[118949-61-4]  · C17H23N3O2  · (MW 301.38)

(reagent used as a ligand for various asymmetric metal-catalyzed reactions)

Physical Data: crystalline solid, mp 152-153 °C; [a]D26 -116.8 (c 1.01, CH2Cl2).

Solubility: soluble in most organic solvents.

Form Supplied in: solid; commercially available.

Handling, Storage, and Precautions: toxicity unknown; as with all organic chemicals, use only in a well-ventilated fume hood is recommended.

Iso-propyl-substituted pyridinyl bisoxazoline (1) has been used exclusively as a ligand for metals, primarily late transition metals and lanthanides. The resulting complexes are effective in a variety of enantioselective transformations.

Reductive Transformations

The utility of 1 was first demonstrated in the enantioselective hydrosilylation of ketones. Uniformly high enantioselectivity, yield, and turnover were observed for aromatic (and some aliphatic) ketones when using the complex derived from RhCl3 (1).1 Lower enantioselection is observed with t-Bu-pybox or i-Pr-pybox·cobalt(I).2 The derived 1·Sn(OTf)2 complex gives alcohol products with up to 58% ee using methanolic polymethylhydrosiloxane.3 A cationic ruthenium(III) catalyst diverts the usual reduction pathway to enolsilane formation, particularly when the nature of the silane is modified (2).4

Oxidative Transformations

The use of 1 in enantioselective oxidations remains limited at the present time. Among the promising developments, allylic perester oxidation proceeds with significant enantioselection.5 The copper(I)-catalyzed oxidation of cyclohexene furnished the protected cyclic allylic alcohol with modest enantioselection (3).6

Epoxidation of simple olefins can be effected using a ruthenium catalyst employing a mixed ligand system (4).7 Using this method, epoxystilbene was generated in 74% ee. Bis(acetoxy)iodobenzene is used as the oxidant in the enantioselective epoxidation of trans-stilbene. Both homogeneous and heterogeneous aziridination proceed with low levels of enantioselection using 1.8

Carbon-Carbon Bond Forming Reactions

The effectiveness of 1 in asymmetric transformations is most pronounced in those resulting in the formation of carbon-carbon bonds. Highly enantioselective aldol addition of enolsilanes to benzyloxyacetaldehyde and 1,2-diketones are possible (5).9 Use of less nucleophilic olefins is less effective as evidenced by low levels of enantioselection in the glyoxylate ene reaction.10 Organometal addition to aldehydes using diethylzinc11 and allylindium reagents are moderately effective, with the latter providing homollylic alcohols in 92% ee with stoichiometric cerium(III) triflate hydrate.12 1,2-Addition of phenyllithium or phenylmagnesium bromide to a discrete i-Pr-pybox ruthenium(III)-acrolein complex furnished the allylic alcohol in 63-87% ee.13 Cyanohydrin synthesis with metal complexes of 1 can be effective. Although the aluminum(III) complex of 1 provides the silylated cyanohydrin in moderate ee, recent studies using lanthanides offer a slight improvement (to 89% ee).14

Alkylation reactions of ketones and esters using 1 have been reported with good enantioselection. Free radical-mediated alkylation of a g-lactam proceeded with good enantioselection (6).15 Malonate alkylation provides the 1,3-diphenyl allylation product with 86% ee (45% yield) through the intermediacy of the 1·Pd(0) complex.16

Numerous highly enantioselective ring-forming reactions have also been discovered with the assistance of 1. Cyclopropanation with the rhodium complex of 1 furnishes trans-cyclopropanes selectively (7).17 A discrete ruthenium vinyl carbene was similarly successful in the stoichiometric cyclopropanation,18 whereas enantioselection in the copper(I)-catalyzed variant was nonselective.19

Both Diels-Alder and hetero-Diels-Alder reactions can be rendered stereoselective using 1·copper(II) salts, but inferior levels of stereoselection were observed relative to other pybox derivatives.20 Lanthanide-catalyzed 1,3-dipolar cycloaddition also exhibited moderate (61%) enantioselection.21

Lanthanide catalysis was again effective in ring-opening reactions of cyclic epoxides (8). Finally, MAO-activated 1·RuCl3 provides block copolymers of ethylene and hex-1-ene.22

1. (a) Nishiyama, H.; Sakaguchi, H.; Nakamura, T.; Horihata, M.; Kondo, M.; Itoh, K., Organometallics 1989, 8, 846. (b) Nishiyama, H.; Kondo, M.; Nakamura, T.; Itoh, K., Organometallics 1991, 10, 500.
2. Brunner, H.; Amberger, K., J. Organometallic Chem. 1991, 417, C63.
3. Lawrence, N. J.; Bushell, S. M., Tetrahedron Lett. 2000, 41, 4507.
4. Nagashima, H.; Ueda, T.; Nishiyama, H.; Itoh, K., Chem. Lett. 1993, 347.
5. Schulz, M.; Kluge, R.; Gelalcha, F. G., Tetrahedron: Asymm. 1998, 9, 4341.
6. Gokhale, A. S.; Minidis, A. B. E.; Pfaltz, A., Tetrahedron Lett. 1995, 36, 1831.
7. Nishiyama, H.; Shimada, T.; Itoh, H.; Sugiyama, H.; Motoyama, Y., Chem. Commun. 1997, 1863.
8. (a) Rasmussen, K. G.; Jorgensen, K. A., J. Chem. Soc., Perkin Trans. I 1997, 1287. (b) Langham, C.; Piaggio, P.; Bethell, D.; Lee, D. F.; McMorn, P.; Bulman Page, P. C.; Witlock, D. J.; Sly, C.; Hancock, F. E.; King, F.; Hutchings, G., J. Chem. Commun. 1998, 1601.
9. (a) Evans, D. A.; Kozlowski, M. C.; Murry, J. A.; Burgey, C. S.; Campos, K. R.; Connell, B. T.; Staples, R. J., J. Am. Chem. Soc. 1999, 121, 669. (b) Evans, D. A.; Burgey, C. S.; Kozlowski, M. C.; Tregay, S. W., J. Am. Chem. Soc. 1999, 121, 686.
10. Qian, C.; Wang, L., Tetrahedron: Asymm. 2000, 10, 2347.
11. Ding, K.; Ishii, A.; Mikami, K., Angew. Chem., Int. Ed. Engl. 1999, 38, 497.
12. Loh, T. P.; Zhou, J. R., Tetrahedron Lett. 1999, 40, 9115.
13. Motoyama, Y.; Kurihara, O.; Murata, K.; Aoki, K.; Nishiyama, H., Organometallics 2000, 19, 1025.
14. (a) Iovel, I.; Popelis, Y.; Fleisher, M.; Lukevics, E., Tetrahedron: Asymm. 1997, 8, 1279. (b) Aspinall, H. C.; Greeves, N.; Smith, P. M., Tetrahedron Lett. 1999, 40, 1763.
15. Porter, N. A.; Feng, H.; Kavrakova, I. K., Tetrahedron Lett. 1999, 40, 6713.
16. Chelucci, G.; Deriu, S.; Pinna, G. A.; Saba, A.; Valenti, R., Tetrahedron Lett. 1999, 10, 3803.
17. (a) Nishiyama, H.; Itoh, Y.; Matsumoto, H.; Park, S. B.; Itoh, K., J. Am. Chem. Soc. 1994, 116, 2223. (b) Nishiyama, H.; Itoh, Y.; Sugawara, Y.; Matsumoto, H.; Aoki, K.; Itoh, K., Bull. Chem. Soc. Jpn. 1995, 68, 1247.
18. Nishiyama, H.; Park, S. B.; Itoh, K., Chem. Lett. 1995, 599.
19. Muller, P.; Bolea, C., Synlett 2000, 6, 826.
20. (a) Evans, D. A.; Barnes, D. M.; Johnson, J. S.; Lectka, T.; von Matt, P.; Miller, S. J.; Murry, J. A.; Norcross, R. D.; Shaughnessy, E. A.; Campos, K. R., J. Am. Chem. Soc. 1999, 121, 7582. (b) Qian, C.; Wang, L., Tetrahedron Lett. 2000, 41, 2203.
21. Sanchez-Blanko, A. I.; Gothelf, K. V.; Jorgensen, K. A., Tetrahedron Lett. 1997, 38, 7923.
22. Nomura, K.; Sikokmai, W.; Imanishi, Y., Bull. Chem. Soc. Jpn. 2000, 73, 599.

Jeffrey N. Johnston

Indiana University, Bloomington, Indiana, USA

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.