Ruthenium complexes of phosphine-aminophosphine ligands

Article abstract of DOI:10.1016/j.tetlet.2006.04.009

Ruthenium complexes of phosphinoferrocenylaminophosphine ligands (BoPhoz ligands) have been prepared by combining the ligands with tris(triphenylphosphine)ruthenium dichloride and precipitating the complexes. The optimal species exhibit high enantioselectivities for the asymmetric hydrogenation of functionalized ketones, particularly β-ketoesters.

Full text of DOI:10.1016/j.tetlet.2006.04.009

Tetrahedron Letters 47 (2006) 4033–4035
Ruthenium complexes of phosphine–aminophosphine ligands
Neil W. Boaz,* James A. Ponasik, Jr. and Shannon E. Large
Research Laboratories, Eastman Chemical Company, PO Box 1972, Kingsport, TN 37662, USA
Received 17 January 2006; revised 31 March 2006; accepted 5 April 2006
Abstract—Ruthenium complexes of phosphinoferrocenylaminophosphine ligands (BoPhozTM ligands) have been prepared by com-
bining the ligands with tris(triphenylphosphine)ruthenium dichloride and precipitating the complexes. The optimal species exhibit
high enantioselectivities for the asymmetric hydrogenation of functionalized ketones, particularly b-ketoesters.
Ó 2006 Elsevier Ltd. All rights reserved.
Asymmetric catalysis is a powerful technology for gener-
ating single enantiomer materials. Asymmetric hydroge-
nation is perhaps the most useful asymmetric reaction,
as it utilizes an inexpensive reagent (hydrogen) with an
often relatively inexpensive unsaturated substrate to
afford a high value single enantiomer product. Of parti-
cular interest has been the asymmetric hydrogenation of
functionalized ketones to afford the corresponding chi-
ral alcohols.1 Within this area, the hydrogenation of b-
ketoesters has found the widest application, as the
resulting b-hydroxyesters can be utilized for the prepa-
ration of a variety of materials, including pharmaceuti-
cals2 and chiral polymers.3 The most effective catalysts
for the asymmetric hydrogenation of b-ketoesters are
ruthenium complexes prepared from axially chiral
ligands, as first demonstrated with the BINAP ligand.4
This methodology has found wide use for the prepara-
tion of a wide variety of chiral b-hydroxyesters in high
enantiomeric purity. We have recently described a series
of phosphine–aminophosphine ligands 1 that afford
excellent activities and enantioselectivities as rhodium
complexes for the asymmetric hydrogenation of dehy-
droamino acids, itaconates, and a-ketoesters,5 and were
interested in determining the viability of ruthenium
complexes of these ligands for asymmetric catalysis.
There are a number of methods available for the prepa-
ration of ruthenium complexes of bidentate phosphine
ligands. Unfortunately, many of the methods use strong
acid or base during the preparation, conditions that
are not compatible with ligands 1. Other potential pre-
cursors, such as dichloro(benzene)ruthenium(II) dimer
and dichloro(p-cymene)ruthenium(II) dimer, afforded
catalytically inactive materials with ligands 1. A notable
exception was the procedure developed by Mezetti and
co-workers, which involves the exchange of two triphen-
ylphosphine moieties of dichlorotris(triphenylphos-
phine)ruthenium(II) for a chelating bis-phosphine.6
This methodology is perhaps the simplest process for
the preparation of a catalytically active material, as it in-
volves just a single step from readily available materials
and utilizes no harsh reagents.
Combining ligands 1 with dichlorotris(triphenylphos-
phine)ruthenium(II) in dichloromethane overnight affor-
ded ruthenium complexes 2, which were isolated as air-
stable green precipitates by dilution of the reaction mix-
ture with isopropanol and removal of the dichlorometh-
ane under reduced pressure. The complexes prepared are
indicated below. The antipodal complexes have also been
prepared using the enantiomer of 1.
R
N
PR'2
Fe
PPh2
These materials were examined for the asymmetric
hydrogenation of a variety of b-ketoesters as indicated
in Figure 1, with the results obtained detailed in Table 1.
1
*
The ruthenium complexes 2 showed a wide variety
of reactivities and selectivities depending upon the
Corresponding author. Tel.: +1 423 229 8105; fax: +1 423 224
7582; e-mail: nwboaz@eastman.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.009

4034
N. W. Boaz et al. / Tetrahedron Letters 47 (2006) 4033–4035
substitution and afforded the best results for rhodium-
R
PR'2
PPh3
catalyzed hydrogenations. Complex 2a afforded good
enantioselectivities for the hydrogenation of b-ketoest-
ers 3a–c, but poorer selectivity for the more challenging
phenyl-substituted species 3d. Changing the size of the
alkyl group on the nitrogen (either smaller or larger)
had a decidedly negative effect on the enantioselectivities
(entries 2–4). Converting the aminophosphine of 1 to a
phosphoramidite resulted in extremely poor enantio-
selectivities for b-ketoester hydrogenations (entries 16–
20). In particular, the BINOL derived species 2t and
2u afforded the poorest enantioselectivities, a reversal
of the excellent results obtained with some of these spe-
cies for rhodium-catalyzed reactions.5c,7
N
Cl
Ru
Cl
P
Fe
Ph2
2
a: R = Me, R' = Ph
b: R = H, R' = Ph
k: R = Me, R' = 4-FPh
m: R = Me, R' = 3,4-F2Ph
n: R = Me, R' = 3,4-Cl2Ph
o: R = Me, R' = 3,5-F2Ph
p: R = Me, R' = 3,5-Cl2Ph
q: R = Me, R' = PhO
c: R = Et, R' = Ph
d: R = CH2Ph, R' = Ph
e: R = Me, R' = cyclohexyl
f: R = Me, R' = Et
g: R = Me, R' = i-Pr
r: R = Me, R' = 4-MeOPhO
s: R = Me, R' = 4-CF3PhO
t: R = Me, R' = R-BINOL
u: R = Me, R' = S-BINOL
Modification of the aryl groups of the aminophosphine
of 1 had a significant effect on the selectivities of the
reactions. Complexes with electron-donating aryl spe-
cies on the phosphorus afforded slightly poorer results
than 2a (entries 8 and 9). In contrast, electron-withdraw-
ing aryl substituents on the aminophosphine afforded
good to excellent enantioselectivities and high reactivi-
ties (entries 10–15). The optimum results were obtained
with a 3,4-difluorophenyl group as R0 (entry 12, 2m),
affording the overall highest enantioselectivities, even
for the demanding phenyl-substituted substrate 3d.
h: R = Me, R' = 3,5-Me2Ph
i: R = Me, R' = 4-MeOPh
j: R = Me, R' = 3-FPh
substituents on the aminophosphine portion of ligands
1. The results with complex 2a (from ligand 1a) can be
employed as a baseline, as this ligand has fairly generic
300 psig H2
OH
O
O
O
2
R1
OR2
R1
OR2
R2OH, RT
Of particular note are complexes 2e, 2f, and 2g, which
have alkyl groups on the phosphorus of the aminophos-
phine. These complexes afforded products with reversed
(albeit moderate) enantioselectivities. Although the rea-
son for this is not well understood, it is likely due to ste-
rics rather than electronics, as other electron-donating
phosphines did not show this reversal.
4
3
a: R1 = R2 = Me
b: R1 = Me, R2 = Et
c: R1 = Et, R2 = Me
d: R1 = Ph, R2 = Et
Figure 1. Asymmetric hydrogenation reactions.
A pronounced improvement in enantioselectivity was
observed for the asymmetric hydrogenations upon
switching the solvent from methanol to ethanol for a
number of catalysts (Table 2). This effect was in general
most evident with the best catalysts. However, reduced
activity was also often observed in ethanol as compared
to methanol, and was more pronounced in going to
higher alcohol solvents (n-propanol, isopropanol, n-
butanol), although these solvents also afforded higher
enantioselectivities than the reactions in methanol.
Table 1. Asymmetric hydrogenation of b-ketoesters 3 with complex 2a
Entry
2
% ee (% Conversion)
4a
4b
4c
4d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
a
b
c
d
e
f
90.7 (100)
45.4 (82)
76.2 (100)
62.2 (100)
16.4 (65)b
24.1 (51)b
57.2 (25)b
82.5 (100)
85.4 (97)
92.9 (100)
89.6 (100)
93.9 (99)
87.9 (100)
84.4 (100)
64.5 (100)
17.3 (99)
17.2 (99)
11.5 (25)
0.4 (80)
88.6 (100)
47.6 (73)
71.6 (85)
48.6 (90)
52.2 (17)b
59.6 (58)b
49.2 (7)b
81.7 (100)
92.7 (34)
92.7 (100)
91.6 (100)
95.0 (100)
94.0 (59)
92.5 (100)
63.4 (40)
31.5 (79)
10.7 (36)
nd (<1)
89.4 (100)
29.2 (1)
56.8 (70)
60.6 (14)
33.0 (60)
54.6 (39)
87.2 (26)b
1.8 (13)b
75.6 (17)b
83.0 (37)
63.3 (43)
80.1 (99)
70.3 (91)
94.9 (99)
91.3 (87)
95.0 (6)
92.6 (33)
58.2 (39)
82.8 (2)b
65.7 (16)b
38.2 (15)b
1.2 (5)b
82.0 (91)
52.8 (87)
45.0 (11)b
37.2 (93)b
36.4 (6)b
79.3 (100)
84.9 (24)
94.3 (100)
91.9 (98)
95.3 (100)
89.7 (100)
86.1 (100)
64.4 (90)
15.7 (93)
21.8 (45)
17.2 (2)
There was also interest in applying these complexes
to the asymmetric hydrogenation of halo-substituted
g
h
i
Table 2. Solvent effects on asymmetric hydrogenation of 3a and 3c
with complex 2a
j
k
m
n
o
p
q
r
Entry
2
% ee (% Conversion)
4a (MeOH) 4a (EtOH) 4c (MeOH) 4c (EtOH)
1
2
3
4
5
6
7
a
i
90.7 (100)
85.4 (97)
92.9 (100)
89.6 (100)
93.9 (99)
87.9 (100)
84.4 (100)
90.8 (58)
94.0 (60)
94.2 (100) 94.3 (100)
94.2 (90) 91.8 (98)
96.0 (100) 95.3 (100)
89.4 (100)
84.9 (24)
91.4 (48)
93.4 (41)
94.0 (68)
94.6 (79)
95.4 (100)
84.6 (1)
j
s
k
m
n
o
t
2.3 (55)
2.7 (68)
1.1 (91)
1.7 (96)
u
3.5 (100)
94.6 (74)
96.6 (44)
89.7 (100)
86.1 (100)
a Reactions were run for 6 h at rt under 300 psig hydrogen using
0.5 mol % catalyst. nd indicates the result was not determined.
b Enantioselectivity reversal was observed.
93.8 (34)
a Reactions were run for 6 h at ambient temperature under 300 psig
hydrogen using 0.5 mol % catalyst.

N. W. Boaz et al. / Tetrahedron Letters 47 (2006) 4033–4035
4035
simple step from dichlorotris(triphenylphosphine)ruthe-
nium(II), afford good to high enantioselectivities for the
asymmetric hydrogenation of functionalized ketones,
particularly b-ketoesters. The complex with two 3,4-
difluorophenyl substituents on the phosphorus of the
aminophosphine affords the highest enantioselectivities
(and good reactivities) for these transformations.
300 psig H2
O
OH
2
OH
n
OH
n
R3
R3
solvent, RT
6
5
Figure 2. Asymmetric hydrogenation of hydroxyketones 5.
References and notes
Table 3. Asymmetric hydrogenation of hydroxyketones 5 with com-
plex 2a
1. For recent reviews, see: (a) Ohkuma, T.; Kitamura, M.;
Noyori, R. In Catalytic Asymmetric Synthesis, 2nd ed.;
Ojima, I., Ed.; Wiley: New York, 2000; pp 34–54; (b)
Ohkuma, T.; Noyori, R. In Comprehensive Asymmetric
Catalysis; Jacobsen, E. N., Pfalz, A., Yamamoto, H., Eds.;
Springer: Berlin, 1999; Vol. 1, pp 199–220.
2. Noyori, R. Asymmetric Catalysis in Organic Synthesis;
Wiley: New York, 1994; pp 68–70.
3. Kessler, Birgit; Witholt, Bernard Macromol. Symp. 1998,
130, 245–260.
Entry
2
R3
n
Solvent
ee (%)
1
2
3
4
5
6
a
Et
Et
Et
Et
Me
Ph
1
1
1
1
2
1
MeOH
EtOH
MeOH
EtOH
MeOH
EtOH
85.6
86.6
87.4
88.8
81.8
77.6
a
m
m
m
m
a Reactions were run for 6 h at ambient temperature under 300 psig
hydrogen using 0.5 mol % catalyst.
4. (a) Kitamura, M.; Ohkuma, T.; Inoue, S.; Sayo, N.;
Kumobayashi, H.; Akutagawa, S.; Ohta, T.; Takaya, H.;
Noyori, R. J. Am. Chem. Soc. 1988, 110, 629; (b) Noyori,
R.; Ohkuma, T.; Kitamura, M.; Takaya, H.; Sayo, N.;
Kumobayashi, H.; Akutagawa, S. J. Am. Chem. Soc. 1987,
109, 5856; (c) Noyori, R.; Takaya, H. Acc. Chem. Res.
1990, 23, 345–350; (d) Kitamura, M.; Tokunaga, M.;
Ohkuma, T.; Noyori, R. Org. Synth. 1992, 71, 1–13.
5. (a) Boaz, N. W.; Debenham, S. D.; Mackenzie, E. B.;
Large, S. E. Org. Lett. 2002, 4, 2421–2424; (b) Boaz, N. W.;
Mackenzie, E. B.; Debenham, S. D.; Large, S. E.;
Ponasik, J. A., Jr. J. Org. Chem. 2005, 70, 1872–1880; (c)
Boaz, N. W.; Ponasik, J. A., Jr.; Large, S. E. Tetrahedron:
Asymmetry 2005, 16, 2063–2066.
6. (a) Mezzetti, A.; Consiglio, G. J. Chem. Soc., Chem.
Commun. 1991, 1675–1677; (b) Mezzetti, A.; Tschumper,
A.; Consiglio, G. J. Chem. Soc., Dalton Trans. 1995, 49–56;
(c) Stoop, R. M.; Mezzetti, A.; Spindler, F. Organometallics
1998, 17, 668–675; (d) Maienza, F.; Santoro, F.; Spindler,
F.; Malan, C.; Mezzatti, A. Tetrahedron: Asymmetry 2002,
13, 1817–1824.
b-diketones (3, R1 = XCH2). Surprisingly, the hydro-
genation of these substrates with complexes 2 afforded
uniformly poor reactivities and enantioselectivities. This
anomaly is unfortunate, as the products of these reac-
tions have great utility for the preparation of a number
of biologically active materials.2
Complexes 2 were examined for the asymmetric hydro-
genation of other functionalized ketones. Positive results
were obtained for the hydrogenation of hydroxy-
substituted ketones. As shown in Figure 2 and Table
3, various a- and b-hydroxyketones 5 were hydro-
genated with complexes 2 with good enantioselectivities.
Although these selectivities are not as high as those
obtained with the b-ketoesters, these reactions do afford
synthetically interesting chiral diols in reasonably high
enantiomeric purity.
7. (a) Jia, X.; Li, X.; Lam, W. S.; Kok, S. H. L.; Xu, L.; Lu,
G.; Yeung, C.-H.; Chan, A. S. C. Tetrahedron: Asymmetry
2004, 15, 2273–2278; (b) Hu, X.-P.; Zheng, Z. Org. Lett.
2004, 6, 2585–3588.
Thus, we have found that ruthenium complexes of phos-
phine–aminophosphine ligands, prepared in a single