Preparation of nitriles

Abstract

A process for the preparation of aromatic or heteroaromatic nitriles is described.

Description

[0001] The present invention describes a method for preparing aromatic or heteroaromatic nitriles.

[0002] Aromatic or heteroaromatic nitriles are important compounds in organic synthesis and are widely used in multiple fields. For example, these compounds can be used as intermediates in the production of drugs or materials for electronic devices.

[0003] A reliable method for synthesizing from aryl halides is palladium-catalyzed cyanation using Zn(CN)2. From the perspective of "green chemistry", this process is rather harsh because it generates zinc waste that is toxic to the environment and uses highly toxic metal cyanides. In addition to methods using metal cyanides, nitriles can also be prepared from the corresponding amides by dehydration reactions. Generally, this transformation requires heating, drying, and harsh conditions using reagents such as dangerous phosphorus pentoxide or oxalyl chloride.

[0004] An improved method for preparing aromatic or heteroaromatic nitriles involves dehydrating amides through a palladium-catalyzed water-shuffle reaction, as described by Maffioli et al. (Org. Lett. 2005, 7, 5237 - 5339), using 10 mol% PdCl2 in an aqueous acetonitrile solution (70 equivalents of CH3CN).

[0005] Although the above methods can be used to prepare aromatic or heteroaromatic nitriles, there is still a need for improvement, especially in terms of cost efficiency, particularly in terms of yield, safety, and the environment.

[0006] An object of the present invention is to provide a method for preparing aromatic or heteroaromatic nitriles with high cost efficiency, high safety, and environmentally friendly standards.

[0007] In particular, the method should have a high yield. In addition, the method should provide the product without forming a large amount of by-products. In addition, the method should be achievable without using expensive materials that are not recyclable. In addition, the method should avoid using or by-producing compounds that are harmful to the environment.

[0008] Surprisingly, it has been found that a specific method for producing aromatic or heteroaromatic nitrile compounds, which will be defined in more detail below, has improvements compared to the prior art, especially in terms of cost efficiency and environmental considerations.

[0009] The method of the present invention is cost-effective because it provides improved yields without using expensive compounds. In addition, the method provides improvements in terms of environmental friendliness. The method offers other advantages in industrial facilities.

[0010] Accordingly, the present invention provides a method for producing aromatic or heteroaromatic nitrile compounds, the method comprising the following steps:

[0011] A) Provide an aromatic or heteroaromatic primary amide;

[0012] B) Provide an aliphatic or heteroaliphatic nitrile; and

[0013] C) Mix the aromatic or heteroaromatic primary amide with the aliphatic or heteroaliphatic nitrile; and

[0014] D) React the aromatic or heteroaromatic primary amide with the aliphatic or heteroaliphatic nitrile using a Pd catalyst to obtain an aromatic or heteroaromatic nitrile compound;

[0015] wherein the reaction of the aromatic or heteroaromatic primary amide with the aliphatic or heteroaliphatic nitrile is carried out using an acid.

[0016] In step A), an aromatic or heteroaromatic primary amide is provided. The aromatic or heteroaromatic primary amide is not limited and is known in the prior art.

[0017] Preferably, the aromatic or heteroaromatic primary amide provided in step A) is an amide compound according to formula (I),

[0018]

[0019] wherein

[0020] Ar is an aromatic ring system having 6 to 40 aromatic ring atoms or a heteroaromatic ring system having 5 to 40 aromatic ring atoms, each aromatic or heteroaromatic ring system being optionally substituted by one or more R 1 groups;

[0021] R 1 is the same or different in each case and is H, D, F, Cl, Br, I, C(=O)R 2 , CN, Si(R 2 )3, N(R 2 )2, C(=O)N(R 2 )2, P(=O)(R 2 )2, OR 2 , S(=O)R 2 , S(=O)2R 2 , a straight-chain alkyl, alkoxy or thioalkoxy group having 1 to 40 carbon atoms or a branched or cyclic alkyl, alkoxy or thioalkoxy group having 3 to 40 carbon atoms, each group being optionally substituted by one or more R 2 groups, wherein one or more non-adjacent CH2 groups may be replaced by -R 2 C=CR 2 -, -C≡C-, Si(R 2 )2, C=O, C=S, C=NR 2, -C(=O)O-, -C(=O)NR 2 -, NR 2 , P(=O)(R 2 ), -O-, -S-, SO or SO2, and one or more hydrogen atoms may be replaced by D, F, Cl, Br, I, CN or NO2, or an aromatic or heteroaromatic ring system having 5 to 40 aromatic ring atoms, each aromatic or heteroaromatic ring system may be substituted by one or more R 2 groups, or an aryloxy or heteroaryloxy group having 5 to 40 aromatic ring atoms, each aryloxy or heteroaryloxy group may be substituted by one or more R 2 groups, or a combination of these systems; simultaneously, two or more adjacent R 1 substituents may also form a ring system with each other, preferably a monocyclic or polycyclic aliphatic or aromatic ring system;

[0022] R 2 is the same or different in each case and is H, D, F, Cl, Br, I, CN or an aliphatic hydrocarbon group having 1 to 20 carbon atoms, one or more hydrogen atoms of which may be replaced by D or F, or an aromatic or heteroaromatic ring system having 5 to 30 carbon atoms, one or more hydrogen atoms of which may be replaced by D or F; simultaneously, two or more adjacent R 2 substituents may also form a ring system together, preferably a monocyclic or polycyclic aliphatic or aromatic ring system.

[0023] Ar is an aromatic or heteroaromatic ring system having 5 to 40 aromatic ring atoms, preferably 6 to 18 aromatic ring atoms, more preferably an aromatic ring system having 6 to 12 aromatic ring atoms or a heteroaromatic ring system having 5 to 12 aromatic ring atoms, each ring system may be substituted by one or more R 1 wherein R 1 may have the definition given above, especially in formula (I).

[0024] Examples of suitable Ar groups are selected from phenyl, o-, m- or p-biphenyl, terphenyl, especially branched terphenyl, quaterphenyl, especially branched quaterphenyl, 1-, 2-, 3- or 4-fluorenyl, 1-, 2-, 3- or 4-spirobifluorenyl, pyridyl, pyrimidinyl, 1-, 2-, 3- or 4-dibenzofuranyl, 1-, 2-, 3- or 4-dibenzothiophenyl and 1-, 2-, 3- or 4-carbazolyl, each group may be substituted by one or more R 1 groups.

[0025] Preferably, the symbol Ar represents an aryl or heteroaryl group such that the aromatic or heteroaromatic group of the aromatic or heteroaromatic ring system is directly (i.e., via the atoms of the aromatic or heteroaromatic group) connected to the corresponding atoms of other groups (such as R 1(bonded to a carbon, nitrogen or phosphorus atom of the group).

[0026] Adjacent carbon atoms in the context of the present invention are carbon atoms directly bonded to each other. In addition, "adjacent groups" in the definition of a group means that these groups are bonded to the same carbon atom or adjacent carbon atoms. These definitions apply accordingly in particular to the terms "adjacent groups" and "adjacent substituents".

[0027] In the context of this specification, the expression "two or more groups may together form a ring" should be understood to mean in particular that two groups are connected to each other by a chemical bond, with the formal elimination of two hydrogen atoms. This is illustrated by the following scheme:

[0028] .

[0029] However, in addition, the above expression should also be understood to mean that if one of the two groups is hydrogen, the second group combines with the position to which the hydrogen atom is bonded, thereby forming a ring. This is illustrated by the following scheme:

[0030] .

[0031] Fused aryl groups in the context of the present invention are groups in which two or more aromatic groups are fused to each other along a common edge (i.e., ring fusion), such that, for example, two carbon atoms belong to at least two aromatic or heteroaromatic rings, as is the case in naphthalene. In contrast, for example, fluorene is not a fused aryl group in the context of the present invention because the two aromatic groups in fluorene do not have a common edge.

[0032] Aryl groups in the context of the present invention contain 6 to 40 carbon atoms, preferably 6 to 24 C atoms; heteroaryl groups in the context of the present invention contain 2 to 40 carbon atoms, preferably 2 to 24 C atoms and at least one heteroatom, provided that the sum of the carbon atoms and heteroatoms is at least 5. The heteroatoms are preferably selected from N, O and / or S. An aryl group or heteroaryl group is understood herein to mean a simple aromatic ring, i.e., benzene, or a simple heteroaromatic ring, such as pyridine, pyrimidine, thiophene, etc., or a fused aryl or heteroaryl group, such as naphthalene, anthracene, phenanthrene, quinoline, isoquinoline, etc.

[0033] An aromatic ring system in the context of the present invention contains from 6 to 60 carbon atoms in the ring system. A heteroaromatic ring system in the context of the present invention contains from 1 to 40 carbon atoms and at least one heteroatom in the ring system, provided that the sum of the carbon atoms and the heteroatoms is at least 5. The heteroatoms are preferably selected from N, O and / or S. An aromatic or heteroaromatic ring system in the context of the present invention is to be understood as referring to the following systems: which do not have to contain only aryl or heteroaryl groups, but in which two or more aryl or heteroaryl groups can also be interrupted by non-aromatic units (preferably less than 10% of the non-H atoms) such as carbon, nitrogen or oxygen atoms or carbonyl groups. For example, systems such as 9,9'-spirobifluorene, 9,9-diarylfluorene, triarylamine, diaryl ether, stilbene, etc., and systems in which two or more aryl groups are interrupted, for example, by a straight-chain or cyclic alkyl group or by a silyl group, are also to be regarded as aromatic ring systems in the context of the present invention. In addition, systems in which two or more aryl or heteroaryl groups are bonded directly to one another, such as biphenyl, terphenyl, quaterphenyl or bipyridine, are likewise to be regarded as aromatic or heteroaromatic ring systems.

[0034] A cyclic alkyl, alkoxy or thioalkoxy group in the context of the present invention is to be understood as referring to a monocyclic, bicyclic or polycyclic group.

[0035] In the context of the present invention, C1 to C in which individual hydrogen atoms or CH2 groups can also be substituted by the abovementioned groups 20The alkyl group should be understood to mean, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, 2-methylbutyl, n-pentyl, sec-pentyl, tert-pentyl, 2-pentyl, neopentyl, cyclopentyl, n-hexyl, sec-hexyl, tert-hexyl, 2-hexyl, 3-hexyl, neohexyl, cyclohexyl, 1-methylcyclopentyl, 2-methylpentyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, cycloheptyl, 1-methylcyclohexyl, n-octyl, 2-ethylhexyl, cyclooctyl, 1-bicyclo[2.2.2]octyl, 2-bicyclo[2.2.2]octyl, 2-(2,6-dimethyl)octyl, 3-(3,7-dimethyl)octyl, adamantyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 1,1-dimethyl-n-hex-1-yl, 1,1-dimethyl-n-hept-1-yl, 1,1-dimethyl-n-oct-1-yl, 1,1-dimethyl-n-dec-1-yl, 1,1-dimethyl-n-dodec-1-yl, 1,1-dimethyl-n-tetradec-1-yl, 1,1-dimethyl-n-hexadec-1-yl, 1,1-dimethyl-n-octadec-1-yl, 1,1-diethyl-n-hex-1-yl, 1,1-diethyl-n-hept-1-yl, 1,1-diethyl-n-oct-1-yl, 1,1-diethyl-n-dec-1-yl, 1,1-diethyl-n-dodec-1-yl, 1,1-diethyl-n-tetradec-1-yl, 1,1-diethyl-n-hexadec-1-yl, 1,1-diethyl-n-octadec-1-yl, 1-(n-propyl)cyclohex-1-yl, 1-(n-butyl)cyclohex-1-yl, 1-(n-hexyl)cyclohex-1-yl, 1-(n-octyl)cyclohex-1-yl and 1-(n-decyl)cyclohex-1-yl groups. The alkenyl group should be understood to mean, for example, vinyl, propenyl, butenyl, pentenyl, cyclopentenyl, hexenyl, cyclohexenyl, heptenyl, cycloheptenyl, octenyl, cyclooctenyl or cyclooctadienyl. The alkynyl group should be understood to mean, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl or octynyl. C1 to C 40 The alkoxy group should be understood to mean, for example, methoxy, trifluoromethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy or 2-methylbutoxy.

[0036] An aromatic or heteroaromatic ring system having 5 to 40 aromatic ring atoms and which may in each case also be substituted by the abovementioned groups and may be linked to an aromatic or heteroaromatic system via any desired position is to be understood as meaning a group derived from the following substances: benzene, naphthalene, anthracene, benzanthracene, phenanthrene, benzophenanthrene, pyrene, chrysene, perylene, fluoranthene, benzofluoranthene, tetracene, pentacene, benzopyrene, biphenyl, bibenzylidene, terphenyl, terbenzylidene, fluorene, spirobifluorene, dihydrophenanthrene, dihydropyrene, tetrahydropyrene, cis- or trans-indeno[1,2-b]fluorene, cis- or trans-monobenzoindeno[1,2-b]fluorene, cis- or trans-dibenzoindeno[1,2-b]fluorene, triphenylene, isotriphenylene, spirotriphenylene, spiroisotriphenylene, furan, benzofuran, isobenzofuran, dibenzofuran, thiophene, benzothiophene, isobenzothiophene, dibenzothiophene, pyrrole, indole, isoindole, carbazole, indolocarbazole, indeno[1,2-b]carbazole, pyridine, quinoline, isoquinoline, acridine, phenanthridine, benzo[5,6]quinoline, benzo[6,7]quinoline, benzo[7,8]quinoline, phenothiazine, phenoxazine, pyrazole, indazole, imidazole, benzimidazole, naphthimidazole, phenanthrimidazole, pyridinimidazole, pyrazinimidazole, quinoxalinimidazole, oxazole, benzoxazole, naphthoxazole, anthroxazole, phenanthroxazole, isoxazole, 1,2-thiazole, 1,3-thiazole, benzothiazole, pyridazine, benzopyridazine, pyrimidine, benzopyrimidine, quinoxaline, 1,5-diazaphenanthrene, 2,7-diazapyrene, 2,3-diazapyrene, 1,6-diazapyrene, 1,8-diazapyrene, 4,5-diazapyrene, 4,5,9,10-tetraazaperylene, pyrazine, phenazine, phenoxazine, phenothiazine, fluoranthene ring, naphthyridine, azacarbazole, benzocarbazole, phenanthroline, 1,2,3-triazole, 1,2,4-triazole, benzotriazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,3,5-triazine, 1,2,4-triazine, 1,2,3-triazine, tetrazole, 1,2,4,5-tetrazine, 1,2,3,4-tetrazine, 1,2,3,5-tetrazine, purine, pteridine, indolizine and benzothiadiazole.

[0037] Preferably, the compound comprising the structure of formula (I) has a molecular weight of not more than 5000 g / mol, preferably not more than 4000 g / mol, particularly preferably not more than 3000 g / mol, especially preferably not more than 2000 g / mol and most preferably not more than 1200 g / mol.

[0038] Another case may be that, in the structure of formula (I) and / or its preferred embodiments, the group Ar is selected from formula (Ar-1) to (Ar-44),

[0039]

[0040]

[0041]

[0042]

[0043] The symbols used are as follows:

[0044] Y 1 is O, S or NR 1 , preferably O or S;

[0045] i is independently 0, 1 or 2 in each case, preferably 0 or 1;

[0046] j is independently 0, 1, 2 or 3 in each case, preferably 0, 1 or 2;

[0047] h is independently 0, 1, 2, 3 or 4 in each case, preferably 0, 1 or 2;

[0048] g is independently 0, 1, 2, 3, 4 or 5 in each case, preferably 0, 1 or 2;

[0049] R 1 may have the definitions given above, especially for formula (I), and

[0050] The dashed bond marks the connection position.

[0051] It is preferably the case that the sum of the marks i, j, h and g in the structures of formulas (Ar-1) to (Ar-44) does not exceed 8 in each case, preferably does not exceed 7, and more preferably does not exceed 5.

[0052] In another preferred embodiment of the present invention, R 1 , for example in the structure of formula (I) and / or in the preferred embodiments of these structures or in the structures referring to these formulas, is the same or different in each case and is selected from H, D, an aliphatic hydrocarbon group having 1 to 10 carbon atoms, preferably having 1, 2, 3 or 4 carbon atoms, or an aromatic or heteroaromatic ring system having 5 to 30 aromatic ring atoms, preferably having 5 to 24 aromatic ring atoms, more preferably having 5 to 13 aromatic ring atoms, which may be substituted by one or more alkyl groups each having 1 to 4 carbon atoms, but is preferably unsubstituted.

[0053] In another preferred embodiment of the present invention, R 2, for example, in the structures of formula (I) and / or the preferred embodiments of these structures or the structures referring to these formulas, the same or different in each case and selected from H, D, F, CN, aliphatic hydrocarbon groups having 1 to 10 carbon atoms, preferably having 1, 2, 3 or 4 carbon atoms, or aromatic or heteroaromatic ring systems having 5 to 30 aromatic ring atoms, preferably having 5 to 24 aromatic ring atoms, more preferably having 5 to 13 aromatic ring atoms, which may be substituted by one or more alkyl groups each having 1 to 4 carbon atoms, but preferably are unsubstituted.

[0054] In step B), an aliphatic or heteroaliphatic nitrile is provided. The aliphatic or heteroaliphatic nitrile is not limited and is known in the prior art. Available aliphatic or heteroaliphatic nitrile compounds include, for example, acetonitrile, propionitrile, butyronitrile, valeronitrile, dichloroacetonitrile, methoxyacetonitrile or fluoroacetonitrile.

[0055] Preferably, the aliphatic or heteroaliphatic nitrile includes acetonitrile. For example, a mixture of two, three or more aliphatic or heteroaliphatic nitrile compounds can be used as the aliphatic or heteroaliphatic nitrile. According to this embodiment, acetonitrile is preferably used in combination with dichloroacetonitrile, methoxyacetonitrile or fluoroacetonitrile. Such mixtures can improve the yield and shorten the reaction time. However, such mixtures will increase additional costs without bringing reasonable improvements. In addition, some aliphatic or heteroaliphatic nitrile compounds that can be used in combination with, for example, acetonitrile may cause environmental disadvantages.

[0056] In a preferred embodiment, exactly one nitrile compound is preferably used as the aliphatic or heteroaliphatic nitrile. Based on cost efficiency and reactivity, the aliphatic or heteroaliphatic nitrile is preferably acetonitrile.

[0057] In step C), the aromatic or heteroaromatic primary amide is mixed with the aliphatic or heteroaliphatic nitrile. Preferably, based on the molar amount of the aromatic or heteroaromatic primary amide, the amount of the aliphatic or heteroaliphatic nitrile used is twice the excess or more, more preferably four times the excess or more, and even more preferably ten times the excess or more.

[0058] In step D), the aromatic or heteroaromatic primary amide is reacted with the aliphatic or heteroaliphatic nitrile using a Pd catalyst to obtain an aromatic or heteroaromatic nitrile compound.

[0059] Preferably, the Pd catalyst is a Pd salt containing an organic anion. More preferably, the organic anion of the Pd salt is derived from an organic acid. Even more preferably, the organic acid from which the anion of the Pd salt is derived is a carboxylic acid. The carboxylic acid is preferably selected from formic acid, acetic acid, propionic acid, butyric acid, valeric acid and hexanoic acid, more preferably selected from formic acid and acetic acid, and even more preferably selected from acetic acid.

[0060] According to a preferred embodiment, an aromatic or heteroaromatic primary amide can be reacted with an aliphatic or heteroaliphatic nitrile using a Pd(II) salt according to step D), and the Pd(II) salt is preferably Pd(OAc)2. More preferably, there is no reagent for oxidizing the Pd(II) salt in the reaction mixture. This embodiment has advantages in terms of cost improvement, safety, and the environment.

[0061] The amount of the Pd catalyst can be 20 mol% or less, preferably 10 mol% or less, and more preferably 5 mol% or less, relative to the aromatic or heteroaromatic primary amide provided in step A). In addition, the amount of the Pd catalyst can be 0.05 mol% or more, preferably 0.5 mol% or more, and more preferably 1 mol% or more, relative to the aromatic or heteroaromatic primary amide provided in step A).

[0062] An acid is used to react an aromatic or heteroaromatic primary amide with an aliphatic or heteroaliphatic nitrile. The acid is not limited. A Brønsted acid is preferably used. Preferably, the pK a value of the acid used to react the aromatic or heteroaromatic primary amide with the aliphatic or heteroaliphatic nitrile is lower than the pK a value of the acid corresponding to the anion of the Pd salt. Preferably, the pK a value of the acid used to react the aromatic or heteroaromatic primary amide with the aliphatic or heteroaliphatic nitrile is 4 or less, preferably 3 or less, and more preferably 2 or less.

[0063] The organic acid from which the anion of the Pd salt is derived can have a higher pK a value than the acid used to react the aromatic or heteroaromatic primary amide with the aliphatic or heteroaliphatic nitrile.

[0064] More preferably, the acid used to react the aromatic or heteroaromatic primary amide is based on a non-coordinating anion. The term "non-coordinating" refers to a Pd complex containing Cl - as a ligand. That is, a Pd complex containing Cl - as a ligand is more stable than a similar Pd complex containing the anion of the acid used to react the aromatic or heteroaromatic primary amide as a ligand. The term "non-coordinating" refers to an anion that is regarded by those skilled in the art as a weak ligand, and examples of the corresponding acids are provided below. Such anions are referred to as weakly coordinating in the literature (e.g., Krossing et al., Angew. Chem. Int. Ed. 2004, 43, 2066-2090). The stability of the Pd complex or the weakness of the anion coordination can be determined by standard methods or by ligand exchange using Cl - .

[0065] Acids having non-coordinating anions are well known in the art and are preferably selected from oxoacids or fluorine-based acids.

[0066] Useful oxygen-containing acids are, for example, H2SO4, HClO4, CF3COOH, CF3SO3H, CH3SO3H. Fluorine-based acids that can be used to react with aromatic or heteroaromatic primary amides are, for example, HSbF6, HBF4, HPF6 and similar compounds.

[0067] Preferably, the acids used to react aromatic or heteroaromatic primary amides with aliphatic or heteroaliphatic nitriles do not include HCl, HBr and HI. HCl, HBr and HI are acids with coordinating anions.

[0068] Relative to the palladium catalyst provided in step D), the amount of acid used to react aromatic or heteroaromatic primary amides with aliphatic or heteroaliphatic nitriles can be 2000 mol% or less, preferably 1000 mol% or less, more preferably 500 mol% or less. In addition, relative to the palladium catalyst provided in step D), the amount of acid used to react aromatic or heteroaromatic primary amides with aliphatic or heteroaliphatic nitriles can be 50 mol% or more, preferably 100 mol% or more, more preferably 200 mol% or more.

[0069] In one specific embodiment, water can be present to cause the aromatic or heteroaromatic primary amide to react with the aliphatic or heteroaliphatic nitrile according to step D). Preferably, the amount of water is 20% to 80% by weight of the reaction mixture, preferably 30% to 80% by weight. Surprisingly, the presence of water improves the reaction of the aromatic or heteroaromatic primary amide with the aliphatic or heteroaliphatic nitrile in step D).

[0070] The reaction can be carried out under ambient conditions. However, higher temperatures and pressures can also be employed. Temperatures from about 0°C to about 100°C are useful, with a preferred temperature of about 10°C to about 50°C. Higher temperatures can lead to the formation of more by-products, such as by-products formed by the acidic hydrolysis of the amide or nitrile.

[0071] The reaction mixture provided in step C) or used in step D) may contain an organic solvent. Suitable and preferred solvents are, for example, toluene, anisole, o-xylene, m-xylene or p-xylene, methyl benzoate, mesitylene, decalin, o-dimethoxybenzene, THF, methyl-THF, THP, chlorobenzene, dioxane, phenoxytoluene, especially 3-phenoxytoluene, (-)-fenchone, 1,2,3,5-tetramethylbenzene, 1,2,4,5-tetramethylbenzene, 1-methylnaphthalene, 2-methylbenzothiazole, 2-phenoxyethanol, 2-pyrrolidone, 3-methylanisole, 4-methylanisole, 3,4-dimethylanisole, 3,5-dimethylanisole, acetophenone, α-terpineol, benzothiazole, butyl benzoate, cumene, cyclohexanol, cyclohexanone, cyclohexylbenzene, decahydronaphthalene, dodecylbenzene, ethyl benzoate, indane, methyl benzoate, NMP, p-cymene, phenetole, 1,4-diisopropylbenzene, dibenzyl ether, diethylene glycol monobutyl methyl ether, triethylene glycol monobutyl methyl ether, diethylene glycol dibutyl ether, triethylene glycol dimethyl ether, diethylene glycol monobutyl ether, tripropylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, 2-isopropylnaphthalene, pentylbenzene, hexylbenzene, heptylbenzene, octylbenzene, 1,1-bis(3,4-dimethylphenyl)ethane, hexamethylindane or mixtures of these solvents. In a preferred embodiment, the amount of the organic solvent is preferably limited to 20% by weight or less, more preferably limited to 10% by weight or less. In a highly preferred embodiment, the reaction mixture provided in step C) or used in step D) does not contain a significant amount of the organic solvent.

[0072] The process according to the invention provides high-quality aromatic or heteroaromatic nitrile compounds in a low-cost and environmentally friendly manner.

[0073] By these processes, optionally followed by purification, such as recrystallization or sublimation, aromatic or heteroaromatic nitrile compounds of high purity, preferably greater than 99% (determined by 1 1H NMR and / or HPLC) can be obtained.

[0074] Aromatic or heteroaromatic primary amides are preferably prepared by an aminocarbonylation process. The aminocarbonylation processes for the preparation of aromatic or heteroaromatic primary amides are well known in the art.

[0075] Preferred aminocarbonylation processes include the catalytic reaction of aromatic or heteroaromatic halides with amines and carbon monoxide. Preferred aromatic or heteroaromatic halides are chlorides, bromides and iodides. For cost reasons, chlorides are more preferably used. Considering reactivity, bromides and iodides are more preferably used. The aromatic or heteroaromatic residue of the aromatic or heteroaromatic halide contains the formula Ar-Q, where Q is halogen and Ar is as defined above.

[0076] Preferably, the co-reactant is ammonia (NH3) to form a primary amide. In an alternative embodiment, a primary amine can be used.

[0077] Preferably, the aminocarbonylation process is catalyzed by a Pd catalyst. More preferably, the catalyst system is formed from a palladium source and a ligand (more preferably a bidentate phosphine ligand). The palladium source is suitably palladium carboxylate, and palladium acetate, palladium propionate, dipalladium tris(dibenzylideneacetone), palladium butyrate, and palladium hexanoate are all desirable. Palladium acetate is a particularly preferred palladium source.

[0078] The carbonylation is a homogeneous or heterogeneous reaction, but is preferably carried out as a homogeneous process in an aprotic solvent. Suitable aprotic solvents include ketones (such as acetone and methyl ethyl ketone), ethers (such as diethylene glycol dimethyl ether, tetrahydrofuran, anisole, and diphenyl ether), aromatic hydrocarbons (such as toluene and xylene), nitriles (such as acetonitrile and benzonitrile), and esters (such as ethyl butyrate and methyl benzoate). Acyclic ethers are preferred solvents, and diethylene glycol dimethyl ether (diglyme) is particularly preferred.

[0079] The carbonylation conditions preferably include high temperature and usually also high pressure. Temperatures from about 70 °C to about 200 °C are useful, with a preferred temperature of from about 90 °C to about 150 °C. The reaction pressure is from about 1 bar to about 100 bar, but more commonly a pressure of from about 10 bar to about 70 bar is used.

[0080] Document US 5,344,961 A provides more information about the aminocarbonylation process.

[0081] According to a preferred embodiment, the Pd catalyst used to react an aromatic or heteroaromatic primary amide with an aliphatic or heteroaliphatic nitrile according to step D) can be recycled in the recycling step E).

[0082] Preferably, the recycling step E) includes washing with an aqueous complexing agent. Complexing agents useful for the recycling step E) are well known in the art and include, for example, N-acetylcysteine.

[0083] The method for producing aromatic or heteroaromatic nitrile compounds has one or more of the following surprising advantages compared to the prior art:

[0084] 1. The method according to the invention provides a surprisingly increased yield.

[0085] 2. The method according to the invention can be carried out at low cost. For example, the Pd catalyst used is cost-effective, and the Pd catalyst can be used without an oxidant.

[0086] 3. The method according to the invention is environmentally friendly and provides high safety standards. For example, high yields can be obtained without adding a second aliphatic or heteroaliphatic nitrile; water can be used as a solvent, thus achieving low flammability.

[0087] The above advantages are not accompanied by deterioration of other electronic properties.

[0088] It should be noted that various variations of the embodiments described in the present invention are included within the scope of the present invention. Any feature disclosed in the present invention may be replaced by an alternative feature for the same purpose, equivalent or similar purpose, unless explicitly excluded. Therefore, unless otherwise stated, any feature disclosed in the present invention should be regarded as an instance of a general series or an equivalent or similar feature.

[0089] All features of the present invention can be combined with each other in any way, unless specific features and / or steps are mutually exclusive. This is especially true for the preferred features of the present invention. Similarly, features that are not necessarily combined can be used alone (instead of in combination).

[0090] It should also be noted that many features of the present invention, especially those of the preferred embodiments, are inventive in themselves and should not be regarded merely as part of the embodiments of the present invention. For these features, independent protection can be sought as a supplement or alternative to any currently claimed invention.

[0091] The technical teachings disclosed in the present invention can be extracted and combined with other examples.

[0092] The present invention is illustrated in detail by the following examples, without intending to limit the present invention thereby.

[0093] Those skilled in the art can use the details given to produce other electronic devices of the present invention without creative effort and can thus implement the present invention within the entire scope claimed. Examples

[0094] Example 1

[0095] Synthesis of 2-formamido-9,9-dimethylfluorene

[0096]

[0097] 2-Bromo-9,9-dimethylfluorene (1, 500.0 g, 1.83 mol) was dissolved in 1,4-dioxane (5.15 kg). A solution of palladium acetate (6.16 g, 27.46 mmol, 1.5 mol%) and XantPhos (31.77 g, 54.91 mmol, 3.0 mol%) in 250 mL of tetrahydrofuran was added to the solution of 1. Then ammonia (64 g, 3.77 mol, 2.06 eq) was condensed into the autoclave containing the solution of 1. Subsequently, a CO pressure of 10 bar was applied, and the mixture was stirred at 120 °C for 4 h. Then the reaction mixture was concentrated in vacuo, stirred in hot toluene (2 kg) and filtered. After adding n-heptane (2 kg), crystallization occurred, and the title compound 2 was isolated in 96.7% yield (422.0 g).

[0098] GC-MS (EI): 237.1 [M] + , 98.7 area% (FID).

[0099] Synthesis of 2-cyano-9,9-dimethylfluorene

[0100]

[0101] 9,9-Dimethylfluorene-2-carboxamide (1, 2.00 g, 8.43 mmol) and palladium acetate (38 mg, 0.17 mmol, 2 mol%) were dissolved in acetonitrile (11.79 g, 15.0 mL, 287 mmol, 34 eq) and 15.0 mL of water, and the mixture was stirred at room temperature for 24 h, then a certain amount of the required acid (e.g., CF3COOH: 192 mg, 129 μL, 1.69 mmol, 20 mol%) was added. The mixture was extracted twice with ethyl acetate (10 mL), and the combined organic phases were filtered through a silica gel plug. After removing the solvent and drying in vacuo, the title compound 3 was obtained as a colorless solid in 1.74 g (94%) yield.

[0102] 1 1H-NMR (500 MHz, CDCl3, 298 K, δ, in ppm): 7.73 - 7.65 (m, 2H), 7.62 (dd, J = 1.5, 0.7 Hz, 1H), 7.56 (dd, J = 7.8, 1.5 Hz, 1H), 7.44 - 7.36 (m, 1H), 7.35 - 7.29 (m, 2H), 1.42 (s, 6H).

[0103] GC-MS (EI): 219.2 (M +, 35%), 204.2 (M-CH3) + , 100%)

[0104] The reactants can be purchased from commercial sources.

[0105] Examples 2 to 5 and Comparative Examples 1 and 2

[0106] The synthesis of 2-cyano-9,9-dimethylfluorene was substantially repeated as described above, except that:

[0107] The component amounts were modified to 100 mg of 9,9-dimethylfluorene-2-carboxamide (2) in an H2O / CH3CN (1:1; v / v) solution, 34 equivalents of acetonitrile and the corresponding amount of water, 25 °C, 18 h, GC area %, 2 mol% palladium. The specific catalysts used and the results are shown in Table 1.

[0108] Table 1

[0109]

[0110] PdCl2 (the same catalyst as in Org. Lett. 2005, 7, 5237 - 5339) does not result in a significant conversion from 2 to 3, nor does Pd(OAc)2. However, the combination of Pd(OAc)2 with a sub-stoichiometric amount of an acid (preferably a Bronsted acid with a non-coordinating anion) enables almost complete conversion of 2 to 3.

Claims

1. A method for producing an aromatic or heteroaromatic nitrile compound, the method comprising the following steps: A) providing an aromatic or heteroaromatic primary amide; B) providing an aliphatic or heteroaliphatic nitrile; and C) mixing the aromatic or heteroaromatic primary amide with the aliphatic or heteroaliphatic nitrile; and D) reacting the aromatic or heteroaromatic primary amide with the aliphatic or heteroaliphatic nitrile using a Pd catalyst to obtain an aromatic or heteroaromatic nitrile compound; wherein the reaction of the aromatic or heteroaromatic primary amide with the aliphatic or heteroaliphatic nitrile is carried out using an acid.

2. The method according to claim 1, wherein the Pd catalyst is a Pd salt containing an organic anion.

3. The method according to claim 2, wherein the organic anion of the Pd salt is derived from an organic acid.

4. The method according to claim 3, wherein the organic acid from which the anion of the Pd salt is derived is a carboxylic acid.

5. The method according to claims 1 to 4, wherein the acid used for reacting the aromatic or heteroaromatic primary amide with the aliphatic or heteroaliphatic nitrile is based on a non-coordinating anion.

6. The method according to claim 5, wherein the acid used for reacting the aromatic or heteroaromatic primary amide with the aliphatic or heteroaliphatic nitrile is an oxyacid or a fluorine-based acid.

7. The method according to one or more of claims 2 to 6, wherein the organic acid from which the anion of the Pd salt is derived has a higher pK a value than the acid used to react the aromatic or heteroaromatic primary amide with the aliphatic or heteroaliphatic nitrile.

8. The method according to one or more of claims 1 to 7, wherein the aliphatic or heteroaliphatic nitrile is acetonitrile.

9. The method according to one or more of claims 1 to 8, wherein based on the molar amount of the aromatic or heteroaromatic primary amide, the amount of the aliphatic or heteroaliphatic nitrile used is two-fold excess or more.

10. The method according to one or more of claims 1 to 9, wherein water is present to enable the reaction of the aromatic or heteroaromatic primary amide with the aliphatic or heteroaliphatic nitrile according to step D).

11. The method according to one or more of claims 1 to 10, wherein a Pd(II) salt is used to enable the reaction of the aromatic or heteroaromatic primary amide with the aliphatic or heteroaliphatic nitrile according to step D).

12. The method according to one or more of claims 1 to 11, wherein there is no reagent for oxidizing the Pd(II) salt.

13. The method according to one or more of claims 1 to 12, wherein the aromatic or heteroaromatic primary amide is provided by an aminocarbonylation method.

14. The method according to claim 13, wherein the aminocarbonylation method is catalyzed using a Pd catalyst.

15. The method according to one or more of claims 1 to 14, wherein the Pd catalyst used for reacting the aromatic or heteroaromatic primary amide with the aliphatic or heteroaliphatic nitrile according to step D) is recycled in a recycling step E).

16. The method according to one or more of claims 1 to 15, wherein the aromatic or heteroaromatic primary amide provided in step A) is an amide compound according to formula (I), wherein Ar is an aromatic ring system having 6 to 40 aromatic ring atoms or a heteroaromatic ring system having 5 to 40 aromatic ring atoms, each aromatic or heteroaromatic ring system being optionally substituted by one or more R 1 groups; R 1 the same or different in each case and being H, D, F, Cl, Br, I, C(=O)R 2 , CN, Si(R 2 )3, N(R 2 )2, C(=O)N(R 2 )2, P(=O)(R 2 )2, OR 2 , S(=O)R 2 , S(=O)2R 2 , a straight-chain alkyl, alkoxy or thioalkoxy group having from 1 to 40 carbon atoms or a branched or cyclic alkyl, alkoxy or thioalkoxy group having from 3 to 40 carbon atoms, each group being optionally substituted by one or more R 2 groups, wherein one or more non-adjacent CH2 groups may be replaced by -R 2 C=CR 2 -, -C≡C-, Si(R 2 )2, C=O, C=S, C=NR 2 , -C(=O)O-, -C(=O)NR 2 (-), NR 2 , P(=O)(R 2 ), -O-, -S-, SO or SO2, and wherein one or more hydrogen atoms may be replaced by D, F, Cl, Br, I, CN or NO2, or an aromatic or heteroaromatic ring system having from 5 to 40 aromatic ring atoms, each aromatic or heteroaromatic ring system being optionally substituted by one or more R 2 groups, or an aryloxy or heteroaryloxy group having from 5 to 40 aromatic ring atoms, each aryloxy or heteroaryloxy group being optionally substituted by one or more R 2 groups, or a combination of these systems; simultaneously, two or more adjacent R 1 substituents may also form a ring system with each other, preferably a monocyclic or polycyclic aliphatic or aromatic ring system; R 2 identical or different in each case and being H, D, F, Cl, Br, I, CN or an aliphatic hydrocarbon radical group having 1 to 20 carbon atoms, where one or more hydrogen atoms may be replaced by D or F, or an aromatic or heteroaromatic ring system having 5 to 30 carbon atoms, where one or more hydrogen atoms may be replaced by D or F; simultaneously, two or more adjacent R 2 substituents may also together form a ring system, preferably a monocyclic or polycyclic aliphatic or aromatic ring system.

17. The method according to claim 16, wherein the group Ar is selected from phenyl, o-, m- or p-biphenyl, terphenyl, especially branched terphenyl, quaterphenyl, especially branched quaterphenyl, 1-, 2-, 3- or 4-fluorenyl, 1-, 2-, 3- or 4-spirobifluorenyl, pyridyl, pyrimidinyl, 1-, 2-, 3- or 4-dibenzofuranyl, 1-, 2-, 3- or 4-dibenzothiophenyl and 1-, 2-, 3- or 4-carbazolyl, each group being optionally substituted by one or more R 1 groups.

18. The method according to claim 16 or 17, wherein the group Ar is selected from formulas (Ar-1) to (Ar-44), wherein the symbols used are as follows: Y 1 is O, S or NR 1 , preferably O or S; i is independently 0, 1 or 2 in each case, preferably 0 or 1; j is independently 0, 1, 2 or 3 in each case, preferably 0, 1 or 2; h is independently 0, 1, 2, 3 or 4 in each case, preferably 0, 1 or 2; g is independently 0, 1, 2, 3, 4 or 5 in each case, preferably 0, 1 or 2; R 1 may have the definitions given above, in particular those given for formula (A), (I) and / or (II), and The dashed-line key marks the connection position.

Images