AMINE-N-OXIDE COMPOUNDS

Abstract

Amine N-oxide compounds having formula (I) or (II), a preparation method, and a surfactant containing the compounds:

##STR00001##

R.sup.1 is a hydrocarbon residue with 4 to 26 carbon atoms and optionally at least one O or S; R.sup.2, R.sup.3 and R.sup.5 are each hydrogen, R.sup.1O, R.sup.8 and in formula (I) also optionally CH.sub.2N.sup.+(O.sup.?)R.sup.6R.sup.6; R.sup.8 is a hydrocarbon radical with 1 to 26 carbon atoms and optionally at least one O or S; R.sup.4 is hydrogen or R.sup.8; and each R.sup.6 is a hydrocarbon radical with 1 to 6 carbon atoms and optionally at least one N, O or S. Optionally two radicals R.sup.6 on the same nitrogen atom are connected to form a five- or six-membered, nitrogen-containing ring, or optionally radical(s) R.sup.6 of a moiety N.sup.+(O.sup.?)R.sup.6R.sup.6 may be linked to radical(s) R.sup.6 of another formula (I) molecule, forming a bridge having the structure

##STR00002##

and a dimer of formula (II).

Claims

1. A method for preparing an amine N-oxide compound according to the following formula (I) or (II): ##STR00052## wherein each R.sup.1 is selected from linear, branched or cyclic hydrocarbon radicals having 4 to 26 carbon atoms, wherein optionally at least one carbon atom may be replaced by an oxygen or sulfur atom; R.sup.2, R.sup.3 and R.sup.5 are each independently selected from hydrogen, R.sup.1O, R.sup.8, and in formula (I) also from CH.sub.2N.sup.+(O.sup.?)R.sup.6R.sup.6, wherein R.sup.1 represents a linear, branched or cyclic hydrocarbon radical having 1 to 26 carbon atoms, wherein optionally at least one carbon atom may be replaced by an oxygen or sulfur atom; R.sup.4 is selected from hydrogen and R.sup.8; and each radical R.sup.6 is independently selected from saturated, linear or branched hydrocarbon radicals having 1 to 6 carbon atoms, wherein optionally at least one carbon atom may be replaced by a nitrogen, oxygen or sulfur atom; wherein optionally two radicals R.sup.6 being bound to the same nitrogen atom may be connected to form a five- or six-membered, nitrogen-containing ring, or wherein optionally one or both radical(s) R.sup.6 of an amine N-oxide moiety N.sup.+(O.sup.?)R.sup.6R.sup.6 may be linked to one or both radical(s) R.sup.6 of such a moiety of another molecule of formula (I), thus forming a bridge having the structure ##STR00053## wherein the dashed line designates an optional bond between the two radicals R and the asterisks designate the connections of the bridge to the two aromatic rings, thereby forming a dimer according to formula (II); wherein the method comprising the following steps: 1) reacting a phenol derivative according to the following formula (III): ##STR00054## wherein each R.sup.7 is independently selected from hydrogen, hydroxy, and R.sup.8, with a secondary amine HNR.sup.6R.sup.6 by means of an amino alkylation reaction according to Betti/Mannich in the presence of formaldehyde in a polar solvent, thereby substituting the hydrogen atom in the ortho position to the phenolic OH group, and optionally another substitutable hydrogen atom R.sup.7 of the phenol derivative of formula (II), by a CH.sub.2NR.sup.6R.sup.6 moiety (each), resulting in a corresponding Betti base according to formula (IV) or (V): ##STR00055## wherein each R.sup.7 is independently selected from hydrogen, hydroxy, R.sup.8, and in formula (IV) also from CH.sub.2N.sup.6R.sup.6; 2) reacting the (two) phenolic OH group(s), and optionally any further free OH group(s) R.sup.7, of the respective Betti base of formula (IV) or (V) with a compound according to the formula R.sup.1X, wherein X represents a leaving group selected from halides and sulfonates, by means of an etherification reaction according to Williamson in the presence of a base, in an organic solvent or without any solvent, resulting in a corresponding ether according to formula (VI) or (VII): ##STR00056## wherein each R.sup.7 is independently selected from hydrogen, R.sup.1O, R.sup.8, and in formula (VI) also from CH.sub.2NR.sup.6R.sup.6; and 3) oxidizing any amino groups NR.sup.6R.sup.6 of the respective ether of formula (VI) or (VII) by reaction with an oxidizing agent in water, an organic solvent or a mixture thereof, resulting in the amine N-oxide compound of formula (I) or (II).

2. The method according to claim 1, wherein, in step 1), the phenol derivative of formula (III) is reacted with 1.5 equivalents each of the secondary amine and of formaldehyde, the reaction being optionally carried out in water at room temperature.

3. The method according to claim 1, wherein, in step 2), a solid-liquid phase-transfer reaction is carried out using a solid base and in the presence of a phase transfer catalyst; and/or chloride or bromide is used as said leaving group X; and/or an anhydrous solvent is used.

4. The method according to claim 3, wherein, in step 2), powdered KOH is used a said solid base; tetra-n-butylammonium bromide (TBAB) is used as said phase-transfer catalyst; bromide is used as said leaving group X; and anhydrous 2-methyltetrahydrofuran is used as a solvent.

5. The method according to claim 1, wherein, in step 3), an aqueous solution of H.sub.2O.sub.2 is used as said oxidation agent, wherein optionally formic acid methyl ester may be added as an additional solvent; and/or the ether of formula (VI) or (VII) is reacted with 2.5 to 3 equivalents of H.sub.2O.sub.2.

6. An amine N-oxide compound according to the following formula (I) or (II), prepared according to the method according to claim 1: ##STR00057## wherein each R.sup.1 is selected from linear, branched or cyclic hydrocarbon radicals having 4 to 26 carbon atoms, wherein optionally at least one carbon atom may be replaced by an oxygen or sulfur atom; R.sup.2, R.sup.3 and R.sup.5 are each independently selected from hydrogen, R.sup.1O, R.sup.8, and in formula (I) also from CH.sub.2N.sup.+(O.sup.?)R.sup.6R.sup.6, wherein R.sup.8 represents a linear, branched or cyclic hydrocarbon radical having 1 to 26 carbon atoms, wherein optionally at least one carbon atom may be replaced by an oxygen or sulfur atom; R.sup.4 is selected from hydrogen and R.sup.8; and each radical R.sup.6 is independently selected from saturated, linear or branched hydrocarbon radicals having 1 to 6 carbon atoms, wherein optionally at least one carbon atom may be replaced by a nitrogen, oxygen or sulfur atom; wherein optionally two radicals R.sup.6 being bound to the same nitrogen atom may be connected to form a five- or six-membered, nitrogen-containing ring, or wherein optionally one or both radical(s) R.sup.6 of an amine N-oxide moiety N.sup.+(O.sup.?)R.sup.6R.sup.6 may be linked to one or both radical(s) R.sup.6 of such a moiety of another molecule of formula (I), thus forming a bridge having the structure ##STR00058## wherein the dashed line designates an optional bond between the two radicals R.sup.6 and the asterisks designate the connections of the bridge to the two aromatic rings, thereby forming a dimer according to formula (II).

7. The amine N-oxide compound according to claim 6, wherein R.sup.1 is C.sub.6-C.sub.22 alkyl; and/or R.sup.2 is selected from C.sub.1-C.sub.22 alkyl, C.sub.1-C.sub.22 alkoxy, and CH.sub.2N.sup.+(O.sup.?)R.sup.6R.sup.6; and/or R.sup.3 and R.sup.5 are each selected from hydrogen and CH.sub.2N.sup.+(O.sup.?)R.sup.6R.sup.6; and/or R.sup.4 is selected from hydrogen, C.sub.1-C.sub.4 alkyl, and C.sub.1-C.sub.4 alkoxy.

8. The amine N-oxide compound according to claim 7, wherein R.sup.1 is C.sub.8-C.sub.18 alkyl; and/or R.sup.2 is selected from C.sub.1-C.sub.18 alkoxy and CH.sub.2N.sup.+(O.sup.?)R.sup.6R.sup.6; and/or R.sup.4 and R.sup.5 are each selected from hydrogen and C.sub.1-C.sub.4 alkyl.

9. The amine N-oxide compound according to claim 7, wherein R.sup.1 is C.sub.8-C.sub.18 alkyl; R.sup.2 is C.sub.1-C.sub.18 alkoxy; one of R.sup.3 and R.sup.5 is hydrogen and the other is CH.sub.2N.sup.+(O.sup.?)R.sup.6R.sup.6; and R.sup.4 is C.sub.1-C.sub.4 alkyl.

10. The amine N-oxide compound according to claim 7, wherein R.sup.1 is C.sub.8-C.sub.18 alkyl; R.sup.2 is C.sub.1-C.sub.18 alkoxy; R.sup.3 and R.sup.5 each are hydrogen; and R.sup.4 is C.sub.1-C.sub.4 alkyl.

11. The amine N-oxide compound according to claim 10, wherein R.sup.2 is methoxy; and R.sup.4 is ethyl or propyl.

12. The amine N-oxide compound according to claim 7, wherein R.sup.1 is C.sub.8-C.sub.18 alkyl; R.sup.2 is CH.sub.2N.sup.+(O.sup.?)R.sup.6R.sup.6; R.sup.3 and R.sup.5 each are hydrogen; and R.sup.4 is C.sub.1-C.sub.4 alkyl.

13. The amine N-oxide compound according to claim 6, wherein each radical R.sup.6 is independently selected from methyl, ethyl, and dimethylaminoethyl; and/or two radicals R.sup.6 being bound to the same nitrogen atom are connected to form, together with the nitrogen atom, one of the following groups: ##STR00059## wherein the asterisks designate the respective connections to the aromatic ring; and/or all radicals R.sup.6 are methyl and one or both methyl group(s) of a moiety N.sup.+(O.sup.?)(CH.sub.3).sub.2 is/are linked to one or both methyl group(s) R.sup.6 of such a moiety of another molecule of formula (I), thus forming a bridge having the structure ##STR00060## wherein the dashed line designates an optional bond between the two methyl groups and the asterisks designate the connections of the bridge to the two aromatic rings, thereby forming a dimer of the amine N-oxide compound according to formula (II).

14. The amine N-oxide compound according to claim 6, wherein it is selected from the following compounds: N,N-dimethyl-1-(5-ethyl-3-methoxy-2-octyloxyphenyl)methanamine N-oxide (1) ##STR00061## N,N-dimethyl-1-(2-decyloxy-5-ethyl-3-methoxyphenyl)methanamine N-oxide (2) ##STR00062## N,N-dimethyl-1-(2-dodecyloxy-5-ethyl-3-methoxyphenyl)methanamine N-oxide (3) ##STR00063## N,N-dimethyl-1-(5-ethyl-3-methoxy-2-tetradecyloxyphenyl)methanamine N-oxide (4) ##STR00064## N,N-dimethyl-1-(5-ethyl-2-hexadecyloxy-3-methoxyphenyl)methanamine N-oxide (5) ##STR00065## N,N-dimethyl-1-(5-ethyl-3-methoxy-2-octadecyloxyphenyl)methanamine N-oxide (6) ##STR00066## 1-(2-dodecyloxy-5-ethyl-3-methoxybenzyl)pyrrolidine-1-oxide (7) ##STR00067## 1-(2-dodecyloxy-5-ethyl-3-methoxybenzyl)piperidine-1-oxide (8) ##STR00068## 1-(2-dodecyloxy-5-ethyl-3-methoxybenzyl)-4-methylpiperazine-1,4-dioxide (9) ##STR00069## N,N-dimethyl-N-(2-dodecyloxy-5-ethyl-3-methoxybenzyl)-N-methylethane-1,2-diamine di-N-oxide (10) ##STR00070## 1,1-(2,3-dioctyloxy-5-ethyl-1,4-phenylene)-bis(N,N-dimethylmethanamine N-oxide) and 1,1-(2,3-dioctyloxy-5-ethyl-1,6-phenylene)-bis(N,N-dimethylmethanamine N-oxide) (11) ##STR00071## 1,1-(5-ethyl-2-octyloxy-1,3-phenylene)-bis(N,N-dimethylmethanamine N-oxide) (12) ##STR00072## 1,1-(2-dodecyloxy-5-ethyl-1,3-phenylene)-bis(N,N-dimethylmethanamine N-oxide) (13) ##STR00073## 1,1-(5-ethyl-2-hexadecyloxy-1,3-phenylene)-bis(N,N-dimethylmethanamine N-oxide) (14) ##STR00074## 1,1-(5-ethyl-2-octadecyloxy-1,3-phenylene)-bis(N,N-dimethylmethanamine N-oxide) (15) ##STR00075## 1,4-bis(5-ethyl-3-methoxy-2-octyloxybenzyl)piperazine-1,4-dioxide (16) ##STR00076## 1,4-bis(2-dodecyloxy-5-ethyl-3-methoxybenzyl)piperazine-1,4-dioxide (17) ##STR00077## N,N-bis(5-ethyl-3-ethyl-2-octyloxybenzyl)-N,N-dimethylethane-1,2-diamine di-N-oxide (18) ##STR00078##

15. A surfactant comprising the amine N-oxide compound of formula (I) or (II) according to claim 6, wherein the total number of carbon atoms of the radicals R.sup.1 to R.sup.5 is at least 9.

Description

BRIEF DESCRIPTION OF THE FIGURE

[0078] The only FIG. 1 shows a cryogenic electron microscope image of an aqueous solution of the amine N-oxide compound (13) from Example 13 together with a schematic representation of the micelles to be observed therein.

EXAMPLES

[0079] The present invention will be described in more detail below by way of examples, which, however, should not be construed as limiting the scope of protection. For illustration purposes, two representative model compounds for the common lignin depolymerization products preferred as starting substances in the method according to the invention were used.

[0080] For this purpose, one phenol and one diphenol derivative, namely 4-ethylguaiacol (4-ethyl-2-methoxyphenol) and 4-ethylcatechol (1,2-dihydroxy-4-ethylbenzene), were reacted to the amine N-oxide compounds according to the invention:

##STR00033##

[0081] These were first aminomethylated, once or twice, with various secondary amines and diamines in the presence of formaldehyde to obtain corresponding Betti bases, which were then etherified once or twice with a series of fatty alkyl halides and finally oxidized to the amine N-oxides.

Example 1

Preparation of N,N-dimethyl-1-(5-ethyl-3-methoxy-2-octyloxyphenyl)methanamine N-oxide (1)

[0082] ##STR00034##

Step 1:

Variant 1.1:

[0083] An aqueous solution of 4-ethylguaiacol (15.20 g, 100 mmol) was added dropwise to a 40 wt % aqueous solution of dimethylamine (6.76 g, 150 mmol) in an iced water bath within 15 minutes with constant stirring. Paraformaldehyde (4.50 g, 150 mmol) was added in aliquots of 0.5 g every 10 min and stirred for 3 h in an iced water bath and then for 9 h at room temperature. The volatile components were then removed on a rotary evaporator at room temperature, whereafter the water was removed at 50? C. in vacuo and the residue was completely dried in a vacuum desiccator. The aminomethylated intermediate product, 2-dimethylaminomethyl-4-ethyl-6-methoxyphenol, was obtained as a viscous, yellow oil (yield: 20.83 g; 99.5% of theory).

Variant 1.2:

[0084] An aqueous solution of 4-ethylguaiacol (15.20 g, 100 mmol) was added dropwise to a 40 wt % aqueous solution of dimethylamine (4.56 g, 101 mmol) in an iced water bath within 15 minutes with constant stirring. Paraformaldehyde (4.50 g, 150 mmol) was added in aliquots of 0.5 g every 10 min and stirred for 3 h in an iced water bath and then for 72 h at room temperature. The reaction mixture was then extracted 5 times with 25 ml of petroleum ether (bp.: 40-60? C.), and the combined organic phases were concentrated in vacuo on a rotary evaporator, whereafter the residue was completely dried in a vacuum desiccator. The aminomethylated intermediate, 2-dimethylaminomethyl-4-ethyl-6-methoxyphenol, was obtained as a viscous, yellowish oil (yield: 19.43 g; 93.0% of theory).

Step 2:

Variant 2.1:

[0085] 2-Dimethylaminomethyl-4-ethyl-6-methoxyphenol (1.05 g, 5 mmol), 1-bromooctane (0.95 g, 4.9 mmol) and tetrabutylammonium bromide (TBAB) (0.16 g, 0.5 mmol) as a catalyst in 10 ml of 2-methyltetrahydrofuran (2-MeTHF) as solvent were stirred vigorously at room temperature until a homogeneous solution was obtained, whereafter solid powdered KOH (0.56 g, 10 mmol) was added and stirred at room temperature for 8 h. The inorganic solid was then centrifuged off and washed 3 times with 10 ml of diethyl ether. The combined organic phases were concentrated on a rotary evaporator, the residue was redissolved in 45 ml of petroleum ether and washed 4 times with 5 ml of water. The organic phase was then concentrated on a rotary evaporator and the residue was completely dried in a vacuum desiccator. The etherified intermediate, N,N-dimethyl-1-(5-ethyl-3-methoxy-2-octyloxyphenyl)methanamine, was obtained as a viscous, yellow oil (yield: 1.45 g; 92.3% of theory).

Variant 2.2:

[0086] 2-Dimethylaminomethyl-4-ethyl-6-methoxyphenol (1.05 g, 5 mmol), 1-bromooctane (1.06 g, 5.5 mmol) and tetrabutylammonium bromide (TBAB) (0.16 g, 0.5 mmol) in 10 ml 2-MeTHF were stirred vigorously at room temperature until a homogeneous solution was obtained, whereafter solid powdered KOH (0.56 g, 10 mmol) was added and stirred at room temperature for 8 h. Then 25 ml Et.sub.2O and 5 ml H.sub.2O were added, and the aqueous phase was extracted 3 times with 10 ml Et.sub.2O. The combined organic phases were concentrated on a rotary evaporator and the residue was stored over 5 g of silica gel. The residue was purified using flash chromatography on a filter column, the etherified intermediate product, at which N,N-dimethyl-1-(5-ethyl-3-methoxy-2-octyloxyphenyl)methanamine eluted together with Et.sub.2O and, after evaporation of the ether, was obtained as a viscous, yellow oil (yield: 1.45 g; 92.9% of theory).

Step 3:

[0087] N,N-Dimethyl-1-(5-ethyl-3-methoxy-2-octyloxyphenyl)methanamine (0.96 g, 3 mmol) was charged and 3 equivalents of a 30 wt % aqueous solution of H.sub.2O.sub.2 (9 mmol) were added at once. The turbid reaction mixture was stirred at room temperature overnight or until it appeared clear and homogeneous, indicating complete consumption of the starting material. A catalytic amount of active carbon or MnO.sub.2 was then added and the mixture was stirred for 24 h, or oven-dried Na.sub.2CO.sub.3 (1.06 g, 10 mmol) in 5 ml of ethanol was added and the mixture was stirred for 30 min to decompose the excess H.sub.2O.sub.2. The solid precipitate was then centrifuged off and washed 3 times with abs. EtOH. The combined organic phases were filtered through a 0.2 ?m syringe filter and then concentrated in vacuo on a rotary evaporator, mixed with hexane and concentrated again to completely remove the EtOH. The residue was then completely dried in vacuo, giving the title compound (1) as a clear, yellow oil (yield: 0.98 g; 97.3% of theory).

[0088] .sup.1H NMR: ?.sub.H (600 MHz, Chloroform-d) 6.90 (d, J=2.0 Hz, 1H, C3), 6.81 (d, J=2.0 Hz, 1H, C5), 4.54 (s, 2H, C12), 3.94 (t, J=6.9, 6.9 Hz, 2H, C17), 3.86 (s, 3H, C11), 3.18 (s, 6H, C14, C15), 2.61 (q, J=7.6, 7.6, 7.6 Hz, 2H, C7), 1.77 (p, J=7.1, 7.1, 7.1, 7.1 Hz, 2H, C18), 1.41 (p, J=7.1, 7.1, 6.8, 6.8 Hz, 2H, C19), 1.35-1.19 (m, 11H, C8, C20-23), 0.88 (t, J=6.9, 6.9 Hz, 3H, C24). .sup.13C NMR: (151 MHz, CDCl.sub.3) ?.sub.C 152.7 (C6), 146.0 (C1), 140.4 (C4), 124.6 (C3), 123.9 (C2), 114.0 (C5), 74.0 (C17), 70.5 (C12), 57.4 (C14, C15), 55.9 (C11), 32.0 (C18), 30.4 (C19), 29.5 (C20), 29.4 (C21), 28.7 (C7), 26.1 (C22), 22.8 (C23), 15.7 (C8), 14.2 (C24); HRMS: (ESI.sup.+, m/z) calculated for C.sub.20H.sub.36NO.sub.3 [M+H].sup.+: 338.26929; found: 338.26292.

Example 2

Preparation of N,N-dimethyl-1-(2-decyloxy-5-ethyl-3-methoxyphenyl)methanamine N-oxide (2)

[0089] ##STR00035##

Step 1:

[0090] The synthesis and the product were identical to Example 1.

Step 2:

[0091] The reaction was carried out in an analogous manner to that in Example 1, except that 1-bromodecane was used instead of 1-bromooctane, giving N,N-dimethyl-1-(2-decyloxy-5-ethyl-3-methoxyphenyl)methanamine as a viscous, yellow oil.

Variant 2.1:

[0092] Yield: 1.50 g; 87.6% of theory

Variant 2.2:

[0093] Yield: 1.63 g; 93.2% of theory

Step 3:

[0094] The reaction was carried out in an analogous manner to that in Example 1, except that only 2 mmol of N,N-dimethyl-1-(2-decyloxy-5-ethyl-3-methoxyphenyl)methanamine were used, giving the title compound (2) as a clear, yellow oil (yield: 0.70 g; 96.1% of theory).

[0095] .sup.1H NMR: ?.sub.H (600 MHz, Chloroform-d) 6.89 (d, J=2.0 Hz, 1H, C3), 6.79 (d, J=2.0 Hz, 1H, C5), 4.52 (s, 2H, C17), 3.93 (t, J=6.9, 6.9 Hz, 2H, C18), 3.84 (s, 3H, C11), 3.16 (s, 6H, C14, C15), 2.60 (q, J=7.6, 7.6, 7.6 Hz, 2H, C7), 1.76 (p, J=7.1, 7.1, 7.1, 7.1 Hz, 2H, C18), 1.39 (p, J=7.4, 7.4, 6.9, 6.9 Hz, 2H, C19), 1.34-1.17 (m, 16H, C8, C20-C25), 0.86 (t, J=7.0, 7.0 Hz, 3H, C26). .sup.13C NMR: ?.sub.C (151 MHz, Chloroform-d) 152.6 (C6), 145.9 (C1), 140.3 (C4), 124.5 (C3), 124.0 (C2), 113.9 (C5), 74.0 (C17), 70.5 (C12), 57.5 (C14, C15), 55.8 (C11), 32.0 (C18), 30.4 (C19), 29.7 (C20, C21), 29.5 (C22), 29.4 (C23), 28.7 (C7), 26.1 (C24), 22.8 (C25), 15.6 (C8), 14.2 (C26). HRMS: (ESI.sup.+, m/z) calculated for C.sub.22H.sub.40NO.sub.3 [M+H].sup.+: 366.30027; found: 366.30049.

Example 3

Preparation of N,N-Dimethyl-1-(2-dodecyloxy-5-ethyl-3-methoxyphenyl)methanamin-N-oxid (3)

[0096] ##STR00036##

Step 1:

[0097] The synthesis and the product were identical to Example 1.

Step 2:

[0098] The reaction was carried out in an analogous manner to that in Example 1, except that 1-bromododecane was used instead of 1-bromooctane, giving N,N-dimethyl-1-(2-dodecyloxy-5-ethyl-3-methoxyphenyl)methanamine as a viscous, yellow oil.

Variant 2.1:

[0099] Yield: 1.77 g; 96.0% of theory

Variant 2.2:

[0100] Yield: 1.67 g; 88.4% of theory

Step 3:

[0101] The reaction was carried out in an analogous manner to that in Example 1, except that only 2 mmol of N,N-dimethyl-1-(2-dodecyloxy-5-ethyl-3-methoxyphenyl)methanamine were used, giving the title compound (3) as a clear, yellow oil (yield: 0.50 g; 95.2% of theory).

[0102] .sup.1H NMR: ?.sub.H (600 MHz, Chloroform-d) 6.90 (d, J=2.0 Hz, 1H, C3), 6.81 (d, J=2.0 Hz, 1H, C5), 4.54 (s, 2H, C12), 3.94 (t, J=6.9, 6.9 Hz, 2H, C18), 3.86 (s, 3H, C11), 3.18 (s, 6H C14, C15), 2.61 (q, J=7.6, 7.6, 7.6 Hz, 2H, C7), 1.77 (p, J=7.1, 7.1, 7.1, 7.1 Hz, 2H, C18), 1.41 (p, J=7.3, 7.3, 6.9, 6.9 Hz, 2H, C19), 1.37-1.20 (m, 20H, C8, C20-C27), 0.87 (t, J=6.9, 6.9 Hz, 3H, C28). .sup.13C NMR: ?.sub.C (151 MHz, Chloroform-d) 152.7 (C6), 146.0 (C1), 140.4 (C4), 124.5 (C3), 123.9 (C2), 114.0 (C5), 74.0 (C17), 70.5 (C12), 57.5 (C14, C15), 55.9 (C11), 32.0 (C18), 30.4 (C19), 29.8 (C20), 29.8, (C21), 29.8 (C22), 29.7 (C23), 29.6 (C24), 29.5 (C25), 28.7 (C7), 26.1 (C26), 22.8 (C27), 15.7 (C8), 14.3 (C28); HRMS: (ESI.sup.+, m/z) calculated for C.sub.24H.sub.44NO.sub.3 [M+H].sup.+: 394.33157; found: 394.33176.

Example 4

Preparation of N,N-dimethyl-1-(5-ethyl-3-methoxy-2-tetradecyloxyphenyl)methanamine N-oxide (4)

[0103] ##STR00037##

Step 1:

[0104] The synthesis and the product were identical to Example 1.

Step 2:

[0105] The reaction was carried out in an analogous manner to that in Example 1, except that 1-bromotetradecane was used instead of 1-bromooctane, giving N,N-dimethyl-1-(5-ethyl-3-methoxy-2-tetradecyloxyphenyl)methanamine as a viscous, yellow oil.

Variant 2.1:

[0106] Yield: 1.91 g; 96.1% of theory

Variant 2.2:

[0107] Yield: 1.85 g; 91.1% of theory

Step 3:

[0108] The reaction was carried out in an analogous manner to that in Example 1, except that only 2 mmol of N,N-dimethyl-1-(5-ethyl-3-methoxy-2-tetradecyloxyphenyl)methanamine were used, giving the title compound (4) as a clear, yellow oil (yield: 0.80 g; 94.3% of theory).

[0109] .sup.1H NMR: ?.sub.H (600 MHz, Chloroform-d) 6.89 (d, J=2.0 Hz, 1H, C3), 6.80 (d, J=2.0 Hz, 1H, C5), 4.55 (s, 2H, C12), 3.93 (t, J=6.9, 6.9 Hz, 2H, C17), 3.85 (s, 3H, C11), 3.19 (s, 6H, C14, C15), 2.60 (q, J=7.6, 7.6, 7.6 Hz, 2H, C7), 1.76 (p, J=7.1, 7.1, 7.1, 7.1 Hz, 2H, C18), 1.40 (p, J=7.3, 7.3, 6.9, 6.9 Hz, 2H, C19), 1.34-1.19 (m, 23H, C18, C20-C29), 0.86 (t, J=7.0, 7.0 Hz, 3H, C30). .sup.13C-NMR: ?.sub.C (151 MHz, Chloroform-d) 152.6 (C6), 145.9 (C1), 140.4 (C4), 124.6 (C3), 123.7 (C2), 114.0 (C5), 74.0 (C17), 70.2 (C12), 57.2 (C14, C15), 55.9 (C11), 32.0 (C18), 30.4 (C19), 29.8 (C20, C21), 29.8 (C22, C23), 29.8 (C24), 29.7 (C25), 29.5 (C26), 29.5 (C27), 28.7 (C7), 26.1 (C28), 22.8 (C29), 15.7 (C8), 14.2 (C30); HRMS: (ESI.sup.+, m/z) calculated for C.sub.26H.sub.48NO.sub.3 [M+H].sup.+: 422.36287; found: 422.36323.

Example 5

Preparation of N,N-dimethyl-1-(5-ethyl-2-hexadecyloxy-3-methoxyphenyl)methanamine N-oxide (5)

[0110] ##STR00038##

Step 1:

[0111] The synthesis and the product were identical to Example 1.

Step 2:

[0112] The reaction was carried out in an analogous manner to that in Example 1, except that 1-bromohexadecane was used instead of 1-bromooctane, giving N,N-dimethyl-1-(5-ethyl-2-hexadecyloxy-3-methoxyphenyl)methanamine as a viscous, yellow oil.

Variant 2.1:

[0113] Yield: 2.00 g; 94.0% of theory

Variant 2.2:

[0114] Yield: 2.11 g; 97.4% of theory

Step 3:

[0115] The reaction was carried out in an analogous manner to that in Example 1, except that only 2 mmol of N,N-dimethyl-1-(5-ethyl-2-hexadecyloxy-3-methoxyphenyl)methanamine were used, giving the title compound (5) as a clear, yellow oil (yield: 0.87 g; 97.0% of theory).

[0116] .sup.1H NMR: ?.sub.H (600 MHz, Chloroform-d) 6.90 (d, J=1.9 Hz, 1H, C3), 6.81 (d, J=1.9 Hz, 1H, C5), 4.53 (s, 2H, C11), 3.94 (t, J=6.9, 6.9 Hz, 2H, C17), 3.86 (s, 3H, C11), 3.18 (s, 6H, C14, C15), 2.62 (q, J=7.6, 7.6, 7.6 Hz, 2H, C7), 1.77 (p, J=7.1, 7.1, 7.1, 7.1 Hz, 2H, C18), 1.41 (p, J=7.3, 7.3, 6.9, 6.9 Hz, 2H, C19), 1.36-1.20 (m, 29H, C8, C20-C31), 0.87 (t, J=6.9, 6.9 Hz, 3H, C32). .sup.13C NMR: ?.sub.C (151 MHz, Chloroform-d) 152.7 (C6), 146.0 (C1), 140.4 (C4), 124.5 (C3), 123.9 (C2), 114.0 (C5), 74.0 (C17), 70.5 (C12), 57.5 (C14, C15), 55.9 (C11), 32.1 (C18), 30.4 (C19), 29.8 (C20), 29.8 (C21, C22), 29.8 (C23, C24), 29.8 (C25), 29.7 (C26), 29.6 (C27), 29.5 (C28), 28.7 (C29) (C7), 26.1 (C30), 22.8 (C31), 15.7 (C8), 14.3 (C32). HRMS: (ESI.sup.+, m/z) calculated for C.sub.28H.sub.52NO.sub.3 [M+H].sup.+: 450.39417; found: 450.39428.

Example 6

Preparation of N,N-dimethyl-1-(5-ethyl-3-methoxy-2-octadecyloxyphenyl)methanamine N-oxide (6)

[0117] ##STR00039##

Step 1:

[0118] The synthesis and the product were identical to Example 1.

Step 2:

[0119] The reaction was carried out in an analogous manner to that in Example 1, except that 1-bromooctadecane was used instead of 1-bromooctane, giving N,N-dimethyl-1-(5-ethyl-2-octadecyloxy-3-methoxyphenyl)methanamine as a viscous, yellow oil (Variant 2.1; yield: 2.06 g; 91.0% of theory) or as a white, waxy solid (Variant 2.2; yield: 2.00 g; 86.3% of theory.

Step 3:

[0120] The reaction was carried out in an analogous manner to that in Example 1, except that only 2 mmol of N,N-dimethyl-1-(5-ethyl-2-octadecyloxy-3-methoxyphenyl)methanamine were used and 0.5 ml MeOH were added for enhancing solubility, giving the title compound (6) as a white, waxy solid (yield: 0.916 g; 95.9% of theory).

[0121] .sup.1H NMR: ?.sub.H (600 MHz, Chloroform-d) 6.91 (d, J=2.0 Hz, 1H, C3), 6.82 (d, J=2.0 Hz, 1H, C5), 4.56 (s, 2H, C12), 3.95 (t, J=6.9, 6.9 Hz, 2H, C17), 3.86 (s, 3H, C11), 3.19 (s, 6H, C14, C15), 2.62 (q, J=7.6, 7.6, 7.6 Hz, 2H, C7), 1.77 (p, J=7.1, 7.1, 7.1, 7.1 Hz, 2H, C18), 1.41 (p, J=7.2, 7.2, 6.9, 6.9 Hz, 2H, C19), 1.36-1.19 (m, 30H, C8, C20-C33), 0.87 (t, J=7.0, 7.0 Hz, 3H, C34). .sup.13C NMR: ?.sub.C (151 MHz, Chloroform-d) 152.7 (C6), 146.0 (C1), 140.4 (C4), 124.5 (C3), 123.7 (C2), 114.0 (C5), 74.0 (C17), 70.3 (C12), 57.3 (C14, C15), 55.9 (C11), 32.1 (C18), 30.4 (C19), 29.8 (C20, C21, C22, C23), 29.8 (C24, C25, C26, C27), 29.8 (C28), 29.7 (C29), 29.6 (C30), 29.5 (C31), 28.7 (C7), 26.1 (C32), 22.8 (C33), 15.7 (C8), 14.3 (C34); HRMS: (ESI.sup.+, m/z) calculated for C.sub.30H.sub.56NO.sub.3 [M+H].sup.+: 478.42547; found: 478.42540.

Example 7

Preparation of 1-(2-dodecyloxy-5-ethyl-3-methoxybenzyl)pyrrolidine-1-oxide (7)

[0122] ##STR00040##

Step 1:

[0123] An aqueous solution of 4-ethylguaiacol (4.56 g, 30 mmol) was added dropwise to an aqueous solution of pyrrolidine (2.21 g, 31 mmol) in an iced water bath within 15 minutes with constant stirring. Paraformaldehyde (1.35 g, 45 mmol) was added in aliquots of 0.5 g every 10 min and stirred for 3 h in an iced water bath and then for 72 h at room temperature. The reaction mixture was then extracted 5 times with 25 ml of petroleum ether, and the combined organic phases were concentrated in vacuo on a rotary evaporator, whereafter the residue was completely dried in a vacuum desiccator. The aminomethylated intermediate, 4-ethyl-6-methoxy-2-(pyrrolidinomethyl)phenol, was obtained as a viscous, yellowish oil (yield: 6.50 g; 92.1% of theory).

Step 2:

[0124] The reaction was carried out in an analogous manner to that in Example 1, Variant 2.1, except that 1-bromododecane was used instead of 1-bromooctane, giving 1-(2-dodecyloxy-5-ethyl-3-methoxybenzyl)pyrrolidine as a viscous, yellowish oil (yield: 1.93 g; 97.6% of theory).

Step 3:

[0125] The reaction was carried out in an analogous manner to that in Example 1, except that only 2 mmol of 1-(2-dodecyloxy-5-ethyl-3-methoxybenzyl)pyrrolidine were used, giving the title compound (7) as a clear, yellow oil (yield: 0.80 g; 95.5% of theory).

[0126] .sup.1H NMR: ?.sub.H (300 MHz, Chloroform-d) 6.94 (d, J=2.0 Hz, 1H, 2), 6.76 (d, J=2.0 Hz, 1H, 4), 4.64 (s, 2H, 12), 3.91 (t, J=6.9 Hz, 2H, 19), 3.83 (s, 3H, 9), 3.50-3.21 (m, 4H, 14, 17), 2.58 (q, J=7.6 Hz, 2H, 10), 2.49-2.34 (m, 2H, 20), 1.87-1.69 (m, 4H, 15, 16), 1.37-1.15 (m, 21H, 11, 21, 22, 23, 24, 25, 26, 27, 28, 29), 0.85 (t, J=6.9 Hz, 3H, 30). .sup.13C NMR: ?.sub.C (75 MHz, Chloroform-d) .sup.13C-NMR: ?.sub.C (75 MHz, Chloroform-d) 152.5 (5), 145.7 (6), 140.2 (3), 125.1 (2), 124.3 (1), 113.4 (4), 73.9 (19), 65.5 (14, 17), 65.5, (12), 55.8 (9), 32.0 (20), 30.3 (21), 29.7 (22, 23), 29.7 (24, 25), 29.7 (26), 29.5 (27), 29.4 (28), 28.6 (10), 26.1, 22.8, (15, 16), 21.3 (29), 15.6 (11), 14.2 (30); HRMS: (ESI.sup.+, m/z) calculated for C.sub.26H.sub.46NO.sub.3 [M+H].sup.+: 420.34777; found: 420.347257.

Example 8

Preparation of 1-(2-dodecyloxy-5-ethyl-3-methoxybenzyl)piperidine-1-oxide (8)

[0127] ##STR00041##

Step 1:

[0128] The reaction was carried out in an analogous manner to that in Example 7, except that piperidine (2.64 g, 31 mmol) was used instead of pyrrolidine, giving 4-ethyl-6-methoxy-2-(piperidinomethyl)phenol as a yellowish oil (yield: 7.06 g; 94.4% of theory).

Step 2:

[0129] The reaction was carried out in an analogous manner to that in Example 1, Variant 2.1, except that 10 mmol of 4-ethyl-6-methoxy-2-(piperidinomethyl)phenol and 1-bromododecane instead of 1-bromooctane were used, giving 1-(2-dodecyloxy-5-ethyl-3-methoxybenzyl)piperidine as a yellowish oil (yield: 3.93 g; 94.1% of theory).

Step 3:

[0130] The reaction was carried out in an analogous manner to that in Example 1, except that 5 mmol of 1-(2-dodecyloxy-5-ethyl-3-methoxybenzyl)piperidine were used, giving the title compound (8) as a clear, yellow oil (yield: 2.10 g; 96.8% of theory).

[0131] .sup.1H NMR: ?.sub.H (300 MHz, Chloroform-d) 6.99 (d, J=2.0 Hz, 1H), 6.79 (d, J=2.0 Hz, 1H), 4.50 (s, 2H), 3.92 (t, J=1 6.9 Hz, 2H), 3.85 (s, 3H), 3.29 (d, J=11.8 Hz, 2H), 3.04 (td, J=12.2, 3.1 Hz, 2H), 2.61 (q, J=7.6 Hz, 2H), 2.47-2.26 (m, 2H), 1.85-1.02 (m, 28H), 0.87 (t, J=7.0, 6.2 Hz, 3H). .sup.13C NMR: ?.sub.C (75 MHz, Chloroform-d) 152.4, 146.0, 140.1, 125.3, 123.5, 113.5, 74.0, 70.6, 63.7, 55.8, 32.0, 30.4, 29.8, 29.8, 29.8, 29.6, 29.5, 28.7, 26.2, 22.8, 22.0, 20.6, 15.6, 14.2. HRMS: (ESI.sup.+, m/z) calculated for C.sub.27H.sub.48NO.sub.3 [M+H].sup.+: 434.36342; found: 434.362833.

Example 9

Preparation of 1-(2-dodecyloxy-5-ethyl-3-methoxybenzyl)-4-methylpiperazine-1, 4-dioxide (9)

[0132] ##STR00042##

Step 1:

[0133] An aqueous solution of 4-ethylguaiacol (3.04 g, 20 mmol) was added dropwise to an aqueous solution (5 ml) of 1-methylpiperazine (2.64 g, 30 mmol) in an iced water bath within 15 minutes with constant stirring. A 37 wt % aqueous solution of paraformaldehyde (0.90 g, 30 mmol) was added in aliquots of 0.1 g every 10 min and stirred for 3 h in an iced water bath and then for 9 h at room temperature. The precipitated solid was then centrifuged off and re-dissolved in 45 ml of Et.sub.2O. The solution was washed 5 times with 5 ml of water and then concentrated in vacuo on a rotary evaporator, giving the aminomethylated intermediate, 4-ethyl-6-methoxy-2-(4-methylpiperazinomethyl)phenol, as a white powder (yield: 1.65 g; 31.1% of theory).

Step 2:

[0134] The reaction was carried out in an analogous manner to that in Example 1, Variant 2.2, except that 1-bromododecane was used instead of 1-bromooctane, giving 1-(2-dodecyloxy-5-ethyl-3-methoxybenzyl)-4-methylpiperazine as an off-white powder (yield: 0.28 g; 12.9% of theory).

Step 3:

[0135] The reaction was carried out in an analogous manner to that in Example 1, except that 0.125 mmol of 1-(2-dodecyloxy-5-ethyl-3-methoxybenzyl)-4-methylpiperazine were used, giving the title compound (9) as an off-white powder (yield: 0.058 g; 99.9% of theory).

[0136] .sup.1H NMR: ?.sub.H (300 MHz, CDCl.sub.3) 6.97 (d, J=2.0 Hz, 1H), 6.79 (d, J=2.0 Hz, 1H), 4.46 (s, 2H), 4.39-4.18 (m, 4H), 3.95 (t, J=7.0, 7.0 Hz, 2H), 3.83 (s, 3H), 3.25 (s, 3H), 3.01 (dd, J=15.4, 9.6 Hz, 4H), 2.60 (q, J=7.6, 7.6, 7.6 Hz, 2H), 1.81-1.68 (m, 2H), 1.45-1.13 (m, 22H), 0.85 (d, J=6.8 Hz, 3H). .sup.13C NMR: ?.sub.C (75 MHz, CDCl.sub.3) 152.2, 145.8, 140.3, 125.4, 121.6, 114.4, 74.0, 69.3, 60.0, 59.1, 57.8, 55.8, 32.0, 29.9, 29.8, 29.8, 29.7, 29.5, 29.4, 28.6, 25.8, 22.8, 15.5, 14.2. HRMS: (ESI.sup.+, m/z) calculated for C.sub.27H.sub.48N.sub.2O.sub.4 [M+H].sup.+: 465.368684 found: 465.367767.

Example 10

Preparation of N,N-dimethyl-N-(2-dodecyloxy-5-ethyl-3-methoxybenzyl)-N-methylethane-1,2-diamine di-N-oxide (10)

[0137] ##STR00043##

Step 1:

[0138] The reaction was carried out in an analogous manner to that in Example 7, except that N,N,N-trimethylethane-1,2-diamine (3.07 g, 30 mmol) was used instead of pyrrolidine, giving 2-(2-dimethylaminoethyl)aminomethyl-4-ethyl-6-methoxyphenol as an off-white powder (yield: 4.59 g; 86.3% of theory).

Step 2:

[0139] The reaction was carried out in an analogous manner to that in Example 1, Variant 2.2, except that 1-bromododecane was used instead of 1-bromooctane, giving N,N-dimethyl-N-(2-dodecyloxy-5-ethyl-3-methoxybenzyl)-N-methylethane-1,2-diamine as an off-white powder (yield: 1.17 g; 53.8% of theory).

Step 3:

[0140] The reaction was carried out in an analogous manner to that in Example 1, except that 1 mmol of N,N-dimethyl-N-(2-dodecyloxy-5-ethyl-3-methoxybenzyl)-N-methylethane-1,2-diamine was used, giving the title compound (10) as as an off-white powder (yield: 0.97 g; 69.0% of theory).

[0141] .sup.1H NMR: ?.sub.H (300 MHz, CDCl.sub.3) 6.95 (d, J=2.0 Hz, 1H), 6.80 (d, J=2.0 Hz, 1H), 4.49 (d, J=12.4 Hz, 1H), 4.36 (d, J=12.4 Hz, 1H), 4.07-3.92 (m, 2H), 3.91-3.79 (m, 3+3H), 3.67 (q, J=7.0, 7.0, 7.0 Hz, 1H), 3.33-3.17 (m, 6H), 3.04 (s, 3H), 2.70-2.56 (m, 2H), 1.75 (dd, J=10.8, 4.7 Hz, 2H), 1.45-1.35 (m, 2H), 1.35-1.17 (m, 28H), 0.85 (t, J=6.9 Hz, 3H). .sup.13C NMR: ?.sub.C (75 MHz, CDCl.sub.3) 152.6, 146.0, 140.4, 124.2, 114.1, 74.0, 64.6, 55.9, 32.0, 30.4, 29.8, 29.7, 29.6, 29.5, 28.7, 26.1, 22.8, 15.7, 14.2.

Example 11

Preparation of 1,1-(2,3-dioctyloxy-5-ethyl-1,4-phenylene)-bis(N,N-dimethylmethanamine N-oxide) and 1,1-(2,3-dioctyloxy-5-ethyl-1,6-phenylene)-bis(N,N-dimethylmethanamine N-oxide) (11)

[0142] ##STR00044##

Step 1:

[0143] An aqueous solution of 4-ethylcatechol (1.0 g, 7.24 mmol) was added dropwise and under argon atmosphere to a 40 wt % aqueous solution of dimethylamine (0.98 g, 21.7 mmol) in an iced water bath within 15 minutes with constant stirring. 10 ml of a 37 wt % aqueous solution of paraformaldehyde (0.65 g, 21.7 mmol) were added in 5 aliquots every 10 min and stirred for 2 h in an iced water bath and then for 58 h at room temperature. The reaction mixture was then extracted 5 times with 10 ml of Et.sub.2O, and the combined organic phases were washed 5 times with 5 ml of water and then concentrated in vacuo on a rotary evaporator, whereafter the residue was completely dried in a vacuum desiccator, giving a mixture of the twice aminomethylated intermediates, 3,4- and 3,6-bis(dimethylaminomethyl)-5-ethylcatechol as an off-white powder (yield: 1.20 g; 65.5% of theory).

Step 2:

[0144] The reaction was carried out in an analogous manner to that in Example 1, Variant 2.2, except that it was carried out under argon atmosphere for 12 h and that flash chromatography was conducted using a petroleum ether/ethyl acetate gradient, giving a mixture of 1,1-(2,3-dioctyloxy-5-ethyl-1,4-phenylene)-bis(N,N-dimethylmethanamine) and 1,1-(2,3-dioctyloxy-5-ethyl-1,6-phenylene)-bis(N,N-dimethylmethanamine) as a yellow oil (yield: 0.15 g; 12.3% of theory).

[0145] .sup.1H NMR: ?.sub.H (300 MHz, Chloroform-d) ? 6.91 (s, 1H), 3.92 (dt, J=8.2, 6.7 Hz, 4H), 3.40 (d, J=7.1 Hz, 4H), 2.71 (q, J=7.5 Hz, 2H), 2.24 (d, J=6.6 Hz, 12H), 1.75 (dt, J=8.3, 6.3 Hz, 4H), 1.53-1.39 (m, 4H), 1.36-1.25 (m, 18H), 1.19 (t, J=7.5 Hz, 3H), 0.94-0.83 (m, 6H). .sup.13C NMR: ?.sub.C (75 MHz, Chloroform-d) 151.5, 148.9, 139.9, 131.4, 129.7, 125.3, 73.4 (d, J=2.2 Hz), 58.2, 54.2, 45.7, 32.0, 30.7 (d, J=2.0 Hz), 29.7, 29.5, 26.4 (d, J=1.5 Hz), 25.3, 22.8, 15.7, 14.3. Elemental Analysis: Expected: C, 75.57; H, 11.84; N, 5.88; Found: C, 75.34; H, 11.85; N, 5.56; HRMS: (ESI.sup.+, m/z) calculated for C.sub.30H.sub.57N.sub.2O.sub.2 [M+H].sup.+: 477.4420; found: 477.441284.

Step 3:

[0146] The reaction was carried out in an analogous manner to that in Example 1, except that 0.25 mmol of the amine mixture were used; however, as a result of side reactions, the title compounds (11) were obtained in a mixture with several by-products. The optimization of this oxidation reaction is currently the subject of the inventors' research.

Example 12

Preparation of 1,1-(5-ethyl-2-octyloxy-1,3-phenylene)-bis(N,N-dimethylmethanamine N-oxide) (12)

[0147] ##STR00045##

Step 1:

[0148] An aqueous solution of 4-ethylphenol (6.11 g, 50 mmol) was added dropwise to a 40 wt % aqueous solution of dimethylamine (6.76 g, 150 mmol) in an iced water bath within 15 minutes with constant stirring. Paraformaldehyde (4.50 g, 150 mmol) was added in aliquots of 1.5 g every 10 min and stirred for 2 h in an iced water bath and then for 58 h at room temperature. The reaction mixture was then extracted 5 times with 25 ml of petroleum ether, and the combined organic phases were washed 5 times with 4 ml of water and then concentrated in vacuo on a rotary evaporator, whereafter the residue was completely dried in a vacuum desiccator. The twice aminomethylated intermediate, 2,6-bis(dimethylaminomethyl)-4-ethylphenol, was obtained as a viscous, clear oil (yield: 11.02 g; 93.3% of theory).

Step 2:

[0149] The reaction was carried out in an analogous manner to that in Example 1, Variant 2.2, except that the KOH was added in two portions (0.28 g each at the start and after 2 h) and that flash chromatography was conducted using a petroleum ether/ethyl acetate gradient, giving 1,1-(5-ethyl-2-octyloxy-1,3-phenylene)-bis(N,N-dimethylmethanamine) as a yellow oil (yield: 1.54 g; 8.6% of theory).

Step 3:

[0150] The reaction was carried out in an analogous manner to that in Example 1, giving the title compound (12) as a viscous, clear, yellow oil (yield: 1.12 g; 97.9% of theory).

[0151] .sup.1H NMR: ?.sub.H (300 MHz, Chloroform-d) 7.51 (s, 2H, C2, C4), 4.48 (s, 4H, C8, C11), 3.71 (t, J=6.8, 6.8 Hz, 2H, C19), 3.16 (s, 12H, C13, C14, C16, C17), 2.67-2.54 (m, 2H, C9), 1.89-1.76 (m, 2H, C20), 1.45-1.34 (m, 2H, C21), 1.33-1.04 (m, 14H, C10, C22-C25), 0.85 (t, J=6.7 Hz, 3H, C26). .sup.13C NMR: ?.sub.C (75 MHz, Chloroform-d) 156.4 (C6), 141.1 (C3), 136.7 (C1, C5), 124.0 (C2, C4), 69.4 (C8, C11), 57.6 (C13, C14, C16, C17), 31.9 (C20), 30.4 (C21), 29.5 (C22), 29.3 (C23), 28.0 (C9), 26.2 (C24), 22.7 (C25), 15.3 (C10), 14.2 (C26). HRMS: (ESI.sup.+, m/z) calculated for C.sub.22H.sub.41NO.sub.3 [M+H].sup.+: 381.31172; found: 381.310922.

Example 13

Preparation of 1,1-(2-dodecyloxy-5-ethyl-1,3-phenylene)-bis(N,N-dimethylmethanamine N-oxide) (13)

[0152] ##STR00046##

Step 1:

[0153] The synthesis and the product were identical to Example 12.

Step 2:

[0154] The reaction was carried out in an analogous manner to that in Example 1, Variant 2.2, except that 1-bromododecane was used instead of 1-bromooctane, that the KOH was added in two portions (0.28 g each at the start and after 2 h) and that flash chromatography was conducted using a petroleum ether/ethyl acetate gradient, giving 1,1-(2-dodecyloxy-5-ethyl-1,3-phenylene)-bis(N,N-dimethylmethanamine) as a yellow oil (yield: 1.53 g; 75.7% of theory).

Step 3:

[0155] The reaction was carried out in an analogous manner to that in Example 1, except that only 2.5 mmol of 1,1-(2-dodecyloxy-5-ethyl-1,3-phenylene)-bis(N,N-dimethylmethanamine) were used, giving the title compound (13) as an off-white, waxy solid (yield: 0.70 g; 96.1% of theory).

[0156] .sup.1H NMR: ?.sub.H (300 MHz, Chloroform-d) 7.53 (s, 2H, C2, C4), 4.49 (s, 4H, C8, C11), 3.74 (t, J=6.8 Hz, 2H, C19), 3.19 (s, 12H, C13, C14, C16, C17), 2.64 (q, J=7.6 Hz, 2H, C9), 1.84 (t, J=7.4 Hz, 2H, C20), 1.46-1.37 (m, 2H, C21), 1.32-1.17 (m, 22H, C10, C22-C29), 0.87 (t, J=6.9 Hz, 3H, C30). .sup.13C NMR: ?.sub.C (75 MHz, Chloroform-d) 156.4 (C6), 141.2 (C3), 136.8 (C1, C5), 123.9 (C2, C4), 69.4 (C8, C11), 57.6 (C13, C14, C16, C17), 32.0 (C20), 30.5 (C21), 29.8 (C22, C24, C25), 29.6 (C26), 29.5 (C27), 28.1 (C9), 26.3 (C28), 22.8 (C29), 15.4 (C10), 14.3 (C30). HRMS: (ESI.sup.+, m/z) calculated for C.sub.26H.sub.49NO.sub.3 [M+H].sup.+: 437.37432; found: 437.373256.

Example 14

Preparation of 1,1-(5-ethyl-2-hexadecyloxy-1,3-phenylene)-bis(N,N-dimethylmethanamine N-oxide) (14)

[0157] ##STR00047##

Step 1:

[0158] The synthesis and the product were identical to Example 12.

Step 2:

[0159] The reaction was carried out in an analogous manner to that in Example 13, except that 1-bromohexadecane was used instead of 1-bromooctane, giving 1,1-(5-ethyl-2-hexadecyloxy-1,3-phenylene)-bis(N,N-dimethylmethanamine) as a yellow oil (yield: 1.57 g; 68.1% of theory).

Step 3:

[0160] The reaction was carried out in an analogous manner to that in Example 13, giving the title compound (14) as an off-white, waxy solid (yield: 1.20 g; 97.2% of theory).

[0161] .sup.1H NMR: ?.sub.H (300 MHz, Chloroform-d) 7.54 (s, 2H, C2, C4), 4.50 (s, 4H, C8, C11), 3.74 (t, J=6.8 Hz, 2H, C19), 3.17 (s, 12H, C13, C14, C16, C17), 2.65 (q, J=7.5 Hz, 2H, C9), 1.88-1.82 (m, 2H, C20), 1.48-1.39 (m, 2H, C21), 1.30-1.21 (m, 29H, C10, C22-C33), 0.86 (t, J=7.0 Hz, 3H, C34). .sup.13C NMR: ?.sub.C (75 MHz, Chloroform-d) 156.4 (C6), 141.2 (C3), 136.7 (C1, C5), 124.2 (C2, C4), 69.6 (C8, C11), 57.8 (C13, C14, C16, C17), 32.0 (C20), 30.5 (C21), 30.0-29.3 (m) (C22-C31), 28.1 (C9), 26.3 (C32), 22.8 (C33), 15.4 (C10), 14.3 (C34). HRMS: (ESI.sup.+, m/z) calculated for C.sub.30H.sub.57N.sub.2O.sub.3 [M+H].sup.+: 493.43692; found: 493.436311.

Example 15

Preparation of 1,1-(5-ethyl-2-octadecyloxy-1,3-phenylene)-bis(N,N-dimethylmethanamine N-oxide) (15)

[0162] ##STR00048##

Step 1:

[0163] The synthesis and the product were identical to Example 12.

Step 2:

[0164] The reaction was carried out in an analogous manner to that in Example 13, except that 1-bromooctadecane was used instead of 1-bromododecane, giving 1,1-(5-ethyl-2-octadecyloxy-1,3-phenylene)-bis(N,N-dimethylmethanamine) as an off-white, waxy solid (yield: 1.61 g; 66.0% of theory).

Step 3:

[0165] The reaction was carried out in an analogous manner to that in Example 13, giving the title compound (15) as a yellowish, waxy solid (yield: 1.00 g; 96.2% of theory).

[0166] .sup.1H NMR: ?.sub.H (300 MHz, Chloroform-d) 7.51 (s, 2H, C2, C4), 4.40 (s, 4H, C8, C11), 3.72 (t, J=6.8 Hz, 2H, C19), 3.08 (s, 12H, C13, C14, C16, C17), 2.65 (q, J=7.7 Hz, 2H, C9), 1.88-1.77 (m, 2H, C20), 1.45-1.36 (m, 2H, C21), 1.26-1.18 (m, 33H, C10, C22-C35), 0.84 (t, J=7.0 Hz, 3H, C36). .sup.13C NMR: ?.sub.C (75 MHz, Chloroform-d) 156.2 (C6), 141.2 (C3), 136.3 (C1, C5), 124.6 (C2, C4), 70.2 (C8, C11), 58.1 (C13, C14, C16, C17), 32.0 (C20), 30.5 (C21), 29.9-29.6 (m) (C.sub.22-C.sub.31), 29.5 (C32), 29.4 (C33), 28.1 (C9), 26.2 (C34), 22.8 (C35), 15.3 (C10), 14.2 (C36); HRMS: (ESI.sup.+, m/z) calculated for C.sub.32H.sub.61NO.sub.3 [M+H].sup.+: 521.46822; found: 521.467246.

Example 16

Preparation of 1,4-bis(5-ethyl-3-methoxy-2-octyloxybenzyl)piperazine-1,4-dioxide (16)

[0167] ##STR00049##

Step 1:

[0168] An aqueous solution of 4-ethylguaiacol (3.04 g, 20 mmol) was added dropwise to an aqueous solution (10 ml) of piperazine (1.29 g, 15 mmol) in an iced water bath within 15 minutes with constant stirring. A 37 wt % aqueous solution of formaldehyde (0.90 g, 30 mmol) was added in aliquots of 0.1 g every 10 min and stirred for 3 h in an iced water bath and then for 9 h at room temperature. The precipitated solid was then filtered off (glass frit, porosity 4), suspended in 10 ml petroleum ether, mixed by sonication, then centrifuged off and completely dried in a vacuum desiccator, giving the dimeric intermediate, 6,6-(piperazine-1,4-dimethylene)-bis(4-ethyl-2-methoxyphenol), in the form of white needles (yield: 3.40 g; 82.1% of theory).

Step 2:

[0169] The reaction was carried out in an analogous manner to that in Example 1, Variant 2.2, except that 2.12 g (11 mmol) 1-bromooctane were used, that 40 ml 2-MeTHF were used as a solvent, and that flash chromatography was conducted using a petroleum ether/ethyl acetate gradient, giving 1,4-bis(5-ethyl-3-methoxy-2-octyloxybenzyl)piperazine as a white powder (yield: 1.45 g; 45.4% of theory).

Step 3:

[0170] The reaction was carried out in an analogous manner to that in Example 1, except that only 1 mmol of 1,4-bis(5-ethyl-3-methoxy-2-octyloxybenzyl)piperazine was used and that methyl formate (15 ml) was added as an additional solvent, giving the title compound (16) as a white, waxy solid (yield: 0.21 g; 31.6% of theory).

[0171] .sup.1H NMR: ?.sub.H (300 MHz, Chloroform-d) 6.94 (d, J=2.0 Hz, 2H), 6.77 (d, J=2.0 Hz, 2H), 4.45 (s, 4H), 4.28 (d, J=8.3 Hz, 4H), 3.93 (t, J=7.0 Hz, 4H), 3.82 (s, 6H), 3.02 (d, J=8.1 Hz, 4H), 2.59 (q, J=7.6 Hz, 4H), 1.74 (q, J=7.0 Hz, 4H), 1.44-1.15 (m, 26H), 0.93-0.82 (m, 6H). .sup.13C NMR: ?.sub.C (75 MHz, Chloroform-d) 152.4, 139.8, 125.2, 122.4, 114.1, 73.7, 58.6, 55.9, 32.0, 30.4, 29.5, 29.4, 28.6, 26.0, 22.8, 15.4, 14.3. HRMS: (ESI.sup.+, m/z) calculated for C.sub.40H.sub.67N.sub.2O.sub.6 [M+H].sup.+: 671.49991; found: 671.498929.

Example 17

Preparation of 1,4-bis(2-dodecyloxy-5-ethyl-3-methoxybenzyl)piperazine-1,4-dioxide (17)

[0172] ##STR00050##

Step 1:

[0173] The synthesis and the product were identical to Example 16.

Step 2:

[0174] The reaction was carried out in an analogous manner to that in Example 16, except that 1-bromododecane was used instead of 1-bromooctane, giving 1,4-bis(2-dodecyloxy-5-ethyl-3-methoxybenzyl)piperazine as a white powder (yield: 1.61 g; 79.6% of theory).

[0175] .sup.1H NMR: ?.sub.H (600 MHz, Chloroform-d) 6.77 (2H, d, J 2.0), 6.63 (2H, d, J 2.0), 3.89 (4H, t, J 6.8), 3.82 (6H, s), 3.52 (4H, s), 2.66-2.32 (12H, m), 1.75 (4H, p, J 6.9), 1.48-1.40 (4H, m), 1.37-1.23 (36H, m), 1.22 (6H, t, J 7.6), 0.88 (6H, t, J 7.0). .sup.13C NMR: ?.sub.C (151 MHz, Chloroform-d) 152.7, 145.2, 139.5, 131.8, 121.9, 110.9, 73.6, 56.8, 55.9, 53.4, 32.1, 30.5, 29.9-29.8 (m), 29.7, 29.5, 28.9, 26.3, 22.8, 15.8, 14.3. Elemental Analysis: Expected: C, 76.75; H, 11.00; N, 3.73; Found: C, 76.18; H, 10.51; N, 3.67; HRMS: (ESI.sup.+, m/z) calculated for C.sub.48H.sub.83N.sub.2O.sub.4 [M+H].sup.+: 751.63474; found: 751.63595.

Step 3:

[0176] The reaction was carried out in an analogous manner to that in Example 1; however, as a result of the poor solubility of 1,4-bis(2-dodecyloxy-5-ethyl-3-methoxybenzyl)piperazine in water, only very low conversion was observed. The optimization of this oxidation reaction using methyl formate as an additional solvent is currently the subject of the inventors' research.

Example 18

Preparation of N,N-bis(5-ethyl-3-methoxy-2-octyloxybenzyl)-N,N-dimethylethane-1,2-diamine di-N-oxide (18)

[0177] ##STR00051##

Step 1:

[0178] The reaction was carried out in an analogous manner to that in Example 16, except that N,N-dimethylethylenediamine was used instead of piperazine, giving 6,6-(N,N-dimethylethan-1,2-diamine-N,N-dimethylene)-bis(4-ethyl-2-methoxyphenol) as a yellowish oil (yield: 1.90 g; 91.4% of theory).

Step 2:

[0179] The reaction was carried out in an analogous manner to that in Example 16, giving N,N-bis(5-ethyl-3-methoxy-2-octyloxybenzyl)-N,N-dimethylethan-1,2-diamine as an off-white powder (yield: 0.91 g; 28.5% of theory).

Step 3:

[0180] The reaction was carried out in an analogous manner to that in Example 16 using methyl formate (15 ml) as an additional solvent, giving the title compound (17) as a white, waxy solid. However, since decomposition reactions of the diamine occurred in the course of the oxidation, the desired product was obtained in admixture with a number of by-products which could hardly be separated even using column chromatography. The optimization of this oxidation reaction is currently the subject of the inventors' research.

Example 19

Tests Regarding the Suitability of the Isolated Amine N-Oxide Compounds According to Formulae (I) and (II) as Surfactants

[0181] As a parameter for the surfactant properties of the novel amine-N-oxide compounds, as usual, the critical micelle concentration (CMC), i.e. the concentration of the protonated or cationic form of the surfactants at which micelles can form was used and was determined using a K100C Force Tensiometer from Kr?ss Scientific according to the Wilhelmy plate method at 25? C. and pH 3. For comparison, dodecyldimethylamine N-oxide (C1) was measured under the same conditions. The results are given in Table 1 below, with lower values indicating a stronger surfactant effect of the respective substance.

TABLE-US-00001 TABLE 1 Compound CMC (mmol/l) (1) 4.1 ? 10.sup.3 (2) 5.7 ? 10.sup.2 (3)/(3)* 89/19 (4) 5.2 (5) 4.0 (6) 1.3 (7) 36 (8) 1.3 ? 10.sup.2 (13) 1.9 ? 10.sup.2 (14) 75 (15) 29 C1 4.2 ? 10.sup.3

[0182] It can be seen that the examples according to the invention, with the exception of Example 1, have lowerand in the majority significantly lowerCMC values than the comparison substance C1, which is used in a large number of commercially available products. However, the highest CMC value of 4.1 mol/l for the amine N-oxide (1) from Example 1, which contains the lowest number of carbon atoms in the radicals R.sup.1 to R.sup.5, also proves its suitability as a surfactant, since this value is almost identical to that of the commercially available compound C1.

[0183] Due to the analogies or high similarities in the substitution patterns of the other compounds according to the invention which have not yet been tested, the relevant person skilled in the art can expect that a strong surfactant effect will also be detectable for the majority of these.

[0184] In addition, when solutions of these amine N-oxide surfactants were examined in double distilled water at concentrations of 10 mg/ml each using cryogenic electron microscopy, a previously unknown phenomenon was surprisingly discovered: The ends of the worm-like micelles formed by the surfactants are folded, i.e. they are not present in an elongated form, as has been consistently reported so far. As an example, a cryogenic electron microscope image of such a solution of the amine N-oxide compound (13) from Example 13 is shown in FIG. 1 together with a schematic representation of the worm-like micelles observed therein, which have a size of 40 nm to 76 nm.

[0185] The present invention thus provides a method for the preparation of novel amine N-oxide compounds which comprises only three relatively simple synthesis steps and through which the novel amine N-oxides can be obtained in very good yields and in an economical and environmentally friendly manner, the vast majority of which are suitable for use as surfactants.