Amberlite-IR 120 catalyzed three-component synthesis of α-amino phosphonates in one-pot

Article abstract of DOI:10.1016/j.tetlet.2008.02.102

A simple, efficient, and environmentally benign method for a three-component reaction of an amine, an aldehyde or a ketone, and diethyl phosphite catalyzed by Amberlite-IR 120 resin has been developed to afford α-amino phosphonates in high yields and short reaction times under solvent-free reaction conditions. The major advantages of the present method are good yields, inexpensive, ecofriendly and reusable catalyst, mild and solvent-free reaction conditions and tolerance towards various functionalities present in the substrates.

Full text of DOI:10.1016/j.tetlet.2008.02.102

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2598–2601
Amberlite-IR 120 catalyzed three-component synthesis
of a-amino phosphonates in one-pot
Asish K. Bhattacharya *, Kalpeshkumar C. Rana
Combi Chem-Bio Resource Centre and Division of Organic Chemistry, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
Received 3 December 2007; revised 14 February 2008; accepted 16 February 2008
Available online 21 February 2008
Abstract
A simple, efficient, and environmentally benign method for a three-component reaction of an amine, an aldehyde or a ketone,
and diethyl phosphite catalyzed by Amberlite-IR 120 resin has been developed to afford a-amino phosphonates in high yields and short
reaction times under solvent-free reaction conditions. The major advantages of the present method are good yields, inexpensive,
ecofriendly and reusable catalyst, mild and solvent-free reaction conditions and tolerance towards various functionalities present in
the substrates.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: a-Amino phosphonates; Aldehydes; Amines; Alkyl phosphite; Ion-exchange resin; Multi-component reaction
1. Introduction
come by one of our recent methods utilizing bismuth
nitrate pentahydrate as an efficient Lewis acid as it is able
to tolerate trace amounts of water.10 As a-amino phospho-
nate synthesis via three-component reactions is important
acid-mediated reactions, the development of a reaction that
uses an environmentally benign and reusable catalyst
should be of great interest.
The use of solid acidic catalysts has gained importance
in organic synthesis due to several advantages such as,
operational simplicity, nontoxicity, reusability, low cost,
and ease of isolation after completion of the reaction.
Amberlite-IR 120 resin has emerged as an efficient hetero-
geneous catalyst for various chemical transformations.11–13
Owing to the numerous advantages associated with this
cheap and nonhazardous catalyst, we considered Amber-
lite-IR 120 resin to be an ideal heterogeneous acid catalyst
for the synthesis of a-amino phosphonates. Also, it is
widely reported in the literature14–18 that application of
microwave irradiation enables realization of reactions,
which otherwise require harsh conditions and are too slow
for practical purposes. Moreover, microwave-assisted reac-
tions are believed to satisfy the demands of ‘green chemis-
try’ allowing for solvent-free conditions to be employed.
The synthesis of a-amino phosphonates has attracted
much attention recently due to their significant biological
activities and structural analogy to a-amino acids. They
have been reported to act as peptide mimics,1 haptens of
catalytic antibodies,2 antibiotics and pharmacological
agents3 and herbicides.4 Further, phosphinic acid and
phosphinic amino acid analogues have also been reported
to be enzyme inhibitors.5 Various synthetic approaches
have been reported for the synthesis of a-amino phospho-
nates, however, nucleophilic addition reaction of phos-
phites with imines is one of the most preferred methods,
which is usually catalyzed by an alkali metal alkoxide,
for example, NaOEt or Lewis acids6 such as ZnCl2, SnCl2,
SnCl4, BF3ÁEt2O and MgBr2.7,8 However, these reactions
cannot proceed in one-pot from a carbonyl compound,
an amine and a phosphite because the water that is gener-
ated during the course of the reaction can decompose or
deactivate the Lewis acid.9 This drawback has been over-
*
Corresponding author. Tel.: +91 20 2590 2309; fax: +91 20 2590 2624.
E-mail address: ak.bhattacharya@ncl.res.in (A. K. Bhattacharya).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.102

A. K. Bhattacharya, K. C. Rana / Tetrahedron Letters 49 (2008) 2598–2601
2599
O
O
P
O
P OEt
H
H
N
OEt
OEt
+
+
NH2
R1
R1
Amberlite-IR 120
MWI
R
H
EtO
R
2
3
1
4
Scheme 1.
Herein, we report a novel one-pot synthesis of a-amino
phosphonates catalyzed by Amberlite-IR 120 resin under
solvent-free reaction conditions using microwave irradia-
tion (Scheme 1).
were taken in a Pyrex test tube and exposed to microwave
irradiation (Kenstar Model No. OM-9918 C; 2450 MHz,
2350 W) for the appropriate time (see Table 1). After com-
pletion of the reaction (TLC), the reaction mixture was
cooled and DCM (25 mL) was added. The catalyst was
filtered from the reaction mixture and the filtrate was con-
centrated under vacuum. The residue was purified by silica
gel column chromatography (100–200 mesh) eluting with
petroleum ether–ethyl acetate (15–30%) to afford the corres-
ponding pure a-amino phosphonates. All the products
were characterized from their spectral data.
2. Results and discussions
Initially, benzaldehyde was reacted with aniline and
diethyl phosphite in the presence of Amberlite-IR 120
and irradiated with microwaves for 2 min to give the corres-
ponding a-amino phosphonate in 90% yield (Table 1, entry
1). Several structurally diverse carbonyl compounds and
aniline/substituted anilines were subjected to this novel
procedure to give the corresponding a-amino phospho-
nates in high to excellent yields. The results are summarized
in Table 1. The presence of electron-donating groups on
the aldehyde resulted in the corresponding products in
low yields and the reaction was sluggish, however, alde-
hydes possessing electron-withdrawing groups afforded
the corresponding a-amino phosphonates in shorter reac-
tion times and in higher yields. Also, amines possessing
electron-donating groups gave the corresponding products
in good yields. However, in the case of a diene aldehyde
(entry 24), the corresponding product was obtained in poor
yield. The wide applicability of the present method is
evident from the fact that it is tolerant towards various
functional groups including alkoxy, halides, nitro, methyl-
enedioxy, carboxylic and hydroxy groups. Moreover, the
catalyst can be reused without affecting the yield of the
desired product and reaction time thus, making it environ-
mentally friendly.
4.1.1. Compound 4d
Solid; mp 98–99 °C; H NMR (200 MHz, Acetone-d6,
TMS): d = 7.41–6.56 (m, 9H), 4.70 (d, JPH = 23.0 Hz,
1
1
1H), 4.19–3.63 (m, 4H), 3.77 (s, 3H), 1.28 (t, J = 7.1 Hz,
3H), 1.13 (t, J = 7.2 Hz, 3H); 13C NMR (50 MHz, Ace-
tone-d6, TMS): d = 159.3, 146.5, 129.2, 129.0, 128.9,
2
127.7, 118.4, 114.1, 114.0, 113.9, 63.37 (d, JPC = 7.3 Hz,
2
–OCH2CH3), 63.23 (d, JPC = 7.0 Hz, –OCH2CH3), 55.3
1
3
(d, JPC = 152.2 Hz, –CHP), 55.2, 16.5 (d, JPC = 5.5 Hz,
3
–OCH2CH3), 16.3 (d, JPC = 5.5 Hz, –OCH2CH3); MS
(ESI): m/z = 388 [M+K]+, 372 [M+Na]+, 350 [M+H]+.
Anal. Calcd for C18H24NO4P: C, 61.88; H, 6.92; N, 4.01.
Found: C, 61.90; H, 6.86; N, 3.95.
4.1.2. Compound 4m
1
Solid; mp 97–98 °C; H NMR (200 MHz, Acetone-d6,
1
TMS): d = 7.99–7.29 (m, 9H), 5.57 (d, JPH = 12.8 Hz,
1H), 3.92–3.44 (m, 4H), 0.94 (m, 6H); 13C NMR
(50 MHz, Acetone-d6, TMS): d = 167.6, 138.0, 137.4,
132.2, 132.0, 129.2, 128.8, 126.5, 125.2, 124.6, 124.4, 63.8
2
2
3. Conclusion
(d, JPC = 7.0 Hz, –OCH2CH3), 62.6 (d, JPC = 7.3 Hz,
1
–OCH2CH3), 59.2 (d, JPC = 153.7 Hz, –CHP), 16.0 (d,
3
In conclusion, Amberlite-IR 120 was found to be an effi-
cient catalyst for the one-pot reaction of aldehydes, amines,
and diethyl phosphite to afford a-amino phosphonates in
good to excellent yields. The main advantages of the pres-
ent synthetic protocol are mild, solvent-free conditions,
ecofriendly catalyst and easy reaction work-up procedure.
It is expected that the present methodology will find appli-
cation in organic synthesis.
3JPC = 5.1 Hz, –OCH2CH3), 15.8 (d, JPC = 6.9 Hz,
–OCH2CH3); MS (ESI): m/z = 384 [MÀH2O+ K]+, 368
[M –H2O+Na]+, 346 [MÀH2O+H]+. Anal. Calcd for
C18H22NO5P: C, 59.50; H, 6.10; N, 3.85. Found: C,
59.15; H, 6.02; N, 3.78.
4.1.3. Compound 4s
Solid; mp 168–169 °C; 1H NMR (200 MHz, Acetone-d6,
TMS): d = 6.95–6.42 (m, 7H), 5.81 (s, 2H), 4.63 (d,
1JPH = 24.3 Hz, 1H), 4.05–3.56 (m, 4H), 1.11 (t,
J = 7.1 Hz, 3H), 0.98 (t, J = 7.1 Hz, 3H); 13C NMR
(50 MHz, Acetone-d6, TMS): d = 149.7, 147.7, 147.1,
140.0, 131.1, 121.9, 115.4, 115.5, 108.5, 107.6, 101.1, 62.5
4. Experimental
4.1. Typical experimental procedure
2
2
Carbonyl compound (1 mmol), amine (1 mmol), di-
ethylphosphite (1 mmol) and Amberlite-IR 120 (100 mg)
(d, JPC = 7.3 Hz, –OCH2CH3), 62.3 (d, JPC = 7.3 Hz,
1
–OCH2CH3), 55.9 (d, JPC = 153.3 Hz, –CHP), 15.9 (d,

2600
A. K. Bhattacharya, K. C. Rana / Tetrahedron Letters 49 (2008) 2598–2601
Table 1
Table 1 (continued)
One-pot synthesis of a-amino phosphonates catalyzed by Amberlite-IR
120
Entry
16
R–CHO
R1–NH2
Product Time Yielda
(min) (%)
Entry R–CHO
R1–NH2
Product Time Yielda
(min) (%)
CHO
NH2
4p
2
90
CHO
NH2
HO
1
2
4a
4b
2
5
90
81
OCH3
CHO
NH2
NH2
HO
CHO
NH2
NH2
17
18
19
20
21
22
23
4q
4r
4s
4t
2
2
3
2
2
1
1
87
92
98
79
91
81
87
H3CO
H3CO
CHO
CHO
CHO
CHO
CHO
CHO
O
O
3
4c
1
92
OCH3
NH2
CHO
O
O
NH2
NH2
NH2
NH2
NH2
4
5
6
7
8
4d
4e
4f
1
87
89
91
87
70
HO
OCH3
NH2
CHO
O
O
1
OH
H3C
NH2
CHO
OH
O
O
4u
4v
4w
1.5
1
OCH3
CHO
CH2NH2
O
O
4g
4h
F
CHO
CHO
CHO
CH2NH2
3
H3C
N
CH3
CHO
NH2
NH2
24
25
4x
1
11
9
4i
2
67
OH
O
OH
O
O
NH2
CHO
NH2
NH2
NH2
4y
4z
3
2
78
84
10
11
12
4j
1
95
88
75
O2N
CHO
CH2NH2
4k
4l
2.5
3
26
NO2
a
CHO
NO2
Yields refer to those of pure isolated products fully characterized by
spectral data.
3
3JPC = 5.9 Hz, –OCH2CH3), 15.7 (d, JPC = 5.9 Hz,
CHO
NH2
–OCH2CH3); MS (ESI): m/z = 418 [M+K]+, 402
[M+Na]+, 380 [M+H]+. Anal. Calcd for C18H22NO6P:
C, 56.99; H, 5.85; N, 3.69. Found: C, 56.60; H, 5.73; N,
3.62.
13
14
15
4m
4n
4o
1
2
2
78
90
95
COOH
OH
H3CO
H3CO
CHO
NH
2
4.1.4. Compound 4t
NH2
Solid; mp 132–133 °C; 1H NMR (200 MHz, Acetone-d6,
TMS): d = 6.97–6.47 (m, 7H), 5.87 (s, 2H), 4.79 (d,
1JPH = 25.0 Hz, 1H), 4.32–3.69 (m, 4H), 1.29 (t,
H3CO
CHO

A. K. Bhattacharya, K. C. Rana / Tetrahedron Letters 49 (2008) 2598–2601
2601
J = 7.1 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H); 13C NMR
Acknowledgments
(50 MHz, Acetone-d6, TMS): d = 147.9, 147.3, 145.3,
135.0, 129.6, 121.6, 119.9, 118.4, 114.3, 112.0, 108.5,
A.K.B. is grateful to the Department of Biotechnology
(DBT), Government of India, New Delhi, India for finan-
cial support. K.C.R. is grateful to the Council of Scientific
and Industrial Research, New Delhi, India for the award of
a Senior Research Fellowship. The authors are grateful to
Dr. Ganesh Pandey, FNA, Head, Division of Organic
Chemistry for constant support and encouragement.
2
108.3, 101.1, 64.2 (d, JPC = 7.0 Hz, –OCH2CH3), 63.7 (d,
1
2JPC = 7.0 Hz, –OCH2CH3), 55.7 (d, JPC = 155.9 Hz,
3
–CHP), 16.4 (d, JPC = 5.9 Hz, –OCH2CH3), 16.2 (d,
3JPC = 5.9 Hz, –OCH2CH3); MS (ESI): m/z = 402
[M+Na]+, 380 [M+H]+. Anal. Calcd for C18H22NO6P:
C, 56.99; H, 5.85; N, 3.69. Found: C, 56.65; H, 5.77; N,
3.60.
Supplementary data
4.1.5. Compound 4u
1
Syrupy liquid; H NMR (200 MHz, Acetone-d6, TMS):
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2008.02.102.
d = 6.96–6.39 (m, 7H), 5.93 (s, 2H), 5.27 (t, J = 8.0 Hz,
1
1H), 4.67 (dd, JPH = 24.0, 8 Hz, 1H), 4.16–3.85 (m, 4H),
3.88 (s, 3H) 1.28 (t, J = 7.2 Hz, 3H), 1.20 (t, J = 7.1 Hz,
3H); 13C NMR (50 MHz, Acetone-d6, TMS): d = 148.0,
147.9, 147.3, 136.0, 129.8, 121.4, 121.0, 117.7, 111.2,
References and notes
2
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Nature 1978, 272, 56; (c) Allen, J. G.; Atherton, F. R.; Hall, M. J.;
Hassall, C. H.; Lambert, R. W.; Nisbet, L. J.; Ringrose, P. S.
Antimicrob. Agents Chemother. 1979, 15, 684; (d) Atherton, F. R.;
Hall, M. J.; Hassall, C. H.; Lambert, R. W.; Ringrose, P. S.
Antimicrob. Agents Chemother. 1979, 15, 677; (e) Atherton, F. R.;
Hall, M. J.; Hassall, C. H.; Lambert, R. W.; Lloyd, W. J.; Ringrose,
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43, 2045; Chem. Abstr. 1975, 82, 43486; (b) Kirby, A. J.; Warren, S.
G. The Organic Chemistry of Phosphorus; Elsevier: Amsterdam, 1967.
7. Laschat, S.; Kunz, H. Synthesis 1992, 90.
109.6, 108.3, 108.2, 101.1, 63.4 (d, JPC = 7.0 Hz,
2
–OCH2CH3), 63.2 (d, JPC = 7.0 Hz, –OCH2CH3), 55.6
1
3
(d, JPC = 152.6 Hz, –CHP), 16.5 (d, JPC = 5.8 Hz,
3
–OCH2CH3), 16.3 (d, JPC = 5.8 Hz, –OCH2CH3); MS
(ESI): m/z = 432 [M+K]+, 416 [M+Na]+, 394 [M+H]+.
Anal. Calcd for C19H24NO6P: C, 58.01; H, 6.15; N, 3.56.
Found: C, 57.78; H, 6.10; N, 3.46.
4.1.6. Compound 4v
1
Syrupy liquid; H NMR (200 MHz, Acetone-d6, TMS):
d = 7.35–6.77 (m, 8H), 5.97 (s, 2H), 4.13–3.77 (m, 6H),
1
3.52 (d, JPH = 13.3 Hz, 1H), 1.29 (t, J = 7.1 Hz, 3H),
1.18 (t, J = 7.1 Hz, 3H); 13C NMR (50 MHz, Acetone-d6,
TMS): d = 147.9, 147.4, 139.3, 129.4, 128.4, 128.3, 127.2,
2
122.4, 108.7, 108.2, 101.1, 62.9 (t, JPC = 6.6, 7.3 Hz,
1
–2OCH2CH3), 59.2 (d, JPC = 155.2 Hz, –CHP), 51.0 (d,
3
3JPC = 17.6 Hz, –NHCH2Ph), 16.4 (t, JPC = 6.2, 5.6 Hz,
–2OCH2CH3); MS (ESI): m/z = 416 [M+K]+, 400
[M+Na]+, 378 [M+H]+. Anal. Calcd for C19H24NO5P:
C, 60.47; H, 6.41; N, 3.71. Found: C, 60.29; H, 6.28; N,
3.62.
8. Zon, J. Pol. J. Chem. 1981, 55, 643.
4.1.7. Compound 4x
1
9. Genet, J. P.; Uziel, J.; Port, M.; Touzin, A. M.; Roland, S.;
Thorimbert, S.; Tanier, S. Tetrahedron Lett. 1992, 33, 77.
10. Bhattacharya, A. K.; Kaur, T. Synlett 2007, 745.
11. Tewari, N.; Katiyar, D.; Tiwari, V. K.; Tripathi, R. P. Tetrahedron
Lett. 2003, 44, 6639.
12. Akagawa, K.; Sakamoto, S.; Kudo, K. Tetrahedron Lett. 2007, 48,
985.
13. Park, T.-J.; Weiwer, M.; Yuan, X.; Baytas, S. N.; Munoz, E. M.;
Murugesan, S.; Linhardt, R. J. Carbohydr. Res. 2007, 342, 614.
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15. Varma, R. S. Green Chem. 1999, 43.
Syrupy liquid; H NMR (200 MHz, Acetone-d6, TMS):
d = 7.13–6.54 (m, 5H), 5.12–4.95 (m, 2H), 4.38 (dd, 1H,
3
1JPH = 20.7 Hz, JCH = 9.4 Hz), 4.15–3.97 (m, 4H), 2.06–
1.97 (m, 2H), 1.72–1.71 (m, 2H), 1.61 (s, 3H), 1.54 (s,
3H), 1.49 (s, 3H), 1.27–1.17 (m, 6H); 13C NMR (50
MHz, Acetone-d6, TMS): d = 146.8, 141.6, 131.8, 129.1,
2
123.6, 119.9, 118.4, 113.9, 63.1 (d, JPC = 6.6 Hz,
2
–OCH2CH3), 62.8 (d, JPC = 7.3 Hz, –OCH2CH3), 50.6
1
(d, JPC = 158.5 Hz, –CHP), 39.6, 26.2, 25.6, 17.7, 17.1,
16. Caddick, S. Tetrahedron 1995, 51, 10403.
17. Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001,
57, 9225.
16.5, 16.4; MS (ESI): m/z = 404 [M+K]+, 388 [M+Na]+,
366 [M+H]+. Anal. Calcd for C20H32NO3P: C, 65.73; H,
8.83; N, 3.83. Found: C, 65.62; H, 8.76; N, 3.72.
18. Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199.