Metal-free catalytic hydrogenation of polar substrates by frustrated Lewis pairs

Article abstract of DOI:10.1021/ic200663v

In 2006, our group reported the first metal-free systems that reversibly activate hydrogen. This finding was extended to the discovery of "frustrated Lewis pair" (FLP) catalysts for hydrogenation. It is this catalysis that is the focal point of this artic

Full text of DOI:10.1021/ic200663v

FORUM ARTICLE
pubs.acs.org/IC
Metal-Free Catalytic Hydrogenation of Polar Substrates by Frustrated
Lewis Pairs
Douglas W. Stephan,*,† Sharonna Greenberg,† Todd W. Graham,† Preston Chase,†,‡ Jeff J. Hastie,†,‡
Stephen J. Geier,† Jeffrey M. Farrell,† Christopher C. Brown,† Zachariah M. Heiden,† Gregory C. Welch,§ and
Matthias Ullrich†
†Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, Canada M5S3H6
§Department of Chemistry and Biochemistry, University of Windsor, 401 Sunset Avenue, Windsor, Ontario, Canada N9B3P4
S Supporting Information
b
ABSTRACT: In 2006, our group reported the first metal-free
systems that reversibly activate hydrogen. This finding was
extended to the discovery of “frustrated Lewis pair” (FLP)
catalysts for hydrogenation. It is this catalysis that is the focal
point of this article. The development and applications of such
FLP hydrogenation catalysts are reviewed, and some previously
unpublished data are reported. The scope of the substrates is
expanded. Optimal conditions and functional group tolerance
are considered and applied to targets of potential commercial significance. Recent developments in asymmetric FLP hydrogenations
are also reviewed. The future of FLP hydrogenation catalysts is considered.
’ INTRODUCTION
With these well-established precedents, it was generally ac-
cepted dogma within inorganic and organometallic chemistry
that the activation of H2, and small molecules, required the action
of a coordinatively unsaturated transition-metal center. Nonme-
tal catalysts for hydrogenation reactions had received very limited
attention. Organocatalytic hydrogenations of enones and imines
was possible; however, these systems required a Hantzsch ester
as the stoichiometric source of H2.6ꢀ10 In some sense, these
systems mimic NADH11 in natural systems because the transfer
of H2 is thought to proceed via proton and hydride transfer. Such
reductions have been extended to asymmetric systems with the
use of chiral Brønsted acids.8,12ꢀ15 While these systems support
the view that consecutive transfer of proton and hydride to a
substrate can be mediated by non-transition-metal species, the
development of nonmetal hydrogenation catalysts that employ
H2 seemed unlikely because so few main-group species were
known to react with H2. Sander et al.16,17 reported that the
reaction of H2 with difluorovinylidene generated in an argon
matrix at 20ꢀ30 K to give 1,1-difluoroethene (F2CdCH2;
Scheme 1b) and showed no significant activation barrier.16ꢀ20
This work clearly foreshadowed the more recent work of
Bertrand and co-workers,21 in which the reaction of H2 with
monoaminocarbenes resulted in conversion to the correspond-
ing amine (Scheme 1c). An early report described the use of
KOtBu as a catalyst to hydrogenate benzophenone at 200 °C and
>100 bar of H2 (Scheme 1a).22 In a similar sense, strong acids
such as HF-TaF5, HF-SbF5, or HBr-AlBr3 were used to catalyze
The addition of molecular hydrogen (H2) to an unsaturated
organic molecule defines a process known as hydrogenation.
This seemingly facile transformation is used in a very diverse
range of applications. Indeed, the breadth of the application of
this chemical process is unparalleled in the chemical industry.
Large-scale commercial use of hydrogenation is required for the
upgrading of crude oil, production of bulk commodity materials,
as well as fine chemicals used in the food, agricultural, and
pharmaceutical industries.1 The atom economy and cleanliness
of the transformation makes hydrogenation “arguably the most
important catalytic method in synthetic organic chemistry both
on the laboratory and the production scale”.2
Catalytic hydrogenation of unsaturated compounds began
with the discovery by Sabatier in 1897 that traces of nickel could
mediate the catalytic addition of H2 to olefins. This discovery of
the use of nickel as a heterogeneous catalyst culminated in a share
of the 1912 Nobel Prize with Grignard. The onset of organome-
tallic chemistry and the discoveries of ruthenium- and rhodium-
based hydrogenation catalysts by Wilkinson and others in the
1960s prompted the evolution of homogeneous transition-metal-
based hydrogenation catalysts for a variety of substrates. These
catalysts operated by the interaction of H2 with the metal to effect
oxidative addition, affording intermediate dihydride com-
plexes.3 In the 1990s, Noyori discovered that transition-metal
complexes incorporating amido ligands effect heterolytic
cleavage of H2. This results in a metal hydride and protonation
of the amide ligand to give an amine. Outer-sphere transfer of
the proton and hydride to a substrate affords a distinct strategy
to hydrogenation.4,5
Received: March 31, 2011
Published: May 02, 2011
r
2011 American Chemical Society
12338
dx.doi.org/10.1021/ic200663v Inorg. Chem. 2011, 50, 12338–12348
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Inorganic Chemistry
FORUM ARTICLE
Scheme 1. Nonmetal Reactions with H2
the reduction of aromatics, cyclic alkenes, and dienes using H2 at
elevated pressure, although in some cases, rearrangement of the
carbon frameworks was observed.23ꢀ25 In related work, K€oster
et al. reported the complete or partial reduction of arenes using
BH3 as the catalyst at 200 °C and high H2 pressures.26,27
A
related borane-catalyzed process has also been described by
Haenel to effect the liquefaction of coal.28
In terms of isolable molecular nonmetal species that react with
H2, Power and co-workers were the first to report the uncata-
lyzed addition of H2 to a main-group substrate. In that work,
digermanium and ditin alkyne analogues were reduced with H2
to gives mixtures of products.29,30 Subsequently, in 2006, we
reported the first reversible activation of H2 by a nonmetal
system with the interconversion of phosphonium borate (2,4,
6-Me3C6H2)2PH(C6F4)BH(C6F5)2 (1; Scheme 1d) and the
corresponding phosphineꢀborane species (2,4,6-Me3C6H2)2P-
(C6F4)B(C6F5)2. Heating of the salt 1 above 140 °C liberates H2,
while the zwitterion 1 is regenerated by simple exposure of the
phosphineꢀborane to H2 at 25 °C.31 In a subsequent report, we
demonstrated that this ability to activate H2 was not limited to
this novel linked phosphineꢀborane system but rather that
simple, sterically demanding combinations of monomolecular
phosphines and boranes could effect such an activation of H2.32
Figure 1. Catalysts for FLP hydrogenation.
hydrogenation catalysts, integrating a review of recent progress
with the report of previously unpublished data. The latter work
expands the scope of substrates, describes optimal conditions,
and evaluates functional group tolerance. In addition, recent
work on the aspects of catalytic asymmetric hydrogenation
and the hydrogenation of targets of commercial significance is
reported.
’ RESULTS AND DISCUSSION
t
For example, while the combination of Bu3P and B(C6F5)3
results in no apparent reaction, the addition of H2 results in an
immediate reaction, affording [tBu3PH][HB(C6F5)3] (Scheme 1e).
In subsequent papers, we and others have described a series of
combinations of sterically encumbered Lewis acids and bases that
are capable of similar activation of H2. Such systems are now
commonly referred to as “frustrated Lewis pairs” (FLPs), and
their general reactivity with small molecules has recently been
reviewed.33ꢀ36
The ability to activate H2 with non-transition-metal systems
presents questions about the potential for hydrogenation cata-
lysis. The concept is simple. Activation of H2 by an FLP followed
by the delivery of proton and hydride to an organic substrate
would regenerate the FLP and provide the saturated product.
Thus, in this Forum Article, we focus on the development of FLP
Initial FLP Hydrogenation of Imines, Nitriles, and Aziridines.
The reduction of imines is a synthetic method to generate
secondary and primary amines used in the pharmaceutical and
fine chemical industries.37ꢀ39 In our first report of metal-free
catalytic hydrogenation using H2 and mild conditions, we
described the reduction of imines using the phosphonium borate
t
(R2PH)(C6F4)BH(C6F5)2 [R = 2,4,6-Me3C6H2 (1), Bu (2);
Figure 1].40 For example, imines, which include sterically de-
manding substituents on nitrogen, are reduced cleanly in high
yield at 80ꢀ120 °C under H2 pressures of 1ꢀ5 atm using 5 mol % 1
or 2 as the catalyst (Scheme 2a and Table 1). Separation of the
amine products involves simple filtration through a plug of silica
gel, affording pure amine product, as evidenced by NMR
spectroscopy. In a similar fashion, catalytic reductive ring opening
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Inorganic Chemistry
FORUM ARTICLE
Scheme 2. Examples of FLP Hydrogenation
of imines and 1 at 25 °C afforded generation of ((2,4,
6-Me3C6H2)2P)(C6F4)B(C6F5)2(tBuNHCH2Ph), while under
H2, the ion pair [tBuNH2CH2Ph][tBu2PC6F4BH(C6F5)2] is
generated. These observations are also consistent with the
proposed mechanism in which elevated temperatures between
80 and 120 °C promote amine dissociation and enhance the rate
of catalytic reduction. It is important to note that while imines,
nitriles, and aziridines are efficiently reduced in a catalytic manner,
aldehydes react in a stoichiometric fashion, affording the phos-
phonium alkoxyborate zwitterions R2PHC6F4B(C6F5)2OCH2Ph
exclusively. This view is consistent with the oxophilicity of boron
and the strength of the BꢀO bond. The proposed mechanism
based on these experimental data was subsequently supported by
the computational studies of Papai and co-workers.43
Lewis Acid Catalyzed Hydrogenation. The discovery of
metal-free hydrogenation by FLPs prompted the suggestion that
when using a sterically encumbered basic substrate, it should be
possible to effect hydrogenation using only a catalytic amount of
Lewis acid. Indeed, the combination of a catalytic amount of
B(C6F5)3 (3) (Figure 1) with an imine substrate under H2 with
mild heating was shown to afford the corresponding amines,
which were isolable in high yields44 (Table 1). Mechanistically,
this is thought to be similar to the process described above, with
the only difference being that the initial activation of H2 results
from the action of an FLP derived from 3 and the sterically
demanding imine. This activation generates a transient iminium
hydridoborate. Subsequent transfer of the hydride from boron to
the iminium carbon affords the amineꢀborane adduct, while
thermally induced release of the amine regenerates free 3, which
is then available for further H2 activation. In support of this view,
it is noteworthy that efforts to hydrogenate the ketimine
(C6H2Me3)NdCMe(tBu) fail, affording only the intermediate
iminium hydroborate [(C6H2Me3)HNdCMe(tBu)][HB(C6F5)3]
(Scheme 4). Presumably, this is attributable to the steric de-
mands about the iminium carbon, which precludes hydride
transfer. While these observations suggest that phosphine is
not required for FLP hydrogenation of imines, it is noteworthy
that, in cases where the imine is a poor base, the addition of a
catalytic equivalent of P(C6H2Me3)3 accelerated hydrogenation
as a result of the enhanced ability of the phosphineꢀborane to
effect heterolytic cleavage of H2.
of an unactivated N-arylaziridine functionality is achieved under
similar conditions (Scheme 2b and Table 1).
In the case of sterically less demanding imines, only stoichio-
metric reduction is observed.40 Similarly, nitriles are not cataly-
tically reduced. These observations are attributable to the for-
mation of classical Lewis acidꢀbase adducts. Such strong binding
to the boron center of the catalyst inhibits the catalytic cycle.
Recognizing that B(C6F5)3 is more Lewis acidic than the boron
center in the dehydrogenated phosphineꢀborane catalyst 1, one
strategy to reduce a sterically unencumbered imine or nitrile is to
employ the corresponding B(C6F5)3 adducts as substrates. In this
fashion, the phosphonium borate 1 can be used as a hydrogenation
catalyst to reduce a borane-bound imine or nitrile to give the
corresponding amineꢀborane adducts.41 For example, the imineꢀ
borane adduct (PhCHdNCH2Ph)B(C6F5)3 is reduced to
(PhCH2NHCH2Ph)B(C6F5)3, while (PhCN)B(C6F5)3 and
(CH2CH2CN)2(B(C6F5)3)2 are reduced to (PhCH2NH2)B-
(C6F5)3 and (CH2CH2CH2NH2)2(B(C6F5)3)2, respectively
(Scheme 2c and Table 1). It is certainly true that using B(C6F5)3
as a “protecting group” is hardly a practical approach; nonetheless,
these transformations do demonstrate that the principle of FLP
reduction can be extended to sterically unencumbered CꢀN
double and triple bonds.
The mechanism of these metal-free reductions is thought to
proceed via protonation of the imine, followed by hydride
transfer from the hydridoborate (Scheme 3). This results in
liberation of the FLP, which is then available to react with H2,
regenerating phosphonium borate. The fact that the electron-
rich imine tBuNdCPh(H) is reduced significantly faster than the
electron-poor imine PhSO2NdCPh(H) is consistent with this
proposed mechanism. In addition, it was shown that there is
no stoichiometric reaction of the phosphonium borate (Cy3P)-
(C6F4)BH(C6F5)242 with the imine tBuNdCPh(H), indicating
that the reductions are initiated by proton transfer and not
delivery of the BꢀH hydride. Further, stoichiometric reactions
Expanding the Scope of FLP Hydrogenation Catalysts and
Substrates. Shortly after our initial reports, the Erker group
developed the phosphonium borate (C6H2Me3)2PHC2H4BH-
(C6F5)2 4 (Figure 1), which proved to be an even more active
catalyst, effecting the metal-free hydrogenation of imines at
ambient conditions (Table 1).45 For example, this catalyst effects
t
t
the reduction of BuNdCHPh and BuN=CMePh at 25 °C
under 1.5 bar of H2. In the former case, there is a need for higher
catalyst loadings, which is not unambiguously understood.
However, this may be attributable to residual moisture in the
imine (vide infra).
The linked amineꢀborane species derived from tetramethyl-
piperidine, C5H6Me4NHCH2C6H4BH(C6F5)2 (5; Figure 1)
was developed by the research groups of Repo and Rieger. This
species has been shown to be effective for the hydrogenation of
several imines and enamines,46 affording near-quantitative yields
of the reduced products. As appears typical, this catalyst was also
less effective in the case of sterically less encumbered imine
substrates such as PhCH2C(Me)dNMe (Table 1).
With the target of expanding the scope of FLP reductions, the
Erker group recognized that FLP hydrogenation could be applied
12340
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Inorganic Chemistry
FORUM ARTICLE
Table 1. FLP Hydrogenation of Imines, Enamines, Azirdines, Nitriles, and Silylenol Ethers
substrate
catalyst (mol %)
T (°C)
P (atm)
t (h)
yield (%)
ref
Aldimines
PhCHdNtBu
1 (5)
80
120
140
120
120
80
1
5
1
11
1
79
97
88
5
40
40
40
40
40
40
40
44
44
44
58
58
58
58
58
58
58
45
46
46
50
50
50
50
50
50
50
51
51
51
51
51
51
51
51
51
51
47
47
PhCHdNSO2Ph
PhCHdNCHPh2
PhCHdNCH2Ph
1 (5)
1 (5)
5
1 (5)
5
48
46
1
PhCHdNCH2Ph(B(C6F5)3)
PhCHdNtBu
1 (5)
5
57
98
87
89
94
99
7
2 (5)
1
PhCHdNSO2Ph
PhCHdNtBu
2 (5)
120
80
5
16
2
3 (5)
1
PhCHdNSO2Ph
3 (5)
120
120
80
5
41
1
PhCHdNCHPh2
3 (5)
5
PhCHdN(SO2C6H4Me)
PhCHdN(SO2C6H4Me)
PhCHdN(SO2C6H4Me)
PhCHdN(SO2C6H4Me)
C6H4CMe2CMedN
C6H4CMe2CMedN
C6H4CMe2CMedN
PhCHdNtBu
3 (10)
3 (10)
3 (10)
3 (10)
3 (10)
3 (10)
3 (10)
4 (20)
5 (8)
10
20
20
30
40
20
40
2.5
2
22
22
22
22
22
22
22
80
97
91
99
0
100
100
100
140
140
25
21
53
87
99
4
PhCHdNCH2Ph
110
110
120
120
120
120
120
120
120
20
12
24
1
PhCHdNMe
5 (4)
2
PhCHdNCHPh2
PhCHdNtBu
7 (5)
15
15
15
15
15
15
15
4
99
99
78
5
7 (10)
7 (10)
7 (10)
7 (10)
7 (10)
7 (10)
8 (10)
8 (10)
8 (10)
8 (10)
8 (10)
9 (10)
9 (10)
9 (10)
9 (10)
9 (10)
10 (6)
10 (2)
1
PhCHdNPh
1
PhCHdNCH2Ph
6
PhCHdNC6H4Cl
1
99
99
99
81
75
49
72
97
99
98
16
99
24
99
99
ClC6H4CHdNC6H4Cl
NO2C6H4CHdNPh
PhCHdNtBu
1
1
42
42
42
42
42
42
42
42
42
42
MeOC6H4CHdNtBu
20
4
PhCHdNCH2Ph
20
4
MeO(CH2CHCH2O)C6H3CHdNtBu
CH3CHdCHCHdNtBu
PhCHdNtBu
20
4
20
4
20
4
MeOC6H4CHdNtBu
20
4
PhCHdNCH2Ph
20
4
MeO(CH2CHCH2O)C6H3CHdNtBu
CH3CHdCHCHdNtBu
tBuCHdNC6H3Me2
20
4
20
4
25
2
tBuCHdNC6H3 Pr2
25
2
i
Ketimines
Ph2CdNtBu
3 (5)
3 (5)
3 (2.5)
3 (5)
3 (10)
3 (10)
3 (5)
4 (5)
5 (4)
5 (4)
5 (4)
5 (4)
120
120
80
5
5
1
8
98
94
19
68
99
29
99
70
99
99
4
44
44
58
58
58
58
58
45
46
46
46
46
PhCMedNC6H2Me3
PhCMedNPh
10
10
10
10
20
2.5
2
22
22
22
22
22
3
PhCMedNPh
80
PhCMedNPh
80
PhCMedNPh
50
PhCMedNPh
PhCMedNtBu
80
25
PhCMedNCH2Ph
PhCMedNMe
110
110
110
110
6
2
12
24
6
PhCH2CMedNMe
MeOC6H4CMedNCH2Ph
2
2
99
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Inorganic Chemistry
FORUM ARTICLE
Table 1. Continued
substrate
catalyst (mol %)
T (°C)
P (atm)
t (h)
yield (%)
ref
46
ClC6H4CMedNCH2Ph
5 (4)
110
2
6
99
Protected Nitriles
MeCtN(B(C6F5)3
1 (5)
1 (5)
1 (10)
120
120
120
5
5
5
24
24
48
75
84
99
40
40
40
PhCtN(B(C6F5)3)
(CH2CH2CtN(B(C6F5)3)2
Aziridines
Enamines
PhCHCHPhNPh
PhCHCHPhNPh
1 (10)
3 (5)
120
120
5
5
1.5
2
98
95
40
44
PhC(NC5H10)dCH2
4 (10)
4 (5)
25
25
2.5
2.5
2.5
2
99
88
78
85
73
92
45
45
45
46
51
51
(C5H10N)CdCH(CH2)4
O(CH2CH2)2NCdCH(CH2)4
(C5H10N)CdCH(CH2)4
O(CH2CH2)2NCdCH(CH2)4
O(CH2CH2)2NCdCH(CH2)4
4 (3)
25
5 (4)
110
20
12
42
42
8 (10)
9 (10)
4
20
4
Silyl Enol Ethers
6 (20)
Ph(Me3SiO)CdCH2
tBu(Me3SiO)CdCH2
(Me3SiO)CdCH(CH2)4
(Me3SiO)CdCH(CH2)3
Me(Me3SiO)CdCH2
tBu(Me3SiO)CdCH2
25
25
25
25
25
25
2
2
20
20
20
20
3
93
89
86
85
99
85
49
49
49
49
49
47
6 (20)
6 (20)
6 (20)
6 (20)
10 (5)
2
2
60
2
Eneone
(CH2dCMe)C6H6MeO
9 (20)
20
4
14
87
51
Dieneamines
(CH2C(C5H4)CHdC(NMe2)C5H4)ZrCl2
(CH2C(C5H4)CHdC(NMe2)C5H4)Fe
4 (20)
4 (5)
4 (5)
4 (5)
25
25
25
25
2.5
2.5
2.5
2.5
27
77
99
99
48
48
48
48
(CH2C(C5H4)CHdC(N(CH2CH2)2CH)2C5H4)Fe
(CH2C(C5H4)CHdC(N(CH2CH2)2O)2)C5H4)Fe
Scheme 3. Proposed Mechanism of Hydrogenation
Scheme 4. Hydrogenation of Sterically Encumbered Imine
amine C5H10NC6H12 at 25 °C and 1.5 bar of H2 in a toluene
solution.45 In a similar sense, this strategy was applied to a series
of enamines with catalyst loadings as low as 3 mol % catalyst
(Scheme 2d and Table 1).47 The very bulky enamine PhC-
(NC5H10)dCH2 was reduced to the corresponding amine
in >80% yield yet required more forcing conditions of 50 bar
of H2, 70 °C, and 10 mol % catalyst.
Employing a related strategy, Erker et al.48 further broadened
the scope of FLP reductions, uncovering that a 20 mol %
bis(phosphine) C10H6(PPh2)2ꢀB(C6F5)3 combination gener-
ated [C10H6(PPh2)2H][HB(C6F5)3] (6; Figure 1), which is an
effective catalyst for hydrogenation of silylenol ethers to give silyl
ether products under comparatively mild conditions, 2 bar of H2
pressure and 25 °C (Scheme 2e and Table 1).49 The less
sterically hindered silyl enol ether Me3SiO(Me)CdCH2 it was
necessary to employ the more forcing reaction conditions of
to species where an iminium ion intermediate was accessible.
Employing this creative approach, they showed that 10 mol % of
4 effected the reduction of the enamine C5H10NC6H10 to the
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Inorganic Chemistry
FORUM ARTICLE
60 bar of H2 at 70 °C to effect the catalytic reduction of silyl enol
ether to the corresponding silyl ether.
Table 2. Product Yields of Catalytic Hydrogenation in the
Presence of a Stoichiometric Additivea
Modified Lewis acid catalysts were probed by Berke and co-
workers.50 These researchers explored the use 1,8-bis(dipen-
tafluorophenylboryl)naphthalene, C10H6(B(C6F5)2 (7; Figure 1),
to reduce a variety of imines under 15 bar of H2 at 120 °C
(Table 1). These authors also explored the mechanism of action
of this bis(borane) and suggested that hydrogen activation via the
so-called “super Lewis acidic activation pathway” involving both
boron centers has a higher barrier than the “external” access of H2
to just one boron center.
catalyst
catalyst
additive
2
3
additive
2
3
naphthalene
MeOtBu
100
100
100
5
100
16
Me3Si methacrylate
iPrPhNC(O)OtBu
tBuNH2
0
0
0
0
0
0
In a related approach to Lewis acid modification, the group of
Soos et al. has demonstrated that the straightforward modifica-
tion of the borane to B(C6F5)2(C6H2Me3) had a significant
impact on the range of substrates that could be reduced.51 In
combination with CH(CH2CH2)3N or N(CH2CH2)3N, the
borane B(C6F5)2(C6H2Me3) was used to generate catalysts 8
and 9 (Figure 1), respectively which were effective for the
reduction of conventional aldimines (Table 1). In addition,
these catalysts lead to the reduction of MeO(CH2CHCH2O)-
C6H3CHdNtBu, which incorporates both ether and vinyl func-
tional groups. Interestingly, these catalyst systems led to the full
reduction of CH3CHdCHCHdNtBu to nBuNHtBu. Even
more dramatic, however, was the finding that the conjugated
olefinic bond in carvone was reduced, although this required
6 days of reaction (Scheme 2f).
MeOPh
100
0
2,4,6-Me3C6H2OH
trimethylphenol
2,6-tBu2C6H3OH
p-anisaldehyde
4-heptanone
(t-Bu)2CO
iPr2NH
49
82
100
0
100
0
2-tBuC6H4NH2
PhNMe2
0
4
0
31
6
0
Ph2NMe
100
100
100
0
100
100
85
12
98
100
3
Ph3N
L-(ꢀ)-fenchone
hexyl acrylate
0
C6H2Me3Br
PhCH2Br
C8H17Br
100
0
100
95
a Reaction conditions: 80 °C, 10 atm of H2, 5 mol % catalyst,
imineꢀadditive ratio 1:1.
The Erker group47 has also expanded the realm of FLP
catalysts to include unusual metallocene derivatives. For exam-
reduction. This finding is interesting because it points out the
dileterious effect of trace H2O on the catalyst efficiency. None-
theless, at this catalyst loading, FLP reductions become cost
competitive with stoichiometric LiAlH4 reductions. In addition,
this approach offers the advantage of minimal workup because
simple flash chromatography removes the catalyst from the product.
This stands in contrast to stoichiometric reductions, where workup
by quenching of the reaction generates heat, H2 gas, and significant
amounts of aqueous aluminum hydroxide waste.
Functional Group Tolerance. The classical method for func-
tional group tolerance testing would involve the preparation of a
large series of substrates that incorporate a variety of additional
functional groups. Such an approach would require labor-
intensive and tediously repetitive synthesis of substrate molecules.
In an effort to acquire a large array of data in an expeditious manner,
we chose an alternative that would allow an automated and
combinatorial methodology. In this approach, the catalyst effi-
ciency for the hydrogenation of a standard substrate was assessed
in the presence of an equal amount of an additive containing a
functional group. PhCHdNtBu was used as our standard sub-
strate, and a large variety of additives were screened employing a
Chem-Speed ASW1000 robotic reactor system (Table 2). While
this approach provides information on the catalyst tolerance for a
particular functional group. It does not provide information on
the more subtle impact of electronic perturbations to the sub-
strate as a result of the incorporation of a particular functional
group. Nonetheless, this approach is expeditous and should be
useful as a primary screen.
i
ple, the zirconocene salt [(C5H4CH2NH(C6H3 Pr2))2ZrCl2]-
[HB(C6F5)3]2 (10; Figure 1), which incorporates pendant bulky
ammonium fragments, was shown to act as an FLP catalyst for the
hydrogenation of bulky imines and silyl enol ethers to corresponding
saturated products. In these examples, catalyst loadings ranged
between 2 and 6 mol % (Table 1). These same authors also showed
that FLP reductions could be applied to metallocene-based sub-
strates. Thus, the dieneamine complexes (H2CdC(C5H4)CHd
C(NR2)C5H4)Fe and (H2CdC(C5H4)CHdC(NR2)C5H4)-
ZrCl2 were reduced under H2 in the presence of the phosphonium
borate 4 to give (CH3C(C5H4)dCHCH(NR2)C5H4)Fe
and (CH3C(C5H4)CHdCH(NR2)C5H4)ZrCl2, respectively
(Table 1).48 In the case of the ferrocene derivatives, the products
were isolated in yields ranging from 77 to 99%, whereas the
zirconocene product was isolated in 27% yield.
Optimized Conditions for Catalysis. Efforts to uncover
optimized conditions for the reduction of PhCHdNtBu as a
standard imine were undertaken with the catalysts 2 or 3, with
variations in the pressures of H2 ranging from 25 to 120 atm, in
the reaction temperatures from 25 to 130 °C, and in the catalyst
loadings from 5 to 0.1 mol %. Increasing H2 pressures had a
dramatic impact on the reaction time. When 2 mol % catalysts
were employed, increasing the pressure of H2 from 25 to 103 atm
at 25 °C led to increased conversion as a function of time. In the
case of 1, the species PhCHdNtBu was quantitatively reduced in
2 h, whereas with 3, this reaction was complete in 1 h. In general,
reduction of the catalyst loading slowed the reaction. However,
this could be overcome by altering the reaction conditions and
time. For example, reduction of the catalyst from 5 mol % to as
low as 0.3 mol % catalyst resulted in quantitative reduction in
18 h at 120 atm of H2 and 100 °C. Further reduction to 0.1 mol %
catalyst was also possible if the temperature was raised to 130 °C.
However, in this case, it was necessary to remove traces of water
from the imine substrate by distillation from Al(iBu)3 prior to
Automated hydrogenation trials were performed at 80 °C
under 10 atm of H2 pressure, and the reactions were allowed to
run for 8 h using 5 mol % 2 or 3 as the catalyst. In all cases, the
reactions were conducted at least in triplicate to ensure reprodu-
cibility. Following the reaction, samples were dispensed to NMR
tubes for spectroscopic examination. To support the validity
of this additive approach, the imines (p-MeOC6H4)CHdNtBu,
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Inorganic Chemistry
FORUM ARTICLE
(m-MeOC6H4)CHdNtBu, and (p-(Me2)NC6H4)CHdNtBu
were prepared and employed as substrates. For both catalysts 2
and 3, the efficiency of the imine reductions mimicked the data
acquired from the corresponding additive experiments. While this
does not constitute a comprehensive evaluation of the method,
these data do suggest that this bimolecular approach to functional
group tolerance is a valid first approximation.
Scheme 5. Reduction of N-Heterocycles
The combinatorial hydrogenation data confirm that the
efficient reduction of PhCHdNtBu was achieved for both
catalysts in the presence of naphthalene, MeOPh, n-hexyl
acrylate, MePh2N, Ph3N, and alkyl and aryl halides. It should be
noted that while PhCH2Br does not inhibit hydrogenation of the
imine, the product amine is quarternized to the benzylammo-
nium bromide salt. In the case of MeOtBu, catalysis by
tBu2PC6F4B(C6F5)2 is quantitative, whereas with B(C6F5)3, only
16% conversion is observed, consistent with competitive binding
of the additive to the borane. Higher conversions with the
bifunctional phosphineꢀborane catalyst are also consistent with
the reduced Lewis acidity. In a similar observation, the phosphineꢀ
borane catalyst 2 tolerates the presence of L-fenchone,
whereas 3 does not. While both catalysts give sigificant conver-
sion in the presence of iPr2NH, both are much less effective in the
presence of PhNMe2 tBuNH2, carbamate esters, ketones, or
aldehydes. These latter observations are consistent with the
known stoichiometric reaction of R2PHC6F4BH(C6F5)2 with
aldehyde to give R2PHC6F4B(OCH2R0)(C6F5)2. In a similar
sense, both catalysts were not functional in the presence of 2,4,6-
Me3C6H2OH. Surprisingly, these catalysts tolerate the presence
of 2,6-tBu2C6H3OH, where quantitative hydrogenation of the
imine is observed. Thus, these functional group data infer that
FLP catalysts for the reduction of imines are tolerant of weakly
donating arenes, halides, ethers, and amines. In addition, these
catalyst also tolerate sterically encumbered amines, ketones, and
alcohols in some cases. Collectively, the present data, together
with extensive hydrogenation data reported to date, suggest that
it may be possible to design new Lewis acidic catalyst partners for
FLP activation of H2 that are contrived to avoid deactivation by
coordinating donor fragments in substrates. In this fashion, the
breadth of applications could be broadened.
More Substrates. In an effort to further expand the substrate
scope for FLP reductions, we have recently probed the reduction
of substituted N-heterocycles such as substituted quinolines,
phenanthrolines, and acridines (Scheme 5aꢀd and Table 3).
These are reduced to varying degrees catalytically by B(C6F5)3
under an atmosphere of H2.52 While acridine was shown to take
up 1 equiv of H2, substituted quinolines and phenanthrolines
were shown to take up 2 equiv of H2 to saturate the N-containing
ring. This is attributed to tautomerization of the initial hydride
attack product. This view was supported by isolation of the
NSiEt3 analogue derived from the catalytic hydrosilylation of
2-phenylquinoline using Et3SiH, a reaction that is mechanisti-
cally similar to hydrogenation.53 Herein, we also report the
hydrogenation of several indole derivatives to the corresponding
dihydroindoles54ꢀ56 (Scheme 5eꢀg), using B(C6F5)3, higher
pressures of H2 (103 bar), and 80 °C for 18 h. While as little as
1 mol % affected the reaction to some extent, 10 mol % catalyst
was required for an effective reduction.
(Table 1). In a similar fashion, the pyridineꢀdiimines (C5H3N)-
(MeCdNR)2 (R = C6H4-4-iPr, C6H2-2,4,6-Me3, C6H3-2,6-iPr2)
are reduced quantitatively to the diamines using 4 atm of H2
(Table 1). In the case of (C5H3N)(MeCHNH(C6H3 Pr2))2, the
nature of the product was confirmed unambiguously by X-ray
crystallography (Figure 2).
i
When optimized conditions are employed and with the
recognized functional group tolerance limitations of the present
FLP catalysts, hydrogenation that could yield reductions of
relevant to commercially significant amines can be investigated
(Table 4). One such case involves hydrogenation of the imine
with a pendant pyridine fragment (Figure 3a) because this
species is a potential herbicide. However, attempts to effect
FLP-catalyzed high-pressure reductions yielded generally low
yields. Maximum yields of 54% were achieved using 4 mol % 1 as
the catalyst for 4 h at 124 bar of H2 pressure and 120 °C. In a
similar sense, the imine precursor to fentanyl, a potent analgesic
narcotic (Figure 3b), was only reduced to a limited extent with
the hydrogenation catalysts 1 and 2. This observation was
attributed, in part, to coordination of the amine to the boron
center of the catalysts and the loss of C6F5H, as suggested by 19
F
NMR spectra of the reaction mixtures. In contrast, the N-propyl
analogue of the antidepressant sertraline (Figure 3c) showed
good conversion to amine products with 5 mol % catalysts 1
(78%) and 2 and 3 (100%) at 124 bar over the course of 20 h at
120 °C. Freshly prepared samples of the corresponding benzy-
limine (Figure 3d) were also reduced in high yields using 5 mol %
1 or 2 under similar conditions, although the reaction time could
be reduced in these cases to 4 h. Similarly, the ketimine
CF3C6H4CMedNCH2Ph (Figure 3e), a precursor to anticancer
and herbicide candidates, was effectively reduced in 16 h at 117
bar and 120 °C using 2 mol % phosphonium borate catalyst 1.
Toward Catalytic Asymmetric Hydrogenation by FLPs.
The ability of FLP systems to effect hydrogenation prompts
questions about controlling the stereochemistry of hydrogen
Another useful application of FLP reductions was derived
from the hydrogenation of diimines (Scheme 6). Thus, for
example, the diimines (CH2dNR)2 and (MeCHdNR)2 (R =
i
C6H2Me3, C6H3 Pr2) are quantitatively reduced to the corre-
sponding diamines,57 using 5 mol % 3 and 5 atm of H2 at 120 °C
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Inorganic Chemistry
FORUM ARTICLE
Table 3. FLP Hydrogenation of N-Heterocycles and Diimines
substrate
catalyst (mol %)
T (°C)
P (atm)
t (h)
yield (%)
ref
Indoles
C6H4CHdCHNMe
3 (1)
80
80
80
80
80
80
103
103
103
103
103
103
18
18
18
18
18
18
0
98
21
98
37
91
herein
herein
herein
herein
herein
herein
C6H4CHdCHNMe
C6H4CHdCMeNMe
C6H4CHdCMeNMe
C6H4CHdCPhNMe
C6H4CHdCPhNMe
3 (10)
3 (1)
3 (10)
3 (1)
3 (10)
Quinolines
C9H6N(2-Ph)
C9H6N(2-Me)
C9H6N(8-Me)
3 (5)
3 (5)
3 (10)
25
50
80
4
4
4
4
16
6
80
74
88
52
52
52
N-Heterocycles
C13H9N (acridine)
3 (5)
3 (5)
25
25
4
4
2
3
80
84
52
52
C13H9N (phenanthroline)
Dimines
120
(CH2dNC6H2Me3)2
3 (5)
3 (5)
3 (5)
3 (5)
3 (5)
4
4
4
4
4
24
24
24
24
24
99
99
99
99
99
herein
herein
herein
herein
herein
i
(CH2dNC6H4 Pr)2
120
(C5H3N)(MeCdN(C6H4-4- iPr)2
(C5H3N)(MeCdN(C6H3-2,6- iPr2)2
(C5H3N)(MeCdN(C6H2-2,4,6- Me3)2
120
120
120
Scheme 6. Reduction of Diimines
Figure 2. ORTEP of the reduced pyridineꢀdiamine (C5H3N)(MeCH-
i
NH(C6H3 Pr2))2.
addition. That is, can one perform asymmetric hydrogenation
employing chiral analogues of FLPs? One strategy to this end
involves the use of chiral phosphines, a class of chiral Lewis bases
that has been well studied (Table 5). However, efforts to reduce
PhCMedNPh under 4 atm of H2 using catalyst loadings of
20 mol % B(C6F5)3 and a chiral phosphine required heating of
the reactions to 50ꢀ100 °C to produce PhCHMeNHPh. Use of
the ligand (R)-binap or (S,S)-chiraphos gave exclusively racemic
mixtures of the amine, while the corresponding catalysis using
the ligand (S,S)-diop at 100 °C gave a modest enantiomeric
excess of 25%. In retrospect, it is perhaps not surprising that this
approach appears flawed. Mechanistic studies of hydrogenation
by FLPs suggest that the role of the phosphonium cation is to
transfer the proton to the imine. Employing a chiral phosphine is
only going to impact the induced chirality if it remains in close
proximity to the iminium as the hydride is transferred to the
Given that above, a better strategy would be based on the use
of a chiral borane. In the first report demonstrating the possibility
of chiral induction by an FLP catalyst, Chen and Klankermayer58
described the asymmetric hydrogenation of PhNdCPh(Me)
to the corresponding amine by employing the chiral borane
(R-pinenyl)B(C6F5)2 (11; Table 5). This particular system gave
only a 13% enantiomeric excess in the product amine. In a more
recent report, these same authors59 synthesized the related
hydrogenation catalysts 12 and 13 derived from camphor. These
systems dramatically improved the asymmetric induction, afford-
ing hydrogenation of prochiral imines with enantiomeric ex-
cesses as high as 83% (Table 5).
In a very recent study,60 we have shown that B(C6F5)3
catalyzes the hydrogenation of chiral imines with diastereoselec-
tivity. In the case of phenethylamine derivatives, diastereomeric
excesses ranged from 0 to 68% (Figure 4 and Table 6). However,
imine carbon center. The above data suggest that NH
P
3 3 3
hydrogen bonding is weak at best and thus has a minimal effect.
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Inorganic Chemistry
FORUM ARTICLE
Table 4. Hydrogenation of Commercially Relevant Imines
(Figure 3)
ketones, aldehydes, or even olefins. While the latter target seems
extremely challenging, it should be noted that the ability to effect
hydrogenation of any kind without a transition metal seemed
highly unrealistic just 5 years ago. With this in mind, there can be
no doubt that, as the substrateꢀcatalyst space expands for FLP
hydrogenation, this approach will continue to blossom as a new
tool in the synthetic chemists’ tool kit.
substrate
catalyst (mol %)
P (atm)
T (°C)
t(h)
yield (%)
a
a
a
a
a
a
b
b
c
c
c
c
d
d
d
e
1(5)
2(5)
3(5)
1(5)
2(5)
3(5)
2(5)
1(5)
2(5)
1(5)
2(5)
1(5)
3(5)
2(5)
1(5)
3(2)
124
120
120
124
117
120
120
117
120
120
124
120
124
124
124
117
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
4
4
54
10
4
13
20
20
20
20
20
4
46
’ EXPERIMENTAL SECTION
10
31
General Considerations. All preparations and manipulations
were performed on a double-manifold N2/vacuum line with Schlenk-
type glassware or in a N2-filled VAC glovebox. Solvents (Aldrich)
were dried using an Innovative Technologies solvent system and
degassed before use. NMR spectra were obtained on a Bruker Avance
400 MHz spectrometer, and spectra were referenced to residual
25
26
90
4
93
20
20
20
20
20
16
100
100
100
100
78
solvent (1H and 13C) or externally (11B, BF3 OEt2; 19F, CFCl3; 31P,
3
85% H3PO4). Chemical shifts are reported in ppm. NMR solvents
were purchased from Cambridge Isotopes, dried over CaH2 or
sodium benzophenone, vacuum distilled prior to use, and stored
over 4 Å molecular sieves in the glovebox. B(C6F5)3 was purchased
from Boulder Scientific Co. Combustion analysis was performed in-
house on a Perkin-Elmer CHN analyzer. A series of hydrogenation
experiments were performed in a combinatorial manner employing
the Chem-Speed ASW1000 robotic reactor system. In some cases,
hydrogenation experiments were done in a Parr pressure reactor.
Details are provided below.
95
General Procedure for FLP Hydrogenation Catalysis. In a N2-filled
glovebox, the imine substrate (0.5 mmol) was weighed in a vial
and dissolved in toluene (2 mL). To this was added catalyst (5 mol %),
and the imineꢀcatalyst solution was thoroughly mixed and then trans-
ferred to a 31 mL Parr pressure reactor equipped with a magnetic stir bar.
The reactorwas assembled and sealedinsidethe glovebox. Once removed,
it was further tightened. The reactor and its contents were purged three
times with H2, which was first passed through a gas purifier (Matheson
model 8010). The reactor was then heated to the appropriate tempera-
ture, pressurized with H2, and stirred for the listed reaction time.
Conversions were determined through 1H NMR spectroscopy.
Example Procedures. Reduction of C6H4CHdCHNMe. The cat-
alyst 3 (9.7 mg, 0.0184 mmol, 10 mol %) was transferred to a vial
containing 1-methylindole (24.8 mg, 0.189 mmol) with 1 mL of toluene-d8.
The vial was equipped with a stir bar and sealed in a Parr bomb. The
bomb was pressurized with 103 atm of H2 at 80 °C and stirred for 18 h.
The bomb was depressurized and cooled to room temperature. The
reaction mixture was then transferred to an NMR tube. Indoline
products were identified by comparison of 1H NMR spectra to literature
values.54ꢀ56
Figure 3. Examples of Commercially Relevant Imines.
camphor- or menthone-derived imines were reduced with
>95% diastereomeric excess (Figure 4 and Table 6), although
for high yields they require 10ꢀ20 mol % B(C6F5)3 as a
catalyst at 115 °C, 4 atm, and up to 5 days of reaction time. In
contrast, stoichiometric reductions of these imines using
Na[BH3(CN)] or Na[BH(OAc)3] gave high chemical yields
but significantly lower diastereoselectivities. Thus, these FLP
reductions offer high diastereoselectivities and the atom
economy of catalysis.
Reduction of Pyridinediimines. These reductions were done in
an analogous manner, and thus only one preparation is detailed.
To a Schlenk tube fitted with a Teflon tap was added the imine
(C5H3N)(MeCdN(C6H3-2,6-iPr2)2 (337 mg, 0.70 mmol) followed
by B(C6F5)3 (18 mg, 0.0035 mmol, 5 mol %). The reaction was
freezeꢀpumpꢀthawed three times, and then 4 atm of H2 was added.
The sealed tube was then heated to 120 °C for 24 h. Conversions were
monitored by NMR spectroscopy, which showed them to be
quantitative.
Future Directions. The catalytic incorporation of H2 into
organic substrates mediated by hetero- or homogeneous transi-
tion-metal materials has been known for over 100 years. In
contrast, the analogous transformation mediated by main-group
systems was reported less than 5 years ago. These findings offer a
new paradigm for hydrogenation. The development of catalysts
of this kind has been applied to an increasing variety of polar
organic substrates. These developments have been reviewed and
augmented herein. In addition, innovations targeting asymmetric
synthesis or the ability to reduce a broader range of substrates
may be useful products of commercial interest. The work of Soos
et al. demonstrates that altering the substituents on boron is one
viable approach to this end. Alternatively, we are exploring the
ability of other Lewis acidic centers to both activate H2 and effect
hydride transfer to a broader range of substrates. Of parti-
cular interest would be FLP systems, which effect reductions of
(C5H3N)(MeCHNH(C6H3-2,6-iPr2)2. 1H NMR (C6D5CD3):
δ
12.04ꢀ12.16 (Ar, 10H), 6.81 (py, 1H), 6.46 (py, 2H), 4.39 (br,
2H, NH), 4.29 (q, 2H, CH(CH3)), 3.42 (sept, 2H, CH(CH3)2), 1.65
(d, 6H, CH3(CH)), 1.31 (d, 12H, (CH3)2(CH)), 1.15 (d, 12H,
(CH3)2(CH)). X-ray crystals were obtained by slow evaporation
from a toluene solution.
(C5H3N)(MeCHNH(C6H4-4-iPr)2. 1H NMR (C6D5CD3): 8.32
(d, Ar), 8.09 (t, Ar),7.81 (t, Ar), 7.66 (t, Ar), 7.50 (t, Ar), 7.70ꢀ7.25
12346
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Inorganic Chemistry
FORUM ARTICLE
Table 5. Enatioselective Hydrogenation of Ketimines
substrate
catalyst (mol %)
T (°C)
P (atm)
t (h)
yield (%)
ee
ref
PhCMedNPh
3/(R)-binap (20)
3/(S,S)-chiraphos (20)
3/(S,S)-diop (20)
3/(S,S)-diop (20)
11 (10)
50
50
50
100
65
65
65
65
65
65
65
65
65
65
4
4
240
240
240
96
99
99
33
99
99
99
99
95
37
0
0
0
herein
herein
herein
herein
58
PhCMedNPh
PhCMedNPh
PhCMedNPh
PhCMedNPh
PhCMedNPh
PhCMedNPh
PhCMedNPh
PhCMedN(C6H4Me)
4
6
4
25
13
20
48
79
74
20
25
25
25
25
25
25
25
25
25
22
12/13 (5)
13 (5)
15
59
15
59
13 (5)
15
59
13 (5)
15
59
i
PhCMedN(C6H3 Pr2)
13 (5)
15
59
MeOC6H4CMedNPh
PhCMedNC6H4OMe
(C10H7)CMedNPh
13 (5)
15
96
99
93
96
81
81
80
83
59
13 (5)
15
59
13 (5)
15
59
(C10H7)CMedNC6H4OMe
13 (5)
15
59
Table 6. Diastereoselective Hydrogenation of Chiral Imines
with B(C6F5)3 (Figure 4)
catalyst
T
P
t
yield
(%)
major
substrate
(mol %)
(°C)
(atm)
(h)
de
isomer
a
b
c
c
d
e
f
10
10
10
10
10
10
10
10
10
10
20
10
80
80
5
5
48
48
100
100
72
0
11
36
62
39
45
65
99
98
99
99
96
S,R
80
5
48
S,S
25
115
5
23
100
100
100
100
100
92
S,S
80
48
S,S
80
5
48
S,R
80
5
24
S,S
g
h
i
115
115
115
115
115
5
120
120
120
120
120
R,R,R
R,R,R
R,S,R
R,S,S
R,S,S
5
5
100
100
66
j
5
j
5
model and coupled isotropic temperature factors (see the Supporting
Information).
Figure 4
’ ASSOCIATED CONTENT
(m, Ar), 4.60 (CH(CH3)), 4.42 (br, NH), 2.90 (CH(CH3)2), 2.73
(CH(CH3)2), 2.39 (d, CH3(CH)), 1.47ꢀ1.55 (m, CH3(CH)), 1.27
(d, CH3(CH)),1.15 (d, CH3(CH)).
S
Supporting Information. Crystallographic data in CIF
b
format. This material is available free of charge via the Internet at
http://pubs.acs.org.
1
(C5H3N)(MeCHNH(C6H2-2,4,6-Me3)2. H NMR (C6D5CD3): 8.45
(d, Ar), 8.20 (d, Ar), 7.87 (t, Ar), 7.65 (t, Ar), 7.46 (t, Ar), 6.70ꢀ7.23
(m, Ar), 4.41 (CH(CH3)), 4.15 (br, NH), 2.14ꢀ2.28 (m, CH3), 1.98
(m, CH3), 1.35ꢀ1.45 (m, CH3), 1.47ꢀ1.55 (m, CH3(CH)), 1.27
(d, CH3(CH)), 1.15 (d, CH3(CH)).
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: dstephan@chem.utoronto.ca.
X-ray Data Collection, Reduction, Solution, and Refine-
ment. Single crystals were coated in Paratone-N oil in the glovebox,
mounted on a MiTegen Micromount, and placed under a N2 stream.
The data were collected on a Bruker Apex II diffractometer. The data
were collected at 150((2) K for all crystals. Data reduction was
performed using the SAINT software package, and an absorption
correction was applied using SADABS. The structures were solved by
direct methods using XS and refined by full-matrix least squares on F2
using XL as implemented in the SHELXTL suite of programs.61 All non-
hydrogen atoms were refined anisotropically. Carbon-bound hydrogen
atoms were placed in calculated positions using an appropriate riding
Present Addresses
‡GreenCentre Canada, 945 Princess Street, Kingston, Ontario,
Canada K7L3N6.
’ ACKNOWLEDGMENT
The authors thank NSERC of Canada for financial support.
D.W.S. is grateful for the award of a Canada Research Chair and a
Killam Research Fellowship. S.G. is grateful for the award of an
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Inorganic Chemistry
FORUM ARTICLE
NSERC-CGS. Z.M.H. is grateful for the award of an Ontario
Postdoctoral Fellowship.
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