Choline chloride·2ZnCl2 ionic liquid: An efficient and reusable catalyst for the solvent free Kabachnik-Fields reaction

Article abstract of DOI:10.1016/j.tetlet.2012.02.054

The choline based Zn containing deep eutectic mixture was applied as an efficient and eco-friendly ionic liquid catalyst for the one pot three-component synthesis of α-aminophosphonates under solvent-free condition at room temperature. The reactions were completed in short times and products were obtained in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2012.02.054

Tetrahedron Letters 53 (2012) 2277–2279
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Choline chlorideÁ2ZnCl2 ionic liquid: an efficient and reusable catalyst for
the solvent free Kabachnik–Fields reaction
Shamrao T. Disale a, Sandip R. Kale a, Sandeep S. Kahandal a, Thandankorai G. Srinivasan b,
Radha V. Jayaram a,
⇑
a Department of Chemistry, Institute of Chemical Technology, N.Parekh Marg, Matunga, Mumbai 400019, India
b Fuel Chemistry Division, Indira Gandhi Centre for Atomic Research, Kalpakkam 603102, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The choline based Zn containing deep eutectic mixture was applied as an efficient and eco-friendly ionic
Received 7 January 2012
Revised 9 February 2012
Accepted 11 February 2012
Available online 25 February 2012
liquid catalyst for the one pot three-component synthesis of
condition at room temperature. The reactions were completed in short times and products were obtained
in good to excellent yields.
a-aminophosphonates under solvent-free
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Choline
a-Aminophosphonate
Deep eutectic mixture
Solvent free reaction
One-pot synthesis
a
-Aminophosphonates which are structural analogues of
a
-
the synthesis of biologically important compounds, the develop-
ment of an eco-friendly synthesis of -aminophosphonates is
amino acids, have attracted much attention due to their wide range
of applications in biological and medicinal chemistry as enzyme
inhibitors,1,2 antibiotics,3 herbicides, fungicides,4,5 plant growth
regulators,6 pharmacological agents,7 and peptide mimics.8 Several
synthetic methodologies have been developed for the synthesis of
a
desirable. In this era of chemical synthesis, the improvement of
reaction efficiency, avoidance of the toxic reagents, reduction of
waste, and the responsible utilization of resources have become
the critical objectives.14 Deep eutectic mixtures have gained much
recognition than toxic imidazolium based ionic liquids. An eutectic
mixture of choline chloride: MCl2 (M = Zn or Sn) forms a moisture
stable Lewis acidic ionic liquid15 and acts as a powerful replace-
ment for the more commonly employed alkyl imidazolium–chlo-
roaluminates.16 Choline chloride–zinc chloride based ionic liquid
has been successfully used for the Diels–Alder reaction,17 Fischer
indole synthesis,18 O-acetylation of cellulose and monosaccha-
rides,19 and protection of carbonyl compounds.20 We report herein
our results in the three- component ChClÁ2ZnCl2 catalyzed Kabach-
nik–Fields reaction.
a
-aminophosphonates. The Kabachnik–Fields9 reaction represents
one of the most direct and appealing approach for the preparation
of -aminophosphonates. The process involves a three-component
a
reaction between an aldehyde, amine, and dialkyl or trialkyl phos-
phite promoted by Lewis or Bronsted acids such as Yb(OTf)3,10a
Cu(OTf)2,10b InCl3,10c SmI2,10d ZnCl2,10e SnCl4,10f TaCl5–SiO2,10g alu-
mina supported reagents,10h MgClO4,10i LiClO4,10j Sn(OTf)2,10k
CF3CO2H,10l Sc(DS)3,10m BF3ÁEt2O.10n However these methods suffer
from drawbacks such as longer reaction time, use of hazardous and
expensive catalysts, low yield of products, use of solvents, and
harsh reaction conditions hence do not comply with green chemis-
try protocols. Along with this, most Lewis acids cannot be used in
this one pot reaction because of the presence of free amines and
water produced in the imine formation.
In continuation of our efforts for environmentally benign proto-
col for various organic transformations,21 we herein report a
simple and mild procedure for the one pot synthesis of
a-amino-
phosphonates via a multicomponent reaction between aryl alde-
hyde, aniline, and diethyl phosphite in the presence of
ChClÁ2ZnCl2 as a catalyst (Scheme 1).
To overcome these drawbacks, recent methodologies based on
microwave,11 ultrasound,12 and use of ionic liquid13 have been re-
ported. Due to their valuable roles as versatile building blocks in
The one pot three-component reaction between diethyl phos-
phite (2 mmol), benzaldehyde (2 mmol), and aniline (2 mmol)
was chosen as a model reaction. All the reaction conditions were
optimized using ChClÁ2ZnCl2 as a catalyst. The reaction mixture
was stirred at room temperature under solvent-free condition. It
⇑
Corresponding author. Tel.: +91 22 3361 2607; fax: +91 22 2269 2102.
E-mail address: rv.jayaram@ictmumbai.edu.in (R.V. Jayaram).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.02.054

2278
S. T. Disale et al. / Tetrahedron Letters 53 (2012) 2277–2279
O
P
OEt
OEt
O
H
N
O
R2
H
R2
NH2
Choline chloride 2 ZnCl2
rt
HP(OEt)
2
solvent free ,
R1
R1
4
2
1
3
Scheme 1. One pot synthesis of
a-aminophosphonates using ChClÁ2ZnCl2.
Table 1
Table 2
a
Effect of catalyst loading on the Kabachnik–Fields reaction catalyzed by ChClÁ2ZnCl2
Three component reaction of various aldehydes, aniline, and diethyl phosphite
catalyzed by ChClÁ2ZnCl2
a
Entry
Catalyst (mol %)
Time (h)
Yieldb (%)
Entry
P
R1
R2
Time (min)
Yieldb (%)
1
2
3
4
5
—
5
10
15
20
5
1
1
1
1
07
50
70
96
96
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
PhCH2
4-FC6H4
4-ClC6H4
4-ClC6H4
4-BrC6H4
4-BrC6H4
4-FC6H4
60
60
90
60
30
45
50
90
30
120
45
60
45
30
60
96
89
70
85
98
90
92
85
98
70
87
83
90
94
80
3-BrC6H4
4-O2NC6H4
3-ClC6H4
4-MeOC6H4
4-HOC6H4
4-BrC6H4
2-ClC6H4
Ph
a
Reaction conditions: benzaldehyde (2 mmol), aniline (2 mmol), diethyl phos-
phite (2 mmol), 15 mol % catalyst, solvent free, rt.
b
Isolated yield.
Ph
Ph
was observed that initially the reaction mixture was clear and after
10 min the solid product formation started. It is noteworthy that,
no significant product formation was observed under similar reac-
tion conditions in the absence of catalyst even after 5 h (Table 1,
entry 1). Quantitative conversion of the starting material was ob-
tained using 15 mol % of the catalyst (Table 1, entry 4).
3-ClC6H4
Ph
4-CH3OC6H4
4-CH3OC6H4
a
Reaction conditions: aldehyde (2 mmol), aniline (2 mmol), diethyl phosphite
(2 mmol), 15 mol % catalyst, solvent free, rt.
Further increase in the catalyst loading did not enhance the
yield of the product (Table 1, entry 5).
b
Isolated yield. P-product.
At these reaction conditions, no
a-hydroxyphosphonate was
observed. Also, the order of addition of the starting materials did
not have any influence on the product yield. Choline based other
eutectic mixtures such as choline chloride-urea, choline chlo-
rideÁ2SnCl2 were also tested as catalysts for the model reaction.
The reaction is also successful with the less Lewis acidic choline
containing Sn ionic liquid and gave 85% yield after 2 h while cho-
line chloride-urea which has no Lewis acidity gave only 10% yield
after 2 h.
Table 3
Reusability of the catalysta
Run
1
2
3
4
5
Yield (%)b
98
95
92
87
86
a
Reaction conditions: 4-methoxybenzaldehyde (2 mmol), aniline (2 mmol),
diethyl phosphite (2 mmol), 15 mol % catalyst, solvent free, rt.
b
Isolated yield.
The generality of this protocol was tested using various alde-
hydes and amines as reactants in order to determine the scope of
the ChClÁ2ZnCl2 catalyzed Kabachnik–Fields reaction (Table 2).
All the compounds are reported and well characterized.23 It is
important to note that the ChClÁ2ZnCl2 ionic liquid catalyst was
recycled by simple extraction of the product with MTBE from the
reaction mixture. The viscous ionic liquid that remains in the reac-
tion flask is thoroughly washed with ether and reused in subse-
quent reactions without further purifications. Moreover the
catalytic system is reusable for at least five catalytic cycles after
activating the ionic liquid at 80 °C under vacuum in each cycle.
The average yield of the reaction between 4-methoxybenzalde-
hyde, aniline and diethyl phosphite after five recycle of the catalyst
was found to be 92% as shown in Table 3.
benzaldehyde (1710 cmÀ1
)
was shifted to
a lower value
(1690 cmÀ1). Hence it is possible that the catalyst complexes with
the aldehyde as shown in the mechanism (Scheme 2). However
further studies are needed to support the proposed mechanism
of the reaction.
It was found that the electronic effects of the substituents had
an influence on the yield. It was observed that both the electron
donating and electron withdrawing substituents on the aromatic
aldehydes gave good to excellent yields (Table 2, entries 1–15).
However, as electron donating effect on aromatic aldehyde in-
creases, the yield of the product increases as compared to that of
electron withdrawing groups. The increased electron density on
the nitrogen atom of the imine may help to increase the interaction
of Lewis acid (ZnCl2) and Lewis base (imine nitrogen). This makes
the iminum ion a better electrophilic center which is subsequently
On the basis of the experimental results and the literature,22
possible mechanisms for the formation of aminophosphonates
are presented in Scheme 2. Macias et al.20 have reported that the
reaction between dialkyl phosphite and imine is the rate determin-
ing step when aniline is the amine. Abbott et al.15 have shown that
the actual species present in the Lewis acidic ionic liquid
ChClÁ2ZnCl2 can be [ZnCl3]À, [ZnCl5]À, [ZnCl7]À. [ZnCl3]À may act
as Lewis base and abstract a proton from diethyl phosphite to gen-
erate an anionic phosphite species. In the present reaction, the
ChClÁ2ZnCl2 catalyst can form a complex either with the aldehyde
or the imine formed in the first step of the reaction. It was observed
that on addition of the catalyst the >C@O stretching frequency of
attacked by the nucleophilic phosphite species to give the
a-
aminophosphonate product. Substituted anilines also give good
to excellent yields (Table 2, entries 10–15) but lower than the pri-
mary amine (Table 2, entry 9).
In conclusion, we have shown a facile and efficient procedure
for the one pot synthesis of a-aminophosphonates using environ-
mentally safe ionic liquid. This method avoids the use of acidic
and highly toxic reagents as catalysts and foul smelling triethyl
phosphite. In addition operational simplicity, mild reaction

S. T. Disale et al. / Tetrahedron Letters 53 (2012) 2277–2279
2279
(k) Gallardo-Macias, R.; Nakayama, K. Synthesis 2010, 1, 57; (l) Akiyama, T.;
Sanada, M.; Fuchibe, K. Synlett 2003, 1463; (m) Manabe, K.; Kobayashi, S. Chem.
Commun. 2000, 669; (n) Ha, H. J.; Nam, G. S. Synth. Commun. 1992, 22, 1143.
11. Kabachnik, M. M.; Zobnina, E. V.; Beletskaya, I. P. Synlett 2005, 1393.
12. Xia, M.; Lu, Y. D. Ultrason. Sonochem. 2007, 14, 235.
13. Yadav, J. S.; Reddy, B. V. S.; Sreedhar, P. Green Chem. 2002, 4, 436.
14. (a) Ramachari, D. B.; Kishor, M. J. Org. Chem. 2007, 72, 5056; (b) Yadav, L. D. S.;
Singh, S.; Rai, V. K. Green Chem. 2009, 72, 5056; (c) Leitner, W. Green Chem.
2009, 11, 603.
Cl2Zn
H
N
O
OC2H5
OC2H5
P
O
H
H2N
+
ChCl 2 ZnCl2
-H2O
15. Abbott, A. P.; Capper, G.; Davies, D. L.; Munro, H.; Rasheed, R. K.; Tambyrajah, V.
Chem. Commun. 2001, 2010.
16. Abbott, A. P.; Capper, G.; Davies, D. L.; Munro, H.; Rasheed, R. K. Inorg. Chem.
2004, 43, 3447.
17. Abbott, A. P.; Capper, G.; Davies, D. L.; Rasheed, R. K.; Tambyrajah, V. Green
Chem. 2002, 4, 24.
Cl2Zn
N
N
H
18. Morales, R. C.; Tambyrajah, V.; Jenkins, P. R.; Davies, D. L.; Abbott, A. P. Chem.
Commun. 2004, 158.
Cl2Zn
19. Abbott, A. P.; Bell, T. J.; Handa, S.; Stoddart, B. Green Chem. 2005, 7, 705.
20. Duan, Z.; Gu, Y.; Deng, Y. Cat. Commun. 2006, 7, 651.
N
H+
OC2H5
OC2H5
21. (a) Parghi, K. D.; Jayaram, R. V. Green Chem. Lett. Rev. 2011, 4, 14, 3–9.; (b)
Parghi, K. D.; Jayaram, R. V. Catal. Commun. 2010, 11, 1205–1210; (c)
Shrikhande, J. J.; Gawande, M. B.; Jayaram, R. V. Tetrahedron Lett. 2008, 49,
4799–4803; (d) Singh, S. J.; Jayaram, R. V. Tetrahedron Lett. 2008, 49, 4249–
4251; (e) Gawande, M. B.; Polshettiwar, V.; Varma, R. S.; Jayaram, R. V.
Tetrahedron Lett. 2007, 48, 8170–8173.
P
O
Cl2Zn
N
Ch Cl2Zn
OH
Cl
H
:
P
OC2H5
22. Cherkasov, R. A.; Galkina, I. V. Russ. Chem. Rev. 1998, 67, 85.
OC2H5
23. All of the
a-aminophosphonates are known compounds to which the
spectroscopic data were compared.
Table 2, 4a: 31P NMR (120 MHz, CDCl3): d = 21.066. 1H NMR (300 MHz, CDCl3):
d = 1.08–1.14 (t, 3H, –OCH2CH3), 1.25–1.31(t, 3H, –OCH2CH3), 3.6–3.72 (m, 1H,
–OCH2CH3), 3.87–3.98 (m, 1H, –OCH2CH3), 4.02–4.18 (m, 2H, –OCH2CH3), 4.72
(d, 1H, CH), 4.8 (s, 1H, NH), 6.59 (d, 2H, C6H5), 6.68(t, 1H, C6H5), 7.10 (t, 2H,
C6H5), 7.24–7.36 (m,3H, C6H5),7.44–7.49 (d, 2H, C6H5). GC–MS (m/z): 319 (M+),
182 (100), 167, 152, 104, 77, 51.
O
P
OC2H5
OC2H5
H
Table 2, 4b: 31P NMR (120 MHz, CDCl3): d = 20.188. 1H NMR (300 MHz, CDCl3):
d = 1.12–1.19 (t, 3H, –OCH2CH3), 1.25–1.33 (t, 3H, –OCH2CH3), 3.72–3.84, 3.92–
4.02, 4.04–4.18 (m, 4H, –OCH2CH3),4.67 (d, 1H, CH), 4.78 (s, 1H, NH), 6.57 (d,
2H, C6H4, C6H5), 6.73 (t, 1H, C6H4,C6H5), 7.08–7.26 (m, 3H, C6H4, C6H5),7.37–
7.42(m, 2H, C6H5, C6H4),7.7 (d, 1H, C6H4, C6H5). GC–MS (m/z): 399,397 (M+),
262, 260 (100), 182,180, 152, 104, 77, 45.
Scheme 2. Plausible mechanism.
conditions, considerably short reaction time, high yields, reusabil-
ity of the catalyst, and cost effectiveness make this protocol an
Table 2, 4d: 31P NMR (120 MHz, CDCl3) d = 20.197. 1H NMR (300 MHz, CDCl3):
d = 1.12–1.20 (t, 3H, –OCH2CH3),1.27–1.33(t, 3H, OCH2CH3), 3.72–3.84, 3.92–
4.04,4.06–4.2 (m, 4H, –OCH2CH3), 4.68 (d, 1H, CH), 4.76 (s, 1H, NH), 6.57 (d, 2H,
C6H5, C6H4), 6.74 (t, 1H, C6H5, C6H4),7.13 (t, 2H, C6H5, C6H4), 7.24–7.48 (m, 4H,
C6H5, C6H4).
important addition to the existing methods of
a-aminophospho-
nate synthesis. Further work is in progress to broaden the scope
of choline chloride based moisture stable ionic liquids to the other
organic transformations.
GC–MS (m/z): 353(M+), 216 (100), 180, 104, 77, 51.
Table 2, 4e: 31P NMR (120 MHz, CDCl3): d = 21.284. 1H NMR (300 MHz, CDCl3):
d = 1.03–1.17 (t, 3H,–OCH2CH3), 1.25–1.32 (t, 3H,–OCH2CH3), 3.78 (s, 3H, CH3),
3.62–3.74, 3.88–3.98, 4.01–4.18 (m, 4H, –OCH2CH3), 4.66 (d, 1H, CH), 4.73 (s,
1H, NH), 6.58–6.62 (d, 3H, C6H4, C6H5), 6.66–7.4 (m, 6H, C6H4,C6H5). GC–MS
(m/z): 349 (M+), 212,195, 168, 134, 111, 104, 77, 51.
Acknowledgment
Table 2, 4g: 31P NMR (120 MHz, CDCl3): d = 20.197. 1H NMR (300 MHz, CDCl3):
d = 1.14–1.20 (t, 3H, –OCH2CH3), 1.26–1.33(t, 3H,–OCH2CH3), 3.72–3.86, 3.93–
4.21 (m, 4H, –OCH2CH3), 4.68 (d, 1H, CH), 4.78 (s, 1H, NH), 6.64 (d, 2H, C6H5,
C6H4), 6.72 (t, 1H, C6H4, C6H5), 7.12 (t, 2H, C6H5, C6H4), 7.32–7.38 (m, 2H, C6H5,
C6H4), 7.47(d, 2H, C6H5, C6H4). GC–MS (m/z): 399, 397 (M+), 262, 260 (100),
180, 182, 104, 77, 51.
Financial assistance from the Indira Gandhi Center for Atomic
Research (IGCAR) is gratefully acknowledged.
References and notes
Table 2, 4j: 31P NMR (120 MHz, CDCl3): d = 20.915. 1H NMR (300 MHz, CDCl3):
d = 1.08–1.15 (t, 3H,–OCH2CH3), 1.25–1.32 (t, 3H, OCH2CH3), 3.6–3.74, 3.88–
3.98, 4.04–4.18 (m, 4H,–OCH2CH3), 4.64 (d, 1H, CH), 4.71 (s, 1H, NH), 6.5–6.54
(m, 2H, C6H5,C6H4), 6.76–6.84 (m,2H, C6H5, C6H4), 7.24–7.44(m, 5H, C6H5,C6H4).
Table 2, 4n: 31P NMR (120 MHz, CDCl3): d = 20.887. 1H NMR (300 MHz, CDCl3):
d = 1.09–1.17 (t, 3H, –OCH2CH3), 1.26–1.32 (t, 3H, –OCH2CH3), 3.78 (s, 3H, CH3),
3.61–3.72, 3.88–3.98, 4.04–4.18 (m, 4H, –OCH2CH3),4.62 (d, 1H), 6.4 (d,2H,
C6H4, C6H5),6.86 (d, 2H, C6H4, C6H5), 7.18–7.36(m, 2H, C6H5). GC–MS (m/z):
427,429 (M+), 291, 293, 275, 247, 249, 211, 183, 181, 157, 155, 109, 65, 44.
Catalyst preparation: In this study, the ionic liquids used were synthesized
according to the procedure reported in the literature.15
1. Peyman, A.; Budt, K. H.; Paning, J. S.; Stowasser, B.; Ruppert, D. Tetrahedron Lett.
1992, 33, 4549.
2. Alonso, E.; Solis, A.; Del Pozo, C. Synlett 2000, 698.
3. Allerberger, F.; Klare, I. J. J. Antimicrob. Chemother. 1999, 43, 211.
4. Maier, L. Phosphorus, Sulfur Silicon Relat. Elem. 1990, 47, 43.
5. Maier, L.; Sporri, H. Phosphorus, Sulfur Silicon Relat. Elem. 1991, 61, 69.
6. Emsley, J.; Hall, D. Chemistry of Phosphorus; Harper & Row: London, 1976. pp
494.
7. Chung, S. K.; Kang, D. H. Tetrahedron: Asymmetry 1996, 7, 21.
8. Kafarski, P.; Lejczak, B. Phosphorus, Sulfur Silicon Relat. Elem. 1991, 63, 193.
9. (a) Kabachnik, M. J.; Medved, T. Izv. Akad. Nauk SSSR 1953, 1126; (b) Kabachnik,
M. J.; Medved, T. Izv. Akad. Nauk SSSR 1954, 1024; (c) Fields, E. K. J. Am. Chem.
Soc. 1952, 74, 1528.
10. (a) Qian, C.; Huang, T. J. Org. Chem. 1998, 63, 4125; (b) Paraskar, A. S.; Sudalai, A.
Arkivok 2006, 183; (c) Ranu, B. C.; Hajra, A.; Jana, U. Org. Lett. 1999, 1, 1141; (d)
Xu, F.; Luo, Y.; Deng, M.; Shen, Q. Eur. J. Org. Chem. 2003, 4728; (e) Zon, J. Pol. J.
Chem. 1981, 55, 643; (f) Laschat, S.; Kunz, H. Synthesis 1992, 90; (g)
Chandrasekhar, S.; Prakash, S. J.; Jagadeshwar, V.; Narsihmulu, C. Tetrahedron
Lett. 2001, 42, 5561; (h) Kaboudin, B.; Nazari, R. Tetrahedron Lett. 2001, 42,
8211; (i) Bhagat, S.; Chakraborti, A. K. J. Org. Chem. 2007, 72, 1263; (j) Heydari,
A.; Zarei, M.; Alijanianzadeh, R.; Tavakol, H. Tetrahedron Lett. 2001, 42, 3629;
Typical experimental procedure: To
a stirred mixture of benzaldehyde
(2.0 mmol), amine (2.0 mmol), and dialkyl phosphite (2.0 mmol), ChClÁ2ZnCl2
(15 mol %) was added. The reaction mixture was stirred at rt for the time
indicated in Table 2 (progress of the reaction was followed by TLC). The
product formed was extracted with MTBE (2 Â 5 mL). The solid product
obtained after concentrating the combined ether extract on rotary evaporator
was further washed with sodium metabisulphite solution (2 Â 5 mL) and
hexane (2 Â 5 mL) to give pure product. The remaining viscous ionic liquid was
further washed with MTBE and dried at 80 °C to retain its catalytic activity.