Selective Asymmetric Transfer Hydrogenation of α-Substituted Acetophenones with Bifunctional Oxo-Tethered Ruthenium(II) Catalysts

Article abstract of DOI:10.1002/adsc.201701227

A practical method for the asymmetric transfer hydrogenation of α-substituted ketones was developed utilizing oxo-tethered N-sulfonyldiamine-ruthenium complexes. Reduction by HCO₂H and HCO₂K in a mixed solvent of EtOAc/H₂O allowed for the selective synthesis of halohydrins from 2-bromoacetophenone (98%) and 2-chloroacetophenone (>99%), leading to suppressed undesired side reactions stemming from formylation under the typical reaction conditions using an azeotropic 5:2 mixture of HCO₂H and Et₃N. A range of functional groups, such as halogens, methoxy, nitro, dimethylamino, and ester groups, were well tolerated, highlighting the potential of this method. Nearly complete selectivity with a preferable ee was maintained even with a substrate/catalyst (S/C) ratio of 5000. This catalyst system was also effective for the asymmetric reduction of α-sulfonated ketones without eroding the leaving group. (Figure presented.).

Full text of DOI:10.1002/adsc.201701227

Title: Selective Asymmetric Transfer Hydrogenation of α-Substituted
Acetophenones with Bifunctional Oxo-Tethered Ruthenium(II)
Catalysts
Authors: Yamato Yuki, Taichiro Touge, Hideki Nara, Kazuhiko
Matsumura, Mitsuhiko Fujiwhara, Yoshihito Kayaki, and
Takao Ikariya
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10.1002/adsc.201701227
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Selective Asymmetric Transfer Hydrogenation of -Substituted
Acetophenones with Bifunctional Oxo-Tethered Ruthenium(II)
Catalysts
Yamato Yuki,a,* Taichiro Touge,a Hideki Nara,a Kazuhiko Matsumura,a Mitsuhiko
Fujiwhara,a Yoshihito Kayaki,b,* and Takao Ikariyab,c
a
Corporate Research & Development Division, Takasago International Corporation, 1-4-11 Nishi-Yawata, Hiratsuka,
Kanagawa, 254-0043, Japan
b
Department of Chemical Science and Engineering, School of Materials and Chemical Technology, Tokyo Institute of
Technology, 2-12-1-E4-1 O-okayama, Meguro-ku, Tokyo 152-8552, Japan
Email: yamato_yuki@takasago.com, ykayaki@o.cc.titech.ac.jp
Deceased on April 21, 2017.
c
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
production of chemical compounds, particularly
Abstract. A practical method for the asymmetric transfer
hydrogenation of -substituted ketones was developed active pharmaceutical ingredients (APIs).[2] In the
utilizing
oxo-tethered
N-sulfonyldiamine-ruthenium
context of our ongoing interest in accessing
complexes. Reduction by HCO2H and HCO2K in a mixed
solvent of EtOAc/H2O allowed for the selective synthesis
of halohydrins from 2-bromoacetophenone (98%) and 2-
chloroacetophenone (>99%), leading to suppressed
undesired side reactions stemming from formylation under
the typical reaction conditions using an azeotropic 5:2
mixture of HCO2H and Et3N. A range of functional groups,
such as halogens, methoxy, nitro, dimethylamino, and ester
groups, were well tolerated, highlighting the potential of
this method. Nearly complete selectivity with a preferable
ee was maintained even with a substrate/catalyst (S/C) ratio
of 5000. This catalyst system was also effective for the
asymmetric reduction of -sulfonated ketones without
eroding the leaving group.
synthetically valuable chiral alcohols, the ATH of -
bromoacetophenone is
a
remaining challenge.
Optically pure 2-bromo-1-arylethanols and the related
2-amino-1-arylethanols are key intermediates of
pharmaceuticals, such as -adrenergic receptor
agonists;[2d,3] however, it has been reported that -
bromoketones decompose under ATH conditions
using a mixture of HCO2H/Et3N.[2d,4a] The Corey-
Bakshi-Shibata (CBS) reduction[3c,3e-f,5] and
a
biocatalytic reaction[6] have been alternatively
executed for this purpose. In reasonable efforts to
utilize formic acid and its analogues as convenient
reducing agents for the enantioselective reduction of
-bromoketone,[3e,4] specially modified water-soluble
ligands or surfactants were treated in an aqueous-
phase ATH reaction to dissolve hydrophobic metal
complexes in the reaction media. Although some
rhodium and iridium catalysts have provided more
satisfactory results than the ruthenium system, a
comparatively substantial amount of expensive
catalyst was used (typically with a substrate/catalyst
ratio (S/C) of 100).[4d,e,j] A one-pot sequential process
Keywords: asymmetric catalysis; asymmetric transfer
hydrogenation; ruthenium; -haloketones; halohydrins
Asymmetric transfer hydrogenation (ATH) of
prochiral ketones is one of the most extensively
researched areas in the synthesis of chiral secondary
involving
a
Au-catalyzed hydration of aryl-
alcohols.[1]
Compared
with
asymmetric
substituted bromoalkynes and the ATH of the
resulting bromomethyl ketones, which was recently
examined as a practical approach for the construction
of chiral aromatic bromohydrins, was conducted
using 1.5 mol% each of IPrAuNTf2 and
hydrogenation, ATH without hazardous hydrogen gas
ensures several advantages, such as mild reaction
conditions and a simple and safe operation. Based on
the crucial role of protic amine ligands in the
asymmetric reduction of polar carbon-oxygen and
carbon-nitrogen double bonds, Noyori’s well-defined
RuCl(TsDPEN)(6 mesitylene).[4i]
-
In our previous studies, advanced oxo-tethered
ruthenium complexes (S,S)-2 and (S,S)-3[7,8] showed
much higher activity in the ATH of acetophenone
(with up to S/C = 30,000) than the prototypical ATH
catalyst 1 (Figure 1).[1a-e,7a] Herein, we report a new
application of the oxo-tethered complexes for the
chiral Ru() catalysts, such as RuCl(TsDPEN)(p-
cymene) (1; TsDPEN = N-(p-toluenesulfonyl)-1,2-
diphenylethylenediamine), have proven to be
applicable to ATH of various prochiral ketones. ATH
has become a viable option in the industrial
1
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10.1002/adsc.201701227
Advanced Synthesis & Catalysis
reduction of -bromoketone and related substituted
acetophenones having good leaving groups, leading
to exceptionally high product selectivity.
and a formate derivative (B) were produced in 53%
and 35% yields, respectively, accompanied with
small amounts of -hydroxyketone (C) and glycol
diformate (D) as shown in Scheme 1. Debrominated
acetophenone or 1-phenylethanol was not confirmed
in the product mixture. The formation of A and B is
Figure 1. Structure of non-tethered and tethered Ru-
DPEN catalysts.
in accordance with previously reported results[2d,4a]
.
Scheme 1. Formation of byproducts in the typical ATH
system using HCO2H/Et3N.
Our initial study started with the ATH of 2-
bromoacetophenone (4a) as a model substrate at
60 °C for 4 h. The results are summarized in Table 1.
When (R,R)-1 was used as a catalyst in a 5:2 mixture
of HCO2H and Et3N (run 1), 4a was mostly
consumed as expected, and only a trace amount of
bromohydrin (5a) was detected by GC analysis. Upon
changing the catalyst to the oxo-tethered complex
(S,S)-2, the yield of 5a slightly increased to 4% (run
2). Although no marked effect was observed using
EtOAc as a solvent (run 3), the addition of water was
found to give (R)-5a with 40% selectivity and 96% ee
(run 4). Gratifyingly, a combined use of HCO2H and
HCO2K, instead of a HCO2H/Et3N azeotrope,
drastically enhanced the selectivity up to 98% (run 5).
Among the tested solvents (runs 5-10), BuOAc and
toluene also showed acceptable selectivities, albeit
with somewhat lower catalytic activities (runs 6 and
7). The use of methanol and THF gave rise to rather
poor product selectivities (runs 8 and 9). Although a
more favorable result with an excellent yield and
97% ee was obtained for CHCl3 (run 10), we
preferred to use EtOAc as a desirable solvent from
both an environmental and practical point of view.
When the reaction was conducted without HCO2K,
the catalytic activity, selectivity, and optical purity
dropped noticeably (run 11). It should be noted that
the conversion and selectivity to (R)-5a dramatically
reverted in the presence of only 0.1 equiv. of HCO2K
(run 12), and the further addition of an excess amount
of HCO2K led to an increase in the enantioselectivity
and a slight decrease in the chemoselectivity (run 13).
A considerable decrease in the product selectivity
using HCO2K as the sole hydrogen source signified
that HCO2H and HCO2K were both indispensable for
the exquisite catalytic performance (run 14).
Eventually, it turned out that the combined use of 3.0
equiv. of HCO2H and 1.0 equiv. of HCO2K was
optimal for this reaction.
According to the relevant carbonate formation
mechanism in the ATH of -sulfonated acetophenone
by the Wills’ group, the formation of A by
debromination of 4a is conceivable, as shown in
Scheme 2.[9] With the progress of the ATH of 4a, the
alcoholic group of 5a can trap CO2 in the presence of
Et3N, followed by concomitant cyclization and
debromination to afford A. Considering the formate
anion in the azeotrope, debromination leading to B is
ascribed to the nucleophilic substitution of 4a or 5a
-
by HCO2 . Based on these mechanistic aspects, high
selectivity of the present HCO2H/HCO2K ATH
system was realized by eliminating Et3N, which is
intimately involved in the formation of the
debromination products A and B. Actually, formate B
was obtained as a sole product in 32% yield, when
bromohydrin 5a was treated under the ATH
conditions using HCO2H/Et3N. Carbonate A was not
formed in this experiment because of the absence of
CO2. When 5a was subject to the ATH conditions
under CO2 atmosphere, formation of carbonate A
from bromohydrin was verified by GC/MS analysis.
In contrast, the Et3N-free HCO2H/HCO2K system in a
mixture of EtOAc and H2O could suppress such
excessive side reactions via 5a.
Further study on the ATH of 4a with (S,S)-2 in a
HCO2H/Et3N azeotrope (run 2 of Table 1) by GC and
LC-MS analyses revealed that cyclic carbonate (A)
2
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10.1002/adsc.201701227
Advanced Synthesis & Catalysis
Table 1. ATH of 4a using bifunctional DPEN-derived Ru catalysts.[a]
Run
Catalyst
Reducing agent (equiv.)
Solvent
Conv. [%][b]
Select. for 5a [%][b] Ee [%][b]
1[c]
(R,R)-1
(S,S)-2
(S,S)-2
(S,S)-2
(S,S)-2
(S,S)-2
(S,S)-2
(S,S)-2
(S,S)-2
(S,S)-2
(S,S)-2
(S,S)-2
(S,S)-2
(S,S)-2
HCO2H/Et3N
HCO2H/Et3N
HCO2H/Et3N
HCO2H/Et3N
-
-
100
100
100
100
100
86
88
100
93
100
69
100
100
83
trace
4
6
n.d.
87
97
96
95
95
96
94
94
97
93
93
96
96
2[c]
3[c][d]
4[c][d][e]
5[d][e]
6[d][e]
7[d][e]
8[d][e]
9[d][e]
10[d][e]
11[d][e]
12[d][e]
13[d][e]
14[d][e]
EtOAc
EtOAc/H2O
EtOAc/H2O
BuOAc/H2O
toluene/H2O
MeOH/H2O
THF/H2O
CHCl3/H2O
EtOAc/H2O
EtOAc/H2O
EtOAc/H2O
EtOAc/H2O
40
98
>99
97
71
90
>99
94
98
96
63
HCO2H(3)/HCO2K(1)
HCO2H(3)/HCO2K(1)
HCO2H(3)/HCO2K(1)
HCO2H(3)/HCO2K(1)
HCO2H(3)/HCO2K(1)
HCO2H(3)/HCO2K(1)
HCO2H(3)
HCO2H(3)/HCO2K(0.1)
HCO2H(3)/HCO2K(4)
HCO2K(2)
[a] Typical reaction conditions; substrate (5 mmol), ruthenium catalyst (S/C = 100 for (R,R)-1 or S/C = 1000 for (S,S)-2).
[b] Determined by GC analysis using a CHIRALSIL-DEX-CB column.
[c] The amount of HCO2H/Et3N (5:2 azeotropic mixture) used was 2.5 mL.
[d] The amount of organic solvent used was 2.5 mL.
[e] The amount of H2O used was 4 mL.
Scheme 2. Plausible mechanism of the formation of
byproduct A.
8
h
and resulted in
a
somewhat lower
enantioselectivity (87% ee, run 8). When the catalyst
amount was reduced to S/C = 5000, 6a was
successfully converted to the corresponding (R)-
alcohol with same selectivity and ee in a prolonged
reaction time of 13.5 h (run 9).
Table 3 summarizes the substrate scope of -
bromoacetophenones for the HCO2H/HCO2K ATH
system. In some cases (runs 4 and 5 in Table 3),
slightly lower isolated yields were obtained for the
reaction of 4d and 4e, compared with the results of
the -chloroacetophenone derivatives 6d and 6e in
runs 4 and 5 of Table 2. The substrate with an
electron withdrawing group on the aromatic ring
resulted in a reduced optical purity (run 6), whereas
electron-donating groups led to satisfactory results
(runs 1-2, 4). Halogen atoms attached to the aromatic
ring remained intact under the ATH conditions (runs
3, 7, and 9). These tendencies are similar to the
outcomes of the -chlorinated acetophenones in
Table 2. It is striking that the unprecedented iodine-
substituted substrates (4i and 6g) and the
corresponding products (5i and 7g) did not deteriorate
the catalyst performance.[11] A substrate with an ester
group 4j could also be chemoselectively transformed
into the desired alcohol in a favorable isolated yield
and enantioselectivity (run 10). In addition, the oxo-
tethered Ru complexes were able to reduce aliphatic
This ATH system was also found to be applicable
to 2-chloroacetophenone 6a under similar conditions
as the reaction of 4a with S/C of 1000.[8c,10] As
summarized in Table 2, the oxo-tethered catalyst
bearing a Ms group, (S,S)-3, exhibited prominent
catalytic performance identical to the Ts-substituted
analog, (S,S)-2. Both substrates having an electron-
donating group (run 3) and an electron withdrawing
group (runs 2, 5 and 7) on the aromatic ring were
converted to the corresponding (R)-alcohols in
preferable enantioselectivities, whereas the ortho-
fluorinated substrate 6f provided a lower optical
purity (run 6). Despite the electron-donating nature of
the dimethylamino substituent on the aromatic ring,
the ATH of 6h required an extended reaction time of
tert-butyl
halomethyl
ketones
in
good
enantioselectivities of 50–70% (Table S1).[12]
3
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10.1002/adsc.201701227
Advanced Synthesis & Catalysis
Table 2. ATH of 2-chloroacetophenone derivatives catalyzed by oxo-tethered Ru complexes.[a]
Run
Catalyst
R1
R2
Product
Isolated yield [%]
Ee [%]
1
2
3
4
5
6
7
(S,S)-3
(S,S)-3
(S,S)-2
(S,S)-2
(S,S)-3
(S,S)-3
(S,S)-3
(S,S)-2
(S,S)-3
-H
-H
-H
-H
-H
-H
-F
-H
-H
-H
92
94
98
94
94
92
96
90
95
95[b] (R)
93[b] (R)
94[b] (R)
95[b] (R)
92[b] (R)
79[b] (R)
94[c] (R)
87[c] (–)
96[b] (R)
7a
7b
7c
7d
7e
7f
7g
7h
7a
-Cl
-OMe
-Ph
-F
-F
-I
8[d]
9[e]
-NMe2
-H
[a] Typical reaction conditions: substrate (5 mmol), EtOAc (2.5 mL), H2O (4 mL).
[b] Determined by GC analysis using a CHIRALSIL-DEX-CB column.
[c] Determined by HPLC analysis.
[d] Reaction time = 8 h.
[e] Substrate (50 mmol), EtOAc (25 mL), H2O (40 mL), S/C = 5000, 13.5 h.
Table 3. ATH of 2-bromoacetophenone derivatives catalyzed by oxo-tethered Ru complexes.[a]
Run
Catalyst
R1
R2
Product
Isolated yield [%]
Ee [%]
1
2
3
4
5
6
7
8
(S,S)-2
(S,S)-2
(S,S)-2
(S,S)-3
(S,S)-3
(S,S)-3
(S,S)-2
(S,S)-2
(S,S)-3
(S,S)-2
-H
-H
-H
-H
-H
-H
-NO2
-H
-H
-H
93
88
90
86
86
86
92
94
96
93
96[b] (R)
96[b] (R)
94[b] (R)
97[b] (R)
93[b] (R)
82[b] (R)
93[b] (R)
94[b] (R)
91[c] (R)
95[c] (–)
5a
5b
5c
5d
5e
5f
5g
5h
5i
-OMe
-Br
-Ph
-F
-H
-Cl
-CF3
-I
-OAc
9
10[d]
-H
5j
[a] Typical reaction conditions: substrate (5 mmol), EtOAc (2.5 mL), H2O (4 mL).
[b] Determined by GC analysis using a CHIRALSIL-DEX-CB column.
[c] Determined by HPLC analysis.
[d] An elongated reaction time of 6 h.
The ATH of -sulfonated acetophenones[10b,13] is
also of interest because sulfonates substituents, such
as mesylate and tosylate, are good leaving groups
accessible to further transformations.[14] Nevertheless,
the previous study has been confined to the use of
expensive Rh catalysts bearing a bifunctional N-
sulfonyl DPEN ligand. From the results shown in
Scheme 3, these substrates could be hydrogenated
successfully in similar high isolated yields and
enantioselectivities even with a S/C ratio of 1000 as
above demonstrated for the -chloroacetophenone
family.
4
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10.1002/adsc.201701227
Advanced Synthesis & Catalysis
Scheme 3. ATH of -sulfonated acetophenone derivatives.
In summary, we developed the effective ATH
reaction system for -substituted acetophenones, as
typified by -bromoketone derivatives. The oxo-
tethered Ru complexes (S,S)-2 and (S,S)-3 served
well as
a
catalyst in combination with
HCO2H/HCO2K in aqueous EtOAc to provide a
range of chiral secondary alcohols with useful
functional
groups
accessible
to
further
transformations. This ATH system is a more practical
way to ensure extremely high selectivity than
previously reported methods, associated with a
significant reduction of the byproduct formation.
Regarding the derivatization of the obtained
optically active haloalcohols, (R)-2-chloro-1-
phenylethan-1-ol 7d was completely converted into
the corresponding chiral (R)-epoxide 10 which is
convertible to various important chiral compounds
Experimental Section
such as 2-amino-1-alcohol[15a,b], -azido alcohol[15b]
and -methoxy alcohol[15d] (Scheme 4).
,
Procedure for the asymmetric transfer hydrogenation
of 2-bromoacetophenone 4a
Scheme 4. Derivatization of chiral -chlorohydrin.
To a 20-mL Schlenk tube, Ru complex (S,S)-2 (3.3 mg,
S/C = 1000), 4a (995 mg, 5 mmol), HCO2K (421 mg, 5
mmol), H2O (4 mL), EtOAc (2.5 mL), and HCO2H (0.57
mL, 15 mmol) were added under a N2 atmosphere, and the
mixture was stirred vigorously for 4 h at 60 °C. After
completion of the reaction was confirmed by GC analysis,
the reaction mixture was extracted with 5 mL of EtOAc
three times. The combined organic layer was concentrated
under vacuum, and then, the residue was purified by flash
chromatography (hexane:EtOAc = 5:1) to afford the pure
product 5a in 93% yield.
The catalytic ATH system also proved effective for
the stereoselective synthetic route to BMS-960, a
potent S1P1 receptor agonist, as an alternative to the
reported borane and enzymatic reaction[15c,e]. With
slightly modified reaction conditions, the highlighted
asymmetric reduction of bromomethyl 4-cyanophenyl
ketone 11 with (S,S)-3 afforded (R)-(–)-4-(2-bromo-
1-hydroxyethyl)benzonitrile 12 in 87% isolated yield
and 88% ee (Scheme 5). Unlike the biocatalytic and
CBS reduction, the ATH system using the (R,R)-
catalyst appropriate for the desired alcohol offers a
highly reliable catalytic method free from the
concerns of substrate specificity and generating
equivalent amounts of boron waste.
Acknowledgements
We are grateful to Messrs. Yoshihiro Yaguchi, Akihiro Kawaraya,
Hiroaki Izumi, Tsuyoshi Kobayashi, and Satoru Moriya and Mses.
Chikako Kawata, Yumi Kusano, and Noriko Yamamoto of
Takasago International Corporation for NMR measurements,
mass spectroscopy, and experimental assistance. We also thank
Prof. Takeshi Nakai and Prof. Masahiro Terada for helpful
discussions.
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Advanced Synthesis & Catalysis
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Goswami, J. L. Gilmore, J. E. Sheppeck, A. J.
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UPDATE
Selective Asymmetric Transfer Hydrogenation of
-Substituted Acetophenones with Bifunctional
Oxo-Tethered Ruthenium(II) Catalysts
Adv. Synth. Catal. Year, Volume, Page – Page
Yamato Yuki*, Taichiro Touge, Hideki Nara,
Kazuhiko Matsumura, Mitsuhiko Fujiwhara,
Yoshihito Kayaki*, and Takao Ikariya
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