Schöllkopf oxazole synthesis

What is Schöllkopf oxazole synthesis?

The Schöllkopf oxazole synthesis, also known as the Schöllkopf reaction, was initially reported by Schöllkopf and Schröder in 1971. This reaction involves the condensation of an α-metalated isocyanide with an acylating reagent, resulting in the formation of a 2-unsubstituted oxazole derivative.

Schöllkopf oxazole synthesis - general reaction scheme - Schöllkopf reaction
Schöllkopf oxazole synthesis
  • R1 = alkyl, aryl, sulfonyl, etc.
  • R2 = alkyl, aryl
  • X = halo, carboxyl, alkoxyl, imidazole (see list of acronyms)

The α-alkali metalated isocyanide acts as both a nucleophile and an electrophile and reacts with various acylating reagents, including acyl halide, amide, ester, anhydride, and acyl imidazole, to produce oxazole.

Notably, the intermediate of α-isocyanoketone is not isolable, and it cyclizes to form oxazole during the workup stage. The substituents at the 4- and 5-positions of the oxazole are derived from the group on the methylene carbon of the isonitriles and the acylating reagent, respectively.

The Schöllkopf oxazole synthesis has a significant application in the preparation of amino esters and amino ketones with high yields. Additionally, this reaction can be extended to form chain-extended primary amines, 2-oxazolines, 2-thiazoline-4-carboxylic esters, 2-imidazolines, 2-pyrrolines, pyrroles, thiazoles, 2-imidazolin-5-ones, and 2-imidazolinones, among others.

For example, the reaction between lithiomethyl isocyanide and two equivalents of piperonal followed by acetylation with acetic anhydride can yield the corresponding oxazoline.

References

Schöllkopf, U. and Schröder, R. (1971), 2-Unsubstituted Oxazoles from α-Metalated Isocyanides and Acylating Agents. Angew. Chem. Int. Ed. Engl., 10: 333-333. https://doi.org/10.1002/anie.197103331

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