Ultrasonic and Lewis acid ionic liquid catalytic system for Kabachnik-Fields reaction

Article abstract of DOI:10.2478/s11696-013-0516-4

A combination of ultrasonic (US) and [bmim]AlCl₄ ionic liquid is used as an alternative to conventional acid catalysts in the Kabachnik-Fields reaction of an amine and aryl aldehyde with phosphite leading to the formation of aminophosphonates.

Full text of DOI:10.2478/s11696-013-0516-4

Chemical Papers 68 (6) 834–837 (2014)
DOI: 10.2478/s11696-013-0516-4
SHORT COMMUNICATION
Ultrasonic and Lewis acid ionic liquid catalytic system
for Kabachnik–Fields reaction
Sadegh Rostamnia*, Mojtaba Amini
Organic & Nano Group (ONG), Department of Chemistry, University of Maragheh, P.O. Box 55181-83111, Maragheh, Iran
Received 4 June 2013; Revised 6 October 2013; Accepted 14 October 2013
4
A combination of ultrasonic (US) and [bmim]AlCl ionic liquid is used as an alternative to conven-
tional acid catalysts in the Kabachnik–Fields reaction of an amine and aryl aldehyde with phosphite
leading to the formation of aminophosphonates. The reaction time was significantly reduced and
the reaction progressed very smoothly.
ꢀ
c 2013 Institute of Chemistry, Slovak Academy of Sciences
Keywords: ionic liquid, ultrasound, aminophosphonate, Kabachnik–Fields reaction, multi-com-
ponent reaction
Intense research has recently focused on the ap-
plication of ionic liquids as catalysts for a wide
variety of organic synthetic processes. Ionic liquids
provide vapour-free, thermally stable and “green”
auxiliary substances for chemical reactions (Fumino
et al., 2011). Active Lewis acid catalysis based on
ionic liquids is regarded as important because of
the widespread air- and solvent-stable demand for
the use of Lewis acid catalysts in synthetic and in-
dustrial chemical applications (Dupont et al., 2002).
Very recently, Lewis acidic ionic liquids have at-
tracted increased attention as replacements for con-
ventional mineral acid catalysts because of their neg-
ligible vapour pressure, outstanding acidity and pre-
determined solubility for some organic species (Gor-
don et al., 2001). On the other hand, ultrasound has
been shown to have potential applications in organic
synthesis, “green” chemistry and industry. Compared
with traditional methods, this method is more conve-
nient and more readily controlled (Rostamnia, 2011).
Due to the importance of aminophosphonates, the
synthesis of these units is important in their use as in-
hibitors and a wide range of antibacterial or antifungal
applications (Pratt, 1989; Rostamnia & Lamei, 2003).
Several methods of synthesising α-aminophosphonate
have been reported in the literature (Ranu & Ha-
jra, 2002; Azizi & Saidi, 2003; Ramalingam & Ku-
mar 2008; Niralwad et al., 2010; Ordo n˜ ez et al., 2010;
Mandhane et al., 2011). However, the use of IL and
ultrasound (US) contributes to a clean environment.
The current study reports the results of the applica-
tion of the US/IL catalytic system (Fig. 1) as a rapid
catalyst for the three-component condensation of an
amine, aldehyde and phosphite with excellent yields
of α-aminophosphonates.
The ongoing programme (Rostamnia & Zabar-
dasti, 2003; Rostamnia et al., 2012a, 2012b) focuses
on the development of efficient and environmentally
friendly methods in synthetic organic chemistry. The
aim has been to investigate and design a catalyst and
energy resources to achieve the desired chemical trans-
formations with minimal formation of by-products or
waste, as well as to decrease reaction time using ultra-
sound and porous catalysts. Building on earlier suc-
cess in the “green” application of ultrasound in or-
ganic synthesis, we sought to combine achievements
in the IL area with ultrasound. The current study
presents the results of an extended investigation into
the simultaneous use of the [bmim]AlCl and ultra-
4
sound as a rapid approach to synthesis of the α-
aminophosphonate III via three-component coupling
(Fig. 1).
The reaction of aniline and p-chlorobenzaldehyde
with dimethyl phosphite was precisely monitored. The
*Corresponding author, e-mail: rostamnia@maragheh.ac.ir, srostamnia@gmail.com

S. Rostamnia, M. Amini/Chemical Papers 68 (6) 834–837 (2014)
835
Table 1. Study of optimised conditions for model reaction (high-speed stirrer vs ultrasound)a
Yield/%
◦
Solvent
Temperature/ C
Time/min
HSS
US
MeOH
EtOH
EtOH
PhMe
PhMe
CH3CN
50
50
a.t.
a.t.
60
10
5
5
10
10
10
22
19
14
33
45
40
75
87
93
74
93
92
60
a) Reaction scale: aniline (2 mmol), p-chlorobenzaldehyde (2.2 mmol), dimethyl phosphite (2 mmol) and catalyst (10 mol %) in
0 mL of solvent.
1
Table 2. Clean one-pot synthesis of IIIa–IIIi by US/IL catalytic systema
ꢀ
Entry
Amine
Ar(R )CHO
Time/min
Product
Isolated yield/%
1
2
3
4
5
6
7
8
9
PhNH2
PhNH2
PhNH2
4-Cl-C6H4
C6H5
5
5
6
5
4
7
5
5
10
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
IIIg
IIIh
IIIi
93
91
92
91
90
89
92
87
88
3-NO2-C6H4
2-Cl-C6H4
4-NO2-C6H4
2-MeO-C6H4
3-NO2-C6H4
2-MeO-C6H4
(CH2)5CO
4-Me-C6H4NH2
4-Me-C6H4NH2
4-Me-C6H4NH2
Et2NH
(CH2)4NH
PhNH2
a) Reaction scale: amine (1 mmol), aldehyde (1 mmol), dimethyl phosphite (1.1 mmol) and catalyst (10 mol %) in 5 mL EtOH.
1
5 min in toluene. A further increase in the amount of
catalyst (from 6 mol % to 20 mol %) had no significant
effect on the product yield or reaction time (Fig. 2).
The model reaction in the presence of 10 mol %
of [bmim]AlCl4 was examined in different media (Ta-
ble 1). Remarkably, in the comparative study of
a one-pot, three-component synthesis of IIIa, the
ultrasonically-mediated (US) procedure was com-
pleted in 5 minutes and the reaction time using the
high-speed stirrer (HSS) method was 3 hours. Soni-
cation in the model reaction led to reduced time and
higher yield.
Fig. 1. US/[bmim]AlCl4 system in Kabachnik–Fields reac-
tion.
To demonstrate the diversity of this combined ul-
trasonic and IL catalytic system and to expand the
scope of the process, the optimised conditions (EtOH,
a.t. and US irradiation with 10 mol % of IL) were
applied to a series of III via a three-component con-
densation. The results are summarised in Table 2.
The synthesis of IIIa with high level (5 mmol) of
reactant was carried out in 25 mL EtOH. When the
p-chlorobenzaldehyde and aniline were coupled with
dimethylphosphite under optimal conditions, a yield
of 89 % was obtained, demonstrating the efficiency of
this method in large amount of substrates.
Fig. 2. Catalyst amounts of IL in synthesis of IIIa.
For a chemoselectivity investigation, the reactivity
of dimethyl phosphite in the presence of the mixture of
aldehydes, ketones and aniline may demonstrate the
chemoselectivity in the present method. To demon-
strate the chemoselectivity, dimethyl phosphite was
treated with the mixture of aniline, benzaldehyde and
◦
model reaction (60 C) was carried out using different
amounts of IL as the catalyst and irradiation with
ultrasound. A high yield of α-aminophosphonate IIIa
93 %) was obtained with 10 mol % of the catalyst over
(

8
36
S. Rostamnia, M. Amini/Chemical Papers 68 (6) 834–837 (2014)
Table 3. Spectral data of Kabachnik–Fields products
Compound
Spectral data
IIIa
IIIb
IIIc
IIId
1H NMR (CDCl3), δ: 3.55 (d, 3JHP = 10.8 Hz, 3 H), 3.77 (d, 3JHP = 10.8 Hz, 3 H), 4.52 (br, 1 NH), 4.79 (d, 2JHP
24.3 Hz, 1 H), 6.59–7.44 (m, 9 H)
1H NMR (CDCl3), δ: 3.47 (d, 3JHP = 10.5 Hz, 3 H), 3.78 (d, 3JHP = 10.5 Hz, 3 H), 4.84 (d, 2JHP = 24.3 Hz, 1
H), 5.02 (br, 1 NH), 6.51–7.51 (m, 10 H)
1H NMR (CDCl3), δ: 3.64 (d, 3JHP = 10.8 Hz, 3 H), 3.83 (d, 3JHP = 10.4 Hz, 3H), 5.00 (d, 2JHP = 25.1 Hz, 1 H),
=
5.25 (br, 1 NH), 6.62–8.41 (m, 9 H)
1
H NMR (CDCl3), δ: 2.16 (m, 3 H), 3.43 (d, 3JHP = 9.9 Hz, 3 H), 3.83 (d, 3JHP = 9.9 Hz, 3 H), 4.85 (br, 1 NH),
.39 (d, JHP = 24.9 Hz, 1 H), 6.49–7.56 (m, 8 H)
C NMR (CDCl3), δ: 20.34, 50.39 (d, 3JCP = 6.6 Hz), 53.03 (d, 1JCP = 152.1 Hz), 113.67, 127.42, 127.46, 127.97,
2
5
13
129.78, 133.83, 137.78, 146.00
IIIe
1H NMR (CDCl3), δ: 2.24 (m, 3 H), 3.50 (d, 3JHP = 10.5 Hz, 3 H), 3.78 (d, 3JHP = 10.5 Hz, 3 H), 4.80 (d, 2JHP
=
24.3 Hz, 1 H), 6.02 (br, 1 NH), 6.54–7.38 (m, 8 H)
C NMR (CDCl3), δ: 21.15, 53.84 (d, 3JCP = 6.9 Hz), 55.43 (d, 1JCP = 152.1 Hz), 113.92, 118.49, 127.66, 127.74,
1
3
129.49, 132.43, 137.78, 149.26
1
H NMR (CDCl3), δ: 2.18 (m, 3 H), 3.45 (d, 3JHP = 10.5 Hz, 3 H), 3.82 (d, 3JHP = 10.5 Hz, 3 H), 3.93 (s, 3 H),
IIIf
IIIg
IIIh
IIIi
4
1
.06 (br, 1 NH), 5.43 (d, 2JHP = 24.0 Hz, 1 H), 6.54–7.49 (m, 8 H)
H NMR (CDCl3), δ: 0.95 (t, J = 7.2 Hz, 6 H), 2.21 (m, 2 H), 2.88 (m, 2 H), 3.37 (d, 3JHP = 9.3 Hz, 3 H), 3.77
d, JHP = 9.3 Hz, 3 H), 4.12 (d, 2JHP = 24.9 Hz, 1 H), 7.17–7.38 (m, 5 H)
3
(
1
H NMR (CDCl3), δ: 31.69 (m, 4 H), 2.16 (m, 2 H), 2.64 (m, 2 H), 3.46 (d, 3JHP = 6.3 Hz, 3 H), 3.77 (d, 3JHP =
.3 Hz, 3 H), 3.85 (s, 3 H), 4.66 (d, 2JHP = 18.0 Hz, 1 H), 6.89–7.75 (m, 4 H)
6
1H NMR (CDCl3), δ: 1.13–2.13 (m, 10 H), 3.45 (br, 1 NH), 3.55 (d, 3JHP = 10.5 Hz, 6 H), 6.66–7.06 (m, 5 H)
ganic molecules of aminophosphonates via the three-
component Kabachnik–Fields reaction. Undoubtedly,
as part of the continuing investigation of ultrasonic/IL
system for organic synthesis, these reaction methods
represent potential applications in organic syntheses,
pharmacy and industrial processes, hence this report
opens an important field for use of the Lewis acid-
mediated strategy in the organic process.
All reagents were obtained from Merck (Germany)
and Fluka (Switzerland) and used without further
Fig. 3. Chemoselective addition of phosphite to different car-
bonyl compounds.
purification. [Bmim][AlCl ] > 95 mass % was ob-
4
tained from Sigma–Aldrich (China). Melting points
were measured on an Electrothermal 9100 appara-
1
cyclohexanone. Analysis of the mixture after 10 min
showed that only benzaldehyde reacted with aniline
to form IIIb (Fig. 3).
Many of the synthetic protocols reported for the
synthesis of aminophosphonates suffer from one or
more disadvantages such as harsh reaction conditions,
lengthy reaction time and use of hazardous heavy
metal catalysts (Beers et al., 1996; Danila et al., 2008;
Cativiela et al., 2009; Gallardo-Macias & Nakayama.,
tus. H NMR spectra were recorded on a Bruker AV-
300 instrument (300 MHz) with CDCl3 as solvent.
A multi-wave ultrasonic generator (Sonicator 3000;
Misonix, Farmingdale, NY, USA), equipped with a
converter/transducer and titanium oscillator (horn),
12.5 mm in diameter, generating continuous irradia-
tion with a maximum power output of 600 W, was
used for the ultrasonic irradiation.
General procedure for preparation of compound
III: A mixture of p-chlorobenzaldehyde (140 mg,
1 mmol), aniline (93 mg, 1 mmol), dimethyl phosphite
(121 mg, 1.1 mmol) and [Bmim][AlCl4] (31 mg, 10
mol %) in EtOH (5 mL in a small-diameter beaker)
was irradiated with ultrasound at ambient tempera-
ture (initial temperature value) for the required re-
action time. The progress of the reaction was moni-
tored by TLC. After completion, the reaction mixture
was quenched with water (10 mL) and extracted with
EtOAc (3 × 10 mL). Evaporation of the solvent fol-
lowed by purification on silica gel (EtOH : hexane, 1 : 5
2
010; Ohara et al., 2011; Orsini et al., 2010; Tibhe et
al., 2012; Disale et al., 2012; Ordó n˜ ez et al., 2012).
These results clearly indicate the efficiency of the pro-
posed methodology in both the activity and efficiency
of the US/IL’s catalytic system as compared with
literature reports involving several homogeneous and
heterogeneous systems under various conditions.
In conclusion, the results reported here con-
cern the simultaneous application of ultrasound and
an ionic liquid as a combined catalytic system in
the preparation of some biologically interesting or-

S. Rostamnia, M. Amini/Chemical Papers 68 (6) 834–837 (2014)
837
vol.) afforded pure α-aminophosphonate IIIa (303 mg
Ohara, M., Nakamura, S.,
enantioselective three-component Kabachnik–Fields reac-
tion catalyzed by chiral bis(imidazoline)-zinc(II) catalysts.
&
Shibata, N. (2011). Direct
gum, 93 %). All products listed in Table 3 were known
and characterised by comparison of their physical and
spectral data with those already reported.
Advanced Synthesis
& Catalysis, 353, 3285–3289. DOI:
10.1002/adsc.201100482.
Ordó n˜ ez, M., Sayago, F. J., & Cativiela, C. (2012). Synthesis of
References
quaternary α-aminophosphonic acids. Tetrahedron, 68, 6369–
6412. DOI: 10.1016/j.tet.2012.05.008.
Azizi, N., & Saidi, M. R. (2003). Synthesis of tertiary α-amino
phosphonate by one-pot three-component coupling mediated
by LPDE. Tetrahedron, 59, 5329–5332. DOI: 10.1016/s0040-
Orsini, F., Sello, G., & Sisti, M. (2010). Aminophospho-
nic ccids and derivatives. Synthesis and biological appli-
cations. Current Medicinal Chemistry, 17, 264–289. DOI:
10.2174/092986710790149729.
4020(03)00759-2.
Beers, S. A., Schwender, C. F., Loughney, D. A., Malloy, E.,
Demarest, K., & Jordan, J. (1996). Phosphatase inhibitors
Ramalingam, S., & Kumar, P. (2008). Synthesis of α-amino-
phosphonates by three-component condensation of carbonyl
compound, amine, and dialkyl phosphite using yttria–
zirconia based Lewis acid catalyst. Catalysis Letters, 125,
315–319. DOI: 10.1007/s10562-008-9562-x.
–
III. Benzylaminophosphonic acids as potent inhibitors of
human prostatic acid phosphatase. Bioorganic & Medicinal
Chemistry, 4, 1693–1701. DOI: 10.1016/0968-0896(96)00186-
1
.
Ranu, B. C., & Hajra, A. (2002). A simple and green procedure
for the synthesis of α-aminophosphonate by a one-pot three-
component condensation of carbonyl compound, amine and
diethyl phosphite without solvent and catalyst. Green Chem-
istry, 4, 551–554. DOI: 10.1039/b205747f.
Rostamnia, S., & Lamei, K. (2003). A rapid, catalyst-free,
three-component synthesis of rhodanines in water using ul-
trasound. Synthesis, 2011, 3080–3082. DOI: 10.1055/s-0030-
1260158.
Rostamnia, S., & Zabardasti, A. (2003). SBA-15/TFE (SBA-
15/2,2,2-trifluoroethanol) as a suitable and effective metal-
free catalyst for the preparation of the tri- and tetra-
substituted imidazoles via one-pot multicomponent method.
Journal of Fluorine Chemistry, 144, 69–72. DOI: 10.1016/j.
jfluchem.2012.07.006.
Danila, D. C., Wang, X. Y, Hubble, H., Antipin, I. S.,
Pinkhassik, E. (2008). Increasing permeability of phos-
&
pholipid bilayer membranes to alanine with synthetic α-
aminophosphonate carriers. Bioorganic & Medicinal Chem-
istry Letters, 18, 2320–2323. DOI: 10.1016/j.bmcl.2008.02.
081.
Disale, S. T., Kale, S. R., Kahandal, S. S., Srinivasan, T. G.,
&
uid: An efficient and reusable catalyst for the solvent free
Kabachnik–Fields reaction. Tetrahedron Letters, 53, 2277–
Jayaram, R. V. (2012). Choline chloride·2ZnCl2 ionic liq-
2279. DOI: 10.1016/j.tetlet.2012.02.054.
Dupont, J., de Souza, R. F., & Suarez, P. A. Z. (2002). Ionic
liquid (molten salt) phase organometallic catalysis. Chemical
Reviews, 102, 3667–3692. DOI: 10.1021/cr010338r.
Fumino, K., Peppel, T., Roth, C., Geppert-Rybczynska, M.,
Zaitsau, D. H., Lehmann, J. K., Verevkin, S. P., K ¨o ckerling,
M., & Ludwig, R. (2011). The influence of hydrogen bond-
ing on the physical properties of ionic liquids. Physi-
cal Chemistry Chemical Physics, 13, 14064–14075. DOI:
Rostamnia, S. (2011). Eco-friendly supported nanoparticles as
a green approach. Research Journal of Chemistry and Envi-
ronment, 15, 89–91.
Rostamnia, S., Karimi, Z., & Ghavidel, M. (2012a). Cetyltri-
methylammonium bromide-surfactant aqueous micelles as a
green and ultra-rapid reactor for synthesis of 5-oxo-2-thioxo-
2,5-dihydro-3-thiophenecarboxylate derivatives. Journal of
Sulfur Chemistry, 33, 313–318. DOI: 10.1080/17415993.2012.
662980.
Rostamnia, S., Lamei, K., Mohammadquli, M., Sheykhan, M.,
& Heydari, A. (2012b). Nanomagnetically modified sulfu-
ric acid (γ-Fe2O3@SiO2-OSO3H): An efficient, fast and
reusable green catalyst for the Ugi-like Groebke–Blackburn–
Bienaymé three-component reaction under solvent-free con-
ditions. Tetrahedron Letters, 53, 5257–5260. DOI: 10.1016/j.
tetlet.2012.07.075.
Tibhe, G. D., Reyes-González, M. A., Cativiela, C., & Ordó n˜ ez,
M. (2012). Microwave-assisted high diastereoselective synthe-
sis of α-aminophosphonates under solvent and catalyst free-
conditions. Journal of the Mexican Chemical Society, 56,
183–187.
10.1039/c1cp20732f.
Gallardo-Macias, R., & Nakayama, K. (2010). Tin(II) com-
pounds as catalysts for the Kabachnik–Fields reaction under
solvent-free conditions: Facile synthesis of α-aminophospho-
nates. Synthesis, 2010, 57–62. DOI: 10.1055/s-0029-1217091.
Gordon, C. M. (2001). New developments in catalysis using
ionic liquids. Applied Catalysis A: General, 222, 101–117.
DOI: 10.1016/s0926-860x(01)00834-1.
Mandhane, P. G., Joshi, R. S., Nagargoje, D. R., & Gill, C.
H. (2011). Thiamine hydrochloride (VB1): An efficient cata-
lyst for one-pot synthesis of α-aminophosphonates under ul-
trasonic irradiation. Chinese Chemical Letters, 22, 563–566.
DOI: 10.1016/j.cclet.2010.11.021.
Niralwad, K. S., Shingate, B. B., & Shingare, M. S. (2010).
Solvent-free sonochemical preparation of α-aminophospho-
nates catalyzed by 1-hexanesulphonic acid sodium salt.
Ultrasonics Sonochemistry, 17, 760–763. DOI: 10.1016/j.
ultsonch.2010.02.002.
Pratt, R. F. (1989). Inhibition of a class C beta-lactamase by a
specific phosphonate monoester. Science, 246, 917–919. DOI:
10.1126/science.2814513.