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DOI: 10.1055/a-1784-1973
Copper-Mediated C–O/C–N Bond Formation: A Facile Synthesis of 3-Amidocoumarin, 3-Amidoazacoumarin, and N-Aroylindole Derivatives
Thailand Research Fund (BRG6080013), Thailand Science Research and Innovation (TSRI) (2536703/42320), Thailand Science Research and Innovation (FRB650039/0240,Project code 165423), Chulabhorn Graduate Institute (631-CS02).
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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).
Supporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/a-1784-1973.
- Supporting Information
Publication History
Received: 01 February 2022
Accepted after revision: 01 March 2022
Accepted Manuscript online:
01 March 2022
Article published online:
24 March 2022
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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%); Rf = 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; Rf = 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; Rf = 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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