Regioselective O-alkylation: Synthesis of 1-{2-[(2-chloroquinolin-3-yl) methoxy]-6-chloro-4-phenylquinolin-3-yl}ethanones

Article abstract of DOI:10.1007/s11164-011-0447-z

An efficient and regioselective O-alkylation of amides with a variety of electrophiles in the presence of silver nanoparticles is reported as part of our recent research on building blocks for synthesis of natural products. The nano-silver catalyst initiates O-alkylation of the amides by heteroalkyl halides. Reaction of equimolar 3-acetyl-6-chloro-4-phenylquinolin-2(1H)-one and 2-chloro-3-(chloro-methyl)quinolines in the presence of silver nanoparticles in DMSO solution under reflux condition leads to the formation of 1-{1-[2-chloroquinolin-3-yl)methoxy]-6-chloro-4-phenylquinolin-3-yl}ethanones. Springer Science+Business Media B.V. 2011.

Full text of DOI:10.1007/s11164-011-0447-z

Res Chem Intermed (2012) 38:1111–1118
DOI 10.1007/s11164-011-0447-z
Regioselective O-alkylation: synthesis of 1-{2-[(2-
chloroquinolin-3-yl)methoxy]-6-chloro-4-
phenylquinolin-3-yl}ethanones
•
Machhindra Gund S. Mohana Roopan
•
•
Fazlur-Rahman Nawaz Khan Jong Sung Jin
•
•
Rajesh Kumar A. Sudheer Kumar
Received: 3 August 2011 / Accepted: 22 November 2011 / Published online: 6 December 2011
Ó Springer Science+Business Media B.V. 2011
Abstract An efficient and regioselective O-alkylation of amides with a variety of
electrophiles in the presence of silver nanoparticles is reported as part of our recent
research on building blocks for synthesis of natural products. The nano-silver cat-
alyst initiates O-alkylation of the amides by heteroalkyl halides. Reaction of
equimolar 3-acetyl-6-chloro-4-phenylquinolin-2(1H)-one and 2-chloro-3-(chloro-
methyl)quinolines in the presence of silver nanoparticles in DMSO solution under
reflux condition leads to the formation of 1-{1-[2-chloroquinolin-3-yl)methoxy]-6-
chloro-4-phenylquinolin-3-yl}ethanones.
Keywords Regioselectivity Á Heteroalkyl halides Á Quinolone Á
Silver nanoparticles
Introduction
Major attention has been devoted to the development of regioselective reactions
[1–4]. Amides are reported to undergo O-alkylation in the presence of metal salt in a
suitable solvent. In continuation of the regioselective N-alkylation reaction [3], we
report here regioselective O-alkylation of aromatic amides.
Quinoline derivatives are known to have interesting biological properties ranging
from microbial activity to cytotoxicity [5]. Recent studies have, moreover, identified
quinolones which inhibit mammalian topoisomerase II [6] as potential lead
compounds in the development of anticancer drugs. Quinolines have also been used
M. Gund Á S. Mohana Roopan Á F.-R. Nawaz Khan (&) Á Rajesh Kumar Á A. Sudheer Kumar
Organic Chemistry Division, School of Advanced Sciences, VIT University, Vellore 632 014,
Tamil Nadu, India
e-mail: nawaz_f@yahoo.co.in
F.-R. Nawaz Khan Á J. S. Jin
Division of High Technology Materials Research, KBSI, Busan 618 230, South Korea
123

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M. Gund et al.
as substituents to impart the desired pharmacological and pharmacokinetic
properties to quinolone antibiotics [7].
Use of metal salts is of substantial importance in organic synthesis because of
high selectivity, enhanced reaction rates, and simple workup. In alkylation
reactions, alkali metal salts (K, Na, Li) promote N-alkylation whereas silver salts
promote O-alkylation [8, 9]. In continuation of our work on catalysis and
heterocyclics [3, 5, 10–32], we have investigated an O-alkylation of 3-acetyl-6-
chloro-4-phenylquinolin-2(1H)-one with 2-chloro-3-(chloromethyl)quinolines in the
presence of silver nanoparticles (Scheme 1).
Results and discussion
The results from synthesis of 1-{1-[2-chloroquinolin-3-yl)methoxy]-6-chloro-4-
phenylquinolin-3-yl}ethanones are summarized in Tables 1 and 2. Interestingly, the
O-alkylation reaction took less time (20–45 min) for completion (Tables 1, 2). The
effect of solvent and the scope of the reaction have also been investigated (Table 1).
When 1-{1-[2-chloroquinolin-3-yl)methoxy]-6-chloro-4-phenylquinolin-3-yl}etha-
nones 1 were treated with silver nanoparticles and DMSO with conventional heating
in the presence of 2-chloro-3-(chloromethyl)quinoline, 2a, the product 3a was
obtained in quantitative yield (entry 14, Table 1).
The same reaction carried out with different catalysts in the absence of solvent
did not proceed (Table 1, entries 1, 3, 5, 7, 9, 11 and 13). These experimental results
clearly suggest that the reaction involves a heterogeneous process and the silver
nanoparticles act as an efficient catalyst. The same reaction when carried out with
bentonite in DMSO gave two products (Table 1, entry 2), whereas in the presence of
silver nanoparticles in DMSO (Table 2, entry 14) only the O-alkylated regioselec-
tive product 3a was formed. The results suggest that the reaction proceeds well
under the optimized conditions (Table 1, Entry 14). When the O-alkylation was
carried out in a variety of solvents of different dielectric constant a high yield was
obtained in DMSO (high dielectric constant) whereas the N-alkylated product was
formed in THF (low dielectric constant).
Thus optimization of the reaction suggested that silver nanoparticles with DMSO
is the appropriate combination for good regioselective product yield (Table 1). To
R
H
N
O
O
N
O
Ag nanoparticles
DMSO, 110 oC
+
R
Cl
Cl
Cl
O
1
3
2
Scheme 1 Synthesis of 1-{1-[2-chloroquinolin-3-yl)methoxy]-6-chloro-4-phenylquinolin-3-yl}ethanones
(3a–f)
123

Regioselective O-alkylation
1113
Table 1 Optimization of the synthesis of 1-{1-[2-chloroquinolin-3-yl)methoxy]-6-chloro-4-phenylqui-
nolin-3-yl}ethanone 3a
No.
Catalyst
Solvent
Yield (%)a
1
Bentonite
Nil
NRb
2
Bentonite
DMSO
Nil
25 (trace)c
NRb
3
Amberlyst
4
Amberlyst
DMSO
Nil
NRb
NRb
5
Montmorillonite K-10
Montmorillonite K-10
Montmorillonite KSF
Montmorillonite KSF
Kaolin
6
DMSO
Nil
Unexpected product
NRb
NRb
7
8
DMSO
Nil
9
NRb
10
11
12
13
14
15
Kaolin
DMSO
Nil
Trace (42)c
NRc
2 (52)c
NRc
LiCl
LiCl
DMSO
Nil
Ag2SO4
Ag2SO4
DMSO
DMSO
82
Ag (0) nanoparticles
93
Reactions were carried out with 1.0 equiv 1 and 2a, 10 mol% catalyst, and 5 mL solvent at 110 °C for
20 min
a
Isolated yield
b
No reaction
c
The value in parentheses is for the N-alkylated product
investigate the scope of this reaction, a variety of halides were investigated
(Table 2, entries 1–7). Substituted 2-chloro-3-(chloromethyl)quinoline 2 afforded
the corresponding product 3 in good yields. The proposed mechanism of the
reaction is depicted in Fig. 1.
The reaction of silver nanoparticles with alkyl halides may proceeds via
carbonium ion formation by electrophilic attack by silver on the halogen through an
SN1 mechanism and further reaction of this carbonium ion with amide will take
place through covalent bond formation to the most electronegative atom of the
ambident anion possessing two different reactive positions. In this reaction, the
acetyl group oxygen atom and the amide group oxygen atom share the negative
charge whereas the nitrogen atom of the amide group is essentially neutral and
hence facilitates the regioselective O-alkylation.
In the course of this work, a few compounds with different substitution of the
aromatic ring of the quinoline skeleton have been synthesized. Electron-
withdrawing groups present in the 3-position of the quinoline ring 1 facilitated
the reactions. This method was found to be completely regioselective. The
spectral and analytical data of products 3 were in accordance with the assigned
structures. Similarly, in all cases the disappearance of the –NH peak confirmed the
formation of products 3b–f.
123

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M. Gund et al.
Table 2 Regioselective O-alkylation reaction using silver nanoparticles
R
O
H
N
N
O
Ag nanoparticles
DMSO, 110 oC
+
R
Cl
Cl
Cl
O
1
O
3
2
Entry
1
R (2/3)
Product
Time (min)
20
Yield of 3 (%)a
93
3a
N
N
Cl
Cl
2
3b
30
92
3
4
5
3c
3d
3e
25
30
45
78
85
74
N
Cl
N
Cl
N
Cl
OCH3
6
3f
40
82
H3CO
N
Cl
Reactions were carried out on 1.0 equiv 1 and 2 in 5 mL DMSO with 10 mol% catalyst at 110 °C for the
specified period of time
a
Isolated yield
Experimental
Solvents and reagents were commercially sourced and used without further
purification. Melting points were taken on Elchem microprocessor-based DT
apparatus in open capillary tubes and are corrected with reference to benzoic acid.
IR spectra were obtained on a Nucon infrared spectrophotometer using KBr pellets.
The NMR spectra were recorded on a Bruker Avance 400 MHz spectrometer using
TMS as internal standard (chemical shifts d in ppm). LC–MS was performed with a
Flash 1112 analyser in EI mode; the electron energy was 70 eV. Data are reported in
the form of m/z intensity relative to the base peak. Silver nanoparticles were
123

Regioselective O-alkylation
1115
Silver Nanoparticles
+
DMSO
Cl
Cl
O
O
Ag
N
H
O
O
N
H
1
Cl
N
Cl
2a
N
Cl
O
O
N
3a
Cl
Fig. 1 Proposed mechanism of O-alkylation using silver nanoparticles
prepared by use of a reported method [33]. Silver sulfate (1.0 mM, 10 mL) was
added dropwise to 30 mL 2.0 mM sodium borohydride solution that had been
chilled in an ice bath. The reaction mixture was stirred vigorously on a magnetic stir
plate. The solution turned light yellow after addition of 2 mL Ag2SO4, then a
brighter yellow, after which the stirring was stopped and the stir bar removed. The
clear yellow colloidal solution was then subjected to centrifugation at 5000 rpm for
30 min, after which the pellet were separated and characterized by TEM by use of
an Hitachi 800, using an accelerating voltage of 120 kV; a fairly uniform particle
size of 25 0.5 nm was evident (Fig. 2).
General procedure for regioselective O-alkylation (3a–f)
In a typical procedure, heteroalkylhalide 2 (1 mmol) and silver nanoparticles
(10 mol%) were added to a solution of the cyclic amide 1 (1 mmol) in DMSO
(5 mL) and the mixture was heated under reflux at 110 °C. The reaction was
complete within 20–45 min. The reaction mixture was then filtered and the
supernatant liquid was added dropwise on to crushed ice. The solution was
neutralized with dilute HCl. The precipitate was isolated by filtration and
recrystallized from ethanol.
123

1116
M. Gund et al.
Fig. 2 TEM image of Ag nanoparticles
Synthesis of 1-{1-[2-chloroquinolin-3-yl)methoxy]-6-chloro-4-phenylquinolin-3-
yl} ethanones (3a)
To a mixture of 3-acetyl-6-chloro-4-phenylquinolin-2(1H)-one 1 (1 mmol) and
silver nanoparticles (10 mol%) in 5 mL DMSO, 2-chloro-3-chloromethylquinoline
2a (1 mmol) was added dropwise at 110 °C. Completion of the reaction was
monitored by TLC. The reaction mixture was poured into 5% HCl to give 1-{1-[2-
chloroquinolin-3-yl)methoxy]-6-chloro-4-phenylquinolin-3-yl}ethanones 3a as pale
yellow solids which were recrystallized from ethanol. Product identity was
confirmed by IR, NMR, and MS analysis. Data for new compounds 3a–f, which
have not been reported elsewhere, are given below.
3a: Pale yellow solid, M.p. 167–169 °C, IR (KBr): 1710 cm-1
,
1H NMR
(400 MHz, CDCl3): dH = 2.22 (3H, s, –CH3), 5.84 (2H, s, –CH2), 7.34 (2H, t), 7.48
(1H, d), 7.52 (3H, t), 7.57–7.67 (2H, m), 7.73 (1H, t), 7.87 (2H, q), 8.03 (1H, d),
8.33 (1H, s) ppm, 13C NMR (125 MHz, CDCl3): dC = 32.1 (–CH3), 64.7 (–CH2),
125.5, 126.7, 4 9 127.0, 2 9 128.1, 2 9 129.2, 2 9 129.3, 2 9 129.4, 2 9 130.7,
131.2, 134.1, 136.2, 138.3, 2 9 144.6, 2 9 146.3, 201.4 ppm, LC–MS: m/z 473
[M ? 1]? for C27H18Cl2N2O2 requires 472.
1
3b: White solid, M.p. 162–164 °C, IR (KBr): 1708 cm-1, H NMR (400 MHz,
CDCl3): dH = 2.27 (3H, s, –CH3), 2.78 (3H, s, –CH3), 5.82 (2H, s, –CH2), 7.23–7.39
(3H, m), 7.44 (1H, d, J 7.6 Hz), 7.47–7.61 (5H, m), 7.69 (1H, d, J 8 Hz), 7.87 (1H, d,
J 9.2 Hz), 8.28 (1H, s) ppm, 13C NMR (125 MHz, CDCl3): dC = 17.8 (–CH3), 32.0
(–CH3), 64.9 (–CH2), 125.5, 126.8, 4 9 127.1, 2 9 128.2, 2 9 129.0, 3 9 129.4,
2 9 129.6, 2 9 130.7, 131.0, 134.0, 136.4, 138.3, 2 9 144.5, 2 9 146.5, 201.8 ppm,
LC–MS: m/z 487 [M ? 1]? for C28H20Cl2N2O2 requires 486.
1
3c: White solid, M.p. 176–178 °C, IR (KBr): 1704 cm-1, H NMR (400 MHz,
CDCl3): dH = 2.22 (3H, s, –CH3), 2.56 (3H, s, –CH3), 5.81 (2H, s, –CH2), 7.33 (2H,
s), 7.34 (2H, t), 7.40 (1H, d, J 8 Hz), 7.47 (1H, d), 7.52 (2H, m), 7.59 (1H, d,
123

Regioselective O-alkylation
1117
J 8 Hz), 7.75 (1H, d, J 8 Hz), 7.87 (1H, d, J 8.8 Hz), 8.26 (1H, s) ppm, LC–MS:
m/z 487 [M ? 1]? for C28H20Cl2N2O2 requires 486.
3d: Pale yellow solid, M.p. 165–167 °C, IR (KBr): 1706 cm-1
,
1H NMR
(400 MHz, CDCl3): dH = 2.21 (3H, s, –CH3), 2.78 (3H, s, –CH3), 5.84 (2H, s,
–CH2), 7.34 (2H, t), 7.48 (1H, d), 7.52 (2H, t), 7.57–7.67 (2H, m), 7.73 (1H, t), 7.87
(2H, two d), 8.02 (1H, d), 8.31 (1H, s) ppm, LC–MS: m/z 487 [M ? 1]? for
C28H20Cl2N2O2 requires 486.
1
3e: White solid, M.p. 154–156 °C, IR (KBr): 1706 cm-1, H NMR (400 MHz,
CDCl3): dH = 2.24 (3H, s, –CH3), 3.92 (3H, s, –OCH3), 5.82 (2H, s, –CH2), 7.33
(2H, d, J 7.6 Hz), 7.41 (2H, d, J 8.8 Hz), 7.47–7.51 (2H, m), 7.60 (2H, d, J 9.6 Hz),
7.87 (1H, t, J 9.6 Hz), 7.90–7.97 (2H, m), 8.73 (1H, s) ppm, 13C NMR (125 MHz,
CDCl3): dC = 17.8 (–OCH3), 32.0 (–CH3), 64.9 (–CH2), 125.5, 126.8, 4 9 127.1,
2 9 128.2, 2 9 129.0, 3 9 129.4, 2 9 129.6, 2 9 130.7, 131.0, 134.0, 136.4,
138.3, 2 9 144.5, 2 9 146.5, 201.8 ppm, LC–MS: m/z 503 [M ? 1]? for
C28H20Cl2N2O3 requires 502.
3f: Pale yellow solid, M.p. 148–150 °C. IR (KBr): 1708 cm-1
.
1H NMR
(400 MHz, CDCl3): dH = 2.27 (3H, s, –CH3), 4.05 (3H, s, –OCH3), 5.82 (2H, s,
–CH2), 6.98 (2H, d, J 7.6 Hz), 7.21–7.31 (4H, m), 7.42–7.50 (4H, m), 7.59 (1H, d,
J 8.4 Hz), 8.73 (1H, s) ppm. LC–MS: m/z 503 [M ? 1]? for C28H20Cl2N2O3
requires 502.
Conclusion
In the work discussed in this report we developed a simple and effective method for
facile O-alkylation using silver nanoparticles. The method has very attractive
features, for example reduced reaction times, higher yields, and economic viability
of the catalyst. The operational simplicity of the procedure is also attractive.
Acknowledgments This study was supported by Department of Science and Technology Government
of India (grant no. SR/FTP/CS-99/2006). We also acknowledge IISc, Bangalore, for providing the NMR
facility.
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