STATEMENT OF GOVERNMENT SUPPORT This invention was made in part with government support by the National Institutes of Health grant R29-6M-55382. The government has certain rights in this invention.

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to generation of aniline compounds from aryl compounds, and more particularly to generation of aniline compounds from aryl halide compounds using an alkali metal bis (trimethylsilyl) amide as a reactant and a transition metal catalyst.

2. Brief Description of the Related Art Palladium-catalyzed aromatic C-N bond formation has become a convenient and general method to form arylamines from aryl halides and sulfonates (Hartwig, J. F. In Modern Amination Methods ; A. Ricci, Ed.; Wiley-VCH: Weinheim, 2000; Hartwig, J. F.

Angew. Chem., Int. Ed. Engl. 1998, 37, 2046; Hartwig, J. F. Synlett 1997, 329 ; Yang, B.

H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125; Wolfe, J. P.; Wagaw, S.; Marcoux, J. -F. ; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805). This reaction occurs with a variety of primary amines, secondary amines, and related nitrogen substrates such as hydrazones, ( Hartwig, J. F. Angew. Chem., Int. Ed. Engl. 1998, 37, 2090; Wagaw, S.; Yang, B.; Buchwald, S. J. Am. Chem. Soc. 1999, 121, 10251), carbamates (Hartwig, J. F.; Kawatsura, M.; Hauck, S. I. ; Shaughnessy, K. H.; Alcazar-Roman, L. M. J. Org. Chem.

1999, 64, 5575), amides (Shakespeare, W. Tetrahedron Lett. 1999, 40, 2035; Yang, B. H.; Buchwald, S. L. Organic Lett. 1999, 1, 35 ; Yin, J.; Buchwald, S. L. Org. Lett. 2000,2, 1101), and sulfonimines (Bolm, C.; Hildebrand, J. P. J. Org. Chem. 2000, 65, 169).

Interestingly, this reaction does not occur with ammonia to form the parent aniline.

Instead, the transformation is conducted in two steps using ammonia surrogates, such as allyl and diallylamine (Jaime-Figueroa, S.; Liu, Y.; Muchowski, J. M.; Putman, D. G.

Tetrahedron Lett. 1998, 39, 1313), benzyl and diphenylmethylamine, and benzophenone imine (Mann, G.; Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120, 827; Wolfe, J. P.; Ahman, J.; Sadighi, J. P.; Singer, R. A.; Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6367).

U. S. Patent No. 6,323, 366 issued on November 27,2001 to Buchwald et al. discloses a method of preparing primary arylamines using an activated aryl group and an imine group (RN=CRlR2) in the presence of a transition metal catalyst. This reaction produces an arylimine intermediate, that is converted to a primary aryl amine.

Present processes that form arylamines from aryl halides suffer several disadvantages. Some of the substrates require metal-catalyzed cleavage of the protective group, and others are relatively expensive. What is needed in the art are inexpensive and readily available substrates that are effective as ammonia equivalents, and that provide for facile conversion of substituted aryl halides to aryl amines. 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 method of converting an aryl compound to an aniline compound, comprising the steps of : (1) providing an aryl compound containing a halide group or a sulfur-containing group; (2) reacting the aryl compound with an a reactant having the structure wherein Rl, R2, and R3 are each independently selected from the group consisting substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, and combinations thereof ; R4 is selected from the group consisting hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted

heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, and SiRlR2R3 ; and A is H or an alkali metal; the reacting step taking place in the presence of a Group 8 transition metal catalyst under reaction conditions that form an aryl silylamine intermediate, with the proviso that when A is H in the reactant, the reacting step further comprises a base; and (3) converting the aryl silylamine intermediate to the aniline compound.

In another aspect, the present invention is directed to a method of converting an aryl compound to an aniline compound, comprising the steps of : (1) providing an aryl compound containing a halide group or a sulfur-containing group; (2) reacting said aryl compound with an a reactant having the structure Li I<BR> Me3Si/SiMe3 in the presence of Pd (dba) 2 and P (t-Bu) 3 for from 30 minutes to 24 hours and from about 20°C to about 100°C at atmospheric pressure, to form an aryl silylamine intermediate; and (3) converting said aryl silylamine intermediate to said aniline compound.

These and other aspect will be described in more detail in the following detailed description of the invention.

DETAILED DESCRIPTION OF THE INVENTION It has now been surprisingly found that substituted or unsubstituted aryl compounds that contain a halogen or sulfur-containing leaving group may be efficiently and effectively converted to the corresponding anilines in the presence of a Group 8 transition metal catalyst using an silyl amide as a substrate. Advantageously, the reaction is simple to perform, and takes place under mild conditions. The general reaction scheme is shown in Eqn. I. x A NH2 t/+ X N R 1. Group 8 Catalyst (1 : 1) R4 Si- 2. HCI, neutralization

In Eqn. I, a substituted or unsubstituted aryl compound containing a leaving group (X) is reacted with a silyl amide reactant, such as an alkali metal bis (trimethylsilyl) amide reactant (or silylamine and base), in the presence of a Group 8 transition metal catalyst to form the corresponding substituted or unsubstituted aryl amine (aniline).

With respect to the aryl compound shown in Eqn. I, the leaving group X may be a halogen group, such as chloride, bromide, fluoride, iodide, and the like, or a sulfur- containing leaving group (e. g., triflate, sulfonate, tosylate, and the like). Examples of suitable aryl compounds include substituted or unsubstituted aryl bromides, substituted or unsubstituted aryl chlorides, substituted or unsubstituted aryl fluorides, and substituted or unsubstituted aryl iodides. In one embodiment, aryl halides such as aryl bromides and aryl chlorides, are preferred. R may be a substituted or unsubstituted alkyl group, substituted or unsubstituted aryl group, or other substituted or unsubstituted group as described in more detail below. Additionally, R may be in any position on the aryl ring, however the para and meta positions are preferred.

Examples of useful aryl halide compounds include substituted or unsubstituted aryl bromides and substituted or unsubstituted aryl chlorides such as the following compounds: Additional examples of suitable aryl halides are shown in Table 2 below.

The method of the present invention includes a reactant having the general structure A | I R,<BR> R4 R<BR> R3 In this structure, RI, R2, and R3 are each independently selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, and combinations thereof.

Particularly useful groups are short chain alkyl groups and aryl groups, such as methyl, ethyl, propyl, n-butyl, t-butyl, isopropyl, phenyl, and the like.

The R4 group in the above reactant is selected from the group consisting hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, and SiRlR2R3, wherein Ri, R2, and R3 are defined above.

The A component of the above reactant may be H or an alkali metal such as lithium, sodium, potassium, and the like. Lithium is a preferred alkali metal for use in the present invention. A preferred reactant is lithium bis (trimethylsilyl) amide, having the structure Li I<BR> N<BR> MesSK SiMe3 The reaction preferably takes place in the presence of a Group 8 transition metal catalyst. Any Group 8 transition metal may be used, such as iron, cobalt, nickel, ruthenium, rhodium, palladium, osmium, iridium, and platinum. 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 Group 8 transition metal atom is preferably complexed with 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. The Group 8 transition metal may also be complexed with a divalent anionic ligand, such as sulfonate or carbonate.

Alternatively, the Group 8 transition metal can be complexed by a neutral dative ligand such as dibenzylidene acetone, cyclooctadiene, ethylene, triphenylphosphine, or other neutral ligand. Preferably, the Group 8 transition metal is complexed with dibenzylidene acetone.

The Group 8 transition metal complex is further complexed with an additional ligand to form the Group 8 transition metal catalyst. Examples of useful complexing ligands are shown in Table 1, and include tributyl phosphine (P (t-Bu) 3), PCy3, P (o-Tol) 3, PPh3, 1, 1'-bis (diphenylphosphino) ferrocene <BR> <BR> (DPPF), 1, 1'-bis (diphenylphosphino) -2, 2'-binaphthyl (BINAP), and 1, 1'-bis (di-p-<BR> tolylphosphino) -2,2'-binaphthyl (Tol-BINAP). A particularly preferred ligand is P (t-Bu) 3.

The transition metal catalyst may be synthesized first and thereafter employed in the reaction process. Alternatively, the catalyst can be prepared in situ in the reaction mixture. If the latter mixture is employed, then a Group 8 catalyst precursor compound and the desired 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 an added 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).

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 Group 8 transition metal 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.

Generally, the quantity of catalyst used in the reaction is a catalytic amount, which means that the catalyst is used in an amount which is less than stoichiometric relative to the reactants. The amount of transition metal catalyst useful in the reaction preferably ranges from about 0.1 mol% to about 10 mol%, based on the total moles of the aryl compound, and more preferably from about 0.2 mol% to about 5 mol%, based on the total moles of the aryl compound.

A proviso with respect to the method of the present invention is that when A is hydrogen in the reactant, a base is added to the reaction mixture. Non-limiting examples of suitable bases include alkali metal hydroxides, such as lithium, sodium and potassium hydroxides; alkali metal alkoxide, 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, lithium diisopropyl amide, or lithium hexamethyldisilazide ; 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 CI-10 alkoxide.

The quantity of base which is used can be any quantity which allows for the formation of the aniline 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 above reaction produces an aryl silylamine intermediate, which is subsequently converted to the corresponding aniline by aqueous workup with acid, or by addition of fluoride. Any acid may be used, however, HCl is preferred.

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 reactants 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 product.

Any solvent can be used in the process of the invention provided that it does not interfere with the formation of the 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 tetrahydrofuran. 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. 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. The process of the invention may also be conducted without any solvent.

Generally, the reactants may be mixed together 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 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 20°C, to about 150°C, and preferably, from about 20°C to about 100°C. The process may be run above or below atmospheric 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 starting materials to product as possible. The reaction time is less than 40 hours (typically between about 30 minutes and 24 hours).

The 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 product recovered. Typically, the yield of product is greater than about 30 mole percent. Preferably, the yield of product is greater than about 60 mole percent, and more preferably, greater than about 80 mole percent.

EXAMPLES Table 1 summarizes reactions of lithium bis-trimethylsilamide with 4-t-butyl bromobenzene catalyzed by palladium complexes of several ligands.

Table 1. Evaluation of ligands for aromatic C-N coupling of lithium bis (trimethylsilyl) amide

r Br Lj 5% Pd (dbaj/Ligand (1 : 1) SN (TNS) 2 Me3SiSiMe3 touene rt, 12h/9 (fC, 12h Entry Ligand Temp. Conversion GC-Yield 1 RT 2% 1% 2 TBF, 90°C 56% 13% t 3 RT 8 RT 14% 2% 4 N 90°C 75% 16% 5 PCY3 RT 8% 6% 6 90°C 100% 83% 7 P (tBu) RT 100% 95% 8 P (o-b i) 3 RT 0% 0% 9 90°C 39% 7% 10 PPh3 RT 8% 0% 11 90°C 90% 51 % 12 w RT 29% 22% 13 (t-Bu) 2P 90°C 100% 45% 14 » RT 100% 82% -f'-f Pu dz 15 RT 10% 1 % 16 t _ J 90°C 100% 45% t-Bu) 2 17 » RT 13% 11% 18 w 90°C 100% 92% PCy2 19'CZD-P (f-Bu) y RT 14% 6% 20 Fe 90°C 100% 63% 'C==Ph, 21 BNAP RT 0% 0% 22 90°C 100% 65% 23 DPPF RT 0% 0% 24 90°C 94% 22% 25 no ligand RT 0% 0% 26 90°C 33% 0% 27 no Uno Pd RT 0% 0% 28 90°C 0% 0% These results show that the first-and second-generation catalysts based on arylphosphines gave coupled product at elevated temperatures. The catalyst system in entry 4 that is comprised of Pd (dba) 2 and P (t-Bu) 3, led to the most efficient formation of the aryl silylamine product. This catalyst system has been used previously for room- temperature amination (Hartwig, J. F.; Kawatsura, M.; Hauck, S. I. ; Shaughnessy, K. H.; Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575) and carbonyl a-arylation (Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 1473), as well as high temperature reactions (Nishiyama, M.; Yamamoto, T.; Koie, Y. Tetrahedron Lett. 1998,

39, 617). Some of the ligands developed by Wolfe and Buchwald (Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J. J.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1158) were also suitable at high temperatures.

The relative importance of countercation, ligand: metal ratio, solvent, and equivalents of silylamide on the reaction yields were evaluated using 4-t-butyl bromobenzene as a model substrate. Reactions with any of the alkali metal bis (trimethylsilyl) amides occurred in yields exceeding 95% by GC with this substrate. For consistency, we focused our studies on a single alkali metal derivative, the least expensive lithium salt. Unlike the amination of aryl bromides, (Hartwig, J. F.; Kawatsura, M.; Hauck, S. I. ; Shaughnessy, K. H.; Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575), reactions of the silylamide base occurred with similar rates using 0.5 : 1,1 : 1, or 2: 1 ratios of ligand to metal. Reactions occurred most readily in alkane, arene, and dialkylether solvents. The reactions were less facile in cyclic ether solvents such as dioxane and THF, and they occurred in less than 20% yield in DMF, mono-and diglyme, and weakly acidic solvents such as acetonitrile. No excess silylamide was necessary to observe high yields, although a slight excess of reagent was not detrimental.

In addition, reactions with the silylamine in the presence of base instead of using the alkali metal salts of the silylamine were conducted. Reactions in the presence of sodium t-butoxid base occurred, although in lower yield than those conducted in the presence of the silylamide directly. Without being bound to any particular theory, it is likely that these bases operate in the amination of aryl halides by deprotonating an arylpalladium complex with coordinated amine, and the silylamide is too sterically hindered to effectively bind palladium.

The scope of the reaction of lithium bis (trimethylsilyl) amide with various aryl halides is presented in Table 2.

Table 2. Scope of the aromatic C-N coupling of lithium bis (trimethylsilyl) amide using P (t-Bu) 3 and Pd (dba) 2 (1: 1). Li 1. Pd (dbaitP (t-Bu) 3 (1 : 1) + N R-$- me, si 1, neutralization Entry Substrate Cat. Loading Temp. Time Yield Br 1 2% rt. 12h 90% t-Bu 2 tfT'=Br 2% rt. 16hr 92% tl X=Ct 5% 50°C 20h 89% X 3 it X=Br 3% rt. 20h 95% w. J X=CI 5% ri. 14h 97% 2 <Br 4 Ph CBr 5% rt. 20h 89% ICI S tt X=Br 5% rt. 18h 97% >t X=CI 5% 50°C 20h 95% x 6 X=Br 5% rt. 14h 92% n-BU I X=CI 5% sorJc 20h 95% ^'ber ! ! J 5% rt. 14h 87% Me2N Br 2% rt. 16h 75% F, C' 9 I \ X 9 t X=Br 5% rt. 14h 85% /X=CI 5 % 50°C 12h 90 % X 10 A X=Br 5% rt. 1 4h 85% a 5 % 50°C 16h 74% F Br 11 phi 2% rt. 16h 79% Oh' Br 12 2% rt. 14h 87% Ph0' 13 M X X=Br 2% rt. 16h 87% XI 5 % 50°C 10h 96% 0 14 b ( sr 14 Br 2% rt. 14h 99% F3CS/Br 15 5% rt. 16h 84% U 16 XCt 2% 50°C 14h 87% F Br '\, Br 17 h ! 5% rt. 12h 92% Ber p Br 18 5% 500C 10h 98% b-' 19 Br 2% rt. 16h 76% bu 20 ! 2% rt. 7h 92% X X 21 X=Br 2% rt. 16h 88% 1 X= () 5% rt. 14h 64% Br 22 BrAd ri. 20h 80% Br Br Br 23 W 5% rt. 20h 85%

As demonstrated in Table 2, with few exceptions, the reaction of meta-and para- substituted aryl bromides and chlorides gave high yields of the coupled product. Electron- donating groups were tolerated in the process with aryl bromide substrates. Electron- withdrawing groups, such as a trifluoromethyl or an ester group, would generally favor generation of benzyne intermediates. However, substrates with electron-withdrawing groups reacted at low temperatures and generated the coupled product regiospecifically in high yield. Aryl halides with esters in conjugation with the aryl halide reacted cleanly at the halide and not the ester.

Aryl chlorides are generally less reactive than bromides and often require higher temperatures for reaction. If this were the case for reactions of the silylamide reagent, then benzyne and possibly radical intermediates would be generated. However, the high activity of the catalyst derived from Pd (dba) 2 and P (t-Bu) 3 allowed for reaction of the aryl chlorides under relatively mild conditions. The results in Table 2 show that many aryl chlorides underwent regiospecific reaction with bis (trimethylsilyl) amide to form the parent aniline in high yield. In general, the substrate scope for reactions of aryl chlorides was similar to that for reactions of aryl bromides, but reactions required 50°C with 5 mol% catalyst to occur at reasonable rates.

In addition to evaluating reaction scope, reactions conducted with low catalyst loadings were evaluated. Table 3 summarizes these results.

Table 3. Aromatic C-N coupling of lithium bis (trimethylsilyl) amide at low loadings ofP (t-Bu) 3 and Pd (dba) 2 (1: 1) . X 1. Pd (db3i2/P (t-BUh (1 : 1) NH2 N, R-_ y 2 Me3Si'SiMe3 2. HCI, neutralization Entry Substrate Cat. Loading Temp. Time Yield fr 1 » Br 0. 2% 70°C 12h 89% f-B n X X=Br 0. 5% 70°C 18h 76% w x=a 0 5% 90°C 16h 90% X t X=Br 0. 5% 70°C 14h 96% /X=CI 1°h 90°C i6h 98% MeOzC Br 4 Ph 0. 5% 70°C 16h 93% p X fjf X=Br 0. 5% 70°C 14h 92% 5 x=a o. s% 90°C 16h 99% X X=Br 0. 5% 70°C 12h 90% /XI 0. 5 % 90°C 16h 74% bu /Br 70°C 30h 86% - Br bu 8 0. 5% 70°C 18h 65% F3C X 9 X=Br ° 5% 70°C 36h 83% MeO- ° % SO°C 16h 90% X 10 > X=Br 0 5% 70°C 12h 77% JU X=CI 1% 900C 14h 71% F Br 11 0. 5% 70°C ? 94% Ph bu 12 ¢yBr 70°C 8h 88% Ph0 M2 X MeO X X=Br 0. 2% 70°C 12h 91% vl X=CI 0. 5% 90°C 14h 92% Br 14 70°C 14h 99% / FaGY' Br 15 0 5% 70°C 12h 75% U I 16 1% 901C 18h 85% F Br PhDBr 70°C 18h 86% Ph p ^'Br 18 1% 70'C 16h 99% Ber Br bu 70C 12h 87% \/ , <Br 20'I I 0. 2% 70°C 16h 95% X X A X=Br 0. 5% 70°C 18h 86% 21 UN X=Q 1% 90°C 20h 62% Br 22 Br 70°C 14h 81% Bu ber 23 I J 1% 70°C 12h 82%

Reactions with lower loadings did require higher temperatures, but evidently these

temperatures were still low enough to prevent generation of benzyne intermediates. Each reaction in the absence of catalyst at temperatures up to 120°C was evaluated. In only a few cases was any aniline product observed. 3-Bromoanisole and the dioxolane in entry 14 gave 10% and 6% of the aniline after 12 h at 70°C, and 4-butylbromobenzene and 4- bromobenzophenone gave roughly 40 and 30% yield after 12 h at 120°C. Although the protected bromocatechol in entry 18 gave a reasonable 53% yield under these conditions, this yield for the high temperature, uncatalyzed reaction was much lower than the 99% yield observed at 70°C using 1% palladium catalyst.

In some cases high turnover numbers were obtained. For example, 4-t-butyl bromobenzene and 3-bromoanisole formed the coupled product in 89 and 91% yield with only 0.2 mol% catalyst at 70°C, and 2-bromo-6-methoxynaphthalene reacted in 92% yield with only 0.1 mol catalyst. Reactions of aryl chlorides also occurred with lower loadings than the 5% used in the reactions of Table 2, but generally 0.5-1 mol% catalyst was still necessary for full conversion at temperatures low enough to generate single regioisomeric products.

Although the ligand and silylamide reagent used in this reactions are air sensitive, convenient procedures can be followed without a drybox. Both the silylamide and ligand are commercially available as a solution in hydrocarbon solvents and can, therefore, be delivered to the reaction solution by syringe.

Alternatively, the preformed Pd (0) catalyst Pd [P (t-Bu) 3] 2 is commercially available and is air stable. Combining this air-stable species with the air-stable and commercially available Pd (dba) 2 or Pd2 (dba) 3 in a 1: 1 molar ratio to metal, as done previously by Fu (Littke, A.; Dai, C.; Fu, G. J. Am. Chem. Soc. 2000, 122, 4020-4028) generates a catalyst that is more active than Pd [P (t-Bu) 3] 2, albeit less active than the catalyst generated in situ from Pd (dba) 2 and P (t-Bu) 3. Use of 2.5 mol% of these two catalyst precursors gave 92% yield of the aryl silylamine after 24 h at room temperature for reaction of 4-t-butyl bromobenzene with lithium bis (trimethylsilyl) amide. Br 1. 2. 5% Pd [P (t-Bu) S] 2/ 2. 5% Pd (dba) (1 (1 : 1 (2) N 2. HCI, neutralization t-BU + Me3Si'-SIM83 92% Without wishing to be bound by any particular theory, 3'P NMR spectra obtained on reactions of aryl chlorides using a 1: 1 ratio of Pd (dba) and P (t-Bu) 3 show that the Pd (0) complex Pd [P (t-Bu) 3] 2 is the major palladium-phosphine complex in solution. Roughly 20

h after consumption of the aryl chloride 40% cyclometallated complex is formed. In contrast, little Pd [P (t-Bu) 3] 2 is observed during the reaction of aryl bromides. Two identified complexes with chemical shifts 10-20 ppm upfield of free ligand were observed by 31p NMR spectrometry. These are not formed by reaction of aryl halide or by reaction of the silylamide with Pd [P (t-Bu) 3] 2. Further studies will be needed to determine the structures of these species.

The invention is further described by the following Examples, but not intended to be limited by the Examples. All parts and percentages are by weight and all temperatures are in degrees Celsius unless explicitly stated otherwise.

General Methods. Reactions were conducted using standard drybox techniques.'H and 13C NMR spectra were recorded on a Bruker DPX 400 MHz spectrometer with residual protiated solvent used as a reference and coupling constants reported in Hertz (Hz). All 13C NMR spectra were proton decoupled. GC analyses were performed on an HP-6890 instrument using a DB-1301 narrow bore column for high temperature ramp applications (max. 120 °C/min). GCMS spectra were recorded on an HP5890 instrument equipped with a HP5971A Mass Spectral Analyzer using an HP-1 methyl silicone column.

Elemental analyses were performed by Robertson Microlabs, Inc. , Madison, NJ.

Chromatographic purifications were performed by flash chromatography using silica gel (200-400 mesh) from Natland International Corporation. Yields for final products in Tables 2 and 3 refer to isolated yields and are the average of at least two runs.

Spectroscopic data and combustion analyses are reported for all new compounds.

Previously reported products were isolated in greater than 95% purity as determined by'H NMR spectroscopy and capillary gas chromatography (GC).

General Procedures. In a screw-capped vial containing aryl halide (1.0 mmol) were placed PtBu3 (0.05-0. 002 mmol), Pd (dba) 2 (0.05-0. 002 mmol), and LiHMDS (1.1 mmol), followed by toluene (2.5 mL). The vial was sealed with a cap fitted with a PTFE septum and removed from the dry box. The reaction mixture was stirred at room temperature, and the reaction progress was monitored by GC.

Work-up Procedure 1. Upon consumption of aryl halide, the crude reaction mixture was diluted with Et20 (20 mL), and the silylamide was deprotected by adding one drop of aqueous 1 N HCI. The mixture was transferred to a separatory funel and washed with aqueous 1 N NaOH (20mL). The organic layer was dried over MgS04, filtered, and concentrated at reduced pressure. The residue was purified by chromatography on silica gel using EtOAc as eluent.

Work-up Procedure 2. Upon consumption of the aryl halide, the crude mixture was diluted with Et20. The silylamide was deprotected, and the corresponding aniline was precipitated as the hydrochloride salt by addition of 2 N HCl in Et20 (3 mL). The precipitate was isolated by filtration and washed with Et20. After air-drying, the precipitate was dissolved in CH2C12 (20 mL). The resulting was solution transferred to a separatory funel and extracted with 2 N NaOH (20 mL). The aqueous phase was diluted with saturated aqueous NH4C1 (20 mL) and extracted with CH2C12 (20 mL). The combined organic layers were dried over MgS04 and concentrated in vacuo to afford the pure anilines.

Work-up procedures 1 and 2 gave similar yields in all cases, except for reactions of the acid-sensitive products (3- (1, 3-dioxolan-2-yl) aniline and 1, 3-benozodioxol-5-amine (Tables 2 and 3, entries 14 and 18) ). These products were isolated by method 1.

Example 1. N-4- (tert-Butylphenyl)-N, N-bis (trimethylsilyl) amine.

'H NMR: 6 7.18 (d, J= 8.4 Hz, 2H), 6.79 (d, J= 8.4 Hz, 2H), 1.30 (s, 9H), 0.05 (s, 18H). 13C NMR: 6 146.82, 145.40, 130.18, 125.74, 34.85, 32.22, 2.77. Anal. Calc'd for Cl6H3lNSi2 : C, 65.45 ; H, 10.64 ; N, 4.77. Found: C, 65.25 ; H, 10.58 ; N, 4.95.

Example 2. 4-tert-Butylaniline (Table 2 and 3, entry 1).

'H NMR : 8 7.19 (d, J= 8.6 Hz, 2H), 6.63 (d, J= 8.6 Hz, 2H), 3.54 (s, 2H), 1.33 (s, 9H). 13C NMR : 8 144. 21,141. 87,126. 5,115. 3,77. 67,31. 98.

Example 3. Aniline (Tables 2 and 3, entry 2).

'H NMR: 8 7.17 (ddd, J= 7.4, 6.6, 0.8 Hz, 2H), 6.77 (dt, J= 7. 4,1. 0 Hz, 1H), 6.69 (ddd, J= 6. 6,1. 0,0. 8 Hz, 2H), 3.65 (s, 2H). 3C NMR: 8 147.01, 129.96, 119.22, 115.77.

Example 4. Methyl 4-aminobenzoate (Tables 2 and 3, entry 3).

'H NMR: 8 7.86 (dd, J= 8.7, 0.9 Hz, 2H), 6.63 (dd, J= 8.7, 0.9 Hz, 2H), 4.06 (s, 2H), 3.86 (s, 3H). 13C NMR: 8 167.13, 150.74, 131. 51, 119.67, 113.73, 51. 51.

Example 5. (4-Aminophenyl) (phenyl) methanone (Tables 2 and 3, entry 4).

1 H NMR: 8 7.66 (m, 2H), 7.65 (d, J= 8.8 Hz, 2H), 7.47 (dt, J= 7.3, 1.5 Hz, 1H), 7.37 (ddd, J= 8.3, 7.3, 1.3 Hz, 2H), 6. 61 (d, J= 8.8 Hz, 2H), 4.07 (s, 2H). 13C NMR: 8 195.1, 150.83, 183.68, 132.81, 131.28, 129.44, 127.92, 127.31, 113.54.

Example 6. p-Toluidine (Tables 2 and 3, entry 5).

1H NMR ; 8 7.02 (d, J= 8.3 Hz, 2H), 6.65 (d, J= 8.3 Hz, 2H), 3.57 (s, 2H), 2.31 (s, 3H). I3C NMR : 8 144.33, 130.22, 128.17, 115.73, 20.93.

Example 7. 4-Butylaniline (Tables 2 and 3, entry 6).

'H NMR: 8 6.98 (d, J= 8.2 Hz, 2H), 6.63 (d, J= 8.2 Hz, 2H), 3.53 (s, 2H), 2.50 (t, J = 7. 6 Hz, 2H), 1.51 (dt, J= 7.6, 7.4 Hz, 2H), 1.35 (tq, J= 7.4, 7.2 Hz, 2H), 0.92 (t, J= 7.2 Hz, 3H).'3C NMR: 8 43.83, 132.95, 129.01, 115.06, 34.63, 33.87, 22.19, 13.87.

Example 8. N, N-Dimethylbenzene-1, 4-diamine (Tables 2 and 3, entry 7).

'H NMR: 8 6.73-6. 66 (m, 4H), 3.35 (s, 2H), 2.84 (s, 6H). 13C NMR: g 144.79, 137.85, 116.53, 115.54, 42.09.

Example 9. 4- (Trifluoromethyl) aniline (Tables 2 and 3, entry 8).

1 H NMR: 8 7. 30 (d, J= 8.5 Hz, 2H), 6.60 (d, J= 8.5 Hz, 2H), 3.86 (s, 2H). 13C NMR: 8 150.04, 127.36 (q, J= 3.6 Hz), 125.50 (q, J= 270.5 Hz), 120.84 (q, J= 32.4 Hz), 114.85.

Example 10. 4-Methoxyaniline (Tables 2 and 3, entry 9).

'H NMR: 8 6.74 (d, J= 8.7 Hz, 2H), 6.64 (d, J= 8.7 Hz, 2H), 3.73 (s, 3H), 3.41 (s, 2H). 13CNMR : 8 152.74, 139.56, 116.39, 114.65, 55.71.

Example 11. 4-Fluoroaniline (Tables 2 and 3, entry 10).

¹HNMR : 8 8. 86 (m, 2H), 6.63 (m, 2H), 3.50 (s, 2H). 13C NMR : 8 157. 10 (d, J= 235.5 Hz), 143.00, 116.75 (d, J= 7.5 Hz), 116.33 (d, J= 22.3 Hz).

Example 12. 1, 1'-Biphenyl-4-amine (Tables 2 and 3, entry 11).

'H NMR: 8 7.54 (dd, J= 6.6, 1.2 Hz, 2H), 7.47-7. 36 (m, 4H), 7.27 (dt, J= 7.4, 1.2 Hz, 1H), 6.77 (d, J= 8.9 Hz, 2H).'3CNMR : 8 145.69, 141.02, 131.45, 128.53, 127.89, 126.27, 126.13, 115.26.

Example 13. 4-Phenoxyaniline (Tables 2 and 3, entry 12).

'H NMR: 8 7.27 (dd, J= 8. 6,7. 5 Hz, 2H), 7.02 (dt, J= 7.5, 1.0 Hz, 1H), 6. 93 (dd, J = 8. 6,1. 0 Hz, 2H), 6.88 (d, J= 8.4 Hz, 2H), 6.68 (d, J= 8.5 Hz, 2H), 3.58 (s, 2H).'C NMR : 8 158.70, 153.40, 141.85, 129.42, 122.00, 120.98, 117.15, 116.44.

Example 14. 3-Methoxyaniline (Tables 2 and 3, entry 13).

'H NMR: 8 7.06 (dd, J= 8.1, 8.1 Hz, 1H), 6.33 (ddd, J= 8.1, 2.4, 0.7 Hz, 1H), 6.30 (ddd, J= 8.1, 2.3, 0.7 Hz, 1H), 6.25 (dd, J= 2.4, 2.3 Hz, 1H), 3.78 (s, 3H), 3.65 (s, 2H).

¹³C NMR : 8 160.89, 147.92, 130.31, 108.12, 104.08. 101.18, 55.34.

Example 15. 3- (1, 3-Dioxolan-2-yl) aniline (Tables 2 and 3, entry 14).

'H NMR: 6 7.17 (t, J= 7.8 Hz, 1H), 6.87 (d, J= 7. 6 Hz, 1H), 6.81 (t, J= 1.9 Hz, 1H), 6.68 (m, 1H), 5.74 (s, 1H), 4.11-4. 02 (m, 4H), 3.71 (s, 2H). 13C NMR: 8 147.14, 139.63, 129.96, 117.25, 116.54, 113.42, 104.29, 65.84.

Example 16. 3- (Trifluoromethyl) aniline (Tables 2 and 3, entry 15).

'H NMR: 8 7.24 (dd, J= 8.0, 7.6 Hz, 1H), 6.98 (dd, J = 7.6, 0.4 Hz, 1H), 6.89 (broad s, 1H), 6. 81 (dd, J= 8.0, 0.4 Hz, 1H), 3.84 (s, 2H). 13C NMR: 146. 58, 131. 35 (q, J=22. 2Hz), 129.60, 124.07 (q, J=272. 2Hz), 117.82, 114.87 (q, J=3. 9Hz), 111. 17 (q, J=3. 5Hz).

Example 17. m-Toluidine (Tables 2 and 3, entry 16).

'H NMR: 8 7.08 (t, J= 7.6 Hz, 1H), 6.61 (d, J= 7.5 Hz, 1H), 6.54-6. 52 (m, 2H), 3.58 (s, 2H), 2.30 (s, 3H). 13C NMR: 8 146.96, 139.76, 129.80, 120.08, 116.55, 112.88, 22.08.

Example 18. 2-Fluoro-1, 1'-biphenyl-4-amine (Tables 2 and 3, entry 17).

'H NMR: 8 7.36 (m, 1H), 7.34 (s, 1H), 7.25 (m, 2H), 7.15 (m, 1H), 7.07 (t, J= 8.5 Hz, 1H), 6.36 (dd, J= 8. 2,2. 3 Hz, 1H), 6.30 (dd, J= 10.2, 2.2 Hz, 1H), 3.65 (s, 2H).'3CNMR : 8 160.96 (d, J= 246.0 Hz), 147 (d, J = 11. 0 Hz), 136.60, 131. 71 (d, J= 3. 4 Hz), 129.07 (d, J = 2. 9 Hz), 128.79, 127.16, 119.39 (d, J= 13.9 Hz), 111. 58,102. 91 (d, J= 105.2 Hz). Anal.

Calc'd for C12H, OFN : C, 76.99 ; H, 5.38 ; N, 7.48. Found: C, 77.19 ; H, 5.55 ; N, 7.36.

Example 19. 1, 3-Benozodioxol-5-amine (Tables 2 and 3, entry 18).

'H NMR: 8 6.64 (d, J= 8.1 Hz, 1H), 6.29 (d, J= 2.2 Hz, 1H), 6.13 (dd, J= 8.1, 2.2 Hz, 1H), 5.86 (s, 2H), 3.44 (s, 2H). 13C NMR : 8 148.82, 142.02, 140.97, 109.21, 107. 50, 101.30, 98.70.

Example 20. 2-Naphthylamine (Tables 2 and 3, entry 19).

'H NMR: 8 7.69 (d, J= 8.0 Hz, 1H), 7.66 (d, J= 8.4 Hz, 1H), 7.59 (d, J= 8. 4 Hz, 1H), 7. 36 (dd, J = 6.8, 1.2 Hz, 1H), 7.22 (dd, J= 8.0, 1.6 Hz, 1H), 6.95 (d, J = 2.1 Hz, 1H), 6. 55 (dd, J= 8.4, 2.1 Hz, 1H), 3.83 (s, 2H).'3C NMR : 8 143.96, 134.78, 129.09, 128.49, 127.58, 126.22, 125.67, 122.35, 118.20, 108.47.

Example 21. 6-Methoxy-2-naphthylamine (Tables 2 and 3, entry 20).

'H NMR: 8 7.57 (d, J= 8.4 Hz, 1H), 7.52 (d, J= 8. 7 Hz, 1H), 7.09 (dd, J= 8.9, 2.6 Hz, 1H), 7.04 (d, J= 2. 6 Hz, 1H), 6.98 (d, J= 2. 1 Hz, 1H), 6.94 (dd, J = 8.3,2. 1 Hz, 1H), 3.89 (s, 3H), 3.72 (s, 2H). 13C NMR : 8 155.22, 142.15, 130.03, 128.51, 127.77, 127.18, 118.83, 118.59, 109.10, 105.91, 55.14.

Example 22. Pyridin-2-amine (Tables 2 and 3, entry 21).

'H NMR: 8 8.03 (m, 1H), 7.38 (m, 1H), 6.60 (m, 1H), 6.46 (d, J= 8.3 Hz, 1H), 4.60 (s, 2H). 13C NMR : 8 159.12, 148.63, 138.29, 114.45, 109.2.

Example 23. Benzene-1, 4-diamine (Tables 2 and 3, entry 22).

'H NMR: 8 6.60 (s, 4H), 3.35 (s, 4H).'3CNMR : 8 139.25, 117.40.

Example 24. Benzene-1, 3-diamine (Tables 2 and 3, entry 23).

'H NMR : 8 6.94 (t, J= 7.8 Hz, 1H), 6.12 (dd, J= 7.8, 2.3 Hz, 2H), 6.04 (t, J= 2. 3 Hz, 1H), 3.57 (s, 4H). 13C NMR : 8 147.37, 130.09, 105.87, 101.79.

While the invention has been described in combination with embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art in light of the foregoing description. Accordingly, it is intended to embrace all such alternatives, modifications and variations as fall within the spirit and broad scope of the appended claims.