Ultrafast Iron-Catalyzed Reduction of Functionalized Ketones: Highly Enantioselective Synthesis of Halohydrines, Oxaheterocycles, and Aminoalcohols

Article abstract of DOI:10.1002/anie.201806196

A molecularly defined chiral boxmi iron alkyl complex catalyzes the hydroboration of various functionalized ketones and provides the corresponding chiral halohydrines, oxaheterocycles (oxiranes, oxetanes, tetrahydrofurans, and dioxanes) and amino alcohols with excellent enantioselectivities (up to >99 %ee) and conversion efficiencies at low catalyst loadings (as low as 0.5 mol %). Turnover frequencies of greater than 40000 h^?1 at ?30 °C highlight the activity of this earth-abundant metal catalyst which tolerates a large number of functional groups.

Full text of DOI:10.1002/anie.201806196

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Ultrafast Iron-Catalyzed Reduction of Functionalized
Ketones: Highly Enantioselective Synthesis of Halohydrines,
Oxaheterocycles and Aminoalcohols
Authors: Lutz Gade, Clemens Blasius, and Vladislav Vasilenko
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201806196
Angew. Chem. 10.1002/ange.201806196
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10.1002/anie.201806196
Angewandte Chemie International Edition
COMMUNICATION
Ultrafast Iron-Catalyzed Reduction of Functionalized Ketones:
Highly Enantioselective Synthesis of Halohydrines,
Oxaheterocycles and Aminoalcohols
Clemens K. Blasius, Vladislav Vasilenko, Lutz H. Gade*
Dedicated to Professor Dietmar Stalke on the occasion of his 60th birthday.
Abstract: A molecularly defined chiral boxmi iron alkyl complex
catalyzes the hydroboration of various functionalized ketones and
provides the corresponding chiral halohydrines, oxaheterocycles
(oxiranes, oxetanes, tetrahydrofurans and dioxanes) or amino
alcohols with excellent enantioselectivity (up to >99 %ee) and
conversion efficiency at low catalyst loadings (as low as 0.5 mol%).
Turnover frequencies of >40000 h1 at 30 °C highlight the activity of
this earth-abundant metal catalyst which tolerates a large number of
functional groups.
rely on expensive and partly toxic noble metal catalysts to
efficiently transfer the stereochemical information.[8] More
importantly, to the best of our knowledge, no base metal
protocols for the reduction of ketones beyond -haloketones
have been reported to date.
In this context, the development of novel catalytic systems
based on environmentally benign and earth-abundant base
metals still provides a challenge in this field of research.[9-11] This
has been the focus of many recent studies in which the potential
of 3d metals in enantioselective catalysis for the reduction of
carbon-carbon and carbon-heteroatom multiple bonds has been
reported.[12] The majority of these studies is limited to simple
diaryl, aryl alkyl and dialkyl ketones as the substrates, with more
complex structures being explored only in selected cases.[13-19]
In 2006, Lipshutz and coworkers first introduced a copper
hydride catalyst with a biaryl diphosphine spectator ligand for the
stereoselective reduction of a halo-substituted ketone,[16] while
Wu and co-workers subsequently explored the reduction of a
broader range of ω-haloketones by a related copper catalyst and
obtained excellent yields and selectivities.[17] More recently,
Morris and Lu reported several cases employing iron and cobalt
catalysts, respectively.[18,19] However, the general applicability of
such catalytic methods to substrates bearing reactive functional
groups, such as ω-haloketones or even aminoketones, has not
been published to date.
Optically pure functionalized alcohols and oxaheterocycles
are attractive starting materials for the synthesis of biologically
active compounds and medicinal products (Figure 1).[1] The
preparation of a number of pharmaceutically active compounds
for the therapy of psychiatric disorders or cardiac arrhythmias is
dependent on the availability of suitable protocols to provide
these compounds in sufficient enantiopurity.
Table 1. Screening of reaction conditions for the enantioselective reduction of
α–haloketones.
Figure 1. Selected bioactive molecules based on chiral alcohols and
derivatives thereof.
There are two standard synthetic approaches for these
precursors: (i) the stereoselective reduction of the respective
catalyst
[mol%]
temp.
[°C]
conv.
[%][b]
ee,
%
#
HY
work-up[a]
[b]
-haloketones[2,3]
–
readily
α-halogenation,[4] Friedel-Crafts acylation of aromatics,[5] and
hydration of haloalkynes[6]
followed by nucleophilic
available
via
ketone
[c]
1
2
3
4
5
6
7
HBPin
HBPin
HBPin
HBPin
HBPin
HBPin
HBPin
K2CO3
2.5
2.5
2.5
2.5
1.0
0.5
0.25
+26
+26
+26
40
40
40
40
>99 (3a)
>99 (3a)
>99 (4a)
>99 (4a)
>99 (4a)
>99 (4a)
98 (4a)
92
92
92
95
95
95
87
TBAF[d]
–
substitution; (ii) initial functionalization prior to the reduction
step.[7] However, methods for the ketone reduction frequently
SiO2
SiO2
SiO2
SiO2
[a]
C. K. Blasius, V. Vasilenko, Prof. L. H. Gade
Anorganisch-Chemisches Institut
SiO2
Universität Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
E-mail: lutz.gade@uni-heidelberg.de
[a] direct addition of the respective reagent to the reaction mixture; [b]
determined by HPLC analysis; the obtained product is given in
parenthesis; [c] as saturated solution in MeOH; [d] as 1 M solution in
THF.
Supporting information for this article is given via a link at the end
of the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201806196
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COMMUNICATION
In previous reports,[20] we established the potential of the
chiral bis(oxazolinyl-methylidene)isoindoline (“boxmi”) pincer
ligand[21] as an ancillary ligand in iron-based catalysts for the
enantioselective hydrosilylation of ketones. However, the
hydrosilylation was mostly limited to simple unhindered aryl alkyl
ketones. In order to overcome this limitation, which we attributed
to a significant catalyst deactivation during the reduction of the
more challenging substrates, we aimed to further increase the
activity of the catalytic system. Since our mechanistic work for
the hydrosilylation identified the σ-bond metathesis step
between the silane and the iron alkoxide to be rate-
determining,[20b] a careful choice of the hydride source was
thought to meet this prerequisite (vide infra).
The iron precatalyst 1 used in this study can be readily
synthesized from the protioligand Phboxmi-H and the crystalline
and isolable alkyl precursor (tmeda)Fe(CH2SiMe3)2 (Table 1, see
SI).[22] We first focused on the reduction of α-haloketones, given
their potential to provide the corresponding chiral halohydrines
or styrene oxides depending on the reaction conditions
employed. The reduction of α-chloroacetophenone 2a was
chosen as starting point for an initial screening due to the
surprisingly unsatisfying results obtained in the hydrosilylation of
this substrate (see Supporting Information). On the other hand,
hydroboration of 2a with pinacol borane (HBPin) proceeded
smoothly to the corresponding boronic ester and afforded the
styrene oxide 3a with improved enantioselectivity (92 %ee,
entries 1-2 in Table 1). In addition, hydrolysis of the boronic
ester on silica gave the chiral halohydrine 4a with identical
selectivity, thus enabling the synthesis of two valuable building
blocks via the same reaction setup. The high activity of the
catalyst allowed the reduction of the temperature to –40 °C and
of the catalyst loading to 0.5 mol%, obtaining the desired
product 4a with 95 %ee after warming the reaction mixtures to rt
over a period of 2 h (Table 1, entry 4-6).
Investigation of the reduction of 4’-fluoroacetophenone by
in situ FT-IR techniques established an initial TOF value of up to
43 500 h1 at 30 °C for the hydroboration which is an order of
magnitude higher than the one reported for the hydrosilylation,
highlighting the enhanced activity of this catalytic system. We
hypothesize a direct insertion step analogous to our previous
proposal for the hydrosilylation, and ascribe the faster kinetics to
a lower barrier for the metathesis step of the hydroboration as
compared to the hydrosilylation mechanism.[20b] Notably, the
newly developed protocol also proved very useful for several
substrates which were previously inaccessible in the
hydrosilylation (see SI).[20a]
Scheme 1. Substrate scope of the iron-catalyzed hydroboration of α-
haloketones to chiral styrene oxides (3) and 2-halohydrines (4). [a] for product
3: addition after removal of the solvent as 1 M solution, 12 h, rt; [b] for product
4: direct addition to the reaction mixture, 1 h, rt; [c] determined by HPLC
analysis; [d] isolated yield; [e] performed with 2.5 mol% catalyst loading.
The observed activity and enantioselectivity of the iron
catalyst 1 in the reduction of α-haloketones to 2-halohydrines
and their facile in situ conversion to the corresponding epoxides
upon basic work-up led us to investigate derivatives containing
longer alkyl chains (Scheme 2). The increased chain length in β-
and γ-haloketones 5 and 8 gave rise to a slightly enhanced
enantiodiscrimination in all cases.
Upon work-up under acidic conditions, the halohydrines 6a-c
and 9a-c were isolated in high yields and excellent
enantioselectivities. The corresponding basic work-up produced
the related chiral oxetanes 7a-c and tetrahydrofurans 10a-c with
identical selectivities (Scheme 2). Whereas all γ-halo derivatives
could smoothly be converted to the tetrahydrofuran derivatives
via direct addition of K2CO3/MeOH to the reaction mixture,
incomplete cyclisation of the boronic esters precluded such an in
situ approach in the case of oxetanes 7a-c. Therefore, β-
halohydrines 6a-c were isolated prior to ring closure with
KOtBu/THF.[23]
The optimized protocol was applied to the reduction of a
broad range of α-chloromethyl aryl ketones 2 (Scheme 1). In
analogy to our previous results for the hydrosilylation of non-
functionalized carbonyls,[20a] we observed excellent conversion
and stereoselectivity. Changing the work-up procedure to
TBAF/THF furnished the corresponding styrene oxides with
identical selectivities in a single step (Scheme 1).
Scheme 2. Synthesis of chiral ω-halohydrines (6 and 9) and corresponding
oxaheterocycles (7 and 10). [a] for products 6 and 9: direct addition to the
reaction mixture, 1 h, rt; [b] KOtBu (3 eq.), 12 h, rt; [c] for product 10: direct
addition to the reaction mixture as saturated solution, 12 h, rt; [d] determined
by HPLC analysis; [e] isolated yield.
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10.1002/anie.201806196
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COMMUNICATION
Given the importance of chiral 1,4-dioxanes as building
blocks in natural products and pharmaceutical agents along with
the successful reduction of haloketones 5 and 8, we explored
synthetic strategies for this class of products based on the
methods developed in this work. To this end, the previously
unknown reduction of chloro keto ethers, which in turn are
readily available by Grignard addition to 2-chloro ethoxy
acetonitrile,[24] was thought to provide a convenient starting point
for the preparation of such oxaheterocycles.
excellent enantioselectivity and good to excellent yields
(Scheme 5). This is the first example of a base metal mediated
reduction of functionalized ketones beyond
substituent.
a
halogen
Application of the standard protocol to the hydroboration of
chloro keto ethers 11a-c produced alcohols 12a-c with good
yields and enantioselectivities after work-up on silica. In analogy
to the preparation of the oxetanes 7a-c, the respective 1,4-
dioxanes 13a-c were obtained after addition of KOtBu/THF to
the isolated alcohols (Scheme 3). In fact, the addition of
TBAF/THF to the catalytic mixture allowed the synthesis of
dioxanes 13a-c in a single step in good yields. Notably, the high
enantioselectivity observed for phenanthryl (12b,13b) and
thienyl (12c,13c) derivatives illustrates the potential of this
method to tolerate poly- and heterocycles.
Scheme 5. Synthesis of chiral 1,2-aminoalcohols via stereoselctive
hydroboration of N,N-disubstituted- -amino ketones 14.
In conclusion, the catalytic enantioselective reduction of a
broad range of functionalized ketone derivatives using a chiral
pincer iron catalyst has provided access to chiral halohydrines,
the respective oxaheterocycles and amino alcohols in excellent
yields and enantioselectivities. The catalytic method presented
herein is a significant improvement in activity and substrate
scope compared to the previously reported hydrosilylation using
the same precatalyst. The iron-catalyzed hydroboration is
unprecedented in both activity and selectivity for this type of
metal and tolerates various functional groups which had been
limiting in previous studies. The low toxicity of iron and the
reduced catalyst loading combined with the readily available
stereodirecting pincer ligand "boxmi" render this approach
particularly promising for future applications in the synthesis of
natural products or pharmaceutical ingredients.
Scheme 3. Synthesis of chiral 2-chloroethoxy alcohols (12) and corresponding
1,4-dioxanes (13).
The iron-catalyzed hydroboration protocol was applied to the
gram scale synthesis of 3-chloro-1-phenylpropan-1-ol 7a, which
forms the basis for the preparation of antidepressant (R)-
fluoxetine following the original synthesis by Corey and co-
workers.[25] Employing a catalyst loading of 0.5 mol%, we were
able to reduce 1 g of β-chloropropiophenone 5a in
quantitative yield and with 95 %ee (Scheme 4).
Acknowledgements
We acknowledge the award of a doctoral fellowship to V. V. from
the Landesgraduiertenförderung (LGF Funding Program of the
state of Baden-Württemberg) and generous funding by the
University of Heidelberg as well as the Deutsche
Forschungsgemeinschaft (DFG-Ga488/9-2). The authors thank
Deborah Hartmann and Philipp Erdmann for experimental
support.
Keywords: iron • hydroboration • enantioselective catalysis •
chiral halohydrines • chiral amino alcohols
Scheme 4. Formal synthesis of (R)-fluoxetine via stereoselective
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COMMUNICATION
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10.1002/anie.201806196
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
C. K. Blasius, V. Vasilenko, L. H. Gade*
Page No. – Page No.
Ultrafast Iron-Catalyzed Reduction of
Functionalized Ketones: Highly
Enantioselective Synthesis of
Halohydrines, Oxaheterocycles and
Aminoalcohols
Fe-nomenal:
A
molecularly defined iron complex catalyzes the highly
enantioselective hydroboration of functionalized ketones. The reduction of a broad
range of substrates gives access to preparatively useful chiral halohydrines,
oxaheterocycles and amino alcohols in high yields and enantioselectivities. This
earth-abundant metal catalyst features an unprecedented high activity and tolerates
various functional groups.
This article is protected by copyright. All rights reserved.