Transition metal-catalyzed process for preparing N-aryl amine compounds

The present invention is directed to a process for the preparation of N-aryl amine compounds. The process of the present invention involves reacting a compound having an amino group with an arylating compound in the presence of a base and a transition metal catalyst under reaction conditions effective to form an N-aryl amine compound, the transition metal catalyst comprising a Group 8 metal and at least one chelating ligand selected from the group consisting of bisphosphines having at least one stearically hindered alkyl substituent. The formed products are valuable intermediates in the pharmaceutical and polymer fields.

DESCRIPTION OF THE RELATED ART
 N-Aryl amines compounds are important substructures in natural products and
 industrial chemicals, such as pharmaceuticals, dyes, and agricultural
 products, and are useful for screening for pharmaceutical and biological
 activity and in the preparation of commercial polymers. It would be
 advantageous to prepare N-aryl amine compounds from arylating compounds
 such as aryl halides and/or aryl tosylates because aryl halides are
 generally inexpensive and readily available, while aryl tosylates are
 easily prepared from phenols. However, to date, methods of producing
 N-aryl amines are inefficient or economically unattractive. Many known
 processes that generate a aryl-nitrogen bond must be performed under harsh
 reaction conditions, or must employ activated substrates which are
 sometimes not available. Examples of procedures that generate aryl amine
 compounds include nucleophilic substitution of aryl precursors as
 exemplified by Hattori et al., Synthesis 1994, 199 (1994) and Bunnett, J.
 F., Acc. Chem. Res. 11:4132 (1978). Synthesis of arylamines via
 copper-mediated Uhlmann condensation reactions has also been reported
 (Paine, A. J., J. Am Chem. Soc. 109:1496 (1987)).
 U.S. Pat. No. 5,576,460 to Buchwald et al. discloses preparation of
 arylamines by reacting a metal amide, such as aminostannanes or
 aminoboranes, with an aromatic compound having an activated substituent in
 the presence of a transition metal catalyst such as complexes of platinum,
 palladium, iron, and nickel.
 In view of the above, a need exists for a general and efficient process of
 synthesizing N-aryl amine compounds from readily available arylating
 compounds. The discovery and implementation of such a method would
 simplify the preparation of commercially significant organic N-aryl amines
 and would enhance the development of novel polymers and pharmacologically
 active compounds. The present invention is believed to be an answer to
 that need.
 SUMMARY OF THE INVENTION
 In one aspect, the present invention is directed to a process for the
 preparation of N-aryl amine compounds, comprising reacting a compound
 having an amino group with an arylating compound in the presence of a base
 and a transition metal catalyst under reaction conditions effective to
 form an N-aryl amine compound, the transition metal catalyst comprising a
 Group 8 metal and at least one chelating ligand selected from the group
 consisting of bisphosphines having at least one stearically hindered alkyl
 substituent.
 In another aspect, the present invention is directed to a process for the
 preparation of N-aryl amine compounds, comprising reacting a primary amine
 compound with an arylating compound selected from the group consisting of
 aryl chlorides and aryl tosylates, in the presence of a base and a
 transition metal catalyst selected from the group consisting of (R)-(-)
 1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldicyclohexylphosphine,
 (R)-(-)1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyldi-t-butylphcosphine,
 and combinations thereof, under reaction conditions effective to form an
 N-arylated amine compound.
 These and other aspects will become apparent upon reading the following
 detailed description of the invention.
 DETAILED DESCRIPTION OF THE INVENTION
 It now has been surprisingly found, in accordance with the present
 invention, that a solution is provided to the problem of providing a
 general and efficient process of synthesizing N-aryl amine compounds from
 a compound having an amino group, and an arylating compound. The present
 inventors have solved this problem by utilizing reaction conditions that
 include a base and a transition metal catalyst comprising a Group 3 metal
 and at least one chelating ligand selected from the group consisting of
 bisphosphines having at least one stearically hindered alkyl substituent.
 In one embodiment, the catalyst is represented by the formula:
 (LL).sub.1 or 2 MX.sub.y
 wherein (LL) is the chelating ligand, M is the Group 8 transition metal,
 each X is independently a monovalent anionic ligand, including, for
 example, a halide such as chloride or bromide; a carboxylate such as
 acetate; or an alkyl sulfonate such as triflate or tosylate; or X is a
 divalent anionic ligand, such as carbonate; and wherein y represents the
 total number of anionic ligands X required to balance charge, typically
 from 0 to about 4. In one preferred embodiment, the catalyst comprises a
 palladium complex of (R)-(-)1-[(S)-2-(dicyclohexylphosphino) ferrocenyl]
 ethyldicyclohexylphosphine and/or
 (F))-(-)1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyldi-t-butylphosphine.
 The method of the present invention provides a general process for
 production of N-aryl amine compounds, an important class of compounds
 which are particularly significant in the development of pharmacologically
 active compounds and processing of polymers and oligomers.
 The term "aryl" is defined herein as a compound whose molecules have the
 ring structure characteristic of benzene, naphthalene, phenanthroline,
 anthracene, heterocyclic, and the like. "Arylating compound" is defined as
 a compound which provides an aryl substituent in an organic reaction.
 "N-Aryl amine compounds" are those compounds in which a nitrogen atom of
 the compound is substituted with an aryl group. The term "bisphosphine" is
 herein defined as any chemical moiety having two phosphorous atoms having
 3 substituents each. The phrase "stearically hindered alkyl substituent"
 refers to any secondary or tertiary alkyl group bonded to the phosphorous
 atom of the phosphine catalyst. "Ph" as defined herein is understood to
 represent a phenyl group.
 The process of the present invention is directed to the synthesis of N-aryl
 amine compounds. The process of the invention comprises reacting an
 amine-containing compound, such as a primary amine or a secondary amine,
 with an arylating compound in the presence of a base and a transition
 metal catalyst under reaction conditions effective to form an N-aryl amine
 compound. The transition metal catalyst comprises a Group 8 metal and at
 least one chelating ligand selected from bisphosphines having at least one
 stearically hindered alkyl substituent.
 More specifically, the process of this invention can be represented by
 Scheme I:
 ##STR1##
 Briefly, in Scheme I, an arylating compound is reacted with an amine
 compound in the presence of a base, a chaelating ligand (LL), and a Group
 8 metal (M) to form an N-aryl armine compound. Each of these reactions and
 their components are described in more detail below.
 The arylating compound used in the process of the present invention may be
 any arylating compound of the formula (II):
 ##STR2##
 In formula II, X may be any halide atom (F, Cl, Br, I), or any
 sulfur-containing leaving group (e.g., triflate, sulfonate, tosylate, and
 the like) known in the art. Chlorides are especially preferred in the
 process of the present invention. R.sub.1, R.sub.2, R.sub.3, R.sub.4, and
 R.sub.5 are independently selected from H; CN; alkyl, such as methyl,
 ethyl, propyl, n-butyl, t-butyl, and the like; alkoxy, vinyl, alkenyl,
 formyl; CF.sub.3 ; CCl.sub.3 ; halide, C.sub.6 H.sub.5 ; amide such as
 C(O)N(CH.sub.3).sub.2, C(O)N(CH.sub.2 CH.sub.3).sub.2, C(O)N(CH.sub.2
 CH.sub.2 CH.sub.3).sub.2, and the like; acyl, such as C(O)--C.sub.6
 H.sub.5, and the like; ester, amino, thioalkoxy, phosphino, and the like.
 Arylating compound may also be a heterocyclic aromatic compound such as an
 azole or azole derivative, aryl phosphates, aryl trifluoroacetates, and
 the like. Alternatively, the arylating compound may be the process of
 claim 1, wherein said arylating compound any aromatic or heteroaromatic
 halide, such as an aromatic or heteroaromatic chloride.
 Preferred arylating compounds used in the process of the invention include
 include aryl bromides such as chlorobenzene, 4-chloro-benzonitrile,
 4-chloro-t-butyl benzene, 3-chloro-methoxy benzene, 2-chloro toluene,
 p-formyl pheryl chloride, p-CF.sub.3 phenyl chloride, p-phenyl phenyl
 chloride, p-C(O)N(CH.sub.2 CH.sub.3).sub.2 phenyl chloride, and
 p-C(O)--C.sub.6 H.sub.5 phenyl chloride.
 According to the method of the invention, amine-containing compounds
 include primary amine (e.g., R or R' is hydrogen) or secondary amine
 compounds (e.g., R and R' are not H). Examples of useful primary amines
 include aniline (NH.sub.2 Ph) and aminobutane (NH.sub.2 Bu). Examples of
 useful secondary amines include morphiline (C.sub.4 H.sub.9 NO) and
 piperidine (C.sub.5 H.sub.11 N)
 The base shown in Scheme I is required for the process of the invention.
 Any base may be used so long as the process of the invention proceeds to
 the N-aryl amine product. It may be important in this regard that the base
 does not displace all of the chelating ligands on the catalyst. Nuclear
 magnetic resonance, infrared, and Raman spectroscopies, for example, are
 useful in determining whether the chelating ligands remain bonded to the
 Group 8 metal or whether the ligands have been displaced by the base.
 Non-limiting examples of suitable bases include alkali metal hydroxides,
 such as sodium and potassium hydroxides; alkali metal alkoxides, such as
 sodium t-butoxide; metal carbonates, such as potassium carbonate, cesium
 carbonate, and magnesium carbonate; phosphates; alkali metal aryl oxides,
 such as potassium phenoxide; alkali metal amides, such as lithium amide;
 tertiary amines, such as triethylamine and tributylamine;
 (hydrocarbyl)ammonium hydroxides, such as benzyltrimethylammonium
 hydroxide and tetraethylammonium hydroxide; and diaza organic bases, such
 as 1,8-diazabicyclo[5.4.0]-undec-7-ene and
 1,8-diazabicyclo-[2.2.2.]-octane. Preferably, the base is an alkali
 hydroxide or alkali alkoxide, more preferably, an alkali alkoxide, and
 most preferably, an alkali metal C.sub.1-10 alkoxide.
 The quantity of base which is used can be any quantity which allows for the
 formation of the N-aryl amine product. Preferably, the molar ratio of base
 to arylating compound ranges from about 1:1 to about 3:1, and more
 preferably between about 1:1 and 2:1.
 The catalyst, designated (LL)M in Scheme I, is characterized as comprising
 a metal atom or ion (M) and at least one or more chelating ligands (LL).
 The metal atom or ion is required to be a Group 8 transition metal, that
 is, a metal selected from iron, cobalt, nickel, ruthenium, rhodium,
 palladium, osmium, iridium, and platinum. More preferably, the Group 8
 metal is palladium, platinum, or nickel, and most preferably, palladium.
 The Group 8 metal may exist in any oxidation state ranging from the
 zero-valent state to any higher variance available to the metal.
 The chelating ligand may be a neutral molecule or charged ion. A chelating
 ligand possesses a plurality of coordination sites, typically two, three,
 or four. Preferably, the chelating ligand is a bidentate ligand, that is,
 one having two coordination sites. The chelating ligand is also required
 to contain at least one element from Group 15 of the Periodic Table,
 preferably, at least one element of nitrogen, phosphorus, or arsenic, and
 more preferably phosphorus. If only one of the Group 15 elements is
 present, then at least a second chelating element is required, for
 example, oxygen or sulfur. More specifically, the chelating ligand is
 selected from Group 15-substituted metallocenes, such as 1,1'- or
 1,2-disubstituted ferrocenes having two phosphino groups, one of which
 having at least one stearically hindered alkyl substituent. Addition of a
 stearically hindered alkyl group is advantageous in the catalyst of the
 present invention because the inventors have found that such substitutions
 allows aryl chlorides and aryl tosylates to be reacted with primary amines
 in highly specific and high-yielding reactions.
 The term "Group 15-substituted metallocenes" as used herein includes
 metallocenes which are substituted with at least one Group 15-containing
 moiety, preferably at least one dialkyl or diaryl Group 15 moiety or
 hybrid thereof. Other chelating elements, for example, oxygen or sulfur,
 may be present. The metallocene itself comprises a transition metal atom
 or ion which is bonded to one or more C.sub.4-8 multiply unsaturated
 hydrocarbon ring compounds. Suitable non-limiting examples of transition
 metal atoms in the metallocene include iron, titanium, vanadium, chromium,
 manganese, cobalt, nickel, molybdenum, and ruthenium. Preferably, the
 transition metal atom in the metallocene is iron. The C.sub.4-8 multiply
 unsaturated hydrocarbon ring compounds suitably include cyclobutadiene,
 cyclopentadienyl, benzene, cycloheptatrienyl, and cyclooctatetraene.
 Representative metallocenes include ferrocene, ruthenocene, bis
 (benzene)chromium, bis (benzene)-molybdenum, bis(benzene)tungsten, and
 cobaltocenium. Non-limiting examples of ligands which classify as
 (helating Group 15-substituted metallocenes include
 1,1'bis(diphenylphosphino)ferrocene,
 1-diphenylphosphino-2-(1-dimethylamino)ethyl ferrocene,
 1-diphenylarsino-1'-diphenyl-phosphino ferrocene, 1-
 diphenylphosphino-2-(1-diphenylphosphino)ethyl ferrocene,
 1-diphenylphosphino-2-(1-di-t-butylphosphino)ethyl ferrocene,
 1-diphenylphosphino-2-(1-dicyclohexylphosphino)ethyl ferrocene,
 1-dicyclohexylphosphino-2-(1-diphenylphosphino)ethyl ferrocene,
 1-dicyclohexylphosphino-2-(1-dicyclohexylphosphino)ethyl ferrocene,
 1-dicyclohexylphosphino-2-(1-dimethylamino)ethyl ferrocene,
 1-di-t-butylphosphino-2-(1-dimethylamino)ethyl ferrocene,
 1-di-i-propylphosphino-2-(1-dimethylamino)ethyl ferrocene,
 1-diphenylphosphino-2-(1-dimethylamino)ethyl ferrocene,
 1-[2-(diphenylphosphino)ferrocenyl]ethyl methyl ether,
 1-[2-(dicyclohexylphosphino)ferrocenyl]ethyl methyl ether,
 1-[2-(di-i-propylphosphino)ferrocenyl]ethyl methyl ether,
 1-[2-(di-t-butylphosphino)ferrocenyl]ethyl methyl ether,
 (-)-(R)-N,N-dimethyl-1-[(S)-1',2-bis(diphenylphosphino)ferrocenyl]ethylami
 ne, (+)-(S)-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethyl methyl ether, and
 N,N-dimethyl-1,2-bis(di-t-butylphosphino) ferrocenyl]ethylamine. Analogous
 phosphine and amine substituted derivatives of the aforementioned
 metallocenes may also be employed. Preferably, the Group 15-substituted
 metallocene is a Group 15-substituted ferrocene, more preferably, a
 phosphoferrocene, and most preferably
 (R)-(-)1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldicyclohexylphosphi
 ne or
 (R)-(-)1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyldi-t-butylphosphine.
 Many of the aforementioned metal catalysts which are beneficially employed
 in the process of this invention can be represented by the following
 formula:
EQU (LL).sub.1 or 2 MX.sub.y
 wherein (LL) is the chelating ligand, M is the Group 8 transition metal,
 each X is independently a monovalent anionic ligand, including for example
 a halide, such as chloride or bromide; a carboxylate, such as acetate; or
 an alkyl sulfonate, such as triflate; or X is a divalent anionic ligand,
 such as sulfonate or carbonate; and wherein y represents the total number
 of anionic ligands X required to balance charge, typically from 0 to about
 4. Alternatively, X can be a neutral dative ligand such as dibenzylidene
 acetone, cyclooctadiene, ethylene, triphenylphosphine, or other neutral
 ligand. It is to be understood that any of the chelating ligands described
 earlier may be used in the above formula. Non-limiting examples of
 suitable transition metal complexes include
 dichloro-[1,1'-bis(diphenylphosphino) ferrocene]palladium (II),
 dichloro-[1,1'-bis(diphenylphosphino)-2,2'-binapthyl]palladium (II),
 dichloro-[1,2-bis(diphenylarsino)benzene]platinum (II),
 1,2-bis[(diphenylphosphino)benzene]platinum (II) acetate,
 dichloro-[1-diphenylphosphino-2-(1-dimethylamino)ethylferrocene]palladium
 (II), and analogous complexes containing bidentate ligands mentioned
 hereinbefore with iron, cobalt, nickel, ruthenium, rhodium, osmium, and
 iridium as the metal component.
 Methods for preparing the aforementioned catalysts are known to those
 skilled in the art. For a description of general synthetic techniques, see
 Inorganic Synthesis: Reagents for Transition Metal Complex and
 Organometallic Systems; R. J. Angelici, Ed., Wiley-Interscience: New York,
 1990, Vol. 28, pp. 77-135 (Chapter 2), incorporated herein by reference,
 wherein representative preparations of Group 8 complexes containing
 chelating amine, phosphine, and arsine ligands are taught.
 As an alternative embodiment of this invention, the catalyst may be
 anchored or supported on a catalyst support, including a refractory oxide,
 such as silica, alumina, titania, or magnesia; or an aluminosilicate clay,
 or molecular sieve or zeolite; or an organic polymeric resin.
 Heretofore, the transition metal catalyst has been described as comprising
 a transition metal and a chelating ligand. It is not precisely known,
 however, whether both, one, or neither donor atoms of the chelating ligand
 are bound to the transition metal during the entire process of this
 invention or whether the chelating ligand is in a labile or non-bonded
 configuration relative to the transition metal during part or all of the
 process. Generally, it is believed that the chelating ligand is bonded
 through the Group 15 element to the transition metal; however, such a
 theory should not be binding upon the invention in any manner. Modern
 analytical techniques, such as nuclear magnetic resonance spectroscopy
 (.sup.13 C, .sup.1 H, .sup.31 P), infrared and Raman spectroscopies, and
 X-ray diffraction, may assist in the determination of initial catalyst
 structure and changes in structure throughout the process.
 The transition metal catalyst may be synthesized first and thereafter
 employed in the arylation process. Alternatively, the catalyst can be
 prepared in situ in the arylation reaction mixture. If the latter mixture
 is employed, then a Group 8 catalyst precursor compound and the desired
 chelating ligand are independently added to the reaction mixture wherein
 formation of the transition metal catalyst occurs in situ. Suitable
 precursor compounds include alkene and diene complexes of the Group 8
 metals, preferably, di(benzylidene)acetone (dba) complexes of the Group 8
 metals, as well as, monodentate phosphine complexes of the Group 8 metals,
 and Group 8 carboxylates. In the presence of the chelating ligand, in situ
 formation of the transition metal catalyst occurs. Non-limiting examples
 of suitable precursor compounds include
 [bis-di(benzylidene)acetone]palladium (0),
 tetrakis-(triphenylphosphine)-palladium (0),
 tris-[di(benzylidene)acetone]palladium (0), tris-[di(benzylidene)
 acetone]-dipalladium (0), palladium acetate, and the analogous complexes
 of iron, cobalt, nickel, ruthenium, rhodium, osmium, iridium, and
 platinum. Any of the aforementioned catalyst precursors may include a
 solvent of crystallization. Group 8 metals supported on carbon,
 preferably, palladium on carbon, can also be suitably employed as a
 precursor compound. Preferably, the catalyst precursor compound is
 bis-[di(benzylidene)acetone]palladium(0).
 The quantity of transition metal catalyst which is employed in the process
 of this invention is any quantity which promotes the formation of the
 N-aryl product. Generally, the quantity is a catalytic amount, which means
 that the catalyst is used in an amount which is less than stoichiometric
 relative to the unsaturated organic sulfonate. Typically, the transition
 metal catalyst ranges from about 0.01 to about 20 mole percent, based on
 the number of moles of the compound having at least one unsaturated
 nitrogen atom used in the reaction. Preferably, the quantity of transition
 metal catalyst ranges from about 1 to about 10 mole percent, and more
 preferably from about 3 to about 8 mole percent, based on the moles of the
 unsaturated nitrogen-containing compound.
 The process described herein may be conducted in any conventional reactor
 designed for catalytic processes. Continuous, semi-continuous, and batch
 reactors can be employed. If the catalyst is substantially dissolved in
 the reaction mixture as in homogeneous processes, then batch reactors,
 including stirred tank and pressurized autoclaves, can be employed. If the
 catalyst is anchored to a support and is substantially in a heterogeneous
 phase, then fixed-bed and fluidized bed reactors can be used. In the
 typical practice of this invention the compound having an amino group,
 arylating compound, base, and catalyst are mixed in batch, optionally with
 a solvent, and the resulting mixture is maintained at a temperature and
 pressure effective to prepare the N-arylated product.
 Any solvent can be used in the process of the invention provided that it
 does not interfere with the formation of the N-aryl amine product. Both
 aprotic and protic solvents and combinations thereof are acceptable.
 Suitable aprotic solvents include, but are not limited to, aromatic
 hydrocarbons, such as toluene and xylene, chlorinated aromatic
 hydrocarbons, such as dichlorobenzene, and ethers, such as
 tetrahydroturan. Suitable protic solvents include, but are not limited to,
 water and aliphatic alcohols, such as ethanol, isopropanol, and
 cyclohexonol, as well as glycols and other polyols. The amount of solvent
 which is employed may be any amount, preferably an amount sufficient to
 solubilize, at least in part, the reactants and base. A suitable quantity
 of solvent typically ranges from about 1 to about 100 grams solvent per
 gram reactants. Other quantities of solvent may also be suitable, as
 determined by the specific process conditions and by the skilled artisan.
 Generally, the reagents may be mixed togethe(r or added to a solvent in any
 order. Air is preferably removed from the reaction vessel during the
 course of the reaction, however this step is not always necessary. If it
 is desirable or necessary to remove air, the solvent and reaction mixture
 can be sparged with a non-reactive gas, such as nitrogen, helium, or
 argon, or the reaction may be conducted under anaerobic conditions. The
 process conditions can be any operable conditions which yield the desired
 N-aryl product. Beneficially, the reaction conditions for this process are
 mild. For example, a preferred temperature for the process of the present
 invention ranges from about ambient, taken as about 22.degree. C., to
 about 150.degree. C., and preferably, from about 80.degree. C. to about
 110.degree. C. The process may be run at subatmospheric pressures if
 necessary, but typically proceeds sufficiently well at about atmospheric
 pressure. The process is generally run for a time sufficient to convert as
 much of the unsaturated nitrogen-containing compound to product as
 possible. Typical reaction times range from about 30 minutes to about 24
 hours, but longer times may be used if necessary.
 The N-arylated amine product can be recovered by conventional methods known
 to those skilled in the art, including, for example, distillation,
 crystallization, sublimation, and gel chromatography. The yield of product
 will vary depending upon the specific catalyst, reagents, and process
 conditions used. For the purposes of this invention, "yield" is defined as
 the mole percentage of N-aryl amine product recovered, based on the number
 of moles of unsaturated nitrogen-containing compound employed. Typically,
 the yield of N-aryl amine product is greater than about 25 mole percent.
 Preferably, the yield of N-aryl amine product is greater than about 60
 mole percent, and more preferably, greater than about 80 mole percent.