Synthesis and Ring Transformation of Oxygen and Nitrogen Spiro Bisheterocycles

Abstract

A facile and rapid access to bridgehead oxygen- and nitrogen-containing spiro bisheterocycles is reported. It involves a one-pot spiro-to-spiro ring transformation of the key spiro[chromanone-hydantoin] compounds into new substituted spiro [hydantoin-diazole], spiro [hydantoin-isoxazole], spiro [hydantoin-diazepine], spiro [hydantoin-oxazepine], and spiro [hydantoin-benzodiazepine] upon reaction with appropriate bisnucleophilic agents. The hydantoin cycle is preserved during these chemical reactions affording the spiro bisheterocycles in optimal yields (42–71%). This relevant spiro-to-spiro ring transformation was confirmed by NMR and single-crystal X-ray diffraction studies.

Key words

spiro bisheterocycles - oxygen and nitrogen heterocycles - bisnucleophiles - NMR - X-ray diffraction

• References and Notes

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• 18 Synthesis of (R,S)-1′,3′-Dicyclohexyl-3-(2′′-hydroxyphenyl)-spiro[1-methyl-4,5-dihydro-1H-pyrazole-5,4′-imidazolidine]-2′,5′-dione (2a)C₂₄H₃₂N₄O₃ (white crystal, molecular weight 424.53 g/mol, 0.65 g, yield 61%, mp 118–120 °C). Compound 1a (1 g, 2.5 mmol) was added to of methylhydrazine (1 mL, 18.8 mmol) in CH₂Cl₂ (20 mL). The reaction mixture was stirred at r.t. for 1 h. After that, the volume of CH₂Cl₂ was reduced to ca. 5 mL to be purified in short plug column chromatography using CH₂Cl₂ as eluent. The purified product 2a was recrystallized from hexane–acetone (5:1) solution by slow evaporation at 6 °C. ¹H NMR (300.13 MHz, CDCl₃): δ = 1.09–2.25 (m, 20 H, CH₂, cyclohexyl), 2.88 (s, 3 H, NCH₃), 3.13 (tt, J = 12.0, 3.7 Hz, 1 H, H-1′′′b), 3.35 and 3.63 (AB, J = 17.7 Hz, 2 H, H-4), 3.91 (tt, J = 12.4, 3.9 Hz, 1 H, H-1′′′a), 6.89 (ddd, J = 7.4, 5.4, 1.2 Hz, 1 H, H-5′′), 6.98–7.02 (m, 2 H, H-3′′), 7.08 (dd, J = 7.4, 1.7 Hz, 1 H, H-6′′), 7.23–7.29 (m, 1 H, H-4′′), 10.39 (s, 1 H, 2′′-OH) ppm. ¹³C NMR (75.47 MHz, CDCl₃): δ = 24.9, 25.0, 25.71, 25.71, 26.02, 26.03, 29.3, 29.5,30.2 and 30.9 (CH₂, cyclohexyl), 34.9 (NCH₃), 40.5 (C-4), 51.4 (C-1′′′a), 53.5 (C-1′′′b), 83.7 (C-5/4′), 115.7 (C-1′′), 116.7 (C-3′′), 119.2 (C-5′′), 126.8 (C-6′′), 130.5 (C-4′′), 149.5 (C-3), 153.9 (C-2′), 157.2 (C-2′′), 170.2 (C-5′) ppm. HRMS (ESI⁺): m/z calcd for [C₂₄H₃₂N₄O₃ + Na]⁺: 447.2372; found: 447.2385.
• 19 Synthesis of (R,S)-1′,3′-Dicyclohexyl-3-(2′′-hydroxyphenyl)-spiro[4,5-dihydroisoxazole-5,4′-imidazolidine]-2′,5′-dione (3a)C₂₃H₂₉N₃O₄ (yellowish white solid, molecular weight 411.49 g/mol, 0.43 g, yield 42%, mp 91–92 °C). Compound 1a (1 g, 2.5 mmol) was added to K₂CO₃ (1 g, 7.5 mmol) in acetone (40 mL). The reaction mixture was stirred at reflux to which hydroxylammonium chloride (1 g, 14.4 mmol) was gradually added over a period of 10 min. After 15 h, K₂CO₃ was filtered off, and the solution was reduced to ca. 5 mL to which hexane (25 mL) was added. The purified product 3a was directly recrystallized from this hexane–acetone (5:1) solution by slow evaporation at 6 °C without any further purification steps. ¹H NMR (300.13 MHz, DMSO-d ₆): δ = 1.00–1.99 (m, 20 H, CH₂, cyclohexyl), 3.37 (tt, J = 12.1, 3.6 Hz, 1 H, H-1′′′b), 3.67 (tt, J = 12.1, 3.6 Hz, 1 H, H-1′′′a), 3.68 and 3.71 (AB, J = 15.4 Hz, 2 H, H-4), 7.40 (ddd, J = 7.9, 5.8, 2.1 Hz, 1 H, H-5′′), 7.62–7.66 (m, 2 H, H-3′′, H-4′′), 7.87–7.91 (m, 1 H, H-6′′) ppm. ¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 25.8, 26.1, 26.3, 26.4, 26.80, 26.84, 29.3, 30.2, 31.4 and 31.8 (CH₂, cyclohexyl), 31.0 (C-4), 51.3 (C-1′′′a), 53.0 (C-1′′′b), 86.1 (C-5/4′), 110.2 (C-3′′), 122.5 (C-1′′), 123.1 (C-6′′), 124.2 (C-5′′), 131.0 (C-4′′), 153.8 (C-3), 154.5 (C-2′), 163.5 (C-2′′), 172.4 (C-5′) ppm. HRMS (ESI⁺): m/z calcd for [C₂₃H₂₉N₃O₄ + Na]⁺: 434.2056; found: 434.2075.
• 20 Synthesis of (R,S)-1′,3′-Dicyclohexyl-7-(2′′-hydroxyphenyl)-spiro[(E)-3,4,5,6-tetrahydro-2H-1,4-diazepine-5,4′-imidazolidine]-2′,5′-dione (4a) and (R,S)-1′,3′-Diisopropyl-7-(2′′-hydroxyphenyl)-spiro[(E)-3,4,5,6-tetrahydro-2H-1,4-diazepine-5,4′-imidazolidine]-2′,5′-dione (4b)Compound 1a (1 g, 2.5 mmol) or 1b, (0.8 g, 2.5 mmol) was added to ethylenediamine (1 mL, 15 mmol) in CH₂Cl₂ (20 mL). The reaction mixture was stirred at r.t. for 4 h. After that, the volume of CH₂Cl₂ was reduced to ca. 5 mL to be purified in short plug column chromatography using CH₂Cl₂ as eluent. The purified products 4a or 4b were recrystallized from hexane–CH₂Cl₂ (5:1) solution by slow evaporation at 6 °C. In the case of compound 4b synthesis, the byproduct 7b was isolated by column chromatography and precipitated in hexane.Compound 4a: C₂₅H₃₄N₄O₃ (pale yellow solid, molecular weight 438.56 g/mol, 0.49 g, yield 45%, mp 178–179 °C). ¹H NMR (300.13 MHz, CDCl₃): δ = 1.06–2.34 (m, 20 H, CH₂, cyclohexyl), 3.00–3.07 and 3.61–3.69 (2 m, 2 H, CH₂, H-3), 3.25 and 3.34 (AB, J = 14.6, 2 H, H-6), 3.24 and 3.80 (2 tt, J = 12.3, 3.8 Hz, 2 H, H-1′′′a, H-1′′′b), 3.88 (ddd, J = 14.1, 9.1, 2.3 Hz, 1 H, H-2), 4.17 (ddd, J = 14.1, 6.6, 1.8 Hz, 1 H, H-2), 6.73 (ddd, J = 8.2, 7.2, 1.2 Hz, 1 H, H-5′′), 6.93–6.98 (m, 1 H, H-3′′), 7.22 (dd, J = 8.1, 1.5 Hz, 1 H, H-6′′), 7.27–7.31 (m, 1 H, H-4′′), 15.79 (s, 1 H, 2′′-OH) ppm. ¹³C NMR (75.47 MHz, CDCl₃): δ = 24.81, 24.88, 25.68, 25.71, 26.03, 26.1, 29.0, 29.4, 30.9 and 31.3 (CH₂, cyclohexyl), 35.9 (C-6), 41.2 (C-3), 49.9 (C-2), 50.9 and 52.5 (C-1′′′a and C-1′′′b), 72.1 (C-5/4′), 117.1 (C-5′′), 118.93 and 118.98 (C-3′′, C-1′′), 127.2 (C-6′′), 132.8 (C-4′′), 153.3 (C-2′), 163.5 (C-2′′), 171.5 (C-7), 171.9 (C-5′) ppm. HRMS (ESI⁺): m/z calcd for [C₂₅H₃₄N₄O₃ + H]⁺: 439.2709; found: 439.2742.Compound 4b: C₁₉H₂₆N₄O₃ (bright yellow crystal, molecular weight 358.43 g/mol, 0.60 g, yield 67%, mp 193–195 °C). ¹H NMR (300.13 MHz, CDCl₃): δ = 1.32, 134 and 1.47 (3d, J = 6.9 Hz, 3 × 3 H, CH₃, isopropyl), 1.43 (d, J = 6.8 Hz, 3 H, CH₃, isopropyl), 1.86–1.97 (m, 1 H, NH), 3.00–3.07 and 3.62–3.69 (2 m, 2 H, H-3), 3.27 and 3.32 (AB, J = 15.0 Hz, 2 H, H-6), 3.82–3.88 and 4.13–4.19 (2 m, 2 H, H-2), 3.70–3.81 and 4.19–4.28 (2 m, 2 H, H-1′′′a, H-1′′′b), 6.71–6.75 (m, 1 H, H-5′′), 6.95 (dd, J = 8.3, 1.1 Hz, 1 H, H-3′′), 7.22 (dd, J = 8.1, 1.4 Hz, 1 H, H-6′′), 7.26–7.30 (m, 1 H, H-4′′), 15.75 (s, 1 H, 2′′-OH) ppm. ¹³C NMR (75.47 MHz, CDCl₃): δ = 19.5, 19.8, 21.2 and 21.7 (CH₃, isopropyl), 36.0 (C-6), 41.5 (C-3), 43.4 and 44.5 (C-1′′′a and C-1′′′b), 50.2 (C-2), 72.2 (C-5/4′), 117.2 (C-5′′), 119.0 (C-3′′), 119.1 (C-1′′), 127.3 (C-6′′), 132.9 (C-4′′), 153.2 (C-2′), 163.5 (C-2′′), 171.5 (C-7), 172.0 (C-5′) ppm. HRMS (ESI⁺): m/z calcd for [C₁₉H₂₆N₄O₃ + H]⁺: 359.2083; found: 359.2115.(E,Z)-5-[2′-(2′′-Hydroxyphenyl)-2′-oxoethylidene]-1,3-diisopropylimidazolidine-2,4-dione (7b)C₁₇H₂₀N₂O₄ (yellow solid, molecular weight 316.35 g/mol, 0.06 g, yield 8%, mp 144–145 °C). ¹H NMR (300.13 MHz, CDCl₃): δ = 1.46 and 1.49 (2d, J = 6.9 Hz, 2 × 6 H, CH₃, isopropyl), 4.32–4.55 (m, 2 H, H-1′′′a, H-1′′′b), 6.82 (s, 1 H, H-1′), 6.98–6.99 (m, 1 H, H-5′′), 7.02 (d, J = 8.4 Hz, 1 H, H-3′′), 7.47–7.57 (m, 1 H, H-4′′), 7.84 (d, J = 8.1 Hz, 1 H, H-6′′), 12.27 (s, 1 H, 2′′-OH) ppm. ¹³C NMR (75.47 MHz, CDCl₃): δ = 19.7 and 20.0 (CH₃ isopropyl), 44.5 and 50.5 (C-1′′′a and C-1′′′b), 100.5 (C-1′), 118.6 (C-3′′), 119.2 (C-5′′), 120.8 (C-1′′), 130.8 (C-6′′), 137.0 (C-4′′), 137.2 (C-5), 153.9 (C-2), 162.9 (C-2′′), 1623.0 (C-4), 194.8 (C-2′) ppm. HRMS (ESI⁺): m/z calcd for [C₁₇H₂₀N₂O₄ + Na]⁺: 339.1321; found: 339.1315.
• 21 Synthesis of (R,S)-1′,3′-Dicyclohexyl-5-(2′′-hydroxyphenyl)-spiro[(E)-2,3,6,7-tetrahydro-2H-1,4-oxazepine-7,4′-imidazolidine]-2′,5′-dione (5a)C₂₅H₃₃N₃O₄ (yellowish white solid, molecular weight 439.54 g/mol, 0.65 g, yield 59%, mp 96–97 °C). Compound 1a (1g, 2.5 mmol) was added to hydroxyethylene amine (or 2-aminoethanol) (1 mL, 16.5 mmol) in CH₂Cl₂ (20 mL). The reaction mixture was stirred at r.t. for 4 h. The volume of CH₂Cl₂ was then reduced to ca. 5 mL to be purified in short plug column chromatography using CH₂Cl₂ as eluent. The purified product 5a was precipitated in hexane. ¹H NMR (300.13 MHz, CDCl₃): δ = 0.93–2.30 (m, 20 H, CH₂, cyclohexyl), 2.57–2.60 (m, 2 H, H-2), 3.11 (tt, J = 12.0, 3.5 Hz, 1 H, H-1′′′a), 3.47 and 3.65 (AB, J = 17.8 Hz, 2 H, H-6), 3.62–3.73 (m, 2 H, H-3), 3.97 (tt, J = 12.0, 3.5 Hz, 1 H, H-1′′′b), 6.86–7.01 (m, 2 H, H-5′′, H-3′′), 7.45–7.53 (m, 1 H, H-4′′), 7.65 (dd, J = 8.1, 1.2 Hz, 1 H, H-6′′), 11.74 (s, 1 H, 2′′-OH) ppm. ¹³C NMR (75.47 MHz, CDCl₃): δ = 25.07, 25.13, 25.81, 25.87, 26.1, 26.2, 29.2, 29.3, 30.2 and 30.5 (CH₂, cyclohexyl), 42.4 (C-6), 42.7 (C-2), 51.5 (C-1′′′b), 52.1 (C-1′′′a), 61.5 (C-3), 75.5 (C-7/4′), 118.7 (C-1′′), 118.9 (C-5′′), 119.2 (C-3′′), 129.2 (C-6′′), 137.1 (C-4′′), 155.1 (C-2′), 162.6 (C-2′′), 173.5 (C-5′), 200.5 (C-5) ppm. HRMS (ESI⁺): m/z calcd for [C₂₅H₃₃N₃O₄ Na]⁺: 462.2369; found: 462.2342.
• 22 Synthesis of (R,S)-1′,3′-Dicyclohexyl-4-(2′′-hydroxyphenyl)-spiro[(E)-2,3-dihydro-1H-benzo[b][1,4]diazepine-2,4′-imidazolidine]-2′,5′-dione (6a) and (R,S)-1′,3′-Diisopropyl-4-(2′′-hydroxyphenyl)-spiro[(E)-2,3-dihydro-1H-benzo[b][1,4]diazepine-2,4′-imidazolidine]-2′,5′-dione (6b)Compound 1a (1 g, 2.5 mmol) or 1b (0.8 g, 2.5 mmol), was added to ortho-phenylenediamine (0.54 g, 5 mmol) in THF (40 mL) in the presence of a catalytic amount of DBU (few drops). The reaction mixture was stirred at reflux overnight. After that, the solution was reduced to ca. 5 mL to be purified in short plug column chromatography using CH₂Cl₂ as eluent. The purified product 6a or 6b, was recrystallized from a hexane–CH₂Cl₂ (5:1) solution by slow evaporation at 6 °C.Compound 6a: C₂₉H₃₄N₄O₃ (pale yellow crystal, molecular weight 486.60 g/mol, 0.86 g, yield 71%, mp 147–149 °C). ¹H NMR (300.13 MHz, CDCl₃): δ = 0.69–2.29 (m, 20 H, CH₂, cyclohexyl), 2.99 and 3.33 (AB, J = 14.0 Hz, 2 H, H-3), 3.06–3.19 and 3.82–3.97 (2 m, 2 H, H-1′′′a, H-1′′′b), 3.77 (s, 1 H, NH), 6.82–6.88 (m, 1 H, H-5′′), 6.89–6.93 (m, 1 H, H-7), 7.04 (d, J = 8.8 Hz, 1 H, H-3′′), 7.14–7.19 (m, 2 H, H-8 and H-9), 7.28–7.41 (m, 3 H, H-4′′, H-6′′, H-6), 14.71 (s, 1 H, 2′′-OH) ppm. ¹³C NMR (75.47 MHz, CDCl₃): δ = 22.6, 24.8, 25.7, 25.8, 25.9, 26.1, 29.2, 29.4, 30.8 and 31.5 (CH₂, cyclohexyl), 33.5 (C-3), 51.3 and 51.7 (C-1′′′a and C-1′′′b), 87.4 (C-2/4′), 118.1 (C-5′′), 118.5 (C-3′′), 119.1 (C-1′′), 121.5 (C-7), 123.6 (C-9), 127.6 (C-8), 128.1 (C-6), 128.5 (C-6′′), 133.4 (C-4′′), 135.3 (C-9a), 136.0 (C-5b), 152.7 (C-2′), 162.1 (C-2′′), 167.0 (C-4), 170.5 (C-5′). HRMS (ESI⁺): m/z calcd for [C₂₉H₃₄N₄O₃ + Na]⁺: 509.2529; found: 509.2527.Compound 6a: C₂₃H₂₆N₄O₃ (bright yellow crystal, molecular weight = 406.47 g/mol, 0.64 g, yield 63%, mp 181–182 °C). ¹H NMR (300.13 MHz, CDCl₃): δ = 1.33 and 1.47 (2 d, J = 6.7 Hz, 2 × 3 H, CH₃, isopropyl), 1.41 and 1.44 (2 d, J = 7.2 Hz, 2 × 3 H, CH₃, isopropyl), 3.00 and 3.32 (AB, J = 14.0 Hz, 2 H, H-3), 3.56–3.69 and 4.25–4.39 (2 m, 2 H, H-1′′′a, H-1′′′b), 3.83 (s, 1 H, NH), 6.80–6.88 (m, 1 H, H-5′′), 6.90–6.96 (m, 1 H, H-7), 7.04 (d, J = 8.2 Hz, 1 H, H-3′′), 7.10–7.21 (m, 2 H, H-8 and H-9), 7.24–7.42 (m, 3 H, H-4′′, H-6′′, H-6), 14.74 (s, 1 H, 2′′-OH) ppm. ¹³C NMR (75.47 MHz, CDCl₃): δ = 19.6, 19.7, 22.0 and 21.6 (CH₃, isopropyl), 33.5 (C-3), 43.7 and 45.6 (C-1′′′a and C-1′′′b), 87.1 (C-2/4′), 118.1 (C-5′′), 118.6 (C-3′′), 119.2 (C-1′′), 121.6 (C-7), 123.6 (C-9), 127.7 (C-8), 128.3 (C-6), 128.6 (C-6′′), 133.4 (C-4′′), 135.3 (C-9a), 135.8 (C-5b), 152.5 (C-2′), 162.2 (C-2′′), 166.7 (C-4), 170.6 (C-5′). HRMS (ESI⁺): m/z calcd for [C₂₃H₂₆N₄O₃ + Na]⁺: 407.2083; found: 407.2100.
• 23 Crystal Data for Compound 2a2 × C₂₄H₃₂N₄O₃ + C₃H₆O, M = 907.15, monoclinic, space group C2/c, Z = 4, a = 29.894(3) Å, b = 8.2853(8) Å, c = 22.364(2) Å, β = 120.814(4)º, V = 4757.1(8) Å³, μ(Mo Kα) = 0.085 mm^–1, D _c = 1.267 g cm^–3, colorless block, crystal size of 0.26 × 0.20 × 0.18 mm³. Of a total of 68339 reflections collected, 6395 were independent (R _int = 0.0615). Final R1 = 0.0438 [I > 2σ(I)] and wR2 = 0.1201 (all data). Data completeness to θ = 25.24°, 99.7%. CCDC 1024617.
• 24 Crystal Data for Compound 4bC₁₉H₂₆N₄O₃, M = 358.44, monoclinic, space group P2₁/c, Z = 4, a = 10.3118(13) Å, b = 10.8672(14) Å, c = 17.551(2) Å, β = 105.671(4)º, V = 1893.7(4) Å³, μ(Mo Kα) = 0.087 mm^–1, D _c = 1.257 g cm^–3, yellow block, crystal size of 0.30 × 0.28 × 0.24 mm³. Of a total of 50806 reflections collected, 5091 were independent (R _int = 0.0341). Final R1 = 0.0453 [I > 2σ(I)] and wR2 = 0.1219 (all data). Data completeness to θ = 25.24°, 99.9%. CCDC 1024618.
• 25 Crystal Data for Compound 6bC₂₃H₂₆N₄O₃ + CH₂Cl₂, M = 491.40, monoclinic, space group P2₁/c, Z = 4, a = 14.4092(9) Å, b = 9.1504(5) Å, c = 18.5751(11) Å, β = 98.7540(19)º, V = 2420.6(2) Å³, μ(Mo Kα) = 0.302 mm^–1, D _c = 1.348 g cm^–3, yellow prism, crystal size of 0.20 × 0.20 × 0.16 mm³. Of a total of 19864 reflections collected, 6504 were independent (R _int = 0.0332). Final R1 = 0.0741 [I > 2σ(I)] and wR2 = 0.1817 (all data). Data completeness to θ = 25.24°, 99.8%. CCDC 1024619.