What is Huisgen pyrrole synthesis?
The Huisgen pyrrole synthesis is a widely used method for synthesizing pyrrole derivatives, particularly penta-substituted pyrroles. This reaction involves the 1,3-dipolar cycloaddition of mesoionic 2-oxazilium-5-olates, which are also known as munchnones, to acetylenic or olefinic dipolarophiles, followed by carbon dioxide CO2 evolution and subsequent aromatization or tautomerization.
The munchnones can be easily prepared by the acetic anhydride-induced dehydrative cyclization of N-alkyl-N-acyl-α-amino acids at high temperatures. Depending on the nature of dipolarophiles, either pyrrolidines, dihydropyrroles, or pyrroles can be prepared from the Huisgen pyrrole synthesis. The resulting dihydropyrroles can be converted into pyrroles directly by the oxidation from manganese dioxide MnO2 or sulfur.
- R1, R2 = H, alkyl, aryl
- R3, R4, R5 = alkyl, aryl
- R = R4 or R5 (no regioselectivity for monocyclic munchnones)
The regioselectivity of the Huisgen pyrrole synthesis is controlled by the nature of substituents on the 1,3-dipoles. It has been found that the reaction between asymmetric electron-deficient dipolarophiles and monocyclic munchnones gives a mixture of regioisomers, whereas the reaction between such dipolarophiles and polycyclic munchnones is regiospecific. The azomethine ylides can also be generated by the ring opening of aziridines and can combine stereospecifically with dipolarophiles, even weak ones. In contrast, the 1,3-dipolar cycloaddition of cis-azomethine ylides with dipolarophiles is competed by the isomerization to transazomethine ylides.
References
Huisgen, R. and Laschtuvka, E. (1960), Eine neue Synthese von Derivaten des Pyrrols. [A new synthesis of derivatives of pyrrole.] Chem. Ber., 93: 65-81. https://doi.org/10.1002/cber.19600930113
