Sciencemadness Discussion Board - Anybody knows synthesis of 5-Cyanosalicylaldehyde

Anybody knows synthesis of 5-Cyanosalicylaldehyde

huanrenze - 14-4-2009 at 08:24

I tried to use 4-cyanophenol reacting with MgCl2, (CH2O)n and triethylamine, dissapointedly, so poor yield(15%) and difficult to purify.
besides I tried to use HMT under acid condition, which was still very low yield.
anybody has good ideal on synthesis of 5-cyanosalicylaldehyde?
there is such a strong electon-drawing group on the ring.
so boring chemical, I have spent over one month on it.

huanrenze - 14-4-2009 at 08:27

Ps: I don't want to use any CN salt.
Thank you very much

sparkgap - 14-4-2009 at 08:41

Why not look into subjecting p-cyanophenyl formate to a Fries rearrangement?

sparky (~_~)

huanrenze - 14-4-2009 at 08:54

Quote: Originally posted by sparkgap

Why not look into subjecting p-cyanophenyl formate to a Fries rearrangement?

sparky (~_~)

Cheers.
is 4-cyanophenyl formate commercially available?

sparkgap - 14-4-2009 at 08:59

You did say you have p-cyanophenol, did you not?

Start from there!

sparky (~_~)

huanrenze - 14-4-2009 at 09:03

Quote: Originally posted by sparkgap

You did say you have p-cyanophenol, did you not?

Start from there!

sparky (~_~)

A great idea, Thanks sparky. I will try it....

Nicodem - 14-4-2009 at 23:36

The preparation of aryl formates is anything but trivial.

Also, the Fries rearrangements of aryl formates is even less trivial since under most classical conditions used for this reaction the formate aryl esters fragmentate with the loss of CO. It only works on aryl formates not containing any electron withdrawing groups, preferably containing methoxies, methyls, condensed benzene rings, and other activating groups. The literature examples are sparse, the most thorough study being in Zeitschrift fuer Naturforschung, B: Chemical Sciences, 56 (2001) 1178-1187 using BCl3 in ClCH2CH2Cl.

5-Cyanosalicylaldehyde has been made via the modified Duff formylation in 41% yield: Chemical & Pharmaceutical Bulletin, 31 (1983) 1751-1753. The Ullmann reaction with CuCN in NMP on 5-bromosalicylaldehyde is poor yielding anyway, it only gave 17% yield (Liebigs Annalen der Chemie (1982) 1836-1869).

PS: Huanrenze, when you open a thread without providing a single reference, please do so in the Beginnings section where this is tolerated, or else I will move it there anyway. Members here are not mind readers and the least you could have done was to refer to the procedure in Acta Chemica Scandinavica, 53 (1999) 258-262 that you seem to have been following.

huanrenze - 15-4-2009 at 03:19

Quote: Originally posted by Nicodem

The preparation of aryl formates is anything but trivial.

Also, the Fries rearrangements of aryl formates is even less trivial since under most classical conditions used for this reaction the formate aryl esters fragmentate with the loss of CO. It only works on aryl formates not containing any electron withdrawing groups, preferably containing methoxies, methyls, condensed benzene rings, and other activating groups. The literature examples are sparse, the most thorough study being in Zeitschrift fuer Naturforschung, B: Chemical Sciences, 56 (2001) 1178-1187 using BCl3 in ClCH2CH2Cl.

5-Cyanosalicylaldehyde has been made via the modified Duff formylation in 41% yield: Chemical & Pharmaceutical Bulletin, 31 (1983) 1751-1753. The Ullmann reaction with CuCN in NMP on 5-bromosalicylaldehyde is poor yielding anyway, it only gave 17% yield (Liebigs Annalen der Chemie (1982) 1836-1869).

PS: Huanrenze, when you open a thread without providing a single reference, please do so in the Beginnings section where this is tolerated, or else I will move it there anyway. Members here are not mind readers and the least you could have done was to refer to the procedure in Acta Chemica Scandinavica, 53 (1999) 258-262 that you seem to have been following.

Sorry about that, Nicodem.
thank you very much for the knowledge.
the procedure reported by Chemical & Pharmaceutical Bulletin uses TFA as solvent, it is quite difficult to remove TFA, even washed by water over 10 times along with hydrolysis of CN group.

[Edited on 15-4-2009 by huanrenze]

sparkgap - 15-4-2009 at 06:45

Quote: Originally posted by Nicodem

Also, the Fries rearrangements of aryl formates is even less trivial since under most classical conditions used for this reaction the formate aryl esters fragmentate with the loss of CO. It only works on aryl formates not containing any electron withdrawing groups, preferably containing methoxies, methyls, condensed benzene rings, and other activating groups. The literature examples are sparse, the most thorough study being in Zeitschrift fuer Naturforschung, B: Chemical Sciences, 56 (2001) 1178-1187 using BCl3 in ClCH2CH2Cl.

Hmm, I think it was encountering the one using boron trichloride that made me look at ths thread. I only got to see the abstract so I may have been a little too hasty... I did assume he'd do more digging on his own.

Also I thought the presence of the -OH group makes up pretty much for the electron-withdrawing cyanide.

sparky (~_~)

Nicodem - 15-4-2009 at 13:05

Quote: Originally posted by huanrenze

How can it be difficult to remove CF3COOH? It is such a volatile acid and the other products in the modified Duff formylation are just CF3COOMe (even more volatile) and the ammonium salts (water soluble). Usually you just rotavap the reaction mixture, take it up with ethyl acetate and with a single wash with aqueous NaHCO3 you can be sure no CF3COOH is left. I think it is much more of a problem to separate the starting material from the product, that is, to recrystallize it without much loss. How much nitrile hydrolysis did you got? And how exactly did you work up the reaction? There is no way anybody can give you a proper advice unless you give us proper and complete information. Like I already said, nobody can not read your mind...

huanrenze - 16-4-2009 at 07:40

Quote: Originally posted by Nicodem

Quote: Originally posted by huanrenze

My Procedure:
the mixture was refluxed at 100'C for 9hrs. and was then cooled by ice . Hydrochloric acid(dilute) was added and stirred for 30mins at room temperature. the residual was extracted by diethyl ether followed by washing with water.
finally, I got the crude containing 20% byproduct(by HNMR, mainly from nitrile hydrolysis ). fortunately, no cyanophenol found from H1NMR spectra. so 5-cyanosalicylaldehyde was then separated by column(cyanophenol and cyanosalicylaldehyde are very close to each other on TLC).
still low yield(20.3%), however, much easier to purify by column.
The reaction time is important, I just got 6.1% yield when the reaction was refluxed for 24hrs.

I would like to take your advices. Next time when I repeat the reaction, I will remove TFA by rotavapor and then try to wash the crude by NaHCO3 and water.

Nicodem - 17-4-2009 at 11:10

You can skip the addition of aqueous HCl. It is obsolete and might be the main cause on why you got also the amide byproduct. See the work up of the Duff formylation as done in ARKIVOC 2000 (iii) 240-251. The intermediate iminium salt should hydrolyse fairly rapidly even if you just quench it with water after concentrating the whole reaction mixture on the rotavapor.
That you found no more starting material and that longer reaction times lead to yield reduction indicates that there is a competing reaction decomposing the salycaldehyde product. You should try reducing reaction time even further or try the reaction at bellow reflux temperature (By the way, how can you reflux at 100°C when the bp of CF3COOH is 72°C? Maybe you are talking about the bath temperature?).
Also, out of curiosity... Given that you separated the product on a column, I can only assume you need the product in a few grams quantities. If so, why do you care about the low yields when p-cyanophenol and trifluoroacetic acids are not really that expensive? And how come you previously said you got the product contaminated with CF3COOH. Surely it couldn't have travelled with the product on silicagel - it elutes with the solvent. And how do you know it was CF3COOH when it only has a singlet in 1H NMR and even this is wide and uncharacteristic. Are you sure it was not something else? Can you post the spectral data?

huanrenze - 20-4-2009 at 04:57

Yes, bath temperature is 100°C and reaction time is 9hrs.(from the literature).
and I just need about 10 grams salicylaldehyde, at the beginning, however, It was very difficult to purify the product by using procedure reported by Acta Chemica Scandinavica, because over 80% of the crude product was cyanophenol and anther byproduct and the reaction took quite a long time(48hrs).
It was really a good news when I found no starting material existing in my reaction by using Duff formylation,and at the beginning, I did not want to run a column, I hoped just simply washing up and recrystalization would work. possibly because of my improper working up, there still had a very strong acid smell(I assume it should be TFA) from my white solid even after 10 times washing up by water.
I then ran a column and got my product with a highly pure H1NMR(TFA not here any more).
I don`t know how to paste the spectral here. Sorry
thanks a lot for you and sparkgap for the literatures and knowledge. this BBS is really nice one.

[Edited on 20-4-2009 by huanrenze]

[Edited on 20-4-2009 by huanrenze]

Nicodem - 11-8-2013 at 05:05

The above discussed synthesis from Chem. Pharm. Bull. has now been reported also on Synthetic Pages:
o-formylation of 4-hydroxybenzonitrile in trifluoroacetic acid; 3-formyl-4-hydroxhybenzonitrile
The reported yield is 33%.