The diisopropyl ethyl ammonium acetate (DIPEAc)-promoted Biginelli protocol has been developed for the first time by a successive one-pot three-component reaction of aldehydes, ethylcyanoacetate/ethyl acetoacetate, and thiourea/urea to afford pharmacologically promising 1,2,3,4-tetrahydropyrimidines in high yields at room temperature. The key benefits of the present scheme are the capability to allow a variability of functional groups, short reaction times, easy workup, high yields, recyclability of the catalyst, and solvent-free conditions, thus providing economic and environmental advantages. In addition, a series of 4-oxo-6-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitriles analogues were synthesized and selected for their in vitro antifungal and antibacterial activities.
The diisopropyl ethyl ammonium acetate (DIPEAc)-promoted Biginelli protocol has been developed for the first time by a successive one-pot three-component reaction of aldehydes, ethylcyanoacetate/ethyl acetoacetate, and thiourea/urea to afford pharmacologically promising 1,2,3,4-tetrahydropyrimidines in high yields at room temperature. The key benefits of the present scheme are the capability to allow a variability of functional groups, short reaction times, easy workup, high yields, recyclability of the catalyst, and solvent-free conditions, thus providing economic and environmental advantages. In addition, a series of 4-oxo-6-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitriles analogues were synthesized and selected for their in vitro antifungal and antibacterial activities.
Room-temperature ionic liquids (RTILs)
have taken the attention
of the chemical community all over the globe as a green alternative
option to traditional ecofriendly media for catalysis, synthesis,
separation, and other several chemical tasks.[1−7] RTILs include numerous exclusive properties, such as extensive liquid
range, nonvolatility, low toxicity, high thermal stability, noncombustible,
excellent solubility, and recyclability.[8] RTILs act as “neoteric solvents” for a wide range
of industrial and chemical processes. In recent times, RTILs have
been originating to be valuable as environmental friendly media for
multitudinous organic revolutions.[9,10] On the other
hand, multicomponent reactions (MCRs) are one of the more dominant
and practical tackles in organic synthesis for the creation of pharmacologically
relevant frameworks from the point of view of green chemistry. MCRs
give benefits of atom economy, high yields, flexibility, target specificity,
and especially one-pot operation;[11−13] the discrimination and
returns of the MCRs are significantly affected by the choice of an
appropriate catalyst. Thus, the introduction of a dynamic, inexpensive,
mild, and environmental friendly catalyst for significant MCRs superior
to analogues of pharmaceutical and biological prominence is in demand.
In this paper, we have validated DIPEAc as ionic liquid catalyzed the efficient synthesis
of 4-oxo-6-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile
analogues via one-pot multicomponent reactions under ecofriendly reaction
conditions (Schemes and 2).
Scheme 1
Synthesis of 4-Oxo-6-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile
(4a) by Using DIPEAc as RTIL
Scheme 2
Synthesis of Diisopropylethylammonium Acetate (DIPEAc)
The pyrimidine moiety is an essential part of
RNA and DNA, providing
various biological properties such as potent fungicide and bactericide.[14] Some pyrimidine analogues are also known to
acquire anticancer,[15] antimalarial,[16] antiviral,[17] antibacterial,[18,19] antifungal,[20,21] anticonvulsant,[22] and antihistamine[23] activities.
Certain 3,4-dihydropyrimidines have developed as essential props of
numerous calcium antihypertensive agents, adrenergic, channel blockers,
and neuropeptide antagonists.[24] A number
of natural marine products accommodate the 3,4-dihydropyrimidine nucleus,
described in the literature for remarkable anti-HIV alkaloid batzelladine
B activities (Figure ).[25,26]
Figure 1
Pyrimidine-incorporated bioactive molecules.
Thus, the enlargement of synthetic
strategies for the creation
of this molecule using an inexpensive, reusable, mild, and nontoxic
catalyst is of enormous significance from the industrial and academic
points of view. Even though various modes have been reported in the
literature, the Biginelli MCR is moderately versatile because it can
be implemented with numerous chemical takes in all three key components
(i.e., aldehyde, β-ketoester, and thiourea or urea) paramount
to a manifold of thiones/dihydropyrimidinones.[27] These reactions can be accomplished under a variability
of tentative conditions, and several improvements have been reported
in recent years, such as p-TsOH·H2O,[28] H3BO3,[29] [Al(H2O)6](BF4)3,[30] thiamine hydrochloride,[31] imidazole-1-yl-acetic acid,[32] l-(+)-tartaric acid-dimethylurea,[32] HClO4–SiO2,[33,34] SnCl2·2H2O,[35] polymer-supported benzimidazolium-based ionic liquid,[36] basic IL,[37] Al-plante
MCM-41,[38] (NH4)2CO3,[39] CeCl3·7H2O,[40] CaCl2,[39] Ce(NH4)2(NO3)6polyvinylsulfonic acid,[34] and Fe(OTs)3·6H2O.[41] However, numerous of these testified methods become infected
with several disadvantages such as strong acidic conditions, use of
hazardous or costly reagents, long reaction times, low yields of products,
and sophisticated treatment. Moreover, many of these schemes utilize
organic solvents as the reaction medium. Hence, innovative, competent,
and ecofriendly procedures are still powerfully needed to generate
pharmacologically active molecules.As per our investigation, the existential of this work is to begin a rapid and efficient
Biginelli multicomponent synthetic protocol for obtaining 1,2,3,4-tetrahydropyrimidines
under ecofriendly conditions. As an extension of emerging economic
and efficient MCR strategy to develop pharmaceutically and biologically
significant molecules,[42] herein, we reported
a first-time three-component method in DIPEAc at room temperature
to access a library of 1,2,3,4-tetrahydropyrimidine in good to excellent
yields.
Results and Discussion
Chemistry
To achieve optimized conditions for the Biginelli
protocol based on the reaction of benzaldehyde (1a) (3
mmol), ethylcyanoacetate (2) (3 mmol), and thiourea (3) (3.2 mmol) as model substrates, we checked altered catalysts,
temperatures, and solvents, and the results of this study are summarized
in Table . It was
found that when the reaction was carried out in the nonappearance
of the catalyst in ethanol, no product was perceived, even after 9
h (Table , entry 1).
To obtain the preferred product (4a), we tested the reaction
using different catalysts such as Cs2CO3, p-TSA, β-CD, CTAB, SDS, ChCl:2urea, ChCl:2ZnCl2, PEG-400, DIPEAc, and dicationic ionic liquid (Table , entries 2–11). Thus,
room-temperature DIPEAc as the pre-eminent catalyst was tested for
this reaction. In the presence of DIPEAc, compound 4a was isolated in 93% yield after only 45 min at room temperature.
The model reaction in water using phase transfer catalysts is found
to be sluggish and formed the desired 4a in less yields.
Therefore, it can be thought that DIPEAc is green and a superior solvent
and catalyst compared to the others shown in Table .
Table 1
Efficiency Comparison of Various Catalysts
for the Synthesis of 4-Oxo-6-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile
(4a)a
entry
catalyst
medium
time
yieldb (%)/time (h)
1
EtOH
9 h
trace
2
Cs2CO3
EtOH
7 h
61
3
p-TSA
H2O
7 h
68
4
β-CD
H2O
6 h
65
5
CTAB
H2O
6 h
59
6
SDS
H2O
6 h
52
7
ChCl:2urea
ChCl:2urea
2 h
80
8
ChCl:2ZnCl2
ChCl:2ZnCl2
3 h
76
9
PEG-400
PEG-400
6 h
74
10
DIPEAc
DIPEAc
45 min
94
11
dicationic ionic liquid
dicationic ionic liquid
7 h
73
Reaction conditions: aldehyde (3
mmol), ethylcyanoacetate (3 mmol), thiourea (3.2 mmol) in medium (5
mL), stirred at room temperature.
Isolated yields b: no condensation.
Bold values are for highlighting the good result.
Reaction conditions: aldehyde (3
mmol), ethylcyanoacetate (3 mmol), thiourea (3.2 mmol) in medium (5
mL), stirred at room temperature.Isolated yields b: no condensation.
Bold values are for highlighting the good result.The amount of the catalyst is another critical parameter
in terms
of reaction efficiency. To confirm the amount of the DIPEAc, the model
reaction was examined by a set of experiments by the varying amounts
from 1 to 5 mL; as the amount of DIPEAc increases gradually, a steady
increase was observed in the product yield. DIPEAc (4 mL) furnishes 4a in 96% yield at room temperature (Table , entries 1). Further increase in the amount
of DIPEAc does not increase in the yield of the product. The model
reaction was carried out without any catalyst and solvent; the trace
amount of the product was achieved after a long period (Table , entry 1). Further, the efficiency
of DIPEAc was checked by using 20 mol % DIPEAc in various solvents
(Table , entries 7–12).
In ethanol, the reaction takes place smoothly with high yield. While
in water, MeOH, acetonitrile, DCM, CH2Cl2, and
DMF reaction proceeds with lower yields at reflux temperature. None
of the solvents exist the advantage of time and yield over the solvent-free
condition. Hence, the solvent-free condition was regarded as the finest
for the cost and environmental suitability.
Table 2
Solvent Effects on the Reaction of
Aldehyde, Ethylcyanoacetate, and Thiourea for the Synthesis of 4-Oxo-6-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile
(4a)a
entry
DIPEAc
temp. (°C)
solvent
time (min)
yield (%)b
1
0
RT
24h
trace
2
1 mL
RT
45
60
3
2 mL
RT
45
75
4
3 mL
RT
45
80
5
4 mL
RT
45
96
6
5 mL
RT
45
95
7
20 mol %
reflux
H2O
320
75
8
20 mol %
reflux
EtOH
320
80
9
20 mol %
reflux
MeOH
320
75
10
20 mol %
reflux
CH3CN
320
55
11
20 mol %
reflux
CH2Cl2
320
52
12
20 mol %
reflux
DMF
320
50
Reaction conditions: aldehyde (3
mmol), ethylcyanoacetate (3 mmol),thiourea (3.2 mmol) in solvent (5
mL), stirred at room temp.
Isolated yields. Bold values are
for highlighting the good result.
Reaction conditions: aldehyde (3
mmol), ethylcyanoacetate (3 mmol),thiourea (3.2 mmol) in solvent (5
mL), stirred at room temp.Isolated yields. Bold values are
for highlighting the good result.In summary, the highest efficiency and fastest reaction
time for
the model Biginelli reaction was observed at room temperature by using
4 mL of DIPEAc. Having ideal conditions in hand, the adaptability
of the protocol was examined for the construction of 4-oxo-6-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitriles
(4a–v). Various substituents on aldehyde including
methyl, methoxy, cyano, nitro, halogen (−Cl, −F, −Br),
and hydroxyl moieties were used. The results of all reactions performed
under these conditions are shown in Table . Aldehyde containing electron-donating groups
such as −Me, −OMe, and electron-withdrawing group such
as −NO2 on the aromatic ring was compatible with
this transformation, and corresponding 4-oxo-6-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitriles
(4a–v) were obtained in good to high yields. To
our enchantment, halogen-substituted 2-benzylidene malononitrile gave
the products with high yields (4g, 4h, and 4l). Moreover, sterically crowded di- and trisubstituted benzaldehyde
provided the desired products in high yields (4i, 4j, and 4r). The heteroaryl aldehydes and aliphatic
aldehydes also keep well under the present reaction conditions without
any difficulties (4m, 4t, and 4w–4zz).
Table 3
Recycling of DIPEAc (IL) for The Synthesis
of Compounds 4a and 4aaa
run
catalyst recovery
product yield (%)
1
96
96
2
92
93
3
91
90
4
90
89
5
80
78
Reaction conditions: aldehyde (3
mmol), ethylcyanoacetate (3 mmol),thiourea/urea(3.2 mmol) in solvent
(4 mL), stirred at room temp. Bold values are for highlighting the
good result.
Reaction conditions: aldehyde (3
mmol), ethylcyanoacetate (3 mmol),thiourea/urea(3.2 mmol) in solvent
(4 mL), stirred at room temp. Bold values are for highlighting the
good result.For assessing the generality of optimized reaction
conditions,
we considered the scope of the reaction by the cyclocondensation of
aldehydes, ethyl acetoacetate, and urea/thiourea in DIPEAc at room
temperature. DIPEAc also acts as an efficient promoter to catalyze
the synthesis of ethyl 6-methyl-4-(4-substitutedphenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
in high yields (Table , entries 21–30).The Biginelli formation of 1,2,3,4-tetrahydropyrimidine
derivatives
has been confirmed by spectroscopic techniques and physical data such
as IR, 1H NMR, 13CNMR, and liquid chromatography–mass
spectrometry (LCMS). According to the 1H NMR spectrum
of representative compound 4a, the characteristic two
singlet’s at 11.71 and 8.96 for two protons of −NH group
present in pyrimidine ring, 7.52–7.56 ppm and a doublet at
7.78–7.81 four protons present in phenyl ring confirmed the 4a. 13CNMR spectral data, in which the carbon
signals of −SCH2 and −NCH2 groups,
were resonated at 183.29 and 183.53 ppm, respectively. The signals
at 166.22 point out the presence of the carbonyl carbon atom, while
all further carbons gave peaks at expected values. Again, the construction
of compound 4a was confirmed by LCMS: m/z [M + Na]+. The calculated m/z for compound 4a C11H7N3OSNa+ is 252.2 and observed
at 252.2 [M + Na]+.Pyrimidine-incorporated bioactive molecules.
Recycling of the Catalyst
Effectual reusability and
recovery of the ionic liquid are other significant features of our
proposed protocol. We check the reusability of the catalyst. The reaction
was performed between aldehyde, ethylcyanoacetate, and thiourea under
the optimized reaction conditions. DIPEAc was disconnected from the
reaction mixture by the following procedure. After completion of the
reaction, the reaction mixture was cooled to room temperature, and
then, water and ethyl acetate were added. The product (4a) was extracted with ethyl acetate. As the DIPEAc is highly water-soluble,
it goes into the aqueous layer. Evaporation of the aqueous layer under
reduced pressure provided the catalyst (DIPEAc). Recyclability graph
of catalytic efficiency of DIPEAc was tested for four consecutive
cycles; the isolated yields were almost alike until the fourth recycling
(Figure ), but a reduction
in the catalytic activity of DIPEAc was observed after the fifth cycle;
the outcomes are summarized in Table . Furthermore, in order to explore the stability of
DIPEAc during four consecutive runs, the IR spectra of the recovered
DIPEAc (after four cycles) were matched with those of the fresh sample.
As documented in Figure , the IR spectra displayed by the recovered
catalyst were found to be almost similar to the fresh one.
Figure 2
Reuse and recovery
of DIPEAc and its effect on yield.
Figure 3
IR spectrum of reuse and recovery of DIPEAc (pink spectrum:
fresh;
green spectrum: after IV recycles).
Reuse and recovery
of DIPEAc and its effect on yield.IR spectrum of reuse and recovery of DIPEAc (pink spectrum:
fresh;
green spectrum: after IV recycles).Structure–activity relationship of hybrid compounds.
Plausible Reaction Mechanism
To explain the mechanism
of this one-pot three-component cyclocondensation leading to 1,2,3,4-tetrahydropyrimidine
is accredited to the exclusive role of DIPEAc as a medium. It has
the capacity to dissolve a number of inorganic/organic solutes readily.
This might sensibly maintain the high concentrations of the reactants
while initiating the reaction and even the progress of the reaction.
Hence high to saturate the solutions of the reactants in the reaction
mass would be responsible for degree acceleration of Biginelli reaction.The stronger hydrogen bonding capability of DIPEAc and the motives
for this could be elucidated as follows: (1) The use of DIPEAc elevated
the solubility of reactants, which leads to superior interfacial area
and lower mass transfer resistance.[43] (2)
The stimulating effects of DIPEAc to the reaction could be endorsed
to its polarity, hydrobonding, and hydrophobic effects.[44] Hydrophobic effect: The hydrophobic effect leads
to extraordinary negative volume of initiation which means better
stabilization of activated complexes than hydrophobic reactants in
the reaction. Polarity effect: The high polarity of
DIPEAc outcomes in the extra polar interpreted states than primary
states, so the reaction promptness can be improved. Hydrogen-bonding
effect: DIPEAc could initiate the reactants and intermediate products
by forming the hydrogen bonds with the hydroxyl oxygen and carbonyl
oxygen, respectively (Schemes and 4), constructing them easy to form consistent products. It
was assumed that only polar protic solvents could give the preferred
product, and the hydrogen-bonding effect is the core difference between
polar protic solvents and other solvents, so the hydrogen-bonding
effect may be the important factor to promote the reaction. Then,
it might improve the electrophilic character of carbonyl carbon of
the reactants, namely, aldehyde and intermediate. It also increases
the rate of in situ formation of catenation from ethylcyanoacetate/ethyl
acetoacetate. They may be causing the rate of acceleration resulting
in high yields of the 1,2,3,4-tetrahydropyrimidine, subsidiary the
role of DIPEAc in a rate enhancement. The proposed mechanism has gone
through the Knoevenagel condensation followed by Michael addition
and then intermolecular cyclization that is presented in Scheme .
Scheme 3
Synthesis of 4-Oxo-6-aryl-2-thioxo-1,2,3,4-Tetrahydropyrimidine-5-carbonitriles
(4a–z) by Using DIPEAc as RTIL
Reaction conditions:
Aldehydes
(1a–z) (3 mmol), ethylcyanoacetate/ethyl acetoacetate
(3 mmol), and thiourea/urea (3.2 mmol) in DIPEAc (4 mL) stirred at
room temp;
isolated yields,
melting points are in good
contact with those reported in the literature.[36,50,51]
Scheme 4
Synthesis of Ethyl 6-Methyl-2-oxo-4-aryl-1,2,3,4-tetrahydropyrimidine-5-carboxylates
(4aa–nn) by Using DIPEAc as RTIL
Synthesis of 4-Oxo-6-aryl-2-thioxo-1,2,3,4-Tetrahydropyrimidine-5-carbonitriles
(4a–z) by Using DIPEAc as RTIL
Reaction conditions:
Aldehydes
(1a–z) (3 mmol), ethylcyanoacetate/ethyl acetoacetate
(3 mmol), and thiourea/urea (3.2 mmol) in DIPEAc (4 mL) stirred at
room temp;isolated yields,melting points are in good
contact with those reported in the literature.[36,50,51]
Antimicrobial Screening
Twenty analogues of 4-oxo-6-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitriles
(4a–t) were evaluated against four bacterial Streptococcus pyogenes, Escherichia
coli,S. aureus, and Pseudomonas aeruginosa, and two fungal C. Albicans and Aspergillus niger strains. Ampicillin, rifampicin, and rifapentine were described
to have enormously highly antibacterial activities[45] in the middle of these three antibacterial standard drugs;
ampicillin was used as an antibacterial standard to match with the
synthesized compounds (4a–t). The results of antifungal
and antibacterial screening were summarized in Table . The results exposed that maximum of the
compounds have shown adequate to superb inhibitory activity against
the three tested bacteria. The electronic property of the compounds
has an adjacent correlation with their biological activity.[46] Compounds 4e, 4f,
and 4i showed decent antibacterial activity against all
four bacterial pathogens because of the presence of withdrawing groups
(−NO2 and −CF3) and electron-donating
groups (−OH and −OCH3) in the molecule (Figure ). Compound 4f showed good antibacterial activity against the Gram-positive
strains, P. aeruginosa, E. coli, Staphylococcus aureus, and S. pyogenes. We imagine that
the presence of −OH and −OCH3 moieties in
the molecule could contribute significantly to the antibacterial activities.
Compound 4e and 4i showed decent antibacterial
activity against P. aeruginosa and E. coli and less activity against S. aureus. Compounds 4e, 4f, 4i, and 4n showed decent antibacterial activity against all bacterial strains
(Schemes and 5).
Table 4
Antimicrobial Screening of 4-Oxo-6-aryl-2-thioxo-1,2,3,4-Tetrahydropyrimidine-5-carbonitriles
(4a–t)a
minimum
inhibitory concentration (MIC) in μg/mL
compound
E. c. MTCC (443)
P. a. MTCC (1688)
S. a. MTCC (96)
S. p. MTCC (442)
C. a. MTCC (227)
A. n. MTCC (282)
4a
500
100
250
250
100
500
4b
250
500
500
100
500
100
4c
100
100
100
100
500
250
4d
100
200
250
250
500
100
4e
50
25
500
50
500
250
4f
50
12.5
25
250
100
250
4g
500
100
500
250
250
500
4h
100
100
200
250
100
100
4i
12.5
25
100
50
500
250
4j
100
500
100
100
100
25
4k
500
500
500
250
12.5
50
4l
500
250
500
250
50
100
4m
100
100
250
50
50
100
4n
25
100
250
100
500
250
4o
50
100
100
100
500
250
4p
100
200
100
250
500
200
4q
200
100
250
200
100
100
4r
500
200
200
250
100
250
4s
250
500
100
500
250
100
4t
50
50
200
200
250
100
ampicillin
100
100
250
100
griseofulvin
500
100
E. c., Escherichia coli; P. a., Pseudomonas aeruginosa; S. a.,Staphylococcus aureus; S. p., Streptococcus pyogenes; C.a., Candida albicans; A. n., Aspergillus niger.
Figure 4
Structure–activity relationship of hybrid compounds.
Synthesis of Ethyl 6-Methyl-2-oxo-4-aryl-1,2,3,4-tetrahydropyrimidine-5-carboxylates
(4aa–nn) by Using DIPEAc as RTIL
Reaction conditions:
aldehyde
(1aa–nn) (3 mmol), ethylcyanoacetate/ethyl acetoacetate
(3 mmol), thiourea/urea (3.2 mmol) in DIPEAc (4 mL), stirred at room
temp;isolated yields,melting points are in good
contact with those reported in the literature.[36,50,51]E. c., Escherichia coli; P. a., Pseudomonas aeruginosa; S. a.,Staphylococcus aureus; S. p., Streptococcus pyogenes; C.a., Candida albicans; A. n., Aspergillus niger.Compounds 4-oxo-6-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitriles
(4a–t) were also screened for their in vitro antifungal
activity against two fungal strains such as A. niger and Candida albicans by using the
microdilution method.[47] The results of
antifungal screening were summarized in Table . Antifungal screening results revealed that
several compounds showed excellent inhibition against the tested fungal
strains compared to standard drug griseofulvin. Compounds 4j, 4k, and 4m showed potent activities against
all of the tested fungal strains. It may be because of the presence
of the active pyrimidine ring and electron-donating and electron-withdrawing
groups on the phenyl ring and presence of thiophene.
Conclusions
In conclusion, an environmentally and highly
efficient green methodology
has been established for the synthesis of functionalized 1,2,3,4-tetrahydropyrimidine
derivatives using an inexpensive and recoverable room-temperature
DIPEAc catalytic solvent-free system. This, to the best of our knowledge,
has no examples. This reaction scheme exposes a number of advantages,
such as uniqueness, high atom efficiency, mild reaction conditions,
clean reaction profiles, easy workup procedure, and ecofriendliness.
Furthermore, the prevention of hazardous organic solvents during the
entire procedure (synthesis, ionic liquid preparation, and workup
procedure) makes it a convenient and attractive method for the synthesis
of these important compounds. In addition, a series of 4-oxo-6-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitriles
analogs were screened for their in vitro antifungal and antibacterial
activities. The consequences exposed that compounds 4e, 4f, and 4i presented better antibacterial
potency which is equal to the reference drug ampicillin. Compounds 4j, 4k, and 4m were originated to
be decent antifungal activity matched to the standard drug griseofulvin.
Experimental Section
Materials and Methods
All of the reagents used were
of laboratory grade. Melting points of all of the synthesized analogues
were resolute in an open capillary tube and are uncorrected. The progress
of the reaction was monitored by thin-layer chromatography on Merck’s
silica plates, and imagining was accomplished by iodine/ultraviolet
light. IR spectra were acquired on a Bruker ALPHA (Eco-ATR) spectrometer. 1H NMR spectra were recorded with a Bruker AvIII HD-400 MHz
spectrometer operating at 400 MHz using DMSO solvent and tetramethylsilane
(TMS) as the internal standard and chemical shift in δ ppm.
Mass spectra were recorded on a Waters UPLCTQD (ESI-MS and APCI-MS)
instrument, and elemental analysis was recorded on the CHNS auto-analyzer
(Thermo Fischer EA1112 SERIES). Chemical shifts (δ) are reported
in parts per million using TMS as an internal standard. The splitting
pattern abbreviations are designed as singlet (s); doublet (d); double
doublet (dd); bs (broad singlet), triplet (t); quartet (q); and multiplets
(m).
Preparation of DIPEAc
General Procedure for the Synthesis of Diisopropylethylammonium
Acetate (DIPEAc)
A mixture of N,N-diisopropylethylamine (3 mmol) and acetic acid (3 mmol)
was stirred at 0–10 °C for 20 min. The viscous liquid,
diisopropylethylammonium acetate, was achieved.[48,49]
General Procedure for Synthesis of 4-Oxo-6-phenyl-2-thioxo-1,2,3,4-(tetrahydropyrimidine-5-carbonitrile)
A mixture of aldehyde (1a) (1 mmol), ethylcyanoacetate/ethyl acetoacetate
(2) (1 mmol), and thiourea/urea (3) (1.2 mmol) in DIPEAc (4 mL) was
stirred at room temperature; the evolution of reaction was supervised
by thin-layer chromatography [ethyl acetate/N-hexane
(3:7)] as a solvent after a stirring reaction mixture was cooled for
45 min and a poured on crushed ice. Thus, acquired solid was filtered,
dried, and purified by crystallization using ethanol as a solvent.
The result is summarized in Table . The synthesis compound is confirmed by mp, IR, NMR,
and mass spectra.
Authors: Gao-Feng Zha; Jing Leng; N Darshini; T Shubhavathi; H K Vivek; Abdullah M Asiri; Hadi M Marwani; K P Rakesh; N Mallesha; Hua-Li Qin Journal: Bioorg Med Chem Lett Date: 2017-05-13 Impact factor: 2.823
Authors: Lingala Suresh; Y Poornachandra; S Kanakaraju; C Ganesh Kumar; G V P Chandramouli Journal: Org Biomol Chem Date: 2015-06-09 Impact factor: 3.876
Authors: Francisco Sánchez-Sancho; Marcos Escolano; Daniel Gaviña; Aurelio G Csáky; María Sánchez-Roselló; Santiago Díaz-Oltra; Carlos Del Pozo Journal: Pharmaceuticals (Basel) Date: 2022-07-30
Scheme 1
Scheme 2
Figure 1
Figure 2
Figure 3
Scheme 3
Scheme 4
Scheme 5
Figure 4