Synthesis of N4, N4-diphenyl-N4,N4-di-m-tolyl-biphenyl-4,4'-diamine from an unsymmetrical amine

This invention relates to the nickel catalyzed formation of novel unsymmetrical tertiary amines. More particularly, the invention relates to

(4-halo-phenyl)-phenyl-m-tolyl-amines  (I)

which may be converted to

N 4 ,N 4 ′-diphenyl-N 4 ,N 4 -di-m-tolyl-biphenyl-4,4′diamine  (II)

by nickel catalyzed coupling.

It is known to produce (II) by palladium catalyzed amination using m-methyldiphenylamine, 4,4′-dibromobiphenyl and tri-tert-butyl phosphine. See Yamamoto, T., et al., Tetrahedron Letters (1998) 39:2367-2370. It is also known to produce (II) by reaction of m-methyldiphenyl amine with 4,4′-diiodobiphenyl under copper powder in potassium hydroxide or other bases in high boiling solvents at 150-200° C. See, e.g., U.S. Pat. No. 4,764,625. 1,10-phenanthroline has been used to ligate copper and the use of Cu(I) salts has been reported to reduce the temperature of this reaction to 125° C. See Goodbrand, J. Org. Chem . (1999) 64:4290 and U.S. Pat. Nos. 5,654,482; 5,648,539; 5,648,542; 5,705,697; 5,723,669 and 5,723,671. Coupling of chlorobenzene to afford biphenyl and 4-chloroaniline to afford 4,4′-diaminobiphenyl using NiCl 2 , triphenylphosphine, zinc and DMF with and without 2,2′ bipyridyl is described in J. Org. Chem . (1986) 51:2367-2370. U.S. Pat. No. 4,263,466 describes a method for coupling aryl chlorides in which a nickel catalyst is generated in situ from nickel salts and excess reducing agents.

In general, a problem exists in that prior art procedures for producing (II) and similar compounds entail the use of biphenyl starting material including expensive dihalobiphenyls and harsh high temperature conditions.

A need exists for a more cost effective method for producing such compounds.

There is a particular need for a mild, low temperature nickel catalyzed synthesis of an intermediate which may be converted to compounds typified by (II).

Pursuant to this invention, the biphenyl moiety of compounds such as (II) is assembled after the amine moieties are in place. A novel intermediate (I) is synthesized. The intermediate is then coupled in a mild nickel catalyzed reaction. A novel intermediate, e.g., unsymmetrical, triarylamine (4-halo-phenyl)phenyl-m-tolyl amine (I) is first synthesized from cheap building blocks, typically m-toluidine, bromobenzene, and 1,4 bromo-chlorobenzene to yield triaryl amine chloride (I). The synthesis is accomplished via two, sequential palladium catalyzed aminations in one pot. The compound (I) may be crystallized in good yield, e.g., above 80% yield, and high purity, e.g., 95% purity. (II) is produced by nickel catalyzed coupling of (I).

Synthesis of (I) (4-Chloro-Phenyl-M-Tolyl Amines)

In the first step, the pot is charged under nitrogen with palladium acetate, tri-tert-butyl phosphine and dry deoxygenated toluene. A first reaction mixture of a red color results. Bromobenzene, sodium t-butoxide and m-toluidine are added sequentially under nitrogen. The reaction is heated with stirring under reflux for a time sufficient, e.g., 1 to 2.5 hours, to produce a reaction mixture containing 95-97% of m-methyl diphenyl amine. 1,4-bromo chlorobenzene and sodium t-butoxide are then added, and the reaction is stirred to reflect overnight to afford (I). The reaction is illustrated by Equation 1:

In Equation 1, m-toluidine may be replaced by an compound of the formula:

in which R is an ortho, meta, or para C 1 to C 10 alkyl substituent,

may be replaced by any compound of the formula:

in which X is any halogen or triflate.

Preparation of (4-chloro-phenyl)-phenyl-m-tolyl amine (I)

Under nitrogen, a flask is charged with 138 mg (0.0006 mol) of palladium acetate, 0.48 g (0.002 mol) of tri-tert-butylphosphine, 180 grams of dry, deoxygenated toluene. The solution is stirred for 5 minutes until the pale yellow color changed to a red color. The other reagents are added sequentially under nitrogen: 22 mL (0.2 mol) of bromobenzene, 25.3 g (0.26 mol) of sodium t-butoxide and m-toluidine (22 mL, 0.2 mol). The reaction is heated with stirring to reflux for 2.5 hours, at the end of which it was cooled down and analyzed by GC/MS to contain 95-97% of m-methyldiphenylamine. 25.8 g (0.26 mol) of sodium t-butoxide and 38.8 g (0.2 mol) of 1,4-bromochlorobenzene are added; the reaction is filled with nitrogen, and heated to reflux with stirring for 18 hours. The reaction is cooled, water is added, extract the aqueous with toluene. The combined organic layers are dried over sodium sulfate, filtered through a pad of neutral alumina, and the filtrate is distilled to remove the bulk of the solvent. The concentrated solution is treated with MeOH slowly with stirring. The solid is collected to afford 50 g (83%) of (4-chloro-phenyl)-phenyl-m-tolyl amine as an off-white solid.

Synthesis of (II)

Coupling of (I) to produce (II) may be accomplished in two steps, preferably in one pot.

In a first step, a dry nitrogen filled pot is charged with zinc powder, triphenyl phosphine 2,2′ bipyridyl, anhydrous NiCl 2 deoxygenated DMF and activated molecular sieves. Presently preferred coupling conditions are 0.5 eq NiCl 2 , 0.05 eq 2,2′ pyridyl, 0.26 eq triphenylphosphine, 1.5 eq zinc in 60-70° C. DMF. The mixture is heated under conditions effective to produce a color change from gray to dark brown. Appropriate conditions include heating at a temperature of 50° C. to 100° C., preferably about 65° C., for about 10-15 minutes.

Thereafter, in a second step, the pot temperature is maintained at about 50-60° C., a solution of (4-chloro-phenyl)-phenyl-m-tolyl amine (I) in DMF is added dropwise. The reaction mixture is maintained at about 60-65° C. with stirring, preferably until complete consumption of (I) as may be evidenced by TLC analysis is achieved. The reaction mixture may then be diluted with an inert diluent, such as dichloromethane, diethyl ether, or toluene, and filtered to remove excess zinc and solids. The filtrate is washed with water several times resulting in the formation of an aqueous layer and a dichloromethane layer which is separated, treated with silica gel, filtered, and the filtrate is treated with neutral alumina. The product (I) is recovered by crystallization.

The reaction is illustrated by Equation 2:

In Equation 2, the reactant (a) may be replaced by a similar compound in which —CH 3 is replaced by any ortho, meta, or para C 1 to C 10 alkyl group, and Cl is replaced by bromine or fluorine.

Preparation of N 4 ,N 4 ′-Diphenyl-N 4 ,N 4 ′-di-m-tolyl-biphenyl-4,4′-diamine:

Charge a dry, nitrogen filled flask with 4.9 g (0.07 mol of zinc powder), 3.4 g (0.01 mol) of triphenylphosphine. 0.4 g (0.002 mol) of 2,2′-bipyridyl, 0.3 g (0.002 mol) of anhydrous NiCl 2 , 30 mL of dry, deoxygenated DMF, and 2 g of activated 3A molecular sieves. The mixture is heated under nitrogen to 65° C. until the gray color changed to dark brown (about 10-15 minutes). Maintaining a pot temperature of 60° C., a solution of (4-chloro-phenyl)-phenyl-m-tolyl amine (13.4 g, 0.04 mol) in 40 mL of DMF is added dropwise. After addition is over, the reaction is stirred between 60-65° C. for 2-5 hours, until TLC analysis revealed complete consumption of starting aryl chloride. The reaction is diluted with dichloromethane, filtered to remove excess zinc and solids. The filtrate washed four times with water. The dichloromethane layer is dried over sodium sulfate, filtered and concentrated to a reduced volume. The dichloromethane solution is treated with silica gel, filtered, and solution is treated with neutral alumina until the solution is pale yellow. The product is crystallized twice to afford 8.7 g (80%) of N 4 ,N 4 ′-diphenyl-N 4 ,N 4 ′-di-m-tolyl-biphenyl-4,4′- diamine as a white solid. An analytical sample can be obtained by chromatography using a slow gradient of 0-5% ethyl acetate in hexane.