Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
1999-06-10
2001-05-22
Killos, Paul J. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S405000
Reexamination Certificate
active
06235938
ABSTRACT:
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)
1 or 2
MX
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:
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):
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
1
, R
2
, R
3
, R
4
, and R
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
3
; CCl
3
; halide, C
6
H
5
; amide such as C(O)N(CH
3
)
2
, C(O)N(CH
2
CH
3
)
2
, C(O)N(CH
2
CH
2
CH
3
)
2
, and the like; acyl, such as C(O)—C
6
H
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
3
phenyl chloride, p-phenyl phenyl chloride, p-C(O)N(CH
2
CH
3
)
2
phenyl chloride, and p-C(O)—C
6
H
5
phenyl chloride.
According to the method of the invention, amine-containing compou
Hamann Blake C.
Hartwig John F.
Garobedian Todd E.
Killos Paul J.
Wiggin & Dana
Yale University
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