Asymmetric Transfer Hydrogenation of Ketones Using New Iron(II) (P-NH-N-P′) Catalysts: Changing the Steric and Electronic Properties at Phosphorus P′

Article abstract of DOI:10.1002/ijch.201700019

The asymmetric transfer hydrogenation (ATH) of ketones is an efficient method for producing enantio-enriched alcohols which are used as intermediates in a variety of industrial processes. Here we report the synthesis of new iron ATH precatalysts (S,S)-[FeBr(CO)(Ph₂PCH₂CH₂NHCHPhCHPhNC=CHCH₂PR′₂)][BPh₄] (R′=Et, and ortho-tolyl (o-Tol)) where one of the phosphine groups is modified with small alkyl and large aryl substituents to probe the effect of this change on the activity and selectivity of the catalytic system. A simple reversible equilibrium kinetic model is used to obtain the initial TOF and the inherent enantioselectivity S=k_R/k_S of these catalysts along with those for the previously reported catalysts with R′=Ph and Cy for the ATH of acetophenone. With an increase in the size of the PR′₂ group, the TOF goes through a maximum at PPh₂ while the S value goes through a maximum of 510 at R′=Cy. The complex with R′=o-Tol starts with a high S value of 200 but is rapidly changed to a second catalyst with an S value of 28. For the reduction of acetophenone to (R)-1-phenylethanol, turnover numbers of up to 5200 and ee up to 98 % were achieved. The chemotherapeutic pharmaceutical precursor (R)-(3′,5′-bis(trifluoromethyl))-1-phenylethanol is synthesized in up to 95 % ee. Several other alcohols can be prepared in greater than 90 % ee by choosing the precatalyst with the correctly matched steric properties. A hydride complex derived from the catalyst with R′=Cy is characterized by NMR spectroscopy. It is proposed that low concentration trans-hydride carbonyl complexes with the FeH parallel to the NH of the ligand are the active catalysts in all of these systems.

Full text of DOI:10.1002/ijch.201700019

Full Paper
DOI: 10.1002/ijch.201700019
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Asymmetric Transfer Hydrogenation of Ketones Using New
Iron(II) (P-NH-N-P’) Catalysts: Changing the Steric and
Electronic Properties at Phosphorus P’
Samantha A. M. Smith,[a] Demyan E. Prokopchuk,[a] and Robert H. Morris*[a]
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Abstract: The asymmetric transfer hydrogenation (ATH) of goes through a maximum of 510 at R’=Cy. The complex with
ketones is an efficient method for producing enantio- R’=o-Tol starts with a high S value of 200 but is rapidly
enriched alcohols which are used as intermediates in a changed to a second catalyst with an S value of 28. For the
variety of industrial processes. Here we report the synthesis reduction of acetophenone to (R)-1-phenylethanol, turnover
of new iron ATH precatalysts (S,S)-[FeBr(CO)(Ph2PCH2CH2 numbers of up to 5200 and ee up to 98% were achieved. The
NHCHPhCHPhNC=CHCH2PR’2)][BPh4] (R’=Et, and ortho- chemotherapeutic pharmaceutical precursor (R)-(3’,5’-bis(tri-
tolyl (o-Tol)) where one of the phosphine groups is modified fluoromethyl))-1-phenylethanol is synthesized in up to 95%
with small alkyl and large aryl substituents to probe the effect ee. Several other alcohols can be prepared in greater than
of this change on the activity and selectivity of the catalytic 90% ee by choosing the precatalyst with the correctly
system. A simple reversible equilibrium kinetic model is used matched steric properties. A hydride complex derived from
to obtain the initial TOF and the inherent enantioselectivity the catalyst with R’=Cy is characterized by NMR spectro-
S=kR/kS of these catalysts along with those for the previously scopy. It is proposed that low concentration trans-hydride
reported catalysts with R’=Ph and Cy for the ATH of carbonyl complexes with the FeH parallel to the NH of the
acetophenone. With an increase in the size of the PR’2 group, ligand are the active catalysts in all of these systems.
the TOF goes through a maximum at PPh2 while the S value
Keywords: homogeneous catalysis · iron catalysis · asymmetric transfer hydrogenation
31 1. Introduction
32
33 The asymmetric reduction of ketones is a challenging process
34 that is useful for many industries including pharmaceutical
35 and fine chemical. Usually precious-metal-based catalysts are
36 employed.[1] The use of abundant metals such as iron for this
37 transformation is attractive due to their lower cost and toxicity,
38 and this has been a topic of much interest in the last decade.[2]
39 Recently discovered iron catalysts stand out for their high
40 enantioselectivity and activity in the asymmetric transfer
41 hydrogenation of ketones.[2b,c,m,3]
Figure 1. Three generations of ATH Precatalysts.
42
The activity and selectivity of our iron-based ATH
whether some of the complexes with R=alkyl were inactive
due to a high energy barrier to the reduction of the imine of
the ligand that is needed for activation or due to a higher
barrier for catalysis after imine reduction. The work described
below helps to answer this question.
The design of the third generation precatalysts C (Fig-
ure 1) eliminates this activation barrier by providing the
amine-imine ligandstructure. This dramatically increases the
43 catalysts (Figure 1) has steadily improved using the reduction
44 of acetophenone by isopropanol as a test case. Our first
45 generation ATH precatalyst (R,R)-A in isopropanol produced,
46 after activation by isopropoxide, (S)-1-phenylethanol in 63%
47 ee (TOF 400, TON 1630 hÀ1 at 248C)[2h,4] although this ATH
48 system likely involves iron nanoparticles.[5] Kinetic and
49 mechanistic studies uncovered a high energy barrier for the
50 activation of our more active second generation ATH
51 precatalysts B that involved the reduction of one of the imine
52 groups of the B.[2i,l,3a] Our group conducted a stereo-electronic
53 study of complexes B that involved varying the substituents R
54 of the phosphine moieties of the PÀN-NÀP ligand and found
55 that only the use of aryl groups led to very active catalysts for
56 the ATH of ketones.[6] It was unclear from these studies
[a] S. A. M. Smith, D. E. Prokopchuk, R. H. Morris
Department of Chemistry, University of Toronto, 80 Saint George
St. Toronto, Ont. Canada M5S 3H6
E-mail: rmorris@chem.utoronto.ca
Supporting information for this article is available on the WWW
under https://doi.org/10.1002/ijch.201700019
Isr. J. Chem. 2017, 57, 1–13
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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ATH activity of the catalyst systems in basic isopropanol
when aryl groups are on the phosphine donors. The ATH of
acetophenone catalyzed by C1 (R=R’=Ph) produces (R)-1-
phenylethanol in 78% ee (R) with a turnover number (TON)
of 5000 and turnover frequency (TOF) 100,000 hÀ1 at 288C
while that by C2 gives 90% ee (R).[3b] The use of other aryl
ketones yielded alcohols with ee greater than 90% (R) in
certain cases.[3b,7] The initial work showed that a complex
could be prepared with phosphorus donors with different
Herein, we introduce two other PR’2 substituents into the
Fe(II) complexes trans-[FeBr(CO)(PPh2ÀNHÀNÀPR’2)]+, the
small, basic PEt2 donor and the large, less basic P(o-Tol)2
donor while keeping the PPh2 group constant. This work
explores a wider range of stereochemical and electronic
properties in order to better understand the relationship
between the structures and the resulting activity and enantiose-
lectivity of the catalysts for the reduction of a variety of
ketone structures. Simulating the reaction progress of the
reductions also sheds light on the factors that determine how
quickly the ee of the product alcohol is lost after the reaction
reaches equilibrium. We also investigate the properties of the
active hydride-containing species.
10 groups on each side, namely C3 with R=Ph, R’=4-MeC6H3.
11 The C3 system reduced acetophenone with comparable
12 activity to C1 but with lower enantioselectivity, 70% ee (R).[3b]
13
Complex C4 with R=Ph and R’=Cy (Figure 2) was
14 found to be more stereoselective but much less active for
15 ketone reduction than C1-C3.[3c] For example the C4 system
16 catalyzed the reduction of acetophenone to (R)-1-phenyl-
2. Results and Discussion
17 ethanol in 98% ee.[3c] The complex was assumed to have a
18 trans configuration shown on the left of Figure 2. Recently,
2.1 Preparation and Characterization of Complexes
19 C4 was crystallized and was found to adopt an unexpected
20 cis-b geometry (Figure 2, right).[8] An objective of the current
21 work is to investigate whether this cis-b geometry is of
22 relevance to the activity and selectivity of C4 relative to C1.
The syntheses of the new iron(II) precatalysts were carried out
using routes developed in our lab previously.[3b,6b,9] Complexes
(S,S)-1 with R’ =Et and (S,S)-2 with R’=o-Tol were
synthesized using the enantiopure (S,S)-PPh2CH2CH2
NHCHPhCHPhNH2 compound and the phosphonium dimers
D1 or D2,[10] respectively, in two main steps (Scheme 1).
First an intermediate complex is made in situ by the
reaction of the appropriate phosphonium dimer with base,
Fe(II), and an enantiopure (S,S)-PNN ligand in acetonitrile.
On the basis of previous work[3b,6b,9] this is assumed to be a
trans-bis(acetonitrile) complex. This is then treated with 1 atm
CO and excess KBr. The complexes (S,S)-1 and (S,S)-2 were
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À
precipitated as the BPh4 salts in 35 and 56% yield,
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respectively, with respect to the starting (S,S)-P-NH-NH2
compound. Complex (S,S)-1 was produced as a mixture of
two trans diastereomers with structures E and E’ (Figure 3)
with 31P{1H} NMR properties very similar to C1 and C4 in
Figure 2. Previously proposed and recently discovered geometries of
C4 with a cis-b stereochemistry
Samantha Smith studied Honours Chemistry
and Mathematics as a double major at Wilfrid
Laurier University where she was first exposed
to research. She continued on to the University
of Toronto’s Department of Chemistry where
she is currently working on a Ph. D.
chemistry for applications in small molecule
activation.
Bob Morris is a professor of chemistry at the
University of Toronto. He was born in Ottawa
in 1952. He received his PhD from the
University of British Columbia in 1978. After
postdoctoral work at the Nitrogen Fixation
Laboratory, University of Sussex and the Penn-
sylvania State University he joined the faculty
of the University of Toronto in 1980. He was
appointed full Professor there in 1989 and
served as Acting Chair and Chair of the
Chemistry Department from 2008–2013. His
research interests include inorganic, organic
and catalytic chemistry with applications in the
fine chemical industry. He is a Fellow of the
Royal Society of Canada and of the Chemical
Institute of Canada and a Killam Research
Fellow (2015-2017).
Demyan Prokopchuk was born in Saskatoon,
Canada. He received his undergraduate degree
from the University of Saskatchewan in 2009
and his PhD from the University of Toronto in
2015 under the supervision of Prof. Robert
Morris. He is currently a postdoctoral fellow at
Pacific Northwest National Laboratory in the
Center for Molecular Electrocatalysis, directed
by R. Morris Bullock. His current research
interests include ligand design and electro-
Isr. J. Chem. 2017, 57, 1–13
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One relatively broad (w1/2 20 cmÀ1) CO absorption (nCO) is
observed in the IR spectrum for the iron(II) complexes as
mixtures of isomers as listed in Table 2 for the two complexes
as well as the complexes C1 and C4 for comparison (Table 2).
Only one peak maximum representing an averaged electronic
property of the various isomers present is reported because
separate peak maxima were not resolved. There is no clear
trend in the nCO values. The steric parameters of the PR’2CH2-
group can be expressed in terms of Tolman’s cone angles q of
the corresponding PR’2Et ligands as also listed in Table 2.[11]
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Table 2. Stereoelectronic effects represented by Tolman’s cone angle
and IR wavenumbers of the CO ligand.
Complex PR’2
IR nCO (cmÀ1
)
Tolman’s Cone Angle (q)[a]
(S,S)-1
C1-Br[b]
C4
PEt2
PPh2
PCy2
1956
132
141
157
173
1979[b]
1960
Scheme 1. The two-step synthesis of complexes (S,S)-1 and (S,S)-2
(S,S)-2
Po-Tol2 1963
[a] Cone angle of R’2PEt representing the PR’2CH2 fragment of the
complex. [b] Like C1 from Figure 1, but synthesized with a bromo
instead of a chloro ligand for better comparison.
Figure 3. Geometries of the trans tetradentate complexes.
2.2 Analysis of the Structures of the Isomers in Solution
29 addition to a small fraction (17%) of two other isomers with
30 poorly resolved doublet resonances at 62, 59 and 55 ppm
31 (Table 1). These minor isomers might have the cis-b geo-
32 metries shown in Figure 2 but this could not be definitively
33 established. Similarly (S,S)-2 appears to have two trans
34 isomers (75% of mixture) and at least one additional isomer at
35 58 and 63 ppm in the 31P{1H} NMR spectrum. Each
Complex C3 has been characterized crystallographically in the
trans configuration with the NH locked anti with respect to
the hydrogen of the adjacent CHPh group with (S) chirality as
shown in Figure 1. All of the 43 racemic or enantiopure dpen
metal derivatives in the Cambridge Crystallographic Databank
have the NH and CH locked anti except for isomer C4-SNH
(see the Supporting information). The similarity of the NMR
spectra of complexes C1 to C3 suggest that the major isomers
all have this trans structure as do a wide variety of more
symmetrical trans-[Fe(CO)Br(PR2-NÀN-PR2)]+ complexes re-
ported by our group with a wide range of substituents (Et, Cy,
aryl).[2l,6]
2
36 diastereomer has a characteristic set of doublets with JPP
37 ranging from 33 to 41 Hz (see Table 1). The use of the R’=iPr
38 substituent led to a complex mixture of products. Attempts to
39 make a complex with R’=3,5-(CF3)2C6H4 by adapting a
40 template synthesis method under acidic conditions[6b] also led
41 to a complex mixture. These will not be discussed here.
42
The cis-b structure of C4 in the solid state introduces
another possibility for structural assignments and it has been
observed in related iron and ruthenium complexes with
tetradentate phosphorus and nitrogen ligands[2b,12]. However in
solution the main isomer of C4 (75%) has the trans
configuration with either the NH next to the CO ligand
(structure E) or the Br ligand (E’) as in Figure 3. This is
determined by assigning all of the protons around the back-
bone of the ligand using 2D NMR experiments and spin
simulations and demonstrating the similarity to the proton
spectra of trans complex C1 (see the Supporting Information).
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Table 1. 31P{1H} NMR resonances of the trans isomers of C1, C4,
(S,S)-1 and (S,S)-2 with structures E or E’ of Figure 3.
Complex PR’2
Isomer PR’2
fraction (ppm)
(%)
PPh2
(ppm)
2JPP
(Hz)
Struct.
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54
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C1
C4
PPh2 100
PCy2 75
62.6
58.0
47.3
59.3
53.7
55.4
40
33
38
36
41
E
78.4
65.1
67.1
61.6
E or E’
E’ or E
E or E’
E or E’
(S,S)-1-1 PEt2
(S,S)-1-2 PEt2
(S,S)-2-1 Po-
Tol2
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3
In particular the JHH coupling constants of the PPh2CH2CH2
NH part of the ligand backbone should be sensitive to the
differences in dihedral angles between the trans and the cis-b
configurations where this part of the tetradentate ligand that
(S,S)-2-2 Po-
Tol2
34
63.7
54.1
39
E’ or E
3
folds away from the PNN plane. The simulated JHH couplings
Isr. J. Chem. 2017, 57, 1–13
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are similar for the C1, (S,S)-1 and C4 isomers in the assigned
trans-configuration. The large JHH coupling (12-14 Hz)
(Figure 6). C4 and (S,S)-2 were again slower than (S,S)-1 at
reducing acetophenone; however the ee for C4 was much
higher (98% R) at maximum conversion. The reaction slows
after 40% conversion and attains only 80% of the possible
conversion at 120 min. This is also true for (S,S)-2. This is
attributed to some modification of the active catalyst over
time. (S,S)-2 produces the alcohol in 89% ee (R) after 120
minutes. (S,S)-1 has the higher activity to a maximum
conversion of 87% after 50 min, but also a lower ee of 85%.
For comparison C1 with PPh2 groups produces 1-phenethanol
at 82% ee at the time of maximum conversion.[3b]
3
indicative of anti-vicinal CH groups in the trans structure is
present in the 1H spectra of all of these compounds. The minor
isomer of C4 with 31P{1H} NMR signals at 76.0 and 75.5 ppm
probably has a cis-b-C4 structure, but it is in too low a
concentration to provide definitive proton assignments. In
another sample prepared for HMBC NMR analysis, another
trans-isomer, (E or E’) with 31P{1H} NMR resonances at 73.0
2
10 (d) and 51.8 ppm (d, JPP 35 Hz) was also observed. Thus the
11 PPh2CH2CH2 arm of C4 is mobile and allows a switch that is
12 slow on the NMR timescale between the structures shown in
The reaction progress and changes in ee for the ATH of
acetophenone (AP) were semi-quantitatively fit for the first
time to a simple kinetic model[13] for a reversible equilibrium
using the program Dynafit[14] (Figures 7–10). The progress of
the reactions catalyzed by (S,S)-1, (S,S)-2, C1 and C4 were fit
to only three parameters: two rate constants kR and kS for
pseudo first order reactions producing (R)- and (S)-1-phenyl-
ethanol (abbreviated RPE and SPE, respectively) and one
equilibrium constant (Krac =2kR/k-R =2kS/k-S) for the reversible
reaction of acetophenone with isopropanol to give 1-phenyl-
ethanol and acetone. The same Krac =12 applies to all of the
reactions of Figures 5 and 6. From the rate constants the
intrinsic enantioselectivity of the catalyst is obtained (S=kR/
kS).[13] The value of S determines the initial ee of the system.
The initial TOF is given by (kR +kS)[AP]/[Cat] and the initial
e.e. (%) is given by 100(kR-kS)/(kR +kS) = 100(S-1)/(S+1).
This simple approach makes the following assumptions:
1. The forward reaction to produce RPE is first order in AP
with a steady-state catalyst concentration included in the
rate constant kR.
13 Figure 2.
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1
A H-31P HMBC experiment and spin simulations were
15 used to assign the structures of the trans isomers of complex
16 (S,S)-1, although it was not possible to distinguish which of
17 the two diastereomers was E vs E’ of Figure 3 (PR’2 =PEt2).
18 Table 1 lists the 31P{1H} chemical shifts and coupling
19 constants of these isomers. Obtaining good NMR spectra for
20 (S,S)-2 was challenging but its 31P{1H} NMR spectra appear
21 to be similar to those of (S,S)-1.
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2.2 Catalytic Results
2.2.1 Acetophenone Reduction and Reaction Progress
27 Modelling
28
29 The ATH of acetophenone (Figure 4) was carefully examined
30 for catalysts (S,S)-1, (S,S)-2 as well as C1 and C4 for
31 comparison under a range of conditions.
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2. The forward reaction to produce SPE is first order in AP
with a steady-state catalyst concentration included in the
rate constant kS.
3. At equilibrium, the concentrations of RPE and SPE will be
equal (0 ee) and the equilibrium constant will be Krac
=
2KR =2KS =12.0 for the conditions described here.
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4. The backward reaction to produce AP from RPE is first
order in RPE with a steady-state catalyst concentration
included in the rate constant k-R =kR/KR =2kR/Krac.
5. The backward reaction to produce AP from SPE is first
order in SPE with a steady-state catalyst concentration
included in the rate constant k-S =kS/KS =2kS/Krac.
Assumptions 4 and 5 explain why the ee of the product
degrades with the progress of the reaction if kS is non-
negligible.
The model was validated using data from the well-defined
catalyst C1 (Figure 7). The parameters obtained are listed in
Table 3. Catalyst C1 with two moderately sized PPh2 groups
has an extremely high TOF of 250 sÀ1 as documented
elsewhere[3b] and an inherent selectivity S of 12, resulting in a
starting ee of 85% which degrades to 78% at maximum
conversion at 120 s. The experimental ee have larger
uncertainties early in the reaction because of the low
concentration of the (S)-1-phenylethanol in the sample but the
model fits the general trends in the ee.
Figure 4. Conditions for the ATH of acetophenone.
Initial catalytic reactions were done with acetophenone
42 (K1) with a precatalyst/KOtBu/substrate ratio (C/B/S) of 1/2/
43 500 with [K1] 0.70 M in iPrOH at 288C. Figure 5 shows that
44 complexes (S,S)-1 with the small PEt2 group reduces
45 acetophenone to 1-phenylethanol to the equilibrium point of
46 86% conversion with a high initial TOF of approx. 12 sÀ1 as
47 determined by reaction profile fitting (see below). The
48 conversion can be increased to over 90% by using a lower
49 concentration of ketone (e.g. 0.1 M). The complexes C4 and
50 (S,S)-2 with bulkier PCy2 and Po-Tol2 groups have lower
51 initial TOF and lose activity before reaching equilibrium. On
52 the other hand the last two complexes maintain a high ee in
53 the product while (S,S)-1 has significant losses in ee over time
54 because of its poor selectivity. There is less ee degradation
55 over the course of the reaction when using a lower catalyst
56 loading[3b] with the C/B/S ratio 1/8/6121 with [ketone] 0.63 M
Isr. J. Chem. 2017, 57, 1–13
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Figure 5. ATH of acetophe-
none (K1) with (S,S)-1,
(S,S)-2 and C4. Reaction
conditions: 288C, 1.43
10À3
M
precatalyst, 2.8
x10À3
M KOtBu, 0.70 M
acetophenone,
6 mL
iPrOH, C/B/S=1/2/500;
% conversion and % ee
determined by chiral GC.
Figure 6. ATH of K1 with
(S,S)-1, (S,S)-2 and C4. Re-
action conditions: 288C,
1.03 10À4
M
precatalyst,
83 10À4 M KOtBu, 0.63 M
acetophenone, 6 mL
iPrOH, C/B/S=1/8/6121;
% conversion and % ee
determined by chiral GC.
The fits to the reaction progress for (S,S)-1 (Figure 8)
value of 99% R over the course of the first 250 seconds. This
is modelled by a more enantioselective catalyst (S=200)
being completely replaced by a less selective one (with S=28)
over this time period. This is likely to be caused by the
dissociation and repositioning of the bulky CHCHP(o-Tol)2
arm of the ligand in an as-of-yet, undefined way. Complex C4
with the slightly smaller PCy2 group is more stable and
produces the alcohol in exceptionally high ee up to maximum
conversion.
48 show that this system is slower (TOF 14 sÀ1) than C1 but more
49 enantioselective (S 20). Thus there are dramatic effects in
50 changing one PPh2 (on C1) with one PEt2 group.
51
(S,S)-2 and C4 do not fit the simple model (Figures 9 and
52 10). The reactions slow more than expected with conversion
53 and this indicates that the catalyst concentration is being
54 reduced over the course of the catalytic run. This may be due
55 to inhibition due to binding of the product alcohol. It is
56 interesting that for (S,S)-2, the ee drops rapidly from a high
Isr. J. Chem. 2017, 57, 1–13
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Figure 7. (Left) Kinetic fit to the changes in concentration in the ATH of acetophenone catalyzed by C1. (Right) Fit to the changes in ee for the
reaction.
25 Table 3. Results of fitting the reaction profiles.1
while no induction period is observed for the catalyst systems
discussed here.
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Catalyst kR (sÀ1) kS (sÀ1) TOF (sÀ1) S
ee
ee
TON
However as far as the intrinsic enantioselectivity S is
concerned, it rises from less than 20 for the smaller
substituents (PEt2, PPh2) to a maximum of 510 for bulky PCy2
(98% ee) and then falls again to 200 and then to 28 for the
very bulky Po-Tol2 as discussed above (Figure 12).
initial (at time
(% R) in min)
C12
3.6e–2 3.2e–3 235
12 85
78 (2)
80 (40)
93 (4)
5900
5000
500
(S,S)-1 2.1e–3 1.1e–4 14
20 90
200 99
28 92
(S,S)-23 4.0e–4 2.0e–6
6
3
3
(S,S)-23 4.1e–4 1.7e–5
90 (90)
3700
C4
4.5e–4 1e–6
510 99.6 98.5 (120) 4400
2.2.2 Other Substrates
1
[FeBr(CO)(PR’2CH2CHNCHPhCPhNHCH2CH2PPh2)]BPh4: [Cat]=
1.05e–4 M, [KOtBu]=8e–4 M, [AP]=0.63 M, 288C in isopropanol,
2
The ATH of a range of ketones shown in Figure 13 were tested
for the complexes, (S,S)-1 and (S,S)-2 (Figure 14). All of the
catalytic results from this study were compared to those of C4,
and those of C1, retested under the conditions of the present
study for ease of comparison.
K
rac =12.0.
[FeCl(CO)(PPh2CH2CHNCHPhCPhNHCH2CH2PPh2)]
BF4: [Cat]=6.8e–5 M, [KOtBu]=5.4e–4 M, [AP]=0.41 M, 288C in
isopropanol, Krac =12.0. 3 There is a change in catalyst structure over
the course of the first 250 seconds.
The best results are summarized in Table 4; a more
complete Table can be found in the SI. Included are results for
C4 as reported elsewhere.[3c] All of the chiral alcohol products
are enriched in the R-enantiomer which is consistent with our
previous findings.[3b,c,15]
The TOF and S values obtained from fitting the reaction
43 profiles are plotted as a function of the cone angle of the PR’2-
44 CH2 group in the complex (Figures 11 and 12). Variations in
45 the electronic environment as reflected in the n(CO) of the
46 complexes are too small to show a meaningful variation with
47 TOF or S. As far as activity (TOF) is concerned there is a
48 region in the plot around the size of the PPh2 group where the
49 TOF is high (Figure 11). The PPh2 complex C1 is an order of
50 magnitude more active than the PEt2 and PiPr2 complexes. The
51 use of bulky PCy2 and Po-Tol2 groups result in lower TOF.
52 This is consistent with our earlier stereoelectronic study of
53 precatalysts B (Figure 1) indicating that both studies reflect
54 the actual activity of the catalyst and not the activation of the
55 precatalyst; an induction period was observed for catalysis
56 with B because an imine in B has to be reduced to an amine[3a]
First the series of substrates with one phenyl group and
one R group of increasing size (H to Me to Et to iPr) are
considered. All of the complexes quantitatively convert
benzaldehyde (A1) to benzyl alcohol within a few minutes.
The reduction of propiophenone, K2, is achieved with around
80% conversion for each complex. Complexes C4 and (S,S)-2
with the bulky substituents make product with ee greater than
90% ee while (S,S)-1 is less enantioselective (86% ee) but
much more active; C1 produces a low ee product. The bulkier
K3, i-butyrophenone, is only reduced by (S,S)-1 and C1 with
the smaller PR’2 substituents (q<1428) but the enantioselec-
Isr. J. Chem. 2017, 57, 1–13
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Figure 8. Simulation of the reaction progress of (S,S)-1 of Figure 6.
Figure 9. Simulation of the reaction progress of (S,S)-2 of Figure 6. The catalyst is converted over 250 s from one that is very enantioselective
(S= 200) to one that is less (S=28).
52 tivity is poor; this suggests that the active sites of the other
53 catalysts are too restricted in size.
The series of methylketones MeCOAr (K4 to K9) provide
55 a range of functional groups to test the catalysts. The reduction
56 of K4 and K5 with chloro substituents on the phenyl ring is
achieved with high conversions, with the ortho-chloro sub-
stituent in K5 producing much higher ee (84-94% depending
on the catalyst) than with the para-chloro group in K4 (6-58%
ee). High enantiopurity is beneficial for the production of (R)-
2’-chloro-1-phenylethanol as it is a key intermediate for a
54
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Figure 10. Simulation of the reaction progress of C4 of Figure 6.
Figure 11. TOF (sÀ1) for the ATH of acetophenone catalyzed by
complexes as a function of cone angle (8) of the PR’2 group (see
Tables 2 and 3). Reaction conditions are as in Figure 6
Figure 12. The intrinsic enantioselectivity S=kR/kS for the ATH of
acetophenone catalyzed by (S,S)-1, (S,S)-2, C1 and C4 as a function
of cone angle (8) of the PR’2CH2 group. Reaction conditions are as in
Figure 6. The selectivity of (S,S)-2 drops over the first 250 s of the
reaction.
48 chemotherapeutic drug.[16] The bis-CF3-substituted arylketone
49 K6 is fully reduced to the alcohol in >90% ee by C1 and
50 (S,S)-2 that contain PAr2 groups while (S,S)-1 with a more
51 basic PEt2 group appears to be deactivated by the acidic
52 alcohol product after 40–60% conversion. The enantiopure
53 alcohol is valuable as it is a key intermediate for the synthesis
54 of Aprepitant.[17] Para-methylacetophenone (K7) was more
55 difficult to reduce than the chloro analogue, and relatively low
56 ee are achieved. The presence of a potentially coordinating
pyridyl group in K8 is conducive, not detrimental, to the
complete reduction of the ketone. However, the furan in K9
deactivates all of the complexes except C1.[3b] 3-Methyl-2-
butanone (K10) is reduced to 90% conversion but with low ee
by C1, while both C4 and (S,S)-2 are less active but give
higher ee at 43% and 55%, respectively. The complete
reduction of cyclohexanone (K11) is achieved with (S,S)-2
and C1, while only partial conversion is observed for (S,S)-1.
Isr. J. Chem. 2017, 57, 1–13
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Table 4. Results for the ATH of ketones in Figure 13 using complexes
C1, (S,S)-1 to (S,S)-2, and previously reported results using C4 [a]
3
4
5
6
7
8
9
10
11
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23
Entry Substrate[b] Precatalyst Conv.
(%)[c]
Time
(min)
ee
TON
(%)[c]
1
2
K2
(S,S)-2
C4
82
80
30
60
3
60
40
10
10
1
10
1
30
1
40
20
3
5
2
60
60
40
20
60
2
50
30
40
40
60
20
20
20
1
90
94
86
12
40
52
58
90
94
94
93
91
63
65
N/A
N/A
N/A
N/A
43
55
23
N/A
N/A
N/A
23
82
59
53
N/A
N/A
N/A
N/A
46
410
400
395
260
440
460
460
500
500
500
500
500
300
300
500
500
500
0
220
375
450
165
500
500
405
440
420
55
3
4
5
6
7
8
9
(S,S)-1
(S,S)-1
C1
79
52
88
92
K3
K4
K5
C4
(S,S)-2
(S,S)-1
C4
C1
(S,S)-2
C1
(S,S)-2
C4
(S,S)-1
(S,S)-2
C1
(S,S)-1
C4
(S,S)-2
C1
(S,S)-1
(S,S)-2
C1
(S,S)-1
C4
(S,S)-2
C4
(S,S)-1
C4
92
>99
>99
>99
>99
>99
60
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
Figure 13. Substrate scope for ATH using complexes (S,S)-1, (S,S)-2,
C1 and C4.
K6
K7
K8
60
>99
>99
>99
0
44
75
90
33
>99
>99
81
88
84
11
90
89
91
89
22
Figure 14. Conditions of ATH catalysis.
K9
K10
24 C4 is the most enantioselective catalyst for the ATH of the 2-
25 naphthyl ketone K12 with 82% ee, and it was the only
26 complex that successfully reduced cyclohexylphenyl ketone
27 (K13), although with only 11% conversion. All of the
28 catalysts reduce benzophenone (K14) efficiently. The presence
29 of a C=C bond in benzylidene acetone (K15) proved to be a
30 complicating factor as all of the complexes with the exception
31 of (S,S)-2 are unselective and reduced both the C=O and C=C
32 bonds. For the unselective catalysts, the GC traces show the
33 three possible reduction products of C=O reduction, C=C
34 reduction, and both, even at 1 min, with the fully reduced
35 product growing in over time. (S,S)-2 is selective for the
36 formation of the allyl alcohol product with less than <1%
37 conversion to the doubly saturated product after 60 min. In
38 summary, while C1 is a very active catalyst with a high TOF,
39 replacing one of its PPh2 groups with a PCy2 group results in a
40 more enantioenriched alcohol for all of the ketones except K5.
41 The change to a P(o-Tol)2 group gave superior ee for K2, K4,
42 K6 and K10. Surprisingly even the small PEt2 group of (S,S)-
43 1 provided comparable or greater enantioselectivity to that of
44 the PPh2 group in complex C1 for K2, K4, K7 and K10.
45
K11
K12
K13
K14
450
445
455
445
110
(S,S)-2
C1
(S,S)-2
K15
30
[a] Reaction conditions: 28 C, 8.9x10À2 mmol catalyst, 0.18 mmol
KOtBu, 44.3 mmol substrate, 6 mL iPrOH. [b] C/B/S=1/2/500. [c]
% conversion and % ee determined by chiral GC.
Scheme 2. Generation of Iron(II) Hydride Species Starting with C1
as Reported Previously
46
47 2.3 Observation of Hydride Species
48
49 The precatalyst solution of C4 was treated with base and
50 iPrOH in order to characterize possible catalytically active
51 species by use of NMR and IR spectroscopy as has been done
52 already for C1.[3b] When C1 was treated by first the addition
53 of KOtBu in THF, then evaporation, dissolution in C6D6, a
54 mixture of amido-enamido complexes was identified.[3b] Then
55 the addition of iPrOH produced first, a transient hydride
56 isomer G1-1 (Scheme 2) which rearranged over time to a
second isomer G1-2. Based on NOE studies, isomer G1-1 has
a trans configuration with the FeÀH group parallel to the NÀH
group while G1-2 is thought to have the trans configuration
with Fe-CO moiety parallel to the NÀH group.[3b]
The precatalyst C4 was mixed with 8 equivalents of
KOtBu in THF for 5 min, then dried in vacuo and dissolved in
C6D6. The solution at this stage produce complicated NMR
spectra with features reported previously for amido-eneamido
Isr. J. Chem. 2017, 57, 1–13
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complexes generated from C1 (see the Supporting Materi-
3 Density Functional Theory Calculations
al).[3b,7,15] The mixture of complexes was then dissolved and
i
stirred in PrOH for 1 min, or until the residue was completely
Due to the difficulties in establishing the coordination geo-
metries of the products upon reacting C4 with base, we
employed Density Functional Theory to compare relative
ground state energies of various diastereomers. Details of the
calculations and the three dimensional Cartesian coordinates
are provided in the Supporting Information. The calculated
geometries of cis-b complexes C4-RNH and C4-SNH correspond
well with the X-ray structural data reported previously for
C4,[8] with C4-SNH being only 1.8 kcal/mol higher in energy
(SI, Scheme S1). The cis-b stereochemistry of the two
diastereomers can be further characterized as D-cis-b-C4-RNH
and L- cis-b-C4-SNH. Deprotonation of C4 with at least two
equivalents of base could lead to the formation of at least four
possible amido-eneamido complexes (S,S)-4 (Scheme 4) and
the trans-amido structure by analogy to mechanistic studies
based on C1.[15,21] We found that the trans-(S,S)-4 isomer is
slightly lower in energy (3.2 kcal/mol) relative to the D-cis-b-
(S,S)-4 amido complex (Scheme 4). The trans isomer can
produce, via the transfer of a proton/hydride equivalent from
iPrOH, the high energy, catalytically active, octahedral, FeH-
NH complex, trans-(S,S)-3’, with FeH and NH parallel as
proposed for the trans-amido-eneamido from C1. In the
absence of substrate, the formation of the hydride D-cis-b-
(S,S)-3A is calculated to be most favorable (-13.3 kcal/mol)
among the various cis-b structures. The relative energy of the
kinetically-formed hydride complex trans-(S,S)-3’ is calcu-
lated to be -8.9 kcal/mol, 4.4 kcal/mol higher than the D-cis-b
isomer and 2 kcal/mol higher than the observed hydride (S,S)-
3.
dissolved. It was then dried immediately affording the new
hydride species trans-(S,S)-3 (Scheme 3, Table 5). Its NMR
properties are similar to those of hydride G1-2 and so we
tentatively assign the structure as trans with the NH parallel to
the FeCO group. The 31P{1H} NMR resonances associated
2
with these hydride complexes have JPP 25–27 Hz, consistent
10 with cis phosphorus nuclei (Table 5). G1-2 and trans-(S,S)-3
11 show a similar doublet of doublet hydride pattern in the region
2
12 of À9.3 to À10.3 ppm with JPH of 59–60 and 80–82 Hz.
13 These coupling constants are typical of cis phosphorus and
14 hydride nuclei on Fe(II) and thus the stereochemistry of these
15 hydride complexes is likely to be trans. In all cases found so
16 far, the magnitude of JP-Fe-Htrans is smaller than that of JP-Fe-H
2
2
cis
2
trans
17 for terminal iron hydride complexes: JP-Fe-H
is in the range
18 12–35 Hz[18] whereas 2JP-Fe-Hcis is in the range 30–85 Hz.[18a–e,i,19]
2
trans
2
cis
19 In some instances the JP-Fe-H
and JP-Fe-H in iron hydride
20 polyphosphine complexes are averaged to a small value due to
21 nuclear exchange caused by molecular fluxionality.[20]
22
23
24
25
26
27
28
29
30
31
Scheme 3. Generation of Iron(II) Hydride Species (S,S)-3
32
33
34
35
36
37
38
39
40
41
42
43
44
45
Table 5. NMR properties of the hydride complexes
Precursor to Hydride
Complex
PR’2 d31P
(ppm)
2JPP
d1H
2JHP
4. Proposed Mechanism
(Hz) (ppm) (Hz)
C1 hydride
G1-1
C1 hydride
G1-2
PPh2 84.9,
70.4
PPh2 75.7,
71.4
PCy2 91.2,
83.0
33.2
27.5
36.6
-2.3
71, 62a
80, 60b
Thus, we suggest that the activity of the system is determined
by the relative stability of a catalytic trans-hydride like trans-
(S,S)-3’ and the off cycle trans hydride trans-(S,S)-3 or D-cis-
b-(S,S)-3 hydride species and of the catalytic trans amido-
eneamido species as indicated in Scheme 5. The larger and/or
more basic PR’2 groups favor the off-cycle structures and thus
are less reactive. The similarity of the structure of the ketone
adduct with the unobserved active hydride (Scheme 5) to that
of the one proposed for the PPh2 catalyst system C1[15,21] could
explain why the (R)-aryl alcohols are produced by the trans-
(S,S)-hydride catalysts using a transition state structure similar
to that described for C1.[15,21]
DFT calculations (see SI) indicate that G1-2 may have a
D-cis-b geometry for the off-cycle structure shown in
Scheme 5; this structure is 3 kcal/mol more stable than the
trans-isomer G1-1. Thus it is possible that the off-cycle
hydride complexes with a D-cis-b geometry rearrange to low
concentration catalytically active isomers with the NH and
FeH parallel as shown in Scheme 5.
-9.2
(S,S)-3
-10.3
82.2,
59.8
a
previously reported as 70 Hz[3b] bpreviously reported as 79 Hz[3b]
Treating (S,S)-1 and (S,S)-2 in a similar fashion also
46 produces hydride resonances in this region but the hydrides
47 are very reactive and unstable so that the 31P{1H} NMR
48 spectra are complex with some unidentified species and
49 signals for uncoordinated phosphorus species.
50
Thus hydride complex trans-(S,S)-3, like G1-2, is thought
51 to have the NH of the ligand parallel to the Fe-CO group and
52 not in a suitable position for an outersphere hydride and
53 proton attack on the ketone.[3b]
54
55
56
Isr. J. Chem. 2017, 57, 1–13
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Scheme 4. Ground state energy comparison of some isomers of Cy-amido complexes (S,S)-4 and the hydride isomers (S,S)-3 derived from
them by reaction with 2-PrOH. All energies are given in kcal/mol and relative to D-cis-b-(S,S)-4 plus relevant small molecules. M06 L/TZVP/
TZVPfit-IEF-PCM(THF).
degradation of ee over the course of the reaction. We found
that by increasing the steric bulk at one phosphine, the
enantioselectivity increases (to greater than 98% in case of
C4) with a concomitant decrease in activity.
This work provides evidence for a correct matching of
catalyst structure with substrate structure to produce superior
activity and selectivity. The bulky isobutyrophenone (K3) is
only reduced by (S,S)-1 and C1 probably because these
catalysts have the small PEt2 or PPh2 groups. Surprisingly
(S,S)-1 provides (R)-1-ortho-chlorophenylethanol in high ee
(90%) from K5, despite the small size of the PEt2 group.
Cyclohexanone (K11) was only reduced by the (S,S)-2 and C1
catalyst systems. We also found that the steric and electronic
Scheme 5. Proposed mechanism for the ATH catalyzed by complexes
properties can be varied to introduce chemoselectivity, as in
(S,S)-1, (S,S)-2, C1 and C4. The observed hydride trans-(S,S)-3 when
the case of the selective C=O reduction of benzylidene acetone
R’ is Cy is proposed to be off cycle.
by complex (S,S)-2 and none other.
We provided spectroscopic and computational character-
ization of hydride complexes that provide an understanding of
the mechanism of the catalytic ATH using these iron
complexes.
5. Summary
49 In conclusion, two new precatalyst complexes have been
50 synthesized with different steric and electronic properties at
51 one phosphine (PEt2 vs Po-Tol2) coordination site of our third
52 generation iron(II) (P-NHÀN-P’) system. These have been
53 tested in the catalytic ATH of ketones and compared to the
54 previously reported complexes C1 and C4. The progress of the
55 catalytic reactions could be fit for the first time to a simple
56 three parameter kinetic model which describes the activity and
Acknowledgements
NSERC Canada is thanked for a Discovery Grant to RHM and
scholarship funding to DEP. SAM thanks Digital Specialty
Chemicals Ltd. for an OGSST Scholarship. The authors
acknowledge the Canadian Foundation of Innovation, project
Isr. J. Chem. 2017, 57, 1–13
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[12] R. Bigler, R. Huber, M. Stöckli, A. Mezzetti, ACS Catalysis
2016, 6, 6455–6464.
[13] L. Hintermann, C. Dittmer, Eur. J. Org. Chem. 2012, 2012,
5573–5584.
[14] P. Kuzmic, Anal. Biochem. 1996, 237, 260.
[15] W. Zuo, D. E. Prokopchuk, A. J. Lough, R. H. Morris, ACS
Catal. 2016, 6, 301–314.
1
2
3
4
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number 19119, and the Ontario Research Fund for funding of
the Centre for Spectroscopic Investigation of Complex
Organic Molecules and Polymers and Compute Canada for
providing computational resources.
6
7
8
[16] T. Eixelsberger, J. M. Woodley, B. Nidetzky, R. Kratzer,
Biotechnol. Bioeng. 2013, 100, 2311–2231.
References
[17] K. M. J. Brands, J. F. Payack, J. D. Rosen, T. D. Nelson, A.
Candelario, M. A. Huffman, M. M. Zhao, J. Li, B. Craig, Z. J.
Song, D. M. Tschaen, K. Hansen, P. N. Devine, P. J. Pye, K.
Rossen, P. G. Dormer, R. A. Reamer, C. J. Welch, D. J. Mathre,
N. N. Tsou, J. M. McNamara, P. J. Reider, J. Am. Chem. Soc.
2003, 125, 2129–2135.
9
[1] a) L. Cotarca, M. Verzini, R. Volpicelli, Chimica Oggi-Chem.
Today 2014, 32, 36–41; b) P. Dupau, in Organometallics as
Catalysts in the Fine Chemical Industry, Vol. 42 (Eds.: M. Beller,
H. U. Blaser), Springer-Verlag, Berlin, 2012, pp. 47–63; c) R.
Noyori, Adv. Synth. Catal. 2003, 345, 15–32; d) L. A. Saudan,
Acc. Chem. Res. 2007, 40, 1309–1319.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
[18] a) C. A. Tolman, S. D. Ittel, A. D. English, J. P. Jesson, J. Am.
Chem. Soc. 1978, 100, 4080–4089; b) N. Bampos, L. D. Field,
Inorg. Chem. 1990, 29, 587–588; c) C. Bianchini, M. Peruzzini,
A. Polo, A. Vacca, F. Zanobini, Gazz. Chim. Ital. 1991, 121,
543–549; d) G. Jia, S. D. Drouin, P. G. Jessop, A. J. Lough, R. H.
Morris, Organometallics 1993, 12, 906–916; e) N. Bampos, L. D.
Field, B. A. Messerle, Organometallics 1993, 12, 2529–2535;
f) D. G. Gusev, R. Huebener, P. Burger, O. Orama, H. Berke, J.
Am. Chem. Soc. 1997, 119, 3716–3731; g) D. Schott, P.
Callaghan, J. Dunne, S. B. Duckett, C. Godard, J. M. Goicoe-
chea, J. N. Harvey, J. P. Lowe, R. J. Mawby, G. Müller, R. N.
Perutz, R. Poli, M. K. Whittlesey, Dalton Trans. 2004, 3218–
3224; h) R. J. Trovitch, E. Lobkovsky, P. J. Chirik, Inorg. Chem.
2006, 45, 7252–7260; i) P. Bhattacharya, J. A. Krause, H. Guan,
Organometallics 2011, 30, 4720–4729.
[19] a) M. Bautista, K. A. Earl, R. H. Morris, A. Sella, J. Am. Chem.
Soc. 1987, 109, 3780–3782; b) M. T. Bautista, K. A. Earl, R. H.
Morris, Inorg. Chem. 1988, 27, 1124–1126; c) M. T. Bautista,
E. P. Cappellani, S. D. Drouin, R. H. Morris, C. T. Schweitzer, A.
Sella, J. Zubkowski, J. Am. Chem. Soc. 1991, 113, 4876–4887;
d) E. Rocchini, P. Rigo, A. Mezzetti, T. Stephan, R. H. Morris,
A. J. Lough, C. E. Forde, T. P. Fong, S. D. Drouin, J. Chem. Soc.,
Dalton Trans. 2000, 3591–3602; e) R. Langer, G. Leitus, Y. Ben-
David, D. Milstein, Angew. Chem. Int. Ed. 2011, 50, 2120–2124;
f) B. Bichler, C. Holzhacker, B. Stoger, M. Puchberger, L. F.
Veiros, K. Kirchner, Organometallics 2013, 32, 4114–4121; g) F.
Bertini, N. Gorgas, B. Stoger, M. Peruzzini, L. F. Veiros, K.
Kirchner, L. Gonsalvi, Acs Catal. 2016, 6, 2889–2893; h) F.
Schneck, M. Assmann, M. Balmer, K. Harms, R. Langer,
Organometallics 2016; i) S. Elangovan, B. Wendt, C. Topf, S.
Bachmann, M. Scalone, A. Spannenberg, H. J. Jiao, W. Bau-
mann, K. Junge, M. Beller, Adv. Synth. Catal. 2016, 358, 820–
825.
[2] a) J. S. Chen, L. L. Chen, Y. Xing, G. Chen, W. Y. Shen, Z. R.
Dong, Y. Y. Li, J. X. Gao, Acta Chimica Sinica (Huaxue Xuebao)
2004, 62, 1745–1750; b) R. Bigler, R. Huber, A. Mezzetti, Synlett
2016, 27, 831–847; c) R. Bigler, A. Mezzetti, Org. Process Res.
Dev. 2016, 20, 253–261; d) T. Bleith, H. Wadepohl, L. H. Gade,
J. Am. Chem. Soc. 2015, 137, 2456–2459; e) F. Foubelo, C.
Nájera, M. Yus, Tetrahedron Asymmetry 2015, 26, 769–790;
f) J. P. Hopewell, J. E. D. Martins, T. C. Johnson, J. Godfrey, M.
Wills, Org. Biomol. Chem. 2012, 10, 134–145; g) Y. Y. Li, S. L.
Yu, W. Y. Shen, J. X. Gao, Acc. Chem. Res. 2015, 48, 2587–
2598; h) R. H. Morris, Chem. Soc. Rev. 2009, 38, 2282–2291;
i) R. H. Morris, Acc. Chem. Res. 2015, 48, 1494–1502; j) A.
Naik, T. Maji, O. Reiser, Chem. Commun. 2010, 46, 9265–9265;
k) B. Stefane, F. Pozgan, Catal. Rev. Sci. Eng. 2014, 56, 82–174;
l) P. E. Sues, K. Z. Demmans, R. H. Morris, Dalton Trans. 2014,
43, 7650–7667; m) S. L. Yu, W. Y. Shen, Y. Y. Li, Z. R. Dong,
Y. Q. Xu, Q. Li, J. N. Zhang, J. X. Gao, Adv. Synth. Catal. 2012,
354, 818–822.
[3] a) A. A. Mikhailine, M. I. Maishan, A. J. Lough, R. H. Morris, J.
Am. Chem. Soc. 2012, 134, 12266–12280; b) W. Zuo, A. J.
Lough, Y. Li, R. H. Morris, Science 2013, 342, 1080–1083;
c) S. A. M. Smith, R. H. Morris, Synthesis 2015, 47, 1775–1779;
d) R. Bigler, R. Huber, A. Mezzetti, Angew. Chem. Int. Ed. 2015,
54, 5171–5174; e) R. Bigler, A. Mezzetti, Org. Lett. 2014, 16,
6460–6463; f) R. Bigler, E. Otth, A. Mezzetti, Organometallics
2014, 33, 4086À4099.
[4] C. Sui-Seng, F. Freutel, A. J. Lough, R. H. Morris, Angew. Chem.
Int. Ed. 2008, 47, 940–943.
[5] J. F. Sonnenberg, N. Coombs, P. A. Dube, R. H. Morris, J. Am.
Chem. Soc. 2012, 134, 5893À5899.
[6] a) P. O. Lagaditis, A. J. Lough, R. H. Morris, Inorg. Chem. 2010,
49, 10057–10066; b) P. E. Sues, A. J. Lough, R. H. Morris,
Organometallics 2011, 30, 4418–4431.
[20] G. Guilera, G. S. McGrady, J. W. Steed, R. P. L. Burchell, P.
Sirsch, A. J. Deeming, New. J. Chem. 2008, 32, 1573–1581.
[21] D. E. Prokopchuk, R. H. Morris, Organometallics 2012, 31,
7375–7385.
[7] W. Zuo, S. Tauer, D. E. Prokopchuk, R. H. Morris, Organo-
metallics 2014, 33, 5791–5801.
[8] S. A. M. Smith, A. J. Lough, R. H. Morris, UICrData 2017,
https://doi.org/10.1107/S2414314617004527.
[9] W. Zuo, R. H. Morris, Nature Prot. 2015, 10, 241–257.
[10] A. A. Mikhailine, P. O. Lagaditis, P. Sues, A. J. Lough, R. H.
Morris, J. Organometal. Chem. 2010, 695, 1824–1830.
[11] C. A. Tolman, Chem. Rev. 1977, 77, 313–348.
Received: March 31, 2017
Accepted: August 4, 2017
Published online on && &&, 0000
Isr. J. Chem. 2017, 57, 1–13
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.ijc.wiley-vch.de
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Asymmetric Transfer Hydrogena-
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