Method for preparing α,β-unsaturated ketone

Abstract

A method for preparing an α,β-unsaturated ketone, the method comprising oxidizing an unsaturated hydrocarbon having a -CH2- adjacent to a carbon-carbon double bond to an α,β-unsaturated ketone by passing air or oxygen through a solution containing a catalyst consisting of N-hydroxyphthalimide (NHPI) and cobalt diacetate tetrahydrate at standard temperature and pressure over a period of at least 12 hours.

Description

[0001] The present invention relates to a method for preparing α,β-unsaturated ketone (enone) by olefin oxidation. The method is suitable for industrial processes and is particularly suitable for preparing α,β-unsaturated ketones of interest in the field of perfumes.

[0002] Allylic oxidation of alkenes to enones is a chemical transformation that provides a straightforward way to obtain high-value products from readily available compounds or renewable resources.

[0003] Therefore, allylic oxidation of alkenes to enones has been widely used in the preparation of agricultural, pharmaceutical and flavoring products. Various methods have been used (reviewed in Weidmann, V. and 15 Maison, W. in "Allylic Oxidations of Olefins to Enones", Synthesis 2013, 452201-2221).

[0004] Among them, the most commonly used method for the allylic oxidation of alkenes to enones involves the use of stoichiometric amounts of chromium(VI) reagents such as chromium(VI) oxide, tert-butyl chromate, sodium chromate, sodium dichromate, and chromium(VI)-containing complexes (e.g., with pyridine, pyrazole, or benzotriazole).

[0005] However, this approach is complicated by the need for harsh reaction conditions to achieve acceptable conversions within a suitable time frame and by the difficulty in removing the chromium (VI) reagent from the crude reaction product.

[0006] Furthermore, this method is not particularly suitable for industrial processes due to the amounts of chromium (VI) reagents involved and environmental regulations restricting chromium-containing chemical wastes.

[0007] Therefore, industrial chemists have sought alternative methods for the allylic oxidation of alkenes to enones. These methods rely on the use of catalytic amounts of chromium (VI) salts and / or other metal salts and stoichiometric amounts of oxidizing agents such as tert-butyl hydroperoxide, sodium perborate, potassium persulfate.

[0008] However, catalytic methods often do not provide significant improvements over stoichiometric methods. Harsh reaction conditions are often still required because of the difficulty in removing chromium (VI) salts and / or other metal salts from the crude reaction product.

[0009] Furthermore, catalytic methods are not suitable for industrial processes because the amount of catalyst used is often high and poses challenges in complying with environmental regulations restricting chromium- or other metal-containing chemical wastes.

[0010] NHPIs are known to catalyze the oxidation of alkanes to a variety of oxygenated compounds, including alcohols, ketones, and carboxylic acids, under relatively mild conditions.

[0011] NHPI-catalyzed alkane oxidation generally requires heating to temperatures above 70°C in the presence of oxygen at atmospheric pressure and one or more metal promoters, typically cobalt(II) salts.

[0012] The oxidation proceeds via a free radical chain reaction, with NHPI acting as a free radical accelerator. The free radical initiator generates a phthalimide N-oxyl (PINO) radical by abstracting a hydrogen from NHPI. In the propagation stage, the PINO radical abstracts a hydrogen atom from a C-H bond to form an alkyl radical R·. The alkyl radical is captured by oxygen to generate an alkyl peroxyl radical ROO-, which abstracts a hydrogen atom from NHPI to form an alkyl hydroperoxide ROOH.

[0013] When a cobalt(II) salt is present, the initiator is considered to be a Co(III)OO· radical. The alkyl hydroperoxide ROOH formed in the propagation stage is decomposed into an alkoxy group RO·, which abstracts a hydrogen atom from NHPI to form an alkyl alcohol ROH.

[0014] This method has been applied to the oxidation of primary and secondary alkylbenzenes to phenols, aldehydes and ketones, as well as the oxidation of alcohols to aldehydes and ketones, the oxidation of alkynes to alkynyl ketones, and the epoxidation of alkenes (see, for example, Ishii, Y., Sakaguchi, S. and Iwahama, T. in "Innovation of Hydrocarbon Oxidation with Molecular Oxygen and Related Reactions in Advances in Synthetic Catalysis, 2001, 343, 393-427).

[0015] Aerobic oxidation of NHPIs (using air or oxygen) provides an alternative method for the allylic oxidation of alkenes to enones. This method has attracted the interest of industrial chemists because NHPIs are nontoxic and can be easily prepared from phthalic anhydride and hydroxylamine.

[0016] However, the use of NHPI as a catalyst for the aerobic oxidation of olefins to enones has generally not proven successful. The polarity of NHPI and its limited operating temperature range (NHPI decomposes at temperatures above 80°C) means that large amounts of polar solvents (often toxic) are usually required to dissolve the NHPI in order to achieve acceptable conversions. These solvents often complicate the separation of the reaction products.

[0017] Therefore, recent processes for the aerobic oxidation of olefins to enones using NHPIs have mainly used co-oxidants and / or co-catalysts, such as tert-butyl hydroperoxide and dibenzoyl peroxide, chromium (VI) salts, copper (II) salts, manganese (II) salts and cobalt (III) complexes, such as tris(acetylacetonato)cobalt (III).

[0018] These methods are not suitable for industrial processes because they use stoichiometric amounts of NHPI and provide only modest conversion of olefins with low selectivity for enones (compared to alcohols). In addition, the co-oxidants and / or co-catalysts can be explosive, difficult to remove from the crude reaction product and are often toxic.

[0019] US 2004 / 0014985 A1 discloses a successful process for the aerobic oxidation of organic compounds using NHPI or NHPI derivatives. These derivatives are said to enable efficient and simple separation of the reaction products from the catalyst or an altered form of the catalyst.

[0020] In the examples, the allylic oxidation of valencene to nootkatone using NHPI in combination with two or more cocatalysts consisting of a cobalt(II) salt and a cobalt(III) complex is described.

[0021] Although detectable levels of nootkatol were still produced, reasonable conversion and selectivity of nootkatol relative to nootkatol were achieved after 3 to 4 hours of oxidation. The reaction also required relatively large amounts of NHPI, large amounts of acetonitrile as a solvent, an elevated temperature of 40°C, and the use of elevated pressure (1.3 MPa; 11.3 bar). Although air flow into the reaction mixture could be provided under standard conditions, elevated temperature and pressure were maintained throughout the reaction.

[0022] Although allylic oxidation is performed on a large scale, the applicability of this method to industrial processes is limited by the requirement for two or three cobalt-containing promoters and the use of high pressures and temperatures, as well as relatively large amounts of solvent.

[0023] In particular, the use of high pressures and temperatures on an industrial scale carries a significant risk of explosion – especially if hydrogen peroxide accumulates in the reaction mixture.

[0024] EP1164131 also discloses a method for aerobic oxidation of organic compounds using NHPI or its derivatives. In one embodiment of the production of nootkatol by oxidation of valencene, the method requires the use of relatively large amounts of NHPI and two or more cocatalysts consisting of cobalt (II) salts and cobalt (III) complexes. The process is also carried out at high temperatures (40°C) for at least 4 hours. Large amounts of solvent (acetonitrile) are required and detectable levels of nootkatol are produced. Therefore, the method is clearly not suitable for industrial production of α,β-unsaturated ketones.

[0025] Therefore, there remains a need for a method for the allylic oxidation of alkenes to enones which is suitable for use in industrial processes.

[0026] The present invention meets this need by providing NHPI-catalyzed aerobic oxidation of olefins to enones at standard temperature and pressure.

[0027] Compared to the above methods, this method uses less NHPI and other catalysts. This method can also use much less solvent than these methods. Compared with other methods, this method also minimizes the risk of explosion and has much less impact on the environment.

[0028] Thus, in a first aspect, the present invention provides a process for making an α,β-unsaturated ketone, the process comprising oxidizing an unsaturated hydrocarbon having a -CH2- adjacent to a carbon-carbon double bond (also referred to herein as an "olefin") to an α,β-unsaturated ketone by passing air or oxygen through a solution containing a catalyst consisting of N-hydroxyphthalimide (NHPI) and cobalt diacetate tetrahydrate at standard temperature and pressure over a period of at least 12 hours.

[0029] "Standard conditions" means that the reaction can be carried out in the absence of heating (or cooling), ie, at ambient conditions ("room temperature"), and without the application of increased pressure.

[0030] Reference to an "unsaturated hydrocarbon having a -CH2- adjacent to a carbon-carbon double bond" refers to a molecule containing only carbon and having a chemical structure containing one or more >C=C-CH2-, and such materials are also referred to herein as "olefins."

[0031] Although the process is potentially applicable to any unsaturated hydrocarbon (including alkylbenzenes and even molecules having the requisite >C=C-CH2- and atoms other than carbon), in the most practical embodiments, the unsaturated hydrocarbon having a -CH2- adjacent to the carbon-carbon double bond is an olefin having 4-30 carbon atoms.

[0032] The process is particularly useful for making aromatic compounds comprising simply α,β-unsaturated ketones, especially when the olefin is commercially available or easily prepared or isolated.

[0033] Thus, the olefin may contain 5 to 20 carbon atoms, for example 8 to 20 carbon atoms. The olefin may be replaced by, for example, a C1-C5 alkyl, a C1-C5 alkenyl, a C5 or C6 cycloalkyl, a C5 or C6 cycloalkenyl or a C6 or C6 cycloalkyl group on the benzene ring or on the -CH2- in the alkyl group. 10 Aryl substitution.

[0034] In certain embodiments, the olefin is a linear or branched olefin having from 4 to 20 carbon atoms and having the formula:

[0035]

[0036] in

[0037] R, R 1 and R 2 are independently hydrogen, C1-C5 straight or branched alkyl, C1-C5 straight or branched alkenyl, or C6 or C 10 aryl; and

[0038] R 3 is C1-C5 alkyl, C1-C5 alkenyl or C6 or C 10 Aryl.

[0039] In one such embodiment, R and R 3 Each is C6 or C 10 Aryl, and R 1 and R 2 Each is hydrogen.

[0040] Thus, in other embodiments, the olefin comprises a 5- or 6-membered unsaturated carboxylic acid ring and has the formula:

[0041]

[0042] in

[0043] R vs R 3 Connected, R 1 and R 2 are each independently hydrogen, C1-C5 alkyl, C1-C5 alkenyl or C6 or C 10 Aryl and

[0044] The unsaturated carbocyclic ring is optionally bridged by one or more -CH2- groups, C1-C5 alkyl groups, C1-C5 alkenyl groups, C6 or C 10 The aryl group is substituted or fused with another 5- or 6-membered saturated carbocyclic ring, which is optionally substituted with one or more C1-C5 alkyl, C1-C5 alkenyl, C6 or C 10 Aryl substitution; or

[0045] R vs R 3 Connected, R 1 With R2 are connected to form a 5- or 6-membered saturated carbocyclic ring, which is fused to a 5- or 6-membered unsaturated carbocyclic ring; and

[0046] One or both of the carbocyclic rings are optionally substituted with one or more bridging -CH2- groups, C1-C5 alkyl, C1-C5 alkenyl, or fused with another 5- or 6-membered saturated carbocyclic ring, which is optionally substituted with C1-C5 alkyl, C1-C5 alkenyl, C6 or C 10 One or more substitutions in the aryl group.

[0047] In these embodiments, the olefin can be a hemiterpenoid, a monoterpenoid, or a sesquiterpenoid.

[0048] The olefins may include, among others, any of the following cyclic olefins:

[0049]

[0050] In a particularly preferred embodiment of the invention, the olefin is valencene.

[0051] In embodiments, the method comprises passing air (rather than oxygen) through the solution.

[0052] Although reasonable conversion of the olefin to enone can be obtained by passing air through the solution within 12 hours, good conversion may take longer.

[0053] Thus, in certain embodiments, the duration of the method may be between 12 hours and 36 hours, in particular between 20 hours and 30 hours, for example 24 hours.

[0054] As described herein, the catalyst in the olefin solution used in the process of the present invention consists of NHPI and cobalt diacetate tetrahydrate. Thus, both NHPI and cobalt diacetate tetrahydrate are present in the solution, NHPI as the main catalyst and cobalt diacetate tetrahydrate as a cocatalyst, and substantially no other catalyst (or cocatalyst) is present.

[0055] Advantageously, the process may use an NHPI catalyst in an amount less than or equal to 15% molar equivalent of the olefin. Preferably, the amount of NHPI used in the process of the present invention is 12% molar equivalent or less, more preferably 10% molar equivalent or less.

[0056] In the process of the present invention, the molar ratio of cobalt(II) acetate tetrahydrate to NHPI catalyst is advantageously between 1:4 and 1:6, for example about 1:5.

[0057] The olefin solution through which air or oxygen passes in the present invention can be obtained by dissolving the olefin in a solvent in any convenient manner. However, although allylic oxidation can be carried out in a variety of solvents, the conversion of olefin to enone seems to depend to some extent on the choice of solvent. For example, when the solvent is one or more of toluene, tetrahydrofuran, dioxane or methylene chloride, aerobic oxidation does not occur. The technician will know more suitable solvents, but it should be noted that when the solvent is one or more of acetone, cyclohexanone, tert-butyl alcohol, ethyl acetate and diethyl ether, the conversion of unsaturated hydrocarbons may be very low (between 20% and 30%) and / or some alcohols (about 5 mole %) are produced.

[0058] Furthermore, although polar solvents methyl ethyl ketone, dimethylformamide, and acetonitrile provide good conversions (close to 70%), their use may still result in the production of alcohols (up to 5 mol%) and also make the isolation of α,β-unsaturated ketones difficult by standard workup procedures due to their partial solubility in water.

[0059] Therefore, preferably, the method of the present invention uses one or more of methyl propyl ketone (MPK), methyl isopropyl ketone (MIPK), methyl butyl ketone (MBK) and methyl isobutyl ketone (MIBK) as solvent.

[0060] In a preferred embodiment, the process uses methyl isobutyl ketone (MIBK) as solvent.

[0061] The process may use 0.75 to 9.0 liters / kg of olefin, preferably 1 to 7.5 liters / kg, more preferably 1 to 6 liters / kg of solvent.

[0062] When methyl isobutyl ketone (MIBK) is used as solvent, the amount of solvent per kg of olefin may in particular be between 3.0 and 6.0 l / kg.

[0063] The method can provide a conversion of olefins to α,β-unsaturated ketones of greater than or equal to 65%, such as greater than or equal to 70%. The conversion of the olefins can be monitored, for example, by gas chromatography, and when the desired conversion is obtained, the oxidation is quenched. Alternatively, the oxidation can be quenched after a predetermined period of time, such as 24 hours.

[0064] The method can provide allylic oxidation of olefins with high selectivity to α,β-unsaturated ketones (compared with alcohols). In other words, the α,β-unsaturated ketones obtained are substantially free of the corresponding alcohols. "Substantially free" of the corresponding alcohols means that less than 1% by weight (% w / w) is produced. In a preferred embodiment of the invention, the amount of alcohol produced is less than 0.5% w / w, and most preferably substantially no alcohol is produced, i.e., alcohol cannot be detected using conventional test procedures.

[0065] The process can also provide allylic oxidation with 95% to 100% regioselectivity. In other words, when the unsaturated hydrocarbon contains two or more -CH2- adjacent to a carbon-carbon double bond, the process essentially provides an α,β-unsaturated ketone.

[0066] The method does not require any special measures for working up the reaction mixture. It also does not require the NHPI derivatives mentioned in US 2004 / 0014985 A1 - although it is envisaged that these derivatives can be used in place of NHPI.

[0067] Thus, in embodiments, the method further comprises quenching the oxidation with water, extracting the α,β-unsaturated ketone into an organic solvent, and washing the extract with a 5 wt / wt % aqueous sodium hydroxide solution.

[0068] As mentioned above, the process is particularly suitable for producing flavor compounds comprising α,β-unsaturated ketones.

[0069] The process provides at least the following flavor compounds in good yield (70% or more) and 100% regioselectivity:

[0070]

[0071] In a preferred embodiment, the flavor compound produced is nootkatone.

[0072] In one embodiment of the invention, the method is suitable for manufacturing α,β-unsaturated ketones on an industrial scale. "Industrial scale" means that the production of α,β-unsaturated ketones is sufficient for industrial use, i.e., the production is large enough to make the process commercially viable and effectively meet the requirements for product cost.

[0073] Therefore, in a second aspect, the present invention provides an industrial process for preparing α,β-unsaturated ketones according to the process of the first aspect. "Industrial process" means that the process is carried out on a commercially viable scale, has an acceptable level of safety and cost considerations, and can produce products on a scale as described above.

[0074] Embodiments of this aspect will be apparent from the foregoing description in relation to the first aspect of the invention.

[0075] In a third aspect, the present invention provides an industrial plant for making an α,β-unsaturated ketone according to the process of the first aspect. It will be understood that an industrial plant is a plant suitable for producing a final product or products on an industrial scale as defined herein.

[0076] Apparatus suitable for use in an industrial setting will be apparent to the skilled person when considering the first aspect of the invention.

[0077] The present invention will now be described in more detail with reference to the following non-limiting examples and accompanying drawings, in which:

[0078] Figure 1 is a schematic diagram illustrating the chemical transformation of allylic oxidation of an olefin to an α,β-unsaturated ketone; and

[0079] Figure 2 is a schematic diagram illustrating the aerobic oxidation of olefins to α,β-unsaturated ketones according to one embodiment of the present invention.

[0080] refer to Figure 1 , showing the allylic oxidation of an olefin having a -CH2- adjacent to a carbon-carbon double bond to an a,β-unsaturated ketone (R 3 It can be seen that allylic oxidation involves the chemical transformation of an olefin, providing that the two hydrogen atoms of -CH2- adjacent to the carbon-carbon double bond are replaced by a carbon-oxygen double bond.

[0081] The allylic oxidation is shown to result from aerobic oxidation of an olefin solution over at least ten hours using air and a catalyst comprising a mixture of NHPI and cobalt(II) acetate tetrahydrate without heating, i.e., at room temperature and atmospheric pressure (i.e., at standard temperature and pressure (STP)).

[0082] refer to Figure 2 , similar aerobic oxidation was applied to the synthesis of the flavor compound nootkatone from valencene (a sesquiterpene obtained cheaply from Valencia oranges).

[0083] The synthesis of nootkatone was achieved by aerobic oxidation of the olefin in methyl isobutyl ketone (MIBK) solution at room temperature and atmospheric pressure (i.e., at standard temperature and pressure (STP)) for 24 hours using air and a catalyst comprising a mixture of NHPI and cobalt (II) acetate tetrahydrate.

[0084] The following examples describe the synthesis of laboratory scale and pilot scale. In each case, the production of Nootkatol (and the absence of Nootkatol) was carried out by 1 H and 13 C NMR spectroscopy confirmed with reference to the NMR spectrum of nootkatone.

[0085] Example 1 - Laboratory Scale

[0086] Over a period of 24 hours at room temperature, a stream of air at a rate sufficient to generate microbubbles was introduced into a stirred solution of N-hydroxyphthalimide (1.76 g, 0.01 mol, 0.1 eq), Co(OAc)2 (0.58 g, 0.002 mol, 0.025 eq) and (+)valencene (20 g, 0.1 mol, 1 eq) in methyl isobutyl ketone (MIBK, 120 ml, f = 6) in a 250 ml round-bottom flask.

[0087] The reaction was monitored by gas chromatography of an aliquot of the solution to assess the conversion of (+)-valencene to (+)-nootkatone, and the reaction was quenched when the conversion reached 70%. After the air flow was removed, the reaction mixture was washed twice with 50 ml of distilled water and then once with 50 ml of a 5% aqueous sodium hydroxide solution. 1 H and 13 C NMR spectroscopy confirmed the presence of nootkatone, and nootkatol was detected.

[0088] Example 2 - Pilot Scale

[0089] Over a period of 24 hours at room temperature, an air stream was introduced at a flow rate sufficient to generate microbubbles into a stirred solution of N-hydroxyphthalimide (87.81 g, 0.489 mol, 0.1 eq.), Co(OAc)2 (29.5 g, 0.108 mol, 0.022 eq.) and (+)valencene (1000 g, 4.89 mol, 1 eq.) in methyl isobutyl ketone (MlBK, 3000 ml, f = 3) in a 10-liter reactor.

[0090] The reaction was monitored by gas chromatography of an aliquot of the solution to assess the conversion of (+)-valencene to (+)-nootkatone, and the reaction was quenched when the conversion reached 70%. After the air flow was removed, the reaction mixture was washed twice with 1000 ml of distilled water and then once with 750 ml of a 5% aqueous sodium hydroxide solution.

[0091] After removing the MlBK solvent by vacuum distillation, 694 g (65%) of nootkatol were obtained by distillation. The purity of (+)-nootkatol was 95%, and it was determined that no (+)-nootkatol was present.

[0092] Thus, it can be seen that the present invention provides a method for aerobic oxidation of olefins to α,β-unsaturated ketones, which is suitable for industrial scale. The method does not require oxygen or heating and is carried out at atmospheric pressure, thus reducing the risk of explosion and reducing energy consumption compared to the above methods.

[0093] Compared with the above method, this method uses less catalyst (in type and quantity) and can use less solvent. It can highly convert olefins into α, β-unsaturated ketones, and has high selectivity and high regioselectivity.

[0094] Low catalyst, low solvent, minimal energy consumption and high conversion, selectivity and regioselectivity mean that this method is very suitable as a green (environmentally friendly) industrial process for the manufacture of flavor compounds containing α,β-unsaturated ketones.

Claims

1. A process for making an α,β-unsaturated ketone, the process comprising oxidizing an unsaturated hydrocarbon having a -CH2- group adjacent to a carbon-carbon double bond to an α,β-unsaturated ketone by passing air or oxygen through an olefin solution containing a catalyst consisting of N-hydroxyphthalimide and cobalt diacetate tetrahydrate at standard temperature and pressure for a period of at least 12 hours; wherein Olefins are selected from the group consisting of The solvent is methyl isopropyl ketone; The amount of N-hydroxyphthalimide catalyst used is less than 15 mole equivalents of the olefin; and The molar ratio of cobalt diacetate tetrahydrate to N-hydroxyphthalimide catalyst is 1:4 to 1:

6.

2. A method according to claim 1 comprising passing air through the solution at standard temperature and pressure for a period of at least 12 hours.

3. A method according to claim 2 comprising passing air through the solution at standard temperature and pressure over a period of 20 to 30 hours.

4. The process of claim 1, wherein the olefin is valencene.

5. The method according to claim 1, wherein the amount of N-hydroxyphthalimide catalyst used is less than 12 mol% or less.

6. The method according to claim 5, wherein the amount of N-hydroxyphthalimide catalyst used is less than 10 mol% or less.

7. The method according to claim 1, wherein the molar ratio of cobalt acetate tetrahydrate to N-hydroxyphthalimide catalyst is 1:

5.

8. The process according to any one of claims 1 to 7, wherein the amount of solvent is from 0.75 to 9.0 liters per kg of olefin.

9. The process according to claim 8, wherein the amount of solvent is 1 to 7.5 liters per kg of olefin.

10. The process according to claim 9, wherein the amount of solvent is 1 to 6 liters per kg of olefin.

11. The process of any one of claims 1 to 6, providing an olefin conversion greater than or equal to 70%.

12. The process of any one of claims 1 to 6, providing an α,β-unsaturated ketone substantially free of the corresponding alcohol.

13. The method according to any one of claims 1 to 6, having a regioselectivity greater than 95%.

14. The method according to any one of claims 1 to 6, further comprising quenching the oxidation with water, extracting the α,β-unsaturated ketone into an organic solvent, and washing the extract with a 5 wt / wt% aqueous sodium hydroxide solution.

15. The method according to any one of claims 1 to 6, wherein the α,β-unsaturated ketone is a flavor compound.

16. The method of claim 15, wherein the α,-unsaturated ketone is nootkatone.

17. The process according to any one of claims 1 to 6, suitable for the production of α,β-unsaturated ketones on an industrial scale.

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