Chiral [RuCl2(dipyridylphosphane)(1,2-diamine)] catalysts: Applications in asymmetric hydrogenation of a wide range of simple ketones

Article abstract of DOI:10.1002/chem.200204688

The dipyridylphosphane/diamine - Ru complex combined with tBuOK in 2-propanol acts as a very effective catalyst system for the enantioselective hydrogenation of a diverse range of simple ketones including heteroaromatic ketones, substituted benzophenones, alkenyl ketones, and cyclopropyl ketones. The combination of desirable features, such as quantitative chemical yields within hours, broad substrate scope, excellent enantioselectivities (up to 99%), and high substrate-to-catalyst ratios, among others, makes the present catalyst system of high practical interest.

Full text of DOI:10.1002/chem.200204688

FULL PAPER
Chiral [RuCl2(dipyridylphosphane)(1,2-diamine)] Catalysts: Applications in
Asymmetric Hydrogenation of a Wide Range of Simple Ketones
Jing Wu, Jian-Xin Ji, Rongwei Guo, Chi-Hung Yeung,* and Albert S. C. Chan*[a]
Abstract: The dipyridylphosphane/diamine Ru complex combined with tBuOK in
2-propanol acts as a very effective catalyst system for the enantioselective hydro-
genation of a diverse range of simple ketones including heteroaromatic ketones,
substituted benzophenones, alkenyl ketones, and cyclopropyl ketones. The combi-
nation of desirable features, such as quantitative chemical yields within hours, broad
substrate scope, excellent enantioselectivities (up to 99%), and high substrate-to-
catalyst ratios, among others, makes the present catalyst system of high practical
interest.
Keywords: asymmetric catalysis
enantioselectivity ¥ hydrogentation
¥ P ligands ¥ ruthenium
¥
metric hydrogenation of a wide range of unfunctionalized
prochiral ketones in 2-propanal.[9] Among these catalysts,
trans-RuCl2[(S)-Xylbinap][(S)-daipen][10] or its enantiomer
gave the best results.[11, 12] Another catalyst system Phane-
Phos/ruthenium/diamine[13] also showed high activity and
enantioselectivity in the asymmetric hydrogenation of simple
ketones.
Introduction
Since many enantiomerically pure secondary alcohols are
very valuable intermediates for the manufacture of structur-
ally interesting and biologically active compounds, the devel-
opment of highly effective systems for the synthesis of chiral
alcohols is not only of interest to the academic world but also
of substantial interest to industrial scientists. Accordingly, a
number of strategies for the asymmetric reduction of prochi-
ral ketones to single enantiomer alcohols have been devel-
oped.[1] From both scientific and commercial points of view,
asymmetric hydrogenation is more efficient and beneficial
than either stoichiometric[2] or other catalytic reduction
We have recently prepared a new family of chiral dipyr-
idylphosphane ligands P-Phos (1a),[14a] Tol-P-Phos (1b),[14b]
and Xyl-P-Phos (1c),[14c] and have established their effective-
ness in many catalytic asymmetric hydrogenation reactions.
We found their Ru/diamine complexes 2a 2c to be highly
effective in the asymmetric hydrogenation of a variety of
aromatic ketones. In particular, with the use of the trans-
[RuCl2{(R)-1c}{(R,R)-dpen}] ((R,RR)-2c, dpen ˆ 1,2-diphe-
nylethylenediamine) in combination with tBuOK in 2-prop-
anol, various ortho-, meta-, and para-substituted acetophe-
nones were hydrogenated quantitatively under mild condi-
tions in consistently excellent enantioselectivities (up to
>99.9%), even with very high substrate-to-catalyst ratios
(S/C up to 100000).[14d] Unlike the Ru binap catalyst system,
which often needs an expensive diamine daipen[12a] for good
results, the Ru (P-Phos) catalyst system can be used in
combination with a substantially less expensive diamine,
dpen, to give excellent results. In addition, catalysts 2a 2c
are air-stable even in solution. The combination of these
desirable features makes them of high practical interest and
prompts us to explore their applications in the asymmetric
hydrogenation of a wide scope of simple ketones.
systems.[3 Ru phosphane complexes, especially the Ru-
5]
binap catalyst system, have been demonstrated to be highly
enantioselective in the hydrogenation of various functional-
ized ketones[1, 6] and industrial processes for the synthesis of
the key intermediates of antibiotic carbapenems[7] and anti-
bacterial Levofloxacin[8] have been well established. How-
ever, these catalysts often fail to give good results with simple
ketones that lack neighboring heteroatoms to enable the
substrate to anchor strongly to the metal center. Recently, a
significant breakthrough in this area was achieved by Noyori
and co-workers, who discovered that an appropriate diphos-
phane/Ru/chiral diamine/inorganic base catalyst system ex-
hibited high efficiency and steroselectivities for the asym-
[a] Prof. Dr. A. S. C. Chan, Dr. C.-H. Yeung, Dr. J. Wu, J.-X. Ji, Dr. R. Guo
Open Laboratory of Chirotechnology of the Institute of Molecular
Technology for Drug Discovery and Synthesis
In this study, we have found that catalyst (R,RR)-2c acted
as a very efficient catalyst precursor for highly enantioselec-
tive hydrogenation of a diverse range of simple ketones
including heteroaromatic ketones, substituted benzophe-
Department of Applied Biology and Chemical Technology
The Hong Kong Polytechnic University (Hong Kong)
Fax : (‡852)236-49932
E-mail: bcachan@polyu.edu.h
Chem. Eur. J. 2003, 9, 2963 2968
DOI: 10.1002/chem.200204688
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2963

A. S. C. Chan and C.-H. Yeung et al.
FULL PAPER
Table 1. Asymmetric hydrogenation of 2-acetylthiophene 3a catalyzed by 2.[a]
Entry Catalyst
S/B [M/M] PH [psi] Time [h] Conv. [%][b] ee [%][b]
2
1[c]
2
3
4
5
6
7
8
9
(R,RR)-2c
350
350
350
350
350
150
600
350
350
12
12
12
12
12
12
12
12
12
[d]
(R,RR)-2c 100
(R,RR)-2c 200
(R,RR)-2c 500
(R,RR)-2c 700
(R,RR)-2c 200
(R,RR)-2c 200
(R,RR)-2a 200
(R,RR)-2b 200
2.4
> 99.9
> 99.9
> 99.9
98.8
> 99.9
87.2
> 99.9
98.3 (S)
98.2 (S)
98.1 (S)
97.8 (S)
98.1 (S)
71.0 (S)
71.5 (S)
[a] Reaction conditions: 46 mg substrate, substrate concentration ˆ 1.5m, S/C
(M/M) ˆ 4000, 25 288C. [b] The conversions were determined by NMR and
GC analysis. The ee values were determined by chiral GC with a 25 m Â
0.25 mm ChrompackChirasil-DEX CB column. The absolute configuration
was determined by comparing the retention times with those in referen-
ce [12c) ]. [c] The reaction was performed without the addition of tBuOK and
no product was detected. [d] The ee value could not be determined accurately
because of the low conversion.
high activity of the catalyst. For instance, no desirable product
was detected after 12 h when 3a was hydrogenated without
the addition of tBuOK or with an S/B ratio of 100 (Table 1,
entries 1 and 2). In contrast, when the S/B varied from 200 to
700, complete conversions were observed within 12 h and the
ee values of the desired product (S)-4a were essentially
identical (Table 1, entries 3 5). The hydrogen pressure was
found to have almost no effect on the enantioselectivity
(Table 1, entries 3, 6, and 7) but lower pressure resulted in a
somewhat slower rate (Table 1, entry 6 versus entry 7). In
addition, the enantioselectivity was markedly influenced by
the structure of the chiral dipyridylphosphane ligands. The use
of Xyl-P-Phos (1c) provided far superior ee to those obtained
with the parent ligand P-Phos (1a) or Tol-P-Phos (1b)
(Table 1, entry 3 versus entries 8 and 9).
Similarly excellent results were obtained in the hydro-
genation of some other heteroaromatic ketones (Table 2). The
hydrogenation of 3-thienyl ketone 3b gave (S)-4b quantita-
tively in 98.9% ee after 5 h (Table 2, entry 1) under the same
conditions as those for the hydrogenation of 2-thienyl ketone
3a. The enantioselectivity remained consistently high
(99.0% ee, Table 2, entry 2), even when the S/C ratio was
increased to 10000. The rate of the hydrogenation of 3-pyridyl
ketone 3c was faster than that of 4-pyridyl ketone 3d. For
example, 3c was hydrogenated with an S/C of 4000 under
350 psi H2 to provide (S)-4c in 99.2% conversion and with
97.0% ee after 10 h (Table 2, entry 4). In contrast, under
otherwise identical conditions, the hydrogenation of 3d
offered (S)-4d in only 50.8% conversion within 12 h (Table 2,
entry 5) and the reaction was completed in 24 h with 97.9% ee
(Table 2, entry 6). In a manner similar to the Ru-binap
catalyst system,[12c] the hydrogenation of 2-acetylpyridine was
very sluggish (2.4% conversion after 24 h) with catalyst
(R,RR)-2c, probably as a result of the tight coordination of
the pyridyl functionality causing saturation of the catalyst and
leading to the diminution of activity.
nones, alkenyl ketones, and cyclopropyl ketones. To our
knowledge, no other catalyst has so far been reported, which
approaches the effectiveness of the Xylbinap-Ru-daipen
system in the hydrogenation of simple ketones with such a
wide variety of substrates.[12]
Results and Discussion
Asymmetric hydrogenation of heteroaromatic ketones and 1'-
acetonaphthone: The asymmetric hydrogenation of hetero-
aromatic ketones offers an especially attractive route to chiral
alcoholic products, which serve as valuable intermediates and
building blocks for a variety of biologically active compounds
and chiral ligands.[15] For example, (R)-1-(3-pyridyl)ethanol is
an intermediate in the synthesis of heteroyohimbine alkaloids
such as reserpinin and arcin[15a] and the synthetically useful
chiral a-hydroxy aldehydes can be obtained from alkyl(2-
thiazolyl)methanol products.[16] Other examples include (S)-
duloxetine,[15c] an inhibitor of serotonin and norepinephrine
uptake carriers, and Singulair for treatment of chronic
asthma.[17]
Our study began with 2-acetylthiophone (3a), and the
results are summarized in Table 1. The catalytic activity of
catalyst 2 was not disturbed by the sulfur-containing hetero-
cycle. When the hydrogenation was conducted in 2-propanol
containing (R,RR)-2c and tBuOK with S/C ˆ 4000 and a
substrate-to-base (S/B) molar ratio of 200 under 350 psi of H2
at ambient temperature, the corresponding alcohol (S)-4a was
obtained in quantitative yield and 98.3% ee (Table 1, entry 3).
Consistent with the results observed in the (R,RR)-2c
catalyzed hydrogenation of acetophenone,[14d] the presence
of a base and the substrate-to-base ratio were crucial for the
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Asymmetric Hydrogenation with Ru Catalysts
2963 2968
Table 2. Asymmetric hydrogenation of heteroaromatic ketones and 1'-acetonaphthone.[a]
were hydrogenated to the de-
sired products with high ee
values (Table 3, entries 1 4).
For instance, the hydrogenation
of o-flurobenzophenone (5b) at
ambient temperature under
300 psi of initial hydrogen pres-
sure was completed in 15 h to
give the desired product in
97.6% ee (Table 3, entry 3).
The substrate 5c, which has an
electron-donating methyl sub-
stituent, provided the R alcohol
in 95.9% ee (Table 3, entry 4).
Simple meta- and para-substi-
tuted benzophenones were con-
verted to the corresponding
alcohols with moderate enan-
tioselectivity, as expected (Ta-
ble 3, entries 5 8). The results
compared favorably with those
Entry
Ketone
Catalyst
S/C [M/M]
S/B (M/M)
PH [psi]
Time [h]
Conv. [%][b]
ee [%][b,c]
2
1
2
3b
3b
3c
3c
3d
3d
3e
3e
3e
(R,RR)-2c
(R,RR)-2c
(R,RR)-2c
(R,RR)-2c
(R,RR)-2c
(R,RR)-2c
(R,RR)-2a
(R,RR)-2b
(R,RR)-2c
4000
10000
2000
4000
4000
4000
4000
4000
4000
200
200
100
100
100
100
200
200
200
350
500
350
350
350
350
300
300
300
5
16
5
10
12
24
8
> 99.9
> 99.9
> 99.9
99.2
50.8
> 99.9
64.8
98.9(S)
99.0 (S)
97.2 (S)
97.0 (S)
97.9 (S)
97.9 (S)
91.9 (S)
93.1 (S)
98.6 (S)
3[d]
4[d]
5[d]
6[d]
7
8
9
8
8
> 99.9
> 99.9
[a] Reaction conditions: 50 100 mg substrate, substrate concentration ˆ 1.0 2.5m, 25 288C. [b] The conver-
sions were determined by NMR and GC analysis. The ee values were determined by chiral GC with a 25 m Â
0.25 mm ChrompackChirasil-DEX CB column. [c] The absolute configuration was determined by comparison of
the sign of optical rotation or the retention times with those in references [9e, 12c) ]. [d] The conversion was
determined by NMR and GC with a 30 m  0.25 mm J & W Scientific INNOWAX column. The ee values were
determined by chiral HPLC analysis with a 25 cm  4.6 mm Daicel Chiralcel OB-H column.
Under the standard conditions, other aromatic ketones such
as 1'-acetonaphthone (3e) were hydrogenated smoothly in
high enantioselectivity, irrespective of the use of 1a, 1b, or 1c
as the chiral ligand (Table 2, entries 7 9) and 1c was found to
be the best choice again (entry 9).
obtained from the use of Ru-Xylbinap-daipen complex. For
example, using (R,RR)-2c, p-trifluoromethyl benzophenone
5g was hydrogenated to (R)-6g in 77.2% ee (Table 3, entry 8);
whereas the Ru-Xylbinap complex afforded 6g in only
47% ee under similar conditions.[12b]
Asymmetric hydrogenation of substituted benzophenones:
Benzhydrol and its derivatives are widely used in the synthesis
of pharmaceuticals.[18] The current industrial processes for
producing benzhydrols mainly rely on stoichiometric reduc-
tion using NaBH4 or through the addition of arylmetals to
benzaldehydes. From a practical standpoint, it is highly
desirable to develop effective catalytic asymmetric hydro-
genation methods for the economical synthesis of chiral
benzhydrols from substituted benzophenones. Noyori and co-
workers reported the highly enantioselective hydrogenation
of a range of unsymmetrical diaryl ketones using a Ru-
Xylbinap-daipen system.[12b] To our best knowledge, no other
catalyst system reported so far
Asymmetric hydrogenation of alkenyl ketones to chiral allylic
alcohols: The effectively selective asymmetric hydrogenation
of alkenyl ketones to chiral allylic alcohols has long remained
difficult because most existing homogeneous or heteroge-
ˆ
neous catalysts tend to catalyze the hydrogenation of the C C
[19]
ˆ
bond preferentially over a coexisting C O bond.
In
addition, some simple enones are very sensitive to basic
conditions. Noyori and co-workers recently resolved this
enduring problem by using Ru-Xylbinap-daipen in combina-
tion with K2CO3, a weakbase, in place of conventional KOH
or tBuOK.[12a]
can attain the effectiveness of
Table 3. Asymmetric hydrogenation of substituted benzophenones catalyzed by (R,RR)-2c.[a]
the Ru-Xylbinap-daipen cata-
lyst in this type of hydrogena-
tion reaction.
In this study, we discovered
that the present catalyst
(R,RR)-2c with a much less
expensive diamine, dpen, ex-
hibited comparable or even
higher efficiency and enantio-
selectivity than Ru-Xylbinap-
daipen in the hydrogenation of
a variety of substituted benzo-
phenones (Table 3). This hydro-
genation can be performed with
an S/C molar ratio as high as
10000 (Table 3, entry 2). In the
presence of (R,RR)-2c, ortho-
substituted substrates 5a 5c
Entry
Ketone
S/C [M/M]
S/B [M/M]
PH [psi]
Time [h]
Conv. [%][b]
ee [%][c]
2
1
2
3
4
5
6
7
8
5a
5a
5b
5c
5d
5e
5f
2000
10000
2000
2000
2000
2000
2000
2000
100
75
100
100
100
50
300
500
300
300
300
300
300
300
15
35
15
13
48
15
15
15
> 99.9
> 99.9
99.7
98.6
> 99.9
99.0
97.2 (R)
97.4 (R)
97.6 (R)
95.9 (R)
43.2 (‡)
47.3 (R)
3.9 (R)
75
50
99.3
> 99.9
5g
77.2 (R)
[a] Reaction conditions: 30 60 mg substrate, substrate concentration ˆ 1.0m, 25 288C. [b] The conversion was
determined by NMR and GC with a 30 m  0.25 mm J & W Scientific INNOWAX column. [c] The ee values were
determined by chiral HPLC analysis with a 25 cm  4.6 mm Daicel Chiralcel OB-H or 25 cm  4.6 mm Daicel
Chiralcel OD column. The absolute configuration was determined by comparison of the sign of optical rotation or
the retention times with those in reference [12b) ].
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A. S. C. Chan and C.-H. Yeung et al.
FULL PAPER
To further explore the scope of substrates, we also inves-
tigated the effectiveness of catalyst (R,RR)-2c for chemo-
selective hydrogenation of the carbonyl group of three a,b-
unsaturated ketones (7a 7c). In the presence of either
ophenyl ketone (9b) was complete in 14 h (Table 5, entry 2),
whereas the reaction rate was substantially lower (33.5%
conversion after 24 h) in the case of cyclopropyl 4-methox-
yphenyl ketone (9d, Table 5, entry 5).
Conclusion
In summary, the chiral RuCl2(dipyridylphosphane)(1,2-dia-
mine) complex 2c, combined with an appropriate inorganic
base in 2-propanol, is a highly effective catalyst system for the
enantioselective hydrogenation of a wide range of simple
ketones, such as heteroaromatic, alkenyl, and cyclopropyl
ketones, as well as substituted benzophenones. The present
catalyst system is of high practical potential because of its high
efficacy, enantioselectivity, and flexibility.
K2CO3 or tBuOK, the hydrogenation reaction of benzalace-
tone 7a in 2-propanol containing (R,RR)-2c with an S/C ratio
of 10000 furnished the corresponding allylic alcohol 8a in
97.0% ee and 97.1% ee, respectively (Table 4, entries 2 and 4).
ˆ
No over-reduction of the C C functionality was detected.
With the S/C ratio of up to 12000, both mesityl oxide 7b and
highly base-sensitive 3-nonen-2-one 7c were transformed to
allylic alcohols (8b and 8c) in 93.3% and 90.3% ee (Table 4,
entries 5 7), respectively.
Experimental Section
General methods: All manipulations with air-sensitive reagents were
carried out under a dry nitrogen atmosphere using standard Schlenk
techniques or in a nitrogen-filled MBRAUN Lab Master 130 glovebox. The
Asymmetric hydrogenation of cyclopropyl ketones: The
cyclopropyl group is of interest in synthetic methodologies.[20]
Takaya and co-workers[21] and
hydrogenation reactions were performed in
a 50 mL stainless-steel
autoclave from Parr company. 1H NMR and 31P NMR spectra were
Noyori and co-workers[12a] have
Table 4. Asymmetric hydrogenation of alkenyl ketones catalyzed by (R,RR)-2c.[a]
reported the hydrogenation of
cyclopropyl phenyl ketone 9a.
To our knowledge, the hydro-
genation of substituted phenyl
cyclopropyl ketones such as
9b 9d have not been reported
so far, although the enantiose-
lective cyclopropylation of al-
dehydes using dicycolpropyl-
zinc to provide substituted phe-
nyl cyclopropyl alcohols has
been studied.[22]
Entry
Ketone
S/C[M/M]
Base
S/B [M/M]
PH2 [psi]
Time [h]
Conv. [%][b]
ee [%][c]
1
2
3
4
5
6
7
7a
7a
7a
7a
7b
7b
7c
2000
10000
2000
10000
2000
K2CO3
K2CO3
tBuOK
tBuOK
tBuOK
tBuOK
K2CO3
20
20
350
500
350
500
350
500
350
10
15
10
15
8
> 99.9
> 99.9
> 99.9
> 99.9
99.2
97.0 (S)
97.1 (S)
96.9 (S)
97.0 (S)
90.2 (S)[d]
90.3 (S)[d]
93.4 (S)[d]
500
500
250
250
250
12000
2000
16
15
99.1
91.8
[a] Reaction conditions: 20 50 mg substrate, substrate concentration ˆ 0.1 1.0m, 25 288C. [b] The conversion
was determined by NMR and GC with a 30 m  0.25 mm J & W Scientific INNOWAX column. [c] The ee values
were determined by chiral HPLC analysis with a 25 cm  4.6 mm Daicel Chiralcel OD column. The absolute
configuration was determined by comparison of the sign of optical rotation or the retention times with those in
reference [12a) ]. [d] The ee values were determined by chiral GC with a 25 m  0.25 mm ChrompackChirasil-
DEX CB column.
By using (R,RR)-2c as cata-
lyst, 9a was hydrogenated
smoothly in the presence of
tBuOK with an S/C ratio of
5000 under 350 psi H2 to give
(S)-10a in 97.6% ee (Table 5,
entry 1) without cleavage of the
three-membered ring. Similarly
high enantioselectivities were
observed in the hydrogenation
of various substituted phenyl
cyclopropyl ketones (Table 5,
entries 2 4 and 6). The sub-
strate possessing an electron-
withdrawing group in the para
position of the phenyl group
was more reactive than that
with an electron-donating sub-
stituent. For example, with an
S/C ratio of 2000, the hydro-
genation of cyclopropyl 4-chlor-
Table 5. Asymmetric hydrogenation of cyclopropyl ketones catalyzed by (R,RR)-2c.[a]
Entry
Ketone
S/C [M/M]
S/B [M/M]
PH [psi]
Time [h]
Conv. [%][b]
ee [%]
2
1
2
3
4
5
6
9a
5000
2000
5000
2000
2000
1000
250
250
250
250
250
100
350
350
500
350
350
350
18
14
24
24
24
48
> 99.9
> 99.9
87.2
97.6 (S)[c]
92.3 ( ‡ )
92.3 ( ‡ )
92.0 ( ‡ )
9b[d]
9b
9c[d]
9d
9d
86.3
33.5
[e]
-
> 99.9
96.1 (À)[f]
[a] Reaction conditions: 30 mg substrate, substrate concentration ˆ 1.0m, 25 288C. [b] The conversion was
determined by NMR and GC with a 30 m  0.25 mm J & W Scientific INNOWAX column. [c] The ee values were
determined by chiral HPLC analysis with a 25 cm  4.6 mm Daicel Chiralcel OD column. The absolute
configuration was determined by comparison of the retention times with those in reference [12a) ]. [d] The
conversions were determined by NMR and GC analysis. The ee values were determined by chiral GC with a
25 m  0.25 mm ChrompackChirasil-DEX CB column. [e] The ee value has not been determined. [f] The ee value
was determined by chiral HPLC analysis with a 25 cm  4.6 mm Daicel Chiralcel AD column.
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Asymmetric Hydrogenation with Ru Catalysts
2963 2968
recorded in CDCl3 on a Varian AS 500 at room temperature, and the
chemical shifts were expressed in ppm. Gas chromatographic analyses were
conducted on an HP 4890A or HP 5890 series II system. Optical rotations
were measured on a Perkin-Elmer Model 341 polarimeter. The ketone
substrates were stirred over CaH2 to remove acidic impurities and distilled
prior to use. DMF and 2-propanol were freshly distilled over CaH2 before
use. Other commercial reagents were used as received without further
purification unless otherwise stated. Optically pure P-Phos (1a), Tol-P-
Phos (1b), and Xyl-P-Phos (1c) were synthesized according to previously
determined by chiral HPLC analysis with
a
25 cm  4.6 mm Daicel
Chiralcel OB-H column (eluent, 2-propanal/hexane 10:90; flow rate ˆ
1.0 mLminÀ1
19.02 min.
;
detection: 254 nm light); tR(R) ˆ 13.13 min; tR(S) ˆ
p-Methylbenzhydrol (6 f): The conversion was determined by capillary GC
with a 30 m  0.25 mm J & W Scientific INNOWAX column; 2308C;
isothermal; tR(5 f) ˆ 8.20 min; tR(6 f) ˆ 12.35 min. The ee value was deter-
mined by chiral HPLC analysis with a 25 cm  4.6 mm Daicel Chiralcel
OB-H column (eluent, 2-propanal/hexane 10:90; flow rate ˆ 0.5 mLminÀ1
detection: 254 nm light). tR(R) ˆ 19.25 min; tR(S) ˆ 21.97 min.
;
c]
reported procedures.[14a Catalysts 2a 2c were prepared and character-
ized by our reported method.[14d]
p-Trifluromethylbenzhydrol (6g): The conversion was determined by
capillary GC with a 30 m  0.25 mm J & W Scientific INNOWAX column;
2308C; isothermal; tR(5g) ˆ 4.48 min; tR(6g) ˆ 9.27 min. The ee value was
A typical procedure of asymmetric hydrogenation: A 1.56 Â 10À3 m solution
of (R,RR)-2c in 2-propanol (59 mL, 9.20 Â 10À5 mmol), 2-acetylthiophene
(3a, 40 mL, 0.368 mmol), 2-propanol (130 mL), and a 0.1m tBuOK solution
in tBuOH (18.5 mL, 1.85 Â 10À3 mmol) were added to a 50 mL autoclave
under a nitrogen atmosphere. Hydrogen was initially introduced into the
autoclave at a pressure of 300 psi before being reduced to 10 20 psi by
carefully releasing the stop valve. After this procedure was repeated three
times, the vessel was pressurized to 350 psi. The reaction mixture was
stirred at room temperature for 12 h before releasing the H2. The
conversion and the enantiomeric excess of the product (S)-1-(2-thienyl)e-
thanol [(S)-4a] were determined by NMR spectroscopy and chiral GC
analysis to be >99.9% and 98.3%, respectively (column, Chirasil-DEX
CB; 25 m  0.25 mm, CHROMPACK, carrier gas, N2).
determined by chiral HPLC analysis with
a
25 cm  4.6 mm Daicel
Chiralcel OB-H column (eluent, 2-propanal/hexane 10:90; flow rate ˆ
0.8 mLminÀ1; detection: 254 nm light); tR(R) ˆ 9.17 min; tR(S) ˆ 11.95 min.
(E)-4-Phenyl-3-buten-2-ol (8a): The conversion was determined by
capillary GC with a 30 m  0.25 mm J & W Scientific INNOWAX column;
1808C; isothermal; tR(7a) ˆ 9.43 min; tR(8a) ˆ 11.31 min. The ee value was
determined by chiral HPLC analysis with
a
25 cm  4.6 mm Daicel
Chiralcel OD column (eluent, 2-propanal/hexane 10:90; flow rate ˆ
0.5 mLminÀ1
22.38 min.
;
detection: 254 nm light); tR(R) ˆ 16.08 min; tR(S) ˆ
4-Methyl-3-penten-2-ol (8b): The conversion was determined by capillary
GC with a 30 m  0.25 mm J & W Scientific INNOWAX column; 708C;
isothermal; tR(7b) ˆ 5.50 min; tR(8b) ˆ 10.17 min. The ee value was deter-
mined by capillary GC with a 25 m  0.25 mm Chirasil-DEX CB column;
708C; isothermal; tR(R) ˆ 10.62 min; tR(S) ˆ 16.26 min.
1-(2-Thienyl)ethanol (4a): Capillary GC, Chirasil-DEX CB column;
1208C; isothermal; tR(3a) ˆ 5.45 min; tR(R) ˆ 10.46 min; tR (S) ˆ 11.34 min.
1-(3-Thienyl)ethanol (4b): Capillary GC, Chirasil-DEX CB column;
1208C; isothermal; tR(3b) ˆ 6.60 min; tR(R) ˆ 12.92 min; tR(S) ˆ 13.79 min.
1-(3-Pyridyl)ethanol (4c): The conversion was determined by capillary GC
with a 30 m  0.25 mm J & W Scientific INNOWAX column; 1608C;
isothermal; tR(3c) ˆ 7.11 min; tR(4c) ˆ 18.08 min. The ee value was deter-
mined by chiral HPLC analysis with a 25 cm  4.6 mm Daicel Chiralcel
(E)-3-Nonen-2-ol (8c): The conversion was determined by capillary GC
with a 30 m  0.25 mm J & W Scientific INNOWAX column; 1008C;
isothermal; tR(7c) ˆ 12.48 min; tR(8c) ˆ 14.84 min. The ee value was
determined by capillary GC with a 25 m  0.25 mm Chirasil-DEX CB
column; 808C; isothermal; tR(R) ˆ 41.48 min; tR(S) ˆ 44.07 min.
OB-H column (eluent, 2-propanal/hexane 10:90; flow rate ˆ 1.0 mLminÀ1
detection: 254 nm light); tR(S) ˆ 8.40 min; tR(R) ˆ 13.42 min.
;
Cyclopropyl(phenyl)methanol (10a): The conversion was determined by
capillary GC with a 30 m  0.25 mm J & W Scientific INNOWAX column;
1708C; isothermal; tR(9a) ˆ 7.67 min; tR(10a) ˆ 11.47 min. The ee value was
1-(4-Pyridyl)ethanol (4d): The conversion was determined by capillary GC
with a 30 m  0.25 mm J & W Scientific INNOWAX column; 1608C;
isothermal; tR(3d) ˆ 6.49 min; tR(4d) ˆ 19.38 min. The ee value was deter-
mined by chiral HPLC analysis with a 25 cm  4.6 mm Daicel Chiralcel
determined by chiral HPLC analysis with
a
25 cm  4.6 mm Daicel
Chiralcel OD column (eluent, 2-propanal/hexane 5:95; flow rate ˆ
0.5 mLminÀ1
21.61 min.
;
detection: 254 nm light); tR(R) ˆ 18.06 min; tR(S) ˆ
OB-H column (eluent, 2-propanal/hexane 10:90; flow rate ˆ 1.0 mLminÀ1
detection: 254 nm light); tR(S) ˆ 10.05 min; tR(R) ˆ 12.94 min.
;
Cyclopropyl(p-chlorophenyl)methanol (10b): Capillary GC, Chirasil-DEX
CB column; 1608C; isothermal; tR(9b) ˆ 10.84 min. The retention times of
two enantiomers of 10b are: tR ˆ 21.27 min (minor) and tR ˆ 22.10 min
(major).
1-(1'-Naphthyl)ethanol (4e): Capillary GC, Chirasil-DEX CB column;
1708C; isothermal; tR(3e) ˆ 7.43 min; tR(S) ˆ 13.89 min; tR(R) ˆ 14.87 min.
o-Chlorobenzhydrol (6a): The conversion was determined by capillary GC
with a 30 m  0.25 mm J & W Scientific INNOWAX column; 2308C;
isothermal; tR(5a) ˆ 9.85 min; tR(6a) ˆ 17.12 min. The ee value was deter-
mined by chiral HPLC analysis with a 25 cm  4.6 mm Daicel Chiralcel OD
column (eluent, 2-propanal/hexane 10:90; flow rate ˆ 1.0 mLminÀ1; detec-
tion: 254 nm light); tR(R) ˆ 7.86 min; tR(S) ˆ 9.81 min.
o-Fluorobenzhydrol (6b): The conversion was determined by capillary GC
with a 30 m  0.25 mm J & W Scientific INNOWAX column; 2308C;
isothermal; tR(5b) ˆ 6.18 min; tR(6b) ˆ 9.83 min. The ee value was deter-
mined by chiral HPLC analysis with a 25 cm  4.6 mm Daicel Chiralcel OD
column (eluent, 2-propanal/hexane 4:96; flow rate ˆ 0.5 mLminÀ1; detec-
tion: 254 nm light); tR(R) ˆ 22.71 min; tR(S) ˆ 25.99 min.
o-Methylbenzhydrol (6c): The conversion was determined by capillary GC
with a 30 m  0.25 mm J & W Scientific INNOWAX column; 2308C;
isothermal; tR(5c) ˆ 6.10 min; tR(6c) ˆ 11.65 min. The ee value was deter-
mined by chiral HPLC analysis with a 25 cm  4.6 mm Daicel Chiralcel OD
column (eluent, 2-propanal/hexane 4:96; flow rate ˆ 0.8 mLminÀ1; detec-
tion: 254 nm light); tR(R) ˆ 18.98 min; tR(S) ˆ 21.22 min.
Cyclopropyl(p-fluorophenyl)methanol (10c): Capillary GC, Chirasil-DEX
CB column; 1408C; isothermal; tR(9c) ˆ 8.76 min. The retention times of
two enantiomers of 10c are: tR ˆ 16.47 min (minor) and tR ˆ 17.24 min
(major).
Cyclopropyl(p-methylphenyl)methanol (10d): The conversion was deter-
mined by capillary GC with a 30 m  0.25 mm J & W Scientific INNOWAX
column; 2108C; isothermal; tR(9d) ˆ 15.12 min; tR(10d) ˆ 17.46 min. The
ee value was determined by chiral HPLC analysis with a 25 cm  4.6 mm
Daicel Chiralcel AD column (eluent, 2-propanal/hexane 5:95; flow rate ˆ
0.5 mLminÀ1; detection: 254 nm light); tR ˆ 29.85 min (minor) and tR
ˆ
33.60 min (major).
Acknowledgement
We thankthe Hong Kong Research Grants Council (Project number PolyU
5177/99P), The University Grants Committee Area of Excellence Scheme
in Hong Kong (AoE P/10 01) and The Hong Kong Polytechnic University
ASD Fund for financial support of this study.
m-Methylbenzhydrol (6d): The conversion was determined by capillary
GC with a 30 m  0.25 mm J & W Scientific INNOWAX column; 2308C;
isothermal; tR(5d) ˆ 7.48 min; tR(6d) ˆ 11.70 min. The ee value was deter-
mined by chiral HPLC analysis with a 25 cm  4.6 mm Daicel Chiralcel
OB-H column (eluent, 2-propanal/hexane 10:90; flow rate ˆ 1.0 mLminÀ1
detection: 254 nm light); tR ˆ 13.48 min (minor) and 23.37 min (major).
;
[1] For comprehensive reviews, see: a) R. Noyori, Asymmetric Catalysis
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p-Chlorobenzhydrol (6e): The conversion was determined by capillary GC
with a 30 m  0.25 mm J & W Scientific INNOWAX column; 2308C;
isothermal; tR(5e) ˆ 10.09 min; tR(6e) ˆ 22.02 min. The ee value was
Chem. Eur. J. 2003, 9, 2963 2968
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2967

A. S. C. Chan and C.-H. Yeung et al.
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Received: December 19, 2002 [F4688]
2968
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 2963 2968