Highly active CpIr catalyst at low temperatures bearing an N-heterocyclic carbene ligand and a chelated primary benzylamine in transfer hydrogenation

Article abstract of DOI:10.1021/om500888d

The synthesis of new Cp Ir complexes bearing an N-heterocyclic carbene ligand and a chelated primary benzylamine is described. The new complexes are chiral at metal and have a stereogenic carbon at the benzylamine ligand. The synthesis is diastereoselective, and the origin is thermodynamically controlled. The chiral complexes have been fully characterized. The catalytic results show that the complexes are very active in transfer hydrogenation: for example, acetophenone is reduced to 1-phenylethanol in 2 h at 50 °C using a catalyst loading of 1 mol %. More interestingly is that no base, apart from the required for catalyst activation, is needed in the process. The enantioselectivities obtained range from low to moderate, with a maximum of 58% ee in the case of 2'-methylacetophenone. Initial mechanistic studies by means of DFT calculations suggest that the mechanism is based on a direct hydrogen transfer via a highly ordered transition state centered at the iridium amido group. The calculations are in good agreement with the experimental data and support a concerted one-step mechanism process.

Full text of DOI:10.1021/om500888d

Article
pubs.acs.org/Organometallics
Highly Active Cp*Ir Catalyst at Low Temperatures Bearing an
N‑Heterocyclic Carbene Ligand and a Chelated Primary Benzylamine
in Transfer Hydrogenation
Sara Sabater,† Miguel Baya,*,‡ and Jose A. Mata*,†
†
́
Departamento de Quımica Inorgan
́
ica y Organ
́
ica, Universitat Jaume I, Avda. Sos Baynat s/n, 12071, Castellon
́
, Spain
‡
́
́
́
Instituto de Sıntesis Quımica y Catal
́
isis Homogen
́
ea (ISQCH), Departamento de Quımica Inorgan
́
ica, CSIC-Universidad de
Zaragoza, C/Pedro Cerbuna 12, E-50009 Zaragoza, Spain
S
* Supporting Information
ABSTRACT: The synthesis of new Cp*Ir complexes bearing an N-heterocyclic carbene ligand and a chelated primary
benzylamine is described. The new complexes are chiral at metal and have a stereogenic carbon at the benzylamine ligand. The
synthesis is diastereoselective, and the origin is thermodynamically controlled. The chiral complexes have been fully
characterized. The catalytic results show that the complexes are very active in transfer hydrogenation: for example, acetophenone
is reduced to 1-phenylethanol in 2 h at 50 °C using a catalyst loading of 1 mol %. More interestingly is that no base, apart from
the required for catalyst activation, is needed in the process. The enantioselectivities obtained range from low to moderate, with a
maximum of 58% ee in the case of 2′-methylacetophenone. Initial mechanistic studies by means of DFT calculations suggest that
the mechanism is based on a direct hydrogen transfer via a highly ordered transition state centered at the iridium amido group.
The calculations are in good agreement with the experimental data and support a concerted one-step mechanism process.
hydrogen transfer mechanism directly links with Noyori’s
bifunctional catalysts and proposes an outer-sphere process
through a relatively ordered transition state, in which both a
proton transfer and a hydride transfer to the unsaturated
substrate happen with a certain degree of synchronicity.2c,k,m
The key species proposed in these mechanisms are depicted in
Chart 1.
Today a plethora of efficient transition-metal catalysts for TH
based on Ru,7 Rh,8 and Ir9 are known. Among them, the Cp*Ir
systems are emerging powerfully due to their stability and
INTRODUCTION
■
Transition-metal-catalyzed transfer hydrogenation (TH) is a
well-established process for the reduction of carbonyls and
imines under mild reaction conditions.1 The asymmetric
version gained considerable interest after the work developed
by Noyori et al., who introduced chiral ruthenium complexes
bearing primary amines that catalyze the transfer hydrogenation
of ketones with iPrOH with high enantioselectivities.2 Since
then, many of the most effective catalysts involve the presence
of primary or secondary amines as ligands.3 The active catalytic
species are formed after addition of a strong base to form the
unsaturated metal-amido complexes.4 From a mechanistic point
of view, three main types of transfer hydrogenation pathways
have been described either involving hydride derivatives or
unsaturated metal species in the catalytic process. The direct
hydrogen transfer mechanism (also known as Meerwein−
Ponndorf−Verley, and Opennauer for the reverse cycle)
involves a six-membered transition state in which the metal
acts as a Lewis acid and no participation of hydride
intermediates is required.5 The most common is the migratory
insertion mechanism, which consists of an inner-sphere stepwise
process that involves the insertion of the unsaturated bond into
a metal hydride as a first step, followed by the proton transfer
and elimination of the hydrogenated substrate.6 The concerted
Chart 1. Key Species Proposed in the Mechanisms (A)
Direct Hydrogen Transfer, (B) Migratory Insertion Inner
Sphere, and (C) Concerted Hydrogen Transfer
Received: August 29, 2014
© XXXX American Chemical Society
A
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activity,9d,10 and even the first industrial application has recently
been reported.11 Encouraged by the catalytic abilities of Ir-NH
type catalysts complexes developed by Ikariya12 and Pfeffer,13
and in light of our experience in metal catalysts based on N-
heterocyclic carbene ligands we became interested in
developing chiral Ir-NH catalysts with NHC ligands for transfer
hydrogenation. In this work, we describe the synthesis of
cationic highly active Cp*Ir catalysts at low temperatures
bearing an N-heterocyclic carbene ligand and a chelate primary
benzylamine which we have used in transfer hydrogenation of
prochiral ketones.14 The Iridium complexes are chiral-at-metal
and have a stereogenic carbon at the benzylamine ligand.
Density functional theory studies have provided a mechanistic
proposal which is consistent with the experimental observations
and catalytic results. Interestingly, the transfer hydrogenation
proceeds through a highly ordered transition state centered at
the iridium amido group which does not properly fit into any of
the three types of mechanisms discussed above.
The molecular structure of complex 4 was confirmed by
means of X-ray diffractometry (Figure 1). Single crystals were
RESULTS AND DISCUSSION
■
Synthesis and Characterization of Racemic Catalysts.
Transfer Hydrogenation of Ketones. The reaction of
[Cp*Ir(Cl)2(Me2Im)] (1) or [Cp*Ir(Cl)2(nBu2Im)] (2) with
a racemic mixture of the primary amine [1-(1-naphthyl)ethyl]-
amine in the presence of 2 equiv of AgOAc affords the ortho-
metalated iridium complexes 3 and 4, respectively (Scheme 1).
Figure 1. Molecular diagram of complex 4. Ellipsoids are given at the
50% probability level. Only hydrogen atoms bonded to N(2), C(3),
and C(4) are shown. The counterion PF6 has been omitted for clarity.
Selected bond lengths (Å) and angles (deg): Ir(1)−C(15) 2.044(4),
Ir(1)−N(2) 2.128(3), Ir(1)−C(6) 2.061(4), Ir(1)−Cp(cent) 1.861;
C(6)−Ir(1)−N(2) 77.51(14), C(6)−Ir(1)−C(15) 94.34(15),
C(15)−Ir(1)−N(2) 91.25(15).
Scheme 1
obtained by slow evaporation of dichloromethane/hexane
mixtures. Complex 4 crystallizes in the achiral space group
P1 and contains a single molecule in the asymmetric unit. This
̅
indicates that only one diasteroisomer is obtained as a pair of
1
enantiomers, as confirmed previously by H and 13C NMR.
The absolute configuration of the diastereoisomer shown in
Figure 1 is RIrSc according to the ligand priority sequence
C5Me5 > NH2 > Ccarbene > Ph.16 The geometry of the complex
is the expected three-legged piano stool with dihedral angles
close to 90° except for the C(6)−Ir(1)−N(2) angle of
77.51(14)° due to the chelate coordination of the [1-(1-
naphthyl)ethyl]amine. The C−N ortho-metalated amine forms
a five-membered ring in an envelope conformation, where the
N atom is out of the plane by 0.34 Å. The methyl group C(4)
attached at the benzylic carbon adopts an axial disposition
enforced by the naphthyl group, as previously described for
other complexes with this ligand.17 The iridium distances are
Ir(1)−Ccarbene 2.044(4) Å, Ir(1)−C(6) 2.061(4) Å, and Ir(1)−
N(2) 2.128(3) Å and lie in the expected range for
Cp*Ir(NHC) complexes.
Complexes 3 and 4 were evaluated as catalyst precursors in
transfer hydrogenation of ketones. Both complexes require the
addition of a strong base to be active. The reactions were
carried out using in iPrOH in the presence of catalytic amounts
of tBuONa and a catalyst loading of 1 mol % (Table 1).
Aromatic and aliphatic carbonyls are reduced to the
corresponding alcohols in quantitative yields in 2 h at 70 °C,
although most of the substrates only required 2 h at 50 °C to
achieve yields over 95% (Table 1, entries 1−14). Acetophenone
was converted into 1-phenylethanol quantitatively in 2 h at 50
°C using catalyst 3. When the same reaction was carried out
using catalyst 4, only a 27% yield was obtained (entries 1 and
2). In all cases the catalyst activity of 3 is higher than that
shown by catalyst 4 (entries 1−6), but for some substrates the
difference is small even at 50 °C (entries 7−10). p-
Both complexes were obtained in high yields (92% and 85%,
respectively) after being purified by column chromatography in
silica gel. The cyclometalated iridium complexes are stable in an
air atmosphere in the solid state and solution. The character-
ization of the complexes was made by means of NMR, high-
resolution mass spectroscopy, and elemental analysis. The
ortho-metalated nature of the compounds was initially
confirmed by the data resulting from the electrospray mass
spectrometry (ESI-MS) on the basis of the mass/charge
relation and the isotopic pattern of peaks. Positive ion
electrospray mass spectra analysis of complexes 3 and 4 in
MeCN showed an intense peak for [M]+ at m/z 594 and 678,
respectively. High-resolution mass spectrometry (HRMS)
confirmed the exact mass of these peaks with relative errors
of less than 2 ppm. Direct evidence of cyclometalation is found
1
in the H NMR spectra. Complexes 3 and 4 show a doublet
and a multiplet, respectively (7.96 ppm, d, J = 8.4 Hz, 1H, CHAr
for 3; 7.82−7.71 ppm, m, 2H, CHAr for 4), assigned to the CH
proton next to the ortho-metalated Ir−C bond.15 The ortho-
metalated complexes 3 and 4 are chiral at metal and have a
stereogenic carbon; thus, in principle two diastereomers could
be formed. The 1H NMR and 13C NMR spectra of complexes 3
and 4 show only one set of signals, indicating that only one
diasteroisomer is formed (vide infra). The most characteristic
signals in the 13C NMR are those assigned to the metalated
carbenes at δ 152.9 (complex 3) and 152.2 (complex 4).
B
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a
column chromatography in silica gel. Characterization by ESI-
MS and HRMS gave the same results as previously observed for
Table 1. Transfer Hydrogenation using Complexes 3 and 4
1
complexes 3 and 4. The H NMR and 13C NMR spectra of
complexes 5 and 6 show only one set of signals, indicating that
only one diasteroisomer is formed. In both cases the isomer
obtained is that where the methylene of the [1-(1-naphthyl)-
ethyl]amine is pointing away from the Cp* ligand, as will be
1
described below. The H and 13C NMR spectra of complex 5
are identical with those of 3. This is the first indication that the
same diastereomer is obtained, although in this case there is just
one enantiomer. The molecular structures of complexes 5 and 6
were obtained by X-ray crystallography and confirm the
absolute configuration (vide infra). The circular dichroism
(CD) spectrum of 5 shows three signals at λ 254, 281, and 327
nm for −10.2, 5.3, and 6.1 mdeg, respectively, and in the case of
complex 3 no band is observed (Figure 2). The CD spectrum
of 6 shows three signals at λ 251, 283, and 323 nm for −7.6,
2.6, and 3.5 mdeg, respectively, while complex 4 does not show
any bands.
a
Reactions were carried out with 0.5 mmol of substrate, tBuONa (5
mol %), catalyst (1 mol %), and 2 mL of 2-propanol for 2 h at 50 °C.
b
Yields determined by GC analyses using anisole as internal standard.
c
Yields in parentheses after 2 h at 70 °C.
Bromoacetophenone is converted to the corresponding alcohol
in short times and high yields using both catalysts (entries 7
and 8). No significant differences are observed for o-
bromoacetophenone (entries 9 and 10).
Synthesis and Characterization of Enantiomerically
Pure Catalysts. Asymmetric Transfer Hydrogenation of
Ketones. Once we demonstrated the catalytic activity of the
racemic complexes 3 and 4, we decided to prepare the chiral
version of these catalysts. Following the same procedure
described in Scheme 1, the reaction of [Cp*Ir(Cl)2(Me2Im)]
(1) or [Cp*Ir(Cl)2(nBu2Im)] (2) with the chiral primary
amine (S)-[1-(1-naphthyl)ethyl]amine in the presence of 2
equiv of AgOAc affords the enantiopure iridium complexes 5
and 6 (Scheme 2). Complexes 5 and 6 were also obtained in
high yields (92% and 85%, respectively) after being purified by
Figure 2. Circular dichroism spectra recorded in chloroform at 25 °C:
(top) complex 3 (- - -) and complex 5 (); (bottom) complex 4
(- - -) and complex 6 ().
The molecular structure of complex 5 was confirmed by
means of X-ray diffraction (Figure 3). Single crystals were
obtained by slow evaporation of dichloromethane/hexane
mixtures. Complex 5 crystallizes in the chiral space group
P212121 and contains a single molecule in the asymmetric unit.
This indicates that only one enantiomer is obtained. The
absolute configuration of the enantiomer shown in Figure 3 is
RIrSc according to the ligand priority sequence C5Me5 > NH2 >
Scheme 2
C
carbene > Ph. The geometry of complex 5 and bond lengths and
angles are similar to those described for complex 4 (Figure 1).
C
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absolute configuration of the enantiomer shown in Figure 4 is
RIrSc. The geometry of complex 6 and bond lengths and angles
are similar to those described for complexes 4 and 5 (Figures 1
and 3). The five-membered-ring C−N ortho-metalated amine
is in an envelope conformation, and the N atom is out of the
plane by 0.41 Å. The methyl group C(4) attached at the
benzylic carbon also adopts an axial disposition.
Complexes 5 and 6 were evaluated as catalysts in the
asymmetric transfer hydrogenation of ketones (Table 2). The
Table 2. Asymmetric Transfer Hydrogenation using
a
Complexes 5 and 6
Figure 3. Molecular diagram of complex 5. Ellipsoids are given at the
50% probability level. Only hydrogen atoms bonded to N(2), C(3),
and C(4) are shown. The counterion PF6 and solvent CH2Cl2 have
been omitted for clarity. Selected bond lengths (Å) and angles (deg):
Ir(1)−C(15) 2.043(7), Ir(1)−N(2) 2.138(6), Ir(1)−C(6) 2.063(8),
Ir(1)−Cp(cent) 1.870; C(6)−Ir(1)−N(2) 76.5(3), C(6)−Ir(1)−
C(15) 90.2(3), C(15)−Ir(1)−N(2) 90.1(3).
The five-membered-ring C−N ortho-metalated amine is in an
envelope conformation, and the N atom is out of the plane by
0.43 Å. The methyl group C(4) attached at the benzylic carbon
also adopts an axial disposition.
The molecular structure of complex 6 was confirmed by
means of X-ray diffractometry (Figure 4). Single crystals were
obtained by slow evaporation of dichloromethane/hexane
mixtures. Complex 6 crystallizes in the chiral space group P21
and contains a single molecule in the asymmetric unit, as a
consequence of the presence of only one enantiomer. The
a
Reactions were carried out with 0.5 mmol of substrate, tBuONa (5
mol %), catalyst (1 mol %), and 2 mL of 2-propanol for 8 h at 30 °C.
b
Yields determined by GC analyses using anisole as internal standard.
c
ee values determined using chiral GC.
reaction conditions used in these experiments were the same as
those described previously, but the temperature was decreased
to 30 °C. The catalysts are active at 30 °C, but the yields after 8
h varied depending on the substrate. For example acetophe-
none was quantitatively reduced to the corresponding alcohol
(entries 1 and 2) but 2-acetonaphthone was only partially
reduced (entries 7 and 8). The enantiomeric excesses displayed
by catalysts 5 and 6 ranged from low to moderate. The results
show that catalyst 6 leads to better results than 5, most
probably due to the presence of the bulkier nBu instead of Me
groups (entries 1−10). The best ee values were obtained using
catalyst 6 for the reduction of acetophenone (ee 55%) and 2′-
methylacetophenone (ee 58%) (entries 2 and 6).
DFT Studies on the Reaction Mechanism. Mechanistic
studies have been carried out at the DFT/M06 level of theory
(see Computational Details). As the experimental work was
intended to achieve pure chiral molecules, we believed in the
importance of using the full metal complex for the calculations,
avoiding any simplification from the original catalyst. Thus, we
decided to investigate the mechanism on the basis of the
methyl-substituted NHC complex 5. We avoided the n-butyl-
substituted complex 6 in order to prevent collateral problems
Figure 4. Molecular diagram of complex 6. Ellipsoids are given at the
50% probability level. Only hydrogen atoms bonded to N(2), C(3),
and C(4) are shown. The counterion PF6 has been omitted for clarity.
Selected bond lengths (Å) and angles (deg): Ir(1)−C(15) 2.047(3),
Ir(1)−N(2) 2.135(2), Ir(1)−C(6) 2.068(3), Ir(1)−Cp(cent) 1.858;
C(6)−Ir(1)−N(2) 77.14(10), C(6)−Ir(1)−C(15) 91.98(12),
C(15)−Ir(1)−N(2) 89.57(11).
D
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derived from the presence of different conformers. The transfer
hydrogenation reaction was studied using isopropyl alcohol and
acetophenone as hydrogen source and hydrogen acceptor,
respectively, as model substrates.9c,18
The experimental results show that the iridium(III) catalytic
systems obtained in this work are highly active in the transfer
hydrogenation process at low temperatures. The reaction
proceeds at relatively low temperatures (30 °C), and the ee
values obtained ranged from low to moderate. Other points
that deserve further discussion are the following. (i) We have
not observed decoordination of any of the ligands in the metal
coordination sphere during the course of the experimental
studies, although very recently catalyst activation by loss of Cp*
has been reported in Cp*Ir complexes bearing two NHCs.10b
(ii) We did not find any evidence supporting either the
formation of a hydride complex or the participation of a such
type of species in the catalytic cycle. These and the imperative
need for a strong base in the reaction media to activate the
catalyst (5:1 base to catalyst molar ratio) suggest an outer-
sphere mechanism involving an iridium amido derivative as the
active species in the catalytic cycle, with the iridium amine
precursor remaining as the resting state.
Figure 5. Molecular diagrams of the DFT optimized complexes and
adducts A-DFT, B-DFT, C-DFT, and D-DFT. Most hydrogen atoms
have been omitted for clarity.
Scheme 3. Relative Free Energies in Solution (iPrOH) of the
Iridium Alkoxide (A-DFT) and Amido Alcohol Species (B-
Whereas important efforts have been devoted to the
determination of the mechanisms operating in Ru-catalyzed
TH reactions by means of theoretical calculations,10d,18b,19
analogous studies on TH processes promoted by iridium
systems are scarce.7b,9c,20 As a starting point, the relative
energies of the two pairs of enantiomers were evaluated. The
RIrSC/SIrRC pair (5a-DFT) is found to be 1.6 kcal/mol more
stable (ΔGiPrOH) than the RIrRC/SIrSC pair (5b-DFT) (Scheme
S1, Supporting Information). Although small barriers have to
be taken with caution, this relative energy order is in agreement
with the experimental results found in the synthesis of
complexes 3 and 4 (Scheme 1), suggesting that the process is
thermodynamically controlled. The converged structure of 5a-
DFT compares well with that found for 5 by X-ray
crystallography, with the five-member aza-irida-metallacycle
ring showing an envelope conformation in which the N atom is
slightly out of the plane, by 0.46 Å. The Ir−Ccarbene, Ir−
a
DFT and C-DFT)
a
Relative free energies in the gas phase are shown in parentheses.
C
metallacycle, and Ir−N bond distances in 5a-DFT are 2.06, 2.08,
the iridium amido complex D-DFT would dehydrogenate
isopropyl alcohol to give an iridium amine η4-cyclopentadiene
species (P1-3-DFT) that would subsequently transfer H2 to the
prochiral ketone in the second step (Scheme 4). This latter
transfer could happen with two possible substrate orientations,
thus leading to the formation of the two alcohol enantiomers
(R and S).
and 2.19 Å, respectively.
A second issue that has been addressed is the interaction of
the base with the catalyst precursor. Both the interaction of the
alkoxide with any of the two hydrogen NH atoms and the
formation of an iridium alkoxide complex via amine
decoordination have been considered. The three most
remarkable adducts found are shown in Figure 5 and their
relative energies in Scheme 3. The most favored alkoxide
species (A-DFT) lies 22.5 kcal/mol higher in free energy in
solution with regard to the most favored amido alcohol species
(B-DFT) and 17.9 kcal/mol higher than a second amido
alcohol isomer (C-DFT). These relative energies highlight the
unlikeness of the participation of an iridium alkoxide species in
the cycle.
The structure of the putative iridium amido complex
resulting from the deprotonation of 5 was optimized (D-
DFT; Figure 5). This species is most likely the catalyst of the
studied TH process, as pointed out by the experimental and
theoretical evidence. Two mechanisms consistent with the
discussion presented above have been considered. The first one
(pathway 1-P1, Scheme 4) can be described as a concerted, two-
step, outer-sphere process, involving the participation of the
cyclopentadienyl ring and the amido group.21 In the first step,
The key species of this depicted cycle is the iridium amine η4-
cyclopentadiene P1-3-DFT, which would result from the
alcohol to catalyst transfer hydrogenation. Notably, the
calculated transition state for the first step (P1-1-DFT) is
46.6 kcal/mol higher in ΔG(iPrOH) value with regard to the
free reactants. Consistent with this barrier, the subsequent
transfer hydrogenations from P1-3-DFT to the prochiral
ketone in any of the two possible orientations, therefore
rendering (S)- or (R)-1-phenylethanol, also require 46.0 and
45.7 kcal/mol, respectively (transition states P1-6-DFT and
P1-7-DFT). Thus, the high energy barriers calculated for these
processes (dehydrogenation−transfer hydrogenation) clearly
dismiss this reaction pathway.
The second mechanism would consist of the transfer
hydrogenation from the iridium amido−isopropyl alcohol
adduct (either B-DFT or C-DFT, see above) to the prochiral
ketone, in a concerted, one-step, outer-sphere process. Thus,
E
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Scheme 4. DFT-Calculated Energy Profile for the Concerted, Two-Step, Outer-Sphere Hydrogen Transfer Mechanism
a
(Pathway 1)
a
i
Relative free energies in PrOH solution and in the gas phase (in parentheses) are shown. Only TSs are shown for clarity.
Scheme 5. DFT-Calculated Energy Profile for One of the Four Possible Concerted, One-Step, Outer-Sphere Hydrogen
a
Mechanisms (Pathway 2-1a)
a
i
Relative free energies in PrOH solution and in the gas phase (in parentheses) are shown. Only the TS is shown for clarity.
depending on the relative orientation of the alcohol and the
prochiral ketone with regard to the iridium catalyst, four
variants can be envisaged, alternatively leading to the formation
of one of the two enantiomers. For clarity, only one of these
pathways is shown in the main text (Scheme 5). The complete
series, including the four different variants of the mechanism
and the species involved, can be found in the Supporting
Information (Scheme S2-5).
Four different transition states were found (Figure 6), two of
them leading to (R)-1-phenylethanol (P2-1a-2-DFT, P2-2b-2-
DFT), and the other two leading to (S)-1-phenylethanol (P2-
1b-2-DFT, P2-2a-2-DFT). Interestingly, the calculated energy
barriers (ΔGsolv) of these concerted processes lay in the 24.3−
25.7 kcal/mol range (18.6−21.2 kcal/mol in ΔGgas), data that
seem consistent with the experimental results. Furthermore, the
relative energies of the TSs found leading to either the R or the
S alcohol enantiomers present very similar values with regard to
each other. In other words, the DFT calculations do not predict
remarkable ee values in favor of any of the enantiomers. This
result also seems in good agreement with the poor
enantiomeric excess obtained in the studied experiment.
The whole set of transition states found for this mechanism
are “hydrogen-bonding organized” TSs. All of them are markedly
synchronous, thus supporting concerted processes. The most
significant geometric parameters are collected in Table 3. The
H···O distances in the referred transition states only vary from
1.77 to 1.93 Å (distances c and d), whereas the H···C distances
remain in the 1.33−1.39 Å range (distances g and h). Hydrogen
bonding organized transition states have been proposed
previously in a few catalytic reactions, including the Ru-
catalyzed enantioselective Michael addition of 1,3-dicarbonyl
compounds to cyclic enones and the Ir-catalyzed asymmetric
transfer hydrogenation of nitroalkenes.20b,22
In order to gain additional experimental evidence for the
proposed mechanism, replacement of the NH group by an N-
alkyl group was investigated. The introduction of this alkyl
group should inhibit the formation of the hydrogen bonding
organized transition state and have an effect on the catalytic
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activation of certain substrates, which can afford improved
catalytic activities and/or selectivities. The catalysts presented
in this work also constitute a rare and remarkable example
showing that inert, octahedral, chiral at metal complexes can
have successful applications in catalysis. Thus, despite the
inertness toward substitution reactions of our Cp*Ir(III)
systems, transfer hydrogenation processes efficiently proceed
mediated by the NH ligand. Substitutionally inert species, if
catalytically active, may lead to robust catalysts, therefore
presenting higher turnover numbers. Although up to now our
complexes only induce low to moderate ee values, the synergy
among Cp*Ir moieties, NHC ligands, and primary amines
holds great promise for the design of bulky systems showing
improved performances in asymmetric transfer hydrogenations,
and also in other catalytic processes. Further studies are
currently underway in our laboratory and will be reported in
due course.
CONCLUSIONS
■
We have described the synthesis on new Cp*Ir complexes
bearing an N-heterocyclic carbene ligand and a chelated
primary benzylamine. The complexes are chiral at metal and
have a stereogenic carbon at the benzylamine ligand. The
synthesis is diastereoselective, and the origin is thermodynami-
cally controlled. From the catalytic results, we conclude that
cyclometalated iridium complexes based on chiral primary
benzylamines are very active in transfer hydrogenation: for
example, acetophenone is reduced to 1-phenylethanol in 2 h at
50 °C using catalyst 3. More interestingly is that no base, apart
from that required for catalyst activation, is needed in the
process. Unfortunately, the enantioselectivities obtained using
the chiral benzylamines are from low to moderate, achieving a
maximum of 58% ee in the case of 2′-methylacetophenone.
Preliminary mechanistic studies by means of DFT calculations
suggest that the mechanism is based on a direct hydrogen
Figure 6. Molecular diagrams of the DFT optimized transition states
P2-1a-2-DFT, P2-1b-2-DFT, P2-2a-2-DFT, and P2-2b-2-DFT. Most
hydrogen atoms have been omitted for clarity.
activity. The reaction of [Cp*Ir(Cl)2(Me2Im)] (1) or [Cp*Ir-
(Cl)2(nBu2Im)] (2) with the secondary amine (S)-N,α-
dimethylbenzylamine in the presence of 2 equiv of AgOAc
under the same conditions as described in Scheme 1 did not
afford any ortho-metalated complex. Modifying the reaction
conditions by increasing the temperature gave the same result.
It is well-known that NH moieties of ligands have unique
functions that can give rise to wide applications in organo-
metallic catalysis.3 These include the recognition and/or
Table 3. Relative Energies and Representative Geometric Parameters of the Four Transition States Found for the Concerted,
a
One-Step, Outer-Sphere Hydrogen Mechanism (Pathway 2)
distance
P2-1a-2-DFT (R1a = Ph)
P2-1b-2-DFT (R1b = Ph)
P2-2a-2-DFT (R2a = Ph)
P2-2b-2-DFT (R2b = Ph)
enantiomer
ΔG(iPrOH)
ΔG(gas)
N−H
N−H
H···O
R
S
S
R
24.3
19.4
1.04
1.04
1.85
1.77
1.27
1.28
1.39
1.34
24.6
18.6
1.04
1.04
1.85
1.89
1.28
1.28
1.34
1.35
24.7
18.8
1.04
1.04
1.81
1.93
1.29
1.28
1.33
1.36
25.7
21.2
1.04
1.04
1.79
1.81
1.28
1.28
1.33
1.35
a
b
c
d
e
f
H···O
OC
OC
C···H
g
h
C···H
a
Energies are expressed in kcal/mol and distances in Å.
G
dx.doi.org/10.1021/om500888d | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Synthesis of Compounds 3 and 4. In a Schlenk flask were
placed 0.17 mmol of the corresponding iridium compound (1 or 2),
0.34 mmol of silver acetate, and 10 mL of deoxygenated acetonitrile.
The mixture was stirred at room temperature for 15 min. To the
suspension was added 0.17 mmol of 1-(1-naphthyl)ethylamine, and
the mixture was stirred at room temperature for 4 h. The resulting
mixture was filtered over Celite, and the solvent was removed under
reduced pressure. The crude product was purified by column
chromatography. Elution with acetone−KPF6 solution afforded the
separation of a yellow band that contained the title compound.
Crystallization from dichloromethane/hexane gave the corresponding
compound as a yellow crystalline solid.
transfer via highly ordered transition state centered at the
iridium amido group. An understanding of the mechanism will
allow the rational design of new and more efficient catalysts for
asymmetric hydrogen transfer. Further mechanistic investiga-
tions and the preparation of Cp*Ir complexes with different
chiral primary amines are currently underway in our laboratory.
EXPERIMENTAL SECTION
■
General Procedures. All manipulations were carried out under
nitrogen using standard Schlenk techniques and high vacuum, unless
otherwise stated. Compounds 1 and 2 were prepared according to
literature procedures. Anhydrous solvents were dried using a solvent
purification system or were purchased from commercial suppliers and
degassed prior to use by purging with dry nitrogen and kept over
molecular sieves. NMR spectra were recorded on Varian Innova
spectrometers operating at 300 or 500 MHz (1H NMR) and 75 and
125 MHz (13C NMR), respectively, using CDCl3 as solvent at room
temperature unless otherwise stated. Elemental analyses were carried
out in an EA 1108 CHNS-O Carlo Erbaanalyzer. Electrospray mass
spectra (ESI-MS) were recorded on a MicromassQuatro LC
instrument, and nitrogen was employed as drying and nebulizing
gas. Circular dichroism (CD) measurements were recorded on a
JASCO J-810 spectropolarimeter in chloroform solutions.
Compound 3. Yield: 117 mg (92%). 1H NMR (300 MHz,
CD3CN): δ 7.96 (d, J = 8.4 Hz, 1H, CHAr), 7.80 (d, J = 8.5 Hz, 1H,
CHAr), 7.65−7.53 (m, 2H, CHAr), 7.41−7.27 (m, 2H, CHAr), 7.19 (d, J
= 1.9 Hz, 1H, CHimidazole), 6.97 (d, J = 1.9 Hz, 1H, CHimidazole), 5.07
(broad s, 1H, NH2), 5.01−4.87 (m, 1H, CHCH3), 3.90 (s, 3H,
NCH3), 3.80 (broad s, 1H, NH2), 3.32 (s, 3H, NCH3), 1.72 (s, 15H,
C5(CH3)5), 0.66 (d, J = 6.8 Hz, 3H, CHCH3). 13C{1H} NMR (75
MHz, CD3CN): δ 152.9 (Ccarbene-Ir), [148.2, 142.6, 138.8, 131.8, 129.1,
128.7, 126.7, 126.1, 125.5, 124.2 (CAr)], [123.9, 123.8 (CHimidazole)],
92.2 (C5(CH3)5), 59.3 (CHCH3), [39.2, 39.0 (NCH3)], 18.9
(CHCH3), 9.2 (C5(CH3)5). Anal. Calcd for C27H35N3IrPF6
(738.77): C, 43.89; H, 4.77; N, 5.68. Found: C, 44.25; H, 4.26; N,
5.74. Electrospray MS (cone 20 V; m/z, fragment): 594.2 [M]+.
HRMS ESI-TOF-MS (positive mode): [M]+ monoisotopic peak
594.2464; calcd 594.2462, εr 0.3 ppm.
X-ray Studies. Diffraction data were collected on a Agilent
SuperNova diffractometer equipped with an Atlas CCD detector using
Mo Kα radiation (λ = 0.71073 Å). Single crystals were mounted on a
polymer tip in a random orientation. Absorption corrections based on
the multiscan method were applied.23 The structures were solved by
direct methods in SHELXS-97 and refined by the full-matrix method
based on F2 with the program SHELXL-97 using the OLEX software
package.24 CCDC-1010664 (4), CCDC-1010665 (5), and CCDC-
1010666 (6) contain 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.
Compound 4. Yield: 120 mg (85%). 1H NMR (300 MHz,
CD2Cl2): δ 7.82−7.71 (m, 2H, CHAr), 7.61−7.48 (m, 2H, CHAr),
7.39−7.23 (m, 2H, CHAr), 7.17 (d, J = 2.1 Hz, 1H, CHimidazole), 6.93 (d,
J = 2.1 Hz, 1H, CHimidazole), 5.06−4.91 (m, 1H, CHCH3), 4.72 (broad
s, 1H, NH2), 4.30−4.13 (m, 1H, NCH2-), 4.13−3.94 (m, 2H,
NCH2−), 3.85 (broad s, 1H, NH2), 3.71−3.55 (m, 1H, NCH2-),
2.16−1.98 (m, 1H, −CH2-), 1.98−1.79 (m, 1H, −CH2−), 1.74−1.58
(m, 17H, C5(CH3)5, −CH2−), 1.14−0.98 (m, 7H, −CH2−, −CH3),
0.66 (d, J = 6.8 Hz, 3H, CHCH3), 0.58 (t, J = 7.1 Hz, 3H, −CH3).
13C{1H} NMR (75 MHz, CD3CN): δ 152.2 (Ccarbene-Ir), [148.1, 142.7,
137.9, 131.7, 129.1, 128.4, 127.0, 126.8, 124.3 (CAr)], [123.9, 123.7 8
(CHimidazole)], 122.0 (CAr), 92.3 (C5(CH3)5), 59.5 (CHCH3), [51.5,
50.4 (N−CH2 n-Bu)], [33.6, 33.5(−CH2−CH2 n-Bu)], [21.0, 20.4
(−CH2−CH3 n-Bu)], 19.3 (CHCH3), [14.2, 13.8 (−CH3 n-Bu)], 9.2
(C5(CH3)5). Anal. Calcd for C33H47N3IrPF6 (822.93): C, 48.16; H,
5.75; N, 5.10. Found: C, 48.46; H, 5.97; N, 5.33. Electrospray MS
(cone 20 V; m/z, fragment): 678.5 [M]+. HRMS ESI-TOF-MS
(positive mode): [M]+ monoisotopic peak 678.3411; calcd 678.3401,
εr 1.5 ppm.
Synthesis of Compounds 5 and 6. In a Schlenk flask were
placed 0.17 mmol of the corresponding iridium compound and 0.34
mmol of silver acetate, and 10 mL of deoxygenated acetonitrile was
added. The mixture was stirred at room temperature for 15 min. To
the suspension was added 0.172 mmol of (S)-(−)-1-(1-naphthyl)-
ethylamine, and the mixture was stirred at room temperature for 4 h.
The resulting mixture was filtered over Celite, and the solvent was
removed under reduced pressure. The crude product was purified by
column chromatography. Elution with acetone−KPF6 solution
afforded the separation of a yellow band that contained the compound
and residual KPF6, which was filtered off. Crystallization from
dichloromethane/hexane gave the corresponding compound as a
yellow crystalline solid.
Computational Details. Quantum mechanical calculations were
performed with the Gaussian09 package25 at the DFT/M06 level of
theory.26 The SDD basis set and its corresponding effective core
potentials (ECPs) were used to describe the iridium atom.27 An
additional set of f-type functions was also added.28 Carbon, nitrogen,
oxygen, and hydrogen atoms were described with a 6-31G** basis
set.29,30 Frequency calculations have been performed in order to
determine the nature of the stationary points found (no imaginary
frequencies for minima, only one imaginary frequency for transition
i
states). Free Gibbs energies in PrOH solution (ε = 19.264) were
calculated by computing the energy in the solvent by means of single-
point calculations on the gas-phase optimized geometries with the
SMD continuum solvation model,31 and subsequently applying the
expression
GiPrOH = EiPrOH + (Ggas phase − Egas phase
)
The TS’s connecting two minima were investigated by using a
freeze-scan strategy. C···H distances involved in the C−H bond
forming processes have been frozen in subsequent 0.05 Å steps, and
the structures have been optimized with the referred restriction. The
optimized geometry for the first point has been used as a starting one
for the following point in the profile, and the process has been
repeated for subsequent points. A first approximation for the C−H···C
to C···H−C reaction energy profile is therefore obtained. The highest
energy structure in each studied profile is then used as a starting
geometry in order to find the corresponding TS. In all cases the shape
of the transition vector provided by the frequency calculation in each
of the TS’s is consistent with the proposed mechanism. IRC
computations have been additionally carried out in order to connect
minima and TSs and further strengthen the mechanism proposal.
Three-dimensional visualization of all the optimized structures
discussed is accessible as Supporting Information.
Compound 5. Yield: 102 mg (80%). 1H NMR (300 MHz,
CD3CN): δ 7.96 (d, J = 8.3 Hz, 1H, CHAr), 7.80 (d, J = 7.6 Hz, 1H,
CHAr), 7.65−7.53 (m, 2H, CHAr), 7.42−7.24 (m, 2H, CHAr), 7.19 (d, J
= 1.9 Hz, 1H, CHimidazole), 6.97 (d, J = 1.9 Hz, 1H, CHimidazole), 5.07
(broad s, 1H, NH2), 5.01−4.89 (m, 1H, CHCH3), 3.90 (s, 3H,
NCH3), 3.80 (broad s, 1H, NH2), 3.32 (s, 3H, NCH3), 1.73 (s, 15H,
C5(CH3)5), 0.66 (d, J = 6.6 Hz, 3H, CHCH3). 13C{1H} NMR (75
MHz, CD3CN): δ 152.9 (Ccarbene-Ir), [148.2, 142.6, 138.8, 131.8, 129.1,
128.7, 126.7, 126.1, 125.5, 124.2 (CAr)], [123.9, 123.8 (CHimidazole)],
92.2 (C5(CH3)5), 59.3 (CHCH3), [39.2, 39.0 (NCH3)], 18.9
(CHCH3), 9.2 (C5(CH3)5). Anal. Calcd for C27H35N3IrPF6
H
dx.doi.org/10.1021/om500888d | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
(738.77): C, 43.89; H, 4.77; N, 5.68. Found: C, 44.36; H, 4.61; N,
5.80. Electrospray MS (cone 20 V; m/z, fragment): 594.2 [M]+.
HRMS ESI-TOF-MS (positive mode): [M]+ monoisotopic peak
594.2465; calcd 594.2462, εr 0.4 ppm.
́
de Biocomputacion
the Centro de Supercomputacion
́
y Fısica de Sistemas Complejos (BIFI) and
́
de Galicia (CESGA) for
generous allocation of computational resources.
Compound 6. Yield: 133 mg (94%). 1H NMR (300 MHz,
CD2Cl2): δ 7.82−7.71 (m, 2H, CHAr), 7.61−7.48 (m, 2H, CHAr),
7.39−7.23 (m, 2H, CHAr), 7.17 (d, J = 2.1 Hz, 1H, CHimidazole), 6.93 (d,
J = 2.1 Hz, 1H, CHimidazole), 5.06−4.91 (m, 1H, CHCH3), 4.72 (broad
s, 1H, NH2), 4.30−4.13 (m, 1H, NCH2−), 4.13−3.94 (m, 2H,
NCH2−), 3.85 (broad s, 1H, NH2), 3.71−3.55 (m, 1H, NCH2−),
2.16−1.98 (m, 1H, −CH2−), 1.98−1.79 (m, 1H, −CH2−), 1.74−1.58
(m, 17H, C5(CH3)5, −CH2−), 1.14−0.98 (m, 7H, −CH2−, −CH3),
0.66 (d, J = 6.8 Hz, 3H, CHCH3), 0.58 (t, J = 7.1 Hz, 3H, −CH3).
13C{1H} NMR (75 MHz, CD3CN): δ 152.2 (Ccarbene-Ir), [148.1, 142.7,
137.9, 131.7, 129.1, 128.4, 127.0, 126.8, 124.3 (CAr)], [123.9, 123.7 8
(CHimidazole)], 122.0 (CAr), 92.3 (C5(CH3)5), 59.5 (CHCH3), [51.5,
50.4 (N−CH2- n-Bu)], [33.6, 33.5 (−CH2−CH2 n-Bu)], [21.0, 20.4
(−CH2−CH3 n-Bu)], 19.3 (CHCH3), [14.2, 13.8 (−CH3 n-Bu)], 9.2
(C5(CH3)5). Anal. Calcd for C33H47N3IrPF6·3C6H14 (1081.45): C,
56.64; H, 8.29; N, 3.88. Found: C, 56.21; H, 8.31; N, 3.96.
Electrospray MS (cone 20 V) (m/z, fragment): 678.3 [M]+. HRMS
ESI-TOF-MS (positive mode): [M]+ monoisotopic peak 678.3412;
calcd 678.3401, εr 1.6 ppm.
Catalytic Studies. General Procedure for Transfer Hydro-
genation. The iridium complex (1 mol %) and tBuONa (5 mol %)
were placed together in a Schlenk tube with a Teflon cap. The tube
was then evacuated and filled with nitrogen three times. 2-Propanol (2
mL) and the corresponding ketone (0.5 mmol) were added, and the
mixture was stirred at 50 °C for 2 h. Yields were determined by GC
analyses using anisole (0.5 mmol) as internal standard.
General Procedure for Asymmetric Transfer Hydrogenation. The
iridium complex (1 mol %) and tBuONa (5 mol %) were placed
together in a Schlenk tube with a Teflon cap. The tube was then
evacuated and filled with nitrogen three times. 2-Propanol (2 mL) and
the corresponding ketone (0.5 mmol) were added, and the mixture
was stirred at 30 °C for 8 h. Yields were determined by GC analyses
using anisole (0.5 mmol) as internal standard. The ee was determined
using chiral GC.
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AUTHOR INFORMATION
Corresponding Authors
*M.B.: e-mail, mbaya@unizar.es; fax, (+34) 976761187; tel,
(+34) 976761184.
■
*J.A.M.: e-mail, jmata@uji.es; tel, (+34) 964387516; fax, (+34)
964387522.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We acknowledge financial support from the Ministerio de
■
Ciencia e Innovacion
the Gobierno de Aragon
́
of Spain (CTQ2011-24055/BQU) and
́
́
(Grupo Consolidado E21: Quımica
Inorganica y de los Compuestos Organometal
́
́
icos). We also
thank the “Generalitat Valenciana” for a fellowship (S.S.). The
authors are grateful to the “Serveis Centrals d”Instrumentacio
́
́
Cientıfica (SCIC)” of the Universitat Jaume I and the Instituto
I
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dx.doi.org/10.1021/om500888d | Organometallics XXXX, XXX, XXX−XXX