Method for hydrogenation of oxime derivatives

Abstract

The present invention relates to a novel process for the iridium-catalyzed hydrogenation of oximes. The present invention also relates to novel iridium catalysts for the iridium-catalyzed hydrogenation of oximes, and methods for preparing these catalysts. The present invention further relates to the use of these novel iridium catalysts in the ionic hydrogenation of other unsaturated substrates.

Description

[0001] The present invention relates to a novel process for the iridium-catalyzed hydrogenation of oximes. The present invention also relates to novel iridium catalysts for the iridium-catalyzed hydrogenation of oximes, and methods for preparing these catalysts. The present invention further relates to the use of these novel iridium catalysts in the ionic hydrogenation of other unsaturated substrates.

[0002] The reduction of oximes and oxime ethers to the corresponding hydroxylamine derivatives is a useful step in many organic syntheses;

[0003]

[0004] The reduction of oximes and oxime ethers using sodium cyanoborohydride or borane complexes (such as trimethylamine borane complex) is described in WO 13 / 127764. The main disadvantages of the borane reduction process are the high cost of the reducing agent, the low atom economy of the process leading to the formation of stoichiometric waste and the toxicity of the cyanoborohydride. In many cases, the borane oxime reduction leads to overreduction to the corresponding primary amine (J. Chem. Soc. Perkin Trans. I, 1985, 2039).

[0005] WO 13 / 127764 discloses the heterogeneous hydrogenation of oximes and oxime ethers to hydroxylamines in the presence of a platinum-carbon catalyst and a strong acid such as sulfuric acid or hydrochloric acid. The main disadvantages of this method are the harsh reaction conditions and limited scope, for example, other easily reducible functional groups on the substrate such as nitro or alkenyl are not tolerated. In some cases, the heterogeneous hydrogenation of oximes to hydroxylamines is subject to overreduction to the corresponding primary amines and catalyst poisoning.

[0006] There are few reports on the homogeneous hydrogenation of oximes and oxime ethers to hydroxylamines. Transition metal-catalyzed hydrogenation of oximes is generally plagued by overreduction to the corresponding primary amines and low catalytic efficiency (cobalt catalysts - Bull. Chem. Soc. Jpn. [Bulletin of the Chemical Society of Japan] 1963, 36, 763; ruthenium catalysis - Tetrahedron: Asymmetry [Tetrahedron: Asymmetry] 1992, 3, 1283; rhodium catalysis - J. Chem. Soc. Chem. Commun. [Journal of Chemical Society Chemical Communications] 1995, 1767; Org. Lett. [Journal of Organic Chemistry] 2013, 15, 484; Tetrahedron: Asymmetry [Tetrahedron: Asymmetry] 2016, 27, 268; iridium catalysis - Synth. Commun. [Synthetic Communications] 2001, 31, 2767).

[0007] EP1862446 discloses the homogeneous iridium-catalyzed hydrogenation of ethyl 3-methoxyiminobutyrate derivatives using a combination of 60 bar of hydrogen, bis(1,5-cyclooctadiene)iridium(I) tetrafluoroborate and (R)-1-[(S)-2-diphenylphosphinoferrocenyl]ethyldi-tert-butylphosphine. However, in practice this method is limited to the scope of oximes of 3-ketoesters. This substrate tautomerizes to 2,3-unsaturated esters, so the oxime hydrogenation reaction is actually a carbon-carbon double bond reduction.

[0008] Angew.Chem.Int.Ed. [German Angewandte Chemie] 2014, 53, 13278 and Chem.Eur.J. [European Journal of Chemistry] 2015, 21, 17583 disclose the homogeneous hydrogenation of oxime derivatives using tris(pentafluorophenyl)borane catalyst, however, the method is limited to oxime ethers with bulky oxygen substituents (tert-butyl or Si[(CH3)2CH]3) and uses relatively harsh reaction conditions (5% catalyst, 60-100 bar H2).

[0009] Org.Biomol.Chem [Organic and Biomolecular Chemistry] 2013, 11, 6934 and related patent applications WO 13 / 153407 and WO 13 / 153408 disclose certain cyclopentadienyl iridium catalysts for the reductive amination of ketones and aldehydes by the corresponding imines. However, it has been found that the disclosed catalysts are inefficient for the reduction of oximes.

[0010] We have now found that by using certain selected iridium catalysts, oximes can be reduced using hydrogen under relatively mild conditions.

[0011] According to the present invention, there is provided a method for hydrogenating an oxime of formula (I) to produce a hydroxylamine salt of formula (II) by reacting oxime (I) with hydrogen in the presence of an iridium catalyst of formula (IIIa) or formula (IIIb) and an acid;

[0012]

[0013]

[0014] Where R 1 , R 2 and R 3each independently is hydrogen, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 cyanoalkyl, C1-C6 alkoxy C1-C8 alkyl, di(C1-C6 alkoxy)C1-C8 alkyl, C1-C8 haloalkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, phenyl, phenylC1-C3 alkyl or heteroaryl, and wherein the cycloalkyl and phenyl moieties are each optionally substituted with 1 to 5 groups selected from hydroxyl, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, phenyl, heteroaryl, C1-C6 alkoxycarbonyl, acylamino, amido, cyano, nitro and C2-C6 alkenyl; or

[0015] R 1 and R 2 Together with the carbon atoms to which it is attached, it can form a 4- to 8-membered saturated cycloalkyl or heterocyclyl ring, wherein the heterocyclic moiety is a non-aromatic monocyclic ring containing 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from N, O and S.

[0016] Preferably, R 1 , R 2 and R 3 each independently is hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 cyanoalkyl, C1-C3 alkoxy C1-C4 alkyl, di(C1-C3 alkoxy)C1-C4 alkyl, C1-C4 haloalkyl, C2-C3 alkenyl, C3-C6 cycloalkyl, phenyl, phenylC1-C2 alkyl or heteroaryl, and wherein the cycloalkyl and phenyl moieties are each optionally substituted with 1, 2 or 3 groups selected from hydroxy, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 haloalkyl, C1-C3 alkoxy, phenyl, heteroaryl, C1-C3 alkoxycarbonyl, acylamino, amido, cyano, nitro and C2-C3 alkenyl; or

[0017] R 1 and R 2 Together with the carbon atoms to which they are attached, they can form a 4- to 6-membered saturated cycloalkyl or heterocyclyl ring, wherein the heterocyclic moiety is a non-aromatic monocyclic ring containing 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from N, O and S.

[0018] More preferably, R 1 , R 2 and R 3Each is independently hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C3 alkoxy C1-C4 alkyl, di(C1-C3 alkoxy) C1-C4 alkyl, C1-C4 haloalkyl, C2-C3 alkenyl, phenyl and phenyl C1-C2 alkyl, and wherein the phenyl portion may be optionally substituted by halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 alkoxycarbonyl, hydroxyl and nitro, preferably by 1, 2 or 3 groups selected from chlorine, methyl, methoxy, methoxycarbonyl and nitro.

[0019] In one set of embodiments, R 1 represents tert-butyl, methoxycarbonyl, 1,1-dimethoxymethyl, cyclopropyl, phenyl or benzyl, wherein the aromatic ring of each phenyl or benzyl moiety is optionally substituted by 1, 2 or 3 groups independently selected from chlorine, methyl, methoxy, methoxycarbonyl and nitro;

[0020] R 2 represents hydrogen, methyl or ethyl; and

[0021] R 3 represents hydrogen, methyl, ethyl, isopropyl, tert-butyl, allyl or benzyl.

[0022] In another set of embodiments, R 1 represents tert-butyl, methoxycarbonyl, 1,1-dimethoxymethyl, cyclopropyl, 2-methylphenyl, 2-chlorophenyl, 4-nitrophenyl, 4-methoxyphenyl, 2-bromobenzyl, 4-methoxybenzyl or 2,4,6-trichlorobenzyl;

[0023] R 2 represents hydrogen, methyl or ethyl; and

[0024] R 3 represents hydrogen, methyl, ethyl, isopropyl, tert-butyl, allyl or benzyl.

[0025] In one set of embodiments, R 1 represents phenyl or benzyl, wherein the aromatic ring of each phenyl or benzyl moiety is optionally substituted by 1, 2 or 3 groups independently selected from chloro, methyl, methoxy, methoxycarbonyl or nitro;

[0026] R 2 represents hydrogen or methyl; and

[0027] R 3 represents hydrogen, methyl, ethyl, isopropyl, tert-butyl, allyl or benzyl.

[0028] In a most preferred embodiment, the hydroxylamine having formula (II) is N-methoxy-1-(2,4,6-trichlorophenyl)propane-2-amine (II-1).

[0029] R 6 , R 7 , R 8 , R 9 and R 10 are each independently hydrogen or C1-C3 alkyl. 6 , R 7 , R 8 , R 9 and R 10 are each independently hydrogen or methyl, more preferably, R 6 , R 7 , R 8 , R 9 and R 10 Each represents a methyl group.

[0030] Means a bidentate chelating ligand comprising at least one carbon atom coordinated to the iridium and at least one nitrogen atom coordinated to the iridium. Many metal chelating ligands are known to those skilled in the art and will be suitable for use in the present invention. Particularly suitable bidentate chelating ligands are those in which the coordinated nitrogen has a 1,4-relationship with the carbon atom, preferably those in which the coordinated carbon atom forms part of a benzene ring, wherein the benzene ring is substituted in the ortho position.

[0031] Preferred bidentate chelating C,N ligands are those having structure (IV), (IVa) or (IVb):

[0032]

[0033] Where R 11A , R 11B , R 11C , R 11D , R 11E , R 13A , R 13B , R 13C and R 13D Each is independently hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, hydroxy C1-C8 alkoxy, C1-C8 alkoxy C1-C6 alkoxy, C1-C8 alkoxycarbonyl, C1-C8 alkoxycarbonyl C1-C6 alkoxy, C1-C8 alkylcarbonyl C1-C6 alkoxy, phenoxy or nitro;

[0034] R 12 is hydrogen, C1-C8 alkyl or phenyl; and wherein each phenyl moiety is optionally substituted with 1 to 5 groups selected from C1-C8 alkyl and C1-C8 alkoxy; or

[0035] Wherein the bidentate chelating ligand is (IVa) or (IVb), R11A and R 13D Together with the carbon atom to which it is attached, it can form a 5- or 6-membered unsaturated ring. 11A and R 13D Together with the carbon atom to which it is attached, it can form a 6-membered unsaturated ring; or

[0036] R 12 and R 13D Together with the carbon atom to which it is attached, it can form a 5- to 8-membered partially saturated or unsaturated cycloalkyl or heterocyclyl ring, wherein the heterocyclyl moiety is a non-aromatic ring containing 1 or 2 heteroatoms, and wherein the heteroatoms are independently selected from N, O and S. In one embodiment, R 12 and R 13D Together with the carbon atoms to which they are attached, they can form a 6- to 8-membered partially saturated or unsaturated cycloalkyl or heterocyclyl ring, wherein the heterocyclic moiety is a non-aromatic ring containing 1 or 2 heteroatoms, wherein the heteroatoms are independently selected from N, O and S.

[0037] Preferably, R 11A , R 11B , R 11C , R 11D , R 11E , R 13A , R 13B , R 13C and R 13D are each independently hydrogen, halogen, C1-C3 alkoxy, hydroxy C1-C3 alkoxy, C1-C3 alkoxy C1-C3 alkoxy, C1-C3 alkoxycarbonyl C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkoxy or nitro, and R 12 is hydrogen, C1-C3 alkyl or phenyl; and wherein each phenyl moiety is optionally substituted by 1 to 3 groups selected from C1-C3 alkyl and C1-C3 alkoxy; more preferably, R 11A , R 11B , R 11C , R 11D , R 11E , R 13A , R 13B , R 13C and R 13D are each independently hydrogen, halogen, C1-C3 alkoxy, hydroxy C1-C3 alkoxy, C1-C3 alkoxy C1-C3 alkoxy or C1-C3 alkoxycarbonyl C1-C3 alkoxy, and R 12 is hydrogen, C1-C3 alkyl or phenyl; and wherein each phenyl moiety is optionally substituted with 1 to 3 groups selected from C1-C3 alkyl and C1-C3 alkoxy; or

[0038] Wherein the bidentate chelating ligand is (IVa) or (IVb), R 11A and R 13D Together with the carbon atom to which it is attached, it can form a 5-membered or 6-membered unsaturated ring, preferably a 6-membered unsaturated ring; or

[0039] R 12 and R 13D Together with the carbon atom to which it is attached, it can form a 5- to 7-membered, preferably 6- or 7-membered, partially saturated cycloalkyl or heterocyclyl ring, wherein the heterocyclic moiety is a non-aromatic ring containing one O atom. In one embodiment, R 12 and R 13D Together with the carbon atom to which it is attached it can form a 5- or 6-membered partially saturated cycloalkyl or heterocyclyl ring, wherein the heterocyclic moiety is a non-aromatic ring containing one O atom.

[0040] More preferably, R 11A , R 11B , R 11C , R 11D , R 11E , R 13A , R 13B , R 13C and R 13D are each independently hydrogen, methyl, methoxy, ethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, methoxycarbonyl-methoxy, isopropyloxycarbonyl-methoxy or nitro, and R 12 is hydrogen, methyl or phenyl; and wherein each phenyl moiety is optionally substituted with a single methoxy group; more preferably, R 11A , R 11B , R 11C , R 11D , R 11E , R 13A , R 13B , R 13C and R 13D are each independently hydrogen, methyl, methoxy, ethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, methoxycarbonyl-methoxy, or isopropyloxycarbonyl-methoxy, or

[0041] R 12 and R 13D Together with the carbon atom to which it is attached it can form a 6- or 7-membered partially saturated cycloalkyl or heterocyclyl ring, wherein the heterocyclic moiety is a non-aromatic ring containing one oxygen atom.

[0042] In one embodiment, R 11A , R 11B , R 11C , R 11D , R 11E , R 13A, R 13B , R 13C and R 13D Each is independently hydrogen, C1-C8 alkyl, C1-C8 alkoxy or nitro.

[0043] Examples of bidentate chelating ligands are compounds having formula (IV-1), (IV-2), (IV-3), (IV-5), (IV-6), (IV-7), (IV-8), (IV-9), (IV-10), (IV-11) or (IV-12), as shown below:

[0044]

[0045] X represents an anionic group, i.e. a group with a net negative charge, and wherein X is not a halogen. In complex (IIIa) wherein X is a halogen, we have found that the anionic group binds too tightly to the metal and such complexes do not produce sufficient amounts of catalytically active hydride intermediates under neutral or acidic hydrogenation conditions. Examples of suitable anionic groups X include those having the formula R 14 -SO2O- or R 15 -C(O)O- anionic ligand, where

[0046] R 14 Halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 haloalkyl or phenyl, wherein the phenyl moiety is optionally substituted by 1, 2, 3 or 4 groups which may be the same or different and are selected from R 16 Substituents are substituted;

[0047] R 16 It is C 1-4 Alkyl, C 1-4 Haloalkyl, nitro or halogen, preferably methyl, ethyl, trifluoromethyl, nitro or halogen, more preferably methyl or halogen, even more preferably methyl, chlorine or fluorine.

[0048] Preferably, R 14 is hydroxy, methyl, trifluoromethyl, phenyl or tolyl.

[0049] R 15 It is C 1-6 haloalkyl or phenyl, wherein the phenyl moiety is optionally substituted by 1, 2, 3 or 4 groups which may be the same or different and are selected from R 17 substituted by a substituent.

[0050] R 17 It is C 1-4 Alkyl, C 1-4 Haloalkyl, nitro or halogen.

[0051] Preferably, R 15 It is trifluoromethyl.

[0052] In one embodiment, X represents a compound having the formula R 14 In one embodiment, X is methanesulfonate, toluenesulfonate, nosylate, sulfate, bisulfate, trifluoromethanesulfonate or trifluoroacetate.

[0053] Y represents a neutral ligand, i.e. a ligand without an overall charge. Examples of neutral ligands include, but are not limited to, H2O, alcohols, ethers, ketones, esters, amides and nitrile. Preferably, Y is H2O, PhCN or MeCN, more preferably H2O or MeCN, and most preferably Y is H2O.

[0054] Z represents an anionic group, i.e. a group with a net negative charge, and wherein Z is not a halogen. Examples of anionic groups include those having the formula R 14 -SO2O - The ligand (where R 14 is described above), tetrafluoroborate, hexafluorophosphate, perchlorate, tetraphenylborate, tetrakis(3,5-bis(trifluoromethyl)phenyl)borate, tetrakis(pentafluorophenyl)borate, fluorinated alkoxyaluminate, methanesulfonate, trifluoromethanesulfonate, toluenesulfonate, nitrate, hydrogensulfate or sulfate, and other weakly coordinating anionic groups. Preferably, Z has the formula R 14 -SO2O - (where R 14 The sulfonate is a methanesulfonate, a sulfate, a hydrogensulfate, a tetrafluoroborate, a hexafluorophosphate, a tetraphenylborate or a tetrakis(3,5-bis(trifluoromethyl)phenyl)borate as described above, more preferably a methanesulfonate or a tetrafluoroborate.

[0055] Also provided is a process wherein N-methoxy-1-(2,4,6-trichlorophenyl)propane-2-amine (II-1) as produced above is further reacted with 3-(difluoromethyl)-1-methyl-pyrazole-4-carbonyl chloride (XII) to provide 3-(difluoromethyl)-N-methoxy-1-methyl-N-[1-methyl-2-(2,4,6-trichlorophenyl)ethyl]pyrazole-4-carboxamide (XIII):

[0056]

[0057] In one embodiment of the present invention, the iridium catalyst is a compound having formula (III-1), (III-11), (III-17), (III-18) or (III-19), preferably the iridium catalyst is a compound having formula (III-1), and further provided are compounds having formula (III-1), (III-11), (III-17), (III-18) or (III-19), preferably provided are compounds having formula (III-1):

[0058]

[0059] In another embodiment of the present invention, a compound having formula (IIIc) or (IIId) is provided:

[0060]

[0061] Where R 6 , R 7 , R 8 , R 9 and R 10 are each independently hydrogen or C1-C3 alkyl. 6 , R 7 , R 8 , R 9 and R 10 are each independently hydrogen or methyl, more preferably R 6 , R 7 , R 8 , R 9 and R 10 Each represents a methyl group;

[0062] Where R 11A , R 11B , R 11C , R 11D , R 11E , R 13A , R 13B , R 13C and R 13D Each is independently hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, hydroxy C1-C8 alkoxy, C1-C8 alkoxy C1-C6 alkoxy, C1-C8 alkoxycarbonyl, C1-C8 alkoxycarbonyl C1-C6 alkoxy, C1-C8 alkylcarbonyl C1-C6 alkoxy, phenoxy or nitro;

[0063] R 12 is hydrogen, C1-C8 alkyl or phenyl; and wherein each phenyl moiety is optionally substituted with 1 to 5 groups selected from C1-C8 alkyl and C1-C8 alkoxy; or

[0064] R 12 and R 13D Together with the carbon atom to which it is attached, it can form a 5- to 8-membered partially saturated or unsaturated cycloalkyl or heterocyclyl ring, wherein the heterocyclic moiety is a non-aromatic ring containing 1 or 2 heteroatoms, and wherein the heteroatoms are independently selected from N, O and S. In one embodiment, R 12 and R 13D Together with the carbon atoms to which it is attached, it can form a 6- to 8-membered partially saturated or unsaturated cycloalkyl or heterocyclyl ring, wherein the heterocyclic moiety is a non-aromatic ring containing 1 or 2 heteroatoms, wherein the heteroatoms are independently selected from N, O and S;

[0065] X is methanesulfonate, toluenesulfonate, nitrobenzenesulfonate, sulfate, hydrogensulfate, trifluoromethanesulfonate or trifluoroacetate;

[0066] Y is H2O, PhCN or MeCN; and

[0067] Z is methanesulfonate, toluenesulfonate, nitrobenzenesulfonate, sulfate, hydrogensulfate, trifluoromethanesulfonate, tetrafluoroborate, hexafluorophosphate, tetraphenylborate or tetrakis(3,5-bis(trifluoromethyl)phenyl)borate.

[0068] Preferably, R 11A , R 11B , R 11C , R 11D , R 11E , R 13A , R 13B , R 13C and R 13D are each independently hydrogen, halogen, C1-C3 alkoxy, hydroxy C1-C3 alkoxy, C1-C3 alkoxy C1-C3 alkoxy, C1-C3 alkoxycarbonyl C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkoxy or nitro, and R 12 is hydrogen, C1-C3 alkyl or phenyl; and wherein each phenyl moiety is optionally substituted by 1 to 3 groups selected from C1-C3 alkyl and C1-C3 alkoxy; more preferably, R 11A , R 11B , R 11C , R 11D , R 11E , R 13A , R 13B , R 13C and R 13D are each independently hydrogen, halogen, C1-C3 alkoxy, hydroxy C1-C3 alkoxy, C1-C3 alkoxy C1-C3 alkoxy or C1-C3 alkoxycarbonyl C1-C3 alkoxy, and R12 is hydrogen, C1-C3 alkyl or phenyl; and wherein each phenyl moiety is optionally substituted with 1 to 3 groups selected from C1-C3 alkyl and C1-C3 alkoxy; or

[0069] R 12 and R 13D Together with the carbon atom to which it is attached, it can form a 5- to 7-membered, preferably 6- or 7-membered partially saturated cycloalkyl or heterocyclyl ring, wherein the heterocyclic moiety is a non-aromatic ring containing one O atom. In one embodiment, R 12 and R 13D Together with the carbon atom to which it is attached it can form a 5- or 6-membered partially saturated cycloalkyl or heterocyclyl ring, wherein the heterocyclic moiety is a non-aromatic ring containing one O atom.

[0070] More preferably, R 11A , R 11B , R 11C , R 11D , R 11E , R 13A , R 13B , R 13C and R 13D are each independently hydrogen, methyl, methoxy, ethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, methoxycarbonyl-methoxy, isopropyloxycarbonyl-methoxy or nitro, and R 12 is hydrogen, methyl or phenyl; and wherein each phenyl moiety is optionally substituted with a single methoxy group; more preferably, R 11A , R 11B , R 11C , R 11D , R 11E , R 13A , R 13B , R 13C and R 13D are each independently hydrogen, methyl, methoxy, ethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, methoxycarbonyl-methoxy, or isopropyloxycarbonyl-methoxy; or

[0071] R 12 and R 13D Together with the carbon atom to which it is attached, it can form a 6- or 7-membered, preferably 6-membered, partially saturated cycloalkyl or heterocyclyl ring, wherein the heterocyclic moiety is a non-aromatic ring containing one O atom.

[0072] As used herein, the term "halogen" or "halo" refers to fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo), preferably fluorine, chlorine or bromine. Most preferably, the halogen is chlorine.

[0073] As used herein, cyano refers to a -CN group.

[0074] As used herein, the term "hydroxyl" or "hydroxy" refers to an -OH group.

[0075] As used herein, amino refers to a -NH2 group.

[0076] As used herein, acylamino means -NH(C=O)R a Group, where R a is a C1-C4 alkyl group as generally defined below.

[0077] As used herein, amide refers to -(C=O)NR a R a Group, where R a is independently selected from hydrogen or a C1-C4 alkyl group as generally defined below.

[0078] As used herein, nitro refers to a -NO2 group.

[0079] As used herein, the term "C1-C8 alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to six carbon atoms, and attached to the remainder of the molecule by a single bond. C1-C6 alkyl, C1-C4 alkyl, C1-C3 alkyl, and C1-C2 alkyl should be interpreted accordingly. 1-8 Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, and 1-dimethylethyl (tert-butyl). A "C1-C2 alkylene" group refers to the corresponding definition of C1-C2 alkyl, except that such a group is attached to the remainder of the molecule by two single bonds. Examples of C1-C2 alkylene groups are -CH2- and -CH2CH2-.

[0080] As used herein, the term "C2-C6 alkenyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one double bond which may have an (E)- or (Z)-configuration, having from two to six carbon atoms, attached to the remainder of the molecule by a single bond. Examples of C2-C6 alkenyl include, but are not limited to, ethenyl (vinyl), prop-1-enyl, prop-2-enyl (allyl), and but-1-enyl.

[0081] As used herein, the term "C1-C8 alkoxy" refers to a group having the formula -OR a A group in which R a is C as defined above 1-8 Alkyl groups. The terms C1-C6 alkoxy, C1-C4 alkoxy, C1-C3 alkoxy and C1-C2 alkoxy should be interpreted accordingly. Examples of C1-C6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy and tert-butoxy.

[0082] As used herein, the term "C1-C8 haloalkyl" refers to a C1-C8 alkyl group as generally defined above, which is substituted by one or more halogen atoms, which may be the same or different. Examples of C1-C8 haloalkyl include, but are not limited to, fluoromethyl, fluoroethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and 3,3,3-trifluoropropyl.

[0083] As used herein, the term "C1-C8 haloalkoxy" refers to a C1-C8 alkoxy group as generally defined above, substituted by one or more halogen atoms which may be the same or different.

[0084] As used herein, the term "hydroxy C1-C8 alkyl" refers to a C1-C8 alkylene group as generally defined above, substituted with one or more hydroxy groups as defined above.

[0085] As used herein, the term "hydroxy C1-C8 alkoxy" refers to a C1-C8 alkoxy group as generally defined above, substituted by one or more hydroxy groups as defined above.

[0086] As used herein, the term "cyano C1-C8 alkyl" refers to a C1-C8 alkylene group as generally defined above, substituted with one or more cyano groups as defined above.

[0087] As used herein, the term "C1-C8 alkoxy C1-C6 alkoxy" refers to a b OR a O-group, where R b is a C1-C8 alkyl group as generally defined above, and R ais a C1-C6 alkylene group as generally defined above.C1-C8 alkoxy Examples of C1-C6 alkoxy groups include, but are not limited to, methoxymethoxy, ethoxymethoxy, and methoxyethoxy.

[0088] As used herein, the term "C1-C8 alkoxycarbonyl" refers to a a OC(O)-, where R a is a C1-C8 alkyl group as generally defined above.

[0089] As used herein, the term "C1-C6 alkoxy C1-C8 alkyl" refers to a a OR b - a group, wherein R a are each independently a C1-C6 alkyl group as generally defined above, and R b is a C1-C8 alkylene group as generally defined above.

[0090] As used herein, the term "di(C1-C6 alkoxy)C1-C8 alkyl" refers to a a O)2R b - a group, wherein R a are each independently a C1-C6 alkyl group as generally defined above, and R b is a C1-C8 alkylene group as generally defined above.

[0091] As used herein, the term "C1-C8 alkoxycarbonyl C1-C6 alkoxy" refers to a a OC(O)R b - a group, wherein R a is a C1-C8 alkyl group as generally defined above, and R b is a C1-C6 alkyl group as generally defined above.

[0092] As used herein, the term "C1-C8 alkylcarbonyl C1-C6 alkoxy" refers to a a C(=O)OR b O-group, where R a is a C1-C8 alkyl group as generally defined above, and R b is a C1-C6 alkyl group as generally defined above.

[0093] As used herein, the term "C3-C8 cycloalkyl" is a monocyclic group that is saturated or partially unsaturated and contains 3 to 8 carbon atoms. C3-C6 cycloalkyl and C3-C5 cycloalkyl should be interpreted accordingly. Examples of C3-C8 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentene-1-yl, cyclopentene-3-yl and cyclohexene-3-yl.

[0094] As used herein, the term "phenyl C1-C3 alkyl" refers to a benzene ring attached to the remainder of the molecule via a C1-C3 alkyl group as defined above. Examples of phenyl C1-C3 alkyl include, but are not limited to, benzyl.

[0095] As used herein, the term "heteroaryl" generally refers to a 5 or 6-membered monocyclic aromatic ring group containing 1 or 2 heteroatoms selected individually from nitrogen, oxygen and sulfur. The heteroaryl group may be bonded to the remainder of the molecule via a carbon atom or a heteroatom. Examples of heteroaryl groups include, but are not limited to, furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyrimidinyl and pyridyl.

[0096] As used herein, =0 represents an oxo group such as found in a carbonyl (-C(=0)-) group.

[0097] As used herein, O-mesyl or mesylate refers to a group having the formula -OS(O)2CH3.

[0098] As used herein, O-toluenesulfonyl or tosylate refers to a group having the formula -OS(O)2C6H4-p-CH3.

[0099] As used herein, O-nitrobenzenesulfonyl or nitrobenzenesulfonate refers to a group having the formula -OS(O)2C6H4-p-NO2.

[0100] As used herein, O-trifluoromethanesulfonyl or triflate refers to a group having the formula -OS(O)2CF3.

[0101] As used herein, O-trifluoroacetyl or trifluoroacetate refers to a group having the formula -OC(O)CF3.

[0102] As used herein, tetrafluoroborate refers to a tetrafluoroborate having the formula BF4 - The group.

[0103] As used herein, tetraphenylborate refers to a tetraphenylborate having the formula B(C6H5)4 - The group.

[0104] As used herein, tetrakis(3,5-bis(trifluoromethyl)phenyl)boryl refers to a group having the formula B(3,5-(CF3)2C6H3)4 - The group.

[0105] As used herein, hexafluorophosphate refers to a phosphate having the formula PF6 - The group.

[0106] As used herein, sulfate refers to a compound having the formula SO42- The group.

[0107] As used herein, bisulfate refers to a compound having the formula HSO4 - The group.

[0108] As described in WO 10 / 063700, certain hydroxylamines and hydroxylamine salts of the general formula (II) are known to be intermediates for pesticidally active compounds.

[0109] Suitable iridium catalysts (IIIa) can be prepared by halogen exchange from known cyclometallated chlorocomplexes (VI) Org. Biomol. Chem. [Organic and Biomolecular Chemistry], 2013, 11, 6934; WO 2013 / 153407 uses suitable metal salts (XM, wherein X is as defined in (IIIa), and M represents a metal), such as silver methanesulfonate, silver sulfate, silver p-toluenesulfonate. Alternatively, iridium catalysts (IIIa) can be prepared by cyclometallation of iridium complexes (VII) (wherein X is as defined in (IIIa)) and suitable C, N ligands (e.g., N, 1-bis(4-methoxyphenyl)ethyleneimine). This reaction is preferably carried out in a non-coordinating or weakly coordinating solvent (e.g., dichloromethane, chloroform, 1,2-dichloroethane or tetrahydrofuran).

[0110]

[0111] If the catalyst synthesis is carried out in the presence of a coordinating solvent such as nitrile or water, the complex of structure (IIIb) (Y and Z are as defined above) can be isolated.

[0112] According to the process of the present invention, the amount of the iridium catalyst is generally between 0.001 mol% and 5 mol%, preferably between 0.01 mol% and 1 mol%, based on the moles of the oxime substrate.

[0113] According to the process of the present invention, the hydrogen pressure is generally between 1 and 100 bar, preferably between 5 and 80 bar, more preferably between 7 and 60 bar, and most preferably between 10 and 50 bar.

[0114] According to the process of the present invention, the reaction temperature is usually between -20°C and 120°C, preferably between 0°C and 100°C, more preferably between 0°C and 80°C, and even more preferably between 10°C and 60°C.

[0115] Oxime hydrogenation is preferably carried out in the presence of at least a stoichiometric amount of acid. Therefore, the molar amount of the acid should be equal to or higher than the amount of the oxime substrate to be reduced, for example at least 1 to 3 molar equivalents, preferably 1 to 2 molar equivalents and particularly 1, 1.1 or 2 molar equivalents. The pKa of the acid must enable it to at least partially protonate the oxime substrate and the hydroxylamine product. Therefore, the pKa of the acid is preferably lower than the pKa of the product hydroxylamine salt (II). Acids suitable for most oxime substrates include but are not limited to methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, sulfuric acid, trifluoroacetic acid and trifluoromethanesulfonic acid, preferably methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, sulfuric acid and trifluoromethanesulfonic acid. More preferably, the acid is selected from methanesulfonic acid, camphorsulfonic acid and sulfuric acid.

[0116] Typically, the oxime hydrogenation reaction is carried out in the presence of a solvent, preferably an organic solvent such as an alcohol, an ester, an ether or a hydrocarbon. Preferred solvents are alcohols such as methanol, ethanol, isopropanol, 2-methyl-2-butanol and 2-butanol, and ethers such as tetrahydrofuran, 1,2-dimethoxyethane and methyltetrahydrofuran. The most preferred solvents are secondary alcohols such as isopropanol and 2-butanol, and ethers such as tetrahydrofuran and methyltetrahydrofuran. Preferably, the solvent is isopropanol.

[0117] The present invention also relates to a process for the ionic hydrogenation of other unsaturated substrates, such as acyl enamines, imines, enamines, heterocycles, aldehydes and ketones, with hydrogen in the presence of an iridium catalyst having formula (IIIa) or formula (IIIb) and optionally an acid.

[0118] Examples

[0119] The following examples serve to illustrate the present invention.

[0120] The following abbreviations are used: s = singlet; bs = broad singlet; d = doublet; br d = broad doublet; dd = double of doublets; dt = double of triplets; t = triplet, tt = triplet of triplets, q = quartet, sept = septet; m = multiplet; RT = room temperature, R t = retention time, MH + = molecular weight of the molecular cation; DCM = dichloromethane.

[0121] Recorded on a Bruker Avance III 400 spectrometer equipped with a BBFOplus probe at 400 MHz / 376.6 MHz, respectively 1 H and 19 F NMR spectrum.

[0122] The following starting materials are commercially available:

[0123] Chloro(pentamethylcyclopentadienyl)[(2-pyridinyl-kN)phenyl-kC]iridium(III) (CAS=945491-51-0);

[0124] Chloro(pentamethylcyclopentadienyl){5-nitro-2-{1-[(4-methoxyphenyl)imino-kN]ethyl}phenyl-kC}iridium(III) (CAS=1439402-25-1);

[0125] 7-(2-Methoxyethoxy)tetralin-1-one (CAS=1697644-15-7);

[0126] Methyl 2-(4-oxotetralin-6-yl)oxyacetate (CAS=1937197-95-9);

[0127] 7-(2-Hydroxyethoxy)tetralin-1-one (CAS=1260011-13-9).

[0128] The following starting materials were prepared according to literature procedures:

[0129] Iridium, chloro[5-(ethylmethylamino)-2-(2-pyridyl-κN)phenyl-κC][(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl] (CAS=1379114-67-6), according to Chem. Eur. J. [European Chemical Journal] 2012, 18, 6063, 6078.

[0130] Iridium, chloro[4,5-dimethoxy-2-[1-[(4-methoxyphenyl)imino-κN]ethyl]phenyl-κC][(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl] (CAS=1507388-46-6), according to Chem. Eur. J. [European Journal of Chemistry] 2014, 20, 245-252.

[0131] Iridium, chloro[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl][5,6,7,8-tetrahydro-3-methoxy-8-[(4-methoxyphenyl)imino-κN]-1-naphthyl-κC] (CAS=1469468-10-7), according to SYNLETT [Synthesis Express] 2014, 25, 81-84.

[0132] Iridium, chloro[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl][5,6,7,8-tetrahydro-8-[(4-methoxyphenyl)imino-κN]-1-naphthyl-κC] (CAS=1469468-08-3), according to SYNLETT [Synthesis Express] 2014, 25, 81-84.

[0133] Iridium, chloro[4,5-dimethoxy-2-[1-[(4-methoxyphenyl)imino-κN]ethyl]phenyl-κC][(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl] (CAS=1507388-46-6), according to Chem. Eur. J. [European Chemical Journal] 2014, 20, 245-252.

[0134] Iridium (2+), [(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]-, sulfate trihydrate (CAS=254734-81-1) according to WO 2008 / 093668.

[0135] General Procedure 1 :Synthesis of N-aryl ketimine ligands having formula (IV)

[0136] The corresponding ketone (1.0 equivalent), 4-methoxyaniline (1.1 equivalents) and triethylamine (6.0 equivalents) and DCM (0.4M) are loaded into a dry reaction flask. At -78 ° C, a DCM solution of titanium tetrachloride (0.6eq.) is added dropwise (making the reaction 0.2M in total). The reaction mixture is stirred for 2-80h. The reaction mixture is quenched with saturated Na2CO3 solution, and the mixture is filtered through a diatomaceous earth bed. The water layer is extracted with DCM, the organic layer is dried with Na2SO4, filtered and concentrated in vacuo to obtain a crude product. The crude product is purified by (a) using Et2O or cyclohexane crystallization, (b) column chromatography or (c) as a crude product.

[0137] Table 1: Ligands prepared according to general procedure 1:

[0138]

[0139]

[0140]

[0141] General Procedure 2: Synthesis of Iridium-Chloro-Complexes of Formula (VI)

[0142] Dichloro(pentamethylcyclopentadienyl)iridium(III) dimer (1.0 eq.), sodium acetate (10.0 eq.) and the corresponding ligand (2.2 eq.) were charged into a dry reaction flask. DCM (40 mL / mmol [Ir]) was added under argon and the reaction mixture was stirred at room temperature. After the reaction was complete (by 1 H-NMR monitoring of conversion), the reaction mixture was The mixture was filtered through a plug and washed with DCM. The mother liquor was concentrated to dryness to afford the iridium-chloro complex. For further purification procedures, please refer to the detailed description under each product.

[0143] Example 1: Preparation of (N,1,1-tri(4-methoxyphenyl)methylamine iridium chloride complex (VI-1)

[0144]

[0145] 4-Methoxyaniline (0.598 g), bis(4-methoxyphenyl)methanone (1.00 g), molecular sieves and toluene (8.0 mL) were placed in a single-necked round-bottom flask equipped with a magnetic stirrer and a condenser, and the reaction mixture was stirred under reflux for 24 h. The reaction mixture was cooled to RT and filtered through filter paper. The resulting filtrate was concentrated under vacuum to obtain N,1,1-tri(4-methoxyphenyl)methanamine.

[0146] In a single-necked round-bottom flask equipped with a magnetic stirrer, N,1,1-tri(4-methoxyphenyl)methanimine (324 mg), DCM (4.3 mL), dichloro(pentamethylcyclopentadienyl)-iridium(III) dimer (300 mg) and sodium acetate (150.0 mg) were placed, and the reaction mixture was stirred at reflux for 3 h. N,1,1-tri(4-methoxyphenyl)methanimine (100 mg) was added, and the mixture was stirred at reflux for another 30 minutes. The reaction mixture was then filtered through a pad of silica gel, and the filtrate was reduced under vacuum. The resultant solid was dissolved in boiling dichloroethane (5 mL), and MeOH (15 mL) was added. The mixture was placed in a freezer (-22° C.) overnight, and the resulting crystals were separated by decantation, washed with MeOH, and dried under vacuum to obtain 361 mg of the title compound (VI-1) as red crystals.

[0147] 1 H NMR (CDCl3) δ = 7.38 (d, J = 2.6Hz, 1H), 6.57-7.36 (m, 9H), 6.49 (dd, J = 8.4Hz, J = 2.6Hz, 1H), 3.90 (s, 3H), 3.77 (s, 3H), 3.75 (s, 3H), 1.47 (s, 15H) ppm.

[0148] Table 2: Iridium-chloro-complexes of formula (VI) prepared according to general procedure 2:

[0149]

[0150]

[0151]

[0152] General Procedure 3: Synthesis of Iridium-Mesylate Complexes of Formula (III)

[0153] Under argon, iridium-chloro complex (1.0 equiv.) and silver methanesulfonate (1.1 equiv.) were charged into a reaction flask and the reaction flask was wrapped with aluminum foil (silver methanesulfonate is photosensitive). CDCl3 (2.5 mL / mmol) was added and the reaction mixture was stirred under argon for 20 h. The reaction mixture was diluted with CDCl3 and filtered through a syringe filter (0.22 μm). The filtrate was concentrated under reduced pressure to provide iridium methanesulfonate complex. For further purification procedures, please see the detailed description under each product.

[0154] Example 2 :Preparation of (E)-4-methoxy-N-(1-(4-methoxyphenyl)ethylidene)aniline methanesulfonic acid iridium complex (III-1)

[0155]

[0156] Under argon, (E)-4-methoxy-N-(1-(4-methoxyphenyl)ethylidene)aniline iridium chloride complex (400 mg, CAS=1258964-48-5) and silver methanesulfonate (136 mg) were loaded into the reaction flask, and the reaction flask was wrapped with aluminum foil (silver methanesulfonate is photosensitive). CDCl3 (2 mL) was added, and the reaction mixture was stirred under argon for 20 h. The reaction mixture was diluted with another portion of CDCl3 (2 mL) and filtered through a syringe filter (0.22 μm). The filtrate was concentrated under reduced pressure to provide the title compound (III-1, 401 mg) as a yellow solid.

[0157] 1 H NMR(CDCl3)δ7.70(bd,J=2.6Hz,1H),7.46(d,J=8.4Hz,1H),6.98(bs,4H),6.63(dd,J=8. 4Hz, J=2.6Hz, 1H), 3.94 (s, 3H), 3.86 (s, 3H), 2.32 (s, 3H), 1.78 (s, 3H), 1.42 (s, 15H) ppm.

[0158] 13 C NMR (CDCl3) δ 182.2, 168.8, 162.3, 157.8, 143.4, 142.8, 129.8, 121.0, 108.5, 88.3, ​​55.5, 55.3, 39.1, 16.7, 8.8 ppm. The two carbon signals were not observed due to signal broadening.

[0159] Table 3: Iridium methanesulfonate complexes of formula (III) prepared according to General Procedure 3:

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166] Example 3 :Preparation of (E)-4-methoxy-N-(1-(4-methoxyphenyl)ethylidene)aniline iridium sulfate complex (III-14)

[0167]

[0168] Under argon, a reaction vial was charged with pentamethylcyclopentadienyl iridium sulfate complex (143 mg, CAS = [254734-81-1]) (E)-N,1-bis(4-methoxyphenyl)ethyleneimine (76 mg) and CD3OD (1.2 mL). The reaction vial was stirred overnight. 1 H NMR analysis indicated that the cyclometalated iridium complex was formed in 73% NMR yield.

[0169] 1 H NMR (CDCl3) δ7.65 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 2.2 Hz, 1H), 6.77 (dd, J = 8.4 Hz, J = 2.2 Hz, 1H), 3.94 (s, 3H), 3.87 (s, 3H), 2.42 (s, 3H), 1.42 (s, 15H) ppm. The four proton signals were not observed due to signal broadening.

[0170] Example 4 :Preparation of (E)-4-methoxy-N-(1-(4-methoxyphenyl)ethylidene)aniline iridium (acetonitrile) tetrafluoroborate complex (III-15)

[0171]

[0172] (E)-4-methoxy-N-(1-(4-methoxyphenyl)ethylidene)aniline iridium chloride complex (250 mg, CAS=1258964-48-5), sodium tetrafluoroborate (89 mg) and acetonitrile (1.6 mL) were charged into a reaction vial. The reaction mixture was stirred at RT for 48 h and filtered through a celite pad (washed with DCM). The filtrate was concentrated under vacuum and the solid residue was triturated with ether to give 246 mg of the title compound as a yellow solid.

[0173] 1 H NMR(CDCl3)δ7.52(d,J=8.4Hz,1H),7.27(d,J=2.4Hz,1H),7.00-7.20(bs,4H),6.72(dd,J= 8.4Hz, J=2.4Hz,1H),3.94(s,3H),3.88(s,3H),2.60(s,3H),2.42(s,3H),1.49(s,15H)ppm.

[0174] Example 5 :Preparation of (E)-4-methoxy-N-(1-(4-methoxyphenyl)ethylidene)aniline trifluoroacetic acid iridium complex (III-16)

[0175]

[0176] Into a reaction vial was charged (E)-4-methoxy-N-(1-(4-methoxyphenyl)ethylidene)aniline iridium chloride complex (250 mg, CAS=1258964-48-5), silver trifluoroacetate (107 mg) and CDCl3 (1.0 mL). The reaction mixture was stirred at RT for 20 h and filtered through a diatomaceous earth pad (washed with dichloromethane). The filtrate was concentrated and purified by column chromatography (silicon dioxide, ethyl acetate-cyclohexane gradient). The separated solid was dissolved in a minimum amount of dichloromethane and diluted with n-pentane. The product was crystallized in a refrigerator overnight. The product was recovered by decantation, washed with n-pentane and dried under vacuum to obtain 129 mg of the title compound as a yellow solid.

[0177] 1H NMR (CDCl3) δ7.66 (d, J = 2.2 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 6.09-7.10 (bm, 2H), 6.55-6.65 (m, 1H), 3.91 (s, 3H), 3.87 (s, 3H), 2.29 (s, 3H), 1.43 (s, 15H) ppm. Due to signal broadening, the two proton signals were not observed.

[0178] Example 6: Synthesis of hydroxylamine (II-1) via oxime hydrogenation

[0179]

[0180] In a 100mL Hastelloy (Hastelloy) reactor, (E)-N-methoxy-1-(2,4,6-trichlorophenyl)propane-2-imine (2.00g, 99:1=E / Z, 95%NMR purity) and a solid catalyst (III-1) (5.0mg) were loaded, the reactor was closed and flushed with argon. iPrOH (10mL, anhydrous, degassed with argon) and methanesulfonic acid (0.72mL) were added to the reactor under argon, and the reactor was purged with hydrogen (3x5 bar), pressurized to 50 bar H2 and stirred overnight at 23°C. Hydrogen was released, and the reactor was purged with argon again. GC and NMR analysis of the crude reaction mixture indicated complete conversion. The reaction mixture was slowly added to a saturated NaHCO3 solution (15mL) and water (10mL), and extracted with dichloromethane (2x15 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to give 1.97 g (97% NMR purity) of the desired product (II-1).

[0181] Example 7: Synthesis of hydroxylamine (II-1) by oxime hydrogenation under various conditions

[0182]

[0183] Conditions: Catalyst III-1, 1.5 eq methanesulfonic acid, iPrOH solvent (200 g substrate / 1 L solvent) unless otherwise specified.

[0184] Table 4: Reaction conditions and results according to Example 7

[0185]

[0186] In all reactions, there was high selectivity (>95%) towards the desired products.

[0187] Example 8: Synthesis of hydroxylamine (II-1) by oxime hydrogenation using various catalysts

[0188]

[0189] Conditions: 1.5 eq methanesulfonic acid, iPrOH solvent (200 g substrate / 1 L solvent), 0.1 mol% catalyst, 30 bar H2, RT, 16 h unless otherwise stated.

[0190] Table 5: Reaction conditions and results according to Example 8

[0191]

[0192] In all reactions, high selectivities (>95%) to the desired products were observed.

[0193] Example 9: Synthesis of hydroxylamine(II) via oxime hydrogenation, substrate range

[0194]

[0195] Conditions: 1.5 eq methanesulfonic acid, iPrOH solvent, 1 mol% catalyst III-1, 50 bar

[0196] H2, RT, 16h

[0197] Table 6: Hydroxylamine product (II) prepared according to Example 9:

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204] Example 10: Ionic Hydrogenation of Other Substrates - Synthesis of cis-N-[2-(2,4-dichlorophenyl)cyclobutyl]acetamide via Hydrogenation of Acyl Enamines

[0205]

[0206] N-[2-(2,4-dichlorophenyl)cyclobutenyl-1-yl]acetamide (256 mg), catalyst (III-1) (6.8 mg), methanesulfonic acid (48 mg) and isopropanol (4 mL) were loaded into a 50 mL glass vial. The glass vial was placed in a parallel autoclave purged with hydrogen (3 times) and hydrogenated for 16 h at 50 bar hydrogen and 23 ° C. Hydrogen was released and the reactor was purged with argon. GC and NMR analysis of the crude reaction mixture indicated complete conversion. The reaction mixture was slowly added to a saturated NaHCO solution (15 mL) and water (10 mL) and extracted with DCM (2x15 mL). The combined organic layer was dried with Na2SO4, filtered and evaporated to give 250 mg of cis-N-[2-(2,4-dichlorophenyl)cyclobutyl]acetamide. The analytical data are consistent with the literature: WO 15 / 003951.

[0207] Example 11: Ionic Hydrogenation of Other Substrates - Synthesis of 2-(Trifluoromethyl)piperidine via Heterocyclic Hydrogenation

[0208]

[0209] 2-trifluoromethylpyridine (144 mg), catalyst (III-1) (6.8 mg), methanesulfonic acid (144 mg) and isopropanol (4 mL) were loaded into a 50 mL glass vial. The glass vial was placed in a parallel autoclave purged with hydrogen (3 times) and hydrogenated for 16 h at 50 bar hydrogen and 50 ° C. Hydrogen was released and the reactor was purged with argon. GC and NMR analysis of the crude reaction mixture indicated complete conversion. The reaction mixture was evaporated and analyzed by NMR. It was found that the starting material was completely converted and formed 2-(trifluoromethyl)piperidine (CAS=154630-93-0).

[0210] Comparative Example 1:

[0211]

[0212] 96 diverse homogeneous catalysts - metal precursors (Rh, Ir, Pt, Ru, neutral / cationic) / ligand classes (monodentate / bidentate, phosphine, phosphite, etc.) were screened at 2% catalyst loading in two solvents (THF / TFA and MeOH) at T = 60°C, pressure H2 = 50 bar. The conversion to the desired product (II-1, labeled "Product" in the table below) was determined by GC and is based on area percentage.

[0213] Table 7:

[0214]

[0215]

[0216]

[0217]

[0218] These experiments demonstrate that commonly used combinations of metal precursors and ligands are not capable of homogeneously hydrogenating oxime substrates such as (I-1), as the content of the product (II-1) formed in all cases was <1%.

[0219] Comparative Example 2:

[0220]

[0221] Hydrogenation conditions: temperature = 60°C and pressure H2 = 60 bar, time = 20 h. Reaction conditions are as described in EP1862446. Conversion to the desired product ((II-1), marked as "Product" in the table below) was determined by GC and is based on area percentage.

[0222] Table 8:

[0223]

[0224] *SL-J002-1=(R)-1-[(SP)-2-(diphenylphosphino)ferrocenyl]ethyl di-tert-butylphosphine

[0225] In all cases, low selectivity was observed with no or very low yields of the desired product (II-1 in the table above labeled "Product"). These experiments demonstrate that the catalysts and conditions described in EP1862446A2 do not allow efficient hydrogenation of oxime substrates such as (II-1).

[0226] Comparative Example 3:

[0227]

[0228] As described in Org. Biomol. Chem., 2013, 11, 6934, the formation of the desired product (II-1) was not observed under the reaction conditions described above.

[0229] Comparative Example 4:

[0230]

[0231]

[0232] Under the reaction conditions described in the present invention, the formation of the desired product (II-1) was not observed, but using Iridium chloride complex (VI) (e.g., reported in Org. Biomol. Chem., 2013, 11, 6934; WO2013 / 153407). These experiments prove that Iridium halogen complex It cannot be used effectively as a catalyst in current processes.

[0233] Comparative Example 5:

[0234]

[0235] When using the present invention Acid-free Under the reaction conditions of , the formation of the desired product (II-1) was not observed. This experiment proves that the stoichiometric amount of a suitable acid is crucial in the process according to our invention.

Claims

1. A method for hydrogenating an oxime of formula (I) to produce a hydroxylamine salt of formula (II) by reacting oxime (I) with hydrogen in the presence of an iridium catalyst of formula (IIIa) or formula (IIIb) and an acid; in R 1 represents tert-butyl, methoxycarbonyl, 1,1-dimethoxymethyl, cyclopropyl, phenyl or benzyl, wherein the aromatic ring of each phenyl or benzyl moiety is optionally substituted by 1, 2 or 3 groups independently selected from chlorine, methyl, methoxy, methoxycarbonyl and nitro; R 2 represents hydrogen, methyl or ethyl; and R 3 represents hydrogen, methyl, ethyl, isopropyl, tert-butyl, allyl or benzyl; or R 1 and R 2 Together with the carbon atoms to which it is attached, it can form a 4- to 8-membered saturated cycloalkyl or heterocyclyl ring, wherein the heterocyclic moiety is a non-aromatic monocyclic ring containing 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from N, O and S; R 6 , R 7 , R 8 , R 9 and R 10 Each is independently hydrogen or C1-C3 alkyl; represents a bidentate chelating ligand having structure (IV), (IVa) or (IVb) comprising at least one carbon atom coordinated to iridium and at least one nitrogen atom coordinated to iridium: Where R 11A , R 11B , R 11C , R 11D , R 11E , R 13A , R 13B , R 13C and R 13D are each independently hydrogen, methyl, methoxy, ethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, methoxycarbonyl-methoxy or isopropyloxycarbonyl-methoxy, and R 12 is hydrogen, methyl or phenyl, and wherein each phenyl moiety is optionally substituted with a single methoxy group; or R 12 and R 13D Together with the carbon atom to which it is attached, it can form a 6- or 7-membered partially saturated cycloalkyl or heterocyclyl ring, wherein the heterocyclic moiety is a non-aromatic ring containing one oxygen atom; X represents a compound having the formula R 14 -SO2O- or R 15 -C(O)O- anionic group, wherein R 14 is hydroxy, methyl, trifluoromethyl, phenyl or tolyl; R 15 It is C 1-6 haloalkyl or phenyl, wherein the phenyl moiety is optionally substituted by 1, 2, 3 or 4 groups which may be the same or different and are selected from R 17 Substituents are substituted; R 17 It is C 1-4 Alkyl, C 1-4 haloalkyl, nitro or halogen; Y is H2O or MeCN; and Z is methanesulfonate or tetrafluoroborate.

2. The method according to claim 1, wherein: R 6 , R 7 , R 8 , R 9 and R 10 Each represents hydrogen or methyl.

3. The method according to claim 1 or claim 2, wherein: X represents a compound having the formula R 14 -SO2O - The group.

4. The method according to claim 1 or claim 2, wherein: The bidentate chelating ligand is selected from compounds having formula (IV-1), (IV-2), (IV-3), (IV-4), (IV-5), (IV-6), (IV-7), (IV-8), (IV-9), (IV-10), (IV-11) and (IV-12):

5. The method according to claim 1 or claim 2, wherein: The acid is methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, sulfuric acid or trifluoromethanesulfonic acid.

6. The method according to claim 1 or claim 2, wherein: The iridium catalyst is a compound having formula (III-1), (III-11), (III-17), (III-18) or (III-19):

7. The method according to claim 1 or claim 2, wherein: The hydroxylamine having the formula (II) is N-methoxy-1-(2,4,6-trichlorophenyl)propane-2-amine (II-1).

8. The method according to claim 7, wherein: N-methoxy-1-(2,4,6-trichlorophenyl)propan-2-amine (II-1) is further reacted with 3-(difluoromethyl)-1-methyl-pyrazole-4-carbonyl chloride (XII) to provide 3-(difluoromethyl)-N-methoxy-1-methyl-N-[1-methyl-2-(2,4,6-trichlorophenyl)ethyl]pyrazole-4-carboxamide (XIII):

9. A compound having formula (IIIc) or (IIId): Where R 6 , R 7 , R 8 , R 9 and R 10 Each is independently selected from hydrogen or C1-C3 alkyl; R 11A , R 11B , R 11C , R 11D , R 11E , R 13A , R 13B , R 13C and R 13D Each is independently hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, hydroxy C1-C8 alkoxy, C1-C8 alkoxy C1-C6 alkoxy, C1-C8 alkoxycarbonyl, C1-C8 alkoxycarbonyl C1-C6 alkoxy, C1-C8 alkylcarbonyl C1-C6 alkoxy, phenoxy or nitro; R 12 is hydrogen, C1-C8 alkyl or phenyl, wherein each phenyl moiety is optionally substituted with 1 to 5 groups selected from C1-C8 alkyl and C1-C8 alkoxy; or R 12 and R 13D Together with the carbon atom to which it is attached, it can form a 6- to 8-membered partially saturated cycloalkyl or heterocyclyl ring, wherein the heterocyclic moiety is a non-aromatic ring containing 1 or 2 heteroatoms, wherein the heteroatoms are independently selected from N, O and S; X is methanesulfonate, toluenesulfonate, nitrobenzenesulfonate, sulfate, hydrogensulfate, trifluoromethanesulfonate or trifluoroacetate; Y is H2O; and Z is methanesulfonate, toluenesulfonate, nitrobenzenesulfonate, sulfate, hydrogensulfate, trifluoromethanesulfonate, tetrafluoroborate, hexafluorophosphate, tetraphenylborate or tetrakis(3,5-bis(trifluoromethyl)phenyl)borate.

10. Compounds of formula (III-1), (III-11), (III-17), (III-18) and (III-19):

Images