Palladium-Catalyzed Benzylic Cross-Couplings of Pyridine N-Oxides

Abstract

Palladium-catalyzed C-H couplings (C _SP ^³ -C _SP ^² ) of pyridine N-oxides with benzyl chloride derivatives is reported. It provides a novel and easy process for the synthesis of 2-benzylpyridine derivatives through benzylic cross-couplings of pyridine N-oxides.

palladium - benzylation - pyridine N-oxide - C-H couplings

References and Notes

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General Procedure: An 50-mL vial was charged with magnetic stir bar, pyridine N-oxide (1a; 1.5 mmol), benzyl chloride (2a; 1.0 mmol), Pd(OAc)₂ (0.05 mmol), t-Bu₃P-HBF₄ (0.1 mmol), K₂CO₃ (2.0 mmol), followed by anhyd toluene (3 mL). After stirring at 110 ˚C for 16 h, the reaction mixture was filtered through Celite (washed with MeOH and CH₂Cl₂). The combined organic phase was then evaporated under reduced pressure and the isolated yield was obtained by flash chromatography column on silica gel (gradient eluent of MeOH in CH₂Cl₂: 1-5%).
2-Benzylpyridine N -Oxide (3aa): yellow solid. ^¹H NMR (400 MHz, CDCl₃): δ = 8.32 (d, J = 2.8 Hz, 1 H), 7.33-7.40 (m, 2 H), 7.28-7.31 (m, 3 H), 6.95-7.19 (m, 2 H), 6.93-6.95 (m, 1 H), 4.28 (s, 2 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 151.9, 139.4, 136.2, 129.7, 128.8, 127.1, 125.8, 125.6, 123.6, 36.5. MS (ESI): m/z = 186.0 [M + 1]⁺. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₂H₁₂NO⁺: 186.0919; found: 186.0913.
2-(2-Methylbenzyl)pyridine N -Oxide (3ab): ^¹H NMR (400 MHz, CDCl₃): δ = 8.32 (d, J = 6.4 Hz, 1 H), 7.10-7.27 (m, 6 H), 6.71 (d, J = 7.2 Hz, 1 H), 4.25 (s, 2 H), 2.19 (s, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 151.3, 139.4, 137.2, 134.4, 130.6, 127.5, 126.5, 125.7, 125.9, 125.1, 123.4, 34.4, 19.3. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₃H₁₄NO⁺: 200.1075; found: 200.1073.
2-(4-Fluorobenzyl)pyridine N -Oxide (3ac): pale yellow solid. ^¹H NMR (400 MHz, CDCl₃): δ = 8.35 (d, J = 5.2 Hz, 1 H), 7.19-7.28 (m, 4 H), 6.99-7.07 (m, 3 H), 4.26 (s, 2 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 163.2, 160.7, 151.6, 149.5, 131.9, 131.2, 125.7, 123.7, 123.9, 115.8, 35.8. HRMS (ESI): m/z [M+H]⁺ calcd for C₁₂H₁₁FNO⁺: 204.0825; found: 204.0827.
2-(3-Trifluoromethylbenzyl)pyridine N -Oxide (3ad): ^¹H NMR (400 MHz, CDCl₃): δ = 8.28-8.30 (m, 1 H), 7.44-7.55 (m, 4 H), 7.18-7.21 (m, 2 H), 7.00-7.03 (m, 1 H), 4.32 (s, 2 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 150.8, 139.6, 137.3, 137.1, 133.0, 131.2, 130.9, 128.6, 129.3, 126.2, 126.17, 126.13, 126.1, 125.9, 125.7, 125.4, 124.1, 123.99, 123.95, 123.91, 122.66, 36.4. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₃H₁₁F₃NO⁺: 254.0793; found: 254.0796.