A new procedure for synthesis of α -aminophosphonates by aqueous formic acid as an effective and environment-friendly organocatalyst

Article abstract of DOI:10.1007/s12039-017-1394-z

Abstract: Aqueous formic acid (37%) as a green organocatalyst was used to synthesis of α -aminophosphonates in one-pot, three-component Kabachnik–Fields reaction. The structures of compounds were determined by FT-IR, ¹H -NMR and ¹³C -NMR spectroscopy. After optimization of the experimental?conditions, the reaction was carried out at 65°C under solvent- free condition. Use of a nontoxic effective organocatalyst, easy work up process and low-cost cleaning procedure are from the main advantages of this research. Graphical Abstract: Synthesis and characterization of α -aminophosphonates in one-pot, three-component Kabachnik–Fields reaction by formic acid in solvent free condition are reported. Using of a nontoxic effective organocatalyst, easy work up process and low-cost cleaning procedure are from the main advantages of this research.

Full text of DOI:10.1007/s12039-017-1394-z

J. Chem. Sci.
© Indian Academy of Sciences
DOI 10.1007/s12039-017-1394-z
REGULAR ARTICLE
α
A new procedure for synthesis of -aminophosphonates by
aqueous formic acid as an effective and environment-friendly
organocatalyst
ESMAEIL MOHAMMADIYANa, HOSSEIN GHAFURIb,∗ and ALI KAKANEJADIFARDa
aDepartment of Chemistry, Faculty of science, University of Lorestan, Khorramabad, Iran
bCatalysis and Organic Synthesis Research Laboratory, Department of Chemistry, Iran University of Science
and Technology, Tehran, Iran
E-mail: ghafuri@iust.ac.ir
MS received 14 March 2017; revised 3 October 2017; accepted 3 October 2017
α
Abstract. Aqueous formic acid (37%) as a green organocatalyst was used to synthesis of -aminophosphonates
in one-pot, three-component Kabachnik–Fields reaction. The structures of compounds were determined by FT-
IR, 1H-NMR and 13C-NMR spectroscopy. After optimization of the experimental conditions, the reaction was
carried out at 65 ◦C under solvent- free condition. Use of a nontoxic effective organocatalyst, easy work up
process and low-cost cleaning procedure are from the main advantages of this research.
α
Keywords. Organocatalyst; -aminophosphonate; formic acid; kabachnik–fields reaction; green chemistry.
1. Introduction
promotion of one-pot Kabachnik-Fields reaction such
as microwave irradiation, heating21 and acidic or basic
catalysts. Some Lewis acid catalysts, such as ZrOCl2 ·
5H2O,22 Mg(ClO4)2,23 FeCl3,24 Al(H2PO4),25 BiCl3,26
InCl3,27 YbCl3,28 In(OTf)3,29 Ce(OTf)4,30 Fe3O4@ZrO2
/SO24−,31 CAN,32 TaCl5SiO2,33 SmI2,34 LiClO4,35 and
some solid acids (montmorillonite KSF), silica sul-
phuric acid, and also some base catalysts like CaCl2,
PPh3 and other catalysts such as ZnO, TiO2, tosyl
chloride and mesoporous aluminosilicate nanocage36
have been used to succeed this reaction. In spite of all
researches, still there are some serious limitations such
as hard work up process, long reaction time and expen-
sive and toxic catalyst in these methods. With regard
to importance of removal of toxic and hazardous cata-
lysts from organic reactions, we decided to introduce
formic acid as an efficient and green organocatalyst
α
The -aminophosphonates and their derivatives are very
useful compounds with wide range of applications in
organic chemistry especially in medicinal chemistry.1
α
A large number of - aminophosphonate derivatives are
known as antiviral,2 antifungal,3 antibacterial4 and anti-
tumor5 agents. Thus, they form an important class of
compounds with diverse biological activities (Figure 1).
Some other activities such as peptidomimetic,6 enz-
yme inhibitors,7 pharmacogenic agent,8 haptens of cat-
alytic antibodies,9 inhibitors of UDP-galactopyranose
mutase10 and antitumor agents11–13 have been rec-
ognized for these compounds. Some of significant
α
studies for synthesis of - aminophosphonate deriva-
tives are such as: synthesis of di or tri-alkyl phos-
phite derivatives,14 hydrogenation of aziridinylphos-
phonate,15 aldol-type reactions of (isocyanomethyl)
phosphonates with aldehydes,16 addition of phosphites
to sulphimines17 and catalyzed Mannich-type reac-
tion.18 Among the versatile procedures, the Kabachnik
- Fields reaction is one of the basic methods for prepa-
α
for synthesis of -aminophosphonates with interest-
ing specifications in Kabachnik-Fields reaction. Formic
acid is a colourless liquid with a pungent, penetrating
odour and often used in an aqueous solution. Formica,
is Latin word of ant and name of formic acid has
been derived from its root referring to its early iso-
lation by the distillation of ants’ bodies. In nature,
formic acid has been found in the stings and bites
α
ration of -aminophosphonate which was discovered
in 1952 independently by Kabachnik19 and Fields.20
Recently some new researches have been reported for
*
For correspondence
Electronic supplementary material: The online version of this article (https://doi.org/10.1007/s12039-017-1394-z) contains
supplementary material, which is available to authorized users.

Esmaeil Mohammadiyan et al.
α
Figure 1.
- aminophosphonate with biological activities.
of many insects of the order Hymenoptera, including 2.1 General procedure for the synthesis of
bees and ants. Furthermore formic acid is used as a α-aminophosphonate
preservative and antibacterial agent in livestock feed.
α
For synthesis of -aminophosphonate 1c, in a 5 mL dry bal-
Also it has been known as an important intermediate
in chemical synthesis. In synthetic organic chemistry,
it is used as a source of hydride ion which has been
reported in some reactions like Eschweiler-Clarke and
the Leuckart-Wallach. So its azeotrope with triethy-
lamine is applied as a source of hydrogen in transfer
hydrogenation. Sometime formic acid is employed as
a volatile pH modifier in HPLC and capillary elec-
trophoresis like acetic acid and trifluoroacetic acid.
loon, a mixture of 15 μL catalyst (formic acid (37%)) and
1 mmol aldehyde was combined, after that 1 mmol amine
and 1.2 mmol dimethylphosphite were added to the mixtu◦re.
The reaction proceeds under solvent free condition and 65 C
temperature for a period of time on a vigorous magnetic stir-
rer. The progress of reaction by TLC in solvent samples 1: 1
hexane / ethyl acetate was followed. Finally, after completion
of the reaction, the solid product was filtered, washed with
deionized water. After recrystalization it was dried at room
Also, formic acid can be a convenient source of carbon temperature.
monoxide by being readily decomposed by sulphuric
acid. Another important chemical activity of formic
acid, is its useas reductant in combination with a cat-
2.2 Spectral data of representative compounds
alyst, for the transfer hydrogenation of anilines37 and 2.2a Dimethyl [(phenyl) (phenylamino) methyl] phos-
phonate 1a: M.p.: 90–92 ◦C, 1H NMR (400 MHz, CDCl3):
reduction of alkynes can selectively produce cis, trans-
39
alkenes and alkanes,38 -substituted acetophenones,
δ 3.67 (d, J = 10.8 Hz, 3H), 3.89 (d, J = 11.2 Hz, 3H),
α
5.86 (m, 1H), 5.93 (d, 1H), 7.28-8.09 (m, 7 H) ppm. 13C
β-keto esters40 and nitroarenes. In aspect of physical
2
NMR (CDCl3, 100 MHz): δ = 53.70 (d, JP,C = 6.7 Hz),
description it is a strong oxidizer, and with strong caustic
properties. In our previous work, we showed formic acid
54.4 (d, 2 JP,C = 7.6 Hz), 54.7 (d, 1 JP,C = 152.0 Hz), 114.3,
118.7, 123.0, 128.1, 129.0 (d, 2 JP,C = 4.4 Hz),131.0, 134.7
as an efficient organocatalyst for synthesis of imines and
(d, 2 JP,C = 2.5 Hz), 146.6 (d,2 JP,C = 14.9 Hz) ppm.
41
α
-aminonitriles in Strecker reaction. In this work, in
order to favour environmental considerations, we used
aqueous formic acid as a green organocatalyst in the
2.2b Dimethyl[(2-chlorophenyl)(phenylamino)
methyl]phosphonate 1b: M.p.: 128–129 ◦C, FT-IR (KBr,
α
synthesis of -aminophosphonates through kabachnik -
cm−1); 3311(N-H), 1602, 1519, 1232, 1033; 1H NMR
νmax
field reaction.
(CDCl3, 500 MHz) = 3.4 (d, J = 10.4 Hz, 3H), 3.8 (d,
J = 10.7 Hz, 3H), 5.0 (br, NH, 1H), 5.36 (d, J = 24.6 Hz,
1H), 6.6 (d, J = 7.6 (m, 9H).13C NMR (CDCl3, 125 MHz):
51. 04, 52.26, 54.24 (m), 114. 02, 119.13, 127.87, 129.39,
129.72, 130.05, 134.18, 134.41 (d, 2 JP,C =7.12 Hz), 145.87
(d, 2 JP,C = 14.7 Hz).
2. Experimental
All of the chemicals were obtained from Merck and used with-
out further purification. Infrared (IR) spectra were obtained
on a Shimadzu FT-IR-8400S spectrophotometer using a KBr
pellet. Melting points were measured by an Electro thermal 2.2c Dimethyl [(4-chlorophenyl) (phenylamino)
◦
ν
9100 apparatus. Analytical TLC was performed on Merck methyl] phosphate 1c: M.p.: 139-140 C, IR (KBr,
max
0.2 mm silica gel 60 F-254 Al-plates. 1H NMR and 13C NMR cm−1): 3319(N-H), 1602, 1494, 1232, 1033; 1H NMR (500
spectra were recorded using Bruker DRX-500 Avance, Bruker MHz, CDCl3): δ 3. 55 (d, J = 10.8 Hz, 3H), 3.79 (d, J =
DRX-400 Avance and Bruker DRX-250 Avance spectrome- 10.5 Hz, 3H), 4.98(d, 1 JP−H = 24 Hz, 1H), 7.3-8.2 (m, 9H).
ters at ambient temperature, respectively.
13C NMR (125MHz, CDCl3): δ = 53.8, 54.2, 56.1, 114.3,

α
A new procedure for synthesis of -aminophosphonates
126.8, 128.2(d, 3 Jp−c = 5.5 Hz), 128.4 (d, 3 Jp−c = 3.0 Hz), (d, J = 10.8 Hz, 3H), 3.90 (d, J = 11.2 Hz, 3H), 5.90 (d
131.1, 132.2, 141.0, 146.6 (d, 2 Jp−c = 14.5 Hz) ppm.
d, J = 9.2 Hz, J = 30.8 Hz 2 H),5.87(s br, 1H), 6.62 (d,
J = 9.2 Hz, 2H) 7.22 (t,d, J = 8Hz, J = 2Hz 1 H), 7.30 (d,
J = 1.2 Hz, 1H) 7.40 (d, t, J = 8 Hz, J = 1.2 Hz, 1H), 8.1
(d, J = 9.2 Hz, 2H) ppm.
2.2d Dimethyl (4-Dimethyl amino phenyl) (N-pheny-
lamino) methylphosphonate 1d:: M.p.: 144 ◦C; IR (KBr,
cm−1); 3446, 2926, 1350, 1251, 1167, 1030. 1H NMR
νmax
(CDCl3, 400 MHz): δ = 2.12 (s, 1H), 2.93 (s, 6 H), 3.51(d, 2.2j Dimethyl(4-nitrophenyl)(4-nitrophenylamino)
J = 10.4 Hz, 3 H), 3.78 (d, J = 10.4 Hz, 3 H), 4.70 (d, methylphosphonate 1l: M.p.: 123 ◦C; IR (KBr,
νmax
1
1 JP−H = 23.6 Hz, 2 H), 6.63(d, d, J = 8.6 Hz, J = 0.8 Hz, cm−1): 3310, 1602, 1498, 1237, 1027cm−1; H NMR (500
2 H), 6.68 (m, 3 H), 7.12(m, 2 H), 7.32(t, t J = 6.8 Hz, MHz, CDCl3): δ 3.18 (d, J = 10.5 Hz, 3H), 3.85 (d, J =
J = 2 Hz, 2 H) ppm.
10.6 Hz, 3H), 5.69 (d, J = 24.0, 1H), 6.58 (d, J = 8.0 Hz,
2H), 6.69 (t, J = 7.6 Hz, 1H), 7.06 (t, J = 7.7 Hz, 2H), 7.47
(t, 7.7 Hz, 1H), 7.57 (t, J = 7.3 Hz, 1H), 7.65 (t, 7.8 Hz, 1H),
7.83 (d, J = 7.3 Hz, 2H), 7.94 (d, J = 8.1 Hz, 1H), 8.26
(d, J = 8.7 Hz, 1H) ppm. 13C NMR (CDCl3, 125 MHz):
δ = 50.96, 52.18, 54.13 (d, J = 7.1 Hz), 114.04, 118.89,
2.2e Dimethyl(4- methoxy phenyl)(◦N-phenylamino)
ν
methylphosphonate 1e: M.p.: 123-124 C; IR (KBr,
max
cm−1): 3290, 1602, 1508, 1240, 1024 cm−1; 1H NMR
(CDCl3, 400 MHz): 2.93 (s 3H), 3.50 (3H, d, J = 10.4 Hz),
3.77 (d, J = 10.8 Hz 3H), 4.74 (1H, d, 1 JP−H = 24.08 Hz),
6.60 (d, d, J = 8.6 Hz, J = 1.2 Hz, 2H), 6.72(t, J = 7.2 Hz
1H),6.90(d, J = 8.4 Hz, 2H), 7.13(t, J = 8.2 Hz, 2H),7.40(t,
t, J = 2.4 Hz, 2.4 Hz, 2H), ppm; 13C NMR (CDCl3, 100
3
123.03, 125.96 (m), 126.95, 129.10 (d. JC−P = 3.6 Hz),
129.55, 129.66, 131.79 (d, 3 JC−P = 4.5 Hz), 134.30, 146.30
(d, 2 JC−P = 14.1 Hz) ppm.
MHz): 54.01, 55.82, 57.52, 115.05, 115.74, 120.05, 128.87, 2.2k Dimethyl (Terephthal) (N-4-nitrophenylamino)
methylphosphonate 1m: M.p.: 237 ◦C, IR (KBr,
cm−1); 3446, 2926, 1350, 1251, 1167, 1030. 1H NMR
(DMSO, 250 MHz): δ = 3.45 (m, 6H) 3.70 (m, 6H), 4.90(s
br), 5.05 (dd, J = 23.5 Hz, J = 5.2 Hz 2H), 6.70 (m, 4H),
7.39 (m, 6 H), 7.94(d, J = 8.5 Hz 4H) ppm.
νmax
129.45, 129.73, 146.60, 146.90, 159.96 ppm.
2.2f Dimethyl(4-methylphenyl)(N-phenylamino)meth-
◦
ν
ylphosphonate 1f: M.p.: 128 C; IR (KBr,
cm−1):
max
3313, 1602, 1498, 1232, 1031 cm−1; H NMR(400 MHz,
1
CDCl3): δ 2.18 (s, 3H), 3.49 (d, J = 10.4 Hz, 3H), 3.79 (d,
J = 10.8 Hz, 3H), 4.82 (d, 1 JP−H = 23.6 Hz, 1H), 6.60 (d,d 2.2l Dimethyl (4-methylphenyl) (N-4-nitrophenyla-
J = 8.6 Hz, J=1.2 Hz, 2H), 6.71 (t, J = 7.2 Hz, 1H), 6.90 mino) methylphosphonate 1n: M.p.: 158 ◦C; IR (KBr,
1
(d, J = 8.4 Hz, 2H), 7.12 (t, J = 7.8 Hz, 2H), 7.40 (t, t,
J = 6.4 Hz, J = 2.4 Hz 2H) ppm.
cm−1) 3306, 1600, 1500, 1313, 1240, 1027. H NMR
(400 MHz, CDCl3 d6): δ = 2.34(s, 3H), 3.47 (d, J = 10.8Hz,
2H), 3.8 (d, J = 11.2, 3H), 4.83(d, J = 24 Hz, 3H), 5.9 (s, br
1H), 6.6 (d, J = 9.2 Hz, 2H), 7.2 (d, J = 8.0 Hz, 2H), 7.35
(d d, J = 12.4Hz, J = 2.0 Hz, 2H)8.0 (d, J = 10.8 Hz, 2H)
ppm.
νmax
2.2g Dimethyl(Terephthal)(N◦-phenylamino)methylph-
ν
osphonate 1g: M.p.: 130-135 C; IR (KBr,
cm−1):
max
3290, 1602, 1508, 1240, 1024 cm−1; 1H NMR (CDCl3, 400
MHz): 2.83 (br, s 1H), (3.51 (3H, d, J = 10.4 Hz), 3.77
24.08 Hz). 6.60-7.41 (9H, m) ppm; 13C NMR (CDCl3, 100 mino)methylphosphonate 1p: M.p.: 165◦C, IR (KBr,
MHz):54.01, 55.82, 57.52, 115.05, 115.74, 120.05, 128.87,
129.45, 129.73, 146.60, 146.90, 159.96 ppm.
1
(s, 3H), 3.80 (d, J = 1.2 Hz, 3H), 4.77 (1H, d, JP−H
=
2.2m Dimethyl (3-hydroxyphenyl) (N-4-nitrophenyla-
cm−1) 3301, 2950, 1612, 1514, 1458, 1337, 1238,
νmax
1
1178, 1058, 1027. H NMR(CDCl3, 250 MHz): δ 3.41 (d,
J = 10.5 Hz, 3 H), 3.68 (d, J = 14.2 Hz, 3H), 4.71 (d,
J = 23.7, 1H), 5.49 (s, br, 1 H), 6.52 (d, J = 3.2 Hz, 1H),
6.76 (d, J = 7.7Hz, 1H), 6.9 (m, 2 H), 7.14 (t, J = 7.7 Hz,
1H) 7.96 (d, J = 7.2Hz, 1H) ppm.
2.2h Dimethyl(4-chlorophenyl)(N-4-nitrophenyla-mino)
◦
ν
methylphosphonate 1J: M.p.: 160-162 C; IR (KBr,
max
cm−1): 3413(N-H), 3176(br O-H), 1602, 1504, 1231, 1029;
1H NMR (500 MHz, CDCl3): δ 3.45 (d, J = 10.5 Hz, 3H),
3.74 (d, J = 10.7 Hz, 3H), 4.73 (d, 1 JP−H = 23.8 Hz, 1H), 2.2n Dimethyl(4-hydroxyphenyl)(N-4-nitrophenyla-
5.82(br 2H) 6.60 (d, J = 7.5 Hz, 2H), 6.70 (t, J = 7.2 Hz, mino)methylphosphonate 1q: M.p.: 166◦C, IR (KBr,
νmax
1H), 6.79(d, J = 8.0 Hz, 1H), 6.91 (d, J = 6.51 Hz 1H), 7.07
cm−1) 3298, 3074, 2921, 2852, 2432, 1600, 1546, 1490,
1
(d, J = 7.6 Hz, 2H), 7.17(m, 2H) ppm. 13C NMR (CDCl3, 1328, 1278, 1234, 1178, 1112, 1091, 1051, 1024, H NMR
125 MHz): 54.0, 54.1, 54.7-56.3(d, 1 Jc−p = 152 Hz), 113.9, (CDCl3, 250 MHz): δ 3.4 (d, J = 10.5 Hz, 3H), 3.70 (d,
114.4, 115.8, 118.7, 119.7, 129.2, 129.9, 136.7, 145.9, 146.0,
157.3 ppm.
J = 10.7Hz, 3 H), 4.74 (d, 1 JP−H = 23.5 Hz, 1 H), 5.6 (s,
2H), 6.52 (d, J = 9Hz, 2H), 6.80 (d, J = 8.5Hz, 2H) 7.20
(d, J = 9.4, 2H), 7.96 (d, J = 9.2Hz, 2H) ppm.
2.2i Dimethyl(2,6-dichlorophenyl)(4-nitrophenyla-
◦
mino)methylphosphonate 1k: M.p.: 135 C; IR (KBr, 2.2o Dimethyl(2-chlorophenyl)(4-methylphenyla-mino)
cm−1): 3303, 2952, 1602, 1498, 1315, 1240, 1180, methylphosphonate 1r: M.p.: 158◦C, IR (KBr,
νmax
νmax
1051, 1029 cm−1; H NMR (CDCl3, 400 MHz): δ = 3.65 cm−1) 3271, 3070, 2954, 2923, 2848, 1483, 1182.1H NMR
1

Esmaeil Mohammadiyan et al.
O
P
O
OMe
NH
OMe
MeO
MeO
R2
O
P
O
P
R1
NH
10 mol%, HCOOH(37%)
SF, 65°C
H
R2
R1
or
R1
MeO
+
OMe
H
+
NH2
HN
MeO
R1
P
OMe
1a- 1w
O
Scheme 1. Kabachnik-Fields reaction by aqueous formic acid as organocatalyst.
α
Table 1. Optimization of reaction conditions for the synthesis of -
aminophosphonate by aqueous formic acid as green organocatalyst.a
Entry Temp. (oC) Solvent Time(min) Catalyst(mL) Yield (%)
1
2
3
4
5
6
7
8
25
25
40
65
80
65
65
65
65
65
65
65
-
-
-
-
2h
25
25
25
25
25
25
25
25
25
25
25
0
Trace
45
50
85
80
-
80
80
83
60
50
55
15
10
10
10
10
10
10
10
15
20
25
-
H2O
EtOH
Toluene
n-Hexane
9
10
11
12
-
-
-
a 1 mmol aldehyde, 1 mmol amine and 1.2 mmol dimethylphosphate.
(CDCl3, 250 MHz): δ = 2.20 (s, 3 H), 3.46 (d, J = 10.5 Hz, 3.1 Optimization of synthetic conditions for
3 H), 3.70 (d, J = 11 Hz, 3 H), 3.71 (s, 3 H), 5.40 (d,
kabachnik-fields reaction catalyzed by aqueous formic
acid
1 JP−H = 24.7Hz, 1H), 5.86 (s, br 1H), 6.53 (d, J = 8.3 Hz,
2 H), 6.92 (d, J = 8.3 Hz, 2 H), 7.25 (m, 2 H), 7.40 (d,
J = 8.2 Hz, 1 H), 7.60 (d, J = 8.2 Hz, 1 H) .13C NMR
To determine the best experimental conditions, the reac-
tion of, 4-chlorobenzaldehyde, aniline and dimethyl-
phosphite was considered as the model of reaction
(CDCl3, 62.9 MHz): δ 20.3, 50.1, 52.5, 53.8(m), 113.7, 126.8,
127.4 (d), 127.9, 128.8 (d), 129.2 (d), 129.5 (d), 129.8 ppm.
(Table 1).
For optimization of the best condition to carry out the
reaction different conditions were tested and the results
summarized in Table 1.
2.2p Dimethyl[(4-nitrophenyl)-(N-2-methylphenyla-
mino)methyl]phosphonate 1t: M.p.: 146-150 ◦C; IR
(KBr, max cm−1): 3331, 1602, 1498, 1449, 1230, 1028 cm−1
;
ν
1H NMR(250 MHz, CDCl3): δ 2.19 (s, 3H), 3.70 (d, J ==
8.0 Hz, 2H) 7.67 (d, J = 8.5Hz, 2H), 8.2 (d, J = 8.2 Hz,
2H);13C NMR (CDCl3, 62.9MHz): δ 20.3, 54.2(m), 57.0(d),
114.0(d), 123.8(d), 123.9, 128.6(d), 129.8, 142.9 (d), 143.7
(d), 147.8(d) ppm.
Positive effect of aqueous formic acid in promotion
of this reaction has been indicated in Table 1. With-
out using catalyst, No significant amount of product is
obtained after 2 h. To determine the optimum amount of
catalyst, we compared four diverse amounts of catalyst
and the results show that 10% is the best amount for this
reaction. More or lower than this range, can decrease the
yield percentage. To determination the best solvent con-
dition, some current solvent were tested and compared
with solvent free (SF) condition and SF had shown the
best result in this reaction. In aspect of temperature con-
ditions, among the various temperatures, the best result
was obtained at 65 ◦C (Table 2).
3. Results and Discussion
α
-
Aqueous formic acid was used to synthesis of
aminophosphonate by a one-pot, three-component reac-
tion of aldehyde, amine and dimethylphosphite under
solvent-free conditions (Scheme 1).

α
A new procedure for synthesis of -aminophosphonates
α
Table 2. Synthesized derivatives of -aminophosphonate in the presence of aqueous formic acid as reaction
organocatalysta.
Entry Amine
Aldehyde
PhCHO
Product
Time Yield
(min) (%)
M.p (oC)
(found)
M.p (◦C)
(Ref)
1
2
Aniline
Aniline
30
85
94
90–9240
O
P
OMe
OMe
NHPh
1a
1b
Cl
O
P
2-(Cl)C6H4CHO
4-(Cl)C6H4CHO
25
80
130
128–12941
OMe
OMe
NHPh
3
4
5
Aniline
Aniline
Aniline
18
30
25
85
87
78
138
139–14042
Cl
O
P
OMe
OMe
NHPh
1c
Me
N
4-[N(Me)2]PhCHO
4-(MeO)C6H4CHO
145-150
123-125
14443
Me
O
P
OMe
OMe
NHPh
1d
1e
MeO
O
P
123–12440
OMe
OMe
NHPh
O
P
125–12831
164–16544
OMe
OMe
6
7
Aniline
Aniline
4-(Me)C6H4CHO
Terephthaldehyde
30
15
80
86
129
NHPh
1f
NHPh
130-135
O
OMe
P
O
P
MeO
MeO
MeO
NHPh
1g
8
Aniline
Aniline
1-naphthaldehyde
30
25
20
62
78
78
144
127
168
143–145
OMe
PhHN
O2N
P
O
OMe 1h
9
4-(NO2)C6H4CHO
127–12840
160–16245
O
P
OMe
OMe
NHPh
1i
NO2
10
4-Nitroaniline 4-(Cl)C6H4CHO
4-Nitroaniline 2,6-(Cl)2C6H3CHO
HN
O
OMe
P
MeO
Cl
1J
1k
NO2
11
35
85
135
(New)
Cl HN
O
OMe
P
MeO
CL

Esmaeil Mohammadiyan et al.
Table 2. (contd.)
Entry Amine
Aldehyde
Product
Time Yield
(min) (%)
M.p (oC)
(found)
M.p (◦C)
(Ref)
NO2
12
13
4-Nitroaniline 4-(NO2)C6H4CHO
25
70
123
18646
HN
O
OMe
P
MeO
O2N
O2N
1l
4-Nitroaniline Terephthaldehyde
15
80
237
(New)
NH
O
P
O
MeO
OMe
P
OMe
OMe
NH
NO2
1m
NO2
14
4-Nitroaniline 4-(Me)C6H4CHO
45
80
158
(New)
HN
O
OMe
P
MeO
1n
NO2
15
16
4-Nitroaniline 4-(OMe)C6H4CHO
4-Nitroaniline 3-(OH)C6H4CHO
35
35
80
72
153
165
150–15246
(New)
HN
O
OMe
P
MeO
MeO
HO
1o
NO2
HN
O
P
OMe
MeO
1p
NO2
17
18
4-Nitroaniline 4-(OH)C6H4CHO
30
25
68
80
166
158
(New)
(New)
HN
O
OMe
P
MeO
HO
1q
1r
Me
p-Toluidine
2-(Cl)C6H4CHO
CL HN
O
P
OMe
MeO
Me
19
20
p-Toluidine
p-Toluidine
4-(Cl)C6H4CHO
20
25
80
83
137
134–137
HN
O
P
OMe
MeO
Cl
1s
Me
4-(NO2)C6H4CHO
146–150
209–21146
HN
O
OMe
P
MeO
O2N
1t

α
A new procedure for synthesis of -aminophosphonates
Table 2. (contd.)
Entry Amine
Aldehyde
Product
Time Yield
(min) (%)
M.p (oC)
(found)
M.p (◦C)
(Ref)
Me
21
p-Toluidine
p-Toluidine
4-(MeO)C6H4CHO
35
75
90
96–9946
HN
O
OMe
P
MeO
MeO
1u
Me
22
23
PhCHO
25
40
77
70
70
65
68–7146
HN
O
OMe
P
MeO
1v
Br
4-Bromoaniline PhCHO
6047
HN
O
OMe
P
MeO
1w
a1 mmol aldehyde, 1 mmol amine and 1.2 mmol dimethylphosphate, 15 μL catalyst (formic acid (37%)), 65 ◦C
temperature.
O
H
0
Cl
O
P
Aqueous formic acid (37%)
Cl
OMe
OMe
P
H
SF, 65°C
OMe
MeO
NH2
NHPh
α
Scheme 2. The reaction of, 4-chlorobenzaldehyde, aniline and dimethylphosphite to preparation of
–aminophosphonates.
After optimization of the reaction condition, in order
to generalize the method, it was expanded with versatile
aldehydes and amines for synthesis of other derivatives
NH2
2
R
H2O
O
H
O
H
H
H
O
O
α
R2
R1
of -aminophosphonates and the results were summa-
O
O
P
H
N
R2
R1
rized in (Table 2). Six derivatives including (Entry 11,
13, 14, 16, 17, 18) have been synthesized for the first
time in this work.
R
OMe
MeO
(II)
(I)
3
O
R2
R1
1
3.2 The proposed mechanism of the
Kabachnik–Fields reaction in the presence of aqueous
formic acid
H2O
O
H
O
H
MeO
OMe
O
P
H
O
H
H
N
O
R2
α
The suggested mechanism to synthesis of -amino-
R
MeO
MeO
R1
O
phosphonate by aqueous formic acid as organocatalyst
is shown in Scheme 3.
As shown in Scheme 3, the first step is the acti-
vation of carbonyl groups in aldehydes by hydrogen
bond interaction with HCOOH (I). Second, a nucle-
ophilic addition of amine to activated carbonyl, cause
4
P
N
R
H
R2
R1
formic acid
=
(III)
Scheme 3. The proposed mechanism of the Kabachnik—
Fields reaction by aqueous formic acid as organocatalyst.

Esmaeil Mohammadiyan et al.
8. Baylis E K, Campbell C D and Dingwall J G 1-
the formation of an imine intermediate (II). The forma-
tion of imine intermediate by formic acid was reported
in our former research41. Also, the addition of nucle-
ophilic phosphonate 3 to imine cause the formation of
Aminoalkylphosphonous acids Part 1 Isosteres of the
protein amino acids J. Chem. Soc. Perkin.1 2845
9. Smith A B, Taylor C M, Benkovic S J and Hirschmann
R 1994 Peptide bond formation via catalytic antibodies:
Synthesis of a novel phosphonate diester hapten Tetra-
hedron Lett. 35 6853
α
-aminophosphonate 4. After the separation of catalyst,
the pure product can be obtained.
10. Pan W, Ansiaux C and Vincent S P 2007 Synthesis
of acyclic galactitol-and lyxitol-aminophosphonates as
inhibitors of UDP-galactopyranose mutase Tetrahedron
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4. Conclusions
11. Bloemink M J, Diederen J J, Dorenbos J P, Heetebrij R
J, Keppler B K and Reedijk J 1999 Calcium Ions Do
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Shen Q, Zhang W, Sheng L, Shi X-X, Tang Y, Li J, Chen
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of triazole-linked amino acid–glucoside conjugates as
novel PTP1B inhibitors New J. Chem. 35 622
Aqueous formic acid was demonstrated as a green and
effective organocatalyst in Kabachnik-Fields reaction to
α
synthesize -aminophosphonate derivatives. The eco-
friendly and low cost organocatalysts and solvent free
condition provide considerable advantages for this pro-
cedure. Also, this method has shown several benefits
such as: easy work up process, short reaction time and
lack of toxicity. Six of the reported derivatives were syn-
thesized for the first time in this study.
13. Rao X, Song Z, Yao X, Gao H and Ye B 2008 The
green approaches for the synthesis of N-dehydroabietic
α
-aminophosphonates Nat. Prod. Res. 22 890
Supplementary Information (SI)
14. Gautier I, Ratovelomanana-Vidal V, Savignac P and
Genêt J-P 1996 Asymmetric hydrogenation of β-
ketophosphonates and β-ketothiophosphonates with chi-
ral ru (II) catalysts Tetrahedron Lett. 37 7721
Additional experimental data and spectroscopic character-
ization data are given in the Supplementary Information.
Supplementary Information is available at www.ias.ac.in/
chemsci.
α
15. Kim D Y and Rhie D Y 1997 Synthesis of
-
aminoalkylphosphonates from vinylphosphonates via
aziridinylphosphonates Tetrahedron 53 13603
16. Sawamura M, Ito Y and Hayashi T 1989 Asymmetric
synthesis of (1-aminoalkyl) phosphonic acids via asym-
metric aldol reaction of (isocyanomethyl) phosphonates
catalyzed by a chiral ferrocenylphosphine-gold (I) com-
plex Tetrahedron Lett. 30 2247
Acknowledgements
This work was supported by the Research Council of Depart-
ment of Chemistry Iran University of Science.
17. Lefebvre I M and Evans S A 1997 Studies toward the
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