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Synlett 2004(5): 0803-0806  
DOI: 10.1055/s-2004-817784
LETTER
© Georg Thieme Verlag Stuttgart · New York

Solvent-Free Cyclocondensation of Lactim Ethers with Anthranilic Acid under Microwave Irradiation

Pilar Cledera, J. Domingo Sánchez, Esmeralda Caballero, Carmen Avendaño, M. Teresa Ramos, J. Carlos Menéndez*
Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
e-Mail: josecm@farm.ucm.es;
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Publication History

Received 12 December 2003
Publication Date:
17 February 2004 (online)

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Abstract

Microwave irradiation greatly improves the results of the cyclocondensation between anthranilic acid and lactim ethers derived from 2,5-piperazinediones in terms of reaction times, yields and stereocenter integrity, leading to pyrazino[2,1-b]quinazoline-3,6-diones. The microwave-assisted reaction was also much better than the thermal one when applied to a bis-lactim ether, leading to the corresponding pentacyclic pyrazino [2,1-b:5,4-b′]diquinazol­ine-5,13-dione in excellent yield, and it also improved the preparation of compounds containing the ring system of the anti-MDR natural product N-acetylardeemin.

Key words

microwave irradiation - iminoethers - cyclizations - antitumor agents - heterocycles

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Representative Procedure: A 10 mL flask containing a mixture of (3S)-5-ethoxy-1,3-dimethylpiperazin-2-one [16] (100 mg, 0.59 mmol) and anthranilic acid (88 mg, 0.65 mmol) was submerged in alumina, contained in a beaker, and irradiated for 1 min at 600 W in a domestic microwave oven. The reaction was left to cool for 2 min and submitted to two additional irradiation-cooling cycles. The solid thus obtained was purified by chromatography on silica gel, eluting with 6:1 petroleum ether-EtOAc mixture to yield 90 mg (63%) of compound 3a, as an off-white solid. Mp 150-152 °C; lit. [16b] 153-156 °C. [α]25 D +142.9 (c = 0.135 g/100 mL in CHCl3); lit. [16b] +149.2 (c = 2 g/100 mL, EtOH). IR (KBr): 1673 (CO) cm-1. 1H NMR (250 MHz, CDCl3) δ = 8.27 (dd, J = 8.0, 1.3 Hz, 1 H, H-7), 7.76 (td, J = 7.8, 1.3 Hz, 1 H, H-8), 7.62 (d, J = 7.6 Hz, 1 H, H-10), 7.49 (td, J = 8.1, 1.2 Hz, 1 H, H-9), 5.45 (q, J = 7.1 Hz, 1 H, H-4), 4,75 (d, J = 16.8 Hz, 1 H, H-1 pseudoequatorial), 4.37 (d, J = 16.8 Hz, 1 H, H-1 pseudoaxial), 3.12 (s, 3 H, NCH3), 1.59 (d, J = 7.2 Hz, 3 H, C4-CH3). 13C NMR (63 MHz, CDCl3) δ = 167.7 (C-3), 160.1 (C-6), 147.8 (C-11a), 147.3 (C-10a), 134.9 (C-9), 127.4 (C-7), 127.0 (C-8 and C-10), 120.1 (C-6a), 52.2 (C-4), 51.6 (C-1), 33.9 (N-CH3), 17.0 (C4-CH3). Anal. Calcd for C13H13N2O3 (243): C, 64.19; H, 5.39; N, 17.27. Found: C, 63.91; H, 5.61; N, 16.98.