[Et3NH][HSO4]-catalyzed one-pot, solvent-free synthesis and biological evaluation of α-amino phosphonates

Article abstract of DOI:10.1007/s11164-015-2348-z

Abstract: A series of dimethyl (phenyl(phenylamino)methyl)phosphonates and novel dimethyl ((phenylamino)(2-(prop-2-yn-1-yloxy)phenyl)methyl)phosphonates as potential antifungal agents were synthesized via one-pot, three-component condensation of aldehydes, amines and trimethyl phosphite in solvent-free conditions using [Et₃NH][HSO₄] as an efficient, eco-friendly and reusable catalyst. Compared to other methods, this new method consistently has advantages, including excellent yields, a short reaction time, mild reaction conditions and catalyst reusability. The newly synthesized propargylated ether containing α-amino phosphonates were evaluated for antifungal and antioxidant activity and were also analyzed for absorption, distribution, metabolism and excretion (ADME) properties. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s11164-015-2348-z

Res Chem Intermed
DOI 10.1007/s11164-015-2348-z
[Et3NH][HSO4]-catalyzed one-pot, solvent-free
synthesis and biological evaluation of a-amino
phosphonates
Mubarak H. Shaikh1 Dnyaneshwar D. Subhedar1
•
•
•
Firoz A. Kalam Khan2 Jaiprakash N. Sangshetti2
•
Bapurao B. Shingate1
Received: 25 August 2015 / Accepted: 30 October 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract A series of dimethyl (phenyl(phenylamino)methyl)phosphonates and novel
dimethyl ((phenylamino)(2-(prop-2-yn-1-yloxy)phenyl)methyl)phosphonates as poten-
tial antifungal agents were synthesized via one-pot, three-component condensation
of aldehydes, amines and trimethyl phosphite in solvent-free conditions using
[Et3NH][HSO4] as an efficient, eco-friendly and reusable catalyst. Compared to other
methods, this new method consistently has advantages, including excellent yields, a
short reaction time, mild reaction conditions and catalyst reusability. The newly syn-
thesized propargylated ether containing a-amino phosphonates were evaluated for
antifungal and antioxidant activity and were also analyzed for absorption, distribution,
metabolism and excretion (ADME) properties.
Electronic supplementary material The online version of this article (doi:10.1007/s11164-015-2348-z)
contains supplementary material which is available to authorized users.
&
Bapurao B. Shingate
bapushingate@gmail.com
1
2
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University,
Aurangabad 431 004, India
Department of Pharmaceutical Chemistry, Y. B. Chavan College of Pharmacy, Dr. Rafiq
Zakaria Campus, Aurangabad 431 001, India
123

M. H. Shaikh et al.
Graphical Abstract
Keywords Ionic liquid Á a-Aminophosphonate Á Antifungal Á Antioxidant Á ADME
prediction
Introduction
Multi-component reactions have been developed as efficient and influential tools in
modern synthetic organic chemistry, facilitating the facile creation of several new
bonds in one-pot reactions. These days, greener (eco-friendly) reaction media are
gaining greater importance in safe organic transformations. Ionic liquids, referred to
as ‘designer solvents’ due to their physical and chemical properties, can be adjusted
by a careful choice of cations and anions. Ionic liquids have become a promising
alternative media for various chemical processes due to their good solvating
capability, non-inflammability, negligible vapor pressure, ease of recyclability,
controlled miscibility and high thermal stability [1, 2]. In particular, acidic Bronsted
ionic liquids (ABILs) are of special importance, because they simultaneously
possess proton acidity and the characteristic properties of ionic liquids [3]. ABILs
offer environmentally friendly catalyst properties due to the combination of the
advantages of liquid acids and solid acids, such as uniform acid sites, stability in
water and air, easy separation and reusability. Ionic liquids have been proved to be
very excellent catalysts, as well as solvents, for many organic transformations [4].
Phosphonic acids and phosphonates are of immense interest in synthetic organic
chemistry due to their widespread biological activities [5, 6]. They are employed in
the synthetic operations leading to carbon–carbon bond formation [7], and as
transition state analogues in production of antibody catalysts for a wide variety of
reactions [8]. a-Aminophosphonates are an important class of compounds in
pharmaceutical chemistry. In recent years, considerable interest has been focused on
the synthesis of a-aminophosphonates, because they are considered to be structural
analogues of the corresponding a-amino acids and transition-state mimics of peptide
hydrolysis. The utilities of a-aminophosphonates as antibiotics and pharmacologic
agents [9], enzymes inhibitors [10], peptide mimics [11] and haptens of catalytic
antibodies [12] are well documented.
123

[Et3NH][HSO4]-catalyzed one-pot, solvent-free synthesis and…
Numerous syntheses of a-aminophosphonates have been carried out under
various solvents using different types of catalysts: In(OTf)3/MgSO4 [13], GaI3 [14],
BiCl3 [15], Cu(OTf)2 [16], SbCl3/Al2O3 [17], InCl3 [18] and ZrCl4 [19] are well
documented. The synthesis of a-aminophosphonates has also been carried out in the
presence of ionic liquids [20–25], Lewis acid–surfactant-combined catalysts [26]
even in the absence of a solvent and catalyst [27], Lewis acids like ZnCl2 [28],
BF.3Et2O [29], CdI2/Benzene [30] and CdI2/microwave [31]. Under solvent-free
conditions using trifluoroacetic acid (TFA) [32], TsCl [33], LiClO4 [34], Mg(ClO4)2
[35], metal triflate [36], Na2CaP2O7 [37] and ZrOCl2Á8H2O or ZrO(ClO4)2Á6H2O
[38] as catalysts for the preparation of a-aminophosphonates are also reported.
However, most of these procedures are sluggish, require long reaction times, use
strong acidic conditions, give unsatisfactory yields and also suffer from the
formation of many side products.
Consequently, there is still a need to develop a more efficient, simple, mild and
high-yield protocol for the synthesis of a-aminophosphonates. In this regards,
ABILs [Et3NH][HSO4] would be a good candidate as it is prepared via a simple and
atom-economical, acid-base neutralization reaction from a cheap amine and acid
[39].
Results and discussion
Considering the significance of a-aminophosphonates and in continuation of our
earlier work on solvent-free reactions using catalyst\s such as camphor sulfonic acid
[40], 1-hexanesulphonic acid sodium salt [41] and alum [42] for the synthesis of a-
aminophosphonates, herein, we would like to report a new method for the synthesis
of a-aminophosphonates via a one-pot, multi-component reaction using ABILs
[Et3NH][HSO4] under solvent-free conditions.
In search of an efficient catalyst and the best experimental reaction conditions,
the reaction of benzaldehyde 1, aniline 2 and trimethyl phosphite 3 at room
temperature was considered as a standard model reaction (Scheme 1).
Initially, the reaction was carried out in the absence of the catalyst; the product
formed in a trace amount (Table 1, entry 1). To determine the appropriate
concentration of the catalyst [Et3NH][HSO4], we investigated the model reaction at
different concentrations of [Et3NH][HSO4], such as 5, 10, 15, 20 and 25 mol%. The
a-aminophosphonates formed in 70, 82, 89, 95 and 95 % yields, respectively
(Table 1, entries 2–6).
Scheme 1 Standard model reaction
123

M. H. Shaikh et al.
Yield (%)a
Table 1 Effect of catalyst
concentration
Entry
[Et3NH][HSO4]
mol%
Time
(min)
1
2
3
4
5
6
–
60
60
45
15
10
10
Trace
70
5
Reaction conditions Aldehyde
(1.25 mmol), aniline
(1.25 mmol), trimethyl
10
15
20
25
82
89
phosphite (1.25 mmol), solvent-
free at room temperature
95
95
a
Isolated yield
The increase in concentration of catalyst from 20 to 25 mol% does not increase
the yield of product. This indicates that 20 mol% of [Et3NH][HSO4] is sufficient for
the reaction by considering the product yield.
In the next step, we also compared the reported methods [20, 21, 43] using
various ionic liquids for the synthesis of a-aminophosphonates (Table 2, entries
1–8). In comparison with the above methods, [Et3NH][HSO4] provided better
results in terms of high yield and a solvent-free protocol, and the reaction was
carried out at room temperature (Table 2, entry, 8).
To evaluate the effect of solvents, dichloromethane, tetrahydrofuran, 1,4-
dioxane, toluene, acetonitrile and ethanol were used for the model reaction. It was
observed that the use of solvents retards the reaction rate and affords the desired
product in lower yields than that for neat conditions (Table 3).
The recyclability of the ionic liquid [Et3NH][HSO4] was also studied and the
results are summarized in Table 4. After the completion of the reaction, the reaction
mixture was quenched with ice crystals and extracted with ethyl acetate. The
residual ionic liquid was washed with diethyl ether, dried under vacuum at 60 °C
and reused for subsequent reactions. The recovered ionic liquid could be used for
five times without obvious loss of catalytic activity (Table 4, entries 1–5).
With these optimized reaction conditions for the model reaction, i.e. 20 mol%
[Et3NH][HSO4] catalyst, room temperature and solvent-free conditions, we
Table 2 Comparison of ionic liquids used for the synthesis of a-aminophosphonate
Entry Ionic liquid
Catalyst
Condition Time
Yield (%)a References
1
2
3
4
5
6
7
[bmim]PF6
–
–
RT
RT
8 h
82
90
55
72
86
99
96
80
[20]
[bmim]BF4
5 h
[20]
[bmim]OTf
Yb(OTf)3 MW
Yb(OTf)3 MW
Yb(OTf)3 MW
Yb(OTf)3 MW
2 min
2 min
2 min
2 min
1–3 h
27 h
[21]
[bmim]SbF6
[21]
[bmim]PF6
[21]
[bmim]BF4
[21]
[bnmim][HSO4] (50 mol%)
[bmim]PF6
–
RT
RT
RT
[23]
Sc(OTf)3
–
[43]
8
[Et3NH][HSO4]
10 min 95
Present work
a
Isolated yield
123

[Et3NH][HSO4]-catalyzed one-pot, solvent-free synthesis and…
Table 3 Screening of solvents
Entry
Solvent
Yielda (%)
1
2
3
4
5
6
7
Dichloromethane
Tetrahydrofuran
1,4-Dioxane
Toluene
42
45
48
54
56
60
95
Acetonitrile
Ethanol
ILb
Reaction conditions Aldehyde (1.25 mmol), aniline (1.25 mmol), trimethyl phosphite (1.25 mmol),
[Et3NH][HSO4] at room temperature for 20 min
a
Isolated yield
b
20 mol% [Et3NH][HSO4]
Table 4 Reusability of catalyst
for model reaction
Entry
Run
Timea (min)
Yieldb
1
2
3
4
5
1
2
3
4
5
10
10
10
10
10
95
95
92
90
90
a
Reaction progress monitored
by thin layer chromatography
b
(TLC); Isolated yield
Scheme 2 Synthesis of a-amino phosphonates 4a–n
synthesized a series of a-aminophosphonates (4a–n) by reacting benzaldehyde/
anisaldehyde (1a and 1b), anilines (2a–k) (with electron-donating and withdrawing
groups) and trimethyl phosphite (3) in excellent yields (Scheme 2). The physical
data of the synthesized a-aminophosphonates are in good agreement with the
literature reports (Table 5).
The compounds having terminal alkynes are useful intermediates for a 1,3-
dipolar cycloaddition reaction, i.e. click reaction [55–57], and also display various
123

M. H. Shaikh et al.
Table 5 Synthesis of derivatives of dimethyl (phenyl(phenylamino)methyl)phosphonate 4a–n
Compound
Structure
Yield
(%)
Melting point
(found; °C)
Melting point
(reported; °C)
4a
MeO
MeO
95
93
92
93
95
85–86
86 [44, 45]
O
P
P
P
P
N
H
4b
4c
4d
4e
MeO
MeO
60–61
60 [46]
Br
O
N
H
MeO
MeO
129–130
48–49
130 [46]
48 [46]
O
N
H
NO2
MeO
MeO
O
N
H
MeO
MeO
112–113
112 [47, 48]
NO2
O
P
N
H
MeO
4f
4g
4h
4i
MeO
MeO
92
93
93
90
94
148–149
105–106
98–99
148 [47, 48]
105 [49]
98 [50]
O
P
P
P
P
P
N
H
NO2
Br
MeO
MeO
MeO
MeO
MeO
MeO
MeO
O
N
H
MeO
MeO
O
N
H
Br
MeO
MeO
51–52
52 [50]
O
N
H
Br
4j
MeO
MeO
52–53
52 [51, 52]
F
O
N
H
123

[Et3NH][HSO4]-catalyzed one-pot, solvent-free synthesis and…
Table 5 continued
Compound
Structure
Yield
(%)
Melting point
(found; °C)
Melting point
(reported; °C)
4k
MeO
MeO
94
92
91
95
95–96
96 [44, 45]
O
P
P
P
N
H
MeO
MeO
MeO
MeO
4l
MeO
MeO
86–87
86 [50]
O
N
H
4m
4n
MeO
MeO
65–66
66 [53]
O
N
H
MeO
MeO
118–119
120 [54]
OMe
O
P
N
H
Reaction conditions Aldehyde (1.25 mmol), aniline (1.25 mmol), trimethyl phosphite (1.25 mmol),
[Et3NH][HSO4] at room temperature for 10 min
biological activities [58]. For the applicability of the above-developed methodology
for the synthesis of a-amino phosphonates, herein, we utilized the same for the
synthesis of new propargylated ether containing a-amino phosphonates. The
propargylated ether group containing aldehydes 5a–b were synthesized from the
corresponding salicylaldehydes using propargyl bromide in the presence of K2CO3
in good yields. The one-pot, solvent-free, multi-component reaction of aldehydes
5a–b with various anilines (2b, 2f, 6a–e) and trimethyl phosphate 3 in the presence
of 20 mol% [Et3N][HSO4] at room temperature afforded the corresponding
propargylated ether containing new a-amino phosphonates (7a–j) in excellent
yields (Scheme 3). The formation of a-aminophosphonate derivatives 7a–j has been
confirmed by physical data and spectroscopic methods such as proton nuclear
magnetic resonance (1H NMR) and carbon-13 (13C) NMR. In the starting material
compound 5a, the proton of alkyne C–H was observed at d 2.57 ppm, and the
singlet at d 4.79 ppm for methylene protons attached to the oxygen heteroatom and
singlet for aldehyde proton were observed at d 9.91 ppm. According to the 1H NMR
spectrum of representative compound 7b, the singlet observed at d 2.47 ppm was
for the proton of alkyne C–H, and the singlet at d 4.77 ppm was for the methylene
proton attached to the oxygen heteroatom. Similarly, a doublet was observed at d
3.37 and 3.75 ppm for methoxy protons. In addition to this, a doublet observed at d
5.29 ppm was assigned to the proton present on the methine carbon attached to
phosphorous and nitrogen heteroatoms, and a signal for an aldehydic proton was not
123

M. H. Shaikh et al.
Scheme 3 Synthesis of new propargylated ether containing a-amino phosphonates
observed, thus confirming the formation of a-amino phosphonates. Furthermore, all
the aromatic protons appeared at expected chemical shifts and integral values. The
synthesis of a-aminophosphonates was further confirmed by 13C NMR spectral data,
in which the carbon signals of –OCH3 groups were resonated at d 46.1 and
49.2 ppm, respectively. The signals at d 53.8 ppm indicate the presence of
methylene carbon attached to the oxygen heteroatom, and d 56.1 ppm indicates the
methine carbon attached to the nitrogen and phosphorous heteroatoms. In addition
to this, the signal observed at d 75.8 and 78.3 ppm indicates the presence of alkyne
carbon, while all other carbons gave peaks at expected values. The physical data,
yield and time required to complete the reactions are given in spectroscopic data.
1
The proposed structures were confirmed by H NMR and 13C NMR (supporting
information).
Plausible mechanism
The two-step reaction mechanism is similar to that reported in the literature using an
acid catalyst. The first step involves the activation of a carbonyl group via
protonation by acidic ionic liquid [Et3N][HSO4] and then a nucleophilic attack of
aromatic amine produces imine after removal of water (Fig. 1). In the second step,
the nucleophilic attack of trimethyl phosphite on imine gives a phosphonium
intermediate, which, followed by the attack of water, gave the a-amino phospho-
nate, methanol and regeneration of [Et3NH][HSO4].
Antifungal activity
All the synthesized, new propargylated ethers containing a-amino phosphonate
derivatives 7a–j showed good to excellent antifungal activity against the five fungal
strains (Table 6). Compound 7d having bromo- at the R1 position and fluoro- at the
R4 position and compound 7h having bromo- at the R1position, chloro- at R2 and R5
123

[Et3NH][HSO4]-catalyzed one-pot, solvent-free synthesis and…
Fig. 1 Plausible mechanism for the formation of a-amino phosphonates
positions of the phenyl ring has been found to be a good inhibitor of C. albicans
with a minimum inhibitory concentration (MIC) value of 25 lg/mL were equipotent
to the standard drug miconazole and less potent as compared to fluconazole.
Compounds 7c (chloro- group at R4) and 7j (bromo- group at R1 and R3) with MIC
values of 25 lg/mL showed equivalent potency for fungal strain A. niger as
compared to the standard drug miconazole.
Antioxidant activity
According to the 1,1-diphenyl-1-picrylhydrazyl (DPPH) assay, compounds 7d
having bromo- at the R1 position and fluoro- at the R4 position, 7e having bromo- at
the R1 and R4 positions, 7f having bromo- at the R1 position and chloro- at the R4
position, 7g having bromo- at the R1 position and methoxy- at the R3 position, and 7i
having bromo- at the R1 position and fluoro- at the R2 position exhibited better
radical scavenging activity than the synthetic commercial antioxidant butylated
hydroxytoluene (BHT), with half maximal inhibitory concentration (IC50) values of
12.74, 15.76, 14.30, 12.90 and 14.23 lg/mL, respectively (Table 6). Similarly,
compounds 7d having bromo- at the R1 position and fluoro- at the R4 position, and
7g having bromo- at the R1 position and methoxy- at the R3 position shows excellent
antioxidant activity compared to the standard antioxidant drug ascorbic acid with
IC50 values of 12.74 and 12.90 lg/mL, respectively.
123

M. H. Shaikh et al.
Table 6 In vitro antifungal and antioxidant evaluation of new propargylated ether containing a-
aminophosphonates
Entry
Structure
Antifungal activity
Antioxidant activity
IC50 (lg/mL)
DPPH scavenging
activity
MIC Values in lg/mL
CA
FO
AF
AN
CN
7a
100
150
100
50
*
22.11
18.24
19.14
12.74
15.76
14.30
12.90
7b
7c
7d
7e
7f
150
100
25
125
150
150
*
75
75
25
50
50
50
100
125
50
50
50
125
150
50
100
125
125
100
150
150
100
7g
50
125
123

[Et3NH][HSO4]-catalyzed one-pot, solvent-free synthesis and…
Table 6 continued
Entry
Structure
Antifungal activity
Antioxidant activity
IC50 (lg/mL)
DPPH scavenging
activity
MIC Values in lg/mL
CA
FO
AF
AN
CN
7h
25
50
50
*
*
16.80
14.23
16.83
7i
7j
75
100
100
*
*
150
150
100
25
*
MA
FA
–
–
–
–
25
6.25
–
25
6.25
–
12.5
6.25
–
25
12.5
–
25
6.25
–
NT
NT
BHT
AA
16.47
12.69
–
–
–
–
–
CA Candida albicans, FO Fusarium oxysporum, AF Aspergillus flavus, AN Aspergillus niger, CN
Cryptococcus neoformans, MA Miconazole, FA Fluconazole, BHT Butylated Hydroxy Toluene, AA
Acsorbic acid
* and – No activity was observed up to 200 lg/mL
In silico ADME prediction
A computational study was performed for prediction of ADME properties and it was
observed that the compounds exhibited a good % absorption (% ABS) ranging from
86.21 to 89.40 % (Table 7). Furthermore, none of the synthesized compounds
violated Lipinski’s rule of five. Therefore, a molecule likely to be developed as an
orally active drug candidate should show no more than one violation of the
following four criteria: miLog P (octanol–water partition coefficient) B5, molecular
weight B500, number of hydrogen bond acceptors B10 and number of hydrogen
bond donors B5 [59]. The larger the value of the drug likeness model score, the
higher is also probability that the particular molecule will be active. Therefore,
compound 7c was found to be most active of the synthesized compounds. All the
tested compounds followed the criteria for an orally active drug and, therefore, these
compounds may have a good potential for eventual development as oral agents.
123

M. H. Shaikh et al.
Table 7 Pharmacokinetic parameters important for good oral bioavailability
Entry
%
TPSA n-
MV
MW
miLog n-
n-
ON OHNH violation likeness
model score
Lipinski Drug-
ABS (A2)
ROTB
P
Rule
7a
7b
7c
7d
7e
7f
–
–
–
8
8
8
8
8
8
9
8
8
8
–
\500
B5
\10 \5
B1
0
–
89.40 56.80
89.40 56.80
89.40 56.80
89.40 56.80
89.40 56.80
89.40 56.80
86.21 66.03
89.40 56.80
89.40 56.80
89.40 56.80
317.10 363.32 2.99
330.05 424.23 3.64
325.70 379.78 3.50
334.98 442.22 3.77
347.94 503.13 4.42
343.59 458.68 4.29
355.60 454.26 3.64
357.12 493.12 4.90
334.98 442.22 3.73
347.94 503.13 4.40
5
5
5
5
5
5
6
5
5
5
1
1
1
1
1
1
1
1
1
1
0.30
0
0.12
0
0.48
0
-0.40
-0.37
-0.25
-0.48
-0.03
-0.25
-0.41
1
0
7g
7h
7i
0
0
0
7j
1
ABS absorption; TPSA topological polar surface area; n-ROTB number of rotatable bonds; MV molecular
volume; MW molecular weight; lmiLog P logarithm of partition coefficient; n-ON number of hydrogen
bond acceptors; n-OHNH number of hydrogen bonds donors.
Conclusion
In summary, we have developed an efficient, greener and expeditious synthetic
protocol for a-amino phosphonates as antifungal and antioxidant agents. This
technique overcomes some of the problems associated with excessive or wasteful
heating. Remarkable advantages of this synthetic strategy over others are: (1)
reaction performs at ambient room temperature, (2) reduced reaction time, (3) non-
toxic and economically viable catalyst, (4) omission of solvent and (5) simplified
work-up procedure. This is the first report on the use of [Et3NH][HSO4] catalyst for
the syntheses of a-amino phosphonates.
Experimental
All the solvents and reagents were purchased from commercial suppliers
Spectrochem Pvt. Ltd., Sigma Aldrich and Rankem India Ltd., and were used
without further purification. The progress of each reaction was monitored by
ascending TLC using TLC aluminum sheets, pre-coated silica gel F254 (Merck,
Germany) and by locating the spots using ultraviolet (UV) light as the visualizing
agent or iodine vapors. Melting points were taken in an open capillary method and
1
are uncorrected. H NMR spectra were recorded [deuterated chloroform (CDCl3)]
on a Bruker Avance 200 NMR spectrometer. 13C NMR spectra were recorded
(CDCl3) on a Bruker Avance 50 NMR spectrometer. Chemical shifts (d) are
reported in parts per million (ppm) using tetramethylsilane (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 multiplet (m).
123

[Et3NH][HSO4]-catalyzed one-pot, solvent-free synthesis and…
Synthesis of [Et3NH][HSO4]
Sulfuric acid (1.96 g, 0.02 mol) 98 % solution in water was dropped into
triethylamine (2.02 g, 0.02 mol) with stirring at 60 °C for 1 h. After the addition,
the reaction mixture was stirred for another 1 h at 70 °C. The water molecule was
removed by heating the residue at 80–90 °C under a high vacuum until the weight
of the residue remained constant.
General procedure for the one-pot synthesis of dimethyl
(phenyl(phenylamino)methyl)phosphonates (4a–n) and dimethyl ((phenylamino)(2-
(prop-2-yn-1-yloxy)phenyl)methyl)phosphonate (7a–j)
A mixture of aldehyde (1.25 mmol), aniline (1.25 mmol), trimethyl phosphite
(1.25 mmol) and [Et3NH][HSO4] (20 mol%) was magnetically stirred at room
temperature for 10 min. The progress of the reaction was monitored by TLC using
ethyl acetate:hexane as a solvent system. The reaction mixture was quenched with
crushed ice and extracted with ethyl acetate (2 9 25 mL). The organic extracts
were washed with brine (2 9 25 mL) and dried over anhydrous sodium sulphate.
The solvent was evaporated under reduced pressure to afford the corresponding
crude compounds. The obtained crude compounds were recrystallized using
ethanol.
Spectral data
2-(prop-2-yn-1-yloxy)benzaldehyde (5a) Compound 5a, as an off-white solid, was
obtained via alkylation of salicylaldehyde with propargyl bromide using K2CO3 as a
base in 2 h with a 95 % yield. Melting point (Mp.) 48–50 °C. 1H NMR (400 MHz,
CDCl3, ppm): d 2.57 (s, 1H, alkyne C–H), 4.79 (s, 2H, –OCH2), 7.10 (d, 2H, Ar–H,
J = 8 Hz), 7.87 (d, 2H, Ar–H, J = 8 Hz), and 9.91 (s, 1H, CHO).
Dimethyl (((4-fluorophenyl)amino)(2-(prop-2-yn-1-yloxy)phenyl)methyl)phospho-
nate (7a) Compound 7a, as an off-white solid, was obtained via one-pot, three-
component condensation between 2-(prop-2-yn-1-yloxy)benzaldehyde (5a), 4-flu-
oroaniline (6a) and trimethylphosphite (3) using 20 mol% of catalyst [Et3-
1
NH][HSO4] in 10 min with a 95 % yield. Mp. 124–125 °C. H NMR (200 MHz,
CDCl3, ppm): d 2.47 (s, 1H), 3.38 (d, 3H, J = 6 Hz), 3.76 (d, 3H, J = 6 Hz), 4.76
(s, 2H), 5.28 (d, 1H, J = 12 Hz), 6.50 (d, 2H, J = 2 Hz), 6.69–6.73 (m, 2H),
6.91–6.95 (m, 2H), 7.18 (s, 1H) and 7.41 (d, 1H, J = 4 Hz).
Dimethyl (((4-bromophenyl)amino)(2-(prop-2-yn-1-yloxy)phenyl)methyl)phospho-
nate (7b) Compound 7b as an off-white solid was obtained via one-pot, three-
component condensation between 2-(prop-2-yn-1-yloxy)benzaldehyde (5a), 4-bro-
moaniline (2b) and trimethylphosphite (3) using 20 mol% of catalyst [Et3-
NH][HSO4] in 10 min with a 95 % yield. Mp. 110 °C. 1H NMR (200 MHz,
CDCl3, ppm): d 2.47 (s, 1H), 3.37 (d, 3H, J = 4 Hz), 3.75 (d, 3H, J = 4 Hz), 4.77
123

M. H. Shaikh et al.
(s, 2H), 5.29 (d, 1H, J = 10 Hz), 6.43 (d, 2H, J = 4 Hz), 6.89–6.95 (m, 2H), 7.09
(d, 2H, J = 4 Hz), 7.18–7.21 (t, 1H) and 7.40 (d, 1H, J = 2 Hz). 13C NMR
(50 MHz, CDCl3, ppm): d 46.1, 49.2, 53.8, 56.1, 75.8, 78.3, 112, 114.9, 122.1, 123,
124.3, 128.4, 129, 144.4, 144.7 and 155.1.
Dimethyl (((4-chlorophenyl)amino)(2-(prop-2-yn-1-yloxy)phenyl)methyl)phospho-
nate (7c) Compound 7c as an off-white solid was obtained via one-pot, three-
component condensation between 2-(prop-2-yn-1-yloxy)benzaldehyde (5a),
4-chloroaniline (6b) and trimethylphosphite (3) using 20 mol% of catalyst
1
[Et3NH][HSO4] in 10 min with a 95 % yield. Mp. 110 °C. H NMR (200 MHz,
CDCl3, ppm): d 2.47 (s, 1H), 3.37 (d, 3H, J = 4 Hz), 3.75 (d, 3H, J = 4 Hz), 4.77
(s, 2H), 5.29 (d, 1H, J = 10 Hz), 6.48 (d, 2H, J = 2 Hz), 6.89–6.96 (m, 4H),
7.17–7.20 (t, 1H) and 7.40 (d, 1H, J = 4 Hz). 13C NMR (50 MHz, CDCl3, ppm): d
46.6, 49.7, 53.9, 56.1, 75.7, 78.4, 112, 114.6, 114.7, 115.4, 115.8, 122, 124.5, 128.4,
128.5, 129.1 and 155.
Dimethyl ((5-bromo-2-(prop-2-yn-1-yloxy)phenyl)((4-fluorophenyl)amino)methyl)
phosphonate (7d) Compound 7d as an off-white solid was obtained via one-pot,
three-component condensation between 5-bromo-2-(prop-2-yn-1-yloxy)benzalde-
hyde (5b), 4-fluoroaniline (6a) and trimethylphosphite (3) using 20 mol% of
catalyst [Et3NH][HSO4] in 10 min with a 95 % yield. Mp. 118 °C. 1H NMR
(200 MHz, CDCl3, ppm): d 2.57–2.60 (m, 1H), 3.58 (d, 3H, J = 10 Hz), 3.84 (d,
3H, J = 10 Hz), 4.87 (d, 2H, J = 2 Hz), 5.20–5.51 (m, 2H), 6.50 (d, 1H,
J = 2 Hz), 6.59–6.69 (m, 1H), 6.95 (d, 1H, J = 8 Hz), 7.15 (d, 1H, J = 8 Hz),
7.36–7.42 (m, 1H) and 7.54–7.56 (t, 1H). 13C NMR (50 MHz, CDCl3, ppm): d 46.6,
49.7, 53.9, 56.4, 76.2, 77.8, 113.8, 113.9, 114.5, 114.6, 115.5, 115.9, 127.2, 131.2,
131.9, 154 and 158.8.
Dimethyl ((5-bromo-2-(prop-2-yn-1-yloxy)phenyl)((4-bromophenyl)amino)methyl)
phosphonate (7e) Compound 7e as an off-white solid was obtained via one-pot,
three-component condensation between 5-bromo-2-(prop-2-yn-1-yloxy)benzalde-
hyde (5b), 4-bromoaniline (2b) and trimethylphosphite (3) using 20 mol% of
catalyst [Et3NH][HSO4] in 10 min with a 95 % yield. Mp. 136 °C.
Dimethyl ((5-bromo-2-(prop-2-yn-1-yloxy)phenyl)((4-chlorophenyl)amino)methyl)
phosphonate (7f) Compound 7f as an off-white solid was obtained via one-pot,
three-component condensation between 5-bromo-2-(prop-2-yn-1-yloxy)benzalde-
hyde (5b), 4-chloroaniline (6b) and trimethylphosphite (3) using 20 mol% of
catalyst [Et3NH][HSO4] in 10 min with a 95 % yield. Mp. 140 °C. 1H NMR
(200 MHz, CDCl3, ppm): d 2.49 (s, 1H), 3.46 (d, 3H, J = 4 Hz), 3.76 (d, 3H,
J = 6 Hz), 4.76 (s, 2H), 5.21 (d, 1H, J = 12 Hz), 6.46 (d, 2H, J = 2 Hz), 6.84 (d,
1H, J = 4 Hz), 6.98 (d, 2H, J = 2 Hz), 7.29 (d, 1H, J = 4 Hz) and 7.50 (s, 1H).
13C NMR (50 MHz, CDCl3, ppm): d 46.1, 49.2, 54, 56.3, 76.2, 77.8, 113.8, 114.8,
123.3, 127.1, 129.1, 131.1, 131.2, 131.9, 144.1, 144.4 and 154.
123

[Et3NH][HSO4]-catalyzed one-pot, solvent-free synthesis and…
Dimethyl((5-bromo-2-(prop-2-yn-1-yloxy)phenyl)((3-methoxyphenyl)amino)methyl)
phosphonate (7g) Compound 7g as an off-white solid was obtained via one-pot,
three-component condensation between 5-bromo-2-(prop-2-yn-1-yloxy)benzalde-
hyde (5b), 3-methoxyaniline (6c) and trimethylphosphite (3) using 20 mol% of
catalyst [Et3NH][HSO4] in 20 min with a 95 % yield. Mp. 102 °C.
Dimethyl
((5-bromo-2-(prop-2-yn-1-yloxy)phenyl)((2,5-dichlorophenyl)amino)-
methyl) phosphonate (7h) Compound 7h as an off-white solid was obtained via
one-pot, three-component condensation between 5-bromo-2-(prop-2-yn-1-
yloxy)benzaldehyde (5b), 2,5-dichloroaniline (6d) and trimethylphosphite (3) using
20 mol% of catalyst [Et3NH][HSO4] in 30 min with a 95 % yield. Mp. 142 °C.
Dimethyl ((5-bromo-2-(prop-2-yn-1-yloxy)phenyl)((2-fluorophenyl)amino)methyl)
phosphonate (7i) Compound 7i as an off-white solid was obtained via one-pot,
three-component condensation between 5-bromo-2-(prop-2-yn-1-yloxy)benzalde-
hyde (5b), 2-fluoroaniline (6e) and trimethylphosphite (3) using 20 mol% of
catalyst [Et3NH][HSO4] in 30 min with a 95 % yield. Mp. 92–93 °C.
Dimethyl((5-bromo-2-(prop-2-yn-1-yloxy)phenyl)((3-bromophenyl)amino)methyl)
phosphonate (7j) Compound 7j as an off-white solid was obtained via one-pot,
three-component condensation between 5-bromo-2-(prop-2-yn-1-yloxy)benzalde-
hyde (5b), 3-bromoaniline (2f) and trimethylphosphite (3) using 20 mol% of
catalyst [Et3NH][HSO4] in 20 min with a 95 % yield. Mp. 158 °C. 1H NMR
(200 MHz, CDCl3, ppm): d 2.53–2.60 (m, 1H), 3.54 (d, 3H, J = 10 Hz), 3.83 (d,
3H, J = 12 Hz), 4.83 (s, 2H), 5.26 (d, 1H, J = 22 Hz), 6.50–6.57 (m, 2H),
6.77–6.93 (m, 3H), 7.33–7.39 (m, 1H) and 7.57–7.68 (m, 1H).
Experimental protocol for biological activity
Antifungal activity
The antifungal activity was evaluated against five human pathogenic fungal strains,
such as Candida albicans (NCIM 3471), Fusarium oxysporum (NCIM 1332),
Aspergillus flavus (NCIM 539), Aspergillus niger (NCIM 1196), Cryptococcus
neoformans (NCIM 576), which are often encountered clinically and were
compared with standard drug miconazole. MIC values were determined using the
standard agar method [60].
DPPH radical scavenging antioxidant activity
The hydrogen atom or electron donation ability of the some compounds were
measured from the bleaching of the purple-colored methanol solution of DPPH [61].
The spectrophotometric assay uses the stable radical DPPH as a reagent. 1 mL of
various concentrations of the test compounds (5, 10, 25, 50 and 100 lg/mL) in
methanol was added to 4 mL of 0.004 % (w/v) methanol solution of DPPH. The
123

M. H. Shaikh et al.
reaction mixture was incubated at 37 °C. The scavenging activity on DPPH was
determined by measuring the absorbance at 517 nm after 30 min. All tests were
performed in triplicate and the mean values were entered. The percent of inhibition
(I %) of free radical production from DPPH was calculated by the following
equation: % of scavenging = [(Acontrol - Asample)/(Asample 9 100)], where Acontrol is
the absorbance of the control (DPPH radical without the test sample) and Asample is
the absorbance of the test sample (DPPH radical with the test sample). The control
contains all reagents except the test samples.
In silico ADME prediction
The success of a drug is determined not only by good efficacy but also by an
acceptable ADME profile. In the present study, we calculated molecular volume
(MV), molecular weight (MW), logarithm of partition coefficient (miLog P),
number of hydrogen bond acceptors (n-ON), number of hydrogen bonds donors
(n-OHNH), topological polar surface area (TPSA), number of rotatable bonds
(n-ROTB) and Lipinski’s rule of five [62] using a Molinspiration online property
calculation toolkit [63]. Absorption (% ABS) was calculated by:
%
ABS = 109 - (0.345 9 TPSA) [64]. Drug-likeness model score (a collective
property of physical–chemical properties, pharmacokinetics and pharmacodynamics
of a compound represented by a numerical value) was computed by Mol Soft
software [65].
Acknowledgments The authors, M.H.S. and D.D.S., are very grateful for the award of senior research
fellowship bestowed by the Council of Scientific and Industrial Research (CSIR), New Delhi. The authors
are also thankful to the head of the Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada
University, for providing laboratory facilities.
References
1. Z. Lei, C. Dai, B. Chen, Chem. Rev. 114, 1289 (2014)
2. M.V. Fedorov, A.A. Kornyshev, Chem. Rev. 114, 2978 (2014)
3. X.X. Han, H. Du, C.T. Hung, L.L. Liu, P.H. Wu, D.H. Ren, S.J. Huang, S.B. Liu, Green Chem. 17,
499 (2015)
4. Z.N. Siddiqui, K. Khan, ACS Sustain. Chem. Eng. 2, 1187 (2014). (reference cited their in)
5. L.D. Quin, G.S. Quin, A Guide to Organophosphorus Chemistry (Wiley, New York, 2000)
6. D.E.C. Corbridge, Phosphorus Chemistry, Biochemistry and Technology (Elsevier, Amsterdam,
2000)
7. R. Engel, Chem. Rev. 77, 349 (1977)
8. R.A. Lerner, S.J. Benkovic, P.G. Schultz, Science 252, 659 (1991)
9. M.R. Saidi, N. Azizi, Synlett 8, 1347 (2002)
10. M. Sienczyk, J. Oleksyszyn, Curr. Med. Chem. 16, 1673 (2009)
11. K. Panigrahi, M.J. Eggen, J.H. Maeng, Q. Shen, D.B. Berkowitz, Chem. Biol. 16, 928 (2009)
12. R. Hirschmann, A.B. Smith, C.M. Taylor, P.A. Benkovic, S.D. Taylor, K.M. Yager, P.A. Sprengler,
S. Venkovic, J. Sci. 265, 234 (1994)
13. R. Ghosh, S. Maiti, A. Chakraborty, D. Maiti, J. Mol. Cat. Chem. 53, 210 (2004)
14. P.P. Sun, Z.X. Hu, Z.H. Huang, Synth. Commun. 34, 4293 (2004)
15. Z.P. Zhan, J.P. Li, Synth. Commun. 35, 2501 (2005)
16. A.S. Paraskar, A. Sudalai, Arkivoc X, 183 (2006)
123

[Et3NH][HSO4]-catalyzed one-pot, solvent-free synthesis and…
17. K.S. Ambica, S.C. Taneja, M.S. Hundal, K.K. Kapoor, Tetrahedron Lett. 49, 2208 (2008)
18. B.C. Ranu, A. Hajra, U. Jana, Org. Lett. 1, 1141 (1999)
19. J.S. Yadav, B.V.S. Reddy, S. Raj, K.B. Reddy, A.R. Prasad, Synthesis 15, 2277 (2001)
20. J.S. Yadav, B.V.S. Reddy, P. Sreedhar, Green Chem. 4, 436 (2002)
21. S. Lee, J.K. Lee, C.E. Song, D.C. Kim, Bull. Korean Chem. Soc. 23, 667 (2002)
22. Z. Zhou, Y. Pei, L. Wu, Org. Chem. Int. (2012). doi:10.1155/2012/375656
23. S.A. Sadaphal, S.S. Sonar, A.H. Kategaonkar, M.S. Shingare, Bull. Korean Chem. Soc. 30, 1054
(2009)
24. S. Lee, J.H. Park, J. Kang, J.K. Lee, Chem. Commun. 1698 (2001)
25. S.A. Dake, D.S. Raut, K.R. Kharat, R.S. Mhaske, S.U. Deshmukh, R.P. Pawar, Bioorg. Med. Chem.
Lett. 21, 2527 (2011)
26. K. Manabe, S. Kobayashi, Chem. Commun. 669 (2000)
27. S. Chandrasekhar, C. Narsihmulu, S.S. Sultana, B. Saritha, S.J. Prakash, Synlett 4, 505 (2003)
28. J. Zou, Pol. J. Chem. 55, 643 (1981)
29. S. Laschat, H. Kunz, Synthesis 90 (1992)
30. M.M. Kabachnik, T.N. Ternovskaya, E.V. Zobnina, I.P. Beletskaya, Russ. J. Org. Chem. 38, 480
(2002)
31. M.M. Kabachnik, E.V. Zobnina, I.P. Beletskaya, Russ. J. Org. Chem. 41, 505 (2005)
32. T. Akiyama, M. Sanada, K. Fuchibe, Synlett 10, 1463 (2003)
33. B. Kaboudin, E. Jafari, Synlett 12, 1837 (2008)
34. N. Azizi, F. Rajabi, M.R. Saidi, Tetrahedron Lett. 45, 9233 (2004)
35. S. Bhagat, A.K. Chakraborti, J. Org. Chem. 72, 1263 (2007)
36. H. Firouzabadi, N. Iranpoor, S. Sobhani, Synthesis 16, 2692 (2004)
37. A. Elmakssoudi, M. Zahouily, A. Mezdar, A. Rayadh, S. Sebti, Comptes Rendus Chim. 8, 1954
(2005)
38. S. Bhagat, A.K. Chakraborti, J. Org. Chem. 73, 6029 (2008)
39. J. Weng, C. Wang, H. Li, Y. Wang, Green Chem. 8, 96 (2006)
40. P.V. Shinde, A.H. Kategaonkar, B.B. Shingate, M.S. Shingare, Tetrahedron Lett. 52, 2889 (2011)
41. K.S. Niralwad, B.B. Shingate, M.S. Shingare, Ultra. Sonochem. 17, 760 (2010)
42. S.S. Sonar, S.A. Sadaphal, N.V. Shitole, N.R. Jogdand, B.B. Shingate, M.S. Shingare, Bull. Korean
Chem. Soc. 30, 1711 (2009)
43. S. Lee, J.H. Park, J. Kang, J.K. Lee, Chem. Commun. 1698 (2001)
44. C. Qian, T. Huang, J. Org. Chem. 63, 4125 (1998)
45. X.J. Mu, M.Y. Lei, J.P. Zou, W. Zhang, Tetrahedron Lett. 47, 1125 (2006)
46. B. Karmakar, S. Paul, J. Banerji, Arkivoc ii, 161 (2011)
47. R. Ghosh, S. Maiti, A. Chakraborty, D.J. Maiti, Mol. Catal. A: Chem. 210, 53 (2004)
48. M. Xia, Y.D. Lu, Ultra. Sonochem. 14, 235 (2007)
49. B.C. Ranu, A. Hajra, Green Chem. 4, 551 (2002)
50. M.H. Sarvari, Tetrahedron 64, 5459 (2008)
51. R.K. Reddy, A. Vijender, P. Krishnaiah, G. Venkataramana, V.L. Reddy, Venkateswarlu. Synth.
Commun. 34, 1677 (2004)
52. X.Y. Lv, J.M. Zhang, C.H. Xing, W.Q. Du, S.Z. Zhu, Synth. Commun. 37, 743 (2007)
53. M. Zahouily, A. Elmakssoudi, A. Mezdar, A. Rayadh, S. Sebti, Catal. Commun. 8, 225 (2007)
54. S. Chandrasekhar, S.J. Prakash, V. Jagadeswar, C. Narsihmulu, Tetrahedron Lett. 42, 5561 (2001)
55. H.C. Kolb, M.G. Finn, K.B. Sharpless, Angew. Chem. Int. Ed. 40, 2004 (2001)
56. V.V. Rostovtsev, L.G. Green, V.V. Fokin, K.B. Sharpless, Angew. Chem. Int. Ed. 41, 2596 (2002)
57. C.W. Tornoe, C. Christensen, M. Meldal, J. Org. Chem. 67, 3057 (2002)
58. C. Arkona, J. Rademann, Angew. Chem. Int. Ed. 52, 8210 (2013)
59. P. Ertl, B. Rohde, P. Selzer, J. Med. Chem. 43, 3714 (2000)
60. D. Greenwood, R.C.B. Slack, J.F. Peutherer, Medical Microbiology, 14th edn. (ELBS, London, 1992)
61. M. Burits, F. Bucar, Phytother. Res. 14, 323 (2000)
62. C.A. Lipinski, L. Lombardo, B.W. Dominy, P.J. Feeney, Adv. Drug Deliv. Rev. 46, 3 (2001)
63. Molinspiration Chemoinformatics Brastislava, Slovak Republic. http://www.molinspiration.com/cgi-
bin/properties (2014)
64. Y. Zhao, M.H. Abraham, J. Lee, A. Hersey, N.C. Luscombe, G. Beck, B. Sherborne, I. Cooper,
Pharm. Res. 19, 1446 (2002)
65. Drug-likeness and molecular property prediction, available from: http://www.molsoft.com/mprop/
123