Synthesis and structural characterization of a highly effective chiral dipyridylphosphine ligand and its application in the Ru-catalyzed asymmetric hydrogenation of β-ketoesters

Article abstract of DOI:10.1055/s-2001-14659

A new chiral dipyridylphosphine ligand Tol-P-Phos has been synthesized and the structure of the complex of (R)-Tol-P-Phos oxide with (-)-dibenzoyl-L-tartaric acid [(-)-DBT] was determined by single crystal X-ray diffraction. The ruthenium complex of Tol-P-Phos, Ru(R-Tol-P-Phos)(C₆H₆)Cl₂, has been found to be a highly active and enantioselective catalyst in the asymmetric hydrogenation of β-ketoesters (up to 98.2% e.e.). The catalyst is also found to be air-stable even in solution.

Full text of DOI:10.1055/s-2001-14659

1050
LETTER
Synthesis and Structural Characterization of a Highly Effective Chiral
Dipyridylphosphine Ligand and Its Application in the Ru-Catalyzed
Asymmetric Hydrogenation of -Ketoesters
Jing Wu, Hua Chen, Zhong-Yuan Zhou, Chi Hung Yeung, Albert S. C. Chan*
Open Laboratory of Chirotechnology and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic
University, Hong Kong
Fax +852 23649932; E-mail: bcachan@polyu.edu.hk
Received 1 April 2001
tivity by designing new ligands remains to be an area of
Abstract: A new chiral dipyridylphosphine ligand Tol-P-Phos has
active research.
been synthesized and the structure of the complex of (R)-Tol-P-
Phos oxide with ( )-dibenzoyl-L-tartaric acid [( )-DBT] was deter-
mined by single crystal X-ray diffraction. The ruthenium complex
of Tol-P-Phos, Ru(R-Tol-P-Phos)(C6H6)Cl2, has been found to be a
highly active and enantioselective catalyst in the asymmetric hydro-
genation of -ketoesters (up to 98.2% e.e.). The catalyst is also
found to be air-stable even in solution.
Over the past two decades, tremendous success has been
achieved in the use of chiral arylphosphine ligands such as
BINAP, BIPHEP, MeO-BIPHEP, and DuPhos, etc. in Rh-
or Ru-catalyzed asymmetric hydrogenation reactions.1 As
an effort to expand the scope of the arylphosphine ligands
and their application in homogeneous catalysis, transi-
tion-metal complexes containing pydridylphosphine
ligands have been synthesized and tested in homogeneous
catalysis.3 Unfortunately, the tested complexes were
found to be inactive in the homogeneous hydrogenations
owing to the pyridyl group which coordinated to the metal
center and rendered the complex coordinately saturated.4
By preventing the coordination of the pyridyl groups via
the use of bulky substituents, we found that the resulting
rhodium(I) complex was effective for the hydrogenation
of aldehydes, olefins, and imines.5
Key words: asymmetric catalysis, hydrogenation, dipyridylphos-
phine ligands, ruthenium complex, -ketoester
The search for new chiral ligands is an ongoing process in
the field of asymmetric synthesis.1 Although more than a
thousand chiral nonracemic diphosphines have been syn-
thesized and the efficiency of catalysts derived from these
ligands have been established,1,2 the possibility of discov-
ering catalysts with improved utility, activity, and selec-
P
CH3
2
1. LDA, THF, -78oC
2.(4-CH3C6H4)2PCl(3), -78oC
Br
H2O2, acetone, 0oC
Br
Br2
CCl4, -30~ -40oC
CH3O
N
OCH3
CH3O
N
OCH3
CH3O
N
OCH3
1
2
4
OCH3
O
N
N
O
P
P
CH3
2
CH3
CH3
CH3O
CH3O
2
2
Cu, DMF, 140oC
1. (-)-L-DBTor (+)-D-DBT
(R)-6 and (S)- 6
Br
2. fractionnal crystalization
3. 10% aqueous NaOH
P
O
CH3O
N
OCH3
OCH3
(±)-6
5
OCH3
OCH3
N
N
N
N
P
CH3
CH3
P
P
CH3
2
CH3O
CH3O
HSiCl3
(C2H5)3N
CH3O
CH3O
2
2
and
P
CH3
2
OCH3
OCH3
(S)-Tol-P-Phos
(R)-7
(R)-Tol-P-Phos
(S)-7
Scheme Synthesis of Tol-P-Phos
Synlett 2001, SI, 1050–1054 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Highly Effective Chiral Dipyridylphosphine Ligand
1051
Figure ORTEP Drawing of the Complex (R)-(+)-6-( )-DBT with Numbering Schemes. Selected distances(Å) and angles (deg): C(19)
C(22) = 1.502 (5), P (1) C (15) = 1.806 (3), P (2) C (29) = 1.796 (3), P (1) O (1) = 1.486 (2), P (2)-O (2) = 1.487 (2), O (1)···O
(10A) = 2.530, O (2)···O (8) = 2.487
Inspired by the success of the modified pyridylphosphine vealed that the crystals are built up of infinite close-
ligand, we have developed a chiral dipyridylphosphine packed chains in which equimolar (+)-6 and (–)-DBT are
ligand 2,2’,6,6’-tetramethoxy-4,4’-bis(diphenylphosphi- connected in a regularly alternating way through two in-
no)-3,3’-bipyridine (P-Phos),6 which was found to be very ter-molecular hydrogen bonds between oxygen atoms
effective in the Ru catalyzed asymmetric hydrogenation [O(1) and O(2)] of the P=O groups in compound 6 and hy-
of 2-(6’-methoxy-2’-naphthyl)propenoic acid to give the drogen atoms of the COOH groups of DBT.
nonsteroidal anti-inflammatory drug naproxen.6,7 In this
paper, we report the synthesis, characterization and appli-
The low solubility of complex (+)-6-( )-DBT is attribut-
able to such a linear polymeric structure. From the internal
cation of a new dipyridylphosphine ligand, 2,2’,6,6’-tet-
comparison with (2R, 3R)-( )-DBT, the absolute config-
ramethoxy-4,4’-bis[di(p-tolyl)phosphino]-3,3’-bipyrid-
uration of (+)-6 was determined to be R. Subsequent de-
ine (Tol-P-Phos).
composition of complex (+)-6-( )-DBT with aq. NaOH
The synthetic route of Tol-P-Phos is outlined in the provided enatiomerically pure (R)-(+)-6 in 91% yield
Scheme. The slow addition of bromine to commercially based on the ( )-6 used. (S)-( )-6 was recovered from the
available 1 in CCl4 between –30 C to 40 C gave 3-bro- mother liquor of the recrystallization by treatment with
mo-2,6-dimethoxypyridine (2) in 76% yield.8 The regio- aq. NaOH. This crude product could be further purified
selective lithiation9 of 2 with lithium diisopropylamide via the formation of the complex with (+)-DBT. Thus,
(LDA) in THF at 78 C, followed by the addition of di(4- both (R)-(+)-6 and (S)-( )-6 enatiomers were effectively
methylphenyl)phosphine chloride (3) provided 3-bromo- obtained by choosing the handedness of the resolving
2,6- dimethoxy-4-di(p-methylphenyl)phosphinopyridine agents. Reduction of enantiomerically pure 6 with trichlo-
(4, 55% yield), while 3 was prepared according to the lit- rosilane in the presence of triethylamine led to the target-
erature method in 73% yield.10 Oxidation of 4 with hydro- ed enantiomers of atropisomeric ligands 7 (92% yield),
1
gen peroxide in acetone at 0 C produced 5 in 99% yield. the structure of which was confirmed by H, 13C, 31P
The racemic dipyridylphosphine oxide 6 was obtained via NMR, and elemental analysis.
Ullmann coupling11 of 5.
Using Mashima et al’s method,13 Ru(R-Tol-P-
The resolution of racemate ( )-6 was achieved by the use Phos)(C6H6)Cl2 (8) was prepared by mixing
of enantiomers of DBT.12 When a solution of (2R,3R)- [RuCl2(C6H6)]2 with R-Tol-P-Phos in an 8:1 mixture of
( )-DBT in ethyl acetate was added to a boiling solution ethanol-benzene and the complex was isolated as a red-
of racemic compound 6 in chloroform, a 1:1 complex of dish brown solid. The structure of the complex was char-
(+)-6 and ( )-DBT [(+)-6-( )-DBT] precipitated as a acterized by 1H, and 31P NMR.14
crystalline solid. X-ray structure analysis (Figure) re-
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1052
J. Wu et al.
Table 1 Asymmetric Hydrogenation of -Ketoesters Catalyzed by 8a
LETTER
aReaction conditions: 200 mg substrate; substrate concentration = 1.78-2.38 M in EtOH/CH2Cl2;
The substrate and catalyst were added to the stainless steel autoclave under N2 and the solvents were
degassed and dried prior to use.
bThe convertion yield and the ee were determined by chiral GC with a Chrompack Chirasil-DEX
CB columns after converting the products to the corresponding acetyl derivatives.
cThe conversion yield and the ee were determined by 500 MHz 1H NMR and HPLC analysis (Chir-
alcel OD column).
8 was found to be a highly effective catalyst for the asym- when the substrate (9c) and the Ru(R-Tol-P-Phos) catalyst
metric hydrogenation of -ketoesters (Table 1).The reac- were added to the stainless steel autoclave in air and when
tions proceeded smoothly at 80-90 C and under 300 psi the solvents were not degassed and dried prior to use, the
of H2 in two hours and the ee value is up to 98.2% (entry activity and enatioselectivity of the catalyst (8) remained
1).
to be unchanged (96.4% ee, entry 14) from the air-proved
system (96.2% ee, entry 8). Further investigation showed
that the activity and enatioselectivity of 8 remained to be
the same even its solution in EtOH and CH2Cl2 were
stirred for 10 hours under air prior to its application
(95.7% ee, entry 15). These results compared favorably
with those obtained from the use of Ru(R-Bi-
nap)(C6H6)Cl2 as catalyst precursor in a side by side com-
parison study.
The hydrogenation of 9c leads to a useful pharmaceutical
intermediate, (S)-3-hydroxy- 3-phenyl propionate (10c).15
Table 2 indicates that the rate and enantioselectivity of
this reaction were influenced by the choice of solvent, H2
pressure and the molar ratio of substrate to catalyst (S/C).
The mixed solvent of EtOH – CH2Cl2 (1:1) and lower H2
pressure are favorable for higher enatioselectivity. Entry
11-13 were carried out in a larger scale (30 g substrate)
and the results indicated that no substantial decrease of ee The air-stability of 8 was also supported by a 31P NMR
(95.9% ee, entry 11) with high S/C ratio. Although enati- study (Figure 2). After the catalyst solution was exposed
oselectivity is a major concern in modern asymmetric syn- to air for 10 h, its 31P NMR spectrum showed no variation
thesis, the reactivity and productivity are also important in comparison with that determined under N2 [CDCl3, 500
factors of consideration in determining the commercial MHz, 31.15 (d, J = 62.7 1 Hz), 38.28 (d, J = 62.71
feasibility of a reaction.2e Thus the demonstration of car- Hz)].14 These results showed excellent potential for the
rying out the reaction at high S/C ratio without losing practical applications of the P-Phos type ligands in asym-
enantioselectivity was encouraging. Other desirable fea- metric catalytic reactions.
tures of a good catalyst system include the ease of catalyst
preparation and handling as well as the operational sim-
plicity of the experimental procedures. A usual problem
associated with the use of noble metal phosphine catalysts
In conclusion, we have developed a new dipyridylphos-
phine ligand and its Ru complex 8 has been found to be a
highly effective catalyst in the asymmetric hydrogenation
of -ketoesters. It is of high interest to note that 8 is stable
is the air-sensitivity of the catalysts. The oxidation of the
to air, which makes the experiments convenient to operate
active catalysts by trace amounts of air in the reaction sys-
and also shows a good potential for its industrial applica-
tem often makes irreproducible results in many reactions.
tion.
This problem is even more severe in industrial applica-
tions in which the rigorous de-gassing is usually more dif-
Acknowledgement
ficult than the laboratory-scale operations. Therefore, it is
highly desirable to develop effective catalysts with good
air-stability. In this study we were delighted to find that
We thank the Hong Kong Research Grants Council (Project number
PolyU 5177/99P) and The Hong Kong Polytechnic University
the Ru(R-Tol-P-Phos)(C6H6)Cl2 catalyst system to be (ASD) for financial support of this study.
highly air-stable. In a simple stability test we found that
Synlett 2001, SI, 1050–1054 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Highly Effective Chiral Dipyridylphosphine Ligand
1053
Table 2 The Effect of Reaction Conditions on the Asymmetric Hydrogenation of 9c Catalyzed by 8
a90 °C; 200 mg substrate; substrate concentration = 1.73 M.
b90 °C; 30 g substrate; substrate concentration = 4.11 M.
c The substrate and catalyst were added to the stainless steel autoclave under N2 and the solvents were degassed
and dried prior to use.
dThe substrate and catalyst were added to the stainless steel autoclave in air and the solvents were not degassed
and dried prior to use.
eThe catalysts solution in EtOH and CH2Cl2 were stirred for 10 hours under air before the addition of substrate
and H2.
f The absolute configurations were assigned according to ref. 16. g The numbers in bracket were obtained by
using Ru(R-Binap)(C6H6)Cl2 as catalyst under the same reaction conditions.
(4) Kurtev, K.; Bibola, D.; Jones, R. A.; Cole-Hamilton, D. J.;
Wilkinson, G. J. Chem. Soc., Dalton. Trans. 1990, 55.
(5) (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, 3214. (c) Hu,
W.; Chen, C. C.; Xue, G. Chan, A. S. C. Tetrahedron:
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(6) Pai, C.-C.; Lin, C.-W.; Lin, C.-C.; Chen, C.-C.; Chan, A. S.
C.; Wong, W. T. J. Am. Chem. Soc. 2000, 122, 11513.
(7) Harrington, P. J.; Lodewijk, E. Org. Process Res. Dev. 1997,
1, 72.
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J. Wu et al.
LETTER
(13) Mashima, K.; Kusano, K.; Sato, N.; Matsumura, Y.; Nozaki,
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(14) Spectral data for 8: 1H NMR (CDCl3, 500MHz): 2.31 (s, 6H,
PhCH3), 2.35 (s, 6H, PhCH3), 3.48 (s, 3H, OCH3), 3.58 (s, 3H,
OCH3), 3.61 (s, 3H, OCH3), 3.73(s, 3H, OCH3), 5.75 (s, 6H,
C6H6), 5.94 (d, J = 12.0 Hz, 1H, PyH), 6.38 (d, J = 10.5 Hz,
1H, PyH), 7.18-7.20 (m, 6H, PhH), 7.29-7.45 (m, 10H, PhH).
31P NMR (CDCl3, 500MHz): 31.15 (d, J = 62.71 Hz), 38.26
(d, J = 62.71 Hz).
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Article Identifier:
1437-2096,E;2001,0,SI,1050,1054,ftx,en;Y08201ST.pdf
Synlett 2001, SI, 1050–1054 ISSN 0936-5214 © Thieme Stuttgart · New York