Synthesis and structure of arene ruthenium(II) complexes: One-pot catalytic approach to synthesis of bioactive quinolines under mild conditions

Article abstract of DOI:10.1002/aoc.4582

Efficient catalytic one-step synthesis of substituted quinoline derivatives using newly synthesized Ru(II) half-sandwich complexes of the type [Ru(η⁶-p-cymene)Cl(L)] (L = pyrrole-2-aldehydehydrazones) under mild conditions is described. The synthesized complexes exhibit excellent catalytic activity towards the coupling of 2-amino alcohol with functionalized ketones and secondary alcohols in the optimal conditions and afforded the corresponding quinoline derivatives. The synthetic pathway proceeds with high atom efficiency via a sequence of acceptorless dehydrogenation and condensation steps. The maximum isolated yield of the product obtained was up to 97% using 0.3?mol% of catalyst loading for 5?h. These findings significantly advance the scope of the synthesis of bioactive heterocyclic compounds from readily available starting materials.

Full text of DOI:10.1002/aoc.4582

Received: 10 July 2018
DOI: 10.1002/aoc.4582
Revised: 7 August 2018
Accepted: 11 August 2018
F U L L P A P E R
Synthesis and structure of arene ruthenium(II) complexes:
One‐pot catalytic approach to synthesis of bioactive
quinolines under mild conditions
Muthumari Subramanian
| Saranya Sundar
| Ramesh Rengan
Centre for Organometallic Chemistry,
School of Chemistry, Bharathidasan
University, Tiruchirappalli 620 024Tamil
Nadu, India
Efficient catalytic one‐step synthesis of substituted quinoline derivatives using
newly synthesized Ru(II) half‐sandwich complexes of the type [Ru(η6‐p‐
cymene)Cl(L)] (L = pyrrole‐2‐aldehydehydrazones) under mild conditions is
described. The synthesized complexes exhibit excellent catalytic activity
towards the coupling of 2‐amino alcohol with functionalized ketones and sec-
ondary alcohols in the optimal conditions and afforded the corresponding
quinoline derivatives. The synthetic pathway proceeds with high atom effi-
ciency via a sequence of acceptorless dehydrogenation and condensation steps.
The maximum isolated yield of the product obtained was up to 97% using
0.3 mol% of catalyst loading for 5 h. These findings significantly advance the
scope of the synthesis of bioactive heterocyclic compounds from readily avail-
able starting materials.
Correspondence
Ramesh Rengan, Centre for
Organometallic Chemistry, School of
Chemistry, Bharathidasan University,
Tiruchirappalli 620 024, Tamil Nadu,
India.
Email: ramesh_bdu@yahoo.com
KEYWORDS
arene Ru(II) benzhydrazone complexes, mild reaction condition, one‐pot synthesis, quinoline
derivatives
1 | INTRODUCTION
Doebner–von Miller and Povarov protocols, have been
used to synthesize the quinoline core because of the
The synthesis of quinolines is the subject of extensive
research in synthetic organic chemistry because of the
presence of these motifs in many pharmacologically active
compounds.[1] Quinolines find many applications in
medicinal chemistry, since they are antimalarial,[2]anti‐
inflammatory,[3] anti‐asthmatic,[4] antibacterial,[5] antihy-
pertensive,[6] anaesthetic,[7] antipsychotic[8] and tyrosine
kinase inhibitory agents[9] (Scheme 1). Quinoline‐based
polymers have been reported recently for applications as
thermally stable transparent materials in the fields of
electronics, optoelectronics and nonlinear optics.[10] In
addition, nanostructures and mesostructures with
improved electronic and photonic properties have been
prepared using various quinolines.[11]
excellent activities of the quinoline motif.[12] However,
harsh reaction conditions, low stereoselectivity, multiple
steps and low yields limit the applicability of these
methods.[13] It is worth noting that quinolines have been
successfully synthesized by the simple and widely used
Friedlander method.[14] Further, the use of Pd,[15–18]
Ni,[19] Rh,[20,21] Co,[22,23] Ir,[24] Fe[25] and Cu[26] com-
plexes for transition metal‐mediated quinoline synthesis
has been reported. The Grubbs catalyst has been pro-
posed as one of the best for quinoline synthesis.[27] Shim
and co‐workers have reported the synthesis of 2,3‐disub-
stituted quinolines from anilines with easily available
trialkylamines in the presence of a ruthenium/SnCl2 cat-
alyst at a reaction temperature of 180°C for 20 h
(Scheme 2a).[28] Subsequently, the synthesis of
polysubstituted quinolines has been reported by Yus
A number of synthetic methods, including the
Skraup, Comps, Conrad–Limpach, Gould–Jacobs,
Appl Organometal Chem. 2018;e4582.
wileyonlinelibrary.com/journal/aoc
© 2018 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.4582

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SUBRAMANIAN ET AL.
catalysts for various reactions,[33] we describe here an
efficient one‐step synthesis of substituted quinolines from
the coupling of amino alcohol and ketones/alcohols
catalysed by newly synthesized ruthenium(II) arene
benzhydrazone catalysts of 0.3 mol% loading in 5 h.
2 | EXPERIMENTAL
2.1 | Materials and Methods
The complex [(η6‐p‐cymene)RuCl2(μ‐Cl)]2, benzhydrazide,
pyrrole‐2‐aldehyde and substrates for the quinoline
synthesis reaction were purchased from Sigma Aldrich
and used without further purification. All other reagents
used were purchased from commercial sources and used
as received. Pyrrole‐2‐carboxaldehyde hydrazone ligand
was prepared according to a literature procedure.33b
SCHEME 1 Quinoline‐based biologically active compounds
Melting points were recorded with a Boetius micro
heating table and are uncorrected. The microanalysis of
carbon, hydrogen, nitrogen and sulfur was conducted
with an Elementar Vario EL III analyser. The infrared
(IR) spectra of the complexes were recorded in KBr pel-
lets with a PerkinElmer 597 spectrophotometer in the
range 400–4000 cm−1. The electronic spectra of the com-
plexes in acetonitrile solution were recorded with a Cary
300 Bio UV–Vis Varian spectrophotometer in the range
1
260–800 nm using cuvettes of 1 cm path length. The H
NMR and 13C NMR spectra were recorded with a Bruker
400 MHz spectrometer at frequencies of 400, 100 and
160 MHz. Chemical shifts are given in ppm referenced
to the deuterated solvents. Electrospray ionization (ESI)
mass spectra were recorded with a Thermo Fisher Hybrid
Quadrupole‐Orbitrap mass spectrometer in positive ion
ESI mode.
SCHEME 2 Synthetic strategies of quinoline synthesis
and co‐workers using 2 mol% of RuCl2(dmso)4 catalyst
loading in toluene at 100°C for 48 h (Scheme 2b).[29]
Verpoort and co‐workers have improved the synthesis of
quinolines using ruthenium arene complexes by coupling
of alcohols and various ketones using 1 mol% catalyst
loading at 80°C (Scheme 2c).[30] One‐step synthesis of
substituted quinoline derivatives via consecutive C─N
and C─C bond formation in 24 h has been described
(Scheme 2d) with the help of a bipyridyl‐based ruthenium
pincer complex.[31] Interestingly, quinoline derivatives
were obtained from coupling cyclization of γ‐amino alco-
hols and secondary alcohols using a ruthenium hydride
complex in 24 h (Scheme 2e).[32] However, these reported
methods show some significant drawbacks such as long
reaction time, high loading of catalyst and base, need of
additives, harsh reaction conditions as well as workup
and recyclability of catalysts. To address the above needs
and also as a continuation of our effort in developing Ru
2.2 | Synthesis of Arene Ruthenium(II)
Benzhydrazone Complexes
One equivalent of the starting precursor [(η6‐p‐cymene)
RuCl2(μ‐Cl)]2 was mixed with two equivalents of pyr-
role‐2‐carboxaldehyde benzhydrazone ligand (0.1 mmol)
in benzene (20 ml). The reaction mixture was allowed
to stir at room temperature for 2 h in the presence of
triethylamine (TEA; 0.3 ml). Then, the solution was con-
centrated to 2 ml and precipitated by the addition of hex-
ane. The reaction was monitored using TLC.
2.2.1 | [Ru(η6‐p‐cymene)Cl(L1)] (1)
Yield: 85%; m.p. 148°C. Anal. Calcd (%) for
C22H24N3OClRu: C, 54.71; H, 5.00; N, 8.70. Found (%):
C, 54.67; H, 5.20; N, 8.66. IR (KBr, cm−1): 2982 ν(N─H)
,
1516 ν(C═N), 1095 ν(C─O). UV–visible (DMF, λmax, nm (e,

SUBRAMANIAN ET AL.
3 of 12
dm3 mol−1 cm−1)): 365 (976), 303 (4490), 224 (9769). H
NMR (400 MHz, CDCl3, δ, ppm): 11.03 (br, 1H, pyrrole
N─H), 8.78 (s, 1H, HC═N), 6.38–8.06 (m, 8H, aromatic),
5.43 (d, 1H, p‐cym‐H), 5.32 (d, 1H, p‐cym‐H), 5.04 (d,
1H, p‐cym‐H), 4.09 (d, 1H, p‐cym‐H), 2.69 (m, 1H, p‐
cym CH(CH3)2), 2.23 (s, 3H, p‐cym CCH3), 1.39 (d, 3H,
p‐cym CH(CH3)2), 1.19 (d, 3H, p‐cym CH(CH3)2). 13C
NMR (100 MHz, CDCl3, δ, ppm): 172.14, 152.38, 132.41,
128.55, 122.66, 110.98, 81.42, 30.84, 8.85. ESI‐MS: m/z
484.04 (M + H)+ (calcd 483.06).
dm3 mol−1 cm−1): 366 (738), 291 (5893), 235 (9901). H
1
1
NMR (400 MHz, CDCl3, δ, ppm): 11.18 (br, 1H, pyrrole
N─H), 9.34 (s, 1H, OH), 8.65 (s, 1H, HC═N), 6.31–7.82
(m, 8H, aromatic), 5.39 (d, 1H, p‐cym‐H), 5.26 (d, 1H, p‐
cym‐H), 4.99 (d, 1H, p‐cym‐H), 4.69 (d, 1H, p‐cym‐H),
2.60 (m, 1H, p‐cym CH(CH3)2), 2.14 (s, 3H, p‐cym
CCH3), 1.30 (d, 3H, p‐cym CH(CH3)2), 1.18 (d, 3H, p‐
cym CH(CH3)2). 13C NMR (100 MHz, CDCl3, δ, ppm):
172.98, 159.13, 129.71, 125.48, 122.48, 114.40, 101.37,
83.96, 45.46, 30.26, 21.51, 17.96, 8.23. ESI‐MS: m/z
500.06 (M + H)+ (calcd 499.06).
2.2.2 | [Ru(η6‐p‐cymene)Cl(L2)] (2)
2.3 | Coupling Cyclization of 2‐
Aminobenzyl Alcohol with Aryl,
Heteroaryl and Cyclic Ketones
Yield: 84%; m.p. 141°C. Anal. Calcd (%) for
C23H26N3O2ClRu: C, 53.84; H, 5.10; N, 8.19. Found (%): C,
53.91; H, 5.29; N, 8.08. IR (KBr, cm−1): 3062 ν(N─H), 1520
ν
(C═N), 1079 ν(C─O). UV–visible (DMF, λmax, nm (e,
A mixture of 1 mmol of 2‐aminobenzyl alcohol, 1.2 mmol
of ketone and 0.003 mmol of Ru catalyst in toluene with
KOH (1 mmol) under open air was stirred at 80°C for
5 h. Then, the reaction mixture was cooled to room tem-
perature and the aqueous layer was separated using
diethyl ether (3 × 3 ml). Further, the organic layer was
concentrated and was purified by column chromatogra-
phy (n‐hexane–EtOAc).
dm3 mol−1 cm−1): 365 (794), 295 (4527), 252 (7763). H
NMR (400 MHz, CDCl3, δ, ppm): 11.09 (br, 1H, pyrrole
N─H), 8.05 (s, 1H, HC═N), 6.27–7.98 (m, 8H, aromatic),
5.23 (d, 1H, p‐cym‐H), 5.08 (d, 1H, p‐cym‐H), 4.26 (d, 1H,
p‐cym‐H), 4.25 (d, 1H, p‐cym‐H), 3.74 (s, 3H, OCH3), 2.50
(m, 1H, p‐cym CH(CH3)2), 2.49 (s, 3H, p‐cym CCH3), 1.18
(d, 3H, p‐cym CH(CH3)2), 0.80 (d, 3H, p‐cym CH(CH3)2).
13C NMR (100 MHz, CDCl3, δ, ppm): 172. 41, 160. 36, 129.
24, 125. 03, 121.54, 112.17, 109.93, 83.49, 54.30, 43.50,
29.80, 21.34, 17.12, 7. 76. ESI‐MS: m/z 514.08 (M + H)+
(calcd 513.07).
1
2.4 | Coupling Cyclization of 2‐
Aminobenzyl Alcohol with Secondary
Alcohols
2.2.3 | [Ru(η6‐p‐cymene)Cl(L3)] (3)
In a Schlenk tube, 1 mmol of 2‐aminobenzyl alcohol,
1.2 mmol of secondary alcohol and 0.003 mmol of Ru cat-
alyst (1.2 equiv.) in toluene and KOH (1 equiv.) were
stirred at 80°C for 35 h under nitrogen atmosphere. The
reaction mixture cooled in room temperature and
quenched by adding water. After extraction with diethyl
ether–water mixture and the collection of organic layer,
removal of solvent left the product and it was further
purified by column chromatography using ethyl acetate–
hexane as eluent to yield the product.
Yield: 88%; m.p. 143°C. Anal. Calcd (%) for
C22H23Cl2N3ORu: C, 51.06; H, 4.48; N, 8.12. Found (%):
C, 51.13; H, 4.55; N, 8.20. IR (KBr, cm−1): 3217 ν(N─H)
,
1525 ν(C═N), 1086 ν(C─O). UV–visible (DMF, λmax, nm (e,
dm3 mol−1 cm−1): 370 (674), 238 (5245), 232 (6806). H
1
NMR (400 MHz, CDCl3, δ, ppm): 10.93 (br, 1H, pyrrole
N─H), 8.68 (s, 1H, HC═N), 6.38–7.98 (m, 8H, aromatic),
5.36 (d, 1H, p‐cym‐H), 5.25 (d, 1H, p‐cym‐H), 4.96 (d,
1H, p‐cym‐H), 4.64 (d, 1H, p‐cym‐H), 2.60 (m, 1H, p‐
cym CH(CH3)2), 2.13 (s, 3H, p‐cym CCH3), 1.29 (d, 3H,
p‐cym CH(CH3)2), 1.19 (d, 3H, p‐cym CH(CH3)2). 13C
NMR (100 MHz, CDCl3, δ, ppm): 172.52, 150.65, 136.18,
130.60, 129.94, 122.85, 111.10, 100.49, 84.50, 46.00,
30.84, 22.35, 22.03, 18.52, 8.75. ESI‐MS: m/z 518.03 (M
+ H)+ (calcd 517.02).
3 | RESULTS AND DISCUSSION
The benzhydrazone ligands were obtained in excellent
yields by the reaction of pyrrole‐2‐aldehyde and
substituted benzhydrazone in equimolar ratio in ethanol
at room temperature. The formation of new
ruthenium(II) benzhydrazone complexes was accom-
plished from the reaction of 2 mol of ligands and 1 mol
of [Ru2(η6‐p‐cymene)2Cl2] in the presence of a few drops
of TEA in dry benzene under reflux conditions for 5 h
(Scheme 3). All the complexes were isolated as yellow
crystals and are air stable in both solid and liquid states.
2.2.4 | [Ru(η6‐p‐cymene)Cl(L4)] (4)
Yield: 88%; m.p. 143°C. Anal. Calcd (%) for
C22H24N3O2ClRu: C, 52.92; H, 4.84; N, 8.42. Found (%):
C, 52.92; H, 4.84; N, 8.42. IR (KBr, cm−1): 2982 ν(N─H)
,
1516 ν(C═N), 1095 ν(C─O). UV–visible (DMF, λmax, nm (e,

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SUBRAMANIAN ET AL.
SCHEME 3 Synthesis of ruthenium(II)
arene complexes of pyrrole‐2‐aldehyde
benzhydrazones
The complexes are soluble in common solvents such as
chloroform, dichloromethane, acetonitrile, DMF and
DMSO producing intense brown‐coloured solutions. The
elemental analysis data for the Ru(II) arene
benzhydrazone complexes match well with the general
molecular formula proposed.
The IR stretching frequency of N─H functional group
of the ligands shows a band in the region of 2968–
3217 cm−1. The absence of this band and the appearance
of new band in the region of 1603–1647 cm−1 confirm
coordination through the deprotonated oxygen to the
Ru(II) ion via enolization of N─NH─C═O. A decrease
in C═N band of the ligand at around 1508–1525 cm
−1indicates the coordination of the azomethine nitrogen
to the Ru(II) ion. The electronic absorption spectra of
all the complexes in acetonitrile showed highly intense
ligand‐centred π–π* and n–π* transitions at around
219–303 nm and ligand‐to‐metal charge transfer bands
FIGURE 1 The ORTEP diagram of the complex 1 with 50%
probability. All the hydrogens are omitted for clarity
1
in the region 365–370 nm. The H NMR spectra for all
angles of 133.2(4)° (C(16)–Ru(1)–N(2)), 112.8(4)° (O(1)–
Ru(1)–C(7)) and 85.7(1)° (N(2)–Ru(1)–Cl(1)). The bond
lengths of Ru(1)─N(2) and Ru(1)─O(1) were 2.070(5)
and 2.066(4) Å, respectively. The Ru─Cl bond length
was found to be 2.427(2) Å which is in agreement with
other structurally established arene ruthenium com-
plexes.[34] The average C─C bond length in the arene ring
is 1.41(1) Å with alternating short and long bonds and an
average Ru─C distance of 2.187(7) Å is observed for
ruthenium arene bond.
Our effort is to initiate the oxidative cyclization of
amino alcohol and a range of ketones towards synthesis
of derivatives of quinoline using the Ru(II)
benzhydrazone catalysts. Ketones are readily available
inexpensive precursors for many organic syntheses and
it is possible to alter the electronic properties of quinoline
through a suitable substitution of the ketones. Hence, it is
interesting to investigate the catalytic property of ruthe-
nium benzhydrazone catalysts for quinoline synthesis
using substituted ketones. Therefore, the reaction of 2‐
aminobenzyl alcohol with 4‐methylacetophenone in open
atmosphere with catalyst 1 (1 mol%) in 5 h is considered
as a model reaction to establish the practicability of our
study and to optimize the various reaction parameters
together with catalyst loading, temperature, time, sol-
vents and bases (Tables 1 and 2). When the reaction
was conducted in dioxane with 1.0 equiv. of KOH at
the complexes were recorded in CDCl3 solution and the
results were consistent with the molecular structures con-
firmed using the single‐crystal X‐ray diffraction method.
Multiplets were observed at around 6.22–8.06 ppm due
to aromatic protons of the ligands. In addition, the signal
of downfield shift at 8.66–8.78 ppm is attributed to the
coordinated azomethine proton. The free ligand
undergoes tautomerization and coordinates to the Ru(II)
ion via imidolate oxygen. This is further supported by
the disappearance of signal due to ─NH proton of the free
ligand. The other characteristic arene ligand signals are
presented in Section 2.2.
The molecular structure of complex 1 was determined
using single‐crystal X‐ray analysis. Single crystals of com-
plex 1 were grown by slow evaporation of dichlorometh-
ane–petroleum ether solutions and crystallized in the
monoclinic system with P21/c space group. A summary
of the data collection and refinement parameters are
given in the supporting information (Tables S1 and S2).
Based on these results, the azomethine nitrogen and
imidolate oxygen of the ligand coordinate to ruthenium
in a bidentate manner. A piano‐stool geometry has been
observed for the complexes similar to other reported
half‐sandwich arene Ru(II) complexes (Fig. 1). The
benzhydrazone ligand bonded to the metal centre at N
and O forming a five‐member chelate ring with bite

SUBRAMANIAN ET AL.
5 of 12
TABLE 1 Optimization of reaction conditionsa
Entry
Solvent
Base
Yield (%)b
TONc
1
Dioxane
THF
KOH
90
64
97
34d
37
—
81
85
81
65
66
12
10
—
—
90
64
97
34
37
—
81
85
81
65
66
12
10
—
—
2
KOH
3
Toluene
Dioxane
H2O
KOH
4
KOH
5
KOH
6
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
—
7
NaOH
tBuOK
tBuONa
Bu4NOH
K3PO4
K2CO3
Na2CO3
Et3N
8
9
10
11
12
13
14
15
Pyridine
aReaction conditions: 4‐methylaceophenone (1.2 mmol), 2‐aminobenzyl alcohol (1 mmol), base (1 mmol), catalyst 1 (1 mol%) and solvent (2 ml) at 80°C for 5 h
under open air.
bIsolated yield after column chromatography based on 4‐methylacetophenone (average of two runs).
cTON: mol product/mol catalyst.
dReaction at room temperature for 22 h.
TABLE 2 Effect of catalyst loadinga
Entry
Catalyst (mol%)
Yield (%)b
TONc
1
2
3
4
5
6
7
8
1.0
99
99
198
0.5
99
0.3
97
323
0.1
74
740
0.05
0.01
0.001
0.0001
69
1 380
4 300
31 000
—
43
31
Trace
aReaction conditions: 4‐methylacetophenone (1.2 mmol), 2‐aminobenzyl alcohol (1 mmol), base (1 mmol) and solvent (2 ml) at 80 °C, under open air for 5 h.
bIsolated yield after column chromatography based on 4‐methylacetophenone (average of two runs).
cTON: mol product/mol catalyst.
80°C, the yield of product was 90% (Table 1, entry 1).
Hence, attempts were made to increase the rate of the
reaction by optimizing the various solvents and co‐
solvent. Tetrahydrofuran (THF) solvent with KOH gave
a decreased yield of 64% (entry 2). A maximum yield of
97% was obtained when toluene as the choice of solvent

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SUBRAMANIAN ET AL.
(entry 3). A further drop in the yield to 37% was noticed
when water was used. No reaction was observed in the
absence of base, indicating that base is essential for the
reaction (entry 6). Therefore, a series of bases, namely
the scope of the modified Friedlander reaction for the
synthesis of quinolines under optimized conditions
(Tables 4 and 5). Initially, electronically activated and
deactivated acetophenones were readily coupled and
cyclized with 2‐aminobenzyl alcohol and offered the
expected quinolines in moderate to good yields (92–60%)
indicating good activity and high selectivity (Table 4,
entries 1–7) of the catalyst. Among the substrates, 4‐
chloroacetophenone was easily coupled and cyclized with
2‐aminobenzyl alcohol and provided excellent yield of 2‐
(4‐chlorophenyl)quinoline (Table 4, entry 4). Interest-
ingly, with an electron‐withdrawing group in the ortho
position of acetophenone, the yield was not significantly
affected, indicating that the position of the substituent
had no major effect on the yield of the product (Table 4,
entry 6). When 4‐hydroxyacetophenone was used, a con-
siderable decrease in the yield (60%) was encountered
(Table 4, entry 7). Based on these results, it is generalized
that lower yields are generally observed for substrates
with electron‐donating substituents compared with those
with electron‐withdrawing substituents. Moreover, this
methodology is more useful for the preparation of
quinoline derivatives from alkyl heteroaryl ketones.
Accordingly, 2‐acetylfuran afforded 76% of 2‐(furan‐2‐yl)
quinoline without affecting any heterocyclic ring
(Table 4, entry 8). Moreover, 2‐acetylpyridine was coupled
and cyclized with γ‐amino alcohol and afforded the
desired product in a high yield of 89% (Table 4, entry 9).
Reaction of pyrrole‐2‐ketone with amino alcohol
proceeded to give quinoline product in 76% isolated yield
(Table 4, entry 10). In addition, 2‐acetylthiophene under
the same experimental conditions afforded 82% yield
(Table 4, entry 11). In the case of aryl(methyl) ketones,
the corresponding quinolines were obtained as a regio‐iso-
meric mixture, favouring cyclization at less hindered posi-
tion of α‐methylene. It was observed that the reactivity and
product yield for heteroaryl ketones were found to be
lower than those for aryl(methyl) ketones. Moreover, the
t
t
KOH, NaOH, BuOK, BuONa, K3PO4, Bu4NOH, K2CO3,
Na2CO3, NEt3 and pyridine, were screened with KOH
affording the highest yield. Among the bases used, inor-
ganic bases (entries 7–13) furnished better results than
organic bases because the latter may coordinate with
metal and result in no product (entries 14 and 15). In
t
addition, bases such as hydroxides or BuOK facilitate
the reaction. Based on the results, we chose KOH as base
and toluene as solvent for further studies. With regard to
the industrial use of catalytic systems for the synthesis of
quinoline derivatives, different catalyst‐to‐substrate (C/S)
ratios were used to optimize the reaction. The corre-
sponding yields are listed in Table 2. The reaction of 4‐
methylacetophenone with 2‐aminobenzyl alcohol gave
the maximum yield of 99% when a catalyst loading of
1.0 or 0.5 mol% was used (entries 1 and 2). A marginal
decrease of yield (97%) was obtained when 0.3 mol% of
catalyst was used (entry 3). It is worth noting that the
reaction with a catalyst loading of 0.01 mol% proceeds
with a drop in isolated yields with high turnover number
(entry 6). To our great surprise, a catalyst loading of
0.001 mol% gave the highest turnover number of 31 000
(entry 7). Hence, 0.3 mol% catalyst loading was chosen
for further studies based on the results. For any synthetic
protocol the stability and longevity of the catalyst are
important. So, the performance of the catalyst was exam-
ined by changing R on the ligand coordinated to ruthe-
nium (Table 3). In this regard, the catalytic activity of
all complexes 1–4 in the quinoline synthesis was deter-
mined using 0.3 mol% catalyst loading. Based on the
quantitative yield, complex 1 was chosen for further
studies.
The coupling of γ‐ amino alcohols with various func-
tionalized ketones/alcohols was carried out to evaluate
TABLE 3 Substituent effect on quinoline synthesisa
Entry
Catalyst
Yield (%)b
1
2
3
4
1
2
3
4
97
93
96
92
aConditions: 4‐methylacetophene (1.2 mmol), 2‐aminobenzyl alcohol (1 mmol), catalyst (0.3 mol%), KOH (1.0 mmol), toluene (3 ml), 80°C, under open air for
5 h.
bIsolated yields.

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TABLE 4 Effect of catalyst on quinoline synthesis from ketonesa
Entry
Ketone
Product
Yield (%)b
TONc
1
96
320
2
3
94
91
313
303
4
5
6
7
96
95
96
60
320
316
320
200
8
9
92
89
306
296
10
11
12
76
82
96
253
273
320
13
14
15
95
91
90
316
303
300
(Continues)

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SUBRAMANIAN ET AL.
TABLE 4 (Continued)
Entry
Ketone
Product
Yield (%)b
TONc
16
63
210
aReaction conditions: substituted acetophenone or cyclic ketone (1.2 mmol), 2‐aminobenzyl alcohol (1 mmol), KOH (1 mmol), catalyst 1 (0.3 mol%) and solvent
(2 ml) at 80°C for 5 h under open air.
bIsolated yield after column chromatography based on corresponding alcohols (average of two runs).
cTON: mol product/mol catalyst.
TABLE 5 Effect of catalyst on quinoline synthesis from secondary alcoholsa
Entry
Alcohol
Product
Yield (%)b
TONc
1
96
300
2
3
4
85
81
76
283
270
253
5
6
61
75
203
250
aReaction conditions: secondary alcohols (1.2 mmol), 2‐aminobenzyl alcohol (1 mmol), KOH (1 mmol), catalyst 1 (0.3 mol%) and solvent (2 ml) at 80°C for 35 h
under nitrogen atmosphere.
bIsolated yield after column chromatography based on alcohols (average of two runs).
cTON: mol product/mol catalyst.
protocol operated well with aliphatic ketones and afforded
excellent results (Table 4, entries 12–16). Cyclooctanone
underwent coupling followed by cyclization to the corre-
sponding quinoline product in 96% isolated yield
(Table 4, entry 12). When cycloheptanone was used, a sig-
nificantly lower yield was obtained which might be due to
ring constraints (Table 4, entry 13). From the results it has
been presumed that the smaller the ring of the cyclic
ketone used, the lower the yield of the corresponding
product. It is noteworthy that electron‐donating substitu-
tion on the cyclic ketone further decreased the product
yield (Table 4, entry 15). Long‐chain 2‐pentanone gave
the corresponding quinoline product in lower yield (63%)
without any side product (Table 4, entry 16).
An adventitious activity of our catalyst, we were moti-
vated to synthesize quinoline derivatives from the cata-
lytic coupling cyclization of secondary alcohols as an
alternative to ketones (Table 5, entries 1–6). Syntheses
of quinoline derivatives from readily available alcohols
are a judicious methodology in modern organic synthesis.
Recently, Milstein and co‐workers reported coupling
cyclization reactions of alcohols using Ru(II) bipyridine

SUBRAMANIAN ET AL.
9 of 12
pincer complexes in toluene–THF solvent system under
argon atmosphere in 24 h.[31] Moreover, an efficient irid-
ium complex‐catalysed coupling cyclization reaction of
alcohols in THF with high reaction temperature (130°C)
has been described by Kempe and co‐workers.[24] Liu
et al. have reported PNN‐type R(II) pincer complexes as
TABLE 6 Recycling of catalysta
Catalyst recycle
Yield (%)b
TONc
1
2
3
4
5
97
323
300
276
220
—
90
83
66
Trace
aConditions: 4‐methyloacetophene (1.2 mmol), 2‐aminobenzyl alcohol (1 mmol), catalyst 1 (0.3 mol%), KOH (1.0 mmol), toluene (3 ml), 80°C, under open air
for 5 h.
bIsolated yields.
cTON: mol product/mol of catalyst.
SCHEME 4 Plausible mechanism for
quinoline synthesis

10 of 12
SUBRAMANIAN ET AL.
catalysts for coupling cyclization reaction of γ‐amino
alcohols and secondary alcohols under argon atmosphere
for 72 h.[32] Still, the development of coupling cyclization
of γ‐amino alcohols and secondary alcohols remains
challenging. Herein, we developed a methodology for
quinoline synthesis by one‐step reaction using readily
available starting materials like γ‐amino alcohol and
secondary alcohols using the aforementioned optimal
conditions under nitrogen atmosphere. The coupling
cyclization of γ‐amino alcohol with various cyclic
4 | CONCLUSIONS
In summary, the present study describes an environmen-
tally benign, sustainable and practical synthesis of
substituted quinolines catalysed by well‐characterized
arene Ru(II) benzhydrazone complexes. Quinolines can
be accessed in good to excellent yields from cyclization
of γ‐amino alcohol with various functionalized ketones
and secondary alcohols under mild reaction conditions.
The experimental results seem to reveal that the mecha-
nism involves oxidation of alcohol followed by intramo-
lecular aldol‐type condensation. The optimized reaction
conditions allow the presence of a wide range of organic
functional groups. The synthetic procedure is very simple
and works well with 0.3 mol% catalyst loading in 5 h. The
excellent activity of these catalysts makes this methodol-
ogy very useful for the synthesis of biologically important
heterocyclic compounds. A detailed mechanistic study of
this reaction is under way.
alcohols,
including
cyclooctanol,
cycloheptanol,
cyclohexanol, 3‐methylcyclohexanol, cyclohexanol and
2‐pentanol, was carried out. It was observed that second-
ary alcohols having larger rings reacted smoothly with
excellent yield of corresponding quinolines compared to
secondary alcohols with smaller rings. Methyl substituent
on cyclohexanol decreased the yield of quinoline product
from 81 to 76% (Table 5, entry 4). When 2‐pentanone was
employed under the same experimental conditions, it
afforded 61% yield of the corresponding quinoline deriva-
tive (Table 5, entry 5). Interestingly, 1‐phenylethanol
readily reacted with amino alcohol and furnished 2‐
phenylquinoline in 75% isolated yield (Table 5, entry 6).
Based on these results, complexes under investigation
have proven to be efficient catalysts for quinoline
synthesis.
The reaction of 2‐aminobenzyl alcohol with 4‐
methylacetophenone was carried under optimal reaction
conditions in order to verify the recyclability of catalyst 1
(Table 6). It was observed that the recovered catalyst
could be successfully reused for three cycles leading to
97, 90 and 83% isolated yields, respectively (Table 6,
entries 1–3). The formation of product was considerably
reduced in the fourth cycle (Table 6, entry 4) and a
marked decrease in yield was observed after the fifth run
(Table 6, entry 5).
ACKNOWLEDGEMENTS
One of the authors (S.M.) sincerely thanks UGC‐RFSMS,
New Delhi, India for financial support. S.S. thanks DST‐
INSPIRE for a research fellowship. We are sincerely grateful
to DST‐FIST, India for NMR instrument facility at the School
of Chemistry, Bharathidasan University, Tiruchirappalli.
ORCID
Muthumari Subramanian
8358-9583
Saranya Sundar http://orcid.org/0000-0002-1151-3114
Ramesh Rengan http://orcid.org/0000-0002-0257-8792
http://orcid.org/0000-0001-
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How to cite this article: Subramanian M,
Sundar S, Rengan R. Synthesis and structure of
arene ruthenium(II) complexes: One‐pot catalytic
approach to synthesis of bioactive quinolines under
mild conditions. Appl Organometal Chem. 2018;
e4582. https://doi.org/10.1002/aoc.4582
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