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

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

References

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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, NH_indole), 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.