Metal complexes

Abstract

Metal complexes such as those of formula (I) are contemplated by the present invention. The metal complexes may be used in catalytic reactions as a catalyst. The catalytic reaction may be an autotransfer process, for example hydrogen borrowing. Improved catalytic activity has been observed with certain metal complexes of the invention. ##STR00001##

Claims

1. A metal complex of formula (I) ##STR00067## wherein M is iridium; L.sup.1 and L.sup.2 are independently selected from: a halogen, a nitrile, an amine, a phosphine, a phosphite, a sulfonate ester, a N-heterocyclic carbene or a 5 or 6 membered heterocyclic ring or L.sup.1 and L.sup.2 taken together are a bidentate ligand selected from: a diamine, a diphosphine, a diphosphite, a disulfonate ester, an amino acid or derivative thereof, an amino alcohol, aminosulfonamides, an N-heterocyclic carbene, a diketonate and substituted or unsubstituted bipyridine, wherein L.sup.1 and L.sup.2 groups are unsubstituted or optionally substituted by halo, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, OR.sup.A, NR.sup.AR.sup.B, CN, SO.sub.2R.sup.A; R.sup.1 is H; R.sup.2 is represented by H, substituted or unsubstituted: C.sub.1-14 alkyl, C.sub.1-14 haloalkyl, a C.sub.3-8 carbocyclic ring, or a 3 to 8 membered heterocyclic ring, or a C.sub.1-14 alkyl substituted with phenyl, a fluorous tag, or a solid support; R.sup.3 and R.sup.4 are each independently selected from: H, halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl, phenyl, a 5 or 6 membered heteroaryl ring and OR.sup.A1; or R.sup.3 and R.sup.4 along with the shared, adjacent or non-adjacent carbon atoms to which they are attached together form a 3 to 8 membered carbocyclic ring, or R.sup.2 and one of R.sup.3 and R.sup.4, together with the atoms to which they are attached, form a 3 to 8 membered heterocyclic ring; R.sup.5 is selected from halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl and C.sub.3-6 cycloalkyl, C.sub.6 aryl or 5 or 6 membered heteroaryl or two adjacent R.sup.5 groups, together with the atoms to which they are attached, form a 5 or 6 membered carbocyclic ring; p is 0 or 1 or more; n is selected from 1 to 10; m is selected from 0, 1, 2, 3 or 4; and R.sup.A, R.sup.B and R.sup.A1 are at each occurrence independently selected from: H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl.

2. The metal complex of claim 1, wherein R.sup.3 and R.sup.4 are each independently selected from: H, halo, C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.3-6 cycloalkyl, phenyl, or a 5 or 6 membered heteroaryl ring and OR.sup.A1; or R.sup.3 and R.sup.4 along with the shared, adjacent or non-adjacent carbon atoms to which they are attached together form a 5 or 6 membered carbocyclic ring.

3. The metal complex of claim 1, wherein p is 0.

4. The metal complex of claim 1, wherein R.sup.5 is C.sub.1-6 alkyl.

5. The metal complex of claim 1, wherein m is 0 or 4.

6. The metal complex of claim 1 wherein L.sup.1 and L.sup.2 are independently is a halogen, a nitrile, an amine, a phosphine or a 5 or 6 membered heterocyclic ring or L.sup.1 and L.sup.2 taken together are a bidentate ligand selected from the group consisting of a diamine, a diphosphine, and substituted or unsubstituted bipyridine, wherein L.sup.1 and L.sup.2 groups are unsubstituted or optionally substituted by halo, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, OR.sup.A, NR.sup.AR.sup.B, CN, or SO.sub.2R.sup.A.

7. The metal complex of claim 1 wherein L.sup.1 and L.sup.2 are independently halo, C.sub.1-10 alkylnitriles, or a 5 or 6 membered heteroaryl ring or L.sup.1 and L.sup.2 taken together are bipyridine or C.sub.1-10 alkyldiphosphine.

8. The metal complex of claim 1, wherein R.sup.2 is independently H, methyl, ethyl, phenyl, benzyl, iso-propyl, tert-butyl, a fluorous tag, a solid support or R.sup.2 and one of R.sup.3 and R.sup.4 together with the atoms to which they are attached form a 5 or 6 membered heterocyclic ring.

9. The metal complex of claim 1 wherein n is 2, 3 or 4.

10. A catalytic hydrogen autotransfer process comprising adding the metal complex of claim 1 to a reaction mixture.

11. A metal complex may be a compound according to formula (II): ##STR00068## wherein X is 1, 2 or 3 anion molecules and M is iridium; L.sup.1 and L.sup.2 are independently selected from: a halogen, a nitrile, an amine, a phosphine, a phosphite, a sulfonate ester, a N-heterocyclic carbene or a 5 or 6 membered heterocyclic ring or L.sup.1 and L.sup.2 taken together are a bidentate ligand selected from: a diamine, a diphosphine, a diphosphite, a disulfonate ester, an amino acid or derivative thereof, an amino alcohol, aminosulfonamides, an N-heterocyclic carbene, a diketonate and substituted or unsubstituted bipyridine, wherein L.sup.1 and L.sup.2 groups are unsubstituted or optionally substituted by halo, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, OR.sup.A, NR.sup.AR.sup.B, CN, SO.sub.2R.sup.A; R.sup.1 is H R.sup.2 is represented by H, substituted or unsubstituted: C.sub.1-14 alkyl, C.sub.1-14 haloalkyl, C.sub.3-8 carbocyclic ring, or a 3 to 8 membered heterocyclic ring, or a C.sub.1-14 alkyl substituted with phenyl, a fluorous tag, or a solid support; R.sup.3 and R.sup.4 are each independently selected from: H, halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl, phenyl, a 5 or 6 membered heteroaryl ring and OR.sup.A1; or R.sup.3 and R.sup.4 along with the shared, adjacent or non-adjacent carbon atoms to which they are attached together form a 3 to 8 membered carbocyclic ring, or R.sup.2 and one of R.sup.3 and R.sup.4, together with the atoms to which they are attached, form a 3 to 8 membered heterocyclic ring; R.sup.5 is selected from halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl and C.sub.3-6 cycloalkyl, C.sub.6 aryl or 5 or 6 membered heteroaryl or two adjacent R groups, together with the atoms to which they are attached, form a 5 or 6 membered carbocyclic ring; p is 1 or more; n is selected from 1 to 10; m is selected from 0, 1, 2, 3 or 4; and R.sup.A, R.sup.B and R.sup.A1 are at each occurrence independently selected from: H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl.

12. The metal complex of claim 11, wherein R.sup.3 and R.sup.4 are each independently selected from: H, halo, C.sub.1-6 alkyl, C.sub.1-6haloalkyl, C.sub.3-6 cycloalkyl, phenyl, or a 5 or 6 membered heteroaryl ring and OR.sup.A1; or R.sup.3 and R.sup.4 along with the shared, adjacent or non-adjacent carbon atoms to which they are attached together form a 5 or 6 membered carbocyclic ring.

13. The metal complex of claim 11, wherein X is a monoanionic, dianionic or trianionic molecule.

14. The metal complex of claim 11, wherein p is 2.

15. The metal complex of claim 11, wherein X is a hydroxide, fluoride, chloride, bromide, iodide, acetate, formate, fluorate, fluorite, bromate, bromite, iodate, iodite, chlorate, chlorite, hydrogen carbonate, hypofluorite, hypochlorite, hypobromite, hypoiodite, perfluorate, perchlorate, perbromate, periodate, chromate, cyanate, cyanide, dihydrogen phosphate, dihydrogen phosphite, nitrate, hydrogen oxalate, hydrogen sulfate, hydrogen sulfite, permanganate, nitrite, thiocyanate, hydride, hexafluorophosphate, hexafluoroantiminate, tetrafluoroborate, peroxide, [B[3,5-(CF.sub.3).sub.2C.sub.6H.sub.3].sub.4].sup., B(C.sub.6F.sub.5).sub.4.sup., Al(OC(CF.sub.3).sub.3).sub.4.sup., sulfate, sulfite, sulfide, persulfate, thiosulfate, hyposulfite, hydrogen phosphate, hydrogen phosphite, metasilicate, carbonate, percarbonate, oxalate, benzoate, tartrate, borate, boride, citrate, hypophosphite, nitride, phosphate, phosphide, or phosphite.

16. A metal complex of claim 11, wherein the compound is ##STR00069##

17. A metal complex wherein the complex is ##STR00070## ##STR00071##

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) Embodiments of the invention are further described hereinafter with reference to the accompanying drawings, in which:

(2) FIG. 1 is a graph showing the reaction rate of metal complexes of the invention with different N substituents and a comparative complex.

(3) FIG. 2 is a graph showing the reaction rate of metal complexes of the invention with different counterions and a comparative complex.

(4) FIGS. 3a and 3b are graphs showing the reaction rate of an iridium complex and a rhodium complex in two different solvents.

(5) FIG. 4 is a bar chart showing the yields for an iridium complex of the invention and a comparative iridium complex in a range of solvents.

(6) FIG. 5 is a bar chart showing the yields for a rhodium complex and a comparative rhodium complex in a range of solvents.

(7) FIG. 6a-d are graphs showing the reaction rate of an iridium complex and a comparative iridium complex in different solvents.

(8) FIG. 7 shows some substrate scope and functional group tolerances of an iridium complex of the invention with some data for a comparative complex [Cp*IrCl.sub.2].sub.2.

(9) FIGS. 8 and 9 are graphs showing the reaction rate of neutral and ionic iridium complexes and neutral and ionic rhodium complexes.

(10) FIG. 10 is a bar chart showing the yields for iridium complexes of the invention and a comparative iridium complex in a range of solvents.

(11) FIGS. 11a-c are graphs showing the temperature dependence of iridium complexes.

(12) FIGS. 12 and 13 are graphs showing the reaction rate for different iridium complex loadings.

(13) FIG. 14 is a graph showing the effect of chain length on catalytic activity.

DETAILED DESCRIPTION

(14) Given below are definitions of terms used in this application. Any term not defined herein takes the normal meaning as the skilled person would understand the term.

(15) The term halo refers to one of the halogens, group 17 of the periodic table. In particular the term refers to fluorine, chlorine, bromine and iodine. Preferably, the term refers to iodine or chlorine.

(16) The term alkyl refers to a linear or branched hydrocarbon chain. An alkyl ring may be a C.sub.1-14 alkyl containing 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms. For example, the term alkyl encompasses methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. Alkylene groups may likewise be linear or branched and may have two places of attachment to the remainder of the molecule. Furthermore, an alkylene group may, for example, correspond to one of those alkyl groups listed in this paragraph. The alkyl and alkylene groups may be unsubstituted or substituted by one or more substituents. Possible substituents are described below. Substituents for the alkyl group may be halogen, e.g. fluorine, chlorine, bromine and iodine, OH, C.sub.1-6 alkoxy.

(17) The term alkoxy refers to an alkyl group which is attached to a molecule via oxygen. This includes moieties where the alkyl part may be linear or branched and may contain, for example in a C.sub.1-6 alkoxy 1, 2, 3, 4, 5 or 6 carbon atoms, for example methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, ten-butyl, n-pentyl and n-hexyl. Therefore, the alkoxy group may be methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, ter-butoxy, n-pentoxy and n-hexoxy. The alkyl part of the alkoxy group may be unsubstituted or substituted by one or more substituents. Possible substituents are described below. Substituents for the alkyl group may be halogen, e.g. fluorine, chlorine, bromine and iodine, OH, C.sub.1-6 alkoxy.

(18) The term C.sub.1-4 haloalkyl or C.sub.1-6 haloalkyl refers to a hydrocarbon chain substituted with at least one halogen atom independently chosen at each occurrence, for example fluorine, chlorine, bromine and iodine. The halogen atom may be present at any position on the hydrocarbon chain. For example, C.sub.1-4 haloalkyl or C.sub.1-6 haloalkyl may refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl e.g. 1-chloromethyl and 2-chloroethyl, trichloroethyl e.g. 1,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl e.g. 1-fluoromethyl and 2-fluoroethyl, trifluoroethyl e.g. 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl.

(19) The term C.sub.2-6 alkenyl refers to a branched or linear hydrocarbon chain containing at least one double bond and having 2, 3, 4, 5 or 6 carbon atoms. The double bond(s) may be present as the E or Z isomer. The double bond may be at any possible position of the hydrocarbon chain. For example, the C.sub.2-6 alkenyl may be ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.

(20) The term C.sub.2. alkynyl refers to a branched or linear hydrocarbon chain containing at least one triple bond and having 2, 3, 4, 5 or 6 carbon atoms. The triple bond may be at any possible position of the hydrocarbon chain. For example, the C.sub.2-6 alkynyl may be ethynyl, propynyl, butynyl, pentynyl and hexynyl.

(21) The term C.sub.1-6 heteroalkyl refers to a branched or linear hydrocarbon chain containing 1, 2, 3, 4, 5, or 6 carbon atoms and at least one heteroatom selected from N, O and S positioned between any carbon in the chain or at an end of the chain. For example, the hydrocarbon chain may contain one or two heteroatoms. The C.sub.1-6 heteroalkyl may be bonded to the rest of the molecule through a carbon or a heteroatom. For example, the C.sub.1-6 heteroalkyl may be C.sub.1-6 N-alkyl, C.sub.1-6 N,N-alkyl, or C.sub.1-6 O-alkyl.

(22) The term carbocyclic refers to a saturated or unsaturated carbon containing ring system. A carbocyclic system may be monocyclic or a fused polycyclic ring system, for example, bicyclic or tricyclic. A carbocyclic moiety may contain from 3 to 14 carbon atoms, for example, 3 to 8 carbon atoms in a monocyclic system and 7 to 14 carbon atoms in a polycyclic system. Carbocyclic encompasses cycloalkyl moieties, cycloalkenyl moieties, aryl ring systems and fused ring systems including an aromatic portion.

(23) The term heterocyclic refers to a saturated or unsaturated ring system containing at least one heteroatom selected from N, O or S. A heterocyclic system may contain 1, 2, 3 or 4 heteroatoms, for example 1 or 2. A heterocyclic system may be monocyclic or a fused polycyclic ring system, for example, bicyclic or tricyclic. A heterocyclic moiety may contain from 3 to 14 carbon atoms, for example, 3 to 8 carbon atoms in a monocyclic system and 7 to 14 carbon atoms in a polycyclic system. Heterocyclic encompasses heterocycloalkyl moieties, heterocycloalkenyl moieties and heteroaromatic moieties. For example, the heterocyclic group may be: oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran.

(24) The term C.sub.3-8 cycloalkyl refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms. For example, the C.sub.3-8 cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

(25) The term C.sub.3-6 cycloalkenyl or C.sub.3-8 cycloalkenyl refers to an unsaturated hydrocarbon ring system containing 3, 4, 5 or 6 carbon atoms or 3, 4, 5, 6, 7 or 8 carbon atoms respectively that is not aromatic. The ring may contain more than one double bond provided that the ring system is not aromatic. For example, the C.sub.3-8 cycloalkyl may be cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienly, cycloheptenyl, cycloheptadiene, cyclooctenyl and cycloatadienyl.

(26) The term C.sub.3-10 heterocycloalkyl refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms and at least one heteroatom within the ring selected from N, O and S. For example there may be 1, 2 or 3 heteroatoms, optionally 1 or 2. The C.sub.3-10 heterocycloalkyl may be bonded to the rest of the molecule through any carbon atom or heteroatom. The C.sub.3-10 heterocycloalkyl may have one or more, e.g. one or two, bonds to the rest of the molecule: these bonds may be through any of the atoms in the ring. For example, the C.sub.3-10 heterocycloalkyl may be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran.

(27) The term C.sub.3-10 heterocycloalkenyl refers to an unsaturated hydrocarbon ring system, that is not aromatic, containing 3, 4, 5, 6, 7 or 8 carbon atoms and at least one heteroatom within the ring selected from N, O and S. For example there may be 1, 2 or 3 heteroatoms, optionally 1 or 2. The C.sub.3-10 heterocycloalkenyl may be bonded to the rest of the molecule through any carbon atom or heteroatom. The C.sub.3-10 heterocycloalkenyl may have one or more, e.g. one or two, bonds to the rest of the molecule: these bonds may be through any of the atoms in the ring. For example, the C.sub.3-10 heterocycloalkyl may be tetrahydropyridine, dihydropyran, dihydrofuran, pyrroline.

(28) The term aromatic when applied to a substituent as a whole means a single ring or polycyclic ring system with 4n+2 electrons in a conjugated system within the ring or ring system where all atoms contributing to the conjugated system are in the same plane.

(29) The term aryl refers to an aromatic hydrocarbon ring system. The ring system has 4n+2 electrons in a conjugated r system within a ring where all atoms contributing to the conjugated r system are in the same plane. For example, the aryl may be phenyl and naphthyl. The aryl system itself may be substituted with other groups.

(30) The term heteroaryl refers to an aromatic hydrocarbon ring system with at least one heteroatom within a single ring or within a fused ring system, selected from O, N and S. The ring or ring system has 4n+2 electrons in a conjugated r system where all atoms contributing to the conjugated r system are in the same plane. For example, the heteroaryl may be imidazole, thiene, furane, thianthrene, pyrrol, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine and indole.

(31) By acyl is meant an organic radical derived from, for example, an organic acid by the removal of the hydroxyl group, e.g. a radical having the formula RC(O), where R may be selected from H, C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, phenyl, benzyl or phenethyl group, eg R is H or C.sub.1-3 alkyl. In one embodiment acyl is alkyl-carbonyl. Examples of acyl groups include, but are not limited to, formyl, acetyl, propionyl and butyryl. A particular acyl group is acetyl.

(32) By phosphine it is meant an organophosphorous compound with three organic groups attached to a phosphorous atom, for example triphenylphosphine, tricyclohexylphosphine, or biscyclohexylphenylphosphine. The phosphine may be a phosphorous atom attached to three of the same groups or three different groups, for example the phosphine may be P(R.sup.C).sub.3, or the phosphine may be attached to three different groups (PR.sup.C1R.sup.C2R.sup.C3) or two of the same groups and one other different group (PR.sup.C1(R.sup.C2).sub.2). Accordingly, the phosphine of any compound of the present invention may be PR.sup.C1R.sup.C2R.sup.C3 wherein R.sup.C1, R.sup.C2 and R.sup.C3 are each independently selected at each occurrence from: C.sub.1-10 alkyl, C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, C.sub.5-10 heteroaryl, and C.sub.3-10 heterocycloalkyl. Optionally, R.sup.C1, R.sup.C2 and R.sup.C3 are each independently selected at each occurrence from: C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, for example, phenyl and cyclohexyl.

(33) A diphosphine is similarly an organophosphorous compound with two phosphorous atoms each having 2 organic substituents with a further substituent attached to both phosphorous atoms for example 2,2-bis(diphenylphosphino)-1,1-binaphthyl (BINAP). Accordingly, a diphosphine may be R.sup.C1R.sup.C2PR.sup.DPR.sup.C4R.sup.C5), wherein R.sup.C1, R.sup.C2, R.sup.C4, and R.sup.C5 are each independently selected at each occurrence from: C.sub.1-10 alkyl, C.sub.1-10 aryl, C.sub.3-10 cycloalkyl, C.sub.5-10 heteroaryl, and C.sub.3-10 heterocycloalkyl and R.sup.D is selected from C.sub.1-10 alkylene, C.sub.6-10 arylene, C.sub.3-10 cycloalkylene, C.sub.5-10 heteroarylene, C.sub.3-10 heterocycloalkylene, bi-C.sub.6-10 arylene, bi-C.sub.3-10 cycloalkylene, bi-C.sub.5-10 heteroarylene, and bi-C.sub.3-10 heterocycloalkylene. Optionally, R.sup.C1, R.sup.C2, R.sup.C4, and R.sup.C5 are each independently selected at each occurrence from: C.sub.1-10 alkyl, C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, and R.sup.D is selected from C.sub.1-10 alkylene, C.sub.6-10 arylene, C.sub.3-10 cycloalkylene, bi-C.sub.6-10 arylene, bi-C.sub.3-10 cycloalkylene, for example phenyl, cyclohexyl napthyl, and binapthyl.

(34) A bidentate ligand is a single molecule with two atoms capable of bonding to a metal centre. The bidentate ligand may be a nitrile, an amine, a phosphine or a sulfonate ester, it will be appreciated by the person skilled in the art that the presence of a single amine group, etc, will result in a molecule being termed as an amine. Therefore, a bidentate ligand that is an amine, for example, may comprise a single amine group (acting as a first point of attachment to the metal centre) and the same or a different functional group (acting as a second point of attachment to the metal centre.

(35) A fluorous tag is a highly fluorinated group. The flourous tag is sufficiently fluorinated to provide an affinity towards fluorinated solvents or to flourous solid-phase extraction. A fluorous tag may be bonded directly to the metal complex or a linker group may be present between the metal complex and the flourous tag. For example, the flourous tag may be C.sub.8F.sub.17. An exemplary flourous tag and linker is CH.sub.2CH.sub.2OCH.sub.2CH.sub.2C.sub.8F.sub.17.

(36) Where a moiety is substituted, it may be substituted at any point on the moiety where chemically possible and consistent with atomic valency requirements. The moiety may be substituted by one or more substituents, e.g. 1, 2, 3 or 4 substituents; optionally there are 1 or 2 substituents on a group. Where there are two or more substituents, the substituents may be the same or different. The substituent(s) may be selected from: OH, NHR, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, C(O)H, acyl, acyloxy, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo, nitro, halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.3-8 cycloalkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, aryl, heteroaryl or alkaryl. Where the group to be substituted is an alkyl group the substituent may be O. R may be selected from H, C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, phenyl, benzyl or phenethyl group, e.g. R is H or C.sub.1-3 alkyl. Where the moiety is substituted with two or more substituents and two of the substituents are adjacent the adjacent substituents may form a C.sub.4-8 ring along with the atoms of the moiety on which the substituents are substituted, wherein the C.sub.4-8 ring is a saturated or unsaturated hydrocarbon ring with 4, 5, 6, 7, or 8 carbon atoms or a saturated or unsaturated hydrocarbon ring with 4, 5, 6, 7, or 8 carbon atoms and 1, 2 or 3 heteroatoms.

(37) Substituents are only present at positions where they are chemically possible, the person skilled in the art being able to decide (either experimentally or theoretically) without inappropriate effort which substitutions are chemically possible and which are not.

(38) The invention contemplates salts of the metal complex of the invention. These may include the acid addition and base salts of the metal complex. These may be acid addition and base salts of the compounds. In addition the invention contemplates solvates of the compounds. These may be hydrates or other solvated forms of the compound.

(39) Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 1,5-naphthalenedisulfonate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts.

(40) Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts. For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

(41) Salts of metal complex of formula (I) may be prepared by one or more of three methods:

(42) (i) by reacting the compound of the invention with the desired acid or base;

(43) (ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of the invention or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base;

(44) (iii) by converting one salt of the compound of the invention to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column;

(45) (iv) or by salt metatheis.

(46) All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.

(47) The metal complex of the invention may exist in both unsolvated and solvated forms. The term solvate is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term hydrate is employed when said solvent is water.

(48) Hereinafter all references to metal complex of any formula include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.

(49) The metal complex of the invention include metal complex of a number of formula as herein defined, including all polymorphs and crystal habits and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labelled metal complex of the invention.

(50) The present invention also includes all industrially acceptable isotopically-labelled metal complexes of the invention wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.

(51) Examples of isotopes suitable for inclusion in the metal complex of the invention include isotopes of hydrogen, such as .sup.2H and .sup.3H, carbon, such as .sup.11C, .sup.13C and .sup.14C, chlorine, such as Cl, fluorine, such as .sup.18F, iodine, such as .sup.123I and .sup.125I, nitrogen, such as .sup.13N and .sup.15N, oxygen, such as .sup.15O, .sup.17O and .sup.18O, phosphorus, such as UP, and sulphur, such as .sup.35S.

(52) For some of the steps of the process of preparation of the metal complex of the invention, it may be necessary to protect potential reactive functions that are not wished to react, and to cleave said protecting groups in consequence. In such a case, any compatible protecting radical can be used. In particular methods of protection and deprotection such as those described by T. W. Greene (Protective Groups in Organic Synthesis, A. Wiley-Interscience Publication, 1981) or by P. J. Kocienski (Protecting groups, Georg Thieme Verlag, 1994), can be used. All of the above reactions and the preparations of novel starting materials used in the preceding methods are conventional and appropriate reagents and reaction conditions for their performance or preparation as well as procedures for isolating the desired products will be well-known to those skilled in the art with reference to literature precedents and the examples and preparations hereto.

(53) Also, the metal complex of the present invention as well as intermediates for the preparation thereof can be purified according to various well-known methods, such as for example crystallization or chromatography. The Metal complex of the invention may exist in a single crystal form or in a mixture of crystal forms or they may be amorphous.

EXAMPLES

(54) General synthetic procedure for alcohol amination reactions using catalyst metal complex of the invention. To a stirred suspension of iridium complex example 3 (4.4 mg, 0.01 mmol) in toluene (0.5 ml) under nitrogen were added the corresponding alcohol (1.0 mmol) and the corresponding amine (1.0 mmol). The resulting solution was heated at 110 C. for 18 hours. The solvent was removed under reduced pressure and purification by filtration or by flash chromatography gave the product amines.

Ligand and Ligand Precursor Synthesis

Intermediate 1: N-Boc-4-(2-Aminoethyl)-3,5-dimethyl-hepta-2,5-dien-4-ol

(55) ##STR00021##

(56) Lithium wire (516 mg, 74.0 mmol) was washed with hexane, cut into small pieces and suspended in Et.sub.2O (15 ml). 2-Bromo-2-butene (1.8 ml, 18 mmol, mixture of cis and trans isomers) was added in one portion to the mixture and stirred until the reaction started, observed by the reflux of the solvent; another aliquot of 2-bromo-2-butene (2.0 ml, 20 mmol) in Et.sub.2O (10 ml) was added dropwise to maintain a gentle reflux. The suspension was stirred for 2 hours at RT and then cooled to 78 C. A solution of N-Boc--alanine methyl ester (2.40 g, 12.0 mmol) in Et.sub.2O (10 ml) was added dropwise, the mixture was warmed to RT, stirred overnight and quenched with careful addition of saturated aqueous NH.sub.4Cl (60 ml). The phases were separated and the product was extracted with Et.sub.2O (230 ml). The combined organic extracts were dried with Na.sub.2SO.sub.4 and the solvent was removed under reduced pressure. Purification by flash chromatography (SiO.sub.2, eluting with hexane-EtOAc (95:5)) gave Intermediate 1 as a colourless oil as a 1:1 mixture of trans-trans and cis-trans isomers which was used without any other purification (1.50 g, 5.30 mmol, 44%).

(57) R.sub.f=0.30 (hexane-EtOAc 80:20); .sup.1H NMR (500 MHz, CDCl.sub.3, /ppm): 5.65-5.59 (2H, m, 2CH for the trans-trans isomer), 5.44-5.34 (2H, m, 2CH for the trans-cis isomer), 5.18-5.10 (2H, m, 2NH), 3.30-3.22 (4H, m, 2H-2), 1.95-1.86 (4H, m, 2H-1), 1.77 (6H, s, 2CH.sub.3), 1.69-1.60 (18H, m, 6CH.sub.3), 1.44 (18H, s, 2C(CH.sub.3).sub.3); .sup.13C NMR (125 MHz, CDCl.sub.3, /ppm): 156.1 (C(O)), 139.7 (C.sub.qCH.sub.3), 139.0 (C.sub.qCH.sub.3), 137.7 (C.sub.qCH.sub.3), 123.1 (CH for the trans-cis isomer), 118.6 (CH for the trans-trans isomer), 80.7 (C(CH.sub.3).sub.3), 79.8 (C-4), 78.9 (C-4), 39.1 (C-1), 36.7 (C-2), 28.4 (C(CH.sub.3).sub.3), 23.3 (CH.sub.3), 22.7 (CH.sub.3), 14.7 (CH.sub.3), 14.4 (CH.sub.3), 13.2 (CH.sub.3), 12.5 (CH.sub.3); IR (v.sub.max, neat, cm.sup.1): 3387 (NH and OH), 2976, 2933, 1696 (CO), 1509, 1452, 1366, 1279, 1250, 1173; HRMS (ESI+) m/z: Calculated for C.sub.16H.sub.29NNaO.sub.3 (M+Na.sup.+): 306.2040, found: 306.2034.

Intermediate 2: N-Boc-4-(3-Aminopropyl)-3,5-dimethyl-hepta-2,5-dien-4-ol

(58) ##STR00022##

(59) Lithium wire (340 mg, 48.6 mmol) was washed with hexane, cut into small pieces and suspended in Et.sub.2O (10 ml). A solution of 2-bromo-2-butene (2.4 ml, 24 mmol, mixture of cis and trans isomers) in Et.sub.2O (10 ml) was added dropwise and the suspension was stirred for 2 hours at RT. N-Boc-2-pyrrolidinone (1.50 g, 8.10 mmol) dissolved in Et.sub.2O (8.0 ml) was added dropwise, the mixture was stirred for 2 hours at RT and quenched with careful addition of saturated aqueous NH.sub.4Cl (40 ml). The two phases were separated and the product was extracted with Et.sub.2O (320 ml). The combined organic phases were dried with Na.sub.2SO.sub.4 and the solvent was removed under reduced pressure. Purification by flash chromatography (SiO.sub.2, eluting with hexane-EtOAc (90:10 to 80:20)) gave Intermediate 2 as a colourless oil as a mixture of trans-trans and trans-cis isomers (fraction major (trans-cis)/minor (trans-trans): 2/1) which was used without any other purification (1.10 g, 5.70 mmol, 70%).

(60) R.sub.f=0.60 (hexane-EtOAc 70:30); .sup.1H NMR (500 MHz, CDCl.sub.3, /ppm): 5.58 (2H, dq, J=1.0, 6.5 Hz, 2CH for the trans-trans isomer), 5.35 (2H, dq, J=1.0, 6.5 Hz, 2CH for the trans-cis isomer), 4.59 (2H, br s, 2NH), 3.14 (4H, br s, 2H-3), 1.84-1.81 (2H, m, 2OH), 1.76-1.75 (4H, m, 2H-1), 1.67-1.59 (24H, m, 8CH.sub.3), 1.53-1.49 (4H, m, 2H-2), 1.43 (18H, s, 2C(CH.sub.3).sub.3); .sup.13C NMR (125 MHz, CDCl.sub.3, /ppm): 156.1 (C(O)), 140.0 (C.sub.qCH.sub.3), 139.5 (C.sub.qCH.sub.3), 138.0 (C.sub.qCH.sub.3), 122.7 (CH for the trans-cis isomer), 122.6 (CH for the trans-cis isomer), 118.3 (CH for the trans-trans isomer), 80.6 (C(CH.sub.3).sub.3), 79.5 (C-4), 79.0 (C-4), 41.1 (C-3), 36.8 (C-1), 35.0 (C-1), 28.4 (C(CH.sub.3).sub.3), 24.5 (C-2), 24.2 (C-2), 23.4 (CH.sub.3), 22.8 (CH.sub.3), 14.7 (CH.sub.3), 14.4 (CH.sub.3), 13.2 (CH.sub.3), 12.6 (CH.sub.3); HRMS (ESI+) m/z: Calculated for C.sub.17H.sub.31NNaO.sub.3 (M+Na.sup.+): 320.2196, found: 320.2200. Spectroscopic data consistent with literature values (M. Ito, N. Tejima, M. Yamamura, Y. Endo and T. Ikariya, Organometallics, 2010, 29, 1886-1889).

Intermediate 3: N-Boc-4-(4-Aminobutyl)-3,5-dimethyl-hepta-2,5dien-4-ol

(61) ##STR00023##

(62) Lithium wire (4.37 mg, 63.0 mmol) was washed with hexane, cut into small pieces and suspended in Et.sub.2O (10 ml). 2-Bromo-2-butene (1.3 ml, 13 mmol, mixture of cis and trans isomers) was added in one portion to the mixture and stirred until the reaction started, observed by the reflux of the solvent; another aliquot of 2-bromo-2-butene (2.0 ml, 20 mmol) in Et.sub.2O (10 ml) was added dropwise and the suspension was stirred for 2 hours at RT. A solution of N-Boc-2-piperidinone (3.00 g, 15.0 mmol) in Et.sub.2O (20 ml) was added dropwise, the mixture was stirred for 1 hour and quenched with careful addition of saturated aqueous NH.sub.4Cl (60 ml). The phases were separated and the product was extracted with Et.sub.2O (230 ml). The combined organic phases were dried with Na.sub.2SO.sub.4 and the solvent was removed under reduced pressure. Purification by flash chromatography (SiO.sub.2, eluting with hexane-EtOAc (90:10)) gave Intermediate 3 as a colourless oil as a mixture of trans-trans and trans-cis isomers (fraction major (trans-cis)/minor (trans-trans): 3/2) which was used without any other purification (940 mg, 3.00 mmol, 20%).

(63) R.sub.f=0.50 (hexane-EtOAc 70:30); .sup.1H NMR (500 MHz, CDCl.sub.3, /ppm): 5.57 (2H, q, J=6.5 Hz, 2CH for the trans-trans isomer), 5.34 (2H, dq, J=1.3, 7.5 Hz, 2CH for the trans-cis isomer), 4.54 (2H, br s, 2NH), 3.12 (4H, br s, 2H-4), 1.84-1.71 (6H, m, 2H-1 and 2OH), 1.69-1.60 (24H, m, 8CH.sub.3), 1.53-1.46 (8H, m, 4CH.sub.2), 1.44 (18H, s, 2C(CH.sub.3).sub.3); .sup.13C NMR (125 MHz, CDCl.sub.3, /ppm): 156.1 (C(O)N), 140.2 (C.sub.qCH.sub.3), 139.6 (C.sub.qCH.sub.3), 138.1 (C.sub.qCH.sub.3), 122.5 (CH for the trans-cis isomer), 122.4 (CH for the trans-cis isomer), 118.9 (CH for the trans-trans isomer), 118.1 (CH for the trans-trans isomer), 80.8 (C(CH.sub.3).sub.3), 79.4 (C-4), 79.1 (C-4), 40.4 (C-4), 39.4 (C-1), 37.6 (C-1), 28.4 (C(CH.sub.3).sub.3), 23.4 (CH.sub.3), 22.8 (CH.sub.3), 20.7 (CH.sub.2), 20.5 (CH.sub.2), 14.8 (CH.sub.3), 14.4 (CH.sub.3), 13.4 (CH.sub.3), 13.2 (CH.sub.3), 12.6 (CH.sub.3), 12.4 (CH.sub.3); IR (v.sub.max, neat, cm.sup.1): 3364 (NH and OH), 2975, 2933, 2865, 1695 (CO), 1515, 1454, 1366, 1251, 1172, 1003; HRMS (ESI+) m/z: Calculated for C.sub.18H.sub.33NNaO.sub.3 (M+Na.sup.+): 334.2353, found: 334.2357.

Intermediate 4: N-Boc-N-Methyl-4-(3-aminopropyl)-3,5-dimethyl-hepta-2,5-dien-4-ol

(64) ##STR00024##

(65) Lithium wire (150 mg, 22.0 mmol) was washed with hexane, cut into small pieces and suspended in Et.sub.2O (10 ml). A solution of 2-bromo-2-butene (1.2 ml, 12 mmol, mixture of cis and trans isomers) in Et.sub.2O (10 ml) was added dropwise and the suspension was stirred for 2 hours at RT. A solution of methyl N-Boc-N-methyl-4-aminobutanoate (1.20 g, 5.19 mmol) in Et.sub.2O (10 ml) was added dropwise, stirred for 90 minutes at RT and quenched with careful addition of saturated aqueous NH.sub.4Cl (40 ml). The phases were separated and the product was extracted with Et.sub.2O (320 ml). The combined organic extracts were dried with Na.sub.2SO.sub.4 and the solvent was removed under reduced pressure. Purification by flash chromatography (SiO.sub.2, eluting with hexane-EtOAc (90:10)) gave Intermediate 4 as a colourless oil in a 1:1 mixture of trans-trans and trans-cis isomers which was used without any other purification (540 mg, 1.74 mmol, 33%).

(66) R.sub.f=0.40 (hexane-EtOAc 80:20); .sup.1H NMR (500 MHz, CDCl.sub.3, /ppm): 5.62-5.56 (2H, m, 2CH for the trans-trans isomer), 5.42-5.30 (2H, m, 2CH for the trans-cis isomer), 3.27-3.24 (4H, m, 2H-3), 2.87 (6H, br s, 2H-1), 1.86-1.76 (4H, m, 2H-1), 1.74 (2H, s, 2OH), 1.69-1.61 (18H, m, 6CH.sub.3), 1.62-1.59 (4H, m, 2CH.sub.2), 1.46 (24H, s, 2CH.sub.3 and 2C(CH.sub.3).sub.3); .sup.13C NMR (125 MHz, CDCl.sub.3, /ppm): 156.0 (C(O)N), 140.1 (C.sub.qCH.sub.3), 139.6 (C.sub.qCH.sub.3), 138.1 (C.sub.qCH.sub.3), 122.5 (CH), 119.0 (CH), 118.2 (CH), 80.7 (C(CH.sub.3).sub.3), 79.1 (C-4), 51.6 (C-3), 34.0 (C-1), 29.7 (C-1), 28.4 (C(CH.sub.3).sub.3), 23.4 (CH.sub.3), 22.8 (CH.sub.3), 21.9 (C-2), 14.8 (CH.sub.3), 14.4 (CH.sub.3), 13.4 (CH.sub.3), 13.2 (CH.sub.3), 12.6 (CH.sub.3), 12.4 (CH.sub.3); IR (v.sub.max, neat, cm.sup.1): 3474 (OH), 2973, 2931, 1759 (CO), 1695 (CC), 1481, 1454, 1395, 1365, 1171; HRMS (ESI+) m/z: Calculated for C.sub.18H.sub.33NNaO.sub.3 (M+Na.sup.+): 334.2353, found: 334.2349.

Intermediate 5: 4-(3-Dimethylaminopropyl)-3,5-dimethyl-hepta-2,5-dien-4-ol

(67) ##STR00025##

(68) Lithium wire (530 mg, 76.0 mmol) was washed with hexane, cut into small pieces and suspended in Et.sub.2O (10 ml). 2-Bromo-2-butene (1.5 ml, 15 mmol, mixture of cis and trans isomers) was added in one portion to the mixture and stirred until the reaction started, observed by the reflux of the solvent; another aliquot of 2-bromo-2-butene (2.5 ml, 25 mmol) in Et.sub.2O (15 ml) was added dropwise and the suspension was stirred for 2 hours at RT. A solution of ethyl N,N-Dimethyl-4-aminobutanoate (2.80 g, 18.0 mmol) in Et.sub.2O (15 ml) was added dropwise, stirred for 60 minutes at RT and quenched with careful addition of saturated aqueous NH.sub.4Cl (50 ml). The phases were separated and the product was extracted with Et.sub.2O (240 ml). The combined organic phases were dried with Na.sub.2SO.sub.4 and the solvent was removed under reduced pressure. Purification by flash chromatography (SiO.sub.2, eluting with hexane-EtOAc (60:40 to 0:100)) gave Intermediate 5 as a colourless oil as a 1:1 mixture of trans-trans and trans-cis isomers which was used without any other purification (1.70 g, 7.54 mmol, 41%).

(69) R.sub.f=0.38 (DCM-MeOH 80:20); .sup.1H NMR (500 MHz, CDCl.sub.3, /ppm): 5.65 (2H, q, J=5.7 Hz, 2CH for the trans-trans isomer), 5.58 (1H, q, J=6.5 Hz, CH for the trans-cis isomer), 5.40 (1H, q, J=7.3 Hz, CH for the trans-cis isomer), 2.33-2.28 (4H, m, 2CH.sub.2), 2.24 (6H, s, 2H-1), 2.20 (6H, s, 2H-1), 2.07-1.91 (4H, m, 2CH.sub.2), 1.83-1.61 (18H, m, 6CH.sub.3), 1.59-1.51 (4H, m, 2CH.sub.2), 1.49-1.46 (6H, m, 2CH.sub.3); .sup.13C NMR (125 MHz, CDCl.sub.3, /ppm): 139.8 (C.sub.qCH.sub.3), 139.0 (C.sub.qCH.sub.3), 138.8 (C.sub.qCH.sub.3), 122.9 (CH for the trans-cis isomer), 118.5 (CH for the trans-trans isomer), 117.5 (CH for the trans-cis isomer), 79.8 (C-4), 78.9 (C-4), 60.6 (C-3), 45.1 (C-1), 37.6 (C-1), 36.4 (C-1), 23.6 (CH.sub.3), 22.1 (CH.sub.2), 21.9 (CH.sub.2), 14.8 (CH.sub.3), 13.5 (CH.sub.3), 13.3 (CH.sub.3), 12.5 (CH.sub.3), 12.4 (CH.sub.3); IR (v.sub.max, neat, cm.sup.1): 3394 (OH), 2944, 2919, 2859, 2821, 2779, 1459, 1378, 1039, 1014; HRMS (ESI+) m/z: Calculated for C.sub.14H.sub.28NO (M+H.sup.+): 226.2165, found: 226.2167.

Intermediate 6: N,N-Dimethyl-3-(tetramethylcyclopentadienyl)propan-1-amine hydrochloride

(70) ##STR00026##

(71) To a stirred solution of Intermediate 5 (970 mg, 4.30 mmol) in methanol (2.5 ml) was added a 2 M solution of HCl in Et.sub.2O (2.6 ml, 5.2 mmol). The solution was stirred at room temperature for 2 hours and the solvent was removed under reduced pressure. The resulting yellow precipitate (1.14 g) was used in the following reactions without any other purification. Purification of a small amount of crude material (478 mg) by flash chromatography (SiO.sub.2, eluting with DCM-MeOH (90:10)) gave Intermediate 6 as a pale yellow solid in a mixture of isomers used for characterization (239 mg, 0.984 mmol, 55%).

(72) R.sub.f=0.50 (DCM-MeOH 90:10); mp 117.5-118.6 C. (DCM-Et.sub.2O); .sup.1H NMR (500 MHz, CDCl.sub.3, /ppm): 8.54 (1H, br s, NH), 2.73-2.66 (2H, m, H-1), 2.68-2.41 (1H, m, CH), 2.59-2.53 (6H, m, 2H-1), 2.48-2.23 (2H, m, CH.sub.2), 1.92-1.63 (2H, m, CH.sub.2), 1.80-1.75 (9H, m, 3CH.sub.3), 0.98 (3H, d, J=7.5 Hz, CH.sub.3); .sup.13C NMR (125 MHz, CDCl.sub.3, /ppm): 139.7 (C.sub.qCH.sub.3), 139.6 (C.sub.qCH.sub.3), 139.0 (C.sub.qCH.sub.3), 136.7 (C.sub.qCH.sub.3), 136.4 (C.sub.qCH.sub.3), 136.1 (C.sub.qCH.sub.3), 134.5 (C.sub.qCH.sub.3), 133.9 (C.sub.qCH.sub.3), 132.9 (C.sub.qCH.sub.3), 58.6 (C-1), 58.2 (C-1), 55.3 (CH), 51.6 (CH), 49.1 (CH), 43.7 (C-1), 43.6 (C-1), 43.5 (CH.sub.2), 43.3 (CH.sub.2), 25.8 (CH.sub.2), 25.1 (CH.sub.2), 24.7 (CH.sub.2), 23.3 (CH.sub.2), 22.9 (CH.sub.2), 14.2 (CH.sub.3), 11.9 (CH.sub.3), 11.8 (CH.sub.3), 11.6 (CH.sub.3), 11.3 (CH.sub.3), 11.0 (CH.sub.3); IR (v.sub.max, neat, cm.sup.1): 3403 (NH), 2961, 2856, 2763, 2580, 2517, 2479, 1655, 1487, 1443, 1377, 1172, 1058, 1041, 1020, 1006; HRMS (ESI+) m/z: Calculated for C.sub.14H.sub.26N (M+H.sup.+): 208.2060, found: 208.2062.

Intermediate 7: Ethyl 4-(2-1H,1H,2H,2H-perfluorodecyloxyacetamido)butanoate

(73) ##STR00027##

(74) To a stirred suspension of DMAP (3.48 g, 28.5 mmol), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (2.73 g, 14.3 mmol) and ethyl 4-aminobutanoate hydrochloride (1.59 g, 9.50 mmol) in DCM (160 ml) at 0 C. was added 1H1H,2H,2H-perfluorodecyloxyacetic acid in small aliquots (4.96 g, 9.50 mmol). The reaction mixture was warmed at RT and stirred for 18 hours. The solvent was removed under reduced pressure, the residue was dissolved in EtOAc (100 ml) and 1 M aqueous HCl (100 ml) and the two phases were separated. The product was extracted with EtOAc (3100 ml) and the combined organic extracts were washed with brine (100 ml) and dried with Na.sub.2SO.sub.4. The solvent was removed under reduced pressure to afford Intermediate 7 as a colourless oil (5.77 g, 9.09 mmol, 96%).

(75) .sup.1H NMR (500 MHz, CDCl.sub.3, /ppm): 6.67 (1H, br s, NH), 4.13 (2H, q, J=7.0 Hz, OCH.sub.2), 3.98 (2H, s, H-2), 3.83 (2H, t, J=6.4 Hz, H-1), 3.35 (2H, q, J=7.0 Hz, H-4), 2.52-2.42 (2H, m, H-2), 2.36 (2H, t, J=7.2 Hz, H-2), 1.87 (2H, ap quint, J=7.1 Hz, H-3), 1.25 (3H, t, J=7.0 Hz, CH.sub.3); .sup.13C NMR (125 MHz, CDCl.sub.3, /ppm): 173.2 (C-1 or C-1), 168.9 (C-1 or C-1), 70.5 (C-2), 63.5 (C-1), 60.5 (OCH.sub.2), 38.3 (C-4), 31.7 (C-2), 31.4 (t, J=21.7 Hz, C-2), 24.6 (C-3), 14.1 (CH.sub.3), 8 carbons (7CF.sub.2, 1CF.sub.3) not observed; .sup.19F NMR (282 MHz, CDCl.sub.3, /ppm): 80.8 (t, J=10.0 Hz), 113.2 (quint, J=14.4 Hz), 121.6, 121.9, 122.7, 123.6, 126.1, 1 fluorous not observed; IR (v.sub.max, neat, cm.sup.1): 3339 (NH), 2938, 1732 (CO), 1666 (CO), 1536, 1446, 1372, 1348, 1325, 1235, 1199, 1144, 1116, 1029; HRMS (ESI+) m/z: Calculated for C.sub.18H.sub.19F.sub.17NO.sub.4 (M+H.sup.+): 636.1037, found: 636.1041.

Intermediate 8: Ethyl 4-((2-1H,1H,2H,2H-perfluorodecyloxyethyl)amino)butanoate

(76) ##STR00028##

(77) To a stirred solution of intermediate 7 (2.20 g, 3.47 mmol) and 2-fluoropyridine (328 l, 3.82 mmol) in DCM (8.0 ml) at 78 C. was added dropwise trifluoromethanesulfonic anhydride (613 l, 3.64 mmol). The solution was stirred at 78 C. for 10 minutes and then warmed at 0 C. Triethylsilane (610 l, 3.82 mmol) was added dropwise, the solution was stirred at 0 C. for 10 minutes and for 5 hours at RT. Diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.23 g, 4.86 mmol) was added and the resulting mixture was stirred for 15 hours, before quenching with DCM (15 ml) and saturated aqueous NaHCO.sub.3 (10 ml). The two phases were separated and the product was extracted with DCM (230 ml). The combined organic phases were dried with Na.sub.2SO.sub.4 and the solvent was removed under reduced pressure. Purification by flash chromatography (SiO.sub.2, eluting with DCM-MeOH (95:5)) gave Intermediate 8 as a colourless oil (688 mg, 1.11 mmol, 32%).

(78) R.sub.f=0.35 (DCM-MeOH 90:10); .sup.1H NMR (500 MHz, CDCl.sub.3, /ppm): 4.12 (2H, q, J=7.0 Hz, OCH.sub.2), 3.75 (2H, t, J=6.8 Hz, H-1), 3.61 (2H, t, J=5.0 Hz, H-2), 3.35 (1H, br s, NH), 2.84 (2H, t, J=5.0 Hz, H-1), 2.73 (2H, t, J=7.2 Hz, H-4), 2.47-2.38 (2H, m, H-2), 2.73 (2H, t, J=7.2 Hz, H-2), 1.87 (2H, ap quint, J=7.2 Hz, H-3), 1.24 (3H, t, J=7.0 Hz, CH.sub.3); .sup.13C NMR (125 MHz, CDCl.sub.3, /ppm): 173.4 (C-1), 69.8 (C-2), 62.9 (C-1), 60.4 (OCH.sub.2), 48.8 (C-4 or C-1), 48.6 (C-4 or C-1), 32.0 (C-2), 31.5 (t, J=21.3 Hz, C-2), 24.6 (C-3), 14.1 (CH.sub.3), 8 carbons (7CF.sub.2, 1CF.sub.3) not observed; .sup.19F NMR (282 MHz, CDCl.sub.3, /ppm): 80.8 (t, J=9.9 Hz), 113.4, 121.7, 121.9, 122.7, 123.6, 126.1, 1 fluorous not observed; IR (v.sub.max, neat, cm.sup.1): 3342 (NH), 2935, 1729 (CO), 1656, 1543, 1444, 1370, 1348, 1199, 1145, 1134, 1016, 1029; HRMS (ESI+) m/z: Calculated for C.sub.18H.sub.20F.sub.17NNaO.sub.3 (M+Na.sup.+): 644.1064, found: 644.1066.

Intermediate 9: Ethyl 4-(N-Boc-(2-1H,1H,2H,2H-perfluorodecyloxyethyl)amino)butanoate

(79) ##STR00029##

(80) To a stirred solution of di-tert-butyl dicarbonate (600 mg, 2.73 mmol) in DCM (8.0 ml) at 0 C. was added a solution of Intermediate 8 (1.54 g, 2.49 mmol) in DCM (4.0 ml). The solution was stirred at 0 C. for 30 minutes and then at RT for 16 hours. The solvent was removed under reduced pressure and a purification by flash chromatography (SiO.sub.2, eluting with hexane-EtOAc (85:15)) gave Intermediate 9 as a colourless oil (1.30 g, 1.80 mmol, 72%).

(81) R.sub.f=0.36 (hexane-EtOAc 80:20); .sup.1H NMR (500 MHz, CDCl.sub.3, /ppm): 4.12 (2H, q, J=7.0 Hz, OCH.sub.2), 3.72 (2H, t, J=6.7 Hz, H-1), 3.57 (2H, br s, H-1 or H-2), 3.37 (2H, br s, H-1 or H-2), 3.27 (2H, br s, H-4), 2.44-2.32 (2H, m, H-2), 2.28 (2H, t, J=7.3 Hz, H-2), 1.84 (2H, ap quint, J=7.3 Hz, H-3), 1.45 (9H, s, C(CH.sub.3).sub.3), 1.25 (3H, t, J=7.0 Hz, CH.sub.3); .sup.13C NMR (125 MHz, CDCl.sub.3, /ppm): 173.2 (C-1), 155.6 (C(O)N), 79.6 (C(CH.sub.3).sub.3), 69.9 & 69.7 (CH.sub.2, rotamers), 62.9 (CH.sub.2), 60.3 (CH.sub.2), 47.7 & 47.2 (CH.sub.2, rotamers), 46.9 (CH.sub.2), 31.6 (t, J=21.2 Hz, C-2), 31.5 (C-2), 28.4 (C(CH.sub.3).sub.3), 23.9 & 23.5 (CH.sub.2, rotamers), 14.2 (CH.sub.3), 8 carbons (7CF.sub.2, 1CF.sub.3) not observed; .sup.19F NMR (282 MHz, CDCl.sub.3, /ppm): 80.8 (t, J=10.0 Hz), 113.4 (quint, J=15.5 Hz), 121.7, 121.9, 122.7, 123.6, 126.1, 1 fluorous not observed; IR (v.sub.max, neat, cm.sup.1): 2980, 2935, 1736 (CO), 1729, 1693 (CO), 1656, 1543, 1479, 1444, 1413, 1370, 1367, 1348, 1236, 1201, 1199, 1144, 1134, 1132, 1116, 1030; HRMS (ESI+) m/z Calculated for C.sub.23H.sub.29F.sub.17NO.sub.5 (M+H.sup.+): 722.1769, found: 722.1778.

Intermediate 10: 4-(N-Boc-(2-1H,1H,2H,2H-Perfluorodecyloxyethyl)aminopropyl)-3,5-dimethyl-hepta-2,5-dien-4-ol

(82) ##STR00030##

(83) Lithium wire (300 mg, 43.2 mmol) was washed with hexane, cut into small pieces and suspended in Et.sub.2O (10 ml). 2-Bromo-2-butene (1.0 ml, 10 mmol, mixture of cis and trans isomers) was added in one portion to the mixture and stirred until the reaction started, observed by the reflux of the solvent; another aliquot of 2-bromo-2-butene (1.33 ml, 13.0 mmol) diluted in Et.sub.2O (10 ml) was added dropwise and the suspension was stirred for 2 hours at RT. The concentration of the organolithium was determined by titration with menthol (1.0 mmol) and 2,2-bipyridyl (0.1 mmol). Intermediate 9 (1.35 g, 1.87 mmol) was dissolved in Et.sub.2O (10 ml) and cooled at 78 C. The titrated organolithium (7.48 mmol) was added dropwise and the solution was stirred for 30 minutes at 78 C. before warming up to RT for 60 minutes. Saturated aqueous NH.sub.4Cl (15 ml) was added and the two phases were separated. The aqueous phase was extracted with Et.sub.2O (350 ml), the combined organic extracts were dried with Na.sub.2SO.sub.4 and the solvent was removed under reduced pressure. Purification by flash chromatography (SiO.sub.2, eluting with hexane-EtOAc (90:10 to 85:15)) gave Intermediate 10 as a pale yellow oil as a 1:1 mixture of trans-trans and trans-cis isomers (849 mg, 1.08 mmol, 58%). A pure fraction of trans-trans isomer has been obtained after purification by chromatography and it has been used for characterisation.

(84) R.sub.f=0.36 (hexane-EtOAc 80:20); .sup.1H NMR (500 MHz, CDCl.sub.3, /ppm): 5.63-5.59 (2H, m, H-2 and H-6), 3.75-3.70 (2H, m, H-1), 3.57 (2H, br s, H-1 or H-2), 3.37 (2H, br s, H-1 or H-2), 3.26 (2H, br s, H-3), 2.486-2.33 (2H, m, H-2), 1.86-1.58 (10 OH, m, 2CH.sub.2 and 2CH.sub.3), 1.55-1.44 (15H, m, 2CH.sub.3 and C(CH.sub.3).sub.3); .sup.13C NMR (125 MHz, CDCl.sub.3, /ppm): 155.7 (C(O)N), 138.1 (C.sub.qCH.sub.3), 118.9 (CH), 80.3 (C-4), 79.4 (C(CH.sub.3).sub.3), 69.8 (CH.sub.2), 62.9 (C-1), 48.8 (CH.sub.2), 46.7 (CH.sub.2), 31.6 (t, J=21.2 Hz, C-2), 28.4 (C(CH.sub.3).sub.3), 22.9 (CH.sub.2), 12.3 (CH.sub.3), 11.6 (CH.sub.3), 9 carbons (1CH.sub.2, 7CF.sub.2, 1CF.sub.3) not observed; .sup.19F NMR (282 MHz, CDCl.sub.3, /ppm): 80.7 (t, J=9.7 Hz), 113.4, 121.7, 121.9, 122.7, 123.6, 126.1, 1 fluorous not observed; IR (v.sub.max, neat, cm.sup.1): 3449 (OH), 2976, 1674 (CO), 1479, 1416, 1367, 1237, 1202, 1170, 1144, 1006; HRMS (ESI+) m/z: Calculated for C.sub.29H.sub.38F.sub.17NNaO.sub.4 (M+Na.sup.+): 810.2422, found: 810.2417.

Intermediate 11: (R)N-Boc-4-(3-Amino-3-isopropyl)propyl-3,5-dimethyl-hepta-2,5-dien-4-ol

(85) ##STR00031##

(86) Lithium wire (300 mg, 43.2 mmol) was washed with hexane, cut into small pieces and suspended in Et.sub.2O (10 ml). 2-Bromo-2-butene (1.0 ml, 10 mmol, mixture of cis and trans isomers) was added in one portion to the mixture and stirred until the reaction started, observed by the reflux of the solvent; another aliquot of 2-bromo-2-butene (1.3 ml, 13 mmol) in Et.sub.2O (10 ml) was added dropwise and the suspension was stirred for 2 hours at RT. The concentration of the organolithium was determined by titration with menthol (1.0 mmol) and 2,2-bipyridyl (0.1 mmol). (R)N-t-Butoxycarbonyl-5-isopropyl-2-pyrrolidinone (prepared according to Smrcina et al, Tetrahedron, 1997, 53, 12867) (500 mg, 2.20 mmol) was diluted in Et.sub.2O (6.0 ml) and cooled at 0 C. The titrated organolithium (4.40 mmol) was added dropwise, the solution was stirred at 0 C. for 30 minutes before warming up to RT for 60 minutes. Saturated aqueous NH.sub.4Cl (30 ml) was carefully added and the two phases were separated. The product was extracted with Et.sub.2O (230 ml). The combined organic phases were dried with Na.sub.2SO.sub.4 and the solvent was removed under reduced pressure. Purification by flash chromatography (SiO.sub.2, eluting with hexane-EtOAc (90:10)) gave Intermediate 11 as a colourless oil in a mixture of trans-trans and trans-cis isomers (fraction major (trans-cis)/minor (trans-trans): 3/1) which was used without further purification (184 mg, 0.542 mmol, 25%).

(87) R.sub.f=0.74 (hexane-EtOAc 80:20); [].sub.D=+7.8 (c=1.0, CHCl.sub.3); .sup.1H NMR (500 MHz, CDCl.sub.3, /ppm): 5.57 (2H, q, J=6.2 Hz, 2CH for the trans-trans isomer), 5.43-5.27 (2H, m, 2CH for the trans-cis isomer), 4.30 (2H, br s, 2NH), 3.49-3.37 (2H, m, 2H-3), 1.96-1.51 (30H, m, 8CH.sub.3 and 2CH.sub.2 and 2H-1), 1.43 (18H, s, 2C(CH.sub.3).sub.3), 1.39-1.16 (4H, m, 2CH.sub.2), 0.91-0.85 (12H, m, 4H-2); .sup.13C NMR (125 MHz, CDCl.sub.3, /ppm): 156.2 (C(O)), 140.2 (C.sub.qCH.sub.3), 139.7 (C.sub.qCH.sub.3), 138.2 (C.sub.qCH.sub.3), 122.6 (CH), 122.5 (CH), 122.4 (CH), 118.1 (CH), 80.8 (C(CH.sub.3).sub.3), 79.5 (C-4), 78.8 (C-4), 56.1 (C-3), 36.3 (CH.sub.2), 34.3 (CH), 32.5 (CH.sub.2), 28.4 (C(CH.sub.3).sub.3), 27.0 (CH.sub.2), 26.6 (CH.sub.2), 23.5 (CH.sub.2), 22.8 (CH.sub.3), 19.2 (CH.sub.2), 17.8 (CH.sub.2), 14.8 (CH.sub.3), 14.7 (CH.sub.3), 14.4 (CH.sub.3), 13.2 (CH.sub.3), 12.6 (CH.sub.3); HRMS (ESI+) m/z: Calculated for C.sub.20H.sub.37NNaO.sub.3 (M+Na.sup.+): 362.2666, found: 362.2672.

Intermediate 12: 4-(3-Diethylaminopropyl)-3,5-dimethyl-hepta-2,5-dien-4-ol

(88) ##STR00032##

(89) Lithium wire (470 mg, 67.0 mmol) was washed with hexane, cut into small pieces and suspended in Et.sub.2O (15 ml). 2-Bromo-2-butene (1.6 ml, 16 mmol, mixture of cis and trans isomers) was added in one portion to the mixture and stirred until the reaction started, observed by the reflux of the solvent; another aliquot of 2-bromo-2-butene (2.0 ml, 20 mmol) in Et.sub.2O (15 ml) was added dropwise and the suspension was stirred for 2 hours at RT. A solution of ethyl N,N-diethyl-4-aminobutanoate (3.00 g, 16.0 mmol) in Et.sub.2O (10 ml) was added dropwise, stirred for 90 minutes at RT and quenched with careful addition of saturated aqueous NH.sub.4Cl (100 ml). The phases were separated and the product was extracted with Et.sub.2O (240 ml). The combined organic extracts were dried with Na.sub.2SO.sub.4 and the solvent was removed under reduced pressure. Purification by flash chromatography (SiO.sub.2, eluting with hexane-EtOAc (80:20 to 0:100)) gave Intermediate 12 as a colourless oil as a 1:1 mixture of trans-trans and trans-cis isomers which was used without any other purification (3.70 g, 14.7 mmol, 92%).

(90) R.sub.f=0.39 (DCM-MeOH 90:10); .sup.1H NMR (500 MHz, CDCl.sub.3, /ppm): 5.63 (2H, q, J=6.7 Hz, 2CH for the trans-trans isomer), 5.59-5.55 (1H, m, CH for the trans-cis isomer), 5.38 (1H, q, J=7.2 Hz, CH for the trans-cis isomer), 2.56-2.48 (8H, m, 4H-1), 2.45-2.35 (4H, m, 2H-3), 2.04-1.87 (4H, m, 2CH.sub.2), 1.78-1.73 (4H, m, 2CH.sub.2), 1.64-1.46 (24H, m, 8CH.sub.3), 1.04-0.99 (12H, m, 4H-2); .sup.13C NMR (125 MHz, CDCl.sub.3, /ppm): 139.9 (C.sub.qCH.sub.3), 139.3 (C.sub.qCH.sub.3), 122.5 (CH for the trans-cis isomer), 118.3 (CH for the trans-trans isomer), 117.4 (CH for the trans-cis isomer), 79.7 (C-4), 79.0 (C-4), 54.4 (C-3), 54.1 (C-3), 45.8 (C-1), 45.6 (C-1), 37.5 (C-1), 36.4 (C-1), 23.7 (CH.sub.3), 21.8 (CH.sub.2), 21.6 (CH.sub.2), 14.8 (CH.sub.3), 14.2 (CH.sub.3), 13.4 (CH.sub.3), 13.2 (CH.sub.3), 12.6 (CH.sub.3), 10.5 (C-2), 10.2 (C-2); IR (v.sub.max, neat, cm.sup.1): 3408 (OH), 2970, 2813, 2813, 1455, 1377, 1293, 1195, 1066; HRMS (ESI+) m/z: Calculated for C.sub.16H.sub.32NO (M+H.sup.+): 254.2478, found: 254.2484.

Intermediate 13: N,N-Diethyl-3-(tetramethylcyclopentadienyl)propan-1-amine

(91) ##STR00033##

(92) Prepared by a slightly modified version of the general method for the synthesis of cyclopentadienyls reported by Ito et al. (Organometallics, 2010, 29, 1886) as follows. To a stirred solution of intermediate 12 (1.29 g, 5.09 mmol) in methanol (3.0 ml) was added a 2 M solution of HCl in Et.sub.2O (3.0 ml, 6.0 mmol). The resulting solution was stirred at room temperature for 4 hours and the solvent was removed under reduced pressure. Purification by flash chromatography (Al.sub.2O.sub.3 pH 9.5 t 0.5, eluting with DCM-MeOH (99:1)) gave Intermediate 13 as a pale yellow oil in an unresolved mixture of three isomers (705 mg, 2.99 mmol, 60%).

(93) R.sub.f=0.60 (Neutral aluminium oxide, DCM-MeOH 95:5); .sup.1H NMR (500 MHz, CDCl.sub.3, /ppm): 2.65-2.40 (1H, m, CH), 2.52 (4H, q, J=7.3 Hz, 2H-1), 2.47-2.41 (2H, m, H-1), 2.35-2.11 (2H, m, H-3), 1.82-1.77 (9H, m, 3CH.sub.3), 1.75-1.78 (2H, m, H-2), 1.05-0.96 (9H, m, CH.sub.3 and 2H-2); .sup.13C NMR (125 MHz, CDCl.sub.3, /ppm): 142.2 (C.sub.qCH.sub.3), 138.4 (C.sub.qCH.sub.3), 138.3 (C.sub.qCH.sub.3), 138.1 (C.sub.qCH.sub.3), 135.6 (C.sub.qCH.sub.3), 135.3 (C.sub.qCH.sub.3), 134.5 (C.sub.qCH.sub.3), 134.0 (C.sub.qCH.sub.3), 133.6 (C.sub.qCH.sub.3), 55.9 (CH), 53.4 (CH.sub.2), 53.1 (CH.sub.2), 52.7 (CH.sub.2), 52.0 (CH.sub.2), 51.5 (CH), 49.4 (CH), 46.9 (C-1), 27.8 (CH.sub.2), 26.7 (CH.sub.2), 25.6 (CH.sub.2), 24.3 (CH.sub.2), 23.7 (CH.sub.2), 22.4 (CH.sub.2), 21.0 (CH.sub.2), 14.2 (CH.sub.3), 14.1 (CH.sub.3), 11.8 (CH.sub.3), 11.7 (CH.sub.3), 11.6 (CH.sub.3), 11.1 (CH.sub.3), 11.0 (CH.sub.3); IR (v.sub.max, neat, cm.sup.1): 2968, 2934, 2870, 2799, 1742, 1656, 1445, 1381, 1294, 1201, 1070; HRMS (ESI+) m/z: Calculated for C.sub.16H.sub.30N (M+H.sup.+): 236.2373, found: 236.2376.

Intermediate 14: N-Boc-4-(4-Aminobutyl)-3,5-dimethyl-hepta-2,5-dien-4-ol

(94) ##STR00034##

(95) Lithium wire (437 mg, 63.0 mmol) was washed with hexane, cut into small pieces and suspended in Et.sub.2O (10 ml). 2-Bromo-2-butene (1.3 ml, 13 mmol, mixture of cis and trans isomers) was added in one portion to the mixture and stirred until the reaction started, observed by the reflux of the solvent; another aliquot of 2-bromo-2-butene (2.0 ml, 20 mmol) in Et.sub.2O (10 ml) was added dropwise and the suspension was stirred for 2 hours at RT. A solution of N-Boc-2-piperidinone (3.00 g, 15.0 mmol) in Et.sub.2O (20 ml) was added dropwise, the mixture was stirred for 1 hour and quenched with careful addition of saturated aqueous NH.sub.4Cl (60 ml). The phases were separated and the product was extracted with Et.sub.2O (230 ml). The combined organic phases were dried with Na.sub.2SO.sub.4 and the solvent was removed under reduced pressure. Purification by flash chromatography (SiO.sub.2, eluting with hexane-EtOAc (90:10)) gave Intermediate 14 as a colourless oil as a mixture of trans-trans and trans-cis isomers (fraction major (trans-cis)/minor (trans-trans): 3/2) which was used without any other purification (940 mg, 3.00 mmol, 20%).

(96) R.sub.f=0.50 (hexane-EtOAc 70:30); .sup.1H NMR (500 MHz, CDCl.sub.3, /ppm): 5.57 (2H, q, J=6.5 Hz, 2CH for the trans-trans isomer), 5.34 (2H, dq, J=1.3, 7.5 Hz, 2CH for the trans-cis isomer), 4.54 (2H, br s, 2NH), 3.12 (4H, br s, 2H-4), 1.84-1.71 (6H, m, 2H-1 and 2OH), 1.69-1.60 (24H, m, 8CH.sub.3), 1.53-1.46 (8H, m, 4CH.sub.2), 1.44 (18H, s, 2C(CH.sub.3).sub.3); .sup.13C NMR (125 MHz, CDCl.sub.3, /ppm): 156.1 (C(O)N), 140.2 (C.sub.qCH.sub.3), 139.6 (C.sub.qCH.sub.3), 138.1 (C.sub.qCH.sub.3), 122.5 (CH for the trans-cis isomer), 122.4 (CH for the trans-cis isomer), 118.9 (CH for the trans-trans isomer), 118.1 (CH for the trans-trans isomer), 80.8 (C(CH.sub.3).sub.3), 79.4 (C-4), 79.1 (C-4), 40.4 (C-4), 39.4 (C-1), 37.6 (C-1), 28.4 (C(CH.sub.3).sub.3), 23.4 (CH.sub.3), 22.8 (CH.sub.3), 20.7 (CH.sub.2), 20.5 (CH.sub.2), 14.8 (CH.sub.3), 14.4 (CH.sub.3), 13.4 (CH.sub.3), 13.2 (CH.sub.3), 12.6 (CH.sub.3), 12.4 (CH.sub.3); IR (v.sub.max, neat, cm.sup.1): 3364 (NH and OH), 2975, 2933, 2865, 1695 (CO), 1515, 1454, 1366, 1251, 1172, 1003; HRMS (ESI+) m/h: Calculated for C.sub.18H.sub.33NNaO.sub.3 (M+Na.sup.+): 334.2353, found: 334.2357.

Intermediate 15: (S)-tert-Butyl 2-{(4E/Z)-3-[(2E)-but-2-en-2-yl]-3-hydroxy-4-methylhex-4-en-1-yl}pyrrolidine-1-carboxylate

(97) ##STR00035##

(98) Lithium wire (300 mg, 43.2 mmol) was washed with hexane, cut into small pieces and suspended in Et.sub.2O (10 ml). 2-Bromo-2-butene (1.0 ml, 10 mmol, mixture of cis and trans isomers) was added in one portion to the mixture and stirred until the reaction started, observed by the reflux of the solvent. Following this the remainder of the 2-bromo-2-butene (1.3 ml, 13 mmol) in Et.sub.2O (10 ml) was added dropwise and the suspension was stirred for 1 hour at RT. The concentration of the organolithium was determined by titration with menthol (1.0 mmol) and 2,2-bipyridyl (0.1 mmol). (2S)N-t-Butoxycarbonyl-2-(3-methoxy-3-oxo-1-propyl)pyrrolidine (Org. Lett., 2008, 10, 3045) (100 mg, 0.40 mmol) was diluted in Et.sub.2O (3.0 ml) and cooled at 78 C. The titrated organolithium (1.60 mmol) was added dropwise, the solution was stirred for 5 minutes before warming up to RT and stirring for 90 minutes. Saturated aqueous NH.sub.4Cl (25 ml) was carefully added and the two phases were separated. The product was extracted with Et.sub.2O (320 ml). The combined organic phases were dried with Na.sub.2SO.sub.4 and the solvent was removed under reduced pressure. Purification by flash chromatography (SiO.sub.2, eluting with hexane-EtOAc (80:20)) gave Intermediate 15 as a colourless oil in a 3:1 mixture of trans-trans and trans-cis isomers which was used without further purification (91 mg, 0.27 mmol, 61%).

(99) R.sub.f=0.32 (hexane-EtOAc 80:20); [].sub.D=30.5 (c=1.0, CHCl.sub.3); .sup.1H NMR (500 MHz, CDCl.sub.3, /ppm): 5.61 (2H, q, J=6.6, 2CH for trans-trans isomer), 5.40-5.31 (2H, m, 2CH for the trans-cis isomer), 3.43-3.38 (2H, m, 2 NCH), 3.36-3.31 (4H, m, 4NHCH.sub.2), 1.93-1.77 (10H, m, 2CH.sub.3 and 2CH.sub.2), 1.73-1.55 (30H, m, 10CH.sub.3), 1.35-1.25 (4H, m, 2CH.sub.2); .sup.13C NMR (125 MHz, CDCl.sub.3, /ppm): 154.8, 139.5, 138.3, 137.8, 122.5, 122.5, 118.9, 78.9, 57.5, 56.9, 46.4, 46.1, 33.1, 30.8, 28.7, 28.5, 23.7, 23.4, 23.2, 14.8, 14.4, 13.4, 13.2, 12.3 (one C signal missing from C.sub.qOH); HRMS (ESI+) m/r Calculated for C.sub.20H.sub.35NNaO.sub.3 (M+Na.sup.+): 360.2515, found: 360.2509.

Metal Complex Synthesis

Example 1: RhCl.SUB.2.[.SUP.5.:.SUP.1.-C.SUB.5.(CH.SUB.3.).SUB.4.(CH.SUB.2.).SUB.3.N(CH.SUB.2.CH.SUB.2.OCH.SUB.2.CH.SUB.2.C.SUB.8.F.SUB.17.)H]

(100) ##STR00036##

(101) To a stirred solution of Intermediate 10 (386 mg, 0.490 mmol) in methanol (4.0 ml) was added RhCl.sub.3.hydrate (51 mg, 0.25 mmol). The mixture was heated at reflux for 20 hours and the solvent was removed under reduced pressure. Purification by flash chromatography (SiO.sub.2, eluting with DCM-MeOH (97:3 to 95:5)) gave the title compound as a red solid (74 mg, 88 mol, 35%).

(102) R.sub.f=0.53 (DCM-MeOH 97:3); mp 133.3-134.6 C. (DCM-hexane, v/v=1/2); .sup.1H NMR (500 MHz, CDCl.sub.3, /ppm): 3.85-3.76 (1H, m, CH.sub.2), 3.73-3.49 (4H, 2CH.sub.2), 2.91-2.84 (1H, m, CH.sub.2), 2.79-2.67 (2H, m, CH.sub.2), 2.45-2.31 (2H, m, H-2), 2.25-1.91 (4H, m, 2CH.sub.2), 1.76 (3H, s, CH.sub.3), 1.73 (3H, s, CH.sub.3), 1.67 (3H, s, CH.sub.3), 1.64 (3H, s, CH.sub.3); .sup.13C NMR (125 MHz, CDCl.sub.3, /ppm): 103.0 (d, J=7.5 Hz, C.sub.qRh), 94.3 (d, J=8.8 Hz, C.sub.qRh), 93.2 (d, J=8.0 Hz, C.sub.qRh), 92.0 (d, J=9.1 Hz, C.sub.qRh), 85.1 (d, J=9.6 Hz, C.sub.qRh), 69.0 (C-3), 62.7 (CH.sub.2), 50.7 (CH.sub.2), 48.3 (CH.sub.2), 31.4 (t, J=21.2 Hz, C-2), 27.0 (CH.sub.2), 19.4 (CH.sub.2), 9.9 (CH.sub.3), 9.4 (CH.sub.3), 9.1 (CH.sub.3), 9.1 (CH.sub.3), 8 carbons (7CF.sub.2, 1CF.sub.3) not observed; .sup.19F NMR (282 MHz, CDCl.sub.3, /ppm): 80.8 (t, J=9.8 Hz), 113.3, 121.6, 121.9, 122.7, 123.5, 126.1, 1 fluorous not observed; IR (v.sub.max, neat, cm.sup.1): 3272 (NH), 2918, 1487, 1440, 1370, 1331, 1243, 1200, 1145, 1114, 1006; HRMS (ESI+) m/z: Calculated for C.sub.24H.sub.27F.sub.17.sup.35ClNORh (MCl.sup., 100%): 806.0559, found: 806.0552, calculated for C.sub.24H.sub.27F.sub.17.sup.37ClNORh (MCl.sup., 35%): 808.0539, found: 808.0533; Anal. Calcd. For C.sub.24H.sub.27Cl.sub.2F.sub.17NORh: C, 34.22; H, 3.23; N, 1.66. Found C, 34.40; H, 3.20; N, 1.60.

Example 2: [Rh({.SUP.5.:.SUP.1.-C.SUB.5.(CH.SUB.3.).SUB.4.(CH.SUB.2.).SUB.3.NH.SUB.2.}{CH.SUB.3.CN}.SUB.2.][SbF.SUB.6.].SUB.2

(103) ##STR00037##

(104) To a stirred solution of known rhodium complex [Cl.sub.2Rh{.sup.5:.sup.1-C.sub.5(CH.sub.3).sub.4(CH.sub.2).sub.3NH.sub.2}](Ito et al, Organometallics, 2010, 29, 1886) 2 (50 mg, 0.14 mmol) in acetonitrile (4.0 ml) was added silver hexafluoroantimonate (96 mg, 0.28 mmol). The mixture was heated at 70 C. for 24 hours, the crude was filtered through a pad of Celite, washed with MeCN and the solvent was removed under reduced pressure. Purification by crystallization from MeCN-Et.sub.2O (v/v=1/2) gave the title compound as a yellow powder (71 mg, 90 mol, 61%). Single crystals were achieved by recrystallization from MeCN-Et.sub.2O (v/v=1/2).

(105) mp >250 C. (MeCN); .sup.1H NMR (500 MHz, DMSO, /ppm): 4.22 (2H, br s, NH.sub.2), 2.59 (2H, br s, H-3), 2.17-2.11 (2H, m, H-1), 2.06-2.01 (8H, m, H-2 and 2CH.sub.3CN), 1.70 (6H, s, 2CH.sub.3), 1.44 (6H, s, 2CH.sub.3); .sup.13C NMR (125 MHz, DMSO, /ppm): 119.0 (CN), 102.7-101.4 (m, C.sub.qRh), 86.1-85.2 (m, C.sub.qRh), 41.3 (C-3), 29.8 (C-2), 18.7 (C-1), 7.4 (CH.sub.3), 7.2 (CH.sub.3), 2.1 (CH.sub.3CN), one carbon (C.sub.qRh) not observed; IR (v.sub.max, neat, cm.sup.1): 3328 (NH), 3284 (NH), 2321, 2291, 1594, 1455, 1370, 1163, 1083, 1021; HRMS (ESI+) m/z: Calculated for C.sub.12H.sub.20F.sub.6NRh.sup.121Sb (M[SbF.sub.6.sup.]-2MeCN, 100%): 515.9593, found: 515.9588; calculated for C.sub.12H.sub.20F.sub.6NRh.sup.123Sb (M[SbF.sub.6.sup.]-2MeCN, 68%): 517.9598, found: 517.9590; Anal. Calcd. For C.sub.16H.sub.26F.sub.12N.sub.3RhSb.sub.2: C, 23.02; H, 3.14; N, 5.03. Found C, 23.20; H, 3.10; N, 4.90.

Example 3: IrCl.SUB.2.[.SUP.5.:.SUP.1.-C.SUB.5.(CH.SUB.3.).SUB.4.(CH.SUB.2.).SUB.3.NH.SUB.2.]

(106) ##STR00038##

(107) To a stirred suspension of IrCl.sub.3.hydrate (670 mg, 2.24 mmol) and NaHCO.sub.3 (190 mg, 2.24 mmol) in methanol (15 ml) was added Intermediate 2 (1.34 g, 4.48 mmol). Microwave heating was applied to the reaction mixture with a set temperature of 130 C. for 2 hours with a pressure of 120 psi and, after cooling at RT, the solvent was removed under reduced pressure. Purification by flash chromatography (SiO.sub.2, eluting with DCM-MeOH (98:2)) gave the title compound as a yellow solid (427 mg, 0.968 mmol, 44%). Single crystals were achieved by recrystallization from DCM-hexane (v/v=1/3).

(108) R.sub.f=0.67 (DCM-MeOH 90:10); mp >250 C. (DCM-hexane, v/v=1/3); .sup.1H NMR (500 MHz, CDCl.sub.3, /ppm): 3.94 (2H, brs, NH.sub.2), 2.72-2.68 (2H, m, H-3), 2.18 (2H, t, J=6.3 Hz, H-1), 1.96-1.91 (2H, m, H-2), 1.78 (6H, s, 2CH.sub.3), 1.67 (6H, s, 2CH.sub.3); .sup.13C NMR (125 MHz, CDCl.sub.3, /ppm): 90.8 (C.sub.qIr), 88.7 (C.sub.qIr), 41.9 (C-3), 30.7 (C-2), 19.2 (C-1), 9.2 (CH.sub.3), 9.0 (CH.sub.3), one carbon (C.sub.qIr) not observed; IR (v.sub.max, neat, cm.sup.1): 3234 (NH), 3153 (NH), 2948, 2877, 1593, 1444, 1376, 1269, 1240, 1165, 1083, 1038; HRMS (ESI+) m/z: Calculated for C.sub.12H.sub.20.sup.35Cl.sup.193IrN (MCl.sup., 50%): 404.0885, found: 404.0883; calculated for C.sub.12H.sub.20.sup.37Cl.sup.191IrN and C.sub.12H.sub.20.sup.35Cl.sup.192IrN (MCl.sup., 100%): 406.0900, found: 406.0901; calculated for C.sub.13H.sub.22.sup.37Cl.sup.193IrN (MCl.sup., 26%): 408.0879, found: 408.0878; Anal. Calcd. For C.sub.12H.sub.20Cl.sub.2IrN: C, 32.65; H, 4.57; N, 3.17; Cl, 16.06. Found C, 32.95; H, 4.50; N, 3.00, Cl, 16.00.

Example 4: IrCl.SUB.2.[.SUB.5.:.SUP.1.-C.SUB.5.(CH.SUB.3.).SUB.4.(CH.SUB.2.).SUB.3.N(CH.SUB.3.)H]

(109) ##STR00039##

(110) To a stirred suspension of IrCl.sub.3.hydrate (70 mg, 0.23 mmol) and NaHCO.sub.3 (20 mg, 0.23 mmol) in methanol (3.0 ml) was added the intermediate 4 (143 mg, 0.46 mmol). Microwave heating was applied to the reaction mixture with a set temperature of 140 C. for 2 hours with a pressure of 200 psi and, after cooling at RT, the solvent was removed under reduced pressure. Purification by flash chromatography (SiO.sub.2, eluting with DCM-MeOH (98:2)) gave the title compound as a yellow solid (32 mg, 0.070 mmol, 30%). Single crystals were achieved by slow recrystallization from DCM.

(111) R.sub.f=0.47 (DCM-MeOH 90:10); mp 186.4-187.0 C. (DCM-hexane); .sup.1H NMR (500 MHz, CDCl.sub.3, /ppm): 4.22 (1H, br s, NH), 2.86-2.81 (1H, m, H.sub.A-3), 2.77-2.73 (1H, m, He-3), 2.72 (3H, d, J=6.0 Hz, NCH.sub.3), 2.24-2.17 (1H, m, CH.sub.2), 2.15-2.10 (2H, m, CH.sub.2), 2.00-1.93 (1H, m, CH.sub.2), 1.71 (3H, s, CH.sub.3), 1.70 (3H, s, CH.sub.3), 1.66 (3H, s, CH.sub.3), 1.64 (3H, s, CH.sub.3); .sup.13C NMR (125 MHz, CDCl.sub.3, /ppm): 97.5 (C.sub.qIr), 85.7 (C.sub.qIr), 85.4 (C.sub.qIr), 53.3 (C-3), 39.6 (NCH.sub.3), 26.1 (CH.sub.2), 19.3 (CH.sub.2), 9.3 (CH.sub.3), 9.2 (CH.sub.3), 9.1 (CH.sub.3), 9.0 (CH.sub.3), two carbons (C.sub.qIr) not observed; IR (v.sub.max, neat, cm.sup.1): 3178 (NH), 2990, 2970, 2923, 1738, 1455, 1374, 1228, 1217, 1064, 1028; HRMS (ESI+) m/z: Calculated for C.sub.13H.sub.22.sup.35Cl.sup.191IrN (MCl.sup., 50%): 418.1041, found: 418.1044; calculated for C.sub.13H.sub.22.sup.37Cl.sup.191IrN and C.sub.13H.sub.22.sup.35Cl.sup.191IrN (MCl.sup., 100%): 420.1056, found: 420.1052; calculated for C.sub.13H.sub.22.sup.37Cl.sup.193IrN (MCl.sup., 23%): 422.1035, found: 422.1029; Anal. Calcd. For C.sub.13H.sub.22Cl.sub.2IrN: C, 34.28; H, 4.87; N, 3.08; Cl, 15.57. Found C, 34.40; H, 4.80; N, 3.00; Cl, 15.30.

Example 5: Ir.SUB.2.Cl.SUB.4.[.SUP.5.-C.SUB.5.(CH.SUB.3.).SUB.4.(CH.SUB.2.).SUB.3.NMe.SUB.2..HCl].SUB.2

(112) ##STR00040##

(113) To a stirred suspension of IrCl.sub.3.hydrate (100 mg, 0.334 mmol) in methanol (3.0 ml) was added the Intermediate 6 (321 mg, 1.32 mmol). Microwave heating was applied to the reaction mixture with a set temperature of 120 C. for 1 hour with a pressure of 90 psi. From the resulting mixture, the orange solid was filtered and dried under reduced pressure to give the title compound as an orange powder (155 mg, 0.153 mmol, 93%). The formation of the hydrochloride salt was determined by comparing the NMR signals with a similar complex reported in the literature (Organometallics, 2010, 29, 1886)

(114) .sup.1H NMR (500 MHz, DMSO, /ppm): 10.11 (2H, br s, NH), 3.11-3.08 (4H, m, 2H-3), 2.72 (12H, s, 4NCH.sub.3), 2.10 (4H, t, J=8.3 Hz, 2H-1), 1.84-1.79 (4H, m, 2H-2), 1.70 (12H, s, 4CH.sub.3), 1.64 (12H, s, 4CH.sub.3); .sup.13C NMR (125 MHz, DMSO, /ppm): 94.1 (C.sub.qIr), 92.1 (C.sub.qIr), 89.9 (C.sub.qIr), 56.1 (C-3), 42.0 (NCH.sub.3), 22.1 (C-2), 20.2 (C-1), 8.3 (CH.sub.3), 8.2 (CH.sub.3); IR (v.sub.max, neat, cm.sup.1): 3011, 1453, 1406, 1375, 1031; HRMS (ESI+) m/z: Calculated for C.sub.28H.sub.48.sup.35Cl.sub.2.sup.37Cl.sup.191Ir.sub.2N.sub.2 and C.sub.28H.sub.48.sup.35Cl.sub.3.sup.191Ir.sup.193IrN.sub.2 (M[2HCl]Cl.sup., 63%): 901.2102, found: 901.2112; calculated for C.sub.28H.sub.48.sup.35Cl.sup.37Cl.sub.2.sup.191Ir.sub.2N.sub.2, C.sub.28H.sub.48.sup.35Cl.sub.2.sup.37Cl.sup.191Ir.sup.193IrN.sub.2 and C.sub.28H.sub.48.sup.35Cl.sup.37Cl.sup.193Ir.sub.2N.sub.2 (M[2HCl]Cl.sup., 100%): 903.2106, found: 903.2109; calculated for C.sub.28H.sub.48.sup.37Cl.sub.3.sup.191Ir.sub.2N.sub.2, C.sub.28H.sub.48.sup.35Cl.sup.37Cl.sub.2.sup.191Ir.sup.193IrN.sub.2 and C.sub.28H.sub.48.sup.35Cl.sub.2.sup.37Cl.sup.193Ir.sub.2N.sub.2 (M[2HCl]Cl.sup., 65%): 905.2097, found: 905.2102; Anal. Calcd. For C.sub.28H.sub.50Cl.sub.6Ir.sub.2N.sub.2: C, 33.24; H, 4.98; N, 2.77; Cl, 21.02. Found C, 33.10; H, 4.90; N, 2.60; Cl, 20.60.

Example 6: IrCl.SUB.2.[.SUP.5.:.SUP.1.-C.SUB.5.(CH.SUB.3.).SUB.4.(CH.SUB.2.).SUB.3.N(CH.SUB.3.)N(CH.SUB.3.).SUB.2.]

(115) ##STR00041##

(116) To a suspension of Example 5 (107 mg, 0.106 mmol) in DCM (10 ml) was added potassium tert-butoxide (25 mg, 0.22 mol) and the reaction mixture was stirred at room temperature for 15 hours. The mixture was filtered through a pad of Celite, washed with DCM and the solvent was removed under reduced pressure. Crystallization from DCM-hexane gave the title compound as an orange solid (93 mg, 0.20 mmol, 90%). Single crystals were achieved by slow recrystallization from DCM-hexane (v/v=1/2).

(117) R.sub.f=0.90 (DCM-MeOH 90:10); mp 198.3-199.5 C. (DCM-hexane, v/v=1/2); .sup.1H NMR (500 MHz, CDCl.sub.3, /ppm): 2.77 (6H, s, 2NCH.sub.3), 2.60-2.58 (2H, m, H-3), 2.15-2.08 (4H, m, 2CH.sub.2), 1.60 (6H, s, 2CH.sub.3), 1.59 (6H, s, 2CH.sub.3); .sup.13C NMR (125 MHz, CDCl.sub.3, /ppm): 89.1 (C.sub.qIr), 84.7 (C.sub.qIr), 80.6 (C.sub.qIr), 64.2 (C-3), 52.7 (NCH.sub.3), 25.3 (CH.sub.2), 19.0 (CH.sub.2), 9.3 (CH.sub.3), 9.1 (CH.sub.3); IR (v.sub.max, neat, cm.sup.1): 2917, 1477, 1448, 1435, 1375, 1029, 1002; HRMS (ESI+) m/z: Calculated for C.sub.14H.sub.24.sup.37Cl.sup.191IrN (MCl.sup., 49%): 432.1198, found: 432.1197; calculated for C.sub.14H.sub.24.sup.37Cl.sup.191IrN and C.sub.14H.sub.24.sup.35Cl.sup.193IrN (MCl.sup., 100%): 434.1213, found: 434.1215; calculated for C.sub.14H.sub.24.sup.37Cl.sup.193IrN (MCl.sup., 27%): 436.1195, found: 436.1193; Anal. Calcd. For C.sub.14H.sub.24Cl.sub.2IrN: C, 35.82; H, 5.15; N, 2.98; Cl, 15.10. Found C, 36.20; H, 5.15; N, 2.90; Cl, 14.75.

Example 7: IrI.SUB.2.[.SUP.5.:.SUP.1.-C.SUB.5.(CH.SUB.3.).SUB.4.(CH.SUB.2.).SUB.3.NH.SUB.2.]

(118) ##STR00042##

(119) To a stirred solution of Example 3 (70 mg, 0.16 mmol) in degassed acetone (10 ml) was added sodium iodide (52 mg, 0.35 mmol). The reaction mixture was heated at reflux for 18 hours, cooled to RT and the solvent was removed under reduced pressure. The residue was dissolved in DCM (20 ml) and water (15 ml) and the two phases were separated. The product was extracted with DCM (220 ml) and the combined organic phases were washed with brine (40 ml) and dried with Na.sub.2SO.sub.4. The solvent was removed under reduced pressure. Purification by crystallization from DCM-hexane (v/v=1/2) gave the title compound as an orange solid (72 mg, 0.12 mmol, 75%).

(120) R.sub.f=0.88 (DCM-MeOH 90:10); mp >250 C. (DCM); .sup.1H NMR (500 MHz, CDCl.sub.3, /ppm): 3.92 (2H, br s, NH.sub.2), 2.58-2.54 (2H, m, H-3), 2.20 (2H, t, J=6.3 Hz, H-1), 2.05 (6H, s, 2CH.sub.3), 1.92 (6H, s, 2CH.sub.3), 1.85-1.81 (2H, m, H-2); .sup.13C NMR (125 MHz, CDCl.sub.3, /ppm): 89.8 (C.sub.qIr), 89.7 (C.sub.qIr), 81.1 (C.sub.qIr), 42.5 (C-3), 29.1 (C-2), 19.3 (C-1), 12.2 (CH.sub.3), 10.1 (CH.sub.3); IR (v.sub.max, neat, cm.sup.1): 3214 (NH), 3139 (NH), 2908, 1579, 1458, 1371, 1309, 1262, 1157, 1070, 1022; HRMS (ESI+) m/z: Calculated for C.sub.12H.sub.20I.sup.191IrN (MI.sup., 64%): 496.0241, found: 496.0237; calculated for C.sub.12H.sub.20I.sup.193IrN (MI.sup., 100%): 498.0264, found: 498.0263; Anal. Calcd. For C.sub.12H.sub.20I.sub.2IrN: C, 23.09; H, 3.23; N, 2.24. Found C, 23.55; H, 3.30; N, 2.20. Elemental analysis data for C outside the range (+0.4), but best value to date.

Example 8: IrI.SUB.2.[.SUP.5.:.SUP.1.-C.SUB.5.(CH.SUB.3.).SUB.4.(CH.SUB.2.).SUB.3.N(CH.SUB.3.).SUB.2.]

(121) ##STR00043##

(122) To a stirred solution of Example 6 (93 mg, 0.20 mmol) in degassed acetone (12 ml) was added sodium iodide (66 mg, 0.44 mmol). The reaction mixture was heated at reflux for 17 hours, it was cooled to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in DCM (30 ml) and water (30 ml) and the two phases were separated. The product was extracted with DCM (230 ml), the combined organic phases were dried with Na.sub.2SO.sub.4 and the solvent was removed under reduced pressure. Purification by crystallization from DCM-hexane (v/v=1/2) gave the title compound as bright red crystals (125 mg, 0.192 mmol, 96%).

(123) mp 203.0-204.7 C. (CHCl.sub.3); H NMR (500 MHz, CDCl.sub.3, /ppm): 3.13 (6H, s, 2NCH.sub.3), 2.57 (2H, br s, H-3), 2.05 (4H, s, 2CH.sub.2), 1.87 (6H, s, 2CH.sub.3), 1.82 (6H, s, 2CH.sub.3); .sup.13C NMR (125 MHz, CDCl.sub.3, /ppm): 88.0 (C.sub.qIr), 86.7 (C.sub.qIr), 85.1 (C.sub.qIr), 64.9 (C-3), 58.9 (NCH.sub.3), 24.9 (CH.sub.2), 18.4 (CH.sub.2), 12.4 (CH.sub.3), 11.0 (CH.sub.3); IR (v.sub.max, neat, cm.sup.1): 2906, 1452, 1439, 1374, 1364, 1029; HRMS (ESI+) m/z: Calculated for C.sub.14H.sub.24I.sup.191IrN (MI.sup., 54%): 524.0554, found: 524.0551; calculated for C.sub.14H.sub.24I.sup.193IrN (MI.sup., 100%): 526.0578, found: 526.0574; Anal. Calcd. For C.sub.14H.sub.24I.sub.2IrN: C, 25.78; H, 3.71; N, 2.15; I, 38.91. Found C, 26.15; H, 3.70; N, 2.00; I, 38.45. Elemental analysis data for I outside the range (+0.4), but best value to date.

Example 9: (R)IrCl.SUB.2.[.SUP.5.:.SUB.1.-C.SUB.5.(CH.SUB.3.).SUB.4.(CH.SUB.2.).SUB.2.(CH(CH(CH.SUB.3.).SUB.2.)NH.SUB.2.]

(124) ##STR00044##

(125) To a stirred suspension of IrCl.sub.3.hydrate (80 mg, 0.27 mmol) and NaHCO.sub.3 (23 mg, 0.27 mmol) in methanol (3.0 ml) was added Intermediate 11 (184 mg, 0.542 mmol). Microwave heating was applied to the reaction mixture with a set temperature of 125 C. for 2 hours with a pressure of 130 psi and, upon cooling down to RT, the solvent was removed under reduced pressure. Purification by flash chromatography (SiO.sub.2, eluting with DCM-MeOH (97:3)) followed by crystallisation from DCM-hexane (v/v=1/3) gave the title compound as a yellow solid (35 mg, 0.072 mmol, 27%). Single crystals were achieved by recrystallization from DCM-hexane (v/v=1/3).

(126) R.sub.f=0.71 (DCM-MeOH 95:5); [].sub.D=12.18 (c=1.0, CHCl.sub.3); mp 250.8-252.9 C. (decomposition, DCM-hexane, v/v=1/3); .sup.1H NMR (500 MHz, CDCl.sub.3, /ppm): 4.08 (1H, br s, NH), 3.27 (1H, br s, NH), 2.43-2.30 (2H, m, H-3 and H.sub.A-1), 2.19-2.02 (2H, m, H.sub.B-1 and H.sub.A-2), 1.94-1.82 (1H, m, H-1), 1.78 (3H, s, CH.sub.3), 1.77 (3H, s, CH.sub.3), 1.69 (6H, s, 2CH.sub.3), 1.57-1.42 (1H, m, He-2), 0.98-0.95 (6H, m, 2H-2); .sup.13C NMR (125 MHz, CDCl.sub.3, /ppm): 90.6 (C.sub.qIr), 90.2 (C.sub.qIr), 90.0 (C.sub.qIr), 59.2 (C-3), 33.4 (C-2), 33.3 (C-1), 20.3 (C-1), 18.2 (C-2), 18.1 (C-2), 9.3 (CH.sub.3), 9.1 (CH.sub.3), 9.0 (CH.sub.3), 8.9 (CH.sub.3), two carbons (C.sub.qIr) not observed; IR (v.sub.max, neat, cm.sup.1): 3299 (NH), 3207 (NH), 2962, 2920, 2876, 1575, 1478, 1455, 1369, 1338, 1282, 1261, 1186, 1168, 1102, 1059, 1034; HRMS (ESI+) m/z: Calculated for C.sub.15H.sub.26.sup.37Cl.sup.191IrN and C.sub.15H.sub.26.sup.35Cl.sup.193IrN (MCl.sup., 100%): 448.1369, found: 448.1368; Anal. Calcd. For C.sub.15H.sub.26Cl.sub.2IrN: C, 37.26; H, 5.42; N, 2.90; Cl, 14.67. Found C, 37.60; H, 5.40; N, 2.80; Cl, 14.40.

Example 10: [Ir{.SUP.5.:.SUP.1.-C.SUB.5.(CH.SUB.3.).SUB.4.(CH.SUB.2.).SUB.3.NH.SUB.2.}{bipyridyl}][Cl].SUB.2

(127) ##STR00045##

(128) To a stirred solution of Example 3 (70 mg, 0.16 mmol) in chloroform (3.0 ml) was added 2,2-bipyridyl (25 mg, 0.16 mmol). The reaction mixture was stirred overnight at RT and the solvent was slowly evaporated to half of its volume. The resulting precipitate was filtered to give the title compound as pale yellow crystals (90 mg, 0.15 mmol, 94%). Single crystals were achieved by slow crystallization from chloroform.

(129) mp 197.6-199.2 C. (decomposition, CHCl.sub.3); .sup.1H NMR (500 MHz, MeOD, /ppm): 8.92 (2H, d, J=5.7 Hz, 2H-5), 8.65 (2H, d, J=8.0 Hz, 2H-2), 8.30 (2H, ap dt, J=8.0, 1.4 Hz, 2H-3), 7.84 (2H, ddd, J=8.0, 5.7, 1.3 Hz, 2H-4), 2.49-2.45 (2H, m, H-3), 2.44-2.41 (2H, m, H-1), 1.96-1.92 (2H, m, H-2), 1.80 (6H, s, 2CH.sub.3), 1.41 (6H, s, 2CH.sub.3); .sup.13C NMR (125 MHz, MeOD, /ppm): 157.4 (C-1), 153.6 (C-5), 142.5 (C-3), 130.6 (C-4), 126.0 (C-2), 101.2 (C.sub.qIr), 97.5 (C.sub.qIr), 80.3 (C.sub.qIr), 43.1 (C-3), 29.7 (C-2), 19.4 (C-1), 8.2 (CH.sub.3), 8.1 (CH.sub.3); IR (v.sub.max, neat, cm.sup.1): 3448 (NH), 3365 (NH), 3116, 3043, 1698, 1607, 1472, 1446, 1314, 1210, 1162, 1076, 1033; HRMS (ESI+) m/z: Calculated for C.sub.22H.sub.28.sup.191IrN.sub.3 (M2Cl.sup., 56%): 262.5939, found: 262.5944; calculated for C.sub.22H.sub.28.sup.193IrN.sub.3 (M2Cl.sup., 100%): 263.5951, found: 263.5960; Anal. Calcd. For C.sub.22H.sub.28Cl.sub.2IrN.sub.3.2H.sub.2O: C, 41.70; H, 5.09; N, 6.63; Cl, 11.19. Found C, 41.60; H, 5.40; N, 6.20; Cl, 11.20. Elemental analysis data for N outside the range (t 0.4), but best value to date.

Example 11: [Ir{.SUP.5.:.SUP.1.-C.SUB.5.(CH.SUB.3.).SUB.4.(CH.SUB.2.).SUB.3.NH.SUB.2.}{CH.SUB.3.CN}.SUB.2.][SbF.SUB.6.].SUB.2

(130) ##STR00046##

(131) To a stirred solution of example 3 (120 mg, 0.272 mmol) in acetonitrile (8.0 ml) was added silver hexafluoroantimonate (200 mg, 0.582 mmol). The mixture was stirred at RT for 4 hours, the crude was filtered through a pad of Celite, washed with MeCN and the solvent was removed under reduced pressure. Purification by precipitation from DCM gave the title compound as a pale yellow powder (174 mg, 0.188 mmol, 70%). Single crystals were achieved by recrystallization from MeCN-Et.sub.2O (v/v=1/4).

(132) mp >250 C. (MeCN-Et.sub.2O, v/v=1/4); .sup.1H NMR (500 MHz, CD.sub.3CN, /ppm): 4.38 (2H, br s, NH.sub.2), 2.60-2.56 (2H, m, H-3), 2.30-2.25 (2H, m, H-1), 1.97 (6H, s, 2CH.sub.3CN), 1.92-1.87 (2H, m, H-2), 1.86 (6H, s, 2CH.sub.3), 1.65 (6H, s, 2CH.sub.3); .sup.13C NMR (125 MHz, CD.sub.3CN, /ppm): 100.6 (C.sub.qIr), 98.9 (C.sub.qIr), 81.4 (C.sub.qIr), 42.7 (C-3), 29.8 (C-2), 18.9 (C-1), 9.4 (CH.sub.3), 9.1 (CH.sub.3), two carbons (CN and CH.sub.3CN) not observed; IR (v.sub.max, neat, cm.sup.1): 3313 (NH), 3274 (NH), 2946, 2315, 1654, 1597, 1457, 1365, 1279, 1191, 1083, 1030; HRMS (ESI+) m/z: Calculated for C.sub.12H.sub.20F.sub.6N.sup.191Ir.sup.121Sb (M[SbF.sub.6.sup.]-2MeCN, 43%): 604.0139, found: 604.0139; calculated for C.sub.12H.sub.20F.sub.6N.sup.191Ir.sup.123Sb and C.sub.12H.sub.20F.sub.6N.sup.193I.sup.121Sb (M[SbF.sub.6.sup.]-2MeCN, 100%): 606.0156, found: 606.0157; calculated for C.sub.12H.sub.20F.sub.6N.sup.193Ir.sup.123Sb (M[SbF.sub.6.sup.]-2MeCN, 53%): 608.0167, found: 608.0164; Anal. Calcd. For C.sub.16H.sub.26F.sub.12N.sub.3IrSb.sub.2: C, 20.80; H, 2.84; N, 4.55. Found C, 21.20; H, 2.80; N, 4.50.

Example 12: Rh.SUB.2.Cl.SUB.4.[.SUP.5.-C.SUB.5.(CH.SUB.3.).SUB.4.(CH.SUB.2.).SUB.3.NEt.SUB.2..HCl].SUB.2

(133) ##STR00047##

(134) To a stirred solution of intermediate 13 (182 mg, 0.672 mmol) in methanol (5.0 ml) was added RhCl.sub.3.hydrate (70 mg, 0.33 mmol). The reaction mixture was heated at reflux for 22 hours, cooled to room temperature and the solvent removed under reduced pressure. Crystallization from DCM-hexane (v/v=1/3) gave the title compound as a red solid (130 mg, 0.147 mmol, 89%). The formation of the hydrochloride salt was determined by comparing the NMR signals with a similar complex reported in the literature. (Organometallics, 2010, 29, 1886)

(135) mp >250 C. (MeOH); .sup.1H NMR (500 MHz, DMSO, /ppm): 10.14 (2H, br s, 2NH), 3.09-3.06 (12H, m, 6NCH.sub.2), 2.22 (4H, t, J=8.3 Hz, 2H-1), 1.84-1.80 (4H, m, 2H-2), 1.70 (12H, s, 4CH.sub.3), 1.63 (12H, s, 4CH.sub.3), 1.19 (12H, t, J=7.3 Hz, 4NCH.sub.2CH.sub.3); .sup.13C NMR (125 MHz, DMSO, /ppm): 100.1 (d, J=8.8 Hz, C.sub.qRh), 99.1 (d, J=7.5 Hz, C.sub.qRh), 97.9 (d, J=8.0 Hz, C.sub.qRh), 50.2 (NCH.sub.2), 46.0 (NCH.sub.2), 21.4 (C-2), 20.5 (C-1), 8.6 (CH.sub.3), 8.4 (CH.sub.3), one carbon (CH.sub.3) not observed; IR (v.sub.max, neat, cm.sup.1): 3214, 3140, 2933, 2856, 2756, 2724, 1581, 1491, 1453, 1370, 1355, 1309, 1263, 1157, 1114, 1070, 1023; Anal. Calcd. For C.sub.32H.sub.58Cl.sub.6N.sub.2Rh.sub.2: C, 43.22; H, 6.57; N, 3.15. Found C, 43.65; H, 6.35; N, 2.90. Elemental analysis data for C outside the expected range (t 0.4), but best value to date.

Example 13: RhCl.SUB.2.[.SUP.5.:.SUP.1.-C.SUB.5.(CH.SUB.3.).SUB.4.(CH.SUB.2.).SUB.3.N(CH.SUB.2.CH.SUB.3.)H]

(136) ##STR00048##

(137) To a suspension of Example 12 (40 mg, 50 mol) in DCM (5.0 ml) was added potassium tert-butoxide (11 mg, 0.10 mmol). The mixture was stirred at room temperature for 72 hours, filtered through a pad of Celite, washed with DCM and the solvent was removed under reduced pressure. Purification by flash chromatography (SiO.sub.2, eluting with DCM-MeOH (99:1)) gave the title compound as an orange solid (6 mg, 16 mol, 16%).

(138) R.sub.f=0.57 (DCM-MeOH 90:10); mp 175.1-176.4 C. (DCM); .sup.1H NMR (500 MHz, CDCl.sub.3, /ppm): 3.58-3.53 (1H, m, H.sub.A-3), 3.30 (1H, br s, NH), 2.84-2.73 (2H, m, NCH.sub.2), 2.68-2.61 (1H, m, He-3), 2.19-1.99 (4H, m, 2CH.sub.2), 1.77 (3H, s, CH.sub.3), 1.72 (3H, s, CH.sub.3), 1.67 (3H, s, CH.sub.3), 1.62 (3H, s, CH.sub.3), 1.10 (3H, t, J=7.3 Hz, CH.sub.3); .sup.13C NMR (125 MHz, CDCl.sub.3, /ppm): 105.1 (d, J=7.5 Hz, C.sub.qRh), 94.8 (d, J=8.8 Hz, C.sub.qRh), 93.1 (d, J=8.8 Hz, C.sub.qRh), 90.1 (d, J=7.5 Hz, C.sub.qRh), 83.8 (d, J=8.8 Hz, C.sub.qRh), 45.3 (NCH.sub.2), 44.6 (NCH.sub.2), 26.0 (C-2), 19.3 (C-1), 13.7 (CH.sub.3), 9.9 (CH.sub.3), 9.4 (CH.sub.3), 9.3 (CH.sub.3), 9.2 (CH.sub.3); IR (v.sub.max, neat, cm.sup.1): 3469 (NH), 3217 (NH), 2917, 1651, 1448, 1374, 1063, 1028; HRMS (ESI+) m/h: Calculated for C.sub.14H.sub.24.sup.35ClNRh (MCl.sup., 100%): 344.0640, found: 344.0640.

Example 14: Rh.SUB.2.Cl.SUB.4.[.SUP.5.-C.SUB.5.(CH.SUB.3.).SUB.4.(CH.SUB.2.).SUB.4.NH.SUB.3.Cl].SUB.2

(139) ##STR00049##

(140) To a stirred solution of intermediate 14 (298 mg, 0.964 mmol) in methanol (8.0 ml) was added RhCl.sub.3.hydrate (100 mg, 0.478 mmol). The reaction mixture was heated at reflux for 22 hours, then cooled to room temperature and the solvent was removed under reduced pressure. Crystallization from MeOH-Et.sub.2O (v/v=1/2) gave the title compound as an orange solid (65 mg, 0.081 mmol, 34%). The formation of the hydrochloride salt was determined by comparing the NMR signals with a similar complex reported in the literature. (Organometallics, 2010, 29, 1886)

(141) .sup.1H NMR (500 MHz, DMSO, /ppm): 8.05 (6H, br s, 2NH.sub.3), 2.75 (4H, br s, 2H-4), 2.15 (4H, br s, 2H-1), 1.67 (12H, s, 4CH.sub.3), 1.63-1.57 (16H, m, 2CH.sub.2 and 4CH.sub.3), 1.48 (4H, br s, 2CH.sub.2); .sup.13C NMR (125 MHz, DMSO, /ppm): 99.4 (d, J=7.5 Hz, C.sub.qRh), 99.3 (d, J=7.5 Hz, C.sub.qRh), 99.1 (d, J=7.5 Hz, C.sub.qRh), 38.3 (C-4), 26.9 (CH.sub.2), 23.9 (CH.sub.2), 22.7 (C-1), 8.7 (CH.sub.3), 8.6 (CH.sub.3); IR (v.sub.max, neat, cm.sup.1): 3370 (NH), 3100 (NH), 2965, 2914, 1706, 1591, 1567, 1479, 1400, 1367, 1024; HRMS (ESI+) m/z: Calculated for C.sub.26H.sub.44N.sub.2Rh.sub.2.sup.35Cl.sub.3 (M[2HCl]Cl.sup., 100%): 695.0675, found: 695.0673, calculated for C.sub.26H.sub.44N.sub.2Rh.sub.2.sup.35Cl.sub.2.sup.37Cl (M[2HCl]Cl.sup., 100%): 697.0649, found: 697.0647; calculated for C.sub.26H.sub.44N.sub.2Rh.sub.2.sup.35Cl.sup.37Cl.sub.2 (M[2HCl]Cl.sup., 33%): 699.0627, found: 699.0620.

Example 15: RhCl.SUB.2.[.SUP.5.:.SUP.1.-C.SUB.5.(CH.SUB.3.).SUB.4.(CH.SUB.2.).SUB.4.NH.SUB.2.]

(142) ##STR00050##

(143) To a stirred solution of example 14 (52 mg, 0.065 mmol) in DCM (10 ml) was added potassium tert-butoxide (16 mg, 0.14 mmol) and the mixture was stirred at room temperature for 72 hours. It was filtered through a pad of Celite, washed with DCM and the solvent was removed under reduced pressure. Purification by flash chromatography (SiO.sub.2, eluting with DCM-MeOH (97:3)) gave the title compound as an orange solid (14 mg, 38 mol, 29%).

(144) R.sub.f=0.53 (DCM-MeOH 90:10); .sup.1H NMR (500 MHz, CDCl.sub.3, /ppm): 3.23-3.19 (2H, m, H-4), 2.87 (2H, br s, NH.sub.2), 2.11-2.09 (2H, m, CH.sub.2), 2.07-2.01 (2H, m, CH.sub.2), 1.86-1.79 (2H, m, CH.sub.2), 1.66 (6H, s, 2CH.sub.3), 1.64 (6H, s, 2CH.sub.3); .sup.13C NMR (125 MHz, CDCl.sub.3, /ppm): 100.9 (d, J=11.3 Hz, C.sub.qRh), 96.7 (d, J=10.0 Hz, C.sub.qRh), 89.3 (d, J=10.0 Hz, C.sub.qRh), 43.9 (C-4), 28.9 (CH.sub.2), 22.9 (CH.sub.2), 21.5 (CH.sub.2), 9.7 (CH.sub.3), 9.0 (CH.sub.3); HRMS (ESI+) m/z: Calculated for C.sub.13H.sub.22NRh.sup.35Cl (MCl.sup., 100%): 330.0490, found: 330.0492, calculated for C.sub.13H.sub.22NRh.sup.37Cl (MCl.sup., 33%): 332.0461, found: 332.0457.

Example 16: RhI.SUB.2.[.SUP.5.:.SUP.1.-C.SUB.5.(CH.SUB.3.).SUB.4.(CH.SUB.2.).SUB.3.NH.SUB.2.]

(145) ##STR00051##

(146) To a stirred solution of the known (Organometallics, 2010, 29, 1886) rhodium complex RhCl.sub.2[.sup.5:.sup.1-C.sub.5(CH.sub.3).sub.4(CH.sub.2).sub.3NH.sub.2] (30 mg, 85 mol) in degassed acetone (5.0 ml) was added sodium iodide (28 mg, 0.19 mmol). The reaction mixture was heated at reflux for 20 hours, then cooled to RT and the solvent was removed under reduced pressure. The residue was dissolved in DCM (15 ml), washed with water (215 ml) and brine (15 ml). The organic phase was dried with Na.sub.2SO.sub.4 and the solvent was removed under reduced pressure. Purification by flash chromatography (SiO.sub.2, eluting with DCM-MeOH (98:2)) gave the title compound as a dark red solid (27 mg, 0.050 mmol, 60%).

(147) R.sub.f=0.87 (DCM-MeOH 90:10); mp >250 C. (DCM-hexane, v/v=1/2); .sup.1H NMR (500 MHz, CDCl.sub.3, /ppm): 3.17 (2H, br s, NH.sub.2), 2.56-2.53 (2H, m, H-3), 2.17-2.13 (2H, m, H-1), 2.14 (6H, s, 2CH.sub.3), 2.00 (6H, s, 2CH.sub.3), 1.94-1.89 (2H, m, H-2); .sup.13C NMR (125 MHz, CDCl.sub.3, /ppm): 97.5 (d, J=7.5 Hz, C.sub.qRh), 97.0 (d, J=7.5 Hz, C.sub.qRh), 90.5 (d, J=7.5 Hz, C.sub.qRh), 40.0 (C-3), 28.8 (C-2), 19.5 (C-1), 12.7 (CH.sub.3), 10.6 (CH.sub.3); IR (v.sub.max, neat, cm.sup.1): 3223 (NH), 3149 (NH), 2942, 2908, 1580, 1458, 1370, 1354, 1145, 1129, 1015, 924; HRMS (ESI+) m/z: Calculated for C.sub.12H.sub.20NRhI (MI.sup.): 407.9690, found: 407.9693; Anal. Calcd. For C.sub.12H.sub.20I.sub.2NRh: C, 26.96; H, 3.77; N, 2.62. Found C, 27.50; H, 3.80; N, 2.50. Elemental analysis data for C outside the expected range (t 0.4), but best value to date.

Example 17: (R)IrCl.SUB.2.[.SUP.5.:.SUP.1.-C.SUB.5.(CH.SUB.3.).SUB.4.(CH.SUB.2.).SUB.2.CH{CH.SUB.2.CH.SUB.2.CH.SUB.2.}NH]

(148) ##STR00052##

(149) A stirred suspension of IrCl.sub.3 hydrate (70 mg, 0.20 mmol) and NaHCO.sub.3 (19.7 mg, 0.20 mmol) was prepared in methanol (3.0 mL) and put under nitrogen. The intermediate 15 (158 mg, 0.50 mmol) was added to the suspension. Microwave heating was applied at a set temperature of 125 OC for 2 hours with a pressure of 130 psi. Following this, the solvent was removed under reduced pressure. Purification by silica gel chromatography (eluent DCM/MeOH, 95:5) gave a yellow solid (42.9 mg, 0.10 mmol, 38%). Single crystals were achieved by recrystallization using DCM/hexane (v/v=1:3).

(150) R.sub.f=0.51 (DCM/MeOH, 95:5). mp (decomposition) 250.6-251.5 C. (DCM-hexane, v/v=1/3). .sup.1H NMR (500 MHz, CDCl.sub.3, /ppm): (mixture of diastereomers) 4.59-4.57 (1H, m, NH), 3.78-3.72 (1H, m, CH.sub.2), 3.43-3.29 (2H, m, CH.sub.2), 3.12-3.07 (1H, m, NCH), 2.87-2.77 (1H, m, CH.sub.2), 2.66-2.58 (1H, m, CH), 2.41-1.78 (14H, m, 14CH.sub.2), 1.73-1.71 (24H, m, 24CH.sub.3), 1.53-1.46 (2H, m, CH.sub.2) (missing 1NH signal); .sup.13C NMR (125 MHz, CDCl.sub.3, /ppm): (mixture of diastereomers) 95.2 (C.sub.qIr), 93.0 (C.sub.qIr), 91.6 (C.sub.qIr), 89.9 (C.sub.qIr), 89.0 (C.sub.qIr), 88.6 (C.sub.qIr), 85.0 (C.sub.qIr), 81.9 (C.sub.qIr), 63.8 (NCH), 59.8 (NCH), 49.8 (CH.sub.2), 48.6 (CH.sub.2), 35.0 (CH.sub.2), 31.4 (CH.sub.2), 31.3 (CH.sub.2), 31.2 (CH.sub.2), 23.2 (CH.sub.2), 22.9 (CH.sub.2), 20.4 (CH.sub.2), 20.2 (CH.sub.2), 9.2 (Cp*CH.sub.3), 9.1 (Cp*CH.sub.3), 9.1 (Cp*CH.sub.3), 9.1 (Cp*CH.sub.3), 9.0 (Cp*CH.sub.3), 9.0 (Cp*CH.sub.3), 8.9 (Cp*CH.sub.3), 8.9 (Cp*CH.sub.3), missing 2 C.sub.qIr signals. IR (v.sub.max, neat, cm.sup.1): 3427, 3150, 2959, 2920, 2854, 1451, 1368, 700; HRMS (ESI+) m/z: Calculated for C.sub.15H.sub.24.sup.35Cl.sup.191IrN (MCl.sup., 50%): 444.1204, found: 444.1198; calculated for C.sub.15H.sub.24.sup.37Cl.sup.191IrN and C.sub.15H.sub.24.sup.35Cl.sup.193IrN (MCl.sup., 100%): 446.1201, found: 446.1213; calculated for C.sub.15H.sub.24.sup.37Cl.sup.193IrN (MCl.sup., 26%): 448.1197, found: 448.1195; Analysis calculated for C.sub.15H.sub.24Cl.sub.2IrN: C, 37.42%; H, 5.02%; N, 2.91%. Found: C, 37.00%; H, 4.90%; N, 2.80%.

Example 18: [Ir({.SUP.5.:.SUP.1.-C.SUB.5.(CH.SUB.3.).SUB.4.(CH.SUB.2.)NH.SUB.2.}{2,4-difluoro-N-phenylpicolinamide}][PF.SUB.6.]

(151) ##STR00053##

(152) A suspension of Example 3 (50 mg, 0.11 mmol) and 2,4-difluoro-N-phenylpicolinamide (30.4 mg, 0.13 mmol) in ethanol (20 ml) was stirred and refluxed for 30 minutes. NH.sub.4PF.sub.6 (42.4 mg, 0.26 mmol) in ethanol (10 ml) was added and the mixture was refluxed overnight. After cooling to RT, the remaining solids were filtered, and the solvent removed from the filtrate under reduced pressure. Purification by precipitation from EtOH/hexane gave the title compound as a bright yellow powder (63.5 mg, 0.0848 mmol, 77%). Single crystals were achieved by recrystallisation from MeOH/Et.sub.2O.

(153) .sup.1H NMR (500 MHz, CD.sub.3OD, /ppm): 8.80 (1H, d, J=5.3 Hz, H-4), 8.27 (1H, td, J=7.7, 1.3 Hz, H-6), 8.15 (1H, d, J=7.9 Hz, H-7), 7.86 (1H, ddd, J=7.4, 5.7, 1.4 Hz, H-5), 7.41-7.12 (2H, m, H-8, H-10), 7.08 (1H, br s, H-9), 2.81 (1H, br s, H-3), 2.52-2.44 (2H, m, H-3, H-1), 2.24 (1H, m, H-1), 2.09 (1H, m, H-2), 1.88, (3H, s, CH.sub.3), 1.85 (1H, br s, H-2), 1.57 (3H, s, CH.sub.3), 1.45 (3H, s, CH.sub.3), 0.89 (3H, s, CH.sub.3); .sup.13C NMR (125 MHz, CD.sub.3OD, /ppm): 211.0 (CO), 154.5 (C.sub.q-Py), 152.9 (C-4), 141.9 (C-6), 130.8 (C-5), 128.1 (C-7), 112.8 (C-9), 105.4 (C-10), 98.1 (C-8), 91.4 (C.sub.qIr), 86.2 (C.sub.qIr), 43.7 (C-3), 30.3 (C-2), 19.9 (C-1), 8.6 (CH.sub.3), the other carbon atoms are not observed; IR (v.sub.max, neat, cm.sup.1): 3589 (NH), 3111 (NH), 1629, 1603, 1501, 840, 557; HRMS (ESI+) m/z: Calculated for C.sub.24H.sub.27F.sub.2.sup.191IrN.sub.3O (MPF.sub.6.sup., 60%): 602.1728, found: 602.1722; calculated for C.sub.24H.sub.27F.sub.2.sup.193IrN.sub.3O (MPF.sub.6.sup., 100%): 604.1751, found: 604.1749.

Example 19: [Ir{.SUP.5.:.SUP.1.-C.SUB.5.(CH.SUB.3.).SUB.4.(CH.SUB.2.).SUB.3.NH.SUB.2.}{4-fluoro-N-phenyl-2-methylthiopicolinamide}][PF.SUB.6.].SUB.2

(154) ##STR00054##

(155) A suspension of Example 3 (50 mg, 0.11 mmol) and 4-fluoro-N-phenyl-2-methylthiopicolinamide (32 mg, 0.13 mmol) in ethanol (20 ml) was stirred and refluxed for 30 minutes. NH.sub.4PF.sub.6 (42.4 mg, 0.26 mmol) in ethanol (10 ml) was added and the mixture was refluxed overnight. After cooling to RT, the remaining solids were filtered, and the solvent removed from the filtrate under reduced pressure. Purification by precipitation from EtOH/hexane gave the title compound as a bright orange powder (78.6 mg, 0.10 mmol, 94%). Single crystals were achieved by recrystallisation from EtOH/hexane.

(156) .sup.1H NMR (500 MHz, CD.sub.3OD, /ppm): 8.14 (1H, dd, J=7.9, 1.1 Hz, H-7), 8.01 (1H, t, J=7.8 Hz, H-6), 7.74 (1H, dd, J=7.7, 1.5 Hz, H-5), 7.17 (4H, m, H-8-11), 2.99 (3H, s, CH.sub.3-4), 2.82 (1H, m, H-3), 2.38 (2H, m, H-3, H-1), 2.17 (1H, m, H-1), 2.10 (3H, s, CH.sub.3), 2.01 (1H, m, H-2), 1.84 (1H, m, H-2), 1.61 (3H, s, CH.sub.3), 1.43 (3H, s, CH.sub.3), 1.36 (3H, s, CH.sub.3); .sup.13C NMR (125 MHz, CD.sub.3OD, /ppm): 197.0 (CS), 163.6 (C.sub.qF), 140.8 (C-6), 129.1 (C-5), 124.7 (C-7), 123.3 (C-8, C-11), 116.6 (C-9, C-10), 91.1 (C.sub.qIr), 88.5 (C.sub.qIr), 88.0 (C.sub.qIr), 81.9 (C.sub.qIr), 44.7 (C-3), 30.5 (C-2), 29.9 (CH.sub.3-4), 20.0 (C-1), 10.7 (CH.sub.3), 9.4 (CH.sub.3), 9.1 (CH.sub.3), 8.3 (CH.sub.3), the other carbon atoms are not observed; IR (v.sub.max, neat, cm.sup.1): 3315 (NH), 3271 (NH), 3128, 3044, 1601, 1543, 1509, 1470, 1405, 1237, 1190, 1162, 1044, 837, 762, 556; HRMS (ESI+) m/z: Calculated for C.sub.25H.sub.30F.sup.193IrN.sub.3S (MH-2PF.sub.6.sup., 60%): 614.1750, found: 614.1737; calculated for C.sub.25H.sub.30F.sup.193IrN.sub.3S (MH-2PF.sub.6.sup., 100%): 616.1774, found: 616.1762.

Example 20: [Ir{.SUP.5.:.SUP.1.-C.SUB.5.(CH.SUB.3.).SUB.4.(CH.SUB.2.).SUB.3.NH.SUB.2.}{dppm}][BF.SUB.4.].SUB.2

(157) ##STR00055##

(158) A suspension of Example 3 (50 mg, 0.11 mmol), bis(diphenylphosphino)methane (42.3 mg, 0.11 mmol) and NaBF.sub.4 (24.2 mg, 0.22 mmol) in ethanol (10 ml) was stirred and heated to reflux overnight. After cooling to RT, the solvent was removed under reduced pressure and the residue treated with methanol and filtered. The solvent from the filtrate was removed again under reduced pressure. Purification by precipitation from MeOH/Et.sub.2O gave the title compound as a pale yellow powder (72.7 mg, 0.078 mmol, 71%). Single crystals were achieved by recrystallisation from MeOH/Et.sub.2O or MeCN/Et.sub.2O.

(159) .sup.1H NMR (500 MHz, CD.sub.3OD, /ppm): 7.74 (6H, m, Ph), 7.67 (6H, m, Ph), 7.58 (4H, m, Ph), 7.38 (4H, m, Ph), 5.49 (2H, s, H-4), 2.69 (2H, m, H-3), 2.33 (6H, t, J=4.0 Hz, 2CH.sub.3), 2.23 (2H, m, H-1), 1.95 (2H, m, H-2), 1.26 (6H, m, 2CH.sub.3); .sup.13C NMR (125 MHz, CD.sub.3OD, /ppm): 134.6 (Ph), 133.5 (Ph), 133.1 (Ph), 131.7 (Ph), 130.9 (Ph), 99.3 (C.sub.qIr), 54.9 (C-4), 42.4 (C-3), 26.0 (C-2), 19.9 (C-1), 10.7 (CH.sub.3), 9.1 (CH.sub.3), the other carbon atoms are not observed; .sup.31P NMR (121 MHz, CD.sub.3OD, /ppm): 46.3; IR (v.sub.max, neat, cm.sup.1): 3391 (NH), 1574, 1437, 1097, 1058, 721, 699, 650, 621, 541, 508; HRMS (ESI+) m/z: Calculated for C.sub.37H.sub.41.sup.191IrNP.sub.2 (MH-2BF.sub.4.sup., 60%): 752.2320, found: 752.2335; calculated for C.sub.37H.sub.41.sup.193IrNP.sub.2 (MH-2BF.sub.4.sup., 100%): 754.2343, found: 754.2341.

Example 21: [IrCl{.SUP.5.:.SUP.1.-C.SUB.5.(CH.SUB.3.).SUB.4.(CH.SUB.2.).SUB.3.NH.SUB.2.}{pyridine}][BF.SUB.4.]

(160) ##STR00056##

(161) A suspension of Example 3 (50 mg, 0.11 mmol) and NaBF.sub.4 (24.2 mg, 0.22 mmol) in ethanol (5 ml) was stirred, and pyridine (18 l, 0.22 mmol) added. The mixture was heated to reflux overnight. After cooling to RT, the mixture was filtered and the solvent removed under reduced pressure. Purification by precipitation from MeOH/Et.sub.2O gave the title compound as a pale yellow powder (43.6 mg, 0.076 mmol, 69%). Single crystals were achieved by recrystallisation from MeOH/Et.sub.2O.

(162) .sup.1H NMR (500 MHz, CD.sub.3OD, /ppm): 8.83 (2H, m, H-4), 8.04 (1H, tt, J=7.7, 1.6 Hz, H-6), 7.61 (2H, m, H-5), 2.86 (1H, m, H-3), 2.60 (1H, m, H-3), 2.34 (2H, m, H-1), 2.05 (2H, m, H-2), 1.76 (3H, s, CH.sub.3), 1.66 (3H, s, CH.sub.3), 1.62 (3H, s, CH.sub.3), 1.15 (3H, s, CH.sub.3); .sup.13C NMR (125 MHz, CD.sub.3OD, /ppm): 154.8 (C-4), 140.8 (C-6), 128.2 (C-5), 96.6 (C.sub.qIr), 93.8 (C.sub.qIr), 90.1 (C.sub.qIr), 83.1 (C.sub.qIr), 77.8 (C.sub.qIr), 43.6 (C-3), 30.3 (C-2), 19.8 (C-1), 9.1 (CH.sub.3), 8.8 (CH.sub.3), 8.7 (CH.sub.3), 8.2 (CH.sub.3); IR (v.sub.max, neat, cm.sup.1): 3276 (NH), 3221 (NH), 1579, 1449, 1058, 1020, 767, 697, 551, 527, 518; HRMS (ESI+) m/z: Calculated for C.sub.12H.sub.20Cl.sup.191IrN (MPy-BF.sub.4.sup., 60%): 404.0890, found: 404.0879; calculated for C.sub.12H.sub.20Cl.sup.193IrN (MPy-BF.sub.4.sup., 100%): 406.0914, found: 406.0897.

Example 22: Iridium CatalystEffect of N-Substituents

(163) ##STR00057##

(164) Metal complexes of Examples 3, 4, and 6 were submitted to the reaction shown above along with a comparative example, metal complex [Cp*IrCl.sub.2].sub.2. The yield for each of the metal complexes is measured over time and is shown in FIG. 1. The simple amino (Example 3) and methylamino (Example 4) metal complexes are almost equally active and much more active than [Cp*IrCl.sub.2].sub.2. The tertiary amine-derived catalyst Example 6 has a slightly reduced rate compared to [Cp*IrCl.sub.2].sub.2; however, the final conversion after 24 hours was comparable.

Example 23: Iridium Catalyst: Effect of Counterion

(165) ##STR00058##

(166) Metal complexes of Example 3 and Example 7 were submitted to the above reaction, along with [Cp*IrCl.sub.2].sub.2. The yield for each of the metal complexes is measured over time and is shown in FIG. 2. The dichloro complex is more active than the diiodo complex, presenting a higher reaction rate. However, both complexes provide a near identical final yield at 24 hours. Both Example 3 and Example 7 are significantly more active than the comparative complex [Cp*IrCl.sub.2]z

Example 24: Comparison of Neutral Rhodium and Iridium Complexes

(167) ##STR00059##

(168) A metal complex of Example 3 was submitted to the above reaction in two different solvents, toluene and t-amyl alcohol. The equivalent known rhodium catalyst, shown in the scheme above, was submitted to the same reactions. The yield over time of the two reactions is shown in FIG. 3a (toluene) and FIG. 3b (t-amyl alcohol). The iridium catalyst of Example 3 is reliably more active than the equivalent rhodium complex, though the degree of differential performance shows some solvent sensitivity.

Example 25: Iridium ComplexSolvent Tolerance

(169) ##STR00060##

(170) The metal complex of Example 3 and the comparative complex [Cp*IrCl.sub.2].sub.2 were tested in a number of solvents with the reaction shown above. The final yield after 24 hours for the two complexes in each solvent is shown in FIG. 4. In all solvents (except for TBME) the final yield was higher for the metal complex of the present invention.

(171) Similarly, the known rhodium metal complex of Example 13 was tested in a range of solvents in an identical reaction to that shown above but with different solvents. The yields are shown in FIG. 5. Comparing the yields for the rhodium catalyst to the iridium catalyst, the iridium complex of the present invention is significantly better than the equivalent rhodium complex.

(172) FIGS. 6a-d show the yields over time for metal complex of Example 3 in a selection of the solvent systems tested above. The complex of Example 3 shows better solvent tolerance than [Cp*IrCl.sub.2].sub.2, as measured both by absolute conversion at 24 h (FIG. 4) or individual kinetic analyses (FIG. 6a-d).

Example 26: Substrate Scope Using Iridium Catalysts

(173) FIG. 7 shows the substrate tolerance and the yields for a range of functional groups. The reaction conditions are as follows:

(174) ##STR00061##
The following letters represent deviations from this general procedure for certain compounds as indicated in FIG. 7: reaction performed at 130 C.; .sup.b 2 eq of amine were used; .sup.c 2 eq of alcohol were used; .sup.d 2 mol % of iridium was used. Wide substrate scope is achieved by the complex of Example 3; superior performance to [Cp*IrCl.sub.2].sub.2 is demonstrated explicitly in some cases.

Example 27: Comparison of Rhodium Neutral Versus Ionic Catalysts

(175) ##STR00062##

(176) The ionic rhodium complex of Example 2 and the rhodium complex first shown in Example 13 were submitted to the above reaction. A plot of the reaction rates is shown in FIG. 8. The ionic rhodium complex of Example 2 showed a higher reaction rate than the known neutral rhodium complex.

Example 28: Comparison of Iridium Neutral Versus Ionic Catalysts

(177) ##STR00063##

(178) In a similar manner to Example 27 above, a neutral iridium complex (Example 3) and an ionic iridium complex (Example 11) were submitted to the above reaction. The reaction rates are shown in FIG. 9. The ionic iridium complex (Example 11) is significantly more active than the neutral dichloride complex, which in turn is significantly more active than the comparative complex [Cp*IrCl.sub.2].sub.2, see FIGS. 1 and 2.

Example 29: Iridium ComplexSolvent Tolerance

(179) As in Example 14, the ionic complex of Example 11 was tested in a range of solvents. The final yield for reactions with the ionic complex after 24 hours are shown in FIG. 10 with a comparison to the results shown in FIG. 4 and Example 14. The ionic complex shows solvent compatibility at least as broad as the dichloride complex, and is usually more active.

Example 30: Temperature Performance of Iridium Catalyst

(180) ##STR00064##

(181) Iridium catalyst of Example 3, ionic complex of Example 11, and a comparative complex, [Cp*IrCl.sub.2].sub.2, were subjected to the above reaction over a range of different temperatures. The resulting reaction rates are shown in FIGS. 11a (Example 3), 11b (Example 11) and 11c (comparative complex). The complex of Example 3 appears to be less sensitive to reaction at lower temperatures than the comparative complex, [Cp*IrCl.sub.2].sub.2. The ionic complex (Example 11) shows good activity down to 80 C. with better activity at 80 C. than the comparative complex at 110 C.

Example 31 Iridium ComplexPerformance at Low Catalyst Loading

(182) ##STR00065##

(183) Under the reaction conditions shown above, the metal complexes of Examples 3 and 11 provided excellent (near complete) conversion at 24 h down to a loading of 0.1 mol % Ir and 0.075 mol % Ir, respectively. FIGS. 12 and 13 show the results. In contrast, the comparative complex, [Cp*IrCl.sub.2].sub.2 is unable to achieve 100% conversion at 2 mol %, see FIGS. 1 and 2.

Example 32 Effect of n (Linker Length in Tether) on Catalytic Activity

(184) ##STR00066##

(185) The effect of chain length on catalytic activity of rhodium catalysts was investigated. Three catalysts with tethered ligands where the tether were different lengths (n=2, 3 and 4) were tested against a comparative rhodium dimer, [Cp*RhCl.sub.2].sub.2. Complexes with a tether carbon chain length of 2, 3 and 4 carbon atoms were tested. The catalytic activity of the complex with three carbon atoms (n=3 (o=1 in FIG. 14)) in the tether chain was significantly better than the catalytic activity of other tested tethered ligands and the comparative dimer. The data is shown in FIG. 14

(186) Throughout the description and claims of this specification, the words comprise and contain and variations of them mean including but not limited to, and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

(187) Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

(188) The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.