Vilsmeier-Haack reaction

What is Vilsmeier-Haack reaction?

The Vilsmeier-Haack reaction is a chemical reaction that was first reported by Vilsmeier and Haack in 1927. It involves the formylation of an electron-rich aromatic or heterocyclic compound using N,N-disubstituted formamide (e.g., DMF, see list of acronyms) as the acylating agent in the presence of an activating reagent like POCl3.

Because of its discoverers, the reaction is known as the Vilsmeier-Haack reaction, or Vilsmeier formylation, or Vilsmeier-Haack formylation. Moreover, it has been referred to by various names, such as Vilsmeier acylation, Vilsmeier-Haack-Arnold reaction, Vilsmeier-Haack aroylation, and Vilsmeier-Haack acylation.

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

The reaction is applicable for aromatics that are more reactive than benzene, such as those activated by an N,N-dimethylamino group and heterocycles, including pyrroles, carbazoles, indoles, acridines, and ferrocenes. Additionally, the Vilsmeier-Haack reaction has a similar trend of regioselectivity as observed in the Friedel-Crafts acylation, depending primarily on the electron density of the attacked site on the substrate. For example, among the annulated furans, thiophenes, and pyrroles, indoles are the most active heterocycles to undergo the formylation at the 3-position, unless blocked by an existing group.

Besides the activated aromatics and heteroaromatics, the Vilsmeier-Haack reaction can also be used on simple olefins when activated by a strong electron-donating group, such as vinyl ethers, O-silylated enolates of carboxylic esters, and 3-(dimethylamino)acroleins. Even aliphatic ketones or aldehydes can be formylated through this reaction in the presence of a strong activating reagent (e.g., POCl3).

One of the main advantages of the Vilsmeier-Haack reaction is that it allows for the formylation of both primary and secondary amines, which is not possible with other methods such as the Hofmann reaction or the Gabriel synthesis. It is also a useful method for synthesizing aldehydes or ketones from readily available amines, and can be carried out under mild reaction conditions..

However, there are also some limitations to the Vilsmeier–Haack reaction. It requires the use of toxic and corrosive reagents, such as POCl3 and DMF, and can produce undesirable by-products if not carefully controlled. In addition, it is not applicable to tertiary amines or those containing alpha-hydrogen atoms..

In conclusion, the Vilsmeier–Haack reaction is a versatile reaction that has been widely used in organic synthesis for over a century. It can be applied to a variety of substrates and has been used to produce numerous useful compounds.

References

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