Highly efficient synthesis of pyrazolylphosphonate derivatives in biocompatible deep eutectic solvent

Article abstract of DOI:10.1016/j.mcat.2019.110396

A straightforward and highly efficient one-pot preparation of biologically interesting pyrazolylphosphonate derivatives via a three-component reaction between pyrazolone or phenylpyrazolone, various aromatic, fused aromatic, heterocyclic, and aliphatic al

Full text of DOI:10.1016/j.mcat.2019.110396

MolecularCatalysis473(2019)110396
Contents lists available at ScienceDirect
Molecular Catalysis
journal homepage: www.elsevier.com/locate/mcat
Highly efficient synthesis of pyrazolylphosphonate derivatives in
biocompatible deep eutectic solvent
Reddi Mohan Naidu Kalla, Il Kim⁎
BK21 PLUS Center for Advanced Chemical Technology, Department of Polymer Science and Engineering, Pusan National University, Busandaehak-ro 63, Busan 46241,
Republic of Korea
A R T I C L E I N F O
A B S T R A C T
Keywords:
A straightforward and highly efficient one-pot preparation of biologically interesting pyrazolylphosphonate
derivatives via a three-component reaction between pyrazolone or phenylpyrazolone, various aromatic, fused
aromatic, heterocyclic, and aliphatic aldehydes, and triethyl or trimethyl phosphite in presence of an ammo-
nium-based deep eutectic solvent (DES) at 25 °C has been developed. The ammonium-based DES was easily
prepared from choline chloride and urea (1:2) at 80 °C for 2 h. It is biodegradable, fairly inexpensive, easily
separated from the reaction mixture using water, and can be reused at least four times without loss of its catalytic
activity. The most important features of this method are its eco-friendliness, high yields, high atom economy,
and the fact that it does not require column chromatographic purification for isolation of the products. Thus, it
represents an alternative method for the synthesis of a wide range of pyrazolylphosphonates with shorter re-
action times.
Atom economy
Deep eutectic solvent
Green chemistry
Multi-component reaction
Pyrazolylphosphonates
1. Introduction
requirements, while retaining many of the attractive solvent properties
of ionic liquids, such as their high thermal stabilities, low volatilities,
Awareness of environmental issues and the need to decrease the use
of hazardous chemicals in medicinal, chemical, and commercial re-
search are rising. Thus, green solvents such as ionic liquids (ILs) and
deep eutectic solvents (DESs), which have immense potential in many
chemical, electro-chemical, metal nanoparticles, and biotransformation
applications, have emerged [1]. The 21 st century concept of “green
chemistry”, which aims to develop alternative methods to eliminate the
production and waste of harmful materials, is important in both syn-
thetic laboratories and industry. Recently, sustainable routes for the
generation of carbon–carbon and carbon–phosphorus bonds have be-
come an important area in the organic and medicinal chemistry fields
[2]. Furthermore, reactions of three or more chemical components in a
single step, known as multi-component reactions, are considered to be
eco-friendly and in accordance with the goals of sustainable chemistry.
DESs are a new generation of ionic solvents that consist of two or
more components; typically, one component is a quaternary ammonium
salt and the other is a metal salt or hydrogen bond donor. DESs over-
come some of the drawbacks of ionic liquids, such as the high prices,
high melting temperatures, environmental toxicity, and high purity
wide liquid ranges, high solvation capacities, and conductivities [3–5].
In addition to these properties, DESs have other advantages over ionic
liquids. DESs can be prepared by simple mixing of the components
without any additional purification methods. They also have low
manufacturing costs due to their fairly inexpensive starting materials.
Most DESs are biodegradable, nontoxic, biocompatible, and chemically
inert in water [1,6]. Thus, DESs are presently attracting extensive sci-
entific and commercial interest as low cost alternatives to conventional
and alternative solvents such as ionic liquids.
Organophosphorus compounds play a significant role in medicinal
chemistry due to their extensive biological activities, and have also
been used as intermediates for the synthesis of organic complexes and
materials. Moreover, phosphonates and their derivatives have im-
portant activities, including antimicrobial, anticancer, antioxidant,
antibiotic, and peptide mimetic activities. Due to their broad range of
properties, the sustained improvement of efficient methods for the
commercially viable preparation of phosphonate derivatives is im-
portant [7]. Various techniques to produce phosphonate derivatives
through carbon–phosphorus bond formation catalyzed by acids [8],
Abbreviations: AE, atom economy; AEf, atom efficiency; BP, bis-pyrazole; ChCl, choline chloride; ChOH, choline hydroxide; DES, deep eutectic solvent; EDDF,
ethylenediammonium diformate; E, E-factor; HPP, α-hydroxyphosphonates; IL, ionic liquid; KC, knoevenagel condensation; MI, mass intensity; OE, optimum effi-
ciency; PPs, pyrazolylphosphonate; RME, reaction mass efficiency; SI, solvent intensity; TLC, thin layer chromatography; WI, water intensity
⁎ Corresponding author.
E-mail address: ilkim@pusan.ac.kr (I. Kim).
https://doi.org/10.1016/j.mcat.2019.110396
Received 7 March 2019; Received in revised form 2 May 2019; Accepted 6 May 2019
2468-8231/©2019ElsevierB.V.Allrightsreserved.

R.M.N. Kalla and I. Kim
MolecularCatalysis473(2019)110396
Scheme 1. Previously reported two-component and three-component methods for the synthesis of pyrazolylphosphonates. EDDA = Ethylenediammonium diacetate;
PdNPs = Palladium nanoparticles.
Scheme 2. Synthesis of series of pyrazolylphosphonates.
Scheme 3. Possible products during the one-pot synthesis of pyrazolylphosphonates.
bases [9–11], radical inhibitors [12,13], ultrasound [7], and microwave
irradiation [14] have been developed and reported in the literature.
Recently, we described the one-pot preparation of various phos-
phonates including chromenyl phosphonates [15,16], β-phosphono-
malonates [2], tertiary α-amino phosphonates [7], and α-hydro-
xyphosphonates (HPPs) [17] in presence of an organobase catalyst
using an ultrasound promoted catalyst-free method and ionic liquids. In
continuation of the studies on preparation of phosphonate derivatives,
we have focused on the preparation of pyrazolylphosphonates (PPs), as
compounds with a pyrazole backbone having a wide range of potent
biological properties, such as antimicrobial [18], antitumor [19], an-
tipsychotic [20], hypolipidemic [21], hypoglycemic [22], anti-oxidant
[23], and HIV-1 inhibitory [24] properties. Furthermore, pyrazoles are
potent synthetic intermediates for the synthesis of pharmaceuticals
such as apixaban [25], and rivaroxa-ban [26], and are also used as
pesticides [27], herbicides [28], and fungicides [29].
Four important general methods for the preparation of PPs are
presented in (Scheme 1). The first method involves the condensation
reaction of formaldehyde with malonic esters and triethyl phosphite
followed by the addition of hydrazine [30], In the second method, a
phosphorous nucleophile is added to unsaturated pyrazolone [31], The
third method is the three-component reaction of pyrazolones with al-
dehydes and trialkyl phosphites, for which two catalytic methods have
been reported so far [23,32]. The fourth method is the four-component
2

R.M.N. Kalla and I. Kim
MolecularCatalysis473(2019)110396
Table 1
Melting points were determined using a digital Stuart SMP3 apparatus
(Bibby Scientific Limited, Staffordshire, UK) and were uncorrected.
FTIR spectra were recorded using a Shimadzu IR Prestige 21 spectro-
meter at 25 °C. KBr discs were used for solid samples; for liquids, the
Effects of different catalysts on the synthesis of pyrazolylphosphonatesa.
Entry Catalyst
Amount, mgb Solvent Time, min Yield (%)c
PPd HPPd BPd
ATR method was used in the range of 3500–500 cm−1
.
1H (400 MHz)
and 13C (100 MHz) NMR spectra were recorded in CDCl3 using a Varian
INOVA 400 MHz NMR spectrometer at 25 °C using tetramethylsilane
(TMS) as internal standard. Chemical shifts (δ) are expressed as ppm.
Multiplicities in the 1H NMR spectra are described as: s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet, brs = broad
singlet; coupling constants are reported in J (Hz).
1
2
Catalyst free
–
–
–
24
nre
35
–
–
–
–
H2O:EtOH (1:1
v/v)
180
3
FeCl3
8.1
6.8
11.0
7.0
10
–
180
180
180
180
180
180
12 h
180
180
60
87
86
87
85
–
–
–
4
ZnCl2
–
–
–
5
InCl3
–
–
–
6
BF3.O(Et)2
SiO2-SO3H
p2NPh-OSO3H
p2NPh-OSO3H
Cs2CO3
–
–
–
7
–
55.9
44.1
2.2. Synthesis of 3-methyl-5-pyrazolone
8
10
–
–
55.9
44.1
–
9
10
–
–
95.0
–
10
11
10
12
13
14
15
16
17
18
19
20
21
22
23
24
16.2
2.0
4.3
4.2
5.0
7.6
7.6
6.0
6.9
4.6
3.0
–
75
78
86
88
87
90
95
92
50
55
30
85
90
93
96
96
–
A 50 mL reaction flask was equipped with a magnetic stirrer, and
ethyl acetoacetate (1.301 g, 10 mmol) and hydrazine monohydrate
(0.500 g, 10 mmol) were added to the reaction flask. Immediate for-
mation of the solid product was observed, and the reaction was con-
tinued for 3 h. The solid product was then washed two times with water
(4 mL) and vacuum dried at 25 °C. The identity of the product was
confirmed using 1H NMR (Fig. S1, Supporting Information (SI)).
LiOH.H2O
Morpholine
Piperidine
Triethylamine
DBU
–
–
–
–
–
–
–
60
–
–
–
60
–
–
–
60
–
–
EDDF
–
30
–
–
ChOH
–
45
–
–
ChCl
–
180
180
180
45
–
–
Glycerol
Urea
–
–
–
–
–
–
2.3. Synthesis of DES
ChCl:Glycerol
ChCl:Urea
ChCl:Urea
ChCl:Urea
ChCl:Urea
2 g
0.6 g
0.8 g
1 g
1.2 g
–
–
30
–
–
The DES was synthesised according to a method previously reported
in the literature [33]. Choline chloride (16.754 g, 120 mmol) and urea
(14.414 g, 240 mmol) were placed in a 100 mL reaction flask equipped
with a magnetic stirrer. The resulting solid mixture was stirred at 80 °C
until a clear solution without any solid residue was obtained. The re-
sulting clear solution (DES) was used directly in subsequent reactions
without any further purification. No by-products related to the DES
solvent and catalyst were observed; hence, isolation of the products was
easy and did not require column chromatography.
30
–
–
30
–
–
30
–
–
a
Experimental conditions: benzaldehyde =0.5 mmol, pyrazolone
=0.5 mmol, triethyl phosphite =0.5 mmol, and DES at 25 °C.
b
All catalysts correspond to 10 mol% except SiO2-SO3H and p2NPh-OSO3H.
Note that the molecular weight of the silica and cross-linked p2NPh -SO3H
cannot be measured for the estimation of mol%.
c
d
Isolated yields.
PP = pyrazolylphosphonate, BP = bis-pyrazole, and HPP=α-hydroxy-
2.4. General procedure for the synthesis of pyrazolylphosphonate in
presence of DES
phosphonate. No Knoevenagel condensation products are formed.
e
No reaction.
reaction of ethyl acetoacetate, hydrazine/phenylhydrazene, aldehydes,
and trialkyl phosphites, of which there are no reports to the best of our
knowledge. Among these, the third method is most appropriate for the
preparation of pyrazolone phosphonates, as it reduces the number of
synthetic steps, time, and laborious work-up procedures are not re-
quired. This method is based on the in situ formation of benzylidene
pyrazolone and its subsequent reaction with a phosphorus nucleophile.
From the perspective of sustainable chemistry, DESs are considered
to be safe and uniquely stable green solvents, and are advantageous to
the selectivity and reactivity of a wide variety of applications such as
the organic transformations, electrolytes for dye-sensitized solar cells,
and synthesis of silica materials with high porosities. Owing to their
multiple applications and fairly high availability, we synthesized a
choline chloride–urea mixture and used it as a catalyst for the synthesis
of PPs (Scheme 2).The advantages of this protocol are its clean reaction
profile, mild reaction conditions at 25 °C, energy efficiency, use of
readily accessible and fairly inexpensive components, avoidance of
column chromatographic purification and toxic organic solvents, high
atom economy (87.7 − 90.8%), and good yields.
Benzaldehyde 1{1} (0.053 g, 0.5 mmol), 3-methyl-5-pyrazolone
2{1} (0.049 g, 0.5 mmol), triethyl phosphite 3{2} (0.083 g, 0.5 mmol),
and DES were mixed at 25 °C with stirring. The progress of the reaction
was monitored using TLC (hexane:ethyl acetate, 6:4). When the reac-
tion was complete, water (4 mL) was added and the reaction mixture
was stirred to mix in the solid. The solid product was removed by fil-
tration, and the filtrate was concentrated using a rotary evaporator. The
solid product was further recrystallized from ethanol (4 mL) to afford
the desired product. The same experimental procedure was used for all
the target compounds. The liquid products were extracted using ethyl
acetate (5 mL). The solvent was then concentrated to obtain the pro-
ducts in good yields. Detailed spectral data for the new compounds and
previously reported compounds is given in the SI.
3. Results and discussion
Chemical transformations under green chemical conditions have
attracted considerable attention for their fast reaction rates, eco-
friendliness, low cost, good yields, and easy workup procedures. We are
very interested in improving chemical conversions using en-
vironmentally friendly methods [15–17]. With the aim of developing an
eco-friendly method, we have used two deep eutectic solvents for their
biocompatible nature and as the catalyst for the synthesis of potent
pyrazolylphosphonates in high yields, while preventing of the forma-
tion of bis-pyrazoles (BPs), α-hydroxy-phosphonates, and Knoevenagel
condensation (KC) products (Scheme 3). Thus, we have developed a
bio-friendly one-pot method for the preparation of pyrazolylpho-
sphonates.
2. Experimental
2.1. General
3-Methyl-1-phenyl-5-pyrazolone, choline chloride (Alfa Aesar), the
various aldehydes (Merck Chem., Germany), trimethyl phosphite (TCI),
triethyl phosphite (Fulka), and urea (Daejung) were used as received.
All reactions were conducted in DES; pre-coated silica gel plates (Merck
Chem., Germany) developed with iodine were used for analytical TLC.
We first screened a model reaction between 0.5 mmol of pyrazolone,
3

R.M.N. Kalla and I. Kim
MolecularCatalysis473(2019)110396
Fig. 1. Reagents used to study the reaction scope.
benzaldehyde, and triethyl phosphite in absence of the catalyst under
neat conditions. After 4 h, we monitored the evolution of the reaction
using thin layer chromatography (TLC). No new products were formed
and no further reaction was occurred after 24 h. The reaction was then
conducted in presence of a water-ethanol mixture (1:1 v/v, 3 mL). After
3 h, the progress of the reaction was observed by TLC. The formation of
new product was observed; however, their isolated yield was only 35%.
Based on these results, the use of a catalyst was determined to be ne-
cessary for the synthesis of PPs at high yields within a short time frame.
Hence, we then tested various catalysts under the neat conditions; the
results are presented in Table 1. Initially, the Lewis acids FeCl3, ZnCl2,
InCl3, and BF3•O(Et)2 were utilized under neat conditions at 25 °C for
3 h, and the target PPs were obtained about 85–87% yield, respectively
(Table 1, entries 3–6). We also used two heterogeneous acid catalysts,
silica sulfonic acid (SiO2-SO3H) and sulfonated hyper crosslinked poly
naphthol (p2Np-OSO3H). After 3 h, the reaction mixture contained the
HPP and BP products in a 1:0.79 ratio (Fig. S2, SI).When the reaction
was continued for 12 h under the same conditions, the reaction
products were completely converted to HPPs (Fig. S3, SI). PPs were not
formed in the presence of the strong acid catalysts.
Subsequently, we turned to inorganic and organic base catalysts
such as LiOH•H2O, Cs2CO3, morpholine, piperidine, triethylamine, and
DBU, which furnished the targeted pyrazolyl phosphonates in good
yields, without the formation of KC, HPP, or BP products (Table 1,
entries 10–14). Compared to the inorganic bases, the organic bases
furnished the reaction products very quickly. However, these bases are
toxic to the environment, have an objectionable odour, are not re-
cyclable, and require treatment with an acidic solution for their re-
moval.
Owing to these environmental problems, we focused on eco-friendly
recyclable catalysts such as ILs and DESs, namely 1,2-ethanediaminium
diformate (EDDF), choline hydroxide (ChOH), and choline chloride
(ChCl):urea (1:2), and ChCl:glycerol (1:2). Pleasantly, these reactions
were proceeded efficiently, producing pyrazolylphosphonates in good
yields within a short time (Table 1, entries 20–24). To determine the
role of the ChCl:urea (1:2), the reaction was performed in the presence
4

R.M.N. Kalla and I. Kim
MolecularCatalysis473(2019)110396
Table 2
Substrate scope of the reactiona.
Entry
Product
Time (min)
Yield (%)b
1
4{1,1,2}
4{2,1,2}
4{3,1,2}
4{4,1,2}
4{5,1,2}
4{6,1,2}
4{7,1,2}
4{8,1,2}
4{9,1,2}
4{10,1,2}
4{11,1,2}
4{12,1,2}
4{13,1,2}
4{14,1,2}
4{15,1,2}
4{16,1,2}
4{17,1,2}
4{18,1,2}
4{19,1,2}
4{20,1,2}
4{21,1,2}
4{22,1,2}
4{1,2,2}
4{2,2,2}
4{3,2,2}
4{4,2,2}
4{5,2,2}
4{6,2,2}
4{7,2,2}
4{8,2,2}
4{9,2,2}
4{10,2,2}
4{11,2,2}
4{12,2,2}
4{13,2,2}
4{14,2,2}
4{15,2,2}
4{16,2,2}
4{17,2,2}
4{18,2,2}
4{19,2,2}
4{20,2,2}
4{21,2,2}
4{22,2,2}
4{1,2,1}
4{2,2,1}
4{17,2,1}
30
40
33
36
30
45
240
35
30
25
32
30
28
32
40
45
50
45
30
28
40
50
30
34
30
31
28
34
40
26
22
20
25
23
20
25
35
38
44
39
20
18
40
45
30
35
50
96
92
94
91
95
89
nrc
95
97
95
94
96
96
94
90
89
88
90
94
96
89
85
96
91
94
92
95
88
90
96
96
95
93
96
95
94
88
87
85
89
94
96
85
84
93
90
87
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
Fig. 2. Effect of DES recycling on the yield of the PPs. Experimental conditions:
benzaldehyde =0.5 mmol, pyrazolone =0.5 mmol, triethyl phosphite
=0.5 mmol, and DES at 25 °C.
using 0.6, 0.8, 1, and 1.2 g of DES at 25 °C, which led to yields of 90, 93,
96, and 96%, respectively. Further increasing the amount of DES had no
further effect on the product yield and reaction time.
With the optimized conditions in hand, we investigated the opti-
mized catalytic system using aldehydes 1{1 − 22}, pyrazolones 2{1,2},
and trialkyl phosphites 3{1,2} for library validation (Fig. 1). The re-
action of benzaldehyde 1{1}, pyrazolone 2{1}, and trialkyl phosphite
3{2} was evaluated first. The results shown in Table 2 indicate that this
multicomponent reaction gave the desired pyrazolylphosphonates in
less than 1 h with good yields. The position of the functional group and
nature of the aromatic ring had negligible influences on the reaction
time and product yield. The reactions involving aldehydes containing
electron-donating groups (OMe, Me) were faster and gave good yields.
Aldehydes with more than one electron-donating group on the aromatic
ring exhibited much faster reaction rates than the singly substituted
aldehydes. The halogen-substituted aldehydes also gave high yields
within the time frame, with the reactions of the ortho-substituted halo
aldehydes also completing in less than 1 h with good yields. For the
aldehyde containing an electron-withdrawing nitro group, the reaction
rate was relatively slow and the product yield was also lower than those
of the halo (Cl, Br) substituted aldehydes due to its electron deficiency.
The fluorine group made the rate of the reaction slower than that with a
nitro group regardless of its lower electronegativity than the nitro
group.
a
Experimental conditions: benzaldehyde =0.5 mmol, pyrazolone
=0.5 mmol triethyl phosphite =0.5 mmol, and DES at 25 °C.
b
c
Isolated yields.
No reaction.
Furthermore, fused benzaldehydes, such as naphthalene-1-carbal-
dehyde and anthra-cene-9-carboxaldehyde, also readily participated in
this reaction, and produced PPs in good yields. The formation of PPs
from the heterocyclic aldehydes indole-3-carboxaldehyde, pyridine-2-
carboxaldehyde, furan-2-carboxaldehyde, 5-methylfurfural, and thio-
phene-2-carboxaldehyde also proceeded smoothly. Among these, thio-
phene-2-carboxaldehyde was the least reactive, due to the low elec-
tronegativity of the sulphur atom. Similarly, indole and pyridine
carboxaldehyde were also less reactive than furfural and 5-methylfur-
fural, due to their lower electronegativity. Hence, their reaction rates
and product yields were relatively low. On the other hand, the aliphatic
aldehyde isobutyraldehyde showed good reactivity. We used two dif-
ferent pyrazolones, 3-methyl-5-pyrazolone and 3-methyl-1-phenyl-5-
pyrazolone; 3-methyl-5-pyrazolone was more reactive than 3-methyl-1-
phenyl-5-pyrazolone. Two different phosphorus nucleophiles, namely,
trimethyl phosphite and triethyl phosphite, were used. In most of the
cases, the pyrazolylphosphonates were formed in good yields.
Table 3
Comparison of previous catalysts used for the synthesis of PPs.
Compound
Catalyst (mole %)
Solvent
Time (h)
Yield (%)
Ref
4{1,2,2}
4{8,2,2}
4{10,2,2}
4{1,2,2}
PdNPs (5)
EDDA (10)
β-CD (10)
DES
EtOH
EtOH
Neat
DES
8
93
95
95
96
32
3
23
0.5
0.5
34
This worka
a
Experimental conditions: Aldehydes=0.5 mmol, pyrazolone =0.5 mmol,
triethyl phosphite =0.5 mmol, and DES at 25 °C.
of ChCl, urea, and glycerol individually, but it takes long reaction times
and the resultant yields were low (Table1, entries17–19). The less
performance of the individual DES components clearly showed the
basic function of ChCl and urea or glycerol in promoting the reaction;
the increased reactivity of ChCl as a result of hydrogen bonding with
urea made the DES medium favorable in terms of product yield. To
determine the optimal DES loading, the model reaction was carried out
In order to determine the superiority of DES over the other catalysts
for this transformation, the current results were compared with
5

R.M.N. Kalla and I. Kim
MolecularCatalysis473(2019)110396
Scheme 4. A plausible reaction mechanism for the formation of PPs in the presence of DES.
Table 4
adding water (4 mL) to the reaction mixture; the solid products were
separated by simple filtration and the soluble DES was concentrated
using a rotary evaporator, and used for the next cycle. For liquid pro-
ducts, the product was extracted by using ethyl acetate (5 mL); the
solvent was then concentrated to obtain the products with good yields.
The DES can be used 4 times without loss of its catalytic activity is
shown in Fig. 2.
Green metrics (AE, EMY, AEf, RME, and OE) for six compoundsa.
Entry Product
Yield (%) AE (%) EMY (%) AEf (%) RME (%) OE (%)
1
2
3
4
5
6
4{1,1,2}
4{9,1,2}
96
97
87.51
90.84
88.39
87.65
89.60
90.84
84.32
86.95
84.42
83.42
81.97
86.95
84.01
87.21
84.85
84.15
86.02
87.21
84.32
86.95
84.42
83.42
81.97
86.95
94.51
95.71
95.51
95.17
91.48
95.71
4{13,1,2} 96
4{20,1,2} 96
The synthesised target compounds were identified using 1H and 13
C
4{1,2,2}
4{9,2,2}
96
96
NMR spectroscopy. The 1H-NMR spectrum of 4{1,1,2} showed the
characteristic amine and a hydroxyl group as a singlet at 10.15 ppm and
the signal of a methine on the CeP bond as a doublet at 4.19 ppm (d,
J=28.0 Hz, eP−CH). The eOCH2 protons attached to phosphorus
were observed as multiplets at 4.12–3.84 (3H, m, eOCH2) and
3.66–3.56 (1H, m, eOCH2), while two methyl groups were recorded at
1.16 (t, J = 7.0 Hz, 3H, eCH3) and 1.05 (t, J = 7.1 Hz, 3H, eCH3). In
the 13C NMR spectra, a doublet at 40.4 ppm (J = 138.0 Hz) confirmed
the presence of a methine carbon directly attached to a phosphorus
atom.
a
Higher values represent a greener process.
Table 5
Green metrics (MI, PMI, E-Factor, SI, and WI) for six compoundsa.
Entry
Product
MI (g/g)
PMI (g/g)
E (g/g)
SI (g/g)
WI (g/g)
1
2
3
4
5
6
4{1,1,2}
4{9,1,2}
4{13,1,2}
4{20,1,2}
4{1,2,2}
4{9,2,2}
7.59
6.49
7.13
7.60
6.40
5.69
33.10
27.78
30.82
33.12
27.29
23.78
0.18
0.14
0.18
0.19
0.16
0.15
6.41
5.40
5.95
6.42
5.23
4.54
25.51
21.28
23.69
25.51
20.83
18.09
We proposed a possible mechanism for the DES-mediated synthesis
of pyrazolylphosphonates via the three-component reaction of an al-
dehyde, pyrazolone, and trialkyl phosphite (Scheme 4). First, the deep
eutectic solvents activates the aldehyde and pyrazolone via hydrogen
bonding to form an enone, followed by the nucleophilic addition of
phosphite to afford the target pyrazolylphosphonates.
a
Lower is the value, greener is the process.
previously reported results, as shown in Table 3. Lee et al. reported that
the synthesis of PPs using palladium nanoparticles (PdNPs) and ethy-
lene diammonium diacetate (EDDA) takes long time to complete, re-
quires an excess of the phosphorous nucleophile, and also leads to the
formation of HPP by-products and they studied only the various sub-
stituted 3-methyl-1-phenyl-5-pyrazolone derivatives, while we delib-
erate the synthesis of new PPs derived from 3-methyl-5-pyrazolone.
Reddy et al. reported that the synthesis of PPs using supramolecular
catalysts such as β-cyclodextrin (β-CD) [34] requires a short time for
the completion of the reaction. However, they used diethylphosphite,
which is less reactive than triethyl phosphite, and they studied only 3-
methyl-1-phenyl-5-pyrazolone derivatives. Compared to the above-
mentioned catalysts, the DES in this work had clear advantages for the
synthesis of PPs, in that it does not require solvents, excess molar ratios
of reactants, or laborious work-up procedures such as column chro-
matography.
In order to measure the effectiveness of the present method, we
calculated the green chemistry related parameters atom economy (AE),
effective mass yield (EMY), atom efficiency (AEf), reaction mass effi-
ciency (RME), optimum efficiency (OE), mass intensity (MI), process
mass intensity (PMI), E-factor, solvent intensity (SI), and water in-
tensity (WI). The high AE (87.7 − 90.8%) and small E-factor
(0.14 − 0.19) values demonstrated that the present method was sig-
nificantly green. The EMY and RME (82.0 − 87.0%) values also in-
dicated the green nature of the present method. The formulas for these
green metrics and their calculations are presented in the SI; Tables 4
and 5 list the values of the parameters for five representative com-
pounds.
4. Conclusions
A straightforward, efficient, and suitably practical route for the
synthesis of a wide range of biologically active PPs has been developed
using a one-pot reaction of 3-methyl-5-pyrazolone or 3-methyl-1-
Furthermore, the recyclability of the DES for the synthesis of pyr-
azolylphosphonates was examined. The DES was recovered by simply
6

R.M.N. Kalla and I. Kim
MolecularCatalysis473(2019)110396
phenyl-5-pyrazolone, aromatic aldehydes, and trialkyl phosphites in the
presence of DES at 25 °C. The most significant features of the present
method include its eco-friendly reaction conditions, operational sim-
plicity, good yields, high atom economy, and the biodegradability of
the catalyst. Furthermore, the use of fairly inexpensive starting mate-
rials and the simple isolation of the products without need for the te-
dious column chromatography are additional advantages of the present
method. Thus, the method was designed from the viewpoint of green
and sustainable chemistry, and the reaction mixture can be used for up
to 4 reaction cycles without significant loss of catalytic activity. The
green metrics of the method were also evaluated and found to be good.
In light of the synthetic significance of such biologically potent phos-
phorus organic compounds, the present environmentally friendly and
facile DES-based method may also afford the large-scale synthesis of the
significant compounds.
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