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Synlett 2021; 32(19): 1969-1973
DOI: 10.1055/s-0040-1720888
letter

Pyrroloimidazolediones Derived from Aminomalonates and Benzaldehydes

Lewis O’Shaughnessy
a   The Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK
,
Charles Hutchinson
a   The Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK
,
Adam Waldron
a   The Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK
,
Kirsten E. Christensen
a   The Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK
,
Mark G. Moloney∗
a   The Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK
b   Oxford Suzhou Centre for Advanced Research, Building A, 388 Ruo Shui Road, Suzhou Industrial Park, Jiangsu, 215123, P. R. of China
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Abstract

Bicyclic lactams can be prepared from diethyl aminomalonate and substituted benzaldehydes by formation of a dimerised imidazolidine cycloadduct followed by a Dieckmann ring closure. The resulting N,N-heterocycles are metal-chelating but show no antibacterial activity.

Key words

amino acids - heterocycles - cyclization - lactams - ­Dieckmann reaction

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0040-1720888.
  • Supporting Information


Publication History

Received: 09 August 2021

Accepted after revision: 03 September 2021

Article published online:
28 September 2021

© 2021. Thieme. All rights reserved

Georg Thieme Verlag KG
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  • References and Notes

  • 2 Andrews MD, Brewster AG, Crapnell KM, Ibbett AJ, Jones T, Moloney MG, Prout K, Watkin D. J. Chem. Soc., Perkin Trans. 1 1998; 223
  • 5 Diethyl (±)-(2R ∗,5S ∗)-1-[2-Ethoxy-1-(ethoxycarbonyl)-2-oxoethyl]-2,5-diphenylimidazolidine-4,4-dicarboxylate (6a); Typical Procedure Diethyl aminomalonate (1000 mg, 5.71 mmol), benzaldehyde (606 mg, 5.71 mmol, 1.0 equiv), and MgSO4 were added to dry CH2Cl2 (20 mL), and the mixture was refluxed for 16 h. The mixture was then filtered and the solvent was evaporated to yield a crude product that was purified by column chromatography [silica gel, EtOAc–PE (10 to 40%)] to give colourless crystals; yield: 1192.4 mg (79%); mp 109–110 °C; Rf = 0.733 (30% EtOAc). IR: 1741, 1725, 1169 cm–1. 1H NMR (200 MHz, CDCl3, TMS): δ = 0.78 (t, J = 7.1, 3 H, CH3CH2), 1.05 (t, J = 7.1 Hz, 3 H, CH3CH2), 1.12 (t, J = 7.1 Hz, 3 H, CH3CH2), 1.28 (t, J = 7.1 Hz, 3 H, CH3CH2), 3.30 (dq, J = 10.7, 7.2 Hz, 1 H, CH2 CH3), 3.65 (d, J = 10.0 Hz, 1 H, NH), 3.79 (m, 5 H, CH2 CH3), 4.07 [s, 1 H, CH(N)(CO2Et)2], 4.27 (dq, J = 10.7, 7.1 Hz, 1 H, CH2 CH3), 4.45 (dq, J = 10.7, 7.2 Hz, 1 H, CH2 CH3), 5.28 [d, J = 10.0 Hz, 1 H, (N)CH(N)(Ph)], 5.63 [s, 1 H, CHPh(N)(C)], 7.44 (m, 10 H, aromatic). 13C (400 MHz, CDCl3, TMS): δ = 13.33, 13.73, 13.85, 13.99 (CH3), 61.11, 61.11, 62.11, 62.18 (CH2CH3), 62.21 [CH(N)(CO2Et)2], 67.64 [CH(N)(Ph)(C)], 77.11 [C(N)(C)(CO2Et)2], 78.36 [CH(N)2(Ph)], 127.85, 127.98, 128.51, 128.59, 129.27 (H–C Ar), 137.99, 138.88 (C–C Ar), 166.59, 166.77, 168.32, 169.59 (C=O). HRMS (ESI+): m/z [M + H]+ calcd for C28H35N2O8; 527.23829; found: 527.23847. Diethyl (±)-(2S ∗,5S ∗)-1-[2-Ethoxy-1-(ethoxycarbonyl)-2-oxoethyl]-3-(3-ethoxy-3-oxopropanoyl)-2,5-diphenylimidazolidine-4,4-dicarboxylate (8a); Typical Procedure Diester 6a (285.0 mg, 0.542 mmol) was dissolved in CH2Cl2 (20 mL) together with pyridine (85.4 mg, 1.08 mmol, 2.0 equiv) and DMAP (6.6 mg, 0.054 mmol, 0.1 equiv). The mixture was stirred and cooled to 0 °C, and a solution of ethyl 3-chloro-3-oxopropanoate (163.1 mg, 1.084 mmol, 2.0 equiv) in CH2Cl2 (5 mL) was added dropwise. The mixture was stirred for a further 15 minutes at 0 °C then refluxed for 16 h. The resulting mixture was diluted with CH2Cl2 (30 mL), washed successively with sat. aq NH4Cl, 10% aq NaHCO3, and brine. The organic layers were dried (MgSO4), combined, and evaporated under vacuum to yield a crude product that was purified by column chromatography (silica gel, 20% EtOAc–PE) to give a pale oil; yield: 302 mg (87%). Rf = 0.269 (50% EtOAc–PE). IR: 2981.33, 1736.66, 1668.24, 1235.45, 155.15, 1030.11, 700.24 cm–1. 1H NMR (400 MHz, CDCl3, TMS): δ = 0.92 (t, J = 7.1 Hz, 3 H, CH3 CH2), 1.05–1.12 (2 × t, J = 7.2 Hz, 6 H, CH3 CH2), 1.20 (t, J = 7.1 Hz, 3 H, CH3 CH2), 1.38 (t, J = 7.1 Hz, 3 H, CH3 CH2), 2.56 [d, J = 15.7 Hz, 1 H, C(O)CH2 C(O)], 2.92 [d, J = 15.6 Hz, 1 H, C(O)CH2C(O)], 3.41 (m, 1 H, CH3 CH2 ), 3.65 (dq, J = 10.8, 7.2 Hz, 1 H, CH3 CH2 ), 3.76 (dq, J = 13.5, 6.8 Hz, 2 H, CH3 CH2 ), 3.87 (dq, J = 13.5, 6.8 Hz, 2 H, CH3CH2), 4.05 (q, J = 6.9 Hz, 2 H, CH3 CH2 malonate), 4.06 [s, 1 H, CH(CO2Et)2(N)], 4.37, (m, 2 H, CH3 CH2 ), 5.04 [s, 1 H, CH(Ph)(N)(C)], 6.25 [s, 1 H, CH(Ph)(N)2], 7.31–7.86 (m, 10 H, CHAr). 13C (400 MHz, CDCl3, TMS): δ = 13.46, 13.72, 13.80, 14.03 (CH3CH2), 42.93 [CH2(CO2Et)(CON)], 61.17, 61.45, 61.54, 62.37 (CH3 CH2), 61.82 [CH(CO2Et)2(N)], 70.10 [CH(Ph)(N)(C)], 78.06 [CH(Ph)(N)2], 128.21 (C–CAr), 128.66, 128.87, 130.28 (H–CAr), 165.63, 165.73, 166.22, 166.36 [C(O)OEt]. HRMS (ESI+): m/z [M + H]+ calcd for C33H41N2O11: 641.27049; found: 641.26913. Diethyl (±)-(1S *,3S *)-2-[2-Ethoxy-1-(ethoxycarbonyl)-2-oxoethyl]-5,7-dioxo-1,3-diphenyltetrahydro-1H-pyrrolo[1,2-c]imidazole-6,7a(5H)-dicarboxylate (10a); Typical Procedure Diester 8a (1195 mg, 1.86 mmol) was dissolved in dry THF (50 mL) with KOt-Bu (220.0 mg, 1.05 equiv, 1.96 mmol), and the mixture was refluxed for 16 h. The mixture was then concentrated and the residue was redissolved in Et2O (50 mL) and extracted with H2O (2 × 50 mL). The aqueous phase was acidified with 2 M aq HCl to pH 2 and extracted with EtOAc (3 × 100 mL). The organic phases were combined, dried (MgSO4), and concentrated to yield a crude product that was then purified by column chromatography (silica gel, 50% EtOAc–PE to 10% MeOH–EtOAc). The resulting product was washed twice with 2 M aq HCl and once with sat. aq NH4Cl to yield the pure product as colourless crystals; yield: 388.9 mg (35%); mp 93 °C; 388.9; Rf  = 0.706 (10% MeOH–EtOAc). IR: 2984, 2361, 1733, 1243, 1186, 1029 cm–1. 1H NMR (400 MHz, CDCl3, TMS): δ = 0.67 (t, J = 7.1 Hz, 3 H, CH2 CH3 ), 0.97 (t, J = 7.1 Hz, 3 H, CH2 CH3 ), 1.13 (t, J = 7.2 Hz, 3 H, CH2 CH3 ), 1.43 (t, J = 7.1 Hz, 3 H, CH2 CH3 ), 3.55 (3 H, m, 3 H, CH2 CH3), 3.67 (dd, J = 10.8, 7.1 Hz,1 H, CH2 CH3), 3.73 (m, 1 H, CH2 CH3), 3.97 (m, 2 H, CH2 CH3), 4.34 [s, 1 H, CH(CO2Et)2(N)], 4.42 (q, J = 6.7 Hz, 2 H, CH2 CH3), 4.95 [s, 1 H, CHPh(N)(C)], 6.37 [s, 1 H, CHPh(N)2], 7.17–7.77 (m, 10 H, HCAr). 13C (400 MHz, CDCl3, TMS): δ = 113.16, 13.46, 13.83, 14.20 (CH3CH2), 61.65, 61.81, 61.96, 62.06 (CH3 CH2), 63.92 [CH(CO2Et)2(N)], 69.50 [CHPh(N)(C)], 74.93 [CHPh(N)2], 127.27, 127.49, 127.83, 127.96, 128.45, 128.57, 128.92 (CAR), 134.55 [C(CO2Et)(N)(CO)(C)], 165.79 (C=O). HRMS (ESI–): m/z [M – H]– calcd for C31H33N2O10: 593.21407; found: 593.21393.
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