Copper-Mediated C–O/C–N Bond Formation: A Facile Synthesis of 3-Amidocoumarin, 3-Amidoazacoumarin, and N-Aroylindole ­Derivatives

Rattana Worayuthakarn; Nattanit Suddee; Prattya Nealmongkol; Somsak Ruchirawat; Nopporn Thasana

doi:10.1055/a-1784-1973

Synlett, Table of Contents

Synlett 2022; 33(14): 1431-1437
DOI: 10.1055/a-1784-1973

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Organic Chemistry in Thailand

Copper-Mediated C–O/C–N Bond Formation: A Facile Synthesis of 3-Amidocoumarin, 3-Amidoazacoumarin, and N-Aroylindole Derivatives

Rattana Worayuthakarn

^aLaboratory of Medicinal Chemistry, Chulabhorn Research Institute, 54 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand

,

Nattanit Suddee

^bChemical Sciences Program, Chulabhorn Graduate Institute, Chulabhorn Royal Academy, 906 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand

,

Prattya Nealmongkol

^bChemical Sciences Program, Chulabhorn Graduate Institute, Chulabhorn Royal Academy, 906 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand

,

Somsak Ruchirawat

^aLaboratory of Medicinal Chemistry, Chulabhorn Research Institute, 54 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand

^bChemical Sciences Program, Chulabhorn Graduate Institute, Chulabhorn Royal Academy, 906 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand

^cCenter of Excellence on Environmental Health and Toxicology (EHT), OPS, Ministry of Higher Education, Science, Research and Innovation, Bangkok 10400, Thailand

,

Nopporn Thasana∗

^aLaboratory of Medicinal Chemistry, Chulabhorn Research Institute, 54 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand

^bChemical Sciences Program, Chulabhorn Graduate Institute, Chulabhorn Royal Academy, 906 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand

^cCenter of Excellence on Environmental Health and Toxicology (EHT), OPS, Ministry of Higher Education, Science, Research and Innovation, Bangkok 10400, Thailand

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Abstract

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Abstract

Three different heterocyclic systems (3-amidocoumarins, 3-amidoazacoumarins, and N-benzoylindol-2-carboxamides) were synthesized based on the strikingly different selectivity of copper-mediated C–O/C–N bond formation from azlactones under various heating conditions. The stereochemistry of the double bond dictated the nature of the products. Microwave irradiation played an important role in the isomerization of the trisubstituted olefin leading to the formation of 3-amidocoumarins and 3-amidoazacoumarins. Three products showed promising-to-good cytotoxic activities against a panel of cancer cell lines, including HepG2 (hepatoblastoma) and MOLT-3 (T-lymphoblast acute lymphoblastic leukemia).

Key words

copper catalysis - coumarins - azacoumarins - indoles - azlactones - microwave heating

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References

References and Notes

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26 N-(2-Oxo-1,2-dihydroquinolin-3-yl)benzamides 11; General ProcedureThe appropriate carbamate 10 (0.10 mmol), BCH (0.2 equiv), and CuTC (1.0–1.2 equiv) in DMSO (1 mL) were subjected to microwave irradiation at 90 °C (200 W, 100 psi) for 20 min, then cooled to rt. The reaction was quenched with sat. aq NH₄Cl and the mixture was extracted with EtOAc (3 × 5 mL). The organic layers were combined, washed with H₂O and brine, dried (Na₂SO₄), and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, 60% EtOAc–hexane or 2–10% EtOAc–CH₂Cl₂) or by precipitation with CH₂Cl₂ in hexane to give the desired product 11 with a trace amount of byproduct 13. N-(7-Methoxy-2-oxo-1,2-dihydroquinolin-3-yl)benzamide (11b)White solid; yield: 9.0 mg (31%); R_f = 0.23 (EtOAc–CH₂Cl₂, 0.4:9.6); mp 255–256 °C (CH₂Cl₂/hexane). IR (UATR): 3370, 2958, 2924, 2851, 1655, 1630, 1575, 1542, 1513, 1478, 1449, 1421 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 12.27 (br s, 1 H), 9.34 (br s, 1 H), 8.65 (s, 1 H), 7.93 (d, J = 8.0 Hz, 2 H), 7.62 (t, J = 8.2 Hz, 2 H), 7.55 (t, J = 7.4 Hz, 2 H), 6.87 (d, J = 2.4 Hz, 1 H), 6.84 (s, 1 H), 3.80 (s, 3 H). ¹³C NMR (100 MHz, DMSO-d₆ ): δ = 164.8, 159.9, 158.0, 136.2, 133.9, 132.1, 129.0, 128.9 (2C), 127.1 (2C), 125.7, 122.2, 113.4, 111.5, 98.2, 55.3. HRMS (microTOF): m/z [M + Na]⁺ calcd for C₁₇H₁₄N₂NaO₃: 317.0897; found: 317.0896(5Z)-1-Benzoyl-5-(2-bromo-4-methoxybenzylidene)imidazolidine-2,4-dione (13b)Light-yellow solid : yield: 15.6 mg (39%); mp 156-158 °C. IR (UATR): 3211, 3065, 2926, 2855, 2744, 1786, 1740, 1661, 1597, 1493, 1457 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.18 (br s, 1 H), 7.79 (d, J = 7.2 Hz, 2 H), 7.62 (tt, J = 7.6, 1.2 Hz, 1 H), 7.46 (t, J = 7.8 Hz, 2 H), 7.32 (s, 1 H), 7.08 (d, J = 2.8 Hz, 1 H), 6.97 (d, J = 8.4 Hz, 1 H), 6.59 (dd, J = 8.8, 2.4 Hz, 1 H), 3.74 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 165.9, 162.2, 160.6, 151.6, 134.1, 132.8, 130.5, 130.2 (2C), 128.4 (2C), 125.7, 125.6 (2C), 119.4, 118.1, 113.3, 55.5. HRMS (microTOF): m/z [M + H]⁺ calcd for C₁₈H₁₄BrN₂O₄: 401.0131; found: 401.0134.
27 Structure of byproduct (5Z)-1-benzoyl-5-(2-bromo-4-methoxybenzylidene)imidazolidine-2,4-dione (13b) (Figure 3.
28 N-Benzoylindole-2-carboxamides 12; General ProcedureA solution of 2-benzamido-3-(2-bromoaryl)acryloylcarbamates 10 (0.10 mmol), CuTC (19.0 mg, 0.10 mmol), CsOAc (48.0 mg, 0.25 mmol) in anhyd DMSO (1 mL) was heated at 90 °C for 1 h. The resulting mixture was cooled to rt and the reaction was quenched with sat. aq NH₄Cl. The mixture was extracted with EtOAc (3 × 5 mL) and the organic layers were combined, washed with brine, dried (Na₂SO₄), filtered, and concentrated in vacuo. The residue was purified by preparative TLC (40–60% EtOAc–hexane). tert-Butyl 1-benzoyl-1H-indole-2-carbonylcarbamate (12a)Pale-yellow solid; yield: 36 mg (quant); mp 143–144 °C; R_f = 0.57 (EtOAc–hexane, 3:2). IR (UATR): 3248, 2979, 1740, 1717, 1678, 1509, 1489 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 9.38 (s, 1 H), 8.12 (d, J = 8.4 Hz, 1 H), 7.89 (d, J = 7.5 Hz, 2 H), 7.64–7.55 (m, 2 H), 7.49 (t, J = 7.5 Hz, 2 H), 7.44–7.36 (m, 1 H), 7.30–7.22 (m, 1 H), 6.96 (s, 1 H), 1.59 (s, 9 H). ¹³C NMR (75 MHz, CDCl₃): δ = 164.7, 163.2, 149.4, 136.1, 133.3, 132.9, 132.4, 129.0 (2 C), 128.2, 127.8 (2C), 126.4, 123.3, 122.0, 115.5, 111.9, 85.2, 27.9 (3 C). EI-MS: m/z (%) = 364 (2) [M]⁺, 264 (20), 143 (13), 105 (100), 77 (21). HRMS (microTOF): m/z [M + H]⁺ calcd for C₂₁H₂₁N₂O₄: 365.1496; found: 365.1500
29 3-Amidocoumarins 1; General Procedure Conditions A: In a 10 mL microwave vessel, a suspension of 2-bromoarylazlactone 9 (1.0 equiv) and CuTC (1.2 equiv) in 1:1 DMF–H₂O (1 mL) was irradiated with microwaves with a microwave run time of 5 min at 250 W, 150 °C, and 150 psi, and these parameters were held for 10–20 min. When the reaction was complete, sat. aq NH₄Cl (5–10 mL) was poured into the suspension and the mixture was partitioned with EtOAc (3 × 25 mL). The solvent was removed by rotary evaporation, and the crude product was purified by flash column chromatography (silica gel, 10–50% EtOAc–hexane).Conditions B: In a 10 mL microwave vessel, a suspension of 2-bromoarylazlactone 9 (1.0 equiv) and CuTC (1.2 equiv) in DMF (1 mL) was irradiated with a microwave run time of 5 min at 250 W, 150 °C, and 150 psi and these parameters were held for 5–35 min. When the reaction was complete, sat. aq NH₄Cl (5–10 mL) was poured into the suspension and the mixture was partitioned with EtOAc (3 × 25 mL). The solvent was removed by rotary evaporation, and the crude product was purified by flash column chromatography (silica gel, 10–50 % EtOAc–hexane) or by preparative TLC (silica gel, 40–60% EtOAc–hexane). N-(2-Oxo-2H-chromen-3-yl)benzamide (1a)Brown solid; yield: 30.0 mg (77%); mp 160–161 °C; R_f = 0.52 (EtOAc–hexane, 2:3). IR (UATR): 3365, 3086, 2925, 2326, 1708, 1664, 1530, 1360, 1256, 755, 701 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 8.86 (s, 1 H), 8.85 (s, 1 H), 7.93 (d, J = 7.2 Hz, 2 H), 7.64–7.28 (m, 7 H). ¹³C NMR (75 MHz, CDCl₃): δ = 166.0, 158.9, 149.9, 133.4, 132.4, 129.6, 128.8 (2 C), 127.8, 127.1 (2C), 125.1, 124.1, 123.3, 119.8, 116.3. EI-MS: m/z (%) = 266 (1) [M + H]⁺, 265 (7) [M]⁺, 149 (6), 132 (4), 106 (7), 105 (100), 77 (33). HRMS (microTOF): m/z [M + H]⁺ calcd for C₁₆H₁₂NO₃: 266.0806; found: 266.0811.
30 Gao L, Tang H, Wang Z. Chem. Commun. 2014; 50: 4085

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Supporting Information

Copper-Mediated C–O/C–N Bond Formation: A Facile Synthesis of 3-Amidocoumarin, 3-Amidoazacoumarin, and N-Aroylindole ­Derivatives

Copper-Mediated C–O/C–N Bond Formation: A Facile Synthesis of 3-Amidocoumarin, 3-Amidoazacoumarin, and N-Aroylindole Derivatives