Homogenous Iron-Catalysed Deuteration of Electron-Rich Arenes and Heteroarenes

Abstract

Deuterated organic molecules are of interest for many applications ranging from mechanistic investigations in basic organic and physical chemistry to the development of new pharmaceuticals. Thus, methodologies for isotope-labelling reactions continue to be important. Here, a convenient methodology for hydrogen/deuterium exchange reactions in electron-rich arenes is reported using simple iron salts and deuterium oxide as isotope source.

Key words

catalysis - deuterium - heavy water - isotopic labelling - Lewis acid

Publication History

Received: 04 November 2022

Accepted after revision: 27 November 2022

Accepted Manuscript online:
04 December 2022

Article published online:
03 January 2023

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• 27 General Procedure for the Labelling of Electron-Rich (Hetero)arenes A 4 mL vial was charged under argon with the substrate (0.5 mmol), Fe(OTf)₃ (1 mL from a stock solution of 14 mg in 10 mL CH₃CN) and D₂O (180 μL, 20 equiv). The reaction mixture was stirred overnight at 90 °C in an aluminium bloc. After return to room temperature, the media was diluted with EtOAc (2 mL) and a saturated aqueous NaHCO₃ solution (1 mL). The aqueous phase was further extracted with EtOAc (3 × 2 mL). The combined organic phases were dried over MgSO₄, filtered, and concentrated under reduced pressure. Obtained products were submitted for NMR analyses to determine the deuterium content. Typical reaction with 1,2,3,4-tetrahydroquinoline (1a, 65.5 mg) as substrate provided 1,2,3,4-tetrahydroquinoline-6,8-d ₂ (2a, brown oil, quantitative). ¹H NMR (300 MHz, CDCl₃): δ = 7.07–6.96 (m, 2 H), 6.66 (t, J = 7.4 Hz, 7% ¹H, 1 H), 6.58–6.44 (m, 8% ¹H, 1 H), 3.81 (s, 1 H), 3.38–3.29 (m, 2 H), 2.82 (t, J = 6.4 Hz, 2 H), 2.06–1.91 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 144.8, 129.4 (m), 126.5 (m), 121.5, 116.7 (m), 113.9 (m), 42.0, 27.0, 22.2. ESI-MS: m/z calcd for C₉H₉D₂N: 135; found: 135 (81), 134 (100), 133 (29), 132 (18), 131 (7), 120 (27), 106 (11), 93 (7), 79 (10), 66 (6).