Varying the ratio of formic acid to triethylamine impacts on asymmetric transfer hydrogenation of ketones

Article abstract of DOI:10.1016/j.molcata.2012.02.002

Asymmetric transfer hydrogenation (ATH) is frequently carried out in the azeotropic mixture of formic acid (F) and triethylamine (T), where the F/T molar ratio is 2.5. This study shows that the F/T ratio affects both the reduction rate and enantioselectivity, with the optimum ratio being 0.2 in the ATH of ketones with the Ru-TsDPEN catalyst. Under such conditions, a range of substrates have been reduced, affording high yields and good to excellent enantioselectivities. In comparison with the common azeotropic F-T system, the reduction is faster. This protocol improves both the classic azeotropic and the aqueous-formate system when using water-insoluble ketones.

Full text of DOI:10.1016/j.molcata.2012.02.002

Journal of Molecular Catalysis A: Chemical 357 (2012) 133–140
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Journal of Molecular Catalysis A: Chemical
journal homepage: www.elsevier.com/locate/molcata
Varying the ratio of formic acid to triethylamine impacts on asymmetric transfer
hydrogenation of ketones
Xiaowei Zhoua,b, Xiaofeng Wub, Bolun Yanga,∗, Jianliang Xiaob,∗
a Department of Chemical Engineering, State Key Laboratory of Multiphase Flow in Power Engineering, Xi’an Jiaotong University, Xi’an 710049, China
b Department of Chemistry, University of Liverpool, Crown Street, L69 7ZD, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Asymmetric transfer hydrogenation (ATH) is frequently carried out in the azeotropic mixture of formic
acid (F) and triethylamine (T), where the F/T molar ratio is 2.5. This study shows that the F/T ratio affects
both the reduction rate and enantioselectivity, with the optimum ratio being 0.2 in the ATH of ketones
with the Ru-TsDPEN catalyst. Under such conditions, a range of substrates have been reduced, affording
high yields and good to excellent enantioselectivities. In comparison with the common azeotropic F-T
system, the reduction is faster. This protocol improves both the classic azeotropic and the aqueous-
formate system when using water-insoluble ketones.
Received 19 December 2011
Received in revised form 2 February 2012
Accepted 4 February 2012
Available online 18 February 2012
Keywords:
Transfer hydrogenation
Asymmetric hydrogenation
Ketones
© 2012 Elsevier B.V. All rights reserved.
Ruthenium
Solvent effect
1. Introduction
complexes and organocatalysts have been reported, their reduction
rates and/or enantioselectivities are generally inferior [9–12].
ATH has emerged as a powerful and practical tool for reduction
reactions in both academia and industry. It is simple to oper-
ate, requiring neither the hazardous hydrogen gas nor pressure
vessels, and there are a number of chemicals that are easily avail-
able and can be used as hydrogen donors [1]. The first example
of ATH appeared as enantioface discriminating reduction in the
1970s from the groups of Ohkubo and Sinou, who explored the
catalysis with [RuCl2(PPh3)3] in the presence of a chiral monophos-
phine or chiral hydrogen donor [2]. However, the optical purity of
products was generally low before the 1990s, with few ee values
exceeding 90% [3]. Among the catalysts developed for ATH so far,
the most notable and successful one is the TsDPEN-coordinated
(TsDPEN = N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine, 1)
Ru(II) complex (Ru-1) discovered by Noyori and co-workers in 1995
[4]. The application of the TsDPEN type ligand has led to the reduc-
tion of a wide range of substrates containing C = X (X = O, N, C)
bonds with excellent ee’s (up to 99%), including especially aromatic
ketones and imines [5]. This significant breakthrough has inspired
intense research into this field. As a result, a variety of related
metal catalysts have been developed. Generally, the catalysts of
choice are complexes based on the platinum metals rhodium [6]
iridium [7] and ruthenium [8]. While other catalysts such as iron
The reaction medium and hydrogen sources employed are
also important for the ATH reactions. Most often, the metal-
catalyzed ATH reactions are performed in 2-propanol (IPA) or in
the azeotropic mixture of formic acid (HCOOH) and triethylamine
(NEt3) (F-T), in which the F/T molar ratio is 2.5:1 [5d,h,i,8a,c,13]. A
drawback regarding ATH in IPA is the reversibility of the reduction
process. The equilibrium is regulated by the oxidation poten-
tials of the relevant carbinol/ketone couples. The reaction gives a
high stereoselectivity at low conversions, but the reverse reaction
gets faster and the enantioselectivity declines as the conversion
increases [14]. To optimize the conversion in IPA, the catalytic
reaction is generally performed at a low substrate concentration.
The azeotropic F-T, which acts as both the solvent and hydrogen
donor, is a better hydrogen-donor than IPA because the result-
ing carbon dioxide is thermodynamically much more stable and
can be removed, thus making the reaction irreversible. Further-
more, it gives a single phase at room temperature and is miscible
with many organic compounds at 20–60 ◦C, allowing for high sub-
strate concentrations without reverse reaction and racemization.
The main drawback for ATH in the azeotropic F-T is that some
catalysts undergo fast decomposition in it and some may lose com-
pletely the catalytic activity [14]. Another downside is that a long
induction period may exist, necessitating a long reaction time to
achieve good conversion [15].
Recently, we reported that water can be used as green solvent in
ATH catalyzed by Ru(II), Rh(III) and Ir(III) complexes [5o,8d,15–20].
∗
Corresponding authors. Tel.: +44 151 7942937; fax: +44 151 7943588.
E-mail addresses: blunyang@mail.xjtu.edu.cn (B. Yang), j.xiao@liv.ac.uk (J. Xiao).
1381-1169/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.molcata.2012.02.002

134
X. Zhou et al. / Journal of Molecular Catalysis A: Chemical 357 (2012) 133–140
The reduction affords fast reaction rate, excellent enantioselectiv-
ity and high chemoselectivity in a short reaction time for a wide
range of substrates at substrate to catalyst ratios (S/C) ranging
from 100:1 to 10,000:1. Moreover, it is easy to conduct, requir-
ing no modification to the ligands, no organic solvents, and often
no inert gas protection throughout. Additional advantage includes
the use of HCO2Na, a safe inexpensive reductant. This aqueous-
phase reduction provides a new method that is simple, economical
and eco-friendly, and can be readily adopted for laboratory syn-
thesis and commercial scale production of chiral alcohols [16f,17].
However, not all ketones can be reduced in water with high con-
version and good ee’s, partly due to their limited solubility in water
[1,5h,u,9c,14,16d,18]. Although surfactant can be used for ATH in
water, [6b,18c,19] they obviously add further complication to the
reaction.
During our study, we found that the pH of the reaction
solution plays a crucial role in the catalyst performance in the
aqueous-phase ATH [15,16a,c]. Both the reduction rate and enan-
tioselectivity can be dependent on the solution pH. Further studies
have revealed that this pH regulation is common for ATH of ketones
and imines in water [5u,6b,l,8d,n,o,9e,j–l,n,10,12b,15,16,18d,20].
These observations prompted us to investigate the effect of the
F/T molar ratios on ATH of ketones in F-T mixtures, in the hope
to improve this powerful transformation. Surprisingly somehow,
there are only two examples in the literature, where the F/T ratio
was reduced to 1/1, and in each case, only one ketone substrate was
examined [21].
mixture at 40 ◦C for 0.5 h, the suspension was directly used for the
subsequent reduction reactions.
2.4. General procedure for ATH of ketones
A typical procedure for the ATH of acetophenone (acp) with Ru-
1 in a F-T mixture is as follows. The precatalyst was prepared by
reacting [RuCl2(p-cymene)]2 (3.1 mg, 0.005 mmol) and 1 (4.4 mg,
0,012 mmol) in degassed F-T (2 mL) with different F/T molar ratios
(0.09/1 to 4.6/1) at 40 ◦C for 0.5 h under N2. Then acp (0.11 mL,
1 mmol) was added and the reaction mixture was allowed to react
at 40 ◦C for a certain period of time, and monitored by analytical
TLC. The reaction mixture was then cooled to room temperature,
followed by extraction with CH2Cl2 (DCM, 3 × 3 mL). The organic
phase was then collected, a small amount of which was passed
though a short silica gel column before being subjected to GC analy-
sis. For isolation, the mixture was then dried over Na2SO4, filtered,
concentrated and purified by silica gel column using hexane and
ethyl acetate as eluent to give the expected product. The prod-
ucts were routinely analyzed by comparing their GC/HPLC and
NMR (1H and 13C) data with the literature data, and additionally
by mass spectroscopy and elemental analysis when it was neces-
sary. The stereochemistry of products was assigned by comparing
the GC/HPLC retention time with the literature data. The products
under question have been reported in the literature [5,14–17].
(R)-1-Phenylethanol: [5j,16c] GC (Chirasil Dex CB): carrier gas:
helium, 80 psi; injector temperature: 250 ◦C; column temperature:
120 ◦C; 8.17 min (R); 8.29 min (S). 1H NMR (400 MHz, CDCl3/TMS):
ı = 1.49 (d, J = 6.5 Hz, 3 H), 1.83 (bs, 1 H), 4.88 (q, J = 6.5 Hz, 1 H),
7.24–7.28 (m, 2 H), 7.32–7.38 ppm (m, 3 H). 13C NMR (100 MHz,
CDCl3/TMS): ı = 25.5, 70.8, 125.8, 127.8, 128.9, 146.2 ppm. MS CI m/z
(%): 140 ([M+NH4+], 29), 122 (M+, 100). Elemental analysis calcd (%)
for C8H10O (122.16): C, 78.65; H, 8.25. Found: C, 78.47; H, 8.35.
(R)-1-(4ꢀ-Nitrophenyl)ethanol, (Entry 1, Table 2):[16c] GC
(Chirasil Dex CB): carrier gas: helium, 80 psi; injector temperature:
250 ◦C; column temperature: 175 ◦C; 8.36 min (R); 9.27 min (S).
HPLC (Chiral OD); eluent: 2-propanol/hexane 5/95; tempt, r.t.; flow
rate, 1.0 mL/min; detection, 254 nm light): 15.40 min (S), 16.41 min
(R). 1H NMR (400 MHz, CDCl3/TMS): ı = 1.52 (d, J = 6.5 Hz, 3 H), 2.10
(bs, 1 H), 5.03 (q, J = 6.5 Hz, 1 H), 7.52–7.58 (m, 2 H), 8.19–8.23 ppm
(m, 2 H). 13C NMR (100 MHz, CDCl3/TMS): ı = 25.9, 69.9, 124.2,
126.5, 147.6, 153.4 ppm. Elemental analysis calcd (%) for C8H9NO3
(167.16): C, 57.48; H, 5.43; N, 8.38. Found: C, 57.30; H, 5.50; N, 8.44.
(R)-1-(4ꢀ-Chlorophenyl)ethanol (Entry 2, Table 2): [5j,16c] GC
(Chirasil Dex CB): carrier gas: helium, 80 psi; injection tempera-
ture: 250 ◦C; column temperature: 150 ◦C; 5.01 min (R); 5.17 min
(S). 1H NMR (400 MHz, CDCl3/TMS): ı = 1.45 (d, J = 6.0 Hz, 3 H),
2.04 (bs, 1 H), 4.85 (q, J = 6.0 Hz, 1 H), 7.26–7.32 ppm (m, 4 H).
13C NMR (100 MHz, CDCl3/TMS): ı = 25.7, 70.1, 127.4, 129.0, 133.5,
144.6 ppm. MS CI m/z (%):174 ([M+NH4+], 100), 156 (M+, 37). Ele-
mental analysis calcd (%) for C8H9ClO (156.61): C, 61.35; H, 5.79.
Found: C, 61.29; H, 5.58.
2. Experimental
2.1. Instruments
1H (400 MHz, 298 K) and 13C (100 MHz, 298 K) NMR spectra
were recorded on a 400 MHz Bruker spectrometer in CDCl3 solu-
tion. Chemical shifts are reported as ı (in ppm) relative to the
residual solvent (CDCl3) peak for 1H and 13C. Gas chromatographic
(GC) analyses for chiral alcohol products were performed on a
Varian CP-3380 GC equipped with a Chrompack Chirasil-Dex CB
column (25 m × 0.25 mm, 80 psi helium carrier gas, 60 psi hydrogen
gas and 250 ◦C injector temperature) or a GILSON UV/VIS-151 HPLC
equipped with a Chiral OD or OD-H column (ambient temperature,
254 nm detection). MS spectra were measured on Finnigan Mat TSQ
700 instrument. Analytical TLC was carried out utilizing 0.25 mm
precoated plates (silica gel 60 UV254) and spots were visualized by
use of UV light and silica-I2 revelation. Column chromatography
was performed with silica gel 60 (70–230 mesh, Fluka).
2.2. Chemicals
[RuCl2(p-cymene)]2, [Cp*RhCl2]2, [Cp*IrCl2]2, TsDPEN, ketones,
HCOONa, HCOOH, NEt3, and N,N-diisopropylethylamine were pur-
chased from Johnson Matthey, Aldrich, Fluka, Strem, or Lancaster,
and used without further purification unless otherwise noted.
Water was deionized before use as solvent.
(R)-1-(4ꢀ-Trifluoromethylphenyl)ethanol (Entry 3, Table 2):
[15b,16c] GC (Chirasil Dex CB; carrier gas: helium, 80 psi; injection
temperature: 250 ◦C; column temperature: 150 ◦C; 2.75 min (R),
3.02 min (S). 1H NMR (400 MHz, CDCl3/TMS): ı = 1.50 (d, J = 6.0 Hz,
3 H), 2.11 (bs, 1 H), 4.95 (q, J = 6.0 Hz, 1 H), 7.48 (d, J = 8.0 Hz,
2H), 7.60 ppm (d, J = 8.0 Hz, 2 H); 13C NMR (100 MHz, CDCl3/TMS):
2.3. General procedure for preparation of catalysts
1
3
ı = 25.8, 70.2, 124.6 (q, JC-F = 271.0 Hz), 125.8 (q, JC-F = 4.0 Hz),
126.0, 130.0 (q, 2JC-F = 32.0 Hz), 150.1 ppm. MS CI m/z (%): 190 (M+,
100). Elemental analysis calcd (%) for C9H9F3O (190.16): C, 56.84;
H, 4.77. Found: C, 56.75; H, 4.65.
All the reactions were carried out under a nitrogen atmosphere
using standard Schlenk techniques, and all glassware was oven-
dried for a minimum of two hours before use, unless otherwise
stated.
(R)-4ꢀ-(1-Hydroxy-1-phenylethyl)benzonitrile
(Entry
4,
The M-1 catalysts were generated in situ by reacting M
([RuCl2(p-cymene)]2, [Cp*RhCl2]2, or [Cp*IrCl2]2, 0.005 mmol) and
1 ((R,R)-TsDPEN, 0.012 mmol) in 2 mL of solvent. After stirring the
Table 2): [5j,16c] GC (Chirasil Dex CB): carrier gas: helium, 40 psi;
injection temperature: 250 ◦C; column temperature: 150 ◦C;
19.77 min (R); 25.47 min (S). 1H NMR (400 MHz, CDCl3/TMS):

X. Zhou et al. / Journal of Molecular Catalysis A: Chemical 357 (2012) 133–140
135
ı = 1.49 (d, J = 6.6 Hz, 3 H), 2.05 (d, J = 4.4 Hz, 1 H), 4.96 (q, J = 6.6 Hz,
1 H), 7.48 (d, J = 8.0 Hz, 2 H), 7.36 ppm (d, J = 8.0 Hz, 2 H); 13C NMR
(100 MHz, CDCl3/TMS): ı = 25.42, 69.67, 111.09, 118.86, 126.07,
132.36, 151.09 ppm.
H), 5.42 (q, J = 6.3 Hz, 1 H), 7.24 (t, J = 8.0 Hz, 1 H), 7.65 (t,
J = 8.0 Hz, 1 H), 7.84 (d, J = 8.0 Hz, 1 H), 7.90 ppm (d, J = 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3/TMS): ı = 24.19, 65.59, 124.33, 127.58,
128.13,133.63, 140.89, 147.88 ppm.
(R)-1-(Pyridin-2-yl)ethanol (Entry 5, Table 2): [15,16c] GC
(Chirasil Dex CB): carrier gas: helium, 40 psi; injection tempera-
ture: 250 ◦C; column temperature: 100 ◦C; 22.50 min (R); 23.00 min
(S). 1H NMR (400 MHz, CDCl3/TMS): ı = 1.51 (d, J = 6.5 Hz, 3 H), 4.37
(bs, 1 H), 4.90 (q, J = 6.5 Hz, 1 H), 7.19 (dd, J = 7.5 Hz, 4.8 Hz, 1 H), 7.30
(d, J = 8.0 Hz, 1 H), 7.65–7.72 (m, 1 H), 8.52 ppm (d, J = 4.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3/TMS): ı = 24.7, 68.9, 119.8, 122.2, 136.8,
148.1, 163.2 ppm. MS CI m/z (%): 123 (M+, 100). Elemental analysis
calcd (%) for C7H9NO (123.15): C, 68.27; H, 7.37; N, 11.37. Found:
C, 68.23; H, 7.38; N, 11.36.
(R)-1-(Pyridin-3-yl)ethanol (Entry 6, Table 2): [15,16c] GC
(Chirasil Dex CB): carrier gas: helium, 80 psi; injection tempera-
ture: 250 ◦C; column temperature: 130 ◦C; 8.51 min (R); 8.94 min
(S). 1H NMR (400 MHz, CDCl3/TMS): ı = 1.53 (d, J = 6.5 Hz, 3 H), 4.65
(bs, 1 H), 4.87 (q, J = 6.5 Hz, 1 H), 7.22 (dd, J = 7.8 Hz, 4.80 Hz, 1 H),
7.71–7.75 (m, 1 H), 8.32 (dd, J = 4.8 Hz, 1.8 Hz, 1 H), 8.42 ppm (d,
J = 2.0 Hz, 1 H). 13C NMR (100 MHz, CDCl3/TMS): ı = 25.1, 67.3, 123.6,
133.7, 142.0, 146.9, 147.8 ppm. MS CI m/z (%): 123 (M+, 100). Ele-
mental analysis calcd (%) for C7H9NO (123.15): C, 68.27; H, 7.37; N,
11.37. Found: C, 68.28; H, 7.29; N, 11.33.
(1R,1ꢀR)-1,1ꢀ-(1,3-Phenylene)diethanol (Entries 1–2, Table 3):
[5l,24] GC (Chirasil Dex CB, 80 psi helium as carrier gas, 250 ◦C injec-
tion temperature, 160 ◦C column temperature): (meso) 11.00 min;
(S, S) 11.20 min; (R, R) 11.35 min. 1H NMR (400 MHz, CDCl3/TMS):
ı = 1.48 (d, J = 6.8 Hz, 6 H), 2.17 (bs, 2 H), 4.87 (q, J = 6.8 Hz, 2 H),
7.24–7.27(m, 2 H), 7.30–7.34 (m, 1 H), 7.37 ppm (s, 1 H). 13C NMR
(100 MHz, CDCl3/TMS): ı = 25.16, 70.36, 122.44, 124.53, 128.65,
146.10 ppm. MS CI m/z (%): 166.2 (M+, 100).
(1R,1ꢀR)-1,1ꢀ-(1,4-Phenylene)diethanol (Entries 3–4, Table 3):
[5l,24] GC (Chirasil Dex CB, 80 psi helium as carrier gas, 250 ◦C
injection temperature, 160 ◦C column temperature): 160 ◦C, (R, R)
15.99 min; (meso) 17.50 min; (S, S) 17.92 min. 1H NMR (400 MHz,
CDCl3/TMS): ı = 1.50 (d, J = 1.6 Hz, 6 H), 4.85-4.93 (m, 2 H), 1.82 (s,
2 H), 7.36 ppm (s, 4 H). 13C NMR (100 MHz, CDCl3/TMS): ı = 25.1,
25., 70.2, 125.6, 145.1 ppm. MS CI m/z (%): 166.1 (M+, 6), 131.0
[(M−(OH) × 2)+, 100].
(1R,1ꢀR)-1,1ꢀ-(Biphenyl-4,4ꢀ-diyl)diethanol (Entries 5–6,
Table 3): [24] GC (Chirasil Dex CB, 80 psi helium as carrier gas,
250 ◦C injection temperature, 168 ◦C column temperature): 168 ◦C,
(R, R) 36.02 min; (S, S) 38.50 min. 1H NMR (400 MHz, CDCl3/TMS):
ı = 1.54 (d, J = 6.6 Hz, 6 H), 1.84 (d, J = 2.6 Hz, 2 H), 4.93–4.99 (m,
2H), 7.45 (d, J = 8.0 Hz, 4 H), 7.58 ppm (d, J = 8.0 Hz, 4 H). 13C NMR
(100 MHz, CDCl3/TMS): ı = 25.2, 70.2, 125.9, 127.2 ppm. MS CI m/z
(%): 242.2 (M+, 6), 207.1 [(M-(OH) × 2)+, 100].
(R)-1-(3ꢀ-Bromophenyl)ethanol (Entry 7, Table 2): [16c] GC
(Chirasil Dex CB): carrier gas: helium, 80 psi; injectiontemperature:
250 ◦C; column temperature: 150 ◦C; 10.146 min (R), 11.140 min
(S). 1H NMR (400 MHz, CDCl3/TMS): ı = 1.53 (d, J = 6.5 Hz, 3 H), 2.58
(bs, 1 H), 4.95 (q, J = 6.5 Hz, 1 H), 7.10 (dd, J = 7.5 Hz, 1.50 Hz, 1H),
7.14–7.20 (m, 1 H), 7.32 (dd, J = 4.8 Hz, 1.50 Hz, 1 H), 7.32–7.38 ppm
(m, 1 H). 13C NMR (100 MHz, CDCl3/TMS): ı = 24.4, 70.8, 122.4,
125.6, 128.9, 129.5, 133.8, 148.7 ppm. MS CI m/z (%): 201 (M+, 100).
Elemental analysis calcd (%) for C8H9BrO (201.06): C, 47.79; H, 4.51.
Found: C, 47.65; H, 4.44.
(R)-1-(9ꢀ-Phenanthryl)ethanol (1st, Scheme 2): [16c] HPLC
(Chiral OD-H); eluent: 2-propanol/hexane 5/95; tempt, r.t.; flow
rate, 1.0 mL/min; detection, 254 nm light): 22.49 min (R); 26.99 min
(S). 1H NMR (400 MHz, CDCl3/TMS): ı = 1.72 (d, J = 6.5 Hz, 3 H),
2.0 (bs, 1 H), 5.67 (q, J = 6.5 Hz, 1 H), 7.57–7.68 (m, 4 H), 7.89 (d,
J = 6.5 Hz, 1 H), 7.93 (s, 1 H), 8.15 (d, J = 8.0 Hz, 1 H), 8.65 (d, J = 8.0 Hz,
1H), 8.74 ppm (d, J = 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3/TMS):
ı = 24.15, 67.24, 122.46, 122.75, 123.37, 123.90, 126.31, 126.64,
126.78, 128.79, 129.59, 130.04, 130.79, 131.53, 139.50 ppm. MS CI
m/z (%): 222.3 (M+, 11), 205.3 [(M-OH)+, 100].
(R)-1-(3ꢀ-Nitrophenyl)ethanol (Entry 8, Table 2): [15,16c] GC
(ChirasilDex CB): carrier gas: helium, 80 psi; injectiontemperature:
250 ◦C; column temperature: 160 ◦C; 7.94 min (R); 8.40 min (S).
HPLC (Chiral OD); eluent: 2-propanol/hexane 5/95; tempt, r.t.; flow
rate, 1.0 mL/min; detection, 254 nm light): 14.80 min (S), 15.71 min
(R). 1H NMR (400 MHz, CDCl3/TMS): ı = 1.54 (d, J = 6.5 Hz, 3 H), 1.99
(d, J = 3.3 Hz, 1 H), 5.03 (q, J = 6.5 Hz, 1H), 7.53 (t, J = 8.0 Hz, 1 H), 7.72
(d, J = 6.8 Hz, 1 H), 8.13 (dd, J = 7.8 Hz, 1.5 Hz, 1 H), 8.27 ppm (s, 1H).
13C NMR (100 MHz, CDCl3/TMS): ı = 25.56, 69.46, 120.47, 122.42,
129.48, 131.60 ppm.
(R)-1,2-Diphenylethan-1-ol (2nd, Scheme 2): [16c,g] HPLC
(Chiral OD-H); eluent: 2-propanol/hexane 5/95; tempt, r.t.; flow
rate, 1.0 mL/min; detection, 254 nm light): 12.99 min (R); 16.47 min
(S). 1H NMR (400 MHz, CDCl3/TMS): ı = 1.96 (bs, 1 H), 2.99 (dd,
J = 14.0 Hz, 8.0 Hz, 1H), 3.05 (dd, J = 14.0 Hz, 5.2 Hz, 1H), 4.90 (dd,
J = 8.0 Hz, J = 4.8 Hz, 1 H), 7.19–7.38 ppm (m, 10 H). 13C NMR
(100 MHz, CDCl3/TMS): ı = 47.0, 76.2, 126.8, 127.5, 128.5, 129.3,
129.4, 130.4, 138.9, 144.7 ppm; MS CI m/z (%): 198 (M+, 100), 181
(32). Elemental analysis calcd (%) for C14H14O (198.26): C, 84.81; H,
7.12. Found: C, 84.70; H, 7.18.
(R)-1-(4ꢀ-Methylphenyl)ethanol (Entry 9, Table 2): [15j,16c]
GC (Chirasil Dex CB): carrier gas: helium, 80 psi; injection temper-
ature: 250 ◦C; column temperature: 120 ◦C; 5.85 min (R); 6.28 min
(S). 1H NMR (400 MHz, CDCl3/TMS): ı = 1.47 (d, J = 6.0 Hz, 3 H),
1.91 (bs, 1 H), 2.35 (s, 3 H), 4.85 (q, J = 6.0 Hz, 1 H), 7.13–7.19 (m,
2 H), 7.24–7.28 ppm (m, 2 H). 13C NMR (100 MHz, CDCl3/TMS):
ı = 21.5, 25.5, 70.7, 125.8, 129.6, 137.6, 143.3 ppm. MS CI m/z (%):
154 ([M+NH4+], 100), 136 (M+, 80). Elemental analysis calcd (%) for
C9H12O (136.19): C, 79.37; H, 8.88. Found: C, 79.35; H, 8.85.
(R)-1-(4ꢀ-Methoxyphenyl)ethanol (Entry 10, Table 2):
[15j,16c] GC (Chirasil Dex CB): carrier gas: helium, 80 psi; injection
temperature: 250 ◦C; column temperature: 130 ◦C; 12.10 min (R);
13.10 min (S). 1H NMR (400 MHz, CDCl3/TMS): ı = 1.5 (d, J = 6.4 Hz,
3 H), 2.39 (bs, 1 H), 3.79 (s, 3 H), 4.83 (q, J = 6.4 Hz, 1 H), 6.87 (d,
J = 8.7 Hz, 2 H), 7.28 ppm (d, J = 8.7 Hz, 2 H). 13C NMR (100 MHz,
CDCl3/TMS): ı = 24.8, 55.2, 69.8, 113.8, 126.5, 137.8, 159.0 ppm. MS
CI m/z (%): 152 (M+, 100). Elemental analysis calcd (%) for C9H12O2
(152.19): C, 71.03; H, 7.95. Found: C, 70.95; H, 7.88.
(R)-1-(4ꢀ-Biphenylyl)-1-ethanol (3rd, Scheme 2): [22,23] HPLC
(Chiral OD-H); eluent: 2-propanol/hexane 5/95; tempt, r.t.; flow
rate, 1.0 mL/min; detection, 254 nm light): 15.80 min (S), 16.68 min
(R). 1H NMR (400 MHz, CDCl3/TMS): ı = 1.54 (d, J = 6.0 Hz, 3 H), 1.85
(bs, 1H), 4.95 (q, J = 6.0 Hz, 1 H), 7.32–7.38 (m, 1 H), 7.41–7.47 (m,
4 H), 7.58 ppm (d, J = 8.0 Hz, 4 H). 13C NMR (100 MHz, CDCl3/TMS):
ı = 25.2, 70.2, 125.9, 127.1, 127.3, 128.8, 140.5, 140.9, 144.8 ppm.
MS CI m/z (%): 198.2 (M+, 13), 181.2 [(M-OH)+, 100].
3. Results and discussion
The experiment was conducted initially using acp as a model
substrate. The M-1 catalyst was prepared in situ from a metal pre-
cursor (M, 0.005 mmol; see Section 2.3) and ligand 1 (TsDPEN,
0.012 mmol) in 2 mL of a solvent to be used for the ATH. After
stirring at 40 ◦C for 1 h, the suspension was used directly for the
(R)-1-(2ꢀ-Nitrophenyl)ethanol: [15,16c] GC (Chirasil Dex CB):
carrier gas: helium, 80 psi; injection temperature: 250 ◦C; col-
umn temperature: 150 ◦C; 8.84 min (R), 10.25 min(S). 1H NMR
(400 MHz, CDCl3/TMS): ı = 1.58 (d, J = 6.3 Hz, 3 H), 2.36 (bs, 1

136
X. Zhou et al. / Journal of Molecular Catalysis A: Chemical 357 (2012) 133–140
Fig. 1. Conversion (a) and ee (b) versus reaction time for ATH of acp with Ru-1 in F-T mixtures at different initial F/T ratios at 40 ◦C.
subsequent reduction reactions without any further purification.
The precatalyst can be isolated with high yield [15,16a,c].
In particular, when the F/T ratio was lowered to 0.9/1–0.2/1, the
reduction started immediately and completed in a short reaction
time (Fig. 1a). However, the reaction was incomplete at the F/T
ratio of 0.09/1 after 2 h, possibly due to the hydrogen source being
exhausted; the total quantity of HCOOH was only 1.2 equivalents
relative to the substrate in this case.
Using a simply mixed F-T solution at different initial F/T molar
ratios, ATH of acp catalyzed by Ru-1 was carried out to examine the
effects of the F/T ratio on the performance of this catalyst. Repre-
sentative results are shown in Fig. 1. As can be seen, the reduction
of acp requires a very long time to achieve a high conversion under
acidic conditions. The higher the F/T ratios, the longer the reaction
takes. For example, ATH of acp gave 39% conversion in 150 h at a
initial F/T molar ratio of 4.6/1 (Fig. 1a). It is noteworthy that there
exists a very long induction period for the reduction under these
conditions. Thus, the reaction afforded less than 1% conversion in
the first 48 h and 4% conversion in 60 h. Thereafter, the reaction
speeded up, achieving over 30% conversion in 12 h. The reaction
was sluggish again after 70 h, possibly due to insufficient hydrogen
source. It has been revealed that formic acid can be decomposed
by the catalyst to produce CO2 and H2 during the reaction, which
would result in a decrease in the F/T ratio with time and thereby
initiate the reaction [15,16c]. Similar induction periods were also
observed from the reduction carried out at initial F/T molar ratio of
3.7/1 and 3.1/1 (Fig. 1a). When the initial F/T ratios were lowered,
meaning that the reaction media became more basic, the reaction
rate increased significantly. The average reaction rate increased 4
times when the initial molar ratio of F/T varied from 3.7/1 to 0.2/1.
Interestingly, as shown in Fig. 1b, the ee’s of the product varied
dramatically as well when the initial F/T ratio was higher (From
4.6/1 to 3.1/1, Fig. 1b), whilst it remained high in the cases of lower
F/T ratios (F/T < 2.5/1, Fig. 1b). This finding resembles that made in
aqueous ATH [15,16] but is the first one revealed for ATH in a F-T
mixture. On the basis of previous studies of ATH in water, [15,16a,c]
we propose that two different catalytic cycles are likely to operate
in this reduction, depending on the F/T molar ratios (Scheme 1).
ATH of acp at low F/T ratios is more efficient, affording faster rates
and higher enantioselectivities (Cycle I, Scheme 1). At higher F/T
ratios, protonation occurs at both the hydride and TsDPEN ligands,
driving the catalyst into a less active and less enantioselective cycle
(Cycle II, Scheme 1). Our results thus show that the catalysis in
F-T mixtures is similar to that in water, where both the reaction
rates and enantioselectivities are pH-regulated [8,15,16d]. Taken
together, the screening suggests that in terms of reaction rate and
enantioselectivity, the optimum F/T molar ratio is 0.2/1. Hereafter,
this mixture will be referred to as 0.2 F/T.
Scheme 1. Proposed catalytic cycles for ATH of acp under near neutral (I) and acidic (II) conditions in a F-T solution.

X. Zhou et al. / Journal of Molecular Catalysis A: Chemical 357 (2012) 133–140
137
Table 1
Comparison of ATH of acp with M-1 under various conditions.a
Table 2
ATH of simple ketones with Ru-1 in 0.2 F/T.a
Entry
Ketones
Time (h)
Conv. (%)b
>99 (96)
99 (95)
Ee (%)c
Entry
Catalysts
Solvent
Time (h)
Conv. (%)b
Ee (%)b
5
5
99
1
2
3
4
5
6
7
8
Ru-1
Ru-1
Ru-1
Ru-1
Ru-1
Ru-1
Rh-1
Ir-1
IPAc
24
16
1
12
5
5
80
23
81
98
>99
98
>99
98
89
97
94
97
97
97
86
82
2.5 F/Td
H2O-HCOONae
H2O-2.5 F/Tf
0.2 F/Tg
94d
0.2 F/Dh
0.2 F/T
0.2 F/T
>99
74
a
Reaction conditions: 1 mmol acp, 0.01 mmol M-1, 2 mL solution, 40 ◦C.
Determined by GC equipped with a chiral column. The alcohol configuration
b
5
>99 (87)
95d
was R.
c
0.01 equiv. KOH was added.
Azeotropic F/T solution.
5 equiv. HCOONa.
d
e
f
Vazeotrope = VH = 1 mL.
O
88d
>99
2
5
5
>99 (95)
93 (89)
g
h
HCOOH/Et3N = 0.2/1.
HCOOH/N,N-diisopropylethylamine = 0.2/1.
Other reaction conditions were also compared. As shown in
Table 1, the performance of the Ru-1 catalyst is much better than
that of Rh-1 and Ir-1 under the optimized conditions (0.2 F/T). Ru-
1 delivered >99% conversion with 97% ee in 5 h (Entry 5, Table 1)
while Rh-1 and Ir-1 afforded >99% conversion with 86% ee in 80 h
(Entry 7, Table 1) and 74% conversion with 82% ee in 23 h (Entry 8,
Table 1), respectively. The poor performance of Rh-1 and Ir-1 may
be due to there being different optimum pH windows for them.
These results are again reminiscent of the ATH of ketones in water
with these catalysts [8d,15,16]. Comparison of the Ru-1 catalyzed
ATH of acp in different reaction media show that the reaction run
in IPA gave the poorest performance (entry 1, Table 1), while the
reduction in water afforded the fastest rate (entry 3, Table 1). The
reaction in the azeotropic F-T (2.5 F/T) was markedly slower (entry
2, Table 1) than in the 0.2 F/T, while adding water to the 2.5 F/T
shortened the reaction time by 4 h. The ATH of acp in a HCOOH and
N,N-diisopropylethylamine mixture with a molar ratio of 0.2 gave a
faster reaction as well, affording 98% conversion and 97% ee in 5 h.
The comparison above shows that the 0.2 F/T affords faster
reduction than the azeotropic 2.5 F/T without compromising the
ee. In the previous two studies, the F/T ratio was set at 1:1 and
the reduction was also shown to be faster than in 2.5 F/T [21].
These results clearly establish that the ATH could be made faster
with a smaller amount of HCO2H. Although the M-1 (M = Ru, Rh, Ir)
catalyzed ATH of ketones in water has proved to be successful as
aforementioned, not all ketones can be reduced efficiently in aque-
ous solution to give high conversion and ee values. Combining M-1
with 0.2 F/T could provide a new option, however.
5
5
5
98 (93)
88d
94d
75
>99 (93)
>99 (94)
50
97(91)
93d
95
50
(86)
Reaction condition: 1 mmol acp,1% mmol Ru-1, 2 mL 0.2 F/T at 40 ◦C.
Determined by GC or NMR. The number in bracket refers to the isolated yield.
Determined by GC with a chiral column. The alcohol configuration was R and
a
b
c
was determined by comparison of GC retention time or sign of optical rotation with
literature data.
d
Determined by HPLC with a chiral OD-H or OD column.
Aiming to determine the potential applicability of the protocol,
the reduction was then extended to a range of aromatic ketones,
using the simply mixed 0.2 F/T as reductant and solvent. The results
of the ATH are summarized in Table 2 and Scheme 2. As shown
in Table 2, for the simple ketones, the Ru-1 catalyzed reduction
furnished high conversions within 5 h and the enantioselectivities
were excellent in most cases. For instance, 4ꢀ-nitro-acp, 4ꢀ-chloro-
acp, 4ꢀ-(trifluoromethyl)-acp and 4ꢀ-acetylbenzonitrile were all
converted into the corresponding alcohols in 99% conversion and
up to 99% ee in 5 h (Entries 1–4, Table 2). In contrast, it took 24 h to
achieve 99% conversion and 88% ee for the reduction of 4ꢀ-CF3-acp
in the azeotropic 2.5 F/T solution (2.5 F/T) [13e]. The reduction of 4ꢀ-
chloro-acp and 4ꢀ-acetylbenzonitrile afforded full conversion and
95% ee in 24 h, and >99% conversion and 90% ee in 21 h in the 2.5 F/T,
respectively [5,13,j,b]. When it comes to the meta-substituted acp,
for example, 3ꢀ-Br-acp and 3ꢀ-NO2-acp, the ketones were almost
fully converted with ee’s of 94% and 75% in 5 h, respectively (Entries
7 and 8, Table 2). The heterocyclic 2ꢀ-acetylpyridine gave a 93% con-
version and >99% ee in 5 h (Entry 5, Table 2), while 3ꢀ-acetylpyridine
afforded 98% conversion and 88% ee at the same reaction time
(Entry 6, Table 2). However, 4ꢀ-Me-acp and 4ꢀ-MeO-acp, which are
often problematic in ATH, required 50 h to achieve a conversion
of >90% (Entries 9 and 10, Table 2). For comparison, when using
the 2.5 F/T, ATH of the 4ꢀ-OMe-acp took 65 h to arrive at a similar
conversion [4]. There appeared to be strong correlation between
the electronic properties of the substitutes with the reaction rate
but none with enantioselectivity. Thus with electron withdrawing
substituted group, such as NO2-, CF3- and CN-, the reaction gave
fast reaction rate while with electron donating group, such as Me-

138
X. Zhou et al. / Journal of Molecular Catalysis A: Chemical 357 (2012) 133–140
O
HO
Ru-1
S/C=100, 40 oC
7 h, 91% yield, 86% ee
OH
O
Ru-1
o
S/C=100, 40 C
5 h, 93% yield, 98% ee
OH
O
Ru-1
S/C=100, 40 oC
6 h, 93% yield, 97% ee
Water, 8 h, 33% yiel d, 91% ee
Scheme 2. ATH of water-insoluble ketones in 0.2 F/T.
and MeO-, the reaction rate decreased dramatically (e.g. Entries
1–4 vs 9 and 10). Steric bulk inhibits the reduction as well. The
reduction of isobutyrophenone afforded only 2% conversion and
87% ee in 5 h and it took 80 h to complete the ATH of 2ꢀ-NO2-acp,
affording 78% ee. Furthermore, there was no reaction observed for
ketones with very bulky substitutions at either the ␣ methyl posi-
tion or the phenyl ring. For instance, 2ꢀ-benzoyl-5-norbornene and
4ꢀ-tert-butyl-2,6-dimethyl-3,5-dinitro-acp could not be reduced at
all under these conditions.
Comparing ATH of 4ꢀ-acetylbiphenyl in different reaction media
showed that the aqueous reduction by HCOONa afforded (R)-1-(4ꢀ-
biphenylyl)-1-ethanol with a lower yield 33% and an ee value of
91% in 8 h, demonstrating that not all the ketones are suitable for
reduction in water. In contrast, an isolated yield of 93% and an ee
Table 3
ATH of diketones with Ru-1 in F-T mixture.a
Entry
Diketones
Products
F/T ratio
Time (h)
Yieldb (%)
Eec (%)
dec
1
2
0.2
25
95
90
63
>99
>99
90/10
90/10
2.5d
3
4
0.2
25
95
91
44
>99
>99
94/6
94/6
2.5d
5
6
0.2
25
25
94
30
>99
>99
>99
>99
2.5d
a
Reaction Conditions: 1 mmol diketone, 1% mmol Ru-1, in a 4 mL of F/T solution at 40 ◦C.
Isolated yield.
Determined by GC or HPLC equipped with chiral column.
Azeotropic F/T mixture.
b
c
d

X. Zhou et al. / Journal of Molecular Catalysis A: Chemical 357 (2012) 133–140
139
value of 97% were achieved within 6 h in the 0.2 F/T. Scale up is
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A simple, easy-to-operate reduction system for the ATH of
ketones has been developed. The Ru-1/0.2 F/T system is particularly
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reduced in or sensitive to the azeotropic 2.5 F/T. In comparison with
the commonly-used azeotropic 2.5 F/T system, this new protocol is
more efficient and easy to scale-up. Whilst ATH in azeotropic 2.5
F/T has been widely exploited, the effect of the F/T molar ratios on
the efficacy of the reduction has seldom been subjected to scrutiny.
This study shows that the F/T ratio has a significant effect on both
theATHrateandenantioselectivity, a findingreminiscentof thepH-
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Financial support from the Graduate School of Xi’an Jiaotong
University and the Scholarship Award for Excellent Doctoral Stu-
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acknowledged. Thanks also go to the University of Liverpool for
financial support.
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