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Synlett 2005(7): 1158-1160  
DOI: 10.1055/s-2005-865205
LETTER
© Georg Thieme Verlag Stuttgart · New York

Solvent-Free, Efficient Synthesis of 2,5-Piperazinediones from Boc-Protected Dipeptide Esters under Microwave Irradiation

Alberto López-Cobeñas, Pilar Cledera, J. Domingo Sánchez, Rafael Pérez-Contreras, Pilar López-Alvarado, M. Teresa Ramos, Carmen Avendaño, J. Carlos Menéndez*
Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
e-Mail: josecm@farm.ucm.es;
Further Information

Publication History

Received 20 November 2005
Publication Date:
14 April 2005 (online)

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Abstract

Microwave irradiation allows the efficient, solvent-free transformation of N-Boc dipeptide esters into 2,5-piperazinediones. The microwave-assisted conditions were found to be much better than traditional heating in terms of reaction time, yield and stereocenter integrity.

Key words

microwave irradiation - diketopiperazines - dipeptides - cyclizations - heterocycles

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13

Representative Procedure.
A glass vial containing N′-Boc-Val-(N-3-indolylmethyl)-Gly-OEt (170 mg, 0.39 mmol) was submerged in alumina, contained in a beaker, and irradiated for 5 min at 600 W in a domestic microwave oven. Recrystallization from acetone gave diketopiperazine 3e (91 mg, 90%) as a white solid; mp 228-229 °C; [α]D 23 6.0 (c 0.4 g/100 mL in MeOH). IR (KBr): 3403, 3559, 1682, 1647, 742 cm-1. 1H NMR (250 MHz, CDCl3): δ = 8.23 (br s, 1 H, NHindole), 7.71 (d, 1 H, J = 7.5 Hz, H-4′), 7.37 (d, 1 H, J = 8.0 Hz, H-7′), 7.20-7.09 (m, 3 H, H-2′,5′,6′), 6.15 (br s, 1 H, H-4), 4.90 and 4.71 (AB system, 2 H, J = 14.5 Hz, N-CH2), 3.92-3.89 (m, 1 H, H-3), 3.85 (s, 2 H, H-6), 2.51-2.41 [m, 1 H, CH(CH3)2], 1.00 and 0.82 [2 d, 3 H, J = 7.0 Hz, CH(CH 3)2] ppm. 13C NMR (63 MHz, CDCl3): δ = 166.3, 165.2, 136.2, 127.7, 124.7, 122.8, 120.3, 119.2, 111.4, 110.1, 61.0, 48.3, 40.8, 33.0, 19.0, 16.1 ppm. Anal. Calcd for C16H19N3O2 (M = 285): C, 67.36; H, 6.66; N, 14.73. Found: C, 66.92; H, 6.33; N, 14.53.