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

Ramarao Parella; Srinivasarao Arulananda Babu

doi:10.1055/s-0033-1341242

Synlett, Table of Contents

Synlett 2014; 25(10): 1395-1402
DOI: 10.1055/s-0033-1341242

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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

Ramarao Parella

Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Manauli P.O., Sector 81, SAS Nagar, Mohali, Knowledge City, Punjab 140306, India Fax: +91(172)2240266 Email: sababu@iisermohali.ac.in

,

Srinivasarao Arulananda Babu*

Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Manauli P.O., Sector 81, SAS Nagar, Mohali, Knowledge City, Punjab 140306, India Fax: +91(172)2240266 Email: sababu@iisermohali.ac.in

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Abstract

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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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References

References and Notes

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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.

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