A One-Pot Preparation of 5-Oxo 2,4-Disubstituted 2,5-Dihydro-1H-imidazol-2-carboxylates from α-Bromo Esters

Abstract

Nucleophilic substitution of a bromine atom by the azide group in aryl- and heteroaryl-α-bromoacetates triggers cascade reactions leading to imidazolin-5-ones formation. The α-azidoacetate intermediates undergo a transformation into non-isolable 2-imino esters that dimerize giving the heterocyclic imidazoline system. The process described is strongly promoted by dipolar aprotic solvents (DMF, DMSO) and could be realized under base- and metal-free conditions.

azides - cyclization - substitution - imidazolin-5-ones - nitrenes

References and Notes

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^¹H NMR (600 MHz, DMSO-d ₆): δ = 11.25 (s, 1 H, NH), 8.38 (d, 2 H, J _HH = 7.8 Hz, CH_Ar), 7.62 (m, 2 H, CH_Ar), 7.54 (t, 2 H, J _HH = 7.8 Hz, CH_Ar), 7.44 (t, 2 H, J _HH = 7.8 Hz, CH_Ar), 7.40 (t, 2 H, J _HH = 7.2 Hz, CH_Ar), 4.17 (q, 2 H, J _HH = 7.2 Hz, CH₃CH ₂O), 1.14 (t, 3 H, J _HH = 7.2 Hz, CH ₃CH₂O). ^¹³C NMR (150 MHz, DMSO-d ₆): δ = 167.7, 164.8, 162.9, 137.3, 132.3, 129.6, 128.8, 128.7, 128.4, 128.3, 126.5, 86.5, 62.5, 13.8. All 2D NMR experiments for 3a were carried out using DMSO-d ₆ as a solvent. COSY correlation list: δ [ppm]-δ [ppm](assignment): 1.14-4.17 (CH ₃CH₂O), 4.17-1.14 (CH₃CH ₂O), 7.40-7.44 (p-CH), 7.44-7.40, 7.62 (m-CH), 7.54-7.62, 8.38 (m-CH), 7.62-7.54 (p-CH), 7.62-7.44 (o-CH), 8.38-7.54 (o-CH). HSQC: correlation list: ^¹³C shift [ppm]-^¹H shift [ppm](assignment): 13.7-1.14 (CH ₃CH₂O), 62.5-4.17 (CH₃ CH ₂O), 126.5-7.62 (o-CH), 128.3-8.38 (o-CH), 128.4-7.44 (m-CH), 128.7-7.54 (m-CH), 128.8-7.40 (p-CH), 132.3-7.62 (p-CH). HMBC: correlation list: ^¹H shift [ppm]-^¹³C shifts [ppm] (atom connectivity): 1.14-62.5 (ester group CH ₃ CH₂O), 4.17-13.7 and 167.7 (ester group CH₃CH ₂OCO), 7.40-126.5 (p-CH and C-2, phenyl group A), 7.44-126.5, 128.8 and 137.4 (m-CH and C-2, C-4, C-1, phenyl group A), 7.54-128.3, 129.6 (m-CH and C-2, C-1, phenyl group B), 7.62-86.9, 126.5 and 128.8 (o-CH and quaternary C-2 of the imidazolidine ring, C-2, C-4, phenyl group A), 7.62-128.3 (p-CH and C-2, phenyl group B), 8.38-128.7, 132.3 and 162.9 (o-CH and C-3, C-4 in phenyl group B and C=N in the imidazolidine ring), 11.25-86.9, 162.9 and 164.8 (NH group and quaternary C-2, C=N and C=O in the imidazolidine ring). According to HMBC data, phenyl substituents A and B were attached to the imidazolidine ring at C-2 and C-4, respectively.

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General Method for Preparation of Imidazolin-5-ones 3 from α-Bromoacetates; Representative One-Pot Synthesis of Ethyl 2,4-Bis(4-ethoxyphenyl)-5-oxo-2,5-dihydro-1 H -imidazole-2-carboxylate (3d): Ethyl α-bromo-2-(4-ethoxyphenylacetate) (4d; 1.254 g, 4.4 mmol) and sodium azide (0.428 g, 6.6 mmol, 1.5 equiv) were added to DMF (20 mL). The suspension was stirred and heated for 24 h at 80 ˚C. After cooling, the reaction mixture was poured into H₂O (100 mL) and extracted with EtOAc (3 × 30 mL). The combined extracts were washed with H₂O (2 × 50 mL) and dried over anhyd Na₂SO₄. The mixture was filtered and the solvent was removed under reduced pressure. The crude product was purified by column chromatography using silica gel (230-400 mesh; CHCl₃-MeOH, 30:1) to give 3d as colorless crystals (TLC silica gel; Fluka 60778; CHCl₃-MeOH, 30:1; R _f 0.55); mp 132 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 8.48 (d, 2 H, J _HH = 9.1 Hz, CH_Ar), 8.40 (br s, 1 H, NH), 7.50 (d, 2 H, J _HH = 9.0 Hz, CH_Ar), 6.95 (d, 2 H, J _HH = 9.1 Hz, CH_Ar), 6.89 (d, 2 H, J _HH = 9.0 Hz, CH_Ar), 4.25 (2 × dq, 2 H, J _HH = 7.11, 7.14, 10.7 Hz, OCH₂), 4.10 (q, 2 H, J _HH = 7.0 Hz, OCH₂), 4.02 (q, 2 H, J _HH = 7.0 Hz, OCH₂), 1.44 (t, 3 H, J _HH = 7.0 Hz, Me), 1.40 (t, 3 H, J _HH = 7.0 Hz, Me), 1.26 (t, 3 H, J _HH = 7.1 Hz, Me). ^¹³C NMR (75 MHz, CDCl₃): δ = 168.3 (COOEt), 165.7 (CONH), 162.3 (C=N), 161.6 (C4), 159.5 (C4), 130.8 (C3), 129.0 (C1), 127.4 (C3), 122.3 (C1), 114.6 (C2), 114.4 (C2), 86.0 (C2-imidazolidine), 63.6 (OCH₂), 63.5 (OCH₂), 62.9 (OCH₂), 14.7 (Me), 14.7 (Me), 14.0 (Me). IR (neat): 3168, 3071, 2979, 2936, 1742, 1705, 1595, 1571, 1512, 1237, 1172 cm^-¹. Anal. Calcd for C₂₂H₂₄N₂O₅: C, 66.65; H, 6.10; N, 7.06. Found: C, 66.45; H, 6.01; N, 7.10.

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Standard Procedure for Synthesis of α-Bromoacetates from Commercial Ethyl Aryl- and Heteroarylacetates; Representative Preparation of Ethyl Bromo(4-ethoxy-phenyl) Acetate (4d): Ethyl 4-ethoxyphenylacetate (1.695 g, 8.14 mmol) was treated with NBS (1.449 g, 1 equiv) and Luperox® A70S (0.176 g, 0.50 mmol) in CCl₄ (30 mL). The reaction mixture was stirred and heated for 30 h at 74 ˚C. After cooling the solution was filtered through a Celite pad and the solvent was evaporated. The crude product, ethyl bromo(4-ethoxyphenyl) acetate (4d), was pure enough to be used for the next step.

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Partial NMR data for diethyl iminomalonate were determined from the crude reaction mixture. ^¹H NMR (300 MHz, CDCl₃): δ = 11.76 (br s, 1 H, NH), 4.29 (q, 2 H, J _HH = 7.1 Hz, OCH₂), 1.30 (t, 3 H, J _HH = 7.1 Hz, Me). ^¹³C NMR (75 MHz, CDCl₃): δ = 161.0 (COOEt), 152.3 (C=NH), 61.6 (OCH₂), 14.3 (Me).