Highly efficient one-pot synthesis of α-aminophosphonates using nanoporous AlSBA-15 catalyst in a three-component system

Article abstract of DOI:10.1007/s11164-018-3458-1

Nanoporous AlSBA-15 catalysts with different nSi/nAl ratios (41, 129, and 210) were synthesized using a hydrothermal method. These catalysts were characterized by XRD, N₂ sorption, TPD-NH₃, FT-IR, SEM and TEM. XRD analyses of AlSBA-15 catalysts confirmed the presence of well-ordered crystalline structure with p6mm symmetry. The specific surface area and specific pore volume of the AlSBA-15 catalysts are in the range of 480 to 757?m²/g and 0.65 to 0.95?cm³/g, respectively. The catalytic performance of nanoporous AlSBA-15 catalysts are used as an outstanding catalytic system for one-pot synthesis of α-aminophosphonates via Kabachnik-Fields reaction in a three-component system using amines (primary/secondary), carbonyl compounds (aldehydes/ketones) and diethyl phosphite. The major advantages of the present contributions are excellent yields, short reaction time, simple experimental technique, high chemo-selectivity, catalyst recyclability, easy work-up procedure and green approach. Three-component synthesis of α-aminophosphonates follows first imine formation from amine and aldehyde/ketone followed by phosphate addition. The experimental findings suggest that the nanoporous AlSBA-15 catalysts can be recycled and reused up to six cycles without any loss in the catalytic performance.

Full text of DOI:10.1007/s11164-018-3458-1

Res Chem Intermed
https://doi.org/10.1007/s11164-018-3458-1
Highly efficient one-pot synthesis of
a-aminophosphonates using nanoporous AlSBA-15
catalyst in a three-component system
Murali Krishna Kolli1,3 Elamathi Palani1
•
•
Chandrasekar Govindasamy1,2 Vishweshwar Rao Katta3
•
Received: 9 December 2017 / Accepted: 3 May 2018
Ó Springer Science+Business Media B.V., part of Springer Nature 2018
Abstract Nanoporous AlSBA-15 catalysts with different nSi/nAl ratios (41, 129,
and 210) were synthesized using a hydrothermal method. These catalysts were
characterized by XRD, N2 sorption, TPD-NH3, FT-IR, SEM and TEM. XRD
analyses of AlSBA-15 catalysts confirmed the presence of well-ordered crystalline
structure with p6mm symmetry. The specific surface area and specific pore volume
of the AlSBA-15 catalysts are in the range of 480 to 757 m2/g and 0.65 to 0.95 cm3/
g, respectively. The catalytic performance of nanoporous AlSBA-15 catalysts are
used as an outstanding catalytic system for one-pot synthesis of a-aminophospho-
nates via Kabachnik-Fields reaction in a three-component system using amines
(primary/secondary), carbonyl compounds (aldehydes/ketones) and diethyl phos-
phite. The major advantages of the present contributions are excellent yields, short
reaction time, simple experimental technique, high chemo-selectivity, catalyst
recyclability, easy work-up procedure and green approach. Three-component syn-
thesis of a-aminophosphonates follows first imine formation from amine and
aldehyde/ketone followed by phosphate addition. The experimental findings suggest
that the nanoporous AlSBA-15 catalysts can be recycled and reused up to six cycles
without any loss in the catalytic performance.
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11164-
018-3458-1) contains supplementary material, which is available to authorized users.
&
Chandrasekar Govindasamy
gc_sekar78@yahoo.co.in
1
2
Chemistry Division, School of Advanced Sciences, VIT University, Chennai 600 127, India
Institute of Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal
University, Dammam 31441, Kingdom of Saudi Arabia
3
Department of Medicinal Chemistry, GVK Biosciences Pvt. Ltd., IDA Nacharam,
Hyderabad 500 076, India
123

M. K. Kolli et al.
Keywords a-Aminophosphonates Á Amines Á AlSBA-15 Á Heterogeneous
nanoporous catalysis Á Solid acid catalyst
Introduction
a-Aminophosphonates play an important role in medicinal chemistry and
biosciences as their core moiety is used as a novel pharmacophore in drug design.
a-Aminophosphonates and their derivatives possess an excellent bioactivity such as
anti-HIV [1], anti-cancer [2–6], anti-tumor [7–9], anti-inflammatory [10–14], anti-
bacterial [15–17], and antibiotic [18, 19] activities. Owing to the potential
importance of a-aminophosphonate and its derivatives, several researchers have put
forth much effort in the development of synthesis methodology. Various catalysts
have been applied thus far for the synthesis of a-aminophosphonates using various
homogeneous and heterogeneous Lewis and Brønsted acid catalysts [20–36]. But
some of the methodologies endure a few setbacks such as unavailable starting
materials, use of corrosive catalysts, multi-step process, high temperature, long
reaction time, non-compatible solvent, and low product yields. Use of these
homogeneous Lewis acid and Brønsted acids catalysts cannot be easily separated
from the reaction mixture, recycled and reused for the next reaction run. The one-
pot synthesis method in organic synthesis is very attractive in modern synthetic
chemistry as it has the following advantages: (1) avoids the reaction work-up
process at each stage, (2) eco-friendly and economical by avoiding many reagents
and solvents, (3) purification of intermediate compounds saves time and resources,
(4) high product yield. Thus, effort in the development of inexpensive and
environmentally acceptable method for the synthesis of a-aminophosphonates is
highly desirable. One-pot synthesis of a-aminophosphonates cannot be synthesized
directly from amine, carbonyl compound and dialkyl phosphite due to the formation
of water molecules during intermediate step of imine formation, which deactivates
the Lewis and Brønsted acid sites of the catalysts [19]. This drawback is partly
overcome using some catalysts such as lanthanide triflates/MgSO4 [37], InCl3 [38],
TaCl5–SiO2 [39], bismuth nitrate pentahydrate [30], MgClO4 [40], TiO2 [41],
Amberlite-IR 120 [35], sulfamic acid [32], H3PW12O40 [31], trimethylanilinium
chloride [42], lithium perchlorate [43], Amberlyst-15 [44], and ZrOCl2.8H2O [45].
Several research groups focused their interest on the synthesis of simple aromatic
derived a-aminophosphonates using simple aromatic amines, aldehydes and
phosphites, but limited by heterocyclic derived a-aminophosphonates. Among
various heterocyclic compounds known, the pyrazole [46–48] and pyrimidine
[49, 50] skeleton is considered to be the most ‘‘privileged’’ structure due to its
biological and pharmaceutical properties. Thus, finding suitable new catalytic
system for the synthesis of heterocycle derived a-aminophosphonates is an
important task for organic chemists. In recent years, heterogeneous catalysis has
emerged as a sustainable and competitive alternative to conventional homogeneous
catalysis [51–58] due to the ease of separation, recovery, and catalyst reusability.
Few attempts have been made to perform the Kabachnik-Fields reaction using
123

Highly efficient one-pot synthesis of a-aminophosphonates…
different heterogeneous catalytic system [59–65]. But the experimental results
showed poor catalytic performance due to low specific surface area, irregular pore
system, which leads to low conversion and product selectivity [63, 64, 66–74].
The nanoporous AlSBA-15 aluminosilicates possess excellent characteristics of a
large specific surface area (* 700 m2/g), uniform narrow pore size distribution
ranging from 4.5 to 30 nm with considerable thicker pore wall (3 to 6 nm), high
thermal/hydrothermal stability (800 °C), and strong Brønsted/Lewis acidity. All
these characteristics made these materials are attractive for a wide range of
applications in heterogeneous catalysis [75–77].
Therefore, to best of our knowledge, for the first time we report the one-pot
synthesis of a-aminophosphonate via Kabachnik-Fields reaction with a three-
component system of amines, aldehydes/ketones and diethyl phosphite using
nanoporous AlSBA-15 solid acid catalyst at 50 °C with short reaction time in a neat
reaction condition.
Experimental
Catalyst preparation
The nanoporous AlSBA-15 silica with different nSi/nAl ratios (41, 129 and 210)
was synthesized by employing optimized procedure with the molar gel composition
of TEOS: 0.03–0.14 Al2O3: 0.016 P123: 0.96 HCl: 126 H2O as described elsewhere
[78]. In a typical synthesis procedure of AlSBA-15 materials, triblock copolymer of
P123 was stirred for 3 h. Thereafter, the required amount of HCl was added and
stirred for another 2 h. Then, the required amount of tetraethyl orthosilicate and
aluminium isopropoxide were added, and the resulting mixture was continuously
stirred at 40 °C for 24 h and then aged at 100 °C for 48 h. The crystallized product
was filtered, washed, dried, and calcined at 550 °C for 36 h. The AlSBA-15 samples
were designated as AlSBA-15 (x), where x denotes nSi/nAl ratio in the final
product.
General procedure for the synthesis of a-aminophosphonates
In a typical synthesis of a-aminophosphonates, amines (3 mmol), aldehydes
(3 mmol), and diethyl phosphite (3 mmol) were stirred well with 15 mg of AlSBA-
15 nanoporous catalyst at 50 °C. The progress and completion of the catalytic
reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate
(5 mL), and then filtered through Whatman filter paper and washed with ethyl
acetate (1 mL). The organic layer washed with saturated brine solution (3 mL),
dried over sodium sulfate, filtered and concentrated under reduced pressure. The
residue was purified by washing with diethyl ether or by using column
chromatographic separation technique with silica gel (100–200 mesh size)
stationary phase and hexane/ethyl acetate mobile phase of increasing polarity.
123

M. K. Kolli et al.
Results and discussion
The powder XRD patterns of AlSBA-15 catalysts with different nSi/nAl ratios are
shown in Fig. 1. The low angle XRD patterns (a) of AlSBA-15 samples show a very
intense peak due to (100) reflection at 2h = 0.87 and two weak peaks at 2h = 0.93
and 0.96 due to (110) and (200) reflections, respectively. This clearly indicates the
persistence of p6mm hexagonal symmetry in the nanoporous AlSBA-15 alumi-
nosilicate. It is interesting to note that the lattice parameters (d spacing and ao) of
AlSBA-15 increases significantly with the increase of aluminium content in the
synthesis gel (Table 1) due to the substitution of Al3? with ionic radii 0.57 A in
˚
place of Si4? having ionic radii of 0.26 A in the SiO2 framework. The high angle
˚
XRD patterns (b) of AlSBA-15 samples showed a broad peak at the 2h value of 24
due to the amorphous silica and there were no peaks due to aluminium oxide in
AlSBA-15. It clearly indicates that there were no agglomerated aluminum oxide
species found in AlSBA-15 samples [79].
The nitrogen sorption isotherms (a) and BJH pore size distribution (b) of AlSBA-
15 samples are shown in Fig. 2 and the textural properties are indicated in Table 1.
AlSBA-15 samples exhibit type IV adsorption isotherm with H1 hysteresis loop as
defined by IUPAC indicating the presence of a cylindrical narrow pore size
distribution in the catalytic materials. The specific surface area and the pore volume
are gradually decreased with increase in the amount of aluminium content in the
silica matrix. BJH pore size distribution of AlSBA-15 showed a narrow pore size
distribution with the maximum average pore diameter at ca. 55 A° [76, 80, 81].
The temperature programmed desorption (TPD) of pyridine data are presented in
Table 1. Three distinct weight losses were observed in the samples of AlSBA-15,
which are assumed to be the acid sites of weak (weight loss between 120 and
Fig. 1 The XRD patterns of nanoporous AlSBA-15 aluminosilicate catalysts a low angle and b high
angle
123

Highly efficient one-pot synthesis of a-aminophosphonates…
Table 1 Elemental composition and textural properties of the AlSBA-15 material
nSi/nAl
(gel)
nSi/nAl
(product)
ao
˚
(A)
d100
˚
(A)
SBET (m2/ Dp
Vp (m3/ Total acidic sites
˚
(A)
g)
g)
(mmol/g)
7
41
129
210
116
109
102
101
94
480
563
757
54
53
49
0.65
0.76
0.93
0.42
0.20
0.11
14
28
91
SBET = specific surface area, Vp = pore volume, Dp = pore diameter, ao = unit cell constant was calcu-
lated as, ao = 2 9 d100/H3
Fig. 2 a Nitrogen sorption isotherms and b BJH pore size distribution of AlSBA-15 samples
350 °C), moderate (351 and 450 °C) and strong (451 and 600 °C). The weak acid
sites are due to surface hydroxyl group, and the medium and strong acid sites are
originated from the incorporation of aluminum into the SBA-15 framework. The
weak acid sites increase as the nSi/nAl increases. This can be attributed to the weakly
held hydrogen bonded pyridine on terminal silanol group increases. However, the
medium and strong acid sites decrease with increase of nSi/nAl ratio (Scheme 1).
i
l
A
/
t
R1
O
e
O
PH
R2
H
/
r
H
N
a
A
A
r
N
/
H
e
t
/A
p
i
l
OEt
EtO
p
i
l
A
R1
A
/
R2
li
t
e
H
Scheme 1
t/
e
/
r
A
H
/
r
EtO
P
OEt
O
A
Ar: Aryl group; Het: Heterocyclic; Ali: Aliphatic group; R1, R2: H, aliphatic group
Scheme 1 One-pot synthesis of a-aminophosphonates via Kabachnik–Fields reaction using AlSBA-15
catalyst. aReaction conditions: compound 1a (3 mmol), compound 2a (3 mmol), diethyl phosphite
(3 mmol) and AlSBA-15 (15 mg) as neat reaction at 50 °C
123

M. K. Kolli et al.
The surface morphology of AlSBA-15 samples is studied by SEM and TEM
corresponding micrographs are presented in Fig. 3. Elemental compositions of
AlSBA-15 samples are provided in Table 1. The nSi/nAl ratio of calcined AlSBA-15
catalysts is higher than the nSi/nAl ratio in the synthesis gel. This is due to the high
solubility of aluminum isopropoxide in the acidic medium. However AlSBA-15
samples with nSi/nAl ratios ranging from 41 to 210 have been synthesized
hydrothermally. The SEM image (a) of AlSBA-15 sample shows aggregates of
worm-like regular rod-shaped particles of ca. 3 lm size with the co-existence of
smaller particles of ca. 1 lm size. The TEM image (b) of AlSBA-15 (41) materials
shows well-ordered hexagonal arrays of mesopores with one-dimensional nano
channels indicating the presence of 2D hexagonal (p6mm) symmetry.
FT-IR spectra of AlSBA-15 samples are shown in Fig. 4. The predominant bands
at 1088, 803, 956, 3400–3500 and 1376 cm-1 were found in FT-IR spectra of
AlSBA-15 samples. The bands at 1082 cm-1 and 798 cm-1 are assigned to an anti-
symmetric and symmetric stretching vibration of Si–O–Si. The absorption band at
964 cm-1 is due to anti-symmetric Si–O–Al vibration bands. A broad band in the
range of 3400–3500 cm-1 due to presents of free Si–OH groups in the framework.
The absorption band at 1641 cm-1 is due to adsorbed water molecules and the
deformation vibrations of the adsorbed molecules on AlSBA-15 samples [79].
Initially, we have examined the preparation of compounds (6a–c) and compound
(10) by following the reported literature with some modifications in order to
Fig. 3 a SEM image and
b TEM image of AlSBA-15 (41)
(a)
5 µm
(b)
50 nm
123

Highly efficient one-pot synthesis of a-aminophosphonates…
Fig. 4 FT-IR spectra of
AlSBA-15 catalysts with
different nSi/nAl ratio
improve the product yields. In this connection, the reaction of compounds (4a–c)
and phenyl hydrazine in ethanol medium in the presence of acetic acid resulted in
the production of compounds (5a–c) [82]. It was later treated with Vilsmeier–Haack
reagent (DMF-POCl3) to obtain the compounds (6a–c) [83]. The details were
mentioned as shown in Scheme 2. The reaction of compound (7) and DMF-DMA at
100 °C for 4 h as neat reaction resulted in the production of compound (8). It was
later treated with compound 9 (guanidine) in methanol medium in the presence of
NaOMe as base resulted in the production of compounds (10) [84]. The details were
mentioned as shown in Scheme 3. Detailed procedure is available in the supporting
information (Fig. 5).
After the successful preparation and characterization of AlSBA-15 with different
(nSi/nAl = 41, 129 and 210) catalysts, we examined their catalytic activity in the
Kabachnik-Fields reaction in one pot. In order to establish the optimum condition,
O
NH
N
N
N
O
R1
b
a
R1
R1
R2
4a-c
5a-c
6a-c
R2
R2
4a R1 = H, R2 = Cl
4b R1 = Cl, R2 = H
5a R1 = H, R2 = Cl
6a R1 = H, R2 = Cl
6b R1 = Cl, R2 = H
6c R1 = H, R2 = OEt
5b R1 = Cl, R2 = H
4c R1 = H, R2 = OEt
5c R1 = H, R2 = OEt
Scheme 2 Preparation of various pyrazole carboxaldehyde compounds (6a–6c). Reaction conditions:
(a) compounds 4a–c (1 mmol), phenyl hydrazine (1 mmol), acetic acid (0.1 mmol), ethanol (10 ml),
80 °C, 1–2 h; (b) compounds 5a–c (1 mmol), DMF-POCl3 (1 mmol), 80 °C, 6–8 h
123

M. K. Kolli et al.
O
O
N
NH
NH2
N
c
d
N
NH2
N
H2N
N
N
O
O
O
O
O
O
7
8
9
10
Scheme 3 Preparation of pyrimidine amine compound 10. Reaction conditions: (c) compound 7
(1 mmol), DMF-DMA (1 mmol), 100 °C, 4 h; (d) compound 8 (1 mmol), compound 9 (1 mmol), sodium
methoxide (1 mmol), methanol (10 ml), RT, 12 h
Fig. 5 Time courses for the
formation of compound 3a using
various nanoporous
heterogeneous catalysts.
Reaction conditions: compound
1a (3 mmol), compound 2a
(3 mmol), diethyl phosphite
(3 mmol) and catalyst (20 mg)
as neat reaction condition at
50 °C
we selected the model reaction between 3-chloroaniline and 4-fluorobenzaldehyde
in the presence of various heterogeneous catalysts and medium.
The catalytic activity of various catalysts studied and depicted in Table 1. The
model reactions were performed by varying the solvent and temperature with
constant catalyst loading of 20 mg. Increase in product formation with increase in
temperature were observed in the solvent medium such as toluene, ethanol (EtOH),
dichloromethane (DCM), 1,4-dioxane, acetonitrile (ACN), and N,N-dimethylfor-
mamide (DMF) (Table 2, entries 1–6). The reaction did not proceed well in water
medium at RT and 50 °C (Table 2, entry 7). When we carried the reaction in neat
condition at RT/50/100 °C, the reaction proceeded very well at 50 °C with 98%
compound 3a yield in 20 min of reaction time (Table 2, entry 8–9).
AlSBA-15 (41) shows a very high product yield of compound 3a (98%) within
20 min of reaction time compared to the other two catalysts, namely, AlSBA-15
(129) and AlSBA-15 (210). This is due to the low nSi/nAl ratio of AlSBA-15 (41),
123

Highly efficient one-pot synthesis of a-aminophosphonates…
Table 2 Screening of various catalysts for the synthesis of a-aminophosphonates
Entry
Catalyst
Time
Solvent
Temp. (°C)
Yielda (%)
1
AlSBA-15 (41)
AlSBA-15 (41)
AlSBA-15 (41)
AlSBA-15 (41)
AlSBA-15 (41)
AlSBA-15 (41)
AlSBA-15 (41)
AlSBA-15 (41)
AlSBA-15 (41)
AlSBA-15 (129)
AlSBA-15 (210)
FeMCM-41 (50)
FeMCM-41 (100)
Without Catalyst
24 h
24 h
24 h
24 h
24 h
24 h
24 h
6 h
Toluene
EtOH
DCM
Dioxane
ACN
DMF
Water
Neat
RT/50
RT/50
RT/50
RT/50
RT/50
RT/50
RT/50
RT
15/45
38/65
25/72
55/81
30/71
62/84
5/15
2
3
4
5
6
7
8
86
9
20 min
30 min
45 min
2 h
Neat
50/100
RT/50
RT/50
RT/50
RT/50
RT/50
98/90
75/94
65/92
22/85
20/82
NP/5
10
11
12
13
14
Neat
Neat
Neat
2 h
Neat
12 h
DMF
Reaction conditions: amine 1a (3 mmol), aldehyde 2a (3 mmol), diethyl phosphite (3 mmol) and catalyst
(20 mg) using various solid catalysts and medium
NP no product
aIsolated yield
which provides more acidity in comparison to AlSBA-15 (129) and AlSBA-15
(210), the latter of which possess two and four times less acidity than AlSBA-15
(41) (Table 1). Thus, the formation of compound 3a takes a little long reaction time
over AlSBA-15 (129) and AlSBA-15 (210) with product yields of 94 and 92% in 30
and 45 min, respectively. The Al content in catalysts AlSBA-15 (129) and AlSBA-
15 (210) is low accordingly, which resulted a low product yield and required long
reaction time.
However, the decrease in the product yield over AlSBA-15 (129) and (210) is not
considerable in comparison with AlSBA-15 (41). The decrease in nSi/nAl ratio, that
increases the acid strength of AlSBA-15 samples, which is an important parameter
in addition to density of acid sites of the catalyst.
The product yield of compound 3a was compared by carrying out the reactions
with FeMCM-41 (50) and FeMCM-41 (100) catalysts and without catalyst to study
the efficiency of AlSBA-15 catalysts. The FeMCM-41 (50) and FeMCM-41(100)
catalysts showed the compound 3a yields of 22 and 20% at RT, 85 and 82% at
50 °C, respectively (Table 2, entry 12, 13). There was no product formation on the
reaction performed without catalyst (Table 2, entry 14). Therefore, this clearly
indicates that the reaction is very well initiated and activated by the AlSBA-15
catalysts for high product yield of compound 3a in water medium.
It is very interesting that there is no formation of side product formation of a-
hydroxy phosphonates as observed in many cases [82]. Since we mix three
components in a one-pot system, first imine forms rapidly on the catalyst surface
123

M. K. Kolli et al.
and then it attack the diethyl phosphite and leads to absolute formation of a-
aminophosphonates.
We required a low loading catalyst ratio to carry out the reaction in economical
large scale synthesis. Hence, we studied the effect of catalyst amount of AlSBA-15
(41) on a-aminophosphonates synthesis with different catalyst loading of 5, 10, 15,
and 20 mg. The product yield increased from 75 to 98% as the catalyst amount
increased from 5 to 15 mg (Table 3, entries 1–3), and there was no increase in the
product yield observed when we further increased the catalyst amount to 20 mg
(Table 3, entry 4). A blank reaction was carried out without catalyst for 100 min,
and there was no compound of interest obtained (Table 3, entry 5). The details were
mentioned in Table 3.
We have examined the recyclability of AlSBA-15 (41) catalyst in a-aminophos-
phonates synthesis for six consecutive cycles. After completion of the reaction
(monitored through TLC), the reaction mixture was diluted with ethyl acetate and
the catalyst was recovered from the reaction mixture by simple filtration, followed
by washing with ethyl acetate and then drying under vacuum at RT for 1 h. The
recovered catalyst maintained a high catalytic activity with the product yield of 98%
for three runs without any loss in its performance. This is of much significance for
the exploitation of the catalyst for different reactions. But the catalytic activity of
AlSBA-15 (41) started to decrease in the fourth, fifth and sixth reaction runs with
product yields of 84, 75 and 65%, respectively (Fig. 6), due to the coke formation
on the active sites of the catalyst or pore blockage.
To understand the decrease in catalytic efficiency after three reaction runs, we
carried out NH3-TPD experiment for fresh and reused AlSBA-15 (41) catalyst after
the 6th cycle to find the acid sites concentration on the catalyst surface (Fig. 7). To
do this, after the completion of reaction, the reaction mixture was dissolved in ethyl
acetate (2 mL), followed by filtration through Whatman filter paper and the solid
was washed twice with the ethyl acetate (1 mL) to avoid the loss of product yield.
The organic layer contains the desired product. The recovered catalyst was dried at
100 °C in order to remove the volatiles and reuse the same catalyst in subsequent
reaction runs. The NH3-TPD profile of fresh AlSBA-15 (41) catalyst showed three
Table 3 Reactivity based on the amount of AlSBA-15 (41) for the synthesis of compound 3a
Entry
Amount of AlSBA-15 (41)
Time (min.)
Yielda (%)
1
2
3
4
5
5 mg
20
20
75
91
98
98
NP
10 mg
15 mg
20
20 mg
20
Without catalyst
100
Reaction conditions: catalyst (5, 10, 15 and 20 mg), compound 1a (3 mmol), compound 2a (3 mmol),
diethyl phosphite (3 mmol) as neat reaction at 50 °C
NP no product
aIsolated yield
123

Highly efficient one-pot synthesis of a-aminophosphonates…
Fig. 6 Catalyst recycle test of
nanoporous AlSBA-15 (41) on
the a-aminophosphonate
(compound 3a) synthesis.
Reaction conditions: compound
1a (3 mmol), compound 2a
(3 mmol), diethyl phosphite
(3 mmol) and catalyst (15 mg)
in neat reaction at 50 °C for
20 min
Fig. 7 NH3-TPD profile of
AlSBA-15 (41): a fresh catalyst
and b reused after sixth cycle
123

M. K. Kolli et al.
peaks at around 216, 483 and 734 °C due to weak, medium, and strong acid sites,
respectively. The reused AlSBA-15 catalyst showed only two peaks at around 242
and 496 °C due to weak and medium acid sites, respectively, with the complete
disappearance of strong acid sites at around 734 °C. The considerable decrease in
peak intensity was observed in the reused catalyst than the fresh catalyst. The
decrease in peak intensity and the disappearance of strong acid sites is due to the
strong adsorption of reactants or product or intermediate on the acid sites and
decreases in acid site concentration on the AlSBA-15 (41) surface. The decrease in
acid site concentration of AlSBA-15 (41) is the major cause for the drop in product
yield.
To clarify the catalytic role, reaction pathway and rate of the reaction in one-pot
synthesis, we analysed the crude samples obtained at various time intervals of 5, 10,
1
15, and 20 min using 31P and H NMR (DMSO-d6, 500 MHz) and the spectra are
shown in Figs. 8 and 9, respectively. The 31P NMR spectrum (a) showed that our
catalyst promoted the conversion of diethyl phosphite to desired compound 3a, and
corresponding peaks due to diethyl phosphite and compound 3a were observed at
7.32 and 21.83 ppm, respectively. The 31P NMR spectra (b and c) of crude obtained
at 10 and 15 min showed a decrease in peak intensity at 7.32 ppm and
corresponding increase in peak intensity at 21.83 ppm with increase in reaction
time. This clearly indicates that the conversion of diethyl phosphite into the desired
compound 3a. The 31P NMR spectrum (d) shows the complete conversion and
formation of compound 3a after 20 min. The 1H NMR spectrum of (a) crude sample
obtained at 5 min shows the presence of aldehyde, amine and initiation of
compound 3a. The 1H NMR spectrum of (b) and (c) of crude sample obtained at 10
and 15 min showed a decrease in peak intensity of amine, aldehyde, phosphite and
the corresponding increase in peak intensity of compound 3a with increase in
Fig. 8 31P NMR tracing experiment for the synthesis of compound 3a at various time intervals of
a 5 min, b 10 min, c 15 min, and d 20 min
123

Highly efficient one-pot synthesis of a-aminophosphonates…
F
(a)
O
O
P
H
O
Cl
Cl
O
P
H
O
EtO
NH
NH2
EtO
F
10.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
ppm
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
F
Cl
(b)
O
O
P
H
O
O
Cl
Et
O
NH
P
EtO
H
O
NH2
F
10.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
f1 (ppm)
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
Cl
O
O
F
O
P
P
H
O
EtO
NH
(c)
EtO
Cl
F
H
O
NH2
10.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
ppm
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
Cl
O
P
EtO
NH
EtO
(d)
F
10.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
ppm
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
Fig. 9 1H NMR tracing experiment for the synthesis of compound 3a at various time intervals of
a 5 min, b 10 min, c 15 min and d 20 min
reaction time. The 1H NMR spectrum (d) shows the complete conversion and
formation of desired compound 3a after 20 min. This study also evidence with
respect to the rate of the reaction. The corresponding peaks were marked in Fig. 9.
The scope and the limitations of this reaction methodology were studied using
various electron-donating and electron-withdrawing substituted amines, as well as
aryl/heterocyclic/aliphatic aldehydes/ketone with diethyl phosphite in the presence
of AlSBA-15. Aromatic, heterocyclic aromatic and aliphatic aldehydes were used in
123

M. K. Kolli et al.
Table 4 AlSBA-15 catalyzed one-pot synthesis of a-aminophosphonates
H
N
AlSBA-15
neat 50°C
R2
H
EtO OEt
P
O
NH2
R1
R1
+
+
P
O
-
m n
i
R2
20 60
O
EtO
OEt
-
85 98%
1a-1s
1a-1w
3a-3z
26 compounds
=
R1
,
R
Alkyl/aryl/hetroarylgrops
2
Br
O
H
OEt
NO2
EtO
N
P
F
HN
OEt
HN
H
OEt
O
HN
N
OEt
O
OEt
HO
HO
P
P
P
NH
O
O P OEt
OEt
EtO
O
EtO
EtO
O
H3CO
P
Cl
EtO
O
CH3
[86], b
OCH3
[85], b
[86], b
[86], b
[87], b
3a30,b (98%, 20 min) 3b31,b (96%, 20 min) 3c31,b (97%, 20 min) 3d31,b (85%, 50 min)
3e3[8 bb (94%, 20 min) 3f32,b (92%, 35 min)
6],
1,
Cl
O
O
P
OEt
O
O
P
OEt
N
O
P
OEt
O
OEt
N
EtO
P
OEt
N
O
O
O
P
HN
OEt
H
N
OEt
HN
OEt
O
S
OEt
HN
P
OEt
P
OEt
NBoc
EtO
EtO
N
O
O
[89],b
3g3[8 (95%, 50 min) 3h[87],b (96%, 50 min) 3i(94%, 45 min) 3j(93%, 45 min) 3k (95%,60 min) 3l3[8 ]b(95%,60 min) 3m34,b(95%,60 min)
3
8
,
]
b
,b
32,b
34,b
[89],b
49,,b
N
N
Boc
S
N
O
H
N
OEt
EtO
P
P
OEt
OEt
N
F
N
O
H
N
Cl
N
N
N
HN
EtO
HN
Cl
N
N
OEt
OEt
P
P
Cl
O
O
EtO
3n (90%, 40 min)
3o (88%, 45 min)
3p (91%, 30 min)
3q (92%, 35 min)
O
O
N
OEt
EtO
Boc
N
S
P
O
P
O
O
HN
N
N N
N
N
N
N
N
N
HN
N
N
O
S
O
O
P
N
O
NH
P
EtO
H
OEt
OEt
EtO
O
OEt
OEt
3r (86%, 60 min) Cl
3s (88%, 60 min)
3t (87%, 20 min)
3u (88%, 40 min)
N
N
N
Boc
Boc
N
O
N
Boc
N
N
N
N
N
Boc
N
N
OEt
N
P
OEt
O
P
OEt
HN
N
P
OEt
O
OEt
HN
HN
EtO
HN
OEt
OEt
P
N
N
O
Br
N
N
Cl
3x (85%, 60 min)
HN
3v (89%, 45 min)
3w (88%, 45 min)
3y (85%, 60 min) OEt
O
a=isolated yield.
b=the spectral data (1H, 13C NMR) of known compounds were found to be identical with those
reported in the literature.
123

Highly efficient one-pot synthesis of a-aminophosphonates…
Fig. 10 Plausible mechanism pathway for the one-pot synthesis of a-aminophosphonates by using
AlSBA-15
a short reaction time (20–60 min) to get desired product with excellent yield
(85–98%). We studied the possibility of this method to be a convenient scale-up
process (Table 4, entry 1) on 10 g scale and 25 g scale and the experimental results
showed a product yield of 90 and 91%, respectively. This study clearly indicates
that this methodology is a convenient for scale-up process and there is no
remarkable product yield difference between R&D scale (Table 4, entry 1) and
scale up process.
With the optimized conditions in hand, we endeavoured to catalyse the
Kabachnik-Fields reaction for the synthesis of different a-aminophosphonate
compounds 3a–3y at 50 °C in the absence of solvent at different reaction time
(20–60 min) with variable product yields (85–98%). The results are summarized in
Table 4. The molecular structures of the prepared a-aminophosphonates were
1
1
determined from their H, H-D2O exchange, 31P and 13C NMR, IR, LCMS and
HRMS studies and they are described in the supporting information. The NH proton
of a-aminophosphonates was confirmed by D2O exchange NMR experiments.
From these results, to the best of our knowledge, a plausible mechanism is
proposed for this reaction as shown in Fig. 10. The imine (intermediate II)
formation is the slowest step in the Kabachnik-Fields reaction. Therefore, we may
surmise that the presence of our AlSBA-15 catalysts resulted in an improvement in
the reaction rate of a-aminophosphonates intermediate synthesis. First, the aldehyde
interacts with Lewis acid site on the AlSBA-15 resulting complex (I). Second, the
aniline attacks complex (I) and results in the corresponding imine (II) with the
removal of H2O. After this step, imine (II) undergoes an attack of diethyl
123

M. K. Kolli et al.
phosphonate from diethyl phosphite and produces compound (III), which on
hydrolysis yields compound 3a.
Conclusion
In this work we report, for the first time, an efficient protocol for the one-pot
synthesis of a-aminophosphonates using a three-component system of amine
(primary/secondary), carbonyl compounds (aldehydes/ketones) and diethyl phos-
phite via Kabachnik-Fields reaction using nanoporous AlSBA-15 catalyst with an
excellent product yield in the range from 85 to 98%. The novel approach of
applying nanoporous heterogeneous AlSBA-15 solid acid catalyst replaces the
conventional use of mineral acids in the synthesis of a-aminophosphonates,
provides the possibility of catalyst recovery and opportunity for the catalyst to reuse
many (six) reaction runs. We found that this methodology is a convenient scale-up
process and tolerate a variety of functional groups having various electron-
donating/electron-withdrawing groups with wide substrate scope. The advantages of
this method are (1) solventless reaction, (2) recycling and reusability of the catalyst,
(3) high chemo-selectivity, (4) short reaction time, (5) excellent product yield, (6)
easy isolation/purification, and (7) two-step synthesis reduced to one-pot synthesis
in a green approach.
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