Elazur
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Guanidines from S-methylisothiouronium salt
Greetings,
I am currently working on guanidine synthesis and I would be really grateful for someone sharing some knowledge on the matter.
From thiosemicarbazide, I carry out a S-alkylation with methyl iodide to form the S-methylisothiouronium hydroiodide. Then, the salt is reacted with
primary and secondary amines in refluxing ethanol. Lastly, guanidine formed is condensed with aromatic aldehydes.
1- During guanidine formation, all S-methylisothiouronium salt is consumed because I see no trace of it in TLC plates. I also note several by-products
(like 4-5). Is that normal for this procedure?
2- After I removed the solvent from reaction medium, I get a dark browm oily residue. I triturated it with anhydrous diethyl ether, but nothing
precipitated. In some instances, the oily residue is soluble in the ether.
3- Tried to make something crystallize with several solvents, but I was unsuccessful. It does not crystallize at all, and forms again the oily residue
when low boiling solvents evaporate.
4- I tried a separation by flash chromatography in MeOH/CHCl3 with this oily residue. I managed to separate a fraction that crystallized, but
apparently it was still contaminated with amine as I can see from NMR data. I can not get this, because in TLC plates the stain from amines is always
the least retained. It should be eluted during the first chromatographic fractions. How come the product that ellutes during last chromatographic
fractions is still contaminated?
5 - Is there any significative change in reactivity during guanylation if I first condense the S-methylisothiouronium salt with the aldehyde, and then
promote guanylation?
6- In some papers, authors add triethylamine or potassium carbonate to the reaction media during guanidine formation stage. II can not get this
either, because this would cause a decrease in electrophilicity of the S-methylisothiourea. Am I mistaken?
7- One fraction from flash chromatography separation had formed a precipitate. I evaporated the solvent under reduced pressure, washed it, and
recovered a light yellow powder. Then, after some days, I noticed that it turned back to a dark brown oily residue. Should I convert the hydroiodide
salt in any other salt, like hydrochloride?
I would appreciate some clarifying on the subject. Thanks.
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Boffis
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If you want a guanidine you must start with thiourea. If you react the alkylisothiouronium salt with ammonia or an amine you get guanidine or a
substituted guanidine, with hydrazine aminoguanidine. If you start with the thiosemicarbazide thiouronium salt you will get aminoguanidine with
ammonia, an N1 substituted-N2-aminoguanidine with a secondary amine and with hydrazine diaminoguanidine, indeed this is the best preparation of this
last compound. The main "byproduct" is a mercaptan (very smelly!) and possible its oxidation product, a dialkyl disulphide. I have some papers on
these reaction latter reactions somewhere.
I don't know if it is better to react thiosemicarbazide with a aldehyde first or generate the aminoguanidine and then react it with the aldehyde. I am
not sure about the addition of a base such as K2CO3 but it may be necessary to liberate hydrazine from its salt or where the amine itself is weekly
basic such as with aniline, its hard to say without a reference to look at.
Here are a couple of papers with experimental details for the reaction thiosemicarbazide methylisothiouronium iodide with hydrazine. Also check out
Vogel on the forum library/online, I am pretty sure there is synthesis of mercaptoacetic acid from thiourea and chloroacetic acid in it. I have seen
numerous related syntheses using variations of this reaction there is plenty more out there!
Attachment: Observations on the preparation of diaminoguanidine JAppC Scott et al 1952.pdf (391kB)
This file has been downloaded 641 times
Attachment: Oxidation & preparation of Diaminoguanidine & Triaminoguanidine JACS Keim et al 1950.pdf (381kB)
This file has been downloaded 538 times
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Elazur
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Thank you Boffis, it was really helpful. I am indeed trying to synthesize N1-substituted-N2-aminoguanidines.
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