The First Examples of Planar Chiral Organic Benzimidazole Derivatives

Abstract

The synthesis of a number of novel planar chiral benz­imidazoles from [2.2]paracyclophane is reported. The key steps ­include a Buchwald-Hartwig amination of a sterically demanding triflate and the functionalisation of the C-2 bromide.

planar chirality - heterocycles - cyclophanes - amination

References and Notes

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4-(4-Methoxyphenylamino)[2.2]paracyclophan-5-yl Carboxylic Acid Methyl Ester (8); Typical Procedure: A solution of triflate 7 (4.00 g, 9.66 mmol) in toluene (20 mL) was added dropwise over 1 h to a mixture of p-anisidine (1.46 g, 11.59 mmol), tris(dibenzylideneacetone)dipalla-dium(0) (0.44 g, 0.48 mmol), (±)-BINAP (0.45 g, 0.72 mmol) and Cs₂CO₃ (4.31 g, 13.23 mmol) in toluene (10 mL) at reflux. The mixture was stirred at this temperature for a further 12 h. The reaction was cooled to r.t., filtered through celite and concentrated. The crude product was purified by flash column chromatography (4% Et₂O-PE → 8% Et₂O-PE) to afford 8 as a bright yellow crystalline solid (2.90 g, 78%); mp 174-176 °C. IR (CHCl₃): 3336, 2947, 1680, 1574, 1514, 1461, 1439, 1415, 1240 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 8.61 (1 H, s, NH), 7.04 (1 H, dd, J = 7.8, 1.8 Hz, H-15 or H-16), 6.88 (2 H, d, J = 8.4 Hz, MeOAr-H), 6.78 (2 H, d, J = 8.4 Hz, MeOAr-H), 6.61 (1 H, dd, J = 7.8, 1.5 Hz, H-15 or H-16), 6.52-6.45 (3 H, m, H-12, H-13 and H-7 or H-8), 6.39 (1 H, d, J = 7.8 Hz, H-7 or H-8), 3.85 (3 H, s, OMe), 3.71 (3 H, s, OMe), 3.63 (1 H, ddd, J = 12.6, 9.6, 2.4 Hz, H-9), 3.12 (1 H, ddd, J = 12.0, 9.6, 2.1 Hz, H-10), 2.97-2.61 (5 H, m, 5 × CH₂), 2.59-2.45 (1 H, m, CH₂). ¹³C NMR (75 MHz, CDCl₃): δ = 170.3 (C=O), 154.8 (C), 144.0 (CH), 142.1 (C), 139.9 (C), 139.5 (CH), 138.7 (C), 137.6 (C), 133.5 (C), 133.4 (CH), 132.1 (CH), 130.9 (CH), 129.5 (CH), 127.8 (CH), 121.5 (C), 118.9 (CH), 114.8 (CH), 56.1 (CH₃), 52.2 (CH₃), 36.6 (CH₂), 35.3 (CH₂), 35.3 (CH₂), 34.3 (CH₂). MS (EI): m/z = 387 [M]⁺, 355, 354 [M - CH₃OH]⁺, 283, 268, 251, 236, 220, 208, 192. HRMS (EI): m/z calcd for C₂₅H₂₅NO₃ (MH⁺): 388.1907; found: 388.1905.

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2-Bromo-3-(4-methoxyphenylamino)[2.2](4,7)benzimida-zoloparacyclophane (14); Typical Procedure: A solution of 11 (0.41 g, 1.12 mmol) and phosphorus(V) oxybromide (0.80 g, 2.80 mmol) in toluene (16 mL) was heated to reflux for 5 h. The reaction mixture was cooled to r.t. and washed with a sat. aq soln of NaHCO₃ (25 mL). The organic layer was separated and the aq layer extracted with CH₂Cl₂ (3 × 20 mL). The combined extracts were filtered to remove any insoluble impurities, dried (MgSO₄), concentrated and purified by flash column chromatography (10% heptane-Et₂O→ 20% heptane-Et₂O) to afford 14 as a white crystalline solid (0.41 g, 85%); mp 156-159 °C. IR (CHCl₃): 3010, 2959, 2932, 2954, 1609, 1585, 1511, 1456, 1300, 1253, 1169 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.65 (1 H, dd, J = 8.7, 2.4 Hz, H-2 or H-6 of MeOC₆H₄), 7.08 (1 H, dd, J = 8.7, 2.7 Hz, H-2 or H-6 of MeOC₆H₄), 7.02 (1 H, dd, J = 8.7, 2.4 Hz, H-3 or H-4 of MeOC₆H₄), 6.90 (1 H, dd, J = 8.7, 3.0 Hz, H-3 or H-4 of MeOC₆H₄), 6.51 (1 H, d, J = 7.5 Hz, H-5 or H-6), 6.39-6.41 (2 H, m, H-5 or H-6 and pseudo-p N-1 or pseudo-p N-3), 6.28 (1 H, dd, J = 7.8, 1.5 Hz, pseudo-p N-1 or pseudo-p N-3), 6.22 (1 H, dd, J = 7.8, 1.8 Hz, pseudo-gem N-1 or pseudo-gem N-3), 6.05 (1 H, dd, J = 7.8, 1.8 Hz, pseudo-gem N-1 or pseudo-gem N-3), 3.84 (3 H, s, OMe), 3.67-3.75 [1 H, m, (C-7)-CH₂], 3.03 [1 H, ddd, J = 14.4, 12.3, 4.2 Hz, (C-7)-CH₂CH₂], 2.96-2.71 (2 H, m, CH₂), 2.53-2.37 (1 H, m, CH₂), 2.11 [1 H, ddd, J = 12.9, 9.6, 7.2 Hz, (C-4)-CH₂]. ¹³C NMR (75 MHz, CDCl₃): δ = 160.3 (C), 145.4 (C), 139.3 (C), 138.1 (C), 138.0 (C), 133.0 (CH), 132.0 (C), 131.8 (CH), 131.3 (CH), 129.7 (C), 129.6 (C), 129.5 (CH), 129.3 (C), 129.0 (CH), 128.7 (CH), 127.1 (CH), 125.4 (CH), 125.1 (C), 115.1 (CH), 114.7 (CH), 56.1 (CH₃), 35.4 (CH₂), 34.9 (CH₂), 31.9 (CH₂), 30.8 (CH₂). MS (EI): m/z = 435 [⁸¹M]⁺, 433 [⁷⁹M]⁺, 330, 328, 297, 299, 249, 205. HRMS (EI): m/z calcd for C₂₄H₂₁N₂OBr (⁷⁹MH⁺): 433.0910; found: 433.0903.

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CCDC 611020 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge at www.ccdc.cam.ac.uk/conts.retrieving.html [or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: [phone]; e-mail: [e-mail]].

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CCDC 611019 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge at www.ccdc.cam.ac.uk/conts.retrieving.html [or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: [phone]; e-mail: [e-mail]].