Organophotoredox-Catalyzed Oxidative C(sp²)–H Alkylation of N-Heteroarenes with Dihydroquinazolinones by C–C Cleavage

Dedicated to Professor Matthias Beller on his 60^th birthday

Abstract

We report a visible-light-mediated, organophotoredox-catalyzed, C(sp²)–H alkylation of N-heteroarenes with dihydroquinazolines, prepared from aliphatic ketones, under oxidative conditions. This protocol represents a metal-free approach to the effective construction of C–C bonds through a Minisci-type reaction, formally activating the native C–H bond of the N-heteroarene and an α-C–C bond of a readily available ketone. The mild nature of this method accommodates a wide variety of N-heteroarenes and ketones, tolerating a wide range of functional groups.

Key words

photoredox catalysis - heteroarenes - ketone - C–C bond cleavage - alkylation

Publication History

Received: 24 December 2022

Accepted after revision: 08 February 2023

Accepted Manuscript online:
08 February 2023

Article published online:
09 March 2023

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• 16 Compounds 3; General Procedure In a heat-gun-dried Schlenk tube equipped with a Teflon-coated stirrer bar, the appropriate N-heteroarene 1 (0.2 mmol, 1.0 equiv), dihydroquinazolinone substrate 2 (0.5 mmol, 2.5 equiv), 4CzIPN (0.004 mmol, 2 mol%), and K₂S₂O₈ (0.4 mmol, 2.0 equiv) were dissolved in anhyd DMF (1 mL) under an inert atmosphere. The mixture was stirred at rt for 18 h in the presence of light from blue LEDs. The reaction was then quenched by the addition of aq Na₂CO₃ (2 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with H₂O (5 mL) and brine (5 mL), and the solvents were removed under reduced pressure. The crude residue was purified by flash column chromatography (silica gel, PE–EtOAc).2-Cyclohexyl-4-methylquinoline (3aa)Colorless liquid; yield: 73%. ¹H NMR (500 MHz, CDCl₃): δ = 8.15 (d, J = 8.4 Hz, 1 H), 8.03 (d, J = 8.3 Hz, 1 H), 7.75 (ddd, J = 8.3, 6.9, 1.4 Hz, 1 H), 7.60 (ddd, J = 8.2, 6.9, 1.2 Hz, 1 H), 7.26 (s, 1 H), 2.98 (tt, J = 12.1, 3.4 Hz, 1 H), 2.75 (s, 3 H), 2.10–2.12 (m, 2 H), 1.98 (dt, J = 12.8, 3.0 Hz, 2 H), 1.77–1.81 (m, 1 H), 1.62 (qd, J = 12.6, 3.1 Hz, 2 H), 1.62 (qt, J = 12.8, 3.3 Hz, 2 H), 1.44 (tt, J = 12.8, 3.6 Hz, 1 H). ¹³C NMR (126 MHz, CDCl₃): δ = 166.7, 147.8, 144.4, 129.7, 129.1, 127.2, 125.5, 123.7, 120.4, 47.8, 33.0, 26.7, 26.3, 19.0.4-Methyl-2-(1-phenylcyclopropyl)quinoline (3af)Colorless liquid; yield: 77%. ¹H NMR (500 MHz, CDCl₃): δ = 8.03 (d, J = 8.5 Hz, 1 H), 7.90 (d, J = 8.3 Hz, 1 H), 7.67 (ddd, J = 8.4, 6.9, 1.3 Hz, 1 H), 7.48 (ddd, J = 8.2, 6.9, 1.2 Hz, 1 H), 7.43–7.45 (m, 2 H), 7.36–7.39 (m, 2 H), 7.28–7.30 (m, 1 H), 6.95 (s, 1 H), 2.55 (s, 3 H), 1.81 (dd, J = 6.2, 3.5 Hz, 2 H), 1.36 (dd, J = 6.5, 3.8 Hz, 2 H). ¹³C NMR (126 MHz, CDCl₃): δ = 163.9, 147.8, 144.0, 143.6, 130.3, 129.8, 129.1, 128.7, 126.8, 126.7, 125.5, 123.7, 122.1, 32.3, 18.8, 17.3.(4-Cyclohexylquinolin-2-yl)(piperidin-1-yl)methanon (3da)Colorless liquid; yield: 51%. ¹H NMR (500 MHz, CDCl₃): δ = 8.01–8.31 (m, 2 H), 7.70 (t, J = 7.6 Hz, 1 H), 7.58 (t, J = 7.7 Hz, 1 H), 7.51 (s, 1 H), 3.78–3.80 (m, 2 H), 3.47–3.49 (m, 2 H), 3.30–3.36 (m, 1 H), 2.00–2.02 (m, 2 H), 1.91–1.94 (m, 2 H), 1.82–1.85 (m, 1 H), 1.67–1.74 (m, 4 H), 1.49–1.61 (m, 6 H), 1.29–1.37 (m, 1 H). ¹³C NMR (126 MHz, CDCl₃): δ = 168.3, 154.8, 154.6, 147.2, 130.9, 129.4, 127.0, 126.8, 123.1, 116.8, 48.5, 43.4, 39.3, 33.6, 27.0, 26.7, 26.4, 25.7, 24.8.1-Cyclohexyl-6-(4-methoxyphenyl)isoquinoline (3ha)White solid; yield: 76%; mp 118 °C. ¹H NMR (500 MHz, CDCl₃): δ = 8.48 (d, J = 5.7 Hz, 1 H), 8.26 (d, J = 8.9 Hz, 1 H), 7.93 (d, J = 1.6 Hz, 1 H), 7.80 (dd, J = 8.8, 1.8 Hz, 1 H), 7.66–7.68 (m, 2 H), 7.50 (d, J = 5.7 Hz, 1 H), 7.03–7.05 (m, 2 H), 3.88 (s, 3 H), 3.57 (tt, J = 11.7, 3.2 Hz, 1 H), 1.93–2.01 (m, 4 H), 1.80–1.88 (m, 3 H), 1.50–1.57 (m, 2 H), 1.38–1.44 (m, 1 H). ¹³C NMR (126 MHz, CDCl₃): δ = 165.7, 160.0, 142.5, 141.9, 137.0, 132.8, 128.7, 126.4, 125.5, 125.2, 124.5, 119.2, 114.6, 55.6, 41.8, 32.8, 27.1, 26.4.