Chiral bisoxazoline ligands designed to stabilize bimetallic complexes

Chiral bisoxazoline ligands containing naphthyridine, pyridazine, pyrazole, and phenol bridging units were prepared and shown to form bimetallic complexes with various metal salts. X-ray crystal structures of bis-nickel naphthyridine-bridged, bis-zinc pyridazine-bridged, and bis-nickel as well as bis-palladium pyrazole-bridged complexes were obtained.


Introduction
Metal-centered asymmetric catalysis most commonly relies on monometallic complexes of various chiral ligands, among which chiral bisoxazolines have been highly successful in facilitating various Lewis acid-catalyzed asymmetric transformations [1][2][3]. In addition to monometallic catalysis, it has long been recognized that catalysts possessing two or more metal centers in close proximity can be uniquely effective in catalyzing certain types of reactions [4][5][6]. Serving as a main source of inspiration in the design of chiral small-molecule systems, nature utilizes a variety of bimetallic and multimetallic protein complexes to perform a host of biological functions [7]. Urease [8], hemerythrin [9], methane monooxygenase [10], ribonucleotide reductase [11], catechol oxidase [12], and arginase [13], are prominent examples of such bimetallic enzymes.
A range of bi-and multi-metallic complexes have been utilized in asymmetric catalysis ( Figure 1) [6]. For instance, Shibasaki and co-workers introduced a number of chiral multi-metallic complexes such as the hetero-bimetallic complex 1, in which the two different metals play distinct roles [14,15]. Jacobsen and co-workers reported dimeric salen complexes 2 which show cooperative reactivity between the two metal centers in the asymmetric ring opening of meso-epoxides [16]. Trost et al. disclosed the synthesis of dinuclear zinc complexes 3 and their application to enantioselective Aldol reactions [17,18] and a host of other asymmetric transformations [18]. Other notable contributions in this area were provided by the groups of Martell [19,20], Maruoka [21,22], Wuest [4,[23][24][25], and others . In the majority of cases where bimetallic complexes are used as the catalytically active species, the two metal centers perform different functions [47,48].

Results and Discussion
A number of bisoxazoline ligands with different bridging units were designed. We rationalized that the presence of three binding sites per metal center would be ideal in order to achieve the desired 1:2 ligand to metal ratio, and to prevent the potential formation of 2:2 or other higher order complexes. Variation of the bridging moiety should allow for modulation of the distance between the metal centers. An important criterion for selecting bridging units was their known ability to engage in metal-binding, along with being readily available. This led to the selection of naphthyridine, pyridazine, pyrazole, and phenol building blocks. We opted to connect these linkers to oxazolines via amide bonds. The reasoning for this was twofold. Firstly, this should provide ligands with significantly improved stabilities over for instance imine linkers. In addition, each amide moiety, upon deprotonation (a requirement for complex formation), would provide a formal negative charge on the ligand, thus resulting in increased complex stability while reducing the number of spectator anions associated with the two metals. Different combinations of five-and six-membered chelate rings were considered, as those allow for further modu- lation of metal-metal distances. Convenient synthetic sequences were developed for six different ligands.
Naphthyridine-bridged bisoxazoline ligands. The synthesis of naphthyridine bridged bisoxazoline ligand 16-H 2 is outlined in Scheme 1. 1,8-Naphthyridine-2,7-diacyl chloride 14, obtained via a known procedure from the corresponding diacid [49], was allowed to react with aminoindanol-derived aminophenyloxazo-line 15 [55] to provide bisoxazoline ligand 16-H 2 in 65% yield. Upon deprotonation, 16-H 2 provides a dianionic ligand with three nitrogen donor atoms per metal center. Ligand 16-H 2 was found to undergo complex formation with various copper, zinc, palladium and nickel salts. Figure 3 shows the X-ray crystal structure of 16·Ni 2 (OAc) 2 , obtained from ligand 16-H 2 and two equivalents of nickel(ΙΙ) acetate. The asymmetric unit of the crystal 16·Ni 2 (OAc) 2 contains two nickel(ΙΙ) centers held in close proximity by three donor nitrogen atoms per metal center and two differently bridged acetate ions inside the coordination sphere. The nitrogen atoms on the naphthyridine and amide moieties bind to the nickel(ΙΙ) center to form a five-membered metallacycle, subtending N(2)-Ni(1)-N(3) and N(5)-Ni(2)-N(6) angles of 81.53° and 80.34°, respectively. Additionally, the nitrogen atoms on the oxazoline and amide moieties form six-membered rings with the nickel(ΙΙ) center with N(1)-Ni(1)-N(2) and N(4)-Ni(2)-N(5) angles of 93.03° and 90.24°, respectively. All of the Ni-N distances are between 2.003 and 2.129 Å, typical for complexes of this type [56,57]. Interestingly, while one of the two acetate ions bridge the two nickel(ΙΙ) centers by binding through the two oxygens, the second acetate unit has a somewhat different binding pattern: one oxygen binds to Ni(1) and the other oxygen acts as the bridge between Ni(1) and Ni (2). The Ni(1)•••Ni(2) distance is 3.448 Å, which is slightly longer than the corresponding Ni•••Ni distance in the structurally related 10. The sixth coordination of Ni (2) is fulfilled by the amide oxygen of a second molecule of the complex (not shown in the figure for clarity). Apparently, the coordination environment involving three O-atoms from acetate groups (the Ni(1) situation) for one of the two metals is preferred in 16·Ni 2 (OAc) 2 , presumably for steric reasons, as crystal packing motivations would likely favor two situations as found for Ni (2), and possibly favoring formation of the 1D polymeric chain found here extending along the crystal b-axis. When this interaction is taken into account, both the nickel(ΙΙ) centers are in distorted octahedral environment. Overall, the ligand backbone of complex 16·Ni 2 (OAc) 2 shows a helical arrangement. This helicity is facilitated by the innate stereogenic centers of the oxazoline moieties which is further extended by the flexibility afforded by the amide connections.  pyrazol-3,5-dicarboxylic acid with thionyl chloride, with aminophenyloxazoline 24 [59] provided ligand 25-H 3 in 85% yield.
Treatment of 25-H 3 with nickel(II) acetate provided the binuclear complex 25·Ni 2 (OAc), the X-ray structure of which is shown in Figure 4. Each unit of the complex is comprised of two nickel(II) centers, each bound by three nitrogen atoms from the ligand skeleton and bridged by an acetate anion. The nitrogen atoms from pyrazole and amide moieties coordinate to the two nickel centers to form five-membered metallacycles, subtending N(1)-Ni (1) Initial experiments have shown that the trianionic ligand 30-H 3 readily forms complexes with various nickel, copper and palladium salts. Figure 5 shows the X-ray crystal structure of 30·Pd 2 Br, obtained from ligand 30-H 3 and two equivalents of palladium(ΙΙ) bromide. Each of the two palladium(ΙΙ) centers of the complex 30·Pd 2 Br is confined in a slightly distorted square planar geometry by three donor nitrogen atoms from the ligand and a bridging bromide ion. Unlike the situation in 16·Ni 2 (OAc) 2 , where the Ni-O bond from the carbonyl of an adjacent molecule yields both the five-coordinate Ni and 1D polymeric chain, there are no Pd-O bonds (not even dative) in 30·Pd 2 Br and the Pd atoms remain nearly square planar. The donor nitrogen atoms from pyrazole, amide and oxazoline moieties coordinate to the palladium centers, forming fivemembered chelate rings, with the subtended N-Pd-N angles ranging from 79.43° to 82.16°. The two palladium centers are bridged by the bromide ion and the pyrazole segment. All of the Pd-N bond lengths fall within a relatively narrow range of  1.925 to 2.025 Å, and are typical for Pd-N bonds with this coordination geometry. As expected, the Pd-Br bond lengths are slightly longer (2.519 and 2.529 Å) than the Pd-N bonds. The bromide ion bridges the two palladium centers with a Pd-Br-Pd angle of 98.48°. The two nitrogen donor atoms from the pyrazole moiety forms the second bridging link between the two metal centers, thereby restricting the N(1)-Pd(1)-Br(1) and N(4)-Pd(2)-Br(1) angles to 89.89° and 89.73°, respectively. The resulting Pd(1)•••Pd(2) distance was observed to be 3.824 Å.
Upon deprotonation, 32-H 2 provides a dianionic ligand with three donor nitrogen atoms per metal center. Ligand 32-H 2 forms complexes with different nickel, copper, zinc and palladium salts. Shown in Figure 6 is the molecular structure of 32·Zn 2 Cl 2 . Each unit of the complex 32·Zn 2 Cl 2 consists of two zinc(ΙΙ) centers, with each bound by three donor nitrogen atoms from the ligand skeleton and bridged by a chloride ion. The nitrogen atoms on the pyridazine and amide moieties form fivemembered chelate rings upon coordination to the zinc centers, subtending N(2)-Zn(1)-N(1) and N(5)-Zn(2)-N(4) angles of 74.74° and 77.04°, respectively. The coordination of the nitrogen atoms on oxazoline and amide moieties with the two zinc centers forms six-membered rings with N(3)-Zn(1)-N (2) and N(6)-Zn(2)-N(5) angles of 87.05° and 88.55°, respectively. All of the Zn-N distances are within 2.023-2.177 Å, as expected for such complexes. Interestingly, the two chloride ions   (1) and Zn(2) in 32·Zn 2 Cl 2 . Zn(1) is found to exist in a square planar environment that experiences a significant tetrahedral distortion. In contrast, a distorted square pyramidal binding mode is observed for Zn (2).
Phenol-bridged bisoxazoline ligands. Ligands incorporating naphthyridine, pyridazine and pyrazole linkers discussed thus far bridge two metal atoms by attachment to two different nitrogen donor atoms. As a result, metal•••metal distances tend to be relatively long. Ligand 34-H 3 was designed to explore the effect of a single atom linker, namely a phenoxy bridge. The tert-butyl group in the para-position was incorporated as it would likely increase the overall solubility of the ligand as well as its associated complexes. DCC-mediated coupling of 33 [49] with two equivalents of aminophenyloxazoline 15 led to the for-  mation of phenol-bridged bisoxazoline ligand 34-H 3 in a single step and moderate yield (Scheme 6). While X-ray quality crystals have not yet been obtained, preliminary experiments have shown that ligand 34-H 2 forms complexes with nickel, copper and palladium salts [58].

Conclusion
We have achieved the synthesis of chiral bisoxazoline ligands that incorporate naphthyridine, pyrazole, pyridazine and phenol bridges. These compounds readily form complexes with various transition metal salts and may provide a platform for the development of new catalytic enantioselective transformations.

Supporting Information
Supporting Information File 1 Experimental procedures and characterization data.