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

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

Publication History

Received: 01 February 2022

Accepted after revision: 01 March 2022

Accepted Manuscript online:
01 March 2022

Article published online:
24 March 2022

• References and Notes

• 1a Brühlmann C, Ooms F, Carrupt P, Testa B, Catto M, Leonetti F, Altomare C, Carotti A. J. Med. Chem. 2001; 44: 3195
• 1b Gnerre C, Catto M, Leonetti F, Weber P, Carrupt P.-A, Altomare C, Carotti A, Testa B. J. Med. Chem. 2000; 43: 4747
• 1c Shen Q, Peng Q, Shao J, Liu X, Huang Z, Pu X, Ma L, Li Y.-M, Chan AS. C, Gu L. Eur. J. Med. Chem. 2005; 40: 1307
• 2 Manojkumar P, Ravi TK, Subbuchettia G. Acta Pharm. (Zagreb, Croatia) 2009; 59: 159
• 3 Lin H.-C, Tsai S.-H, Chen C.-S, Chang Y.-C, Lee C.-M, Lai Z.-Y, Lin C.-M. Biochem. Pharmacol. 2008; 75: 1416
• 4 Raad II, Hachem RY, Abi-Said D, Rolston KV, Whimbey E, Buzaid AC, Legha S. Cancer 1998; 82: 403
• 5 Walsh TJ, Standiford HC, Reboli AC, John JF, Mulligan ME, Ribner BS, Montgomerie JZ, Goetz MB, Mayhall CG, Rimland D. Antimicrob. Agents Chemother. 1993; 37: 1334
• 6a Berger U, Batcho AD. J. Chromatogr. Libr. 1978; 15: 101
• 6b Cheenpracha S, Vider NB, Yoshida WY, Devies J, Chang LC. J. Nat. Prod. 2010; 73: 880
• 7a Gormley NA, Orphanides G, Meyer A, Cullis PM, Maxwell A. Biochemistry 1996; 35: 5083
• 7b Maxwell A, Lawson DM. Curr. Top. Med. Chem. (Sharjah, United Arab Emirates) 2003; 3: 283
• 7c Kampranis SC, Gormley NA, Tranter R, Orphanides G, Maxwell A. Biochemistry 1999; 38: 1967
• 8a Bishop SC, Burlison JA, Blagg BS. J. Curr. Cancer Drug Targets 2007; 7: 369
• 8b McCarty MF. Integr. Cancer Ther. 2004; 3: 349
• 8c Hanahan D, Weinberg RA. Cell 2000; 100: 57
• 8d Blagg BS. J, Kerr TD. Med. Res. Rev. 2006; 26: 310
• 9 Burlison JA, Neckers L, Smith AB, Maxwell A, Blagg BS. J. J. Am. Chem. Soc. 2006; 128: 15529
• 10 Zhao H, Donnelly AC, Kusuma BR, Brandt GE. L, Brown D, Rajewski RA, Vielhauer G, Holzbeierlein J, Cohen MS, Blagg BS. J. J. Med. Chem. 2011; 54: 3839
• 11 Donnelly AC, Mays JR, Burlison JA, Nelson JT, Vielhauer G, Holzbeierlein J, Blagg BS. J. J. Org. Chem. 2008; 73: 8901
• 12 Burlison JA, Avila C, Vielhauer G, Lubbers DJ, Holzbeierlein J, Blagg BS. J. J. Org. Chem. 2008; 73: 2130
• 13 Shaw KN. F, McMillan A, Armstrong MD. J. Org. Chem. 1956; 21: 601
• 14 Dakin HD. J. Biol. Chem. 1929; 82: 439
• 15 Gagey N, Emond M, Neveu P, Benbrahim C, Goetz B, Aujard I, Baudin J.-B, Jullian L. Org. Lett. 2008; 10: 2341
• 16a Audisio D, Messaoudi S, Peyrat J.-F, Brion J.-D, Alami M. J. Org. Chem. 2011; 76: 4995
• 16b Soussi MA, Audisio D, Messaoudi S, Provot O, Brion J.-D, Alami M. Eur. J. Org. Chem. 2011; 5077

For reviews, see:
• 17a Ley SV, Thomas AW. Angew. Chem. Int. Ed. 2003; 42: 5400
• 17b Beletskaya IP, Cheprakov AV. Coord. Chem. Rev. 2004; 248: 2337
• 17c Ma D, Cai Q. Acc. Chem. Res. 2008; 41: 1450
• 18a You H, Vegi SR, Lagishetti C, Chen S, Reddy RS, Yang X, Guo J, Wang C, He Y. J. Org. Chem. 2018; 83: 4119
• 18b Bhunia S, Pawar GG, Kumar SV, Jiang Y, Ma D. Angew. Chem. Int. Ed. 2017; 56: 16136
• 18c Maiti D, Buchwald SL. J. Org. Chem. 2010; 75: 1791
• 18d Maiti D, Buchwald SL. J. Am. Chem. Soc. 2009; 131: 17423
• 18e Altman RA, Shafir A, Choi A, Lichtor PA, Buchwald SL. J. Org. Chem. 2008; 73: 284
• 18f Nordmann G, Buchwald SL. J. Am. Chem. Soc. 2003; 125: 4978
• 19a Thasana N, Worayuthakarn R, Kradanrat P, Hohn E, Young L, Ruchirawat S. J. Org. Chem. 2007; 72: 9379
• 19b Nealmongkol P, Tangdenpaisan K, Ruchirawat S, Thasana N. Tetrahedron 2013; 69: 9277
• 20 Nealmongkol P, Calmes J, Ruchirawat S, Thasana N. Tetrahedron 2017; 73: 735
• 21 Worayuthakarn R, Nealmongkol P, Ruchirawat S, Thasana N. Tetrahedron 2012; 68: 2864
• 22 Boonya-udtayan S, Yotapan N, Woo C, Bruns CJ, Ruchirawat S, Thasana N. Chem. Asian J. 2010; 5: 2113
• 23a Lynn J. J. Org. Chem. 1959; 24: 1030
• 23b Boekelheide V, Schramm LM. J. Org. Chem. 1949; 14: 298
• 23c Lamb J, Robson W. Biochem. J. 1931; 25: 1231
• 23d Monk KA, Sarapa D, Mohan RS. Synth. Commun. 2000; 30: 3167
• 23e Paul S, Nanda P, Gupta R, Loupy A. Tetrahedron Lett. 2004; 45: 425
• 23f Chandrasekhar S, Karri P. Tetrahedron Lett. 2007; 48: 785
• 23g Worayuthakarn R, Thasana N, Ruchirawat S. Org. Lett. 2006; 8: 5845
• 24 Yeung Y.-Y, Corey EJ. Tetrahedron Lett. 2007; 48: 7567
• 25a Kubo T, Katoh C, Yamada K, Okano K, Tokuyama H, Fukuyama T. Tetrahedron 2008; 64: 11230
• 25b Okano K, Tokuyama H, Fukuyama T. Org. Lett. 2003; 5: 4987
• 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