Diversity-oriented functionalization of 2-pyridones and uracils

Abstract

Heterocycles 2-pyridone and uracil are privileged pharmacophores. Diversity-oriented synthesis of their derivatives is in urgent need in medicinal chemistry. Herein, we report a palladium/norbornene cooperative catalysis enabled dual-functionalization of iodinated 2-pyridones and uracils. The success of this research depends on the use of two unique norbornene derivatives as the mediator. Readily available alkyl halides/tosylates and aryl bromides are utilized as ortho-alkylating and -arylating reagents, respectively. Widely accessible ipso-terminating reagents, including H/DCO2Na, boronic acid/ester, terminal alkene and alkyne are compatible with this protocol. Thus, a large number of valuable 2-pyridone derivatives, including deuterium/CD3-labeled 2-pyridones, bicyclic 2-pyridones, 2-pyridone-fenofibrate conjugate, axially chiral 2-pyridone (97% ee), as well as uracil and thymine derivatives, can be quickly prepared in a predictable manner (79 examples reported), which will be very useful in new drug discovery.

Benzo-Fused-Ring Toolbox Based on Palladium/Norbornene Cooperative Catalysis: Methodology Development and Applications in Natural Product Synthesis

“…The hexahydro-2,6-methano-1-benzazocine structural motif is a unique bridged skeleton frequently found in complex bioactive natural products. 36 In 2019, we developed a Pd/NBE-promoted annulation between aryl iodides (1) and bifunctional amination reagents (33) for the construction of benzo-fused N-containing bridged scaffolded hexahydro-2,6-methano-1-benzazocines (35), which involved an ortho C−H amination 37 and an intramolecular Heck cascade (Scheme 8A). 21 The desired products 35 were obtained in moderate to good yields.…”

“…After our work, these bifunctional alkylating reagents were used by other research groups in Catellani-type annulations, , further demonstrating their synthetic utility.…”

“…Moreover, the asymmetric version of the reaction was also investigated in which N 3 and Carreira ligand 32 were found to be superior NBE cocatalyst and chiral ligand, respectively, which afforded the products 31 with up to 78% ee (Scheme 7B). After our work, these bifunctional alkylating reagents were used by other research groups in Catellani-type annulations, 34,35 further demonstrating their synthetic utility.…”

Ruthenium(II)-Catalyzed Remote C–H Sulfonylation of 2-Pyridones

“…It is noteworthy that C3,C5-diolefination has been readily achieved and the coupled products were isolated in high yields . Additionally, Pd/norbornene cooperative catalysis enabled C3,C4-difunctionalization of iodinated 2-pyridones and uracils . As no sulfonylation was observed at any positions of 2-pyridones, it is thus highly imperative to explore a practical approach to access sulfones.…”

Catalytic Transformations of 2-Pyridones by Rhodium-Mediated Carbene Transfer

“…2-Pyridone is one of the prevalent heterocycles. Because many nature products and pharmaceuticals contain a 2-pyridone moiety, the development of the selective functionalization of 2-pyridone derivatives has attracted much attention . Typically, the ambident nucleophilic nature of 2-pyridone makes the selective N- or O-functionalization a significant challenge (Scheme a) .…”