ZnO nanoparticles in the synthesis of AB ring core of camptothecin

Article abstract of DOI:10.2478/s11696-010-0058-y

For the first time, synthesis of AB ring core of camptothecin synthons such as (2-chloroquinolin-3-yl)methanols (Va-Vg) using zinc oxide nanoparticles is reported. The desired attractive products were obtained in high yields, short reaction time, using a simple work-up procedure with the purification of products by non-chromatographic methods.

Full text of DOI:10.2478/s11696-010-0058-y

Chemical Papers 64 (6) 812–817 (2010)
DOI: 10.2478/s11696-010-0058-y
ORIGINAL PAPER
ZnO nanoparticles in the synthesis of AB ring core of camptothecin
Selvaraj Mohana Roopan, Fazlur Rahman Nawaz Khan*
Organic & Medicinal Chemistry Research Laboratory, Organic Chemistry Division, School of Advanced Sciences,
VIT University, Vellore, India
Received 14 March 2010; Revised 8 June 2010; Accepted 11 June 2010
For the first time, synthesis of AB ring core of camptothecin synthons such as (2-chloroquinolin-
3-yl)methanols (Va–Vg) using zinc oxide nanoparticles is reported. The desired attractive products
were obtained in high yields, short reaction time, using a simple work-up procedure with the pu-
rification of products by non-chromatographic methods.
ꢀ
c 2010 Institute of Chemistry, Slovak Academy of Sciences
Keywords: ZnO nanoparticles, camptothecin synthons, (2-chloroquinolin-3-yl)methanol
Introduction
Reaction of the AB ring core of camptothecin with
DE rings in the Comins synthetic approach (Comins
et al., 1994) (Fig. 2) has been used by several research
groups for the assembly of camptothecin.
The search for new anticancer drugs from na-
ture continues to be a fruitful activity as evidenced
by the successes of natural products as pharma-
ceutical agents (Rath et al., 2009; Niizuma et al.,
In view of the on going active analogue develop-
ment programs of CPT in our laboratory, it is apt to
mention the synthesis of synthons (AB ring core). Re-
duction of different derivatives of 2-chloroquinoline-3-
carbaldehyde by the catalytic hydrogenation method
in the presence of zinc oxide nanoparticles provides a
convenient method for the preparation of the corre-
sponding alcohols. Synthetic chemists continue to ex-
plore new methods of chemical transformations. One
such method includes reactions on the surface of solids
with high product yield and purity, which is more
desirable compared to reactions proceeding in a so-
lution. Several classes of solids have commonly been
2
009). Camptothecin (CPT), a pentacyclic alkaloid
isolated from the Chinese tree Camptotheca acumi-
nata (Wall et al., 1966), is an outstanding lead com-
pounds in anticancer drug development. Due to its
toxicity, poor solubility and unstable nature of the
lactone ring, camptothecin was not ideal for phar-
maceutical use. Substituted quinolines are a common
structural feature in a number of biologically active
alkaloids, see for example camptothecin (I ) and its
derivatives such as Diflomotecan (II ) and S39625 (III )
(Fig. 1).
F
F
O
O
O
O
O
N
N
N
N
N
N
O
O
O
HO
HO
O
O
HO
I
II
III
Fig. 1. Biologically active alkaloids.
*Corresponding author, e-mail: nawaz f@yahoo.co.in

S. M. Roopan, F. R. Nawaz Khan/Chemical Papers 64 (6) 812–817 (2010)
813
O
O
N
OH
HN
O
N
+
O
N
Br
O
HO
DE ring
HO
O
AB ring
Fig. 2. Retrosynthesis of the Comins approach for camptothecin construction.
used for surface organic chemistry including alumina,
silica gels, and clays.
Table 1. Synthesis of some AB ring cores of camptothecin us-
ing S-ZONPs
Zinc oxide (Kim & Varma, 2004; Maghsoodlou et
al., 2007; Roopan & Khan, 2010) is certainly one of
the most interesting of these solids because its sur-
face properties suggest that many organic reactions
can occur there. The majority of aldehydes reduc-
tion was done using reagents transferring a hydride
from boron or aluminum such as sodium borohydride,
lithium borohydride in the presence of an organic sol-
vent medium. Some inorganic clay materials such as
montmorillonite have been used as the catalyst for
organic reactions and they are superior to classical
acids due to their strong acidity, non-corrosive nature,
cheapness, mild reaction conditions, high yields and
selectivity, and the simplicity of the process set-up and
work-up. In continuation of our work (Roopan et al.,
i
R
O
R
OH
IVa–IVg
Va–Vg
◦
Time/s M.p./ C Yield/%
a
Compound
R
Va
56
58
161
137
146
190
99
96
92
88
N
Cl
Cl
Vb
Vc
Vd
Ve
Vf
N
CH
3
64
H C
N
Cl
2
008, 2009, 2010; Roopan & Khan, 2008), nanopar-
3
ticles were utilized in our synthesis as nanoparticle
catalysts have offered great opportunities for a wide
range of applications in organic synthesis (Sapkal et
al., 2009; Kidwai et al., 2009; Chaicharoenwimolkul et
al., 2008).
110
N
Cl
OCH
3
H CO
3
82
62
124
246
92
97
Experimental
N
Cl
Chemicals used for the reaction were purchased
from Sigma–Aldrich Co. (India). The substances were
used as provided without purification. Melting points
were taken in open capillary tubes and are corrected
with reference to benzoic acid. FTIR spectra in KBr
pellets were recorded on a Nucon Infrared spectropho-
H C
N
Cl
3
CH3
Vg
55
173
94
N
Cl
1
13
tometer. H (400 MHz and 500 MHz) and C (100
MHz and 125 MHz) NMR spectra were recorded
on Bruker Spectrospin Avance DPX400 and Bruker
AVANCE III (AV 500) spectrometers, respectively,
using TMS as an internal reference. High resolution
scanning electron microscope (HRSEM) spectra were
recorded on a FEI Quanta FEG 200. Mass spectra
were recorded on a Finnigan Mat 8230 mass spectro-
meter.
a) Isolated yield; reaction conditions: i) 1 mmol of aldehyde
IVa–IVg, 1 mmol of NaBH4, 0.1 mL of H2O, 5 mole % of S-
ZONPs, room temperature.
min at room temperature to give the correspond-
ing (2-chloroquinolin-3-yl)methanol derivative (Va–
Vg, Table 1). Ethyl acetate was added to the reac-
tion mixture and the catalyst was recovered by fil-
tration. Filtrate and catalyst were washed with sat-
urated NH4Cl solution to remove unreacted sodium
borohydride. The organic layer was dried and the
solvent was evaporated to give products (Table 1).
Structures of all products were confirmed by FTIR,
(2-Chloroquinolin-3-yl)methanols (Va–Vg) were
synthesized using the following general procedure.
Starting 2-chloroquinoline-3-carbaldehyde derivative
(IVa–IVg, 1 mmol) (Srivastava & Singh, 2005),
sodium borohydride (1 mmol), zinc oxide nanoparti-
cles (5 mole %), and distilled water (0.1 mL) were
well mixed in a beaker and then kept for about 1

8
14
S. M. Roopan, F. R. Nawaz Khan/Chemical Papers 64 (6) 812–817 (2010)
Table 2. Spectral data of newly prepared compounds
Compound
Spectral data
IR, ν˜ /cm 1: 3315 (OH)
−
Vf
1
H NMR (400 MHz, CDCl3), δ: 8.16 (s, 1H), 7.57 (dt, J = 8.0 Hz, 1H), 7.37 (dt, J = 8.4 Hz, 1H), 4.90 (s, 2H), 2.65
s, CH3, 3H), 2.49 (s, CH3, 3H), 2.20 (s, 1H)
(
1
3C NMR (100 MHz, CDCl3), δ: 148.02, 146.27, 138.21, 136.54, 133.78, 130.70, 129.98, 125.73, 124.40, 62.24 (CH2),
2
0.68 (CH3), 13.36 (CH3)
LCMS, m/z (Ir): 222 (M + 1); HRMS, m/z (found/calc.): 221.1002/221.6827 (M+, C12H12ClNO)
+
IR, ν˜ /cm 1: 3435 (OH)
−
Vg
1
H NMR (500 MHz, CDCl3), δ: 9.22 (s, 1H), 8.33 (s, 1H), 7.93 (t, 1H), 7.86 (dt, J = 9.0 Hz, 1H), 7.72–7.77 (m,
3
H), 5.00 (s, 2H, CH2), 2.23 (s, 1H, OH)
1
3
C NMR (125 MHz, CDCl3), δ: 147.96, 145.54, 136.19, 133.73, 132.76, 130.36, 128.61, 128.37, 127.80, 127.32,
25.56, 124.62, 124.59, 62.11
HRMS, m/z (found/calc.): 243.3570/243.6883 (M+, C14H10ClNO)
1
Table 3. Selection of nanoparticlesa
Cl
N
Nanoparticle
Catalyst/mole % Time/s Yield of V
N
Cl
O
+
Na+
BH4
Co(O)
Fe(O)
Ni–Fe
5
5
5
5
5
> 60
> 60
> 60
60
nr
nr
nr
OH
IVg
–
Vg
ZnO
nanoparticles
Commercial ZnO
Synthesized ZnO
moderate
high
60
a) Reaction conditions: aldehyde IV (1 mmol), NaBH4 (1 mmol),
H2O (0.1 mL), room temperature; nr – no reaction at given con-
ditions.
Cl
N
O
Screening, optimization, and reutilization of
nanoparticles
NaOH
H+ –OH
Selection of nanoparticles was done (Table 3) in-
cluding Fe, Co, Ni–Fe, and ZnO (Fig. 4). The re-
duction of 2-chloroquinoline-3-carbaldehyde (IVa) was
first studied. This compound was reduced fast to
the corresponding alcohol in good isolated yield only
in the presence of ZnO nanoparticles. Two different
nanosized ZnO, one commercial and one synthesized
in the range of < 100 nm, were screened.
Using this methodology, optimization of the cata-
lyst amount was also done (Table 4). Substituted 2-
chloroquinoline-3-carbaldehydes (IVa–IVg) (Table 1)
were reduced fast to the corresponding alcohols in
modest to good isolated yields. 2-Chloroquinoline-3-
carbaldehyde (IVa) was used as a model substrate
in order to optimize the amount of the catalyst (Ta-
ble 4). The amount of 4 mole % of S-ZONPs showed
to be effective to complete the conversion into (2-
chloroquinolin-3-yl)methanol (Va) (Entry 5, Table 4).
The reaction with 5 mole % of ZnO led also to the
product in a relatively short time and high yield (En-
try 6, Table 4).
Fig. 3. Mechanistic pathway for the synthesis of AB ring core
of camptothecin.
1H and 13C NMR, and LCMS and HRMS analy-
ses. Spectral data of the new compounds, Vf and
Vg, are given in Table 2. Data of compounds Va–Ve
were identical with those already reported (Roopan
&
Khan, 2009). We proposed a mechanistic path-
way to synthesize the AB ring core of camptothecin
Fig. 3).
(
Synthesis of ZnO nanoparticles
Zinc oxide nanoparticles (ZONPs) were prepared
from zinc nitrate (Zn(NO3)2 · 6H2O) according to an
already described method (Wu et al., 2006). Sam-
ples were used for the reduction of 2-chloroquinoline-
3
-carbaldehyde (IVa) with NaBH4 as the reduc-
ing agent. Synthesized zinc oxide nanoparticles (S-
ZONPs) were found to be superior compared to com-
mercial zinc oxide nanoparticles (CM-ZONPs). The
above results indicate that the efficiency of the cat-
alytic activity is dependent on the particle size of ZnO.
Reusability of nanoparticles was explored by suc-
cessive runs of reactions using recycled catalyst; i.e.
after the first reaction, catalyst was recovered by
washing with methanol, centrifuged, removed, and

S. M. Roopan, F. R. Nawaz Khan/Chemical Papers 64 (6) 812–817 (2010)
815
a
b
c
d
Fig. 4. SEM images of nanoparticles: CM-ZONPs (a), S-ZONPs (b), Ni–Fe (c), Co (d).
Table 4. Optimization of catalyst (CM-ZONPs, S-ZONPs) for the synthesis of AB ring core of camptothecina
Optimized parameters
CM-ZONPs/mole % Time/s
Optimized parameters
S-ZONPs/mole % Time/s
Entry
Yield/%b
Yield/%b
1
2
3
4
5
6
None
> 150
90
83
73
72
23
83
85
86
87
87
None
> 150
84
78
65
58
23
87
88
92
95
99
1
2
3
4
5
1
2
3
4
5
72
56
a) Reaction conditions: aldehyde IV (1 mmol), NaBH4 (1 mmol), H2O (0.1 mL), room temperature; b) isolated and not optimized
yield.
reused for four consecutive runs without any appar-
ent loss of activity for the same reaction. It was
noticed that the use of recycled catalyst in sub-
sequent experiments resulted in similar yields (Ta-
ble 5, Figs. 5 and 6). Thus, the catalyst did not
leach.
Table 5. Reutilization of ZONPs by hydrogen transfer reduc-
tion
Yield
Run
CM-ZONPs
S-ZONPs
1
2
3
4
5
6
7
8
92
90
86
82
68
66
58
52
99
99
97
96
89
88
86
78
Results and discussion
The required 2-chloroquinoline-3-carbaldehydes
(
IVa–IVg) were readily prepared from acetanilides
◦
with the Vilsmeier-Haack reagent at 80–90 C, which
upon treatment with sodium borohydride and dis-
tilled water in the presence of zinc oxide nanoparti-
cles afforded AB synthons such as (2-chloroquinolin-

8
16
S. M. Roopan, F. R. Nawaz Khan/Chemical Papers 64 (6) 812–817 (2010)
From the HRSEM analysis of the ZnO sample it
1
00
can be observed that the particles contain nanoparti-
cles. Fig. 4a shows the HRSEM image of commercial
zinc oxide nanoparticles where a fairly uniform parti-
cle size of (48 ± 0.5) nm is evident. Fig. 4b shows the
particle size of (18 ± 0.5) nm of the synthesized ZnO
nanoparticles. From the HRSEM image, the average
particle size of the zinc oxide catalyst was found to be
8
6
4
2
0
0
0
0
0
<
100 nm and the particles were spherical in nature.
High yield of the product is based on the particle size
of zinc oxide.
IR data were normalized to 100 % absorption for a
−
1
1
2
3
4
5
peak at approximately 491.66 cm for the pure form;
after the reaction, the catalyst showed peaks at 491.05
Mole/ %
−
1
cm indicating non-leachability of the catalyst.
Fig. 5. Yield comparison between commercial ( CM-ZONPs)
and synthesized ( S-ZONPs) ZnO nanoparticles.
Conclusions
In conclusion, the application of catalytic zinc ox-
ide nanoparticles as a catalyst for the reduction of
several substituted 2-chloroquinoline-3-carbaldehydes
at room temperature, a simple, economical, and envi-
ronmentally benign method avoiding volatile and toxic
organic solvents is reported for the first time.
1
00
8
6
4
2
0
0
0
0
0
Acknowledgements. We gratefully acknowledge financial
support from the Department of Science and Technology, Gov-
ernment of India (Grant No. SR/FTP/CS-99/2006). The au-
thors are thankful to the VIT University management for their
generous support. We also acknowledge SAIF, IIT Madras,
Chennai for providing NMR and MS facilities.
1
2
3
4
5
6
7
8
Multiplicityof utilization
Fig. 6. Comparison of multiplicity of commercial
(
CM-
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