Transfer Hydrogenation of Nitriles, Olefins, and N-Heterocycles Catalyzed by an N-Heterocyclic Carbene-Supported Half-Sandwich Complex of Ruthenium

Article abstract of DOI:10.1021/acs.organomet.5b00967

In the presence of KOBu^t, N-heterocyclic carbene-supported half-sandwich complex [Cp(IPr)Ru(pyr)₂][PF₆] (3) (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) catalyzes transfer hydrogenation (TH) of nitriles, activated N-heterocycles, olefins, and conjugated olefins in isopropanol at the catalyst loading of 0.5%. The TH of nitriles leads to imines, produced as a result of coupling of the initially formed amines with acetone (produced from isopropanol), and showed good chemoselectivity. Reduction of N-heterocycles occurs for activated polycyclic substrates (e.g., quinoline) and takes place exclusively in the heterocycle. The TH also works well for linear and cyclic olefins but fails for trisubstituted substrates. However, the C = C bond of α,β-unsaturated esters, amides, and acids is easily reduced even for trisubstituted species, such as isovaleriates. Mechanistic studies suggest that the active species in these catalytic reactions is the trihydride Cp(IPr)RuH₃ (5), which can catalyze these reactions in the absence of any base. Kinetic studies are consistent with a classical inner sphere hydride-based mechanism of TH.

Full text of DOI:10.1021/acs.organomet.5b00967

Article
pubs.acs.org/Organometallics
Transfer Hydrogenation of Nitriles, Olefins, and N‑Heterocycles
Catalyzed by an N‑Heterocyclic Carbene-Supported Half-Sandwich
Complex of Ruthenium
Van Hung Mai and Georgii I. Nikonov*
Chemistry Department, Brock University, Niagara Region, 1812 Sir Isaac Brock Way, St. Catharines, Ontario L2S 3A1, Canada
S
* Supporting Information
ABSTRACT: In the presence of KOBut, N-heterocyclic
carbene-supported half-sandwich complex [Cp(IPr)Ru(pyr)2]-
[PF6] (3) (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-
ylidene) catalyzes transfer hydrogenation (TH) of nitriles,
activated N-heterocycles, olefins, and conjugated olefins in
isopropanol at the catalyst loading of 0.5%. The TH of nitriles
leads to imines, produced as a result of coupling of the initially
formed amines with acetone (produced from isopropanol),
and showed good chemoselectivity. Reduction of N-hetero-
cycles occurs for activated polycyclic substrates (e.g., quino-
line) and takes place exclusively in the heterocycle. The TH also works well for linear and cyclic olefins but fails for trisubstituted
substrates. However, the CC bond of α,β-unsaturated esters, amides, and acids is easily reduced even for trisubstituted species,
such as isovaleriates. Mechanistic studies suggest that the active species in these catalytic reactions is the trihydride Cp(IPr)RuH3
(5), which can catalyze these reactions in the absence of any base. Kinetic studies are consistent with a classical inner sphere
hydride-based mechanism of TH.
secondary amines by isopropanol (IPA) at 120 °C.12 Both
INTRODUCTION
■
these Ru-catalyzed processes require elevated temperatures and
Transfer hydrogenation (TH) from alcohols and formates has
emerged as a powerful method for the conversion of
unsaturated organic molecules into value added products.1
TH offers certain advantages over other reduction methods due
to the easy operational setup, low toxicity of reactants and
byproducts (e.g., acetone for isopropanol and CO2 for
formates), and much reduced flammability in comparison
with pressurized hydrogen or main-group metal hydrides. The
asymmetric versions as well as the application of base metal
catalysts have recently become available.1a,j,k
the catalyst load of 1−2%.13
We have recently reported that the half-sandwich complex
[Cp(iPr3P)Ru(NCCH3)2][BF4] (1, Chart 1) catalyzes chemo-
selective reduction of nitriles and heterocycles by using silanes
as reducing reagents.14 More recently we found that the same
complex 1 catalyzes room temperature reduction of nitriles by a
Chart 1. Structures of Half-Sandwich Complexes of
Ruthenium
The prevailing substrates for catalytic TH are ketones and
imines, whereas applications to other unsaturated systems are
much less known. The TH of olefins is scarce2−4 and, with a
few exceptions,3 is limited to activated substrates.5 Unlike
catalytic hydrogenation, the TH of heterocycles is much less
developed and usually involves hydrogen transfer from
dearomatized heterocycles, such as Hantzsch esters, which is
very waste intensive.6 The TH of nitrogen heterocycles by
more benign reductants, such as alcohols7 or formates,8 is little
studied but offers great potential for mild synthesis of
biologically active molecules, such as tetrahydroquinolines.9
The TH of nitriles has been known since 1982, but the yields
and/or substrate scope were rather limited.2i,10 In 2013, the
Beller group disclosed the reduction of aromatic and aliphatic
nitriles to amines by 2-butanol at 120 °C catalyzed by [Ru(p-
cymene)Cl2]2/DPPB) (DPPB = 1,4-bis(diphenylphosphino)-
butane).11 The same workers showed that the related catalyst
RuCl2(PPh3)3 catalyzes tandem TH/alkylation of nitriles to
Received: November 23, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.5b00967
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
much cheaper reagent, IPA. The products of this reaction were
imines formed by the in situ coupling of the intermediate amine
with acetone produced as a result of hydrogen transfer from
IPA.15 Several important functionalities were tolerated in this
process but the catalyst load was relatively high (5%). Another
ruthenium half-sandwich catalyst for the TH of ketones
supported by a diimine ligand has been recently reported by
Tamm et al.16 The Crabtree group showed that a pyrimidyl-
substituted N-heterocyclic carbene (NHC) complex of Ru [(η6-
cymene)(N-C)RuCl][PF6] catalyzes the TH of acetophenone,
cyclohexanone, and N-benzylideneaniline.17 Albrecht et al.
studied several half-sandwich Ru catalysts supported by NHCs
and showed their ability to reduce PhCN and conjugated
olefins.3d In light of these literature precedents and as part of
our interest in the chemistry of half-sandwich complexes of Ru
supported by NHCs,18 we became interested in the catalytic
activity of the related complex [Cp(IPr)Ru(NCCH3)2][PF6]
(2, IPr = 1,3-bis(2,6-disopropylphenyl)imidazol-2-ylidene).
Here we report an improved TH of nitriles by IPA catalyzed
by NHC-supported complexes and the application of this
catalytic system to the reduction of heterocycles and olefins.
were chosen as the test substrates to determine optimized
reaction conditions. Complex 3 showed the superior catalytic
activity in comparison with 2 and 4 (Table S1). Some catalyst
turnover was observed for both substrates at room temperature
(entry 1 in both Tables 1 and 2), but further optimization of
the reduction of acetophenone determined the best conditions
to be 0.05% catalyst load at 80 °C (Table 1, entry 7). In the
case of benzonitrile, a comparable activity was reached at the
0.5% load (Table 2, entry 6). Although the TH of ketone by 3
is significantly improved in comparison with the catalyst 1, it
still falls short of the benchmark Noyori’s catalyst [(η6-
arene)Ru(diamido)],19 Baratta’s catalyst [RuCl(κ3-CNN)-
(dppb)] (5 min at 0.005 mol%),20 and Stradiotto’s catalyst
[(η6-cymene)Ru(κ2-P,N)(Cl)] (5 min at 0.05 mol%).21 We
next optimized the amount of base (KOBut) and observed a
saturation behavior at loads greater than 3 equiv (Table S2).
Transfer Hydrogenation of Nitriles. With the optimized
conditions in hand (0.5 mol% catalyst, 1.5 mol% KOBut),
complex 3 was then applied to the catalytic TH of a series of
substituted nitriles (Table 3). Reactions of functionalized
Table 3. 3-Catalyzed Transfer Hydrogenation of Nitriles
RESULTS AND DISCUSSION
■
Catalyst Optimization. The preparation of complexes
[Cp(IPr)Ru(NCCH3)2][PF6] (2) and [Cp(IPr)Ru(pyr)2]-
[PF6] (3, pyr = pyridine) has been recently reported.18 The
activity of 2, 3, and the commercially available compound
[CpRu(NCCH3)3]PF6 (4) was tested in the TH of ketones and
nitriles in isopropanol (IPA) at 70 °C in the presence of a base
(KOtBu). Acetophenone (Table 1) and benzonitrile (Table 2)
c
entry
product
yield (%)
time
1
2
3
4
5
6
7
4-MeCH(OH)C6H4CH2NCMe2
4-(MeO)C6H4CH2NCMe2
4-(H2N)C6H4CH2NCMe2
4-(EtO2C)C6H4CH2NCMe2
4-(HOCH2)C6H4CH2NCMe2
NC5H4-3-CH2NCMe2
Me(CH2)5CH2NCMe2
Me3CCH2NCMe2
97
98 (57)
87 (68)
90
45m
50m
90m
195m
120m
165m
48h
97
Table 1. Optimization of Catalytic Conditions for the 3-
Catalyzed Transfer Hydrogenation of Acetophenone
95
59
a
8
a
32
48h
9
MeCH2CH2NCMe2
98
48h
a
10
Me(CH2)2CH2NCMe2
Me(CH2)3CH2NCMe2
C6H4CH2NCMe2
99 (83)
48h
a
d
11
87 (73)
48h
a
b
entry
%C
B:C
2:1
temp (°C)
yield (%)
time
b
12
83
120m
48h
1
2
3
4
5
6
7
1
RT
RT
RT
40
83
67
17h
7h20m
24h
e
13
14
3-NO2-C6H4-CH2NCMe2
35
1
10:1
10:1
10:1
10:1
10:1
10:1
HCC-(CH2)4NCMe2
24
48h
c
0.05
0.1
<10
40
a
b
At 90 °C. 1% 5 was used as a catalyst without added base. NMR
yield, isolated yield of ammonium salt after treatment with HCl in
parentheses. Isolated yield of amine after aqueous workup with
NaOH. Catalyst was deactivated upon the disappearance of tris-
20h
d
0.1
70
76
3h
e
0.05
70
83
7h
0.05
80
82
1h20m
hydride peak, and color of sample turned black.
a
b
B = base KOBut, C = catalyst 3. NMR yield.
Table 2. Optimization of Catalytic Conditions for the 3-
Catalyzed Transfer Hydrogenation of Benzonitrile
benzonitriles bearing the methoxy, amino, and ester groups in
the 4-position proceeded chemoselectively, giving the corre-
sponding imine derivatives in good to excellent yields (entries
2, 3, and 4).
Reactions of aromatic nitriles bearing more reactive carbonyl
groups, such as acetyl and aldehyde groups, first resulted in
selective reduction of the CO bond followed by the TH of
the CN bond (entries 1 and 5). A pyridyl-substituted nitrile
was also successfully reduced (entry 6). As for catalyst 1, the
nitro substituent in the aromatic ring suppressed the catalytic
activity (entry 13), resulting in a low yield of the imine product.
Moreover, the more challenging aliphatic nitriles were also
reduced but the yields dropped significantly, and longer
reaction times were required to complete the reactions (entries
7−11). Longer chain and branched aliphatic nitriles are more
a
b
entry
%C
temp (°C)
yield (%)
time
1
2
3
4
5
6
0.05
0.1
0.1
0.5
0.5
70
80
63
99
4h50m
1h50m
24h
RT
50
<10
87
8h50m
5h10m
2h15m
60
93
0.5
b
70
94
a
C = catalyst 3. NMR yield.
B
DOI: 10.1021/acs.organomet.5b00967
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
difficult to hydrogenate (entries 7 and 8). And elevated
temperature (90 °C) is required to complete the reaction.
Transfer Hydrogenation of Imines. Given the activity of
3 in the TH of the CN triple bond, we became interested in
the application of this catalyst to other unsaturated nitrogen
substrates. Unexpectedly, ketimines PhMeCNPh, PhMeC
N(2,6-Me2C6H3), and (p-MeOC6H4)MeCNPh were re-
duced only in trace amounts (<5%) even after 48 h at 70 °C.
The aldimine PhHCNPh was converted to PhH2C-NHPh in
only 45% yield after 8 h at 90 °C at 1% catalyst load. However,
an aldimine activated by a tosyl group was successfully reduced
to amine at only 0.5% catalyst load (Table 4, entry 5). The
Table 5. 3-Catalyzed Transfer Hydrogenation of Imines
Table 4. 3-Catalyzed Transfer Hydrogenation of Imines
a
NMR yields, isolated yields of amine in parentheses.
was observed for pyridine, isoquinoline, pyrimidine, pyrole, and
imidazole.
Transfer Hydrogenation of Esters. In our previous work
with the catalyst 1, we observed partial TH of activated esters,
such as phenyl acetates and trifluoroacetates, to alcohols.15 But
in all cases studied the main process was the transesterification
of the substrate with IPA. Very similar results were obtained
with the catalyst 3 (Table S3). For comparison, Albrecht et al.
have previously observed only partial saponification of methyl
benzoate under the action of an NHC-supported Ru complex
under the TH conditions (IPA/KOH (aq)).2i
Transfer Hydrogenation of Olefins. In order to establish
further the applicability of this catalytic system for the
reduction of functionally loaded substrates, we tested catalyst
3 in the TH of CC bonds. To our delight, several
unfunctionalized olefins could be reduced well to the
corresponding alkanes (Table 6). The yields are high for
both linear and cyclic substrates (entries 1 and 2, respectively)
but drop for trisubstituted olefins (entries 5 and 6). No
reduction occurred for a tetrasubstituted olefin (entry 7). For
styrene we observed formation of an insoluble gum at the
bottom of NMR tube, suggesting formation of a polymer (entry
8). To the best of our knowledge, previously the catalytic TH
of unactivated CC bonds by IPA has been observed only for
the complex [(η6-cymene)(η3-CC-NHC)RuCl][BF4]
(where CC-NHC is a chelating NHC with a pendant olefin
group),3d for the catalysis by Ni nanoparticles,3b and in the
tandem ring closure metathesis/TH reactions.4 Attempted TH
of alkynes was unsuccessful, as no reduction was observed after
48 h (entries 9 and 10).
a
b
NMR yields, isolated yield of amine in parentheses. At 90 °C.
related activated ketimine derived from acetophenone was
reduced to 82% yield in 16 h (entry 6). Interestingly, N-aryl
dialdimines were also reduced but more sluggishly (entries 7−
9) even at a higher catalyst loading (5%).
Transfer Hydrogenation of Heterocycles. The scope of
substrates for TH was then extended to a range of N-
heterocycles. We were delighted to see that quinoline and 1,5-
napthyridine could be hydrogenated in good yields (Table 5,
entries 1 and 2). As expected, less aromatically stabilized
substrates, such as 1,3,5-triazine, acridine, and phenanthridine,
can be easily reduced (entries 3−5). In contrast, bulkier
substrates, such as 2-phenylquinoline (entry 6), and more
electron rich substrates, such as 8-aminoquinoline (entry 7)
were inert under these conditions. Unfortunately, no reactivity
Given the relative inactivity of ester, amido, and carboxy
groups in TH, we became interested in studying conjugated
C
DOI: 10.1021/acs.organomet.5b00967
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Table 6. 3-Catalyzed Transfer Hydrogenation of Olefins and
Alkynes
Table 7. 3-Catalyzed Transfer Hydrogenation of Conjugated
Substrates
a
b
Cp(IPr)RuH3/tBuOK was used as a catalyst. Cp(IPr)RuH3 was
c
d
used as a catalyst without added base. At 80 °C. NMR yields.
e
Styrene polymerized.
systems. Monitoring the reactions of α,β-unsaturated esters
revealed fast (<20 min) formation of β-isopropoxy-substituted
esters formed as a result of Michael addition of IPA. These
compounds were formed as kinetic products because further
heating at 70 °C resulted in a slow reduction of the ethereal
moiety RH2C-O-iPr to RH2C-H (Table 7, entries 1−7). As
could be expected, the ester part of both Michael and
hydrogenation products contained the isopropoxy group
instated as a result of concomitant transesterification. The
hydrogenation process most likely occurs via a reversible
dissociation of IPA (a retro-Michael reaction) followed by the
TH of the re-formed CC double bond. Analogous
observations were made for the TH of enamides (entries 8−
10). To our delight, 3,3-dimethylacrylic acid also could be
reduced to the isovaleric acid (entry 11). In contrast, attempted
reduction of methacrylic acid resulted in fast deactivation of the
catalyst (entry 12). The reasons behind this divergent reactivity
are not clear at the moment.
a
b
NMR yields, isolated yields in parentheses. Isolated yields for ester
c
obtained after transesterification with ethanol or methanol. The
catalyst was premixed with base in IPA prior to addition of the
substrate. After the TH, the isovaleric acid was converted to ester by
acid-catalyzed esterification. However, prior conversion of crotonic
acid into isopropyl ester resulted in 65% isolated yield of isopropyl
isobutyrate.
d
Mechanistic Studies. A careful inspection of the 1H NMR
spectra of different catalytic mixtures allowed for the
observation that the trihydride Cp(IPr)RuH3 (5) is the resting
state of the catalyst. Indeed, complex 5 can be cleanly generated
under the conditions of our catalytic mixtures, i.e., by the
e
t
reaction of [Cp(IPr)Ru(pyr)2]+ (3) with 1 equiv of BuOK in
(e.g., Table 2, entry 6 vs Table 3, entry 12). These observations
suggested that the role of base is solely to convert the precursor
3 into complex 5 which is the true catalyst.
To get more insight into the nature of this catalytic system,
kinetic studies using the initial rate analysis were carried out. p-
Methoxybenzonitrile was chosen as the substrate because it
IPA. The trihydride 5 was synthesized on the preparative scale
and isolated in 80% yield after recrystallization from a mixture
of toluene/hexane (1:3). The 1H NMR spectrum of 5 in C6D6
shows a typical hydride signal at −10.67 ppm as a time-
averaged singlet for three hydrides and the Cp peak at 4.30
ppm (5H), in addition to the signals of the IPr ligand.18
The catalytic activity of trihydride 5 was tested in the TH of
benzonitrile (Table 3, entry 12) and in the TH of cyclohexene
(Table 6, entries 3 and 4). Interestingly, in both cases the
reduction occurred without addition of any base and at reaction
1
allows for the monitoring of the MeO signal by H NMR.
Complex 5 was employed as the catalyst to suppress any effect
of the catalyst generation stage. Nevertheless, we chose to use
some additional base to mimic the actual catalytic conditions
better. The reaction rates were measured in chlorobenzene with
the catalyst/base ratio 1:3 and by using a large but controlled
t
times well comparable with cases when BuOK was employed
D
DOI: 10.1021/acs.organomet.5b00967
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
amount of IPA (the range 10−40 equiv). A first-order
dependence of the reaction rate on the concentration of
substrate was observed (Figures S8−12). Plotting the reaction
rate vs the amount of IPA revealed a saturation behavior at
large concentrations of the alcohol (Figure 1). This kinetic
been previously studied by Nolan et al. in a combined
experimental and theoretical study of alcohol racemization
catalyzed by the related complex Cp*(NHC)RuCl.23 It is
interesting to compare the mechanistic proposal of Figure 2
with our previous studies on the phosphine catalyst 1. In that
case we also observed the formation of a hydride species, which
however was different from the known trihydride Cp(iPr3P)-
RuH3 and whose exact nature remained unclear. The main
difference is that for 1 we observed the first-order kinetics in
IPA in the range of 10−30 equiv of IPA, which prevented us
from drawing a reliable conclusion about the exact sequence of
mechanistic events. The reason for the different mechanistic
behavior of the catalysts 1 and 5 likely lies in their structural
features. In the phosphine species 1, the substituents at the
phosphorus center are oriented backward, thus creating a more
open space around the ruthenium atom. In the NHC
complexes 3 and 5, the bulky Ar groups at nitrogen look
forward, toward the positions occupied by the pyridine and
hydride ligands, respectively. This structural difference, on one
hand, hampers the coordination of bulkier substrates to
ruthenium atom but, on the other hand, facilitates ligand
dissociation from 3 (e.g., pyridine) and insertion reactions (step
2 in Figure 2).
Figure 1. Dependence of the 5-catalyzed transfer hydrogenation on
the amount of IPA.
behavior suggests the occurrence of a pre-equilibrium involving
the substrate. To elucidate the effect of base, the kinetic
measurements were repeated under the pseudo-first-order
conditions (15 equiv of IPA relative to substrate) for varying
amounts of tBuOK. In contrast to the results of the initial tests
with the catalyst 2, increasing the amount of base had a
detrimental effect on catalysis (Figure S13). This experiment
confirms our conclusion that in the case of TH of benzonitrile
the base plays no other role in catalysis but converts the
precatalyst 2 into the true catalyst 5 (vide supra). All together
these kinetic data agree with a classical hydride mechanism of
TH (Figure 2).22 The key steps 2, 3, and 4 of this cycle have
Further experiments, however, revealed that the effect of base
can be substrate sensitive. Thus, screening various catalytic
conditions for the TH of methyl acrylate showed that the
cationic complexes 4 and [CpRu(pyr)3]PF6 (4a) show
comparable (Table 8, entries 1 and 2) but reduced activity in
Table 8. Transfer Hydrogenation of Methyl Acrylate under
Different Conditions
a
entry
conditions
4 + 3KOtBu
yield
time
1
2
3
4
5
6
7
8
85% M, 15% H
85% M, 15% H
17% M, 83% H
18% H
72h
72h
16h
24h
24h
8h
4a + 3KOtBu
3 + 3KOtBu
Cp(IPr)RuH3
Cp(IPr)RuH3 + KOtBu
Cp(IPr)RuH3 + 3KOtBu
KOtBu
98% H
11% M, 89% H
99% M, 0% H
0% M, 0% H
20m
24h
no catalyst + no base
a
NMR yield.
comparison with the NHC-supported complex [Cp(IPr)Ru-
(pyr)2]+ (3) (Table 8, entry 3). The trihydride Cp(IPr)RuH3
(5) taken alone can mediate the reduction too but its activity is
significantly increased upon addition of KOBut (entries 4−6).
On the other hand, a control experiment showed that the base
alone does not catalyze this reaction (entry 7). The latter fact is
of significance because Ouali et al. have previously reported that
simple bases can catalyze TH of ketones in the absence of any
transition metal.24
CONCLUSIONS
■
The NHC-supported half-sandwich complexes [Cp(IPr)Ru-
(NCCH3)2][PF6] (2) and [Cp(IPr)Ru(pyr)2][PF6] (3) are
effective catalysts for the transfer hydrogenation of nitriles and
actually perform this reaction much better (at lower catalyst
load and faster rates) than the isolobal phosphine complex
Figure 2. Proposed mechanism for 3-catalyzed transfer hydrogenation.
E
DOI: 10.1021/acs.organomet.5b00967
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
[Cp(iPr3P)Ru(NCCH3)2][BF4]. Complex 3 also catalyzes the
TH of activated heterocycles (including quinoline) and cyclic
and acyclic olefins. In the latter case, good results were obtained
for mono- and bis(substituted) olefins but the yield drops
significantly for a tri(substituted) system. In the case of
activated olefins (conjugated esters, amides, and acids) the TH
works well for mono-, bis-, and tri(substituted) CC bonds.
Mechanistic studies showed that the resting state in this
catalysis is the trihydride Cp(IPr)RuH3 (5) which can catalyze
the reduction of nitriles without any additional base and that
the external base actually has a detrimental effect on catalysis.
Therefore, the role of base in the 3-catalyzed reaction is merely
to effect the conversion of the precatalyst into a reactive
hydride. However, the efficiency of reduction increases in the
presence of a base when methyl acrylate was used as substrate.
The reason for this discrepancy is not yet understood. Kinetic
studies for the 5-catalyzed TH of 4-methoxybenzonitrile
suggested a classical hydride mechanism of reduction based
on substrate coordination to a metal hydride complex,
migratory insertion, and release of the product after a
metathesis with IPA.
The product was then isolated by chromatography on silica gel, using a
mixture of hexane and ethyl acetate (4:1).
General Procedure for the Reduction of Olefins. In a
glovebox, a 10 mL flame-dried Schlenk tube equipped with a magnetic
stirring bar was charged with 3 (0.5 mol%), olefin (0.8 mmol), and
KOBut (1.5 mol%) in IPA (4 mL). The Schlenk flask was brought out
of the glovebox, equipped with a condenser under N2 atmosphere and
heated to 70 °C. The progress of the reaction was monitored by NMR
spectroscopy and TLC. The reaction was stopped when the highest
amount of the hydrogenated products was observed. Then the reaction
mixture was treated by two portions of a 10 mL mixture of diethyl
ether and water (2:1 v/v). The organic phase was separated and dried
over MgSO4. In the case of ester substrates, the initially formed
mixture of the starting ester (methyl or ethyl), reduced ester, and their
isopropyl analogues, formed by the transesterification in IPA, was
converted into the ethyl or methyl ester by transesterification with
corresponding alcohol. For example, to convert a mixture of isopropyl
butyrate and ethyl butyrate into ethyl butyrate, excess amount of
ethanol was added with a drop of H2SO4, and the mixture was refluxed
for 2 h, followed by a standard workup.
Dependence of the Reaction Rate on Isopropanol. In a
glovebox, seven NMR samples were prepared each containing 0.5 mol
% (0.527 mmol) of Cp(IPr)RuH3 (5, from a stock solution in IPA),
1.5 mol% of KOBut (1.577 mmol, from a stock solution in PhCl), p-
methoxybenzonitrile (105.1 mmol), and an additional amount of IPA
with the total amount of IPA in the range of 10−40 equiv with respect
to p-methoxybenzonitrile (250 μL, 105.1 mmol). For each sample, a
timer was started when the sample was placed inside a Bruker DPX-
EXPERIMENTAL SECTION
■
General Details. All manipulations were carried out, using
conventional inert atmosphere glovebox and Schlenk techniques.
Solvents were dried by Grubbs-type columns, except for THF which
was distilled from a sodium benzophenone ketyl solution. NMR
spectra were obtained with Bruker DPX-400 and Bruker DPX-600
instruments (1H, 400 and 600 MHz; 13C, 100.6 and 151 MHz). The
1H and 13C{1H} NMR spectra of isolated organic products were
recorded in CDCl3. Complexes [Cp(IPr)Ru(NCCH3)2][PF6] (2),
[Cp(IPr)Ru(pyr)2][PF6] (3), [CpRu(pyr)3][PF6] (4a), [CpRu-
(NCCH3)3][PF6] (4), and Cp(IPr)RuH3 (5) were prepared as
previously described.18,25
1
600 NMR spectrometer preheated to 70 °C, and H NMR spectra
were obtained every 5 min for 1.5 h. The rate of the reaction was
determined from the decrease of the MeO signal of p-methoxybenzo-
1
nitrile in the H NMR spectra as the reaction progressed. Under the
pseudo-first-order conditions, the linearity of the plot of −ln-
([MePhCN]t/[MePhCNe]0) versus time reveals that the reaction
rate is first-order with respect to substrate (Figures S1−S7). The
slopes of the regression lines (keff) were then plotted versus the
equivalents of IPA (Figure 1). The reaction showed saturation
behavior at high concentrations of IPA.
General Procedure for the Reduction of Nitriles. Stock
solutions of catalysts 1, 2, 3, 4, and 5 in IPA and KOBut in IPA were
prepared separately before use. In a glovebox, a 10 mL, flame-dried
Schlenk tube equipped with a magnetic stirring bar was charged with 3
(0.5 mol%), nitrile (0.8 mmol) and KOBut (1.5 mol%) in IPA (4 mL).
The Schlenk flask was brought out of the glovebox and equipped with
a condenser under N2 atmosphere. The progress of the reaction was
monitored by NMR spectroscopy at 70 °C. The imine RCH2N
C(CH3)2 was obtained as the major product. After the reaction was
completed, the resulting solution was treated with aqueous HCl (1 M,
1.8 mL). Then the mixture was stirred for 1 h at room temperature to
ensure the complete hydrolysis of imine. After the removal of volatiles
under vacuum, 5 mL fresh water was added into solid residue to
extract ammonium salts. The water solution of ammonium salts was
then recrystallized with (1 mL) addition of hexane (5:1 v/v) to yield
corresponding ammonium microcrystal salts, which are analytically
clean, as confirmed by NMR. The ammonium salt [RCH2NH3]Cl was
obtained as a pale yellow or brownish solid, depending on the nitrile
used. The ammonium salt was converted to amine by treatment with a
3 M NaOH solution (3 mL) in a 2 × 10 mL mixture of diethyl ether
and water (2:1 v/v). The organic phase was separated and dried over
MgSO4.
General Procedure for the Reduction of N-Heterocycles. In a
glovebox, a 10 mL flame-dried Schlenk tube equipped with a magnetic
stirring bar was charged with 3 (0.5 mol%), N-heterocycle (0.8 mmol),
and KOBut (1.5 mol%) in IPA (4 mL). The Schlenk flask was brought
out of the glovebox, equipped with a condenser under N2 atmosphere
and heated to 70 °C. The progress of the reaction was monitored by
NMR spectroscopy and TLC. The reaction was stopped when the
highest amount of the partially hydrogenated product was observed.
After the removal of volatiles under vacuum, hexane was used to
extract the product and the remaining substrate from the solid residue.
Dependence of the Reaction Rate on Base. In a glovebox, five
NMR samples were prepared, each containing 0.5 mol% of
Cp(IPr)RuH3 (5, 1.577 mmol, from a stock solution in IPA), an
additional amount of IPA up to the total amount of IPA of 112.5 μL
(mmol), p-methoxybenzonitrile (105.1 mmol), and a variable amount
of KOBut (from a stock solution in IPA) in the range 1.25−4 equiv
with respect to catalyst 5. For each sample, a timer was started when
the sample was placed inside a Bruker DPX-600 NMR spectrometer
1
preheated to 70 °C, and H NMR spectra were obtained every 5 min
for 1.5 h. The rate of the reaction under the pseudo-first-order
conditions was determined from the decrease of the MeO signal of p-
methoxybenzonitrile in the 1H NMR spectra as the reaction
progressed (Figures S8−S12). The slopes of the regression lines
(keff) were then plotted versus the equivalents of KOBut (Figure S13).
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.5b00967.
Further experimental details, characterization data, and
kinetic plots (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: gnikonov@brocku.ca. Tel.: +1 (905) 688-5550, ext.
3350. Fax: +1 (905) 682-9020.
■
Notes
The authors declare no competing financial interest.
F
DOI: 10.1021/acs.organomet.5b00967
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
(f) Talwar, D.; Li, H. Y.; Durham, E.; Xiao, J. Chem. - Eur. J. 2015,
21, 5370−5379.
ACKNOWLEDGMENTS
■
Dedicated to Prof. Dmitry A. Lememovskii on the occasion of
his 70th birthday. This research was supported by a DG
NSERC grant (326899-2012) to G.I.N.
́
(9) Sridharan, V.; Suryavanshi, P. A.; Menendez, J. C. Chem. Rev.
2011, 111, 7157−7259.
(10) (a) Brown, G. R.; Foubister, A. J. Synthesis 1982, 1982, 1036.
(b) Horn, S.; Gandolfi, C.; Albrecht, M. Eur. J. Inorg. Chem. 2011,
2011, 2863. (c) Mizushima, E.; Yamaguchi, M.; Yamagishi, T. J. Mol.
Catal. A: Chem. 1999, 148, 69. (d) Mebane, R. C.; Jensen, D. R.;
Rickerd, K. R.; Gross, B. H. Synth. Commun. 2003, 35, 3373.
(e) Nixon, T. D.; Whittlesey, M. K.; Williams, J. J. Tetrahedron Lett.
2011, 52, 6652. (f) Gowda, S.; Gowda, D. C. Tetrahedron 2002, 58,
2211.
REFERENCES
■
(1) (a) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97.
(b) Clapham, S. E.; Hadzovic, A.; Morris, R. H. Coord. Chem. Rev.
2004, 248, 2201. (c) Fujita, K.-H.; Yamaguchi, R. Synlett 2005, 4, 560.
(d) Gladiali, S.; Alberico, E. Chem. Soc. Rev. 2006, 35, 226. (e) Ikariya,
T.; Blacker, J. Acc. Chem. Res. 2007, 40, 1300. (f) Baratta, W.; Rigo, P.
Eur. J. Inorg. Chem. 2008, 2008, 4041. (g) Morris, R. H. Chem. Soc. Rev.
2009, 38, 2282. (h) Malacea, R.; Poli, R.; Manoury, E. Coord. Chem.
Rev. 2010, 254, 729. (i) Fukuzumi, S.; Suenobu, T. Dalton Trans. 2013,
42, 18. (j) Sues, P. E.; Demmans, K. Z.; Morris, R. H. Dalton Trans.
2014, 43, 7650. (k) Wang, D.; Astruc, D. Chem. Rev. 2015, 115, 6621−
6686.
(11) Werkmeister, S.; Bornschein, C.; Junge, K.; Beller, M. Chem. -
Eur. J. 2013, 19, 4437.
(12) Werkmeister, S.; Bornschein, C.; Junge, K.; Beller, M. Eur. J.
Org. Chem. 2013, 2013, 3671.
(13) For the use of formic acid in the TH of nitriles, see: Vilches-
Herrera, M.; Werkmeister, S.; Junge, K.; Borner, A.; Beller, M. Catal.
̈
Sci. Technol. 2014, 4, 629−632.
(2) (a) Spogliarich, R.; Tencich, A.; Kaspar, J.; Graziani, M. J.
̌
Organomet. Chem. 1982, 240, 453−459. (b) Dobrovolna, Z.; Cerveny,
́
́
(14) (a) Gutsulyak, D. V.; Nikonov, G. I. Angew. Chem., Int. Ed. 2010,
49, 7553. (b) Gutsulyak, D. V.; Nikonov, G. I.; van der Est, A. Angew.
Chem., Int. Ed. 2011, 50, 1384. (c) Lee, S.-H.; Gutsulyak, D. V.;
Nikonov, G. I. Organometallics 2013, 32, 4457.
L. Res. Chem. Intermed. 1998, 24, 679−686. (c) Frediani, P.; Salvini, A.;
Bessi, M.; Rosi, L.; Giannelli, C. Inorg. Chem. Commun. 2005, 8, 94−
95. (d) Black, P. J.; Cami-Kobeci, G.; Edwards, M. G.; Slatford, P. A.;
Whittlesey, M. K.; Williams, J. M. J. Org. Biomol. Chem. 2006, 4, 116−
125. (e) Frediani, P.; Rosi, L.; Cetarini, L.; Frediani, M. Inorg. Chim.
Acta 2006, 359, 2650−2657. (f) Burling, S.; Paine, B. M.; Nama, D.;
Brown, V. S.; Mahon, M. F.; Prior, T. J.; Pregosin, P. S.; Whittlesey, M.
K.; Williams, J. M. J. J. Am. Chem. Soc. 2007, 129, 1987−1995.
(g) Brunel, J. M. Synlett 2007, 2007, 0330−0332. (h) Gnanamgari, D.;
Moores, A.; Rajaseelan, E.; Crabtree, R. H. Organometallics 2007, 26,
1226−1230. (i) Horn, S.; Gandolfi, C.; Albrecht, M. Eur. J. Inorg.
Chem. 2011, 2011, 2863−2868. (j) Yang, P.; Xu, H.; Zhou, J. Angew.
Chem., Int. Ed. 2014, 53, 12210−12213.
(15) Lee, S. H.; Nikonov, G. I. ChemCatChem 2015, 7, 107−113.
(16) Gloge, T.; Jess, K.; Bannenberg, T.; Jones, P. G.; Langenscheidt-
̈
Dabringhausen, N.; Salzer, A.; Tamm, M. Dalton Trans. 2015, 44,
11717−11724.
(17) Gnanamgari, D.; Sauer, E. L. O.; Schley, N. D.; Butler, C.;
Incarvito, C. D.; Crabtree, R. H. Organometallics 2009, 28, 321−325.
(18) Mai, V. H.; Kuzmina, L. G.; Churakov, A. V.; Korobkov, I.;
Howard, J. A. K.; Nikonov, G. I. Dalton Trans. 2016, 45, 208−215.
(19) (a) Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008. (b) Haack,
K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R. Angew. Chem., Int.
Ed. Engl. 1997, 36, 285. (c) Fujii, A.; Hashiguchi, S.; Uematsu, N.;
Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 2521.
(20) Baratta, W.; Chelucci, G.; Gladiali, S.; Siega, K.; Toniutti, M.;
Zanette, M.; Zangrando, E.; Rigo, P. Angew. Chem., Int. Ed. 2005, 44,
6214−6219.
(3) (a) Brunel, J. M. Tetrahedron 2007, 63, 3899−3906. (b) Huang,
L.; Zhu, Y.; Huo, C.; Zheng, H.; Feng, G.; Zhang, C.; Li, Y. J. Mol.
Catal. A: Chem. 2008, 288, 109−115. (c) Alonso, F.; Riente, P.; Yus,
M. Tetrahedron 2009, 65, 10637−10643. (d) Horn, S.; Albrecht, M.
Chem. Commun. 2011, 47, 8802−8804.
(21) Lundgren, R. J.; Rankin, M. A.; McDonald, R.; Schatte, G.;
Stradiotto, M. Angew. Chem., Int. Ed. 2007, 46, 4732−4735.
(22) (a) Chakraborty, S.; Guan, H. Dalton Trans. 2010, 39, 7427−
(4) (a) Schmidt, B.; Krehl, S.; Sotelo-Meza, V. Synthesis 2012, 44,
́
1603−1613. (b) Zielinski, G. K.; Samojłowicz; Wdowik, T.; Grela, K.
Org. Biomol. Chem. 2015, 13, 2684−2688.
7436. (b) Backvall, J.-E. J. Organomet. Chem. 2002, 652, 105−111.
̈
(5) For selected examples of semi-transfer hydrogenation of alkyne,
see: (a) Hauwert, P.; Boerleider, R.; Warsink, S.; Weigand, J. J.;
(c) Samec, J. S. M.; Backvall, J.-E.; Andersson, P. G.; Brandt, P. Chem.
̈
Soc. Rev. 2006, 35, 237−248.
Elsevier, C. J. J. Am. Chem. Soc. 2010, 132, 16900. (b) Wienhofer, G.;
̈
(23) Bosson, J.; Poater, A.; Cavallo, L.; Nolan, S. P. J. Am. Chem. Soc.
2010, 132, 13146−13149.
Westerhaus, F. A.; Jagadeesh, R. V.; Junge, K.; Junge, H.; Beller, M.
Chem. Commun. 2012, 48, 4827−4829. (c) Belger, C.; Neisius, N. M.;
Plietker, B. Chem. - Eur. J. 2010, 16, 12214.
(24) Ouali, A.; Majoral, J.-P.; Caminade, A.-M.; Taillefer, M.
ChemCatChem 2009, 1, 504−509.
(6) (a) Wu, J.; Tang, W.; Pettman, A.; Xiao, J. Adv. Synth. Catal.
2013, 355, 35. (b) Rueping, M.; Antonchick, A. P. Angew. Chem., Int.
Ed. 2007, 46, 4562. (c) Tu, X. F.; Gong, L.-Z. Angew. Chem., Int. Ed.
2012, 51, 11346. (d) Rueping, M.; Antonchick, A. P.; Theissmann, T.
Angew. Chem., Int. Ed. 2006, 45, 3683. (e) Rueping, M.; Tato, F.;
Schoepke, F. R. Chem. - Eur. J. 2010, 16, 2688. (f) Guo, Q.-S.; Du, D.-
M.; Xu, J. Angew. Chem., Int. Ed. 2008, 47, 759. (g) Wang, D.-W.;
Zeng, W.; Zhou, Y.-G. Tetrahedron: Asymmetry 2007, 18, 1103−1107.
(h) Ferry, A.; Stemper, J.; Marinetti, A.; Voituriez, A.; Guinchard, X.
Eur. J. Org. Chem. 2014, 2014, 188. (i) Rueping, M.; Theissmann, T.
Chem. Sci. 2010, 1, 473−476.
(25) [CpRu(NCCH3)3][PF6] was synthesized according to the
following: Kundig, E. P.; Monnier, F. R. Adv. Synth. Catal. 2004, 346,
̈
901−904.
(7) (a) Fujita, K.; Kitatsuji, C.; Furukawa, S.; Yamaguchi, R.
Tetrahedron Lett. 2004, 45, 3215. (b) Voutchkova, A. M.; Gnanamgari,
D.; Jakobsche, C. E.; Butler, C.; Miller, S. J.; Parr, J.; Crabtree, R. H. J.
Organomet. Chem. 2008, 693, 1815−1821.
(8) For example: (a) Wang, C.; Li, C.; Wu, X.; Pettman, A.; Xiao, J.
Angew. Chem., Int. Ed. 2009, 48, 6524. (b) Wu, J.; Wang, C.; Tang, W.;
Pettman, A.; Xiao, J. Chem. - Eur. J. 2012, 18, 9525−9529. (c) Parekh,
V.; Ramsden, J. A.; Wills, M. Tetrahedron: Asymmetry 2010, 21, 1549−
1556. (d) Tan, J.; Tang, W. J.; Sun, Y. W.; Jiang, Z.; Chen, F.; Xu, L. J.;
Fan, Q. H.; Xiao, J. L. Tetrahedron 2011, 67, 6206. (e) Kulkarni, A.;
Gianatassio, R.; Torok, B. Synthesis 2011, 2011, 1227−1232.
̈
̈
G
DOI: 10.1021/acs.organomet.5b00967
Organometallics XXXX, XXX, XXX−XXX