Ruthenium-catalysed asymmetric transfer hydrogenation of para-substituted α-fluoroacetophenones

Article abstract of DOI:10.1016/j.jfluchem.2009.03.011

The first examples of asymmetric transfer hydrogenation of α-fluoroacetophenones are reported. Eight para-substituted α-fluoroacetophenones have been reduced using four catalytic systems constructed of [RuCl₂(p-cymene)₂]₂ or [RuCl₂(mesitylene)₂]₂ in combinations with each of the ligands (1R,2R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine ((R,R)-TsDPEN) and (1R,2R)-N-(p-toluenesulfonyl)-1,2-cyclohexanediamine ((R,R)-TsCYDN). All reactions were performed in both water and formic acid/triethylamine. The highest enantioselectivity was obtained using the (R,R)-TsDPEN ligand in a formic acid/triethylamine mixture, giving the (S)-1-aryl-2-fluoroethanols in high to moderate enantiomeric excess (97.5-84.5%). For this solvent system the presence of electron withdrawing groups in the para position reduced the enantioselectivity. Reactions performed in water generally gave lower enantioselectivity and reaction rate, although RuCl(mesitylene)-(R,R)-TsDPEN yielded the product alcohols with enantiomeric excess in the range of 95.5-76.5%.

Full text of DOI:10.1016/j.jfluchem.2009.03.011

Journal of Fluorine Chemistry 130 (2009) 600–603
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Short communication
Ruthenium-catalysed asymmetric transfer hydrogenation of para-substituted
-fluoroacetophenones
a
Erik Fuglseth a, Eirik Sundby b, Ba˚ rd H. Hoff a,
*
a Norwegian University of Science and Technology, Department of Chemistry, Høgskoleringen 5, NO-7491 Trondheim, Norway
b Sør-Trøndelag University College, E. C. Dahls gate 2, 7004 Trondheim, Norway
A R T I C L E I N F O
A B S T R A C T
Article history:
The first examples of asymmetric transfer hydrogenation of
a-fluoroacetophenones are reported. Eight
Received 8 December 2008
Received in revised form 26 March 2009
Accepted 28 March 2009
Available online 5 April 2009
para-substituted a-fluoroacetophenones have been reduced using four catalytic systems constructed of
[RuCl2(p-cymene)2]2 or [RuCl2(mesitylene)2]2 in combinations with each of the ligands (1R,2R)-N-(p-
toluenesulfonyl)-1,2-diphenylethylenediamine ((R,R)-TsDPEN) and (1R,2R)-N-(p-toluenesulfonyl)-1,2-
cyclohexanediamine ((R,R)-TsCYDN). All reactions were performed in both water and formic acid/
triethylamine. The highest enantioselectivity was obtained using the (R,R)-TsDPEN ligand in a formic
acid/triethylamine mixture, giving the (S)-1-aryl-2-fluoroethanols in high to moderate enantiomeric
excess (97.5–84.5%). For this solvent system the presence of electron withdrawing groups in the para
position reduced the enantioselectivity. Reactions performed in water generally gave lower
enantioselectivity and reaction rate, although RuCl(mesitylene)-(R,R)-TsDPEN yielded the product
alcohols with enantiomeric excess in the range of 95.5–76.5%.
Keywords:
a
-Fluoroacetophenone
1-Aryl-2-fluoroethanols
Asymmetric transfer hydrogenation
Ruthenium
TsDPEN
TsCYDN
ß 2009 Elsevier B.V. All rights reserved.
1. Introduction
Acetophenones are usually the benchmark substrates for
asymmetric reductions. Numerous investigations on the effects
The importance and utilisation of optically pure secondary
alcohols has been well recognised. Due to their somewhat
troublesome preparation, fluorinated secondary alcohols have
received considerably less attention. We have recently described
of different catalysts, metal species, solvent systems, additives,
temperature and pH on the rate and selectivity of asymmetric
transfer hydrogenations have been reported [7,9,10,13–21].
Sterk et al. [22] has described the ATH of trifluoromethylk-
etones with mediocre enantioselectivity, but the ATH of mono-
fluoroketones is an unexplored area. As part of our ongoing
research, we have recently investigated chiral oxazaborolidine-
routes to
a-fluorinated ketones, rendering their corresponding
alcohols easy accessible [1]. The potential use of such optically
enriched fluorinated alcoholic building blocks is vast, and includes
among others pharmaceuticals, advanced materials and agro-
chemicals [2–6].
catalysed borane reductions of a series of
a-fluoroketones to the
corresponding chiral secondary alcohols [23]. In order to develop a
more robust and environmental friendly catalytic process, we have
now turned our attention to ATH. Herein we wish to report an
improved method for the preparation of enantioenriched 1-aryl-2-
fluoroethanols using ruthenium catalysed asymmetric transfer
hydrogenation.
Asymmetric transfer hydrogenation (ATH) using various metal
complexes has emerged as an excellent alternative to established
asymmetric reduction methods [7,8]. The easily available hydro-
gen sources, mild reaction conditions and simple experimental
setup have made it an area of interest for both industrial and
academic researchers [9–12]. Moreover, ATH can be performed in
water [7,9,13–16], which is the ideal solvent seen from an
environmental point of view, and potentially provides cost savings
for commercial processes. In contrast to most transition metal
catalysed reactions, asymmetric transfer hydrogenations have also
been done in presence of air [16,17], without significant loss in
enantioselectivity.
2. Result and discussion
The a-fluoroketones 4a–e (Scheme 1) were most conveniently
prepared by fluorination of the corresponding trimethylsilyl enol
ethers, 2a–e, using SelectfluorTM (1-chloromethyl-4-fluoro-1,4-
diazoniabicyclo[2.2.2]octane bis-(tetrafluoroborate) [1], while
4f–h were obtained in highest yield by reacting the acetophe-
nones, 1f–h, with SelectfluorTM in methanol. The dimethoxyace-
tals, 3f–h formed as the major products were hydrolysed using
trifluoroacetic acid [1].
* Corresponding author. Tel.: +47 7359 3973; fax: +47 7359 4256.
E-mail address: bhoff@chem.ntnu.no (B.H. Hoff).
0022-1139/$ – see front matter ß 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2009.03.011

E. Fuglseth et al. / Journal of Fluorine Chemistry 130 (2009) 600–603
601
Scheme 1. Preparation and asymmetric transfer hydrogenation of the fluoroketones, 4a–h, using the catalysts 5–8.
The ATH of 4a–h were studied using four different catalysts, 5–
8, which were prepared by mixing the ruthenium arene complexes,
[RuCl2(p-cymene)]2 and [RuCl2(mesitylene)]2 with (R,R)-TsDPEN
and (R,R)-TsCYDN, respectively. The pre-catalyst [RuCl2(mesity-
lene)]2 was synthesised from RuCl3 and 1,3,5-trimethyl-1,4-
cyclohexadiene according to literature procedures [24,25]. All
reactions were performed without solvent degassing and without
inert atmosphere protection [16].
Initially, 4a–h were reduced with catalysts 5–8 in water at 40 8C
using sodium formate as hydrogen donor. The reactions were
monitored by HPLC for determination of conversion and enantio-
meric excess. The results are summarised in Table 1. All reactions
proceeded with preference of the (S)-enantiomer [23]. The ee of the
reactions depended on both catalyst and substrate structure. The
highest selectivity was obtained using catalyst 7, giving the
alcohols (S)-9a, (S)-9c and (S)-9f in ꢀ95% ee. The catalysts 5 and 8
gave comparable, but lower ee-values than was the case with 7,
while catalyst 6 gave only moderate enantioselectivity with ee-
values ranging from 77.0 to 47.5%.
reaction times. As expected, the ketones substituted with electron
donating substituents tended to react slower than their more
electron deficient counterparts [18]. Observed differences in
conversion could also be due to the low solubility and crystalline
nature of several of the a-fluoroacetophenones in water. Solubility
effects might therefore overshadow electronic effects caused by
the para-substituents.
A formic acid/triethylamine solvent mixture has previously
been used in reductions of acetophenone using catalysts 5 and 7
[15,27]. The reactions yielded 1-arylethanols with high enantio-
meric excess, but proceeded with a moderate reaction rate. The
introduction of a fluorine atom in the
a-position of the carbonyl
group increases the electrophilicity at the reaction centre, and it
was therefore considered worthwhile to investigate this solvent in
reduction of 4a–h. The reactions were performed using catalysts
5–8 at 40 8C, using S/C = 100, and a physical mixture of formic acid/
triethylamine (5:2 mol ratio). The conversions and enantiomeric
excess are summarised in Table 2.
Phase transfer limitations are less profound in the triethyla-
The effect of the substituents on the enantioselectivity seems
complex. A general trend was that the reductions of 4c (R = H)
and 4f (R = CF3) gave some of the highest ee-values for all
catalysts, whereas the reduction of 4g (R = CN) and 4h (R = NO2)
gave the lowest selectivities. Moderate enantioselectivity
has also been the results in asymmetric transfer hydrogenation
of 4-nitroacetophenone (1h) in similar catalytic systems
[13,16,26].
mine system, since the a-fluoroacetophenones are soluble in the
reaction medium. Less variance in rates was also observed within
each catalytic system. The highest rates were observed in
reductions using the catalysts 5 and 7, where all starting materials
were consumed within 2 h. Using catalyst 6, the time needed to
reach full conversion was increased to 24 h, whereas the reactions
catalysed by 8 were terminated after 10 days, reaching only 20–
66% conversion.
The reaction rate was also dependant on both catalysts and
substrate structures. Generally, the highest rates were observed in
reductions using catalyst 5, while catalyst 6 gave the longest
Reductions catalysed by 5–7 in formic acid/triethylamine gave
overall higher selectivity than the reductions in water, and only the
reduction of substrate 4f (R = CF3) resulted in lower ee-values. The
Table 1
Asymmetric transfer hydrogenation of 4a–h using catalysts 5–8 in water.a
Substrate
Cat. 5
Cat. 6
Cat. 7
Cat. 8
Conv. (hours)
ee (%)
Conv. (hours)
ee (%)
Conv. (hours)
ee (%)
Conv. (hours)
ee (%)
4a
4b
4c
4d
4e
4f
OMe
OBn
H
>99 (2)
>99 (10)
>99 (2)
>99 (2)
>99 (2)
>99 (2)
>99 (2)
>99 (2)
90.0
88.0
91.5
87.0
87.0
91.5
66.0
70.0
18 (24)
49 (24)
67.0
74.0
81.5
77.0
76.5
77.0
51.0
47.5
>99 (5)
71 (20)
>99 (2)
>99 (5)
>99 (5)
>99 (5)
45 (20)
99 (20)
95.0
90.0
95.5
91.0
90.5
96.0
84.0
76.5
88 (5)b
83 (5)b
>99 (2)
82 (5)b
>99 (5)
>99 (2)
>99 (2)
>99 (5)
87.0
89.0
90.5
87.0
87.5
88.0
68.5
63.0
>99 (24)
>99 (24)
>99 (24)
>99 (24)
>99 (24)
>90 (24)
F
Br
CF3
CN
NO2
4g
4h
a
A suspension of [RuCl2(arene)]2 (0.001 mmol) and the ligand (0.0027 mmol) in H2O (0.5 mL) were stirred at 40 8C for 1 h. Sodium formate (34 mg, 0.5 mmol) and the
ketone (0.1 mmol) were then added and the mixture was stirred vigorously at 40 8C for the specified number of hours.
b
Full conversion was obtained within 20 h reaction time.

602
E. Fuglseth et al. / Journal of Fluorine Chemistry 130 (2009) 600–603
Table 2
Asymmetric transfer hydrogenation of 4a–h using catalysts 5–8 in formic acid/triethylamine.a
Substrate
Cat. 5
Cat. 6
Cat. 7
Cat. 8
Conv. (hours)
ee (%)
Conv. (hours)
ee (%)
Conv. (hours)
ee (%)
Conv. 10 days
ee (%)
4a
4b
4c
4d
4e
4f
OMe
OBn
H
>99 (2)
>99 (2)
>99 (2)
>99 (2)
>99 (2)
>99 (2)
>99 (2)
>99 (2)
95.5
96.5
97.0
92.0
90.5
91.0
84.5
85.0
>99 (24)
>99 (24)
>99 (24)
>99 (24)
>99 (24)
>99 (24)
>99 (24)
>99 (24)
91.0
90.0
89.0
86.0
83.5
83.0
75.5
76.5
>99 (2)
>99 (2)
>99 (2)
>99 (2)
>99 (2)
>99 (2)
>99 (2)
>99 (2)
96.0
97.5
97.0
93.5
91.0
90.5
88.0
84.5
29
28
30
24
30
20
50
66
44.0
64.0
72.0
41.0
46.5
25.0
21.0
29.0
F
Br
CF3
CN
NO2
4g
4h
a
A suspension of the [RuCl2(arene)]2 (0.001 mmol) and ligand (0.0027 mmol) in CH2Cl2 (0.5 mL) were stirred at 20 8C for 30 min. After removal of CH2Cl2 by a stream of N2,
the ketone (0.1 mmol) in HCO2H/Et3N (5:2, 0.25 mL) was added. The reaction mixture was stirred vigorously at 40 8C for the specified time.
use of catalysts 5 and 7 yielded products with higher enantiomeric
excess than was the case with 6, and the alcohols, (S)-9a–h, could
be obtained with ee-values ranging from 97.5 to 84.5%. On the
other hand, catalyst 8, which performed reasonable well in water,
gave only moderate to low enantioselectivity in formic acid/
triethylamine.
Using catalysts 5–7 in formic acid/triethylamine, a trend
regarding the effect of substituents on the enantioselectivity could
be noticed. A drop in ee of the product alcohols were observed
going from 4a–c to substrates bearing more electron withdrawing
substituents. Fujii et al. [27] has previously reduced a series of
para-substituted acetophenones using (S,S)-7 as catalyst in formic
acid/triethylamine. At 28 8C using a catalyst/substrate ratio of
200:1, reduction of 1a (60 h), 1c (20 h) and 1g (14 h) gave the
corresponding alcohols in 97, 98 and 90% ee, respectively [27]. The
ee of the products in our study are comparable to that obtained in
reductions of the corresponding acetophenones. Substituting a
methyl- with a fluoromethyl group increases the size of the
substituent, and alters the electron density at the carbonyl carbon.
4. Experimental
4.1. General experimental procedures
Solvents and reagents were used as received from the suppliers.
[RuCl2(p-cymene]2, (R,R)-TsDPEN, (R,R)-TsCYDN and ruthenium(III)
chloride hydrate were from Aldrich, while 1,3,5-trimethyl-1,4-
cyclohxadienewasfromAlfaAesar. [RuCl2(mesitylene]2 [24,25], and
a-fluoroacetophenones [1], were prepared as described previously.
Reactions were performed in an incubator shaker from Brunswic
Scientific Co. Inc. NMR spectra were recorded with Bruker Avance
DPX 400 operating at 400 MHz for 1H, 375 MHz for 19F and 100 MHz
for 13C. The ee of the alcohols were determined by HPLC using an
Agilent 1100 series system equipped with a Bruker DAD detector
andaChiracelODcolumn(0.46 cm  25 cm), mobilephase:hexane/
2-propanol, 98:2, flow rate 1.0 mL/min [23].
4.2. Asymmetric transfer hydrogenation in water
It was noteworthy that the reduction of
a
-fluoroacetophenone (4c)
A suspension of [RuCl2(arene)]2 (0.001 mmol) and the ligand
was completed in less than 2 h using catalyst 5, whereas
acetophenone (1c) under identical conditions in our hands
required 20 h to reach full conversion with 97% ee. Evidently,
the introduction of one electron withdrawing fluorine increases
the reaction rate significantly. Somewhat surprisingly the enan-
tiodiscrimination process was not affected to a large extent by this
substitution. The fact that the relative difference in activation
energy leading to the (R)- and (S)-enantiomers is almost equal in
(0.0027 mmol) in H2O (0.5 mL) were stirred at 40 8C for 1 h.
Sodium formate (34 mg, 0.5 mmol) and the a-fluoroacetophenone
(0.1 mmol) was then added and the mixture was stirred vigorously
at 40 8C for the specified number of hours. Samples were
withdrawn from the reaction mixture, extracted with Et2O and
filtered through silica before analysis by HPLC for determination of
conversion and enantiomeric excess.
the acetophenone and the
a
-fluoroacetophenone series, implies
4.3. Asymmetric transfer hydrogenation in formic acid/triethylamine
that the drop in selectivity for substrates containing electron
withdrawing aromatic substituents is not solely related to the
electronic content of the carbonyl carbon. This effect can rather be
A suspension of the [RuCl2(arene)]2 (0.001 mmol) and ligand
(0.0027 mmol) in CH2Cl2 (0.5 mL) were stirred at 20 8C for 30 min.
After removal of CH2Cl2 by a stream of N2, the ketone (0.1 mmol) in
a physical mixture of HCO2H/Et3N (5:2 mol ratio, 0.25 mL) was
added. The reaction mixture was stirred vigorously at 40 8C for the
specified number of hours. Samples were withdrawn from the
reaction mixture and the solvent was removed under a stream of
N2. The samples were then dissolved in the HPLC-eluent, filtered
through silica and analysed by HPLC for determination of
conversion and enantiomeric excess.
explained by other factors such as change in
p–p interactions,
solvation effects or dispersion interactions as suggested by Brandt
et al. [28].
3. Conclusion
Asymmetric transfer hydrogenation of para-substituted
a-
fluoroacetophenones, 4a–h, using the RuCl-(p-cymene)-(R,R)-
TsDPEN and RuCl-(mesitylene)-(R,R)-TsDPEN provides the corre-
sponding chiral 1-aryl-2-fluoroethanols, 9a–h, in high to moderate
ee. The formic acid/triethylamine system was found to give higher
enantioselectivity than for reactions in water using sodium
formate as hydrogen donor. Compared to the acetophenone series,
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