Sciencemadness Discussion Board - Successful "green" PTC-mediated methylation of syringaldehyde to 3,4,5 trimethoxybenzaldehyde using DMC without...

Successful "green" PTC-mediated methylation of syringaldehyde to 3,4,5 trimethoxybenzaldehyde using DMC without...

Digital Hepatitis - 18-11-2012 at 07:51

3,4,5 trimethoxybenzaldehyde is typically prepared from syringaldehyde by the reacting with dimethyl sulfate in acetone containing a base (K2CO3/KOH/NaOH) and possibly phase-transfer catalyst (e.g., Adogen 464) [1,2] While procedurally simple and high-yielding, this methylation unfortunately relies on the use of the highly toxic dimethyl sulfate (DMS) as the methylating agent. 3,4,5 trimethoxyebenzaldehyde can also be produced in high (82%) yield [3] using the "green" reagent dimethyl carbonate (DMC), but this requires the use of a sealed autoclave or pressure vessel to perform the methylation [4,5]. In lieu of a desire to avoid both DMS and the need for expensive pressure reaction vessels, a search for a "green" procedure for preparing 3,4,5 trimethoxybenzaldehyde from syringaldehyde with DMC under normal temperature and pressure was undertaken.

Ouk, et al. [6] report that phenolic compounds can be methylated by DMC at ambient temperature and pressure using a concomitant phase-transfer catalyst (K2CO3 &/or tetrabutylammonium bromide [TBAB].) The authors methylate 2,4 dihydroxybenzophenone, phenol, and p-cresol using various substrate/PTC/DMC ratios with varying (but usually high) degrees of success; however, an attempt to prepare 3,4,5 trimethoxybenzaldehyde by refluxing syringaldehyde, TBAB, K2CO3, and DMC in a 1:.5:.75:8 molar ratio for 8 hours produced abysmal yields of 3,4,5 TMB. Due to the egregious (over)use of reagents suggested by the Ouk, et al. this method was discarded.

It was subsequently discovered that syringaldehyde can be methylated with DMC and PTC under standard temperature and pressure conditions in a scheme that makes a much more efficient use of reagents than even the smaller reagent ratios employed by Ouk, et al. This procedure is a modification of US Patent 6326501, "Methylation of Indole Compounds Using Dimethyl Carbonate." [7] The authors successfully methylate a host of indole compounds with DMC and PTC in a high boiling solvent (either N-methylpyrrolidone or dimethylformamide). This procedure is a slight modification of this procedure and suggestions for improvements would be greatly appreciated. If there's any interest in this at all I should have PDF's of all documents, although I could not find an electronic copy of the Chinese citation, just an old hard copy printout. I'm not sure if "365915" is the patent number or (much more likely) some proprietary document identifier; all interested readers fluent in Mandarin Chinese can search www.ceps.com.tw for this reference if they so desire.

Reagents Employed:
Syringaldehyde: Molar mass 182.17 g/mol
Potassium carbonate (anhydrous): Molar mass 138.205 g/mol
Tetrabutylammonium bromide: Molar mass 322.268 g/mol
Dimethyl carbonate: Molar mass 90.08 g mol−1

Dimethylformamide and Cyclohexane (both made anhydrous by drying over 4a molecular sieves)

Procedure:

20 g syringaldehyde (.11 mol), 100 ml anhydrous tech grade DMF, 10 g anhydrous potassium carbonate, 6 g tetrabutylammonium bromide, and 22 g dimethyl carbonate were added to a 3 neck flask equipped with a condenser, addition funnel, and thermometer and an additional 11 g of dimethyl carbonate was placed into the addition funnel.

Heat was applied until reflux was reached. After reflux, the remaining dimethyl carbonate was slowly dripped in over the course of 3 hours. Reflux was continued for five more hours at approximately 130 degrees Celsius.

The reaction was cooled and poured into 1000 ml of ice water which caused the product to instantly crystallize out. After the ice melted it was subsequently filtered and dried to yield 14.7 g crude 3,4,5 trimethoxybenzaldehyde (~70%) which was then recrystallized with cyclohexane.

Regarding the recrystallization with cyclohexane: cyclohexane is the textbook recrystallization solvent for recrystallizing 3,4,5 trimethoxybenzaldehyde. It was found that after heating the crude 3,4,5 TMB and cyclohexane to boiling, the undesired brown polymerized gunk simply settled to the bottom and the cyclohexane/3,4,5 TMB could be separated by simply pouring out the hot cyclohexane such that the dirty residue could be separated manually. Recovery of the clean light beige 3,4,5 trimethoxybenzaldehyde is approximately 90%.

[1] Manchand, P.; Belica, P.S.; Wong, H. Synth. Communication 20(17) (1990) 2659-2666.

[2] Rao, D.; Stuber, F. Synthesis (1983) 308.

[3] Qu, X.-s. Wang, Y.-h. Zhu, B. Journal of the Jilin Institute of Chemical Technology. Vol. 23; No. 2 (2006) 3-6.

[4] Tundo, P. Pure Appl. Chem., Vol. 73, No. 7 (2001) 1117-1124.

[5] Maurizio, S.; Tundo,P. Acc. Chem. Res 35, (2002) 706-716.

[6] Ouk, S.; Thiebaud, S.; Borredon, E.; Legars, P.; Lecomte, L. Tetrahedron Letters 43 (2002) 2661–2663,

[7] US Patent 6,326,501.

[Edited on 19-11-2012 by Digital Hepatitis]

Nicodem - 18-11-2012 at 09:37

Digital Hepatitis, thank you very much for sharing your experience. I moved this thread to Prepublication because the contribution is formated in a publication style, complete of the literature review and all that's needed. I hope you do not mind, but if you don't want your report to be part of SM publications, just say so and I'll move it back to Organic chemistry section. This does not mean that a discussion cannot follow, but all that is yet to discuss are details that can be discussed in Prepublication as well.

Quote: Originally posted by Digital Hepatitis

Ouk, et al. [6] report that phenolic compounds can be methylated by DMC at ambient temperature and pressure using a concomitant phase-transfer catalyst (K2CO3 &/or tetrabutylammonium bromide [TBAB].)

It is my understanding that their procedure calls for a reflux temperature, not ambient temperature as you wrote.

Quote:

I could not find an electronic copy of the Chinese citation, just an old hard copy printout. I'm not sure if "365915" is the patent number or (much more likely) some proprietary document identifier

A patent or patent application CN365915 does not exist according to Espacenet or the Chinese patent office search engine. Surely the number is wrong (too little numbers anyway). Do you have any other data, like inventor names or application tittle?

Quote:

Heat was applied until reflux was reached. After reflux, the remaining dimethyl carbonate was slowly dripped in over the course of 3 hours. Reflux was continued for five more hours at approximately 130 degrees Celsius.

I assume this is the temperature of the bath. Did you follow the reaction temperature as well? I suspect better yields could be obtained if the formed methanol could be continuously removed from the reaction mixture, for example by a distillation column setup, and the dimethyl carbonate fed at such a slow rate to maintain the reaction temperature as high as possible. The methanol only reduces the reflux temperature (inhibiting the reaction toward the end) and removing it as it forms could allow for a better conversion.

Quote:

filtered and dried to yield 14.7 g crude 3,4,5 trimethoxybenzaldehyde (~70%) which was then recrystallized with cyclohexane.

Did you check the purity of the crude product in any way? TLC, mp...

Quote:

Recovery of the clean light beige 3,4,5 trimethoxybenzaldehyde is approximately 90%.

Do you have any characterization data available?

[Edited on 18/11/2012 by Nicodem]

Ephesian - 18-11-2012 at 18:17

Great write up! We need characterization data, at least I want to see it.

Digital Hepatitis - 18-11-2012 at 23:08

Quote: Originally posted by Nicodem

Digital Hepatitis, thank you very much for sharing your experience. I moved this thread to Prepublication because the contribution is formated in a publication style, complete of the literature review and all that's needed.

Thanks. To be honest, I only peruse this board infrequently and didn't even know there was a prepublication section! It's now been a good decade since I've been in graduate school and it undoubtedly shows. The brevity of this writeup belies the amount of time I spent on working this theory out, although I must confess there's still a sort of "then a miracle occurs" moment in the middle of it.

Quite honestly, I'm fascinated with phase transfer catalysts, but as far as determining the appropriate amount of them it seems to be largely a function of trial and error.

Quote: Originally posted by Nicodem

It is my understanding that their procedure calls for a reflux temperature, not ambient temperature as you wrote.

You are correct. Would it be fair to employ the verbiage "standard reaction conditions" (i.e., no pressure vessel necessary?)

Quote: Originally posted by Nicodem

I was able to do a little more digging and did find a reference to this (I couldn't find it before). Here it is:

http://en.cnki.com.cn/Article_en/CJFDTOTAL-JHXY200602001.htm

Research on synthetic technology of 3,4,5-trimethoxybenzaldehyde from vanillin
QU Xiao-shu,WANG Ya-hong,ZHU Bo(Dept.of Pharmacy and Applied Chemistry,Jilin Institute of Chemical Technology,Jilin City 132022,China)

3,4,5-trimethoxybenzaldehyde is synthesized in 71% yield by vanillin method.5-bromovanillin is afforded in 96% yield by the bromination of vanillin with bromine as brominating agents.Treatment of 5-bromovanillin in DMF with sodium methoxide in the presence of cuprous chloride as catalyst gives syringaldehyde in 90% yield,from which 3,4,5-trimethoxybenzaldehyde is obtained by methylation with dimethylcarbonate in 82% yield.

Alas, I am relegated to a feeling of ignorance and powerlessness when confronted by Mandarin Chinese, which is not a language you can "pick apart" like French or German. This is too bad, as Chinese chemistry is, per my completely anecdotal and statistically insignificant analysis, sometimes more concerned with refining and clarifying existing synthetic pathways as opposed to employing exotic ten-syllable catalysts and equally esoteric methodologies (microwave and ultrasound chemistry just doesn't resonate with me) that seems to be the bulk of the output of Tetrahedron Letters, et al these days. Then again, I like to construct elaborate psychological defense mechanisms in order to make myself feel better when people smarter than me present me with information I don't really understand, so go figure.

Quote: Originally posted by Nicodem

Yes, this was the bath temperature, as I did not have access to a reaction flask with a thermometer inlet. As to why I refrained from pushing the reaction up to the boiling point of DMF, I was concerned about the decomposition of tetrabutylammonium bromide at higher temperature levels (cf. http://tinyurl.com/ckafd9u) as it tends to decompose at higher temperatures.

Quote: Originally posted by Nicodem

Did you check the purity of the crude product in any way? TLC, mp...

MP was 71-73 per a crude Thiele tube measurement. TLC is a bit out of my purview right now for reasons I won't go into. If anyone wants to help a chemhack walk through an appropriate TLC procedure I would be most grateful.

Quote: Originally posted by Nicodem

Do you have any characterization data available?

Not right now. Thanks again for your input; glad to know someone might make use of this information. In the author's view, dimethyl sulfate is one of those reagents (although with carbon tetrachloride) that should be avoided if at all possible. TBAB is not only much greener, but is such a damned useful reagent for so many different operations that it is truly indispensable (at least in my little world.)

Kind regards,
Digital Hepatitis

_{Edit by Nicodem: Corrected the quote-markup error.}

[Edited on 22/11/2012 by Nicodem]

Nicodem - 19-11-2012 at 08:21

Quote: Originally posted by Digital Hepatitis

You are correct. Would it be fair to employ the verbiage "standard reaction conditions" (i.e., no pressure vessel necessary?)

Yes, and note also that in Prepublication you can edit your report even after the normal 24 h limit. So I suggest you do the corrections directly above.

Quote:

I was able to do a little more digging and did find a reference to this (I couldn't find it before). Here it is:

http://en.cnki.com.cn/Article_en/CJFDTOTAL-JHXY200602001.htm

Then it is not a patent application, but an article which should be cited in the references as: "X.-S. Qu, Y.-H. Wang, B. Zhu, Journal of Jilin Institute of Chemical Technology 2006, 2" and with that link. But can't see the page numbers.

Quote:

This is too bad, as Chinese chemistry is, per my completely anecdotal and statistically insignificant analysis, sometimes more concerned with refining and clarifying existing synthetic pathways as opposed to employing exotic ten-syllable catalysts and equally esoteric methodologies (microwave and ultrasound chemistry just doesn't resonate with me) that seems to be the bulk of the output of Tetrahedron Letters, et al these days.

That's because the Chinese chemist often have to support their growing chemical industry which needs fast solutions. For this reason they need to focus on the process development, rather than synthesis development. I think they do the synthesis development only after they implement a preliminary process in the production. As a side effect of this strategy, there is a lot of publications on the process development, something that elsewhere is not even published or is only published in patents and the few journals such as the Organic Process Research & Development.

Digital Hepatitis - 19-11-2012 at 09:23

I was finally able to ascertain the page numbers by consulting this page here and made the edit:

http://direct.bl.uk/bld/PlaceOrder.do?UIN=191209540&ETOC...

[Edited on 19-11-2012 by Digital Hepatitis]

Nicodem - 22-11-2012 at 08:45

Quote: Originally posted by Digital Hepatitis

TBAB decomposes in the presence of strong nucleophiles and/or in relatively basic medium at high temperatures (for example, in the presence of thiolates, cyanides or hydroxides). The decomposition (via S_N2 and/or Hofmann elimination) usually takes a couple of hours (except with thiolates with which it is quite rapid even bellow 100 °C). But in your case, where the most nucleophilic species is the phenolate and the most basic is the carbonate, you can expect TBAB would stable enough even at 130 °C (reaction temperature) for the time of the reaction. See JOC 1977, 42, 4275 for a study on the stability of TBAB in the presence of strong nucleophiles.
The problem is more in that you can not easily achieve such reaction temperatures in an open vessel due to the volatility of dimethyl carbonate and the formed methanol. I think once this problem is solved about 90% yields could be achieved without resorting to an autoclave.

Quote:

That is a very narrow mp range for what something you call a crude product. You can find instructions for a homemade TLC plate in some other thread on this forum. If the polymeric crap you observed during the recrystallization stays on the starting point on TLC and there are no other side products you could skip the recrystallization by filtering a solution through a plug of silica-gel.

Quote:

Quote: Originally posted by Nicodem

Do you have any characterization data available?

Not right now.

Given the circumstances, we can be satisfied with the melting point measurement.

Quote:

In the author's view, dimethyl sulfate is one of those reagents (although with carbon tetrachloride) that should be avoided if at all possible.

For some reason, ways of avoiding dimethyl sulfate or carbon tetrachloride are always hot topics on this forum. Another methylating reagent that was donated to the forum audience is trimethylsulfonium bromide.