Copper-Catalyzed Alkynylation/Cyclization/Isomerization Cascade for Synthesis of 1,2-Dihydrobenzofuro[3,2-b]pyridines and Benzofuro[3,2-b]pyridines

Abstract

An efficient copper-catalyzed cascade alkynylation/cyclization/isomerization reaction of aurone-derived azadienes with terminal alkynes has been developed, giving a series of 1,2-dihydrobenzofuro­[3,2-b]­pyridines with excellent yields. The obtained 1,2-dihydrobenzofuro­[3,2-b]­pyridines can be conveniently transformed into the corresponding benzofuro­[3,2-b]­pyridines under basic conditions. Additionally, benzofuro­[3,2-b]­pyridines can also be prepared from azadienes and terminal alkynes in a one-pot reaction. The synthetic utility was demonstrated by the synthesis of three bioactive molecules with potent topoisomerase inhibition in high yields. This strategy provides a facile approach to 1,2-dihydrobenzofuro­[3,2-b]­pyridines and benzofuro­[3,2-b]­pyridines.

Recent Advances in the Cycloaddition Reactions of 2‐Benzylidene‐1‐benzofuran‐3‐ones, and Their Sulfur, Nitrogen and Methylene Analogues

“…Zhou's group then developed methods to synthesize 1,2-dihydrobenzofuro [3,2-b]pyridines through copper-catalyzed alkynylation, cyclization, and isomerization cascade (Scheme 16d). [72] Three bioactive molecules with potent topoisomerase inhibition were synthesized. In 2019, Xu's group reported the reductive coupling/clization reaction between unsaturated imines 41/81 and alkenes 103, and obtained benzofurans, benzothiophenes, and medium-size benzofuranfused heterocycles (Scheme 16e).…”

Base-Catalyzed Sequential 1,4-Addition/Intramolecular Cyclization/Aromatization Reaction: Synthesis of Benzofuro[3,2-b]pyridines

“…Polyheterocyclic frameworks are ubiquitous in natural products and pharmacologically active molecules . Among them, benzofuro­[3,2- b ]­pyridines (BFPs) (Figure ) represent an important class of heterocyclic compounds. − Various strategies for their construction have been established. − However, some of these methods suffer from multistep procedures and the limitation of a narrow substrate range. Therefore, it still is highly desirable to develop a simple method for the construction of this important scaffold.…”

“…In recent years, aurone-derived 1-azadienes have been used as highly reactive intermediates in organic synthesis, due to the driving force of aromatization. − With these aurone-derived 1-azadienes as the starting material, several elegant methods for the construction of benzofuro­[3,2- b ]­pyridine were established. In 2019, Chen, Jiang and co-workers developed an intriguing base-promoted [4+1+1] annulation reaction of aurone-derived 1-azadienes with α-bromo carbonyls, providing a complex benzofuro­[3,2- b ]­pyridines scaffold in an efficient manner (Scheme a) .…”

“…In 2019, Chen, Jiang and co-workers developed an intriguing base-promoted [4+1+1] annulation reaction of aurone-derived 1-azadienes with α-bromo carbonyls, providing a complex benzofuro­[3,2- b ]­pyridines scaffold in an efficient manner (Scheme a) . By using a copper catalyst, Zhou achieved formal [4+2] cycloaddition of aurone-derived 1-azadienes with terminal alkynes, which elegantly produced 1,2-dihydrobenzofuran­[3,2- b ]­pyridines through a complex nucleophilic addition/cyclization/isomerization process (Scheme b) . In 2021, Jiang, Tu, Hao, and co-workers presented a Lewis acid-catalyzed [2+2] cycloaddition/retroelectrocyclization/1,6-addition relay of aurone-derived 1-azadienes and 1-alkynylnaphthalen-2-ols, resulting in the regio- and diastereoselective synthesis of 1,2-dihydrobenzofuro­[3,2- b ]­pyridine with a chiral carbon center and an axial chirality in good yields (Scheme c) .…”

Diastereoselective Synthesis of 1,2-Dihydrobenzofuro[3,2-b]pyridines via a Carbon–Carbon Double-Bond Cleavage/Rearrangement Cascade

“…During this project, we questioned whether the selective double-bond skeletal rearrangement could be harnessed to establish a new [2 + 2] CA-RE strategy by adopting aurone-derived 1-azadienes as electron-deficient olefins. A survey revealed that Zhou, Xie, and co-workers recently reported an elegant copper-catalyzed formal [4 + 2] cycloaddition of 1-azadienes with terminal alkynes, which led to poly-substituted 1,2-dihydrobenzofuro­[3,2- b ]­pyridines through a complex nucleophilic addition/cyclization/isomerization process (Scheme a) . To enrich the benzofuro­[3,2- b ]­pyridine library and realize the skeletal rearrangement of 1-azadienes, we considered exploiting 1-alkynylnaphthalen-2-ols 2 as electron-donating internal alkynes to react with 1-azadienes 1 in view of their previously successful applications .…”