Ferrocenyl phosphite ligands for asymmetric catalysis and a method for their production

BACKGROUND OF THE INVENTION 1. FIELD OF THE INVENTION

Phosphoramidites [(RO) ₂ PNR ₂ I are recent additions to the set of so-called "privileged" ligands leading to superlative asymmetric catalysis when coordinated to a range of metal centres for a variety of processes. The very high levels of enantioselectivity that are often realised with these ostensibly monodentate ligands are not expected if free rotation about the P-M _ca t bond in the active catalyst [L _n M _car P(OR) ₂ (NR ₂ )] is present. We have found a novel class of catalysts which can attain a (P ₁ C=C) chelate coordination mode in certain reactions including: nickel-catalysed alkene dimerisation, ruthenium-catalysed cyclopropanation and nickel-promoted additions of AIMe ₃ to aldehydes, which we call "ferrophites". Throughout this patent (R) planar, axial and centrosymmetric stereochemical chemistry are distinguished by the descriptors (R _p ), (R _a ) and (R _c ), respectively, for clarity. An initial aspect of the present invention relates to new states of matter: the chiral 1 ,2-substituted ferrocenyl phosphite ligands 1 that are useful for coordination to transition metals or their derived compounds. A second aspect relates to a new method for the preparation of the species 1. The resulting metal-ligand complexes or mixtures are of widespread utility in asymmetric catalysis for the production of fine chemicals, pharmaceutical intermediates and other chiral organic products.

Both cyclic or acyclic R ¹ structures can be used. = H, alkyl, aryl or substituted versions thereof or alkenyl or substituted versions thereof

2. DESCRIPTION OF THE PRIOR ART

Kagan disclosed the preparation of the 1 ,2-disubstituted ferrocenyl species (I) which are chiral due to the presence of appropriate substituents on the upper cyclopentadienyl ring [O. Riant, G. Argouarch, D. Guillaneux, O. Samuel, H. Kagan, J. Org. Chem. 1998, 63, 3511-3514; L ¹ = PPh ₂ , R ² = CO ₂ Me, PCy ₂ (Cy = cyclo-C _β Hu)]- The phosphorus substituent is typically introduced by the reaction of (I) (L ¹ = M ₁ typically Li) followed by trapping with XPR ₂ (X = a halogen, R = alkyl, aryl). Similar phosphine species have been prepared by Johannsen (I L ¹ = PPh ₂ , PCy ₂ ; L ² = Aryl) [J. F. Jensen, I. Søtofe, H. Sørensen, M. Johannsen, J. Org. Chem. 2003, 68, 1258-1265; J. F. Jensen, M. Johannsen, Org. Lett. 2003, 5, 3025-3028]. Importantly however, no 1,2-disubstituted ferrocenyl phosphite species have been prepared by this approach as attempted preparations of (I) with L ¹ = P(QR ¹ I ₂ , (R = alkyl aryl) using XP(OR^ (X = a halogen, R = alkyl, arvO all fail to give synthetically useful yields. Ferrocenyl species containing asymmetric phosphite units are presently limited to species of types (II) introduced

erørøKMAlϊϋN COPY

by Reetz [M. T. Reetz, A. Gosberg, R. Goddard, S.-H. Kyung, Suk-Hun, Chem. Commun. 1998, 2077- 2078.] and others (111) by separate workers [G. R. Knox, P. L. Pauson, D. Willison, Organometallics 1992, 11, 2930-2933; Compounds (H) and (III) are prepared indirectly through introduction of a P(NR ₂ ) ₂ , substituent, its subsequent chlorination to a PCI ₂ group and reaction with binol or other alcohols. Ferrocenyl ligands based on (I) where L ¹ = PR ₂ and L ² = a chiral substituent such as CHMeX (X = PR ₂ , NR ₂ , etc.) form the basis of the Josiphos family of ligands [H.-U. Blaser, W. Brieden, B. Pugin, F. Spindler, M. Studer, A. Togni, Solvias Josiphos ligands: from discovery to technical applications. Topics in Catalysis 2002, 19, 3-16] but these are different from the structures claimed herein. No prior publication disclosed the constitution of (I) such that L ¹ = P(OR) ₂ and L ² = Ar together with a strategy for their rapid synthesis in good yield. Two companies have independently claimed 1 ,2- substituted diphosphines of structural type (IV) but in these cases no phosphite structures were described by either Degussa AG [P. Knochel, P. J. J. Almena, K. Drauz, I. Klement, Eur. Pat. Appl. 1999, 10 pp. EP 965574 (Chem. Abs. 132, 35472], or the Kawaken Fine Chemical Co Ltd [T. Ito, T. Aoki, PCT Int. Appl. 2004, 29 pp, WO2004078686-A1 (Chem Abs. 141, 260264)].

thereof

L ¹ = PAr ₂ , PAlkyl ₂

L ² = Alkyl, Ar, or substituted version thereof

IV

SUMMARY OF THE INVENTION

This invention discloses new states of matter (1) that are prepared by the union of the widely available fragments (2) and (3) whereby: R ¹ is derived from two suitable monoalcohols or one diol; R ² -R ⁹ are H, C ₁ -C ₂₀ alkyl, alkenyl, or aryl substituents or heteroatom substituents thereof; Z is a C ₂ -C ₂₀ unit or heteroatom substituted derivative thereof such that the initially attached carbon is sp ² hybridised (representative examples of Z include vinyl or aryl groups or heteroatom substituted variants thereof); M is a Group 1-2 or 12-13 metal; R ¹⁰ -R ¹¹ is a C ₁ -C ₂₀ alkyl, alkenyl, or aryl substituent or heteroatom substituted version thereof. The drawing (1) is not intended to represent or limit the invention to any specific stereoisomer. All potential stereoisomers arising from planar, axial or centrosymmetric stereoelements are claimed herein. The species (1) are useful additives in transition metal-promoted transformations of organic molecules such as hydrogenations, additions of organometallic neucleophiles to carbonyl compounds and Michael acceptors.

< λ^ Both cyclic or acyclic R ¹ structures can be used.

According to the present invention, there is provided a compound of Formula 1, wherein each R ¹ is independently selected from the group comprising: C _1-20 alky!, Ci _-20 haloalkyl, C _2-20 alkenyl, and C _2-20 alkynyl, wherein each of these groups may be optionally substituted by 1 to 3 substituents independently selected from the group comprising: C _1-7 alkyl, C _1-7 haloa!kyl, C _1-7 alkoxy, halogen, -CN, and -CF ₃ ;

or the two R ¹ groups may together with the oxygen atoms to which they are attached and the phosphorus atom form a monocyclic ring of up to 9 members, or a fused or conjugated polycyclic ring system containing up to to 24 atoms in the ring system, the or each ring being optionally substituted with from 1 to 3 substituents independently selected from the group comprising: Ci. ₇ alkyl, C _t . yhaloalkyl, C-ι _-7 alkoxy, halogen, -CN, and -CF ₃ ;

each of R ² to R ⁹ is independently selected from the group comprising: H, C _1-20 alkyl, C _1-20 haloalkyl, C _2-20 alkenyl, C _2-20 alkynyl, CH ₂ OC _1-20 alkyl, CH ₂ SC _1-20 alkyl, aryl and het, wherein each of these groups may be optionally substituted by 1 to 3 substituents independently selected from the group comprising: C _1-7 alkyl, Ci _-7 haloalkyl, C _1-7 alkoxy, halogen, -CN, and -CF ₃ ;

and / or independently any adjacent two of the R ² to R ⁹ groups joined to the same carbon, may together with the carbons to which they are attached form a ring of up to 6 members, the ring being optionally substituted with from 1 to 3 substituents independently selected from the group comprising: Ci _-7 alkyl, C _1-7 haloalkyl, C-ι _-7 alkoxy, halogen, -CN, and -CF ₃ ;

het is an aromatic or aliphatic heterocyclic group containing from 5 to 10 ring members and containing 1, 2 or 3 independently chosen N, O or S atoms; and

Z is a group including an sp2 hybridised atom through which Z is bound to the ferrocene ring.

Preferably, each R ¹ is independently selected from the group comprising: C _1- - _I0 alkyl, CM ₀ haloalkyl, C _2-I0 alkenyl, and C _2- i ₀ alkynyl, wherein each of these groups may be optionally substituted by 1 to 3 substituents independently selected from the group comprising: C _1-7 alkyl, C _1-7 haloalkyl, C _1-7 alkoxy, halogen, -CN, and -CF ₃ ;

or the two R ¹ groups may together with the oxygen atoms to which they are attached and the phosphorus atom form a ring of up to 9 members, the ring being optionally substituted with from 1 to 3

substituents independently selected from the group comprising: C _1-7 alkyl, C _1-7 haloalkyl, C _1-7 alkoxy, halogen, -CN, and -CF ₃ ;

More preferably, each R ¹ is independently selected from the group comprising: Ci _-6 alkyl, Ci _-60 haloalkyl, and C _2-6 alkenyl, wherein each of these groups may be optionally substituted by 1 to 3 substituents independently selected from the group comprising: C _1-7 alkyl, C _1-7 haloalkyl, C _1-7 alkoxy, halogen, -CN, and -CF ₃ .

Another preferred embodiment is that in which the two R ¹ groups may together with the oxygen atoms to which they are attached and the phosphorus atom form a ring of up to 9 members, or a fused or conjugated polycyclic ring system containing up to 24 atoms in the ring system, the or each ring being optionally substituted with from 1 to 3 substituents independently selected from the group comprising: Ci _-7 alkyl, Ci _-7 haloalkyl, Ci _-7 alkoxy, halogen, -CN, and -CF ₃ .

In an embodiment, the fused or polycyclic ring may contain 1 to 4 atoms independently selected from N, O, or S.

A fused or polycyclic ring preferably has up to 20 members.

It is further preferred that the two R ¹ groups may together with the oxygen atoms to which they are attached and the phosphorus atom form a ring of 5, 6 or 7members, the ring being optionally substituted with from 1 to 3 substituents independently selected from the group comprising: C _1-7 alkyl, C _1-7 haloalkyl, C _1-7 alkoxy, halogen, -CN ₁ and -CF ₃ .

Preferably het is selected from the group comprising: C-linked pyrrolyl, imidazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, quinazolinyl, phthalazinyl, benzoxazolyl and quinoxalinyl.

Preferably, Z is selected from the group comprising: het, C _2-20 alkenyl, and aryl.

As used herein, the term "aryl", alone or in combination, means an unsaturated aromatic carbocyclic group having 6-14 carbon atoms having a single ring, for example, but not limited to, phenyl or multiple fused rings such as naphthyl. Aryl may optionally be further fused to an aliphatic or aryl group or can be substituted with one or more substituents such as, for example, but not limited to, halogen, hydroxy, CrC ₇ alkyl, CrC ₇ alkoxy or aryloxy, CrC ₇ alkylthio or arylthio, alkylsulfonyl, cyano or primary or nonprimary amino.

Examples of aryl include: phenyl, naphthyl and indenyl.

In an embodiment, each of R ² to R ⁹ is independently selected from the group comprising: H, Ci _-7 alkyl, C _1-7 haloalkyl, C _2-7O alkenyl, C _2-7 alkynyl, CH ₂ OC _1-7 alkyl, CH ₂ SCi _-7 alkyl, aryl and het, wherein each of these groups may be optionally substituted by 1 to 3 substituents independently selected from the group comprising: C _1-7 alkyl, Ci _-7 haloalkyl, C _1-7 alkoxy, halogen, -CN, and -CF ₃ ;

and / or independently any adjacent two of the R ² to R ⁹ groups joined to the same carbon, may together with the carbons to which they are attached form a ring of up to 6 members, the ring being optionally substituted with from 1 to 3 substituents independently selected from the group comprising: Ci _-7 alkyl, Ci _-7 haloalkyi, Ci _-7 alkoxy, halogen, -CN, and -CF ₃ .

In a further embodiment, each of R ² to R ⁹ is independently selected from the group comprising: H, Ci _-7 alkyl, Ci _-7 haloalkyl, and C _2-70 alkenyl, wherein each of these groups may be optionally substituted by 1 to 3 substituents independently selected from the group comprising: Ci _-7 alkyl, Ci _-7 haloalkyl, Ci- ₇ alkoxy, halogen, -CN, and -CF ₃ .

In an alternative embodiment, each of R ² to R ⁹ is independently selected from the group comprising: C _2-7 alkynyl, CH ₂ OC _1-7 alkyl, CH ₂ SCi _-7 alkyl, aryl and het, wherein each of these groups may be optionally substituted by 1 to 3 substituents independently selected from the group comprising: C _{1- 7} alkyl, C _1-7 haloalkyl, Ci _-7 alkoxy, halogen, -CN, and -CF ₃ .

In another embodiment, any adjacent two of the R ² to R ⁹ groups joined to the same carbon, may together with the carbons to which they are attached form a ring of up to 6 members, the ring being optionally substituted with from 1 to 3 substituents independently selected from the group comprising: C _1-7 alkyl, Ci _-7 haloalkyl, C _1-7 alkoxy, halogen, -CN, and -CF ₃ .

DETAILED DESCRIPTION OF THE INVENTION

Our synthetic route began with (S _c )-1 prepared from ferrocene by Kagan's method by use of the known Andersen sulfoxide (Scheme 1). All of the ligands in this patent could be prepared in either enantiomeric series, but are shown throughout as originating from natural L-mentho! for consistency. Stereoselective lithiation and trapping with B(OMe) ₃ allows access to (R _p S _c )-2 using literature procedures. Optimal coupling of (R _p S _c )-2 with suitable ArX (X = I, Br) occurred with 8 mol-% Pd(dppf)CI ₂ and sodium hydroxide promotion at reflux within 4 hours to give good yields for both sterically encumbered and electron-deficient aryl halides (R _p S _c )-3a-c (Scheme 1). The sulfoxide auxiliary of (R _p S _c )-3a was cleaved under Kagan's conditions to afford the derived oranolithium species (S _p )-4a (Scheme 2). The change in stereochemical descriptor is caused only by the peculiarities of the CIP nomenclature (C has greater priority than Li).

Addition of P(OPh) ₃ to organolithium species (Sp)-4a resulted in an almost immediate (<2 min at -78 ⁰ C) colour change in the reaction mixture from deep orange-red to pale orange-yellow. On workup

the desired product (R _p )-7a was isolated as an orange oil (69%). Compounds (R _p )-7b,c were similarly prepared in 33 and 56% yield, respectively (Scheme 2).

We performed the equivalent reaction of the anions 4a-c, both with 1,1-bi-naphthol- and 1 ,1-biphenol- derived phosphates. The precursor phosphates were easily prepared by the reaction of PCI ₃ with the appropriate diol in the presence of Net ₃ , to yield the chlorophosphites 6b-c (Scheme 3). Subsequent addition of phenol and further Net3 allowed the isolation of 5b-c in moderate yield (53-74% based on the diol) after column chromatography on silica.

Reaction of 5b-c with the organolithiums 4a-c proceeded in a modular fashion to complete a small library of ferrophite ligands (Scheme 2).

Scheme 1

Scheme 2

Scheme 3

The novel ligands (1) are prepared by phosphorus-carbon coupling of fragments (2) and (3) examples of some of which are known.

Fragment (2): The precursor fragment (2) is available through literature procedures. Thus, Lithiation of ferrocene [D. Guillaneux, H. B. Kagan, J. Org. Chem. 1995, 60, 2502-2505]] followed by trapping with menthyl-p-tolunenesulfinate to afford (4) is available in the open literature (R ² -R ⁹ = H, R ¹¹ = 4-tolyl). Either stereoisomer of the sulfinate can be prepared by use of the (R) or (S) menthol-derived auxiliary [J. M. Klunder, K. B. Sharpless, J. Org. Chem. 1987, 52, 2598-2602]. Highly stereospecific deprotonation of (4) with LiNZPr ₂ generates the organolithium species (5, M = Li) which can be transmetallated to a range of species including M = ZnCI, ZnCI, B(OH) ₂ , B(OR) ₂ etc. Under palladium catalysis (5) can be coupled with sp ² hybridised electrophiles such as 6, 7 where R ¹² -R ¹⁹ are H, alkyl alkenyl, aryl, halogen, OR, NR ₂ , CO ₂ R, COR, CONH ₂ , SO ₃ R derivatives and X is a halogen, triflate (OSO ₂ CF ₃ ) or nonaflate (OSO ₂ C ₄ F ₉ )] to afford (8). Examples of (8) are documented in the open literature [J. F. Jensen, I. Søtofe, H. Sørensen, M. Johannsen, J. Org. Chem. 2003, 68, 1258-1265; J. F. Jensen, M. Johannsen, Org. Lett. 2003, 5, 3025-3028; H. K. Cotton, F. F. Huerta, Fernando J.-E. Backvall, Eur. J. Org. Chem. 2003, 2756-2763] and these include the fragments (8a-b) which constitute preferred embodiments for the synthesis of the unreported compounds (1). Reaction of (8) with te/f-BuLi is known [G. Argouarch, O. Samuel, O. Riant, J. -C. Daran, H. B. Kagan, Eur. J. Org. Chem. 2000, 2893-2899.] to result in cleavage of the sulfoxide leading to direct formation of (2, M = Li)

Fragment (3): Fragment (3) is available through routine application of known prior art. Direct reaction of PCI ₃ with suitable mono (R ¹ OH) or diols (of general formula 9a-9b, where R ²⁰ -R ²⁷ = H, halogen, C ₁ - C ₂₀ alkyl, alkenyl, halogen, OR, NR ₂ , CO ₂ R, COR, CONR ₂ , SO ₃ R or aryl substituent or heteroatom substituented version thereof) affords CIP(0R ¹ ) ₂ as exemplified by (10a-b). Subsequent reaction of these monochloro phosphorus species with R ² OH (halogen, C ₁ -C ₂₀ alkyl, alkenyl, halogen, OR, NR ₂ , CO ₂ R, COR, CONR ₂ , SO ₃ R or aryl substituent or heteroatom substituented version thereof) affords the mixed species (3). Preferred forms of the present invention, for reaction with fragment (2) include: P(OPh) ₃ (3a) and the biphenyl (3b)and binaphthyi (3c) derived ligands. Either potential stereoisomer is implied by the representation of the binaphthyi. Compound (3c) is known [P. H. Dussault, K. R. Woller, J. Org. Chem. 1997, 62, 1556-1559]. A process route to compounds (3b-c) has been claimed [U. Scholz, E. Vogl, A. Gerlach, J. Hassfeld, B. Meseguer, Benjamin. Eur. Pat. Appl. 2004, 24 pp. CODEN: EPXXDW EP 1394168 A1 20040303 Chem Abs. 140, 217810] but this involves use of R ¹ PCI ₂ not 10a.

9b

A new class of chiral ferrocenyi-based phosphate (ferrophite) ligands has been prepared that mimic the π contacts thought to be realised in Feringa's phosphoramidite ligand 14.

EXAMPLES

General. The precursor fragments (2, M = Li and 3) were prepared by the literature approaches given above. New states of mater 1 were prepared by the union of these as outlined below. For compounds 1, the first letter represents the sp ² (ary! or alkenyl) group attached to the cyclopentadienyl ring: a = Ph, b = 1-naphthyl, c = 2-naphthyl, d = 4-(CF ₃ )Ph. The second letter the substituents at phosphorus: a = (OPh) ₂ , b = 1 ,1'-biphenol derived, c = 1,1'-binaphthyl derived. Thus, compound Ida has one attached 4-trifluoromethylphenyl group and one P(OPh) ₂ group in a 1,2 relationship on one cyclopentadienyl ring. These representative preparations the planar chirality stereodiscriptor is indicated first followed by either the centrosymmetric or axial chirality. However it will be understood here within that all potential stereiosomers can be accessed by routes described herein.

Representative preparation of aryl sulfoxides - compound 8b

To a mixture of sulfoxide (R ₁ S)-S (R ² -R ⁹ = H; R ¹¹ = 4-ToIyI ₁ M = B(OH) ₂ ) (1.95 g, 5.23 mmol), PdCI ₂ (dppf)-CH ₂ CI ₂ (340 mg, 0.41 mmol), 1-iodonaphthalene (1.14 ml, 7.80 mmol) and toluene (60 ml) under argon was added sodium hydroxide (2 N, 5.10 ml). The solution was heated at reflux for 4 hours then allowed to cool and concentrated under reduced pressure. The crude oil was purified by column chromatography on silica gel (8:1:1 petrokethyl acetate:dichloromethane) to give (R,S)-8b (1.90 g, 81 %) as an orange crystalline solid. Similarly prepared were: (R,S)-8a (1.57 g, 75 %), [R ₁ S)Sc (443 mg, 64 %), (R,S)-8d (608 mg, 84 %). Compounds 8a-b had properties concordant with literature values [[J. F. Jensen, I. Søtofe, H. Sørensen, M. Johannsen, J. Org. Chem. 2003, 68, 1258-1265; J. F. Jensen, M. Johannsen, Org. Lett. 2003, 5, 3025-3028; H. K. Cotton, F. F. Huerta, Fernando J.-E. Backvall, Eur. J. Org. Chem. 2003, 2756-2763].

Compound (R,S)-8c is previously unreported: ¹ H NMR (500.1 MHz, CDCI ₃ ) δ _H 8.29 (br s, 1 H ₁ Ar), 8.03 (d, J = 8.5 Hz, 1 H, PhMe), 7.95-7.86 (m, 3 H, Ar and PhMe), 7.79 (br s, 2 H, Ar), 7.54-7.52 (m, 2 H, Ar), 7.37 (br s, 2 H, Ar), 4.90 (d, J = 1.7 Hz, 1 H, C ₅ H ₃ ), 4.54 (br s, 1 H, C _s Hs) 4.24 (m, 1 H, C ₅ H ₃ ) overlapped by 4.24 (s, 5 H, C ₅ H ₅ ), 2.47 (s, 3 H, PhMe); Anal, calcd. for C ₂₇ H ₂₂ FeOS: C, 71.99%; H 4.93%; found: C, 71.96%; H ₁ 4.92%. MS (ES) m/z 451 (M+H \ 10%), 312 (M+H-S(O)tol ⁺ , 20%); HRMS m/z (ES) found [M+H] ⁺ 451.0850; C ₂₇ H ₂₃ FeOS requires 451.0819.

Compound (R,S)-8d is previously unreported: ¹ H NMR (400.1 MHz, CDCI ₃ ) δ _H 7.89 (d, J = 8.0 Hz, 2 H, C ₆ H ₄ ), 7.61 (d, J = 8.0 Hz ₁ 2 H, C ₆ H ₄ ), 7.56 (d, J = 8.0 Hz, 2 H ₁ C ₆ H ₄ ), 7.27 (d, J = 8.0 Hz, 2 H, C ₆ H ₄ ), 4.74 (app. dd, J = 2.6, 1.5 Hz, 1 H, C ₅ H ₃ ), 4.49 (app. t, J = 2.6 Hz, 1 H, C ₅ H ₃ ), 4.27 (app. dd, J = 2.6, 1.5 Hz, 1 H ₁ C ₅ H ₃ ), 4.22 (s, 5 H ₁ C ₅ H ₅ ), 2.42 (s, 3 H, PhMe); ¹⁹ F NMR (282 MHz, CDCI ₃ ) δ _F -63.0; MS (ES) m/z 469 (M+H ⁺ , 10%), 330 (M+H-S(O)tol ⁺ , 70%);HRMS (ES) m/z found [M+H] ⁺ 469.0516; C ₂₄ H ₂₀ FeF ₃ OS requires 469.0536.

Representative preparation of phosphites - compound 3c

Under an atmosphere of argon a mixture of (S)-BINOL (2.00 g, 6.98 mmol) and THF (40 ml) was cooled to -40 ⁰ C. To this solution was added a solution of phosphorus trichloride (0.98 ml, 11.2 mmol) in THF (10 ml). After 10 mins triethylamine (1.95 ml, 14.0 mmol) was added and the reaction mixture allowed to warm to room temperature. After a further 4 hours the mixture was filtered through a frit and concentrated under reduced pressure. The mixture was then diluted with THF (50 ml) followed by addition of triethylamine (1 ml, 7.16 mmol) and phenol (470 mg, 5.00 mmol). After 1 hour the mixture was evaporated to dryness. The product was purified by column chromatography on silica gel (9:1 petrolrether, dry loaded) to give (S)-3c (1.44 g, 50% based on BINOL) as a white solid. Compound 3b was similarly prepared (1.20 g, 56% based on 1 ,1'-biphenol). ³¹ P NMR (162 MHz, CDCI ₃ ) δ _P +146.1. For 3b: ³¹ P NMR (162 MHz, CDCI ₃ ) δ _P +144.9.

Representative preparation of the novel ligands 1 - (S ₁ R)- 1-(phenyl)-2-(3,5-Dioxa-4-phospha- cycloheptal2 _l 1-a;3,4-a']dinaphthalen-4-yl)ferrocene lCpFe(η ⁵ -1,2-C ₅ H ₃ (Ph)(P(OzC ₂ oHi ₂ )))]1ac

Under at atmosphere of argon a solution of sulfoxide 8a (280 mg, 0.70 mmol) in THF (20 ml) was cooled to -78 ⁰ C. To the solution was added ¹ BuLi (1.7 M, 0.5 ml, 0.85 mmol). After 5 minutes a solution of phosphite 3c (300 mg, 0.74 mmol) in THF (3.5 ml) was added. The solution turned from dark orange in colour to yellow over 2 minutes and the reaction was stirred for 5 minutes before the addition of water (1 ml) The mixture was stirred for a further 45 minutes before the phases were separated. The aqueous layer was extracted with Et ₂ O (5 ml) then the combined organic phases were washed with water (10 ml), dried (MgSO ₄ ) and evaporated to dryness. The crude reaction mixture was purified by column chromatography on silica gel (9:1 petrol:ether dry loaded) to give the product as an orange crystalline solid.

Yield 285 mg, 71%. ¹ H NMR (500.1 MHz ₁ [D ₆ ]benzene): δ _H 8.03 (d, J = 8.0 Hz, 2 H, Ar), 7.82 (t, J = 8.7 Hz, 2 H, Ar), 7.75 (t, J = 8.7 Hz, 2 H, Ar), 7.65 (t, J = 7.5 Hz, 2 H, Ar), 7.62 (d, J = 8.7 Hz, 1 H ₁ Ar), 7.34 (t, J = 5.8 Hz, 2 H, Ar), 7.31-7.22 (m, 3 H, Ar), 7.20 (d, J = 8.7 Hz, 1 H, Ar), 7.13-7.07 (m, 2 H, Ar), 4.60 (dd, J = 3.9, 2.0 Hz ₁ 1 H ₁ C ₅ H ₃ ), 4.18 (s, 5 H, C ₅ H ₅ ), 4.00-3.98 (m, 2 H, C ₅ H ₃ ); ³¹ P NMR (162 MHz, CDCI ₃ ) δ _P +189.3; HRMS (El) m/z found [M+Hf 577.0975; C ₃₆ H ₂₆ FeO ₂ P requires 577.1020. Anal, calcd. for C ₃₆ H ₂₅ FeO ₂ P: C ₁ 75.01%; H 4.37%; found: C, 75.19%; H ₁ 4.32%. [α] _D -386.0 (c = 1.00, chloroform). X-ray crystal structure obtained (see Figure 1).

Additional representative examples:

Ligand (S)-1~(phenyl)-2-(diphenylphosphonityl)ferrocene [CpFe(η ⁵ -1, 2-C ₅ H ₃ (Ph)(P(OPh) ₂ )] 1aa

Yield 66 g, 69%. ¹ H NMR (400.1 MHz, CDCI ₃ ) δ _H 7.96 (dd, J = 7.2, 1.2 Hz, 2 H, Ph-O) ₁ 7.45 (dd, J = 7.6, 1.2 Hz, Ph-o), 7.32-6.85 (m, 11 H, Ph-m+p), 4.88 (m, 1 H, C ₅ H ₃ ), 4.60 (m, 1 H, C ₅ H ₃ ), (app. t, J = 2.4 Hz), 4.12 (s, 5 H, C ₅ H ₅ ); ³¹ P NMR (162 MHz, CDCI ₃ ) δ _P +174.3; MS (El) m/z 479 (M+H ⁺ , 70%), 385 (M -OPh ⁺ , 30%), 262 (M+H-P(OPh) ₂ ⁺ , 100%); HRMS (El) m/z found [M+H] ⁺ 479.0872; C ₂₈ H ₂₄ FeO ₂ P requires 479.0863.

Ligand (S)-1-(4-trifIuoromethylphenyl)-2~(diphenylphosphonityl)ferr ocene [CpFe(η ⁵ - 1, 2-C ₃ H ₃ (4- CF ₃ Ph)(P(OPh) ₂ )] Ida

Yield 71 g, 56%. ¹ H NMR (400.1 MHz, [D ₆ ]benzene) δ _H 7.67 (d, J = 8.0 Hz, 2 H, Ph-o), 7.35-7.29 (m, 4 H, Ar), 7.12-7.08 (m, 2 H, Ar), 6.98-6.91 (m, 4 H, Ar), 6.90-6.86 (m, 1 H ₁ Ph-p), 6.80-6.77 (m, 1 H, Ph- p), 4.75 (m, 1 H, C ₅ H ₃ ), 4.38 (m, 1 H, C ₅ H ₃ ), 4.15 (app. t, J = 2.5 Hz, 1 H, C ₅ H ₃ ), 3.95 (s, 5 H, C ₅ H ₅ ); ³¹ P NMR (162 MHz, [D ₆ ]benzene) δ _P +173.4; ¹⁹ F NMR (282 MHz, CDCI ₃ ) δ _F -62.3; MS (ES) m/z 547 (M+H ⁺ , 35%), 453 (M -OPh ⁺ , 50%), 330 (M+H-P(OPh) ₂ ⁺ , 10%); HRMS (ES) m/z found [M+Hj ⁺ 547.0716; C ₂₉ H ₂₃ FeF ₃ O ₂ P requires 547.0737.

Ligand (S, R)-1-(4-trifiuoromethylphenyl)-2-(3, 5-Dioxa-4-phospha-cyclohepta[2, 1-a;3, 4-a 'Jdinaphthalen- 4-yl)ferrocene [CpFe(η ⁵ -1,2-C ₅ H ₃ (4-CF ₃ Ph)(P(O ₂ C ₂₀ H ₁₂ ))] 1dc

Yield 285 mg, 44%. ¹ H NMR (500.1 MHz, [D ₆ ]benzene): δ _H 7.86-7.83 (m, 3 H, Ar) ₁ 7.80 (d, J = 8.2 Hz, 1 H, Ar), 7.77-7.75 (m, 2 H, Ar), 7.66-7.62 (m, 3 H, Ar), 7.47 (d, J = 8.2 Hz, 2 H, Ar), 7.31-7.27 (m, 2 H, Ar), 7.16 (d, J = 8.7 Hz, 1 H, Ar), 7.07-7.11 (m, 2 H, Ar), 4.74 (dd, J = 3.7, 2.0 Hz, 1 H, C ₅ H ₃ ), 4.13 (s, 5 H, C ₅ H ₅ ), 4.00-3.98 (m, 2 H, C ₅ H ₃ ); ³¹ P NMR (162 MHz ₁ CDCI ₃ ) δ _P +187.6; ¹⁹ F NMR (282 MHz, CDCI ₃ ); [α] _D -285.8 (c = 1.00, chloroform). X-ray crystal structure obtained (see Figure 2).

Ligand (S,R)-1-(44rifluoromethylphenyl)-2-(3,5-Dioxa-4φhospha-cycl ohepta[2,1-a;3,4-a']biphenalen-4- yOferrocene [CpFe(η ³ -1,2-C ₅ H ₃ (4-CF ₃ Ph)(P(O ₂ C ₁₂ H ₈ ))] 1db

Yield 73 mg, 14%. ¹ H NMR (400.1 MHz, [D ₆ ]benzene) δ _H 7.69 (d, J = 8.0 Hz, 2 H ₁ C ₆ H ₄ CF ₃ ), 7.32 (d, J = 8.0 Hz, 2 H ₁ C ₆ H ₄ CF ₃ ), 7.27 (dd, J = 7.4, 1.9 Hz, 1 H, biphenyl-H3 or 3'), 7.26 (dd, J = 7.5, 1.7 Hz, 1 H, biphenyl-H3 or 3'), 7.19 (dt, J = 8.0, -0.8 Hz, 1 H, biphenyl-H6 or 6'), 7.11 (td, J = 7.5, 1.6 Hz, 1 H, biphenyl-H4,4' or 5,5'), 7.01 (tdd, J = 7.5, 1.6, -0.8 Hz, 1 H ₁ biphenyl-H4,4' or 5,5"), 6.95 (td, J = 7.5, -0.8 Hz, 1 H, biphenyl-H4,4" or 5,5'), 6.92 (td, J = 7.5, 1.6 Hz, 1 H, biphenyl-H4,4' or 5,5'), 6.77 (dd, J = 7.5, -0.8 Hz, 1 H, bipheπyl-H6 or 6'), 4.39 (m, 1 H, C ₅ H ₃ ), 4.23 (m, 1 H, C ₅ H ₃ ), 4.03 (app. t J = 2.4 Hz, 1 H, C ₅ H ₃ ) overlapped by 4.02 (s, 5 H, C ₅ H ₅ ); ³¹ P NMR (162 MHz, [D ₆ ]benzene) δ _P +203.7; ¹⁹ F NMR (282 MHz, CDCI ₃ ) δ _F -62.3; MS (ES) m/z 545 (M+H ⁺ , 100%), 330 (M+H-P(Obiphen) ⁺ , 90%); HRMS (ES) m/z found [M+Hf 545.0557; C ₂₉ H ₂₁ FeF ₃ O ₂ P requires 545.0581. [α] _D -85.4 (c = 1.08, chloroform).

Ligand (S)-1-(1'naphthyl)-2-(diphenylphosphinityl)ferrocene [CpFe(η ⁵ -1,2'CsH ₃ (1-CioH ₈ )(P(OPh) ₂ )] 1ba

Yield 40 mg, 33%. ¹ H NMR (500.1 MHz, [D ₆ ]benzene) δ _H 8.46 (dt, J = 7.0, 1.0 Hz, 1 H, C ₁₀ H ₇ ), 8.20 (d, J = 8.0 Hz, 1 H, C ₁₀ H ₇ ), 7.77-7.73 (m 2 H, Ar), 7.47 (dd, J = 8.5, 7.5 Hz, 1 H, C ₁₀ H ₇ ), 7.35-7.24 (m, 4 H, Ar), 7.17-7.11 (m, 2 H, Ph-m), 6.94 (t, J = 7.5 Hz + unresolved long range couplings, 1 H, Ph-p), 6.90-6.84 (m, 2 H, Ph-m), 6.75 (t, J = 7.5 Hz + unresolved long range couplings, 1 H, Ph-p), 6.66 (d, J = 8.5 Hz, 2 H, Ar), 4.96 (app dd, J = 1.0, -0.6 Hz, 1 H, C ₅ H ₃ ), 4.52 (app q, J = 2.06 Hz, 1 H ₁ C ₅ H ₃ ), 4.35 (app. t, J = 2.5 Hz, 1 H C ₅ H ₃ ), 4.29 (s, 5 H, C ₅ H ₅ ); ³¹ P NMR (162 MHz, CDCI ₃ ) δ _P 177.9; MS (ES) m/z 529 (M+H ⁺ , 35%), 435 (M -OPh ⁺ , 50%), 312 (M+H-P(OPh) ₂ ⁺ , 10%); HRMS (ES) m/z found [M+Hf 529.1023; C ₃₂ H ₂₆ FeO ₂ P requires 529.1020.

Ligand (S, S)-1-(1-naphthyl)-2-(3, 5-Dioxa-4-phospha-cyclohepta[2, 1-a;3, 4-a ']dinaphthalen-4- yl)ferrocene [CpFe(η ^s -1,2-C ₃ H ₃ (4-CF ₃ Ph)(P(0 ₂ C ₂ oH ₁₂ ))] 1bc

Yield 40 mg, 8%. ¹ H NMR (500.1 MHz, [D ₆ ]benzene) δ _H 8.26 (dd, J = 7.1 , 1.1 Hz, 1 H, Ar), 7.66 (br d, J = 7.0 Hz, 1 H, Ar), 7.69-7.63 (m, 3 H, Ar), 7.54 (d, J = 7.8 Hz, 1 H, Ar), 7.46 (dd, J = 8.6, 2.8 Hz, 1 H, Ar), 7.44-7.34 (m, 5H, Ar), 7.32-7.22 (m, 3H, Ar), 7.21-7.17 (m, 1 H, Ar), 7.14-7.10 (m, 1 H, Ar), 7.04- 7.01 (m, 1 H, Ar), 6.99-6.95 (m, 1 H, Ar), 4.67-4.65 (m, 1 H, C ₅ H ₃ ) 4.46 (s, 5 H, C ₅ H ₅ ), overlapped by 4.48-4.45 (m, 1 H, C ₅ H ₃ ), 4.28 (app. t J = 2.5 Hz, 1 H, C ₅ H ₃ ); ³¹ P NMR (162 MHz, CDCI ₃ ) δ _P +196.8; X- ray crystal structure obtained (see Figure 3).

Ligand (S, R)-1 -(phenyl)-2-(3, 5-Dioxa-4-phospha-cyclohepta[2, 1 -a;3, 4~a ']biphenalen-4-yl)ferrocene [CpFe(η ⁵ -1, 2-C ₅ H ₃ (Ph)(P(O ₂ C ₁₂ H ₃ ))! 1ab

Yield 48 mg, 43%. ¹ H NMR (400.1 MHz, [D ₆ ]benzene) δ _H 7.87 (d, J = 8.0 Hz, 2 H, C ₆ H ₄ CF ₃ ), 7.27 (dt, J = 7.6, 2.0 Hz ₁ 2 H, Ar), 7.21-7.16 (m, 3 H, Ar), 7.12-7.06 (m, 2 H, Ar), 7.00 (tdd, J = 7.5, 1.6, -0.8 Hz, 1 H, biphenyl-H4,4' or 5,5'), 6.95, (td, J = 7.5, 1.1 Hz, 1 H, biphenyl-H4,4' or 5,5'), 6.89 (td, J = 7.4, 1.8 Hz, 1 H, biphenyl-H4,4' or 5,5'), 6.77 (dd, J = 7.6, -0.8 Hz, 1 H, biphenyl-H6 or 6'), 4.50 (m, 1 H, C ₅ H ₃ ), 4.22 (m, 1 H, C ₅ H ₃ ), 4.08 (s, 5 H, C ₅ H ₅ ) 4.03 (app. T J = 2.4 Hz, 1 H, C ₅ H ₃ ); ³¹ P NMR (121.5 MHz ₁ [D ₆ ]benzene) δ _P 206.25 (s); m/z (ES) 527 (M+H ⁺ , 100%), 312 (M+H-P(Obiphen) ₂ ⁺ , 100%); m/z (ES) found [M+H] ⁺ 527.0863; C ₃₂ H ₂₄ FeO ₂ P requires 527.0863. [α] _D -386.0 (c = 1.00, chloroform).

Representative use of 1 in a catalytic asymmetric process

A representative use of the ligands described herein is in asymmetric conjugate addition reactions two examples of which are described with reference to Figure 5 below.

11

Ligand (f?,S)-1ac (11.5 mg, 4 mol%) was added to a suspension of Cu(OTf) ₂ (3.6 mg, 2 mol%) in diethyl ether (1 ml) at -30 ⁰ C. Subsequently either organoaluminium reagent A or B (0.70 mmol) was added together with cyclohex-2-en-1-one (0.50 mmol). The reactions were carried out using appropriate procedures from the literature [A. Alexakis, V. Albrow, K. Biswas, M. d'Augustin, O. Prieto, S. Woodward, Chem. Commun. 2005, 2843-2845]. After an appropriate time the reaction mixtures were analysed and the products 11 found to be attained in improved stereoselectivities compared to previous optimal ligands for this process. Chemical yields were comparable to the literature procedures using phosphoramidites.

SUMMARY

This invention relates to the following technical areas:

1. The preparation of new states of matter of composition 1 where R ¹ is derived from two suitable monoalcohols or one diol; R ² -R ⁹ are H, C ₁ -C _2O alkyl, alkenyl, or aryl substituents or heteroatom substituents thereof; Z is a C ₂ -C ₂₀ unit or heteroatom substituted derivative thereof such that the

initially attached carbon is sp ² hybridised (representative examples of Z include vinyl or aryl groups or heteroatom substituted variants thereof);

thereof thereof

2. A novel route for the preparation of 1 through the reaction of organometallic anion sources 2 and phosphite structures (3) where: R ¹ is derived from two suitable monoalcohols or one diol; R ² -R ⁹ are H, C ₁ -C ₂₀ alkyl, alkenyl, or aryl substituents or heteroatom substituents thereof; Z is a C ₂ -C ₂₀ unit or heteroatom substituted derivative thereof such that the initially attached carbon is sp ² hybridised (representative examples of X include vinyl or aryl groups or heteroatom substituted vvaarriiaannttss tthheerreeooff));; MM iiss aa GGrroouupp 11--22 oorr 1122--1133 mmeettaall;; R ^1Q -R ¹¹ is a CrC ₂₀ alkyl, alkenyl, or aryl substituent or heteroatom substituted version thereof.

Both cyclic or acyclic R ¹ structures can be used.

3. A preparative route to phosphites 3 attained by successive reaction of PCI ₃ with diols of type 9a (general) or 9b (specific), where: R ²⁰ -R ²⁷ = H, halogen, C ₁ -C ₂₀ alkyl, alkenyl, halogen, OR, NR ₂ , CO ₂ R, COR, CONR ₂ , SO ₃ R or aryl substituent or heteroatom substituented version thereof, where each R is independently selected from the group comprising: C _1-20 alkyl, C _1-20 haloalkyl, C _2-20 alkenyl, and C _2-20 alkynyl, wherein each of these groups may be optionally substituted by 1 to 3 substituents independently selected from the group comprising: C _h alky!, C _1-7 haloalkyl, Ci _-7 alkoxy, halogen, -CN, and -CF ₃ . Preferably R ²⁰ -R ²⁷ are independently selected from: H, halogen, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkenyl, and aryl.

9b

Application of ligands 1 in fields of use encompassing the preparation of fine chemicals and pharmaceutical intermediates via the medium of asymmetric catalysis.