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46157-G1
Chiral Acyclic Carbene Ligands for the Asymmetric Suzuki Coupling Reaction

Sukwon Hong, University of Florida

I. Result Summary

1.1. Synthesis of Acyclic Carbene-Pd complexes. The novel electron rich acyclic diaminocarbenes (ADC) based on C₂-symmetric azacycles were designed to create a chiral environment close to the metal center. We first explored synthetic routes to these acyclic carbene architectures using 2-substituted pyrrolidines (1) either commercially available (R = Me, CHPh₂) or prepared from reduction of the 5-alkylpyrrolidin-2-one compounds (R= i-Pr, CH₂Ph) (Scheme 1). Deprotonation of the formamidinium ion (3) with LDA was unsuccessful although we didn't extensively screen different bases or reaction conditions. On the other hand, oxidative addition of the chloroamidinium ion (5) by Pd(PPh₃)₄  proceeded smoothly to form the chiral ADC Pd complex, [(ADC)Pd(PPh₃)₂Cl]⁺BF₄^- (6-Me-Pd) which was characterized by X-ray crystallography (Figure 1B). Note that X-ray structures of ureas show alkyl substituents at the 2-positions are located at the proximal side to carbonyl (Figure 1A), however, when complexed with Pd(PPh₃)₄, the alkyl substituents moved to the distal side to carbonyl apparently reducing steric interactions with PPh₃ ligands.  The ADC-Pd complex is an active catalyst for sterically demanding asymmetric Suzuki coupling reactions, however, observed enantiomeric excesses were low (5-7% ee) presumably due to the conformational flexibility.

C₂-symmetric trans-2,5-diphenylpyrrolidine (12-Ph) was prepared by the known methods. Attempts at synthesis of a tetra-alkyl-substituted urea (13-Ph) using phosgene were unsuccessful, affording a surprisingly stable carbamoyl chloride compound (14) instead. The tetra-alkyl-substituted urea formation seems to be sensitive to steric demands.     

1.2. Biisoquinoline-based chiral diaminocarbene ligands. We have synthesized several biisoquinoline-based tricyclic chiral diaminocarbene ligands (BIQ) and their Pd and Cu complexes. The chiral environment is created in close proximity to the metal center, which is confirmed by an X-ray crystal structure (Figure 2). This feature can be clearly seen from the overlaid X-ray structures of an imidazolidine-based carbene ligand and the BIQ ligand (Figure 2B). The concise ligand synthesis is highlighted by a modified Bischler-Napieralski cyclization of bisamides (16) prepared from readily available chiral phenethylamines (15), and allows easy variation of the stereodifferentiating groups (Scheme 3). After a brief survey of reaction conditions and ligand structures, it was found that the cyclohexyl-BIQ-copper complex is an efficient catalyst for enantioselective S_N2' allylic alkylation with Grignard reagents, showing S_N2' regioselectivity higher than 5:1 and enantioselectivity in the range of 68-77% ee (Table 1). In addition, when the dihydroimidazolium-based chiral NHC ligand was tested under the same reaction conditions, similarly high S_N2' regioselectivity (90:10) was obtained but the observed enantioselectivity (26% ee) was lower than those with BIQ ligands (eq. 1).

 1.3. In situ generation of the Cu-carbene catalyst from a chloroamidinium ion and CuCl. While we were screening the reaction conditions, we found that CuCl₂ gave almost identical results compared to CuCl (Scheme 4). Rather surprisingly, the X-ray structure obtained from a single crystal of CuCl₂ complex was not the carbene-Cu(II) complex but an ion pair of the chloroimidazolium cation and [CuCl₂]^- anion (27) (Figure 3). When chloroamidinium ions were mixed with CuCl₂ (or CuCl or CuTC) and used in the allylic alkylation reaction of Grignard reagent, allylic alkylation products were obtained in high yields with excellent S_N2′ regioselectivity, suggesting that presumably the active Cu-carbene catalyst might be generated in situ from the chloroamidinium salt and CuCl₂ (or CuCl) in the presence of Grignard reagent (eq. 2). It is important to note that the acyclic carbene-Cu complexes can be easily generated by this route and the chloroamidinium ions can be prepared from the corresponding ureas. Currently, we are studying asymmetric catalysis by chiral acyclic carbene-Cu complexes prepared through this in-situ generation route.

II. Impact on the Principal Investigator's Career 

The ACS PRF grant has been very helpful to initiate the proposed research project. This grant made possible a research assistantship for one graduate student (David R. Snead) during the summer of 2007 and resulted in one publication and three other manuscripts in various stages of publications. Thanks to the early support by ACS-PRF, we obtained important preliminary results, and this research is evolved into other research program that is now funded by Florida Department of Health (James & Esther King Biomedical Research Program) for the next three years.        

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