Water mediated eco-friendly green protocol for one-pot synthesis of α-aminophosphonates at ambient conditions

Article abstract of DOI:10.1007/s12039-014-0608-x

Increasing environmental awareness and economic concerns have led to the consideration of highly efficient one-pot, three-component, green approaches for important organic synthons. We describe here a simple, elegant and high yielding protocol for the synthesis of α-aminophosphonates in totally solvent-free, catalyst-free conditions by reacting aldehydes, amines and trimethyl phosphite at ambient temperature.

Full text of DOI:10.1007/s12039-014-0608-x

c
J. Chem. Sci. Vol. 126, No. 3, May 2014, pp. 793–799. ꢀ Indian Academy of Sciences.
Water mediated eco-friendly green protocol for one-pot synthesis
of α-aminophosphonates at ambient conditions
SANTHOSH REDDY MANDHA, MANJULA ALLA∗ and VITTAL RAO BOMMENA
Crop Protection Chemicals, CSIR-Indian Institute of Chemical Technology, Tarnaka,
Hyderabad 500 607, India
e-mail: manjula@iict.res.in
MS received 19 June 2013; revised 30 December 2013; accepted 31 December 2013
Abstract. Increasing environmental awareness and economic concerns have led to the consideration of highly
efficient one-pot, three-component, green approaches for important organic synthons. We describe here a
simple, elegant and high yielding protocol for the synthesis of α-aminophosphonates in totally solvent-free,
catalyst-free conditions by reacting aldehydes, amines and trimethyl phosphite at ambient temperature.
Keywords. α-Aminophosphonates; aldehydes; amines; trimethyl phosphite; solvent-free.
1. Introduction
an efficient synthesis of these organophosphorus com-
pounds is of great interest in recent times. A num-
ber of synthetic methods have been developed dur-
ing the past two decades for the preparation of α-
aminophosphonates through one-pot multicomponent
reactions (MCRs).
Design and development of products and processes that
minimize the usage as well as generation of toxic sub-
stances have been the aim of green chemistry. Avoid-
ing addition of supplementary chemicals, such as sol-
vents, catalysts, promoters, etc. either in the reaction
sequence or work-up process constitutes a significant
step in accomplishing environmentally friendly reaction
protocol. Further, designing synthetic methods at ambi-
ent temperature and pressure goes a long way in making
the reaction totally clean, hazard-free and energy effi-
cient. In continuation of our interest in developing envi-
ronmentally benign efficient solvent-free protocols for
the synthesis of important products, we describe here a
simple, elegant and high yielding protocol for the syn-
thesis of α-aminophosphonates in totally solvent-free,
catalyst-free conditions at ambient temperature.
Organophosphorus compounds due to their high
degree of biological and pharmacological spectrum
have become the subject of immense interest in recent
years.1 Phosphorus analogues of the amino acids in
which the carboxylic acid group is replaced by a phos-
phonate group have attracted particular interest in the
preparation of isosteric analogues of numerous natural
products.2 Their utility as antagonists in the metabolism
of amino acids as enzyme inhibitors and as pharma-
cological agents such as antibiotics, antiviral, etc. and
many other applications are well-documented.3 Thus,
Of all the reported methods, nucleophilic addi-
tion of dimethyl phosphite or trimethyl phosphite to
imines (generated in situ from aldehydes and amines)
catalysed by an acid, has emerged as an important
method for the synthesis of α-aminophosphonates.
One-pot synthesis of α-aminophosphonates directly
from aldehyde, amine, and phosphite was first achieved
with lanthanide triflate4 as catalyst. Subsequently,
many methods using different catalytic systems such
as SnCl4, BF3.OEt2,6 MgBr2,7 InCl3,8 TaCl5-SiO2,9
5
ZrCl4,10 Sc(DS)3,11 H3PW12O40,12 BiNO3.5H2O,13 Mg
(ClO4)2,14 β-cyclodextrin,15 AlCl3,16 amberlyst-15,17
TFA,18 sulphamic acid,19 SbCl3/Al2O3,20 TiO2,21
Al2O3-MW,22 ZrOCl2.8H2O,23 ZrO(ClO4)2.6H2O,24
SmI2,25 LiClO4,26 Oxalic acid,27 ionic liquid,28
FeCl3,29 silica sulphuric acid,30 CSA,31 (Bromodi-
methyl)sulphonium bromide,32 H3BO3,33 Bi(OTf)3,34
NaHSO4-SiO2,35 Yttria-zirconia,36 HClO4-SiO2,37
and microwave38 have been reported. Earlier Ranu
et al.39 reported the similar reaction under solvent-
free conditions at higher temperature wherein the
diethylphosphite is used as a nucleophile. Many of the
reported methods have limitations that include use of
organic solvents, expensive catalysts, harsh reaction
conditions and low yields. Though few of the reported
Lewis acids are less expensive and readily available,
their efficiency is low owing to the fact that they are
∗For correspondence
793

794
Santhosh Reddy Mandha et al.
either deactivated or decomposed by the presence of (d, JCP = 6.58 Hz), 59.55, 61.57, 126.03, 127.88,
amines and/or water generated in situ during imine 128.25, 128.49, 129.33, 135.45, 137.43, 139.54;
formation.40 In order to overcome such limitations, MS (ESI): m/z = 320 [M+H]+; Anal. Calcd for
there is a need for an efficient and convenient method C17H22NO3P: C, 63.94; H, 6.94; N, 4.39. Found: C,
for construction of such significant scaffolds. Most of 64.00; H, 6.90; N, 4.45.
the reported procedures claim only trace amount of
products in a solvent less neat conditions at ambient
2.3b Dimethyl(phenylamino)(4-{3,5,6-trichloro-
temperature. To the best of our knowledge, this is the
pyridin-2-yloxy}phenyl)methylphosphonate (table 1,
report where in the water generated in situ catalyses the
entry 13): White solid, m.p. 165–167◦C; IR (KBr):
synthesis of α-aminophosphonates in a solvent-free,
3327, 1602, 1412, 1236, 1036 cm−1; 1H NMR
and catalyst-free environment at ambient conditions.
(300 MHz, CDCl3): δ 3.46 (d, J = 10.57 Hz, 3H), 3.76
(d, 3H, J = 10.57 Hz), 4.72-4.83 (m, 2H), 6.57 (d, 2H,
(m, 4H), 7.49–7.55 (m, 2H), 7.81 (s, 1H); 13C NMR
J = 7.55 Hz), 6.68 (t, 1H, J12 = 7.55 Hz), 7.04–7.16
2. Experimental
2.1 Materials, methods and instruments
(75 MHz, CDCl3): δ 53.79 (d, JCP = 6.58 Hz), 54.05 (d,
JCP = 8.78 Hz), 54.17, 56.18, 113.81, 117.85, 118.61,
121.46, 128.96, 129.20, 132.75, 140.72, 143.48,
144.56, 145.78, 152.65, 155.96; MS (ESI): m/z = 509
[M+Na]+; Anal. Calcd for C20H18Cl3N2O4P: C, 49.25;
H, 3.72; N, 5.74. Found: C, 49.45; H, 3.68; N, 5.79.
All the chemicals used were of synthetic grade
obtained. Analytical thin-layer chromatography (TLC)
using E-Merck 0.25 mm silica gel plates monitored
completion of the reactions time to time. Visualization
was accomplished with UV light (256 nm) and iodine.
Melting points were determined on Fisher John’s and
2.3cDimethyl(phenylamino)(heptyl)methylphosphonate
(table 1, entry 14): Yellow viscous liquid; IR (neat):
1
are uncorrected. All the H-NMR spectra are recorded
on AVANCE 300 MHz in CDCl3. Chemical shifts
reported are on the δ-scale relative to TMS internal stan-
dard. The IR spectra recorded on SHIMADZU FT-IR
SPECTROPHOTOMETER using 1% potassium bro-
mide discs. Mass spectra recorded on Waters quadruple
mass spectrometry.
1
3310, 1607, 1478, 1025 cm−1; H NMR (300 MHz,
CDCl3): δ 0.86 (t, 3H, J = 6.98 Hz), 1.21–1.73 (m,
10H), 1.79–1.93 (m, 1H), 3.64 (d, 3H, J = 10.57 Hz),
3.72 (d, 3H, J = 10.57 Hz), 3.91 (brs, NH), 6.57–6.69
(m, 3H), 7.07–7.15 (m, 2H); 13C NMR (75 MHz,
CDCl3): δ 13.62, 22.11, 25.46, 28.58, 30.33, 31.16,
50.36, 52.08 (d, JCP = 7.15 Hz), 53.17 (d, JCP
=
2.2 General procedure for preparation
of α-aminophosphonates
6.60 Hz), 112.83, 117.41, 128.86, 146.98; MS (ESI):
m/z = 322 [M+Na]+; Anal. Calcd for C15H26NO3P: C,
60.18; H, 8.75; N, 4.68. Found: C, 60.27; H, 8.69; N,
4.85.
A mixture of aldehyde (1 mmol) and amine (1 mmol)
was stirred at room temperature for 2 min and then
trimethyl phosphite (1 mmol) was added. After comple-
tion of the reaction, as indicated by TLC, the reaction
mixture was diluted with water (in case of solid pro-
ducts) and the products were separated by filtration and
dried. The products obtained were pure enough for all
practical purposes.
2.3d Dimethyl(pyridin-2-ylamino)(thiophen-2-yl)
methylphosphonate (table 1, entry 15): White solid,
m.p. 145–147◦C; IR (KBr): 3300, 1602, 1481, 1228,
1
1054, 1025 cm−1; H NMR (300 MHz, CDCl3): δ
3.62 (d, 3H, J = 10.57 Hz), 3.71 (s, 1H), 3.76 (d,
3H, J = 10.57 Hz), 5.13 (brs, NH), 6.01 (q, 1H), 6.45
(d, 1H, J = 8.31 Hz), 6.60 (q, 1H, J12 = 3.77 Hz,
2.3 Spectral data of unreported compounds
2.3a Dimethyl(phenethylamino)(phenyl)
methylphosphonate (table 1, entry 12): Pale yellow
solid, m.p. 217–219◦C; IR (neat): 3384, 3036, 1524,
1
763 cm−1; H NMR (300 MHz, CDCl3): δ 2.40 (brs,
NH), 2.65–2.81 (m, 4H), 3.46 (d, 3H J = 10.57 Hz),
3.66 (d, 3H, J = 10.57 Hz), 3.99 (d, 1H, J =
20.39 Hz), 7.06–7.31 (m, 10H); 13C NMR (75 MHz,
CDCl3): δ 36.04, 48.94 (d, JCP = 17.01 Hz), 53.24
Scheme 1. Eco friendly synthesis of α-aminophospho-
nates.

Water mediated eco-friendly green protocol for one-pot synthesis of α-aminophosphonates at ambient conditions 795
Table 1. Synthesis of α-aminophosphonates in noncatalytic and solvent free conditions.
Sl. No.
Aldehyde
Amine
Product
Time (h)
Yield (%)
Melting point (◦C) ref
1
8
81
87–8827
2
8
83
94–95
3
4
5
7
7
6
84
78
84
118–119
90–9127
124–12538
6
9
86
70–7138

796
Santhosh Reddy Mandha et al.
Table 1. (continued).
Sl. No.
Aldehyde
Amine
Product
Time (h) Yield (%) Melting point (◦C) ref
7
9
80
134–135
8
9
12
70
88
92–9416
5
211–21328c
10
11
12
12
80
68
142–143
135–136
12
13
6
8
88
70
217–219
165–167

Water mediated eco-friendly green protocol for one-pot synthesis of α-aminophosphonates at ambient conditions 797
Table 1. (continued).
Sl. No.
Aldehyde
Amine
Product
Time(h) Yield (%) Melting point (◦C) ref
14
12
71
liqud
15
16
12
82
72
145–147
70–7126c
8
17
12
58
Gummy solid
J13 = 6.04 Hz), 6.96 (q, 1H, J12 = 3.77 Hz, J13
=
3. Results and discussion
5.28 Hz), 7.15–7.24 (m, 1H), 7.37 (m, 1H), 8.08 (d,
1H, J = 6.04 Hz); 13C NMR (75 MHz, CDCl3): δ
At the outset, taking the one-pot reaction of benzalde-
hyde, aniline and trimethyl phosphite (or triethyl phos-
phite) as a typical example, solvent-free noncatalytic
protocol was attempted at ambient temperature. The
reaction proceeds smoothly in 8 h to yield the corre-
sponding α-aminophosphonates in 81% (with trimethyl
phosphite) and 84% (with triethyl phosphite), with an
optimum ratio of reactants being 1:1:1.1 (scheme 1).
45.87, 48.01, 53.52 (d, JCP = 6.58 Hz), 53.85 (d, JCP
=
6.58 Hz), 109.20, 114.01, 125.05, 126.51, 126.99,
137.23, 139.38, 147.70, 156.38; MS (ESI): m/z = 321
[M+Na]+; Anal. Calcd for C12H15 N2O3PS: C, 48.32;
H, 5.07; N, 9.39. Found: C, 48.39; H, 5.08; N, 9.47.
R
H
O
NHR1
NR1
H2O
-H2O
R1NH2
CH3
P
O
R
H
H3CO
P(OCH3)3
R
Cl
anhydrous
conditions
OCH3
OH
No Reaction
Cl
8hrs
-CH3OH
P(OCH3)3
N
O
water
6hrs
O
P
R
NHR1
O
H
NH
P
O
H3CO
OCH3
Scheme 3. Synthesis of aminophosphonates from Schiff’s
base and trimethyl phosphite.
Scheme 2. Plausible mechanism.

798
Santhosh Reddy Mandha et al.
Table 2. Comparison of product yields in various methods.
Substrates
Yield (%) of α-aminophosphonates
Sl. No.
Aldehyde
Amine
BDMS 32
AlCl136
ZrCl140
No catalyst
1
2
3
4
Aromatic
Aromatic
Aliphatic
Aromatic
Aromatic
Aliphatic
Aromatic
80
83
Trace
Trace
80
80
Trace
Trace
82
85
Trace
Trace
81
88
71
58
Aromatic secondary
To explore the scope of this protocol, we examined 4. Conclusion
various aldehydes, amines as shown in table 1 with
A simple, efficient and elegant protocol for the one-
pot synthesis of α-aminophosphonates from variety of
aldehydes, amines and trimethyl phosphite in catalyst-
free and solvent-free conditions at ambient temperature
is presnted. The major highlight of the protocol is that
it is in total agreement with the green chemistry prin-
ciples: free of any chemical auxiliaries (solvent, cata-
lyst, etc.) and energy efficient (ambient temperature).
This approach for biologically significant compounds
is an attractive and useful method fits very well in to
the green synthetic procedures, compared to the exist-
ing innumerable methodologies. Further, this approach
highlights the importance and relevance of water in
promoting the reaction for the first time.
trimethyl phosphite. In general, all the reactions with
variety of aryl, alkyl and heteroaryl aldehydes and aryl,
arylalkyl and heteroaryl amines are clean and the α-
aminophosphonates were obtained in high yields, under
optimized conditions. Another salient feature of this
approach is that the reaction proceeds well with the se-
condary amines also (table 1, entry 17). The electronic
effects i.e., electron withdrawing groups on aldehydes
(table 1, entry 5 and 9) and electron releasing groups on
amines (table 1, entries 6, 7 and 9) increased the rate
of reaction and yield of the products. Further, the reac-
tion is also facile for the solid substrates i.e., when the
aldehydes and amines involved are solids.
The mechanism of reaction (as shown in scheme 2)
involves the nucleophilic addition of trimethyl phos-
phite on imine (generated in situ from aldehyde and
amine) to produce a phosphonium intermediate, which
in the presence of water looses methanol to give the
desired aminophosphonates.
In order to prove the involvement of water in the reac-
tion mechanism unambiguously, the reaction was per-
formed with pre-synthesized imine, thereby avoiding
water generated in situ. As expected, the reaction of the
preformed imine with trimethyl phosphite did not pro-
ceed under moisture-free conditions where as the addi-
tion of water to the reaction medium in stoichiometric
amount facilitated the progress in reaction (as shown in
scheme 3). Intriguing aspect being that water is detri-
mental to the stability of trimethyl phosphite but it is the
same water does help in completion of the reaction.39
A comparative evaluation of the method was done by
with respect to other methods reported, such as Lewis
acid catalysed and solvent-free protocol as shown in
table 2. It was found that the present method takes
longer time than others, the yields are comparable. Fur-
ther, it is found that the method is superior when the
aldehyde involved is aliphatic as well as with aromatic
secondary amines and when aldehydes and amines
involved are both solids.
Acknowledgements
We thank the Director, CSIR-IICT and Head, Crop Pro-
tection Chemicals Division, for the facilities, encour-
agement and support. SRM is thankful to the Council of
Scientific and Industrial Research (CSIR), New Delhi,
India, for the fellowship.
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