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. 2025 Jun 20;90(24):8145-8151.
doi: 10.1021/acs.joc.5c00488. Epub 2025 Jun 5.

Synthesis of Isoquinoline N-Oxides via Hypervalent Iodine-Mediated Oxidative Cyclization of Ketoximes with Alkenes

Aurapat Ngamnithiporn  1   2 , Padon Chuentragool  1   2 , Supakarn Punnita  1 , Wachirawit Thitseesaeng  1 , Teesuda Sirichai  1 , Shinji Harada  3   4 , Tetsuhiro Nemoto  3 , Poonsakdi Ploypradith  1   5   2 , Somsak Ruchirawat  1   5   2
Affiliations

Synthesis of Isoquinoline N-Oxides via Hypervalent Iodine-Mediated Oxidative Cyclization of Ketoximes with Alkenes

Aurapat Ngamnithiporn et al. J Org Chem. .

Abstract

Reported herein is the development of an intramolecular oxidative cyclization of ketoximes with alkenes for the preparation of isoquinoline N-oxides. The reaction, which utilizes phenyliodine bis(trifluoroacetate) (PIFA) as an oxidant and 2,2,2-trifluoroethanol (TFE) as a solvent, proceeds to afford various N-heterocyclic products, including aryl/heteroaryl-fused pyridine N-oxides, isoindole N-oxides, and 2-benzazepine derivatives. Preliminary experimental and computational mechanistic studies suggest that the ionic pathway is the primary mechanism. The synthetic utility of the developed method was highlighted via several product transformations.

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Figures

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1. Available Methods for the Synthesis of Isoquinoline N-Oxides
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2. Substrate Scope
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3. Isoindole vs Isoquinoline N-Oxides Selectivity
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4. Preparation of 2-Benzazepine Derivatives
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Mechanistic investigation using a DFT calculation. Energy profile was calculated at the (u)­wB97xD/def2TZVP [SMD (TFE)] level of theory.
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5. Derivatizations of Isoquinoline N-Oxides
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    1. A report stated that the use of ketoxime substrates resulted in a decomposition of the starting material, see ref .

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