Preparation of single enantiomers of chiral at metal bis-cyclometallated iridium complexes

Complexes of the type [Ir(C^N)2(X^Y)] usually occur as a single geometric isomer, with cis carbon atoms and trans nitrogen atoms of the cyclometallated ligand (Fig. 1). The complexes have a stereogenic metal centre and exist as a mixture of  and  15 enantiomers. However, unlike [Ru(bipy)3] 2+ the resolution of Ir(III) complexes is still in its infancy and very few reports have been published so far. Separation by HPLC of the enantiomers of [Ir(ppy)3] (Hppy = phenylpyridine) was reported in 2007, 3 and of [Ir(ppy-R)2(acac)] (R = F, OMe, Ph) in 2008. 4 Single 20

Our strategy was to prepare diastereomeric complexes [Ir(C^N) 2 (X^Y*)], separate the diastereomers, then remove the 30 chiral auxiliary by protonation and replace it with another bidentate ligand.A similar strategy has recently been applied by Meggers for the synthesis of homochiral trisbidentate ruthenium complexes, 10 and in 2012 was applied to iridium complexes for the first time.The dimer [Ir(ppz) 2 Cl] 2 (a, Hppz = phenylpyrazole) was reacted with 2.2 equiv of (S)-Na(L1) 11,12  (1:1) mixture of diastereomers, ∆S and ΛS, in good combined 45 yields (>75%) (Scheme 1).The reaction was repeated with only 0.8 equiv of (S)-Na(L1) per dimer and the 1 H NMR spectrum of the product showed a 1:1 ratio of the two diastereomers along with the unreacted excess dimer.This suggests that there is no diastereoselectivity in the synthesis and there is an equal 50 probability for the formation of the two diastereomers.The diastereomers of 1a could be separated by crystallisation from different solvents and they do not interconvert in solution, suggesting the chirality at the metal is stable at room temperature.The absolute configuration of both diastereomers was determined 55 by X-ray crystallography 13 and the structures of Sand S-1a are shown in Fig. 2. 14 The structures show that both isomers have cis carbon atoms and trans nitrogen atoms for the C^N ligands and S configuration at the chiral carbon atom of the oxazoline ligand; one isomer has a Λ configuration at the Ir centre (Fig.   in CHCl 3 , of +582 for the ΛS isomer compared to -593 for the ∆S isomer; these are much higher than the free ligand (-29 in CHCl 3 ).This suggests that the chirality imposed by the metal has a bigger effect on the specific rotation than the chirality at the carbon of the ligand.

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A similar reaction of (S)-Na(L1) with [Ir(ppy) 2 Cl] 2 gave 1b as a 1:1 mixture of diastereomers.In this case both diastereomers crystallised from the same solvent mixture but the crystals could be separated by hand picking due to a significant variation in colour and shape.Partial separation was also achieved by column chromatography over alumina, providing a pure fraction of the ΛS isomer which was characterised by X-ray crystallography (ESI Fig S2).The 1 H and 13 C-{ 1 H} NMR spectra of 1b are similar to those of 1a.
Using a similar procedure, chiral imine (S)-Na(L2) 15 reacted 20 with dimers a, b to form compounds 2a, b, each as a 1:1 ratio of diastereomers, (∆S and ΛS), in good combined yield (>75%).For 2a crystallisation from methanol gave pure ∆S-2a, the mother liquors being significantly enriched in ΛS-2a.For 2b both diastereomers crystallised together but they could be separated by 25 hand-picking due to a significant variation in colour and shape of the crystals.The crystal structures 16 of ΛS-and ∆S-2b are shown in Fig. 3; (that of ∆S-2a is in Fig S3).In complexes 2 there is free rotation about the N-CH(Me)Ph bond of the ligand which can alleviate steric congestion.In ∆S-2b, the salicylimine fragment is almost planar and the phenyl substituent [C(32)-C(37)] and ppy [C(1)-C(11) including N(1)] are in a face to face orientation (a similar interaction is present in ∆S-2a).In ΛS-2b (Fig 3 left) there is some distortion of the imine, the N is 0.34 Å out of the best plane of the rest of the salicylimine and the N^O chelate angle is smaller, at 85.90 (11), than in the ∆S isomer, 88.50(19).
The optical properties of the complexes were investigated via circular dichroism.Where the ∆S and ΛS-isomers were obtained pure, 1a ( To our knowledge there are no studies on the stability of chirality at the metal in complexes of the type [Ir(C^N) 2 (X^Y)].The lack of diastereoselectivity in the syntheses and the fact that solutions of single diastereomers show no epimerisation (by 1 H NMR spectroscopy) over several days suggests that chirality at the metal is stable at room temperature.To investigate this further (1:1.4)showed no change in ratio by 1 H NMR spectroscopy when heated to 120 C in DMSO-d 6 .Therefore we conclude that the chirality is stable up to 120 C.This is consistent with conversion 55 of mer to fac isomers of [Ir(ppy) 3 ] requiring heating to > 200 C. 17The previous reports of non-equal ratio of diastereomers with amino acidates 5,8 and phenol oxazolines 6 may reflect difficulties in isolation by column chromatography rather than an intrinsic diastereoselectivity.

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Having separated single diastereomers the next step was to remove the X^Y ligand by protonation without racemisation at the metal.Bubbling HCl gas through a dichloromethane solution of ∆S-2a led to formation of [Ir(ppz) 2 Cl] 2 .However when this was reacted with (S)-Na(L2) 2a was reformed as a 1.3:1 ∆S:S 65 mixture of diastereomers showing some racemisation had occurred. 18Hence a milder acid treatment was used; ∆S-2a was reacted with TFA in a biphasic mixture of DCM:H 2 O (1:1) at room temperature for 48 hrs.Monitoring the reaction by 1 H NMR spectroscopy showed a spectrum very similar to that of 70 [Ir(ppz) 2 Cl] 2 .The FAB mass spectrum showed an ion at m/z 1071 corresponding to [Ir 2 (ppz) 4 (CF 3 CO 2 )] + hence the product is proposed to be ΛΛ-[Ir(ppz) 2 (CF 3 CO 2 )] 2 3a. 19To determine the chirality at the metal centre, 3a was reacted separately with (S)-Na(L1) and (S)-Na(L2) which gave ∆S-1a and ∆S-2a 75 respectively, in good yields (>70%).In each case the Sdiastereomer was formed, and the ΛS isomer was hardly detectable by 1 H NMR spectroscopy (< 2%) in either case.Thus, the overall process of removal of the original chiral ligand and replacement with a second ligand occurred with complete 80 retention of configuration at the metal with no significant racemisation.
To make the process more efficient we combined removal of the chiral auxiliary and coordination of a new ligand.Thus, ∆S-2a was reacted with TFA in the presence of bipy to form ∆-85 [Ir(ppz) 2 (bipy)][CF 3 CO 2 ] 4a in which the only chirality is at the metal, in 72% yield.Using a similar procedure Λ-4a was synthesised from ΛS-1a via ΛΛ-3a.Thus the two enantiomers of 4a were synthesised independently from two different precursors.The enantiomeric excesses of -4a and Λ-4a were assessed by 1 H 90 NMR spectroscopy in the presence of  [Bu 4 N][trisphat]. 20The spectra (see Fig 5) show very high enantiopurity, in both cases the minor isomer is not observed.The enantiopurity of Λ-4a was also checked by HPLC (see ESI) and. was found to be >98% ee.The CD spectra of the two enantiomers are mirror images (see 95 ESI).

Fig 3 X
Fig 3 X-ray structures of ΛS-2b (left )and ∆S-2b(right) Me B respectively).However, protons H 5 and H 7 [δ 3.76 (H 5 ) and 3.04 (H 7 )] are now affected by a ring current of a ppz and so are at higher field than in the ΛS isomer [ca.δ 4.3 (H 5 ) and 3.93 (H 7 )].The compounds are chiral with a specific rotation 5

Fig 4 )
and 2b (Fig S4) the CD spectra are almost mirror 40 images suggesting that the configuration at the metal is the dominant factor in the appearance of the spectra.

Fig 4
Fig 4 CD spectra of ∆S and ΛS-1a

Fig 5
Fig 5 Selected parts of 1H NMR spectra of 4a, racemic (top), ∆ (middle) and Λ (bottom) Conclusions Diastereomeric complexes [Ir(C^N) 2 (X^Y)]1a, b and 2a, bare easily prepared as a 1:1 ratio of diastereomers.In all cases at least one diastereomer can be obtained pure by crystallisation.The chirality at the metal is stable in solution up to 120 C.The X^Y ligands can be easily removed from the metal by treatment with TFA to give a homochiral dimer which can be used to make homochiral complex or -[Ir(ppz) 2 (bipy)][CF 3 CO 2 ] 4a which is only chiral at the metal.The use of an appropriate strength acid is crucial since, unlike corresponding [Ru(bipy) 3 ] 2+ derivatives the chirality is not stable to moderately strong acid.This work will pave the way for the use of enantiopure Ir(III) complexes in many fields such as DNA probes which have previously relied heavily on Ru(II) polypyridine complexes.The authors thank the University of Leicester for funding, Johnson Mathey for a loan of IrCl 3 , Chiral Technologies 20