Vilsmeier formylation

What is Vilsmeier formylation?

In 1927, Vilsmeier and Haack introduced a reaction for formylation of an electron-rich aromatic or heterocyclic compound. The reaction is performed using N,N-disubstituted formamide (DMF) as an acylating agent and an activating reagent, typically POCl3, and is called the Vilsmeier formylation. The reaction has been referred to by various names, including Vilsmeier-Haack reaction, Vilsmeier-Haack formylation, and Vilsmeier acylation.

Vilsmeier formylation - general reaction scheme - Vilsmeier-Haack reaction - Vilsmeier-Haack formylation - Vilsmeier acylation
Vilsmeier formylation

The Vilsmeier complex or Vilsmeier reagent is formed by the combination of an N,N-disubstituted formamide and an activating reagent or by the complex of an iminium salt formed from formamide and the activating reagent. The reaction is applicable only for aromatics that are more reactive than benzene, such as benzenes activated by an N,N-dimethylamino group, pyrroles, carbazoles, indoles, acridines, and ferrocenes.

The regioselectivity of the Vilsmeier formylation is similar to that of the Friedel-Crafts acylation, depending on the electron density of the attacked site on the substrate. For example, indoles are the most active heterocyles to undergo the formylation at the 3-position, unless it is blocked by an existing group. However, benzo[b]thiophene forms the formylated product in a poor yield, whereas 4-methyl-, 4-methoxy-, 4-hydroxy-, and 4,4′-dimethoxystilbenes are inert to the Vilsmeier formylation, leading to the recovery of starting materials.

In addition to activated aromatics and heteroaromatics, simple olefins activated by a strong electron-donating group, such as vinyl ethers, O-silylated enolates of carboxylic esters, and 3-(dimethylamino)acroleins, can undergo the Vilsmeier formylation. Even aliphatic ketones or aldehydes can be formylated through this reaction, via the intermediate of enols or vinyl ether in the presence of a strong activating reagent, such as POCl3. Other cycloalkanones can be converted into 2-chloro-vinyl aldehydes in a similar manner, known as chloroformylation. The reaction is also feasible for the formylation of olefinic moieties when they are conjugated to an aromatic or heteroaromatic ring, and the formylation takes place at the olefinic component rather than the aromatic part, probably due to the higher degree of electron density. Porphyrin rings can be formylated when they are activated via coordination with certain cations, including Ni(II), Cu(II), Pd(II), Pt(II), Zn(II), Cr(III), Mn(III), Fe(III), Al(III), Si(IV), or Pt(IV).

References

Vilsmeier, A. and Haack, A., Ber., 1927, 60, 119

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