Facile Synthesis of Benzo[c]chromen-6-ones via Base-Promoted Reaction of 4-Chloro-3-formylcoumarin and α,α-Dicyanoolefins

Abstract

Herein, a chemoselective protocol for the facile and efficient synthesis of substituted benzo[c]chromen-6-ones is presented. The reaction took place under green and mild conditions with group-assisted purification (GAP) by using inexpensive and readily available precursors.

Key words

4-chloro-3-formylcoumarin - α,α-dicyanoolefins - benzo[c]chromen-6-ones - chemoselective reactions - group-assisted purification

Publication History

Received: 02 February 2022

Accepted after revision: 08 May 2022

Article published online:
12 July 2022

• References and Notes

• 1a Garazd L, Garazd MM. Chem. Nat. Compd. 2016; 52: 1
• 1b Mao Z, Sun W, Fu L, Luo H, Lai D, Zhou L. Molecules 2014; 19: 5088
• 1c Raistrick H, Stickings CE, Thomas R. Biochem. J. 1953; 55: 421
• 1d Pero RW, Harvan D, Blois MC. Tetrahedron Lett. 1973; 14: 945
• 1e Lv H.-N, Tu P.-F, Jiang Y. Med. Chem. 2014; 14: 603
• 2 Altemöller M, Gehring T, Cudaj J, Podlech J, Goesmann H, Feldmann C, Rothenberger A. Eur. J. Org. Chem. 2009; 2009: 2130
• 3 Vattem DA, Setty K. J. Food Biochem. 2005; 29: 234
• 4 Tomita F, Takahashi K, Tamaoki T. J. Antibiot. (Tokyo) 1982; 35: 1038
• 5a Sashidhara KV, Kumar A, Kumar M, Singh S, Jain M, Dikshit M. Bioorg. Med. Chem. Lett. 2011; 21: 7034
• 5b Sashidhara KV, Rosaiah JN, Kumar A, Bhatia G, Khanna AK. Bioorg. Med. Chem. Lett. 2010; 20: 3065
• 5c Lv H.-N, Wang S, Zeng K.-W, Li J, Guo X.-Y, Ferreira D, Zjawiony JK, Tu P.-F, Jiang Y. J. Nat. Prod. 2015; 78: 279
• 5d Strelitz F, Flon H, Asheshov IN. J. Bacteriol. 1955; 69: 280
• 5e Weiss U, Yoshihira K, Highet RJ, White RJ, Wei TT. J. Antibiot. (Tokyo) 1982; 35: 1194
• 5f Sehgal SN, Czerkawski H, Kudelski A, Pandev K, Saucier R, Vezina C. J. Antibiot. (Tokyo) 1983; 36: 355
• 6a Coghlan MJ, Kym PR, Elmore SW, Wang AX, Luly JR, Wilcox D, Stashko M, Lin CW, Miner J, Tyree C, Nakane M, Jacobson P, Lane BC. J. Med. Chem. 2001; 44: 2879
• 6b Novak J, Salemink CA. J. Chem. Soc., Perkin Trans. 1 1983; 2867 c) Teska J. A., Deiters A.; Org. Lett.; 2008, 10: 2195
• 7a Heerden FR, Brandt EV, Ferrira D, Roux DG. J. Chem. Soc., Perkin Trans. 1 1981; 2483
• 7b Burger AP. N, Brandt EV, Roux DG. Phytochemistry 1983; 22: 2813
• 7c Ishii H, Ishikawa T, Murota M, Aoki Y, Harayama T. J. Chem. Soc., Perkin Trans. 1 1993; 1019
• 8a Huang L, Weix DJ. Org. Lett. 2016; 18: 5432
• 8b Ramirez NP, Bosque I, Gonzalez-Gomez JC. Org. Lett. 2015; 17: 4550
• 8c Jung ME, Allen DA. Org. Lett. 2009; 11: 757
• 8d Zhang Y, Tian Y, Xiang P, Huang N, Wang J, Xu J.-H, Zhang M. Org. Biomol. Chem. 2016; 14: 9874
• 8e Inamoto K, Kadokawa J, Kondo Y. Org. Lett. 2013; 15: 3962
• 8f Dai JJ, Xu WT, Wu YD, Zhang WM, Gong Y, He XP, Zhang XQ, Xu HJ. J. Org. Chem. 2015; 80: 911
• 8g Luo S, Luo FX, Zhang XS, Shi ZJ. Angew. Chem., Int. Ed. 2013; 52: 10598
• 9 Dao PD. Q, Ho SL, Lim H.-J, Cho CS. J. Org. Chem. 2018; 83: 4140
• 10 Pottie IR, Nandaluru PR, Benoit WL, Miller DO, Dawe LN, Bodwell GJ. J. Org. Chem. 2011; 76: 9015
• 11 Singha R, Dhara S, Ghosh M, Ray JK. RSC Adv. 2015; 5: 8801
• 12 Patra P. New J. Chem. 2021; 45: 14269
• 13a Cuia HL, Chen YC. Chem. Commun. 2009; 4479
• 13b Curti C, Sartori A, Battistini L, Zanardi F. Synlett 2018; 29: 266
• 14 Benzo[c]chromen-6-ones 3a–3f; General Procedure Et₃N (1 mmol) was added to a mixture of 4-chloro-3-formylcoumarin (1) (1 mmol), and α,α-dicyanoolefin 2 (1 mmol) in EtOH (2 mL). The reaction mixture was magnetically stirred at 80 °C for 6 h (monitored by TLC). The target product 3 was isolated by filtration and washed with EtOH (96%). 6-Oxo-9-phenyl-6H-benzo[c]chromene-8-carbonitrile (3a) White powder; mp = 222–225 °C; 0.21 g; yield: 72%. IR (KBr): 2221 (CN), 1733 (C=O), 1596, 1572, and 1536 (Ar), 1128, 1102, and 1007 (C–O). Anal. Calcd. for C₂₀H₁₁NO₂ (297.31): C, 80.80; H, 3.73; N, 4.71. Found: C, 80.82; H, 3.71; N, 4.73. ¹H NMR (300 MHz, CDCl₃): δ = 7.41 (1 H, td, ³ J _HH = 7.8 Hz, ⁴ J _HH = 1.2 Hz, CH² of coumarin), 7.43 (1 H, dd, ³ J _HH = 8.4 Hz, ⁴ J _HH = 1.0 Hz, CH⁴ of coumarin), 7.55–7.69 (5 H, m, 5 CH of Ph), 7.66 (1 H, t, ³ J _HH = 8.0 Hz, ⁴ J _HH = 2.5 Hz, CH³ of coumarin), 8.11 (1 H, d, ³ J _HH = 7.9 Hz, CH¹ of coumarin), 8.22 (1 H, s, CH¹⁰), 8.80 (1 H, s, CH⁷). MS (EI, 70 eV): m/z (%) = 297 (M⁺, 100), 269 (23), 240 (34), 213 (15). The solubility of this product was too low for us to record a ¹³C NMR spectrum. 9-(4-Bromophenyl)-6-oxo-6H-benzo[c]chromene-8-carbonitrile (3b) White powder; mp = 294–297 °C; 0.30 g; yield: 82%. IR (KBr): 2219 (CN), 1736 (C=O), 1595, 1574, 1550, and 1429 (Ar), 1130, 1099, 1074, and 1002 (C–O). Anal. Calcd. for C₂₀H₁₀BrNO₂ (376.20): C, 63.85; H, 2.68; N, 3.72. Found: C, 63.84; H, 2.70; N, 3.69. ¹H NMR (300 MHz, DMSO-d ₆): δ = 7.43 (1 H, t, ³ J _HH = 8.3 Hz, CH² of coumarin), 7.45 (1 H, d, ³ J _HH = 8.6 Hz, CH⁴ of coumarin), 7.66 (1 H, t, ³ J _HH = 7.9 Hz, CH³ of coumarin), 7.70 (2 H, d, ³ J _HH = 8.5 Hz, 2 CH of Ar), 7.82 (2 H, d, ³ J _HH = 8.4 Hz, 2 CH of Ar), 8.54 (1 H, dd, ³ J _HH = 8.2 Hz, ⁴ J _HH = 1.1 Hz, CH¹ of coumarin), 8.63 (1 H, s, CH¹⁰), 8.66 (1 H, s, CH⁷). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 110.73 (C⁸), 116.65 (CN), 117.32 (C^6a), 117.47 (CH⁴ of coumarin), 120.49 (C _ipso –Br), 123.50 (C¹⁰), 124.34 (CH² of coumarin), 125.05 (C^10b), 125.12 (CH¹ of coumarin), 131.23 (2CH of Ar), 131.77 (2 CH of Ar), 132.61 (CH³ of coumarin), 135.83 (CH⁷ and C of Ar), 138.13 (C^10b), 148.30 (C⁹), 151.69 (C^4a), 158.74 (CO₂). MS (EI, 70 eV): m/z (%) = 377 (M⁺, 100), 349 (14), 296 (28), 267 (25), 240 (61), 213 (29). Crystal data for 3b (C₂₀H₁₀BrNO₂; CCDC 2092628): M _W = 376.20, monoclinic, P 1 21/c 1, a = 7.8474(16) Å, b = 14.652(3) Å, c = 13.751(3) Å, α = 90, β = 103.77(3), γ = 90, V = 1535.6(6)ų, Z = 4, D _calc = 1.627 mg/m³, F (000) = 752, crystal dimension 0.30 × 0.10 × 0.10 mm, Mo Kα radiation (λ = 0.71073 Å), 2.063 ≤ 2θ ≤ 24.997, intensity data were collected at 290.0 K with a Bruker APEX area-detector diffractometer by employing the ω/2θ scanning technique, in the range of –9 ≤ h ≤ 9, –17 ≤ k ≤ 17, –15 ≤ l ≤ 16; the structure was solved by a direct method, all non-hydrogen atoms were positioned and anisotropic thermal parameters were refined from 2567 observed reflections with R (into) = 0.0992 by a full-matrix least-squares technique converged to R1 = 0.0388, and wR2 = 0.1013 [I > 2σ(I)]. 9-(2-Chlorophenyl)-6-oxo-6H-benzo[c]chromene-8-carbonitrile (3c) White powder; mp = 260–261 °C; 0.25 g; yield: 76%. IR (KBr): 2223 (CN), 1736 (C=O), 1594, 1559, 1483, and 1400 (Ar), 1134, 1104, and 1016 (C–O). Anal. Calcd. for C₂₀H₁₀ClNO₂ (331.75): C, 72.41; H, 3.04; N, 4.22. Found: C, 72.43; H, 3.05; N, 4.20. ¹H NMR (300 MHz, DMSO-d ₆): δ = 7.41 (1 H, t, ³ J _HH = 7.7 Hz, CH² of coumarin), 7.47 (1 H, d, ³ J _HH = 8.3 Hz, CH⁴ of coumarin), 7.55–7.62 (3 H, m, 3 CH of Ar), 7.66 (1 H, t, ³ J _HH = 7.3 Hz, CH³ of coumarin), 7.72 (1 H, dd, ³ J _HH = 6.5 Hz, ³ J _HH = 1.1 Hz, CH of Ar), 8.53 (1 H, d, ³ J _HH = 8.0 Hz, CH¹ of coumarin), 8.66 (1 H, s, CH¹⁰), 8.74 (1 H, s, CH⁷). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 112.49 (C⁸), 116.54 (CN), 117.42 (C^6a), 120.93 (CH⁴ of coumarin), 125.05 (CH² of coumarin), 127.71 (C¹⁰), 129.50 (C^10b), 129.77 (CH¹ of coumarin), 131.22 (CH of Ar), 131.44 (CH of Ar), 132.68 (CH³ of coumarin), 132.49 (CH⁷), 132.68 (C of Ar), 134.72 (CH of Ar), 134.79 (C _ipso –Cl), 138.06 (C^10b), 147.35 (C⁹), 151.67 (C^4a), 158.66 (CO₂). MS (EI, 70 eV): m/z (%) = 331 (M⁺, 100), 303 (47), 267 (51), 239 (82), 212 (35). 9-(4-Chlorophenyl)-6-oxo-6H-benzo[c]chromene-8-carbonitrile (3d) White powder; mp = 285–289 °C; 0.26 g; yield: 79%. IR (KBr): 2220 (CN), 1736 (C=O), 1594, 1574, 1472, and 1429 (Ar), 1122, 1094, and 1004 (C–O). Anal. Calcd. for C₂₀H₁₀ClNO₂ (331.75): C, 72.41; H, 3.04; N, 4.22. Found: C, 72.39; H, 3.02; N, 4.21. ¹H NMR (300 MHz, DMSO-d ₆): δ = 7.44 (1 H, t, ³ J _HH = 7.8 Hz, CH² of coumarin), 7.45 (1 H, d, ³ J _HH = 8.7 Hz, CH⁴ of coumarin), 7.67 (1 H, t, ³ J _HH = 8.9 Hz, CH³ of coumarin), 7.69 (2 H, d, ³ J _HH = 8.0 Hz, 2 CH of Ar), 7.78 (2 H, d, ³ J _HH = 7.8 Hz, 2 CH of Ar), 8.56 (1 H, d, ³ J _HH = 7.2 Hz, CH¹ of coumarin), 8.64 (1 H, s, CH¹⁰), 8.67 (1 H, s, CH⁷). MS (EI, 70 eV): m/z (%) = 332 (M⁺, 100), 303 (59), 267 (27), 240 (72), 213 (19). The solubility of this product was too low for us to record a ¹³C NMR spectrum. 9-(3,4-Dimethoxyphenyl)-6-oxo-6H-benzo[c]chromene-8-carbonitrile (3e) White powder; mp = 245–248 °C; 0.27 g; yield: 77%. IR (KBr): 2217 (CN), 1735 (C=O), 1596, 1522, 1473, and 1430 (Ar), 1146, 1104, and 1024 (C–O). Anal. Calcd. for C₂₂H₁₅NO₄ (357.36): C, 73.94; H, 4.23; N, 3.92. Found: C, 73.95; H, 4.21; N, 3.93. ¹H NMR (300 MHz, DMSO-d ₆): δ = 3.86 (3 H, s, OCH₃), 3.88 (3 H, s, OCH₃), 7.18 (1 H, d, ³ J _HH = 8.3 Hz, CH of Ar), 7.34 (1 H, d, ³ J _HH = 8.3 Hz, CH of Ar), 7.37 (1 H, s, CH of Ar), 7.45 (1 H, t, ³ J _HH = 7.7 Hz, CH² of coumarin), 7.47 (1 H, d, ³ J _HH = 8.3 Hz, CH⁴ of coumarin), 7.67 (1 H, t, ³ J _HH = 8.8 Hz, CH³ of coumarin), 8.60 (1 H, d, ³ J _HH = 8.7 Hz, CH¹ of coumarin), 8.62 (1 H, s, CH¹⁰), 8.66 (1 H, s, CH⁷). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 55.72 (OCH₃), 55.94 (OCH₃), 110.62 (C⁸), 111.66 (CH of Ar), 112.67 (CH of Ar), 112.71 (CH of Ar), 116.67 (CN), 117.42 (C^6a), 117.77 (CH⁴ of coumarin), 119.62 (C¹⁰), 121.86 (CH² of coumarin), 123.86 (C^10b), 125.01 (CH¹ of coumarin), 128.82 (CH³ of coumarin), 132.57 (C of Ar), 135.91 (CH⁷), 137.84 (C^10b), 148.66 (C⁹), 150.07 (C _ipso –OCH₃), 150.07 (C _ipso –OCH₃), 151.60 (C^4a), 158.79 (CO₂). MS (EI, 70 eV): m/z (%) = 357 (M⁺, 2), 331 (12), 191 (30), 103 (66), 76 (100), 50 (100). 9-(4-Methylphenyl)-6-oxo-6H-chromene-8-carbonitrile (3f) White powder; mp = 262–264 °C; 0.22 g; yield: 73%. IR (KBr): 2224 (CN), 1733 (C=O), 1664, 1593, 1572, and 1427 (Ar), 1162, 1120, and 1102 (C–O). Anal. Calcd. for C₂₁H₁₃NO₂ (311.33): C, 81.01; H, 4.21; N, 4.50. Found: C, 81.02; H, 4.23; N, 4.47. ¹H NMR (300 MHz, CDCl₃): δ = 2.47 (3 H, s, CH₃), 7.38 (2 H, d, ³ J _HH = 8.2 Hz, 2 CH of Ar), 7.39 (1 H, t, CH² of coumarin), 7.40 (1 H, dd, ³ J _HH = 8.2 Hz, ⁴ J _HH = 1.5 Hz, CH⁴ of coumarin), 7.58 (2 H, d, ³ J _HH = 8.2 Hz, 2 CH of Ar), 7.59 (1 H, td, ³ J _HH = 8.6 Hz, ⁴ J _HH = 1.6 Hz, CH³ of coumarin), 8.09 (1 H, dd, ³ J _HH = 8.2 Hz, ⁴ J _HH = 1.4 Hz, CH¹ of coumarin), 8.19 (1 H, s, CH¹⁰), 8.73 (1 H, s, CH⁷). MS (EI, 70 eV): m/z (%) = 311 (M⁺, 100), 283 (34), 255 (26), 226 (22), 113 (21), 83 (24). The solubility of this product was too low for us to record a ¹³C NMR spectrum.