[131833-90-4]  · C13H22N2O2  · (MW 238.33)

(chiral ligand for enantiocontrol of metal-catalyzed reactions)

Physical Data: [a]D20 -113 (c 1.08, CH2Cl2).

Solubility: soluble in most organic solvents.

Form Supplied in: clear, oily, low-melting solid.

Preparative Methods: Bis[(4S)-(1-methylethyl)oxazolin-2-yl]methane is prepared by acylation of L-valinol followed by cyclization (1).1,2,3 Thus, transamination of dimethyl malonate with 2 equiv of L-valinol afforded the corresponding amide in 72% yield. Chlorination with SOCl2 followed by cyclization with LiOMe in refluxing MeOH afforded bis[(4S)-(1-methylethyl)oxazolin-2-yl]methane in 79% yield.

Handling, Storage, and Precautions: stable at ambient temperature.

Bis(oxazoline)-Metal Complexes

Metal complexes of bis[(4S)-(1-methylethyl)oxazolin-2-yl]methane are efficient catalysts in numerous asymmetric reactions. The ligand-metal complex is prepared in situ by mixing the metal salt and ligand. The formation of a monomeric or dimeric complex depends upon the reaction conditions and the reactivity of the metal ion. In the asymmetric reaction, the C2-symmetric axis in the ligand minimizes the number of possible transition states in a reaction.4 The metal chelate is conformationally constrained and the chiral centers are located in close proximity to the donor ligands, thereby imposing a strong directing effect on the catalytic site. The metal complexes of bis[(4S)-(1-methylethyl)oxazolin-2-yl]methane with Ti(IV),5 zinc(II)6 and magnesium(II)7 have been reported.

The Ti(IV) complexes were prepared by treatment of bis[(4S)-(1-methylethyl)oxazolin-2-yl]methane with TiX4 (X=Cl, NEt2, O-i-Pr) in toluene. In the infrared spectra the absence of absorption for an (NH) vibration in the region 3500-3200 cm-1, suggests that the ligand is deprotonated. The presence of absorption due to the (C=N) and (C=C) vibrations in the region 1602-1540 cm-1 indicate a bidentate ligand pattern.8 The far-infrared region contains contributions from (Ti-O) at 472 cm-1, (Ti-N)9 at 360 cm-1 and (Ti-Cl)10 at 280 cm-1 supporting a monomeric trigonal bipyramidal structure where the ligand is coordinated to Ti(IV) in a bidentate fashion and the nitrogen atoms of the ligand occupy the equatorial sites. The structure of the TiX3L complex (X=Cl, O-i-Pr2, NEt2) is shown (reprinted from reference 5, pg 157 and 160, by courtesy of Marcel Decker. Inc.).

The zinc(II) complex ClZnL was prepared by treatment of EtZnCl with bis[(4S)-(1-methylethyl)oxazolin-2-yl]methane. Treatment of ClZnL with 1.0 or 2.0 equiv of PhSH yielded (PhS)ZnL and (PhS)2ZnLH, respectively. The infrared spectra of ClZnL and (PhS)ZnL reveal that the ligand acts as a bidentate donor to zinc(II). However, the infrared spectra of (PhS)2ZnLH show a band at 3200 cm-1 due to coordinated (NH) and bands at 1660-1550 cm-1 due to (C=N) and (C=C) vibrations. Contributions from (Zn-N)11 at 485-470 cm-1, (Zn-S)12 at 388-355 cm-1 and (Zn-Cl)13 at 280-260 cm-1 are also evident, consistent with a dimeric structure for ClZnL and (PhS)ZnL and a monomeric structure for (PhS)2ZnLH.

The magnesium(II) complex ClMgL was prepared by treatment of EtMgCl with bis[(4S)-(1-methylethyl)oxazolin-2-yl]methane. Treatment of Et2Mg with 1.0 or 2.0 equiv bis[(4S)-(1-methylethyl)oxazolin-2-yl]methane afforded EtMgL and MgL2, respectively. As observed with the other complexes, the infrared spectra reveal that the ligand acts as a bidentate donor to magnesium(II).14 The far infrared region contains contributions from (Mg-C)15 at 820 cm-1, (Mg-N)16 at 355 cm-1 and (Mg-Cl)17 at 280 cm-1, consistent with a dimeric structure for ClMgL and EtMgL and a monomeric structure for MgL2) (reprinted from reference 7, p 1716, with permission from Elsevier Science).

The 1H and 13C NMR data for all complexes are similar. The most significant difference in 1H NMR spectra of the complexes relative to the free ligand is the shift in the C-CH2-C of the ligand from d 3.3 ppm to d 4.7 ppm for C-CH-C in the complex upon deprotonation (2). In the 13C NMR spectra, the CH2 carbon of C-CH2-C appeared at d 28.4 ppm in the free ligand but was shifted to d 55 ppm upon complexation. In addition, the carbon resonance due to C=N which appeared in the ligand at d 161 ppm shifted to d 172 ppm. It is interesting to note that 13C NMR spectra of (PhS)2ZnLH showed little shifting due to the coordination of the ligand in the protonated form.

A carboxylate-bridged triiron(II) complex of bis[(4S)-(1-methylethyl)oxazolin-2-yl]methane has also been prepared and its antiferromagnetic properties examined.18

Asymmetric Reactions19


A number of reports on the use of bis[(4S)-(1-methylethyl)oxazolin-2-yl]methane in the asymmetric cyclopropanation of styrene have been reported (3, 1).20 Although the yields of the cyclopropanes are good, the enantioselectivities are not as high as those observed with other bis(oxazoline) ligands.2,20


Epoxidation of styrene or stilbene with the ruthenium [RuCl2(cod)L] complex of bis[(4S)-(1-methylethyl)oxazolin-2-yl]methane afforded only racemic epoxide, suggesting that the reaction is not metal centered.21 In fact, mechanistic studies of this reaction indicate that the metal acts as a promoter for the production of i-PrO3H and that it is this species that carries out the epoxidation, either directly or by the formation of an intermediate oxo-ruthenium species.

Allylation and Addition Reactions

The enantioselective allylzincation of cyclopropyl acetals catalyzed by bis[(4S)-(1-methylethyl)oxazolin-2-yl]methane has been reported (4, 2).22 The allylzinc complex, prepared by reaction of deprotonated ligand with allylzinc bromide, reacted readily with cyclopropenone acetals 1 and 2 at room temperature to provide the optically active cyclopropanone acetals in good yield and high enantioselectivity (2, entries 1-6). The ethyl-substituted cyclopropenone acetal 3 afforded the optically active cyclopropanone acetal possessing a quaternary chiral center (2, entry 7).

The chiral allylzinc complex also reacts with chiral aldimines to afford allylated secondary amines in high enantioselectivity.23 For the acyclic (E)-benzaldehyde N-phenylimine, the amine was obtained in high yield (95%), although the enantioselectivity was low (6%) (5). However cyclic imines afforded good yields and enantioselectivities (6 and 7).

The reaction is thought to proceed through a chair-like transition state in which the steric interactions between the imine substituents and the C4-substitutent of the ligand are minimized. This model is consistent with the observed selectivities.

(5-7, the transition state model, and portions of the text relating to allylzincation reactions of bis[(4S)-(1-methylethyl)oxazolin-2-yl]methane were reproduced from reference 21 with permission from Elsevier Science.)


Enantioselective hydrosilylation of acetophenone using either bis[(4S)-(1-methylethyl)oxazolin-2-yl]methane or its rhodium(I) complex has been reported, although the enantioselectivity was only 12% (8).24

Reduction of a-Alkoxy Ketones

Enantioselective reduction of a-alkoxy ketones with catecholborane and the Zn(OTf)2-ligand complex afforded the diol in 70% yield albeit with low enantioselectivity (15%) (9).25

Radical Cyclizations

Cyclization of N-trichloroacetamides using copper(I)-bis[(4S)-(1-methylethyl)oxazolin-2-yl]methane complex afforded the corresponding g-lactams in high yield (85-95%) but low diastereoselectivity (6%) (10).26

Incorporation of substituents in the alkenyl side chain resulted in the formation of the trans-g- and d-lactams in high conversion and 60% diastereoselectivity (11 and 12). In all experiments, the diastereoselectivity was similar to that previously reported by Nagashima et al.27 using a 2,2-bipyridine complex.

Synthesis of Optically Active Polyguanidines

Polyguanidines have been prepared from achiral carbodimiides using the copper(II)-bis[(4S)-(1-methylethyl)oxazolin-2-yl]methane as a catalyst, although the yield and enantioselectivity was low (13).28

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3. Helmchen, G.; Krotz, A.; Ganz, K. T.; Hansen, D., Synlett 1991, 4, 257.
4. Whitesell, J. K., Chem. Rev. 1989, 89, 1581.
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6. Singh, R. P., Bull. Soc. Chim. Fr. 1997, 134, 765.
7. Singh, R. P., Spectrochimica Acta A 1997, 53, 1713.
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16. Einarsrud, M. A.; Justnes, H.; Tytter, E.; Oyb, H. A., Polyhedron 1987, 6, 975.
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19. Lowenthal, R. E.; Abiko, A.; Masamune, S., Tetrahedron Lett. 1990, 31, 6005.
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21. (a) Nakamura, M.; Arai, M.; Nakamura, E., J. Am. Chem. Soc. 1995, 117, 1179. (b) Nakamura, M.; Inoue, T.; Sato, A.; Nakamura, E., Org. Lett. 2000, 2, 2193.
22. Nakamura, M.; Hirai, A.; Nakamura, E., J. Am. Chem. Soc. 1996, 118, 8489.
23. Bandini, M.; Cozzi, P. G.; de Angelis, M.; Umani-Ronchi, A., Tetrahedron Lett. 2000, 41, 1601.
24. Clark, A. J.; De Campo, F.; Deeth, R. J.; Filik, R. P.; Gatard, S.; Hunt, N. A.; Lastécouères, D.; Thomas, G. H.; Verlhac, J.-B.; Wongtap, H., J. Chem. Soc. Perkin Trans. 1. 2000, 5, 671.
25. Nagashima, H.; Ozaki, N.; Ishii, M.; Seki, K.; Washiyama, M.; Itoh, K., J. Org. Chem. 1993, 58, 464.
26. Heintz, A. M.; Novak, B. M., Polym. Prepr. (Am. Chem. Soc., Div. Polym. Chem) 1998, 39, 429.

Margaret M. Faul

Eli Lilly and Company, Indianapolis, Indiana, USA

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