Ruthenium(II) pyrazolyl-pyridyl-oxazolinyl complex catalysts for the asymmetric transfer hydrogenation of ketones

Article abstract of DOI:10.1002/chem.201201703

Lowering the ketone: Ru^II complexes containing a chiral pyridyl-based 1H-pyrazolyl-oxazolinyl NNN ligand were synthesized and structurally characterized by X-ray crystallographic studies. These complex catalysts efficiently catalyzed the asymmetric transfer hydrogenation of ketones, reaching up to 99a % ee for the desired products (see scheme). Copyright

Full text of DOI:10.1002/chem.201201703

COMMUNICATION
DOI: 10.1002/chem.201201703
Ruthenium(II) Pyrazolyl–Pyridyl–Oxazolinyl Complex Catalysts for the
Asymmetric Transfer Hydrogenation of Ketones
Wenjing Ye,[a] Miao Zhao,[a] and Zhengkun Yu*[a, b]
À
Asymmetric transfer hydrogenation (ATH) is an attrac-
tive synthetic method for the reduction of ketones to form
enantiopure alcohols.[1] Ruthenium(II) complexes have been
found to be the most powerful catalysts for this purpose.
The Noyori RuII complexes containing a monotosylated 1,2-
diamine[2] or aminoalcohol ligand[3] can offer high catalytic
activity and selectivity in the ATH of ketones. Baratta and
co-workers[4] have reported the highly efficient rutheni-
Copper-catalyzed C N coupling was employed to synthe-
size the intermediate compound 2. The reaction of 1[12] with
K4[Fe(CN)6] in N-methylimidazole in the presence of CuI
formed the cyanation product 2, which was then trans-
formed into imidate 3 by use of sodium and methanol. Con-
densation of compound 3 with a chiral aminoalcohol in
chlorobenzene yielded tridentate ligands 4. Treatment of
compounds 4a and 4b with [RuCl2ACHTNUGTRENUNG(PPh3)3] in toluene
A
heated at reflux afforded RuII complexes 5a (59%) and 5b
(37%), respectively (Scheme 1). Compounds 2–5 were char-
acterized by NMR spectroscopy, HRMS, and elemental
analysis, which were consistent with the stated compositions.
plexes for which the ampy ligand clearly accelerates the re-
action rate of the ATH of ketones. The well-established
À
“N H” effect is rationalized in terms of an outer-sphere
mechanism involving the concerted transfer of hydrogen
À
from the intermediate of type [(H)Ru NHR] to the ketone
substrate.[5] PP[6] and PN,[7] symmetric NNN,[8] NNPP,[9] and
tethered ligands[7,10] have also been reported for constructing
transition-metal-complex catalysts in this area.
Recently, we have reported versatile unsymmetrical pyrid-
yl-based NNN ligands and their exceptionally active RuII
complexes for the transfer hydrogenation (TH) and ATH of
ketones.[11] These complex catalysts were constructed by
means of the following strategy: two different N-donor coor-
dinating arms are tethered to the 2,6 positions of the pyridyl
backbone of the ligand. When one of the coordinating arms
contains a convertible NH moiety, the resultant RuII com-
plex catalysts usually exhibit very high catalytic activity for
the TH or ATH of ketones due to easy in situ generation of
coordinatively unsaturated 16-electron RuII precatalysts.
Herein, we report the synthesis of ruthenium(II) NNN com-
Scheme 1. Synthesis of chiral RuII NNN complexes 5. i) CuI,
K4[Fe(CN)6], N-methylimidazole, 1608C, 16 h, 91%; ii) Na, MeOH,
408C, 24 h, 40%; iii) 1,2-aminoalcohol, HCl (37%), chlorobenzene, 808C,
12 h; iv) [RuCl2ACTHUNTRGNE(UNG PPh3)3], toluene, N2 (0.1 MPa), reflux, 2 h.
plexes containing
a chiral pyrazolyl–pyridyl–oxazolinyl
ligand, featuring a pyrazolyl NH functionality and their ap-
plication as catalysts for the ATH of ketones.
Heating a mixture of 6[13] and N,N-dimethylformamide di-
methyl acetal at reflux, followed by reacting with hydrazine
hydrate, produced 7 in 63% yield. Cyanation of 7 led to the
formation of compound 8, which was treated with chiral 1,2-
aminoalcohols to give ligands 9, containing a pyrazolyl NH
functionality. Complexes 10a (69%) and 10b (<30%) were
synthesized in a similar fashion to the preparation of com-
plexes 5 (Scheme 2). The NMR analysis of 10a in solution is
consistent with its composition. Its 31P{1H} NMR spectrum
revealed a singlet at 46.8 ppm, suggesting one PPh3 ligand is
present in the complex. The molecular structure of 10a was
further confirmed by X-ray crystallographic determination
(Figure 1). In the solid state, complex 10a exhibits a neutral
molecular structure with a nearly planar tridendate NNN
ligand and the ruthenium atom is surrounded by one PPh3
[a] W. J. Ye, Dr. M. Zhao, Prof. Dr. Z. K. Yu
Dalian Institute of Chemical Physics
Chinese Academy of Sciences (CAS)
457 Zhongshan Road, Dalian
Liaoning 116023 (P.R. China)
Fax : (+86)411-8437-9227
E-mail: zkyu@dicp.ac.cn
[b] Prof. Dr. Z. K. Yu
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry, CAS
354 Fenglin Road, Shanghai 200032 (P.R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201703.
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torted bipyrimidal environment. It should be noted that the
single-crystal structure of complex 10b was preliminarily de-
termined although it was not successfully purified by
column chromatography and recrystallization (see the Sup-
porting Information).
Complexes 5 and 10 were then tested as catalysts for the
ATH reactions of acetophenone, 3’-bromoacetophenone,
and 3’-chloroacetophenone in the presence of the iPrOK
base in 2-propanol (Table 1). At 408C, acetophenone was
Table 1. The ATH of ketones catalyzed by complexes 5 and 10.[a]
Ketone
Catalyst
[mol%]
T
[8C]
t
A
Conv.[b]
[%]
ee[b]
[%]
G
1
2
3
4
5
5a (0.5)
5b (1.0)
10a (0.3)
10a (0.4)
10b (0.4)
40
40
40
30
40
98
36 (R)
27 (R)
93 (S)
90 (S)
23 (R)
Scheme 2. Synthesis of chiral RuII NNN complexes 10. i) N,N-Dimethyl-
formamide dimethyl acetal, reflux, 12 h; ii) NH2NH2·H2O, EtOH, reflux,
12 h, 63%; iii) CuI, K4[Fe(CN)6], N-methylimidazole, 1608C, 16 h, 63%;
iv) 1,2-aminoalcohol, ZnCl2, chlorobenzene, reflux, 60 h; v) [RuCl2-
120
8
10
15
94
96[c]
93
97
ACHTUNGTRENNUNG(PPh3)3], toluene, reflux, 8 h.
6
7
10a (0.3)
10a (0.4)
40
30
5
10
99
84 (S)
85 (S)
98[c]
8
10a (0.4)
30
20
97[c]
84 (S)
[a] Conditions: ketone (2.0 mmol; 0.1m in 20 mL iPrOH), iPrOK/cat.=
20:1; N2 (0.1 MPa). [b] Determined by GC analysis using a chiral column
b-DEX 225 (supelco). [c] iPrOK/cat.=10:1.
exclusively reduced to the coresponding alcohol in 98%
yield with 36% ee within 60 min by using 0.5 mol% 5a as
the catalyst, whereas 5b exhibited a much lower catalytic ac-
tivity (Table 1, entries 1 and 2). Complex 10a showed
a decent catalytic activity, reaching 93–96% yields and 90–
93% ee over a period of 8–10 min at 30–408C (Table 1, en-
tries 3 and 4). Although 10b also exhibited good catalytic
activity, the desired product was only formed with a poor
enantiopurity (23% ee) presumably due to the low purity of
the catalyst (Table 1, entry 5). These results suggest that the
convertible NH group in the ligand has a remarkable en-
hancing effect on the catalyst activity (Table 1, entries 1–5).
We assume that complexes 10 could be easily converted into
the coordinatively unsaturated 16-electron complexes in situ
under the basic conditions [Eq. (1)],[11a,f] which were then
transformed into the catalytically active RuH species and
thus facilitated the catalytic reaction. Screening of the ATH
of 3’-bromoacetophenone and 3’-chloroacetophenone re-
vealed the optimal reaction conditions to be 30–408C with
0.3–0.4 mol% 10a as the catalyst.
Figure 1. The molecular structure of complex 10a.[14]
ligand, the three pyridyl, pyrazolyl, and oxazolinyl nitrogen
donor atoms, and one chloride atom. The PPh3 ligand is
positioned trans to and far from the isopropyl group to
À
À
reduce the steric hindrance. The Ru N(2), Ru N(3), and
À
Ru N(4) bond lengths are 2.101, 1.960, and 2.120 ꢁ, respec-
tively, demonstrating that 4a is a tridentate ligand. The
three P-Ru-N angles are in the range 91.6–94.58, and the P-
Ru-Cl(1) and N(2)-Ru-N(4) angles are 178.88 and 155.38, re-
spectively, revealing that the metal atom is situated in a dis-
Next, the ATH reactions of various aromatic ketones
were explored under the optimized conditions (Table 2). At
408C and with 0.3 mol% 10a as the catalyst, propiophe-
none, 3’-methylacetophenone, and 2’-bromoacetophenone
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Catalysts for the Asymmetric Transfer Hydrogenation of Ketones
COMMUNICATION
Table 2. (Continued)
Ketone
t
Conv.[b]
[%]
ee[b]
[%]
final TOF
[hÀ1
[min]
N
]
14
5
93
83
1395
15
16
17
10
20
10
99[e]
99
99
77
89
743
743
728
Table 2. The ATH reactions of ketones catalyzed by complex 10a.[a]
Ketone
t
Conv.[b]
[%]
ee[b]
final TOF
[hÀ1
A
[%]
A
]
97[e]
1
2
3
4
8
96[c]
96[c]
97
93
94
98
90
2400
480
18
19
20
20
75[e]
78
86
281
360
40
5
96[e]
2910
423
[a] Conditions: ketone (2.0 mmol; 0.1m in 20 mL iPrOH), iPrOK/cat.=
10:1; N2 (0.1 MPa), 308C. [b] Determined by GC analysis using a chiral
column b-DEX 225 (supelco). All the major secondary alcohol products
had the S configuration. The absolute configuration was determined by
comparing the optical rotations of the products with the literature values.
[c] 10a (0.3 mol%), 408C. [d] 10a (0.6 mol%). [e] 10a (0.8 mol%).
45
95[c]
5
30
91[c]
90
303
were reduced to the corresponding alcohols in 95–99%
yields with 90–97% ee within 5–45 min, reaching final TOFs
of up to 3960 hÀ1 (Table 2, entries 2, 4, and 6). By using
0.6 mol% of the catalyst, the reaction of 4’-methylacetophe-
none gave the product in 91% yield and 90% ee (Table 2,
entry 5). 2’-Methylacetophenone, 4’-bromoacetophenone,
and chloro-substituted acetophenones reached 97–98% con-
versions with 73–98% ee for their reduction products over
a period of 5–20 min (Table 2, entries 3 and 8–11). The
ATHs of fluoro-substituted acetophenones were also accom-
plished, but afforded less enantioselective products (67–
86% ee, Table 2, entries 12–14). Surprisingly, 2’-trifluoro-
6
7
5
99[c]
98
97
85
3960
1470
10
8
20
98
80
735
9
20
20
98
97
96
84
735
728
ACHUTNGERNmNUG ethHCATUNGTRNEyNUGN lacetophenone underwent the ATH reaction to give
the desired product in 99% yield and 99% ee (Table 2,
entry 15), whilst 3’-CF3-, 3’-MeO-, and 4’-MeO-substituted
acetophenones and 2-acetylnaphthalene underwent the
ATH reactions much less efficiently (Table 2, entries 16–19).
It is noteworthy that all of the major alcohol products had
an S configuration.
10
11
20
98
73
735
In summary, we have developed a strategy to construct
highly active RuII NNN complex catalysts containing
a chiral pyridyl-based 1H-pyrazolyl–oxazolinyl ligand for
the asymmetric transfer hydrogenation of ketones. These
complex catalysts exhibited much higher catalytic activity
than RuII pyridyl–pyrazolyl–oxazolinyl complexes featuring
no NH functionality.
12
13
30
30
96[d]
67
86
320
485
94
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Z. K. Yu et al.
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Experimental Section
Typical procedure for the ATH of ketones: Under a nitrogen atmos-
phere, a mixture of a ketone (2 mmol), iPrOH (18.2 mL), and the chiral
catalyst solution (1 mL) containing the RuII complex (8 mmol) in iPrOH
was stirred at 308C for 15 min. Then, iPrOK (0.8 mL, 0.1m) in iPrOH
was introduced to initiate the reaction. During the reaction, 0.1 mL of
the reaction mixture was sampled and immediately diluted with pre-
cooled (08C) iPrOH (0.5 mL) for GC analysis by means of a chiral b-
DEX 225 (supelco) coulmn. After the reaction was complete, the reac-
tion mixture was condensed under reduced pressure and subjected to pu-
rification by silica gel column chromatography to afford the correspond-
ing alcohol product, which was identified by comparison with the authen-
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Natural Science Foundation of China (20972157) for support of this re-
search.
Keywords: asymmetric catalysis · ketones · ligand design ·
ruthenium · transfer hydrogenation
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¯
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Received: May 15, 2012
Revised: June 13, 2012
Published online: && &&, 0000
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Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Catalysts for the Asymmetric Transfer Hydrogenation of Ketones
COMMUNICATION
Lowering the ketone: RuII complexes
containing a chiral pyridyl-based 1H-
pyrazolyl–oxazolinyl NNN ligand were
synthesized and structurally character-
ized by X-ray crystallographic studies.
These complex catalysts efficiently cat-
alyzed the asymmetric transfer hydro-
genation of ketones, reaching up to
99% ee for the desired products (see
scheme).
Asymmetric Catalysis
W. J. Ye, M. Zhao,
Z. K. Yu* ...................... &&&& — &&&&
Ruthenium(II) Pyrazolyl–Pyridyl–
Oxazolinyl Complex Catalysts for the
Asymmetric Transfer Hydrogenation
of Ketones
Chem. Eur. J. 2012, 00, 0 – 0
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www.chemeurj.org
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These are not the final page numbers!