NiSO4·6H2O as a new, efficient, and reusable catalyst for the α-aminophosphonates synthesis under mild and eco-friendly conditions

Article abstract of DOI:10.1007/s11164-015-2283-z

Abstract: Nickel (II) sulfate hexahydrate is used for the first time as an efficient catalyst for the one-pot synthesis of α-aminophosphonates by three-component condensation reaction of aromatic aldehyde, primary amine, and diethylphosphite under mild and eco-friendly conditions. NiSO₄·6H₂O was used with a catalytic amount of 5?mol% at room temperature, without solvent in the reaction. A series of the desired α-aminophosphonates are obtained after a simple work-up procedure, with excellent yields (up to 92?%) within a short reaction time of 10–20?min in all cases. This heterogeneous catalyst was reused several times with the same activity. The present approach offers the advantages of a clean reaction, simple methodology, easy purification, and economic availability of the catalyst. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s11164-015-2283-z

Res Chem Intermed
DOI 10.1007/s11164-015-2283-z
NiSO4Á6H2O as a new, efficient, and reusable catalyst
for the a-aminophosphonates synthesis under mild
and eco-friendly conditions
Samia Guezane Lakoud1 Mounia Merabet-Khelassi1
•
•
Louisa Aribi-Zouioueche1
Received: 29 June 2015 / Accepted: 12 September 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract Nickel (II) sulfate hexahydrate is used for the first time as an efficient
catalyst for the one-pot synthesis of a-aminophosphonates by three-component con-
densation reaction of aromatic aldehyde, primary amine, and diethylphosphite under
mild and eco-friendly conditions. NiSO4Á6H2O was used with a catalytic amount of
5 mol% at room temperature, without solvent in the reaction. A series of the desired a-
aminophosphonates are obtained after a simple work-up procedure, with excellent yields
(up to 92 %) within a short reaction time of 10–20 min in all cases. This heterogeneous
catalyst was reused several times with the same activity. The present approach offers the
advantages of a clean reaction, simple methodology, easy purification, and economic
availability of the catalyst.
Graphical Abstract
NH2
NiSO4.6H
5 mol%
O
P
2O
O
P
Et
O
H
N
OEt
OEt
O
H
+
+
Et
O
R1
H
Neat, rt
R1
R2
10-20 min
R2
14 examples
Yields a92-98%
- Solvant free
R1 = Aryl, heteroaryl, ect
R2 = H, CH3, CF3
- Under mild conditions
- Short reaction time
- Catalyst reuse
Keywords Nickel (II) sulfate hexahydrate Á a-Aminophosphonates Á Solvent-free Á
Catalyst reuse Á Green protocol
&
Louisa Aribi-Zouioueche
louisa.zouioueche@univ-annaba.dz
1
Eco-compatible Asymmetric Catalysis Laboratory (LCAE), Badji Mokhtar Annaba-University,
B.P 12, 23000 Annaba, Algeria
123

S. Guezane Lakoud et al.
Introduction
The a-aminophosphonate derivatives are well known as potential bioactive
molecules for their multifarious therapeutic activities [1, 6, 17, 23, 24, 30]. They
are used fruitfully in various domains, in agrochemistry as plant growth regulators,
herbicides, insecticides, and fungicides [25, 26]. They are also known for their
physical properties and are used as retardants for fire materials [2]. During the past
few years, various methods have been developed for the synthesis of a-
aminophosphonate. One of the main efficient known target reactions for developing
new a-aminophosphonate derivatives is the Kabachnik–Fields reaction [11, 15]. The
key step of this approach is the addition of the pentavalent phosphorus nucleophile
to imine formed in situ between aldehyde and primary amine.
Similar methods are described [38] using variety of catalysts, Lewis acids, and
others such as; TiO2 [13], SnCl4 [21], ZnCl2 [39], Sn(OTf)2 [12], Cu(OTf)2Á7H2O
[14], BiNO3Á5H2O [8], BF3–SiO2 [28], ZrOCl2Á8H2O or ZrO(ClO4)2Á6H2O [7],
Cp2Zr(OSO2C4F9)2Á2H2O [22], Cd(ClO4)2ÁH2O [10], CoCl2Á6H2O [18], Sulfamic-
acid [27], TsCl [16], Fe/SWCNTs [31], FeCl3 [29], etc. In spite of their advantages,
these methods show some flaws. Among their disadvantages, we quote the low
afforded yield, tedious work-up procedures, the long reaction time [22], large
amount of catalyst [18], heating or addition of some bases as activator factor [31],
and an excessive use of organic solvents presenting a serious danger to the
environment [29].
The international tendency imposes the improvement of green and sustainable
chemical processes, without generating waste. Therefore, researchers have elabo-
rated new methods obeying environmental concerns which favor the development
of new eco-friendly synthesis processes. These new paths must be designed to
reduce the steps, using catalysis and avoid organic solvents, thereby contributing to
the implementation of some greener criteria [3–5, 33–35].
In this paper, we propose a new soft and clean protocol for the synthesis of a set
of a-aminophosphonate derivatives through multi-component condensation reaction
in one pot, of an aldehyde, amine, and diethylphosphite, in the presence of a
catalytic amount of NiSO4Á6H2O, under solvent-free conditions and without any
activation (heating or base). The NiSO4Á6H2O catalyst presents several advantages,
no toxic, commercially available, cheap, easily removed, and recovered after
achievement of the reaction, for an eventual recycling.
Experimental
General
All starting materials and reagents used in this study were obtained commercially
from Aldrich and Acros and were used without purification. All reactions were
monitored by thin-layer chromatography (TLC) carried out on 0.25-mm Merck
silica-gel plates (60F-254) using ultraviolet light (254 nm) as the visualizing agent
123

NiSO4Á6H2O as a new, efficient, and reusable catalyst for…
1
and KMnO4 solution as developing agents. H NMR and 13C NMR spectra were
1
recorded on Bruker spectrometers (300 MHz for H, 75 MHz for 13C). Chemical
shifts were reported downfield from CDCl3 (d = 7.26 ppm). For 13C NMR,
chemical shifts were reported in the scale relative to the solvent of CDCl3
(d = 77 ppm) used as internal reference. Coupling constants (J) are given in Hertz.
The following abbreviations classify the multiplicity: s = singulet, d = doublet,
t = triplet, q = quartet, m = multiplet, br = broad signal. Melting points were
measured using Bu¨chi Melting Point Model B-545.
General procedure for the synthesis of a-aminophosphonates (3a–3m)
In a round-bottomed flask, a mixture of aldehyde (1 mmol), aniline (1 mmol), and
diethylphosphite (1.2 mmol), and a catalytic amount of NiSO4Á6H20 (5 mol%) were
added. The mixture was stirred at room temperature for an appropriate time. The
evolution of the reaction was monitored by TLC. After achieving the reaction,
dichloromethane (2 9 10 ml) was added and the catalyst was filtered; water (10 ml)
was then added. The organic layers were combined and dried over anhydrous
sodium sulfate and removed under reduced pressure. The residue obtained was
crystallized in hexane/ether to give desired pure crystals. All mentioned yields are
those obtained after crystallization.
Spectral data of all the synthesized a-aminophosphonates (3a–3m)
Diethyl (phenyl)(phenylamino)methylphosphonate (3a) White crystalline solid.
1
Mp 88 °C. HNMR (300 MHz, CDCl3, 25 °C): d = 1.13 (t, 3H, J = 7 Hz, –
OCH2–CH3), 1.30 (t, 3H, J = 7.1 Hz, –OCH2–CH3), 3.59–3.75 (1H, m, –OCH2
Me), 3.87–4.01 (1H, m, –OCH2–Me), 4.03–4.21 (2H, m, OCH2–Me), 4.74–4.82 (d,
1H, JHP = 24.3 Hz, CHP), 6.61 (dd, 2H, J = 8.6, 0.9 Hz, HAr), 6.71 (dd, 1H,
J = 10.5, 4.1 Hz, HAr), 7.12 (dd, 2H, J = 8.5, 7.4 Hz, HAr), 7.22–7.43 (m, 3H,
H
Ar), 7.49 (d, 2H, J = 7.2, Hz, HAr). 13CNMR: (75 MHz, CDCl3, 25 °C):
d = 146.28) d, J = 14.7 Hz (136.00, 129.16, 128.59,127.83, 118.37, 113.83, 63.29
(d, JCP = 4.0 Hz), 57.16, 55.16, 31.09, 16.61 (d, J3CP = 18.3), 16.53 (d, J3CP = 5.8 -
Hz). 31P NMR: (121 MHz, CDCl3, 25 °C): d = 23.24 ppm.
Diethyl (4–nitrophenyl)(phenylamino) methylphosphonate (3b) Yellow crystalline
solid. Mp 89.2 °C. 1HNMR (300 MHz, CDCl3, 25 °C): d = 1.13 (t, 3H,
J = 7.1 Hz, –OCH2–CH3), 1.29 (t, 3H, J = 7.1 Hz, –OCH2–CH3), 3.77–3.88 (m,
1H, –OCH2–CH3), 3.90–4.05 (m, 1H, –OCH2–CH3), 4.10–4.15 (m, 2H, OCH2–
CH3), 4.73–4.85 (d, 1H, JHP = 24.2 Hz, CHP), 6.59–6.71 (m, 3H, HAr), 6.73–6.85
(t, 2H, J = 15.5 Hz, HAr), 7.12–7.19 (m, 2H, HAr), 7.50–7.61 (d, 2H, JHP = 7.2 -
Hz,
H
Ar). 13CNMR: (75 MHz, CDCl3, 25 °C): d = 146.28 (d,
J = 14.7 Hz(,136.09, 129.38, 128.82, 128.79, 128.12, 128.09, 118.60, 114.06,
63.56 (d, J = 4.0 Hz), 55.50, 56.99, 31.15 16.67 (d, J3HP = 18.3 Hz), 16.61 (d,
J3HP = 5.8 Hz). 31P NMR: (121 MHz, CDCl3, 25 °C): d = 22.71 ppm.
123

S. Guezane Lakoud et al.
Diethyl (4–chlorophenyl)(phenylamino) methylphosphonate (3c) White crystalline
solid. Mp 86.8 °C. 1HNMR (300 MHz, CDCl3, 25 °C): d = 1.18 (t, 3H,
J = 7.0 Hz, –OCH2–CH3), 1.30 (t, 3H, J = 7.0 Hz, –OCH2–CH3), 3.75–3.80 (m,
1H, –OCH2–Me), 3.92–4.06 (m, 1H, –OCH2–Me), 4.05–4.21 (m, 2H, OCH2–Me),
4.75 (d, 1H, JHP = 24.5 Hz, CHP), 6.58 (dd, 2H, J = 8.6, 0.9 Hz, HAr), 6.73(t, 1H,
J = 7.4 Hz, HAr), 7.13(dd, J = 8.5, 7.4 Hz, 2H, HAr), 7.21–7.38 (m, 2H, HAr),
7.44 (dd, J = 8.6, 2.3 Hz, 2H, HAr). 13CNMR: (75 MHz, CDCl3, 25 °C):
d = 146.01 (d, J = 14.6 Hz), 134.60, 133.70, 129.26 128.19, 128.89, 128.86,
118.66, 113.83, 63.38 (d, J2 = 6.8 Hz), 56.60, 54.61, 30.94, 16.36 (d,
J3 = 13.7 Hz), 16.36 (d, J3 = 5.7 Hz). 31P NMR: (121 MHz, CDCl3, 25 °C):
d = 23.24 ppm.
Diethyl(4-methoxyphenyl)(phenylamino) methylphosphonate (3d) White crys-
1
talline solid. Mp 103 °C. HNMR (300 MHz, CDCl3, 25 °C): d = 1.14 (t, 3H,
J = 7.0 Hz, –OCH2–CH3), 1.28 (t, 3H, J = 7.0 Hz, –OCH2–CH3), 3.65–3.74 (m,
1H, –OCH2–CH3), 3.77 (s, 3H, –OCH3), 3.91 (m, 1H, –OCH2–CH3), 4.15 (m, 2H,
OCH2–CH3), 4.72 (d, J = 24.4 Hz, 1H, CHP), 6.58 (d, 2H, J = Hz, HAr), 6.66 (t,
J = 16.0 Hz, 1H, HAr), 6.85 (d, J = Hz, 2H, HAr), 7.07–7.13 (m, 2H, HAr),
7.36–7.30 (m, 2H, HAr). 13CNMR: (75 MHz, CDCl3, 25 °C): d = 159.40, 143.54
(d, J = 15.4 Hz), 129.24, 129.08, 129.01, 127.77, 127.73, 118.43, 114.16, 114.13,
63.39 (dd, J2 = 6.9, 3.9 Hz), 56.45, 55.33, 54.43, 16.60 (d, J3 = 14.9 Hz), 16.52 (d,
J3 = 5.9 Hz).31P NMR: (121 MHz, CDCl3, 25 °C): d = 23.47 ppm.
Diethyl (4-biphenyl)(phenylamino) methylphosphonate (3e) White crystalline solid.
1
Mp 158 °C. HNMR (300 MHz, CDCl3, 25 °C): d = 1.18 (t, 3H, J = 7.1 Hz, –
OCH2–Me), 1.33 (t, 3H, J = 7.1 Hz, –OCH2–Me), 3.79 (m, 1H, –OCH2–Me),
3.90–4.08 (m, 1H, –OCH2–CH3), 4.06–4.26 (m, 2H, OCH2–CH3), 4.68–4.97 (m, 2H,
CH and NH), 6.66 (d, 2H, J = 7.7 Hz, HAr), 6.74 (t, 1H, J = 7.3 Hz, HAr), 7.16 (dd,
J = 8.3, 7.5 Hz, 2H, HAr), 7.21–7.51 (m, 3H, HAr), 7.49–7.67 (m, 6H, HAr).
13CNMR: (75 MHz, CDCl3, 25 °C): d = 146.31 (d, J = 14.6 Hz), 140.85, 140.80,
140.67, 135.04, 135.00, 129.32, 128.87, 127.83, 127.42, 127.39, 127.12, 118.57,
113.98, 63.35 (d, JCP = 6.9 Hz), 56.82, 54.82, 16.37 (d, J3 = 16.9 Hz), 16.37 (d,
J3 = 5.8 Hz). 31P NMR: (121 MHz, CDCl3, 25 °C): d = 23.12 ppm.
Diethyl (phenyl)(p-tolylamino) methylphosphonate (3f) White crystalline solid.
1
Mp 99 °C (litt. 101–102). HNMR (300 MHz, CDCl3, 25 °C): d = 1.11 (t, 3H,
J = 7.1 Hz, –OCH2–CH3), 1.28 (t, 3H, J = 7.0 Hz, –OCH2–CH3), 2.18 (s, 3H,
CH3–Ph), 3.64–3.72 (m, 1H, –OCH2–CH3), 3.90–3.98 (m, 1H, –OCH2–CH3),
4.08–4.15 (m, 2H, OCH2–CH3), 4.70 (d, J = 24.4 Hz, 2H, CHP and NH), 6.50 (d,
2H, J = 8.5 Hz, HAr), 6.90 (d, J = 16.0 Hz, 2H, HAr), 7.23–7.35 (m, 3H, HAr),
7.44–7.48 (m, 2H, HAr). 13CNMR: (75 MHz, CDCl3, 25 °C): d = 143.74 (d,
J = 15.4 Hz), 138.71, 138.68, 129.35, 128.27, 128.24, 127.56, 127.49, 127.30,
113.66, 63.01 (dd, J2 = 6.9, 2.9 Hz), 57.01, 55.01, 20.06, 16.18 (d, J3 = 14.0 Hz),
16.10 (d, J3 = 5.8 Hz).31P NMR: (121 MHz, CDCl3, 25 °C): d = 23.36 ppm.
123

NiSO4Á6H2O as a new, efficient, and reusable catalyst for…
Diethyl (4-nitrophenyl)(p-tolylamino) methylphosphonate (3g) Yellow crystallin.
1
Mp 158 °C. HNMR (300 MHz, CDCl3, 25 °C): d = 1.19 (t, 3H, J = 7.0 Hz, –
OCH2–CH3), 1.30 (t, 3H, J = 7.0 Hz, –OCH2–CH3), 2.18 (s, 3H, CH3–Ph),
3.87–3.92 (m, 1H, –OCH2–CH3), 4.00–4.10 (m, 1H, –OCH2–CH3), 4.11–4.17 (m,
2H, –OCH2–CH3), 4.72 (dd, J = 10.5, 7.1 Hz, 1H, CH), 4.85 (dd, J = 24.7,
7.0 Hz, 1H, NH), 6.47(d, J = 8.5 Hz, 2H, HAr), 6.91 (d, 2H, J = 8.2 Hz, HAr),
7.67 (dd, J = 8.8, 2.3 Hz, 2H, HAr), 8.18 (dd, J = 8.8, 0.6 Hz, 2H, HAr). 13CNMR:
(75 MHz, CDCl3, 25 °C): d = 147.69, 144.73 (d, J = 3.2 Hz), 143.33 (d,
J = 14.6 Hz), 129.96, 128.79, 128.73, 128.54, 128.84, 126.84, 114.03, 63.58 (dd,
J2 = 23.8, 6.9 Hz), 55.41, 20.47, 16.59 (d, J3 = 12.6, 5.8 Hz), 16.52 (d,
J3 = 5.8 Hz). 31P NMR: (121 MHz, CDCl3, 25 °C): d = 21.47 ppm.
Diethyl(4-chlorophenyl)(p-tolylamino) methylphosphonate (3h) White crystalline
solid. Mp 119.5 °C 1HNMR (300 MHz, CDCl3, 25 °C): d = 1.18 (t, 3H,
J = 7.1 Hz, –OCH2–CH3), 1.31 (t, 3H, J = 7.1 Hz, –OCH2–CH3), 2.21 (s, 3H,
CH3–Ph), 3.79–3.85 (m, 1H, –OCH2–CH3), 3.97–4.05 (m, 1H, –OCH2–CH3),
4.10–4.17 (m, 2H, OCH2–CH3), 4.64–4.78 (m, 2H, CH ?NH), 6.48 (d, 2H,
J = 8.5 Hz, HAr), 6.93 (d, 2H, J = 8.2 Hz, HAr), 7.26 (m, 2H, HAr), 7.43 (dd,
J = 12.0, 4.0 Hz, 2H, HAr). 13CNMR: (75 MHz, CDCl3, 25 °C): d = 143.85 (d,
J = 15.0 Hz), 134.84, 133.80, 133.76, 133.71, 129.83, 129.28, 128.21, 127.89,
127.86, 128.03, 114.06, 63.59 (dd, J2 = 12.1, 7.0 Hz), 56.89, 54.89, 20.47, 16.59
(d, J3 = 13.7 Hz), 16.52 (d, J3 = 5.8 Hz). 31P NMR: (121 MHz, CDCl3, 25 °C):
d = 22.69 ppm.
Diethyl(4-methoxyphenyl)(p-tolylamino) methylphosphonate (3i) White crys-
1
talline solid. Mp 99 °C. HNMR (300 MHz, CDCl3, 25 °C): d = 1.14 (t, 3H,
J = 7.1 Hz, –OCH2–CH3), 1.28 (t, 3H, J = 7.1 Hz, –OCH2–CH3), 2.18 (s, 3H,
CH3–Ph), 3.66–3.74 (m, 1H, –OCH2–CH3), 3.77 (s, 3H, –OCH3), 3.91–3.96 (m,1H,
–OCH2–CH3), 3.99–4.15 (m, 2H, OCH2–CH3), 4.70 (d, J = 24.5 Hz, 2H,
CHP ? NH), 6.49 (d, 2H, J = 8.4 Hz, HAr), 6.92 (dd, J = 16.0, 8.5 Hz, 4H,
HAr), 7.26–7.39 (m, 2H, HAr). 13CNMR: (75 MHz, CDCl3, 25 °C): d = 159.20,
144.20 (d, J = 15.4 Hz), 129.76, 129.08, 129.01, 127.92, 127.88, 127.68, 114.12,
63.38 (dd, J2 = 6.9, 2.9 Hz), 56.74, 55.34, 54.72, 20.49, 16.63 (d, J3 = 14.0 Hz),
16.55 (d, J3 = 5.8 Hz).31P NMR: (121 MHz, CDCl3, 25 °C): d = 23.59 ppm.
Diethyl (4-biphenyl)(p-tolylamino) methylphosphonate (3j) White crystalline
solid. Mp 140 °C. 1HNMR (300 MHz, CDCl3, 25 °C): d = 1.17 (t, 3H,
J = 7.1 Hz, –OCH2–CH3), 1.32 (t, 3H, J = 7.1 Hz, –OCH2–CH3), 2.21 (s, 3H,
CH3–Ph), 3.77–3.83 (m, 1H, –OCH2–CH3), 3.97–4.05 (m, 1H, –OCH2–CH3),
4.12–4.20 (m, 2H, –OCH2–CH3), 4.82 (d, 1H, J = 24.5 Hz, CHP), 6.56 (d, 2H,
J = 8.3 Hz, HAr), 6.94 (d, 2H, J = 8.3 Hz, HAr), 7.26–7.38 (m, 1H, HAr),
7.42–7.47 (m, 2H, HAr), 7.54–7.60 (m, 6H, HAr). 13CNMR: (75 MHz, CDCl3,
25 °C): d = 144.15 (d, J = 15.1 Hz), 140.72 (d, J = 4.3 Hz), 135.16, 135.13,
129.82, 128.87, 128.37, 128.30, 127.81, 127.44, 127.41, 127.38, 127.12, 110.10,
63.44 (t, J2 = 6.9 Hz), 57.16, 55.17, 20.50, 16.62 (d, J3 = 17.0 Hz), 16.55 (d,
J3 = 5.8 Hz). 31P NMR: (121 MHz, CDCl3, 25 °C): d = 23.24 ppm.
123

S. Guezane Lakoud et al.
Diethyl(phenyl)(4-trifluoromethyl)phenylamino) methylphosphonate (3k) White
1
crystalline solid. Mp 140 °C. HNMR (300 MHz, CDCl3, 25 °C): d = 1.12 (t,
3H, J = 7.0 Hz, –OCH2–CH3), 1.31 (t, 3H, J = 7.1 Hz, –OCH2–CH3), 3.61–3.70
(m, 1H, –OCH2–CH3), 3.90–4.08 (dp, J = 10.1, 7.1 Hz, 1H, –OCH2–CH3),
4.10–4.20 (m, 2H, OCH2–CH3), 4.79 (dd, 1H, J = 24.2, 7.5 Hz, Ph–CH),
5.16–5.31 (m, 1H, NH), 6.62 (d, 2H, J = 8.5 Hz, HAr), 7.26–7.40 (m, 5H, HAr),
7.49 (dd, J = 7.7, 2.1 Hz, 2H, HAr). 13CNMR: (75 MHz, CDCl3, 25 °C):
d = 148.90 (d, J = 14.4 Hz), 135.13 (d, J = 3.0 Hz), 128.91, 128.87, 128.38,
128.34, 127.90, 127.83, 126.68, 126.63, 113.16, 63.75 (dd, J2 = 22.9, 7.0 Hz),
56.77, 54.77, 16.59 (d, J3 = 19.0 Hz), 16.51 (d, J3 = 5.8 Hz). 31P NMR:
(121 MHz, CDCl3, 25 °C): d = 22.54 ppm.
Diethyl(4-methoxyphenyl)(4-trifluoromethylphenylamino) methylphosphonate (3l)
White crystalline solid. Mp 111 °C. 1HNMR (300 MHz, CDCl3, 25 °C):
d = 1.15 (t, 3H, J = 7.0 Hz, –OCH2–CH3), 1.31 (t, 3H, J = 7.1 Hz, –OCH2–
CH3), 3.63–3.72 (ddd, J = 10.1, 8.3, 7.1 Hz, 1H, –OCH2–CH3), 3.80 (s, 3H, –
OCH3), 3.95 (dt, J = 10.1, 7.1 Hz, 1H, –OCH2–CH3), 4.13 (m, 2H, –OCH2–CH3),
4.73 (dd, 1H, J = 23.8, 7.6 Hz, CHP), 5.15 (dd, J = 9.7, 7.8 Hz, 1H, –NH), 6.63
(d, 2H, J = 8.5 Hz, HAr), 6.90 (d, 2H, J = 8.5 Hz, HAr), 7.26–7.40 (m, 4H, HAr).
13CNMR: (75 MHz, CDCl3, 25 °C): d = 159.60, 148.16 (d, J = 14.3 Hz), 128.97,
126.96, 126.67, 114.35 (d, J = 2.3 Hz), 113.19, 63.70 (dd, J2 = 24.1, 7.0 Hz),
56.10, 55.38, 54.08, 16.61 (d, J3 = 13.9 Hz), 16.54 (d, J3 = 5.8 Hz). 31P NMR:
(121 MHz, CDCl3, 25 °C): d = 22.77 ppm.
Diethyl(4-chlorophenyl)(4-trifluoromethylphenylamino) methylphosphonate (3m)
White crystalline solid. Mp 129 °C. 1HNMR (300 MHz, CDCl3, 25 °C):
d = 1.18 (t, 3H, J = 6.9 Hz, –OCH2–CH3), 1.32 (t, 3H, J = 7.1 Hz, –OCH2–
CH3), 3.72–3.81 (m, 1H, –OCH2–CH3), 3.96–4.01 (m, 1H, –OCH2–CH3),
4.04–4.18 (m, 2H, –OCH2–CH3), 4.70 (dd, 1H, J = 24.4, 7.3 Hz, CHP), 5.16
(dd, 1H, J = 10.2, 7.5 Hz, –NH), 6.60 (d, 2H, J = 8.6 Hz, HAr), 77.28–7.43 (m,
6H, HAr). 13CNMR: (75 MHz, CDCl3, 25 °C): d = 148.61 (d, J = 14.2 Hz),
134.24 (d, J = 3.9 Hz), 134.19, 133.96, 133.92, 129.19, 129.12, 126.76, 126.71,
113.19, 63.71 (dd, J2 = 11.2, 7.0 Hz), 56.27, 54.27, 16.60 (d, J3 = 13.9 Hz), 16.53
(d, J3 = 5.7 Hz). 31P NMR: (121 MHz, CDCl3, 25 °C): d = 21.87 ppm.
Results and discussion
The aim of this study is to develop an efficient and eco-friendly protocol to access a-
aminophosphonate compounds with a green chemistry approach. Firstly, we have
explored the reactivity and the activation threshold of NiSO4Á6H2O as heteroge-
neous catalyst for the three-component condensation. For this study, we chose these
three components, p-methoxy-benzaldehyde, p-toluidine, and diethyl phosphite
(Scheme 1). It is the ideal combination for our study, the methoxy-group on para-
position of the aromatic ring of the aldehyde reduces the electrophilicity, and methyl
123

NiSO4Á6H2O as a new, efficient, and reusable catalyst for…
O
P
NH2
O
OEt
OEt
H
N
O
NiSO4.6H2O (mol%)
Solvent-free, rt
EtO
+
+
PH
EtO
MeO
3l
OMe
Scheme 1 General reaction
Table 1 Effect of catalytic amount of NiSO4Á6H2O on the synthesis of 3i
Entrya
NiSO4Á6H2O (mol%)
Time (min)
Yield (%)b
1
2
3
4
5
6
Without
120
60
NR
97
20
15
10
5
60
96
60
93
10
98
2
120
Traces
The bold values indicate the best results
a
Reaction conditions: p-methoxylbenzaldehyde (1 mmol), p-toluidine (1 mmol), diethylphosphite
(1.2 mmol), NiSO4Á6H2O (mol%), at room temperature and solvent-free conditions
Isolated yield after crystallization with ether/hexane
b
group on para-position of the aromatic ring of the toluidine reduces the
nucleophilicity.
We have used a mixture of 1 equivalent of aldehyde, 1 equivalent of aniline and
1.2 equivalent of diethylphosphite and different catalytic rates of NiSO4Á6H2O from
20 to 2 mol%, in a solvent-free condition at room temperature. The reactions were
monitored by TLC analysis. The reaction mixtures were quenched, by simple
extraction and the desired pure products have been recovered by simple
crystallization in ether/hexane. The obtained results are summarized in Table 1.
The a-aminophosphonate 3i is obtained in high yields (93 % B yield B 98 %)
(Table 1, entries 2–5) using a catalytic amount from 20 to 5 mol% of NiSO4Á6H2O. The
results described in Table 1 show a significant effect of the amount of the catalyst. It is
found that the decrease of the catalytic amount of NiSO4Á6H2O leads to a considerably
increased reaction rate, from 1 h with 20 mol% to 10 min using just 5 mol% of this
catalyst (Table 1, entries 2–5). For quantities of catalysts between 10 and 20 mol%, the
reaction time is 60 min and the yields range from 93 % B yield B 97 % (Table 1,
entries 2–4). Furthermore, without a catalyst, no product formation (Table 1, entry 1)
and with 2 mol% the traces of 1 are detected (Table 1, entry 6). These results affirm not
only the utility of this catalyst to achieve the three-component condensation but also its
efficiency with an optimal catalytic amount of 5 mol%.
The activity of the recycled catalyst was also examined under the optimized
conditions (Scheme 1). After the completion of reaction, NiSO4Á6H2O was removed
123

S. Guezane Lakoud et al.
98
96
94
92
90
88
86
84
82
80
78
98
98
96
93
90
85
1
2
3
4
5
6
Number of reuse
Fig. 1 Reusing of the NiSO4Á6H2O catalyst
O
O
O
H
N
O
.
(5mol%)
NiSO4 6H2O
EtO
P
+
R2
+
NH2
PH
R2
O
Solvent-free, rt
R1
EtO
R1
[3a-3m]
[2a-2c]
[1a-1f]
Scheme 2 Application of the reaction with new catalyst NiSO4Á6H2O
by filtration, washed with methanol, and directly reused in another reaction. The
recovered catalyst was reused for six consecutive cycles without any significant loss
in catalytic activity, proving its efficiency. Until the fifth reuse, the a-aminophos-
phonate 3l is obtained with excellent yield between 90 % \ yield \ 98 %.
However, from the sixth recycling, a loss of the catalytic performance of
NiSO4Á6H2O is recorded, the recovered yield decreases to 85 % (Fig. 1).
To validate this new catalyst (NiSO4Á6H2O) and extend its use and its catalytic
reactivity, the reaction conditions are applied on a series of variously substituted
aldehydes coupled with diverse aromatic amines in the presence of diethylphosphite
and 5 mol% of NiSO4Á6H2O at room temperature without a solvent (Scheme 2).
The a-aminophosphonates [3a–3m] are obtained after a simple work-up
procedure (extraction-crystallization) with excellent yields (up to 92 %) within
10–20 min. The results are presented in Table 2. The structures of all products are
1
determined by H 13C and 31P NMR analysis.
The results in Table 2 show various aldehydes and amines as reactants were
screened with 5 mol% of NiSO4Á6H2O in Kabachnik–Fields reaction, and good-to-
excellent yields ([92 %) were obtained in very short time (t \ 20 min). The
reaction between aniline and aromatic aldehydes substituted by electron-withdraw-
ing groups provides excellent yields in 20 min, due to mesomeric and inductive
effects in the presence of diethylphosphate (Table 2, entries 1–5). When aniline is
substituted with electron donating, the catalysis with NiSO4Á6H2O (5 mol%) leads
to a-aminophosphonate compounds with excellent yields an even faster time of
10 min (Table 2, entries 6–10). The use of 4-trifluoroaniline is carried out with a
123

NiSO4Á6H2O as a new, efficient, and reusable catalyst for…
Table 2 Scope of the NiSO4Á6H2O catalyst in the synthesis of a series of a-aminophosphonates
Time
(min)
Yield
(%)(b)
Entry (a)
Aldehyde
Amine
Product
O
H
N
OEt
OEt
O
P
NH2
1
20
20
96
92
2a
3a
1a
O
P
H
N
OEt
OEt
O
2a
2
O2N
3b
1b
NO2
O
H
N
OEt
OEt
O
P
2a
2a
3
4
20
20
94
96
Cl
3c
1c
Cl
O
P
H
N
OEt
OEt
O
MeO
3d
1d
OMe
O
H
N
OEt
OEt
O
P
5
20
10
10
97
97
95
2a
Ph
3e
1e
Ph
O
O
H
OEt
OEt
NH2
N
P
6
7
2b
1a
3f
O
P
H
N
OEt
OEt
O
2b
O2N
3g
1b
NO2
O
H
N
OEt
OEt
O
P
2b
2b
8
9
10
10
96
98
Cl
1c
3h
Cl
O
P
H
N
OEt
OEt
O
MeO
1d
3i
OMe
123

S. Guezane Lakoud et al.
Table 2 continued
Time
(min)
Yield
(%)(b)
Entry (a)
Aldehyde
Amine
2b
Product
O
P
H
N
OEt
OEt
O
10
10
98
Ph
1e
3j
Ph
O
O
H
N
OEt
OEt
NH2
P
11
12
15
20
96
96
F3C
F3C
2c
3k
1a
O
P
H
N
OEt
OEt
O
2c
F3C
MeO
1b
3l
OMe
O
H
N
OEt
OEt
O
P
2c
2a
13
14
20
94
--
F3C
Cl
1c
3m
Cl
--
120
O
1f
a
All reactions were carried out with 1 mmol of aldehyde, 1 mmol of amine, 1.2 mmol of
diethylphosphite and 5 mol% of NiSO4ÁH2O
Isolated yield after crystallization with ether/hexane
b
high yield in spite of the property of the electron-withdrawing group (–CF3); this
group could have reduced the nucleophilicity of the amine, nevertheless the a-amino
phosphonates are obtained in 15–20 min with a yield[94 %, due, definitely, to the
efficiency of the catalyst NiSO4Á6H2O (Table 2, entries 11–13).
In the presence of NiSO4Á6H2O as a catalyst, the a-aminophosphonates are
readily obtained, without substantial involvement of the electronic effects of various
substituents of amine in the condensation reaction. We observe a slight acceleration
of the reaction when using anilines substituted by an electron-donating group on the
–para potion of the aromatic ring with a reaction time of 10 min, compared with the
electron-withdrawing groups with a reaction time of 20 min. Albeit, with the
3-furyl-benzaldehyde, the corresponding a-aminophosphonate is not formed after
123

NiSO4Á6H2O as a new, efficient, and reusable catalyst for…
Table 3 Comparison of NiSO4Á6H2O with various catalysts
Entry
Catalyst (mol%)
T (°C)
Time
Yield (%)
References
1
2
3
4
5
6
7
8
a
NiSO4Á6H2O (5)a
TiO2(20)
rt
50
rt
20 min
4 h
98b
98
90
87
90
97
95
94
[13]
[22]
[27]
[36]
[28]
[31]
[20]
Cp2Zr(OSO2C4F9)2Á2H2O(5)
Sulfamic-acid (20)
2.5 h
2 h
rt
Cu(OTf)2 (5)/Ligand
BF3SiO2 (5)/[bmim][HCl]
Fe/SWCNTs (5)
rt
6 h
rt
5 min
60 min
12 min
50
rt
Acid 1-hexanesulphonic (10)/ultrasonication
Reaction conditions: 4-methoxylbenzaldehyde (1mmom), aniline (1 mmol), diethylphosphite
(1.2 mmol), NiSO4Á6H2O (5 mol%), ambient temperature, 20 min
Isolated yield after crystallization with ether/hexane
b
120 min of stirring. This fact is probably due to the electronic effects related to the
presence of oxygen in this position (Table 2, entry 14).
Asasupplementary,andinordertodelineate the efficiencyofuseofthe NiSO4Á6H2O
as novel robust catalyst, we have compared it to other described protocols selected from
the literature using diverse catalysts to elaborate the Kabachnik–Fields reaction for the
synthesis of a-aminophosphonates. Our comparison is based on the following
parameters: temperature, duration, and yield. The results are reported in Table 3.
The results of the literature described in Table 3 show that with 20 mol% TiO2,
the reaction is carried out at 50 °C with a 98 % yield in 4 h (Table 3, entry 2). The
sulfamic-acid catalyst (20 mol%) led to a-aminophosphonate compounds with 87 %
yield after 2 h of stirring at room temperature (Table 3, entry 4). Using 5 mol%
Cu(OTf)2 combined to bis-fluoro-oxazolines, as ligand, gives the a-amino
phosphonates with 90 % yield at room temperature in 6 h (Table 3, entry 5). In
the presence of 5 mol% of BF3SiO2, the reaction is completed in 5 min in ionic
liquid [bmim] [HCl] (Table 3, entry 6). The use of iron-doped single-walled carbon
nanotubes (Fe/SWCNT) (5 mol%) for 60 min at 50 °C gives a 95 % yield (Table 3,
entry 7). The 1-hexanesulphonique acid and sodium salt (10 mol%) under
ultrasound as source of activation leads to the desired product with a yield of
94 % in 12 min (Table 3, entry 8). Recently, the complex Cp2Zr(OSO2C4F9)2Á2H2O
(5 mol%) was used as a catalyst for the same reaction at room temperature; the yield
is 90 % in 2.5 h (Table 3, entry 3). In Table 3, several catalysts were evaluated by
for the synthesis of a-aminophosphonates via Kabachnik–Fields reaction. Compar-
ing the reaction conditions with the NiSO4Á6H2O catalyst, it is found that the
reaction time is longer, the catalytic rate is higher, and more expensive. The reaction
is carried out in the presence of solvents, heating, or the addition of some bases as
activator factor. Moreover, the catalyst must be prepared in some instances.
The present methodology reveals many benefits of the use of NiSO4Á6H2O
(5 mol%) as a new robust heterogeneous catalyst for the synthesis to a-
aminophosphonates by one-pot, three-component condensation. The reaction is
carried in a maximum time of 20 min, with an excellent yield 98 %, without solvent
and without heating activation or introducing additives (Table 3, entry 1).
123

S. Guezane Lakoud et al.
O
OEt
R1
HP
R NH
+
+
NiSO4.6H2O
CH
2
2
OEt
O
R1 CH NH R2
P OEt
O
OEt
Ni+2
O
R1
R1 CH N R2
CH
R2NH2
+
Ni+2
EtO
EtO
P O
H
H2O
O
EtO
EtO
PH
Scheme 3 The proposed mechanism of the one-pot reaction catalyzed by NiSO4Á6H2O
On the basis of the experimental results and the literature which describe
plausible mechanisms for the formation of a-aminophosphonates [19, 32, 37], we
propose one possibility in Scheme 3. So, in our case, the pathway most probable is
via the imine formation, knowing that the aromatic amine reacts very quickly with
the benzaldehyde and derivatives [9]. It is estimated that, in the first time, nickel
coordinates the oxygen of the aldehyde and creates a good electrophilic site
followed by a nucleophilic attack of primary amine to form in situ an imine and the
elimination of the water formed. Then, the nickel coordinates again, with both
nitrogen of the imine and the oxygen of diethylphosphite in parallel to accelerating
the nucleophilic reaction of the phosphite on the imine to give the expected product.
Conclusion
We have described a new catalyst, the nickel (II) sulfate hexahydrate, to access the
a-aminophosphonates by a one-pot, three-component condensation: aldehyde,
amine, and diethyl phosphate, at room temperature, under solvent-free conditions.
This catalyst presents several advantages such as low catalytic amount of
5 mol%, short reaction times between 10 and 20 min, easy purification, and the
desired products are recovered with excellent chemical yields. NiSO4Á6H2O is a
catalyst that is commercially available, cheap, stable, easily recovered, and it can be
reused six times keeping the same catalytic efficiency. It is in favor of this new
123

NiSO4Á6H2O as a new, efficient, and reusable catalyst for…
catalyst, high level of activity at room temperature with low catalytic rate, without
solvent or activation; it is also an inexpensive recyclable catalyst. The approach
described is simple and environmentally friendly.
Acknowledgments The Algerian Ministry of Education and Scientific Research (FNR 2000 and PNR)
is gratefully acknowledged for financial support of this work. Professor Olivier Riant (IMCN/MOST,
´
Universite Catholique de Louvain, Belgium) and F-Z BELKACEMI are acknowledged for carrying out
the NMR analysis.
References
1. M.C. Allen, W. Fuhrer, B. Tuck, R. Wade, J.M. Wood, J. Med. Chem. 32, 1652 (1989)
2. D.W. Allen, E.C. Anderton, C. Bradley, L.E. Shiel, Polym. Degrad. Stab. 47, 67 (1995)
3. P.T. Anastas, N. Eghbali, Chem. Soc. Rev. 39, 301 (2010)
4. P.T. Anastas, P.T. Li, Water as a green solvent (Wiley, Hoboken, 2010)
5. P.T. Anastas, J.C. Warner, Green chemistry: theory and practice (Oxford University Press, New
York, 1998)
6. F.R. Atherton, C.H. Hassal, R.W. Lambert, J. Med. Chem. 30, 1603 (1987)
7. S. Bhagat, A.K. Chakraborti, J. Org. Chem. 73, 6029 (2008)
8. A.K. Bhattacharya, T. Kaur, Synlett 5, 745 (2007)
9. R.A. Cherkasov, V.I. Galkin, Russ. Chem. Rev. 67, 857 (1998)
10. S.D. Dindulkar, M.V. Reddy, Y.T. Jeong, Catal. Commun. 17, 114 (2012)
11. E. Fields, J. Am. Chem. Soc. 74, 1528 (1952)
12. A. Heydari, M. Zarei, R. Alijanianzadeh, H. Tavakol, Tetrahedron Lett. 42, 3629 (2001)
13. M. Hosseini-Sarvari, Tetrahedron 64, 5459 (2008)
14. A.A. Jafari, M. Nazarpour, M. Abdollahi-Alibeik, Heteroat. Chem. 21, 6 (2010)
15. M.I. Kabachnik, T.Y. Medved, Dokl. Akad. Nauk SSSR 83, 689 (1952)
16. B. Kaboudin, E. Jafari, Synlett 12, 1837 (2008)
17. P. Kafarski, B. Lejczak, Curr. Med. Chem Anti-Cancer Agent 1, 301 (2001)
18. Z. Karimi-Jaberi, H. Zare, M. Amiri, N. Sadeghi, Chin. Chem. Lett. 22, 559 (2011)
´
19. G. Keglevich, E. Balint, Molecules 17, 12821 (2012)
20. S.N. Kirti, B.S. Bapurao, S.S. Murlidhar, Ultrason. Sonochem. 17, 760 (2010)
21. S. Lashat, H. Kunz, Synthesis. 1, 90 (1992)
22. N. Li, X. Wang, R. Qiu, X. Xu, J. Chen, X. Zhang, S. Chen, S. Yin, Catal. Commun. 43, 184 (2014)
23. S.D. Lombaert, L. Blanchard, J. Tan, Y. Sakane, C. Berry, R.D. Ghai, Bioorg. Med. Chem. Lett. 5,
145 (1995)
24. L. Maier, Phosphorus, Sulfur Silicon Relat. Elem. 53, 43 (1990)
25. L. Maier, H. Spoerri, Phosphorus. Sulfur Silicon Relat. Elem. 61, 69 (1991)
26. D. Miliszkiewicz, P. Wieczorek, B. Lejczak, E. Kowalik, P. Kafarski, Pestic. Sci. 34, 349 (1992)
27. S.D. Mitragotri, D.M. Pore, U.V. Desai, P.P. Wadgaonkar, Catal. Commun. 9, 2008 (1822)
28. M.V. Reddy, S.D. Dindulkar, Y.T. Jeong, Tetrahedron Lett. 52, 4764 (2011)
29. Z. Rezaei, H. Firouzabadi, N. Iranpoor, A. Ghaderi, M.R. Jafari, A.A. Jafari, H.R. Zare, Eur. J. Med.
Chem. 44, 4266 (2009)
30. R. Rozenfeld, X. Iturrioz, M. Okada, B. Maigret, C. Lorens-Cortes, Biochemistry 42, 14785 (2003)
31. H. Sharghi, S. Ebrahim Pourmoghaddam, M.M. Doroodmand, Tetrahedron 69, 4708 (2013)
32. J. Tang, L. Wanga, W. Wang, L. Zhang, W. Shengying, D. Mao, J. Fluor. Chem. 132, 102 (2011)
33. B.M. Trost, Angew. Chem. Int. Ed. 107, 285 (1995)
34. B.M. Trost, Angew. Chem. Int. Ed. 34, 259 (1995)
35. B.M. Trost, Science. 254, 1471 (1991)
36. H. Wang, T. Deng, C. Cai, J. Fluor. Chem. 168, 144 (2014)
37. M. Yamanaka, T.J. Hirata, J. Org. Chem. 74, 3266 (2009)
38. N.S. Zefirov, E.D. Matveeva, ARKIVOC 1(11), 1–17 (2008)
39. J. Zon, Pol. J. Chem. 55, 643 (1981)
123