A Novel Method for the Asymmetric Synthesis of α,α-Disubstituted Alkylamines via Grignard Additions to Ketimines

Journal of Organic Chemistry

Volumn 62, Issue 16, 1997, Pages 5537-5541

  Spero, Denice M ^a   Kapadia, Suresh R ^a  

^a BOEHRINGER INGELHEIM PHARMACEUTICALS INC   (United States)

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[No Author keywords available]

Indexed keywords

EID: 0000935673     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo9623595     Document Type: Article

References (37)

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18. Hua, D. H.; Miao, S. W.; Chen, J. S.; Iguchi, S. J. Org. Chem. 1991, 56, 4. For elegant examples to form cyclic secondary amines see Huffman, M. A.; Yasuda, N.; DeCamp, A. E.; Grabowski, E. J. J. J. Org. Chem. 1995, 60, 1590 and Meyers, A. I. Tetrahedron 1992, 48, 2589
19. Hua, D. H.; Miao, S. W.; Chen, J. S.; Iguchi, S. J. Org. Chem. 1991, 56, 4. For elegant examples to form cyclic secondary amines see Huffman, M. A.; Yasuda, N.; DeCamp, A. E.; Grabowski, E. J. J. J. Org. Chem. 1995, 60, 1590 and Meyers, A. I. Tetrahedron 1992, 48, 2589
20. Hua, D. H.; Miao, S. W.; Chen, J. S.; Iguchi, S. J. Org. Chem. 1991, 56, 4. For elegant examples to form cyclic secondary amines see Huffman, M. A.; Yasuda, N.; DeCamp, A. E.; Grabowski, E. J. J. J. Org. Chem. 1995, 60, 1590 and Meyers, A. I. Tetrahedron 1992, 48, 2589
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24. 2 shows four species present in the following ratios: 21.0% (E imine), 34.9% and 30.8% (cis and trans oxazolidines), and 13.2% (Z imine). Such ratios were determined only for imine 1.
25. Generation of the (o-fluorobenzyl)magnesium chloride in either THF of MTBE gave exclusively benzyl dimer.
26. The absolute configuration of 7 is presumed to be (S) based on a correlation with the biological activity of a closely related series for which an X-ray crystal structure was obtained. All other chiral amines are presumed to have the (S) configuration based on our model.
27. We have observed that the yields for the Grignard additions are slightly higher using 3 equiv of the Grignard reagent rather than 2 equiv. The Grignard reagents typically contain 10% of the unreacted alkyl bromide and 10% of the Wurtz homodimer.
28. Keck, G. E.; Andrus, M. B.; Romer, D. R. J. Org. Chem. 1991, 56, 417.
29. Audoye, P.; Gaset, A.; Lattes, A. J. Organomet. Chem. 1975, 88, 303.
30. 4 oxidation see Pridgen, L. N.; Mokhallalati, M. K. Synth. Commun. 1993, 23, 2055, An alternative facile method which we have developed is to reflux substrate 5a or 5b in a mixture of bleach and EtOH in a sealed vessel. Typical yields for this reaction are 60% and it has the advantage of ease of workup while giving no toxic lead byproducts.
31. 3N (900:100:1) as eluant.
32. Methylation of (S)-phenylglycinol was carried out according to Meyers, A. I.; Poindexter, G. S.; Brich, Z. J. Org. Chem. 1978, 43, 892.
33. Silylation of (S)-phenylglycinol was carried out with TBSCl, imidazole, DMF at 0 °C in 83% yield.
34. Two alternative auxiliaries have been examined, (S)-valinol and (1S,2R)-(+)-norephedrine. (S)-Valinol gives similar results to (S)-phenylglycihol, but (1S,2R)-(+)-norephedrine is a less effective auxiliary. For alternative conditions using (S)-valinol see Sorcek, R.; Lazer, E.; Wong, H.-C.; Spero, D.; Miao, C.; Potocki, I. U.S. Patent 021581, 1996, also, Miao, C.; Potocki, I., submitted for publication.
35. Alternatively, Mg could have an octahedral geometry, and the phenylglycinol oxygen could act as one of the ligands. Mechanistic studies and molecular modeling will be the topic of a future publication.
36. 3 bond, with the large phenyl group blocking the top face of the molecule.
37. We speculate that if the mechanism of enolization involves complexation of the Grignard reagent with the imine nitrogen followed by a syn elimination, the geometry shown in Figure 1 would prevent deprotonation.