Enantioselective addition of Grignard reagents to aldehydes

Article abstract of DOI:10.3390/50300598

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

Full text of DOI:10.3390/50300598

598
Molecules 2000, 5
Enantioselective Addition of Grignard Reagents to Aldehydes
Pablo Englebienne, Hernan Schulz and Norma Nudelman
Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos
Aires. Pabellón II, Piso 3. Ciudad Universitaria. 1428. Buenos Aires, Argentina
E-mail: nudelman@qo.fcen.uba.ar
Abstract: The addition of Grignard reagents to aldehydes in the presence of chiral aminoal-
cohols 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 -78ºC. 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 pres-
ence of asymmetric ligands derived from 2-aminobutanol and ephedrine in different solvents and rea-
gent:ligand:substrate ratio (see Table ). Several new ligands were designed and synthesized.

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Molecules 2000, 5
Table. Reactions of PrMgBr with 3-phenylpropanal, 1, and benzaldehyde, 2, in the presence of chiral
ligands.
Chiral
Alde-
hyde
Reagent:Ligand: Solvent Yield Absolute Con-
%
ee
5
2
5
7
3
8
Liganda
Aldehyde ratio
1.2:0.2:1.0
2.0:0.5:1.0
1.2:0.2:1.0
1.2:0.2:1.0
4.0:2.0:1.0
4.0:2.0:1.0
6.0:2.0:1.0
6.0:2.0:1.0
4.0:2.0:1.0
3.0:1.0:1.0
(%)
77
98
98
100
98
90
85
figuration
S-(+)
R-(-)
toluene
ether
toluene
ether
THF
THF
toluene
toluene
THF
3
4
5
1
1
1
1
2
1
1
2
2
1
S-(+)
S-(+)
R-(+)
S-(+)
S-(+)
S-(-)
6
7
29
40
9
51
60
96
R-(+)
R-(-)
8
9
toluene
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.
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 sub-
stitution 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 conforma-
tional 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.