Asymmetric Transfer Hydrogenation of o-Hydroxyphenyl Ketones: Utilizing Directing Effects That Optimize the Asymmetric Synthesis of Challenging Alcohols

Article abstract of DOI:10.1021/acs.orglett.0c01213

A systematic range of o-hydroxyphenyl ketones were reduced under asymmetric transfer hydrogenation conditions using the C3-tethered catalyst 2. Two directing effects, i.e., an o-hydroxyphenyl coupled to a bulky aromatic on the opposite side of the ketone substrate, combine in a matched manner to deliver reduction products with very high enantiomeric excess.

Full text of DOI:10.1021/acs.orglett.0c01213

pubs.acs.org/OrgLett
Letter
Asymmetric Transfer Hydrogenation of o‑Hydroxyphenyl Ketones:
Utilizing Directing Effects That Optimize the Asymmetric Synthesis
of Challenging Alcohols
Ye Zheng, Guy J. Clarkson, and Martin Wills*
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ABSTRACT: A systematic range of o-hydroxyphenyl ketones were
reduced under asymmetric transfer hydrogenation conditions using
the C3-tethered catalyst 2. Two directing effects, i.e., an o-
hydroxyphenyl coupled to a bulky aromatic on the opposite side of
the ketone substrate, combine in a matched manner to deliver
reduction products with very high enantiomeric excess.
symmetric transfer hydrogenation (ATH) of ketones
Ausing [(arene)Ru(TsDPEN)Cl]-type catalysts such as 1
or tethered derivatives such as 2 or 3 (Figure 1A) is now a
well-established method for the enantioselective synthesis of
alcohols.1 In most cases, a combination of formic acid and
trimethylamine (FA/TEA, typically a 5:2 azeotrope) is used as
the reducing agent and solvent. Although acetophenone
derivatives, which contain a combination of an aromatic ring
and an alkyl group flanking the ketone, are the most commonly
studied targets (Figure 1B),1,2 there remains a need to expand
the methodology to more challenging substrates.3 For some
time,1b it has been known that electronic differences alone can
exert some control over the reduction of benzophenones by
complex 1 and its derivatives (Figure 1B). In recent research,
Ikariya and co-workers reported the ATH of benzophenones
using catalyst 3 and found that the addition of an ortho
substituent to one of the aromatic rings flanking the ketone
resulted in the formation of products with very high ee (Figure
1B).4 The increased enantioselectivity is believed to arise
through an out-of-plane orientation of the hindered group that
results in its positioning distal to the η6-arene ring of the
catalyst (Figure 1C).5 The same principles of electronic- and
steric-driven differentiation have also been applied to the
reductions of aromatic/2-pyridyl (and closely related) ketones
to good effect by Zhou et al.6
Although we used the “3C-tethered” complex 2 throughout
the study,1 we also employed “benzyl-linked” 4,8a “OMe-
substituted” 5,8b and the untethered “Ru/TsDPEN” catalyst
6,1 all of which have previously been either used and/or
developed in our research group (Figure 2). The (R,R) forms
of catalysts 2, 4, and 5 were used, but the (S,S) enantiomer of
6 was employed.
In the ATH of o-hydroxyacetophenones and o-methoxyace-
tophenones, the former are reduced using (R,R)-2 with
typically >98% ee2b and the latter with ca. 70−80% ee,9
although there are some exceptions.8b While an o-methoxy
group may result in the movement of an aryl group out of the
plane with the ketone, an o-hydroxyphenyl group will remain
in-plane because of its lower steric demand and the potential
hydrogen bond between the OH and the ketone.
Asymmetric reductions of a systematic range of o-
hydroxyphenyl ketones 7a−k were carried out in DCM (to
aid solubility) with a catalyst loading of 1 mol % at rt to give
products 8a−k (Figure 3. Alcohol 8a was formed with 73.4%
ee in the S configuration, which was confirmed by comparison
of chiral HPLC and optical rotation data with the reported
details for this compound.9a In contrast, 2-(hydroxy(phenyl)-
methyl)phenol 8b generated by ATH using the same catalyst
(R,R)-2 was formed as the R enantiomer with 80% ee, and the
configuration was confirmed by comparison of the HPLC data
The related reductions of propargylic ketones containing a
hindered ortho-substituted aromatic ring with high enantio-
meric excesses operate through an analogous directing effect.7
Herein we report a systematic study of substrates containing
the o-hydroxyphenyl group. We demonstrate how the correct
choice of substituents can be used to deliver products with very
high enantiomeric excess, including examples that would
otherwise be very difficult to access by other methods.
Received: April 6, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01213
© XXXX American Chemical Society
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Figure 1. (A) [(arene)Ru(TsDPEN)Cl] complexes for ATH. (B)
Reductions of acetophenone and benzophenone derivatives using
[(arene)Ru(TsDPEN)Cl] complexes ((R,R)-configured ligand) cata-
lysts such as 1−3. (C) Mode of hydrogen transfer for each class of
substrate.
Figure 3. General procedure for ATH of o-hydroxyphenyl ketones
using (R,R)-2 and the products obtained. The alcohol products are
illustrated with the right-hand ring being the one closest to the η6-
arene ring of the catalyst during the reduction (Figure 4).
Figure 2. Other ATH catalysts employed in this study.
to those reported.9b The configuration was also confirmed by
methylation of our sample of (R)-8b to afford (R)-(2-
methoxyphenyl)(phenyl)methanol 8a (see the Supporting
Information). With knowledge of the individual, and opposite,
directing effects of o-OH and o-OMe on benzophenone
reduction, it was gratifying to find that 7c, containing both
groups, was reduced to 8c with an exceptionally high 99% ee.
The X-ray crystallographic structure (see the Supporting
Information) revealed the expected S configuration of the
product, presumably formed through reinforcement of the
individual directing effects of each substituent. The other
catalysts were tested for the reduction of 7c and gave less
satisfactory results (Figure 3B); even at extended reaction
times of 168 h (7 days), the reductions were incomplete, and
the ee’s were lower. Finally within this series, the reduction of
7d to product 8d with a much lower 64% ee served to confirm
that it is the steric effect of the o-OMe in 7c that improves the
ee, not its high electron density. In fact, as illustrated by 7d,
increasing the electron density of the ring opposing the the o-
hydroxyphenyl serves to reduce the enantioselectivity of the
ATH reaction.
and another sterically demanding ortho-substituted ring in the
substrate deliver the products with the highest ee. For product
8e, formed with 93% ee, the X-ray structure confirmed the S
configuration (see the Supporting Information). Tests of other
catalysts were completed on 7e, and the products were formed
with full conversion but slightly lower ee’s. In this case, the less
electron-rich opposing ring does not create a significant
countereffect to the ee if the chlorine is at the para position
(8f), and even the o-OMe substrate can deliver the product 8g
with good ee (an X-ray structure confirmed the S
configuration; see the Supporting Information). The high
ee’s of 99% for o-bromo product 8h and 97.2% for 1-naphthyl-
substituted 8i also highlight the potential for excellent ee when
a hindered arene is present in the substrate. Furan-containing
substrates can also give alcohols with good ee when an
opposing bulky substituent is present in the substrate (67−
81% ee for 8j) but essentially no selectivity if the furan opposes
an o-hydroxyphenyl (racemic formation of 8k).
The results indicate that the electron-donating o-hydrox-
ylphenyl group makes its aryl ring more electron-rich without
distorting the geometry of the ketone, possibly maintaining it
via a hydrogen bond to the ketone. This favors electrostatic
In further tests with chlorine-substituted substrates, the
configurations and ee’s of products 8e−g reveal the same
pattern, in which the combination of one o-hydroxyphenyl ring
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interaction with the η6-arene ring of the catalyst in the ATH in
the proposed reduction transition state. A bulky ortho
substituent on the opposing aromatic ring, however, forces
that ring out of plane and provides an additional directing
effect in the reduction step (Figure 4).
Figure 4. Proposed approach of the substrate to catalyst (R,R)-2 for
the formation of 8c, 8e, 8h, and 8i. The combination of one o-
hydroxyphenyl group opposing a hindered aryl ring delivers products
with the highest ee.
The high ee’s of products 8c, 8e, 8h, and 8i also follow what
would be predicted from the general model (Figure 4). Using
catalyst (R,R)-2 in the ATH of (2-chlorophenyl)(2-
methoxyphenyl)methanone gave 8g with 86% ee. In this
case, the high ee likely derives from the electronic differences
between the arene rings, even though both contain an ortho
substituent (the MeO-substituted ring adopts the position
adjacent to the η6-arene ring).
In an illustration of the application of the methodology to an
otherwise challenging ATH product, alcohol product (R)-8l
was prepared by ethylation of (S)-8c, which had been obtained
from ATH with 99% ee (Figure 5A). The ee of 8l was
Figure 6. Extension of the o-hydroxyphenyl directing group to a
broader range of substrates 7m−s and comparisons.
However, the reduction to 8n was achieved with full
conversion and a much higher enantioselectivity of 94% ee,
which illustrates that the o-hydroxyphenyl group can be
successfully combined within a highly hindered substrate to
good effect. The importance of the hydroxyl group itself to the
high enantioselectivity was underlined by the lower ee’s (and
incomplete conversions) obtained for products 8o and 8p,
which contain equally electron-rich substituents in varying
positions on the aromatic ring. Additionally, the amide-
containing ketone 7q (Figure 6C) was reduced to 8q with 87%
ee, which is high for a complex and sterically hindered
substrate of this type. In contrast, the o-methoxy ketone 7r
gave product 8r with just 11% ee and very low conversion
(20%), reflecting its hindered nature. However, 8r was formed
with 86% ee by O-methylation of 8q, again reflecting the value
of the o-hydroxy directing group route for the synthesis of a
product that would otherwise be essentially inaccessible with
high ee by direct ATH of a precursor.
Figure 5. Synthesis of 8l with high ee can be achieved via the o-
hydroxyphenyl intermediate but not by direct reduction of the direct
precursor ketone.
measured as 97%; the slight decrease was due to a small
amount of racemization. Notably, the same alcohol (R)-8l was
produced with just 13% ee by direct ATH of ketone 7l (Figure
5B). This result underlines the value of the o-hydroxy directing
effect and its application to the highly enantioselective
synthesis of a product (8l) that would otherwise be extremely
difficult to generate with high ee by direct reduction or other
synthetic approaches.
Given the results above, and having established the
requirements for high enantioselectivity in reductions, we
investigated the compatibility of the o-hydroxyphenyl-directed
approach with a broader range of substrates (Figure 6). ATH
of the corresponding amide-containing substrate 7m gave the
product 8m with moderate enantioselectivity (61% ee),
ATH of o-aminophenyl containing ketone 7s with catalyst
(R,R)-2 gave the alcohol product 8s with the R configuration
(Figure 6D, confirmed by comparison of the optical rotation to
the published value) but only 46% ee, indicating that a free o-
amino group is less effective in directing benzophenone ATH
than the o-hydroxyphenyl group.
Catalysts (R,R)-2 and 4−6 were also employed in the
asymmetric reduction of imines 9−11 derived from o-
hydroxyphenyl ketones. An excellent precedent for this class
of substrate was reported by Mangion et al.,10 and we took the
opportunity to investigate its scope (Figure 7).
The ATH of imines 9−11 was carried out using ammonium
formate in DCM (70 °C, sealed tube)10 in order to avoid
hydrolysis, following the literature procedent. Full reduction of
C
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Figure 8. (A) Potential route to 16 from ketone 17 related to those in
this report. (B) Conversion of 8h to the phenyl-substituted derivative
18.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01213.
Synthesis procedures, crystallographic data, NMR
spectra, and HPLC chromatograms related to ee and
dr determination (PDF)
Accession Codes
Figure 7. Imines 9−11 and reduction products of all imines
investigated. Reduction was carried out using ammonium formate
in DCM at 70 °C in a sealed tube overnight.
CCDC 1978883−1978886 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
imine 9 was obtained using all four catalysts in ATH reactions,
and the ee’s of asymmetric amine 12 were good in all cases
apart from catalyst 6, which gave a product with lower ee.
Catalyst (S,S)-2 gave a product with ee essentially identical to
that obtained using the (R,R) catalyst. The product
configuration follows that reported by Mangion et al. for the
reduction of the molecule, which provided a precedent for our
study.10 However, only catalyst (R,R)-2 gave 100% conversion
of imine 10 to amine 13, which had 75% ee; the other three
catalysts did not give any conversion. For imine 11 bearing the
larger groups on both sides of the ketone, no catalysts were
effective. Two more chiral amines, 14 and 15, both containing
chloro-substituted aromatic rings, were formed by reduction of
the precursor imines with full conversions and excellent ee’s.
Following the earlier precedents, the o-chlorophenyl product
was formed with higher ee than the p-chlorophenyl product,
reflecting the additional steric directing component in addition
to the difference in electron density between the two aromatic
rings flanking the ketone. The reduction of the imine derived
from o-hydroxyacetophenone was not successful (see the
Supporting Information).
AUTHOR INFORMATION
Corresponding Author
■
Martin Wills − Department of Chemistry, The University of
Warwick, Coventry CV4 7AL, U.K.; orcid.org/0000-0002-
1646-2379; Email: m.wills@warwick.ac.uk
Authors
Ye Zheng − Department of Chemistry, The University of
Warwick, Coventry CV4 7AL, U.K.
Guy J. Clarkson − Department of Chemistry, The University of
Warwick, Coventry CV4 7AL, U.K.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01213
Notes
The authors declare no competing financial interest.
The research data (and/or materials) supporting this
publication can be accessed at http://wrap.warwick.ac.uk/.
The reductions have the potential to create enantiomerically
enriched precursors to otherwise challenging synthetic targets.
For example, compound 16, a sphingosine 1-phosphate
receptor inhibitor,11 could potentially be prepared from a
precursor such as 17. The potential for this is demonstrated by
the conversion of enantiomerically enriched 8h to compound
18 using a Suzuki reaction (Figure 8) with only a small loss of
ee.
ACKNOWLEDGMENTS
■
The X-ray diffraction instrument was obtained through the
Science City Project with support from Advantage West
Midlands (AWM) and funded in part by the European
Regional Development Fund (ERDF). The catalysts (R,R)-
and (S,S)-2 used in this project were a generous gift from
Johnson Matthey CCT.
In conclusion, hindered ketones and imines can be reduced
effectively in ATH using a range of catalysts, provided that an
o-hydroxyphenyl ring opposes a sterically hindered aromatic
ring on the substrate. The low conversions and ee’s of
asymmetric reduction of certain direct ketone substrates can in
several cases be improved by generating the product via the
corresponding o-hydroxyphenyl ketones. Where tested, (R,R)-
2 proved to be the best catalyst of the series used here.
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