Conventional and Microwave-Activated the Synthesis of a Novel Series of Imidazoles, Pyrimidines, and Thiazoles Candidates

Article abstract of DOI:10.1002/jhet.3176

A novel series of imidazoles, pyrimidines, and thiazoles were synthesized using microwave irradiation and conventional method from commercial available p-aminobenzoic acid. Thus, one-pot condensation of p-aminobenzoic acid, urea, and chloroacetic acid have been provided two types of imidazole derivatives as separated mixture 2a and 2b. [3?+?2?+?1] Cyclocondensation of 2a, benzaldehyde, and urea/thiourea in acidic medium afforded imidazolo oxazine derivative 3 and Imidazolothiazine 4. Coupling of 2a with benzene diazonium salt gave the phenyldiazenyl imidazolidine 5. While the reaction of 2a, thiourea, and benzaldehyde in sodium ethoxide afforded imidazolothiazine 6. Oxidative cyclization of thiourea derivative 7 resulted a mixture of benzithiazole derivative 7a and oxathiazole derivative 7b. Cyclocondensation of 7a with phenylenediamine and 4-methyl phenylenediamine furnished imidazole 8 and 9, respectively. Reaction of P-aminobenzioc acid with potassium cyanate followed by Biginelli reaction with (acetyl acetone, ethyl acetoacetate, and diethyl malonate) and salicyladehyde in HCl tolerated pyrimidine derivatives 10a–c, respectively. In the same manner, the reactions and short reaction time make microwave technique one of the greenest methodology for synthesis of this class of heterocyclic system.

Full text of DOI:10.1002/jhet.3176

Month 2018 Conventional and Microwave-Activated the Synthesis of a Novel Series of
Imidazoles, Pyrimidines, and Thiazoles Candidates
a
and Mohamed H. M. Abd El-Azimb
*
Yasser Selim
aFaculty of Specific Education, Zagazig University, Zagazig 44519, Egypt
bDepartment of Chemistry, Faculty of Science, Zagazig University, Zagazig 44519, Egypt
*
E-mail: y2selem@yahoo.com
Received January 15, 2018
DOI 10.1002/jhet.3176
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
A novel series of imidazoles, pyrimidines, and thiazoles were synthesized using microwave irradiation
and conventional method from commercial available p-aminobenzoic acid. Thus, one-pot condensation of
p-aminobenzoic acid, urea, and chloroacetic acid have been provided two types of imidazole derivatives
as separated mixture 2a and 2b. [3 + 2 + 1] Cyclocondensation of 2a, benzaldehyde, and urea/thiourea in
acidic medium afforded imidazolo oxazine derivative 3 and Imidazolothiazine 4. Coupling of 2a with ben-
zene diazonium salt gave the phenyldiazenyl imidazolidine 5. While the reaction of 2a, thiourea, and benz-
aldehyde in sodium ethoxide afforded imidazolothiazine 6. Oxidative cyclization of thiourea derivative 7
resulted a mixture of benzithiazole derivative 7a and oxathiazole derivative 7b. Cyclocondensation of 7a
with phenylenediamine and 4-methyl phenylenediamine furnished imidazole 8 and 9, respectively. Reaction
of P-aminobenzioc acid with potassium cyanate followed by Biginelli reaction with (acetyl acetone, ethyl
acetoacetate, and diethyl malonate) and salicyladehyde in HCl tolerated pyrimidine derivatives 10a–c, re-
spectively. In the same manner, the reactions and short reaction time make microwave technique one of
the greenest methodology for synthesis of this class of heterocyclic system.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
activity [14]. The new trend for the synthetic of
compounds uses microwave irradiation (MWI) as
a powerful technique for rapid and efficient synthesis
[15–17]. The utility of MWI as alternative synthetic tool
has advantages such as shorter reaction time, pure
products, significant reaction yield, fewer side products,
and greater selectivity [18–20]. In continuation of our
previous studies on the development of new heterocyclic
systems using simple and efficient procedures [21], we
report here a facile and clean protocol for the synthesis of
a new class of imidazoles, pyrimidines, and thiazoles
using MWI as alternate energy source starting from
readily available p-aminobenzoic acid.
Heterocyclic compounds are acquiring more importance
in recent years because of their pharmacological activities.
The imidazole nucleus is an important synthetic strategy in
drug discovery [1] and plays an important role in areas
such as natural products [2,3] and medicinal chemistry [2].
Thiazoles are important class of heterocyclic compounds,
found in many potent biologically active molecules such
as
sulfathiazole
(antimicrobial
drug),
ritonavir
(antiretroviral drug), abafungin (antifungal drug), and
tiazofurin (antineoplastic drug) [4,5]. Recently, several
protocols have already been described the synthesis of
thiazoles and benzothiazoles derivatives [6–8].
Pyrimidines and its condensed derivatives are considered
as privileged structures with a large spectrum of biological
activities and considered as components of RNA and
DNA. Several pyrimidine derivatives exhibit diverse
pharmacological activities [9,10], as antimicrobial [11],
analgesic [12], anti-inflammatory [13], and antitumor
RESULTS AND DISCUSSION
Three components cyclocondensation of p-aminobenzoic
acid, urea, and chloroacetic acid using microwave irradiated
for 5 min to provide two types of imidazole derivatives 2a
and 2b in high yield (85% and 9%, respectively) (Table 1).
© 2018 Wiley Periodicals, Inc.

Y. Selim, and M. H. M. Abd El-Azim
Vol 000
3325, 1670, and 1654 cmÀ1, respectively. IR spectrum
also showed signals at 12.63 ppm (exchange with D2O)
for COOH proton and NH2 at 9.21 ppm (exchange with
D2O). 13C NMR showed signals at 167.5 and 152.4 ppm
for two C═O group.
Table 1
Comparative data of conventional and microwave (MW) methods for the
synthesis of compounds 2–10.
Conventional
method (A)
Time (h)
MW
Yield method
Yield
(%)
Entry Cpd no.
(%)
(min)
The formation of oxazine 3 via 1,4-addition of urea to 2a
to give the intermediate II, followed by oxidation and
subsequent [1,5] hydride shift under MWI for 8 min. The
imidazolothiazine 4 was also obtained by addition of 2a,
thiourea, and benzaldehyde under reflux in acidic
medium for 4 h (Scheme 3). Thiazine derivative 4 proved
the presence of OH and NH at 3317 and two C═O at
1
2a
2b
3
4
5
6
7
7a
7b
8
0.3
60
60
50
45
45
60
-
55
40
35
30
-
5
85
90
90
73
-
2
3
4
5
6
7
4
4
1
4
7
8
-
7
3
3
74
-
1
1690 and 1654 cmÀ1. While H NMR (exchange with
0.5
70
65
75
68
-
84
85
80
1
D2O) signal was observed at 12.64 ppm for COOH
proton and NH at 9.17 ppm (exchange with D2O). Upon
treatment of imidazole 2a with phenyl diazonium, salt
undergo coupling on (N) not (C) afforded azoimidazole 5
(Scheme 3). The structure of 5 potentiated by the
presence of OH and absence of NH in IR spectrum which
8
6
6
1
6
6
6
10
12
3
10
12
11
9
9
10
11
12
13
10
10a
10b
10c
45
35
25
-, Time only.
1
revealed two C═O groups at 1670 and 1654 cmÀ1. Its H
NMR showed signal at 10.61 ppm (exchange with D2O)
for COOH proton in addition to Ar─H at 6.97–8.13 ppm
and CH2 protons at 4.69 ppm. 13C NMR also detected
three C═O signals at 169.2, 168.5, and 168.1 ppm.
The imidazolothiazine 6 was obtained by heating of 2a,
thiourea, and benzaldehyde under MWI in basic medium
for 7 min in 74% yield (Scheme 3, Table 1). IR spectrum
of thiazine derivative 6 revealed the presence of bands at
3325, 3186, 1670, 1654, and 1589 cmÀ1 characterized
for OH and NH. While 1H NMR showed signal at
7.57–7.88 ppm for aromatic protons and signal at
9.17 ppm for two NH groups, in addition to, at 12.64 ppm
for OH group which agreement with the structure.
Microwave irradiation assisted the oxidative cyclization
of thiourea derivative 7 to benzothiazole and thiazole 7a,b
via the reaction with Br2 in acidic medium for 3 min. The
IR spectrum of benzithiazole derivative 7a revealed OH,
NH, and C═O stretching absorbing bands at 3174, 3132,
and 1678 cmÀ1, respectively. 1H NMR revealed the
presence of aromatic protons as multiplet at 7.57–8.17 ppm,
signal at 8.86 ppm for NH, and signal at 13.03 ppm for
COOH. 13C NMR displayed signal at carbon at 167.5 and
166.7 ppm for two C═O and at 162.4 ppm for C═N.
Oxathiazole derivative 7b showed stretching absorbing
The formation of 2b may be resulted from the condensation
of the second molecule of p-aminobenzoic acid with
electrophilic carbonyl carbon of 2a (Scheme 1). The
infrared (IR) spectrum of imidazole derivative 2a showed
peaks at 3325, 3186, 1720, and 1651 cmÀ1 characteristic
for OH, NH, and C═O. While 1H NMR revealed signals at
12.71 and 9.31 ppm (exchange with D2O) for carboxyl
group and NH, respectively, in addition to, ArH's and CH2
signals at 7.6–8.11 ppm and CH2 signals at 4.67 ppm. 13
C
NMR showed signals at 170.6, 169.0, and 168.1 ppm for
three C═O group. While IR spectrum of 2b revealed peaks
at 3367 and 3186 cmÀ1 characteristic for OH and NH,
respectively, and 1774, 1716, and 1678 cmÀ1
corresponding to three C═O groups.1H NMR showed
signals at 12.75 and 11.34 ppm (exchange with D2O) for
carboxyl group and NH, respectively.
[3 + 2 + 1] Cyclocondensation of urea, imidazole
derivative 2a, and benzaldehyde under MWI for 7 min
resulted oxazine cyclization forming imidazolo oxazine
derivative 3 in high yield (90%) as shown in Table 1 and
none of pyrimidine derivative III (Scheme 2), the
conventional need
4 h of heating. Compound 3
characterized by OH, NH, and C═O absorption peaks at
Scheme 1. One-pot synthesis of imidazoles 2a,b. MWI, microwave irradiation. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
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Month 2018
Novel Series of Imidazoles, Pyrimidines, and Thiazoles Candidates
Scheme 2. One-pot synthesis of imidazolo [4,5-d]oxazine 3. MWI, microwave irradiation. [Color figure can be viewed at wileyonlinelibrary.com]
Scheme 3. Synthetic routes of imidazoles 4–6. MWI, microwave irradiation. [Color figure can be viewed at wileyonlinelibrary.com]
band at 1685 cmÀ1 for C═O group. The 1H NMR provided
signal at 12.81 ppm for COOH (exchange with D2O), in
addition to aromatic multiplet at 7.43–8.26 ppm.
Cyclocondensation using MWI for compound 7a and
phenylenediamine, 4-methyl phenylenediamine afforded
imidazole 8 and 9 for (Scheme 4) (Table 1). IR spectrum of
8 and 9 gave broad absorption bands at 3340 cmÀ1 due to
stretching vibration of two NH of imidazole and anilide.
The 1H NMR spectra of 8 and 9 showed downfield protons
for four NH at 12.25, 12.54, 12.18, and 12.21 ppm.
Treatment of p-aminobenzioc acid with potassium
cyanate afforded the urea derivative 10, which underwent
one-pot Bignelli reaction in MW (Table 1) via the reaction
with salicylaldehyde and active methylene dicarbonyl
compounds (viz, acetyl acetone, ethyl acetoacetate, and
diethyl malonate) in the presence of HCl for 10–12 min
afforded pyrimidine derivatives 10a–c, respectively
(Scheme 5). The structures of pyrimidine derivatives
10a–c were confirmed by spectral data. Thus, IR spectra of
the products 10a–c showed bands at 1662, 1716, 1685,
1
and 1708 cmÀ1 for ester and amide carbonyl groups. H
NMR data of pyrimidine 10a showed four signals at 2.74,
2.89, 9.59, and 9.71 ppm for two CH3 and two OH
groups, in addition to aromatic signals between
6.77–7.52 ppm as multiplet. 13C NMR spectrum of 10b
showed signals at 117.1, 126.3, 126.8, 127.0, 127.9,
128.7, 130.7, 132.1, 133.0, 138.0, 156.06, 163.2, 164.1,
and 168.5 ppm characteristic for Ar─C and four C═O. 1H
NMR spectrum of 10c showed signals at 1.3 and 4.33 ppm
as triplet and quartet at 4.33 ppm for CH3CH2, signals at
7.89 and 10.05 ppm for two OH and signal at 8.61 ppm
for NH (exchange with D2O).
Journal of Heterocyclic Chemistry
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Y. Selim, and M. H. M. Abd El-Azim
Vol 000
Scheme 4. Synthetic pathways of imidazoles 7–9. MWI, microwave irradiation. [Color figure can be viewed at wileyonlinelibrary.com]
Scheme 5. Synthetic routes of pyrimidines 10a–c. MWI, microwave irradiation. [Color figure can be viewed at wileyonlinelibrary.com]
CONCLUSION
solvents. Products were purified by recrystallization. All
reaction was carried out under microwave (Discover™ by
CEM, 2450 MHz, 20 bar, 300 W, 180°C). The IR
spectrum (KBr discs) was recorded on a Pye Unicam Sp-3-
300 (UK) or a Shimadzu FTIR 8101 PC infrared
In summary, we investigate the utility of MWI in
heterocyclization of p-aminobenzoic acid to synthesize a
new series of imidazoles, pyrimidines, and thiazoles. A
significant short reaction time, high pure products, and in
addition to very good yields were observed with MW
method. These results encourage us to do further work on
such synthetic method.
1
spectrophotometer (Japan). The H NMR 400 MHz and
13C NMR 100 MHz spectrum were measured on a JEOL-
JNM-LA spectrometer (Tokyo, Japan) using dimethyl
sulfoxide as a solvent. All chemical shifts were expressed
on the δ (ppm) scale using tetramethylslane as an internal
standard reference. The coupling constant (Ј) values are
given in Hz. Analytical data were obtained from the Micro
analytical Center, Faculty of Pharmacy, Cairo University,
Cairo, Egypt. The mass spectra were recorded on a MS-
S988 instrument (New Jersey, USA) operating at 70 eV.
EXPERIMENTAL
Melting points were measured using an Electro thermal IA
9100 apparatus (Stone, UK) with open capillary tube and are
uncorrected. All experiments were carried out using drying
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Month 2018
Novel Series of Imidazoles, Pyrimidines, and Thiazoles Candidates
4-(2,4-Dioxoimidazolidin-1-yl)benzoic acid and 4-((1-(4-
Carboxyphenyl)-2-oxo-2,3-dihydro-1H-imidazol-4-yl)amino)
benzoic acid (2a, b). Conventional method. A mixture of
p-aminobenzoic acid 1 (0.01 mol), urea (0.01 mol), and
chloroacetic acid (0.01 mol) was heated for about 20 min
at 100°C, and then hot water was added, filter off
compound 2a on hot, and was crystallized from water. To
separate the compound 2b, the filtrate was cooled, filter
exchangeable). 13C NMR (DMSO-d6): δ = 113.0, 117.8,
124.4, 127.0, 128.1, 128.8, 129.5, 130.2, 131.01, 144.1,
152.4, 167.5 and 169.0 (SP2-C). Mass spectrometry:
m/e = 347.80 (12%). Anal. Calcd for C18H12N4O4
(348.31): C, 62.07; H, 3.47; N, 16.09. Found: C, 62.00;
H, 3.35; N, 15.90.
4-(8-Oxo-6-phenyl-2-thioxo-2,3,8 and 9-tetrahydro-1H-
purin-7(6H)-yl) benzoic acid (4). Conventional method.
off, and crystallization from water.
Microwave method. A mixture of p-aminobenzoic acid
A mixture of compound 2a (0.01 mol), benzaldehyde
(0.01 mol), and thiourea (0.01 mol) in acidic medium
(2 mL hydrochloric acid) was refluxed for about 4 h and
then pour the mixture into dilute acetic acid. The
obtained precipitate was filtered and recrystallized from
water/ethanol to give compound 4. The faint brown
crystal of compound 4 was obtained by filtration and
recrystallization from water and ethanol.
1 (1 mmol), urea (1 mmol), and chloroacetic acid (1 mmol)
was sealed in a 10 mL septum reaction vial with magnetic
stirrer bar and irradiated with microwave 5 min (Table 1).
The reaction mixture was processed as described for the
conventional method.
Compound 2a.
Silver crystals; Yield: 60%; m.p.
255–260°C. IR (KBr): 3325, 3186 cmÀ1 (OH, NH),
Microwave method.
A mixture of compound 2a
1720, 1651 cmÀ1 (C═O). H NMR (DMSO-d6): δ = 4.67
1
(1 mmol), benzaldehyde (1 mmol), and thiourea
(1 mmol) in acidic medium (2 mL hydrochloric acid) was
sealed in a 10 mL septum reaction vial with magnetic
stirrer bar and irradiated with microwave 8 min (Table 1).
The reaction mixture was processed as described for the
conventional method.
(s, 2H, Himidazol), 7.60 (d, 1H, J = 8.76 Hz, HAryl), 7.88
(d, 1H, J = 8.76 Hz, HAryl), 9.31 (s, 1H, NH), 12.71 (s,
1H, COOH). 13C NMR (DMSO-d6): δ = 50.45 (SP3-C),
113.0, 127.3, 130.3, 131.3, 168.1, 169.0 and 170.6
(SP2-C). Anal. Calcd for C10H8N2O4 (220.18): C, 54.55;
H, 3.66; N, 12.72. Found: C, 54.45; H, 3.54; N, 12.66.
Compound 2b. Pale brown; Yield: 60%; m.p. > 300°C.
The faint brown crystal of compound 4 was obtained by
filtration and recrystallization from water and ethanol,
yield: 45%; m.p. > 300°C. IR (KBr): 3317 cmÀ1 (OH),
IR (KBr): 3367, 3186 cmÀ1 (OH, NH), 1774, 1716,
1678 cmÀ1 (C═O). 1H NMR (DMSO-d6/D2O):
δ = 7.29–8.10 (m, 9H, Himidazol and HAryl), 11.34 (s,
1H, NH, D2O-exchangeable), 12.75 (b, 1H, COOH,
D2O-exchangeable). Anal. Calcd for C17H13N3O5
(339.30): C, 60.18; H, 3.86; N, 12.38. Found: C, 60.05;
1
3186 cmÀ1 (NH), 1670 and 1654 cmÀ1 (C═O). H NMR
(DMSO-d6/D2O): δ = 7.55–7.95 (m, 9H, HAryl), 9.17 (s,
1H, NH, D2O-exchangeable), 12.63 (b, 1H, COOH, D2O-
exchangeable). 13C NMR (DMSO-d6): δ = 114.5, 117.6,
117.8, 118.8, 124.4, 127.8, 129.2, 130.6, 131.0, 144.1,
152.4, 162.7 and 167.4 (SP2-C). Anal. Calcd for
C18H14N4O3S (366.39): C, 59.01; H, 3.85; N, 15.29.
Found: C, 58.90; H, 3.72; N, 15.20.
H, 3.77; N, 12.33.
4-(5-Amino-2-oxo-7-phenylimidazo[4,5-d]1,3oxazin-1(2H)-
yl)benzoic acid (3). Conventional method. A mixture of
compound 2a (0.01 mol), benzaldehyde (0.01 mol), and
urea (0.01 mol) in acidic medium (2 mL hydrochloric
acid) was refluxed for about 4 h and then pour the
mixture into dilute acetic acid. The obtained precipitate
was filtered and recrystallized from water/ethanol to give
compound 3. The golden crystal of compound 3 was
obtained by filtration and recrystallization from water and
ethanol.
4-(2,4-Dioxo-3-(phenyldiazenyl) imidazolidin-1-yl) benzoic
acid (5).
A mixture of compound 2a (0.01 mol) was
coupled with phenyl diazonium salt (0.01 mol) in ice bath
to give the azo derivative 5. The obtained precipitate was
filtered and recrystallized from ethanol to give compound 5.
The black crystal of compound 5 was obtained by
filtration and recrystallization from water and ethanol,
yield: 45%; m.p. > 300°C. IR (KBr): 3317 cmÀ1 (OH),
1670, 1654 cmÀ1 (C═O). 1H NMR (DMSO-d6/D2O):
δ = 4.69 (s, 2H, Himidazol), 6.97–8.13 (m, 9H, HAryl),
10.61 (b, 1H, COOH, D2O-exchangeable). 13C NMR
(DMSO-d6): δ = 50.47 (SP3-C), 116.4, 117.7, 126.8,
128.8, 129.1, 129.7, 130.8, 134.6, 153.1, 168.1 and 169.2
(SP2-C). Anal. Calcd for C16H12N4O4 (324.29): C, 59.26;
H, 3.73; N, 17.28. Found: C, 59.15; H, 3.68; N, 17.20.
4-(5-Imino-2-oxo-7-phenyl-2,3,4,5-tetrahydroimidazo[4,5-
Microwave method.
A mixture of compound 2a
(1 mmol), benzaldehyde (1 mmol), and urea (1 mmol) in
acidic medium (2 mL hydrochloric acid) was sealed in a
10 mL septum reaction vial with magnetic stirrer bar and
irradiated with microwave 7 min (Table 1). The reaction
mixture was processed as described for the conventional
method.
The golden crystal of compound 3 was obtained by
filtration and recrystallization from water and ethanol,
yield: 50%; m.p. > 300°C. IR (KBr): 3325 cmÀ1 (OH,
NH), 1670, 1654 cmÀ1 (C═O). 1H NMR (DMSO-d6/
D2O): δ = 7.57–7.95 (m, 9H, HAryl), 9.21 (s, 2H, NH2,
D2O-exchangeable), 12.63 (b, 1H, COOH, D2O-
d][1,3]thiazin-1(7H)-yl)benzoic acid (6).
method.
Conventional
A mixture of compound 2a (0.01 mol),
benzaldehyde (0.01 mol), and thiourea (0.01 mol) in
sodium ethoxide solution [prepared from sodium metal
Journal of Heterocyclic Chemistry
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Y. Selim, and M. H. M. Abd El-Azim
Vol 000
(0.23 g) in absolute ethanol (20 mL)]; was refluxed for
about 4 h and then pour the mixture into water. The
obtained precipitate was filtered and recrystallized from
water/ethanol to give compound 6. The flaxen crystal of
Compound 7b. The gray crystal of compound 7b was
obtained by filtration and recrystallization from ethanol/
DMF, Yield: 40%; m.p. 240–242°C. IR (KBr):
1
3371 cmÀ1 (OH), 1685 cmÀ1 (C═O). H NMR (DMSO-
compound
6
was obtained by filtration and
d6/D2O): δ = 7.43–8.26 (m, 9H, HAryl), 12.81 (b, 1H,
recrystallization from ethanol.
COOH,
D2O-exchangeable).
Anal.
Calcd
for
Microwave method.
A mixture of compound 2a
C15H10N2O3S (298.32): C, 60.39; H, 3.38; N, 9.39.
Found: C, 60.30; H, 3.28; N, 9.25.
(1 mmol), benzaldehyde (1 mmol), and thiourea
(1 mmol) in sodium ethoxide solution [prepared from
sodium metal (0.023 g) in absolute ethanol (6 mL)] was
sealed in a 10 mL septum reaction vial with magnetic
stirrer bar and irradiated with microwave 7 min (Table 1).
The reaction mixture was processed as described for the
conventional method.
The flaxen crystal of compound 6 was obtained by
filtration and recrystallization from ethanol, yield: 60%;
m.p. 292–295°C. IR (KBr): 3325, 3186 cmÀ1 (NH, OH),
1670, 1654 cmÀ1 (C═O) and 1589 cmÀ1 (C═N). 1H
NMR (DMSO-d6/D2O): δ = 7.57 (d, 2H, J = 8.72 Hz, H
aryl), 7.88 (d, 2H, J = 8.72 Hz, H aryl), 9.17 (s, 2H,
2NH), 12.64 (s, 1H, OH). Mass spectrometry:
m/e = 366.0 (5%). Anal. Calcd for C18H14N4O3S
(366.39): C, 59.01; H, 3.85; N, 15.29. Found: C, 58.90;
Synthesis of N-(6-(1H-benzo[d]imidazol-2-yl) benzo[d]
thiazol-2-yl)benzamide (8) and N-(6-(6-methyl-1H-benzo[d]
imidazol-2-yl) benzo[d]thiazol-2-yl) benzamide (9).
Conventional method. A mixture of 7a (0.01 mol) and
phenylenediamine or 4-methyl phenylenediamine
(0.01 mol) was refluxed for 4 h in DMF. After then, the
mixture was poured into water. The obtained precipitate
was filtered to give compounds 8 and 9.
Microwave method. A mixture of 7a (0.01 mol) and
phenylenediamine or 4-methyl phenylenediamine
(0.01 mol) in DMF (6 mL) was sealed in a 10 mL
septum reaction vial with magnetic stirrer bar and
irradiated with microwave for 10 and 12 min (Table 1).
The reaction mixture was processed as described for the
conventional method.
Compound 8. The canary crystal of compound 8 was
obtained by filtration and recrystallization from ethanol
and DMF, yield: 35%; m. p. 286–290°C. IR (KBr): 3340,
H, 3.72; N, 15.20.
2-Benzamidobenzo[d]thiazole-6-carboxylic acid and 4-((5-
phenyl-3H-1,2,4-oxathiazol-3-ylidene)amino) benzoic acid
1
3170 cmÀ1 (NH), 1666 cmÀ1 (C═O). H NMR (DMSO-
(7a, b).
Conventional method.
A mixture of benzoyl
chloride (0.01 mol), ammonium thiocyanate (0.01 mol),
and p-aminobenzoic acid (0.01 mol) was refluxed in
acetone for 1 h. The obtained precipitate was filtered to
thiourea derivative 7. Approximately, 0.01 mol of
compound 7 was refluxed for 0.5 h in Br2/ACOH. The
mixture was poured into water; it gave precipitate upon
filtration we obtained compound 7a, while compound 7b
was obtained when filtrate left to cool.
d6/D2O): δ = 7.11–8.15 (m, 12H, HAryl), 12.25, 12.51
(2 s, 2H, 2NH, D2O-exchangeable). Mass spectrometry:
m/e = 369.98 (7%). Anal. Calcd for C21H14N4OS
(370.43): C, 68.09; H, 3.81; N, 15.12. Found: C, 68.00;
H, 3.75; N, 15.05.
Compound 9. The brown crystal of compound 9 was
obtained by filtration and recrystallization from ethanol
and DMF, yield: 30%; m p. 252–254°C. IR (KBr):
3336, 3178 cmÀ1 (NH), 1658 cmÀ1 (C═O). 1HNMR
(DMSO-d6/D2O): δ = 2.39 (s, 3H, Hmethyl), 6.95–8.15
(m, 12H, HAryl), 12.18, 12.21 (2 s, 2H, 2NH, D2O-
exchangeable). Anal. Calcd for C22H16N4OS (384.45):
C, 68.73; H, 4.19; N, 14.57. Found: C, 68.60; H,
4.10; N, 14.45.
Microwave method.
A mixture of benzoyl chloride
(1 mmol), ammonium thiocynate (1 mmol), and p-
aminobenzoic acid (1 mmol) in acetone (6 mL) was
sealed in a 10 mL septum reaction vial with magnetic
stirrer bar and irradiated with microwave 3 min (Table 1).
The obtained compound 7 was microwave irradiated with
Br2 (1.1 mmol) for 3 min. The reaction mixture was
4-(5-Acetyl-4-(4-hydroxyphenyl)-6-methyl-2-oxopyrimidin-
processed as described for the conventional method.
Compound 7a. The faint yellow crystal of compound
1(2H)-yl)benzoic
2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)benzoic acid, and
4-(2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)benzoic acid
(10a–c). Conventional method.
acid,
4-(5-acetyl-4-(4-hydroxyphenyl)-
7a was obtained by filtration and recrystallization from
ethanol and dimethylformamide (DMF), Yield: 55%; m.p.
> 300°C. IR (KBr): 3174, 3132 cmÀ1 (OH, NH),
A
mixture of p-
aminobenzoic acid (0.01 mol) and potassium cyanate was
refluxed for 1 h to give compound 10. The compound 10
was used in further step without purification.
Microwave method. A mixture of p-aminobenzoic acid
(1 mmol) and potassium cyanate (1.1 mmol) was sealed in
a 10 mL septum reaction vial with magnetic stirrer bar
and irradiated with microwave (Table 1). The reaction
mixture was processed as described for the conventional
method.
1
1678 cmÀ1 (C=O). H NMR (DMSO-d6/D2O): δ = 4.20
(s, 2H, Himidazol), 7.57–8.17 (m, 8H, HAryl), 8.86 (s, 1H,
NH, D2O-exchangeable), 13.03 (b, 1H, COOH, D2O-
exchangeable). 13C NMR (DMSO-d6): δ = 49.0 (SP3-C),
120.4, 124.3, 126.3, 127.8, 128.8, 129.1, 132.0, 132.1,
133.5, 1582.0, 162.4, 166.7and 167.5 (SP2-C). Anal.
Calcd for C15H10N2O3S (298.32): C, 60.39; H, 3.38; N,
9.39. Found: C, 60.39; H, 3.38; N, 9.39.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Novel Series of Imidazoles, Pyrimidines, and Thiazoles Candidates
Conventional method.
A mixture of compound 10
8.61(s, 1H, NH), 10.05(s, 1H, OH). Anal. Calcd for
(0.01 mol), salicyladehyde (0.01 mol), and acetyl acetone,
ethyl acetoacetate, or diethyl malonate (0.01 mol) in acidic
medium (2 mL hydrochloric acid) was refluxed for 6 h;
the obtained solid was crystalized from ethanol.
C11H8N2O5 (248.19): C, 53.23; H, 3.25; N, 11.29.
Found: C, 53.20; H, 3.15; N, 11.20.
REFERENCES AND NOTES
Microwave method.
A mixture of compound 10
(1 mmol), salicylaldehyde (1 mmol), and acetyl acetone,
ethyl acetoacetate, or diethyl malonate (1 mmol) in acidic
medium (2 ml hydrochloric acid) as sealed in a 10 mL
septum reaction vial with magnetic stirrer bar and
irradiated with microwave (Table 1). The reaction mixture
[1] Gupta, P.; Gupta, J. K. Chem Sci J 2015, 6, 1.
[2] Brown, E. G. Ring Nitrogen and Key Biomolecules; Kluwer
Academic Press: U. K (Chapter 2), 1998.
[3] Forte, B.; Malgesini, B.; Piutti, C.; Quartieri, F.; Scolaro, A.;
Papeo, G. A. Drugs 2009, 7, 705.
[4] King, F. E.; Kidd, D. A. A. Org Prep Proceed Int 1948, 162, 776.
[5] Quahog, J.; Hernandez, P.; Insuasty, B.; Abonia, R.; Cobo, J.;
Sanchez, A.; Nogueras, M.; Low, J. N. J Chem Soc Perkin Trans 2002,
4, 555.
[6] Nguyen, T. B.; Ermolenko, L.; Dean, W. A.; Al-Mourabit, A.
Org Lett 2012, 14, 5948.
was processed as described for the conventional method.
Compound 10a. Dark brown powder of compound 10a
was obtained by filtration and recrystallization from
ethanol, yield: 45%; m.p. 208–211°C. IR (KBr, υ, cmÀ1):
3232 (OH), 1716, 1662 (C═O). 1H NMR (400 MHz,
DMSO-d6) δ (ppm): 2.74, 2.89 (2 s, 1H, 2CH3), 6.77–7.52
(m, 8H, Ar─H), 7.96 (s, 1H, OH), 9.63 (s, 1H, OH). Mass
spectrometry: m/e = 364 (22%). Anal. Calcd for
C20H16N2O5 (364.35): C, 65.93; H, 4.43; N, 7.69. Found:
C, 65.85; H, 4.40; N, 7.60.
Compound 10b. Black powder of compound 10b was
obtained by filtration and recrystallization from ethanol,
[7] Yang, Z.; Chen, X.; Wang, S.; Liu, J.; Xie, K.; Wang, A.; Tan,
Z. J Org Chem 2012, 77, 7086.
[8] Bastug, G.; Eviolitte, C.; Markó, I. E. Org Lett 2012, 14, 3502.
[9] Malik, V.; Singh, P.; Kumar, S. Tetrahedron 2006, 62, 5944.
[10] Novikov, M. S.; Buckheit, R. W. Jr.; Temburnikar, K.;
Khandazhinskaya, A. L.; Ivanov, A. V.; Seley-Radtke, K. L. Bioorg
Med Chem 2010, 18, 8310.
[11] Deshmukh, M. B.; Salunkhe, S. M.; Patil, D. R.; Anbhule, P. V.
Eur J Med Chem 2009, 44, 2651.
[12] Sondhi, S. M.; Jain, S.; Dinodia, M.; Shukla, R.; Raghubir, R.
Bioorg Med Chem 2007, 15, 3334.
[13] Sondhi, S. M.; Dinodia, M.; Rani, R.; Shukla, R.; Raghubir, R.
Indian J Chem 2009, 49b, 273.
[14] Russowsky, D.; Canto, R. F. S.; Sanches, S. A. A.; D’Oca, M.
G. M. Bioorg Chem 2006, 34, 173.
[15] Waseem, M. A.; Lone, A. M.; Ibad, F.; Ibad, A.; Yadav, V. B.;
Ansari, K.; Shairjogrey, B. A.; Watal, G.; Siddiqui, I. R. J Heterocyclic
Chem 2017, 54, 1061.
[16] El-Sayed, H. A.; Moustafa, A. H.; Haikal, A. Z.; El-Ashry, E.
S. H. Nucleosides Nucleotides Nucleic Acids 2009, 28, 184.
[17] El-Sayed, H. A.; Moustafa, A. H.; Haikal, A. Z.;
Abu-El-Halawa, R.; El Ashry, E. H. Eur J Med Chem 2011, 46, 2948.
[18] Tierney, J. P.; Lidstrom, P. Microwave Assisted Organic
Synthesis; Blackwell: Oxford, 2005.
yield: 35%; m.p. 196–199°C. IR (KBr, υ, cmÀ1): 3430,
3194 and 1685 (OH, NH and C═O). 1H NMR (400 MHz,
DMSO-d6) δ (ppm): 2.3 (s, 3H, CH3), 6.76–7.53 (m, 8H,
Ar─H), 7.95 (s, 1H, OH), 8.20 (s, 1H, NH), 9.04 (s, 1H,
OH). 13CNMR (100 MHz, DMSO-d6) δ (ppm): 14.73
(CH3), 117.1, 126.3, 126.8, 127.0, 127.9, 128.7, 130.7,
132.1, 133.0, 138.0, 156.0, 163.2, 164.1, 168.5 (SP2-C).
Anal. Calcd for C19H14N2O6 (366.32): C, 62.30; H,
3.85; N, 7.65. Found: C, 62.22; H, 3.75; N, 7.55.
Compound 10c. Yellow crystal of compound 10c was
obtained by filtration and recrystallization from ethanol,
yield: 25%; m.p. 180–182°C. IR (KBr, υ, cmÀ1): 3367,
3271, 1708 and 1604 (OH, NH, C═O and C═N). 1H
NMR (400 MHz, DMSO-d6) δ (ppm): 1.3 (t, 3H,
J = 6.80 Hz, CH3CH2), 4.33(q, 2H, J = 6.80 Hz,
CH3CH2), 6.55–7.60 (m, 8H, Ar─H), 7.89 (s, 1H, OH),
[19] Kappe, C. O. Angew Chem Int Ed, 43, 2004.
[20] Kappe, C. O. Angew Chem Int Ed, 116, 2004.
[21] Selim, Y.; EL-Ahwany, M. Chem Heterocyc Comp 2017, 53,
867.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet