Homogeneous Nickel-Catalyzed Sustainable Synthesis of Quinoline and Quinoxaline under Aerobic Conditions

Article abstract of DOI:10.1021/acs.joc.0c01819

Dehydrogenative coupling-based reactions have emerged as an efficient route toward the synthesis of a plethora of heterocyclic rings. Herein, we report an efficacious, nickel-catalyzed synthesis of two important heterocycles such as quinoline and quinoxaline. The catalyst is molecularly defined, is phosphine-free, and can operate at a mild reaction temperature of 80 °C. Both the heterocycles can be easily assembled via double dehydrogenative coupling, starting from 2-aminobenzyl alcohol/1-phenylethanol and diamine/diol, respectively, in a shorter span of reaction time. This environmentally benign synthetic protocol employing an inexpensive catalyst can rival many other transition-metal systems that have been developed for the fabrication of two putative heterocycles. Mechanistically, the dehydrogenation of secondary alcohol follows clean pseudo-first-order kinetics and exhibits a sizable kinetic isotope effect. Intriguingly, this catalyst provides an example of storing the trapped hydrogen in the ligand backbone, avoiding metal-hydride formation. Easy regeneration of the oxidized form of the catalyst under aerobic/O2 oxidation makes this protocol eco-friendly and easy to handle.

Full text of DOI:10.1021/acs.joc.0c01819

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Article
Homogeneous Nickel-Catalyzed Sustainable Synthesis of Quinoline
and Quinoxaline under Aerobic Conditions
Amreen K. Bains, Vikramjeet Singh, and Debashis Adhikari*
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ABSTRACT: Dehydrogenative coupling-based reactions have
emerged as an efficient route toward the synthesis of a plethora
of heterocyclic rings. Herein, we report an efficacious, nickel-
catalyzed synthesis of two important heterocycles such as quinoline
and quinoxaline. The catalyst is molecularly defined, is phosphine-
free, and can operate at a mild reaction temperature of 80 °C. Both
the heterocycles can be easily assembled via double dehydrogen-
ative coupling, starting from 2-aminobenzyl alcohol/1-phenyl-
ethanol and diamine/diol, respectively, in a shorter span of reaction time. This environmentally benign synthetic protocol employing
an inexpensive catalyst can rival many other transition-metal systems that have been developed for the fabrication of two putative
heterocycles. Mechanistically, the dehydrogenation of secondary alcohol follows clean pseudo-first-order kinetics and exhibits a
sizable kinetic isotope effect. Intriguingly, this catalyst provides an example of storing the trapped hydrogen in the ligand backbone,
avoiding metal-hydride formation. Easy regeneration of the oxidized form of the catalyst under aerobic/O2 oxidation makes this
protocol eco-friendly and easy to handle.
amino aldehyde was the starting material.4 Despite the ease of
assembling this heterocyclic product adopting this method, the
INTRODUCTION
■
Quinoline is an important heterocycle that is ubiquitously
̈
Friedlander synthesis is fraught with multiple difficulties
found in natural products, medicinally useful molecules, and
pharmaceuticals.1 The presence of quinoline derivatives in
biologically relevant molecules is widespread, and some of the
prototypical examples are described in Figure 1. In addition,
there is a considerable use of quinoline-based architectures in
including instability of the starting molecule under basic
reaction conditions.5 As a viable alternative, the modified
̈
Friedlander synthesis started with an amino alcohol to
circumvent the problem of intermediate instability. In recent
times, oxidative annulation methods provided some attractive
solution in this direction by the in situ generation of the
carbonyl motif from alcohols.6 To this end, a wide array of
transition-metal catalysts have been employed toward the
synthesis of quinoline relying on dehydrogenative cyclization-
based protocols. Adopting a one-pot dehydrogenation
approach ensures that sensitive carbonyl compounds are
generated in situ and thus maintain a low concentration, so
that unwanted side reactions are minimized as well as tedious
purifications are avoided.
the preparation of functional materials.2 The early synthesis of
3
̈
quinolines was based on the Friedlander synthesis, where an
Toward the utilization of oxidative dehydrogenation
methodology, earlier examples were heavily dominated by
noble metals. The catalytic synthesis of quinolines via modified
̈
Friedlander synthesis including either alcohols or ketones was
described by the group of Shim,7 Milstein,8 Yus,9 Kaneda,10
Received: July 29, 2020
Figure 1. Quinoline skeletons present in important drugs/natural
products.
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Nagoka,11 and others12 employing Ru catalysis. Parallel to
these efforts, other noble metals such as Re,13 Pd,14 and Ir15
have been deployed for acceptorless dehydrogenation reac-
tions16 en route to the synthesis of heterocycles. Lately, the
urge for sustainable and eco-friendly synthesis has switched the
attention more toward base metals as a surrogate to their
heavy-metal congeners.17 First, base-metal-catalyzed annula-
a
Table 1. Screening of Optimal Reaction Conditions
S. No
catalyst loading
base
yield % (1a)
tion for the synthesis of quinoline was attempted by Sortais
1
2
3
4
5
6
7
8
KOtBu (0.4 equiv)
KOtBu (0.25 equiv)
KOtBu (0.4 equiv)
KOtBu (0.5 equiv)
KOtBu (0.4 equiv)
KOH (0.4 equiv)
NaOH (0.4 equiv)
K2CO3 (0.4 equiv)
NaOtBu (0.4 equiv)
-
23
56
89
92
70
36
11
-
64
-
65
trace
18
̈
and Darcel using a Knolker-type iron complex. Since then,
1 (5 mol %)
1 (5 mol %)
1 (5 mol %)
1 (2.5 mol %)
1 (5 mol %)
1 (5 mol %)
1 (5 mol %)
1 (5 mol %)
1 (5 mol %)
1 (5 mol %)
NiCl2
other earth-abundant 3d transition metals such as Mn,19 Co,20
and Ni21 have been used for the synthesis of quinoline via
oxidative dehydrogenation approaches. Despite the successful
implementation of a few base metals in this synthesis, high-
temperature, stoichiometric base loading leaves scope for
further improvement. Additionally, multistep synthesis of
designer ligands or the cost of some expensive metal precursor
often overshadows the cost-benefit associated with base metals.
To this end, a cheap, phosphine-free, and air-stable catalyst
that can operate under mild reaction conditions is highly
desirable. Herein, we report an inexpensive, isolable nickel
catalyst that works in an aerobic atmosphere for the easy
synthesis of quinoline and quinoxaline under very mild
reaction conditions. We showcase that the ligand’s intimate
participation in the reaction, avoiding a relatively unstable or
sensitive metal-hydride formation can be a useful strategy to
bring the reaction conditions down to a milder one.
9
10
11a
12
KOtBu (0.4 equiv)
KOtBu (0.4 equiv)
a
Reaction conditions: 1 (5 mol %), 2-aminobenzyl alcohol (1 mmol),
1-phenylethanol (1 mmol), KOtBu (0.4 mmol), toluene (2 mL), 80
°C (oil bath), O2 balloon, 8 h (isolated yield). awithout O2 balloon, in
air.
reductant.26 (Table 1, entry 3). The amount of base loading
for the reaction was screened further (Table 1, entries 2−5).
Interestingly, 0.5 equiv of base gave the optimum yield, while
further reduction to 0.4 equiv diminished the yield slightly
(entries 3−4). While the reaction can be best performed under
neat O2 (provided by O2-filled balloon), the reaction can also
be carried out in open air, albeit offering a lower yield (entry
11, 65%). A reaction performed under inert conditions
expectedly generated only a trace amount of product. The
reaction with a simple metal salt NiCl2 gives only a trace
amount of product. Notably, the amount of base loading in our
synthetic protocol is substoichiometric (0.4 equiv) that helps
in the tolerance of base-susceptible functional groups in the
substrate. To examine the substrate scope, multiple secondary
alcohols were chosen starting from the substituted 1-phenyl-
ethanol to molecules containing aliphatic and heterocyclic
rings (Table 2). The electron-withdrawing groups at the p-
position of the phenyl ring in a secondary alcohol survived
well, offering good to very good yield of quinolines (2b−2d,
78−85% yields). Similarly, the presence of a highly electron-
withdrawing group such as −CF3 did not hamper the smooth
formation of quinoline 2h in a high yield (75%).
Furthermore, electron-donating groups such as −Me,
−OMe, and −SMe present in the phenyl ring of the secondary
alcohol offered the respective products (2e−2g) in good yields
(71−89%). Encouragingly, secondary alcohols containing
heterocyclic rings such as 1-(pyridine-2-yl)ethanol and 1-
(thiophene-2-yl)ethanol both gave the respective quinolines
(2i, 2j) in nearly 80% yield. A strained cyclopropyl methanol
was also found to be a viable dehydrogenative coupling partner
that furnished the quinoline 2k in 69% yield. To survey the
scope of the reaction further, we scanned a set of aliphatic
alcohols as the substrate. When some cyclic alcohols such as
cyclopentanol, cyclohexanol, and cycloheptanol were used as
the starting substrates, quinoline products 2l−2n were isolated
in good yields (68−82%). This outcome is significantly
different from that of Sortais’ rhenium catalyst where aliphatic
alcohols failed to generate any quinoline product.13
RESULTS AND DISCUSSION
■
We are motivated to develop sustainable synthetic methods
employing base metals, where a redox-active ligand backbone
works in tandem with metals and exhibits cooperative bond
activation. This is one of the emerging trends in base-metal
catalysis, where ligands play a preponderant role in tuning the
electronic structure of the molecule and as a consequence
often elicits chemical noninnocence.22 The use of ligand redox
noninnocence in catalysis became one of the effective strategies
where the proclivity of the 3d metals for one-electron
chemistry can be tuned to emulate the two-electron chemistry
of noble metals.23 We have recently developed a bis-
(azophenolate) nickel complex, 1 (Table 1), where the low-
lying π* orbital of the azo motif generates an azo-based radical
at a low reduction potential, and the radical promotes the
hydrogen atom-transfer (HAT) event.24 This nickel catalyst
successfully performed N-alkylation of a series of amines
employing alcohols as the cheap and abundant source of alkyl
groups. Moreover, the HAT step further assists the
dehydrogenation of saturated N-heterocycles to furnish
benzazoles and pyrimidines.25 Realizing the radical-promoted
dehydrogenating ability of the catalyst, we reasoned its ability
for the synthesis of quinoline and quinoxaline as the alcohol
dehydrogenation is a pivotal step toward their syntheses, when
amino alcohol or diols are their respective starting substrates.
We commenced our study toward the synthesis of quinoline
starting with 2-aminobenzyl alcohol and 1-phenylethanol as
the model substrates (Table 1).
Through a series of optimization studies, it was figured out
that 5 mol % catalyst loading at a temperature of 80 °C for 8 h
fabricated 2-phenylquinoline (2a) in excellent yield (92%).
While scanning the effect of bases (Table 1, entries 6−9), it
was observed that KOH, NaOH, and K2CO3 were very
ineffective in resulting in the product quinoline in 11−36%
yields. Conversely, KOtBu was proved to be very efficient
because parallel to its basic property it is also a mild
B
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Table 2. Variation of Secondary Alcohols for the Synthesis
of Quinoline
Table 3. Scope of Diamine and Diols for the Synthesis of
Quinoxaline
a
a
a
Reaction conditions: 1 (5 mol %), diamine (1 mmol), diol (1
mmol), KOtBu (0.5 mmol), toluene (2 mL), 80 °C (oil bath), O2
balloon, 8 h (isolated yield).
diphenyl-1,2-ethanediol underwent dehydrogenative coupling
with o-phenylenediamine to result in 2,3-diphenyl quinoxaline
(3k) in 70% yield. An aliphatic diol was examined further to
test the efficiency of the protocol in making the respective
quinoxalines. Accordingly, 3,4-hexane diol furnished two
quinoxalines (3l−3m) in 76−77% yields.
a
Reaction conditions: 1 (5 mol %), 2-aminobenzyl alcohol (1 mmol),
secondary alcohol (1 mmol), KOtBu (0.4 mmol), toluene (2 mL), 80
°C (oil bath), O2 balloon, 8 h (isolated yield).
Under this synthetic protocol, a disubstituted quinoline, 2o,
was prepared by applying 2-pentanol as the coupling partner.
Quinoline with fused rings was conveniently synthesized using
1,2,3,4-tetrahydro-6-methoxy-1-naphthalenol, 4-methyl cyclo-
hexanol, and 4-tert-butyl cyclohexanol as coupling partners to
furnish 2p−2r in 64−75% yields. To examine the scalability of
the reaction protocol further, we set a gram-scale synthesis of
quinoline. It was observed that for the large-scale reaction, the
yield remains 73%, justifying that the method is scalable.
After the successful synthesis of a variety of quinolines, we
turned our attention to another important heterocycle
quinoxaline.27 Previously, Milstein,28 Cho,29 Kempe,30 and
Balaraman31 have employed dehydrogenative coupling to
assemble quinolines using a range of transition metals from
Ru, Ir to Mn as catalysts. A recent nickel catalyst example by
Kundu claimed that both homogeneous and heterogeneous
phases have to be active to make quinoxalines albeit at a very
high temperature, 150 °C.32
In our synthesis method, when o-phenylenediamine was
condensed with a series of 1,2-diols, quinoxalines were
prepared conveniently at 80 °C within only 8 h of reaction
time (Table 3). The reaction proceeds via the oxidation of diol
to dione, which upon condensation with diamine liberated two
molecules of water to result in the annulated product. Five
quinoxalines (3a−3e) were prepared in high yields (69−92%)
under our reaction protocol when 1,2-ethanediol was chosen as
the coupling partner. The efficiency of the synthesis procedure
was further tested by changing the nature of the diols. When 1-
phenyl-1,2-ethanediol was surveyed as the diol substrate,
several quinoxalines (3f−3j) were synthesized in 69−80%
yields. As a further variation in the substrate scope, o-
phenylenediamines were substituted by multiple groups
including −Me, −OMe, −Cl, and −Br, all of which offered
substituted 2-phenyl quinoxalines in high yields. Similarly, 1,2-
Mechanistically, quinoline synthesis is a double dehydrogen-
ative coupling, as both the amino alcohol and the secondary
alcohol require dehydrogenation to make a more reactive
carbonyl in situ. We have studied the oxidation of a secondary
alcohol under the reaction conditions to conclude that the
catalyst follows pseudo-first-order kinetics over alcohol (Figure
2). The reaction also exhibits the first-order dependence on the
catalyst loading (see the Supporting Information, Figure S1).
The pseudo-first-order rate constant, kobs, calculated from the
experiment at 80 °C is 2.2 × 10−4 −1 when the catalyst loading
s
is 5 mol %. It is conceivable that our previous mechanistic
details established for primary alcohol oxidation holds true in
the case of secondary alcohol oxidation as well.24 The low-
lying π*-orbital of the azo motif houses an electron by the
reduction of KOtBu, and this azo radical facilitates a hydrogen-
transfer event en route to alcohol oxidation.
To unambiguously ascertain that a hydrogen atom-transfer
step from a bound secondary alcohol to the reduced azo is the
rate-determining step, we measured the primary kinetic isotope
effect (KIE) of the secondary alcohol oxidation step at 80 °C,
the reaction temperature. The measured KIE was observed to
be 8.3 (Scheme 1a). Additionally, the KIE for aminobenzyl
alcohol was also measured at 80 °C to reveal a large value, 9.4
(Scheme 1b, Figure S4). Both values strongly support the fact
that the HAT step is rate-limiting for the oxidation of alcohol.
The HAT step leaves a ketyl radical, which converts to a
ketone upon prompt reduction to another azo ligand in the
backbone. Indeed, the intermediacy of the radical throughout
the reaction is very clear, as an archetypal radical inhibitor such
as TEMPO (1 equiv) results in no product detection (Scheme
1c). The involvement of radicals and a subsequent hydrogen
atom transfer make this catalyst different from other reported
nickel catalysts where the intermediacy of the nickel hydride
was conceived.21a,33 As a conclusive evidence of the azo−
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Figure 2. Kinetic profile of dehydrogenation of 1-phenylethanol (substrate equivalence variation). (a) Growth of product observed by UV−vis
spectroscopy over time and (b) plots for rate constant calculation.
Notably, the optimized reaction conditions for our synthesis
protocol are fairly mild considering the high temperature and
stoichiometric base loading required for a wide variety of
transition-metal catalysts employed for this purpose. We
attribute the efficacy of the process to the abstracted hydrogen
stored in the ligand arm which is fully facilitated by the azo−
hydrazo reversible redox couple. The easy regeneration of the
catalyst is facilitated by aerobic oxidation of the hydrazo
intermediate in the catalytic cycle. The byproduct of this
oxidation is H2O2, which we were able to identify by
performing an iodometric experiment (see the Supporting
Information, Section 4). Although H2O2 is an oxidant, it does
not have further effect on the reaction as it decomposes under
the basic conditions of the reaction. Of note, H2O2 generation
is a stepwise process, and en route to its formation, the
hydroperoxo radical is generated. We did not observe any side
product formed from such radicals, largely attributed to the
lower stability of these intermediates. By relying on hydrogen
storage on the ligand arm, we avoid the metal-hydride
formation, which often confers low stability to the catalyst.
Moreover, metal-hydride formation often requires special
handling in an inert atmosphere owing to the potential
instability of 3d-transition-metal hydrides under aerobic milieu.
A multitude of pincer-type ligands have been developed which
capitalize on metal−ligand cooperativity, and the cooperative
bond activation almost inevitably generates a metal hydride.34
From that perspective, this protocol establishes an alternative
avenue for dehydrogenation. Avoiding that traditional metal-
hydride pathway emerges as a better alternative because the
sustainability of the catalyst may be improved considerably.
Furthermore, the regeneration of the catalyst in conventional
metal−ligand cooperativity requires liberation of H2 by a
pathway where a protic and hydridic hydrogen can form a
bond. This process is often energy demanding35 and a series of
studies tried to establish the role of solvent in assisting the
dehydrogenation of the catalyst.36 The energy demand could
be tuned with the nature of the metal, whose electronic
structure is responsible for imparting hydridic character to the
metal hydride. In the present case, a simple aerobic oxidation
to regenerate the catalyst provides a distinct advantage as this
process is much faster. Indeed, a separate study elucidating the
oxidation of a hydrazo intermediate clearly reveals the process
to follow fast kinetics. Overall, the temperature and time
required for the reaction are reduced considerably compared to
many methods where the process is fully metal-based. Instead,
the noninnocence of the ligand backbone offers a viable
Scheme 1. KIE for Oxidative Dehydrogenation of (a) 1-
Phenylethanol and (b) 2-Aminobenzyl Alcohol by 1, and (c)
Radical Quenching Experiment
hydrazo redox couple responsible for secondary alcohol
dehydrogenation, the hydrazo form of the catalyst was isolated
from a stoichiometric reaction and characterized by multiple
analytical tools.24 The ketone obtained from alcohol oxidation
undergoes a cross-aldol condensation reaction to furnish an
α,β-unsaturated ketone, whose presence is detected during
GC−MS analysis of the reaction progress. Cyclization
following this condensation step leads to the desired quinoline
(Scheme 2).
Scheme 2. Mechanistic Depiction of Quinolone Synthesis
by 1
D
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1H NMR (400 MHz, C6D6): δ 8.33−8.31 (d, J = 8.0 Hz, 2H),
7.75−7.66 (m, 3H), 7.10−7.08 (d, J = 8.0 Hz, 3H), 6.91−6.83 (m,
6H), 4.14 (s, br, 2H), 1.29 (s, 18H), 1.02 (s, 18H). 13C{1H} NMR
(100 MHz, C6D6): δ 155.1, 151.1, 150.9, 148.0, 143.9, 141.7, 139.6,
138.3, 137.7, 130.7, 130.6, 129.4, 128.5, 127.8, 125.9, 124.8, 122.3,
35.7, 35.6, 34.4, 34.0, 31.5, 31.3, 29.8, 29.6 ppm.
alternative to store hydrogen from the substrate alcohol whose
facile regeneration makes the process a milder one.
CONCLUSIONS
■
In summary, we report a very inexpensive, air-stable nickel
catalyst that can successfully synthesize quinoline and
quinoxalines under mild reaction conditions. The ease of
dehydrogenation of the starting substrates is underpinned on
the facile 2e−/2H+ redox reaction of the azo−hydrazo couple,
so that explicit nickel-based chemistry can be avoided. This
report also indicates that the nickel catalyst is efficient for both
borrowing hydrogenation and dehydrogenative coupling
reactions. We further assume that the mild reaction temper-
ature and the short reaction time stem from the combination
of easy dehydrogenation of alcohol via HAT and facile
regeneration of the catalyst under aerobic conditions. We are
actively pursuing the usage of redox non-innocent ligands for
borrowing hydrogen-based reactions where milder reaction
conditions are sought after.
General Procedure for the Synthesis of Quinolines. In a
typical reaction, a 5 mL vial was charged with secondary alcohols (1
mmol), 2-aminobenzyl alcohol (1 mmol), KOtBu (0.4 mmol), and 1
(5 mol %) in 2 mL toluene and was closed with a rubber septum. The
resulting solution was kept under a O2-filled balloon added to the
neck of the reaction flask. The reaction mixture was stirred at 80 °C
for 8 h. The reaction mixture was cooled to room temperature upon
completion and concentrated in vacuo. The residue was purified by
column chromatography using hexane/ethyl acetate (10:1) as an
eluent to afford pure products. The desired coupling products were
1
fully characterized by H and 13C NMR spectroscopy.
General Procedure for the Synthesis of Quinoxalines. In a
typical reaction, a 5 mL vial was charged with ethanediol (1.1 mmol),
o-phenylenediamine (1 mmol), KOtBu (0.5 mmol), and 1 (5 mol %)
in 2 mL toluene and was closed with a rubber septum. The resulting
solution was kept under a O2-filled balloon added to the neck of the
reaction flask. The reaction mixture was stirred at 80 °C for 8 h. The
reaction mixture was cooled to room temperature upon completion
and concentrated in vacuo. The residue was purified by column
chromatography using hexane/ethyl acetate (10:1) as an eluent to
afford pure products. The desired coupling products were fully
EXPERIMENTAL SECTION
■
General Considerations. All the starting compounds employed
in this study were procured from commercial suppliers and were used
without further purification. Potassium tert-butoxide, potassium
hydroxide, and o-phenylene diamine were purchased from Sigma-
Aldrich. Glassware was dried overnight at 160 °C. Solvents such as
methanol, ethanol, and toluene were used as received from the
suppliers. For thin-layer chromatography (TLC), 60 F254 precoated
silica gel (Merck) was used. Column chromatography was performed
using SD Fine silica gel 60−120 mesh using a gradient of ethyl acetate
and hexane as the mobile phase. High-resolution mass spectra were
recorded on a Waters QTOF mass spectrometer. IR spectra were
recorded on a PerkinElmer FT IR spectrometer as KBr pellets, as
1
characterized by H and 13C NMR spectroscopy.
2-Phenylquinoline (2a). White solid (181 mg, 89%); eluent
combination: hexane/ethyl acetate (10:1). Spectroscopic data
matched with those reported in the literature.15b 1H NMR (CDCl3,
400 MHz): δ 8.23−8.18 (m, 4H), 7.88−7.81 (m, 2H), 7.76−7.73 (t,
1H), 7.57−7.47 (m, 4H); 13C{1H} NMR (CDCl3, 100 MHz): δ
157.4, 148.3, 139.7, 136.8, 129.7, 128.9, 127.6, 127.5, 126.3, 119.0
ppm.
2-(4-Fluorophenyl)quinoline (2b). Yellow solid (178 mg, 80%);
eluent combination: hexane/ethyl acetate (10:1). Spectroscopic data
matched with those reported in the literature.13 1H NMR (CDCl3,
400 MHz): δ 8.21−8.15 (m, 4H), 7.83−7.81 (d, 2H), 7.75−7.71 (t,
1H), 7.55−7.51 (m, 1H), 7.23−7.19 (t, 2H); 13C{1H} NMR (CDCl3,
100 MHz): δ 165.1, 162.6, 156.3, 148.3, 137.0, 135.9, 135.8, 129.9,
127.5, 126.4, 118.7, 115.9, 115.7; 19F NMR (CDCl3, 376 MHz): δ
−112.4 ppm.
2-(4-Chlorophenyl)quinoline (2c). White solid (187 mg, 78%);
eluent combination: hexane/ethyl acetate (10:1). Spectroscopic data
matched with those reported in the literature.15b 1H NMR (CDCl3,
400 MHz): δ 8.22−8.11 (m, 4H), 7.83−7.81 (d, 2H), 7.76−7.72 (t,
1H), 7.55−7.48 (m, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ
156.0, 148.3, 138.1, 137.0, 129.9, 129.7, 129.1, 128.9, 127.6, 127.3,
126.6, 118.7 ppm.
2-(4-Bromophenyl)quinoline (2d). Yellow solid (241 mg, 85%);
eluent combination: hexane/ethyl acetate (10:1). Spectroscopic data
matched with those reported in the literature.15b 1H NMR (CDCl3,
400 MHz): δ 8.22−8.15 (t, 2H), 8.05−8.03 (d, 2H), 7.81−7.79 (d,
2H), 7.75−7.72 (t, 1H), 7.65−7.63 (d, 2H), 7.55−7.52 (t, 1H);
13C{1H} NMR (CDCl3, 100 MHz): δ 156.0, 148.3, 138.5, 137.0,
132.0, 129.9, 129.7, 129.1, 127.5, 127.3, 126.6, 124.0, 118.5 ppm.
2-(4-Tolyl)quinoline (2e). White solid (195 mg, 89%); eluent
combination: hexane/ethyl acetate (10:1). Spectroscopic data
matched with those reported in the literature.15b 1H NMR (CDCl3,
400 MHz): δ 8.20−8.17 (t, 2H), 8.10−8.08 (d, 2), 7.86−7.80 (t, 2H),
7.75−7.71 (t, 1H), 7.53−7.50 (m, 1H), 7.36−7.34 (d, 2H), 2.45 (s,
3H); 13C{1H} NMR (CDCl3, 100 MHz): δ 157.3, 148.3, 139.4,
136.9, 136.7, 129.7, 129.6, 127.5, 126.1, 118.9, 21.4 ppm.
1
indicated, with νmax in inverse cm. H NMR and 13C NMR spectra
were recorded on a 400 MHz Bruker Biospin Advance III FT-NMR
spectrometer. NMR shifts were reported as delta (δ) units in parts per
million (ppm) and coupling constants (J) in Hertz (Hz). The
following abbreviations are utilized to describe peak patterns when
appropriate: s = singlet, d = doublet, t = triplet, q = quartet, and m =
multiplet. Chemical shifts (δ) are quoted to the nearest 0.01 ppm
relative to tetramethylsilane (δ 0.00 ppm) in CDCl3 (δ 7.26 ppm).
Carbon chemical shifts are internally referenced to the deuterated
solvent signals in CDCl3 (δ 77.1 ppm).
Synthesis of 1. The azo-phenolate ligand (L) was synthesized
following our reported procedure.24 A methanolic solution of 1 mmol
L was taken in a 100 mL round-bottomed flask and to it 1 mmol
KOH was added and the mixture was stirred at rt for 30 min. Then,
0.5 mmol Ni(OAc)2 was added to the reaction mixture and refluxed
for another 30 min. Immediate precipitate was obtained during the
reflux. After completion of the reaction, the solution was filtered to
obtain 535 mg of a dark brown-colored crystalline solid, 79% yield.
1
The desired product was fully characterized by H and 13C NMR
spectroscopy.
1H NMR (400 MHz, CDCl3): δ 8.45−8.44 (d, 2H), 7.35−7.25 (m,
5H), 1.29 (s, 9H), 1.01 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3):
δ 148.8, 144.3, 139.5, 130.8, 128.6, 125.7, 124.8, 124.8, 122.4, 122.1,
35.7, 34.3, 31.6, 29.5 ppm.
Preparation of Ni(H2L)L. In a 25 mL Schlenk flask, 1 mmol 1 was
suspended in THF solution of 1 mmol benzyl alcohol and 1 mmol
KOtBu and connected to a condenser under nitrogen flow. The
solution was heated to reflux for 4 h. The color of the solution became
maroon quickly. The reaction mixture was dried in vacuo and the
crude was washed with dry hexane (5 mL × 3 times). The crystalline
red color precipitate was dried, collected in 461 mg amount, 68%
2-(4-Methoxyphenyl)quinoline (2f). White solid (167 mg,
71%); eluent combination: hexane/ethyl acetate (10:1). Spectro-
scopic data matched with those reported in the literature.15b 1H NMR
(CDCl3, 400 MHz): δ 8.17−8.14 (m, 4H), 7.82−7.77 (t, 2H), 7.73−
7.69 (m, 1H), 7.51 (m, 1H), 7.06−7.04 (d, 2H), 3.87 (s, 3H);
13C{1H} NMR (CDCl3, 100 MHz): δ 160.8, 156.9, 148.3, 136.6,
1
yield. The desired product was fully characterized by H and 13C
NMR spectroscopy.23
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132.2, 129.6, 129.5, 128.9, 127.5, 126.9, 125.9, 118.5, 114.2, 55.4
ppm.
2.47 (s, 3H), 1.38−1.35 (t, 3H); 13C{1H} NMR (CDCl3, 100 MHz):
δ 154.1, 141.3, 129.8, 125.7, 123.3, 123.0, 122.0, 121.6, 120.3, 28.9,
22.4, 13.7 ppm.
2-(4-(Methylthio)phenyl)quinolone (2g). White solid (201 mg,
80%); eluent combination: hexane/ethyl acetate (10:1). Spectro-
scopic data matched with those reported in the literature.37 1H NMR
(CDCl3, 400 MHz): δ 8.21−8.11 (m, 4H), 7.86−7.81 (m, 2H),
7.74−7.71 (t, 1H), 7.53−7.50 (t, 1H), 7.40−7.38 (d, 2H), 2.55 (s,
3H); 13C{1H} NMR (CDCl3, 100 MHz): δ 156.7, 148.4, 140.5,
136.8, 136.4, 129.8, 129.7, 127.9, 127.5, 126.5, 126.3, 118.7, 15.6
ppm.
2-(4-(Trifluoromethyl)phenyl)quinoline (2h). White solid
(205 mg, 75%); eluent combination: hexane/ethyl acetate (10:1).
Spectroscopic data matched with those reported in the literature.15b
1H NMR (CDCl3, 400 MHz): δ 8.29−8.26 (t, 3H), 8.20−8.18 (d,
1H), 7.90−7.89 (m, 2H), 7.79−7.78 (m, 3H), 7.57 (t, 1H); 13C{1H}
NMR (CDCl3, 100 MHz): δ 155.8, 148.4, 143.1, 137.2, 130.1, 130.0,
128.0, 127.6, 127.0, 125.9, 125.8, 118.9; 19F NMR (CDCl3, 376
MHz): δ −61.2 ppm.
2-(Pyridin-2-yl)quinoline (2i). Pale-yellow solid (160 mg, 78%);
eluent combination: hexane/ethyl acetate (10:1). Spectroscopic data
matched with those reported in the literature.10 1H NMR (CDCl3,
400 MHz): δ 8.76 (d, 1H), 8.68 (dt, 1H), 8.59 (d, 1H), 8.29 (d, 1H),
8.21 (d, 1H), 7.90−7.85 (m, 2H), 7.75 (m, 1H), 7.56 (m, 1H), 7.36
(m, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 152.1, 144.1, 142.1,
141.1, 136.4, 133.9, 131.5, 131.0, 120.5, 129.3, 123.4 ppm.
2-(Thiophen-2-yl)quinoline (2j). White solid (171 mg, 81%);
eluent combination: hexane/ethyl acetate (10:1). Spectroscopic data
matched with those reported in the literature.10 1H NMR (CDCl3,
400 MHz): δ 8.14−8.08 (m, 2H), 7.80−7.76 (m, 2H), 7.74−7.68 (m,
2H), 7.51−7.46 (m, 2H), 7.17−7.15 (dd, 1H); 13C{1H} NMR
(CDCl3, 100 MHz): δ 153.6, 145.2, 133.7, 126.7, 12.6, 124.8, 124.4,
123.4, 123.1, 115.5 ppm.
2-Cyclopropylquinoline (2k). Colorless oil (116 mg, 69%);
eluent combination: hexane/ethyl acetate (15:1). Spectroscopic data
matched with those reported in the literature.13 1H NMR (CDCl3,
400 MHz): δ 7.99−7.95 (m, 2H), 7.72−7.70 (d, 1H), 7.66−7.62 (m,
1H), 7.44−7.40 (t, 1H), 7.14−7.12 (d, 1H), 2.27−2.21 (m, 1H),
1.19−1.15 (m, 2H), 1.11−1.08 (m, 2H); 13C{1H} NMR (CDCl3, 100
MHz): δ 163.3, 147.8, 135.7, 129.1, 128.5, 127.3, 126.6, 125.0, 119.2,
18.0, 10.2 ppm.
3-Methoxy-5,6-dihydrobenzo[c]acridine (2p). Light yellow
solid (167 mg, 64%); eluent combination: hexane/ethyl acetate
(15:1). Spectroscopic data matched with those reported in the
literature.38 1H NMR (CDCl3, 400 MHz): δ 8.20−8.18 (d, 2H), 7.86
(s, 1H), 7.73−7.65 (m, 2H), 7.49−7.46 (m, 1H), 7.20−7.18 (m, 1H),
6.99−6.96 (m, 1H), 3.98 (s, 3H), 3.06 (t, 2H), 2.94−2.92 (m, 2H)
ppm; 13C{1H} NMR (CDCl3, 100 MHz): δ 159.0, 153.2, 147.5,
135.6, 133.7, 131.8, 130.6, 129.3, 129.0, 128.6, 127.9, 126.9, 126.0,
116.9, 109.6, 55.5, 29.0, 27.5 ppm.
2-Methyl-1,2,3,4-tetrahydroacridine (2q). Yellow solid (144
mg, 73%); eluent combination: hexane/ethyl acetate (15:1).
Spectroscopic data matched with those reported in the literature.38
1H NMR (CDCl3, 400 MHz): δ 7.97−7.96 (m, 1H), 7.74 (s, 1H),
7.67−7.65 (m, 1H), 7.60−7.57 (m, 1H), 7.42−7.39 (m, 1H), 3.24−
3.18 (m, 1H), 3.12−2.96 (m, 2H), 2.59−2.53 (m, 1H), 2.07−2.02
(m, 2H), 1.60−1.56 (m, 1H), 1.11−1.10 (d, 3H) ppm; 13C{1H}
NMR (CDCl3, 100 MHz): δ 159.0, 146.7, 135.0, 130.6, 128.5, 128.3,
127.2, 126.9, 125.5, 37.8, 33.1, 31.4, 29.1, 21.7 ppm.
2-tert-Butyl-1,2,3,4-tetrahydroacridine (2r). Light yellow solid
(179 mg, 75%); eluent combination: hexane/ethyl acetate (15:1).
Spectroscopic data matched with those reported in the literature.38 1H
NMR (CDCl3, 400 MHz): δ 7.99−7.96 (m, 1H), 7.82 (s, 1H), 7.71−
7.68 (m, 1H), 7.63−7.57 (m, 1H), 7.45−7.40 (m, 1H), 3.32−3.23
(m, 1H), 3.11−3.01 (m, 2H), 2.77−2.72 (m, 1H), 2.20−2.12 (m,
1H), 1.65−1.52 (m, 2H), 1.00 (s, 9H) ppm; 13C{1H} NMR (CDCl3,
100 MHz): δ 159.5, 146.6, 135.4, 131.3, 128.6, 128.3, 127.2, 126.9,
125.6, 44.7, 34.3, 32.6, 30.8, 27.3, 24.6 ppm.
2-(2-Chlorophenyl)quinoline (2s). White solid (182 mg, 76%);
eluent combination: hexane/ethyl acetate (10:1). Spectroscopic data
matched with those reported in the literature.33a 1H NMR (CDCl3,
400 MHz): δ 8.24−8.17 (m, 2H), 7.89−7.87 (d, 1H), 7.76−7.74 (t,
2H), 7.71−7.69 (d, 1H) 7.61−7.57 (d, 1H), 7.44−7.42 (d, 1H),
7.40−7.37 (m, 2H); 13C{1H} NMR (CDCl3, 100 MHz): δ 135.8,
131.8, 130.2, 130.0, 129.8, 127.7, 127.3, 126.9, 122.9 ppm.
Quinoxaline (3a). White solid (119 mg, 92%); eluent
combination: hexane/ethyl acetate (10:1). Spectroscopic data
matched with those reported in the literature.31 1H NMR (CDCl3,
400 MHz): δ 8.79 (s, 2H), 8.07−8.03 (m, 2H), 7.72−7.70 (m, 2H);
13C{1H} NMR (CDCl3, 100 MHz): δ 145.4, 143.4, 130.5, 129.9.
6-Chloroquinoxaline (3b). Brown solid (139 mg, 85%); eluent
combination: hexane/ethyl acetate (10:1). Spectroscopic data
matched with those reported in the literature.39 1H NMR (CDCl3,
400 MHz): δ 8.85−8.83 (d, 2H), 8.11−8.10 (d, 1H), 8.06−8.04 (d,
1H), 7.74−7.71 (d, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 146.0,
145.3, 143.5, 141.7, 136.1, 131.4, 131.0, 128.6 ppm.
2,3-Dihydro-1H-cyclopenta[b]quinolone (2l). Light yellow oil
(120 mg, 71%); eluent combination: hexane/ethyl acetate (15:1).
Spectroscopic data matched with those reported in the literature.13 1H
NMR (CDCl3, 400 MHz): δ 8.04−8.02 (d, 1H), 7.81 (s, 1H), 7.67−
7.65 (d, 1H), 7.59−7.55 (t, 1H), 7.41−7.37 (t, 1H), 3.18−3.08 (m,
4H), 2.08−2.03 (t, 2H) ppm; 13C{1H} NMR (CDCl3, 100 MHz): δ
163.7, 150.9, 139.4, 135.4, 132.9, 132.6, 131.6, 131.3, 129.9, 37.9,
33.6, 27.3 ppm.
1,2,3,4-Tetrahydroacridine (2m). Light yellow oil (150 mg,
82%); eluent combination: hexane/ethyl acetate (15:1). Spectro-
scopic data matched with those reported in the literature.13 1H NMR
(CDCl3, 400 MHz): δ 7.98−7.96 (d, 1H), 7.78 (s, 1H), 7.69−7.67
(d, 1H), 7.59−7.57 (m, 1H), 7.44−7.40 (m, 1H), 3.14−3.11 (t, 2H),
2.98−2.94 (t, 2H), 1.99−1.97 (m, 2H), 1.89−1.88 (m, 2H) ppm;
13C{1H} NMR (CDCl3, 100 MHz): δ 159.4, 146.6, 135.1, 131.0,
128.6, 128.3, 127.3, 126.9, 125.6, 33.6, 29.3, 23.3, 23.0 ppm.
7,8,9,10-Tetrahydro-6H-cyclohepta[b]quinoline (2n). White
solid (134 mg, 68%); eluent combination: hexane/ethyl acetate
(15:1). Spectroscopic data matched with those reported in the
literature.13 1H NMR (CDCl3, 400 MHz): δ 8.00−7.98 (d, 1H), 7.73
(s, 1H), 7.66−7.64 (d, 1H), 7.58−7.57 (t, 1H), 7.42−7.39 (t, 1H),
3.19−3.16 (m, 2H), 2.87−2.86 (m, 2H), 1.85−1.84 (m, 2H), 1.76−
1.69 ppm (m, 4H). 13C{1H} NMR (CDCl3, 100 MHz): δ 160.9,
148.1, 136.9, 132.8, 130.0, 129., 128.7, 128.4, 127.1, 31.4, 29.1, 27.8,
22.3, 13.9 ppm.
6-Bromoquinoxaline (3c). White solid (159 mg, 76%); eluent
combination: hexane/ethyl acetate (10:1). Spectroscopic data
matched with those reported in the literature.40 1H NMR (CDCl3,
400 MHz): δ 8.77 (s, 2H), 8.20 (s, 1H), 7.90−7.87 (d, 1H), 7.77−
7.75 (d, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 145.6, 145.1,
143.4, 141.6, 133.6, 131.7, 130.8, 124.0 ppm.
6-Methylquinoxaline (3d). Orange oil (111 mg, 77%); eluent
combination: hexane/ethyl acetate (10:1). Spectroscopic data
matched with those reported in the literature.39 1H NMR (CDCl3,
400 MHz): δ 8.70−8.67 (d, 2H), 7.91−7.88 (d, 1H), 7.77 (s, 1H),
7.50−7.48 (d, 1H), 2.49 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz):
δ 144.8, 144.0, 142.9, 141.4, 140.6, 132.3, 128.9, 128.1, 21.8 ppm.
6-Methoxyquinoxaline (3e). Yellow solid (110 mg, 69%); eluent
combination: hexane/ethyl acetate (10:1). Spectroscopic data
matched with those reported in the literature.39 1H NMR (CDCl3,
400 MHz): δ 8.75 (s, 1H), 8.69 (s, 1H), 7.99−7.96 (d, 1H), 7.43−
7.41 (d, 1H), 7.37 (s, 1H), 3.97 (s, 3H); 13C{1H} NMR (CDCl3, 100
MHz): δ 160.9, 145.0, 144.7, 142.5, 139.3, 130.5, 123.6, 106.7, 55.9
ppm.
3-Ethyl-2-methylquinoline (2o). Light yellow oil (121 mg,
71%), eluent combination: hexane/ethyl acetate (15:1). Spectro-
scopic data matched with those reported in the literature.11 1H NMR
(CDCl3, 400 MHz): δ 8.03−8.01 (d, 1H), 7.81 (s, 1H), 7.69−7.67
(d, 1H), 7.62−7.58 (m, 1H), 7.45−7.41 (m, 1H), 3.01−2.96 (t, 2H),
2-Phenylquinoxaline (3f). Yellow oil (146 mg, 71%); eluent
combination: hexane/ethyl acetate (10:1). Spectroscopic data
matched with those reported in the literature.32 1H NMR (CDCl3,
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400 MHz): δ 9.32 (s, 1H), 8.20−8.11 (m, 4H), 7.79−7.72 (m, 2H),
7.58−7.50 (m, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ 151.9,
143.4, 142.3, 141.6, 136.8, 130.3, 130.2, 129.7, 129.6, 129.2, 129.2,
127.6, 127.6 ppm.
7-Methyl-2-phenylquinoxaline (3g). White solid (152 mg,
69%); eluent combination: hexane/ethyl acetate (10:1). Spectro-
scopic data matched with those reported in the literature.31 1H NMR
(CDCl3, 400 MHz): δ 9.27−9.25 (d, 1H), 8.18 (d, 2H), 8.17−8.16
(m, 1H), 8.01−7.99 (m, 4H), 2.6 (s, 3H); 13C{1H} NMR (CDCl3,
100 MHz): δ 151.8, 151.1, 143.3, 142.5, 142.4, 140.9, 140.2, 140.1,
137.0, 132.7, 131.9, 130.1, 130.0, 129.2, 129.2, 128.7, 128.5, 128.0,
127.6, 127.5, 21.9, 21.9 ppm.
7-Methoxy-2-phenylquinoxaline (3h). White solid (170 mg,
72%); eluent combination: hexane/ethyl acetate (10:1). Spectro-
scopic data matched with those reported in the literature.32 1H NMR
(CDCl3, 400 MHz): δ 9.16 (s, 1H), 8.17−8.15 (d, 2H), 8.00−7.98
(d, 1H), 7.56−7.51 (m, 3H), 7.44−7.38 (m, 2H), 3.99 (s, 3H);
13C{1H} NMR (CDCl3, 100 MHz): δ 156.9, 149.9, 127.5, 137.5,
131.4, 130.4, 122.7, 121.9, 117.9, 111.6, 56.1 ppm.
7-Chloro-2-phenylquinoxaline (3i). White solid (180 mg,
75%); eluent combination: hexane/ethyl acetate (10:1). Spectro-
scopic data matched with those reported in the literature.30 1H NMR
(CDCl3, 400 MHz): δ 9.31 (s, 1H), 8.18−8.16 (dd, 2H), 8.10−8.06
(m, 2H), 7.72−7.70 (m, 1H), 7.58−7.53 (m, 3H); 13C{1H} NMR
(CDCl3, 100 MHz): δ 152.5, 143.4, 142.6, 140.1, 136.3, 136.1, 130.6,
130.5, 130.4, 129.2, 128.5, 127.6 ppm.
7-Bromo-2-phenylquinoxaline (3j). White solid (228 mg,
80%); eluent combination: hexane/ethyl acetate (10:1). Spectro-
scopic data matched with those reported in the literature.31 1H NMR
(CDCl3, 400 MHz): δ 9.32 (s, 1H), 8.34−8.33 (d, 1H), 8.19−8.18
(d, 2H), 7.98−7.97 (d, 1H), 7.82−7.80 (d, 1H), 7.58−7.55 (m, 3H);
13C{1H} NMR (CDCl3, 100 MHz): δ 156.2, 156.1, 149.1, 127.9,
136.9, 136.7, 129.8, 129.5, 128.3, 127.6, 126.7, 124.0, 121.8, 118.9
ppm.
2,3-Diphenylquinoxaline (3k). White solid (197 mg, 70%);
eluent combination: hexane/ethyl acetate (10:1). Spectroscopic data
matched with those reported in the literature.39 1H NMR (CDCl3,
400 MHz): δ 8.20−8.18 (dd, 2H), 7.79−7.77 (dd, 2H), 7.54−7.52
(m, 4H), 7.37−7.34 (m, 6H); 13C{1H} NMR (CDCl3, 100 MHz): δ
153.6, 141.3, 139.2, 130.0, 129.9, 129.3, 128.9, 128.4 ppm.
2,3-Diethylquinoxaline (3l). White solid (141 mg, 76%); eluent
combination: hexane/ethyl acetate (10:1). Spectroscopic data
matched with those reported in the literature.41 1H NMR (CDCl3,
400 MHz): δ 7.93−7.91 (m, 2H), 7.54−7.52 (m, 2H), 2.95−2.89 (m,
4H), 1.34−1.30 (m, 6H); 13C{1H} NMR (CDCl3, 100 MHz): δ
157.0, 140.9, 128.9, 128.4, 28.2, 12.3 ppm.
Authors
Amreen K. Bains − Department of Chemical Sciences, Indian
Institute of Science Education and Research Mohali, 140306
Mohali, India
Vikramjeet Singh − Department of Chemical Sciences, Indian
Institute of Science Education and Research Mohali, 140306
Mohali, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c01819
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank SERB (DST), India (grant no. ECR/2017/001764)
for financial support and IISER Mohali for start-up funding.
Central facility in IISER Mohali is acknowledged for providing
analytical data. A.K.B. and V.S. thank IISER Mohali and CSIR
for a research fellowship, respectively.
REFERENCES
■
(1) (a) Jones, G. Comprehensive Heterocyclic Chemistry II; Pergamon:
Oxford: 1996. (b) Lilienkampf, A.; Mao, J.; Wan, B.; Wang, Y.;
Franzblau, S. G.; Kozikowski, A. P. Structure−Activity Relationships
for a Series of Quinoline-Based Compounds Active against
Replicating and NonreplicatingMycobacterium tuberculosis. J. Med.
Chem. 2009, 52, 2109−2118. (c) Shruthi, T. G.; Eswaran, S.;
Shivarudraiah, P.; Narayanan, S.; Subramanian, S. Synthesis,
antituberculosis studies and biological evaluation of new quinoline
derivatives carrying 1,2,4-oxadiazole moiety. Bioorg. Med. Chem. Lett.
2019, 29, 97−102.
(2) Jenekhe, S. A.; Lu, L.; Alam, M. M. New Conjugated Polymers
with Donor−Acceptor Architectures: Synthesis and Photophysics of
Carbazole−Quinoline and Phenothiazine−Quinoline Copolymers
and Oligomers Exhibiting Large Intramolecular Charge Transfer.
Macromolecules 2001, 34, 7315−7324.
̈
(3) (a) Friedlander, P. Ueber o-Amidobenzaldehyde. Ber. Dtsch.
Chem. Ges. 1882, 15, 2572−2575. (b) Climent, M. J.; Iborra, S.;
Sabater, M. J.; Vidal, J. D. Bifunctional acid-base ionic liquid for the
one-pot synthesis of fine chemicals: Thioethers, 2H-chromenes and
2H-quinoline derivatives. Appl. Catal., A 2014, 481, 27−38.
(4) Marco-Contelles, J.; Perez-Mayoral, E.; Samadi, A.; Carreiras, M.
d. C.; Soriano, E. Recent Advances in the Friedlander Reaction. Chem.
́
̈
2,3-Diethyl-6-methyl-quinoxaline (3m). White solid (154 mg,
77%); eluent combination: hexane/ethyl acetate (10:1). Spectro-
scopic data matched with those reported in the literature.41 1H NMR
(CDCl3, 400 MHz): δ 7.77−7.75 (d, 1H), 7.65 (s, 1H), 7.32−7.30
(m, 1H), 2.89−2.84 (m, 4H), 2.40 (s, 3H), 1.30−1.27 (m, 6H);
13C{1H} NMR (CDCl3, 100 MHz): δ 156.7, 155.9, 140.8, 139.2,
138.5, 130.5, 127.8, 127.3, 28.0, 28.0, 21.4, 12.3, 12.2 ppm.
Rev. 2009, 109, 2652−2671.
(5) Kouznetsov, V.; Mendez, L.; Gomez, C. Recent Progress in the
Synthesis of Quinolines. Curr. Org. Chem. 2005, 9, 141−161.
(6) (a) Hamid, M. H. S. A.; Slatford, P. A.; Williams, J. M. J.
Borrowing Hydrogen in the Activation of Alcohols. Adv. Synth. Catal.
2007, 349, 1555−1575. (b) Crabtree, R. H. Homogeneous Transition
Metal Catalysis of Acceptorless Dehydrogenative Alcohol Oxidation:
Applications in Hydrogen Storage and to Heterocycle Synthesis.
Chem. Rev. 2017, 117, 9228−9246.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c01819.
■
sı
(7) Cho, C. S.; Kim, B. T.; Kim, T.-J.; Shim, S. C. Ruthenium-
catalysed oxidative cyclisation of 2-aminobenzyl alcohol with ketones:
modified Friedlaender quinoline synthesis. Chem. Commun. 2001,
2576−2577.
Experimental procedure, spectroscopic data, and
scanned spectra (PDF)
(8) Srimani, D.; Ben-David, Y.; Milstein, D. Direct synthesis of
pyridines and quinolines by coupling of γ-amino-alcohols with
secondary alcohols liberating H2 catalyzed by ruthenium pincer
complexes. Chem. Commun. 2013, 49, 6632−6634.
AUTHOR INFORMATION
Corresponding Author
■
́
(9) Martínez, R.; Brand, G. J.; Ramon, D. J.; Yus, M. [Ru-
(DMSO)4]Cl2 catalyzes the α-alkylation of ketones by alcohols.
Tetrahedron Lett. 2005, 46, 3683−3686.
(10) Motokura, K.; Mizugaki, T.; Ebitani, K.; Kaneda, K.
Multifunctional catalysis of a ruthenium-grafted hydrotalcite: one-
pot synthesis of quinolines from 2-aminobenzyl alcohol and various
Debashis Adhikari − Department of Chemical Sciences, Indian
Institute of Science Education and Research Mohali, 140306
Mohali, India; orcid.org/0000-0001-8399-2962;
Email: adhikari@iisermohali.ac.in
G
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Article
carbonyl compounds via aerobic oxidation and aldol reaction.
Tetrahedron Lett. 2004, 45, 6029−6032.
(11) Chaudhari, C.; Sato, K.; Ogura, Y.; Miayahara, S. I.; Nagaoka,
K. Pr2 O3 Supported Nano-layered Ruthenium Catalyzed Accept-
orless Dehydrogenative Synthesis of 2-Substituted Quinolines and
1,8-Naphthyridines from 2-Aminoaryl Alcohols and Ketones.
ChemCatChem 2020, 12, 2198−2202.
(12) (a) Pan, B.; Liu, B.; Yue, E.; Liu, Q.; Yang, X.; Wang, Z.; Sun,
W.-H. A Ruthenium Catalyst with Unprecedented Effectiveness for
the Coupling Cyclization of γ-Amino Alcohols and Secondary
Alcohols. ACS Catal. 2016, 6, 1247−1253. (b) Xie, F.; Zhang, M.;
Chen, M.; Lv, W.; Jiang, H. Convenient Synthesis of Quinolines from
α-2-Nitroaryl Alcohols and Alcohols via a Ruthenium-catalyzed
Hydrogen Transfer Strategy. ChemCatChem 2015, 7, 349−353.
(13) Wei, D.; Dorcet, V.; Darcel, C.; Sortais, J. B. Synthesis of
Quinolines Through Acceptorless Dehydrogenative Coupling Cata-
lyzed by Rhenium PN(H)P Complexes. ChemSusChem 2019, 12,
3078−3082.
(23) van der Vlugt, J. I. Radical-Type Reactivity and Catalysis by
Single-Electron Transfer to or from Redox-Active Ligands. Chem.
Eur. J. 2019, 25, 2651−2662.
(24) Bains, A. K.; Kundu, A.; Yadav, S.; Adhikari, D. Borrowing
Hydrogen-Mediated N-Alkylation Reactions by a Well-Defined
Homogeneous Nickel Catalyst. ACS Catal. 2019, 9, 9051−9059.
(25) (a) Bains, A. K.; Adhikari, D. Mechanistic insight into the azo
radical-promoted dehydrogenation of heteroarene towards N-hetero-
cycles. Catal. Sci. Technol. 2020, 10, 6309−6318. (b) Bains, A. K.;
Dey, D.; Yadav, S.; Kundu, A.; Adhikari, D. Nickel catalysed
construction of benzazoles via hydrogen atom transfer reactions.
Catal. Sci. Technol. 2020, 10, 6495−6500.
(26) Nocera, G.; Young, A.; Palumbo, F.; Emery, K. J.; Coulthard,
G.; McGuire, T.; Tuttle, T.; Murphy, J. A. Electron Transfer
Reactions: KOtBu (but not NaOtBu) Photoreduces Benzophenone
under Activation by Visible Light. J. Am. Chem. Soc. 2018, 140, 9751−
9757.
̈
(27) (a) Lindner, B. D.; Zhang, Y.; Hofle, S.; Berger, N.; Teusch, C.;
(14) Chen, B. W. J.; Chng, L. L.; Yang, J.; Wei, Y.; Yang, J.; Ying, J.
Y. Palladium-Based Nanocatalyst for One-Pot Synthesis of Poly-
substituted Quinolines. ChemCatChem 2013, 5, 277−283.
(15) (a) Ruch, S.; Irrgang, T.; Kempe, R. New Iridium Catalysts for
the Selective Alkylation of Amines by Alcohols under Mild
Conditions and for the Synthesis of Quinolines by Acceptor-less
Dehydrogenative Condensation. Chem.Eur. J. 2014, 20, 13279−
̧ S.; Arslan, B.; Gulcemal, S.; Gunnaz, S.; Çetinkaya,
̈ ̈
Jesper, M.; Hardcastle, K. I.; Qian, X.; Lemmer, U.; Colsmann, A.;
Bunz, U. H. F.; Hamburger, M. N-Fused quinoxalines and
benzoquinoxalines as attractive emitters for organic light emitting
diodes. J. Mater. Chem. C 2013, 1, 5718−5724. (b) Dailey, S.; Feast,
W. J.; Peace, R. J.; Sage, I. C.; Till, S.; Wood, E. L. Synthesis and
device characterisation of side-chain polymer electron transport
materials for organic semiconductor applications. J. Mater. Chem.
2001, 11, 2238−2243.
(28) Daw, P.; Kumar, A.; Espinosa-Jalapa, N. A.; Diskin-Posner, Y.;
Ben-David, Y.; Milstein, D. Synthesis of Pyrazines and Quinoxalines
via Acceptorless Dehydrogenative Coupling Routes Catalyzed by
Manganese Pincer Complexes. ACS Catal. 2018, 8, 7734−7741.
(29) Cho, C. S.; Oh, S. G. A new ruthenium-catalyzed approach for
quinoxalines from o-phenylenediamines and vicinal-diols. Tetrahedron
Lett. 2006, 47, 5633−5636.
13285. (b) Genc,
B.; Gu
̈
lcemal, D. Iridium(I)-Catalyzed C-C and C-N Bond Formation
Reactions via the Borrowing Hydrogen Strategy. J. Org. Chem. 2019,
84, 6286−6297. (c) Chelucci, G.; Porcheddu, A. Synthesis of
Quinolines via a Metal-Catalyzed Dehydrogenative N-Heterocycliza-
tion. Chem. Rec. 2017, 17, 200−216.
(16) Gunanathan, C.; Milstein, D. Applications of Acceptorless
Dehydrogenation and Related Transformations in Chemical Syn-
thesis. Science 2013, 341, 1229712.
(30) Hille, T.; Irrgang, T.; Kempe, R. The Synthesis of
Benzimidazoles and Quinoxalines from Aromatic Diamines and
Alcohols by Iridium-Catalyzed Acceptorless Dehydrogenative Alkyla-
tion. Chem.Eur. J. 2014, 20, 5569−5572.
(17) Alig, L.; Fritz, M.; Schneider, S. First-Row Transition Metal
(De)Hydrogenation Catalysis Based On Functional Pincer Ligands.
Chem. Rev. 2019, 119, 2681−2751.
(18) Elangovan, S.; Sortais, J.-B.; Beller, M.; Darcel, C. Iron-
Catalyzed α-Alkylation of Ketones with Alcohols. Angew. Chem., Int.
Ed. 2015, 54, 14483−14486.
(31) Mondal, A.; Sahoo, M. K.; Subaramanian, M.; Balaraman, E.
Manganese(I)-Catalyzed Sustainable Synthesis of Quinoxaline and
Quinazoline Derivatives with the Liberation of Dihydrogen. J. Org.
Chem. 2020, 85, 7181−7191.
(19) Barman, M. K.; Jana, A.; Maji, B. Phosphine-Free NNN-
Manganese Complex Catalyzed α-Alkylation of Ketones with Primary
(32) Shee, S.; Panja, D.; Kundu, S. Nickel-Catalyzed Direct
Synthesis of Quinoxalines from 2-Nitroanilines and Vicinal Diols:
Identifying Nature of the Active Catalyst. J. Org. Chem. 2020, 85,
2775−2784.
(33) (a) Parua, S.; Sikari, R.; Sinha, S.; Das, S.; Chakraborty, G.;
Paul, N. D. A nickel catalyzed acceptorless dehydrogenative approach
to quinolines. Org. Biomol. Chem. 2018, 16, 274−284. (b) Arora, V.;
Dutta, M.; Das, K.; Das, B.; Srivastava, H. K.; Kumar, A. Solvent-Free
N-Alkylation and Dehydrogenative Coupling Catalyzed by a Highly
Active Pincer-Nickel Complex. Organometallics 2020, 39, 2162−2176.
(c) Balamurugan, G.; Ramesh, R.; Malecki, J. G. Nickel(II)-NΛNΛO
Pincer Type Complex-Catalyzed N-alkylation of Amines with
Alcohols via the Hydrogen Autotransfer Reaction. J. Org. Chem.
2020, 85, 7125−7135.
̈
Alcohols and Friedlander Quinoline Synthesis. Adv. Synth. Catal.
2018, 360, 3233−3238.
(20) (a) Shee, S.; Ganguli, K.; Jana, K.; Kundu, S. Cobalt complex
catalyzed atom-economical synthesis of quinoxaline, quinoline and 2-
alkylaminoquinoline derivatives. Chem. Commun. 2018, 54, 6883−
6886. (b) Zhang, G.; Wu, J.; Zeng, H.; Zhang, S.; Yin, Z.; Zheng, S.
Cobalt-Catalyzed α-Alkylation of Ketones with Primary Alcohols. Org.
Lett. 2017, 19, 1080−1083.
(21) (a) Das, S.; Maiti, D.; De Sarkar, S. Synthesis of Polysubstituted
Quinolines from α-2-Aminoaryl Alcohols Via Nickel-Catalyzed
Dehydrogenative Coupling. J. Org. Chem. 2018, 83, 2309−2316.
(b) Singh, K.; Vellakkaran, M.; Banerjee, D. A nitrogen-ligated nickel-
catalyst enables selective intermolecular cyclisation of β- and γ-amino
alcohols with ketones: access to five and six-membered N-hetero-
cycles. Green Chem. 2018, 20, 2250−2256. (c) Arun, V.; Mahanty, K.;
De Sarkar, S. Nickel-Catalyzed Dehydrogenative Couplings. Chem-
CatChem 2019, 11, 2243−2259. (d) Chakraborty, G.; Sikari, R.; Das,
S.; Mondal, R.; Sinha, S.; Banerjee, S.; Paul, N. D. Dehydrogenative
Synthesis of Quinolines, 2-Aminoquinolines, and Quinazolines Using
Singlet Diradical Ni(II)-Catalysts. J. Org. Chem. 2019, 84, 2626−
2641. (e) Sikari, R.; Sinha, S.; Chakraborty, G.; Das, S.; Leest, N. P.;
Paul, N. D. C−N Cross-Coupling Reactions Under Mild Conditions
Using Singlet Di-Radical Nickel(II)-Complexes as Catalyst: N-
Arylation and Quinazoline Synthesis. Adv. Synth. Catal. 2019, 361,
4342−4353.
(34) (a) Jana, A.; Das, K.; Kundu, A.; Thorve, P. R.; Adhikari, D.;
Maji, B. A Phosphine-Free Manganese Catalyst Enables Stereo-
selective Synthesis of (1 + n)-Membered Cycloalkanes from Methyl
Ketones and 1,n-Diols. ACS Catal. 2020, 10, 2615−2626.
(b) Kallmeier, F.; Kempe, R. Manganese Complexes for (De)-
Hydrogenation Catalysis: A Comparison to Cobalt and Iron Catalysts.
Angew. Chem., Int. Ed. 2018, 57, 46−60. (c) Mastalir, M.; Glatz, M.;
Pittenauer, E.; Allmaier, G.; Kirchner, K. Sustainable Synthesis of
Quinolines and Pyrimidines Catalyzed by Manganese PNP Pincer
Complexes. J. Am. Chem. Soc. 2016, 138, 15543−15546.
(35) Spasyuk, D.; Gusev, D. G. Acceptorless Dehydrogenative
Coupling of Ethanol and Hydrogenation of Esters and Imines.
Organometallics 2012, 31, 5239−5242.
(22) Luca, O. R.; Crabtree, R. H. Redox-active ligands in catalysis.
Chem. Soc. Rev. 2013, 42, 1440−1459.
H
https://dx.doi.org/10.1021/acs.joc.0c01819
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(36) Smith, N. E.; Bernskoetter, W. H.; Hazari, N. The Role of
Proton Shuttles in the Reversible Activation of Hydrogen via Metal-
Ligand Cooperation. J. Am. Chem. Soc. 2019, 141, 17350−17360.
(37) Azizi, K.; Akrami, S.; Madsen, R. Manganese(III) Porphyrin-
Catalyzed Dehydrogenation of Alcohols to form Imines, Tertiary
Amines and Quinolines. Chem.Eur. J. 2019, 25, 6439−6446.
(38) Forberg, D.; Schwob, T.; Kempe, R. Catalytic condensation for
the formation of polycyclic heteroaromatic compounds. Nat.
Commun. 2018, 9, 1751.
(39) Bhutia, Z. T.; Prasannakumar, G.; Das, A.; Biswas, M.;
Chatterjee, A.; Banerjee, M. A Facile, Catalyst-Free Mechano-
Synthesis of Quinoxalines and their In-Vitro Antibacterial Activity
Study. ChemistrySelect 2017, 2, 1183−1187.
(40) Wang, Q.; Chai, H.; Yu, Z. Acceptorless Dehydrogenation of
N-Heterocycles and Secondary Alcohols by Ru(II)-NNC Complexes
Bearing a Pyrazoyl-indolyl-pyridine Ligand. Organometallics 2018, 37,
584−591.
(41) Micheletti, G.; Delpivo, C.; Carla, B. A Green Synthesis of
Quinoxalines and 2,3-Dihydropyrazines. Synthesis 2013, 45, 1546−
1552.
I
https://dx.doi.org/10.1021/acs.joc.0c01819
J. Org. Chem. XXXX, XXX, XXX−XXX