Choline Chloride Based Deep Eutectic Solvents as a Tuneable Medium for Synthesis of Coumarinyl 1,2,4-Triazoles: Effect of Solvent Type and Temperature

Article abstract of DOI:10.1002/ejoc.201900249

A study of 1,2,4-triazole synthesis from 2-((4-methyl-2-oxo-2H-chromen-7-yl)oxy)acetohydrazide (1) or 2-(7-hydroxy-2-oxo-2H-chromen-4-yl)acetohydrazide (2) and various isothiocyanates, in deep eutectic solvents, was performed. In order to find the best conditions for 1,2,4-triazole formation, a model reaction on 1 and phenylisothiocyanate was performed in 14 different choline chloride based deep eutectic solvents, at two different temperatures (40 °C and 80 °C). Pure 1,2,4-triazoles were obtained in choline chloride/urea (1:2) and choline chloride/N-methyl urea (1:3) deep eutectic solvents at 80 °C. Pure thiosemicarbazides were obtained in choline chloride/ethane-1,2-diol (1:2), choline chloride/malic acid (1:1), choline chloride/malonic acid (1:1), choline chloride/butane-1,4-diol (1:3) and choline chloride/glycerole (1:2) at 40 °C. The ratio of 1,2,4-triazoles and thiosemicarbazides in reaction mixtures was determined by HPLC and ¹H NMR. After the best conditions for 1,2,4-triazole synthesis were found, some coumarinyl 1,2,4-triazoles were synthesized from two different coumarinyl hydrazides (1 and 2) and various alkyl and aryl isothiocyanates in one step reaction.

Full text of DOI:10.1002/ejoc.201900249

A Journal of
Accepted Article
Title: Choline chloride based deep eutectic solvents as a tuneable
media for synthesis of coumarinyl 1,2,4-triazoles: effect of solvent
type and temperature
Authors: MAJA MOLNAR, Ivana Periš, and Mario Komar
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10.1002/ejoc.201900249
European Journal of Organic Chemistry
FULL PAPER
Choline chloride based deep eutectic solvents as a tuneable
media for synthesis of coumarinyl 1,2,4-triazoles: effect of
solvent type and temperature
Maja Molnar,[a] Ivana Periš,[b] and Mario Komar*[a]
Abstract: A study of 1,2,4-triazole synthesis from 2-((4-methyl-2-oxo-
2H-chromen-7-yl)oxy)acetohydrazide (1) or 2-(7-hydroxy-2-oxo-2H-
chromen-4-yl)acetohydrazide (2) and various isothiocyanates, in
deep eutectic solvents, was performed. In order to find the best
conditions for 1,2,4-triazole formation, a model reaction on 1 and
phenylisothiocyanate was performed in 14 different choline chloride
based deep eutectic solvents, at two different temperatures (40°C and
80°C). Pure 1,2,4-triazoles were obtained in choline chloride:urea
(1:2) and choline chloride:N-methyl urea (1:3) deep eutectic solvents
at 80°C. Pure thiosemicarbazides were obtained in choline
chloride:ethane-1,2-diol (1:2), choline chloride:malic acid (1:1),
choline chloride:malonic acid (1:1), choline chloride:butane-1,4-diol
(1:3) and choline chloride:glycerole (1:2) at 40°C. The ratio of 1,2,4-
triazoles and thiosemicarbazides in reaction mixtures was determined
by HPLC and 1H NMR. After the best conditions for 1,2,4-triazole
synthesis were found, a some coumarinyl 1,2,4-triazoles were
synthesized from two different coumarinyl hydrazides (1 and 2) and
various alkyl and aryl isothiocyanates in one step reaction.
Triazoles are biologically active five-membered nitrogen
containing heterocyclic compounds, which can exist in two
isomeric forms (Scheme 1), 1,2,3-triazole and 1,2,4-triazole,
exhibiting tautomerism depending on the hydrogen atom
position.[15–17]
Scheme 1. Triazole isomers.
Introduction
1,2,4-Triazoles are proven to act as antibacterials,[18]
antifungals,[19] antitumor agents,[20] as well as anticonvulsant,
antiinflammatory and antimicrobial agents.[21] Some commercially
available drugs, like estazolam, anastrazole, ribavirin and
triazolam, contain 1,2,4-triazole ring in their structures.[17] Some
coumarinyl triazoles, like compound 4b synthesized within this
research, have already proven to possess a good antimicrobial
activity against Klebsiella pneumonia and Aspergillus
fumigates.[22]
1,2,4-Triazoles are often prepared from thiosemicarbazides, in
basic conditions with sodium hydroxide[23–25] or trimethylamine,[26]
as well as from 1,3,4-oxadiazoles and substituted hidrazides[27] or
by reductive rearrangement of 1,2,4-oxadiazoles in reaction with
hydrazine.[28] Azzouni et al. synthesized 1,2,4-triazoles from
acryloylimidates with hydrazines at room temperature in methanol,
expanding the possibilities of introducing substituents in positions
N(1), C(3) and C(5) of 1,2,4-triazole ring.[29] An effect of different
solvents on formation of triazoles from substituted hydrazines and
isothiocyanates, followed by iodine mediated cyclization, was
studied by Jiao et al.[30] The type of the solvent greatly influenced
the reaction rate and product yield, and ethanol was suggested
as optimal for this type of reaction. An influence of solvent type
was also studied in formation of 1,2,4-triazoles from hydrazines
and imides followed by filtration on Al2O3, where DMF was found
to be the most convenient and alumina crucial for cyclization into
triazole ring system.[31]
Thiosemicarbazides and triazoles are an interesting group of
organic compounds, due to their wide range of biological activities.
Thiosemicarbazides are good antitumor,[1–3] anticancer,[4]
antimicrobial,[5–8] anti-inflammatory[9] and antiviral[10] agents, but
are also employed in many synthetic routes as the starting
compounds. Synthesis of triazoles, oxadiazoles, thiadiazoles,
thiazolidinones is often performed from thiosemicarbazides as a
starting compounds, involving different reaction conditions.
Thiosemicarbazides are often synthesized in reaction of
hydrazides and isothiocyanates in different organic solvents,[11]
like ethanol[12,13] and anhydrous diethyl ether.[14]
[a]
[b]
associate prof. M. Molnar, assist.prof. M. Komar
Department of Applied Chemistry and Eecology
Faculty of Food Technology Osijek
F. Kuhača 20 31000 Osijek Croatia
E-mail: maja.molnar@ptfos.hr, mkomar@ptfos.hr
Homepage: http://www.ptfos.unios.hr/
I. Periš
Department of Biology
Josip Juraj Strossmayer University of Osijek
Cara Hadrijana 8/A, 31000 Osijek, Croatia
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201900249
European Journal of Organic Chemistry
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Many other methods for triazole synthesis are available, and are
summarized in a review of Holm and Straub,[32] most of them
utilizing toxic organic solvents or catalysts, producing a large
amounts of reaction waste upon completion of reaction.
The formation of either 1,2,4-triazole (3a) or thiosemicarbazide
(TSC) was highly affected by the DES employed. Reactions in
certain DESs yielded TSC, while in some DESs a mixture of TSC
and 3a was formed (in different ratios shown in Table 1), and in
some DESs pure 3a was formed. All reactions were performed at
two different temperatures, 40°C and 80°C, respectively (Table 1).
For DESs with high viscosity, like choline chloride:N-methylurea,
choline chloride:thiourea, choline chloride:xylitol, choline
chloride:glucose and choline chloride:tartaric acid, reactions were
performed only at 80°C.
Therefore, the formation of 1,2,4-triazoles was highly affected by
the solvent and temperature as well. These data are summarized
in Table 1. For 1,2,4-triazole synthesis, the best results were
obtained in choline chloride:urea (1:2) and choline chloride:N-
methylurea (1:3) DESs at 80°C. Pure thiosemicarbazides were
obtained in choline chloride:ethane-1,2-diol (1:2), choline
chloride:malic acid (1:1), choline chloride:acetamide (1:2), choline
chloride:malonic acid (1:1), choline chloride:butane-1,4-diol (1:3)
and choline chloride:glycerole (1:2) at 40°C. Other DESs, at
different temperatures, yielded mixtures of TSC and 3a in different
ratios, shown in Table 1. A proposed mechanism for 1,2,4-triazole
formation is shown in Scheme 3. Our assumption is that in each
reaction a TSC was formed, with the possibility of subsequent
formation of 1,2,4-triazole in some DESs. TSC is formed upon
nucleophilic addition to isothiocyanate (Scheme 3) and according
to the data in Table 1., it is not pH dependent, since the formation
of pure TSC was detected in both acidic (ChCl:ethan-1,2-diol;
ChCl:malic acid; ChCl:malonic acid; ChCl:glycerol) and basic
(ChCl:acetamide) DESs.
Our ongoing study includes synthesis of coumarinyl 1,2,4-
triazoles from corresponding thiosemicarbazides, in choline
chloride (ChCl) based deep eutectic solvents (DESs). DESs are
characterized as “green” solvents due to their non-toxicity, low
vapor pressure, biodegradability, chemical stability and
environmentally benign effect.[33–35] Our focus is on choline
chloride based DESs, where choline chloride acts as a hydrogen
bond acceptor (HBA) and is combined with different hydrogen
bond donors (HBD), like urea, carboxylic acids, sugars or
alcohols,[36–38] in order to form a low melting point eutectic
mixtures. Combination of choline chloride with different HBDs
affects DES’ physical and chemical properties, like pH, viscosity,
melting point, etc.[36,39,40] Due to these variations in
physicochemical properties, a type of DES can greatly influence
a synthetic path of different compounds. We have noticed that in
the case of thiosemicarbazides and 1,2,4-triazoles, both can be
obtained from the same starting compounds, hydrazides and
isothiocyanates, but their formation depends on the type of DES
employed. Therefore, a screening of 14 different choline chloride
based DESs, at two different temperatures (40 °C and 80 °C), was
performed in order to examine the effect of solvent type and
temperature on the formation of desired compounds. A screening
was performed on a model reaction of 2-((4-methyl-2-oxo-2H-
chromen-7-yl)oxy)acetohydrazide (1) and phenyl isothiocyanate,
followed by the synthesis of some triazole derivatives in the
chosen DES and temperature.
Subsequent formation of 3a is temperature dependent and greatly
influenced by the solvent. A proposed mechanism includes a
nucleophilic attack of a nitrogen atom to carbon atom from the
carbonyl group, which leads to the cyclization into 1,2,4-triazole
ring. It is evident that the basicity and the ability of the DES to form
hydrogen bonds favors this cyclization. DESs formed between
ChCl and urea is basic [41] and its low melting point indicates there
are strong hydrogen bonds within the solvent,[42] while ChCl:N-
methylurea DES is less basic. But when compared to
ChCl:acetamide DES, which is basic, ChCl:N-methylurea DES
possess much stronger hydrogen bonds,[42] obviously contributing
to the formation of 1,2,4-triazole. Therefore, two DESs with the
most favorable combination of pH and hydrogen bond strength
were the most convenient for formation of 3a from TSC. Since
DESs exhibit a wide range of different physicochemical properties
depending on the components, which are mixed together to form
DES, all other solvent properties and their combination affecting
the reaction route are to be investigated.
Results and Discussion
1,2,4-Triazoles were synthesized from hydrazides 1 and 2 in
combination with various isothiocyanates, in choline chloride:urea
(1:2) DES, in good to excellent yields. Prior to their synthesis, a
screening of fourteen (14) DESs was performed, in order to find
the best DES for 1,2,4-triazole synthesis (Table 1). As the model
reaction for this optimization, a reaction of 1 and phenyl
isothiocyanate was performed (Scheme 2). The results of reaction
yield and type of product obtained for a model reaction are
tabulated in Table 1.
Scheme 2. A model reaction in synthesis of 1,2,4-trazoles performed in different
DESs.
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10.1002/ejoc.201900249
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Scheme 3. A proposed mechanism for formation of 1,2,4-trazoles in different DESs.
A TSC:3a ratio in the reaction mixtures was determined by HPLC
and 1H NMR (Figure 1). 1H NMR spectra of pure TSC is shown in
Supplementary material. H NMR spectra of TSC and 3a show
mixture of these two compounds (molar ratio of compounds in the
Table 1) or a pure 1,2,4-triazole (entry 2 and 17).
1
When we established that the best DES for formation of 1,2,4-
triazoles from 1 and phenyl isothiocyanate was the one with
choline chloride:urea (1:2) and temperature of 80°C, a series of
1,2,4-triazoles (3a-d and 4a-c) was synthesized from 1 and 2 and
various isothiocyanates (Scheme 4).
characteristic peaks for each type of compound. Methyl group in
position 4 of coumarin core shows a peak of 2.37 ppm for 3a and
2.41 ppm for TSC. Furthermore, -CH2- group of 3a shows a
characteristic peak of 5.12 ppm and 4.78 ppm for TSC. Coumarin
C-3 proton shows a peak at 6.22-6.24 ppm for both types of
compounds, while –SH group from 3a shows a peak at 14 ppm.
A TSC:3a ratio in the mixture can be determined considering any
of these peaks, therefore for our calculations an integrated –CH2-
peaks were compared. Similar results were also obtained in
determination of the ratio using HPLC method.
Also, an interesting effect can be observed considering the effect
of the temperature on the reaction route. Lower temperature of
40°C favors thiosemicarbazide formation, and as temperature
rises, formation of 1,2,4-triazoles is observed, thus forming a
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10.1002/ejoc.201900249
European Journal of Organic Chemistry
FULL PAPER
12
13
14
Malonic
acid[44]
1:1
1:3
1:3
80
40
80
1.7:1
TSC
4:1
Table 1. Triazole (3a) and thiosemicarbazide (TSC) formation in choline
chloride based deep eutectic solvents with different HBDs.
Butane-1,4-
diol[45]
entry
HBD
Molar ratio
HBA:HBD
T (°C)
Product
ratio
Butane-1,4-
diol[45]
TSC:3a
15
16
17
Glycerole[44]
Glycerole[44]
1:2
1:2
1:3
40
80
80
TSC
2.5:1
TRI
1
2
3
Urea[33]
Urea[33]
1:2
1:2
1:2
40
80
40
MIX[a]
TRI
N-
Ethane-1,2-
diol[41]
TSC
methylurea[33]
18
19
20
21
22
Thiourea[33]
Xylitol[36]
1:2
1:1
2:1
2:1
1:1
80
80
80
80
80
4:1
4
Ethane-1,2-
diol[43]
1:2
80
1.6:1
1:1.26
1:1.78
1:1.11
MIX[a]
5
Sorbitol[36]
1:1
1:1
1:1
1:1
1:2
1:2
1:1
40
80
40
80
40
80
40
2:1
Glucose[44]
Fructose[44]
6
Sorbitol[36]
MIX[a]
TSC
MIX[a]
TSC
6:1
7
Malic acid[43]
Malic acid[43]
Acetamide[33]
Acetamide[33]
Tartaric
acid[46]
8
9
[a] a mixture of thiosemicarbazide, triazole and unidentified byproducts were
observed
10
11
Malonic
acid[44]
TSC
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10.1002/ejoc.201900249
European Journal of Organic Chemistry
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Figure 1. A typical HPLC and 1H NMR spectra of the mixture of TSC and 3a: HPLC spectra – triazole 3a RT 1.45 min, TSC RT 1.31; 1H NMR – peak 4.78 ppm is
attributed to TSC –CH2-, and peak at 5.12 to 3a –CH2- group (entry 18).
The main advantage of this method is its green character
accomplished through one-step reaction of hydrazide and
substituted isothiocyanates without any catalyst added employing
non-toxic and biodegradable deep eutectic solvents. This method
results in a simple work up of the final product, which includes
addition of water and filtration, while products are pure and there
is a slight or no need for further purification. Deep eutectic
solvents can also be reused and recycled for a several times,
which was described in our previous publications,[47] causing no
negative effect on the yield of the final product. DESs are easily
formed when components are mixed together and heated forming
a eutectic mixture, with 100% atom economy.
We have also performed a recyclability test to investigate the
DESs reuse on the product yield (Table 2). DES was used for the
same reaction between TSC and phenyl isothiocyanate for three
cycles, and as evident from Table 2, the final product yield was
not decreased. Therefore, as already stated, this also contributes
to the “greenness” of DESs.
Scheme 4. Synthesized derivatives of 1,2,4-triazoles.
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10.1002/ejoc.201900249
European Journal of Organic Chemistry
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General procedure for synthesis of 1,2,4-triazoles or thiosemicarbazides
A mixture of 2-((4-methyl-2-oxo-2H-chromen-7-yl)oxy)acetohydrazide (1.6
mmol) and phenyl isothiocyanate (1.6 mmol) was added to chosen DES
and stirred at 40°C or 80°C. After completion of reaction (monitored by
TLC), water was added, the crude product was collected by filtration and
recrystallized from ethanol.
Table 2. Influence of DES recycle on final product yield shown for model
reaction.
solvent
3a yield (%)
choline chloride/urea
1st recycle
63
60
64
61
General procedure for synthesis of triazoles in choline chloride:urea DES
A mixture of 2-((4-methyl-2-oxo-2H-chromen-7-yl)oxy)acetohydrazide (1.6
mmol) or 2-(7-hydroxy-2-oxo-2H-chromen-4-yl)acetohydrazide (1.6 mmol)
and corresponding isothiocyanate (1.6 mmol) was added to choline
chloride:urea DES and stirred 80°C. After completion of reaction
(monitored by TLC), water was added and the crude product was collected
by filtration.
2nd recycle
3rd recycle
DES recycling procedure
After the crude product was precipitated by addition of water and filtered,
a water was evaporated under vacuum from the mixture with DES.
Afterwards, the same reaction was performed in this DES. The same
procedure was repeated for several cycles.
Also, in order to confirm the greenness of this process the
Sheldon E-factor was calculated (Experimetnal section), taking
into account the data from the model reaction and it was 0.666.
Calculation of Sheldon E-factor
Conclusions
(
)
푘푔 푤푎푠푡푒
0.2554 ∗ 10−3 푘푔
0.3834 ∗ 10−3 푘푔
퐸 − 푓푎푐푡표푟 =
=
= 0.666
(
)
푘푔 푝푟표푑푢푐푡
Choline chloride deep eutectic solvents were efficiently employed
in the synthesis of 1,2,4-triazoles. A type of deep eutectic solvent
and temperature exhibited a great influence on the formation of
1,2,4-triazole ring. Generally, lower temperatures (40°C) favor the
formation of thiosemicarbazides and higher temperatures (80°C)
favor the formation of 1,2,4-triazoles. Pure 1,2,4-triazoles were
formed in choline chloride:urea (1:2) and choline chloride:N-
methyl urea (1:3) deep eutectic solvents at 80°C. Furthermore, for
reactions where mixtures of thiosemicarbazides and triazoles
were formed, their ratio was determined with 1H NMR and HPLC.
Total amount of reactants: 0.413 g + 0.2258 g = 0.6388 g
Amount of the final product: 0.3834 g
Amount of waste: 0.6388 g – 0.3834 g = 0.2554 g
HPLC analysis
HPLC analyses of thiosemicarbazides and 1,2,4-triazoles was performed
on a Agilent 1260 Infinity II (Analytical Instruments, CA, USA) consisted of
1260 Quat Pump (G7111B), 1260 Vialsampler (G7117C), 1260 Quat
Pump (G7111B). Chromatographic separation was obtained on
a
Experimental Section
ZORBAX Eclipse Plus C18 (Agilent, USA) column, 100 mm long with
internal diameter of 4.6 mm. Separation of analyzed compound was
performed with isocratic elution for 10 minutes, where acetonitrile was
used as phase B and milipore water as phase A, in 50:50 ratio of A:B. The
flow rate was 1.0 mL/min, injection volume was 20 μL, UV detection
wavelength 230 and 280 nm and chromatography was performed at room
temperature. Standard stock solutions for TSC and 3a was prepared in a
methanol as solvent and calibration was obtained at eight concentrations
(concentration range 20.0, 30.00, 50.0, 75.0, 100.0, 150.00, 200.0 mg/L).
Linearity of the calibration curve for TSC was confirmed by R2= 0.9994 and
for TRI was R2= 0.9998. TSC limit of detection (LOD) was 0.0021 mg/L,
limit of quantification (LOQ) was 0.0070 mg/L and compound retention
time was 1.31 min. Triazole 3a limit of detection (LOD) was 0.002 mg/L,
limit of quantification (LOQ) was 0.007 mg/L and compound retention time
was 1.45 min. Samples were diluted in methanol HPLC grade, filtered
through 0.45 μm PTFE filters and subjected to HPLC analyses.
All chemicals were purchased from commercial suppliers. 1H and 13C
NMR spectra were recorded on a Bruker Avance 600 MHz NMR
Spectrometer (Bruker Biospin GmbH, Rheinstetten, Germany) at 293 K
with DMSO-d6 was as a solvent and tetramethylsilane (TMS) as an
internal standard. The mass spectra were recorded by LC/MS/MS API
2000 (Applied Biosystems /MDS SCIEX, CA, USA). HPLC analyses of was
performed on a Agilent 1260 Infinity II (Analytical Instruments, CA, USA)
consisted of 1260 Quat Pump (G7111B), 1260 Vialsampler (G7117C),
1260 Quat Pump (G7111B). Chromatographic separation was obtained on
a ZORBAX Eclipse Plus C18 (Agilent, USA) column, 100 mm long with
internal diameter of 4.6 mm. The FT-IR spectra were recorded on Cary
630 portable FT-IR System (Agilent technologies, USA).
DESs preparation
A mixture of 5 g (35.8 mmol) choline chloride and various hydrogen bond
donors (HBDs) in corresponding molar ratio (Table 1) was heated and
stirred at 80°C until the clear liquid was formed. After cooling to desired
temperature, DES was used in reactions as such.
NMR analysis
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10.1002/ejoc.201900249
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Determination of the products ratio was performed on 1H NMR spectra in
model reaction of 1 and phenylisothiocyanate. A ratio of TSC and 3a was
determined according to Malz and Jancke.[48]
4H, arom.), 10.58 (s, 1H, OH), 13.85 (s, 1H, SH); 13C NMR (DMSO-d6 )
δ (ppm): 168.1, 161.2, 159.7, 154.9, 149.3, 148.7, 133.3, 129.7, 129.4,
128.3, 126.6, 112.9, 111.8, 110.7, 102.2, 28.4.; IR (cm-1) ν: 3377 (OH
stratching), 1699 (lactone carbonyl C=O stretching), 1610 (N-H stretching
of triazole ring), 1490 (C-O-C coumarin ring stretching). MS: m/z: 350.00
(M-) (351.38)
Spectral data of synthesized compounds
7-((5-mercapto-4-phenyl-4H-1,2,4-triazol-3-yl)methoxy)-4-methyl-2H-
chromen-2-one (3a)[22]
4-((4-ethyl-5-mercapto-4H-1,2,4-triazol-3-yl)methyl)-7-hydroxy-2H-
chromen-2-one (4b)
Yield 63%; Rf = 0.49; Mp = 245-247 °C; 1H NMR (300 MHz, ppm, DMSO-
d6): 2.37 (s, 3H, CH3), 5.12 (s, 2H, CH2), 6.22 (s, 1H, coum.), 6.84 (dd,
J=8.80, 2.20 Hz, 1H, arom.), 6.95 (d, J=2.20 Hz, 1H, arom), 7.45-7.56 (m,
5H, arom.), 7.63 (d, J=8.80 Hz, 1H, arom.), 14.10 (s, 1H, SH); 13C NMR
(DMSO-d6) δ (ppm): 159.9, 153.2, 147.5, 133.3, 129.5, 129.2, 128.0,
126.5, 113.9, 112.3, 111.7, 101.9, 60.5, 18.1; IR (cm-1) ν: 1707 (lactone
carbonyl C=O stretching), 1610 (N-H stretching of triazole ring), 1490 (C-
O-C coumarin ring stretching). MS: m/z: 366.10 (M+) (365.40)
Yield 59 %; Rf = 0.30; Mp = >300 °C; 1H NMR (300 MHz, ppm, DMSO-
d6): 1.24-1.19 (t, J=7.16 Hz, 3H, -CH2CH3), 4.03 (q, J=7.16 Hz, 2H, -
CH2CH3), 4.31 (s, 2H, -CH2-), 6.10 (s, 1H, coum.), 6.72 (s, 1H, arom.),
6.81-6.77 (m, 1H, arom.), 7.62 (d, J=8.67 Hz, 1H, arom.); 13C NMR
(DMSO-d6) δ (ppm): 166.9, 161.9, 160.5, 155.5, 150.8, 149.1, 127.5,
113.6, 112.0, 111.4, 102.8, 28.1, 13.7; IR (cm-1) ν: 3108 (OH stratching),
1684 (lactone carbonyl C=O stretching), 1602 (N-H stretching of triazole
ring), 1490 (C-O-C coumarin ring stretching). MS: m/z: 302.10 (M-)
(303.34).
7-((5-mercapto-4-(4-methoxyphenyl)-4H-1,2,4-triazol-3-yl)methoxy)-4-
methyl-2H-chromen-2-one (3b)[22]
7-hydroxy-4-((4-(2-methoxyphenyl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-
3-yl)methyl)-2H-chromen-2-one (4c)
Yield 67%; Rf = 0.49; Mp = 190-192°C; 1H NMR (300 MHz, ppm, DMSO-
d6): 2.38 (s, 3H, CH3), 3.78 (s, 3H, OCH3), 5.09 (s, 2H, CH2), 6.22 (s, 1H,
coum.), 6.87-6.90 (m, 1H, arom.), 6.96-6.97 (m, 1H, arom), 7.02-7.05 (m,
2H, arom.), 7.34-7.37 (d, J=8.67 Hz, 2H, arom.), 7.63-7.66 (d, J=8.67 Hz,
1H, arom.), 14.05 (s, 1H, SH); 13C NMR (DMSO-d6 ) δ (ppm): 169.4,
160.4, 160.2, 154.8, 153.7, 148.2, 129.8, 127.0, 126.2, 114.9, 112.9, 112.1,
102.4, 60.9, 55.9, 18.6; IR (cm-1) ν: 1684 (lactone carbonyl C=O stretching),
1610 (N-H stretching of triazole ring), 1513 (C-O-C coumarin ring
stretching). MS: m/z: 396.20 (M+) (395.43)
Yield 68 %; Rf = 0.31; Mp = 248-250°C; 1H NMR (300 MHz, ppm, DMSO-
d6): 3.76 (s, 3H, OCH3), 4.06 (s, 2H, CH2), 5.86 (s, 1H, coum.), 6.77-6.69
(m, 2H, arom.), 7.01-6.98 (m, 3H, arom.), 7.51-7.40 (m, 2H, arom.), 10.6
(s, 1H, OH), 13.85 (s, 1H, SH); 13C NMR (DMSO-d6) δ (ppm): 168.5,
161.7, 160.2, 155.4, 149.8, 149.2, 134.8, 130.7, 127.2, 120.8, 115.9, 114.6,
113.4, 112.4, 111.2, 102.7, 55.9, 28.8; IR (cm-1) ν: 3131 (OH stratching),
1684 (lactone carbonyl C=O stretching), 1595 (N-H stretching of triazole
ring), 1490 (C-O-C coumarin ring stretching). MS: m/z: 380.10 (M-)
(381.40)
7-((4-ethyl-5-mercapto-4H-1,2,4-triazol-3-yl)methoxy)-4-methyl-2H-
chromen-2-one (3c)
Yield 84 %; Rf = 0.48; Mp = 235-237 °C; 1H NMR (300 MHz, ppm, DMSO-
d6): 1.24-1.29 (t, J=6.97 Hz, 3H, CH3), 2.39 (s, 3H, CH3), 4.02-4.04 (q,
J=7.34 Hz, 2H, CH2), 5.38 (s, 2H, CH2), 6.25 (s, 1H, coum.), 7.05-7.07 (d,
J=8.80, 2.20 Hz, 1H, arom.), 7.16 (s, J=2.20 Hz, 1H, arom), 7.71-7.74 (d,
J=8.80 Hz, 1H, arom.), 13.88 (s, 1H, SH); 13C NMR (DMSO-d6) δ (ppm):
167.2, 159.9, 154.5, 153.2, 147.4, 126.6, 113.9, 112.5, 111.7, 101.9, 60.3,
18.1, 13.3; IR (cm-1) ν: 1707 (lactone carbonyl C=O stretching), 1610 (N-
H stretching of triazole ring), 1483 (C-O-C coumarin ring stretching). MS:
m/z: 318.20 (M+) (317.36)
Acknowledgments
The authors are grateful to the Josip Juraj Strossmayer University
of Osijek, Republic of Croatia for financial support.
Keywords: 1,2,4-Triazole • Thiosemicarbazide • Isothiocyanate
• Deep eutectic solvents • green synthesis
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Triazoles*
A successful synthesis of 1,2,4-triazoles was
performed using deep eutectic solvents from
hydrazides and isothiocyanates. A great influence of
DES type and reaction temperature was observed.
Lower temperatures (40°C) favor the formation of
thiosemicarbazides and higher temperatures (80°C)
favor the formation of 1,2,4-triazoles. Pure 1,2,4-
triazoles were formed in choline chloride:urea (1:2)
and choline chloride:N-methyl urea (1:3) deep
eutectic solvents at 80°C. Furthermore, for reactions
where mixtures of thiosemicarbazides and triazoles
were formed, their ratio was determined with 1H
NMR and HPLC.
Maja Molnar, Mario Komar*, Ivana
Periš
Page No. – Page No.
Choline chloride based deep
eutectic solvents as a tuneable
media for synthesis of coumarinyl
1,2,4-triazoles: effect of solvent type
and temperature
*one or two words that highlight the emphasis of the paper or the field of the study
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