General and Easy Access to 11-Substituted 4-Hydroxy-2,3,4,5-tetrahydro[1,4]diazepino[1,2-a]indol-1-one Derivatives

Abstract

An efficient route to prepare the 4-hydroxy-2,3,4,5-tetrahydro[1,4]diazepino[1,2-a]indol-1-one scaffold is described. The key reactions of the synthesis are an iodolactonisation followed by a lactone-to-lactam rearrangement. Various 11-substituted derivatives were obtained by palladium-mediated cross-coupling reactions.

Key words

diazepinoindole - seven-membered ring - iodolactonisation - palladium

References and Notes

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8

Typical Procedure for Iodolactonisation.
Under a N₂ atmosphere, to a solution of 1-allyl-1H-indole-2-carboxylic acid (3a, 1.49 g, 7.4 mmol) in anhyd CH₂Cl₂ (90 mL), was added at -20 °C, 2,6-lutidine (1.30 mL, 11.1 mmol, 1.5 equiv) and NIS (3.83 g, 17.0 mmol, 2.3 equiv). The solution was stirred at -20 °C for 3.5 h. The reaction mixture was extracted with CH₂Cl₂ (2 × 20 mL). The organic phase was washed with 1 M HCl solution (10 mL), sat. aq solution of Na₂S₂O₃ (2 × 30 mL), brine solution (2 × 30 mL), and sat. aq solution of NaHCO₃. The organic phases were combined, dried over Na₂SO₄ and evaporated in vacuo. The crude solid was purified by recrystallisation from CH₂Cl₂ to afford 4a (2.73 g, 81%) as a white solid; mp 169 °C (dec., CH₂Cl₂). IR (KBr): 3020, 2950, 1710, 1100, 750 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 3.42 (dd, 1 H, J = 8.7, 10.6 Hz, CH₂I), 3.59 (dd, 1 H, J = 4.4, 10.6 Hz, CH₂I), 4.27 (dd, 1 H, J = 9.0, 12.8 Hz, NCH₂), 4.74 (dd, 1 H, J = 3.3, 12.8 Hz, NCH₂), 4.80-4.89 (m, 1 H, CH), 7.31 (t, 1 H, J = 8.0 Hz, H_ar), 7.36 (d, 1 H, J = 8.0 Hz, H_ar), 7.50 (t, 1 H, J = 8.0 Hz, H_ar), 7.62 (d, 1 H, J = 8.0 Hz, H_ar). ¹³C NMR (75 MHz, CDCl₃): δ = 1.1 (CH₂I), 44.9 (NCH₂), 68.9 (C), 76.2 (CH), 110.4 (CH), 121.9 (C), 122.7 (CH), 124.2 (CH), 127.8 (CH), 131.1 (C), 136.8 (C), 157.4 (CO). ESI-MS:
m/z = 454 [M + H]⁺. Anal. Calcd for C₁₂H₉I₂NO₂: C, 31.82; H, 2.00; N, 3.09. Found: C, 32.11; H, 2.13; N, 2.95.

9

Typical Procedure for Lactam Formation.
A solution of iodolactone 4a (3.60 g, 7.95 mmol) in anhyd MeOH (60 mL) and anhyd THF (30 mL) was added dropwise over a period of 20 min to an ice-cold sat. NH₃ in MeOH solution (30 mL). The reaction mixture was allowed to warm up to r.t. for 48 h. The solvents were then removed by evaporation and the crude residue was purified by recrystallisation from EtOAc-EtOH to afford 5a (1.75 g, 64%) as a white solid. The filtrate was then purified by flash chromatography on silica gel (CH₂Cl₂-MeOH, 94:6) to give 0.11 g of 5a (overall yield 68%) as a white solid; mp 199 °C (dec., EtOAc-EtOH). IR (KBr): 3410, 3320-3200, 3060, 2920, 1635, 1515, 1090, 745 cm^-1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 2.73-2.80 (m, 1 H, CH₂NH), 3.15-3.21 (m, 1 H, CH₂NH), 4.18-4.29 (m, 2 H, NCH₂ and CH), 4.43-4.49 (m, 1 H, NCH₂), 5.38 (d, 1 H, J = 3.4 Hz, OH), 7.19 (t, 1 H, J = 7.9 Hz, H_ar), 7.35 (t, 1 H, J = 7.9 Hz, H_ar), 7.39 (d, 1 H, J = 7.9 Hz, H_ar), 7.58 (d, 1 H, J = 7.9 Hz, H_ar), 8.30 (t, 1 H, J = 5.5 Hz, NH). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 45.3 (CH₂), 48.7 (CH₂), 61.3 (CI), 69.5 (CH), 111.0 (CH), 120.8 (CH), 121.7 (CH), 124.6 (CH), 129.2 (C), 133.4 (C), 137.2 (C), 164.0 (CO). ESI-MS: m/z = 343 [M + H]⁺. Anal. Calcd for C₁₂H₁₁IN₂O₂: C, 42.13; H, 3.24; N, 8.19. Found: C, 41.87; H, 3.12; N, 8.05.

11

Physical Data of Compound 6. Mp >210 °C (washing EtOAc). IR (KBr): 3420, 3310-3250, 3070, 2980, 1640, 1550, 1490, 1085, 750, 700 cm^-1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 2.82-2.91 (m, 1 H, CH₂NH), 3.20-3.30 (m, 1 H, CH₂NH), 4.25-4.30 (m, 2 H, NCH₂ and CH), 4.42-4.48 (m, 1 H, NCH₂), 5.38 (d, 1 H, J = 3.4 Hz, OH), 7.12 (t, 1 H, J = 7.5 Hz, H_ar), 7.29-7.64 (m, 8 H, H_ar), 8.25 (t, 1 H, J = 5.9 Hz, NH). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 45.3 (CH₂), 47.9 (CH₂), 69.6 (CH), 110.5 (CH), 118.4 (C), 119.9 (CH), 120.3 (CH), 123.8 (CH), 125.4 (C), 126.4 (CH), 128.1 (2 CH), 129.7 (2 CH), 129.9 (C), 133.7 (C), 136.3 (C), 164.8 (CO). ESI-MS: m/z = 293 [M + H]⁺. Anal. Calcd for C₁₈H₁₆N₂O₂: C, 73.96; H, 5.52; N, 9.58. Found: C, 74.33; H, 5.67; N, 9.63.