Dibenzo[b,e][1,4]diazepin-1-ones and their Ring-Opened Derivatives: Revisited Synthesis, 2D NMR and Crystal Structure

Abstract

The synthesis of 2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-ones was revisited and a catalyst-free method was established, by exploring the reactivity of 3-[(2-aminoaryl)amino]dimedones towards carbonylated electrophiles. 2D NMR and single-crystal X-ray diffraction studies were used to characterize the structures unequivocally and to review the mechanism leading to the formation of supposed positional isomers. The action of 3-[(2-aminoaryl)amino]dimedones on chromene-3-carboxylic acid, fumaryl, and oxalyl chloride has led to dibenzo[b,e][1,4]diazepin-1-one ring opening to produce novel Z-configured enaminone and linear diamides.

Key words

3-[(2-aminoaryl)amino]dimedones - carbonylated electrophiles - dibenzo[b,e][1,4]diazepin-1-ones - reaction mechanism - 2D NMR - single-crystal X-ray diffraction

• References and Notes

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• 9 General Procedure for the Synthesis of Compounds 2–7 To a solution of 3-[(2-aminoaryl)amino]dimedone derivative 1a–c (0.001 mol) in EtOH (20 mL), the carbonylic derivative (0.001 mol) was added, and the resulting reaction mixture was stirred at r.t. for 4–5 h. In all the cases, a precipitate formed which was filtered-off, dried, and recrystallized from EtOH to give pure products 2–7. Note: In the case of the synthesis of the diamides 6 and 7, 2 molar equiv of the 3-[(2-aminoaryl)amino]dimedones 1a–c (0.002 mol) were used for 1 molar equiv of oxalyl chloride or fumaryl chloride. The reaction also works with an equimolar mixture of the reagent but excess of 1a–c remain in the reaction mixture.
• 10 11-(2-Hydroxyphenyl)-3,3,8-trimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one (2b) C₂₂H₂₄N₂O₂ (colorless crystals, 0.30 g, 87%, mp 175–177 °C). ¹H NMR (300 MHz, DMSO-d ₆): δ = 1.06 and 1.08 (2 s, 6 H, 3-CH₃), 1.99 (s, 3 H, 8-CH₃), 2.04 and 2.19 (AB, J = 15.9 Hz, 2 H, H-2), 2.60 (s, 2 H, H-4), 5.28 (d, J = 5.6 Hz, 1 H, 10-NH), 5.89 (d, J = 5.6 Hz, 1 H, H-11), 6.26 (d, J = 1.1 Hz, 1 H, H-9), 6.38 (dd, J = 8.0, 1.1 Hz, 1 H, H-7), 6.39–6.45 (m, 1 H, H-5′), 6.57 (dd, J = 7.5, 1.3 Hz, 1 H, H-6′), 6.71–6.74 (m, 1 H, H-3′), 6.82 (d, J = 8.0 Hz, 1 H, H-6) 6.84–6.91 (m, 1 H, H-4′), 8.76 (s, 1 H, 5-NH), 9.70 (s, 1 H, 2′-OH) ppm. ¹³C NMR (75 MHz, DMSO-d ₆): δ = 20.2 (8-CH₃), 27.4 and 28.6 (3-CH₃), 31.8 (C-3), 44.2 (C-4), 49.6 (C-2), 52.1 (C-11), 108.9 (C-11a), 114.8 (C-3′), 118.0 (C-5′), 119.9 (C-6), 120.5 and 120.6 (C-7, C-9), 126.6 (C-6′), 127.4 (C-4′), 128.4 (C-5a), 129.9 (C-1′), 131.3 (C-8), 138.3 (C-9a), 155.1 and 155.3 (C-4a, C-2′), 191.8 (C-1, C=O) ppm. HRMS (ESI⁺): m/z calcd for [C₂₂H₂₄N₂O₂ + Na]⁺: 371.1730; found: 371.1721.
• 11 3,3-Dimethyl-11-(4-oxo-4H-chromen-3-yl)-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one (3a) C₂₄H₂₂N₂O₃ (colorless crystals, 0.22 g, 57%, mp 183–184 °C). ¹H NMR (300 MHz, DMSO-d ₆): δ = 1.06 and 1.08 (2 s, 6 H, 3-CH₃), 2.13 and 2.19 (AB, J = 16.2 Hz, 2 H, H-2), 2.52 and 2.75 (AB, J = 16.2 Hz, 2 H, H-4), 5.46 (d, J = 5.5 Hz, 1 H, 10-NH), 5.78 (d, J = 5.5 Hz, 1 H, H-11), 6.47 (dd, J = 7.6, 1.7 Hz, 1 H, H-9), 6.52–6.70 (m, 2 H, H-7, H-8), 7.01 (dd, J = 7.7, 1.6 Hz, 1 H, H-6), 7.41–7.55 (m, 3 H, H-6′, H-8′, H-2′), 7.74 (ddd, J = 8.6, 7.1, 1.7 Hz, 1 H, H-7′), 8.09 (dd, J = 8.0, 1.7 Hz, 1 H, H-5′), 8.95 (s, 1 H, 5-NH) ppm. ¹³C NMR (75 MHz, DMSO-d ₆): δ = 27.4 and 28.6 (3-CH₃), 31.7 (C-3), 44.0 (C-4), 49.3 (C-2), 49.8 (C-11), 106.5 (C-11a), 118.3 (C-8′), 120.4, 120.7 and 120.8 (C-6, C-7, C-9), 123.0 (C-8), 123.1 (C-4a′), 124.8 and 125.0 (C-5′, C-3′), 125.5 (C-6′), 131.0 (C-5a), 134.2 (C-7′), 137.8 (C-9a), 152.5 (C-2′), 155.7 and 155.9 (C-4a, C-8a′), 176.4 (C-4′), 192.1 (C-1) ppm. HRMS (ESI⁺): m/z calcd for [C₂₄H₂₂N₂O₃ + H]⁺: 387.1703; found: 387.1729.
• 12 (E)-8-Chloro-3,3-dimethyl-11-styryl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one (4a) C₂₃H₂₃ClN₂O (beige solid, 0.21 g, 55%, mp 160–161 °C). ¹H NMR (300 MHz, DMSO-d ₆): δ = 1.00 and 1.05 (2 s, 6 H, 3-CH₃), 2.08 and 2.20 (AB, J = 15.9 Hz, 2 H, H-2), 2.51 (s, 2 H, H-4), 5.25 (dd, J = 6.0, 5.9 Hz, 1 H, H-11), 6.03 (dd, J = 15.8, 6.0 Hz, 1 H, H-1′), 6.20 (d, J = 15.8 Hz, 1 H, H-2′), 6.26 (d, J = 5.9 Hz, 1 H, 10-NH), 6.70 (dd, J = 8.6, 2.4 Hz, 1 H, H-7), 6.83 (d, J = 2.4 Hz, 1 H, H-9), 7.01 (d, J = 8.6 Hz, 1 H, H-6), 7.11–7.29 (m, 5 H, H-2′′,6′′, H-3′′,5′′ H-4′′), 8.86 (s, 1 H, 5-NH) ppm. ¹³C NMR (75 MHz, DMSO-d ₆): δ = 27.3 and 28.5 (3-CH₃), 31.9 (C-3), 44.0 (C-4), 49.5 (C-2), 53.2 (C-11), 110.3 (C-11a), 119.0 and 119.1 (C-7, C-9), 121.6 (C-6), 126.0 and 126.2 (C-2′′,6′′, C-8), 127.3 (C-4′′), 128.73 and 128.74 (C-3′′,5′′, C-2′), 129.6 (C-5a), 131.8 (C-1′), 136.6 (C-1′′), 140.0 (C-9a), 154.0 (C-4a), 192.2 (C-1) ppm. HRMS (ESI⁺): m/z calcd for [C₂₃H₂₃ClN₂O + H]⁺: 379.1572; found: 379.1586.
• 13 (Z)-3-[(2-{[3-(2-Hydroxyphenyl)-3-oxoprop-1-en-1-yl]amino}phenyl)amino]-5,5-dimethylcyclohex-2-en-1-one (5a) C₂₃H₂₄N₂O₃ (yellow crystals, 0.18 g, 47%, mp 234–235 °C). ¹H NMR (300 MHz, DMSO-d ₆): δ = 1.09 (2 s, 6 H, 5-CH₃), 2.03 (s, 2 H, H-6), 2.53 (s, 2 H, H-4), 4.46 (s, 1 H, H-2), 6.28 (d, J = 8.0 Hz, 1 H, H-2′′), 6.86–6.94 (m, 2 H, H-5′′′, H-3′′′), 7.14–7.26 (m, 2 H, H-5′, H-6′), 7.36–7.49 (m, 2 H, H-4′′′, H-4′), 7.71 (d, J = 8.0 Hz, 1 H, H-3′), 7.90–7.93 (m, 1 H, H-6′′′), 8.10 (dd, J = 12.8, 8.0 Hz, 1 H, H-1′′), 8.74 (s, 1 H, 3-NH), 11.82 (d, J = 12.8 Hz, 1 H, 1′′-NH), 13.12 (s, 1 H, 2′′′-OH) ppm. ¹³C NMR (75 MHz, DMSO-d ₆): δ = 28.1 (5-CH₃), 32.3 (C-5), 41.6 (C-4), 50.2 (C-6), 93.2 (C-2′′), 96.6 (C-2), 114.9 (C-3′), 117.8 (C-3′′′), 118.9 (C-5′′′), 119.8 (C-1′′′), 124.3 (C-5′), 126.9 (C-1′), 128.6 and 128.8 (C-4′, C-6′), 129.0 (C-6′′′), 134.9 (C-4′′′), 136.1 (C-2′), 146.5 (C-1′′), 161.6 (C-2′′′), 162.3 (C-3), 193.1 (C-3′′), 195.0 (C-1) ppm. HRMS (ESI⁺): m/z calcd for [C₂₃H₂₄N₂O₃ + H]⁺: 377.1860; found: 377.1871.
• 14 N ¹,N ⁴-Bis{2-[(5,5-dimethyl-3-oxocyclohex-1-en-1-yl)amino]phenyl}fumaramide (6a) C₃₂H₃₆N₄O₄ (brown solid, 0.40 g, 73%, mp 219–221 °C). ¹H NMR (300 MHz, DMSO-d ₆): δ = 1.04 (s, 12 H, 5′′-CH₃), 2.28 (s, 4 H, H-4′′), 2.56 (s, 4 H, H-6′′), 5.36 (s, 2 H, H-2′′), 7.30 (s, 2 H, H-2), 7.31–7.35 (m, 4 H, H-3′, H-4′), 7.36–7.49 (m, 2 H, H-5′), 7.84 (d, J = 8.0 Hz, 2H, H-6′), 10.41 (s, 2 H, N¹H), 10.70 (s, 2 H, N⁴H) ppm. ¹³C NMR (75 MHz, DMSO-d ₆): δ = 27.7 (5-CH₃), 32.6 (C-5′′), 41.3 (C-6′′), 46.1 (C-4′′), 95.6 (C-2′′), 125.0 (C-6′), 125.9 (C-3′) 127.1 (C-4′), 128.0 (C-5′), 129.5 (C-1′), 132.8 (C-2′), 134.0 (C-2), 162.3 (C-1), 170.6 (C-1′′), 191.2 (C-3′′) ppm. HRMS (ESI⁺): m/z calcd for [C₃₂H₃₆N₄O₄ + H]⁺: 541.2815; found: 541.2776.
• 15 N ¹,N ²-Bis{2-[(5,5-dimethyl-3-oxocyclohex-1-en-1-yl)amino]phenyl}oxalamide (7a) C₃₀H₃₄N₄O₄ (white solid, 0.42 g, 81%, mp 200–202 °C). ¹H NMR (300 MHz, DMSO-d ₆): δ = 1.03 (s, 12 H, 5′′-CH₃), 2.02 (s, 4 H, H-4′′), 2.39 (s, 4 H, H-6′′), 4.70 (s, 2 H, H-2′′), 7.27–7.40 (m, 6 H, H-3′, H-4′, H-5′), 7.96 (d, J = 7.9 Hz, 2 H, H-6′), 8.58 (s, 2 H, N²H), 9.96 (s, 2 H, N¹H) ppm. ¹³C NMR (75 MHz, DMSO-d ₆): δ = 28.0 (5-CH₃), 32.5 (C-5′′), 41.6 (C-6′′), 50.1 (C-4′′), 96.8 (C-2′′), 123.2 (C-6′), 126.3 (C-3′) 127.2 (C-4′), 127.6 (C-5′), 130.5 (C-1′), 131.9 (C-2′), 157.6 (C-1′′), 162.3 (C-1), 195.2 (C-3′′) ppm. HRMS (ESI⁺): m/z calcd for [C₃₀H₃₄N₄O₄ + Na]⁺: 537.2472; found: 537.2449.
• 16 Crystal Data for Compound 2b·EtOH C₂₄H₃₀N₂O₃, M = 394.50, monoclinic, space group P2₁/c, Z = 4, a = 9.5603(7) Å, b = 18.5619(12) Å, c = 12.7403(11) Å, β = 111.863(3), V = 2098.3(3) ų, μ(MoKα) = 0.082 mm^–1, D _c = 1.249 g cm^–3, colorless needle, crystal size of 0.13 × 0.05 × 0.04 mm³. Of a total of 20015 reflections collected, 3827 were independent (R _int = 0.0548). Final R1 = 0.0455 [I > 2σ(I)] and wR2 = 0.1092 (all data). Data completeness to θ = 25.24°, 99.6%. CCDC 1531504 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
• 17 Crystal Data for Compound 3a·5H₂O C₂₄H₃₂N₂O₈, M = 476.51, triclinic, space group Pī, Z = 2, a = 9.3720(6) Å, b = 11.4969(8) Å, c = 13.0910(9) Å, α = 113.510(2), β = 90.028(2), γ = 92.865(2), V = 1291.51(15) ų, μ(Mo Kα) = 0.092 mm^–1, D _c = 1.225 g cm^–3, colorless plate, crystal size of 0.12 × 0.12 × 0.04 mm³. Of a total of 26256 reflections collected, 6884 were independent (R _int = 0.0266). Final R1 = 0.0501 [I > 2σ(I)] and wR2 = 0.1459 (all data). Data completeness to θ = 25.24°, 99.7%. CCDC 1531506 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
• 18 Maleki A. Kamalzare M. Tetrahedron Lett. 2014; 55: 6931
• 19 Crystal Data for Compound 5a·EtOH C₂₅H₃₀N₂O₄, M = 422.51, monoclinic, space group P2₁/c, Z = 4, a = 13.8692(12) Å, b = 15.4961(10) Å, c = 11.3368(12) Å, β = 113.249(6), V = 2238.6(4) ų, μ(MoKα) = 0.085 mm^–1, D _c = 1.254 g cm^–3, yellow plate, crystal size of 0.17 × 0.15 × 0.13 mm³. Of a total of 12149 reflections collected, 4011 were independent (R _int = 0.1114). Final R1 = 0.0764 [I > 2σ(I)] and wR2 = 0.2393 (all data). Data completeness to θ = 25.24°, 98.3%. CCDC 1531505 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The ­Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.