Synlett 2012; 23(16): 2337-2340
DOI: 10.1055/s-0031-1290446
letter
© Georg Thieme Verlag Stuttgart · New York

Efficient Synthesis of 2,5-Diketopiperazines by Staudinger-Mediated Cyclization

Lucas K. Beagle
a  Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA, Fax: +1(352)3929199   Email: Katritzky@chem.ufl.edu
,
Finn K. Hansen
a  Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA, Fax: +1(352)3929199   Email: Katritzky@chem.ufl.edu
b  Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University of Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany
,
Jean-Christophe M. Monbaliu
a  Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA, Fax: +1(352)3929199   Email: Katritzky@chem.ufl.edu
c  Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, 9000 Ghent, Belgium
,
Michael P. DesRosiers
a  Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA, Fax: +1(352)3929199   Email: Katritzky@chem.ufl.edu
,
Angela M. Phillips
a  Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA, Fax: +1(352)3929199   Email: Katritzky@chem.ufl.edu
,
Christian V. Stevens
c  Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, 9000 Ghent, Belgium
,
Alan R. Katritzky*
a  Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA, Fax: +1(352)3929199   Email: Katritzky@chem.ufl.edu
d  Chemistry Department, King Abdulaziz University, Jeddah 21589, Saudi Arabia
› Author Affiliations
Further Information

Publication History

Received: 30 April 2012

Accepted after Revision: 25 June 2012

Publication Date:
10 September 2012 (online)


Abstract

Solution- and solid-phase Staudinger-mediated cyclizations were assessed to efficiently prepare hetero-2,5-diketopiperazines from their protected azido dipeptide thioesters under microwave irradiation. Short reaction time, good yields and ease of purification are the main assets of this methodology.

Supporting Information

 
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  • 43 General Procedure for the Solution-Phase Synthesis of 2,5-Diketopiperazines from Azido Peptide Thioesters 1ac: To a stirred solution of 1ac (1 mmol) in anhyd CH2Cl2 (4 mL), tributylphosphine (0.37 mL, 1.5 mmol) was added and stirring was continued for 5 min at r.t. H2O (0.1 mL, 5 mmol) was added and stirring was continued again for 5 min. The vial was then subjected to microwave irradiation (50 W, 50 °C, 5 min). Hexanes (4 mL) was added to the reaction to induce crystallization and placed in the freezer. The reaction mixture was filtered and the remaining solid was washed with CH2Cl2 (5 mL) and hexanes (15 mL) and dried under vacuum to yield pure 2ac. General Procedure for the Solid-Phase Synthesis of 2,5-Diketopiperazines from Supported Azido Peptide Thioesters 1df: To a stirred suspension of 1df (1 mmol) in anhyd CH2Cl2 (4 mL), tributylphosphine (0.37 mL, 1.5 mmol) was added and stirring was continued for 5 min at r. t. H2O (0.1 mL, 5 mmol) was added and stirring was continued again for 5 min. The vial was then subjected to microwave irradiation (50 W, 50 °C, 5 min). The solids were filtered and washed with CH2Cl2, the remaining solid was treated with hot MeOH and the resulting mother liquor was collected. The mother liquor was cooled in the freezer and the precipitate was collected and dried under vacuum to yield pure 2ac. (S)-3-Isobutylpiperazine-2,5-dione (2a): Yield: 78% (0.13 g); white microcrystals; mp 248.0–250.0 °C. 1H NMR (300 MHz, DMSO-d 6): δ = 8.26 (br s, 1 H), 7.99 (br s, 1 H), 3.79–3.89 (m, 1 H), 3.56–3.70 (m, 2 H), 1.69–1.84 (m, 1 H), 1.49–1.56 (m, 2 H), 0.89 (d, J = 6.7 Hz, 3 H), 0.87 (d, J = 6.6 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ = 168.8, 166.3, 52.9, 44.2, 42.1, 23.6, 22.9, 21.8. Anal. Calcd for C8H14N2O2: C, 56.45; H, 8.29; N, 16.46. Found: C, 56.63; H, 8.41; N, 16.28. (S)-3-Benzylpiperazine-2,5-dione (2b): Yield: 74% (0.15 g); white microcrystals; mp 251.0–252.0 °C. 1H NMR (300 MHz, DMSO-d 6): δ = 8.11–8.18 (m, 1 H), 7.84–7.90 (m, 1 H), 7.21–7.32 (m, 3 H), 7.10–7.18 (m, 2 H), 4.02–4.09 (m, 1 H), 3.26–3.42 (m, 2 H), 3.08 (dd, J = 13.5, 4.4 Hz, 1 H), 2.87 (dd, J = 13.5, 4.9 Hz, 1 H). 13C NMR (75 MHz, CDCl3): δ = 167.4, 166.0, 136.1, 130.2, 128.3, 127.0, 55.7, 43.8. Anal. Calcd for C11H12N2O2: C, 64.49; H, 5.92; N, 13.72. Found: C, 64.43; H, 6.06; N, 13.65. (S)-3-Methylpiperazine-2,5-dione (2c): Yield: 78% (0.10 g); white microcrystals; mp 236–238 °C. 1H NMR (300 MHz, DMSO-d 6): δ = 8.17 (br s, 1 H), 7.99 (br s, 1 H), 3.88 (dq, J = 0.6, 6.9 Hz, 1 H), 3.76 (s, 2 H), 1.30 (d, J = 6.9 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ = 168.8, 166.2, 49.7, 44.5, 18.6. HRMS (ESI): m/z [M + H] calcd for C5H9N2O2: 129.0795; found: 130.1637