Aqueous biphasic iron-catalyzed asymmetric transfer hydrogenation of aromatic ketones

Article abstract of DOI:10.1039/c6ra22538a

For the first time, an iron(ii) catalyst is used in the biphasic asymmetric transfer hydrogenation (ATH) of ketones to enantioenriched alcohols employing water and potassium formate as the proton and hydride source, respectively. The precatalyst [FeCl(CO)(P-NH-N-P)]BF₄ (P-NH-N-P = (S,S)-PPh₂CH₂CH₂NHCHPhCHPhNCHCH₂PPh₂) in the organic phase with the substrate is activated by base to produce a system that rivals the best ruthenium biphasic ATH catalysts in activity but not enantioselectivity. Biorenewable 2-methyltetrahydrofuran as a cosolvent and biodegradable TWEEN80 as a surfactant were added to the reaction mixture to greatly decrease the mass-transfer limitations caused by the biphasic reaction mixture. The enantioselectivity of the reduction was as high as 76% depending on the substitution pattern of the arylketone employed. NMR studies verified the formation of an iron hydride [FeH(CO)(PPh₂CH₂CH₂NHCHPhCHPhNCHCHPPh₂)] intermediate as was observed in our 2-propanol-based ATH studies.

Full text of DOI:10.1039/c6ra22538a

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DOI: 10.1039/C6RA22538A
Journal Name
ARTICLE
Aqueous Biphasic Iron-Catalyzed Asymmetric Transfer
Hydrogenation of Aromatic Ketones
K. Z. Demmans,a O. W. K. Ko,a and R. H. Morris*a
Received 00th January 20xx,
Accepted 00th January 20xx
For the first time, an iron (II) catalyst is used in the biphasic asymmetric transfer hydrogenation (ATH) of ketones to
enantioenriched alcohols employing water and potassium formate as the proton and hydride source, respectively. The
precatalyst [FeCl(CO)(P-NH-N-P)]BF4 (P-NH-N-P = (S,S)-PPh2CH2CH2NHCHPhCHPhNCHCH2PPh2) in the organic phase with
the substrate is activated by base to produce a system that rivals the best ruthenium biphasic ATH catalysts in activity but
not enantioselectivity. Biorenewable 2-methyltetrahydrofuran as a cosolvent and biodegradable TWEEN80 as a surfactant
were added to the reaction mixture to greatly decrease the mass-transfer limitations caused by the biphasic reaction
mixture. The enantioselectivity of the reduction was as high as 76% depending on the substitution pattern of the
arylketone employed. NMR studies verified the formation of an iron hydride
DOI: 10.1039/x0xx00000x
www.rsc.org/
[FeH(CO)(PPh2CH2CH2NHCHPhCHPhNCHCHPPh2)] intermediate as was observed in our 2-propanol-based ATH studies.
Introduction
The asymmetric hydrogenation of ketones is a widely studied
area of chemistry that has seen a recent surge in iron-
catalyzed reactions employing various tridentate and
tetradentate ligands.1
Our group has focused on the
asymmetric transfer hydrogenation (ATH) of ketones,
Fig. 1 (a) The reversible ATH of ketones when using 2-propanol and (b) the
irreversible ATH when using water and sodium formate as the proton and
hydride sources.
a
strategy that removes the dangers of using pressurized
hydrogen by utilizing 2-propanol as the proton and hydride
source.2
In the ATH with 2-propanol, acetone is formed which can be
reduced back into 2-propanol. However, when employing
sodium formate, the CO2 that is produced can be purged from
the system thus favouring the forward reaction and reducing
the ketone substrate completely. In principle, the CO2 could
be hydrogenated in a separate process to regenerate the
formate. It is important to note that the reaction becomes
more basic as sodium hydroxide is formed as a byproduct of
Over the past two decades, the library of proton and hydride
sources has been expanded to include azeotropic mixtures of
formic acid and triethylamine for catalysts active in acidic
conditions,3 sodium formate and water for catalysts active in
basic conditions,3c, 4 and even using glycerol as the proton and
hydride source.5 All of these studies involve the use of
expensive ruthenium, rhodium, or iridium catalysts to obtain
enantiomerically pure alcohols. Alcohols produced in this way
can be valuable intermediates for the synthesis of
pharmaceuticals.4c, 6 Interestingly, a recent study by Hu et al.
employs an iron (II) PONOP pincer catalyst with sodium
formate in methanol to reduce various aldehydes
quantitatively.7 Concurrently, we sought to replace our 2-
propanol-based ATH with water and sodium formate to shift
the equilibrium to favour full conversion to the product alcohol
as shown schematically in Fig. 1.
the deprotonation of water.
This can affect the
enantioselectivity of the process as discussed in this study.
Fig. 2 Iron (II) catalyst precursor trans-(S,S)-[FeCl(CO)(P-NH-N-P)][BF4].2d
Another disadvantage was the formation of a biphasic reaction
mixture; the substrate and catalyst form an organic top layer
while the bottom was a polar basic aqueous layer. Fortunately,
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extensive mechanistic studies about the ATH in water with Optimization of the reaction conditions
ruthenium have been reported by several groups.4a, 8
With these studies in mind, the iron catalyst
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DOI: 10.1039/C6RA22538A
To begin, the sodium formate concentration was adjusted to
shown in Fig. 2 1000, 4000, and 8000 equivalents relative to 1 (Table 1, Entries
1
was successfully used in conjunction with water and sodium 1-3).
formate for the enantioselective reduction of ketones for the
Table 1 Sodium formate, potassium hydroxide, and phase transfer catalyst
effects on the ATH of acetophenone.a
first time. Due to its large abundance and lower toxicity, iron
serves as a greener alternative to ruthenium, rhodium, and
iridium, metals that are typically used in such a process.4c, 6, 8-9
Results and discussion
Starting reaction conditions and hypothesis of reaction
mechanism
a
All
value
are
in
Entry
1
TBA+X- (Eq.)
Conversion (%)
e.e. (%)
76
79
79
77
74
77
77
67
s
X=Br
1
1
1
2
5
0
1
1
1
5
1
9
20
25
7
5
10
9
2b
3c
4
Our previously reported conditions for the ATH with 2-
propanol were adapted to a mixture of water, sodium
formate, and a strong base such as potassium hydroxide (to
equiv
alent
s
relati
ve to
the
5
ensure activation of 1). This solution was placed in a flask and
6
7d
8e
9
sealed under argon gas against a mercury bubbler set at
about 1.5 atm pressure. In contrast to the homogeneous 2-
propanol system, the mass-transfer limitations caused by the
formation of the biphasic system require the addition of a
phase transfer catalyst such as tetrabutylammonium bromide
9
iron
catal
yst:
X=BF4
18
15
23
80
78
79
10
11f
0.006
mmol
(TBA+Br-) to ease the activation of the non-polar iron catalyst
by the basic water.
1
1
, 1000 eq. NaHCOO, 8 eq. KOH, 200:1 acetophenone : catalyst ratio, 4 mL
water, 600 RPM stirring rate. The (R) enantiomer is always the main product.
b4000 eq. of NaHCOO. c 8000 eq of NaHCOO. No KOH was added. 32 eq. of
d
e
KOH. f 100:1 acetophenone : catalyst ratio.
Fig. 3 presents a possible mechanism of biphasic catalysis. It is
based on the homogenous ATH mechanism using 2-propanol
as the solvent and reductant as elucidated earlier.2d, 10 In the
two phase system, the iron-containing species are thought to
remain in the organic phase on the basis of the colour of the
phases while salts such as KOH, KCl, and KHCOO remain almost
exclusively in the aqueous phase as indicated by the blue
boxes.
As expected, the conversion greatly increases with the
concentration of formate anions in the water. Increasing the
equivalents of TBA+Br- (1, 2, and 5) decreases the conversion in
accordance with what has been previously observed (Table 1,
Entries 1, 4, 5).4a, 8 Interestingly, when TBA+Br- was omitted
from the reaction a slight increase in catalytic activity was
observed (Table 1, Entry 6). We concluded that the
introduction of more halide anions could deactivate the
catalyst by coordinating to the open site as shown in the
proposed catalytic reaction mechanism (Fig. 3). Therefore the
phase transfer catalyst’s counteranion was switched to
In the mechanism, the catalyst precursor iron chloride complex
1
reacts with base, either hydroxide or formate from the
aqueous phase, and loses one equivalent of HCl to form the
amido-eneamido complex in the original 2-propanol
2
;
mechanism, potassium 2-propoxide acts as the base.
tetrafluoroborate to match that of 1, resulting in a doubling of
activity (Table 1, Entry 9). Once again as the concentration of
-
TBA+BF4 is increased beyond the optimal one equivalent, the
activity decreases. Lastly, removing the potassium hydroxide
had no impact on the activity which demonstrated that the
water layer was basic enough to activate
1 (Table 1, Entry 7
compared to Entry 1). Furthermore, adding a large excess of
potassium hydroxide causes a sharp decrease in enantiomeric
excess (e.e.) (Table 1, Entry 8), presumably by some
modification of the catalyst structure. Therefore potassium
hydroxide was not used in subsequent studies.
With all of the aforementioned catalytic reactions, regardless
of how extreme the reaction conditions were pushed, an
asymptote of approximately 25% conversion was observed.
Even lowering the acetophenone : catalyst ratio to 100 : 1 did
not lead to a high conversion (Table 1, Entry 10). The
experimental set-up was not allowing for the carbon dioxide
Fig. 3 Proposed catalytic cycle.
The results below are discussed in the light of this proposed
mechanism.
2 | J. Name., 2012, 00, 1-3
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being produced in the reaction flask to be purged from the iron complex to form the product lithium formateV.i1e2wTAhrtieclreeOfnolirnee
DOI: 10.1039/C6RA22538A
the catalytic cycle and the reaction rate found herein should
system efficiently. Therefore, an argon flow through
a
condenser to the external bubbler (filled with mineral oil) was also be cation sensitive.
added to the experimental set-up, as well as decreasing the
reaction volume to 1 mL and using 2000 eq. of sodium formate
to match the concentration used in Table 1, Entry 3. These
changes increased the conversion to 74% after 4 h (Table 2,
Entry 1).
Substrate scope
With the optimized reaction conditions in hand, a substrate
scope was conducted using bio-renewable MeTHF as the
cosolvent (Fig. 4).
Table 2 Catalysis with an improved catalytic setup and the use of a cosolvent.a
Entry
1
Time (h)
Conversion (%)
e.e. (%)
53
57
4
1
1
74
83
>99
2b
3b,c
57
a
Constant argon flow was used to purge the reaction flask. All values are in
equivalents relative to the iron catalyst: 0.006 mmol 1, 2000 eq. NaHCOO, 1 eq.
-
TBA+ BF4 , 100:1 acetophenone : catalyst ratio, 1 mL water, 600 RPM stirring rate,
65 °C. b MeTHF was added (1 mL). c 2000 eq. of KHCOO was used.
While the conversion greatly increased, a large increase in the
amount of hydroxide anions produced lead to a decrease in
e.e. from 78% to 53%. This was proposed to be due to the
modification of
2 into alternate iron complexes with a lower
enantioselectivity under very basic conditions.2a, 2d, 9e Most of
the active ruthenium biphasic ATH catalysts described in the
literature are found in the aqueous layer along with a formate
salt while the substrate is found in an organic layer.3c, 4 This
allows the ruthenium catalyst to be in constant contact with
the proton and hydride source. In contrast, the biphasic
Fig. 4 Substrate scope under optimized conditions.a
Constant argon flow was used to purge the reaction flask. All values are in
a
equivalents relative to the iron catalyst: 0.006 mmol 1, 2000 eq. KHCOO, 1 eq.
-
b
TBA+BF4 , 2 mL reaction volume (1:1 water:MeTHF), 600 RPM stirring rate.
c
Isolated yield using the specifications found in the SI. Gas Chromatography
could not separate the (R) and (S) alcohols accurately.
system studied herein has the substrate and
1 in the non-polar
The ketones with bulky substrates on the right side as drawn in
Fig. 4, such as cyclohexylphenylketone and isobutyrophenone,
were the only substrates that were not reduced to
quantitative conversion. In all other cases, the ketones were
quantitatively converted to their respective alcohols with
moderate to high enantioselectively. An exceptional case
displaying high enantioselectivity was 2’-chloroacetophenone
layer, with sodium formate and water in the polar layer. This
causes the transfer of the proton and hydride from water and
sodium formate to
1 to be slow while subsequent transfer of
this dihydrogen equivalent from the iron catalyst to the ketone
substrate in the organic layer should be very rapid if the
mechanism is the same as the one established for ATH with 2-
propanol. For this reason a cosolvent for the organic layer was
added to increase the size of the interphase region and
with 76%. Iron precatalyst
1 displayed some functional group
tolerance, converting 2-acetylfuran and 2-acetylpyridine to the
alcohols to near quantitative yields within one hour. A major
benefit of the protocol presented here was the reduction of
ketones that are soluble in MeTHF but not soluble in 2-
propanol, such as 2,4’-dichloroacetophenone; the use of 2-
propanol gave no conversion (see SI, S15). 3’,5’-
Bis(trifluoromethyl)acetophenone was converted at 200:1
substrate:catalyst ratio in one hour, albeit with a moderate
enantioselectivity. The product alcohol is a precursor to
Aprepitant, a drug to relieve nausea caused by chemotherapy
treatment.13
The scale of the reaction can be increased tenfold to
successfully convert 1.4 mL of acetophenone in an hour while
maintaining the e.e. at 55%. An increased RPM and larger
stirring bar must be used to efficiently mix the two immiscible
layers.
promote the interaction of
2 with the proton and hydride
sources. 2-Methyltetrahydrofuran (MeTHF) was chosen over
tetrahydrofuran as the cosolvent due to its higher boiling
point, allowing for higher reaction temperatures, and for its
bio-renewability as it is derived from C6 sugars.11 With MeTHF,
83% conversion was obtained in only an hour (Table 2, Entry
2). Switching the hydride source to potassium formate allowed
for the quantitative conversion in an hour (Table 2, Entry 3)
and therefore the potassium salt was used hereafter. The
difference in reactivity of the two salts cannot be attributed to
solubility differences in the organic phase. We measured the
concentration of a saturated solution of KHCOO or NaHCOO in
a dry MeTHF/acetone mixture (V/V = 4/0.2) at 65 °C to be
approximately 0.01 M. However the sodium salt would be
expected to be more strongly ion paired in the organic phase
and therefore less reactive. It has been shown in the
hydrogenation of CO2 that the densely positive charge from a
lithium cation eases the release of the O-formato from the
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Moderate Reaction Conditions and Study on Additives
Comparing to the standard catalytic run (TableVi4ew, AErtnictleryOn1lin)e,
there was little to no conversion whenDbOoIt:h10.t1h0e39p/Cr6oRtAo2n25a3n8dA
hydride source are removed from the mixture, while only 6%
conversion was obtained by solely removing the proton
source. As the amount of TWEEN80 was increased, the
conversion also increases, demonstrating that TWEEN80 may
act as a proton source; although it mainly contributes as a
surfactant to increase conversion employing water as the
proton source.
In order to determine whether the lower activity of the iron
catalyst compared to the 2-propanol system was due to the
formation of a biphasic reaction mixture or due to using
formate as the hydride source, HDBU formate was synthesized
according to literature procedures.16 HDBU formate dissolves
in MeTHF at 65 °C, forming a single phase containing the
required proton and hydride source. Since only 10%
conversion was obtained in an hour, it does appear that there
is an inherent barrier to the transfer of the hydride from
formate to the iron.
All aforementioned studies involved in the optimization of this
system involved a constant flow of argon through the reaction
mixture to purge the CO2 produced and shift the equilibrium
towards the alcohol product. This wastes a large volume of
argon over the course of an hour. By only purging the system
at the beginning of catalysis for 10 seconds then leaving the
reaction flask open to an oil bubbler with no subsequent
purging, the conversion decreased from >99% to 43% (Table 3,
Entry 3).
Table 3 Effect of purging and using TWEEN80 as a surfactant.a
Entry
Flow
Additive
Conversion
e.e.
(%)
55
40
50
57
59
59
(%)
>99
53
-
1
2
3
4
5
6
Constant Argon
Constant Nitrogen
Static
TBA+BF4
TBA+BF4
TBA+BF4
-
-
43
Constant Argon
Constant Nitrogen
Static
TWEEN80
TWEEN80
TWEEN80
>99
69
Lastly, an attempt to decrease the temperature to 40 °C led to
a large decrease in activity.
97
a
All values are in equivalents relative to the iron catalyst: 0.006 mmol 1, 2000
eq.KHCOO, 1 eq. TBA+BF4- or 5 eq. TWEEN80, 200:1 acetophenone:catalyst ratio,
2 mL reaction volume (1:1 water:MeTHF), 600 RPM stirring rate, 65 °C, 1 h.
Cosolvent Screen
Acetophenone was used as a representative substrate for the
catalysis using water and potassium formate with various
cosolvents by studying the activity with an increased substrate:
catalyst ratio of 500:1. The conversion and e.e. were studied
(Table 5).
Purging with nitrogen does not yield a high conversion as
nitrogen may coordinate to the open site of the active catalyst
2
. Purging with a non-coordinating, heavier gas such as argon
was necessary to achieve greater reaction rates. Fortunately
when 5 eq. of the biodegradable THF-based surfactant,
TWEEN80, was used the activity increased readily allowing for
near quantitative conversion without constant argon purging.
Upon the addition of TWEEN80, micelles may form which
greatly increase the interphase area and decreases mass-
transfer limitations. A study comparing the hydrophilic-
lipophilic balance of many surfactants determined that
TWEEN80 is highly soluble in water due to the long
polyethylene glycol chains and also helps solubilize organics
containing alkenes or aromatic groups due to the long chain
alkene found
Table 5 Effect of the cosolvent on catalysis of acetophenone.a
Entry
1
2
3
4
Cosolvent
DMF
Conversion (%)
e.e. (%)
73
64
19
40
59
55
57
59
2
MeOH
Toluene
MeTHF
MeCN
MeTHF
MeTHF
DCM
11
14
23
30
35
67
41
44
45
49
5
6b
7c
8
in the structure of TWEEN80.14 This surfactant has been used
in a catalytic hydroxylation reaction. 15
To confirm that TWEEN80 was not providing protons or
hydrides for the ketone reduction process, a few blank tests
were run to determine its role in catalysis (Table 4).
9
10
11
Heptanes
Et2O
41
46
61
THF
a
Constant Argon flow was used to purge the reaction flask. All values are in
equivalents relative to the iron catalyst: 0.006 mmol , 2000 eq.KHCOO, 1 eq.
mL reaction volume (1:1
1
TBA+ BF4 , 500:1 acetophenone:catalyst ratio,
water:cosolvent), 600 RPM stirring rate, 65 °C, 1 h. Uses 5 eq. of TWEEN80
instead of TBA+BF4-. C Uses both 1 eq. of TBA+BF4- and 5 eq. of TWEEN80.
2
-
b
Table 4 TWEEN80 blank catalysis runs.a
Entry
Condition
TWEEN80 (eq.)
Conversion
While no immediate trend was observed based on the polarity
of the cosolvent, there were a few important observations.
DMF had the lowest conversion because of its ability to
(%)
>99
1
1
2
3
4
5
1 mL Water, 2000 eq. KHCOO
No Water, No KHCOO
5
5
coordinate to the open site of
2 and deactivate the catalyst.
No Water, 2000 eq. KHCOO
No Water, 2000 eq. KHCOO
No Water, 2000 eq. KHCOO
5
6
There is a weak trend in increasing conversion with decreasing
cosolvent boiling point. This is most likely due to an increase in
the catalyst concentration over time as the cosolvent
evaporates. While MeTHF was chosen as the cosolvent for
most of the studies here, THF provides the best activity and
the highest enantioselectivity. This can be explained by the
100
200
33
49
a
All values are in equivalents relative to the iron catalyst: 0.006 mmol 1, 200:1
acetophenone:catalyst ratio, 1 mL MeTHF, 600 RPM stirring rate, 65 °C, 1 h.
4 | J. Name., 2012, 00, 1-3
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formation of the active hydrido-eneamido iron complex (
ARTICLE
With each temperature increment as shown in Table 6, ruthenium
5
in
View Article Online
Fig. 3). When THF was used as the cosolvent, the 1H NMR
revealed the presence of a similar iron hydride species to the
active species observed in our 2-propanol studies,2d while
three iron hydride species were formed using MeTHF (see SI,
S16). These extra hydride species may also be active in transfer
hydrogenation, but produce alcohols with at a lower e.e.
(Table 5, Entries 4 and 11).
DOI: 10.1039/C6RA22538A
complexes tend to be the least active. In general, the activity
increases from ruthenium to rhodium to iridium as demonstrated
by Xiao et al. with a series of metal complexes employing L11.25
While it is hard to directly compare the activity of these complexes
at different temperatures, iron catalyst 1 was shown to be more
active than the ruthenium complexes from entries 5, 12, 14, 16.
Several rhodium complexes were active at low temperatures and
quite active at 40 °C, while the iridium complexes (entries 11 and
15) had the largest TOF of 388 h-1 at 40 °C and 1780 h-1 at 80 °C.
Switching to TWEEN80 lead to increased conversions of 35%,
while using the phase-transfer catalyst and the surfactant in
combination lead to a drastic increase in activity with 67%
conversion in an hour (Table 5, Entries 4, 6, and 7).
Xiao et al. offer
a more comprehensive review of transfer
hydrogenation which includes use of supported catalysts,
biomimetic catalysts working in conjunction with NADH, as well as
Brønsted acid organocatalysts.13
Literature comparison of catalytic activity
Various biphasic systems using sodium formate and formic acid
with water were collected in Table 6 to compare the turnover
frequency (TOF). The ligands are shown in Fig. 5.
The proposed catalytic cycle
The cycle is entered by the dehydrohalogenation of the chloro
or bromo precursor complex
1 (Fig. 3) in the same fashion as
Table 6 Catalytic activity for the biphasic ATH of acetophenone
Entry
Precatalyst
Temp. (°C)
TOFa (h-1)
e.e.
(%)
73 (R)
Ref.
the activation of the catalyst for use in ATH using 2-propanol
as the reductant.2d, 10 The addition of excess halide apparently
reverses this process and causes a reduction in catalytic
activity (Table 1). The major difference between this biphasic
mechanism (Fig. 3) and mechanisms that utilize 2-propanol is
1
2
[IrCl2Cp*]2 + L1
[RhCl2Cp*]2 + L2
[RhCl2Cp*]2 + L3
[RhClL4]
24
25
28
28
40
40
40
40
40
40
40
60
65
80
80
90
7
94
17
18
91 (S)
94 (R)
96 (R)
56 (S)
99 (R)
97 (R)
93 (R)
-
3
96
19
4
67
3b
the conversion of
mechanism an equivalent of formic acid is postulated to add to
to form with a formate bound via oxygen to the iron and
via a hydrogen bond to the N-H group that is formed by
protonation of the amido nitrogen of (see SI S15). These
2 to the iron hydride 5. In the current
5
[RuCl(p-cymene)L5]
[RhCl2Cp*]2 + L6
[RuCl(p-cymene)L7]
[RhCl2Cp*]2 + L8
[Ir(H2O)Cp*L9]2+
4
20
6
70
21
2
3
7
110
199
248
310
388
9
3a
8
22
2
9
23
steps may not be concerted, as suggested by kinetic isotope
effect studies of a similar reaction by Xiao et al.4a A similar
reaction and bonding mode was observed in the structure of
RuH(O2CH)(NH2CMe2CMe2NH2)(PPh3)2.28 The O-formate
10
11
12
13
14
15
[RhClCp*L10
]
97 (R)
99 (R)
82 (S)
55 (R)
28 (R)
-
24
[IrClCp*L11
]
25
[RuCl2(p-cymene)]2+ L12
26
1
199
20
this work
9f
complex
between the unbound oxygen of the formato and the amino
group of the ligand. As such, the transformation from to the
required to H-formate complex would not be
3 would be very stable due to the hydrogen bond
[RuCl2(p-cymene)]2 + L13
[IrClCp*L14
]
1780
16
9d
+
3
16
[RuCl(p-cymene)L15
]
-
27
, where the time was taken at
( )
a
4
(
)
TOF =
thermodynamically favoured, and indeed literature detailing
near quantitative conversion.
the mechanisms of the reverse reaction (i.e. the
29
Fig. 5 Ligand reference library for Table 6
hydrogenation of CO2 to formate) suggests this.9k,
This
barrier is estimated to be larger than the proton and hydride
donation in our 2-propanol system (17 kcal/mol), and this
would contribute to the lower rates which are observed in the
biphasic system and in the system where DBU-formate is used
in one phase.9j Subsequently, complex
hydride complex . The reaction between
4
loses CO2 to give the
and is thought to
5
3
5
be reversible because we observed that a pressure of CO2 (for
example from conducting the reaction in a closed flask) slows,
and even stops, catalysis. CO2 might also form an adduct with
the basic amido nitrogen of 2, an adduct with the eneamido
carbon next to phosphorus of
2 or 5 as observed by Milstein
and co-workers30 or even reversibly functionalize a C-H bond
of the eneamido of
2 or 5 as observed by Song and co-
workers.31 We have no evidence for these ideas as yet. If
present, these processes would have to be reversible because
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catalysis is restored when the pressure of CO2 is released by
purging with an inert gas.
Elmer Clarus 400 Chromatograph equipped with a chiral column (CP
chirasil-Dex CB 25 m x 2.5 mm) and using hydrogen gas as the
View Article Online
DOI: 10.1039/C6RA22538A
mobile phase. All experiments were repeated three times for
accuracy using 1,4-di-tert-butylbenzene (DTBB) as an external
standard. All extraction solvents were distilled for reuse.
From the active iron hydride species 5, the ketone is reduced
in an outer-sphere mechanism via a six-membered ring
intermediate with subsequent release of the alcohol product
and formation of
2 thus completing the cycle. This
General procedure for asymmetric transfer hydrogenation of
acetophenone (Table 1)
enantioselective ketone hydrogenation step is the same as that
detected in the 2-propanol ATH mechanism.2d, 32 When the reaction
is conducted in the presence of DMF, the catalysis is thought to be
slower due to the coordination of DMF to 2 or to 1 with
displacement of a halide.
In a glovebox, sodium formate (808 mg, 11.90 mmol) and
potassium hydroxide (6 mg, 0.10 mmol) were placed in a 25
mL Schlenk flask which was then removed from the glovebox.
Distilled water (8 mL) was added to form the basic water stock
solution containing a concentration of 101 mg/mL and 0.75
mg/mL of sodium formate and potassium hydroxide,
respectively. This solution was then freeze-pump-thawed
three times to remove any oxygen. Concurrently in a glovebox,
Conclusions
A highly active, air-sensitive iron P-NH-N-P catalyst for ATH in
basic 2-propanol was tested for its activity in a biphasic
reaction employing water and potassium formate as the
proton and hydride sources, respectively. The catalyst was
found to be less active for the reduction of ketones in a
biphasic system, but quite active using as little as 0.5 mol%
catalyst loading. The observed reactivity rivals that of most
ruthenium-based catalysts employing a biphasic water and
formate-based system, albeit with a lower enantioselectivity.
Due to the nature of the biphasic mixture, the product alcohols
can be easily separated by removing the MeTHF layer from the
reaction vessel and extracting with as little as 2 mL of MeTHF,
but purification of the product alcohols still required a silica
plug with hexanes and ethylacetate to remove the iron
catalyst. While argon purging was not necessary at lower
substrate:catalyst loadings when employing TWEEN80 as a
surfactant, the use of argon purging does lead to increased
TOF. Future improvement to this system includes using a
cosolvent which does not produce multiple active hydrides or
removing the need for a cosolvent entirely. The catalyst
stability could also be improved by maintaining the pH of the
reaction at 7.5. Hydroxide anions are produced as the reaction
proceeds and the iron catalyst is known to be sensitive to
harsher basic conditions. These changes would lead to an even
more sustainable and environmentally benign catalytic process
that might use formate produced in a solar process33 and iron
complexes with low synthetic E factors.
a stock solution of
1
(10 mg, 0.012 mmol) and TBA+Br- or
TBA+BF4- (4 mg, 0.006 mmol, in both cases) in dichloromethane
(1 mL) was prepared. This was evenly split into two 10 mL
Schlenk flasks charged with a stir bar, then the solvent was
removed in vacuo. Two syringes with acetophenone (143 mg,
1.189 mmol each) were speared into a rubber stopper.
Everything was removed from the glovebox. The basic water
stock solution was heated to 65 °C, while the Schlenk flasks
were placed under argon. Once the temperature was reached,
the acetophenone was injected into the Schlenk flask, quickly
followed by the hot basic water solution (4 mL). The stirring
plate was set to 600 RPM to begin the reaction. After 16 h, the
reaction was removed from heat and exposed to oxygen. The
product was extracted with MeTHF (3x6 mL).
Note: Each Schlenk flask contained sodium formate (404 mg,
1000 eq.), potassium hydroxide (3 mg, 8 eq.), TBA+Br- or
-
TBA+BF4 (2 mg, 1 eq.), and acetophenone (143 mg, 200 eq.).
Various stock solutions were made to change the equivalents
for the studies found herein.
General procedure for the argon purged asymmetric transfer
hydrogenation of ketones (Tables 2-5 and Fig. 4)
Procedure follows above with the following changes. The basic
stock solution was either 808 mg/mL of sodium formate in water or
1000 mg/mL of potassium formate in water. The substrates were
dissolved in the cosolvent (1 mL), then speared into a rubber
stopper. All Schlenk flasks and syringes were removed from the
glovebox. The basic water solution was heated to 65 °C, while the
Schlenk flasks were placed under argon. Once the temperature was
reached, the substrate and cosolvent were injected into the Schlenk
flask, quickly followed by the hot basic water solution (1 mL). A
condenser (outsourced to an external bubbler) was attached to
each Schlenk flask, which was then submerged into the oil bath at
65 °C. The stirring plate was set to 600 RPM to begin the reaction.
After the allotted time, the reaction was removed from heat and
exposed to oxygen. All ketones were extracted with MeTHF (3 x 6
Experimental
General remarks
All manipulations were performed under an inert atmosphere of
argon using Schlenk or standard glovebox techniques, unless
otherwise stated. Solvents and liquid substrates were dried and
degassed under standard procedures prior to use. All solid
substrates were heated to 80 °C under vacuum to remove any
traces of water before being stored in the glovebox. HDBU formate
was synthesized according to literature.16 NMR spectra were
recorded at ambient temperature and pressure using an Agilent
DD2 600 MHz spectrometer [1H (600 MHz)]. The conversions and
enantiomeric excess for each reaction were obtained on a Perkin
mL), then diluted to 20 mL. For
a reaction using 200:1
substrate:catalyst ratio 0.1 mL of the product alcohol solution was
added to a GC vial containing 0.9 mL of a 0.011 M solution of DTBB.
For a reaction using 100:1 substrate:catalyst ratio 0.2 mL of the
6 | J. Name., 2012, 00, 1-3
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5 O. Prakash, H. Joshi, K. N. Sharma, P. L. Gupta anVdiewA.ArKtic.leSOinnglinhe,
product alcohol solution was added to a GC vial containing 0.8 mL
of a 0.0125 M solution of DTBB. In this way, the final concentration
of DTBB was 0.01 M in the GC vial.
Organometallics, 2014, 33, 3804-3812.
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Alterations include: addition of TWEEN80 (39 mg, 5 eq., 0.029
mmol) or HDBU formate (2.36 g, 11.90 mmol), purging with
nitrogen, or purging with argon for 10 seconds then shutting off the
argon.
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Hydride 1H NMR Study
-
In a glovebox,
1
(10 mg, 0.012 mmol), TBA+BF4 (2 mg, 0.003
mmol, 1 eq.), and potassium formate (10 mg, 0.120 mmol, 10
eq.) were dissolved in either THF (1 mL) or MeTHF (1 mL) in a
Schlenk flask. This was brought out onto the Schlenk line and
stirred under argon at 65 °C for 5 minutes. Degassed distilled
water (1 mL) was added and the reaction was stirred for
another 5 minutes. The solvent was removed in vacuo and the
Schlenk flask was brought into the glovebox. The residue was
dissolved in benzene-d6 and filtered through a 13 mm syringe
filter with a 0.45 µm PTFE membrane. 1H NMR was taken
immediately afterwards.
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Acknowledgements
R. 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 K. Z. Demmans. The
authors wish to acknowledge the Canadian Foundation for
Innovation, project number 19119, and the Ontario Research
Fund for funding of the Centre for Spectroscopic Investigation
of Complex Organic Molecules and Polymers. S. A. M. Smith is
thanked for her help with these studies, as well as W. Zuo for
his help preparing the iron catalyst.
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