Enantioselective Transfer Hydrogenation of Ketones Catalyzed by a Manganese Complex Containing an Unsymmetrical Chiral PNP′ Tridentate Ligand

Article abstract of DOI:10.1002/cctc.201700042

Manganese complexes of the types [Mn(PNP′)(Br)(CO)₂] and [Mn(PNP′)(H)(CO)₂] containing a tridentate ligand with a planar chiral ferrocene and a centro chiral aliphatic unit were synthesized, characterized, and tested in the enantiose

Full text of DOI:10.1002/cctc.201700042

Accepted Article
Title: Enantioselective Transfer Hydrogenation of Ketones Catalyzed
by a Manganese Complex Containing an Unsymmetrical Chiral
PNP′ Tridentate Ligand
Authors: Afrooz Zirakzadeh, Sara R. M. M. de Aguiar, Berthold Stöger,
Michael Widhalm, and Karl Kirchner
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10.1002/cctc.201700042
ChemCatChem
COMMUNICATION
Enantioselective Transfer Hydrogenation of Ketones Catalyzed by
a Manganese Complex Containing an Unsymmetrical Chiral PNP′
Tridentate Ligand
Afrooz Zirakzadeh,*[a] Sara R. M. M. de Aguiar,[a] Berthold Stöger,[b] Michael Widhalm,[c] Karl
Kirchner,*[a]
Abstract: Manganese complexes of the types [Mn(PNPʹ)(Br)(CO)2]
and [Mn(PNPʹ)(H)(CO)2] containing a tridentate ligand with a planar
chiral ferrocene and a centro chiral aliphatic unit were synthesized,
characterized and tested in enantioselective transfer hydrogenations
of 13 ketones. The catalytic reactions proceed with conversions up to
96% and e.e. values of up to 86%. The absolute configuration of all
products was determined to be (S). It has to be noted that the
presence of dihydrogen (up to 20 bar) did not affect the reduction.
Based on DFT calculations preliminary mechanistic details including
the origin of the (S)-selectivity are presented. The molecular structure
of [Mn(PNPʹ)(Br)(CO)2] was studied by X-ray diffraction.
chiral ferrocene and a centro chiral aliphatic unit which are
connected through an imino nitrogen.
Results and Discussion
Synthesis of (R,R,SFc)-2. Treatment of Mn(CO)5Br with 1.1
equivalents of the ligand (R,R,SFc)-1 in dioxane afforded the bis-
carbonyl complex [Mn(PNPʹ)(Br)(CO)2] (R,R,SFc)-2 in essentially
1
quantitative yield (Scheme 1). The H and 31P{1H} NMR spectra
of the crude reaction mixture revealed the presence of two
isomers (ratio: 4:1). The major isomer (R,R,SFc)-2a could be
purified by crystallization and its structure was unequivocally
determined by X-ray crystallography. A molecular view of
(R,R,SFc)-2a is depicted in Figure 1 with selected bond distances
and angles given in the caption. The 31P{1H} NMR spectrum
contained two doublets centered at 54.4 and 86.1 ppm with a 2JPP
coupling constant of 97 Hz. In the IR spectrum two strong ѵCO
absorptions at 2022 and 1927 cm-1 were observed.
In recent years, research in the field of hydrogenation catalysis for
the synthesis of enantiopure alcohols and amines in the
pharmaceutical, fragrance and fine chemical industries for
economic reasons as well as the idea of developing green and
environmentally friendly catalysts has moved towards developing
complexes with non-platinum group metals such as iron and
manganese.[1-12] To date, efficient manganese catalysts have
been developed by Beller,[10] Milstein[11] and Kempe[12] for
hydrogenations and transfer hydrogenations of ketones,
aldehydes, nitriles and esters but none of them are
enantioselective. Very recently, as part of our continuing search
for novel asymmetric hydrogenation catalysts, we reported a
group of chiral PNPʹ pincer ligands with a ferrocene-aliphatic
scaffold which were tested in the asymmetric hydrogenation of
ketones in the presence of an iron center.[13] Of all the ligands
tested, (R,R,SFc)-1 performed best and the enantioselectivities of
up to 81% e.e. were obtained. Hence, we were curious to
ascertain whether our new ferrocenyl-containing 6.5.-ring PNPʹ
ligands (Scheme 1) could be transformed into active precatalysts
of the type [Mn(PNPʹ)(Br)(CO)2] and [Mn(PNPʹ)(H)(CO)2] for the
asymmetric reduction of ketones. Herein, we report the first
asymmetric transfer hydrogenations of ketones with manganese
complexes of chiral PNPʹ pincer ligands consisting of a planar
Scheme 1. Synthesis of [Mn(PNPʹ)(Br)(CO)2] (R,R,SFc)-2.
[a]
Dr. A. Zirakzadeh, S. R. M. M. de Aguiar, Prof. Dr. K. Kirchner
Institute of Applied Synthetic Chemistry
Vienna University of Technology
Figure 1. Structural view of (R,R,SFc)-2a showing 50% thermal ellipsoids (most
H atoms and solvent molecules are omitted for clarity). Selected bond lengths
(Å) and bond angles (°): Mn1–Br1 2.5541(8), Mn1–C39 1.778(5), Mn1–C40
1.771(5), Mn1–P1 2.318(1), Mn1–P2 2.281(1), Mn1–N1 2.098(4), P1–Mn1–Br1
92.37(4), P2–Mn1–Br1 91.39(4), P1–Mn1–N1 95.4(1), P2–Mn1–N1 80.1(1),
Br1–Mn1–N1 85.6(1), P1–Mn1–P2 173.92(5).
Getreidemarkt 9, A-1060 Vienna
E-mail: afrooz.zirakzadeh@tuwien.ac.at, karl.kirchner@tuwien.ac.at
Dr. B. Stöger
Institute of Chemical Technologies and Analytics
Vienna University of Technology
Getreidemarkt 9, A-1060 Vienna
[b]
[c]
Prof. Dr. M. Widhalm
Institute of Chemical Catalysis
University of Vienna
Währinger Straße 38, A-1090 Vienna
Synthesis of (R,R,SFc)-3. Manganese hydride complexes of the
type [Mn(PNPʹ)(H)(CO)2] ((R,R,SFc)-3) were synthesized by
treatment of (R,R,SFc)-2a with NaBH4 in EtOH at room
Supporting information for this article can be found under:
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10.1002/cctc.201700042
ChemCatChem
COMMUNICATION
1
temperature for 2 hours (Scheme 2). The H NMR spectrum of
(R,R,SFc)-3 confirmed the presence of two hydride species in a ca.
6:1 ratio exhibing signals at -3.8 and -4.9 ppm as well-resolved
ratio of 100/1/4. It was observed that the product enantiomeric
excess was slightly dependent on the reaction time due to product
racemization. Therefore, the maximum product e.e. values
obtained at the given reaction time are listed together with the
corresponding conversion. The results for 13 substrates are
provided in Table 2. The best results were obtained with the
acetophenone and para-substituted acetophenones. In these
cases e.e. values of up to 85% were observed at nearly
quantitative yield. The influence of para-substituents turned out to
be small. Moreover, (R,R,SFc)-2a was found to catalyze also the
reduction of phenyl ethyl ketone and phenyl benzyl ketone with
high conversions and e.e. values of 82-84% (Table 2, entries 8
and 9). In case of 1-tetralone and acetylferrocene a significant
drop in conversion and e.e’s was observed (Table 2, entries 11
and 12). The absolute configuration of all products was
determined to be (S).
2
triplets with JHP coupling constants of 19.7 and 47.0 Hz,
respectively. These isomers could not be separated and attempts
to obtain crystals suitable for an X-ray diffraction study were
unsuccessful. The 31P{1H} NMR spectra revealed two doublets
centered at 75.6 and 107.4 ppm with a 2JPP coupling constant of
56 Hz for the major isomer and two doublets centered at 83.4 and
2
109.3 ppm with a JPP of 57 Hz for the minor isomer. In the IR
spectrum the strong bands for the CO stretching frequencies
appeared at 1918 and 1853 cm–1 for the major isomer. The
structures of the two possible cis-CO isomers (R,R,SFc)-3a and
(R,R,SFc)-3b were established by DFT calculations and are
depicted in Figure 2. It was found that (R,R,SFc)-3b is slightly more
stable than (R,R,SFc)-3a which may suggest that the latter is the
experimentally observed major isomer which, in fact, possess
different configuration at the metal center than (R,R,SFc)-2a.
Table 1. THY and HY results obtained for acetophenone with complexes
(R,R,SFc)-2a and (R,R,SFc)-3.a
S/C
Pressure
Base
Time
%
%
e.e.b
entry
complex
ratio
(bar)
equiv.
(h)
conv.
1
2
(R,R,SFc)-2a
(R,R,SFc)-2a
(R,R,SFc)-2a
(R,R,SFc)-3
(R,R,SFc)-3
(R,R,SFc)-3
(R,R,SFc)-2a
(R,R,SFc)-2a
(R,R,SFc)-2a
(R,R,SFc)-2a
(R,R,SFc)-3
(R,R,SFc)-3
(R,R,SFc)-3
(R,R,SFc)-3
(R,R,SFc)-2a
(R,R,SFc)-2a
(R,R,SFc)-3
(R,R,SFc)-3
100/1
100/1
100/1
100/1
100/1
100/1
100/1
100/1
100/1
100/1
100/1
100/1
100/1
100/1
200/1
200/1
200/1
200/1
0
5
4
4
4
4
4
4
8
4
2
0
8
4
2
0
4
4
4
4
5
5
5
2
2
2
5
5
5
5
2
2
2
2
5
5
2
2
95
95
95
96
96
96
95
95
93
–
85
85
85
86
86
86
79
85
85
0
3
20
0
4
5
5
Scheme 2. Preparation of monohydride complexes (R,R,SFc)-3a and (R,R,SFc)-
3b.
6
20
0
7
8
0
9
0
10
11
12
13
14
15
16
17
18
0
0
97
96
93
5
81
86
86
-
0
0
0
0
80
80
89
88
85
85
85
85
20
0
Figure 2. Energies (kcal/mol) for the optimized structures of the two isomers
[Mn(PNPʹ)(H)(CO)2] (R,R,SFc)-3a and (R,R,SFc)-3b (most hydrogen atoms
omitted for clarity).
20
a Reaction conditions: Acetophenone (1 mmol), iPrOH (5 mL), 25 °C. b determined by GC on
a Beta DexTM 110 (30 m) column.[14]
Catalysis. The catalytic activities of (R,R,SFc)-2a and (R,R,SFc)-3
(as a mixture of (R,R,SFc)-3a and (R,R,SFc)-3b) were investigated
in the asymmetric transfer hydrogenation (THY) and asymmetric
hydrogenation under transfer hydrogenation conditions (HY) of
acetophenone as a function of dihydrogen pressure, amount of
Mechanistic and Theoretical Investigations. To gain insight
into a possible mechanism of this THY, NMR investigations were
carried out by treating complex (R,R,SFc)-2a with tBuOK in iPrOH
(and 5% THF-d8) at room temperature. After 2 hours, the
formation of the hydride complexes (R,R,SFc)-3a and (R,R,SFc)-
3b was observed by 1H and 31P{1H} NMR spectroscopy. In
addition, a third minor species was detected in the 31P{1H} NMR
spectrum giving rise to doublets centered at 110.2 and 74.0 ppm
i
base, and substrate-to-catalyst ratio (S/C) in PrOH (Table 1).
Interestingly, it turned out that dihydrogen does not have any
influence on the conversion and the e.e. values. In fact, in the
absence of dihydrogen the same conversions and e.e’s were
found (Table 1, entries 1-6) and, thus, this process clearly
proceeds exclusively via transfer hydrogenation. Complex
(R,R,SFc)-3 as compared to (R,R,SFc)-2a led to a faster THY
process and after 2 hours (instead of 5 hours) the product was
obtained with 95% conversion and 86% e.e. For both complexes
base was necessary and in the absence of base no conversion
was observed. Since with (R,R,SFc)-2a and (R,R,SFc)-3 similar
results were obtained the more easily accessible complex
(R,R,SFc)-2 was used as precatalyst for substrate screening. All
reactions were carried out at room temperature with S/C/base
2
with a JHP coupling constant of 70.2 Hz (Figure S10). This
species could as yet not be identified.
Based on the experimental findings, the catalytic reaction
clearly proceeds via a monohydride complex. Moreover, it
seemed likely the hydrogen transfer proceeds through an outer
sphere pathway taken into consideration the inertness of bis-
carbonyl Mn(I) complexes as found for several related Mn(I)
systems utilized in hydrogenation/dehydrogenation reactions
recently.[10-12,15-17] Whether or not this reaction proceeds via metal
ligand bifunctional catalysis cannot be unequivocally established
as yet. Preliminary DFT calculations reveal that the formation of
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10.1002/cctc.201700042
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the hydride complex (R,R,SFc)-3a by reacting the cationic complex
[Mn(PNPʹ)(CO)2]+ (A) (formed upon liberation of the bromide
ligand of (R,R,SFc)-2a in the presence tBuOK in alcoholic
solutions) with isopropoxide is very facile as shown in Figure 3.
The hydrogen transfer reaction proceeds in an outer sphere
fashion without ligand participation with a barrier of only 4.9
kcal/mol and the reaction is exothermic by -21.5 kcal/mol. The
approach of the alkoxide is guided by a weak hydrogen bonding
between the acidic C-H bond adjacent to the PPh2 moiety of the
ligand and the oxygen atom of the isopropoxide.
Based on these results, the (S)-selectivity of the catalytic
reaction may be explained, on the one hand, by hydrogen bonding
between the ligand and the oxygen atom of the substrate together
with steric restrictions on the other hand. This is demonstrated for
acetophenone in Figure 4. In the case of isomer (R,R,SFc)-3a (a,b)
a Re-face approach of the ketone to the hydride ligand is feasible
as it minimizes unfavorable steric interactions, while a Si-face
approach due to steric repulsions between the phenyl substituent
of acetophenone and a Cp ring of the ferrocenyl moiety is highly
unlikely. Moreover, this reaction is facilitated by a weak hydrogen
bonding, which is not possible for isomer (R,R,SFc)-3b (c,d). In the
case of (R,R,SFc)-3b, the steric repulsion allows only for a Si-face
attack of the ketone. Accordingly, we believe that the key
intermediate for the THY process is the hydride complex
(R,R,SFc)-3a.
Table 2. THY results obtained with complex (R,R,SFc)-2a.a
entry
time (h)
% conv.
% e.e.b
substrate
1
5
95
85
2
3
4
5
6
16
16
5
73
77
94
90
95
65
69
83
76
84
5
5
7
8
5
6
96
93
62
58
60
85
84
82
79
46
9
6
10
11
16
16
12
13
16
5
37
80
20
74
a Reaction conditions: Substrate (1 mmol), catalyst (0.01 mmol), KOtBu (0.04 mmol), iPrOH (5
mL), 25 °C. b ACP, 2-F-ACP, 2-Cl-ACP, 4-CF3-ACP, 4-MeO-ACP, 4-Me-ACP, PEK and TETN
determined by GC on a Beta DexTM 110 (30 m) column and PBK and DPP determined by
HPLC on a Chiralcel OD-H column. AcFc determined by HPLC on a Chiralcel OJ column.[14]
Figure 3. Energy profile (in kcal/mol) for the reaction of the cationic
[Mn(PNPʹ)(CO)2]+ fragment (A) with isopropoxide to give the acetone adduct of
(R,R,SFc)-3a (denoted as B) (in iPrOH as solvent).
Conclusions. We have developed the first enantioselective
transfer hydrogenation of ketones catalyzed by a well-defined Mn-
based complex. Key intermediates are two isomeric bis-carbonyl
Mn(I) hydride complexes of the type [Mn(PNPʹ)(H)(CO)2]
((R,R,SFc)-3a,b) which are readily prepared from the
corresponding
bromide
compound
[Fe(PNPʹ)(Br)(CO)2]
((R,R,SFc)-2a) upon treatment with NaBH4. These complexes
contain a ligand with a planar chiral ferrocene and a centro chiral
aliphatic unit. All complexes were tested in the asymmetric
transfer hydrogenation of ketones and gave similar conversion
and enantioselectivity. Since (R,R,SFc)-2a is more readily
accessible from a synthetic point of view, transfer hydrogenations
of 13 ketones were performed with this catalyst precursor under
mild condition at room temperature in the presence of tBuOK. The
catalytic reactions proceed with conversions up to 96% and e.e.
values of up to 86%. The absolute configuration of all products
was determined to be (S). It has to be noted that the presence of
dihydrogen (up to 20 bar) did not affect the reduction. Based on
Figure 4. Re and Si-face addition of acetophenone to the two isomers (R,R,SFc)-
3a (a, b) (R,R,SFc)-3b (c, d). View along the C (acetophenone)-H-Fe-CO axis.
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[18] (a) M. Mastalir, M. Glatz, N. Gorgas, B. Stöger, E. Pittenauer, G.
Allmaier, L. F. Veiros, K. Kirchner, Chem. Eur. J. 2016, 22,
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Allmaier, K. Kirchner, J. Am. Chem. Soc. 2016, 138, 15543–
15546.
DFT calculations preliminary mechanistic details including the
origin of the (S)-selectivity are presented. More detailed
explorations on the mechanism are in progress.
Supporting Information. Experimental procedure, spectral and
complete crystallographic data and technical details in CIF format
for (R,R,SFc)-2a (CCDC entry 1435577). This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgements. Financial support from the Austrian
Science Fund (FWF) is gratefully acknowledged (Projects T631-
N28 and P29584-N28). The authors wish to express sincere
appreciation and gratitude to Professor Walter Weissensteiner for
his kind support and helpful discussions and comments during the
course of this research. The X-ray center of Vienna University of
Technology is also acknowledged for financial support and for
providing access to the single-crystal diffractometer.
Keywords: Chiral ligands, Manganese, Hydride complexes,
Ferrocenes, Asymmetric transfer hydrogenation.
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Entry for the Table of Contents (Please choose one layout)
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Author(s),
Afrooz Zirakzadeh, Sara R. M. M. de
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The first enantioselective transfer hydrogenation of ketones catalysed by a well-defined
Mn-based complex containing a chiral PNPʹ pincer ligand with a planar chiral ferrocene
and a centro chiral aliphatic unit is reported. The asymmetric transfer hydrogenation
reactions procced under mild conditions with conversions up to 96% and e.e. values of
up to 86%.
Title
Enantioselective
Transfer
Hydrogenation of Ketones Catalyzed by
a Manganese Complex Containing an
Unsymmetrical Chiral PNP′ Tridentate
Ligand
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