ORGANIC
LETTERS
2012
Vol. 14, No. 17
4370–4373
Room Temperature, Palladium-Mediated
PÀArylation of Secondary Phosphine
Oxides
Aaron J. Bloomfield and Seth B. Herzon*
Department of Chemistry, Yale University, New Haven, Connecticut 06520,
United States
Received July 3, 2012
ABSTRACT
We show that a broad range of aryl iodides are efficiently coupled with secondary phosphine oxides using 1 mol % of a catalyst formed in situ from
tris(dibenzylideneacetone)dipalladium and Xantphos (1). Scalemic (S)-methylphenylphosphine oxide [(S)-2e] is shown to undergo arylation
without detectable stereoerosion. The application of this method to the synthesis of novel P-chiral phosphines and PCP ligands is demonstrated.
The widespread use of tertiary phosphines in transition
metal chemistry and catalysis continues to motivate methods
for their synthesis.1 A direct route to tertiary phosphines
involves functionalization of secondary phosphines;
however, the latter are unstable toward oxidation and
require rigorously oxygen-free conditions in their synthesis
and manipulation. An approach that minimizes the hand-
ling of oxygen-sensitive intermediates comprises the func-
tionalization of secondary phosphine oxides (SPOs) to form
tertiary phosphine oxides (TPOs), followed by reduction.2
We recently described a practical single-step synthesis
of SPOs of wide structural variability.3 Here we describe
a highly useful method for the synthesis of TPOs by
the direct P-arylation of SPOs. We show that a catalyst
formed in situ from tris(dibenzylideneacetone)dipalladium
(Pd2dba3) and Xantphos (1)4 is broadly active for the
arylation of SPOs with a range of aryl and heteroaryl
iodides. In most cases, the arylations proceed to comple-
tion within 2 h at 24 °C, employ equimolar amounts of
coupling partners, and require only 1 mol % of palla-
dium. Thesearylations occur withretention ofstereochem-
ical integrity at phosphorus, and by employing enantio-
merically enriched SPO starting materials and a stereoselective
reduction,2e P-chiral tertiary phosphines of high stereo-
chemical purity may be obtained. Although palladium5
and copper-mediated6 SPO arylations have been reported,
these typically employ high catalyst loadings (10À20 mol %)
and reaction temperatures (90À120 °C) or require extended
(4) (a) Kranenburg, M.; van der Burgt, Y. E. M.; Kamer, P. C. J.;
qvan Leeuwen, P. W. N. M.; Goubitz, K.; Fraanje, J. Organometallics
1995, 14, 3081. Xantphos (1) has also been employed in the cross-
coupling H-phosphonate diesters with benzyl halides, see: (b) Laven, G.;
Kalek, M.; Jezowska, M.; Stawinski, J. New J. Chem. 2010, 34, 967.
(5) (a) Xu, Y.; Xia, J.; Guo, H. Synthesis 1986, 691. (b) Xu, Y.; Wei,
H.; Xia, J. Liebigs Ann. Chem. 1988, 1139. (c) Uozumi, Y.; Tanahashi,
A.; Lee, S. Y.; Hayashi, T. J. Org. Chem. 1993, 58, 1945. (d) Toffano, M.;
Dobrota, C.; Fiaud, J.-C. Eur. J. Org. Chem. 2006, 2006, 650.
(6) (a) Huang, C.; Tang, X.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem.
2006, 71, 5020. (b) Rao, H.; Jin, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Chem.;
Eur. J. 2006, 12, 3636. (d) Matano, Y.; Matsumoto, K.; Terasaka, Y.;
Hotta, H.; Araki, Y.; Ito, O.; Shiro, M.; Sasamori, T.; Tokitoh, N.;
Imahori, H. Chem.;Eur. J. 2007, 13, 891. (e) McDougal, N. T.; Streuff,
J.; Mukherjee, H.; Virgil, S. C.; Stoltz, B. M. Tetrahedron Lett. 2010, 51,
5550. For a review, see: (f) Tappe, F. M. J.; Trepohl, V. T.; Oestreich, M.
Synthesis 2010, 3037.
€
(1) Borner, A., Ed. Phosphorus Ligands in Asymmetric Catalysis;
Wiley-VCH: Weinheim, 2008; Vol. 3.
(2) Selected methods for the reduction of TPOs: (a) Horner, L.;
Balzer, W. D. Tetrahedron Lett. 1965, 6, 1157. (b) Naumann, K.; Zon,
G.; Mislow, K. J. Am. Chem. Soc. 1969, 91, 7012. (c) Marsi, K. L. J. Org.
Chem. 1974, 39, 265. (d) Coumbe, T.; Lawrence, N. J.; Muhammad, F.
Tetrahedron Lett. 1994, 35, 625. (e) Imamoto, T.; Kikuchi, S.-i.; Miura,
T.; Wada, Y. Org. Lett. 2001, 3, 87. (f) Berthod, M.; Favre-Reguillon,
A.; Mohamad, J.; Mignani, G.; Docherty, G.; Lemaire, M. Synlett 2007,
1545. (g) Busacca, C. A.; Raju, R.; Grinberg, N.; Haddad, N.; James-
Jones, P.; Lee, H.; Lorenz, J. C.; Saha, A.; Senanayake, C. H. J. Org.
Chem. 2008, 73, 1524.
(3) Bloomfield, A. J.; Qian, J. M.; Herzon, S. B. Organometallics
2010, 29, 4193.
r
10.1021/ol301831k
Published on Web 08/20/2012
2012 American Chemical Society