Improving the industrial feasibility of metal-free hydrogenation catalysts using chemical scavengers

Article abstract of DOI:10.1021/op4000847

A modified process using inexpensive poison scavengers has been developed that allows for more economical and practical scale-up of metal-free catalytic hydrogenation. The scavengers remove impurities such as water and aldehydes that can hinder catalysis allowing for the use of commercial-grade solvents, substrates and gases. In addition, the scavengers have the unique ability to regenerate poisoned catalysts, allowing for increased turnover numbers and longer catalyst lifetimes. Hydrogenations of unpurified imine substrates proceed with high yield using a variety of metal-free hydrogenation catalysts, demonstrating the general compatibility of this process.

Full text of DOI:10.1021/op4000847

Article
pubs.acs.org/OPRD
Improving the Industrial Feasibility of Metal-Free Hydrogenation
Catalysts Using Chemical Scavengers
Jordan W. Thomson,† Jillian A. Hatnean,‡ Jeff J. Hastie,† Andrew Pasternak,† Douglas W. Stephan,‡
and Preston A. Chase*,†
†GreenCentre Canada, 945 Princess Street, Kingston, Ontario K7L 3N6, Canada
‡Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario M5S 3H6, Canada
S
* Supporting Information
ABSTRACT: A modified process using inexpensive poison scavengers has been developed that allows for more economical and
practical scale-up of metal-free catalytic hydrogenation. The scavengers remove impurities such as water and aldehydes that can
hinder catalysis allowing for the use of commercial-grade solvents, substrates and gases. In addition, the scavengers have the
unique ability to regenerate poisoned catalysts, allowing for increased turnover numbers and longer catalyst lifetimes.
Hydrogenations of unpurified imine substrates proceed with high yield using a variety of metal-free hydrogenation catalysts,
demonstrating the general compatibility of this process.
broadened the scope of substrates to include commercially
relevant imines, for example precursors to sertraline and
intermediates to herbicides and anticancer compounds, as well
as silyl enol ethers and enamines using catalyst loadings as low
as 0.1 mol %.8 In addition, syntheses of catalysts 1a and 1b have
been demonstrated at a 100 g scale.9 These advances have been
recently reviewed.10 Mechanistically, this process generates a
borohydride intermediate, and thus exhibits reactivity similar to
stoichiometric borohydride reagents, but without the safety
issues of quenching excess reagent or the cost and environ-
mental impact of disposing of large amounts of waste or
removing toxic metals from products.
These catalysts possess advantages over stoichiometric
reductants and transition metal catalysts; however, they are
sensitive to trace impurities present in solvents, gas streams,
and substrates such as water and aldehydes which must be
removed for optimal catalytic activity to be observed.8a
Whereas drying solvents and purifying substrates in a research
laboratory is common, improvements in the tolerance of
impurities and untreated solvents must be implemented to
make these catalysts suitable for scale-up and manufacturing.
Achieving this goal removes the need for expensive drying of
solvents and gases, increases the turnover number of catalysts
(decreased materials cost), and gives more consistent yields
under different conditions (i.e., due to different batches of
solvent, gas, humidity, etc.). In this report, we present an
inexpensive and general solution to this problem through the
use of poison scavengers.
INTRODUCTION
■
The hydrogenation of unsaturated organic substrates is a widely
used and important reaction in the chemical industry.1 This
transformation can be accomplished through the use of
stoichiometric reductants such as LiAlH4 or NaBH4, transfer
hydrogenation, organocatalysis as well as direct addition of
hydrogen mediated by transition metal catalysts.2 The
stoichiometric Al and B hydride-based reductants offer altered
chemoselectivity compared to metal-based systems. However,
they suffer from safety, environmental, and cost concerns on-
scale due to quenching excess reagent and disposing of large
amounts of generated waste. Homogeneous transition metal
catalysts offer the atom economy and clean reactivity of directly
using hydrogen gas. However, they often consist of expensive
and toxic metals. While removal of heterogeneous transition
metal catalysts (e.g., Pd/C) is facile, removal of homogeneous
transition metal catalysts can be difficult and costly and require
removal to increasingly lower legislated levels.3
In 2006, the Stephan group demonstrated that the novel
phosphonium hydridoborate 1a (Figure 1) could achieve
Figure 1. Metal-free hydrogenation catalysts used in this study.
Chemical scavengers have found use in a variety of industrial,
homogeneous catalyzed processes, notably in the polymer-
ization of ethylene using Ziegler−Natta chemistry.11 In this
reversible metal-free activation of H2.4 This unique reactivity
has since been observed in a number of sterically demanding
combinations of Lewis acids and bases, now commonly termed
‘Frustrated Lewis Pairs (FLPs).5 Soon after the initial report of
H2 activation, it was found that catalytic hydrogenation of
imines and aziridines can be performed using these materials.6
Note that, in the case of catalyst 2, the Lewis basic partner is
the imine substrate itself.7 Since then, a number of reports have
Special Issue: Engineering Contributions to Chemical Process
Development
Received: April 2, 2013
© XXXX American Chemical Society
A
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case, scavengers are typically alkylaluminiums such as
trimethylaluminium or methyl aluminoxane (MAO), which
are premixed with the substrate solution. These reagents react
with impurities, such as water and alcohols that would
otherwise poison the catalyst. As the active catalytic sites in
the metal-free systems would be similar in composition to the
precatalysts in olefin polymerization systems, these types of
scavengers were deemed to be potentially applicable. Also,
known work from the Piers group has shown that the Lewis
acid B(C6F5)3 and derivatives will catalyze reaction of silanes
with a variety of unsaturated substrates and can be used to
mediate the reaction of alcohols and silanes.12 As such, a variety
of silanes were also included in screening for scavenging agents.
triphenylsilane and triisopropylsilane did not show significant
improvement above the standard scavenger-free hydrogena-
tions. However, both chlorodimethylsilane and triethylsilane
showed near quantitative conversions, an improvement of 30−
40% over the control experiments. The similar conversions of
triethylsilane and chlorodimethylsilane imply that sterics are
predominantly responsible for the improved reactivity
compared to the phenyl and isopropyl substituted silanes as
the chlorosilane Si−H should be less hydridic compared to
triethylsilane. These types of steric effects are similar to those
noted by Piers et al.12a These improvements are thought to
arise from reaction of impurities, such as residual aldehyde or
trace water by scavenger, preventing catalyst poisoning and
effectively providing a higher concentration of active catalyst in
solution.
MAO, a scavenger commonly used in Ziegler−Natta
chemistry, was also tested. In addition to MAO, we also used
the alkylaluminiums triisobutylaluminium (TIBAL) and
diisobutylaluminium hydride (DIBAL). In the initial screening
results, it was found that all alkylaluminiums tested showed
significant improvement over the control reactions with near
quantitative conversions for TIBAL and DIBAL. MAO also
showed improved reactivity, although conversions were less
consistent than for TIBAL and DIBAL. The variable
composition of commercial MAO in toluene could be
responsible for this. We hypothesize that the improved
conversions using alkylaluminiums also arise from the
prevention of catalyst poisoning. It is known that alkyl-
aluminiums can react directly with impurities such as water and
aldehydes.11
Molecular sieves and an electron-rich borane, 9-borabicylco-
[3.3.1]nonane dimer (9-BBN), were also tested. Molecular
sieves showed only moderate improvement above the control
reaction. Triplicate runs would likely show an average
conversion within the error of the control experiments. It
should be noted that given the solid-state nature of sieves and
size of the particles used, the effective molar percentage is
significantly higher than 1%. It is expected that molecular sieves
would show an improvement were the toluene not predried.
Surprisingly, 9-BBN showed lower conversion than the control
experiments. This demonstrates that simply being water
reactive is not sufficient for a scavenger to be effective and
other considerations, including interaction and compatibility
with the catalysts, need to be satisfied. Of the scavengers tested,
alkylaluminiums and sterically moderate Si−H containing
silanes were found to be the most promising.
RESULTS AND DISCUSSION
■
To apply this concept to metal-free hydrogenation catalysts, we
initially screened a number of possible scavengers, as shown in
Table 1. Scavengers were chosen on the basis of their potential
Table 1. Initial scavenger screening reactions
a
catalyst
(2.5 mol %)
conversion
(%)
scavenger (1 mol %)
1b
1b
1b
1b
1b
1b
none
64 (9)
67
triisopropylsilane
triphenylsilane
64
chlorodimethylsilane
triethylsilane
98
95 (5)
65
9-borabicyclo[3.3.1]-
nonane dimer (9-BBN)
1b
1b
1b
1b
2
diisobutylaluminium hydride (DIBAL)
triisobutylaluminium (TIBAL)
methylaluminoxane (MAO)
molecular sieves
none
96
97 (3)
86 (8)
75
72 (9)
79
2
triisopropylsilane
triphenylsilane
2
80
2
chlorodimethylsilane
triethylsilane
91 (2)
99.7 (5)
61
2
2
9-BBN
2
DIBAL
100
2
TIBAL
98 (4)
94
2
MAO
Notably the form of the FLP catalysts containing a
borohydride reacts directly with typical impurities, such as
water, leading to catalytically inactive products. In essence, in
the absence of added scavenger the FLP catalysts act as
scavengers themselves; however, the catalyst is typically much
more expensive than the general classes of identified
scavengers. For instance, 1a, 1b, and 2 cost $527,000/mol,
$164,000/mol, and $64,000/mol at research scale, respectively,
compared to $115/mol for Me2SiHCl and $265/mol for
TIBAL.14 Thus, the use of scavengers is clearly advantageous
from a base materials cost perspective. In addition, the
associated costs of reagent and solvent purification are also
avoided (vide infra).
a
Standard deviations calculated from triplicate runs using GC-FID.
ability to irreversibly react with water and/or carbonyl-
containing impurities such as aldehydes. Initially, rigorously
dry conditions were used, and N-benzylidene-tert-butylamine
was employed as the model substrate. At a catalyst loading of
2.5 mol %, 60−70% imine reduction was achieved in 2 h at 100
atm H2 and 25 °C with catalysts 1b and 2, which provided a
baseline for activity using these specific substrates, apparatus,
and conditions. The remaining 30−40% consisted of unreacted
imine with no other byproducts observed by 1H NMR
spectroscopy. Conversions13 were then measured with the
addition of 1 mol % scavenger to observe differences in
reactivity.
The reaction of scavengers with poisoned catalysts was also
probed to determine if the scavenger systems are simply
preferentially reacting with the impurities or if the scavengers
can regenerate deactivated catalyst. To this end, benzaldehyde
A range of Si−H containing silanes were tested with varying
steric and electronic properties. Sterically bulky silanes such as
B
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(2.5 mol %, 0.025 mmol)15 was added to a solution of N-
benzylidene-tert-butylamine in toluene followed by either
catalyst 1b/2 (2.5 mol %, 0.025 mmol) inside a glovebox and
then subjected to hydrogenation conditions of 100 atm H2 for 2
h at room temperature. An aliquot taken for GC analysis
showed essentially no reaction with detected yields of product
amine between 0 and 2%. The reactor was brought back into
the glovebox, a scavenger (5 mol %, 0.05 mmol) was then
added to the reaction mixture, and the hydrogenation was
restarted (Table 2).
Scheme 1. Proposed mechanism of catalyst regeneration
Table 2. Catalyst poisoning and regeneration experiment
a
results
The corresponding reaction of 5 with one equivalent of
MAO, which did not regenerate an active catalyst, showed a 11
B
NMR spectrum consistent with the formation of a 4-coordinate
boron containing a B−CH3 bond as evidenced by a singlet at
−14.5 ppm.17 This implies that alkyl-alkoxide exchange
between Al and B is a chemically active pathway and, in this
case, results in the formation of the phosphonium alkylborate 6,
which is not an active hydrogenation catalyst (Scheme 1). The
mechanism of the methyl group transfer has not been
investigated, but it is known that MAO contains a number of
Lewis acidic sites within its complex structure as well as some
amounts of AlMe3.11 It is possible that a Lewis acidic site
coordinates to the oxygen atom of 5 in a similar manner to
TIBAL, ultimately leading to the formation of 6.
conver. after add’n
of benzaldehyde
conver. after add’n
of scavenger
catalyst
scavenger
(2.5
mol %)
(2.5 mol %)
(5 mol %)
1b
2
TIBAL
0
0
2
2
82
64
2
TIBAL
Et3SiH
1b
1b
Et3SiH/
0.25% B(C6F5)3
94
1b
MAO
2
2
a
Conditions: 100 atm H2, 25 °C for 2 h.
The addition of one equivalent of triethylsilane to the
phosphonium alkoxyborate 5 in CD2Cl2 resulted in no
spectroscopic change at room temperature. However, upon
addition of 0.1 equiv of B(C6F5)3 to the mixture, the immediate
appearance of a doublet in the 11B NMR spectrum was
observed, consistent with the regeneration of 1b; correspond-
The most promising scavengers identified from Table 1 were
tested with poisoned catalyst. The addition of 5 mol % TIBAL
to the catalytically inactive solution resulted in yields of 82%
and 64% of the amine product for catalysts 1b and 2,
respectively, a remarkable result given the strength of the
boron−oxygen bond and stability of the poisoned catalysts. In
the case of triethylsilane, no catalytic activity was initially noted;
addition of a small amount of B(C6F5)3 (0.25 mol %, 0.0025
mmol) showed excellent conversion of 94% with 1b after
deactivation with benzaldehyde. Interestingly, MAO failed to
improve substrate conversion after addition to the poisoned
catalyst, despite initial screening results.
1
ing peaks in the H, 19F, and 31P NMR spectra confirm this
assignment. In addition, the formation of benzyloxytriethylsi-
18
1
lane was observed in the H NMR spectrum. Free B(C6F5)3
was also observed, suggesting the regeneration of poisoned
catalyst occurs by catalytic Lewis acid activation of the silane
(Scheme 2). Here, the added free Lewis acid B(C6F5)3 is
needed to activate the Si−H bond, which generates a more
reactive, silylium-like Si center to interact with the oxygen of
the alkoxyborate. This chemistry is reminiscent of the direct
silylation of alcohols with B(C6F5)3 as observed by Piers.12a
Complexation of the oxygen with silicon activates it for
separation from the boron center, and the hydride is transferred
to the more Lewis acidic phosphonium borane (see Scheme
2).5a To our knowledge, alkyl/hydride exchange with these
types of reagents and the resulting regeneration of poisoned
FLP catalyst with chemical scavengers has not been previously
demonstrated. Practically speaking, this strategy allows for
increased turnover numbers, longer catalyst lifetimes, and less
purification of reaction components. In addition, this allows for
alternative synthetic methods to be used for the construction of
new FLP catalysts or other complex borohydrides.
To probe the mode by which the scavenger acts to increase
reactivity and regenerate the active catalyst, a number of small-
scale experiments were undertaken. Stoichiometric mixtures of
separately synthesized phosphonium alkoxyborate salt 5, which
is the product of reaction with trace aldehyde and is known to
be an inactive form of the FLP hydrogenation catalyst, and
various scavengers were examined via multinuclear NMR
spectroscopy. Compound 5 can be independently generated
by addition of benzaldehyde to 1b.6 Subsequent addition of one
equivalent of TIBAL to 5 in CD2Cl2 resulted in the immediate
appearance of a doublet in the 11B NMR spectrum at −24.9
1
ppm. This, together with H, 19F and 31P NMR spectroscopic
data, is consistent with the regeneration of the catalyst 1b. It is
possible that the source of hydride is the β-hydrogens of
TIBAL, which are known to be active for reduction of ketones
and aldehydes.16 In this case, we hypothesize that the Lewis
acidic TIBAL first coordinates to the oxygen of 5, forming an
oxonium ion. This could then react further either intra-
molecularly or with another equivalent of TIBAL to form an
aluminium alkoxide, isobutylene and 1b (Scheme 1).
In order to test the limits of the scavenger strategy and to
provide insight on the potential practical application of these
FLP catalysts, hydrogenations were performed using commer-
cial reagents without further purification. Inside a nitrogen-filled
glovebox, the imine was dissolved in ACS reagent grade toluene
directly from a freshly opened bottle without drying (∼225
ppm H2O, 6.2 mol %), and additional catalyst poison
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Scheme 2. Proposed mechanism for regeneration of poisoned catalyst using triethylsilane and B(C6F5)3
benzaldehyde (2.5 mol %) was added. Catalyst (0.5 mol %) was
added to the mixture, and the reactor was then pressurized to
100 atm H2 (no gas purifier) and heated to 80 °C for 18 h. As
expected, this led to no detectable product formation. On the
basis of the relative concentrations of the catalyst poisons, 10
mol % scavenger was found to be decidedly sufficient to
consume all trace water and added benzaldehyde. The
experiment was repeated, but the solvent, benzaldehyde, and
substrate were premixed with 10 mol % scavenger before
catalyst addition. Hydrogenation resulted in conversions
comparable, if not superior, to those achieved under rigorously
dry and pure conditions (Table 3).19
demonstrate that scavengers are effective under conditions with
significant amounts of impurities and allow for comparable if
not superior performance compared to reactions performed
under rigorously dry and pure conditions.
While the results presented in Table 3 demonstrate the
efficacy of the scavengers, they are limited to an electron-rich
and sterically bulky imine, N-benzylidene-tert-butylamine,
which is easily hydrogenated by the catalysts. In order for the
scavengers to be used in manufacturing processes, tolerance of
a range of substrates and catalysts is necessary. Thus, we
expanded the number of substrates to include a range of steric
and electronic properties, as well as increasing the number of
catalysts in analogous reactions, as shown in Table 4.
Table 3. Hydrogenation results under demanding
conditions
a
Table 4. Hydrogenation reactions with additional substrates
and catalysts
a
catalyst
scavenger
conversion (%)
catalyst
scavenger
conversion
(%)
entry
(mol %)
substrate
(10 mol %)
1b
2
TIBAL
99
68
c
I
1a (0.5%)
3 (0.5%)
1b (0.5%)
2 (0.5%)
1a (1%)
PhCHNtBu
PhCHNtBu
TIBAL
61
TIBAL
c
II
TIBAL
96
2
Et3SiH
100
100
d
III
IV
V
PhCHNCHPh2
PhCHNCHPh2
PhCHNSO2Ph
PhCHNSO2Ph
PhCHNSO2Ph
PhCHNSO2Ph
4-BrPhCHNPh
4-BrPhCHNPh
4-FPhCHNMes
PhCHNCH2Ph
PhCHNCH2Ph
PhCHNCH2CH3
PhCHNCH2CH3
TIBAL
100
2
Me2SiHCl
d
a
Me2SiHCl
100
Conditions: 80 °C, 100 atm H2, 18 h, 0.5 mol % catalyst, 2.5 mol %
benzaldehyde, 10 mol % scavenger, 1 mmol N-benzylidene-tert-
butylamine.
b
d
Et3SiH
49
d
VI
VII
VIII
IX
X
1b (1%)
1b (2.5%)
2 (2.5%)
1b (1%)
1b (2.5%)
1b (1%)
4 (7.5%)
4 (7.5%)
4 (7.5%)
4 (7.5%)
TIBAL
TIBAL
Me2SiHCl
TIBAL
TIBAL
TIBAL
TIBAL
22
d
100
26
Chlorodimethylsilane and triethylsilane showed quantitative
conversion with 2 at 0.5 mol % loading. Lower loadings were
not tested, but given that no imine starting material was
detected by GC-FID we anticipate loadings as low as 0.1 mol %
are possible on the basis of previous results8a with ultrarigorous
conditions. In this case, temperatures of 120 °C and pressures
of 120 bar were needed, but less harsh conditions may be
possible with the use of scavengers.
A conversion of 68% was observed for catalyst 2 and TIBAL.
Alkylaluminiums are known to undergo exchange reactions
with B(C6F5)3 at room temperatures, leading to the formation
of Al−C6F5 bonds.20 TIBAL shows very little exchange at room
temperature, but it is possible that at 80 °C, the extent of
exchange is increased and may lead to less catalytically active
species. This could, in part, explain why lower conversions are
observed with TIBAL compared to silanes for 2. On the other
hand, TIBAL showed near quantitative conversion with 1b.
This suggests that at higher temperatures, silanes are more
appropriate scavengers for 2, while TIBAL is highly effective
with 1b. In any case, the results presented in Table 3
d
85
d
100
d
XI
XII
XIII
XIV
XV
100
d
100
b
d
Me2SiHCl
44
d
TIBAL
100
b
d
Et3SiH
26
a
b
Conditions: 80 °C, 100 atm H2, 18 h, 10 mol % scavenger. 0.25 mol
% B(C6F5)3 was used in addition to the scavenger and catalyst.
Measured by GC-FID. Measured by H NMR.
c
d
1
The electron-rich and sterically demanding imines, N-
benzylidene-tert-butylamine and N-benzylidenediphenyl
ethanamine, showed excellent conversions at loadings of 0.5
mol % for catalysts 1b, 2 and 3 (entries II−IV). A lower
conversion of 61% was observed for 1a with N-benzylidene-tert-
butylamine and TIBAL as scavenger (entry I) compared to a
quantitative conversion with 1b. The P−H proton in 1a is more
acidic than in 1b, leading to faster proton transfer to the
D
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substrate (the first step of hydrogenation of the imine6).
However, the lower basicity also results in a slower reaction
with hydrogen gas, which in this case likely lowers the rate of
reaction leading to a lower conversion. In the case of electron-
poor and sterically nondemanding imines such as N-
benzylidenephenylsulfonamide, 1a shows superior reactivity
(entry V) compared to 1b and 2 (entries VI and VIII,
respectively). The rate-determining step is proton transfer to
the weakly basic imine nitrogen,6 which is significantly faster
with the more acidic P−H of 1a. As a result of the slow proton
transfer, even with 1a, higher catalyst loadings are needed,
consistent with previous results.6 Nonetheless, reasonable
conversions are observed using triethylsilane (49% conversion
with 1 mol % 1a) and TIBAL (100% using 2.5 mol % 1b). The
sterically bulky and electron poor imine N-(4-fluoro-
benzylidene)-2,4,6-trimethylaniline was also hydrogenated in
quantitative conversion with 1 mol % 1b using TIBAL as a
scavenger (entry XI).
The four earliest incarnations of FLP hydrogenation
catalysts, 1a/b, 2 and 3, allow for the hydrogenation of bulky
and electron-rich substrates, as well as electron-poor substrates.
Electron-rich/nonbulky imines are hydrogenated only stoichio-
metrically due to the strong adduct formed between the
product amine and the borane catalyst, which prevents catalytic
turnover.6 More recently, a linked aminoborane catalyst 48d has
been shown to catalytically hydrogenate electron-rich/non-
bulky imines in refluxing toluene with catalyst loadings of 8 mol
%. We tested 4 with two electron-rich/nonbulky substrates with
both TIBAL and silane scavengers. Catalyst 4 has significantly
different electronic and steric properties from those of catalysts
1−3, with the presence of the much more reactive B−CH2
bond in 4 compared to B−C6F5 bonds present in 1−3.
Quantitative conversion of both N-benzylideneethylamine and
N-benzylidenebenzylamine were observed using TIBAL as a
scavenger with a catalyst loading of 7.5 mol % (entries XIV and
XII, respectively). Our results are consistent with conversions
under ideal conditions in the original report,8d albeit with
significantly lower temperatures (80 °C vs 110 °C) in the
presence of a large quantity of water and aldehyde impurities.
Lower conversions (25−44%) were observed when using
silanes/B(C6F5)3 (entries XIII and XV). Remarkably, these
results show the scavengers are compatible with a range of
catalysts of varying steric and electronic character allowing for
the efficient hydrogenation of a variety of substrates.
Interestingly, we found catalyst 4 to show significantly lower
catalytic activity with electron-rich/bulky imines such as N-
benzylidene, even under rigorously dry conditions. For
instance, N-benzylidene-tert-butylamine shows virtually no
conversion at room temperature with loadings of 2 mol % 4
over 2 h, and requires 6 mol % loading to give 67.6%
conversion over 2 h at 100 atm H2 and 80 °C. This indicates
that all of the currently identified FLP catalysts should have
utility, and the type of substrate would dictate the choice of
catalyst.
significant cost savings associated with this approach together
with the ease of using commercial-grade solvents, substrates,
and hydrogen gas without the need for the rigorous exclusion
of water or impurities greatly enhances the potential for metal-
free catalysts as a commercially viable option in hydrogenation
catalysis.
EXPERIMENTAL SECTION
■
General Considerations. All synthetic manipulations were
carried out under an atmosphere of dry, O2-free N2, employing
a glovebox. Dry toluene was prepared by distillation from Na/
benzophenone and thoroughly degassed after purification
(three freeze−pump−thaw cycles). CD2Cl2 was degassed by
three freeze−pump−thaw cycles and dried over molecular
sieves. Hydrogen gas was purchased from Air Liquide and was
optionally passed through a drying unit (Harris model 8010)
prior to use. AlphaGaz 2 purity was used for all experiments
except those described in Table 3, in which AlphaGaz 1 purity
gas was used. Hydrogenations were performed using a high-
pressure Parr Multiple Reactor System in stainless steel reactors
equipped with glass reaction sleeves. 11B, 19F, and 31P NMR
spectra were referenced to external standards: BF3·OEt2 (0
ppm), CFCl3 (0 ppm), and 85% H3PO4 (0 ppm), respectively.
B(C6F5)3 was obtained from Boulder Scientific. Scavengers
were purchased from Aldrich and used as received. The
compounds (4-di-[2,4,6-trimethylphenyl]phosphonium-2,3,5,6-
tetrafluorophenyl)bis(pentafluorophenyl)borohydride (1a), (4-
di-tert-butylphosphonium-2,3,5,6-tetrafluorophenyl)bis-
(pentafluorophenyl)borohydride (1b), tri-tert-butyl-
phosphonium tris(pentafluorophenyl)borohydride (3), and
hydrido[bis(pentafluorophenyl)]{2-[(2,2,6,6-tetramethyl-
piperidinium-1-yl)methyl]phenyl}borate (4) were prepared by
literature methods4,5b,e Compounds 1a and 1b are commer-
cially available from Sigma Aldrich. The commercially available
substrates N-benzylidenephenylsulfonamide (97%), N-benzyl-
idene-N-(diphenylmethyl)amine (97%), N-benzylidenebenzyl-
amine (99%), and N-benzylidene-ethylamine (97%) were
purchased from Aldrich and used as received. The remaining
imines were synthesized using standard methods via con-
densation of the corresponding aldehyde and amine in
dichloromethane in the presence of a drying agent. N-
benzylidene-tert-butylamine was distilled once and contained
1
0.2% benzaldehyde as determined by H NMR spectroscopy.
N-(4-bromobenzylidene)aniline was recrystallized (no benzal-
dehyde present by 1H NMR spectroscopy) and N-(4-
fluorobenzylidene)-2,4,6-trimethylaniline was used after drying
1
in vacuo (3% 4-fluorobenzaldehyde present by H NMR).
General Hydrogenation Procedure. Hydrogenation
reactions were prepared inside a nitrogen-filled glovebox. In a
typical experiment, the imine substrate (1 mmol) was added to
a glass sleeve containing a 0.75-in Teflon-coated stirbar
followed by toluene (5 mL). Dry, degassed toluene was used
for experiments described in Tables 1 and 2, while degassed
toluene out of the bottle was used for Tables 3 and 4.
Scavenger (0.01−0.1 mmol) was then added to the solution
and allowed to stand for approximately 10 min. Catalyst
(0.005−0.075 mmol) was then added, and the reactors were
sealed. The gas manifold on the Parr reactor system was
thoroughly flushed with nitrogen gas for several minutes to
purge the lines. If heated, the reactor was allowed to reach the
desired temperature before being being pressurized to 100 atm
H2 and sealed. The stirring rate was set to 1000 rpm. After the
set time (2−18 h), the reactor was slowly depressurized in a
CONCLUSIONS
■
In summary, we have developed a simple and general solution
to the problem of catalyst sensitivity in this new class of metal-
free hydrogenation catalysts using inexpensive scavengers. The
ability to employ low catalyst loadings in the presence of water
and aldehyde impurities should greatly simplify the implemen-
tation of these catalysts into industrial-scale processes for
hydrogenation and other potential FLP reactivity. The
E
dx.doi.org/10.1021/op4000847 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
(b) Welch, G. C.; Stephan, D. W. J. Am. Chem. Soc. 2007, 129, 1880−
fumehood. An aliquot was taken and the solvent removed
under reduced pressure. The resulting product was dissolved in
CDCl3 and a crude NMR spectrum acquired. For N-
benzylidene-tert-butylamine samples, the reaction mixture was
filtered through a 0.45 μm PTFE syringe filter, and 100 μL of
filtered reaction solution was combined with 6.8 μL of decane
(internal standard) and diluted to a total volume of 1 mL with
toluene. This sample was analyzed using GC-FID.
Catalyst Poisoning and Regeneration. Hydrogenation
Representative Procedure. The hydrogenation procedure
detailed above was followed, except that benzaldeyhde (2.5
μL, 0.025 mmol) was added to the imine solution prior to
catalyst addition. After 2 h under 100 atm of H2, the reactor was
brought back into the glovebox and a small aliquot removed for
GC analysis. Scavenger (0.05 mmol) was then added to the
solution and the reactor resealed and pressurized to 100 atm H2
for 2 h before standard workup and GC analysis. When
triethylsilane was employed as scavenger, B(C6F5)3 (1.28 mg,
0.0025 mmol) was introduced after the addition of
triethylsilane.
1881. (c) Spies, P.; Erker, G.; Kehr, G.; Bergander, K.; Frohlich, R.;
̈
Grimme, S.; Stephan, D. W. Chem. Commun. 2007, 47, 5072−5074.
(d) Stephan, D. W.; Erker, G. Angew. Chem., Int. Ed. 2010, 49, 46−76.
(e) Sumerin, S.; Schulz, F.; Atsumi, M.; Wang, C.; Nieger, M.; Leskela,
M.; Repo, T.; Pyykko, P.; Rieger, B. J. Am. Chem. Soc. 2008, 130,
14117−14119.
(6) Chase, P. A.; Welch, G. C.; Jurca, T.; Stephan, D. W. Angew.
Chem., Int. Ed. 2007, 46, 8050−8053.
(7) Chase, P. A.; Jurca, T.; Stephan, D. W. Chem. Commun. 2008,
1701−1703.
(8) (a) Stephan, D. W.; Greenberg, S.; Graham, T. W.; Chase, P.;
Hastie, J. J.; Geier, S. J.; Farrell, J. M.; Brown, C. C.; Heiden, Z. M.;
Welch, G. C.; Ullrich, M. Inorg. Chem. 2011, 50, 12338−12348.
(b) Rokob, T. A.; Hamza, A.; Stirling, A.; Soos, T.; Papai, I. Angew.
Chem., Int. Ed. 2008, 47, 2435−2438. (c) Eros, G.; Mehdi, H.; Papai,
I.; Rokob, T. A.; Kiraly, P.; Tarkanyi, G.; Soos, T. Angew. Chem., Int.
Ed. 2010, 49, 6559−6563. (d) Sumerin, V.; Chernichenko, K.; Nieger,
M.; Leskela, M.; Rieger, B.; Repo, T. Adv. Synth. Catal. 2011, 353,
̈
2093−2110. (e) Wang, H.; Frohlich, R.; Kehr, G.; Erker, G. Chem.
̈
Commun. 2008, 45, 5966−5968.
(9) Chase, P. A. Unpublished results.
(10) Stephan, D. W. Org. Biomol. Chem. 2012, 10, 5740−5746.
(11) Pedeutour, J. N.; Radhakrishnan, K.; Cramial, H.; Deffieux, A.
Macromol. Rapid Commun. 2001, 22, 1095−1123.
(12) (a) Blackwell, J. M.; Foster, K. L.; Beck, V. H.; Piers, W. E. J.
Org. Chem. 1999, 64, 4887−4892. (b) Blackwell, J. M.; Sonmor, E. R.;
Scoccitti, T.; Piers, W. E. Org. Lett. 2000, 2, 3921−3923. (c) Parks, D.
J.; Blackwell, J. M.; Piers, W. E. J. Org. Chem. 2000, 65, 3090−3098.
(d) Parks, D. J.; Piers, W. E. J. Am. Chem. Soc. 1996, 118, 9440−9441.
(13) These conditions were modeled after those reported in ref 7,
and conversions are comparable to those observed.
NMR Experiments Representative Procedure. To a small
vial was added 1b (25 mg, 0.039 mmol) in 0.8 mL of CD2Cl2
inside a nitrogen-filled glovebox. To this solution was added
benzaldehyde (4.8 μL, 0.047 mmol). The solution was then
added to a J. Young NMR tube, and the NMR spectra were
acquired. When complete reduction of benzaldehyde was
observed, triisobutylaluminium solution (25 wt % in toluene, 47
μL, 0.051 mmol) was then added, and the NMR spectra were
acquired.
(14) Aldrich research scale pricing as of March 14, 2013. http://
www.sigmaaldrich.com/. Catalogue numbers for 1a and 1b are 703095
and 703087, respectively.
ASSOCIATED CONTENT
* Supporting Information
Characterization data for regeneration of poisoned catalysts and
product amines. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
(15) Reaction of benzaldehyde with a variety of boron-based H2-
activated FLPs are known to give alkoxyborate complexes. These have
been found to be inactive as catalysts. See refs 5c and 6.
(16) (a) Diisobutylaluminium hydride (DIBAL-H) and Other Isobutyl
Aluminium Alkyls (DIBAL-BOT, TIBAL) as Specialty Organic Synthesis
Reagents, Azko-Nobel Technical Bulletin, OMS 06.388.03/April
2013. (b) Ashby, E. C.; Yu, S. H. J. Org. Chem. 1970, 35, 1034−1040.
(17) Neu, R. C.; Otten, E.; Lough, A.; Stephan, D. W. Chem. Sci.
2011, 2, 170−176.
(18) Park, S.; Brookhart, M. Organometallics 2010, 29, 6057−6064.
(19) Near quantitative conversion to the product amine is achieved at
0.5 mol % catalyst loading, 120 atm H2, and 100 °C under dry
conditions. See ref 8a.
AUTHOR INFORMATION
Corresponding Author
*E-mail: preston.chase.gcc@gmail.com.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank NSERC of Canada for funding this work through an
Ideas to Innovationg Grant.
■
(20) Janiak, C.; Lassahn, P.-G. Macromol. Symp. 2006, 236, 54−62.
REFERENCES
■
(1) Vries, J. G. d.; Elsevier, C. J. The Handbook of Homogeneous
Hydrogenation; Wiley-VCH: Weinheim, Germany, 2007.
(2) (a) Brown, H. C.; Ramachandran, P. V. Sixty Years of Hydride
Reductions. In Reductions in Organic Synthesis; Abdel-Magid, A. F., Ed.;
ACS Symposium Series; American Chemical Society: Washington,
DC, 1996; Chapter 1, pp 1−30. (b) Crabtree, R. H. The
Organometallic Chemistry of the Transition Metals, 2nd ed.; John
Wiley & Sons: New York, 1994. (c) Dalko, P. I.; Moisan, L. Angew.
Chem., Int. Ed. 2004, 43, 5138−5175.
(3) (a) United States Pharmacopeia, 2010 standards. Pd, Pt, Ir, Rh
cannot exceed 100 μg/day for a 50 kg person. Boron limit is 10,000
μg/day. The United States Pharmacopeia; United States Pharmacopeial
Convention; Rockville, MD, 2010.
(4) Welch, G. C.; San Juan, R. R.; Masuda, J. D.; Stephan, D. W.
Science 2006, 314, 1124−1126.
(5) (a) Welch, G. C.; Cabrera, L.; Chase, P. A.; Hollink, E.; Masuda,
J. D.; Wei, P.; Stephan, D. W. Dalton Trans. 2007, 31, 3407−3414.
F
dx.doi.org/10.1021/op4000847 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX