Molecularly Defined Manganese Pincer Complexes for Selective Transfer Hydrogenation of Ketones

Article abstract of DOI:10.1002/cssc.201601057

For the first time an easily accessible and well-defined manganese N,N,N-pincer complex catalyzes the transfer hydrogenation of a broad range of ketones with good to excellent yields. This cheap earth abundant-metal based catalyst provides access to useful secondary alcohols without the need of hydrogen gas. Preliminary investigations to explore the mechanism of this transformation are also reported.

Full text of DOI:10.1002/cssc.201601057

DOI: 10.1002/cssc.201601057
Communications
Very Important Paper
Molecularly Defined Manganese Pincer Complexes for
Selective Transfer Hydrogenation of Ketones
Marc Perez, Saravanakumar Elangovan, Anke Spannenberg, Kathrin Junge, and
[a]
Matthias Beller*
For the first time an easily accessible and well-defined manga-
nese N,N,N-pincer complex catalyzes the transfer hydrogena-
tion of a broad range of ketones with good to excellent yields.
This cheap earth abundant-metal based catalyst provides
access to useful secondary alcohols without the need of hydro-
gen gas. Preliminary investigations to explore the mechanism
of this transformation are also reported.
The development of benign catalytic transformations that are
in accordance with the principles of green chemistry is ongo-
[1]
ing goal for both academic and industrial researchers. As an
example, the reduction of C=O bonds evolved from the use of
stoichiometric reducing agents, such as metal hydrides to the
application of catalysts. In this field, mainly two reactions are
Figure 1. Structure of the complexes used in our investigations.
[
2]
commonly employed, namely hydrogenation and transfer hy-
In preliminary experiments, transfer hydrogenation of aceto-
phenone was investigated as a benchmark test system using
3 mol% of complexes 1–5 in the presence of tBuOK and iPrOH
(Table 1). To exclude well known base-catalyzed transfer hydro-
[
3]
drogenation. The latter one is operationally simple and in-
trinsically safe, avoiding pressurized hydrogen. Until today,
transfer hydrogenation of carbonyl compounds mainly relies
[
4]
[5]
[6]
[14]
on precious metal-based catalysts, such as Ru, Rh, Os, or
genation of ketones a control experiment was performed
[
7]
Ir, which are expensive and raise toxicity concerns. To circum-
vent these problems, base metal complexes have been devel-
with 10 mol% tBuOK yielding only 10% conversion after 24 h
at 708C (Entry 1). Under the same conditions, the addition of
complex 1 led to an encouraging yield of 70% of the corre-
sponding alcohol (Entry 2). Using complex 2 bearing a central
pyridine backbone had a detrimental effect on reactivity
(Entry 3). In the presence of other PNP pincer-type complexes,
[
8]
[9]
oped using either Fe or Co. Among the different first-row
transition metals, currently also Mn-based catalysts are emerg-
[
10]
ing, but their applications are still limited. For example, the
reduction of polar double bonds by Mn-based catalysts is limit-
[
11]
ed to reductive amination of ketones with Eco-Mnꢀ and the
[
12]
hydrosilylation of carbonyl compounds.
Very recently, we established the first hydrogenation of ke-
tones, aldehydes, nitriles, and esters as well as the hydrogen-
borrowing alkylation of amines with alcohols in the presence
[
a]
Table 1. Manganese-catalyzed transfer hydrogenation of acetophenone.
[
13]
of Mn. Based on these works, we became interested in the
development of more operator-friendly Mn-based transfer hy-
drogenations. Here, we present our findings using well-defined
Mn pre-catalysts 1–5 (Figure 1) in combination with inexpen-
sive isopropanol as the hydrogen source.
[
b]
[c]
Entry
Complex [mol%]
tBuOK [mol%]
Conv. [%]
Yield [%]
1
2
3
4
5
6
7
8
9
none
1 (3)
2 (3)
3 (3)
4 (3)
5 (3)
4 (1)
5 (1)
5 (1)
5 (1)
6 (1)
10
10
10
10
10
10
10
10
10
2
10
74
8
n.d.
70
n.d.
90
91
91
n.d.
90
n.d.
96
95
96
96
24
96
[
a] Dr. M. Perez, S. Elangovan, Dr. A. Spannenberg, Dr. K. Junge, Prof. M. Beller
Leibniz-Institut fꢀr Katalyse e.V. an der Universitꢁt Rostock
Albert-Einstein Straße 29a
Rostock 18059 (Germany)
E-mail: matthias.beller@catalysis.de
[d]
0
Supporting Information and the ORCID identification number(s) for the
author(s) of this article can be found under http://dx.doi.org/10.1002/
cssc.201601057.
10
11
96
96
2
96
[
2
a] Reaction conditions: acetophenone (0.5 mmol), iPrOH (2.5 mL), 708C,
4 h. [b] Conversion was determined by GC. [c] GC yield. [d] Reaction run
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such as 3 and 4, phenylethanol was obtained in up to 91%
[
a]
Table 2. Transfer hydrogenation of ketones with complex 5.
yield (Entries 4 and 5). Finally, using the phosphine-free com-
[
15]
plex 5 excellent yields were reached as obtained with the
best PNP-based complex 4 (Entry 6).
To evaluate the most efficient precatalyst, experiments were
conducted at a lower catalyst loading of 4 and 5. Interestingly,
in the presence of 1 mol% of 4 the catalytic activity complete-
ly dropped down, while complex 5 still afforded 96% conver-
sion and 90% yield (Entries 7 and 8). However, attempts to
conduct the reaction at room temperature left the starting ma-
terial untouched (Entry 9). Noteworthy, the base concentration
could be reduced to 2 mol% without affecting the catalytic ac-
tivity and affording the product with almost quantitative con-
version in 96% yield (Entry 10).
[
b]
Entry
1
Substrate
Product
Conv. [%] Yield [%]
[
e]
96
96
97
86
96
91
90
84
2
3
4
After establishing optimal conditions, we investigated the
substrate scope of this first Mn-catalyzed transfer hydrogena-
tion reaction. As shown in Table 2, 5 is an efficient precatalyst
for the reduction of a variety of (hetero)aromatic and aliphatic
ketones. Acetophenone derivatives bearing electron-donating
substituents were effectively converted to the corresponding
alcohols with yields ranging from 84% to 91% (Entries 2–5).
Various halogen containing substrates produced the desired al-
cohols with yields up to 99% (Entries 6–9). Other electron-poor
aromatic ketones were also tested in the reaction to investi-
gate the chemoselectivity of the catalyst (Entries 10–12). Grati-
fyingly, nitrile and ester functionalities are not reduced and led
to the 1-phenylethanol analogues with excellent yields al-
though transesterification is being observed (Entries 10 and
[
c]
5
6
7
8
9
97
84
79
95
99
91
99
97
>99
>99
>99
>99
[
[
c]
c]
12). 1,4-Diacetylbenzene was reduced to the corresponding
diol in 72% yield (Entry 11) next to the monoalcohol (18%
yield). Using longer reaction times (48 h) led to an increased
ratio of diol/alcohol of 95:5. Other aromatics ketones such as
10
2
-acetonaphthone and benzophenone were suitable for this
reaction delivering the reduced products with yields reaching
8% (Entries 13 and 14). Furthermore, a number of aliphatic
ketones were investigated (Entries 16–19).
-Nonanone was reduced to the corresponding alcohol in
[
c]
c]
1
1
>99
>99
72
96
9
5
[
moderate yield (64%; Entry 16). On the other hand, cyclic ke-
tones, such as cyclohexanone or 1-ethyl-4-piperidone, could be
transformed to the corresponding alcohols in high to excellent
yields of 90% and 85%, respectively (Entries 17 and 18). The
synthesis of the later product is of relevance as it serves as
a key intermediate in the production of Genentech ’s GDC-
12
1
3
4
95
95
98
1
>99
0425 an inhibitor of ChK1 (Checkpoint Kinase 1) that is being
currently investigated in clinical phase I for the treatment of
[
[
c]
c]
[
16]
15
77
73
64
90
cancer.
Noteworthy, dihydro-b-ionone, an aliphatic ketone
containing an alkene function, was reduced to the correspond-
ing alcohol in 97% without affecting the alkene moiety
1
1
6
7
96
(Entry 19). Finally, the catalytic system also promoted the re-
>99
duction of heteroaromatic ketones (Entries 20–23), although
a higher metal loading was required to achieve high conver-
sions and excellent yields. Surprisingly, aldehydes were found
[
d]
[
17]
18
>99
>99
90
97
to be unreactive under our reaction conditions.
After studying the scope and limitation of the reaction, we
explored the mechanism of this novel Mn-catalyzed transfer
hydrogenation process. To distinguish between the possible
[
c]
19
[
18]
monohydride and dihydride pathways, the reaction was per-
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ing Information for details). Surprisingly, also complex 6 was
active in the transfer hydrogenation of acetophenone yielding
comparable results to 5 (Table 1, Entries 10 and 11). Neverthe-
less, when 6 was engaged in the same deuterium labelling ex-
periment as 5, a strong kinetic isotope effect was observed
with the corresponding alcohol being isolated in only 49%
yield also with no noticeable D incorporation in the a-position
Table 2. (Continued)
Entry Substrate
[
b]
Product
Conv. [%] Yield [%]
[
c]
c]
[e]
2
0
1
97
96
93
[
2
>99
(
Scheme 1). Obviously, cooperation of the NH moiety with the
metal center is not mandatory for the Mn-catalyzed transfer
hydrogenation of ketones and activation of the benzylic hydro-
gen atoms might take place similar to other pyridine-type PNP
[
c]
c]
2
2
2
3
>99
>99
97
96
[21]
complexes.
[
In conclusion, we have developed the first transfer hydroge-
nation of ketones using an earth abundant Mn-based complex.
Notably, no phosphine ligands are required to stabilize this cat-
alyst, instead a commercially available tridentate amine pro-
vides sufficient stability and activity. The mild reaction condi-
tions are tolerant towards various functional groups and offer
an efficient route towards valuable secondary alcohols, which
make it a promising alternative to previously reported proce-
dures. More detailed explorations on mechanism are in prog-
ress.
[
a] Reaction conditions: substrate (0.5 mmol), complex 5 (0.005 mmol),
tBuOK (0.01 mmol), iPrOH (2.5 mL), 708C, 24 h. [b] Conversion was deter-
mined by GC. Isolated yield is given. [c] Reaction conditions: substrate
(
7
0.50 mmol), complex (0.025 mmol), tBuOK (0.030 mmol), iPrOH (2.5 mL),
08C, 24 h. [d] Isolated as the HCl salt. [e] GC yield.
formed using deuterated isopropanol as the hydride source.
The corresponding deuterated 1-phenylethanol was formed in
8
5% isolated yield with no noticeable D incorporation in the
1
2
[9,19]
a-position as judged by H and H NMR (Scheme 1).
This
result indicates that the reaction does not proceed through Experimental Section
the formation of Mn-dihydride species, but through a monohy-
General procedure for the catalytic transfer hydrogenation: Mn
dride mechanism.
complex 5 (0.005 mmol) was placed in a Schlenk tube (25 mL)
under Ar. Then, dry isopropanol (2.5 mL) was added by syringe.
After addition of potassium tert-butoxide (0.01 mmol), the mixture
was stirred for 5 min at room temperature. The ketone (0.5 mmol)
was added in one portion and the reaction vessel was placed at
7
08C for 24 h in a preheated alloy block. After this period of time,
the reaction was left to cool at room temperature. An aliquot was
taken for determination of conversion by GC analysis, the mixture
was concentrated using a rotary evaporator. Purification by silica
gel column chromatography afforded the corresponding alcohol.
Scheme 1. Deuterium labelling experiments.
In this monohydride mechanism the hydrogen transfer can
proceed through an inner or an outer sphere pathway. For the
later one, metal ligand bifunctional catalysis is discussed, Acknowledgements
where the hydrogen is transferred in a concerted or stepwise
[
20]
manner. To elucidate a possible participation of the central
NÀH moiety of the ligand in catalyst 5, this position was
blocked by methylation. The introduction of an alkyl group in
this position is expected to shut down the catalytic activity in
case of an outer sphere mechanism involving the NÀH group.
To confirm this hypothesis, the methyl substituted complex 6
was tested in the catalytic reaction (Figure 2, see the Support-
The analytic department of LIKAT is acknowledged for excellent
analytical and technical support.
Keywords: homogeneous catalysis · ketones · manganese
complex · pincer ligands · transfer hydrogenation
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Received: August 2, 2016
Published online on && &&, 0000
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Broad application: A manganese com-
plex is applied for the first time in the
transfer hydrogenation of a broad varie-
ty of ketones with 2-propanol in good
to excellent yields and excellent chemo-
selectivity. The mild reaction conditions
are tolerant towards various functional
groups and offer an efficient route to-
wards valuable secondary alcohols,
which make it a promising alternative
to previously reported procedures.
M. Perez, S. Elangovan, A. Spannenberg,
K. Junge, M. Beller*
&& – &&
Molecularly Defined Manganese
Pincer Complexes for Selective
Transfer Hydrogenation of Ketones
ChemSusChem 2016, 9, 1 – 5
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ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ