BACKGROUND Chelating phosphine compounds when bound to metal atoms are generally known to be useful as catalysts. One reaction which uses palladium phosphine catalysts is the coupling of aryl halides with amines for the production of arylamines, as reviewed by Hartwig, SYNLETT, 1997, (4), pg. 329-340. An example of this reaction is the coupling of chlorobenzene and piperidine to form N-phenylpiperidine : Another reaction in which palladium/phosphine catalysts have been used is the Suzuki reaction, where biaryls are produced through the coupling of arylboronic acids and aryl halides, as reviewed by Suzuki, A, J. Orgmet. Chem., 576 (1999), pg. 147. One example of this reaction is the preparation of biphenyl from phenylboronic acid and chlorobenzene : Both of these products are important classes of compounds widely used in the manufacture of pharmaceuticals, advanced materials, liquid polymers and ligands, and much work has been done on their preparation. However, there is an expanding need for stable, easily prepared catalysts that result in good yields and mild reaction conditions.

Preparation of new ligands has traditionally been performed one at a time after tedious synthesis and purification protocols. Combinatorial techniques have greatly accelerated the discovery of new ligands, but new synthetic schemes are needed. One valuable technique uses solid-phase supports. This solid-phase

protocol allows reactions on a polymer-bound scaffold to be driven to completion by using large excesses of reagents in solution that can be easily filtered away from the polymer support. After the scaffold has been modified, an additional cleavage step then frees the small molecule from the polymer support into solution for isolation.

Phosphine oxide compounds and libraries have been prepared using polymer scaffolds in U. S. Application No. 09/415, 347 (US 99/23509) which is incorporated in its entirety by reference. Lacking is a process for the convenient preparation of stable arylamines of the formula Rl-NR2R3 or biaryls of the formula R I-R6 using a stable phosphine catalyst under mild conditions and producing good yields.

SUMMARY OF THE INVENTION This invention is directed to the use of phosphine oxide compounds complexed with transition metals to produce biaryls and arylamines via cross-coupling reactions with aryl halides and arylboronic acids or amines.

More specifically, the invention is directed to a process to prepare arylamines of the formula Rl-NR2R3 comprising contacting an amine of the formula HNR2R3 with an aryl compound of the formula R1-X in the presence of a catalytic amount of a coordination compound comprising one or more transition metals complexed to a phosphine oxide ligand of the formula HP (O) R4R5 ; wherein X is a halogen ; RI is an optionally substituted aryl ; R2 and R3 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, hydrocarbylamino, alkoxy, aryloxy, and heterocyclic, and optionally R2 and R3 can together form a ring ; and R4 and R5 are independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, heterocyclic, organometallic, C1, Br, I, SQ1, OQ2, PQ3Q4, and NQ5Q6, where Ql, Q2, Q3, Q4, Q5, and Q6 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, hydrocarbylamino, alkoxy, aryloxy, and heterocyclic, and optionally R4 and R5 can together form a ring.

Preferably, RI is an optionally substituted phenyl, and the transition metal is selected from Periodic Group VIII. More preferably, R4 and R5 are independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl and heterocyclic, the transition metal is Pd, and R2 and R3 are selected from the group consisting of hydrogen, optionally substituted aryl, and wherein R2 and R3 are hydrocarbyl and together form a ring. Most preferably X is Cl, RI is selected from the group consisting of phenyl, 4-methylphenyl, 4-methoxyphenyl, and 4-trifluoromethylphenyl ; R2 and R3 are selected from the

group consisting of hydrogen, phenyl, 4-methylphenyl, and together form a piperidyl ring ; and R4 and R5 are selected from the group consisting of t-butyl, phenyl, i-propyl, and 2, 4-methoxyphenyl.

The invention is further directed to a process to prepare biaryls of the formula R1-R6 comprising contacting a boronic acid of the formula R6-B (OH) 2 with an aryl compound of the formula R1-X in the presence of a catalytic amount of a coordination compound comprising one or more transition metals complexed to a phosphine oxide ligand of the formula HP (O) R4R5 wherein X is a halogen ; R1 is an optionally substituted aryl ; R6 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, hydrocarbylamino, alkoxy, aryloxy, and heterocyclic ; and R4 and R5 are independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, heterocyclic, organometallic, Cl, Br, I, SQI, OQ2, PQ3Q4, and NQ5Q6, where Q1, Q2, Q3, Q4, Q5, and Q6 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, hydrocarbylamino, alkoxy, aryloxy, and heterocyclic, and optionally R4 and R5 can together form a ring.

Preferably RI is an optionally substituted phenyl, and the transition metal is selected from Periodic Group VIII. More preferably R4 and R5 are independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl and heterocyclic, the transition metal is Pd, and R6 is an optionally substituted aryl. Most preferably X is Cl, R1 is selected from the group consisting of of phenyl, 4-methoxyphenyl, 2-methoxyphenyl and 4-methylphenyl ; R6 is selected from the group consisting of 4-methoxyphenyl, and phenyl ; and R4 and R5 are selected from the group consisting of t-butyl, phenyl, i-propyl, and 2, 4-methoxyphenyl.

The invention is further directed to a process to prepare biaryls of the formula R1-R7 comprising contacting a Grignard reagent of the formula R7-MgX with an aryl compound of the formula Rl-X in the presence of a catalytic amount of a coordination compound comprising one or more transition metals complexed to a phosphine oxide compound of the formula HP (O) R4R5, wherein X is a halogen ; RI is an optionally substituted aryl ; R7 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, hydrocarbylamino, alkoxy, aryloxy, and heterocyclic ; and R4 and R5 are independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, heterocyclic, organometallic, Cl, Br, I, SQ1, OQ2, PQ3Q4, and NQ5Q6, where Ql, Q2, Q3, Q4 Q5, and Q6 are independently selected from the group consisting of hydrogen,

hydrocarbyl, substituted hydrocarbyl, hydrocarbylamino, alkoxy, aryloxy, and heterocyclic, and optionally R4 and R5 can together form a ring.

Preferably R1 is an optionally substituted phenyl, and the transition metal is selected from Periodic Group VIII. More preferably R4 and RS are independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl and heterocyclic, the transition metal is Ni, and R7 is an optionally substituted aryl. Most preferably X is Cl, RI is selected from the group consisting of 4-chloroanisole and chlorobenzene ; R7 is o-tolyl ; and R4 and R5 are t-butyl.

Further, the invention includes the method of using phosphine oxides as ligands for homogeneous catalysis of arylarnines of the formula Rl-NR2R3 or biaryls of the formula R1-R6 or biaryls of the formula R1-R7 comprising (1) preparing a coordination compound comprising one or more transition metals complexed to a phosphine oxide compound of the formula HP (O) R4R5, wherein X is a halogen ; RI is an optionally substituted aryl ; R6 and R7 are independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, hydrocarbylamino, alkoxy, aryloxy, and heterocyclic ; and R4 and RS are independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, heterocyclic, organometallic, Cl, Br, I, SQ1, OQ2, PQ3Q4, and NQ5Q6, where Q1, Q2, Q3, Q4, Q5, and Q6 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, hydrocarbylamino, alkoxy, aryloxy, and heterocyclic, and optionally R4 and R5 can together form a ring ; and (2) contacting either (i) a boronic acid of the formula R6-B (OH) 2 or (ii) an amine of the formula HNR2R3 or (iii) a Grignard reagent of the formula R7-MgX with an aryl compound of the formula R1-X in the presence of a catalytic amount of the coordination compound prepared in step (1) to form, respectively, arylamines of the formula R1-NR2R3 or biaryls of the formula R1_R6.

DETAILED DESCRIPTION OF THE INVENTION This disclosure sets out methods for the use of phosphine oxide compounds complexed with transition metals to produce biaryls and arylamines via cross-coupling reactions with aryl halides and arylboronic acids or amines.

Phosphine oxides were not previously used as ligands in homogeneous catalysis, primarily because the P-atoms do not have coordinated atoms with lone-pair electrons which were considered essential.

The processes of the instant invention are an improvement over similar processes in the art. The phosphine oxide compounds used in the instant processes are air-stable solids and are easily handled, and can be easily

synthesized in a variety of forms using the methods described in U. S. Patent Application No. 09/415, 347 (US 99/23509). The processes are easily adapted to combinatorial procedures and can be used to construct libraries of biaryls and arylamines, which are themselves widely used in the manufacture of pharmaceuticals, advanced materials, liquid polymers and as ligands. Two examples of compounds or derivatives thereof that could be made by these processes are the synthetic dye Quinizarin Green and p-aminobiphenyl, used as an antioxidant.

Phosphine Oxide Compound and Libraries Phosphine oxide compounds of the formula HP (O) R4R5 are known to exist in two tautomeric forms : The phosphine oxide compounds can be prepared by any method. One such method is via the use of polymer scaffolds as described in U. S. Application No. 09/415, 347 (US 99/23509), herein incorporated by reference. This scheme comprises the steps of contacting (i) a phosphine selected from the group consisting of XPR4R5 and HP (=O) R4R5, wherein X is a halogen, and R4 and R5 are independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl and heterocyclic, organometallic, Cl, Br, I, SQt, OQ2, PQ3Q4 and NQ5Q6, when Ql, Q2, Q3, Q4, Q5 and Q6 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, hydrocarbyl amino, alkoxy, aryloxy, and heterocyclic, and optionally R4 and R5 can together form a ring, with (ii) a solid support, resulting in at least one P in the phosphine attached indirectly or directly to the solid support via one or more covalent bonds, and optionally replacing one or more of R4 and R5 with any other R4 and R5 defined above.

Virtually any solid material may be used as a support to prepare the phosphine oxide compounds provided it meets the following criteria : The material is insoluble in organic, aqueous, or inorganic solvents.

Organic polymer supports are acceptable in this regard but they generally need to be crosslinked. Inorganic support, such as metal oxides (Si02, A1203, TiO2, ZrO2, etc.), clays, and zeolites, and

modified carbons are generally insoluble in these solvents and also may be used as supports.

* The support contains reactive sites, which can be used for the covalent attachment of the phosphorus.

* The reactive sites are isolated to prevent additional crosslinking during further chemical transformations.

'The reactive sites are exposed to the reaction medium. With a polymer resin support this is achieved through the use of a resin which swells in a reaction solvent or is sufficiently porous to allow transport of the reaction medium through the polymer matrix.

The term solid support refers to a material having a rigid or semi-rigid surface that contains or can be derivatized to contain functionality, which covalently links a compound to the surface thereof. Other modifications may be made in order to achieve desired physical properties. Such materials are well known in the art and include, by way of example, polystyrene supports, polyacrylamide supports, polyethyleneglycol supports, metal oxides such as silica, and the like. Such supports will preferably take the form of small beads, pellets, disks, films, or other conventional forms, although other forms may be used.

A preferred solid support is an organic or inorganic polymer to which the phosphorus can be covalently attached through a side chain or pendant group of the polymeric backbone. The polymer may be crosslinked or modified. Suitable preferred polymers useful in the preparation of a supported phosphine compound or a combinatorial library of supported phosphine compounds includes polyolefins, polyacrylates, polymethacrylates, and copolymers thereof that meet the general criteria described above. A more preferred polymeric support is polystyrene wherein the phosphorus is attached to a pendant phenyl group on the polystyrene backbone. Most preferred is polystyrene, crosslinked with divinylbenzene. Specifically, polystyrenes commonly used for solid phase synthesis have been used. These particular resins are crosslinked with from 1 to 10 wt % divinylbenzene. The styrene moieties are substituted in the para or meta positions. Only a portion of the styrene moieties are substituted, typically resulting in functional group loadings of approximately 0. 2 to 2. 0 mmole per gram of resin, although this value may be higher or lower.

A combinatorial library of phosphine oxides can be used in the instant invention as well as single compounds. To create a library, one or more phosphines are reacted with one or more solid supports, generating a plurality of supported phosphine compounds. Alternatively, a library may be created by

reacting one supported phosphine compound with a plurality of cleaving agents, as described below.

As used herein, a combinatorial library is an intentionally created collection of a plurality of differing molecules which can be prepared by selected synthetic means and screened for a desired activity or characteristic in a variety of formats (e. g., libraries of soluble molecules, libraries of compounds attached to resin beads, silica chips, or other solid supports). The libraries are generally prepared such that the compounds are in approximately equimolar quantities, and are prepared by combinatorial synthesis. Combinatorial synthesis refers to the parallel synthesis of diverse compounds by sequential additions of multiple choices of reagents which leads to the generation of large chemical libraries containing related molecules having molecular diversity. Screening methods for libraries vary greatly and are dependent upon a desired activity, the size of library, and the class of compounds in the library.

The libraries can be of any type. These types include but are not limited to arrays and mixtures. Arrays are libraries in which the individual compounds are simultaneously synthesized in spatially segregated locations, typically identified by their location on a grid. Mixture libraries contain a mixture of compounds that are simultaneously synthesized and assayed. Identification of the most active compound is then performed by any of several techniques well known in the combinatorial art, such as deconvolution. (Proc. Natl. Acad. Sci. USA, 91, pg. 10779 (1994)).

A preferred solid support for the combinatorial libraries of the instant invention is an organic or inorganic polymer as described above, to which the phosphorus can be covalently attached through a side chain or pendant group of the polymeric backbone.

One scheme used in attaching the P to the solid support is via the reaction of the halogen or hydrogen bonded to the phosphorus in the phosphine with a nucleophilic group that is covalently attached to a solid support. The term nucleophilic group is well recognized in the art and refers to chemical moieties having a reactive pair of electrons. This scheme can easily be adapted for combinatorial synthesis.

Examples of reactions to prepare the phosphine oxide compounds are shown but not limited to those in Scheme 1 below, where SS is the solid support, X is a halogen, M is any metal, R can be one or more of R4 or R5 as defined above, Z is a divalent attaching group covalently attached to at least one phosphorus in the phosphine, selected from the group consisting of

hydrocarbylene, substituted hydrocarbylene,-O-,-S-, and-NR'-, where R'is selected from the group consisting of an optionally-substituted hydrocarbyl and halogen, and the Z, O, S, and N substituents are covalently attached to the solid support.

SCHEME 1 SS X RN- SS RNH Sus Xi~ base SS X XM- SS Z-MX XP--_ SS Z PH XP SS OH-- SS O P XP~ SS SH = SS S P Hop OH r 5 4 5 SS CH o SS C P^_ XP-^^ = XPR4R5 XP (=O) R4R5 HP. = HPR4R5 HP (=o) R4R5 Any of the substituents in the above compounds may be replaced by other functional groups using any procedure known in the art. One or all of the substituents can be reacted in a single reaction, depending on the choice of reactants and reaction conditions. These reactions can easily be adapted for combinatorial processes. Examples of suitable procedures are shown by but not limited to those depicted in Scheme 2 below, where X, and M are as defined above, and R indicates any of R4 or R5, as defined above. Examples of suitable definitions for M include Mg, Li, and Zn. Cp indicates a cyclopentadienyl ring.

SCHEME 2

The phosphine oxide compounds are formed by cleaving the compound from the solid support by contacting the supported phosphine with a compound of the Formula ER", wherein E is an electrophilic group and R"is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocycle, organometal, Cl, Br, I, SQ1, OQ2, PQ3Q4, and NQ5Q6, where Q1, Q2, Qs, Q4, Q5 and Q6 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, hydrocarbylamino, alkoxy, aryloxy, and heterocycle. R"can be optionally replaced by any of R4 or R5. To create a library, one or more supported phosphines are reacted with one or more compounds of the Formula ER", generating a plurality of phosphine compounds.

In the above process, E is any electrophilic group that will cleave the covalent bond attaching the phosphorus to the solid support. The term electrophilic group is a term well recognized in the art and refers to chemical moieties, which can accept a pair of electrons from a nucleophilic group as defined above. Suitable electrophilic groups include H, trimethylsilyl, PC12, halogens, and protons donated from compounds such as acids, alcohols, or amines.

In the instance where ER"is water, the resulting POH group would rearrange to yield to form the phosphine oxide compounds used in the instant invention. These compounds can also be formed from any other phosphine of the formula RPR4R5 via the replacement of R with an-OH group using any method

known in the art. An equivalent rearrangement occurs when a PSH group is present.

Another method for preparing the phosphine oxide compounds is to prepare a phosphine oxide attached to the solid support, as explained above, then to cleave the phosphine oxide directly from the solid support.

After cleavage from the solid support, R4 and RS may be replaced with any other substituent using any method known in the art, in order to prepare a further range of compounds, such as those described in Encyclopedia of Inorganic Chemistry (John Wiley & Sons, Vol. 6, pg. 3149-3213).

Reactions of Amines with Aryl Halides to Prepared Arvlamines of the Formula NHR2R3 A process is described to prepare arylamines of the formula Rl-NR2R3 comprising contacting an amine of the formula HNR2R3 with an aryl compound of the formula RI-X in the presence of a catalytic amount of a coordination compound comprising one or more transition metals complexed to a phosphine oxide compound of the formula HP (O) R4R5.

In this process, X is a halogen, RI is an optionally substituted aryl radical, R2 and R3 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, hydrocarbylamino, alkoxy, aryloxy, and heterocyclic, and optionally R2 and R3 can together form a ring, and R4 and R5 are independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, heterocyclic, organometallic, Cl, Br, I, SQl, °Q2, PQ3Q4 and NQsQ6, where Ql, Q2, Q3, Q4, Q5 and Q6 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, hydrocarbylamino, alkoxy, aryloxy, and heterocyclic, and optionally R4 and R5 can together form a ring. Optionally, the process can be performed intramolecularly ; i. e. the amine functionality and the aryl functionality are both located on the same compound and the process results in a cyclization.

The amine and the aryl compound can be prepared by any method, including any of the well-known processes in the art.

"Coordination compound"refers to a compound formed by the union of a metal ion (usually a transition metal) with a non-metallic ion or molecule called a ligand or complexing agent.

The transition metals are defined as metals of atomic number 21 through 83. Preferably, the transition metal is from Periodic Group VIII (defined as Fe, Co, Ni, Ru, Rh, Pd, Os, Ir, and Pt). More preferred is Pd and Ni. The complex

can be made by any synthetic method known in the art, either through direct reaction or via the use of a transition metal precursor.

The phosphine oxide compound is prepared as disclosed above. The phosphine oxide used in the instant invention can exist in either tautomeric form when present as a component of the complex. The complex can be isolated and purified before use, or be prepared and used in situ. Many of these techniques are described in Hartley, F. R. (Ed),"Chem. Met.-Carbon Bond', 1987, vol. 4, pp. 1163-1225).

By hydrocarbyl is meant a straight chain, branched or cyclic arrangement of carbon atoms connected by single, double, or triple carbon to carbon bonds and/or by ether linkages, and substituted accordingly with hydrogen atoms. Such hydrocarbyl groups may be aliphatic and/or aromatic. Examples of hydrocarbyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylcyclopentyl, cyclohexyl, methyl- cyclohexyl, benzyl, phenyl, o-tolyl, m-tolyl, p-tolyl, xylyl, vinyl, allyl, butenyl, cyclohexenyl, cyclooctenyl, cyclooctadienyl, and butynyl. Examples of substituted hydrocarbyl groups include methoxy, phenoxy, toluyl, chlorobenzyl, fluoroethyl, p-CH3-S-C6H5, 2-methoxy-propyl, and (CH3) 3SiCH2.

By aryl is meant an aromatic carbocyclic group having a single ring (e. g., phenyl), multiple rings (e. g., biphenyl), or multiple condensed rings in which at least one is aromatic, (e. g., 1, 2, 3, 4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl), which is optionally mono-, di-, or trisubstituted with, e. g., halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, aryl, heteroaryl, and hydroxy. By aryl is also meant heteroaryl groups where heteroaryl is defined as 5-, 6-, or 7-membered aromatic ring systems having at least one hetero atom selected from the group consisting of nitrogen, oxygen and sulfur.

Examples of heteroaryl groups are pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, pyrazinyl, pyridazinyl, oxazolyl, furanyl, quinolinyl, isoquinolinyl, thiazolyl, and thienyl, which can optionally be substituted with, e. g., halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, aryl, heteroaryl, and hydroxy.

A preferred process is where R1 is an optionally substituted phenyl, R4 and R5 are independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl and heterocyclic, and where R2 and R3 are selected from the group consisting of hydrogen, optionally substituted aryl, and where R2 and R3 are hydrocarbyl and together form a ring. More preferred is where X is Cl, R1 is selected from the group consisting of phenyl, 4-methylphenyl, 4-methoxyphenyl

and 4-trifluoromethylphenyl, R2 and R3 are selected from the group consisting of hydrogen, phenyl, 4-methylphenyl, and together form a piperidyl ring, and R4 and R5 are selected from the group consisting of t-butyl, phenyl, i-propyl, and 2, 4-methoxyphenyl. Also preferably, the transition metal is from Periodic Group VIII. More preferred is Pd.

Reactions of Arylboronic Acids with Aryl Halides to Prepare Biaryls of the Formula R1-R6 The instant invention also describes a process to prepare biaryls of the formula R1-R6 comprising contacting a boronic acid of the formula R6-B (OH) 2 with an aryl compound of the formula Rl-X in the presence of a catalytic amount of a coordination compound comprising one or more transition metals complexed to a phosphine oxide compound of the formula HP (O) R4R5 ; where X is a halogen, RI is an optionally substituted aryl, R6 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, hydrocarbylamino, alkoxy, aryloxy, and heterocyclic, and R4 and RS are independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, heterocyclic, organometallic, Cl, Br, I, SQ1, OQ2, PQ3Q4, and NQ5Q6, where Ql, Q2, Q3, Q4) Q5, and Q6 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, hydrocarbylamino, alkoxy, aryloxy, and heterocyclic, and optionally R4 and R5 can together form a ring. Optionally, the process can be performed intramolecularly ; i. e., the boronic acid functionality and the aryl functionality are both located on the same compound and the process results in a cyclization.

A preferred process is where RI is an optionally substituted phenyl, R4 and RS are independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl and heterocyclic, and where R6 is an optionally substituted aryl. More preferred is where X is Cl, Rl is selected from the group consisting of of phenyl, 4-methoxyphenyl, 2-methoxyphenyl and 4-methylphenyl ; R6 is selected from the group consisting of 4-methoxyphenyl, and phenyl ; and R4 and R5 are selected from the group consisting of t-butyl, phenyl, i-propyl, and 2, 4-methoxyphenyl. Also preferably, the transition metal is from Periodic Group VIII. More preferred is Pd.

Reactions of Aryl Grignards with Aryl Halides to Prepare Biaryls of the Formula RI-R6 The instant invention also describes a process to prepare biaryls of the formula R1-R7 comprising contacting a Grignard reagent of the formula R7-MgX with an aryl compound of the formula Rl-X in the presence of a catalytic amount

of a coordination compound comprising one or more transition metals complexed to a phosphine oxide compound of the formula HP (O) R4R5 ; where X is a halogen, RI is an optionally substituted aryl, R7 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, hydrocarbylamino, alkoxy, aryloxy, and heterocyclic, and R4 and R5 are independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, heterocyclic, organometallic, Cl, Br, I, SQl, OQ2, PQ3Q4, and NQ5Q6 where Ql, Q2, Q3, Q4, Q5, and Q6 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, hydrocarbylamino, alkoxy, aryloxy, and heterocyclic, and optionally R4 and R5 can together form a ring. Optionally, the process can be performed intramolecularly ; i. e., the Grignard functionality and the aryl functionality are both located on the same compound and the process results in a cyclization.

A preferred process is where RI is an optionally substituted phenyl, R4 and R5 are independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl and heterocyclic, and where R7 is an optionally substituted aryl. More preferred is where X is Cl, RI is selected from the group consisting of 4-chloroanisole and chlorobenzene, R7 is o-tolyl, and R4 and RS are t-butyl. Also preferably, the transition metal is from Periodic Group VIII. More preferred is Ni.

Schemes 1 and 2 to form phosphine oxides, the cleaving procedures, and the coupling reactions disclosed above are preferably performed under dry, inert atmosphere with dry, deoxygenated solvents. Any solvent is suitable provided that it is inert to all reagents and products. Suitable temperatures for homogeneous catalysis range from-80°C to 200°C. Preferred temperatures are about 0° C to about 150° C. Except for the Grignard coupling, preferably a base should be added in the coupling reactions disclosed. Preferred bases are CsF, CsC03, and NaOtBu.

The following non-limiting Examples are meant to illustrate the invention but are not intended to limit it in any way.

Materials and Methods All manipulations of air-sensitive materials were carried out with rigorous exclusion of oxygen and moisture in flame-dried Schlenk-type glassware on a dual manifold Schlenk line, interfaced to a high-vacuum (10-4-10-5 Torr) line, or in a nitrogen-filled Vacuum Atmospheres glovebox with a high-capacity recirculator (1-2 ppm of 02). Before use, all solvents were distilled under dry nitrogen over appropriate drying agents (such as sodium benzophenone ketyl and metal hydrides except for chlorinated solvents). Deuterium oxide, THF-Dg, C6D6 and

chloroform-d were purchased from Cambridge Isotopes (Andover, MA). All organic and inorganic starting materials were purchased from Aldrich Chemical Co. (Milwaukee WI), Farchan Laboratories Inc. (Gainesville, FL), Strem Chemicals (Newburyport, MA), Calbiochem-NovaBiochem Corp. (San Diego, CA), Rieke Metals, Inc. (Lincoln, NE), or Lancaster Synthesis Inc. (Windham, NH), and when appropriate were distilled prior to use.

List of abbreviations dba Bis (dibenzylideneacetone) DVB Divinylbenzene GC/MS Gas chromatography/mass spectroscopy FT Fourier transform h Hour i. d Inner diameter in. Inch Me Methyl mg milligram NMR Nuclear magnetic resonance tBu tert-butyl Physical and Analytical Measurements NMR spectra were recorded on either a Nicolet NMC-300 wide-bore (FT, 300 MHz, 1H ; 75 MHz, 13C, 121 MHz 31p), or GE QM-300 narrow-bore (FT, 300 MHz, IH) instrument. Chemical shifts (8) for 1H, 13C are referenced to internal solvent resonances and reported relative to SiMe4. 31p NMR shifts are reported relative to external phosphoric acid. Analytical gas chromatography was performed on a Varian Model 3700 gas chromatograph with FID detectors and a Hewlett-Packard 3390A digital recorder/integrator using a 0. 125 in. i. d. column with 3. 8% w/w SE-30 liquid phase on Chromosorb W support. GC/MS studies were conducted on a VG 70-250 SE instrument with 70 eV electron impact ionization.

The polymer bound monophosphines were prepared as described in U. S.

Patent Application No. 09/415, 347 (US 99/23509). The functional groups on the phosphines can be added in two steps to yield unsymmetrical substitutions, or in one step to yield more symmetrical substitution.

A solution of t-butylamine (276 g, 3. 78 moles) and KI (0. 3 g, 2 mmol) in 1000 mL of THF was treated with chloromethylpolystyrene-divinylbenzene (Merrifield resin, 2% DVB, 75 g, 1. 26 mmol/g, 94. 5 mmol) while stirring at room

temperature for 30 min. The suspension was then refluxed for 24 h before the solution was filtered off. The resulting resin was washed with H20 (3 X 250 mL), THF (3 X 150 mL), then hexane (3 X 200 mL). After drying in vacuum overnight, 75 g of the resin were obtained (98% yield according to N elemental analysis. Anal. calculated for polymer-NHC (Me) 3 : N, 1. 25. Found : N, 1. 22).

Also the disappearance of 1H resonances of polymer-Ph-CH2-Cl (CH2= -4. 5 ppm) and the appearance of 1H resonances of polymer-Ph-CH2-NHC (Me) 3 (CH2= 7 ppm) indicates that the chloromethyl groups were completely transformed to tert-butylaminometyl groups. Hereafter this will be referred to as Resin I.

A solution of PC13 (26 g, 189 mmol) in 400 mL of THF was treated slowly with Resin I from above (25 g, 1. 21 mmol/g, 30. 3 mmol) while stirring at room temperature for a period of 30 min. before Et3N (16 g, 157. 5 mmol) was added.

The resulting suspension was stirred at room temperature overnight before the solution was filtered off. The resin was washed with hexane (2 X 50 mL), CH2Cl2 (5 X 80 mL), and hexane (5 X 30 mL). The resulting polymer-bound PCl3 resin was dried in vacuum overnight. 31P NMR (122 MHz, CDC13) : 6 179. 1 ppm.

A suspension of the polymer-bound PC12 resin from above (5. 0 g, 1. 12 mmol/g, 5. 6 mmol) in 150 mL of THF was treated slowly with phenylmagnesium bromide (2 M solution in diethylether, 64 mmol). The resulting mixture was stirred at room temperature for 30 min. before the solution was filtered off and the resin was washed with THF (3 X 50 ml), Me2CHOH/THF (20% Me2CHOH, 10 mL), hexane (3 X 30 mL). The resulting resin was dried in vacuum overnight to yield polymer-bound PPh2. 31p NMR (122 MHz, CDC13) : 5 52. 3 ppm.

A solution of Cl2PPh (33. 8 g, 189 mmol) and Et3N (16. 0 g, 157. 5 mmol) in 500 mL of THF was treated slowly with Resin I (25. 0 g, 1. 21 mmol/g, 30. 3 mmol) while stirring at room temperature for a period of 10 min. The resulting suspension was stirred at room temperature overnight before the solution was filtered off. The resin was washed with THF (50 mL), hexane (3 X 50 mL), CH2Cl2 (4 X 50 mL), and hexane (2 X 50 mL). The resulting polymer-bound PPhCl resin was dried in vacuum overnight. 31p NMR (122 MHz, CDC13) : 8 135. 4 ppm.

A suspension of the resulting resin, the polymer-bound PPhCI, (5. 0 g, 1. 03 mmol/g, 5. 2 mmol) in 150 mL of THF was treated slowly with i-propylmagnesium chloride (0. 5 M solution in diethylether, 32. 0 mmol). The

resulting mixture was stirred at room temperature for 2 h before the solution was filtered off and the resin was washed with THF (3 X 10 mL), Me2CHOH/THF (20% Me2CHOH, 5 mL), hexane (3 X 30 mL). The resulting resin was dried in vacuum overnight to afford polymer-bound (i-C3H7) PPh. 31p NMR (122 MHz, CDCl3) : 555. 5 ppm.

The following Experiments illustrate the preparation of the phosphine oxide catalyst used in the method.

Experiment 1 Synthesis of (Me2CH) PH (O) (Ph) A suspension of polymer-bound PPh (CHMe2) prepared as described above (1. 25 g, 1. 02 mmol/g, 1. 28 mmol, 31p NMR (121 MHz, CDCl3) : 8 55. 5 ppm) and H20 (0. 1 g, 4. 8 mmol) in THF (10 mL) was refluxed overnight before the resin was filtered off and washed with THF (2 X 5 mL). The filtrate was dried under vacuum to remove the solvent and excess H20. The resulting residue was 80 mg (37% yield) of (Me2CH) PH (O) (Ph). It was >95% pure by 1H NMR and GC/MS.

31p NMR (121 MHz, CDC13, IH-decoupled) : 5 47. 8. 31p NMR (121 MHz, CDC13, 1H-coupled) : 5 47. 8 (d, Jp. n = 487. 7 Hz). 1H NMR (500 MHz, CDC13) : 5 7. 74-7. 53 (m, 5H), 7. 25 (d, JpH = 487. 5 Hz, 1H), 2. 33 (m, 1H), 1. 12 (m, 6H).

13C NMR (125 MHz, DCL3) : 8 133. 8, 131. 1, 129. 4, 125. 4, 28. 0, 14. 7. HRMS : Calculated for CgH13PO (M+) : 168. 0704. Found : 168. 0704.

Experiment 2 Synthesis of (Me3C) PH (O) (CMe3) A solution of (Me3C) 2PCI (3. 0 g, 16. 6 mmol, Aldrich) in 5. 0 mL of CH2C12 was treated with H20 (0. 5 g, 27. 8 mmol) over a period of 5 min. The resulting reaction mixture was stirred at room temperature for an additional 30 min. Removal of solvent and excess H20 afforded 2. 45 g (91% yield) of (Me3C) PH (O) (CMe3). It was >95% pure by 1H NMR and GC/MS. The pure product was obtained by sublimation (ca. 130°C/10-3 torr), 31p NMR (121 MHz, CDC13, lH-decoupled) : 6 69. 8 ppm. 31p NMR (121 MHz, CDC13, IH-coupled) : 8 69. 8 (d, Jp-H = 434. 2 Hz). 1H NMR (500 MHz, CDC13) : # 5. 96 (d, JP-H = 434. 7 Hz, 1H), 1. 14 (d, Jp-H = 156. 4 Hz, 18H). 13C NMR (125 MHz, CDC13) : b 33. 8 ppm 14 (d, Jpc = 58. 0 Hz), 25. 6 ppm. MS : Calculated for C8H19PO (M+) : 162. 1. Found : 163. 4 (M+ + H).

Experiment 3 Synthesis of 2-PH(O)(i-Pr)-1,5-(MeO) 2C6H3 A solution of PBr3 (2. 5 g, 9. 2 mm) in 15 mL of pyridine was treated with 1, 3-dimethoxybenzene (2. 5 g, 18. 1 mm) over a period of 5 min. The resulting

mixture was then refluxed for 4 h to give the crude 1-dibromophosphino-2, 4- dimethoxybenzene (31P NMR : 8 159. 2 ppm). This compound was used directly for the next step without further purification. Next, polymer-supported secondary amines (10. 0 g, 1. 1 mmol/g, 11. 0 mmol) was slowly added into the mixture above while stirring at room temperature for a period of 10 min. The resulting suspension was stirred at room temperature overnight before the solution was filtered off. The resin was washed with THF (50 mL), hexane (3 X 50 mL), CH2Cl2 (4 X 50 mL), and hexane (2 X 50 mL). The resulting resin was dried in vacuum overnight to yield the polymer-supported P (Br)-2, 4-(MeO) 2-C6H3. 31P NMR (122 MHz, CDCl3) : 8 153. 8 ppm.

A suspension of this polymer-bound compound (2. 0 g, 1. 82 mmol, 0. 908 mm/g) and I-PrMgBr (12. 0 mmol, 1. 0 M in THF solution) in 10 mL of THF was refluxed overnight before the solution was filtered off. The resulting resin was washed with THF (3 X 20 mL), CH2C12 (3 X 10 mL), Me2CHOH (2 X 10 mL), THF/H20 (70/30 volume ratio, 2 X 20 mL) and hexane (3 X 10 mL).

The resin was dried in vacuum overnight. 31P NMR (122 MHz, CDCl3) : 6 60. 7 ppm.

A suspension of polymer-bound P (i-Pr)-2, 4- (MeO) 2-C6H3 (2. 0 g, 1. 876 mmol, 0. 938 mm/g) and H2O (0. 5 g, 28 mm) in 10 mL of THF was refluxed overnight before the resin was filtered off and washed with hexane (3 X 10 mL).

Removal of solvents and excess H2O from the filtrates by vacuum afforded 100 mg (23% yield) of P (i-Pr)-2, 4-(MeO) 2-C6H3. It was >95% pure by 1H NMR and GC/MS. 31p NMR (202 MHz, CDCl3) : 8 35. 8 (s) ppm. 31p NMR (1H-coupled, 202 MHz, CDCl3) : 6 35. 8 (d, JP-H = 485. 8 Hz) ppm. 1H NMR (500 MHz, CDC13) : # 7. 57 (m, 1H), 7. 25 (d, Jpn = 485. 2 Hz, 1H), 6. 48 (m, 1H), 6. 37 (m, 1H), 3. 76 (d, J = 15. 2 Hz, 3H), 3. 70 (d, J = 38. 7 Hz, 3H), 2. 18 (m, 1H), 1. 12-0. 81 (m, 6H). 13C NMR (125 MHz, CDCl3) : 165. 0, 161. 8, 135. 1, 105. 6, 105. 5, 98. 2, 67. 9, 55. 6, 27. 4, 14. 5 ppm. MS : 229. 2 (M + 1).

EXAMPLES A. Reactions of Amines with Aryl Halides EXAMPLE 1 In a drybox, 14. 4 mg (0. 087 mmol) of (Me3C) 2PH (O) from Experiment 2, 20. 0 mg (0. 0218 mmol) of Pd2 (dba) 3 (dba = bis (dibenzylideneacetone)) and 4. 0 mL of toluene were loaded into a reactor (20 mL) equipped with a magnetic stir bar.

The resulting mixture was stirred at room temperature overnight. Next, 144 mg (1. 5 mmol) of NaOtBu was added into the mixture above, followed by syringing 122 p1 (1. 2 mmol) of PhCl, and 100 ul (1. 0 mmol) of piperidine into the reactor.

The resulting mixture was refluxed for 5 h. The reaction mixture was then cooled to room temperature, chromatographed on silicon gel using ethyl acetate/hexane (5% volume ratio) as eluant. The eluate was concentrated by rotary evaporation followed by high vacuum to yield 82 mg (51% yield) of N-phenylpiperidine. It was >95% pure by IH NMR and GC/MS. IH NMR (500 MHz, CDC13) : 6 7. 15 (m, 2H), 6. 84 (m, 2H), 6. 72 (m, 1H), 3. 06 (t, J = 5. 48 Hz, 4H), 1. 61 (m, 4H), 1. 48 (m, 2H) ppm.

13C NMR (125 MHz, CDC13) : d 152. 3, 129. 0, 119. 2, 116. 5, 50. 7, 25. 9, 24. 4 3 ppm.

MS : Calculated for Cl lHz5N (M+) : 161. 3. Found : 162. 3 (M+ + H).

EXAMPLE 2 The general procedure from Example 1 was followed using 4-chlorobenzo- trifluoride (650 mg, 3. 6 mmol) and piperidine (258 mg, 3. 0 mmol) with Pd2 (dba) 3 (55 mg, 0. 081 mmol) and (Me3C) 2PH (O) (21. 0 mg, 0. 126 mmol) and NaOtBu (432 mg, 4. 5 mmol) in 6. 0 mL of toluene. After 48 h, the reaction mixture was chromatographed with 5% ethyl acetate/hexane to give 161 mg (23% yield) of 4-piperidinobenzotrifluoride. It was >95% pure by IH NMR and GC/MS. 1H NMR (500 MHz, CDC13) : 8 7. 36 (d, J = 8. 78 Hz, 2H), 6. 82 (d, J = 8. 79 Hz, 2H), 3. 18 (m, 4H), 1. 60 (m, 4H), 1. 54 (m, 2H) ppm. 13C NMR (125 MHz, CDC13) : d 153. 7, 127. 6, 126. 3, 114. 5, 49. 2, 25. 4, 24. 2 ppm. MS : Calculated for C12Hl4F3N (M+) : 229. 1. Found : 230. 2 (M+ + H).

EXAMPLE 3 The general procedure from Example 1 was followed using chlorobenzene (135 mg, 1. 2 mmol) and aniline (93 mg, 1. 0 mmol) with Pd2 (dba) 3 (25 mg, 0. 027 mmol) and (Me3C) 2PH (O) (7. 0 mg, 0. 042 mmol) and NaOtBu (144 mg, 1. 5 mmol) in 2. 0 mL of toluene. After 24 h, the reaction mixture was chromatographed with 5% ethyl acetate/hexane to give 51 mg (30% yield) of diphenylamine. It was >95% pure by 1H NMR and GC/MS. 1H NMR (500 MHz, CDC13) : 8 7. 18 (m, 4H), 6. 99 (d, J = 7. 68 Hz, 4H), 6. 84 (t, J = 7. 34 Hz, 2H), 5. 59 (br, 1H) ppm. 13C NMR (125 MHz, CDC13) : d 143. 1, 129. 3, 120. 9, 117. 8 ppm.

MS : Calculated for Cl2HllN (M+) : 169. 1. Found : 170. 3 (M+ + H).

EXAMPLE 4 The general procedure from Example 1 was followed using chlorobenzene (135 mg, 1. 2 mmol) and piperidine (86 mg, 1. 0 mmol) with Pd2 (dba) 3 (20 mg, 0. 0218 mmol) and (Me2CH) PH (O) (Ph) from Experiment 1, (7. 1 mg, 0. 0424 mmol) and NaOtBu (144 mg, 1. 5 mmol) in 2. 0 mL of 1, 2-dimethoxyethane. After 5 h, the reaction mixture was chromatographed with 5% ethyl acetate/hexane to give 17 mg (11% yield) of 4-phenylpiperidine. It was >95% pure by 1H NMR and GC/MS. 1H NMR (500 MHz, CDC13) : 8 7. 15 (m, 2H), 6. 84 (m, 2H), 6. 72 (m, 1H), 3. 06 (t, J =

5. 48 Hz, 4H), 1. 61 (m, 4H), 1. 48 (m, 2H) ppm. 13C NMR (125 MHz, CDC13) : 8 152. 3, 129. 0, 119. 2, 116. 5, 50. 7, 25. 9, 24. 4 3 ppm. MS : Calculated for CHi5N (M+) : 161. 3. Found : 162. 3 (M++H).

EXAMPLE 5 The general procedure from Example 1 was followed using 4-methyl- chlorobenzene (152 mg, 1. 2 mmol) and piperidine (100 ul, 1. 0 mmol) with Pd2 (dba) 3 (20 mg, 0. 0218 mmol) and (Me3C) 2PH (O) (14. 5 mg, 0. 0878 mmol) and NaOtBu (144 mg, 1. 5 mmol) in 3. 0 mL of toluene. After 12 h, the reaction mixture was chromatographed with 5% ethyl acetate/hexane to give 106 mg (61% yield) of N- (4-methylphenyl) piperidine. It was >95% pure by 1H NMR and GC/MS. 1H NMR (500 MHz, CDC13) : 8 6. 92 (d, J = 8. 4 Hz, 2H), 6. 72 (d, J = 8. 5 Hz, 2H), 2. 95 (t, J = 5. 5 Hz, 4H), 2. 13 (s, 3H), 1. 58 (m, 4H), 1. 43 (m, 2H) ppm. 13C NMR (125 MHz, CDC13) : 6 150. 3, 129. 5, 128. 6, 116. 9, 51. 2, 25. 9, 24. 3, 20. 3 ppm. MS : Calculated for C12Hl7N (M+) : 175. 1. Found : 176. 1 (M+ + H).

EXAMPLE 6 The general procedure from Example 1 was followed using PhCl (122 p1, 1. 2 mmol) andp-toluidine (108 mg, 1. 0 mmol) with Pd2 (dba) 3 (20 mg, 0. 0218 mmol) and (Me3C) 2PH (O) (14. 5 mg, 0. 0878 mmol) and NaOtBu (144 mg, 1. 5 mmol) in 3. 0 mL of toluene. After 12 h, the reaction mixture was chromatographed with 5% ethyl acetate/hexane to give 80 mg (44% yield) of N-phenyl-p-toluidine. It was >95% pure by 1H NMR and GC/MS. 1H NMR (500 MHz, CDC13) : 8 7. 13 (t, J = 7. 91 Hz, 2H), 6. 98 (m, 2H), 6. 89 (m, 4H), 6. 78 (t, J = 7. 32 Hz, 1H), 5. 46 (s, br. 1H), 2. 20 (s, 3H) ppm. 13C NMR (125 MHz, CDC13) : d 143. 9, 140. 3, 130. 8, 129. 8, 129. 2, 120. 2, 118. 9, 116. 8, 20. 6 ppm. MS : Calculated forCz3Hl3N (M+) : 183. 3. Found : 184. 1 (M++H).

EXAMPLE 7 The general procedure from Example 1 was followed using 4-chloroanisole (171 mg, 1. 2 mmol) and piperidine (100 nl, 1. 0 mmol) with Pd2 (dba) 3 (20 mg, 0. 0218 mmol) and (Me3C) 2PH (O) (14. 5 mg, 0. 0878 mmol) and NaOtBu (144 mg, 1. 5 mmol) in 4. 0 mL of toluene. After 12 h, the reaction mixture was chromatographed with 5% ethyl acetate/hexane to give 128 mg (67% yield) of N- (4- methoxyphenyl) piperidine. It was >95% pure by 1H NMR and GC/MS. 1H NMR (500 MHz, CDC13) : 8 6. 81 (d, J = 9. 11 Hz, 2H), 6. 72 (d, J = 9. 11 Hz, 2H), 3. 65 (s, 3H), 2. 92 (t, J = 5. 46 Hz, 4H), 1. 60 (m, 4H), 1. 46 (m, 2H) ppm. 13C NMR (125 MHz, CDC13) : 8 153. 5, 146. 8, 118. 6, 114. 3, 55. 4, 52. 2, 26. 1, 24. 1 ppm.

EXAMPLE 8 In the drybox, 20. 0 mg (0. 087 mmol) of (Me2CH) PH (O) (2, 4-(MeO) 2C6H3) from Experiment 3, 20. 0 mg (0. 0218 mmol) of Pd2 (dba) 3 and 3. 0 mL of dioxane were loaded into a reactor (20 mL) equipped with a magnetic stir bar. The resulting mixture was stirred at room temperature for 10 min. Next, 144 mg (1. 5 mmol) of NaOtBu was added into the mixture above, followed by syringing 122 pl (1. 2 mmol) of PhCl, and 100 p1 (1. 0 mmol) of piperidine into the reactor. The resulting mixture was refluxed for 8 h. The reaction mixture was then cooled to room temperature, chromatographed on silicon gel using ethyl acetate/hexane (5% volume ratio) as eluant. The eluate was concentrated by rotary evaporation followed by high vacuum to yield 59 mg (37% yield) of 1-phenylpiperidine. It was >95% pure by IH NMR and GC/MS. 1H NMR (500 MHz, CDCI3) : 6 7. 15 (m, 2H), 6. 84 (m, 2H), 6. 72 (m, 1H), 3. 06 (t, J = 5. 48 Hz, 4H), 1. 61 (m, 4H), 1. 48 (m, 2H) ppm.

13C NMR (125 MHz, CDCl3) : 8 152. 3, 129. 0, 119. 2, 116. 5, 50. 7, 25. 9, 24. 4 3 ppm.

MS : CalcdforC1lHl5N (M+) : 161. 3. Found : 162. 3 (M++H).

The results of Examples 1-8 are summarized in Table 1 below.

TABLE 1 Example Phosphine oxide Aryl compoud Amine Product Yield 1 (Me3C)2PH(O) chlorobenzene piperidine 1-phenylpiperidine 51% 2 (Me3C)2PH(O) 4-chlorobenzotrifluoride piperidine 4-piperidinobenzotrifluoride 23% 3 (Me3C)2PH(O) chlorobenzene aniline diphenylamine 30% 4 (Me2CH)PH(O)(Ph) chlorobenzene piperidine N-phenylpiperidine 11% 5 (Me3C)2PH(O) 4-methylchlorobenzene piperidine N(4-methylphenyl)piperidine 61% 6 (Me3C)2PH(O) chlorobenzene p-toluidine N-phenyl-p-toluidine 44% 7 (Me3C)2PH(O) 4-chloroanisole piperidine N-(4-methoyphenyl)piperidine 67% 8 (Me2CH)PH(O)(2,4-(MeO)2C6H3) chlorobenzene piperidine 1-phenylpiperidine 37% 21

B. Reactions of Arylboronic Acids with Arvl Halides EXAMPLE 9 In the drybox, 14. 4 mg (0. 087 mmol) of (Me3C) 2PH (O) from Experiment 2, 20. 0 mg (0. 0218 mmol) of Pd2 (dba) 3 and 4. 0 mL of 1, 4-dioxane were loaded into a reactor (20 mL) equipped with a magnetic stir bar. The resulting mixture was stirred at room temperature overnight. Next, 651 mg (2. 0 mmol) of CsCO3 and 146. 3 mg (1. 2 mm) of PhB (OH) 2 were added into the mixture above, followed by syringing 122 ul (1. 2 mmol) of PhC1 into the reactor. The resulting mixture was refluxed for 24 h. The reaction mixture was then cooled to room temperature, chromatographed on silicon gel using ethyl acetate/hexane (5% volume ratio) as eluant. The eluate was concentrated by rotary evaporation followed by high vacuum to yield 163 mg (88% yield) of biphenyl. It was >95% pure by 1H NMR and GC/MS. IH NMR (500 MHz, CDC13) : 6 7. 77 (d, J = 7. 75 Hz, 4H), 7. 60 (t, J = 7. 65 Hz, 4H), 7. 50 (t, J = 7. 38 Hz, 2H). ppm. 13C NMR (125 MHz, CDC13) : õ 141. 2, 128. 7, 127. 2, 127. 1 ppm.

EXAMPLE 10 The general procedure from Example 9 was followed using 4-methylchlorobenzene (152 mg, 1. 2 mmol) and PhB (OH) 2 (1. 2 mmol) with Pd2 (dba) 3 (20 mg, 0. 0218 mmol) and (Me3C) 2PH (O) from Experiment 2 (14. 5 mg, 0. 0878 mmol) and CsCO3 (651 mg, 2. 0 mmol) in 4. 0 mL of 1, 4-dioxane. After 24 h, the reaction mixture was chromatographed with 5% ethyl acetate/hexane to give 127 mg (63% yield) of 4-phenyltoluene. It was >95% pure by IH NMR and GC/MS. 1H NMR (500 MHz, CDC13) : 8 7. 74 (d, J = 7. 50 Hz, 2H), 7. 65 (d, J = 8. 05 Hz, 2H), 7. 57 (m, 2H), 7. 47 (m, 1H), 7. 40 (m, 2H), 2. 54 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3) : 8 141. 1, 138. 3, 136. 9, 129. 4, 128. 6, 126. 9, 126. 8, 21. 0 ppm.

EXAMPLE 11 The general procedure above was followed using 4-methylchlorobenzene (127 mg, 1. 0 mmol) and PhB (OH) 2 (183 mg, 1. 5 mmol) with Pd2 (dba) 3 (20 mg, 0. 0218 mmol) and PhPH (O) (CHMe2) from Experiment 1 (14. 7 mg, 0. 0874 mmol) and CsF (456 mg, 3. 0 mmol) in 4. 0 mL of 1, 4-dioxane. After 12 h, the reaction mixture was chromatographed with 5% ethyl acetate/hexane to give 52 mg (31% yield) of 4-phenyltoluene. It was >95% pure by IH NMR and GC/MS.

EXAMPLE 12 In the drybox, 9. 6 mg (0. 058 mmol) of (Me3C) 2PH (O) from Experiment 2, 13. 3 mg (0. 0145 mmol) of Pd2 (dba) 3 and 3. 0 mL of 1, 4-dioxane were loaded into a reactor (20 mL) equipped with a magnetic stir bar. The resulting mixture was

stirred at room temperature overnight. Next, 143. 0 mg (1. 0 mm) of 4-chloroanisole, 182. 9 mg (1. 5 mm) of PhB (OH) 2 and 456 mg (3. 0 mmol) of CsF were added into the reactor. The resulting mixture was refluxed for 24 h. The reaction mixture was then cooled to room temperature, chromatographed on silicon gel using ethyl acetate/hexane (5% volume ratio) as eluant. The eluate was concentrated by rotary evaporation followed by high vacuum to yield 179 mg (97% yield) of 4-phenylanisole. It was >95% pure by IH NMR and GC/MS. 1H NMR (500 MHz, CDCl3) : 8 7. 45 (m, 4H), 7. 32 (m, 2H), 7. 21 (m, 1H), 6. 88 (d, J = 8. 72 Hz, 2H), 3. 74 (s, 3H) ppm. 13C NMR (125 MHz, CDC13) : 6 159. 2, 140. 8, 133. 8, 128. 7, 128. 1, 126. 7, 126. 6, 114. 2, 55. 3 ppm.

EXAMPLE 13 The general procedure from Example 12 was followed using 2-chloroanisole (143 mg, 1. 0 mmol) and 4-MeC6H4B (OH) 2 (204 mg, 1. 5 mmol) with Pd2 (dba) 3 (13. 3 mg, 0. 0145 mmol) and (Me3C) 2PH (O) from Experiment 2 (9. 6 mg, 0. 058 mmol) and CsF (456 mg, 3. 0 mmol) in 4. 0 mL of 1, 4-dioxane.

After 24 h, the reaction mixture was chromatographed with 5% ethyl acetate/hexane to give 165 mg (83% yield) of 2- (4-methylphenyl) anisole. It was >95% pure by IH NMR and GC/MS. IH NMR (500 MHz, CDCl3) : 6 7. 32 (d, J = 8. 06 Hz, 2H), 7. 18 (m, 2H), 7. 10 (d, J = 7. 88 Hz, 2H), 6. 92-6. 84 (m, 2H), 3. 67 (s, 3H), 2. 28 (s, 3H) ppm. 13C NMR (125 MHz, CDCI3) : 6 156. 5, 136. 5, 135. 6, 130. 7, 129. 4, 128. 7, 128. 3, 120. 8, 111. 2, 55. 5, 21. 1 ppm.

EXAMPLE 14 The general procedure from Example 12 was followed using 4-chloro- anisole (143 mg, 1. 0 mmol) and 4-MeOC6H4B (OH) 2 (228 mg, 1. 5 mmol) with Pd2 (dba) 3 (13. 3 mg, 0. 0145 mmol) and (Me3C) 2PH (O) from Experiment 2 (9. 6 mg, 0. 058 mmol) and CsF (456 mg, 3. 0 mmol) in 3. 0 mL of 1, 4-dioxane.

After 24 h, the reaction mixture was chromatographed with 5% ethyl acetate/hexane to give 213 mg (99% yield) of 4- (4-methoxyphenyl) anisole. It was >95% pure by IH NMR and GC/MS. 1H NMR (500 MHz, CDC13) : 6 7. 38 (d, J = 8. 68 Hz, 4H), 6. 86 (d, J = 8. 68 Hz, 4H), 3. 74 (s, 6H) ppm. 13C NMR (125 MHz, CDC13) : S 158. 7, 133. 5, 127. 7, 114. 2, 55. 3 ppm.

EXAMPLE 15 In the drybox, 20. 0 mg (0. 0876 mmol) of (Me2CH) PH (0) (2, 4- (MeO) 2C6H3) from Experiment 3, 20 mg (0. 0218 mm) of Pd2 (dba) 3 and 5. 0 mL of 1, 4-dioxane were loaded into a reactor (20 ml) equipped with a magnetic stir bar. The resulting mixture was stirred at room temperature overnight. Next, 143. 0 mg (1. 0 mm) of 4-chloroanisole, 228 mg (1. 5 mm) of 4-MeOC6H4B (OH) 2

and 456 mg (3. 0 mmol) of CsF were added into the reactor. The resulting mixture was refluxed for 60 h. The reaction mixture was then cooled to room temperature, chromatographed on silicon gel using ethyl acetate/hexane (5% volume ratio) as eluant. The eluate was concentrated by rotary evaporation followed by high vacuum to yield 213 mg (99% yield) ofp- (4-methoxyphenyl) anisole. It was >95% pure by IH NMR and GC/MS. 1H NMR (500 MHz, CDC13) : 6 7. 38 (d, J = 8. 68 Hz, 4H), 6. 86 (d, J = 8. 68 Hz, 4H), 3. 74 (s, 6H) ppm. 13C NMR (125 MHz, CDC13) : 6 158. 7, 133. 5, 127. 7, 114. 2, 55. 3 ppm. Anal Calcd for C14H14O2: C, 78. 48 ; H, 6. 59. Found : C, 78. 44 ; H, 6. 53.

The results of Examples 9-15 are summarized in Table 2 below.

TABLE 2 Example Phosphine oxide Aryl compound Acid product Yield 9 (Me3C)2PH(O) chlorobenzene hB(OH)2 biphenyl 88% 10 (Me3C)2PH(O) 4-methylchlorobenzene PhB(OH)2 4-phenyltoluene 63% 11 PhPH(O)(CHMe2) 4-methylchlorobenzen PhB(OH)2 4-phenyltoluene 31% 12 (Me3C)2PH(O) 4-chloroanisole PhB(OH)2 4-phenylanisole 97% 13 (Me3C)2PH(O) 2-chloroanisole 4-MeC6H4B(OH)2 2-(4-methylphenyl)- 83% anisole 14 (Me3C)2PH(O) 4-chloroanisole 4-MeOC6H4B(OH)2 4-(4-methoxyphenyl)- 99% anisole 15 (Me2CH)PH(O)(2,4-(MeO)2C6H3) 4-chloroanisole 4-MeOC6H4B(OH)2 4-(4-methoxyphenyl)- 99% anisole

EXAMPLE 16 In a drybox, 50 mg (0. 303 mmol) of (Me3C) 2PH (O) from Experiment 2, 83. 4 mg (0. 303 mmol) of Ni (COD) 2 (COD = 1, 5-cyclooctadiene) and 5. 0 mL of THF were loaded into a reactor (100 mL) equipped with a magnetic stir bar. The resulting mixture was stirred at room temperature over 10 min. Next, 1. 43 g (10. 0 mmol) of 4-chloroanisole was added into the mixture above, followed by adding 15 ml (15. Ommol, 1. 0 M solution in THF) of o-tolylmagnesium chloride, and 15 mL of THF into the reactor. The resulting mixture was stirred at room temperature for 15 h. before the reaction mixture was quenched with 10 mL of H2O. The mixture above was extracted with 3 X 50 mL of diethyl ether. The combined ether extracts were dried over MgS04, filtered, and the ether and THF removed from the filtrate by rotary evaporation. The resulting residues were chromatographed on silicon gel using ethyl acetate/hexane (5% volume ratio) as eluant. The eluate was concentrated by rotary evaporation followed by high vacuum to yield 1. 85 g (93% yield) of 4-o-tolylanisole. It was >95% pure by IH NMR. 1H NMR (500 MHz, CDC13) : 8 7. 47-7. 19 (m, 8H), 4. 03 (s, 3H), 2. 53 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3) : 6 158. 5, 141. 5, 135. 3, 134. 3, 130. 2, 130. 1, 129. 8, 126. 8, 125. 7, 113. 4, 55. 0, 20. 4. ppm.

EXAMPLE 17 The general procedure from Example 16 was followed using chlorobenzene (1. 126 g, 10. 0 mmol) and o-tolylmagnesium chloride (15 mL, 15. 0 mmol) with Ni (COD) 2 (83. 4 mg, 0. 303 mmol) and (Me3C) 2PH (O) (50. 0 mg, 0. 303 mmol) in 20. 0 mL of THF. After 15 h at room temperature, the reaction mixture was quenched with 10 mL of H2O. The mixture above was extracted with 3 X 50 mL of diethyl ether. The combined ether extracts were dried over MgSO4, filtered, and the ether and THF removed from the filtrate by rotary evaporation. The resulting residues were chromatographed on silicon gel using ethyl acetate/hexane (5% volume ratio) as eluant. The eluate was concentrated by rotary evaporation followed by high vacuum to yield 1. 62 g (96% yield) of 2-phenyltoluene. It was >95% pure by IH NMR. 1H NMR (500 MHz, CDC13) : 8 7. 62-7. 47 (m, 9H), 2. 50 (s, 3H) ppm. 13C NMR (125 MHz, CDC13) : 8 142. 0, 141. 9, 135. 2, 130. 3, 129. 7, 129. 1, 128. 0, 127. 2, 126. 7, 125. 7, 20. 4. ppm.