A proton-responsive annulated mesoionic carbene (MIC) scaffold on IR complex for proton/hydride shuttle: An experimental and computational investigation on reductive amination of aldehyde

Article abstract of DOI:10.1021/acs.organomet.0c00568

A Cp*Ir(III) complex (1) bearing a proton-responsive hydroxy unit on an annulated imidazo[1,2-a][1,8]naphthyridine based mesoionic carbene scaffold was synthesized by two different synthetic routes. The molecular structure of 1 revealed an anionic lactam form of the ligand. The acid?base equilibrium between the lactam-lactim tautomers on the ligand scaffold was examined by ¹H NMR and UV?vis spectra. The pK_a of the appendage ?OH group in the lactim form of 1 was estimated to assess the proton transfer property of the catalyst. The catalytic efficacy of 1 for reductive amination of aldehyde was evaluated by utilizing three different hydrogen sources: molecular H₂ⁱPrOH/KO^tBu combination, and HCOOH/Et₃N (5:2) azeotropic mixture. The HCOOH/Et₃N (5:2) azeotropic mixture rotocol was found to be the best amon the three different h dro enation methods. Catalyst 1 hydrogenates imines chemoselectively over carbonyls under the reaction conditions. A range of aldehydes was reductively aminated to the corresponding secondary amines using the HCOOH/Et₃N (5:2) azeotropic mixture. Further, catalyst 1 showed high efficiency for the reduction of a wide variety of N-heterocyclic imine derivatives. The lactam-lactim tautomerization of the ligand system is proposed for direct hydrogenation, whereas only the lactam form operates in the strongly basic medium (ⁱPrOH/KO^tBu). Under HCOOH/Et₃N (5:2) conditions, the lactam scaffold is not protonated; rather, an outer-sphere hydride transfer from formate to the Ir is proposed, which is supported by ¹H NMR and DFT calculations. Finally, ligand-promoted hydride transfer from metal-hydride to the protonated imine affords the corresponding amine. A close agreement between the experimentally estimated and computed thermodynamic/kinetic parameters gives credence to the metal-ligand cooperative mechanism for the imine hydrogenation reaction using the HCOOH/Et₃N (5:2) azeotropic mixture.

Full text of DOI:10.1021/acs.organomet.0c00568

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Article
A Proton-Responsive Annulated Mesoionic Carbene (MIC) Scaffold
on Ir Complex for Proton/Hydride Shuttle: An Experimental and
Computational Investigation on Reductive Amination of Aldehyde
̈
Pragati Pandey, Prosenjit Daw, Noor U Din Reshi, Kira R. Ehmann, Markus Holscher,* Walter Leitner,
and Jitendra K. Bera*
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ABSTRACT: A Cp*Ir(III) complex (1) bearing a proton-responsive hydroxy unit
on an annulated imidazo[1,2-a][1,8]naphthyridine based mesoionic carbene
scaffold was synthesized by two different synthetic routes. The molecular structure
of 1 revealed an anionic lactam form of the ligand. The acid−base equilibrium
1
between the lactam-lactim tautomers on the ligand scaffold was examined by H
NMR and UV−vis spectra. The pKa of the appendage −OH group in the lactim
form of 1 was estimated to assess the proton transfer property of the catalyst. The
catalytic efficacy of 1 for reductive amination of aldehyde was evaluated by utilizing
i
three different hydrogen sources: molecular H2, PrOH/KOtBu combination, and
HCOOH/Et3N (5:2) azeotropic mixture. The HCOOH/Et3N (5:2) azeotropic
mixture protocol was found to be the best among the three different hydrogenation
methods. Catalyst 1 hydrogenates imines chemoselectively over carbonyls under the reaction conditions. A range of aldehydes was
reductively aminated to the corresponding secondary amines using the HCOOH/Et3N (5:2) azeotropic mixture. Further, catalyst 1
showed high efficiency for the reduction of a wide variety of N-heterocyclic imine derivatives. The lactam-lactim tautomerization of
the ligand system is proposed for direct hydrogenation, whereas only the lactam form operates in the strongly basic medium
(iPrOH/KOtBu). Under HCOOH/Et3N (5:2) conditions, the lactam scaffold is not protonated; rather, an outer-sphere hydride
transfer from formate to the Ir is proposed, which is supported by 1H NMR and DFT calculations. Finally, ligand-promoted hydride
transfer from metal-hydride to the protonated imine affords the corresponding amine. A close agreement between the experimentally
estimated and computed thermodynamic/kinetic parameters gives credence to the metal-ligand cooperative mechanism for the
imine hydrogenation reaction using the HCOOH/Et3N (5:2) azeotropic mixture.
hydrogenation and dehydrogenation reactions.3 Among differ-
INTRODUCTION
■
ent PRUs, the −OH/−O− couple has been exploited widely in
A protic functionality suitably placed on a ligand scaffold
accelerates the hydrogenation/dehydrogenation reactions.1
(de)hydrogenation related reactions. Shvo’s catalyst and its
other metal analogues with hydroxy/keto functionality have
been studied extensively for a wide range of hydrogenation and
transfer hydrogenation reactions of aldehydes, ketones, imines,
alkynes, and alkenes.4 Fujita and Yamaguchi examined the
interconversion between lactam and lactim forms of the 2-
pyridonate and bipyridonate ligands on Ir for the reversible
dehydrogenation/hydrogenation of organic molecules.1b,5
Himeda has developed an array of bidentate protic ligands
based on bipyridine, bipyrimidine, and azole-pyridine/
pyrimidine scaffolds and studied the catalytic efficacies of
The protic ligand is capable of adapting between two distinct
electronic states on gaining or losing a proton. The ligand
electronics influences the proton transfer at the secondary
coordination sphere and the hydride transfer at the metal
center to/from a suitable partner. Several factors must be
considered to develop an efficient hydrogen transfer catalyst
that include the spatial position of the proton-responsive unit
(PRU) with respect to the metal, the acid/base properties of
the PRU, and the metal hydricity.2 The metal-ligand
cooperative action activates a hydrogen molecule (or another
hydrogen source) to generate the hydrogenated form of the
catalyst that features a nucleophilic hydride at the metal center
and a proton on the ligand, which are subsequently transferred
to a suitable substrate. The hydrogenated form of the catalyst
is then regenerated by abstracting a hydride and a proton from
the primary reductant.
Received: August 27, 2020
In recent years, significant advances have been made on the
design and development of protic catalysts for a wide variety of
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their Ir compounds for CO2/HCOOH hydrogenation/
dehydrogenation reactions.1c,d,6 The catalyst bearing a
pyrazole-pyrimidine based ligand (Scheme 1a) where the
hydroxy group on the imidazo-naphthyridine platform with an
aim to access bifunctional hydrogenation and transfer hydro-
genation chemistry (Scheme 2). We argued that a strong σ-
donor abnormal carbene carbon would promote the hydride
transfer from the metal to a substrate and the chelate ligand
would suppress ligand dissociation.15 Annulation with a π-
conjugated system has been demonstrated to modulate the
ligating properties of carbenes.16 The extended π-conjugated
system may sustain the reversible lactam/lactim switch, and
the ligand annulation would avoid undesired “rollover”
cyclometalation.17
Scheme 1. Protic Catalysts Featuring Proton-Responsive
Hydroxy/Keto Functionality
An effort to design such a system led to the isolation of a
Cp*Ir compound bearing the lactam form of the annulated
MIC ligand (Scheme 1e). The ability of this Ir(III) catalyst for
the activation of different reductants (hydrogen source) and
the delivery of proton/hydride to a substrate is examined
through the imine hydrogenation. DFT calculations are
undertaken to gain insight on the (transfer) hydrogenation
mechanisms.
RESULT AND DISSCUSION
■
Synthesis and Structure of 1. Condensation of 7-
hydroxy-2-aminonaphthyridine with α-chloroacetaldehyde af-
forded 7-hydroxy imidazo[1,2-a][1,8]naphthyridine (L1H2)
(see the Supporting Information (SI)), which, upon
quaternization with benzyl bromide, provided the imidazolium
salt [L2H2]Br (Scheme 3). The 1H NMR spectrum of
hydroxy groups are attached to the pyrimidine unit turned out
to be one of the most efficient systems for formic acid
dehydrogenation.7 Szymczak introduced hydroxy groups on
the NNN-type pincer ligand and demonstrated efficient
hydroboration of ketone and nitrile catalyzed by its Ru(II)
complex (Scheme 1b).8 It was shown that not merely the
presence but the position of the PRU is also crucial for metal-
ligand cooperation.9 An N-heterocyclic carbene (NHC) based
protic catalyst bearing a 2-hydroxypyridine moiety (Scheme
1c) was reported by Grotjhan, Webster, and Papish for CO2
hydrogenation and HCOOH dehydrogenation.10 Later,
Yamaguchi employed the same catalyst for alcohol dehydro-
genation in water under base-free conditions.11 A related
picolyl-functionalized NHC ligand featuring an ortho-OH
group showed high catalytic activity in aqueous media for
the N-alkylation of anilines and sulfonamides with alcohols in
the absence of a base.12 In 2019, Choudhury reported a Cp*Ir
catalyst based on a mesoionic carbene (MIC)−uracil hybrid
ligand platform (Scheme 1d), exploiting the lactam−lactim
switch, for the hydrogenation of quinoxalines.13
Scheme 3. Two Different Synthetic Routes of 1
[L2H2]Br exhibits two doublets at δ 8.70 and 8.14 ppm
which are assigned to the imidazolium ring protons. ESI-MS
exhibits a signal at m/z 276.1150 corresponding to [L2H2]+.
The annulated ligand precursor [L2H2]Br is further charac-
terized by X-ray crystallography (see Figure S15).
n
Reaction of [L2H2]Br with excess BuLi and subsequent
We earlier reported an annulated imidazo[1,2-a][1,8]-
naphthyridine platform for the Ru-catalyzed oxidative scission
of olefin to aldehyde where the ligand L was constructed on an
annulated imidazo[1,2-a][1,8]naphthyridine platform
(Scheme 2a).14 Herein, we sought to introduce an ortho-
treatment with 0.5 equiv of [IrCp*(μ-Cl)Cl]2 afforded
1
[IrCp*(L2)Br] (1) in good yield (82%). The H NMR of 1
exhibits a signal for Cp* protons at δ 1.85 ppm. The
appearance of a singlet imidazole proton signal at δ 7.19 ppm
indicates metalation at the imidazole carbon. The carbonyl and
carbene carbons resonate at δ 171.6 and 140.6 ppm,
respectively, in the 13C NMR spectrum. The FT-IR spectrum
of 1 exhibits absorption at 1638 cm−1 for ν(CO) and
suggests the lactam form of the ligand upon metalation. ESI-
MS exhibits signals at m/z 682.1045 and 602.1782 that are
assigned for [1 + H]+ and [1 − Br]+, respectively. The
molecular structure of 1, depicted in Figure 1, confirms chelate
binding of the ligand involving the carbene carbon (Ir1−C1 =
2.064(9) Å) and the naphthyridine nitrogen (Ir1−N3 =
2.130(7) Å). The most interesting feature of 1 is the
dearomatized lactam form of the ligand, revealed by a short
C−O (C9−O1 = 1.208(11) Å) and a long C−N (C9−N3 =
1.393(11) Å) distances. A comparison of the metrical
Scheme 2. Installation of a −OH PRU on an Annulated
MIC Scaffold
B
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[{IrCp*(L1)} + H]+. Treatment of 2 with benzyl bromide at
60 °C for 12 h afforded 1 with 60% yield. The in situ carbene
generation, followed by the metalation, is preferred over the
metalation/quaternization method19 because of overall higher
yield.
Lactam-Lactim Tautomerization of the Ligand Scaf-
fold. The acid−base equilibrium between the lactam and
1
lactim tautomers of the ligand in 1 was studied by H NMR
and UV−vis spectra. Complex 1 was treated with 1 equiv of
trifluoroacetic acid in CD3OD for 10 min and then subjected
to 1H NMR analysis. Downfield shifts were observed for
naphthyridine and imidazole ring protons (Figure 2B; also see
Figure 1. Molecular structure (40% probability thermal ellipsoids) of
1 with important atoms labeled. Hydrogen atoms are omitted for
clarity. Selected bond lengths (Å) and angles (deg): Ir1−C1 2.064(9),
Ir1−N3 2.130(7), Ir1−Br1 2.529(1), Ir1−C18 2.135(9), Ir1−C20
2.180(8), C9−O1 1.208(11), C9−C8 1.486(14), C8−C7 1.339(14),
C7−C6 1.402(13), C6−C10 1.364(12), C10−N3 1.332(10), and
C9−N3 1.393(11). C1−Ir1−N3 78.4(3), N3−Ir1−Br1 83.5(2), N3−
C10−N2 113.9(8), O1−C9−N3 122.4(10).
parameters with a related complex [Ru(L)(COD)Br2]
(Scheme 2a),14 which is devoid of the ortho-hydroxy group,
reveals an interesting pattern. The C−C bond distances of the
metal-bound naphthyridine pyridyl ring in [Ru(L)(COD)Br2]
show the expected intermediate values between single and
double bonds (1.386(11), 1.391(11), 1.400(10), 1.393(9) Å),
typical of an aromatic ring (see the SI). In 1, however, the
long-short pattern of the corresponding C−C distances
(1.486(14), 1.339(14), 1.402(13), and 1.364(12) Å) is
indicative of the dearomatized lactam form of the ligand.
The loss of resonance energy due to ligand dearomatization is
compensated by a stronger iridium−amido bond. A bromide is
coordinated to complete the piano-stool geometry around the
metal.
An alternate route to 1 involves cyclometalation, followed by
N-functionalization (Scheme 3). In a typical cyclometalation
reaction, treatment of 0.5 equiv of [IrCp*(μ-Cl)Cl]2 with
L1H2 in the presence of excess NaOAc under refluxing
dichloroethane for 12 h afforded a hexameric complex
[Cp*IrL1]6 (2). The molecular structure and the topology of
2 are similar to those of a cyclometalated Pd complex with a
related imidazo-naphthyridine ligand reported by us earlier.18
The 1H NMR spectrum of 2 confirms cyclometalation with the
disappearance of one of the imidazole backbone protons. The
X-ray structure of 2 reveals a hexanuclear cluster with a circular
topology (see Figure S16). The asymmetric unit comprises
three crystallographically independent [IrCp*(L1)] units
related to the other half by a center of inversion. The
geometry around each Ir is very similar, and we briefly describe
one [IrCp*(L1)] unit here. The L1 ligand chelates the metal
center through the imidazo carbon and the naphthyridine
nitrogen (Ir1−C1 = 2.046(7) Å, Ir1−N3 = 2.158(5) Å). The
metal is further coordinated to one Cp* and an imidazole
nitrogen from a neighboring molecule (Ir1−N4 = 2.082(6) Å).
The ligand displays a dearomatized lactam form as evident
from a short carbonyl (C9−O1 (1.247(9) Å) and a long C9−
N3 (1.370(9) Å) distances. The 13C NMR signal correspond-
ing to the cyclometalated carbon appears at δ 139.3 ppm. ESI-
MS of 2 exhibits signal at m/z 512.1337 which is assigned for
1
Figure 2. H NMR spectra of 1 in CD3OD (A); with 1 equiv of
CF3COOH (B); after neutralization with 1 equiv of Et3N (C).
Table S3), indicating diminished electron density on the ligand
upon protonation. The naphthyridine protons underwent
significantly higher downfield shifts (0.45−0.67 ppm)
compared to the imidazole proton (0.34 ppm). It suggests
that protonation likely occurs at the lactam oxygen, leading to
the formation of the aromatized and neutral lactim form of the
ligand. Further, when protonated species [1 + H]+ in solution
was treated with 1 equiv of Et3N, the signals of the
naphthyridine and imidazole protons reverted back to the
1
original lactam form (Figure 2C). The H NMR studies thus
reveal a lactam-lactim interconversion of the ligand in 1 on
protonation/deprotonation.
The lactam-to-lactim transformation was further monitored
by UV−vis spectra. Gradual addition of trifluoroacetic acid to a
methanolic solution of 1 led to the disappearance of peaks at
354 and 368 nm and the emergence of two new absorptions at
323 and 336 nm (Figure 3). The wavelength shifts can be
rationalized by the change in the electronic properties of the
ligand upon protonation/deprotonation of PRUs.20 Being a
weaker donor ligand compared to the anionic lactam form, the
neutral lactim ligand decreases the electron density at the
C
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convenient route to one-pot synthesis of substituted amines
(Scheme 4). This method avoids the isolation of in situ
Scheme 4. Reductive Amination Reaction
generated imine products which is tedious due to their limited
stability. Conventionally, stoichiometric amounts of boron
hydrides such as NaBH3CN in acetic acid or NaBH(OAc)3 are
used for RA which afford the nonselective aminated products
and generate copious toxic wastes.25 Further, the noncatalytic
Leuckart−Wallach reaction and the Eschweiler−Clarke meth-
ylation reaction are the classical examples of RA but require an
excess of formic acid and a higher temperature (>100 °C).26
RA methods are also developed under heterogeneous
conditions using Raney nickel or Pd/Al2O3 under high
pressure of H2, but they have shown poor chemoselectivity
for various reducible functional groups such as CO, CN,
NO2, CC over CN.27 An attractive alternative for the RA
is direct hydrogenation or transfer hydrogenation catalyzed by
a transition metal under homogeneous conditions.28 Bifunc-
tional catalysts are particularly interesting since they deliver a
hydride and a proton to the imine and provide a low energy
pathway with high functional group tolerance.29 Hence, we
have chosen reductive amination as a test case to evaluate the
catalytic utility of 1 for proton and hydride delivery to the
imine.
Figure 3. UV−vis titration of 1 with CF3COOH.
metal. The metal d(π) orbital is stabilized, resulting in an
increased metal-to-ligand excitation energy. Thus, the observed
blue shift can be regarded as the reflection of the lactam-to-
lactim transformation upon protonation. Conversely, a red
shift is attributed to lactim-to-lactam conversion upon
deprotonation of 6,6′-dihydroxy-2,2′-bipyridine (DHBP) on
a Cp*Ir complex following a similar argument.21 A gradual
addition of Et3N results in the disappearance of the high-
energy absorption bands, and the original low-energy
absorptions corresponding to the lactam complex 1 reappear.
The pKa of the proton-responsive unit is an important
parameter to gauge the acid/base properties of a protic
catalyst. Among the different methods available,22 we
employed the potentiometric titration for reliable pKa
determination.23 Compound 1 was treated with 1 equiv of
CF3COOH, and the resulting 1:1 (m/m) mixture of [1 + H]+
in methanol/water at room temperature was titrated against a
0.01 M standard solution of NaOH. A sigmoidal curve is
observed from which a pKa of 3.57 is calculated (Figure 4).
Optimization of Reaction Conditions. Direct Hydro-
genation Using H2. Use of H2 gas for the hydrogenation is
preferred over other reducing agents which generate
stoichiometric amounts of waste. The heterolytic cleavage of
H2 is favored by a bifunctional catalyst by polarizing the H−H
bond via cooperative interactions with the metal and the basic
unit of the ligand. Initially, an equimolar mixture of
benzaldehyde and benzylamine was subjected to direct
hydrogenation (5 bar) in the presence of 10 mol % KPF6
and 1 mol % catalyst 1 at 45 °C in toluene, and a quantitative
conversion to dibenzylamine was obtained (see the SI for
optimization study, Table S4). In the polar aprotic solvents
THF, DMSO, and DCM, 1 showed moderate to good activity.
However, the activity improved significantly in polar protic
i
solvents MeOH and PrOH. The use of water as solvent was
Figure 4. Potentiometric titration of [1 + H]+ with NaOH (0.01 M)
solution.
detrimental to the catalytic activity, and only 30% yield was
obtained. Sluggish reactivity of 1 was observed in the
fluorinated solvent 2,2,2-trifluoroethanol (TFE). The attempts
to lower the reaction temperature from 45 °C to room
temperature or to reduce the H2 pressure (1 atm) led to poor
amine conversions. When the reaction was conducted in the
absence of catalyst 1, only 12% conversion was observed.
Eventually, we observed that the reaction was completed
within 3 h in the presence of 1 mol % 1, KPF6(10 mol %), and
5 bar H2 in toluene at 45 °C (Scheme 5).
The corresponding value for the protonated ligand [L2H2]+ is
4.51 (Figure S19). The pKa values in the range of ∼4.0−5.0 are
reported for hydroxy pyridine and dihydroxy bipyridine in
Cp*Ir complexes.13,20a,6e,21 A lower pKa value of [1 + H]+
suggests higher acidity of the lactim form. The 1H NMR, UV−
vis, and pKa experiments thus suggest that 1 is protonated with
trifluoroacetic acid, resulting in the aromatized lactim form of
the ligand that can readily deliver a proton to a substrate.
Reductive Amination of Aldehydes. Amines are widely
found in natural products, fine chemicals, pharmaceuticals, and
agrochemicals.24 Reductive amination (RA) of aldehydes or
ketones with amines in the presence of a reducing reagent is a
i
Transfer Hydrogenation. Use of PrOH/Base. The
transfer hydrogenation (TH) method, due to its operational
simplicity, is considered to be a convenient route.30 Initial
i
studies were carried out with different PrOH/base combina-
tions. The reaction between benzaldehyde (0.5 mmol) and
benzylamine (0.5 mmol) using 1 (1 mol %) and KOtBu (5 mol
D
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Scheme 5. Optimized Conditions for Reductive Amination
via Direct Hydrogenation
Scheme 8. Reductive Amination of Aldehyde with
HCOOH/Et3N
a
i
%) in PrOH after 12 h of reflux afforded only 12%
dibenzylamine (Table S5). Variation of base showed no
improvement in the product formation. However, with the
increase in catalyst (5 mol %) and base loadings (15 mol %),
the yield improved to 83% (Scheme 6). No product formation
was observed in the absence of the catalyst (Table S5). Clearly,
a
Reagents are added together (a) and stepwise (b).
i
the TH using PrOH/KOtBu is not as effective as the direct
loading from 1 mol % to 0.2 mol %, efficiency of the catalytic
system improved. However, further lowering of the catalyst
loading had a detrimental effect on the product formation.
Varying the solvents of different polarity had no significant
effect on the reactivity; however, the conversion was reduced
to 60% in THF. The reaction in neat condition gave the best
results with complete conversion to the amine. In the absence
of any solvent, this method is greener with minimal waste
generation. In the absence of the catalyst under the optimized
conditions, only the imine product was observed.
hydrogenation method.
Scheme 6. Optimized Conditions for Reductive Amination
i
Using PrOH/KOtBu
The catalytic efficacy of 1 for reductive amination of
aldehyde clearly depends on the reaction conditions. For TH
Use of Formic Acid. In recent years, formic acid is
increasingly being used as a convenient hydrogen source for
the reduction of a variety of substrates due to its high
gravimetric hydrogen content (4.4 wt %), nontoxic and
environmentally benign nature.31 The reaction of 1.0 mmol
each of benzaldehyde and benzylamine in the presence of 7/14
mmol of a formic acid/sodium formate combination catalyzed
by 1 mol % of 1 at 75 °C for 6 h in aqueous solution did not
give the desired product dibenzylamine; instead, the hydrolysis
of the imine was observed. To circumvent this undesired
i
using PrOH/KOtBu (basic medium), the reaction is sluggish
and it requires higher catalyst loading, elevated temperature,
and longer reaction time. For direct hydrogenation in neutral
medium, the catalytic activity is improved. The best results are
obtained with the HCOOH/Et3N (5:2) azeotropic mixture
(acidic medium). The reaction profiles of these three different
protocols were studied under respective optimized reaction
conditions (Figures S20−S22). The experimental TOF values
and the Gibbs free energies of activation (ΔGexp) were
estimated,32 which clearly suggest that the protocol employing
the HCOOH/Et3N (5:2) azeotropic mixture is evidently more
efficient compared to hydrogenation using H2 or TH using
iPrOH/KOtBu (Scheme 9).
i
reaction, the solvent was changed from water to PrOH which
led to 85% conversion to dibenzylamine (Scheme 7).
Scheme 7. Reductive Amination with Formic Acid/Sodium
Formate
Scheme 9. Comparison of Different Reductive Amination
Methods
The commercially available HCOOH/Et3N (5:2) azeotropic
mixture (pH = 4.6) was also examined, which is an effective
hydrogen source in both neat and nonaqueous mediums. The
reaction of 1.0 mmol each of benzaldehyde and benzylamine in
the presence of 1 mol % of 1 and 1.0 mL of a HCOOH/Et3N
(5:2) azeotropic mixture under neat condition afforded 55% of
N-benzylformamide along with desired dibenzylamine (45%)
(Scheme 8a). The origin of the N-formylated product is the
direct reaction of benzylamine with formic acid. To avoid the
formation of the side product, instead of adding all the
reagents together, at first imine formation was allowed to take
place and then catalyst and a HCOOH/Et3N (5:2) azeotropic
mixture was added to obtain the hydrogenated amine
exclusively without any trace of N-formylated product
(Scheme 8b). Depending on the nature of the carbonyls and
the amines, different times were allowed for the completion of
the imine formation.
Chemoselectivity of CN over CO. The chemo-
selectivity of catalyst 1 for the reduction of CN over C
O was also investigated. A competitive reaction between imine
and ketone led to the full conversion to amine (100%), and
only 18% of alcohol conversion was observed (Scheme 10a).
When 4-acetyl-N-(4-methoxybenzylidene)aniline was used as a
substrate, selective conversion to the corresponding amine was
observed with a trace of amino alcohol (Scheme 10b). These
results suggest that the imine hydrogenation is preferred over
the carbonyl.29a,33 Under acidic conditions, imine nitrogen is
protonated to the iminium ion which accepts a hydride faster
than the carbonyl.34 It is thus preferable to perform reductive
amination under acidic conditions.
The TH protocol using the HCOOH/Et3N (5:2) azeotropic
mixture was further optimized, and results are summarized in
the SI (Table S6). Interestingly, upon reducing the catalyst
Substrate Scope. On the basis of the results mentioned
above, the protocol using HCOOH/Et3N (5:2) was opted to
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albeit at a slightly elevated temperature of 50 °C (Table 2).
The unsubstituted and 2-, 6-, and 8-substituted quinolines
Scheme 10. Intermolecular (a) and Intramolecular (b)
Chemoselective Reductive Aminations of Imine over
Carbonyl
Table 2. Substrate Scope for Transfer Hydrogenation of N-
a b
,
Heterocyclic Imines Catalyzed by 1
examine the substrate scope. A range of aldehydes were
reductively aminated to the corresponding amines in moderate
to high yields (Table 1).
Table 1. Substrate Scope for Reductive Amination of
a
Aldehyde Catalyzed by 1
a
Reaction conditions: Imine 1.5 mmol, cat. 0.2 mol %, temperature
50 °C, time 2 h, 0.5 mL of HCOOH/Et3N (5:2) azeotropic mixture.
b
Yields were determined by GC−MS using mesitylene as an internal
standard; Isolated yields are given in parentheses. n.d = not detected
a
Reaction conditions: 1.5 mmol of aldehyde, 1.5 mmol of primary
were efficiently hydrogenated in excellent yields (entries 4a−
4f). The hydroxyquinolines were reduced to excellent yields
(entries 4g, 4h). The moderate yield of 57% for 8-
aminoquinoline is probably due to the binding of the substrate
with the metal center (entry 4i). Fused heterocycles 1,10-
phenanthroline and 2,7-dimethyl-1,8-napthyridine were also
reduced to the corresponding products in excellent yields
(entries 4j, 4k). However, for 2-methyl-1,8-naphthyridine, a
mixture of products was obtained where one and both rings are
hydrogenated in equal amounts (entry 4l). A substrate having
both a quinoline moiety and an imine functionality was also
hydrogenated in 98% yield (entry 4m). However, only the
imine could be selectively hydrogenated when the reaction
temperature was restricted to 30 °C. Hydrogenations of inert
N-heterocycles isoquinoline and 2-phenylpyridine proved
difficult (entries 4n, 4o). As expected, the double bond of
the indole was not reduced even at a longer reaction time
under the reaction conditions (entry 4p).
amine, cat. 0.2 mol %, temperature 30 °C, time 1 h, 0.5 mL of
HCOOH/Et3N (5:2) azeotropic mixture. The catalyst and HCOOH/
Et3N were added after 10−30 min of mixing of aldehyde and amine.
Yields were determined by GC−MS using mesitylene as an internal
standard. Isolated yields are given in parentheses.
Both in situ formed N-benzyl aldimine as well as N-phenyl
imine were hydrogenated efficiently (entries 3a, 3b, Table 1).
Reductive amination of aldehydes bearing electron-donating
groups afforded the corresponding products in excellent yields
(entries 3c−3e). Aromatic imines with electron-withdrawing
groups gave high yields. The potentially reducible groups NO2
and CN were tolerated, which is usually not achieved with
boron hydride reduction and heterogeneous catalysis (entries
3f−3h). Long chain aliphatic aldimine was hydrogenated to
give a moderate yield of 67% (entry 3i). An α,β-unsaturated
aldehyde was reductively aminated with the retention of the
CC bond (57%, entry 3j). Aliphatic cyclic aldimine was also
hydrogenated in good yield (74%, entry 3k). Efficient
hydrogenation of heterocyclic aldimine was also realized
(78%, entry 3l). However, the reaction of hexanal with
tridecylamine did not give reductive aminated product.
The saturated N-heterocycle scaffolds of pyridine, indole,
and quinolines are the key entities in various biologically active
molecules, natural products, and drugs.35 The 1,2,3,4-
tetrahydroquinolines are widely found in various natural
products and drugs such as galipinine, oxamniquine,
flumequine, and salsolinol.36 Accordingly, hydrogenations of
N-heterocyclic imines were carried out with excellent yields,
Mechanistic Investigation. Reaction of 1 with HCOOH/
Et3N (5:2) Azeotropic Mixture. To understand the reaction of
1
the HCOOH/Et3N (5:2) azeotropic mixture with 1, a H
NMR study was performed. In a screw cap NMR tube, 1 was
reacted with HCOOH/Et3N (5:2) (10 equiv) in CD3OD at
room temperature for 30 min and then the 1H NMR spectrum
was recorded. Unlike the protonation with trifluoroacetic acid,
no significant chemical shifts were observed for the
naphthyridine proton signals (Figure 5). A new peak at δ
−13.84 ppm appeared with about 80% conversion (calculated
with respect to the methyl proton signals of Cp*) which is
assigned to a metal-hydride.
F
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active species (I). In the direct hydrogenation method, the
active form of the catalyst heterolytically cleaves a H2 molecule
utilizing both the metal center and the lactam oxygen as shown
in II, resulting in the reduced form of the catalyst featuring an
Ir−H and the lactim form of the ligand (intermediate III). It is
then followed by synchronous proton/hydride (H+/H−)
transfer to imine via IV to afford the amine with the
regeneration of catalytic species I. Under the basic reaction
i
conditions with PrOH/KOtBu, an anionic form of the ligand,
stabilized by solvated potassium metal ion, in V is
proposed.9a,37 In the next step, outer-sphere metal-hydride
formation takes place to give VI. Finally, hydride and proton
transfer from metal-hydride and solvent, respectively, to imine
(VII) affords the amine with the regeneration of I.
Figure 5. 1H NMR study of 1 with HCOOH/Et3N (5:2) in CD3OD.
Formation of the metal-hydride intermediate via decarbox-
ylation of the formic acid can follow three pathways: (1) inner-
sphere β-hydride elimination of the metal-formate,38 (2) outer-
sphere hydride transfer through an ion-pair,39 and (3) ligand-
assisted hydride transfer of the formate.40 The presence of a
vacant site at the metal of a putative metal-formate complex is
the prerequisite for a β-hydride elimination pathway. Although
Cp* ring slippage is a possibility,41 it is unlikely as the
reactions are carried out at moderate temperatures (30−50
°C) and for a short duration of 1−2 h. The ligand ensemble
around the metal is not conducive to offer a vacant site, and
Furthermore, a significant upfield shift (0.37 ppm) was
observed for the imidazole proton, indicating higher electron
density at the metal center, likely caused by the hydride ligand.
These observations suggest that the protonation does not
occur at the lactam oxygen; rather, the metal interacts with the
formate anion to generate an Ir−H via decarboxylation (vide
infra). Notably, a stronger acid CF3COOH protonates the
lactam oxygen of the ligand to the lactim, but the HCOOH/
Et3N (5:2) azeotropic mixture is not sufficiently acidic to alter
the ligand electronic structure.
Reaction Mechanism. Herein, we propose different path-
ways for RA of aldehyde with three different hydrogenating
reagents, i.e., hydrogenation with H2, transfer hydrogenations
1
hence, an inner-sphere pathway is discarded. Further, the H
NMR experiments do not support the protonation of lactam
oxygen of the ligand with HCOOH/Et3N. Therefore, a ligand-
assisted hydride transfer pathway is unlikely. An outer-sphere
hydride transfer through an ion-pair VIII is thus proposed for
i
using PrOH/KOtBu and a HCOOH/Et3N (5:2) azeotropic
mixture (Scheme 11). In the initial step, the bromide in the
precatalyst is removed by KPF6 or base to generate a cationic
Scheme 11. Reaction Mechanism
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Figure 6. Gibbs free energy profile for the hydrogenation of N-benzyl-1-phenylmethanimine with H2 in toluene at 45 °C.
Figure 7. Energy profile for the hydrogenation of N-benzyl-1-phenylmethanimine with/in HCOOH/Et3N at 30 °C.
the generation of IX which is supported by the computational
study (vide infra).
Subsequently, a hydride transfer to the protonated imine via
X gives the product. This mechanism is known as outer-sphere
ionic hydrogenation.33,34,42
Computational Study. To gain further insight into the
reaction mechanism, computational studies were performed.
DFT calculations (MN12-L/def2-TZVP(SMD)) were run for
both the direct hydrogenation and the most efficient
HCOOH/Et3N method using the unsaturated cationic iridium
complex A as the catalytically active species (for computational
details, see the SI). The Gibbs free energies of all minima and
transition states were computed for the reaction temperature
which were chosen experimentally (see legends to Figures 6
and 7).
Hydrogenation with H2. The obvious initiation of the imine
hydrogenation is the coordination of one H2 molecule at the
vacant coordination site of A (A = I in Scheme 11), generating
K (Figure 6), with subsequent H2 cleavage under transfer of a
hydride onto the iridium center while the proton is transferred
to the carbonyl oxygen atom of the ligand (TS-KD). The
process requires passing a low barrier of 11.6 kcal/mol and
should be possible even at room temperature at high rate,
leading to the exergonic product D (−5.6 kcal/mol). One
imine molecule then adds to D by forming a hydrogen bridge
between the imine nitrogen atom and the −OH group of the
ligand (E), and the proton transfer leads via TS-EH to H.43 In
H
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transition state TS-HF, the hydride center is transferred from
the metal onto the carbon atom of the former CN double
bond and the hydrogenation product forms a N−H−O bridge
to the carbonyl oxygen atom of the ligand (F). The
dissociation of the amine regenerates the active catalyst species
(A′) and releases a Gibbs free reaction energy of 10.1 kcal/
mol, indicating a clearly exergonic process. The energy span for
this reaction sequence is defined by D (turn over determining
intermediate, TDI) and TS-HF (turn over determining
transition state, TDTS), and amounts to 16.9 kcal/mol.
However, this is true only for the first catalytic cycle. Starting
from the second cycle, the amine being the final product of the
hydrogenation can react in two different ways.
Either it can approach K and initiate the formation of an
ammonium ion by passing the reaction sequence L, TS-LM,
M, in which the H2 molecule of K is heterolytically cleaved,
yielding the neutral iridium hydride M with the ammonium ion
forming a hydrogen bridge with the carbonyl oxygen atom of
the ligand. Alternatively, the amine can approach D and react
to M via the sequence D, N, TS-MN, M, in which the proton
from the −OH group of the ligand is transformed to a carbonyl
group with transfer of the proton to the nitrogen center of the
amine. Either way, the reaction would have to pass via the
lowest lying intermediate in the whole reaction pathway which
is M (−9.0 kcal/mol), and therefore, the energy span is defined
by M being the TDI and the TDTS TS-HF (11.3 kcal/mol)
amounting to an energy span of 20.3 kcal/mol.44 This matches
very well with the experimentally determined value of 21.6
kcal/mol.
Hydrogenation with HCOOH/Et3N. In this mechanistic
scenario, one could either assume that the formate transfers a
hydride to cationic A by first coordinating to it (O) and
reacting via TS-OP to P with the liberation of CO2 (Figure 7)
which is in accordance to the experimental observations. Then,
the triethylammonium ion protonates P via the sequence Q,
TS-QK, resulting in the cationic nonclassical dihydrogen
complex K. H2 cleavage via TS-KD would be the next step, and
D subsequently would hydrogenate the imine as was described
in the previous section. If this sequence was operative, the
energy span would amount to 26.3 kcal/mol at least (sum of
the relative energies of P and TS-KD). In principle, the span
could even be higher depending on the energy of TS-QK.
However, the sequence via Q, TS-QK, and K was not
computed as there is an energetically more favorable pathway.
Instead of producing the nonclassical dihydrogen complex
K, the neutral iridium complex P can interact with a
protonated form of the imine, leading to H. The underlying
metal-free protonation sequence is separately described and
shown in the SI. As a result, the partially cationic carbon atom
of the N-protonated imine interacts with the hydride of P
entering the metal-catalyzed cycle, generating H. The hydride
center subsequently is transferred from the metal complex via
TS-HF (12.3 kcal/mol). The barrier height is 13.9 kcal/mol
while the energy span (sum of the energies of P and TS-HF)
amounts to 18.6 kcal/mol.44 This value also agrees very nicely
with the experimentally determined value of 18.8 kcal/mol.
Furthermore, it should be noted that this reaction sequence is
clearly distinct energetically from the entirely metal-free
alternative as shown in the SI (Figure S24). The completely
metal-free hydrogenation of the imine requires an energy span
of either 20.1 or 23.3 kcal/mol, depending if a pathway with or
without the assistance of Et3N, respectively, is selected. As the
metal-catalyzed energy span is clearly lower and in good
agreement with the experimentally determined span, this result
hints strongly at the metal-catalyzed cycle to be operative in
this imine reduction.
i
For the transfer hydrogenation with PrOH/KOtBu, we
expect the correct computational treatment of charged species
including K+ ions and solvent molecules to be extremely
demanding, which refrained us from studying this presumably
very large and complex energy landscape of the iPrOH/KOtBu
hydrogenation by DFT.
CONCLUSION
■
A proton-responsive iridium(III) catalyst based on an
annulated imidazo[1,2-a][1,8]naphthyridine mesoionic car-
bene platform was synthesized which shows lactam-lactim
acid−base equilibrium. The ability of this protic catalyst to
i
activate H2, PrOH/KOtBu, and HCOOH/Et3N (5:2) and
subsequent delivery of a proton and hydride to an imine is
examined. The best results were obtained with the HCOOH/
Et3N (5:2) azeotropic mixture which requires reduced catalyst
loading and lower operating temperature. The title catalyst
hydrogenates imine chemoselectively in the presence of a
carbonyl functionality. Further, it shows high efficiency toward
the reduction of N-heterocyclic imine derivatives. The pH of
the HCOOH/Et3N (5:2) medium is not sufficiently acidic to
protonate the ligand lactam oxygen. Instead, a hydride transfer
via ion-pair decarboxylation from the formate is proposed to
afford an Ir−H species where the lactam form of the ligand
remains unaltered. Finally, the anionic lactam ligand facilitates
a hydride transfer to the protonated iminea mechanistic
proposal that is supported by DFT calculations. Whereas the
direct hydrogenation in a neutral medium involves the lactam/
lactim interconversion of the ligand scaffold, the anionic lactam
form of the ligand dominates the reaction pathway for iPrOH/
KOtBu (basic medium). In essence, each of the three reduction
systems behaves mechanistically differently, governed by the
acid−base properties of the ligand framework. The dehydro-
genation ability of the catalyst deploying the same lactam/
lactim mode for challenging substrates is currently being
studied in our laboratory.
EXPERIMENTAL SECTION
■
General Procedures. All reactions with metal complexes were
carried out under an atmosphere of purified nitrogen using standard
Schlenk-vessel and vacuum line techniques. Glasswares were flame-
dried under vacuum prior to use. NMR spectra were obtained on
1
JEOL JNM-LA 400 and 500 MHz spectrometers. H NMR chemical
shifts were referenced to the residual hydrogen signal of the
deuterated solvents. The chemical shift is given as dimensionless δ
1
values and is frequency referenced relative to TMS for H and 13C
NMR spectroscopy. Elemental analyses were performed on a
Thermoquest EA1110 CHNS/O analyzer. The crystallized com-
pounds were powdered, washed several times with dry petroleum
ether, and dried in vacuum for at least 48 h prior to elemental
analyses. Infrared spectra were recorded in the range 4000−400 cm−1
on a Vertex 70 Bruker spectrophotometer on KBr pellets. ESI-MS
were recorded on a Waters Micromass Quattro Micro triple-
quadrupole mass spectrometer. The GC−MS experiments were
performed by using an Agilent 7890 A GC and 5975C MS system.
Potentiometric titration was carried out at 25 °C using a Metrohm
794 Basic Titrino instrument connected to a Metrohm AG 9101
Herisau pH glass electrode and a ground-joint diaphragm. Prior to the
experiment, the calibration was carried out with aqueous buffer
solutions at pH 4.00 and 7.00. The ionic strength of the medium was
maintained at I = 0.1 M NaNO3.
I
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1
Materials. Solvents were dried by conventional methods, distilled
under nitrogen, and deoxygenated prior to use. IrCl3·xH2O was
purchased from Arora Matthey Kolkata, India. The compounds
[IrCp*(μ-Cl)Cl]2,45 2-amino-7-hydroxy-1,8-naphthyridine,46 and 1-
(8-bromoquinolin-2-yl)-N-mesitylmethanimine47 were synthesized by
literature procedures.
diethyl ether and dried under vacuo. Yield: 690 mg (90%). H NMR
(400 MHz, CD3OD, 292 K): δ 8.70 (d, J = 2.44, Hz, 1H, Im), 8.42
(d, J = 8.52 Hz, 1H, NP), 8.32 (d, J = 9.16 Hz, 1H, NP), 8.14 (d, J =
2.44 Hz, 1H, Im), 7.87 (d, J = 9.16 Hz, 1H, NP), 7.43−7.36 (m, 5H,
Ph), 7.14 (d, J = 8.52 Hz, 1H, NP), 5.73 (s, 2H, CH2). 13C NMR
(100 MHz, CD3OD, 294 K): 166.3, 141.4, 140.1, 134.5, 134.0, 129.1,
128.8, 128.4, 127.8, 124.5, 113.2, 112.8, 112.5, 105.1, 50.7. HRMS
(ESI) m/z: [M − Br]+ Calcd for C17H14N3O 276.1137; Found
276.1150.
X-ray Data Collections and Refinement. Single crystal X-ray
structural studies were performed on a CCD Bruker SMART APEX
diffractometer equipped with an Oxford Instruments low-temperature
attachment. Data were collected at 100(2) K using graphite-
monochromated Mo Ka radiation (la = 0.71073 Å). The frames
were indexed, integrated, and scaled using SMART and SAINT
software packages,48 and the data were corrected for absorption using
the SADABS program.49 The structures were solved and refined using
the SHELX suite of programs.50 Additional crystallographic
calculations and the masking of the disordered solvents molecules
in 2 were performed by the program Olex-2. A total electron density
of 270 was removed in a unit cell which can be ascribed to six CH2Cl2
and two H2O molecules. The crystallographic figures have been
generated using Diamond 3 software51 (40% probability thermal
ellipsoids). The hydrogen atoms of ligands were included into
geometrically calculated positions in the final stages of the refinement
and were refined according to “riding model”. The hydrogen atom of
OH of [L2H2]Br was located from the difference Fourier map, and
the bond lengths and bond angles were constrained geometrically.
The crystallographic data and pertinent refinement parameters for
[L2H2]Br, 1, and 2 are presented in Tables S1 and S2. CCDC
numbers 1976340−1976342 contain the supplementary crystallo-
graphic data for compounds [L2H2]Br, 1, and 2. These data can be
obtained free of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
n
Synthesis of 1. 0.4 mL of a 1.6 (M) THF solution of BuLi was
added dropwise to a suspension of [L2H2]Br (0.053 g, 0.149 mmol)
in 15 mL at −78 °C. The mixture was allowed to attain −20 °C, and
then 0.059 g (0.074 mmol) of [Cp*IrCl2]2 was added. The mixture
was allowed to attain room temperature and then refluxed for 12 h.
The volatiles were evaporated, the crude solid was redissolved in 15
mL of dichloromethane, and the red mixture was filtered through a
small pad of Celite. The filtrate was evaporated to dryness and
dissolved in a minimum amount of dichloromethane. 15 mL of diethyl
ether was added with stirring to induce precipitation. The obtained
brownish yellow solid was washed with diethyl ether and dried under
vacuum. Crystals suitable for X-ray diffraction were grown by layering
diethyl ether over a concentrated dichloromethane solution of the
solid. Yield: 0.079 g (82%). 1H NMR (400 MHz, CD3OD, 292 K): δ
7.72 (d, J = 8.56 Hz, 1H, NP), 7.61 (d, J = 9.16 Hz, 1H, NP), 7.36−
7.28 (m, 5H), 7.19 (s, 1H, Im), 7.05 (d, J = 9.16 Hz, 1H, NP), 6.45
(d, J = 8.56 Hz, 1H, NP), 5.50 (s, 2H, CH2), 1.85 (s, 15H, Cp*Me).
13C NMR (100 MHz, CD3OD, 292 K): 171.6, 140.6, 137.0, 136.9,
133.1, 130.1, 129.5, 128.6, 124.3, 120.2, 108.7, 101.2, 93.6, 90.2, 51.2,
10.2. ESI-MS, m/z: 682.1045 [M + H]+, 602.1782 [M − Br]+ (z = 1)
(M = Ir(L2)Cp*Br). Anal. Calcd for C27H27N3OBrIr: C, 47.57; H,
3.99; N, 6.16. Found C, 47.52; H, 3.96; N, 6.13.
Computational Details. The computations in this work were
carried out using the Gaussian 09 program package.52 All compounds
were optimized using the MN12-L53 density functional and the def2-
TZVP54 basis set for all elements with the corresponding ECP55 for
iridium. During optimizations, solvent influences were included
implicitly by applying the IEF-PCM-formalism56 with the SMD57
radii model. The automatic density fitting approximation was
activated.58 In order to correct for standard state conditions, pressures
of p = 234 and 648 atm were chosen for solvents toluene and
HCOOH, respectively.59 All optimized structures were subjected to
frequency calculations to prove the existence of local minima and
transition states (i = 0 and 1, respectively). In selected cases, IRC
calculations were carried out to prove the localized transition state to
connect the independently localized preceding/following minimum.
The energies obtained are listed in Tables S8 and S9 for solvents
toluene and HCOOH, respectively, and the thermochemical
parameters were computed using the reaction temperatures
mentioned in the tables and in the main text.
Synthesis of 2. A mixture of [Cp*IrCl2]2 (44 mg, 0.06 mmol) and
NaOAc (28 mg, 0.34 mmol) was dissolved in dichloroethane (10 mL)
and stirred for 30 min. Then L1H2 (21 mg, 0.12 mmol) was added,
and the mixture was refluxed for 24 h under nitrogen. The resulting
yellow suspension was filtered through a small bed of Celite. The
filtrate was then concentrated under reduced pressure, followed by the
addition of 15 mL of diethyl ether with stirring to induce
precipitation. Repeated washings, followed by prolonged drying in
vacuum, provided cyclometalated compound 2 as a yellow solid.
Crystals suitable for X-ray study were grown by slow vapor diffusion
of diethyl ether into a saturated dichloromethane solution of the
1
compound. Yield: 47 mg (84%). H NMR (400 MHz, CDCl3, 292
K): δ 7.59 (d, J = 9.12 Hz, 1H, NP), 7.41 (d J = 9.16 Hz, 1H, NP),
6.80 (s, 1H, Im), 6.69 (d J = 8.72 Hz, 1H, NP), 6.54 (d J = 9.16 Hz,
1H, NP), 1.87 (s, 15H, Cp*Me). 13C NMR (125 MHz, CDCl3, 292
K): 169.0, 139.3, 134.4, 133.9, 131.9, 122.3, 121.0, 107.1, 97.5, 89.4,
88.7, 10.1. ESI-MS, m/z 512.1337 [M + H]+ where M = Ir(L1)Cp*.
Anal. Calcd For C20H20N3OIr: C, 47.04; H, 3.94; N, 8.22 Found: C,
46.91; H, 3.91; N, 8.19.
Synthesis of 1 from 2. In a flame-dried Schlenk flask, 45.0 mg of
2 was taken and dissolved in 10 mL of dichloroethane. To the yellow
solution was added an excess of benzyl bromide, and the reaction
mixture was heated at 60 °C for 12 h. The resulting yellow solution
was filtered through a small bed of Celite. The filtrate was then
concentrated under reduced pressure, followed by the addition of 15
mL of diethyl ether with stirring to induce precipitation. Repeated
washings, followed by drying in vacuum, provided 1 as a brownish
yellow solid. Crystals suitable for X-ray study were grown by slow
vapor diffusion of diethyl ether into a saturated dichloromethane
solution of the compound. Yield: 47 mg (71%).
General Procedure for the Substrate Scope of Reductive
Amination of Aldehyde Catalyzed by 1 Using HCOOH/Et3N
(5:2) Azeotropic Mixture. An aldehyde (1.5 mmol) and primary
amine (1.5 mmol) were mixed together and stirred for 10−30 min.
Then in situ generated imine was hydrogenated by 1 (0.2 mol %) in
the presence of 0.5 mL of the HCOOH/Et3N (5:2) azeotropic
mixture inside a flame-dried 10 mL Schlenk tube for 1 h at 30 °C. The
reaction mixture was neutralized with a saturated solution of
NaHCO3 and extracted with ethyl acetate (EtOAc) (3 × 3 mL).
Synthesis of 7-Hydroxy-imidazo[1,2-a][1,8]naphthyrinide
(L1H2). 2-Amino-7-hydroxy-1,8-naphthyridine (500 mg, 3.1 mmol)
was refluxed in DMF with a small excess of α-choloacetaldehyde (0.7
mL, 4.6 mmol) for 12 h in the presence of an equivalent amount of
NaHCO3 (400 mg, 4.7 mmol). After cooling, the solution was
evaporated to dryness, and the residue was soluble in 1/5 methanol/
dichloromethane solution and filtered. The filtrate was evaporated and
chromatographed on silica and eluted with methanol/dichloro-
1
methane to give the pure product. Yield: 402 mg (70%). H NMR
(500 MHz, DMSO-d6, 292 K): δ 8.30 (d, J = 1.1 Hz,1H, Im), 8.16 (d,
J = 8.6 Hz, 1H, NP), 7.58 (d, J = 9.15 Hz, 1H, NP), 7.52 (d, J = 0.92
Hz, 1H, Im), 7.33 (d, J = 9.2 Hz, 1H, NP), 6.81 (d, J = 8.6 Hz, 1H,
NP). 13C NMR (125 MHz, DMSO-d6, 294 K): 163.8, 141.5, 132.0,
126.1, 113.1, 111.7, 110.7, 110.5, 110.6. HRMS (ESI), m/z: [M + H]+
Calcd for C10H8N3O 186.0667; Found 186.0577.
Synthesis of [L2H2]Br. Benzyl bromide (10 mL) was added to a
solution of 8-hydroxy-imidazo[1,2-a][1,8]naphthyrinide (400 mg,
2.20 mmol) in 3 mL of dry THF, and the solution was heated at 80
°C for 3 days in a closed pressure tube. An off-white precipitate
started to form during the course of reaction. After cooling, the solid
was collected by filtration and washed thoroughly with benzene and
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The diluted solution was passed through a short column of silica and
was subjected to GC−MS analysis using mesitylene as an internal
standard to determine yield. The volatiles were then evaporated under
vacuo, and the residue was purified by column chromatography on
silica gel using petroleum ether/EtOAc and triethylamine (1%) to
isolate the desired secondary amine.
General Procedure for Transfer Hydrogenation of N-
Heterocycle Imines Catalyzed by 1 Using HCOOH/Et3N (5:2)
Azeotropic Mixture. The N-heterocycle (1.5 mmol) and 1 (0.2 mol
%) in the presence of 0.5 mL of the HCOOH/Et3N (5:2) azeotropic
mixture in a flame-dried 10 mL Schlenk tube were mixed and stirred
for 2 h at 50 °C. The reaction mixture was neutralized with a
saturated solution of NaHCO3 and extracted with ethyl acetate
(EtOAc) (3 × 3 mL). The diluted solution was passed through a
short column of silica and was subjected to GC−MS analysis using
mesitylene as internal standard to determine yield. The volatiles were
then evaporated under vacuo, and the residue was purified and
isolated by column chromatography on silica gel (petroleum ether/
EtOAc) to get the desired product (Table 2).
Mu
6100-9656
̈
lheim an der Ruhr, Germany; orcid.org/0000-0001-
Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the anonymous reviewers for valuable suggestions
and Dr. Ramesh Ramapanicker for useful discussions. Financial
support from the Science and Engineering Research Board
(SERB) and the Department of Atomic Energy (DAE) are
gratefully acknowledged. J.K.B. thanks SERB, India, for a J. C.
Bose fellowship. P.P. thanks CSIR, India, for a fellowship.
N.U.D.R. thanks IIT Kanpur for a post-doctoral fellowship.
REFERENCES
■
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.organomet.0c00568.
■
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Additional experimental details, supporting schemes, and
characterization data (PDF)
Cartesian coordinates of the calculated structures (XYZ)
Accession Codes
CCDC 1976340−1976342 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,
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AUTHOR INFORMATION
Corresponding Authors
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Markus Holscher − Institut fur Technische und
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Email: hoelscher@itmc.rwth-aachen.de
Jitendra K. Bera − Department of Chemistry and Center for
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Prosenjit Daw − Department of Chemistry and Center for
Environmental Science and Engineering, Indian Institute of
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Noor U Din Reshi − Department of Chemistry and Center for
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