Chiral bicyclic NHC/Ir complexes for catalytic asymmetric transfer hydrogenation of ketones

Article abstract of DOI:10.1039/c5cc05318h

A diverse series of chiral bicyclic NHC/Ir complexes were prepared via a previously developed divergent synthesis of chiral imidazolium salts. Among the complexes, 8dz was found to be an excellent catalyst precursor for the Ir-catalyzed asymmetric transfer hydrogenation of ketones. The reaction of ketones with 8dz proceeded smoothly to give corresponding alcohols with high enantioselectivities (up to 98%) and productivities (TON up to 4500).

Full text of DOI:10.1039/c5cc05318h

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Chiral Bicyclic NHC/Ir Complexes for Catalytic Asymmetric
Transfer Hydrogenation of Ketones
View Article Online
DOI: 10.1039/C5CC05318H
Received 00th January 20xx,
Kazuhiro Yoshida,* Takumi Kamimura, Hiroshi Kuwabara and Akira Yanagisawa*
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A diverse series of chiral bicyclic NHC/Ir complexes were prepared via a previously developed divergent synthesis of chiral
imidazolium salts. Among the complexes, 8dz was found to be an excellent catalyst precursor for the Ir-catalyzed
asymmetric transfer hydrogenation of ketones. The reaction of ketones with 8dz proceeded smoothly to give
corresponding alcohols with high enantioselectivities (up to 98%) and productivities (TON up to 4,500).
Introduction
Results and discussion
One of the important considerations in the development of
new chiral ligands is whether the chiral ligands can be
divergently prepared or not, because it is directly linked to the
efficiency of finding an appropriate catalyst for each
asymmetric reaction at the stage of catalyst screening.1 In
2010, we reported a modular synthesis of chiral bicyclic
imidazolium salts 2 and 3 based on the alkylation of newly
prepared imidazoles 1 (Fig. 1).2 We expected that the N-
heterocyclic carbenes (NHCs)3 generated from those salts
would have superior asymmetric induction ability when used
as chiral ligands, because the restriction of internal rotation
around the N-C axis by the fused bicyclic molecular structure
should be favorable for a chiral environment.4 Unfortunately,
scant attention has been given to the study of transition metal
catalyzed asymmetric reactions using the bicyclic NHCs as
chiral ligands, and therefore, little is known about the utility of
those compounds as chiral ligands.5 Taking advantage of our
divergent synthetic procedure, we have investigated the
performance of our ligands in transition metal catalyzed
asymmetric reactions. Here we report the results of our
attempt to accomplish the Ir-catalyzed asymmetric transfer
hydrogenation of ketones.6,7
As we were originally interested in the application of C2
symmetric transition metal catalysts bearing chiral bis-NHC
ligands, the conversion of our imidazolium salts 3 into
chelating Ir complexes 4 was conducted (Scheme 1). In
practice, desired Ir complexes 4a and 4b were obtained from
3a and 3b by the carbene transfer strategy through Ag
complexes in 51% and 22% yields, respectively. The modest
yields were mainly caused by the formation of by-products 5,
in which the ligands bridge two Ir units.
PF6
N
N
N
N
1) Ag2O, MS4A
2) [IrCl(cod)]2
N
N
N
N
Ir
2PF6
Ar
Ar
Ar
Ar
(+)-4a (51% yield, after treatment with KPF6)
(+)-4b (22% yield, after treatment with KPF6)
3
=
=
3a:
3b:
+
Cl Ir
Ar
Ar
Ar
Ph
N
N
N
N
Ar
Ir Cl
=
=
(+)-5a (25% yield)
(+)-5b (35% yield)
Mes
chiral module
Scheme 1 Preparation of bis-NHC/Ir complexes 4.
X
X
N
N
X
X
N
N
R'
N
N
N
N
R
R
or
1
2
3
Table 1 Asymmetric transfer hydrogenation of 6a with by 4
and 5a
R
R
X = CH2 or O
O
OH
4 or 5 (1 mol%)
Fig. 1 Modular synthesis of chiral bicyclic imidazolium salts 2
and 3.
Me
Me
KOH (1 mol%), i-PrOH
60 °C, 15 h
6a
(R)-7a
Entry
Ir complex
(R,R)-(+)-4a
(+)-4b
Yieldb (%)
% Eec
1
2
3
4
77
88
70
85
0
0
(R,R)-(+)-5a
(+)-5b
8
19
a
The transfer hydrogenation was carried out with acetophenone (6a)
in i-PrOH (65 eq) in the presence of KOH (1 mol%) and Ir complex 4 or
5 (1 mol%) at 60 °C for 15 h under N2. b Isolated yield. c Determined by
HPLC analysis with chiral stationary phase column.
Department of Chemistry, Graduate School of Science, Chiba University, Yayoi-
cho, Inage-ku, Chiba 263-8522, Japan. E-mail: kyoshida@faculty.chiba-u.jp,
ayanagi@faculty.chiba-u.jp
†Electronic Supplementary Information (ESI) available: Experimental procedures
and compound characterization data are provided. See DOI: 10.1039/x0xx00000x

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whereas use of the bis(p-(trifluoromethyl)phenyl)methyl group
View Article Online
DOI: 10.1039/C5CC05318H
To our disappointment, the application of 4 to the transfer having an electron-withdrawing p-trifluoromethyl group gave
hydrogenation reaction of acetophenone (6a) was a failure, the best enantioselectivity in this screening (entry 8). Finally, Ir
and no asymmetric induction was observed (Table 1, entries 1 complex containing chiral oxazolidine-fused NHC 9 and Ir(III)
and 2). Those results were, however, interpreted by the crystal complex 10 also exhibited catalyst activity. The results were,
structure of 4a in which the cis-chelating bis-NHC ligand however,
unsatisfactory
from
the
viewpoint
of
adopted the C1 symmetric coordination mode toward the Ir enantioselectivity (entries 9 and 10).
center instead of the C2 symmetric mode.8 The 1H-NMR
spectra of 4a measured at room temperature also
demonstrated that the C1 symmetric structure remained even Table 2 Catalyst screening for Ir-catalyzed asymmetric transfer
in the solution state. A similar degradation of C2 symmetry was hydrogenation of 6aa
also confirmed in the 1H-NMR spectra of 4b. We found,
O
OH
Me
8, 9, or 10 (5 mol%)
however, that dinuclear Ir complexes 5a and 5b, the by-
products of 4 in Scheme 1, showed a certain degree of
enantioselectivity, namely, (R)-7a having 8% and 19% ee was
obtained, respectively (Table 1, entries 3 and 4).
The results inspired us to investigate an Ir-monodentate
NHC system for this reaction. Parts of the structures of the
new Ir complexes we prepared are shown in Fig. 2. Using our
synthetic procedure, a variety of complexes having flexibility at
the substituents R and R’ were prepared.
Me
KOH (1 mol%), i-PrOH
60 °C, 15 h
6a
(R)-7a
Entry
Ir complex
(R)-(+)-8av
(+)-8bv
Yieldb (%)
% Eec
22
38
53
60
55
68
30
73
17e
1
1
2
80
43
79
80
89
83
40
78
89
92
3
(R)-(+)-8cv
(+)-8dv
4
i-Pr
Me5
R'
R
N
R'
N
N
5
(+)-8dw
(+)-8dx
O
Ir
N
Cl
Cl
Ir
N
Ir
Cl
Cl
6
N
R
R
R'
10
8
9
7
(+)-8dy
8
(+)-8dz
Me
i-Pr
9
(R)-9awd
(R)-10cvf
R =
Me
i-Pr
,
,
,
10
Me
a
b
c
d
a
The transfer hydrogenation was carried out with acetophenone (6a)
in i-PrOH (65 eq) in the presence of KOH (1 mol%) and Ir complex 8-10
b
c
Me
OMe
CF3
(5 mol%) at 60 °C for 15 h under N2. Isolated yield. Determined by
d
HPLC analysis with chiral stationary phase column. The complex was
generated by mixing an NHC/Ag complex and [IrCl(cod)]2 in situ. e The
R' =
absolute configuration was S. f An impure complex was used.
,
,
,
,
Me
OMe
CF3
v
w
x
y
z
Optimization of the reaction conditions was then carried
out using Ir complex 8dz, which showed the best
enantioselectivity in Table 2 (Table 3). Although the yield was
decreased, a substantial improvement of the selectivity was
observed when we shortened the reaction time from 15 h to 1
Fig. 2 Structures of NHC/Ir complexes for asymmetric transfer
hydrogenation.
h, (entry
1
vs. 2).
The results implied that the
The results of catalyst screening for the asymmetric
transfer hydrogenation are shown in Table 2. First, it was
found that increasing the steric hindrance of the substituent R
in the NHC ligand tended to increase the enantioselectivity of
the reaction (entries 1-4). Second, as for the substituent R’ in
the ligand, replacement of the diphenylmethyl group with the
less bulky benzyl group decreased the selectivity, whereas
replacement with the bulkier di-p-tolylmethyl group increased
the selectivity (entries 4-6). Use of the bis(p-
methoxyphenyl)methyl group having an electron-donating p-
methoxy group decreased the selectivity considerably (entry 7),
enantioselectivity is high at the beginning but worsens with
time. Then, we tried to improve the reaction rate by raising the
temperature from 60 to 70 °C. Although the enantioselectivity
was decreased slightly, the product yield was high as expected
(entry 2 vs. 3). Several bases were then screened to further
optimize the reaction conditions, and t-BuOK was chosen as
the base (entries 3-7). Reinvestigation of the temperature with
the latter conditions revealed that 70 °C is the best after all
(entries 7-9). Finally, we attempted to decrease the catalyst
loading and found that almost the same yields and
2 | J. Name., 2012, 00, 1-3
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enantioselectivities were achieved even when the catalyst additional information on the mechanistic study of this
View Article Online
DOI: 10.1039/C5CC05318H
loading was lowered from 5 mol% to 0.5 or 0.1 mol% (entries 7 reaction which is still under debate.6b
vs. 10 and 11). To our surprise, further decrease of the catalyst
loading to 0.05 mol% led to an even higher enantioselectivity
(entry 12), and the enantioselectivity improvement was Table 4 Asymmetric transfer hydrogenation of ketones with
maintained even with 0.01 mol% of the catalyst loading to give 8dza
the product with 97% ee (entry 13). Under the last set of
conditions (S/C = 10,000), the turnover number (TON) of 8dz
was estimated to be 4,500.
(–)-8dz (x mol%)
O
OH
R1 R2
R1 R2
t-BuOK (1 mol%), i-PrOH
70 °C, 1 h
6
(S)-7
x
Yieldb
Entry
6
R1
R2
Et
% Eec
Table 3 Optimization of reaction conditions with 8dza
(mol%)
(%)
O
OH
Me
1
2
6b
6c
6d
6e
6f
Ph
Ph
0.1
0.05
0.1
95
93
94
79
87
15
88
86
65
20
98
66
95
90
91
trace
82
83
83
60
75
55
55
37
96
97
96
97
95
97
87
92
83
83
96
98
89
92
95
-
(–)-8dz (x mol%)
Me
base (1 mol%), i-PrOH
temp, time
3
Pr
Bu
6a
(S)-7a
x
Temp
(°C)
Time
(h)
Yieldb (%)
Entry
Base
% Eed
4
0.05
0.1
(mol%)
(Convc (%))
5
Ph
1
2
5
5
KOH
KOH
60
60
70
70
70
70
70
60
80
70
70
70
70
15
1
1
1
1
1
1
1
1
1
1
1
1
78 (88)
50 (60)
90 (98)
90 (97)
88 (96)
89 (98)
90 (97)
70 (82)
90 (98)
89 (96)
95 (96)
87 (88)
45 (45)
73
88
85
89
90
86
92
91
89
91
91
95
97
6
0.05
0.1
7
4-MeC6H4
3- MeC6H4
Ph
Me
Me
PhCH2
Me
Me
Me
Me
Me
Me
3
5
KOH
8
0.05
0.1
4
5
CsOH
9
5
5
i-PrONa
t-BuONa
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
0.05
0.1
6
5
6g
6h
6i
7
5
0.05
0.1
8
5
4-FC6H4
4-ClC6H4
4-BrC6H4
4-IC6H4
4-MeOC6H4
2-Naphthyl
9
5
0.05
0.1
10
11
12
0.5
0.1
0.05
0.01
0.05
0.1
6j
93
93
94
95
81
94
77
83
13e
0.05
0.1
a
The transfer hydrogenation was carried out with acetophenone (6a)
in i-PrOH (65 eq) in the presence of base (1 mol%) and Ir complex (–)-
6k
6l
8dz (0.01-5 mol%) under N2. b Isolated yield. c Conversion based on H
1
0.05
0.1
d
NMR analysis of the crude reaction mixture. Determined by HPLC
analysis with a chiral stationary phase column. e 0.1 mol% of t-BuOK
and 6.5 eq of i-PrOH were used.
0.05
0.1
6m
Then, the asymmetric transfer hydrogenation of several
ketones was accomplished. The results are summarized in
Table 4. In all cases, new Ir complex 8dz displayed high
enantioselectivities, affording corresponding chiral alcohols.
The important point is that the tendency of enantioselectivity
increase with catalyst loading emerged distinctly as a general
phenomenon (odd numbered entries vs. even numbered
entries). Although the reason for the dilute catalyst condition
is unclear at present, we expect that this would provide
0.05
a
The transfer hydrogenation was carried out with ketone 6 in i-PrOH
(65 eq) in the presence of t-BuOK (1 mol%) and Ir complex (–)-8dz
(0.05-0.1 mol%) at 70 °C for 1 h under N2. b Isolated yield. c Determined
by HPLC analysis with a chiral stationary phase column.
Complexes
8 were obtained as light yellow solids
sufficiently stable for purification by silica gel chromatography,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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and have high solubility in various organic solvents. As 8dz that We appreciate the financial support in the form of a Grant-in-
View Article Online
gave the best results in the present reaction is soluble even in Aid for Scientific Research (Grant #D1O5KI:0105.4109349)/C5frCoCm0531t8hHe
hexane, we were unable to obtain good crystals of 8dz for X- Ministry of Education, Culture, Sports, Science and Technology,
ray crystallography. However, the crystallization of 8av and 8cv, Japan. We also gratefully acknowledge financial support from
which have different substituents on the basic structure of 8, the next generation training program in Chiba University.
was successful (Fig. 3).9 The crystal structures revealed that
the NHC ligands coordinated to the iridium center with the
heterocyclic plane facing vertically toward the square planar
Notes and references
coordination plane. Intriguingly, the two types of NHC ligands
differed in spatial orientation on coordination to iridium: the
diphenylmethyl group was observed at the lower side of the
coordination plane in 8av, whereas it was observed at the
1
2
3
For an example, see: L. Lefort, J. A. F. Boogers, A. H. M. de
Vries and J. G. de Vries, Topics in Catalysis 2006, 40, 185-191.
K. Yoshida, S. Horiuchi, T. Takeichi, H. Shida, T. Imamoto and
A. Yanagisawa, Org. Lett. 2010, 12, 1764-1767.
For recent reviews on NHCs, see; (a) S. Díez-González, N.
Marion and S. P. Nolan, Chem. Rev. 2009, 109, 3612-3676;
(b) N-Heterocyclic Carbenes in Transition Metal Catalysis and
Organocatalysis, C. S. J. Cazin, Ed., Springer; Dordrecht
Heidelberg London New York, 2011; (c) F. Wang, L.-j. Liu, W.
Wang, S. Li and M. Shi, Coord. Chem. Rev. 2012, 256, 804-
853; (d) Contemporary Carbene Chemistry, R. A. Moss and M.
P. Doyle, Ed., Wiley-VCH; Hoboken, NJ, 2014.
NHCs generated from structurally similar bicyclic azolium
salts or imidazolium salts to 2 are well-known chiral carbene
catalysts. For reviews, see; (a) D. Enders, O. Niemeier and A.
Henseler, Chem. Rev. 2007, 107, 5606-5655; (b) A. J.
Arduengo, III and L. I. Iconaru, Dalton Transactions 2009,
6903-6914.
For examples, see; (a) D. Hirsch-Weil, K. A. Abboud and S.
Hong, Chem. Commun. 2010, 46, 7525-7527; (b) L. Zhao, Y.
Ma, W. Duan, F. He, J. Chen and C. Song, Org. Lett. 2012, 14,
5780-5783; (c) D. Sureshkumar, V. Ganesh, N. Kumagai and
M. Shibasaki, Chem. Eur. J. 2014, 20, 15723-15726.
1
upper side in 8cv. The H-NMR spectra of 8av indicated that
conformational isomers derived from the restricted rotation
around the carbene-Ir bond axis exist in a 2:1 ratio in the
solution state. The rotation barrier was, however, not as high
as to isolate one isomer from the other at room
temperature,10 because 1H-NMR analysis of 8av that was
prepared by dissolving the same lot of crystals as that used for
X-ray crystallography showed also a 2:1 ratio of the isomers.
4
1
On the other hand, a single species was observed in the H-
NMR spectra of 8cv, which has a bulkier substituent R than 8av.
We believe that controlling the equilibrium between
conformational isomers, which is influenced by the bulkiness
of the substituent R, would be related to the
enantioselectivities in Table 1 (entries 1-4). Indeed, no
conformational isomer was observed in the 1H-NMR spectra of
8dz, which gave the best enantioselectivity of the reaction.
5
6
For recent reviews on the Ir-catalyzed transfer
hydrogenation, see; (a) R. Malacea, R. Poli and E. Manoury,
Coord. Chem. Rev. 2010, 254, 729-752. (b) O. Saidi and J. M. J.
Williams in Iridium Catalysis (Ed.: P. G. Andersson), Springer;
Dordrecht Heidelberg London New York, 2011, pp. 77-106;
(c) A. Bartoszewicz, N. Ahlsten and B. Martín-Matute, Chem.
Eur. J. 2013, 19, 7274-7302.
7
For reports on the transfer hydrogenation catalyzed by chiral
NHC/Ir complexes, see; (a) H. Seo, B. Y. Kim, J. H. Lee, H.-J.
Park, S. U. Son and Y. K. Chung, Organometallics 2003, 22,
4783-4791; (b) R. Hodgson and R. E. Douthwaite, J.
Organomet. Chem. 2005, 690, 5822-5831; (c) W. A.
Herrmann, D. Baskakov, E. Herdtweck, S. D. Hoffmann, T.
Bunlaksananusorn,
F.
Rampf
and
L.
Rodefeld,
Organometallics 2006, 25, 2449-2456; (d) G. Dyson, J.-C.
Frison, A. C. Whitwood and R. E. Douthwaite, Dalton
Transactions 2009, 7141-7151; (e) C. Diez and U. Nagel,
Applied Organometallic Chemistry 2010, 24, 509-516.
Refer to Electronic Supplementary Information (ESI). Also
see; S. Anezaki, Y. Yamaguchi and M. Asami, J. Organomet.
Chem. 2011, 696, 2399-2405.
Fig. 3 Crystal structures of (S)-(–)-8av and (S)-(–)-8cv:
Hydrogen atoms and CH2Cl2 (only for (S)-(–)-8cv) are omitted
for clarity.
8
9
The crystallographic coordinates have been deposited with
the Cambridge Crystallographic Data Centre; deposition no.
1059389 ((S)-(–)-8av) and 1059390 ((S)-(–)-8cv). These data
Conclusions
We have developed bench-stable, easily manipulable, and
highly soluble NHC/Ir complex 8dz as an excellent catalyst
precursor for the asymmetric transfer hydrogenation. The
present catalyst screening based on our synthesis of chiral
bicyclic imidazolium salts is not limited to the Ir system.
Investigations aimed at applying the screening procedure to
other asymmetric reactions are in progress in our laboratory.
can
be
obtained
free
of
charge
via
http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from
The Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 IEZ, UK; fax (+44) 1223-336-033; E-mail
deposit@ccdc.cam.ac.uk).
10 For reports on restricted rotation around the carbene-metal
bond axis, see; (a) C. P. Newman, R. J. Deeth, G. J. Clarkson
and J. P. Rourke, Organometallics 2007, 26, 6225-6233; (b) M.
C. Cassani, M. A. Brucka, C. Femoni, M. Mancinelli, A.
Mazzanti, R. Mazzoni and G. Solinas, New J. Chem. 2014, 38,
1768-1779.
Acknowledgements
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