Chemoselective Luche-Type Reduction of α,β-Unsaturated Ketones by Magnesium Catalysis

Article abstract of DOI:10.1021/acs.orglett.9b03131

The chemoselective reduction of α,β-unsaturated ketones by use of an economic and readily available Mg catalyst has been developed. Excellent yields for a wide range of ketones have been achieved under mild reaction conditions, short times, and low catalyst loadings (0.2-0.5 mol %).

Full text of DOI:10.1021/acs.orglett.9b03131

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Chemoselective Luche-Type Reduction of α,β-Unsaturated Ketones
by Magnesium Catalysis
Yoon Kyung Jang,† Marc Magre,*,† and Magnus Rueping*,†,‡
†Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
‡KAUST Catalysis Center (KCC), King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi
Arabia
S
* Supporting Information
ABSTRACT: The chemoselective reduction of α,β-unsaturated ketones by use of an economic and readily available Mg
catalyst has been developed. Excellent yields for a wide range of ketones have been achieved under mild reaction conditions,
short times, and low catalyst loadings (0.2−0.5 mol %).
Table 1. Reaction Optimization for the Mg-Catalyzed
Hydroboration of Enone 1a
raditionally, the selective reduction of α,β-unsaturated
TCO bonds has been achieved using stoichiometric
amounts of metal hydrides,1 such as NaBH4 and stoichiometric
amounts of Lewis acid, for instance, CeCl3·7H2O in the Luche
reduction (Scheme 1a).2 Additionally, transition-metal-cata-
lyzed high-pressure hydrogenations have been applied.3,4 In
this respect, in recent decades, the use of pinacolborane
(HBpin) as a mild and sustainable carbonyl group reductant
has attracted attention.5,6 While the hydroboration of polarized
bonds such as ketones and aldehydes has been achieved, the
reduction of α,β-unsaturated ketones remains challenging due
to problems associated with the chemoselectivity (CO vs
unsaturated CC bond reduction).5
a
b
entry
MgBu2 (mol %)
solvent
yield (%)
1
2
3
4
5
6
7
2
2
2
1
toluene
THF
DCM
toluene
toluene
toluene
toluene
>95
>95
>95
>95
>95
0.5
0.2
none
95 (93)
0
The application of alkaline-earth abundant metals in
catalysis has attracted interest as an alternative to transition-
metal-catalyzed processes.7−9 In spite of their abundance in the
Earth’s crust, low toxicity, and low cost, their application has
a
General conditions: 1a (0.5 mmol), HBpin (1.5 equiv), MgBu2 (0.5
b
M heptane solution), solvent (1 M), 23 °C for 90 min. Yields
determined by H NMR using 1,3,5-trimethoxybenzene as internal
1
standard. Isolated yield in parentheses.
Scheme 1. MgBu2-Catalyzed Chemoselective
Hydroboration of Ketones
been limited to a few catalytic transformations.7 In this regard,
magnesium catalysis has been limited to the hydrofunctional-
ization of polarized and unpolarized unsaturated bonds.10−12
However, a general and synthetically applicable magnesium-
catalyzed hydroboration protocol for the chemoselective
reduction of both enones and ynones and propargylic ketones
with low catalyst loading has not been reported. Recently, we
developed the selective hydroboration of terminal and internal
Received: September 3, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03131
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Scope for the MgBu2-Catalyzed Hydroboration
of Enones
Scheme 3. Scope and Limitations for the MgBu2-Catalyzed
Hydroboration of Propargylic Ketones
a
a
a
General conditions: 3a−3h (0.5 mmol), HBpin (1.5 equiv), MgBu2
(0.2 mol %, 0.5 M heptane solution), solvent (1 M), 23 °C for 2 h.
b
1
Isolated yields. Yield determined by H NMR of the boronic ester.
c
d
MgBu2 (0.5 mol %). MgBu2 (0.5 mol %) for 5 h.
Scheme 4. Large-Scale Transformation
a
General conditions: 1a−1r (0.5 mmol), HBpin (1.5 equiv), MgBu2
(0.2 mol %, 0.5 M heptane solution), solvent (1 M), 23 °C for 90
b
c
min. Isolated yields. MgBu2 (0.5 mol %) for 2 h. Yield determined
d
by 1H NMR of the boronic ester. Diastereoselectivity determined by
1H NMR. Absolute configurations were determined by comparison
e
with literature values. 2.5 equiv of HBpin was used.
alkynes using low-cost and commercially available MgBu2 as an
efficient catalyst.13 Despite the circumstances where the latter
reaction allowed the reduction of carbon−carbon multiple
bonds, we decided to examine a chemoselective magnesium-
catalyzed reduction of enones and ynones since a successful
accomplishment of such a method would be a valuable
alternative to the existing protocols. Hence, chemoselectivity
would be the key to a successful development of such a
protocol.
Herein, we present the application of readily available
MgBu2 as an efficient catalyst for the chemoselective
hydroboration of α,β-unsaturated ketones. Moreover, we
prove that MgBu2 is not only active for the hydroboration of
alkynes but can also be chemoselective toward CO
reduction for propargylic ketones by fine-tuning the reaction
conditions (Scheme 1b).
We started our investigation by using MgBu2 as catalyst,
HBpin as reducing agent, and ketone 1a as model substrate
(Table 1). Different solvents were examined at ambient
temperature (Table 1, entries 1−3). However, we found that
the choice of solvent had no influence on the catalytic activity.
We were pleased to see that the catalyst loading could be
decreased (Table 1, entries 4−6) to yield product 2a
quantitatively by using only 0.2 mol % of MgBu2. In the
absence of the catalyst (Table 1, entry 7) no desired product
was observed.
With the optimized conditions in hand, we decided to study
the scope and limitations of our catalytic system (Scheme 2).
The good performance observed for benzylideneacetone 1a
could be extended to other substrates with different electronic
and steric properties (1b−1d). In this case, allylic alcohols
2b−2d were isolated in excellent yields. Likewise, we observed
that trans-chalcone 1e underwent reduction selectively and in
excellent yields. We also studied various α,β-unsaturated
ketones containing a substituent in the α-position (1f−1l).
The presence of different electronic and steric substituents in
the aromatic ring (1f−1k) and the α-position (1l) did not
dramatically affect the selective reduction, affording the
corresponding allylic alcohols (2f−2l) in good-to-excellent
yields. We also tested our MgBu2−HBpin catalytic system for
the selective reduction of cyclic α,β-unsaturated ketones. In all
cases (2m−2o), excellent yields and selectivities could be
achieved for 5- and 6-membered rings and also with a
substituent present in the β-position. Finally, we studied the
selective hydroboration of natural α,β-unsaturated ketones
such as (1S)-(−)-verbenone 1p, (−)-carvone 1q, and
testosterone 1r. We were pleased to see that in all cases the
corresponding allylic alcohols could be isolated in good-to-
B
DOI: 10.1021/acs.orglett.9b03131
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
regenerates active BuMgH A species to afford the correspond-
ing boronic ester D which undergoes hydrolysis in the
presence of methanol, providing the allylic or propargylic
alcohols 2 and 4.
Scheme 5. Control Experiment and Proposed Mechanism
for the MgBu2-Catalyzed Chemoselective Hydroboration of
α,β-Unsaturated Ketones
In summary, we report a Luche-type reduction of α,β-
unsaturated ketones catalyzed by low cost and commercially
available MgBu2. Good yields and chemoselectivities have been
achieved for a wide range of ketones, including linear and
cyclic substrates and natural products, showing the great
versatility and group tolerance that the MgBu2−HBpin system
presents. Moreover, the low catalyst loading (0.1−0.5 mol %)
and the short reaction times highlight the high activity of the
Mg catalyst for the reduction of enones as well as ynones, and
thus, the method represents a valuable alternative to existing
procedures.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03131.
Experimental procedures, characterization and NMR
spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: marc.magre@oc.rwth-aachen.de.
excellent yields, chemoselectivities, and diastereoselectivities.
We were delighted to see that our commercially available
alkaline earth metal-based catalyst competes favorably with the
best reports to date using transition-metal catalysts.6 Thus, we
decided to expand the catalytic system by testing the reduction
of propargylic ketones (Scheme 3).
*E-mail: magnus.rueping@rwth-aachen.de.
ORCID
Yoon Kyung Jang: 0000-0002-9227-8995
Magnus Rueping: 0000-0003-4580-5227
Notes
We observed that the Mg-catalyzed hydroboration of
propargylic ketones was effective for a wide range of substrates,
bearing different aromatic (3a−3c) as well as alkyl groups
(3d). We also found out that propargylic ketones bearing
different silyl groups (3e−3f) were tolerated. Finally, we could
also demonstrate the high chemoselectivity of MgBu2, by
selectively reducing substrates 3g and 3h bearing not only an
alkynyl but also an alkenyl group. In both cases, excellent
chemoselectivities were obtained.
Previously, our group demonstrated the high activity that
commercially available MgBu2 presents toward the hydro-
boration of terminal and internal alkynes.13 Herein, we prove
that by fine-tuning the reaction conditions MgBu2 can also be
selective toward CO reduction for propargylic ketones.
The practical applicability of the MgBu2−HBpin catalytic
system is demonstrated by performing the chemoselective
reduction of model substrate benzylideneacetone 1a at a 10
mmol scale (Scheme 4). In this case, by using only 0.1 mol %
of low cost MgBu2, allylic alcohol 2a can be isolated in
quantitative yield after 3 h.
Regarding the mechanism, when mixing MgBu2 and HBpin,
an active BuMgH species is formed along with BuBpin
(Scheme 5a). Thus, we propose a mechanism for the
chemoselective magnesium-catalyzed hydroboration of unsa-
turated ketones as depicted in Scheme 5b. Commercially
available MgBu2 A reacts with HBpin to generate active
BuMgH species B. This active species undergoes hydro-
magnesiation of CO bond of ketone 1 or 3, providing the
corresponding Mg alkoxide species C. Finally, HBpin
The authors declare no competing financial interest.
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DOI: 10.1021/acs.orglett.9b03131
Org. Lett. XXXX, XXX, XXX−XXX