Preparation of nitriles

Abstract

The present invention describes a process for the preparation of aromatic or heteroaromatic nitriles.

Description

Detailed Description of the Invention

[0001] The present invention describes a process for the preparation of aromatic or heteroaromatic nitriles.

[0002] Aromatic and heteroaromatic nitriles are important compounds in organic synthesis across a variety of application areas. For example, these compounds can be used as intermediates for the production of materials for use in pharmaceuticals or electronic devices.

[0003] A reliable method for their synthesis from aryl halides is palladium-catalyzed cyanation, typically using Zn(CN). Such methods are quite disadvantageous from the perspective of "green chemistry," generating environmentally toxic zinc waste and utilizing highly toxic metal cyanides. Apart from the metal cyanide method, nitriles can be obtained, inter alia, from the corresponding amides by dehydration. Typically, this transformation requires heat and harsh, dry conditions using reagents such as phosphorus pentoxide or oxalyl chloride, which are hazardous.

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

[0005] Although the above-mentioned processes can be used for the preparation of aromatic or heteroaromatic nitriles, there is still a need for improvement, especially with regard to cost-effectiveness, especially yield, safety and environmental aspects.

[0006] The object of the present invention is to provide a process for the preparation of aromatic or heteroaromatic nitriles which is highly cost-effective and has high standards in terms of safety and environmental friendliness.

[0007] In particular, the method should provide a high yield. Additionally, the method should provide the product without forming significant amounts of by-products. Furthermore, the method should be accomplished without the use of expensive materials that cannot be recycled. Furthermore, the method should avoid the use or by-production of environmentally significant compounds.

[0008] Surprisingly, it has been found that certain processes for producing aromatic or heteroaromatic nitrile compounds, as defined in more detail herein below, have improvements over the prior art, particularly with respect to cost-efficiency and environmental friendliness.

[0009] The method of the present invention is cost-effective as it improves yield without using expensive compounds. Furthermore, the method offers improvements in environmental friendliness. The method offers further advantages in industrial setups.

[0010] Accordingly, the present invention provides a process for producing an aromatic or heteroaromatic nitrile compound, comprising the steps of: A) providing an aromatic or heteroaromatic primary amide; B) providing an aliphatic or heteroaliphatic nitrile; C) mixing an aromatic or heteroaromatic primary amide with an aliphatic or heteroaliphatic nitrile; and D) reacting an aromatic or heteroaromatic primary amide with an aliphatic or heteroaliphatic nitrile using a Pd catalyst to obtain an aromatic or heteroaromatic nitrile compound; Here, an acid is used to react an aromatic or heteroaromatic primary amide with an aliphatic or heteroaliphatic nitrile.

[0011] In step A), an aromatic or heteroaromatic primary amide is provided. The aromatic or heteroaromatic primary amide is not limited and is well known in the prior art.

[0012] Preferably, the aromatic or heteroaromatic primary amide provided in step A) is of formula (I)

[0013] [ka]

[0014] (In the formula, 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 of which may be joined by one or more R 1 optionally substituted by radicals); R 1 are the same or different in each case and are 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 of which may be selected from the group consisting of one or more R 2 radicals) wherein one or more non-adjacent CH groups are substituted 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 of which may be replaced by one or more R 2radicals), or an aryloxy or heteroaryloxy group having 5 to 40 aromatic ring atoms (each of which may be substituted by one or more R 2 radicals), or a combination of these systems; at the same time, two or more adjacent R 1 The substituents may also together form a ring system, preferably a monocyclic or polycyclic aliphatic or aromatic ring system; R 2 are in each occurrence the same or different and are H, D, F, Cl, Br, I, CN or an aliphatic hydrocarbyl radical having 1 to 20 carbon atoms (wherein 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 (wherein one or more hydrogen atoms may be replaced by D or F); at the same time, two or more adjacent R 2 The substituents may also be amide compounds, with the substituents together forming a ring system, preferably a monocyclic or polycyclic aliphatic or aromatic ring system.

[0015] Ar is an aromatic or heteroaromatic ring system having 5 to 40 aromatic ring atoms, preferably 6 to 18 aromatic ring atoms, and 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 of which may be joined by one or more R 1 where R 1 may have the definition given above, especially in formula (I).

[0016] Examples of suitable Ar groups are phenyl, ortho-, meta- or para-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-dibenzothienyl and 1-, 2-, 3- or 4-carbazolyl (each of which may be substituted with one or more R1 and optionally substituted by a radical.

[0017] Preferably, the symbol Ar represents an aryl or heteroaryl radical, whereby the aromatic or heteroaromatic group of the aromatic or heteroaromatic ring system is substituted with each atom of a further group, e.g., R 1 It is bonded directly to a carbon, nitrogen, or phosphorus atom of the group, that is, through an atom of an aromatic or heteroaromatic group.

[0018] In the context of the present invention, adjacent carbon atoms are carbon atoms that are directly bonded to one another. Furthermore, in the definition of radicals, "adjacent radicals" means that these radicals are bonded to the same carbon atom or adjacent carbon atoms. These definitions also apply, in particular, to the terms "adjacent groups" and "adjacent substituents."

[0019] In the context of this specification, the expression that two or more radicals may together form a ring should be understood to mean, in particular, that the two radicals are linked to one another by a chemical bond involving the formal departure of two hydrogen atoms. This is illustrated by the following scheme:

[0020] [ka]

[0021] However, the above expression should also be understood to mean that if one of the two radicals is hydrogen, the second radical will bond to the position where the hydrogen atom was attached to form a ring. This is exemplified by the following scheme:

[0022] [ka]

[0023] In the context of the present invention, a fused aryl group is a group in which two or more aromatic groups are fused together along a common edge, i.e., fused rings, such as in the case of naphthalene, for example, so that two carbon atoms belong to at least two aromatic or heteroaromatic rings. In contrast, for example, fluorene is not a fused aryl group in the context of the present invention, since the two aromatic groups in fluorene do not share a common edge.

[0024] In the context of the present invention, an aryl group contains 6 to 40 carbon atoms, preferably 6 to 24 C atoms; in the context of the present invention, a heteroaryl group contains 2 to 40 carbon atoms, preferably 2 to 24 C atoms, and at least one heteroatom, provided that the sum of carbon atoms and heteroatoms is at least 5. The heteroatoms are preferably selected from N, O and / or S. An aryl or heteroaryl group is understood herein to mean either a simple aromatic ring, i.e., benzene, or a simple heteroaromatic ring, such as, for example, pyridine, pyrimidine, thiophene, etc., or a fused aryl or heteroaryl group, such as, for example, naphthalene, anthracene, phenanthrene, quinoline, isoquinoline, etc.

[0025] In the context of the present invention, an aromatic ring system contains 6 to 40 carbon atoms in the ring system. In the context of the present invention, a heteroaromatic ring system contains 1 to 40 carbon atoms and at least one heteroatom in the ring system, provided that the total number of carbon atoms and heteroatoms is at least 5. The heteroatom is preferably selected from N, O, and / or S. In the context of the present invention, an aromatic or heteroaromatic ring system is understood to mean a system that does not necessarily contain only aryl or heteroaryl groups, but in which two or more aryl or heteroaryl groups may be interrupted by non-aromatic units (preferably less than 10% atoms other than H), such as carbon, nitrogen, or oxygen atoms, or carbonyl groups. For example, systems such as 9,9'-spirobifluorene, 9,9-diarylfluorene, triarylamine, diaryl ether, and stilbene are also considered aromatic ring systems in the context of the present invention, as are systems in which two or more aryl groups are interrupted, for example, by linear or cyclic alkyl groups or by silyl groups. Additionally, systems in which two or more aryl or heteroaryl groups are directly bonded to one another, such as biphenyl, terphenyl, quaterphenyl, or bipyridine, shall likewise be considered aromatic or heteroaromatic ring systems.

[0026] In the context of this invention, a cyclic alkyl, alkoxy or thioalkoxy group is understood to mean a monocyclic, bicyclic or polycyclic group.

[0027] In the context of the present invention, C1-C2 groups in which individual hydrogen atoms or CH2 groups may be further substituted by the above-mentioned groups. 20Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, cyclopropyl, n-butyl, i-butyl, s-butyl, t-butyl, cyclobutyl, 2-methylbutyl, n-pentyl, s-pentyl, t-pentyl, 2-pentyl, neopentyl, cyclopentyl, n-hexyl, s-hexyl, t-hexyl, 2-hexyl, 3-hexyl, neohexyl, cyclohexyl, 1-methylcyclopentyl, 2-methylpentyl, n-heptyl, and 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, It is understood to mean the radicals 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. An alkenyl group is understood to mean, for example, ethenyl, propenyl, butenyl, pentenyl, cyclopentenyl, hexenyl, cyclohexenyl, heptenyl, cycloheptenyl, octenyl, cyclooctenyl or cyclooctadienyl.An alkynyl group is understood to mean, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl or octynyl. C1-C. 40 An alkoxy group is understood to mean, for example, methoxy, trifluoromethoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy or 2-methylbutoxy.

[0028] Aromatic or heteroaromatic ring systems having 5 to 40 aromatic ring atoms, which may in each case be further substituted by the above-mentioned radicals and which may be linked to the aromatic or heteroaromatic system via any desired position, are, for example, benzene, naphthalene, anthracene, benzanthracene, phenanthrene, benzophenanthrene, pyrene, chrysene, perylene, fluoranthene, benzofluoranthene, naphthacene, pentacene, benzopyrene, biphenyl, biphenylene, terphenyl, terphenylene, fluorene, spirobifluorene, dihydrazine, dihydrophenanthrene, dihydropyrene, tetrahydropyrene, cis- or trans-indenofluorene, cis- or trans-monobenzoindenofluorene, cis- or trans-dibenzoindenofluorene, truxene, isotruxene, spirotruxene, spiroisotruxene, furan, benzofuran, isobenzofuran, dibenzofuran, thiophene, benzothiophene, isobenzothiophene, dibenzothiophene, pyrrole, indole, isoindole, carbazole, indolocarbazole, indenocarbazole benzol, 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, pyridoimidazole, pyrazineimidazole, quinoxalineimidazole, oxazole, benzoxazole, naphthoxazole, anthroxazole, phenanthroxazole, isoxazole, 1,2-thiazole, 1,3- Thiazole, benzothiazole, pyridazine, benzopyridazine, pyrimidine, benzopyrimidine, quinoxaline, 1,5-diazaanthracene, 2,7-diazapyrene, 2,3-diazapyrene, 1,6-diazapyrene, 1,8-diazapyrene, 4,5-diazapyrene, 4,5,9,10-tetraazapyrylene, pyrazine, phenazine, phenoxazine, phenothiazine, fluorubine, naphthyridine, azacarbazole, benzocarboline, phenanthroline, 1,2,3-triazole, 1,2,4-triazole, benzotriazole, 1,2,It is understood to mean groups derived from 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.

[0029] Preferably, the compound comprising the structure of formula (I) has a molecular weight of 5000 g / mol or less, preferably 4000 g / mol or less, particularly preferably 3000 g / mol or less, especially preferably 2000 g / mol or less, and most preferably 1200 g / mol or less.

[0030] Furthermore, in the structure of formula (I) and / or its preferred embodiments, the group Ar is selected from the group represented by the formulae (Ar-1) to (Ar-44):

[0031] [ka]

[0032] [ka]

[0033] [ka]

[0034] [ka]

[0035] [ka]

[0036] (wherein the symbols used are as follows: Y 1 is O, S or NR 1 , preferably O or S; i is independently in each occurrence 0, 1 or 2, preferably 0 or 1; j is independently in each occurrence 0, 1, 2 or 3, preferably 0, 1 or 2; h is independently in each occurrence 0, 1, 2, 3 or 4, preferably 0, 1 or 2; g is independently in each occurrence 0, 1, 2, 3, 4, or 5, preferably 0, 1, or 2; R 1 may have the definition given above in particular with respect to formula (I), The dotted bond indicates the position of the bond).

[0037] In the structures of formulae (Ar-1) to (Ar-44), it is preferred that the sum of the subscripts i, j, h and g is in each case 8 or less, preferably 7 or less, and more preferably 5 or less.

[0038] In a further preferred embodiment of the present invention, R 1 are, for example, in the structures of formula (I) and / or preferred embodiments of these structures or structures to which these formulas refer, in each case the same or different and are selected from the group consisting of H, D, aliphatic hydrocarbyl radicals 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 which are preferably unsubstituted.

[0039] In a further preferred embodiment of the present invention, R 2are, for example, in the structures of formula (I) and / or preferred embodiments of these structures or structures to which these formulas refer, in each case the same or different and are selected from the group consisting of H, D, F, CN, aliphatic hydrocarbyl radicals 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 which are preferably unsubstituted.

[0040] In step B), an aliphatic or heteroaliphatic nitrile is provided. The aliphatic or heteroaliphatic nitrile is not limited and is well known in the prior art. Useful aliphatic or heteroaliphatic nitrile compounds include, for example, acetonitrile, propanenitrile, butanenitrile, pentanenitrile, dichloroacetonitrile, methoxyacetonitrile, or fluoroacetonitrile.

[0041] Preferably, the aliphatic or heteroaliphatic nitrile comprises 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 a mixture can improve yield and shorten reaction time. However, such a mixture incurs additional costs without reasonable improvement. Furthermore, some aliphatic or heteroaliphatic nitrile compounds that may be used in combination with, for example, acetonitrile may cause environmental disadvantages.

[0042] In a preferred embodiment, it is preferred that exactly one nitrile compound is used as the aliphatic or heteroaliphatic nitrile. Based on cost-effectiveness and reactivity, the aliphatic or heteroaliphatic nitrile is preferably acetonitrile.

[0043] In step C), an aromatic or heteroaromatic primary amide is mixed with an aliphatic or heteroaliphatic nitrile. Preferably, the aliphatic or heteroaliphatic nitrile is used in a 2-fold or greater excess, more preferably a 4-fold or greater excess, and even more preferably a 10-fold or greater excess, based on the moles of aromatic or heteroaromatic primary amide.

[0044] In step D), aromatic or heteroaromatic primary amides are reacted with aliphatic or heteroaliphatic nitriles using a Pd catalyst to give aromatic or heteroaromatic nitrile compounds.

[0045] 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 methanoic acid, ethanoic acid, propanoic acid, butanoic acid, pentanoic acid, and hexanoic acid, more preferably from methanoic acid and ethanoic acid, and even more preferably from ethanoic acid.

[0046] According to a preferred embodiment, it can be provided that a Pd(II) salt, preferably Pd(OAc)2, is used to react an aromatic or heteroaromatic primary amide with an aliphatic or heteroaliphatic nitrile according to step D). More preferably, no agent for oxidizing the Pd(II) salt is present in the reaction mixture. This embodiment offers cost improvements and advantages in terms of safety and environmental aspects.

[0047] It may be provided that the Pd catalyst is applied in an amount of 20 mol % or less, preferably 10 mol % or less, more preferably 5 mol % or less, based on the aromatic or heteroaromatic primary amide provided in step A. It may also be provided that the Pd catalyst is applied in an amount of 0.05 mol % or more, preferably 0.5 mol % or more, more preferably 1 mol % or more, based on the aromatic or heteroaromatic primary amide provided in step A).

[0048] An acid is used to react an aromatic or heteroaromatic primary amide with an aliphatic or heteroaliphatic nitrile. The acid is not limited. Preferably, a Bronsted acid is used. Preferably, the acid used to react an aromatic or heteroaromatic primary amide with an aliphatic or heteroaliphatic nitrile has a lower pK than the acid corresponding to the anion of the Pd salt. a Preferably, the acid used to react the aromatic or heteroaromatic primary amide with the aliphatic or heteroaliphatic nitrile has a pK value of 4 or less, preferably 3 or less, more preferably 2 or less. a It has a value.

[0049] The organic acids from which the anions of the Pd salts are derived have a higher pK than the acids used to react aromatic or heteroaromatic primary amides with aliphatic or heteroaliphatic nitriles. a It may be provided that it has a value.

[0050] 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 the use of Cl as a ligand. - It refers to a Pd complex containing Cl. -Pd complexes containing as ligands are more stable than similar Pd complexes containing as ligands the anions of acids used to react aromatic or heteroaromatic primary amides. The term non-coordinating refers to anions that are considered weak ligands by those skilled in the art, and examples of corresponding acids are provided below. Such anions are referred to in the literature as weakly coordinating (e.g., Krossing et al., Angew. Chem. Int. Ed. 2004, 43, 2066-2090). The stability of Pd complexes or the weakness of anion coordination can be determined by standard methods, or by Cl. - The cation exchange can be determined by ligand exchange using

[0051] Acids with non-coordinating anions are well known in the art and are preferably selected from oxoacids or fluoroacids.

[0052] Useful oxoacids are, for example, H2SO4, HClO4, CF3COOH, CF3SO3H, CH3SO3H. Fluorine-based acids useful as acids for reacting aromatic or heteroaromatic primary amides are, for example, HSbF6, HBF4, HPF6, and similar compounds.

[0053] Preferably, HCl, HBr, and HI are excluded from the acids used to react aromatic or heteroaromatic primary amides with aliphatic or heteroaliphatic nitriles. HCl, HBr, and HI are acids with coordinating anions.

[0054] It may be provided that the acid used to react the aromatic or heteroaromatic primary amide with the aliphatic or heteroaliphatic nitrile is applied in an amount of 2000 mol % or less, preferably 1000 mol % or less, more preferably 500 mol % or less, relative to the palladium catalyst provided in step D).Furthermore, it may be provided that the acid used to react the aromatic or heteroaromatic primary amide with the aliphatic or heteroaliphatic nitrile is applied in an amount of 50 mol % or more, preferably 100 mol % or more, more preferably 200 mol % or more, relative to the palladium catalyst provided in step D).

[0055] In certain embodiments, the presence of water can be provided for reacting an aromatic or heteroaromatic primary amide with an aliphatic or heteroaliphatic nitrile according to step D). Preferably, the amount of water is in the range of 20 to 80% by weight, preferably 30 to 80% by weight, based on the reaction mixture. Surprisingly, the presence of water improved the reaction of an aromatic or heteroaromatic primary amide with an aliphatic or heteroaliphatic nitrile in step D).

[0056] The reaction can be carried out under ambient conditions. However, higher temperatures and pressures can also be applied. Temperatures of about 0°C to about 100°C are useful, with preferred temperatures being about 10°C to about 50°C. Higher temperatures can result in higher formation of by-products, for example, formed by acidic hydrolysis of the amide or nitrile.

[0057] The reaction mixture provided in step C) or used in step D) may comprise an organic solvent. Suitable preferred solvents are, for example, toluene, anisole, o-, m- or p-xylene, methyl benzoate, mesitylene, tetralin, veratrole, 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-pyrrolidinone, 3-methylanisole, 4-methylanisole, 3,4-dimethylanisole, 3,5-dimethylanisole, acetophenone, α-terpineol, benzothiazole, butyl benzoate, cumene, cyclohexanol, cyclohexanone ... The organic solvent may be xylbenzene, decalin, dodecylbenzene, ethyl benzoate, indane, methyl benzoate, NMP, p-cymene, phenetole, 1,4-diisopropylbenzene, dibenzyl ether, diethylene glycol butyl methyl ether, triethylene glycol butyl 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 a mixture of these solvents. In a preferred embodiment, the amount of organic solvent is preferably limited to 20% by weight or less, more preferably 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 an essential amount of organic solvent.

[0058] The process according to the present invention provides high quality aromatic or heteroaromatic nitrile compounds at low cost in an environmentally friendly manner.

[0059] These methods, optionally followed by purification, e.g., recrystallization or sublimation, can produce aromatic or heteroaromatic nitrile compounds in high purity, preferably greater than 99% purity ( 1 1 H NMR and / or HPLC).

[0060] The aromatic or heteroaromatic primary amides are preferably provided by aminocarbonylation methods. Aminocarbonylation methods for the preparation of aromatic or heteroaromatic primary amides are well known in the art.

[0061] A preferred aminocarbonylation method involves the catalytic reaction of an aromatic or heteroaromatic halide with an amine and carbon monoxide. Preferred aromatic or heteroaromatic halides are chlorides, bromides, and iodides. Based on cost, chlorides are more preferred. In terms of reactivity, bromides and iodides are more preferred. The aromatic or heteroaromatic moiety of the aromatic or heteroaromatic halide has the formula Ar-Q, where Q is a halide and Ar is defined as above.

[0062] Preferably, the co-reactant is ammonia (NH3) to form a primary amide. In an alternative embodiment, a primary amine can be used.

[0063] 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 a palladium carboxylate, with palladium acetate, palladium propionate, di-palladium-tris(dibenzylideneacetone), palladium butyrate, and palladium hexanoate being satisfactory. Palladium acetate is particularly preferred as the palladium source.

[0064] The carbonylation may be 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, with diethylene glycol dimethyl ether (diglyme) being particularly preferred.

[0065] Carbonylation conditions preferably include elevated temperatures, and typically elevated pressures. Temperatures of about 70° C. to about 200° C. are useful, with preferred temperatures being about 90° C. to about 150° C. Reaction pressures range from about 1 bar to about 100 bar, although pressures of about 10 bar to about 70 bar are more frequently used.

[0066] Further information on the aminocarbonylation process is provided in document US Pat. No. 5,344,961A.

[0067] According to a preferred embodiment, it can be provided that the Pd catalyst used to react aromatic or heteroaromatic primary amides with aliphatic or heteroaliphatic nitriles according to step D) is recycled in a recycling step E).

[0068] Preferably, recycling step E) comprises washing with an aqueous complexing agent. Complexing agents useful for recycling step E) are well known in the art and include, for example, N-acetylcysteine.

[0069] The process for producing aromatic or heteroaromatic nitrile compounds is notable for one or more of the following surprising advantages over the prior art: 1. The process according to the present invention results in a surprising increase in yield. 2. The process according to the invention can be carried out at low cost, for example the Pd catalyst used is quite cost-effective and the Pd catalyst can be used without an oxidizing agent. 3. The process according to the present invention is environmentally friendly and offers a high level of safety. For example, the addition of a second aliphatic or heteroaliphatic nitrile is not necessary to achieve high yields; water can be used as a solvent, so that low flammability is achieved.

[0070] These above mentioned advantages are not accompanied by any further degradation of the electronic properties.

[0071] It should be pointed out that variations of the embodiments described in the present invention are covered by the scope of the present invention. Any feature disclosed in the present invention may be replaced with an alternative feature serving the same purpose, or an equivalent or similar purpose, unless this is explicitly excluded. Therefore, any feature disclosed in the present invention should be considered as an example of a general series, or an equivalent or similar feature, unless otherwise specified.

[0072] All features of the present invention may be combined with one another in any way, unless certain features and / or steps are mutually exclusive. This is particularly true for preferred features of the present invention. Similarly, features of non-essential combinations may be used individually (and not in combination).

[0073] It should further be pointed out that many features, particularly those of the preferred embodiments of the invention, are inventive in themselves and should not be considered as merely part of an embodiment of the invention: they may seek independent protection in addition to, or as an alternative to, any invention presently claimed.

[0074] The technical teachings disclosed by the present invention may be extracted and combined with other examples.

[0075] The present invention will be illustrated in more detail in the following examples, which are not intended to limit the invention in any way.

[0076] Using the details provided, a person skilled in the art can manufacture further electronic devices of the present invention without resorting to inventive techniques, and can thus practice the present invention throughout the scope of the claims.

[0077] example [Example 1] Synthesis of 2-carboxamido-9,9-dimethylfluorene

[0078] [ka]

[0079] 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. Ammonia (64 g, 3.77 mol, 2.06 equiv.) was then condensed into the autoclave containing the solution of 1. Then, 10 bar of CO pressure was applied, and the mixture was stirred at 120 °C for 4 h. The reaction mixture was then concentrated in vacuo, stirred in hot toluene (2 kg), and filtered. After the addition of n-heptane (2 kg), the title compound 2 crystallized and was isolated in 96.7% (422.0 g) yield.

[0080] GC-MS(EI):237.1[M] + , 98.7 area% (FID).

[0081] Synthesis of 2-cyano-9,9-dimethylfluorene

[0082] [ka]

[0083] 9,9-Dimethylfluorene-2-carboxamide (1, 2.00 g, 8.43 mmol) and palladium acetate (38 mg, 0.17 mmol, 2 mol%) were stirred at room temperature for 24 h in acetonitrile (11.79 g, 15.0 mL, 287 mmol, 34 equiv.) and 15.0 mL of water, to which a given amount of the desired 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 plug. After removal of the solvent and drying under vacuum, the title compound 3 was obtained as a colorless solid in 1.74 g (94%) yield.

[0084] 1 H-NMR (500MHz, CDCl3, 298K, δ in ppm): 7.73-7.65(m,2H),7.62(dd,J=1.5,0.7Hz,1 H),7.56(dd,J=7.8,1.5Hz,1H),7.44-7.36(m,1H),7.35-7.29(m,2H),1.42(s,6H).

[0085] GC-MS(EI):219.2(M + ,35%),204.2(M-CH3) + ,100%)

[0086] The reactants can be purchased from commercial sources.

[0087] [Examples 2 to 5 and Comparative Examples 1 and 2] The synthesis of 2-cyano-9,9-dimethylfluorene described above was essentially repeated with the following exceptions: The amounts of components were adjusted to 100 mg of 9,9-dimethylfluorene-2-carboxamide (2) in HO / CHCN (1:1; v / v), 34 equivalents of acetonitrile, and the corresponding amount of water, at 25 °C for 18 h, GC area %, and 2 mol% palladium. The specific catalysts used and the results are shown in Table 1.

[0088] [Table 1]

[0089] On the other hand, PdCl2 (the same catalyst as in Org. Lett. 2005, 7, 5237-5339) does not result in appreciable conversion of 2 to 3, and the same is true for Pd(OAc)2. However, the combination of Pd(OAc)2 with a substoichiometric amount of an acid, preferably one with a Brønsted acid and a non-coordinating anion, results in virtually complete conversion of 2 to 3.

Claims

1. 1. A process for producing an aromatic or heteroaromatic nitrile compound, comprising: A) providing an aromatic or heteroaromatic primary amide; B) providing an aliphatic or heteroaliphatic nitrile; C) mixing the aromatic or heteroaromatic primary amide with the aliphatic or heteroaliphatic nitrile; 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; The process wherein an acid is used to react said aromatic or heteroaromatic primary amide with said aliphatic or heteroaliphatic nitrile.

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

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

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

5. 5. The process of any one of claims 1 to 4, wherein the acid used to react the aromatic or heteroaromatic primary amide with the aliphatic or heteroaliphatic nitrile is based on a non-coordinating anion.

6. 6. The method of claim 5, wherein the acid used to react the aromatic or heteroaromatic primary amide with the aliphatic or heteroaliphatic nitrile is an oxoacid or a fluoroacid.

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

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

9. 9. The process of claim 1, wherein the aliphatic or heteroaliphatic nitrile is used in a 2-fold or greater excess based on the moles of aromatic or heteroaromatic primary amide.

10. 10. The process according to any one of claims 1 to 9, wherein water is present for reacting the aromatic or heteroaromatic primary amide with the aliphatic or heteroaliphatic nitrile according to step D).

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

12. 12. The method of any one of claims 1 to 11, wherein no agent is present to oxidize the Pd(II) salt.

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

14. 14. The process of claim 13, wherein the aminocarbonylation process is catalyzed by a Pd catalyst.

15. 15. The process according to any one 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 recycling step E).

16. The aromatic or heteroaromatic primary amide provided in step A) is of formula (I) 【Chemistry 1】 (In the formula, 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 of which may be joined by one or more R １ optionally substituted by radicals); R １ are in each case the same or different and are 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) ２ R 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 of which may be one or more R ２ and optionally substituted by one or more non-adjacent CH radicals. ２ The group is -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 SO ２ and one or more hydrogen atoms may be replaced by D, F, Cl, Br, I, CN or NO ２ or an aromatic or heteroaromatic ring system having 5 to 40 aromatic ring atoms (each of which may be replaced by one or more R ２ radicals), or an aryloxy or heteroaryloxy group having 5 to 40 aromatic ring atoms (each of which may be substituted by one or more R ２ radicals), or a combination of these systems; at the same time, two or more adjacent R １ The substituents may also together form a ring system, preferably a monocyclic or polycyclic aliphatic or aromatic ring system; R ２ are in each occurrence the same or different and are H, D, F, Cl, Br, I, CN or an aliphatic hydrocarbyl radical having 1 to 20 carbon atoms, in which 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, in which one or more hydrogen atoms may be replaced by D or F; at the same time, two or more adjacent R ２ 16. The method according to any one of claims 1 to 15, wherein the substituents may also together form a ring system, preferably a monocyclic or polycyclic aliphatic or aromatic ring system.

17. The Ar group may be phenyl, ortho-, meta- or para-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-dibenzothienyl and 1-, 2-, 3- or 4-carbazolyl, each of which may be selected from the group consisting of one or more R １ 17. The method of claim 16, wherein the aryl group is selected from the group consisting of aryl, aryl ...

18. The group Ar is represented by the formulas (Ar-1) to (Ar-44): 【Chemistry 2-1】 【Chemistry 2-2】 [Chemistry 2-3] [Chemistry 2-4] (wherein the symbols used are as follows: Y １ is O, S or NR １ , preferably O or S; i is independently in each occurrence 0, 1 or 2, preferably 0 or 1; j is independently in each occurrence 0, 1, 2 or 3, preferably 0, 1 or 2; h is independently in each occurrence 0, 1, 2, 3 or 4, preferably 0, 1 or 2; g is independently in each occurrence 0, 1, 2, 3, 4 or 5, preferably 0, 1 or 2; R １ may have the definitions given above with respect to, inter alia, formula (A), (I) and / or (II), The method of claim 16 or 17, wherein the bond shown with a dotted line indicates the position of the bond.

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