Synthesis and Evaluation of Antimicrobial Activity of Some Novel Heterocyclic Compounds from 5-Bromosalicylaldehyde

Article abstract of DOI:10.1002/jhet.2970

A novel series of coumarins, thiadiazoles, thiazoles, and pyridines were synthesized via reaction of 5-bromosalicylaldehyde with different reagents. Thus, 5-bromosalicylaldehyde 1 was reacted with compounds 2a–d affording iminocoumarins 3a–d, which on hydrolysis with 10% hydrochloric acid, afforded coumarins 4a–d, respectively. On the other hand, reaction of 1 with benzylhydrazinecarbodithioate 5 afforded derivative 6, which reacted with hydrazonoyl halides 7a–f, afforded 1,3,4-thiadiazoles 11a–f, respectively. Moreover, thiazoles 15 and 16 were obtained via reaction of 1 with thiocarbohydrazide 13 and hydrazonoyl halides. However, condensation of 2-acetyl-5-bromobenzofuran 17 with benzaldehyde afforded chalcone 18, which reacted with pyridiniumbromides 19a–c, afforded pyridines 20a–c, respectively. Furthermore, pyridines 21–24 were synthesized from the reaction of chalcone 18 with different active methylene compounds. Reaction of 24 with ethylchloroacetate, chloroacetone, and chloroacetonitrile afforded thienopyridines 26a–c, respectively. The structures of the newly synthesized compounds were established based on their spectral data and elemental analyses. Also, selected newly synthesized compounds were screened for their antimicrobial activity against various microorganisms by disk diffusion method.

Full text of DOI:10.1002/jhet.2970

Month 2017
Synthesis and Evaluation of Antimicrobial Activity of Some Novel
Heterocyclic Compounds from 5-Bromosalicylaldehyde
a
Anhar Abdel-Aziem,
Basma S. Baaiu,b and Abdou O. Abdelhamidc
*
aDepartment of Chemistry, Faculty of Science (Girls), Al-Azhar University, Nasr City, Cairo 11754, Egypt
bDepartment of Chemistry, Faculty of Science, Benghazi University, Benghazi, Libya
cDepartment of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
*
E-mail: anharabdelaziem@gmail.com
Received March 24, 2017
DOI 10.1002/jhet.2970
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
A novel series of coumarins, thiadiazoles, thiazoles, and pyridines were synthesized via reaction of 5-
bromosalicylaldehyde with different reagents. Thus, 5-bromosalicylaldehyde 1 was reacted with compounds
2a–d affording iminocoumarins 3a–d, which on hydrolysis with 10% hydrochloric acid, afforded coumarins
4a–d, respectively. On the other hand, reaction of 1 with benzylhydrazinecarbodithioate 5 afforded deriva-
tive 6, which reacted with hydrazonoyl halides 7a–f, afforded 1,3,4-thiadiazoles 11a–f, respectively. More-
over, thiazoles 15 and 16 were obtained via reaction of 1 with thiocarbohydrazide 13 and hydrazonoyl
halides. However, condensation of 2-acetyl-5-bromobenzofuran 17 with benzaldehyde afforded chalcone
18, which reacted with pyridiniumbromides 19a–c, afforded pyridines 20a–c, respectively. Furthermore,
pyridines 21–24 were synthesized from the reaction of chalcone 18 with different active methylene com-
pounds. Reaction of 24 with ethylchloroacetate, chloroacetone, and chloroacetonitrile afforded
thienopyridines 26a–c, respectively. The structures of the newly synthesized compounds were established
based on their spectral data and elemental analyses. Also, selected newly synthesized compounds were
screened for their antimicrobial activity against various microorganisms by disk diffusion method.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
On the other hand, pyridine derivatives are very
interesting heterocycles, having wide range of
a
Due to the interesting activity of coumarins as biological
agents, considerable attention has been focused on this
class of heterocycles. The pharmaceutical importance of
these compounds lies in the fact that they can be utilized
as anti-inflammatory [1], anticancer [2], anticoagulant [3],
antimicrobial, and antioxidant activities [4,5]. A literature
survey revealed that a special attention was given to
1,3,4-thiadiazole derivatives that proved to have
promising biological activities such as antimicrobial [6–8],
anticancer [9–11], antioxidant [12], antiamoebic [13],
anticonvulsant [14], anti-inflammatory, and analgesic
activities [15]. Also, 1,3-thiazoles have promising
biological activities such as antimicrobial [16,17],
anticancer [18], anti-inflammatory, analgesic, and
anti-ulcerogenic activities [19].
biological activities. They are known to exhibit
anticancer and antimicrobial [20,21], anti-inflammatory,
anti-ulcer, analgesic, anticonvulsant, and antiparkinsonian
activities [22,23]. In view of all these facts, we report
herein a convenient general method for synthesis of
coumarins, thiadiazoles, thiazoles, and pyridines and
evaluating their antimicrobial activity.
RESULTS AND DISCUSSION
In the interest of the aforementioned suggestion,
Knoevenagel condensation of 5-bromosalicylaldehyde (1)
with 2-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl)acetonitrile
(2a) [24], 2-(4-(5-bromobenzofuran-2-yl)thiazol-2-yl)
© 2017 Wiley Periodicals, Inc.

A. Abdel-Aziem, B. S. Baaiu, and A. O. Abdelhamid
Vol 000
acetonitrile (2b) [25], 3-(5-bromobenzofuran-2-yl)-3-
oxopropanenitrile (2c), and 2-(benzo[d]thiazol-2-yl)
acetonitrile (2d) [26] under solvent-free condition led to
formation of the corresponding iminocoumarins 3a–d,
respectively (Scheme 1). The structure of the reaction
products was ascertained on the basis of their elemental
analysis and spectral data, where the IR spectra showed the
absence of cyano function and displayed an absorption
bands at 3280–3210 cmÀ1 characteristic to NH group.
On the other hand, grinding of 5-bromosalicylaldehyde
(1) with benzylhydrazinecarbodithioate (5) [27] in the
presence of two drops of acetic acid afforded benzyl 2-(5-
bromo-2-hydroxybenzylidene)hydrazine-1-carbodithioate
(6) (Scheme 2). The structure of 6 was confirmed via
spectral data, elemental analysis, and chemical
transformation. The IR spectrum of compound 6 revealed
the disappearance of carbonyl group and the presence of
characteristic band at 3209 cmÀ1 for NH group. Thus,
1
Also, their H NMR spectra showed the absence of CH2
benzylhydrazinecarbodithioate derivative
6
and the
proton and revealed a new signal at δ = 8.50–10.80 ppm
corresponding to NH group of imino in addition to other
signals due to the rest of the molecule.
Furthermore, iminocoumarins 3a–d undergo hydrolysis
upon grinding with few drops of concentrated
hydrochloric acid affording the corresponding coumarin
derivatives 4a–d (Scheme 1). The structure of compounds
4a–d was established through elemental analyses and
spectroscopic data. (See Experimental section.)
appropriate hydrazonoyl halides 7a–f [28–33] were mixed
and grinded with three drops of triethylamine underwent
cyclization affording 1,3,4-thiadiazole derivatives 11a–f,
respectively (Scheme 2). The structure of 11a–f was
established based on elemental analyses, spectroscopic data,
and alternative synthetic routes. Thus, ethyl 5-hydrazono-
4-phenyl-4,5-dihydro-1,3,4-thiadiazole-2-carboxylate (12)
[34] was reacted with 1 giving product identical in all
aspects (mp, mixed mp, and spectra) with 11a. The IR
spectra of 11a–f revealed absorption bands in the range of
1652–1716 cmÀ1 due to the carbonyl group. The 1H
NMR spectrum of 11a as an example showed new signals
at δ = 1.42 and 4.44 ppm correspond to triplet and quartet
signals of the ester group, respectively. The formation of
compounds 11a–f could be interpreted through the
elimination of benzyl mercaptan from the corresponding
cycloadduct 10, which are assumed to be formed from
thiohydrazonate 9, which undergo intermolecular
cyclization as soon as it is formed to yield the
intermediate 10 or via 1,3-dipolar cycloaddition of
Scheme 1. Synthesis of coumarins 3a–d and 4a–d.
Scheme 2. Synthesis of 1,3,4-thiadiazoles 11a–f.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
nitrileimine
Synthesis and Evaluation of Antimicrobial Activity of Some Novel Heterocyclic
Compounds from 5-Bromosalicylaldehyde
8
[prepared in situ from 7a–f with
agreement is between the calculation of 15 and the
triethylamine] to the C═S double bond of 6. The
formation of 9 and 10 is similar to the reaction of
hydrazonoyl chloride with 1-phenyl-1,4-dihydrotetrazole-
5-thione [35] and 5-phenyl-1,3,4-thiadiazole-2(3H)-thione
[36] as shown in Scheme 2.
experimental data.
Similarly, compounds 7b and 7c were reacted with 14 to
afford 1,3-thiazoles 16a and 16b, respectively, as shown in
Scheme 3. Structure 16A was ruled out based on molecular
orbital calculation. The value of the total energy for the
structure 16 is more stable than 16A (À2551646.4 and
À2551615.667 kcal/mol), respectively. The UV spectrum
for the product shows main bands at 408 and 468 nm; the
calculated transitions for two possible structures showed
that 16 is 444.1 and 364.8 nm while 16A 384.8 and
347 nm. Comparison between the calculated values and
the experimental confirmed that structure 16 is the
possible structure.
Moreover, 5-bromosalicylaldehyde (1) condenses easily
with hydrazine carbothiohydrazide (13) [37] in acetic
acid,
afforded
1-(5-bromo-2-hydroxybenzylidene)
thiocarbonohydrazide (14) in excellent yield (Scheme 3).
The IR spectrum of 14 showed absorption bands in the
region 3417, 3387, 3290, and 3132 cmÀ1 due to OH, NH2
and N–H stretching and 1280 cmÀ1 was attributed to C═S
bond vibration. Compound 14 was used as the key
intermediate in the synthesis of the desired thiazoles via
its reaction with the appropriate hydrazonoyl halides
7a–c. Thus, compound 14 was reacted with C-
ethoxycarbonyl-N-phenylhydrazonoyl chloride 7a in
ethanol containing few drops of trietylamine under reflux,
afforded one isolable product that may be formulated as
15 or 15A. To get evidence for the correct product,
molecular orbital calculation is carried out. The
calculation using Gaussian 9 package for the two possible
structures uses basis set b3lyp/6-31G*; the total energy
values for 15 are more stable than 15A according to the
Furthermore, treatment of 2-acetyl-5-bromobenzofuran
17 [38] with benzaldehyde in ethanol in the presence of
potassium hydroxide gave 1-(5-bromobenzofuran-2-yl)-3-
Scheme 4. Synthesis of pyridines 20a–c.
two
values
respectively
(À2529077.4
and
À2529026.1 kcal/mol). The UV spectrum for the product
shows main band at 350.5 nm; the calculation transitions
for the two structures (15 and 15A) give 348.0 and
339.8 nm, respectively. This gives evidence that the
Scheme 3. Synthesis of 1,3-thiazoles 15 and 16a,b.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Abdel-Aziem, B. S. Baaiu, and A. O. Abdelhamid
Vol 000
phenyl-prop-2-en-1-one (18) (Scheme 4). Structure of the
product 18 was confirmed on the basis of its correct
elemental analysis, spectral data, and chemical
transportation. Thus, 1H NMR spectrum of 18 showed
signals at δ = 7.26–7.94 (m, 11H, Ar-H’s + –CH═CH–).
In addition, mass spectrum of 18 showed a molecular ion
peak at 328 with a base peak at 327. Thus, compound 18
was reacted with the appropriate of 1-(2-oxo-2-substituted
ethyl)pyridinium bromides 19a–c in acetic acid containing
ammonium acetate, afforded 2-(5-bromobenzofuran-2-yl)-
4-phenyl-6-substituted pyridines 20a–c (Scheme 4).
Structures 20a–c were elucidated on the basis of elemental
analyses and spectral data. (See Experimental section)
Finally, one-pot reaction of 2-acetyl-5-bromobenzofuran
17, benzaldehyde and each of malononitrile, ethyl
cyanoacetate, benzoyl acetonitrile or cyanothioacetamide in
acetic acid containing ammonium acetate afforded pyridine
derivatives 21–24, respectively (Scheme 5). The structures of
21–24 were confirmed on the basis of their elemental
analyses and spectral data. For example, the IR spectrum of
21 revealed new bands at 3467 and 3367 cmÀ1 for NH2
function and 2214 cmÀ1 assigned to CN function. The
structure of 21 was also supported by its 1H NMR spectrum,
which showed signals at δ = 6.82 ppm for NH2 beside
aromatic protons. Structure 24 was also confirmed by
chemical transformation. Thus, compound 24 was reacted
with each of iodomethane, ethylchloroacetate, chloroacetone,
and chloroacetonitrile in ethanolic potassium hydroxide
solution at room temperature, afforded the corresponding
products 25 and 26a–c, respectively (Scheme 5).
newly synthesized compounds displayed intermediate to
low activity in comparison with standards against tested
organisms. The organisms were tested against the activity
of solutions with two concentrations, 100 and 50 mg/mL,
and then 10 μL of each preparation was dropped on disk
of 6 mm in diameter and the concentrations became 1
and 0.5 mg/disk, respectively. In the case of insoluble
compounds, the compounds were suspended in
dimethylformamide (DMF) and vortexed then processed.
Chloramphencol was used as standard reference in the
case of Gram-negative bacteria, cephalothin was used as
standard reference in the case of Gram-positive bacteria,
and cycloheximide was used as standard reference in the
case of yeasts and fungi evaluating the potency of the
tested compounds under the same conditions. The results
were depicted in Table 1.
From antibacterial activity data (Table 1), the results
demonstrated that for high and low concentrations,
compounds 3a, 11e, and 14 showed low inhibition
activity against Gram-positive bacteria Staphylococcus
aureus, compound 11b showed intermediate activity, and
the other tested compounds showed no effect. Compounds
6, 11b, and 11e showed low inhibition activity against
Gram-positive bacteria Bacillus subtilis while compounds
3a, 14, and 16b were capable of intermediate inhibition
activity. All the tested compounds exhibited no activity
against Gram-positive bacteria Salmonella typhimurium
except compound 14 that shows low activity. In the case
of Escherichia coli, only compounds 11b, 11e, and 14
were capable intermediate inhibition activity.
From in vitro antifungal activity (Table 1), it was shown
that compounds 3a, 14, 15, and 16b were capable of
intermediate inhibition activity towards Candida
albicans, and compounds 4c, 11b, and 11e showed low
activity. On the other hand, compound 14 was highly
active towards Aspergillus fumigatus. Compounds 3c and
4a show no effect with all tested microorganisms.
ANTIMICROBIAL ACTIVITY
All the tested microorganisms were chosen on the bases
of their pathogenicity. The investigation of antibacterial
and antifungal screening data revealed that most of the
Scheme 5. Synthesis of pyrindines 21–26.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Synthesis and Evaluation of Antimicrobial Activity of Some Novel Heterocyclic
Compounds from 5-Bromosalicylaldehyde
Table 1
Response of various microorganisms to some synthesized compounds in vitro culture.
Meana of zone diameter, nearest whole mm
Gram-positive bacteria
Gram-negative bacteria
Yeast and fungib
Staphylococcus
aureus
Salmonella
typhimurium
Aspergillus
fumigatus
Bacillus subtilis
Escherichia coli
Candida albicans
Organism
Conc.
sample
1 mg/
mL
0.5 mg/
mL
1 mg/
mL
0.5 mg/
mL
1 mg/
mL
0.5 mg/
mL
1 mg/
mL
0.5 mg/
mL
1 mg/
mL
0.5 mg/
mL
1 mg/
mL
0.5 mg/
mL
3a
3c
4a
4c
11 L
—
—
—
—
12 I
9 L
10 L
—
—
35
8 L
—
—
—
—
7 L
7 L
8 L
—
—
26
13 I
—
—
9 I
—
—
—
—
—
—
—
—
—
11 L
—
—
—
—
—
—
—
—
—
9 L
—
—
28
—
—
—
—
—
14 I
15 I
13 I
—
—
38
—
—
—
—
—
11 I
13 I
10 I
—
—
27
14 I
—
—
10 L
—
11 L
10 L
15 I
15 I
14 I
35
12 I
—
—
8 L
—
8 L
8 L
13 I
12 I
12 I
28
22 I
—
—
13 I
12 L
8 L
8 L
24 I
—
17 I
—
—
—
—
9 I
6
10 L
9 L
9 L
14 I
8 L
12 I
35
7 L
7 L
7 L
12 I
7 L
9 I
8 L
7 L
7 L
20 H
—
11b
11e
14
15
16b
Control #
19 I
37
16 I
26
25
36
—, no effect; L, low activity = mean of zone diameter ≤ 1/3 of mean zone diameter of control; I, intermediate activity = mean of zone diameter ≤ 2/3 of
mean zone diameter of control; H, high activity = mean of zone diameter > 2/3 of mean zone diameter of control; #, chloramphenicol in the case of Gram-
positive bacteria and cephalothin in the case of Gram-negative bacteria.
aCalculated from three values.
bIdentified on the basis of routine culture, morphological, and microscopical characteristics.
CONCLUSIONS
units using TMS as an internal reference. Mass spectra
were recorded on a GC–MS QP1000 EX Shimadzu.
Elemental analyses were carried out at Microanalytical
Center of Cairo University, Cairo, Egypt. Screening of an-
timicrobial activity was performed at a Microbiology Lab
in Faculty of Agriculture, Al-Azhar University, Cairo,
Egypt.
In this work, we carried out a highly effective and simple
synthetic procedure to obtain coumarins, thiadiazoles,
thiazoles, and pyridines via reaction of 5-
bromosalicylaldehyde with different reagents. Also,
selected newly synthesized compounds were screened for
their antimicrobial activity against four bacterial species
including Gram-positive bacteria and Gram-negative
bacteria as well as two fungal species. The results
revealed that compounds 3a, 14, and 16b were capable of
intermediate inhibition activity against Gram-positive
bacteria B. subtilis. Compounds 11b, 11e, and 14 were
capable of intermediate inhibition activity against E. coli.
For antifungal activity, it is evident that compounds 3a,
14, 15, and 16b shows intermediate inhibition activity
towards C. albicans, while only compound 14 was highly
active towards A. fumigatus.
Synthesis. Synthesis of 3-(5-bromobenzofuran-2-yl)-3-
oxopropanenitrile (2c).
A
mixture 2-bromo-1-(5-
bromobenzofuran-2-yl)ethanone (3.17 g, 10 mmol) and
potassium cyanide (3.17 g, 10 mmol) in ethanol (20 mL)
and water (5 mL) was heated at 80°C while stirring for
30 min. The reaction mixture was cooled and diluted
with water then, acidified with hydrochloric acid (6 M).
The solid so formed was collected and recrystallized from
ethanol giving 2c.
Paige powder; yield: 75%; mp: 144–46°C; FTIR (KBr,
1
v, cmÀ1): 3087, 2918 (CH), 2212 (CN), 1676 (C═O); H
NMR (300 MHz, DMSO-d6, δ, ppm): 4.54 (s, 2H, CH2),
7.42–7.91 (m, 4H, ArH’s). Anal. Calcd for C11H6BrNO2
(264.07): C, 50.03; H, 2.29; Br, 30.26; N, 5.30. Found:
C, 50.12; H, 2.37; Br, 30.17; N, 5.19.
EXPERIMENTAL
Measurements. All melting points were determined on
an electrothermal apparatus and are uncorrected. IR spectra
were recorded (KBr disks) on a Shimadzu FTIR 8201 PC
spectrophotometer. 1H NMR spectra were recorded in
CDCl3 and (CD3)2SO solutions on a Varian Gemini
300 MHz and JNM-LA 400 FT-NMR system
spectrometer, and chemical shifts are expressed in ppm
Synthesis of iminocoumarin derivatives 3a–d.
To 5-
bromosalicyaldehyde (1) (1 g,
5
mmol) and
appropriate of 2-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl)
acetonitrile (2a), 2-(4-(5-bromobenzofuran-2-yl)thiazol-
2-yl)acetonitrile (2b), 3-(5-bromobenzofuran-2-yl)-3-
oxopropanenitrile (2c), and 2-(benzo[d]thiazol-2-yl)
acetonitrile (2d) (5 mmol each), three drops of piperidine
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Abdel-Aziem, B. S. Baaiu, and A. O. Abdelhamid
Vol 000
were added and grinded using a pestle in an open mortar for
6-Bromo-3-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl)-2H-
chromen-2-one (4a).
Yellow powder; yield: 87%; mp:
5 min until the mixture turned into a melt. The grinding was
continued for 3 min until the mixture solidify. The solid was
washed with ethanol, and recrystallized from N,N-
dimethylformamide to afford the corresponding 3a–d,
>300°C; FTIR (KBr, v, cmÀ1): 3074 (CH-aroma), 1732,
1647 (2C═O), 1604 (C═N), 1558 (C═C); 1H NMR
(300 MHz, DMSO-d6, δ, ppm): 7.12 (d, 1H, J = 8 Hz),
7.31–7.65 (m, 4H, ArH’s), 7.79 (d, 1H, J = 8 Hz), 7.91
(s, 1H), 8.44 (s, 1H), 8.60 (s, 1H), 8.89 (s, 1H); MS (EI,
m/z (%): 452.9 (4.24), 451.9 (3.52), 450.9 (2.8), 449.9
(3.11). Anal. Calcd for C21H10BrNO4S (452.28): C,
respectively.
3-(2-(6-Bromo-2-imino-2H-chromen-3-yl)thiazol-4-yl)-2H-
chromen-2-one (3a).
Yellow powder; yield: 85%; mp:
260–62°C; FTIR (KBr, v, cmÀ1): 3262 (NH), 3062 (CH-
aroma), 1716 (C═O), 1604 (C═N), 1558 (C═C); 1H NMR
(300 MHz, DMSO-d6, δ, ppm): 7.13 (d, 1H, J = 8 Hz),
7.38–7.66 (m, 4H, ArH’s), 7.81 (d, 1H, J = 8 Hz), 7.94 (s,
1H), 8.48 (s, 1H), 8.61 (s, 1H), 8.90 (s, 1H), 9.10 (s, 1H,
NH); MS (EI, m/z (%): 451.9 (5.51), 450.9 (3.52), 449.9
(5.12). Anal. Calcd for C21H11BrN2O3S (451.29): C, 55.89;
H, 2.46; Br, 17.71; N, 6.21; S, 7.11. Found: C, 55.74; H,
55.77; H, 2.23; Br, 17.67; N, 3.10; S, 7.09. Found: C,
55.67; H, 2.12; Br, 17.78; N, 3.01; S, 7.19.
6-Bromo-3-(4-(5-bromobenzofuran-2-yl)thiazol-2-yl)-2H-
chromen-2-one (4b).
Yellow powder; yield: 86%; mp:
270–71°C; FTIR (KBr, v, cmÀ1): 3062 (CH-aroma), 1660
1
(C═O), 1604 (C═N), 1589 (C═C); H NMR (300 MHz,
CDCL3, δ, ppm): 7.07 (d, 1H, J = 8 Hz), 7.20–7.40 (m,
3H, ArH’s), 7.51 (d, 1H, J = 8 Hz), 7.71 (s, 1H), 7.75 (s,
1H), 7.86 (s, 1H), 8.90 (s, 1H); MS (EI, m/z (%): 504.9
(8.35), 502.9 (63), 500.9 (7.85). Anal. Calcd for
C20H9Br2NO3S (503.16): C, 47.74; H, 1.80; Br, 31.76;
N, 2.78; S, 6.37. Found: C, 47.82; H, 1.69; Br, 31.64; N,
2.57; Br, 17.59; N, 6.32; S, 7.20.
6-Bromo-3-(4-(5-bromobenzofuran-2-yl)thiazol-2-yl)-2H-
chromen-2-imine (3b).
Yellow powder; yield: 83%; mp:
250–51°C; FTIR (KBr, v, cmÀ1): 3280 (NH), 3062 (CH-
1
aroma), 1604 (C═N), 1589 (C═C); H NMR (300 MHz,
CDCl3, δ, ppm): 7.08 (d, 1H, J = 8 Hz), 7.23–7.42 (m, 3H,
ArH’s), 7.54 (d, 1H, J = 8 Hz), 7.70 (s, 1H), 7.77 (s, 1H),
7.88 (s, 1H), 8.96 (s, 1H), 10.80 (s, 1H, NH); MS (EI, m/z
(%): 503.9 (8.01), 501.9 (62), 499.9 (7.23). Anal. Calcd for
C20H10Br2N2O2S (502.18): C, 47.83; H, 2.01; Br, 31.82;
N, 5.58; S, 6.39. Found: C, 47.72; H, 2.10; Br, 31.71; N,
2.88; S, 6.28.
(6-Bromo-2-oxo-2H-chromen-3-yl)(5-bromobenzofuran-2-
yl)methanone (4c). Yellow powder; yield: 85%; mp: 275–
76°C; FTIR (KBr, v, cmÀ1): 3089 (CH-aroma), 1728, 1643
1
(2C═O), 1608 (C═N), 1554 (C═C); H NMR (300 MHz,
DMSO-d6, δ, ppm): 6.99 (d, 1H, J = 8 Hz), 7.22–7.30
(m, 4H, ArH’s), 7.36 (d, 1H, J = 8 Hz), 7.60 (s, 1H),
8.63 (s, 1H); MS (EI, m/z (%): 449.91 (3), 447.90 (25),
445.90 (9). Anal. Calcd for C18H8Br2O4 (448.06): C,
48.25; H, 1.80; Br, 35.67. Found: C, 48.36; H, 1.68; Br,
5.49; S, 6.28.
(6-Bromo-2-imino-2H-chromen-3-yl)(5-bromobenzofuran-2-
yl)methanone (3c). Yellow powder; yield: 86%; mp: 170–
72°C; FTIR (KBr, v, cmÀ1): 3232 (NH), 3093 (CH-aroma),
1702 (C═O), 1627 (C═N), 1594 (C═C); 1H NMR
(300 MHz, DMSO-d6, δ, ppm): 6.91 (d, 1H, J = 8 Hz),
7.25–7.31 (m, 4H, ArH’s), 7.38 (d, 1H, J = 8 Hz), 7.59 (s,
1H), 8.60 (s, 1H), 8.56 (s, 1H, NH); MS (EI, m/z (%):
448.9 (6), 446.90 (24), 444.90 (8). Anal. Calcd for
C18H9Br2NO3 (447.08): C, 48.36; H, 2.03; Br, 35.75; N,
35.80.
3-(Benzo[d]thiazol-2-yl)-6-bromo-2H-chromen-2-one
(4d). Yellow powder; yield: 86%; mp: 260–61°C; FTIR
(KBr, v, cmÀ1): 3086 (CH-aroma), 1728 (C═O), 1600
1
(C═N), 1554 (C═C); H NMR (300 MHz, DMSO-d6, δ,
ppm): 6.54 (d, 1H, J = 8 Hz), 7.15 (d, 1H, J = 8 Hz),
7.40 (s, 1H), 7.39 (s, 1H), 7.53–8.23 (m, 4H, ArH’s); MS
(EI, m/z (%): 359 (5.81), 358 (4.41), 457 (5.70). Anal.
Calcd for C16H8BrNO2S (358.21): C, 53.65; H, 2.25; Br,
22.31; N, 3.91; S, 8.95. Found: C, 53.77; H, 2.14; Br,
22.40; N, 3.80; S, 8.84.
3.13. Found: C, 48.28; H, 2.10; Br, 35.67; N, 3.20.
3-(Benzo[d]thiazol-2-yl)-6-bromo-2H-chromen-2-imine
(3d). Yellow powder; yield: 88%; mp: 240–41°C; FTIR
(KBr, v, cmÀ1): 3210 (NH), 3062 (CH-aroma), 1593
1
(C═N), 1554 (C═C); H NMR (300 MHz, DMSO-d6, δ,
ppm): 6.59 (d, 1H, J = 8 Hz), 7.17 (d, 1H, J = 8 Hz),
7.41 (s, 1H), 7.43 (s, 1H), 7.56–8.20 (m, 4H, ArH’s),
8.50 (s, 1H, NH). MS (EI, m/z (%): 359 (3.13), 358
(4.85), 457 (4.98). Anal. Calcd for C16H9BrN2OS
(357.22): C, 53.80; H, 2.54; Br, 22.37; N, 7.84; S, 8.98.
Found: C, 53.71; H, 2.43; Br, 22.26; N, 7.72; S, 8.89.
Synthesis of coumarin derivatives 4a–d. A mixture of
the appropriate iminocoumarins 3a–d (5 mmoles) and
few drops of hydrochloric acid were grinded with a pestle
in an open mortar at room temperature for 7–10 min. The
solid was collected, washed with ethanol, and
recrystallized from N,N-dimethylformamide, afforded 4a–
d, respectively.
Benzyl
carbodithioate
2-(5-bromo-2-hydroxybenzylidene)hydrazine-1-
(6) [39]. mixture of 5-
A
bromosalicylaldehyde (1) (2.01 g, 10 mmol) and
benzylhydrazine carbodithioate (5) (1.97 g, 10 mmol)
was grinded with a pestle in an open mortar at room
temperature for 3–5 min. The initial syrupy continued for
5–7 min. The solid was collected, washed with ethanol,
and recrystallized from N,N-dimethylformamide to afford
6 as white powder; yield: 89%; mp: 220–21°C; FTIR
(KBr, v, cmÀ1): 3375 (OH), 3209 (NH), 3097, 2973
1
(CH), 1615 (C═N), 1324 (C═S); H NMR (300 MHz,
DMSO-d6, δ, ppm): 4.60 (s, 2H, SCH2), 6.88–7.89 (m,
8H, ArH’s), 7.91 (s, 1H, CH═N), 10.25 (s, 1H, NH),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Synthesis and Evaluation of Antimicrobial Activity of Some Novel Heterocyclic
Compounds from 5-Bromosalicylaldehyde
11.28 (s, 1H, OH); MS (EI, m/z (%): 381 (6.5), 379 (5.5).
Anal. Calcd for C15H13BrN2OS2 (381.31): C, 47.25; H,
3.44; Br, 20.96; N, 7.35; S, 16.82. Found: C, 47.13; H,
3.57; Br, 20.84; N, 7.43; S, 16.70.
J = 8 Hz), 8.41 (s, 1H, CH═N), 8.90 (s, 1H, NH), 11.10
(s, 1H, OH); MS (EI, m/z (%): 494 (5), 492 (4). Anal.
Calcd for C22H16BrN5O2S (494.36): C, 53.45; H, 3.26;
Br, 16.16; N, 14.17; S, 6.49. Found: C, 53.34; H, 3.34;
Br, 16.05; N, 14.08; S, 6.37.
Synthesis of 2-(5-substituted 3-phenyl-1,3,4-thiadiazol-2
5-(5-Bromo-2-hydroxybenzylidene)hydrazono)-4-phenyl-
4,5-dihydro-1,3,4-thiadiazol-2-yl)(thiophen-2-yl)methanone
(11e). Orange powder; yield: 81%; mp: 185°C; FTIR
(3H)-ylidene)-1-(5-bromo-2-hydroxybenzylidene)hydrazines
(11a–f).
Benzylhydrazine carbodithioate derivative 6
(1.90 g, 5 mmol), the appropriate hydrazonoyl halides
7a–f (5 mmoles), and two drops of triethylamine were
mixed and grinded with a pestle in an open mortar at
room temperature. The grinding was continued for 3 min.
The solid was washed with ethanol and recrystallized
from N,N-dimethylformamide giving 2,3-dihydro-1,3,4-
thiadiazoles 11a–f, respectively.
Ethyl-5-[(5-bromo-2-hydroxybenzylidene)-hydrazono]-4-phenyl-
(KBr, v, cmÀ1): 3402 (OH), 3068, 2981 (CH), 1712
1
(C═O), 1612 (C═N), 1539 (C═C); H NMR (300 MHz,
DMSO-d6, δ, ppm): 6.84 (d, 2H, J = 8 Hz), 7.25 (s,
1H), 7.26–7.55 (m, 7H, ArH’s), 7.91 (d, 1H, J = 8 Hz),
8.43 (s, 1H, CH═N), 10.95 (s, 1H, OH); MS (EI, m/z
(%): 485 (10), 483 (8). Anal. Calcd for
C20H13BrN4O2S2(485.38): C, 49.49; H, 2.70; Br, 16.46;
N, 11.54; S, 13.21. Found: C, 49.39; H, 2.81; Br, 16.34;
4,5-dihydro-[1,3,4]thiadiazole-2-carboxylate (11a).
Yellow
crystals; yield: 82%; mp: 189°C; FTIR (KBr, v, cmÀ1):
3414 (OH), 3066, 2978, 2866 (CH), 1716 (C═O), 1612
(C═N), 1550 (C═C); 1H NMR (300 MHz, CDCl3, δ,
ppm): 1.42 (t, 3H, J = 7 Hz, CH3), 4.44 (q, 2H, J = 7 Hz,
CH2), 6.91 (d, 2H, J = 8 Hz), 7.27 (s, 1H), 7.35–7.48 (m,
2H), 7.49 (t, 2H, J = 7.8 Hz), 7.93 (d, 1H, J = 8 Hz),
8.42 (s, 1H), 10.91 (s, 1H, OH); MS (EI, m/z (%): 447
(20), 445 (18). Anal. Calcd for C18H15BrN4O3S (447.31):
N, 11.46; S, 13.32.
5-[(5-Bromo-2-hydroxybenzylidene)-hydrazono]-4-phenyl-
4,5-dihydro-[1,3,4] thiadiazole-2-yl-naphthalen-2-yl-methanone
(11f). Orange powder; yield: 82%; mp: 190–91°C; FTIR
(KBr, v, cmÀ1): 3417 (OH), 3059, 2981, 2866 (CH), 1650
1
(C═O), 1604 (C═N), 1582 (C═C); H NMR (300 MHz,
DMSO-d6, δ, ppm): 6.87 (d, 2H, J = 8 Hz), 7.26 (s, 1H),
7.28–7.54 (m, 11H, ArH’s), 7.94 (d, 1H, J = 8 Hz), 8.38
(s, 1H, CH═N), 11.03 (s, 1H, OH); MS (EI, m/z (%): 529
(6.5), 528 (4), 527 (5). Anal. Calcd for C26H17BrN4O2S
(529.41): C, 58.99; H, 3.24; Br, 15.09; N, 10.58; S, 6.06.
Found: C, 58.87; H, 3.36; Br, 15.22; N, 10.70; S, 6.18.
C, 48.33; H, 3.38; Br, 17.86; N, 12.53; S, 7.17. Found:
C, 48.42; H, 3.25; Br, 17.75; N, 12.64; S, 7.29.
1-{5-[(5-Bromo-2-hydroxybenzylidene)-hydrazono]-4-phenyl-
4,5-dihydro-[1,3,4]thiadiazol-2-yl}-ethanone (11b).
Yellow
powder; yield: 83%; mp: 190°C; FTIR (KBr, v, cmÀ1):
3370 (OH), 3074, 2916, 2877 (CH), 1678 (C═O), 1608
(C═N), 1562 (C═C); 1H NMR (300 MHz, CDCl3, δ, ppm):
2.63 (s, 3H, CH3), 6.89 (d, 2H, J = 8 Hz), 7.26 (s, 1H),
7.27–7.40 (m, 2H), 7.50 (t, 2H, J = 7.8 Hz), 7.95 (d, 1H),
8.39 (s, 1H, CH═N), 10.90 (s, 1H, OH); MS (EI, m/z (%):
417 (5), 416 (3), 415 (4). Anal. Calcd for C17H13BrN4O2S
(417.28): C, 48.93; H, 3.14; Br, 19.15; N, 13.43; S, 7.68.
Synthesis
of
1-(5-bromo-2-hydroxybenzylidene)
thiocarbonohydrazide (14).
A mixture of compound 1
(2.01 g, 10 mmol) and hydrazine carbothiohydrazide
(1.06 g, 10 mmol) (13) in acetic acid was refluxed for 1 h.
The solid that separated on hot was filtered, washed with
ethanol, and recrystallized from acetone, afforded 14 as
white crystals; yield: 85%; mp: 302–04°C; FTIR (KBr, v,
cmÀ1): 3417 (OH), 3387, 3290, 3132 (NH2, NH), 3074,
1
2989, 2866 (CH), 1593 (C═N), 1280 (C═S); H NMR:
Found: C, 48.82; H, 3.03; Br, 19.02; N, 13.34; S, 7.56.
5-[(5-Bromo-2-hydroxybenzylidene)-hydrazono]-4-phenyl-
4,5-dihydro-[1,3,4]thiadiazol 2-yl)phenyl-methanone (11c).
(300 MHz, CDCl3, δ, ppm): 3.98 (br, 2H, NH2), 6.86 (d,
1H, J = 8 Hz), 7.38 (d, 1H, J = 8 Hz), 7.92 (s, 1H), 8.70
(s, 1H, CH═N), 10.40 (s, 1H, NH), 11.67 (s, 1H, NH),
12.11 (s, 1H, OH); MS (EI, m/z (%): 289 (13), 287 (10).
Anal. Calcd for C8H9BrN4OS (289.15): C, 33.23; H, 3.14;
Br, 27.63; N, 19.38; S, 11.09. Found: C, 33.32; H, 3.23;
Br, 27.52; N, 19.49; S, 11.20.
Yellow powder; yield: 82%; mp: 190°C; FTIR (KBr, v,
cmÀ1): 3387 (OH), 3097, 2974, 2897 (CH), 1652 (C═O),
1604 (C═N), 1562 (C═C); 1H NMR (300 MHz,
DMSO-d6, δ, ppm): 6.80 (d, 2H, J = 8 Hz), 7.24 (s, 1H),
7.24–7.52 (m, 9H, ArH’s), 7.90 (d, 1H, J = 8 Hz), 8.41
(s, 1H, CH═N), 11.12 (s, 1H, OH). MS (EI, m/z (%): 479
(10), 478 (5), 477 (6). Anal. Calcd for C22H15BrN4O2S
(479.35): C, 55.12; H, 3.15; Br, 16.67; N, 11.69; S, 6.69.
Found: C, 55.23; H, 3.03; Br, 16.56; N, 11.57; S, 6.81.
5-[(5-Bromo-2-hydroxybenzylidene)-hydrazono]-4-phenyl-2-
phenyl-carbamoyl-4,5-dihydro-[1,3,4]thiadiazole (11d).
Yellow powder; yield: 84%; mp: 200°C; FTIR (KBr, v,
cmÀ1): 3375 (OH), 3271 (NH), 3105, 2974, 2854 (CH),
1685 (C═O), 1604 (C═N), 1523 (C═C); 1H NMR
(300 MHz, DMSO-d6, δ, ppm): 6.86 (d, 2H, J = 8 Hz),
7.26 (s, 1H), 7.27–7.55 (m, 9H, ArH’s), 7.93 (d, 1H,
General method for synthesis of 15, 16a, and 16b.
A
mixture of thiocarbohydrazone 14 (1.44 g, 5 mmol) and
the appropriate hydrazonoyl halides 7a–c (5 mmoles) in
ethanol (15 mL) containing triethylamine (0.75 mL,
5 mmol) was heated under reflux for 8 h. The solid that
separated after cooling was filtered and recrystallized
from DMF/EtOH, which afforded the corresponding 15,
16a, and 16b, respectively.
3-amino-2-((5-bromo-2-hydroxybenzylidene)hydrazono)-5-
(2-phenylhydrazono)thiazolidin-4-one (15). Yellow powder;
yield: 80%; mp: 259–60°C; FTIR (KBr, ν, cmÀ1): 3421
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Abdel-Aziem, B. S. Baaiu, and A. O. Abdelhamid
Vol 000
(OH), 3387, 3178, 3113 (NH, NH2), 3055 (CH-aroma),
1735 (C═O), 1608 (C═N), 1597 (C═C); 1H NMR:
(300 MHz, DMSO-d6, δ, ppm): 6.91–6.99 (m, 2H), 7.28–
7.34 (t, 2H, J = 8 Hz), 7.47 (d, 1H, J = 8 Hz ), 7.58 (d,
1H, J = 8 Hz), 7.88–7.97 (m, 2H), 8.77 (s, 1H, CH═N),
9.44 (s, 1H, NH), 10.83 (s, 2H, NH2), 11.00 (s, 1H, OH);
MS (EI, m/z (%): 433 (2), 431 (1.5). Anal. Calcd for
C16H13BrN6O2S (433.28): C, 44.35; H, 3.02; Br, 18.44;
N, 19.40; S, 7.40. Found: C, 44.23; H, 3.12; Br, 18.33;
was allowed to cool, and the resulting solid was
collected, washed with water, and recrystallized from
dioxane affording 20a–c, respectively.
2-(5-Bromobenzofuran-2-yl)-4,6-diphenylpyridine (20a).
White crystals; yield: 82%; mp: 190–92°C; FTIR (KBr, ν,
1
cmÀ1): 3031 (CH-aroma), 1608 (C═N), 1546 (C═C); H
NMR (300 MHz, DMSO-d6, δ, ppm): 7.50–7.87 (m, 16H,
ArH’s); MS (EI, m/z (%): 426 (1.40), 425 (0.9), 424 (1.2).
Anal. Calcd for C25H16BrNO (426.3): C, 70.43; H, 3.78; Br,
18.74; N, 3.29. Found: C, 70.34; H, 3.66; Br, 18.63; N, 3.18.
2-(5-Bromobenzofuran-2-yl)-4-phenyl-6-(p-tolyl)pyridine
(20b). Paige crystals; yield: 80%; mp: 150–52°C; FTIR
N, 19.31; S, 7.29.
2-(((3-amino-4-methyl-5-(phenyldiazenyl)thiazol-2(3H)-
ylidene)hydrazono)methyl)-4-bromophenol (16a).
Brown
(KBr, ν, cmÀ1): 3031, 2916, 2858 (CH), 1612 (C═N),
powder; yield: 79%; mp: 190–91°C; FTIR (KBr, ν,
1
cmÀ1): 3452 (OH), 3278, 3190, 3120 (NH, NH2), 3109,
1546 (C═C); H NMR (300 MHz, DMSO-d6, δ, ppm):
1
2.34 (s, 3H, CH3), 7.13–8.11 (m, 15H, ArH’s); MS (EI,
m/z (%): 440 (1.6), 438 (2). Anal. Calcd for C26H18BrNO
(440.33): C, 70.92; H, 4.12; Br, 18.15; N, 3.18. Found:
C, 70.80; H, 4.25; Br, 18.01; N, 3.30.
2958, 2854 (CH), 1600 (C═N),1531 (C═C); H NMR:
(300 MHz, CDCl3, δ, ppm): 2.55 (s, 3H, CH3), 6.93 (d,
1H, J = 8 Hz), 7.11 (t, 2H, J = 7.5 Hz), 7.26 (s, 1H),
7.27–7.53 (m, 5H, ArH’s + NH2), 7.95 (d, 1H, J = 8 Hz),
8.63 (s, 1H, CH═N), 11.56 (s, 1H, OH); MS (EI, m/z
(%): 433 (0.9), 432 (1.2), 431 (9.7), 430 (2.5). Anal.
Calcd for C17H15BrN6OS (431.31): C, 47.34; H, 3.51;
Br, 18.53; N, 19.48; S, 7.43. Found: C, 47.23; H, 3.63;
2,6-Bis (5-bromobenzofuran-2-yl)-4-phenylpyridine (20c).
Paige crystals; yield: 82%; mp: 224–26°C; FTIR (KBr, ν,
1
cmÀ1): 3031 (CH-aroma), 1616 (C═N), 1546 (C═C); H
NMR (300 MHz, DMSO-d6, δ, ppm): 7.18–8.20 (m, 15H,
ArH’s); MS (EI, m/z (%): 545 (4), 544 (2), 543 (3). Anal.
Calcd for C27H15Br2NO2 (545.22): C, 59.48; H, 2.77; Br,
29.31; N, 2.57. Found: C, 59.57; H, 2.65; Br, 29.23; N, 2.65.
Br, 18.42; N, 19.69; S, 7.32.
2-(((3-amino-4-phenyl-5-((E)-phenyldiazenyl)thiazol-2(3H)-
ylidene)hydrazono)methyl)-4-bromophenol (16b).
Brown
powder; yield: 78%; mp: 189–90°C; FTIR (KBr, ν,
cmÀ1): 3452 (OH), 3270, 3220, 3155, (NH, NH2), 3059,
2931 (CH), 1612 (C═N), 1570 (C═C); 1H NMR:
(300 MHz, CDCl3, δ, ppm): 6.93 (d, 1H, J = 8 Hz), 7.12–
7.30 (m, 5H, ArH’s + NH2), 7.42 (s, 1H), 7.45–7.51 (m,
8H, ArH’s), 8.63 (s, 1H, CH═N), 11.60 (s, 1H, OH); MS
(EI, m/z (%): 495 (2), 494 (3), 493 (4). Anal. Calcd for
C22H17BrN6OS (493.38): C, 53.56; H, 3.47; Br, 16.20; N,
17.03; S, 6.50. Found: C, 53.65; H, 3.33; Br, 16.32; N,
Synthesis of pyridine derivatives 21–25. A mixture of 2-
acetyl-5-bromobenzofuran (17) (1.2 g,
5
mmol),
benzaldehyde (0.5 g, mmol), the appropriate
5
malononitrile, ethyl cyanoacetate, benzoylacetonitrile, or
cyanothioacetamide (5 mmol each) and ammonium
acetate (4.3 g, 6 mmol) in acetic acid was heated (10 mL)
under reflux for 3 h. The reaction mixture was cooled;
the separated solid was collected, filtered, and
recrystallized from N,N-dimethylformamide, which
afforded 21–24, respectively.
17.12; S, 6.62.
Synthesis of 1-(5-bromobenzofuran-2-yl)-3-phenyl-prop-2-
2-Amino-4-phenyl-6-(5-bromobenzofuran-2-yl)pyridine-3-
en-1-one (18).
Potassium hydroxide (10 mL, 10%)
carbonitrile (21).
Orange powder; yield: 75%; mp:
>300°C; FTIR (KBr, ν, cmÀ1): 3467, 3367 (NH2), 3066
was added dropwise to mixture of 2-acetyl-5-
a
bromobenzofuran (17) (1.2 g, 5 mmol) and benzaldehyde
(0.5 mL, 5 mmol) in ethanol (20 mL) with stirring at 0–
5°C for 2 h. The resulting solid was collected and
recrystallized from ethanol to give 18 as paige powder;
yield: 80%; mp: 128–30°C; FTIR (KBr, v, cmÀ1): 3074
1
(CH-aroma), 2214 (CN), 1627 (C═N), 1581 (C═C); H
NMR (300 MHz, DMSO-d6, δ, ppm): 6.82 (br, 2H, NH2),
7.30 (s, 1H, Ar-H), 7.54–7.65 (m, 7H, ArH’s), 7.83 (s,
1H, Ar-H), 8.02 (s, 1H, Ar-H); MS (EI, m/z (%): 390 (5),
388 (4). Anal. Calcd for C20H12BrN3O (390.23): C,
61.56; H, 3.10; Br, 20.48; N, 10.77. Found: C, 61.42; H,
1
(CH-aroma), 1662 (C═O), 1600 (C═N), 1546 (C═C); H
NMR: (300 MHz, CDCL3, δ, ppm): 7.26–7.94 (m, 11
ArH’s and –CH═CH–); MS (EI, m/z (%): 328 (75), 327
(100), 326 (78). Anal. Calcd for C17H11BrO2 (327.17): C,
62.41; H, 3.39; Br, 24.42. Found: C, 62.34; H, 3.47; Br,
24.53.
3.22; Br, 20.60; N, 10.65.
6-(5-Bromobenzofuran-2-yl)-1,2-dihydro-2-oxo-4-
phenylpyridine-3-carbonitrile (22). Yellow powder; yield:
80%; mp: >300°C; FTIR (KBr, ν, cmÀ1): 3213 (NH),
3089 (CH-aroma), 2218 (CN), 1643 (C═O), 1616
1
Synthesis of trisubstituted pyridines 20a–c. A mixture
of 18 (1.63 g, 5 mmol), the appropriate l-(2-oxo-2-
substituted ethyl)pyridinium bromides 19a–c (5 mmoles),
and ammonium acetate (0.65 g, 5 mmol), in acetic acid
(10 mL), was heated under reflux for 4 h. The mixture
(C═N), 1539 (C═C); H NMR (300 MHz, DMSO-d6, δ,
ppm): 7.56–8.04 (m, 11H, ArH’s + NH); MS (EI, m/z
(%): 391 (6), 389 (5). Anal. Calcd for C20H11BrN2O
(391.22): C, 61.40; H, 2.83; Br, 20.42; N, 7.16. Found:
C, 61.32; H, 2.78; Br, 20.34; N, 7.07.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Synthesis and Evaluation of Antimicrobial Activity of Some Novel Heterocyclic
Compounds from 5-Bromosalicylaldehyde
6-(5-Bromobenzofuran-2-yl)-2,4-diphenylpyridine-3-carbonitrile
3-Amino-6-(5-bromobenzofuran-2-yl)-4-phenylthieno[2,3-b]
pyridine-2-carbonitrile (26c).
(23). White powder; yield: 72%; mp: 256–58°C; FTIR
Brown powder from
(KBr, ν, cmÀ1): 3055 (CH-aroma), 2221 (CN), 1596
dioxane; yield: 79%; mp: 296–98°C; FTIR (KBr, ν,
1
(C═N), 1558 (C═C); H NMR (300 MHz, DMSO-d6, δ,
cmÀ1): 3433 broad (NH2), 3063 (CH-aroma), 2209 (CN),
1
ppm): 7.54–8.06 (m, 15H, ArH’s); MS (EI, m/z (%): 451
(3), 450 (1.9), 449 (2). Anal. Calcd for C26H15BrN2O
(451.31): C, 69.19; H, 3.35; Br, 17.70; N, 6.21. Found: C,
69.30; H, 3.23; Br, 17.82; N, 6.32.
6-(5-bromobenzofuran-2-yl)-2-mercapto-4-
1589 (C═N), 1549 (C═C); H NMR (300 MHz, CDCl3,
δ, ppm): 4.15 (br, 2H, NH2), 7.27–7.89 (m, 10H, ArH’s);
MS (EI, m/z (%): 446.9 (16), 445.9 (20), 444.9 (10).
Anal. Calcd for C22H12BrN3OS (446.32): C, 59.20; H,
2.71; Br, 17.90; N, 9.41; S, 7.18. Found: C, 59.09; H,
2.82; Br, 17.82; N, 9.53; S, 7.26.
phenylnicotinonitrile (24).
Orange powder; yield: 75%;
mp: 226–28°C; FTIR (KBr, ν, cmÀ1): 3060 (CH-aroma),
2210 (CN), 1590 (C═N), 1553 (C═C); 1H NMR
(300 MHz, CDCl3, δ, ppm): 3.71 (s, 1H, SH), 7.25–7.84
(m, 10H, ArH’s); MS (EI, m/z (%): 407 (7), 406 (6), 405
(3). Anal. Calcd for C20H11BrN2OS (407.28): C, 58.98;
H, 2.72; Br, 19.62; N, 6.88; S, 7.87. Found: C, 58.86; H,
2.61; Br, 19.50; N, 6.84; S, 7.75.
Biological screening.
Antimicrobial activity of the
newly synthesized compounds was determined in vitro by
standardized disk – agar diffusion method [40]. Cultures of
one fungi, namely, A. fumagitus and, one yeast fungus, C.
albicans, as well as four bacterial species, namely, Gram-
positive bacteria: S. aureus (ATCC 25923) and B. subtilis
(ATCC 6635); Gram-negative bacteria: E. coli (ATCC
25922) and S. typhimurium (ATCC 14028), were used to
investigate the antimicrobial activity of the newly
synthesized compounds. The tested compounds were
dissolved in DMF solvent and prepared in two
concentrations, 100 and 50 mg/mL, and then 10 μL of each
preparation was dropped on disk of 6 mm in diameter and the
concentrations became 1 and 0.5 mg/disk, respectively. In
the case of insoluble compounds, the compounds were
suspended in DMF and vortexed then processed.
2-(Substituted 6-(5-bromobenzofuran-2-yl)-4-phenylpyridine-
3-carbonitrile 25 and 26a–c.
A mixture of 24 (2.03 g,
5 mmol) and potassium hydroxide (0.28 g, 5 mmol) in
ethanol (10 mL) was stirred for 2 h at room temperature.
The appropriate of iodomethane, ethyl chloroacetate,
chloroacetone or chloroacetonitrile (5 mmol each) was
added. Stirring was continued for 2 h. The resulting solid
was collected and recrystallized from a proper solvent,
which afforded 25 and 26a–c, respectively.
6-(5-Bromobenzofuran-2-yl)-2-(methylthio)-4-phenylpyridine-3-
carbonitrile (25). Paige powder recrystallized from acetic
Testing for antibacterial and yeasts activity.
Bacterial
cultures were grown in nutrient broth medium at 30°C.
After 16 of growth, each microorganism, at
acid; yield: 73%; mp: 264–66°C; FTIR (KBr, ν, cmÀ1):
3061, 2925 (CH), 2210 (CN), 1593 (C═N), 1549 (C═C);
1H NMR (300 MHz, CDCl3, δ, ppm): 2.76 (s, 3H, SCH3),
7.21–7.80 (m, 10H, ArH’s); MS (EI, m/z (%): 423 (20) 421
(100), 420 (62), 419 (20). Anal. Calcd for C21H13BrN2OS
(421.31): C, 59.87; H, 3.11; Br, 18.97; N, 6.65; S, 7.61.
Found: C, 59.76; H, 3.23; Br, 18.85; N, 6.76; S, 7.54.
Ethyl 3-amino-6-(5-bromobenzofuran-2-yl)-4-phenylthieno[2,3-
b]pyridine-2-carboxylate (26a). Paige powder recrystallized
h
a
concentration of 108 cells/mL, was inoculated on the
surface of Mueller–Hinton agar plates using sterile cotton
swab. Subsequently, uniform size filter paper disks (6 mm
in diameter) were impregnated by equal volume (10 μL)
from the specific concentration of dissolved compounds and
carefully placed on surface of each inoculated plate. The
plates were incubated in the upright position at 36°C for
24 hours. Three replicates were carried out for each extract
against each of the test organism. Simultaneously, addition
of the respective solvent instead of dissolved compound
was carried out as negative controls. After incubation, the
diameters of the growth inhibition zones formed around the
disk were measured with transparent ruler in millimeter,
averaged, and the mean values were tabulated. The
antibiotic chloramphencol was used as standard reference in
the case of Gram-negative bacteria; cephalothin was used as
standard reference in the case of Gram-positive bacteria.
The results are summarized in Table 1.
from acetic acid; yield: 73%; mp: 197–99°C; FTIR (KBr, ν,
cmÀ1): 3400 broad (NH2), 3061, 2969 (CH), 1732 (C═O),
1
1593 (C═N), 1549 (C═C); H NMR (300 MHz, CDCl3, δ,
ppm): 1.42 (t, 3H, J = 7 Hz, CH3), 4.04 (br, 2H, NH2), 4.25
(q, 2H, J = 7.5 Hz, CH2), 7.26–7.81 (m, 10H, ArH’s). Anal.
Calcd for C24H17BrN2O3S (493.37): C, 58.43; H, 3.47; Br,
16.20; N, 5.68; S, 6.50. Found: C, 58.55; H, 3.34; Br, 16.34;
N, 5.57; S, 6.61.
1-(3-Amino-6-(5-bromobenzofuran-2-yl)-4-phenylthieno[2,3-b]
pyridin-2-yl)ethanone (26b). Yellow powder from dioxane;
yield: 79%; mp: 226–28°C; FTIR (KBr, ν, cmÀ1): 3370,
3286 (NH2), 3073 (CH-aroma); 1H NMR (300 MHz,
CDCl3, δ, ppm): 2.40 (s, 3H, COCH3), 4.03 (br, 2H,
NH2), 7.27–7.86 (m, 10H, ArH’s); MS (EI, m/z (%): 463
(10), 462 (5), 461 (11), 460 (12). Anal. Calcd for
C23H15BrN2O2S (463.35): C, 59.62; H, 3.26; Br, 17.24;
N, 6.05; S, 6.92. Found: C, 59.71; H, 3.15; Br, 17.33; N,
6.15; S, 6.83.
Testing for antifungal activity.
Active inoculum for
experiments was prepared by transferring many loopfuls
of spores from the stock cultures to test tubes of sterile
distilled water that were agitated and diluted with sterile
distilled water to achieve optical density corresponding to
2.0 × 105 spore/mL. Inoculum of 0.1% suspension was
swabbed uniformly, and the inoculum was allowed to dry
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Abdel-Aziem, B. S. Baaiu, and A. O. Abdelhamid
Vol 000
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet