Divergent Reactivity of 1,2,3-Benzotriazin-4(3H)-ones: Photocatalytic Synthesis of 3-Substituted Isoindolinones Achieved through a Nitrogen-Mediated Hydrogen Atom Shift
Fostino R. B. Bokosi, Oisin J. Shiels, Christopher Richardson, Adam J. Trevitt, Sinead T. Keaveney*
*Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, New South Wales 2522, Australia,
Email: sineadkuow.edu.au
F. R. B. Bokosi, O. J. Shiels, C. Richardson, A. J. Trevitt, S. T. Keaveney, J. Org. Chem., 2024, 89, 1777-1783.
DOI: 10.1021/acs.joc.3c02545
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Abstract
A regioselective visible-light-mediated denitrogenative alkene insertion of 1,2,3-benzotriazin-4(3H)-ones provides 3-substituted isoindolinones. The photocatalytic reaction is compatible with activated terminal alkenes and cyclic α,β-unsaturated esters and ketones, with wide functional group tolerance for N-substitution of the 1,2,3-benzotriazin-4(3H)-ones.
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proposed mechanism
Details
This study explores the regioselective visible-light-mediated denitrogenative alkene insertion of 1,2,3-benzotriazin-4(3H)-ones to synthesize 3-substituted isoindolinones, a key structural motif in many biologically active molecules. The research highlights the divergent reactivity achieved by switching from nickel catalysis, which forms C3-substituted 3,4-dihydroisoquinolin-1(2H)-ones, to photocatalysis, which leads to exclusive 3-substituted isoindolinone formation. The developed photocatalytic reaction is compatible with various alkenes and shows broad functional group tolerance. The study includes a gram-scale synthesis and postsynthetic amidation, demonstrating the practical utility of the method. Mechanistic studies, both experimental and computational, reveal that the unique product selectivity arises from a nitrogen-mediated hydrogen atom shift rather than a direct 1,2-hydride shift. The research underscores the potential of photocatalysis in discovering new reactivity and achieving complementary product selectivity compared to traditional thermal approaches. The findings are significant for the synthesis of isoindolinones, which are important in pharmaceuticals and natural products. The study also identifies areas for future research, particularly in improving photocatalytic denitrogenation for N-alkyl-substituted benzotriazinones.
General procedure for the reactions between 1,2,3-benzotriazin-4(3H)-one and alkene
In an inert atmosphere glovebox (argon), 1,2,3-benzotriazin-4(3H)-one (0.2 mmol, 1.0 equiv), Ir[(ppy)2(dtbbpy)]PF6 (0.002 mmol, 1 mol%), alkene (0.6 mmol, 3.0 equiv), DIPEA (0.3 mmol, 1.5 equiv) and DMSO (0.3 mL) were added to a 4 mL vial charged with a magnetic stirrer bar. The vial was sealed, removed from the glovebox and stirred under blue LED irradiation for either 2 h or 16 h. After the reaction was complete, the mixture was poured into a separating funnel containing 20 mL of H2O and 20 mL of Et2O. The layers were separated and the aqueous layer was extracted with Et2O (2 × 20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography, and dried in vacuo, to afford the desired product.
Photoreactor details
The photocatalytic reactor (left) consisted of a 14 cm diameter crystallizing dish that was lined with 10 W blue LED strips purchased from LED Expo (SMD3528), with a peak intensity of 468 nm (spectrum shown on right).The photocatalytic reactions were performed in 4 mL borosilicate glass reaction vials purchased from LabCo Scientific (355.100.300), with the vials positioned in the center of the photoreactor (up to 4 vials at a time) – with an approximate LED to vial distance of 6 cm.
Key Words
isoindolinones, photochemistry
ID: J42-Y2024