HYDROGENATION PROCESS OF OXIME DERIVATIVES

Abstract

The present invention relates to a novel process for the iridium-catalysed hydrogenation of oximes. The invention also relates to novel iridium catalysts for use in the iridium-catalysed hydrogenation of oximes and to processes of preparation of these catalysts. The invention further relates to the use of the novel iridium catalysts in ionic hydrogenation of other unsaturated substrates.

Claims

1. A process for the hydrogenation of 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; ##STR00072## wherein R.sup.1, R.sup.2 and R.sup.3 are each independently hydrogen, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8hydroxyalkyl, C.sub.1-C.sub.8cyanoalkyl, C.sub.1-C.sub.6alkoxyC.sub.1-C.sub.8alkyl, di(C.sub.1-C.sub.6alkoxy)C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8haloalkyl, C.sub.2-C.sub.6alkenyl, C.sub.3-C.sub.8cycloalkyl, phenyl, phenylC.sub.1-C.sub.3alkyl or heteroaryl, and wherein the cycloalkyl and phenyl moieties are each optionally substituted with 1 to 5 groups selected from hydroxyl, halogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkoxy, phenyl, heteroaryl, C.sub.1-C.sub.6alkoxycarbonyl, acylamino, amido, cyano, nitro and C.sub.2-C.sub.6alkenyl; or R.sup.1 and R.sup.2 together with the carbon atom to which they are attached may form a 4- to 8-membered saturated cycloalkyl or heterocyclyl ring, wherein the heterocyclic moiety is a non-aromatic monocyclic ring which comprises 1, 2 or 3 heteroatoms, wherein the heteroatoms are individually selected from N, O and S; R.sup.6, R.sup.7, R.sup.8, R.sup.9 and R.sup.10 are each independently hydrogen or C.sub.1-C.sub.3alkyl; ##STR00073## represents a bidentate chelating ligand comprising at least one carbon atom which coordinates to iridium and at least one nitrogen atom which coordinates to iridium; X represents an anionic group of the formula R.sup.14—SO.sub.2O— or R.sup.15—C(O)O—, wherein R.sup.14 is hydroxy, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.1-6haloalkyl, or phenyl, wherein the phenyl moieties are optionally substituted by 1, 2, 3 or 4 substituents, which may be the same or different, selected from R.sup.16; R.sup.16 is C.sub.1-4alkyl, C.sub.1-4haloalkyl, nitro, or halogen; R.sup.15 is C.sub.1-6haloalkyl or phenyl, wherein the phenyl moieties are optionally substituted by 1, 2, 3 or 4 substituents, which may be the same or different, selected from R.sup.17; R.sup.17 is C.sub.1-4alkyl, C.sub.1-4haloalkyl, nitro or halogen; Y represents a neutral ligand; and Z represents an anionic group.

2. The process according to claim 1, wherein R.sup.6, R.sup.7, R.sup.8, R.sup.9 and R.sup.10 each represent hydrogen or methyl.

3. The process according to claim 1 or claim 2, wherein X represents a group of the formula R.sup.14—SO.sub.2O.sup.−.

4. The process according to claim 1, wherein the bidentate chelating ligand is selected from a compound of formula (IV-1), (IV-2), (IV-3), (IV-5), (IV-6), (IV-7), (IV-8), (IV-9), (IV-10), (IV-11) and (IV-12): ##STR00074## ##STR00075## ##STR00076##

5. The process according to claim 1, wherein Z is R.sup.14—SO.sub.2O.sup.−, mesylate, sulfate, hydrogenosulfate, tetrafluoroborate, hexafluorophosphate, tetraphenylborate, or tetrakis(3,5-bis(trifluoromethyl)phenyl)borate.

6. The process according to claim 1, wherein the acid is methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, sulfuric acid or triflic acid.

7. The process according to claim 1, wherein Y is H.sub.2O or MeCN.

8. The process according to claim 1, wherein the iridium catalyst is a compound of formula (III-1), (III-11), (III-17), (III-18), or (III-19): ##STR00077##

9. The process according to claim 1, wherein the hydroxylamine of formula (II) is N-methoxy-1-(2,4,6-trichlorophenyl)propan-2-amine (II-1).

10. The process according to claim 9, 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): ##STR00078##

11. A compound of formula (IIIc) or (IIId): ##STR00079## wherein R.sup.6, R.sup.7, R.sup.8, R.sup.9 and R.sup.10 are each independently selected from hydrogen or C.sub.1-C.sub.3alkyl; R.sup.11A, R.sup.11B, R.sup.11C, R.sup.11D, R.sup.11E, R.sup.13A, R.sup.13B, R.sup.13C, and R.sup.13D are each independently hydrogen, halogen, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8alkoxy, C.sub.1-C.sub.8haloalkyl, C.sub.1-C.sub.8haloalkoxy, hydroxyC.sub.1-C.sub.8alkoxy, C.sub.1-C.sub.8alkoxyC.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.8alkoxycarbonyl, C.sub.1-C.sub.8alkoxycarbonylC.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.8alkylcarbonylC.sub.1-C.sub.6alkoxy, phenoxy, or nitro; R.sup.12 is hydrogen, C.sub.1-C.sub.8 alkyl or phenyl, wherein each phenyl moiety is optionally substituted by 1 to 5 groups selected from C.sub.1-C.sub.8alkyl and C.sub.1-C.sub.8alkoxy; or R.sup.12 and R.sup.13D together with the carbon atoms to which they are attached may form a 6- to 8-membered partially saturated cycloalkyl or heterocyclyl ring, wherein the heterocyclic moiety is a non-aromatic ring which comprises 1 or 2 heteroatoms, wherein the heteroatoms are individually selected from N, O and S; X is mesylate, tosylate, nosylate, sulfate, hydrogenosulfate, triflate or trifluoroacetate; Y is H.sub.2O, PhCN or MeCN; and Z is mesylate, tosylate, nosylate, sulfate, hydrogenosulfate, triflate, tetrafluoroborate, hexafluorophosphate, tetraphenylborate or tetrakis(3,5-bis(trifluoromethyl)phenyl)borate.

12. The compound of claim 11, wherein the compound is a compound of formula (III-1), (III-11), (III-17), (III-18), and (III-19): ##STR00080##

13. A process for ionic hydrogenation of acylenamines, imines, enamines, heterocycles, aldehydes and ketones with hydrogen in the presence of an iridium catalyst of formula (IIIa) or formula (IIIb) of claim 1 and optionally an acid.

Description

EXAMPLES

[0107] The Examples which follow serve to illustrate the invention.

[0108] The following abbreviations are used: s=singlet; bs=broad singlet; d=doublet; br d=broad doublet; dd=double doublet; dt=double triplet; t=triplet, tt=triple triplet, q=quartet, sept=septet; m=multiplet; RT=room temperature, Rt=retention time, MH.sup.+=molecular mass of the molecular cation; DCM=dichloromethane.

[0109] .sup.1H and .sup.19F NMR spectra were recorded on a Bruker Avance III 400 spectrometer equipped with a BBFOplus probe at 400 MHz/376.6 MHz, respectively.

[0110] The following starting materials are commercially available:

[0111] Chloro(pentamethylcyclopentadienyl)[(2-pyridinyl-κN)phenyl-κC]iridium(III) (CAS=945491-51-0);

[0112] Chloro(pentamethylcyclopentadienyl){5-nitro-2-{1-[(4-methoxyphenyl)imino-κN]ethyl}phenyl-κC}iridium(III) (CAS=1439402-25-1);

[0113] 7-(2-methoxyethoxy)tetralin-1-one (CAS=1697644-15-7);

[0114] methyl 2-(4-oxotetralin-6-yl)oxyacetate (CAS=1937197-95-9);

[0115] 7-(2-hydroxyethoxy)tetralin-1-one (CAS=1260011-13-9).

[0116] Following starting materials were prepared according literature procedures:

[0117] Iridium, chloro[5-(ethylmethylamino)-2-(2-pyridinyl-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. 2012, 18, 6063-6078.

[0118] 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. 2014, 20, 245-252.

[0119] 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-naphthalenyl-κC] (CAS=1469468-10-7), according to SYNLETT 2014, 25, 81-84.

[0120] 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-naphthalenyl-κC] (CAS=1469468-08-3), according to SYNLETT 2014, 25, 81-84.

[0121] 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. 2014, 20, 245-252.

[0122] Iridium(2+), triaqua[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]-, sulfate (CAS=254734-81-1), according to WO 2008/093668.

General Procedure 1: Synthesis of N-Aryl Ketimine Ligands of Formula (IV)

[0123] The corresponding ketone (1.0 eq.), 4-methoxyaniline (1.1 eq.) and triethylamine (6.0 eq.) and DCM (0.4M) were charged in a dry reaction flask. Titanium tetrachloride (0.6 eq.) solution in DCM (to make the reaction 0.2M overall) was added dropwise at −78° C. The reaction mixture was stirred for 2-80 h. The reaction mixture was quenched with sat. Na.sub.2CO.sub.3 solution and the mixture was filtered through a bed of celite. The aqueous layer was extracted with DCM, the organic layers dried with Na.sub.2SO.sub.4, filtered and concentrated in vacuum to give a crude product. The crude product was either purified by (a) crystallization with Et.sub.2O or cyclohexane, (b) column chromatography or (c) used as crude.

TABLE-US-00001 TABLE 1 Ligands prepared according to General Procedure 1: Cpd No. Structure Comments (IV-7) [00012] (E)-7-(2-methoxyethoxy)-N-(4-methoxy- phenyl)tetralin-1-imine 51% yield (the crude product purified by column chromatography - silica, ethyl acetate/ cyclohexsane/triethylamine) .sup.1H NMR (CDCl.sub.3): δ 7.87 (d, J = 2.94 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 7.03 (dd, J = 2.57 Hz, 8.44 Hz, 1H), 6.92 (m, 2H), 6.77 (m, 2H), 4.22 (m, 2H), 3.84 (s, 3H), 3.78 (m, 2H), 3.47 (s, 3H), 2.84 (t, J = 5.87, 2H), 2.54 (t, J = 6.24, 2H), 1.90 (m, 2H) ppm. .sup.13C NMR (CDCl.sub.3): δ 165.8, 157.4, 155.8, 144.7, 134.9, 134.1, 129.8, 120.8, 119.6, 114.3, 109.2, 71.1, 67.4, 59.2, 55.5, 29.7, 29.2, 23.3 ppm. (IV-8) [00013] methyl 2-[(4E)-4-(4-methoxyphenyl)imino- tetralin-6-yl]oxyacetate 60% yield (crude product 85% NMR purity was used in the next step without further purification) .sup.1H NMR (CDCl.sub.3): δ 7.83 (d, J = 2.9 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 7.05 (dd, J = 8.1, 2.6 Hz, 1H) 6.95-6.91 (m, 2H), 6.79-6.75 (m, 2H), 4.73 (s, 2H), 3.84 (s, 3H), 3.82 (s, 3H), 2.88- 2.82 (m, 2H), 2.54 (m, 2H), 1.93-1.85 (m, 2H) ppm. (IV-9) [00014] 2-[(4E)-4-(4-methoxyphenyl)iminotetralin-6- yl]oxyethanol 14% yield (the crude product was purified by column chromatography - silica, ethyl acetate/ cyclohexane/triethylamine) .sup.1H NMR (CDCl.sub.3): δ 7.87 (d, J = 2.9 Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 7.00 (dd, J = 8.4 Hz, J = 2.9 Hz, 1H) 6.95-6.90 (m, 2H), 6.80-6.75 (m, 2H), 4.20-4-16 (m, 2H), 4.00-3.95 (m, 2H), 3.84 (s, 3H), 2.85 (t, J = 6.2 Hz, 2H), 2.55 (t, J = 6.2 Hz, 2H), 1.95-1.85 (m, 2H) ppm. .sup.13C NMR (CDCl.sub.3): δ 165.9, 157.2, 155.9, 144.6, 135.0, 134.3, 129.9, 120.9, 119.2, 114.3, 109.6, 69.4, 61.5, 55.5, 29.7, 29.2, 26.9, 23.3 ppm.

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

[0124] Dichloro(pentamethylcyclopentadienyl)iridium(III)dimer (1.0 eq.), sodium acetate (10.0 eq.) and corresponding ligand (2.2 eq.) were charged in a dry reaction flask. DCM (40 mL/mmol [Ir]) was added under argon, and the reaction mixture stirred at room temperature. After completion of the reaction (conversion monitored by .sup.1H-NMR), the reaction mixture was filtered through a plug of Celite® and washed with DCM. The mother liquor was concentrated to dryness to afford the iridium-chloro-complex. For further purification procedures see detailed explanations under each product.

Example 1: Preparation of (N,1,1-tris(4-methoxyphenyl)methanimine Iridium Chloro Complex (VI-1)

[0125] ##STR00015##

[0126] A one-necked round bottom flask, equipped with a magnetic stirrer bar and a condenser, was charged with 4-methoxyaniline (0.598 g), bis(4-methoxyphenyl)methanone (1.00 g), molecular sieves and toluene (8.0 mL), and the reaction mixture stirred at reflux for 24 h. The reaction mixture was cooled to RT and filtered through filter paper. The resulting filtrate was reduced under vacuum to afford N, 1,1-tris(4-methoxyphenyl)methanimine.

[0127] A one-necked round bottom flask, equipped with a magnetic stirrer bar, was charged with N,1,1-tris(4-methoxyphenyl)methanimine (324 mg), DCM (4.3 mL), dichloro(pentamethylcyclopentadienyl)-iridium(III)dimer (300 mg), and sodium acetate (150.0 mg), and the reaction mixture stirred at reflux for 3 h. Another portion of N,1,1-tris(4-methoxyphenyl)methanimine (100 mg) was added and the mixture was stirred for a further 30 min at reflux. The reaction mixture was then filtered through a pad of silica and the filtrate reduced under vacuum. The resultant solid was dissolved in boiling dichloroethane (5 mL), and MeOH (15 mL) was added. The mixture was left overnight in a freezer (−22° C.), and the resultant crystals were isolated by decantation, washed with MeOH and dried under vacuum to afford 361 mg of the title compound (VI-1), as red crystals.

[0128] .sup.1H NMR (CDCl.sub.3) 5=7.38 (d, J=2.6 Hz, 1H), 6.57-7.36 (m, 9H), 6.49 (dd, J=8.4 Hz, J=2.6 Hz, 1H), 3.90 (s, 3H), 3.77 (s, 3H), 3.75 (s, 3H), 1.47 (s, 15H) ppm.

TABLE-US-00002 TABLE 2 Iridium-chloro-complexes of formula (VI) prepared according to General Procedure 2: Cpd No. Structure Comments (VI-2) [00016] 87% yield (crude product triturated with Et.sub.2O/n-Hexane = 1:2) .sup.1H NMR (CDCl.sub.3) δ 7.83 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 2.6 Hz, 1H), 6.79-6.84 (m, 1H), 6.73-6.77 (m, 1H), 6.60 (dd, J = 8.4 Hz, J = 2.6 Hz, 1H), 3.91 (s, 3H), 3.84 (s, 3H), 2.30 (s, 3H), 2.05 (s, 3H), 1.46 (s, 15) ppm. .sup.13C NMR (CDCl.sub.3) δ 180.5, 168.9, 161.9, 157.3, 143.3, 141.6, 131.0, 130.0, 125.3, 119.2, 114.1, 112.5, 107.7, 89.4, 55.5, 55.0, 18.0, 16.8, 8.8 ppm. (VI-3) [00017] 80% yield (solid washed with Et.sub.2O) .sup.1H NMR (CDCl.sub.3) δ 7.81 (m, 1H), 7.65 (bs, 1H), 7.30 (bs, 1H), 7.21 (d, J = 8.4 Hz, 1H), 6.57 (dd, J = 8.4 Hz, J = 1.5 Hz, 1H), 6.49 (bs, 1H), 3.86 (s, 3H), 1.75 (s, 15H) ppm. .sup.13C NMR (CDCl.sub.3) δ 158.2, 147.3, 137.3, 136.9, 124.4, 121.8, 111.2, 107.7, 107.7, 88.1, 55.4, 9.0 ppm. (VI-4) [00018] 67% yield (crude product was purified via filtration over a pad of silica eluted with DCM and via trituration with Et.sub.2O/n-pentane = 1:2) .sup.1H NMR (CDCl.sub.3) δ 7.29-7.38 (m, 3H), 7.12-7.19 (m, 1H), 6.89-7.96 (m, 2H), 6.43-6.51 (m, 1H), 4.20-4.30 (m, 1H), 4.10-4.18 (m, 1H), 3.85 (s, 3H), 3.13-3.26 (m, 1H), 2.67- 2.81 (m, 1H), 1.46 (s, 15H) ppm. (VI-5) [00019] 47% yield (the cyclometalation reaction was done in presence of 4-methoxybenzaldehyde additive (1 eq.). The crude product was purified by column chromatography (silica, ethyl acetate - cyclohexane gradient) followed by crystallization from dichloromethane-Et.sub.2O-pentane) .sup.1H NMR (CDCl.sub.3) δ 8.15 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.48-7.52 (m, 2H), 7.35-7.37 (m, 1H), 6.86-6.92 (m, 2H), 6.59 (dd, J = 8.4 Hz, J = 2.6 Hz, 1H), 3.91 (s, 3H), 3.84 (s, 3H), 1.49 (s, 15H) ppm. (VI-6) [00020] 84% yield (the crude product purified by column chromatography - silica, ethyl acetate/cyclohexane gradient and trituration using n-pentane) .sup.1H NMR (acetone-d6) δ 7.90 (dd, J = 7.7 Hz, J = 1 Hz, 1H), 6.88-7.61 (m, 12H), 6.82 (br d, J = 7.7 Hz, 1H), 1.48 (s, 15H) ppm. (VI-7) [00021] 80% yield (the crude product was purified via trituration with diethyl ether/n-hexane = 1:4) .sup.1H NMR (CDCl.sub.3) δ 7.57-7.23 (m, 2H), 6.95 (d, J = 9.2 Hz, 2H), 6.82 (dd, J = 21.3 Hz, J = 8.1 Hz, 2H), 4.23 (m, 2H), 3.87 (s, 3H), 3.81-3.66 (m, 2H), 3.45 (s, 3H), 3.05-2.83 (m, 2H), 2.78-2.61 (m, 2H), 1.91-1.80 (m, 2H), 1.47 (s, 15H) ppm. (VI-8) [00022] 21% yield (the crude product purified by column chromatography on silica, dichloromethane/methanol gradient .sup.1H NMR (CDCl.sub.3) δ 7.65-7.13 (m, 2H), 6.99-6.92 (m, 2H), 6.80-6.72 (m, 2H), 4.83 (d, J = 17.2 Hz, 1H), 4.55 (d, J = 16.9 Hz, 1H), 3.87 (s, 3H), 3.81 (s, 3H), 3.07-2.96 (m, 1H), 2.90-2.81 (m, 1H), 2.79-2.70 (m, 1H), 2.69-2.61 (m, 1H), 1.93-1.76 (m, 2H), 1.47 (s, 15H) ppm. (VI-9) [00023] 82% yield (the crude product was purified via trituration with diethyl ether) .sup.1H NMR (CDCl.sub.3) δ 7.30-7.50 (m, 2H), 6.95 (dd, J = 7.70, 1.5 Hz, 2H), 6.78 (dd, J = 9.9 Hz, J = 8.07 Hz, 2H), 4.52- 4.45 (m, 1H), 4.28-4.20 (m, 1H), 3.87 (s, 3H), 3.83-3.73 (m, 2H), 3.09-2.97 (m, 1H), 2.94-2.83 (m, 1H), 2.79-2.60 (m, 2H), 1.96-1.76 (m, 2H), 1.46 (s, 15H) ppm.

General Procedure 3: For Synthesis of Iridium-Mesylate-Complexes of Formula (III)

[0129] A reaction flask was charged with iridium-chloro-complex (1.0 eq.) and silver mesylate (1.1 eq.) under argon, and the reaction flask wrapped with aluminium foil (silver mesylate is light-sensitive). CDCl.sub.3 (2.5 mL/mmol) was added and the reaction mixture was stirred under argon for 20 h. The reaction mixture was diluted with CDCl.sub.3 and filtered through a syringe filter (0.22 μm). The filtrate was concentrated under reduced pressure to provide the iridium-mesylate-complexes. For further purification procedures see detailed explanations under each product.

Example 2: Preparation of (E)-4-methoxy-N-(1-(4-methoxyphenyl)ethylidene)aniline Iridium Mesylate Complex (III-1)

[0130] ##STR00024##

[0131] A reaction flask was charged with (E)-4-methoxy-N-(1-(4-methoxyphenyl)ethylidene)aniline iridium chloride complex (400 mg, CAS=1258964-48-5) and silver mesylate (136 mg) under argon, and the reaction flask wrapped with aluminium foil (silver mesylate is light-sensitive). CDCl.sub.3 (2 mL) was added and the reaction mixture was stirred under argon for 20 h. The reaction mixture was diluted with a further portion of CDCl.sub.3 (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.

[0132] .sup.1H NMR (CDCl.sub.3) δ 7.70 (bd, J=2.6 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 6.98 (bs, 4H), 6.63 (dd, J=8.4 Hz, J=2.6 Hz, 1H), 3.94 (s, 3H), 3.86 (s, 3H), 2.32 (s, 3H), 1.78 (s, 3H), 1.42 (s, 15H) ppm.

[0133] .sup.13C NMR (CDCl.sub.3) 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. Two carbon signals not observed due to signal broadening.

TABLE-US-00003 TABLE 3 Iridium-mesylate complexes of formula (III) prepared according to General Procedure 3: Cpd No. Structure Comments (III-2) [00025] 91% yield .sup.1H NMR (CDCl.sub.3) δ 8.99 (d, J = 5.1 Hz, 1H), 8.13 (d, J = 7.3 Hz, 1H), 7.73-7.87 (m, 2H), 7.69 (dd, J = 7.7 Hz, J = 1.1 Hz, 1H), 7.25-7.30 (m, 1H), 7.21 (td, J = 6.4 Hz, J = 1.5 Hz, 1H), 7.11 (td, J = 7.5 Hz, J = 1.1 Hz, 1H), 1.76 (bs, 3H), 1.69 (s, 15H) ppm. (III-3) [00026] Quantitative yield .sup.1H NMR (CDCl.sub.3) δ 8.93 (d, J = 5.9 Hz, 1H), 7.60-7.72 (m, 4H), 7.07-7.15 (m, 1H), 6.67 (dd, J = 8.4 Hz, J = 2.6 Hz, 1H), 3.93 (s, 3H), 1.82 (bs, 3H), 1.68 (s, 15H) ppm. (III-4) [00027] 98% yield .sup.1H NMR (CDCl.sub.3) δ 7.93 (s, 1H), 7.87 (bs, 1H), 7.59 (bs, 1H), 7.25 (d, J = 8.4 Hz, 1H), 6.60- 6.68 (m, 1H), 6.57 (bs, 1H), 3.89 (s, 3H), 1.74 (s, 15H) ppm. One proton signal not observed due to signal broadening. .sup.13C NMR (CDCl.sub.3) δ 158.3, 147.9, 139.0, 137.8, 124.5, 122.4, 111.1, 108.7, 108.1, 87.5, 55.5, 39.2, 9.4 ppm. (III-5) [00028] 72% yield .sup.1H NMR (CDCl.sub.3) δ 8.91 (d, J = 2.6 Hz, 1H), 7.93 (dd, J = 8.4 Hz, J = 2.2 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 6.95-7.30 (bm, 4H), 3.89 (s, 3H), 2.46 (s, 3H), 1.97 (s, 3H), 1.45 (s, 15H) ppm. (III-6) [00029] Quantitative yield .sup.1H NMR (CDCl.sub.3) δ 7.65 (s, 1H), 6.9-7.1 (m, 3H), 4.60 (s, 3H), 3.88 (s, 3H), 3.85 (s, 3H), 2.34 (s, 3H), 1.75 (bs, 3H), 1.42 (s, 15H) ppm. Signals of two protons not observed due to signal broadening. (III-7) [00030] Quantitative yield .sup.1H NMR (CDCl.sub.3) δ 7.51 (bs, 1H), 6.96 (bd, 2H), 6.39 (bs, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 1.60-2.90 (m, 9H), 1.42 (s, 15H) ppm. Signals of two protons not observed due to signal broadening. (III-8) [00031] 90% yield (crude product triturated with pentane) .sup.1H NMR (CDCl.sub.3) δ 7.61-7.70 (m, 1H), 7.24- 7.29 (m, 3H), 6.91-7.02 (m, 2H), 6.50-6.60 (m, 1H), 4.22-4.34 (m, 1H), 3.98-4.11 (m, 1H), 3.86 (s, 3H), 3.02-3.21 (m, 1H), 2.63-2.76 (m, 1H), 1.83 (s, 3H), 1.44 (s, 15H) ppm. (III-9) [00032] 84% yield (the crude product dissolved in CDCl.sub.3 and filtered through a short pad of silica, evaporated and recrystallized from a minimum amount of dichloromethane- pentane) .sup.1H NMR (CDCl.sub.3) δ 8.20 (s, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.40-7.45 (m, 2H), 6.92-6.97 (m, 2H), 6.63 (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 3.94 (s, 3H), 3.86 (s, 3H), 1.87 (s, 3H), 1.47 (s, 15H) ppm. (III-10) [00033] 98% yield (the crude product was dissolved in CDCl.sub.3 and filtered through a short pad of silica, evaporated and the solid residue triturated using pentane) .sup.1H NMR (CDCl.sub.3) δ 8.24 (d, J = 7.7 Hz, 1H), 7.43 (br d, J = 4.0 Hz, 2H), 6.95-7.35 (m, 10H), 6.85 (br d, J = 7.7 Hz, 1H), 1.71 (s, 3H), 1.45 (s, 15H) ppm. (III-11) [00034] 91% yield (the crude product was dissolved in CDCl.sub.3 and filtered through a short pad of silica, evaporated and the solid residue triturated using pentane) .sup.1H NMR (CDCl.sub.3) δ 7.75 (d, J = 2.2 Hz, 1H), 6.60-7.40 (m, 9H), 6.52 (dd, J = 7.6 Hz, J = 2.4 Hz, 1H), 3.93 (s, 3H), 3.78 (s, 3H), 3.76 (s, 3H), 1.78 (s, 3H), 1.45 (s, 15H) ppm. (III-12) [00035] Quantitative yield .sup.1H NMR (CDCl) δ 7.66 (bs, 1H), 7.40-7.64 (m, 2H), 6.25-6.90 (m, 2H), 6.64 (m, 1H), 3.94 (s, 3H), 3.85 (s, 3H), 2.22 (s, 3H), 2.08 (bs, 3H), 1.43 (s, 15H) ppm. Signal of three protons not observed due to signal broadening. (III-13) [00036] 86% yield (triturated using diethylether and n- pentane) .sup.1H NMR (CDCl.sub.3) δ 9.25 (d, J = 4.8 Hz, 1H), 8.36 (d, J = 7.0 Hz, 1H), 8.25 (dd, J = 7.1 Hz, J = 1 Hz, 1H), 7.80-7.88 (m, 1H), 7.55-7.70 (m, 4H), 1.75 (s, 15H), 1.36 (bs, 3H) ppm. (III-17) [00037] Quantitative yield .sup.1H NMR (CD.sub.3CN) δ 7.22-7.17 (m, 2H), 7.08- 7.03 (m, 2H), 6.94 (d, J = 8.1 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 4.29-4.21 (m, 1H), 4.17-4.11 (m, 1H), 3.87 (s, 3H), 3.79-3.74 (m, 2H), 3.38 (s, 3H), 3.22-3.11 (m, 1H), 2.95-2.83 (m, 1H), 2.79-2.70 (m, 1H), 2.68-2.58 (m, 1H), 2.55- 2.22 (brs, 2H), 2.47 (s, 3H), 1.74-1.60 (m, 2H), 1.49 (s, 15H) ppm. (III-18) [00038] 51% yield (triturated using diethylether) .sup.1H NMR (CDCl.sub.3) δ 7.73-7.11 (br m, 2H), 7.45- 6.97 (bm, 2H), 6.86-6.79 (m, 2H), 6.62 (d, J = 8.1 Hz, 1H), 5.02-4.80 (bm, 1H), 4.75-4.57 (bm, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 2.95-2.54 (m, 4H), 1.93 (bs, 3H), 1.80-1.55 (s, 2H), 1.45 (s, 15H) ppm. (III-19) [00039] 82% yield .sup.1H NMR (CD.sub.3CN) δ 7.47-7.12 (m, 2H), 7.00 (d, J = 9.2 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 4.82-4.70 (m, 1H), 4.49-4.28 (m, 2H), 4.06-3.91 (m, 2H), 3.88 (s, 3H), 2.96-2.59 (m, 4H), 1.92 (s, 3H), 1.76-1.56 (m, 2H), 1.44 (s, 15H) ppm.

Example 3: Preparation of (E)-4-methoxy-N-(1-(4-methoxyphenyl)ethylidene)aniline Iridium Sulfate Complex (III-14)

[0134] ##STR00040##

[0135] A reaction vial was charged with pentamethylcyclopentadienyl iridium sulfate complex (143 mg, CAS=[254734-81-1]), (E)-N,1-bis(4-methoxyphenyl)ethanimine (76 mg) and CD.sub.3OD (1.2 mL) under argon. The reaction vial was stirred overnight. .sup.1H NMR analysis of the reaction mixture revealed formation of the cyclometalated iridium complex in 73% NMR yield.

[0136] .sup.1H NMR (CDCl.sub.3) δ 7.65 (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. Signal of four protons not observed due to signal broadening.

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

[0137] ##STR00041##

[0138] A reaction vial was charged with (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). The reaction mixture was stirred at RT for 48 h and filtered through a pad of celite (washed with DCM). The filtrate was concentrated under vacuum and the solid residue was triturated using diethylether providing 246 mg of the title compound as a yellow solid.

[0139] .sup.1H NMR (CDCl.sub.3) δ 7.52 (d, J=8.4 Hz, 1H), 7.27 (d, J=2.4 Hz, 1H), 7.00-7.20 (bs, 4H), 6.72 (dd, J=8.4 Hz, J=2.4 Hz, 1H), 3.94 (s, 3H), 3.88 (s, 3H), 2.60 (s, 3H), 2.42 (s, 3H), 1.49 (s, 15H) ppm.

Example 5: Preparation of (E)-4-methoxy-N-(1-(4-methoxyphenyl)ethylidene)aniline Iridium Trifluoroacetate Complex (III-16)

[0140] ##STR00042##

[0141] A reaction vial was charged with (E)-4-methoxy-N-(1-(4-methoxyphenyl)ethylidene)aniline iridium chloride complex (250 mg, CAS=1258964-48-5), silver trifluoroacetate (107 mg) and CDCl.sub.3 (1.0 mL). The reaction mixture was stirred at RT for 20 h and filtered through a pad of celite (washed with dichloromethane). The filtrate was concentrated and purified by column chromatography (silica, ethylacetate-cyclohexane gradient). The isolated solid was dissolved in a minimal amount of dichloromethane and diluted with n-pentane. The product crystallised in a freezer overnight. The product was recovered by decantation, washed with n-pentane and dried under vacuum to afford 129 mg of the title compound as a yellow solid.

[0142] .sup.1H NMR (CDCl.sub.3) δ 7.66 (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. Signals of two protons not observed due to signal broadening.

Examples 6: Synthesis of Hydroxylamine (II-1) Via Oxime Hydrogenation

[0143] ##STR00043##

[0144] A 100 mL Hastelloy reactor was charged with (E)-N-methoxy-1-(2,4,6-trichlorophenyl)propan-2-imine (2.00 g, 99:1=E/Z, 95% NMR purity) and catalyst (III-1) (5.0 mg) as a solid, the reactor was closed and flushed with argon. iPrOH (10 mL, anhydrous, degassed with argon) and methanesulfonic acid (0.72 mL) were added to the reactor under argon, and the reactor was purged with hydrogen (3×5bar), pressurized to 50 bar H.sub.2 and stirred overnight at 23° C. Hydrogen was released and the reactor was again purged with argon. GC and NMR analysis of the crude reaction mixture indicated full conversion. The reaction mixture was added slowly onto sat. NaHCO.sub.3 solution (15 mL) and water (10 mL), and extracted with dichloromethane (2×15 mL). The combined organic layers were dried with Na.sub.2SO.sub.4, filtered and evaporated to give 1.97 g (97% NMR purity) of the desired product (II-1).

Example 7: Synthesis of Hydroxylamine (II-1) Via Oxime Hydrogenation, Various Conditions

[0145] ##STR00044##

[0146] Conditions: catalyst III-1, 1.5 eq methanesulfonic acid, iPrOH solvent (200 g substrate/1 L solvent) unless otherwise indicated.

TABLE-US-00004 TABLE 4 Conditions and outcome of reactions according to Example 7 Conditions Outcome 0.1 mol % cat., 50 bar H.sub.2, 50° C., 2 h 100% conv. (>95% NMR yield, 2 g scale) 0.1 mol % cat., 50 bar H.sub.2, RT, 16 h 100% conv. 0.1 mol % cat., 50 bar H.sub.2, 10° C., 16 h 100% conv. 0.05 mol % cat., 30 bar H.sub.2, RT, 15 h 100% conv. 0.05 mol % cat., 20 bar H.sub.2, RT, 15 h 100% conv. 0.1 mol % cat., 10 bar H.sub.2, RT, 15 h 100% conv. 0.1 mol % cat., 50 bar H.sub.2, RT, 100% conv. 3 equivalents of methanesulfonic acid, 16 h 0.1 mol % cat., 50 bar H.sub.2, RT,  97% conv. 1 equivalent H.sub.2SO.sub.4, 16 h 0.1 mol % cat., 50 bar H.sub.2, RT, 1.5  96% conv. equivalent (+)-camphorsulfonic acid, 16 h 0.01 mol % cat 50 bar H.sub.2, RT, 91 h  76% conv. 1 mol % cat., 1.5 equivalents (+)-camphorsulfonic acid, THF, 50 bar Hz, 60° C., 24 h  90% conv.

[0147] In all reactions gave high selectivity (>95%) towards the desired product.

Example 8: Synthesis of Hydroxylamine (II-1) Via Oxime Hydrogenation Using Various Catalysts

[0148] ##STR00045##

[0149] Conditions: 1.5 eq methanesulfonic acid, iPrOH solvent (200 g substrate/1 L solvent), 0.1 mol % catalyst, 30 bar H.sub.2, RT, 16 h, unless otherwise indicated.

TABLE-US-00005 TABLE 5 Conditions and outcome of reactions according to Example 8 Reaction Outcome Catalyst Time (h) (% Conversion) (III-8) 16 100 (III-9) 16 99 (III-10) 16 100 0.01 mol % (III-11), 91 h 91 76 1 mol % (III-13) 16 90 (III-15) 16 75 (III-16) 16 100 0.1 mol % (III-17), 3 h 3 97 0.025 mol % (III-17), 3 h 3 91 0.1 mol % (III-18), 3 h 3 100 0.025 mol % (III-18), 3 h 3 95 0.1 mol % (III-19), 3 h 3 97 0.025 mol % (III-19), 3 h 3 74

[0150] In all reactions high selectivity towards the desired product (>95%) was observed.

Example 9: Synthesis of Hydroxylamines (II) Via Oxime Hydrogenation, Substrate Scope

[0151] ##STR00046##

[0152] Conditions: 1.5 eq methanesulfonic acid, iPrOH solvent, 1 mol % catalyst ill-1, 50 bar H.sub.2, RT, 16 h

TABLE-US-00006 TABLE 6 Hydroxylamine products (II) prepared according to Example 9: Cpd No. Structure Comments (II-2) [00047] N-methoxy-1-(4-methoxyphenyl)ethanamine Quantitative yield .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.26 (d, 2H, J = 8.8 Hz), 6.86 (d, 2H, J = 8.4 Hz), 5.56 (d, 1H, J = 5.1 Hz), 4.19 (q, 1H, J = 6.2 Hz), 3.79 (s, 3H), 3.47 (s, 3H), 1.34 (d, 3H, J = 6.6 Hz) ppm. .sup.13C NMR (400 MHz, CDCl.sub.3): δ 158.94, 134.86, 128.22, 113.81, 62.51, 59.85, 55.28, 19.84 ppm. LCMS: Mass = 181, R.sub.t = 4.29 (II-3) [00048] N-benzyloxy-1-(4-methoxyphenyl)ethanamine 89% yield .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.24-7.32 (m, 7H), 6.85 (d, 2H, J = 8.4 Hz), 5.56 (bs 1H), 4.57-4.66 (m, 2H), 4.11 (q, 1H, J = 6.6 Hz), 3.78 (s, 3H), 1.33 (d, 3H, J = 6.6 Hz) ppm. .sup.13C NMR (400 MHz, CDCl.sub.3): δ 159.00, 137.99, 134.96, 128.53, 128.41, 127.81, 113.81, 60.02, 55.32, 19.96 ppm. LCMS: Mass = 258, R.sub.t = 7.43 (II-4) [00049] N-isopropoxy-1-(4-methoxyphenyl)ethanamine 90% yield .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.18 (d, 2H, J = 8.4 Hz), 6.77 (d, 2H, J = 8.4 Hz), 5.20 (bs, 1H), 3.97 (q, 1H, J = 6.4 Hz), 3.71 (s, 3H), 3.60-3.75 (m, 1H), 1.27 (d, 3H, J = 6.5 Hz), 1.05 (d, J = 6.2 Hz, 3H), 0.96 (d, J = 6.2 Hz, 3H) ppm. (II-5) [00050] N-tert-butoxy-1-(4-methoxyphenyl)ethanamine Quantitative yield, reaction, conducted at 50° C. .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.17 (d, 2H, J = 8.4 Hz), 6.77 (d, 2H, J = 8.4 Hz), 4.78 (bs, 1H), 3.90 (q, 1H, J = 6.4 Hz), 3.71 (s, 3H), 1.27 (d, 3H, J = 6.5 Hz) ppm. .sup.13C NMR (400 MHz, CDCl.sub.3): δ 158.86, 135.11, 128.58, 127.13, 113.60, 59.75, 55.24, 26.91, 19.84 ppm. LCMS: Mass = 223, R.sub.t = 5.32 (II-6) [00051] N-allyloxy-1-(4-methoxyphenyl)ethanamine 49% yield, product isolated by column chromatography .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.23 (d, 2H, J = 8.8 Hz), 6.85 (d, 2H, J = 8.4 Hz), 5.95 (ddt, 1H, J.sub.1 = 16.8 Hz, J.sub.2 = 10.5 Hz, J.sub.3 = 6.6 Hz), 5.11-5.15 (m, 2H), 3.78-3.83 (m, 4H), 3.26-3.31 (m, 1H), 3.16 (d, 1H, J = 5.9 Hz), 1.46 (d, 3H, J = 6.6 Hz) ppm. .sup.13C NMR (400 MHz, CDCl.sub.3): δ 158.90, 134.36, 129.21, 118.35, 113.76, 65.49, 59.88, 55.27, 19.53 ppm. LCMS: Mass = 207, R.sub.t = 5.65 (II-7) [00052] N-[1-(4-methoxyphenyl)ethyl]hydroxylamine 77% yield, reaction done at 50° C. The product analytical data are in agreement with the literature: Org. Proc. Res. Dev. 2009, 13, 49-53. (II-8) [00053] N-methoxy-1-(4-methoxyphenyl)methanamine 88% yield The product analytical data are in agreement with the literature: Heterocycles 2009, 78, 463-470. (II-9) [00054] 1-(3-chlorophenyl)-N-methoxy-propan-1-amine 62% yield .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.33 (s, 1H), 7.19-7.25 (m, 3H), 5.68 (bs, 1H), 3.84 (bs, 1H), 3.43 (s, 3H), 1.73-1.83 (m, 1H), 1.53-1.63 (m, 1H), 0.82 (t, 3H, J = 7.5 Hz) .sup.13C NMR (400 MHz, CDCl.sub.3): δ 144.10, 134.19, 129.55, 127.78, 127.53, 125.94, 66.90, 62.49, 26.67, 10.51 LCMS: Mass = 199, R.sub.t = 4.30 (II-10) [00055] N-methoxy-1-(4-nitrophenyl)ethanamine 94% yield .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.12 (d, 2H, J = 8.5 Hz), 7.47 (d, 2H, J = 8.5 Hz), 5.15 (bs, 1H), 4.18 (q, 1H, J = 6.6 Hz), 3.35 (s, 3H), 1.26 (d, 3H, J = 6.6 Hz) ppm. (II-11) [00056] N-methoxy-1-(o-tolyl)ethanamine 48% yield .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.33-7.38 (m, 1H), 7.05- 7.18 (m, 4H), 5.51 (bs, 1H), 4.30-4.38 (m, 1H), 3.44 (s, 3H), 2.30 (s, 3H), 1.26 (d, J = 6.6 Hz, 3H) ppm. (II-12) [00057] N-methoxy-1-(4-methoxyphenyl)propan-2-amine 80% yield .sup.1H NMR (400 MHz, CDCl.sub.3): δ = 7.11 (d, 2H, J = 8.5 Hz), 6.84 (d, 2H, J = 8.5 Hz), 5.5 (bs, 1H), 3.79 (s, 3H), 3.56 (s, 3H), 3.13-3.25 (m, 1H), 2.70-2.80 (m, 1H), 2.50- 2.62 (m, 1H), 1.08 (d, J = 6.6 Hz, 3H) ppm. (II-13) [00058] methyl 2-(methoxyamino)propanoate 77% yield, isolated as mesylate salt The product analytical data are in agreement with the literature values: WO2015/052076 (II-14) [00059] N-(2,2-dimethoxy-1-methyl-ethyl)hydroxylamine 70% yield .sup.1H NMR (400 MHz, CDCl.sub.3): δ 5.90 (br s, 1H), 4.32 (d, J = 6.2 Hz, 1H), 3.54 (s, 3H), 3.44 (d, J = 5.1 Hz, 6H), 3.15-3.05 (m, 1H), 1.13 (d, J = 6.6 Hz, 3H) ppm. (II-15) [00060] N-(1-cyclopropylethyl)hydroxylamine 49% yield .sup.1H NMR (400 MHz, CDCl.sub.3): δ 6.39 (br s, 2H), 2.25 (dq, J = 9.2, 6.2 Hz, 1H), 1.23 (d, J = 6.6 Hz, 3H), 0.81-0-7 (m, 1H), 0.56-0.46 (m, 2H), 0.35-0.25 (m, 1H), 0.22- 01.4 (m, 1H) ppm. (II-16) [00061] N-tert-butoxy-1-(4-methoxyphenyl)ethanamine 97% yield Analytical data are in agreement with Angew. Chem. Int. Ed. 2014, 53, 13278-13281. (II-17) [00062] N-tert-butoxy-1-(2,4,6-trichlorophenyl)propan-2-amine 90% yield .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.33 (s, 2H), 4.70 (br s, 1H), 3.38-3.27 (m, 1H), 3.17 (dd, J = 13.6, 6.2 Hz, 1H), 2.85 (dd, J = 13.2, 7.7 Hz, 1H), 1.15 (s, 9H), 1.1 (d, J = 6.2 Hz, 3H) ppm. (II-18) [00063] 1-(2-bromophenyl)-N-methoxy-propan-2-amine 93% yield .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.57 (d, J = 7.7 Hz, 1H), 7.29-7.24 (m, 2H), 7.14-7.06 (m, 1H), 5.52 (br s, 1H), 3.58 (s, 3H), 3.41-3.31 (m, 1H), 3.03 (dd, J = 13.2, 7.0 Hz, 1H), 2.75 (dd, J = 13.6, 7.0 Hz, 1H), 1.14 (d, J = 6.2 Hz, 3H) ppm. (II-19) [00064] N-benzyloxy-3,3-dimethyl-butan-2-amine 99% yield .sup.1H NMR (400 mHz, CDCl.sub.3): δ 7.42-7.28 (m, 5H), 5.48 (br s, 1H), 4.70 (s, 2H), 2.78 (q, J = 6.24 Hz, 1H), 1.20 (d, J = 6.2 Hz, 3H), 0.92 (s, 9H) ppm.

Example 10: Ionic hydrogenation of other substrates—Synthesis of cis-N-[2-(2,4-dichlorophenyl)cyclobutyl]acetamide Via Acylenamine Hydrogenation

[0153] ##STR00065##

[0154] A 50 mL glass vial was charged with N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]acetamide (256 mg), catalyst (III-1) (6.8 mg), methanesulfonic acid (48 mg), and isopropanol (4 mL). The glass vial was placed in a parallel autoclave purged with hydrogen (3 times) and hydrogenated at 50 bar hydrogen and 23° C. for 16 h. Hydrogen was released and the reactor was purged with argon. GC and NMR analysis of the crude reaction mixture indicated full conversion. The reaction mixture was added slowly onto a sat. NaHCO.sub.3 solution (15 mL) and water (10 mL), and extracted with DCM (2×15 mL). The combined organic layers were dried with Na.sub.2SO.sub.4, filtered and evaporated to give 250 mg of cis N-[2-(2,4-dichlorophenyl)cyclobutyl]acetamide. The analytical data are in agreement with the literature: WO15/003951.

Example 11: Ionic Hydrogenation of Other Substrates—Synthesis of 2-(trifluoromethyl)piperidine Via Heterocycle Hydrogenation

[0155] ##STR00066##

[0156] A 50 mL glass vial was charged with 2-trifluoromethylpyridine (144 mg), catalyst (III-1) (6.8 mg), methanesulfonic acid (144 mg) and isopropanol (4 mL). The glass vial was placed in a parallel autoclave purged with hydrogen (3 times) and hydrogenated at 50 bar hydrogen and 50° C. for 16 h. Hydrogen was released and the reactor was purged with argon. GC and NMR analysis of the crude reaction mixture indicated full conversion. The reaction mixture was evaporated and analysed by NMR. Full conversion of the starting material and formation of 2-(trifluoromethyl)piperidine (CAS=154630-93-0) was found.

Comparative Example 1

[0157] ##STR00067##

[0158] Screening of 96 diverse homogeneous catalysts—metal precursors (Rh, Ir, Pt, Ru, neutral/cationic)/ligand classes (monodentate/bidentate, phosphine, phosphite, etc.) in two solvents (THF/TFA and MeOH) at T=60° C. and pressure H.sub.2=50 bar, at a catalyst loading of 2%. The conversion towards the desired product (II-1, labeled ‘Product’ in the table below) was determined by GC and is based on area percentages.

TABLE-US-00007 TABLE 7 Product Metal Precursor, Ligand Solvent (II-1) A1 Rh(COD).sub.2BF.sub.4, (R)-Monophos THF/TFA 0% B1 Rh(COD).sub.2BF.sub.4, (S)-Tol-Binap THF/TFA 0% C1 Rh(COD).sub.2BF.sub.4, (R)-DM-Segphos THF/TFA 0% D1 Rh(COD).sub.2BF.sub.4, (S)-MeO-Biphep THF/TFA 0% E1 Rh(COD).sub.2BF.sub.4, (S,S,R,R)-Tangphos THF/TFA 0% F1 Rh(COD).sub.2BF.sub.4, (R,S)-Binaphos THF/TFA 0% G1 Rh(COD).sub.2BF.sub.4, (R,R)-Kelliphite THF/TFA 0% H1 Rh(COD).sub.2BF.sub.4, (R)-(+)-2-[2-diphenylphosphino)-phenyl]-4- THF/TFA 0% isopropyl-oxazoline A2 [Rh(COD)Cl].sub.2, (R)-Monophos THF/TFA 0% B2 [Rh(COD)Cl].sub.2, (S)-Tol-Binap THF/TFA 0% C2 [Rh(COD)Cl].sub.2, (R)-DM-Segphos THF/TFA 0% D2 [Rh(COD)Cl].sub.2, (S)-MeO-Biphep THF/TFA 0% E2 [Rh(COD)Cl].sub.2, (S,S,R,R)-Tangphos THF/TFA 0% F2 [Rh(COD)Cl].sub.2, (R,S)-Binaphos THF/TFA 0% G2 [Rh(COD)Cl].sub.2, (R,R)-Kelliphite THF/TFA 0% H2 [Rh(COD)Cl].sub.2, (R)-(+)-2-[2-diphenylphosphino)-phenyl]-4- THF/TFA 0% isopropyl-oxazoline A3 Ir(COD).sub.2BF.sub.4, (R)-Monophos THF/TFA 0.09%   B3 Ir(COD).sub.2BF.sub.4, (S)-Tol-Binap THF/TFA 0% C3 Ir(COD).sub.2BF.sub.4, (R)-DM-Segphos THF/TFA 0% D3 Ir(COD).sub.2BF.sub.4, (S)-MeO-Biphep THF/TFA 0% E3 Ir(COD).sub.2BF.sub.4, (S,S,R,R)-Tangphos THF/TFA 0% F3 Ir(COD).sub.2BF.sub.4, (R,S)-Binaphos THF/TFA 0% G3 Ir(COD).sub.2BF.sub.4, (R,R)-Kelliphite THF/TFA 0% H3 Ir(COD).sub.2BF.sub.4, (R)-(+)-2-[2-diphenylphosphino)-phenyl]-4- THF/TFA 0% isopropyl-oxazoline A4 [Ir(COD)Cl].sub.2, (R)-Monophos THF/TFA 0.02%   B4 [Ir(COD)Cl].sub.2, (S)-Tol-Binap THF/TFA 0% C4 [Ir(COD)Cl].sub.2, (R)-DM-Segphos THF/TFA 0.02%  D4 [Ir(COD)Cl].sub.2, (S)-MeO-Biphep THF/TFA 0.03%  E4 [Ir(COD)Cl].sub.2, (S,S,R,R)-Tangphos THF/TFA 0% F4 [Ir(COD)Cl].sub.2, (R,S)-Binaphos THF/TFA 0% G4 [Ir(COD)Cl].sub.2, (R,R)-Kelliphite THF/TFA 0% H4 [Ir(COD)Cl].sub.2, (R)-(+)-2-[2-diphenylphosphino)-phenyl]-4- THF/TFA 0% isopropyl-oxazoline A5 Pt(COD)Cl.sub.2, (R)-Monophos THF/TFA 0% B5 Pt(COD)Cl.sub.2, (S)-Tol-Binap THF/TFA 0% C5 Pt(COD)Cl.sub.2, (R)-DM-Segphos THF/TFA 0% D5 Pt(COD)Cl.sub.2, (S)-MeO-Biphep THF/TFA 0% E5 Pt(COD)Cl.sub.2, (S,S,R,R)-Tangphos THF/TFA 0% F5 Pt(COD)Cl.sub.2, (R,S)-Binaphos THF/TFA 0% G5 Pt(COD)Cl.sub.2, (R,R)-Kelliphite THF/TFA 0.02%   H5 Pt(COD)Cl.sub.2, (R)-(+)-2-[2-diphenylphosphino)-phenyl]-4- THF/TFA 0% isopropyl-oxazoline A6 [Ru(cymene)Cl.sub.2].sub.2, (R)-Monophos THF/TFA 0.02%  B6 [Ru(cymene)Cl.sub.2].sub.2, (S)-Tol-Binap THF/TFA 0% C6 [Ru(cymene)Cl.sub.2].sub.2, (R)-DM-Segphos THF/TFA 0% D6 [Ru(cymene)Cl.sub.2].sub.2, (S)-MeO-Biphep THF/TFA 0% E6 [Ru(cymene)Cl.sub.2].sub.2, (S,S,R,R)-Tangphos THF/TFA 0% F6 [Ru(cymene)Cl.sub.2].sub.2, (R,S)-Binaphos THF/TFA 0% G6 [Ru(cymene)Cl.sub.2].sub.2, (R,R)-Kelliphite THF/TFA 0% H6 [Ru(cymene)Cl.sub.2].sub.2, (R)-(+)-2-[2-diphenylphosphino)-phenyl]-4- THF/TFA 0% isopropyl-oxazoline A7 Rh(COD).sub.2BF.sub.4, (R)-Monophos MeOH 0% B7 Rh(COD).sub.2BF.sub.4, (S)-Tol-Binap MeOH 0% C7 Rh(COD).sub.2BF.sub.4, (R)-DM-Segphos MeOH 0% D7 Rh(COD).sub.2BF.sub.4, (S)-MeO-Biphep MeOH 0% E7 Rh(COD).sub.2BF.sub.4, (S,S,R,R)-Tangphos MeOH 0% F7 Rh(COD).sub.2BF.sub.4, (R,S)-Binaphos MeOH 0% G7 Rh(COD).sub.2BF.sub.4, (R,R)-Kelliphite MeOH 0% H7 Rh(COD).sub.2BF.sub.4, (R)-(+)-2-[2-diphenylphosphino)-phenyl]-4- MeOH 0% isopropyl-oxazoline A8 [Rh(COD)Cl].sub.2, (R)-Monophos MeOH 0% B8 [Rh(COD)Cl].sub.2, (S)-Tol-Binap MeOH 0% C8 [Rh(COD)Cl].sub.2, (R)-DM-Segphos MeOH 0% D8 [Rh(COD)Cl].sub.2, (S)-MeO-Biphep MeOH 0% E8 [Rh(COD)Cl].sub.2, (S,S,R,R)-Tangphos MeOH 0% F8 [Rh(COD)Cl].sub.2, (R,S)-Binaphos MeOH 0% G8 [Rh(COD)Cl].sub.2, (R,R)-Kelliphite MeOH 0% H8 [Rh(COD)Cl].sub.2, (R)-(+)-2-[2-diphenylphosphino)-phenyl]-4- MeOH 0% isopropyl-oxazoline A9 Ir(COD).sub.2BF.sub.4, (R)-Monophos MeOH 0.02%  B9 Ir(COD).sub.2BF.sub.4, (S)-Tol-Binap MeOH 0% C9 Ir(COD).sub.2BF.sub.4, (R)-DM-Segphos MeOH 0% D9 Ir(COD).sub.2BF.sub.4, (S)-MeO-Biphep MeOH 0% E9 Ir(COD).sub.2BF.sub.4, (S,S,R,R)-Tangphos MeOH 0% F9 Ir(COD).sub.2BF.sub.4, (R,S)-Binaphos MeOH 0% G9 Ir(COD).sub.2BF.sub.4, (R,R)-Kelliphite MeOH 0% H9 Ir(COD).sub.2BF.sub.4, (R)-(+)-2-[2-diphenylphosphino)-phenyl]-4- MeOH 0% isopropyl-oxazoline A10 [Ir(COD)Cl].sub.2, (R)-Monophos MeOH 0.75%  B10 [Ir(COD)Cl].sub.2, (S)-Tol-Binap MeOH 0% C10 [Ir(COD)Cl].sub.2, (R)-DM-Segphos MeOH 0% D10 [Ir(COD)Cl].sub.2, (S)-MeO-Biphep MeOH 0% E10 [Ir(COD)Cl].sub.2, (S,S,R,R)-Tangphos MeOH 0% F10 [Ir(COD)Cl].sub.2, (R,S)-Binaphos MeOH 0.05%  G10 [Ir(COD)Cl].sub.2, (R,R)-Kelliphite MeOH 0.02%  H10 [Ir(COD)Cl].sub.2, (R)-(+)-2-[2-diphenylphosphino)-phenyl]-4- MeOH 0% isopropyl-oxazoline A11 Pt(COD)Cl.sub.2, (R)-Monophos MeOH 0.02%  B11 Pt(COD)Cl.sub.2, (S)-Tol-Binap MeOH 0.04%  C11 Pt(COD)Cl.sub.2, (R)-DM-Segphos MeOH 0% D11 Pt(COD)Cl.sub.2, (S)-MeO-Biphep MeOH 0% E11 Pt(COD)Cl.sub.2, (S,S,R,R)-Tangphos MeOH 0% F11 Pt(COD)Cl.sub.2, (R,S)-Binaphos MeOH 0% G11 Pt(COD)Cl.sub.2, (R,R)-Kelliphite MeOH 0.73%  H11 Pt(COD)Cl.sub.2, (R)-(+)-2-[2-diphenylphosphino)-phenyl]-4- MeOH 0% isopropyl-oxazoline A12 [Ru(cymene)Cl.sub.2].sub.2, (R)-Monophos MeOH 0% B12 [Ru(cymene)Cl.sub.2].sub.2, (S)-Tol-Binap MeOH 0% C12 [Ru(cymene)Cl.sub.2].sub.2, (R)-DM-Segphos MeOH 0% D12 [Ru(cymene)Cl.sub.2].sub.2, (S)-MeO-Biphep MeOH 0% E12 [Ru(cymene)Cl.sub.2].sub.2, (S,S,R,R)-Tangphos MeOH 0% F12 [Ru(cymene)Cl.sub.2].sub.2, (R,S)-Binaphos MeOH 0.04%  G12 [Ru(cymene)Cl.sub.2].sub.2, (R,R)-Kelliphite MeOH 0% H12 [Ru(cymene)Cl.sub.2].sub.2, (R)-(+)-2-[2-diphenylphosphino)-phenyl]-4- MeOH 0% isopropyl-oxazoline

[0159] These experiments demonstrate that combinations of commonly used metal precursors and ligands doesn't allow homogeneous hydrogenation of oxime substrates such as (I-1) as in all cases, the amount of product (II-1) formed was <1%.

Comparative Example 2

[0160] ##STR00068##

[0161] Hydrogenation conditions: Temperature=60° C. and pressure H.sub.2=60 bar, Time=20 h. Reaction conditions as described in EP1862446. The conversion towards the desired product ((II-1), labeled ‘Product’ in the table below) was determined by GC and is based on area percentages.

TABLE-US-00008 TABLE 8 Product Conditions (II-1)% Rh(COD).sub.2BF.sub.4 (1.2 mol %), SL-J002-1* (2 mol %),    0% HBF.sub.4•Et.sub.2O (4 eq.), THF Rh(COD).sub.2BF.sub.4 (0.12 mol %), SL-J002-1* (0.2 mol %),    0% HBF.sub.4•Et.sub.2O (4 eq.), THF Rh(COD).sub.2BF.sub.4 (1.2 mol %), SL-J002-1* (2 mol %),    0% CF.sub.3COOH (4 eq.), CF.sub.3CH.sub.2OH Rh(COD).sub.2BF.sub.4 (0.12 mol %), SL-J002-1* (0.2 mol %),    0% CF.sub.3COOH (4 eq.), CF.sub.3CH.sub.2OH Ir(COD).sub.2BF.sub.4 (1.2 mol %), SL-J002-1* (2 mol %), <10% HBF.sub.4•Et.sub.2O (4 eq.), THF Ir(COD).sub.2BF.sub.4 (0.12 mol %), SL-J002-1* (0.2 mol %), Trace HBF.sub.4•Et.sub.2O (4 eq.), THF (<1%) Ir(COD).sub.2BF.sub.4 (1.2 mol %), SL-J002-1* (2 mol %),    0% CF.sub.3COOH (4 eq.), CF.sub.3CH.sub.2OH Ir(COD).sub.2BF.sub.4 (0.12 mol %), SL-J002-1* (0.2 mol %),    0% CF.sub.3COOH (4 eq.), CF.sub.3CH.sub.2OH *SL-J002-1 = (R)-1-[(SP)-2-(Diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine

[0162] In all cases, low selectivity and no or very low yield of the desired product (II-1, labeled ‘Product’ in the table above) was observed. These experiments demonstrate that the catalysts and conditions described in EP 1862446 A2 do not allow efficient hydrogenation of oxime substrates such as (II-1).

Comparative Example 3

[0163] ##STR00069##

[0164] No formation of the desired product (II-1) was observed under reaction conditions as described in Org. Biomol. Chem., 2013, 11, 6934.

Comparative Example 4

[0165] ##STR00070##

TABLE-US-00009 Conversion Product Conditions % (II-1)% Catalyst 0.5 mol %, 0% 0% Solvent = THF, 50° C. Catalyst 0.1 mol %, 0% 0% Solvent = iPrOH, RT

[0166] No formation of the desired product (II-1) was observed under reaction conditions as described in our invention, but using an iridium chloro complex (VI) (as reported for example in Org. Biomol. Chem., 2013, 11, 6934; WO 2013/153407). These experiments demonstrate that iridium halogen complexes are not efficient as catalysts in the current process.

Comparative Example 5

[0167] ##STR00071##

[0168] When utilizing the reaction conditions of the present invention without acid, the formation of the desired product (II-1) was not observed. This experiment demonstrates that a stoichiometric amount of a suitable acid is essential in the process according our invention.