Quantative 3,4,5-TMB to syringaldehyde

[imp]

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

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.

[Antoncho]

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

(Masquerade: "Re: SCREW Alkoxides!", Chemistry Discourse)). But we have yet to see the scientific sources of the information. Maybee that was just a guess.

[imp]

Masquerade was quite close. The reaction turns out as he/she predicted, but not with the predominately desired selectivity...

5-Hydroxyvanillin (16.8 g., 0.1 mole) was treated with 7.7 g. (0.1 mole) of potassium hydroxide in 60 cc. of water and with 12.6 g. (0.1 mole) of dimethyl sulfate in the same manner employed for the complete methylation noted above*. The cooled reaction mixture was extracted with ether and the ether was washed with 5% sodium hydroxide solution and then with water. The alkaline solution and washings were acidified and extracted with ether to yield 16.0 g. of oily product. The original ether solution, when dried and distilled, yielded 3.3 g. of crude 3,4,5-trimethoxybenzaldehyde melting at 70 C. Recrystallization from pet. ether (b.p. 65-120 C) yielded crystals melting at 74-75 C which did not depress a mixed melting point with authentic 3,4,5-trimethoxybenzaldehyde.

The oil phenolic product was chromatographed from benzene on acid-washed Magnesol and developed with benzene-ethanol (100:1). The bands were located by streaking with 2,4,-dinitrophenylhydrazine, potassium permanganate and ferric chloride. The leading band was eluted with acetone to yield 40% of 5-hydroxyveratraldehyde melting at 63-64 C and not depressing a mixed melting point with authentic 5-hydroxyveratraldehyde. The next band, upon elution, yielded 13% syringaldehyde melting at 109-110 C, and the upper band yielded 20% of unchanged 5-hydroxyvanillin melting at 132-133 C.

* To come soon.

As far as syringaldehyde is concerned, SWIM is currently contemplating vanillin --> 5-nitrovanillin --> 5-aminovanillin --> 5-diazovanillin --> syringaldehyde

Vanillin to 5-nitrovanillin has already been done with KNO3/H2SO4 (SWIM has regioselective nitration ref.), but reduction with SnCl2/HCl was inconclusive (it was not performed very scientifically). Maybe, as with 6-nitropiperonal, FeSO4/NH4OH will be needed.
Unfortunately, SWIM has not been able to dig up a single ref. detailing something similar to this route. In any case, as usual, it is a project for another time   .

[Antoncho]

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

2. Complexing the amino moiety with some Lewis acid as in

Post 428537

(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

(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

[imp]

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(, 1125-1137 (1993):


Regioselective Nitration Procedure
----------------------------------
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

(imp: "2-Alkoxy-4,5-methylenedioxybenzaldehyde Synthesis", Novel Discourse).

[Rhodium]

The procedures below are taken from R.M.Hann, JACS 47, 1998-2002 (1925) and the topic of the article is something completely uninteresting, but in the experimental section there are pointers for the preparation of several 5-substituted vanillins.


5-Bromovanillin
This aldehyde has been prepared by Tiemann and Haarmann¹⁰, Brady and Dunn¹¹ and Dakin¹². The method of Dakin with slight modification gave quantitative yields of a pure white product which may be used without further purification.

5-Nitrovanillin
Nitration of vanillin with fuming nitric acid according to the method of Bentley¹³ gave excellent yields. The compound may be conveniently recrystallized from alcohol or glacial acetic acid.

5-Iodovanillin
This derivative was prepared by the previously described¹⁴ modification of the procedure of Carles.¹⁵ The compound melts at 180°C¹⁶ instead of 174°C as reported by Carles. It crystallizes in the rare monoclinic domatic class. The needles are pleochroic, appearing yellow when light vibrates crosswise and colorless when lengthwise.

5-Chlorovanillin
The available chemical literature does not include a description of a chlorinated  3-methoxy-4-hydroxybenzaldehyde. It is easily prepared by direct chlorination of vanillin in glacial acetic acid in the presence of fused sodium acetate. 5-Chlorovanillin crystallizes readily from acetic acid in brilliant, colorless, tetragonal plates, possesses a slight appreciable odor and melts at 165°C to a clear oil.


References
[10] Tiemann, Ber., 32, 3408 (1899).
[11] Brady and Dunn, J. Chem. Soc., 107, 1859 (1915).
[12] Dakin, Am. Chem. J., 42, 493 (1909).
[13] Bentley, Am. Chem. J., 24, 172 (1900).
[14] Hann, J. Washington Acad. Sci., 14, 79 (1924).
[15] Carles, Bull. soc. chim., 17, 14 (1872).
[16] See also Bougault and Robin, Compt. rend., 172,452 (1921).

[imp]

5-allylvanillin
---------------
ref: L. Claisen and O. Eisleb, Ann., 401, 112 (1913).

This is just allylation of vanillin, then claisen rearrangement with heat to give the 5-allylvanillin. SWIM would be grateful if someone could translate...

Vanillinallylather, durch sechstundiges Kochen von Vanillin mit Alkohol, Pottasche und Allylbromid in theoretischer Menge gewinnbar, ist ein farbloses Liquidum, da, wie an einer Probe festgestellt wurde, beim Destillieren im Vakuum schon merkliche Umlagerung in C-Allylvanillin erleidet. Es wurde daher in undestilliertem Zustande verwandt.

5-allylvanillin: Die Reaktion beim Erhitzen des Allylathers ist lebhafter als in allen fruheren Fallen: mit einem Ruck steigt das Thermometer von 210 C auf nahezu 300 C, die Flussigkeit kommt in starkes Kochen. Es empfiehlt sich daher, die Operation in kleineren Mengen (nicht uber 50 g) vorzunehmen. Trotz der Lebhaftigkeit der Umlagerung verlauft dieselbe sehr glatt; wird nach Ablauf des Siedens noch eine Viertelstunde im Olbad auf 220 C erhitzt und dann im Vakuum destilliert, so erhalt man in einer Menge von 80 Proz. der Theorie ein fast farbloses Destillat, das sofort under vollstandig zu einer krystallinischen Masse erstarrt. Das Produkt wird gepulvert und aus heiBem Benzin unter Zustaz von etwas Benzol umkrystallisiert. Es riecht dann noch etwas nach Vanillin, dessen Vorhandensein sich auch in den folgenden Analysen kundgibt...
5-Allylvanillin krystallisiert (besonders schon aus heiBer verdunnter Essigsaure) in langen, flachen, glanzenden, farblosen Prismen. Schmelzp. 85-86 C, beobachtete Siedepunkte 178 C (12 mm) under 173 C (9 mm)...

This article is interesting, because they do a lot of similar stuff with eugenol. Also, if one allylates 5-allylvanillin to 5-allyl-4-allyloxy-3-methoxybenzaldehyde, then does another claisen, the product becomes 5-allyleugenol (Diallylguajacol). Furthermore, if one starts from eugenol and allylates to 4-allyloxy-3-methoxyallylbenzene and does a claisen we also get 5-allyleugenol (Diallylguajacol).

5-propenylvanillin
------------------
ref: JACS, 74, pp.4263 (1952)

A mixture of 500 g. of potassium hydroxide and 150 cc. of water was heated by means of an electric hot-plate in a stainless steel beaker to 140 C and treated with virorous stirring with 200 g. of 5-allylvanillin. The mixture becaome thick and orange colored. The temperature was raised to 160 C, at which point the hot plate was turned off. The temperature continued to rise to 180 C, and the mixture became quite fluid. Stirring was continued, and the temperature remained above 160 C for about 15 minutes. When the temperature reached 120 C, the mixture was diluted with 4 liters of water to effect solution of the fused mass and was stirred until cool. The cold alkaline solution was acidified with dilute sulfuric acid, and teh oil which separated solidified upon stirring and cooling. The yield of crude 5-propenylvanillin was 200 g. or 100%. Recrystallization from either water or pet. ether gave white needles melting at 73 C.

5-formylvanillin
-----------------
ref: JACS, 74, pp.4263 (1952)

Similar treatment of cis-5-propenylvanillin with 250 g. of nitrobenzene, 100 g. of sodium hydroxide and 1000 g. of water at 165 C for one hour gave a reaction mixture which was diluted, cooled, and extracted with ether. The aqueous alkaline solution was acidified with sulfur diozide, cooled, and extracted with ether; the ether was dried and sitlled to yield 5.2 g. . of crude 5-carboxyvanillic acid which was recrysatllized from water to give colorless crystals melting at 280-281 C. The sulfur dioxide-saturated solution was acidified with sulfuric acid and boiled. The solution was cooled and extracted with ether. The ether was dried and distilled to yiled 44.0 g of 5-formylvanillin which, upon recrystallization from pet. ether (b.p. 65-110 C), gave colorless spherical crystals melting at 125-126 C.


They also have a synthesis for 5-carboxyvanillin starting from 5-propenyl-orthovanillic acid. It's a bit involved, but the yields are always good in every step.

So, give some ideas on what we can do with these. SWIM will give it some thought later this week.

[Flippie]

vanillin allyl ether [in theoretical amounts producible by 6 hours refluxing of vanillin with ethanol, potassium and allyl bromide] is a colorless liquid because [as experimentally ascertained] during vacuum distillation already perceptible conversion in C-allyl vanillin takes place. Therefore it is used in undistilled condition.

5-allyl vanillin: The reaction during heating the allyl ether is more vigorous than in all previous cases: the temperature shoots from 210°C till about 300°C and the liquid starts boiling heavily. Therefore it is recommended to do the reaction only with small amounts (not more than 50g). Nevertheless the vigorous character of the reaction it goes very smoothly; after the boiling is finished the reaction is heated in an oil bath for another 15 minutes and then vacuum distilled, this way you get a theoretical 80% yield of an almost colorless distillate that immediately crystallizes. Recrystallize the grounded product from hot "Benzin" in the presence of a little benzol. There is still a little vanillin smell left in the product which is also detected in the following analysis...
5-allyl vanillin crystallizes (extremely beautiful from hot diluted Acetic acid) in long, flat, shiny, colorless prisms. Meltingpoint 85-86°C, boilingpoint 178°C (12mm) and below 173°C (9mm)...

Nevertheless my German is not that bad, I still have to translate it to chemistry English. I want to apologize for possibly strange builded sentences. The translation is scientifically correct though.

I did not want to translate "Benzin" since this word always confuses me   

I checked and found that benzol is German for benzene, which makes me conclude that Benzin is German for benzine/petrol.

Maybe it is time to start a German-English chemical name dictionary.

[imp]

Thank you very much for the translation, it was excellent. SWIM wanted to re-type the 5-formylvanillin procedure from the previous post because of some bad errors. So here it is again, now much improved!...

5-formylvanillin
-----------------
ref: JACS, 74, pp.4263 (1952)

Similar treatment of 75 g. cis-5-propenylvanillin with 250 g. of nitrobenzene, 100 g. of sodium hydroxide and 1000 g. of water at 165 C for one hour gave a reaction mixture which was diluted, cooled, and extracted with ether. The aqueous alkaline solution was acidified with sulfur dioxide, cooled, and extracted with ether; the ether was dried and distilled to yield 5.2 g. of crude 5-carboxyvanillic acid which was recrystallized from water to give colorless crystals melting at 280-281 C. The sulfur dioxide-saturated solution was acidified with sulfuric acid and boiled. The solution was cooled and extracted with ether. The ether was dried and distilled to yield 44.0 g of 5-formylvanillin which, upon recrystallization from pet. ether (b.p. 65-110 C), gave colorless spherical crystals melting at 125-126 C.


Sorry for that, it won't happen again.

[Rhodium]

Benzin = Petroleum Ether, usually the fraction containing the hexane and heptane isomers.

[Rhodium]

A rather byzantine alternative to

Post 462313

(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)

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%)