This is a nice one girls and boys. Demethylation of 3,4,5-trimethoxybenzaldehyde to syringaldehyde using H2SO4 in near quantative yield. Yes, H2SO4 as an effective demethylation agent as in Patent US3367972 (http://l2.espacenet.com/dips/viewer?PN=US3367972&CY=gb&LG=en&DB=EPD)
but now for 3,4,5-TMB.
JACS, vol. 74, pp.4262 (1952)
A mixture of 10 g. of recrystallized 3,4,5-trimethoxybenzaldehyde and 56 g. of concentrated sulfuric acid was maintained at 40 C in a water-bath for 8 hours and then allowed to stand overnight at room temperature. The mixture was stirred into 100 cc. of cold water and cooled. The clear solution was decanted from the little tar that separated and was extracted with ether. The ether was dried and distilled to yield 8.9 g. (96%) of almost pure (as indicated by chromatography) syringaldehyde which, upon crystallization from pet. ether melted at 109 C and did not depress the melting point of a mixture with authentic syringaldehyde.
The use of crude 3,4,5-trimethoxybenzaldehyde or of longer reaction times resulted in poorer yields and in much cruder products.
The article also describes selective methylation of 5-hydroxyvanillin, but the yields were bad and they got a mixture of 3,4,5-TMB, 3,4-dimethoxy-5-hydroxybenzaldehyde (good for metaescaline), syringaldehyde, and unreacted 5-hydroxyvanillin. SWIM has the article, so if anybody is interested the procedure can be posted.
Subj.
There was one guy whose name was Masquerade - he once said that incubation of 5-OH-vanillin together with MeI will selectively produce syringaldehyde (Post 229321 (https://www.thevespiary.org/talk/index.php?topic=7131.msg22932100#msg22932100)
(Masquerade: "Re: SCREW Alkoxides!", Chemistry Discourse)). But we have yet to see the scientific sources of the information. Maybee that was just a guess.
Now we have another piece of info that will bee useful in working out the best strategy for selectively methylating that meta-hydroxyl.
Masquerade was quite close. The reaction turns out as he/she predicted, but not with the predominately desired selectivity...
Well, Masquerade was talking about MeI, not DMS - which is a BIG difference. Moreover, carrying out the rxn at bp hardly favors selectivity - it should bee much better at lower temps (meta-OH is more activated than ortho-).
As far as syringaldehyde is concerned, SWIM is currently contemplating vanillin --> 5-nitrovanillin --> 5-aminovanillin --> 5-diazovanillin --> syringaldehyde
YES! I've been interested in that pathway for some time, too.
Vanillin to 5-nitrovanillin has already been done with KNO3/H2SO4 (SWIM has regioselective nitration ref.)
PLEASE, post that ref!!! I've been trying hard to find smth relevant on EspaceNet, but to no avail...
but reduction with SnCl2/HCl was inconclusive (it was not performed very scientifically). Maybe, as with 6-nitropiperonal, FeSO4/NH4OH will be needed.
I really think that there are much better ways to reduce a nitroaldehyde... The main problem with them is their tendency to polymerize - which can bee overcome by one of the following ways:
1. Complexing the aldehyde function with ammonia followed by immediately isolating the aldehyde by steam-distillation - as in both the procedure you posted for aminopiperonal and http://orgsyn.org/orgsyn/prep.asp?prep=cv3p0056 (http://orgsyn.org/orgsyn/prep.asp?prep=cv3p0056)
2. Complexing the amino moiety with some Lewis acid as in Post 428537 (https://www.thevespiary.org/talk/index.php?topic=7409.msg42853700#msg42853700)
(Antoncho: "Another nice nitro- to hydroxy- procedure!", Chemistry Discourse)
3. Finally, immediately diazotizing the aldehyde in situ so it has no time to polymerize - as in Post 428075 (https://www.thevespiary.org/talk/index.php?topic=7409.msg42807500#msg42807500)
(Antoncho: "Benzaldehydes: from nitro to hydroxy in one step!", Chemistry Discourse). I should also note that you really ought to read that thread - it is dedicated specifically to this route.
Sincerely,
Antoncho
The vanillin to 5-nitrovanillin was performed by SWIM, and not taken out of a reference. The compound forms very long yellow needles from EtOH/water and as an aromatic nitro compound, it likes to stain everything orange/yellow. A similar nitration procedure was found later in Syn. Comm., 23(8), 1125-1137 (1993):
Regioselective Nitration Procedure
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Calcium nitrate in sulfuric acid has been demonstrated as a new nitrant for the regioselective nitration of substituted phenols, which compares well with known and the more studied nitrant (eg Sodium Nitrate) under identical conditions. Furthermore, the product selectivity is temperature dependant, as shown.
General Procedure for Nitration:
(a) Using Calcium Nitrate (at ~2 C).
To a stirred Sulfuric acid (37.2 g., 98%, 0.379 moles, and ice 37.2 g.) was added an aqueous solution of Calcium nitrate (23 g., 0.125 moles dissolved in 22 ml. of water) at 25-27 C. To the above mixture cooled to 2 C, para cresol, 27 g., 0.25 mole was added gradually (1.25 hr, reaction is exothermic) such that temperature maintains at 2 C (+- 2 C). At the end of reaction (5 hr, checked by GC neutralized aliquot in ethyl acetate), the reaction mass was extracted with ethyl acetate (100 ml X 2), dried over anhydrous sodium sulfate and the solvent was stripped off to give a crude product (37.4 g., 98% yield). The crude product was chromatographed on silica gel column, the fraction eluted with pet. ether, ethyl acetate 99:1 was pure (6) [1-nitro-4-methylphenol] in 96% yield.
(b) Using Sodium Nitrate, yield 87%.
Rhodium: Do you recognize who SWIM is? Maybe not, but if you do please keep it a secret ;)
Also, Antoncho, you exaggerate the speed at with aminobenzaldehydes will polymerize. They are stable for a while and can be isolated usually from crystallization in water. A good example is for 6-aminopiperonal...See Post 464339 (https://www.thevespiary.org/talk/index.php?topic=11785.msg46433900#msg46433900)
(imp: "2-Alkoxy-4,5-methylenedioxybenzaldehyde Synthesis", Novel Discourse).
A rather byzantine alternative to Post 462313 (https://www.thevespiary.org/talk/index.php?topic=11385.msg46231300#msg46231300)
(Rhodium: "2,6-Dimethoxyphenol -> Syringaldehyde", Novel Discourse)
Synthesis of Syringaldehyde
Irwin A. Pearl
J. Am. Chem. Soc. 70, 1746-1748 (1948) (https://www.thevespiary.org/rhodium/Rhodium/pdf/syringaldehyde.pearl1948.pdf)
(https://www.thevespiary.org/rhodium/Rhodium/pdf/syringaldehyde.pearl1948.pdf)
2,6-Dimethoxyphenol -> 2-Allyloxy-1,3-dimethoxybenzene (95%)
2-Allyloxy-1,3-dimethoxybenzene -> 4-Hydroxy-3,5-dimethoxyallylbenzene (90%)
4-Hydroxy-3,5-dimethoxyallylbenzene -> 4-Hydroxy-3,5-dimethoxypropenylbenzene -> Syringaldehyde (75%)