Title of Invention	A PROCESS FOR THE MANUFACTURE OF AN ALPHA, BETA-UNSATURATED CYCLIC KETONE
Abstract	A process for the manufacture of an alpha, beta-unsaturated cyclic ketone, such as carvone, comprises the dehydrogenation of a secondary allylic cyclic alcohol, such as carveol, in the presence of metal carboxylate. The process can be performed in a batchwise or continuous mode. Examples of suitable metal carboxylates include magnesium stearate, calcium 2-ethylhexanoate, and zinc 2-ethylhexanoate.

Title of Invention

A PROCESS FOR THE MANUFACTURE OF AN ALPHA, BETA-UNSATURATED CYCLIC KETONE

Abstract

A process for the manufacture of an alpha, beta-unsaturated cyclic ketone, such as carvone, comprises the dehydrogenation of a secondary allylic cyclic alcohol, such as carveol, in the presence of metal carboxylate. The process can be performed in a batchwise or continuous mode. Examples of suitable metal carboxylates include magnesium stearate, calcium 2-ethylhexanoate, and zinc 2-ethylhexanoate.

Full Text	Field of the Invention The present invention relates generally to the field of organic synthesis and more particularly to a process for the manufacture of an alpha, beta-unsaturated cyclic ketone, comprising the dehydrogenation of a secondary allylic alcohol in the presence of at least one metal carboxylate. Background of the Invention It is known that many alcohols can be catalytically dehydrogenated to the corresponding carbonyl compounds (for general information see Hydlicky Milos, Oxidations in Organic Chemistry, ACS Monograph 186, American Chemical Society, Washington, DC, 1990, p. 132 and Smith M.B. and March J. Advanced Organic Chemistry, 5th edition, John Wiley and Sons, Inc., New York, 2001, pp. 1515-1516). Usually, dehydrogenation of alcohols allows preparation of the target carbonyl compounds with high yields and throughputs. To that end, copper, nickel, and palladium based catalysts have been typically used to carry out the dehydrogenation of alcohols. An attempt to produce alpha, beta-unsaturated cyclic ketones, such as carvone, by catalytic dehydrogenation of a corresponding secondary allylic cyclic alcohol, such as carveol, was made in 1927 (Treibs W. and Schmidt H, Ber., 1927, 60 B, pp. 2335- 2341). However, this attempt failed as both copper and nickel based catalysts converted the carveol into carvacrol and tetrahydrocarvone, but not to carvone. This was due, in part, to two potential side reactions that can accompany the catalytic dehydrogenation of a secondary allylic cyclic alcohol, such as carveol. First, both the starting material and the product possess double bonds, which can react with hydrogen that is produced as a result of dehydrogenation. Secondly, these double bonds easily isomerize at high temperature in the presence of catalysts to provide an aromatic structure. The scheme below represents these side reactions that can occur during, for example, the dehydrogenation of carveol. Prior to the discovery of the present invention, most known methods for the preparation of alpha, beta-unsaturated cyclic ketones from a corresponding secondary allylic cyclic alcohol, such as the preparation of carvone from carveol. involve some type of an oxidation reaction. These methods can be divided in two categories. The first of these two methods is known as the Oppenauer oxidation, where hydrogen is transferred from carveol to an auxiliary carbonyl compound. Japanese patent JP 50/58031 describes carveol oxidation in the presence of aluminum isopropoxide as catalyst, cyclohexanone as hydrogen acceptor, and xylene as solvent. The yield of the 88% pure carvone was 82%. A better yield of carvone (91%) was obtained by employing of a complex aluminum catalyst and three equivalents of pivalaldehyde as hydrogen acceptor in a methylene chloride solution (Takashi Ooi, et al, Synthesis, 2002, No. 2, pp. 279-291). The new aluminum complex catalyst used in this method (2,7-dimethyl-l,8-biphenyldioxy)bis(diallcoxya]uminum) has to be prepared from trialkylaluminum, which imposes safety concerns on an industrial scale. Common disadvantages of all Oppenauer type oxidation methods include the catalyst sensitivity toward hydrolysis, the necessity of use of an auxiliary carbonyl compound (sometimes a large excess) and a lengthy and labor intensive work-up. The second of these methods is known as oxidation with a reagent. Above mentioned Japanese patent JP 50/58031 also describes carveol oxidation to carvone with chromic trioxide in concentrated sulfuric acid with 93% yield. Among other reagents suggested for carveol oxidation to carvone are, hydrogen peroxide in the presence of molybdenum catalyst (Trost, B.M. et al., Israel Journal of Chemistry, 1984, Vol. 24, pp. 134-143); N-methybnorpholine-N-oxide in the presence of ruthenium catalyst (Sharpless K.B. et al., Tetrahedron Letters, 1976, No. 29, pp. 2503-2506); hydroperoxides in the presence of molybdenum and vanadium catalysts (Lempers H.E.B. et al., J. Org. Chem., 1998, Vol. 63, pp. 1408-1413); and copper catalysts (Rothenberg G., J. Chem. Soc, Perkin Trans. 1998, No. 2, pp. 2429-2434). In most, if not all, of these reactions expensive reagents or toxic catalysts are used and a large excess of the oxidation reagent is required, which makes a reagent oxidation very unattractive for commercialization. The double bond in carvone mat is conjugated with the carbonyl group is markedly active as hydrogen acceptor. This is why under commonly used dehydrogenation conditions dihydrocarvone becomes the major product of carveol dehydrogenation (see, for example, US 4160786 which describes isomerization of cycloalkenols to cycloalkanones in the presence of copper-chromite catalysts and specifically mentions carveol conversion to dihydrocarvone). Supported palladium, platinum and ruthenium catalysts, which are frequently used in dehydrogenation reaction, afford phenols and cyclohexanones upon dehydrogenation of cycloalkenols (carveol) or cycloakenones (carvone). Examples of such transformations can be found in US 4929762 and US 5817891. In some instances a method called oxidative dehydrogenation is employed to produce alpha,beta-unsaturated carbonyl compounds from the corresponding allylic alcohols. Catalysts utilized in this process include metallic copper or silver. Using this process geraniol was converted to citral (US 5241122) and prenol to prenal (US 6013843) at the temperature above 360°C. The name of this process - oxidative dehydrogenation - suggests that this is not a true dehydrogenation, as it requires the presence of oxygen, which could be either an oxidant or a hydrogen acceptor. Nonetheless, the oxidative dehydrogenation has never been successfully used to produce carvone, probably because it proceeds at the temperature above 360°C, which causes decomposition of carveol and carvone and leads to low yields and poor quality. In other attempts, some enzymes have been found to affect this kind of chemical transformation (Hirata, T., et al., Phytochemistry, 2000, vol. 55, No. 4, pp. 297-303). The enzymatic method has mostly a theoretical interest and cannot be used for a large-scale production of carvone. In general, homogeneous catalysts are rarely used in dehydrogenation process (Blum, J., Biger, S. Tetrahedron Letters, 1970, No. 21, pp. 1825-1828). In particular, in the presence of those homogeneous catalysts that could possibly affect dehydrogenation of the allylic alcohols the isomerization to saturated carbonyl compounds but not dehydrogenation to corresponding unsaturated carbonyl compounds was observed (see review by van der Drift, R.C. et al., J. Organomet. Chem., 2000, No. 650, pp. 1-24). There are a few examples of the homogeneous dehydrogenation of alcohols. However, only saturated alcohols were used as substrates (Fragale, C. et al. J. Molecular Catalysis, 1979, Vol. 5, pp. 65-73). Interestingly, most of the reported examples were not dehydrogenation, but rather hydrogen transfer reactions, which involved hydrogen acceptors. Thus, there is no indication in the patent or scientific literature that carvone or any other conjugated alpha, beta-unsaturated cyclic ketones can be prepared by catalytic dehydrogenation of the corresponding allylic alcohol. Moreover, the homogeneous dehydrogenation catalysts that have been used are complex compounds of the transition metals chosen from groups six to ten of the Periodic Table. In contrast, the present invention further provides a method that utilizes carboxylates of the metals chosen from groups two and twelve of the Periodic Table. As discussed below, and in accordance with the present invention, these carboxylates are effective homogeneous dehydrogenation catalysts that allow for selective production of alpha, beta-unsaturated cyclic ketones from the corresponding secondary allylic cyclic alcohol via a true dehydrogenation mechanism. Summary of the Invention Among other aspects, the present invention is based in part on the surprising discovery that carboxylates of metals from groups two and twelve of the Periodic Table can act as selective homogeneous catalysts for the dehydrogenation of a secondary allylic cyclic alcohol to form an alpha, beta-unsaturated cyclic ketone. In a first aspect, the present invention provides a process for the manufacture of an alpha, beta-unsaturated cyclic ketone, comprising the dehydrogenation of a secondary allylic cyclic alcohol in the presence of at least one metal carboxylate, in a reaction environment under conditions effective to provide an alpha, beta-unsaturated cyclic ketone. In a second aspect, the present invention further provides alpha, beta- unsaturated cyclic ketones produced by the processes described herein. Additional advantages and embodiments of the invention will be obvious from the description, or may be learned by practice of the invention. Further advantages of the invention will also be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. Thus, it is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory of certain embodiments of the invention, and are therefore not restrictive of the invention as claimed. Detailed Description of the Invention The present invention may be understood more readily by reference to the following detailed description and any examples provided herein. It is also to be understood that this invention is not limited to the specific embodiments and methods described below, as specific components and/or reaction conditions may vary. Furthermore, the terminology used herein is used only for the purpose of describing particular embodiments of the present invention and is not intended to be limiting in any way. It must also be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" comprise plural referents unless the context clearly dictates otherwise. For example, reference to a component in the singular is intended to comprise a plurality of components. Ranges may be expressed herein as from "about" or "approximately" one particular value and/or to "about" or "approximately" another particular value. When such a range is expressed, another embodiment comprises from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment. As used herein, Group II and XXII metals are intended to include those metals belonging to Groups II and XXII of the Periodic Table. As used herein, the term "alkyl" refers to a paraffmic hydrocarbon group which may be derived from an alkane by dropping one hydrogen from the formula. Non-limiting examples include C1 - C20 alkane derivatives such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and isobutyl. To this end, it should be understood that an alkyl substituent suitable for use in the present invention can be a branched or straight chain alkyl substituent. As used herein, the term "alkenyl" is intended to refer to a substituent derived from the class of unsaturated hydrocarbons having one or more double bonds. Those containing only one double bond are referred to as allcenes or alkenyl substituents. Those with two or more double bonds are called alkadienes (alkadienyl), alkatrienes (alkatrienyl) and so on. Non-limiting examples include ethylene, propylene, butylene and the like. To this end, it should be understood that an alkenyl substituent suitable for use in the present invention can be substituted or unsubstituted. As used herein, the term "aryl" refers to a compound or substituent whose molecules have the ring structure characteristic of benzene, naphthalene, phenanthrene, anthracene, and the like. That is to say, an aryl group typically contains either the 6-carbon ring of benzene or the condensed 6 carbon rings of other aromatic derivatives. For example, an aryl group can be a phenyl or naphthyl group. To this end, it should be understood that aryl substituents suitable for use with the present invention can be substituted or unsubstituted. As used here, alpha, beta-unsaturated cyclic ketone refers to cyclic ketones having the following structure: wherein R1 and R2 are independently selected from among straight chain or branched C1 -C5 alkyl groups, C1- C5 alkenyl groups, or C6-C10 aryl groups. As used herein, secondary allylic cyclic alcohol refers to an allylic cyclic alcohol having the following generic structure: wherein R1 and R2 are independently selected from among straight chain or branched C1 -C5 alkyl groups, C1- C5 alkenyl groups, or C6-C10 aryl groups. As used herein, a beta, gamma-unsaturated cyclic ketone refers to a cyclic ketone having the following general structure: wherein R1 and R2 are independently selected from among straight chain or branched C1 -C5 alkyl groups, C1-C5 alkenyl groups, or C6-C10 aryl groups. As used herein, by use of the term "effective," "effective amount," or "conditions effective to" it is meant that such amount or reaction condition is capable of performing the function of the compound or property for which an effective amount is expressed. As will be pointed out below, the exact amount required will vary from one embodiment to another, depending on recognized variables such as the compounds or materials employed and the processing conditions observed. Thus, it is not always possible to specify an exact "effective amount" or "condition effective to." However, it should be understood that an appropriate effective amount will be readily determined by one of ordinary skill in the art using only routine experimentation. As used herein, the term "reaction environment" refers to the medium in which the dehydrogenation reaction takes place. For example, and without limitation, the reaction environment or reaction medium in which the dehydrogenation reaction of the present invention takes place can be a secondary allylic cyclic alcohol. Alternatively, the reaction environment or reaction medium can comprise at least one optional solvent. As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, the phrase "optionally substituted lower alkyl" means that the lower allcyl group may or may not be substituted and that the description includes both unsubstituted lower alkyl and lower alkyl where there is substitution. As set forth above, in a first aspect the present invention provides a process for the manufacture of an alpha, beta-unsaturated cyclic ketone, comprising the dehydrogenation of a secondary allylic cyclic alcohol in the presence of at least one metal carboxylate, in a reaction environment under conditions effective to provide an alpha, beta-unsaturated cyclic ketone. According to the invention, suitable secondary allylic cyclic alcohols include those alcohols having the general structure of formula (I): wherein R1 and R2 are independently selected from among straight chain or branched C1 -C5 allcyl groups, C1- C5 alkenyl groups, or C6-C10 aryl groups. In a preferred aspect of the invention, the secondary allylic cyclic alcohol is carveol and is represented by the structure of formula (HI) below: As stated above, the dehydrogenation process of the present invention proceeds in the presence of at least one metal carboxylate catalyst. The metal carboxylate catalysts are carboxylates of the metals selected from Groups II and XXII of the periodic table, including magnesium, calcium, and zinc. According to one aspect of the invention, the metal carboxylates comprise a carboxylate moiety having the general structure: wherein R3 is selected from among C1-C20 straight chain or branched alkyl groups, which groups can be further substituted by one or more additional C1-C20 straight chain or branched alkyl radicals. In one aspect, a preferred carboxylate is stearate. Alternatively, in another aspect, the carboxylate is an ethylhexanoate or octanoate. Therefore, in accordance with these aspects, suitable metal carboxylate catalyst for use in the present invention includes, without limitation, magnesium stearate (commercially available from the Aldrich company), calcium 2-ethylhexanoate (commercially available from Shepherd Chemical Company) and zinc 2- ethylhexanoate (also commercially available from Shepherd Chemical Company). As described herein, the process of the present invention is useful for the manufacture of a variety of alpha, beta-unsaturated cyclic ketones having the generic structure: wherein R1 and R2 are independently selected from among straight chain or branched C1 -C5 alkyl groups, C1- C5 alkenyl groups, or C6-C10 aryl groups. To that end, it will be understood and appreciated by one of ordinary skill in the art the particular alpha, beta-unsaturated cyclic ketone desired to be manufactured will be dependent upon the starting secondary allylic cyclic alcohol as previously described herein. In one aspect, the process of the present invention is particularly useful for the preparation of carvone, an alpha, beta-unsaturated cyclic ketone having the structure as follows. Using appropriate reaction conditions, not only allylic but also some other alcohols could be converted to the corresponding carbonyl compounds. For example, dihydrocarveol was converted to dihydrocarvone, although the rate of this reaction was slower, which indicates that allylic alcohols undergo metal carboxylate catalyzed dehydrogenation faster than their saturated analogues. In the presence of metal carboxylates a noticeable rate of carveol dehydrogenation can be observed at about 210°C. However, to achieve a reasonable reaction rate the process should be carried out at 215-260°C. At higher temperature the selectivity of carveol dehydrogenation to carveol starts to decrease. According to present invention, dehydrogenation of carveol is carried out in the presence of metal carboxylate at elevated temperature under atmospheric or reduced pressure as a batch or semi-continuous process with an optional addition of a solvent. To this end, optimization of the process, as described herein, would be possible using only routine experimentation. For example, by controlling the residual pressure (e.g., vacuum), the reaction mixture can be refluxed at the desired temperature in the system. In addition, the choice of a desired temperature and residual pressure combination can control the carveol concentration in the system and, thus, the contact time between the catalyst and carveol. And, finally, this combination of parameters, e.g., pressure, carveol concentration, and contact time, can be used to select a feed rate of, e.g., carveol or carveol containing mixture to the system. The reaction does not require a solvent, though addition of solvent can be beneficial in achieving high yields in a batch mode or for improving heat transfer and lowering the viscosity in a semi-continuous mode. Examples of solvents include but are not limited to high boiling individual hydrocarbons and their mixtures (pentadecane, white mineral oils, etc.), ethers (diphenyl ether, tetraethylene glycol dimethyl ether, etc.) or mixtures of hydrocarbons and ethers. The amount of solvent may vary from 10% to 200% based on starting carveol. Even larger amount of solvent can be employed. However, it would lead to less effective equipment utilization. the process of the present invention as described herein can be successfully performed on virtually any scale. The amount of catalyst can be expressed in terms of the starting secondary alcohol or the total reaction mixture. For example, the amount of the carboxylate can vary from about 0.5% by weight or less to about 100% by weight or more relative to the secondary alcohol. For example, specific examples of suitable amounts can include 1, 5,10,20,30,40,50,60,70, 80 and 90 % by weight and ranges therebetween. Moreover, the amount of metal carboxylate catalyst is selected to provide the desired reaction rate and can vary depending on the reaction technique employed. For example, where the process is carried out in a batchwise mode, the carboxylate can be present in an amount of about 1% to about 4% by weight based on the starting secondary alcohol or about 0.5% to about 2 wt % based on the total reaction mixture. For processes carried out in the continuous mode, the metal carboxylate can be present in the system, based on throughput, of about 0.01 to about 1 g of secondary alcohol per 1 g of catalyst per hour. To carry out a batch dehydrogenation carveol or carveol containing streams are mixed with catalyst and possibly a solvent in any sequence. Then the resulting mixture is heated at desired temperature. It is advisable, although not required, to remove any water contained in the optional solvent or in the feed by distillation (possibly adding an azeotrope forming agent) prior to catalyst addition in order to protect the catalyst from hydrolysis. Various hydrocarbons with appropriate boiling points can serve as azeotrope forming agents. Dehydrogenation can be carried out at reflux temperature, atmospheric pressure or under vacuum. The reflux temperature can be controlled by addition of one or more solvents or by adjusting pressure. To carry out a semi-continuous process, a mixture of catalyst and solvent can be heated at the desired temperature (typically 220-250°C) and pressure (typically 10- 100 mm Hg) in the still pot of a distillation column efficient enough to separate carvone from carveol. Then carveol or carveol containing stream is continuously added through the still pot at a specified rate. As carvone has a lower boiling point, it is continuously removed from the top of distillation column, while carveol remains in the pot. Addition of carveol and removal of carvone are continued until the catalyst loses its activity (typically 96-120 hours). Semi-continuous process affords better yield of carvone comparing with batch process because the product is removed from the reaction zone as soon as it is formed thus preventing formation of by-products. At high temperatures in the presence of catalyst, it is possible that the desired alpha, beta-unsaturated cyclic ketone will exists in equilibrium with its unconjugated isomer, a beta, gamma-unsaturated cyclic ketone, as illustrated below. In instances where the unconjugated beta, gamma-unsaturated isomer has a lower boiling point than the target conjugated alpha, beta-unsaturated cyclic ketone, the beta, gamma-unsaturated cyclic ketone would be removed first during reflux conditions. For this reason, a product of a semi-continuous dehydrogenation of a suitable secondary allylic alcohol may contain a noticeable amount of the beta, gamma-unsaturated cyclic ketone in addition to the target alpha, beta-unsaturated cyclic ketone. For example, spicatone, the unconjugated beta, gamma-unsaturated isomer of carvone, has a lower boiling point than carvone and under reflux conditions is removed first. For this reason, a product of a semi-continuous dehydrogenation of carveol can contain a noticeable amount of spicatone, an amount typically in the range of from about 4 to about 8%. A beta, gamma-unsaturated cyclic ketone, such as spicatone, can be isomerized back to the target alpha, beta-unsaturated cyclic ketone by heating the product of the dehydrogenation reaction to a temperature above 200°C or by treating the product of the dehydrogenation reaction with a sodium hydroxide solution at or above 80°C in a batch process. For example, according to the process of the present invention, the preparation of carvone from carveol can provide a minimum undesired amount of spicatone, the unconjugated alpha, gamma-unsaturated cyclic ketone isomer of carvone. By heating the product of dehydrogenation at above 200°C or by treating with a sodium hydroxide solution at above 80oC in a batch process, the spicatone can therefore be isomerized back to provide a higher yield of the desired product. After the spicatone isomerization step, semi-continuous dehydrogenation of carveol affords 97% weight yield of 95% pure carvone (the rest 5% is mostly dihydrocarvone, which by itself is a valuable component of the spearmint oil). Further fractionation affords 99.6% pure (or higher) fragrance and flavor quality carvone with 90% yield based on starting carveol. It will further be appreciated upon practicing the process of the present invention that the dehydrogenation process described herein does not alter the optical activity of starting secondary allylic cyclic alcohol. Therefore, a levorotatory secondary allylic cyclic alcohol, such as 1-carveol, can be successfully converted to a levorotatory alpha, beta-unsaturated cyclic ketone, such as 1-carvone. Likewise, the same holds true if the dextrorotatory alpha, beta-unsaturated cyclic ketone is the desired product. Thus, the present invention offers a convenient, practical, selective, relatively inexpensive and environmentally friendly process for the preparation of pure optical isomers of alpha, beta-unsaturated cyclic ketones, when they possess an asymmetric center. EXAMPLES The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and/or methods claimed herein are made and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.); however, some errors and deviations may have occurred. Unless indicated otherwise, parts are parts by weight, temperature is degrees C. EXAMPLE 1 A mixture of 30 g of 1-carveol and 0.6 g of zinc octoate (zinc content 18%, Shepherd Chemical Company) was heated at 228-230°C in a flask equipped with a stirrer, temperature probe, and reflux condenser. Periodically the reaction mixture was sampled and analyzed by GC on a polar 30-meter capillary column. After 2 hours the reaction mixture contained 79% 1-carvone and 8% of unreacted 1-carveol (92% conversion of 1-carveol and 85.8% selectivity to 1-carvone). EXAMPLE 2 A mixture of 100 g 1-carveol, 3 g zinc octoate (zinc content 22%, Shepherd Chemical Company), 80 g dodecane was refiuxed at 215-217°C. Water was removed using Dean-Stark trap. The reaction mixture was periodically sampled for GC analysis. After 10 hours the reaction mixture contained 79% carvone and 17% carveol (83% conversion, 95% selectivity). EXAMPLE 3 A mixture of 80 g 1-carveol, 2.5 g calcium octoate (calcium content 10%, Shepherd Chemical Company), 80 g tetraethylene glycol dimethyl ether, and 20 g cis- pinane was refiuxed at 224-225 °C. Water was removed using Dean-Stark trap. The reaction mixture was periodically sampled for GC analysis. After 5 hours the reaction mixture contained 28% carvone and 61% carveol (39% conversion, 71.8% selectivity). EXAMPLE 4 A mixture of 80 g carveol, 2.7 g magnesium stearate, 80 g tetraethylene glycol dimethyl ether, and 20 g cis-pinene was refiuxed at 224-225°C.Water was removed using a Dean-Stark trap. The reaction mixture was periodically sampled for GC analysis. After 5 hours the reaction mixture contained 20% carvone and 69% carveol (31% conversion, 64.5% selectivity). EXAMPLE 5 A mixture of 80 g carveol, 3 g zinc octoate (zinc content 22%, Shepherd Chemical Company), 80 g diphenyl ether, and 16 g cis-pinene was refluxed at 224- 225°C. Water was removed using a Dean-Stark trap. The reaction mixture was periodically sampled for GC analysis. After 6 hours the reaction mixture contained 82% carvone and 3% carveol (97% conversion, 84% selectivity). EXAMPLE 6 Semi-continuous dehydrogenation of I-carveoI. A mixture of 450 g mineral oil and 200 g zinc octoate (22% zinc) was heated in a 2-liter pot of a distillation column (25 theory plates) to 240°C at 50 mm Hg. Then 7080 g of 1-carveol containing mixture (10.5% 1-carvone and 72.5% 1-carveol) was added through the pot at a rate of 60 g/h over 118 hours. The reflux ratio and the product take-off rate were adjusted in such a way so as to maintain pot temperature at 240-250°C and the residual carveol content in the product (distillate) below 3.5%. Total 6800 g of product of dehydrogenation was collected. It contained 4.1% spicatone, 74.3% carvone, and 3.2% carveol (carveol conversion was 95.7%, and selectivity to carvone plus spicatone was 93%). Isomerization of spicatone to carvone. The product of dehydrogenation was agitated at 100°C for 2 hours with 25% (weight) of 10% aqueous solution of sodium hydroxide. The spicatone concentration decreased to 0.2% and carvone concentration increased to 78.2%. After the caustic solution was separated, the organic layer was neutralized with acetic acid and washed with water. Fragrance and flavor quality 99.6% pure 1-carvone was isolated using conventional methods of separation. Isomerization of spicatone to carvone (alternative method). The product of dehydrogenation was agitated at 225°C for 3 hours. The spicatone concentration decreased to 0.2% and carvone concentration increased to 78.1%. Fragrance and flavor quality 99.6% pure 1-carvone was isolated using conventional methods of separation. Throughout this application, where various publications are referenced, the entire disclosures of these publications are hereby incorporated by reference into this application for all purposes. While this invention has been described in connection with preferred embodiments and specific examples, it is not intended to limit the scope of the invention to the particular embodiments set forth, but on the contrary, it is intended to cover such alternatives, modifications, and equivalents as may be included within the spirit and scope of the invention as defined by the appended claims. For example, there are numerous variations and combinations of components and or conditions, e.g., the secondary allylic alcohol compound, the particular metal carboxylate, and the reaction conditions that can be used to optimize the results obtained from the described embodiments. To this end, one skilled in the art will appreciate that in practicing the present invention, only reasonable and routine experimentation will be required to optimize such conditions for the desired result. WE CLAIM: 1. A process for the manufacture of an alpha, beta-unsaturated cyclic ketone, comprising the dehydrogenation of a secondary allylic cyclic alcohol having the general structure: in the presence of a metal carboxylate, in a reaction environment under conditions effective to provide an alpha, beta-unsaturated cyclic ketone of the general structure: wherein the metal is selected from Groups 2 and 12 of the periodic table and wherein R1 and R2 are independently selected from among straight chain or branched C1 -C5 alkyl groups, C1- C5 alkenyl groups, or C6-C10 aryl groups. 2. The process as claimed in claim 1, wherein the secondary allylic cyclic alcohol is carveol and has the structure: 3. The process as claimed in claim 1, wherein the alpha, beta-unsaturated cyclic ketone is carvone and has the structure: 4. The process as claimed in claim 1, wherein the metal is magnesium, calcium, zinc, or any combination thereof. 5. The process as claimed in claim 1, wherein the metal is zinc. 6. The process as claimed in claim 1, wherein the metal carboxylate is magnesium stearate, calcium 2-ethylhexanoate, zinc 2-ethylhexanoate or any combination thereof. 7. The process as claimed in claim 1, wherein the metal carboxylate is zinc 2- ethylhexanoate. 8. The process as claimed in claim 1, wherein the reaction environment comprises solvent. 9. The process as claimed in claim 8, wherein the solvent comprises an aliphatic hydrocarbon. 10. The process as claimed in claim 8, wherein the solvent comprises an ether. 11. The process as claimed in claim 8, wherein the solvent comprises cis- pinane, dodecane, pentadecane, mineral oil, diphenyl ether, tetraethylene glycol dimethyl ether or any combination thereof. 12. The process as claimed in claim 8, wherein the solvent is present in an amount of from 0.5 wt. % to 400 wt. % based on the secondary alcohol. 13. The process as claimed in claim 1, wherein the metal carboxylate is present in an amount of from 0.5% by weight to 100% by weight relative to the secondary alcohol. 14. The process as claimed in claim 1, wherein the conditions effective to provide an alpha, beta-unsaturated cyclic ketone comprise heating the reaction environment. 15. The process as claimed in claim 14, wherein the reaction environment is heated to a temperature within the range of from 210°C to 260°C. 16. The process as claimed in claim 1, wherein the conditions effective to provide an alpha, beta-unsaturated cyclic ketone comprise maintaining the reaction environment at or below atmospheric pressure. 17. The process as claimed in claim 1, wherein the condition effective to provide an alpha, beta-unsaturated cyclic ketone comprise refluxing the reaction environment. 18. The process as claimed in claim 1, wherein the process is carried out in a batchwise mode. 19. The process as claimed in claim 18, wherein the metal carboxylate is present in an amount of 1-4 wt. % based on starting secondary alcohol. 20. The process as claimed in claim 18, wherein the metal carboxylate is present in an amount of 0.5-2 wt. % based on total reaction mixture. 21. The process as claimed in claim 1, wherein the process is carried out in a continuous mode. 22. The process as claimed in claim 21, wherein the metal carboxylate is present in the reaction environment, based on throughput, of 0.1-1 g of secondary alcohol per 1 g catalyst per hour. 23. The process as claimed in claim 21, wherein the alpha, beta-unsaturated cyclic ketone is continuously removed from the reaction environment. 24. The process as claimed in claim 1, wherein the process comprises removing water from the reaction environment. 25. The process as claimed in claim 1, wherein the process provides a beta, gamma-unsaturated cyclic ketone. 26. The process as claimed in claim 25, wherein the beta, gamma-unsaturated cyclic ketone is spicatone. 27. The process as claimed in claim 25, wherein the process comprises an isomerization step to isomerize beta, gamma-unsaturated cyclic ketone to an alpha, beta-unsaturated cyclic ketone. 28. The process as claimed in claim 25, wherein the isomerization step is performed thermally by heating beta, gamma-unsaturated cyclic ketone to a temperature in the range of from 200°C to 240°. 29. The process as claimed in claim 25, wherein the isomerization step is performed by treating beta, gamma-unsaturated cyclic ketone with a sodium hydroxide solution. 30. An alpha, beta-unsaturated cyclic ketone produced by the process as claimed in claim 1. A process for the manufacture of an alpha, beta-unsaturated cyclic ketone, such as carvone, comprises the dehydrogenation of a secondary allylic cyclic alcohol, such as carveol, in the presence of metal carboxylate. The process can be performed in a batchwise or continuous mode. Examples of suitable metal carboxylates include magnesium stearate, calcium 2-ethylhexanoate, and zinc 2-ethylhexanoate.

Full Text

Field of the Invention
The present invention relates generally to the field of organic synthesis and
more particularly to a process for the manufacture of an alpha, beta-unsaturated cyclic
ketone, comprising the dehydrogenation of a secondary allylic alcohol in the presence
of at least one metal carboxylate.
Background of the Invention
It is known that many alcohols can be catalytically dehydrogenated to the
corresponding carbonyl compounds (for general information see Hydlicky Milos,
Oxidations in Organic Chemistry, ACS Monograph 186, American Chemical Society,
Washington, DC, 1990, p. 132 and Smith M.B. and March J. Advanced Organic
Chemistry, 5th edition, John Wiley and Sons, Inc., New York, 2001, pp. 1515-1516).
Usually, dehydrogenation of alcohols allows preparation of the target carbonyl
compounds with high yields and throughputs. To that end, copper, nickel, and
palladium based catalysts have been typically used to carry out the dehydrogenation
of alcohols.
An attempt to produce alpha, beta-unsaturated cyclic ketones, such as carvone,
by catalytic dehydrogenation of a corresponding secondary allylic cyclic alcohol, such
as carveol, was made in 1927 (Treibs W. and Schmidt H, Ber., 1927, 60 B, pp. 2335-
2341). However, this attempt failed as both copper and nickel based catalysts
converted the carveol into carvacrol and tetrahydrocarvone, but not to carvone. This
was due, in part, to two potential side reactions that can accompany the catalytic
dehydrogenation of a secondary allylic cyclic alcohol, such as carveol. First, both the
starting material and the product possess double bonds, which can react with
hydrogen that is produced as a result of dehydrogenation. Secondly, these double
bonds easily isomerize at high temperature in the presence of catalysts to provide an
aromatic structure. The scheme below represents these side reactions that can occur
during, for example, the dehydrogenation of carveol.
Prior to the discovery of the present invention, most known methods for the
preparation of alpha, beta-unsaturated cyclic ketones from a corresponding secondary
allylic cyclic alcohol, such as the preparation of carvone from carveol. involve some
type of an oxidation reaction. These methods can be divided in two categories.
The first of these two methods is known as the Oppenauer oxidation, where
hydrogen is transferred from carveol to an auxiliary carbonyl compound. Japanese
patent JP 50/58031 describes carveol oxidation in the presence of aluminum
isopropoxide as catalyst, cyclohexanone as hydrogen acceptor, and xylene as solvent.
The yield of the 88% pure carvone was 82%. A better yield of carvone (91%) was
obtained by employing of a complex aluminum catalyst and three equivalents of
pivalaldehyde as hydrogen acceptor in a methylene chloride solution (Takashi Ooi, et
al, Synthesis, 2002, No. 2, pp. 279-291). The new aluminum complex catalyst used in
this method (2,7-dimethyl-l,8-biphenyldioxy)bis(diallcoxya]uminum) has to be
prepared from trialkylaluminum, which imposes safety concerns on an industrial
scale. Common disadvantages of all Oppenauer type oxidation methods include the
catalyst sensitivity toward hydrolysis, the necessity of use of an auxiliary carbonyl
compound (sometimes a large excess) and a lengthy and labor intensive work-up.
The second of these methods is known as oxidation with a reagent. Above
mentioned Japanese patent JP 50/58031 also describes carveol oxidation to carvone
with chromic trioxide in concentrated sulfuric acid with 93% yield. Among other
reagents suggested for carveol oxidation to carvone are, hydrogen peroxide in the
presence of molybdenum catalyst (Trost, B.M. et al., Israel Journal of Chemistry,
1984, Vol. 24, pp. 134-143); N-methybnorpholine-N-oxide in the presence of
ruthenium catalyst (Sharpless K.B. et al., Tetrahedron Letters, 1976, No. 29, pp.
2503-2506); hydroperoxides in the presence of molybdenum and vanadium catalysts
(Lempers H.E.B. et al., J. Org. Chem., 1998, Vol. 63, pp. 1408-1413); and copper
catalysts (Rothenberg G., J. Chem. Soc, Perkin Trans. 1998, No. 2, pp. 2429-2434).
In most, if not all, of these reactions expensive reagents or toxic catalysts are used and
a large excess of the oxidation reagent is required, which makes a reagent oxidation
very unattractive for commercialization.
The double bond in carvone mat is conjugated with the carbonyl group is
markedly active as hydrogen acceptor. This is why under commonly used
dehydrogenation conditions dihydrocarvone becomes the major product of carveol
dehydrogenation (see, for example, US 4160786 which describes isomerization of
cycloalkenols to cycloalkanones in the presence of copper-chromite catalysts and
specifically mentions carveol conversion to dihydrocarvone). Supported palladium,
platinum and ruthenium catalysts, which are frequently used in dehydrogenation
reaction, afford phenols and cyclohexanones upon dehydrogenation of cycloalkenols
(carveol) or cycloakenones (carvone). Examples of such transformations can be found
in US 4929762 and US 5817891.
In some instances a method called oxidative dehydrogenation is employed to
produce alpha,beta-unsaturated carbonyl compounds from the corresponding allylic
alcohols. Catalysts utilized in this process include metallic copper or silver. Using this
process geraniol was converted to citral (US 5241122) and prenol to prenal (US
6013843) at the temperature above 360°C. The name of this process - oxidative
dehydrogenation - suggests that this is not a true dehydrogenation, as it requires the
presence of oxygen, which could be either an oxidant or a hydrogen acceptor.
Nonetheless, the oxidative dehydrogenation has never been successfully used to
produce carvone, probably because it proceeds at the temperature above 360°C, which
causes decomposition of carveol and carvone and leads to low yields and poor quality.
In other attempts, some enzymes have been found to affect this kind of
chemical transformation (Hirata, T., et al., Phytochemistry, 2000, vol. 55, No. 4, pp.
297-303). The enzymatic method has mostly a theoretical interest and cannot be used
for a large-scale production of carvone.
In general, homogeneous catalysts are rarely used in dehydrogenation process
(Blum, J., Biger, S. Tetrahedron Letters, 1970, No. 21, pp. 1825-1828). In particular,
in the presence of those homogeneous catalysts that could possibly affect
dehydrogenation of the allylic alcohols the isomerization to saturated carbonyl
compounds but not dehydrogenation to corresponding unsaturated carbonyl
compounds was observed (see review by van der Drift, R.C. et al., J. Organomet.
Chem., 2000, No. 650, pp. 1-24). There are a few examples of the homogeneous
dehydrogenation of alcohols. However, only saturated alcohols were used as
substrates (Fragale, C. et al. J. Molecular Catalysis, 1979, Vol. 5, pp. 65-73).
Interestingly, most of the reported examples were not dehydrogenation, but rather
hydrogen transfer reactions, which involved hydrogen acceptors. Thus, there is no
indication in the patent or scientific literature that carvone or any other conjugated
alpha, beta-unsaturated cyclic ketones can be prepared by catalytic dehydrogenation
of the corresponding allylic alcohol.
Moreover, the homogeneous dehydrogenation catalysts that have been used
are complex compounds of the transition metals chosen from groups six to ten of the
Periodic Table. In contrast, the present invention further provides a method that
utilizes carboxylates of the metals chosen from groups two and twelve of the Periodic
Table. As discussed below, and in accordance with the present invention, these
carboxylates are effective homogeneous dehydrogenation catalysts that allow for
selective production of alpha, beta-unsaturated cyclic ketones from the corresponding
secondary allylic cyclic alcohol via a true dehydrogenation mechanism.
Summary of the Invention
Among other aspects, the present invention is based in part on the surprising
discovery that carboxylates of metals from groups two and twelve of the Periodic
Table can act as selective homogeneous catalysts for the dehydrogenation of a
secondary allylic cyclic alcohol to form an alpha, beta-unsaturated cyclic ketone.
In a first aspect, the present invention provides a process for the manufacture
of an alpha, beta-unsaturated cyclic ketone, comprising the dehydrogenation of a
secondary allylic cyclic alcohol in the presence of at least one metal carboxylate, in a
reaction environment under conditions effective to provide an alpha, beta-unsaturated
cyclic ketone.
In a second aspect, the present invention further provides alpha, beta-
unsaturated cyclic ketones produced by the processes described herein.
Additional advantages and embodiments of the invention will be obvious from
the description, or may be learned by practice of the invention. Further advantages of
the invention will also be realized and attained by means of the elements and
combinations particularly pointed out in the appended claims. Thus, it is to be
understood that both the foregoing general description and the following detailed
description are exemplary and explanatory of certain embodiments of the invention,
and are therefore not restrictive of the invention as claimed.
Detailed Description of the Invention
The present invention may be understood more readily by reference to the
following detailed description and any examples provided herein. It is also to be
understood that this invention is not limited to the specific embodiments and methods
described below, as specific components and/or reaction conditions may vary.
Furthermore, the terminology used herein is used only for the purpose of describing
particular embodiments of the present invention and is not intended to be limiting in
any way.
It must also be noted that, as used in the specification and the appended
claims, the singular forms "a," "an," and "the" comprise plural referents unless the
context clearly dictates otherwise. For example, reference to a component in the
singular is intended to comprise a plurality of components.
Ranges may be expressed herein as from "about" or "approximately" one
particular value and/or to "about" or "approximately" another particular value. When
such a range is expressed, another embodiment comprises from the one particular
value and/or to the other particular value. Similarly, when values are expressed as
approximations, by use of the antecedent "about," it will be understood that the
particular value forms another embodiment.
As used herein, Group II and XXII metals are intended to include those metals
belonging to Groups II and XXII of the Periodic Table.
As used herein, the term "alkyl" refers to a paraffmic hydrocarbon group
which may be derived from an alkane by dropping one hydrogen from the formula.
Non-limiting examples include C1 - C20 alkane derivatives such as methyl, ethyl,
propyl, isopropyl, butyl, t-butyl, and isobutyl. To this end, it should be understood
that an alkyl substituent suitable for use in the present invention can be a branched or
straight chain alkyl substituent.
As used herein, the term "alkenyl" is intended to refer to a substituent derived
from the class of unsaturated hydrocarbons having one or more double bonds. Those
containing only one double bond are referred to as allcenes or alkenyl substituents.
Those with two or more double bonds are called alkadienes (alkadienyl), alkatrienes
(alkatrienyl) and so on. Non-limiting examples include ethylene, propylene, butylene
and the like. To this end, it should be understood that an alkenyl substituent suitable
for use in the present invention can be substituted or unsubstituted.
As used herein, the term "aryl" refers to a compound or substituent whose
molecules have the ring structure characteristic of benzene, naphthalene,
phenanthrene, anthracene, and the like. That is to say, an aryl group typically
contains either the 6-carbon ring of benzene or the condensed 6 carbon rings of other
aromatic derivatives. For example, an aryl group can be a phenyl or naphthyl group.
To this end, it should be understood that aryl substituents suitable for use with the
present invention can be substituted or unsubstituted.
As used here, alpha, beta-unsaturated cyclic ketone refers to cyclic ketones
having the following structure:
wherein R1 and R2 are independently selected from among straight chain or branched
C1 -C5 alkyl groups, C1- C5 alkenyl groups, or C6-C10 aryl groups.
As used herein, secondary allylic cyclic alcohol refers to an allylic cyclic
alcohol having the following generic structure:
wherein R1 and R2 are independently selected from among straight chain or branched
C1 -C5 alkyl groups, C1- C5 alkenyl groups, or C6-C10 aryl groups.
As used herein, a beta, gamma-unsaturated cyclic ketone refers to a cyclic
ketone having the following general structure:

wherein R1 and R2 are independently selected from among straight chain or branched
C1 -C5 alkyl groups, C1-C5 alkenyl groups, or C6-C10 aryl groups.
As used herein, by use of the term "effective," "effective amount," or
"conditions effective to" it is meant that such amount or reaction condition is capable
of performing the function of the compound or property for which an effective
amount is expressed. As will be pointed out below, the exact amount required will
vary from one embodiment to another, depending on recognized variables such as the
compounds or materials employed and the processing conditions observed. Thus, it is
not always possible to specify an exact "effective amount" or "condition effective to."
However, it should be understood that an appropriate effective amount will be readily
determined by one of ordinary skill in the art using only routine experimentation.
As used herein, the term "reaction environment" refers to the medium in
which the dehydrogenation reaction takes place. For example, and without limitation,
the reaction environment or reaction medium in which the dehydrogenation reaction
of the present invention takes place can be a secondary allylic cyclic alcohol.
Alternatively, the reaction environment or reaction medium can comprise at least one
optional solvent.
As used herein, the term "optional" or "optionally" means that the
subsequently described event or circumstance may or may not occur, and that the
description includes instances where said event or circumstance occurs and instances
where it does not. For example, the phrase "optionally substituted lower alkyl" means
that the lower allcyl group may or may not be substituted and that the description
includes both unsubstituted lower alkyl and lower alkyl where there is substitution.
As set forth above, in a first aspect the present invention provides a process for
the manufacture of an alpha, beta-unsaturated cyclic ketone, comprising the
dehydrogenation of a secondary allylic cyclic alcohol in the presence of at least one
metal carboxylate, in a reaction environment under conditions effective to provide an
alpha, beta-unsaturated cyclic ketone.
According to the invention, suitable secondary allylic cyclic alcohols include
those alcohols having the general structure of formula (I):
wherein R1 and R2 are independently selected from among straight chain or branched
C1 -C5 allcyl groups, C1- C5 alkenyl groups, or C6-C10 aryl groups. In a preferred
aspect of the invention, the secondary allylic cyclic alcohol is carveol and is
represented by the structure of formula (HI) below:
As stated above, the dehydrogenation process of the present invention
proceeds in the presence of at least one metal carboxylate catalyst. The metal
carboxylate catalysts are carboxylates of the metals selected from Groups II and XXII
of the periodic table, including magnesium, calcium, and zinc. According to one
aspect of the invention, the metal carboxylates comprise a carboxylate moiety having
the general structure:
wherein R3 is selected from among C1-C20 straight chain or branched alkyl groups,
which groups can be further substituted by one or more additional C1-C20 straight
chain or branched alkyl radicals. In one aspect, a preferred carboxylate is stearate.
Alternatively, in another aspect, the carboxylate is an ethylhexanoate or octanoate.
Therefore, in accordance with these aspects, suitable metal carboxylate catalyst for
use in the present invention includes, without limitation, magnesium stearate
(commercially available from the Aldrich company), calcium 2-ethylhexanoate
(commercially available from Shepherd Chemical Company) and zinc 2-
ethylhexanoate (also commercially available from Shepherd Chemical Company).
As described herein, the process of the present invention is useful for the
manufacture of a variety of alpha, beta-unsaturated cyclic ketones having the generic
structure:
wherein R1 and R2 are independently selected from among straight chain or branched
C1 -C5 alkyl groups, C1- C5 alkenyl groups, or C6-C10 aryl groups. To that end, it will
be understood and appreciated by one of ordinary skill in the art the particular alpha,
beta-unsaturated cyclic ketone desired to be manufactured will be dependent upon the
starting secondary allylic cyclic alcohol as previously described herein. In one aspect,
the process of the present invention is particularly useful for the preparation of
carvone, an alpha, beta-unsaturated cyclic ketone having the structure as follows.

Using appropriate reaction conditions, not only allylic but also some other
alcohols could be converted to the corresponding carbonyl compounds. For example,
dihydrocarveol was converted to dihydrocarvone, although the rate of this reaction
was slower, which indicates that allylic alcohols undergo metal carboxylate catalyzed
dehydrogenation faster than their saturated analogues.
In the presence of metal carboxylates a noticeable rate of carveol
dehydrogenation can be observed at about 210°C. However, to achieve a reasonable
reaction rate the process should be carried out at 215-260°C. At higher temperature
the selectivity of carveol dehydrogenation to carveol starts to decrease.
According to present invention, dehydrogenation of carveol is carried out in
the presence of metal carboxylate at elevated temperature under atmospheric or
reduced pressure as a batch or semi-continuous process with an optional addition of a
solvent.
To this end, optimization of the process, as described herein, would be
possible using only routine experimentation. For example, by controlling the residual
pressure (e.g., vacuum), the reaction mixture can be refluxed at the desired
temperature in the system. In addition, the choice of a desired temperature and
residual pressure combination can control the carveol concentration in the system and,
thus, the contact time between the catalyst and carveol. And, finally, this combination
of parameters, e.g., pressure, carveol concentration, and contact time, can be used to
select a feed rate of, e.g., carveol or carveol containing mixture to the system.
The reaction does not require a solvent, though addition of solvent can be
beneficial in achieving high yields in a batch mode or for improving heat transfer and
lowering the viscosity in a semi-continuous mode. Examples of solvents include but
are not limited to high boiling individual hydrocarbons and their mixtures
(pentadecane, white mineral oils, etc.), ethers (diphenyl ether, tetraethylene glycol
dimethyl ether, etc.) or mixtures of hydrocarbons and ethers. The amount of solvent
may vary from 10% to 200% based on starting carveol. Even larger amount of solvent
can be employed. However, it would lead to less effective equipment utilization.
the process of the present invention as described herein can be successfully
performed on virtually any scale.
The amount of catalyst can be expressed in terms of the starting secondary
alcohol or the total reaction mixture. For example, the amount of the carboxylate can
vary from about 0.5% by weight or less to about 100% by weight or more relative to
the secondary alcohol. For example, specific examples of suitable amounts can
include 1, 5,10,20,30,40,50,60,70, 80 and 90 % by weight and ranges
therebetween.
Moreover, the amount of metal carboxylate catalyst is selected to provide the
desired reaction rate and can vary depending on the reaction technique employed. For
example, where the process is carried out in a batchwise mode, the carboxylate can be
present in an amount of about 1% to about 4% by weight based on the starting
secondary alcohol or about 0.5% to about 2 wt % based on the total reaction mixture.
For processes carried out in the continuous mode, the metal carboxylate can be
present in the system, based on throughput, of about 0.01 to about 1 g of secondary
alcohol per 1 g of catalyst per hour.
To carry out a batch dehydrogenation carveol or carveol containing streams
are mixed with catalyst and possibly a solvent in any sequence. Then the resulting
mixture is heated at desired temperature. It is advisable, although not required, to
remove any water contained in the optional solvent or in the feed by distillation
(possibly adding an azeotrope forming agent) prior to catalyst addition in order to
protect the catalyst from hydrolysis. Various hydrocarbons with appropriate boiling
points can serve as azeotrope forming agents. Dehydrogenation can be carried out at
reflux temperature, atmospheric pressure or under vacuum. The reflux temperature
can be controlled by addition of one or more solvents or by adjusting pressure.
To carry out a semi-continuous process, a mixture of catalyst and solvent can
be heated at the desired temperature (typically 220-250°C) and pressure (typically 10-
100 mm Hg) in the still pot of a distillation column efficient enough to separate
carvone from carveol. Then carveol or carveol containing stream is continuously
added through the still pot at a specified rate. As carvone has a lower boiling point, it
is continuously removed from the top of distillation column, while carveol remains in
the pot. Addition of carveol and removal of carvone are continued until the catalyst
loses its activity (typically 96-120 hours). Semi-continuous process affords better
yield of carvone comparing with batch process because the product is removed from
the reaction zone as soon as it is formed thus preventing formation of by-products.
At high temperatures in the presence of catalyst, it is possible that the desired
alpha, beta-unsaturated cyclic ketone will exists in equilibrium with its unconjugated
isomer, a beta, gamma-unsaturated cyclic ketone, as illustrated below.

In instances where the unconjugated beta, gamma-unsaturated isomer has a
lower boiling point than the target conjugated alpha, beta-unsaturated cyclic ketone,
the beta, gamma-unsaturated cyclic ketone would be removed first during reflux
conditions. For this reason, a product of a semi-continuous dehydrogenation of a
suitable secondary allylic alcohol may contain a noticeable amount of the beta,
gamma-unsaturated cyclic ketone in addition to the target alpha, beta-unsaturated
cyclic ketone. For example, spicatone, the unconjugated beta, gamma-unsaturated
isomer of carvone, has a lower boiling point than carvone and under reflux conditions
is removed first. For this reason, a product of a semi-continuous dehydrogenation of
carveol can contain a noticeable amount of spicatone, an amount typically in the range
of from about 4 to about 8%.
A beta, gamma-unsaturated cyclic ketone, such as spicatone, can be
isomerized back to the target alpha, beta-unsaturated cyclic ketone by heating the
product of the dehydrogenation reaction to a temperature above 200°C or by treating
the product of the dehydrogenation reaction with a sodium hydroxide solution at or
above 80°C in a batch process. For example, according to the process of the present
invention, the preparation of carvone from carveol can provide a minimum undesired
amount of spicatone, the unconjugated alpha, gamma-unsaturated cyclic ketone
isomer of carvone. By heating the product of dehydrogenation at above 200°C or by
treating with a sodium hydroxide solution at above 80oC in a batch process, the
spicatone can therefore be isomerized back to provide a higher yield of the desired
product.
After the spicatone isomerization step, semi-continuous dehydrogenation of
carveol affords 97% weight yield of 95% pure carvone (the rest 5% is mostly
dihydrocarvone, which by itself is a valuable component of the spearmint oil). Further
fractionation affords 99.6% pure (or higher) fragrance and flavor quality carvone with
90% yield based on starting carveol.
It will further be appreciated upon practicing the process of the present
invention that the dehydrogenation process described herein does not alter the optical
activity of starting secondary allylic cyclic alcohol. Therefore, a levorotatory
secondary allylic cyclic alcohol, such as 1-carveol, can be successfully converted to a
levorotatory alpha, beta-unsaturated cyclic ketone, such as 1-carvone. Likewise, the
same holds true if the dextrorotatory alpha, beta-unsaturated cyclic ketone is the
desired product. Thus, the present invention offers a convenient, practical, selective,
relatively inexpensive and environmentally friendly process for the preparation of
pure optical isomers of alpha, beta-unsaturated cyclic ketones, when they possess an
asymmetric center.
EXAMPLES
The following examples are put forth so as to provide those of ordinary skill in
the art with a complete disclosure and description of how the compounds,
compositions, articles, devices and/or methods claimed herein are made and
evaluated, and are intended to be purely exemplary of the invention and are not
intended to limit the scope of what the inventors regard as their invention. Efforts
have been made to ensure accuracy with respect to numbers (e.g., amounts,
temperature, etc.); however, some errors and deviations may have occurred. Unless
indicated otherwise, parts are parts by weight, temperature is degrees C.
EXAMPLE 1
A mixture of 30 g of 1-carveol and 0.6 g of zinc octoate (zinc content 18%,
Shepherd Chemical Company) was heated at 228-230°C in a flask equipped with a
stirrer, temperature probe, and reflux condenser. Periodically the reaction mixture was
sampled and analyzed by GC on a polar 30-meter capillary column. After 2 hours the
reaction mixture contained 79% 1-carvone and 8% of unreacted 1-carveol (92%
conversion of 1-carveol and 85.8% selectivity to 1-carvone).
EXAMPLE 2
A mixture of 100 g 1-carveol, 3 g zinc octoate (zinc content 22%, Shepherd
Chemical Company), 80 g dodecane was refiuxed at 215-217°C. Water was removed
using Dean-Stark trap. The reaction mixture was periodically sampled for GC
analysis. After 10 hours the reaction mixture contained 79% carvone and 17% carveol
(83% conversion, 95% selectivity).
EXAMPLE 3
A mixture of 80 g 1-carveol, 2.5 g calcium octoate (calcium content 10%,
Shepherd Chemical Company), 80 g tetraethylene glycol dimethyl ether, and 20 g cis-
pinane was refiuxed at 224-225 °C. Water was removed using Dean-Stark trap. The
reaction mixture was periodically sampled for GC analysis. After 5 hours the reaction
mixture contained 28% carvone and 61% carveol (39% conversion, 71.8%
selectivity).
EXAMPLE 4
A mixture of 80 g carveol, 2.7 g magnesium stearate, 80 g tetraethylene glycol
dimethyl ether, and 20 g cis-pinene was refiuxed at 224-225°C.Water was removed
using a Dean-Stark trap. The reaction mixture was periodically sampled for GC
analysis. After 5 hours the reaction mixture contained 20% carvone and 69% carveol
(31% conversion, 64.5% selectivity).
EXAMPLE 5
A mixture of 80 g carveol, 3 g zinc octoate (zinc content 22%, Shepherd
Chemical Company), 80 g diphenyl ether, and 16 g cis-pinene was refluxed at 224-
225°C. Water was removed using a Dean-Stark trap. The reaction mixture was
periodically sampled for GC analysis. After 6 hours the reaction mixture contained
82% carvone and 3% carveol (97% conversion, 84% selectivity).
EXAMPLE 6
Semi-continuous dehydrogenation of I-carveoI. A mixture of 450 g mineral
oil and 200 g zinc octoate (22% zinc) was heated in a 2-liter pot of a distillation
column (25 theory plates) to 240°C at 50 mm Hg. Then 7080 g of 1-carveol containing
mixture (10.5% 1-carvone and 72.5% 1-carveol) was added through the pot at a rate of
60 g/h over 118 hours. The reflux ratio and the product take-off rate were adjusted in
such a way so as to maintain pot temperature at 240-250°C and the residual carveol
content in the product (distillate) below 3.5%. Total 6800 g of product of
dehydrogenation was collected. It contained 4.1% spicatone, 74.3% carvone, and
3.2% carveol (carveol conversion was 95.7%, and selectivity to carvone plus
spicatone was 93%).
Isomerization of spicatone to carvone. The product of dehydrogenation was
agitated at 100°C for 2 hours with 25% (weight) of 10% aqueous solution of sodium
hydroxide. The spicatone concentration decreased to 0.2% and carvone concentration
increased to 78.2%. After the caustic solution was separated, the organic layer was
neutralized with acetic acid and washed with water. Fragrance and flavor quality
99.6% pure 1-carvone was isolated using conventional methods of separation.
Isomerization of spicatone to carvone (alternative method). The product of
dehydrogenation was agitated at 225°C for 3 hours. The spicatone concentration
decreased to 0.2% and carvone concentration increased to 78.1%. Fragrance and
flavor quality 99.6% pure 1-carvone was isolated using conventional methods of
separation.
Throughout this application, where various publications are referenced, the
entire disclosures of these publications are hereby incorporated by reference into this
application for all purposes.
While this invention has been described in connection with preferred
embodiments and specific examples, it is not intended to limit the scope of the
invention to the particular embodiments set forth, but on the contrary, it is intended to
cover such alternatives, modifications, and equivalents as may be included within the
spirit and scope of the invention as defined by the appended claims. For example,
there are numerous variations and combinations of components and or conditions,
e.g., the secondary allylic alcohol compound, the particular metal carboxylate, and the
reaction conditions that can be used to optimize the results obtained from the
described embodiments. To this end, one skilled in the art will appreciate that in
practicing the present invention, only reasonable and routine experimentation will be
required to optimize such conditions for the desired result.
WE CLAIM:
1. A process for the manufacture of an alpha, beta-unsaturated cyclic ketone,
comprising the dehydrogenation of a secondary allylic cyclic alcohol having
the general structure:

in the presence of a metal carboxylate, in a reaction environment under
conditions effective to provide an alpha, beta-unsaturated cyclic ketone of
the general structure:
wherein the metal is selected from Groups 2 and 12 of the periodic table and
wherein R1 and R2 are independently selected from among straight chain or
branched C1 -C5 alkyl groups, C1- C5 alkenyl groups, or C6-C10 aryl groups.
2. The process as claimed in claim 1, wherein the secondary allylic cyclic
alcohol is carveol and has the structure:

3. The process as claimed in claim 1, wherein the alpha, beta-unsaturated
cyclic ketone is carvone and has the structure:
4. The process as claimed in claim 1, wherein the metal is magnesium,
calcium, zinc, or any combination thereof.
5. The process as claimed in claim 1, wherein the metal is zinc.
6. The process as claimed in claim 1, wherein the metal carboxylate is
magnesium stearate, calcium 2-ethylhexanoate, zinc 2-ethylhexanoate or
any combination thereof.
7. The process as claimed in claim 1, wherein the metal carboxylate is zinc 2-
ethylhexanoate.
8. The process as claimed in claim 1, wherein the reaction environment
comprises solvent.
9. The process as claimed in claim 8, wherein the solvent comprises an
aliphatic hydrocarbon.
10. The process as claimed in claim 8, wherein the solvent comprises an ether.
11. The process as claimed in claim 8, wherein the solvent comprises cis-
pinane, dodecane, pentadecane, mineral oil, diphenyl ether, tetraethylene
glycol dimethyl ether or any combination thereof.
12. The process as claimed in claim 8, wherein the solvent is present in an
amount of from 0.5 wt. % to 400 wt. % based on the secondary alcohol.
13. The process as claimed in claim 1, wherein the metal carboxylate is present
in an amount of from 0.5% by weight to 100% by weight relative to the
secondary alcohol.
14. The process as claimed in claim 1, wherein the conditions effective to
provide an alpha, beta-unsaturated cyclic ketone comprise heating the
reaction environment.
15. The process as claimed in claim 14, wherein the reaction environment is
heated to a temperature within the range of from 210°C to 260°C.
16. The process as claimed in claim 1, wherein the conditions effective to
provide an alpha, beta-unsaturated cyclic ketone comprise maintaining the
reaction environment at or below atmospheric pressure.
17. The process as claimed in claim 1, wherein the condition effective to
provide an alpha, beta-unsaturated cyclic ketone comprise refluxing the
reaction environment.
18. The process as claimed in claim 1, wherein the process is carried out in a
batchwise mode.
19. The process as claimed in claim 18, wherein the metal carboxylate is present
in an amount of 1-4 wt. % based on starting secondary alcohol.
20. The process as claimed in claim 18, wherein the metal carboxylate is
present in an amount of 0.5-2 wt. % based on total reaction mixture.
21. The process as claimed in claim 1, wherein the process is carried out in a
continuous mode.
22. The process as claimed in claim 21, wherein the metal carboxylate is present
in the reaction environment, based on throughput, of 0.1-1 g of secondary
alcohol per 1 g catalyst per hour.
23. The process as claimed in claim 21, wherein the alpha, beta-unsaturated
cyclic ketone is continuously removed from the reaction environment.
24. The process as claimed in claim 1, wherein the process comprises removing
water from the reaction environment.
25. The process as claimed in claim 1, wherein the process provides a beta,
gamma-unsaturated cyclic ketone.
26. The process as claimed in claim 25, wherein the beta, gamma-unsaturated
cyclic ketone is spicatone.
27. The process as claimed in claim 25, wherein the process comprises an
isomerization step to isomerize beta, gamma-unsaturated cyclic ketone to an
alpha, beta-unsaturated cyclic ketone.
28. The process as claimed in claim 25, wherein the isomerization step is
performed thermally by heating beta, gamma-unsaturated cyclic ketone to a
temperature in the range of from 200°C to 240°.
29. The process as claimed in claim 25, wherein the isomerization step is
performed by treating beta, gamma-unsaturated cyclic ketone with a sodium
hydroxide solution.
30. An alpha, beta-unsaturated cyclic ketone produced by the process as
claimed in claim 1.
A process for the manufacture of an alpha, beta-unsaturated cyclic ketone,
such as carvone, comprises the dehydrogenation of a secondary allylic cyclic alcohol,
such as carveol, in the presence of metal carboxylate. The process can be performed
in a batchwise or continuous mode. Examples of suitable metal carboxylates include
magnesium stearate, calcium 2-ethylhexanoate, and zinc 2-ethylhexanoate.

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Patent Number

225197

Indian Patent Application Number

02314/KOLNP/2005

PG Journal Number

45/2008

Publication Date

07-Nov-2008

Grant Date

05-Nov-2008

Date of Filing

21-Nov-2005

Name of Patentee

MILLENNIUM SPECIALTY CHEMICALS

Applicant Address

601 CRESTWOOD STREET, BUILDING 68, JACKSONVILLE, FL 32208

Inventors:

#	Inventor's Name	Inventor's Address
1	KOLOMEYER GENNADIY G	2506 WINGED ELM DRIVE EAST, JACKSONVILLE, FL 32246
2	OYLOE JACOB S	1514 N. RHODES STREET #305, ARLINGTON, 22209 VA

PCT International Classification Number

C07C 45/00

PCT International Application Number

PCT/US2004/014483

PCT International Filing date

2004-05-07

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	10/449,859	2003-05-30	U.S.A.