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Synlett 2006(17): 2785-2790  
DOI: 10.1055/s-2006-950279
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Simple Procedure for the Synthesis of 4-Aza-podophyllotoxin Derivatives in Water under Microwave Irradiation Conditions

Shujiang Tu*a, Yan Zhanga, Junyong Zhanga, Bo Jianga, Runhong Jiaa, Jinpeng Zhangb, Shunjun Ji*b
a Department of Chemistry, Key Laboratory of Biotechnology for Medicinal Plants, Xuzhou Normal University, Xuzhou, Jiangsu 221116, P. R. of China
Fax: +86(516)83403164; e-Mail: laotu@xznu.edu.cn;
b College of Chemistry and Chemical Engineering, Key Laboratory of Organic Synthesis of Jiangsu Province, Suzhou University, Suzhou, Jiangsu 215006, P. R. of China
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Publikationsverlauf

Received 8 June 2006
Publikationsdatum:
09. Oktober 2006 (online)

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Abstract

4-Aza-podophyllotoxin derivatives were synthesized via the three-component reaction of an aldehyde, an aromatic amine, and either tetronic acid or 1,3-indanedione in water under microwave irradiation conditions. This new protocol has the advantages of higher yield, lower cost, reduced environmental impact, and ­convenient procedure.

Key words

multicomponent reactions - heterocycles - indenoquinoline - 4-aza-podophyllotoxin - microwave irradiation

9

Compounds 6; General Procedure: All reactions were performed in a monomodal EmrysTM Creator from Personal Chemistry, Uppsala, Sweden. In a 10-mL EmrysTM reaction vial, aldehyde 3 (1 mmol), aromatic amine 4 (1 mmol), tetronic acid 5 (1 mmol), and H2O (2 mL) were mixed and then capped. The mixture was irradiated at 150 W and 100 °C for a given time. The reaction mixture was cooled to r.t. and filtered to give the crude product, which was further purified by recrystallization (DMF-EtOH) to give pure 4-aza-podophyllotoxin derivatives 6.
Compound 6c: Yellow solid; mp > 300 °C. IR (KBr): 3233, 3181, 3119, 3075, 2985, 2931, 1712, 1640, 1545, 810, 756, 689 cm-1. 1H NMR (DMSO-d 6, 400 MHz): δ = 10.01 (1 H, s, NH), 7.46 (2 H, d, J = 8.4 Hz, ArH), 7.16 (2 H, d, J = 8.0 Hz, ArH), 6.96 (1 H, d, J = 7.6 Hz, ArH), 6.85-6.82 (2 H, m, ArH), 5.00 (1 H, s, CH), 4.97-4.85 (2 H, m, CH2), 2.13 (3 H, s, CH3). Anal. Calcd for C18H14BrNO2: C, 60.69; H, 3.96; N, 3.93. Found: C, 60.75; H, 3.90; N, 3.89. Compound 6h: Yellow solid; mp >300 °C. IR (KBr): 3276, 3059, 2927, 2858, 1727, 1645, 1538, 1509, 1488, 803, 782, 758, 733, 723 cm-1. 1H NMR (DMSO-d 6, 400 MHz): δ = 10.28 (1 H, s, NH), 8.22 (1 H, d, J = 8.4 Hz, ArH), 7.86 (1 H, d, J = 8.0 Hz, ArH), 7.65-7.49 (3 H, m, ArH), 7.30-7.27 (2 H, m, ArH), 7.19-7.07 (3 H, m, ArH), 5.24 (1 H, s, CH), 5.11-4.97 (2 H, m, CH2). Anal. Calcd for C21H14FNO2: C, 76.12; H, 4.26; N, 4.23. Found: C, 76.23; H, 4.20; N, 4.16. Compound 6q: Yellow solid; mp >300 °C. IR (KBr): 3231, 3108, 3057, 2958, 2934, 1722, 1650, 1600, 1584, 1532, 814, 777, 742 cm-1. 1H NMR (DMSO-d 6, 400 MHz): δ = 10.27 (1 H, s, NH), 7.86-7.79 (3 H, m, ArH), 7.39-7.27 (3 H, m, ArH), 7.11 (2 H, d, J = 8.8 Hz, ArH), 6.75 (2 H, d, J = 8.4 Hz, ArH), 5.61 (1 H, s, CH), 4.98-4.87 (2 H, m, CH2), 3.64 (3 H, s, OCH3). Anal. Calcd for C22H17NO3: C, 76.95; H, 4.99; N, 4.08. Found: C, 77.01; H, 4.95; N, 4.02.

11

Compounds 8; General Procedure: In a 10-mL EmrysTM reaction vial aldehyde 3 (1 mmol), aromatic amine 4 (1 mmol), 1:3-indanedione 7 (1 mmol), and H2O (2 mL) were mixed and then capped. The mixture was irradiated at 150 W and 100 °C for a given time. The reaction mixture was cooled to r.t. and filtered to give the crude product which was further purified by recrystallization (DMF-EtOH) to give pure indeno[1,2-b]quinoline derivatives 8. Compound 8m: Yellow solid; mp >300 °C. IR (KBr): 3220, 3065, 2855, 1710, 1662, 1574, 1533, 1485, 858, 738, 645 cm-1. 1H NMR (DMSO-d 6, 400 MHz): δ = 10.99 (1 H, s, NH), 7.94 (1 H, d, J = 8.8 Hz, ArH), 7.87 (2 H, t, J = 8.0 Hz, ArH), 7.63 (1 H, d, J = 7.2 Hz, ArH), 7.53 (1 H, d, J = 8.8 Hz, ArH), 7.49-7.34 (6 H, m, ArH), 7.27 (1 H, d, J = 8.0 Hz, ArH), 7.20 (2 H, d, J = 8.4 Hz, ArH), 5.80 (1 H, s, CH). Anal. Calcd for C26H16BrNO: C, 71.25; H, 3.68; N, 3.20. Found: C, 71.34; H, 3.62; N, 3.10.

13

Compound 9f: In a 10-mL EmrysTM reaction vial 3-nitro-benzaldehyde (3e, 2 mmol), p-toluidine (4b, 2 mmol), and H2O (3 mL) were mixed and then capped. The mixture was irradiated at 150 W and 100 °C for 2 min. The reaction mixture was cooled to r.t. and filtered to give the crude product which was further purified by recrystallization (EtOH) to give pure N-(3-nitrobenzylidene)-4-methyl-benzenamine (9f). Yellow solid; mp 87-88 °C. IR (KBr): 3092, 3026, 2879, 1622, 1572, 1440, 1268, 1044, 860, 765 cm-1. 1H NMR (DMSO-d 6, 400 MHz): δ = 8.76 (1 H, s, CH), 8.58 (1 H, s, ArH), 8.33 (1 H, d, J = 8.0 Hz, ArH), 8.27 (1 H, d, J = 7.6 Hz, ArH), 7.68 (1 H, d, J = 8.0 Hz, ArH), 7.29-7.20 (4 H, m, ArH), 2.41 (3 H, s, CH3). Anal. Calcd for C14H12N2O2: C, 69.99; H, 5.03; N, 11.66. Found: C, 70.09; H, 4.95; N, 11.60.

14

Reaction of Schiff Base 9f and Tetronic Acid (5): In a 10-mL EmrysTM reaction vial, N-(3-nitrobenzylidene)-4-methyl-benzenamine (9f, 1 mmol), tetronic acid (5, 1 mmol), H2O (2 mL) were mixed and then capped. The mixture was irradiated at 150 W and 100 °C for 7 min. The reaction mixture was cooled to r.t. and filtered to give the crude product, which was further purified by recrystallization (DMF-EtOH) to give pure 7-methyl-9-(3-nitrophenyl)-4,9-dihydrofuro[3,4-b]quinolin-1 (3H)-one(6f). Yellow solid; mp >300 °C. IR (KBr): 3237, 3183, 3121, 3077, 2932, 1714, 1640, 1544, 1348, 1205, 1109, 934, 861 cm-1. 1H NMR (DMSO-d 6, 400 MHz): δ = 10.11 (1 H, s, NH), 8.05 (2 H, d, J = 7.2 Hz, ArH), 7.69 (1 H, d, J = 7.6 Hz, ArH), 7.60 (1 H, t, J = 8.0 Hz, ArH), 7.00 (1 H, d, J = 8.4 Hz, ArH), 6.89 (2 H, t, J = 8.0 Hz, ArH), 5.26 (1 H, s, CH), 5.02-4.88 (2 H, m, CH2), 2.13 (3 H, s, CH3). Anal. Calcd for C18H14N2O4: C, 67.07; H, 4.38; N, 8.69. Found: C, 67.15; H, 4.29; N, 8.54.

15

The single crystal growth was carried out in EtOH-DMF at r.t. X-ray crystallographic analysis was performed with a Siemens SMART CCD and a Semens P4 diffractometer (graphite monochromator, Mo Kα radiation λ = 0.71073 Å). Crystal data for 6n: Empirical formula C21H14FNO2, yellow, crystal dimension 0.23 × 0.18 × 0.16 mm, monoclinic, space group C2/c, a = 21.010 (7) Å, b = 11.388 (4) Å, c = 15.123 (5) Å, α = 90°, β = 121.380 (5)°, γ = 90°, V = 3089.3 (16) Å3, Mr = 331.33, Z = 8, Dc = 1.425 Mg/m3, λ = 0.71073 Å, µ (Mo-Kα) = 0.100 mm-1, F(000) = 1376, S = 0.991, R1 = 0.049, wR2 = 0.136. Crystallographic data for the structures of 6n reported in this letter have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication No. CCDC-608399.