Moisture-Tolerant Frustrated Lewis Pair Catalyst for Hydrogenation of Aldehydes and Ketones

Article abstract of DOI:10.1021/acscatal.5b01299

In this paper, we report on the development of a bench-stable borane for frustrated Lewis pair catalyzed reduction of aldehydes, ketones, and enones. The deliberate fine-tuning of structural and electronic parameters of Lewis acid component and the choice of Lewis base provided for the first time, a moisture-tolerant FLP catalyst. Related NMR and DFT studies underpinned the unique behavior of this FLP catalyst and gave insight into the catalytic activity of the resulting FLP catalyst.

Full text of DOI:10.1021/acscatal.5b01299

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Moisture Tolerant Frustrated Lewis Pair Catalyst for
Hydrogenation of Aldehydes and Ketones
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Ádám Gyömöre, Mária Bakos, Tamás Földes, Imre Pápai*, Attila Domján, Tibor Soós*
Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of
Sciences, Magyar tudósok körútja 2, 1117 Budapest, Hungary
KEYWORDS: frustrated Lewis pair; hydrogenation; catalysis; moisture tolerant; carbonyl
ABSTRACT: In this paper, we report on the development of a benchꢀstable borane for frustrated
Lewis pair catalyzed reduction of aldehydes, ketones and enones. The deliberate for fineꢀ
tuning of structural and electronic parameters of Lewis acid component and the choice of Lewis
for the first time, a moisture tolerant FLP catalyst. Related NMR and DFT
base provided
studies
underpinned the unique behavior of this FLP catalyst and gave insight into the catalytic
activity of the resulting FLP catalyst.
1. INTRODUCTION
Frustrated Lewis pair (FLP) chemistry, introduced by Stephan and coworkers, is a new paradigm
in smallꢀmolecule activation and catalysis.[1] This approach employs sterically encumbered Lewis
consequence, a “quasiꢀ
acidꢀbase pairs that impedes stable Lewis adduct formation. As a
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metastable”
activation
state emerges that can abruptly release the strain energy in the ensuing bond
step.[2]
FLP chemistry has actually empowered main group elements to emulate the
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cooperative donorꢀacceptor properties of transition metals, and it has significantly expanded the
capacity of bifunctional, cooperative catalysis.[3]
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FLPꢀcatalyzed hydrogenation, a striking and emblematic application of the field, is undergoing a
surge of upheaval that is largely fueled by the aspirations to develop metalꢀfree hydrogenation
technology.[4] A number of papers have been published in this area that chronicle the constant
interplay between conceptual catalyst development and exploration of applicability.[5] Recently,
one of the longꢀunsolved limitations could be resolved, namely Ashley[6a] and Stephan[6b,c]
described the FLP mediated reduction of aldehydes and ketones. Despite the many advances,
the scope and practicality of FLP mediated hydrogenation still lag behind transition metalꢀ
based strategies. Because of the appreciably hard nature of the Lewis acidity of the boron
center,[6e] the FLP catalyst improvement always confronts with the dilemma of substrate and/or
product inhibition and moisture sensitivity. As such, the substrate scope is restricted as certain
functionalities are not tolerated, and the hydrogenation process requires the rigorous exclusion
of water.[7] This restriction represents a considerable synthetic hurdle that must be overcome
to realize the full potential of FLP catalysis.
In a dual attempt to further the FLPꢀcatalyzed hydrogenation in the scope and practicality, we
group
aimed to develop new catalysts that combine improved substrate scope and functional
tolerance with a significantly upgraded userꢀfriendliness. Herein, we report the
development of
such an FLP system that has both an amplified application profile and also an unprecedented
moisture tolerance.
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2. DISCUSSION
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The most common, privileged Lewis acid that has been used for the FLPꢀbased smallꢀmolecule
activation and catalytic hydrogenation is the tris(pentafluorophenyl)ꢀborane (1a). Despite its
availability and proven worthiness in hydrogenation, the applicability of this borane has been
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,
limited owing to its low functional group tolerance and moisture sensitivity. Accordingly
efforts have been directed to modify the parent Lewis acid 1a to reduce the incompatibility with
substrates encompassing nitrogen or oxygen centered Lewis basic sites (Scheme 1). So far, two
strategies have been successfully implemented: the mitigation of electronꢀdeficiency of the
boron center[8] (Scheme 1, FLPꢀ2, 1b) that tempers the strength of competing dative bonds, and
the sizeꢀexclusion approach (Scheme 1, FLPꢀ3, 1c–e)[9,10] that retards the binding to Lewis
acidic center via enhanced sterical repulsion (Fꢀstrain). Although the sizeꢀexclusion
developments provided Lewis acids 1d,e that have stabilities toward moisture in the solid state
and could be weighed in air, their catalytic applications in hydrogenation still require rigorously
dried solvents and reagents.[9a,10a] Thus, the tempting
prospect of moisture tolerant FLP
hydrogenation catalysis has not been realized.
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Scheme 1. Design concepts in FLP hydrogenation
Apparently, the water inhibition of FLP hydrogenation catalysts should be considered as the
consequence of an FLP reactivity (i.e. a cooperative interaction of the Lewis acidꢀbase pair
with water) and not only a boraneꢀwater interaction.[7] Whereas the appropriate fineꢀtuning of
the Lewis acidic boron can attenuate the strength of the dative complex with water, the
applied Lewis base can restore or even enhance the inhibitory effect via strong Hꢀbonding
interactions or even deprotonation of the bound water. Accordingly, an attractive, dual acidꢀbase
optimization approach was considered to address the challenge of moisture tolerant FLP
hydrogenation catalysis. This development requires the first and foremost identification of a
suitable class of Lewis basic component of the FLP, which guides the selection of the Lewis
acidic component as well (and also the selection of tolerated functional groups in the substrate).
In this regard, careful design of steric and electronic factors of Lewis acid is required to maintain
the preferential hydrogen activation ability while minimizing the side reaction of the water with
the FLP. We thus envisioned that using a Lewis acid with an appropriate sizeꢀexclusion design in
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moisture tolerant FLP hydrogenation
a weakly basic ethereal type solvent might result in a
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catalyst. (Scheme 1, FLPꢀ4).
Initial attempts to employ our previously developed Lewis acid 1d,
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however, were not successful. The 1d/THF combination was found to be inactive in the
hydrogenation of activated olefins. Obviously, deliberate enhancement of the Lewis acidity was
required to afford boranes that could activate hydrogen with THF.[11] Therefore, we envisaged
the development of isosteric analogues of 1d having chlorines instead of methyl groups at ortho
position of the mesityl ring. This replacement was expected not only to increase the Lewis
acidity, but also to hinder the protodeborylative decomposition of boranes during the FLP
catalysis.
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3. RESULTS
3.1 CATALYST DEVELOPMENT
With these structural requirements in mind, we embarked on the synthesis of a series of Lewis
acidic triarylꢀboranes 4a–d endowed with the same steric bulk around the boron atom.
Scheme 2. Synthesis of boranes 4a-d with sizeꢀexclusion design
The introduction of halogen atoms (F or Cl) in meta positions was expected to permit the
electronic fineꢀtuning of boranes to secure the necessary acidity strength for FLP hydrogen
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activation in THF. Although varieties of routes have been probed, the synthetic route outlined in
Scheme 2 was the method of choice owing to its simplicity, scalability and high yields. This
methodology provided a rapid and unified entry to various unsymmetrical borane derivatives 4a–
d in multi 10g scales from easily accessible fluoroborates 2a,b and commercially available
fluorinated aryls 3a,b.
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3.2 CATALYTIC APPLICATION
To explore the feasibility of the synthesized Lewis acid components 4a–d in catalytic
hydrogenation, we selected the hydrogenation of benzaldehyde (5), transꢀchalcone (6) and
cyclohexanone 7 in THF as model reactions. Gratifyingly, all boranes 4a–d (Table 1, entries 1–
4) were found to be amenable to promote the reduction of benzaldehyde (5) to corresponding
alcohol 8a and its condensation side product dibenzylether (8b). Whereas, every borane 4a-d
could reduce the sterically more accessible olefin bond[12] in 6 to afford 1,3ꢀdiphenylpropaneꢀ1ꢀ
one (9a) (Table 1, entries 5–8), only tetrafluoroꢀboranes (4a,b) could convert it further to 1,3ꢀ
diphenylpropanꢀ1ꢀol (9b) (Table 1, entries 5, 6). Next, the effect of the ethereal solvents, the
Lewis basic component of the FLP, on catalytic efficiencies was investigated. As highlighted in
Table 1 (entries 9–14), the catalytic hydrogenations could be accomplished in a variety of
ethereal solvents ranging from the relatively basic MeꢀTHF to the weakly basic diethyl ether.
Nevertheless, we observed that these solvents influenced the selectivity of the hydrogenation.
Not only higher conversion can be achieved (Table 1, entry 5 vs. 9), but also the formation of the
10b condensation sideꢀproduct could be suppressed by the choice of the solvent (Table 1, entry
12 vs. entries 14). These results demonstrate that the selectivity of FLPꢀcatalyzed hydrogenation
(i.e. olefin vs. keto, keto vs. aldehyde) can be beneficially altered by deliberate tuning of the
Lewis acidity and/or choice of ethereal solvent.
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Table 1. FLP hydrogenation of carbonyls 5ꢀ7 in ethereal solvents.a
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Entry Catalyst
Solvent
THF
THF
THF
THF
THF
THF
THF
THF
Substrate
Conversionb
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99% (93% 8a, 7% 8b)
99% (88% 8a, 12% 8b)
99% (94% 8a, 6% 8b)
99% (91% 8a, 9% 8b)
99% (30% 9a, 70% 9b)
99% (30% 9a, 70% 9b)
83% (9a)
4a
4b
4c
4d
4a
4b
4c
4d
4a
4a
4a
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99% (9a)
2ꢀMeꢀTHF
1,4ꢀdioxane
Et2O
THF
2ꢀMeꢀTHF
1,4ꢀdioxane
99% (21% 9a, 79% 9b)
99% (84% 9a, 16% 9b)
99% (67% 9a, 33% 9b)
87% (87% 10a, 13% 10b)
99% (90% 10a, 10% 10b)
99% (97% 10a, 3% 10b)
a Reaction conditions: 100 bar H2, 50 °C, 10 mol% catalyst, 1.0 mmol substrate in 1.25 mL of abs. ethereal
b
solvents, 40h for benzaldehyde (5) and 112h for transꢀchalcone (6) and 4ꢀtBuꢀcyclohexanone (7). All
conversions were determined by 1HꢀNMR integration of crude products and reinforced by GCꢀMS
measurements.
Having identified boranes 4a,b as competent, and easily available Lewis acids for carbonyl
reductions, we next focused on exploring their scope and limitation (Table 2). A variety of
electronꢀdeficient and electronꢀrich aromatic aldehydes underwent the hydrogenation to give
benzyl alcohols 19–24 (entries 1–6). Most importantly, the applied pressure of hydrogen could
be reduced from 100 bar to 20 bar in most cases of aldehydes. The process tolerated functional
groups such as nitro, halogen and methoxy (entries 1–4). Notably, there was no detectable
dehalogenation during the reduction of 4ꢀchloro and 4ꢀbromobenzaldehydes (entries 2, 4). To our
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surprise, not only ester (entry 5), but also carboxylic group was tolerated during the catalytic
reduction. Thus 4ꢀformylbenzoic acid (17) could be reduced to the alcohol 24 (entry 6), although
it was necessary to apply higher pressure and more acidic catalyst 4b to realize a full conversion.
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Table 2. Substrate scope of the catalytic FLP hydrogenation with 4a,b.
Entry
1
Substrate
Product
Conversiona
99%b
Yield
95%b
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99%b
99%c
93%b
73%c
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98%b
99%b
75%b
76%b
76%d
60%e
60%b,f
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O
HOOC
81%b, 99%d
85%e
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14
85%b
21% 9a, 45%
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99% (33% 9a, 66% 9b)e
98% (95% 10a, 5% 10b)g
99% (88% 8a, 12% 8b)b
9be
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9b
O
OH
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11
65%g
75%b
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5
10a
8a
All conversions were determined by 1HꢀNMR integration of crude products and reinforced by GCꢀMS
a
measurements. b Reaction conditions: 1.0 mmol substrate in 1.25 mL of THF, 40h, 10 mol% catalyst 4a, 20 bar,
c
d
55°C. Reaction conditions: 1.0 mmol substrate in 1.25 mL of THF, 40h, 10 mol% catalyst 4a, 20 bar, 80°C.
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e
Reaction conditions: 1.0 mmol substrate in 1.25 mL of THF, 136h, 10 mol% catalyst 4b, 100 bar, 55°C. Reaction
conditions: 1.0 mmol substrate in 1.25 mL of THF, 137h, 10 mol% catalyst 4a, 100 bar, 55°C. f Beside the isolation
of 26, 21% dicinnamicꢀether was also isolated. g Reaction conditions: 1.0 mmol substrate in 1.25 mL of Et2O, 88 h,
10 mol% catalyst 4a, 20 bar, 55°C.
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In addition to aromatic aldehydes, the FLP reduction of some challenging ketones and aldehydes
were also examined. We found that acetophenone (18) could be converted cleanly to the
corresponding benzylalcohol 25 as no ether formation and no water elimination (to afford
styrene) occurred, however, utilization of a hydrogen pressure of 100 bar and longer reaction
time was required. Interestingly, cinnamaldehyde (14) was chemoselectively hydrogenated at the
carbonyl without the saturation of the olefin bond. The only observed side reaction was ether
formation. 4ꢀtBuꢀcyclohexanone (7) could be reduced selectively to the corresponding cis
alcohol 10a (entry 10) at lower pressure (20 bar). Thus, the transiently formed borohydride only
attacks the carbonyl group of 7 equatorially, because of the steric demand of the reducing agent.
Next, our major objective, the enticing prospect of moisture tolerant hydrogenation was probed.
Notably, when borane 4a was brought out from the glove box and stored in an open vial, it
quickly, within a few hours, absorbed 1.5 equivalent of water. However, the resulting hydrate
displayed a remarkable stability in the solid state and retained the same unvaried chemical and
physical properties after a 2ꢀmonth storage.[13] Encouraged by the stability of 4a hydrate, we
pursued to investigate whether the water interferes with the hydrogenation activity of 4a (Table
3, entry 1–5). To our delight, water, being present in more than one equivalent with respect to the
catalyst, was found to be compatible with this catalyst in THF; even technical grade THF could
be used as a solvent without compromising the conversion. Notably, the presence of water had
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an impact on the selectivity of the reduction: cinnamaldehyde (14) could be reduced more
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efficiently (entry 5).
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Table 3. Investigation of the moisture tolerance in the FLP hydrogenation of carbonyls.a
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Entry Catalyst
Solvent
THF
Substrate
Product
Conversionb
99%
4a
1
5
8a
19
20
23
26
8a
THF
THF
4a
2
99%
99%
99%
99%c
29%
5%d
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5
4a
3
4
5
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7
THF
THF
4a
4a
1a
1a
1,4ꢀ
dioxane
1,4ꢀ
dioxane
8a
5
5
8
9
THF
THF
18%
0%d
1a
1a
8a
8a
5
a
Reaction conditions: 1.0 mmol substrate in 1.25 mL of puriss. grade THF, 50 °C, 40h, 10 mol% 4a·1.5 H2O, 100
b
1
bar H2. All conversions were determined by HꢀNMR integration of crude products and reinforced by GCꢀMS
c
measurements. Beside the formation of 26 (83%), the following side products were detected: 12% 3ꢀphenylꢀ1ꢀ
propanol, 5% propanol, 5% dicinnamicꢀether. d Borane 1a was exposed to moisture in an open vial for 3 days.
Since the desired catalytic reduction could be performed when more than one and half equivalent
of water to the borane 4a was present, our catalyst development rendered the water binding to 4a
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reversible in the applied etheralꢀtype basic solvent.[14] The efficiency and superior moisture
tolerance of 4a was also demonstrated in a sideꢀbyꢀside comparison to the benchmark borane
catalyst 1a. Despite its outstanding application profile in FLP chemistry, catalyst 1a was
markedly less efficient catalyst in aldehyde 5 reduction using THF or 1,4ꢀdioxane as solvents
(Table 3, entries 6, 8).[15] Most importantly, this catalyst required rigorously inert conditions,
otherwise markedly reduced or no conversion were observed (Table 3, entries 6, 8 vs. 7, 9).
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To our knowledge, the application of 4a/THF catalyst is the first example in the FLP field that
process does not require inert techniques containment (without glove box and Schlenkꢀline
technique) during the entire synthetic operation. So, reaction mixtures were conveniently
prepared in an open flask using technical grade solvent and charged into a pressure vessel,
allowing to upgrade the practicality of the FLPꢀcatalyzed hydrogenation.
3.3 NMR AND THEORETICAL STUDIES
Despite the established importance of structural fineꢀtuning of the Lewis acid component in
moisture tolerant FLPꢀcatalyzed hydrogenation, our understanding regarding the structural and
electronic factors that affect water coordination in 4a/THF, substrate/product bindings and also
the hydrogenation process itself is limited. Thus, our investigations were extended toward NMR
complexation studies and DFT calculations to gain a deeper insight and provide structural and
thermochemical foundations for the above observations.
First, a variableꢀtemperature complexation study was undertaken to probe the strength and
dynamic behavior of borane 4a complexes relevant to the hydrogenation of benzaldehyde (5).
We explored the association ability of borane 4a with benzaldehyde (5), benzylalcohol (8a) and
water in the applied THF solvent. As summarized in Figure 1, these combinations were
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characterized by B NMR spectroscopy at 20 °C and 50 °C temperatures (blue and red lines,
respectively). Importantly, the Lewis acid 4a formed a dative complex with the Lewis basic
solvent THF (Figure 1, blue spectra a). However, the 4aꢀTHF adduct is sufficiently weak, so the
solvent molecule can easily dissociate at higher temperature or it can be displaced by
benzaldehyde (5), benzyl alcohol (8a) and water. Both substrate 5 and product 8a could bind to
the reactive boron center, however, we observed a balanced population of free and datively
bound states at higher temperature as the resonance signals moved downfield (δ = 63.4 ppm for
free 4a in benzene).[16] Finally, the complexation capacity of water was assessed by using 3
molar excess of water over borane 4a. It is apparent that water formed the strongest dative
complex and could exert the highest inhibitory effect on the catalytic cycle among the
investigated Lewis bases. Nevertheless, the dative adduct was kinetically labile at elevated
temperature, as evidenced by the observation of a resonance signal around 28 ppm. As a
consequence of dynamic equilibrium between the free and the datively bound states, a small
amount of free borane 4a is always available for FLP reactions, which is in accord with the
observed catalytic FLP reactivity in the presence of water. Finally, it is important to note that
catalyst 4a was found to be quite robust in the presence of water, as no hydrolytic decomposition
of 4a was observed when the THF solutions (in experiments d and e) were held at 50 °C for 2
hours and cooled back to 20 °C.[16]
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Figure 1. 10B NMR complexation study of borane 4a, 10B NMR spectra in THF at 20 °C – blue
lines and at 50 °C ꢀred lines: (a) borane 4a, (b) 4a and 10 equiv. benzaldehyde (5), (c) 4a and 10
equiv. benzylalcohol (8a), (d) 4a and 3 equiv. water, (e) 4a and 3 equiv. water and 10 equiv.
benzaldehyde (5).
Datively bound 1:1 complexes formed between borane 4a and selected oxygenꢀbased Lewis
bases (5, 8a, THF and H2O) were subject to computational analysis.[17] Our results indicated that
the experimentally observed trend regarding the strength of complexation could only be
reproduced with the inclusion of explicit solvent (THF) molecules in the model. We found that
THF formed strong hydrogen bonds with the OH group of the complexed alcohol and water,
which provided significant stabilization for these species. As a result of these stabilizing Hꢀ
bonding interactions, the 4aꢀ8a(THF) and 4aꢀH2O(THF)2 adducts (see Figure 2) become
thermodynamically more favored than the 4aꢀ5 and 4aꢀTHF complexes, which is consistent with
our NMR observations.
The association ability of the predecessor Lewis acids 1a and 1e with water and benzylalcohol
(8a) was also considered for comparison (Figure 2). While water tends to form a moderately
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strong adduct with 4a (with association free energy of ∆G = ꢀ5.3 kcal/mol), the more acidic
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boranes, 1e, but especially 1a, gave notably stronger THFꢀstabilized water complexes (∆G = ꢀ8.0
and ꢀ13.7 kcal/mol for 1e and 1a, respectively).[18] The THF induced aqua complex stabilization
in this series can range from the competitive to the irreversible water inhibition and it can also
result in the complete loss of hydrogenation reactivity as observed in previous reports.
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The mechanism of catalytic hydrogenation of carbonyl compounds using borane 4a was also
investigated computationally. The free energy diagram of the entire catalytic cycle is shown in
Figure 3. In these calculations, benzaldehyde (5) was used as a substrate and we aimed to
identify and characterize the main elementary steps of the catalytic process. The envisioned
catalytic cycle is initiated by the heterolytic H2 splitting, which may occur via two alternative
pathways corresponding to H2 activation by the 4a/THF and 4a/5 pairs. According to the
computed free energies, H2 activation by 4a/THF is clearly favored kinetically (computed
barriers are 21.5 and 25.1 kcal/mol, respectively).
Figure 2. Optimized structures of THFꢀstabilized 4aꢀ8a and 4aꢀH2O adducts. Computed
association Gibbs free energies (in kcal/mol, at 25 °C; with respect to dissociation limits) are
shown in parentheses (data in italics refer to boranes 1e and 1a, respectively). O···H bond
distances are given in Å.
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The ion pair intermediate [4aꢀH]–[THFꢀH]+ can be stabilized considerably by the association of
an additional solvent molecule yielding the [4aꢀH]–[THFꢀHꢀTHF]+ species.[5m] In this ion pair,
the proton is solvated by two THF molecules via strong Hꢀbonds, nevertheless, the H2 splitting
step remains still rather endergonic. The substrate molecule 5 can similarly associate with [4aꢀ
H]−[THFꢀH]+ resulting in the [4aꢀH]−[THFꢀHꢀ5]+ ion pair. This intermediate involves a highly
electrophilic substrate, therefore, the hydride transfer from [4aꢀH]− can easily occur yielding the
alcohol product 8a and regenerating the borane. The free energy of transition state of hydride
transfer is predicted to be 21.1 kcal/mol.
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It is apparent that the transition states associated with the three basic steps of the cycle (H2
cleavage, substrate activation and hydride transfer) are found to have very similar free energies,
therefore none of these steps can be identified as rateꢀdetermining in the catalytic process. Our
results, however, provide solid support for the mechanism proposed previously by Stephan and
Ashley,[6a,b] which considers the borane/ether pair to induce H2 splitting and Brønsted acid
activation of the substrate.
Figure 3. Gibbs free energy diagram computed for the entire catalytic cycle.
CONCLUSION
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In summary, new FLP catalysts for the hydrogenation of carbonyls have been developed. The
dual steric and electronic fineꢀtuning of Lewis acidic component not only allowed to markedly
expand the substrate scope in carbonyl reduction, but also rendered the water inhibition of the
catalyst reversible. Accordingly, this advance alleviates one of the key restrictions of the FLP
chemistry, the enhanced sensitivity toward water. Therefore, all synthetic manipulations can be
performed at laboratory bench without the reliance and dependence on inert techniques and there
is no need for purification of the solvents and reagents. Continuing investigation of the catalyst
design and application of this catalyst in other hydrogenation processes are currently underway
and will be reported in due course.
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ASSOCIATED CONTENT
The Supporting Information is available free of charge on the ACS Publication website at DOI:
Detailed synthesis of the new boranes with their full characterization, reaction conditions and
NMR spectra, detailed NMR investigation of borane (4a)ꢀH2O complex, theoretical studies,
calculation data, and supplementary figures
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: soos.tibor@ttk.mta.hu, papai.imre@ttk.mta.hu. Tel.: +36ꢀ1ꢀ382ꢀ6401, +36ꢀ1ꢀ382ꢀ6979.
ACKNOWLEDGEMENT
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Á. Gy., M. B., and T. S. acknowledge the Lendület program for financially supporting this work.
This work was also supported by the Hungarian Scientific Research Fund (OTKA, Kꢀ81927).
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REFERENCES
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(1) Pioneering work: a) Welch, G. C.; San Juan, R. R.; Masuda, J. D.; Stephan, D. W. Science
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(2) Recent selected examples of FLP reactivities: a) Chernichenko, K.; Kótai, B.; Pápai, I.;
Zhivonitko, V.; Nieger, M.; Leskelä, M.; Repo, T. Angew. Chem. Int. Ed. 2015, 54, 1749;
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Int. Ed. 2015, 54, 2223–2227. c) Longobardi, L. E.; Wolter, V.; Stephan, D. W. Angew. Chem.
Int. Ed. 2015, 54, 809–812. d) Xu, X.; Kehr, G.; Daniliuc, C. G.; Erker, G. J. Am. Chem. Soc.
2014, 136, 12431–12443. e) Courtemanche, M.ꢀA.; Legare, M.ꢀA.; Maron, L.; Fontaine, F.ꢀG. J.
Am. Chem. Soc. 2014, 136, 10708–10717. f) Liedtke, R.; Scheidt, F.; Ren, J.; Schirmer, B.;
Cardenas, A. J. P.; Daniliuc, C. G.; Eckert, H.; Warren, T. H.; Grimme, S.; Kehr, G.; Erker, G. J.
Am. Chem. Soc. 2014, 136, 9014–9027. g) Holthausen, M. H.; Mahdi, T.; Schlepphorst, C.;
Hounjet, L. J.; Weigand, J. J.; Stephan, D. W. Chem. Commun. 2014, 50, 10038–10040. h)
Stephan, D. W.; Erker, G. Chem. Sci. 2014, 5, 2625–2641. i) Klatt, T.; Markiewicz, J. T.;
Samann, C.; Knochel, P. J. Org. Chem. 2014, 79, 4253–4269. j) Lawrence, E. J.; Oganesyan, V.
S.; Hughes, D. L.; Ashley, A. E.; Wildgoose, G. G. J. Am. Chem. Soc. 2014, 136, 6031–6036. k)
Sajid, M.; Kehr, G.; Daniliuc, C. G.; Erker, G. Angew. Chem. Int. Ed. 2014, 53, 1118–1121. l)
Wang, X.; Kehr, G.; Daniliuc, C. G.; Erker, G. J. Am. Chem. Soc. 2014, 136, 3293–3303. m) Xu,
T.; Chen, E. Y.ꢀX. J. Am. Chem. Soc. 2014, 136, 1774–1777. n) Pereira, J. C. M.; Sajid, M.;
Kehr, G.; Wright, A. M.; Schirmer, B.; Qu, Z.ꢀW.; Grimme, S.; Erker, G.; Ford, P. C. J. Am.
Chem. Soc. 2014, 136, 513–519. o) Sajid, M.; Lawzer, A.; Dong, W.; Rosorius, C.; Sander, W.;
Schirmer, B.; Grimme, S.; Daniliuc, C. G.; Kehr, G.; Erker, G. J. Am. Chem. Soc. 2013, 135,
18567–18574. p) Li, H.; Aquino, A. J. A.; Cordes, D. B.; HungꢀLow, F.; Hase, W. L.; Krempner,
C. J. Am. Chem. Soc. 2013, 135, 16066–16069. q) Unsinn, A.; Wunderlich, S. H.; Jana, A.;
Karaghiosoff, K.; Knochel, P. Chem. Eur. J. 2013, 19, 14687–14696. r) PiedraꢀArroni, E.;
Ladaviere, C.; Amgoune, A.; Bourissou, D. J. Am. Chem. Soc. 2013, 135, 13306–13309. s)
Kelly, M. J.; Gilbert, J.; Tirfoin, R.; Aldridge, S. Angew. Chem. Int. Ed. 2013, 52, 14094–14097.
t) Mahdi, T.; Stephan, D. W. Angew. Chem. Int. Ed. 2013, 52, 12418–12421. u) Jiang, Y.;
Blacque, O.; Fox, T.; Berke, H. J. Am. Chem. Soc. 2013, 135, 7751–7760. v) Menard, G.;
Hatnean, J. A.; Cowley, H. J.; Lough, A. J.; Rawson, J. M.; Stephan, D. W. J. Am. Chem. Soc.
2013, 135, 6446–6449. w) HoltrichterꢀRosmann, T.; Isermann, J.; Rosener, C.; Cramer, B.;
Daniliuc, C.ꢀG.; Kosters, J.; Letzel, M.; Wurthwein, E.ꢀU.; Uhl, W. Angew. Chem. Int. Ed. 2013,
52, 7135–7138. x) Groll, K.; Manolikakes, S. M.; Jourdin, X. M.; Jaric, M.; Bredihhin, A.;
Karaghiosoff, K.; Carell, T.; Knochel, P. Angew. Chem. Int. Ed. 2013, 52, 6776–6780.
(3) Recent investigations about the activation mode of FLP: a) Pu, M.; Privalov, T.
ChemPhysChem 2014, 15, 3714–3719. b) Pu, M.; Privalov, T. Inorg. Chem. 2014, 53, 4598–
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4609. c) Rocchigiani, L.; Ciancaleoni, G.; Zuccaccia, C.; Macchioni, A. J. Am. Chem. Soc. 2014,
136, 112–115. d) Ponec, R.; Beran, P. J. Phys. Chem. A 2013, 117, 2656–2663. e) Rokob, T. A.;
Bakó, I.; Stirling, A.; Hamza, A.; Pápai, I. J. Am. Chem. Soc. 2013, 135, 4425–4437. f) Zeonjuk,
L. L.; Vankova, N.; Mavrandonakis, A.; Heine, T.; Roschenthaler, G.ꢀV.; Eicher, J. Chem. Eur.
J. 2013, 19, 17413–17424. g) Dang, L. X.; Schenter, G. K.; Chang, T.ꢀM.; Kathmann, S. M.;
Autrey, T. J. Phys. Chem. Lett. 2012, 3, 3312–3319. h) Wiegand, T.; Eckert, H.; Ekkert, O.;
Frohlich, R.; Kehr, G.; Erker, G.; Grimme, S. J. Am. Chem. Soc. 2012, 134, 4236–4249.
(4) a) Shi, L.; Zhou, Y.ꢀG. ChemCatChem 2015, 7, 54–56. b) Hounjet, L. J.; Stephan, D. W.
Org. Process Res. Dev. 2014, 18, 385–391. c) Paradies, J. Angew. Chem Int. Ed. 2014, 53, 3552–
3557. d) Fontaine, F.ꢀG.; Courtemanche, M.ꢀA.; Legare, M.ꢀA. Chem. Eur. J. 2014, 20, 2990–
2996. e) Stephan, D. W. Org. Biomol. Chem. 2012, 10, 5740ꢀ5746.
(5) Recent examples of FLP mediated reductions: a) Tussing, S.; Greb, L.; Tamke, S.;
Schirmer, B.; MuhleꢀGoll, C.; Luy, B.; Paradies, J. Chem. Eur. J. 2015, 21, 8056ꢀ8059. b)
Lindqvist, M.; Borre, K.; Axenov, K.; Kótai, B.; Nieger, M.; Leskelä, M.; Pápai, I.; Repo, T. J.
Am. Chem. Soc. 2015, 137, 4038–4041. c) Eisenberger, P.; Bestvater, B. P.; Keske, E. C.;
Crudden, C. M. Angew. Chem. Int. Ed. 2015, 54, 2467–2471. d) Chatterjee, I.; Oestreich, M.
Angew. Chem. Int. Ed. 2015, 54, 1965–1968. e) Zhang, Z.; Du, H. Angew. Chem. Int. Ed. 2015,
54, 623–626. f) Mohr, J.; Oestreich, M. Angew. Chem. Int. Ed. 2014, 53, 13278–13281. g) Clark,
E. R.; Ingleson, M. J. Angew. Chem. Int. Ed. 2014, 53, 11306–11309. h) Kalz, K. F.; Brinkmeier,
A.; Dechert, S.; Mata, R. A.; Meyer, F. J. Am. Chem. Soc. 2014, 136, 16626–16634. i) Wei, S.;
Du, H. J. Am. Chem. Soc. 2014, 136, 12261–12264. j) Wang, G.; Chen, C.; Du, T.; Zhong, W.
Adv. Synth. Catal. 2014, 356, 1747–1752. k) Jochmann, P.; Stephan, D. W. Angew. Chem. Int.
Ed. 2013, 52, 9831–9835. l) Chernichenko, K.; Madarász, A.; Pápai, I.; Nieger, M.; Leskelä, M.;
Repo, T. Nat. Chem. 2013, 5, 718–723. m) Hounjet, L. J.; Bannwarth, C.; Garon, C. N.; Caputo,
C. B.; Grimme, S.; Stephan, D. W. Angew. Chem. Int. Ed. 2013, 52, 7492–7495. n) Wang, Y.;
Chen, W.; Lu, Z.; Li, Z. H.; Wang, H. Angew. Chem. Int. Ed. 2013, 52, 7496–7499. o) Menard,
G.; Tran, L.; Stephan, D. W. Dalton Trans. 2013, 42, 13685–13691. p) Ines, B.; Palomas, D.;
Holle, S.; Steinberg, S.; Nicasio, J. A.; Alcarazo, M. Angew. Chem. Int. Ed. 2012, 51, 12367–
12369. r) Mahdi, T.; Heiden, Z. M.; Grimme, S.; Stephan, D. W. J. Am. Chem. Soc. 2012, 134,
4088–4091.
(6) a) Scott, D. J.; Fuchter, M. J.; Ashley, A. E. J. Am. Chem. Soc. 2014, 136, 15813–15816.
b) Mahdi, T.; Stephan, D. W. J. Am. Chem. Soc. 2014, 136, 15809–15812. c) Mahdi, T. Stephan
D. W. Angew. Chem. Int. Ed. 2015, 54, 8511–8514. d) For nonꢀcatalytic version, see: Lindqvist,
M.; Sernala, N.; Sumerin, V.; Chernichenko, K.; Leskelä, M.; Repo, T. Dalton Trans. 2012, 41,
4310ꢀ4312. e) Britovsek, G. J. P.; Ugolotti, J.; White, A. J. P. Organometallics 2005, 24, 1685–
1691. f) Longobardi, L. E.; Tang, C.; Stephan, D. W. Dalton Trans. 2014, 43, 15723–15726.
(7) The coordination of water to 1a is known to be reversible in toluene. Accordingly without
appropriately strong base, the water binding to this borane is reversible (for a relevant work, see:
Bergquist, C.; Harlan, C. J.; Norton, J. R.; Friesner, R. A.; Parkin, G. J. J. Am. Chem. Soc. 2000,
122, 10581–10590). In the presence of amines, however, the borane catalyst 1a becomes
sensitive even to trace amount of water and aldehydes. Therefore, appropriate scavengers were
utilized during FLP hydrogenation (see in Thomson, J. W.; Hatnean, J. A.; Hastie, J. J.;
Pasternak, A.; Stephan, D. W.; Chase, P. A. Org. Process Res. Dev. 2013, 17, 1287–1292).
Interestingly, even ethereal type of solvent can be a sufficiently strong base to render water
binding irreversible. For example, complete loss of FLP hydrogenation activity was reported by
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Ashley and coworkers when adding 1.0 equiv. of water to 1e/dioxane FLP hydrogenation
catalyst (see in ref. 6a).
(8) a) Greb, L.; Daniliuc, C.ꢀG.; Bergander, K.; Paradies, J. Angew. Chem. Int. Ed. 2013, 52,
5876–5879. b) Greb, L.; Daniliuc, C.ꢀG.; Bergander, K.; Paradies, J. Angew. Chem. Int. Ed.
2013, 52, 5876–5879. c) Nicasio, J. A.; Steinberg, S.; Ines, B.; Alcarazo, M. Chem. Eur. J. 2013,
19, 11016–11020.
(9) a) Erős, G.; Nagy, K.; Mehdi, H.; Pápai, I.; Nagy, P.; Király, P.; Tárkányi, G.; Soós, T.
Chem. Eur. J. 2012, 18, 574–585. b) Soós, T. Pure Appl. Chem. 2011, 83, 667–675. c) Erős, G.;
Mehdi, H.; Pápai, I.; Rokob, T. A.; Király, P.; Tárkányi, G.; Soós, T. Angew. Chem. Int. Ed.
2010, 49, 6559–6563.
(10) a) Scott, D. J.; Fuchter, M. J.; Ashley, A. E. Angew. Chem. Int. Ed. 2014, 53, 10218–
10222. b) Ashley, A. E.; Herrington, T. J.; Wildgoose, G. G.; Zaher, H.; Thompson, A. L.; Rees,
N. H.; Kraemer, T.; O’Hare, D. J. Am. Chem. Soc. 2011, 133, 14727–14740.
(11) Ashley and coworkers reported that borane 1e having highly electronꢀdeficient boron
center is a poor catalyst for catalytic FLP hydrogenation of acetone, see ref. 6a.
(12) Similar selectivity has been observed during FLP reduction of carvone and unsaturated
crotylꢀaldimine (see ref. 9c).
(13) Borane 4b shows the same water tolerance as 4a in catalytic hydrogenation, further work
in progress.
(14) Although the water binding to 4a was rendered reversible, large excess of water (> 20
equiv.) inhibited the hydrogenation reaction.
(15) THF is more basic than 1,4ꢀdioxane that might be the reason that it was less efficient
donor solvent for catalysis in case of 1a (see also ref. 6a).
(16) For more details see the Supporting Information.
(17) For the applied computational methodology and a detailed analysis, see the Supporting
Information.
(18) The relative stabilities of boraneꢀH2O(THF)2 adducts obtained for the borane = 4a, 1e, 1a
series parallel well with the Lewis acidities of boranes. The computed hydride affinities are 40.7,
44.5, 49.4 kcal/mol. (see Supporting Information).
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TABLE OF CONTENT:
H
CHO
OH
HOOC
99% conversion
OH
HOOC
10 mol% FLP
20-100 bar H2
No Schlenk-line or
glove box
Cl
F
Cl
O
O
F
H
B
F
F
95% conversion, axial
H
At the bench
F
F
F
F
OH
O
FLP
85% conversion
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