An efficient multi-component synthesis of (2-amino-3-cyano-4H-chromen-4-yl) phosphonic acid diethyl ester

Article abstract of DOI:10.1016/j.crci.2011.03.001

(2-Amino-3-cyano-4H-chromen-4-yl) phosphonic acid diethyl esters are prepared via a single-step multi-component reaction of structurally diverse salicylaldehydes with malononitrile and triethyl phosphite using a catalytic amount of potassium phosphate in ethanol at ambient temperature. Use of potassium phosphate as an inexpensive catalyst makes the protocol more economical. Mild reaction conditions, simple work-up procedure are the added advantages of the present method.

Full text of DOI:10.1016/j.crci.2011.03.001

C. R. Chimie 14 (2011) 865–868
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Preliminary communication/Communication
An efficient multi-component synthesis of (2-amino-3-cyano-4H-
chromen-4-yl) phosphonic acid diethyl ester
*
D.S. Gaikwad, K.A. Undale, T.S. Shaikh, D.M. Pore
Department of Chemistry, Shivaji University, Kolhapur 416 004, India
A R T I C L E I N F O
A B S T R A C T
Article history:
(2-Amino-3-cyano-4H-chromen-4-yl) phosphonic acid diethyl esters are prepared via a
single-step multi-component reaction of structurally diverse salicylaldehydes with
malononitrile and triethyl phosphite using a catalytic amount of potassium phosphate in
ethanol at ambient temperature. Use of potassium phosphate as an inexpensive catalyst
makes the protocol more economical. Mild reaction conditions, simple work-up procedure
are the added advantages of the present method.
Received 22 December 2010
Accepted after revision 8 March 2011
Available online 13 April 2011
Keywords:
Multi-component reaction
Triethyl phosphite
Potassium phosphate
One-pot synthesis
Chromene
´
ß 2011 Academie des sciences. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction
natural products [4] and can be converted into pyridine
systems which relate to pharmacologically important
Recently, synthetic chemists have focused their atten-
tion towards the transformations involving C-P bond
formation [1]. In this endeavor Michaelis-Arbuzov [2],
Michaelis-Becker [3] and phospha-Michael addition [1] are
most prominent because of the versatile chemistry of their
products. Amongst these, the phospha-Michael addition,
i.e. the addition of a phosphorus nucleophile to an
acceptor-substituted alkene or alkyne represents one of
the most versatile and powerful tools for the formation of a
C-P bond since many different electrophiles and phospho-
rus nucleophiles can be combined with each other. This
offers the possibility to access many diversely function-
alized products.
calcium antagonists of the dihydropyridine[DHP] [5] type.
Along with this, it accounts an important application in the
field of drugs and pharmaceuticals as anti-coagulant,
diuretic, spasmolytic, anticancer and anti-anaphylactin
agent [6]. Also, it can be used as cognitive enhancer for the
treatment of neurodegenerative disease including Alzhei-
mer’s disease, amyoprophic lateral sclerosis, Huntington’s
disease, Parkinson’s disease, AIDS associated dementia,
and Down’s syndrome as well as for the treatment of
schizophrenia and myoclonus [7]. Besides biological
significance, some 2-aminochromenes have been widely
used as photoactive materials [8] which led the scientific
community to synthesize derivatives of 2-aminochro-
mens.
One of the important application of the phospha-
Michael addition is the synthesis of (2-amino-3-cyano-
4H-chromen-4-yl) phosphonic acid diethyl ester, which
retains the basic skeleton of 2-amino chromene. This
skeleton is an important structural motif in a series of
Recently, the synthesis of novel derivatives of 2-
aminochromens, viz (2-amino-3-cyano-4H-chromen-4-
yl) phosphonic acid diethyl esters, was carried out by
Perumal et al. using InCl3 [9] as Lewis acid catalyst at
ambient temperature as well as by Nageswar et al. using b-
cyclodextrin [10] at 60–70 8C. The thorough scrutiny of
literature revealed that these are the only reports on
synthesis of (2-amino-3-cyano-4H-chromen-4-yl) phos-
* Corresponding author.
E-mail address: p_dattaprasad@rediffmail.com (D.M. Pore).
1631-0748/$ – see front matter ß 2011 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.crci.2011.03.001

866
D.S. Gaikwad et al. / C. R. Chimie 14 (2011) 865–868
phonic acid diethyl ester. Hence, an economical protocol
with an easily available basic catalyst operable at ambient
temperature for synthesis of (2-amino-3-cyano-4H-chro-
men-4-yl) phosphonic acid diethyl ester is highly desired.
O
O
P
O
O
O
O
P
CHO
OH
3
K3PO4, rt
EtOH
CN
2. Result and discussion
+
CN
X
O
NH2
X
In our continuous interest in potassium phosphate as
well as synthesis of pyrans [11,12]. We would like to report
a mild, cost-effective procedure for the one-pot multi-
component synthesis of (2-amino-3-cyano-4H-chromen-
4-yl) phosphonic acid diethyl esters (4) by the condensa-
tion of salicylaldehydes (1), malononitrile (2) and triethyl
phosphite (3) in the presence of a catalytic amount of
potassium phosphate at ambient temperature in ethanol
medium (Scheme 1).
1
NC
4
2
Scheme 1. Multi-component synthesis of 2-amino-3-cyano-4H-
chromen-4-yl) phosphonic acid diethyl ester.
group on the cyano group to form imino coumarin (6)
and subsequent phospha-Michael addition of triethyl
phosphite (3) affording the target compound (4).
A
We envisioned that K3PO4 could be a suitable catalyst
for the present transformation, since the anion PO4 is
sufficiently basic for the formation of cyanoolefin (5)
followed by ring closure via nucleophilic attack of the OH
3À
plausible mechanism for the multi-component synthesis
of (2-amino-3-cyano-4H-chromen-4-yl) phosphonic acid
diethyl ester using K3PO4 in EtOH is depicted in Scheme 2.
EtO
EtO
O--Et
P
+
EtO
:
P
CN
EtO
:OC2H5
H
EtO
-
O
NH
3
K+
EtO
O
EtO
P
CN
NH
CN
O
6
O
NH2
K3PO4
4
K+
CN
CN
H
CN
+
-
3
PO4
H
N
OH
2
..
5
CN
_
OH
CN
OH
O
H
CN
CN
H
OH
1
Scheme 2. A plausible mechanism for formation of 2-amino-3-cyano-4H-chromen-4-yl) phosphonic acid diethyl ester.

D.S. Gaikwad et al. / C. R. Chimie 14 (2011) 865–868
867
Table 2
In an initial study, optimization of the amount of K3PO4
as well as the solvent effect were examined by the reaction
of 1 (1 mmol), 2 (1 mmol) with 3 (1 mmol) in different
solvents (Table 1). The best conditions employ K3PO4 as a
catalyst, 1, 2, 3 in a 0.20:1:1:1 mole ratio at room
temperature using EtOH as a solvent. It is worthy of note
that in solvents like H2O, MeCN and MeOH (Table 1, entries
1,3,4) a mixture of products 4 and 6 (Scheme 3) was
obtained while in CHCl3 there is no progress in reaction
after 3 h (Table 1, entry 2) under the same reaction
conditions. The catalytic activity of other catalysts
generating K+ and PO43À ions such as K2HPO4, and KH2PO4
is also tested and we found that they resulted in inferior
results, 74 and 66% yield of product respectively under the
same conditions. The experimental procedure for this
reaction is remarkably simple and synthesis could not be
achieved in absence of catalyst even though reflux
condition was applied for 5 h (entry 8, Table 1).
Under these optimized conditions, the reaction be-
tween various substituted salicylaldehydes (1), 2 and 3 in
the presence of potassium phosphate were investigated
(Scheme 1, Table 2). It was found that all the reactions
proceed smoothly to give the corresponding phosphonic
acid diethyl esters in high yields (Table 2). Both
salicylaldehyde bearing electron-donating substituents
(entries 4c–4e) and electron-withdrawing groups (entries
4b, 4f–4i) gave excellent yields. The mildness of the
procedure makes it very selective, as it tolerates a variety
of functionalities, including chloro, bromo, methyl, meth-
oxy, nitro, and naphthyl groups. The results are summa-
rized in Table 2, which clearly demonstrates the generality
and scope of the protocol.
Potassium phosphate catalyzed multicomponent synthesis of (2-amino-
3-cyano-4H-chromen-4-yl) phosponic acid diethyl ester at room
temperature.
Entry
Product (4)
Time (min)
Yield (%)a,b
O
O
a
40
90
P
O
CN
O
NH2
O
O
b
30
35
45
93
88
81
P
O
Cl
CN
O
NH2
O
O
c
P
O
Me
CN
O
NH2
O
O
d
P
O
CN
Table 1
Effect of solvent and optimization of amount of K3PO4 on the yield of
O
NH2
product 4.
OMe
Entry
Solventa
Product
Catalyst
(Mol %)
Time
Yield (%)
(min)
1
2
3
4
5
6
7
8
H2O
4 + 6
———
4 + 6
4 + 6
4
20
20
20
20
10
15
20
—
120
180
120
65
28b + 56c
O
P
CHCl3
MeCN
MeOH
EtOH
EtOH
EtOH
EtOH
——
O
72b + 12.8c
e
45
88
O
47b + 41c
MeO
CN
70
81
86
90
—
4
60
O
NH2
4
40
———
300
a
Reaction conditions: Salicylaldehyde (1 mmol), malononitrile
(1 mmol), triethylphosphite (1 mmol), solvent (5 mL), temp.: r.t.
b
O
Corresponds to yields of product 4 by LCMS.
O
c
Corresponds to yields of product 6 by LCMS.
P
O
f
35
94
Br
CN
O
NH2
O
O
O
P
CN
CN
O
O
P
O
g
20
89
O
NH
Cl
CN
O
NH2
6
4
O
NH2
Cl
Scheme 3. Mixture of products obtained in H2O, MeCN and MeOH.

868
D.S. Gaikwad et al. / C. R. Chimie 14 (2011) 865–868
Table 2 (Continued )
4.3. Spectral data of representative compounds
Entry
Product (4)
Time (min)
Yield (%)a,b
˚
Entry 4e: mp 172–174 C; IR (KBr): 3342, 3160, 2979,
2191, 1658, 1499, 1232, 1040, 971 cmÀ1 1H NMR
(400 MHz, DMSO-d6): = 1.16 (t, 3H, CH3, J = 7.2 Hz),
1.21 (t, 3H, CH3, J = 7.2 Hz), 3.73 (s, OCH3), 3.95 (m, 4H, -
CH2), 4.05 (d, 1H, 2JPH = 18 Hz), 6.82 (t, 1H, J = 2.4 Hz), 6.86
(dt, 1H, J = 2.4, J = 9.2 Hz), 6.96 (d, 1H, J = 8.8 Hz), 7.07 (bs,
2H, -NH2, D2O exchangeable); 13C NMR (100 MHz, DMSO-
;
O
d
h
55
79
O
P
O
O2N
CN
NH2
O
d6):
d 16.1, 16.2, 34.1, 35.5, 46.9, 55.4, 62.1, 62.2, 114.0,
116.6, 118.6, 120.1, 143.8, 155.3, 162.8; 31P-NMR
(162 MHz, DMSO-d6):
Entry 4g: mp 169–170 C; IR (KBr): 3444, 3343, 2891,
2194, 1646, 1426, 1248, 1034, 864 cmÀ1
d
23.39.
˚
O
O
P
O
;
1H NMR
i
30
95
CN
NH2
Br
(400 MHz, DMSO-d6): = 1.14 (t, 3H, CH3, J = 7.2 Hz),
d
1.18 (t, 3H, CH3, J = 7.2 Hz), 3.98 (m, 4H, -CH2), 4.25 (d, 1H,
2JPH = 18.8 Hz), 7.27 (t, 1H, J = 2.4 Hz), 7.38 (bs, 2H, -NH2,
D2O exchangeable), 7.64 (t, 1H, J = 2.4 Hz); 13C NMR
O
Br
(100 MHz, DMSO-d6):
d 16.1, 33.9, 35.3, 47.3, 62.3, 62.5,
119.2, 121.2, 121.7, 127.7, 127.9, 128.5, 144.8, 161.8; 31P-
NMR (162 MHz, DMSO-d6):
d 22.47.
O
O
j
55
74
O
P
CN
Acknowledgement
O
NH2
Authors DMP and KAU thank UGC, New Delhi for
a
All products showed satisfactory spectroscopic data (IR, 1H, 13C and
financial assistance [F.2-3/2007(Policy/SR)] and for
Research Fellowship, respectively.
a
31P NMR).
b
Yields refer to pure, isolated products.
References
3. Conclusion
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yl) phosphonic acid diethyl ester using potassium phos-
phate as an inexpensive catalyst at ambient temperature.
High yields along with simple reaction conditions as well
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(1 mmol), triethylphosphite (1 mmol) and K3PO4 (20 mol
%) in ethanol (5 mL) was stirred at r.t. till the completion of
reaction as monitored by TLC. (Table 2). Then the reaction
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