Enantioselective Synthesis of Dihydropyrazolo[3,4‐b]pyridin‐6‐ones via N‐Heterocyclic Carbene Catalyzed [3+3] Cycloaddition of α‐Bromoenals with 5‐Aminopyrazoles

Abstract

An N-heterocyclic carbene (NHC) catalyzed asymmetric [3 + 3] annulation of α-bromoenals with 5-aminopyrazoles is described. Using the established methodology, a structurally diverse set of high value dihydropyrazolo[3,4-b]pyridine-6ones were efficiently constructed in high yields (up to 99%) with excellent enantioselectivities (up to > 99%). The easily available starting materials, broad substrate scope, mild reaction conditions, excellent yield and enantioselectivity make this strategy attractive for the asymmetric construction of pyrazolo-fused pyridone derivatives.

Asymmetric synthesis of chiral pyrazolo[3,4-b]pyridin-6-ones under carbene catalysis

“…The absolute configuration of the products 3 was established by comparison with that of the molecules reported in Wang's work. 22 On the basis of the experimental results and previous work, 25 a plausible mechanism is shown in Scheme 1. Deprotonation of NHC precursors resulted in the formation of free carbene, which attacked the unsaturated aldehyde 2a to generate the homoenolate intermediate I, which subsequently underwent oxidation to give the unsaturated acyl triazolium intermediate II.…”

“…1a). 1 For example, TM-N1324 was identified as a highly selective and highly potent synthetic agonist for the Zn 2+ -sensing G-protein-coupled receptor 39 (GPR39). 2 I2 not only was identified as a novel anticancer agent having activity against MDA-MB-231, HeLa, MCF-7, HepG2, CNE2 and HCT116 tumor cell lines, but also showed potent cytotoxicity against adriamycin-resistant human breast and hepatocarcinoma cells.…”

“…Notably, the synthesis of chiral pyrazolo[3,4- b ]pyridin-6-ones commonly relied on the separation of racemates by chiral HPLC. 1,3 Further development of catalytically asymmetric synthetic methods is highly desirable.…”

“…1c). Notably, during the preparation of this work, the groups of Li 21 and Wang and Lang 22 independently reported carbene-catalyzed [3 + 3] annulation of bromoenals with pyrazol-5-amines for the synthesis of diverse pyrazolo[3,4- b ]pyridin-6-ones with good outcomes.…”

“…The absolute configuration of the products 3 was established by comparison with that of the molecules reported in Wang's work. 22…”