Efficient synthesis of some pyrimidine and thiazolidine derivatives bearing quinoline scaffold under microwave irradiation

Article abstract of DOI:10.1080/00397911.2020.1769673

An efficient and facile approach for the synthesis of new quinoline derivatives was accomplished via reactions of 2-chloroquinoline-3-carbaldehyde with active methylene compounds, for example, 1,3-dimethylbarbituric acid, thiobarbituric acid and 2,4-dioxo

Full text of DOI:10.1080/00397911.2020.1769673

Synthetic Communications
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Efficient synthesis of some pyrimidine and
thiazolidine derivatives bearing quinoline scaffold
under microwave irradiation
Abeer M. El-Naggar & Sayed K. Ramadan
To cite this article: Abeer M. El-Naggar & Sayed K. Ramadan (2020): Efficient synthesis of some
pyrimidine and thiazolidine derivatives bearing quinoline scaffold under microwave irradiation,
Synthetic Communications, DOI: 10.1080/00397911.2020.1769673
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https://doi.org/10.1080/00397911.2020.1769673
Efficient synthesis of some pyrimidine and thiazolidine
derivatives bearing quinoline scaffold under microwave
irradiation
Abeer M. El-Naggar and Sayed K. Ramadan
Faculty of Science, Chemistry Department, Ain Shams University, Cairo, Egypt
ABSTRACT
ARTICLE HISTORY
Received 15 December 2019
An efficient and facile approach for the synthesis of new quinoline
derivatives was accomplished via reactions of 2-chloroquinoline-3-
carbaldehyde with active methylene compounds, for example, 1,3-
dimethylbarbituric acid, thiobarbituric acid and 2,4-dioxothiazolidine
and aromatic amines through one-pot multi-component reaction
(MCR) as sources of pyrimidine and thiazolidine derivatives bearing
quinoline moiety. All compounds were synthesized via conventional
and Microwave Irradiation conditions. The best results (short reaction
times, pure products, high yield) were obtained by microwave irradi-
ation. The synthesized derivatives were characterized by various
physicochemical and spectral techniques from their analytical and
spectral data.
KEYWORDS
Green chemistry; quinoline;
pyrimidines; thiazolidine;
ultraviolet
GRAPHICAL ABSTRACT
CONTACT Abeer M. El-Naggar
elsayedam@sci.asu.edu.eg; Sayed K. Ramadan
sayed.karam2008@sci.asu.edu.eg
Chemistry Department, Faculty of Science, Ain Shams University, Elkhalifa Elmamoun St., Abbassia, Cairo
11566, Egypt.
Supplemental data for this article is available online at https://doi.org/10.1080/00397911.2020.1769673
ß 2020 Taylor & Francis Group, LLC

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A. M. EL-NAGGAR AND S. K. RAMADAN
Introduction
Quinoline (1-azanaphthalene) compounds are widely utilized as parental compounds to
synthesize a variety of heterocycles with a broad range of pharmacological activities
including anti-inflammatory, antitumor, antiviral, antileishmanial, antimicrobial, and
antituberculosis.[1–6] Also, it has been reported the utilization of quinoline derivatives in
the preparation of some dyes and pigments.[7] In recent years, barbituric acids and thio-
barbiturate derivatives have attracted the attention of the pharmaceutical scientists due
to their various biological effects such as antibacterial, anticancer,[8,9] as well as inhib-
ition collagenase-3[10] matrix metalloproteinases,[11] recombinant cytochrome P450
enzymes,[12] methionine aminopeptidase-1,[13] tyrosinase,[14] and urease.[15–18]
Multicomponent reaction (MCR) is still one of the main objectives in heterocyclic
synthesis to enhance the reaction efficiency and atom economy.[1,9] Due to the above
importance of such type of compounds, the development of an efficient and ecofriendly
methodology for the synthesis of polyfunctional compounds was studied. The applica-
tion of microwave irradiation as an important green tool in the organic synthetic field
has a promising future. The improvement of the reaction rate, reaction selectivity, reac-
tion yield, product purity, and waste minimization are desired advantages of such green
methods.[10,19–22] Herein, we outline the synthesis of pyrimidine and thiazolidine deriva-
tives encompassing a quinoline scaffold, starting with 2-chloroquinoline-3-carbaldehyde
under both conventional and microwave techniques.
Scheme 1. Reaction of quinoline aldehyde 1 with barbituric acid.

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Scheme 2. Behavior of 1 toward 1,3-dimethylbarbituric acid.
Results and discussion
Our investigation utilized the key starting material 2-chloroquinoline-3-carbaldehyde
(1)[23] in an attempt for the synthesis of some pyrimidine and thiazolidine derivatives
bearing a quinoline scaffold. Indeed, the reaction of 1 with barbituric acid 2 in both
conditions; refluxing ethanol or under microwave irradiation failed to give the desired
barbiturate derivative 3 and afforded the 2-pyrimidinylquinoline derivative 4. The IR
spectrum of compound 4 displayed the characteristic stretching absorption bands for
1
C ¼ O and NH groups. The H NMR spectrum showed its existence as a mixture of
enol-keto tautomers and exhibited singlet integrated to one proton attributable for alde-
hydic proton (CHO) and singlet of CH2 protons in addition to exchangeable singlet of
OH (enol form). Furthermore, compelling evidence for the assigned structure was
gained from its mass spectrum which showed the correct molecular ion peak at m/z 283
(12.9%) as well as some of the important abundant peaks (cf. Section “Experimental”).
The reaction could be explained via the elimination of HCl molecule (to produce com-
pound 4) instead of water (to produce compound 3) as displayed in Scheme 1. The
driving force behind this reaction pathway may be the stabilization of the product 4a by
the intramolecular hydrogen bonding as shown in 4b.

4
A. M. EL-NAGGAR AND S. K. RAMADAN
Scheme 3. Possible pathway for the formation of Schiff base 9.
Chemical evidence for the structure of compound 4 was the condensation of the alde-
hydic functionality with 4-toluidine in refluxing ethanol to afford Schiff base 5 (Scheme 1).
The IR spectrum of 5 displayed the absence of the absorption band of aldehyde CHO.
The 1H NMR spectrum provided singlet in the upfield region integrated to three
protons attributable for methyl protons as well as the aromatic protons corresponding to 4-
toluidine moiety.
To exclude the chance of HCl elimination, barbituric acid 2 was replaced with 1,3-
dimethylbarbituric acid 6. It was fortunate that when the reaction was executed in
refluxing ethanol, the 1,3-dimethylbarbiturate derivative 8 was obtained (Scheme 2).
The structure of 8 was established based on its spectral data and supported by an
authentic sample prepared from condensation of 2-oxoquinoline-3-carbaldehdye (10)
with 1,3-dimethylbarbituric acid 6 in boiling ethanol. Formation of barbiturate 8 could
be postulated via elimination of water molecule to give the barbiturate 7 as a non-isol-
able intermediate followed by hydrolysis in case of using 2-chloroquinoline-3-carbalde-
hyde (1). In turn, methyl 4-aminobenzoate reacted with barbiturate 8 in refluxing
dioxane to furnish a mixture of 1,3-dimethylbarbituric acid 6 and Schiff base 9
(Scheme 2). Presumably, this reaction took place via aza-Michael addition of NH2 of
amine on the b-carbon followed by rearrangement (cf. Scheme 3).
Similarly, some primary aromatic amines, for example, p-aminoacetophenone and
2-aminobenzothiazole condensed with 1 under both conventional and microwave

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Scheme 4. Condensation of quinoline 1 with some aromatic amines.
irradiation to furnish 2-substituted quinoline derivatives 11a and 11b. The formation
of compounds 11a and 11b may be arising from the stability of this product by
intramolecular H-bonding (Scheme 4). The structures of 11a and 11b were deduced
from their spectral data. Thus, the IR spectra displayed the characteristic absorption
1
bands for NH and C ¼ O groups. Their H NMR spectra showed singlets of NH at
the region d 10–11 ppm (cf. Section “Experimental”). It was interesting to synthesize
quinoline derivatives bearing benzimidazole moiety but unfortunately, treatment of
quinoline 1 with benzimidazole under both conventional and microwave irradiation
failed to afford the desired product 2-benzimidazolylquinoline and prompted the
construction of 2-oxoquinoline-3-carbaldehyde 10 (Scheme 4). The structure of alde-
hyde 10 was substantiated from its spectral data and supported by direct comparison
with an authentic sample prepared from refluxing a solution of quinoline 1 in 70%
acetic acid.[24]
From the biological and synthetic point of view, three components one-pot condensa-
tion of
1
with the above mentioned primary amines and some active
methylene compounds namely, 1,3-dimethylbarbituric acid 6, thiobarbituric acid 12 and
2,4-dioxothiazolidine 13 afforded 1,3-dimethylbarbiturates 14, thiobarbiturates 15 and
2,4-dioxothiazolidines 16 under microwave irradiation method. The synthesis of the tar-
get compounds was carried out as outlined in Scheme 5. The structures of these prod-
ucts were inferred from their spectral data. The IR spectra of compounds 14–16
exhibited the characteristic stretching absorption bands for C ¼ O and NH groups.
Their 1H NMR spectra were compatible with the assigned structures (cf. Section
“Experimental”). It was observed that the microwave approach proved to be extremely
fast providing good to excellent yields (82–90%).
On the other hand, it was fortunate that one-pot condensation of quinoline 1 with
benzimidazole and the active methylene compounds under microwave irradiation

6
A. M. EL-NAGGAR AND S. K. RAMADAN
Scheme 5. One-pot condensation of 1 with primary Aromatic amines and active methy-
lene compounds.
afforded 2-oxoquinoline derivatives 8, 17, and 18 (Scheme 6). The same compounds 8,
17, and 18 were also obtained from the condensation of 2-oxoquinoline-3-carbaldehyde
(10) with barbituric acid derivatives or 2,4-dioxothiazolidine, respectively under the
same reaction conditions. Presumably, the formation of these products could be inter-
preted via Scheme 7. Thus, in the first step, it gave the condensation products [I] as
non-isolable intermediates followed by hydrolysis in the second step. The structures
of 2-oxoquinolines were deduced from their spectral data and supported by
authentic samples prepared from condensation of 2-oxoquinoline-3-carbaldehyde (10)

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Scheme 6. Synthesis of 2-oxoquinoline derivatives 17 and 18.
with 1,3-dimethylbarbituric acid, thiobarbituric acid and 2,4-dioxothiazolidine, respect-
ively under the same reaction conditions. Table 1 displayed the microwave approach as
compared with the conventional method.
UV Spectroscopy
The electronic absorption spectra of quinoline derivatives (4–18) were recorded in polar
solvent DMSO at room temperature at the concentration of 1 ꢀ 10ꢁ5 M from the range
of 200–800 nm. The scans and data have been presented in Figure 1 and Table 2,
respectively. The quinoline derivatives have shown absorption maximum (kmax) at
416–384 nm, 344–322 nm, and small bands in the range of 322–306 nm. The kmax may
ꢂ
ꢂ
be assigned to n–p and p–p transitions in the chromophoric –C¼S– group, C¼O
group and other unsaturated groups present in the aromatic rings. The increased oxy-
genation on the ring generally results in bathochromic shifts. The quinoline derivatives
with ester derivatives moiety substitution have shown absorption maximum at a higher

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A. M. EL-NAGGAR AND S. K. RAMADAN
Scheme 7. Plausible pathway for the formation of compounds 8, 17, and 18.
Table 1. Comparison between conventional and microwave irradiation methods.
Yield (%)
Time (min)
Comp. no.
Ca
Mb
Ca
Mb
4
5
8
9
59
69
57
68
63
54
65
67
60
55
54
67
60
54
62
85
93
86
91
89
88
91
92
88
88
92
90
89
87
89
360
480
420
480
360
540
480
420
360
350
320
430
410
370
410
3
4
3
4
4
6
4
4
4
4
5
4
3
4
3
10
11a
11b
14a
14b
15a
15b
16a
16b
17
18
aC: conventional; bM: microwave.
Figure 1. Electronic absorption spectra of pyrimidine and thiazolidine derivatives based quinoline
scaffold (4–18) in DMSO at a concentration of 1 ꢀ 10ꢁ5 M.

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Table 2. Absorption maximum (kmax) of quinoline derivatives.
Comp.
Wavelength (kmax
)
Comp.
Wavelength (kmax
324
410, 416
388, 330
404, 394, 336
)
5
8
9
11a
14a
14b
328, 410, 344
306
15a
15b
16a
16b
17
308
330
328, 388
314, 308, 342, 382
346, 384
390, 410
18
wavelength as compared to the quinoline derivatives with benzothiazole substitution.
(Table 2 and Fig. 1).
Conclusion
In our study, a new series of valuable heterocycles bearing quinoline moiety was synthe-
sized, using conventional and microwave irradiation technology. The best results (short
reaction times, pure products, high yield) were obtained by microwave irradiation.
Experimental
All reagents and solvents were of analytical grade, obtained from commercial suppliers,
purified and dried by standard techniques. The Microwave reactions were carried out
by Microsynth instrument type MA143 (Microwave flux). All melting points were meas-
ured on a GALLENKAMP electric melting point apparatus and are uncorrected.
Elemental analyses were performed on CHN analyzer, and all compounds were within
0.4 of the theoretical values. The infrared (IR) spectra were recorded using potassium
bromide disks on Fourier Transform Infrared Thermo Electron Nicolet iS10
Spectrometer (Thermo Fisher Scientific Inc., Waltham, MA) at Chemistry Department
1
Laboratory, Faculty of Science, Ain Shams University. The H NMR spectra were run at
400 MHz on a GEMINI NMR Spectrometer (GEMINI, Manufacturing & Engineering
Inc., Anaheim, CA) using tetramethylsilane as an internal standard in deuterated
dimethyl sulfoxide (DMSO-d6) at the Main Defense Chemical Laboratory, Cairo.
Chemical shifts (d) are quoted in ppm. The abbreviations used are as follows: s, singlet;
d, doublet; t, triplet; m, multiplet. All coupling constant (J) values are given in hertz.
The mass spectra (MS) were recorded on a Shimadzu GC-MS-QP-1000EX mass spec-
trometer (Shimadzu Scientific Instruments, Inc., Columbia, MD) operating at 70 eV at
the Regional Center for Mycology and Biotechnology (RCMB) of Al-Azhar University,
Nasr City, Cairo, Egypt. The electronic absorption spectra were recorded on the spec-
trophotometer (UV-1240, Shimadzu, Japan) at the Chemistry department, Faculty of
Science, Ain Shams University. The reactions were monitored by TLC using Merck
Kiesel gel 60 F254 analytical sheets obtained from Fluka, Switzerland. The starting 2-
chloroquinoline-3-carbaldehyde (1) was previously reported.[23]
Condensation of quinoline aldehyde 1 with barbituric acid 2
Conventional method
A mixture of 2-chloroquinoline-3-carbaldehyde (1) (2 mmol) and barbituric acid 2
(2 mmol) in ethanol (20 mL) was heated under reflux for 3 h. The precipitated solid

10
A. M. EL-NAGGAR AND S. K. RAMADAN
while hot was collected by filtration and recrystallized from ethanol/dioxane mixture
(2:1) afforded compound 4.
Microwave irradiation
An equimolar mixture of 2-chloroquinoline-3-carbaldehyde (1), barbituric acid 2
(2 mmol) in acetic acid (2 mL) was allowed to react under microwave irradiation at
200–400 W power for 2-4 min. The solvent was evaporated under reduced pressure. The
residue was recrystallized from ethanol/dioxane mixture (2:1) afforded compound 4.
2-(2,4,6-Trioxotetrahydropyrimidin-1(2H)-yl)quinoline-3-carbaldehyde (4)
Red crystals, mp >360 ꢃC, IR (KBr, ꢀ, cmꢁ1): 3441 (br. OH, lactim form), 3215 (NH),
1
1747, 1711 (C ¼ O barbituric), 1676 (CHO). H NMR (400 MHz, DMSO-d6, d, ppm):
12.15 (s, 1H, NH, exchangeable), 11.39 (s, 1H, OH, lactim form, exchangeable), 11.26
(s, 1H, OH, enol form, exchangeable), 9.14 (s, 1H, CHO), 8.48 (s, 1H, C4-H quinoline),
7.73–7.71 (dd, 1H, C5-H, J ¼ 7.6 Hz), 7.63-7.59 (dd, 1H, C7-H quinoline, J ¼ 8.4 and
7.2 Hz), 7.33–7.31 (d, 1H, C8-H quinoline, J ¼ 8.4 Hz), 7.25–7.21 (dd, 1H, C6-H quin-
oline, J ¼ 8.0 and 6.8 Hz), 3.15 (s, 2H, CH2). MS (70 eV, m/z, %): 283 (12.9), 267 (96.1),
251 (16.1), 207 (15.2), 193 (17.6), 158 (23.2), 130 (18.3), 119 (63.4), 93 (100.0), 77
(33.1), 64 (36.7). Anal. Calcd. for C14H9N3O4 (283.24): C, 59.37; H, 3.20; N, 14.84.
Found: C, 59.22; H, 3.01; N, 14.80%.
Full Experimental details, Tables, Figures, and Spectroscopic data can be found in
Supplemental files.
Acknowledgments
Technical support from the Chemistry Department, Faculty of Science, Ain Shams University is
gratefully acknowledged. Our special thanks are extended to Prof. Khaled A. M. Abouzid, from
Faculty of Pharmacy, the University of Sadat City for his guidance, moral supports, encourage-
ments, and valuable criticism.
Disclosure statement
The authors declare no conflict of interest.
ORCID
Sayed K. Ramadan
http://orcid.org/0000-0003-2743-6544
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