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Molecules 2000, 5(3), 598-599; doi:10.3390/50300598

Article
Enantioselective Addition of Grignard Reagents to Aldehydes
Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires. Pabellón II, Piso 3. Ciudad Universitaria. 1428. Buenos Aires, Argentina
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Author to whom correspondence should be addressed.
Published: 22 March 2000

Abstract

:
The addition of Grignard reagents to aldehydes in the presence of chiral aminoalcohols shows a moderate enantioselectivity. The study carried out with a series of ligands allows the correlation between the structural characteristics and their reactivity.

Introduction

The use of chiral aminoalcohol to lead asymmetrically nucleophilic additions of organometallics to carbonyl compounds is a field of great potentiality in synthesis [1]. It is based on the coordination of amines and ethers to organolithium and Grignard reagents; the efficiency of the asymmetric induction depends, among other factors, on the characteristics of the metal [2], its aggregation state [3] and on the chiral ligand structure [4].

Experimental

General Procedure

To a mixture of 1 mmol of aldehyde and the corresponding amount of chiral ligand in the reaction solvent, 1.7 mL of a 0.6M of PrMgBr in the same solvent were added at -78°C. The quenching was carried out using 1 mL of HCl 5%. The products in the reaction mixture were investigated by GC and polarimetry.

Results and Discussion

The addition of PrMgBr to 3-phenylpropanal, 1, and benzaldehyde, 2, was carried out in the presence of asymmetric ligands derived from 2-aminobutanol and ephedrine in different solvents and reagent:ligand:substrate ratio (see Table ). Several new ligands were designed and synthesized.
Several conclusions can be extracted from this table:
  • Donor solvents influence negatively the effectivity of the asymmetric catalysis, likely because these solvents compete in the coordination of the attacking reagent.
  • The ligands with two asymmetric centers have higher effect in the asymmetric addition. The substitution by bigger groups in the nitrogen leads to lower selectivities.
  • The use of oxazolidines does not lead to fine enantiomeric excess, probably due to the conformational rigidity.
  • The asymmetric induction in the formation of aromatic secondary alcohols is more pronounced than in the aliphatic secondary alcohols.

Acknowledgements:

H.S. is a grateful recipient of a fellowship from the Universidad de Buenos Aires. Financial support from the UBA, CONICET, ANPCyT and the CEE is gratefully acknowledged.

References and Notes

  1. Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 2282.
  2. Yanagisawa, A.; Nakashima, H.; Ishiba, A.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 4723.
  3. Nudelman, N. S.; Schulz, H. G.; García, G. V. J. Phys. Org. Chem. 1998, 11, 722.
  4. Prasad, K. R. K.; Joshi, N. N. J. Org. Chem. 1997, 62, 3770.
Table. Reactions of PrMgBr with 3-phenylpropanal, 1, and benzaldehyde, 2, in the presence of chiral ligands.
Table. Reactions of PrMgBr with 3-phenylpropanal, 1, and benzaldehyde, 2, in the presence of chiral ligands.
Chiral LigandaAlde-hydeReagent:Ligand: Aldehyde ratioSolventYield (%)Absolute Con-figuration% ee
311.2:0.2:1.0toluene77S-(+)5
412.0:0.5:1.0ether98R-(-)2
511.2:0.2:1.0toluene98S-(+)5
11.2:0.2:1.0ether100S-(+)7
624.0:2.0:1.0THF98R-(+)3
714.0:2.0:1.0THF90S-(+)8
16.0:2.0:1.0toluene85S-(+)29
26.0:2.0:1.0toluene51S-(-)40
824.0:2.0:1.0THF60R-(+)9
913.0:1.0:1.0toluene96R-(-)2
a 3 = (-)-2-dipropylaminobutanol, 4 = (-)-(1-benciloxymethylpropyl)-dipropylamine, 5 = (-)-4-ethyl-2,2-dimethyl-oxazolidine, 6 = (-)-ephedrine, 7 = (-)-pseudoephedrine, 8 = (-)-2,2,3,4-tetramethyl-5-phenyl-oxazolidine, 9 = (-)-N-propylephedrine.
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