Jamide - 17-4-2025 at 22:36
Hello All, I am looking for assistance or ideas on an accessible and practical synthesis of 5-Bromo-6-Methyl-Nicotinic Acid. When attempting to
UTFSE, I was unsuccessful in answering my own problems.
A few main questions to lead with; How can pyridine be methylated on the aromatic ring? How does this compare to say a Friede-Crafts with benzene?
What does the selectivity of this methylation look like as far as the products? As far as the bromination, is this as simple as bromination of a
6-methyl pyridine? I imagine not, as that carbon hanging off of the pyridine looks quite susceptible to halogenation by the usual aromatic
halogenation techniques, or no?
Any feedback would be greatly appreciated, thank you!
Lionel Spanner - 18-4-2025 at 02:34
Friedel-Crafts doesn't work on pyridine in any way, as the aluminium chloride forms a complex with the nitrogen on the ring. It does work with
pyridine N-oxide, but it acylates at the wrong position (3/5 instead of 2/4/6.)
I found a paper from 2015 describing the 2-methylation of pyridine N-oxide with dimethyl benzyl peroxide; I would guess that if the ring were substituted
at the 3 position, methylation at the 6 position would be favoured instead.
As for bromination, there are many different ways this can be done, though I understand acidic bromine is a good choice of reagent for reaction on the
ring itself.
Boffis - 18-4-2025 at 03:28
I think you need to consult "Chemistry of Heterocyclic Compounds Vol 14 Pyridine and Its Derivatives" there are at least 5 volumes in "volume 14" and
numerous supplements. The primary volumes are available on the internet to download, try Libgen or the likes. You may find that you have to assemble
the 6-methylnicotinic acid from aliphatic fragments; this is often the case with pyridine chemistry as against say benzene chemistry where almost any
possible arrangement can be form by substitution
Niklas - 20-4-2025 at 01:24
Surprisingly hard to come up with something good and short honestly..
As it’s a 3-bromopyridine I thought of potentially using a Ciamician-Dennstedt rearrangement, to go back to a pyrrol which may be somewhat easier to
prepare by classic carbonyl reactions. Knorr-pyrrol synthesis is the obvious option for that, and with that I came up with this path starting from
tert-butyl pyruvate (should be available by simple Fischer esterification) and ethyl acetylacetonate (available by Claisen condensation, but also
cheaply commercially).
Due to the conditions of the second and third step both being similar one may be able to combine those in a one-pot sequence (with some trail and
error).
MaeBorowski - 27-4-2025 at 16:13
2-Picoline -> sulfonic acid -> nitrile -> bromonitrile (questionable) -> the desired compound
https://doi.org/10.1021/ja01251a063
Jamide - 9-10-2025 at 10:51
@Niklas What is going on in the first 3 reactions shown?
Niklas - 10-10-2025 at 09:01
First step is a crossed Knorr pyrrol synthesis (the aminoketone being made in-situ by making the oxime by nitrosation followed by zinc reduction) (https://de.wikipedia.org/wiki/Knorr-Pyrrolsynthese), the second step is a simple ester hydrolysis (t-butyl ester being resistant because of
sterics), and the third reaction is a Ciamician Dennstedt reaction (https://de.wikipedia.org/wiki/Ciamician-Dennstedt-Umlagerung).