Rhodium(III)-Catalyzed C–H Activation: Annulation of Petrochemical Feedstocks for the Construction of Isoquinolone Scaffolds

This manuscript is dedicated to the memory ofProf. Keith Fagnou in celebration of his impact on the field of heterocycle synthesis and functionalization through metal-catalyzed C–H activation

Abstract

We describe a simple and robust procedure for the Rh(III)-catalyzed [4+2] cycloaddition of feedstock gases enabled through C–H activation. A diverse set of 3,4-dihydroisoquinolones and 3-methylisoquinolones have been prepared in good to excellent yields. The effects of using ethylene and propyne as coupling partners on C–H site selectivity have also been explored with a representative set of substrates and are discussed herein.

Key words

heterocycle synthesis - medicinal chemistry - rhodium catalysis - C–H activation - C–C bond formation - isoquinolone - feedstocks - annulation

Publication History

Received: 25 August 2020

Accepted after revision: 29 September 2020

Article published online:
05 January 2021

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• 17 General Procedure for Ethylene (2) Insertion To a vial, equipped with a magnetic stir bar and rubber septum, was added O-pivaloyl benzhydroxamic acid (1, 1.00 mmol, 1.0 equiv), [Cp*RhCl₂]₂ (0.025 mmol, 2.5 mol%), and CsOPiv (2.00 mmol, 2.0 equiv). The vial was purged with ethylene (2) under dynamic vacuum for 10 s. Then trifluoroethanol (5.0 mL, 0.2 M) was added, and the reaction mixture was sparged with ethylene (2) for 2 min. The vial was stirred under a balloon of ethylene (2; atmospheric pressure) at room temperature for 16–20 h. After 16–20 h, the reaction was filtered using EtOAc, and the filtrate was concentrated under reduced pressure. The crude residue was purified via flash column chromatography to afford dihydroisoquinolones 3. Representative Compound 3g Following the general procedure using 1g (424 mg, 1.00 mmol, 1.0 equiv), purification via flash column chromatography (12 g SiO₂, Isco, 0–10% MeOH/DCM) afforded dihydroisoquinolone 3g (335.4 mg, 96% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.87 (br s, 1 H), 7.61–7.50 (m, 2 H), 7.45–7.34 (m, 3 H), 7.34–7.26 (m, 1 H), 5.18 (s, 2 H), 3.33–3.28 (m, 2 H), 2.86 (t, J = 6.2 Hz, 2 H). ¹³C NMR (101 MHz, DMSO-d ₆): δ = 161.5 (d, J = 2.2 Hz), 154.7 (d, J = 2.2 Hz), 149.0 (d, J = 236.2 Hz), 136.9, 129.5 (d, J = 19.8 Hz), 128.2, 127.5, 127.0, 119.3 (d, J = 2.2 Hz), 117.3, 111.4 (d, J = 23.5 Hz), 70.6, 38.2, 22.8 (d, J = 2.2 Hz). ¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –122.1 (s).
• 18 General Procedure for Propyne (4) Insertion To a vial, equipped with a magnetic stir bar and rubber septum, was added O-pivaloyl benzhydroxamic acid (1, 0.300 mmol, 1.0 equiv), [Cp*RhCl₂]₂ (0.0075 mmol, 2.5 mol%), and CsOPiv (0.600 mmol, 2.0 equiv). The vial was purged with propyne (4) under dynamic vacuum for 10 s. Then trifluoroethanol (1.5 mL, 0.2 M) was added, and the reaction mixture was sparged with propyne (4) for 2 min. The vial was stirred under a balloon of propyne (4; atmospheric pressure) at room temperature for 16–20 h. The balloon deflated slowly overnight but this did not inhibit the reaction. After 16–20 h, the reaction was transferred to a flask using EtOAc and concentrated under reduced pressure. The crude residue was purified via flash column chromatography to afford isoquinolones 5. Representative Compound 5a Following the general procedure using 1a (86 mg, 0.300 mmol, 1.0 equiv), purification via flash column chromatography (4 g SiO₂, Biotage, 0–10% MeOH/DCM) afforded isoquinolone 5a (62 mg, 92% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d ₆): δ = 11.57 (br s, 1 H), 8.30 (d, J = 8.4 Hz, 1 H), 7.97 (s, 1 H), 7.66 (dd, J = 8.4, 1.6 Hz, 1 H), 6.48 (s, 1 H), 2.24 (s, 3 H). ¹³C NMR (101 MHz, DMSO-d ₆): δ = 161.7, 140.6, 138.4, 132.1 (q, J = 31.7 Hz), 128.1, 126.4, 123.9 (q, J = 272.70 Hz), 122.8 (q, J = 4.12 Hz), 120.9 (q, J = 3.4 Hz), 102.6, 18.8. ¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –61.6.
• 19 Small-molecule X-ray crystal structures corroborating the regiochemical assignment of 5b (CCDC 2024479) and 5g (CCDC 2024480) have been obtained and deposited. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
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