PROCESS FOR PREPARING TERTIARY AMINES

Abstract

Provided is a simple and environmentally friendly process for preparing tertiary amines by the aminomethylation of alkenes. This process features relatively mild reaction conditions and no metal catalyst.

Claims

1. A process for preparing a tertiary amine by a reaction of an alkene comprising a liner alkene represented by formula (I) or a cycloalkene and a secondary amine represented by formula (II) in the presence of formaldehyde and a reducing agent, ##STR00004## wherein: R.sup.1, R.sup.2, and R.sup.3 are the same or different and each independently are H or a hydrocarbon radical, wherein the hydrocarbon radical is optionally interrupted by one or more heteroatoms and/or heteroatom(s) containing groups and/or which is optionally substituted with one or more functional groups.

2. The process according to claim 1, wherein R.sup.1 is an alkyl having carbon atoms from 1 to 24, an aryl or heteroaryl, and is optionally substituted or optionally further substituted with one or more functional groups.

3. The process according to claim 1, wherein R.sup.2 and R.sup.3 are the same or different and each independently comprise a C.sub.1-C.sub.24 alkyl, and are optionally substituted or optionally further substituted with one or more functional groups.

4. The process according to claim 1, wherein R.sup.2 and R.sup.3 are the same or different and each independently comprise aryl or heteroaryl, and are optionally substituted or optionally further substituted with one or more functional groups.

5. The process according to claim 1, wherein the cycloalkene comprises a heteroatom in the ring.

6. The process according to claim 1, wherein the cycloalkene is selected from the group consisting of cyclohexene, cyclooctene, norbornene and mixtures thereof.

7. The process according to claim 1, wherein the liner alkene is selected from the group consisting of 1-pentene, 1-hexene, 1-heptene, 1-octene, 1-nonene, 1-decene, 1-undecene, 1-dodecene, 1-tridecene, and mixtures thereof.

8. The process according to claim 1, wherein the liner alkene is selected from the group consisting of styrene, 1-fluoro-4-vinylbenzene, 1-chloro-4-vinylbenzene, 1-chloro-2-vinylbenzene, 1-chloro-3-vinylbenzene, 1-bromo-3-vinylbenzene, 1-methyl-2-vinylbenzene, 4-vinyl-1,1-biphenyl, 1-(tert-butyl)-4-vinylbenzene, and mixtures thereof.

9. The process according to claim 1, wherein the secondary amine is selected from symmetrical secondary amines; or unsymmetrical secondary amines.

10. The process according to claim 1, wherein the reducing agent is selected from the group consisting of formic acid, sodium cyanoborohydride, sodium borohydride, sodium tetrahydroborate, potassium borohydride, potassium tetrahydroborate, and mixtures thereof.

11. The process according to claim 10, wherein the reducing agent is selected from formic acid, sodium cyanoborohydride or sodium borohydride.

12. The process according to claim 1, wherein the reaction is in the presence of a solvent having the following general formula (III), ##STR00005## wherein p is an integer from 0 to 10.

13. The process according to claim 12, wherein the solvent is hexafluoroisopropanol.

14. The process according to claim 1, wherein a molar ratio of the alkene to the formaldehyde and the secondary amine is from 1:1.2:1.2 to 1:10:10.

15. The process according to claim 1, wherein a molar ratio of the alkene to the reducing agent is from 1:1.2 to 1:16.

16. The process according to claim 1, wherein the reaction temperature is in the range of 20 C. to 60 C.

17. The process according to claim 1, wherein the reaction time is from 10 to 120 hours.

18. The process according to claim 1, the process comprising the steps of: a) mixing formaldehyde, and the alkene comprising a liner alkene represented by formula (I) or the cycloalkene and the secondary amine represented by general formula (II); b) adding the reducing agent, and optionally a solvent represented by the formula (III) to the mixture obtained in step a) to obtain a reaction mixture; c) maintaining the reaction mixture obtained in step b) under proper reaction temperature and proper reaction time to obtain at least one tertiary amine, wherein, the alkene, the secondary amine represented by general formula (II), and the reducing agent are as defined as claim 1, the solvent represented by formula (III), ##STR00006## wherein p is an integer from 0 to 10, the reaction temperature is in the range of 20 C. to 60 C., and the reaction time is from 10 to 120 hours.

19. A composition comprising: (i) formaldehyde, (ii) an alkene, (iii) a secondary amine, (iv) a reducing agent, and (v) optionally a solvent represented by formula (III), ##STR00007## wherein p is an integer from 0 to 10, and wherein the alkene comprising a liner alkene represented by formula (I) or a cycloalkene, the secondary amine represented by general formula (II), the reducing agent are as defined as claim 1.

20. The process according to claim 1, wherein R1 is an alkyl having carbon atoms from 1 to 18, an aryl or heteroaryl, and is optionally substituted or optionally further substituted with one or more functional groups.

Description

DETAILS OF THE INVENTION

[0022] The present invention provides a process for preparing a tertiary amine by a reaction of an alkene comprising a liner alkene represented by formula (I) or a cycloalkene and a secondary amine represented by formula (II) in the presence of formaldehyde and a reducing agent,

##STR00002##

[0023] wherein: [0024] R.sup.1, R.sup.2, and R.sup.3 are same or different and each independently H or a hydrocarbon radical which is optionally interrupted by one or more heteroatoms and/or heteroatom(s) containing groups and/or which is optionally substituted with one or more functional groups.

[0025] In some embodiments, R.sup.1 is an alkyl having carbon atoms from 1 to 24, preferably from 1 to 18, even more preferably from 1 to 16 (such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl or decyl), an aryl or heteroaryl, optionally substituted or optionally further substituted with one or more functional groups.

[0026] In some embodiments, R.sup.1 is H.

[0027] As previously expressed, R.sup.2 and R.sup.3 are same or different and each independently a hydrocarbon radical which is optionally interrupted by one or more heteroatoms and/or heteroatom(s) containing groups and/or which is optionally substituted with one or more functional groups.

[0028] In some embodiments, R.sup.2 and R.sup.3 are different and each independently a C.sub.1-C.sub.24 alkyl, preferably a C.sub.1-C.sub.16 alkyl, more preferably C.sub.1-C.sub.12 alkyl, even more preferably C.sub.1-C.sub.10 alkyl, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl or decyl, optionally substituted or optionally further substituted with one or more functional groups.

[0029] In some embodiments, R.sup.2 and R.sup.3 are same, such as a C.sub.1-C.sub.24 alkyl, preferably a C.sub.1-C.sub.16 alkyl, more preferably C.sub.1-C.sub.12 alkyl, even more preferably C.sub.1-C.sub.10 alkyl, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl or decyl, optionally substituted or optionally further substituted with one or more functional groups.

[0030] In some embodiments, R.sup.2 and R.sup.3 are same or different and each independently aryl or heteroaryl, optionally substituted or optionally further substituted with one or more functional groups, such as benzyl group, phenethyl group and etc.

[0031] In some embodiments, the secondary amines can be selected from symmetrical amines such as diethylamine, dibutylamine, dipropyl, dibenzylamines or the mixture thereof.

[0032] In some embodiments, the secondary amines can be selected from unsymmetrical secondary amines comprising N-ethyl, N-propyl, N-pentyl- and N-octylmethylamine, a mixture of N-dimethylated and N-monomethylated amines, such as N-methyl-ethylamine, N-methyl-propylamine, N-methyl-propylamine, N-methyl-octylamine or mixture thereof.

[0033] In some embodiments, the alkene represented by general formula (I) can be styrene or styrene substituted with alkyl, phenyl, halo or alkoxy. Said alkyl can be a C.sub.1-C.sub.16 straight or branched chain alkyl. Preferably, C.sub.1-C.sub.6 straight chain alkyl can be selected from the group consisting of methyl, ethyl, 1-propyl, n-butyl and n-pentyl. Preferably, C.sub.1-C.sub.6 branched chain alkyl can be isopropyl or isobutyl. Said alkoxy preferably can be a C.sub.1-C.sub.6 alkoxy and more preferably methoxy or ethoxy. Said halo can be F, Cl, Br or I.

[0034] In some embodiments, the liner alkene represented by general formula (I) is selected from 1-pentene, 1-hexene, 1-heptene, 1-octene, 1-nonene, 1-decene, 1-undecene, 1-dodecene, 1-tridecene, or the mixture thereof.

[0035] In some embodiments, the liner alkene represented by general formula (I) is selected from 1-fluoro-4-vinylbenzene, 1-chloro-4-vinylbenzene, 1-chloro-2-vinylbenzene, 1-chloro-3-vinylbenzene, 1-bromo-3-vinylbenzene, 1-methyl-2-vinylbenzene, 4-vinyl-1,1-biphenyl, 1-(tert-butyl)-4-vinylbenzene, or the mixture thereof.

[0036] Cyclic alkene or cycloalkene are hydrocarbons containing a ring of carbon atoms and one or more double bonds in the cycle that do not form an aromatic ring, such as five-membered ring, six-membered ring, seven-membered ring, eight-membered ring. It can be monocyclic, bicyclic or polycyclic alkene, which can be substituted, optionally further substituted, with one or more functional groups.

[0037] In some embodiments, the cyclioalkene is selected from cyclohexene, cyclooctene or norbornene, which is optionally substituted or optionally further substituted with one or more functional group.

[0038] The reducing agent as used herein is to prevent the reduction of alkene and provide hydride donor to prevent the formation of quaternary amines.

[0039] In some embodiments, the reducing agent is selected from formic acid, sodium cyanoborohydride, sodium borohydride, sodium tetrahydroborate, potassium borohydride, potassium tetrahydroborate, preferably selected from formic acid, sodium cyanoborohydride or sodium borohydride, more preferably selected from formic acid or sodium cyanoborohydride, most preferably selected from formic acid.

[0040] In some embodiments, according to the process of the present invention, at least one solvent is further employed and can be a compound having the following general formula (III).

##STR00003##

[0041] wherein p is an integer from 0 to 10.

[0042] Non limitative examples of the compound having the general formula (III) is hexafluoroisopropanol (HFIP).

[0043] The term alkyl as used herein refers to a linear, branched, or cyclic saturated hydrocarbon group, which typically (though not necessarily) contains 1 to about 24 carbon atoms, or 1 to about 18 carbon atoms, or 1 to about 16 carbon atoms, or 1 to about 16 carbon atoms. The alkyl can be substituted alkyl, optionally further substituted, with one or more functional groups. Certain embodiments provide that the alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, octyl, decyl, etc., and cycloalkyl groups such as cyclopentyl group, cyclohexyl, etc. Generally, although it is not necessary again, the alkyl group here contains 1 to about 14 carbon atoms. The term cycloalkyl means a cyclic alkyl group, typically having 4 to 8, preferably 5 to 8 carbon atom. The term substituted alkyl refers to an alkyl group substituted with one or more substituent groups, and includes heteroatom-containing alkyl and heteroalkyl, these terms refer to where a heteroatom replaces at least one carbon atom of the alkyl group. If not otherwise specified, the term alkyl include linear, branched, cyclic, unsubstituted, substituted, and/or heteroatom-containing alkyl, respectively.

[0044] As used herein, the term aryl means a monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms which is optionally substituted independently with one to four substituents, preferably one, two, or three substituents selected from alkyl, alkenyl, alkynyl, aryl, halo, nitro, cyano, hydroxy, alkoxy, amino, mono-alkylamino, di-alkylamino and heteroalkyl.

[0045] As used herein, the term heteroaryl means a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C, with the understanding that the attachment point of the heteroaryl radical will be on an aromatic ring. The heteroaryl ring is optionally substituted independently with one to four substituents, preferably one or two substituents, selected from alkyl, aryl, halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino, mono-alkylamino, di-alkylamino, heteroalkyl. More specifically the term heteroaryl includes, but is not limited to, pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl.

[0046] Functional as in functional groups means that in the alkyl, aryl, alkene, cycloalkene, amines or other moiety or group, it is at least one hydrogen atom bound on a carbon (or other) atom is replaced with one or more functional groups (such as those described here and above). The term functional group is meant to include any functional species suitable for the use described herein. Specifically, as used herein, the functional group will have to have the ability to react with or bind to the corresponding functional group on the surface of the substrate.

[0047] The terms cyclic and cyclo refer to alicyclic or aromatic groups, which may or may not be substituted and or heteroatom-containing, and which may be monocyclic, bicyclic, or polycyclic. The term alicyclic is used in the conventional sense to refer to an aliphatic cyclic moiety, as opposed to an aromatic cyclic moiety, and may be monocyclic, bicyclic, or polycyclic.

[0048] In addition, if the specific group permits, the above-mentioned functional group may be further substituted with one or more additional functional groups (such as those specifically listed above). Similarly, the aforementioned groups may be further substituted with one or more functional groups (such as those specifically enumerated).

[0049] As used herein, the indication that a group can be optionally substituted or optionally further substituted generally means that such a group unless explicitly or further defined by the context of such reference The group can be substituted by one or more inorganic or organic substituents (such as alkyl, alkenyl, aryl, aralkyl, alkaryl, heteroatom, or heterocyclic group), or can be coordinated by one or more functional groups to metal ions (such as hydroxyl, carbonyl, carboxyl, amino, imino, amido, phosphonic acid, sulfonic acid, or arsenate, or inorganic and organic esters thereof, such as sulfate or phosphate, or salts thereof) replace.

[0050] According to the process of the present invention, formaldehyde can be introduced in the form of an aqueous solution. The concentration of formaldehyde in the aqueous solution can be from 35% to 55% and preferably from 35% to 40%. In a preferred embodiment, the aqueous solution of formaldehyde can be formalin.

[0051] Advantageously, the molar ratio of the alkene to the formaldehyde and the secondary amine is from 1:1.2:1.2 to 1:10:10, preferably 1:2:2 to 1:9:9, more preferably 1:4:4 to 1:8:8.

[0052] Advantageously, the molar ratio of the alkene to the reducing agent is from 1:1.2 to 1:16, preferably 1:2 to 1:14, more preferably 1:3 to 1:10, even more preferably 1:4 to 1:8.

[0053] According to the process of the present invention, the reaction temperature can be lower than 80 C., preferably lower than 60 C. and most preferably lower than 55 C. Advantageously, the reaction temperature is in the range of 20 C. to 60 C., preferably in the range of 25 C. to 55 C., even more preferably in the range of 30 C. to 50 C.

[0054] According to the process of the present invention, the reaction time is not particularly limited. The preferred reaction time can be from 10 to 120 hours, such as 16, 17, 18, 96, 110 hours.

[0055] The process of the present invention may comprise following steps: [0056] a) mixing formaldehyde, an alkene comprising a liner alkene represented by formula (I) or a cycloalkene and a secondary amine represented by general formula (II); [0057] b) adding a reducing agent, optional a solvent represented by the formula (III) to the mixture obtained in step a) to obtain a reaction mixture; [0058] c) maintaining the reaction mixture obtained in step b) under proper reaction temperature and proper reaction time to obtain at least one tertiary amine.

[0059] The alkene, the secondary amine represented by general formula (II), the reducing agent and the solvent represented by the formula (III), the reaction temperature and the reaction time are as defined above.

[0060] Advantageously, the process of the present invention can be a one-pot reaction as there is no need to hydrolysis of a tertiary amine salt to obtain the tertiary amine.

[0061] An aspect of the present invention also provides a composition comprising: [0062] (i) formaldehyde, [0063] (ii) at least one alkene comprising a liner alkene represented by formula (I) or a cycloalkene, [0064] (iii) at least one secondary amine represented by general formula (II), [0065] (iv) a reducing agent, and [0066] (v) optionally a solvent represented by the formula (III).

[0067] The alkene comprising a liner alkene represented by formula (I) or a cycloalkene, the secondary amine represented by general formula (II), the reducing agent and the solvent represented by the formula (III) are as defined above.

[0068] The following examples are included to illustrate embodiments of the invention. Needless to say, the invention is not limited to describe examples.

Experimental Part

Materials

[0069] Dimethylamine (DMA) aqueous (38 wt % aqueous, reagent grade), cas: 100-42-5, Merck [0070] Formalin (37 wt % aqueous, reagent grade), cas: 124-40-3, Merck [0071] HCOOH (reagent grade), cas: 64-18-6, Aladin [0072] Hexafluoroisopropanol (HFIP) (reagent grade), cas: 920-66-1, Aladin [0073] 1-octene (reagent grade), cas: 111-66-0, Aladin [0074] 1-Pentene (reagent grade), cas: 109-67-1, Aladin [0075] 1-Hexene (reagent grade), cas: 592-41-6, Aladin [0076] 1-Heptene (reagent grade), cas: 592-76-7, Aladin [0077] 1-Decene (reagent grade), cas: 872-05-9, Aladin [0078] 1-Undecene (reagent grade), cas: 821-95-4, Aladin [0079] 1-Dodecene (reagent grade), cas: 112-41-4, Aladin [0080] 1-Tridecene (reagent grade), cas: 2437-56-1, Aladin [0081] 1-Cyclooctene (reagent grade), cas: 931-87-3, Aladin [0082] Styrene (reagent grade), cas: 100-42-5, Aladin [0083] Norbornene (reagent grade), cas: 498-66-8, Aladin [0084] Diethylamine (reagent grade), cas: 109-89-7, Aladin [0085] Dipropylamine (reagent grade), cas: 142-84-7, Aladin [0086] Dibutylamine (reagent grade), cas: 111-92-2, Aladin [0087] Dibenzylamine (reagent grade), cas: 103-49-1, Aladin [0088] N-methyl-ethylamine (reagent grade), cas: 624-78-2, Aladin [0089] N-methyl-propylamine (reagent grade), cas: 627-35-0, Aladin [0090] N-methyl-pentylamine (reagent grade), cas: 25419-6-1, Aladin [0091] N-methyl-octylamine (reagent grade), cas: 2439-54-5, Aladin

Analytical Method

[0092] After completion of the reaction, the mixture was filtrated and analyzed using an Agilent 7890 GC equipped with an HP-5 capillary column bearing 5 wt % phenyl groups (length 30 m; inner diameter 0.25 mm). Analytical methods were adjusted for the different mixtures depending on the boiling point and polarity of the reagents and products. In all the methods, the injector temperature was set at 250 C., the detector temperature was 300 C. and the sample injection volume was 1 L. The calibration of the gas chromatography was performed using dodecanol as an internal standard.

NMR Spectroscopy

[0093] The product was analyzed by NMR on a Bruker Avance III 300 MHz spectrometer operating at 300 MHz resonance frequencies, equipped with a BBO probe.

Example 1: Preparation of Tertiary Amines from 1-Octene/Formaldehyde/DMA/HCOOH

[0094] A round-bottom flask was charged with HCHO (4 mmol, 37 wt %, formalin), DMA (4 mmol, 38 wt % in water) and HFIP (10 mL). Then, 1-octene (112 mg, 1 mmol, 1 equiv.) and HCOOH (184 mg, 4 mmol) was added at room temperature and the reaction mixture was stirred at 30 C. After 96 h, the mixture was filtrated and analyzed using an Agilent 7890 GC equipped with an HP-5 capillary column bearing 5 wt % phenyl groups (length 30 m; inner diameter 0.25 mm).

TABLE-US-00001 TABLE 1 Reactant Product Selectivity Yield EX (alkene) (tertiary amine) (%) (%) 1 1-octene N,N-dimethylamine 85 64

Examples 2-11: Preparation of Tertiary Amines from Different Alkenes

[0095] General procedure of Examples 2-11 is same as Example 1. The results are summarized in Table 2.

TABLE-US-00002 TABLE 2.sup.a Reactant Product Yield.sup.b EX (alkene) (tertiary amine) (%) 2 1-Pentene N,N-dimethyl-hexylamine (36.sup.c) 3 1-Hexene N,N-dimethyl-heptylamine 50 4 1-Heptene N,N-dimethyl-octylamine 51(45.sup.c) 5 1-Decene N,N-dimethyl-undecylamine 60 6 1-Undecene N,N-dimethyl-dodecylamine 70(56.sup.c) 7 1-Dodecene N,N-dimethyl-tridecylamine 68 8 1-Tridecene N,N-dimethyl-tetradecylamine 72 9 1-Cyclooctene N,N-dimethyl-cyclooctane methylamine 58 10 Styrene N,N-dimethyl-amphetamine 73 11 Norbornene N,N-dimethyl-norbornane methylamine 65 .sup.aReaction conditions: 1 mmol alkene, 4 mmol DMA, 4 mmol HCHO (formalin solution), 4 mmol HCOOH, 10 mL HFIP, 30 C.; .sup.bGC yield; .sup.cisolated yield.

Examples 12-19: Preparation of Tertiary Amines from Different Amines

[0096] Regarding other secondary alkylamines (examples 12-20), a same experimental procedure was used as example 1, except that the temperature of the reaction was raised to 50 C., the reaction time prolong to 120 h. The results are summarized in Table 3.

TABLE-US-00003 TABLE 3.sup.a Reactant Product Yield.sup.c EX (amines) (tertiary amine) Ratio.sup.b (%) 12 diethylamine N-methyl-N-ethyl-nonylamine 36 13 dipropylamine N-methyl-N-propyl-nonylamine 67 14 dibutylamine N-methyl-N-butyl-nonylamine 53 15 dibenzylamine N-methyl-N-benzyl-nonylamine 65 16 N-methyl-ethylamine N-methyl-N-ethyl-nonylamine: 50:50 57 N,N-dimethyl-nonylamine 17 N-methyl-propylamine N-methyl-N-propyl-nonylamine: 50:50 74 N,N-dimethyl-nonylamine 18 N-methyl-pentylamine N-methyl-N-pentyl-nonylamine: 50:50 68 N,N-dimethyl-nonylamine 19 N-methyl-octylamine N-methyl-N-octyl-nonylamine: 56:44 80 N,N-dimethyl-nonylamine .sup.aReaction conditions: 1 mmol 1-octene, 4 mmol amine, 4 mmol HCHO (formalin solution), 4 mmol HCOOH, 10 mL HFIP, 50 C., 120 h; .sup.bratio of former to latter amine (products); .sup.cGC yield of total amines.