an underestimated way to 3,4,5-trimethoxybenzaldehyde

PSY420 · Thu Jun 30, 2005 5:35 pm

Have a look at the reactions [3], [4] and [5], they could make for a nice alternative to the 'traditional' way over 5-bromovanilline, it's also very intresting that you can get from guaiacol [1] to 5-hydroxyvanilline in only to steps with not much more at hand then simple chems like hexamine, GAA and H2O2. Rxn [2] could come in handy for those after (3C-)meta-escaline. [6] is here because it fitted in here much more so then anywhere else...

[1] Arch. Pharm. Ber. Dtsch. Pharm. Ges., 297;292-298 (1964)

TRANSLATION

preparation of 4-hydroxy-5-ethoxy-isophtaldehyde

10g 2-ethoxyphenol were cooked at reflux with 20g hexamine in 60 mL 50% AcOH for 2.5 h. Then 15 mL conc. HCl were added, the cooking continued for another 10 min, the reaction mix poured into a lot of water and the crystals separated by filtration. Yield up to 7g (50%), mp 109° from EtOH/H2O

preparation of preparation of 4-hydroxy-5-methoxy-isophtaldehyde from guaiacol

TRANSLATION

12g guaiacol were cooked at reflux with 25g hexamine in 60 mL 50% AcOH for 2.5h. Workup is done as above. Yield up to 6.2g (35,5%), yellowish crystals, mp 119-120°C

[2] Arch. Pharm. Ber. Dtsch. Pharm. Ges., 297;292-298 (1964)

preparation of 4-hydroxy-5-ethoxy-isophtaldehyde from bourbonal

TRANSLATION

5g bourbonal are cooked at reflux with 9g hexamine in 10 mL 50 % AcOH for 2.5 h. Then 5 mL conc. HCl is added and the cooking continued for another 10 min. After cooling a lot of water is added, the mix left alone for a while and then the crystalls collected by filtration. Yield: 2.9g (64%), mp 109°C.

[3] Arch. Pharm. Ber. Dtsch. Pharm. Ges., 298;148 (1965)

TRANSLATION

30g vanilline are cooked at reflux with 50g hexamine in 170 mL 50% AcOH for 2.5 h. Then 75 mL conc. HCl are added and the cooking continued for another 10 min. The intensely yellow colored reaction mixture was poured on ice whereupon citron yellow crystals precipitated (mp 112-116°C). These were dissolved in 25% KOH and precipitated by the slow addition of dilute HCl. The result is pale yellow crystals melting at 120 - 120,5 °C (water). Yield 24g (66,6%).

[4] DE530650

TRANSLATION

18g 4-hydroxy-5-methoxy-isophtaldehyde [see Helv. chim. acta, 13;482 (1930)] are dissolved in 100 mL n-NaOH (hm, this is from 1931, it probably means 'normality' which would mean 1 mol OH- per L and thus 40g NaOH / L H2O). 120 mL 3% (yes, not 30%!) H2O2 are added. The yellow solution warms up and turns dark red. The reaction mixture is extracted with ether to give a crude product that is cleaned by recrystallisation from toluene. The 5-hydroxyvanilline has a mp of
133°C.
In the beginning of the text they say the reaction gives very good yields.

The japanese are also into this, check out JP57072932 :

PURPOSE:To obtain the titled compond useful as an intermediate for drugs selectively in high yield, by oxidizing a specific 2-substituted 4,6-diformylphenol as a raw material with hydrogen peroxide in the presence of a catalyst, e.g., copper compound in a basic aqueous solution. CONSTITUTION:A 2-substituted 4,6-diformylphenol shown by the formulaI(X is alkoxy, alkyl, halogen, or H) is neutralized with an equivalent weight of a basic aqeuous solution of NaOH, etc. Afte
adding a catalyst of a copper compound or silver compound to the phenol, it is oxidized with hydrogen peroxide in the form an aqueous solution while being kept at 0-25 deg.C until a pH value of the reaction solution exhibits apporoximately 4 at 0-45 deg.C, to give the desired compound shown by the formula II. A water-soluble compound, e.g., CuSO4, AgNO3, CuCl2 ,Cu (NO3)2, Cu(PO4)2, etc. is used as the catalyst. USE:A raw material especially for 3,4,5-trimethoxybenzaldehyde, etc.

[5] US4065504

just wanted to remind everyone of this nice patent, I think Antoncho dug it up a long time ago at the Hive. It features the solventless methylation of (poly)phenols w/DMS in near quant. yields. So you see 5-hydroxyvanillin is not only interesting as starting material for myristicinaldehyde but also for 3,4,5-trimethoxybenzaldehyde.

[6] US4933498

Getting from 5-bromovanilline to 5-hydroxyvanilline features a 'continous extraction' step in all the published literature methods, yields are also not always very high, Uemura had solved this problem quite nicely by using, I think, a soxhlet w/DCM. But in this patent they do not even bother to extract the 5-hydroxyvanilline, instead they directly methylate it. Unfortunately they exclusively use MeCl under pressure, still I think it's an interesting read.

--PSY420--

Charles de Gaulle · Thu Jun 30, 2005 10:08 pm

Very interesting post, merci bien!

kid a · Fri Jul 15, 2005 4:29 am

I have a hard time believing the Duff reaction in 50% aq. HOAc gives yields that high with either vanillin or ethyl vanillin. It would interesting to hear some confirmation of these results. Trifluoroacetic acid maybe..

My reasoning behind this is simply that, eugenol, which is a more activated substrate, differing from vanillin only in that there is an allyl side-chain in place of a formyl, gives much lower yields than are reported here for vanillin. This particular reaction was used to obtain myristicin or elemicin from eugenol, and can easily be found in the rhodium archives.

Of course this applies to 2-ethoxyphenol or guaiacol as well, since ethyl vanillin and vanillin are obvious intermediates.

By varying the reaction conditions of the Dakin reaction, it is supposedly possible to achieve a very high ortho-selectivity in the oxidation of polyformyl phenols. However, I have not had very much success.

I believe I recall this being discussed on the Hive a long time ago.. Or at least some of these patents were mentioned; though don't remember hearing any reports of anyone having success with it.

Kid A

Vitus · Psychoscientist

kid a · Sat Jul 16, 2005 4:31 am

proxy · Tue Aug 02, 2005 3:48 pm

PSY420 · Wed Aug 03, 2005 2:19 am

proxy : Ethylvanillin (=bourbonal) is formylated w/hexamine (see picture), the resulting diformyl-compound is used in the Dakin-rxn (substitute for diformylguaiacol in example 1 of US4435601), the product is 3,4-dihydroxy-5-ethoxybenzaldehyde which can be methylated to get 3,4-dimethoxy-5-ethoxybenzaldehyde, the perfect starting material for ME and it's (currently yet unknown) amphetamine-analog.

The other possibility starting from ethylvanillin would be bromination, methoxylation and methylation giving the same subst. benzaldehyde.

--PSY420--

PSY420 · Wed Aug 03, 2005 2:54 am

What do you guys think about the possibility of formylating vanillin via the Mg(OMe)2 / paraformaldehyde method (JCS Perkin 1,1823-1831 [1994], it's in Rh's archive) or maybe even the MgCl2/Et3N/(HCOH)n variation, which gives 97% 2-hydroxy-5-methoxybenzaldehyde from p-methoxyphenol (Acta Chemica Scandinavica, 53, 258-262 [1999]) ???

--PSY420--

proxy · Wed Aug 03, 2005 6:41 am

thanks, wasnt really that confident on a reply due to circumstances... but hey , where there's life there's hope , right Very Happy

i just got a copy of US4435601 from the patent site, is there other documentation/discussion about this process, or on the Dakin ??

as for the methylation, there's the method on rhodium, Zn/NaBH4, are there other suitables ?

i figure you mean:

anime · Wed Aug 03, 2005 9:41 pm

PSY, the bromination of ethylvanillin will result in a 2-bromo,3-methoxy-4-ethoxy compound along with the desired 5-bromo,3-methoxy-4-ethoxy compound. I'm sure the yields on this would be low.

PSY420 · Thu Aug 04, 2005 2:16 am

proxy : methylation and NaBH4 ? Don't you think you mix smth. up there ? What I'm talking about is forming the methyl ether of the phenolic OH groups, which is usually done with dimethylsulfate or trimethylphosphate or toluenesulfonic acid methyl ester.

you figured right on the subst. benzaldehyde issue... ; the mysterious analog would simply be 3,4-dimethoxy-5-ethoxy-amphetamine, check M against TMA for comparison.

anime : J. Org. Chem., 23;120 (1958)

25 g (0.15 mol) of bourbornal and 15.2 g NaOAc were dissolved in GAA. Br2 was added slowly and with shaking until the bromine color persisted. The reaction mixture was poured into 500 mL of cold water and a white precipitate formed, 25.7 g (70%). recr. EtOH/H2O, mp 143°C

--PSY420--

anime · Thu Aug 04, 2005 2:33 am

ah heh yes it does work. I stand corrected, I completely forgot about the aldehyde directing to the m position. I wonder if someone can try this with 3,4-dimethoxybenzaldhyde Wink

bromination in the 5th positon followed by a substituion with NaOMe to yield the benzaldhyde withouth need for methylating agents Smile

.

In that case using NBS or NIS with an Fe catalyst in CH3CH should give higher yields. 90+ yields on deactivated compounds. I'll see if I can find the proceedure.

Reaction conditions: Substrate 10 mmol, NBS 10 mmol, CH3 CN 5 mL. FeCl3 is used as the catalyst in 10% amount. >90% yields for all brominations including ones with deactivated groups (NO2). Reactions are run from 10min - 7hr depending on the substance.

Halogenation of Aromatic Compounds by N-chloro-, N-bro
mo-, and N-iodosuccinimide
Chemistry Letters Vol.32, No.10 (2003)

(edit: just noticed there are waaay to many smiley faces in this post)

PSY420 · Thu Aug 04, 2005 2:51 am

anime : AFAIK brominating 3,4-dimethoxybenzaldehyde in the usual manner gives the wrong isomere. But : a solid phase bromination with NBS gives 3,4-dimethoxy-5-bromobenzaldehyde (only ~40% yield though IIRC, J.Chem.Soc., Perkin Trans.2, 2000, 1119-1123)

Can you get a bit more into detail on the NBS/FeCl3 article, like for example what are some prominent substrates ? Overall that sounds very intresting !!

methoxylation of 3,4-dimethoxy-5-bromobenzaldehyde can be found in Indian J.Chem.Sect.B, 24.1985;294-295 they use an autoclave though.

--PSY420--

proxy · Thu Aug 04, 2005 4:20 am

apparently a good substitute for an autoclave is a pressure cooker ... Wink

anime · Thu Aug 04, 2005 5:15 am

heh, my stoned ass though Ethyl vanillin was 3-meo-4-eto compoud. But yes, the paper, I have on the laptop and will post later.

A variety of activated and deactivated groups. COOMe, NO2, Br, Cl, and then the slightly active , Et and Me. (Cl, Et, Me gave high yields but two isomers) Me, MeO, di-Meo.

All yields were in the 90% range.

Do you think dimethyl carbonate can be used to methylate the hydroxyvanillin. I know it can methylate gallic to a 3,4,5-trimethoxygallic acid methyl ester.

Temp is done at <160 for 6? hours.