ORGANIC
LETTERS
2007
Vol. 9, No. 13
2529-2531
A Facile and Modular Synthesis of
Phosphinooxazoline Ligands
Kousuke Tani, Douglas C. Behenna, Ryan M. McFadden, and Brian M. Stoltz*
The Arnold and Mabel Beckman Laboratories of Chemical Synthesis, DiVision of
Chemistry and Chemical Engineering, California Institute of Technology,
Pasadena, California 91125
Received April 16, 2007
ABSTRACT
The copper(I) iodide catalyzed phosphine/aryl halide coupling procedure of Buchwald et al. provides modular, robust, and scaleable access
to phosphinooxazoline (PHOX) ligands. The advantages of this method are highlighted by the convenient synthesis of PHOX ligands with
varied steric and electronic properties, which would be challenging to synthesize by other protocols.
Phosphinooxazoline (PHOX) ligands, pioneered by Pfaltz,
Helmchen, and Williams,1 have become a preeminent class
of N/P ligands in organometallic transformations, such as
allylic alkylation2 and amination,3 Heck reactions,4 Diels-
Alder5 and [3+2] dipolar cycloadditions,6 Ru-based transfer
hydrogenation,7 and Ir-catalyzed hydrogenation.8 During our
recent research into enantioselective Tsuji allylation and
decarboxylative protonation,9 we desired ready access to
PHOX ligands of varied structure and in substantial quantity.
Herein, we demonstrate the utility of Buchwald’s P-C bond-
forming reaction for the synthesis of a wide range of
sterically and electronically varied PHOX ligands.10
Despite the broad utility of PHOX ligands and the
multitude of known derivatives, access to certain substitution
patterns on the ligand framework was challenging using the
common synthetic methods for uniting the diarylphosphine
and phenyloxazoline fragments.11 Most commonly, the P-C
bond was formed by anionic displacement, with a phosphine
anion displacing an aryl fluoride, or by organometallic (e.g.,
Grignard or organolithium) displacement of a chlorophos-
phine (Scheme 1). In our hands, both routes had significant
(1) (a) von Matt, P.; Pfaltz, A. Angew. Chem., Int. Ed. 1993, 32, 566-
568. (b) Sprinz, J.; Helmchen, G. Tetrahedron Lett. 1993, 34, 1769-1772.
(c) Dawson, G. J.; Frost, C. G.; Coote, S. J.; Williams, J. M. J. Tetrahedron
Lett. 1993, 34, 3149-3150.
(2) (a) Garc´ıa-Yebra, C.; Janssen, J. P.; Rominger, F.; Helmchen, G.
Organometallics 2004, 23, 5459-5470. (b) Bartels, B.; Helmchen, G. Chem.
Commun. 1999, 741-742. (c) Blacker, A. J.; Clark, M. L.; Loft, M. S.;
Williams, J. M. J. Chem. Commun. 1999, 913-914. (d) Pre´toˆt, R.; Lloyd-
Jones, G. C.; Pfaltz, A. Pure Appl. Chem. 1998, 70, 1035-1040. (e) See
also ref 2. For an excellent review see: Helmchen, G.; Pfaltz, A. Acc. Chem.
Res. 2000, 33, 336-345.
(8) (a) Lightfoot, A.; Schnider, P.; Pfaltz, A. Angew. Chem., Int. Ed.
1998, 37, 2897-2899. (b) Kainz, S.; Brinkmann, A.; Leitner, W.; Pfaltz,
A. J. Am. Chem. Soc. 1999, 121, 6421-6429.
(9) (a) Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126,
15044-15045. (b) Mohr, J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B.
M. Angew. Chem., Int. Ed. 2005, 44, 6924-6927. (c) Mohr, J. T.; Nishimata,
T.; Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11348-
11349.
(10) Gelman, D.; Jiang, L.; Buchwald, S. L. Org. Lett. 2003, 5, 2315-
2318.
(11) Peer, M.; de Jong, J. C.; Kiefer, M.; Langer, T.; Rieck, H.; Schell,
H.; Sennhenn, P.; Sprinz, J.; Steinhagen, H.; Wiese, B.; Helmchen, G.
Tetrahedron 1996, 52, 7547-7583.
(3) Welter, C.; Koch, O.; Lipowsky, G.; Helmchen, G. Chem. Commun.
2004, 896-897.
(4) (a) Loiseleur, O.; Hayashi, M.; Keenan, M.; Schmees, N.; Pfaltz, A.
J. Organomet. Chem. 1999, 576, 16-22. (b) Ripa, L.; Hallberg, A. J. Org.
Chem. 1997, 62, 595-602.
(5) (a) Hiroi, K.; Watanabe, K. Tetrahedron: Asymmetry 2002, 13, 1841-
1843. (b) Carmona, D.; Lahoz, F. J.; Elipe, S.; Oro, L. A. Organometallics
2002, 21, 5100-5114.
(6) Stohler, R.; Wahl, F.; Pfaltz, A. Synthesis 2005, 1431-1436.
(7) (a) Langer, T.; Helmchen, G. Tetrahedron Lett. 1996, 37, 1381-
1384. (b) Sammakia, T.; Stangeland, E. L. J. Org. Chem. 1997, 62, 6104-
6105.
10.1021/ol070884s CCC: $37.00
© 2007 American Chemical Society
Published on Web 05/31/2007