Synthesis of Novel Bicyclic Nitroxides Using Partial Favorskii Rearrangement

Abstract

3-Bromo-2,2,6,6-tetramethyl-4-oxopiperidine-1-oxyl was reacted with several C-nucleophiles to give novel bicyclic pyrrolidine nitroxides through partial Favorskii rearrangement. Further reduction with sodium borohydride gave spin probes with free hydroxyl groups and under harsh reduction conditions allowed the Favorskii rearrangement to proceed to completion.

Key words

bicyclic compounds - rearrangements - nitroxide free radicals - spin probes - ring opening

References and Notes

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22

Typical Procedure for the Synthesis of Products 6a-h
3-Bromo-2,2,6,6-tetramethyl-1-oxyl-piperidine-4-one (1, 400 mg, 1.61 mmol) was dissolved in anhyd THF (20 mL). The sodium salt of the appropriate C-nucleophile was dissolved in anhyd THF (5 mL) and added dropwise to the stirred solution of 1 over a period of 5 min under argon. The reaction mixture was refluxed at 50 °C for 1.5 h. After that time the solvent was evaporated under reduced pressure and the yellow solid dissolved in cold citric acid (10 mL, pH 3.5). The aqueous phase was immediately extracted with EtOAc. The organic phase was washed with brine, dried with Na₂SO₄, and the solvent evaporated under reduced pressure. The crude product was purified using circular chromatography (Et₂O-hexane, 3:1). A bright yellow solid was obtained.

23

Methyl 2-Cyano-2-{6-hydroxy-3-oxyl-2,2,4,4-tetramethyl-3-azabicyclo[3.1.0]hex-6-yl}acetate (6g) Yield 37%; yellow solid; mp 120-124 °C. IR (KBr): 3213, 2984, 2257, 1738, 1442, 1306, 1220, 1016, 928, 712 cm^-1. MS (EI): m/z = 267 [M]⁺. ¹H NMR (300 MHz, CDCl₃): δ = 1.28 (s, 2 H, CH), 1.32 (s, 12 H, CH₃), 3.30 (s, 1 H, CH), 3.84 (s, 3 H, COOCH₃) ppm. EPR: a_N = 1.55 mT. Anal. Calcd for C₁₃H₁₉N₂O₄ (%): C, 58.41; H, 7.19; N, 10.48. Found: C, 58.17; H, 7.33; N, 10.71.

24

Dimethyl 2-{6-Hydroxy-3-oxyl-2,2,4,4-tetramethyl-3-azabicyclo[3.1.0]hex-6-yl} Malonate (6e) Yield 75%; yellow solid; mp 146-150 °C. IR (KBr): 3442, 2981, 1742, 1438, 1253, 1179, 1011, 914, 715, 624 cm^-1. MS (EI): m/z = 300 [M]⁺. ¹H NMR (300 MHz, CDCl₃): δ = 1.21 (s, 12 H, CH₃), 1.30 (s, 2 H, CH), 3.15 (s, 1 H, CH), 3.67 (s, 6 H, COOCH₃) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 23.21, 25.36, 31.58, 52.89, 58.09, 61.71, 65.92, 168.32 ppm. EPR: a_N = 1.55 mT. Anal. Calcd for C₁₄H₂₂NO₆ (%): C, 55.98; H, 7.38; N, 4.66. Found: C, 55.78; H, 7.57; N, 4.69.

25

NMR spectra were obtained after reduction with phenyl hydrazine. The compound was dissolved in perdeuterated solvent, transferred into a NMR tube, and flushed with argon. Phenyl hydrazine (2 equiv) was added and the NMR tube shaken to allow the reduction to proceed to completion prior to the NMR spectroscopic analysis.

26

Preparation of tert -Butyl 3-Hydroxy-2-{6-hydroxy-3-oxyl-2,2,4,4-tetramethyl-3-azabicyclo[3.1.0]hex-6-yl)butanoate} (8) tert-Butyl 2-{6-hydroxy-3-oxyl-2,2,4,4-tetramethyl-3-azabicyclo[3.1.0]hex-6-yl}-3-oxobutanoate (6c) (200 mg, 0.61 mmol) was dissolved in MeOH (10 mL) and cooled to 0 °C. Sodium borohydride (24 mg, 0.61 mmol) was added with stirring. The temperature was maintained at 0 °C for 2 h, after which the reaction was quenched with citric acid and the pH adjusted to 6. The solvents were evaporated under reduced pressure and citric acid (10%) was added to adjust the pH to 3. The water phase was extracted with EtOAc. The organic phase was washed with brine, dried with Na₂SO₄, and the solvent evaporated under reduced pressure. The crude product was purified using circular chromatography (Et₂O-hexane, 3:1). A bright yellow solid was obtained; yield 93%; mp 101-108 °C. IR (KBr): 3460, 2976, 1702, 1477, 1375, 1160, 993, 646 cm^-1. MS (EI): m/z = 328 [M]⁺. MS-FAB: m/z = 330 [M + 2]⁺. HRMS (EI): m/z calcd for C₁₇H₃₀N₁O₅: 328.212398 [MH]⁺; found: 328.213250.

27

Preparation of 2-{6-Hydroxy-3-oxyl-2,2,4,4-tetramethyl-3-azabicyclo[3.1.0]hex-6-yl}-1-phenyl-propane-1,3-diol (7) Ethyl 2-{6-hydroxy-3-oxyl-2,2,4,4-tetramethyl-3-azabicyclo[3.1.0]hex-6-yl}-3-oxo-3-phenylpropanoate (6f, 170 mg, 0.47 mmol) was dissolved in MeOH (10 mL) and cooled to 0 °C. While being stirred, NaBH₄ (42 mg, 1.06 mmol) was added. The same amount of NaBH₄ (42 mg, 0.53 mmol) was again added after 1 h and 2 h. After the third addition the reaction mixture was allowed to warm to ambient temperature. Then, 12 h later, citric acid was added and the pH adjusted to 6. The solvents were evaporated under reduced pressure and citric acid (10%) was added to adjust the pH to 3. The water phase was extracted with EtOAc. The organic phase was washed with brine, dried with Na₂SO₄, and the solvent evaporated under reduced pressure. The crude product was purified using circular chromatography (CH₂Cl₂-MeOH, 15:1). A bright yellow solid was obtained; yield 73%; mp 147-157 °C. IR (KBr): 3421, 2978, 1649, 1457, 1287, 1174, 1032, 705 cm^-1. MS (EI): m/z = 320 [M]⁺. HRMS (EI): m/z calcd for C₁₈H₂₆N₁O₄: 320.186184 [MH⁺]; found: 320.187330.

28

Preparation of 1-(1-Oxyl-2,2,5,5-tetramethylpyrrolidine-3-yl)-2-hydroxymethyl-3-phenylpropane-1,3-diol (9a)
Ethyl 2-{6-hydroxy-3-oxyl-2,2,4,4-tetramethyl-3-azabicyclo[3.1.0]hex-6-yl}-3-oxo-3-phenylpropanoate (6f, 300 mg, 0.83 mmol) was dissolved in THF (10 mL), and NaBH₄ (148 mg, 3.72 mmol) was added. The reaction mixture was refluxed at 40 °C and MeOH (0.5 mL) was added over 0.5 h. Following the addition of MeOH the temperature was maintained at 40 °C for another 2.5 h. Several drops of H₂O were then added and the solvents evaporated under reduced pressure, giving a bright yellow foam. Citric acid (10%, 10 mL) was added and the water phase extracted with EtOAc after the evolution of hydrogen stopped. The organic phase was washed with brine, dried with Na₂SO₄, and the solvent evaporated under reduced pressure. The crude product was purified using circular chromatography (CH₂Cl₂-MeOH, 15:1). A bright yellow solid was obtained; yield 21%; mp 157-163 °C. IR (KBr): 3290, 2976, 1474, 1411, 1367, 1295, 1257, 1050, 763, 706 cm^-1. MS (EI): m/z = 322 [M]⁺. MS-FAB: m/z = 322 [M]⁺, 324 [M + 2]⁺. HRMS (EI): m/z calcd for C₁₈H₂₈N₁O₄: 322.201834 [M]⁺; found: 322.202650.