Vilsmeier without POCl3

[Nicodem]

Looks like POCl₃ is not the only reagent capable of creating a good enough electrophile from DMF for the Vilsmeier formylations!

(CF₃SO₂)₂O or aka Tf₂O

cited from:
Sandipan Sarkar. Trifluoromethanesulfonic (triflic) Anhydride. SYNLETT 2004, pp 000A–000B (Spotlight 82).

"Tf₂O has been utilised as a mild activation reagent in Vilsmeyer–Haack formylation. Less nucleophilic aromatics can be formylated with DMF/Tf₂O."

Me₂N-CHO + Tf₂O --[ 0°C ]--> Me₂N⁺=CH-OTf + TfO^- --[ i)+ArH; ii) aq. NaOH ]--> Ar-CHO
yield: 25-90%

Martínez, A. G.; Álvarez, R. M.; Barcina, J. O.; Cereo, S. M.; Vilar, E. T.; Fraile, A. G.; Hanack, M.; Subramanian, L. R. J. Chem. Soc., Chem. Commun. 1990, 1571.

Pyrophosphoryl chloride (P₂O₃Cl₄)

cited from:
Pansare and Ravi. Steric and electronic effects in arene formylations involving pyrophosphoryl chloride. SYNLETT 1994, 823-824.

"A significant development has been the recent demonstrations that the use of pyrophosphoryl chloride (P₂O₃Cl₄) in the Vilsmeier formylations offer significant advantages in both reactivity and regioselectivity over over the conventional phosphoryl chloride (POCl₃) derived reagent."

Cheung et al. SYNLETT 1992, 77.
Downie et al. Tetrahedron 49, 1993, 4015.


OK, I know Tf₂O and P₂O₃Cl₄ are not cheap and easy to get but it is nice to see there are even better alternativatives to POCl₃. If only tionyl chloride or P₂O₅ would work .
Anybody else knows of other reagents for the Vilsmeier?

[Rhodium]

Post 17068 (missing)

(Rhodium: "Pyrophosphoryl Chloride Vilsmeyer", Chemistry Discourse)

Post 409706

(demorol: "Preparation of pyrophosphoryl chloride", Methods Discourse)

[azole]

Anybody else knows of other reagents for the Vilsmeier?

A quick TFSE search revealed the following alternatives:

Post 62910 (missing)

(cesium: "Modification of Vilsmeier-Haack reaction", Chemistry Discourse)

Post 207345 (missing)

(Antoncho: "Vilsmeier mechanism: the alternatives to POCl3", Chemistry Discourse)

Post 335428

(hypo: "formylation using triformamide", Novel Discourse)

Btw., POCl₃ can be prepared by cautious heating of the mixture of PCl₅ and P₂O₅ (molar ratio 3:1) until complete dissolution. Pure product can be obtained by fractional distillation of the resulting liquid.

[slappy]

SOCl2 will also work, as will PCl3, PBr3, MsCl, Etc. In fact, anything that can dehydrate the amide to form the haloimidate will work.

[Vitus_Verdegast]

That would be very interesting!  
Can you provide any references which use this?

[Nicodem]

I'm sorry I did not UTFSE prior posting. That discovery made me a little to impulsive . And today again I did not USTFE , but did go trough all the links given and attempted a small resume. Hey, at least this opened a new discussion that might clear some mistaken concepts, or in short: ”Did anybody ever had any success with the Vilsmeier-Haack with anything but POCl₃?”

The thing is that I don’t belive SOCl₂/DMF works with anything but a highly nucleophilic aromatic like dimethylaniline in the example given by

Post 207567 (missing)

(lunatic_asylum: "Re: Vilsmeier mechanism: the alternatives to POCl3", Chemistry Discourse). Must I remind that of all benzene derivatives that are not phenols or N-unsubstituted anilines the N,N-dimethylaniline is the most nucleophilic of them all. This makes it activated toward many electrophiles that would otherwise react only with the phenol/aniline type of aromatics.
Therefore, until somebody gives an example I will restrain on wasting my precious thionyl chloride. Well, maybe I will loose patience and at least give it a try on the most activated methoxybenzene viable (1,3,5-trimethoxybenzene) especially if someone comes up with some good news. (I also have similar reconsiderations about COCl₂/DMF) Someone might say “look at the

Patent US4157333

!” but they use N-alkylformanilides that form the appropriate electrophile much easier than DMF.

Also, the triflic anhydride with DMF is reputably somewhat more reactive formylation combinations than POCl₃/DMF. Meaning that it might give (better) yields with some less nucleophilic aromatics (I have 4-halogeno-1,4-dimethoxybenzene in mind). Yeah, I know, Tf₂O is not laying around just anywhere and is also expensive as gold but triflic acid is at least two times cheaper (not to mention more common). Tf₂O is made by distilling it out of the mixture of P₂O₅/TfOH and I had this thought of possibly using TfOH in catalytic amounts in P₂O₅/DMF for Vilsmeier-Haack formylations. If the temperature would be high enough the Tf₂O should be constantly recycled and should react with a new molecule of DMF. The P₂O₅ and its products are unreactive toward the substrate and should not cause any side products. The idea can be formulated like the following all going on in the DMF solution:

P₂O₅ + Tf-OH ==> Tf₂O + polyphosphoric acids
Tf₂O + Me₂N-CHO ==> Me₂N⁺=CH-OTf + TfO^-
Me₂N⁺=CH-OTf + ArH ==> Ar-CH=N⁺Me₂ + Tf-OH
The Tf-OH goes back in to the first reaction…

However if the T is to high the formed Ar-CH=N⁺Me₂ might react with Ar-H but I don’t know if at the normal T used in the Vilsmeier the P₂O₅ would dehydrate Tf-OH efficiently enough. Especially when more and more of the Tf-OH gets deprotonated during the second reaction. The polyphosphoric acid is nearly not acidic enough to protonate Tf-O^- but to compensate it is at least thirsty as hell anywhere above 50°C and will dehydrate just anything. Well forgive my constant and long theorizations but I almost love that more than the preparations themselves . Comments are very welcome.

[Vitus_Verdegast]

The thing is that I don’t belive SOCl2/DMF works with anything but a highly nucleophilic aromatic like dimethylaniline in the example given by

Post 207567 (missing)

(lunatic_asylum: "Re: Vilsmeier mechanism: the alternatives to POCl3", Chemistry Discourse) . Must I remind that of all benzene derivatives that are not phenols or N-unsubstituted anilines the N,N-dimethylaniline is the most nucleophilic of them all. This makes it activated toward many electrophiles that would otherwise react only with the phenol/aniline type of aromatics.

In

Patent GB607920

, "Improvements in or relating to the preparation of tertiary amino aromatic aldehydes", the authors state that POCl₃ can be substituted with PCl₃, SOCl₂, SO₂Cl₂ and S₂Cl₂. I found the last one very interesting, as it is easily prepared.

So I can assume that this will not work on anything but (N,N-dialkyl-) anilines and maybe phenols?


Well forgive my constant and long theorizations but I almost love that more than the preparations themselves

I find them very interesting really..
At least I didn't stink up my neighbourhood for nothing..  

[Nicodem]

So I can assume that this will not work on anything but (N,N-dialkyl-) anilines and maybe phenols?

I'm afraid so, but I don't know exactly why the patent is limited to N,N-disubstituted anilines while we know that POCl3/DMF work with alkoxybenzenes as well. Maybe exactly because of the other presumably less efective reagents that might not work on other substrates. Or maybe other substrates were alredy covered by other patents by the time of issue. I don't know, but it would be still interesting to find out some more examples that where they use PCl3, SO2Cl2 and S2Cl2 with DMF.

[carl]

Stumbled upon this thread.
I researched that a while ago because I did not want to buy POCl3, and apparently you can even use SOCl2 or oxalyl chloride to create the vilsmeier reagent from DMF.