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Novel chiral pyrazole ligands for enantioselective addition of diethylzinc to benzaldehyde

Hiyoshizo Kotsuki,* Masahiro Wakao and Hiroyuki Hayakawa

Department of Chemistry, Faculty of Science, Kochi University, Akebono-cho, Kochi 780, Japan


The molecular design of enantiomerically pure chiral ligands for use in catalytic asymmetric reactions is one of the most challenging issues in modern organic chemistry.1 In our extensive efforts in this area, we recently disclosed an efficient procedure to obtain chiral pyridine,2 diamine,3 and diazole derivatives.4 Herein, we describe a general procedure for preparing a variety of chiral diazole ligands having an alcoholic side chain and also demonstrate their utility in catalytic asymmetric alkylation of benzaldehyde with diethylzinc.

Results and discussion

Our new procedure for the synthesis of chiral diazole derivative ligands relies on high pressure promoted N-alkylation of pyrazoles or imidazoles with optically active epoxides as depicted in Scheme 1.5

The results are summarized in Table 1. For example, the reaction of (+)-camphorpyrazole 46 with (R)-(+)-styrene oxide 5 at 10 kbar in the presence of 1.0 equiv. of Bu4NF gave 16, mp 150.5-152 oC (from hexane-Et2O); [a]25D +65.7 (c 0.35, EtOH), and 17, [a]25D +47.8 (c 1.38, EtOH), in 41 and 50% yield, respectively (Run 6). Similarly, other derivatives were also prepared without difficulty.

With these ligands in hand, the catalytic activities of 11-23 for the enantioselective addition of diethylzinc to benzaldehyde was then examined (Scheme 2 and Table 2).7

As expected, a relatively high enantiomeric excess (83% ee) was obtained when the pyrazolyl ligand 11 was employed as a chiral catalyst (Entry 1), whereas the corresponding imidazole homologues were all fruitless (Entries 6 and 7). These results can be understood by considering the favourable coordination structure of 11 to form a six-membered organozinc intermediate. After numerous attempts to improve the enantioselectivity, we finally found that the sterically congested ligand 16 gave the best result: 93% ee was achieved in favour of an R-enantiomer (Entry 10). Interestingly, simply by using the diastereomer 18, in which the stereogenic carbon centre bearing a hydroxy function has an S-configuration, the completely reversed enantioselectivity was effected in 93% ee (Entry 14). Interestingly, the catalytic activity of these ligands survived even at low concentration (0.05 equiv., Entries 12 and 16).

From these results, we proposed the transition state structures for the present reaction as outlined in Fig. 1 wherein the steric environment around the hydroxy group plays an important role to provide the desired enantioselectivity.


We were successful in developing a convenient method to synthesize a variety of diazole chiral ligands using high pressure-promoted epoxide opening reactions, and in clarifying the novel catalytic activity of these ligands in enantioselective addition of diethylzinc to benzaldehyde. The best results for the chiral catalysts 16 and 18 were 93% ee in either case, wherein reversed asymmetric induction was achieved. In view of the ready accessibility of these chiral ligands, the present method offers potential utility for the design of other types of chiral ligands.


The present work was partially supported by Scientific Research Grants (Nos. 05453063 and 07304047) from the Ministry of Education, Science and Culture of Japan. We also thank the Asahi Glass Foundation and the Naito Foundation for financial support of this work.


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  2. Kotsuki, H.; Nakagawa, Y.; Moriya, N.; Tateishi, H.; Ochi, M.; Suzuki, T.; Isobe, K. Tetrahedron: Asymmetry, 1995, 6, 1165.
  3. Kotsuki, H.; Kuzume, H.; Gohda, T.; Fukuhara, M.; Ochi, M.; Oishi, T.; Hirama, M.; Shiro, M. Tetrahedron: Asymmetry, 1995, 6, 2227.
  4. Kotsuki, H.; Hayakawa, H.; Wakao, M.; Shimanouchi, T.; Ochi, M. Tetrahedron: Asymmetry, 1995, 6, 2665.
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