Palladium-catalyzed intramolecular aminoalkylation of unactivated alkenes for synthesis of nitrogen-containing heterocycles

Abstract

Palladium-catalyzed carboamination (simultaneous formation of C-N and C-C bonds from an olefin) has emerged as an efficient protocol for the synthesis of diversely functionalized N-heterocycles, which are widely displayed in natural products and pharmaceuticals. Compared with the well-documented aminoarylation, aminovinylation and aminoalkynylation, analogous aminoalkylation remains a challenge. This project aims at developing innovative strategies for aminoalkylation to construct a broad array of N-containing heterocycles.

An efficient and general palladium-catalyzed intramolecular aminoalkylation of alkenyl aromatic α-halo acetamides with a wide substrate scope under mild conditions has been developed, yielding diverse dihydropyrroloindole derivatives of pharmaceutical interest. Preliminary mechanistic studies suggest that the reaction involves a Pd(0)/Pd(II) catalytic cycle, initiated by oxidative addition of α-halogen of amide with Pd(0) complex. The formation of an unprecedented four-membered-ring Pd(alkyl)amido complex is also supported by ESI-MS analysis. The synthetic utility of this aminoalkylation has been demonstrated by the synthesis of bioactive compounds A, B and C.

Then the aminoalkylation reaction has been expanded to the more challenging alkenyl aliphatic α-halo acetamide substrates. This transformation features no requirement for air and moisture sensitive phosphine ligands and provides a straightforward access to a variety of bicyclic pyrrolizidine derivatives. Detailed mechanism studies support the hypothesis that the formation of a four-coordinate intermediate 3-IV is crucial for the realization of this transformation. An isotopic labeling experiment indicates that the aminopalladation proceeds through syn-insertion of alkene into Pd-N bond.

The application of this aminoalkylation reaction to construct bicyclic isoxazolidines from α-halo oxy-acetamides has been explored. The reaction proceeds well at room temperature for α-iodo substrates. In addition, α-bromo and α-chloro substrates are also compatible, affording the desired products in good yields with moderate diastereoselectivity. The observation of different effects from externally added phosphine ligands indicates a distinct catalytic cycle, which may involve an initial aminopalladation followed by bimetallic transmetallation or oxidative addition. This tandem cyclization may offer a novel route to natural products and bioactive compounds containing this core.

Finally, the enantioselective intramolecular aminoalkylation for the construction of chiral bicyclic isoxazolidines has been attempted. After screening of a variety of reaction parameters and a series of SPINOL-based ligands, a catalytic system has been disclosed, which utilizes 7 mol% Pd(TFA)2, 20 mol% (R)-Siphos-PE, 300 mol% sodium bromide and 100 mol% sodium carbonate. The desired product can be obtained in 70% yield with 60% enantiomeric excess. A general structure-activity-relationship (SAR) for SPINOL-based ligands is obtained, which provides a platform for further modification.