Natural Science Forum / Chemistry / Organic Synthesis / January 2004

Hi Aubrey

It´s no wondering that you find it curious, that the
4-aminosalicylaldehyde is difficult to locate in literature.  The
reason is obvious, since the free 4-aminosalicylaldehyde will condense
with itself to form a polymer of imin structure as soon as you has
formed it in your reaction pot. That´s the reason nobody is working
with the free 4-aminosalicylaldehyde. Thus you has to go side ways to
form a derivate of it, which is stable to isolate, and with which you
could do the chemistry you are planning to do. First off all, think of
the simplest derivatives as the hydrochloride of
4-aminosalicylaldehyde, but this will cause problems as soon as you
want to condense it when it is in contact with a base (or even in
neutral conditions). Better you use the 4-acetylaminosalicylaldehyde
as aprotected version of this.

There is the following procedure to the 4-acetylaminosalicylaldehyde:

Step 1: Preparation of
2,4-Dioxo-1,2,3,4-tetrahydro-1,3,5-trimethyl-s-triazinium-bromide

15,7 g (0,1 mole) 2,4-Dioxo-hexahydro-l,3,5-trimethyl-s-triazine were
dissolved in 30 ml Methylene chloride and 24 g (0,15 mole) bromine
were added dropwise. The temperature of the reaction mixture is held
between 20 and 30 °C through external cooling. After addition of
bromine is finished, stir for 30 minutes. After few minutes the
addition product of bromine to
2,4-Dioxo-1,2,3,4-tetrahydro-l,3,5-trimethyl-s-triazinium bromide is
precipitated in orange coloured crystals. They were isoalted by
filtration with suction and were recrystalliszed from isopropanol.
Yield: 20 g (85 %) of
2,4-Dioxo-1,2,3,4-tetrahydro-1,3,5-trimethyl-s-triazinium-bromide as
colourless crystals , mpt. 217 °C.

Step 2: Use of 2,4-Dioxo-1,2,3,4-tetrahydro-1,3,5-trimethyl-s-triazinium-bromide
(Step 1) for the Preparation of 4-Acetylaminoaalicylaldehyde

23,6 g  (0,1 mole) of
2,4-Dioxo-1,2,3,4-tetrahydro-l,3,5-trimethyl-s-triazinium-bromide were
dissolved in 50 ml water and 10,9 g ( 0,1  mole) m-Aminophenol were
added. After some minutes a clear solution is formed and then 8 g if
sodium hydrogencarbonate are added in portions. 25 g (89 mmole) of a
precipitate of 2,4-Dioxo-hexahydro-1,3,5-trimethyl-6-(2-hydroxy-4-amino-phenyl)-s-triazine
as white crystals after recrystallisation were isolated: mpt: 240 °C.

113 g (0,4 mole) of the obtained
2,4-Dioxo-hexahydro-1,3,5-trimethyl-6-(2-hydroxy-4-amino-phenyl)-s-triazine
were introduced into a solution of 120 g potassium hydroxide in 640 ml
n-butanol (no water present) and were stirred at 110 °C for 3 hours.
After the heating period is ended, the solution is cooled to ambient
temperature and the product (the potassium salt of
4-aminosalicylaldehyde) is isolated by quick filtration with suction
(protect from humitidy).

The potassium salt of 4-aminosalicylaldehyde is added to 150 ml of
acet anhydride. After the reaction is done, the product is heated in
water to remove the salts. After cooling there is obtained
4-acetylaminosalicylaldehyde with mpt. 186 °C.

This preparation is taken from the French Patent FR FR 2295030
(corresponding German Patent DE 2460823 (both to BASF), cited in Chem.
Abstr. Vol. 85, 143146.

For a more difficult preparation of this compound also see A.A.
Goldberg: J. Chem. Soc. (London) 1954, pp. 2641.

Check out also the following references:

Justoni et al.: Il Farmaco Vol. 6, 1951, pp. 849-855.
Ikeda et al.: Shionogi Kenkyusho Nempo Vol. 5, 1955, pp. 551 (in
Japanese, cited in Chem. Abstr. 1956; 15530).

See Ya

Steven