Processes for the Conversion of Myrcene to Nerol and Citral

BACKGROUND OF THE INVENTION

Oxygenated derivatives of monoterpenes, such as nerol and citral, are of great importance to a number of industries. Although some processes for their commercial production are available, new and/or better synthetic routes are needed.

The application of organo etallic chemistry to monoterpene transformation has been the subject of a number of studies. Early experiments are reported in McQuillin et al., J. Chem. Soc. Per in Trans. I, pp. 809-815 (1974), and Dunne et al., J. Chem. Soc. (C) , pp. 2196-2200, 2200-2203, and 2203-2206 (1970) . In these studies, the authors prepared several allyl palladium complexes of terpene compounds, including those resulting from the reaction of palladium with myrcene. Cyclization of myrcene, however, was found to be a problem, and neither nerol nor citral resulted from the described processes.

Building on the earlier work of these authors, Takahashi et al., Journal of Organometallic Chemistry, Vol. 266, pp. 327-336 (1984) successfully prepared a mixture of citral and nerol utilizing a two-step method. First, myrcene was reacted with dichlorobis(acetonitrile)palladium in the solvent hexamethylphosphoric triamide (HMPA) or in the presence of a base such as Li ₂ C0 ₃ using dimethylformamide (DMF) as solvent, to yield a non-cyclized palladium-myrcene complex. Although the reported yield for the Li ₂ C0 ₃ /DMF process was relatively good, the HMPA process yield was somewhat low, approximately 33%. In the second step of the reported process, the complex was isolated, and then treated with base to yield terpene aldehydes and alcohols such as citral and nerol. One major drawback of these processes, however, is that they necessitate two steps, requiring isolation of the intermediate before further processing. Moreover, the product obtained using these methods is a mixture of both citral and nerol. Furthermore, these reactions are saddled with the additional disadvantage of a temperature limitation, since at high temperatures the solvents HMPA and DMF are decomposed by the palladium species. See Bombieri et al., Inor anica Chimica Acta- Vol. 86, pp. 121-125 (1984) ; Fahey et al., Journal of Organic Chemistry, Vol. 39, pp. 3276-77 (1974) . Finally, the use of HMPA in any process is undesirable, since HMPA is an extremely potent toxin, as well as a suspected carcinogen.

Nerol and citral are compounds of high significance to the flavor, fragrance and synthetic vitamin industries. Additional and/or better processes for their commercial production, particularly processes employing the readily available starting material myrcene, are needed. The present invention is directed to this important end.

SUMMARY OF THE INVENTION

The present invention provides a novel process for producing a palladium-myrcene complex of the formula

comprising contacting myrcene with palladium (II) chloride in the presence of an aqueous cycloamide solvent, preferably a substituted aqueous cycloamide solvent, and a lithium salt. The complex thus formed provides a key intermediate for further conversion to the important compounds citral and nerol. The subject invention also encompasses novel methods for carrying out such conversions.

In accordance with the present invention, citral may be produced by a novel process in which a palladium- myrcene complex of the formula

is contacted with a phosphine compound.

Citral may also be produced by a novel process in which a palladium-myrcene complex of the formula

is contacted with a metal oxoanionic salt in the presence of an inert aqueous organic solvent. Preferably, the process is carried out at a temperature of at least about

80°C.

The present invention also provides another novel and highly efficient process for the production of citral comprising contacting myrcene with palladium (II) chloride in the presence of an inert aqueous alkylamide solvent and a metal oxoanionic salt at a temperature of at least about

80°C. Preferably, the process is carried out in the presence of an oxidizing agent. The present invention further provides a novel process for producing nerol comprising contacting a palladium-myrcene complex of the formula

with a nitrogen-donor compound in the presence of hydrogen gas.

Using one or more of the foregoing processes, citral and/or nerol production can be efficiently and effectively carried out with a high yield of and/or high selectivity to these very important end products.

DETAILED DESCRIPTION OF THE INVENTION

The subject invention involves, in one aspect, the production of a key palladium-myrcene complex. This key complex provides an intermediate for further reaction to citral (that is, 3,7-dimethyl-(E,Z)-2,6-octadienal) and nerol (that is,

3,7-dimethyl-(Z)-2,6-octadien-l-ol) , compounds of significant importance to the flavor, fragrance and synthetic vitamin industries.

Specifically, the present invention provides a process for producing a palladium-myrcene complex of the formula

comprising contacting myrcene with a palladium (II) chloride in the presence of an aqueous cycloamide solvent and a lithium salt.

The term cycloamide, as used herein in connection with the phrase aqueous cycloamide solvent, denotes a ring

hydrocarbon compound which contains an amide moiety, that is, a moiety of the formula -CONH ₂ , wherein one or both of the H atoms on the N atom may or may not be replaced by a bond to the ring compound and/or with a C _x to C ₅ alkyl or a like moiety. Such cycloamide compounds wherein the H atoms on the amide moiety are both so replaced are termed herein substituted aqueous cycloamide solvents, such substituted aqueous cycloamide solvents being preferred. The term aqueous, used in connection with the phrase cycloamide solvents, denotes water solubility. Suitable aqueous cycloamide solvents include substituted and unsubstituted pyrrolidones, such as N-methyl- pyrrolidone, substituted and unsubstituted imidazolidinones, and substituted and unsubstituted pyrimidones. Other suitable aqueous cycloamide solvents will be apparent to those skilled in the art. Preferably, the aqueous cycloamide solvent is aqueous N-methylpyrrolidone, a compound of the formula

Not only does aqueous N-methylpyrrolidone promote appropriate and efficient complexation of myrcene and palladium (II) chloride, it also lacks the toxic and carcinogenic properties found in HMPA. N-methylpyrrolidone is also less prone to decomposition by palladium than DMF.

Examples of lithium salts suitable for use with the present invention include, but are not limited to, Li ₃ P0 ₄ , Li ₂ B ₄ 0 ₇ , Li ₂ Cr0 ₄ , Li ₂ SO _< ,, LiN0 ₃ , Li ₂ 0 ₄ , LizMoO,,, and Li ₂ C0 ₃ . Other suitable lithium salts will be apparent to those skilled in the art. Preferably, the lithium salts are selected from the group consisting of Li ₃ P0 ₄ , Li ₂ B ₄ 0 ₇ , Li ₂ Cr0 ₄ , Li ₂ S0 ₄ , Li ₂ WO,,, Li ₂ Mo0 ₄ , and Li ₂ C0 ₃ . Most preferably, the lithium salt is Li ₂ B ₄ 0 ₇ and Li ₂ SO _< ,. LiN0 ₃ is least preferred in that it forms only a relatively small amount of the desired palladium-myrcene complex. As one skilled in the art will recognize, such salts may, if desired, be formed in situ.

The palladium-myrcene complex-forming reaction proceeds best at or above room temperature. Elevating the temperature results in increased reaction rates. Most preferably, the reaction is carried out at temperatures ranging from room temperature to about 70°C. The reaction may be conducted at atmospheric pressure, and generally runs to completion within a few hours. To maximize yields, continual stirring by manual or mechanical means may be employed. Ultrasound may also be used in conjunction with, or in place of, the continual stirring.

The palladium-myrcene complex thus formed provides a suitable intermediate for the production of nerol or citral, and the present invention also includes processes for producing these important compounds. Such processes, which are described in detail below, provide high yields of the desired product, nerol or citral, as the

case may be. Moreover, the citral processes result in a citral product, substantially free of nerol, and similarly, the nerol processes result in a nerol product, substantially free of citral. Thus, the present invention further contemplates a process for producing citral in high yields and substantially free of nerol, comprising contacting a palladium-myrcene complex of the formula

with a phosphine compound.

Surprisingly, the phosphine compound acts to stabilize an otherwise unstable citral end product to the both palladium metal and the thermal conditions of the subject reaction process. By the phrase phosphine compound it is meant a compound derived from phosphine, a compound of the formula PH ₃ , by the replacement of H atoms. Suitable phosphine compounds include, but are not limited to, PR _X R ₂ R ₃ wherein R _lf R ₂ , and R ₃ are the same or different and each represents a substituted or unsubstituted alkyl, substituted or unsubstituted C _z -C _zo alkenyl, substituted or unsubstituted C ₂ -C ₂₀ alkynyl, or substituted or unsubstituted C ₆ -C ₂₀ aryl. Other suitable phosphine compounds will be apparent to those skilled in the art.

Preferred phosphine compounds are wherein R _x , R ₂ , and/or R ₃ are substituted or unsubstituted phenyl. Particularly preferred phosphine compounds are those where R _α , R ₂ , and/or R ₃ are unsubstituted phenyl or para- substituted trifluoromethyl phenyl. If desired, the phosphine compounds may be supported on a suitable support material. As those skilled in the art will recognize, providing supported phosphine compounds will result in easier separation and recovery of the palladium species. Such support materials are conventional and include polymeric and inorganic materials. An example of a suitable polymeric material is polystyrene cross-linked with divinyl benzene. A preferred embodiment includes wherein R _1; R ₂ and/or R ₃ are phenyl and wherein said PR.R ₂ R ₃ is supported on polymeric polystyrene cross-linked with divinyl benzene, a commercially available product from Aldrich Chemical Company, Milwaukee, WI. Other polymeric and inorganic materials suitable for supporting the phosphine compounds for use in the subject process will be apparent to those skilled in the art. The foregoing citral-producing reaction proceeds best in temperatures of about 110°C.

The palladium-myrcene complex may be first isolated, and then contacted with the phosphine compound to yield citral. Accordingly, the present invention also encompasses a process for producing citral comprising: (i) contacting myrcene with palladium (II) chloride in the

presence of an aqueous cycloamide solvent and a lithium salt to form a palladium-myrcene complex of the formula

(ii) isolating the resultant palladium-myrcene complex; and (iii) contacting the isolated palladium-myrcene complex with a phosphine compound. Suitable techniques for isolating the palladium-myrcene complex will be readily apparent to those skilled in the art, and include techniques such as the column chromatography procedures set forth in Takahashi et al. , Journal of Organometallic Chemistry. Vol. 266, pp. 327-336 (1984).

Surprisingly, it has also been found that the palladium-myrcene complex need not be isolated prior to contacting with the phosphine compound, thereby providing a "one-pot" process. Moreover, it has been surprisingly discovered that the palladium-myrcene complex-forming, and the citral-forming reactions need not be carried out in a two-step fashion. Instead, the phosphine compound may be added directly to the myrcene along with the palladium- myrcene complex forming reagents, to yield, in one step, the desired citral product. Thus, an additional aspect of the invention involves a process for producing citral

comprising contacting myrcene with: (i) palladium (II) chloride in the presence of an aqueous cycloamide solvent and a lithium salt; and (ii) a phosphine compound. Reagents (i) and (ii) can be added in step-wise order, that is, reagents (i) first, and then reagent (ii) , or alternatively, reagents (i) and (ii) can be added simultaneously. When reagents (i) and (ii) are added simultaneously, the best results are achieved where the ratio of Pd ⁺² to Cl ^" is 1 to 1. For maximum yields, at least step (ii) in these reactions should be carried out at about 110°C to about 140°C, most preferably at about 110°C.

The present invention also contemplates a process for producing citral comprising contacting a palladium- myrcene complex of the formula

with a metal oxoanionic salt in the presence of an inert aqueous organic solvent.

The phrase metal oxoanionic salt, as used herein, denotes a salt comprising a metal cation and an oxygen- containing anion. Any of the variety of metal oxoanionic salts available may be employed in the present process.

Preferable metal oxoanionic salts include Li ₂ B^0 ₇ , Li ₂ B ₁₀ O ₁₆ , Li ₂ Si0 ₃ , Li ₃ P0 , Li ₂ W0 ₄ , __.i_.CrO ₄ , Li ₂ Mo0 ₄ , LiTi0 ₃ , LiCo0 ₂ , Li ₂ C0 ₃ , Li ₂ S0,, Li ₂ SnO , Li ₃ V0 ₄ , Li ₂ Te0 ₄ , Na ₂ B ₄ 0 ₇ , Na ₂ B ₁₀ O ₁₆ ,

Na ₂ Si0 ₃ , Na ₃ P0 ₄ , Na ₂ W0 ₄ , Na ₂ Cr0 ₄ , Na ₂ Mo0 ₄ , NaTi0 ₃ , NaCo0 ₂ , Na ₂ C0 ₃ , Na ₂ S0 ₄ , Na ₂ Sn0 ₄ , Na ₃ VO , Na ₂ Te0 ₄ , K ₂ B ₄ 0 ₇ , K ₂ B ₁₀ O ₁₆ , K ₂ Si0 ₃ , K ₃ P0 ₄ , K ₂ W0 ₄ , K ₂ Cr0 ₄ , K ₂ Mo0 ₄ , KTi0 ₃ , KCo0 ₂ , K ₂ C0 ₃ , K ₂ S0 ₄ , K ₂ Sn0 ₄ , K ₃ V0 ₄ , K ₂ Te0 ₄ , MgB ₄ 0 ₇ , MgB ₁₀ O _16/ MgSi0 ₃ , Mg ₃ (P0 ₄ ) _2/ MgW0 ₄ , MgCr0 ₄ , MgMo0 ₄ , Mg(Ti0 ₃ ) ₂ , Mg(Co0 ₂ ) _2/ MgC0 ₃ , MgS0 ₄ , CaB ₄ 0 ₇ , CaB ₁₀ O ₁₆ , CaSi0 ₃ , Ca ₃ (P0 ₄ ) ₂ , CaW0 ₄ , CaCr0 _4/ Ca(Ti0 ₃ ) ₂ , Ca(Co0 ₂ ) ₂ , CaC0 ₃ , CaS0 ₄ , Cu ₂ B ₄ 0 ₇ , Cu ₂ B ₁₀ O ₁₆ , Cu ₂ Si0 ₃ , Cu ₃ P0 ₄ , Cu ₂ W0 ₄ , Cu ₂ Cr0 ₄ , Cu ₂ Mθ0 ₄ , CuTi0 ₃ , CuCo0 ₂ , Cu ₂ C0 ₃ , Cu ₂ S0 , CuB ₄ 0 ₇ , CuB ₁₀ O ₁₆ , CuSi0 ₃ , Cu ₃ (P0 ₄ ) ₂ , CuW0 ₄ , CuCr0 ₄ , CuMθ0 ₄ , Cu(Ti0 ₃ ) ₂ , Cu(Cθ0 ₂ ) ₂ r CuC0 ₃ , CuS0 ₄ , Ag ₂ B ₄ 0 ₇ , Ag ₂ B ₁₀ O ₁₆ , Ag ₂ Si0 ₃ , Ag ₃ P0 ₄ , Ag ₂ W0 ₄ ,

Ag ₂ Cr0 ₄ , AgTi0 ₃ , AgCo0 ₂ , Ag ₂ C0 ₃ , Ag ₂ S0 ₄ , A1 ₂ (B ₄ 0 ₇ ) ₃ , Al ₂ (B ₁₀ O ₁₆ ) ₃ , Al ₂ (Si0 ₃ ) ₃ , A1P0 ₄ , A1 ₂ (W0 ₄ ) ₃ , Al ₂ (Cr0 ₄ ) ₃ , Al ₂ (Mo0 ₄ ) _3/ Al(Ti0 ₃ ) ₃ , Al(Co0 ₂ ) _3f A1 ₂ (C0 ₃ ) ₃ , A1 ₂ (S0 ₄ ) ₃ , SnB ₄ 0 ₇ , SnB ₁₀ O ₁₆ , SnSi0 ₃ , Sn ₃ (P0 ₄ ) ₂ , SnW0 ₄ , SnCr0 ₄ , SnMoθ ₄ , Sn(Ti0 ₃ ) ₂ , Sn(Co0 ₂ ) ₂ , SnC0 ₃ , SnS0 ₄ , Sn(B ₄ 0 ₇ ) ₂ , Sn(B ₁₀ O ₁₆ ) ₂ , Sn(Si0 ₃ ) ₂ , Sn ₃ (P0 ₄ ) ₄ , Sn(W0 ₄ ) ₂ ,

Sn(Cr0 ₄ ) ₂ , Sn(Mo0 ₄ ) ₂ , Sn(Ti0 ₃ ) ₄ , Sn(Co0 ₂ ) ₄ , Sn(C0 ₃ ) ₂ , Sn(S0 ₄ ) ₂ , PdB ₄ 0 ₇ , PdB ₁₀ 0 ₁₆ , PdSi0 ₃ , Pd ₃ (P0 ₄ ) ₂ , PdW0 ₄ , PdCr0 ₄ , PdMo0 ₄ , Pd(Ti0 ₃ ) ₂ , Pd(Co0 ₂ ) ₂ , PdC0 ₃ , PdS0 ₄ , Pd(B ₄ 0 ₇ ) ₂ , Pd(B ₁₀ O ₁₆ ) ₂ , and Pd(Si0 ₃ ) ₂ . More preferably, the metal oxoanionic salt is selected from the group consisting of Li ₂ B ₄ 0 ₇ , Li ₂ B ₁₀ O ₁₆ , Li ₂ Siθ ₃ , Li ₂ Teo ₄ , Li ₂ Sn0 ₃ , Li ₂ Mo0 ₄ , Li ₃ V0 ₄ , Na ₂ B ₄ 0 ₇ , Na ₂ B ₁₀ O ₁₆ , Na ₂ Siθ ₃ , Na ₂ Sn0 ₃ , Na ₂ Mo0 , Na ₂ Te0 ₄ , Na ₃ V0 ₄ , K ₂ B ₄ 0 ₇ , K ₂ B ₁₀ O ₁₆ K ₂ Si0 ₃ , K ₂ Sn0 ₃ , K ₃ V0 ₄ , K ₂ TeO , K ₂ Mo0 ₄ , MgB ₄ 0 ₇ , MgB ₁₀ O ₁₆ , MgSi0 ₃ , MgMθ0 ₄ , Cu ₂ B ₄ 0 ₇ , Cu ₂ B ₁₀ O ₁₆ , Cu ₂ Si0 ₃ , Cu ₂ Mo0 ₄ , CuB ₄ 0 ₇ , CuB ₁₀ O ₁₆ , CuSi0 ₃ CuMo0 ₄ , SnB ₄ 0 ₇ , SnB ₁₀ O ₁₆ , SnSi0 ₃ , SnMo0 ₄ , Sn(B ₄ 0 ₇ ) ₂ , Sn(B ₁₀ O ₁₆ ) ₂ , Sn(Si0 ₃ ) ₂ and Sn(Mo0 ₄ ) ₂ . Most preferably, the metal oxoanionic salt is selected from the group consisting

of Na ₂ Mo0 ₄ , Li ₂ Mo0 ₄ , Li ₂ B ₄ 0 ₇ , Li ₂ B ₁₀ O ₁₆ , K ₂ B ₄ 0 ₇ , K ₂ Mo0 ₄ and K ₂ B ₁₀ O ₁₆ .

As one skilled in the art would recognize, such salts may, if desired, be formed in situ. As used herein, the term inert, employed in connection with the phrase aqueous organic solvent, denotes those aqueous organic solvents which are substantially unreactive with the palladium species under the conditions of the subject process. The term aqueous, used in conjunction with the phrase organic solvents, denotes water solubility. Suitable inert aqueous organic solvents include substituted aqueous pyrrolidones such as aqueous N- methylpyrrolidone and aqueous N-ethylpyrrolidone, substituted aqueous caprolactams such as aqueous N- methylcaprolactam, substituted aqueous acetamides such as aqueous N,N-dimethylacetamide, aqueous N,N- diethylacetamide, and also aqueous N,N-dimethylpropionamide and N,N-diethylpropionamide, and substituted and unsubsti¬ tuted toluene in water. Other suitable solvents will be readily apparent to those skilled in the art. Preferably, the inert aqueous organic solvent is N-methylpyrrolidone or toluene in water.

The amount of palladium-myrcene complex, metal oxoanionic salt and solvent employed in the foregoing process can vary widely, as will be recognized by those skilled in the art. By way of guidance, however, the metal oxoanionic salt is preferably employed in a molar amount equal to about 5 to about 20 times the molar amount of

palladium-myrcene complex employed. The inert aqueous organic solvent preferably comprises about 70% to about 90% of the total reaction mixture volume, the aqueous solvent itself being comprised of about 70% to about 90% of solvent, and a corresponding about 10% to about 30% of water on a total aqueous solvent volume basis. Preferably, the reaction is carried out at a temperature of at least about 80°C, most preferably at a temperature of at least about 90°C. In still another aspect, the present invention provides a process for the direct production of citral comprising contacting myrcene with a palladium (II) chloride in the presence of an inert aqueous alkylamide solvent and a metal oxoanionic salt at a temperature of at least about 80°C.

As used herein the term alkyamide, used in connection with the phrase aqueous alkylamide solvent, denotes a straight chain or ring hydrocarbon compound which contains an amide moiety, that is, a moiety of the formula -CONH ₂ , wherein one or both of the H atoms on the N atom may or may not be replaced by a bond to the ring or straight chain compound and/or with a C _x to C ₅ alkyl or a like moiety. Such alkylamide compounds wherein the H atoms on the amide moiety are both so replaced are termed herein substituted aqueous alkylamide solvents. The term aqueous, used in conjunction with the phrase alkylamide solvents, denotes water solubility. The term inert, employed in connection with the phrase aqueous alkylamide solvent

denotes those aqueous alkylamide solvents which are substantially unreactive with palladium species under the conditions of the subject process. Preferable inert aqueous alkylamide solvents include those alkylamide solvents wherein the alkylamide is fully substituted.

Examples of suitable solvents include substituted aqueous pyrrolidones such as aqueous N-methylpyrrolidone and aqueous N-ethylpyrrolidone, substituted aqueous caprolactams such as aqueous N-methylcaprolactam, and substituted aqueous acetamides such as aqueous N,N- dimethylacetamide, and aqueous N,N-diethylacetamide, as well as aqueous N,N-dimethylpropionamide and aqueous N,N- diethylpropionamide. Other suitable inert aqueous alkylamide solvents will be apparent to those skilled in the art. Preferably, the inert aqueous alkylamide solvent is aqueous N-methylpyrrolidone, a compound of the formula

Not only does aqueous N-methylpyrrolidone promote the appropriate and efficient conversion of myrcene to citral, it also lacks the toxic and carcinogenic properties found in HMPA.

The foregoing reaction requires temperatures of at least about 80°C, proceeding best at temperatures of at

least about 90°C. The reaction may be conducted at atmospheric pressure, and generally runs to completion within a few hours. To maximize yields, slow but continual stirring, such as by use of a magnetic stirrer, may be employed. If desired, the reaction may be carried out in an inert atmosphere, such as in the presence of, for example, nitrogen, carbon dioxide, or argon gas.

In a preferable embodiment, the foregoing process is carried out in the presence of an oxidizing agent. Such oxidizing agents include, for example, hydrogen peroxide, benzoquinone, copper (II) salts such as copper chloride, cerium (IV) salts, iron (III) salts and silver (I) salts. Other suitable oxidizing agents will be apparent to those skilled in the art. As a skilled artisan would recognize, where copper (II) or iron (III) salts are employed, for example, oxygen or air may, if desired, be introduced into the reaction vessel to assist in reoxidation of the metal salts. Preferably, the oxidizing agent is selected from the group consisting of hydrogen peroxide, benzoquinone and copper (II) salts, particularly copper chloride. Most preferably, the oxidizing agent is hydrogen peroxide or copper (II) salts, particularly copper chloride. The amount of oxidizing agent employed can vary widely as will be readily apparent to those skilled in the art. Preferably, the oxidizing agent is added in a molar amount equal to about 1 to about 5 times the molar amount of the palladium (II) chloride utilized.

The foregoing discoveries clearly provide efficient and commercially viable pathways to the important compound citral. A further aspect of the present invention involves a process for producing nerol in high yields and substantially free of citral, comprising contacting a palladium-myrcene complex of the formula

with a nitrogen-donor compound in the presence of hydrogen gas. Suitable nitrogen-donor compounds include, but are not limited to, unsubstituted pyridine, substituted pyridines such as 2-methyl-pyridine and 2-phenyl-pyridine, pyridine-N-oxide, triethylamine and N,N-diethyl-aniline. Preferably, the nitrogen-donor compounds are selected from 2-substituted pyridines such as 2-methyl-pyridine and 2- phenyl-pyridine. Most preferably, the nitrogen donor compound is 2-methyl-pyridine.

Preferably, the reaction is carried out at room temperature and at a hydrogen gas pressure of three atmospheres, although other temperatures and pressures may also be employed. The palladium-myrcene complex may be first isolated, and then contacted with the nitrogen-donor compound in the presence of hydrogen gas. Accordingly, the present invention also encompasses a process for producing

nerol comprising: (i) contacting myrcene with palladium (II) chloride in the presence of an aqueous cycloamide solvent and a lithium salt to form a palladium-myrcene complex of the formula

(ii) isolating the resultant palladium-myrcene complex; and (iii) contacting the isolated palladium-myrcene complex with a nitrogen-donor compound in the presence of hydrogen gas. Suitable techniques for isolating the palladium- myrcene complex will be readily apparent to those skilled in the art, and include techniques such as the column chromatography procedures set forth in Takahashi, et al. , Journal of Organometallic Chemistry, Vol. 266, pp. 327-336 (1984) . Alternatively, the palladium-myrcene need not be isolated prior to contacting with the nitrogen-donor compound and the hydrogen gas, thereby providing a "one pot" process.

Accordingly, an additional aspect of the invention involves a process for producing nerol comprising contacting myrcene with, in order, (i) palladium (II) chloride in the presence of an aqueous cycloamide solvent

and a lithium salt; and (ii) a nitrogen-donor compound in the presence of hydrogen gas. Reagents (i) and (ii) are added in step-wise order, that is, reagents (i) first, and then reagents (ii) . The myrcene employed in the processes of the invention may be pure myrcene or other suitable mixtures of compounds containing myrcene, as will be apparent to those skilled in the art. One readily available and relatively inexpensive source of myrcene is a myrcene and limonene mixture in a ratio of about 80 to about 20, respectively, a product which is commercially available from various sources, including Union Camp Corporation, Wayne, NJ. Since myrcene is relatively unstable to oxygen, a myrcene mixture containing an antioxidant such as 2,6-di-tertiary- butyl-4-methylphenol, commonly referred to as butylated hydroxy toluene (BHT) and sold under the tradename Ionol ^® by Shell Chemical Company, New York, NY, may be used, if desirable.

The palladium (II) chloride as used in the foregoing processes may be added directly as PdCl ₂ .

Alternatively, it may be formed in situ by the addition of a source of chloride ion, such as LiCl or NaCl, to a palladium (II) salt, such as PdS0 ₄ , Pd(N0 ₃ ) ₂ , Pd ₃ (P0 ₄ ) ₂ and Pd(BF ₄ ) ₂ . Other sources of chloride ion and palladium (II) salts suitable for in situ generation of the palladium (II) chloride will be apparent to those skilled in the art. In generating the palladium (II) chloride in situ, the chloride ion source and the palladium (II) salt may be

added in varying ratios of Pd ⁺² to Cl ^" , including 2:1 and 1:1. If desired, the PdCl ₂ compound may be co plexed with loosely coordinated ligand donors, such as acetonitrile, benzonitrile, 1,5-cyclooctadiene and dimethyl sulfoxide. Thus, the palladium (II) salt may be in the form of, for example, dichlorobisacetonitrile palladium, that is, PdCl ₂ (CH ₃ CN) ₂ . Other suitable ligand donors for coordination with the PdCl ₂ compound will be apparent to those skilled in the art. These and other obvious variations are intended to be within the ambit of the phrase palladium (II) chloride, as used herein. Preferably, the palladium (II) chloride is PdCl ₂ or PdCl ₂ (CH ₃ CN) ₂ .

The palladium-myrcene complex employed in the foregoing novel processes can be obtained by using methods known to those skilled in the art, such as the methods disclosed in Takahashi et al. , Journal of Organometallic Chemistry, Vol. 266, pp. 327-336 (1984) . Alternatively, the novel methods disclosed herein may be employed to obtain the palladium-myrcene complex utilized in the subject processes.

The amount of myrcene, palladium (II) chloride, lithium salt, metal oxoanionic salt, nitrogen-donor, hydrogen gas, phosphine and/or solvent employed in one or ^• more of the foregoing processes can vary widely, as will be recognized by those skilled in the art. By way of guidance, however, palladium (II) chloride is preferably present in a molar amount equal to about 0.1 to about 0.6

times the molar amount of myrcene employed. Metal oxoanionic salt or lithium salt is preferably present in a molar amount equal to about 4 to about 10 times the molar amount of the palladium (II) chloride utilized. The inert aqueous alkylamide solvent or aqueous cycloamide solvent preferably comprise about 70% to about 90% of the total reaction mixture volume, the aqueous solvent itself being comprised of about 70% to about 90% of solvent and a corresponding amount of about 10% to about 30% of water on a total aqueous solvent volume basis.

The aforementioned processes clearly provide an efficient and commercially viable pathway to the important compound nerol.

The citral and nerol compounds produced by the subject processes are useful in a variety of ways, for example, they may be employed as a fragrance or a flavor additive or as a precursor for the synthesis of vitamins A and E. See Derfer et al., "Terpenoids", pp. 709-762 in Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed. , Vol. 22, Wiley Interscience Publications (New York, 1983), the disclosures of which are incorporated by reference herein.

The present invention is further described in the following Examples. These Examples are not to be construed as limiting the scope of the appended Claims.

Examples

In the Examples which follow, the myrcene employed was a myrcene and limonene mixture in a ratio of about 80 to about 20, respectively, obtained from Aldrich Chemical Company, Milwaukee, WI.

The resulting products were analyzed using gas chromatography (GC) , and yield and selectivity results recorded. Yield calculations in all of the Examples were based on the initial level of the palladium (II) salt. Selectivity data is based on the amount of consumed myrcene. The amount of citral produced and the amount of myrcene remaining were measured by internal or external standard weight % GC.

Example 1 Production of a palladium-myrcene Complex of the Formula

To a solution of N-methylpyrrolidone (25 ml) and Li ₃ P0 ₄ (1.81 gm) or Li ₂ B ₄ 0 ₇ (2.61 gm) was added PdCl ₂ (CH ₃ CN) ₂ (1.0101 gm) and water (2.5 ml). The solution was briefly stirred using mechanical stirring, and myrcene (1.7619 gm) was added by pipet. The mixture was then briskly stirred for 5 hrs at room temperature, and 50 ml of toluene was added. The organic phase was then dried over CaCl ₂

overnight in a hood, and separated by column chromatography on florosil gel with toluene/ethyl acetate.

The resulting isolated product was analyzed by NMR and GC. NMR data confirmed the presence of the desired palladium-myrcene complex. No cyclized complex was detected. The yield and selectivity results are shown below in Table 1. Yield calculations in all of the Examples are based on the initial level of Pd(II) . Selectivity data is based on the amount of consumed myrcene. The amount of citral produced and the amount of myrcene remaining was measured by internal or external standard weight percent GC.

Table 1 Process Yield Selectivity

71' 45%

Li ₃ P0 ₄

N-Methy lpyrrol idone Room temperature 5 Hrs

73% 87*

Li ₂ B.0 ₇

N-Methylpyrrolidone Room temperature 5 Hrs

Example 2

Production of Palladium-Myrcene Complex of the Formula

The procedures of Example 1 were substantially followed, except that the reaction was run at about 70'C for 1.5 hours. The yield and selectivity results are shown in Table 2.

Table 2 Process Yield

Selectivity

Li ₃ P0 ₄ 70% 93%

N-Methylpyrrolidone 70 ^Q C 1.5 Hrs

Example 3

Production of Citial from a Palladium-Myrcene Complex.

To an isolated palladium-myrcene complex (80 mg) of the formula

was added toluene (2 ml) and triphenylphosphine (80 mg) in a flask. A water-cooled condenser was placed over the

flask and the mixture was heated to about 110°C for 1.5 hrs. The mixture was then cooled to room temperature and 4 ml of tridecane was added. The citral was isolated by distillation and analyzed to confirm the presence of citral. The yield is shown in Table 3.

Table 3

Process Yield

Triphenylphosphine 555

110°C

1.5 Hrs

Example 4

Production of Citral from a Palladium-Myrcene Complex. The procedures of Example 3 were substantially followed, except that the reaction was run at about 140°C for 2 hrs. The yield is shown in Table 4.

Table 4

Process Yield

Triphenylphosphine 54%

140°C

2 Hrs

Example 5

Production of Nerol from a Palladium-Myrcene Complex.

To an isolated palladium-myrcene complex (40 mg) of the formula

was added toluene (1 ml) and triethylamine (38 μl) . The resultant mixture was placed in scintillation vials and a magnetic stirrer added. A balloon containing hydrogen gas at atmospheric pressure was placed over each vial and the mixture was allowed to stir for 20 minutes. The resulting product was analyzed and found to contain nerol. The yield is reported in Table 5.

Table 5 Process Yield

Triethylamine 80% H ₂ Gas

Room temperature 20 Mins.

Example 6

Production of Nerol from a Palladium-Myrcene Complex.

To an isolated palladium-myrcene complex (80 mg) of the formula

was added toluene (1 ml) and pyridine (0.1 ml). The mixture was placed in a pressure bottle and the bottle placed on a hydrogenator under 50 psi of hydrogen gas pressure. The mixture was shaken for 3 hrs. The resulting product was analyzed and found to contain nerol. The yield is reported in Table 6.

Table 6

Process Yield

Pyridine 39%

H ₂ Gas Room Temperature

3 Hrs

Example 7

Production of Nerol from a Palladium-Myrcene Complex. The procedures of Example 6 were substantially followed, except that the nitrogen-containing compound employed was pyridine-N-oxide (100 mg) and the reaction was run for 2 hrs. The yield is shown in Table 7.

Example 8

Production of Nerol from a Palladium-Myrcene Complex. The procedures of Example 6 were substantially followed, except that the nitrogen-containing compound employed was 2-methyl-pyridine (2-picoline) (100 μl) and the reaction was run for 2 hrs. The yield is shown in Table 8.

Table 8 Process Yield

2-Picoline

H ₂ Gas 80%

Room Temperature

2 Hrs

Example 9

Production of Citral from Myrcene (One-Pot/Two-Step) .

To a solution of N-methylpyrrolidone (25 ml) and

Li ₂ B0 ₇ (1.63 g ) was added PdCl ₂ (CH ₃ CN ₂ ) (1.0051 gm) and water (2.5 ml). The solution was briefly stirred, and myrcene (1.7522 gm) was added by pipet. The mixture was then briskly stirred for 5 hrs at room temperature, and stored overnight.

To a sample of the solution (0.611 ml) was then added N-methylpyrrolidone (0.889 ml) and triphenylphosphine (0.023 gm) . The solution was heated to about 110°C for 2 hrs. To isolate the citral product, toluene (1.5 ml) was added and the solution washed 5 times with water. The organic phase was then dried by passage through a pipet filled with K ₂ C0 ₃ .

The resulting isolated citral product was analyzed by GC. The yield is shown in Table 9.

Table 9

Process Yield

Step 1 Li ₂ B ₄ 0 ₇ N-Methy lpyrrol idone N/A*

Room Temperature 5 Hrs

Step 2

Triphenylphosphine 110 ^β C

2 Hrs 45%

*N/A = not applicable.

Example 10

Production of Citral from Myrcene (One-Pot/One-Step) . To a solution of N-methylpyrrolidone (7.5 ml) and Li ₂ S0 ₄ (0.63 gm) was added PdS0 ₄ (0.2804 gm) , LiCl (0.0585 gm) , water (0.75 ml) and triphenylphosphine (0.385 gm) . The solution was stirred for about ten minutes, and myrcene (0.5201 gm) was added by pipet. The solution was then heated to about 110"C for 2 hrs.

To isolate the citral product, toluene (1.5 ml) was added and the solution washed 5 times with a sodium chloride and water solution. The organic phase was then dried by passage through a pipet filled with K ₂ C0 ₃ . The resulting isolated product was analyzed by GC. The yield is shown in Table 10.

Table 10

Process Yield

Li ₂ S0 ₄ N-Methylpyrrolidone 21%

110°C 2 Hrs

Example 11

Production of Citral from Myrcene (One-Pot/One-Step) . To a solution of N-methylpyrrolidone (7.5 ml) and Li ₃ P0 ₄ (0.55 gm) was added PdS0 ₄ (0.2836 gm) , LiCl (0.0554 gm) and triphenylphosphine (0.475 gm) supported on a polymer of polystyrene cross-linked with divinyl benzene. The polymer- supported triphenylphosphine was obtained from ^' Aldrich Chemical Company, Milwaukee, WI. The solution was stirred for about ten minutes, and myrcene (0.5287 gm) was added by pipet. The solution was then heated to about 110°C for 2 hrs.

The citral product was then isolated and analyzed as in Example 10. The yield is shown in Table 11.

Table 11

Process Yield

Li ₃ P0 ₄

N-Methy lpyrrol idone 16%

110 ° C

2 Hrs

Example 12

To a solution of N-methylpyrrolidone (0.75 ml) and Li ₂ Mo0 ₄ (0.11 gm) was added PdCl ₂ (CH ₃ CN) ₂ (0.03 gm) and water (0.075 ml). The solution was gently but continuously stirred using a magnetic stirrer for about 5 minutes while nitrogen was employed as an inert purging gas. Myrcene (0.066 ml) was then added to the solution and the mixture was heated to about 90°C for about 2.5 hrs, with gentle and continuous stirring. Tridecane (0.014 gm) was then added to the mixture as an internal standard, and the solution was transferred to a separation funnel. Toluene (1.5 ml) was added, and the solution was extracted five times using a NaCl/H ₂ 0 mixture. The organic phase was then dried over K ₂ C0 ₃ .

The resulting yield of citral was 44%, with a selectivity of 26%.

Example 13

The procedures of Example 12 were substantially followed except that LiTi0 ₃ (0.077 gm) was utilized in lieu of Li ₂ Mo0 ₄ . The resulting yield of citral was 39%, with a selectivity of 22%.

Example 14

The procedures of Example 12 were substantially followed except that LiCo0 ₂ (0.065 gm) was utilized in lieu of Li ₂ Mo0 ₄ .

The resulting yield of citral was 29%, with a selectivity of 16%.

Example 15

The procedures of Example 12 were substantially followed except that Li ₂ C0 ₃ (0.047 gm) was utilized in lieu of Li ₂ Mo0 ₄ .

The resulting yield of citral was 35%, with a selectivity of 25%.

Example 16

The procedures of Example 12 were substantially followed except that Li ₂ S0 ₄ (0.084 gm) was utilized in lieu of Li ₂ Mo0 ₄ . The resulting yield of citral was 14%, with a selectivity of 8%.

Example 17

To a solution of N-methylpyrrolidone (0.75 ml) and Li ₂ Mo0 ₄ (0.11 gm) was added PdS0 ₄ (0.024 gm) , LiCl (0.0054 gm) , benzoquinone (0.03 gm) and H ₂ 0 (0.075 ml). The solution was gently but continuously stirred for about 5 minutes using nitrogen as an inert purging gas. Myrcene (0.066 ml) was added and the solution was heated to about 90°C, for about 2.5 hrs, with gentle and continuous stirring. Tridecane (0.013 gm) was then added to the mixture as an internal standard, and the solution was transferred to a separation funnel, rinsed with toluene (1.5 ml) and extracted five times using a NaCl/H ₂ 0 solution. The organic phase was then dried over K ₂ C0 ₃ , and the resulting product analyzed substantially as described in Example 12.

The resulting yield of citral was 34%, with a selectivity of 17%.

Example 18

The procedures of Example 17 were substantially followed except that PdCl ₂ (CH ₃ CN) ₂ (0.03 gm) was employed in lieu of PdS0 ₄ and LiCl, and CuCl ₂ (0.015 gm) was utilized instead of benzoquinone.

The resulting yield of citral was 53%, with a selectivity of 28%.

Example 19

The procedures of Example 18 were substantially followed except that the amount of PdCl ₂ (CH ₃ CN) ₂ , Li ₂ Mo0 ₄ , CuCl ₂ , N-meth lpyrrolidine and water were increased 10- fold, and the reaction was carried out a temperature of about 80°C.

The resulting yield of citral was 54%, with a selectivity of 28%.

Example 20

The procedures of Example 19 were substantially followed except that the solution was heated at about 80°C for a total of about 5 hours, instead of 2.5 hours. The resulting yield of citral was 62%, with a selectivity of 32%.

Example 21

The procedures of Example 19 were substantially followed except that oxygen was bubbled through the solution at a rate of about 52 liters per minute following addition of myrcene.

The resulting yield of citral was 19%, with a selectivity of 9%.

Example 22

The procedures of Example 20 were substantially followed except that after heating for the indicated 5 hours at 80°C, the solution was refrigerated overnight, and then heated to about 80°C for about 7 additional hours.

The resulting yield of citral was 70%, with a selectivity of 35%.

Example 23

The procedures of Example 22 were substantially followed except that after heating for the indicated additional 7 hours at 80°C, the solution was refrigerated overnight without a cap, and then heated to about 80°C under an inert nitrogen atmosphere for about 2.5 additional hours.

The resulting yield of citral was 49%, with a selectivity of 32%.

Example 24

The procedures of Example 17 were substantially followed except that PdCl ₂ (CH ₃ CN) ₂ (0.03 gm) was utilized in lieu of PdS0 ₄ and LiCl, Li ₂ W0 ₄ (0.17 gm) was utilized in lieu of Li ₂ Mo0 ₄ , and H ₂ 0 ₂ (0.075 ml) was utilized in lieu of benzoquinone and H ₂ 0, and the solution was heated to about 80°C instead of 90°C.

The resulting yield of citral was 33%, with a selectivity of 23%.

Example 25

The procedures of Example 17 were substantially followed except that PdCl ₂ (0.03 gm) was utilized in lieu of PdS0 ₄ and LiCl, 0.21 gm of Li ₂ Mo0 ₄ was employed, and 30% H ₂ 0 ₂ (0.75 ml) was utilized in lieu of benzoquinone and water. The resulting yield of citral was 52%, with a selectivity of 26%.

Example 26

To an isolated palladium-myrcene complex (0.048 gm) was added Li ₂ B ₄ 0 ₇ (0.11 gm) , N-methylpyrrolidone (1.5 ml) and H ₂ 0 (0.150 ml). The mixture was heated to about 70°C for about 1.5 hours with gentle but continuous stirring. Tridecane (0.012 gm) was added to the mixture as an internal standard, and the solution was transferred to a separation funnel, rinsed with toluene (1.5 ml) and extracted five times using a NaCl/H ₂ 0 solution. The

resulting product was then analyzed substantially as described in Example 12.

The resulting yield of citral was 27%.

Example 27 The procedures of Example 26 were substantially followed except that 0.025 gm of the palladium-myrcene complex, 0.750 ml of N-methylpyrrolidone, and 0.075 ml of H ₂ 0 were employed, and the solution was heated to about 90°C. The resulting yield of citral was 45%.

Example 28

The procedures of Example 26 were substantially followed except that 0.025 gm of the palladium-myrcene complex, 0.75 ml of N-methylpyrrolidone, and 0.075 ml of H ₂ 0 were employed, and Li ₂ Si0 ₃ (0.059 gm) was utilized in lieu of Li ₂ B ₄ 0 ₇ .

The resulting yield of citral was 30%.

Example 29

The procedures of Example 26 were substantially followed except that 0.026 gm of the palladium-myrcene complex, 0.75 ml of N-methylpyrrolidone, and 0.075 ml of H ₂ 0 • were utilized, and K ₂ B ₄ 0 ₇ (0.15 gm) was employed in lieu of Li ₂ B ₄ 0 ₇ .

The resulting yield of citral was 45%.

Example 30

The procedures of Example 26 were substantially followed except that 0.024 gm of the palladium-myrcene complex, 0.75 ml of N-methylpyrrolidone, and 0.075 ml of H ₂ 0 were employed, and ₂ B ₁₀ O ₁₆ was utilized in lieu of Li ₂ B ₄ 0 ₇ . The resulting yield of citral was 41%.

Example 31

To a solution of N-methylpyrrolidone (7.5 ml) and K ₂ Mo0 ₄ (1.51 gm) was added PdCl ₂ (CH ₃ CN) ₂ (0.30 gm) , lonol ^® (0.0005 gm) (available from Shell Chemical Company, New York, NY) and H ₂ 0 (0.75 ml). The solution was gently but continuously stirred for about 5 minutes using carbon dioxide as an inert purging gas. Myrcene (669 ml) was then added to the solution and the mixture was heated to about 90°C for about 2.5 hours, with gentle and continuous stirring. Tridecane (0.108 gm) was then added to the mixture as an internal standard, and the solution was transferred to a separation funnel, rinsed with toluene (15 ml) and extracted 5 times using a NaCl/H ₂ 0 solution. The organic phase was then dried over K ₂ C0 ₃ , and the resulting product analyzed substantially as described in Example 12.

The resulting yield of citral was 53%, with a selectivity of 29%.

Example 32

The procedures of Example 31 were substantially followed except that Na ₂ Mo0 ₄ (1.53 gm) was employed in lieu of K ₂ Mo0 ₄ , and 0.0006 gm of lonol ^® was utilized. The resulting yield of citral was 49%, with a selectivity of 28%.

Example 33

The procedures of Example 31 were substantially followed except that PdCl ₂ (0.20 gm) was employed in lieu of PdCl ₂ (CH ₃ CN) ₂ , MgMo0 ₄ (1.16 gm) was employed in lieu of K ₂ Mo0 ₄ , and 0.0006 gm of lonol ^® were utilized.

The resulting yield of geranial was 14%, with a selectivity of 10%.

Various modifications of the invention in addition to those shown and described herein will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended Claims.