Palladium-Catalyzed Double Activation and Arylation of 2° and 3° C(sp³)–H Bonds of the Norbornane System: Formation of a C–C Bond at the Bridgehead Carbon and Bridgehead Quaternary Stereocenter

Abstract

Pd-catalyzed activation and direct arylation of both 2° and the bridgehead 3° (sp³) C–H bonds and an unprecedented C–C bond formation at the bridgehead carbon of the norbornane system are reported. The assembly of bridgehead-substituted norbornane frameworks having contiguous stereocenters was accomplished. X-ray crystal structure analysis of representative molecules unambiguously established the stereochemistry.

Key words

arylation - bridgehead substitution - C–H activation - ­diastereoselectivity - palladium - stereoselective synthesis

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• 7b The stereochemistry was assigned based on X-ray crystal structures of 4a, 3d, 5d, and 7b and the similarity in the NMR spectral pattern.
• 8 General procedure for the direct C–H arylation of norbornane systems and the preparation of 3a–h, 5a–g, and 7a–h: A solution of bridged bicyclic framework 1a, 1i or 4 (0.25 mmol), Pd(OAc)₂ (5.6 mg, 0.025 mmol, 10 mol%), aryl iodide (1 mmol), and Ag₂CO₃ (68.9 mg, 0.25 mmol) in anhydrous t-BuOH (3 mL) was heated at an appropriate temperature and for an appropriate time (73–85 °C, 24–36 h; see the respective tables or schemes for specific examples) under a nitrogen atmosphere. After the reaction period, the reaction mixture was diluted with EtOAc and concentrated in vacuum. Purification of the resulting reaction mixture by column chromatography (silica gel, 100−200 mesh) furnished the corresponding bisarylated bicyclo[2.2.1]heptane-2-carboxamides.
• 9 Analytical data of 3a: Following the general procedure described above, 3a was obtained after purification by column chromatography on silica gel (EtOAc–hexanes, 30:70). Yield: 70% (78 mg); brown solid; mp 172–174 °C (MeOH–hexanes, 1:1). FTIR (KBr): 3401, 1629, 1521, 1322, 667 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 9.27 (br s, 1 H), 8.63 (dd, J = 7.2, 1.6 Hz, 1 H), 8.57 (dd, J = 4.2, 1.6 Hz, 1 H), 8.07 (dd, J = 8.2, 1.6 Hz, 1 H), 7.47–7.34 (m, 5 H), 7.18 (d, J = 8.0 Hz, 2 H), 7.09 (d, J = 8.0 Hz, 2 H), 7.01 (d, J = 8.0 Hz, 2 H), 3.88 (dd, J = 11.0, 2.8 Hz, 1 H), 3.57 (dd, J = 11.0, 1.3 Hz, 1 H), 2.90–2.85 (m, 1 H), 2.80 (br s, 1 H), 2.32 (s, 3 H), 2.30–2.26 (m, 2 H), 2.23 (s, 3 H), 1.93 (dd, J = 9.5, 1.6 Hz, 1 H), 1.83–1.77 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 170.3, 147.6, 141.2, 138.2, 137.6, 136.0, 135.7, 134.9, 134.6, 129.0, 128.6, 128.2, 127.7, 127.3, 127.1, 121.3, 120.9, 116.2, 58.0, 56.2, 49.2, 46.5, 41.6, 29.6, 23.9, 21.1, 21.0. HRMS (ESI): m/z [M + H]⁺ calcd for C₃₁H₃₁N₂O: 447.2436; found: 447.2444.
• 10 Analytical data of 3b: Following the general procedure described above, 3b was obtained after purification by column chromatography on silica gel (EtOAc–hexanes, 30:70). Yield: 81% (84 mg); white solid; mp 135–137 °C (MeOH–hexanes, 1:1). FTIR (KBr): 3300, 1668, 1587, 1321, 1021 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 9.30 (br s, 1 H), 8.63 (dd, J = 7.2, 1.9 Hz, 1 H), 8.56–8.55 (m, 1 H), 8.06 (dd, J = 8.3, 1.8 Hz, 1 H), 7.52–7.49 (m, 1 H), 7.46–7.07 (m, 12 H), 3.92 (dd, J = 13.6, 1.4 Hz, 1 H), 3.63 (dd, J = 13.6, 1.4 Hz, 1 H), 2.92–2.86 (m, 2 H), 2.36–2.31 (m, 2 H), 1.96 (dd, J = 9.4, 1.6 Hz, 1 H), 1.86–1.78 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 170.0, 147.7, 144.1, 140.7, 138.2, 136.0, 134.5, 128.3, 128.1, 127.8, 127.7, 127.3, 127.2, 126.3, 125.6, 121.3, 120.9, 116.1, 58.0, 56.5, 49.5, 46.4, 41.4, 29.6, 23.8. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₇N₂O: 419.2123; found: 419.2123.
• 11 The crystallographic data have been deposited at the Cambridge Crystallographic Data Centre: CCDC-982495 (4a), CCDC-982494 (3d), CCDC-982496 (5d), and CCDC-982497 (7b). These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.