Sciencemadness Discussion Board

Meta-Escaline via Ullmann on Bourbonal

Ullmann - 15-11-2006 at 18:54

Hi all,

Here is a synthesis of Meta-Escaline sulfate (ME.(SO4)1/2) via the Ullmann methoxylation of 5-bromo bourbonal, methylation and usual condensation with nitromethane then reduction with Al. This is an (if you except the methylation step and acquisition of bourbonal) OTC method to make this interesting compound.

Bourbonal is 3-Ethoxy-4-hydroxy-benzaldehyde and is used as a substitute for vanillin in flavoring food. The bromination of it followed by the methoxylation of the 5-bromo leads to the desired syringaldehyde homologue hereafter called bouringaldehyde (3-Ethoxy-4-hydroxy-5-methoxy-benzaldehyde). Methylation of the free hydroxy followed by condensation of the aldehyde with nitromethane and reduction of the nytrostyrene with Al foil provide the wanted amine.

The Ullmann reaction was done here in a closed apparatus called an ullmannisator which is only a metallic pressure bomb capable of withstanding an autogeneous pressure of less than 5 bars. It can also be done in an open vial provided methanol is slowly distilled out of the reaction mixture but this was not done here this way. The sodium methoxyde solution, which must be a concentration of at least 3 mol/liter, was obtained in an OTC way (details not provided here).

Replacement of bourbonal by the more easily obtained vanillin would give the lower homologue mescaline using exaclty the same process. Bromination using KBr and H2O2 is a viable alternative for those who do not which to prepare their own bromine.

The actual post shows that personal amount of those PEAs (mescaline analogs) are available to the skilled chemist using chemicals easily obtained without declinating identity. Altough dimethylsulfate was used here, iodomethane or any other OTC methylating agent can effectively replace this only watched (and toxic) reagent used here.


Bromination of bourbonal:

To 83 g (500 mmol) bourbonal (3-EtO-4-OH-bd) dissolved in 250 ml MeOH there is added during 15 minutes 25.7 ml (500 mmol) bromine using a Teflon syringe. Caution, the addition is exothermic.
The resulting solution is stirred 1 h at RT then 10 g of sodium sulfite in 100 ml water are added. The medium is then cooled to 0°C and the precipitated product is removed by büchner filtration, washed with copious amount of water and finally with 150 ml of 70% aq. MeOH.

After air-drying, the weight of off-white powder amount to 100 g (82%).

Ullmannisation of 5-bromo-bourbonal:

In an ullmannisator of 300 ml equipped with a magnetic bar, 26 g of 5-bromobourbonal (100 mmol) and 1 g of CuCl (10 mol%) are dissolved in 60 ml DMF. To this brown solution 60 ml of 5M NaOMe are then added. The ullmannisator is closed and the blue suspension is stirred for 5 h a 120°C under autogenous pressure.

After cooling, the brown product is taken off the ullmannisator with the help of water and metallic copper is filtrated on celite. The MeOH is stripped in vacuo from the saved filtrate. After acidification with HCl and extraction with EtOAc the combined organic phases are washed with water and brine and finally dried on MgSO4. After removal of the solvent in vacuo, a quantitative yield of a red-brown product is obtained. This oil, which partially crystallize over time, is constituted of 90-95% bouringaldehyde and 5-10% bourbonal (HPLC). There is no bromobourbonal remaining (it precipitates during workup if the ullmannisation is failed).

Recrystallisation of ~20 g of crude product from 10 ml toluene gave 11.5 g bouringaldehyde (3-EtO-4-OH-5-MeO-bd) as a beige powder (59%) that is saved as reference.

The filtrate from the above crystallization is combined with a crude oil of another 100 mmol batch for the following methylation. Purity of the combined fraction is ~90% (10% bourbonal, HPLC).

Methylation of (crude) bouringaldehyde:

26 g of the above crude bouringaldehyde are dissolved in 100 ml MeOH. A solution of 10 g KOH in 100 ml water is then added which provoke precipitation of the K-phenolate. DMS (19 ml) is then added dropwise to the suspension resulting in an exothermic reaction and dissolution of the phenolate. The solution thus obtained is stirred through the night at RT.

The day after, 10 g KOH are added and the solution is then refluxed for 4 h. The MeOH is stripped in vacuo and the residue is partitioned between 300 ml H2O and 200 ml Et2O, the aqueous layer is then twice more extracted with 200 ml Et2O.

The combined ether extracts are washed using 250 ml sat. aq. NaHCO3 then twice with 250 ml water and once 250 ml brine.
The pale yellow ethereal solution is dried on MgSO4 and stripped in vacuo to yield 13.2 g of orange oil (52%).

HPLC: ~95% pure (220 nm and 254 nm), TLC: Rf 0.5 EtOAc/Hex : 1/1 (one spot only at 254 nm).

Nitrostyrene of ME (5-EtO-3,4-diMeO-NS):
In a 100 ml RBF, 13 g of 5-EtO-3,4-diMeO-bd (95% pure, orange oil) are dissolved in 15 ml of MeOH, 150 uL of iPrNH2 are then added followed by one mL of 80% GAA and finally 10 ml CH3NO2.

The resulting solution is stirred open flask 5 h at 80°C. After cooling, crystals are obtained in a red solution. Those are dissolved by addition of 15 mL MeOH and the resulting solution is cooled in a refrigerator overnight to achieve crystallization of the product. The crystalline mass is broken with the help of a bit of glacial MeOH, filtered on a büchner and washed with a small amount of glacial MeOH. The yellow crystals obtained, which amount to 10 g, are recrystallized from MeOH to give after cooling, filtration, washings and drying 7.5 g of yellow nitrostyrene (50% yield).

Reduction of ME-NS:

In a 1 L RBF equipped with a good condenser and a magnetic stir bar there is placed 7.5 g of recrystallized 5-EtO-3,4-diMeO-NS dissolved in 100 mL of 80% GAA. A small amount of mercuric acetate is then added (~200 mg) followed by 25 mL water and 100 mL IPA. To this yellow solution, 18 g of Al foil (2x2 cm foils in small balls) are added in three 6 g portions over 45 min. The initial exothermic reaction is controlled by immersing the flask in a cold bath. The calmed exothermic reaction is then allowed to continue without external cooling for 5 h at which time it is over.

The reaction mixture is then cooled with 100 ml EtOH and filtered once on celite. The filter cake is washed with 200 ml EtOH (until the filtrate is no more colored). The rose solution is concentrated on the steam bath. The aqueous-acetic solution remaining in the flask is diluted by 200 ml water and washed three times with 50 ml DCM to remove the color. The now white aqueous solution is basified with 20% aq. NaOH and extracted with three times 100 ml DCM. The last organic fractions are combined and washed with two times 200 ml water and once brine.

The gold organic layer is dried on MgSO4, filtered and the DCM evaporated away using the steam bath to yield 3.4 g of ME free base (51 % yield). This catches easily CO2 from air to make the carbonate.

The freebase is dissolved in 10 ml EtOH and 0.5 eq. H2SO4 in 10 ml EtOH are added (pH is 7). The crystallization is started by scratching and finished by freezing. The solid mass of crystals is covered by 50 ml acetone and triturated then put in the freezer for two hours before trituration, filtration and washing by cold acetone on a büchner funnel. After drying in air, 3.5 g of ME sulfate (5-EtO-3,4-diMeO-phenethylamine.(H2SO4)1/2) are obtained as a white solid.

Dr Ullmann

aguacate - 13-9-2011 at 04:14

did you assay it? if so, how did you find the experience?

497 - 13-9-2011 at 05:58

Nice work, as always!

If you used normal vanillin and ethylate or propylated it instead of methylating, you would get the more potent and common analogues...

Do you have the capability to o-methoxybenzylate the amine? That would be most interesting.

Hah, didn't see how old the OP was.
While I did enjoy reading a post that I had missed in the archives, it is definitely 5 years too late to bring it up from the depths....

[Edited on 13-9-2011 by 497]

Satan - 13-9-2011 at 12:43

Quote: Originally posted by Ullmann  
posted on 16-11-2006 at 04:54

Last Post: (12-6-2010 at 13:41)

[Edited on 13-9-2011 by Satan]

DrNoiZeZ - 15-9-2011 at 08:12

That arylation to me is always a real pain in the ***
The method using esther is crap. I could get some results using dry Cu+2 salts ( sometimes it works and sometimes just dont ). I distil the MeOH during the reaction and put it in reflux for one more hour after the MeOH goes out. I think the real problem is the DMF if it is not really anhydrous. What do you use to dry the DMF?

Scr0t - 15-2-2012 at 00:34

I tried this reaction and found it to be straightforward.
I applied it to 5-Bromovanillin with quantities used by Ullmann above, the MeOH was distilled out during the course of the reaction (about 2.5hrs, 116-124°C) with no measures to exclude atmospheric moisture during the reaction or mixing of the reagents.
The Bromovanillin solution in DMF and CuCl was deep red for me (not blue) that became a khaki green with solids when NaOMe was added but progressed to beige then to an orange-brown until the end when it was a dark chocolate brown. The MeOH distillate smelled strongly of Dimethylamine.

As suggested by Ullmann elsewhere the NaOMe/MeOH solution was prepared using 3A molecular sieve dried NaOH/MeOH that was dried for 6 weeks (until the very slow effervescence stopped, this might be excessive). The DMF was also dried over Mol. sieves.

Yield was 79% of Syringaldehyde after recrystallization from MeOH/H2O with no evidence of Bromovanillin contamination during workup.

The NaOMe/MeOH used was made as follows:
40g NaOH in 221.4g MeOH and 180g 3A Mol. sieves (~80% excess), 81.1g of this solution is used for 0.1mol substrate.

26hr Mol. sieve (>5% excess) dried NaOH/MeOH failed giving only recovered Bromovanillin.

turd - 16-2-2012 at 02:33

Quote: Originally posted by Scr0t  
Yield was 79% of Syringaldehyde after recrystallization from MeOH/H2O with no evidence of Bromovanillin contamination during workup.

Please more detail on how you rule out 5-bromovanillin contamination. It is very important to remove it at this step, because in later steps the 5-bromo and 5-methoxy compounds tend to co-crystallize. Meaning there is no chance to remove the 5-Br-impurities by crystallization!

DrNoiZeZ - 16-2-2012 at 03:21

Most of the bromovanillin goes out when you add H20 after the reaction. I use to use it to check the course of the reaction putting some water to a sample - if there is some precipitation the reaction is not finished yet. The problem is that sometimes it does not end at all :D. The cristalization is made by me using ethyl acetate or chloroform but it is always contaminated with some bromovanillin by HPLC.

Scr0t - 16-2-2012 at 04:35

DrNoiZeZ is correct. The Bromovanillin estimate is based upon the amount of precipitate after acidification.
A successful reaction in this case resulted no precipitate or turbidity whatsoever after acidification, in line with my experiences with 5-Hydroxyvanillin. Melting point was 106-108°C with small needle crystals i.e. mp depressed but I assume that this is probably dehalogenated contamination

However my interest lies in the drying time of the hydroxide solution. It appeared to need far more than a day of drying (with sieves at least) has anybody else got experience with this? or do I have funky molecular sieves?

[Edited on 16-2-2012 by Scr0t]

turd - 16-2-2012 at 23:56

Quote: Originally posted by DrNoiZeZ  
Most of the bromovanillin goes out when you add H20 after the reaction. [...] The problem is that sometimes it does not end at all :D. The cristalization is made by me using ethyl acetate or chloroform but it is always contaminated with some bromovanillin by HPLC.

So you are saying that even by adding enough H2O there still is bromovanillin contamination?

If this is the case, then we should switch to syringol as syringaldehyde precursor! Sadly it is much less common than vanillin!

Melting point was 106-108°C with small needle crystals i.e. mp depressed but I assume that this is probably dehalogenated contamination

Assuming is always bad. Given the nasty cocrystallization behaviour of 5-bromo and 5-methoxy compounds, my guess would be 5-bromo-vanillin contamination. You could test it by careful recrystallization - it is very unlikely that syringaldehyde and vanillin would cocrystallize (at most coprecipitate, but that is something entirely different).

Scr0t - 17-2-2012 at 10:45

I've recrystallized the Syringaldehyde from CHCl3 (4ml/g, 82% recovery) giving larger crystals of elongated platelets this time with a mp 109-111°C, much improved.

DrNoiZeZ - 23-2-2012 at 02:48

First I would like to corret myself: where is said " Most of the bromovanillin goes out when you add H20 after the reaction" the correct is H2O/HCl (sorry). The contamination with bromovanilin occurs (to me) because the reaction almost never goes to the end and I only do one cristalization from CHCl3 or EtAcetate so the product is always a little bit brown. The HPLC shows the contamination with a peak that runs as bromovanillin that it is not very important but enought to depress the mp. I think another cristalization can get rid all the contamination but I never did it.

497 - 24-4-2012 at 02:20

This might be useful for someone.

This paper described in detail the various steps of the process conditions, discussed and compared the impact of product quality and yield of the main factors that drew the best reaction conditions:
Bromination:reaction temperature 5-10℃,reaction time 6h, vanillin 15.2g, HBr(40%) 180mL, H2O2(30%) 23mL, alcohol 30mL, yield 96.2%.
Methoxylation reaction:reaction temperature 90-95℃, reaction time 2.5h,5-bromovanillin 10g, sodium 4.9g, methanol 100mL, DMF 5mL, yield 84.6%.
Methylation:reaction temperature 90℃, reaction time 12h, syringaldehyde 15.3g, K2CO3 13.8g, DMC9.0g, yield 93.2%.
Phase transfer catalytic reaction:reaction temperature 60℃, reaction time 7h, NaOH(40%), catalysts: CTMBA and PEG-600, yield 70.3%.
Reduction:reaction temperature 80℃, reaction time 5h,3,4,5-trimethoxymandelic acid 9.7g, chlorotri-methylsilane 5.4g, sodium iodide 7.5g, glacial acetic acid 2mL, zinc powder 1g, yield 91%.

Only a few percent DMF and still 85% yield... And NMP is known to work as well.

Problem with syringaldehyde synthesis

jw1095 - 8-8-2013 at 19:19

Using protocol from erowid starting with vanillin. The bromination worked perfect, GC/MS confirmed the product. Ran the nucleophilic substitution with sodium methoxide and CuBr twice, both attempts failed. Used reagent grade CuBr and sodium methoxide. Used a nitrogen atmosphere and DMF dried with 4A mole sieves. Refluxed for 2.5 hours. GC/MS showed only 5-bromovanillin. Will attempt with freshly prepared methoxide and CuCl tomorrow. I may be out of DMF. Any suggestions about were I may have gone wrong on the first two attempts, and a good alternative solvent.

I am also planing on doing a Williamson to methylate the hydroxy. I have never done this reaction before. I have methyl iodide and NaH. I was wondering about solvent and order of addition. I was also was wondering if it needs heated or cooled.

Marvin - 9-8-2013 at 04:06

You could have fused the CuBr, maybe even with some copper powder, to combat moisture and oxidation but it's a black art.

If you try to form the salt for the Williamson are you not at risk of Cannizzaro?

jw1095 - 9-8-2013 at 08:02

I am not familiar with Cannizzaro. I was thinking about mixing the syringaldehyde and methyl iodide then slowly adding the hydride, but I have only seen this reaction on paper, and I don't know the ins and outs. When you say "fuse" the Cu+1 what do you mean? I am guessing you are saying mix and heat the Cu and methoxide first then add 5-bromovanillin, which is what I did. I could defiantly throw in some Cu powder next attempt. If you mean something else please clarify. Thanks for the feedback.

[Edited on 9-8-2013 by jw1095]

Marvin - 9-8-2013 at 08:42

I've never heard of a Williamson done that way, usually you form the alcoholate separately to avoid competition. But then I've not seen phenyl ethers made with a Williams at all, usually it's done with methylating agents and I don't know why.

How well did you remove the excess methanol? Fuse means to heat until it melts but it may be that the bromide just won't work, perhaps for solubility reasons. Cannizzaro is probably a red herring, if it doesn't happen with sodium methoxide in the first step it should be stable enough.

jw1095 - 9-8-2013 at 11:50

Do you know for a fact that the iodine will work? I can make 5-iodovanillin easy enough. Making the phenyl ether that way was an answer on a o-chem test I took, that doesn't mean it was correct, but my professor said it would work. I did not come up with it myself. I have a small amount of methyl sulfate, say 3mL, but not enough to do the amount I was hoping for. I'll settle for what I can get. Could you give me pointers on how to do the methylation with methyl sulfate. I have seen nitrogen methylated with methyl sulfate for a caffeine synthesis, but have not done it my self. My normal advisor is out of town and I have no one to pose questions too. I am preparing fresh methoxide as we peak. I am going to run the reaction in ethanol boiling it off, then just using the the molten vanillin as the solvent. I will post my results.

[Edited on 9-8-2013 by jw1095]

mnick12 - 9-8-2013 at 14:57

5-iodovanillin is more reactive in nucleophilic substitutions than the 5-bromo compound, but the 5-bromovanillin should work. Are you sure your solvents are dry?

As for the methylation there are plenty of options, and this topic has been discussed to death. Methyl iodide will certainly work, and there is no need for sodium hydride. As Marvin mentioned KOH in ethanol is plenty effective for the deprotonation of the of syringaldehyde. Take a look around the forum there are a lot of threads with information pertaining to this topic.

There are many other threads too!

Marvin - 10-8-2013 at 10:01

By bromide, I meant the copper catalyst used instead of cuperous chloride in the text.

I think running it without a solvent is a bad plan.

I didn't mention KOH for deprotonation, it's earlier in the thread, but I do agree. I also agree that NaH is not needed, and it may reduce some of the aldehyde unless used indirectly.

Nicodem - 11-8-2013 at 05:35

An example of an Ullmann condensation using a substrate with only a methoxy group as a very poorly coordinating ortho substituent* has been recently reported on the Synthetic Pages:
Copper cayalysed nucleophilic substitution of an electron rich bromoarene; 2,3,4,5-tetramethoxytoluene

* Ullmann condensations in the absence of ortho coordinating substituents are otherwise also known in the literature. Though, they are more commonly known for nucleophiles that themselves act as good Cu-ligands or in the presence of additional ligands. A high yielding example like this one, with methoxide as the nucleophile, is a rarer case.

jw1095 - 24-8-2013 at 16:06

I was using the Cu(I)bromide. I didn't have any of the chloride. My solvents are being dried overnight with 4A molecular sieves, the sieves are new and stored in a oven at 120C. This all started with a vanillin synthesis that a student attempted, not me, in a lab I was helping with. The Ph.D teaching the lab thought it sounded reasonable and the procedure came from a university. The procedure the student used called for the solvent to be boiled off. I did try it, and it did not work. The rxn was under an inert atmosphere and I was able to recover about half of the 5-bromovanillin. My latest attempt at the reaction was with Cu(I)iodide and elemental copper in dmf with freshly prepared NaOCH3. For 20g of the bromovanillin I used about 3g of Cu(I) and 10g of powdered Cu. There was about 20g of the NaOCH3. I refluxed overnight under argon. GC/MS confirmed that I did produce a small amount the desired product. I used the integration feature on the GC and estimate a yield of about 2%. I am going to try the 5-iodovanillin next. If I can get this reaction to run I am going to try to synthesize vanillin from 4-hydroxybenzaldehyde. I am planning on protecting the hydroxy with a ester then doing the NAS to form the 3-hydroxy then methylation followed by the deprotection of the 4-hydroxy. There is a professor at my school trying to develop a synthesis of capsaicin for a advanced lab and he is interested in starting with 4-hydroxybenaldehyde.