Sciencemadness Discussion Board

aromatic formylation using TCT?

stoichiometric_steve - 31-1-2008 at 11:19

Sauron, i guess you are the most knowledgeable member here regarding TCT and its congeners, but if anybody else is able to answer my question, go ahead! (and YES, i did google a bit ;))

can aromatic aldehydes (phenolic ethers) be made in vilsmeyer-haack style with TCT/DMF also?

Nicodem - 31-1-2008 at 14:42

You would need one hell of a nucleophilic aromatic compound to get it to react with cyanuric chloride activated DMF. Some phenols and N,N-dialkylanilines might react, but aryl alkyl ethers most probably not. Perhaps with N-methylformanilide instead of DMF...

stoichiometric_steve - 31-1-2008 at 23:32

oh, ok. i was under the impression that electron-donating alkyl ethers (+I) of phenols provided even more activation than the phenols alone.

and how is NMFA more reactive than DMF? the phenyl substituent seems to make it more bulky - sterically hindered. i reckon that it's a better leaving group compared to methyl.

regarding vilsmeyer-haack formylation, does anybody have more info than google on the "Clezy modification" on the classical formylation?

Clezy used benzoyl chloride with DMF instead of POCl3. sounds reasonable.

[Edited on 1-2-2008 by stoichiometric_steve]

SecretSquirrel - 1-2-2008 at 06:33

Check the uploaded article for Clezy's modification of Vilsmeier-Haack formylation (thanks to Solo for retrieving it).

The chemistry of pyrrolic compounds. VII. Synthesis of 5,5'-diformyldipyrryl-methanes
R. Chong, P.S. Clezy, A.J. Liepa and A.W. Nichol
Australian Journal of Chemistry, 22(1), 229 - 238

http://mihd.net/frbqsk

Nicodem - 1-2-2008 at 09:53

The pyrrole system is one of the most nucleophilic aromatic systems. You don't need a very much activated Vilsmeier reagent to formylate it. But benzoyl chloride activated DMF will be unlikely to formylate other systems. For the Vilsmeier-Haack formylation of very nucleophilic sytems like phenols and N,N-dialkylanilines even SOCl2 or oxalyl chloride activated DMF suffices.

N-Methylformanilide once activated by POCl3 (or other acid chlorides) gets more reactive than DMF can get, simply because the Vilsmeier reagent formed is more electrophilic (the influence of the phenyl ring...).

stoichiometric_steve - 1-2-2008 at 15:32

Quote:
Originally posted by Nicodem
N-Methylformanilide once activated by POCl3 (or other acid chlorides) gets more reactive than DMF can get, simply because the Vilsmeier reagent formed is more electrophilic (the influence of the phenyl ring...).


i see. i've never attempted V-H formylation, but when doing the layout for syntheses to come, i tried to avoid the formed n-methylaniline due to its toxicity. but looking at the toxicity of POCl3, that may be the greater cause for concern ;)

Nicodem - 8-8-2008 at 07:57

I apologize for bringing up an old thread, but I stumbled upon this abstract and remembered this discussion so here I post it:

Chemical Abstract, 59 (1963) 62074 :
Quote:
The formylation of aromatic compounds with 1:2 adduct of dimethylformamide and cyanuryl chloride.
Oda, Ryohei; Yamamoto, Keiji.
Nippon Kagaku Zasshi, 83 (1962) 1292-1294

Abstract

Cyanuryl chloride (27.5 g.) in 90 ml. HCONMe2 was stirred at 20 for 4-6 hrs. and the mixt. (I) used for the following reactions. PhNMe2 (36.4 g.) was added to I at 25 in 30 min., stirred at 30-40 2 hrs., and poured into 400 ml. 10% aq. Na2CO3 to give 19.5 g. recovered PhNMe2 and 18.5 g. p-Me2NC6H1CHO. Similarly the following aldehydes were obtained (starting material, aldehyde, m.p. or b.p. and % yield (subtracting recovered material) given): pyrrole, pyrrole-2-aldehyde, b15 109-11 (cm. 43-4), 65; 1-dimethylaminonaphthalene, 4-dimethylamino-1-naphthaldehyde (II), b6 160-5 47; 1,3-(MeO)2C6H1, 2,4-(MeO)2C6H3CHO (III), m. 65-6, 36; indole, indole-3-aldehyde, m. 194-5 31; thiophene, thiophene-2-aldehyde, b30 .apprx.120, 5. Also prepd. were II 2,4-dinitrophenylhydrazone, m. 230-1, and III semicarbazone, m. 198-9. Those which failed to give aldehydes on treatment with I were cyclopentadiene, Ph2C:CH2, anthracene, anisole, 2-methoxynaphthalene, BzEt, PhOH, carbazole, and benzothiazole.


So cyanuric chloride can be used, but unfortunately it works only with the most nucleophilic aromatic systems. But then again, neither can DMF/POCl3 formylate anisole, so it might still be worth trying on some substrate of reactivity intermediate between 1,3-dimethoxybenzene and anisole.