ZnO nanorods catalyzed N-alkylation of piperidin-4-one, 4(3H)-pyrimidone, and ethyl 6-chloro-1,2-dihydro-2-oxo-4-phenylquinoline-3-carboxylate

Article abstract of DOI:10.2478/s11696-010-0045-3

An efficient ligand-free cross-coupling reaction of 2-chloro-3-(chloromethyl)benzo[h]quinoline with N-heterocycles such as piperidin-4-one, 4(3H)-pyrimidone, and ethyl 6-chloro-1,2-dihydro-2-oxo-4-phenylquinoline-3-carboxylate using a catalytic amount of

Full text of DOI:10.2478/s11696-010-0045-3

Chemical Papers 64 (5) 678–682 (2010)
DOI: 10.2478/s11696-010-0045-3
SHORT COMMUNICATION
ZnO nanorods catalyzed -alkylation of piperidin-4-one,
4(3 )-pyrimidone, and ethyl
6-chloro-1,2-dihydro-2-oxo-4-phenylquinoline-3-carboxylate
Selvaraj Mohana Roopan, Fazlur Rahman Nawaz Khan*
Organic and Medicinal Chemistry Research Laboratory, Organic Chemistry Division, School of Advanced Sciences,
VIT University, Vellore, India
Received 18 December 2009; Revised 2 March 2010; Accepted 9 March 2010
An efficient ligand-free cross-coupling reaction of 2-chloro-3-(chloromethyl)benzo[h]quinoline with
N-heterocycles such as piperidin-4-one, 4(3H )-pyrimidone, and ethyl 6-chloro-1,2-dihydro-2-oxo-4-
phenylquinoline-3-carboxylate using a catalytic amount of ZnO nanorods as a recyclable catalyst
and KOH as the base in DMSO under reflux at 110◦C is reported.
c
ꢀ 2010 Institute of Chemistry, Slovak Academy of Sciences
Keywords: ZnO nanorods, N-alkylation, nitrogen heterocycles
Nitrogen heterocycles received considerable atten-
tion in literature (Sivasubramanian & Parameswaran,
2007), particularly in terms of the synthetic method-
ology of their preparation (Chinchilla & Nájera, 2007;
Roopan et al., 2008). Among all naturally occur-
ring nitrogen heterocycles, particularly quinoline ana-
logues occupy an important position and have at-
tracted considerable interest because of their sig-
nificant biological properties such as antimicrobial
(Manivel et al., 2008), antioxidant, and cytotoxic
properties (Roopan & Khan, 2009). The chemistry
and applications of N-alkylation have recently received
much attention due to their usefulness as building
blocks in organic synthesis (Nacro et al., 2007). Many
N-alkylation methods have been reported (Eltsov et
al., 2000). However, many of these procedures are not
satisfactory with regard to practical applications due
to environmental and economic considerations.
et al., 2008). In the last few years, literature has high-
lighted the importance of nanosized materials in sev-
eral scientific and technological areas (Richards et al.,
2000). Development of such catalysts has resulted in
more economical and environmentally friendly chem-
istry replacing unstable or toxic catalysts.
Therefore, in continuation of our attempts to de-
velop environmentally benign protocols (Roopan et
al., 2008, 2009b; Roopan & Khan, 2009), we re-
port for the first time ZnO nanorods catalyzed N-
alkylation of piperidin-4-one, 4(3H )-pyrimidone, and
ethyl 6-chloro-1,2-dihydro-2-oxo-4-phenylquinoline-3-
carboxylate (Fig. 1). The nanorods of ZnO were pre-
pared applying a reported procedure (Kawano & Imai,
2008) and confirmed by HRSEM (Fig. 2).
Glassware was dried in hot air-oven prior to use.
All other reagents were purchased from Aldrich Co.
(India), Melting points were taken in open capillary
tubes and were corrected with reference to benzoic
acid.
For the preparation of aldehyde I and hydroxy-
methyl derivative II, reported procedures were used
(Khan et al., 2009a, 2009b; Roopan et al., 2009a).
Compound II, on reaction with thionyl chloride, gave
the corresponding chloromethyl derivative III.
An efficient N-alkylation method is still a chal-
lenge. Designing new specific catalysts and exploring
their catalytic activity has caused profound effects on
the optimization of the efficiency of a wide range of
organic syntheses (Mirjafary et al., 2008). Recently,
nanocrystalline inorganic oxides attracted interest be-
cause of their different topical characteristics (Alonso
*Corresponding author, e-mail: nawaz f@yahoo.co.in

S. M. Roopan, F. R. N. Khan/Chemical Papers 64 (5) 678–682 (2010)
679
R
N
iii
N
O
IVa, IVb
iv
v
i
ii
R
R
OH
R
Cl
O
N
O
R
Ia, Ib
IIa, IIb
IIIa, IIIb
Va, Vb
Compound
Ia–VIa
R
R
N
O
N
Cl
OEt
Cl
O
Ib–VIb
N
Cl
V Ia, VIb
Fig. 1. Synthesis of N-alkylated heterocycles. Reagents and conditions: i) NaBH4, MK-10, MW 500 W, 4–5 min; ii) SOCl2, reflux,
30 min; iii) 4(3H )-pyrimidone, 5 mole % of ZnO nanorods, KOH, DMSO, 110◦C; iv) piperidin-4-one, 5 mole % of ZnO
nanorods, KOH, DMSO, 110◦C; v), ethyl 6-chloro-1,2-dihydro-2-oxo-4-phenylquinoline-3-carboxylate, 5 mole % of ZnO
nanorods, KOH, DMSO, 110◦C.
N-heterocycle (1 mmol of piperidin-4-one, 4(3H)-
pyrimidone, ethyl 6-chloro-1,2-dihydro-2-oxo-4-phenyl-
quinoline-3-carboxylate, respectively) in DMSO
(2 mL), then KOH (1.5 mmol) was added portion-
wise followed by an addition of arylalkyl chloride III
(1 mmol) and the reaction mixture was refluxed at
110◦C for 30 min. The reaction mixture was then
cooled and poured on crushed ice. The precipitate was
filtered, washed with H2O and dried in air. The crude
product was chromatographed on a column of silica
gel using a petroleum ether/ethyl acetate (ϕr = 85 :
15) mixture as an eluent which afforded product IV
in a good yield. Compounds V and VI were obtained
and purified by a similar procedure (Tables 1 and 2).
1
Structures of all derivatives were confirmed by H
and 13C NMR, HRMS, and IR spectral analyses. Spec-
tral data of the new compounds are given in Table 3.
In a preliminary reaction, 2-chloro-3-(chlorome-
thyl)benzo[h]quinoline (IIIa) treated with 4(3H )-pyri-
Fig. 2. SEM image of ZnO nanorods.
midone in the presence of 5 mole % of ZnO nanorods
(Fig. 1) and KOH (1.5 eq) in DMSO (2.0 mL) gave
the corresponding N-alkylated product IVa.
IR measurements were done using KBr pellets for
solids on a Nucon Infrared spectrophotometer. NMR
spectra were recorded on a Bruker Spectrospin Ad-
vance III 500 MHz (AV 500) spectrometer with TMS
as internal standard. Column chromatography was
carried out using silica gel (60–120 mesh). High res-
olution scanning electron microscope (HRSEM) spec-
tra were recorded on a FEI Quanta FEG 200. Mass
spectra were recorded on a Finnigan MAT 8230 spec-
trometer.
To optimize the reaction conditions, different bases
were used for the reaction of IIIa with 4(3H )-
pyrimidone (Table 1). The mixture of ZnO nanorods,
KOH, and DMSO provided N-alkylated products IV–
VI in moderate to excellent yields (Table 1, entry 6)
whereas in the presence of other bases lower yield were
obtained (Table 1, entries 1, 2). This reaction when
carried out in the absence of ZnO nanorods or a base
was not futile (Table 1, entries 1, 7, 8).
Moreover, an optimized amount of 5 mole % of
ZnO nanorods was required for the reaction (Table 1,
entries 2–6). To check recyclability, the catalyst was
centrifuged from the reaction mixture, washed with
General procedure for the synthesis of N-alkylated
products IV–VI was applied. Zinc oxide nanorods
(5 mole %) were added to a stirred solution of

680
S. M. Roopan, F. R. N. Khan/Chemical Papers 64 (5) 678–682 (2010)
Table 1. Optimization of 3-((2-chlorobenzo[h]quinolin-3-yl)methyl)pyrimidin-4(3H )-one (IVa) synthesisa
Optimized parameters
Entry
Yield/%b
Catalyst, base, solvent
Time/h
1
2
3
4
5
6
7
8
ZnO nanorods, DMSOc
1
nr
65
72
87
76
74
30
nr
ZnO nanorods (5 mole %), NaOH, DMSO
ZnO nanorods (5 mole %), tert-BuOK, DMSO
ZnO nanorods (5 mole %), KOH, DMSO
ZnO nanorods (10 mole %), KOH, DMSO
ZnO nanorods (15 mole %), KOH, DMSO
DMF, tert-BuOK, THF
0.5
0.5
0.5
0.5
0.5
1
KOH, DMSOd
1
a) Reaction conditions: 1.0 eq of IIIa, 4(3H )-pyrimidone, 1.5 eq of base, 1.5 eq of ZnO nanorods, 110◦C, specified reaction time; b)
isolated yields; c) reaction run without base; d) reaction run without nanorods; nr = no reaction.
Table 2. Characterization data of newly prepared compounds
Compound
Formula
Mr
Yield/%
M.p./◦C
Appearance
IVaa
IVba
Va
Vb
VIa
VIb
C18H12ClN3O
C14H10ClN3O
321.7603
271.7017
324.8040
274.7454
553.4347
503.3760
87
84
72
82
82
62
195
158
–
78
235
202
White powder
White powder
Pale yellow gummy
Pale yellow powder
White powder
C
19H17ClN2O
C15H15ClN2O
C32H22Cl2N2O3
C
28H20Cl2N2O3
White powder
a) Spectral data matched with the authentic samples (Roopan et al., 2010).
Table 3. Spectral data of newly prepared compounds
Compound Spectral data
Va
IR, ν˜/cm−1: 1718 (C O)
—
—
1H NMR (DMSO-d6), δ: 2.55 (t, 4H), 2.94 (t, 4H), 3.93 (s, 2H), 7.70–7.77 (m, 3H), 7.86 (d, 1H, J = 9.0 Hz), 9.22
(t, 1H), 7.93 (t, 1H), 8.31 (s, 1H)
13C NMR (DMSO-d6), δ: 41.1 (2C), 53.0 (2C), 58.0, 124.3, 124.5, 125.3, 127.2 (2C), 127.6 (2C), 128.5, 130.2, 133.5,
137.8, 145.3, 149.7, 208.13
HRMS, m/z (found/calc.): 324.8181/324.8040 (M+, C19H17ClN2O)
IR, ν˜/cm−1: 1712 (C O)
—
Vb
—
1H NMR (DMSO-d6), δ: 2.50–2.53 (t, 4H), 2.91–2.92 (t, 4H), 3.86 (s, 2H), 7.55–7.59 (m, 1H), 7.70–7.74 (m, 1H),
7.84 (d, 1H, J = 8.4 Hz), 8.02 (d, 1H, J = 8.4 Hz), 8.27 (s, 1H)
13C NMR (DMSO-d6), δ: 41.2, 45.5, 53.1, 58.2, 127.0, 127.1, 127.3, 127.3, 128.2, 130.1, 130.2, 137.9, 146.9, 150.9,
208.5
HRMS, m/z (found/calc.): 274.0193/274.7454 (M+, C15H15ClN2O)
IR, ν˜/cm−1: 1712 (C O)
—
VIa
—
1H NMR (DMSO-d6), δ: 1.03–1.05 (t, 3H, CH3), 4.17–4.18 (d, 2H, CH2), 5.94 (s, 2H, CH2), 7.41–7.43 (t, 2H),
7.51–7.55 (m, 4H), 7.62–7.64 (m, 1H), 7.70–7.78 (m, 3H), 7.84–7.93 (m, 3H), 8.41 (s, 1H), 9.24–9.26 (d, 1H)
13C NMR (DMSO-d6), δ: 13.7, 61.5, 64.4, 124.56, 124.58, 124.9, 125.3, 125.4 (2C), 127.2 (2C), 127.6 (2C), 128.2
(2C), 128.5 (2C), 128.8, 129.10, 129.14, 129.4, 130.2, 130.6, 131.2, 133.6, 134.3, 136.7, 144.7, 148.0, 148.3, 156.8,
165.7
HRMS, m/z (found/calc.): 553.4346/553.4347 (M+, C32H22Cl2N2O3)
IR, ν˜/cm−1: 1732 (C O)
—
VIb
—
1H NMR (DMSO-d6), δ: 1.01 (t, 3H, CH3), 4.13 (m, 2H), 5.86 (s, 2H, CH2), 7.25–7.38 (m, 2H), 7.49–7.62 (m, 6H),
7.70–7.74 (t, 1H), 7.82–7.87 (m, 2H), 8.03(d, 1H, J = 8.4 Hz), 8.36 (s, 1H)
13C NMR (DMSO-d6), δ: 13.7, 61.6, 64.4, 119.6, 125.0, 125.5 (2C), 127.1 (2C), 127.6, 128.3 (2C), 128.5 (2C), 129.0
(2C), 129.2, 130.3, 130.7, 131.3, 134.4, 137.0, 144.8, 147.1, 148.4, 149.2, 156.8, 165.7
HRMS, m/z (found/calc.): 503.8797/503.3760 (M+, C28H20Cl2N2O3)
water, and dried in vacuum. It could then be reused
for further catalytic reactions without any change in
its catalytic activity.
These experimental results clearly suggest that
nanoparticles adsorbed on the nitrogen atom of the
heterocycle in ring nitrogen of the amines (see reaction

S. M. Roopan, F. R. N. Khan/Chemical Papers 64 (5) 678–682 (2010)
681
O
O
+ KOH
N
N
H
ZnO nanorod
N
Cl
N
A
+ H2O
Va
O
Cl
Cl
N
K+
KCl
IIIa
Fig. 3. Role of ZnO nanorods in the synthesis of N-alkylated products.
conditions iv in Fig. 1) produce intermediate A (see
Fig. 3) which can be further involved in the coupling
of arylalkyl chloride IIIa to give product Va (Fig. 3).
In this communication, a simple method of the N-
alkylation of some heterocycles using ZnO nanorods is
reported. A simple experimental procedure combined
with an easy workup and excellent yields of products
are salient features of the presented method.
Khan, F. N., Subashini, R., Roopan, S. M., Hathwar, V.
R., & Ng, S. W. (2009b). 2-Chloro-6-methylquinoline-3-
carbaldehyde. Acta Crystallographica Section E, E65, o2686.
DOI: 10.1107/S1600536809040653.
Manivel, P., Roopan, S. M., & Khan, F. N. (2008). Syn-
thesis of O-substituted benzophenones by Grignard reac-
tion of 3-substituted isocoumarins. Journal of the Chilean
Chemical Society, 53, 1609–1610. DOI: 10.4067/S0717-
97072008000300012.
Manivel, P., Roopan, S. M., Kumar, D. P., & Khan, F. N.
(2009). Isocoumarin thioanalogues as potential antibacterial
agents. Phosphorus, Sulfur, and Silicon and the Related El-
ements, 184, 2576–2582. DOI: 10.1080/10426500802529507.
Mirjafary, Z., Saeidian, H., Sadeghi, A., & Moghaddam, F.
M. (2008). ZnO nanoparticles: An efficient nanocatalyst for
the synthesis of β-acetamido ketones/esters via a multi-
component reaction. Catalysis Communications, 9, 299–306.
DOI: 10.1016/j.catcom.2007.06.018.
Nacro, K., Zha, C., Guzzo, P. R., Herr, R. J., Peace, D., &
Friedrich, T. D. (2007). Synthesis and topoisomerase poi-
soning activity of A-ring and E-ring substituted luotonin A
derivatives. Bioorganic & Medicinal Chemistry, 15, 4237–
4246. DOI: 10.1016/j.bmc.2007.03.067.
Richards, R., Li, W., Decker, S., Davidson, C., Koper, O.,
Zaikovski, V., Volodin, A., Rieker, T., & Klabunde, K.
J. (2000). Consolidation of metal oxide nanocrystals. Re-
active pellets with controllable pore structure that repre-
sent a new family of porous, inorganic materials. Journal
of the American Chemical Society, 122, 4921–4925. DOI:
10.1021/ja994383g.
Roopan, S. M., & Khan, F. R. N. (2009). Synthesis, antioxi-
dant, hemolytic and cytotoxicity activity of AB ring core of
mappicine. ARKIVOC, xiii, 161–169.
Roopan, S. M., Khan, F. R. N., & Mandal, B. K. (2010). Fe nano
particles mediated C–N bond forming reaction: Regioselec-
tive synthesis of 3-[(2-chloroquinolin-3-yl)methyl]pyrimidin-
4(3H )ones. Tetrahedron Letters, 51, 2309–2311. DOI: 10.
1016/j.tetlet.2010.02.128.
Acknowledgements. The authors gratefully acknowledge fi-
nancial support from the Department of Science and Technol-
ogy, Government of India (Grant No. SR/FTP/CS-99/2006).
The authors are also thankful to the VIT University manage-
ment for their generous support and facilities. We also ac-
knowledge SAIF, IIT Madras, Chennai, for providing NMR and
MS facilities.
References
Alonso, F., Riente, P., & Yus, M. (2008). Hydrogen-transfer re-
duction of carbonyl compounds promoted by nickel nanopar-
ticles. Tetrahedron, 64, 1847–1852. DOI: 10.1016/j.tet.2007.
11.093.
Chinchilla, R., & Nájera, C. (2007). The Sonogashira reac-
tion: A booming methodology in synthetic organic chemistry.
Chemical Reviews, 107, 874–922. DOI: 10.1021/cr050992x.
Eltsov, O. S., Mokrushin, V. S., Rybalova, T. V., Gatilov,
Y. V., & Tkachev, A. V. (2000). N-alkylation in the re-
actions of 5-imidazolylphenylthiourea with alkylhalides and
chloroacetone. Mendeleev Communications, 10, 233–234.
DOI: 10.1070/MC2000v010n06ABEH001324.
Kawano, T., & Imai, H. (2008). A simple preparation tech-
nique for shape-controlled zinc oxide nanoparticles: For-
mation of narrow size-distributed nanorods using seeds
in aqueous solutions. Colloids and Surfaces A: Physic-
ochemical and Engineering Aspects, 319, 130–135. DOI:
10.1016/j.colsurfa.2007.05.019.
Khan, F. N., Subashini, R., Kumar, R., Hathwar, V. R., & Ng, S.
W. (2009a). 2-Chloroquinoline-3-carbaldehyde. Acta Crystal-
lographica Section E, E65, o2710. DOI: 10.1107/S160053680
9040665.
Roopan, S. M., Khan, F. N., Subashini, R., Hathwar, V.
R.,
& Ng, S. W. (2009a). 2-Chlorobenzo[h]quinoline-3-
carbaldehyde. Acta Crystallographica Section E, E65, o2711.
DOI: 10.1107/S1600536809040720.

682
S. M. Roopan, F. R. N. Khan/Chemical Papers 64 (5) 678–682 (2010)
Roopan, S. M., Khan, F. N., Vijetha, M., Hathwar, V. R., &
Ng, S. W. (2009b). Ethyl 2,6-dichloro-4-phenylquinoline-3-
carboxylate. Acta Crystallographica Section E, E65, o2982.
DOI: 10.1107/S1600536809045334.
Sivasubramanian, G., & Parameswaran, V. R. (2007). Oxidation
of N-heterocyclics: A green approach. Journal of Heterocyclic
Chemistry, 44, 1223–1230. DOI: 10.1002/jhet.5570440601.
Roopan, S. M., Maiyalagan, T.,
& Khan, F. N. (2008).
Solvent-free syntheses of some quinazolin-4(3H)-ones deriva-
tives. Canadian Journal of Chemistry, 86, 1019–1025. DOI:
10.1139/V08-149.