Synthesis of NHC-Iridium(III) Complexes Based on N-Iminoimidazolium Ylides and Their Use for the Amine Alkylation by Borrowing Hydrogen Catalysis

Article abstract of DOI:10.1021/acs.organomet.0c00726

Anionic NHC ligands recently developed in our group, derived from N-iminoimidazolium ylides, were used to synthesize NHC-iridium(III) complexes. Their catalytic activities were evaluated in the amine alkylation of anilines using borrowing hydrogen catalysis. The high-yielding synthesis of a small library of complexes allowed a rapid screening of the ideal steric bulk of the NHC unit and basicity of the anionic tether for the investigated model reaction. A bulky aromatic N group on the imidazolidene moiety is required to achieve high catalytic activity, and the latter is proportional to the basicity of the anionic group. A selected substrate scope of the reaction was performed, providing fair to excellent yields of the desired alkylated anilines.

Full text of DOI:10.1021/acs.organomet.0c00726

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Article
Synthesis of NHC-Iridium(III) Complexes Based on
N‑Iminoimidazolium Ylides and Their Use for the Amine Alkylation
by Borrowing Hydrogen Catalysis
́
Vincent Guerin and Claude Y. Legault*
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ABSTRACT: Anionic NHC ligands recently developed in our
group, derived from N-iminoimidazolium ylides, were used to
synthesize NHC-iridium(III) complexes. Their catalytic activities
were evaluated in the amine alkylation of anilines using borrowing
hydrogen catalysis. The high-yielding synthesis of a small library of
complexes allowed a rapid screening of the ideal steric bulk of the
NHC unit and basicity of the anionic tether for the investigated
model reaction. A bulky aromatic N group on the imidazolidene
moiety is required to achieve high catalytic activity, and the latter is
proportional to the basicity of the anionic group. A selected substrate scope of the reaction was performed, providing fair to excellent
yields of the desired alkylated anilines.
Scheme 1. Binding Mode Attainable with the N-
Iminoimidazolium Ylides
INTRODUCTION
■
Ligand design in organometallic chemistry has contributed
deeply to the development of powerful methodologies now
considered staple tools for any synthetic chemist.1 Notably, the
development of N-heterocyclic carbenes (NHCs) as potent L-
type ligands had a tremendous effect on homogeneous
catalysis.2 They can be easily synthesized and provide a wide
range of steric and electronic properties. They tend to provide
strong σ donation and important steric shielding, resulting in
complexes with higher stability to light and moisture in
comparison to their phosphine counterparts.3 NHCs can also
present various additional functions that can be modified to
obtain exquisitely tailored ligands for specific tasks.4 In this
class, anionic NHC ligands have shown great potential. Due to
their hard and soft ligation sites, they can provide complexes
which are more stable than those of their neutral counterparts
with specific metals.5 Their chelation potential was also
exploited to access high stereoinduction in stereoselective
methodologies.6
Our group has been involved in ligand design, and we
previously have reported two families of anionic NHC ligands
based on N-acyliminoimidazolium ylides (A)7 and N-
sulfonyliminoimidazolium ylides (B).8 The unique properties
of A revolve around the delocalization of the negative charge in
the exocyclic group (Scheme 1a). In contrast, this delocaliza-
tion is prevented in the case of B (Scheme 1b).9 We were to
use this tunable parameter to achieve topological control in
metal complex formation. Our goal is now to investigate the
behaviors of these unique anionic groups in cooperative
catalysis,10 to ultimately develop synthetic methodologies with
lower environmental impact.11 In this context, we found the
Received: November 13, 2020
Published: January 13, 2021
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concept of borrowing hydrogen catalysis (BHC) especially
appealing, as it allows for complex synthetic transformations
with minimal steps and maximum atom economy.12
investigation on iridium-based complexes, as these types of
catalysts have a wide diversity of applications.24,25 Hence, we
report herein the synthesis of a variety of new iridium(III)
complexes based on the N-iminoimidazolium ylides and the
evaluation of their catalytic properties in the face of their steric
and electronic properties, as well as a selected scope study
using the optimal catalyst.
In this type of chemistry, the N-alkylation of amines using
BHC is particularly important, as it provides fast access to
useful intermediates for the pharmaceutical industry.13
Complex N-alkylated amines can be formed from abundant
and readily available alcohol substrates, with only water as a
byproduct. This approach thus greatly reduces the environ-
mental impact of such transformation, in comparison to
classical reductive amination.14 This strategy calls for
cooperation of the metal center and the ligand and has three
steps (Scheme 2): (1) oxidation of an alcohol moiety by the
RESULTS AND DISCUSSION
■
Proligand Synthesis. We focused on the formation of a
small library of ylide proligands that would provide a good
exploration of the steric and electronic properties of both the
NHC unit and the anionic tether, respectively. To explore the
effect of delocalization on the exocyclic anionic group, we
synthesized proligands from both the N-acyl- and N-
sulfonyliminoimidazolium ylide families. They are easily
synthesized in two steps from the corresponding imidazoles.
The synthesis of salts 5 is performed by electrophilic amination
of the corresponding imidazoles, using the reagent O-(2,4-
dinitrophenyl)hydroxylamine (4; H2NODNP).26 The method
provides high yields of the N-amino salts (DNPO− = 2,4-
dinitrophenolate) for a variety of imidazoles (Scheme 3).
These salts were converted to the desired N-acyliminoimida-
zolium ylides by reaction with numerous electrophiles; the
results are summarized in Table 1.
Scheme 2. Amine Alkylation Using Borrowing Hydrogen
Catalysis
Scheme 3. Synthesis of N-Aminoimidazolium Salts
metal center, (2) bond formation between the resulting
carbonyl intermediate and a coupling partner (e.g., amine,
enolate), and (3) reduction of the coupling product by the
hydrogenated complex, regenerating the active catalyst.
Numerous ligand scaffolds have been explored to achieve
this transformation. They have relied on various elements,
from heavier metals (Ir,15 Ru16) to first-row transition metals
(Ni,17 Co,18 Fe,19 Mn20). More recently, enantioselective,21
solvent-free,22 and aqueous reactions23 variants have been
developed. Two representative NHC-based iridium(III)
complexes that were found to be efficient catalysts for the
amine alkylation by BHC are presented in Figure 1. Complex
Table 1. Synthesis of N-Acyliminoimidazolium Ylides
a
entry
R1
R2
ylide
yield (%)
b
1
2
3
4
5
6
7
Mes
Mes
Mes
Mes
Ph
CF3
Ph
4-OMe-C6H4
OEt
Ph
Ph
6a
6b
6c
6d
6e
6f
100
95
c
94
d
39
100
79
84
n-Bu
t-Bu
Figure 1. Representative NHC-based iridium(III) catalysts.
Ph
6g
a
b
Isolated yield. Reaction performed using TFAA as the electrophile.
c
d
Reaction performed on a 2.6 mmol (1 g) scale. The electrophile
(ethyl chloroformate) was used as the solvent.
1, reported by Martin-Matute and co-workers,15b allows access
́
to various alkylated amines in excellent yields, even at the low
temperature of 50 °C. The water-soluble complex 2, reported
by Ke and co-workers,23d was found to promote amine
alkylation in water.
As illustrated in Scheme 2, an LX-type functional ligand is of
particular interest for this type of cooperative catalysis. We
envisioned that our ylide-derived anionic NHC ligands
presented all the required characteristic to form complexes
able to undertake this type of catalysis. We focused our
This convergent synthesis provides rapid access to a variety
of proligands in usually good yields. The reaction is portable to
the gram scale (Table 1, entry 3). One exception was observed
for the formation of the carbamate-derived ylide 6d. In this
case, the usual reaction conditions proved to be unsatisfactory,
as no desired ylide was isolated.
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Fortunately, conditions using ethyl chloroformate as the
solvent and a reaction time of 16 h gave the desired product
with 39% yield (Table 1, entry 4). These ylides were selected
to explore the steric effect of the imidazole R1 group as well as
evaluate the influence of the basicity and binding mode of the
exocyclic anionic group on the catalytic activity of the resulting
complexes in the borrowing hydrogen methodology.
Table 2. Formation of the NHC-Iridium(III) Complexes
from the N-Acyliminoimidazolium Ylides
a
Four R1 groups were selected (n-Bu (6f), t-Bu (6g), Ph
(6e), and Mes (6a)), as they represent aromatic and aliphatic
groups with widely different steric profiles. For these ylides, the
benzoyl group (R2 = Ph) was selected as a reference on the
exocyclic anionic tether. To modulate the basicity of the
anionic tether, four R2 groups (CF3 (6a), Ph (6b), 4-OMe-
C6H4 (6c), and OEt (6d)) were selected. For these ylides,
2,4,6-trimethylphenyl (Mes) was selected as a reference R1
group, due to the ease of access and purification of the
resulting ylides. Finally, we synthesized the N-sulfonyliminoi-
midazolium ylide 7 (eq 1), to evaluate the effect of charge
localization of the negative charge on the exocyclic nitrogen.
b
entry
R1
R2
[Ir]Cl (%)
X
[Ir]X (%)
1
2
3
4
5
6
7
8
Mes
Mes
Mes
Mes
Mes
Mes
Mes
Mes
Ph
CF3
Ph
8a, 100
8b, 100
SbF6
SbF6
BF4
SbF6
PF6
TfO
BArF
SbF6
SbF6
SbF6
9a, 90
9b, 83
9c, 98
9d, 93
9e, 98
9f, 97
9g, 74
9h, 72
9i, 89
9j, 92
4-MeO-C6H4
4-MeO-C6H4
4-MeO-C6H4
4-MeO-C6H4
4-MeO-C6H4
OEt
8c, 74 (81)
c
8d, 44
9
10
11
Ph
Ph
Ph
8e, 38 (88)
8f, 26 (99)
8g, 81
n-Bu
t-Bu
a
Method A: (i) ylide 6a−g (1 equiv), Ag2O (1 equiv), CHCl3, rt, 48
h; (ii) crude silver complex (1 equiv), [IrCp*Cl2]2 (0.5 equiv), 35 °C,
4 h. Method B: (1) Ylide 6a−g (1 equiv), LiHMDS 1 M in THF (1.2
equiv), CH2Cl2, 0 °C, 1 h; (2) [IrCp*Cl2]2 (0.8 equiv), CH2Cl2, rt,
Synthesis of Iridium Complexes. We have previously
reported that silver complexes from the corresponding N-
iminoimidazolium ylides are efficient ligand transfer agents to
halogenated transition metals.7,8 Consequently, we investigated
their use for the synthesis of the necessary iridium(III)
complexes; the results are illustrated in Table 2. Their
b
24 h. Yields obtained using method A, yields in parentheses obtained
c
using method B, if applicable. BArF = tetrakis[3,5-bis-
(trifluoromethyl)phenyl]borate.
The iridium(III) chloride complex 10, derived from N-
sulfonyliminoimidazolium ylide 7, was obtained in good yield
using method A described in Table 2 (Scheme 4a).
Unfortunately, formation of the cationic analogue 11 using
silver hexafluoroantimonate proved problematic, as the
reaction provided a complex mixture upon isolation,
preventing proper characterization. Furthermore, we were
not able to obtain crystals of 10 suitable for X-ray analysis; we
thus could not determine the precise mode of binding of the
anionic tether. These issues with the isolation of 11 and the
structural determination of 10 led us to focus on the
investigation of the catalytic activity of iridium(III) complexes
derived from ylides 6a−g.
Due to the experimental challenges in confirming the nature
of complex 10, we resorted to computational chemistry to gain
structural insights. We modeled the opened monomer (10),
chelating monomer (12a), the chloride-bridging dimer (12b),
and the exocyclic nitrogen-bridging dimer (12c) using DFT
calculations;28 the results are illustrated in Scheme 4b. The
open-form isomer 10 was found to be the thermodynamically
most stable species, followed by the chelating monomeric form
12a. This might seem surprising, but the optimized structure of
10 suggests that the exocyclic nitrogen is providing donation to
the iridium center; its representation in Scheme 4 reflects this.
While the solvation model does not have a major effect on the
relative energies of 10 vs 12a or 12b, it strongly affects the
stability of 12c; gas-phase calculations suggest that this dimer
is favored by 5.6 kcal/mol.
1
characterization and purity were established by H NMR and
13C NMR spectroscopy and by HRMS.
The silver complexes are fairly stable to light and moisture,
but they tend to degrade slowly over time. For this reason, the
crude silver complexes were used directly for the trans-
metalation step. Adding the commercially available
pentamethylcyclopentadienyliridium(III) chloride dimer
([Cp*IrCl2]2) to a solution of the crude silver complexes
provided in most cases the desired NHC-iridium(III)
complexes in high yields (Table 2, entries 1−3 and 11).
However, this method proved problematic for the synthesis
using ylides with less bulky R1 groups (Table 2, entries 9 and
10), as the resulting silver complexes were insoluble in most
organic solvents. Furthermore, while the reaction was func-
tional for the other ylides, the formation of silver complexes
took at least 48 h of reaction time. Consequently, we
investigated a more direct formation method of the iridium-
(III) complexes. We envisioned that we could deprotonate the
imidazolium ring of the ylides and form the iridium complexes
in one pot by addition of the resulting free carbene on the
iridium source. Several bases were tested, such as inorganic
bicarbonate and carbonate salts, NaH, and triethylamine.
Unfortunately, they all resulted in only low conversions of the
ylides to their iridium(III) complexes, making purification
difficult. However, we were able to achieve complete
conversions using the slow addition of LiHMDS over the
ylides at 0 °C. It is theorized that NHC-Li complexes are
formed, leading to stable species.27 To these putative
complexes were added [Cp*IrCl2]2, yielding the desired
NHC-iridium(III) complexes in 2−12 h.
Most complexes are easily recrystallized, and crystals suitable
for X-ray analysis were obtained for iridium(III) chloride
complexes 8a−c,e,f. As expected, all complexes were
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Scheme 4. (a) Synthesis of the NHC-Iridium(III) Complex
Derived from 7 and (b) Relative Energies (kcal/mol) of
Different Structural States of Complex 10
Figure 3. ORTEP plot of complex 8b. Ellipsoids are drawn at the 30%
probability level. Selected distances (Å) and angles (deg): C1−N1
1.376(11), C1−N2 1.376(10), N2−N3 1.403(10), C13−N3 1.309(11),
C13−O1 1.272(10), Ir1−O1 2.113(5), C1−Ir1 2.042(8), Ir1−Cl1
2.421(2), C1−Ir1−O1 85.7(3).
Figure 4. ORTEP plot of complex 8c. Ellipsoids are drawn at the 30%
probability level. Selected distances (Å) and angles (deg): C19−N3
1.379(6), C19−N2 1.363(6), N1−N2 1.406(5), C11−N1 1.303(6),
C11−O1 1.282(6), Ir1−O1 2.123(3), C19−Ir1 2.031(5), Ir1−Cl1
2.123(3), C19−Ir1−O1 84.85(15).
monomeric in nature and displayed chelation of the anionic
NHC ligands.
Interestingly, the geometrical features of all the complexes
were very similar, despite the different steric properties of R1
and the electronic properties of the R2 group. In particular,
almost identical bond lengths on the exocyclic anionic groups
were observed between complex 8a (Figure 2) vs 8b,c (Figures
3 and 4), despite the different expected basicity profiles.
(118.2°) and a much smaller O4−Ir1−C1 angle (89.9°). The
chloride atom is also influenced by the Cp* ring, with an
observed C11−Ir1−Cl1 angle of 87.3°. Similar values were
found in complexes 8b,c. The large steric repulsion between
1
the mesityl group and Cp* ligand is further supported by H
NMR spectroscopy, as the two o-methyl substituents on the
mesityl group are found to be nonequivalent.
In contrast, when the R1 group is replaced by a much less
bulky N-substituent, such as a phenyl moiety in complex 8e
(Figure 5) or a n-butyl chain in complex 8f (Figure 6), we
notice numerous structural rearrangements. First there is a
Figure 2. ORTEP plot of complex 8a. Ellipsoids are drawn at the 30%
probability level. Selected distances (Å) and angles (deg): C11−N1
1.367(3), C11−N2 1.367(3), N2−N3 1.401(3), C23−N3 1.282(3),
C23−O4 1.276(3), Ir1−O4 2.1229(16), C11−Ir1 2.047(2), Ir1−Cl1
2.4031(7), C11−Ir1−O4 85.41(8), C11−Ir1−C3 118.16(9), O4−Ir1−C1
89.89(8), C11−Ir1−Cl1 87.25(6).
The N−N bond lengths of 1.40−1.41 Å are characteristic of
single bonds, suggesting mostly no endocyclic resonance in the
imidazole ring, meaning that the anionic charge is localized on
the exocyclic tether.
As could be expected, the presence of a mesityl group on the
NHC introduced steric repulsion with the Cp* ligand.
Accordingly, we noticed a fairly large C11−Ir1−C3 angle
Figure 5. ORTEP plot of complex 8e. Ellipsoids are drawn at the 30%
probability level. Selected distances (Å) and angles (deg): C11−N3
1.368(4), C11−N2 1.357(4), N1−N2 1.400(4), C20-N1 1.306(4), C20-
O1 1.288(4), Ir1−O1 2.122(2), C11−Ir1 2.018(3), Ir1−Cl1 2.4001(8),
C11−Ir1−O1 82.88(10), C11−Ir1−C1 113.12(12), O1−Ir1−C4
95.10(11).
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evaluate their catalytic activity in the amine alkylation of
anilines. We selected as a model reaction for our optimization
the use of an equimolar mixture of benzyl alcohol 13 and
aniline 14 as substrates, using a 2 mol % catalyst loading, and
1,2-dichloroethane (DCE) as the reaction solvent. We
investigated the effect of the counterion on catalytic activity
using the cationic complexes 9c−g, all derived from ylide 6c;
the results are summarized in Table 3. All of the reaction
Table 3. Investigation of the Counterion Effect on Catalytic
a
Activity
Figure 6. ORTEP plot of complex 8f. Ellipsoids are drawn at the 30%
probability level. The atoms in blue represent the alternative Cp*
conformation found in the crystal structure. Selected distances (Å)
and angles (deg): C1−N1 1.350(9), C1−N2 1.361(11), N2−N3
1.406(9), C4−N3 1.313(9), C4−O1 1.288(9), Ir1−O1 2.130(6), C1−
Ir1 2.019(7), Ir1−Cl1 2.3867(18), C1−Ir1−O1 81.0(3), C1−Ir1−C16A
103.6(4), O1−Ir1−C18A 107.0(4).
contraction of the CNHC−Ir bond length. We also see that the
Cp* ring repositions itself due to the lesser steric requirements
of the N group. This is clearly observed in complex 8e by
inspection at the C11−Ir1−C1 (113.1°) and O1−Ir1−C4
(95.1°) angles, in comparison to the values from complex
8a. This is even more pronounced in complex 8f, with a
smaller C1−Ir1−C16A angle (103.6°) and larger O1−Ir1−C18A
(107.0°) angle. The lack of steric interactions between the n-
butyl chain and Cp* ligand in 8f resulted in increased disorder
in the position of the ligand in the crystal structure, as
illustrated in Figure 6.
b
entry
complex
X
yield (%)
1
2
3
4
5
9f
TfO
BF4
PF6
SbF6
BArF
16
35
36
66
9c
9e
9d
9g
b
28
1
a
Ar = 4-MeO-C6H4. The yield of 15 was determined by H NMR
spectroscopy of the crude product using an internal standard.
components were mixed in a sealed tube and stirred at 90 °C
for 1 h. At that point, the reaction mixture was cooled and
filtered on Celite, the solvent was removed, and yields were
Crystals suitable for X-ray analysis of the cationic complex
9d were obtained by a slow diffusion of pentane into an
acetonitrile/MTBE solution of the complex. The structure is
reported in Figure 7. It confirms the formation of a cationic
1
determined by H NMR spectroscopy. It is important to note
that for this pair of substrates the reaction is extremely clean;
the yields are thus an indication of the conversions. The
reaction conditions resulted in incomplete conversions that
provided good comparative grounds for the different counter-
ions. As a control experiment, we tested the neutral
iridium(III) chloride complex 8c and found that it was
completely inactive for the amine alkylation reaction, in line
with numerous reports on similar types of catalysts.15
Iridium(III) triflate complex 9f provided some catalytic
activity (Table 3, entry 1). More drastic improvements were
measured using fully dissociated, non-nucleophilic counterions
−
−
−
such at BF4 , PF6 , and SbF6 , with a distinct catalytic activity
increase with the last anion (Table 3, entry 4). Postreaction 1H
NMR spectra suggest that the optimal activity of complex 9d
could be attributed to an increase in stability under the
reaction conditions; analysis of 1H NMR spectra for the
reaction using 9c (X = BF4) show noticeable signs of the
complex degradation over the course of the reaction. In
contrast, 1H NMR analysis of the reaction using 9d (X = SbF6)
show no degradation of the complex throughout the reaction.
We were surprised, however, to find that a fully dissociated
BArF− counterion resulted in lower catalytic activity than for
Figure 7. ORTEP plot of complex 9d. Ellipsoids are drawn at the 30%
probability level. Selected distances (Å) and angles (deg): C12−N1
1.367(9), C12−N2 1.371(9), N2−N3 1.407(8), C15−N3 1.306(9),
C15−O1 1.311(8), Ir1−O1 2.125(5), C12−Ir1 2.034(7), C12−Ir1−O1
79.6(3).
species where the iridium center accommodates one molecule
of acetonitrile. In comparison to the corresponding neutral
complex 8c the bond lengths are nearly identical, although a
longer (1.31 Å (9d) vs 1.28 Å (8c)) C−O bond is observed,
despite identical Ir−O bond lengths. This could be attributed
to the increased ionic character of the Ir−O interaction, due to
the cationic iridium center, resulting in a larger proportion of
the localization of the negative charge on the oxygen atom.
Evaluation of Catalytic Activity. With this selected set of
cationic iridium(III) complexes in hand, we next proceeded to
−
SbF6 (Table 3, entry 5). We hypothesize that this could be
attributed to the enhanced steric bulk from this counterion,
reducing access to the key cationic iridium(III) center. The
SbF6− counterion thus seems to provide the optimal balance of
steric bulk, stability, and dissociation under these reaction
−
conditions. Consequently, the SbF6 -derived cationic com-
plexes were used for the subsequent studies. We next
investigated the effect of the nature of the R1 group and of
the basicity of the anionic tether, through modification of the
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R2 group, on the catalytic activity. The results are summarized
in Table 4. For this set of reactions, we increased the default
complex 8g (Table 4, entry 3); in this case we hypothesize
catalyst stability issues, as we observed decomposition while
attempting isolation of the cationic complex. A nonbulky
aromatic group (R1 = Ph, 9i; Table 4, entry 2) resulted again in
almost no catalytic activity. For this reason, the mesityl moiety
was kept for the remainder of the study as the optimal R1
group. We next evaluated the effect of the R2 group on activity.
We found that an increased basicity of the anionic tether
provided a corresponding increase in catalytic activity. A
particularly striking example is complex 9a (Table 4, entry 7,
R2 = CF3), which is almost inactive. The three most active
complexes (9b,d,h) were tested at 90 °C to provide better
discrimination of their activities, and 9d was found to be
optimal, in line with the increased basicity of the anionic
group.
Finally, the crude cationic complex 11 derived from 10
provided excellent catalytic activity, as a 96% yield of the
product was obtained under the model conditions, in line with
the optimal catalyst 9d, derived for the N-acyliminoimidazo-
lium ylide 6c. This strongly suggests that the nitrogen of the
anionic group is the active ligand site for the borrowing
hydrogen catalysis. Due to the instability and impossibility of
isolating and characterizing 11, complex 9d was selected to
explore the potential of these new iridium(III) species as
catalysts.
Table 4. Investigation of Ligand Effect on Catalytic Activity
a
entry
complex
R1
R2
yield (%)
b
1
2
3
4
5
6
7
8
9
9b
9i
8g
9j
9d
8c
9a
9h
10
Mes
Ph
Ph
Ph
Ph
Ph
100 (18)
2
c
t-Bu
n-Bu
Mes
Mes
Mes
Mes
Mes
2
3
b
4-OMe-C6H4
4-OMe-C6H4
CF3
OEt
Ts
100 (66)
c
96
5
b
99 (30)
c
96
a
1
The yield of 15 was determined by H NMR spectroscopy of the
b
crude product using an internal standard. Yield of the reaction
performed at 90 °C for 1 h. Alternative method to form the cationic
c
complex: AgSbF6 and the neutral iridium(III) complex were dissolved
in MeCN and stirred for 15 min. The AgCl that formed was filtered,
and the solution of the cationic complex was placed in a reaction flask
and concentrated under vacuum. The reactants were added as in the
normal procedure for amine alkylation.
We next investigated the effect of a small set of modifications
of the reaction conditions on the yields; the results are
summarized in Table 5. We first explored the effect of solvent.
Table 5. Optimization of the Reaction Conditions
reaction temperature to 110 °C to improve conversions and
yields. Nonetheless, when quantitative yields were reached
under these standard conditions, the experiments were
repeated at 90 °C for 1 h to discriminate the effects on the
conversions and yields.
a
entry X (mol %)
solvent
[13] (M) T (°C) yield (%)
1
2
3
4
5
6
7
8
2
2
2
2
2
2
2
1
1
1
1
DCE
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.1
1
110
110
110
110
110
110
110
110
110
110
110
98
91
19
A first point to note is the source of the cationic catalyst. As
reported in Table 2, we were able to isolate pure cationic
complexes for most ylide proligands. However, in the case of
ylides 6g and 7, we were limited to the isolation and
characterization of the iridium(III) chloride complexes. In
order to test them in the amine alkylation methodology, we
resorted to a rapid preformation of the cationic species (Table
4, entries 3 and 9). The iridium(III) chloride complexes were
treated in acetonitrile with an equimolar quantity of AgSbF6.
After 15 min of stirring, the suspension was filtered over a
Celite pad and acetonitrile was removed. The crude cationic
complexes were then used as is for the amine alkylation. We
evaluated this protocol (Table 4, entry 6) to generate the most
efficient catalyst, 9d (Table 4, entry 5), and observed almost
identical catalytic activity. We thus assumed that the results
obtained with this alternative protocol for complexes 8g and
10 are a realistic representation of their catalytic activity.
The evaluation of the effect of the N group on the
imidazolidene ring (R1) provided a very unique activity profile
(Table 4, entries 1−4). Indeed, we found that only a bulky
aromatic R1 group would result in an active catalyst. This is
particularly striking, as the most effective iridium(III)
complexes bearing a conceptually similar ligand, reported by
CH2Cl2
MeCN
toluene (Tol)
Tol/CH2Cl2 (1/1)
Tol/DCE (1/1)
PhCl
b
44−96
88
90
c
80(10)
DCE
DCE
DCE
DCE
98
60
86
75
9
10
11
2
a
Yield were determined by 1H NMR spectroscopy of the crude
product using an internal standard. Yields varied widely over
numerous experiments. Yield of imine byproduct measured by H
NMR spectroscopy of the crude product using an internal standard.
b
c
1
In comparison to the optimal conditions (Table 5, entry 1),
the use of dichloromethane provided a similar reactivity profile
and yield (Table 5, entry 2). In contrast, the use of MeCN
drastically decreased the catalytic activity and resulted in only
19% yield under the given conditions (110 °C, 1 h); this is
most probably due to the complexing nature of this solvent.
The use of toluene proved to be problematic, as yields over
numerous experiments ranged from 44 to 96% (Table 5, entry
4). We suspect the culprit to be the solubility of catalyst 9d, as
the latter was not soluble in toluene at room temperature. We
found that the use of mixture of toluene and a halogenated
solvent (CH2Cl2 or DCE; Table 5, entries 5 and 6) provided
́
Martin-Matute and co-workers displays a n-butyl chain as the
N group on the imidazolidene ring.15b The analogous cationic
complex 9j did not provide any catalytic activity, despite being
stable and well characterized (Table 4, entry 4). The same lack
of catalytic activity was observed for the cationic derivative of
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results equivalent to the optimal conditions. We also
determined that chlorobenzene could be an acceptable solvent
for the reaction, although in this special case we discovered the
presence of an imine byproduct, indicative of a loss of
dihydrogen in the process (Table 5, entry 7). A decrease in the
catalyst loading to 1 mol % provided results identical with the
initial optimal conditions (Table 5, entry 8). Using this lower
catalyst loading, we finally evaluated the effect of concentration
of the substrates (Table 5, entries 9−11), and found that a
concentration of 0.5 M was required to achieve optimal yield.
Using the optimized conditions determined in Table 5
(entry 8), we next performed a selective scope study, in terms
of both the alcohols and the anilines. Standard reaction times
were increased between 4 and 24 h to ensure complete
conversion when possible. The results are summarized in
Scheme 5, and isolated yields are reported. For the synthesis of
product 15, catalyst 9d is comparable to catalyst 1 from
electron rich anilines reacted more slowly than the reference
aniline. The lower activity could be attributed to the stronger
binding ability of the aniline to the cationic iridium catalyst,
́
leading to reversible inhibition, as reported by Martin-Matute
and co-workers.15c This enhanced nucleophilicity of the aniline
raised another synthetic challenge, as it reacted with 1,2-
dichloroethane (DCE) to form the corresponding N-
chloroethylaniline. To circumvent these issues with these
substrates, the reactions were conducted in PhCl for up to 24 h
to obtain acceptable yields. As reported in Table 5, entry 7, the
reaction performed in PhCl resulted in the presence of an
imine byproduct. This was even more pronounced for the
electron-rich anilines, as we suspect the resulting imines to be
even more difficult to reduce. For the sake of simplifying the
isolation and reporting of the yield of the desired products in
these cases, the reaction medium was treated with a solution of
NaBH4 in acetic acid to reduce the remaining imine into the
desired aniline. With this modified workup, the products from
electron-rich anilines were obtained with good yields (16 and
17). Sterically hindered anilines also required longer reaction
times in chlorobenzene to achieve complete conversions (18
and 19). In contrast, electron-poor anilines reacted swiftly and
provided excellent yields of the desired substituted anilines
products (20−22).
́
Martin-Matute (1 mol %, 2 h, 92%). We then investigated the
effect of the modification of the steric and electronic properties
of the aniline substrate on the reactivity. We found that more
a
Scheme 5. Scope of the Amine Alkylation
We next explored variations on the benzyl alcohol substrates.
Electron-rich derivatives were found to require longer reaction
times to achieve complete amine alkylation (23 and 24).
Interestingly, pentafluorobenzyl alcohol provided a very good
yield of the desired product in a short reaction time (25). The
4-chloro derivative also provided the alkylated product in good
yield and with a short reaction time (26). Unfortunately, the 4-
bromo and 4-trifluoromethyl derivatives were plagued with low
yields, regardless of the reaction time. Finally, we investigated
aliphatic alcohols as substrates. A very different reactivity
profile was found between 1- and 2-octanol, as the primary
alcohol provided a fairly good yield of the desired product
(29), but only a low yield was obtained with the secondary
alcohol, even after 24 h of reaction (30). Interestingly, the
secondary benzylic alcohol 1-phenylethanol was found to be
completely unreactive under the reaction conditions. It seems
that the low reactivity of secondary alcohols is thus mostly due
́
to their increased steric hindrance. In contrast, Martin-Matute
and co-workers reported the desired alkylation product from 1-
phenylethanol and aniline, using catalyst 1 (2.5 mol %, 16 h,
110 °C, 87%). The increased sensitivity of catalyst 9d to the
substrate size is most probably because of its own steric bulk
around the NHC group, due to the mesityl group.
As stated earlier, this amine alkylation method is a mass-
efficient process to access various substituted amine deriva-
tives, with water as the sole byproduct, with the exclusion of
the solvent. Consequently, we investigated the ability of our
optimal catalyst to promote the transformation in water, to
further lower the environmental effect of the reaction
conditions (Table 6). Under the reaction conditions optimized
for 1,2-dichloroethane the reaction did proceed but resulted in
a poor yield of the desired amine, and the presence of almost
equal quantity of an imine was observed by 1H NMR
spectroscopy (Table 6, entry 1). To improve reduction of
the imine and enhance yields, additives were tested, in
substoichiometric quantities (10 mol %). It is proposed that
these additives activate the imine intermediate, by protonation,
to facilitate its reduction.29 Catechol and H3PO4 were found to
be inefficient to improve the outcome of the reaction.
a
b
Isolated yields reported. Reaction performed in PhCl. Reductive
workup with NaBH4 in AcOH used to reduce remaining imine
byproduct prior to purification.
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Accession Codes
Table 6. Reaction in Water
CCDC 2043041−2043046 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
a
entry
additive
yield (%)
1
2
3
4
17 (16)
17 (6)
10 (5)
86
H3PO4
catechol
(PhO)2P(O)OH
AUTHOR INFORMATION
Corresponding Author
■
Claude Y. Legault − University of Sherbrooke, Department of
Chemistry, Centre in Green Chemistry and Catalysis,
Sherbrooke, Québec J1K 2R1, Canada; orcid.org/0000-
0002-0730-0263; Email: claude.legault@usherbrooke.ca
a
1
The yield was determined by H NMR spectroscopy of the crude
product using an internal standard; the values reported in parentheses
are of the measured imine byproduct.
Gratifyingly, the use of diphenyl phosphate resulted in a drastic
improvement, giving an 86% yield of the desired amine, with
no trace of the imine (Table 6, entry 4). This result is
comparable to what was reported for catalyst 2 from Ke and
co-workers (2 mol %, 24 h in water, 90%). Our catalyst is thus
compatible with water as a solvent, at the cost of longer
reaction time and the requirement to use a small quantity of an
acidic additive.
Author
́
Vincent Guerin − University of Sherbrooke, Department of
Chemistry, Centre in Green Chemistry and Catalysis,
Sherbrooke, Québec J1K 2R1, Canada
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.organomet.0c00726
Notes
The authors declare no competing financial interest.
CONCLUSIONS
■
In conclusion, we have developed two distinct synthetic
procedures to access iridium(III) complexes with anionic
NHC ligand derived N-iminoimidazolium ylides. Of particular
interest, we have now optimized a protocol that allows access
to transition-metal complexes by direct deprotonation of the
corresponding ylides and subsequent halogen/anionic NHC
exchange. A key advantage of these proligands is their ease of
access through a convergent synthesis. By using readily
available starting materials, we were able to develop a set of
cationic complexes with a wide range of steric and electronic
properties on the anionic NHC ligand. The catalytic activities
of these complexes were evaluated in the amine alkylation
reaction of anilines relying on borrowing hydrogen catalysis.
While the insight gained is still limited, the high catalytic
activity of complex 10 strongly suggests that the exocyclic
nitrogen of the anionic group is the ligand atom actively
involved in catalysis. The optimal catalyst provided high yields
of the desired alkylation products under simple reaction
conditions. We found that a more basic anionic tether and a
fully dissociated counteranion provided increased catalytic
activity. Finally, we found the optimal catalyst to remain
efficient when the reaction was preformed in water, through
the addition of diphenyl phosphate as an additive. Of particular
interest, our catalysts require a bulky aromatic N group on the
imidazolidene ring, which could prove useful for the future
design of chiral variants of such catalysts.
ACKNOWLEDGMENTS
■
This work was supported by the National Science and
Engineering Research Council (NSERC) of Canada, the
Canada Foundation for Innovation (CFI), the FRQNT Centre
in Green Chemistry and Catalysis (CGCC), and the Universite
de Sherbrooke. Computational resources were provided by
́
́
Calcul Quebec and Compute Canada. We thank Daniel Fortin
for the X-ray analyses.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.organomet.0c00726.
■
sı
Details of the syntheses and characterization data and
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(XYZ)
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