Selective Pyridine-Directed C–H Activation Enabled Synthesis of Pyridine-pyridone α-Helix Mimics

Abstract

The exploration of pyridine-directed C–H activation in 2-benzyl-6-phenylpyridine revealed selective bromination at the ortho-phenyl position via Rh catalysis, rather than the ortho-benzyl position. In contrast, the corresponding alkylation was unsuccessful, suggesting a preference for the Rh(III) pathway to minimize steric congestion from pyridine disubstitution. This mechanistic insight facilitated the development of a room-temperature C–H activation–bromination method, enabling the synthesis of a pyridine-pyridone α-helix mimic.

Key words

Rh-catalyzed C–H activation - reaction mechanisms - selectivity - C–H activation - heterocycle synthesis - α-helix mimics

Publication History

Received: 20 October 2024

Accepted after revision: 15 December 2024

Article published online:
27 January 2025

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• 22 Selective Rh-Catalyzed Bromination of 10; General Procedure: Into a 250 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 6′-benzyl-2-oxo-2H-[1,2′-bipyridine]-5′-carbonitrile (6.2 g, 15.85 mmol) in dichloroethane (155 mL). Silver(I) hexafluorostibate(V) (0.65 g, 1.9 mmol), Rh catalyst (0.29 mg, 0.48 mmol), and dibromodimethylhydantoin (DBDMH) (4.5 g, 15.85 mmol) were added at room temperature. The reaction solution was stirred at 19 °C for 48 h then concentrated and the crude material was purified by flash column chromatography (SiO₂; EtOAc/PE, 0–85%; 240 min) to afford tert-butyl ((6′-benzyl-6-bromo-2-oxo-2H-[1,2′-bipyridin]-4′-yl)methyl)carbamate (11j). Yield: 3.2 g (6.8 mmol, 43%); yellow solid. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.04–8.06 (m, 1 H), 7.86–7.89 (m, 1 H), 7.45–7.53 (m, 2 H), 7.19–7.32 (m, 6 H), 6.32–6.36 (m, 1 H), 4.12–4.19 (m, 4 H), 1.23–1.37 (s, 9 H). ¹³C NMR (400 MHz, DMSO): δ = 160.98, 157.87, 156.25, 153.15, 151.76, 143.49, 139.52, 137.76, 129.40, 129.00, 126.85, 121.53, 117.55, 116.04, 106.56, 78.69, 43.72, 42.93, 28.63. HRMS: m/z [M+H]⁺ calcd for [C₂₃H₂₄BrN₃O₃+H]: 470.1081; found: 470.1079.