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Author: Subject: Methylation of phenolic aldehydes with MeI in DMF: 2-methoxybenzaldehyde
LSD25
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[*] posted on 16-3-2008 at 17:36


Quick post

Here is an article on the transesterification of phosphorus pentoxide to give triethyl phosphate (uses ethyl orthoformate), whether or not this works with methyl formate or even ethyl acetate remains to be seen:

http://www.4shared.com/file/41002410/c7dcd62d/Phosphorus_eth...

Might be worth looking into - seems easier than DMC, provided it can (1) be made to work with methyl orthoesters; or (2) the triethyl formate can be converted to trimethyl phosphate by heating in methanol




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[*] posted on 17-3-2008 at 01:00


Unfortunately you can not use ethyl or methyl formates or acetates for preparing methy/ethyl phosphates. The reaction is similar as in the preparation of methyl tosylate from TsOH and trimethyl orthoformate (TsOH + (MeO)3CH => TsOMe + MeOH + MeOCHO). As you can see, if you would use MeOCHO instead, the reaction would have to go against the thermodynamics (TsOH + MeOCHO <= TsOMe + HCOOH). A similar situation is true when starting with P2O5, though the thermodynamic difference is less.



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[*] posted on 17-3-2008 at 05:15


Drat,

I also found the relevant article here:

http://psychedelichosting.info/Ionium/Rhodium/chemistry/me3p...

Sorry, dunno why I didn't just g-search....

Off to do more reading on thermodynamics:P




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Ullmann
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thumbup.gif posted on 27-9-2008 at 09:23
New OTC methylating agent - Methyl Ethane Sulfonate (MES)


(A.) Methyl Methane Sulfonate (MMS) generation from Mesyl Chloride and Methylation of Salicylaldehyde therewith followed by (B.) Methyl Ethane Sulfonate (MES) generation from the Ethane Sulfonyl Chloride prepared from the in situ Chlorination of the Bunte salt from Sodium Thiosulfate and Ethyl Bromide. A cheap and easy way to methylating agent for the amator chemist.

A. Preparation of MethylMethaneSulfonate (MMS) from commercially avaiable mesyl chloride. Its use for methylating salicylaldehyde in a one pot reaction. A generation and in situ utilisation of a very toxic methylating agent avoiding the trouble and danger of stocking it.

In a 500 ml three necked RBF with a N2 inlett, a dropping funnel, a condensator with a silicagel tube. To a methanolic solution of 150 mmol methanesulfonyl chloride (MM 115, 17.3 g, d1.48, 11.7 ml) in 100 ml of cold dry MeOH (ice bath/salt), there is added during 15 minutes dropwise with cooling 150 mmol of sodium methoxyde 3M solution in MeOH (50 ml, 150 mmol). NaCl precipitate. After the addition is done the mixture is let reach RT over 15 minutes. There is thus obtained 150 ml of 1M solution of MMS in MeOH (+salt). It is used as such for the next reaction.

To the above prepared 1M solution of MMS in MeOH there is dissolved 12.2 g (MM 122, 100 mmol) salicylaldehyde. There is then added in one portion anhydrous Na2CO3 (2 eq, 200 mmol, MM 106, 21.2g). The N2 inlet is taken off and the mixture is then refluxed for the night. The next morning the conversion was 73% (HPLC vs references), it was homogeneous on chromatography.


Another run was attempted using Na2CO3 as a base for the generation of MMS:

In a 500 ml three necked RBF with a N2 inlett, a dropping funnel, a condensator with a silicagel tube. To a suspension of anhydrous Na2CO3 (300 mmol, MM 106, 32 g) in MeOH (150 ml) there is added via seringue dropwise and with cooling 150 mmol methanesulfonyl chloride (MM 115, 17.3 g, d1.48, 11.7 ml). An exothermic reaction occur. After the addition is done the mixture is let reach RT over 30 minutes. It is used as such for the next reaction. Addition of 100 mmol salicylaldehyde and reflux overnight gave a 70% conversion to o-anisaldehyde (vs references again).

Now having shown the possibility of generating the carcinogenic methylating agent and using it in situ let it become OTC by making our own Ethane Sulfonyl Chloride...

B. Methyl EthaneSulfonate (MES) generation from the Ethane Sulfonyl Chloride prepared from the in situ Chlorination of the Bunte salt from Sodium Thiosulfate and Ethyl Bromide.

------------------------------------------
The Interaction of Chlorine with Different Types of Organic Sulfur Compounds

Ref: JACS 60 1486

In some runs the sodium alkylthiosulfate was formed
by mixing the alkyl halide or sulfate (0.1 mole) with an
equivalent amount of 20% sodium thiosulfate solution and
50-75 cc. of acetone. When the formation of a homogeneous
solution indicated complete reaction the acetone was
removed with steam and the solution cooled and chlorinated
as usual. In this manner a 55% yield of ethylsulfonyl
chloride was obtained. An attempt to form sodium
cyclohexyl thiosulfate using cyclohexyl chloride was
unsuccessful.
----------------------------------


In a one liter RBF:
EtBr : 0.5 mole MW 109 d 1.46 --> 55 g = 38 ml (I add 40ml)
Sodium thiosulfate.5 H20 : 0.5 mole MW 248 --> 124 g dissolved in 400 ml H20
Acetone 250 ml

After one day of stirring a clear homogeneous solution is obtained. Acetone is then evaporated. According to US2293971 there is added 200 ml of GAA to the 300 ml of solution obtained. Meanwhile in another 1L RBF there is placed 300 g sodium dichloroisocyanurate (MW 220, 85%, 1160 mmole, 55% chlorine -> 140 g active chlorine (2 moles)) covered with a small amount of water. With the help of a teflon tubing through septums bridging the two 1L RBF and going into the solution with the bunte salt chlorine is generated for two hours and passed in by dropping at 0-15°C 250 ml of 32% HCl (2.5 mole) on the DCCA. Be cautious of back pressure jump and frothing! Near the end of generation of the chlorine the solution with bunte salt took a permanent yellow-green tinge. It means excess chlorine was present. After ten minutes it was still yellow and workup was started. The solution is pourred in one liter of water which precipitated 30 g of ethane sulfonyl chloride. Four extractions with 4x50 ml CH2Cl2 were done and all fractions are combined then washed once with sulfite and two times with water. The CH2Cl2 evaporated in vacuo and the yellow and fluid residue is weighted : 62 g is obtained MW 128 -> 468 mmol (94%).

The generated ethanesulfonyl chloride is then used for methylation by decomposing it in MeOH with a carbonate.

Although this reaction work as described some tuning must be done in regard to the lot of salts generated and consequent trouble in stirring the reaction. For instance if syringaldehyde is used as substrate instead of salicylaldehyde the sodium salt will be unstirrable because of too much salt/insolubility of Na+/-syringaldehyde. Use of K2CO3 or KOH in MeOH or acetone or DMF will then probably be preferable if ever the K salt of say for instance syringaldehyde is more soluble in MeOH than the Na salt. At worst a cautious filtration or decantation of the methanolic MES solution from the generated NaCl and NaHCO3 may be useful or necessary.

Enjoy!

Kind Regards,

Dr Ullmann

[Edited on by Ullmann]
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[*] posted on 27-9-2008 at 10:31


Splendid! Beautifull! Very impressive work!

This realyl is an advance in safe, practical alkylations! The ethansulfonyl halide can be sued yo form any sulfonate, and used for lots alkyaltions, and the sulfonate salt can be recovered and converete to the acid, which would have many uses as catalyst etc..

And all that from very accesable materials, I must say this really is something big... The formation of the sulfonyl halide is outstandingly high yielding!

If only we could have more experiemantal work like this, we would go very far indeed...

I can only say congratualtions, Ullman, and thanks for sharing this with us!




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[*] posted on 27-9-2008 at 12:01


I agree, very nice.

I really love to see when people just make something; no bullshit, no squabbling, no 5 page discussion without a single experimental report; you just fucking did it! Posts like this are why I came here in the first place.

Great work!

PS same to you klute; I really enjoy reading your experimental reports.

I only wish I didn't spend majority of my life 700miles from my lab so I could make equivalent contributions.

[Edited on 9-27-2008 by smuv]




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[*] posted on 9-11-2008 at 10:03


Nice work klute and ullman!

On the subject of the MES synthesis, i don't see how bromoethane, and sodium methoxide can be considered OTC..? perhaps there is some glaringly obvious synthesis i am missing, or maybe a misunderstanding of the acronym, or even just difference in regional restrictions..?

great idea though, although i cant see myself making this decision soon, im sure i would choose a methylating agent that could be prepared in situ rather than otherwise. how about disposal? can excess of this reagent be easily destroyed when it is no longer needed?
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[*] posted on 9-11-2008 at 11:19


bromoethane from ethanol and NaBr/H2SO4, and sodium ethoxide possibly from NaOH/EtOH/Toluene azeotropic distn, there is a thread on this, but simple NaOH should do the trick to the form the sulfonate, see preparation of methyl tosylate for an example.

Excess alkylating agent can easily be destroyed with aqueous ammonia, like DMS of MeI.




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[*] posted on 10-11-2008 at 14:44


Thank you Klute,

About the alkyl bromide : http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=CV1...

And about the sodium methoxide : it can easily be done from a methanolic NaOH solution (3 molar) by addition of one equivalent of 3A molecular sieves, which can be obtained OTC for conservation of artcraft... also Na2CO3 in MeOH can be use to form it...

Yup, Ammonia will destroy it




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[*] posted on 27-7-2009 at 14:18


Ullman, please post links (or preferably, attached articles) to the references for the formation of the alkoxides, etc. posted above. Thanks
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[*] posted on 15-8-2009 at 12:43


Mhh apparently it needs K2CO3 and not Na2CO3 and this is not quantitative (search the old hive)... For molecular sieves, better use fused KOH instead of NaOH to not have the 3A sieves becomes 4A by a cationic exchange, I have tried with sieves it works.



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[*] posted on 13-2-2010 at 12:03


Please note that a detailled procedure for generation and in situ use of the reagent has been posted here.






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[*] posted on 16-3-2010 at 02:38


hi, Klute thank you for your work.

back on the topic of MeI, would it be advantageous to use a phase transfer catalyst such as TBAB as in-

www.patentstorm.us/patents/4933498.html

or http://pubs.acs.org/doi/abs/10.1021/op050086m

it looks like very high yields are possible 97 or 98% under pressure with use of PTC in aqueous conditions. i'm not sure if this can be duplicated without pressure.

is PTC useful also with other alkylating agents, or are alkyl halides the only ones compatible with water?

[Edited on 16-3-2010 by madprossor]
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[*] posted on 21-9-2010 at 18:10


Great work Klute. Can NaOH be used in place of KOH in the methyl iodide methylation?



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