MXPA01003186A - Process for the synthesis of 4-substituted n-[(alk-2- en-1-yl)oxy]- and n-aralkyloxy- 2,2,6,6- tetraalkylpiperidines - Google Patents

Abstract

An environmentally friendly process for the preparation of the 4-functionalized N-OR derivatives of 2,2,6,6-tetraalkylpiperidines involves the hydrogen peroxide of the corresponding N-H compound to form the corresponding N-oxyl derivative, reacting two equivalents of the N-oxyl compound with one equivalent of a compound having an allylic hydrogen, a benzylic hydrogen or an activated methine hydrogen to form one equivalent of the corresponding N-OH compound and one equivalent of the corresponding N-OR compound, and recycling the N-OH compound back to the corresponding N-oxyl compound using hydrogen peroxide or air.

Description

PROCESS FOR THE SYNTHESIS OF N- [(ALQ-2-EN-1-IL) OXI] - AND N-ARALKYLHOXI-2,2,6,6-TETRAALQUILPIPERIDINAS REPLACED IN POSITION 4 Field of the Invention The present invention pertains to an environmentally friendly process for producing N-OR derivatives of 2, 2, 6, 6-tetraalkylpiperidines functionalized in the 4-position.

BACKGROUND OF THE INVENTION The oxidation of hydrogen peroxide of 2, 2, 6, 6-tetramethylpiperidines with hydrogen peroxide alone, or with carbonate catalyst, with divalent metal catalyst is known. U.S. Patent Nos. 5,654,434 and 5,777,126 disclose oxidation using hydrogen peroxide only. U.S. Patent No. 5,629,426 describes the use of oxidations with hydrogen peroxide catalyzed by carbonate. U.S. Patent No. 5,416,215 discloses the use of divalent metal catalysts for the oxidation reaction with hydrogen peroxide. E. G. Rozantsev et al., Synthesis, 1971, 190 describes the use of the tungstate catalyst for the Oxidation with hydrogen peroxide of the 2, 2, 6, 6-tetra-methylpiperidines. U.S. Patent No. 5,204,473 describes the use of t-butyl hydroperoxide for the oxidation of 2, 2, 6, 6-tetramethylpiperidines to the corresponding N-oxyl compounds. I. Q. Li et al., Macromolecules 1996, 29, 8554 and T. J. Connolly et al., Tetrahedron Letters, 1996, 37, 4919 disclose the use of di-tert-butyl peroxide for the same purpose. G. Barclay et al., Macromolecules, 1997, (30), 1929 describes the formation of a nitroxyl diaduct with an activated double bond (styrene). L. J. Johnson et al., J. of Organic Chem., 1986, (51), 2806 describes the photochemical abstraction of the hydrogen atom by nitroxyl followed by the formation of N-OR. T. J. Connolly et al., Tetrahedron Letters, 1997, (38), 1133 describes the thermal abstraction of benzylic hydrogen atoms followed by the formation of N-OR. I. A. Opeida et al., Kinetics and Catalysts, 1995, (36), 441 (Russian translation) also describes the thermal abstraction of benzylic hydrogen atoms. The process herein differs significantly from each of those prior art references and provides the use of peroxide Environmentally friendly hydrogen with water as a by-product of oxidation. The formation of functionalized N-OR derivatives in position 4 is obtained without the use of organic peroxides or hydroperoxides.

DETAILED DESCRIPTION The process herein involves two steps for the preparation of an N-OR derivative selected from the 2, 2, 6, 6-tetraalkylpiperidines with a third step involving the recycling of the N-OH obtained concomitantly with the N-OR compound back to the corresponding N-oxyl starting material for the second step. The total process is discussed below: Step 1 (prepare an N-oxyl compound by oxidation with hydrogen peroxide Step 2 (reacting two equivalents of N-oxyl with an allyl, benzyl or (R-H) compound activated with methine to form an equivalent of N-OH and one equivalent of the N-OR compound).

Step 3 (recycle the N-OH compound formed in Step 2 back to the N-oxyl compound as needed as an intermediate for Step 2) .H2Q2 In formulas A, B, C and D, Gi and G2 are independently alkyl of 1 to 4 carbon atoms, preferably methyl, or G | and G2 together are pentamethylene; X is hydrogen, hydroxyl, oxo, -NH-CO-E, -0-CO-E or -NH-CO-NH-E, where E is alkyl of 1 to 18 carbon atoms, the alkyl is substituted by hydroxyl or E is aryl of 6 to 10 carbon atoms; and R is as defined below. In Step 2, the RH compound is an allyl, benzyl or methyl-activated compound where the H atom is highly vulnerable to being extracted by the N-oxyl radical, so that the two equivalents of the N-oxyl compounds react essentially with an equivalent of the RH compound to undergo a disproportionation reaction with one equivalent of N-OR and one equivalent of N-OH. Due to environmental and economic concerns, it is more convenient to recycle the N-OH compound prepared in the Step 3 again to the initial N-oxyl intermediate necessary in Step 2. Preferably, in the RH compounds which are allylic in nature, R is an alkenyl of 3 to 20 carbon atoms such as cyclohexene, 1.5. -cyclooctadiene, cyclooctene, 1-octene, allylbenzene, α-methylstyrene or β-methylstyrene (1-phenyl-1-propene), and in the compounds of RH which are benzylic, RH is a compound of formula Y-CH-Z where Y and Z are independently, hydrogen, alkyl of 1 to 18 carbon atoms, aryl of 6 to 10 carbon atoms or the aryl substituted by one to four alkyl groups of 1 to 4 carbon atoms, provided that at least one Y and Z is aryl and where Y is aryl, then Z may be part of a fused ring system having methylene groups such as 1, 2, 3, 4-tetrahydronaphthalene, toluene, o-xylene, m-xylene, p-xylene, diphenylmethane, ethylbenzene, mesitylene or durene. More preferably, in Step 2, the RH compound is cyclohexene, 1,5-cyclooctadiene, cyclo-octene, 1-octene, α-methylstyrene, β-methylstyrene, toluene, m-xylene, p-xylene, diphenylmethane or ethylbenzene. More preferably, in Step 2, the oxyl compound of formula B is l-oxyl-4-hydroxy-2,2,6,6-tetramethylpiperidine, l-oxyl-4-acetamido-2, 2, 6, 6-tetramethyl-piperidine, l-oxyl-4-oxo-2, 2,6,6,6-tetramethylpiperidine or 1-oxyl-4-benzoyloxy-2,2,6,6-tetramethylpiperidine. The present invention also pertains to the independent process of Step 2 and the independent process comprising Step 2 and Step 3 together as follows: Step 2 (reacting two equivalents of N-oxyl with an activated allylic, benzylic or (R-H) compound with methine to form an equivalent of N-OH and one equivalent of the N-OR compound).

Separate the N-OH and N-OR compounds, and Step 3 (recycle the N-OH compound formed in the Step 2 again to the N-oxyl compound as necessary as an intermediate for Step 2) l respectively Step 2 (reacting two equivalents of N-oxyl with an allyl, benzyl or (R-H) compound activated with methine to form an equivalent of N-OH and one equivalent of the N-OR compound).

Separate the N-OH and N-OR compounds. Preferably, in Step 1 and Step 3, the concentration of aqueous hydrogen peroxide is 30% in weight or greater. Aqueous hydrogen peroxide of 30%, 50% or 70% by weight is effective. Step 1 and Step 3 can be carried out according to what has been taught by oxidation with hydrogen peroxide of U.S. Patent Nos. 5,654,434 and 5,777,126 without catalysis; as taught in U.S. Patent No. 5,629,426 using a carbonate catalyst. Oxidation with hydrogen peroxide from Step 1 and Step 3 can also be carried out in the presence of a tungstate catalyst or divalent metal salts. Step 2 can be carried out in the absence of solvent or in the presence of an inert solvent such as chlorobenzene. Step 2 can be carried out at a temperature of 50 to 140 C at atmospheric pressure or from 50 to 140 C in a pressure vessel. The following examples are for illustrative purposes only and are not intended to limit the present invention in any way.

Example 1 1- (Cyclohex-2-en-l-yl) oxy-4-hydroxy-2,6,6,6-tetramethylpiperidine A mixture of 17.05 g (0.10 mol) of l-oxyl-4-hydroxy-2, 2,6,6-tetramethylpiperidine and 100 ml (0.99 mol) of cyclohexene under a nitrogen atmosphere was heated at 70 ° C for 72 hours. The reaction mixture was filtered to remove 1,4-dihydroxy-2,2,6,6-tetramethylpiperidine and the filtrate was washed with 5% w / v ascorbic acid (2 x 50 ml) and distilled water (2). x 50 ml). The organic phase was dried over anhydrous sodium sulfate and the volatiles were removed in vacuo. The residue was recrystallized from acetonitrile to give 4.44 g (36% yield) of a white solid melting at 65-66.5 ° C. ^ H-NMR (CDCL3) (499.8493 MHz) d 1.16 (s, 3H), 1.17 (s, 3H), 1.22 (s, 3H), 1.24 (s, 3H), 1.49 (dd, 2H), 1.50-2.10 (overlapping multiplets, 6H), 1.82 (dd, 2H), 3.97 (tt, 1H) , 4.25 (m, 1H), 5.81 (ddt, 1H). Analysis: Calculated for C15H27NO2: C, 71.10; H, 10.74; N, . 53. Found: C, 71.05; H, 10.59; N, 5.43.

Example 2 1- (3-Methylbenzyl) oxy-4-idroxy-2, 2,6,6-tetramethylpiperidine A mixture of 8.60 g (0.05 mol) of l-oxyl-4-hydroxy-2, 2, 6, 6 -tetramethylpiperidine and 106.17 g (1.0 mol) of m-xylene under a nitrogen atmosphere was heated at 135-136 ° C for 69 hours. The reaction mixture was filtered to remove 1,4-dihydroxy-2,2,6,6-tetramethylpiperidine, and the filtrate was washed with 10% w / v ascorbic acid (3 x 33 ml) and distilled water (2 x 50 ml). The organic phase was dried over anhydrous sodium sulfate and the volatiles were removed in vacuo. The residue was recrystallized from heptane to give 3.50 g (51% yield) of a white solid melting at 66-67 ° C. IR (1% solution in methylene chloride) v 3600 cm "(OH).

^ H-NMR (CDCL3) (499.8493 MHz) d 1.21 (s, 6H), 1.31 (s, 6H), 1.52 (dd, 2H), 1.84 (dd, 2H), 2.37 (s, 3H), 3.99 (tt , 1H), 4.79 (s, 2H), 7.11 (d, 1H), 7.16 (d, 1H), 7.24 (t, 1H). Analysis: Calculated for C 17 H 27 NO 2: C, 73.61; H, 9.81; N, 5.05. Found: C, 73.56; H, 9.70; N, 4.95.

Example 3 1- (4-Methylbenzyl) oxy-4-hydroxy-2, 2,6,6-tetramethylpiperidine A mixture of 8.60 g (0.05 mol) of l-oxyl-4-hydroxy-2, 2, 6, 6 tetramethylpiperidine and 106.17 g (1.0 mol) of p-xylene under a nitrogen atmosphere was heated to reflux for 48 hours. The reaction mixture was filtered to remove 1,4-dihydroxy-2,2,6,6-tetramethylpiperidine, and the filtrate was washed with 10% w / v ascorbic acid (1 x 50 ml) and distilled water (2 x 50 ml). The organic phase was dried over anhydrous sodium sulfate and the volatiles were removed in vacuo. The residue was recrystallized from heptane to give 4.00 g (59% yield) of a white solid that melts at 92.5-93 ° C. IR (1% solution in methylene chloride) v 3600 cm "(OH).

XH-NMR (CDCl3) (499.8493 MHz) d 1.20 (s, 6H), 1.31 (s, 6H), 1.53 (dd, 2H), 1.85 (dd, 2H), 2.36 (s, 3H), 3.99 (tt, 1H), 4.78 (s, 2H), 7.17 (d, 2H), 7.26 (d, 2H). Analysis: Calculated for C 17 H 27 NO 2: C, 73.61; H, 9.81; N, . 05. Found: C, 73.69; H, 9.58; N, 5.02.

EXAMPLE 4 1- (3-Methylbenzyl) oxy-2, 2,6,6,6-tetramethylpiperidin-4-yl benzoate A mixture of 13.77 g (0.05 mol) of l-oxyl-4-benzoyloxy-2, 2, 6, 6-tetramethylpiperidine and 106.17 g (1.0 mol) of m-xylene under a nitrogen atmosphere was heated to reflux for 50 hours. The reaction mixture was filtered to remove the hydroxylamine, and the filtrate was washed with 10% w / v ascorbic acid (1 x 50 ml) and distilled water (2 x 50 ml). The organic phase was dried over anhydrous sodium sulfate and the volatiles were removed in vacuo. The residue was recrystallized from isopropyl alcohol to give 5.62 g (59% yield) of a white solid melting at 64-65 ° C. ^ -RMN (CDCL3) (499.8493 MHz) d 1.32 (s, 6H), 1.35 (s, 6H), 1.78 (dd, 2H), 2.02 (dd, 2H), 2.38 (s, 3H), 4.83 (s, 2H), 5.32 (tt, 1H), 7.12 (d, 1H), 7.18 ( d, 1H), 7.19 (d, 1H), 7.26 (d, 1H), 7.45 (t, 2H), 7.57 (t, 1H), 8.04 (d, 1H). Analysis: Calculated for C2H3? N03: C, 75.54; H, 8.20; N, 3. 67. Found: C, 74.97; H, 8.12; N, 4.01.

Example 5 1- (3-Methylbenzyl) oxy-4-acetamido-2, 2,6,6-tetramethylpiperidine A mixture of 10.67 g (0.05 mol) of l-oxyl-4-acetamido-2, 2, 6, 6 tetramethylpiperidine and 106.17 g (1.0 mol) of m-xylene under a nitrogen atmosphere was heated at 133 ° C for 67 hours. The reaction mixture was filtered to remove the hydroxylamine, and the filtrate was washed with 10% w / v ascorbic acid (3 x 33 ml) and distilled water (2 x 50 ml). The organic phase was dried over anhydrous sodium sulfate and the volatiles were removed in vacuo. The residue was recrystallized from acetonitrile to give 4.03 g (51% yield) of a white solid melting at 163-164.5 ° C. XH-NMR (CDCL3) (499.8493 MHz) d 1.27 (s, 6H), 1.29 (s, 6H), 1.37 (dd, 2H), 1.83 (dd, 2H), 1.96 (s, 3H), 2.37 (s, 3H), 4.17 (m, 1H), 4.70 (s, 2H), 5.18 (d, NH, 1H), 7.11 (d, 1H), 7.15 (d, 1H), 7.16 (d, 1H), 7.24 (t, 1H). Analysis: Calculated for C19H30N2O2: C, 71.66; H, 9.50; N, Found: C, 71.39; H, 9.26; N, 8.99 Example 6 l-Benzyloxy-4-hydroxy-2, 2,6,6-tetramethylpiperidine A mixture of 2.58 g (0.015 mol) of l-oxyl-4-hydroxy-2, 2,6,6-tetramethylpiperidine and 27.64 g ( 0.30 mol) of toluene under a nitrogen atmosphere was heated in a pressure vessel for 53 hours. The reaction mixture was diluted with diethyl ether and the resulting mixture was washed with 10% w / v ascorbic acid (1 x 50 ml) and distilled water (2 x 50 ml). The organic phase was dried over anhydrous sodium sulfate and the volatiles were removed in vacuo. The residue was recrystallized from heptane to give 0.59 g (30% yield) of a white solid that melts at 86-87 ° C. IR (1% solution in methylene chloride) v 3595 cm "(OH).

XH-NMR (CDCL3) (499.8493 MHz) d 1.12 (s, 6H), 1.23 (s, 6H), 1.44 (dd, 2H), 1.59 (m, 2H), 3.65 (tt, 1H), 4.82 (s, 2H), 7.09 (t, 1H), 7.16 (t, 2H), 7.32 (d, 2H). Analysis: Calculated for C | 6H25N02: C, 72.97; H, 9.57; N, . 32. Found: C, 73.18; H, 9.63; N, 4.99.

Example 7 1- (1-Phenyl: .lethyl) oxy-4-hydroxy-2, 2,6,6-tetramethylpiperidine A mixture of 17.23 g (0.10 mol) of l-oxyl-4-hydroxy-2,, 6, 6-tetramethylpiperidine and 106.17 g (1.0 mol) of ethylbenzene under a nitrogen atmosphere was heated at 133 ° C for 26 hours. The volatiles were removed in vacuo and the residue was triturated with diethyl ether. The precipitate of 1,4-dihydroxy-2,2,6,6-tetramethylpiperidine was collected by filtration to give 12.57 g of a white, off-white solid. "JH-NMR (dimethyl sulfoxide-d6) (499.8493 MHz) d 1. 02 (s, 6H), 1.05 (s, 6H), 1.24 (dd, 2H), 1.69 (dd, 2H), 3.32 (s, 1H), 3.73 (m, 1H), 4.36 (d, 1H). The filtrate from the above filtration was washed with 10% w / v ascorbic acid (3 x 33 ml) and distilled water (2 x 50 ml). The organic phase was dried over anhydrous sodium sulfate and the volatiles were removed in vacuo. The residue was recrystallized from acetonitrile to give 0.82 g (yield 6%) of a white solid melting at 97-98 ° C. HL-NMR (CDCL3) (499.8493 MHz) d 0.69 (s, 3H), 1.09 (s, 3H), 1.16 (d, OH, 1H), 1.23 (s, 3H), 1.35 (s, 3H), 1.39 (dd, 1H), 1.49 (dd, 1H), 1.50 (d, 3H), 1.72 (ddd, 1H), 1.85 (ddd, 1H), 3.95 (m, 1H), 4.79 (c, 1H), 7.25 (m, 1H), 7.20- .33 (superimposed m, 4H).

Analysis: Calculated for C 17 H 27 NO 2: C, 73.61; H, 9.81; N, 5.05. Found: C, 73.42; H, 9.68; N, 4.93.

EXAMPLE 8 Reoxidation of 1,4-Dihydroxy-2, 2,6,6-tetramethylpiperidine to l-Oxyl-4-hydroxy-2,6,6,6-tetramethylpiperidine To a solution of 2.0 g of 1,4-dihydroxy 2, 2, 6, 6-tetramethylpiperidine in 25 ml of water at 80 ° C were added dropwise two (2) equivalents of 30% hydrogen peroxide. The conversion of 1,4-dihydroxy-2,2,6,6-tetramethyl-piperidine to l-oxyl-4-hydroxy-2,2,6,6-tetramethylpiperidine was determined by both TLC (Thin Layer Chromatography) as CLG (Gas-Liquid Chromatography) (Gas Chromatography Variety Model 3400; Column J &W Scientific DB 1; 15 m) is 100%.

EXAMPLE 9 1- (4-ethylbenzyl) oxy-4-hydroxy-2, 2,6,6-tetramethylpiperidine A mixture of 8.60 g (0.1 mol) of l-oxyl-4-hydroxy-2, 2, 6, 6 tetramethylpiperidine and 53.09 g (0.5 mol) of p-xylene in 61 ml of chlorobenzene under a nitrogen atmosphere was heated at 140 ° C for 56 hours. The reaction mixture was filtered to remove 1,4-dihydroxy-2,2,6,6-tetramethyl- piperidine, and the filtrate was washed with 10% w / v ascorbic acid (3 x 30 ml) and distilled water (2 x 50 ml). The organic phase was dried over anhydrous sodium sulfate and the volatiles were removed in vacuo. The residue was recrystallized from heptane to give 3.33 g (48% yield) of the title compound as a white solid that melts at 92.5-93 ° C.

EXAMPLE 10 1- (2-Phenylalkyloxy) -4-benzoyloxy-2, 2,6,6-tetramethylpiperidine A mixture of 1.0 g (3.6 mmol) of l-oxyl-4-benzoyloxy-2,2,6,6-tetramethylpiperidine and 10 g (85 mmol) of α-methylstyrene under a nitrogen atmosphere was heated at 120 ° C for 36 hours. The reaction mixture was concentrated in vacuo and the title compound was isolated as a pale yellow oil after column chromatography.

Example 11 1- (3-Phenylalkyloxy) -4-benzoyloxy-2, 2,6,6-tetramethylpiperidine A mixture of 1.0 g (3.6 mmol) of l-oxyl-4-benzoyloxy-2,2,6,6-tetramethylpiperidine and 10 g (85 mmol) of β-methylstyrene under a nitrogen atmosphere was heated at 120 ° C for 36 hours. The reaction mixture was concentrated in went to cuo and the title compound was isolated after column chromatography as a white solid, which melted at 115-116 ° C.

Example 12 1- (Diphenylmethoxy) -4-benzoyloxy-2, 2,6,6-tetramethylpiperidine A mixture of 1.0 g (3.6 mmol) of l-oxyl-4-benzoyloxy-2,2,6,6-tetramethylpiperidine and g (60 mmol) of diphenylmethane under an atmosphere of nitrogen was heated at 100 ° C for 24 hours. The reaction mixture was concentrated in vacuo and the title compound was isolated after column chromatography as a white solid, which melts at 135-136 ° C.

Example 13 1- (Cyclooct-2-enyloxy) -2,2,6,6-tetramethyl-4-hydroxypiperidine A mixture of 15.0 g (0.09 mol) of l-oxyl-4-hydroxy-2, 2, 6, 6 -tetramethylpiperidine and 126.6 g (1.15 mol) of cyclooctene was heated under a nitrogen atmosphere at 87-88 ° C for 40 hours. The reaction mixture was filtered to remove 1,4-dihydroxy-2,2,6,6-tetramethylpiperidine, and the filtrate was washed with 5% ascorbic acid (2 x 50 ml) and distilled water (2 x 50 ml). ). The organic phase was dried over anhydrous magnesium sulfate and the volatiles were removed in va cuo The residue was crystallized from heptane to give 4.40 g (36% yield) of the title compound as a white solid. X H-NMR (CDCl 3) (500 MHz) d 1.14 (s, 3 H), 1.16 (s, r 3 H), 1.21 (s, 3 H), 1.26 (s, 3 H), 1.27-2.20 (m, 14 H), 3.95 (m, 1H), 4.64 (m, 1H), 5.54-5.64 (m, 2H). Analysis : Calculated for C17H3 | N02: C, 72.55; H, 11.10; N, 4.98. Found: C, 72.69; H, 11.13; N, 4.73.

Example 14 1- (Cyclohex-2-enyloxy) -2,2,6,6-tetramethylpiperidin-4-one A mixture of 25.0 g (0.15 mol) of l-oxyl-4-oxo-2, 2, 6, 6 -tetramethylpiperidine and 162.2 g (1.97 mol) of cyclohexene was heated under a nitrogen atmosphere at 85-86 ° C for 56 hours. The reaction mixture was filtered to remove the hydroxylamine, and the solvent was removed in vacuo. The residue was dissolved in heptane and washed with 5% ascorbic acid (2 x 50 ml) and distilled water (2 x 50 ml). The organic phase was dried over anhydrous sodium sulfate and the volatiles were removed in vacuo. The residue was eluted through a column of silica gel with heptane / ethyl acetate (9/1) to give 3.9 g (21% of yield) of the title compound as a yellow oil. ^ -NMR (CDCL3) (500 MHz) d 1.10-2.12 (m, 18H), 2.24 (d, 2H), 2.57 (d, 2H), 4.34 (m, 1H), 5.85 (m, 1H), 5.98 ( m, 1H). Analysis: Calculated for C15H25NO2: C, 71. 67; H, 10 02; N, 5 57 Found: C, 71.79; H, 10.16; N, 5.60.

Example 15 1- (Cycloocta-2,6-dienyloxy) -2,2,6,6-tetramethyl-4-hydroxypiperidine A mixture of 29.4 g (0.17 mol) of l-oxyl-4-hydroxy-2, 2, 6 , 6-tetramethylpiperidine and 148.0 g (1.37 mol) of 1, 5-cyclooctadiene was heated under a nitrogen atmosphere at 100 ° C for 24 hours. The reaction mixture was filtered to remove 1,4-dihydroxy-2,2,6,6-tetramethylpiperidine, and the filtrate was diluted with heptane (250 ml). The organic phase was washed with 5% ascorbic acid (2 x 50 ml) and distilled water (2 x 50 ml). The organic phase was dried over anhydrous magnesium sulfate and the volatiles were removed in vacuo. The residue was subjected to chromatography to give 8.1 g (33% yield) of the title compound as a white solid. XH-NMR (CDCL3) (500 MHz) d 1.10-1.28 (m, 12H), 1.47 (t, 2H), 1.82 (d, 2H), 2.06-2.26 (m, 2H), 2.29 (m, 1H), 2.40 (m, 1H), 2.86 (d, 1H), 3.96 (tt, 1H), 5.01 (m, 1H), 5.40-5.70 (m, 4H).

Example 16 l-0ct-2-enyloxy-2, 2,6,6-tetramethyl-4-hydroxypiperidine A mixture of 20.0 g (0.12 mol) of l-oxyl-4-hydroxy-2, 2,6,6-tetramethylpiperidine and 164.0 g (1.04 mol) of 1-octene was heated under a nitrogen atmosphere at 100 ° C for 24 hours, and then for an additional 24 hours at 115 ° C. The reaction mixture was filtered to remove 1,4-dihydroxy-2,2,6,6-tetramethylpiperidine, and the filtrate was washed with 10% (w / v) ascorbic acid (2 x 50 ml) and distilled water (2 x 50 ml). The organic phase was dried over anhydrous magnesium sulfate and the volatiles were removed in vacuo. The residue was subjected to chromatography to give 14.4 g (83% yield) of the title compound as an amber oil. XH-NMR (CDCL3) (500 MHz) d 0.9 (t, 3H), 1.10-1.36 (m, 16H), 1.39 (m, 2H), 1.45 (t, 2H), 1.82 (d, 2H), 2.04 ( c, 2H), 3. 96 (m, 1H), 4.20-4.33 (broad d, 2H), 5.50 (m, 1H), 5.68 (, 4H).

Example 17 Recycling of Hydroxylamine to N-Oxyl In Examples 1-7 and 9-16, together with the desired N-OR compound, an equivalent amount of the corresponding N-OH compound is also present. The hydroxylamines are insoluble in solvents such as toluene or xylene, and can easily be prepared from the reaction mixtures by simple filtration according to what is indicated by the different working examples. After separation of the reaction mixture and the desired N-OR compound by filtration, the corresponding N-OH compound is oxidized using the hydrogen peroxide again to the corresponding N-oxyl compound necessary as an intermediate of Step 2.

Claims (9)

1. A process, involving two steps for the preparation of an N-OR derivative selected from 2, 2, 6, 6-tetraalkylpiperidines with a third step involving the recycling of the N-OH obtained concomitantly with the N-OR compound again desired to the corresponding N-oxyl starting material for the second step, characterized in that it comprises: in Step 1, preparing an N-oxyl compound by oxidation with hydrogen peroxide and, in Step 2, reacting two equivalents of N-oxyl with an allyl, benzyl or (R-H) compound activated with methine to form an equivalent of N-OH and one equivalent of the N-OR compound separating the N-OH and N-OR compounds, and, in Step 3, recycling the N-OH compound formed in Step 2 back to the N-oxyl compound as needed as an intermediate for Step 2 .H2O2 wherein in the formulas A, B, C and D, Gi and G2 are independently alkyl of 1 to 4 carbon atoms, or G, and G2 together are pentamethylene; X is hydrogen, hydroxyl, oxo, -NH-CO-E, -0-CO-E or -NH-CO-NH-E, where E is alkyl of 1 to 18 carbon atoms, or the alkyl is substituted by hydroxyl or E is aryl of 6 to 10 carbon atoms; and R is an alkenyl of 3 to 20 carbon atoms; Y-CH-Z where Y and Z are independently, hydrogen, alkyl of 1 to 18 carbon atoms, aryl of 6 to 10 carbon atoms or the aryl substituted by one to four alkyl groups of 1 to 4 carbon atoms, always that at least one Y and Z is aryl and where Y is aryl, then Z can be part of a fused ring system having methylene groups.

2. The process according to claim 1, characterized in that Gi and G2 are each methyl.

The process according to claim 1, characterized in that in Step 2, the compound RH is cyclohexene, 1,5-cyclooctadiene, cyclo-octene, 1-octene, allylbenzene, α-methylstyrene, β-methyl-styrene 1 , 2, 3, 4-tetrahydronaphthalene, toluene, o-xylene, m-xylene, p-xylene, diphenylmethane, ethylbenzene, mesitylene or durene.

4. The process according to claim 1, characterized in that in Step 2, the oxyl compound of formula B is l-oxyl-4-hydroxy-2,2,6,6-tetramethylpiperidine, l-oxyl-4-acetamido- 2, 2, 6, 6-tetramethyl-piperidine, l-oxyl-4-oxo-2, 2,6,6-tetramethylpiperidine or 1-oxyl-4-benzoyloxy-2, 2,6,6-tetramethylpiperidine.

5. The process according to claim 1, characterized in that in Step 1 and Step 3, the concentration of aqueous hydrogen peroxide is 30% by weight or greater.

6. The process according to claim 1, characterized in that Step 2 is carried out in the absence of a solvent or in the presence of an inert solvent such as chlorobenzene.

The process according to claim 1, characterized in that Step 2 is carried out at a temperature of 50 to 140 ° C at atmospheric pressure or from 50 to 140 ° C in a pressure vessel.

8. A process for the preparation of an N-OR derivative selected from the 2, 2, 6, 6-tetraalkylpiperidines followed by a subsequent step involving the recycling of the N-OH obtained concomitantly with the desired N-OR compound back to the initial N-oxyl material corresponding to the initial step, characterized in that it comprises reacting two equivalents of N-oxyl with an allyl, benzyl or (R-H) compound activated with methine to form an equivalent of N-OH and one equivalent of the N-O compound separating the N-OH and N-OR compounds, and, recycling the previously formed N-OH compound back to the N-oxyl compound as necessary as an intermediate for the initial reaction l wherein in the formulas A, B, C and D, Gi and G2 are independently alkyl of 1 to 4 carbon atoms, or Gi and G2 together are pentamethylene; X is hydrogen, hydroxyl, oxo, -NH-CO-E, -0-CO-E or -NH-CO-NH-E, where E is alkyl of 1 to 18 carbon atoms, the alkyl is substituted by hydroxyl or E is aryl of 6 to 10 carbon atoms; and R is an alkenyl of 3 to 20 carbon atoms; Y- CH-Z where Y and Z are independently, hydrogen, alkyl of 1 to 18 carbon atoms, aryl of 6 to 10 carbon atoms or the aryl substituted by one to four alkyl groups of 1 to 4 carbon atoms, always that at least one Y and Z is aryl and where Y is aryl, then Z can be part of a fused ring system that has methylene groups.

9. A process for the preparation of an N-OR derivative selected from 2, 2, 6, 6-tetraalkyl-piperidines, characterized in that it comprises reacting two equivalents of N-oxyl with an allyl, benzyl or (RH) compound ) activated with methine to form an equivalent of N-OH and one equivalent of the N-OR compound separating the compounds of N-OH and N-OR, where in the formulas A, B, C and D, Gi and G2 are independently alkyl of 1 to 4 carbon atoms, or G | and G2 together are pentamethylene; X is hydrogen, hydroxyl, oxo, -NH-CO-E, -O-CO-E or -NH-CO-NH-E, where E is alkyl of 1 to 18 carbon atoms, the alkyl is substituted by hydroxyl or E is aryl of 6 to 10 carbon atoms; and R is an alkenyl of 3 to 20 carbon atoms; Y-CH-Z where Y and Z are independently, hydrogen, alkyl of 1 to 18 carbon atoms, aryl of 6 to 10 carbon atoms or the aryl substituted by one to four alkyl groups of 1 to 4 carbon atoms, always that at least one Y and Z is aryl and where Y is aryl, then Z can be part of a fused ring system having methylene groups.