Pyrroloimidazolediones Derived from Aminomalonates and Benzaldehydes

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

• References and Notes

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• 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; R_f = 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%). R_f = 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; R_f  = 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, HC_Ar). 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 (C_AR), 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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