1-Substituted-imidazo[1,5-a]pyridin-3-ylidenes as highly efficient ligands for Rh- and Ir-catalyzed transfer hydrogenation of carbonyl compounds

Article abstract of DOI:10.1246/cl.160740

The transfer hydrogenation of carbonyl compounds catalyzed by Rh and Ir complexes bearing 1-substituted-imidazo[1,5-a]pyridin-3-ylidene ligands is reported. These catalysts, especially the Rh catalyst, showed high efficiency for the reaction. Comparison o

Full text of DOI:10.1246/cl.160740

Advance Publication Cover Page
1-Substituted-imidazo[1,5-a]pyridin-3-ylidenes as Highly Efficient Ligands
for Rh- and Ir-catalyzed Transfer Hydrogenation of Carbonyl Compounds
Yuma Koto, Fumitoshi Shibahara,* and Toshiaki Murai*
Advance Publication on the web September 3, 2016
doi:10.1246/cl.160740
© 2016 The Chemical Society of Japan
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1
1-Substituted-imidazo[1,5-a]pyridin-3-ylidenes as Highly Efficient Ligands
for Rh- and Ir-catalyzed Transfer Hydrogenation of Carbonyl Compounds
Yuma Koto, Fumitoshi Shibahara,* and Toshiaki Murai*
Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Yanagido, Gifu 501-1193
(E-mail: fshiba@gifu-u.ac.jp)
The transfer hydrogenation of carbonyl compounds
(HOMO) and the lowest unoccupied molecular orbital
(LUMO), namely π and π* orbitals, were sensitively and
systematically changed by the introduction of functional
groups at the respective positions.11c,g We envisaged that such
substituent effects also influenced the electronic properties of
the corresponding imidazo[1,5-a]pyridine-derived NHCs. In
addition, due to our current interest in the structural effects of
imidazo[1,5-a]pyridine-derived NHC on the electronic
characteristics of the carbene carbon, we thought that the
pyrido-annulated diaminocarbene structure might increase
their π-accepting character by overlap of the vacant p-orbital
of the carbene carbon and the π*-orbital of the bicyclic
aromatic system. We considered that these features might
provide unique effects in the associated metal complex-
catalyzed reactions. In this context, Bertrand and co-workers
recently reported that cyclic (amino)(aryl)carbenes (CAArCs)
derived from dihydroisoindoles enhance the π-accepting
character of the carbene center, and this results in the unique
reactivity of the corresponding transition metal complexes.12
Herein, we report the unprecedented high catalytic activity of
Rh-1-substituted-imidazo[1,5-a]pyridin-3-ylidene complexes
for the transfer hydrogenation of ketones among transition
metal-monodentate ligand complexes.
catalyzed by Rh and Ir complexes bearing 1-substituted-
imidazo[1,5-a]pyridin-3-ylidene ligands is reported. These
catalysts, especially the Rh catalyst, showed high efficiency
for the reaction. Comparison of the reaction profiles of several
conventional Rh-NHC and -phosphine complexes and the
present system revealed that the present catalytic system
offers several advantages. The present system clearly showed
greater efficiency than the other systems.
Transition metal-catalyzed transfer hydrogenation with
several hydrogen donors is one of the most attractive methods
for the reduction of C=O bonds leading to the corresponding
alcohols, since this reaction does not require highly
pressurized H2 gas or reactive metal hydride reagents.1,2
Group 8, 9, 10, and 11 metals, and in particular Ru, Rh, and
Ir–phosphine complexes have usually been used as a catalyst.1
Meanwhile, N-heterocyclic carbenes (NHCs) have attracted
considerable interest with regard to their use in several
transition metal catalyses as an alternative to conventional
phosphine ligands because they have similar but somewhat
enhanced electronic properties that may lead to improved
reactivities.3 The use of transition metal complexes bearing
NHC ligands in transfer hydrogenation has been extensively
exploited since Nolan and co-workers reported their
pioneering works (Figure 1).4-6 In this regard, Kühn and
Harrman studied the electronic and steric effects of NHC
ligands in the Ir-catalyzed transfer hydrogenation of ketones,
and concluded that the weaker σ-donor strength of NHC
ligands enhanced the catalytic activity.7 In this case, the π-
accepting character of the ligands might also affect the
catalytic activity. They also found that an α-hydrogen on the
N-substituents enhanced the catalytic activity, though the
exact role in the reaction is still unclear.7,8 These results
suggested that the electronic and steric characteristics of NHC
play a key role in the efficiency of transfer hydrogenation.
Subsequently, several groups investigated the transfer
hydrogenation of ketones with Rh and Ir-NHC complexes and
observed similar trends.5d,6c Although the reaction with NHC
is attracting increased interest, modification of the NHC
skeleton remains subject to synthetic limitations,9 and this has
hindered further efforts.
monodentate type
bidentate type
This Work
R
Mes
Mes
N
N
N
N
Mes
OTf
N
N
Me
N
N
TIPB
N
N
Br Rh
Rh
Dipp
Cl
M
Cl Rh
N
R =
Ph 1a (Rh)
2a (Ir)
Çetinkaya, 2014
Gülcemal, 2012
Elsevier, 2014
p-OMe-C6H4 1b (Rh)
p-CF3-C6H4 1c (Rh)
CCPh 1d (Rh)
Figure 1. Recent examples of Rh-mono- and bis-NHC
complexes for transfer hydrogenation
Initially, we conducted the transfer hydrogenation of
acetophenone using 2-propanol as a hydrogen donor in the
presence of 1 mol% of KOtBu with several Rh complexes as a
catalyst at 80 °C under several substrate/catalyst ratios (S/C)
to test the catalytic activity of the complexes.13 As a result, the
reaction with complex 1a was completed within 5 min when
S/C was 100, and this complex showed the best activity
among the catalysts tested (Table 1, entries 2-7, Figure 2).
The Rh complex 1a showed better activity than the
corresponding Ir complex 2a under the condition S/C=1000
(entries 2 vs 3). This result is in sharp contrast with
previously reported reactions with NHC complexes, where Ir
complexes usually showed higher activity.14 In addition, while
Rh complex 1a showed a slight induction period, Ir complex
2a did not. Other conventional NHC ligands, which usually
Meanwhile, since the first example was reported by
Lassaletta, imidazo[1,5-a]pyridines have attracted significant
attention as a versatile architecture for normal and abnormal
NHC-type ligands because of their structural features.10
Recently, we independently developed several methods of
functionalization, and investigated the photophysical
properties of functionalized imidazo[1,5-a]pyridines.11 Our
systematic investigations of their spectra revealed that the
energy levels of the highest occupied molecular orbital

2
act as a strong σ-donor, did not induce the reaction with
satisfactory efficiency (entries 4 and 5). With most phosphine
ligands, rhodium black precipitated in the early stage of the
reaction and the reaction stopped, to result in low conversion,
even though reaction was initially faster than the reaction with
1a (cf. entries 5 and 6). We also attempted to generate the
corresponding complexes of phosphites which may act as an
accepting ligand, but this attempt failed due to several
processes such as dimerization and the elimination of COD.15
The reaction conditions were then further optimized with Rh
complex 1a. Even when S/C was increased to 2000, the
reaction still showed almost complete conversion within a
prolonged yet still practicable reaction time (entries 8 and 9).
The effects of bases were also examined (entries 9-19). To
compare the efficiencies of these reactions, the reaction
profiles were checked (Figure S1), and the respective
conversions at 1 h were determined. Among potassium salts,
KOtBu showed the best performance for the induction step,
initial reaction rate, and final conversion (entries 9-11).
reaction was not smoothly induced when K2CO3 was used as a
base (entry 11), and the catalyst likely deactivated to result in
incompletion of the reaction even when the reaction time was
prolonged (Figure S1). The corresponding sodium, lithium,
and cesium salts were also used in the reaction in place of
potassium salts (entries 12-19). As a result, although the
hydroxyl salts (LiOH, NaOH, and CsOH) showed a better
reaction rate than KOH, KOtBu still gave the best result.
Furthermore, while other hydrogen sources such as MeOH,
EtOH, and HCOOH were also tested, the reactions gave only
a trace amount of alcohol even after 24 h (entries 20-22).
Table 1. Optimization of Transfer Hydrogenationa
cat
O
OH
Me
base (1 mol%)
Figure 2. Time-dependence of substrate conversion on the
transfer hydrogenation of acetophenone with 1a, 2a and 3-6
solvent (0.2 M), 80 ºC
Ph
Me
Ph
cat.: 1a, 2a, Rh(L)(cod)Cl (L = IMes:3, IDM:4, PPh3:5, PCy3:6)
The effects of substituents on the present NHC ligands
were then examined. The time-dependence of conversion with
catalysts 1a-d under S/C=2000 were monitored (Figure 3).
While 1-arylated complexes 1a, 1b, and 1c showed similar
activities and induction periods, the reaction with 1a gave the
best result. 1-Arylalkynylated complex 1d showed lower
activity and a longer induction period than the other
complexes. To the best of our knowledge, 1a showed the
highest activity in both Rh-mono and bis-NHC complex-
catalyzed reactions.5
entry cat S/Cb
base
solvent
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
time
<5 min
0.5 h
0.5 h
1 h
1 h
1 h
1 h
conv.c
98%
96%
44%
12%
38%
56%
29%
93%
97%
(94%)d
30%
11%
26%
66%
1%
34%
62%
<1%
10%
64%
<1%
<1%
<1%
1
2
3
4
5
6
7
8
9
1a
100
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
1a 1000
2a 1000
3
4
5
6
1000
1000
1000
1000
1a 2000
1a 2000
1 h
6 h
10
11
12
13
14
15
16
17
18
19
20
21
22
1a 2000
1a 2000
1a 2000
1a 2000
1a 2000
1a 2000
1a 2000
1a 2000
1a 2000
KOH
K2CO3
NaOtBu
NaOH
Na2CO3
LiOtBu
LiOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
EtOH
1 h
1 h
1 h
1 h
1 h
1 h
1 h
1 h
1 h
Li2CO3
Cs2CO3
1a 2000 CsOH·H2O
1 h
Figure 3. Time-dependence of substrate conversion on
transfer hydrogenation of acetophenone catalyzed by 1a-d
1a 2000
1a 2000
1a 2000
KOtBu
KOtBu
KOtBu
24 h
24 h
24 h
MeOH
HCO2H
To demonstrate the utility of the present system, we
explored the scope of substrates (Table 2). Benzophenone and
acetonaphthone were successfully converted to the
corresponding alcohols in high yields (entries 1 and 2). On the
other hand, the steric bulkiness of the substituents sensitively
influenced the efficiency of the reaction, and 2,4,6-
trimethylacetophenone showed significantly lower conversion
(entry 3). A cycloaliphatic ketone such as cyclohexanone was
readily converted to cyclohexanol with a slightly slower
reaction rate (entry 4). An α,β-unsaturated ketone such as
chalcone was completely converted to the alcohol, whereas
aReaction conditions: acetophenone (2.0 mmol), catalyst,
KOtBu (20 µmol) in iPrOH (10 mL) at 80 ºC.
bSubstrate/Catalyst ratio. cConversions were determined by
GC analysis of the reaction mixture using heptadecane as an
internal standard. dIsolated yield.
cod:
1,5-cyclooctadiene,
trimethylphenyl)imidazol-2-ylidene,
dimethylimidazol-2-ylidene
IMes:
1,3-bis(2,4,6-
IDM: 1,3-
With KOH, the reaction rate was low even though no
significant induction period was observed (entry 10). The
the
alkene
moiety also
reduced
to
give
α-

3
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phenylbenzenepropanol as
a major product (entry 5).
Although the reaction of benzaldehyde showed 85%
conversion after 1 h under identical conditions, the reaction
gave benzylalcohol in only 52% yield, and side products
including 2-propyl benzoate, which may be produced via
dehydrogenative
generated (entry 6).
cross-coupling,16
were
significantly
5
Table 2. Scope of Substratea
1a (S/C=2000)
KOtBu (1 mol%)
O
OH
R2
R1
entry
R2
iPrOH (0.2 M), 80 ºC
R1
substrate
product
OH
time yield
O
6
7
1
2b
3
6 h 83%
O
OH
Me
Me
24 h 99%
24 h 19%
12 h 95 %
Me
O
Me OH
Me
Me
8
9
Me
L. Benhamou, E. Chardon, G. Lavigne, S. Bellemin-Laponnaz, V.
César, Chem. Rev. 2011, 111, 2705.
Me
Me
Me
OH
O
10
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4
OH
O
5
6 h
98%
O
OH
H
6
1 h
52%
aReaction conditions: Ketone or aldehyde (2.0 mmol), Rh
complex (1.0 µmol), KOtBu (20 µmol) in PrOH (10 mL) at
i
80 ºC. bS/C = 1000
In summary, both Rh and Ir complexes bearing 1-
substituted imidazo[1,5-a]pyridin-3-ylidenes promoted the
transfer hydrogenation of acetophenone. Particularly, Rh
complex 1a showed extremely high catalytic activity for the
reaction. Recently, Oro and co-workers reported that
accepting ligands stabilize intermediate hydrido complexes
and enhance the reaction efficiency of transfer
hydrogenation.17 The present system may involve a similar
effect. Asymmetric reactions, the further screening of
catalyses with several complexes of imidazo[1,5-
a]pyridinylidenes, and studies on the electronic character of
carbenes are currently being pursued in our group.
11
12
13
B. Rao, H. Tang, X. Zeng, L. Liu, M. Melaimi, G. Bertrand, Angew.
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Synthesis of complexes 1 and imidazo[1,5-a]pyridylidene ligands
was carried out according to the reported procedures. For further
details, see the Supporting Information.
a) A. Binobaid, M. Iglesias, D. Beetstra, A. Dervisi, I. Fallis, K. J.
Cavell, Eur. J. Inorg. Chem. 2010, 5426. b) S. N. Sluijter, C. J.
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A. M. Whittaker, V. M. Dong, Angew. Chem. Int. Ed. 2015, 54,
1312.
Supporting
http://dx.doi.org/10.1246/cl.xxxxxx
This work was partly supported by JSPS KAKENHI (No.
16K05769).
information
is
available
at
14
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15
16
2
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17
S. A. Popoola, E. A. Jaseer, A. A. Al-Saadi, V. Polo, M. A. Casado,
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4
For selected examples of Ru-NHC catalysis in transfer
hydrogenation, see; a) A. Danopoulos, S. Winston, W. Motherwell,