WO2009138708A1

WO2009138708A1 - Bicyclic monophosphines

Info

Publication number: WO2009138708A1
Application number: PCT/GB2008/001680
Authority: WO
Inventors: Simon Doherty; Catherine Smyth; Julian Knight
Original assignee: University Of Newcastle Upon Tyne
Priority date: 2008-05-15
Filing date: 2008-05-15
Publication date: 2009-11-19

Abstract

A compound of formula (I): wherein: R^P1 and R^P2 are independently selected from C_3-12 alkyl groups; R^C is a C_5-6 aryl group, optionally substituted by one or more groups selected from: C_1-7 alkyl, C_1-7 alkoxy, halo, NH₂, C_1-7alkylamino, di-C_1-7alkylamino, and C_5-6 aryl; R^A1 and R^A2 are independently selected from H, Cl, and an optionally substituted group selected from: C_1-7 alkyl, C_1-7 alkoxy, C_1-7 alkylthio and C_5-6 aryl, wherein the optional substituents are selected from: C_1-7 alkyl, C_1-7 alkoxy, halo, NH₂, C_1-7alkylamino, di-C_1-7alkylamino, and C_5-6 aryl.

Description

Bicyclic monophosphines

The present invention relates to bicyclic monophosphines, methods of making these compounds, use of these compounds as ligands for palladium catalysts, as well as the use of palladium or nickel catalysts comprising these compounds as ligands for C-C and C-N bond forming reactions.

Palladium-catalyzed C-C and C-heteroatom bond formation has evolved into an exceptionally powerful tool which has found wide spread use in many areas of organic synthesis. While the first catalysts for these transformations were typically based on a source of palladium and either a triarylphosphine or a chelating diphosphine such as 2,2'-bis(diphenylphosphino)-1,1'-binapthyl (BlNAP) or 1 ,1'-bis(diphenylphosphino)ferrocene (dppf) high temperatures were often required to achieve acceptable levels of efficiency and they were generally unreactive towards aryl chloride substrates (Wolfe, J. P., et al., Ace. Chem. Res. 1998, 31, 805; Hartwig, J. F., Angew. Chem. Int. Ed. 1998, 110, 2154; Yang, B. H. and Buchwald, Sl.J., Organomet. Chem. 1999, 576, 125; Wolfe, J.P., et al., J. Am. Chem. Soc. 1996, 118, 7215; Driver, M.S. and Hartwig, J.F., J. Am. Chem. Soc. 1996, 118, 7217).

However, recent advances in catalyst development have led to the discovery that electron-rich biaryl monophosphines such as compounds 1 and 2:

(where Cy represents cyclohexyl), and their derivatives, form highly efficient catalysts for C-N as well as C-C and C-O bond formation with aryl chlorides, often at room-temperature and at very low catalyst loadings. (Wolfe, J.P. and Buchwald, S.L., Angew. Chem. Int. Ed. 1999, 38, 2413; Wolfe, J. P., et a/., J. Org. Chem. 2000, 65, 1158; Wolfe, J.P., et a/., J. Am. Chem. Soc. 1999, 121, 9550). The efficiency of these catalyst systems has been attributed to a combination of factors the first of which is their highly electron-rich character which facilitates oxidative addition of less reactive aryl chlorides. Recent studies also suggest that the steric bulk of these biaryl phosphines is critical to achieving high activity by promoting formation of the monophosphine complex (Strieter, E. R., et al., J. Am. Chem. Soc. 2003, 125, 13978). Finally, computational and experimental studies reveal that a weak interaction between palladium and the ortho carbon atom of the non-phosphine-containing ring of the ligand stabilizes the catalyst when the palladium is not involved in a step within the catalytic cycle (Barder, T.E., et al., Organometallics 2007, 26, 2183).

Nickel complexes of monophosphines are also proving to be remarkably efficient catalysts for C-C bond formation e.g. carbonyl-ene type reactions, (Ho, C.Y.; Ng, S. S.; Jamison, T. F. J. Am. Chem. Soc. 2006, 128, 5362) as well as various cross couplings (Lee, C. C; Ke, W. C; Chan, K. T.; Lai, C. L.; Hu, CH. ; Lee, H. M Chem Eur. J. 2007, 13, 582) and in some cases these catalysts are more efficient than their palladium counterparts.

The present inventors have developed a new family of biaryl-like monophosphines which combine with a source Pd(O), Pd(II), Ni(O) or Ni(II) to form highly active catalysts for a range C- C and C- N bond forming reactions. Key features associated with these monophosphines are (i) the biaryl architecture is constructed via a [4+2] cycloaddition between a 1-alkynylphosphine oxide and an anthracene in an operationally straightforward procedure (ii) their modular synthesis enables the steric and electronic properties to be varied to facilitate catalyst optimisation and enables the substitution pattern of the aryl ring of the biaryl-like fragment to be varied since it is derived from a terminal aryl alkyne and (iii) they form highly efficient catalysts for use with aryl chloride substrates.

Accordingly, a first aspect of the present invention provides compounds of formula I:

wherein:

R^P1 and R^P2 are independently selected from C_3-12 alkyl groups;

R^c is a C_5-6 aryl group, optionally substituted by one or more groups selected from: Ci_-7 alkyl, Ci- ₇ alkoxy, halo, NH₂, C_1-7alkylamino, di-Ci.₇alkylamino, and C_5-6 aryl;

R^A1 and R*² are independently selected from H, Cl, and an optionally substituted group selected from: Ci_-7 alkyl, Ci_-7 alkoxy, C_1-7 alkylthio and C₅^ aryl, wherein the optional substituents are selected from: Ci_-7 alkyl, Ci_-7 alkoxy, halo, NH₂, C_1-7alkylamino, di-C_1-7alkylamino, and C_5-6 aryl.

A second aspect of the invention provides a method of synthesising a compound of the first aspect, comprising the step of reducing a corresponding compound of formula (II):

wherein R^P1, R^P2, R^c, R^A1 and R^ are as defined in the first aspect.

A third aspect of the present invention provides the use of a compound of formula I as a ligand for a palladium or nickel catalyst.

A fourth aspect of the present invention provides a palladium or nickel catalyst comprising a ligand of formula I. These catalysts can be formed by reaction of a source of Pd(O), Pd(II) , Ni(O) or Ni(II) with a ligand of formula I (e.g. two equivalents of ligand). Without wishing to be bound by theory, the reaction is thought to result in a catalyst with an equilibrium of (I)M and (I)₂M (M = Ni or Pd).

A fifth aspect of the present invention provides carrying out a C-C or C-N bond forming reaction using a catalyst of the fourth aspect of the invention.

Definitions

Alkyl: The term "alkyl" as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to 20 carbon atoms (unless otherwise specified), which may be aliphatic or alicyclic, and which may be saturated or unsaturated (e.g. partially unsaturated, fully unsaturated). Thus, the term "alkyl" includes the sub-classes alkenyl, alkynyl, cycloalkyl, cycloalkyenyl, cylcoalkynyl, etc., discussed below.

In the context of alkyl groups, the prefixes (e.g. Ci_4, d._7l C_2-7, C_3-7, etc.) denote the number of carbon atoms, or range of number of carbon atoms. For example, the term "C-M alkyl", as used herein, pertains to an alkyl group having from 1 to 4 carbon atoms. Examples of groups of alkyl groups include Ci_-4 alkyl ("lower alkyl") and Ci_-7 alkyl. Note that the first prefix may vary according to other limitations; for example, for unsaturated alkyl groups, the first prefix must be at least 2; for cyclic alkyl groups, the first prefix must be at least 3; etc.

Examples of (unsubstituted) saturated alkyl groups include, but are not limited to, methyl (Ci), ethyl (C₂), propyl (C₃), butyl (C₄), pentyl (C₅), hexyl (C₆), heptyl (C₇), octyl (C₈), nonyl (C₉), decyl (C₁₀), undecyl (C₁₁) and dodecyl (C₁₂). Examples of (unsubstituted) saturated linear alkyl groups include, but are not limited to, methyl (Ci)₁ ethyl (C₂), n-propyl (C₃), n-butyl (C₄), n-pentyl (amyl) (C₅), n-hexyl (C₆), and n-heptyl (C₇).

Examples of (unsubstituted) saturated branched alkyl groups include iso-propyl (C₃), iso-butyl (C₄), sec-butyl (C₄), tert-butyl (C₄), iso-pentyl (C₅), and neo-pentyl (C₅).

Alkenyl: The term "alkenyl", as used herein, pertains to an alkyl group having one or more carbon-carbon double bonds. Examples of groups of alkenyl groups include C_2-4 alkenyl, C_2-7 alkenyl and C₂-₁₂ alkenyl.

Examples of (unsubstituted) unsaturated alkenyl groups include, but are not limited to, ethenyl (vinyl, -CH=CH₂), 1-propenyl (-CH=CH-CH₃), 2-propenyl (allyl, -CH-CH=CH₂), isopropenyl (1- methylvinyl, -C(CH₃)=CH₂), butenyl (C₄), pentenyl (C₅), and hexenyl (C₆).

Alkynyl: The term "alkynyl", as used herein, pertains to an alkyl group having one or more carbon-carbon triple bonds. Examples of groups of alkynyl groups include C_2-4 alkynyl, C_2-7 alkynyl and C_2-i₂ alkynyl.

Examples of (unsubstituted) unsaturated alkynyl groups include, but are not limited to, ethynyl (ethinyl, -C=CH) and 2-propynyl (propargyl, -CH₂-C=CH).

Cycloalkyl: The term "cycloalkyl", as used herein, pertains to an alkyl group which is also a cyclyl group; that is, a monovalent moiety obtained by removing a hydrogen atom from an alicyclic ring atom of a carbocyclic ring of a carbocyclic compound, which carbocyclic ring may be saturated or unsaturated (e.g. partially unsaturated, fully unsaturated), which moiety has from 3 to 7 carbon atoms (unless otherwise specified), including from 3 to 7 ring atoms. Thus, the term "cycloalkyl" includes the sub-classes cycloalkenyl and cycloalkynyl. Preferably, each ring has from 3 to 7 ring atoms. Examples of groups of cycloalkyl groups include C_3-7 cycloalkyl and C₃.i₂ cycloalkyl.

Examples of cycloalkyl groups include, but are not limited to, those derived from: saturated monocyclic hydrocarbon compounds: cyclopropane (C₃), cyclobutane (C₄), cyclopentane (C₅), cyclohexane (C₆), cycloheptane (C₇), methylcyclopropane (C₄), dimethylcyclopropane (C₅), methylcyclobutane (C₅), dimethylcyclobutane (C₆), methylcyclopentane (C₆), dimethylcyclopentane (C₇), methylcyclohexane (C₇), dimethylcyclohexane (C₈) and menthane (C10); unsaturated monocyclic hydrocarbon compounds: cyclopropene (C₃), cyclobutene (C₄), cyclopentene (C₅), cyclohexene (C₆), methylcyclopropene (C₄), dimethylcyclopropene (C₅), methylcyclobutene (C₅), dimethylcyclobutene (C₆), methylcyclopentene (C₆), dimethylcyclopentene (C₇), methylcyclohexene (C₇) and dimethylcyclohexene (C₈); saturated polycyclic hydrocarbon compounds: thujane (C₁₀), carane (C₁₀), pinane (Ci₀), bornane (C_1O), norcarane (C₇), norpinane (C₇), norbornane (C₇), adamantane (C₁₀) and decalin (decahydronaphthalene) (C₁₀); and unsaturated polycyclic hydrocarbon compounds: camphene (C₁₀), limonene (C₁₀) and pinene (C₁₀).

Heterocyclyl: The term "heterocyclyl", as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has from 3 to 7 ring atoms (unless otherwise specified), of which from 1 to 4 are ring heteroatoms. Preferably, each ring has from 3 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms.

In this context, the prefixes (e.g. C_3-7, C_5-6, etc.) denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms. For example, the term "C₅.₆heterocyclyl", as used herein, pertains to a heterocyclyl group having 5 or 6 ring atoms. Examples of groups of heterocyclyl groups include C_3-7 heterocyclyl, C_5-7 heterocyclyl, and C_5-6 heterocyclyl.

Examples of monocyclic heterocyclyl groups include, but are not limited to, those derived from:

N₁: aziridine (C₃), azetidine (C₄), pyrrolidine (tetrahydropyrrole) (C₅), pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole) (C₅), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) (C₅), piperidine (C₆), dihydropyridine (C₆), tetrahydropyridine (C₆), azepine (C₇);

O₁: oxirane (C₃), oxetane (C₄), oxolane (tetrahydrofuran) (C₅), oxole (dihydrofuran) (C₅), oxane (tetrahydropyran) (C₆), dihydropyran (C₆), pyran (C₆), oxepin (C₇);

S₁: thiirane (C₃), thietane (C₄), thiolane (tetrahydrothiophene) (C₅), thiane (tetrahydrothiopyran) (C₆), thiepane (C₇);

O₂: dioxolane (C₅), dioxane (C₆), and dioxepane (C₇);

O₃: trioxane (C₆); N₂: imidazolidine (C₅), pyrazolidine (diazolidine) (C₅), imidazoline (C₅), pyrazoline (dihydropyrazole) (C₅), piperazine (C₆);

N₁Oi: tetrahydrooxazole (C₅), dihydrooxazole (C₅), tetrahydroisoxazole (C₅), dihydroisoxazole (C₅), morpholine (C₆), tetrahydrooxazine (C₆), dihydrooxazine (C₆), oxazine (C₆);

NiS₁: thiazoline (C₅), thiazolidine (C₅), thiomorpholine (C₆);

N₂O₁: oxadiazine (C₆);

O₁S₁: oxathiole (C₅) and oxathiane (thioxane) (C₆); and,

N₁OiSi: oxathiazine (C₆).

Examples of substituted (non-aromatic) monocyclic heterocyclyl groups include those derived from saccharides, in cyclic form, for example, furanoses (C₅), such as arabinofuranose, lyxofuranose, ribofuranose, and xylofuranse, and pyranoses (C₆), such as allopyranose, altropyranose, glucopyranose, mannopyranose, gulopyranose, idopyranose, galactopyranose, and talopyranose.

Spiro-C_3-7 cycloalkyl or heterocyclyl: The term "spiro C_3-7 cycloalkyl or heterocyclyl" as used herein, refers to a C_3-7 cycloalkyl or C_3-7 heterocyclyl ring joined to another ring by a single atom common to both rings.

C_5-20 aryl: The term "C_5-20 aryl" as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of a C_5-20 aromatic compound, said compound having one ring, or two or more rings (e.g., fused), and having from 5 to 20 ring atoms, and wherein at least one of said ring(s) is an aromatic ring. Preferably, each ring has from 5 to 7 ring atoms.

The ring atoms may be all carbon atoms, as in "carboaryl groups" in which case the group may conveniently be referred to as a "C_5-20 carboaryl" group.

Examples of C₅.₂₀ aryl groups which do not have ring heteroatoms (i.e. C_5-20 carboaryl groups) include, but are not limited to, those derived from benzene (i.e. phenyl) (C₆), naphthalene (Ci₀), anthracene (C_i4), phenanthrene (C₁₄), and pyrene (C₁₆). Alternatively, the ring atoms may include one or more heteroatoms, including but not limited to oxygen, nitrogen, and sulfur, as in "heteroaryl groups". In this case, the group may conveniently be referred to as a "C_5-2o heteroaryl" group, wherein "C_5-2o" denotes ring atoms, whether carbon atoms or heteroatoms. Preferably, each ring has from 5 to 7 ring atoms, of which from 0 to 4 are ring heteroatoms.

Examples of C_5-2O heteroaryl groups include, but are not limited to, C₅ heteroaryl groups derived from furan (oxole), thiophene (thiole), pyrrole (azole), imidazole (1 ,3-diazole), pyrazole (1,2-diazole), triazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, tetrazole and oxatriazole; and C₆ heteroaryl groups derived from isoxazine, pyridine (azine), pyridazine (1 ,2-diazine), pyrimidine (1 ,3-diazine; e.g., cytosine, thymine, uracil), pyrazine (1 ,4-diazine) and triazine.

The heteroaryl group may be bonded via a carbon or hetero ring atom.

Examples of C_5-2O heteroaryl groups which comprise fused rings, include, but are not limited to, C₉ heteroaryl groups derived from benzofuran, isobenzofuran, benzothiophene, indole, isoindole; Ci₀ heteroaryl groups derived from quinoline, isoquinoline, benzodiazine, pyridopyridine; Ci₄ heteroaryl groups derived from acridine and xanthene.

The above alkyl, heterocyclyl, and aryl groups, whether alone or part of another substituent, may themselves optionally be substituted with one or more groups selected from themselves and the additional substituents listed below.

Halo: -F, -Cl, -Br, and -I.

Hydroxy: -OH.

Ether: -OR, wherein R is an ether substituent, for example, a Ci_-7 alkyl group (also referred to as a Ci.₇ alkoxy group), a C_3-20 heterocyclyl group (also referred to as a C_3-2O heterocyclyloxy group), or a C_5-20 aryl group (also referred to as a C_5-20 aryloxy group), preferably a Ci_-7 alkyl group.

Nitro: -NO₂.

Cyano (nitrile, carbonitrile): -CN. Acyl (keto): -C(=0)R, wherein R is an acyl substituent, for example, H, a C_1-7 alkyl group (also referred to as C_1-7 alkylacyl or Ci_-7 alkanoyl), a C_3-2O heterocyclyl group (also referred to as C_3-2O heterocyclylacyl), or a C₅.₂o aryl group (also referred to as C_5-20 arylacyl), preferably a Ci.₇ alkyl group. Examples of acyl groups include, but are not limited to, -C(=O)CH₃ (acetyl), -C(=O)CH₂CH₃ (propionyl), -C(=O)C(CH₃)₃ (butyryl), and -C(=O)Ph (benzoyl, phenone).

Carboxy (carboxylic acid): -COOH.

Ester (carboxylate, carboxylic acid ester, oxycarbonyl): -C(=O)OR, wherein R is an ester substituent, for example, a C_1-7 alkyl group, a C_3-20 heterocyclyl group, or a C_5-20 aryl group, preferably a C_1-7 alkyl group (a C_1-7 alkyl ester). Examples of ester groups include, but are not limited to, -C(=O)OCH₃, -C(=O)OCH₂CH₃, -C(=O)OC(CH₃)₃, and -C(=O)OPh.

Amido (carbamoyl, carbamyl, aminocarbonyl, carboxamide): -C(=O)NR¹R², wherein R¹ and R² are independently amino substituents, as defined for amino groups. Examples of amido groups include, but are not limited to, -C(=O)NH₂, -C(=O)NHCH₃, -C(=O)N(CH₃)₂, -C(=O)NHCH₂CH₃, and -C(=O)N(CH₂CH₃)₂, as well as amido groups in which R¹ and R², together with the nitrogen atom to which they are attached, form a heterocyclic structure as in, for example, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, and piperazinylcarbonyl.

Amino: -NR¹R², wherein R¹ and R² are independently amino substituents, for example, hydrogen, a C_1-7 alkyl group (also referred to as C_1-7 alkylamino or di-C_1-7 alkylamino), a C_3-20 heterocyclyl group, or a C₅.₂o aryl group, preferably H or a C_1-7 alkyl group, or, in the case of a "cyclic" amino group, R¹ and R², taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 ring atoms. Examples of amino groups include, but are not limited to, -NH₂, -NHCH₃, -NHCH(CH₃)₂, -N(CH₃J₂, -N(CH₂CH₃J₂, and -NHPh. Examples of cyclic amino groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidino, piperazinyl, perhydrodiazepinyl, morpholino, and thiomorpholino. The cylic amino groups may be substituted on their ring by any of the substituents defined here, for example carboxy, carboxylate and amido.

Acylamido (acylamino): -NR¹C(=O)R², wherein R¹ is an amide substituent, for example, hydrogen, a C_1-7 alkyl group, a C_3-20 heterocyclyl group, or a C_5-20 aryl group, preferably H or a C_1-7 alkyl group, most preferably H, and R² is an acyl substituent, for example, a C_1-7 alkyl group, a C_3-20 heterocyclyl group, or a C_5-20 aryl group, preferably a C_1-7 alkyl group. Examples of acylamide groups include, but are not limited to, -NHC(=O)CH₃ , -NHC(=O)CH₂CH₃, and -NHC(=O)Ph. R¹ and R² may together form a cyclic structure, as in, for example, succinimidyl, maleimidyl, and phthalimidyl:

succinimidyl maleimidyl phthalimidyl

Ureido: -N(R¹)CONR²R³ wherein R² and R³ are independently amino substituents, as defined for amino groups, and R1 is a ureido substituent, for example, hydrogen, a C_1-7alkyl group, a C₃.₂oheterocyclyl group, or a C₅.₂oaryl group, preferably hydrogen or a C_1-7alkyl group. Examples of ureido groups include, but are not limited to, -NHCONH₂, -NHCONHMe, -NHCONHEt, -NHCONMe₂, -NHCONEt₂, -NMeCONH₂, -NMeCONHMe, -NMeCONHEt, - NMeCONMe₂, -NMeCONEt₂ and -NHC(=O)NHPh.

Acyloxy (reverse ester): -0C(=0)R, wherein R is an acyloxy substituent, for example, a Ci_-7 alkyl group, a C_3-20 heterocyclyl group, or a C_5-20 aryl group, preferably a Ci_-7 alkyl group. Examples of acyloxy groups include, but are not limited to, -0C(=0)CH₃ (acetoxy), - OC(=O)CH₂CH₃, -OC(=O)C(CH₃)₃, -OC(=O)Ph, -OC(=O)C₆H₄F, and -OC(=O)CH₂Ph.

Thiol : -SH.

Thioether (sulfide): -SR, wherein R is a thioether substituent, for example, a C_1-7 alkyl group (also referred to as a Ci_-7 alkylthio group), a C_3-20 heterocyclyl group, or a C_5-20 aryl group, preferably a Ci_-7 alkyl group. Examples of Ci_-7 alkylthio groups include, but are not limited to, -SCH₃ and -SCH₂CH₃.

Sulfoxide (sulfinyl): -S(=0)R, wherein R is a sulfoxide substituent, for example, a Ci-₇ alkyl group, a C_3-20 heterocyclyl group, or a C_5-20 aryl group, preferably a Ci_-7 alkyl group. Examples of sulfoxide groups include, but are not limited to, -S(=0)CH₃ and -S(=O)CH₂CH₃.

Sulfonyl (sulfone): -S(=0)₂R, wherein R is a sulfone substituent, for example, a Ci.₇ alkyl group, a C_3-20 heterocyclyl group, or a C_5-20 aryl group, preferably a Ci_-7 alkyl group. Examples of sulfone groups include, but are not limited to, -S(=O)₂CH₃ (methanesulfonyl, mesyl), -S(=O)₂CF₃, -S(=O)₂CH₂CH₃, and 4-methylphenylsulfonyl (tosyl). Thioamido (thiocarbamyl): -C(=S)NR¹R², wherein R¹ and R² are independently amino substituents, as defined for amino groups. Examples of amido groups include, but are not limited to, -C(=S)NH₂, -C(=S)NHCH₃, -C(=S)N(CH₃)₂, and -C(=S)NHCH₂CH₃.

Sulfonamino: -NR¹S(=O)₂R, wherein R¹ is an amino substituent, as defined for amino groups, and R is a sulfonamino substituent, for example, a Ci_-7alkyl group, a C_3-20heterocyclyl group, or a C₅.₂₀aryl group, preferably a C_1-7alkyl group. Examples of sulfonamino groups include, but are not limited to, -NHS(=O)₂CH₃, -NHS(=O)₂Ph and -N(CH₃)S(=O)₂C₆H₅.

Siloxy (silyl ether): -OSiR₃, where R is H or a C^alkyl group. Examples of silyloxy groups include, but are not limited to, -OSiH₃, -OSiH₂(CH₃), -OSiH(CH₃J₂, -OSi(CH₃)₃ , -OSi(Et)₃, - OSi(JPr)₃, -OSi(tBu)(CH₃)₂, and -OSi(tBu)₃.

As mentioned above, the groups that form the above listed substituent groups, e.g. Cw alkyl, C_3-20 heterocyclyl and C_5-20 aryl, may themselves be substituted. Thus, the above definitions cover substituent groups which are substituted.

Further preferences and embodiments

First aspect R*¹ and R"²

R^A1 and R*² are independently selected from H, Cl, and an optionally substituted group selected from: C_1-7 alkyl, C_1-7 alkoxy, C_1-7 alkylthio and C_5-6 aryl, wherein the optional substituents are selected from: C_1-7 alkyl, C_1-7 alkoxy, halo, NH₂, Ci.₇alkylamino, di-C_1-7alkylamino, and C₅.₆ aryl. In some embodiments, R^A1 and R^ are the same. In other embodiments, R^A1 and R^ are different.

In particular, in some embodiments R^A1 is H and R^ may be selected from H, Cl, and an optionally substituted group selected from: C_1-7 alkyl, C_1-7 alkoxy, d.₇ alkylthio and C_5-6 aryl, wherein the optional substituents are selected from: C_1-7 alkyl, C_1-7 alkoxy, halo, NH₂, C₁. 7alkylamino, di-C_1-7alkylamino, and C_5-6 aryl.

In other embodiments, R^A1 and R^M are independently selected from H and methyl.

It may be preferred that R^A1 and R^ are both H. FT and R*²

R^P1 and R^P2 are independently selected from C₃-1₂ alkyl groups. These are preferably unsubstituted. In some embodiments, R^P1 and R^P2 are the same. In other embodiments, R^P1 and R^P2 are different.

In some embodiments, R^P1 and R^P2 may be selected from C_3-7 saturated alkyl groups, e.g. propyl, butyl, and in particular, branched C_3-7 saturated alkyl groups, e.g. iso-propyl, tert-butyl.

In other embodiments, R^P1 and R^P2 may be selected from C_5-7 cycloalkyl groups, e.g. cyclopentyl, cyclohexyl, cycloheptyl.

In other embodiments, R^P1 and R^P2 may be selected from C₁₀-₁₂ polycyclic cycloalkyl groups, e.g. adamantyl.

In some embodiments, R^P1 and R^P2 are the same and are selected from: isopropyl, tert-butyl, cyclohexyl and adamantyl.

R^c

R^c is a C_5-6 aryl group, optionally substituted by one or more groups selected from: C_1-7 alkyl, Ci_-7 alkoxy, halo, NH₂, Ci_-7alkylamino, di-Ci.₇alkylamino, and C_5-6 aryl.

In some embodiments, R^c is unsubstituted. In other embodiments, R^c is substituted.

In some embodiments, R^c is a C₆ aryl group. In particular, the C₆ aryl group may be phenyl or pyridyl. If the C₆ aryl group is substituted, the substituents may be those listed above. If the C₆ aryl bears a single substituent, this may be in any available ring position (i.e. on any carbon ring atom), e.g. the 2-, 3- or 4- positions. In some embodiments, the single substituent is in the 2- position. If the C₆ aryl bears two substituents, these may be in the 2- and 3- positions, the 2- and 4- positions, the 2- and 5-positions, the 3- and 4- positions, the 3- and 5- positions (where appropriate). In some embodiments, the two substituents are the same. If the C₆ aryl bears three substituents, these may be in the 2-, 3- and 4- and the 3-, 4- and 5- positions (where appropriate). The three substituents may be the same, two may be the same or all may be different. If the C₆ aryl group is pyridyl, the nitrogen ring atom may be in the 2-, 3- or 4- positions.

In other embodiments, R^c is a C₅ heteroaryl group, for example furanyl or thiophenyl. In some embodiments, these groups are unsubstituted. In other embodiments, the groups may bear 1 , 2 or 3 substituents, which may be any available ring position. The ring heroatom may be in any ring position.

In some embodiments, the R^c substituents are selected from: C_1-7 alkyl, C_1-7 alkoxy, halo, NH₂, C_1-7alkylamino and di-C_1-7alkylamino. They may in particular be selected from: C_1-4 alkyl, C_1-4 alkoxy, halo, NH₂, C^alkylamino and di-Ci-₄alkylamino.

Where appropriate, the above preferences may be taken in combination with each other and may apply to any aspect of the invention.

Second Aspect

In the method of the second aspect, the reduction of the compound of formula Il may be carried out by heating a toluene solution of the compound of formula II, trichlorosilane and triethylamine or other suitable amine. The solution may be heated to a temperature of 100⁰C or greater, e.g 11O⁰C, for at least 12 hours, e.g. for 48 hours.

In the method of the second aspect of the invention, compounds of formula Il may be synthesised by reacting a compound of formula Ilia with a compound of formula NIb:

This Diels-Alder reaction may be carried out under standard conditions, e.g. heating at 200⁰C for 12 to 24 hours.

Compounds of formula Ilia may be synthesised by reaction of compounds of formula IVa with compounds of formula IVb:

wherein Y is either H or trimethylsilyl. The reaction may comprise initial treatment of the compound of IVa with n-BuLi, for example, in tetrahydrofuran followed by oxidation of the resulting compound of formula IVc:

with hydrogen peroxide to afford compounds of formula Ilia.

Fifth aspect

The catalysts of the present invention may be used for a wide range of palladium and nickel catalysed C-C and C-heteroatom bond forming reactions including the amination of aryl, heteroaryl and alkenyl halides, the alpha-arylation of ketone enolates, cross coupling reactions such as Suzuki-Miyaura, Sonogashira and Negishi cross couplings, the Mizoroki-Heck reaction, nickel catalysed coupling of alkenes, aldehdyes and silyl triflates, the palladium-mediated carbonylation of unsaturated hydrocarbons and the palladium catalysed direct arylation of aromatic and heteroaromatic C-H bonds. Compounds of formula I may also be used for ruthenium catalysed metathesis reactions including cross metathesis and ring closing metathesis as well as gold and silver catalysed cyclizations such as carbostanylations, allyl-allyl coupling and cycloadditions.

Reactions of particular interest are:

(a) amination of aryl, heteroaryl and alkenyl halides by primary and secondary amines;

(b) Suzuki-Miyaura coupling of aryl and heteroaryl halides.

Further aspects of the present invention are the compounds of the examples below.

Examples

General Methods

All manipulations involving air-sensitive materials were carried out using standard Schlenk line techniques under an atmosphere of nitrogen or argon in oven-dried glassware. Dichloromethane was distilled from calcium hydride and THF and toluene from sodium under an atmosphere of nitrogen. All amines were purchased from commercial suppliers and purified by passing through a short column of alumina immediately prior to use. Phenylacetylene, 2- ethynylanisole, chlorodicyclohexylphosphine, anthracene, aryl halides and boronic acids were purchased from commercial suppliers and used without further purification. 2-ethynyl-Λ/,Λ/- dimethylaniline (Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem. 2006, 71, 62; Li, H., et a/., J. Org. Chem. 2003, 68, 5512) and [(cycloocta-1 ,5-diene)PdCI₂] (Drew, D. and Doyle, J. R., Inorg. Synth. 1990, 28, 346) were prepared as previously described. ¹H, ³¹P and ¹³C(¹H) NMR spectra were recorded on a JEOL LAMBDA 500 or a Bruker AMX 300 instrument. Elemental analyses were performed by the Advanced Chemical and Materials Analysis Unit, Newcastle University. Thin-layer chromatography (TLC) was carried out on aluminum sheets pre-coated with silica gel 6OF 254 and column chromatography was performed using Merck Kieselgel 60. Gas chromatography was performed on a Shimadzu 2010 series gas chromatograph equipped with a split-mode capillary injection system and flame ionization detection using a Supelco Beta DEX column.

Example 1

3a-c 4a-c

5a-c 6a-c where Cy represents cyclohexyl and X is: a) H; b) OMe; and c) NMe₂.

a) Synthesis of compounds 4a-c (i) (Dicyclohexylphosphinoylethynyl)benzene (4a) (Heller, B., et a!.. Chem Eur J. 2007, 13, 1117)

To a solution of phenylacetylene (0.46 ml_, 4.19 mmol) in THF (20 mL) cooled to -78°C was added BuLi (1.76 mL, 2.38 M, 4.19 mmol). The reaction was allowed to warm to 0⁰C, stirred for 20 minutes and then cooled to -78°C. Chlorodicyclohexylphosphine (0.9 mL, 4.07 mmol) was added dropwise and the solution allowed to warm to room temperature and stirred for a further 2.5 hours. The reaction was then cooled to 0⁰C and hydrogen peroxide (35% aq. solution, 1.53 mL, 5.46 mmol). The solution was allowed to warm to room temperature and stirred for 30 minutes. Water (20 mL) was added and the product extracted with diethyl ether (3 x 20 mL). The combined organics were dried over MgSO₄ and the solvent removed in vacuo to leave a yellow solid. Purification by column chromatography eluting with CH₂Cl₂/ethyl acetate (2:3) gave the desired product as a pale yellow solid in 92% yield (1.20 g). ³¹P(¹H) NMR (202.5 MHz, CDCI₃, δ): 36.3; ¹H NMR (300.0 MHz, CDCI₃, δ): 7.54-7.52 (m, 2H, C₆H₅), 7.42 (m, 3H, C₆H₅), 2.07-1.85 (m, 10H, C₆H₁₁), 1.73 (br, 2H, C₆H₁₁), 1.57-1.51 (m, 4H, C₆H₁₁), 1.27-1.24 (m, 6H, C₆H₁₁); ¹³C(¹H) NMR (75.8 MHz, CDCI₃, δ): 132.4 (C₆H₅ O-C), 130.1 (C₆H₅ p-C), 128.5 (C₆H₅ m- C), 120.8 (d, J = 2.9 Hz, C₆H₅ Q), 103.2 (d, J = 21 Hz, C≡CP), 82.0 (d, J = 136 Hz, C≡CP), 37.4 (d, J = 79 Hz, C₆H₁₁), 26.5 (d, J = 7.4 Hz, C₆H₁₁), 26.3 (d, J = 7.0 Hz, C₆H₁₁), 26.1 (d, J = 2.9 Hz, C₆H₁₁), 26.0 (C₆H₁₁), 25.0 (d, J = 2.9 Hz, C₆H₁₁); LRMS (ESI⁺) mlz 315 [M+H]⁺; HRMS (ESI⁺) exact mass calcd for C₂₀H₂₈OP [M+H]⁺ requires m/z 315.1878, found mlz 315.1879. Anal. Calcd for C₂₀H₂₇OP: C, 76.40; H, 8.66. Found: C, 76.77; H, 8.92.

(H) 2-(Dicyclohexylphosphinoylethynyl)anisole (4b) Compound 4b was prepared according to the procedure described above for 4a on the same scale and isolated as a pale yellow solid in 91 % yield (1.27 g) after purification by column chromatography eluting with CH₂CI₂/ethyl acetate (1 :1 ). An analytically and spectroscopically pure sample was obtained by slow diffusion of a chloroform solution layered with methanol at room temperature. ³¹P(¹H) NMR (202.5 MHz, CDCI₃, δ): 35.5; ¹H NMR (300.0 MHz, CDCI₃, δ): 7.43 (d, J = 7.6 Hz, 1 H, C₆H₄OCH₃), 7.33 (t, J = 7.9 Hz, 1 H, C₆H₄OCH₃), 6.90-6.83 (m, 2H, C₆H₄OCH₃), 3.82 (s, 3H, OCH₃), 1.99-1.82 (m, 1OH, C₆H₁₁), 1.71 (br, 2H, C₆H₁₁), 1.56 (br, 4H, C₆H₁₁), 1.25 (br, 6H, C₆H₁₁); ¹³C{¹H} NMR (125.8 MHz, CDCI₃, δ): 161.2 (C₆H₄OCH₃ Q), 133.9 (C₆H₄OCH₃, o-C), 131.6 (C₆H₄OCH₃, p-C), 120.3 (C₆H₄OCH₃, m-C), 110.6 (C₆H₄OCH₃, m-C), 109.7 (d, J = 3.6 Hz, C₆H₄OCH₃ Q), 99.6 (d, J = 23 Hz, C=CP), 85.3 (d, J = 133 Hz, C≡CP), 55.6 (OCH₃), 36.7 (d, J = 79 Hz, C₆H₁₁), 26.2 (d, J = 12.5 Hz, C₆H₁₁), 26.1 (d, J = 13.7 Hz, C₆H₁₁), 25.8 (C₆H₁₁), 25.6 (d, J = 3.0 Hz, C₆H₁₁), 24.5 (d, J = 3.2 Hz, C₆H₁₁); LRMS (ESI⁺) mlz 345 [M+H]⁺; HRMS (ESI⁺) exact mass calcd for C₂₁H₃₀O₂P [M+H]⁺ requires m/z 345.1983, found mlz 345.1983. Anal. Calcd for C₂₁H₂₉O₂P: C, 73.23 H, 8.49. Found: C, 73.54; H, 8.71.

(Hi) 2-(Dicyclohexylphosphinoylethynyl)-N,N-dimethylaniline (4c)

Compound 4c was prepared according to the procedure described above for 4a on the same scale and isolated as a pale brown oil in 93 % yield (1.29 g) after purification by column chromatography eluting with CH₂CI₂/ethyl acetate (2:3). An analytically and spectroscopically pure sample was obtained by slow diffusion of a chloroform solution layered with methanol at room temperature. . ³¹P(¹H) NMR (202.5 MHz, CDCI₃, <5): 34.9; ¹H NMR (500.0 MHz, CDCI₃, δ): 7.46 (d, J = 9.0 Hz, 1 H, C₆H₄N(CH₃);,), 7.30 (t, J = 7.0 Hz, 1 H, C₆H₄N(CH₃J₂), 6.91-6.83 (m, 2H, C₆H₄N(CHa)₂), 2.96 (s, 6H, N(CH₃)₂), 2.07 (br, 2H, C₆H₁₁), 1.98 (br, 2H, C₆H₁₁), 1.87 (br, 6H, C₆H₁₁), 1.74 (br, 2H, C₆H₁₁), 1.57 (br, 4H, C₆H₁₁), 1.28 (br, 6H, C₆H₁₁); ¹³C(¹H) NMR (125.8 MHz, CDCI₃, δ): 154.8 (C₆H₄N(CH₃)₂ Q), 134.5 (C₆H₄N(CH₃)₂, o-C), 130.3 (C₆H₄N(CH₃J₂, p-C), 119.0 (C₆H₄N(CHa)₂, m-C), 116.0 (C₆H₄N(CH₃);,, m-C), 110.3 (d, J = 3.3 Hz, C₆H₄OCH₃ Q), 103.2 (d, J = 23 Hz, C≡CP), 84.5 (d, J = 139 Hz, C≡CP), 42.5 (N(CH₃J₂), 36.0 (d, J = 79 Hz, C₆H₁₁), 25.4 (d, J = 10.1 Hz, C₆H₁₁), 25.3 (d, J = 9.7 Hz, C₆H₁₁), 25.0 (C₆H₁₁), 24.8 (d, J = 2.6 Hz, C₆H₁₁), 23.9 (d, J = 2.7 Hz, C₆H₁₁); LRMS (ESI⁺) mlz 358 [M+H]⁺; HRMS (ESI⁺) exact mass calcd for C₂₂H₃₃NOP [M+H]⁺ requires m/z 358.2300, found m/z 358.2284. Anal. Calcd for C₂₂H₃₂NOP: C, 73.92 H, 9.02; N, 3.92 Found: C, 74.28; H, 9.11 ; N, 4.03. b) Synthesis of compounds 5a-c i) Synthesis of Monophosphine oxide (5a)

1-Alkynylphosphine oxide 4a (1.25 g, 4.00 mmol) and anthracene (1.07 g, 6.00 mmol) were mixed in a flask which was gradually heated to 220⁰C using a Wood's metal bath. The temperature was then lowered to 200°C and the mixture heated for a further 12 hours. The resulting dark solid residue was purified by column chromatography eluting with CH₂CI₂/ethyl acetate (2:3) to afford 5a as an off-white solid in 80% yield (1.57 g). ³¹P(¹H) NMR (202.5 MHz, CDCI₃, δ): 47.2; ¹H NMR (500.0 MHz, CDCI₃, δ): 7.40 (d, J = 6.4 Hz, 2H, C₆H₄), 7.33-7.31 (m, 5H, C₆H₄, C₆H₅ o/p-H), 7.08-7.05 (m, 2H, C₆H₅ m-H), 7.03-7.01 (m, 4H, C₆H₄), 5.60 (d, J = 6.8 Hz, 1 H, bridgehead CH), 5.23 (d, J = 2.3 Hz, 1 H, bridgehead CH), 1.85-1.81 (m, 2H, C₆H₁₁), 1.71 (m, 2H, C₆H₁₁), 1.57-1.52 (171, 6H₁ C₆H₁₁), 1.32-1.19 (m, 6H, C₆H₁₁), 1.11-1.08 (m, 4H, C₆H₁₁), 1.00-0.95 (m, 2H, C₆H₁₁); ¹³C(¹H) NMR (125.8 MHz, CDCI₃, δ): 163.8 (d, J = 5.0 Hz, C=CP), 144.5 (C₆H₄ Q), 144.2 (C₆H₄ Q), 139.2 (C₆H₅ Q), 136.4 (d, J = 80 Hz, C=CP), 127.9 (C₆H₅ P-C), 127.8 (C₆H₅ O-C), 126.7 (C₆H₅ m-C), 125.0 (C₆H₄), 124.9 (C₆H₄), 123.5 (C₆H₄), 123.1 (C₆H₄), 61.4 (d, J = 8.9 Hz, bridgehead CH), 52.5 (d, J = 8.4 Hz, bridgehead CH), 37.0 (d, J = 67.9 Hz, C₆H₁₁), 26.4 (C₆H₁₁), 26.3 (C₆H₁₁), 25.7 (C₆H₁₁), 25.6 (C₆H₁₁), 25.3 (C₆H₁₁); LRMS (ESI⁺) m/z 493 [M+H]⁺; HRMS (ESI⁺) exact mass calcd for C₃₄H₃₈OP [M+H]⁺ requires m/z 493.2660, found m/z 493.2643. Anal. Calcd for C₃₄H₃₇OP: C, 82.89; H, 7.57. Found: C, 83.11 ; H, 7.93.

(H) Synthesis of Monophosphine oxide (5b)

Compound 5b was prepared according to the procedure described above for 5a on the same scale (200⁰C, 24 hours) and isolated as an analytically pure off-white solid in 83 % yield (1.73 g) after purification by column chromatography eluting with CH₂CI₂/ethylacetate (1 :1 ). ³¹P(¹H) NMR (202.5 MHz, CDCI₃, δ): 47.3; ¹H NMR (500.0 MHz, CDCI₃, δ): 7.38-7.29 (m, 4H, C₆H₄), 7.30 (t, J = 7.9 Hz, 1 H, C₆H₄OCH₃ p-H), 7.01-6.98 (m, 4H, C₆H₄,), 6.89-6.85 (m, 2H, C₆H₄OCH₃ An-H), 6.76 (d, J = 7.4 Hz, 1 H, C₆H₄OCH₃ o-H), 5.67 (d, J = 6.9 Hz, 1 H, bridgehead CH), 5.16 (d, J = 2.9 Hz, 1 H, bridgehead CH), 3.67 (s, 3H, OCH₃), 1.87-1.52 (br m, 10H, C₆H₁₁), 1.30-0.99 (br m, 12H, C₆H₁₁); ¹³C(¹H) NMR (125.8 MHz, CDCI₃, δ): 161.9 (d, J = 6.1 Hz, C=CP), 156.7 (C₆H₄OCH₃ Q), 145.6 (br, C₆H₄ Q), 144.2 (br, C₆H₄ Q), 136.8 (d, J = 81 Hz, C=CP), 129.5

(C₆H₄OCH₃ P-C), 129.0 (d, J = 1.6 Hz, C₆H₅ o-C), 127.8 (d, J = 3.4 Hz, C₆H₄OCH₃ Q), 124.6 (br, 2 x C₆H₄), 123.2 (2 x C₆H₄), 119.7 (C₆H₄OCH₃ m-C), 110.2 (C₆H₄OCH₃ m-C), 60.3 (d, J = 9.1 Hz, bridgehead CH), 54.6 (OCH₃), 52.3 (d, J = 7.8 Hz, bridgehead CH), 36.8 (d, J = 79 Hz, C₆H₁₁), 26.5 (br, C₆H₁₁), 26.4 (br, C₆H₁₁), 26.0 (br, C₆H₁₁), 25.7 (br, C₆H₁₁), 25.1 (br, C₆H₁₁). LRMS (ESI⁺) m/z 523 [M+H]⁺; HRMS (ESI⁺) exact mass calcd for C₃₅H₄₀O₂P [M+H]⁺ requires m/z 523.2766, found m/z 523.2766. Anal. Calcd for C₃₅H₃₉O₂P: C, 80.43; H, 7.52. Found: C, 80.76; H, 7.82.

(Hi) Synthesis of Monophosphine oxide (5c) Compound 5c was prepared according to the procedure described above for 5a on the same scale and isolated as an analytically pure off-white solid in 72% yield after purification by column chromatography eluting with CH₂CI₂/ethyl acetate (2:3).³¹P(¹H) NMR (202.5 MHz, CDCI₃, δ): 45.5; ¹H NMR (500.0 MHz, CDCI₃, δ): 7.38 (d, J = 6.6 Hz, 1 H, C₆H₄), 7.33 (d, J = 6.9 Hz, 2H, C₆H₄), 7.24 (t, J = 7.7 Hz, 1 H, C₆H₄N(CH₃J₂ o-H), 7.19 (d, J = 7.0 Hz, 1 H, C₆H₄), 7.05-7.01 (m, 3H, 2x C₆H₄, C₆H₄N(CH₃J₂ m-H), 6.99-6.93 (m, 3H, 2 x C₆H₄, C₆H₄N(CH₃)₂ p-H), 6.87 (t, J = 7.4 Hz, 1 H, C₆H₄N(CH₃J₂ m-H), 5.38 (d, J = 6.9 Hz, 1 H, bridgehead CH), 5.25 (d, J = 2.6 Hz, 1 H, bridgehead CH), 2.39 (s, 6H, N(CH₃)₂), 2.05-2.01 (m, 1 H, C₆H₁₁), 1.94-1.74 (m, 6H, C₆H₁₁), 1.67 (m, 1 H, C₆H₁₁), 1.61-1.56 (m, 4H, C₆H₁₁), 1.26-1.04 (m, 10H, C₆H₁₁); ¹³C(¹H) NMR (125.8 MHz, CDCI₃, <5): 167.3 (d, J = 3.6 Hz, C=CP), 151.6 (C₆H₄N(CH₃)₂ Q), 145.8 (C₆H₄ Q), 145.4 (C₆H₄ Q), 145.1 (C₆H₄ Q), 143.3 (C₆H₄ Q), 133.8 (d, J = 81 Hz, C=CP), 132.6 (d, J = 3.0 Hz, C₆H₄N(CH₃)₂ Q), 130.6 (C₆H₄N(CHa)₂ p-C), 128.7 (C₆H₄N(CH₃), o-C), 124.8 (2x C₆H₄), 124.6 (C₆H₄), 124.5 (C₆H₄), 123.4 (C₆H₄), 123.4 (C₆H₄), 122.8 (C₆H₄), 122.6 (C₆H₄), 121.0 (C₆H₄N(CH₃), m-C), 117.8 (C₆H₄N(CH₃J₂ m-C), 61.0 (d, J = 9.0 Hz, bridgehead CH), 52.6 (d, J = 10.1 Hz, bridgehead CH), 44.0 (N(CH₃J₂), 37.5 (d, J = 68 Hz, C₆H₁₁), 36.7 (d, J = 69 Hz, C₆H₁₁), 26.9 (C₆H₁₁), 26.8 (C₆H₁₁), 26.7 (d, J = 4.1 Hz, C₆H₁₁), 26.6 (d, J = 4.1 Hz, C₆H₁₁), 26.5 (C₆H₁₁), 26.4 (C₆H₁₁), 26.0 (C₆H₁₁), 25.8 (C₆H₁₁), 25.7 (C₆H₁₁), 25.4 (C₆H₁₁); LRMS (ESI⁺) m/z 536 [M+H]⁺; HRMS (ESI⁺) exact mass calcd for C₃₆H₄₃ONP [M+H]⁺ requires m/z 536.3082, found m/z 536.3052. Anal. Calcd for C₃₆H₄₂NOP: C, 80.71 ; H, 7.91 ; N, 2.61. Found: C, 80.98; H, 8.09; N, 2.77.

c) Synthesis of compounds 6a-c

(i) Synthesis of Compound (6a)

A flame-dried Schlenk flask was charged with 5a (0.70 g, 1.34 mmol), toluene (25 ml_), and triethylamine (7.5 mL, 53.6 mmol). Trichlorosilane (1.35 ml_, 13.4 mmol) was added slowly and the mixture heated at 110°C for 3 days. The reaction mixture was diluted with diethyl ether (20 mL) and added slowly to a mixture of ice (10 g) and 20 % aq NaOH (20 mL). After stirring vigorously at room temperature for 30 minutes, the organic layer was removed and the aqueous phase extracted with diethyl ether (3 x 30 mL). The organic fractions were combined, washed with sat. NaHCO₃ (2 x 20 mL), water (2 x 20 mL) and brine (2 x 20 mL), dried over MgSO₄, filtered and the solvent removed in vacuo. The product was purified by column chromatography eluting with hexane/ethyl acetate (9:1) to afford 6a as a spectroscopically pure white solid in 69% yield (0.44 g). An analytically and spectroscopically pure sample was obtained by slow diffusion of a chloroform solution layered with hexane at room temperature. ³¹P(¹H) NMR (202.5 MHz, CDCI₃, <5): -12.8; ¹H NMR (500.0 MHz, CDCI₃, δ): 7.35-7.31 (m, 6H, C₆H₄, C₆H₅ m- H), 7.26 (t, J = 7.2 Hz, 1H, C₆H₅ P-H), 7.19 (d, J = 7.4 Hz, 2H, C₆H₅O-H), 7.02-6.97 (m, 4H, C₆H₄), 5.54 (s, 1 H₁ bridgehead CH), 5.31 (d, J = 2.0 Hz, 1 H, bridgehead CAV), 1.99 (t, J = 10.6 Hz, 2H, C₆H₁₁), 1.76-1.70 (m, 4H, C₆H₁₁), 1.62 (d, J = 10.6 Hz, 2H₁ C₆H₁₁), 1.54 (d, J = 11.0 Hz₁ 2H, C₆H₁₁), 1.33-1.26 (m, 2H, C₆H₁₁), 1.21-1.18 (m, 2H, C₆H₁₁), 1.08-0.98 (m, 8H, C₆H₁₁); 1³C(¹H) NMR (125.8 MHz₁ CDCI₃, δ): 163.0 (d, J = 26 Hz, C=CP), 145.8 (C₆H₄ Q), 144.9 (C₆H₄ Q), 141.3 (d, J = 29 Hz, C=CP)₁ 140.0 (C₆H₅ Q)₁ 128.1 (d, J = 3.3 Hz₁ C₆H₅ o-C), 127.7 (C₆H₅ m- C), 127.1 (C₆H₅ P-C), 124.6 (C₆H₄), 124.5 (C₆H₄), 122.9 (C₆H₄), 122.7 (C₆H₄), 59.7 (d, J = 6.1 Hz, bridgehead CH), 54.2 (d, J = 6.3 Hz₁ bridgehead CH), 34.4 (d, J = 11.9 Hz₁ C₆H₁₁), 30.6 (d, J = 16.6 Hz₁ C₆H₁₁), 30.3 (d, J = 9.4 Hz₁ C₆H₁₁), 27.3 (d, J = 11.6 Hz₁ C₆H₁₁), 27.0 (d, J = 8.3 Hz, C₆H₁₁), 26.3 (C₆H₁₁); LRMS (ESI⁺) m/z 477 [M+H]⁺; HRMS (ESI⁺) exact mass calcd for C₃₄H₃₈P [M+H]⁺ requires m/z 477.2711 , found m/z 477.2680. Anal. Calcd for C₃₄H₃₇P: C₁ 85.68; H₁ 7.82. Found: C, 85.96; H, 8.02.

(H) Synthesis of Compound (6b)

Compound 5b was reduced according to the procedure described above for 5a on the same scale to afford 6b as an off-white solid in 67% yield (0.455 g) after purification by column chromatography eluting with hexane/ethyl acetate (85:15). An analytically and spectroscopically pure sample was obtained by slow diffusion of a chloroform solution layered with hexane at room temperature. ³¹P(¹H) NMR (202.5 MHz, CDCI₃, δ): -13.1 ; ¹H NMR (500.0 MHz₁ CDCI₃, <5): 7.32-7.30 (m, 2H, C₆H₄), 7.27-7.24 (m, 3H, C₆H₄, C₆H₅ p-H), 6.99-6.97 (m, 4H, C₆H₄, C₆H₅ m-H), 6.89-6.85 (m, 3H, C₆H₄, C₆H₅ O-H), 5.48 (s, 1 H₁ bridgehead CH), 5.20 (s, 1 H₁ bridgehead CH)₁ 3.67 (s, 3H₁ OCH₃), 1.96 (br, 2H₁ C₆H₁₁), 1.69-1.56 (br m, 10H₁ C₆H₁₁), 1.28 (m, 4H, C₆H₁₁), 1.07 (br, 6H₁ C₆H₁₁); ¹³C(¹H) NMR (125.8 MHz₁ CDCI₃, <5): 162.6 (d, J = 28 Hz, C=CP), 157.7 (C₆H₄OCH₃ Q)₁ 145.8 (br, C₆H₄ Q), 145.6 (br, C₆H₄ Q), 141.2 (d, J = 28 Hz₁ C=CP), 131.2 (d, J = 4.7 Hz₁ C₆H₄OCH₃ o-C), 129.1 (d, J = 5.8 Hz₁ C₆H₄OCH₃ Q), 128.7 (C₆H₅ p-C), 124.3 (C₆H₄), 124.1 (C₆H₄), 123.1 (C₆H₄), 122.6 (C₆H₄), 119.9 (C₆H₄OCH₃ m-C), 110.6 (C₆H₄OCH₃ m-C), 58.8 (d, J = 5.8 Hz, bridgehead CH), 54.9 (OCH₃), 54.0 (d, J = 6.3 Hz, bridgehead CH), 34.2 (br, C₆H₁₁), 30.3 (br, C₆H₁₁), 30.1 (br, C₆H₁₁), 27.3 (d, J = 11.5 Hz, C₆H₁₁), 27.1 (d, J = 7.8 Hz, C₆H₁₁), 26.4 (C₆H₁₁); LRMS (ESI⁺) m/z 507 [M+H]⁺; HRMS (ESI⁺) exact mass calcd for C₃₅H₄₀PO [M+H]⁺ requires m/z 507.2817, found m/z 507.2778. Anal. Calcd for C₃₅H₃₉OP: C, 82.97; H, 7.76. Found: C, 83.06; H, 7.91. (Hi) Synthesis of Compound (6c)

Compound 5c was reduced according to the procedure described above for 5a on the same scale to afford 6c as an off-white solid in 87% yield (0.754 g) after purification by column chromatography. An analytically and spectroscopically pure sample was obtained by slow diffusion of a chloroform solution layered with hexane at room temperature. ³¹P(¹H) NMR (202.5 MHz, CDCI₃, δ): -13.9; ¹H NMR (500.0 MHz, CDCI₃, δ): 7.35 (br, 1 H, C₆H₄), 7.31 (br d, J = 7.9 Hz, 2H, C₆H₄), 7.23 (t, J = 8.4 Hz, 1 H, C₆H₄N(CH₃J₂ P-H), 7.13 (br, 1H, C₆H₄), 7.06 (brd, J = 8.0 Hz, 1 H, C₆H₄N(CH₃)₂ m-H), 7.01- 6.93 (br m, 3H, C₆H₄), 6.91-6.88 (br, 1 H, C₆H₄), 6.89 (t, J = 7.3 Hz, 1 H, C₆H₄N(CH₃J₂ m-H), 6.84 (br d, J = 7.5 Hz, 1 H, C₆H₄N(CH₃)₂ o-H), 5.53 (s, 1 H, bridgehead CH), 5.28 (d, J = 2.4 Hz, 1 H, bridgehead CH), 2.35 (s, 6H, N(CH₃J₂), 2.05-1.91 (br m, 2H, C₆H₁₁), 1.78-1.64 (br m, 6H, C₆H₁₁), 1.54 (br, 1 H, C₆H₁₁), 1.42-1.08 (br m, 12H, C₆H₁₁), 0.88 (br, 1 H, C₆H₁₁); ¹³C(¹H) NMR (125.8 MHz, CDCI₃, δ): 165.2 (d, J = 28 Hz, C=CP), 152.4 (C₆H₄N(CH₃)₂ Q), 146.9 (C₆H₄ Q), 146.2 (C₆H₄ Q), 145.5 (C₆H₄ Q), 144.7 (C₆H₄ Q), 139.3 (d, J = 29 Hz, C=CP), 133.7 (d, J = 4.4 Hz, C₆H₄N(CH₃J₂ Q), 131.9 (d, J = 5.0 Hz, C₆H₄N(CH₃)₂ o-C), 128.4 (C₆H₄N(CH₃J₂ p-C), 124.4 (2 x C₆H₄), 124.2 (br, 2 x C₆H₄), 123.1 (2 x C₆H₄), 122.4 (br, 2 x C₆H₄), 121.2 (C₆H₄N(CH₃)₂rn-C), 118.2 (C₆H₄N(CH₃J₂ m-C), 59.2 (d, J = 6.3 Hz, bridgehead CH), 54.0 (d, J = 5.9 Hz, bridgehead CH), 43.8 (N(CH₃)₂), 35.2 (br d, J = 54 Hz, C₆H₁₁), 31.1 (br, C₆H₁₁), 30.7 (br, C₆H₁₁), 27.4 (br, C₆H₁₁), 27.2 (br, C₆H₁₁), 26.4 (C₆H₁₁). LRMS (ESI⁺) m/z 520 [M+H]⁺; HRMS (ESI⁺) exact mass calcd for C₃₆H₄₃NP [M+H]⁺ requires m/z 520.3133, found m/z 520.3087. Anal. Calcd for C₃₆H₄₂NP: C, 83.20; H, 8.14; N, 2.69. Found: C, 83.52; H, 8.33; N, 2.97.

Example 2

Compounds 1 and 6a were used as ligands for the palladium (0) catalysed amination of aryl and heteroaryl bromides with primary and secondary amines.

A flame-dried Schlenk flask was charged with tris(dibenzylideneacetone)palladium (4.6 mg, 0.005 mmol), 1 (4.4 mg, 0.025 mmol) or 6a (11.9 mg, 0.025 mmol), sodium terf-butoxide (134 mg, 1.40 mmol) and toluene (2.0 ml_) under nitrogen. Aryl bromide (1.00 mmol) and amine (1.10 mmol) were added and the resulting red solution heated at 80⁰C with rapid stirring until reaction was complete, as judged by GC analysis. The reaction mixture was allowed to cool to room temperature, diluted with diethyl ether, passed through celite and the solvent removed to leave a yellow solid. Known products were characterised by NMR spectroscopy and mass spectrometry and unknown products by NMR spectroscopy, mass spectrometry and high resolution mass spectrometry (HRMS). The conversions were calculated using GC analysis as an average over three repeats.

Example 4

Compounds 6a, 6b and 6c were used as ligands for the palladium (0) catalysed amination of aryl chlorides with secondary amines using the same conditions as in Example 2, except that the reaction was heated to 100°C.

Entry L Aryl bromide Amine Time (h) % conversion

1 6a 6 44

2 6b 6 62

3 6c 6 66

4 6a 1 72

5 6b o« 1 86

6 6c 1 81

7 6a 1 64

8 6b O^H 1 76

Example 5

Compounds 6a, 6b and 6c were used as ligands for palladium (0) catalysis of the Suzuki- Miyaura coupling of aryl chlorides.

General Procedure for the Suzuki-Miyaura Coupling of Aryl Chlorides in Toluene Using K₃PO₄ as Base (Method A)

A flame-dried Schlenk flask was charged with Pd(OAc)₂ (2.2 mg, 0.01 mmol), KITPHOS (11.9 mg, 0.025 mmol), potassium phosphate (424 mg, 2.00 mmol), boronic acid (1.50 mmol) and toluene

(2.0 mL) under nitrogen. Aryl chloride (1.00 mmol) was added and the resulting mixture heated at the required temperature with rapid stirring until reaction was complete, as judged by GC analysis.

The reaction mixture was allowed to cool to room temperature, diethyl ether (2 mL) and water (2 mL) were added, and the organic layer was passed through a short silica plug and the solvent removed to leave a colourless solid. Known products were characterised by NMR spectroscopy and mass spectrometry and unknown products by NMR spectroscopy, mass spectrometry and high resolution mass spectrometry (HRMS).

General Procedure for the Suzuki-Miyaura Coupling ofAryl Chlorides in THF Using KF as Base (Method B)

A flame-dried Schlenk flask was charged with Pd(OAc)₂ (2.2 mg, 0.01 mmol), 6a (11.9 mg, 0.025 mmol), potassium fluoride (177 mg, 3.00 mmol), boronic acid (1.50 mmol) and THF (2.0 mL) under nitrogen. Aryl chloride (1.00 mmol) was added and the resulting mixture heated at the appropriate temperature (40-60 ⁰C) with rapid stirring until reaction was complete, as judged by GC analysis. The reaction mixture was allowed to cool to room temperature, diluted with diethyl ether, passed through a short silica plug and the solvent removed to leave a colourless solid. Known products were characterised by NMR spectroscopy and mass spectrometry and unknown products by NMR spectroscopy, mass spectrometry and high resolution mass spectrometry (HRMS).

Entry L Aryl bromide Boronic Time Temp %

The Suzuki-Miyaura coupling of hindered substrates is an extremely challenge transformation and is particularly difficult for substrates with large ortho- and ortho.ortho substituents. However, Pd₂(dba)₃/6a appears to be an effective system for coupling challenging substrates as it catalyses the reaction between 2-methylphenylboronic acid and 1-chloro-2,6-dimethylbenzene at 8O⁰C to give 85% conversion after 16 hours. Significantly, this is an improvement on the corresponding system derived from biaryl monophosphine 1 which gave 88% conversion after 17 hours at 100⁰C.

Claims

1. A compound of formula I:

wherein: R^P1 and R^P2 are independently selected from C₃.i₂ alkyl groups;

R^c is a C_5-6 aryl group, optionally substituted by one or more groups selected from: Ci_-7 alkyl, C_1-7 alkoxy, halo, NH₂, Ci_-7alkylamino, di-C_1-7alkylamino, and C_5-6 aryl;

R^A1 and R^ are independently selected from H, Cl, and an optionally substituted group selected from: Ci_-7 alkyl, Ci_-7 alkoxy, C_1-7 alkylthio and C_5-6 aryl, wherein the optional substituents are selected from: Ci.₇ alkyl, C_1-7 alkoxy, halo, NH₂, Ci_-7alkylamino, di-C_1-7alkylamino, and C_5-6 aryl.

2. A compound according to claim 1 , wherein R^A1 and R*² are both H.

3. A compound according to either claim 1 or claim 2, wherein R^P1 and R^P2 are the same.

4. A compound according to either claim 1 or claim 2, wherein R^P1 and R^P2 are different.

5. A compound according to claim 3, wherein R^P1 and R^P2 are the same and are selected from: isopropyl, tert-butyl, cyclohexyl and adamantyl.

6. A compound according to any one of claims 1 to 5, wherein R^c is a C₆ aryl group.

7. A compound according to claim 6, wherein R^c is phenyl or pyridyl.

8. A compound according to any one of claims 1 to 5, wherein R^c is a C₅ heteroaryl group.

9. A compound according to claim 8, wherein R^c is furanyl or thiophenyl.

10. A compound according to any one of claims 1 to 9, wherein the optional substituents for R^c are selected from C₁-₄ alkyl, C_1-4 alkoxy, halo, NH₂, C

^alkylamino and

11. A method of synthesising a compound according to any one of claims 1 to 10, comprising the step of reducing a corresponding compound of formula (II):

wherein R^P1, R^P2, R^c, R^A1 and R^ are as defined in any one of claims 1 to 10.

12. A method according to claim 12, wherein the compound of formula Il is synthesised by reacting a compound of formula Ilia with a compound of formula IMb:

wherein R^P1, R^P2, R^c, R^A1 and R*² are as defined in any one of claims 1 to 10.

13. A method according to claim 13, wherein the compound of formula IMa is synthesised from a compound of formula IVa, including the steps of treating the compound of formula Iva with n-BuLi and then reacting with a compound of formula IVb: pP1 _RP2

Y — R^c (IVa) ^κ ^p^ (IVb)

I Cl wherein Y is either H or trimethylsilyl, and R^P1, R^P2 and R^c are as defined in any one of claims 1 to 10.

14. The use of a compound according to any one of claims 1 to 10 as a ligand for a palladium or nickel catalyst.

15. A palladium or nickel catalyst comprising a ligand according to any one of claims 1 to 10.

16. A method of carrying out a C-C or C-N bond forming reaction using a catalyst according to claim 15.

17. A method according to claim 16, wherein the reaction is selected from: (a) amination of aryl, heteroaryl and alkenyl halides by primary and secondary amines; (b) Suzuki-Miyaura coupling of aryl and heteroaryl halides.