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Author: Subject: a new OTC Mukaiyama-like coupling reagent from thiamin?
clearly_not_atara
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[*] posted on 7-2-2020 at 11:17
a new OTC Mukaiyama-like coupling reagent from thiamin?


https://www.thieme-connect.com/products/ejournals/pdf/10.105...

The Mukaiyama reagent is already one of the easiest coupling agents to synthesize: 2-chloropyridine reacts with methyl iodide. That's it! Direct reaction of pyridine with Cl2 even proceeds at 2 (in the gas phase at 270 C). However, pyridine is already annoying to make, and Cl2 is kind of scary, and the simplicity of this moiety begs for innovation.

The reductive cleavage of thiamin was brought to my attention originally by someone interested in the thiazole fraction, but the pyrimidine can also be recovered. Unfortunately the usual method with bisulfite leaves a sulfonic acid moiety attached, which hampers solubility in aprotic solvents.

However, the cleavage can also be effected by other, less problematic nucleophiles, as described in the attached paper by Zoltewicz et al.

If a suitably inert pyrimidine is obtained, it is only two steps away from the active bromopyrimidinium. This can then be used to couple a variety of carboxylic acids with a variety of nucleophiles. The picture I drew isn't quite substituted right, but you get the idea.

Some reports even mention that ketenes can be obtained by decomposition of the pyri[mi]dinium ester intermediate! This provides an unusually facile route to versatile intermediates like phenylketene.

thiaminmukaiyama.png - 27kB

Attachment: zoltewicz1984.pdf (822kB)
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[Edited on 7-2-2020 by clearly_not_atara]




[Edited on 04-20-1969 by clearly_not_atara]
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monolithic
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[*] posted on 9-2-2020 at 05:55


Can you dumb it down for me and show some examples of what this reagent can do? :D
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clearly_not_atara
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[*] posted on 9-2-2020 at 08:44


The link at the top of the post shows several examples with refs. A particularly dramatic example is the conversion of beta,gamma-unsaturated acids to cyclobutanones:

https://pennstate.pure.elsevier.com/en/publications/generati...

I should mention that a similar starting material can be obtained by the reaction of guanidine and acetylacetone to 2-amino-4,6-dimethylpyrimidine, which can be diazotized and methylated to a similar halopyrimidinium reagent.




[Edited on 04-20-1969 by clearly_not_atara]
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Boffis
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[*] posted on 22-2-2020 at 11:21


Hi c_n_atara, I've been looking into the degradation of thiamine and the resulting products. Rather fascinationg but it looks like the amino group may not function in quite the normal fashion and may not yield a diazonium compound but merely undergo hydrolysis. I may be wwrong but in one of the papers I found (and there are lots of them!) it reports that the pyrimidine part reacts with nitrous acid to give only nitrogen.

Could another nucleophile be used instead of sulphite? The paper you posted above gives another example of sodium azide to give the appropriate azide. Maybe this could be reduced to an amine or eliminated by other means.
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clearly_not_atara
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[*] posted on 22-2-2020 at 13:54


It's likely that the diazonium is very unstable. As such I'm not surprised that nitrous acid gives a pyrimidone in many cases. Also, the sulfite gives a sulfonic acid, so if you work with that it might have extra side rxns. Nitrosyl bromide might be an option if nothing else works.

For other nucleophiles I don't know. I would try methoxide first.




[Edited on 04-20-1969 by clearly_not_atara]
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AvBaeyer
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[*] posted on 22-2-2020 at 19:33


clearly_not_atara:

I know that if you dig a bit deeper you will find that the chemistry of pyridines (the basis of the Mukaiyama reagents) differs considerably from pyrimidines. As Boffis infers above, there is a vast literature on pyrimdine chemistry, in particular aminopyrimidines and their reactions. Without further information your post is merely speculative. Why not do the chemistry proposed and report back to us? Real chemistry, real results - how novel.

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