Industrially viable syntheses of highly enantiomerically enriched 1-aryl alcohols via asymmetric hydrogenation

Article abstract of DOI:10.1021/op025585r

The practicalities of the asymmetric hydrogenation of acetophenone derivatives are addressed. The catalysts used, derived from the precatalysts [(xylylPhanePhos)RuCl₂(DPEN)] (S)-(R,R)-1 and (R)-(S,S)-1, were shown to possess very high reactivity. 4′-Fluoroacetophenone was hydrogenated at a molar substrate-to-catalyst ratio (S/C) of 100,000 with complete conversion effected in as little as 80 min (average turnover ～1200 min^-1, peak turnover ～2500 min^-1). The catalysts are tolerant of a range of commercial grade substrates, in most cases a S/C of 5000-10000 was achieved without the need to purify the ketone. Using precatalyst 1 enantioselectivities of 95 → 99% ee were achieved. The high selectivity and catalyst activity, plus the simplicity of the process, offers significant advantages over other enantioselective ketone reductions.

Full text of DOI:10.1021/op025585r

Organic Process Research & Development 2003, 7, 89−94
Technical Notes
Industrially Viable Syntheses of Highly Enantiomerically Enriched 1-Aryl
Alcohols via Asymmetric Hydrogenation
David Chaplin, Paul Harrison, Julian P. Henschke, Ian C. Lennon, Graham Meek, Paul Moran, Christopher J. Pilkington,
James A. Ramsden,* Simon Watkins, and Antonio Zanotti-Gerosa
Chirotech Technology Limited,† Cambridge Science Park, Milton Road, Cambridge CB4 0WG, UK
Abstract:
ketones. The catalysts are tolerant of various functionalities
within the substrate and offer excellent enantioselectivity.
Molar substrate-to-catalyst ratio as high as 2,400,000 (low
catalyst loading) have been reported.4 To demonstrate the
utility of these types of catalyst we sought to carry out some
larger-scale transformations than have typically been reported
to date. Our primary concern was whether we could effect
the hydrogenation of a range of prochiral ketones, easily
purify the chiral product, and meet an acceptable quality
standard, for example, >95% chemical purity, g98% ee. We
also wished to examine to what extent it is possible to avoid
extensive purification of the ketones prior to hydrogenation.
The practicalities of the asymmetric hydrogenation of acetophe-
none derivatives are addressed. The catalysts used, derived from
the precatalysts [(xylylPhanePhos)RuCl2(DPEN)] (S)-(R,R)-1
and (R)-(S,S)-1, were shown to possess very high reactivity. 4′-
Fluoroacetophenone was hydrogenated at a molar substrate-
to-catalyst ratio (S/C) of 100,000 with complete conversion
effected in as little as 80 min (average turnover ∼1200 min-1
,
peak turnover ∼2500 min-1). The catalysts are tolerant of a
range of commercial grade substrates, in most cases a S/C of
5000-10000 was achieved without the need to purify the ketone.
Using precatalyst 1 enantioselectivities of 95 f 99% ee were
achieved. The high selectivity and catalyst activity, plus the
simplicity of the process, offers significant advantages over other
enantioselective ketone reductions.
Results and Discussion
The precatalysts used throughout this study were [((S)-
xylyl-PhanePhos)Ru((R,R)-DPEN)Cl2] (S)-(R,R)-1 and [((R)-
xylyl-PhanePhos)Ru((S,S)-DPEN)Cl2] (R)-(S,S)-15 (Figure 1).
Introduction
A wide range of methodologies have been developed for
the synthesis of chiral alcohols in high enantiomeric excess
via the reduction or hydrogenation of prochiral ketones.1
Catalytic hydrogenation offers potentially significant advan-
tages over other approaches. Only a small amount of high-
value catalyst is required to facilitate the reaction, the more
active and selective the catalyst, the greater the amplification
of this value in the product. The reagent, hydrogen, is cheap
and can be used in excess as all unreacted hydrogen is very
easily removed at the end of the reaction, leaving a solution
of the product containing trace quantities of the catalyst
residue. The most effective catalysts available for the
asymmetric hydrogenation of ketones to date are those
derived from diphosphine ruthenium dichloride diamine
complexes.2,3 They were shown to be effective for the
asymmetric hydrogenation of a wide range of prochiral
Figure 1.
By variation of the diamine and the diphosphine it is possible
to access a wide range of precatalysts of this type, offering
a variety of chemoselectivities and selectivities for different
substrate types. Catalysts derived from 1 have been shown
to offer high selectivity and reactivity for the ketones
examined in this current study.3 The focus of this work is
primarily on catalyst utilization rather than catalyst selection.
A range of acetophenone substrates 2a-i (Figure 2) were
hydrogenated using (S)-(R,R)-1 and (R)-(S,S)-1 on a 20 mmol
scale in a 50-mL pressure vessel. In these reactions, using
* Author for correspondence. E-mail: jramsden@dow.com.
† Chirotech Technology Limited is a subsidiary of The Dow Chemical
Company.
(1) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109,
5551. (b) Brown J. M.; Hulmes D. I.; Layzell, T. P. J. Chem. Soc., Chem.
Commun. 1993, 1673. (c) Yun J.; Buchwald S. L. J. Am. Chem. Soc. 1999,
121, 5640. (d) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97.
(2) Noyori, R.; Ohkuma, T. Angew. Chem. Int. Ed., 2001, 40, 40 and references
therein.
(4) Doucet, H.; Ohkuma, T.; Murata, K.; Yokozawa, T.; Kozawa, M.;
Katayama, E.; England, A. F.; Ikariya, T.; Noyori, R. Angew. Chem., Int.
Ed. 1998, 37, 1703.
(5) There has been some ambiguity of the assignment of absolute stereochem-
istry of substituted paracyclophanes. The structures as drawn in this
publication are correct, in a previous work4 the structures were incorrectly
drawn but the assignments were correct. Pye, P. J.; Rossen, K. Tetrahe-
dron: Asymmetry 1998, 9, 539.
(3) Burk, M. J.; Hems, W.; Herzberg, D.; Malan, C.; Zanotti-Gerosa, A. Org.
Lett. 2000, 2, 4173.
10.1021/op025585r CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/10/2002
Vol. 7, No. 1, 2003 / Organic Process Research & Development
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89

Table 2. Design of experiment matrix for the hydrogenation
of acetophenone 2a with (R)-(S,S)-1
pressure temp
ketone
selectivity
ee
ratea
entry (atm) (°C) (concn g/mL)
(mol s-1
)
1
2
3
4
5
6
7
8
13
3
3
13
3
13
3
13
8
8
30
30
30
30
10
10
10
10
20
20
20
0.4
0.4
0.2
0.2
0.2
0.2
0.4
0.4
0.3
0.3
0.3
98.1
97.5
97.5
98.4
98.8
98.8
98.4
98.7
98.3
98.3
98.7
6.2 × 10-6
2.1 × 10-6
3.0 × 10-6
11.1 × 10-6
0.8 × 10-6
2.9 × 10-6
0.7 × 10-6
3.2 × 10-6
2.9 × 10-6
4.0 × 10-6
3.4 × 10-6
9
10
11
Figure 2.
8
Table 1. Hydrogenation of acetophenone derivatives with
(S)-(R,R)-1 and (R)-(S,S)-1
a Approximate rate based on time to 50% conversion.
(S)-(R,R)-1
yield %
ee %a
(R)-(S,S)-1
Table 3. Effect of substrate concentration on the
hydrogenation of 3′-trifluoroacetophenone with (R)-(S,S)-1
specified
purity (%)
ketone
yield %
ee %b
2a
2b
2c
2d
2e
2f
2g
2h
2i
99
99
98
98+
97
98
99
88
73
93
77
86
91
82
n/ac
-
96.8
98.5
98.9
98.8
98.8
98.0
94.0
99.0
-
n/ac
94
96
88
90
98.5d
98.8d
98.2
98.5
98.3
98.1
89.3
99.0
98.7
entry ketone concn (v/v) reaction time(min)a selectivity ee
85
99
n/ac
n/ac
1
2
3
4
5
6
7
8
100
83
71
55
38
19
11
6
>310b
119
87
72.9
93.0
94.6
97.4
98.3
98.9
98.7
98.7
99 distilled
99
36
20
25
24
a (S)-aryl alcohol. b (R)-aryl alcohol. c Not isolated. d Molar S/C ) 10,000.
(20 mmol input) molar S/C ) 5000.
typical conditions (8 atm hydrogen, 1-5 mol % t-BuOK,
room temperature in propan-2-ol) these ketones underwent
complete conversion to the corresponding alcohol 3a-i with
a S/C ratio of 5000-10000 in 2-6 h. The hydrogenation of
4′-fluoroacetophenone proved to be more problematic as
some commercially available materials (99% purity) showed
very little reactivity. However, after distillation of the ketone
the hydrogenation was very rapid. In small-scale reactions
(20 mmol) at S/C of 10,000 the reaction was complete in
less than 2 h.
When hydrogen uptake had ceased, the crude reaction
mixture was treated with 1 equiv of hydrochloric acid (with
respect to t-BuOK), solvent was removed in vacuo, and the
residue was partitioned between water and dichloromethane.
After drying, removal of solvent gave a coloured oil or solid,
Kugelrohr distillation gave a colourless product. Analysis
of this product indicated clean conversion in all cases, and
the enantioselectivities were uniformly high (Table 1).
Design of Experiment. Before embarking on larger-scale
experiments with these substrates the profile of a typical
hydrogenation reaction was examined in more detail. The
hydrogenation of acetophenone 2a with (R)-(S,S)-1 under
of a range of temperatures (10, 20, and 30 °C), pressures (3,
8, and 13 atm H2) and substrate concentrations (0.2, 0.3, and
0.4 g/mL) were examined. The effect of these factors on
reaction selectivity and rate are shown in Table 2.
38
a Time for uptake of hydrogen to cease. b 80% of hydrogen uptake after 5 h,
reaction left overnight.
suggest: the variation in selectivity is very slight. In general
lower concentrations and higher pressures enhance reaction
rate and selectivity. Higher temperatures increase the rate
of the reaction but afford lower selectivity. As the target
selectivity is g98% ee conditions were chosen that should
give reasonably high selectivity and a reasonable reaction
rate while still allowing a suitably high substrate concentra-
tion to confer high-volume efficiency. Consequently, most
of the subsequent work was carried out at ∼20 °C, 0.3 g/mL
(30% w/v) and 8 atm H2 pressure.
The hydrogenation of a similar substrate, 3′-trifluoro-
methylacetophenone 2i, was examined over a wider range
of concentration and pressures (Tables 3 and 4). In Table 3
the effect of a range of ketone concentration from 6 to 100%
on reaction time and selectivity are shown. Even at high
concentration of substrate a reasonable rate and high
selectivity are maintained. At very high concentration
selectivity deteriorates as does the reactivity of the system.
In the absence of propan-2-ol the reaction is very sluggish,
and the selectivity falls dramatically.
As the hydrogen pressure is increased, the reaction rate
increases (Table 4). At very high pressure there was no
The data were analysed using the MODDE 6 software
package.6 Computer-based analysis of the data confirmed
what a cursory examination of the crude data would
(6) MODDE 6, Umetric AB, http://www.umetrics.com.
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Vol. 7, No. 1, 2003 / Organic Process Research & Development

Table 4. Effect of pressure the hydrogenation of
3′-trifluoroacetophenone with (R)-(S,S)-1
Scheme 2
conversion (time)
H2
selectivity
ee
a calorimetric study was carried out. By using a 50-mL
calorimetric pressure vessel,8 the hydrogenation of 4′-
fluoroacetophenone was examined, using the conditions
identified previously. It was found that the reaction reached
a maximum heat output of 12.3 W mol-1 and a total energy
flow of -77 kJ mol-1. Interestingly, the maximum power
output occurred approximately 1 h after the reaction was
initiated. This also corresponded to the period of the reaction
where the rate of hydrogen uptake was at a maximum. This
ties in with previous observations where reactions of this
type have been seen to have an induction period between
addition of the base required to activate the catalysts and
uptake of hydrogen.
entry
pressure atm
12 min
45 min
1
2
3
4
1.7
6.9
16
76
99.5
92.3
99
100
100
100
98.6
98.7
98.7
98.6
12.4
27.6
Scheme 1
Judging that the cooling capacity of the reactor was greater
than the heat output of the reaction, the hydrogenation of
acetophenone 2a and 4′-fluoroacetophenone 2h were carried
out on 1-1.4 kg input. The process was straightforward: the
vessel was charged with the ketone, solvent, and a solution
of base. To achieve an oxygen-free environment the vessel
was charged to 6 atm with nitrogen while being stirred, the
vessel was then vented to atmospheric pressure. The process
was repeated several times. The precatalyst was dissolved
in deoxygenated toluene, and the solution was introduced
into the vessel. The vessel was charged with hydrogen to
between 1 and 3 atm, and the reaction proceeded. During
the course of the reaction the hydrogen pressure was
increased to 6.5 atm (∼100 psi). The maximum hydrogen
uptake achieved was ∼6 L min-1 using 0.1 mmol of catalyst;
this corresponds to a turnover frequency of ∼2,500 min-1.
The workup was relatively simple: treatment with hydro-
chloric acid to neutralise the excess base used to activate
the catalyst, filtration of the precipitated potassium chloride,
and removal of solvent followed by wiped film evaporation
of the crude product. The chiral alcohols 3a and 3h were
thus obtained as colourless liquids. In the case of the
hydrogenation of 4′-fluroacetophenone it was found that
much higher S/C catalyst ratios could be achieved if the
substrate was purified by distillation prior to the hydrogena-
tion reaction. Thus, 2h that had been purified by wiped film
distillation was successfully hydrogenated using (S)-(R,R)-1
at a molar S/C of 100,000 which equates to 0.109 mg of
catalyst (S)-(R,R)-1 required to convert 1.38 kg of 2h. After
purification 1.31 kg (94% yield) of (S)-1-(4-fluorophenyl)-
ethanol, 3h was obtained with a 98.3% ee (Scheme 2).
improvement in rate; under these conditions the rate of
reaction is probably limited by the rate at which hydrogen
can be dispersed into the reaction medium rather than the
pressure of hydrogen over the reaction.7
Preparative Scale Hydrogenations, 0.25-0.5 mol. The
asymmetric hydrogenation of ketones 2a-g were repeated
at a 50-80-g scale using conditions similar to those
developed in the design of experiment study (Scheme 1).
The reactions were conducted in a 600-mL glass-lined
pressure vessel equipped with an overhead stirrer. All the
reactions proceeded smoothly; using a molar S/C of 5000
complete conversion was achieved for all the substrates. The
ketones were used as supplied without any purification. After
a similar workup as described for the 20 mmol reactions,
the crude products were isolated by Kugelrohr distillation,
giving the alcohols as colourless oils or solids in good-to-
excellent yields (86-99%). GC, HPLC, and water content
analysis (Karl Fisher) showed that all the samples were of
g98% purity and g98% ee. The only exception was in the
case of (S)- and (R)-1-(4-aminophenyl)ethanol 3g. The ee
of the crude product of the hydrogenation reactions was lower
than required: ∼95% ee. After the product slurried in MTBE,
the ee had increased to g98% ee. The alcohols (S)-3g and
(R)-3g were isolated as a hydrate in yields of 69 and 71%,
respectively.
Kilogram-Scale Hydrogenation (8-10 mol). Next we
focused on scaling up the reaction to ∼1 kg input, utilising
a 10-L pressure reactor. During the synthesis of the 50 g
samples it had become clear that the hydrogenation reaction
was exothermic; thus, prior to scaling up the reaction further
Conclusions
Asymmetric hydrogenation of prochiral ketones with a
diphosphine ruthenium diamine catalyst was demonstrated
up to a kilogram-scale. The key parameters that determine
(7) Sun, Y.; Landau, R. N.; Wang, J.; LeBlond, C.; Blackmond, D. G. J. Am.
Chem. Soc. 1996, 118, 1348.
(8) HEL stainless steel Automate.
Vol. 7, No. 1, 2003 / Organic Process Research & Development
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91

the efficiency and selectivity of the reaction were examined.
The catalyst system was shown to be tolerant of commercial
grade substrates and high substrate-to-catalyst ratios were
achieved without compromising the enantioselectivity of the
product or the robust nature of the reaction.
etophenone gave (R)-1-phenylethanol (R)-(3a) as a clear,
colourless liquid; bp 52 °C 4 mbar (WPD); [R]2D3 ) +44.2
(c 1.3, MeOH); 99.0% ee, >99.4% purity (GC), moisture
(Karl Fischer) 0.09 wt %/wt.
Asymmetric Hydrogenation of 4′Aminoacetophenone
(2g) To Provide (R)-1-(4-Aminophenyl)ethanol (R)-(3g).
4′-Aminoacetophenone (66.8 g, 494 mmol) was hydroge-
nated with (R)-(S,S)-(1) (106 mg, 98.8 µmol) as previously
described. Hydrochloric acid (1 N, 27 mL, 27 mmol) was
added, and the solvents were removed in vacuo. The crude
product was dissolved in ethyl acetate (200 mL) and washed
with a mixture of water and saturated sodium chloride (200
mL, 1:1). The aqueous fraction was re-extracted with ethyl
acetate (100 mL). The combined organic extracts were dried
(MgSO4), filtered, and concentrated in vacuo to ∼300 mL.
This solution was filtered through a pad of silica gel (∼180
g) and eluted with ethyl acetate (3 × 300 mL). The solvent
was removed in vacuo to provide a cream-coloured solid
that was charged to a 250-mL round-bottomed flask equipped
with a stirrer bar and a condenser. MTBE (120 mL) was
charged to the flask, and the stirred suspension was heated
to a gentle reflux. After stirring for 17 h, the suspension was
filtered to provide (R)-1-(4-aminophenyl)ethanol as an off-
Experimental Section
General Procedures. 1H NMR spectra were recorded at
400 MHz (Bruker DPX 400). 13C NMR spectra were
recorded at 100 MHz. Chemical shifts (δ) are quoted in ppm,
and coupling constants (J) are given in Hz. Optical rotations
were determined using a Perkin-Elmer 341 Polarimeter and
are given in 10-1 deg cm2 g-1. Sample purity was analysed
by GC [DB-5, 30 M × 0.25 µm, 60 °C for 5 min ramp 15
°C/min to 270 °C hold 5 min].
Asymmetric Hydrogenation of Acetophenone (2a) To
Provide (S)-1 Phenylethanol (3a). A 600-mL pressure
reactor equipped with a thermostatically controlled cooling
loop and fitted with a glass liner was charged with acetophe-
none (60 mL, 0.50 mol) and propan-2-ol (175 mL). The
reactor was placed in a heating mantle, and the temperature
was set to 20 °C. A nitrogen atmosphere was established by
charging the vessel to 10 bar with nitrogen while stirring
and then gently venting the vessel to 1 atm. This was repeated
three times. A solution of [((S)-xylyl-PhanePhos)Ru((R,R)-
DPEN)Cl2] (S)-(R,R)-1 (21 mg, 20 µmol, molar S/C )
25,000) in propan-2-ol (25 mL) was prepared under nitrogen
using standard Schlenk techniques. This solution was trans-
ferred to the pressure reactor via syringe. The vessel was
charged to 3 bar of nitrogen and vented three more times. A
solution of potassium tert-butoxide in tert-butanol (1.0 M,
5 mL, 5 mmol) was added via syringe. The vessel was
charged to 4.5 bar with hydrogen. As hydrogen was
consumed, the pressure in the vessel was maintained at 2.5-
4.5 bar. After 2.5 h hydrogen uptake appeared to have
stopped. The hydrogen was vented from the vessel which
was then flushed with nitrogen. Hydrochloric acid (1 N, 5
mL, 5 mmol) was added, and the solvents were removed in
vacuo. The crude product was dissolved in dichloromethane
(300 mL) and washed with brine (200 mL, ∼18%). The
organic layer was dried (MgSO4) and filtered, and solvent
was removed to give a brown liquid. The crude product was
purified by wiped film distillation (WPD) (bp 55 °C 3 mbar)
to give a clear, colourless liquid (59.3 g, 96% yield). (lit. bp
81-82 °C, 6 Torr9); [R]2D3 ) -44.4 (c 1, MeOH) [lit.
1
white solid (57.1 g, 88%). H NMR (400 MHz, CDCl3) δ
7.14 (2H, d, 8.4 Hz, ArH), 6.63 (2H, d, 8.4 Hz, ArH), 4.75
(1H, q, 6.4 Hz, CHOH), 3.6 (2H, br, NH2), 2.1 (1H, br,
CHOH), and 1.43 (3H, d, 6.4 Hz, CH3); 13C NMR (100 MHz,
CDCl3) δ 25.2, 70.4, 115.5, 127.0, 136.4, and 146.1; 96.8%
ee [HPLC Chiracel OD, heptane 70%, propan-2-ol 30% 1
mL/min: detector 254 nm, retention times, 13.4 min and
19.2 min]. Karl fisher analysis showed this material to
contain 13% water, and attempts to dry this material led to
extensive decomposition.
(S)-1-(4-Aminophenyl)ethanol (S)-(3g). Following an
identical procedure outlined for (R)-3g, (S)-3g was isolated
in 95.6% ee. After the product was slurried in MTBE, the
enantiopurity had been increased to 98.4% ee. Again, Karl
Fisher analysis showed a high water content (13%), and
attempted drying led to decomposition.
(R)-1-Phenylpropanol (R)-(3b): clear colourless liquid;
bp 62-68 °C 0.9-1.3 mbar (lit. 110 °C, 6 Torr11); [R]D23
)
+47.6 (c 1, CHCl3) [lit. [R]25 ) +48.5 (c 1.2, CHCl3)12].
D
1H NMR (400 MHz, CDCl3) δ 7.38-7.31 (4H, m, ArH),
7.38-7.24 (1H, m, ArH), 4.59 (1H, dt, 3.4 and 6.6 Hz,
CHOH), 1.89 (1H, d, 3.4 Hz, CHOH),1.86-1.69 (2H, m,
CH2CH3) and 0.91 (3H, t, 7.4 Hz, CH2CH3); 13C NMR (100
MHz, CDCl3) δ 10.6, 32.3, 76.3, 126.4, 127.8, 128.8 and
145.1; 98.1% ee, [GC, Chirasil Dex CB, 25 M × 0.25 mm,
120 °C, hold for 9.5 min, ramp to 200 °C at 15 °C/min,
retention time: 10.97 min (+)-(R); 11.05 min (-)-(S)].
99.6% purity (GC) Retention time 8.6 min, moisture Karl
Fischer 0.05 wt %/wt
[R]D25 ) -45 (c 1, MeOH)10]. H NMR (400 MHz, CDCl3)
1
δ 7.39-7.32 (4H, m, ArH), 7.30-7.24 (1H, m, ArH), 4.89
(1H, dq, 3.2 and 6.5 Hz, CHOH), 1.90 (H, br) and 1.49 (3H,
d, 6.5 Hz, CH3); 13C NMR (100 MHz, CDCl3) δ 25.6, 70.8,
125.8, 127.8, 128.9 and 146.2; 99.0% ee, [GC, Chirasil Dex
CB, 25 M × 0.25 mm, 120 °C, hold for 9.5 min, ramp to
200 °C at 15 °C/min, retention time: 9.83 min (+)-(R); 10.10
min (-)-(S)]. 99.5% purity (GC), moisture (Karl Fischer)
0.09 wt %/wt.
(S)-1-Phenylpropanol (S)-(3b): clear colourless liquid;
bp 123 °C 1.6 mbar; [R]D23 ) -48.4 (c 1.6, CHCl3). 98.8%
ee (GC), 99.6% purity (GC), moisture (Karl Fischer) 0.04
wt %/wt.
(R)-1-Phenylethanol (R)-(3a). In a similar fashion [((R)-
xylyl-PhanePhos)Ru((S,S)-DPEN)Cl2] (R)-(S,S)-1 and ac-
(9) Kornblum, D. J. Am. Chem. Soc. 1952, 74, 3079.
(10) Faraldos, J; Arroyo, E; Herrado´n, B. Syn. Lett. 1997, 367.
(11) Davis, F. A.; Reddy, T. R. J. Org. Chem. 1992, 57, 2599.
(12) Lutz, C.; Jones, P.; Knochel, P. Synthesis 1999, 2, 312.
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(R)-1,2-Diphenylethanol (R)-(3c): white solid; mp 66-
Hz, ArH), 4.86 (1H, dq, 3.4 and 6.5 Hz, CHOH), 1.85 (1H,
d, 3.4 Hz, CHOH), and 1.47 (3H, d, 6.5 Hz, CH3); 13C NMR
(100 MHz, CDCl3) δ 25.6, 70.1, 121.5, 127.6, 131.9, and
145.2; 97.7% ee, [GC, (pyridine, Ac2O) Chirasil Dex CB,
25 M × 0.25 mm, 100 °C, hold for 40 min, ramp to 200 °C
at 15 °C/min, retention time: 45.5 min (R)-(+); 45.8 min
(S)-(-)]. 98.6% purity (GC, retention time, 10.9 min),
moisture (Karl Fischer) 0.36 wt %/wt.
23
70 °C (lit. 67 °C13); [R]D ) -52.9 (c 1, EtOH). H NMR
(400 MHz, CDCl3) δ 7.33-7.11 (10H, m, ArH), 4.80 (1H,
m, CHOH), 3.05-2.90 (2H, m, CH2Ph), and 2.12 (1H, d,
2.8 Hz, CHOH); 13C NMR (100 MHz, CDCl3) δ 46.5, 75.8,
126.4, 127.0, 128.0, 128.8, 128.9, 130.0, 138.5, and 144.3;
>98% ee, HPLC Chiracel OD, heptane 96% propan-2-ol 4%
1 mL/min: detector 254 nm, retention times, 12.65 min (R)-
(+); 16.81 min (S)-(-) >99% purity (GC) 14.3 min,
moisture Karl Fischer <0.1 wt %/wt.
1
(S)-1-(4-Bromophenyl)ethanol (S)-(3f): clear colourless
liquid; bp 150-160 °C 1.2-1.4 mbar (Kugelrohr) [R]D23
)
-37.6 (c 1, CHCl3) [lit. [R]23 ) -37.9 (c 1, CHCl3)16].
(S)-1,2-Diphenylethanol (S)-(3c): white solid; [R]D23
)
D
+53.6 (c 1, EtOH) [lit. [R]2D3 ) +53 (c 1, EtOH)14]. 98.6%
ee. (HPLC), 99.0% purity (GC), moisture (Karl Fischer) 0.03
wt %/wt.
98.4% ee, 99.4% purity GC, moisture (Karl Fischer) 0.04
wt %/wt.
(R)-1-(4-Fluorophenyl)ethanol (R)-(3h): clear colourless
liquid; bp 52 °C 3 mbar (WPD), (lit. 70 °C, 4 Torr19);
[R]2D3 ) +38.4 (c 1.2 MeOH). 1H NMR (400 MHz, CDCl3)
δ 7.34 (2H, d, 8.7 and 5.4 Hz, ArH), 7.03 (2H, dd, 8.7 and
8.7 Hz, ArH), 4.89 (1H, dq, 3.6 and 6.4 Hz, CHOH), 1.82
(R)-1-(2-Bromophenyl)ethanol (R)-(3d): white solid; bp
140 °C, 2.3 mbar (Kugelrohr) (lit. 102-105 °C, 2-3 Torr15)
mp 53-54 °C; [R]2D3 ) +55.7 (c 1, EtOH). H NMR (400
1
MHz, CDCl3) δ 7.59 (1H, dd, 7.6, 2 Hz, ArH), 7.51 (1H,
dd, 8.8, 1 Hz, ArH), 7.34 (1H, ddd, 7.6, 7.6, 1.2 Hz, ArH),
7.12 (1H, ddd, 7.6, 7.6, 1.6 Hz, ArH), 5.230 (1H, q, 6 Hz,
CHOH), 2.07 (1H, s, CHOH), and 1.43 (3H, t, 6 Hz, CH3);
13C NMR (100 MHz, CDCl3) δ 24.0, 69.5, 122.1, 127.1,
128.2, 129.1, 133.0, and 145.1; 98.6% ee, [GC, Chirasil Dex
CB, 25 M × 0.25 mm, 120°C, hold for 20 min, ramp to 200
°C at 15 °C/min, retention time: 22.2 min (R)-(+); 23.6 min
(S)-(-)]. >99% purity (GC) retention time: 10.4 min,
moisture (Karl Fischer) 0.1 wt %/wt.
(1H, d, 3.6 Hz, CHOH), and 1.48 (3H, d, 6.4 Hz, CH3); 13
C
NMR (100 MHz, CDCl3) δ 25.6, 70.1, 115.6 (d, 21.3 Hz),
127.5 (d, 8.1 Hz), 141.9, and 162.5 (d, 245.7 Hz); 98.6%
ee, [GC, Chirasil Dex CB, 25 M × 0.25 mm, 40 °C, hold
for 10 min, ramp to 200 °C at 15 °C/min, retention time:
17.8 min (R)-(+); 18.0 min (S)-(-)], 99.2% purity, moisture
(Karl Fischer) 0.04 wt %/wt.
(S)-1-(4-Fluorophenyl)ethanol (S)-(3h): clear colourless
liquid; bp 53 °C 4 mbar (WPD); [R]2D3 ) -37.9 (c 1
MeOH) [lit. [R]2D3 ) -37.7 (c 1.1 MeOH)16]. 98.9% ee,
(GC), 99.7% purity (GC), moisture (Karl Fischer) 0.80 wt
%/wt.
(S)-1-(2-Bromophenyl)ethanol (S)-(3d): off white solid;
mp 49-56 °C; [R]D23 ) -54.7 (c 1, EtOH) [lit. [R]2D4
)
+54.6 (c 1.2, EtOH)16]. 98.7% ee, 98.4% purity (GC),
moisture (Karl Fischer) 0.05 wt %/wt.
1-(3-Trifluromethylphenyl)ethanol (3i): GC, Chirasil
Dex CB, 100 °C, hold for 7 min, ramp to 200 °C at 15 °C/
min, retention time: 10.58 min (+); 10.86 min (-)].
Kilogram Hydrogenation of 4′-Fluoroacetophenone
(2h) To Provide (S)-1-(4-Fluorophenyl)ethanol (S)-(3h).
A glass liner was charged with 4′-fluoroacetophenone (wipe
film distilled, 1.38 kg, 10 mol) and placed in a 10-L pressure
vessel equipped with a heating jacket and cooling coil. The
liner was charged with propan-2-ol (3.6 L) and potassium
tert-butoxide solution in tert-butyl alcohol (1.0 M, 100 mL,
100 mmol). The pressure vessel was assembled, stirring
commenced, and the heating controls were set to 22 °C. A
nitrogen atmosphere was established by charging the vessel
to 10 bar with nitrogen while stirring and then gently venting
the vessel to 0.4 bar overpressure. This was repeated three
times. A solution of [((S)-xylyl-PhanePhos)Ru((R,R)-DPEN)-
Cl2] (S)-(R,R)-1 (109 mg, 0.10 mmol, molar S/C ) 100,000)
in toluene (20 mL) was prepared under nitrogen using
standard Schlenk techniques. This solution was transferred
to the pressure reactor. The vessel was charged to 3 bar of
nitrogen and vented three more times. The vessel was
charged to 2 bar with hydrogen, and the reaction was allowed
to proceed. Over a period of 40 min the reactor pressure
was increased to 6.5 bar, ensuring that the reactor temperature
was maintained at 22-23 °C. After a further 40 min
hydrogen uptake was no longer apparent. The reaction was
allowed to continue for a further 1 h. The contents of the
(R)-1-(3-Bromophenyl)ethanol (R)-(3e): clear colourless
liquid; bp 145-155 °C 1.7-1.9 mbar (Kugelrohr) (lit. 106-
23
108 °C, 2.5 Torr17); [R]D ) +27.3° (c 1.1, EtOH). H
NMR (400 MHz, CDCl3) δ 7.52 (1H, dd, 1.6 and 1.6 Hz,
ArH), 7.39 (1H, ddd, 8, 1.4, and 1.4 Hz, ArH), 7.28 (1H,
ddd, 8, 1.6, and 1.6 Hz, ArH), 7.20 (1H, dd, 8 and 8 Hz,
ArH), 4.85 (1H, dq, 4 and 6.4 Hz, CHOH), 2.00 (1H, d, 4
Hz, CHOH), and 1.47 (3H, d, 6.4 Hz, CH3); 13C NMR (100
MHz, CDCl3) δ 25.6, 70.0, 123.0, 129.0, 130.5, 130.8, and
148.5; 98.7% ee, [GC, Chirasil Dex CB, 25 M × 0.25 mm,
120 °C, hold for 20 min, ramp to 200 °C at 15°C/min,
retention time: 22.4 min (R)-(+); 23.1 min (S)-(1)], 99.4%
purity GC, moisture Karl Fischer 0.05 wt %/wt.
1
(S)-1-(3-Bromophenyl)ethanol (S)-(3e): clear colourless
liquid; bp 136 °C 1.6 mbar (Kugelrohr); [R]2D3 ) -28.3 (c
1, EtOH) [lit. [R]2D3 ) -28.6 (c 1.8, EtOH)16]. 99.2% ee,
99.2% purity GC, moisture (Karl Fischer) 0.03 wt %/wt. (R)-
1-(4-bromophenyl)ethanol (R)-(3f): clear colourless liquid;
bp 150-160 °C 1.2-1.4 mbar (Kugelrohr) (lit. 105-108
23
1
°C, 3 Torr18); [R]D ) +36.9 (c 1, CHCl3). H NMR (400
MHz, CDCl3) δ 7.47 (2H, d, 8.5 Hz, ArH), 7.25 (2H, d, 8.5
(13) Kenyon, G. J. Chem. Soc. 1928, 2565.
(14) Ogura, K.; Fujita, M.; Inaba, T.; Takahashi, K.; Iida, H. Tetrahedron Lett.
1983, 24, 503.
(15) Fleming, I.; Woolias, M. J. Chem. Soc. Perkin Trans. 1, 1979, 829.
(16) Nakamura, K.; Matsuda, T. J. Org. Chem. 1998, 63, 8957.
(17) Shiner, V. J. J. Am. Chem. Soc. 1968, 90, 418.
(18) Kelly, D. P.; Spear, R. J. Aust. J. Chem. 1978, 31, 1209.
(19) Taylor, T. J. Chem. Soc., Perkin Trans. 2 1988, 737.
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93

reactor plus propan-2-ol rinses were transferred to a 10-L
flask. HCl (2 N, ∼50 mL) was added slowly and the pH of
the mixture monitored. At pH 7 the reaction mixture changed
from green to yellow. The precipitated potassium chloride
was removed by filtration, and solvent was removed in vacuo
to give a brown liquid. The crude product was purified by
wiped film distillation (bp 77 °C 0.33 mbar) to give a clear
colourless liquid (1.31 kg, 93% yield). [R]2D3 ) -38.1 (c
1.2, MeOH). 99.3% ee, (GC), 98.9% purity (GC), moisture
(Karl Fischer) 0.03 wt %/wt,(R)-1-(4-fluorophenyl)ethanol
(R)-(3h)0.93 kg, 91% yield. Clear colourless liquid; bp 47
°C 0.3 mbar (WPD), [R]2D3 ) +38.4 (c 0.95, MeOH).
99.1% ee, (GC), 99.6% purity (GC), moisture (Karl Fischer)
0.04 wt %/wt.
(R)-1-Phenylethanol (R)-(3a): yield 1.25 kg, 93%; clear
colourless liquid; bp 40 °C 0.3 mbar (WPD), [R]2D3 ) +43.5
(c 1.3 MeOH). 99.1% ee, (GC), 96.6% purity20 (GC),
moisture (Karl Fischer) 0.13 wt %/wt.
(S)-1-Phenylethanol (S)-(3a): yield 1.17 kg, 93%; clear
colourless liquid; bp 40 °C 0.3 mbar (WPD), [R]2D3 ) -44.3
(c 1.1, MeOH). 98.9% ee, (GC), 99.5% purity (GC), moisture
(Karl Fischer) 0.06 wt %/wt.
Acknowledgment
We are grateful to Catherine Rippe´ for the development
of analytical methods.
(20) About 3% acetophenone found in the product, later shown to be due to
unreacted starting material contamination from a dip tube in the reactor.
On subsequent runs the contents of dip tube were blown into the vessel
with nitrogen once hydrogen uptake had ceased, and the reaction was
allowed to run for a further 30-60 min.
Received for review August 21, 2002.
OP025585R
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