N-Heterocyclic Carbene-Catalyzed [3 + 3] Annulation of 5-Aminopyrazoles with Enals: Enantioselective Synthesis of Pyrazolo[3,4-<i>b</i>]pyridones

Li, Jiahan; Duan, Xiao-Yong; Ren, Xiaojie; Li, Yanting; Qi, Jing

doi:10.1021/acs.joc.3c00793

J. Org. Chem.

2023

DOI: 10.1021/acs.joc.3c00793

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N-Heterocyclic Carbene-Catalyzed [3 + 3] Annulation of 5-Aminopyrazoles with Enals: Enantioselective Synthesis of Pyrazolo[3,4-b]pyridones

Jiahan Li,

Xiao-Yong Duan,

Xiaojie Ren

et al.

Abstract: An enantioselective construction of pyrazolo [3,4-b]pyridones was achieved via N-heterocyclic carbene-catalyzed [3 + 3] annulation of enals with 5-aminopyrazoles. This protocol not only offers a highly efficient synthetic approach for the preparation of various substituted pyrazolo [3,4-b]pyridones but also provides an effective method for the rapid synthesis of enantiopure spirooxindone derivatives.

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Cited by 5 publications

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“…To commence our studies, the reaction between 5-aminopyrazoles 1a and α,β-unsaturated 2-acyl imidazole 2a was conducted in the presence of 11 mol % of L1 and 10 mol % of Ni(OTf) 2 in DCM at room temperature, resulting in the esterified Michael addition/Cyclization product 3a in 97% yield with 98% ee (Table , entry 1). Inspired by this promising result, a variety of Ni(OTf) 2 ions with different chiral ligands were investigated in the title reaction (entries 2–5).…”

mentioning

confidence: 99%

Bipyridine-N,N′-dioxides Catalysts: Design, Synthesis, and Application in Asymmetric Synthesis of 1H-Pyrazolo[3,4-b]pyridine Analogues

Zhu,

Tian,

Liu

et al. 2024

Org. Lett.

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A novel type of highly efficient chiral C2-symmetric bipyridine-N,N′-dioxides ligand application in catalyzing Michael addition/Cyclization of 5-aminopyrazoles with α,β-unsaturated 2acyl imidazoles has been developed, affording the corresponding adducts in 85−97% yield with up to 99% enantioselectivity under mild conditions with a lower catalyst loading and broad scope. Remarkably, this protocol exhibits advantages in terms of reactivity and enantioselectivity, giving the fact that as low as 2.2 mol % of L1 and 2.0 mol % of Ni(OTf) 2 can promote the title reaction on gram scale to afford the desired product with excellent enantioselectivity.

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mentioning

confidence: 99%

Bipyridine-N,N′-dioxides Catalysts: Design, Synthesis, and Application in Asymmetric Synthesis of 1H-Pyrazolo[3,4-b]pyridine Analogues

Zhu,

Tian,

Liu

et al. 2024

Org. Lett.

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Mechanisms and Origins of Regio- and Stereoselectivities in NHC-Catalyzed [3 + 3] Annulation of α-Bromoenals and 5-Aminoisoxazoles: A DFT Study

Zhang,

2024

J. Org. Chem.

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Density functional theory (DFT) calculations were conducted to explore the mechanisms and origins of regio-and stereoselectivities underlying the [3 + 3] annulation reaction between α-bromoenals and 5-aminoisoxazoles with N-heterocyclic carbene (NHC) as the catalyst. The reaction occurs in nine steps:(1) nucleophilic addition of NHC to α-bromoenal, (2) Breslow intermediate formation through 1,2-proton transfer, (3) debromination, (4) α,β-unsaturated acyl azolium intermediate formation via 1,3-proton transfer, (5) addition of α,β-unsaturated acyl azolium intermediate to 5-aminoisoxazole, (6) deprotonation, (7) protonation, (8) ring closure, and (9) elimination of NHC. For the fifth step, 1,2-addition suggested in the experiment was not supported by our results. Instead, we found that Michael addition is energetically the most feasible pathway and the stereocontrolling step that preferentially provides the S-configuration product. DFT-computed results and experimental findings agree well. Analysis of distortion/interaction reveals that lower distortion energy leads to stability of the transition state corresponding to the Sconfiguration product. Global reactivity index analysis indicates that the behavior of the NHC catalyst differs significantly before and after the Breslow intermediate debromination. Before debromination, the nucleophilicity of α-bromoenal is enhanced by addition to NHC. However, after debromination, the α,β-unsaturated acyl azole generates and acts as an electrophilic reagent.

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Regio- and Enantioselective N-Heterocyclic Carbene-Catalyzed Annulation of Aminoindoles Initiated by Friedel–Crafts Alkylation

Dočekal,

Niderer,

Kurčina

et al. 2024

Org. Lett.

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Chiral indoles annulated on the benzene ring are unique and significant in natural and medicinal compounds. However, accessing these enantioenriched molecules has often been overlooked. The present study introduces an organocatalytic protocol to access these compounds efficiently, demonstrated by substrate scope, functional group tolerance, and using only 1 mol % of a chiral conjugated acid catalyst. Additionally, the study explores regioselectivity, gram-scale reactions, and follow-up transformations, underscoring the method’s potential.

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N-Heterocyclic Carbene-Catalyzed [3 + 3] Annulation of 5-Aminopyrazoles with Enals: Enantioselective Synthesis of Pyrazolo[3,4-b]pyridones

Cited by 5 publications

References 52 publications

Bipyridine-N,N′-dioxides Catalysts: Design, Synthesis, and Application in Asymmetric Synthesis of 1H-Pyrazolo[3,4-b]pyridine Analogues

Bipyridine-N,N′-dioxides Catalysts: Design, Synthesis, and Application in Asymmetric Synthesis of 1H-Pyrazolo[3,4-b]pyridine Analogues

Mechanisms and Origins of Regio- and Stereoselectivities in NHC-Catalyzed [3 + 3] Annulation of α-Bromoenals and 5-Aminoisoxazoles: A DFT Study

Regio- and Enantioselective N-Heterocyclic Carbene-Catalyzed Annulation of Aminoindoles Initiated by Friedel–Crafts Alkylation

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