Chiral amino-phosphine and amido-phosphine complexes of Ir and Mg. Catalytic applications in olefin hydroamination

The reactions of rac - and ( S , S )- trans -9,10-dihydro-9,10-ethanoanthracene-11,12-diamine (ANDEN) with PClPh 2 in the presence of NEt 3 yield the chiral amino-phosphine ligands rac -6 and ( S , S )- 6 , respectively, on multi-gram scales. Both forms of 6 react quantitatively with MgPh 2 to afford the C 2 – symmetric, N–bound Mg amidophosphine complexes rac - 7 and ( S , S )- 7 . The former crystallizes as a racemic conglomerate, which is a rare occurrence. Mixing ( S , S )- or rac - 6 with [IrCl(COE) 2 ] 2 leads in both cases to the homochiral dinuclear chloro–bridged P–ligated aminophosphine iridium complexes ( S , S , S , S )- 9 and rac - 9 in excellent yields. X-ray quality single crystals only grow as the racemic compound (or ‘true racemate’) rac - 9 thanks to its lowered solubility. In the coordinating solvent CH 3 CN, rac - 9 transforms in high yield into mononuclear Ir-complex rac - 10 . The crystal structures of compounds rac - 6 , ( S , S )- 7 , rac - 9 , and rac - 10 reveal the ambidentate nature of the P–N function: Amide-coordination


Introduction
Chiral amino-phosphines such as 1-3 are competent ligands for asymmetric hydrogenations of de-hydroaminoacids 1 to the point where ligand 1 has been used industrially for the production of the artificial sweetener aspartame ((S,S)-aspartylphenylalanine). 2 The N-atom in aminophosphines may strategically be functionalized either by bulky substituents for steric control 3 or by leaving a hydrogen atom for reactivity control via H-bridging interactions 4 and possibly η 2 -P,N coordination. 5An indication of the importance of the N-substitution is the observation that the optical yield of hydrogen-ation products obtained with the H-substituted ligand 2 is not only markedly higher than with its N-methylated analogue, but also leads to products with inverted configurations. 6Moreover, the deprotonation of the N-H function in an aminophosphine leads to a vicinal hard-amide/soft-phosphine donor system.The use of trans-9,10-dihydro-9,10-ethanoanthracene-11,12diamine (termed as ANDEN in what follows) as a rigid 1,2diamino scaffold 7 for the construction of effective chiral ligands is exemplified by the success of Trost's ligand 4, 8 which also remains the only example of an ANDEN-derived phosphine ligand.Here, we wish to communicate the synthesis of a new ANDEN-based amino-phosphine ligand and its Ir-and Mg-complexes, which are promising catalysts for the asymmetric hydroamination of olefins. 9Electron-rich Ir(I)complexes figure among the first successful asymmetric intermolecular olefin hydroamination catalysts, 10 and Hultzsch and co-workers recently showed that chiral Mg-complexes catalyze intramolecular hydroaminations with good enantioselectivities. 11 Preliminary results on catalytic olefin hydroamination reactions employing the new chiral Ir-and Mg-complexes are also disclosed.

Results and discussion
The amino phosphines (S,S)-6 and rac-6 are accessible in excellent yields and on multi-gram scales as crystalline materials according to Scheme 1.The solubility of (S,S)-6 is significantly higher than that of rac-6, and the 31 P-NMR spectra of both products are characterized by a singlet resonance at 40.3 ppm.
The protons of the N-H function resonate as dd ( J values of 3.6 and 10.3 Hz) centered at 1.69 ppm, and the two protons of the connecting ethylene bridge appear as multiplets centered at 3.36 ppm.A single crystal X-ray diffraction study of rac-6 revealed that the molecule has approximate C 2 -symmetry (Fig. 1) and co-crystallizes with half an equivalent of n-pentane.The P-N-C bond angles of ca.120°suggest sp 2 Scheme 1 Synthesis of diaminophosphines and their Mg-salts.
hybridization of the N-atoms, while the sum of the angles about P1 and P2 are 308.27(12)°and 306.55 (12)°, respectively.The N-C-C-N torsion angle of 107.88 (14)°is close to the mean value of 111 (5)°found in nine crystal structures of uncomplexed ANDEN-derived molecules (vide infra).The N-H groups are not involved in any hydrogen bonding interactions because they are sterically protected by the surrounding phenyl rings.
The deprotonation of (S,S)-6 with MgPh 2 12 in THF solution followed by addition of benzene affords the off-white crystalline solvento complex (S,S)-7 in good yield (Scheme 1).It has low solubility in benzene and toluene, and the 1 H-NMR spectrum confirms the deprotonation of the amine functions (the dd resonance at 1.60 ppm is no longer present).The multiplet structure of the adjacent bridge-protons collapses to a singlet, which is shifted up-field to 3.17 ppm when compared to 3.36 ppm in 6, while the bridgehead protons exhibit a downfield shift from 3.95 in 6 to 4.55 ppm.The 31 P{ 1 H}-NMR spectrum of 7 in THF-d 8 shows a singlet resonance at 46.5 ppm with only a moderate downfield shift compared to the free aminophosphine 6, which is consistent with the absence of P-coordination (as established by the crystal structure).Complex 7 is stable in the solid state, and a THF-d 8 solution that was heated to 60 °C for 30 min did not show any signs of decomposition.Single crystals suitable for an X-ray diffraction analysis were obtained from the corresponding racemic complex rac-7, which crystallizes in the chiral space group P2 1 as a racemic conglomerate with one equivalent of benzene.
The crystal that was picked contained exclusively the (S,S)-enantiomer, and its molecular structure is depicted in Fig. 2. The formation of a racemic conglomerate of enantiomorphous crystals is also termed 'spontaneous resolution' 13 and does not occur commonly. 14It means that rac-7 could in principle be mechanically separated into its enantiomers (Pasteur's method of triage).The formation of a conglomerate in the case of rac-7 is also consistent with the observed slower rate of crystallization due to its lower entropy of crystallization when compared to (S,S)-7.The coordination sphere around magnesium is distorted tetrahedral with quite a small N-Mg-N bite angle of 91.82(9)°, and the molecule possesses an approximate C 2 symmetry axis passing through the Mg atom and the midpoint of C1-C2 (see insert of Fig. 2). 15While the P-C and P-N bond distances in rac-6 and (S,S)-7 are essentially unchanged, the N atoms in (S,S)-7 display a pyramidal rather than a trigonal planar geometry as observed in rac-6.Their considerable sp 3 character is indicated by the sums of the bond angles around atoms N1 and N2, which are 340.6(3)°and 337.1(3)°, respectively.The sums of the bond angles around P1 and P2 in (S,S)-7 are 304.6(2)°and304.73(2)°, respectively.The N-C-C-N torsion angle of the backbone is very small at 72.1(2)°, 16 with a concomitant large deviation of −24.9(3)°from planarity of the C3-C2-C1-C6 bridge.These large distortions are caused by the five-membered magnesium chelate ring and also prove that the ANDEN backbone is surprisingly flexible (this observation will be discussed further below).The H⋯Mg distances of the hydrogen atoms pertaining to the stereogenic C atoms measure 2.6 and 2.7 Å and span Mg⋯H-C angles of 72.5°and 77.5°, respectively, and thus do not fulfill the criteria for agostic interactions. 17The co-crystallized benzene in the structure links a benzo-group of the backbone of one molecule of 7 with a phenyl substituent on a P atom of the other molecule of 7 via two T-shaped C-H⋯π interactions. 18It should be noted that well characterized N-coordinated amido-phosphine metal complexes are rather rare, 19 and to the best of our knowledge this is the first structurally authenticated chiral example of such a complex.Furthermore, the vicinity of the hard Lewis-acidic Mg 2+ centre to the soft phosphine Lewis-bases creates a bifunctional complex that should facilitate the activation of polar bonds.Preliminary attempts to alkylate the amide functions in 7 with common organic electrophiles only led to inseparable mixtures. 20he enantiopure ligand (S,S)-6 reacts with [IrCl(COE) 2 ] 2 (COE = cyclooctene) in benzene solution to afford almost quantitatively the dimeric orange complex (S,S,S,S)-9 (see Scheme 2). 21The compound is very air-sensitive, turning green within seconds upon exposure to air.The NMR spectra show the complex to be symmetrical, containing no coordinated COE.Furthermore, no hydride resonances are observed even though similar Ir(I) complexes are known to readily activate N-H bonds. 22Attempts to grow crystals of the enantiopure complex (S,S,S,S)-9 were hampered by its high solubility.Therefore, the synthesis of the racemic analogue of homochiral (i.e.non-meso) dimers of 9 was attempted, because racemates often display better crystallinity than enantiopure compounds.Indeed, rac-6 reacts with [IrCl(COE) 2 ] 2 in toluene solution to afford copious amounts of analytically pure orange needles of rac-9.The X-ray diffraction analysis confirmed the exclusive formation of homochiral dimers, and the molecular structure of the (S,S,S,S)-enantiomer is depicted in Fig. 3. 23 In the tetragonal unit cell four dimers are arranged around a large open channel, which runs parallel to the c-axis and is partially occupied by randomly oriented toluene molecules (for more details see the Experimental part).The space group, P4 2 bc, is non-centrosymmetric, but the presence of glide planes requires the crystal to be a racemic compound (or 'true racemate') containing homochiral molecules with R,R,R,R-and S,S,S,S-configuration.The dinuclear complex resides on a crystallographic C 2 -axis.The butterfly-shaped chloro bridged Ir 2 Cl 2 core is perpendicular to this axis and the butterfly wings subtend an angle of 123.68(6)°, which is in line with the conformation in similar chiral dinuclear Ir(I) phosphine complexes.10a, 24 The two anthracenyl backbone units of each halfdimer are almost orthogonal to each other with a dihedral angle of 82.1(5)°between both C3-C2-C1-C6 mean planes.One side of the dimeric complex is sterically protected by four axial phenyl rings resembling a bowl, while the other side exposes the Ir 2 Cl 2 core due to an equatorial arrangement of the remaining four phenyl rings.The seven-membered chelating rings have a twist-boat conformation with the Ir-atoms located approximately above the C1-C2 bridge, but the chelation is not C 2 -symmetrical, unlike that seen in the Mg complex (S,S)-7.The dihedral angle between the square coordination plane around Ir and the best plane fitted through the C3-C2-C1-C6 bridge is 51.9(4)°.
Even though the P donor atoms of the ligand are not symmetry-equivalent in the crystal structure, they display only one resonance in the 31 P NMR spectrum and broadened 1 H-NMR signals, which hints at a fast inversionwith respect to the NMR timescaleof either the chelate rings, or the Ir 2 Cl 2butterfly.rac-9 has very low solubility in benzene, toluene, and THF but readily dissolves in the presence of aniline forming an inseparable mixture of hydride species with 1 H NMR resonances between −19.4 and −19.9 ppm, which are the result of N-H activation and a prerequisite for Ir(I) catalyzed hydroamination of norbornene (vide infra). 25Also acetonitrile initially dissolves rac-9 by splitting the chloro-bridge and forming the mononuclear adduct rac-10.The 31 P NMR spectrum shows a pair of doublets and the proton spectrum is consistent with two diastereotopic half-sides of the ligand backbone. 26The single crystal X-ray diffraction analysis confirms the mono-nuclear nature of the acetonitrile adduct rac-10, which, along selected geometric parameters, is depicted in Fig. 4. The Iratom is in a square planar coordination environment and, as in rac-9, the conformation of the ligand is distorted considerably from the pseudo C 2 symmetry it adopts in the Mg complex (S,S)-7.As in rac-9, the seven-membered chelate ring is boat-shaped, 27 but in contrast to rac-9, where the Ir-atom is located centrally over the C-C bridge of the ligand backbone, it is tilted towards one of the benzo-groups due to more severe puckering of the chelate ring.Similar off-center coordination of the metal with respect to the anthracenyl moiety has been observed in di-NHC complexes with flexible seven-membered chelation. 28The dihedral angle between the mean coordination plane around the Ir atom and the mean plane defined by the C2-C1-C10-C9 bridge of the ligand backbone is 56.25(18)°.Two phenyl rings on each of atoms P1 and P2 are in an axial position and on the same side of the chelate ring, thereby shielding one coordination hemisphere, while the other two phenyl rings are equatorially arranged.The N1-C1-C10-N2 torsion angle in the ligand backbone of rac-10 decreased from 107.88(14)°to 100.1(3)°when compared to the free ligand in rac-6, showing once more the flexibility of the ANDEN backbone under the influence of strain caused by bidentate coordination.7a Table 1 lists the N-C-C-N torsion angles and shows their correlation with the C-C-C-C torsion angle of the ethynyl bridge of the ligand backbone.In 17 published crystal structures that contain the ANDEN substructure, the N-C-C-N torsion angles range between 61°and 119°, and in unstrained molecules (i.e.free ligands and protonated ANDEN) they are usually around 110°. 7,29 In order to model this type of flexibility in the ANDEN backbone we performed DFT calculations by varying the N-C-C-N torsion angle between 55°and 145°.The results shown in Fig. 5 agree well with the experimental data of an almost linear dependence of the two types of torsion angle, and for very strong deviations the linear trend between the angles is even more pronounced than predicted by the DFT-model.Furthermore, the calculations indicate an energy minimum at about 105°for the N-C-C-N angle in ANDEN, while the corresponding H-C-C-H torsion angle in the simple dibenzobicyclo [2,2,2]octane molecule approaches the expected 'ideal' value of 120°.The observation that substitution of the NH 2 groups in ANDEN for CH 3 groups also leads to a minimum at around 105°suggests that torsion angles smaller than 120°are the consequence of steric effects rather than H-bonding or electronegativity effects. 30The experimentally observed flexibility of the ANDEN backbone is consistent with the calculated low strain energies: the bulk of the X-ray crystal structures have N-C-C-N angles between 95°and 115°(i.e.10°deviation from the ideal value), which amounts to less than 5 kJ mol −1 of strain. 31The strain energy in the highly distorted complex 7 is thus estimated to be around 20 kJ mol −1 .
Finally, complexes (S,S)-7 and (S,S,S,S)-9 were tested as catalysts for the hydroamination of olefins (see eqn (1) and (2) and Table 2 below).The Mg-complex (S,S)-7 turned out to be an active catalyst for the intramolecular hydroamination of 2,2′-diphenyl-pent-4-ene-amine to form 2-methyl-4,4′-diphenylcyclopentyl amine (eqn (1)).The reaction proceeds smoothly without the need for any additives and is surprisingly clean when monitored in situ by NMR, forming no side-products and reaching full conversion after only 4 h at room temperature with a catalyst loading of 5 mol% (Table 2, entry 1).However, at lower catalyst loadings, the reaction does not go to completion even after prolonged reaction times (entry 2), which is probably due to catalyst deactivation by trace amounts of water.Unfortunately, enantioselectivities are very low, and the slightly bulkier benzylated amine substrate yields the corresponding pyrrolidine in trace amounts only.For the reaction of eqn (2), the Ir-complex (S,S,S,S)-9 is a promising candidate due to its ability to activate the N-H bond of aniline (vide supra), and indeed, in the presence of co-catalytic amounts of MgPh 2 , LDA, or PhLi, the addition product exo-(2-phenylamino)bornane forms in good yields but low optical purity.Even the notoriously unreactive substrate o-anisidine 32 affords the corresponding norbornylamine in 35% isolated yield.The precise role of Ph 2 Mg, LDA, and PhLi as co-catalysts in the addition of aniline to norbornene is still unclear.Separate experiments, however, showed that these co-catalysts on their own form the Mg-and Li-anilides in situ, which do not catalyze any of the reactions of eqn (1) and ( 2), even under prolonged heating at 75 °C.Not unexpectedly then, the hydroamination of norbornene with aniline is not catalyzed by (S,S)-7, because the magnesium complex reacts quantitatively with aniline to afford free ligand (S,S)-6 and catalytically inert Mg(NHPh) 2 .Conversely, (S,S,S,S)-9 is inactive in the intramolecular hydroamination of 2,2′-diphenyl-pent-4-ene-amine (eqn (1)).
In conclusion, the new ANDEN-based amino-phosphine ligand 6 is accessible in gram quantities and excellent yields as racemate and as optically pure compound.Its coordination chemistry with Mg and Ir highlights the ambidentate nature of the P-N function.The hard Mg(II) is coordinated by the hard amide functions in the C 2 -symmetric complex (S,S)-7, while the soft Ir(I) centres in complexes (rac)-9 and (rac)-10 are P-bound through seven-membered chelate rings of low symmetry.The crystal structures of (rac)-6, (S,S)-7, (rac)-9, and (rac)-10 reveal considerable flexibility within the bicyclic scaffold of the ANDEN backbone, and DFT calculations demonstrate that these distortions do not induce large amounts of strain energy.Thus, the ANDEN backbone is not as rigid as it appears, apart from the fact that it does not allow conformational isomerism.The Mg complex (S,S)-7 and the Ir complex (S,S,S,S)-9 are active catalysts for the intra-and intermolecular hydroamination of olefins, respectively.We are currently modifying ligand 6 by introducing different phosphine groups in an attempt to improve on enenantioselectivities and to expand the substrate scope, and results will be communicated in due course.

Experimental section
All reactions were carried out under anaerobic and anhydrous conditions, using standard Schlenk and glove box techniques, unless otherwise stated.THF, Et 2 O, and benzene were distilled from purple Na/Ph 2 CO solutions, toluene from Na, pentane, C 6 D 6 , and THF-D 8 from Na 2 K alloy, CH 3 CN, CH 2 Cl 2 , and CD 2 Cl 2 from CaH 2 , NEt 3 and 1,4-dioxane from K. CD 3 CN and CDCl 3 were degassed with three freeze-pump-thaw cycles and then kept in a glove box over activated molecular sieves (3 Å and 4 Å, respectively).2-Norbornene was distilled from Na 2 K alloy, aniline from CaH 2 .ANDEN, 33 [IrCl(COE) 2 ] 2 , 34 diphenylmagnesium, 35 lithium diisopropylamide, 36 and 2,2-diphenylpent-4-en-1-amine 37 were prepared according to published procedures.Resolution of rac-ANDEN (5) was simplified by only using the cheaper (R)-enantiomer of the chiral auxiliary mandelic acid to obtain both enantiomers.Optically pure (S-S)-ANDENium-(R)-mandelate was obtained from a single crystallization in methanol, and the (S-S)-ANDEN was freed by treatment with KOH.The mother liquor containing mainly (R, R)-ANDENium-(R)-mandelate (as judged from its optical rotation) was likewise treated with KOH to obtain (R-R)enriched ANDEN.Contrary to Lennon's protocol, 33 this material was not treated with (S)-mandelic acid, but recrystallized from benzene to yield optically pure (R-R)-5.Elemental analysis samples of air sensitive compounds were handled and prepared in a glove box.NMR spectra were recorded on 270 MHz or 400 MHz Jeol Lambda/Eclipse spectrometers, and the solvent residual signals were used as the internal reference for the 1 H-NMR-spectra. 38Optical rotations were measured on a Perkin-Elmer 241 polarimeter.solution are complicated, due to the presence of oligomeric species.Adding 2.2 equiv. of THF to such filtered (GF/B) benzene solutions affords the crystalline tetrahydrofuranate rac-7 in excellent yields (>85%).Single crystals obtained by this method were suitable for X-ray diffraction analysis.NMR spectra of these crystals are identical to those of (S,S)-7 (vide supra).Using toluene instead of benzene affords material of better crystallinity but in lower yield.Toluene (15 g) was added to rac-6 (708 mg, 1.12 mmol) and [IrCl(COE) 2 ] 2 (500 mg, 0.556) in a vial rapidly forming a clear, red solution, which after about 20 min turned orange.Within 2 d large amounts of needle-like orange crystals had grown and were collected by filtration, washed with chilled toluene (5 ml) and n-pentane (2 × 10 ml), and dried in vacuo (717 mg, 72%).The single crystals thus obtained were of X-ray diffraction quality.Elemental analysis found: C, 60.Crystalline rac-[IrCl(ANDEN-PPh 2 )(CH 3 CN)]•1 1 3 CH 3 CN (rac-10) rac-9 (239 mg, 0.144 mmol, used as its toluene solvate) was dissolved in acetonitrile (5 mL) and the solution left undisturbed for 5 d at −32 °C.This afforded copious amounts of yellow, X-ray quality crystals, which were separated from the orange mother liquor by decantation, washed with pentane (5 mL), and dried in HV (151 mg, 55% Once crystals of (rac)-10 have formed, their solubility in CD 3 CN and other common solvents is too low for meaningful NMR-spectra to be recorded.For spectra of (rac)-10 that were recorded before crystallization took place, see the protocol for (rac)-9.

Crystal structure determinations
Compound rac-6 crystallized as its n-pentane hemisolvate.The solvent molecule is disordered about a crystallographic centre of inversion.Similarity and pseudo-isotropic restraints were applied to the anisotropic displacement ellipsoids of the disordered atoms.The asymmetric unit of (S,S)-7 contains one molecule of the Mg-complex plus one molecule of benzene.Refinement of the absolute structure parameter 46 yielded a value of −0.01 (5), which confidently confirms that the refined model represents the true absolute structure.The asymmetric unit of rac-9 contains half of a C 2 -symmetric dinuclear Ircomplex with the metal centres linked by a double Cl-bridge.The structure model, when defined just by the Ir-complex contains two large voids of 1567 Å 3 per unit cell, in which no significant electron density peaks corresponding with obvious solvent molecules could be discerned (Fig. 6).However, based on NMR evidence and elemental analysis, it is clear that highly disordered non-stoichiometric amounts of toluene molecules occupy the cavities.As the solvent molecules could not be modelled, the SQUEEZE routine of the program PLATON 47 was employed.The electron count in each void in the unit cell was calculated to be approximately 225 e.One toluene molecule has 50 e, so it has been assumed that four toluene molecules lie in each void.This approximation has been used in the subsequent calculation of the empirical formula, formula weight, density, linear absorption coefficient and F(000).Based on this assumption, the ratio of Ir-complex to toluene molecules in the structure is 1 : 2. Refinement of the absolute structure parameter 46 yielded a value of −0.025(3), which confidently confirms that the refined model represents the true absolute structure.Although the space group for rac-9 is non-centrosymmetric, the presence of glide planes dictates that the compound in the crystal is racemic.
For rac-10, the Ir-complex crystallized with 1.33 equivalents of MeCN.The solvent molecules are distributed over two crys- tallographic sites and are strongly disordered.One of the solvent molecules lies on a general position while the other is situated on a crystallographic three-fold axis.Two alternative orientations of the solvent molecules were refined at each site while applying bond length, bond angle and bond length similarity restraints.Similarity and pseudo-isotropic restraints were also applied to the anisotropic displacement ellipsoids of the disordered atoms.Three reflections, whose intensities were considered to be extreme outliers, were omitted from the final refinement.
For rac-9, the two unique amine H-atoms were placed in the positions indicated by a difference electron density map, then their positions were geometrically optimised and refined by using a riding model with refined isotropic displacement parameters.The H-atom of one amine group is disordered over the two possible positions on its parent N-atom.The amine H-atoms of rac-6 and rac-10 were placed in the positions indicated by difference electron density maps and their positions were allowed to refine together with a fixed isotropic displacement parameter with a value equal to 1.2U eq of its parent atom.All remaining H-atoms in each structure were placed in geometrically calculated positions and refined using a riding model where each H-atom was assigned a fixed isotropic displacement parameter with a value equal to 1.2U eq of its parent atom (1.5U eq for any methyl groups).The refinement of each structure was carried out on F 2 by using full-matrix leastsquares procedures, which minimised the function ∑w(F o 2 − F c 2 ) 2 .The SHELXL-2014 program 48 was used for the refinement of (S,S)-7 and rac-9, while SHELXTL 45 was used for the other two structures.

Computational details
ANDEN and its modifications were drawn in a standard molecule editor and pre-optimized using the Merck Molecular Force Field MMFF94. 49Calculations were performed using the Turbomole 6.3 suite 50 with the def2-TZVP 51 basis set and the BP-86 exchange correlation functional. 52The calculations were accelerated using the R IJ approximation. 53The energy curves were obtained by iterative increments of a fixed internal redundant coordinate resembling the X-C-C-X torsion angle and starting from the equilibrium geometry.Energy differences were calculated with respect to the SCF-energies only.Gibbs free energies were not taken into consideration because the complex-valued vibrational modes of the non-equilibrium structures would be ignored in their calculation (this would generate an extra error due to the fact that the reference is an equilibrium structure).

Table 1 a
Torsion angles within the ANDEN backbone as measured in the crystal structures of rac-6, (S,S)-7, rac-9 and rac-10 By definition, negative and positive signs for the NCCN and CCCC angles, respectively, refer to the (R,R) enantiomers.The opposite applies to the (S,S) enantiomers.