A Novel Method for the Synthesis of N-Alkoxyamines Starting from Nitroxide Radicals and Ketones

Abstract

A new reaction for the conversion of stable nitroxide radicals into the corresponding N-alkoxyamines by means of a copper-catalyzed ketone-hydrogen peroxide reaction is reported.

Key words

piperidines - radical reactions - peroxides - N-alkoxy­amines - polymer light stabilizer

References and Notes

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  See also ref. 5.

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  See also ref. 3a.

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8

General Procedure for the Synthesis of N -Alkoxyamines Prostab 5198^TM (2.50 g, 14.5 mmol) was dissolved in 4-heptanone (18.5 mL, 132.2 mmol), and 30% aq H₂O₂ (10 mL, 97.1 mmol) was added dropwise. Upon cooling to 10 ˚C, CuCl (100 mg, 7 mol%) was added. The reaction mixture was stirred overnight at r.t. to give a greenish solution. A peroxide test conducted at this stage indicated no residual H₂O₂. EtOAc (80 mL) was added and the two phases were separated. The organic phase was washed successively with 10% ascorbic acid soln, H₂O, 10% Na₂CO₃ soln, and brine. After drying over sodium sulfate and removal of the solvent, a green-brown oil was obtained. The product was purified by column chromatography on SiO₂ (hexane-EtOAc, 15:1) to afford 1.75 g (60%) of 1-propoxy-2,2,6,6-tetramethylpiperidin-4-ol; off-white solid. ^¹H NMR (400 MHz, CDCl₃): d = 3.95 (dddd, J = 14.4, 10.4, 3.6, 3.2 Hz, 1 H), 3.70 (q, J = 9.2 Hz, 2 H), 1.80 (dd, J = 14.4, 3.2 Hz, 2 H), 1.70 (br s, 1 H, OH), 1.53 (m, 2 H), 1.46 (dd, J = 10.4, 3.6 Hz, 2 H), 1.24 (2 s, 6 H), 1.15 (2 s, 6 H), 0.95 (t, J = 10.0 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): d = 78.4 (s), 63.3 (t), 60.0 (2 q), 48.3 (2 s), 33.2 (2 p), 21.9 (s), 21.0 (2 p), 10.9 (p). IR (neat): 3279, 2969, 2933, 2877, 1478, 1470, 1371, 1357, 1256, 1194, 1066, 1044, 984, 950 cm^-¹. MS: m/z = 216 [M - H]⁺.

9

Commercial Product of Ciba Inc.

10

TEMPO works equally well. This method should also be applicable to other nitroxyl radicals.

13

General Procedure for the Synthesis of N -Alkoxyamines Using Solvents Prostab 5198^TM (8.6 g, 49.9 mmol) was added to toluene (100 mL), followed by 1-methoxyacetone (11.0 g, 2.5 equiv) and CuCl (125 mg, 2.5 mol%). The mixture was stirred well while adding 30% aq H₂O₂ (17.8 mL, 3.5 equiv) over a period of 1 h. The reaction mixture was stirred at r.t. overnight. Workup: as reported in ref. 8. Yield 8.89 g (82%) of 1-methoxymethyl-2,2,6,6-tetramethylpiperidin-4-ol, off-white solid; NOCH₂OMe/NOMe ratio = ca. 13.5:1. ^¹H NMR (300 MHz, CDCl₃): d = 4.01 (m, 1 H), 3.82 (s, 3 H), 1.89 (dd, J = 14.2, 3.6 Hz, 2 H), 1.82 (br s, 1 H), 1.67 (dd, J = 11.0, 3.6 Hz, 2 H), 1.21 (2 s, 6 H), 1.15 (2 s, 6 H). ^¹³C NMR (75 MHz, CDCl₃): d = 103.1 (s), 63.5 (2q), 60.1 (t), 56.9 (p), 48.6 (2s), 33.7 (2 p), 21.5 (2 p). IR (neat): 3239, 3005, 2972, 2933, 1467, 1363, 1343, 1245, 1148, 1070, 1003, 929 cm^-¹. MS: m/z = 218 [M - H]⁺.

15

General Procedure for the Synthesis of N -Alkoxyamines under Acidic Conditions Prostab 5198^TM (25.1 g, 145.1 mmol) was dissolved in 2-butanone (105 mL), and 30% aq H₂O₂ (50.0 mL, 485.3 mmol, ca. 3 equiv) was added over 10 min. Upon cooling to 5 ˚C, CuCl (0.71 g, 7.2 mmol, 5 mol%) was added and the temperature was kept between 10 ˚C and 15 ˚C. After 15-30 min, the pH of the reaction mixture was slowly adjusted to ca. 3.2 using 1 N HCl. The brownish solution was stirred overnight at r.t. while keeping the pH value at around 3.5 using a dosimat. A green homogeneous solution was obtained after 12 h. Workup: as reported in ref. 8. Yield: 22.9 g (114 mmol, 78%) of 1-ethoxy-2,2,6,6-tetramethyl-piperidin-4-ol, solid, NOEt/NOMe ratio = ca. 9:1. ^¹H NMR (400 MHz, CDCl₃): d = 3.93 (dddd, J = 14.4, 11.6, 5.6, 3.6 Hz, 1 H), 3.77 (q, J = 9.6 Hz, 2 H), 1.81 (dd, J = 14.4, 5.6 Hz, 2 H), 1.45 (dd, J = 11.6, 3.6 Hz, 2 H), 1.22 (2 s, 6 H), 1.18 (2 s, 6 H), 1.10 (t, J = 9.2 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): d = 72.3 (s), 63.3 (t), 59.8 (2 q), 48.2 (2 s), 33.1 (2 p), 21.0 (2 p), 13.6 (p). MS: m/z = 202 [M - H]⁺.