A highly active bifunctional iridium complex with an alcohol/alkoxide- tethered N-heterocyclic carbene for alkylation of amines with alcohols

Article abstract of DOI:10.1002/chem.201201845

A series of new iridium(III) complexes containing bidentate N-heterocyclic carbenes (NHC) functionalized with an alcohol or ether group (NHC-OR, R=H, Me) were prepared. The complexes catalyzed the alkylation of anilines with alcohols as latent electrophiles. In particular, biscationic Ir^III complexes of the type [Cp*(NHC-OH)Ir(MeCN)]²⁺2[BF₄ ^-] afforded higher-order amine products with very high efficiency; up to >99 % yield using a 1:1 ratio of reactants and 1-2.5 mol % of Ir, in short reaction times (2-16 h) and under base-free conditions. Quantitative yields were also obtained at 50 °C, although longer reaction times (48-60 h) were needed. A large variety of aromatic amines have been alkylated with primary and secondary alcohols. The reactivity of structurally related iridium(III) complexes was also compared to obtain insights into the mechanism and into the structure of possible catalytic intermediates. The Ir^III complexes were stable towards oxygen and moisture, and were characterized by NMR, HRMS, single-crystal X-ray diffraction, and elemental analyses. Copyright

Full text of DOI:10.1002/chem.201201845

FULL PAPER
DOI: 10.1002/chem.201201845
A Highly Active Bifunctional Iridium Complex with an Alcohol/Alkoxide-
Tethered N-Heterocyclic Carbene for Alkylation of Amines with Alcohols
Agnieszka Bartoszewicz,[a, c] Rocꢀo Marcos,[a, c] Suman Sahoo,[b, c] A. Ken Inge,[b, c]
Xiaodong Zou,[b, c] and Belꢁn Martꢀn-Matute*[a, c]
Abstract: A series of new iridium
G
yield using a 1:1 ratio of reactants and
1–2.5 mol% of Ir, in short reaction
times (2–16 h) and under base-free
conditions. Quantitative yields were
also obtained at 508C, although longer
reaction times (48–60 h) were needed.
A large variety of aromatic amines
have been alkylated with primary and
secondary alcohols. The reactivity of
structurally related iridiumACTHNUTRGNEU(GN III) com-
complexes containing bidentate N-het-
erocyclic carbenes (NHC) functional-
ized with an alcohol or ether group
plexes was also compared to obtain in-
sights into the mechanism and into the
structure of possible catalytic inter-
mediates. The IrIII complexes were
stable towards oxygen and moisture,
and were characterized by NMR,
HRMS, single-crystal X-ray diffraction,
and elemental analyses.
À
(NHC OR, R=H, Me) were pre-
pared. The complexes catalyzed the al-
kylation of anilines with alcohols as
latent electrophiles. In particular, bis-
A
ACHTUNGTRENNUNG
ionic IrIII complexes of the type
Keywords: amines
·
carbene li-
ACHTUNGTRENNUNG(NHC-OH)IrACHTUNGTRENNUNG 2CATHNUGTREN[UNNG BF4 ]
(MeCN)]2+
gands · iridium · bifunctional cata-
lyst · synthetic methods
afforded higher-order amine products
with very high efficiency; up to >99%
Introduction
the nature of the donor functionality, bidentate NHCs may
behave as hemilabile ligands and are thus able to create
vacant coordination sites easily.[3] A special group among
donor-functionalized NHCs is those having proton donor/ac-
ceptor capability. Ligands having such donor moieties are
capable of protonating/deprotonating reactants and inter-
mediates, which may have a beneficial influence in catalytic
reactions involving hydrogen transfer. This metal–ligand co-
operation is called bifunctional catalysis.[4,5,6] Additionally,
secondary interactions between the ligand and the substrate
or ligand and catalyst by formation of hydrogen bonds may
N-Heterocyclic carbenes (NHCs) are a very important
family of ligands for the synthesis of stable transition-metal
complexes.[1] The robustness of metal complexes with NHCs
can be attributed to the strong s-donation ability and steric
À
properties of these ligands. The strong metal NHC bond
often makes carbene complexes more thermally, oxygen,
and moisture stable, and, in some instances, more active
than those containing phosphane ligands.[1] Another advant-
age of NHCs is their straightforward synthesis, which allows
easy access to multiple structures that are modified in a de-
sired fashion. A special group of NHCs are those that are
functionalized with an extra donor moiety. Such modifica-
tion introduces a stabilizing chelating effect.[2] Depending on
enhance the reaction rate and/or improve selectivity.[7]
A
number of complexes containing NHCs functionalized with
alcohol,[8] alkoxide,[9] phenoxide,[10] ether,[11] N-heteroar-
yl,[12,13] oxazoline,[9] amino,[14 ] and amido,[15] and other donor
groups have been reported.[9] In several cases, potential
hemilability or metal–ligand bifunctionality has been pro-
AHCTUNGTRENNUNG
[a] A. Bartoszewicz, Dr. R. Marcos, Dr. B. Martꢁn-Matute
Department of Organic Chemistry
Stockholm University
tion,[16] the catalytic redox condensation reaction between
alcohols and amines to give higher-order amines and water
is an attractive approach.[17,18,19] A wide variety of inexpen-
sive alcohols are commercially available and water is the
sole by-product of the reaction, making it an atom economi-
cal and environmentally friendly synthetic method. The re-
action is catalyzed by complexes of Ru, Ir, Pd, and other
metals.[17] The first examples with discrete catalysts[18] were
described independently by Grigg[20] and Watanabe[21] in the
1980ꢀs and, since then, a number of very successful examples
have been reported by the groups of Fujita,[22] Williams,[23]
Beller,[24] Kempe,[25] Madsen,[26] Yus,[27] Peris,[28] and
others.[17,29] Our own group has used this reaction in the syn-
10691 Stockholm (Sweden)
Fax : (+46)8-154908
E-mail: belen@organ.su.se
[b] Dr. S. Sahoo, Dr. A. K. Inge, Prof. X. Zou
Department of Materials and Environmental Chemistry
Stockholm University
10691 Stockholm (Sweden)
[c] A. Bartoszewicz, Dr. R. Marcos, Dr. S. Sahoo, Dr. A. K. Inge,
Prof. X. Zou, Dr. B. Martꢁn-Matute
Berzelii Centre EXSELENT on Porous Materials
Stockholm University
10691 Stockholm (Sweden)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201845.
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thesis of aminosugars and aminoferrocenes.[30] This transi-
tion-metal-catalyzed reaction proceeds through a hydrogen
transfer mechanism, which consists of three steps, namely:
1) oxidation of an alcohol with concomitant formation of a
metal hydride; 2) formation of an imine from the resulting
carbonyl compound and the amine substrate, and 3) rehy-
drogenation of the imine and catalyst regeneration.[17,31]
Transition-metal complexes with NHC ligands have also
been used in the alkylation of amines with alcohols.[14b,28a,32]
As a part of our ongoing research in the synthesis of effi-
cient homogeneous[33] and heterogenized[34] transition-metal
complexes, we aimed towards the preparation of novel bi-
functional metal complexes for reactions involving hydrogen
transfer. Most of the cooperative catalytic systems incorpo-
rate amine/amide[4,6] or aromatic hydroxyl/dearomatized
enone[5] functionalities. In contrast, to the best of our knowl-
edge, no alcohol/alkoxide bifunctional system has ever been
tested in hydrogen transfer reactions or hydrogenations.[35]
ide formed after deprotonation
might act as proton acceptor,
which could play an important
role in the catalytic cycle (bi-
functional catalysis).
Figure 2. Carbene ligand A.
Syntheses of complexes: Com-
plexes 1a–d were synthesized by following the short reac-
tion sequence depicted in Scheme 1. Salt 5 was prepared in
three steps starting from imidazole in an overall yield of
Herein, we report the preparation of iridiumACTHUNRTGNEUNG(III) complexes
having hydroxy-, ether-, and alkoxide-functionalized NHC
ligands, and their catalytic activity in the alkylation of
amines with alcohols. The most active complex (1a) contains
À
a hydroxyl-functionalized NHC [NHC alcohol], and can be
synthesized in high yields in a few steps from commercially
III
À
available starting materials. The [NHC alcohol]Ir complex
1a (Figure 1) was found to have excellent catalytic activity;
Scheme 1. Synthesis of complexes 1a–d.
81%.[37] To obtain iridium complex 7, the corresponding
silver carbene complex (6) was first prepared by addition of
Ag2O to a solution of 5 in CH2Cl2 under light-free condi-
tions. Formation of 6 was confirmed by NMR spectroscopic
Figure 1. Structure of complexes 1a, 2 and 3.
À
analysis, which showed the characteristic Ag Ccarbene signal
it combines the best characteristic of complexes 2[13b] and
3,[28a] reported previously by Crabtree and Peris, respectively
(Figure 1). A low catalyst loading of iridium (1a) affords ex-
cellent yields in the alkylation of amines with alcohols in
short reaction times. No excess of alcohol substrate is re-
quired to reach full conversions, and the reactions proceed
without addition of base. Furthermore, 1a allows, for the
first time, amines to be alkylated with alcohols at tempera-
tures as low as 508C.
at d=180.4 ppm in the 13C NMR spectrum, and the imida-
zole backbone proton signals at d=7.21 and 6.95 ppm in the
1H NMR spectrum. Complex 7 was prepared by transmetal-
lation of the carbene ligand on 6 to [IrCp*Cl2]2. The pres-
ence of the OH proton was confirmed by an exchange ex-
periment with D2O (disappearance of the signal at d=
1
4.5 ppm in the H NMR spectrum upon addition of D2O), as
well as by IR spectroscopic analysis. Single crystal X-ray dif-
fraction analysis of 7 (Figure 3) confirmed the structure of
the complex, and revealed that the OH group of the ligand
was not coordinated to the iridium center. Full characteriza-
tion of complex 7 is given in the Supporting Information.
Dicationic iridium complexes 1a–d were prepared by ad-
dition of two equivalents of AgX (X=BF4, PF6, OTf; for
Results and Discussion
À
Ligand design: Carbene ligand A (NHC alcohol; Figure 2)
was designed to include the following properties: 1) A che-
late effect that would provide higher stability; 2) a potential-
ly labile OH group that could dissociate during the catalytic
cycle, creating a vacant coordination site on iridium; 3) co-
complexes 1a, 1b and 1d, respectively) or LiBACTHUNGTERNNU(G C6F5)4 (for
1c) to a solution of 7 in CH3CN (Scheme 1). Complex 1a
was characterized by H and 13C NMR spectroscopy, two-di-
1
mensional H-13C (HSQC) correlation spectra, and HRMS
1
A
analysis. The presence of the acidic OH proton was further
confirmed by an exchange experiment with D2O (disappear-
ance of the signal at d=7.02 ppm in the H NMR spectrum
lease of the amine product, which has been proposed to be
a turnover-limiting step,[36] and 4) the corresponding alkox-
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Alkylation of Amines with Alcohols
FULL PAPER
Scheme 2. Attempted synthesis of 8.
(as well as those of 1a–d) is expected to be abstracted under
the reaction conditions (see below), we instead prepared
complex 9, which is a deprotonated version of 8. The reac-
tion of complex 7 with KHMDS (potassium bis(trimethyl
ACHTUNGTRENNUNGsil-
AHCTUNGTRENNUNG
Figure 3. Molecular structure of 7 with displacement ellipsoids shown at
À
30% probability. Selected bond lengths (ꢃ) and angles (deg): Ir(1)
low yield (Scheme 3). After recrystallization from a mixture
of pentane and dichloromethane, 9 could be characterized
by NMR spectroscopy, HRMS, and single crystal X-ray dif-
fraction analysis (Figure 5).
À
À
C(15) 2.040(7), Ir(1) Cl(1) 2.425(2), Ir(1) Cl(2) 2.414(2), C(15)-Ir(1)-
Cl(1) 92.1(2), C(15)-Ir(1)-Cl(2) 90.2(2), Cl(1)-Ir(1)-Cl(2) 84.8(8).
upon addition of D2O), as well as by IR spectroscopic analy-
sis. In addition, the structure of complex 1a was character-
ized by single crystal X-ray diffraction analysis (Figure 4). In
Scheme 3. Synthesis of 9.
Figure 4. Molecular structure of 1a with displacement ellipsoids shown at
30% probability. The crystal structure includes two symmetry-independ-
ent complexes (1a-A and 1a-B, only one shown here) in the asymmetric
unit with only small differences in bond distances and bond angles. Se-
À
lected bond lengths (ꢃ) and angles (deg): 1a-A: Ir(1) C(15) 2.03(2),
À
À
Ir(1) O(1) 2.15(1), Ir(1) N(3) 2.08(1), C(15)-Ir(1)-O(1) 84.2(6), C(15)-
À
Ir(1)-N(3) 86.3(6), O(1)-Ir(1)-N(3) 85.7(5). 1a-B: Ir(2) C(38) 2.11(2),
Figure 5. Molecular structure of 9 with displacement ellipsoids shown at
À
À
Ir(2) O(2) 2.18(1), Ir(1) N(6) 2.07(1), C(38)-Ir(2)-O(2) 86.3(7), C(38)-
Ir(2)-N(6) 89.2(6), O(2)-Ir(2)-N(6) 86.4(5).
À
30% probability. Selected bond lengths (ꢃ) and angles (deg): Ir(1)
À
À
C(15) 2.04(1), Ir(1) O(1) 2.071(9), Ir(1) Cl(1) 2.432(3), C(15)-Ir(1)-O(1)
87.6(5), C(15)-Ir(1)-Cl(1) 91.1(4), O(1)-Ir(1)-Cl(1) 85.9(3).
contrast to complex 7, the hydroxyl group in 1a is coordi-
À
À
nated to iridium. The average Ir Ccarbene (2.07 ꢃ) and Ir O
distances (2.17 ꢃ), are both in the expected range.[38] Single
crystal X-ray diffraction of 1a also revealed the presence of
intermolecular hydrogen bonds between the alcohol proton
and the tetrafluoroborate anion.[39]
In addition, complexes 13 and 14, containing a methoxy
group in the pendant chain, were synthesized (Scheme 4).
The precursor imidazolium salt 11 was prepared by treat-
ment of 4 with MeI under basic conditions in tetrahydrofur-
an (THF), followed by reaction with n-butyl chloride. Com-
plexes 13 and 14 were obtained following a synthetic route
similar to that used for the preparation of 7 and 1 (i.e.,
through transmetallation of carbene from silver to iridium
followed by chloride abstraction). In the crystal structures
(see Figure S1 and S2 in the Supporting Information), the
methoxy group is not coordinated to iridium in the case of
neutral complex 13, whereas in biscationic complex 14, the
ether group is bound to the metal.
To understand the influence of the functionalized carbene
moiety on the catalytic activity, we also synthesized the
structurally similar complexes 9, 13, and 14. We initially at-
tempted to synthesize the monocationic complex 8, which is
a structural intermediate between complexes
7 and 1
(Scheme 2). Despite multiple attempts to prepare 8 by treat-
ment of 7 with AgBF4 (1 equiv), a mixture of different com-
plexes was always formed. Because the acidic proton of 8
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B. Martꢁn-Matute et al.
low yield (Table 1, entry 3), suggesting the importance of
the carbene ligand for catalytic activity (see below, Table 1,
entry 5). The yield of N-benzylaniline was improved when
complex 7 was used (Table 1, entry 4). A dramatic increase
in the catalytic activity was obtained when the chloride lig-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
anions, namely 76, 78 and 78% yield after 1 h, respectively.
Complex 1d, having a more coordinating anion (OTf), re-
quired slightly longer reaction time to reach high yields
(Table 1, entry 8). Monochloride complex 9 gave a slightly
better yield than dichloride 7 (Table 1, entry 9 vs. 4), but
was inferior to catalysts 1a–d (Table 1, entries 5–8). This
suggests that the more electrophilic the character of the irid-
Scheme 4. Synthesis of complexes 13 and 14.
AHCTUNGTREGiNNUN um catalyst, the higher the activity. When alkoxide complex
9 was used together with 1 equiv of AgBF4, the reaction was
completed in only 1 h, indicating that the alkoxide complex
might be the active intermediate in the reaction (Table 1,
entry 10). Finally, the activity of complex 14, containing a
methyl ether moiety, was worse than that of catalyst 1a,
Catalytic activity and optimization of reaction conditions:
Preliminary studies of the catalytic activity of NHC–iridium
complexes 1, 7, 9, and 14 were performed to explore their
potential application in the N-alkylation of amines with al-
cohols; for comparison, we also tested [IrCp*Cl2]2. The cou-
pling of aniline with benzyl alcohol was investigated as a
model reaction (Table 1). All reactions were carried out
with 1.0 mol% catalyst loading in toluene under an argon
atmosphere, by using a 1:1 ratio of amine/alcohol, in the ab-
sence of base.
À
with a hydroxyl group (both with BF4 as the counterion,
Table 1, entry 11). Furthermore, catalyst 14 was less stable
than catalysts 1a–d and its loading had to be increased from
1 to 1.5 mol% to reach high conversion levels. These results
indicate that the presence of the acidic proton increases the
reaction rate. Importantly, complexes 1a–d and 14 showed
higher catalytic activity than the structurally related com-
plex 3 (Figure 1),[28a] which points to a possible stabilization
of coordinatively unsaturated catalytic intermediates as well
as minimization of product inhibition by the hemilabile
donor group in 1a.
The reaction was not successful in the absence of any cat-
alyst (Table 1, entry 1), and with [IrCp*Cl2]2 only a small
amount of product was formed (Table 1, entry 2).[40] The
combination of [IrCp*Cl2]2 with AgBF4 resulted in a very
Complex 1a was chosen for further optimization studies
(catalyst loading and temperature) due to its high reactivity,
better accessibility, and lower cost (Table 2). An attempt to
lower the catalyst loading below 1 mol% resulted in a dras-
tic decrease of the catalytic activity (Table 2, entry 1 vs. 2).
We evaluated the possibility of generating the active catalyst
1a in situ from the more stable precursor 7 (Table 2,
entry 3), avoiding the requirement for additional, low-yield-
ing purification. After mixing 7 with AgBF4 in acetonitrile
and filtering off the precipitated AgCl, the catalyst solution
was used directly in the reaction.[41] Such a procedure afford-
ed the N-alkylated product in excellent yield in the same re-
action time as when the isolated catalyst 1a was used
(Table 2, entry 1 vs. 3, respectively). The temperature of the
reaction was found to have a strong impact on the reaction
rate (Table 2, entries 4–8). The temperature could be low-
ered to 908C, but longer reaction time was needed to obtain
high conversion (6 h, 93% conv., Table 2, entry 5). However,
when the acetonitrile used to prepare the catalyst stock sol-
utions was replaced by a noncoordinating solvent (CH2Cl2),
the temperature could be decreased to 508C (Table 2, en-
tries 6–9) without diminishing the yields, albeit requiring
longer reaction times and catalyst loadings of 2 mol%. To
the best of our knowledge, this is first time that the alkyla-
Table 1. N-Alkylation of aniline with benzyl alcohol. Catalyst screen-
ACHTUNGTRENNUNG
ing.[a]
Entry
Catalyst
none
Time [h]
Yield [%][b]
1
2
14
14
0
12
ACHTUNGTRENNUNG
3
G
14
5
4
5
6
7
8
9
7
1a
1b
1c
1d
9
9 +AgBF4
14
2/14
1/2
1/2
1/2
2/5
2/14
1
11/47
76/>99
78/>99
78/>99
50/>99
33/>99
>99
10[c]
11[d]
2
72
[a] Reagents and conditions (unless otherwise noted): BnOH (1.0 mmol),
PhNH2 (1.0 mmol), [Ir] (1 mol%, 0.01 mmol), toluene (0.5 mL), 1108C.
[b] Yield of the N-benzylaniline determined by 1H NMR spectroscopic
analysis using 1,4-di-tert-butylbenzene as internal standard. [c] The active
catalyst was prepared in situ from 9 and AgBF4 (1 equiv) in CH2Cl2
(0.1 mL), AgCl was separated by centrifugation and the remaining solu-
tion was used in the reaction. [d] 1.5 mol% Ir was used. When the reac-
tion was performed with 1.0 mol%, 10% conversion was obtained (moni-
tored from 2 to 24 h).
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Alkylation of Amines with Alcohols
FULL PAPER
Table 2. N-Alkylation of aniline with benzyl alcohol. Reaction tempera-
ture and catalyst loading screening.[a,b]
versions of less than 10% were observed. The low activity
obtained with aliphatic amines compared with aromatic
amines might be due to the higher nucleophilicity of the
former. Strong coordination of the more nucleophilic ali-
phatic amines blocks the empty coordination site on iridium,
preventing coordination of the alcohol substrate, which re-
sults in deactivation of the complex. On the other hand, var-
ious primary or secondary alcohols could be coupled with
aniline, producing monoalkylated amines in high yields
(Table 4). Primary aliphatic alcohols (Table 4, entries 1, 2,
and 6), sec-alcohols with alkyl and aryl substituents (Table 4,
entries 3 and 4), and benzylic alcohols (Table 4, entry 5, and
Table 3, entry 1), afforded the corresponding higher-order
amines in excellent yields. When 1,5-pentanediol was react-
ed with aniline, the cyclic 1-phenylpiperidine was obtained
as the major product, which was isolated in 75% yield
(Table 4, entry 2). The most reactive alcohol could be react-
ed with aniline at 508C (Table 4, entry 5) giving the product
in 95% yield.
Entry
Cat [mol%]
Temp [8C]
Time [h]
Yield [%][b]
1
2
1
0.5
1
1
1
2
1
2
2
110
110
110
100
90
80
80
60
50
2
6
2
6
6
>99
21
>99
>99
93
>99
92
95
3[c]
4
5
6[d]
7[d]
8[d]
9[d]
3
36
24
48
>99
[a] Reaction conditions: BnOH (1.0 mmol), PhNH2 (1.0 mmol), toluene
(0.5 mL). [b] Yield of the N-benzylaniline determined by 1H NMR spec-
troscopic analysis using 1,4-di-tert-butylbenzene as internal standard.
[c] 1a was prepared in situ from 7 and AgBF4 (2 equiv) in MeCN and
used in the reaction after filtration through Celite to remove AgCl. The
reaction was carried out in a mixture of MeCN/toluene (1:2). [d] The
active catalyst was prepared in situ from 7 and AgBF4 (2 equiv) in
CH2Cl2 and used in the reaction after filtration through Celite to remove
AgCl. The reaction was carried out in a mixture of CH2Cl2/toluene (1:4).
Reaction mechanism: Based on the results presented in
Table 1, we propose the general mechanism depicted in
Scheme 5. To become catalytically active, complex 1a must
undergo a two-step activation. First, the acidic OH proton is
tion of amines with alcohols has been performed at temper-
atures below 708C.[25e,f]
Table 3. Amine scope; N-alkylation of amines with benzyl alcohol catalyzed by 1a.[a]
Substrate scope: The optimized conditions involv-
ing in situ generation of the active catalyst
(1 mol% at 1108C, Table 2, entry 3) were applied
to the coupling of various amines and alcohols
(Tables 3 and 4). In some cases, an increase in cat-
alytic loading from 1 to 1.5 or 2.5 mol% was nec-
essary to reach full conversion. Anilines with
either electron-donating or electron-withdrawing
substituents on the aromatic ring were successfully
alkylated with benzyl alcohol in high yields
(Table 3, entries 1–5). Sterically hindered 2,4,6-tri-
methylaniline could also be used, although longer
reaction time was necessary to obtain high conver-
sion (Table 3, entry 3). No cleavage of halogen
atoms was observed when p-bromo- or p-chloro-
substituted substrates were used (Table 3, entries 4
and 5). Moreover, the heteroaromatic moiety in 2-
aminopyridine was also well-tolerated (Table 3,
entry 6). N-Alkyl-N-arylamines reacted efficiently
under similar conditions in 15–16 h (Table 3, en-
tries 7 and 8). Reaction of benzyl alcohol with 4-
amino-N-benzylbenzenesulfonamide resulted in se-
lective alkylation of the sulfonamide group
(Table 3, entry 9).[42] The most reactive anilines
could be alkylated with benzyl alcohol at 508C,
albeit with longer reaction times (Table 3, entries 1
and 4). The corresponding higher-order amines
were formed in quantitative yields.
Entry Amine
Amine product
Time [h] Conv. [%][b] Yield [%][c]
1
2/48[d]
>99
>99
92/>99[d]
2[e]
5
93
3[e]
12
>99
71
4
2.5/60[d]
>99
>99
>99
>99
>99
85/>99[d]
5
3
86
88
74
84
6[e]
7[e]
8[e]
16
16
15
9[f]
16
95
80
[a] Reagents and conditions (unless otherwise noted): benzyl alcohol (1.0 mmol),
amine (1.0 mmol), 1a (0.01 mmol, 1 mol%), toluene (0.3 mL), 1108C. 1a was pre-
pared in situ as described in Table 2, entry 3. [b] Conversion of the alcohol substrate
was determined by 1H NMR spectroscopic analysis. [c] Isolated yield after flash chro-
matography. [d] The active catalyst was prepared in situ from 7 and AgBF4 (2 equiv)
in CH2Cl2 and used in the reaction (Ir=2 mol%) after filtration through Celite to
remove AgCl. The reaction was carried out in a mixture of CH2Cl2/toluene (1:4) at
The catalytic system has also been tested with
aliphatic amines such as benzyl amine, n-hexyla-
mine, and cyclohexylamine but, in all cases, con-
1
508C. The yield was determined by H NMR spectroscopic analysis using naphthalene
as an internal standard. [e] Ir (1.5 mol%). [f] Ir (2.5 mol%).
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B. Martꢁn-Matute et al.
Table 4. Alcohol scope; N-alkylation of aniline with alcohols catalyzed by 1a.[a]
present in the reaction mixture, such as amine or
alcohol. In the second activation step, the weakest
bound ligand L (L=acetonitrile, aniline, alcohol,
solvent) dissociates, forming a bifunctional 16eÀ
complex (II). The importance of generating a
vacant coordination site was demonstrated by the
Entry Alcohol
1[d]
Amine product
Time [h] Conv. [%][b] Yield [%][c]
low catalytic activity of complexes
7 and 9
(Table 1, entries 4 and 9, respectively), containing
strongly bound chloride ligands. Interestingly, the
fact that 9 is a significantly better catalyst than 7
may indicate that the chelating oxygen-containing
arm in the former complex can temporarily dissoci-
ate upon protonation, creating unsaturation. Fur-
thermore, the higher electrophilicity of the Ir
center in monocationic complex 9 may facilitate
coordination of the alcohol substrate. To further
support our assumption that 1a can be deprotonat-
ed by aniline during the reaction, producing the
active alkoxide complex I, we wanted to study the
4
5
>99
84
75
2[d]
80
3[d]
4[d]
5[e]
16
>99
>99
97
87
18
83
2/60[f]
91/95[f]
6[e]
8
>99
88
[a] Reagents and conditions (unless otherwise noted): alcohol (1.0 mmol), aniline
(1.0 mmol), 1a (0.01 mmol, 1 mol%), toluene (0.3 mL), 1108C. 1a was prepared in
situ as described in Table 2, entry 3. [b] Conversion of alcohol substrate was deter-
mined by 1H NMR spectroscopic analysis. [c] Isolated yield after flash chromatogra-
phy. [d] 2.5 mol% Ir. [e] 1.5 mol% Ir. [f] The active catalyst was prepared in situ from
7 and AgBF4 (2 equiv) in CH2Cl2 and used in the reaction (Ir=2 mol%) after filtra-
tion through Celite to remove AgCl. The reaction was carried out in a mixture of
CH2Cl2/toluene (1:4) at 508C. The yield was determined by 1H NMR spectroscopic
analysis using naphthalene as internal standard.
1
deprotonation step by H NMR spectroscopy. Un-
fortunately, titration of 1a with aniline, which is
the base and the substrate used in the reaction, re-
sulted in a complex NMR spectra that was difficult
to interpret due to equilibria between the reactants
(see the Supporting Information). Instead, 1a
could be successfully deprotonated with pro
ACHTUNGTRENNUNGton
sponge (N,N,N’,N’-tetramethylnaphthalene-1,8-dia-
mine), which is a non-nucleophilic amine (Scheme 6). Upon
addition of 0.5 equiv of proton sponge to a solution of 1a,
the 1H NMR spectrum showed immediate formation of I
(0.5 equiv, L=[D6]acetone) together with protonated amine
and remaining unreacted 1a (0.5 equiv; see the Supporting
Information). All the signals were sharp, indicating that
there is no fast equilibrium between the reactants. After ad-
dition of another 0.5 equiv of proton sponge, all starting ma-
terial (1a) was transformed into I. Thus, this experiment
shows that indeed the OH proton of 1a is acidic enough to
become deprotonated under the reaction conditions (the
pKa of the coordinated OH group is several units lower than
usual tertiary alcohols; the reported pKa of proton sponge in
water is 12.1[43]).
Scheme 5. Possible mechanism of alkylation of amines with alcohols
through metal–ligand bifunctional catalytic intermediates II and III.
abstracted by the amine substrate, which is present in abun-
dance in the reaction mixture. The acidity of this proton is
increased due to coordination to the metal center, making
possible its deprotonation by the moderately basic aromatic
amine, forming intermediate I. The weakly bound acetoni-
trile ligand can be exchanged by other potential lig
G
Scheme 6. Two methods for the generation of intermediate complex I.
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Alkylation of Amines with Alcohols
FULL PAPER
solvent was removed under vacuum. After purification by column chro-
matography (SiO2; CH2Cl2/MeOH, 90:10), 7 (149.7 mg, 84% yield) was
obtained as a yellow powder. 1H NMR (CDCl3): d=7.44 (d, J=2 Hz,
1H; CHimidazol backbone), 7.02 (d, J=2 Hz, 1H; CHimidazol backbone), 5.11 (d, J=
Intermediate I was also prepared by an alternative
method from complex 9 and AgBF4, and could be fully char-
acterized by NMR spectroscopic and HRMS analyses. The
1H NMR spectrum of I obtained in this way was identical to
that obtained by reacting 1a with proton sponge. Further-
more, when intermediate I was used as the catalyst, the re-
action time decreased from 2 to 1 h (Table 1, entry 10). This
suggests that alkoxide complex I may be an intermediate in
the reaction cycle.
Bifunctional complex II contains basic (oxygen) and
acidic (iridium) sites. Thus, II is capable of accepting a
proton and a hydride, producing complex III (Scheme 5).
The exact mechanism of the dehydrogenation step is un-
known at this stage of the investigation. Both an outer-
sphere type (proceeding without coordination of the alcohol
to the metal center) and an inner-sphere type (involving
direct coordination of the alcohol to iridium and b-hydride
elimination) may be possible. The aldehyde produced
during the dehydrogenation step condenses with the amine,
forming an imine intermediate. Bifunctional complex III,
which contains both hydride and proton-donating sites, sub-
sequently rehydrogenates the imine, closing the catalytic
cycle. Similar to the dehydrogenation, the imine hydrogena-
tion step may also proceed through inner- or outer-sphere
mechanisms.
14.0 Hz, 1H; NCHHC
butyl), 3.81 (dt, J=12.2, 5.3 Hz, 1H; CHHn-butyl), 3.66 (d, J=14.0 Hz, 1H;
NCHHC(CH3)2OH), 3.06 (brs, 1H; OH), 2.13–1.97 (m, 1H; CHHn-butyl),
1.81–1.65 (m, 1H; CHHn-butyl), 1.57–1.40 (m, 2H; CH2n-butyl), 1.58 (s, 15H;
5A(CH3)5), 1.40 (s, 3H; C(CH3)2OH), 1.39 (s, 3H; C(CH3)2OH), 0.99 ppm
(t, J=7.4 Hz, 3H; CH3n-butyl); C NMR (CDCl3): d=156.0 (Ir C), 122.8
(CHimidazol backbone), 121.1 (CHimidazol backbone), 88.8 (C5A(CH3)5), 70.1 (NCH2C-
(CH3)2O), 59.1 (NCH2C(CH3)2O), 50.7 (CH2n-butyl), 34.0 (CH2n-butyl), 28.7
((CH3)2OH), 27.8 ((CH3)2OH), 20.2 (CH2n-butyl), 14.0 (CH3n-butyl), 9.0 ppm
5A
ACHTUGNRTEN(NGNU CH3)2OH), 4.77 (dt, J=12.2, 5.3 Hz, 1H; CHHn-
AHCTUNGTRENNUNG
C
G
E
ACHTUNGTRENNUNG
13
À
CTHUNGTRENNUNG
A
ACHTUNGTRENNUNG
(C CHUTGNTERN(NUNG CH3)5); HRMS (ESI+): m/z calcd for C21H35ClIrN2O: 559.2062
[MÀCl]+; found: 559.2085; elemental analysis calcd (%) for
C21H37Cl2IrN2O: C 42.27, H 6.25, Cl 11.88, N 4.70; found: C 42.07, H
5.87, Cl 11.16, N 4.33.
Preparation of complex 1a: A solution of AgBF4 (28.8 mg, 0.15 mmol) in
anhydrous and degassed MeCN (0.25 mL) was added to an oven-dried
sealed microwave tube containing complex 7 (44.6 mg, 0.075 mmol) in
acetonitrile (0.5 mL) under an argon atmosphere. The reaction mixture
was stirred for 15 min at RT, then the resulting crude solution was fil-
tered through Celite and the solvent was evaporated. After precipitation
from a CH2Cl2/pentane solution, complex 1a (41.6 mg, 75% yield) was
obtained as a yellow powder. 1H NMR ([D6]acetone): d=7.71 (d, J=
2.1 Hz, 1H; CHimidazol backbone), 7.65 (d, J=2.1 Hz, 1H; CHimidazol backbone),
7.02 (brs, 1H; OH), 4.40 (d, J=15.0 Hz, 1H; NCHHC
(ddd, J=13.3, 10.7, 6.5 Hz, 1H; CHHn-butyl), 4.18 (ddd, J=13.3, 10.7,
6.5 Hz, 1H; CHHn-butyl), 3.89 (d, J=15.0 Hz, 1H; NCHHC(CH3)2OH),
2.80 (s, 3H; CH3CN), 2.14–1.80 (m, 2H; CH2n-butyl), 1.85 (s, 15H; C5-
(CH3)5), 1.61 (s, 3H; C(CH3)2OH), 1.59–1.47 (m, 2H; CH2n-butyl), 1.03 (t,
ACHTUGNTREN(UNNG CH3)2OH), 4.37
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
It is important to mention that the relatively high catalytic
activity of complex 14 (Table 1, entry 11), containing a
methyl substituent on the oxygen atom, indicates that this
complex operates through a different mechanism in which
the proton-accepting capability is not crucial for catalysis.
J=7.5 Hz, 3H; CH3n-butyl), 0.98 ppm (s, 3H;
CACTHNGUTERNNUG
(CH3)2OH); 13C NMR
À
([D6]acetone): d=152.8 (Ir C), 126.8 (CHimidazol backbone), 126.4 (CH3CN),
122.3 (CHimidazol backbone), 93.6 (C
5A
G
(NCH2C
ACHTUNGTRENNUNG
22.7 ((CH3)2OH), 20.6 (CH2n-butyl), 14.1 (CH3n-butyl), 9.4 (C CHTUNGTRENNUNG
3.8 ppm (CH3CN); IR (NaCl, selected bands): n˜ =3625–3500 (br), 1000–
1100 cmÀ1 (two bands overlapping, s); HRMS (ESI+): m/z calcd for
C21H34IrN2O: 523.2295 [M]+; found: 523.2312.
Conclusion
General procedure for the alkylation of amines with alcohols catalyzed
by 1a: A solution of AgBF4 (28.8 mg, 0.15 mmol) in anhydrous and de-
gassed MeCN (0.25 mL) was added to an oven-dried sealed tube contain-
ing pre-catalyst 7 (45 mg, 0.075 mmol) in MeCN (0.5 mL) under an argon
atmosphere. The reaction mixture was stirred for 15 min at RT, then the
resulting solution was filtered by using a cannula under an argon atmos-
phere and used as the stock solution for catalysis. The solution containing
the catalyst (0.1–0.25 mL) was added to a solution of alcohol (1 mmol)
and amine (1 mmol) in anhydrous and degassed toluene (0.4 mL) under
an argon atmosphere. The reaction mixture was stirred at 1108C for the
time indicated in Tables 3 and 4. After completion, the mixture was
cooled, filtered, and concentrated. The products were purified by column
chromatography (SiO2; pentane/CH2Cl2 =90:10 to 80:20; or pentane/
EtOAc=100:0 to 70:30). For those reactions that were run at 508C, the
active catalyst was prepared in situ from 7 and AgBF4 (2 equiv) in
CH2Cl2 and used in the reaction (Ir=2 mol%) after filtration through
Celite to remove AgCl. The reaction was carried out in a mixture of
CH2Cl2/toluene (1:4) for the time indicated in Tables 3 and 4.
We have synthesized new N-heterocyclic carbene ligands
containing a hydroxyl moiety that allow, for the first time,
the preparation of iridium complexes with chelating [NHC
alcohol] ligands. The unique properties of the complexes ac-
count for their high catalytic activity in the N-alkylation of
amines with alcohols. The best catalyst displays a broad sub-
strate scope and is one of the most active catalysts known to
date; it can be used to catalyze the reaction at temperatures
as low as 508C. A reaction mechanism involving complex 1a
has been proposed. Key intermediates are a bifunctional
À
iridACHTUNGTRENNUNGium alkoxide complex (II), which was prepared and char-
acterized, and bifunctional iridium hydride complex III.
Encouraged by these results, we are currently investigat-
ing the mechanism further and developing a solid-supported
version of this catalyst. Our results will be communicated in
due course.
X-ray crystallography: Crystallographic data and refinement are provided
in Table 1 in the Supporting Information. CCDC-867806 (1a), CCDC-
867807 (7), CCDC-868525 (9), CCDC-881979 (13), and CCDC-868780
(14) contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge Crystal-
lographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Experimental Section
Preparation of complex 7: A mixture of [IrCp*Cl2]2 (119 mg, 0.15 mmol)
and silver carbene 6 (101.4 mg, 0.3 mmol, 0.3m in CH2Cl2) was stirred at
358C for 4 h. The reaction mixture was filtered through Celite and the
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Acknowledgements
Financial support from the Swedish Research Council (VR), the Swedish
Governmental Agency for Innovation Systems (VINNOVA), the Knut
and Alice Wallenberg Foundation, the Wenner-Gren Foundation, the
Gçran-Gustafsson Foundation for Nature Sciences and Medical Research
and the Berzelii Center EXSELENT is gratefully acknowledged. We
thank Dr. Kirsten E. Christensen at Diamond Light Source for assistance
with collecting single crystal X-ray data of 1a and 14, Dr. Mikaela Gus-
tafsson for help with 1a and Professor Per-Ola Norrby for helpful discus-
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Alkylation of Amines with Alcohols
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Revised: July 30, 2012
Published online: && &&, 0000
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Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Alkylation of Amines with Alcohols
FULL PAPER
Catalysis
A. Bartoszewicz, R. Marcos, S. Sahoo,
A. K. Inge, X. Zou,
B. Martꢀn-Matute* ........... &&&& — &&&&
A Highly Active Bifunctional Iridium
Complex with an Alcohol/Alkoxide-
Tethered N-Heterocyclic Carbene for
Alkylation of Amines with Alcohols
Working together: A series of novel
iridiumACHTUNGTRENNUNG(III) complexes containing
bidentate N-heterocyclic carbene
anilines using alcohols as latent elec-
trophiles at temperatures as low as
508C (see scheme). The reactivity of
(NHC) ligands functionalized with an
alcohol were prepared. The complexes
are highly active for the alkylation of
structurally related iridiumACTHNGUTERN(UNG III) com-
plexes was also compared to obtain
insights into the mechanism.
Chem. Eur. J. 2012, 00, 0 – 0
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!