α-Unsubstituted Pyrroles by NHC-Catalyzed Three-Component Coupling: Direct Synthesis of a Versatile Atorvastatin Derivative

5 years ago

α-Unsubstituted Pyrroles by NHC-Catalyzed Three-Component Coupling: Direct Synthesis of a Versatile Atorvastatin Derivative

Frank Glorius, Mirco Fleige

A practical one-pot cascade reaction protocol provides direct access to valuable 1,2,4-trisubstituted pyrroles. The process involves an N-heterocyclic carbene (NHC)-catalyzed Stetter-type hydroformylation using glycolaldehyde dimer as a novel C1 building-block, followed by a Paal-Knorr condensation with primary amines. The reaction makes use of simple and commercially available starting-materials and catalyst, an important feature regarding applicability and utility. Low catalyst loading under mild reaction conditions afforded a variety of 1,2,4-substituted pyrroles in a transition-metal-free reaction with high step economy and good yields. This methodology is applied in the synthesis of a versatile Atorvastatin precursor, in which a variety of modifications at the pyrrole core structure are possible. Three at a stroke: Herein, we report a metal-free one-pot three-component coupling using readily available starting materials and catalyst to generate valuable pyrroles. The process involves an N-heterocyclic carbene (NHC)-catalyzed Stetter-type hydroformylation using a glycolaldehyde dimer as a novel C1 building-block, followed by a Paal-Knorr condensation. Furthermore, this methodology is applied in the synthesis of a versatile Atorvastatin precursor and derivatives of it.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/chem.201703008