organichem - 18-9-2013 at 02:21
Hi folks,
I'm new here at the SMDB, I've been reading quite a while and decided to register finally. As german I have quite big trouble optaining chemicals
anyways and prepare a lot of them by myself. I'm very interested in organic chemistry and at the moment I'm looking for a synthesis
of gentisaldehyde aka 2,5-dihydroxybenzaldehyde.
There is the possibility of the elbs-oxidation starting from salicylaldehyde but the yield is not optimal (recovering a lot of unreacted aldehyde)
and the volumes are quite high[1]. My idea was starting from 4-methoxyphenol; I prepared 5-methoxysalicylaldehyde via the Mg-formylation from
Klute[2].
Now I've been thinking of preparing the ethylene acetal and then do an oxidative demethylation to the quinone[3], reducing this with dithionite
and hydrolyse back to the aldehyde with dilute acid. Problem is that the demethylation using oxone would probably cleave the acetal because of it's
acidic nature, and eventually produce the catechol - so I was thinking of using NaHCO3 for buffering as it's done in the oxidation of
aldehydes[4]
Does anyone of you know if it's possible in that way?
[1] W. Baker and N. C. Brown, J. Chem. Soc., 1948, 2303
[2] o-formylation of phenols
[3] An Efficient Catalytic Oxidation of p-Alkoxypenols to p-Quinones Using Tetrabutylammonium Bromide and Oxone®
Chem. Pharm. Bull. 59(1) 132—134 (2011)
[4] Oxidation of Aldehydes with Oxone ® in Aqueous Acetone
Tetrahedron 54 (1998) 401-410
Nicodem - 19-9-2013 at 07:10
I did not check the literature, but such a two step demethylation by oxidation/reduction might not work as you want, even with the acetal protection.
Not to mention that you would have to apply one step to introduce the protecting group and four steps to remove it (including an additional protecting
group just to remove the other). The overall yield would be miserable, if it worked at all. Even the Elbs oxidation would give a better yield.
Your plan is somewhat similar to what has been reported in DOI: 10.1021/jo00905a035 where they use the benzaldehyde diacetate derivative as the
protecting strategy.
I think you would do better with a direct formylation of hydroquinone. There are three types of formylation that are reported to work with
hydroquinone:
- Mg-directed formylation: JP06056732, JP06056731, JP06087783.
- The related Sn-directed formylation is also described: DOI: 10.1039/P19800001862
- The Reimer-Thieman formylation: Journal of Chemical Research, 36, 85-89 (a 33% yield is reported); see also the older references in the
Organic Reactions, 28 review of this reaction.
The modified Duff formylation on the monoacetyl or monobenzoyl ester is reported to give the corresponding 5-acyloxysalicylaldehyde, which can be
deacylated to gentisaldehyde (DOI: 10.1016/j.carres.2012.10.006). Requires three steps from hydroquinone and the yield of the formylation is not really the best (most likely
due to the deacylation during the formylation). The "sulfuric Duff formylation" might work and the O-acylation might be applicable as part of the process. Actually, I'm not even sure the modiffied
Duff formylation would not work on hydroquinone itself - it is certainly worth trying first.
organichem - 22-9-2013 at 06:36
Thanks, Nicodem for the papers, I'll get a look on them next week.
Well I just thought it would be suitable for me starting from mequinol
because I've got about 800 g left and so enough to try.
Nevertheless I think I'll gonna give it a try (the acetal-demethylation)
and report about the results.
Nicodem - 24-9-2013 at 08:18
Given that you prefer to start from p-methoxyphenol and you already formylated it, you might explore the direct demethylation. The examples in the
literature use BBr3 or other predictable reagents that you might or might not have access to. However, you can do some research and try out
more amateur convenient methods. You can try a reflux in 48% hydrobromic acid, for example. Or if you have access to a pressure vessel you can use 37%
hydrochloric acid. It relatively easily demethylates anisols at 120-140 °C. Even reflux in azeotropic hydrochloric acid might work, if you add some
NaI or KI. The 5-methoxysalicylaldehyde might be soluble enough at such temperatures, though I'm not sure if the gentisaldehyde is stable enough.
organichem - 29-9-2013 at 05:28
Yeah, Nicodem - sadly I'm not the person who has access to such things like BBr3...
I got several mLs of 48% HBr and might try a demethylation with it, but I thought it might affect my educt.
Trial and error 
Anyways - this week I have enough work and next week I'm not at home so no time to try.
Has anyone suggestions for the eluent system of tracking the reaction via TLC? I'm not very keen on
them - I would try probably a mixture of MeOH/EtOAc first, because the product is somewhat polar...
DJF90 - 29-9-2013 at 12:40
Try 50% ethyl acetate in heptanes. I reckon that'd do it.