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C2-Symmetric and trans-chelating heterocyclic ligand, 4,4'-disubstituted (dibenzofuran-4,6-diyl)-2,2'-bioxazolines DBFOX. Applications to asymmetric Diels-Alder reactions

Shuji Kanemasa, Yoji Oderaotoshi, Junji Tanaka and Hidetoshi Yamamoto

Institute of Advanced Material Study, Kyushu University, Kasugakoen, Kasuga 816, Japan


Several C2-symmetric bisoxazoline chiral ligands in which two molecules of 4-chiral oxazolines are bound to an appropriate spacer have been prepared. They have been designed to coordinate to a metal ion at the trans-position so that the two chiral oxazolines can produce an effective C2-symmetric space around the metal ion. The efficiency of the metal complexes has been examined in asymmetric hydrosilylation and Diels-Alder reactions.


the proposal of new methodologies by which highly effective chiral induction can be accomplished are now strongly required in the field of catalysed asymmetric synthesis. We now propose a new concept in the molecular design of chiral ligands based on the structure of trans-chelating ligands. Most known chiral ligands are cis-chelating. Their metal complexes have a metal ion which is rather outside of the chiral sphere made by the chiral ligand. This problem would be solved by introducing a trans-chelating ligand. Some preliminary results are presented.

Molecular design

When two molecules of 4-chiral oxazoline rings are bound to a spacer, a variety of chelating ligands are constructed. We selected the four spacers shown in Scheme 1 in the present work. The nitrogen-nitrogen distance is a little longer than 4 A so that metal ions can be tightly captured between the nitrogens. Conformational rigidity of the ligand is also important. On this basis, the DBFOX ligands which involve a dibenzofuran-4,6-diyl spacer have been designed.

Ligand synthesis

Synthesis of the trans-chelating bisoxazoline ligands starts from the corresponding dicarboxylic acids. Scheme 2 shows the synthesis of (R,R)-dibenzofuran-4,6-diyl-bis(4-phenyloxazoline), DBFOX/Ph as a typical example. Commercially available dibenzofuran 1 was lithiated with an excess of butyllithium (3 equiv.) in THF and then treated with carbon dioxide to give dicarboxylic acid 2. This acid 2 is very insoluble in most organic solvents, therefore, a mixture of thionyl chloride and trifluoroacetic acid in DMF was used for its transformation to acid chloride 3. Subsequent reaction with an optically pure amino alcohol and then with thionyl chloride gives chloride 5a. Cyclization of 5a with sodium hydroxide provides DBFOX/Ph in 59% yield based on the dicarboxylic acid 2. Other ligands can be obtained by similar procedures.

Complex formation

In our previous work, the RhIII and RhI complexes were prepared by using ligands A-C. Although the complex formation was confirmed by 1H NMR spectra in which the ring protons of the oxazoline ring were deshielded, their thermodynamic stability was not high enough. Even under heating in dichloromethane they were dissociated to their components together with unidentified and highly insoluble materials. On the other hand, DBFOX/Ph formed highly stable complexes with RhIII, RhI, FeII, Mg, and Zn ions whose formation was again confirmed by similar low field shifts of the corresponding protons. They can be isolated, but their purification by crystallization is so far unsuccessful.

Catalysed reactions

Scheme 4 shows our previous results observed in asymmetric reactions using trans-chelating ligands A-C and DBFOXs. Although the RhIII/A-C complexes showed high catalytic activity in hydrosilylation, racemic alcohols resulted. In contrast, the DBFOX complexes are very inactive, indicating the high thermodynamic stability of the complexes. The RhI/B complex accelerated the Michael addition between 2-methyl-3-oxobutanenitrile and 3-buten-2-one to afford a moderate chiral induction, while the DBFOX complexes were again inactive. DBFOX ligands accelerated the alkylation reactions between diethylzinc and benzaldehyde, but the chiral induction was not effective.

Diels-Alder reactions

Metal complex catalysts of DBFOXs were prepared in situ with copper(II) triflate, magnesium iodide, and iron(III) chloride. The resulting Lewis acid catalysts were utilized in the Diels-Alder reactions of cyclopentadiene 7 with 3-acryloyl-2-oxazolidinone 6a as shown in Scheme 5. The cation complexes of magnesium and iron ions were effective catalysts in the reactions at ­p;40 °C. The shielding substituent at the 4-position of the oxazoline has to be chosen properly, a phenyl substituent being better than an isopropyl moiety. Although the magnesium iodide complex showed a catalytic activity, iron(III) chloride complex did not. Also important was the procedure for cation complexes. The method using magnesium iodide + iodine provided an active catalyst, while AgBF4 was ineffective. The major stereoisomer produced in the DBFOX/Ph-catalysed reaction was characterized to be (4S)-bicyclo[2.2.1]hept-2-ene-4-carboxyamide endo-8a.

The cyclopentadiene Diels-Alder cycloadditions using other oxazolidinone amides 6b-e in the presence of the DBFOX/Ph complex of MgI2/I2 were investigated (Scheme 6). The reactive dienophile 6c showed an absolute chiral induction even at room temperature, while the sluggish substrate 6d gave 8d in low optical yield. Compared with the oxazolidinone amides 6a-e, other chelating dienophiles 9a,b and reactive enals 9c,d resulted in unsatisfactory optical yields (Scheme 7). Monodentate enals 9c,d especially could not be accelerated.

Stability of ligands

It was found that DBFOX ligands were gradually decomposed under the reaction conditions using the magnesium complexes at room temperature. One of the decomposition product was ring-opened 10 (Scheme 8). Although this compound 10 could act as a catalyst in the Diels-Alder reaction, its chiral induction was much less effective than that of DBFOX/Ph. This indicates that the efficiency of chiral induction should be lowered in the latter stage of the reaction, especially if a longer reaction time is required.

Reaction mechanism

Selection of enantiofaces in the above Diels-Alder reactions is well understood when the CHEM3D molecular models for the catalyst/dienophile complexes are utilized. For the complex between the magnesium complex of DBFOX/Ph and 3-acryloyl-2-oxazolidinone, two diastereomeric coordinations of the dienophile are possible. The enantiofaces of the acryloyl moiety are both hindered in the upper complex, while one of the enantiofaces is freely open in the bottom complex. Accordingly, the reaction proceeds through the bottom complex. Dependence of the optical yields observed upon the structures of dienophiles is not so far clear. Any suggestions and comments concerning this point are appreciated.