WO2019162391A1 - Method for producing fluorinated heterocyclic aliphatic compounds - Google Patents

Abstract

The invention relates to a novel method for producing fluorinated heterocyclic aliphatic compounds from the analogous aromatic compounds by hydrogenating with an Rh-catalyst system.

Description

 Process for the preparation of fluorinated heterocyclic aliphatic compounds

Description

The present invention relates to the field of fluorinated heterocyclic aliphatic compounds. Such compounds play a major role in the pharmaceutical or agrochemical field due to the polarity of the C-F bond with concomitant steric similarity to C-H bonds and other effects. Furthermore, additive dipole effects in several identically aligned C-F bonds are of interest for materials chemistry applications.

Despite the importance of these compounds, effective methods of preparation are not always available, so there is a continuing need for synthetic methods of fluorinated heterocyclic aliphatic cyclo compounds. This is especially true for heterocyclic compounds, as these are often important pharmaceuticals.

It is thus an object to provide novel methods for producing such compounds. This object is achieved by a method according to claim 1.

Accordingly, there is provided a process for producing fluorinated heterocyclic aliphatic compounds comprising the step of hydrogenating a heteroaromatic fluorochemical precursor substance with a catalyst comprising at least one

Rhodium atom in the presence of a reducing agent. Surprisingly, it has been found that in this way, often in excellent yield, the corresponding fluorine-containing heterocyclic aliphatic

Cyclo compounds are available and an F-H exchange, as would have been expected in many analogous hydrogenations, either not at all or only to the extent that, nevertheless, the fluorine-containing product can be obtained in an acceptable yield.

Surprisingly, in many applications a whole series of functional groups is tolerated such as e.g. Thioether groups, pinacol borane groups or protected

Hydroxy groups.

Furthermore, it has surprisingly been found that in the case where the starting substance contains two or more fluorine atoms, the r / .v product is preferably produced in many applications, which allows access to sterically defined products.

The term "aromatic fluorine-containing substance" is understood to mean, in particular, fluorinated heterocyclic 5-or 6-membered rings with p-electron sequestrates and fluorinated annelated heteroaromatic multi-cycles.

It should be noted that the term "aromatic fluorine-containing substance" is understood to mean, in particular, that at least one fluorine is present as a substituent on an aromatic ring.

Alternatively preferred are aromatic fluorine-containing precursors containing one or more benzo-fused heteroaromatic rings.

The term "hydrogenation" is understood in particular to mean that in the sum of two hydrogens are added to a "double bond" of the aromatic compound. However, the present invention is not limited to hydrogen as a concrete reducing agent Although this (as described below) is a preferred

Embodiment of the invention.

According to a preferred embodiment of the present invention, the catalyst comprises rhodium with at least one labile ligand, preferably more than one labile ligand.

 These are understood to mean ligands whose bonding to the rhodium is so weak that, if appropriate, they are at least temporarily not bound to the rhodium in the course of the reaction.

Preferred labile ligands are alkenes, cyclic bisalkenes, halides, triflates, acetonitrile, weakly coordinating anions such as tetrafluoroborate or phosphines.

Particularly preferred are alkenes, especially cyclic dialkene such as cyclooctadiene or bicyclo [2.2. l] hepta-2,5-diene.

Preferred catalysts according to a preferred embodiment of the invention are cyclooctadiene rhodium chloride dimer ([Rh (COD) Cl] ₂ ), bis (l, 5-cyclooctadiene) rhodium (I) tetrafluoroborate, bis (acetonitrile) (l, 5-cyclooctadiene) rhodium (I) tetrafluoroborate

([Rh (COD) (MeCN) 2] BL _4), chlorobis (cyclooctene) rhodium (I) dimer [Rh (COE) ₂ Cl] _2, bicyclo [2.2.l] hepta-2,5-dien-rhodium (I) chloride, dimer ([Rh (NBD) Cl] ₂ , rhodium-phosphine complexes analogous to tris (triphenylphosphine) rhodium (I) chloride ([RhfPPhs sCl] or

Tris (tricyclohexylphosphine) rhodium (I) chloride ([Rh (PCys sCl]), or

Bis (ethylene) rhodium chloride dimer ([Rh (C ₂ H 4) ₂ Cl] ₂ .

According to a preferred embodiment of the present invention, the catalyst comprises at least one N-heterocyclic carbene ligand.

According to an alternative preferred embodiment of the present invention, the catalyst does not comprise an N-heterocyclic carbene ligand. The term "N-heterocyclic carbene ligand" is understood to mean electron-rich, nucleophilic compounds of divalent carbon species with electron sequets, such as, for example, Pyrrolidinylidenes, pyrrolidens, imidazolylidenes, imidazolidinylidenes, piperidinylenes, hexahydropyrimidinylenes and triazolylidenes. Particularly preferred are

Pyrrolidinylidenes, pyrrolidens, imidazolylidenes and imidazolidinylidenes, more preferably pyrrolidinylidenes.

In the event that the N-heterocyclic carbene ligand comprises a pyrrolidinylidene compound, it is particularly preferred that there is no hydrogen in the a position to both the nitrogen and the carbene. This has turned out to be particularly effective for the hydrogenation in most applications of the present invention, since so the activity of the catalyst is not lowered by enamine formation, etc.

According to a preferred embodiment, the catalyst is used in substance.

However, according to alternative embodiments, it may also be advantageous to prepare the catalyst in situ. Thus, according to a preferred embodiment of the invention, the process according to the invention comprises two steps: a) in situ synthesis of the catalyst used in step b) from suitable precursors b) carrying out the hydrogenation as described above and in the following

As a suitable rhodium-containing precursor is in particular the

Cyclooctadienrhodiumchloriddimer ([Rh (COD) Cl] ₂ ) in question.

Preferably, step a) is carried out by reacting a suitable salt of the N-heterocyclic carbene with a strong base, preferably selected from NaOtBu, LDA, KOtBu, NaH, KHMDS, LiHMDS with a rhodium-forming precursor, for example [Rh (COD) Cl] ₂ , If necessary, reacted at elevated temperature. Halides, pseudohalides such as oxygen-containing anions, in particular triflates and weak can be used as anions coordinating anions such as tetrafluoroborate, hexafluoroantimonate or

Hexafluorophosphate serve. Preferred solvents here are hexane, diethyl ether or tetrahydrofuran.

If, in step b), a different solvent is used than in step a), the solvent is then optionally removed between the two steps.

According to a preferred embodiment of the invention, the catalyst comprises at least one N-heterocyclic carbene ligand of the following structure:

wobei

in which

R ¹ to R ⁵ independently of one another are alkyl, long-chain alkyl, alkoxy, long-chain alkoxy, cycloalkyl, haloalkyl, aryl, haloaryl, heteroaryl, heterocycloalkylene,

Heterocycloalkyl, haloheteroaryl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, ketoaryl, haloketoaryl, ketoheteroaryl, ketoalkyl, haloketoalkyl, silylalkyl,

Silylalkyloxy, with suitable radicals one or more non-adjacent CH ₂ groups independently of one another by -O-, -S-, -NH-, -NR ° -, -SiR ° R °° -, -CO-, -COO-, -OCO-, -OCO-O-, -S0 ₂ -, -S-CO-, -CO-S-, -CY ^ CY ² or -C = C- can be replaced in such a way that O and / or S atoms are not directly connected to one another, likewise optionally with aryl or heteroaryl preferably containing 1 to 30 C atoms are replaced (terminal CH3 groups are understood as CH ₂ groups in the sense of CH ₂ -H). R ⁶ and R ⁷ independently of one another are hydrogen, alkyl, long-chain alkyl, alkoxy, long-chain alkoxy, cycloalkyl, haloalkyl, aryl, haloaryl, heteroaryl,

Heterocycloalkylenes, heterocycloalkyl, haloheteroaryl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, ketoaryl, haloketoaryl, ketoheteroaryl, ketoalkyl,

Haloalkyl, silylalkyl, silylalkyloxy, where, with suitable radicals, one or more non-adjacent CH ₂ groups independently of one another by -O-, -S-, -NH-, -NR ° -, -SiR ° R °° -, -CO-, -COO-, -OCO-, -OCO-O-, -S0 ₂ -, -S CO-, -CO-S-, -CY ^ CY ² or -C = C- may be replaced such that O and / or S atoms are not directly connected to one another, likewise optionally with aryl or heteroaryl preferably containing 1 to 30 C atoms are replaced (terminal CH3 groups are understood as CH ₂ groups in the sense of CH ₂ - H .) And R ¹ to R ^{7 may} be substituted so that optionally between R ² and R ³ , R ⁴ and R ³ , R ⁶ and R ⁷ , R ¹ and R ⁴ / R ⁵ , R ⁴ / R ⁵ and R ⁶ / R ⁷ or R ² / R ³ and R ⁶ / R ^{7 forms} a ring. General Group Definition: Within the specification and claims, general groups such as: alkyl, alkoxy, aryl, etc. are claimed and described. Unless otherwise specified, the following groups within the generically described groups are preferably used in the context of the present invention: alkyl: linear and branched C 1 -C 8 -alkyls, long-chain alkyls: linear and branched C 5 -C 20 -alkyls alkenyl: C 2 -C 6 -alkenyl , cycloalkyl: C 3 -C 8 -cycloalkyl, alkoxy: C 1 -C 6 -alkoxy, long-chain alkoxy: linear and branched C5-C20 alkoxyalkylenes: selected from the group comprising:

methylene; l, l-ethylene; l, 2-ethylene; l, l-propylidene; l, 2-propylene; 1,3-propylene; 2,2-propylidenes; butan-2-ol-l, 4-diyl; propan-2-ol-l, 3-diyl; 1, 4-butylenes; cyclohexane-l, l-diyl; cyclohexane-l, 2-diyl; cyclohexane-1,3-diyl; cyclohexane-l, 4-diyl; cyclopentane-l, l-diyl;

cyclopentane-l, 2-diyl; and cyclopentane-1,3-diyl, aryl: selected from aromatics having a molecular weight below 300Da arylenes: selected from the group consisting of: 1,2-phenylenes; 1,3-phenylenes; 1,4-phenylenes; l, 2-naphtalenylene; l, 3-naphtalenylene; 1,4-naphthalenylenes; 2,3-naphtalenylene; l-hydroxy-2,3-phenylene; 1-hydroxy-2,4-phenylene; 1-hydroxy-2,5-phenylene; and 1-hydroxy-2,6-phenylene, heteroaryl: selected from the group consisting of: pyridinyl; pyrimidinyl; pyrazinyl; triazolyl; pyridazinyl; l, 3,5-triazinyl; chinoninyl; isochinoninyl; quinoxalinyl; imidazolyl; pyrazolyl; benzimidazolyl; thiazolyl; oxazolidinyl; pyrrolyl; thiophenyl; benzothiophenyl, furyl, benzofuryl, carbazolyl; indolyl; and isoindolyl, wherein the heteroaryl may be linked to the compound via any atom in the ring of the selected heteroaryl. heteroarylenes: selected from the group comprising: pyridinediyl; quinolindiyl; pyrazodiyl; pyrazoldiyl; triazolediyl; pyrazinediyl, thiophenediyl; and imidazolediyl, where the

heteroarylenes as a bridge in the compound of any atom in the ring of the

selected heteroaryl, especially preferred are: pyridine-2, 3-diyl; pyridine-2, 4-diyl; pyridine-2, 5-diyl; pyridine-2, 6-diyl; pyridine-3,4-diyl; pyridine-3,5-diyl; quinoline-2, 3-diyl; quinolin-2,4-diyl; quinoline-2, 8-diyl; isoquinoline-1,3-diyl; isoquinoline-l, 4-diyl; pyrazole-1,3-diyl; pyrazole-3,5-diyl; triazole-3,5-diyl; triazole-1,3-diyl; pyrazin-2,5-diyl; and imidazole 2,4-diyl, thiophene-2,5-diyl, thiophene-3,5-diyl; a -CC-C6 heterocycloalkyl selected from the group comprising: piperidinyl; piperidines; 1, 4-piperazine, tetrahydrothiophene;

tetrahydrofuran; l, 4,7-triazacyclononanes; 1,4,8,11-tetraazacyclotetradecane; 1,4,7,10,13-pentaazacyclopentadecane; l, 4-diaza-7-thia-cyclononane; 1,4-diaza-7-oxa-cyclononanes;

1.4.7.10-tetraazacyclododecanes; l, 4-dioxane; 1,4,7-trithia-cyclononane; pyrrolidine; and tetrahydropyran, wherein the heteroaryl may be linked to the C 1 -C 6 alkyl via any atom in the ring of the selected heteroaryl. heterocycloalkylenes: selected from the group comprising: piperidin-1,2-ylene; piperidine-2,6-ylene; piperidin-4,4-ylidene; l, 4-piperazin-l, 4-ylene; l, 4-piperazin-2,3-ylene; 1,4-piperazine-2,5-ylene; l, 4-piperazin-2,6-ylene; l, 4-piperazin-1, 2-ylene; 1, 4-piperazine-1, 3-ylene; l, 4-piperazin-l, 4-ylene; tetrahydrothiophen-2,5-ylene; tetrahydrothiophen-3,4-ylene; tetrahydrothiophen-2,3-ylene; tetrahydrofuran-2,5-ylene; tetrahydrofuran-3,4-ylene;

tetrahydrofuran-2,3-ylene; pyrrolidin-2,5-ylene; pyrrolidine-3, 4-ylene; pyrrolidin-2,3-ylene; pyrrolidin-1,2-ylene; pyrrolidin-1, 3-ylene; pyrrolidin-2,2-ylidene; l, 4,7-triazacyclonon-1, 4-ylene; 1,4,7-triazacyclonon-2,3-ylene; l, 4,7-triazacyclonon-2,9-ylene; l, 4,7-triazacyclonon-3,8-ylene; 1, 4,7-triazacyclonon-2,2-ylidenes; 1, 4,8, 1-tetraazacyclotetradec-1,4-ylene;

 1.4.8.11- tetraazacyclotetradec-l, 8-ylene; 1,4,8,1-tetraazacyclotetradec-2,3-ylene; 1,4,8,11-tetraazacyclotetradec-2,5-ylene; 1,4,8,11-tetraazacyclotetradec-1,2-ylene; 1,4,8,11-tetraazacyclotetradec-2,2-ylidenes; 1, 4,7,10-tetraazacyclododec-1, 4-ylene; 1, 4,7,10-tetraazacyclododec-l, 7-ylene; 1,4,7,10-tetraazacyclododec-1,2-ylene; 1,4,7,10-tetraazacyclododec-2,3-ylene; 1,4,7,10-tetraazacyclododec-2,2-ylidenes; 1,4,7,10,13 pentaazacyclopentadec-1,4-ylene; 1,4,7,10,13-pentaazacyclopentadec-l, 7-ylene; 1,4,7,10,13-pentaazacyclopentadec-2,3-ylene; l, 4,7, l0, l3-pentaazacyclopentadec-l, 2-ylene; 1,4,7,10,13-pentaazacyclopentadec-2,2-ylidenes; l, 4-diaza-7-thia-cyclonon-l, 4-ylene; l, 4-diaza-7-thia-cyclonone-l, 2-ylene; 1,4-diaza-7thia-cyclonone-2,3-ylene; 1,4-diaza-7-thia-cyclonone-6,8-ylene; 1,4-diaza-7-thia-cyclonone-2,2-ylidenes; l, 4-diaza-7-oxacyclonon-l, 4-ylene; l, 4-diaza-

7-oxa-cyclonon-1, 2-ylene; l, 4diaza-7-oxa-cyclonon-2,3-ylene; l, 4-diaza-7-oxa-cyclonon-6,

8-ylene; l, 4-diaza-7-oxa-cyclonon-2,2-ylidene; l, 4-dioxan-2,3-ylene; 1,4-dioxan-2,6-ylene; 1, 4-dioxane-2,2-ylidenes; tetrahydropyran-2,3-ylene; tetrahydropyran-2,6-ylene; tetrahydropyran-2,5-ylene; tetrahydropyran-2,2-ylidenes; l, 4,7-trithia-cyclonon-2,3-ylene; 1, 4,7-trithia-cyclonone-2,9-ylene; and 1,4,7-trithia-cyclonon-2,2-ylidenes, heterocycloalkyl: selected from the group consisting of: pyrrolinyl; pyrrolidinyl;

morpholinyl; piperidinyl; piperazinyl; hexamethylene imine; l, 4-piperazinyl;

tetrahydrothiophenyl; tetrahydrofuranyl; 1,4,7-triazacyclononanyl; 1,4,8,11-tetraazacyclotetradecanyl; 1,4,7,10,13-pentaazacyclopentadecanyl; 1,4-diaza-7-thiacyclononanyl; 1,4-diaza-7-oxa-cyclononanyl; l, 4,7, l0-tetraazacyclododecanyl; 1,4-dioxanyl; 1,4,7-trithiacyclononanyl; tetrahydropyranyl; and oxazolidinyl, wherein the

Heterocycloalkyl with the compound on each atom in the ring of the selected

Heterocycloalkyls may be connected. amine: the group -N (R) 2 wherein each R is independently selected from: hydrogen; C1-C6-alkyl; Cl-C6-alkyl-C6H5; and phenyl, wherein when both R 'are C1-C6 alkyl, both R' can form a -NC3 to NC5 heterocyclic ring wherein the remaining alkyl chain forms an alkyl substituent on the heterocyclic ring. halogen: selected from the group consisting of: F; Cl; Br and I, haloalkyl: selected from the group consisting of mono-, di-, tri-, poly- and perhalogenated linear and branched C 1 -C 8 -alkyl pseudohalogen: selected from the group consisting of -CN, -SCN, -OCN, N 3, -CNO, -SeCN sulphonate: the group -S (O) 20R, wherein R is selected from: hydrogen; Cl-C6-alkyl; phenyl; Cl-C6-alkyl-C6H5; Li; N / A; K; Cs; mg; and Ca, sulphate: the group -0S (0) 20R, where R is selected from: hydrogen; Cl-C6-alkyl; phenyl; Cl-C6-alkyl-C6H5; Li; N / A; K; Cs; mg; and Ca, sulphone: the group -S (O) 2R, wherein R is selected from: hydrogen; C1-C6-alkyl; phenyl; Cl-C6-alkyl-C6H5 and amine (to give sulphonamide) selected from the group: - NR'2, wherein each R 'is independently selected from: hydrogen; Cl-C6-alkyl; ClC6-alkyl- C6H5; and phenyl, wherein when both R 'are C1-C6 alkyl, both R' can form a -NC3 to NC5 heterocyclic ring, wherein the remaining alkyl chain forms an alkyl substituent on the heterocyclic ring. carboxylate: the group -C (O) OR, where R is selected from: hydrogen; Cl-C6-alkyl; phenyl; Cl-C6-alkyl-C6H5; Li; N / A; K; Cs; mg; and Ca, carbonyl: the group -C (O) R, wherein R is selected from: hydrogen; Cl-C6-alkyl;

phenyl; Cl-C6-alkyl-C6H5 and amine (to give amide) selected from the group: -NR'2, wherein each R 'is independently selected from: hydrogen; Cl-C6-alkyl; Cl-C6-alkyl- C6H5; and phenyl, wherein when both R 'are C1-C6 alkyl, both R' can form a -NC3 to NC5 heterocyclic ring wherein the remaining alkyl chain forms an alkyl substituent on the heterocyclic ring phosphonates: the group -P (O) (OR) 2 wherein each R is independently selected from:

Hydrogen; Cl-C6-alkyl; phenyl; Cl-C6-alkyl-C6H5; Li; N / A; K; Cs; mg; and Ca, phosphates: the group -0P (0) (0R) 2, where each R is independently selected from:

Hydrogen; Cl-C6-alkyl; phenyl; Cl-C6-alkyl-C6H5; Li; N / A; K; Cs; mg; and Ca, phosphines: the group -P (R) 2, wherein each R is independently selected from: hydrogen; Cl-C6-alkyl; phenyl; and C1-C6-alkyl-C6H5, phosphine oxide: the group -P (O) R2, wherein R is independently selected from: hydrogen; Cl-C6-alkyl; phenyl; and C 1 -C 6 -alkyl-C 6 H 5; and amines (to give phosphonamidate) selected from the group: -NR'2, where each R 'is independently selected from:

Hydrogen; Cl-C6-alkyl; Cl-C6-alkyl-C6H5; and phenyl, wherein when both R 'are C1-C6 alkyl, both R' can form a -NC3 to NC5 heterocyclic ring wherein the remaining alkyl chain forms an alkyl substituent on the heterocyclic ring. polyethers: selected from the group consisting of - (0-CH ₂ -CH (R)) _n -0H and - (0-CH ₂ - CH (R)) _n -H wherein R is independently selected from: hydrogen, alkyl, aryl , halogen and n is from 1 to 250 silylalkyl: the group -S1R3 wherein each R is independently selected from: hydrogen; C1-C6-alkyl; phenyl; Cl-C6-alkyl-C6H5 and amine (to give sulphonamide) selected from the group: -NR'2, where each R 'is independently selected from:

Hydrogen; Cl-C6-alkyl; CLC6-alkyl-C6H5; and phenyl, wherein when both R 'are C1-C6 alkyl, both R' can form a -NC3 to NC5 heterocyclic ring wherein the remaining alkyl chain forms an alkyl substituent on the heterocyclic ring silylalkyloxy: the group -OS1R3, each R independently selected is made of: hydrogen; C1-C6-alkyl; phenyl; Cl-C6-alkyl-C6H5 and amine (to give

sulphonamides) selected from the group: -NR'2, where each R 'is independently selected from: hydrogen; Cl-C6-alkyl; CLC6-alkyl-C6H5; and phenyl, wherein when both R 'are C1-C6 alkyl, both R' can form a -NC3 to NC5 heterocyclic ring wherein the remaining alkyl chain forms an alkyl substituent on the heterocyclic ring

Unless otherwise stated, the following groups are more preferred groups within the general group definition: alkyl: linear and branched C 1 -C 6 -alkyl, long-chain alkyls: linear and branched C5-C10 alkyl, preferably C6-C8 alkyls alkenyl: C3-C6 alkenyl, cycloalkyl: C6-C8-cycloalkyl, alkoxy: C1-C4 alkoxy, long-chain alkoxy: linear and branched C5-C10 alkoxy , preferably linear C 6 -C 8 alkoxyalkylenes: selected from the group comprising: methylenes; l, 2-ethylene; l, 3-propylene; butan-2-ol-l, 4-diyl; l, 4-butylene; cyclohexane-l, l-diyl; cyclohexane-l, 2-diyl; cyclohexane-1, 4-diyl; cyclopentane-l, l-diyl; and cyclopentane-1,2-diyl, aryl: selected from the group consisting of: phenyl; biphenyl; naphthyl; anthracenyl; and phenanthrenyl, arylenes: selected from the group comprising: 1, 2-phenylenes; 1,3-phenylenes; 1,4-phenylenes; l, 2-naphtalenylene; l, 4-naphtalenylene; 2,3-naphthalenylenes and 1-hydroxy-2,6-phenylenes, heteroaryl: selected from the group comprising:

pyridinyl; pyrimidinyl; chinoninyl; pyrazolyl; triazolyl; isochinoninyl; imidazolyl; and oxazolidinyl, wherein the heteroaryl may be linked to the compound via any atom in the ring of the selected heteroaryl, heteroarylenes: selected from the group comprising: pyridine, 2,3-diyl; pyridin-2,4-diyl; pyridin-2,6-diyl; pyridine-3,5-diyl; quinolin-2,3-diyl; quinolin-2,4-diyl; isoquinoline-l, 3-diyl; isoquinoline-l, 4-diyl; pyrazol-3,5-diyl; and imidazole-2,4-diyl, heterocycloalkyl: selected from the group comprising:

pyrrolidinyl; morpholinyl; piperidinyl; piperidinyl; 1,4-piperazinyl; tetrahydrofuranyl; 1,4,7-triazacyclononanyl; 1,4,8,1-tetraazacyclotetradecanyl; 1,4,7,10,13-pentaazacyclopentadecanyl; 1,4,7, 10-tetraazacyclododecanyl; and piperazinyl, wherein the heteroaryl may be linked to the compound via any atom in the ring of the selected heteroaryl heterocycloalkylene: selected from the group comprising:

piperidin-2,6-ylene; piperidin-4,4-ylidene; l, 4-piperazin-l, 4-ylene; l, 4-piperazin-2,3-ylene;

1, 4-piperazine-2,6-ylene; tetrahydrothiophen-2,5-ylene; tetrahydrothiophen-3,4-ylene;

tetrahydrofuran-2,5-ylene; tetrahydrofuran-3,4-ylene; pyrrolidin-2,5-ylene; pyrrolidine-2,2-ylidenes; l, 4,7-triazacyclonon-1, 4-ylene; l, 4,7-triazacyclonon-2,3-ylene; 1,4,7-triazacyclonon-2,2-ylidenes; 1,4,8,11-tetraazacyclotetradec-1,4-ylene; 1,4,8,11-tetraazacyclotetradec-l, 8-ylene; 1,4,8,1-tetraazacyclotetradec-2,3-ylene; 1,4,8,11-tetraazacyclotetradec-2,2-ylidenes; 1, 4,7,10-tetraazacyclododec-1, 4-ylene; 1, 4,7,10-tetraazacyclododec-1, 7-ylene; 1, 4,7,10-tetraazacyclododec-2,3-ylene; 1, 4, 7, 10-tetraazacyclododec-2,2-ylidenes; 1,4,7,10,13-pentaazacyclopentadec-1,4-ylene; 1,4,7,10,13-pentaazacyclopentadec-l, 7-ylene; l, 4-diaza-7-thia-cyclonone-1,4-ylene; 1,4-diaza-7-thia-cyclonon-2,3-ylene; l, 4-diaza-7-thie in cyclonon-2,2-ylidenes; 1,4-diaza-7-oxa-cyclonon-1, 4-ylene; 1,4-diaza-7-oxa-cyclonon-2,3-ylene; 1,4-diaza-7-oxa-cyclonone-2,2-ylidenes; 1,4-dioxan-2,6-ylene; l, 4-dioxan-2,2-ylidene; tetrahydropyran-2,6-ylene; tetrahydropyran-2,5-ylene; and tetrahydropyran-2,2-ylidenes, a -CC-C6-alkyl-heterocycloalkyl, wherein the heterocycloalkyl is selected from the group consisting of: piperidinyl; l, 4-piperazinyl;

tetrahydrofuranyl; 1,4,7-triazacyclononanyl; 1,4,8,1-tetraazacyclotetradecanyl; 1,4,7,10, 13-pentaazacyclopentadecanyl; 1,4,7, 10-tetraazacyclododecanyl; and pyrrolidinyl, wherein the Heterocycloalkyl may be joined to the compound via any atom in the ring of the selected heterocycloalkyl amine: the group -N (R) 2, wherein each R is independently selected from: hydrogen; Cl-C6-alkyl; and benzyl, halogen: selected from the group consisting of: F and Cl, sulphonates: the group -S (O) 20R, wherein R is selected from: hydrogen; Cl-C6-alkyl;

N / A; K; mg; and Ca, sulphate: the group -0S (0) 20R, wherein R is selected from: hydrogen; Cl-C6-alkyl; N / A; K; mg; and Ca, sulphone: the group -S (O) 2R, wherein R is selected from: hydrogen; C1-C6-alkyl;

benzyl and amines selected from the group: -NR'2, wherein each R 'is independently selected from: hydrogen; Cl-C6-alkyl; and benzyl, carboxylate: the group -C (O) OR wherein R is selected from hydrogen; N / A; K; mg; Ca; Cl-C6-alkyl; and benzyl, carbonyl: the group: -C (O) R, wherein R is selected from: hydrogen; Cl-C6-alkyl; benzyl and amines selected from the group: -NR'2, wherein each R 'is independently selected from: hydrogen; Cl-C6-alkyl; and benzyl, phosphonates: the group -P (O) (OR) 2, wherein each R is independently selected from:

Hydrogen; Cl-C6-alkyl; benzyl; N / A; K; mg; and Ca, phosphates: the group -OP (O) (OR) 2, where each R is independently selected from:

Hydrogen; Cl-C6-alkyl; benzyl; N / A; K; mg; and Ca, phosphines: the group -P (R) 2, wherein each R is independently selected from: hydrogen; Cl-C6-alkyl; and benzyl, phosphine oxide: the group -P (O) R2, wherein R is independently selected from: hydrogen; Cl-C6-alkyl; benzyl and amines selected from the group: -NR'2, wherein each R 'is independently selected from: hydrogen; Cl-C6-alkyl; and benzyl. polyethers: selected from the group enthaltend- (0-CH ₂ -CH (R)) _n -OH and - (0-CH ₂ - CH (R)) _n -H wherein R is independently selected from: hydrogen, methyl, halogen and n is from 5 to 50, preferably 10 to 25. M, M _n (n is an integer): metals wherein two metals M are independently selected, unless otherwise indicated.

According to a preferred embodiment of the invention, the catalyst comprises at least one N-heterocyclic carbene ligand of the following structure:

wobei R¹ bis R³ unabhängig voneinander Alkyl, langkettiges Alkyl, Alkoxy, langkettiges Alkoxy, Cycloalkyl, Halogenalkyl, Aryl, Halogenaryl, Heteroaryl, Heterocycloalkylene,

in which R ¹ to R ³ independently of one another are alkyl, long-chain alkyl, alkoxy, long-chain alkoxy, cycloalkyl, haloalkyl, aryl, haloaryl, heteroaryl, heterocycloalkylene,

Heterocycloalkyl, haloheteroaryl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, ketoaryl, haloketoaryl, ketoheteroaryl, ketoalkyl, haloketoalkyl, silylalkyl,

Silylalkyloxy, with suitable radicals one or more non-adjacent CH ₂ groups independently of one another by -O-, -S-, -NH-, -NR ° -, -SiR ° R °° -, -CO-, -COO-, -OCO-, -OCO-O-, -SO2-, -S-CO-, -CO-S-, -CY ^ CY ² or -C = C- may be replaced in such a manner that O and / or S atoms are not directly connected to one another, likewise optionally with aryl or heteroaryl preferably containing 1 to 30 C atoms are replaced (terminal CH3 groups are understood as CH ₂ groups in the sense of CH ₂ -H).

R ⁴ to R ⁷ independently of one another are hydrogen, alkyl, long-chain alkyl, alkoxy, long-chain alkoxy, cycloalkyl, haloalkyl, aryl, haloaryl, heteroaryl,

Heterocycloalkylenes, heterocycloalkyl, haloheteroaryl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, ketoaryl, haloketoaryl, ketoheteroaryl, ketoalkyl,

Haloalkyl, silylalkyl, silylalkyloxy, where, with suitable radicals, one or more non-adjacent CH ₂ groups independently of one another by -O-, -S-, -NH-, -NR ° -, -SiR ° R °° -, -CO-, -COO-, -OCO-, -OCO-O-, -S0 ₂ -, -S CO-, -CO-S-, -CY ^ CY ² or -C = C- may be replaced such that O and / or S atoms are not directly connected to one another, likewise optionally with aryl or heteroaryl preferably containing 1 to 30 C atoms are replaced (terminal CH3 groups are understood as CH ₂ groups in the sense of CH ₂ - H .) And R ¹ to R ^{7 may} be substituted so that optionally between R ² and R ³ , R ¹ and R ² / R ³ or R ² / R ³ and R ⁷ or R ⁶ and R ⁷ or R ⁵ and R ⁶ or R ⁴ and R ^{5 forms} a ring.

These two previous N-heterocyclic carbene ligands are particularly preferred. According to a preferred embodiment of the invention, the catalyst comprises at least one N-heterocyclic carbene ligand of the following structure:

wobei

in which

R ¹ or R ² may be either a substituted or unsubstituted carbon or a nitrogen (but R ¹ and R ^{2 are} not both nitrogen), where the substitutions are selected from (independently of one another) alkyl, long-chain alkyl, alkoxy, long-chain alkoxy, Cycloalkyl, haloalkyl, aryl, haloaryl, heteroaryl,

Heterocycloalkylenes, heterocycloalkyl, haloheteroaryl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, ketoaryl, haloketoaryl, ketoheteroaryl, ketoalkyl,

Halo-ketoalkyl, silylalkyl, silylalkyloxy, where suitable radicals include one or more non-adjacent CH ₂ groups independently of one another by -O-, -S-, -NH-, - NR ° -, -SiR ° R °° -, -CO-, -COO-, -OCO-, -OCO-O-, -S0 ₂ -, -S CO-, -CO-S-, -CY ^ CY ² or - C = C- may be replaced such that O and / or S atoms are not directly connected to one another, likewise optionally with aryl or heteroaryl preferably containing 1 to 30 C atoms are replaced (terminal CH3 groups are understood as CH ₂ groups in the sense of CH ₂ - H .)

R ³ and R ⁴ are each independently alkyl, long-chain alkyl, alkoxy, long-chain alkoxy, cycloalkyl, haloalkyl, aryl, haloaryl, heteroaryl, heterocycloalkylene,

Heterocycloalkyl, haloheteroaryl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, ketoaryl, haloketoaryl, ketoheteroaryl, ketoalkyl, haloketoalkyl, silylalkyl,

Silylalkyloxy, with suitable radicals one or more non-adjacent CH ₂ groups independently of one another by -O-, -S-, -NH-, -NR ° -, -SiR ° R °° -, -CO-, -COO- , -OCO-, -OCO-O-, -SO ₂ -, -S-CO-, -CO-S-, -CY ^ CY ² or -C = C- can be replaced in such a way that O and / or S atoms are not directly connected to each other, also optionally with aryl or heteroaryl preferably containing 1 to 30 C atoms are replaced (terminal CH3 groups are understood as CH ₂ groups in the sense of CH ₂ -H.) The bond between R ¹ and R ^{2 may be} a single or double bond and R ¹ and R ³ on the one hand and / or R ² and R ⁴ on the other hand may be substituted so that between R ¹ and R ³ or R ² and R ^{4 is} a ring forms.

According to a preferred embodiment, the catalyst comprises an N-heterocyclic carbene ligand of the following structure:

wobei R³ und R⁴ wie beim vorigen Katalysator definiert sind, R⁵ und R⁶ unabhängig voneinander Wasserstoff, Alkyl, langkettiges Alkyl, Alkoxy, langkettiges Alkoxy,

wherein R ³ and R ⁴ are defined as in the previous catalyst, R ⁵ and R ^{6 are} independently hydrogen, alkyl, long-chain alkyl, alkoxy, long-chain alkoxy,

Cycloalkyl, haloalkyl, aryl, haloaryl, heteroaryl, heterocycloalkylene,

Heterocycloalkyl, haloheteroaryl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, ketoaryl, haloketoaryl, ketoheteroaryl, ketoalkyl, haloketoalkyl, silylalkyl,

Silylalkyloxy, where suitable radicals are one or more non-adjacent CH ₂ groups independently of one another by -O-, -S-, -NH-, -NR ° -, -SiR ° R °° -, -CO-, -COO-, -OCO-, -OCO-O-, -S0 ₂ -, -S-CO-, -CO-S-, -CY ^ CY ² or -C = C- can be replaced in such a way that O and / or S atoms are not directly connected to one another, likewise optionally with aryl or heteroaryl preferably containing 1 to 30 C atoms are replaced (terminal CH3 groups are understood as CH ₂ groups in the sense of CH ₂ -H). and the bond between the ring carbons may be a single or double bond. According to a preferred embodiment of the invention, the catalyst comprises at least one N-heterocyclic carbene ligand of the following structure:

wobei R³, R⁴ und R⁵ wie beim vorigen Katalysator definiert sind.

wherein R ³ , R ⁴ and R ⁵ are defined as in the previous catalyst.

According to a preferred embodiment of the invention, the catalyst comprises at least one N-heterocyclic carbene ligand of the following structure:

R ¹ or R ² may be either a substituted or unsubstituted carbon or a nitrogen (but where R ¹ and R ^{2 are} not both nitrogen)

wherein the bond between R ¹ and R ^{2 may be} a single or double bond wherein R ⁷ , R ⁸ , R ⁹ and R ^{10 are} independently hydrogen, alkyl, long-chain alkyl, alkoxy, long-chain alkoxy, cycloalkyl, haloalkyl, aryl, haloaryl, Heteroaryl, heterocycloalkylene, heterocycloalkyl, haloheteroaryl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, ketoaryl, haloketoaryl, ketoheteroaryl, ketoalkyl,

Haloalkyl, silylalkyl, silylalkyloxy may be konen, where suitable radicals one or a plurality of non-adjacent CH ₂ groups independently of one another by -O-, -S-, -NH-, -NR ° -, -SiR ° R °° -, -CO-, -COO-, -OCO-, -OCO -O-, -S0 ₂ -, -S CO-, -CO-S-, -CY ^ CY ² or - C = C- can be replaced in such a way that O and / or S atoms are not directly connected to each other , optionally also with aryl or heteroaryl preferably containing 1 to 30 C atoms are replaced (terminal CH3 groups are understood as CH ₂ groups in the sense of CH ₂ - H).)

According to a preferred embodiment of the invention, the catalyst comprises at least one N-heterocyclic carbene ligand of the following structure:

wobei R⁷ und R⁹ wie beim vorigen Katalysator definiert sind und Xi und X₂ unabhängig voneinander O, NH oder CH₂ sein können.

wherein R ⁷ and R ⁹ are defined as in the previous catalyst and Xi and X _{2 can} independently be O, NH or CH ₂ .

 According to a preferred embodiment of the invention, the catalyst comprises at least one further ligand on rhodium, preference being given to labile ligands. These are understood to mean ligands whose bonding to the rhodium is so weak that, if appropriate, they are at least temporarily not bound to the rhodium in the course of the reaction.

Preferred such labile ligands are dialkens, preferably COD, or norbornadiene, or alternatively to dialkenene, two ethylenes. Further possible ligands are

Carbonyl compounds, two chloride compounds, acetylacetonate, hydride ligands, halogen ligands, in particular chloride, or two phosphine compounds.

The amount of catalyst before the beginning of the reaction is preferably from> 0.001 mol% to <10 mol% (based on the aromatic precursor substance at the beginning of the reaction) preferably> 0.05 mol% to <5 mol%, more preferably> 0.1 mol% to <3 mol%, and most preferably> 0.2 mol% to <1 mol%. It has been found that even with these relatively small amounts of catalyst, nevertheless, the reaction can often be carried out in high yield.

Preferably, the process is carried out in an organic solvent, have proven particularly useful in practice (and are therefore preferred): methanol, THF, 2-methyl-THF, l, 4-dioxane or mixtures of these solvents. Particularly preferred are THF and 2-methyl-THF.

The process is preferably carried out at a temperature of> 0 ° C. The upper limit is basically limited only by the boiling point of the solvent used. Even more preferred are temperatures from> 10 ° C to <50 ° C, most preferred

Room temperature, ie> 20 ° C to <40 ° C

In the event that gaseous hydrogen is used as the reducing agent, the preferred H ₂ pressure (at the beginning of the reaction)> 3 bar, more preferably ranges from> 10 bar to <150 bar.

The reaction is preferably carried out for a reaction time of> 3h to <2d, particularly preferred reaction times are> 5h to <30h.

Preferably, the reaction is carried out in the presence of an additive selected from the group boranes and silanes. It has been found that so often the yield can be increased even further.

The additive is preferably used in a ratio to the precursor substance of> 0.1: 1 to <10: 1 (mokmol), preferably> 1: 1 to <4: 1 (mokmol). The additive is either a borane or a silane, with boranes being preferred.

Preferred boranes are dialkylborohydrides and / or dioxaborolanes, where

Dioxaborolanes are preferred. Preferably, the additive is selected from the group containing pinacolborane (4,4,5,5-tetramethyl-l, 3,2-dioxaborolane), catecholborane, 9-BBN.

Preferred silanes are silanes of the structure R ¹ R ² SiH ₂ , where R ¹ and R ^{2 are selected} independently of one another from alkyl or aryl. R ¹ is preferably alkyl and R ^{2 is} aryl.

Preferably, the reaction is carried out in the presence of a Lewis acid, preferably a Lewis acid, which has dehydrating properties. It has been found that so often the yield can be increased even further. Preferred additives are selected from the group comprising molecular sieve, preferably molecular sieve 4 A and 3 A,

Aluminum triisopropylate and mixtures thereof.

The ratio of additive to educt (before the reaction) of from> 10 to <200 mg per 1 mmol of starting material is preferred

The above-mentioned and the claimed and described in the embodiments described components to be used in their size, shape design, material selection and technical design are not subject to any special conditions, so that the well-known in the field of application selection criteria can apply without restriction.

Further details, features and advantages of the subject matter of the invention will become apparent from the subclaims and from the following description of the accompanying examples, in which - by way of example - several embodiments of the method according to the invention are shown. General Procedure I:

A reaction-dried oven at 135 ° C (depending on the amount of solvent used either a 9 mL screw-cap vial (to 4 mL) or a 50 mL glass cylinder) filled with magnetic stirrer was allowed to cool under vacuum and washed with powdered activated 4 A molecular sieve (50 mg) catalyst ( 0.50 to 3.0 mol%) and solid starting material (1.0 mmol) - if the educt used is solid - filled in air. The atmosphere in the vial was exchanged with argon via a septum (3 x vacuum / argon cycle). After addition of tetrahydrofuran (1 mL, 1 M) and then gg. Liquid, over calcium hydride distilled starting material (1.0 mmol) - if the reactant used is liquid - and 4,4,5,5-tetramethyl-l, 3, 2-dioxaborolane (HBpin, 2.0-0.4.0 mmol, 2.0-4.0 equiv.) Was transferred under argon to the vessel under argon atmosphere in a 150 mL steel autoclave under argon atmosphere, during which the autoclave cap was opened and the Autoclave was held under an inert gas by means of an argon-flowed hose. The atmosphere in the autoclave was exchanged with hydrogen gas (3 × 10 bar hydrogen pressure / unloading cycle), before 50 bar hydrogen pressure was adjusted and the mixture was stirred for 24 h at the indicated temperature (25 ° C or 40 ° C) in a metal block ( the specified temperature is that of the metal block). After carefully releasing the pressure, dichloromethane (0.5 mL) and trifluoroacetic anhydride (3.0 mmol, 3.0 equiv.) Were added to the reaction mixture and stirred at room temperature for 10 minutes. In an alternative procedure, di- / e / 7-butyl dicarbonate (3.0 mmol, 3.0 equiv.) And triethylamine (3.0 mmol, 3.0 equiv.) Were added to the mixture and stirred for 2 h at room temperature. In both cases, the mixture was subsequently filtered through a glass frit, the residue being washed with ethyl acetate (2 × 5 ml). The combined filtrate was concentrated on a rotary evaporator and purified by column chromatography (silica gel, pentane / ethyl acetate or

Pentane / dichloromethane). The indicated diastereoselectivities were determined by GC MS, GC FID or from the ¹⁹ F NMR spectrum determined directly after the reaction. Based on the general procedure, the following fluorinated heterocyclic aliphatic compounds were prepared, each containing the following catalyst: ((2- (2,6-diisopropylphenyl) -3,3-dimethyl-2-azaspiro [4.5] decan-1-ylidene) (cyclooctadienyl) rhodium (I) chloride) was used:

The results are given in the following table:

 Furthermore, using the above procedure I, various catalysts were tested whose structure and yield (determined according to NMR) are indicated below:

Furthermore, further additives were tested whose structure and yield are shown below:

10% NMR yield 34% NMR yield 12% NMR yield The individual combinations of the constituents and the features of the already mentioned embodiments are exemplary; the exchange and substitution of these teachings with other teachings contained in this document with the references cited are also expressly contemplated. The person skilled in the art recognizes that variations, Modifications and other embodiments described herein may also occur without departing from the spirit and scope of the invention. Accordingly, the above description is illustrative and not restrictive. The word "comprising" used in the claims does not exclude other ingredients or steps. The indefinite article "a" does not exclude the meaning of a plural. The mere fact that certain measures are recited in mutually different claims does not make it clear that a combination of these dimensions can not be used to advantage. The scope of the invention is defined in the following claims and the associated equivalents.

Claims

Patent claims 1. A process for preparing fluorinated heterocyclic aliphatic  A compound comprising the step of hydrogenating a heteroaromatic fluorochemical precursor with a catalyst comprising at least one rhodium atom in the presence of a reducing agent. 2. The method of claim 1, wherein the catalyst comprises rhodium with at least one labile ligand. 3. The method of claim 2, wherein the labile ligands are selected from the group consisting of alkenes, cyclic bisalkenes, halides, triflates, acetonitrile, weakly coordinating anions such as tetrafluoroborate or phosphines 4. The method according to any one of claims 1 to 3, wherein the catalyst  comprises at least one N-heterocyclic carbene ligand. 5. The method according to any one of claims 1 to 4, wherein the hydrogenation in  Presence of an additive is carried out selected from the group boranes and silanes. 6. The method according to any one of claims 1 to 5, wherein the hydrogenation in  Presence of a Lewis acid is performed. 7. The method according to any one of claims 1 to 6, wherein the amount of catalyst prior to the start of> 0.05 mol% to <5 mol% (based on the aromatic precursor substance at the beginning of the reaction). 8. The method according to any one of claims 1 to 7, wherein the method is carried out in an organic solvent. 9. The method according to any one of claims 1 to 8, wherein the method is carried out at a temperature of> 0 ° C. 10. The method according to any one of claims 1 to 9, wherein the method under Use of gaseous hydrogen is carried out as a reducing agent and the H ₂ pressure (at the beginning of the reaction) is> 10 bar.