From imine to amine: An unexpected left turn.: Cis -β Iron(II) PNNP′ precatalysts for the asymmetric transfer hydrogenation of acetophenone

Article abstract of DOI:10.1039/c7sc02558k

A novel PNN ligand bearing an orthophenylene group and a primary amine was synthesized with the aid of a palladium-catalyzed amination and reacted with phosphonium dimers [-PR₂CH₂CH(OH)-]₂[Br]₂ R = Et, iPr, Cy,

Full text of DOI:10.1039/c7sc02558k

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A slight change in the iron catalyst structure (amine arm with PEt
2
to imine arm with PPh ) results
2
in a complete reversal of the enantioselectivity toward ketone reduction

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From Imine to Amine: an Unexpected Left Turn. Cis-β Iron (II)
PNNP’ Precatalysts for the Asymmetric Transfer Hydrogenation of
Acetophenone
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
a
*a
DOI: 10.1039/x0xx00000x
Karl Z. Demmans, Chris S. G. Seo, Alan J. Lough and Robert H. Morris
www.rsc.org/
A novel PNN ligand bearing an orthophenylene group and a primary amine was synthesized with the aid of a palladium-
catalyzed amination and reacted with phosphonium dimers [-PR CH CH(OH)-] [Br] R = Et, iPr, Cy, Ph, Xylyl, and o-Tol, and
to produce a new series of cis-β iron (II) PNNP’ precatalysts cis-β-[Fe(Br)(CO)(PNNP’)]BPh as a pair of
2
2
2
2
2
]
+
[
Fe(OH
2
)
6
4
diastereomers. The more stable orthophenylene group was chosen to imitate and replace the enamido moiety of a highly
active iron precatalyst for the asymmetric transfer hydrogenation (ATH) of ketones in an attempt to prevent its
deactivation caused by reduction of the enamido group. This objective was partially achieved using the complex with a
PEt
-phenylethanol. With a low acetophenone to catalyst ratio of 500 to 1, the catalytic activity was moderate and the
enantiomeric excess (ee) of the product 1-phenylethanol ranged surprisingly from 94% (R) to 95% (S) depending on the
nature of PR and whether the precatalyst contained an imine or amine donor. The amine precatalyst with a PEt - group
2
group which catalyzed the transfer hydrogenation in isopropanol of 150 000 equivalents of acetophenone to racemic
1
2
2
produced a more stable hydride species when activated, allowing the reaction mixture to be heated to 75 °C to obtain a
TON of 8821 for acetophenone while retaining the high ee. The activation pathway in basic isopropanol (iPrOH) was
studied for three precatalysts to elucidate that the cis-β precatalysts rearrange to form trans hydride complexes. The study
suggests that the enantioselectivity of these complexes is determined by which side of the PNNP’ plane the hydride
transfer
occurs.
(
TON) of approx. 5000 and a turnover frequency (TOF) as high
13, 14
-1
Introduction
as 200 s at 28 °C with ee up to 98% for the case of 1b.
The asymmetric hydrogenation of ketones to produce
enantiopure alcohols is a widely studied reaction with
significant importance in the flavour, fragrance, agricultural,
H
H
H
H
Ph
Ph
N H
Ph
N
Ph
N H
Ph
N
Ph
H
Ph
N
Ph
Ph
O
O
2
P
BF
4
BF4
BPh
4
Cl
C
C
N H
NH
N
H
Fe
1
-5
Fe
C
O
Fe
H
Fe
Cl
H
P
H
H
P
and pharmaceutical industries. Due to the fact that industrial
catalysts typically use less earth-abundant metals such as
P
R
P
P
P
P
C
2
R
2
Ph
2
Ph
2
Ph
2
Ph
2
Cy Br
2
O
4, 6, 7
ruthenium
for this reaction, the use of base metals such as
1a: R = Ph
b: R = 3,5-Me
2
3
4
2 6 3
C H
iron for the reduction of polar bonds has recently become a
-12
13, 15, 16
Fig. 1 Select Iron (II) PNNP complexes developed in the Morris group.
8
focus of research.
.
In the field of ATH, our group reported iron (II) PNNP’
precatalysts based on (S,S)-DPEN (Fig. 1) that when activated
in basic iPrOH produced an iron hydride capable of reducing
aromatic ketones enantioselectively at a turnover number
An investigation into the mechanism of action of these
catalyst systems showed that the active hydride in the system,
trans-FeH(CO)(PNNP’) (
2 in Fig. 1) has a ligand with a unique
structure containing a secondary amine and an enamido
1
3,
donor: PNNP’= (S,S)-PPh
2
CH
Precatalyst 1a is deprotonated at the methylene next to the
imino donor to produce a neutral enamido species, which
forms under basic iPrOH solution.
2 2 2
CH NHCHPh-CHPhNCH=CHPPh .
1
7
2
A pathway to deactivation of the catalyst was found to be
the reduction of the C=C bond. The fully saturated precatalyst,
[FeCl(CO)(PNNP)][BF
4
] (3 in Fig. 1), was isolated and shown to
be a very poor catalyst for both direct and transfer
1
7
hydrogenation. The objective of this investigation was to
replace the C=C bond with an orthophenylene group to
prevent reduction and shut down the deactivation pathway
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ARTICLE
and allow the recycling of the catalyst. Recent developments
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DOI: 10.1039/C7SC02558K
Journal Name
1
8-21
in palladium-catalyzed amination
key PNN building blocks needed to prepare the precatalysts
a-f and 6a-e, shown in Fig. 2 in their major diastereomeric
allowed us to afford the
5
form.
a
. Percent overall yield was
Scheme 1 Synthesis of BenzoPPh
calculated based on molar amount of monotosylated-(S,S)-DPEN.
2
DPEN (S,S) isomer
9
Results and discussion
Fig. 2 Imine and amine precatalysts bearing the orthophenylene linker.
Synthesis of the (S,S) isomer of BenzoPPh DPEN and the iron imine
2
precatalysts
This article describes their preparation, catalytic testing, and a
study of their activation in basic iPrOH solution.
Following the work of Liang et al., wherein achiral PNN ligands
2
based on N,N-dimethylethylenediamine were synthesized,
1
a
At first glance, the cis-β ligand structures of 5a-f and 6a-e
are quite different from those of the trans structures of 1-3
due to the steric requirements of our new ligands with the
orthophenylene group. A further goal of this project is to
understand how this change in structure influences catalyst
activity and selectivity.
new chiral PNN ligand precursor bearing a primary amine was
prepared (Scheme 1). A total of four steps were required: a
2
8
monotosylation of (S,S)-DPEN as described by Tietze et al.,
Buchwald-Hartwig amination, nucleophilic aromatic
a
a
substitution to install diphenylphosphine, and
deprotection as shown in Scheme 1.
a tosyl
Examples of iron catalysts with cis-β-PNNP ligands have
been reported by Mezzetti’s and our own group. Mezzetti et
al. have also crystallized cis-β iron (II) PNNP precatalysts (Fig.
In greater detail, 1-bromo-2-fluorobenzene was chosen as
the coupling reagent to monotosylated-(S,S)-DPEN in order to
selectively perform Buchwald-Hartwig amination on bromo
substituent, leaving the fluoro group unaltered for subsequent
3), wherein the phosphine donors are linked via an ethylene or
propylene bridge to create a macrocycle.8, 22-26
1
8-21
phosphination.
This reaction was scaled up to produce 3 g
) at the cost of refluxing in toluene for
Our first iron catalyst to achieve an ee of 99% for ketone
of BenzoFTsDPEN (
7
reduction was iron precatalyst
4 (Fig. 1) bearing a
1
dicyclohexylphosphine group. Interestingly, this precatalyst
6
several days. Nucleophilic aromatic substitution using bulky
potassium diphenylphosphide proceeded slowly in refluxing
THF due to the kinetic barrier imposed by the sterically-
encumbered ortho position. This reaction was also attempted
in refluxing 1,4-dioxane to increase the reaction rate, but low
conversions were obtained due to the lower dielectric
constant of 1,4-dioxane and poor solubility of the starting
crystallizes in the cis-β configuration, placing the more flexible
7
2
ethyldiphenylphosphine group in the apical position. While
more enantioselective, this catalyst system was much less
active than that from 1a,b
. The current study probes the
influence of the cis- structures of complexes 5a-f and 6a-e on
β
the activity and enantioselectivity of transfer hydrogenation
catalyst systems derived from them.
material. The product, BenzoPPh TsDPEN (8), was isolated by
2
simple filtration after stirring the crude residue in diethyl
ether. Attempts were also made to perform Buchwald-Hartwig
amination
with
monotosylated-(S,S)-DPEN
and
(2-
bromophenyl)diphenylphosphine, but as the PNN ligand
formed, it substituted BINAP from the palladium catalyst,
halting the reaction immediately. The tosyl deprotection step
required extremely reducing conditions and could not be
achieved via other reductants such as sonication with
2
9
magnesium powder in anhydrous methanol , or sodium
3
0
naphthalenide in cold THF. A solution of samarium diiodide
in THF was prepared and the deprotection methodology was
Fig. 3 Selected cis-β iron (II) PNNP complexes developed in the Mezzetti group.
3
1
adapted from the literature procedure
BenzoPPh DPEN ( ) as an air-stable colourless oil.
to isolate
9
2
This novel, chiral PNN molecule with a primary amine
condensed readily with aldehydes in the presence of iron salt
2
| J. Name., 2012, 00, 1-3
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ARTICLE
2
X
OH
H
2
Br
C
N
Ph
H
1
) NaOMe, MeOH
Ph
PR
2
2) [Fe(H O) ][BF ] , MeCN
2
6
4 2
∗
H
N
X = Br or BF4
N
R
2
P
3) , MeOH, 28 °C
9
Fe
N
P
C
R
2
OH
PPh
2
+
isomer
10a-f
11a-f
R = Et(a), iPr(b), Cy(c),
Ph(d), Xylyl(e), oTol(f)
1
) KBr, CO(g)
,
Acetone
2) NaBPh
4
,
MeOH, 28 °C
BPh
Ph
4
BPh4
H
H
PPh2
Ph
H
Ph
Ph
Br
∗
H
N
∗
H
N
N
N
H
Fe
+
Fe
Br
C
P
O
R
2
C
P
PPh
2
O
R
2
(
S)-NH
(R)-NH
Major
Minor
5a-f
a 26%
b 31%
c 28%
d 27%
e 35%
f 32%
Scheme 2 Synthesis of iron PNNP’ imine precatalysts 5a-f. Percent values
represent overall yields based on the molar amount of
9
.
following protocols previously established to produce the new
3
iron (II) PNNP’ precatalysts as shown in Scheme 2.
2, 33
In short, various air- and moisture-stable phosphonium
dimers (10a-f) were deprotonated in basic condition to release
phosphine
condensation reaction with
complexes (11a-f) were presumably formed due to the
aldehydes.
Through
the
iron-templated
9, dicationic bis(acetonitrile) iron
1
6, 34
emergence of a typical pink colour for such complexes.
Ligand exchange was performed with potassium bromide
under carbon monoxide gas, followed by salt metathesis in
methanol to isolate the imine precatalysts 5a-f as tan powders.
Chirality was set at the amino nitrogen upon coordination to
iron, creating a pair of diastereomers labelled as (S)-NH and
(R)-NH. In most cases, the phosphorus and proton NMR of the
Fig. 4 ORTEP plot of 5d containing the pair of diastereomers, with (
R)-NH on the
isolated powders suggested an S:R ratio of 95:5. The top and (
S)-NH on the bottom. The molecules have been rotated to display the
difference in the gauche and anti-conformation of the (R)-NH and (S)-NH, respectively
diastereomers 5d co-crystallized in a 1:1 mixture as confirmed
by single crystal X-ray diffraction (Fig. 4). The altered ratio of
diastereomers (from 95:5 to 50:50) after co-crystallization was
with respect to the CH of the adjacent CHPh group. Thermal ellipsoids are drawn at
5
0% probability level. Aromatic ring protons and the BPh
4
counteranions were omitted
for clarity. Selected interatomic distances (Å) and angles (deg): For (R)-NH: Fe1a-N1a
reflected in the NMR data as shown in the supporting 2.077(8), Fe1a-N2a 1.976(8), F1a-P1a 2.247(3), Fe1a-P2a 2.233(3), N1a-C10a 1.440(12),
information (see ESI, Fig. S7-8).
Thus there is slow P1a-C5a 1.819(10), N2a-C3a 1.275(11), C3a-C4a 1.485(14), N1a-C1a 1.521(11), N2a-C2a
1
1
1
1
.485(10); P1a-Fe1a-P2a 103.80(13). For (S)-NH: Fe1b-N1b 2.047(9), Fe1b-N2b
.982(8), Fe1b-P1b 2.260(3), Fe1b-P2b 2.248(3), N1b-C10b 1.472(12), P1b-C5b
.823(10), N2b-C3b 1.263(11), C3b-C4b 1.476(14), N1b-C1b 1.545(10), N2b-C2b
.497(10); P1b-Fe1b-P2b 102.00(13).
interconversion of the diastereomers.
Upon further investigation it was found that the major
isomer (S)-NH contained a more sterically-favoured orientation
by placing the orthophenylene and the adjacent phenyl group
from the DPEN backbone in the anti-conformation. The torsion
angle of the PNNP’ ligand for the major isomer is -56.8° (P2b-
N2b-N1b-P1b Fig. 4), while the torsion angle for the minor
isomer is +64.9° (P2a-N2a-N1a-P1a).
Synthesis of the iron amine precatalysts
The precatalysts bearing two amino ligands were also
synthesized to provide the secondary amine in the structure of
an analogue to the active hydride catalyst (2 in Fig. 1). Amine
precatalysts 6a-e were synthesized as outlined in Scheme 3.
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H
Ph
H
Ph
NaHB(OAc)
3
N H HN
PPh R2P
9
+ 10a-e
THF, 4 Å sieves, 28 °C
2
12a-e
[
Fe(H O) ][BF ]
2 6 4 2
MeCN/MeOH, 28 °C
2
X
H
C
N
Ph
H
Ph
∗
N
X = Br or BF
4
∗
H
N
Fe
H
N
P
C
PPh R
2
2
Fig. 5 Crystal structure of the major diastereomer of 6a. Thermal ellipsoids are drawn at
+
isomers
the 50% probability level. Aromatic ring protons and the BPh
omitted for clarity. Selected interatomic distances (Å) and angles (deg): Fe1-N1
.050(4), Fe1-N2 2.055(5), Fe1-P1 2.2282(14), Fe1-P2 2.2294(14), N1-C9 1.457(6), P2-
4
counteranion were
1
3a-e
2
1
) KBr, CO(g), Acetone
C14 1.818(5), N2-C3 1.495(7), C3-C4 1.536(7), N1-C1 1.513(6), N2-C2 1.502(6); P1-Fe1-
P2 103.04(5).
2
) NaBPh , MeOH, 28 °C
4
Factors contributing to the preferential formation of cis-β isomers
While we had postulated that a cis-β structure was formed as
H
BPh
4
BPh
4
Ph
H
Ph
PPh2
H
Ph
Ph
Br
∗
1
7
∗
H
N
an intermediate during the activation of 1a
,
the
N
∗
∗
H
N
N
Fe
H
+
Fe
27
4 (Fig. 1) raises the question of the
crystallization of
C
H
P
P
H
O
C
PPh R
importance of cis-β structures in catalysis. By comparing the
crystal structures of 1a, 4, 5d, and 6a, two trends dictating the
formation of a trans or cis-β PNNP’ iron precatalyst could be
discerned. First, the steric bulk of the two phosphine donors
play a significant role as they are forced in close contact upon
2
2
O
Br
R
2
(
S,S)-NH,NH
Major
(R,S)-NH,NH
Minor
6
a-e
a 30%
b 34%
c 30%
d 23%
e 31%
R = Et(a), iPr(b), Cy(c),
Ph(d), Xylyl(e)
coordination to the iron centre. Precatalysts 1a and
4 differ in
steric bulk of one phosphine moiety, increasing from
diphenylphosphino to dicyclohexylphosphino, respectively.
Scheme 3 Synthesis of iron PNNP’ amine precatalysts 6a-e. Percent values
represent overall yields based on the molar amount of
9
.
This increase for
4 causes the diphenylphosphino moiety on
The desired PNNP’ ligands (12a-e) were prepared as shown the flexible ethylene linker to move out of the plane to
in Scheme 3 by reductive amination of the phosphine decrease the steric strain. Precatalyst 1a and 5d both contain
aldehyde, released in basic conditions from 10a-e (as in two diphenylphosphino moieties, yet 5d also folds into a cis-β
Scheme 2), with
placed on iron without further purification, presumably connecting the amino donor to the phosphine donor. The
forming the dicationic bis(acetonitrile) iron complexes 13a-e
tetrahedral amino donor would always force the phosphine
9. These ligands as a crude residue were structure. The second factor is the flexibility of the linker
.
Ligand exchange followed by salt metathesis allowed for the donor out of the plane, but precatalysts with a flexible
isolation of the cis-β-[Fe(CO)(Br)(PNNP’)][BPh4] amine ethylene linker may shift to negate this effect. The rigid
precatalysts 6a-e in moderate yields. Four isomers could orthophenylene linker cannot bend; therefore, it acts to
possibly arise due to having two chiral nitrogen centres, but extend the direction forced by the tetrahedral amino, placing
the NMR data showed that only one pair of diastereomers was the phosphine donor either above or below the plane, thus
isolated in the powdered product. The major diastereomer of creating diastereomers. Reducing the steric bulk from
6
a
crystallized as a single isomer as confirmed by single crystal diphenylphosphine in 6d to diethylphosphine in 6a does not
X-ray diffraction as shown in Fig. 5.
produce a trans PNNP’ precatalyst; thus, the cis-β structure is
The major isomer (S,S)-NH,NH contained a more sterically- likely due to the tetrahedral nitrogen and the rigidity of the
favoured alternating anti-disposition of the orthophenylene N- orthophenylene linker.
H, the C-H of the adjacent CHPh group, and ethylene linker N-
H. The torsion angle of the PNNP’ ligand for the major isomer Catalytic testing
is -58.8° (P1-N2-N1-P2).
4
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Precatalysts 5a-f and 6a-e were preliminarily screened for the diethylphosphine group 6a was the most active and
ATH of acetophenone in iPrOH for the set period of 1 h at enantioselective, producing 1-phenylethanol in 95% ee but,
room
remarkably, in the (S) configuration. Explanations for these
a
Table 1 Preliminary precatalyst activity screen for the ATH of acetophenone
observations are provided in the mechanism section.
Precatalyst
Label, R
group
Conversion
(%)
ee (%), 1-
phenethanol
78 (R)
b,c
100
90
trans-
1a, Ph
82
b,c
[
FeCl(CO)(PNNP’)]-
1b, Xylyl
82
90 (R)
8
0
0
[
BF
cis-β-
FeBr(CO)(PNNP’)]-
BPh
4
]
b,d
7
4, Cy
71
98 (R)
[
60
50
40
30
[
4
]
e
5
a, Et
b, iPr
5c, Cy
d, Ph
e, Xylyl
f, oTol
a, Et
b, iPr
6c, Cy
d, Ph
0.7
1.1
70 (R)
e
5
80 (R)
Powered Imine
22.9
22.8
3.2
76 (R)
79 (R)
2
0
0
0
5
1
e
5
90 (R)
e
5
3.4
60 (R)
0
200
400
600
800
1000
6
12.3
0.6
90 (S)
e
Time (min)
6
60 (S)
e
Powdered Amine
2.4
80 (S)
1
00
6
10.5
3.8
15 (R)
8
6
4
2
0
0
0
0
0
e
6
e, Xylyl
50 (R)
a
Reactions
performed
under
argon
at
28
°C.
Time
=
1
h.
Acetophenone:KOtBu:precatalyst ratio was 500:8:1. Volume of iPrOH = 1.5 mL. Final
concentrations: [Acetophenone] = 0.742 M; [KOtBu] = 0.0119 M; [Fe] = 0.00148 M;
-
-
-
20
40
60
-80
-100
[
iPrOH] = 12.0 M. Conversions and ee were determined using a gas chromatograph
containing a chiral column. Di-tert-butylbenzene was used as an external standard.
b
Acetophenone:KOtBu:precatalyst ratio was 6121:8:1. Volume of iPrOH = 9.0 mL. Final
-
4
-5
concentrations: [Acetophenone] = 0.441 M; [KOtBu] = 5.74x10 M; [Fe] = 7.2x10 M;
c
13
d
16 e
[
iPrOH] = 12.4 M. Time = 3 min. Reference: . Time = 2 h. Reference:
. This ee has a
0
200
400
600
800
1000
large error (±10) due to the low conversion.
Time (min)
5d
temperature. The activity of these systems was much lower
than that of 1a,b and which reached completion in seconds
5d Powder
6a
6d
4
1
Fig. 6 ATH of acetophenone with crystals of the precatalysts in optimized
conditions (top – conversion, bottom – ee, positive is (R), negative is (S)). Only
the first 1000 minutes of the catalytic profile was shown to compare the rate of
catalysis for these precatalysts.
3,16
under these conditions.
In summary, the most active catalysts were 5c,d and 6a,d
.
The most intriguing result was that the ee of 1-phenethanol
ranged from 94% (R) to 90% (S). All of the activated imine
precatalysts produced (R)-1-phenethanol with a high ee,
whereas the activated amine precatalysts 6d,e produced (R)-1-
phenethanol in slight excess and 6a-c produced (S)-1-
phenethanol with a high ee. Given the varying activities and
enantioselectivities of all of the precatalysts synthesized, we
decided to focus further studies on 5d and 6d for a direct
comparison of the imine and amine precatalysts as well as 6a
to elucidate the origin of the enantioselectivity.
Catalysis with 6d displayed a steady decrease in the ee of
(
S)-1-phenethanol (an increase in the relative amount of (R)-1-
phenethanol), while 5d and 6a maintained a constant ee
within the allotted reaction time. An intriguing result was
obtained
during
the
ATH
of
3’,5’-
bis(trifluoromethyl)acetophenone, wherein the ee steadily
increased from 0% to +24% (Fig. 7).
The closest analogue to 1a is the amine complex with the
PPh2 groups, 6d, which has disappointing activity and
enantioselectivity.
The minor change of adding an
The reaction progress of these selected catalysts (and
related systems) under more optimized conditions are shown
in Fig. 6 and the yields and ee are listed in Table 2. As
mentioned, samples of the imine-containing complex 5d with
orthophenylene to precatalyst 1a led to a dramatic decrease in
the activity. The triphenylphosphine-like moiety of 5d and 6d is
too sterically demanding and this leads to slow catalyst
2
PPh groups were available as a powder containing 95:5 (S)-
NH:(R)-NH and as crystals containing a 50:50 ratio. Crystals of
the amine-containing complexes 6a and 6d were used in the
following sections instead of the powdered samples as the
crystals contain solely the major isomer. This led to a slight
discrepancy in the ee for complex 6d between Table 1 and
Table 2. The ATH of acetophenone with the crystals occurred
more rapidly. The amine-containing complex with the
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Table 2 ATH of acetophenone to higher conversion catalyzed by crystals of the complexes followed by the formation of hydrides by treatment
a
2
selected catalyst systems, unless otherwise stated
with iPrOH. A summary of the NMR chemical shifts and J
PP
coupling constants of all of the precatalysts and activated
complexes can be found in the supporting information (see
ESI, page S10). All of the structures proposed herein are based
on the data collected from crystal structures. The relative
amounts of the isomers and free ligand in each reaction are
Precatalyst, R
Label
Conversion
%)
ee (%), 1-
phenethanol
78/78 (R)
80/80 (R)
95/95 (S)
20/8 (S)
(
Imine, Ph
Imine, Ph
Amine, Et
Amine, Ph
5d powder
66/91
84/97
93/97
25/38
5d
6a
6d
3
1
estimated based on the integration of their P NMR signals.
From previous studies of the reaction of KOtBu with 1a in
a
Reactions performed under argon at 28 °C. Time = 180/500 min.
Conversion and ee at 180/500 min. Acetophenone:KOtBu:precatalyst ratio
was 500:8:1. Volume of iPrOH 9.0 mL. Final concentrations:
Acetophenone] = 0.037 M; [KOtBu] = 05.74x10 M; [Fe] = 7.2x10 M; the imino group thus producing one amido and one enamido
THF
, it is known that the precatalyst is deprotonated once at
the amino group and once at the methylene group adjacent to
=
-
4
-5
[
1
3
[iPrOH] = 13.1 M. Conversions and ee were determined as in Table 1.
nitrogen donor in a five-coordinate neutral iron complex.
100
9
8
7
6
5
4
3
2
1
0
0
0
0
0
0
0
0
0
0
-10
0
60
120
180
Time (min)
Conversion
240
300
360
ee
Fig. 7 ATH of 3’,5’-bis(trifluoromethyl)acetophenone with crystals of precatalyst
in optimized conditions. ee, positive is ( ), negative is ( ). Values of ee at low
conversions at early times have large errors.
6
d
R
S
Scheme 4 Reaction of 5d with one equivalent of KOtBu.
activation, ligand lability, and catalyst instability. Studies into
the catalyst activation as described in the next section support When isopropanol is added to this solution, it protonates the
these assertions.
nitrogen of the amido donor; the enamido nitrogen is less
basic and is not protonated. The isopropoxide then transfers a
2 2
Decreasing the bulk of one of the donors to PEt CH -
creates a more stable catalyst. When the substrate:precatalyst hydride to iron to form the active neutral iron hydride amine
ratio and temperature are increased to 6121:1 and 75 °C, 5d complex with the release of acetone. We designed the current
deactivated after 4% conversion but 6a displayed no signs of catalytic system so that a weakly basic but unreducible
deactivation. With multiple additions of 6121 equivalents of orthophenylene amido would replace the enamido group of
acetophenone to a heated solution of 6a in a closed vial, a TON 1a; a free orthophenylene amine is expected to be acidic like
of 8821 could be obtained in 8.5 hours (see ESI, Page S12). In aniline and become even more acidic upon coordination to the
this case the 90% ee for (S)-1-phenylethanol was retained. iron(II). Consequently, the orthophenylene amido would
When precatalyst 6a was heated at 85 C with an argon flow remain deprotonated under the basic catalytic conditions in
over the solution to remove some acetone and with an initial iPrOH.
substrate:precatalyst ratio of 54 000:1 an equilibrium was
The reaction of the powder of 5d with one equivalent of
reached after three days. Then another 54 000:1 equivalents potassium tert-butoxide (KOtBu) is shown in Scheme 4. The
of acetophenone was added to the reaction mixture. This acidic aniline-like amine is deprotonated to form 14d as the
process was repeated to reach a TON of 150 000 over 11 days. major species as well as cis-beta-15d and 16d and two other
Due to the equilibrium process, the ee of the product alcohol very minor species. In Scheme 4, 15d is shown to form directly
degraded to zero over the course of the reaction.
from 5d by deprotonation. The proposed cis-β structure of
2
5d is based on the large J coupling constant of 59 Hz in the
1
PP
3
1
Base activation and hydride studies of 5d, 6a, and 6d
P NMR spectrum. The absence of the bromide ligand in 15d
3
1
A study of the activation of the precatalysts and the is based on the large Δδ of the two P doublets, also observed
production of the iron hydride species serves to shed light on for the crystallographically characterized complex 16d
As
the catalytic cycle and the origin of the enantioselectivity. Here drawn, the CO and C H PPh groups have switched positions,
.
6
4
2
we examine the stepwise deprotonation of the complexes with
varying equivalents of base in THF to give mixtures of amido
6
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possibly by dissociation of this bulky phosphine moiety. 14d 87.3(3).
has the NMR characteristics of a trans complex. In order to observe hydride complexes, the powder of 5d
The five-coordinate imine-amido complex 16d crystallized was treated with base and then iPrOH as in ATH catalysis
from the crude mixture produced as in Scheme 4 (Fig. 8). It is conditions, resulting in the formation of three products
square pyramidal with a calculated degree of trigonality
τ
of (Scheme 5). After 1 day the hydride complex 17d and the
The trigonal planar amido nitrogen N1, the imine doubly deprotonated complex 18d became the major species
nitrogen N2 and the rigid orthophenylene group hold Fe1, N2, in the mixture, and the alkoxide complex 19d disappeared. The
3
5
0.38.
1
3
1
N1 and P1 in a plane. The CH
2
CH
2
PPh
2
arm is bent slightly out
-N -N -P
C- H HSQC spectrum revealed that the imine of 5d had been
of the plane, as shown in the top of Fig. 8, with a P
1
1
2
2
H
H
H
torsion angle of -21.3°. Overlap between the filled p orbital on
N1 and an empty d orbital on Fe(II) results in pi-bonding and a
shortening in the nitrogen-iron bond length from 2.047(9) Å in
Ph
NH
Ph
Ph
Ph
N
Ph
Ph
1) 8 eq. KOtBu, THF
H
N
H
H
H
N
X
N
H
5 min.
N
5d-(S)-NH
+
Fe
C
Fe
+
Fe
95%
2) iPrOH, 5 min
P
Ph
P
P
C
O
P
P
C
O
P
Ph
2
Ph
2
Ph
2
Ph
2
Ph
2
2
O
5d-(S)-NH to 1.819(9) Å in 16d
. A bisamido iron complex
17d
18d
19d
formed from orthodiaminobenzene has similar Fe-N distances
X = OiPr, OtBu
3
1.896(2) Å, 1.915(2) Å). The CO and P donor atoms form a
6
2
4
0% (5 min)
0% (1 d)
30% (5 min)
60% (1 d)
50% (5 min)
0% (1 d)
(
2
Y shape across from the Fe1-N1 bond with a P2-Fe1-C17 angle
of
Scheme 5 Products of the activation of 5d
.
reduced since none of the products have imine resonances.
Complex 17d formed slowly upon addition of iPrOH, requiring
at least five minutes to obtain an appreciable amount for NMR
analysis. This was likely due to the hindered approach of iPrOH
to the sterically encumbered iron centre of amido complexes
like 18d. The structure of 16d shows that there is likely to be
an ortho-CH from phenyl groups blocking the open site of the
iron.
Iron complex 17d contains the hydride and the amine
proton on opposite sides of the PNNP’ ligand. This hydride
species is expected to be catalytically less active in ATH than
Fig. 1) which has Fe-H and N-H aligned on the same side of
PNNP ligand to take advantage of the rate enhancing “N-H
2
(
3
7, 38
Effect”.
In order to verify the identity of complexes 17d
crystals of 6d were reacted with one equivalent of KOtBu
Scheme 6). This is a simpler reaction than that of Scheme 5
-19d,
(
which required the reduction of the imine of 5d as one of the
steps. Deprotonation of the acidic orthophenylene amine led
to the formation of the singly deprotonated complex 20d with
a small amount of 18d. Addition of iPrOH led to the formation
of the same mixture of complexes 17d-19d, as in Scheme 5,
confirming that the imine of 5d was indeed reduced.
Activation of 6d led to a much lower concentration of the
hydride species 17d, affording a decreased activity compared
to the imine precatalyst 5d. The major species of the activation
step was the alkoxide complex 19d which shifted to the doubly
deprotonated complex 18d slowly over time (see ESI, Fig. S17).
The activation of 6a bearing the diethylphosphine group
was accomplished in a similar manner. First, the species
resulting from reacting 6a with one equivalent of KOtBu in THF
are shown in Scheme 7. The major product 20a remained
pyramidal at the orthophenylene amido nitrogen, allowing the
bromide to remain fixed on the iron centre. The doubly
Fig. 8 ORTEP plot of the cation of 16d. A torsion angle view of the PNNP ligand (top)
and a view of the open site (bottom). Thermal ellipsoids are drawn at 50% probability deprotonated complex 18a was present in small amount
level. Most aromatic ring protons and the BPh
4
counteranion were omitted for clarity.
alongside the six-coordinate iron complex with the cis-β
structure cis-beta-20a which would logically result from direct
deprotonation of 6a.
Selected interatomic distances (Å), angles (deg), and torsion angles (deg): Fe1-N1
1
1
1
.818(9), Fe1-N2 1.946(8), Fe1-P1 2.230(3), Fe1-P2 2.228(3), N1-C5 1.420(12), P1-C6
.776(11), N2-C3 1.296(12), C3-C4 1.49(1), N1-C1 1.49(1), N2-C2 1.49(1); P1-Fe1-P2
04.4(1); P1-N1-N2-P2 -21.3.
After the reaction of 6a with excess base, the addition of
iPrOH immediately produced the hydride complex 21a as
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shown in Scheme 8. The amine proton of 21a is in the CHPhCHPh backbone due to the steric bulk around the active
thermodynamically favoured location, below the plane of the site in 21 and 23. See the supporting information for the three-
PNNP’ ligand, whereas the carbonyl ligand now can be found dimensional space-filling models of 1-phenylethoxide
above the plane. This places the Fe-H and N-H bonds in hydrogen bonded to the NH in the active site from above or
alignment to participate in the rate enhancing “N-H effect” on below the plane of the PNNP’ ligand. (see ESI, Pages S65-S67).
hydride transfer to the ketone in the outersphere. The In more detail, the reaction of
5 with one equivalent of KOtBu
proposed alkoxide complex 19a was formed as a minor leads to the formation of 16 (Scheme 9) wherein the carbonyl
species, disappearing after 3 days.
ligand is below the plane of the PNNP ligand (as
Scheme 6 Reaction of 6d with one equivalent of KOtBu.
Scheme 8 Products of the activation of 6a.
exemplified for 5d in Scheme 4). The reduction of the imine via
iPrOH in TS16,22 selectively occurs above the plane of the PNNP
ligand to form the unobservable complex 22 in which the lone
pair rests above the plane (Scheme 9). Subsequent formation
of the hydride complex 23 occurs relatively quickly given the
very low concentration of precatalyst in iPrOH. In a step-wise
outer-sphere pericyclic transition state TS23,22 the prochiral
acetophenone is reduced to produce (R)-1-phenylethanol and
reform 22. Over time, intermediate 23d rearranges to the
observed hydride complex 17d, wherein the Fe-H and N-H are
on opposite sides of the PNNP’ ligand and therefore exhibit
the lowest catalytic activity. Although slow, 17 may also
hydrogenate acetophenone via a step-wise hydride transfer to
acetophenone to form a bound (R)-1-phenylethoxide iron
complex, which can be protonated by iPrOH to release (R)-1-
phenylethanol.
Activation of the amine precatalysts
6 is proposed to occur
via deprotonation of both amines and subsequent
rearrangement of a cis-β structure to form the square
pyramidal complexes 18. As complex CO-Up-18 is formed in
the equilibrium, iPrOH may quickly donate a proton and
hydride through an outer-sphere mechanism to produce the
Scheme 7 Reaction of 6a-(S,S)-NH,NH with one equivalent of KOtBu.
Proposed catalytic cycle and explanation of activity and
enantioselectivity of iron precatalysts
active hydride complex 21
. Prochiral acetophenone is
Key evidence such as the reversal of enantioselectivity of preferentially reduced to (S)-1-phenylethanol, reforming CO-
precatalysts 5d and 6a, the askew catalytic profile of 3’,5’- Up-18 in the process.
The activity of the imine precatalyst 5d is an interesting
bis(trifluoromethyl)acetophenone with precatalyst 6d, and
base studies was used to conclude that there is more than one case as the precatalyst is available as a powder containing 95:5
catalytic cycle at work. The nature of the precatalyst (S)-NH:(R)-NH and crystals containing a 50:50 ratio. The
determines which catalytic cycle dominates. We propose that activity of the powder is significantly lower than that of the
the activated imine precatalysts form an unobserved kinetic crystals. We postulate that the minor diastereomer would
hydride (23 in Scheme 9) that has the Fe-H and N-H aligned rearrange more easily to place the carbonyl ligand below the
above the plane of the PNNP’ ligand, while activated amine plane of the PNNP’ ligand. The diastereomeric structures
precatalysts 6a-e produce the hydride species (21 in Scheme 9) shown in Scheme 2 demonstrate that the (S)-NH isomer
that have aligned Fe-H and N-H below the plane. The reversal requires loss of the bromide ligand and for the CO and the
of the enantioselectivity is then caused by altering which side triphenylphosphine-like part of the ligand to swap
of the PNNP’ plane transfer of the hydride to the substrate coordination sites. The (R)-NH isomer, upon loss of the
takes place. In both cases, the phenyl group of the bromide ligand, would simply need to shift the carbonyl and
approaching acetophenone points away from the (S,S)- the triphenylphosphine moiety to produce 16d. The crystals of
8
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6d were also tested in the ATH of acetophenone to obtain a
ARTICLE
1
comparable activity to the crystals of 5d (see ESI, Page S11).
These precatalysts all obtain an ee of 79-80%, demonstrating
that the precatalysts likely produce the same active hydride,
but in varying quantities.
For precatalyst 5d, the more active hydride 23d initially
forms then rearranges to 17d as the reaction proceeds. This
effect on activity was not apparent at low
substrate:precatalyst ratios and temperatures, but when the
substrate:precatalyst ratio was increased to 6121:1 and the
reaction temperature to 75 °C, the catalyst’s activity ceased
after 4% conversion. The increased temperature likely
enhanced the rate of rearrangement from hydride 23d to 17d
.
For precatalyst 6a, complex 21a is the most stable hydride
allowing for the ATH of acetophenone to produce (S)-1-
phenylethanol enantioselectively with the highest activity.
Since 21a is the hydride that is favored by thermodynamics
when R=Et, and 6a is more stable than 5d
, 6a directly produces
more of an active hydride than 5d at increased
substrate:precatalyst
ratio
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Scheme
9
Proposed
mechanism
for
the
reduction
of
acetophenone
with
precatalysts
5
and
6.
and temperature. With multiple additions of substrate, a
TON of 8821 was obtained in 8.5 h while retaining the ee
of 90% for (S)-1-phenylethanol.
to 22d to produce the (R)-1-phenylethanol. Therefore the
powdered precatalyst 6d containing the (R,S)
,
diastereomer would yield a slight excess of the (R)-1-
phenylethanol as shown in Table 1.
Precatalyst 6d presented an unusual result for
investigation. Using the crystals of 6d, a large amount of
In summary, the enantioselectivity and activity of the
activated catalysts depend on two factors: the equilibrium
2
1d was produced, allowing for the production of (S)-1-
phenylethanol in excess. The relative amount of (R)-1-
phenylethanol increased as the reaction proceeded, which
suggests that the active hydride was slowly converted to
between CO-Up-18, CO-Down-18, and 22, as well as the
equilibrium between 23 and 17. Initially imine precatalysts
form an excess of 22, while amine precatalysts form an
2
3d
bis(trifluoromethyl)acetophenone as the ee was initially
%, and increased to +20% over the course of catalysis.
.
This was mirrored in the ATH of 3’,5’-
excess of CO-Down-18
. As the reaction proceeds
precatalysts 5d and 6d create an excess of 17, whereas
0
precatalyst 6a create an excess of 21.
The change in ee coincided perfectly with the rate of ATH,
rapidly increasing during the first 150 minutes, then
subsiding until equilibrium is reached (see Fig. 7). These
tests suggest that a solution of activated 6d contains two
competing hydride species.
CONCLUSION
A highly versatile synthetic protocol via a Buchwald-
Hartwig amination was performed to synthesize the new
air-stable, chiral PNN ligand
9 bearing an orthophenylene
The discrepancy in ee for 6d between Table 1 and
Table 2 is due to the precatalyst being available either as a
powder containing a mixture of the (R,S) and the (S,S)
diastereomers or crystals containing solely the (S,S)
diastereomer. In basic conditions, the bromide of the (S,S)
diastereomer decoordinates to allow for a facile shift of
the carbonyl ligand above the plane of the PNNP. This
produces an excess of CO-Up-18 and thus more of the (S)-
and a primary amine with an overall yield of 68%. A series
of PNNP’ ligands were also synthesized via reductive
amination, but were not isolated. Eleven new cis-β iron (II)
PNNP’ precatalysts 5a-f and 6a-e were isolated as a pair of
diastereomers and preliminarily tested in the ATH of
acetophenone. Two factors contributed to the formation
of cis-β precatalysts: the bulk of the phosphine donors as
well as the flexibility of the linker connecting the amino
donor to the phosphine donor. Imine precatalyst 5d
crystallized as a pair of diastereomers while amine
precatalyst 6a crystallized as a single diastereomer. This
permitted an interesting comparison of the activity of
powdered 5d containing a (S)-NH:(R)-NH ratio of 95:5 with
1
-phenylethanol when using crystals of 6d. Using the (R,S)
diastereomer, the bromide would decoordinate and the
carbonyl would shift down to fill the empty coordination
site below the plane of the PNNP ligand. This produces
more of CO-Down-18 which would rearrange more quickly
1
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the activity of the isolated crystals with a 50:50 ratio. The
data suggested
condensation with aldehydes,
unsymmetrical, chiral tetradentate PNNX (where X = N, P,
O, etc.) ligands may be synthesized. Ligand may also be
a plethora of new
9
Fig. 9 Amine complex 5d and imine complex 6a lead to hydrides that
produce opposite enantiomers.
Scheme 10 Employing
shorten the metallocycle ring size by one.
9 as a substitute for the commonly used ligand 24 to
that the minor isomer may lead to a higher concentration
of the active hydride. While the activity of these
precatalysts were low compared to previously published
used as a building block to study the effect of shortening
the metallocycle ring size by one atom in catalyst systems
which currently use the PNN-fragment 24 and its
iron (II) PNNP’ complexes 1a,b and
4
,
the
enantioselectivity varied dramatically ranging from +94%
with 5e to -95% with 6a. The mechanism of activation was
studied with 5d and 6d, for a direct comparison of an
imine and an amine precatalyst, as well as with 6a to
elucidate the reversal of the ee. The studies revealed that
the imine precatalyst 5d and amine precatalyst 6d form
identical thermodynamic products when activated; it is the
formation of different kinetic hydrides led to the
significant difference in ee between these two
precatalysts. The reversal of the enantioselectivity, from
2
2, 26, 40-46
tetradentate variants (Scheme 10).
Acknowledgements
Robert H. Morris thanks NSERC for a Discovery Grant and
the Canada Council for the Arts for a Killam Research
Fellowship. NSERC is thanked for a PGS D awarded to Karl
Z. Demmans. The authors wish to acknowledge the
Canadian Foundation for Innovation, project number
5d to 6a, is proposed to be caused by the formation of
1
9119, and the Ontario Research Fund for funding of the
hydrides on the opposite sides of the plane of the PNNP’
Centre for Spectroscopic Investigation of Complex Organic
Molecules and Polymers. Digital Specialty Chemicals is
thanked for supplying chemicals.
ligand (Fig. 9). In systems employing a C -symmetric
2
catalyst, the ee would not change regardless of which side
3
9
the substrate approached from, but in the current case a
reversal of the ee is observed due to the formation of a C1-
symmetric catalyst. This proposal is supported by the
structure determinations of the hydride species produced
from 5d and 6a which contained hydrides on opposite
sides of the PNNP’ ligand.
Notes and references
1
S. Hameed P, M. Chinnapattu, G. Shanbag, P. Manjrekar,
K. Koushik, A. Raichurkar, V. Patil, S. Jatheendranath, S.
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Bharath, P. Viswanath, K. Mukherjee, B. Bandodkar, A.
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Latham, L. B. Peterson, R. Rosa, J. V. Pivnichny, X. Tong,
S. S. Xu and P. J. Sinclair, J. Med. Chem., 2011, 54, 4880-
When the ATH of acetophenone was heated to 75 °C
and the substrate:precatalyst ratio was increased from
5
00:1 to 6121:1, 5d deactivated readily while 6a reacted
cleanly. With multiple additions of 6121 equivalents of
acetophenone to a heated solution of 6a, a TON of 8821
was obtained in 8.5 hours while retaining an ee of 90% for
(S)-1-phenylethanol. The objective of this study was to
increase the stability of active hydride 2 by replacing the
2
enamido with an orthophenylene group. This was partially
achieved using the complex with a PEt2 group which
catalyzed the transfer hydrogenation 150 000 equivalents
of acetophenone to racemic 1-phenylethanol.
The methodology described here may prove quite useful
for groups studying asymmetric catalysis. Upon simple
4
895.
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3
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Friggeri, M. Mori, D. Fiorucci, G. Maccari, R. S. Arul
Christopher, C. Zamperini, V. Pau, A. De Logu, S.
35 A. W. Addison, T. N. Rao, J. Reedijk, J. Van Rijn and G. C.
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