Effective microwave synthesis of bioactive thieno[2,3-d]pyrimidines

Article abstract of DOI:10.4067/S0717-97072017000100010

A series of novel 2-Amino-3-cyanothiophenes (2a-2j) were synthesized using heterogeneous base (K₂CO₃) supported Gewald reaction. Cyclization of 2a-j with formamide and urea in conventional heating as well as microwave irradiation gave thieno[2,3-d]pyrimidines (3a-3j) and thieno[2,3-d]pyrimidin-2(1H)-ones(4a-4j) respectively. The reaction rates were faster and yields were higher in the microwave conditions. The structures of the compounds were confirmed with elemental analysis, mass spectral analysis, FTIR, 1H NMR and 13C NMR techniques. All the synthesized compounds were subjected to antimicrobial activity (MIC) in vitro by broth dilution method and exhibited a moderate antimicrobial activity.

Full text of DOI:10.4067/S0717-97072017000100010

J. Chil. Chem. Soc., 62, Nº 1 (2017)
EFFECTIVE MICROWAVE SYNTHESIS OF BIOACTIVE THIENO[2,3-d]PYRIMIDINES
TASLIMAHEMAD T. KHATRI*,a, b, VIRESH H. SHAHc
aDepartment of Chemistry, Lovely Professional University, Phagwara -144411, India
bDepartment of Chemistry, KSKV Kachchh University, Bhuj-370001, India
cDepartment of Chemistry. Saurashtra University, Rajkot-360009, India
ABSTRACT
A series of novel 2-amino-3-cyanothiophenes (2a-2j) were synthesized using heterogeneous base (K2CO ) supported Gewald reaction. Cyclization of 2a-j
with formamide and urea in conventional heating as well as microwave irradiation gave thieno[2,3-d]pyrim3idines (3a-3j) and thieno[2,3-d]pyrimidin-2(1H)-
ones(4a-4j) respectively. The reaction rates were faster and yields were higher in the microwave conditions. The structures of the compounds were confirmed with
elemental analysis, mass spectral analysis, FTIR, 1H NMR and 13C NMR techniques. All the synthesized compounds were subjected to antimicrobial activity (MIC)
in vitro by broth dilution method and exhibited a moderate antimicrobial activity.
Key words: Gewald reaction; thieno[2,3-d]pyrimidines; thieno[2,3-d]pyrimidin-2(1H)-ones; antimicrobial activity
membered hetero aromatic ring; they are structural analogues of biogenic
purines and can be considered as potential nucleic acid antimetabolites. Many
of thienopyrimidines are found to exhibit a variety of biological activities like
antimicrobial,5 analgesic and ulcerogenic,6 anti-inflammatory,6-8 antitubercular,9
EGFR inhibitors,10 inhibition of cancer cell proliferation,11 antagonism of α1
adrenoceptors,12 adenosine receptor antagonists13 and other wide range of
biological activities.14-15
Some recently reported thieno[2,3-d]pyrimidine derivatives have showed
various biological activities (Fig. 1); compound I acts Potent SARS-CoV
3C-Like Protease Inhibitors,16 compound II showed anticancer activity,17
compound III antiproliferative,18 compound IV acts as adenosine A2A receptor
agonist19 and compound V is an anti-bacterial agent.20
1. INTRODUCTION
The Gewald reaction is the most common and reliable reaction to synthesize
2-aminothiophenes since invented first by K. Gewald in 1961.1-4 In the present
work the reaction has been performed in the presence of heterogeneous
catalyst at room temperature with constant stirring, avoiding drastic conditions
and toxic solvents. Hence is an imperative to explore a true green chemistry
approached one spot synthesis of novel 2-amino-3-cyanothiophenes; that can
be constructive intermediate in the synthesis of novel thieno[2,3-d]pyrimidines
and their derivatives.
The thienopyrimidines occupy
a special position among fused
pyrimidines, along with some other pyrimidines containing an annelated five
Figure 1. Structures of some bioactive thieno[2,3-d]pyrimidines and thieno[2,3-d]pyrimidones.
Thienopyrimidines can be prepared via cyclization of diamides
intermediates, generated from amino carbamoyl thiophenes by reaction with
acylating agents such as orthoesters21 acid anhydrides or acid chlorides.22
Alternatively, the synthesis of thienopyrimidines can be achieved from
amino alkoxycarbonyl thiophenes, amidine intermediates, by the reaction
of thiophenes with amides;23 nitrites under acidic conditions,24 and by
intermolecular cyclization of orthoesters and amines.25 Herein we report the
synthesis of 2-amino thiophenes by Gewald synthesis and their cyclization
with formamide and urea in microwave as well as conventional heating. Since
our group is looking for improved options for antimicrobial agents26,27 we have
also tested the synthesized compounds for their antimicrobial activities.
2. EXPERIMENTAL
2.1 General
Melting points were determined in open capillary tubes and are
uncorrected. Formation of the compounds was routinely checked by TLC
(Kieselgel 60, F254) of 0.5 mm thickness and spots were located by iodine and
UV. The microwave-assisted reactions were realized in a QPro-M microwave
synthesizer. IR spectra were recorded on Shimadzu FT-IR-8400 instrument
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J. Chil. Chem. Soc., 62, Nº 1 (2017)
using KBr pellet method. Mass spectra were recorded on Shimadzu GCMS-
QP-2010 model using Direct Injection Probe technique. 1H-NMR and 13C
NMR were determined in DMSO-d6 solution on a Bruker Ac 400 MHz and
some on Bruker Ac 500 MHz FT NMR spectrometer with TMS as internal
standard. Elemental analysis of the all the synthesized compounds was carried
out on Elemental Vario EL III Carlo Erba 1108 model and the results are in
agreements with the structures assigned.
bath (under TLC analysis). The reaction mixture was allowed to cool to room
temperature. The solid thus formed was washed with water (20.0mL) followed
by methanol (20.0 mL), dried and crystallized from dimethylformamide to
afford the desired products (4a-4j).
2.4.1 4-amino-N-(2-methoxyphenyl)-5-methyl-2-oxo-1,2-
dihydrothieno[2,3-d]pyrimidine-6-carboxamide (4h). Colour less crystals;
IR (ν , cm-1): 3358 (NH2), 3223 (NH, amide), 2974 (C-H ), 2881 (CH3),
2.2 General procedure for the synthesis of 5-amino-4-cyano-N-(aryl)-3-
methylthiophene-2-carboxamides (2a-2j).
1701m(aCx =O, amide), 1668 (C=O, amide of pyrimidine ringa)r,om1587 (C=Carom
)
1
1536 (C=N, pyrimidine ring), 1245 (C-N, pyrimidine ring), 664 (C-S-C). H
NMR (400 MHz, DMSO-d ) δH: 2.46 (3H, s, CH ), 3.79 (3H, s, OCH ), 7.21-7.26
(3Harom, m, 3CH), 7.36-7.460 (1H , d, 3JHH 8.03Hz, 1CH), 7.65 (2H,3s, NH2), 9.57
(1H, s, NH, amide), 10.98(1H, s,aNromHamide pyrimidine ring); 13C NMR (100 MHz, DMSO-d6)
δc: 9.05 (-CH3), 56.9 (-OCH3), 109.1 (-C=C-NH2), 112.4 (1Carom), 115.7 (1Carom), 121.5
(1Carom), 122.4 (1C ), 127.7 (=C-CONH-), 128.9 (1Carom), 145.1 (=C-Me), 148.5 (-NH-
CO-N-), 150.5 (1Caaroromm), 155.3 (C-NH2), 164.2 (-CONH-), 182.6 (NH=C-S); MS, m/z
330, 314, 299, 223, 208, 180, 122, 107; Anal. Calcd for C15H14N4O3S: C, 54.53;
H, 4.27; N, 16.96%. Found C, 54.50; H, 4.22; N, 16.93%
An appropriate N-(aryl)-3-oxobutanamides (1a-1j, 10.0 mmoles) was
dissolved in ethanol (10.0 mL), malononitrile (10.0 mmoles) and powdered
sulphur (10.0 mmoles) were added to the same solution. Potassium carbonate
(1.0 g) was added to the resulting solution as inorganic basic support.28 The
heterogeneous mixture was stirred at room temperature for 14-16 h at 600 rpm
(Scheme 1). After the completion of the reaction as monitored by TLC, the
reaction mixture was filtered off to separate K2CO3 as residue and the filtrate
was poured onto of ice-cold water (50.0 mL). The product got precipitated
out, which was filtered and recrystallized from methanol and was extracted in
Chloroform thrice (Table 1).
2.5 Antimicrobial Activity
All the synthesized compounds were tested for their antibacterial and
antifungal activity (MIC) in vitro by broth dilution method29-31 with two Gram-
positive bacteria Staphylococcus aureus (S.a.) MTCC-96, Streptococcus
pyogenes (S.p.) MTCC 443, two Gram-negative bacteria Escherichia coli
(E.c.) MTCC 442, Pseudomonas aeruginosa (P.a.) MTCC 441 and three
fungal strains Candida albicans (C.a.) MTCC 227, Aspergillus niger (A.n.)
MTCC 282, Aspergillus clavatus (A.c.) MTCC 1323 taking ampicillin,
chloramphenicol, ciprofloxacin, norfloxacin, nystatin, and griseofulvin as
standard drugs.
Serial dilutions of the test compounds and reference drugs were prepared
in Muellere-Hinton agar. Drugs (10 mg) were dissolved in dimethylsulfoxide
(DMSO, 1 mL). Further progressive dilutions with melted Muellere-Hinton
agar were performed to obtain the required concentrations of 1.56, 3.12, 6.25,
10.0, 12.5, 25.0, 50.0, 62.5, 100.0, 125.0, 250.0, 500.0 and 1000.0 µg mLP-1P.
The tubes were inoculated with 108 cfu mL-1 (colony forming unit mL-1) and
incubated at 37 ºC for 24 h. The MIC was the lowest concentration of the tested
compound that yields no visible growth (turbidity) on the plate. To ensure that
the solvent had no effect on the bacterial growth, a control was performed
with the test medium supplemented with DMSO at the same dilutions as
used in the experiments and it was observed that DMSO had no effect on the
microorganisms in the concentrations studied.
2.2.1
5-amino-4-cyano-N-(4-chlorophenyl)-3-methylthiophene-2-
carboxamide (2d). Colourless amorphous; IR (ν , cm-1): 3367 and 3351
(NH2), 3242 (N-H, amide), 3049 (C-Harom), 2877 m(aCx H3), 2231 (C≡N), 1711
1
(C=O, amide), 1562, 1489 and 1453 (C=Carom), 700 (C-S-C). H NMR (400
MHz, DMSO-d6) δH: 2.41 (3H, s, CH3), 7.27 (2H, s, NH2),7.40-7.44 (2Harom, d, 3JHH
8.4 Hz, 2CH), 7.78-7.83 (2H, d, J 8.4Hz, 2CH), 9.30 (1H, s, NH); 13C NMR
3
(100 MHz, DMSO-d6) δ : 9.1 (-CH3), 8H5H.7 (=C-CN), 117.3 (-CN), 122.2 (2C ), 130.4
(2C ), 133.3 (1Carom),c136.7 (1C ), 142.2 (C-CONH), 147.0 (C-Me),a1ro5m6.4 (C-
NHar)o,m167.0 (-CONH); MS, m/za2ro9m1, 264, 256, 193, 180, 165, 154, 111; Anal.
Cal2cd. for C13H10ClN3OS: C, 53.52; H, 3.45; N, 14.40%. Found: C, 53.46; H,
3.29; N, 14.30%.
2.3 General Procedure for the Synthesis of 4-amino-5-methyl-N-
phenylthieno[2,3-d]pyrimidine-6-carboxamides (3a-3j)
A mixture of an appropriate 2a-2j (10 mmol) and formamide (10 mL)
was irradiated in the microwave condition (180 MW), at 600 rpm as shown in
scheme 2, the same reaction was carried out under conventional heating (Table
2) on oil bath (under TLC analysis). The reaction mixture was allowed to cool
to room temperature. The solid thus formed was collected by filtration, washed
with methanol (20 mL), dried and crystallized from dimethylformamide to
afford the desired products (3a-3j).
2.3.1
4-amino-N-(4-fluorophenyl)-5-methylthieno[2,3-d]pyrimidine-
6-carboxamide (3j). Colourless crystals; IR (νmax, cm-1): 3443 (NH2), 3231
(NH, amide), 3072 (C-Harom), 2912 (CH ), 1712 (C=O, amide), 1576 (C=N,
pyrimidine ring), 1581 and 1542 (C=Carom3 ), 1217 (C-N, pyrimidine ring), 711
3. RESULTS AND DISCUSSION
3.1 Novel Synthetic Approach
(C-S-C). 1H NMR (400 MHz, DMSO-d6) δH: 2.60 (3H, s, CH3), 7.21-7.25 (2Harom
,
The study began with synthesis of N-phenyl-3-oxobutanamide (1a).
The fusion of ethyl acetoacetate with various substituted aromatic amines
under solvent free condition yielded 1a.18 To carry out the reaction in a green
approach under milder conditions, the Gewald reaction of 1a in heterogeneous
conditions was carried out with malanonitrile, K2CO3 and sulphur powder.
The mixture was stirred at room temperature with constant stirring for 17hr in
absolute ethanol, resulted in 5-amino-4-cyano-N-(phenyl)-3-methylthiophene-
2-carboxamide (2a) in 67% yield (Scheme 1). Based on the remarkable results
obtained with the stated reaction conditions, and in order to show the generality
and scope of this protocol, we used various N-(aryl)-3-oxobutanamides (1a-j).
Different substituents on the phenyl ring didn’t distress the reaction as all the
components provided moderate to good yield of products (Table 1).
d, 3JHH 8.4 Hz, 2CH), 7.57-7.60 (2H , d, 3JHH 7.6 Hz, 2CH), 7.83 (2H, s, NH2),
8.52 (1H, s, -N=CH-NPyrimidine), 10.24 a(ro1mH, s, NH, amide); (100 MHz, DMSO-d6) δ :
9.2 (-CH3), 117.8 (-C=C-NH2), 118.5 (2Carom), 128.2 (2Carom), 134.1 (1Carom), 136.c4
(=C-CONH-), 147.3 (=C-Me), 156.7 (N=C-N), 159.5 (C-NH2), 160.1 (N=C-S), 162.7
(1Carom), 168.7 (-CONH-); MP: 310-312°C; MS, m/z 302, 283, 270, 207, 192,
164, 138, 110, 95;Anal. Calcd. for C14H11FN4OS: C, 55.62; H, 3.67; N, 18.53%.
Found: C, 55.60; H, 3.63; N, 18.51%
2.4 General Procedure for the Synthesis of 4-amino-5-methyl-2-oxo-N-
phenyl-1,2-dihydrothieno[2,3-d]pyrimidine-6-carboxamides (4a-4j).
Amixture of an appropriate 2a-j (10.0 mmol) and urea (3.0 g) was irradiated
in the microwave condition (180 MW), at 600 rpm as shown in scheme 2,
the same reaction was carried out under conventional heating on (Table 2) oil
Scheme 1. Reagents and conditions: i: K2CO3, C2H5OH, stirring, 14-17 hours.
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J. Chil. Chem. Soc., 62, Nº 1 (2017)
Table 1 : Preparation of 5-amino-4-cyano-N-(phenyl)-3-methylthiophene-
2-carboxamides.
The 2-amino-3-cyano thiophenes has been used by Abdelaziz et al.,32 and
Shook et al.,19 to synthesize bioactive thieno pyrimidines, inspired by this
virtuous results and to demonstrate synthetic utility of synthesized 2-amino-
3-cyano thiophenes, the reaction of (2a-2j) was carried out with formamide
and urea under solvent free condition as shown in scheme 2, which yielded
the novel thieno[2,3-d]pyrimidines (3a-3j) and thieno[2,3-d]pyrimidin-2(1H)-
ones (4a-4j). Cyclization of different 2-amino-3-cyano thiophenes have been
previously reported with formamide33 and urea34 under conventional heating
for 4hr, which resulted in 68% and 70% yield respectively. In our protocol we
have also carried out the reactions in Microwave condition, which shortened
the reaction time dramatically, for this microwave magnetron power was varied
for the all the reactions performed, but maximum yield was obtained at lower
irradiation (180 MW). There were substantial differences regarding the nature
of substrate and conventional versus microwave-assisted reactions. 5-amino-
4-cyano-N-(pyridyl)-3-methylthiophene-2-carboxamide have been cyclized in
reflux for 7hrs with formamide35, while the highest time taken in our protocol
for similar synthesis is 16minutes (for 3a and 3i, Table 2). There was a clear
improvement in using microwave heating over conventional heating in all of
our studied substrates. The reaction time for microwave-assisted reactions was
up to twenty times shorter than for comparable reactions under conventional
heating. When the reaction time was shortened, thermal decomposition was
also minimized, resulting in higher isolated yields and more simplified product
purification (Table 2).
M.W.
(g/
mole)
M.P.
(°C)
Yield1
(%)
Code
R
M.F.
2a
2b
2c
2d
2e
2f
H
C13H11N3OS
C14H13N3OS
C13H10ClN3OS
C13H10ClN3OS
C13H10N4O3S
C13H10N4O3S
C13H10BN3OS
C14H13N3O2S
C14H13N3O2S
C13H10FN3OS
257
271
291
291
302
302
334
287
287
275
156-158
154-158
181-183
199-201
201-204
179-181
222-226
221-223
203-205
254-256
67
68
65
73
70
72
69
63
69
51
4-CH3
2-Cl
4-Cl
3-NO2
4-NO2
4-Br
2g
2h
2i
2-OCH3
4-OCH3
4-F
2j
1Isolated yield
Scheme 2. Reagents and conditions: i: formamide, microwave irradiation 180 Watts for or reflux on oil bath. ii: urea,
microwave irradiation 180Watts for or heating on oil bath.
While cyclization of 2a-j with formamide and urea we have observed that
3-NO yields slightly more than that of 4-NO2, may be because of electron
withd2rawing effect of NO2 group at para position. There is a little effect on the
yield due to electron donating and withdrawing groups, hence this protocol
can widely be used for synthesis of different derivatives. To demonstrate the
practicality of the developed microwave protocol, large-scale experiments (30
mmol of 2e and 2g) were carried out in the synthesis of 3e, 3g, 4e and 4g using
a 250 mL Erlenmeyer flask as the reaction vessel. High yields of 3e (79%), 3g
(75%), 4e (72%) and 4g (79%) were afforded under microwave irradiation at
180 MW with mentioned exposure times in Table 2.
3.2 Antimicrobial Activity
Although many antimicrobial agents have been introduced into
therapy; however, the field still needs extensive efforts for the development
of new antimicrobial agents to overcome the highly resistant strains of
microorganisms. Therefore all of the synthesized compounds were tested
for their antibacterial and antifungal activity (MIC) in vitro using two Gram-
positive bacteria Staphylococcus aureus (S.a.), Streptococcus pyogenes (S.p.),
two Gram-negative bacteria Escherichia coli (E.c.), Pseudomonas aeruginosa
(P.a.) and three fungal strains Candida albicans (C.a.), Aspergillus niger (A.n.),
Aspergillus clavatus (A.c), only promising results are shown here (Table 3).
The other compounds’ data can be found in the supplementary material.
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J. Chil. Chem. Soc., 62, Nº 1 (2017)
Table 2: Comparison of microwave and conventional methods for the synthesis of thieno[2,3-d]pyrimidines (3a-3j) and thieno[2,3-d]pyrimidin-2(1H)-ones
(4a-4j).
Conventional
Microwave
M.W.
(g/mole)
M.P.
(°C)
Code
R
M. F.
Time (min)
Yield1 (%)
Time2(min)
Yield1(%)
3a
3b
3c
3d
3e
3f
H
C14H12N4OS
C15H14N4OS
284
298
318
318
329
329
363
314
314
302
300
314
334
334
345
345
379
330
330
318
270-274
292-296
310-312
316-318
280-284
278-280
320-322
286-290
298-300
280-284
240-244
272-274
284-286
280-282
256-258
262-268
296-300
268-274
280-284
270-274
265
250
220
225
210
215
240
255
240
195
360
360
315
315
290
285
330
385
395
350
50
16
15
12
13
15
14
13
14
16
11
20
18
21
18
19
18
16
18
21
22
74
4-CH3
2-Cl
41
71
C14H11ClN4OS
C14H11ClN4OS
C14H11N5O3S
C14H11N5O3S
C14H11BN4OS
C15H14N4O2S
C15H14N4O2S
C14H11FN4OS
C14H12N4O2S
C15H14N4O2S
C14H11ClN4O2S
C14H11ClN4O2S
C14H11N5O4S
C14H11N5O4S
C14H11BN4O2S
C15H14N4O3S
C15H14N4O3S
C14H11FN4O2S
56
69
4-Cl
60
76
3-NO2
4-NO2
4-Br
65
78
53
72
3g
3h
3i
48
68
2-OCH3
4-OCH3
4-F
55
74
51
70
3j
53
73
4a
4b
4c
4d
4e
4f
H
55
73
4-CH3
2-Cl
60
74
62
76
4-Cl
65
74
3-NO2
4-NO2
4-Br
57
78
58
73
4g
4h
4i
57
76
2-OCH3
4-OCH3
4-F
56
72
49
73
4j
52
69
1Isolated yield, 2Continuous irradiation,
Table 3. Antimicrobial activity of the synthesized compounds1
Minimum inhibition concentration (µg mL-1)
Gram-positive
S.a.
Gram-negative
Fungal species
Code
S. p.
100
125
100
100
100
50
E.c.
200
62.5
25
P.a.
100
100
100
100
100
50
C. a.
1000
500
>1000
1000
>1000
500
>1000
>1000
100
-
A. n.
500
500
500
500
500
500
500
500
1000
-
A.c.
500
2d
2e
25
50
50
25
50
25
50
500
50
250
50
50
10
-
500
2g
1000
500
3d
200
25
3g
1000
1000
3j
50
4d
125
500
125
100
50
100
500
250
100
50
200
1000
100
100
50
>1000
4h
125
500
-
4j
Amp
Chl
Cip
Nor
Nys
Gri
-
-
-
50
25
25
-
-
-
10
10
10
-
-
-
-
-
-
100
500
100
100
100
100
-
-
-
-
1Microorganisms selected are as follows: S.a., Staphylococcus aureus; S.p.,Streptococcus pyogenes; E.c. Escherichia coli;P.a., Pseudomonas aeruginosa; C.a.,
Candida albicans; A.n., Aspergillus niger; A.c. Aspergillus clavatus. Standards: Amp,Ampicillin; Chl, Chloramphenicol; Cip, Ciprofloxacin; Nor, Norfloxacin;
Nys, Nystatin; and Gri, Griseofulvin. Values are expressed as mean ± standard deviation of the three replicates.
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J. Chil. Chem. Soc., 62, Nº 1 (2017)
It is worth noting here that compounds 2d and 3d exhibited significant
activity against Staphylococcus aureus, while compound 3g was found active
against Escherichia coli. The compound 2j and 2h didn’t show notable activity
against all the tested microorganism but after cyclization resulted in compound
3j and 4h respectively, the 3j exhibited significant activity against all the
bacterial species while 4h against Aspergillus clavatus fungal species, may be
due to presence of 2-aminopyrimidine precursor in the later ones as all the 2a-j
compounds showed low activity against tested microorganism except 2d. On
the other hand all the other synthesized compounds showed moderate-to-low
activity against bacterial species and very low activity against fungal species.
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4. CONCLUSION
In conclusion, we developed a general approach for the preparation of
some biologically active thieno[2,3-d]pyrimidines and thieno[2,3-d]pyrimidin-
2(1H)-onesvia2-aminothiopheneintermediateusingGewaldsynthesisfollowed
by cyclization reactions in conventional as well as microwave conditions.
Compared to conventional heating, the microwave technique provides a rapid,
simple, and effective method to synthesize such compounds that may have the
potential application in the field of drug discovery. Moreover the reaction is
simple, one pot, solvent free and also gives excellent yields without catalyst at
larger scales. The synthesized compounds were characterized by spectral data
(Mass Spectrum, IR, 1H and 13C NMR) and elemental analysis. The compounds
were subjected to in vitro antimicrobial activity assays. The results showed that
the synthesized compounds (2a to 4j) possessed weak to good antimicrobial
activities against the tested microorganism, with compounds 2d, 3d, 3g, 3j
displaying good activity against bacterial species while all the synthesized
compounds were poor at displaying activities against the fungal species,
however compound 4h showed moderate activity against Aspergillus clavatus.
Further studies are currently underway to establish a definite structure activity
relationship.
30. D. H. Isenberg, Essential Procedure for Clinical Microbiology, American
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5. DECLARATION OF INTEREST
The authors report no conflicts of interest.
34. A. B. A. El-Gazzar, H. A. R. Hossein, H. N. Hafez, Acta Pharmaceutica.
57(4), 395 (2007)
35. A. M. Farag, N. A. Kheder, K. M. Dawood, American Journal of Organic
Chemistry, 5(2), 73 (2015)
6. SUPPLEMENTARY MATERIAL
The spectroscopic data and biological activities of the remaining
compounds are provided in the supplementary material.
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