Danheiser benzannulation

What is Danheiser benzannulation?

In 1984, Danheiser and his team introduced a novel single-step approach for the controlled synthesis of aromatic compounds with multiple substitutions. This technique, known as the Danheiser benzannulation, involved heating cyclobutenone derivatives with activated or unactivated acetylenes to create a convergent annulation process through a vinylketene intermediate.

Danheiser benzannulation
Danheiser benzannulation

Although alkoxyacetylenes proved to be the best reagents, the harsh conditions required to cleave the aryl ether moiety in the products necessitated the use of trialkylsilyloxyalkynes. Typically, the cyclobutenone component was dissolved in CHCl3, benzene, or toluene, along with a slight excess of the heterosubstituted acetylene, and heated to 80-160 ºC in a sealed Pyrex tube.

An alternative strategy involved using the photochemical Wolff rearrangement of an unsaturated α-diazo ketone to generate a vinyl- or arylketene intermediate. This two-step modified Danheiser benzannulation enabled the synthesis of polycyclic aromatic and heteroaromatic systems, such as substituted naphthalenes, benzofurans, benzothiophenes, indoles, and carbazoles, which could not be accessed using the original methodology. This approach had the added advantage of being easily accessible from a variety of simple ketones and carboxylic acid derivatives. The best yields were obtained when 3-alkoxy phenol derivatives were formed, and this modified Danheiser benzannulation complemented the Dötz benzannulation reaction, which resulted in the formation of 4-alkoxy phenol derivatives.

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