Chiral cyclometalated iridium complexes for asymmetric reduction reactions

Article abstract of DOI:10.1039/d0ob02049d

A series of chiral cyclometalated iridium complexes have been synthesised by cyclometalating chiral 2-aryl-oxazoline and imidazoline ligands with [Cp?IrCl2]2. These iridacycles were studied for asymmetric transfer hydrogenation reactions with formic acid as the hydrogen source and were found to display various activities and enantioselectivities, with the most effective ones affording up to 63% ee in the asymmetric reductive amination of ketones and 77% ee in the reduction of pyridinium ions. This journal is

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ARTICLE
Chiral Cyclometalated Iridium Complexes for Asymmetric
Reduction Reactions
Received 00th January 20xx,
Accepted 00th January 20xx
Jennifer Smith, Aysecik Kacmaz, Chao Wang, Barbara Villa-Marcos, Jianliang Xiao*
Abstract: A series of chiral cyclometalated iridium complexes have been synthesised by cyclometalating chiral 2-aryl-
oxazoline and imidazoline ligands with [Cp*IrCl2]2. These iridacycles were studied for asymmetric transfer hydrogenation
reactions with formic acid as the hydrogen source and were found to display various activities and enantioselectivities,
with the most effective ones affording up to 63% ee in the asymmetric reductive amination of ketones and 77% ee in the
reduction of pyridinium ions.
DOI: 10.1039/x0xx00000x
1. Introduction
reported iridium complexes bearing N,O- and N,C-chelating
Cyclometalated Cp*-iridium complexes, or iridacycles, are easily oxazoline ligands for ATH of aromatic ketones; however, the
accessible via base-assisted C-H activation. A number of such cyclometalated N,C-complex was much less active and
complexes have been documented both within our group[1] as enantioselective (up to 7% ee) than the N,O-chelated complex
well as by others with various applications.[2] Examples of their (up to 99% ee).[19] In continuation of our study into iridacycles,
use as catalysts are seen in hydrogenation,[3] transfer we have synthesised a range of chiral iridium catalysts and
hydrogenation,[4] dehydrogenation,[5] reductive amination,[6] examined their ability in direct asymmetric reductive amination
alkylation,[7]
hydrosilylation,[8]
racemisation,[9] (DARA) of ketones and reduction of pyridiniums via ATH.
hydroamination[10] and aerobic oxidation.[11] However, most of Reported herein is the results of these studies.
t-Bu
these complexes are achiral, and the number of reported chiral
iridacycles and their applications in asymmetric catalysis is
much smaller.
Chiral iridacycle complexes have been sporadically reported
PF6
Cl
Cl
Ir
NCMe
Ir
Ir
Ir
N
i-Pr
t-Bu
t-Bu
N
O
Cl
H
N
N
N
H
H
H
Pfeffer, 2011[13]
Davies, 2011[15]
Xiao, 2013[5a]
Ikariya, 2008[12]
t-Bu
over the past years. Selected examples are shown in Scheme 1.
Ikariya et al. reported the use of chiral Cp*Ir(C-N) complexes[12]
for asymmetric transfer hydrogenation (ATH) of acetophenone,
yielding (S)-1-phenylethanol in over 90% yield with up to 66%
ee. Pfeffer and de Vries et al. reported cyclometalated amino
and imidazoline complexes;[13] the latter was used for ATH of
acetophenone and N-phenyl-(1-phenylethylidene)amine,
showing moderate to high yields with low enantioselectivities
up to 19% ee.[13a] Baya et al. also reported the use of
cyclometalated iridium complexes for ATH of ketones, affording
low to moderate enantioselectivities (up to 58% ee).[14] Davies
et al. synthesised iridacycles bearing a chiral oxazoline ligand.[15]
Leung et al. carried out ATH of acetophenone with chiral
iridacycles, providing up to 69% ee at -30 oC.[16] In recent years,
the group of Richards have reported a series of planar chiral
iridacycles bearing ferrocene-type ligands, although their
application in asymmetric catalysis has rarely been seen.[17]
More recently, novel chiral iridacycles have been reported by
the groups of de la Torre, Sierra and Cramer.[18] Our group
H2
PF6
H
Ir
Me
O
N
H
Me
Cl
N
Me
Cl
Me
N
Ir
N
MeO
Ir
Ir
N
N
O
Fe
O
Cl
Me
Richards, 2019[17a,d]
Mata and Baya, 2014[14]
Xiao, 2018[19]
Leung, 2018[16]
Scheme 1. Examples of chiral iridacycles from the literature.
2. Results and discussion
2.1. Synthesis of chiral iridacycles
Base-promoted cyclometallation has been widely studied.[15, 20]
The reaction typically involves C-H bond activation of a chiral
ligand with an iridium precursor to form the cyclometalated
structure. In 1998, Beck et al.[20b] reported iridacycles being
produced from the reaction of [Cp*IrCl2]2 with substituted 2-
phenyl-4-R-5(4H)-oxazolones in the presence of NaOAc. In
2003, Davies[20c] carried out similar cyclometalation of nitrogen-
containing ligands with [Cp*IrCl2]2, [Cp*RhCl2]2 and [RuCl2(p-
cymene)]2, revealing the assisting role of the acetate. In most
subsequent studies, a similar strategy has been deployed.
To access the chiral iridacycles in this study, a range of
ligands consisting of chiral oxazoline and imidazoline motifs
were prepared. These were easily accessible from the reaction
between a benzaldehyde derivative and a chiral amino alcohol
Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, UK.
E-mail: jxiao@liv.ac.uk
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [Experimental procedures
and compound characterization data]. See DOI: 10.1039/x0xx00000x
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ARTICLE
Journal Name
or diamine, using reported methods (Scheme 2).[21] The
subsequent cyclometalation of the iridium precursor [Cp*IrCl2]2
with the chiral oxazoline and imidazoline ligands generally
occurred under mild conditions, affording the chiral iridacycles
1-15 (Scheme 2). However, more forcing conditions were
required for some iridacycles, e.g. 4, likely due to the increased
steric hindrance in the ligands.
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DOI: 10.1039/D0OB02049D
The formation of the iridacycles was confirmed by NMR and
HRMS analysis and by X-ray diffraction in the case of complexes
1 and 2. Chelation of the ligands onto iridium introduces
chirality at the metal centre. However, the iridacycles are
formed generally as a mixture of two diastereoisomers,
presumably due to the small difference between their
thermodynamic stability, as has been observed in analogous
cases.[13, 20c] For example, 1 and 2 exist as a 2:1 and 1:1 mixture,
respectively, in chloroform. The X-Ray diffraction structures of
1 and 2 (Figure 1) were obtained from single crystals by diffusing
n-hexane into a dichloromethane solution of the complexes. As
expected, piano-stool style geometries are observed for both
complexes. The structure of 1, which bears the cis- or (S,R)-
oxazoline ligand, features a S-configured iridium centre in the
solid state. In contrast, the iridium centre of 2, which bears the
trans- or (R,R)-oxazoline ligand, is R-configured. The bond
distances involving the iridium show no notable difference
between the two complexes except for a slightly longer Ir-N
distance in 2 and are in the expected range. A CH/π interaction
appears present between the methyl of the Cp* ring and the
phenyl ring from the oxazoline. For example, in 1, the distance
between a Cp* hydrogen and the closest hydrogen on the
phenyl ring is only 2.640 Å.
Figure 1. Molecular structures of 1 and 2 determined by single crystal
X-ray diffraction. For 1: selected bond distances (Å): Ir1-Cl1 2.402(1),
Ir1-N1 2.084(2), Ir1-C10 2.052(3). Selected bond angles (º): Cl1-Ir1-N1
85.1(1), Cl1-Ir1-C10 83.2(1), N1-Ir1-C10 77.4(2). For 2: selected bond
distances (Å): Ir1-Cl1 2.4056(6), Ir1-N1 2.101(2), Ir1-C17 2.062. Selected
bond angles (º): Cl1-Ir1-N1 86.57(5), Cl1-Ir1-C17 84.18, N1-Ir1-C17
77.48(8).
2.2. Asymmetric reductive amination of ketones
Chiral amines have received considerable attention in fine
chemical and pharmaceutical applications.[22] DARA represents
a
convenient pathway for their synthesis and can be
accomplished through metal-catalysed, organocatalytic or
biocatalytic approaches, using a range of hydrogen sources.[22c,
23]
Among them, DARA reactions utilising hydrogen gas have
been the most widely reported,[24] whilst ATH systems,[25]
exploiting other hydrogen sources, have remained
underdeveloped. DARA via transfer hydrogenation is, however,
highly appealing, as it is likely to be easier and safer in operation
than using hydrogen gas.
Table 1. Screening of iridacycles for DARA
O
O
PMP
iridacycle (1 mol%)
IPA 2.5 mL
Ph
N
O
Ph
OH
Ph
O
HN


i. DCM, 4Å MS, rt, 16h,
ii. NBS, rt, 0.5h



H2
N
Ph
H2N
FT 0.5 mL, 16h
Ph
Ph
O
Ph
Ph
H2
N
Ph
N


i. t-BuOH, rt, 16h
ii. K2CO3 (3 eq.),
I2 (1.25 eq.),


Ph
NH2
N
H
Entry
İridacycle Conv. ee
Entry
İridacycle Conv. ee
70 oC, 3h
(%)
68
83
62
60
95
50
50
80
(%)
23
14
10
0
25
30
17
30
(%)
78
92
72
75
78
75
65
75
(%)
56
56
50
42
21
39
43
43
Cl
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
9
9
9
Ir
Ph
Ph
Ph
Ph
N
X
N
[(Cp*IrCl2) ]
2




X: O or NH
10[a]
11
12
13
14
15
16
NaOAc, DCM, rt, 16h
X
10
11
12
13
14
15
MeO
Cl
Cl
Cl
Cl
Cl
Ir
Ir
Ir
Ir
Ir
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
N
O
N
O
N
N
O
N
O
O
Ph
Reaction conditions: 0.5 mmol acetophenone, 0.6 mmol p-methoxy
aniline, 1 mol% iridacycle, 2.5 mL anhydrous IPA, 0.5 mL FT, sealed in air,
ambient temperature; PMP: p-methoxyphenyl. The product is of R
configuration. [a] Optimization at 23 oC.
1
2
3
4
5
MeO
Cl
Cl
Cl
Cl
Cl
Ir
Ir
Ir
Ir
Ir
O
O
Ph
Ph
Ph
N
N
O
N
O
N
N
O
O
O
O
N
N
H
Ph
Iridacycles 1-15 were initially screened for the DARA of
acetophenone with p-methoxyaniline in isopropanol (IPA),
using formic acid as the hydrogen source in the form of formic
acid-triethylamine azeotrope (FT) (Table 1). All the complexes
showed good to high catalytic activities; however, the
enantioselectivities varied considerably, ranging from 0 to 56%
ee. There appears to be little correlation between the ee’s and
the ligand structure in general, partially due to the diversity of
the ligand structures. Of those screened, complex 9, a 3,4,5-
H
HO
OCH3
HO
O
O
Br
7
6
8
10
9
Cl
O
O
Cl
Cl
O
O
Cl
Cl
Cl
Cl
Ir
Ir
Ir
Ir
Ir
O
Ph
Ph
Ph
Ph
Ph
Ph
N
N
N
N
N
O
O
O
N
N
H
N
N
N
H
H
H
H
O
O
O
O
O
O
O
Br
11
12
13
14
15
Scheme 2. Synthesis of oxazoline and imidazoline ligands and related
chiral iridacycles.
2 | J. Name., 2012, 00, 1-3
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ARTICLE
Table 2.
9 [a]
DARA of ketones with amines catalyzed by
.
Cl
R''
R'
Ir
O
HN

9
(1 mol%)
Ph
Ph
R''
N
H2N
(i) or (ii)
R
R'
O
R
N
H
O
O
9
Yield %[d] ee %[e]
Yield %[d] ee %[e]
Entry
Ketone
Amine
Entry
1
Ketone
Amine
O
O
O
O
97
97[b]
0
5[b]
90
95
56
50
11
Ph
H2N
H2N
O
O
O
O
O
37
82[c]
53
48[c]
2
3
12
13
H2N
H2N
O
94
80[b]
54
48[b]
37
84[c]
55
53[c]
H2N
H2N
Cl
O
O
O
Br
8
42[c]
52
54[c]
4
80
54
14
H2N
H2N
O
O
O
O
O
5
6
47
53
96
95
56
56
15
16
H2N
H2N
H2N
O
F3C
50
65[c]
62
60[c]
H2N
H2N
Cl
O
O
O
O
O
O
80
16
7
8
88
88
34
63
17
18
19
97[c]
10[c]
H2N
O
H2N
66
94[c]
14
16[c]
Ph
H2N
O
O
O
H2N
75
84[c]
38
36[c]
77
93[c]
17
22[c]
9
Ph
OMe
H2N
H2N
O
O
38
76[c]
63
59[c]
H2N
Ph
90
93[c]
10
2[c]
10
Ph
20
Cl
9
[a] Reaction conditions (unless otherwise stated) (i): 0.5 mmol ketone, 0.6 mmol amine, 1 mol% , 2.5 mL anhydrous IPA, 0.5 mL FT, sealed in air, 16 h. We assume
9
the products to be of the same configuraton, i.e. R. [b] Reaction conditions (ii): 0.5 mmol ketone, 0.6 mmol amine, 1 mol% , 3 mL HCO2Na/HCO2H pH 4.5, 0.3 mL 2-
MeTHF, sealed in air, 8h. [c] The same reaction conditions with [b] but 16h. [d] Yield of isolated product. [e] Determined by HPLC.
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DOI: 10.1039/D0OB02049D
trimethoxy imidazoline iridicycle, yielded the highest Brønsted acid to activate the substrate and induce chirality.[29]
enantioselectivity (56% ee) for the DARA (Table 1, Entry 9). With the chiral iridacycles in hand, we also examined their
Therefore, 9 was subjected to a range of different solvents, potential for ATH of pyridinium salts.
additives, hydride sources and temperatures to determine the
The iridacycles were first examined for ATH of N-benzyl-2-
optimal conditions (Supporting Information, Table S5). Finally, phenylpyridinium bromide salt, using FT in IPA, as shown Table
o
it was determined that using the FT in IPA at 20-25 C would
provide the best conversion and enantioselectivity (Table 1,
Entry 10).
Table 3. Screening iridacycles for ATH of pyridinium salt
Subsequently, a range of ketones and amines were
investigated to determine whether the iridacycle 9 could be
exploited for DARA. As can be seen from Table 2, whilst 9
catalysed efficient reductive amination, affording the amine
products generally in high yields, the enantioselectivities were
only moderate in most cases. More specifically, utilising p-
methoxyaniline as the amine source, the para- and meta-
substituted acetophenones provided very high yields and
moderate enantioselectivities (Table 2, Entries 2-6). However,
iridacycle (1 mol %)

FT, IPA, 16 h
N
Ph
N
Ph
Br
Ph
Ph
Entry
iridacycle
ee (%) Entry
Iridacycle
ee %
51
77(97)[b]
1
2
3
4
5
6
7
3
4
5
6
7
8
9
20
10
15
6
8
10
10
11
12
13
14
15
9[a]
10
11
12
13
14
33
24
34
25
44
20
an
ortho-substituted
ketone
displayed
a
lower
46
enantioselectivity (Table 2, Entry 7), indicating that the ortho
substituent interferes with the enantioselectivity-determining
step. Changing R’ to an ethyl or a phenyl group led to enhanced
selectivity (Table 2, Entries 8 and 10); however, lengthening the
alkyl group resulted in a lower selectivity (Table 2, Entry 9),
demonstrating a limit to the functionalisation that can be
tolerated in this position. The reaction with an alkyl ketone
afforded a very high yield (97%), but racemic amine (Table 2,
Entry 11). In the case of other aniline derivatives coupling with
acetophenone, the yields decreased significantly (Table 2,
Entries 12-16), indicating that the electron donating methoxy
group on the amine is crucial, probably assisting in the imine
formation. With the more nucleophilic benzylamines (Table 2,
Entries 17-20), the yields were high; but the enantioselectivity
was disappointingly low, presumably as a result of reduced
steric rigidity in the imine intermediate.
Aiming to improve the yield and enantioselectivity, the
impact of aqueous conditions was also investigated, utilising
NaCO2H/HCO2H(aq.) at pH 4.5 as a hydrogen source for DARA,
with 2-methyltetrahydrofuran (2-MeTHF) as a co-solvent.
Under such conditions, some of the yields were improved;
however, the enantioselectivities showed little change (Table 2,
Entries 3, 9-14, 16). In particular, benzylamines afforded higher
yields but still low enantioselectivities (Table 2, Entry 17-20).
38
Reaction conditions: 0.5 mmol pyridinium salt, 1 mol% Ir cat, 2.5 mL anhydrous
IPA, 0.5 mL FT, sealed, ambient temperature. Enantiomeric excess determined by
chiral HPLC. [a] Reaction conducted at -10 oC.[b] Isolated yield in parentheses.
Table 4.
10[a]
ATH of selected pyridinium salts with
Cl
Ir
O
10
(1 mol%)

Ph
Ph
N
N
R
N
R
O
FT, IPA
Br
N
H
R
Ph
Br
10
Entry
1
Substrate
Product
Yield (%)[b]
97
ee (%)[c]

Ph

77
N
N
Ph
N
N
Ph
Br
Br
Ph
68
75
75
10
2
3
PMP
PMP
Ph
Ph

Ph
Ph
N
N
Br
Br
Br
Ph
Ph
2.3. ATH of pyridinium salts
Ph
Ph
Chiral piperidines are valuable building blocks for natural
products and synthetic bioactive molecules. Asymmetric
hydrogenation of pyridines can be used to obtain chiral
piperidines.[26] However, these reactions are generally difficult
to carry out, due to the coordination ability and the resonance
stability of the pyridines. To overcome these challenges,
4
75
80
N
N
Ph
Ph
5
pyridines can be activated, in the form of pyridinium salts or
N
N
27]
auxiliary-substituted pyridines.[26b,
Whilst transfer
Ph
Ph
hydrogenation of pyridines has been reported,[4a, 28] very little
has been reported for ATH of pyridines. In 2007 Rueping et al.
developed the first organocatalytic ATH system, utilising a
10
[a] Reaction conditions: 0.5 mmol pyridinium salt, 1 mol% , 5 mL anhydrous
IPA, 1 mL FT, -10 oC, sealed, 16 h. [b] Yield of isolated product. [c] Determined
by HPLC; configuration unknown. PMP: p-methoxyphenyl.
4 | J. Name., 2012, 00, 1-3
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3. It appears that the oxazoline-containing iridacycles (Table 3,
Entry 1-6,) generally exhibited a low enantioselectivity (up to
34% ee). Among the imidazoline ligands, the previously used 9
provided 44% ee, and the best enantioselectivity was achieved
with the dioxoleiridacycle 10, which afforded 51% ee (Table 3,
Entry 8). Using 10 as catalyst at a lower temperature of -10 °C,
the selectivity was increased and the piperidine was isolated in
97% yield with an ee of 77% (Table 3, Entry 9).
Under the conditions identified, we examined the ATH of a
range of pyridinium salts. Selected examples are shown in Table
4.§ As can be seen, the iridacycle 10 is active for the substituted
pyridinium salts, affording the corresponding piperidines in high
yields. However, the enantioselectivity varied considerably,
from 77% ee for the 2-aryl substituted substrates to 10% ee for
the less sterically hindered 2-benzyl substituted one (Table 4,
Entries 1-3).
Barrios-Landeros, A. Pfaltz, Andreas, Chem. Sci., 2013, 4,
2760
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DOI: 10.1039/D0OB02049D
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6
Conclusions
Chiral iridacycles can be easily accessed via cyclometalation
reaction of [Cp*IrCl2]2 with a ligand that undergoes C-H
activation and such complexes could serve as catalysts for
asymmetric reactions. In this study, we have synthesised a wide
range of chiral iridacycles and examined their potential
application in DARA via transfer hydrogenation. Among the
iridacycles, the 3,4,5-trimethoxy imidazoline-bearing 9 proved
to be the most effective, affording moderate
enantioselectivities in the DARA of acetophenones with aniline
derivatives. The iridacycles are also active in catalysing the ATH
of pyridiniums, albeit with only good ee’s in the case of 2-aryl
substituted substrates. Research within our group continues to
develop chiral iridacycles, aiming for better enantioselective
catalysts.
7
8
9
Conflicts of interest
There are no conflicts to declare.
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Acknowledgements
We thank AstraZeneca (JS) and the Scientific and Technological
Research Council of Turkey (TUBİTAK) for support and Dr
Ramachandran Gunasekar for technical assistance.
Notes and references
§ The enantioselectivity of the other products could not be
determined due to the lack of chiral HPLC columns at the time.
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Organic & Biomolecular Chemistry
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DOI: 10.1039/D0OB02049D
Graphic Abstract
HCOOH
R''
R'
H3N
R''
O
HN

Cl
R
R
R'
Ir
Ph
Ph
N
N
H

N
R1
N
R1
R
R
HCOOH
A series of chiral iridacycles have been synthesised and shown to be moderately
enantioselective in asymmetric transfer hydrogenation reactions.