MoO2Cl2 catalyzed efficient synthesis of functionalized 3,4-dihydropyrimidin-2(1H)-ones/thiones and polyhydroquinolines: recyclability, fluorescence and biological studies

Article abstract of DOI:10.1039/c5nj02444g

A simple, facile and efficient synthesis of functionalized dihydropyrimidinones and polyhydroquinolines using molybdenum(vi) dichloride dioxide (MoO₂Cl₂) has been developed. The present protocol demonstrates the exceptional tolerance

Full text of DOI:10.1039/c5nj02444g

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MoO2Cl2 catalyzed efficient synthesis of
functionalized 3,4-dihydropyrimidin-2(1H)-ones/
thiones and polyhydroquinolines: recyclability,
fluorescence and biological studies†
Cite this:DOI: 10.1039/c5nj02444g
Sravanthi Devi Guggilapu,a Santosh Kumar Prajapti,a Atulya Nagarsenkar,a
Guntuku Lalita,b Ganga Modi Naidu Vegib and Bathini Nagendra Babu*a
A simple, facile and efficient synthesis of functionalized dihydropyrimidinones and polyhydroquinolines
using molybdenum(VI) dichloride dioxide (MoO2Cl2) has been developed. The present protocol demonstrates
the exceptional tolerance towards acid labile protecting groups such as tert-butyl dimethyl silyl (TBDMS) and
tert-butyl diphenyl silyl (TBDPS). This is the first report of exploring Lewis acid properties of MoO2Cl2 in the
diversity oriented synthesis of Biginelli and Hantzsch reactions. Biologically important and highly structured
conjugates of dihydropyrimidinone and polyhydroquinoline derivatives containing coumarin, pyrazole,
indole and triazole moieties were synthesized in good to excellent yields. Compound 4o exhibited blue
fluorescence at a maximum UV absorbance lmax of 326 nm. In the preliminary MTT [3-(4,5-dimethylthiazol-
2-yl)-2,5-diphenyltetrazolium bromide] assay, compound 4n displayed remarkable cytotoxic activity against
A549 and PC3 cell lines while compound 7q was found to be cytotoxic against HGC-27 and PC3 cancer
cell lines.
Received (in Montpellier, France)
11th September 2015,
Accepted 9th November 2015
DOI: 10.1039/c5nj02444g
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a-bromo 1,3-dicarbonyls,6a the formation of carbamates from
Introduction
alcohols and isocyanates.6b,c Multi-component reactions (MCRs)
Molybdenum coordination chemistry is one of the intriguing have emerged as an efficient and powerful tool in combinatorial
research areas due to the inevitable occurrence of Mo in the chemistry with the facile and rapid creation of several multiple
active sites of molybdoenzymes.1 Some of the potential applica- bonds in a one-pot reaction with minimal waste of time and
tions of molybdenum compounds such as corrosion inhibitors,2a energy.7 Transition-metal catalyzed organic transformations
lubricants,2a,b pigments,2c,d smoke suppressants,3a and fertilizers3b comply with the principles of ‘‘Green Chemistry’’ such as the
have also been reported. Moreover, recently, molybdenum(VI) minimization of waste, clean catalysts/reagents and minimum
dichloride dioxide (MoO2Cl2) has been gaining importance on use of energy. In recent decades, dihydropyrimidinones and poly-
account of its ease of availability, less toxicity, thermal stability hydroquinolines derivatives (Biginelli and Hantzsch products) are
and water tolerant nature.4a,b In addition, many research groups are the promising scaffolds that have gained importance in organic
exploiting the potential of MoO2Cl2 in modern organic synthesis.4c and medicinal chemistry owing to their pharmacological pro-
It has been widely used as an efficient catalyst for several organic perties. Dihydropyrimidinones exhibit a broad range of bio-
transformations such as the hydrosilylation of aldehydes and logical activities such as anticancer, calcium channel modulator,
ketones,5a the hydrophosphonylation of aldehydes,5b the reduction anti-hypertensive, anti-viral, anti-oxidant, anti-bacterial, anti-
of imines, esters, sulfoxides and pyridine N-oxides to the corres- inflammatory, neuropeptide Y (NPY) antagonist and a1a-adrenergic
ponding amines, alcohols, sulfides and pyridines respectively,5c,d antagonist.8 Polyhydroquinolines are often used as antitumor, vaso-
the epoxidation of double bonds, the oxidation of alcohols to dilator, hepatoprotective, antiatherosclerotic, geroprotective,
carbonyl compounds,5e the conversion of b-hydroxycarbonyls into antidiabetic, antiasthmatic, antibacterial, anti-inflammatory
and tyrosine kinase inhibitors.9–11 Very recently, coumarin-
a Department of Medicinal Chemistry, National Institute of Pharmaceutical
Education and Research, Balanagar, Hyderabad, 500037, India.
E-mail: bathini.niperhyd@gov.in; Fax: +91-40-23073751; Tel: +91-40-23073740
b Department of Pharmacology and Toxicology, National Institute of Pharmaceutical
Education and Research (NIPER), Balanagar, Hyderabad 500037, India
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c5nj02444g
dihydropyrimidinone hybrids have been reported to exhibit
fluorescent properties, which can be further utilized in the
synthesis of new biological and chemical probes.12
In view of the biological, industrial and synthetic importance
of polyhydroquinolines and dihydropyrimidinones, a plethora of
protocols and catalytic systems have been developed for these
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Scheme 1 MoO2Cl2 catalyzed synthesis of dihydropyrimidinone/thiones
and polyhydroquinolines.
significant organic transformations. However, the application of
non-noble metal complexes based on molybdenum (MoO2Cl2) as
a Lewis acid catalyst in the diversity oriented synthesis of dihydro-
pyrimidinones/thiones and polyhydroquinolines remains unex-
plored. To the best of our knowledge this is the first report of
using MoO2Cl2 as a homogenous catalyst in the synthesis of
dihydropyrimidinone/thione and polyhydroquinoline deriva-
tives via a Biginelli and Hantzsch reaction (Scheme 1).
Fig. 1 Different dihydropyrimidinone/thiones synthesized via a one-pot
three component Biginelli reaction.
95% yield in a short reaction time (Table 1, entry 4) and a
further increment in catalyst concentration does not affect the
reaction yield (Table 1, entry 5). Moreover, the catalytic effi-
ciency of MoO2Cl2 was examined using different solvents
(Table 1, entries 6–9). The yields and the reaction time required
depict that protic solvents (water, MeOH and EtOH) were more
preferable than aprotic solvents (acetonitrile, THF). Among the
protic solvents, EtOH gave the best results (Table 1, entry 4). A
control experiment in the absence of a catalyst resulted in
nominal yield which proves the emphasis on the importance
of a catalyst (Table 1, entry 10).
With the optimized reaction conditions in hand (Table 1,
entry 4), the generality and scope of the present one-pot, three-
component reaction was explored. The reaction with different
aromatic aldehydes containing electron donating and with-
drawing groups afforded excellent yields of 85–96% in 40 min
to 2 h (Fig. 1). Interestingly, substrates involving acid sensitive
protecting groups such as TBDMS and TBDPS afforded good
yields with the absence of deprotected side products (Fig. 1, 4k
and 4l). The present protocol was amenable to substituted
heterocyclic aldehydes such as coumarin, pyrazole and thiophene
where the reaction proceeded smoothly with excellent yields
(Fig. 1, 4m and 4n) except in the case of coumarin derivatives; a
moderate yield of 75% was obtained after 2 h (Fig. 1, 4o).
Similarly, thiopyrimidinones were also synthesized with high
yields (Fig. 1, 4g–4i and 4p).
Results and discussion
Synthesis of dihydropyrimidinones/thiones and
polyhydroquinolines
A Biginelli test reaction was performed involving a mixture of
benzaldehyde, ethyl acetoacetate, urea in the presence of
MoO2Cl2 (0.5 mol%) in EtOH at room temperature for 24 h
(Table 1, entry 1), and the dihydropyrimidinone product was
obtained in less yield due to the incomplete conversion of the
reactants, thus it was assumed that thermal energy may be
required to drive the reaction to completion. Furthermore, the
effect of variation in temperatures from 50 1C to reflux condi-
tions, along with an increase in catalyst concentrations were
studied (Table 1, entries 2–5). To our delight, it was observed
that 1 mol% of MoO2Cl2 in EtOH at reflux temperature afforded
Table 1 Optimization of reaction conditions for the synthesis of dihydro-
pyrimidinone 4aa
To test the feasibility of the reaction, a 5g scale synthesis
of monastrol (a specific inhibitor of mitotic kinesin Eg5)
was attempted. 3-Hydroxy benzaldehyde, ethyl acetoacetate,
thiourea were stirred under the optimized reaction conditions
and achieved monastrol in 89% yield with 97.99% purity (ESI†)
(Scheme 2).
MoO2Cl2
Entry (mol%)
Solvent Temperature (1C) Time (h) Yieldb (%)
1
2
3
4
5
6
7
8
9
10
0.5
0.5
0.5
1
2
1
1
1
1
—
EtOH
EtOH
EtOH
EtOH
EtOH
Water
MeOH
rt
50
Reflux
Reflux
Reflux
Reflux
Reflux
24
3
2
1
1
2
2
4
35
64
80
95
96
75
72
78
67
15
CH3CN Reflux
THF
Reflux
Reflux
6
12
EtOH
a
Reaction conditions: benzaldehyde (1a, 1 mmol), ethyl acetoacetate
b
Scheme 2 MoO2Cl2 catalyzed 5 g scale synthesis of monastrol.
(2a, 1 mmol), urea (3a, 1.5 mmol) in EtOH (10 mL). Isolated yield.
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Encouraged with the successful synthesis of dihydropyrimi- Triazole and indole containing substrates were also employed in
dinones/thiones, our attention was shifted towards the synthe- the synthesis of polyhydroquinolines and the desired products
sis of polyhydroquinolines. Polyhydroquinolines are generally were accomplished in excellent yields (Table 2, 7q, 7s). Large
synthesized via a Hantzsch reaction (a one-pot, four component scale synthesis of 7k (Table 2) was performed using benzaldehyde,
reaction) using aldehyde, dimedone, b-ketoester and ammo- ethyl acetoacetate, dimedone and ammonium acetate to obtain
nium acetate. Several protocols have been reported for the desired products with 85% yield.
synthesis of polyhydroquinolines13–19 but still emphasis on
the efficacy of the catalyst with high yields of products creates
Recyclability
requisite to explore newer methodologies. Fascinatingly, we From the economical point of view as well as environmental
found the potential utility of MoO2Cl2 in one-pot, four compo- concern, the recyclability of the MoO2Cl2 catalyst was tested
nent synthesis of polyhydroquinolines in admirable yields. upon the condensation of benzaldehyde, 1,3-cyclohexandione,
Various substituted aromatic and heteroaromatic aldehydes ethyl acetoacetate and ammonium acetate using 1 mol% of
(1 mmol) were treated with dimedone/1,3-cyclohexanedione MoO2Cl2 in EtOH (Table 2, entry 1).
(1 mmol), b-ketoesters (1 mmol), ammonium acetate (1.2 mmol)
After the completion of the reaction, EtOH was evaporated
in the presence of MoO2Cl2 (1 mol%) in EtOH at reflux and ethylacetate was added to the reaction mixture followed
temperature. Gratifyingly, the desired products (7a–s) were by usual aqueous workup. The aqueous layer was separated,
formed in 20–40 min with 80–94% yields as shown in Table 2. decanted, and dried to recover MoO2Cl2. Later, the recovered
Polyhydroquinolines with an acid labile protecting group MoO2Cl2 catalyst was reused for 5 consecutive cycles. The yields
(TBDMS) were synthesized in superior yields (Table 2, 7g, 7j). obtained after each run are depicted in Fig. 2.
Table 2 MoO2Cl2 catalyzed synthesis of polyhydroquinolinesa
Entry R1
R2
R3
H
H
H
Time (min) Pdt Yieldb (%) Entry R1
R2
R3
Time (min) Pdt Yieldb (%)
1
2
3
OEt
OEt
OEt
20
25
30
7a
7b
7c
94
88
86
11c
12
13
OEt Me 28
OEt Me 20
OEt Me 24
7k
7l
85
90
7m 89
4
5
6
OEt
OEt
OEt
H
H
H
32
25
30
7d
7e
7f
82
90
87
14
15
16
OEt Me 24
OEt Me 25
OEt Me 22
7n
7o
7p
90
93
91
7
8
9
OEt
OEt
H
H
32
40
7g
7h
7i
92
80
89
17
18
19
OEt Me 29
OEt Me 36
OEt Me 38
7q
7r
7s
85
82
80
OMe Me 23
OMe Me 30
10
7j
90
a
Reaction conditions: aldehyde (1 mmol), b-ketoester (1 mmol), 1,3-cyclohexadione/dimedone (1 mmol), ammonium acetate (1.2 mmol), EtOH
b
c
(10 mL), MoO2Cl2 (1 mol%), reflux. Isolated yield. Reaction performed on a 5 g scale.
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Fig. 2 Catalyst recyclability chart of compound 7a.
Scheme 4 Plausible mechanism for polyhydroquinoline formation using
MoO2Cl2.
Table 3 Fluorescence properties of coumarin derivatives
Absorbance lmax
(nm)
Emission lmax
(nm)
Stoke shift
(nm)
Compound
Umbelliferonea
4o
324
326
392
397
68
71
a
Scheme 3 Plausible mechanism for dihydropyrimidione formation using
Values were obtained from ref. 21.
MoO2Cl2.
A plausible mechanistic pathway for the synthesis of
dihydropyrimidinones/thiones is outlined in Scheme 3, which
is in similarity with the established mechanism as reported in
the literature.20 The one-pot Biginelli reaction may be initiated
with the reaction of aldehyde and urea followed by condensa-
tion activated by the co-ordination of MoO2Cl2 resulting in the
formation of acyl imine intermediate 8, a rate limiting step.
Further, the iminium intermediate 9 undergoes nucleophilic
attack by the b-dicarbonyl ester enolate to produce open chain
intermediate ureide 11, followed by cyclization and subsequent
loss of water to afford dihydropyrimidinone 4a.
A plausible mechanism for the MoO2Cl2 mediated Hantzsch
reaction towards the synthesis of polyhydroquinoline is also
proposed. First, aldehyde is activated by MoO2Cl2 and dimedone in
enol form reacts in the Knoevenagel fashion to give intermediate
13. On the other hand, the MoO2Cl2 activated b-ketoester and
ammonium acetate afford enamine 14. Then, intermediate 13 and
enamine 14 undergo a Michael reaction followed by intramolecular
condensation to produce 7 (Scheme 4).
Fig. 3 (A) Normalized UV-vis spectra of MeOH. (B) Normalized fluores-
cence emission spectra of MeOH with excitation on lmax of the com-
pound. All spectra were recorded at a concentration of 30 mm in MeOH.
(C) Blue fluorescence of compound 4o was observed at lmax 326 nm.
Spectroscopic properties of compound (4o)
Further, we measured the absorbance and emission maxima of
umbelliferone and coumarin-dihydropyrimidinone derivatives
(4o) in methanol at 30 mm concentration (Table 3). The fluo-
rescent emission spectrum of compound 4o was quite similar
to umbelliferone with a Stokes shift of 71 nm. Blue fluorescence
Biological evaluation
In vitro evaluation. Among all the synthesized compounds
was observed when 4o was irradiated at maximum UV absor- 4m, 4n, 4o, 7q and 7s were found to be diverse and highly
bance lmax 326 nm (Fig. 3). This result could be an inception to functionalized molecules. Similar scaffolds have been reported
utilize the properties of compound 4o in further development earlier for their potent biological activities.22 This prompted
of the chemical probes.
us to further examine the in vitro cytotoxic potential of
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Table 4 In vitro anticancer activity (IC50 mM)
General procedure for the synthesis of dihydropyrimidi-
nones/thiones from substituted benzaldehydes (Fig. 1, 4a–p).
A mixture of aldehyde 1 (1 mmol), methyl/ethyl acetoacetate 2
(1 mmol), and urea/thiourea 3 (1.5 mmol) in EtOH (10 mL) was
refluxed in the presence of MoO2Cl2 (1 mol%). After the
completion of the reaction, as indicated by TLC analysis, the
solvent was evaporated. The resulting mass was extracted with
ethyl acetate (3 Â 10 mL) followed by the treatment of brine.
The combined organic layers were evaporated and dried over
anhydrous Na2SO4. Recrystallization using ethanol was performed
S. No. Compound A549
HGC-27
NA
PC3
NA
BT 549
NA
1
2
3
4
5
4m
4n
4o
7q
7s
NA
10.4 Æ 1.7 22.1 Æ 2.2 19.3 Æ 1.3 26.8 Æ 2.7
31.3 Æ 0.9 36.4 Æ 1.3 36.3 Æ 1.2 20.5 Æ 0.7
28.6 Æ 2.6 15.6 Æ 2.4 19.4 Æ 1.6 NA
NA
NA
NA
NA
NA: not active.
aforementioned compounds. These compounds were evaluated to give pure product 4.
against four cancer cell lines namely, A549 (lung cancer), HGC-27
General procedure for the synthesis of polyhydroquinolines
(gastric cancer) and PC3 (prostate cancer), BT-549 (breast cancer) from substituted benzaldehydes (Table 2, 7a–t). To a mixture of
by employing the MTT assay. Concentration response course aldehyde 1 (1 mmol), methyl/ethyl acetoacetate 2 (1 mmol), and
analysis was performed to determine drug concentrations 1,3-cyclohexanedione/dimedone 5 (1 mmol), NH4OAc 6 (1.2 mmol)
required to inhibit the growth of cancer cells by 50% (IC50
)
in EtOH (10 mL) was refluxed in the presence of MoO2Cl2
after incubation for 48 h. The results of in vitro anticancer (1 mol%). After the completion of the reaction, the contents
activity revealed that compound (4n) showed IC50 of 10.4 mM were extracted with EtOAc (3 Â 10 mL). The combined organic
against A549 and 19.3 mM for PC3 cancer cell lines. Compound layers were washed with brine, water, dried over anhydrous
7q showed IC50 of 15.6 mM against HGC-27 and 19.4 mM for PC3 Na2SO4. The solvent was evaporated and the crude product was
cancer cell lines (Table 4). These preliminary results indicate purified by silica gel column chromatography (EtOAc : hexane)
that compounds 4n and 7q could be the potential leads for the as an eluent to give desired product 7.
development of novel anticancer agents.
Acknowledgements
Conclusion
The authors thank Department of Pharmaceuticals, Ministry of
An efficient and operationally simple protocol was developed Chemicals and Fertilizers (Govt. of India) for providing funds.
for the synthesis of dihydropyrimidinones and polyhydroquino-
lines. The MoO2Cl2 catalyst offers striking advantages such as
less-toxicity, water-tolerance, thermal-stability, and most impor-
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