Ruthenium-catalysed efficient asymmetric transfer hydrogenation of aromatic ketones using cinchona alkaloids as chiral ligands

Article abstract of DOI:10.3184/174751913X13845949778485

Cinchona alkaloid derivatives were applied in asymmetric transfer hydrogenation of aromatic ketones in a ruthenium catalytic system using i-PrOH as the hydrogen source. A series of aromatic ketones could be transfer-hydrogenated to the corresponding alcohols with good to excellent conversion and enantioselectivity. The best results were achieved using 9-amino(9-deoxy) epiquinidine as the ligand; the enantioselectivity with acetophenone and 2′-(trifluoromethyl)acetophenone could reach 90% ee.

Full text of DOI:10.3184/174751913X13845949778485

JOURNAL OF CHEMICAL RESEARCH 2013
DECEMBER, 761–763
RESEARCH PAPER 761
Ruthenium-catalysed efficient asymmetric transfer hydrogenation of
aromatic ketones using cinchona alkaloids as chiral ligands
Heyan Jiang*
Key Laboratory of Catalysis Science and Technology of Chongqing Education Commission, Chongqing Key Laboratory of Catalysis and
Functional Organic Molecules, Chongqing Technology and Business University, Chongqing 400067, P.R. China
Cinchona alkaloid derivatives were applied in asymmetric transfer hydrogenation of aromatic ketones in a ruthenium catalytic
system using i‑PrOH as the hydrogen source. A series of aromatic ketones could be transfer‑hydrogenated to the corresponding
alcohols with good to excellent conversion and enantioselectivity. The best results were achieved using 9‑amino(9‑deoxy)
epiquinidine as the ligand; the enantioselectivity with acetophenone and 2’‑(trifluoromethyl)acetophenone could reach 90% ee.
Keywords: cinchona alkaloid, asymmetric transfer hydrogenation, ruthenium, aromatic ketone
Cinchona alkaloids and their derivatives have been widely used
as versatile chiral catalysts, ligands, column packing, and chiral
shift reagents.1 The asymmetric transfer hydrogenation of
aromatic ketones has attracted much attention, since the transfer
hydrogenation products are key intermediates and advanced
materials in the manufacture of pharmaceuticals and organic
synthesis.2,3 In view of the low cost of the reducing agent and
operational simplicity, a metal-catalysed transfer hydrogenation
reaction using i-PrOH as a hydrogen source appears to be a
safe and attractive supplement to catalytic hydrogenation with
hydrogen. In the last decade, some chiral diamine ligands and
chiral N,P ligands have been used to coordinate with metals
such as Ru, Rh and Ir in enantioselective transfer hydrogenation
of aromatic ketones.4–8 Noyori and co-workers developed highly
efficient chiral TsDPEN-base ruthenium or iridium catalysts
for the asymmetric transfer hydrogenation of aromatic ketones
to chiral alcohols with excellent enantiomeric purity.4 Since the
asymmetric transfer hydrogenation of aromatic ketones has
great significance in homogeneous enantioselective industrial
processes, the development of new easily obtained and stable
catalysts that provide high activity and enantioselectivity
remains a scientific challenge. As part of our ongoing research
in the field of reduction of aromatic ketones,9–13 reported
here are the results of our studies on ruthenium catalysed
asymmetric transfer hydrogenation of aromatic ketones using
cinchona alkaloids 1–4 as chiral ligands. The combination with
cinchona alkaloid derivatives and ruthenium has proven to be
highly efficient and enantioselective.8
Result and discussion
The Ru(II) catalyst was generated in situ by mixing cinchona
alkaloids 1–4 with [Ru(COD)Cl2]n (cinchona alkaloid:Ru=1:1)
in i-PrOH at room temperature under argon. Transfer
hydrogenation occurred when base and aromatic ketones
were added to the above catalyst solution. Initial studies were
performed using acetophenone a as a model substrate under
different conditions (Scheme 1). For the transfer hydrogenation
reaction of the acetophenone a, the absolute configuration of
the product was highly dependent upon both the C8-position
and C9-position configuration in the chiral ligands. The results
are summarised in Table 1. 9-Amino(9-deoxy)epiquinine 1
and 9-amino(9-deoxy)epiquinidine 3, acting as diastereomeric
pairs, led to the products with different absolute configurations.
Other chiral ligands, such as quinine 2 and quinidine 4 were
tested, and the amine group in the 9-position of the ligand is
essential.
The amount of catalyst had an important influence on the
reaction. As in Table 2, when 1% catalyst was used, the reaction
did not occur at 0 °C. The transfer hydrogenation conversion
was influenced by an increase of the amount of catalyst, a
lowering of the reaction temperature and by the reaction
time. When the ratio of catalyst increased from 1 to 10%, the
enantioselectivity increased as the ratio of catalyst increased
(entries 1–5). Extension of the ratio of catalyst from 10 to 30%
resulted in a slight erosion of the asymmetric induction (entries
5–7). The effect of temperature on the enantioselectivity
N
N
N
N
H
H
H
H
H
H
H
H
H2N
HO
NH2
OH
H3CO
OCH3
OCH3
H3CO
N
N
N
N
3
4
1
2
OH
R2
O
OH
[Ru(COD)Cl2]n/1-4
O
*
R2
+
R1
+
R1
base
aromatic ethanol
b: R1 = H, R2 = CH2CH3
aromatic ketone
a: R1 = H, R2 = CH3
c: R1 = H, R2 =CH( CH3)2
e: R1 = o-OMe, R2 = CH3
g: R1 = p-OMe, R2 = CH3
d: R1 = o-CF3, R2 = CH3
f: R1 = p-CF3, R2 = CH3
Scheme 1 Cinchona alkaloids used and the asymmetric transfer hydrogenation of aromatic ketones.
* Correspondent. E-mail: orgjiang@163.com
JCR1302210_FINAL.indd 761
29/11/2013 12:09:12

762 JOURNAL OF CHEMICAL RESEARCH 2013
Table 1 Influence of Ru(II)–1–4 complexes on the catalytic transfer
Table 4 Asymmetric transfer hydrogenation of different aromatic ketones
catalysed by Ru(II)–3 complex
hydrogenation of acetophenonea
OH
O
OH
O
OH
[Ru(COD)Cl2]n/3
O
R2
*
OH
[Ru(COD)Cl2]n/1-4
O
R2
+
R1
+
*
R1
+
+
KOH
KOH
Entry
Substrate
Yield/%
83
ee/%
Configurationa
S
Ligands
Yield/%
95
0
93
0
ee/%
36
–
75
–
Configurationb
O
1
2
3
4
R
–
S
–
1
2
3
90
86
66
O
aReactions were carried out using a 0.1 M solution of acetophenone
(1 mmol) in i‑PrOH, acetophenone:Ru:ligand:KOH=100:5:5:10, 35 °C,
48 h.
98
24
96
56
S
S
S
S
O
bDetermined by sign of rotation.
CF3
O
Table 2 Influence of the ratio of catalyst to substrate and temperature on
the transfer hydrogenation of acetophenone catalysed by Ru(II)–3 complex
4
5
90
87
OH
O
OH
[Ru(COD)Cl2]n/3
OMe O
O
*
+
+
KOH
O
Catalyst Temperature Time
Yield
/%
ee
Entry
Configuration
/%
/oC
/h
/%
6
7
97
70
72
63
S
S
1
2
3
4
5
6
7
1
3
5
10
10
20
30
0
48
48
96
48
96
96
48
0
60
81
72
83
90
70
0
–
S
S
S
S
S
S
F3C
20
0–20
0–20
0
68
81
84
90
88
85
O
MeO
0
0
The reaction conditions are the same as in Table 3 (Ru:Base=1:2).
aDetermined by sign of rotation.
The reaction conditions are the same as in Table 1 (ligand 3) except for the
amount of catalyst, the reaction temperature and the reaction time.
ratio of KOH:Ru was lower, the yield and enantioselectivity
decreased dramatically (entries 4 and 5). On the other hand,
when we sequentially increased the amount of base, the yield
and enantioselectivity went down slightly (entries 6 and 7).
Some representative examples are listed in Table 4 for
the asymmetric transfer hydrogenation of aromatic ketones
catalysed by the Ru(II)–3 complex under the optimised
conditions. In general, good to excellent conversions and
enantioselectivities were achieved. The conversion and
enantioselectivity of the reaction was affected by the steric and
electronic properties of the substrates. The enantioselectivity
decreased by increasing the bulkiness of the alkyl group from
methylorprimaryalkyltoisopropyl(entries1–3). Substitutionat
the phenyl ring of acetophenone with an electron-drawing group
gave yields and enantioselectivity that were higher than those
with electron-donating groups (entries 4 and 6 versus 5 and 7).
It was found that when the substituent is in the para position of
acetophenone, the degree of the enantioselection was obviously
decreased in comparison to the ortho-substituted counterparts
(entries 6 and 7 versus 4 and 5). Meanwhile, the degree of the
activity of a para-substituted acetophenone was increased in
comparison to an ortho-substituted counterpart because of
the steric bulk (entries 6 and 7 versus 4 and 5). The highest
enantiomatic excesses were obtained in the hydrogenation of
acetophenone (entry 1) and 2’-(trifluoromethyl)acetophenone
(entry 4).
Table 3 Influence of the base on the transfer hydrogenation of acetophenone
catalysed by Ru(II)–3 complexa
OH
O
OH
[Ru(COD)Cl2]n/3
O
*
+
+
base
Base:Ru
/mol
Yield
/%
ee
/(%)
Entry
Base
Configuration
1
2
3
4
5
6
7
LiOH
2:1
2:1
2:1
0:1
1:1
4:1
8:1
57
72
83
0
27
89
80
78
85
90
–
70
85
82
S
S
S
–
S
S
S
NaOH
KOH
KOH
KOH
KOH
KOH
aReactions were carried out using a 0.1 M solution of acetophenone
(1 mmol) in i‑PrOH, acetophenone:Ru:ligand=100:10:10, 0 °C, 96 h.
of the reaction transfer hydrogenation was significant. The
enantioselectivity increased constantly as the temperature was
lowered, although the rate of reaction was reduced (entries 4
versus 5). The best enantiomeric excess (90% ee) was achieved
at 0 °C with 10% catalyst (entry 5).
As in previous reports, the base could activate the asymmetric
transfer hydrogenation catalyst markedly.4–8 We have studied
the effect of base additives on the reduction of acetophenone
(Table 3). Ru(II)–3 complex was inactive without the base
(entry 4). When alkali metal hydroxides LiOH, NaOH and KOH
were tested in the transfer hydrogenation of acetophenone,
both the activity and the enantioselectivity decreased in the
order of KOH>NaOH>LiOH (entries 1–3). When the molar
In conclusion, we have demonstrated that the combination
of [Ru(COD)Cl2]n and cinchona alkaloid derivatives results
in the formation of efficient catalysts for asymmetric transfer
hydrogenation of aromatic ketones. For a variety of aromatic
ketones, moderate to excellent enantioselectivity are observed.
The work reported here succeeded in the creation of a new
JCR1302210_FINAL.indd 762
29/11/2013 12:09:13

JOURNAL OF CHEMICAL RESEARCH 2013 763
1H), 7.20–7.65 (m, 5H). GC β‑DEX120 capillary column, column
temperature: 115 °C, t (R)=12.7 min, t (S)=13.5 min.
catalyst for the highly enantioselective transfer hydrogenation
of aromatic ketones. Additional work is ongoing.
(S)-(−)-1-Phenyl-1-propanol: Table 4, entry 2; 98% yield, 86% ee (S),
[α]25D = −30.5 (c 5.0, EtOH) [lit.4, [α]23D = −34.0 (c 5.03, EtOH)]. 1H NMR
(400 M, CDCl3),δ 1.15–1.25 (m, 3H), 1.69 (s, 1H), 1.72–1.92 (m, 2H), 4.61
(d, J=4.5 Hz, 1H), 7.20–7.56 (m, 5H). GC β‑DEX120 capillary column,
column temperature: 115 °C, t (R)=14.5 min, t (S)=15.9 min.
(S)-(−)-2-Methyl-1-phenyl-1-propanol: Table 4, entry 3; 24% yield,
66% ee (S), [α]25D = −33.0 (c 0.5, Et2O) [lit.16, [α]23D = −45.7 (c 0.0623,
Et2O)]. 1H NMR (400 M, CDCl3),δ 0.89–1.10 (m, 3H), 1.20–1.35 (m, 3H),
1.86–1.96 (m, 2H), 4.32–4.40 (m, 1H), 7.29–7.46 (m, 5H). GC β‑DEX120
capillary column, column temperature: 115 °C, t (R)=18.6 min, t
(S)=19.8 min.
(S)-(−)-1-o-Trifluoromethylphenylethanol: Table 4, entry 4; 96% yield,
90% ee (S), [α]25D = −36.0 (c 0.7, MeOH) [lit.17,18, [α]20D = −35.4 (c 0.70,
MeOH)]. 1H NMR (400 M, CDCl3),δ 1.49–1.55 (m, 3H), 1.99 (s, 1H), 5.25
(d, J=6.1 Hz, 1H), 7.36–7.81 (m, 4H). GC β‑DEX120 capillary column,
column temperature: 115 °C, t (R)=21.6 min, t (S)=22.5 min.
(S)-(−)-1-o-Methoxyphenylethanol: Table 4, entry 5; 56% yield, 87%
ee (S), [α]25D = −29.6 (c 1.0, MeOH) [lit.4, [α]23D = −32.7 (c 1.0, MeOH)].
1H NMR (400 M, CDCl3),δ 1.50 (m, 3H), 2.19 (s, 1H), 3.87 (s, 3H), 5.10
(m, 1H), 6.96–7.34 (m, 4H). GC β‑DEX120 capillary column, column
temperature: 120 °C, t (R)=24.7 min, t (S)=26.4 min.
Experimental
Quinine and quinidine were purchased from Acros Organics. Cinchona
alkaloid derivatives were synthesised according to the procedures
reported by Brunner et al.14,15 Di-isopropyl azodicarboxylate was
purchased from Fluka. Hydrazoic acid-benzene (3.6%) was prepared
starting from sodium azide and sulfuric acid in our laboratory. All
other reagents were purchased from Kelong Chemical Reagent Co.
Inc. Acetophenone was distilled prior to use. Tetrahydrofuran was
freshly distilled under nitrogen from a deep-blue solution of sodium-
benzophenone. iso-Propanol was treated with sodium and degassed.
1
Other chemicals were used as received. H NMR was performed in
CDCl3 and recorded on a Varian INOVA 400 MHz spectrometer,
1
and H NMR spectra were collected at 400.0 MHz using a 10,000 Hz
spectral width, a relaxation delay of 1.0 s, and Me4Si (0.0 ppm) as the
internal reference. Products were analysed by GC (hydrogen as carrier
gas) with an FID detector and 30 m×0.25 mm×0.15μm β‑DEX120
capillary column. All optical rotations ([α]25D) were measured on a
Perkin-Elmer 341 polarimeter. Optical rotations were measured at the
wavelength of the sodium D-line (589.3 nm) at a temperature of 25 °C.
9-Amino(9-deoxy)epiquinine (1): A well stirred mixture of quinine
2 (3.24 g, 10 mmol) and triphenylphosphine (3.15 g, 12 mmol) in
absolute THF (50 mL) was cooled to 0 °C, and hydrazoic acid-
benzene (3.6%, 12 mmol) was added. Then, DIAD (di-isopropyl
azodicarboxylate; 2.16 mL, 11 mmol) in absolute THF (10 mL) was
added slowly. The mixture was heated to 50 °C and a yellow transparent
solution was obtained. The reaction was stirred for 3 h at 50 °C. Then
triphenylphosphine (2.62 g, 10 mmol) in absolute THF (10 mL) was
added in one portion and the solution was stirred at 40 °C until gas
evolution ceased. Water (2 mL) was added and the solution was stirred
overnight. Solvents were removed in vacuo and the residue was dissolved
in CH2C12 and poured into 2 M hydrochloric acid (1:1, 100 mL). The
aqueous phase was washed with CH2Cl2 (3×30 mL). Then 2 M NaOH
was added until pH>10. The mixture was extracted with diethyl ether
(3×60 mL) and the combined organic phase was washed with saturated
Na2CO3 aqueous solution (3×60 mL) and dried with Na2CO3. The solvent
was removed and the product 1 was obtained following purification on
silica gel (eluent:Et2O–MeOH–Et3N=10:1:0.3), slightly yellow oil,
yield 51%. [α]25D +80.1 (c 1.0 in CHCl3) [lit.14, [α]25D +80 (c 1.1 in CHCl3)].
IR: νmax (KBr)/cm–1 3384, 3290, 2940, 2860, 1630, 1605, 1517. 1H NMR
(400 M, CDCl3), δ 0.81 (m, 1H), 1.27–1.62 (m, 4H), 2.08 (m, 2H), 2.29 (m,
1H), 2.77 (m, 2H), 3.02–3.34 (m, 3H), 3.97 (s, 3H), 4.60 (d, J= 10.1 Hz,
1H), 4.97 (m, 2H), 5.79 (m, 1H), 7.36–8.09 (m, 4H), 8.77 (d, J=4.2 Hz,
1H). MS: m/z 323 (M+).
(S)-(−)-1-p-Trifluoromethylphenylethanol: Table 4, entry 6; 97% yield,
72% ee (S), [α]25D = −12.9 (c 0.1, MeOH) [lit.16, [α]23D = −10.8 (c 0.0578,
1
MeOH)]. H NMR (400 M, CDCl3),δ 1.51 (m, 3H), 2.10 (s, 1H), 4.96
(m, 1H), 7.36–7.54 (m, 4H). GC β‑DEX120 capillary column, column
temperature: 115 °C, t (R)=20.7 min, t (S)=22.4 min.
(S)-(−)-1-p-Methoxyphenylethanol: Table 4, entry 7; 70% yield, 63%
ee (S), [α]25D = −33.9 (c 1.0, CHCl3) [lit.4, [α]23D =−51.9 (c 1.04, CHCl3)].
1H NMR (400 M, CDCl3),δ 1.49 (m, 3H), 1.85 (s, 1H), 3.89 (s, 3H), 4.95
(m, 1H), 6.86–7.34 (m, 4H). GC β‑DEX120 capillary column, column
temperature: 120 °C, t (R)=26.6 min, t (S)=28.2 min.
This work was financially supported by the National Natural
Science Foundation of China (No. 21201184), Natural Science
Foundation Project of CQ (No. CSTC, 2011BA5025) and the
‘100 leading scientists promotion’ project of Chongqing.
Received 29 September 2013; accepted 18 October 2013
Paper 1302210 doi: 10.3184/174751913X13845949778485
Published online: 6 December 2013
References
1
2
3
K.K. Acprzak, J. Gawroñski, Synthesis, 2001, 7, 961.
V. Farina, J.T. Reeves and C.H. Senanayake, Chem. Rev., 2006, 106, 2734.
Z.F. Chen, A.J. Zhang, L.X. Zhang, J. Zhang and X.X. Lei, J. Chem. Res.,
2008, 5, 266.
9-Amino(9-deoxy)epiquinidine (3) was synthesised by a similar
procedure, and isolated as a slightly yellow oil, yield 45%. [α]25D +69.6
(c 2.5 in CHCl3) [lit.15, yield 46%. [α]22D =+69 (c 2.51 in CHCl3)]. IR: νmax
(KBr)/cm–1 3375, 3290, 2940, 2850, 1635, 1600, 1518. 1H NMR (400 M,
CDCl3), δ 0.95 (m, 1H), 1.15–1.22 (m, 1H), 1.46–1.56(m, 3H), 2.16 (m,
2H), 2.28 (m, 1H), 2.79–3.21 (m, 5H), 3.97 (s, 3H), 4.67 (d, J=9.9 Hz, 1H),
5.09 (m, 2H), 5.85 (m, 1H), 7.35–8.19 (m, 4H), 8.75 (d, J=4.5 Hz, 1H).
MS: m/z 323 (M+).
4
5
A. Fujii, S. Hashiguchi, N. Uematsu, T. Ikariya and R. Noyori, J. Am.
Chem. Soc., 1996, 118, 2521.
D.J. Ager, A.H.M. de Vries and J.G. de Vries, Chem. Soc. Rev., 2012, 41,
3340.
6
7
8
Q. Chen, Curr. Org. Chem., 2013, 17, 1303.
Y.M. Zhang, H.L. Zhang and P. Liu, J. Chem. Res., 2011, 1, 26.
R. Jiang, X. Sun, W. He, H. Chen and Y. Kuang, Appl. Organometal.
Chem., 2009, 23, 179.
Asymmetric transfer hydrogenation reaction; general procedure
9
H.Y. Jiang, B. Sun, X.X. Zheng and H. Chen, Appl. Catal. A, 2012, 421–
422, 86.
Cinchona alkaloid was added to [Ru(COD)Cl2]n in dry degassed
i-PrOH (10 mL) and stirred at room temperature for 30 min under
argon. The base was added and the reaction mixture was stirred for
another 30 min. The aromatic ketone was then added in one portion
(0.1 M) and the reduction was conducted at the given temperature
for the time indicated. After completion of the reaction, the resulting
solution was neutralised, and then extracted with Et2O. The organic
phase was dried over MgSO4 and the conversion and enantiomeric
excess were determined by GC analysis according to the literature.4,16–18
(S)-(−)-1-Phenylethanol: Table 4, entry 1; 83% yield, 90% ee (S),
[α]25D = −45.0 (c 1.0, CH2Cl2) [lit.4, [α]23D = −50.0 (c 1.0, CH2Cl2)]. 1H NMR
(400 M, CDCl3), δ 1.40–1.55 (m, 3H), 1.90 (s, 1H), 4.95 (d, J=6.3 Hz,
10 H.Y. Jiang, C.F. Yang, C. Li, H.Y. Fu, H. Chen, R.X. Li and X.J. Li, Angew.
Chem. Int. Ed., 2008, 47, 9240.
11 H.Y. Jiang, X.X. Zheng, Z.Y. Yin and J.J. Xie, J. Chem. Res., 2011, 35, 220.
12 H.Y. Jiang, Z.F. Wu and H. Chen, Acta. Phys-Chim. Sin., 2013, 29, 1572.
13 H.Y. Jiang, H. Chen and R.X. Li, Catal. Commun., 2010, 11, 584.
14 H. Brunner, J. Büegler and B. Nuber, Tetrahedron Asym., 1995, 6, 1699.
15 H. Brunner and P. Schmidt, Eur. J. Org. Chem., 2000, 2119.
16 M.B. Cater, B. Schiott, A. Gutierrez and S.L. Buchward, J. Am. Chem.
Soc., 1994, 116, 11667.
17 H. Shimisu, D. Igarashi, W. Kuriyama, Y. Yusa, N. Sayo and T. Saito, Org.
Lett., 2007, 9, 1655.
18 K. Nakamura and T. Matsuda, J. Org. Chem., 1998, 63, 8957.
JCR1302210_FINAL.indd 763
29/11/2013 12:09:13

Copyright of Journal of Chemical Research is the property of Science Reviews 2000 Ltd. and
its content may not be copied or emailed to multiple sites or posted to a listserv without the
copyright holder's express written permission. However, users may print, download, or email
articles for individual use.