly, so I wanted to confirm that this approach is solid before diving in.
I can make my peace with the yields being shit and it being an in efficient route but It would be comforting to know it would work before starting.




Any insights or experience would be appreciated!

Thanks

 

[FENTAMAS]

Still reinventing new routes?)
My advice for you is to just follow well documented and confirmed convenient preparative methods to the target precursors, at least until you become very well skilled in practical organic and analytical chemistry.

Look how Shulgin prepared alkylated aldehydes for 2C-D, 2C-E, 2C-P, DOPR and DOAM via carbonyl intermediate reduction (prepared by acylation with acyl chloride or by polyphosphoric acid method). There are also some improved procedures on the SM forum that was already mentioned here (look https://www.sciencemadness.org/whisper/viewthread.php?tid=157496&page=3#pid678852).
As for your questions, yes, someone has successfully get this done, and yes, there are also other, more elegant and sophisticated ways to get that 4th position alkylated, like direct lithiation of 1,4-Dimethoxybenzene or 2-Bromo-1,4-Dimethoxybenzene with n-BuLi and then reacting it with alkyl halide, but you should invest money and time in your lab and skills to safely and properly work with such stuff.

 

[Rabidreject]

Yeh okay that’s a fair response. I was mainly just curious if going from the 2,5-DMOBA was even possible but I guess making anything from almost anyway in chem is ‘possible’ just generally not done or efficient!

I do understand that most people go from the 2.5-DMOacetophenone, either to the aldehyde I am asking about - or even from the acetophenone to


Thanks A BUNCH for linking me to that write up above - I know you linked me before but somehow I lost the post that it was linked in and I guess I asked about it before I was even nearly ready to understand what was going on.

Honestly; I was just going to follow the 2c-e and 2c-d procedure that is written up on this forum in the post with all the 2c-x compounds in one place - you may have even written it, I dunno but It uses some WEIRD reactants like hydrazine and this mad, diethyl methyl ethyl ether or some random ass shit!

Also please understand - this is less about having 2c-e to either take or sell and more about the chemistry and understand different chemical routes to modify elements of the phenyl ring.
YES, of course I love 2c-e but I figure, I have done the reduction of the standard b-nitrostyrene to 2c-h, I have done the halogination with both bromine and iodine and so the next logical step would be learning how to alkylate. I had seen someone (I think on poo tube), use bromination on a ring as a means of adding a methyl group, so I figured if that worked, why wouldn’t it work for this…

I am probably more interested in 2c-d than 2c-e as I have done A LOT of 2c-e in my life. So far 2c-e is my fav of the standard 2c compounds but as I say, iv not tried the methyl or any alkyls other than ethyl.

That’s interesting though, I just wondered if it could be done from 2,5-DMOBA as I have a load of it and I def don’t need much 2c-e or 2c-d or whatever alkyl group.
Thanks for your reply!

 

[Rabidreject]

yeah looking into it, if I were to try it, I would probably…


Step 1: Brominate 2,5-DMOBA → Get 2,5-DMO-4-Br-BA.


• Step 2: Ethylate via Negishi coupling (EtZnBr + NiCl₂) → Get 2,5-DMO-4-Et-BA.


• Key optimizations: ZnCl₂ can help transmetalation, and NiCl₂(dppp) could improve yield if needed.

I may try it at some point but honestly yeah you are almost certainly correct about just starting from the ketone…

Another thing I need to buy…

 

[i_can_see-you_can_not]

These methods you think about won't work with the aldehyde, as this functionality is of course reactive against Grignard or organo zinc compounds. It may work after protecting the aldehyde as acetal. The Friedel-Crafts-acylation of 1,4-dimethoxybenzene is very easy, so is the Wolff-Kishner reduction, but of course the latter requires very toxic hydrazine and I don't think you are ready to work with that. The method works very nice though, if you follow newer procedures from Sciencemadness or Hyperlab. If you can find ways to work with pressurised hydrogen, Pd/C reduction of the ketone is a valid option too.

Wolff-Kishner also works flawlessly on 2,5-dimethoxybenzaldehyde towards 2,5-dimethoxytoluene, from there - just like with 1-ethyl-2,5-dimethoxybenzene - sulfuric Duff as shown by Ullmann and Benignium on Sciencemadness, miamiechin on Hyperlab and pyramid on Vespiary to proceed without problems.

If you really want wo work with the benzaldehyde, I think it is more viable to look into the Grignard of 2,5-DMBA with MeMgBr. It should be possible to reduce the resulting benzyl alcohol as its acetate, tosylate or by turning it into the alkyl chloride with NaBH4 and Ni or Co salts (I don't remember exactly, but search the literature).

You can also look into Fe-catalysed coupling methods of 1-halo-2,5-dimethoxybenzenes with Grignards, this I think can also be a quite fruitful endeavour.

I can very much encourage you to overcome the challenges associated with the synthesis. 2C-E is a worthwhile compound and even more so if you made it yourself, maybe even using new methodology. It is not even that hard (the classical route, that is). Oh, and 2C-D is very cool too.

 

[Rabidreject]

Thanks a lot for your reply!
Oh okay so you can go from 2,5-DMOBA
To 2,5-dimethoxytoluene - yeah I actually looked at a method that went from 2,5-DMOT I think but it was probably rubbish chat GPT stuff.

Yeh I did think it might fuck with the aldehyde - I wondered if you could do it on the amine as well but again I don’t think that’s viable.

Yeah it’s not the skill level that puts me off, it’s that I need stuff I don’t have now! Haha

Also yes 2C-E is my favourite phenethylamine that I have tried so far but I have not had any since the good old research chemical days - and VERY early on in that period as well!

I will get there eventually as well as 2c-d.
At the moment I am making TMA with intention of resolving enantiomers and bioassaying.
I also wonder about N-methylation of these psychedelic amphetamines because obviously N-methyl amphetamines tend to have higher lipophilicity than non methylated. So I am curious.
Same with NMTMA 2 as well tbh…

 

[i_can_see-you_can_not]

It is probably better to go via toluhydroquinone to 2,5-dimethoxytoluene, but the Wolff-Kishner works good. I do want to make myself very clear though that hydrazine is nothing to be messed with.

I think the classic outline of the Shulgin route is the way to go with these compounds, although I'd certainly encourage thinking outside the box. Just follow newer experimentals and not the ways in PiHKAL. Also formylation of the electron-rich substrates is more "OTC" with H2SO4 cat. Duff reaction.

Personally I don't believe the N-methylated compounds to be all that worthwhile, at least not in terms of potency. But they may be hidden gems. Make them, taste them.