A facile microwave-assisted "one-Pot" synthesis of piperazino pyrimidinyl acetamides, a class of hybrid bis heterocycles and their structural elucidation using NMR spectral techniques

Article abstract of DOI:10.1002/jhet.1046

An array of novel piperazino pyrimidinyl acetamides, a class of hybrid bis heterocycles are synthesized in "one-pot" by microwave irradiation method catalyzed by heterogeneous NaHSO₄.SiO₂ catalyst in dry media and are characterized by melting point, elemental analysis, MS, FT-IR, one-dimensional NMR (¹H and ¹³C) and two-dimensional ¹H-¹H COSY and ¹H-¹³C HSQC spectral data.

Full text of DOI:10.1002/jhet.1046

396
A Facile Microwave‐Assisted “One‐Pot” Synthesis of Piperazino Pyrimi-
dinyl Acetamides, a Class of Hybrid Bis Heterocycles and Their Structural
Elucidation Using NMR Spectral Techniques
Vol 50
a
b
c
V. Kanagarajan,a,b How Ghee Ang, Siu Choon Ng, and M. Gopalakrishnan
*
aEnergetics Research Institute, Nanyang Technological University, Singapore 639 798, Republic of Singapore
bDivision of Chemical and Biomolecular Engineering, School of Chemical and Biomedical Engineering, College of
Engineering, Nanyang Technological University, Singapore 639 798, Republic of Singapore
cSynthetic Organic Chemistry Laboratory, Department of Chemistry, Annamalai University, Annamalainagar 608 002,
Tamil Nadu, IndiaSynthetic Organic Chemistry Laboratory, Department of Chemistry, Annamalai University,
Annamalainagar 608 002, Tamil Nadu, India
*
E-mail: profmgk@yahoo.co.in
Received March 7, 2011
DOI 10.1002/jhet.1046
Published online 2 April 2013 in Wiley Online Library (wileyonlinelibrary.com).
O
X
Y
X
Y
Cl
Cl
NaHSO4.SiO2
MW, 320 W
180-300 s
N
N
N
N
H
N
HN
N
O
NH2
N
CH3
N
X or Y = electron donating or electronwithdrawing groups
H3C
An array of novel piperazino pyrimidinyl acetamides, a class of hybrid bis heterocycles are synthesized in
“one‐pot” by microwave irradiation method catalyzed by heterogeneous NaHSO4.SiO2 catalyst in dry media
and are characterized by melting point, elemental analysis, MS, FT‐IR, one‐dimensional NMR (1H and 13C)
1
1
and two‐dimensional H‐1H COSY and H‐13C HSQC spectral data.
J. Heterocyclic Chem., 50, 396 (2013).
INTRODUCTION
amifloxacin, fleroxacin, and difloxacin [16]. Furthermore,
acetamide derivatives may serve as simple peptide models
and they were well known for their curative values since
the amide group is an important pharmacophore. Antibiotics
such as penicillins and cephalosporins have an amide group.
Silica gel‐supported sodium hydrogen sulfate (NaHSO4.
SiO2), a nontoxic and inexpensive catalyst, have been used
for one‐pot conversion of ketones to amides, [17]
synthesis of imines, [18] one‐pot synthesis of 1,2,3‐
selenadiazoles [19], 1,2,4‐triazolidin‐3‐thiones [20],
Knoevenagel condensation [21], and morpholino
pyrimidinyl acetamides [22]. 1H NMR and 13C
NMR spectral techniques was a versatile tool for the
structural elucidation of most of the organic
compounds [23–25]. Recently, we have reported quite
a few pyrimidine derivatives namely 2‐morpholino‐
N‐(4,6‐diarylpyrimidin‐2‐yl)acetamides;4‐(4‐morpho-
linophenyl)‐6‐arylpyrimidin‐2‐amines; 2‐phenyl‐3‐(4,
6‐diarylpyrimidin‐2‐yl)thiazolidin‐4‐ones as potent
antibacterial and antifungal agents [26–29]. Moreover, 3‐
(4′‐(4″‐fluorophenyl)‐6′‐phenylpyrimidin‐2′‐yl)‐2‐phe-
nylthiazolidin‐4‐one was used as in vivo modulation of
In recent decades, green chemistry has become a major
driving force for organic chemists to develop environmentally
benign synthetic routes to a variety of compounds [1]. For
example, the possibility of performing multicomponent reac-
tions under solvent‐free conditions to enhance the reaction
efficiency from both economic and ecological points of view
have given to this kind of procedures a remarkable synthetic
value and received a great attention. The huge interest for such
multicomponent reactions during the last years have been ori-
ented toward developing combinatorial chemistry procedures,
because of their high efficiency and convenience of these reac-
tions in comparison with multistage procedures [2–5].
Molecules with pyrimidine nucleus were of great
interest due to their presence in a wide variety of drugs
and biological activities [6–11]. The biological signifi-
cance of N‐methylpiperazine nucleus has led us to the
synthesis of substituted piperazine derivatives [12–15].
Substituted piperazines, key intermediates in the synthesis
of quinolone type antibacterial drugs were used in the syn-
thesis of norfloxacin, ciprofloxacin, norfloxacin, ofloxacin,
© 2013 HeteroCorporation

March 2013 A Facile Microwave‐Assisted “One‐Pot” Synthesis of Piperazino Pyrimidinyl Acetamides, a Class of
397
Hybrid Bis Heterocycles and Their Structural Elucidation Using NMR Spectral Techniques
Scheme 1. Reuse studies of heterogeneous NaHSO4.SiO2 catalyst for the synthesis of 28, 30, and 34 under microwave irradiation.
biomarkers of chemoprevention in the 7,12‐dimethylbenz[a]
anthracene (DMBA) induced hamster buccal pouch carcino-
genesis [30]. These biological activities are highly desirable
and have been the goal of our current research program
[30–33]. These observations prompted us to extend our re-
search in this area to synthesize this biologically active new
series of hybrid pyrimidine based novel bis heterocyclic deri-
vatives with the hope to develop some promising antimicro-
bial and anticancer agents and the work are all under
progress. Owing to our interest on the spectral and biolog-
ical studies of structurally diverse heterocycles, herein we
report the “one‐pot” synthesis of novel piperazino pyrimi-
dinyl acetamides, a class of hybrid bis heterocycles
catalyzed by NaHSO4.SiO2 under microwave irradiation
and their structural elucidation were carried out using var-
ious spectral assignments.
RESULTS AND DISCUSSION
The conventional approach for the synthesis of 2‐
(4‐methylpiperazin‐1‐yl)‐N‐(4,6‐diarylpyrimidin‐2‐yl)aceta-
mides 28‐36 was as follows: E‐1,3‐diarylprop‐2‐en‐1‐ones
1‐9 were synthesized by the Claisen‐Schmidt condensation
of equimolar quantities of appropriate acetophenone and
appropriate benzaldehyde in the presence of sodium hydrox-
ide. Treatment of 1‐9 with guanidine nitrate in the presence
Table 1
Physical and analytical data of 28–36.
Elemental analysis (%)
Reaction
time Δ (h)/ Yield (%) m.p.
C found
H found
N found
m/z (M+H)+.
Compounds
28
X
Y
MW (s)
Δ/MW
(°C)
(calculated)
(calculated)
(calculated)
molecular formula
CH3
F
CH3
F
H
CH3
F
OCH3
F
F
OCH3
H
H
H
OCH3
F
8/240
8/180
9/240
8/240
10/300
9/240
8/180
10/300
8/180
60/92
48/85
52/80
56/88
48/86
52/81
56/90
54/82
46/88
62
71
81
60
80
68
50
53
76
69.51 (69.58)
65.16 (65.24)
68.66 (68.72)
66.11 (66.19)
71.19 (71.29)
71.76 (71.79)
68.06 (68.13)
69.00 (69.04)
68.08 (68.13)
6.69 (6.77)
5.41 (5.47)
6.14 (6.25)
5.96 (6.02)
6.38 (6.50)
6.66 (6.78)
5.88 (5.97)
6.48 (6.52)
5.84 (5.97)
16.14 (16.23)
16.48 (16.54)
16.61 (16.69)
15.98 (16.08)
17.95 (18.07)
17.31 (17.44)
17.18 (17.27)
16.68 (16.77)
17.22 (17.27)
432; C25H29N5O2
424; C23H23F2N5O
420; C24H26FN5O
436; C24H26FN5O2
388; C23H25N5O
402; C24H27N5O
406; C23H24FN5O
418; C24H27N5O2
406; C23H24FN5O
29
30
31
32
33
34
35
36
H
H
Journal of Heterocyclic Chemistry
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V. Kanagarajan, H. G. Ang, S. C. Ng, and M. Gopalakrishnan
Vol 50
Table 2
FT‐IR absorption frequencies (cm−1) for selected functional groups of compounds 28–36.
Amide NH
stretching
Aromatic CH
stretching
Aliphatic CH
stretching
Amide C═O
stretching
C═C
stretching
C―N
stretching
Aromatic
ring stretching
Compounds
28
29
30
31
32
33
34
35
36
3323
3332
3329
3322
3315
3318
3321
3325
3340
3199, 3066, 2998
3207, 3069
2956, 2919, 2849
2952, 2919, 2850
2919, 2850
1676
1664
1680
1676
1676
1680
1672
1687
1682
1574
1540
1573
1573
1557
1569
1573
1569
1601
1362, 1251
1362, 1227
1360, 1226
1362, 1254
1359, 1227
1360, 1231
1360, 1228
1361, 1256
1361, 1225
813, 768, 679
827, 772, 642
815, 768, 664
821, 747, 672
807, 760, 692
813, 770, 694
806, 770, 695
804, 771, 692
819, 769, 693
3196, 3063
3198, 3066
3191, 3057
2959, 2919
2918, 2851
2919, 2850
2963, 2919
3193, 3059, 3028
3196, 3061
3199, 3058
3196, 3061
2959, 2849
2959, 2919, 2850
of ethanolic sodium hydroxide yielded 2‐amino‐4,6‐diaryl-
pyrimidines 10‐18. Compounds 10‐18 were converted to re-
spective 2‐chloro‐N‐(4,6‐diarylpyrimidin‐2‐yl)acetamides
19‐27 using triethyl amine as catalyst and toluene as solvent.
Further reaction of 19‐27 with N‐methylpiperazine in the
presence of triethyl amine as catalyst and hazardous toluene
as solvent yielded the target molecules 28‐36. There were
some problems associated with above synthesis, such as se-
vere conditions, very low yields for the reaction, difficulty in
separating the products from the system and longer reaction
times. In the present “one‐pot” procedure, treatment of
various substituted 0.005 mol of 2‐amino‐4,6‐diarylpyrimi-
dines 10‐18 were treated with 0.005 mol of chloro acetyl
chloride along with a catalytic amount of NaHSO4.SiO2
(20 mg) and irradiated in a microwave oven for 60 s, fol-
lowed by the addition of 0.005 mol of N‐methylpiperazine
and then irradiated to afford the corresponding 2‐(4‐methyl-
piperazin‐1‐yl)‐N‐(4,6‐diarylpyrimidin‐2‐yl)acetamides 28‐
36 (Scheme 1 and Table 1) in high yields in dry media under
MW irradiation. The reaction was monitored by using TLC
method. NaHSO4.SiO2 catalyst was shown to be one of the
most efficient MW absorber with a very high specificity to
MW heating. It was able to reach a temperature of 110°C af-
ter 3 min of irradiation in a domestic oven (320 W). Mere 20
mg of NaHSO4.SiO2 catalyst to 0.005 moles of substrates
was the most acceptable ratio in terms of efficiency and
safety; a power level of 320 W was the most suitable one.
The structures of all the newly synthesized compounds 28‐
36 were discussed with the help of m.p.s, elemental analy-
sis, FT‐IR, MS, 1H, 13C, 1H‐1H COSY, and 1H‐13C HSQC
spectral data.
To determine the structure of the synthesized com-
pounds, N‐(4‐(4‐methylphenyl)‐6‐(4‐methoxyphenyl)pyri-
midin‐2‐yl)‐2‐(4‐methylpiperazin‐1‐yl)acetamide 28 was
taken as the model compound. FT‐IR spectrum of 28
showed characteristic absorption frequency (Table 2) ob-
served at 3323 cm−1 was due to N―H stretching vibration
of the amide group. The absorption frequencies at 3199,
3066, and 2998 cm−1 were assigned to aromatic C―H
stretching vibration. The absorption frequencies at 2956,
2919, and 2849 cm−1 were assigned to aliphatic C―H
stretching vibration. The band at 1676 cm−1 was due to
the presence of amide C═O stretching frequency. The ab-
sorption bands at 1362, 1251 cm−1 were consistent with
C―N stretching vibration. The absorption band at 1574
cm−1 was due to C═C stretching vibration. In addition,
compound 28 displayed characteristic absorption bands
(cm−1) at 813, 768, and 679 cm−1 were due to aromatic
ring stretching; this gives positive evidence for the forma-
tion of compound 28. Mass spectrum of compound 28
Table 3
Proton NMR chemical shifts (δ, ppm) of compounds 28–36.
Piperazine moiety
Acetamide moiety
Pyrimidine moiety
Ar‐protons
N―CH3
Methylene Ha and Hb
(broad signal)
CH2
NH (broad
singlet)
H‐5
(singlet)
Others
Compounds
(singlet)
(singlet)
(multiplet)
(singlet)
28
29
30
31
32
33
34
35
36
2.19
2.21
2.27
2.20
2.19
2.28
2.26
2.07
2.17
2.97
2.99
3.01
3.02
2.99
3.07
3.06
2.98
2.93
3.85
3.82
3.81
3.85
3.85
3.83
3.85
3.86
3.84
10.11
10.21
10.94
10.89
10.15
10.93
10.98
10.13
10.16
6.58
6.63
6.69
6.63
6.62
6.67
6.61
6.72
6.72
7.11–8.33
7.17–8.44
7.15–8.29
7.10–8.42
7.49–8.34
7.26–8.34
7.25–8.44
7.43–8.22
7.28–8.32
2.36 CH3, 3.82 OCH3
–
2.37 CH3
3.85 OCH3
–
2.37 CH3
–
3.83 OCH3
–
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March 2013 A Facile Microwave‐Assisted “One‐Pot” Synthesis of Piperazino Pyrimidinyl Acetamides, a Class of
399
Hybrid Bis Heterocycles and Their Structural Elucidation Using NMR Spectral Techniques
showed molecular ion peak at m/z 432 (M+•+1) which was
consistent with the proposed molecular formula of 28. Ele-
mental analysis have been carried out for the representative
compound 28, Ccal 69.58, Cobs 69.51; Hcal 6.77, Hobs 6.69;
Ncal 16.23, Nobs 16.14 were consistent with the proposed
molecular formula (C25H29N5O2) of 28.
1
The assignments of H NMR signals of 28 have been
done based on total widths and spin multiplicities. A sin-
glet observed at 3.85 ppm for two protons was assigned
to methylene protons of acetamide moiety (Table 3). The
amide proton resonated at 10.11 ppm. An intense unre-
solved broad signal and a very sharp singlet in the aliphatic
region 2.97 and 2.19 ppm with eight and three protons in-
tegral, respectively were observed. These signals were due
to ring methylene protons of N‐methylpiperazine and
methyl protons of N‐methyl piperazine moiety, respec-
tively. The H‐5 proton of pyrimidine moiety was observed
as a singlet at 6.58 ppm. The aromatic protons resonated in
the region 7.11–8.33 ppm. Besides these signals, two sing-
lets observed at 2.36 and 3.82 ppm each corresponding to
three protons were due to methyl and methoxy protons at-
tached to para position of phenyl rings at positions 4 and 6
of pyrimidine moiety.
Among various 13C carbon resonances, (Table 4) the am-
ide carbonyl carbon of 28 resonated at 170.19 ppm. The
methylene carbon attached to amide carbonyl carbon reso-
nated at 66.88 ppm. The 13C resonance at 163.84 ppm was
assigned to the amide group bearing carbon C‐2 of
pyrimidine moiety. The 13C resonance observed at 164.25/
164.42 and 100.68 ppm was due to the C‐4/6 and C‐5
carbons of pyrimidine moiety, respectively. There were
two 13C resonances observed at 60.15 and 52.22 ppm for
the methylene carbons of piperazine moiety viz., C‐a and
C‐b unlike their corresponding protons. The upfield signal
was assigned to C‐b carbons while the downfield signal to
C‐a carbons because the former carbons were present at
γ‐position with respect to the amide carbonyl group thereby
experiencing its electronic effect. The methyl carbon of
N‐methyl piperazine moiety resonated at 45.43 ppm. The
remaining 13C signals at 133.55, 134.66, 140.02, 157.49
ppm were due to ipso carbons. The aromatic carbons were
observed at 113.55–131.17 ppm. Moreover, two carbon
resonances observed at 20.90 and 55.28 ppm were due to
methyl and methoxy carbons attached to para position of
phenyl rings at positions 4 and 6 of pyrimidine moiety. All
the above mentioned assignments were further confirmed
by 1H‐1H COSY and 1H‐13C HSQC spectra.
In the 1H‐1H COSY spectrum of 28, the proton signal at
2.97 ppm showed cross peak with the signal at 2.97 ppm
and vice‐versa (Table 5). This mutual correlation clearly
revealed that these two signals were due to methylene pro-
tons Ha and Hb of piperazine ring, respectively. As the
nitrogen of piperazine moiety was having almost similar
chemical environment on either side, its ring methylene
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V. Kanagarajan, H. G. Ang, S. C. Ng, and M. Gopalakrishnan
Vol 50
Table 5
51H‐1H COSY correlations for 28.
Acetamide
moiety
Piperazine moiety
Pyrimidine moiety
Methylene Methylene
Aromatic
protons
N―CH3 Ha
Hb
CH2
3.85
NH H‐5
Ar‐CH3 Ar‐OCH3
ppm
Protons
2.19
2.97
2.97
10.11 6.58
2.36
3.82
7.11–8.33
Piperazine moiety
N―CH3
Methylene Ha
Methylene Hb
CH2
NH
H‐5
Ar‐CH3
Ar‐OCH3
2.19
2.97
2.97
3.85
10.11
6.58
2.36
3.82
coupled
coupled
Acetamide moiety
Pyrimidine moiety
Aromatic protons 7.11–8.33
coupled
protons become equivalent and therefore the signal was
assigned to ring methylene protons of N‐methyl piperazine
moiety. Moreover, irrespective of the restricted rotation of
the N―CO bond, the rotation about N―C bond of the
piperazinoacetyl moiety was very fast and prevents
the spin‐spin coupling of all the methylene protons of
piperazine moiety. Owing to this, their resonances were
observed as an intense unresolved broad signal. All these
observations strongly confirm the nucleophilic substitution
of piperazine moiety in place of chlorine. Also, the cross
peaks observed around 7.11–8.33 ppm were due to aromatic
protons attached to positions 4 and 6 of pyrimidine moiety.
It is seen that the proton signal at 10.11ppm has no
HSQC correlation (Table 6) with any carbon signal. Thus,
it was obvious that this signal was due to NH proton at-
tached to pyrimidine moiety. Also the carbon signals at
170.19, 163.84, 164.25, and 164.42 ppm show no correla-
tions with any proton signals. Obviously, these signals
were due to different carbons namely amide carbonyl,
C‐2, C‐4, and C‐6 of pyrimidine moiety, respectively.
The 13C resonance observed at 133.55, 134.66, 140.02,
157.49 ppm also did not show any correlation with proton
signals and were due to ipso carbons. A singlet at 2.19
ppm showed cross peaks with the 13C signal at 45.43
ppm. Hence the singlet at 2.19 ppm should be due to the
N‐methyl protons and the carbon resonance observed at
45.43 ppm was due to N‐methyl carbons of piperazine
moiety. The 13C signals observed at 60.15 and 52.22
ppm correlated with the broad signal at 2.97 ppm, which
were due to the Ha and Hb protons of piperazine ring
methyl protons, respectively. Obviously, the carbon sig-
nal at 66.88 ppm showed cross peak with the singlet
proton signal at 3.85 ppm. From the cross peak it was ob-
served that the carbon signal observed at 66.88 ppm and
proton signal observed at 3.85 ppm were due to methy-
lene carbon and protons of acetamide moiety, respec-
tively. A singlet observed at 6.58 ppm showed cross
peak with the 13C signal at 100.68 ppm. Hence the singlet
observed at 6.58 ppm should be due to H‐5 proton of py-
rimidine moiety and the carbon signal observed at 100.68
ppm was due to C‐5 carbon of pyrimidine moiety. Be-
sides these, two singlets observed at 2.36 and 3.82 ppm
showed cross peaks with the carbon signals at 20.90 and
55.28 ppm, respectively due to ring methyl and methoxy
protons and carbons, respectively. Moreover, a multiplet
observed at 7.11–8.33 ppm showed correlation with car-
bon signals around 113.56–131.17 ppm due to aromatic
protons and carbons, respectively. Therefore with refer-
1
1
ence to H‐1H COSY and H‐13C HSQC correlations in
compound 28 the tentative assignments made for pipera-
zine, acetamide, and pyrimidine moieties of 28 protons
and carbons were confirmed. Based on 1H‐1H COSY
1
1
and H‐13C HSQC correlations of 28, the H and 13C
chemical shifts of 28 were assigned unambiguously.
The conversion of 10‐18 into 28‐36 by this method
was believed to be followed via the 2‐chloro‐N‐(4,6‐diaryl-
pyrimidin‐2‐yl)acetamides derivative 19‐27. In the first
step, 2‐amino‐4,6‐diarylpyrimidines 10‐18 were converted
to their respective intermediate acetamides 19‐27 and rap-
idly rearranged to give 28‐36 in the second step.
The attempt to isolate the respective intermediate aceta-
mides 19‐27 from the reaction mixture was unsuccessful.
The formations of 28‐36 via the intermediate acetamides
were confirmed by the same kind of reactions carried
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March 2013 A Facile Microwave‐Assisted “One‐Pot” Synthesis of Piperazino Pyrimidinyl Acetamides, a Class of
401
Hybrid Bis Heterocycles and Their Structural Elucidation Using NMR Spectral Techniques
out using NaHSO4.SiO2 catalyst and 2‐chloro‐N‐(4,6‐dia-
rylpyrimidin‐2‐yl)acetamides derivatives 19‐27 and under
microwave irradiation for 120‐180 s. The products formed
from the above two methods were found to be the same.
A major role was played by NaHSO4.SiO2 heteroge-
neous catalyst, which could be recovered and reused
(Fig. 1) by simple washing with ethanol after each use
and activated in an oven at 110°C for 1 h prior to use,
rendering thus the process more economic and green. To
perform the reuse studies of NaHSO4.SiO2 catalyst, reuse
studies of catalyst were carried out for the synthesis of
28, 30, and 34 from the respective aminopyrimidine 10,
12, and 16. In total, seven successive reuse runs were pos-
sible. However, there was a decrease in the reaction yield
was noted after four runs, since recycling leads to loss of
efficiency of the catalyst owing to the absorption of organ-
ics. Organics on the solid surface result in the reduction of
number of active centers. Organic species could be re-
moved at higher temperature reactivating the catalyst. All
these constitute a green and efficient alternative to the
classical method using benzene as solvent and triethyl
amine as catalyst [26].
EXPERIMENTAL
General. Performing TLC assessed the reactions and the
purity of the products. All the reported melting points were
taken in open capillaries and were uncorrected. BIOTAGE
Initiator microwave synthesizer, Sweden a scientific microwave
oven was used for the irradiation. IR spectra were recorded in
KBr (pellet forms) on a Thermo Nicolet‐Avatar–330 FT‐IR
spectrophotometer (Thermo Fisher Scientific, Waltham, MA)
1
and note worthy absorption values (cm−1) alone were listed. H
and 13C NMR spectra were recorded at 400 and 100 MHz,
respectively on Bruker AMX 400 NMR spectrometer (Bruker
Biospin International, Ag, Aegeristrasse, Switzerland) using
DMSO‐d6 as solvent. 1H‐1H COSY and 1H‐13C HSQC NMR
spectra were recorded on Bruker DRX 500 NMR spectrometer
(Bruker Biospin International, Ag, Aegeristrasse, Switzerland)
using DMSO‐d6 as solvent. The ESI +ve MS spectra were
recorded on a Varian Saturn 2200 MS spectrometer (Varian,
Palo Alto, US). Satisfactory microanalyses were obtained on
Carlo Erba 1106 CHN analyzer (Thermo Fisher Scientific,
Waltham, MA). By adopting the literature precedent 1,3‐diaryl‐
prop‐2‐en‐1‐ones 1‐9 [34], 2‐amino‐4,6‐diarylpyrimidines 10‐18
[26] and 2‐chloro‐N‐(4,6‐diarylpyrimidin‐2‐yl)acetamides 19‐27
[26] were synthesized.
General method for the “one‐pot” microwave‐assisted
synthesis of piperazino pyrimidinyl acetamides catalyzed by
NaHSO4.SiO2 28–36. A mixture of 4,6‐diarylpyrimidin‐2‐
amines 10‐18 (0.005 mol), chloroacetyl chloride (0.005 mol)
and NaHSO4.SiO2 (20 mg) was added in an alumina bath and
mixed properly with the aid of glass rod (10 s) and then
irradiated in
a
microwave oven for 60 s, and N‐
methylpiperazine (0.005 mol) was added and irradiation is
continued up to 180–300 s at 320 W (monitored by TLC). After
completion of the reaction, the reaction mixture was extracted
with dichloromethane (3 × 5 mL). The catalyst and other solid
wastes were removed by filtration. The combined organic layer
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V. Kanagarajan, H. G. Ang, S. C. Ng, and M. Gopalakrishnan
Vol 50
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Figure 1. A facile microwave assisted synthesis of hybrid 2‐(4‐methylpi-
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CONCLUSION
In conclusion, we have developed an efficient, environ-
mentally friendly, one‐pot microwave‐assisted synthesis
of a new series of novel piperazino pyrimidinyl acetamides
by the reaction of 4,6‐diarylpyrimidin‐2‐amines and chlor-
oacetyl chloride with N‐methylpiperazine in the presence
of heterogeneous NaHSO4.SiO2 catalyst under microwave
irradiation in dry media. The structural elucidations of the
synthesized compounds were confirmed unambiguously
by elemental analysis, FT‐IR, MS, 1H, 13C, 1H‐1H COSY,
and 1H‐13C HSQC spectral data. The advantages of this en-
vironmentally benign and safe protocol include a simple
reaction set‐up, high product yields, short reaction times
and the elimination of solvents.
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Acknowledgments. Authors are thankful to NMR Research Centre,
Indian Institute of Science, Bangalore for recording spectra. One of
the authors namely V. Kanagarajan is grateful to Energetics
Research Institute, Nanyang Technological University, Singapore,
Republic of Singapore for the award of Postdoctoral Research
Fellowship and Council of Scientific and Industrial Research
(CSIR), New Delhi, Republic of India for providing financial
support in the form of CSIR‐Senior Research Fellowship (SRF) in
Organic Chemistry.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet