Hello,

I have not seen a thread here on this subject, and frankly I am surprised there is not more interest in this reaction. It is OTC and easy, and it makes the formylation of 4-substituted alkyl and alkylthio benzenes possible without POCl3. It has been done on 2-chloro-1,4-DMB but yield is lower, and it is a dirty reaction.

Anyway, this thread is for discussion, examples/experiments to be compiled and discussed. I have had a lot of failures using the method posted at SM, I can safely say it does not work, and the new method is much easier and actually works.

Basically, you form the hexamine adduct the same way with 2eq hexamine per benzene, 2eq H2SO4 per hexamine resulting in 4 total eq to the benzene. Reflux in AcOH for 1-3 hours and that's it, then water is added along with EtOAc and the two phase mixture stirred overnight. Org layer separated, aq extracted and org layers washed, evaporated and crystallized with MeOH.

 This is a very brief overview, and I do not think it would be appreciated if I copy pasted the examples that are at hyperlab, so go read them they are already in English. However if someone thinks it would not be a problem (making sure to give credit to the author) then I can post them here.

So far I have had one success with the new method, because I have only tried it on one substrate which I will give in a minute. I plan to try many more benzenes and will post results in this thread.
This first example I do not use EtOAc for hydrolysis of the adduct, i did not have any on hand. I can guess the yield would be higher if done that way, but nonetheless this worked and I think it is worthy to share it.

Formylation of 2-isopropylthio-1,4-dimethoxybenzene

  In a 500ml RBF is added the subs. benzene (6.3g, 29.6mmol) followed by AcOH 75ml. Hexamine (8.3g, 59.2mmol, 2eq) is then added and it is stirred until total dissolution. Then with cooling in an ice bath and stirring is added conc. H2SO4 (11.6g, 118.4mmol, 4eq) drop wise. The solution gradually forms a light precipitate and near end of addition it is very thick.
The flask is then heated in an oil bath to reflux (bath temp ~145C) and as it reaches reflux temp the precipitate turns yellow and eventually it is all dissolved giving a dark yellow solution. Reflux held for 1hr 15mins.
After this time it is cooled and then 200ml of dH2O is added and it is stirred vigorously overnight. The next day there were a lot of solids in the flask, they are filtered and washed with water, then a few ml of cold MeOH.
After drying there was obtained 4-isopropylthio-2,5-dimethoxybenzaldehyde as yellow crystals (4.1g, 17mmol, 58%). MP 88-89C (PiHKAL 90C). It underwent condensation with nitromethane, then reduction to afford the correct compound, bioactivity confirmed.   

So this is the first real success for me in my book. I tried the Duff on this substrate 3 times in total, that was the last time i tried it. The previous attempts did not work well, let me explain.

My very first attempt I evaporated most of the AcOH in vacuo before adding water, this was detrimental to yield and only gave 1.1g of the benzaldehyde and a lot of unhydrolized adduct. I did not try to salvage the adduct, but tried another reaction instead.
Next, after hydrolysis like above (this time not evaporating the AcOH) I extracted the mixture with DCM, washed evaporated and crystallized with MeOH. For some reason and I do not know why, I was only able to get 0.9g of the benzaldehyde from about 5g of benzene. I think the DCM also pulled out a lot of crap or tars.
I am thinking the hydrolysis worked because the AcOH helped somewhat to solvate the adduct just enough, and gave me a 58% yield. This can likely be improved if I used EtOAc to help hydrolysis.

So, more to come in a bit. If anyone is going to try it, I advise to use the EtOAc for two phase hydrolysis, 70% yields should be attainable then.
Sorry I do not have more examples right at this moment, but I though there should be a thread for this reaction.

Somebody give this reaction a shot!