Fe nano particles mediated C-N bond-forming reaction: Regioselective synthesis of 3-[(2-chloroquinolin-3-yl)methyl]pyrimidin-4(3H)ones

Article abstract of DOI:10.1016/j.tetlet.2010.02.128

An efficient and regioselective N-alkylation of 4(3H)-pyrimidone with various electrophiles in the presence of Fe nano particle is reported. The catalyst initiates N-alkylation of amides by alkyl chlorides. The reaction of equimolar 4(3H)-pyrimidone and 2

Full text of DOI:10.1016/j.tetlet.2010.02.128

Tetrahedron Letters 51 (2010) 2309–2311
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Tetrahedron Letters
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Fe nano particles mediated C–N bond-forming reaction: Regioselective
synthesis of 3-[(2-chloroquinolin-3-yl)methyl]pyrimidin-4(3H)ones
b
Selvaraj Mohana Roopan a, Fazlur Rahman Nawaz Khan a, , Badal Kumar Mandal
*
a Organic and Medicinal Chemistry Research Laboratory, Organic Chemistry Division, School of Advanced Sciences, VIT University, Vellore 632 014, Tamil Nadu, India
b Analytical and Environmental Chemistry Division, School of Advanced Sciences, VIT University, Vellore 632 014, Tamil Nadu, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and regioselective N-alkylation of 4(3H)-pyrimidone with various electrophiles in the pres-
ence of Fe nano particle is reported. The catalyst initiates N-alkylation of amides by alkyl chlorides. The
reaction of equimolar 4(3H)-pyrimidone and 2-chloro-3-(chloromethyl)quinolines in the presence of
KOH and Fe nano particle (5 mol %) in DMSO solution under reflux condition formed 3-[(2-chloroquino-
lin-3-yl]methyl)pyrimidin-4(3H)ones.
Received 18 December 2009
Revised 17 February 2010
Accepted 20 February 2010
Available online 24 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
The C–N bond formation1,2 is prevalent in the synthesis of
numerous compounds that are of biological, pharmaceutical, and
material interests. N-Alkylated pyrimidones have been frequently
used as intermediates and synthetic precursors for the preparation
of a wide variety of heterocyclic compounds (Fig. 1). Many meth-
ods for the N-alkylation have been reported.3–5 Previous methods
have been excluded from practical applications due to environ-
mental and economic considerations. Efficient method for N-alkyl-
ation is still a challenge. In continuation of our interest in exploring
C–C, C–N bond-forming reactions, and catalytic methodology,6–9
we attempted the nano catalyst-mediated N-alkylation. Catalyst-
mediated reactions are well established and have gained popular-
ity as indicated by the large number of papers currently published
on this topic.10,11 The beneficial effects of catalyst-mediated reac-
tions are finding an increased role in the process of chemistry,
especially in cases when usual methods require forcing conditions
or prolonged reaction times.
O
O
Fe (0)
N
Cl
NH
+
KOH, DMSO
110 oC
N
Cl
N
Cl
N
N
1
2
3
Scheme 1. Synthesis of 3-[(2-chloroquinolin-3-yl)methyl]pyrimidin-4-(3H)ones,13
3a–g.
The present synthetic route leading to the coupled compounds is
summarized in Scheme 1.
Recently, the use of solid-supported reagents2 has also received
considerable importance in organic synthesis because of their ease
of handling, enhanced reaction rates, greater selectivity, simple
work-up, and recoverability of catalysts. The efficiency of heteroge-
neous catalysis in organic synthesis has been improved by employ-
ing nano-sized catalysts12 because of their extremely small size,
high surface area, and reactive morphologies. Furthermore, the
nano-catalyzed reactions provide the advantages of high atom effi-
ciency, simplified isolation of product, and easy recovery and recy-
clability of the catalysts.
While employing traditional addition–elimination chemistry
involving hydroxyl analogue of 2 with nucleophile 1, we were in-
trigued by the possible application of the Mitsunobu reaction to
construct our desired C–N bond and furnish coupled products 3.
In accordance with the significance of N-alkylation reaction,
various synthetic methods have been developed for the construc-
tion of fused heterocycles (Fig. 1). Here we have explored an N-
alkylation of 4(3H)-pyrimidone with 2-chloro-3-(chloromethyl)-
8-methylquinoline in the presence of Fe nano particles to synthe-
size the synthons of fused heterocycles (Fig. 1).
O
O
N
N
N
N
N
N
O
In view of recent surge in the use of heterogeneous catalysis we
have developed N-alkylated pyrimidone employing Fe nano parti-
cles as an inexpensive, non-volatile, recyclable, non-explosive, easy
to handle, and eco-friendly catalyst (Scheme 1). The results of the
synthesis of 3-[(2-chloroquinolin-3-yl)methyl]pyrimidin-4(3H)-
ones are summarized (Tables 1–3). Interestingly the N-alkylation
reaction took less time (30 min) for completion (Tables 1 and 3).
HO
I
II
O
Figure 1. Structures of luotonin A (I), azacamptothecin (II).
* Corresponding author. Tel.: +91 416 220 2334; fax: +91 416 224 3092.
E-mail address: nawaz_f@yahoo.co.in (Fazlur Rahman Nawaz Khan).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.128

2310
S. M. Roopan et al. / Tetrahedron Letters 51 (2010) 2309–2311
Table 1
Table 3
Optimization of 3-[(2-chloro-8-methylquinolin-3-yl]methyl)pyrimidin-4-(3H)onesa
C–N bond-forming reaction using Fe(0) nano particlesa
S.no.
R
Condition
Yield (%)b
Entry
R
Products
Time (min)
Yieldb (%)
2b/3b
3b
2/3
3
1
2
3a
30
30
87
82
1
2
3
4
DMF, KOtBu, THF
KOH, DMSOd
35 (trace)c
N
N
N
N
N
Cl
Cl
Cl
Cl
Cl
N
N
Cl
Cl
3b
NRe
3
4
3c
40
30
76
88
Fe, DMSOf
NRe
N
N
N
Cl
Cl
Cl
3d
Fe (5 mol %), KOH, DMSO
82
5
3e
20
84
5
6
7
Fe (10 mol %), KOH, DMSO
Fe (15 mol %), KOH, DMSO
NaH, DMSO
74
6
7
3f
30
20
67
92
N
Cl
63
N
N
Cl
Cl
3g
52 (23)c
a
Reactions were carried out on 1.0 equiv of 1 and 2, 1.5 equiv of KOH, 1 mL
DMSO, and 5 mol % Fe at 110 °C for the specified period of time.
b
Isolated yields.
8
9
NaH, Fe (5 mol %), DMSO
NaH, Fe (10 mol %), DMSO
75
63
N
N
Cl
Cl
denced from the fact that compounds 1 and 2 were not observed in
the organic phase during the reaction, which clearly indicates that
the N-alkylation occurs in the pores of nano particles.
In order to ascertain the effect of solvent on N-alkylation, the
reaction was carried out using different solvents of varied dielec-
tric constants. The results are summarized (Table 2) which suggest
that solvents with high dielectric constant produced high yield of
N-alkylated products as in DMSO and that with low dielectric con-
stant formed low yield of N-alkylated product as in the case of THF.
Thus, the DMSO-stabilized Fe nano particles may facilitate the
deprotonation/enolate equilibrium of pyrimidone, 1, thereby reac-
tive enolate is formed which later reacts with heteroaryl alkyl chlo-
ride, 2b, and complete the catalytic cycle by reductive elimination
of the product 3b. The HCl formed is neutralized by the base, KOH.
The catalyst regenerated then takes part in further catalysis and
improves the product yield. The role of Fe nano particles in the syn-
thesis of 3-[(2-chloroquinolin-3-yl)methyl]pyrimidin-4(3H)-one is
depicted in Figure 2.
The optimization of the reaction with different amounts of cat-
alyst was carried out and was found that at 5 mol % the yield was
good (Table 1). It is evident that the concoction of KOH and Fe nano
particles in DMSO solution is the best system in terms of regiose-
lective product yield. The efficiency of the recovered catalyst was
verified with the reaction of 2-chloro-3-(chloromethyl)-8-methyl
quinoline, 2b, and 4(3H)-pyrimidone, 1, for the tested three cycles
with almost consistent activity (see graph in Supplementary data).
These experimental observations suggest the eco-friendly and
environmentally benign nature of the reusable iron nano catalyst.
In order to investigate the scope of this reaction, a variety of dif-
ferently substituted halides were subjected to this reaction (Table
a
Reactions were carried out with 1.0 equiv of 1b and 2b, 1.5 equiv of base, and
nano Fe, 1 mL of solvent, refluxed at 110 °C for the specified time period.
b
Isolated yields.
The value in parenthesis indicates the O-alkylated product.
The reaction was carried out without nano Fe.
NR = no reaction.
c
d
e
f
The reaction was carried without base.
Table 2
The effect of solvents on the alkylation of amide
Solvent
KOH (mmol)
RCH2Cl (mmol) 2b
Yield of 3b (%)
THF
DMF
DMF/THF
DMSO
DMSO
1
1
1
1
1
1
1
1
1
40
60
72
79
82
1.5
The effect of solvent and reusability of catalyst in synthesis has
been explored (Table 2). Scope of the reaction has also been inves-
tigated (Table 3). Enhanced reaction rates and improved selectivity
were obtained in the presence of nano particles.
The essence of nano catalyst and base can be understood from
the following observations, that is, when 4(3H)-pyrimidone, 1,
was treated with Fe nano particles and KOH under conventional
heating in presence of 2-chloro-3-(chloromethyl)-8-methylquino-
line, 2b, the product 3b was obtained in quantitative yield (Table
1, entry 4). The same reaction when carried out without either Fe
nanoparticles or KOH was not proceeding (Table 1, entries 2 and
3). These experimental results clearly suggest that the reaction in-
volves a heterogeneous process and the catalysis may occur on the
surface of the Fe nano particles. These observations were also evi-
3, entries 1–7).
A variety of substituted 2-chloro-3-(chloro-
methyl)quinolines afforded their corresponding products in good
yields. The application of the reaction to simple benzyl halide has
also been explored. The results suggest that, irrespective of hetero-
aryl alkyl halides or benzyl halides, the reaction proceeds well in
the optimized conditions (Table 3, entry 4).

S. M. Roopan et al. / Tetrahedron Letters 51 (2010) 2309–2311
2311
O
O
O
N
N
N
N
Fe nanoparticle
N
Cl
N
N
3b
1
O
N
N
KOH
Cl
KCl + H2O
N
Cl
2b
Figure 2. Role of Fe nano particles in synthesis of 3-((2-chloroquinolin-3-yl)methyl)pyrimidin-4(3H)-one.
The reaction efficiency by applying strong base such as sodium
hydride in DMSO was explored. The result indicates that the alkyl-
ation reaction gave a mixture of N-alkylated and O-alkylated prod-
ucts (Table 3, entry 7). The alkylation proceeds through amide/
enolate equilibrium. However, the regioselectivity can be achieved
by effecting the reaction in the presence of iron nanoparticles (Ta-
ble 3, entry 8). The amide deprotonation/enolate equilibrium is dri-
ven by the presence of iron thereby facilitating the alkylation.
In the course of this work, few compounds with different substi-
tutions in the aromatic ring of the quinoline skeleton have been syn-
thesized. The structures of the substances were corroborated by
FTIR, MS, 1H, and 13C NMR spectra. The comparison of the spectra
of the N-alkylated compound, 3b, with those of the O-alkylated
product, 3b0, provided satisfactory evidence for their identification.
The 1H NMR spectra displayed considerable confirmation exhibiting
chemical shifts for N–CH2 protons (d 5.34 for compound 3b) in more
up field than that of O–CH2 protons (d 5.69 for compound 3b0), sim-
ilarly chemical shifts for 13C NMR of 3b shows the appearance of
C@O peak at 160 ppm whereas in compound 3b0 C–O appears at
168 ppm due to the inductive effect (see Supplementary data).
TEM image of the Fe nano particles confirmed a fairly uniform
particle size of 50 nm (see Supplementary data).
In conclusion, we have developed a simple, convenient, and
effective method for the facile N-alkylation using Fe nano particles.
The present methodology offers very attractive features such as re-
duced reaction times, higher yields, and economic viability of the
catalyst, when compared with the conventional method. The sim-
ple procedure combined with the easy recovery and reuse of this
catalyst makes this method an economic chemical process for the
N-alkylation. The operational simplicity of the procedure is also
attractive. To our knowledge, this is the first time report of an effi-
cient general method for N-alkylation by using Fe nano particles.
The catalyst can be recovered and reused with no change in the
yield.
acknowledge SAIF, IIT Madras, Chennai, for providing NMR and
MS facility. We are thankful to the management of VIT University
for the generous support and facilities.
Supplementary data
Supplementary data (experimental procedure, characterization
data 1H and 13C NMR, mass spectra for new compounds, TEM pic-
ture of nanoparticle) associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.02.128.
References and notes
1. Roopan, S. M.; Hathwar, V. R.; Kumar, A. S.; Malathi, N.; Khan, F. N. Acta.
Crystallogr., Sect. E 2009, 65, o571.
2. Roopan, S. M.; Maiyalagan, T.; Khan, F. N. Can. J. Chem. 2008, 86, 1019–1025.
3. Bogdal, D. J. Chem. Res. 1998, 468–469.
4. Bogdal, D.; Pielichowski, J.; Boron, A. Synth. Commun. 1998, 28, 3029–3039.
5. Bogdal, D. Molecules 1999, 4, 333–337.
6. Roopan, S. M.; Khan, F. N. Indian J. Heterocycl. Chem. 2008, 86, 1019–1020.
7. Roopan, S. M.; Reddy, B. R.; Kumar, A. S.; Khan, F. N. Indian J. Heterocycl. Chem.
2009, 19, 81–82.
8. Manivel, P.; Roopan, S. M.; Khan, F. N. J. Chil. Chem. Soc. 2008, 53, 1609–
1610.
9. Khan, F. N.; Jayakumar, R.; Pillai, C. N. Tetrahedron Lett. 2003, 43, 6807–
6809.
10. Filipski, K. J.; Kohrt, J. T.; Garcoa, A. C.; Van Huis, C. A.; Dudley, D. A.; Cody, W.
L.; Bigge, C. F.; Desiraju, S.; Sun, S.; Maiti, S. N.; Jaber, M. R.; Edmunds, J. J.
Tetrahedron Lett. 2006, 47, 7677–7680.
11. Roopan, S. M.; Khan, F. N. ARKIVOC 2009, xiii, 161–169.
12. Kantam, M. L.; Ramani, T.; Chakrapani Garcoa, L.; Choudary, B. M. Catal.
Commun. 2009, 10, 370–372.
13. In a typical procedure, to a solution of KOH (1.5 mmol) in DMSO (1 mL)
solution 4(3H)-pyrimidone
1 (96 mg, 1 mmol), 2-chloro-3-(chloromethyl)-
quinoline, 3a (212 mg, 1 mmol), and Fe nano particles (5 mol %) were totted at
110 °C. The reaction was completed within half an hour, and was monitored by
TLC. The reaction mixture was then filtered and the supernatant liquid was
added dropwise into the crushed ice. The solution was neutralized with dilute
HCl and extracted with CHCl3. The excess solvent was removed under vacuum
and then subjected to column chromatography to give the desired compound
3a as
a
white solid. Spectroscopic data are presented here. Mp 158 °C.
ꢀ1
~
m
= 1681 cm
.
1H NMR (500 MHz, CDCl3): d = 4.84 (2H, s), 6.49–6.51 (1H, d, J
Acknowledgments
6.8), 7.56–7.59 (1H, t, J 7.2, 7.6), 7.73–7.77 (1H, m), 7.81–7.85 (1H, t, J 10.4, 8.0),
7.92–7.95 (1H, t, J 5.2, 6.4), 7.99–8.07 (1H, m), 8.24–8.29 (1H, t, J 4.4, 13.2), 8.41
(1H, s); 13C NMR (125 MHz, CDCl3) d = 48.0, 116.3, 126.9, 127.6, 127.7, 128.2,
131.1, 138.7, 140.0, 147.3, 149.1, 151.4, 153.5, 160.8. HRMS: m/z calcd for
C14H10ClN3O, 271.7017; found 271.7801 M+.
This work was supported by Department of Science & Technol-
ogy Government of India (Grant No. SR/FTP/CS-99/2006). We also