A Novel Entry to 3,4,5-Trisubstituted 2-Pyrrolidones from Isoxazoline-N-oxides

Abstract

A novel strategy for the synthesis of stereochemically defined 3,4,5-trisubstituted 2-pyrrolidones was developed. The suggested approach involves reductive domino-type recyclization of 3-aminomethyl-substituted isoxazolines as a key stage. The latter are prepared via α-C–H functionalization of readily available isoxazoline-N-oxides.

Key words

2-pyrrolidones - isoxazolines - reduction - C–H functionalization - azides

• References and Notes

• 1 Present address: A.N. Nesmeyanov Institute of Organoelement Compounds, Vavilov Str. 28, 119991, Moscow, Russia.
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• 13 Typical Procedure To a stirred solution of isoxazoline-N-oxide 3b (573 mg, 2.3 mmol) in CH₂Cl₂ (10 mL) cooled to –20 °C was added Et₃N (0.96 mL, 6.9 mmol) followed by (CH₃)₃SiBr (0.6 mL, 4.6 mmol) under argon atmosphere. The reaction mixture was stirred for 20 min at –20 °C and then kept in a freezer (ca. –18 °C) for 72 h with occasional shaking. The resulting mixture was warmed up to rt, and a solution of ZnBr₂ (517 mg, 2.3 mmol) in THF (20 mL) was added. The mixture was stirred until dissolution of precipitate and then kept overnight at rt. The resulting solution was poured into methyl tert-butyl ether (100 mL) and 0.25 M NaHSO₄ solution (50 mL). The aqueous layer was back-extracted with methyl tert-butyl ether (50 mL). Combined organic layers were washed with water (50 mL) and brine (50 mL), dried (Na₂SO₄), and evaporated in vacuum to give crude bromide 7b. The latter was dissolved in acetone (25 mL), then NaN₃ (598 mg, 9.2 mmol), NaI (35 mg, 0.23 mmol), and water (3 mL) were added. The reaction mixture was intensively stirred for 3 h at rt and then poured into methyl tert-butyl ether (100 mL) and water (50 mL). The aqueous layer was back-extracted with methyl tert-butyl ether (50 mL). Combined organic layers were washed with water (50 mL) and brine (50 mL), dried (Na₂SO₄), and evaporated in vacuum. The residue was subjected to column chromatography on silica gel (eluent hexane/EtOAc = 7:1 → 5:1 → 3:1) to give 470 mg (74% based on nitronate 3b) of azide 2b as a colorless oil. ¹H NMR spectrum of product 2b is in agreement with literature data.^11a (Alternatively, azide 2b can be prepared from isoxazoline-N-oxide 3b following method described in ref.^11a in 40% yield).

For reduction of isoxazolines, see:
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• 15 Typical Procedure To a stirred solution of azide 2b (700 mg, 2.55 mmol) in THF (13 mL) was added PPh₃ (836 mg, 3.19 mmol) in several portions with intensive stirring. After 30 min (gas evaluation completed) water (0.195 mL, 10.8 mmol) was added. After 16 h di(tert-butyl)dicarbonate (1.30 g, 6.0 mmol) was added, and the mixture was stirred for additional 24 h. Then, volatiles were removed in vacuum, and the residue was subjected to column chromatography on silica gel (eluent hexane/EtOAc = 7:1 → 5:1 → 3:1) to give 860 mg (97%) of Boc-protected amine Boc-8b. Ethyl rel-(4S,5S)-3-{[(tert-Butoxycarbonyl)-amino]methyl}-4-phenyl-4,5-dihydroisoxazole-5-carboxylate (Boc-8b) Oil. R_f = 0.66 (hexane/EtOAc, 1:1). ¹H NMR (300 MHz, CDCl₃): δ = 7.40–7.27 (m, 3 H, m,p- C₆H₅), 7.25–7.15 (d, J = 7.5 Hz, 2 H, o-C₆H₅), 4.95 (br m, 1 H, NH), 4.89 (d, J = 5.2 Hz, 1 H, 5-H), 4.58 (d, J = 5.2 Hz, 1 H, 4-H), 4.25 (q, J = 7.2 Hz, 2 H, OCH ₂CH₃), 3.98–3.86 (br m, 2 H, CH ₂NH), 1.38 (s, 9 H, C(CH₃)₃), 1.30 (t, J = 7.1 Hz, 3 H, OCH₂CH ₃). ¹³C NMR (75 MHz, JMOD, CDCl₃): δ = 169.46 (OC=O), 158.11 and 155.29 (3-C and HNC=O), 136.57 (i-C₆H₅), 129.40, 128.38 and 127.46 (o-C₆H₅, m-C₆H₅, and p-C₆H₅), 85.73 (5-C), 79.78 (O-C(CH₃)₃), 61.95 (OCH₂CH₃), 58.76 (4-C), 36.70 (CH₂NH), 28.21 (C(CH₃)₃), 14.06 (OCH₂ CH₃). HRMS: m/z calcd for [C₁₈H₂₅N₂O₅]⁺: 349.1758; found: 349.1754.
• 16 Unfortunately, direct catalytic hydrogenation of model isoxazoline 2f (conditions: 70 bar H₂, 70 °C, CH₃OH, PtO₂ catalyst, 25 mol%) in the presence of Boc₂O led to a complex mixture of indecipherable products, in which target pyrrolidone Boc-1f was not detected.
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• 18 Typical Procedure Platinum dioxide (30 mg) was placed in a vial equipped with a magnetic stirrer bar and charged with a solution of isoxazoline Boc-8b (180 mg, 0.517 mmol) in CH₃OH (5 mL). The vial was placed in a steel autoclave which was then flushed and filled with H₂ to a pressure of 70 bar and the mixture was stirred at 70°C for 9 h. Then, the autoclave was cooled to rt and slowly depressurized. The solution was filtered through Celite and concentrated in vacuum. The residue was subjected to column chromatography on silica gel (eluent CH₂Cl₂/CH₃OH = 20:1 → 10:1) to give 137 mg (87%) of pyrrolidone Boc-1b as white solid (d.r. 5.1:1). Two fractions were collected, first one contained pure all-cis isomer, second fraction contained ca. 3:1 mixture of all-cis and 4,5-trans isomers. [tert-Butyl (4-hydroxy-3-phenyl-5-oxopyrrolidin-2-yl) methyl]carbamate (Boc-1b) Mp 211–212 °С. R_f = 0.12 (CH₂Cl₂/2-PrOH, 20:1). ¹H NMR (400 MHz, DMSO-d ₆, COSY, NOESY, HSQC, all-cis-Boc-1b): δ = 7.72 (s, 1 H, NH), 7.31–7.12 (m, 5 H, o,m,p-C₆H₅), 6.59 (br t, 1 H, NHBoc), 5.80–5.00 (br, 1 H, OH), 4.41 (d, J = 7.0 Hz, 1 H, 3-H), 3.80–3.72 (m, 1 H, 5-H), 3.66 (dd, J = 7.0, 5.9 Hz, 1 H, 4-H), 2.85–2.71 and 2.45–2.32 (2 m, 1 H and 1 H, CH₂N), 1.35 (s, 9 H, C(CH₃)₃). ¹³C NMR (101 MHz, CDCl₃, HSQC, all-cis-Boc-1b): δ = 176.36 (C=O), 155.32 (OC=O), 135.74 (i-C₆H₅), 129.85, 127.56 and 126.52 (o,m,p-C₆H₅), 77.87 (C(CH₃)₃), 70.51 (3-C), 53.56 (5-C), 48.62 (4-C), 42.84 (CH₂N), 28.12 (C(CH₃)₃). Characteristic 2D NOESY correlations: H-3/H-4, H-3/H-5, H-4/H-5, H-5/CH₂N, Ph/CH₂N. ¹H NMR (400 MHz, DMSO-d ₆, COSY, NOESY, HSQC, 4,5-trans- Boc-1b): δ = 7.85 (s, 1 H, NH), 7.31–7.12 (m, 5 H, o,m,p-C₆H₅), 6.86 (br t, 1 H, NHBoc), 5.80–5.00 (br, 1 H, OH), 4.14 (d, J = 7.2, 1 H, 3-H), 3.71–3.67 (m, 1 H, 5-H), 3.28–3.23 (m, 1 H, 4-H), 3.18–3.06 and 2.99–2.89 (2 m, 1 H and 1 H, CH₂N), 1.35 (s, 9 H, C(CH₃)₃). ¹³C NMR (101 MHz, CDCl₃, HSQC, 4,5-trans- Boc-1b): δ = 175.22 (C=O), 155.66 (OC=O), 138.09 (i-C₆H₅), 129.07, 127.72 and 126.32 (o,m,p-C₆H₅), 79.11 (C(CH₃)₃), 70.39 (3-C), 57.58 (5-C), 48.76 (4-C), 43.75 (CH₂N), 28.12 (C(CH₃)₃). Characteristic 2D NOESY correlations: H-3/H-4, H-4/CH₂N. HRMS: m/z calcd for [C₁₆H₂₃N₂O₄]⁺: 307.1652; found: 307.1647.