KR101161870B1 - Hydrogenation process - Google Patents

Abstract

The present invention relates to a process for the hydrogenation of cyclohexene and dihydropyran derivatives and to compositions comprising cyclohexene or dihydropyran derivatives and transition metal complexes.

Description

Hydrogenation Method {HYDROGENATION PROCESS}

The present invention relates to a process for the hydrogenation of cyclohexene and dihydropyran derivatives and to compositions comprising cyclohexene or dihydropyran derivatives and transition metal complexes. In particular, the present invention relates to a method of trans-selective hydrogenation of cyclohexene and dihydropyran derivatives.

Compounds containing a cyclohexane ring or tetrahydropyran ring as the central constituent of the molecule are for example used in the organic chemistry field as natural or synthetic aroma components, pharmaceutical components or mesogenic or liquid crystal compounds or as precursors for the synthesis of these useful components. It plays an important role.

Specifically, the mesogenic or liquid crystal compound containing a cyclohexane ring or a tetrahydropyran ring is a (mesogenic) substituent at the 1- and 4-positions of the cyclohexane ring or at the 2- and 5-positions of the tetrahydropyran ring, Often have rings and / or ring systems. Here, these radicals in the 1- and 4-positions or 2- and 5-positions allow for the adoption of bisquatorial conformation with the formation of long molecular forms that are important for mesogenic properties. It is usually preferred for them to exist in trans orientation to one another.

Certain preparations of these trans-1,4-disubstituted cyclohexane or trans-2,5-disubstituted tetrahydropyran derivatives have so far been possible only in considerable technical complexity and normal yield. The 1,4-disubstituted cyclohexane derivatives are prepared in the corresponding 1,4-disubstituted cyclo by catalytic hydrogenation on heterotransition metal catalysts, such as Raney nickel (EP 0 415 090 A1), palladium or platinum, usually bonded to the support. It is usually prepared from hex-1-ene derivatives. In the most preferred case, stereoisomeric mixtures comprising cis- and trans-1,4-disubstituted cyclohexane derivatives in which the cis isomer forms the main product are frequently obtained in low yields, and in fact unwanted cis isomers are often isolated from catalytic hydrogenation. It is the only product that can be. Thus, the isomerization of the cis compound into a trans compound as a further reaction step under relatively strong conditions, for example by complex separation of the isomeric mixture using crystallization and / or chromatographic methods, and / or using strong bases such as potassium t-butoxide, for example With subsequent purification). In many cases, this is also associated with low yields.

)에서의 엔도사이클릭 C-C 이중 결합을 갖는 상응하는 다이하이드로피란 유도체로부터의 2,5-이치환 테트라하이드로피란 유도체의 제조에 적용되며, 이는 예컨대 적절히 치환된 에닌 또는 디엔으로부터 에닌 또는 고리-닫기 교차-치환(ring-closing cross-metathesis) 방법에 의해 그 자체로 매우 용이하게 얻을 수 있다(각각 독일 특허출원 DE 10324348.8 호 또는 DE 10324312.7 호 참조). 또한, 테트라하이드로피란 화합물의 부분 분해에 의해 이종으로 촉매화된 수소화 후 통상 수득되는 시스/트랜스 이성질체 혼합물의 이성질화에서 요구되는 트랜스 생성물의 수율이 상당히 감소될 수 있는 것에 주목해야 한다.The corresponding case is the 4-position (

Applies to the preparation of 2,5-disubstituted tetrahydropyran derivatives from the corresponding dihydropyran derivatives having an endocyclic CC double bond in the form of, for example, an enine or ring-closed cross- from an appropriately substituted enine or diene. It can be obtained very easily by itself by a ring-closing cross-metathesis method (see German patent application DE 10324348.8 or DE 10324312.7, respectively). It should also be noted that the yield of trans product required in the isomerization of the cis / trans isomer mixture usually obtained after heterocatalyzed hydrogenation by partial decomposition of the tetrahydropyran compound can be significantly reduced.

It is therefore an object of the present invention to provide a process for the preparation of 1,4-disubstituted cyclohexane derivatives and 2,5-disubstituted tetrahydropyran derivatives in which the trans isomers which are required, in particular with high selectivity and high overall yield, can be more easily obtained. .

This object is achieved by a process for the preparation of a compound of formula 1a or 1b, characterized by hydrogenating a compound of formula 2a or 2b in the presence of a transition metal complex stabilized by one or more identical or different phosphine ligands. Is achieved.

Where

a, b, c, d and e are each independently 0 or 1, e is 1 when W is -CH _2- ,

A ¹¹ , A ¹² , A ¹³ , A ¹⁴ and A ¹⁵ are independently of each other a 1,4-cyclohexylene radical, wherein one or two non-adjacent CH ₂ groups are represented by -O- and / or -S- May be substituted), 1,4-phenylene radicals (wherein also one or two non-adjacent = CH groups may be substituted by = N-), naphthalene-2,6-diyl or 1,2,3 , 4-tetrahydronaphthalene-2,6-diyl radicals, wherein these radicals are unsubstituted or identical or differently mono- or polysubstituted with halogen or CN, or 1,3-cyclobutylene, piperi Din-1,4-diyl or decahydronaphthalene-2,6-diyl radical,

R ¹¹ is hydrogen, an unsubstituted or monosubstituted or polysubstituted alkyl radical having 1 to 15 carbon atoms, wherein at least one CH ₂ group of these radicals is independently of each other -C≡C-, -S- , -O-, -CO-, -COO-, -O-CO- or -O-CO-O- can be substituted in such a way that the heteroatoms (-S- and -O-) are not directly connected to each other. Where a and b are 0 at the same time and Z ¹² is a single bond, then R ¹¹ is not hydrogen,

W is -CH ₂ -or -O-,

Y ¹¹ is hydrogen, halogen, -NCS, -SCN, -SF ₅ , -CN, an alkyl radical having 1 to 15 carbon atoms which is unsubstituted or identically or differently mono- or polysubstituted with halogen or -CN, or is not substituted The same or differently substituted or polysubstituted aralkyl radicals having 7 to 16 carbon atoms which are mono- or polysubstituted with halogen, nitro, alkanyl, alkoxy, -NH ₂ or -N (alkanyl) ₂ , wherein CH ₂ groups of at least one of these radicals Are independently of each other -C≡C-, -S-, -S (O)-, -S (O) _2- , -O-, -CO-, -COO-, -O-CO- or -O- CO-O- may be substituted in such a way that heteroatoms in the chain (-S- and -O-) are not directly connected to each other),

Z ¹¹ , Z ¹³ , Z ^14, and Z ¹⁵ are each independently a single bond, -CH ₂ CH _2- , -CF ₂ CF _2- , -CH ₂ CF _2- , -CF ₂ CH _2- , -CFH-CFH -, -C≡C-, -CH ₂ O-, -OCH _2- , -CF ₂ O-, -OCF _2- , -COO- or -O-CO-,

Z ¹² is a single bond, -CH ₂ CH _2- , -C≡C-, -CH ₂ O-, -OCH _2- , -COO- or -O-CO-.

In the above equations,

f, g, h, i and j are each independently 0 or 1, j is 1 when W is -CH _2- ,

A ²¹ , A ²² , A ²³ , A ²⁴ and A ²⁵ are independently of each other a 1,4-cyclohexylene radical, wherein one or two non-adjacent CH ₂ groups are represented by -O- and / or -S- May be substituted), 1,4-phenylene radicals (wherein also one or two non-adjacent = CH groups may be substituted by = N-), naphthalene-2,6-diyl or 1,2,3 , 4-tetrahydronaphthalene-2,6-diyl radicals, wherein these radicals are unsubstituted or identical or differently mono- or polysubstituted with halogen or CN, or 1,3-cyclobutylene, piperidine -1,4-diyl or decahydronaphthalene-2,6-diyl radical,

R ²¹ is hydrogen, an unsubstituted or monosubstituted or polysubstituted alkyl radical having 1 to 15 carbon atoms, wherein at least one CH ₂ group of these radicals is independently of each other -CH = CH-, -C≡ The heteroatoms (-S- and -O-) are not directly connected to each other by C-, -S-, -O-, -CO-, -COO-, -O-CO- or -O-CO-O- In which case f and g are 0 at the same time and Z ²² is a single bond, R ²¹ is not hydrogen,

W is -CH ₂ -or -O-,

Y ²¹ is hydrogen, halogen, -NCS, -SCN, -SF ₅ , -CN, an alkyl radical having 1 to 15 carbon atoms which is monosubstituted or polysubstituted or unsubstituted or identically or differently substituted with halogen or -CN, or unsubstituted Aralkyl radicals having 7 to 16 carbon atoms, identically or differently mono- or polysubstituted with halogen, nitro, alkanyl, alkoxy, -NH ₂ or -N (alkanyl) ₂ , wherein CH ₂ also has at least one CH ₂ The groups are independently of each other -CH = CH-, -C≡C-, -S-, -S (O)-, -S (O) _2- , -O-, -CO-, -COO-, -O Heteroatoms in the chain (-S- and -O-) may be substituted by -CO- or -O-CO-O- in such a way that they are not directly connected to each other),

Z ²¹ , Z ²³ , Z ²⁴ and Z ²⁵ are each independently a single bond, -CH = CH-, -CH ₂ CH _2- , -CF ₂ CF _2- , -CH ₂ CF _2- , -CF ₂ CH ₂ -, -CFH-CFH-, -C≡C-, -CH ₂ O-, -OCH _2- , -CF ₂ O-, -OCF _2- , -COO- or -O-CO-,

Z ²² is a single bond, —CH═CH—, —CH ₂ CH ₂ —, —C≡C—, —CH ₂ O—, —OCH ₂ —, —COO— or —O—CO—.

In the process according to the invention, it goes without saying that the compound of formula 1a is formed from the compound of formula 2a, and the compound of formula 1b is formed from the compound of formula 2b. When referring to a compound of Formula 1, this means both a compound of Formula 1a and also a compound of Formula 1b, and correspondingly, the term “compound of Formula 2” refers to a compound of Formula 2a and also a compound of Formula 2b. All means.

The process according to the invention proceeds with good or very good overall conversion, which is generally above 90% and in many cases above 95%. Surprisingly, this also applies to "macro" molecules of formula (2) having an extended molecular shape and a large number of rings in the molecule. The required trans isomers of formula (I) have good or very good trans selectivity and are obtained in good or very good yields. Generally, the proportion of trans product of formula 1 in the product mixture is greater than 70%, in many cases greater than 75%. The pure trans product of formula (1) can be separated from other reaction products, in particular cis isomers, in a simple manner by a single crystallization from a suitable solvent, usually after typical workup of the reaction mixture, and subsequently, for example, in a liquid crystalline medium. It can be used as a liquid crystal component or converted to another liquid crystal compound by further functionalization or derivatization. In some cases it is observed that trans isomer major products precipitate or crystallize out of the reaction mixture.

In comparison, heterocatalytic hydrogenation of a compound of formula (2) using, for example, palladium on activated carbon, mainly produces individual unwanted cis isomers of formula (cis-1) with typical cis selectivity of 60 to 75%.

(Tetrahydropyran compounds generally have two trans isomers (mirror isomers) that behave as phases and mirror images of each other, or likewise two cis isomers (mirror isomers) that behave as phases and mirror phases to each other. It is understood herein that reference is made to one trans isomer or one cis isomer and, unless otherwise specified, the terms trans and cis always refer to the stereochemistry of the central cyclohexane or tetrahydropyran ring)

The process according to the invention is usually carried out in a homogeneous phase by the reaction of the starting compound of formula 2 with hydrogen gas (passed into or dissolved in the reaction medium) which takes place in the presence of a transition metal complex dissolved or suspended in the medium. On the other hand, it is also possible to bind or adsorb the transition metal complex to or onto a typical solid phase support and to contact the reaction mixture therewith.

The reaction medium is preferably a liquid solvent or solvent mixture or a medium in a supercritical state such as supercritical carbon dioxide (sc-CO ₂ ). The exact choice of medium depends primarily on the dissolution behavior of the compound of formula 2 being reduced and the transition metal complex used as catalyst. Suitable solvents that can be used alone or in a mixture of two or three solvents as the reaction medium are, for example, water; Hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; Chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, chloroform or dichloromethane; Alcohols such as methanol, ethanol, 2-propanol, n-propanol, n-butanol or t-butanol; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or 1,4-dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol, ethyl glycol or polyethylene glycol) or ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Carbon disulfide; Nitro compounds such as nitromethane or nitrobenzene; Esters such as methyl acetate or ethyl acetate. Hydrocarbons, in particular toluene, alcohols, in particular methanol and ethanol are preferred, chlorinated hydrocarbons, in particular dichloromethane, and mixtures of alcohols and hydrocarbons, in particular methanol / toluene and ethanol / toluene.

The transition metal complexes used as catalysts in the process according to the invention are preferably rhodium, iridium and / or ruthenium complexes, with double rhodium complexes being particularly preferred.

Stabilizing phosphine ligands are phosphines having three radicals linked to a person, and these radicals may be selected to be the same or different, or two of the three radicals are the same and the third different from the other two. The three radicals are preferably the same. Two or three radicals may also be linked to each other. Radicals on the P atom are organic and / or organometallic radicals which together with the phosphorus atom form a chemically sufficiently stable phosphine which can be isolated and used where appropriate under the inert gas atmosphere and / or moisture exclusion. In addition to the phosphine P (A ³¹ A ³² A ³³ ) and P (A ⁴² A ⁴³ A ⁴⁴ ) and other phosphine ligands of formulas 11 and 12 to be mentioned below, Trialkylphosphines with different alkyl radicals such as methyl, ethyl, n-propyl, isopropyl, n-butyl or t-butyl are also suitable stabilizing phosphine ligands. It is also possible to use chelate ligands, in particular, bidentate chelate ligands, in addition to the (videdate) bisphosphine chelate ligands of formula 12, where, for example, the first coordination atom of the ligand is a phosphorus atom and the second of the ligand Coordinating atoms are heteroatoms other than phosphorus, such as nitrogen atoms. Examples of P, N-chelate ligands of this type are described in A. Lightfood et al. "Angew. Chem. 1998, 100, No. 20, 3047-3050) and DE 198 31 137 A1. The phosphine ligand (s) are generally selected to stabilize the transition metal complexes for the hydrogenation reaction according to the invention, ie to support the activity for the required reaction and the chemical stability in the required reaction.

In some embodiments of the invention, the transition metal complex is selected from complexes of the following formulas (3) and (4).

[(P (A ³¹ A ³² A ³³ )) ₃ RhX ³¹ ]

[(Diene) Ir (A ⁴¹ ) (P (A ⁴² A ⁴³ A ⁴⁴ ))] Y ⁴¹

In the above equations,

A ³¹ , A ³² and A ³³ are independently unsubstituted or substituted aryl, biphenyl, heteroaryl, heterocyclyl or cycloalkyl radicals and are the same or different at the three ligands P (A ³¹ A ³² A ³³ ) Meaning, that is, the three ligands P (A ³¹ A ³² A ³³ ) are the same or different,

A ⁴¹ is unsubstituted or substituted heterocyclyl or heteroaryl radical,

A ⁴² , A ⁴³ and A ⁴⁴ are independently unsubstituted or substituted aryl, biphenyl, heteroaryl, heterocyclyl or cycloalkyl radicals, wherein one of the radicals A ⁴² , A ⁴³ and A ⁴⁴ is for example a single bond Or may be bonded to A ⁴¹ through an alkylene bridge to form a chelate ligand,

X ³¹ is Cl, Br, I, PF ₆ , [PF ₃ (C ₂ F ₅ ) ₃ ], SbF ₆ , BF ₄ , BARF, ClO ₄ , CF ₃ SO ₃ , CH ₃ CO ₂ or CF ₃ CO ₂ A ligand or an anion,

Y ⁴¹ is Cl, Br, I, PF ₆ , [PF ₃ (C ₂ F ₅ ) ₃ ], SbF ₆ , BF ₄ , BARF, ClO ₄ , CF ₃ SO ₃ , CH ₃ CO ₂ or CF ₃ CO ₂ A ligand or an anion,

The diene is 1,5-cyclooctadienyl (COD), norbornadienyl, (ethylene) ₂ or (cyclooctene) ₂ .

을 의미한다.)("BARF" is a tetrakis [3,5-bis (trifluoromethyl) phenylborate] anion

Means.)

The complex of formula (3) contains three identical or different phosphine ligands P (A ³¹ A ³² A ³³ ), with these three ligands preferably being the same.

A ^31, A ³² and A ³³ is in each case may have the same meaning or a different meaning, and A ^31, A has a ³² and A ³³ 2 dogs same meaning of A ^31, A ³² and A ³³ 3 second of the It is also possible to have different meanings, preferably A ³¹ , A ³² and A ³³ have the same meaning.

A ^42, A ⁴³ and A ⁴⁴ is in each case may have the same meaning or a different meaning, and A ^42, A has a ⁴³ and A ⁴⁴ 2 dogs same meaning of A ^42, A ⁴³ and A ⁴⁴ 3 second of the It is also possible to have different meanings, preferably A ⁴² , A ⁴³ and A ⁴⁴ have the same meaning.

When A ³¹ , A ³² and A ^{33 in} Formula 3 and A ⁴² , A ⁴³ , A ⁴⁴ in Formula 4 are unsubstituted or substituted aryl substituents, they are preferably unsubstituted phenyl or naphthyl radicals, or Alkanyl, in particular methyl, ethyl, isopropyl, n-butyl, t-butylo, alkoxy, in particular methoxy, -NH ₂ or -N (alkanyl) ₂ , in particular -N (methyl) ₂ , -N Monovalent or polysubstituted phenyl radicals, identically or differently, with (ethyl) ₂ , -N (isopropyl) ₂ or -N (ethyl) (acisopropyl), monosubstituted when substituted. In particular, the aryl substituent is an unsubstituted phenyl radical. Substitution with heterocyclyl or heteroaryl radicals, in particular with 4,5-dihydrooxazole or pyridine, is also preferred.

When A ³¹ , A ³² and A ^{33 in} Formula 3 and A ⁴² , A ⁴³ and A ⁴⁴ in Formula 4 are unsubstituted or substituted biphenyl substituents, they are preferably 2- or 2 ′ of the biphenyl radical. The position is linked to the phosphorus atom of the phosphine ligand. The biphenyl substituent is preferably unsubstituted or-when linked through the 2-position-alkanyl at the 2'-position, in particular methyl, ethyl, isopropyl, n-butyl or t-butyl, alkoxy, in particular methoxy Is substituted with -NH ₂ or with -N (alkanyl) ₂ , in particular -N (methyl) ₂ , -N (ethyl) ₂ , -N (isopropyl) ₂ or -N (ethyl) (isopropyl) . In particular, the biphenyl substituent is unsubstituted.

When A ³¹ , A ³² and A ^{33 in} Formula 3 and A ⁴¹ , A ⁴² , A ⁴³ and A ⁴⁴ in Formula 4 are unsubstituted or substituted heterocyclyl substituents, they are preferably heteroatom (s) As a 5 or 6 membered heterocyclyl ring containing oxygen and / or nitrogen. Heterocyclyl radicals may also be partially unsaturated. Heterocyclyl substituents are particularly preferably dihydroimidazole, dihydropyrazole, dihydroisoxazole, in particular dihydrooxazole.

When A ³¹ , A ³² , A ^{33 in} Formula 3 and A ⁴¹ , A ⁴² , A ⁴³ and A ⁴⁴ in Formula 4 are unsubstituted or substituted heteroaryl substituents, they are preferably heteroatom (s) 5 or 6 membered heteroaryl ring containing oxygen and / or nitrogen. Heteroaryl radicals are particularly preferably furanyl radicals, in particular 2-furanyl radicals, or pyridyl radicals, in particular 2-pyridyl radicals.

When A ³¹ , A ³² and A ^{33 in} Formula 3 and A ⁴² , A ⁴³ and A ⁴⁴ in Formula 4 are unsubstituted or substituted cycloalkyl substituents, they are preferably 5, 6 or 7 membered cycloalkyl rings Which may also be substituted with alkanyls. Cyclohexyl radicals are particularly preferred.

A ⁴¹ is preferably a 5 or 6 membered heteroaryl ring containing nitrogen as an unsubstituted heteroaryl radical, particularly preferably heteroatom (s). A ⁴¹ is very particularly preferably a pyridyl radical complexed with a transition metal via an N atom. A ⁴¹ is also preferably a heterocyclyl radical as defined above for A ³¹ , A ³² , A ³³ , A ⁴² , A ⁴³ and A ⁴⁴ , in particular dihydrooxazole.

In a particularly preferred embodiment of the invention, A ⁴¹ is a 4,5-dihydrooxazolyl radical linked to the 2-position of A ⁴² which is a phenyl ring via a 2-position with a single bond, and A ⁴³ and A ⁴⁴ are Unsubstituted or substituted aryl, in particular phenyl or o-tolyl, thus A ⁴¹ and P (A ⁴² A ⁴³ A ⁴⁴ ) form a bidetate chelate ligand configuration via P and N atoms (Lightfood et al. See Angew. Chem. 1998, 110, No. 20, 3047-3050 and DE 198 31 137 A1).

X ³¹ is preferably Cl or Br, in particular chlorine.

Y ⁴¹ is preferably an anion of PF ₆ , SbF ₆ , BF ₄ , BARF or ClO ₄ , in particular PF ₆ .

The diene in formula (4) is preferably 1,5-cyclooctadienyl (COD) or norbornadienyl, in particular COD.

Of the complexes of the formulas (3) and (4), the complex of the formula (3) is preferred. Particular preference is given to complexes of the formula (3) wherein A ³¹ , A ³² and A ³³ have the same meaning and are unsubstituted or monosubstituted phenyl radicals, and X ³¹ is chlorine. Very particular preference is given to transition metal complexes of the general formula (3a).

[(P (phenyl) ₃ RhCl]

In a particularly preferred embodiment of the invention, the hydrogenation according to the invention is carried out in the presence of complex (3) in which X ³¹ is Cl, in particular in the presence of complex (3a) and of alkali metal or tetraalkylammonium bromide or iodide Is carried out in the presence. Thereby, the conversion and trans selectivity are further increased. In addition to tetramethyl-, tetraethyl- and tetrabutylammonium bromide and iodide, lithium bromide and lithium iodide, in particular lithium bromide, are particularly preferred. The amount of bromide or iodide added is generally about 0.1 to about 50 equivalents, preferably about 1 to about 25 equivalents, especially about 2 to about 15 equivalents, based on the transition metal complex.

In a further embodiment of the invention, the transition metal complex catalyzing the hydrogenation of the compound of formula (2) is not added to the reaction medium as such, but is identical by reaction of the stabilizing phosphine ligand (s) of a suitable transition metal complex precursor. It is formed in the reaction system. The transition metal complex precursor and phosphine ligand (s) are typically used in molar ratios of about 1: 1 to about 1: 5, in particular about 1: 2 to about 1: 3. Preference is given here to using one phosphine ligand (one type). If the process is carried out in this way according to the invention, the actual transition metal complexes catalyzing the hydrogenation are formed in situ, the detailed structure of which is not known in detail.

The transition metal complex precursor is preferably selected from complexes of the formulas 5, 6, 7, 8, 9 and 10 and the phosphine ligand (s) are selected from compounds of the formulas 11 and / or 12.

[(Diene) Ru (allyl) ₂ ]

[(Diene) RhX ⁶¹ ] ₂

[(Diene) ₂ Rh] Y ⁷¹

[(Diene) IrX ⁸¹ ] ₂

[(Diene) ₂ Ir] Y ⁹¹

RhX ¹⁰¹ ₃ ? XH ₂ O

In the above equations,

X ⁶¹ , X ⁸¹ and X ¹⁰¹ are independently of each other Cl, Br or I,

x is 0, 1, 2 or 3,

Y ⁷¹ and Y ⁹¹ are each independently of PF ₆ , [PF ₃ (C ₂ F ₅ ) ₃ ], SbF ₆ , BF ₄ , BARF, ClO ₄ , CF ₃ SO ₃ , CH ₃ CO ₂ or CF ₃ CO ₂ An anion,

The diene is 1,5-cyclooctadienyl (COD), norbornadienyl, (ethylene) ₂ or (cyclooctene) ₂ ,

Allyl is allyl or metallyl.

P (A ¹¹¹ A ¹¹² A ¹¹³ )

In the above equations,

A ¹¹¹ , A ¹¹² , A ¹¹³ , A ¹²¹ , A ¹²² , A ¹²³ and A ¹²⁴ are independently unsubstituted or substituted aryl, biphenyl, heteroaryl, heterocyclyl or cycloalkyl radicals,

G is an alkylene bridge having 1 to 8 carbon atoms or unsubstituted or substituted 1,2-phenylene, 2,3-naphthylene, 2,2'-biphenylene or 1,1'-di (cyclopentadienyl It is iron.

X ⁶¹ and X ⁸¹ are preferably Cl or Br, in particular chlorine.

X ¹⁰¹ is preferably Br or I, especially bromine.

x is preferably 3.                     

Y ⁷¹ and Y ⁹¹ are preferably anions of PF ₆ , SbF ₆ , BF ₄ , BARF or ClO ₄ , in particular BF ₄ or BARF.

The dienes in the formulas 5 to 9 are preferably 1,5-cyclooctadienyl (COD) or norbornadienyl, in particular COD.

Allyl in the formulas (5) to (9) is preferably metallyl.

For the phosphine ligands of Formula 11, A ¹¹¹ , A ¹¹² and A ¹¹³ can each have the same or different meanings, and two of A ¹¹¹ , A ¹¹² and A ¹¹³ have the same meaning and A ¹¹¹ , A ¹¹² It is also possible that the third of A ¹¹³ has a different meaning. A ¹¹¹ , A ¹¹² and A ¹¹³ preferably have the same meaning.

For phosphine ligands of formula 12, A ¹²¹ , A ¹²² , A ¹²³ and A ¹²⁴ may each have the same or different meanings, and also two or three of A ¹²¹ , A ¹²² , A ¹²³ and A ¹²⁴ are the same It is also possible that the other two or fourth of A ¹²¹ , A ¹²² , A ¹²³ and A ¹²⁴ have different meanings. A ¹²³ and A ¹²⁴ as well as A ¹²¹ and A ¹²² preferably have the same meaning. All four of A ¹²¹ , A ¹²² , A ¹²³ and A ¹²⁴ particularly preferably have the same meaning.

When A ¹¹¹ , A ¹¹² and A ¹¹³ in Formula 11 and A ¹²¹ , A ¹²² , A ¹²³ and A ¹²⁴ in Formula 12 are unsubstituted or substituted aryl substituents, they are preferably unsubstituted phenyl or naphthyl Radicals, or alkanyls, in particular methyl, ethyl, isopropyl, n-butyl or t-butylo, alkoxy, in particular methoxy, -NH ₂ or -N (alkanyl) ₂ , in particular -N (methyl) ₂ Mono- or polysubstituted phenyl radicals, identically or differently, -N (ethyl) ₂ , -N (isopropyl) ₂ or -N (ethyl) (isopropyl), wherein monosubstituents are particularly preferred when substituted . Aryl substituents are in particular unsubstituted phenyl radicals or phenyl radicals substituted with methyl (o-, m- and / or p-tolyl).

When A ¹¹¹ , A ¹¹² and A ¹¹³ in Formula 11 and A ¹²¹ , A ¹²² , A ¹²³ and A ¹²⁴ in Formula 12 are unsubstituted or substituted biphenyl substituents, they are preferably 2- Or the phosphorus atom of the phosphine ligand via the 2′-position. The biphenyl substituent is preferably unsubstituted or-in the case of linking via the 2-position-alkanyl, in particular methyl, ethyl, isopropyl, n-butyl or t-butylo, alkoxy, in particular methoxy,- At 2′-position with NH ₂ or with —N (alkanyl) ₂ , in particular —N (methyl) ₂ , —N (ethyl) ₂ , —N (isopropyl) ₂ or —N (ethyl) (isopropyl) Is substituted. In particular, the biphenyl substituent is unsubstituted.

When A ¹¹¹ , A ¹¹² and A ¹¹³ in Formula 11 and A ¹²¹ , A ¹²² , A ¹²³ and A ¹²⁴ in Formula 12 are unsubstituted or substituted heteroaryl substituents, they are preferably as hetero atom (s) 5 or 6 membered heteroaryl ring containing oxygen and / or nitrogen. Heteroaryl radicals are particularly preferably furanyl radicals, in particular 2-furanyl radicals, or pyridyl radicals, in particular 2-pyridyl radicals.

When A ¹¹¹ , A ¹¹² and A ¹¹³ in Formula 11 and A ¹²¹ , A ¹²² , A ¹²³ and A ¹²⁴ in Formula 12 are unsubstituted or substituted heterocyclyl substituents, they are preferably heteroatom (s) As a 5 or 6 membered heterocyclyl ring containing oxygen and / or nitrogen. Heterocyclyl radicals may also be partially unsaturated. Heterocyclyl substituents are particularly preferably dihydroimidazole, dihydropyrazole, dihydroisoxazole, in particular dihydrooxazole.

When A ¹¹¹ , A ¹¹² and A ¹¹³ in Formula 11 and A ¹²¹ , A ¹²² , A ¹²³ and A ¹²⁴ in Formula 12 are unsubstituted or substituted cycloalkyl substituents, they may preferably be substituted with alkanyls. 5, 6 or 7 membered cycloalkyl ring. Especially preferred are cyclohexyl radicals.

When G in Formula 12 is an alkylene bridge, it preferably has 1, 2, 3, 4, 5 or 6 carbon atoms. The alkylene bridge is particularly preferably -CH ₂ CH _2- , -CH ₂ CH ₂ CH ₂ -or-(CH ₂ ) _4- .

When G in Formula 12 is a 1,2-phenylene radical or a 2,3-naphthylene radical, they are mono- or di-substituted, preferably unsubstituted with alkanyl or alkoxy. G is particularly preferably an unsubstituted 1.2-phenylene radical.

When G is a 2,2'-biphenylene radical, it is unsubstituted or identically or differently alkanyl, in particular methyl, ethyl, isopropyl, n-butyl or t-butyl, alkoxy, in particular methoxy, Mono- or multi-substituted with -NH ₂ or -N (alkanyl) ₂ , in particular -N (methyl) ₂ , -N (ethyl) ₂ , -N (isopropyl) ₂ or -N (ethyl) (isopropyl) Is substituted. Substitution positions are the 5-, 6-, 5'- and / or 6'-positions. The biphenyl radicals are particularly preferably unsubstituted.

In an embodiment of the invention, G is a 1,1'-ferrocenyl radical (1,1'-di (cyclopentadienyl) iron).

The phosphine radical added to the transition metal complex precursor is preferably a phosphine ligand of formula (11). It is also preferred that A ¹¹¹ , A ¹¹² and A ¹¹³ are the same and are aryl substituents, which are particularly preferably unsubstituted phenyl radicals or methyl-substituted phenyl radicals (o-, m- and / or p-tolyl) to be.

In a preferred embodiment of the invention, the transition metal complex precursor is a complex of formula 6a and the phosphine ligand (s) are triphenylphosphine or tri (o-tolyl) phosphine.

[(COD) RhCl] ₂

When a transition metal complex precursor of formula 10 is used in the process according to the invention, if appropriate, a base such as triethylamine or the like is added to the reaction mixture in an amount sufficient to eliminate the hydrohalic acid formed during the reaction. It may also be advantageous.

If at least one of the ligands of the transition metal complex or transition metal complex precursor or one of the added phosphine ligands is selected to induce chiral information that catalyzes the hydrogenation according to the invention, it is itself chiral or C ₂ -symmetric In the case of racemic dihydropyranes of the formula (2) having a chiral center in the 2-position, hydrogenation can be carried out trans-selectively as well as diastereoisomers, preferably dynamic racemic separation Based on only one of the two possible trans isomers is preferentially formed. The dihydropyranes of formula (2), already hydrogenated, consist of pure enantiomers (relative to the 2-position), and a second chiral center with uniform chirality at the 5-position is obtained in trans-hydrogenation without the use of chiral ligands. And the use of chiral ligands of corresponding arrangements can enhance chiral induction.

The process according to the invention is usually carried out using hydrogen (H ₂ ) passed through or in the reaction medium. Hydrogen pressure is not critical in itself, and in particular is selected based on the reaction rate. The hydrogenation is carried out at a hydrogen pressure of about 1 bar to about 200 bar, preferably about 3 to 100 bar, in particular about 6 to about 60 bar.

The hydrogenation is carried out in a pressure resistant vessel preferably under the exclusion of oxygen.

Likewise, the choice of reaction temperature is not in itself important if the hydrogenation proceeds sufficiently fast without unwanted decomposition of the reactants and reagents. In general, the reaction temperature ranges from about 0 to about 200 ° C, preferably from about 10 to about 150 ° C, particularly preferably from about 60 to about 130 ° C, in particular from about 80 to about 100 ° C.

The amount of catalyst used is determined by the need to achieve a sufficiently high reaction rate and the best possible conversion, on the other hand economical requirements to keep the amount of catalyst as small as possible, and the duration of catalyst activity or catalyst of the complex used It is determined by the rate at which it is deactivated. The molar ratio between the transition metal complex or transition metal complex precursor used as a catalyst and the substrate, i.e., the compound of formula 2, is from 1: 50,000 to 1:50, i.e., about 0.02 mol% based on the substrate of the transition metal complex or transition metal complex precursor. To about 2 mole%. The amount of catalyst is particularly preferably from about 0.2 mol% to about 1.5 mol%, in particular from about 0.8 mol% to about 1.2 mol%. The transition metal complex or transition metal complex precursor is conventionally added to the reaction mixture at one time, but it may also be added in several portions throughout the reaction process.

The reaction time is essentially determined by the reaction rate, with about 1 minute to about 14 days being typical. Preferably from about 30 minutes to about 48 hours, particularly preferably from about 2 hours to about 24 hours.

The process according to the invention is particularly suitable for the trans-selective hydrogenation of compounds of formula (2) wherein W is oxygen (-O-), ie reduction of the dihydropyran derivatives of formula (2) to tetrahydropyrans of formula (1). The process according to the invention is particularly preferred for the preparation of tetrahydropyrans of formula 1a from dihydropyrans of formula 2a.                     

In addition, when W is CH ₂ , it is preferred to carry out the process according to the invention using the cyclohexene derivative of formula 2b.

It is also preferred that the compound of formula 2 contain at least one additional ring in addition to the central cyclohexene or dihydropyrane ring. It is particularly preferred that the sum of f, g, h, i and j in formula (2) and the sum of a, b, c, d and e in formula (1) are less than or equal to 3. These sums are very particularly preferably 1 or 2, ie the compounds of the formulas (1) and (2) contain 1 or 2 additional rings or ring systems in addition to the central cyclohexene or dihydropyrane rings.

In a preferred embodiment of the invention, the radicals, rings and indices in formulas 1 and 2 are selected as follows:

a, d, f and i are 0,

b and g are 0 or 1,

c and h are 0 or 1,

e and j are 1,

A ¹² and A ²² are unsubstituted 1,4-cyclohexylene radicals when b or g is 1,

A ¹³ and A ²³ are unsubstituted 1,4-cyclohexylene radicals when c or h is 1 or 1,4-phenylene radicals unsubstituted or monosubstituted or polysubstituted with halogen,

A ¹⁵ and A ²⁵ are unsubstituted or mono- or polysubstituted 1,4-phenylene radicals,

R ¹¹ and R ²¹ are alkanyl radicals having 1 to 8 carbon atoms,

Y ¹¹ and Y ²¹ are unsubstituted or mono- or polysubstituted alkanyl or alkoxy radicals having 1 to 8 carbon atoms, unsubstituted or substituted aralkyl or aralkyl-O-radicals, F, Cl, Br or CN,

Z ¹² is a single bond, -CH ₂ CH _2- , -CO-O- or -O-CO-,

Z ¹³ and Z ²³ are a single bond or -CO-O,

Z ¹⁴ and Z ²⁴ are a single bond, -CF ₂ O- or -CO-O-, when c or h is 1,

Z ²² is a single bond, -CH ₂ CH _2- , -CH = CH-, -CO-O- or -O-CO-.

It is particularly preferred here that Z ²² is a CH═CH group which is likewise hydrogenated together with the endocyclic CC double bonds of the central cyclohexene or dihydropyran ring when the process according to the invention is carried out. (The same applies to other aliphatic or cycloaliphtic CC double bonds present in compounds of formula 2). Z ²² very particularly preferably is the CH═CH group of the compound of formula 2a in which W is —O— to be.

Preferred compounds of formula 2a in which W is -O- hydrogenated by the process according to the invention are the following compounds.

In these formulas n is 1, 2, 3, 4, 5, 6, 7 or 8, especially 1, 2, 3, 4 or 5 and is also 0 in the compounds of formulas 2ah, 2ai and 2aj. Y ²¹ is as defined in formula 2a above, preferably F, Cl, Br, CF ₃ , OCH ₃ , OCF ₃ or aralkyl-O—, particularly preferably F. The substituents L ²¹ and L ²² are independently of each other H, Cl, Br or F, preferably at least one is F, in particular both are F.

Preferred compounds of formula 2b wherein W is -CH ₂ -hydrogenated according to the present invention are the following compounds.

In these formulas n is 1, 2, 3, 4, 5, 6, 7 or 8, in particular 1, 2, 3, 4 or 5. Y ²¹ is as defined in Formula 2b, preferably F, Cl, Br, CF ₃ , OCH ₃ , OCF ₃ or aralkyl-O—, particularly preferably F or OCH ₃ . Substituents L ²¹ , L ²² , L ²³ and L ²⁴ are independently of each other H, Cl, Br or F, and it is preferable that two of L ²¹ , L ²² , L ²³ and L ²⁴ are F and the other two are H. Especially preferably, L ²¹ and L ²² are F, L ²³ and L ²⁴ are H, or L ²¹ and L ²³ are F and L ²² and L ²⁴ are H.

Further examples of formula (2) that can be used in the process according to the invention are given in the examples below.

In a preferred embodiment of the invention, the compound of formula 2 is hydrogenated, followed by crystallization of the trans isomer of formula 1 from a suitable solvent such as an alcoholic solvent such as methanol or ethanol as further processing steps.

Cyclohexene compounds of formula (2) are known in the literature. They are also described in, for example, the certified organic synthetic chemistry books of Houben-Weyl, "Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart", etc. Likewise, it can be prepared precisely under reaction conditions suitable and known for these reactions by methods known per se. However, variations that are not mentioned in detail herein but known per se may also be used. Suitable general processes described in exemplary terms for some compounds in EP 0 415 090 A1 are suitable substituted alkyl-, cyclo of cyclohexanone derivatives (which are suitably substituted by themselves) onto carbonyl functional groups. After the addition reaction of the alkyl- or aryl-Grinard compound, subsequently removing the tertiary alcohol functional groups formed in the Grignard reaction and forming an endocyclic CC double bond.

Dihydropyran derivatives of formula (2) are also known from the literature or are known organic synthesis chemistries such as, for example, Houben Vale's "Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart". As described herein, it can be prepared precisely under reaction conditions suitable and known for these reactions by methods known per se. However, variations that are not mentioned in detail herein but known per se may also be used. Dihydro pyran derivative of the general formula (2) is Z ²² is not a double bond CC is ring-close the cross-can be prepared in particularly elegant manner by substitution, and (DE 10324312.7 call), Z ²² a CC double bond dihydro of formula (II) The pyran derivatives can be prepared by enine substitution or by further cross-substitution if required (DE 10324348.8) and in each case in the presence of a suitable metal-carbene complex (eg Grubbs I or Grubbs II catalyst or related catalysts; for example in particular WO 96/04289, WO 97/06185, TM Trnka et al., "Acc. Chem. Res. 2001, 34, 18", SK Armstrong, J. Chem. Soc., Perkin Trans. I, 1998, 371 , J. Renaud et al., "Angew. Chem. 2000, 112, 3231". These two methods are shown schematically in Schemes 1a and 1b for compounds of formula 2a, respectively, and it is also possible to apply the procedure to compounds of formula 2b.

Subsequent cleavage upon completion of the reaction for the protection of all selective reactive functional groups or substituents present in the molecule against unwanted reactions in the reduction process and / or in the preceding or subsequent reaction and / or aftertreatment steps according to the invention. It is possible to use a protector that can be. Methods of using suitable protecting groups are known to those skilled in the art, for example in T.W. Greene, P.G.M. See Wuts, "Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons (1999)".

The reagents used, in particular transition metal complexes and transition metal complex precursors, are known in the literature and are commercially available, for example, usually from Sigam-Aldrich Chemicals, Steinheim, Germany. Alternatively, they may be reacted to the reactions by methods known per se, such as those described in the literature (e.g., "Inorganic Syntheses" (authorized books such as McGraw-Hill or Wiley, New York, 1939 ff.)). It can be prepared clearly under suitable and known reaction conditions. On the other hand, variations that are not mentioned in detail herein but known per se may also be used.

The invention also provides a composition comprising at least one compound of formula 2a or 2b as defined above and a transition metal complex stabilized with the same or different phosphine ligands as defined above, and the preparation of a compound of formula 1a or 1b It relates to the use of this composition for.

In the context of the present invention, the term " alkyl "-unless otherwise defined herein or in the claims-has 1 to 15 carbon atoms (ie 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15) straight or branched aliphatic hydrocarbon radicals, which are unsubstituted or mono- or polysubstituted identically or differently with fluorine, chlorine, bromine, iodine or cyano .                     

If this alkyl radical is a saturated radical, it is also known as "alkanyl". In addition, the term "alkyl" is mono-substituted with F, Cl, Br, I and / or -CN, unless substituted or correspondingly identically or identically-unless otherwise defined herein individually, either herein or in the claims. Polysubstituted hydrocarbon radicals, wherein the CH ₂ group is -O-"(alkoxy" or "oxaalkyl") -S-("thioalkyl"), -CH = CH-("alkenyl"),- C≡C-("alkynyl"), -CO-O-, -O-CO- or -O-CO-O- may be substituted in such a way that the heteroatoms (O or S) are not directly connected to each other. have. (In the compound of formula 1, "alkyl" also does not include alkenyl radicals.) Alkyl is preferably a straight or branched unsubstituted or substituted C1, 2, 3, 4, 5, 6, 7 Or an alkanyl, alkenyl or alkoxy radical of 8. When the alkyl is an alkanyl radical, it is preferably methyl, ethyl, n-propyl, i-propyl-, n-butyl, i-butyl, t-butyl, n-pentyl, neopentyl, n-hexyl, n- Heptyl, n-octyl; CF ₃ , CHF ₂ , CH ₂ F; CF _{2 is} CF ₃ . Alkanyl radicals are particularly preferably straight chain, unsubstituted or substituted with F.

Since one or more CH ₂ groups in an alkyl radical may be substituted by —O—, the term “alkyl” also includes “alkoxy” or “oxaalkyl” radicals. The term alkoxy means an O-alkyl radical in which an oxygen atom is directly bonded to a group substituted with an alkoxy radical or with a substituted ring and alkyl is as previously defined; Alkyl is preferably alkanyl or-if no radical is present in the compound of formula 1-alkenyl. Preferred alkoxy radicals are methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy and octoxy, and it is also possible for each of these radicals to be preferably substituted with one or more fluorine atoms. Alkoxy is particularly preferably -OCH ₃ , -OC ₂ H ₅ , -OnC ₃ H _7- , -OnC ₄ H ₉ , -OtC ₄ H ₉ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F or -OCHFCHF ₂ In the context of the present invention, the term "oxaalkyl" means an alkyl radical wherein one or more non-terminal CH ₂ groups are replaced by -O- in such a way that no adjacent heteroatoms (O or S) are present. The oxaalkyl preferably comprises a straight chain radical of C _e H _{2e + 1} —O— (CH ₂ ) _f −, where e and f are each independently of one another 2, 3, 4, 5, 6, 7 , 8, 9 or 10, particularly preferably e is an integer from 1 to 6 and f is 1 or 2.

When at least one CH ₂ group in the alkyl radical as defined above is substituted by sulfur, there is a “thioalkyl” radical. “Thioalkyl” is preferably a straight chain radical of C _e H _{2e + 1} —S— (CH ₂ ) _f −, where e is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 And f is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, particularly preferably e is an integer from 1 to 6 and f is 0, 1 or 2. Thioalkyl radicals can likewise be substituted with F, Cl, Br, I and / or -CN, preferably unsubstituted.

In the context of the present invention, the term "alkenyl" means an alkyl radical as defined above in which one or more -CH = CH- groups are present. If two -CH = CH- groups are present in a radical, this may also be referred to as "alkadienyl". Alkenyl radicals may contain 2 to 15 (ie, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15) carbon atoms and are branched, preferably It is straight. The radicals are unsubstituted or identical or differently mono- or polysubstituted with F, Cl, Br, I and / or CN. In addition, at least one CH ₂ group is each independently a heteroatom by -O-, -S-, -C≡C-, -CO-O-, -OC-O- or -O-CO-O- (O and S) may be substituted in such a way that they are not directly bonded to each other. If the CH═CH group carries radicals other than hydrogen on both carbon atoms, such as non-terminal groups, the CH═CH group may exist as two coordinations, the E-isomer and the Z-isomer . In general, E-isomers (trans) are preferred. Alkenyl radicals preferably contain 2, 3, 4, 5, 6 or 7 carbon atoms, which are vinyl, 1E-propenyl, 2E-butenyl, 1E-pentenyl, 1E-hexenyl, 1E-hep Tenyl, 2-propenyl, 2E-butenyl, 2E-pentenyl, 2E-hexenyl, 2E-heptenyl, 3-butenyl, 3E-pentenyl, 3E-hexenyl, 3E-heptenyl, 4-phene Tenyl, 4Z-hexenyl, 4E-hexenyl, 4Z-heptenyl, 5-hexenyl or 6-heptenyl. Particularly preferred alkenyl radicals are vinyl, 1E-propenyl and 3E-butenyl.

If at least one CH ₂ group in the alkyl radical is substituted by -C≡C-, an alkynyl radical is present. An alkylketo group is present when one CH ₂ group is substituted by -CO-. Substitution of one or more CH ₂ groups with —CO—O— or —O—CO— is also possible. Preference is given to these radicals as follows: acetoxy, propionyloxy, butyryloxy, pentanoyloxy, hexanoyloxy, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pentanoyloxymethyl, 2-acetyl Methoxyethyl, 2-propionyloxyethyl, 2-butylyloxyethyl, 2-acetoxypropyl, 3-propionyloxypropyl, 4-acetoxybutyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl , Butoxycarbonyl, pentoxycarbonyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, butoxycarbonylmethyl, 2- (methoxycarbonyl) ethyl, 2- (ethoxy Carbonyl) ethyl, 2- (propoxycarbonyl) ethyl, 3- (methoxycarbonyl) -propyl, 3- (ethoxycarbonyl) propyl or 4- (methoxycarbonyl) butyl.

In the context of the present invention, the term "alkylene" or "alkylene bridge" refers to one, two, three, four, five, six, in the chain, unless the term is otherwise defined herein or in the claims. Divalent aliphatic hydrocarbon radical having 7 or 8 carbon atoms, which is optionally mono- or multiply halogen, CN, carboxyl, nitro, alkanyl, alkoxy, -NH ₂ , or -N (alkanyl) ₂ It may be substituted, wherein the polysubstitution may be made of the same or different substituents. "Alkylene" or "alkylene bridge" is preferably a straight-chain, unsubstituted or mono- or polysubstituted saturated aliphatic radical having 1, 2, 3, 4, 5 or 6 carbon atoms, in particular -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -,-(CH ₂ ) ₄ -or -CH ₂ C (CH ₃ ) ₂ CH _2- .

In the context of the present invention, the term "aryl"-unless otherwise stated herein or elsewhere in the claims-refers to aromatic hydrocarbons having 6 to 14 carbon atoms, which are identically or differently halogen, nitro, alkanyl, alkoxy, Optionally mono- or polysubstituted with -NH ₂ or -N (alkanyl) ₂ ), in particular a phenyl or naphthyl radical.

In the context of the present invention, the term "cycloalkyl" means a cyclic aliphatic radical having 3 to 16 carbon atoms, which is saturated or partially unsaturated, equally or differently halogen, carboxyl, nitro, alkanyl, alkoxy, NH ₂ Optionally mono- or polysubstituted with-or -N (alkanyl) ₂ . It is preferably unsubstituted and has 5, 6 or 7 carbon atoms. In particular, cycloalkyl means a cyclohexyl radical.

In the context of the present invention, the term "heteroaryl radical" includes cyclic, containing one or more identical or different heteroatoms in addition to carbon atoms and having 5 to 18 ring atoms selected from nitrogen, oxygen and sulfur, ( Hetero) aromatic organic radicals. Heterocyclic radicals may have one or more rings and may also have two, three or more rings that are optionally fused to each other, one or more of the plurality of rings containing one or more heteroatoms. Equally, as previously defined aryl radicals, heteroaryl radicals may be unsubstituted or identically or differently mono- or polysubstituted with halogen, nitro, alkanyl, alkoxy, -NH ₂ , or -N (alkanyl) ₂ . Can be. Heteroaryl radicals may be bonded via any of their ring atoms. Heteroaryl radicals are preferably pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, furanyl, thienyl, oxazolyl, isoxazolyl, pyranyl, Benzofuranyl and benzothienyl. Heteroaryl is particularly preferably pyridinyl or furanyl.

For the purposes of the present invention, the term "heterocyclyl radical" has from 5 to 18 ring atoms having at least one saturated (endocyclic) bond between two ring atoms in the ring and which is not aromatic and from nitrogen, oxygen and sulfur It means a cyclic organic radical containing one or more selected or different heteroatoms. Heterocyclic radicals can have one or more rings and can also have two, three or more rings that can be optionally fused to each other, one or more of the plurality of rings containing one or more hetero atoms. As with the aryl radicals defined above, the heterocyclyl radicals may be unsubstituted or identical or differently mono- or polysubstituted with halogen, nitro, alkanyl, alkoxy, -NH ₂ , or -N (alkanyl) ₂ . Can be. Heteroaryl radicals may be bonded via any of their ring atoms. Heteroaryl radicals are preferably pyrrolidine, piperidine, piperazine, morpholine, tetrahydrofuran, dioxane, dihydropyrazole, dihydroimidazole, dihydrooxazole, tetrahydrooxazole, dihydroeye Soxazole and tetrahydroisoxazole. The heterocyclyl radical is particularly preferably dihydrooxazole.

In the context of the present invention, the term “aralkyl” means an arylalkyl radical, ie a radical in which an aryl substituent is linked via an alkyl bridge to an atom, chain, other radical or functional group. The alkyl bridge is preferably a saturated divalent hydrocarbon radical, in particular methylene (-CH _2- ) or ethylene (-CH ₂ -CH _2- ). Preferred examples of aralkyl radicals are benzyl and phenethyl. For the purposes of the present invention, "aralkyl-O-radicals" are aralkyl radicals which are connected to further atoms, chains, other radicals or functional groups via an oxygen atom combined with an alkyl bridge. Preferred examples of aralkyl-O-radicals are O-benzyl and O-CH ₂ CH ₂ phenyl.

In the context of the present invention, halogen is fluorine, chlorine, bromine or iodine.

The following examples illustrate the invention in more detail without limiting its scope.

Example

Starting compounds used in the examples were prepared by methods known from the literature.

The transition metal complexes and transition metal catalysts used were purchased from Strem Chemicals or Merck KGaA, Darmstadt, Germany, which was used without further purification.

The solvent was pure by analysis and degassed prior to use.

The reaction was carried out under the exclusion of oxygen.

Hydrogenation conversion was measured using gas chromatography (GC) (Varian Chrompack CP-3800, standard conditions). The composition of the product mixture and the cis / trans selectivity of the reaction were also measured using gas chromatography.                     

Example 1

37 mg (0.04 mmol) tris (triphenylphosphine) rhodium (I) chloride was added to 0.73 g (2.0 mmol) of olefin (1) in a pressurized autoclave. After addition of 6 ml of ethanol and 2 ml of toluene, the autoclave is sealed and degassed three times by vacuum after injection of 5 bar of nitrogen. 6 bar of hydrogen is injected and the mixture is heated to 100 ° C. After 21 hours, the reaction vessel is cooled down and the contents are analyzed using gas chromatography. The starting material reacted by 73%. Product 2 is obtained with a trans content of 76%.

Comparative Example 1

The hydrogenation of olefin (1) was repeated under similar conditions as in Example 1 except that tris (triphenylphosphine) rhodium (I) chloride was replaced with 5% palladium on activated carbon. On 100% reaction in THF at 1 bar hydrogen pressure and room temperature the product 2 is obtained with a trans content of 38%.

Example 2

56 mg (0.06 mmol) tris (triphenylphosphine) rhodium (I) chloride is added to 1.94 g (6.0 mmol) of diene (3) in a pressurized autoclave. After addition of 36 ml of methanol and 12 ml of toluene, the autoclave was sealed and degassed three times by depressurization after injection of 10 bar of nitrogen. Inject 60 bar of hydrogen and heat the mixture to 80 ° C. After 20 hours, the reaction vessel is cooled down and the contents are analyzed using gas chromatography. The starting material reacted by 99%. Product 4 is obtained with a trans content of 73%.

Comparative Example 2

The hydrogenation of olefin (5) was repeated under similar conditions as in Example 2 except that tris (triphenylphosphine) rhodium (I) chloride was replaced with 5% palladium on activated carbon. On 100% reaction in heptane at 1 bar hydrogen pressure and room temperature the product 6 is obtained with a trans content of 27%.

Example 3

141 mg (0.15 mmol) tris (triphenylphosphine) rhodium (I) chloride are added to 6.20 g (16.0 mmol) of diene (7) in a pressurized autoclave. After addition of 50 ml of methanol and 15 ml of toluene, the autoclave was sealed and degassed three times by depressurization after injection of 10 bar of nitrogen. Inject 60 bar of hydrogen and heat the mixture to 80 ° C. After 20 hours, the reaction vessel is cooled down and the contents are analyzed using gas chromatography. The starting material reacted by 96%. Product 8 is obtained with a trans content of 74%.

Example 4

9 mg (0.01 mmol) tris (triphenylphosphine) rhodium (I) chloride and 12 mg lithium bromide are added to 0.10 g (0.3 mmol) of olefin (9) in a pressurized autoclave. After addition of 6 ml of ethanol, the autoclave was sealed and degassed three times by depressurization after injection of 5 bar of nitrogen. 7 bar of hydrogen is injected and the mixture is heated to 100 ° C. After 15 hours, the reaction vessel is cooled down and the contents are analyzed using gas chromatography. The starting material reacted by 88%. Product 10 is obtained with a trans content of 77%.

When the same reaction is carried out under the same conditions except that no lithium bromide is added, a conversion of 80% is achieved and the product 10 is obtained with a trans content of 73%.                     

Example 5

1.8 g (1.95 mmol) tris (triphenylphosphine) rhodium (I) chloride are added to 14.7 g (38.3 mmol) olefin (11) in a pressurized autoclave. After addition of 180 ml of ethanol and 60 ml of toluene, the autoclave is sealed and degassed three times by depressurization after injection of 10 bar of nitrogen. 10 bar of hydrogen is injected and the mixture is heated to 100 ° C. After 45 hours, the reaction vessel is cooled down and the contents are analyzed using gas chromatography. The starting material reacted about 100%. Product 12 is obtained with a trans content of 77%.

Example 6

0.75 g (0.81 mmol) tris (triphenylphosphine) rhodium (I) chloride is added to 11.1 g (40.6 mmol) olefin (13) in a pressurized autoclave. After addition of 60 ml of ethyl methyl ketone and 60 ml of toluene, the autoclave is sealed and degassed three times by depressurization after injection of 10 bar of nitrogen. 11 bar of hydrogen are injected and the mixture is heated to 100 ° C. After 17 hours, the reaction vessel is cooled down and the contents are analyzed using gas chromatography. The starting material reacted about 100%. Product 14 is obtained with a trans content of 61%.

Example 7

4.50 g (4.86 mmol) tris (triphenylphosphine) rhodium (I) chloride is added to 150 g (0.48 mmol) of diene in a pressurized autoclave. After addition of 1200 L of ethanol and 400 ml of toluene, the autoclave is sealed and degassed three times by depressurization after injection of 50 bar of nitrogen. 8 bar of hydrogen is injected and the mixture is heated to 80-95 ° C. After 34 hours, the reaction vessel is cooled down and the contents are analyzed using gas chromatography. The starting material reacted about 100%. Product 16 is obtained with a trans content of 79%.

Example 8

0.40 g (0.43 mmol) tris (triphenylphosphine) rhodium (I) chloride is added to 12.5 g (40.6 mmol) of olefins 17 in a pressurized autoclave. After addition of 100 ml of ethanol and 30 ml of toluene, the autoclave was sealed and degassed three times by depressurization after injection of 50 bar of nitrogen. 16 bar of hydrogen is injected and the mixture is heated to 80 ° C. After 17 hours, the reaction vessel is cooled down and the contents are analyzed using gas chromatography. The starting material reacted about 100%. Product 18 is obtained with a trans content of 79%.

Example 9

The reaction from Example 2 is repeated by modifying experimental conditions using different transition metal complexes or transition metal complex precursors. About 2 or about 3 equivalents of stabilized phosphine are used based on 1 mol% of the individual complexes and, if required, the complex. The reaction period is 15 hours. Additional data and results for the experimental conditions are presented in Table 1.

Example 10

56 g (0.233 mol) of olefins are hydrogenated at 450 mL of methanol and 2.2 mL of toluene containing 2.2 g of tris (triphenylphosphine) rhodium (I) chloride at 8 bar hydrogen pressure and 80 ° C. for 4 hours. After cooling, the reaction mixture is evaporated under reduced pressure and filtered through silica gel with toluene / heptane (3: 7). The remaining filtrate residue after evaporation of the solvent is distilled at 0.8 mbar and the fraction passing at 148-167 ° C. is chromatographed on silica gel (eluent: toluene / heptane (5/95 to 2/8). 33.0 g of hydrogenated product 20 having a trans content of% are obtained as an oil.

Trans-2- (4-chlorophenyl) -5-propyltetrahydropyran was similarly prepared from the corresponding olefins with a trans content of 78% and trans-2- (4-chlorophenyl) -5- (trans-4 -Propylcyclohexyl) tetrahydropyran is prepared similarly with a trans content of 86%.

Example 11

10 g (34 mmol) of olefins in 60 ml of methanol containing 314 mg (339 micromol) of tris (triphenylphosphine) rhodium (I) chloride and 18 ml of toluene at 8 bar and 18 ° C. for 17.5 hours at 80 ° C. Hydrogenate until taken. After cooling the reaction mixture and evaporating the solvent, the residue is filtered through silica gel with toluene / heptane (3: 7). Evaporation of the filtrate leaves 8.1 g of residue, which is present in the ratio of 71:29 trans and cis isomers.

Trans-2- (4-bromophenyl) -5-ethyltetrahydropyran is similarly prepared from the corresponding olefins with a trans content of 76%.

The 1,4-disubstituted cyclohexane derivatives and the 2,5-disubstituted tetrahydropyran derivatives can be prepared by the hydrogenation method according to the present invention to more easily obtain the trans isomers with high selectivity and high yield.

Claims (12)

Characterized by hydrogenating a compound of Formula 2a or a compound of Formula 2b in the presence of at least one transition metal complex stabilized by one or more identical or different phosphine ligands and selected from the group consisting of rhodium, iridium and ruthenium complexes To prepare a compound of Formula 1a or 1b: Formula 1a

1b

Where a, b, c, d and e are each independently 0 or 1, the sum of a, b, c, d and e is 3 or less, e is 1 when W is -CH _2- , A ¹¹ , A ¹² , A ¹³ , A ¹⁴ and A ¹⁵ are each independently a 1,4-cyclohexylene radical or a 1,4-phenylene radical, where these radicals are unsubstituted or identical or differently mono-substituted with halogen Or polysubstituted), R ¹¹ is hydrogen or an alkyl radical of 1 to 15 carbon atoms which is monosubstituted or polysubstituted with unsubstituted or identical or different substituents, wherein at least one CH ₂ group of these radicals is independently of each other -C≡C-, -S -, -O-, -CO-, -COO-, -O-CO- or -O-CO-O- may be substituted in such a way that the heteroatoms (-S- and -O-) are not directly connected to each other. When a and b are 0 at the same time and Z ¹² is a single bond, then R ¹¹ is not hydrogen, W is -CH ₂ -or -O-, Y ¹¹ is hydrogen, halogen, -NCS, -SCN, -SF ₅ , -CN, an alkyl radical having 1 to 15 carbon atoms which is unsubstituted or identically or differently mono- or polysubstituted with halogen or -CN, or is not substituted The same or differently substituted or polysubstituted aralkyl radicals having 7 to 16 carbon atoms which are mono- or polysubstituted with halogen, nitro, alkanyl, alkoxy, -NH ₂ or -N (alkanyl) ₂ , wherein CH ₂ groups of at least one of these radicals Are independently of each other -C≡C-, -S-, -S (O)-, -S (O) _2- , -O-, -CO-, -COO-, -O-CO- or -O- CO-O- may be substituted in such a way that heteroatoms in the chain (-S- and -O-) are not directly connected to each other), Z ^11, Z ^13, Z ¹⁴ and Z ¹⁵ are independently of each other a single _{bond, -CH 2 O-, -OCH 2 -} , -CF 2 O-, -OCF 2 -, -COO- or -O-CO- and , Z ¹² is a single bond; Formula 2a

Formula 2b

In the above equations, f, g, h, i and j are each independently 0 or 1, the sum of f, g, h, i and j is 3 or less, j is 1 when W is -CH _2- , A ²¹ , A ²² , A ²³ , A ²⁴ and A ²⁵ are each independently a 1,4-cyclohexylene radical or a 1,4-phenylene radical, where these radicals are unsubstituted or identical or differently mono-substituted with halogen Or polysubstituted), R ²¹ is hydrogen or an alkyl radical having 1 to 15 carbon atoms which is monosubstituted or polysubstituted with unsubstituted or identical or different substituents, wherein at least one CH ₂ group of these radicals is independently of each other -CH = CH-, -C 헤테로 C-, -S-, -O-, -CO-, -COO-, -O-CO- or -O-CO-O- directly connect heteroatoms (-S- and -O-) to each other Unsubstituted), and when f and g are 0 at the same time and Z ²² is a single bond, then R ²¹ is not hydrogen; W is -CH ₂ -or -O-, Y ²¹ is hydrogen, halogen, -NCS, -SCN, -SF ₅ , -CN, an alkyl radical having 1 to 15 carbon atoms which is monosubstituted or polysubstituted with unsubstituted or identical or different substituents and an aralkyl radical having 7 to 16 carbon atoms (Wherein at least one CH ₂ group of these radicals is independently of each other -CH = CH-, -C≡C-, -S-, -S (O)-, -S (O) _2- , -O-, And -CO-, -COO-, -O-CO- or -O-CO-O- may be substituted in such a way that the heteroatoms in the chain (-S- and -O-) are not directly connected to each other) , Z ^21, Z ^23, Z ²⁴ and Z ²⁵ are independently of each other a single _{bond, -CH 2 O-, -OCH 2 -} , -CF 2 O-, -OCF 2 -, -COO- or -O-CO- and , Z ²² is a single bond. The method of claim 1, The transition metal complex is a rhodium complex, characterized in that for producing a compound of formula 1a or 1b. The method of claim 1, The transition metal complex is selected from complexes of the following formula (3) or (4), method of producing a compound of compound 1a or 1b. Formula 3 [(P (A ³¹ A ³² A ³³ )) ₃ RhX ³¹ ] Formula 4 [(Diene) Ir (A ⁴¹ ) (P (A ⁴² A ⁴³ A ⁴⁴ ))] Y ⁴¹ In the above equations, A ³¹ , A ³² and A ³³ are independently unsubstituted or substituted aryl, biphenyl, heteroaryl, heterocyclyl or cycloalkyl radicals and are the same or different at the three ligands P (A ³¹ A ³² A ³³ ) Have meaning, A ⁴¹ is unsubstituted or substituted heterocyclyl or heteroaryl radical, A ⁴² , A ⁴³ and A ⁴⁴ are independently unsubstituted or substituted aryl, biphenyl, heteroaryl, heterocyclyl or cycloalkyl radicals, wherein one of the radicals A ⁴² , A ⁴³ and A ⁴⁴ is substituted with A ⁴¹ ; Can be combined, X ³¹ is Cl, Br, I, PF ₆ , [PF ₃ (C ₂ F ₅ ) ₃ ], SbF ₆ , BF ₄ , BARF, ClO ₄ , CF ₃ SO ₃ , CH ₃ CO ₂ or CF ₃ CO ₂ , Y ⁴¹ is Cl, Br, I, PF ₆ , [PF ₃ (C ₂ F ₅ ) ₃ ], SbF ₆ , BF ₄ , BARF, ClO ₄ , CF ₃ SO ₃ , CH ₃ CO ₂ or CF ₃ CO ₂ An anion, The diene is 1,5-cyclooctadienyl (COD), norbornadienyl, (ethylene) ₂ or (cyclooctene) ₂ . The method of claim 3, wherein The transition metal complex is a complex of the formula (3a), characterized in that the manufacturing method of the compound of formula (1a) or (1b). Formula 3a [P (phenyl) ₃ RhCl] The method of claim 1, The transition metal complex is formed in situ by the reaction of the transition metal complex precursor and the phosphine ligand (s), method of producing a compound of formula 1a or 1b. 6. The method of claim 5, Wherein the transition metal complex precursor is selected from complexes of the formulas 5, 6, 7, 8, 9 or 10, and the phosphine ligand (s) is selected from compounds of formulas 11 and / or 12, Process for preparing a compound of formula 1a or 1b. Formula 5 [(Diene) Ru (allyl) ₂ ] 6 [(Diene) RhX ⁶¹ ] ₂ Formula 7 [(Diene) ₂ Rh] Y ⁷¹ Formula 8 [(Diene) IrX ⁸¹ ] ₂ Formula 9 [(Diene) ₂ Ir] Y ⁹¹ Formula 10 RhX ¹⁰¹ ₃ ? XH ₂ O In the above equations, X ⁶¹ , X ⁸¹ and X ¹⁰¹ are independently of each other Cl, Br or I, x is 0, 1, 2 or 3, Y ⁷¹ and Y ⁹¹ are each independently of PF ₆ , [PF ₃ (C ₂ F ₅ ) ₃ ], SbF ₆ , BF ₄ , BARF, ClO ₄ , CF ₃ SO ₃ , CH ₃ CO ₂ or CF ₃ CO ₂ An anion, The diene is 1,5-cyclooctadienyl (COD), norbornadienyl, (ethylene) ₂ or (cyclooctene) ₂ , Allyl is allyl or metallyl. Formula 11 P (A ¹¹¹ A ¹¹² A ¹¹³ ) Formula 12

In the above equations, A ¹¹¹ , A ¹¹² , A ¹¹³ , A ¹²¹ , A ¹²² , A ¹²³ and A ¹²⁴ are independently unsubstituted or substituted aryl, biphenyl, heteroaryl, heterocyclyl or cycloalkyl radicals, G is an alkylene bridge having 1 to 8 carbon atoms or unsubstituted or substituted 1,2-phenylene, 2,3-naphthylene, 2,2'-biphenylene or 1,1'-di (cyclopentadienyl It is iron. The method of claim 6, The transition metal complex precursor is a complex of formula (6a), characterized in that the phosphine ligand (s) is triphenylphosphine or tri (o-tolyl) phosphine, the method of producing a compound of formula 1a or 1b. Formula 6a [(COD) RhCl] ₂ The method of claim 1, W is -O- in the formulas (1a), (1b), (2a) and (2b). The method of claim 1, In Formula 1a and 1b or 2a and 2b, a, d, f and i are 0, b and g are 0 or 1, c and h are 0 or 1, e and j are 1, A ¹² and A ²² are unsubstituted 1,4-cyclohexylene radicals when b or g is 1, A ¹³ and A ²³ are unsubstituted 1,4-cyclohexylene radicals when c or h is 1 or 1,4-phenylene radicals unsubstituted or monosubstituted or polysubstituted with halogen, A ¹⁵ and A ²⁵ are unsubstituted or mono- or polysubstituted 1,4-phenylene radicals, R ¹¹ and R ²¹ are alkanyl radicals having 1 to 8 carbon atoms, Alkanyl or alkoxy radicals having 1 to 8 carbon atoms, unsubstituted or monosubstituted or polysubstituted with Y ¹¹ and Y ²¹ , aralkyl or aralkyl-O-radicals having 7 to 12 carbon atoms, unsubstituted or substituted, F, Cl, Br or CN, Z ¹² is a single bond, Z ¹³ and Z ²³ are a single bond or -CO-O, Z ¹⁴ and Z ²⁴ are a single bond, -CF ₂ O- or -CO-O-, when c or h is 1, Z ²² is a single bond, Process for preparing a compound of formula 1a or 1b. delete A composition comprising a compound of formula 2a or 2b and a transition metal complex stabilized by one or more of the same or different phosphine ligands and selected from rhodium, iridium and ruthenium complexes. Formula 2a

Formula 2b

In the above equations, f, g, h, i and j are each independently 0 or 1, the sum of f, g, h, i and j is 3 or less, j is 1 when W is -CH _2- , A ²¹ , A ²² , A ²³ , A ²⁴ and A ²⁵ are each independently a 1,4-cyclohexylene radical or a 1,4-phenylene radical, where these radicals are unsubstituted or identical or differently mono-substituted with halogen Or polysubstituted), R ²¹ is hydrogen, an unsubstituted or monosubstituted or polysubstituted alkyl radical having 1 to 15 carbon atoms, wherein at least one CH ₂ group of these radicals is independently of each other -CH = CH-, -C≡ The heteroatoms (-S- and -O-) are not directly connected to each other by C-, -S-, -O-, -CO-, -COO-, -O-CO- or -O-CO-O- In which case f and g are 0 at the same time and Z ²² is a single bond, R ²¹ is not hydrogen, W is -CH ₂ -or -O-, Y ²¹ is hydrogen, halogen, -NCS, -SCN, -SF ₅ , -CN, an alkyl radical having 1 to 15 carbon atoms which is monosubstituted or polysubstituted or unsubstituted or identically or differently substituted with halogen or -CN, or unsubstituted Aralkyl radicals having 7 to 16 carbon atoms, identically or differently mono- or polysubstituted with halogen, nitro, alkanyl, alkoxy, -NH ₂ or -N (alkanyl) ₂ , wherein CH ₂ also has at least one CH ₂ The groups are independently of each other -CH = CH-, -C≡C-, -S-, -S (O)-, -S (O) _2- , -O-, -CO-, -COO-, -O Heteroatoms in the chain (-S- and -O-) may be substituted by -CO- or -O-CO-O- in such a way that they are not directly connected to each other), Z ^21, Z ^23, Z ²⁴ and Z ²⁵ are independently of each other a single _{bond, -CH 2 O-, -OCH 2 -} , -CF 2 O-, -OCF 2 -, -COO- or -O-CO- and , Z ²² is a single bond. The method of claim 1, A process for preparing a compound of Formula 1a or 1b, wherein W is -CH ₂ -in Formulas 1a, 1b, 2a and 2b.