Asymmetric Reduction of Electron-Rich Ketones with Tethered Ru(II)/TsDPEN Catalysts Using Formic Acid/Triethylamine or Aqueous Sodium Formate

Article abstract of DOI:10.1021/acs.joc.5b00990

The asymmetric transfer hydrogenation (ATH) of ketones under aqueous conditions using tethered Ru(II)/⁶-arene/diamine catalysts is described, as is the ATH of electron-rich substrates containing amine and methoxy groups on the aromatic rings. Although such substrates are traditionally challenging ones for ATH, the tethered catalysts work very efficiently. In the case of amino-substituted ketones, aqueous conditions give excellent results; however, for methoxy-substituted substrates, the more established formic acid/triethylamine system gives superior results.

Full text of DOI:10.1021/acs.joc.5b00990

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Article
pubs.acs.org/joc
Asymmetric Reduction of Electron-Rich Ketones with Tethered Ru(II)/
TsDPEN Catalysts Using Formic Acid/Triethylamine or Aqueous
Sodium Formate
Rina Soni, Thomas H. Hall, Benjamin P. Mitchell, Matthew R. Owen, and Martin Wills*
Department of Chemistry, The University of Warwick, Coventry, CV4 7AL, United Kingdom
*
S Supporting Information
ABSTRACT: The asymmetric transfer hydrogenation (ATH) of
6
ketones under aqueous conditions using tethered Ru(II)/η -arene/
diamine catalysts is described, as is the ATH of electron-rich
substrates containing amine and methoxy groups on the aromatic
rings. Although such substrates are traditionally challenging ones for
ATH, the tethered catalysts work very efficiently. In the case of
amino-substituted ketones, aqueous conditions give excellent results;
however, for methoxy-substituted substrates, the more established
formic acid/triethylamine system gives superior results.
INTRODUCTION
introduced a series of “tethered” Ru(II) complexes (Figure 1),
typified by complex 2, which additionally contain a covalent
linkage between the diamine component and the arene ring.
■
6
The use of Ru(II) catalysts containing a combination of an η -
arene ring and a monosulfonated 1,2-diamine ligand, i.e., 1
Figure 1), for the asymmetric reduction of ketones to alcohols
has become widely adopted in recent years.
catalyst is active in both asymmetric hydrogenation (AH),
where hydrogen gas is used as the reducing agent, and
13
This increases the stability of the complexes and their activity in
reduction reactions, and in some cases, their use may be
advantageous. Since our initial reports on tethered complexes,
related complexes, including 3 and 4, have been reported by
(
1
−3
This class of
2
14
3
−12
other researchers. Most recently, we have described the
asymmetric transfer hydrogenation (ATH),
where iso-
is typically used
3
3
4−12
synthesis of methoxy-substituted complexes 5 and 6 (Figure 1)
propanol, formic acid, or sodium formate
13a
through an arene-displacement strategy.
as the reducing agent. In our own studies, we recently
Alongside the development of catalysts such as 1 for
reductions in the formic acid/triethylamine system, several
researchers have reported their use under aqueous conditions,
using sodium formate or a similar salt as the reducing agent,
4
−12
and for the reduction of CN as well as CO bonds.
This modification affords a number of potential advantages,
most notably the opportunity to use a more environmentally
compatible solvent, as well as the potential to extract the
product using an organic solvent and thus reuse the catalyst. In
many cases, a neutral Ru(II) catalyst, e.g., 1, or the Rh(III) or
4
Ir(III) equivalent can be successfully employed, although it is
likely that a cationic intermediate species may be formed in situ
due to replacement of Cl with a molecule of water; the use of
4
d,g
the cationic aqua derivatives of 1
has been demonstrated.
The control of the pH of the reaction has been found to be
4
important for optimal results, and the pivotal role of hydrogen
Figure 1. Arene/Ru(II)/TsDPEN catalysts used in asymmetric
transfer hydrogenation (ATH). The stereochemical description refers
to the configurations of the carbon atoms of the ligands. Although one
enantiomer of catalyst is illustrated, both enantiomers of each have
been prepared and tested.
bonding by the solvent during the reduction has been studied
by molecular modeling. In some cases the sulphonamide
4k
Received: May 2, 2015
Published: June 12, 2015
©
2015 American Chemical Society
6784
DOI: 10.1021/acs.joc.5b00990
J. Org. Chem. 2015, 80, 6784−6793

The Journal of Organic Chemistry
Article
a
Table 1. ATH of Acetophenone Using 2, 5, and 6 in H O and H O/MeOH
2
2
entry
catalyst
S/C
solvent
T/°C
t/h
conv/%
ee/%
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
(S,S)-2
(R,R)-5
(S,S)-2
(R,R)-5
(R,R)-6
(R,R)-6
(S,S)-2
(R,R)-5
(R,R)-5
(R,R)-6
(R,R)-6
(R,R)-5
(R,R)-5
100
100
100
100
100
500
100
100
500
500
500
100
100
100
100
100
100
H O
40
40
60
60
60
60
60
60
60
60
60
60
60
60
60
60
24
5
>99
97
97 (S)
98 (R)
88 (R)
97 (R)
77 (R)
81 (R)
96 (S)
98 (R)
97 (R)
85 (R)
86 (R)
98 (R)
97 (R)
97 (R)
97 (R)
97 (R)
96 (R)
2
H O
2
H O
2
1
99
H O
2
2
>99
>99
99
H O
2
2
H O
2
5
b
b
b
b
c
H O/MeOH
2
1
>99
96
H O/MeOH
2
0.5
6
H O/MeOH
2
99
0
1
2
3
H O/MeOH
2
3
99
H O/MeOH
2
2
99
HCO NH /H O
22.5
22.5
1
56
2
4
2
SDS/H O
57
2
d
4 (run 1)
5 (run 2)
6 (run 3)
7 (run 4)
(R,R)-5
(R,R)-5
(R,R)-5
(R,R)-5
H O
2
99
d
d
d
H O
2
1
99
H O
2
1.5
6.5
99
H O
2
60
97
a
b
c
d
H O/MeOH or H O refers to reduction using HCO Na (5 equiv), 1:1 water/MeOH. 1:0.5 water/MeOH. n-Pentane (3 × 2 mL) was used to
2
2
2
extract product after each cycle from the reaction mixture. One mole of HCO H was added to regenerate HCO Na.
2
2
diamine component may be modified, for example, by
introduction of hydrophobic groups or fluorine-containing
three-carbon linkers because these have proven to be highly
versatile (Table 1). Although almost complete reduction was
achieved at 40 °C using 2 and 5, the reaction was slow (entries
13
4f,t
groups. Analogous reduction of aldehydes may be catalyzed
4
w,x
by racemic versions of the catalysts.
In several examples, the
1
and 2); however, raising the temperature to 60 °C gave full
5
catalyst has been modified by the introduction of cationic or
anionic groups, which improves their solubility in water and
reduction within 1 to 2 h. While there was only marginal loss of
enantioselectivity using 5 (entries 2 and 4), complex 2 appeared
to be more sensitive to the temperature change (entries 1 and
6
hence facilitates isolation of the reduction product through
extraction with a nonpolar solvent such as hexane, while the
catalyst remains in the aqueous phase and can be reused.
Another strategy used to improve water solubility (and hence
facilitate recyclability) of the catalysts involves their conversion
to a derivative containing a poly(ethylene glycol) (PEG) chain,
which can be attached to a number of positions on the catalyst
3
). Complex 6 containing two methoxy groups was tested, and
this also gave almost complete reduction even at S/C up to
00, although with a lower ee, as had been previously observed
5
13a
(
entries 5 and 6).
Improved results were obtained using a 1:1 mixture of
11j,l
7
methanol and water,
which improves catalyst solubility
structure. Using this method, even substrates that are normally
(
entries 8−11). In this case, essentially complete reduction of
acetophenone was achieved at 60 °C after 1 h or less at S/C
00 using each of the catalysts, with enantioselectivities
susceptible to side reactions (e.g., α-bromo ketones) can be
7b
reduced efficiently. Another widely studied strategy is to
1
include either a surfactant (to form an emulsion) or a phase-
8
−10
matching those obtained at the lower temperatures in each
case. The reaction using 5 at S/C 500 required 6 h for complete
reduction and was followed over time (entry 9; see Supporting
Information). Again, catalyst 6 exhibited high activity, possibly
due to improved aqueous solubility (entries 10, 11), but
moderate enantioselectivity. When using ammonium formate in
place of sodium formate under purely aqueous conditions, the
reaction was also incomplete, although a product of high ee was
obtained (entry 12). The addition of sodium dodecyl sulfate
transfer catalyst to facilitate the reaction,
which is otherwise
biphasic. In several cases, addition of a surfactant is reported to
give improved results, although this appears to be somewhat
catalyst-dependent, since it is not always required. Reductions
in water, of ketones and imines, has also been achieved using
catalysts supported on polystyrene, silica, proteins, or other
1
1,12
media.
The use of a support containing an iron salt permits
separation of the catalyst from the bulk reaction using a
1
2
magnet.
(
SDS) did not lead to an improved result, and incomplete
RESULTS AND DISCUSSION
conversion was observed after 22.5 h (entry 13). Following
literature precedents on catalyst recycling in aqueous
■
Although the use of complex 1 in water has been extensively
4
−12
4
−12
systems,
the formation of the product of the reduction in
described,
the same use of the tethered derivatives has not
water was monitored, and this was then isolated after the
completion of the reduction by extraction with a nonpolar
organic solvent such as pentane or hexane. Addition of formic
acid and fresh substrate to the remaining aqueous phase
facilitated further reduction cycles (entries 14−17 for n-
pentane; other examples are in the Supporting Information).
been reported to date. In this article, we describe the results of
our studies on the applications of tethered Ru(II) catalysts to
the ATH of ketones under aqueous conditions, which can, in
some cases, be advantageous for the reductions of certain
classes of substrates. Initially, we investigated the reduction of
acetophenone using tethered catalysts 2, 5, and 6 containing
6
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Article
Figure 2. ATH of ketones using complexes (R,R)-5 and (R,R)-6 in water; S/C = 100, 60 °C, 5.0 equiv HCO Na.
2
b
Table 2. ATH of Amino Acetophenone Using 2 and 5
c
d
entry
NR2
pNH2
catalyst
S/C
solvent
T/rt or °C
t/h
conv (yield)/%
ee/%
1
2
3
4
5
6
7
8
9
(S,S)-2
(S,S)-2
(R,R)-5
(R,R)-1
(R,R)-5
(S,S)-2
(S,S)-2
(S,S)-2
(R,R)-5
(S,S)-2
(R,R)-2
(R,R)-2
(R,R)-2
(R,R)-2
(S,S)-2
(R,R)-2
(S,S)-2
(R,R)-2
100
100
100
100
100
100
100
100
100
250
100
100
100
100
100
100
100
100
H O/MeOH
40
60
60
60
60
rt
7.5
4.5
4.5
15.5
24
144
3
80 (72)
99 (79)
99 (75)
92 (S)
94 (S)
94 (R)
2
pNH2
H O/MeOH
2
pNH2
H O/MeOH
2
a
pNH2
H O/MeOH
78 (ND )
91 (R)
e
2
pNH2
FA/TEA
ND
pNH2
i-PrOH
50 (ND)
76 (41)
99 (76)
97 (78)
93 (68)
95 (60)
35 (17)
100 (81)
98 (78)
98 (72)
99 (68)
99 (84)
99 (74)
ND
pNMe2
pNMe2
pNMe2
pNMe2
pNMe2
pNMe2
N(CH2)4
N(CH2)4
N(CH2)4
N(CH2)5
N(CH2)5
N(CH2)2
O(CH2)2
N(CH2)2
H O
2
28
40
60
45
40
28
40
40
40
40
40
40
88 (S)
92 (S)
91 (R)
91 (S)
93 (R)
ND
H O/MeOH
5
2
H O/MeOH
4
2
10
11
12
13
14
15
16
17
18
FA/TEA
FA/TEA
i-PrOH
6
45
26
72
69
70
69
24
23
FA/TEA
87 (R)
89 (R)
89 (S)
94 (R)
95 (S)
94 (R)
H O/MeOH
2
H O/MeOH
2
FA/TEA
H O/MeOH
2
FA/TEA
f
f
19
(S,S)-2
100
H O/MeOH
40
45
100 (88)
91 (S)
2
O(CH2)2
a
b
c
ND, not determined. H O/MeOH or H O refers to reduction using HCO Na (5 equiv), FA/TEA refers to a 5:2 HCO H/Et N mixture. 1:1
2
2
2
2
2
3
d
e
f
H O/MeOH throughout. Isolated yield given in parentheses. Polymerization observed. Morpholine.
In each case, however, the conversion took longer for each
repeated run, reflecting the deactivation of the catalyst.
some cases were as high as 99%. Good results were observed
for some substrates with functionality at the ortho position
(tetralone, 1-acetylnaphthylene), which are also known to be
reduced by 5 in high ee using the more established FA/TEA
system. In contrast, the reduction of ortho-trifluoromethyl
acetophenone gave a product in modest ee (69%), unlike that
with the para equivalent, which was reduced in 94% ee. In most
cases, the reactions were monitored over time, and this revealed
little change to the ee as the reaction progressed (see
A series of ketones was reduced using the methoxy-
substituted tethered complexes 5 and 6 under aqueous
conditions in order to demonstrate further applications of
these catalysts (Figure 2). The conversions were almost
complete in most cases, and the ee’s reflected those obtained
13a
1
3,14
in ATH reactions in formic acid/triethylamine.
In the
majority of cases, the ee’s of the products exceeded 95% and in
6
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Article
a
Table 3. Reductions of ortho-Hydroxy- and -Methoxy-Substituted Ketones Using Complexes 2 and 5
b
entry
OR
X
catalyst
S/C
solvent
T/°C
t/h
conv (yield)/%
ee/%
1
2
3
4
5
6
7
8
9
OH
Me
Me
Cl
(S,S)-2
(R,R)-5
(S,S)-2
(R,R)-5
(S,S)-2
(R,R)-5
(S,S)-2
(R,R)-5
(S,S)-2
(S,S)-2
(S,S)-2
(R,R)-5
(R,R)-5
(R,R)-5
(S,S)-2
(R,R)-5
200
200
200
200
200
200
200
200
200
200
100
200
100
200
200
200
FA/TEA
FA/TEA
FA/TEA
FA/TEA
FA/TEA
FA/TEA
FA/TEA
FA/TEA
FA/TEA
40
40
40
40
40
40
40
40
40
60
60
40
60
60
40
40
5.5
23
99 (72)
100 (100)
99 (72)
97 (94)
>99 (65)
98 (42)
92 (24)
91 (84)
>95 (64)
89
94 (S)
95 (R)
90 (S)
93 (R)
91 (S)
94 (R)
93 (S)
93 (R)
68 (S)
55 (S)
58 (S)
96 (R)
95 (R)
96 (R)
69 (S)
90 (R)
OH
OH
4.75
23
OH
Cl
OH
Br
4
OH
Br
5.5
5.5
6.5
3.75
4
OH
OMe
OMe
H
OH
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
10
11
12
13
14
15
16
H
H O
2
H
H O
2
5
98
H
FA/TEA
3.75
2
>98 (70)
99
H
H O
2
H
H O
2
3.5
3.75
3.75
92
OMe
OMe
FA/TEA
FA/TEA
>99 (80)
>99 (87)
a
b
H O/MeOH or H O refers to reduction using HCO Na (5 equiv); FA/TEA refers to a 5:2 HCO H/Et N mixture, Isolated yield, where
2
2
2
2
3
determined, is given in parentheses.
Supporting Information). In the majority of cases, complex 5
was employed since this is known to give improved results over
those obtained with the dimethoxy complex 6. However,
catalyst 6 was used for the reduction of acetyl cyclohexane since
it is known to be more suited to alkyl/alkyl ketones for reasons
untethered complex (entry 4). As expected, attempted
reduction in FA/TEA gave no significant reduction (entry 5),
and the formation of a gum-like precipitate suggested some
degree of polymerization. Attempted reduction in i-PrOH
proved to be very sluggish (entry 6). In contrast, the tertiary
amines, 4-dimethylaminoacetophenone, could be reduced
efficiently under both aqueous and FA/TEA conditions,
although i-PrOH was not effective (entries 7−12). A
combination of water and methanol gave an improved result
over that with pure water, however. Likewise, a series of para-
substituted tertiary amine derivatives could be cleanly reduced
in good conversion and ee (entries 13−19). Presumably, with
these substrates, there is no possibility of a competing
polymerization and hence side product formation is minimized.
As far as we are aware, these are the first examples of
asymmetric reduction by ATH of such highly electron-rich
ketone substrates.
13
that have been previously described.
An advantage of the tethered catalysts relative to untethered
ones is that a higher level of activity and stability is often
1
3
observed. Electron-rich substrates, for example, those
containing amine-functionalized aromatic rings adjacent to
1
5,16
the ketone, are regarded as challenging
and have proven to
be difficult to reduce under formic acid/triethylamine
conditions, primarily due to their low reactivity (see the
Supporting Information for an experimental comparison of
reduction rates) but also due to the possibility of a competing
polymerization due to the reaction between the ketone and
amine and subsequent reduction of an imine/iminium
intermediate. Indeed, there is currently no report of the
application of catalysts such as 1 to the asymmetric reduction of
such substrates. Having demonstrated that the more reactive
tethered catalyst was compatible with water as a solvent, we
investigated the reductions of (aminoaryl)ketones under the
same conditions. In this event, reduction under purely aqueous
conditions proved to be difficult to reproduce reliably, possibly
due to low substrate solubility. However, the use of a water/
methanol combination (1:1) provided a means to achieve
complete and asymmetric reduction of para-amino acetophe-
none, for the first time under ATH conditions, in essentially full
conversion using 1 mol % of catalyst 2 or 5 (ca. 99% by GC)
and a high ee of 94%, even at 60 °C, which was required for full
conversion (Table 2, entries 1−3). In these tests, both 2 and 5
gave comparable results and were more active than the
In addition, an extended investigation into asymmetric
reductions of relatively unreactive electron-rich ketones
containing ortho-hydroxy and -methoxy acetophenones under
17
fully aqueous conditions was carried out (Table 3). While we
have reported that both 2 and 5 are excellent catalysts for the
reduction of ortho-hydroxy acetophenone with FA/TEA (ee’s
13
commonly >99%), ortho-methoxy ketones are reduced in
13a
higher ee using 5 than they are using 2. In this event, all
ortho-hydroxy acetophenones tested for reduction gave
comparable and high ee’s using both catalysts 2 and 5 in FA/
TEA. 2′,5′-Dimethoxyacetophenone was reduced in higher ee
using 5, however. In the majority of cases, reduction of ortho-
hydroxy or -methoxy acetophenones under aqueous conditions
with either catalyst generally gave products in either lower
conversions or ee compared to those with FA/TEA. For
6
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example, with 2-hydroxy-5-methylacetophenone, the best
conversion under aqueous conditions was just 80% in 6 h at
combined, dried over anhyd. Na
give crude product, which was purified by flash column chromatog-
2
SO
4
, filtered, and concentrated to
raphy. For reactions in H O/MeOH, the same procedure was followed
6
0 °C, giving a product with an ee of 87% (R) using catalyst
R,R)-5. For 2-hydroxy-5-chloroacetophenone, the best ee was
3% (with (R,R)-5), and for 2-hydroxy-5-methoxyacetophe-
2
using the solvent ratio (usually 1:1) given in the table.
Protocol B: Recycling of Catalyst Using n-Hexane/Pet.Ether/
n-Pentane. Catalyst (0.01 mmol) was placed in a Schlenk tube under
(
6
none, it was 61% (with (R,R)-5). For 2,5-dimethoxyacetophe-
none, the product ee’s were essentially the same as those in
FA/TEA, but the conversions were lower: 47−52% ee at ca. 9 h
at 60 °C using either catalyst 2 or 5. An exception was ortho-
methoxy acetophenone itself (entries 10, 11, 13, and 14), which
mirrored the FA/TEA results. Hence, this particular class of
electron-rich substrate appears to be, in general, more
compatible with reduction under FA/TEA conditions rather
than aqueous. This may be due to solubility differences
between the substrates.
an inert atmosphere followed by HCO Na (0.340 g, 5.0 mmol) and
2
H O (1 mL). The mixture was degassed three times, and to this was
2
added ketone (1.0 mmol) followed by degassing two times. The
mixture was stirred at 60 °C. The reaction was monitored by chiral GC
following the procedure described for the aqueous reaction. After
completion of the reaction, the reaction mixture was cooled to room
temperature and diluted with n-hexane, pet. ether, or n-pentane (2
mL). The organic layers were separated, and this process was repeated
again two times with the same solvent (2 mL). During this process, the
catalyst separated out as a brown solid. The mixture was degassed two
times followed by addition of HCO H (1 mmol). To this mixture was
2
6
In conclusion, Ru(II)/η -arene/diamine catalysts containing
added ketone (1 mmol), and the mixture was stirred at 60 °C. The
second and later cycles of the reaction were followed by chiral GC
analysis.
Protocol C: Asymmetric Transfer Hydrogenation in FA/TEA.
To a mixture of catalyst (0.002 mmol) in FA/TEA (5:2) (1.0 mL) was
added ketone (2.0 mmol), and the mixture was stirred at the stated
temperature under an inert atmosphere. The reaction was monitored
by TLC following the same procedure as that for the aqueous reaction
and worked up when complete or at the stated time. The reaction
a tethering group have been demonstrated to be effective in the
asymmetric reduction of ketones in water and water/methanol
mixtures. Amino-substituted ketones, known for their low
reactivity, have, for the first time, been reduced by ATH in high
conversion and enantioselectivity under aqueous conditions
and in the FA/TEA system. The reduction of hydroxyl- and
methoxy-substituted ketones, in contrast, is less amenable to
aqueous conditions and gives better results in FA/TEA. In
certain situations, reductions in aqueous media may offer
advantages over the more established FA/TEA conditions, and
in these situations, the tethered catalysts are generally active
and enantioselective.
mixture was diluted with EtOAc (10 mL) and sat. NaHCO soln (10
3
mL). The organic layer was separated, washed with H O (2 × 10 mL),
2
dried over anhyd. Na SO , filtered, and concentrated to give a brown
2
4
1
residue. The crude compound was analyzed by H NMR to give the
conversion and purified by flash chromatography on silica gel, if
required.
1
5,18
Protocol D: Synthesis of Amino Ketones.
Fluoroaceto-
EXPERIMENTAL SECTION
■
phenone (1.00 equiv) was combined with aqueous amine (3.68 equiv)
in a sealed pressure tube and heated at 100 °C for 24 h. The resulting
oil solidified upon cooling on ice and was filtered in vacuo while
washing with water to give the ketone. The solid was recrystallized in
hot heptane and allowed to crystallize on ice. The pure ketone was
collected by vacuum filtration and dried under high vacuum.
Protocol E: Racemic Reduction of Ketone Using Sodium
Borohydride. To a solution of ketone (1.00 equiv) in methanol (0.9
mL per mmol ketone) and water (0.1 mL per mmol ketone) was
added sodium borohydride (2.00 equiv). The reaction mixture was
stirred at rt for 3.5 h. After monitoring by thin-layer chromatography
General Experimental. All reagents and solvents were used as
purchased without further purification. All reactions were carried out
under a nitrogen atmosphere, unless otherwise stated, and at the
temperature specified in experimental procedures. Temperatures
higher than room temperature (28 °C) were controlled using
thermostatically controlled oil baths. NMR spectra were recorded on
a 300 or 400 MHz instrument. Mass spectra were recorded on an ESI-
quad instrument. High-resolution mass spectra were recorded on an
ESI Q-TOF. IR spectra were recorded by FT-IR. Melting points were
recorded using a melting point apparatus. Chiral HPLC measurements
were made by HPLC linked to a PC with a chiral column (250 mm ×
(1:1 petroleum ether/ethyl acetate), the solvent was evaporated in
vacuo and water (5 mL) was added. The compound was extracted
using ethyl acetate (3 × 5 mL), and the combined organic layer was
dried over anhydrous sodium sulfate, filtered, and concentrated in
vacuo to give the racemic alcohol.
4
.6 mm i.d.). Thin-layer chromatography was carried out on
aluminum-backed silica gel 60 (F254) plates and visualized using
2
54 nm UV light or potassium permanganate solution.
1
H NMR chemical shifts are reported in ppm downfield from TMS
at 0 ppm. 1 C chemical shifts are reported relative to CDCl at 77
ppm. Coupling constants (J) are recorded in Hz. Multiplicity in H
3
Protocol F: Reduction of Ketone with Isopropanol. Ketone
3
−
3
1
(1.00 equiv), KOH in isopropanol (0.002 mol dm 0.02 equiv KOH,
0 mL/mol ketone), and (R,R)-Ru/TsDPEN 2 (0.01 equiv) and were
1
NMR are reported as singlet (s), broad singlet (br s), doublet (d),
combined in a Schlenk tube, degassed, and stirred under nitrogen at
room temperature. The reaction was monitored by thin-layer
chromatography (1:1 petroleum ether/ethyl acetate) and visualized
under UV light. After completion, the isopropanol was removed in
vacuo and the reaction mixture was dissolved in dichloromethane (1
mL), washed with water (5 mL), and concentrated in vacuo to give the
crude product, which was purified by flash chromatography on silica
gel.
triplet (t), quartet (q), and multiplet (m). Infrared peaks are reported
−
1
−1
3
−1
in cm . Specific rotations are reported in deg dm cm g . In order
to provide a racemic sample to be used as a standard in HPLC, each
ketone was reduced racemically using sodium borohydride. Catalyst 2
is commercially available in either enantiomeric form. Catalysts 5 and
13a
6
were prepared as previously reported.
Protocol A: Asymmetric Transfer Hydrogenation (ATH) in
Water or Water/Methanol. Catalyst (0.01 mmol) was placed in a
Schlenk tube under an inert atmosphere followed by HCO Na (0.340
(R)-1-Phenylethanol.
2
g, 5.0 mmol) and H O (1 mL). The mixture was degassed three times,
2
and to this was added solution ketone (1.0 mmol) followed by
degassing two times. The mixture was stirred at 60 °C. For chiral GC
analysis during the course of a reaction, a small sample from the
reaction mixture was diluted with Et O and H O. The organic layer
was separated and filtered through a short column of silica using
hexane/EtOAc (1:1). The filtrate was analyzed by chiral GC. After
Table 1, entry 4. Preparation using ketone (120 mg, 1.0 mmol) and
catalyst (R,R)-5 (6.5 mg, 0.01 mmol) following protocol A (to the
silica filtration step followed by removal of solvent) gave the crude
2
2
2
8
completion of the reaction, the reaction mixture was diluted with H O
alcohol product as a clear oil (99% conversion by GC analysis). [α]
2
D
2
7
and extracted with Et O (2 × 5 mL). The organic layers were
+58.1 (c 0.730 in CHCl ) for 97% ee (R) (lit. value [α]D +54.9 (c 1.0
2
3
6
788
DOI: 10.1021/acs.joc.5b00990
J. Org. Chem. 2015, 80, 6784−6793

The Journal of Organic Chemistry
Article
13c
in CHCl ) 96% ee (R)); δ (300 MHz, CDCl ) 7.38−7.24 (5H, m,
(S)-1-[4-(Pyrrolidin-1-yl)phenyl]ethanol.
3
H
3
Ph), 4.87 (1H, q, J 6.5 Hz), 2.07 (1H, br s), 1.48 (3H, d, J 6.5 Hz); δC
75 MHz, CDCl ) 145.2, 127.9, 126.8, 124.8, 69.8, 24.5. Chiral GC
(
3
analysis (CP-Chirasil -Dex-Cβ 25 m × 0.25 mm × 0.25 μm, T = 110
C, P = 18 psi, He gas) 6.56 min (ketone), 14.61 min (R isomer),
6.50 min (S isomer).
R)-1-(4-Aminophenyl)ethanol.
°
1
(
Table 2, entry 15. Preparation using ketone (76 g, 0.40 mmol) and
catalyst (S,S)-2 (2.5 mg, 0.004 mmol) following protocol A gave the
alcohol product (54.6 mg, 0.286 mmol, 72%) as a white solid. mp 67
22
°
C; [α] −17.9 (c 0.07 in CH OH) 89% ee (S); (found (ESI) [M +
D
3
+
+
H] 192.1398, C H NO requires [M + H] 192.1383); ν 3400,
2
12
18
max
−
1
950, 2850, 1650, 1510, 1400, 1300, 1200, 1050, 850, 750, 550 cm ;
Table 2, entry 3. Preparation using ketone (134 mg, 1.0 mmol) and
δ (400 MHz, CDCl ) 7.25 (2H, d, J 8.4 Hz), 6.56 (2H, d, J 8.4 Hz),
H
3
catalyst (R,R)-5 (6.5 mg, 0.01 mmol) following protocol A gave the
4
.82 (1H, q, J 6.5 Hz), 3.32−3.26 (4H, m), 2.03−1.98 (4H, m), 1.49
24
D
alcohol product (102 mg, 0.75 mmol, 75%) as an oil. [α] +43.1 (c
(3H, d, J 6.5 Hz); δ (100 MHz, CDCl ) 147.6, 132.5 126.6, 111.5,
2
7
C
3
0
.570 in MeOH) for 94% ee (R) (lit. value [α] +52.0 (c 0.54 in
+
D
7
0.3, 47.7, 25.5, 24.7; m/z (ESI) 192.1 ([M + H] ). Chiral HPLC
16b
MeOH) 99% ee (R)); δH (300 MHz, CDCl ) 7.16 (2H, d, J 8.6
3
analysis (IC, 25 cm × 4.6 mm column, i-PrOH/hexane 1:9, 1.0 mL/
Hz), 6.66 (2H, d, J 8.6 Hz), 4.78 (1H, q, J 6.4 Hz), 3.61 (2H, br s),
min, T = 25 °C, λ = 256 nm) t = 23.4 min (S isomer), 28.2 min (R
R
1
1
0
.80 (1H, br s), 1.45 (3H, d, J 6.4 Hz); δ (75 MHz, CDCl ) 145.7,
35.9, 126.6, 115.0, 70.1, 24.7. Chiral HPLC analysis (OD-H Column:
.46 cm × 25 cm, hexane/i-PrOH 80:20, 1.0 mL/min, 239 nM, 30 °C)
C 3
isomer).
1-[4-(Piperidin-1-yl)phenyl]ethanone.
tR (min) = 18.61 min (R isomer), 28.76 min (S isomer).
-[4-(Dimethylamino)phenyl]ethanone.
1
Preparation following protocol D from 4-fluoroacetophenone (1.0 g,
0
.88 mL, 7.22 mmol), piperidine (2.64 mL, 26.6 mmol), and deionized
22
Preparation following protocol D using 4-fluoroacetophenone (0.50 g,
.44 mL, 3.61 mmol) and 40% aqueous dimethylamine (1.5 mL, 13.3
mmol) for 22 h gave the ketone (393.7 mg, 2.41 mmol, 66.9%) as a
water (3.96 mL) for 26 h gave the ketone (0.792 g, 3.90 mmol,
53.9%) as a dark yellow solid; mp 86 °C; νmax 2941, 2924, 2845, 1653,
1589, 1510, 1423, 1354, 1223, 1124, 915, 818 cm ; δ
0
19
−1
(500 MHz,
H
light yellow solid. mp 105 °C; νmax 2904, 2811, 2651, 1649, 1585,
CDCl ) 7.86 (2H, d, J 9.1 Hz), 6.86 (2H, d, J 9.1 Hz), 3.38−3.34 (4H,
3
−
1
m), 2.51 (3H, s), 1.70−1.67 (6H, m); δ (125 MHz, CDCl ) 196.4,
1
357, 1229, 1068, 832, 593, 560, and 499 cm ; δ (500 MHz,
C
3
H
1
+
54.4, 130.5, 126.7, 113.2, 48.6, 26.0, 25.4, 24.4; m/z (ESI) 226.1 ([M
Na] ), 204.1 ([M + H] ).
CDCl ) 7.87 (2H, d, J 9.0 Hz), 6.66 (2H, d, J 9.0 Hz), 3.06 (6H, s),
3
+
+
2
4
.51 (3H, s); δ (125 MHz, CDCl ) 196.4, 153.4, 130.5, 125.4, 110.6,
C 3
+
+
(S)-1-[4-(Piperidin-1-yl)phenyl]ethanol.
0.0, 26.0; m/z (ESI) 186.1 ([M + Na] ), 164.1 ([M + H] ).
R)-1-[(4′-Dimethylamino)phenyl]ethanol.
(
Table 2, entry 17. Preparation using ketone (50 mg, 0.25 mmol) and
catalyst (S,S)-2 (1.5 mg, 0.0025 mmol) following protocol A gave the
alcohol product (42.7 mg, 0.21 mmol, 84%) as a white solid. mp 82.4
Table 2, entry 9. Preparation using ketone (81.5 g, 0.50 mmol) and
catalyst (R,R)-5 (3.3 mg, 0.005 mmol) following protocol A gave the
27
alcohol product (65 mg, 0.39 mmol, 78%) as a clear oil. [α] +54.2
D
23
22
21
2
5
°C; [α]
1.434 in CH
400, 1250, 1200, 1150, 1100, 1075, 1050, 1000, 850, 750, 700 cm ;
δ (400 MHz, CDCl ) 7.25 (2H, d, J 8.7 Hz), 6.92 (2H, d, J 8.7 Hz),
D
−10.5 (c 0.1 in CH
3
3
OH) 95% ee (S) (lit. [α]
OH) 97.6% ee (R)); νmax 3300, 2950, 2800, 1650, 1510,
D
+37.6 (c
(
c 0.710 in CHCl ) for 91% ee (R) (lit. value [α] +51.8 (c 21.0 in
3
D
20
CHCl ) 86% ee (R)); δ (400 MHz, CDCl ) 7.25 (2H, d, J 8.7 Hz),
3
H
3
−1
1
6.72 (2H, d, J 8.7 Hz), 4.81 (1H, q, J 6.4 Hz), 2.93 (6H, s), 1.62 (1H,
H
3
br s), 1.47 (3H, d, J 6.4 Hz); δC (100 MHz, CDCl ) 150.3, 133.7,
3
4
1
1
.83 (1H, q, J 6.5 Hz), 3.18−3.14 (4H, m), 1.76−1.70 (4H, m), 1.60−
1
0
26.5, 112.6, 70.1, 40.7, 24.7. Chiral HPLC analysis (OD-H Column:
.46 cm × 25 cm, hexane/i-PrOH 95:5, 1.0 mL/min, 256 nM, 30 °C)
.52 (2H, m), 1.48 (3H, d, J 6.5 Hz); δ (100 MHz, CDCl ) 151.8,
C
3
36.3, 126.3, 116.4, 70.1, 50.7, 25.8, 24.7, 24.3; m/z (ESI) 206.1 ([M +
tR (min) = 15.21 min (R isomer), 17.15 min (S isomer).
+
H] ). Chiral HPLC analysis (IC, 25 cm × 4.6 mm column, i-PrOH/
1-[4-(Pyrrolidin-1-yl)phenyl]ethanone.
hexane 1:9, 1.0 mL/min, T = 25 °C, λ = 256 nm) t = 14.04 min (S
R
isomer), 15.38 min (R isomer).
1-[4-(Morpholin-4-yl)phenyl]ethanone.
Preparation following protocol D using 4-fluoroacetophenone (1.0 g,
.88 mL, 7.22 mmol), pyrrolidine (2.22 mL, 26.6 mmol), and
0
2
1
deionized water (3.34 mL) for 23 h gave the ketone (1061 mg, 3.90
mmol, 72.3%) as a dark yellow solid; mp 129 °C; ν 2962, 2849,
1
Preparation following protocol D from 4-fluoroacetophenone (0.50 g,
max
0.44 mL, 3.61 mmol), morpholine (2.64 mL, 13.3 mmol) and
−1
2
3
650, 1588, 1351, 1181, 1157, and 820 cm ; δ (500 MHz, CDCl )
H 3
deionized water (1.72 mL) for 22 h gave the ketone (396 mg, 1.93
7
.87 (2H, d, J 9.0 Hz), 6.53 (2H, d, J 9.0 Hz), 3.40−3.35 (4H, m), 2.50
mmol, 53.5%) as a light yellow solid; mp 97 °C; ν 2841, 1657, 1592,
max
−1
(
1
3H, s), 2.07−2.02 (4H, m, CH CH ); δ (125 MHz, CDCl ) 196.3,
1513, 1425, 1360, 1240, 1170, 927, 817 cm ; δ (500 MHz, CDCl )
2
2
C
3
H 3
51.0, 130.7, 124.9, 110.6, 47.6, 26.0, 25.5; m/z (ESI) 212.0 ([M +
7.90 (2H, d, J 9.1 Hz), 6.87 (2H, d, J 9.1 Hz), 3.86 (4H, t, J 5.0 Hz),
+
+
Na] ), 190.1 ([M + H] ).
3.31 (4H, t, J 5.0 Hz), 2.53 (3H, s); δC (125 MHz, CDCl ) 196.5,
3
6
789
DOI: 10.1021/acs.joc.5b00990
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The Journal of Organic Chemistry
Article
1
7,25
1
54.2, 130.4, 128.1, 113.3, 66.6, 47.5, 26.2; m/z (ESI) 228.0 ([M +
(R)-2-(1-Hydroxyethyl)-4-methoxyphenol..
+
+
Na] ), 206.1 ([M + H] ).
S)-1-[4-(Morpholin-4-yl)phenyl]ethanol.
(
Table 3, entry 8. Preparation using ketone (166 g, 1.0 mmol) and
catalyst (R,R)-5 (3.2 mg, 0.005 mmol) following protocol C gave the
3
0
alcohol product (142 mg, 0.84 mmol, 84%) as a clear oil. [α]D +9.3
c 0.55 in CHCl ) 92% ee; (R); δ (250 MHz, CDCl ) 7.42 (1H, br
(
Table 2, entry 19. Preparation using ketone (50 mg, 0.24 mmol) and
catalyst (S,S)-2 (1.5 mg, 0.0024 mmol) following protocol A gave the
alcohol product (37.3 mg, 0.18 mmol, 88%) as a brown solid. mp 90
3
H
3
s), 6.79 (1H, d, J 8.8 Hz), 6.71 (1H, dd, J 2.8, 8.8 Hz), 6.54 (1H, d, J
.8 Hz), 5.01 (1H, q, J 6.7 Hz), 3.73 (3H, s), 2.39 (1H, br s), 1.57
3H, d, J 6.7 Hz); δ (100 MHz, CDCl ) 153.0, 149.2, 129.2, 117.6,
2
°
C; [α]D24 −25.3 (c 0.075 in CHCl ) 91% ee (S) (lit. [α]D 45.9 (c
20
25
C
3
(
3
1
1
.0 in CHCl ) 93% ee (R)); ν 3343, 2832, 1609, 1514, 1449, 1262,
113.7, 112.3, 71.6, 55.8, 23.3; Chiral HPLC (IA Column: (0.46 × 25
3
max
−1
208, 1118, 1090, 1062, 920, 818, 624, 560, 446 cm ; δ (400 MHz,
cm), 1 mL/min, 10% i-PrOH/90% Hexane; 256 nm UV, 30 °C) t
11.57 min (S isomer), 12.74 min (R isomer).
(S)-1-(2-Methoxyphenyl)ethanol.
R
=
H
CDCl ) 7.30 (2H, d, J 8.7 Hz), 6.88 (2H, d, J 8.7 Hz), 4.82 (1H, q, J
3
6.5 Hz), 3.82 (4H, t, J 5.0 Hz), 3.12 (4H, m), 1.80 (1H, br s), 1.45
(
7
3H, t, J 6.5 Hz); δ (100 MHz, CDCl ) 150.8, 137.3, 126.4, 115.7,
C
3
+
0.0, 66.9, 49.4, 24.9; m/z (ESI) 230.0 ([M + Na] ), 208.1 ([M +
+
H] ). Chiral HPLC analysis (IC, 25 cm × 4.6 mm column, i-PrOH/
hexane 1:9, 1.0 mL/min, T = 25 °C, λ = 256 nm) t = 29.2 min (S
R
Table 3, entry 9. Preparation using ketone (150 mg, 1.0 mmol) and
isomer), 35.2 min (R isomer).
1
7,24a
(
R)-2-(1-Hydroxyethyl)-4-methylphenol..
catalyst (S,S)-5 (3.2 mg, 0.005 mmol) following protocol C gave the
3
2
alcohol product (98 mg, 0.64 mmol, 64%) as a clear oil. [α] −13.9
D
2
6
20
(
c 0.39 in CHCl ) 68% ee (S) (lit [α]D +32.3 (c 2.0 in CHCl3)
3
9
4% ee (R)); δ (250 MHz, CDCl ) 7.35 (1H, dd, J 1.8, 7.5 Hz), 7.25
H 3
(
1H, ddd, J 1.8, 8.1, 8.1 Hz), 6.97 (1H, ddd, J 1.0, 7.5, 7.5 Hz), 6.89
Table 3, entry 2. Preparation using ketone (150 mg, 1.0 mmol) and
(1H, dd, J 1.0, 8.1 Hz), 5.11 (1H, q, J 6.6 Hz), 3.87 (3H, s), 1.52 (3H,
d, J 6.6 Hz); δ (100 MHz, CDCl ) 156.5, 133.5, 128.3, 126.1, 120.8,
110.4, 66.5, 55.3, 22.9; Chiral GC; (CP-Chirasil-Dex-Cβ, 25 m × 0.25
mm × 0.25 μm column, oven temperature 150 °C, inj.: split 220 °C,
det.: FID 250 °C, 18 psi He) t = 5.84 min (S isomer), 6.30 min (R
isomer).
catalyst (R,R)-5 (3.3 mg, 0.005 mmol) following protocol C gave the
C
3
32
alcohol product (152 mg, 1.0 mmol, 100%) as a clear oil. [α]D +24.1
(
c 0.36 in CHCl ) 95% ee (R); δ (300 MHz, CDCl ) 7.69 (1H, br s),
3 H 3
6
.97 (1H, dd, J 1.8, 8.2 Hz), 6.80−6.73 (2H, m), 5.01 (1H, q, J 6.6
R
Hz), 2.65 (1H, br s, CHOH), 2.25 (3H, s), 1.57 (3H, d, J 6.6 Hz); δC
75 MHz, CDCl ) 152.5, 128.7, 128.4, 127.5, 126.4, 116.3, 71.1, 22.9,
(
3
(S)-1-(2,5-Dimethoxyphenyl)ethan-1-ol.
1
9.9; Chiral HPLC (IA Column: (0.46 × 25 cm), 1 mL/min, 10% i-
PrOH/90% Hexane; 256 nm UV, 30 °C) t = 7.83 min (S isomer),
R
8
.53 min (R isomer).
2
4b
(
R)-4-Chloro-2-(1-hydroxyethyl)phenol.
Table 3, entry 15. Preparation using ketone (147 g, 1.0 mmol) and
catalyst (S,S)-2 (3.2 mg, 0.005 mmol) following protocol C gave the
3
D
2
alcohol product (147 mg, 0.80 mmol, 80%) as a clear oil. [α] −15.8
2
7
27
(
7
c 0.60 in CHCl ) 69% ee (S) (lit [α]D −23.6 (c 1.4 in CHCl3)
3
Table 3, entry 4. Preparation using ketone (170 g, 1.0 mmol) and
catalyst (R,R)-5 (3.3 mg, 0.005 mmol) following protocol C gave the
alcohol product (162 mg, 0.94 mmol, 94%) as a clear oil. [α]D30 +18.5
6% ee (S)); δ (300 MHz, CDCl ) 6.92 (1H, d, J 2.8 Hz), 6.79 (1H,
H 3
d, J 8.9 Hz), 6.73 (1H, dd, J 2.8, 8.9 Hz), 5.04 (1H, dq, J 5.5, 6.4 Hz),
.81 (3H, s), 3.76 (3H, s), 2.60 (1H, d, J 5.5 Hz), 1.47 (3H, d, J 6.4
Hz); δ (100 MHz, CDCl ) 153.8, 150.6, 134.8, 112.4, 112.3, 111.4,
3
(
c 0.46 in CHCl ) 93% ee (R); δ (300 MHz, CDCl ) 8.01 (1H, br s),
3 H 3
C
3
7.11 (1H, dd, J 2.4, 8.7 Hz), 6.95 (1H, d, J 2.4 Hz), 6.78 (1H, d, J 8.7
6
6.4, 55.8, 55.7, 23.0; Chiral GC; (CP-Chirasil-Dex-Cβ, 25 m × 0.25
Hz), 5.01 (1H, q, J 6.6 Hz), 2.80 (1H, br s), 1.56 (3H, d, J 6.6 Hz); δC
75 MHz, CDCl ) 153.9, 129.8, 128.7, 126.3, 124.6, 118.4, 71.1, 23.4;
mm × 0.25 μm column, oven temperature 150 °C, inj.: split 220 °C,
(
3
det.: FID 250 °C, 18 psi He) t = 15.72 min (R isomer), 16.93 min (S
R
Chiral HPLC (IA Column: (0.46 × 25 cm), 1 mL/min, 10% i-PrOH/
0% Hexane; 256 nm UV, 30 °C) t = 7.52 min (S isomer), 8.10 min
isomer).
9
R
(R)-1-Phenyl-1-propanol.
(
R isomer).
2
5
(
S)-4-Bromo-2-(1-hydroxyethyl)phenol.
Preparation using ketone (134 mg, 0.133 mL, 1.0 mmol) and catalyst
R,R)-5 (6.5 mg, 0.01 mmol) following protocol A (to silica filtration
step followed by removal of solvent) gave the crude alcohol product as
(
Table 3, entry 5. Preparation using ketone (215 g, 1.0 mmol) and
catalyst (S,S)-2 (3.3 mg, 0.005 mmol) following protocol C gave the
alcohol product (141 mg, 0.65 mmol, 65%) as a clear oil. [α]D30 −23.6
29
a clear oil (99% conversion by GC analysis). [α] = +53.6 (c 0.75 in
D
2
8
25
CHCl ) 98% ee (R) (lit. [α]D = −47.2 (c 0.65 in CHCl ) 99% ee
(
c 0.68 in CHCl ) 91% ee (S); δ (300 MHz, CDCl ) 7.97 (1H, br s),
3
3
3
H
3
7.26 (1H, dd, J 2.4, 8.6 Hz), 7.10 (1H, d, J 2.4 Hz), 6.76 (1H, d, J 8.6
(S)); δ
H
(400 MHz, CDCl
3
) 7.36−7.25 (5H, m), 4.58 (1H, t, J 6.4
Hz), 5.04 (1H, q, J 6.6 Hz), 2.45 (1H, br s), 1.59 (3H, d, J 6.6 Hz); δC
100 MHz, CDCl ) 154.6, 131.6, 130.4, 129.2, 119.0, 111.8, 71.1, 23.4;
Hz), 2.03 (1H, br s), 1.87−1.68 (2H, m), 1.48 (3H, t, J 7.0 Hz); δ
C
(
(125 MHz, CDCl ) 144.6, 128.4, 127.5, 126.0, 76.0, 31.9, 10.1. Chiral
3
3
Chiral HPLC (IA Column: (0.46 × 25 cm), 1 mL/min, 10% i-PrOH/
0% Hexane; 256 nm UV, 30 °C) t = 7.95 min (S isomer), 8.75 min
GC analysis (CP-Chirasil-Dex-Cβ 25 m × 0.25 mm × 0.25 μm, T =
9
115 °C, P = 18 psi, He gas) t = 8.48 min (ketone), 19.39 min (R
R
R
(R isomer).
isomer), 21.00 min (R isomer).
6
790
DOI: 10.1021/acs.joc.5b00990
J. Org. Chem. 2015, 80, 6784−6793

The Journal of Organic Chemistry
Article
(
R)-1-Tetralol.
Preparation using ketone (170 mg, 0.152 mL, 1.0 mmol) and catalyst
(
R,R)-5 (6.5 mg, 0.01 mmol) following protocol A (to silica filtration
step followed by removal of solvent) gave the crude alcohol product as
32
D
a clear oil (99% conversion by GC analysis). [α] +60.3 (c 0.910 in
3
1
CHCl ) 99% ee (R) (lit. [α] +67.3 (c 0.4 in CHCl ) 100% ee (R));
3
D
3
δ (400 MHz, CDCl ) 8.10 (1H, d, J 8.4 Hz), 7.86 (1H, dd, J 7.2, 2.0
Preparation using ketone (146 mg, 0.0133 mL, 1.0 mmol) and catalyst
R,R)-5 (6.5 mg, 0.01 mmol) following protocol A (to silica filtration
step followed by removal of solvent) gave the crude alcohol product as
H
3
Hz)7.76 (1H, d, J 8.4 Hz), 7.76 (1H, d, J 7.2 Hz), 7.53−7.44 (3H, m),
(
5
.65 (1H, q, J 6.4 Hz), 2.08 (1H, br s), 1.65 (3H, d, J 6.4 Hz); δ (125
C
28
MHz, CDCl ) 141.4, 133.7, 130.3, 128.8, 127.9, 126.0, 125.6, 125.4,
a clear oil (98% conversion by GC analysis). [α] −30.5 (c 1.000 in
3
D
29
1
23.1, 122.0, 67.1, 24.3. Chiral GC analysis (CP-Chirasil-Dex-Cβ 25 m
0.25 mm × 0.25 μm, T = 160 °C, P = 18 psi, He gas) t = 10.37 min
CHCl ) 97% ee (R) (lit. [α] +34.4 (c 1.01 in CHCl ) 98% ee (S));
3
D
3
×
δ (400 MHz, CDCl ) 7.47−7.37 (1H, m), 7.22−7.05 (3H, m), 4.78
R
H
3
(
ketone), 21.01 min (S isomer), 22.40 min (R isomer).
(
1H, br s), 2.89−2.65 (2H, m), 2.03−1.74 (5H, m); δ (125 MHz,
C
(R)-1-(2-Naphthyl)ethanol.
CDCl ) 138.8, 137.1, 129.0, 128.6, 127.6, 126.2, 68.2, 32.2, 29.2, 18.8.
3
Chiral GC analysis (CP-Chirasil-Dex-Cβ 25 m × 0.25 mm × 0.25 μm,
T = 120 °C, P = 18 psi, He gas) t = 24.70 min (ketone), 44.00 min (S
R
isomer), 45.12 min (R isomer).
(
R)-1-(4-Chlorophenyl)ethanol.
Preparation using ketone (170 g, 1.0 mmol) and catalyst (R,R)-5 (6.5
mg, 0.01 mmol) following protocol A (to silica filtration step followed
by removal of solvent) gave the crude alcohol product as a clear oil
28
(
9
99% conversion by GC analysis). [α] +46.4 (c 0.850 in CHCl3)
D
9a
23
6% ee (R) (lit. [α]D +46.7 (c 1.02 in CHCl ) 92% ee (R)); δ
3 H
Preparation using ketone (153.5 mg, 0.130 mL, 1.0 mmol) and (R,R)-
(6.5 mg, 0.01 mmol) following protocol A (to silica filtration step
followed by removal of solvent) gave the crude alcohol product as a
clear oil (99% conversion by GC analysis). [α] +45.0 (c 0.840 in
CHCl ) 95% ee (R) (lit [α] +38.6 (c 1.01 in CHCl ) 88% ee (R));
δ (400 MHz, CDCl ) 7.30 (4H, br s), 4.86 (1H, q, J 6.4 Hz), 2.00
1H, br s), 1.48 (3H, d, J 6.4 Hz); δ (100 MHz, CDCl ) 143.6, 132.4,
28.3, 126.2, 69.1, 24.7. Chiral GC analysis (CP-Chirasil-Dex-Cβ 25 m
(
400 MHz, CDCl ) 7.87−7.73 (4H, m), 7.54−7.40 (3H, m), 5.04
3
5
(1H, q, J 6.4 Hz), 1.98 (1H, br s), 1.48 (3H, d, J 6.4 Hz); δ (125
C
MHz, CDCl ) 143.1, 133.3, 132.9, 128.3, 127.9, 127.7, 126.2, 125.8,
26
D
3
1
0
23.8, 70.6, 25.2. Chiral GC analysis (CP-Chirasil-Dex-Cβ 25 m ×
30
3
D
3
.25 mm × 0.25 μm, T = 150 °C, P = 18 psi, He gas) t = 18.92 min
R
H
3
(ketone), 30.87 min (R isomer), 33.38 min (S isomer).
(
1
C 3
(S)-1-Phenyl-2-chloroethanol.
×
0.25 mm × 0.25 μm, T = 150 °C, P = 18 psi, He gas) t = 4.48 min
R
(
ketone), 7.75 min (R isomer), 8.56 min (S isomer).
R)-1-(4-Methoxyphenyl)ethanol.
(
Preparation using ketone (155 g, 1.0 mmol) and catalyst (R,R)-5 (6.5
mg, 0.01 mmol) following protocol A (to silica filtration step followed
by removal of solvent) gave the crude alcohol product as a clear oil
3
2
(
99% conversion by GC analysis). [α] +61.8 (c 0.810 in CHCl3)
D
32
22
Preparation using ketone (150 mg, 1.0 mmol) and catalyst (R,R)-5
6.5 mg, 0.01 mmol) following protocol following protocol A (to silica
filtration step followed by removal of solvent) gave the crude alcohol
96% ee (S) (lit. [α]D +53.8 (c 1.0 in CHCl ) >99% ee (S)); δ
3 H
(
(400 MHz, CDCl ) 7.39−7.31 (5H, m), 4.75 (1H, m), 3.60 (1H, dd, J
3
11.4, 3.6 Hz), 3.48 (1H, dd, J 11.4, 8.6 Hz), 2.55 (1H, d, J 3.2 Hz); δ
C
26
product as a clear oil (99% conversion by GC analysis). [α] +47.4
(100 MHz, CDCl ) 138.3, 128.1, 127.9, 125.5, 73.5, 50.3. Chiral GC
D
3
13c
27
(
c 0.610 in CHCl ) 97% ee (R) (lit. [α]D +32.3 (c 1.0 in CHCl3)
analysis (CP-Chirasil-Dex-Cβ 25 m × 0.25 mm × 0.25 μm, T = 150
3
9
0% ee (R)); δ (300 MHz, CDCl ) 7.30 (2H, d, J 8.7 Hz), 6.88 (2H,
°C, P = 18 psi, He gas) t = 6.96 min (ketone), 9.00 min (S isomer),
H
3
R
d, J 8.7 Hz), 4.85 (1H, q, J 6.4 Hz), 3.80 (3H, s), 1.88 (1H, br s), 1.48
9.60 min (R isomer).
(
3H, d, J 6.4 Hz); δ (75 MHz, CDCl ) 158.4, 137.4, 126.0, 113.2,
(R)-1-(4-Trifluoromethylphenyl)ethanol.
C
3
69.4, 54.7, 24.4. Chiral GC analysis (CP-Chirasil-Dex-Cβ 25 m × 0.25
mm × 0.25 μm, T = 130 °C, P = 18 psi, He gas) t = 13.20 min
R
(
ketone), 18.04 min (R isomer), 19.81 min (S isomer).
R)-1-(3-Methoxyphenyl)ethanol.
(
Preparation using ketone (188 g, 1.0 mmol) and catalyst (R,R)-5 (6.5
mg, 0.01 mmol) following protocol A (to silica filtration step followed
by removal of solvent) gave the crude alcohol product as a clear oil
2
9
(
9
99% conversion by GC analysis). [α] +32.5 (c 0.690 in CHCl3)
D
33
Preparation using ketone (150 mg, 0.137 mL, 1.0 mmol) and catalyst
R,R)-5 (6.5 mg, 0.01 mmol) following protocol A (to silica filtration
step followed by removal of solvent) gave the crude alcohol product as
22
4% ee (R) (lit. [α]D +29.3 (c 1.0 in CHCl ) >99% ee (R)); δ
3 H
(
(
300 MHz, CDCl ) 7.62−7.60 (2H, m), 7.48−7.46 (2H, m), 4.95
3
(
1H, q, J 6.4 Hz), 2.11 (1H, br s), 1.49 (3H, d, J 6.4 Hz); δ (75 MHz,
28
C
a clear oil (96% conversion by GC analysis). [α] +38.1 (c 0.670 in
D
CDCl ) 149.1, 128.2 (q J 30 Hz, ArCCF ), 125.3, 124.8, 123.3 (q J 270
8b
23
3
3
CHCl ) 97% ee (R) (lit. [α]D +31.8 (c 2.0 in CHCl ) 94% ee (R));
3
3
Hz, CF ), 69.3, 24.8. Chiral GC analysis (CP-Chirasil-Dex-Cβ 25 m ×
0
3
δ (300 MHz, CDCl ) 7.26 (1H, dd, J 8.1, 8.1 Hz), 6.95−6.93 (2H,
H
3
.25 mm × 0.25 μm, T = 120 °C, P = 18 psi, He gas) t = 5.02 min
R
m), 6.82−6.78 (1H, m), 4.86 (1H, q, J 6.3 Hz), 3.81 (3H, s), 1.94 (1H,
br s), 1.48 (3H, d, J 6.3 Hz); δ (75 MHz, CDCl ) 159.2, 147.0, 128.5,
(ketone), 13.92 min (R isomer), 17.19 min (S isomer).
C
3
(R)-1-(2-Trifluoromethylphenyl)ethanol.
117.0, 112.3, 110.3, 69.7, 54.6, 24.5. Chiral GC analysis (CP-Chirasil-
Dex-Cβ 25 m × 0.25 mm × 0.25 μm, T = 140 °C, P = 18 psi, He gas)
tR = 6.45 min (ketone), 11.75 min (R isomer), 12.69 min (S isomer).
(
R)-1-(1-Naphthyl)ethanol.
Preparation using ketone (188 g, 0.149 mL, 1.0 mmol) and catalyst
R,R)-5 (6.5 mg, 0.01 mmol) following protocol A (to silica filtration
(
step followed by removal of solvent) gave the crude alcohol product as
a clear oil (99% conversion by GC analysis). [α]D25 +34.8 (c 1.11 in
6
791
DOI: 10.1021/acs.joc.5b00990
J. Org. Chem. 2015, 80, 6784−6793

The Journal of Organic Chemistry
Article
CHCl ) 69% ee (R) (lit. [α]D22 −45.4 (c 0.661 in MeOH) 97% ee
2
8
(2) (a) Ohkuma, T.; Utsumi, N.; Tsutsumi, K.; Murata, K.; Sandoval,
C.; Noyori, R. J. Am. Chem. Soc. 2006, 128, 8724−8725. (b) Sandoval,
C. A.; Ohkuma, T.; Utsumi, N.; Tsutsumi, K.; Murata, K.; Noyori, R.
Chem.Asian J. 2006, 1−2, 102−110. (c) Li, C. Q.; Villa-Marcos, B.;
Xiao, J. L. J. Am. Chem. Soc. 2009, 131, 6967−6969. (d) Ito, M.; Endo,
Y.; Tejima, N.; Ikariya, T. Organometallics 2010, 29, 2397−2399.
(e) Arai, N.; Satoh, H.; Utsumi, N.; Murata, K.; Tsutsumi, K.;
Ohkuma, T. Org. Lett. 2013, 15, 3030−3033. (f) Wang, T.; Chen, F.;
Qin, J.; He, Y.-M.; Fan, Q.-H. Angew. Chem., Int. Ed. 2013, 52, 7172−
3
(
S)); δ (300 MHz, CDCl ) 7.82 (1H, br d, J 7.8 Hz), 7.61−7.56 (2H,
H
3
m), 7.36 (1H, d, J 7.5 Hz), 5.37−5.29 (1H, m), 2.03 (1H, br s), 1.48
(
1
2
3H, d, J 6.6 Hz); δ (75 MHz, CDCl ) 144.4, 131.8, 126.7, 126.5,
C 3
3
24.6, 123.1 (q, J
280 Hz, CF note outer peaks of q weak), 65.1,
C−F 3;
5.8 (ArCCF not identified). Chiral GC analysis (CP-Chirasil-Dex-
Cβ 25 m × 0.25 mm × 0.25 μm, T = 110 °C, P = 18 psi, He gas) t =
.30 min (ketone), 16.74 min (R isomer), 19.44 min (S isomer).
3
R
5
(
S)-1-Cyclohexylethanol.
7
176.
3) (a) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R. J.
(
Am. Chem. Soc. 1995, 117, 7562−7563. (b) Fujii, A.; Hashiguchi, S.;
Uematsu, N.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118,
2521−2522. (c) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R.
J. Am. Chem. Soc. 1997, 119, 8738−8739. (d) Haack, K. J.; Hashiguchi,
S.; Fujii, A.; Ikariya, T.; Noyori, R. Angew. Chem. 1997, 109, 297−300;
Angew. Chem., Int. Ed. Engl. 1997, 36, 285−288. (e) Murata, K.;
Okano, K.; Miyagi, M.; Iwane, H.; Noyori, R.; Ikariya, T. Org. Lett.
1999, 1, 1119−1121. (f) Corbett, M. T.; Johnson, J. S. J. Am. Chem.
Soc. 2013, 135, 594−597. (g) Steward, K. M.; Corbett, M. T.;
Goodman, C. G.; Johnson, J. S. J. Am. Chem. Soc. 2012, 134, 20197−
Preparation using ketone (126 g, 0.138 mL, 1.0 mmol) and catalyst
R,R)-6 (1.4 mg, 0.002 mmol) following protocol A (to silica filtration
step followed by removal of solvent) gave the crude alcohol product as
(
26
a clear oil (99% conversion by GC analysis). [α] −3.0 (c 0.560 in
D
34
22
CHCl ) 85% ee (lit. [α]D +2.7 (c 0.5 in CHCl ) 75% ee (R)); δH
3
3
(
(
500 MHz, CDCl ) 3.58−3.50 (1H, m), 1.87−1.65 (5H, m), 1.50
3
1H, br s), 1.33−1.18 (4H, m), 1.15 (3H, d, J 6.3 Hz), 1.10−0.89 (2H,
m); δ (125 MHz, CDCl ) 72.2, 45.1, 28.7, 28.4, 26.5, 26.2, 26.1, 20.4.
C
3
Chiral GC analysis of acetate derivative (CP-Chirasil-Dex-Cβ 25 m ×
2
0206. (h) Bradley, P. A.; Carroll, R. L.; Lecouturier, Y. C.; Moore, R.;
0
.25 mm × 0.25 μm, T = 100 °C, P = 18 psi, He gas) t = 13.80 min
R
Noeureuil, P.; Patel, B.; Snow, J.; Wheeler, S. Org. Process Res. Dev.
(S isomer), 18.64 min (R isomer).
2
010, 14, 1326−1336. (i) Carpenter, I.; Clarke, M. L. Synlett 2011,
6
5−68. (j) Bai, J.; Miao, S.; Wu, Y.; Zhang, Y. Chin. J. Chem. 2011, 29,
ASSOCIATED CONTENT
̊
2476−2480. (k) Slungard, S. V.; Krakeli, T.-A.; Thvedt, T. H. K.;
Fuglseth, E.; Sundby, E.; Hoff, B. H. Tetrahedron 2011, 67, 5642−
650. (l) Nakayama, A.; Kogure, N.; Kitajima, M.; Takayama, H.
■
* Supporting Information
S
5
Extended tables of results, including time-course studies,
comparison of rates of electron-rich and electron-poor
Angew. Chem., Int. Ed. 2011, 50, 8025−8028. (m) Geng, Z.; Wu, Y.;
Miao, S.; Shen, Z.; Zhang, Y. Tetrahedron Lett. 2011, 52, 907−909.
1
substrates, H NMR spectra, and chiral GC/HPLC spectra.
(
(
n) Dias, L. C.; Ferreira, M. A. B. J. Org. Chem. 2012, 77, 4046−4062.
o) Hems, W. P.; Jackson, W. P.; Nightingale, P.; Bryant, R. Org.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b00990.
Process Res. Dev. 2012, 16, 461−463. (p) Lemke, M.-K.; Schwab, P.;
Fischer, P.; Tischer, S.; Witt, M.; Noehringer, L.; Rogachev, V.; Jager,
A.; Kataeva, O.; Frohlich, R.; Metz, P. Angew. Chem., Int. Ed. 2013, 52,
1651−11655.
4) (a) Rhyoo, H. Y.; Park, H.-J.; Chung, Y. K. Chem. Commun. 2001,
̈
AUTHOR INFORMATION
̈
■
*
1
(
Corresponding Author
Tel.: +44 24 7652 3260. Fax: +44 24 7652 4112. E-mail: m.
wills@warwick.ac.uk.
2
064−2065. (b) Wu, X.; Li, X.; Hems, W.; King, F.; Xiao, J. Org.
Biomol. Chem. 2004, 2, 1818−1821. (c) Wu, X.; Li, X.; King, F.; Xiao,
J. Angew. Chem., Int. Ed. 2005, 44, 3407. (d) Canivet, J.; Labat, G.;
Notes
Stoeckli-Evans, H.; Su
500. (e) Li, X.; Blacker, J.; Wu, X.; Xiao, J. Synlett 2006, 1155−1160.
f) Jiang, L.; Wu, T.-F.; Chen, Y.-C.; Zhu, J.; Deng, J.-G. Org. Biomol.
Chem. 2006, 4, 3319−3324. (g) Canivet, F.; Suss-Fink, G. Green Chem.
̈
ss-Fink, G. Eur. J. Inorg. Chem. 2005, 4493−
The authors declare no competing financial interest.
4
(
ACKNOWLEDGMENTS
■
̈
We thank the Leverhulme Trust (grant no. RPG-374) for
support to R.S. and the Engineering and Physical Sciences
Research Council (EPSRC) for support to THH through the
Warwick DTC grant. M.R.O. was supported by the Warwick
University URSS scheme, and B.P.M. was a final year project
student supported by Warwick University. We thank Johnson
Matthey for supplying samples of catalyst 2.
2007, 9, 391−397. (h) Cortez, N. A.; Aguirre, G.; Parra-Hake, M.;
Somanathan, R. Tetrahedron Lett. 2007, 48, 4335−4338. (i) Zhou, H.-
F.; Fan, Q.-H.; Huang, Y.-Y.; Wu, L.; He, Y.-M.; Tang, W.-J.; Gu, L.-
Q.; Chan, A. S. C. J. Mol. Catal. A: Chem. 2007, 275, 47−53. (j) Wu,
X.; Li, X.; Zanotti-Gerosa, A.; Pettman, A.; Liu, J.; Mills, A. J.; Xiao, J.
Chem.Eur. J. 2008, 14, 2209−2222. (k) Wu, X.; Liu, J.; di Tommaso,
D.; Iggo, J. A.; Catlow, C. R. A.; Bacsa, J.; Xiao, J. Chem.Eur. J. 2008,
1
4, 7699−7715. (l) Wang, C.; Li, C.; Wu, X.; Pettman, A.; Xiao, J.
Angew. Chem., Int. Ed. 2009, 48, 6524−6528. (m) Evanno, L.; Ormala,
J.; Pihko, P. M. Chem.Eur. J. 2009, 15, 12963−12967. (n) Cortez, N.
A.; Aguirre, G.; Parra-Hake, M.; Somanathan, R. Tetrahedron Lett.
2009, 50, 2228−2231. (o) Soltani, O.; Ariger, M. A.; Vazquez-Villa,
H.; Carreira, E. M. Org. Lett. 2010, 12, 2893−2895. (p) Kabro, A.;
Escudero-Adan, E. C.; Grushin, V. V.; van Leeuwen, P. W. N. M. Org.
Lett. 2012, 14, 4014−4017. (q) Ariger, M. A.; Carreira, E. M. Org. Lett.
2012, 14, 4522−4524. (r) Cortez, N. A.; Aguirre, G.; Parrra-Hake, M.;
Somanathan, R. Tetrahedron: Asymmetry 2013, 24, 1297−1302.
(s) Wang, L.; Zhou, Q.; Qu, C.; Wang, Q.; Cun, L.; Zhu, J.; Deng,
J. Tetrahedron 2013, 69, 6500−6506. (t) Wang, W.-W.; Li, Z.-M.; Su,
L.; Wang, Q.-R.; Wu, Y.-L. J. Mol. Catal. A: Chem. 2014, 387, 92−102.
(u) Bligh, C. M.; Anzalone, L.; Jung, Y. C.; Zhang, Y.; Nugent, W. A. J.
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DOI: 10.1021/acs.joc.5b00990
J. Org. Chem. 2015, 80, 6784−6793