Today I have been looking around at patents which involve the condensation of glyoxylic acid with substituted aromatics of differing types.
This research has been prompted by an interesting patent for the preparation of piperonal that was first brought to the attention of the Hive by pHarmacist:
Post 391475
(pHarmacist: "One More piperonal patent, High-yielding", Novel Discourse)Having looked at much of the information available on Rhodium's site which refers to aromatic formylations, I got to wondering whether this glyoxylic acid condensation and subsequent oxidation could be applied to substrates other than methylenedioxybenzene.
This search has turned up some interesting patents that indicate other substrates can be used with varying conditions and degrees of success.
Patent US4165341
claims that catechol and 2-alkoxyphenols can be used as starting materials to produce protocatechualdehyde or a 3-alkoxy-4-hydroxybenzaldehyde. The patent sites the use of alumina as a catalyst. Yields are good. Oxidation of the mandelic acid intermediate to the aldehyde in this patent is achieved by copper oxide in an autoclave.
Patent FR2830861
covers the production of alkoxy substituted mandelic acids through the condensation of glyoxylic acid with alkoxybenzenes, using strong protonic acids (eg. sulfuric acid) as a catalyst. Claims are made that the process applies to alkoxybenzenes with various other substituents in a catch-all sort of way. It also covers the oxidation of the mandelic acids to aldehydes by oxygen or air in the presence of various metal salt catalysts such as CuCl
2, and oxidation to the aldehydes using nitric acid. Examples are given for the preparation of 4-methoxybenzaldehyde from anisole, and 3,4 methylenedioxymandelic acid from veratrole. Yields vary between 45-72.5%% for the mandelic acids.
Patent WO0196277
covers the conversion of 1,2,3,5 Tetramethylbenzene to 2,3,4,6-Tetramethylmandelic acid and I think O-acetyl-2,3,4,6-Tetramethylmandelic acid (I don't read german) by condensation with glyoxylic acid in acetic acid, using sulfuric acid as a catalyst. Yields look high from what I can understand.
Patent US4227016
covers the production of alpha-chloroarylacetic acids by condensation of glyoxylic acids with alkyl, alkoxy or hydroxy aromatic compounds in the presence of HCl and zinc chloride. Examples given refer to toluene, metaxylene and mesitylene. Yields are crap for toluene but acceptable for the others (presume that toluene is not active enough due to only one methyl substituent).
All this may be of general utility in the preparation of various aromatic aldehydes (especially those with alkoxy or methylenedioxy substituents).
I am currently wondering if it may be possible to use this method to produce Indane-5-carboxaldehyde. The main worries are whether Indane has a suitably activated aromatic nucleus to allow the condensation to occur, and whether the correct positional isomer will be the major product.
I would assume that Indane is less activated than alkoxy benzaldehydes and phenols due to a lesser electron donating character. I would have thought that Indane would be quite a bit more active than toluene, but less so than mesitylene and 1,2,3,5 Tetramethylbenzene.
As for direction, I would expect indane to direct mostly to the 5 position (although am aware that 4-substitution is a possibility).
Does anybody think that it is worth giving this reaction a go on a small scale with indane or is it just not activated enough? Maybe if it was run at a higher temperature than for alkoxybenaldehydes then we could get some result?
In the patent that covers the production of alpha-chloroarylacetic acids does the zinc chloride facilitate the condensation reaction or simply help in substituting the alpha-hydroxy group of the mandelic acid for an alpha-chloro group?
I assume that the patent covering 1,2,3,5 Tertramethoxymandelic acid produces a good amount of the acetate ester because of the higher temperature employed in the condensation than the other reactions (50C as opposed to 5C).
In order to get this reaction on Indane, I am assuming that the temperature will have to be raised to at least 50-60C (I think much higher than this decomposes the glyoxylic acid). Probably best to use ethyl acetate as an organic solvent instead of acetic acid so that the acetate ester is not made.
Edit: actually, would this hydrolyze under the conditions - maybe a ketone would be betterShall I give it a go or is it a waste of time? Is there anything that I could do to make it more likely to work?
