J. Am. Chem. Soc. 2000, 122, 11513-11514
11513
The synthetic route for P-phos ligand is outlined in Scheme 1.
The slow addition of bromine to commercially available 2,6-
dimethoxypyridine (1) in carbon tetrachloride at a temperature
between -30 and -40 °C provided 3-bromo-2,6-dimethoxypy-
ridine (2) in 76% yield.7 The regioselective lithiation8 of 2 with
lithium diisopropylamide (LDA) in THF at -78 °C, followed by
the addition of chlorodiphenylphosphine produced 3-bromo-2,6-
dimethoxy-4-diphenylphosphino-pyridine (3, 95% yield). The
phosphine was converted to 3-bromo-2,6-dimethoxy-4-diphen-
ylphosphinylpyridine (4) by mixing with hydrogen peroxide in
acetone at 0 °C (96% yield). The racemic dipyridylphosphine
oxide 5 was obtained via Ullmann coupling9 of 4. The enantiomers
of 5 were obtained via resolution with a preparative chiral
column.10 The structure of (S)-dipyridylphosphine oxide was
determined by single crystal X-ray diffraction. Subsequent
reduction of enantiomerically pure 5 with trichlorosilane in the
presence of triethylamine led to the targeted enantiomers of
atropisomeric ligands 7 which was characterized by 1H, 31P NMR,
elemental analysis, high-resolution mass spectrometry, and an
X-ray diffraction study of its Ru complex. The enantiomeric purity
of the ligand was verified via its oxidation to the known phosphine
oxide form (5) followed by HPLC analysis. Although an attempt
to resolve racemic 5 by (-)-dibenzoyl-L-tartaric acid ((-)-DBT)
or (1S)-(+)-camphorsulfonic acid was unsuccessful, we found
that the production of optically pure ligand 7 can be achieved
via the conversion of racemic 5 to the dibromo-derivative 6,11
which can be resolved by (-)-DBT or (+)-DBT,12 followed by
reduction with trichlorosilane. All of the synthetic intermediates
are air-stable, and the overall synthesis steps are easy to handle.
Unlike many bipyridines which racemize easily,13 these new
ligands are optically stable even at elevated temperature. (No
racemization was observed at 120 °C).
Highly Effective Chiral Dipyridylphosphine Ligands:
Synthesis, Structural Determination, and
Applications in the Ru-Catalyzed Asymmetric
Hydrogenation Reactions
Cheng-Chao Pai, Ching-Wen Lin, Chi-Ching Lin,
Chih-Chiang Chen, and Albert S. C. Chan*
Open Laboratory of Chirotechnology and
Department of Applied Biology and Chemical Technology
The Hong Kong Polytechnic UniVersity
Hong Kong, China
Wing Tak Wong
Department of Chemistry
The UniVersity of Hong Kong, Hong Kong, China
ReceiVed January 18, 2000
Heteroaromatic compounds constitute an important class of
synthetic and natural products. The chemistry involving this class
of compounds is so rich that the subject has become a major
branch in organic chemistry. However, the catalytic property of
transition-metal complexes containing heteroaromatic organo-
phosphines has been relatively unexplored. Recently Benincori
et al.1,2 and Tietz et al.3 developed a series of substituted
bithiophene- and bibenzo[b]thiophene-containing chiral phos-
phines and found them to be effective in asymmetric hydrogena-
tion and Heck reactions. Rhodium and ruthenium catalysts
containing pyridylphosphine ligands have been previously pre-
pared, and some of them have been tested in homogeneous
catalysis.4 Unfortunately, the tested complexes were found to be
inactive in the homogeneous hydrogenations.5 The inactivity of
the catalysts was attributed to the pyridyl group which coordinated
to the metal center and rendered the complex coordinately
saturated. Recently, we have observed that by intentionally
blocking the coordination of the pyridyl groups via the use of
bulky substituents, the resulting rhodium(I) complex was effective
for the hydrogenation of olefins, aldehydes, and imines.6 Fur-
thermore, the solubility of the new ligands, either in aqueous or
in organic solvents, can be easily controlled simply by adjusting
the acidity of the solution. Separation of the catalyst from the
reaction product in a water-immiscible organic solvent was
achieved by extracting the catalyst with aqueous hydrochloric
acid; the complex remained intact during the extraction process.6a
Building on the success of the modified pyridylphosphine and
expanding the scope of study to the area of asymmetric catalysis,
we have developed a class of highly effective chiral heteroaro-
matic ligands. Herein, we report the synthesis, characterization,
and application of a new class of chiral pyridylphosphine ligand,
2,2′,6,6′-tetramethoxy-4,4′-bis(diphenylphosphino)-3,3′-bipyri-
dine (P-phos).
The new ligand can be used to make discrete transition-metal
complexes without the complication of the coordination of the
pyridyl rings. For example, Ru(R-P-phos)(acac)2 was prepared
by mixing R-P-phos with Ru(acac)3 (acac ) acetylacetonate) in
the presence of a reducing agent, and the complex was character-
1
ized by H, 31P NMR, elemental analysis, and X-ray crystal-
lography.
R-P-phos, Zn powder,
EtOH, reflux
Ru(R-P-phos)(acac)
8
Ru(acac)3
2
97% yield
Ru(R-P-phos)(acac)2 was tested in the asymmetric hydrogena-
tion of 2-(6′-methoxy-2′-naphthyl)propenoic acid as an economi-
cally attractive reaction for the preparation of the nonsteroidal
antiinflammatory drug naproxen.14 It is worth noting that while
there are many good catalysts for the asymmetric hydrogenation
of R-amidoacrylic acids leading to amino acids in high ee, very
few catalysts are effective in the asymmetric hydrogenation of
2-arylacrylic acids.1,2,15 Since naproxen is a large-volume, high-
value product, a good catalyst for this reaction is of substantial
interest. The experimental results are summarized in Table 1. The
addition of a small amount of phosphoric acid to the reaction
mixture improved the ee by one to two percent (entry 4 vs 5, 6
vs 7). In the presence of 0.6 equiv of phosphoric acid at 0 °C
* To whom correspondence should be addressed. Telephone: (852) 2766
(1) Benincori, T.; Brenna, E.; Sannicolo, F.; Trimarco, L.; Antognazza,
P.; Cesarotti, E.; Demartin, F.; Pilati, T. J. Org. Chem. 1996, 61, 6244.
(2) Benincori, T. Cesarotti, E.; Piccolo, O.; Sannicolo, F. J. Org. Chem.
2000, 65, 2043.
(3) Tietz, L. F.; thede, K.; Schimpf, R.; Sannicolo, F. Chem. Commun.
2000, 583.
(4) (a) Newkome, G. R. Chem. ReV. 1993, 93, 2067. (b) Brunner, H.;
Bublak, P. Synthesis 1995, 36. (c) Yang, H.; Alvarez, M.; Lugan, N.; Mathieu,
R. J. J. Chem. Soc., Chem. Commun. 1995, 1721.
(5) Kurtev, K.; Bibola, D.; Jones, R. A.; Cole-Hamilton, D. J.; Wilkinson,
G. J. Chem. Soc., Dalton Trans. 1990, 55.
(6) (a) Chan, A. S. C.; Chen, C. C.; Cao, R. Organometallics 1997, 16,
3469. (b) Hu, W.; Pai, C. C.; Chen, C. C.; Xue, G.; Chan, A. S. C.
Tetrahedron: Asymmetry 1998, 9, 3241. (c) Hu, W.; Chen, C. C.; Xue, G.;
Chan, A. S. C. Tetrahedron: Asymmetry 1998, 9, 4183.
(7) Subhash, K. P.; Edward, B. R. Heterocycles 1998, 27, 2643.
(8) (a) Gu, Y. G.; Erol, B. K. Tetrahedron Lett. 1996, 37, 2565. (b) Gribble,
G. W.; Saulnier, M. G. Heterocycles 1993, 35, 151. (c) Gribble, G. W.;
Saulnier, M. G. Tetrahedron Lett. 1980, 21, 4173.
(9) Fanta, P. E. Synthesis 1974, 9.
(10) The enantiomers of 5 were separated by HPLC with a preparative
Daicel AD column (25 m × 1.2 m). Eluent ) 2-propanol:hexane (20:80);
flow rate ) 3.0 mL/minute; tR ) 12.24 min; tS ) 25.06 min.
(11) Windscheif, P.; Vo¨gtle, F. Synthesis 1994, 87.
(12) Takaya, H.; Akutagawa, S.; Noyori, R. Org. Synth. 1988, 67, 20.
(13) Slany, M.; Stang, P. J. Synthesis 1996, 1019.
(14) Harrington, P. J.; Lodewijk, E. Org. Process Res. DeV. 1997, 1, 72.
10.1021/ja000163n CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/03/2000
Pai
