Arylamine synthesis

Details Arylamine synthesis Arylamine synthesis

1998-07-24

2001-11-27

O'Sullivan, Peter (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C546S181000, C546S311000, C549S451000, C560S019000, C560S035000

Reexamination Certificate

active

06323366

ABSTRACT:

BACKGROUND OF THE INVENTION
The arylamine moiety is a structural component in a variety of synthetic and naturally occurring biologically active compounds. For instance, arylamines are useful in a variety of applications such as in the preparation of dyes, herbicides, insecticides, pharmaceuticals, plant growth agents and antiknock agents for gasoline engines.
To further illustrate, primary anilines find a variety of utilities. p-Aminodiphenylamine is an important intermediate in the synthesis of antioxidants and antiozonants for rubber. Phenylenediamines, particularly C
5
-C
10
alkyl-substituted derivatives thereof, are also useful in stabilizing rubbers. p-Aminophenols are useful as chemical intermediates. For example, p-hydroxyaniline is employed in the manufacture of analgesics and antipyretics. Other substituted phenylamines, such as chloroanilines, are useful in the manufacture of dyes, medicinals, and resins.
Notwithstanding recent progress in the development of methods for the transition metal-catalyzed formation of carbon-heteroatom bonds, construction of the carbon-nitrogen bond of arylamines and vinylamines remains a synthetic challenge in certain cases. See, inter alia: U.S. Pat. No. 5,576,460;
Angew. Chem., Int. Ed. Engl.
1995, 34, 1348
; J Am. Chem. Soc.
1996, 118, 7215
; Tetrahedron Lett.
1996, 52, 7525; and references cited therein. In particular, a number of synthetic methods for the construction of such an aryl-nitrogen bond suffer from severe reaction conditions and/or are only applicable to activated substrates. Typical routes to aromatic amines include nucleophilic aromatic substitution of electron-poor aryl precursors. See, Hattori et al. (1994)
Synthesis
1994:199; and Bunnett, J. F. (1978)
Acc. Chem. Res
1978 11:413. Synthesis of arylamines via copper-mediated Ullmann-like condensation reactions has also been reported. See, for example, Paine (1987)
J. Am. Chem. Soc.
109:1496. The copper-catalyzed preparation of aryl amines, such as anilines and substituted anilines, by amination of an aryl halide is also described in U.S. Pat. No. 4,096,185, which discloses the preparation of p-aminobenzotrifluoride by reaction of p-chlorobenzotrifluoride with ammonia in the presence of a copper halide catalyst.
Primary anilines are often prepared by nitration of an arene, followed by reduction of the resulting nitroarene compound. The success of this approach hinges on three basic issues: 1) the availability of the arene starting material; 2) the ability to prepare the desired nitro compound from the arene; and 3) the ability to reduce selectively the nitro group to the corresponding primary aniline. This approach to anilines has certain inherent limitations. In some instances, the arene starting material is unavailable or difficult to obtain. In other instances, the directing effects of groups on the arene are such that the desired nitro compound is a minor product, or is not produced at all, in the nitration reaction. For example, m-toluidine is important as an intermediate in dyes and agricultural chemicals; application to toluene of the nitration-reduction approach, however, yields a mixture of toluidines comprising only a small percentage of m-toluidine. Finally, conditions required for reduction of the nitro group to the corresponding primary amine may be incompatible with other functional groups contained in the intermediate nitro arene.
SUMMARY OF THE INVENTION
The present invention provides a method for the preparation of a wide range of primary arylamines. The arylamines are prepared in two efficient, straightforward transformations: 1) an activated aryl group and an imine group are combined, in the presence of a transition metal catalyst, under conditions wherein the transition metal catalyst catalyzes the formation of a carbon-nitrogen bond between the activated carbon of the arene and the imine nitrogen; and 2) the resulting N-aryl imine is transformed, via any of a number of standard protocols, to the primary arylamine. The aforementioned method may also be exploited in the preparation of vinylamines.
DETAILED DESCRIPTION OF THE INVENTION
The ability to provide an aryl amination synthesis scheme which can be carried out to produce primary arylamines, such as aniline, has broad application, especially in the agricultural and pharmaceutical industries, as well as in the polymer industry. The present invention provides improvements in, and relating to, amination reactions for a wide range of aryl groups.
As illustrated in the appended examples, imines may be employed as a surrogate for ammonia in transition metal-catalyzed aminations of activated aryls groups to provide a route to primary arylamines. The amination and subsequent deprotection proceed uniformly in high yields. The ketimine functionality of the N-aryl imines produced in the amination reaction may be retained as a means of masking the primary amine, and/or the ketimine adducts may be isolated, e.g, by recrystallization and/or chromatography.
One aspect of the present invention provides a transition metal catalyzed reaction for amination of activated aryl groups using imines as ammonia equivalents. In general, the reaction combines an activated aryl group and an imine group with a transition metal catalyst under conditions wherein the transition metal catalyst catalyzes the coupling of the aryl and imine groups through the imine nitrogen. Either or both of the aryl and imine groups can be provided in reactive form, or as precursors which can be converted to the active form(s) under the reaction conditions. The aryl and imine groups may be on separate molecules (for an intermolecular amination), or may be contained in the same molecule (for an intramolecular amination).
In certain preferred embodiments, the subject reaction between an activated aryl group and an imine can be represented by the generalized reaction depicted in Scheme 1:
wherein:
Ar is selected from the set comprising optionally substituted monocyclic and polycyclic aromatic and heteroaromatic moieties;
X is selected from the set comprising Cl, Br, I, —OS(O)
2
halogen, —OS(O)
2
alkyl, and —OS(O)
2
aryl;
the transition metal catalyst comprises a transition metal selected from Groups 5-12 of the periodic table;
R is selected from the set comprising hydrogen, trialkylstannyl, triarylstannyl, trialkylsilyl, triarylsilyl, lithium, sodium, potassium, magnesium halide, calcium halide, —B(OH)
2
, groups that are replaced by hydrogen under the reaction conditions, and the like;
R
1
and R
2
, each independently represent hydrogen, or an optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl group, or —(CH
2
)
m
—R
8
; or R
1
and R
2
taken together form an optionally substituted ring;
the base is selected from the set comprising alkoxides, carbonates, amides, phosphates, fluorides, and the like;
R
8
represents an optionally substituted aryl, cycloalkyl, cycloalkenyl, heterocycle or polycycle; and
m is an integer in the range of 0 to 8 inclusive.
In preferred embodiments, R
1
and R
2
are not both hydrogen, and in even more preferred embodiments, neither R
1
nor R
2
is hydrogen.
In certain embodiments, the base is selected from the set comprising alkoxides and carbonates.
In certain preferred embodiments, the base is sodium tert-butoxide or cesium carbonate.
The reaction is run in the presence of at least a catalytic amount of a transition metal catalyst which catalyzes the reaction between the imine and activated aryl nucleus. Further guidance for selecting these components is provided below and in the Examples.
The resulting N-aryl imine products may be transformed to a primary amine group (see Scheme 2).
The subject amination reaction can be used as part of a combinatorial synthesis scheme to yield aryl amines (for a discussion of combinatorial libraries and methods, see: Section V). Accordingly, another aspect of the present invention relates to use of the subject method to generate variegated libraries of aryl amines of the general formula Ar—NH
2
and/or aryl ketim

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