Cyclic guanidines. Part 6.¹ Synthesis of benzimidazoles by intramolecular vicarious nucleophilic substitution of hydrogen

Abstract

m-Nitrophenylguanidines, which carry a vicarious leaving group, cyclize under basic conditions yielding nitrobenzimidazoles. Preliminary observations of the regioselectivity of the ring closure reaction are reported.

References

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9. Representative experimental procedure with DMSO as solvent: 5(2.82 g, 10.6 mmol) was dissolved in DMSO (50 ml) and KO^tBu (3 g, 26.4 mmol) was added under nitrogen. The solution, which was stirred at room temperature for 9.5 h changed colour from light brown via dark blue to red–brown. It was poured into ice-cold water (700 ml), extracted with a 1∶1 mixture of ether–ethyl acetate and with ether. The combined organic phases were washed with water, filtered and the solvent evaporated. The crude product was flash chromatographed over silica gel using ethyl acetate–cyclohexane (1∶1) and ethyl acetate as eluents. Apart from unchanged 5(0.55 g, 20%), were obtained 12(1.42 g, 57%), mp 197–200 °C; δ_H(250 MHz, CDCl₃): 10.14 (1H, s, NH), 7.81 (1H, d, J 7.6, ArH⁵), 7.65 (1H, d, J 7.6, ArH⁷), 7.14 (1H, dd, J 7.6, 7.6, ArH⁶), 5.39 (1H, t, J 4.5, NHCH₂), 3.54 (2H, m, NHCH₂), 1.70 (2H, m, CH₂), 1.44 (2H, m, CH₂CH₃), 0.95 (3H, t, J 7.0, CH₃) MS (ion spray)m/z 235 (M + H⁺, 100%)15(0.04 g, 1.6%), mp 182–183 °C; δ_H(250 MHz, CDCl₃–DMSO-d₆= 3∶1): 8.06 (1H, d, J 2.4, ArH⁴), 7.98 (1H, dd, J 8.9, 2.4, ArH⁶), 7.24 (1H, d, J 8.9, ArH⁷), 5.83 (1H, t, J 4.3, NHCH₂), 3.47 (2H, m, NHCH₂), 1.65 (2H, m, CH₂), 1.44 (2H, m, CH₂CH₃), 0.96 (3H, t, J 7.5, CH₃); MS (ion spray)m/z 235 (M + H⁺, 100%) and 18(0.11 g, 4.7%) as a highly viscous oil, δ_H(250 MHz, CDCl₃): 8.37 (1H, s, NH), 6.99–6.86 (2H, m, ArH⁴+ ArH⁷), 6.58 (1H, dd, J 6.4, 2.4, ArH⁶), 5.56 (1H, s, NHCH₂), 3.86 (3H, s, OCH₃), 3.38 (2H, t, J 7.0, NCH₂), 1.50 (2H, m, CH₂), 1.23 (2H, m, CH₂CH₃), 0.78 (3H, t, J 7.5, CH₂CH₃); MS (ion spray)m/z 220 (M + H⁺, 93%), 164 (57), 149 (100).
10. Representative experimental procedure with DMF as solvent: 8(5.05 g, 20 mmol) was dissolved in DMF (90 ml) and KO^tBu (6.72 g, 60 mmol) was added under nitrogen. The solution was stirred at room temperature for 17 h. It was poured into 1 M Na₂CO₃ solution (1 l), which was extracted with ethyl acetate (2 × 0.5 l). The combined extracts were Wltered and concentrated under reduced pressure. The crude product was chromatographed over silica gel using ethyl acetate–cyclohexane (1∶1) as eluent. From the main fraction 13(2.84 g, 65% yield) was obtained as orange coloured crystals, mp 246–249 °C; δ_H(250 MHz, CDCl₃): 9.80 (1H, s, NH), 7.81 (1H, dd, J 8.5, 0.9, ArH⁵), 7.65 (1H, d, J 7.9, ArH⁷), 7.14 (1H, dd, J 8.5, 7.9, ArH⁶), 4.94 (1H, d, J 7.3, NH-CH), 4.15 (1H, m, NH-CH), 1.36 (6H, d, J 6.4, (CH₃)₂CH); MS (ion spray)m/z 221 (M + H⁺, 100%).
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