AU716306B2 - Aryl borates - Google Patents

Description

PCT/AU98/00245 P:\OPER\PDB\ARYLIV.PRV -7/499 Received 07 April 1999 -1- Aryl Borates This invention relates to a process for covalently coupling organic compounds, in particular to a process for covalently linking aromatic ring compounds via an organoboron intermediate to other organic compounds. The invention also relates to a process for the preparation of the organoboron intermediates.

Processes for forming covalent bonds between aromatic ring compounds and organic compounds, both inter- and intra-molecular, are of particular importance to the synthetic organic chemist. Many such reactions are known, each requiring its own special reaction conditions, solvents, catalysts, ring activating groups etc. Some known types of coupling reactions which can involve aromatic ring compounds include the Grignard reaction, Heck reactions and Suzuki reactions Miyaura and A. Suzuki, Chem. Rev. 1995, 2457-2483).

Catalysts of palladium, its complexes and its salts are well recognised for activation of C- H bonds towards coupling reactions. In this regard the Heck reaction of an aryl halide with an aryl or vinyl halide in the presence of palladium derivatives has been the subject of intensive study. However commercial development of the Heck reaction has not progressed as rapidly as could have been expected.

Substituted bi- and tri-aryl compounds are of great interest to the pharmaceutical and agrochemical industries. A great number of these compounds have been found to possess pharmaceutical activity, while others have been found to be useful herbicides. There is also interest from the polymer industry in polymers prepared by the linking together of aromatic ring compounds.

Conventional methods for covalently linking aromatic rings, such as by reaction of an appropriate Grignard reagent, involve harsh conditions and are not suitable for aromatic AMENDED SHEET (Article 34) (IPEA/AU) WO 98/45265 PCT/AU98/00245 -2rings with active hydrogen containing substituents. Substituents with active hydrogen atoms also can become involved in unwanted side reactions leading to undesirable products. Such substituents need to be protected prior to reaction. Boronic acid derivatives required for the Suzuki reaction are traditionally synthesized through highly reactive organo metallic intermediates.

In view of the severity of the reaction conditions the range of substituents which could be present during the linking reaction was considerably limited, and the range of useful reaction media (solvents) was restricted to those which are generally expensive, difficult to remove and/or toxic.

Other difficulties associated with the known coupling reactions are the high temperatures required and the lack of control of the functionality of the products, leading to complex mixtures which can be difficult to separate.

It has now been found that coupling of aromatic ring compounds to other organic compounds can be achieved via an arylboron intermediate in the presence of a Group VIII metal catalyst and a suitable base.

Accordingly the invention provides a process for covalently coupling organic compounds which comprises reacting an aromatic ring compound having a halogen or halogen-like substituent at a ring coupling position with a diboron derivative in the presence of a Group VIII metal catalyst and a suitable base.

In one embodiment this process may be used to prepare a symmetrical product by reacting the diboron derivative with about two equivalents of aromatic ring compound. In this embodiment the coupling proceeds in two steps. In the first step the diboron derivative reacts with about one equivalent of aromatic ring compound in the presence of the Group VIII metal catalyst and suitable base to form an arylboron intermediate, which intermediate reacts in the presence of base with the remaining equivalent of aromatic ring WO 98/45265 PCT/AU98/00245 -3compound. According to this embodiment the covalent coupling comprises a covalent bond between ring coupling positions of two molecules of aromatic ring compound.

Preferably the suitable base used to catalyse the reaction with the boron derivative is also able to catalyse the coupling of the arylboron intermediate to the remaining aromatic compound. However, if necessary, a stronger base can be added after the formation of the arylboron intermediate to catalyse the coupling reaction.

The process according to the invention also allows the preparation of unsymmetrical products. Accordingly in another embodiment of the invention there is provided a process for covalently coupling organic compounds which comprises: reacting an aromatic ring compound having a halogen or halogen-like substituent at a ring coupling position with a diboron derivative in the presence of a Group VIII catalyst and a suitable base to form an arylboron intermediate, and reacting the arylboron intermediate with an organic compound having a halogen or halogen-like substituent at a coupling position in the presence of a Group VIII metal catalyst and a suitable base, whereby the aromatic ring compound is coupled to the organic compound via a direct bond between the respective coupling positions.

The process according to this embodiment allows the preparation of unsymmetrical compounds when the organic compound is different from the aromatic ring compound, although symmetrical products will be obtained if the organic compound is the same as the aromatic ring compound.

It is especially convenient to conduct the process in a single pot without isolation of the arylboron intermediate, however it has been found that the presence of unreacted diboron derivative can interfere with the coupling step, resulting in the formation of unwanted by- WO 98/45265 PCT/AU98/00245 -4products.

Accordingly in another embodiment of the present invention there is provided a process for covalently coupling organic compounds which comprises: reacting an aromatic ring compound having a halogen or halogen-like substituent at a ring coupling position with a diboron derivative in the presence of a Group VIII metal catalyst and a suitable base to form an arylboron intermediate, adding water and a suitable base to decompose excess diboron derivative, reacting the arylboron intermediate with an organic compound having a halogen or halogen-like substituent at a coupling position in the presence of a Group VIII metal catalyst and a suitable base, whereby the aromatic ring compound is coupled to the organic compound via a direct bond between respective coupling positions.

Preferably the reaction is conducted in a single pot, although it is possible to isolate the arylboron intermediate prior to the final coupling step. If the reaction is conducted in a single pot it is preferred that the base added to decompose the diboron derivative is suitable for catalysing the coupling reaction. In this case there is no need to add further base with the organic compound in the coupling reaction.

In cases where there is a need to remove excess diboron derivative but the use of water and/or base is deleterious because of the sensitivity of substituents, etc, or other factors the excess diboron derivative may be decomposed by addition of mild oxidising agents following the formation of the arylboron intermediate.

Accordingly in a further embodiment there is provided a process for covalently coupling organic compounds which comprises: reacting an aromatic ring compound having a halogen or halogen-like substituent at a ring coupling position with a diboron derivative in the presence of a Group VIII metal catalyst and a suitable base to form an arylboron intermediate; adding a mild oxidising agent to decompose excess diboron derivative; reacting the arylboron intermediate with an organic compound having a halogen or halogen-like substituent at a coupling position in the presence of a Group VIII metal catalyst and a suitable base whereby the aromatic ring compound is coupled 10 to the organic compound via a direct bond between respective coupling positions.

The mild oxidising agent may be any compound which will break the B-B bond of the diboron derivative but which is not strong enough to break boron-carbon bonds of the arylboron intermediate. Suitable mild oxidising agents are N-chlorosuccinimide, dimethyl 15 dioxirane, dioxygen gas, chloramine-T, chloramine-B, 1-chlorotriazole, 1,3-dichloro- 5,5-dimethylhydantoin, trichloroisocyanuric acid and dichloroisocyanuric acid potassium salt.

Oxidants such as hydrogen peroxide, ozone, bromine, t-butyl hydroperoxide, potassium persulphate, sodium hypochlorite and peracids, are too strong for use in this process; use of strong oxidants does not form part of this invention.

The term "aromatic ring compound(s)" as used herein refers to any compound which includes or consists of one or more aromatic or pseudoaromatic rings. The rings may be carbocyclic or heterocyclic, and may be mono or polycyclic ring systems. Examples of suitable rings include but are not limited to benzene, biphenyl, terphenyl, quaterphenyl, naphthalene, tetrahydronaphthalene, 1-benzylnaphthalene, anthracene, dihydroanthracene, benzanthracene, dibenzanthracene, phenanthracene, perylene, pyridine, 4-phenylpyridine, 3-phenylpyridine, thiophene, benzothiophene, naphthothiophene, thianthrene, furan, 7 pyrene, isobenzofuram, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, indole, indolizine, isoindole, purine, quinoline, isoquinoline, phthalazine, quinoxaline, quinazoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, phenazine, isothiazole, isooxazole, phenoxazine and the like, each of which may be optionally substituted. The term "aromatic ring compound(s)" includes molecules, and macromolecules, such as polymers, copolymers and dendrimers which include or consist of one or more aromatic or pseudoaromatic rings.

The term "pseudoaromatic" refers to a ring system which is not strictly aromatic, but which is stablized by means of delocalization of r electrons and behaves in a similar manner to aromatic rings. Examples of pseudoaromatic rings include but are not limited 10 to furan, thiophene, pyrrole and the like.

As used herein the term "organic compound having a halogen or halogen-like substituent at a coupling position" refers to any organic compound having a carbon to halogen or carbon to halogen-like substituent bond at a position where coupling to the aromatic ring 15 compound is desired. The organic compound may be aliphatic, olefinic, aromatic, polymeric or dendritic. The compound may be an aromatic ring compound as defined above or part of such an aromatic ring compound. The organic compound may have one or more, preferably between 1 and 6, halogen or halogen-like substituents at coupling positions.

The terms "olefinic" and "olefinic compound" as used herein refer to any organic compound having at least one carbon to carbon double bond which is not part of an aromatic or pseudo aromatic system. The olefinic compounds may be selected from optionally substituted straight chain, branched or cyclic alkenes; and molecules, monomers and macromolecules such as polymers and dendrimers, which include at least one carbon to carbon double bond. Examples of suitable olefinic compounds include but are not limited to ethylene, propylene, but-l-ene, but-2-ene, pent-l-ene, pent-2-ene, cyclopentene, 1-methylpent-2-ene, hex-1-ene, hex-2-ene, hex-3-ene, cyclohexene, hept-1ene, hept-2-ene, hept-3-ene, oct-l-ene, oct-2-ene, cyclooctene, non-l-ene, non-4-ene, dec- ^al3-ene, dec-3-ene, buta-1,3-diene, penta-1,4-diene, cyclopenta-1,4-diene, hex-1,4-diene, -7cyclohexa-1,3-diene, cyclohexa-1,4-diene, cyclohepta-1,3,5-triene and cycloocta-1,3,5,7tetraene, each of which may be optionally substituted. Preferably the straight chain branched or cyclic alkene contains between 2 and 20 carbon atoms.

In one embodiment the organic compound is an olefinic compound of formula I C C R2

X

where R, R 2 and R 3 are each independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, acyl, arylalkyl and heteroaryalkyl, each of which may be optionally substituted: and cyano, isocyano, formyl, carboxyl, nitro, halo, alkoxy, alkenoxy, aryloxy, benzyloxy, haloalkoxy, haloalkenyloxy, haloaryloxy, nitroalkyl, nitroalkenyl, nitroalkynyl, arylamino, diarylamino, dibenzylamino, alkenylacyl, alkynylacyl, arylacyl, "i *acylamino, diacylamino, acyloxy, alkylsulphonyloxy, arylsulphenyloxy, heterocycloxy, arylsulphenyl, carboalkoxy, carboaryloxy, alkylthio, benzylthio, acylthio, sulphonamide, sulfanyl, sulfo, carboxy (including carboxylato), carbamoyl, carboximidyl, sulfinyl, sulfinimidyl, sulfinohydroximyl, sulfonimidyl, sulfondiimidyl, sulfonohydroximyl, sulfamyl, phosphorous containing groups (including phosphinyl, phosphinimidyl, phosphonyl, dihydroxyphosphanyl, hydroxyphosphanyl, phosphone (including phosphonato) and hydrohydroxyphosphoryl), guanidinyl, guanidino, ureido and ureylene, and X is a halogen or halogen-like substituent.

The term "coupling position" as used herein refers to a position on an aromatic ring compound at which coupling to an organic compound is desired. A coupling position on a ring of an aromatic ring compound is also referred to as a "ring coupling position". The term "coupling position" also refers to a position on an organic compound at which 14coupling to an aromatic ring compound is desired. Each aromatic ring compound or WO 98/45265 PCT/AU98/00245 -8organic compound may have one or more, preferably between 1 and 6, coupling positions.

In this specification "optionally substituted" means that a group may or may not be further substituted with one or more groups selected from alkyl, alkenyl, alkynyl, aryl, halo, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, hydroxy, alkoxy, alkenyloxy, aryloxy, benzyloxy, haloalkoxy, haloalkenyloxy, haloaryloxy, isocyano, cyano, formyl, carboxyl, nitro, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroaryl, nitroheterocyclyl, amino, alkylamino, dialkylamino, alkenylamino, alkynylamino, arylamino, diarylamino, benzylamino, imino, alkylimine, alkenylimine, alkynylimino, arylimino, benzylimino, dibenzylamino, acyl, alkenylacyl, alkynylacyl, arylacyl, acylamino, diacylamino, acyloxy, alkylsulphonyloxy, arylsulphenyloxy, heterocyclyl, heterocycloxy, heterocyclamino, haloheterocyclyl, alkylsulphenyl, arylsulphenyl, carboalkoxy, carboaryloxy mercapto, alkylthio, benzylthio, acylthio, sulphonamido, sulfanyl, sulfo and phosphorus-containing groups, alkoxysilyl, silyl, alkylsilyl, alkylalkoxysilyl, phenoxysilyl, alkylphenoxysilyl, alkoxyphenoxy silyl and arylphenoxy silyl.

The aromatic ring compound must include at least one halogen or halogen-like substituent at a ring coupling position to enable reaction with the diboron derivative. Similarly the organic compound must have at least one halogen or halogen-like substituent at a coupling position to enable reaction with the arylboron intermediate. Preferred halogen substituents include I and Br. Cl may also be used although Cl is generally less reactive to substitution by the boron derivative or aryl boron intermediate. The reactivity of chloro substituted aromatic ring compounds can be increased by selection of appropriate ligands on the Group VIII metal catalyst. The terms "halogen-like substituent" and "pseudohalide" refer to any substituent which, if present on an aromatic ring, may undergo substitution with a diboron derivative in the presence of a Group VIII metal catalyst and base to give an arylboron intermediate, or if present on an organic compound may undergo substitution with an arylboron intermediate to give a coupled product. Examples of halogen-like substituents include triflates and mesylates, diazonium salts, phosphates and those described in Palladium Reagents Catalysts (Innovations in Organic Synthesis WO 98/45265 PCT/AU98/00245 -9by J. Tsuji, John Wiley Sons, 1995, ISBN 0-471-95483-7).

The process according to the invention is especially suitable for coupling aromatic ring compounds which have active hydrogen containing substituents on the aromatic ring(s) to be coupled. The term "active hydrogen containing substituent" as used herein refers to a substituent which contains a reactive hydrogen atom. Examples of such substituents include but are not limited to hydroxy, amino, imino, acetyleno, carboxy (including carboxylato), carbamoyl, carboximidyl, sulfo, sulfinyl, sulfinimidyl, sulfinohydroximyl, sulfonimidyl, sulfondiimidyl, sulfonohydroximyl, sultamyl, phosphinyl, phosphinimidyl, phosphonyl, dihydroxyphosphanyl, hydroxyphosphanyl, phosphono (including phosphonato), hydrohydroxyphosphoryl, allophanyl, guanidino, hydantoyl, ureido, and ureylene. Of these substituents it is particularly surprising that the reaction can be conducted with hydroxy and amino substituents in view of their high reactivity. Carboxyl, sulfo and the like acidic) substituents may require additional base.

In the above definitions, the term "alkyl", used either alone or in compound words such as "alkenyloxyalkyl", "alkylthio", "alkylamino" and "dialkylamino" denotes straight chain, branched or cyclic alkyl, preferably C1- 2 0 alkyl or cycloalkyl. Examples of straight chain and branched alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isoamyl, sec-amyl, 1,2-dimethylpropyl, 1,1-dimethyl-propyl, hexyl, 4methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2,trimethylpropyl, 1,1,2-trimethylpropyl, heptyl, 5-methoxyhexyl, 1-methylhexyl, 2,2dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1,2-dimethylpentyl, 1,3dimethylpentyl, 1,4-dimethyl-pentyl, 1,2,3,-trimethylbutyl, 1,1,2-trimethylbutyl, 1,1,3trimethylbutyl, octyl, 6-methylheptyl, 1-methylheptyl, 1,1,3,3-tetramethylbutyl, nonyl, 1- 6- or 7-methyl-octyl, 4- or 5-ethylheptyl, 2- or 3propylhexyl, decyl, 7- and 8-methylnonyl, 5- or 6ethyloctyl, 3- or 4-propylheptyl, undecyl, 8- or 9methyldecyl, 6- or 7-ethylnonyl, 4- or 5-propylocytl, 2- WO 98/45265 PCT/AU98/00245 or 3-butylheptyl, 1-pentylhexyl, dodecyl, 9- or methylundecyl, 7- or 8-ethyldecyl, 5- or 6propylnonyl, 3- or 4-butyloctyl, 1-2-pentylheptyl and the like. Examples of cyclic alkyl include mono- or polycyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.

The term "alkoxy" denotes straight chain or branched alkoxy, preferably C1- 2 0 alkoxy.

Examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy and the different butoxy isomers.

The term "alkenyl" denotes groups formed from straight chain, branched or cyclic alkenes including ethylenically mono-, di- or poly-unsaturated alkyl or cycloalkyl groups as previously defined, preferably C 2 2 0 alkenyl. Examples of alkenyl include vinyl, allyl, 1methylvinyl, butenyl, iso-butenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl, 1methyl-cyclopentenyl, 1-hexenyl, 3-hexenyl, cyclohexenyl, 1-heptenyl, 3-heptenyl, 1octenyl, cyclooctenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3-decenyl, 1,3butadienyl, 1-4,pentadienyl, 1,3-cyclopentadienyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,3cyclohexadienyl, 1,4-cyclohexadienyl, I ,3-cycloheptadienyl, 1,3,5-cycloheptatrienyl and 1,3,5,7-cyclooctatetraenyl.

The term "alkynyl" denotes groups formed from straight chain, branched or cyclic alkyne including alkyl and cycloalkyl groups as previously defined which contain a triple bond, preferably C 2 20 alkynyl. Examples of alkynyl include ethynyl, 2,3-propynyl and 2,3- or 3,4-butynyl.

The term "acyl" either alone or in compound words such as "acyloxy", "acylthio", "acylamino" or "diacylamino" denotes carbanioyl, aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl or a heterocyclic ring which is referred to as heterocyclic acyl, preferably C1- 20 acyl. Examples of acyl include carbamoyl; straight chain or branched alkanoyl such as formyl, acetyl, propanoyl, WO 98/45265 WO 9845265PCT/AU98/00245 -11 Ibutanoyl, 2-methyipropanoyl, pentanoyl, 2, 2-dimethyipropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl and icosanoyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, tpentyloxycarbonyl and heptyloxycarbonyl; cycloalkylcarbonyl such as cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl and cyclohexylcarbonyl; alkylsulfonyl such as methylsulfonyl and ethylsulfonyl; alkoxysulfonyl such as methoxysulfonyl and ethoxysulfonyl; aroyl such as benzoyl, toluoyl and naphthoyl; aralkanoyl such as phenylalkanoyl phenylacetyl, phenyipropanoyl, phenylbutanoyl, phenylisobutylyl, phenylpentanoyl and phenyihexanoyl) and naphthylalkanoyl (e.g.

naphthylacetyl, naphthylpropanoyl and naphthylbutanoyl; aralkenoyl such as phenylalkenoyl phenyipropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl and phenyihexenoyl and naphthylalkenoyl naphthylpropenoyl, naphthylbutenoyl and naphthylpentenoyl); aralkoxycarbonyl such as phenylalkoxycarbonyl benzyloxycarbonyl); aryloxycarbonyl such as phenoxycarbonyl and napthyloxycarbonyl; aryloxyalkanoyl such as phenoxyacetyl and phenoxypropionyl; arylcarbamoyl such as phenylcarbamoyl; aryithiocarbamoyl such as phenyithiocarbamoyl; aryiglyoxyloyl such as phenyiglyoxyloyl and naphthylglyoxyloyl; arylsulfonyl such as phenylsulfonyl and napthylsulfonyl; heterocycliccarbonyl; heterocyclicalkanoyl such as thienylacetyl, thienyipropanoyl, thienylbutanoyl, thienylpentanoyl, thienyihexanoyl, thiazolylacetyl, thiadiazolylacetyl and tetrazolylacetyl; heterocyclicalkenoyl such as heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl and heterocyclichexenoyl; and heterocyclicglyoxyloyl such as thiazolyiglyoxyloyl and thienyiglyoxyloyl.

The terms "heterocyclic", "heterocyclyl" and "heterocyci" as used herein on their own or as part of a group such as "heterocyclicalkenoyl", heterocycloxy" or "haloheterocyclyl" refer to aromatic, pseudo-aromatic and non-aromatic rings or ring systems which contain one or more heteroatoms selected from N, S, 0 and P and which may be optionally substituted. Preferably the rings or ring systems have 3 to 20 carbon atoms. The rings or WO 98/45265 PCT/AU98/00245 -12ring systems may be selected from those described above in relation to the definition of "aromatic ring compound(s)".

The term "aryl" as used herein on its own or as part of a group such as "haloaryl" and "aryloxycarbonyl" refers to aromatic and pseudo-aromatic rings or ring systems composed of carbon atoms, optionally together with one or more heteroatoms. Preferably the rings or ring systems have between 3 and 20 carbon atoms. The rings or ring systems may be optionally substituted and may be selected from those described above in relation to the definition of "aromatic ring compound(s)".

The diboron derivative may be an ester or other stable derivative of diboronic acid.

Examples of suitable esters include those of the formula where R is optionally substituted alkyl or optionally substituted aryl or -B(OR) 2 represents a cyclic group of formula /0\ -B R \o/ where R' is optionally substituted alkylene, arylene or other divalent group comprising linked aliphatic or aromatic moieties. Preferred diboron derivatives include the pinacol ester of diboronic acid, bis(ethanediolato)diboron, bis(n-propanediolato)diboron and bis(neopentanediolato)diboron. Some of the diboron derivatives will be more readily amenable to subsequent hydrolysis than others and may allow for the use of milder reaction conditions. Furthermore, judicious choice of the diboron derivative used may facilitate control over the reaction products formed. The diboron ester derivatives may be made following the method of Brotherton et al. Brotherton, A.L. McCloskey, L.L.

Peterson and H. Steinberg, J. Amer. Chem. Soc. 82, 6242 (196); R.J. Brotherton, A.L.

McCloskey, J.L. Boone and H.M. Manasevit, J. Amer. Chem. Soc. 82, 6245 (1960)]. In this process B(NMe) 3 obtained by reaction of BCI 3 with NHMez, is converted to BrB(NMe 2 )z by reaction with a stoichiometric amount of BBr 3 Reduction in refluxing PCT/AU98/00245 P:\OPER\PDB\ARYLIV.PRV-7/4/99 Received 07 April 1999 -13toluene with sodium metal gives the diboron compound [B(NMe)] 2 which, after purification by distillation, can be reacted with the alcohol (for example, pinacol) in the presence of a stoichiometric amount of HCI to give the desired ester product.

Bis(neopentanediolato)diboron is described by Nguyen et al [Nguyen, Lesley, G., Taylor, Marder, Pickett, Clegg, Elsegood, and Norman, Inorganic Chem. 1994, 33, 4623-24]. Other methods for the preparation of the diboron derivatives would be known to those in the art. The diboron derivatives in Examples 1, 2 and 3 are known, but their use in the formation of aryl boron intermediates has not been disclosed.

The term "Group VIII metal catalyst" as used herein refers to a catalyst comprising a metal of Group VIII of the periodic table described in Chemical and Engineering News, 63(5), 27, 1985. Examples of such metals include Ni, Pt and Pd. Preferably the catalyst is a palladium catalyst as described below, although analogous catalysts of other Group VIII metals may also be used. Examples of suitable Ni catalysts include nickel black, Raney nickel, nickel on carbon and nickel clusters.

The palladium catalyst may be a palladium complex. Examples of suitable palladium catalysts include but are not limited to PdC1 2 Pd(OAc) 2 PdCl 2 (dppf)CH 2 Cl 2 Pd(PPh 3 4 Pd(Ph 2

P(CH

2 )PPh) where n is 2 to 4 and related catalysts which are complexes with phosphine ligands, (such as P(o-tolyl) 3 P(i-Pr) 3 P(cyclohexyl) 3 P(o-MeOPh) 3 P(p- MeOPh) 3 dppp, dppb, TDMPP, TTMPP, TMPP, TMSPP and related water soluble phosphines), related ligands (such as triarylarsine, triarylantimony, triarylbismuth), phosphite ligands (such as P(OEt) 3 P(O-p-tolyl) 3 P(O-o-tolyl) 3 and P(O-iPr) 3 and other suitable ligands including those containing P and/or N atoms for co-ordinating to the palladium atoms, (such as for example pyridine, alkyl and aryl substituted pyridines, 2,2'bipyridyl, alkyl substituted 2, 2'-bipyridyl and bulky secondary or tertiary amines), and other simple palladium salts either in the presence or absence of ligands. The palladium catalysts include palladium and palladium complexes supported or tethered on solid Q supports, such as palladium on carbon, as well as palladium black, palladium clusters, AMENDED SHEET (Article 34) (IPEA/AU) WO 98/45265 PCT/AU98/00245 -14palladium clusters containing other metals, and palladium in porous glass described in J.

Li, A. W-H. Mau and C.R. Strauss, Chemical Communications, 1997, p 1 27 5 The same or different palladium catalysts may be used to catalyse different steps in the process. In certain reactions there are advantages in using ligands with altered basicity and/or steric bulk.

The process may be performed in any suitable solvent or solvent mixture. Examples of such solvents include amides of the lower aliphatic carboxylic acids and lower aliphatic secondary amines, DMSO, aromatic hydrocarbons, nitromethane, acetonitrile, benzonitrile, ethers, polyethers, cyclic ethers, lower aromatic ethers, lower alcohols, and their esters with the lower aliphatic carboxylic acids, pyridine, alkylpyridines, cyclic and the lower secondary and tertiary amines, and mixtures thereof, including mixtures with other solvents.

In a preferred embodiment of the invention the process is performed in a protic solvent.

Examples of suitable protic solvents include water and lower alcohols. Most preferably the solvent is water, ethanol, methanol, isopropanol or mixtures thereof with other solvents. Particularly preferred solvents are ethanol and methanol. Strict exclusion of water from the solvents is generally not essential. The addition of further diboron derivative has been found useful when the solvents are not anhydrous.

The temperature at which each step of the process according to the invention is conducted will depend on a number of factors including the desired rate of reaction, solubility and reactivity of the reactants in the selected solvent, boiling point of the solvent, etc. The temperature of the reaction will generally be in the range of -100 to 250°C. In a preferred embodiment the process is performed at a temperature between 0 and 1200C, more preferably between 0 and 80°C, and most preferably between 15 and The term suitable base" as used herein refers to a basic compound which, when present in the reaction mixture, is capable of catalysing, promoting or assisting reaction between PCT/AU98/00245 P:\OPER\PDB\ARYLIV.PRV-7/4/99 Received 07 April 1999 reactants. The base may be suitable for catalysing a single step, or more than one step, depending on the desired outcome of the reaction. For example a base may be chosen which catalyses reaction between the aromatic ring compound and the diboron derivative, but which is not strong enough to catalyse further reaction of aryl boron intermediate with additional aromatic ring compound or other organic compound. In this case a stronger base (and water) may be added to decompose excess diboron derivative, and which may also catalyse reaction of the arylboron intermediate with the organic compound. It is also preferable that a base is chosen which is soluble in the solvent to which it is added.

Examples of bases which are suitable for catalysing the reaction of the aromatic ring compound with the diboron derivative include, aryl and alkyl carboxylates (for example potassium acetate), fluorides, hydroxides and carbonates of Li, Na, K, Rb, Cs, ammonium, alkylammonium, Mg, Ca, Ba; phosphates and arylphosphates of Li, Na, K, Rb and Cs; phosphate esters (eg. C 6 HsOP(O)(ONa)) of Li, Na, K, Rb and Cs; phenoxides of Li, Na, K, Rb and Cs; alkoxides of Li, Na, K, Rb and Cs; and thallium hydroxide. Some of these bases may be used in conjunction with a phase transfer reagent, such as for example tetraalkylammonium salts or the crown ethers.

Examples of bases suitable for catalysing reaction of the aromatic ring compounds with the diboron derivative, without generally catalysing the further reaction of the arylboron intermediate, include aryl and alkyl carboxylates and phosphates of Li, Na, K, Rb, Cs, ammonium and alkylammonium.

Examples of bases suitable for decomposing excess diboron derivative and/or catalysing reaction of the arylboron intermediate include the stronger bases listed above, including caesium carbonate, potassium carbonate and alkali metal hydroxides.

As used herein the term "arylboron intermediate" refers to the product of the Group VIII metal base catalysed reaction between an aromatic ring compound having a halogen or halogen-like substituent at a ring coupling position and a diboron derivative, the product -0 including a carbon- to -boron bond at the ring coupling position.

AMENDED SHEET (Article 34) (IPEA/AU) WO 98/45265 PCT/AU98/00245 -16- In another aspect of the invention there is provided a process for preparing an arylboron intermediate comprising reacting a diboron derivative with an aromatic ring compound having a halogen or halogen-like substituent and an active hydrogen containing substituent in the presence of a Group VIII metal catalyst and a suitable base.

In a further aspect of the invention there is provided a process for preparing an arylboron intermediate, comprising reacting a diboron derivative with an aromatic ring compound having a halogen or halogen-like substituent in a protic solvent in the presence of a Group VIII metal catalyst and a suitable base.

A first step in the purification of the arylboron intermediate so formed may be the decomposition of any excess diboron derivative by the use of water, water and base, or by the use of a mild oxidising agent.

In a further aspect of the invention there is provided a process for the preparation of an aryl boronic acid including hydrogenolysing or hydrolysing the arylboron intermediate as hereinbefore described using established procedures. The ease of hydrolysis/hydrogenolysis is a function of the diboronic ester used. Some aryl boron intermediates are more amenable to hydrolysis/hydrogenolysis than those derived from the pinacol ester of diboronic acid. This method only relates to arylboron intermediates which are boronic esters.

Some of the arylboron intermediates and aryl boronic acids are novel and represent a further aspect of the present invention. Examples of such novel aryl boron intermediates which may be prepared according to the present invention are listed in Table 2, while some known arylboron intermediates prepared in accordance with the present invention are listed in Table 1.

W;O 98/45265 PCT/AU98/00245 17 TABLE 1 KNOWN BORONATES PREPARED BY DIBORON METHODOLOGY Compound COMPOUND STRUCTURE Calc Found Number MIZ Mtz 1 HCO C- B 262.1 262 3 2 X" jT\ A10 247 (1W-15) 2 H3CO C/-0 246.1 246 (M) C-0 231 3 T 238 238 \l 223 M 4 330.1 330 B 1 315 02N- B O 249. 1 249 249.1 234 6 B 280.2 280 265 7 B 210.1 210 195 WO 98/45265 WO 9845265PCU/AU98/00245 18 248.1 N0 2 249 WO 98/45265 PCT/AU98/00245 19 WO 98/45265 PCT/AU98/00245 20 TABLE 2 NOVEL BORONATES PREPARED BY DIBORON METHODOLOGY WO 98/45265 PCT/AU98/00245 21 WO 98/45265 WO 9845265PCT/AU98/00245 22 39 H2OSB283 284 +1)

H

2 NB 263 264 H0 2

C

0 HN, ,,N

N

42 H 2 N-4BQ/0B( 219 220 +1) 430: 296 298 +2) BrH 2

C

44KK B \0~Z 363 364 (Mr+ 1) 0 /0220 221 (M++i1)

HO

WO 98/45265 PCTIAU98/00245 23 WO 98/45265 PCT/AU98/00245 24 WO 98/45265 WO 9845265PCT/AU98/00245 25 259 0

(H

3

CO)

3 SP

B'I

324 WO 98/45265 PCT/AU98/00245 -26- The term "linking group" as used herein refers to any chain of atoms linking one aryl group to another. Examples of linking groups include polymer chains, optionally substituted alkylene group and any other suitable divalent group.

The process according to the present invention is applicable to chemistry on solid polymer support or resin bead in the same manner as conventional chemistry is used in combinatorial chemistry and in the preparation of chemical libraries. Thus a suitable organic compound having a halogen or halogen-like substituent at a coupling position which is chemically linked to a polymer surface may be reacted with an arylboron intermediate in the presence of a Group VIII metal catalyst and a suitable base to form a coupled product linked to the surface of the polymer. Excess reagents and by-products may then be washed away from the surface leaving only the reaction product on the surface. The coupled product may then be isolated by appropriate cleavage of the chemical link from the polymer surface. The process is also possible using the alternative strategy of reacting an aromatic ring or an aromatic ring compound having a halogen or halogen-like substituent linked to a polymer surface with a diboron derivative in the presence of a Group VIII metal catalyst and a suitable base to form an arylboron intermediate chemically linked to the polymer surface. This intermediate may then be reacted with an organic compound having a halogen or halogen-like substituent at a coupling position in the presence of a Group VIII metal catalyst and a suitable base to prepare the coupled product chemically linked to the polymer. Excess reactants and by-products may be removed by suitable washing and the coupled product may be isolated by chemically cleaving the link to the polymer.

In accordance with the present invention it is also possible to directly functionalise the surface of a polymer, e.g. polystyrene, with a halogen or halogen-like substituent and then convert this functionalised surface to an arylboron surface by reaction of the functionaised polymer with a diboron derivative in the presence of a Group VIII metal catalyst and a suitable base.

The arylboron surface may then be reacted with any suitable organic compound having a halogen or halogen-like substituent. If the aromatic ring compound contains other functional groups, for example carboxylic ester, they may be used as linker groups to further extend the WO 98/45265 PCT/AU98/00245 -27chemical reactions applied to the polymer surface.

It is also possible to prepare polyaryl compounds or other polymers by reaction of aromatic ring compounds having more than one halogen or halogen-like substituent. Such aromatic ring compounds may be reacted with a diboron derivative in the presence of a Group VIII metal catalyst and a suitable base to form an arylboron intermediate having more than one boron functionality. These intermediates may be reacted with aromatic ring compounds or organic compounds having more than one halogen or halogen-like substituent to form a polymer. If the aromatic ring compound has three or more halogen or halogen-like substituents which react with the diboron derivative then it is possible to prepare dendritic molecules in accordance with the process of the present invention.

The aromatic ring compound and the organic compound may be separate molecules or may be linked together such that the arylboron intermediate formed after reaction with the diboron derivative is able to react at a coupling position located elsewhere in the molecule so as to provide for an intramolecular reaction, such as a ring closure reaction. Similarly the process according to the invention allows intramolecular linking to occur between different aromatic rings bearing halogen or halogen-like substituents located at different parts of the molecule.

Reaction of one halide substituent with a diboron ester to form an arylboron intermediate allows reaction of that intermediate with the halide substituent on the other ring to thereby link the aromatic rings.

The process according to the invention is also useful for the preparation of reactive intermediates which are capable of taking part in further reactions or rearrangements. These reactive intermediates may be the aryl boron intermediates or the coupled products. The aryl boron intermediates may take part in one or more of the palladium catalysed reactions of aryl boron compounds described by Miyaura and Suzuki in Chem. Rev. 1995, 95 2457-2483.

The process according to the present invention allows the linking of aromatic rings and WO 98/45265 PCT/AU98/00245 -28aromatic ring compounds to organic compounds in mild conditions and avoids the use of expensive, difficult to remove and/or toxic reagents and solvents. In this regard boron and boron compounds are generally non-toxic. The reactions may also be performed in relatively cheap solvents such as methanol and ethanol and, in view of the improved control over the reaction steps, it is envisaged that it would be possible to perform the reactions on an industrial scale. The process also allows the linking of aromatic rings which contain active hydrogen substituents without the need to protect those substituents during the reaction.

The following examples are provided to illustrate some preferred embodiments of the invention. However it is to be understood that the following description is not to supersede the generality of the invention previously described.

Examples Example 1 Freshly distilled neopentanediol (9.72 g, 0.093 mol) was placed in a dry 250 ml Schlenk flask, anhydrous diethyl ether (100 ml) added under argon, followed by tetrakis- (dimethylamino)diboron (9.24 g; 0.047 mol). The mixture was stirred magnetically under argon and cooled in ice. A solution of hydrogen chloride in dry diethyl ether (76 ml of 2.46 M, 0.187 mol) added from a pressure-equalising dropping funnel over 1 h and the mixture allowed to warm to room temperature with stirring overnight. The solution was filtered from the copious precipitate through a glass filter tube into a second Schlenk flask and the filtrate evaporated to dryness affording a white solid (2.89 g, 23%) whose nmr indicated it was the product. The residual precipitate was extracted with hot benzene (2 x 200 ml) and the extracts filtered and evaporated to provide further product (6.36 g, total yield 74 The combined extracted products were recrystallised from benzene/light petroleum 60-80aC) to afford WO 98/45265 PCT/AU98/00245 -29bis(neopentanediolato)diboron as colourless tetrahedral prisms, m.p. 161-162 0 C. 'H nmr (CDC1,): 5 0.95 (2 x CH and 3.60 ppm (2 x OCHI). "C nmr (CDCI): 6 22.1 (2 x Cl); 31.6 (RC) and 71.5 ppm (2 x OC-H). "B nmr (CDC1,): 5 27.4 ppm Example 2

\B-B

o0 Anhydrous ethylene glycol (9.15 ml, 0.164 mol) was added to tetrakis(dimethylamino)diboron (16.24 g; 0.0820 mol) in anhydrous diethyl ether (170 ml) contained in a 2-neck 500 ml round bottom flask under nitrogen. The mixture was stirred magnetically under nitrogen and cooled in ice. A solution of hydrogen chloride in dry diethyl ether (115 ml of 2.85 M, 0.328 mol) was added from a pressure-equalising dropping funnel over 1 h and the mixture allowed to warm to room temperature with stirring overnight. The solution was filtered from the copious precipitate by suction filtration through a glass sinter funnel and the filtrate evaporated to dryness affording a white solid (3.12 g) whose nmr indicated it was the product along with some dimethylamine hydrochloride salt. The residual precipitate was extracted with hot benzene (2 x 200 ml) and the extracts filtered and evaporated to dryness affording a white solid (8.41 g, 72%) whose nmr showed indicated it was the desired product. The first crop (3.12 g) was extracted with hot benzene (60 ml) and the extract filtered and evaporated to dryness affording a white solid (2.23 g) whose nmr showed indicated it was the desired product. The combined extracted products were recrystallised from benzene/light petroleum 60-80 0 C) to afford bis(ethanediolato)diboron as colourless crystals. Yield 9.90 g (0.0700 mol; 'H nmr (CDCl,, 200 MHz): 5 4.18 ppm (singlet, OCH). 'C nmr (CDC1,, 200 MHz): 6 65.5 ppm (OCIH).

Exmaxle3 WO 98/45265 PCT/AU98/00245 C

B

-B

0 O Freshly distilled 1,3-propanediol (10.22 g; 0.134 mol) was added to tetrakis(dimethylamino)diboron (13.29 g; 0.0671 mol) in anhydrous ether (200 ml) contained in a 2-neck 500 ml round bottom flask, under nitrogen. The mixture was stirred magnetically under nitrogen and cooled in ice. A solution of hydrogen chloride in dry ether (94.5 ml of 2.85 M, 0.269 mol) added from a pressure-equalising dropping funnel over 1 h and the mixture allowed to warm to room temperature with stirring overnight. The solution was filtered from the copious precipitate by suction filtration through a glass sinter funnel and the filtrate evaporated to dryness to give the product as a colourless solid (9.50 g, 'H nmr (CDCI, 200 MHz): 1.87 (quintet, 2H, CCHCH 2 and 3.93 ppm (triplet, 4H, CH 2 "C nmr (CDCl,, 200 MHz): 5 27.4 (CH,CHCH,, 1C) and 61.1 ppm (CH20, 2C).

Example 4 Ph O -T-'Ph ph| B-B\ Ph P< Q0 0 ~Ph Meso-hydrobenzoin (45.66 g; 0.213 mol) was added to tetrakis(dimethylamino)diboron (21.09 g; 0.107 mol) in anhydrous diethyl ether (500 ml) contained in a 2-neck 1 L round bottom flask under nitrogen. The mixture was stirred magnetically under nitrogen and cooled in ice. A solution of hydrogen chloride in dry diethyl ether (150 ml of 2.85 M, 0.428 mol) was added from a pressure-equalising dropping funnel over 1 h and the mixture allowed to warm to room temperature with stirring overnight. The solution was filtered from the copious precipitate by suction filtration through a glass sinter funnel and the filtrate evaporated to dryness affording a small amount of white solid. The standard workup yielded 33.62 g (0.0754 mol; 71%).

WO 98/45265 WO 9845265PCT/AU98/00245 -31 Example 0WCO 0 This diboronic acid ester was prepared following the procedure described above for Example 1 using 1-phenyl-1,2-ethanediol instead of neopentanediol. Yield, 73%. 'H nmr (CDOl, 200MHz): 5 4.04-4.12 (triplet, 2H1; 2 x ILCHCPh), 4.57-4.66 (triplet, 211; HCHCPh), 5.44- 5.52 (triplet, 211; 2 x OCHPh) and 7.28-7.42 ppm (multiplet, 1011; 2 x ArH).

Example 6 This diboronic ester was prepared following the procedure described above for Example 1 using 3,5-di-tert-butylcatechol instead of neopentanediol. Yield, 41 1 H nmr (CDC 3 200 MHz): 6 1. 21-1.51 (multiplet, 3611; 12 x CH 1 and 6.82-7.30 ppm (multiplet, 4H; 2 x ArH).- F. W.:calc for C 28

H,,BO

4 462.25, found m/z 463 (M 1).

Example 7 n In a Schlenk tube, a solution of the pinacol ester of diboronic acid (0.315 g; 1.24 mmol), 1iodo-3,4-methylenedioxybenzene 252 g; 1. 02 mmol), P'dCl,(dppf). CHCl, (24 mg; 0. 029 mmol) and potassium acetate (0.300 g; 3.06 mmol) in an ethanol-water solvent mixture (6 WO 98/45265 PCT/AU98/00245 -32ml, 95 EtOH 5 HI0) was placed under an atmosphere of nitrogen and heated at with stirring. After 2.5 h gc analysis on the reaction mixture showed some decomposition of the diboron compound, 64 unreacted aryl iodide and the formation of the arylboronic acid ester in 36 yield. More diboron compound (173 mg; 0.68 mmol) was added under nitrogen to the reaction mixture and heating at 40 0 C continued. After 4 h gc analysis on the reaction mixture showed absence of diboron compound, 28 unreacted aryl iodide and the formation of the arylboronic acid ester in 72 yield.

Additional diboron compound was added to the reaction mixture until gc analysis indicated the reaction had gone to completion. The product was then isolated by pouring the ethanolic reaction mixture into water (10 ml) and extracting into diethyl ether (2 x 50 ml). The combined ether extracts were dried (MgSO,) and the solvent removed under vacuum to yield the crude product which was then purified by distillation under vacuum (80-120°C/2.5x10 2 atm).

'H nmr (CDCI,, 200 MHz): 6 1.27 (singlet, 12H, C(Cjz), 5.89 (singlet, 2H, Cj 0) and 6.72-7.31 ppm (multiplet, 3H, ArH).

Example 8 200 In a Schlenk tube, a solution of the pinacol ester of diboronic acid (0.327 g; 1.29 mmol), 1bromo-3,4-methylenedioxybenzene (0.211 g; 1.05 mmol), PdCl(dppf).CHC, (24 mg; 0.029 mmol) and potassium acetate (0.302 g; 3.08 mmol) in an ethanol-water solvent mixture (6 ml; 95 EtOH 5 H0) was placed under an atmosphere of nitrogen and heated at with stirring. After 2.5 h gc analysis on the reaction mixture showed absence of the diboron compound, 32 unreacted aryl bromide and the formation of the arylboronic acid ester identified by gc retention time) in 68 yield.

Examples 7 and 8 demonstrate that although additional quantities of diboron derivatives may WO 98/45265 PCT/AU98/00245 -33be required, arylboronic acid esters can be formed from aryl iodides and aryl bromides in aqueous ethanol.

Example 9 NC B In a Schlenk tube, a solution of bis(neopentanediolato)diboron (0.374 g; 1.66 mmol), 4iodobenzonitrile (0.250 g; 1.09 mmol), PdCl,(dppf).CIHCl ,(27 mg; 0.033 mmol) and potassium acetate (0.321 g; 3.27 mmol) in dry methanol (6 ml) was placed under an atmosphere of nitrogen and stirred at room temperature for 3 days. The excess diboron compound, arylboronic acid ester (94 and biaryl compound (3 gave rise to the three peaks in the gc, arylboronic acid ester biaryl 32.0. The reaction mixture was poured into water (20 ml) and extracted into diethyl ether (1 x 75 ml, 1 x 50 ml). The combined ether extracts were washed (water; 2 x 50 ml), dried (MgSO,) and the solvent removed under vacuum to give a pale brown solid. Purification by distillation under vacuum afforded a white solid (80-100°C/2.5xlO 2 atm) Yield 0.17 g 0.79 mmol; 73 'H nmr (CDC1,, 200 MHz): 5 0.95 (singlet, 6H, 3.71 (singlet, 4H, CH 2 O) and 7.52- 7.82 ppm (multiplet, 4H, ArH). F.W. calc for C,,H,,BNO, 215.06; found (CI+ mass spectrum): m/z 216 244 (M+29) and 256 (M+41).

Example NC \'y In a Schlenk tube, a solution of bis(neopentanediolato)diboron (0.370 g; 1.64 mmol), 4iodobenzonitrile (0.250 g; 1.09 mmol), PdCl,(dppf).C-HCl, (27 mg; 0.033 mmol) and potassium acetate (0.325 g; 3.29 mmol) in dry isopropyl alcohol (7 ml) was placed under an -34atmosphere of nitrogen and heated at 60 0 C with stirring. After 24 h the arylboronic acid ester (93 and the symmetrical biaryl compound (7 gave rise to the two peaks observed in the gc, arylboronic acid ester: biaryl 13.3. The reaction mixture was filtered collecting a grey solid which was taken up in chloroform (25 ml). Some insoluble material was removed by suction filtration and the filtrate taken to dryness under vacuum to give a red-brown solid.

Purification of this material by distillation under vacuum afforded a white solid at 100 0 C/2.9xl10 2 atm.

'H nmr (CDCI,, 200 MHz): as in Example 9.

Although the gc analysis indicated that the diboron compound had been exhausted, some of 10 this material was recovered during distillation of the crude product. Accordingly yields determined by gc have not been standardized.

Examples 9 and 10 demonstrate that the neopentanediol ester of diborinic acid can also be used to form arylboronic acid esters, in methanol or isopropyl alcohol.

Example 11 NC B

S

In a Schlenk tube, a solution of the pinacol ester of diboronic acid (0.359 g; 1.41 mmol), 4iodobenzonitrile (0.251 g; 1.10 mmol), PdCl,(dppf).CHCl ,(27 mg; 0.033 mmol) and potassium acetate (0.118 g; 1.20 mmol) in dry methanol (6 ml) was placed under an atmosphere of nitrogen and heated at 60" C. After 18 h gc analysis shows the excess diboron compound, 17 unreacted aryl iodide, 59 arylboronic acid ester as well as 24 of the symmetrical biaryl compound. Arylboronic acid ester Biaryl Examples 9 and 11 demonstrate that the bis(neopentanediolato)diboron compound, when reacted with 4-iodobenzonitrile, produces less biaryl product than a similar reaction with the pinacol ester of diboronic acid.

WO 98/45265 PCT/AU98/00245 Example 12

NC

In a Schlenk tube, a solution of bis(neopentanediolato)diboron (0.321 g; 1.42 mmol), 3iodobenzonitrile (0.251 g; 1.10 mmol), PdCl,(dppf).CHCl, (28 mg; 0.034 mmol) and potassium acetate (0.118 g; 1.20 mmol) in dry methanol (6.5 ml) was placed under an atmosphere of nitrogen and heated at 600C. After 18 h the arylboronic acid ester (83 and the symmetrical biaryl compound (17 gave rise to the two peaks observed in the gc.

Example 13 B/0

NC

In a Schlenk tube, a solution of the pinacol ester of diboronic acid (0.363 g; 1.43 mmol), 3iodobenzonitrile (0.250 g; 1.09 mmol), PdCl,(dppf).CIHC1, (27 mg; 0.033 mmol) and potassium acetate (0.120 g; 1.22 mmol) in dry methanol (7 ml) was placed under an atmosphere of nitrogen and heated at 60*C. After 18 h gc analysis shows the excess diboron compound, 9 unreacted aryl iodide, 73 arylboronic acid ester as well as 18 of the symmetrical biaryl compound.

Example 14 BiXI)K 0<

CN

In a Schlenk tube, a solution of bis(neopentanediolato)diboron (0.322 g; 1.43 mmol), 2iodobenzonitrile (0.250 g; 1.09 mmol), PdCl 2 (dppf).CHC1, (27 mg; 0.033 mmol) and potassium acetate (0.120 g; 1.22 mmol) in dry methanol (6.5 ml) was placed under an WO 98/45265 PCT/AU98/00245 -36atmosphere of nitrogen and heated at 60°C. After 18 h gc analysis shows the absence of diboron compound, some unreacted aryl halide and some product formation. More diboron compound (0.167 g; 0.739 mmol) was added and heating at 60 0 C was continued. After 5 h gc analysis shows excess diboron compound, 30 unreacted aryl iodide, 66 arylboronic acid ester as well as 4 of the symmetrical biaryl compound.

Arylboronic acid ester Biaryl 17.8.

Example 100

CN

In a Schlenk tube, a solution of the pinacol ester of diboronic acid (0.360 g; 1.42 mmol), 2iodobenzonitrile (0.250 g; 1.09 mmol), PdCl 2 (dppf).CHC (27 mg; 0.033 mmol) and potassium acetate (0.120 g; 1.22 mmol) in dry methanol (7 ml) was placed under an atmosphere of nitrogen and heated at 60°C. After 18 h gc analysis shows the excess diboron compound, 30 unreacted aryl iodide, 31 arylboronic acid ester as well as 39 of the symmetrical biaryl compound. Arylboronic acid ester Biaryl 0.80.

Examples 14 and 15 demonstrate that the bis(neopentanediolato)diboron compound, when reacted with 2-iodobenzonitrile, produces less biaryl product than a similar reaction with the pinacol ester of diboronic acid, indicating that choice of diboron ester derivative may allow control over the reaction products formed.

Example 16 WO 98/45265 PCT/AU98/00245 -37- In a Schlenk tube, a solution of the pinacol ester of diboronic acid (0.362 g; 1.43 mmol), 3-iodoacetophenone (0.268 g; 1.09 mmol), PdCl,(dppf).CI-C1, (28 mg; 0.034 mmol) and potassium acetate (0.118g; 1.20 mmol) in dry methanol (6.5 ml) was placed under an atmosphere of nitrogen and heated at 60"C. After 18 h gc analysis shows 14 unreacted aryl iodide, 79 arylboronic acid ester as well as 7 of the symmetrical biaryl compound. Arylboronic acid ester Biaryl 12.1.

Example 17 0 L- 0 In a Schlenk tube, a solution of the pinacol ester of diboronic acid (0.323 g; 1.27 mmol), 1-iodo-3,4-methylenedioxybenzene (0.241 g; 0.972 mmol), PdC1(dppf).CH'C (24 mg; 0.029 mmol) and potassium benzoate (0.469 g; 2.93 mmol) in dry methanol (6.5 ml) was placed under an atmosphere of nitrogen and heated at 60 0 C. After 18 h gc analysis shows the reaction to have gone to completion to form the arylboronic acid ester.

Example 18 o 0 o In a Schlenk tube, a solution of the pinacol ester of diboronic acid (0.347 g; 1.37 mmol), 1-iodo-3,4-methylenedioxybenzene (0.259 g; 1.04 mmol), PdCl,(dppf).CH 2 C1 (26 mg; 0.032 mmol) and sodium fluoroacetate (0.317 g; 3.17 mmol) in dry methanol (7 ml) was placed under an atmosphere of nitrogen and heated at 60 0 C. After 18 h gc analysis shows WO 98/45265 PCT/AU98/00245 -38- 53 unreacted aryl iodide and 47 arylboronic acid ester.

Example 19 0/

O\

In a Schlenk tube, a solution of the pinacol ester of diboronic acid (0.322 g; 1.27 mmol), 1-iodo-3,4-methylenedioxybenzene (0.242 g; 0.976 mmol), PdCl,(dppf).CHCl, (24 mg; 0.029 mmol) and sodium trifluoroacetate (0.403 g; 2.96 mmol) in dry methanol (7 ml) was placed under an atmosphere of nitrogen and heated at 60°C. After 18 h gc analysis shows 82 unreacted aryl iodide, 15 arylboronic acid ester and 3 symmetrical biaryl.

Examples 17, 18 and 19 show that using other bases such as potassium benzoate, sodium fluoroacetate or sodium trifluoracetate in these reactions, instead of potassium acetate, also leads to the formation of the desired arylboronic acid ester.

Example 20 O B In a Schlenk tube, a solution of the pinacol ester of diboronic acid (0.284 g; 1.12 mmol), 1-iodo-3,4-methylenedioxybenzene (0.244 g; 0.984 mmol), potassium acetate (0.316 g; 3.22 mmol) and approx. 0.18 palladium on.porous glass (1.953 g; 0.0336 mmol) in dry methanol (8 ml) at 60 iC. After 18 h gc analysis shows no diboron compound starting material, 47.1 unreacted aryl iodide, 49.7 arylboronic acid ester and 3.2 symmetrical biaryl.

-39- Example 21 In a reaction tube, a solution of the pinacol ester of diboronic acid (1.386 g; 5.46 mmol), bromopolystyrene (1.2-1.3 mmol Br/g resin, 2.001 g; 2.50 mmol), potassium acetate (0.751 g; 7.65 mmol) and PdCl,(dppf).CHC1, (61 mg; 0.075 mmol) in dry dioxane ml) was placed under an atmosphere of nitrogen and heated at 80*C. After 21 h the reaction mixture was cooled to room temperature and the brown-grey resin collected by vacuum filtration. Tetrahydrofuran (40 ml) was added to the product and the mixture heated at 70*C for 30 min. before being filtered hot. This washing was repeated till no 10 trace of the pinacol ester of diboronic acid was detected in the washing by gc. To remove all traces of palladium the resin was washed 5 times with a solution of 0.5 sodium ::dimethyldithiocarbamate and 0.5 diisopropylamine in AR dimethylformamide, using an ultrasonic bath. The resin was washed several times with tetrahydrofuran followed by several washes with a dioxane-water mixture before being dried under vacuum (50oC/28 15 mm Hg) overnight.

Example 22 Aryl borate formation using phenvl triflate 0 In a Schlenk tube, a solution of the pinacol ester of diboronic acid (0.308 g; 1.21 mmol), phenyl triflate (0.249 g; 1.10 mmol), potassium acetate (0.330 g; 3.36 mmol) and PdCl 2 (dppf).CHCl 2 (27 mg; 0.033 mmol) in dry dimethylsulphoxide (6 ml) was placed under an atmosphere of nitrogen and heated at 800C. After 18 h gc analysis shows the reaction to have gone to completion. The reaction mixture was poured into water (20 ml) and extracted into diethyl ether (1 x 75 ml, 1 x 50 ml). The combined ether extracts were washed (water; 2 x 50 ml), dried (MgSO,) and the solvent removed under vacuum to give a green oil. Purification by column chromatography (silica gel 60) eluting with chloroform petroleum spirit 40-60° solvent mixture afforded a colourless oil.

WO 98/45265 PCT/AU98/00245 'H nmr (CDC1,, 200 MHz): 5 1.35 (singlet; 12H, 4 x CH,) and 7.26-7.84 ppm (multiplet; ArH). F. calc for C 2 ,HBO,, 204.08; found (CI/MS) 204 Example 23 Hydrolysis of the pinacol ester of phenylboronic acid 0

H

2 0 0 OH A methanolic solution of the pinacol ester of phenylboronic acid (ArB(pin)) was analysed by HPLC (Waters 600E) using a Zorbax column (ODS) under the following conditions: X 230 nm, 2 ml/min., 20% CH,CN 80% HO0 (initial) to 80% CH,CN 20% HIO (changed linearly from 9-17 min.). Peaks were detected at 5.9 min. and 14.9 min., the former assigned to phenylboronic acid (by spiking the solution with an authentic sample) and the later to ArB(pin). The ratio [area ArB(OH)J/[area ArB(pin)] 0.074.

To another sample of the initial methanolic solution was added some water and after several hours HPLC analysis showed peaks at 5.6 and 14.7 minutes with an area ratio of 0.44. This indicates hydrolysis of the pinacol ester of phenylboronic acid to phenylboronic acid on exposure to water.

Example 24 Hydrolysis of the neopentanediol ester of phenylboronic acid 7 H 2 0 O'

OH

A methanolic solution of the neopentanediol ester of phenylboronic acid was analysed by HPLC (Waters 600E) using a Zorbax column (ODS) under the following conditions: X 230 nm, 2 ml/min., 20% CH,CN 80% H-O (initial) to 80% CH,CN 20% HO0 (changed linearly from 9-17 min.). A single peak was detected at 5.8 minutes. This peak was confirmed to be due to phenylboronic acid by spiking the solution with an authentic WO 98/45265 PCT/AU98/00245 -41sample.

A sample was also collected by semi-preparative HPLC and found to be phenylboronic acid.

This indicates the ready hydrolysis of the neopentanediol ester of phenylboronic acid to phenylboronic acid on exposure to water.

Examples 23 and 24 show that although hydrolysis of the phenyl boronates of pinacol and neopentanediol in water does occur, the phenyl boronate of pinacol is more stable.

Example In a Schlenk tube, a solution of the pinacol ester of diboronic acid (0.513 2.02 mmol), l-bromo-3,4-methylenedioxybenzene (0.250 g; 1.24 mmol), potassium acetate (0.371 g; 3.78 mmol), PdCl,(dppf).CHCl (33 mg; 0.040 mmol) and internal standard biphenyl (0.188 g; 1.22 mmol) in dry methanol (6 ml) was placed under an atmosphere of nitrogen and heated at 60 0 C. After 18 h gc analysis shows the reaction to have gone to completion and the ratio [diboron compound]/[internal standard] 0.36. Water (2.5 ml) was added and heating at 60 0 C was continued. After 5 h no diboron compound is detected by gc.

This example shows that excess pinacol ester of diboronic acid can be decomposed by hydrolysis by addition of water to the reaction solution. This procedure lends itself to the synthesis of unsymmetrical biaryls by minimising the formation of the symmetrical species.

Example 26 Reaction of aryl chloride Boronic acid ester from p-chloronitrobenzene j B Q NO2 d~/Y WO 98/45265 PCT/AU98/00245 -42p-Chloronitrobenzene (2 mmol) was heated at 100 0 C in DMSO for 24 h with 1.1 mmol of the pinacol ester of diboronic acid, 3 mmol Cs 2 CO, and 24 mg PdCl,(dppf).C-HC 2 The reaction solution was extracted with CHICL/water. The gc of the CH 2 C, solution had peaks identified by gc/ms for the ester (m/z 249; M+1) and at longer retention time, dinitrobiphenyl (m/z 245; M+ 1).

When PdCL[(P(C,H,),)j or PdCl,[(C,H,),P(CIH),P(CH )J was used as catalyst, all the boronic acid ester that had formed coupled with p-chloronitrobenzene to form the dinitrobiphenyl.

Example 27 Use of Ni as the catalyst element The pinacol ester of diboronic acid (1.09 mmol), 1-iodo-3,4-methylenedioxybenzene (0.99 mmol), 25 mg NiC 2 (dppf) prepared by the method of A.W. Rudie et al., Inorg. Chem.

1978, 12, 2859, and potassium acetate (3.2 mmol) were stirred in DMSO (5 ml) at 75 iC for 40 h. The ether solution obtained after ether/water extraction of the reaction solution gave only one peak in the gc at a retention time longer than that of the pinacol ester of diboronic acid. The peak was identified by the retention time to be due to the pinacol ester 3,4-methylenedioxyphenylboronic acid.

Example 28 Coupling of arylsulfonic acids. Synthesis of HOaS -SO3H The sodium salt ofp-bromophenylsulfonic acid (2 mmol) and the pinacol ester of diboronic acid (1.1 mmol) were reacted in 5 mis DMSO at 80°C for 21.5 h in the presence of 1 g CsCO, and 26 mg PdCl(dppf).CH,CI 2 The DMSO was removed under reduced pressure and the remainder taken up in water and passed down a Amberlite IR- 120 form] column to remove the inorganic cations and carbonate. The acid was WO 98/45265 PCT/AU98/00245 -43obtained as a solid on freeze drying the aqueous solution after the impurities had been removed with the aid of THF and ethanol. 'H nmr in DO gave an AB type quartet centered at 7.68 ppm, J 8.40 Hz. The mass spectrum (APCI, negative ion) gave peaks at m/z 313 and 233 (M-SO,H).

Example 29 Pinacol ester of phenyltrimethoxysilylboronic acid a0\ tSi(OCH 3 3 In a reaction tube 0.587 g (6 mmol) potassium acetate was dried at 150°C, 3 x 10" mmHg for 3 h. Then, under Ar, PdCl,(dppf).CHCl, (49 mg), pinacol ester of diboronic acid (540 mg, 2.13 mmol), 0.35 ml (2.06 mmol) of bromophenyltrimethoxy-silane (mixture of isomers, Gelest Inc.) and 4 mis dry DMSO were added. The tube was warmed with stirring to 80*C for 21 h. After removal of the DMSO under high vacuum near room temp., the temperature of the Kugelrohr was increased to 30 and then 50*C to remove other volatile impurities. The product was distilled as a colourless liquid at 70-75 C, 3 x mm Hg. The 'H nmr in CDC1,; 1.35 ppm(s, 12H, CCH,); 3.61 ppm, 3.62 ppm (peaks near equal area, 9H, OCH,), 7.35 8.15 ppm (multiplets, 4H). The aromatic protons indicate the presence of the para-substituted compound (AB type quartet; 7.64, 7.68, 7.81, 7.85 ppm) and the meta-substituted compound (7.36 7.75 7.90 8.10 The gc of the material gave two peaks of near equal area and both compounds represented by these peaks gave a parent ion mass of 325 in the gc/ms.

Example 30 Synthesis of 5.5'-dimethvl-2,2'-bipyridine H3IC CH The coupling of 2-bromo-5-methylpyridine can be readily carried out with bases such as -44- Cs,CO, or CHOP(O)(ONa).O 2 0 in ethanol. Pyridine can also be used. Examples are given with PdCl,(dppf).CHCl or palladium acetate as catalyst. Reaction temperatures used varied from 50°C to Placed 330 mg (1.92 mmol) of 2-bromo-5-methylpyridine in a reaction tube together with 274 mg (1.08 mmol) of the pinacol ester of diboronic acid, 26 mg PdCl2(dppf).CH 2 ,C and 0.97 g CsCO,. After addition of 6 ml dry ethanol, the reaction was warmed to 80 0 C for several days (reaction time not optimized). The gc of the extracted (ether/water) reaction :i solution had 2 peaks, a small one being the starting bromopyridine and the large peak S* 10 shown to be by gc/ms (m/z 185; M+1) the product 5,5'-dimethyl-2,2'-bipyridine.

Placed 86 mg (0.50 mmol) of 2-bromo-5-methylpyridine in a reaction tube together with 148 mg (0.58 mmol) of the pinacol ester of diboronic acid, 15 mg PdCl,(dppf).CHCl4 and 369 mg of C,H,OP(O)(ONa),.IH0. After addition of 4 ml pyridine the mixture was warmed to 60 iC for 2 h and then to 80°C for 15.5 h.

Only one peak was observed in the gc of the ether/water extracted reaction product and at a residence time corresponding to that found for the 5,5'-dimethyl-2,2'bipyridine.

S

Placed 332 mg (1.93 mmol) of 2-bromo-5-methylpyridine in a reaction tube together with 270 mg (1.06 mmol) of the pinacol ester of diboronic acid, 25 mg Pd(OAc), and 1.11 g (3.1 mmol) CsCO,. After addition of 6 ml ethanol the mixture was warmed to 60 C. After 3 h the ge of the ether/water extracted reaction solution gave only two peaks, a weak one of retention time characteristic of the starting bromopyridine and the other peak had a retention time characteristic of the 5,5'-dimethyl-2,2'-bipyridine.

Placed 86 mg (0.50 mmol) of 2-bromo-5-methylpyridine in a reaction tube 1 together with 151 mg (0.59 mmol) of the pinacol ester of diboronic acid, 13.5 mg WO 98/45265 PCT/AU98/00245 Pd(OAc), and 360 mg (1.52 mmol) of C,HOP(O)(ONa),.HO. After addition of 3 ml ethanol the mixture was warmed to 60C. After 1.33 h the gc of an aliquot of the reaction mixture (extracted with ether/water) indicated the formation of the 5,5'-dimethyl-2,2'-bipyridine. The reaction was left for 90 h at 60 0 C after which only 5,5'-dimethyl-2,2'-bipyridine was detected in the gc of the ether solution of an ether/water extracted sample of the reaction solution gave only two peaks, a weak one of retention time characteristic of the starting bromopyridine and the other peak had a retention time characteristic of the 5,5'-dimethyl-2,2'-bipyridine.

Placed 86 mg (0.50 mmol) of 2-bromo-5-methylpyridine in a reaction tube together with 151 mg (0.59 mmol) of the pinacol ester of diboronic acid, 13.5 mg Pd(OAc),and 360 mg (1.52 mmol) of C,H,OP(O)(ONa),.HIO. After addition of 3 ml ethanol the mixture was warmed to 60"C. After 1.33 h the gc of an aliquot of the reaction mixture (extracted with ether/water) indicated the formation of the 5,5'-dimethyl-2,2'-bipyridine. The reaction was left for 90 h at 60*C after which only 5,5'-dimethyl-2,2'-bipyridine was detected in the gc of the ether solution of an ether/water extracted sample of the reaction solution.

Example 31 Synthesis of 3,3'-dimethyl-2.2'-bipyridine This example shows that 2-bromo-3-methylpyridine can be coupled in the presence of a weak base, KOAc and Pd(OAc) 2

CH

3

N

H

3

C

Placed 172 mg(1.0 mmol) of 2-bromo-3-methylpyridine in a reaction tube together with 281 mg (1.11 mmol) of the pinacol ester of diboronic acid, 22.5 mg Pd(OAc), and 300 mg (3.06 mmol) of KOAc After addition of 5 ml ethanol the mixture was warmed to 800C.

After 6 h the gc of an aliquot of the reaction mixture (extracted with ether/water) indicated the formation of the 3,3'-dimethyl-2,2'-bipyridine. The reaction was left for 65 h at WO 98/45265 PCT/AU98/00245 -46after which the only peaks detected in the gc, of the ether solution of an ether/water extracted sample of the reaction solution, were 3,3'-dimethyl-2,2'-bipyridine (gc/ms, m/z 185, M+1) and the pinacol ester of diboronic acid.

Example 32 Synthesis of 2,2'-bipvridine 0-0 Placed 14.9 mg Pd(OAc), (0.0665 mmol) and 72 mg P(o-CH,OCH,), (0.204 mmol) in a reaction tube and dissolved the compounds in 2 ml DMSO at 60°C for 10 mins. to form palladium phosphine complex. A dark red solution resulted. Then added 258 mg CsF (1.70 mmol), 144 mg of the pinacol ester of diboronic acid, 105 mg 2-iodopyridine (0.51 mmol) and a further 2 ml DMSO. The reaction mixture was warmed to 80"C for 16 h.

The gc of the ether solution of the ether/water extracted reaction solution showed that the reagents had been exhausted and the main peaks besides that of the phosphine were 2,2'bipyridine (gc/ms; m/z 157, M+1) and o-anisylboronic acid pinacol ester (gc/ms, m/z 235, 2,2'-bipyridine is also formed when HCOOK is used as base.

When the reaction is carried out (80° C, 16 h) using tri-p-tolylphosphine (68 mg), Pd(OAc), (14 mg), 145 mg (0.57 mmol) of the pinacol ester of diboronic acid, 118 mg 2iodopyridine (0.58 mmol) and 513 mg (1.45 mmol) Cs 2 CO, in 4 ml DMSO, the gc of the ether solution of an ether/water extracted sample of the reaction solution indicated the complete exhaustion of the diboron ester and bromopyridine species and the formation of 2,2'-bipyridine. This reaction can also be carried out using tris-2,4,6-trimethoxyphenylphosphine instead of the tri-p-tolylphosphine. The product was identified by gc/ms (m/z 157, M+ An adjacent peak (m/z 169, M+ 1) was assigned to the phosphine derived species, 1,3,5-trimethoxybenzene.

xa-xle 33 WO 98/45265 PCT/AU98/00245 -47- A solution of 1-bromo-3,4-methylenedioxybenzene (0.20 g; 0.99 mmol), the pinacol ester of diboronic acid (0.56 g; 2.2 mmol), disodium phenyl phosphate (0.47 g; 2.2 mmol), PdCl,(dppf).ICHC1, (25 mg; 0.031 mmol) and internal standard biphenyl (0.15 g; 0.97 mmol) in methanol (5 ml) was heated between 30 and 50°C till no aryl bromide was detected by gc analysis. N-Chlorosuccinimide (0.27 g; 2.0 mmol) was added and the reaction mixture stirred at room temperature. After 1 h gc analysis shows no diboron compound.

Example 34 In a Schlenk tube, a solution of the pinacol ester of diboronic acid (2.02 g; 7.95 mmol), 2-iodonitrobenzene (0.981 g; 3.94 mmol), PdClJ(dppf).CHCl 2 (97 mg; 0.12 mmol) and potassium acetate (1.19 g; 12.1 mmol) in dry DMSO (20 ml) was placed under an atmosphere of nitrogen and heated at 80 0 C with stirring. After 5 h gc analysis showed aryl borate as the major product along with diboron compound and small amounts of unreacted aryl iodide, biaryl and evidence of some reduction of the aryl borate to the pinacol ester of 2-aminophenylboronic acid. The reaction mixture was poured into water (40 ml) and extracted into diethyl ether (3 x 100 ml). Each extract was washed with water (30 ml) and dried over MgSO,. The combined extracts were purified on silica gel 60 eluting with a petroleum spirit 60-80° ethyl acetate (80:20) solvent mixture.

One of the fractions collected, which contained unreacted diboron compound, unreacted aryl iodide, the pinacol ester of 2-nitrophenylboronic acid and the pinacol ester of 2aminophenylboronic acid was taken to dryness under vacuum before adding a solution of dimethyldioxirane in acetone. After stirring at room temperature for 3 h gc analysis shows only the pinacol ester of 2-nitrophenylboronic acid and a small amount of unreacted aryl iodide.

Examples 33 and 34 show that N-chlorosuccinimide and dimethyldioxirane can decompose WO 98/45265 PCT/AU98/00245 -48the excess pinacol ester of diboronic acid in the presence of an arylboronic acid ester.

Example 0 B SO 2

NH

2 0^Q -a 470 mg (1.99 mmol) of 4-bromobenzenesulfonamide were placed in a reaction tube together with 560 mg (2.0 mmol) of the pinacol ester of diboronic acid, 50.8 mg PdCl,(dppf).CHCland 600 mg (6.12 mmol) of potassium acetate. After addition of 6 ml DMSO the mixture was warmed to 80"C for 6 h. An aliquot of the reaction mixture was then extracted with CHCl 2 /water. The gc of the CHIC, solution showed that all the 4bromo-benzenesulfonamide had been consumed and only a little of the diboron species remained. The product arylboronic acid ester was the only strong peak (gc/ms, M/z 284, M+1) observed. No evidence of a biaryl species was found.

Example 36 The pinacol ester of diboronic acid (0.154g; 0.607 mmol), 1-iodo-3,4methylenedioxybenzene (0.268g, 1.08 mmol), 24mg PdCl 2 (dppf).CH 2 C1 2 and 0.361g (1.53 mmol) C 6

H

5

OPO

3 Na 2

.H

2 0 were stirred in methanol (3 ml) at 25 0 C for 17.5 h. 90% of the diboron pinacol ester had reacted. After reaction for a further 2 h at 40°C there was no WO 98/45265 PCT/AU98/00245 -49evidence for any diboron pinacol ester and very little dimer species in the reaction solution even though the iodide was present in 100 excess. After addition of more diboron pinacol ester (0.1075g, 0.408 mmol), (to a total of 1.02 mmol. compared to 1.08 mmol for the .iodide) and heating at 40 0 C for 17.5 h, a little of the diboron pinacol ester and iodide was still left in the reaction solution. On addition of 0.96 g Cs 2

CO

3 and 0.5 ml H 20 and warming to C for 18.5 h the reaction medium contained arylboron pinacol ester and a trace of dimer.

A little of the iodide had been dehalogenated. Treatment of this solution with 3-iodo-2,6dimethoxypyridine at 40°C for 4 h led to ca. 25 conversion to the mixed diaryl. After a further 68 h reaction at 40 0 C all the arylboronic acid ester had reacted. By gc, the product contained two constituents, the minor one was (by gcms) shown to be excess 3-iodo-2,6dimethoxypyridine and the main one the unsymmetrical diaryl. The ratio of unsymmetrical to symmetric diaryl as judged from the gc (fid detection) was 96 4. The ratio in favour of the unsymmetric diaryl would be further increased by not using excess of the initial halide and optimising reaction times and temperatures.

This example demonstrates that very little of the symmetric diaryl is formed alongside the arylboron ester using the disodium salt of phenylphosphate as base and methanol as solvent, even when the iodide is present in large excess.

Example 37 WO 98/45265 PCT/AU98/00245 The pinacol ester of diboronic acid (0.282g; 1.11 mmol), 3-iodo-2,6-dimethoxypyridine (0.532g, 2.0 mmol), 24.5 mg PdCl 2 (dppf).CH 2 Cl 2 and 0.974g (2.99 mmol) Cs 2

CO

3 were stirred in ethanol (6 ml) at 40°C. On testing the reaction (gc) after 20 h no trace of reactants or intermediates was found. The gc of the reaction solution, after washing an aliquot dissolved in ether with water, had only one peak (dimethoxypyridine) other than the strong peak due to the diaryl. 0.24 g of crude material was isolated after removal of the ethanol, extraction of an ether solution of the product with water, drying (MgSO4) and removal of the diethylether under vacuum. The reaction conditions (time/temperature) were not optimised.

This reaction demonstrates the utility of ethanol in the formation of symmetric diaryls. The reaction was carried out at 400C, but lower temperatures could be employed.

Example 38 0 0 The pinacol ester of diboronic acid (0.363g; 1.43 mmol), 1-iodo-3,4-methylenedioxybenzene (0.310g, 1.25 mmol), 25 mg PdCl 2 (dppf).CH 2 Cl 2 and 0.365g (3.72 mmol) ofKOAc were stirred in ethanol (8 ml) at 50 0 C for 17 h. The excess diboron compound and arylboronic ester give rise to the two peaks observed in the gc. Cs 2

CO

3 (1.3 g, 4.0 mmol) (but no water) was then added, together with 2-bromo-5-methylpyridine (0.24 g, 1.4 mmol), and the reaction heated at 80°C for a further 22.5 h. The mixed diaryl is the major product together with unreacted 2-bromo-5-methylpyridine and some arylboronic acid ester.

This example demonstrates that certain aryl halides, which do not readily form the arylboronic esters under chosen catalytic conditions, can be coupled with different aryl halides to form the unsymmetrical diaryl, without the water/base decomposition of the excess pinacol ester of diboronic acid before addition of the second aryl halide.

-51- Example 39 Macro crowns supplied by Chiron Mimotopes Pty Ltd as the Fmoc-protected Rink handle 10 crown were deprotected and converted to 4-iodobenzoyl-Rink handle crowns by standard procedures. The crowns were then reacted in the standard deep well plate with reagents as appropriate to convert them to the boron deriviative and then with aryl iodide to form the biaryl. The following solutions were prepared: 15 a) Pinacol ester of diboronic acid (107 mg) in dimethylsulfoxide (3.5 ml) (0.12 M) b) Catalyst PdCl 2 (dppf) (10 mg) in dimethylsulfoxide (1 ml) (0.012 M) c) Sodium diethyldithiocarbamate (0.5 g) and diisopropylethylamine (0.5g) in dimethylformamide (100 ml) d) Iodo-2,4,6-trimethylbenzene (24.6 mg) in DMSO (1 ml) (0.1 M) e) Palladium acetate (0.22 g) in DMSO (10 ml) (10.1 M) f) Triphenylphosphine (0.42 g) in DMSO (10 mi) (0.16M) g) Potassium carbonate (4.14 molar; half-saturated) in water.

Typically, to a single well were added solution a) (500 Ml) followed by solution b) (100 l)f and potassium acetate (18 mg approx), the iodobenzoyl crown added and the tube sealed under nitrogen. The reactants were sonicated for 5 min then heated overnight to 80° in an oven containing a nitrogen atmosphere. The tube was cooled, the crown removed and washed by immersion for 5 min successively in DMF, Solution DMF, methanol and dichloromethane and then air dried. In a fresh well were then placed solution d) (500pl), 0 solution e) (20 1l), solution f) (50 1 l) and solution g) (37 1 l) and the mixture sonicated Sbriefly. The boronated crown prepared above was added, the tube sealed under nitrogen, and WO 98/45265 PCT/AU98/00245 -52the reactants returned to the oven at 800 in a nitrogen atmosphere for 20 h.

The tube was cooled, the crown removed and washed by immersion as above and air dried.

The product was then cleaved from the crown by immersion in trifluoroacetic acid (600 pl) in a titre tube and the acid evaporated under a nitrogen stream. The product residue was analysed by hplc (81% pure) and mass spectrometry (Found: m/z 240.2; calc for C, 6

H

1 NO2, m/z+1=240.1).

This example demonstrates performance of the reaction on a polymer support.

Example 0o- 0 A solution of the pinacol ester of diboronic acid (0.260g; 1 mmol), 1-Bromo-3,4- (methylenedioxy)benzene (0.400g; 2 mmol), 10% Pd on Carbon (80 mg) and Cs 2

CO

3 (1.2; 3.7 mmol) in methanol (10 ml) was placed under nitrogen and heated at 55 C with stirring.

After 16 hrs, gc analysis of the reaction mixture indicated the formation of the product as the major constituent (83.5 with the starting 1-bromo-3,4-(methylenedioxy)benzene accounting for the remainder This example demonstrates that palladium on a solid support (carbon) can be used as a catalyst.

WO 98/45265 PCT/AU98/00245 -53 Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features.

Claims (9)

1. A process for covalently coupling organic compounds which comprises reacting an aromatic ring compound having a halogen or halogen-like substituent at a coupling position with a diboron derivative in the presence of a Group VIII metal catalyst and a suitable base, wherein the aromatic ring compound has an active hydrogen substituent.

2. A process for covalently coupling organic compounds which comprises reacting an aromatic ring compound having a halogen or halogen-like substituent at a coupling position with a diboron derivative in the presence of a Group VIII metal catalyst and a suitable base, wherein said reaction is conducted in the presence of a protic solvent.

3. A one-pot process for covalently coupling organic compounds which comprises reacting an aromatic ring compound having a halogen or halogen-like substituent at a coupling position with a diboron derivative in the presence of a Group VIII metal catalyst and a suitable base, wherein said diboron derivative is reacted with about two equivalents of said aromatic ring compound to form a symmetrical covalently coupled product, said reaction proceeding via an arylboron intermediate formed by reaction of the diboron derivative with about one equivalent of aromatic ring compound, this arylboron intermediate reacting with the remaining aromatic ring compound to form the coupled product, said covalently coupling comprising a covalent bond between ring coupling positions of two molecules of said aromatic ring compound.

4. A process according to claim 3 wherein said suitable base catalyses both the formation of the organoboron intermediate and the subsequent reaction with the remaining aromatic ring compound. AMENDED SHEET (Article 34) (IPEA/AU) PCT/AU98/00245 p:\OPER\PDB\ARYLIV.PRV -7/4/99 Received 07 April 1999 A process according to claim 3 wherein the suitable base only catalyses the formation of the arylboron intermediate, a stronger base being added after the formation of the intermediate to catalyse reaction of the intermediate with the remaining aromatic ring compound.

6. A process according to claim 3 wherein said aromatic ring compound has an active hydrogen containing substituent.

7. A process according to claim 3 wherein said process is conducted in the presence of a protic solvent.

8. A process for covalently coupling organic compounds according to claim 1 which comprises: reacting an aromatic ring compound having a halogen or halogen-like substituent at a ring coupling position with a diboron derivative in the presence of a Group VIII metal catalyst and a suitable base to form an arylboron intermediate, and (ii) reacting the arylboron intermediate with an organic compound having a halogen or halogen-like substituent at a coupling position in the presence of a Group VIII metal catalyst and a suitable base, whereby the aromatic ring compound is coupled to the organic compound via a direct bond between respective coupling positions, wherein said aromatic ring compound has an active hydrogen containing substituent.

9. A process for covalently coupling organic compounds according to claim 1 which comprises: AMENDED SHEET (Article 34) (IPEA/AU) PCT/AU98/00245 P:\OPER\PDB\ARYLIV.PRV-7/4/99 Received 07 April 1999 -56- reacting an aromatic ring compound having a halogen or halogen-like substituent at a ring coupling position with a diboron derivative in the presence of a Group VIII metal catalyst and a suitable base to form an arylboron intermediate, and (ii) reacting the arylboron intermediate with an organic compound having a halogen or halogen-like substituent at a coupling position in the presence of a Group VIII metal catalyst and a suitable base, whereby the aromatic ring compound is coupled to the organic compound via a direct bond between respective coupling positions, wherein said reactions are conducted in the presence of a protic solvent. A process for covalently coupling organic compounds which comprises: reacting an aromatic ring compound having a halogen or halogen-like substituent at a ring coupling position with a diboron derivative in the presence of a Group VIII metal catalyst and a suitable base to form an arylboron intermediate, (ii) adding water and a suitable base to decompose unreacted diboron derivative, and (iii) reacting the arylboron intermediate with an organic compound having a halogen or halogen-like substituent at a coupling position in the presence of a Group VIII metal catalyst and a suitable base, whereby the aromatic ring compound is coupled to the organic compound via a direct bond between respective coupling positions. AMENDED SHEET (Article 34) (IPEA/AU) PCT/AU98/00245 p:\OPER\PDB\ARYLIV.PRV -7/6/99 Received 07 June 1999

57- 11. A process for covalently coupling organic compounds which comprises: reacting an aromatic ring compound having a halogen or halogen-like substituent at a ring coupling position with diboron derivative in the presence of a Group VIII metal catalyst and a suitable base to form an arylboron intermediate; adding a mild oxidising agent to decompose excess diboron derivative; reacting the arylboron intermediate with an organic compound having a halogen or halogen-like substituent at a coupling position in the presence of a Group VIII metal catalyst and a suitable base whereby the aromatic ring compound is coupled to the organic compound via a direct bond between respective coupling positions. 12. A process according to claim 11 wherein the mild oxidizing agent is selected from N-chlorosuccinimide, dimethyldioxirane, dioxygen gas, chloramine-T, chloramine- B, 1-chlorotriazole, 1,3-dichloro-5,5-dimethylhydantoin, trichloroisocyanuric acid and dichloroisocyanuric acid potassium salt. 13. A process for covalently coupling organic compounds which comprises: reacting an aromatic ring compound having a halogen or halogen-like substituent at a ring coupling position with a diboron derivative in the presence of a Group VIII metal catalyst and a suitable base to form an arylboron intermediate, and (ii) reacting the arylboron intermediate with an organic compound having a halogen or halogen-like substituent at a coupling position in the presence of a Group VIII metal catalyst and a suitable base, whereby the aromatic ring compound is coupled to the organic compound via a direct bond between P2,X respective coupling positions AMENDED SHEET (Article 34) (IPEA/AU) PCT/AU98/00245 P:\OPER\PDB\ARYLIV.PRV-7/4/99 Received 07 April 1999 -58- wherein the reaction of step is conducted at a temperature in the range of 0 to 400C. 14. A process according to claim 13 wherein the suitable base for step is selected from the group consisting of aryl and alkyl carboxylates, fluorides, hydroxides and carbonates of Li, Na, K, Rb, Cs, ammonium, alkylammonium, Mg, Ca and Ba; phosphates, and arylphosphates of Li, Na, K, Rb and Cs; phosphate esters of Li, Na, K, Rb and Cs, phenoxides of Li, Na, K, Rb and Cs; alkoxides of Li, Na, K, Rb and Cs; and thallium hydroxide. A process according to any one of claims 8 to 13 wherein the organic compound is different from the aromatic ring compound. 16. A process according to any one of claims 8 to 13 wherein the aromatic ring compound is the same as the organic compound. 17. A process according to any one of claims 8 to 13 conducted in a single pot. 18. A process according to any one of claims 8 to 13 wherein the arylboron intermediate is isolated prior to reaction with the organic compound. 19. A process according to any one of claims 8 to 13 wherein the organic compound is an olefinic compound with a halogen or halogen-like substituent in a vinylic coupling positions. A process according to any one of claims 8 to 13 wherein at least one of the aromatic ring compound and the organic compound has more than one halogen or halogen-like substituent. AMENDED SHEET (Article 34) (IPEA/AU) PCT/AU98/00245 P:\OPER\PDB\ARYLIV.PRV-7/4/99 Received 07 April 1999 -59- 21. A process according to any one of claims 1 to 20 wherein the Group VIII metal catalyst comprises palladium, nickel or platinum. 22. A process according to claim 21 wherein the Group VIII metal catalyst is a palladium catalyst. 23. A process according to claim 22 wherein the palladium catalyst is a palladium complex. 24. A process according to claim 21 wherein the catalyst is a nickel complex. A process according to claim 23 wherein the palladium complex is selected from PdCl 2 Pd(OAc) 2 PdCl 2 (dppf)CH 2 Cl 2 Pd(PPh 3 4 Pd(PhP(CH),PPh where n is 2, 3 or 4, and related catalysts which are complexes of palladium with phosphine ligands. 26. A process according to claim 22 wherein the catalyst is selected from the group consisting of palladium black, palladium on carbon, palladium clusters and palladium in porous glass. 27. A process according to claim 21 wherein the catalyst is selected from the group consisting of nickel black, Raney nickel, nickel on carbon and nickel clusters. 28. A process according to any one of claims 1 to 27 wherein the diboron derivative is an ester or other stable derivative of diboronic acid. 29. A process according to claim 28 wherein the diboron derivative is a compound of the formula 8, (RO) 2 B-B(RO) 2 AMENDED SHEET (Article 34) (IPEA/AU) PCT/AU98/00245 P:\OPER\PDB\ARYLIV.PRV-7/4/99 Received 07 April 1999 wherein R is optionally substituted alkyl or aryl or -B(OR) 2 represents a cyclic group of the formula B R where R 1 is optionally substituted alkylene, arylene or other divalent group comprising linked aromatic and aliphatic moieties. A process of claim 29 wherein the diboron derivative is selected from the group consisting of the pinacol ester of diboronic acid, bis(ethanediolato) diboron, bis(n- propanediolato) diboron and bis(neopentyldiolato) diboron. 31. A process of any one of claims 1, 8, 10, 11 or 13 conducted in the presence of a protic solvent. 32. A process of any one of claims 2, 7 or 9 wherein the protic solvent is water, an alcohol or a mixture thereof. 33. A process of claim 32 wherein the solvent is water, methanol, ethanol, isopropanol or a mixture thereof. 34. A process according to any one of claims 2, 7 or 9 to 11 wherein the aromatic ring compound has an active hydrogen containing substituent. A process of any one of claims 1 to 12 conducted at a temperature between 0° and 120°C. 36. A process of claim 35 wherein the temperature is in the range of 15 to AMENDED SHEET (Article 34) (IPEA/AU) PCT/AU98/00245 P:\OPER\PDB\ARYLIV.PRV-7/4/99 Received 07 April 1999 -61- 37. A process of any one of claims 8 to 13 wherein the suitable base of step is capable of catalysing reaction of the aromatic ring compound with the diboron derivative, but not strong enough to catalyse the further reaction of the arylboron intermediate with the organic compound. 38. A process of claim 37 wherein the suitable base is selected from the group consisting of aryl and alkyl carboxylates and phosphates of Li, Na, K, Rb, Cs, ammonium and alkylammonium. 39. A process of any one of claims 8 to 12 wherein the suitable base is selected from the group consisting of aryl and alkyl carboxylates, fluorides, hydroxides and carbonates of Li, Na, K, Rb, Cs, ammonium, alkylammonium, Mg, Ca and Ba; phosphates, and arylphosphates of Li, Na, K, Rb and Cs; phosphate esters of Li, Na, K, Rb and Cs, phenoxides of Li, Na, K, Rb and Cs; alkoxides of Li, Na, K, Rb and Cs; and thallium hydroxide. A process of any one of claims 8 to 14 wherein the suitable base utilised in the coupling reaction is selected from cesium carbonate, potassium carbonate and alkali metal hydroxides. 41. A process of any one of claims 1, 2 or 8 to 14 wherein one of said aromatic ring compound and said organic compounds is a polymer. 42. A functionalised polymeric solid when prepared in accordance with the process of claim 41. 43. A process of any one of claims 8 to 14 wherein either the aromatic ring compound or the organic compound is chemically linked to a solid polymer support. AMENDED SHEET (Article 34) (IPEA/AU) PCT/AU98/00245 P:\OPER\PDB\ARYLIV.PRV -7/4/99 Received 07 April 1999 -62- 44. A process according to any one of claims 8 to 14 wherein the organic compound is an aromatic ring compound having a halogen or halogen-like substituent. A process for preparing arylboron intermediates comprising reacting an aromatic ring compound having a halogen or halogen-like substituent and an active hydrogen containing substituent with a diboron derivative in the presence of a Group VIII metal catalyst and a suitable base. 46. A process for preparing arylboron intermediates comprising reacting an aromatic ring compound having a halogen or halogen-like substituent with a diboron derivative in a protic solvent in the presence of a Group VIII metal catalyst and a suitable base. 47. A process for preparing arylboron intermediates comprising reacting an aromatic ring compound having a halogen or halogen like substituent with a diboron derivative in the presence of a Group VIII metal and a suitable base at a temperature in the range of 0 to 40 0 C. 48. A process according to claim 47 wherein the suitable base is selected from the group consisting of aryl and alkyl carboxylates, fluorides, hydroxides and carbonates of Li, Na, K, Rb, Cs, ammonium, alkylammonium, Mg, Ca and Ba; phosphates, and arylphosphates of Li, Na, K, Rb and Cs; phosphate esters of Li, Na, K, Rb and Cs, phenoxides of Li, Na, K, Rb and Cs; alkoxides of Li, Na, K, Rb and Cs; and thallium hydroxide. 49. A process according to claim 45 or claim 46 wherein water or water and suitable base are added to decompose unreacted diboron derivative. An organoboron intermediate prepared according to the process of any one of claims 45 to 49. AMENDED SHEET (Article 34) (IPEA/AU) PCT/AU98/00245 P:\OPFR\PDB\ARYLIV.PRV 7/4/99 Received 07 April 1999 63 51. A process for preparing an arylboronic acid by hydrolysing or hydrogenoly sing an arylboron intermediate of claim 52. A polymer prepared according to the process of any one of claims 1, 8 to 11 or 13 wherein the aromatic ring compound has more than one halogen or halogen-like substituent. 53. A dendrimer prepared according to the process of any one of claims 1, 8 to 11 or 13 wherein the aromatic ring compound has more than two halogen or halogen-like substituents. 54. A process according to any one of claims 8 to 14 wherein the aromatic ring compound and the organic compound are linked together such that the arylboron intermediate formned after reaction of the aromatic ring organic compound with the diboron derivative reacts with the organic compound to provide an intramolecular ring closure. Arylboron intermediates selected from: 2-(4-N-Methylcarbamoylphenyl)-4,4, 5,5 -tetramethyl- 1,3 ,2-dioxaborolane, 2-(4-Fluorophenyl)-4,4, 5,5 -tetramethyl- 1,3 ,2-dioxaborolane, 2-(2,6-Dimethoxypyridine-3 -yl)-4 ,4 ,5 ,5-tetramethyl- 1,3 ,2-dioxaborolane, 2-(4,4'-Biphenyl)bis-4,4,5, 5-tetramethyl- 1,3 ,2-dioxaborolane, 2-(4-Acetamidophenyl)-4,4, 5, 5-tetramethyl- 1,3 ,2-dioxaborolane, 2-(2-Methoxy-5-carbethoxyphenyl)-4,4, 5,5 -tetramethyl- 1,3 ,2-dioxaborolane, 2-(2-Bromopyridine-5 5,5 -tetramethyl- 1,3 ,2-dioxaborolane, 2-(3 -Methyl-4-methoxyphenyl)-4,4, 5,5 -tetramethyl- 1,3 ,2-dioxaborolane, 2-(2,4-Dimethylphenyl)-4,4, 5,5-tetramethyl- 1,3 ,2-dioxaborolane, 2-(4-Trifluoromethylphenyl)-4,4, 5, 5-tetramethyl- 1,3 ,2-dioxaborolane, 2-(4-tert-Butylphenyl)-4,4,5, 5-tetramethyl- 1,3 ,2-dioxaborolane, 5-Trimethoxyphenyl)-4,4,5,5 -tetramethyl- 1,3 ,2-dioxaborolane, AMENDED SHEET (Article 34) (WPEA/AUT) I PCT/AU98/00245 P:\OPER\PDB\ARYLIV.PRV 1/4/99 Received 07 April 1999 64 2-(2-Methyl-4-methoxyphenyl)-4,4,5S,5-tetramethyl- 1,3 ,2-dioxaborolane, 2-(2,4-Dimethoxyphenyl)-4,4, 5, 5-tetramethyl- 1,3 ,2-.dioxaborolane, 2-(Thiophene-3 5-tetramethyl- 1,3 ,2-dioxaborolane, 2.-(4-Sulfamylphenyl)-4,4, 5, 5-tetramethyl- 1,3 ,2-dioxaborolane, 2-(3 -carboxy-4-aminophenyl)-4,4, 5, 5-tetramnethyl- 1,3 ,2-dioxaborolane, 2-(2-(l1 H-Tetrazole-5-yl)phenyl)-4,4, 5,5 -tetramethyl- 1,3 ,2-dioxaborolane, 2-(4-Aminophenyl)-4,4, 5, 5-tetramethyl- 1,3 ,2-dioxaborolane, 2-(3 -Hydroxyphenyl)-4,4, 5, 5-tetramethyl- 1,3 ,2-dioxaborolane, 1H-Pyrazole-4-yl)-4,4, 5, 5-tetramethyl- 1,3 ,2-dioxaborolane, 2-(2-cyanophenyl)-4,4, 5, 5-tetramethyl- 1,3 ,2-dioxaborolane, 2-(3 -cyanophenyl)-4,4, 5, 5-tetramethyl- 1,3 ,2-dioxaborolane, 2-(3 -(acetyl)phenyl)-4,4, 5, 5-tetramethyl- 1,3 ,2-dioxaborolane, 2-(2-Cyanophenyl)-5, 5-dimethyl- 1,3 ,2-dioxaborinane, 2-(3 -Cyanophenyl)-5, 5-dimethyl- 1,3 ,2-dioxaborinane, 2-(4-Cyanophenyl)-5, 5-dimethyl- 1,3,2-dioxaborinane, 2-(2,4,6-Trimethylphenyl)-5, 5-dimethyl- 1,3 ,2-dioxaborinane, 2-(2-Cyanophenyl)- 1,3 ,2-dioxaborolane, 2-(4-Cyanophenyl)- 1,3 ,2-dioxaborolane, 1 -Oxoindane-5-yl)-4,4, 5,5 -tetramethyl- 1,3 ,2-dioxaborolane, 2-(3 -Formyl-4-hydroxy-5 -methoxyphenyl)-4,4, 5, 5-tetramethyl- 1,3 ,2-dioxaborolane, 2-(3 ,5 -Dimethylisoxazole-4-yl)- 1,3 ,2-dioxaborolane, 2-(2-Cyano-3 -fluorophenyl)- 1,3 ,2-dioxaborolane, 2-(Thiazole-2-yl)- 1,3 ,2-dioxaborolane, 2-(2-Methoxy-5-cyanomethylphenyl)-5 ,5 -dimethyl- 1,3 ,2-dioxaborinane, 2-(3 -Phenoxyphenyl)- 1,3 ,2-dioxaborinane, 2-(Thiazole-2-yl)-4,4, 5,5 -tetramethyl- 1,3 ,2-dioxaborolane, 2-(3 -Trimethoxysilylphenyl)-4,4, 5, 5-tetramethyl- 1,3 ,2-dioxaborolane, 2-(4-Trimethoxysilylphenyl)-4,4, 5,5-tetramethyl- 1,3 ,2-dioxaborolane, and 2-(2,4,6-Trimethylphenyl)- 1,3 ,2-dioxaborolane. AMENDED SHEET (Article 34) (EPEA/AU) PCT/AU98/00245 Received 07 April 1999 P:\OPER\PDB\ARYLIVPRV -17/4199 65 56. A process according to claim 25 wherein the palladium complex is a complex of palladium with a phosphine ligand selected from the group consisting of P(o- tolYl) 3 P(i-Pr) 3 P(cyclohexyl) 3 P(o-MeOPh) 3 P(p-MeOPh) 3 dppp, dppb, TDMPP, TTMPP, TMPP, TMSPP and related water soluble phosphines. AMENDED SHEET (Article 34) (IPEA/ALU)