Enhanced Catalytic Activity of Oxygen-Tethered IrIII NHC Complexes in Aqueous Transfer Hydrogenative Reductive Amination Reactions: Experimental Kinetic and Mechanistic Study

Article abstract of DOI:10.1002/cctc.201800558

The synthesis and characterization of seven new Ir^III complexes containing o-phenoxide or o-naphthoxide chelated N-heterocyclic carbene ligands is reported herein. The crystal structures of six of the complexes have been determined. These complexes efficiently catalyze the transfer hydrogenative reductive amination (RA) of carbonyls and amines in water. Amongst the complexes tested, the introduction of o-naphthoxide on a nitrogen atom of imidazole based NHC ligand greatly increased the catalytic activity. The catalytic system has a broad substrate scope, which allows the synthesis of a variety of amines in excellent yields and with high turnover numbers up to 490 (for ketones) and 14800 (for aldehydes). The mechanism of aqueous RA reaction with an o-aryloxide chelated NHC-Ir^III catalyst has been investigated by NMR spectroscopy and kinetic measurements. These studies suggest that the transfer hydrogenation (TH) is turnover-limited by the hydride formation step. As a result of the ¹H NMR studies, the higher catalytic activity of o-naphthoxide chelated catalyst (3 g) over o-phenoxide chelated one (3 b) can be attributed partly due to the faster formation of an iridium hydride, the key intermediate in the RA reactions.

Full text of DOI:10.1002/cctc.201800558

Accepted Article
Title: Enhanced Catalytic Activity of Oxygen-Tethered IrIII NHC
Complexes in Aqueous Transfer Hydrogenative Reductive
Amination Reactions: Experimental Kinetic and Mechanism Study
Authors: İbrahim Kayahan Özbozkurt, Derya Gülcemal, Salih Günnaz,
Aytaç Gürhan Gökçe, Bekir Çetinkaya, and Süleyman
Gülcemal
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10.1002/cctc.201800558
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Enhanced Catalytic Activity of Oxygen-Tethered IrIII NHC
Complexes in Aqueous Transfer Hydrogenative Reductive
Amination Reactions: Experimental Kinetic and Mechanism Study
İbrahim Kayahan Özbozkurt,[a] Derya Gülcemal, [a] Salih Günnaz, [a] Aytaç Gürhan Gökçe, [b] Bekir
Çetinkaya, [a] and Süleyman Gülcemal *[a]
Abstract: The synthesis and characterization of seven new IrIII
complexes containing o-phenoxide or o-naphthoxide chelated N-
heterocyclic carbene ligands is reported herein. The crystal
structures of six of the complexes have been determined. These
complexes efficiently catalyze the transfer hydrogenative reductive
amination (RA) of carbonyls and amines in water. Amongst the
complexes tested, the introduction of o-naphtoxide on a nitrogen
atom of imidazole based NHC ligand greatly increased the catalytic
activity. The catalytic system has a broad substrate scope, which
allows the synthesis of a variety of amines in excellent yields and
with high turnover numbers up to 490 (for ketones) and 14800 (for
aldehydes). The mechanism of aqueous RA reaction with an o-
aryloxide chelated NHC-IrIII catalyst has been investigated by NMR
spectroscopy and kinetic measurements. These studies suggest that
the transfer hydrogenation (TH) is turnover-limited by the hydride
formation step. As a result of the 1H NMR studies, the higher
catalytic activity of o-naphtoxide chelated catalyst (3g) over o-
phenoxide chelated one (3b) can be attributed partly due to the
faster formation of an iridium hydride, the key intermediate in the RA
reactions.
copious amount of toxic byproducts.1b,f,3 Progress in developing
homogeneous catalytic systems, including organometallic
hydrogenative4 and transfer hydrogenative RA protocols5, has
been disclosed in recent years. Transfer hydrogenative RA
appears to be the better strategy to follow, whereby using of a
reductant rather than gaseous H2 allows for reductions without
the necessity of a high-pressure environment. Aqueous transfer
hydrogenative RA is obviously a greener and versatile approach
in this regard, in which the use of formic acid (FA) / sodium
formate as a reducing agent presents an economical and safe
hydrogen carrier.
During the past 30 years, N-heterocyclic carbenes (NHCs) and
their transition metal complexes have been extensively studied
in organometallic chemistry and catalysis. Since then, they have
generated great interest owing to the ease of tuning their steric
and electronic properties. NHCs often form stable complexes
with many transition metals irrespective of their oxidation states.6
In the area of catalysis, NHC-bearing transition metal complexes
have found numerous applications. An example is NHC–iridium
complexes, which have been successfully employed as catalysts
for a number of transfer hydrogenation (TH) rections.7,8 However,
there are only two studies of RA reactions using NHC iridium5e
and palladium4n complexes. More recently our group reported a
new type of iridacycle catalyst containing a chelating NHC–
phenoxide ligand (1).9 This complex was found, for the first time,
to efficiently catalyze both transfer hydrogenative and
hydrogenative RA of various ketones and aldehydes with aniline
derivatives (Figure 1).
Introduction
Amines are one of the most important functional groups in
chemical synthesis as they are present in numerous biologically
active
compounds,
agrochemicals,
fine
chemicals,
pharmaceuticals and functionalized materials.1 Reductive
amination (RA) of carbonyl compounds with amines is one of the
most frequently used synthetic method to access higher
functionalized amines in one step.2 This method is highly
valuable from a synthetic point of view since it avoids the
isolation of unstable imine intermediates. In conventional RA
procedures developed, stoichiometric boron hydride reduction
and heterogeneous hydrogenation dominate the scene, but the
use of stoichiometric amount of boron hydrides generates
[a]
I.K. Özbozkurt, D. Gülcemal, S. Günnaz, B. Çetinkaya, S. Gülcemal
Department of Chemistry,
Figure 1. Recently reported NHC-IrIII catalyzed RA reactions by our group.
Ege University,
35100 Bornova, Izmir, Turkey
E-mail (S.G.): suleyman.gulcemal@ege.edu.tr
The previous successful results obtained by a single catalyst in
RA reactions encouraged us to investigate the catalytic activities
of a wide set of topologically similar NHC ligands with different
electronic and steric properties. Our initial aim was to study if
modifying the structure of NHC ligands may add further benefits
in comparison to previously reported catalyst 1 in transfer
hydrogenative RA reactions. Herein, we report the preparation of
[b]
A.G. Gökçe
Department of Physics,
Adnan Menderes University,
09010 Efeler, Aydın, Turkey
Supporting information for this article is given via a link at the end of
the document.
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10.1002/cctc.201800558
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a series of new o-aryloxide (phenoxide and naphtoxide) chelated
neutral NHC–IrIII complexes (3a-g) with different benzyl
substituents and azole skeletons (imidazole and benzimidazole)
and assessment of the catalytic activity of prepared catalysts
precursors in the transfer hydrogenative RA reactions. These
complexes are found to be highly active catalysts for RA of
various ketones and aldehydes by transfer hydrogenation under
legged piano-stool geometry of iridium center (Figure 2). The
chelated bidentate o-aryloxide and NHC ligand and chloride
ligand form the equatorial legs while the three apical positions
are occupied by Cp* ligand. Table 1 presents the selected bond
distances and angles. The Ir–Ccarbene and Ir–O bond distances
9,12
and ligand bite angles are within the typical ranges
shows little variation as may be expected.
and
aqueous conditions with formate as
a hydrogen source.
Compared with our previous results, introduction of o-naphtoxide
on a nitrogen atom of imidazole based NHC ligand greatly
increased the catalytic activity.
Results and Discussion
Scheme 1 outlines the route used for the ligands (L1-L3),
azolium salts (2a-g) and complexes (3a-g). The 1-(2-
hydroxyphenyl)-benzimidazole
imidazole (L2) and 1-(2-hydroxynaphthyl)imidazole (L3) was
synthesized via copper(I) catalyzed N-arylation of
(benz)imidazole with 2-bromoanisole or 2-bromo-3-
(L1),
1-(2-hydroxyphenyl)-
methoxynaphthalene and subsequent demethylation of the
corresponding anisole derivative (Scheme 1).9 The NHC
precursors of (benz)imidazolium salts (2a-g) were synthesized
by the reaction of L1-L3 with corresponding alkyl halides in
refluxing acetonitrile (Scheme 1). The (benz)imidazolium salts
were obtained in 81-94% yields. They have been fully
characterized by 1H and 13C NMR spectra and high-resolution
mass spectrometry (HRMS). The 1H NMR spectra of 2a-g
indicates that the NCHN+ proton appears at δ = 8.67-10.01 ppm
and these downfield signals indicate the formation of
(benz)imidazolium salts. The presence of the phenolic OH
protons was confirmed by an exchange experiment with D2O,
upon addition of which the signals at δ = 10.01-11.38 ppm in the
1H NMR spectrum disappeared.
Recently, transition metal complexes with anion–tethered NHC
ligands have much attention, since the featured anion moieties
can enhance the bond between metal atoms and the NHC
ligands via cyclometallation and inhibit the possibility of ligand
dissociation.10 Following the procedures as described previously
by our group,9 the new neutral aryloxide chelated NHC–IrIII
complexes (3a-g) were synthesized by transmetalation11 from
the in-situ formed NHC–Ag derivatives by employing a two-step
process (Scheme 1). The NHC–Ag species were not isolated,
however. In the second step, addition of [IrCp*Cl2]2 to the
reaction mixtures gave the complexes 3a-g in 83-94% yields as
air and moisture stable yellow solids. Formation of 3a-g were
confirmed by HRMS analysis and NMR spectroscopic analysis,
which showed the characteristic Ir–Ccarbene signals at δ = 159.5-
175.9 ppm in the 13C NMR spectrum. Meanwhile, the
characteristic downfield signals for the NCHN+ protons of 2a-g at
δ = 8.67-10.01 ppm disappeared in the 1H NMR spectrum.
Disappearance of the phenolic OH proton signals at δ = 10.01-
11.38 ppm in 2a-g also supports the formation of o-aryloxide
chelated complexes 3a-g. Finally, the structures of complexes
3a-c and 3e-g were determined by single crystal X-ray
diffraction analysis displaying the presence of the typical three-
Scheme 1. Preparation of ligands and complexes: (i) KOH, Cu2O, DMSO,
140 °C, 24 h; (ii) HBr (47% aqueous solution), reflux, 48 h then NaHCO3; (iii)
R-X, MeCN, reflux, 4-12 h; (iv) Ag2O, CH2Cl2, room temperature, 2 h, then
[IrCp*Cl2]2, 2 h.
Table 1 Selected bond distances (Å) and angles (°) for 3a-c and 3e-g.
Ir–Ccarbene
2.014(6)
2.019(5)
2.017(5)
2.008(5)
2.025(6)
1.991(10)
Ir–O
Ir–Cl
O–Ir–Ccarbene
82.8(2)
3a
3b
3c
3e
3f
2.100(5)
2.101(3)
2.095(4)
2.089(4)
2.097(4)
2.096(5)
2.3998(18)
2.4083(14)
2.4128(14)
2.4025(13)
2.4072(15)
2.399(3)
83.12(16)
81.92(19)
81.77(18)
82.5(2)
3g
83.2(3)
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Figure 2. ORTEP representations of complexes 3a, 3b, 3c, 3e, 3f, and 3g; all structures at 30% probability level, hydrogen atoms and solvent molecules omitted
for clarity.
Recently, we reported a single o-phenoxide chelated NHC–IrIII
complex (1) which catalyzes the transfer hydrogenative RA of
various ketones and aldehydes with aniline derivatives in
aqueous conditions.9 The transfer hydrogenative RA was
affected with formate in water, and controlling the solution pH is
important, with pH 4.8 being optimal.5h,9 Imine formation from the
corresponding ketone and amine and the subsequent reduction
of imine are known to benefit from acidic conditions and under
basic conditions, imine formation is inhibited.5h In this study
aqueous RA of different ketones and aldehydes with p-anisidine
complete conversions to the desired higher amines were
achieved with the molar ratio of the substrate to the catalyst
(S/C) of 100-200 at 50 °C in 8-16 h. Xiao and co-workers have
observed that the nature of the iridacycle catalyst strongly
influences the catalytic activity in transfer hydrogenative RA
reactions.5h Thus, we decided to prepare a set of o-aryloxide
chelated NHC-IrIII complexes (3a-g) in order to explore their
catalytic activities in aqueous RA. Initially, acetophenone (4a)
and p-anisidine (5a) were selected as benchmark substrates to
screen the transfer hydrogenative RA reaction using complexes
3a-g as the catalyst at pH 4.8 (Table 2). The reduction was
carried out at 50 °C with a S/C of 200:1 for 16 h. Within
complexes 1, 3a and 3b with different azole skeletons and 2,4,6-
triisopropylbenzyl as wingtip on the nitrogen atom, the catalyst
3b with imidazole skeleton gave the best result, with 68%
conversion to the desired amine 6aa (entries 1-3). Other
imidazole-based complexes having electron deficient and
electron withdrawing benzyl groups via para-substituents (H,
OMe and CF3) (3c-e) and n-butyl group (3f) effected lower
conversions (23-42%) than 3b (entries 4-7). With this in mind,
imidazole was selected as azole skeleton and 2,4,6-
triisoropylbenzyl as a wingtip group. It is known that for the
cyclometalated iridium complexes, conjugation play an important
role in the catalytic activity.5i We thus decided to replace the
phenyl ring with naphthyl, which offer more extensive
conjugation and steric hinderence, and o-naphthoxide chelated
NHC–IrIII complex (3g) was prepared and tested under same
reaction conditions. Pleasingly, this complex was found to be the
most active catalyst, affording 94% conversion (entry 8). The
substituents on the imidazole skeleton also have an important
effect on the catalytic activity. Decreasing the ratio of p-anisidine
to acetophenone from 2.0 to 1.5 led to 93% conversion to 6aa
as well (entry 9). Further decreasing the 5a:4a ratio to 1.0
resulted in lower conversion to 84% (entry 10). This due to the
formation of the side product (N-(4-methoxyphenyl)formamide),
from the reaction of 5a and FA.5k Therefore, there was no 5a
remaining to react with acetophenone in order to form the
corresponding imine intermediate. Formation of the side product
(N-(4-methoxyphenyl)formamide) via formylation of 5a increased
under acidic conditions (Figure S1). Significantly more
interesting is the observation that this catalytic system can also
afford quantitative formation of 6aa under an air atmosphere
with a 5a:4a ratio of 1.5 in 16 h (entry 11). With a S/C of 500,
69% conversion to 6aa was achieved (entry 12). Pleasingly, in
all the reaction conditions examined no reduction of
acetophenone to byproduct 2-phenylethanol were observed and
the imine intermediate is selectively reduced over carbonyl
groups by the NHC–IrIII catalyst. In contrast, only 9% conversion
was obtained with [IrCl2Cp*]2 (0.5 mol% Ir) under the same
conditions, which emphasizes the importance of the NHC ligand
for the RA reaction. A control experiment was carried out without
any catalyst and no product formation was observed.
Percentage conversion was calculated by comparing the methyl
proton signals of hexamethylbenzene (used as an internal
standard) and 4-methoxy-N-(1-phenylethyl)aniline (6aa) in the
1H NMR spectra of the crude product and the time-dependent
conversions were followed (Figure 3). This led to full conversion
to 6aa after 12 h. Under these conditions, the product was
isolated in an excellent yield of 94% after 12 h.
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calculated from 1H NMR spectra by using hexamethylbenzene as an internal
standard.
With the optimized reaction conditions in hand, we then studied
the scope of the RA, first using various aromatic and aliphatic
ketones and primary amines by using 3g as the catalyst (Table
3). We started by studying the effect of substituents on the
aromatic ring of the acetophenone substrate. Aromatic ketones
with electron-withdrawing or electron-donating substituents and
different steric properties all reacted with p-anisidine, affording
good yields (81-94%) after 12 h at 50 °C with a S/C of 200
(entries 1-7). The electronic effects of these substituents on the
RA are not obvious for these substrates under the conditions
employed.
Reactions of aliphatic ketones with p-anisidine were investigated
next. These ketones showed higher activity than the aromatic
ones. Thus, complete conversions and higher isolated yields
(96-98%) were achieved with both cyclic and noncyclic aliphatic
ketones examined at a higher S/C of 500 (entries 8 and 9).
Similar activities were observed for the reaction of different
aromatic amines with acetophenone. Irrespective of the
electronic nature of the substituent, aniline derivatives reacted
smoothly to give the desired secondary amine products in
excellent yields (81-92%) after 12 h at 50 °C with a S/C of 200
(entries 10-13). In addition, benzyl amine reacted quite well with
acetophenone to afford full conversion and 96% isolated yield
with a S/C of 200 after 12 h.
Table 2 Optimizing reaction conditions of the RA.
Entry[a]
Catalyst
1
(S/C)
200
200
200
200
200
200
200
200
200
200
200
500
Conv.(%)[b]
Table 3 Transfer hydrogenative RA of ketones with amines in water.
1
2
52
53
68
35
38
23
42
94
93
84
>99
69
3a
3
3b
3c
4
5
3d
3e
Yield
Entry[a]
4
5
6
S/C
200
6
[%][b]
7
3f
8
3g
3g
3g
3g
3g
1
6aa
94
9[c]
10[d]
11[e]
12[c]
2
3
4
6ba
6ca
6da
200
200
200
92
87
83
[a] Reaction conditions: acetophenone (0.5 mmol), p-anisidine (1.0 mmol),
3a-g (0.2-0.5 mol%), aqueous HCOOH/HCOONa solution (pH 4.8, 0.8 mL,
10 mol L-1), 50 °C, 16 h, under Ar atmosphere. [b] Conversions were
calculated from 1H NMR spectra by using hexamethylbenzene as an
internal standard. [c] 4a (0.5 mmol), 5a (0.75 mmol). [d] 4a (0.5 mmol), 5a
(0.5 mmol). [e] Under an air atmosphere.
5
6
6ea
6fa
200
200
200
500
500
200
89
94
86
98
96
81
100
90
80
70
60
50
40
30
20
10
0
7
6ga
6ha
6ia
8
0
0,5
1
2
4
6
8
12
9
Time (h)
10
6ab
Figure 3. Time course of the RA in water. Reaction conditions: acetophenone
(1 mmol), p-anisidine (1.5 mmol), 3g (0.5 mol%), aqueous HCOOH/HCOONa
solution (pH 4.8, 1.6 mL, 10 mol L-1), 50 °C, air atmosphere. Conversions were
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Building upon these results, in the aqueous RA of different
aldehydes (7a-h) with aniline derivatives (5a-e) (7:5 ratio of 1.0)
full conversions to the desired amines (8) were achieved in 8-16
h at a S/C of 2000. The corresponding amines were isolated in
79-99% yields (Table 4). It was observed that p-substituted
benzaldehydes containing electron donating or withdrawing
groups were all tolerated under the present reaction conditions
(entries 1-5). More sterically hindered 2-chlorobenzaldehyde (7f),
2-methoxybenzaldehyde (7g) and 2,4,6-trimethylbenzaldehyde
(7h) needed longer reaction times to reach acceptable yields
(entries 6-8), most likely due to their steric hindrance impeding
both imine formation and reduction. Both electron donating and
withdrawing groups on the para position of aniline did not affect
the activity and gave the corresponding amine products in high
yields (entries 9-12). Moreover, we studied the RA of
benzaldehyde with aniline at higher S/C ratios under optimized
conditions. As can be seen, with S/C = 10000, where 10 mmol of
benzaldehyde and aniline were used, the corresponding amine
(8ab) isolated in 94% yield within 24 h (entry 13). At higher S/C
ratios of 20000 the reaction also worked quite well, affording
74% isolated yield within 48 h (entry 14).
11
12
13
14
6ac
6ad
6ae
6af
200
200
200
500
92
89
86
96
[a] Reaction conditions: ketone (1.0 mmol), amine (1.5 mmol), 3g (0.2-0.5
mol%), HCOOH/HCOONa solution (pH 4.8, 1.6 mL), 50 °C, 12 h, air
atmosphere. [b] Isolated yield.
We also explored the RA of aldehydes with aniline derivatives.
As expected, aldehydes were more reactive than aromatic or
aliphatic ketones and could be converted into the corresponding
amine products at higher S/C ratio than ketones. In the case of
aldehydes, we observed that imine formation from benzaldehyde
(7a) and p-anisidine (5a) is very fast and the corresponding
imine (N-benzylidene-1-(4-methoxyphenyl)methanamine) (8ʹaa)
was formed with a complete conversion after 15 min under the
reaction conditions employed. Subsequent reduction of the
imine intermediate afforded amine 8aa with a full conversion
within 8 h (Figure 4). This result would be highly beneficial since
under the optimal conditions, the formylation of amine reagents
(5) would be minimized and no excess amount of p-anisidine will
be needed for the complete conversion to the desired amine 8aa.
Table 4 Transfer hydrogenative RA of aldehydes with anilines in water.
Yield
Entry[a]
7
5
8
S/C
t [h]
[%][b]
1
8aa
2000
8
98
2
3
4
5
6
7
8
9
8ba
8ca
8da
8ea
8fa
2000
2000
2000
2000
2000
2000
2000
2000
8
8
97
95
99
96
79
97
95
97
8
Total Conversion
% 8'aa
% 8aa
100
90
80
70
60
50
40
30
20
10
0
8
16
16
16
8
8ga
8ha
8ab
0,25
0,5
1
2
3
4
6
8
Time (h)
Figure 4. Time course of the RA with aldehydes. Reaction conditions:
benzaldehyde (1 mmol), p-anisidine (1.0 mmol), 3g (0.05 mol%), aqueous
HCOOH/HCOONa solution (pH 4.8, 1.6 mL, 10 mol L-1), 50 °C, air atmosphere.
Conversions were determined by 1H NMR spectroscopy.
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An interesting observation in the NMR study is that when
10
11
12
13
14
8ac
8ad
8ae
8ab
8ab
2000
2000
8
8
99
98
96
94
74
complex 3b was reacted under similar conditions, hydride
formation is much slower. H NMR spectral evidence (Figure 5b
1
and Figure S17) shows that complex 3b fully converted to
cyclometalated product 3b-CM in 10 min. as shown in Scheme 2.
1
The H NMR shows the disappearance of one of the triplet on
the phenoxide ring which is consistent with the cyclometalated
product obtained (Figures S16 and S17).[16] New peaks
attributed to the iridium hydride complex (3b-H) appeared,
including the disappeared triplet of the phenoxide ring, and
about 53% and 85% conversion into 3b-H was achieved within
20 and 30 min. respectively while some 3b and 3b-CM remains.
The characteristic hydride peak of 3b-H was found at δ = ‒
10.61 ppm (Figure 5b).
2000
8
10000
20000
24
48
[a] Reaction conditions: aldehyde (2.5 mmol), amine (2.5 mmol), 3g (0.05-
0.005 mol%), HCOOH/HCOONa solution (pH 4.8, 4 mL), 50 °C, air
atmosphere. [b] Isolated yield.
Transition metal-catalyzed TH reactions with formate involves
three main steps: (i) formate coordination to the metal centre to
afford metal formato complex, (ii) formate decarboxylation to
form a metal hydride, which is the key intermediate during the
catalysis, and (iii) transfer of the hydride to a substrate.[15] When
complex 3g (0.02 mmol) was treated with HCOONa (4 equiv.) in
CD3OD in an NMR tube at room temperature, new peaks
attributed to the iridium hydride complex (3g-H) appeared, with
about 85% conversion of 3g into 3g-H (calculated by integration
of the methyl proton signals of Cp*, 1.73 ppm for 3g-H, and 1.55
1
ppm for 3g, in the H NMR spectrum) in 5 min. (Scheme 2 and
Figure 5a). Almost quantitative formation of 3g-H was achieved
in 10 min. The characteristic hydride peak of 3g-H was found at
δ = ‒ 10.53 ppm (Figure S18).
Figure 5. Cp* and hydride region 1H NMR spectra of the reaction of 3g (a) and
3b (b) with HCOONa (4 equiv.) in CD3OD at room temperature.See full
spectrum in SI (Figure S19).
Similar observations have been made when we monitored the
reaction of 3b and 3g (0.01 mmol) with aqueous
HCOOH/HCOONa solution (pH 4.8, 0.8 mL, 10 mol L-1).
Complexes 3b or 3g were stirred in HCOOH/HCOONa solution
for 10 min. in a Schlenk tube and subsequently extracted into
CDCl3. 1H NMR spectral evidence after reactions shows that
70% of
3b remains, but 30% has been converted to
cyclometalated intermediate 3b-CM and no hydride signal was
detected. In the case of 3g, 14% conversion to 3g-H was
detected while 86% of 3g remains. These observations also
support that the formation of the iridium hydride complex is
Scheme 2. Reaction of 3b and 3g with HCOONa (4 equiv.) in CD3OD at room
temperature. Formation of cyclometalated iridium complex and iridium hydride
complex.* Trace amount (<2%) of 3g-CM was detected after 10 min.
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much faster in 3g when compared with 3b. From the above
studies it can be concluded that, the higher catalytic activity of
3g may be attributed to the faster formation of catalytically active
iridium hydride intermediate 3g-H.
y = -0,0587x - 10,83
-9,8
-10,2
-10,6
-11,0
-11,4
-11,8
-12,2
R² = 0,2843
To gain further insight into the RA mechanism, kinetic
measurements were carried out for the model catalytic reaction
(Figure 6). The reaction was carried out with the concentration of
one of the components, catalyst (3g), HCOOH/HCOONa buffer
or substrate, varied while holding that of the other two constant.
Plotting the ln(initial rate) vs ln[catalyst], ln[HCOOH/HCOONa]
and ln[substrate] leads to Figure 6. With a slope approaching 1,
1 and 0 when the concentration of catalyst, HCOOH/HCOONa
and substrate was varied, respectively. These results suggest
that the RA rate is first order in both catalyst and buffer
concentration and zero order in the substrate. The
independence of rate on the substrate concentration points
again to the catalytic turnover being limited by the hydride
formation step, in line with the experimental NMR observations.
-1,5
-1,0
-0,5
ln [substrate]
0,0
0,5
Figure 6. Variation of ln(initial rate) with ln(concentration) in the RA of
acetophenone with p-anisidine. The rate and concentrations are given in
mol∙L-1∙s-1 and mol∙L-1, respectively.
On the basis of the observations above, a possible mechanism
for the transfer hydrogenative RA reaction is proposed (Figure 7).
Complex A is first converted into B in the presence of the
formate ion and the decarboxylation of the formate leads to the
iridium hydride species D, which is confirmed by NMR studies.15
DFT studies by Xiao and co-workers suggest that the hydride D
is formed via a transition state C in which the formate in B
dissociates from the iridium centre and an ion pair between the
dissociated formate and the cationic 16 electron IrIII complex is
generated. Then the C‒H bond cleavage affords the hydride D
and CO2.15a The generated imine through the condensation of
carbonyl derivative with an amine is protonated under the acidic
conditions and enters the catalytic cycle as the iminium ion,
where it is reduced to the product by hydride transfer.2l,15
Furthermore, we observed the formation of the cyclometalated
species (Aʹ) in the presence of a formate ion. As a result, the
hydride formation step is much faster for complex 3g when
compared with 3b.
-10,2
y = 1,1045x - 13,348
-10,6
-11,0
-11,4
-11,8
-12,2
-12,6
-13,0
R² = 0,9948
0,0
0,5
1,0
1,5
2,0
2,5
ln [HCOOH/HCOONa]
-9,4
-9,8
y = 0,9545x - 5,7385
R² = 0,9975
-10,2
-10,6
-11,0
-11,4
-11,8
-12,2
-12,6
-7,5
-6,5
-5,5
ln [catalyst]
-4,5
-3,5
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10.1002/cctc.201800558
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Figure 7. Proposed transfer hydrogenative RA mechanism catalyzed with a
model NHC-Ir catalyst.
mmol), KOH (1.12 g, 20.0 mmol) and Cu2O (286 mg, 2.0 mmol) under
argon. The resulting mixture was stirred at 140 °C for 24 h under argon.
After cooling to room temperature, the mixture was poured into ethyl
acetate (50 mL) and filtered. The filtrate was washed with water (3 × 50
mL) and dried over anhydrous sodium sulfate. Solvent was evaporated
and to the crude oil an aqueous solution of 47% HBr (5.18 g, 30 mmol)
was added and the brown solution allowed refluxing for 48 h under argon.
The solution was then cooled and basified by the addition of anhydrous
NaHCO3 until the evolution of CO2 ceased and a precipitate formed. The
precipitate was filtered and washed with water. The resulting crude
product was purified via column chromatography on silica gel with ethyl
acetate:methanol (9:1) as eluent, affording an off-white powder.
Conclusions
In this report, we have synthesized a series of new o-aryloxide
chelated [Ir(NHC)Cp*Cl] with different benzyl and alkyl
substituents and azole skeletons. These complexes are found to
effectively catalyze transfer hydrogenative RA of various
ketones and aldehydes with amines. The reactions proceed with
high efficiency to afford corresponding amines in aqueous FA /
sodium formate solution under mild reaction conditions. This RA
system turned out to be very general for a wide range of
carbonyls and amines, including those of poor water-solubility. It
was observed that aliphatic ketones (S/C = 500) are more active
than aromatic ones (S/C = 200), and aldehydes (S/C = 2000-
20000) are more active than ketones in general. In comparison
with all the complexes tested, o-naphthoxide chelated NHC-IrIII
complex (3g) exhibited the highest catalytic activity for this
reaction. The catalytic activity of 3g in RA is generally lower and
requires higher S/C ratio compared to that of imino
cyclometalated iridium complexes by Xiao and co-workers5h, but
has some advantages such as relatively low temperatures are
needed and no excess amount of amine required in the case of
aldehydes. The experimental mechanistic and kinetic studies
suggest that the transfer hydrogenation is turnover-limited by the
hydride formation step. As a result of 1H NMR studies, the higher
catalytic activity of o-naphtoxide chelated catalyst (3g) over o-
phenoxide chelated one (3b) can be attributed partly due to the
faster formation of an iridium hydride which is the key
intermediate in RA reactions. Slower formation of iridium hydride
for complex 3b may be attributed to the formation of
L113. Overall yield: 71%, 1.48 g (based on 2-bromoanisole). m.p. 225 ºC.
1H NMR (400 MHz, DMSO-d6): δ = 10.19 (s, 1H; Ar-OH, exchanges with
D2O), 8.33 (s, 1H, NCHN), 7.75 (m, 1H, Ar-H), 7.41 (d, J = 7.8 Hz, 1H,
Ar-H), 7.38 (t, J = 10.0 Hz, 1H, Ar-H), 7.26 (m, 3H, Ar-H), 7.14 (d, J = 7.4
Hz, 1H, Ar-H), 7.01 (t, J = 7.6 Hz, 1H, Ar-H).
L214. Overall yield: 76%, 1.21 g (based on 2-bromoanisole). m.p. 218 ºC.
1H NMR (400 MHz, DMSO-d6): δ = 10.17 (s, 1H, Ar-OH, exchanges with
D2O), 7.88 (s, 1H, NCHN), 7.45-6.70 (m, 6H, NCHCHN + Ar-H).
L3. Overall yield: 74%, 1.56
g
(based on 2-bromo-3-
methoxynaphthalene). m.p. 264 ºC. 1H NMR (400 MHz, DMSO-d6): δ =
10.67 (s, 1H; Ar-OH, exchanges with D2O), 8.04 (s, 1H, NCHN), 7.98 (s,
1H, NCHCHN), 7.82 (d, J = 8.0 Hz, 1H, Ar-H), 7.74 (d, J = 8.0 Hz, 1H,
Ar-H), 7.56 (s, 1H, NCHCHN), 7.43 (t, J = 7.6 Hz, 1H, Ar-H), 7.38 (s, 1H,
Ar-H), 7.33 (t, J = 7.6 Hz, 1H, Ar-H), 7.08 (s, 1H, Ar-H). 13C NMR (100
MHz, DMSO-d6): δ = 149.3 (NCHN), 133.5 (Ar-C), 128.0 (Ar-C), 127.8
(Ar-C), 127.2 (Ar-C), 127.1 (Ar-C), 126.2 (Ar-C), 124.2 (Ar-C), 123.9 (Ar-
C), 111.1 (Ar-C). Elemental analysis: calcd (%) for C13H10N2O: C 74.27,
H 4.79, N 13.33; found: C 74.42, H 4.75, N 13.26. HRMS (APCI): calcd.
m/z for C13H11N2O [M+H]+: 211.0871; found: 211.0879.
Synthesis of 2a. To a suspension of L1 (420 mg, 2.0 mmol) in
acetonitrile (10 mL) was added 2,4,6-triisopropylbenzyl bromide (653 mg,
2.2 mmol). The resulting mixture was refluxed for 12 h. After cooling to
room temperature, the solvent was evaporated. The resulting solid was
dissolved in dichloromethane (5 mL) and diethyl ether (20 mL) was
added. The colorless solid that separated out was filtered and washed
with diethyl ether (2×20 mL) and dried under reduced pressure. Yield:
94%, 952 mg. m.p. 265 ºC. 1H NMR (400 MHz, CDCl3): δ = 10.01 (s, 1H;
Ar-OH, exchanges with D2O), 8.67 (s, 1H, NCHN+), 7.90 (d, J = 8.0 Hz,
1H, Ar-H), 7.78 (d, J = 8.0 Hz, 1H, Ar-H), 7.69-7.55 (m, 3H, Ar-H), 7.32-
7.26 (m, 2H, Ar-H), 7.13 (s, 2H, Ar-H), 6.94 (t, J = 7.6 Hz, 1H, Ar-H), 5.80
(s, 2H, NCH2Ar), 3.07 (quint, J= 6.8 Hz, 2H, ArCH(CH3)2), 2.92 (quint, J=
6.8 Hz, 1H, ArCH(CH3)2), 1.27 (d, J = 7.2 Hz, 6H, ArCH(CH3)2), 1.18 (d, J
= 7.2 Hz, 12H, ArCH(CH3)2). 13C NMR (100 MHz, CDCl3): δ = 152.2
(NCHN+), 151.8 (Ar-C), 149.0 (Ar-C), 140.2 (Ar-C), 132.6 (Ar-C), 132.2
(Ar-C), 128.1 (Ar-C), 127.8 (Ar-C), 125.7 (Ar-C), 122.5 (Ar-C), 121.1 (Ar-
C), 119.9 (Ar-C), 119.7 (Ar-C), 119.5 (Ar-C), 114.5 (Ar-C), 113.7 (Ar-C),
45.0 (NCH2Ar), 34.3 (ArCH(CH3)2), 30.1 (ArCH(CH3)2), 24.4
(ArCH(CH3)2), 23.8 (ArCH(CH3)2). Elemental analysis: calcd (%) for
C29H35BrN2O: C 68.63, H 6.95, N 5.52; found: C 68.47, H 7.01, N 5.51.
HRMS (APCI): calcd. m/z for C29H35N2O [M–Br]+: 427.2744; found:
427.2720.
1
cyclometalated complex 3b-CM which is detected by H NMR.
This transformation is very little (< 2%) for the o-naphthoxide
chelated complex 3g, this might be due to steric repulsions on
five-membered cyclometalated iridium complex; the second
aromatic ring may hinder the rotation about the C–N bond, thus
preventing the cyclometalation reaction.
Experimental Section
General Considerations. Experiments involving air or moisture sensitive
reagents were performed under an atmosphere of dry argon using
standard Schlenk techniques. Unless otherwise specified, all reagents
were obtained commercially and used without further purification. NMR
spectra were recorded on Varian AS 400 Mercury NMR spectrometer. pH
values were determined using a WTW inoLab pH meter at 25 °C, and
melting points measured on Gallenkamp electrothermal melting point
apparatus without correction. HRMS were carried out on Agilent 6530
Accurate-Mass Q-TOF mass spectrometer at Atatürk University East
Anatolia High Technology Application and Research Centre. Gas
chromatography (GC) analysis was performed on an Agilent 6890N gas
chromatograph with a HP-5 Agilent 19091J-413 column.
Synthesis of 2b. To a suspension of L2 (320 mg, 2.0 mmol) in
acetonitrile (10 mL) was added 2,4,6-triisopropylbenzyl bromide (653 mg,
2.2 mmol). The resulting mixture was refluxed for 12 h. After cooling to
room temperature, the solvent was evaporated. The resulting solid was
dissolved in dichloromethane (5 mL) and diethyl ether (20 mL) was
added. The colorless solid that separated out was filtered and washed
General Procedures for Synthesis of Ligands L1-L3. To a degassed
dimethyl sulfoxide (20 mL) solution of 1-H-(benz)imidazole (15.0 mmol)
was added 2-bromoanisole or 2-bromo-3-methoxynaphthalene (10.0
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10.1002/cctc.201800558
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with diethyl ether (2×20 mL) and dried under reduced pressure. Yield:
92%, 840 mg. m.p. 207 ºC. H NMR (400 MHz, CDCl3): δ = 9.55 (s, 1H,
dissolved in methanol (5 mL) and diethyl ether (20 mL) was added. The
colorless solid that separated out was filtered and washed with diethyl
ether (2×20 mL) and dried under reduced pressure. Yield: 91%, 642 mg.
m.p. 216 ºC. 1H NMR (400 MHz, DMSO-d6): δ = 11.38 (s, 1H; Ar-OH,
exchanges with D2O), 10.01 (dd, 1H, J = 1.6 Hz, NCHN+), 8.11 (dd, J =
1.6 Hz 2H, NCHCHN), 8.09 (dd, J = 1.6 Hz 2H, NCHCHN), 7.78 (s, 4H,
Ar-H), 7.54 (d, J = 8.0 Hz, 1H, Ar-H), 7.36 (d, J = 8.0 Hz, 2H, Ar-H), 7.00-
6.93 (m, 1H, Ar-H), 5.72 (s, 2H, NCH2Ar). 13C NMR (100 MHz, DMSO-
d6): δ = 151.3 (Ar-C), 139.8 (Ar-C), 137.8 (NCHN+), 131.4 (Ar-C), 129.8
(Ar-C), 129.7 (q, JC-F = 32.0 Hz), 126.2 (q, JC-F = 3.8 Hz), 126.1 (Ar-C),
125.1 (q, JC-F = 270.0 Hz), 124.3 (NCHCHN), 122.7 (NCHCHN), 122.6
(Ar-C), 119.8 (Ar-C), 117.8 (Ar-C), 51.8 (NCH2Ar). Elemental analysis:
calcd (%) for C17H14ClF3N2O: C 57.56, H 3.98, N 7.90; found: C 57.45, H
4.03, N 7.85. HRMS (APCI): calcd. m/z for C17H14F3N2O [M–Cl]+:
319.1053; found: 319.0907.
1
NCHN+), 7.64 (d, J = 8.0 Hz, 1H, Ar-H), 7.55 (s, 1H, NCHCHN), 7.32 (d,
J = 8.0 Hz, 1H, Ar-H), 7.26 (s, 1H, NCHCHN), 7.15 (t, J = 8.0 Hz, 1H, Ar-
H), 7.08 (s, 2H, Ar-H), 6.83 (t, J = 8.0 Hz, 1H, Ar-H), 5.73 (s, 2H,
NCH2Ar), 3.08 (quint, J= 6.8 Hz, 2H, ArCH(CH3)2), 2.90 (quint, J= 6.8 Hz,
1H, ArCH(CH3)2), 1.25 (d, J = 7.2 Hz, 6H, ArCH(CH3)2), 1.17 (d, J = 7.2
Hz, 12H, ArCH(CH3)2). 13C NMR (100 MHz, CDCl3): δ = 151.2 (Ar-C),
150.4 (NCHN+), 148.9 (Ar-C), 135.4 (Ar-C), 131.2 (Ar-C), 124.2
(NCHCHN), 123.1 (Ar-C), 122.2 (NCHCHN), 122.0 (Ar-C), 121.8 (Ar-C),
121.0 (Ar-C), 120.1 (Ar-C), 118.9 (Ar-C), 46.5 (NCH2Ar), 34.3
(ArCH(CH3)2), 29.8 (ArCH(CH3)2), 24.4 (ArCH(CH3)2), 23.8 (ArCH(CH3)2).
Elemental analysis: calcd (%) for C25H33BrN2O: C 65.64, H 7.27, N 6.12;
found: C 65.74, H 7.23, N 6.09. HRMS (APCI): calcd. m/z for C25H33N2O
[M–Br]+: 377.2587; found: 377.2634.
Synthesis of 2c. To a suspension of L2 (320 mg, 2.0 mmol) in
acetonitrile (10 mL) was added benzyl chloride (277 mg, 2.2 mmol). The
resulting mixture was refluxed for 4 h. After cooling to room temperature,
the solvent was evaporated. The resulting solid was dissolved in
methanol (5 mL) and diethyl ether (20 mL) was added. The colorless
solid that separated out was filtered and washed with diethyl ether (2×20
mL) and dried under reduced pressure. Yield: 88%, 506 mg. m.p. 118 ºC.
1H NMR (400 MHz, DMSO-d6): δ = 11.38 (s, 1H; Ar-OH, exchanges with
D2O), 9.94 (s, 1H, NCHN+), 8.05 (s, 2H, NCHCHN), 7.53 (d, J = 7.2 Hz,
3H, Ar-H), 7.54-7.36 (m, 5H, Ar-H), 6.97 (t, J = 8.0 Hz, 1H, Ar-H), 5.58 (s,
2H, NCH2Ar). 13C NMR (100 MHz, DMSO-d6): δ = 151.3 (Ar-C), 137.5
(NCHN+), 135.3 (Ar-C), 131.5 (Ar-C), 129.4 (Ar-C), 129.2 (Ar-C), 128.9
(Ar-C), 126.1 (Ar-C), 124.3 (NCHCHN), 122.7 (Ar-C), 122.6 (NCHCHN),
119.8 (Ar-C), 117.8 (Ar-C), 52.5 (NCH2Ar). Elemental analysis: calcd (%)
for C16H15ClN2O: C 67.02, H 5.27, N 9.77; found: C 66.88, H 5.25, N 9.69.
HRMS (APCI): calcd. m/z for C16H15N2O [M–Cl]+: 251.1184; found:
251.1168.
Synthesis of 2f. To a suspension of L2 (320 mg, 2.0 mmol) in
acetonitrile (10 mL) was added n-butyl bromide (301 mg, 2.2 mmol). The
resulting mixture was refluxed for 4 h. After cooling to room temperature,
the solvent was evaporated. The resulting solid was dissolved in
methanol (5 mL) and diethyl ether (20 mL) was added. The yellow
viscous liquid that separated out was washed with diethyl ether (2×20
mL) and dried under reduced pressure. The resulting hydroscopic liquid
was dissolved in acetone (10 mL) and KPF6 (552 mg, 3.0 mmol) was
added and the mixture was stirred for 24 h at room temperature. Upon
completion of reaction, the excess KPF6 was filtered off and the solution
was concentrated under reduced pressure. The yellow viscous liquid that
separated out was washed with diethyl ether (2×20 mL) and dried under
reduced pressure. Overall yield: 85%, 615 mg. 1H NMR (400 MHz,
DMSO-d6): δ = 10.81 (s, 1H; Ar-OH, exchanges with D2O), 9.58 (s, 1H,
NCHN+), 8.03 (dd, J = 2.0 Hz, 1H, NCHCHN), 7.99 (dd, J = 2.0 Hz, 1H,
NCHCHN), 7.52 (dd, J = 1.6 and 8.0 Hz, 1H, Ar-H), 7.40 (ddd, J = 1.6,
7.2 and 8.0 Hz, 1H, Ar-H), 7.15 (dd, J = 1.2 and 8.4 Hz, 1H, Ar-H), 7.01
(ddd, J = 1.2, 7.6 and 8.0 Hz, 1H, Ar-H), 4.27 (t, J = 7.2 Hz, 2H, NCH2Ar),
1.85 (quint, J = 7.6 Hz, 2H, CH2), 1.35-1.22 (m, 2H, CH2) 0.91 (t, J = 7.2
Hz, 3H, CH3). 13C NMR (100 MHz, DMSO-d6): δ = 151.1 (Ar-C), 137.3
(NCHN+), 131.7 (Ar-C), 126 4 (Ar-C), 124.0 (NCHCHN), 122.8 (Ar-C),
122.6 (NCHCHN), 120.1 (Ar-C), 117.6 (Ar-C), 49.4 (NCH2Ar), 31.7 (CH2),
19.3 (CH2), 13.7 (CH3). 19F NMR (376 MHz, DMSO-d6): δ = -70.21 (d, J
= 711.0 Hz). Elemental analysis: calcd (%) for C13H17F6N2OP: C 43.10, H
4.73, N 7.73; found: C 42.95, H 4.70, N 7.68. HRMS (APCI): calcd. m/z
for C13H17N2O [M–PF6]+: 217.1335; found: 217.1321.
Synthesis of 2d. To a suspension of L2 (320 mg, 2.0 mmol) in
acetonitrile (10 mL) was added 4-methoxybenzyl chloride (343 mg, 2.2
mmol). The resulting mixture was refluxed for 4 h. After cooling to room
temperature, the solvent was evaporated. The resulting solid was
dissolved in methanol (5 mL) and diethyl ether (20 mL) was added. The
colorless solid that separated out was filtered and washed with diethyl
ether (2×20 mL) and dried under reduced pressure. The resulting
hydroscopic solid was dissolved in acetone (10 mL) and KPF6 (552 mg,
3.0 mmol) was added and the mixture was stirred for 24 h at room
temperature. Upon completion of reaction, the excess KPF6 was filtered
off and the solution was concentrated under reduced pressure. The
yellow viscous liquid that separated out was washed with diethyl ether
(2×20 mL) and dried under reduced pressure. Overall yield: 81%, 690 mg.
1H NMR (400 MHz, DMSO-d6): δ = 11.12 (s, 1H; Ar-OH, exchanges with
D2O), 9.73 (s, 1H, NCHN+), 8.22 (s, 1H, NCHCHN), 7.94 (s, 1H,
NCHCHN), 7.51 (d, J = 7.6 Hz, 1H, Ar-H), 7.47 (d, J = 8.4 Hz, 2H, Ar-H),
7.38 (t, J = 7.2 Hz, 1H, Ar-H), 7.18 (d, J = 8.4 Hz, 1H, Ar-H), 6.99-6.97 (m,
3H, Ar-H), 5.43 (s, 2H, NCH2Ar), 3.75 (s, 1H, OCH3). 13C NMR (100 MHz,
DMSO-d6): δ = 160.1 (Ar-C), 151.4 (Ar-C), 137.2 (NCHN+), 131.6 (Ar-C),
130.6 (Ar-C), 127.0 (Ar-C), 126.1 (Ar-C), 124.2 (NCHCHN), 122.7 (Ar-C),
122.4 (NCHCHN), 119.8 (Ar-C), 117.7 (Ar-C), 114.8 (Ar-C), 55.7 (OCH3),
52.2 (NCH2Ar). 19F NMR (376 MHz, DMSO-d6): δ = -70.18 (d, J = 711.0
Hz). Elemental analysis: calcd (%) for C17H17F6N2O2P: C 47.90, H 4.02,
N 6.57; found: C 48.07, H 3.99, N 6.62. HRMS (APCI): calcd. m/z for
C17H17N2O2 [M–PF6]+: 281.1290; found: 281.1305.
Synthesis of 2g. To a suspension of L3 (420 mg, 2.0 mmol) in
acetonitrile (10 mL) was added 2,4,6-triisopropylbenzyl bromide (653 mg,
2.2 mmol). The resulting mixture was refluxed for 12 h. After cooling to
room temperature, the solvent was evaporated. The resulting solid was
dissolved in dichloromethane (5 mL) and diethyl ether (20 mL) was
added. The colorless solid that separated out was filtered and washed
with diethyl ether (2×20 mL) and dried under reduced pressure. Yield:
89%, 900 mg. m.p. 265 ºC. 1H NMR (400 MHz, CDCl3): δ = 10.02 (s, 1H;
Ar-OH, exchanges with D2O), 9.67 (s, 1H, NCHN+), 7.84 (s, 1H,
NCHCHN), 7.81 (s, 1H, NCHCHN), 7.63 (d, J = 8.0 Hz, 1H, Ar-H), 7.57 (s,
1H, Ar-H), 7.37 (d, J = 8.0 Hz, 1H, Ar-H), 7.24 (t, J = 7.6 Hz, 1H, Ar-H),
7.16 (t, J = 7.6 Hz, 1H, Ar-H), 7.09 (s, 2H, Ar-H), 7.07 (s, 1H, Ar-H), 5.66
(s, 2H, NCH2Ar), 3.06 (quint, J= 6.8 Hz, 2H, ArCH(CH3)2), 2.90 (quint, J=
6.8 Hz, 1H, ArCH(CH3)2), 1.25 (d, J = 6.8 Hz, 6H, ArCH(CH3)2), 1.18 (d, J
= 6.8 Hz, 12H, ArCH(CH3)2). 13C NMR (100 MHz, CDCl3): δ = 151.4 (Ar-
C), 148.9 (Ar-C), 146.9 (NCHN+), 135.8 (Ar-C), 134.5 (Ar-C), 127.8 (Ar-
C), 127.5 (Ar-C), 127.0 (Ar-C), 124.4 (NCHCHN), 123.6 (Ar-C), 123.4
(Ar-C), 123.3 (Ar-C), 122.2 (NCHCHN), 122.0 (Ar-C), 120.7 (Ar-C), 113.2
(Ar-C), 46.4 (NCH2Ar), 34.3 (ArCH(CH3)2), 29.9 (ArCH(CH3)2), 24.3
(ArCH(CH3)2), 23.8 (ArCH(CH3)2). Elemental analysis: calcd (%) for
C29H35BrN2O: C 68.63, H 6.95, N 5.52; found: C 68.79, H 7.01, N 5.49.
Synthesis of 2e. To a suspension of L2 (320 mg, 2.0 mmol) in
acetonitrile (10 mL) was added 4-(trifluoromethyl)benzyl chloride (428 mg,
2.2 mmol). The resulting mixture was refluxed for 4 h. After cooling to
room temperature, the solvent was evaporated. The resulting solid was
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10.1002/cctc.201800558
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FULL PAPER
HRMS (APCI): calcd. m/z for C29H35N2O [M–Br]+: 427.2744; found:
427.2782.
3d. Yield: 94%, 301 mg. 1H NMR (400 MHz, CDCl3): δ = 7.46 (dd, J = 6.8
Hz, 2H, Ar-H), 7.36 (d, J = 2.0 Hz, 1H, NCHCHN), 7.12 (dd, J = 8.0 Hz,
1H, Ar-H), 7.05-6.98 (m, 2H, Ar-H), 6.89 (dd, J = 6.8 Hz, 2H, Ar-H), 6.75
(d, J = 2.0 Hz, 1H, NCHCHN), 6.57-6.53 (m, 1H, Ar-H), 5.79 (d, J = 14.0
Hz, 1H, NCH2Ar), 4.93 (d, J = 14.0 Hz, 1H, NCH2Ar), 3.80 (s, 1H, OCH3)
1.52 (s, 15H, C5(CH3)5). 13C NMR (100 MHz, CDCl3): δ = 161.0 (Ar-C),
160.8 (Ar-C), 159.7 (Ir-C), 130.6 (Ar-C), 127.4 (Ar-C), 127.0 (Ar-C), 122.4
(Ar-C), 121.2 (Ar-C), 119.0 (Ar-C), 117.5 (NCHCHN), 115.2 (NCHCHN),
114.2 (Ar-C), 87.6 (C5(CH3)5), 55.3 (NCH2Ar), 53.6 (OCH3), 8.8
(C5(CH3)5). Elemental analysis: calcd (%) for C27H30ClIrN2O2: C 50.50, H
4.71, N 4.36; found: C 50.31, H 4.77, N 4.43.HRMS (APCI): calcd. m/z
for C27H30IrN2O2 [M–Cl]+: 607.1937; found: 607.1929.
General Procedures for Synthesis of Complexes 3a-g.Under an
argon atmosphere, a mixture of 2a-g (0.5 mmol) and Ag2O (232 mg, 1.0
mmol) was suspended in degassed and dry dichloromethane (5 mL) and
stirred at ambient temperature for 2 h shielded from light. [IrCp*Cl2]2 (198
mg, 0.25 mmol) was then added to the suspension and the reaction
mixture was stirred at ambient temperature for additional 2 h. The
resulting suspension was filtered over Celite®. The remaining solid was
washed with dichloromethane (2×5 mL) and the solvent of the filtrate was
evaporated. The residue was purified via column chromatography on
silica gel with dichloromethane:methanol (9:1) as eluent, affording a
yellow powder.
3e. Yield: 88%, 298 mg. 1H NMR (400 MHz, CDCl3): δ = 7.64-7.59 (m,
4H, Ar-H), 7.41 (d, J = 2.0 Hz, 1H, NCHCHN), 7.13 (d, J = 7.6 Hz, 1H,
Ar-H), 7.02-6.99 (m, 2H, Ar-H), 6.71 (d, J = 2.0 Hz, 1H, NCHCHN), 6.58-
6.54 (m, 1H, Ar-H), 5.86 (d, J = 14.4 Hz, 1H, NCH2Ar), 5.07 (d, J = 14.4
Hz, 1H, NCH2Ar), 1.50 (s, 15H, C5(CH3)5). 13C NMR (100 MHz, CDCl3):
δ = 161.0 (Ir-C), 139.6 (Ar-C), 130.4 (q, JC-F = 33.0 Hz), 129.3 (Ar-C),
127.2 (Ar-C), 125.7 (q, JC-F = 4.0 Hz), 124.7 (q, JC-F = 270.0 Hz), 122.5
(Ar-C), 121.2 (Ar-C), 119.0 (Ar-C), 118.1 (NCHCHN), 115.4 (NCHCHN),
87.8 (C5(CH3)5), 53.7 (NCH2Ar), 8.8 (C5(CH3)5). Elemental analysis: calcd
(%) for C27H27ClF3IrN2O: C 47.68, H 4.00, N 4.12; found: C 47.61, H 3.98,
N 4.07. HRMS (APCI): calcd. m/z for C27H27F3IrN2O [M–Cl]+: 645.1705;
found: 645.1325.
3a. Yield: 91%, 358 mg. 1H NMR (400 MHz, CDCl3): δ = 7.88 (d, J = 8.0
Hz, 1H, Ar-H), 7.55 (d, J = 8.0 Hz, 1H, Ar-H), 7.16-7.05 (m, 5H, Ar-H),
6.787-6.72 (m, 2H, NCH2Ar+Ar-H), 6.67 (t, J = 8.0 Hz, 1H, Ar-H), 5.84 (d,
J = 8.8 Hz, 1H, Ar-H), 5.34 (d, J = 14.4 Hz, 1H, NCH2Ar), 3.39 (quint, J=
6.4 Hz, 1H, ArCH(CH3)2), 3.25 (quint, J= 6.4 Hz, 1H, ArCH(CH3)2), 3.01
(quint, J= 6.4 Hz, 1H, ArCH(CH3)2), 1.57 (s, 15H, C5(CH3)5), 1.34 (d, J =
6.8 Hz, 9H, ArCH(CH3)2), 1.25 (d, J = 6.8 Hz, 3H, ArCH(CH3)2), 1.19 (d, J
= 6.8 Hz, 3H, ArCH(CH3)2), 0.79 (d, J = 6.8 Hz, 3H, ArCH(CH3)2). 13C
NMR (100 MHz, CDCl3): δ = 175.9 (Ir-C), 163.8 (Ar-C), 151.8 (Ar-C),
150.5 (Ar-C), 148.2 (Ar-C), 135.9 (Ar-C), 132.3 (Ar-C), 130.2 (Ar-C),
127.0 (Ar-C), 125.6 (Ar-C), 122.7 (Ar-C), 122.5 (Ar-C), 122.3 (Ar-C),
122.3 (Ar-C), 121.6 (Ar-C), 120.9 (Ar-C), 114.8 (Ar-C), 112.4 (Ar-C), 88.4
(C5(CH3)5), 48.6 (NCH2Ar), 34.4 (ArCH(CH3)2), 30.3 (ArCH(CH3)2), 29.3
(ArCH(CH3)2), 25.9 (ArCH(CH3)2), 25.4 (ArCH(CH3)2), 24.1 (ArCH(CH3)2),
1
3f. Yield: 83%, 240 mg. H NMR (400 MHz, CDCl3): δ = 7.36 (d, J = 2.0
Hz, 1H, NCHCHN), 7.08 (d, J = 8.0 Hz, 1H, Ar-H) 7.02-6.97 (m, 3H,
NCHCHN + Ar-H), 6.54-6.51 (m, 1H, Ar-H), 4.32-4.25 (m, 1H, NCH2Ar),
3.88-3.81 (m, 1H, NCH2Ar), 1.98-1.94 (m, 1H, CH2), 1.74-1.64 (m, 1H,
CH2), 1.51-1.37 (m, 2H, CH2), 1.49 (s, 15H, C5(CH3)5), 0.98 (t, J = 7.6 Hz,
3H, CH3). 13C NMR (100 MHz, CDCl3): δ = 160.9 (Ir-C), 160.8 (Ar-C),
130.6 (Ar-C), 126.9 (Ar-C), 122.3 (Ar-C), 120.8 (Ar-C), 119.0 (Ar-C),
117.7 (NCHCHN), 115.2 (NCHCHN), 87.3 (C5(CH3)5), 50.5 (NCH2Ar),
33.0 (CH2), 20.3 (CH2), 13.4 (CH3), 8.7 (C5(CH3)5). Elemental analysis:
calcd (%) for C23H30ClIrN2O: C 47.78, H 5.23, N 4.85; found: C 47.93, H
23.1 (ArCH(CH3)2), 23.0 (ArCH(CH3)2),
8.8 (C5(CH3)5). Elemental
analysis: calcd (%) for C39H48ClIrN2O: C 59.41, H 6.14, N 3.55; found: C
59.27, H 6.20, N 3.61. HRMS (APCI): calcd. m/z for C39H49ClIrN2O
[M+H]+: 789.3163; found: 789.3153.
3b. Yield: 92%, 342 mg. 1H NMR (400 MHz, CDCl3): δ = 7.26 (d, J = 2.0
Hz, 1H, NCHCHN), 7.14-7.11 (m, 3H, Ar-H), 7.05-6.99 (m, 2H, Ar-H),
6.57-6.53 (m, 1H, Ar-H), 6.47 (d, J = 2.0 Hz, 1H, NCHCHN), 6.23 (d, J =
14.4 Hz, 1H, NCH2Ar), 4.99 (d, J = 14.4 Hz, 1H, NCH2Ar), 3.23 (quint, J=
6.4 Hz, 1H, ArCH(CH3)2), 3.02 (quint, J= 6.4 Hz, 1H, ArCH(CH3)2), 2.94
(quint, J= 6.4 Hz, 1H, ArCH(CH3)2), 1.54 (s, 15H, C5(CH3)5), 1.31 (d, J =
6.8 Hz, 12H, ArCH(CH3)2), 1.24 (d, J = 6.8 Hz, 3H, ArCH(CH3)2), 1.07 (d,
J = 6.8 Hz, 3H, ArCH(CH3)2). 13C NMR (100 MHz, CDCl3): δ = 161.0 (Ar-
C), 159.5 (Ir-C), 150.9 (Ar-C), 150.1 (Ar-C), 148.0 (Ar-C), 130.6 (Ar-C),
127.0 (Ar-C), 125.1 (Ar-C), 122.5 (Ar-C), 122.3 (Ar-C), 120.9 (Ar-C),
120.6 (NCHCHN), 119.0 (Ar-C), 115.9 (NCHCHN), 115.1 (Ar-C), 87.5
(C5(CH3)5), 46.4 (NCH2Ar), 30.1 (ArCH(CH3)2), 29.2 (ArCH(CH3)2), 25.6
(ArCH(CH3)2), 25.4 (ArCH(CH3)2), 24.0 (ArCH(CH3)2), 23.3 (ArCH(CH3)2),
23.1 (ArCH(CH3)2), 8.9 (C5(CH3)5). Elemental analysis: calcd (%) for
C35H46ClIrN2O: C 56.93, H 6.28, N 3.79; found: C 57.04, H 6.21, N 3.84.
HRMS (APCI): calcd. m/z for C35H46IrN2O [M–Cl]+: 703.3239; found:
703.3235.
5.30,
N
4.83. HRMS (APCI): calcd. m/z for C23H30IrN2O [M–Cl]+:
543.1987; found: 543.1974.
3g. Yield: 93%, 365 mg. 11H NMR (400 MHz, CDCl3): δ = 7.65-7.59 (m,
3H, Ar-H), 7.40 (d, J = 2.4 Hz, 1H, NCHCHN), 7.33-7.29 (m, 2H, Ar-H),
7.15-7.11 (m, 3H, Ar-H), 6.54 (d, J = 2.4 Hz, 1H, NCHCHN), 6.30 (d, J =
14.4 Hz, 1H, NCH2Ar), 4.93 (d, J = 14.4 Hz, 1H, NCH2Ar), 3.35 (quint, J=
6.4 Hz, 1H, ArCH(CH3)2), 3.03 (quint, J= 6.4 Hz, 1H, ArCH(CH3)2), 2.95
(quint, J= 6.4 Hz, 1H, ArCH(CH3)2), 1.57 (s, 15H, C5(CH3)5), 1.33-1.30 (m,
12H, ArCH(CH3)2), 1.26 (d, J = 6.8 Hz, 3H, ArCH(CH3)2), 1.10 (d, J = 6.8
Hz, 3H, ArCH(CH3)2). 13C NMR (100 MHz, CDCl3): δ = 161.0 (Ar-C),
159.5 (Ir-C), 150.9 (Ar-C), 150.2 (Ar-C), 148.0 (Ar-C), 134.2 (Ar-C), 133.6
(Ar-C), 127.0 (Ar-C), 126.0 (Ar-C), 125.6 (Ar-C), 125.4 (Ar-C), 124.9
(Ar-C), 122.4 (Ar-C), 121.7 (Ar-C), 121.0 (Ar-C), 120.8 (NCHCHN),
117.0 (Ar-C), 116.9 (Ar-C), 115.3 (NCHCHN), 87.6 (C5(CH3)5), 46.4
(NCH2Ar), 34.4 (ArCH(CH3)2), 30.1 (ArCH(CH3)2), 29.2 (ArCH(CH3)2),
25.7 (ArCH(CH3)2), 25.4 (ArCH(CH3)2), 24.0 (ArCH(CH3)2), 23.3
(ArCH(CH3)2), 23.2 (ArCH(CH3)2), 8.9 (C5(CH3)5). Elemental analysis:
calcd (%) for C39H48ClIrN2O: C 59.41, H 6.14, N 3.55; found: C 59.49, H
3c. Yield: 86%, 262 mg. 1H NMR (400 MHz, CDCl3): δ = 7.48 (d, J = 6.8
Hz, 2H, Ar-H), 7.37-7.30 (m, 4H, NCHCHN+ Ar-H), 7.13 (d, J = 7.6 Hz,
1H, Ar-H), 7.04-6.98 (m, 2H, Ar-H), 6.76 (d, J = 2.0 Hz, 1H, NCHCHN),
6.57-6.53 (m, 1H, Ar-H), 5.76 (d, J = 14.4 Hz, 1H, NCH2Ar), 5.09 (d, J =
14.4 Hz, 1H, NCH2Ar), 1.50 (s, 15H, C5(CH3)5). 13C NMR (100 MHz,
CDCl3): δ = 161.3 (Ir-C), 161.0 (Ar-C), 135.5 (Ar-C), 130.6 (Ar-C), 129.0
(Ar-C), 128.8 (Ar-C), 128.3 (Ar-C), 127.0 (Ar-C), 122.3 (Ar-C), 121.5 (Ar-
C), 119.1 (Ar-C), 117.7 (NCHCHN), 115.3 (NCHCHN), 87.7 (C5(CH3)5),
54.2 (NCH2Ar), 8.8 (C5(CH3)5). Elemental analysis: calcd (%) for
C26H28ClIrN2O: C 51.01, H 4.61, N 4.58; found: C 50.83, H 4.53, N 4.52.
HRMS (APCI): calcd. m/z for C26H28ClIrN2O [M]: 612.1519; found:
612.1516.
6,08,
N
3.58. HRMS (APCI): calcd. m/z for C39H48IrN2O [M–Cl]+:
753.3396; found: 753.3398.
Typical procedure for the transfer hydrogenative RA in water. A
reaction tube was charged with a magnetic stirrer bar, p-anisidine (1.5
mmol for ketones and 2.5 mmol for aldehydes), and ketone (1.0 mmol) or
aldehyde (2.5 mmol), followed by catalyst (0.5 mol% or 0.02 mol%). To
the mixture was injected a water solution of HCOOH/HCOONa (1.6 mL
for ketones and 4.0 mL for aldehydes, pH 4.8). The resulting mixture was
This article is protected by copyright. All rights reserved.

10.1002/cctc.201800558
ChemCatChem
FULL PAPER
stirred at 1200 rpm at 50 °C for 8-16 h under N2 or open air. After cooling
to room temperature, the solution was adjusted to pH 2-3 with HCl (4 M),
stirred for 10 min and then basified with aqueous NaOH (6 M) to pH 9-10.
The resulting solution was extracted with ethyl acetate (or with diethyl
ether for aliphatic ketones) and dried over anhydrous MgSO4. After
evaporating of the solvent, the product was purified by flash column
chromatography (hexane:ethyl acetate, 20:1-10:1).
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Kinetic measurements. The initial rates (conversions <20%) of
reactions were calculated by extrapolating the conversion of
acetophenone to the starting point of a RA reaction. The conversions
were measured when the concentration of one of HCOOH/HCOONa,
catalyst (3g) and substrate was varied. Variation of [HCOOH/HCOONa]:
A Radley tube with a stirrer bar under air atmosphere, charged with
catalyst 3g (0.0025 mmol), acetophenone (0.5 mmol), p-anisidine (0.5
mmol), HCOOH/HCOONa (0.25, 0.5, 1.0, 1.5 and 2.0 mL, pH = 4.8, 10
mol L-1) and distilled water (volume varied with the volume of
HCOOH/HCOONa used, with the total volume of the mixture being 2 mL),
and the reaction mixture was stirred at 50 ºC for 1 h. After cooling to
room temperature, the solution was adjusted to pH 2-3 with HCl (4 M),
stirred for 10 min and then basified with aqueous NaOH (6 M) to pH 9-10.
The resulting solution was extracted with ethyl acetate and dried over
anhydrous MgSO4 and subjected to GC analysis to obtain the
conversions. Variation of [catalyst] was also done similarly: A Radley
tube with a stirrer bar under air atmosphere, charged with catalyst 3g
(0.0005, 0.00125, 0.0025, 0.005 and 0.001 mmol), acetophenone (0.5
mmol), p-anisidine (0.5 mmol) and HCOOH/HCOONa (1.0 mL, pH = 4.8,
10 mol L-1) and the reaction mixture was stirred at 50 ºC for 1 h. After
similar work-up the crude product was subjected to GC analysis to obtain
the conversions. Variation of [substrate] was done similarly: A Radley
tube with a stirrer bar under air atmosphere, charged with catalyst 3g
(0.0025 mmol), acetophenone (0.25, 0.5, 0.75, 1.0 and 1.25 mmol), p-
anisidine (0.25, 0.5, 0.75, 1.0 and 1.25 mmol) and HCOOH/HCOONa
(1.0 mL, pH = 4.8, 10 mol L-1) and the reaction mixture was stirred at 50
ºC for 1 h. After similar work-up the crude product was subjected to GC
analysis to obtain the conversions.
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X-ray crystallography. Details of data collection and refinement are
presented as Supporting Information (Table S1). CCDC 1813525-
1813530 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
The authors thank to The Scientific and Technological Research
Council of Turkey (TUBITAK, Grant Number: 216Z067), Ege
University (Grant Numbers: 2016FEN048 and 2017FEN065)
and The Turkish Academy of Science (TUBA) for the financial
support. We gratefully acknowledge to Dr. Stephanie Yip for
helpful discussions. The authors also acknowledge Dokuz Eylül
University for the use of the Agilent Xcalibur Eos diffractometer
(Grant Number: 2010.KB.FEN.13).
Keywords: N-heterocyclic carbene • iridium • reductive
amination • kinetic • mechanism
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10.1002/cctc.201800558
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Aqueous transfer hydrogenative
reductive amination (RA) reaction
between carbonyls and amines was
achieved with oxygen-tethered
Cp*IrIII-NHC catalysts with turnover
numbers (TONs) up to 14800 and
mechanism of RA reaction has
been investigated by NMR
İbrahim Kayahan Özbozkurt, Derya
Gülcemal, Salih Günnaz, Aytaç Gürhan
Gökçe, Bekir Çetinkaya, Süleyman
Gülcemal, *
Page No. – Page No.
Enhanced Catalytic Activity of
Oxygen-Tethered IrIII NHC Complexes
in Aqueous Transfer Hydrogenative
Reductive Amination Reactions:
Experimental Kinetic and Mechanism
Study
spectroscopy and kinetic
measurements.
This article is protected by copyright. All rights reserved.