Asymmetric Hydrogenation of Aryl Perfluoroalkyl Ketones Catalyzed by Rhodium(III) Monohydride Complexes Bearing Josiphos Ligands

Article abstract of DOI:10.1002/chem.201902585

The asymmetric hydrogenation of 2,2,2-trifluoroacetophenones and aryl perfluoroalkyl ketones was developed using a unique, well-defined chloride-bridged dinuclear rhodium(III) complex bearing Josiphos-type diphosphine ligands. These complexes were prepared from [RhCl(cod)]₂, Josiphos ligands, and hydrochloric acid. As catalyst precursors, they allow for the efficient and enantioselective synthesis (up to 99 % ee) of chiral secondary alcohols with perfluoroalkyl groups. This system does not require an activating base for the hydrogenation of 2,2,2-trifluoroacetophenones. Additionally, the enantioselective C=O hydrogenations of 2-phenyl-3-(haloacetyl)-indoles, a class of privileged structures in medicinal chemistry, is reported for the first time.

Full text of DOI:10.1002/chem.201902585

A Journal of
Accepted Article
Title: Asymmetric Hydrogenation of Aryl Perfluoroalkyl Ketones
Catalyzed by Rhodium(III) Monohydride Complexes Bearing
Josiphos Ligands
Authors: Antonio Togni, Fabian Brüning, Daniel Käch, Haruki Nagae,
and Kazushi Mashima
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To be cited as: Chem. Eur. J. 10.1002/chem.201902585
Link to VoR: http://dx.doi.org/10.1002/chem.201902585
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Asymmetric Hydrogenation of Aryl Perfluoroalkyl Ketones
Catalyzed by Rhodium(III) Monohydride Complexes Bearing
Josiphos Ligands
Fabian Brüning,[a] Haruki Nagae,[b] Daniel Käch,[a] Kazushi Mashima[b] and Antonio Togni*[a]
Abstract:
The
asymmetric
hydrogenation
of
2,2,2-
protocols. Not surprisingly, optimized catalytic systems for
acetophenones do not proceed efficiently for
trifluoroacetophenones and perfluoroalkyl aryl ketones was
developed using a unique, well-defined chloride-bridged dinuclear
rhodium(III) complex bearing Josiphos-type diphosphine ligands.
These complexes were prepared from [RhCl(cod)]2, Josiphos ligands,
and hydrochloric acid. As catalyst precursors they allow for the
efficient and enantioselective synthesis (up to 99% ee) of chiral
secondary alcohols with perfluoroalkyl groups. This system does not
require an activating base for the hydrogenation of 2,2,2-
trifluoroacetophenones. Additionally, the enantioselective C=O
trifluoroacetophenones and suffer from poor enantioselectivities
due to their vastly different stereoelectronic properties.[20–23] In this
work, we address this challenge by presenting an efficient
protocol for the asymmetric hydrogenation of perfluoroalkyl aryl
ketones using rhodium(III) complexes bearing Josiphos-type
ligands (Scheme 1).
hydrogenations of 2-phenyl-3-(haloacetyl)-indoles,
a
class of
privileged structures in medicinal chemistry, is reported for the first
time.
Chiral secondary alcohols containing a trifluoromethyl group are
an important structural motif found in biologically active molecules
or as essential intermediates en route to complex molecules.[1–3]
Of particular importance is the utilization of 1-aryl-2,2,2-
trifluoroethanol derivatives as building blocks in the synthesis of
drugs or drug candidates, such as tryptophan hydroxylase
inhibitor LX1301.[1,4,5] The rising demand to access such
compounds in an enantioselective manner has led to the
development of several strategies. For example, contemporary
methods include the enantioselective trifluoromethylation of
aldehydes,[6]
kinetic
resolution
of
racemic
1-aryl-
2,2,2-trifluoroethanols[7,8] and enantioselective Hiyama cross-
coupling.[9] However, the most efficient and successful method to
date is the enantioselective reduction of trifluoromethyl ketones
whereby different catalytic methods have been developed. These
include
enzymatic
diethylzinc,[15]
chiral
bio-catalysis,[12–14]
homogenous
oxazoborolidine-catalyzed
reductions,[10,11]
transfer with
metal-catalyzed
β-hydrogen
transition
asymmetric hydrogenation (AH) and asymmetric transfer
hydrogenation (ATH).[16–19] In contrast to the large number of
catalytic methods for the asymmetric (transfer) hydrogenations of
non-fluorinated ketones, the hydrogenation of corresponding
trifluoromethyl (or perfluoroalkyl) derivatives is largely
undeveloped. Indeed, perfluoroalyl ketones are known as low-
yielding substrates in classical asymmetric hydrogenation
Scheme 1. Development and application of chloride-bridged dinuclear
rhodium(III) complexes.
Historically, although the direct asymmetric reduction of
trifluoroacetophenone with hydrogen has been challenging, a few
noteworthy advances have been reported. In particular, Noyori
reported the successful asymmetric hydrogenation of ketones
using a ruthenium catalyst with a chiral diamine ligand in addition
to the BINAP-type diphosphine, albeit in need of a strong base
and a very limited substrate scope.[18] A study by Iseki and co-
workers reports the hydrogenation of trifluoromethyl ketones by a
rhodium-(amidophosphine-phosphinite) catalyst. While their
catalyst demonstrates excellent yields and enantioselectivities for
most substrates, trifluoroacetophenones are only hydrogenated
[a]
[b]
Fabian Brüning, Daniel Käch, Prof. Dr. A. Togni
Department of Chemistry and Applied Biosciences
ETH Zürich
Vladimir-Prelog-Weg 2, 8093 Zürich (Switzerland)
E-mail: atogni@ethz.ch
Dr. H. Nagae, Prof. Dr. K. Mashima
Department of Chemistry, Graduate School of Engineering Science
Osaka University
1-3 Machikaneyama-cho, Toyonaka, Osaka 5608531 (Japan)
Supporting information for this article is given via a link at the end of
the document.
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in moderate yields with poor enantioselectivites.[17] Similar results
were obtained by Mohar and co-workers who reported the
ruthenium-catalysed transfer hydrogenation of fluoroalkyl ketones,
yet trifluoroacetophenones could not be hydrogenated with good
enantioselectivity.[16]
Recently, the synthesis and application of triply chloride-
bridged dinuclear rhodium(III) complexes bearing chiral C2
symmetric diphosphine ligands such as BINAP and SEGPHOS
were reported by Mashima.[24] In analogy to previously developed
dinuclear iridium(III) derivatives, these systems display high
catalytic activity and enantioselectivity in diverse asymmetric
hydrogenation reactions, including that of simple unfunctionalized
alkenes.[25–27]
Inspired by the hydrogenation of polar C=N double bonds
using Ir(III) monohydride catalysts by Verdaguer and co-workers,
we decided to investigate the asymmetric C=O hydrogenation of
trifluoroacetophenones
using
rhodium(III)
monohydride
systems.[28] We began by expanding the scope of available
discrete precatalysts by preparing structurally similar dinuclear
rhodium(III) complexes, albeit with Josiphos-type ligands formally
replacing BINAP and SEGPHOS (Scheme 2a). The synthesis
was carried out by adding ten equivalents of HCl in diethyl ether
to a mixture of [RhCl(cod)]2 and 2.05 equivalents of the
corresponding chiral ligand in toluene. Rhodium(III) complexes in
yields ranging between 65 and 86% could be obtained only in the
case of classical Josiphos ligands, i.e. combining
a
diarylphosphino group directly attached to the ferrocene core with
a bulky dialkylphosphino fragment at the stereogenic center.
According to both their multinuclear NMR spectroscopic
characteristics and NMR diffusion experiments these complexes
Scheme 2. Scheme 2. a) Synthesis of chloride-bridged dinuclear Rh(III)
complexes and b) molecular structure of the dissociated mononuclear form
[Rh(Cl)2(H)J4]; hydrogen atoms are omitted for clarity. Selected distances (Å)
and bond angles (deg): Rh1-P1 2.273(3), Rh1-P2 2.164(3), Rh-Cl1 2.387(3),
Rh1-Cl2 2.406(3); P1-Rh1-P2 96.0(1), P1-Rh1-Cl2 97.1(1), Cl2-Rh1-Cl1
88.7(1), Cl2-Rh1-P2 110.5(1), Cl1-Rh1-P1 161.4(1), P2-Rh1-Cl1 98.4(1).
exist in solution as
a
single diastereomeric dinuclear
monocationic species (see SI for details). However, we were
surprised to find by an XRD study that complex [{Rh(H)(J4)}2(µ-
Cl)3]Cl exists in the solid state in its dissociated, five-coordinate
mononuclear form [Rh(Cl)2(H)J4] (Scheme 2b). The position of
the hydride ligand could not be determined, hence distorted
trigonal bipyramidal or square pyramidal geometries around the
rhodium center are in principle possible. Yet, a distorted square
pyramidal geometry with the hydride in trans position to the
slightly elongated Rh-Cl1 bond seems more likely.
Using these optimized reaction conditions with Rh(III) complexes
bearing Josiphos ligands J1 – J2, we obtained only poor
enantiomeric excess. Additionally, the reaction did not proceed at
all using ligand J3 (entries 9 - 11).
Table 1. Asymmetric hydrogenation of 4-chloro-trifluoroacteophenone.
With the catalysts in hand, we began testing their reactivity
in the asymmetric hydrogenation of trifluoroacetophenone 1a.
Selected results for the optimization of reaction conditions are
shown in Table 1 (for complete tables, see SI). We attempted the
reaction with our new catalyst precursors using polar solvents
such as DMF and THF at 60 °C, resulting already in quantitative
yields but only moderate enantioselectivities of 56% and 35%,
respectively (entries 1-2). We were surprised that the reaction
proceeded at room temperature in MeCN or EtCN with good
enantiomeric excess of 80% and 74%, respectively, albeit in lower
yields (entries 3-4). Inspired by the well-studied hydrogenation
step in the industrial synthesis of Metolachlor,[29] we anticipated
that we could likewise activate the catalysts in AcOH and found
that the reaction proceeds smoothly in 72% yield and 44% ee
(entry 5). To our surprise, the key to successful enantioselective
hydrogenation is the combination of two solvents, an alkyl nitrile
and AcOH (entries 6-8).
O
OH
CF3
catalyst (2 mol%)
H2 (50 bar)
CF3
solvent, temperature,
18 h
Cl
Cl
1a
2a
Entrya
Solvent
Catalyst
T [°C]
Yield [%]b
ee [%]c
1
2
THF
DMF
Rh-4
Rh-4
Rh-4
Rh-4
Rh-4
Rh-4
Rh-4
Rh-4
Rh-1
Rh-2
Rh-3
60
60
>99
>99
12
56
35
80
74
44
85
88
84
3
3
MeCN
EtCN
AcOH
RT
RT
RT
RT
RT
RT
RT
RT
RT
4
25
5
72
6
MeCN/AcOH (1:1)
EtCN/AcOH (1:1)
iPrCN/AcOH(1:1)
EtCN/AcOH (1:1)
EtCN/AcOH (1:1)
EtCN/AcOH (1:1)
>99
>99
77
7
8d
9d
10d
11d
31
>99
5
0
n.d.
aReaction conditions: 0.1 mmol of ketone and 0.02 mmol catalyst in 1.0 mL
solvent. bDetermined by 19F-NMR spectroscopy using α,α,α-trifluorotoluene as
internal standard. cDetermined by chiral GC-analysis. d1 mol-% catalyst used.
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Using the catalyst with ligand J4, we next addressed the
asymmetric hydrogenation of several trifluoroacetophenones and
The functional group tolerance for the acetyl moiety in
substrate 2h sparked our interest to investigate the selectivity
difference between acetophenone and trifluoroacetophenone
(Scheme 3). In contrast to trifluoroacetophenone providing the
corresponding alcohol 2b in quantitative yield, we did not observe
any reactivity with the non-fluorinated analogue (Scheme 3a).
Closer investigation of the hydrogenation towards alcohol 2h,
however, revealed the formation of diol 2h-OH in up to 20% yield.
As alcohol 2h cannot be further hydrogenated to 2h-OH under our
reaction conditions (Scheme 3b), the formation of the diol must
proceed via the corresponding 1-(4-trifluoroacetylphenyl)-ethanol,
the formation of which can be attributed to the strongly electron
withdrawing trifluoroacetyl group in para position.
the
results are summarized in
Table 2. Simple
trifluoroacetophenone and methyl-, methoxy- and bromo para-
substituted derivatives were efficiently hydrogenated to the
corresponding alcohols 2b – 2e in excellent yields of 92 - 99%
and enantioselectivities of 86% for all substrates. Even a
dimethylamino group was tolerated under the reaction conditions
and product 2f was obtained in quantitative yield, albeit only with
66% enantiomeric excess. Trifluoromethyl and acetyl substitution
in para-position are well tolerated with yields of 98% and 71%,
respectively, and 88% ee for both substrates 2g and 2h. In
addition, a methyl ester was also well tolerated and gave alcohol
2i in 99% yield and 89% ee. Substrates with ortho- and meta-
substitutions can also be efficiently hydrogenated with good
enantioselectivities, as demonstrated by compounds 2j – 2l. We
then turned our attention to other fluorinated ketones bearing a
CF2Cl, C2F5 and a C3F7 moiety. Surprisingly, we found that the
increased steric demand results in higher enantioselectivities of
93%, 95%, and 96% for substrates 2m, 2n and 2o, respectively.
Finally, we attempted to hydrogenate perfluorophenyl ketones,
but these afforded the alcohols 2p and 2q in 4% and 27% yields
only. Similarly, alcohol 2r was only obtained in 57% yield and 9%
ee.
Table 2. Rh-catalyzed asymmetric hydrogenation of perfluoroalkyl aryl ketones.
Scheme 3. a) Reactivity comparison of trifluoroacetophenone and
acetophenone. b) Selectivity in the hydrogenation of 4-acetyl-
trifluoroacetophenone. Standard conditions: 1 mol-% [{Rh(H)(J4)}2(µ-Cl)3]Cl,
AcOH/EtCN (1:1), H2 (50 bar), rt, 18 h. Yields were determined by 19F NMR
spectroscopy.
Following the asymmetric hydrogenation of various
fluorinated acetophenones, we turned our attention to indoles, a
particularly important class of heteroarenes. 3-Substituted-2-
phenylindoles have been recognized as privileged structures in
medicinal chemistry with a broad biological activity profile for G
protein-coupled receptor modulation.[30,31] The available synthetic
methods
for
the
installation
of
the
stereogenic,
(trifluoromethyl)hydroxymethyl group at position 3 of indoles are
presently limited to a radical cross-dehydrogenative coupling[32]
and an enantioselective Friedel-Crafts reaction of indoles with
trifluoroacetaldehyde, catalyzed by cinchona alkaloids.[33] The
latter approach, however,
provides
only
very
low
enantioselectivities. Hence, we decided to start our investigation
with the asymmetric hydrogenation of 3-trifluoroacetyl-2-
phenylindole 3a, as there are no reported enantioselective
procedures for the synthesis of the corresponding model alcohol
4a. We obtained 4a in excellent yield of 98% and 88%
enantiomeric excess using 2 mol-% catalyst in EtCN (Table 3)
while the previous reaction conditions using EtCN and AcOH as
solvents gave unsatisfactory results (see SI for full optimization
data). We further examined the influence of substitution at
position 2 of the indole and found decreased yields and
enantioselectivities of only 62% and 73% for indoles 4b and 4c
bearing no substituent or only a methyl group, whereas for 2-
t
naphthyl and Bu groups the corresponding products 4d and 4e
were both obtained in good ee of 87% and 86%. Remarkably, N-
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methyl protected indole 4f could not be obtained under our
reaction conditions but was formed in 60% yield and 77% ee upon
addition of AcOH. Dimethoxy substituted indole 4g was obtained
in an excellent 99% yield and 95% ee. In addition, halogen- or
methoxy substitution on the phenyl ring, as for substrates 4h – 4j
was well tolerated giving excellent yields. Next, we addressed
different fluoroalkyl ketones using the 2-phenylindole scaffold
including 3-difluoroacetyl-2-phenylindole that was obtained in
36% yield and 56% ee. Increasing the size of the fluoroalkyl group
to -CF2Cl or -CF2Br, led to quantitative yields and an increase in
enantiomeric excess to 93% for both substrates. Even higher
enantiomeric excesses of 98% and 99% were obtained for indoles
4n and 4o bearing sterically more demanding -C2F5 and -C3F7
fragments. The increase in enantiomeric excess seemingly
correlates with the size of the fluoroalkyl group on the ketone, as
we had similarly observed for acetophenone-type substrates. The
absolute configuration of all indoles was determined to be S when
utilizing catalysts with (S,R)-Josiphos ligands, as determined by
single crystal analysis of substrate 4m and comparison of the
optical rotation with literature data for indole 4b.[33]
Conventionally, asymmetric hydrogenations of polar C=O
double bonds are associated with Ru catalysts, whereas Rh
catalysts play a pivotal role in the AH of C=C double bonds with a
directing group.[34] Noteworthy, these reactions involve
a
rhodium(I) complex and proceed via their corresponding in-situ
generated rhodium(III) dihydride species. However, the behaviour
of the dinuclear rhodium(III) monohydride species reported herein
is significantly different from that of the well-established
rhodium(I) catalysts. By monitoring the yield as a function of time,
we found a rather long induction period of the reaction of about
five hours. (see SI). This induction period is not observed, when
the catalyst is stirred in the solvent under an argon atmosphere
overnight before applying hydrogen pressure. Based on the
previously reported mechanisms for the dinuclear iridium(III)-
catalyzed
asymmetric
C=N
hydrogenations[35–37]
and
investigations of alkene insertion into the Rh-H bond,[38] we
propose that a plausible mechanism could involve a similar
catalytic cycle. Accordingly, the dinuclear rhodium species slowly
dissociates to form mononuclear species possibly stabilized by
the nitrile solvent. The ketone coordinates to the catalytically
active mononuclear complex (see Scheme 2b) followed by
insertion into the Rh-H bond. The resulting intermediate
alcoholato complex reacts with H2 by heterolytic hydrogen
activation to generate the product and the Rh(III) catalyst.
Considering the dependency of the enantiomeric excess on the
nitrile ranging from zero to 88%, it is reasonable to assume that a
nitrile molecule acts as a ligand during the reaction, whereas a
chloride ligand dissociates. This is consistent with the observation
that a chloride additive such as tetrabutylammonium chloride
reduces the activity of the catalyst. Furthermore, the Rh(III)
complex with ligand J3 bearing electron withdrawing substituents
on one phosphine demonstrated no reactivity in comparison with
the strongly electron donating substituents on J4, favourable for
a cationic Rh(III) intermediate. As this mechanistic hypothesis is
still speculative, further detailed mechanistic investigations are
currently underway in our laboratory.
Table 3. Asymmetric hydrogenation of 3-(trifluoroacetyl)-2-arylindoles and
related substrates.
In conclusion, we have developed a series of chloride-
bridged dinuclear rhodium(III) complexes bearing Josiphos-type
ligands. The complexes were used as catalyst precursors for the
asymmetric hydrogenations of trifluoroacetophenones and similar
perfluoroalkyl aryl ketones with excellent yields, chemoselectivity,
and enantioselectivities under mild reaction conditions. The
optimized Rh-catalyst was applied to the asymmetric
hydrogenation of 3-(haloacetyl)-2-arylindoles, providing the first
efficient enantioselective protocol for the synthesis of the
corresponding alcohols. By extending alkene hydrogenation to
the C=O bond of acetyls, we underscore the versatility of bridged
dinuclear rhodium(III) compounds in catalytic asymmetric
hydrogenations.
Acknowledgements
ETH Zurich is acknowledged for financial support. We thank Dr.
René Verel for assistance with diffusion NMR spectroscopy and
Ewa Pietrasiak for the X-ray crystallographic studies. K. M.
acknowledged financial supports by JSPS KAKENHI Grant
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Keywords: Asymmetric Catalysis • Hydrogenation • Rhodium •
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Fabian Brüning, Haruki Nagae, Daniel
Käch, Kazushi Mashima and Antonio
Togni*
Page No. – Page No.
Dinuclear Rh(III) monohydride complexes bearing Josiphos-type ligands have been
developed. These complexes serve as catalyst precursors for the efficient
enantioselective carbonyl hydrogenation of trifluoroacetophenones. Related
perfluoroalkyl aryl ketones and 3-(haloacetyl)-2-arylindoles are viable substrates,
affording the corresponding secondary alcohols in high yield and enantiomeric
excess.
Asymmetric Hydrogenation of Aryl
Perfluoroalkyl Ketones Catalyzed by
Rhodium(III) Monohydride Complexes
Bearing Josiphos Ligands
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