Sauron - 6-5-2007 at 19:58
Isonicotinic acid is of course pyridine-4-carboxylic acid and is related to the important vitamin Niacin (nicotinic acid or nicotinamide).
In another thread we have been discussing how isonicotinic acid can be prepared from citrazinic acid in two steps in moderate yield. The second step
is a Wolff-Kischner. See Scheme 1 below.
Citrazinic acid is obtained in one step from citric acid in moderate to good yield. See Potential Uses of Citric Acid thread..
Most other routes to isonicotinic acid depend on brute force oxidation of 4-picoline (4-methylpyridine) or 4-ethylpyridine with potassium
permanganate, selenous acid, or nitric acid. The first two oxidizers proceed at moderate temperatures (steam bath for permanganate, 155-185 C for
selenium dioxide) while nitric acid, according to a US patent, requires a catalyst and temperatures of 25-260 C, obviously in a pressure vessel. US
2,505,568.
That places the nitric acid process in the industrial category, leaving us to select between KMnO4 and SeO2. The latter gives a bit better yields. 57%
vs 50%.
KMnO4: Org.Syn. Collected Vol. 3, p. 740 as exemplified for 2-picoline to picolinic acid
Selenium dioxide: JACS 74, 5515 (1952)
Another route was employed in preparation of C14-babelled product. 4-aminopyridine was quaternized with 48% HBr then brominated with Br2. Modified
Sandmeyer conditions were used to prepare the unstable 4-bromopyridine which could be stored in the cold. This compound was lithiated and
carboxylated.
JACS 74, 6289 (1952)
It is my intention to try three of these methods - conversion from citric acid, permanganate oxidation of 4-picoline, and the modified Sandmeyer
reaction.
I want to use the acid to prepare ethyl isonicotinate. This ester is reported to have a pleasing minty wintergreen fragrance.
If anyone is interested in there references I will collect them in a zip file and post them on my 4shared.com folder and put up the link here.
[Edited on 7-5-2007 by Sauron]
anticoplanar - 11-5-2007 at 06:54
Hey, that would be great. I would love to do a Wolff-Kischner, and that ester would be interesting to synthesize. I'm going to sit down with a pad of
paper for a little while to make sure I know what I'm doing but I'll give it a shot.
Sauron - 11-5-2007 at 09:48
See the references in the Potential Uses for Citric Acid thread
tupence_hapeny - 20-5-2007 at 08:39
Cannot see the proposed scheme, is it possible for you to provide it in full? I have a rather long article here on the synthesis of piperidines (which
is mildly off topic, however, it is fairly close to the object of the discussion) which I will be happy to upload once I find where I have put the
sucker.
BTW would this amalgam:
http://www.4shared.com/file/16314305/b83a314e/Birch_reductio...
http://www.4shared.com/file/16314271/f1d409a7/Fragoso-Luna_e...
Being the organic amalgam (discussed by myself elsewhere) based upon a mercury cathode and tetrabutylammonium hydroxide (which I assume could be
sourced rather simply from TBAC/TBAB) be capable of reducing the pyridine to the equivalent piperidine species?
Also, as this article provides that dicarboxylic acids can be used to affect the hydrolysis of nitriles, and that the dicarboxylic acid is
aminated/cyclisised in the process (in fact yields suffer if such cyclization cannot occur):
http://www.4shared.com/file/16246290/b1e580e1/_2__Chemat_F_T...
Wouldn't that be an improved method to that which is sought?
Just some disconnected thoughts on (perhaps not even on) the topic...
tup
PS For the Wolf-Kishner step, try this one out...
http://www.erowid.org/archive/rhodium/pdf/mw.wolff-kishner.p...
[Edited on 21-5-2007 by tupence_hapeny]
Sauron - 20-5-2007 at 12:44
The scheme for citric acid to citrazinic acid is on p.2 of the Potential Uses of Citric Acid thread where you just posted.
If you put it together with the two steps illustrated above, for citrazinic acid to isonicotinic acid, you have the complete scheme.