CN1918110A - Hydroaminomethylation of olefins - Google Patents

Abstract

The present invention relates to a process comprising contacting an olefin, an amine, a rhodium-phosphite ligand, and synthesis gas (syngas) under hydroaminomethylation conditions. In particular, it has been found that, under certain circumstances, neutral rhodium-monodentate phosphite ligands are preferred. The present invention provides a simple means for producing a variety of products, including pharmacologically active products such as ibutilide, terfenadine, fexofenadine, and their derivatives, in high yields and with regiospecificity.

Description

Hydroaminomethylation of Alkenes

Background of the invention

The present invention relates to the hydroaminomethylation of olefins. Aliphatic amines are used in a variety of applications including agrochemical and pharmaceutical products and intermediates, and polymer precursors such as polyurethanes. Homogeneous hydroaminomethylation reactions were reported by Reppe at BASF using homogeneous cobalt carbonyl catalysts (Liebigs Ann. Chem. 1953, 582, 133-161). This reaction consists of a tandem, one-step olefin hydroformylation/reductive amination sequence in which an intermediate aldehyde is reacted with a primary or secondary amine to form an imine or enamine intermediate, which undergoes hydrogenation to form a secondary or tertiary amine amine. US 3,513,200 reports the use of a homogeneous rhodium triphenylphosphine catalyst for the synthesis of tertiary amines by hydroaminomethylation. The use of hydroaminomethylation of ethylene to form n-propylamine is reported by Jones in J. Organomet. Chem. 1989, 366, 403-408. Since ethylene hydroformylation can only produce a single regioisomer of the intermediate propionaldehyde, this reaction is completely selective for the synthesis of n-propylamine. Eilbracht et al. reported in Tetrahedron 1999, 55, 9801-9816 that pharmacologically active amines can be prepared by hydroaminomethylation using a homogeneous [Rh(cod)Cl] _catalyst , however this reaction is regioisomeric to the desired branched Body selectivity is low. Beller et al. reported in J.Am.Chem.Soc.2003, 125, 10311-10318 that by using a rhodium catalyst employing a Xantphos diphosphine ligand, terminal olefins can be synthesized with very high selectivity to linear amine isomers. Hydroaminomethylation. In Science 2002, 297, 1676-1678, Seayad et al. describe the synthesis gas, phosphine ligand, and cationic procatalyst [Rh ⁺ (cycloocta-1,5-diene) ₂ ] [BF ₄ ⁻ ] (also called [Rh ⁺ (cod) ₂ BF ₄ ] procatalyst) in the presence of internal olefins (such as 2-butene, 2-pentene, or 2-octene) and amines (such as piperidine, dimethylamine or di n-hexylamine) to prepare aliphatic amines. The researchers also tested monodentate phosphite ligands under the same reaction conditions but found poor amine selectivity—and no conversion to the desired linear amine—from which they concluded that “due to the Due to the hydrolysis problems encountered, the phosphite ligands are not well suited for the desired reaction." Id. at 1677. The disadvantages of this reported phosphite ligand in hydroaminomethylation are significant because rhodium phosphite catalysts are well suited for the hydroformylation of alkenes, which is the first step in the hydroaminomethylation sequence. one step. Pruett (J. Org. Chem. 1969, 34, 327) reported that homogeneous rhodium triphenylphosphite catalysts give higher linear selectivities than rhodium triphenylphosphine. Bulky monodentate phosphite ligands such as tris(2-tert-butyl-4-methylphenyl)phosphite were found by van Leeuwen et al. (Organometallics 1995, 14, 34-43) to give Very high hydroformylation rate. Bidentate bisphosphite ligands can yield very high selectivity to linear aldehydes from the rhodium-catalyzed hydroformylation of terminal alkenes. These catalysts are highly tolerant to a wide range of functional groups, which makes their application to the synthesis of complex organic molecules possible (J. Am. Chem. Soc. 1993, 115, 2066-2068). Intramolecular examples of hydroaminomethylation of unsaturated amines are reported by Bergmann et al. (Tetrahedron. Lett. 1997, 38, 4315-4318) using highly regioselective bisphosphite ligands.

To ensure the hydrogenation of the enamine intermediate to the desired amine, Seayad et al. reported that "a reaction temperature of 120°C was required" supra at 1677. On the other hand, in a later publication (Angew.Chem.Int.Ed.2003, 42, 5615-5619), the same research group reported the use of a [Rh(CO) ₂ (acac)] procatalyst and a phosphine ligand Selective preparation of enamine intermediates at temperatures ranging from 65°C to 125°C.

Although alkylamines can be prepared in reasonably high yields and selectivities using the method described by Seayad et al., the high temperature requirements make this method suitable only for olefins, amines, catalysts and products that are stable at these high temperatures. Also, long reaction times require extended use of process equipment, which leads to increased processing costs. Therefore, there is a need to find more efficient and effective ways of aminomethylation of alkenes.

Summary of the invention

In a first aspect, the invention is a process comprising the steps of subjecting a) an alkene; b) a primary or secondary amine or ammonia; c) a neutral rhodium-monodontate phosphite ligand under hydroaminomethylation conditions The complex is contacted with d) synthesis gas.

In a second aspect, the invention is a process comprising the steps of complexing a) an alkene of the class ArXCR= _CR2 ; b) a secondary amine; c) a rhodium-phosphorous ligand under hydroaminomethylation conditions and d) synthesis gas contact; wherein Ar is aryl or substituted aryl, each R is independently H, alkyl, cycloalkyl, aryl, aralkyl, substituted alkyl, substituted cycloalkyl, A substituted aryl group, or a heteroatom-containing group, and X is a linking group, with the proviso that when X is _-CH2- or _-OCH2- , the phosphorous ligand is a phosphite ligand.

Detailed description of the invention

In a first aspect, the present invention is a process for the preparation of alkylamines by contacting an olefin, an amine, a neutral rhodium-monodontate phosphite ligand complex, and synthesis gas under hydroaminomethylation conditions. Alkenes can be terminal (e.g. ethylene, propylene, 1-butene, 1-pentene, 4-methyl-1-pentene, 1-hexene, 1-decene, 1-dodecene, vinyl Cyclohexane, vinyl-terminated polypropylene, allylbenzene, allylphenol, styrene, isobutylene, 2-methyl-1-pentene, methylenecyclohexane, norbornene, alpha-formaldehyde styrene, α-cyclohexylstyrene, vinylidene-terminated polypropylene, vinylidene-terminated poly(4-methyl-1-pentene)) or internal (such as 2-butene, 2-pentene ene, 2-hexene, 3-hexene, 2-octene, 3-octene, cyclohexene, stilbene, and methyl oleate and its derivatives). Furthermore olefins may contain more than one olefinic group (e.g. butadiene, isoprene, piperylene, 1,7-octadiene, allene, norbornadiene, dicyclopentadiene , methyl linoleate, methyl linolenate, triglyceride oleate, polybutadiene, and polybutadiene-co-styrene), which may also include ketone- or aldehyde-containing alkenes (such as tetrahydrobenzene formaldehyde), which is considered a diene for the purposes of the present invention.

Amines can be primary amines (such as methylamine, ethylamine, n-propylamine, n-butylamine, isopropylamine, isobutylamine, t-butylamine, n-hexylamine, n-hexylamine, n-octylamine, benzylamine, allylamine, 1-phenylamine phenylethylamine, 2-phenylethylamine, neopentylamine, cyclohexylamine, ethanolamine) or secondary amines (such as dimethylamine, ethylmethylamine, butylmethylamine, di-n-hexylamine, piperidine, pyrrolidine, morpholine , aniline, dibenzylamine, n-methylaniline, diethanolamine, N-methylbenzylamine, N-methylcyclohexylamine, N-methallylamine, and indole) and may contain more than one Amino groups (such as ethylenediamine, 1,2-diaminopropane, 1,3-diaminopropane, hexamethylenediamine, piperazine, N-methylpiperazine, 1-(2,3-dichloro phenyl)piperazine, 1,4-diaminocyclohexane, hydrazine, and N,N'-dimethylpropanediamine). Amines may also contain one or more non-amine functional groups that do not participate in the reaction (eg, 3-methylamino-propionitrile). The mole-to-mole ratio of the N-H groups of the amine to the olefinic groups of the alkene is preferably not less than 0.5:1, more preferably not less than 0.7:1; and most preferably not less than 0.9:1; and preferably not greater than 2:1, more preferably not less than 0.7:1; Preferably not greater than 1.5:1 and most preferably not greater than 1.1:1. By way of example, three moles of 1-butene can be reacted with one mole of ammonia, two moles of 1-butene can be reacted with one mole of ethylamine, and one mole of 1-butene can be reacted with diethylamine.

Neutral rhodium-monodontate phosphite ligand complexes (the following complexes) are usually readily prepared by: in the presence of solvents such as dioxane, THF, cyclohexane, toluene, acetone, or o-xylene It is prepared by contacting a neutral rhodium procatalyst with a preferably stoichiometric excess of monodentate phosphite ligand. Monodentate phosphite ligands can be characterized by the general formula P(OR) ₃ , where each R is independently a carbon-containing substituent. Monodentate denotes the fact that the ligand contains only one phosphite group. Preferably, each R independently includes alkyl, aryl, aralkyl, arylalkoxy, or carbonylaryl. Examples of representative monodentate phosphites include triphenyl phosphite, tris(2,4-di-tert-butylphenyl) phosphite, tri-o-cresyl phosphite, tri-p-cresyl phosphite, Trimethyl phosphite, triethyl phosphite, tri-n-propyl phosphite, tri-n-butyl phosphite, tri-tert-butyl phosphite, tri-1-naphthyl phosphite, tri- 2-naphthyl phosphite, 2,2'-bisphenol phenyl phosphite, 2,2',4,4'-tetra-tert-butyl-2,2'-bisphenol 2,4-di-tert-butyl phenyl phosphite, and tribenzyl phosphite.

A neutral rhodium procatalyst is a rhodium(I) catalyst precursor characterized in that its positive charge is balanced by the negative charge of the supporting binding ligand. For example, rhodium dicarbonylacetonate (also known as [Rh(CO) ₂ (acac)] procatalyst) is a neutral rhodium procatalyst and, therefore, suitable for the process of the first aspect of the invention, since acetone acetate The root is the negatively charged moiety chemically bonded to the rhodium cation. On the other hand, [Rh(cod) ₂ BF ₄ ] is a cationic rhodium procatalyst due to the inability of the tetrafluoroborate anion to chemically bind to the rhodium cation.

Other suitable examples of neutral rhodium procatalysts for use in preparing complexes include [Rh ₄ (CO) ₁₂ ], [Rh ₂ (OAc) ₄ ], [Rh(C ₂ H ₄ ) ₂ (acac)], [Rh (cyclooctadiene)(acac)], [(Rh(norbornene) ₂ (acac)), [(Rh(norbornadiene)(acac)), and [Rh(acac) ₃ ] procatalysts.

The mole-to-mole ratio of monodentate phosphite ligand to neutral rhodium catalyst used to prepare the complex is preferably not less than 2:1, and more preferably not less than 4:1; and preferably not greater than 30:1, and more preferably Not greater than a 20:1 mole to mole excess. Olefins and amines are preferably used in stoichiometric excess to the complex. The mole-to-mole ratio of the complex to the amino group of the amine or the olefinic group of the olefin is preferably not more than 1:500, and more preferably not more than 1:200, and preferably not less than 1:10, and more preferably not less than 1:40 .

The olefin, amine, and complex and optionally the solvent are advantageously saturated with a stoichiometric excess of a mixture of CO and _H (below syngas) and heat and pressure adjustments for a time sufficient to convert the reactants to the desired amino group Methylation products. Alternatively, in a mode that may be advantageous for hindered alkenes such as 1,1′-disubstituted alkenes (e.g. α-cyclohexylstyrene), the amine or ammonia is added sequentially, i.e. after the alkenes are converted to hydroformylation intermediates after. The mole-to-mole ratio of _H2 :CO depends on the application, but is preferably not less than 1:1, more preferably not less than 1.5:1, and most preferably not less than 1.8:1, and preferably not greater than 4:1, more preferably not greater than 3:1, and most preferably no greater than 2.2:1. Preferably, the reaction is not less than 200psi (1380kPa), more preferably not less than 500psi (3450kPa), and most preferably not less than 800psi (5510kPa); and preferably not greater than 3000psi (20700kPa), more preferably not greater than 2000psi (13800kPa), and most preferably It is preferably performed at a pressure of no greater than 1500 psi (10340 kPa). Preferably, the reaction temperature is kept not higher than 140°C, more preferably not higher than 120°C, and most preferably not higher than 100°C; and preferably not lower than 20°C, more preferably not lower than 40°C, and most preferably not lower than at 60°C.

Although the putative reaction of syngas with complexes presumably forms the same products regardless of the use of neutral or cationic rhodium procatalysts, it is believed that the formation of strong acids from the reaction of syngas with complexes derived from cationic rhodium procatalysts (as from [Rh(cod) ₂ BF ₄ ] (HBF ₄ ) inhibits the hydrogenation of enamine intermediates to aminomethylated products. For this reason, neutral rhodium procatalysts are the precursors of choice for the preparation of complexes.

It has surprisingly been found that aminomethylated products can be prepared in high yields, at relatively low temperatures (<100°C), and in relatively short times (<5 hours).

In a second aspect, the present invention is a method for the preparation of aminomethylation products, the method comprising the steps of: making a) an alkene of the class ArXCR=CR ₂ ; b) a secondary amine; c) rhodium under hydroaminomethylation conditions Procatalyst; d) phosphorous-containing ligand; and e) synthesis gas contact; wherein Ar is aryl or substituted aryl, each R is independently H, alkyl, cycloalkyl, aryl, aralkyl , substituted alkyl, substituted cycloalkyl, substituted aryl, or heteroatom-containing groups such as methoxy, ethoxy, primary amino, and tertiary amino, and X is a linking group, provided that when X is In the case of -CH ₂ - or -OCH ₂ -, the phosphorous ligand is a phosphite ligand. The term "phosphorous ligand" as used herein means a phosphorous-containing ligand.

Ar is preferably substituted or unsubstituted phenyl, naphthyl, anthracenyl, phenanthrenyl, or heteroaryl, more preferably substituted or unsubstituted phenyl, most preferably substituted phenyl. Examples of preferred substituted phenyl groups include pY-phenyl or methanesulfonylaminophenyl, wherein Y is C( _CH3 ) _2R ", wherein R" is methyl, cyano, hydroxymethylene, alkoxy methylene, carbonylhydroxy, carbonylmethoxy, carbonylethoxy, carbonylbenzyloxy, amido, orthoformate, formyl, 2-oxazoline, or 2-benzoxazole. More preferred substituted phenyl groups include p-tert-butylphenyl, p-methanesulfonamidophenyl, or p-(α-carbonylmethoxy-α′-methyl)ethylphenyl. X is preferably -CHOH, -CHOSi(CH ₃ ) ₃ , or -C═O, more preferably -CHOH.

Although neutral rhodium procatalysts are preferred for use in this second aspect, cationic rhodium procatalysts such as [Rh(cod) ₂ BF ₄ ], [Rh(cod) ₂ CF ₃ SO ₃ ], [Rh(cod) ₂ PF ₆ ], [Rh(cod) ₂ BPh ₄ ], [Rh(ethylenediamine) ₃ NO ₃ ], [Rh(bipyridine) ₃ Cl] ₃ and [Rh(norbornene) ₂ ClO ₄ ]. The phosphorous ligand is preferably a phosphine or phosphite ligand. If X is _-CH2- or _-OCH2- , the phosphorous ligand is a phosphite ligand; for all other Xs, the phosphorous ligand is not limited. Preferably, X is -CR'OR', C=O, S, or NR-C=O, wherein each R' is independently alkyl, cycloalkyl, aryl, arylalkyl, trialkylmethane Silyl, or H. More preferably, X is -CHOH, -CHOSi( _CH3 ) ₃ , or -C=O; most preferably -CHOH.

Examples of suitable phosphines for use in this second aspect include 2,2'-bis(diphenylphosphinomethyl)-1,1'-binaphthalene (NAPHOS), 2,2'-bis[bis(3, 5-trifluoromethylphenyl)phosphinomethyl]-1,1'-binaphthyl (IPHOS), 2,2'-bis[bis(4-trifluoromethylphenyl)phosphinomethyl]- 1,1'-binaphthyl, and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (XANTPHOS).

Examples of suitable phosphites include the monodentate phosphites described above, and polydentate, preferably bidentate, phosphite ligands, examples of which include ligand 2 as described below:

Ligand 2

Other examples of bidentate ligands are disclosed in U.S. 4,748,261, the teachings of which are incorporated herein by reference.

The process of this second aspect of the invention provides a simple means of reductively coupling amines and alkenes in a single step to prepare various useful compounds, such as pharmaceutical compounds, including ibutilide, terfenadine, and fexofide Phenadine and its derivatives. Certain olefinic substrates are novel compositions for such process applications.

The following examples are for illustrative purposes only and are not intended to limit the scope of the invention. Syngas was obtained from Matheson or Airgas and refers to a 2:1 mole-to-mole mixture of _H2ZCO unless otherwise stated.

Example 1 - Preparation of dimethylaminomethylalkane mixture

A Neodene(R) olefin blend (10/1112/13/12, 319 g, obtained from Shell Chemical) olefin substrate was charged to a 1-gal (4-L) reactor in THF (680 g). To this solution was added dimethylamine (222 g), and [Rh(CO) ₂ (acac)] (3.7 g) and tris(2,4-di-tert-butylphenyl) phosphite (46.2 g, from Aldrich Chemical) solution of the prepared complex in THF (374 g). The final rhodium concentration was about 900 ppm by weight. This mixture was heated to 80°C and pressurized to 600 psi (4140 kPa) with syngas and stirred under these conditions for 7 hours. The reactor was cooled to 21°C overnight and the gas phase was vented. After stirring under nitrogen flow for about 1 hour to remove most of the excess dimethylamine, the reactor contents were decanted, THF stripped and distilled using a Kugelrohr apparatus to give a colorless mobile liquid (427 g, 99% yield).

The hydroaminomethylation of embodiment 2-oleic acid diethanolamide and diethanolamine

Oleamide (13.49 g), diethanolamine (4.51 g) and THF solvent (20 mL) were added via syringe to the nitrogen purged reactor. The reactor was stirred under approximately 200 psi (1380 kPa) syngas to saturate the solution. After degassing, [Rh(CO) ₂ (acac)] (5351 ppm by Rh weight) and tris(2,4-di-tert-butylphenyl)phosphite ligand (5.00 mol ligand/mol Rh) An aliquot (10.4 g) of the pre-prepared catalyst solution in THF was charged to the reactor. The reactor was sealed and pressurized with synthesis gas and heated to 80°C. The pressure was increased to 600 psi (4140 kPa) with additional syngas, and then fed at this pressure throughout the reaction as needed. After 4.5 hours, the reactor was cooled, vented and the reactor contents drained. The amber solution was extracted with cyclohexane, then toluene, and the supernatant was discarded. Acetonitrile was added to the lower brown layer, and stirred briefly. When stirring ceased, the viscous, honey-colored lower layer (16.7 g) was isolated by decantation. H-1 and C-13 NMR spectra showed that the product with excess diethanolamine was desired. Mass spectrum (CI with isobutane) showed a (M+H) ⁺ peak at 489 and a (M+H+isobutene) ⁺ peak at 545, confirming the molecular weight.

Embodiment 3-hydroaminomethylation of terminally unsaturated isopolypropylene and dibenzylamine

Vinylidene terminated polypropylene (5.43 g, obtained from Baker-Hughes Corporation) having a weight average molecular weight Mw of about 1800 g/mol was dissolved in toluene (70 mL). A portion of this solution (65 mL) was transferred to a 100 mL Parr reactor, whereupon dibenzylamine (2 mL, 9.8 mmols) was added and a solution containing the complex (20 mL of a stock solution prepared by dissolving [Rh( CO) ₂ (acac)] (2.56 g), 2,4-di-tert-butylphenyl phosphite (32.09 g) to give a total solution mass of 200.73 g). The reactor was sealed and pressurized to 600 psi (4140 kPa) syngas and heated to 80°C for 130 minutes. After the reaction, the pressure was released and the reactor was opened while the temperature was still at 60°C, and the contents were drained into a glass beaker. The polymer product was precipitated by adding methanol (approximately 2 x volume). The solid material was filtered off and washed with methanol until the washings were colorless. The material was dried in vacuo to give 5.31 g of product, characterized by C-13 and H-1 NMR spectra.

Example 4 - Hydroaminomethylation of cyclohexene with ammonia

A portion of the complex stock solution (10 mL) described in Example 3, THF (10 mL), cyclohexene (0.93 g., 11.07 mmols) and ammonia (30 mL of a 0.5 M solution in dioxane) was added to 100 mL of Parr to react device. The reactor was pressurized and heated to 80° C. with 400 psi (2760 kPa) syngas for 220 minutes, then cooled and sampled for gas chromatographic analysis. The results indicated 94% consumption of cyclohexene and major products were tris(cyclohexylmethyl)amine (90%), di(cyclohexylmethyl)amine (3%) and cyclohexylmethanol (7%).

The hydroaminomethylation of embodiment 5-ethylidene norbornene and morpholine

An aliquot (9.81 g) of the catalyst stock solution from Example 3 was charged to a 100-mL Parr autoclave along with THF (36.54 g) and morpholine (2.02 g). The reactor was stirred for 15 minutes under 200 psi (1380 kPa) syngas. The pressure was vented, whereby ethylidene norbornene (0.96 g) was added. The reactor was pressurized to 400 psi (2760 kPa) with syngas and heated to 80°C for 150 minutes. The reactor was then cooled and the contents were analyzed by gas chromatography/mass spectrometry, showing almost complete conversion of the starting material to isomers of mono- and diamines with molecular weights corresponding to structures 1 (46%) and 2 (54%). mixture.

Embodiment 6-hydroaminomethylation of poly(1,2-butadiene) and diethanolamine

A solution of poly(1,2-butadiene) (obtained from Scientific Design Company, Mw ~ 100,000, 93% vinyl, 7% 1,4-cis, 5.1% by weight in 50 mL THF) and 9.45 g di Ethanolamine was added to the 100-mL Parr reactor. The reactor was purged and vented with syngas, whereby a solution of the complex (157.6 g, from a stock solution of the complex prepared by mixing [Rh(CO) ₂ (acac)]( 2.52 g), 2,4-di-tert-butylphenyl phosphite (31.06 g)). The reactor was pressurized to 400 psi (2760 kPa) with syngas and heated to 80°C for almost 4 hours. Cool the reactor and drain the contents. The insoluble brown polymer was dissolved in methanol, reprecipitated with acetone, then recovered by centrifugation and analyzed by H-1 and C-13 NMR spectroscopy to demonstrate formation of the indicated product.

The hydroaminomethylation of embodiment 7-styrene and morpholine

[Rh(CO) ₂ (acac)] (0.100g), 2,4-di-tert-butylphenyl phosphite (1.355g), tetrahydrofuran (50mL), morpholine (14.62g) and styrene (8.81 g) Charge to a 100-mL Parr reactor and then pressurize to 380 psi (2620 kPa) and heat to 80°C for 4 hours. The reactor was cooled and the contents were analyzed by GC-MS/IR. The product distribution was found to be as follows:

2-Phenylpropionaldehyde - 6%

2-Phenylpropanol - 2%

1-morpholino-2-phenylpropane- 40%

1-Morpholino-3-phenylpropane- 40%

2-Phenylpropanalmorpholine Enamine - 10%

1-2/3-Dimorpholino-3-phenylpropane- 2%

The hydroaminomethylation of embodiment 8-tetrahydrobenzaldehyde and morpholine

[Rh(CO) ₂ (acac)] (127.1 mg), ligand 1 (2.84 g), dioxane (50 mL), hexane (GC internal standard, 1223.5 mg), tetrahydro Benzaldehyde (5.52g) and morpholine (9.08g). The reactor was pressurized with 1000 psi (6890 kPa) of 1:1 _H2 /CO and heated to 90°C for 4 hours. After 90 minutes, the selectivity to the diamine was 94%, no enamines were detected.

Ligand 1

Example 9 - Hydroaminomethylation of polybutadiene with dimethylamine

An aliquot (23.31 g) of the stock solution of poly(cis-1,4-butadiene) (19.47 g in 376.1 g THF) was charged to a 100-mL Parr reactor, which was then sealed and Pressurized with 300 psi (2070 kPa) syngas. After degassing, the complex solution (9.73 g from [Rh(CO) ₂ (acac)] (3.0001 g), 2,4-di-tert-butylphenyl phosphite (37.77 g) and THF (229.2 g)) was added, followed by dimethylamine (3.13 g). The reactor was pressurized to 600 psi (4140 kPa) with syngas and then heated to 80°C. After about 135 minutes, the reactor was cooled and the pressure vented. Open the reactor and transfer the contents to a flask. A 1% by weight Ionol (antioxidant) solution was added, but no precipitate formed. The solvent was removed in vacuo, the product was dissolved in ether and precipitated with acetone to give a beige rubbery material. The product was dried overnight in vacuo and characterized by H-1 NMR spectroscopy. The H-1 spectrum shows an almost total absence of olefinic CH resonances at about 5.4 ppm. The new peaks at 2.145 and _2.064 were _assigned as ( _CH3 ) _2NCH2- and ( _CH3 ) _2NCH2- , respectively. In addition, resonances at 1.1-1.6 due to saturated polymer chains also exist.

Example 10 - Hydroaminomethylation of vinylidene-terminated poly(4-methyl-1-pentene) with 3-aminomethyl-propionitrile

To a 1-gallon stainless steel autoclave was charged poly(4-methyl-1-pentene) (76.04 g, 3.5 mmol olefin-functionalized, Mn ~22,000), 1.5 L of toluene, and 3-aminomethyl-propionitrile (20 mL , 215.6 mmol). The autoclave was pressure tested, briefly purged with _N2 , purged with syngas (2:1 _H2 /CO), and the contents were stirred at 400 psi syngas (2:1 _H2 /CO) for 20 min. The reactor was slowly heated to 60°C, vented and charged through a pressurized (80 psi N ₂ ) Whitey cylinder containing Rh(CO) ₂ (acac) (4.42 g, 17.1 mmol) and tris- Catalyst solution of 2,4-di-tert-butylphenylphosphite (23.34 g, 36.1 mmol). The reactor was then heated to 80° C., pressurized to 400 psi with syngas (2:1 H ₂ /CO) and stirred for 14 h. After cooling to 60 °C, the reactor was purged with _N2 and dumped. An equal volume of MeOH was added to induce polymer precipitation. The obtained solid was filtered and washed with acetone until the filtrate was colorless (-2 L). The filter cake was dried overnight in a vacuum oven and a sample was submitted ^for1H NMR analysis. Analysis of the NMR data revealed incomplete conversion of the starting material with 65-70% conversion to the desired product. The isolated polymer mixture (see below) 68.75 g was charged to the same stainless steel autoclave along with an additional 1.5 L of toluene and 3-aminomethyl-propionitrile (20 mL, 215.6 mmol). After purging and stirring under syngas as described above, the reaction mixture was heated to 60 °C and a mixture comprising Rh(CO) ₂ (acac) (4.31 g, 16.7 mmol) and tris-2,4- in 250 mL THF was added. Catalyst solution of di-tert-butylphenyl phosphite (22.99 g, 35.5 mmol). The reaction mixture was heated to 80° C., pressurized to 400 psi syngas (2:1 H ₂ /CO) and stirred for an additional 14 h. Isolation of the product described above gave 63.58 g of a colorless powder. Samples were submitted ^to1HNMR analysis. Analysis of the NMR data showed complete conversion of this material to the desired aminomethylated product.

The hydroaminomethylation of embodiment 11-α-cyclohexylstyrene and piperidine

A. Synthesis of α-cyclohexylstyrene

α-Cyclohexylstyrene was prepared from cyclohexylphenyl ketone using standard Wittig chemistry (Gupta, P.; Fernandes, RA; Kumar, P. Tet. Lett. 2003, 44, 4231-4232.). Methyltriphenylphosphonium bromide (29.57 g, 82.77 mmol) was slurried in 600 mL THF in the glove box. The mixture was cooled to 2°C, and nBuLi (1.6M in hexanes, 52 mL) was added over 15 min. After 1 h, solid cyclohexyl phenyl ketone (15.18 g, 80.63 mmol) was added and the solution was slowly warmed to room temperature overnight. Water (200 mL) was added. The solution was extracted with _Et2O (3 x 150 mL). The combined organic extracts were washed with brine, dried ( _MgSO4 ) and evaporated under vacuum to give a tan liquid. _Ph3PO crystallized on standing and was removed by filtration and washed with hexane (200 mL). The hexane solution was filtered through a 2 in natural alumina cartridge, washing with an additional 200 mL of hexane. The filtrate was evaporated to a colorless liquid which was distilled (46-49° C./0.1 mm Hg) to give 13.72 g of a colorless liquid (89% yield).

B. General Hydroformylation Process

The hydroformylation solution was prepared by adding the ligand and Rh(CO) ₂ (acac) stock solution to THF solvent followed by the olefin solution. The total amount of liquid in each reactor cell was 4 mL. Ligand solutions (0.11M for monodentate ligands) and Rh(CO) ₂ (acac) (0.05M) were prepared in a dry box by dissolving the appropriate amount of compound in toluene at room temperature. The olefin solution was prepared by mixing 2.3493 g of α-cyclohexylstyrene and 0.6444 g of dodecane (as GC internal standard) (1:0.3 molar ratio). The hydroformylation reaction was performed in an Argonaut Endeavor ^(R) reactor system located in an inert atmosphere glove box. The reactor system consisted of eight parallel, mechanically stirred pressure reactors with individual temperature and pressure controls. While the catalyst solution was being added, the reactor was pressurized with syngas (CO: _H2 - 1:1) and then heated to the desired temperature while stirring at 800 rpm. The test was stopped after 16 hrs by venting the system. Upon opening the reactor, 0.1 mL of each reaction mixture was withdrawn and diluted with 1.6 mL of toluene, and this solution was analyzed by gas chromatography. All GC analyzes were performed on a DB-5 column with the following temperature program: 100 °C for 5 min, then 10 °C/min to 250 °C and then hold for 5 min.

C. Hydroaminomethylation by sequential addition of piperidine

0.085 mL of a 0.05 M solution of Rh(CO) ₂ (acac) and 0.085 mL of a 0.11 M solution of Doverphos (ligand:Rh ratio 2.2) were added to the reactor, followed by 3.2 mL of THF, 0.6 mL of the olefin solution (α - 1:0.3 solution of cyclohexylstyrene and dodecane, 500:1 ratio of olefinic substrate:Rh). The reaction mixture was heated at 90 °C for 18 hrs under 300 psi syngas pressure. The conversion of α-cyclohexylstyrene to the desired 3-cyclohexyl-3-phenyl-propanal was 96.5% according to GC analysis. After cooling to room temperature, the reactor was opened and 0.25 mL of piperidine (1.2:1 ratio of piperidine:aldehyde substrate) was added. The reaction mixture was heated at 90 °C for 18 hrs at 300 psi syngas pressure after closing the reactor. GC analysis showed formation of the desired amine, 1-(3-cyclohexyl-3-phenyl-propyl)-piperidine, in 95% yield. The reaction mixture was removed from the reactor and the solvent was removed under reduced pressure to leave an oil. To this residue was added -13 mL of acetonitrile and the solution was heated using a heat gun. The solution was placed in the refrigerator (~5°C). After 2 days, the solution was decanted and the remaining light yellow oil was washed with cold acetonitrile (2 x 3 mL) and then dried under reduced pressure to give 150 mg of clear product. ¹ H(C ₆ D ₆ ): δ0.65-1.66(m, 1 7H), 1.83(m, 1H), 1.92-2.31(m, 7H), 2.36(m, 1H), 7.04(m, 3H) , 7.13 (m, 2H). ¹³ C{ ¹ H} and APT(C ₆ D ₆ ): δ25.30(CH ₂ ), 26.84(CH ₂ ), 27.09(CH ₂ ), 27.15(CH ₂ ), 30.75(CH ₂ ), 31.58(CH ₂ ), 31.93(CH ₂ ), 43.79(CH), 50.49(CH), 55.09(CH ₂ ), 58.06(CH ₂ ), 126.09(CH), 128.30(CH), 128.86(CH), 144.82(C) . GC-MS (m/e): 285

D. Comparative example: Hydroaminomethylation without sequential addition of piperidine

To the reactor was added 0.085 mL of a 0.05 M solution of Rh(CO) ₂ (acac) and 0.085 mL of tris(2-tert-butyl-4-methylphenyl)phosphite (ligand:Rh ratio of 2.2 ), followed by addition of 3.2 mL THF, 0.6 mL olefin solution (1:0.3 solution of α-cyclohexylstyrene and dodecane, 500:1 ratio of olefin substrate:Rh) and 0.25 mL piperidine ( 1.2:1 ratio of piperidine:alkene substrate). The reaction mixture was heated at 90 °C for 18 hrs under 300 psi syngas pressure. The conversion of α-cyclohexylstyrene according to GC analysis was 11.7%.

Embodiment 12-preparation of ibutilide

                     

A. Preparation of 4-methylsulfonylaminobenzaldehyde

                                                                   

A solution of 4-nitrobenzaldehyde (6.60 g, 43.67 mmol) and p-toluenesulfonic acid monohydrate (153 mg, 0.804 mmol) was dissolved in 150 mL of toluene. Ethylene glycol (5 mL) was added and the solution was refluxed with a Dean-Stark trap to remove water azeotropically. After 1 hour, the reaction was cooled, whereby 100 mL of diethyl ether was added. The solution was washed with saturated NaHCO ₃ solution and then with saturated NaCl solution. The solution was dried over MgSO ₄ and evaporated to give 4-nitrobenzaldehyde ethylene glycol acetal (8.13 g, 95% yield) as a yellow solid.

PtO ₂ (502 mg, 2.21 mmol) and MgSO ₄ (7.34 g, 61.0 mmol) were added to a solution of 4-nitrobenzaldehyde ethylene glycol acetal (5.93 g, 30.4 mmol) in 60 mL of THF. The resulting suspension was stirred under 70 psi _H2 for 5 h. Solids were removed by filtration and the filtrate was evaporated to give 4-aminobenzaldehyde ethylene glycol acetal as a golden liquid.

4-Aminobenzaldehyde ethylene glycol acetal (1.793 g, _10.86 mmol) was dissolved in 25 mL _CH2Cl2 and cooled to 0 °C. Pyridine (925 mg, 11.7 mmol) was added followed by the dropwise addition of methanesulfonyl chloride (1.369 g, 11.9 mmol) over 30 min. The solution was allowed to warm to room temperature with stirring. After 16 h, 6M NaOH (5 mL) was added, followed by 150 mL of water. The aqueous layer _was separated, washed with 50 mL _CH2Cl2 and then acidified to pH 1 with 2M HCl. The obtained suspension was extracted into ethyl acetate (4 x 50 mL), which was dried over MgSO ₄ and evaporated to give 4-methylsulfonylbenzaldehyde (920 mg, 42% yield) as an orange solid.

B. Preparation of 4-MeSO ₂ N(H)C ₆ H ₄ [C(H)(OH)(CH=CH ₂ )]

4-MeSO ₂ N(H)C ₆ H ₄ [C(H)(OH)(CH=CH ₂ )]

A solution of 4-methanesulfonylbenzaldehyde (834 mg, 4.19 mmol) in 13 mL of THF was added to 8.5 mL of 1.0 M ( _H2C = _CH2 )MgBr in THF. The resulting suspension was stirred for 3.5 h and then quenched with 10 mL of saturated _NH4Cl solution. The solution was extracted and separated with diethyl ether (2 x 20 mL). The combined organic extracts were washed with water and saturated NaCl solution. After drying over MgSO ₄ , the solution was evaporated to give 4-MeSO ₂ N(H)C ₆ H ₄ [C(H)(OH)(CH═CH ₂ )] (1.036 g) as an orange liquid.

C. Preparation of ethyl-n-heptane

A solution _of n-heptylamine (10.31 g, 89.4 mmol) in 100 mL of _CH2Cl2 was cooled in an ice bath. Pyridine (7.5 mL, 92.7 mmol) was added. Acetyl chloride (8.0 mL, 11 mmol) was gradually added over a period of 2 min. The ice bath was removed and the solution was allowed to warm to room temperature. After 1 h, water (100 mL) was added, and the organic layer was separated. The aqueous layer was extracted with 100 _{mL CH2Cl2} . The combined organic extracts were washed with 10% aqueous HCl, saturated NaHCO ₃ solution and then saturated NaCl solution. The solution was dried over _MgSO4 and evaporated to give n-heptylacetamide (13.73 g, 98% yield) as a colorless liquid.

A solution of n-heptylacetamide (6.076 g, 38.63 mmol) in 6 mL diethyl ether was added dropwise to a suspension on LiAlH4 (4.60 g, 0.121 mol) in 150 mL diethyl ether. The suspension was refluxed for 8 h, cooled in ice and quenched with 4 mL _H2O , 4 mL 2M NaOH and ₁₂ mL H2O. The obtained suspension _was filtered and the filtrate was dried over _Na2SO4 . The solvent was evaporated to give (nC ₇ H ₁₅ )N(H)C ₂ H ₅ (5.29 g, 95% yield) as a colorless liquid.

D. Preparation of Ibutilide

Rh(CO) ₂ (acac) (6.9 mg, 27 μmol) and Ligand 2 (25.0 mg, 29.8 μmol) were dissolved in 3 mL THF under nitrogen. The solution was transferred to a mechanically stirred autoclave and stirred under 1:1 _H2 /CO at 400 psi (2760 kPa) for 30 min. 4-MeSO ₂ N(H)C ₆ H ₄ [C(H)(OH)(CH=CH ₂ )] (438 mg, 1.93 mmol) and (nC ₇ H ₁₅ )N(H)C ₂ H ₅ ( A solution of 283 mg, 1.97 mmol) in 3 mL THF was injected into the reactor against the flow of _H2 /CO. The reactor was heated at 75°C under 1:1 H2/CO at 400 psi (2760 kPa). After 18 h, the reactor was cooled to ambient temperature and vented. The reaction mixture was evaporated and redissolved in _CH2Cl2 ( ₂₀ mL). The product was extracted into 2M NaOH (2 x 15 mL). The aqueous layer _was then neutralized with 10% HCl and then extracted with _CH2Cl2 (3 x 10 mL). The organic layer was dried over _MgSO4 and evaporated to give the product (410 mg) as an orange liquid. GC-MS indicated that the product consisted of a mixture of ibutilide and branched isomers (linear:branched=25:1).

Ligand 2

Example 13 - Preparation of Aripiprazole

Rh(CO) ₂ (acac) (4.7 mg, 18 pmol) and Ligand 2 (19.7 mg, 23 μmol) were dissolved in 3 mL THF under nitrogen. The solution was transferred to a mechanically stirred autoclave and stirred under 1:1 _H2 /CO at 400 psi (2760 kPa) for 30 min. 1-(2,3-Dichlorophenyl)piperazine (616mg, 2.66mmol, it can be prepared according to the procedure of Morita, et al., Tetrahedron 1998,54,4811) and 7-(allyloxy)-3 , a solution of 4-dihydro-2(1H)-quinoline (547 mg, 2.69 mmol, which can be prepared according to the procedure described in WO 96/02508) in 7 mL THF was injected into the reactor against the flow of _H2 /CO. The reactor was heated at 75°C under 400 psi (2760 kPa) of 1:1 _H2 /CO. After 16 h, the reactor was cooled to ambient temperature and vented. The reaction mixture was evaporated and redissolved in 10 mL _CHCl3 . The solution was washed with 10% HCl solution, saturated NaHCO ₃ solution and then saturated NaCl solution. After drying over MgSO4, the solution was evaporated to an orange oil.

Embodiment 14-preparation of terfenadine

Terfenadine

A. Preparation of pt-BuC ₆ H ₄ [C(H)(OH)(CH=CH ₂ )]

BrMg(vinyl) (1.0 M in THF, 38 mmol) was added dropwise to a solution of pt- _BuC6H4CHO ( _4.199 g, 25.88 mmol) in 15 mL THF under nitrogen. The solution was stirred at room temperature for 18 h and then refluxed for 2 h. Saturated aqueous _NH4Cl (50 mL) was added and the solution was extracted with diethyl ether (2 x 75 mL). The combined organic extracts were washed with saturated aqueous sodium chloride and dried over MgSO ₄ . The solution was evaporated to a yellow oil (5.24g).

B. Preparation of Terfenadine

Rh(CO) ₂ (acac) (5.4 mg, 21 μmol) and Ligand 2 (23.9 mg, 28 μmol) were dissolved in 3 mL THF under nitrogen. The solution was transferred to a mechanically stirred autoclave and stirred under 1:1 _H2 /CO at 250 psi for 2 h. pt-BuC ₆ H ₄ [C(H)(OH)(CH=CH ₂ )] (676 mg, 3.55 mmol) and α,α-diphenyl-4-piperidomethanol (950 mg, 3.55 mmol, purchased from A solution from Acros) was prepared in 7 mL THF. The pressure was vented to the autoclave, and the substrate solution was injected into the reactor against the flow of 1:1 _H2 /CO. The reactor was heated at 75°C under 1:1 _H2 /CO at 400 psi (2760 kPa). After 18 h, the reactor was cooled to ambient temperature and vented. The reaction mixture was evaporated to give 1.82 g of a viscous orange liquid which slowly crystallized on standing.

Example 15 - Preparation of Terfenadine in addition

A. Preparation of pt-BuC ₆ H ₄ [C(H)(OSiMe ₃ )(CH=CH ₂ )]

pt-BuC ₆ H ₄ [C(H)(OSiMe ₃ )(CH=CH ₂ )]

Azidotrimethylsilane (5.0 mL, 37.7 mmol) was added under nitrogen to pt-BuC ₆ H ₄ [C(H)(OH)(CH=CH ₂ )] (5.24 g, 27.5 mmol) in mL without Solution in water CH ₃ CN. The solution was stirred at ambient temperature for 3 days. The solvent was removed in vacuo to give the product (6.27 g, 23.9 mmol, 87% yield) as a yellow liquid.

B. Synthesis of O-trimethylsilyl terfenadine.

     O-Trimethylsilyl Terfenadine

Rh(CO) ₂ (acac) (9.3 mg, 36 μmol) and Ligand 2 (37.5 mg, 44.7 μmol) were dissolved in 3 mL THF under nitrogen. The solution was transferred to a mechanically stirred autoclave and stirred at 400 psi 1:1 _H2 /CO for 15 min. pt-BuC ₆ H ₄ [C(H)(OSiMe ₃ )(CH=CH2)] (1.212g, 4.618mmol) and α,α-diphenyl-4-piperidomethanol (1.240g, 4.638mmol , purchased from Acros Organics) was dissolved in 10 mL THF. The pressure was vented to the autoclave and the substrate solution was injected into the reactor against the flow of 1:1 _H2 /CO. The reactor was heated at 75°C under 1:1 _H2 /CO at 400 psi (2760 kPa). After 18 h, the reactor was cooled to ambient temperature and vented. The reaction mixture was evaporated to give 2.29 g of a viscous orange liquid.

C. Synthetic terfenadine

The crude reaction product from B (2.29 g, 4.21 mmol) was dissolved in 20 mL of anhydrous THF. Solid [(PhCH ₂ )NMe ₃ ] ⁺ F ⁻ (870 mg, 1.20 equiv) was added and the resulting suspension was stirred at ambient temperature for 3 days. Water was added and the solution was extracted with diethyl ether (2 x 20 mL). The combined organic extracts were extracted with _H2O (10 mL) followed by brine (10 mL). The solution was dried over _MgSO4 and evaporated to give 2.146 g of a viscous orange liquid which slowly solidified to the desired product on standing.

Embodiment 16-preparation of fexofenadine methyl ester

                      

A. Preparation of p-[Me ₂ (CO ₂ Me)C]C ₆ H ₄ CHO

p-[Me ₂ (CO ₂ Me)C]C ₆ H ₄ CHO(p-(α-carbonylmethoxy-α′-methyl)ethylbenzaldehyde))

A solution of p-bromobenzaldehyde (15.4 g, 83.2 mmol) and p-toluenesulfonic acid monohydrate (200 mg, 1.05 mmol) was dissolved in 300 mL of toluene. Ethylene glycol (10 mL) was added and the solution was refluxed using a Dean-Stark trap to remove water azeotropically. After 4 hours, 100 mL of ethyl acetate was added. The solution was washed with ice water, saturated NaHCO ₃ solution and then with saturated NaCl solution. The solution was dried over _MgSO4 and evaporated to give p-bromobenzaldehyde ethylene glycol acetal as a colorless oil which crystallized on standing (18.02 g, 95% yield).

Lithium dicyclohexylamide (10.717 g, 57.23 mmol) was dissolved in 90 mL of toluene under nitrogen. Methyl isobutyrate (4.962 g, 48.60 mmol) was added and the resulting solution was stirred for 10 minutes. This solution was then added solid p-bromobenzaldehyde ethylene glycol acetal (10.101 g, 44.09 mmol) and dipalladium tris(benzylideneacetone) (408 mg, 0.891 mmol Pd). Solid tri-tert-butylphosphine (186.4 mg) was added and the resulting solution was stirred overnight. Dichloromethane (400 mL) and 5% HCl solution (400 mL) were added. The reaction mixture was filtered to remove fluffy gray solid. The organic layer was separated and washed with 200 mL of 5% HCl solution, water (200 mL) and saturated sodium chloride solution. The obtained solution was evaporated in vacuo to give a yellow liquid which was dissolved in 150 mL 2:1 acetone- _H2O . Pyridinium p-toluenesulfonate (478 mg) was added and the solution was stirred overnight. Acetone was removed by rotary evaporation, and the product was extracted into diethyl ether. The solution was washed twice with 45 mL of water and then with saturated sodium chloride solution. The solution was dried over _MgSO4 and evaporated to give the product as a light yellow oil. Purification by column chromatography (silica gel, 9:1 hexane-EtOAc) gave the desired product (7.27 g, 80% yield) as a pale yellow liquid.

B. Preparation of p-[ _Me2 ( _CO2Me )C] _{C6H4 [} C(H)(OH)(CH= _CH2 )]

p-[Me ₂ (CO ₂ Me)C]C ₆ H ₄ [C(H)(OH)(CH=CH ₂ )]

BrMg(vinyl) (1.0 M in THF, 14 mmol) was added dropwise to a solution of pt- _BuC6H4CHO ( _2.896 g, 14.04 mmol) in 5 mL THF under nitrogen. The addition resulted in a massive exotherm which boiled the solution. The solution was stirred at room temperature for 1.5 h. Saturated aqueous _NH4Cl (30 mL) was added and the solution was extracted with diethyl ether (2 x 50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride and dried over MgSO ₄ . The solution was evaporated to the desired product (5.24g) as a yellow oil.

C. Preparation of fexofenadine methyl ester

Rh(CO) ₂ (acac) (5.7 mg, 22 μmol) and Ligand 2 (23.5 mg, 28 μmol) were dissolved in 3 mL THF under nitrogen. The solution was transferred to a mechanically stirred autoclave and stirred at 250 psi 1:1 _H2 /CO for 1 h. p-[Me ₂ (CO ₂ Me)C]C ₆ H ₄ [C(H)(OH)(CH=CH ₂ )] (639 mg, 2.73 mmol) and α,α-diphenyl-4-piperidine and a solution of methanol (730 mg, 2.73 mmol) in 10 mL THF was prepared. The pressure was vented to the autoclave, and the substrate solution was injected into the reactor against the flow of 1:1 _H2 /CO. The reactor was heated at 75°C under 400 psi (2760 kPa) of 1:1 _H2 /CO. After 18 h, the reactor was cooled to ambient temperature and vented. The reaction mixture was evaporated to give 1.49 g of the desired product as an orange foamy solid.

Claims (16)

1. a method is included under the hydrogen aminomethylation condition and makes a) alkene; B) primary amine or secondary amine or ammonia; C) step that contacts of synthetic gas neutral rhodium-monodentate phosphite ligands title complex and d).

2. the process of claim 1 wherein and prepare title complex by the neutral rhodium procatalyst is contacted with monodentate phosphite ligands.

3. the method for claim 2, wherein the neutral rhodium procatalyst is selected from [Rh (CO) ₂(acac)], [Rh ₄(CO) ₁₂], [Rh ₂(OAc) ₄], [Rh (C ₂H ₄) ₂(acac)], [Rh (cyclooctadiene) (acac)] or [Rh (acac) ₃].

4. the method for claim 1, wherein alkene is selected from tetrahydrobenzene, oleic acid diethyl amide, the different polypropylene of terminal unsaturation, ethylidene norbornene, polyhutadiene, vinylbenzene, α-phenylcyclohexane ethene or tetrahydrochysene phenyl aldehyde, amine or ammonia are selected from dimethylamine, N, N '-dimethyl trimethylene diamine, morpholine, piperidines, diethanolamine, dibenzylamine or ammonia.

5. the method for claim 1, wherein monodentate phosphite ligands is selected from the triphenyl phosphorous acid ester, three (2, the 4-di-tert-butyl-phenyl) phosphorous acid ester, the tri-o-tolyl phosphorous acid ester, three p-methylphenyl phosphorous acid esters, trimethyl phosphite, triethyl phosphorite, three n-propyl phosphorous acid esters, three normal-butyl phosphorous acid esters, the tri-tert phosphorous acid ester, three-1-naphthyl phosphorous acid ester, three-2-naphthyl phosphorous acid ester, 2,2 '-the bis-phenol phenyl phosphites, 2,2 ', 4,4 '-tetra-tert-2,2 '-bis-phenol 2,4-di-tert-butyl-phenyl phosphorous acid ester, or tribenzyl phosphorous acid ester.

6. the process of claim 1 wherein, primary amine or secondary amine or ammonia are added when the reaction beginning or after conversion of olefines becomes the hydroformylation intermediate product, be sequentially added into.

7. the method for claim 6, wherein alkene be 1,1 '-dibasic, after conversion of olefines becomes the hydroformylation intermediate product, be sequentially added into primary amine or secondary amine or ammonia.

8. method is included in the step that makes following material contact under the hydrogen aminomethylation condition:

A) classification ArXCR=CR ₂Alkene; B) secondary amine; C) rhodium-nickel/phosphorous ligand title complex; And d) synthetic gas; Wherein Ar is aryl or substituted aryl, and each R is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, substituted alkyl, substituted cycloalkyl, substituted aryl or contains heteroatomic group and X is a linking group that condition is to be-CH as X independently ₂-or-OCH ₂In-time, nickel/phosphorous ligand is a phosphite ester ligand.

9. the method for claim 8, wherein Ar is that substituted-phenyl and X are the hydroxyl methylene radical.

10. the method for claim 9, wherein Ar is p-Y-phenyl or methanesulfonamido phenyl, wherein Y is C (CH ₃) ₂R ", wherein R " is methyl, cyano group, hydroxyl methylene radical, alkoxyl group methylene radical, carbonyl hydroxyl, carbo methoxy group, carbonyl oxyethyl group, carbonyl benzyloxy, amido, ortho-formiate, formyl radical, 2-oxazoline or 2-benzoxazole.

11. the method for claim 9, wherein Ar is to tert-butyl-phenyl, to the methanesulfonamido phenyl or to (α-carbo methoxy group-α '-methyl) ethylphenyl.

12. the method for claim 11, wherein amine is α, α-phenylbenzene-4-piperidines and methyl alcohol.

13. the method for claim 12, wherein nickel/phosphorous ligand is a phosphorous acid ester.

14. the method for claim 12, wherein nickel/phosphorous ligand is represented by following structure:

Part 2

15. classification ArXCR=CR ₂Alkene, be selected from the alkene of representing by following structural formula, wherein R is H or trialkylsilkl:

16. the alkene of claim 15, wherein R is H.