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The collective results from the attempted preparation of oxidative addition complex suggest that bis-hydrazone is a weakly coordinating ligand. Ligand exchange experiments show that it is incapable of replacing diamine and phosphine ligands including TMEDA, PPh3, t-Bu3P

and dppp (Scheme 102). Although displacement of bidentate olefin ligand such as 1,5- cyclooctadiene is possible, this process is extremely inefficient (Scheme 114).

Further evidence of the weak coordinating ability of hydrazone ligands may be inferred from the NMR spectrum of a metal complex. The complexation of bis-hydrazone ligand 46 to palladium chloride only causes a minor perturbation of the proton chemical shift and slight broadening of the signals (Scheme 144). Slight downfield shifts of the α-CH and β-CH of piperidine ring are observed which can be rationalized by coordination to the Lewis acidic PdCl2

moiety and resonance contribution of the hydrazone moiety that inductively removes electron density from the adjacent carbons. The distal γ-proton is not affected. In the case of chiral hydrazone complex (S,S,S,S)-(50e)PdCl2, multiple and undefined peaks are observed in solution

suggesting rapid equilibration between various conformers.

Scheme 144

One major problem in the preparation of oxidative addition adduct of palladium- hydrazone ligand complex via transmetalation is the formation of homocoupled biaryl product and concommitant palladium deposition (Scheme 102). The transfer of an aryl group from an organometallic reagent (Aryl-M) to palladium dichloride complex (46)PdCl2 produces a

arylpalladium chloride complex (46)Pd(Aryl)Cl (Scheme 145). This intermediate undergoes disproportionation to form (46)Pd(Aryl)2 and (46)PdCl2 (route a).231 An alternative pathway

involving consecutive displacement of the chloride anions with two aromatic donors is also possible (route b).231 Reductive elimination of the diarylpalladium complex gives the homocoupled product and an equivalent of bis-hydrazone palladium(0), (46)Pd0. Redistribution of ligand generates the observed (46)2PdCl2 and palladium black.

Scheme 145

The feasibility of the above process is dependent on the identity of the transmetalating agent. Whereas the use of diphenylmercury leads to rapid formation of biphenyl, no homocoupled product was detected when the corresponding di(perfluorophenyl) reagent is used. The divergent behavior may originate from the different stability of the (46)Pd(Aryl)Cl complex. The electron-deficient perfluorophenyl renders the palladium(II) more Lewis acidic. Therefore, the bis-hydrazone ligand associates to the metal center more strongly (Scheme 146). Even though an excess amount of (C6F5)2Hg is added, the second displacement of the chloride anion

does not occur easily. This observation is consistent with the explanation that ligand dissociation occurs less readily and the fully coordinated palladium center is too congested for subsequent nucleophilic attack, despite the increased electrophilicity of palladium complex. On the contrary, the corresponding phenylpalladium complex is much more electron-rich and is less capable to have a strong chelation from the hydrazone ligand. Although there appears to be a relationship between the ease of ligand dissociation and formation of homocoupled product, more experimentation is required to confirm this hypothesis.

Scheme 146

3.5.8.1 Future Development

The lessons learnt from the above studies should facilitate future endeavors in the preparation of chiral bis-hydrazone palladium(II) complexes (Scheme 147). The lability of the chiral 2,5-diphenylpyrrolidine-based hydrazone ligand (R = Ph, X = Cl−) has complicated the NMR characterization and crystallization of its palladium dichloride complex. The corresponding dicationic complex using the less coordinating anions232 such as tetrafluoroborate, hexafluoroantimonate and BArF could potentially slow down the dynamic behavior of the ligand by forming a stronger complex because the palladium is more Lewis acidic.

Scheme 147

The key to prepare oxidative addition (OA) complex of bis-hydrazone is also an electron- deficient palladium(II) center. Such complex is stabilized by enhanced coordination from the ligand as demonstrated by the ability to isolate (46)Pd(C6F5)Cl, but not (46)Pd(Ph)Cl. An

additional benefit appears to be the minimization of homocoupling. Therefore, an electron- deficient aromatic substituent is recommended. The installation of this arene should be performed using an organomercury reagent because of its mildness.

The stability of oxidative addition complex may be fine tuned by increasing the electron- density on the ligand, although the impact by modifying 2,5-disubstituents of the pyrrolidine ring may be limited due to considerable distance between these moieties and the nitrogen atoms responsible for chelation.

The preparation of pre-transmetalation (pre-TM) intermediate requires the use of a sterically bulky and electron-deficient arylsilanolate (e.g. 2,4,6- tris(trifluorophenyl)dimethylsilanolate) to minimize accidental transmetalation (TM). The lithium or silver salt of this nucleophile should be employed to minimize activation of the silicon unit. Replacing the dimethylsilyl unit with the diisopropylsilyl unit may also be beneficial.

The diarylpalladium complex of chiral bis-hydrazone ligand is likely the most challenging intermediate to prepare, because the cis relationship of the two aromatic groups predisposes them toward reductive elimination. This process may be delayed if both arenes are electron-deficient.71,233

3.6 Conclusion

In summary, two synthetic routes have been investigated that allows access to various diarylpyrrolidine-based chiral bis-hydrazone ligands. This endeavor enables systematic studies of the ligand effects on the asymmetric cross-coupling reaction of aryldimethylsilanolate. Ligands with electron-rich/neutral and unhindered aromatic substituents on the 2,5-positions of the pyrrolidine ring generally correlate with higher enantioselectivities and reactivities. Preliminary mechanistic studies by donor/acceptor reversal experiments indicate that reductive elimination is likely the stereodeteremining step. Efforts in the preparation of bis-hydrazone palladium complexes have laid the foundation for future investigation of the chiral palladium(II) intermediates. Importantly, the interpretation of the origin of enantioselectivity has been facilitated by computational modeling. The arene-arene interaction has been identified as the culprit of lower selectivity observed for 4-trifluoromethylphenyl substituted ligand 50c. This result implies that eliminating the π-density on the ligand (e.g. cyclohexyl substituent) should enhance the enantioselectivity by raising the transition state energy toward the minor enantiomer.

4 Experimental

4.1 Procedures for Chapter 1