Efficient one-pot synthesis of β-phosphono malonates and 2-amino-4H-chromen-4-ylphosphonate derivatives by ethylenediamine diacetate-catalyzed three-component reactions

Article abstract of DOI:10.1016/j.tet.2011.10.060

One-pot three-component reactions of arylaldehyde or salicylaldehyde with malononitrile (or ethylcyanoacetate) and triethyl phosphite are carried out in the presence of ethylenediamine diacetate (EDDA) as a catalyst for the synthesis of biologically interesting β-phosphono malonates and 2-amino-4H-chromen- 4-ylphosphonate derivatives. The value of this method lies in its mild reaction catalyst and conditions, good yields, and ease of handling.

Full text of DOI:10.1016/j.tet.2011.10.060

Tetrahedron 68 (2012) 226e237
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Efficient one-pot synthesis of b-phosphono malonates and 2-amino-4H-chromen-
4-ylphosphonate derivatives by ethylenediamine diacetate-catalyzed three-
component reactions
*
Srinivasa Rao Kolla, Yong Rok Lee
School of Chemical Engineering and Technology, Yeungnam University, Kyongsan 712-749, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
One-pot three-component reactions of arylaldehyde or salicylaldehyde with malononitrile (or ethyl-
cyanoacetate) and triethyl phosphite are carried out in the presence of ethylenediamine diacetate (EDDA)
Received 20 September 2011
Received in revised form 14 October 2011
Accepted 16 October 2011
as a catalyst for the synthesis of biologically interesting
b-phosphono malonates and 2-amino-4H-
chromen-4-ylphosphonate derivatives. The value of this method lies in its mild reaction catalyst and
conditions, good yields, and ease of handling.
Available online 21 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
b-Phosphono malonates
2-Amino-4H-chromen-4-ylphosphonate
Ethylenediamine diacetate
Three-component reactions
1. Introduction
EtO
EtO
R
O
P(OEt)3
or
P
CN
catalysts
R
CN
CN
+
Organophosphorus compounds are important substrates in the
study of biochemical processes and are widely used as biologically
active compounds.1 Among these, phosphonates and their de-
rivatives have attracted considerable attention due to their bi-
ological activities and application as enzyme inhibitors,
antimetabolites, peptide mimetics, and antibiotics.2e5 For the
synthesis of phosphonate derivatives, phosphorusecarbon (PeC)
bond formations are one of the most versatile and powerful tools.6
The reactions for PeC bond formation are commonly promoted by
bases,7 Lewis acids,8 microwaves,9 transition metals,10 and radical
inhibitors.11
O
CN
HP(OEt)2
Scheme 1.
O
HP
EtO
EtO
R
O
Ph
Ph
R
O
Ph
Ph
O
CN
CN
P
P
P(OEt)3
+
CN
CN
CN
CN
R
H
sodium stearate
TBD
Among the several synthetic approaches for
malonates that have been reported, one method consists of the
b-phosphono
Scheme 2.
conjugate addition of phosphorous nucleophiles to a,b-unsaturated
malonates catalyzed by AP-SiO2,12 HClO4eSiO2,13 or NFeZnO7c
(Scheme 1). Another reported method is three-component con-
densation of aldehydes with malononitrile and diphenylphosphine
oxide or triethyl phosphite catalyzed by 1,5,7-triazabicylo[4.4.0]
dec-5ene14 (TBD) or sodium stearate15 (Scheme 2).
show a variety of biological activities, including anticancer,18 anti-
inflammatory,19 antimalarial,20 and pesticidal activities.21 This wide
range of biological activities and pharmacological properties has
stimulated interest in new approaches for the synthesis of a variety
of phosphonate derivatives with 2-aminochromenyl rings utilizing
multicomponent reactions as a key step.
2-Amino-4H-chromenes are widely employed as cosmetics,
pigments16 and potential biodegradable agrochemicals.17 They also
Recently, two multicomponent reactions for the synthesis of 2-
amino-3-cyano-4H-chromen-4-ylphosphonates have been de-
22
veloped. The methods involve InCl3 and b
-cyclodextrin23 cata-
lyzed condensation of salicylaldehyde with malononitrile and
triethyl phosphite (Scheme 3).
* Corresponding author. Tel.: þ82 53 810 2529; fax: þ82 53 810 4631; e-mail
address: yrlee@yu.ac.kr (Y.R. Lee).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.060

S.R. Kolla, Y.R. Lee / Tetrahedron 68 (2012) 226e237
227
development of organic reactions, we examine ethylenediamine
diacetate-catalyzed three-component reactions of arylaldehyde or
salicylaldehyde with malononitrile and triethyl phosphite to afford
EtO
EtO
O
O
P
P(OEt)3
or
O
catalysts
CN
CN
CN
H
R
+
+
R
a variety of
ylphosphonates. We report herein an efficient one-pot synthesis of
-phosphono malonates and 2-amino-4H-chromen-4-ylphospho-
b-phosphono malonates and 2-amino-4H-chromen-4-
HP(OEt)2
OH
O
NH2
b
Scheme 3.
nate derivatives.
Although several methods for the synthesis of
b-phosphono
malonates and 2-amino-3-cyano-4H-chromen-4-ylphosphonate
derivatives have been reported, the need remains for simpler,
cost effective, and environmentally benign methods.
2. Results and discussion
Three-component reaction of benzaldehyde (1a) with malono-
nitrile (2a) and triethyl phosphite (3a) under 20 mol % of several
Brønsted acid and base catalysts at room temperature in ethanol
was first attempted (Table 1). When no catalyst was used at room
temperature for 12 h in ethanol, no products were produced (entry
1). The use of 20 mol % of ethylenediamine, triethylamine, and N,N-
diisopropylethylamine as Brønsted base catalysts at room temper-
ature for 12 h provided 4a in 22, 61, and 40% yields, respectively
The Brønsted acids24 and bases25,26 have demonstrated their
potential to serve as active catalysts for a variety of synthetically
useful reactions in organic synthesis. Recently, we developed a new
methodology for the synthesis of biologically interesting spiroox-
indoles27 or 3,4-dihydroquinoxalin-2-amines28 by using Brønsted
acid-catalyzed multicomponent reaction. As a part of an ongoing
study into the synthetic efficacy of Brønsted acid as a catalyst for the
Table 1
Reaction of benzaldehyde (1a), malononitrile (2a), and triethyl phosphite (3a) under several catalysts
EtO
EtO
O
P
CHO
CN
catalysts
OEt
P
CN
CN
+
+
ethanol
rt
EtO
OEt
CN
2a
4a
1a
3a
Entry
1
Catalyst
Time (h)
12
Yield (%)
0
Entry
Catalyst
Time (h)
Yield (%)
-
(20 mol%)
+NH3 OCOCF3
2
12
22
9
6
40
H2N
NH2
-
(20 mol%)
(20 mol%)
3
12
61
10
6
45
N
(20 mol%)
-OAc
+NH3
HOOCH2C
CH2COOH
CH2COOH
N
N
4
5
6
12
6
40
68
65
11
12
13
6
5
4
70
72
88
N
HOOCH2C
(20 mol%)
(20 mol%)
(20 mol%)
-
+NH4 OAc
AcOH
(20 mol%)
(20 mol%)
H3N+
AcO-
+NH3
-OAc
+
AcOH
H2N
NH2
10
(10 mol%)
(20 mol%)
H3N+
AcO-
+NH3
-OAc
+
AcOH
(10 mol%)
(10 mol%)
H2N
(20 mol%)
NH2
7
8
10
12
32
65
14
12
86
H3N+
Cl-
+NH3
(20 mol%)
-Cl

228
S.R. Kolla, Y.R. Lee / Tetrahedron 68 (2012) 226e237
(entries 2e4). With acetic acid as a Brønsted acid, 4a was obtained
in 68% yield (entry 5). With 20 mol % of ethylenediamine and
10 mol % of acetic acid as co-catalysts, 4a was produced in 65% yield
(entry 6). When the ratio of co-catalysts was changed, no im-
provement of yield (32%) was observed (entry 7). With Brønsted
acids and bases as a bifunctional catalyst, the desired product was
produced. For examples, reactions under several salts such as eth-
ylenediamine dihydrochloride, o,o-diphenylmethylammonium tri-
fluoroacetic acid, and o,o-diphenylmethylammonium acetic acid
gave 4a in 65, 40, and 45% yields, respectively (entries 8e10).
Similarly, reactions in the presence of ethylenediaminetetraacetic
acid and ammonium acetate provided 4a in 70 and 72% yields,
respectively (entries 11e12). Importantly, when we used 20 mol %
of ethylenediamine diacetate as a catalyst, 4a was produced in high
yield (88%). However, with 10 mol % of ethylenediamine diacetate
as a catalyst, longer reaction time (12 h) was required. Interestingly,
we found that Brønsted acids are better catalysts than Brønsted
bases for the completion of this reaction. Importantly, the use of
salts of ammonium acetate and ethylenediamine diacetate as a bi-
functional catalyst improved the yields. The structure of compound
4a was determined by 1H NMR analysis and by comparison directly
with the reported data.13 1H NMR spectrum of 4a showed the
characteristic methine peak of the CeP bond at 3.56 as a double
doublet (JHH¼8.1 Hz and JHP¼21.0 Hz) and another methine peak
dibromosalicylaldehyde (5g), and 5-nitrosalicylaldehyde (5h)
with electron-withdrawing groups afforded products 6fe6h in 82,
80, and 75% yields, respectively (entries 5e7). With 2-hydroxy-1-
naphthaldehyde (5i), the desired product 6i was produced in 62%
yield (entry 8). When the reaction was carried out by replacing
malononitrile (2a) with ethylcyanoacetate (2b), the desired prod-
ucts 6j and 6k were produced in 75 and 65% yields (entries 9 and
10). These reactions provided rapid access to various 2-amino-4H-
chromen-4-ylphosphonate derivatives 6be6k in good yields.
The formation of 4a can be explained by the proposed mechanism
as shown in Scheme 4. Reaction of benzaldehyde (1a) and malono-
nitrile (2a) in the presence of EDDA first gives 7 through the Knoe-
venagelcondensation. Nucleophilic additionof triethyl phosphiteto 7
gives intermediate 8, which is further reacted to furnish 4a.
The formation of 6a can be also explained by the plausible
mechanism as shown in Scheme 5. Reaction of salicylaldehyde (5a)
and malononitrile (2a) in the presence of EDDA first gives 9 through
the Knoevenagel condensation. Intramolecular cyclization of hy-
droxyl group of 9 on the cyano group leads to imino coumarin 10
through the intramolecular Pinner reaction. Nucleophilic addition
of triethyl phosphite to 10 gives intermediate 11, which is further
reacted to produce 6a.
As further application of this methodology, we extended the
protocol
to
afford
several
2-amino-4H-chromen-4-
appeared at
d
4.48 as a triplet (JHH¼8.4 Hz). In the 13C NMR spec-
ylphosphonate derivatives through transesterification reactions
utilizing triphenyl phosphite or triethyl phosphite in alcohols as
shown in Table 5. Reactions of salicylaldehyde (5a) with malo-
nonitrile (2a) and triphenyl phosphite (3b) in the presence of
20 mol % of EDDA in ethanol at room temperature for 12 h gave
product 6a (41%) through transesterification (entry 1), whereas
treatment in methanol or 1-propanol afforded products 6l and
6m in 55 and 40% yields, respectively (entries 2 and 3). The
structures of 6a, 6l, and 6m were identified by analysis of the
spectroscopic data. Similarly, treatment of 5a with malononitrile
(2a) and triethyl phosphite (3b) in the presence of 20 mol % of
EDDA in methanol or 1-propanol at room temperature for 12 h
afforded products 6l and 6m in 65 and 62% yields, respectively
(entries 4 and 5).
trum, the characteristic carbon peak of the CeP bond appeared at
d
44.4 as a doublet with a coupling constant of 143.4 Hz.
In order to establish the generality of this methodology, addi-
tional reactions of various substituted arylaldehydes 1be1l with
malononitrile (2a) and triethyl phosphite (3a) were carried out in
the presence of 20 mol % of EDDA in ethanol. The results are sum-
marized in Table 2. Reactions of arylaldehydes 1be1g with
electron-donating groups on the benzene ring at room temperature
for 2e5 h produced 4be4e in 72e90% yields (entries 1e6). With
arylaldehydes 1he1j with electron-withdrawing groups on the
benzene ring, the products 4he4j were produced in 82e90% yields
(entries 7e9). With 1 and 2-naphthaldehyde, products 4k and 4l
were also produced in 50 and 73% yields, respectively (entries 10
and 11). These reactions provided a rapid route to the synthesis of
a variety of
b
-phosphono malonates in good yield.
3. Experimental
3.1. General
Next, to expand the utility of this methodology, other three-
component reactions of salicylaldehyde (5a) with malononitrile
(2a), and triethyl phosphite (3a) under 20 mol % of several
Brønsted acid and base catalysts in ethanol at room temperature
were carried out (Table 3). In this reaction, we found that Brønsted
bases are better catalysts than Brønsted acids. Importantly, when
we used 20 mol % of ethylenediamine diacetate as a salt, the de-
sired product 6a was produced in high yield (90%). The structure
of 6a was identified by 1H NMR analysis and by comparison with
the reported data.23 1H NMR spectrum of 6a showed the charac-
All experiments were carried out in an aqueous layer. Merck,
pre-coated silica gel plates (Art. 5554) with a fluorescent indicator
were used for analytical TLC. Flash column chromatography was
performed using silica gel 9385 (Merck). All 1H and 13C NMR
spectra were recorded on a Bruker Model ARX (at 300 and 75 MHz,
respectively) spectrometer in acetone, DMSO, and CDCl3 as the
solvent chemical shift. All IR spectra were recorded on a Jasco FTIR
5300 spectrophotometer. HRMS and MS data were carried out at
the Korea Basic Science Institute.
teristic peak of a methine at d 4.09e3.90 as multiplets because the
methine peak of the CeP bond merged in the two ethoxy protons.
In the 13C NMR spectrum, the characteristic carbon peak of the
CeP bond appeared at
d
34.5 as a doublet with a coupling constant
3.2. General procedure for the preparation of b-phosphono
of 144.9 Hz.
malonates and 2-amino-3-cyano-4H-chromen-4-
Additional reactions of various substituted salicylaldehydes
5ae5i with malononitrile (2a) or ethylcyanoacetate (2b), and tri-
ethyl phosphite (3a) were carried out in the presence of 20 mol % of
EDDA in ethanol. The results are summarized in Table 4. The re-
actions worked well with substituted salicylaldehydes bearing both
electron-donating and electron-withdrawing groups on the ben-
zene ring. For example, reactions of 3-methylsalicylaldehyde (5b),
5-methylsalicylaldehyde (5c), 4-methoxysalicylaldehyde (5d), and
5-methoxysalicylaldehyde (5e) with electron-donating groups
provided products 6be6e in 83, 90, 72, and 70% yields, respectively
(entries 1e4), whereas those of 5-bromosalicylaldehyde (5f), 3,5-
ylphosphonate
EDDA (0.2 mmol) was added to a solution of arylaldehyde
(1.0 mmol) or salicylaldehyde (1.0 mmol) with malononitrile
(1.0 mmol) and triethyl phosphite (1.0 mmol) in 5 mL of ethanol.
The resulting mixture was stirred at room temperature until
completion of the reaction, as indicated by TLC (ethyl acetate/n-
hexane). The reaction mixture was evaporated under reduced
pressure and the crude product was purified by silica gel column
chromatography using EtOAc/n-hexane as the eluent to give the
desired products.

S.R. Kolla, Y.R. Lee / Tetrahedron 68 (2012) 226e237
229
Table 2
Additional reactions of arylaldehydes, malononitrile, and triethyl phosphite in 20 mol % of EDDA
Entry
Arylaldehyde
Malononitrile
Triethyl phosphite
Time (h)
Product
Yield (%)
EtO
EtO
O
P
O
1
4
85
75
90
72
88
75
CN
CN
H
1b
4b
CN
EtO
EtO
O
O
P
2
3
4
5
6
5
4
3
2
3
H
1c
4c
CN
EtO
EtO
O
O
P
MeO
MeO
MeO
MeO
CN
CN
H
1d
4d
CN
EtO
EtO
O
O
P
4e
H
1e
CN
EtO
EtO
O
O
P
CN
H
1f
4f
CN
OEt
P
CN
EtO
OEt
CN
2a
EtO
EtO
O
O
P
3a
MeO
MeO
CN
H
4g
1g
OMe
CN
OMe
EtO
EtO
O
O
P
CN
7
8
2
3
82
86
H
1h
4h
CN
F
F
EtO
EtO
O
O
P
CN
CN
H
1i
4i
Cl
Cl
EtO
EtO
O
O
P
P
CN
4j
9
2
90
H
CN
1j
Br
Br
EtO
EtO
O
O
4k
10
11
3
3
50
73
CN
CN
H
1K
EtO
EtO
O
O
P
CN
CN
H
4l
1l

230
S.R. Kolla, Y.R. Lee / Tetrahedron 68 (2012) 226e237
Table 3
Reaction of salicylaldehyde (5a), malononitrile (2a), and triethyl phosphite (3a) under several catalysts
EtO
EtO
O
P
CN
CHO
OH
CN
catalysts
OEt
P
+
+
ethanol
rt
EtO
OEt
CN
2a
O
6a
NH2
3a
5a
Entry
1
Catalyt (20 mol %)
Time
Yield (%)
0
Entry
7
Catalyt (20 mol %)
Time
12
Yield (%)
50
d
12
2
3
4
AcOH
12
16
60
75
-OAc
+NH3
HOOCH2C
HOOCH2C
CH2COOH
8
8
8
9
12
4
55
71
N
N
H2N
NH2
CH2COOH
+NH4 OAc
-
N
N
H3N+
Cl-
+NH3
-Cl
5
8
70
17
10
11
3
2
75
90
H3N+
AcO-
+NH3
-OAc
6
12
-
+NH3 OCOCF3
Table 4
Additional reactions of salicylaldehydes, malononitrile or ethylcyanoacetate, and triethyl phosphite in 20 mol % EDDA
Entry
Salicyladehyde
Malononitrile or ethylcyanoacetate
Triethyl phosphite
Time (h)
Product
Yield (%)
EtO
EtO
O
P
CHO
OH
CN
NH2
1
2
83
6b
5b
O
EtO
EtO
O
CHO
OH
P
CN
2
3
3
3
90
72
6c
5c
O
NH2
O
EtO
EtO
CHO
OH
P
CN
H3CO
H3CO
6d
5d
H3CO
H3CO
O
P
NH2
CN
OEt
P
EtO
EtO
O
CHO
OH
EtO
OEt
CN
2a
CN
3a
4
3
70
6e
5e
O
NH2

S.R. Kolla, Y.R. Lee / Tetrahedron 68 (2012) 226e237
231
Table 4 (continued )
Entry
Salicyladehyde
Malononitrile or ethylcyanoacetate
Triethyl phosphite
Time (h)
Product
Yield (%)
EtO
EtO
O
P
Br
Br
CHO
OH
Br
Br
CN
5
3
3
3
4
82
80
75
62
6f
5f
O
P
NH2
EtO
EtO
O
CHO
OH
CN
6
7
8
6g
O
NH2
Br
5g
Br
EtO
EtO
O
O2N
CHO
P
O2N
CN
6h
NH2
OH
5h
O
EtO
EtO
O
P
CHO
CN
6i
OH
5i
O
NH2
EtO
EtO
O
CO2Et
CHO
OH
P
CO2Et
6j
9
3
2
75
65
CN
5a
O
NH2
2b
EtO
EtO
O
CHO
OH
P
CO2Et
10
6k
NH2
5c
O
CN
CN
EtO
OEt
OEt
EtO
O
O
P
OEt
H
P
EtO
EtO
2
:
P
CN
CN
CN
EtO
OEt
H
CN
EDDA
Knoevenagel
C
N-
CN
-Et2O
4a
7
8
1a
Scheme 4.
CN
2
EtO
EtO
OEt
OEt
H
OEt
O
P
Pinner
Reaction
:
P
CN
NH
CN
CN
CN
EtO
OEt
H
C
N
EDDA
-Et2O
NH-
O
OH
OH
O
Knoevenagel
5a
9
10
11
EtO
EtO
O
P
CN
NH2
O
6a
Scheme 5.

232
S.R. Kolla, Y.R. Lee / Tetrahedron 68 (2012) 226e237
Table 5
EDDA catalyzed additional reactions of salicylaldehyde (5a), malononitrile (2a), and triphenyl phosphite (3b) in several alcohols
R1O
P
O
R1O
CHO
OH
CN
EDDA
OR
P
CN
(20 mol%)
+
+
R1OH
RO
OR
CN
2a
O
NH2
5a
3b
R1=Me, Et, Pr
R=Et, Ph
Entry
P(OR)3
Solvent
Time (h)
Product
Yield (%)
EtO
EtO
O
O
P
CN
1
R¼Ph
EtOH
12
12
12
12
41
6a
O
P
NH2
MeO
MeO
CN
2
3
4
R¼Ph
R¼Ph
R¼Et
MeOH
1-PrOH
MeOH
55
40
65
6l
O
NH2
PrO
PrO
O
P
CN
6m
O
NH2
MeO
MeO
O
P
CN
6l
O
NH2
PrO
PrO
O
P
CN
5
R¼Et
1-PrOH
12
62
6m
O
NH2
3.3. General procedure for the preparation of 2-amino-3-
cyano-4H-chromen-4-ylphosphonate by transesterification
pressure and crude product was purified by column chromatogra-
phy on silica gel using hexane/ethylacetate (3:2) gave product 4a
(258 mg, 88%) as a solid: mp 56e58 ꢀC; 1H NMR (300 MHz, CDCl3)
3
EDDA (0.2 mmol) was added to a solution of (1 mmol) with
malononitrile (1 mmol) and triphenyl phosphite (1 mmol) in 5 mL
of alcohol. The resulting mixture was stirred at room temperature
until completion of the reaction, as indicated by TLC (ethyl acetate/
n-hexane). The reaction mixture was evaporated under reduced
pressure and the crude product was purified by silica gel column
chromatography using EtOAc/n-hexane as the eluent to give the
desired products.
d
7.42 (br s, 5H), 4.48 (t, 1H, JHH¼8.4 Hz), 4.18e4.12 (m, 2H),
4.02e3.92 (m,1H), 3.78e3.67 (m, 1H), 3.56 (dd,1H, 3JHH¼8.1 Hz and
2JHP¼21.0 Hz), 1.33 (t, 3H, 3JHH¼7.2 Hz), 1.10 (t, 3H, 3JHH¼6.9 Hz); 13
C
3
NMR (75 MHz)
d
130.4, 129.5, 129.4, 129.3, 111.5 (d, JCP¼9.9 Hz),
3
2
2
111.4 (d, JCP¼12.6 Hz), 64.3 (d, JCP¼6.6 Hz), 63.3 (d, JCP¼7.1 Hz),
1
3
44.4 (d, JCP¼143.4 Hz), 25.5, 16.2 (d, JCP¼5.5 Hz), 16.0 (d,
3JCP¼5.5 Hz); IR (KBr) 2988, 2870, 2614, 2487, 2378, 2257, 1456,
1388, 1237, 1036 cmꢁ1; MS (m/z, EI) 292 (Mþ, 12), 155 (17), 154 (22),
138 (27), 129 (100), 111 (15), 109 (18), 91 (10).
3.4. Diethyl 2,2-dicyano-1-phenylethylphosphonate (4a)13
3.5. Diethyl 2,2-dicyano-1-m-tolylethylphosphonate (4b)7c
A mixture of benzaldehyde (1a) (106 mg, 1.0 mmol), malono-
nitrile (2a) (66 mg, 1.0 mmol), and triethyl phosphite (3a) (166 mg,
1.0 mmol) in ethanol (5 mL) in the presence of 20 mol % of EDDA
(36 mg) was stirred at room temperature for 4 h. After completion
of the reaction, the mixture was evaporated under reduced
A mixture of m-tolualdehyde (1b) (120 mg, 1.0 mmol), malo-
nonitrile 2a (66 mg, 1.0 mmol) and triethyl phosphite (3a) (166 mg,
1.0 mmol) in ethanol (5 mL) in the presence of 20 mol % of EDDA
(36 mg) was stirred at room temperature for 4 h. After completion

S.R. Kolla, Y.R. Lee / Tetrahedron 68 (2012) 226e237
233
of the reaction, the mixture was evaporated under reduced pres-
sure and crude product was purified by column chromatography on
silica gel using hexane/ethylacetate (3:2) gave product 4b (261 mg,
of the reaction the mixture was evaporated under reduced pressure
and crude product was purified by column chromatography on
silica gel using hexane/ethylacetate (1:1) gave product 4e (232 mg,
85%) as
a
solid: mp 56e57 ꢀC; 1H NMR (300 MHz, CDCl3)
72%) as
a
solid: mp 57e58 ꢀC; 1H NMR (300 MHz, CDCl3)
3
3
d
7.13e6.99 (m, 4H), 4.27 (t, 1H, JHH¼8.7 Hz), 3.99e3.87 (m, 2H),
d
7.39e7.37 (m, 2H), 6.93 (d, 2H, JHH¼8.7 Hz), 4.43 (dd, 1H,
3.85e3.72 (m,1H), 3.60e3.46 (m,1H), 3.32 (dd,1H, 3JHH¼8.4 Hz and
3JHH¼8.1 Hz and JHP¼8.7 Hz), 4.20e4.09 (m, 2H), 4.03e3.93 (m,
3
2JHP¼21.0 Hz), 2.17 (s, 3H), 1.14 (t, 3H, JHH¼7.2 Hz), 0.90 (t, 3H,
1H), 3.80 (s, 3H), 3.75e3.70 (m, 1H), 3.51 (dd, 1H, JHH¼7.8 Hz and
3
3
3JHH¼6.9 Hz); 13C NMR (75 MHz)
d
139.2, 130.3, 130.0, 129.9, 129.2,
2JHP¼21.3 Hz), 1.33 (t, 3H, 3JHH¼7.2 Hz), 1.13 (t, 3H, 3JHH¼6.9 Hz); 13
C
3
3
126.2, 111.6 (d, JCP¼7.7 Hz), 111.5 (d, JCP¼13.1 Hz), 64.3 (d,
NMR (75 MHz)
d
160.2,130.5 (d, 3JCP¼6.0 Hz),122.0 (d, 3JCP¼5.4 Hz),
2JCP¼7.1 Hz), 63.4 (d, 2JCP¼7.1 Hz), 44.5 (d, 1JCP¼142.8 Hz), 25.5, 21.4,
114.6, 111.6 (d, JCP¼11.0 Hz), 111.5 (d, JCP¼12.6 Hz), 64.1 (d,
3
3
3
3
16.2 (d, JCP¼5.5 Hz), 16.1 (d, JCP¼5.5 Hz); IR (KBr) 2979, 2906,
2609, 2480, 2257, 1605, 1466, 1387, 1241, 1026 cmꢁ1; MS (m/z, EI)
306 (Mþ, 35), 169 (22), 168 (34), 143 (100), 140 (17), 138 (64), 115
(16), 111 (37), 109 (21), 105 (23), 81 (12).
2JCP¼7.1 Hz), 63.1 (d, 2JCP¼7.7 Hz), 55.1, 43.4 (d, 1JCP¼143.9 Hz), 25.6,
3
16.0 (t, JCP¼6.0 Hz); IR (KBr) 2987, 2857, 2607, 2507, 2374, 2256,
1611, 1512, 1248, 1026 cmꢁ1; MS (m/z, EI) 322 (Mþ, 28), 258 (13),
257 (100), 185 (27), 159 (20), 121 (97), 111 (8).
3.6. Diethyl 2,2-dicyano-1-p-tolylethylphosphonate (4c)7c,12
3.9. Diethyl 2,2-dicyano-1-(2,5-dimethylphenyl)
ethylphosphonate (4f)
A mixture of p-tolualdehyde (1c) (120 mg, 1.0 mmol), malononi-
trile (2a) (66 mg, 1.0 mmol) and triethyl phosphite (3a) (166 mg,
1.0 mmol) in ethanol (5 mL) in the presence of 20 mol % of EDDA
(36 mg) was stirred at room temperature for 5 h. After completion of
the reaction the mixture was evaporated under reduced pressure and
crude product was purified by column chromatography on silica gel
using hexane/ethylacetate (7:3) gave product 4c (230 mg, 75%) as
A
mixture of 2,5-dimethlybenzaldehyde (1f) (134 mg,
1.0 mmol), malononitrile (2a) (66 mg, 1.0 mmol), and triethyl
phosphite (3a) (166 mg, 1.0 mmol) in ethanol (5 mL) in the pres-
ence of 20 mol % of EDDA (36 mg) was stirred at room temperature
for 2 h. After completion of the reaction the mixture was evapo-
rated under reduced pressure and crude product was purified by
column chromatography on silica gel using hexane/ethylacetate
(3:2) gave product 4f (282 mg, 88%) as a solid: mp: 73e75 ꢀC; 1H
a solid: mp 88e90 ꢀC; 1H NMR (300 MHz, CDCl3)
d 7.27 (d, 2H,
3
J¼6.6 Hz), 7.15 (d, 2H, J¼6.6 Hz), 4.40 (dd, 1H, JHH¼8.1 Hz and
3JHP¼9.0 Hz), 4.16e4.06 (m, 2H), 3.97e3.90 (m, 1H), 3.73e3.68 (m,
1H), 3.46 (dd, 1H, 3JHH¼8.1 Hz and 2JHP¼21.3 Hz), 2.29 (s, 3H), 1.27 (t,
NMR (300 MHz, CDCl3)
d
7.30 (s, 1H), 7.11 (d, 1H, 3JHH¼7.8 Hz), 7.04
3
3
(d, 1H, JHH¼7.8 Hz), 4.48 (t, 1H, JHH¼9.3 Hz), 4.21e4.02 (m, 2H),
3.95e3.81 (m, 2H), 3.61e3.48 (m, 1H), 2.33 (s, 3H), 2.30 (s, 3H), 1.34
3H, 3JHH¼6.9 Hz),1.06 (t, 3H, 3JHH¼7.2 Hz); 13C NMR (75 MHz)
d 139.2,
3
3
3
3
130.1, 129.2 (d, JCP¼6.0 Hz), 127.2 (d, JCP¼6.0 Hz), 111.6 (d,
(t, 3H, JHH¼7.2 Hz), 1.00 (t, 3H, JHH¼6.9 Hz); 13C NMR (75 MHz,
3
2
3
3JCP¼11.0 Hz), 111.4 (d, JCP¼12.6 Hz), 64.3 (d, JCP¼7.1 Hz), 63.3 (d,
2JCP¼7.2 Hz), 44.2 (d, 1JCP¼143.4 Hz), 25.6, 21.2, 16.2 (d, 3JCP¼6.0 Hz),
16.1 (d, 3JCP¼6.1 Hz);IR(KBr)2989,2858, 2608, 2507, 2375, 2255,1515,
1450, 1387, 1238, 1024 cmꢁ1; MS (m/z, EI) 306 (Mþ, 31), 241 (21), 169
(18), 143 (100), 138 (37), 115 (13), 111 (17), 109 (15), 105 (44), 81 (10).
CDCl3)
d
136.8, 134.4 (d, JCP¼7.7 Hz), 131.4, 130.2, 128.8 (d,
3JCP¼6.0 Hz),128.1,111.6 (d, 3JCP¼6.6 Hz),111.4, 64.5 (d, 2JCP¼7.2 Hz),
63.3 (d, 2JCP¼7.1 Hz), 39.7 (d, 1JCP¼143.9 Hz), 25.3, 21.2, 19.6, 16.3 (d,
3JCP¼6.0 Hz), 16.1 (d, 3JCP¼5.4 Hz); IR (KBr) 2981, 2871, 2609, 2359,
2258, 1690, 1455, 1242, 1041 cmꢁ1; HRMS m/z (Mþ) calcd for
C16H21N2O3P: 320.1290; found: 320.1288.
3.7. Diethyl 2,2-dicyano-1-(3-methoxyphenyl)
ethylphosphonate (4d)12
3.10. Diethyl 2,2-dicyano-1-(2,5-dimethoxyphenyl)
ethylphosphonate (4g)
A mixture of m-anisaldehyde (1d) (136 mg, 1.0 mmol), malo-
nonitrile (2a) (66 mg, 1.0 mmol), and triethyl phosphite (3a)
(166 mg, 1.0 mmol) in ethanol (5 mL) in the presence of 20 mol % of
EDDA (36 mg) was stirred at room temperature for 4 h. After
completion of the reaction the mixture was evaporated under re-
duced pressure and crude product was purified by column chro-
matography on silica gel using hexane/ethylacetate (3:2) gave
product 4d (290 mg, 90%) as an oil: 1H NMR (300 MHz, CDCl3)
A
mixture of 2,5-dimethoxybenzaldehyde (1g) (166 mg,
1.0 mmol), malononitrile (2a) (66 mg, 1.0 mmol), and triethyl
phosphite (3a) (166 mg, 1.0 mmol) in ethanol (5 mL) in the pres-
ence of 20 mol % of EDDA (36 mg) was stirred at room temperature
for 3 h. After completion of the reaction, the mixture was evapo-
rated under reduced pressure and crude product was purified by
column chromatography on silica gel using hexane/ethylacetate
3
3
d
7.24 (t, 1H, JHH¼7.8 Hz), 6.98 (s, 2H), 6.85 (d, 1H, JHH¼8.1 Hz),
(3:2) gave product 4g (265 mg, 75%) as an oil: 1H NMR (300 MHz,
CDCl3)
3
3
4.67 (t, 1H, JHH¼8.7 Hz), 4.10e4.05 (m, 2H), 3.99e3.90 (m, 1H),
d
7.10 (s, 1H), 6.82 (br s, 2H), 4.55 (t, 1H, JHH¼9.0 Hz), 4.26
3.77e3.71 (m, 4H), 3.58 (dd, 1H, 3JHH¼7.8 Hz and 2JHP¼21.3 Hz),1.25
(dd, 1H, JHH¼8.1 Hz and JHP¼21.0 Hz), 4.16e3.92 (m, 4H), 3.76 (s,
3
2
(t, 3H, JHH¼6.6 Hz), 1.05 (t, 3H, JHH¼6.9 Hz); 13C NMR (75 MHz)
3H), 3.70 (s, 3H), 1.27 (t, 3H, 3JHH¼6.9 Hz), 1.09 (t, 3H, 3JHH¼6.9 Hz);
3
3
3
3
3
d
159.9, 131.7 (d, JCP¼6.0 Hz), 130.2, 121.4 (d, JCP¼6.0 Hz), 114.9,
13C NMR (75 MHz)
d
153.7, 151.5 (d, JCP¼7.1 Hz), 119.6 (d,
3
3
3
114.8, 111.6 (d, JCP¼4.9 Hz), 111.5 (d, JCP¼7.2 Hz), 64.2 (d,
3JCP¼5.4 Hz), 115.6, 115.2 (d, JCP¼4.4 Hz), 112.6, 111.7 (d,
2JCP¼6.6 Hz), 63.2 (d, JCP¼7.1 Hz), 55.2, 44.0 (d, JCP¼142.8 Hz),
3JCP¼6.6 Hz), 111.5 (d, JCP¼11.0 Hz), 64.0 (d, JCP¼6.6 Hz), 63.2 (d,
2
1
3
2
3
3
1
25.3, 16.0 (d, JCP¼6.0 Hz), 15.9 (d, JCP¼6.0 Hz); IR (neat) 2980,
2920, 2597, 2257, 1597, 1471, 1249, 1164, 1031 cmꢁ1; MS (m/z, EI)
322 (Mþ, 80), 229 (25), 185 (36), 159 (96), 138 (100), 121 (45), 111
(61), 110 (21), 109 (28), 81 (21).
2JCP¼7.1 Hz), 56.4, 55.7, 36.6 (d, JCP¼145.5 Hz), 24.9, 16.2 (d,
3JCP¼6.0 Hz), 16.1 (d, 3JCP¼6.0 Hz); IR (neat) 2977, 2257, 1616, 1496,
1240, 1034 cmꢁ1; HRMS m/z (Mþ) calcd for C16H21N2O5P: 352.1188;
found: 352.1188.
3.8. Diethyl 2,2-dicyano-1-(4-methoxyphenyl)
ethylphosphonate (4e)7c,12
3.11. Diethyl 2,2-dicyano-1-(4-fluorophenyl)
ethylphosphonate (4h)
A mixture of p-anisaldehyde (1e) (136 mg, 1.0 mmol), malono-
nitrile (2a) (66 mg, 1.0 mmol), and triethyl phosphite (3a) (166 mg,
1.0 mmol) in ethanol (5 mL) in the presence of 20 mol % of EDDA
(36 mg) was stirred at room temperature for 3 h. After completion
A mixture of 4-fluorobenzaldehyde (1h) (124 mg, 1.0 mmol),
malononitrile (2a) (66 mg, 1.0 mmol), and triethyl phosphite (3a)
(166 mg, 1.0 mmol) in ethanol (5 mL) in the presence of 20 mol % of
EDDA (36 mg) was stirred at room temperature for 2 h. After

234
S.R. Kolla, Y.R. Lee / Tetrahedron 68 (2012) 226e237
completion of the reaction, the mixture was evaporated under re-
duced pressure and crude product was purified by column chro-
matography on silica gel using hexane/ethylacetate (3:2) gave
completion of the reaction, the mixture was evaporated under re-
duced pressure and crude product was purified by column chro-
matography on silica gel using hexane/ethylacetate (7:3) gave
product 4h (255 mg, 82%) as a solid: mp 80e82 ꢀC; 1H NMR
product 4k (172 mg, 50%) as a solid: mp 104e106 ꢀC; 1H NMR
3
3
(300 MHz, CDCl3)
d
7.47e7.43 (m, 2H), 7.07 (t, 2H, JHH¼8.4 Hz),
(300 MHz, CDCl3)
d
8.00 (d, 1H, JHH¼7.8 Hz), 7.90 (d, 2H,
3
3
4.57 (dd, 1H, JHH¼7.8 Hz and JHP¼8.7 Hz), 4.17e4.04 (m, 2H),
3JHH¼7.8 Hz), 7.82e7.80 (m, 1H), 7.65e7.50 (m, 3H), 4.69e4.55 (m,
2H), 4.23e4.16 (m, 2H), 3.85e3.74 (m, 1H), 3.45e3.34 (m, 1H), 1.35
4.02e3.91 (m, 1H), 3.85e3.72 (m, 1H), 3.58 (dd,1H, 3JHH¼7.2 Hz and
2JHP¼21.3 Hz), 1.28 (t, 3H, 3JHH¼7.2 Hz), 1.10 (t, 3H, 3JHH¼6.9 Hz); 13
C
(t, 3H, JHH¼7.2 Hz), 0.81 (t, 3H, JHH¼6.9 Hz); 13C NMR (75 MHz)
3
3
NMR (75 MHz, CDCl3)
d
131.4, 131.3, 126.4, 126.3, 116.7, 116.4, 111.5
d 134.2, 131.7, 130.2, 129.5, 127.6, 127.5, 126.6, 126.5, 125.3, 122.1,
3
3
2
3
3
2
(d, JCP¼10.9 Hz), 111.3 (d, JCP¼11.5 Hz), 64.4 (d, JCP¼7.1 Hz), 63.5
111.7 (d, JCP¼7.2 Hz), 111.6 (d, JCP¼15.3 Hz), 64.5 (d, JCP¼7.1 Hz),
2 1
2
3
(d, JCP¼7.7 Hz), 43.7 (d, 1JCP¼144.0 Hz), 25.7, 16.3 (d, JCP¼6.6 Hz),
63.5 (d, JCP¼7.6 Hz), 38.2 (d, JCP¼142.8 Hz), 25.6, 16.3 (d,
3JCP¼6.6 Hz), 15.9 (d, 3JCP¼5.4 Hz); IR (KBr) 2985, 2857, 2612, 2366,
2260,1390, 1243,1025 mꢁ1; HRMS m/z (Mþ) calcd for C18H19N2O3P:
342.1133; found: 342.1134.
3
16.2 (d, JCP¼6.0 Hz); IR (KBr) 2993, 2922, 2261, 1606, 1512, 1387,
1244, 1029 cmꢁ1
;
HRMS m/z (Mþ) calcd for C14H16FN2O3P:
310.0883; found: 310.0884.
3.12. Diethyl 1-(4-chlorophenyl)-2,2-
dicyanoethylphosphonate (4i)12,13
3.15. Diethyl 2,2-dicyano-1-(naphthalen-2-yl)
ethylphosphonate (4l)12,13
A mixture of 4-chlorobenzaldehyde (1i) (140 mg, 1.0 mmol),
malononitrile (2a) (66 mg, 1.0 mmol), and triethyl phosphite (3a)
(166 mg, 1.0 mmol) in ethanol (5 mL) in the presence of 20 mol % of
EDDA (36 mg) was stirred at room temperature for 3 h. After
completion of the reaction, the mixture was evaporated under re-
duced pressure and crude product was purified by column chro-
matography on silica gel using hexane/ethylacetate (3:2) gave
A mixture of 2-napthaldehyde (1l) (156 mg, 1.0 mmol), malo-
nonitrile (2a) (66 mg, 1.0 mmol), and triethyl phosphite (3a)
(166 mg, 1.0 mmol) in ethanol (5 mL) in the presence of 20 mol % of
EDDA (36 mg) was stirred at room temperature for 3 h. After
completion of the reaction the mixture was evaporated under re-
duced pressure and crude product was purified by column chro-
matography on silica gel using hexane/ethylacetate (3:2) gave
product 4l (250 mg, 73%) as a solid: mp 88e90 ꢀC; 1H NMR
product 4i (281 mg, 86%) as a solid: mp 94e96 ꢀC; 1H NMR
3
(300 MHz, CDCl3)
d
7.41 (br s, 4H), 4.45 (t, 1H, JHH¼8.4 Hz),
(300 MHz, CDCl3) d 7.88 (s, 1H), 7.80e7.74 (m, 3H), 7.49e7.40 (m,
4.19e4.11 (m, 2H), 4.07e3.97 (m, 1H), 3.90e3.77 (m, 1H), 3.53 (dd,
3H), 4.68 (t,1H, 3JHH¼8.4 Hz), 4.07e4.05 (m, 2H), 3.95e3.82 (m,1H),
1H, 3JHH¼7.5 Hz and 2JHP¼21.3 Hz), 1.33 (t, 3H, 3JHH¼6.9 Hz), 1.16 (t,
3.79e3.76 (m,1H), 3.67 (dd,1H, 3JHH¼8.1 Hz and 2JHP¼19.2 Hz), 1.23
3
3
3
3H, JHH¼7.2 Hz); 13C NMR (75 MHz)
d
135.7, 130.8, 129.6, 129.0,
(t, 3H, JHH¼6.6 Hz), 0.96 (t, 3H, JHH¼6.9 Hz); 13C NMR (75 MHz)
111.4 (d, 3JCP¼10.9 Hz), 111.2 (d, 3JCP¼13.2 Hz), 64.4 (d, 2JCP¼7.1 Hz),
d 133.3, 133.2, 129.3, 129.1, 128.1, 127.8, 127.7, 127.1, 126.8, 126.0 (d,
2
1
3
3
63.6 (d, JCP¼7.1 Hz), 43.8 (d, JCP¼143.4 Hz), 25.5, 16.3 (d,
3JCP¼6.6 Hz), 16.2 (d, 3JCP¼5.5 Hz); IR (KBr) 2993, 2854, 2612, 2257,
1931, 1587, 1493, 1239, 1021 cmꢁ1; MS (m/z, EI) 326 (Mþ, 16), 189
(14), 165 (31), 163 (100), 138 (19), 125 (18), 109 (27), 81 (12).
3JCP¼4.9 Hz), 111.6 (d, JCP¼7.6 Hz), 111.5 (d, JCP¼12.0 Hz), 64.3 (d,
2JCP¼6.6 Hz), 63.4 (d, 2JCP¼7.2 Hz), 44.5 (d, 1JCP¼142.8 Hz), 25.6, 16.2
3
3
(d, JCP¼5.4 Hz), 16.0 (d, JCP¼5.4 Hz); IR (KBr) 3056, 2984, 2864,
2612, 2494, 2255, 1711, 1605, 1386, 1237, 1015 cmꢁ1; MS (m/z, EI)
342 (Mþ, 89), 291 (65), 277 (60), 205 (45), 204 (44), 179 (78), 172
(21), 141 (100), 138 (52), 127 (36), 111 (27), 109 (14), 81 (13).
3.13. Diethyl 1-(4-bromophenyl)-2,2-
dicyanoethylphosphonate (4j)12
3.16. Diethyl 2-amino-3-cyano-4H-chromen-4-ylphosphonate
A mixture of 4-bromobenzaldehyde (1j) (185 mg, 1.0 mmol),
malononitrile (2a) (66 mg, 1.0 mmol), and triethyl phosphite (3a)
(166 mg, 1.0 mmol) in ethanol (5 mL) in the presence of 20 mol % of
EDDA (36 mg) was stirred at room temperature for 2 h. After
completion of the reaction, the mixture was evaporated under re-
duced pressure and crude product was purified by column chro-
matography on silica gel using hexane/ethylacetate (3:2) gave
(6a)22,23
A mixture of salicylaldehyde (5a) (122 mg, 1.0 mmol), malono-
nitrile (2a) (66 mg, 1.0 mmol), and triethyl phosphite (3a) (166 mg,
1.0 mmol) in ethanol (5 mL) in the presence of 20 mol % of EDDA
(36 mg) was stirred at room temperature for 2 h. After completion
of the reaction, the mixture was evaporated under reduced pres-
sure and crude product was purified by column chromatography on
silica gel using hexane/ethylacetate (2:3) gave product 6a (277 mg,
90%) as a solid: mp 143e145 ꢀC; 1H NMR (300 MHz, acetone-d6)
product 4j (334 mg, 90%) as a solid: mp 96e98 ꢀC; 1H NMR
3
(300 MHz, CDCl3)
d
7.56 (d, 2H, JHH¼8.4 Hz), 7.35 (d, 2H,
3JHH¼8.4 Hz), 4.45 (dd, 1H, 3JHH¼7.8 Hz and 3JHP¼8.7 Hz), 4.19e4.11
(m, 2H), 4.07e3.97 (m, 1H), 3.88e3.77 (m, 1H), 3.52 (dd, 1H,
d
7.39e7.35 (1H, m), 7.33e7.27 (1H, m), 7.19e7.13 (1H, m), 7.00 (1H,
3JHH¼7.5 Hz and 2JHP¼21.3 Hz), 1.33 (t, 3H, 3JHH¼6.9 Hz), 1.16 (t, 3H,
d, J¼8.1 Hz), 6.36 (2H, br s), 4.09e3.90 (5H, m), 1.27 (3H, t,
3JHH¼7.2 Hz); 13C NMR (75 MHz)
d
132.6, 131.0 (d, JCP¼6.0 Hz),
J¼6.9 Hz), 1.17 (3H, t, J¼6.9 Hz); 13C NMR (75 MHz, DMSO-d6)
3
3
3
129.5 (d, JCP¼6.0 Hz), 124.0, 111.4 (d, JCP¼10.5 Hz), 111.2 (d,
d 162.6, 149.9, 129.5, 128.7, 124.2, 120.1, 117.7, 115.9, 62.3 (d,
3JCP¼11.5 Hz), 64.5 (d, JCP¼7.1 Hz), 63.6 (d, JCP¼6.6 Hz), 44.0 (d,
2JCP¼7.2 Hz), 62.1 (d, JCP¼7.1 Hz), 47.4 (d, JCP¼7.6 Hz), 34.5 (d,
1JCP¼144.9), 16.2, 16.1; IR (KBr) 3343, 3167, 2985, 2190, 1656, 1418,
1236, 1034, 967, 766 cmꢁ1; MS (m/z, EI) 308 (Mþ, 4), 172 (12), 171
(100), 143 (3), 116 (3), 89 (2).
2
2
2
2
3
3
1JCP¼143.4 Hz), 25.4, 16.3 (d, JCP¼6.1 Hz), 16.2 (d, JCP¼5.5 Hz); IR
(KBr) 2991, 2853, 2613, 2377, 2256,1492,1238,1020 cmꢁ1; MS (m/z,
EI) 371 (Mþ, 5), 305 (15), 209 (96), 207 (100), 169 (20), 154 (22), 138
(42), 109 (43), 81 (18).
3.17. Diethyl 2-amino-3-cyano-8-methyl-4H-chromen-4-
3.14. Diethyl 2,2-dicyano-1-(naphthalen-1-yl)
ethylphosphonate (4k)
ylphosphonate (6b)
A mixture of 3-methylsalicylaldehyde (5b) (136 mg, 1.0 mmol),
malononitrile (2a) (66 mg, 1.0 mmol), and triethyl phosphite (3a)
(166 mg, 1.0 mmol) in ethanol (5 mL) in the presence of 20 mol % of
EDDA (36 mg) was stirred at room temperature for 2 h. After
completion of the reaction, the mixture was evaporated under
A mixture of 1-napthaldehyde (1k) (156 mg, 1.0 mmol), malo-
nonitrile (2a) (66 mg, 1.0 mmol), and triethyl phosphite (3a)
(166 mg, 1.0 mmol) in ethanol (5 mL) in the presence of 20 mol % of
EDDA (36 mg) was stirred at room temperature for 3 h. After

S.R. Kolla, Y.R. Lee / Tetrahedron 68 (2012) 226e237
235
reduced pressure and crude product was purified by column
chromatography on silica gel using hexane/ethylacetate (1:1) gave
product 6b (267 mg, 83%) as a solid: mp 160e162 ꢀC; 1H NMR
2JPH¼18.0 Hz), 3.78 (3H, s), 1.28 (3H, t, J¼6.9 Hz), 1.19 (3H, t,
J¼6.9 Hz); 13C NMR (75 MHz, DMSO-d6)
d 163.0, 155.5, 144.0, 120.4,
2
2
118.7, 118.6, 116.8, 114.2, 62.5 (d, JCP¼7.1 Hz), 62.3 (d, JCP¼7.1 Hz),
2
1
(300 MHz, acetone-d6)
d
7.18e7.13 (2H, m), 7.06e7.01 (1H, m), 6.40
55.5, 47.0 (d, JCP¼7.6 Hz), 34.9 (d, JCP¼144.5 Hz), 16.3, 16.2; IR
(KBr) 3420, 3151, 2983, 2187, 1647, 1509, 1408, 1221, 1036,
963 cmꢁ1; HRMS m/z (Mþ) calcd for C15H19N2O5P: 338.1032; found:
338.1035.
2
(2H, br s), 4.05e3.94 (4H, m), 3.90 (1H, d, JPH¼15.3 Hz), 2.25 (3H,
s), 1.26 (3H, t, J¼6.9 Hz), 1.17 (3H, t, J¼6.9 Hz); 13C NMR (75 MHz,
DMSO-d6) d 162.8, 148.3, 129.9, 126.9, 124.9, 123.6, 120.1, 117.5, 62.3
2
2
2
(d, JCP¼7.1 Hz), 62.1 (d, JCP¼7.1 Hz), 47.5 (d, JCP¼7.1 Hz), 34.8 (d,
1JCP¼144.5 Hz), 16.2, 16.1, 15.0; IR (KBr) 3348, 3183, 2985, 2189,
1651, 1597, 1412, 1223, 1038, 968 cmꢁ1; HRMS m/z (Mþ) calcd for
C15H19N2O4P: 322.1082; found: 322.1085.
3.21. Diethyl 2-amino-6-bromo-3-cyano-4H-chromen-4-
ylphosphonate (6f)22
A mixture of 5-bromo salicylaldehyde (5f) (201 mg, 1.0 mmol),
malononitrile (2a) (66 mg, 1.0 mmol), and triethyl phosphite 3a
(166 mg, 1.0 mmol) in ethanol (5 mL) in the presence of 20 mol % of
EDDA (36 mg) was stirred at room temperature for 3 h. After
completion of the reaction, the mixture was evaporated under re-
duced pressure and crude product was purified by column chro-
matography on silica gel using hexane/ethylacetate (2:3) gave
product 6f (318 mg, 82%) as a solid: mp 178e180 ꢀC; 1H NMR
3.18. Diethyl 2-amino-3-cyano-6-methyl-4H-chromen-4-
ylphosphonate (6c)22
A mixture of 5-methylsalicylaldehyde (5c) (136 mg, 1.0 mmol),
malononitrile (2a) (66 mg, 1.0 mmol), and triethyl phosphite (3a)
(166 mg, 1.0 mmol) in ethanol (5 mL) in the presence of 20 mol % of
EDDA (36 mg) was stirred at room temperature for 3 h. After
completion of the reaction, the mixture was evaporated under re-
duced pressure and crude product was purified by column chro-
matography on silica gel using hexane/ethylacetate (2:3) gave
product 6c (290 mg, 90%) as a solid: mp 180e182 ꢀC; 1H NMR
(300 MHz, acetone-d6)
d
7.53 (1H, s), 7.46 (1H, d, J¼8.7 Hz), 6.99
(1H, d, J¼8.7 Hz), 6.46 (2H, br s), 4.12e3.98 (5H, m), 1.28 (3H, t,
J¼6.9 Hz), 1.20 (3H, t, J¼6.9 Hz); 13C NMR (75 MHz, acetone-d6)
d
163.2, 150.6, 133.2, 132.5, 121.5, 119.7, 119.1, 117.0, 63.5 (d,
2JCP¼7.1 Hz), 63.3 (d, JCP¼7.2 Hz), 50.6 (d, JCP¼8.2 Hz), 36.1 (d,
1JCP¼146.1 Hz), 16.8, 16.7; IR (KBr) 3342, 3158, 2981, 2919, 2188,
1653, 1420, 1242, 1036, 963 cmꢁ1; MS (m/z, EI) 386 (Mþ, 5), 252
(11), 249 (100), 170 (15), 143 (9), 115 (3), 81 (2).
(300 MHz, acetone-d6)
d
7.16 (1H, s), 7.10 (1H, d, J¼8.4 Hz), 6.90 (1H,
2
2
d, J¼8.4 Hz), 6.48 (2H, br s), 4.08e3.92 (4H, m), 3.88 (1H, d,
2JPH¼17.7 Hz), 2.30 (3H, s), 1.26 (3H, t, J¼7.2 Hz), 1.18 (3H, t,
J¼7.2 Hz); 13C NMR (75 MHz, DMSO-d6)
d 162.8, 148.0, 133.3, 129.7,
129.2, 120.2, 117.4, 115.7, 62.3 (d, 2JCP¼7.2 Hz), 62.2 (d, 2JCP¼7.1 Hz),
2
1
47.3 (d, JCP¼7.6 Hz), 34.5 (d, JCP¼144.4 Hz), 20.3, 16.3, 16.2; IR
(KBr) 3355, 3166, 2985, 2188, 1646, 1496, 1420, 1231, 1030,
811 cmꢁ1; MS (m/z, EI) 322 (Mþ, 3), 186 (12), 185 (100), 149 (3), 140
(2), 130 (1), 103 (1), 81 (1).
3.22. Diethyl 2-amino-6,8-dibromo-3-cyano-4H-chromen-4-
ylphosphonate (6g)22,23
A
mixture of 3,5-dibromosalicylaldehyde (5g) (280 mg,
1.0 mmol), malononitrile (2a) (66 mg, 1.0 mmol), and triethyl
phosphite (3a) (166 mg, 1.0 mmol) in ethanol (5 mL) in the pres-
ence of 20 mol % of EDDA (36 mg) was stirred at room temperature
for 3 h. After completion of the reaction, the mixture was evapo-
rated under reduced pressure and crude product was purified by
column chromatography on silica gel using hexane/ethylacetate
(1:1) gave product 6g (373 mg, 80%) as a solid: mp 198e200 ꢀC; 1H
3.19. Diethyl 2-amino-3-cyano-7-methoxy-4H-chromen-4-
ylphosphonate (6d)
A
mixture of 4-methoxysalicylaldehyde (5d) (152 mg,
1.0 mmol), malononitrile (2a) (66 mg, 1.0 mmol), and triethyl
phosphite (3a) (166 mg, 1.0 mmol) in ethanol (5 mL) in the pres-
ence of 20 mol % of EDDA (36 mg) was stirred at room temperature
for 3 h. After completion of the reaction, the mixture was evapo-
rated under reduced pressure and crude product was purified by
column chromatography on silica gel using hexane/ethylacetate
(3:7) gave product 6d (244 mg, 72%) as a solid: mp 218e220 ꢀC; 1H
NMR (300 MHz, acetone-d6)
d
7.76 (1H, t, J¼2.1 Hz), 7.54e7.53 (1H,
m), 6.73 (2H, br s), 4.12e3.98 (5H, m),1.28 (3H, t, J¼7.2 Hz),1.20 (3H,
t, J¼6.9 Hz); 13C NMR (75 MHz, DMSO-d6)
d 162.1, 146.5, 134.1, 131.5,
122.1, 119.4, 116.0, 110.6, 62.7 (d, JCP¼7.1 Hz), 62.6 (d, 2JCP¼7.1 Hz),
2
2
1
47.5 (d, JCP¼7.7 Hz), 34.6 (d, JCP¼144.5 Hz), 16.3, 16.2; IR (KBr)
3341, 3159, 2984, 2198, 1662, 1412, 1235, 1165, 1040, 861 cmꢁ1; MS
(m/z, EI) 466 (Mþ, 6), 331 (48), 330 (12), 329 (100), 327 (51), 293
(14), 169 (9), 149 (37), 85 (4), 71 (7).
NMR (300 MHz, DMSO-d6)
d
7.22 (1H, dd, J¼8.4 and 1.8 Hz), 7.01
(2H, br s), 6.75 (1H, dd, J¼8.4 and 2.1 Hz), 6.57 (1H, d, J¼2.1 Hz),
4.05e3.90 (5H, m), 3.78 (3H, s), 1.23 (3H, t, J¼7.2 Hz), 1.16 (3H, t,
J¼7.2 Hz); 13C NMR (75 MHz, DMSO-d6)
d 162.6, 159.6, 150.7, 130.2,
120.2, 110.6, 109.3, 101.3, 62.3 (d, 2JCP¼7.2 Hz), 62.2 (d, 2JCP¼6.5 Hz),
55.5, 47.7 (d, 2JCP¼7.1 Hz), 33.8 (d, 1JCP¼145.5 Hz),16.4,16.3; IR (KBr)
3.23. Diethyl 2-amino-3-cyano-6-nitro-4H-chromen-4-
ylphosphonate (6h)
3420, 3151, 2983, 2187, 1647, 1509, 1408, 1221, 1158, 1036 cmꢁ1
;
HRMS m/z (Mþ) calcd for C15H19N2O5P: 338.1032; found: 338.1029.
A mixture of 5-nitrosalicylaldehyde (5h) (167 mg, 1.0 mmol),
malononitrile (2a) (66 mg, 1.0 mmol), and triethyl phosphite (3a)
(166 mg, 1.0 mmol) in ethanol (5 mL) in the presence of 20 mol % of
EDDA (36 mg) was stirred at room temperature for 3 h. After
completion of the reaction, the mixture was evaporated under re-
duced pressure and crude product was purified by column chro-
matography on silica gel using hexane/ethylacetate (3:7) gave
product 6h (265 mg, 75%) as a solid: mp 213e215 ꢀC; 1H NMR
3.20. Diethyl 2-amino-3-cyano-6-methoxy-4H-chromen-4-
ylphosphonate (6e)
A mixture of 5-methoxysalicylaldehyde (5e) (152 mg,1.0 mmol),
malononitrile (2a) (66 mg, 1.0 mmol), and triethyl phosphite (3a)
(166 mg, 1.0 mmol) in ethanol (5 mL) in the presence of 20 mol % of
EDDA (36 mg) was stirred at room temperature for 3 h. After
completion of the reaction, the mixture was evaporated under re-
duced pressure and crude product was purified by column chro-
matography on silica gel using hexane/ethylacetate (3:7) gave
product 6e (237 mg, 70%) as a solid: mp 180e182 ꢀC; 1H NMR
(300 MHz, acetone-d6)
d
8.30 (1H, s), 8.21 (1H, d, J¼9.0 Hz), 7.28
2
(1H, d, J¼9.0 Hz), 6.65 (2H, br s), 4.23 (1H, d, JPH¼18.6 Hz),
4.14e4.00 (4H, m), 1.27 (3H, t, J¼7.2 Hz), 1.21 (3H, t, J¼7.2 Hz); 13C
NMR (75 MHz, DMSO-d6)
d 161.7, 154.4, 143.4, 125.3, 124.7, 119.6,
2
2
(300 MHz, acetone-d6)
d
6.96 (1H, s), 6.93e6.91 (1H, m), 6.87e6.84
119.4, 117.4, 62.6 (d, JCP¼7.1 Hz), 62.5 (d, JCP¼7.1 Hz), 47.1 (d,
(1H, m), 6.30 (2H, br s), 4.08e3.89 (4H, m), 3.92 (1H, d,
2JCP¼7.7 Hz), 34.1 (d, 1JCP¼143.9 Hz), 16.2, 16.1; IR (KBr) 3335, 3154,

236
S.R. Kolla, Y.R. Lee / Tetrahedron 68 (2012) 226e237
2986, 2192, 1654, 1528, 1413, 1345, 1248, 1037 cmꢁ1; HRMS m/z
3.27. Diethyl 2-amino-3-cyano-4H-chromen-4-ylphosphonate
6a from 3b (through transesterification)
(Mþ) calcd for C14H16N3O6P: 353.0777; found: 353.0778.
To a solution of salicylaldehyde (5a) (122 mg, 1.0 mmol), malo-
nonitrile (2a) (66 mg, 1.0 mmol), and triphenyl phosphite (3b)
(310 mg, 1.0 mmol) in 5 mL of ethanol was added 20 mol % of EDDA
(36 mg). The reaction mixture was stirred at room temperature for
12 h. After completion of the reaction, the mixture was evaporated
under reduced pressure and crude product was purified by column
chromatography on silica gel using hexane/ethylacetate (2:3) gave
product 6a (126 mg, 41%). The physical and spectral data are the
same as described above.
3.24. Diethyl 3-amino-2-cyano-1H-benzo[f]chromen-1-
ylphosphonate (6i)
A
mixture of 2-hydroxy-1-naphthaldehyde (5i) (172 mg,
1.0 mmol), malononitrile (2a) (66 mg, 1.0 mmol), and triethyl
phosphite (3a) (166 mg, 1.0 mmol) in ethanol (5 mL) in the pres-
ence of 20 mol % of EDDA (36 mg) was stirred at room temperature
for 4 h. After completion of the reaction, the mixture was evapo-
rated under reduced pressure and crude product was purified by
column chromatography on silica gel using hexane/ethylacetate
(1:4) gave product 6i (222 mg, 62%) as a solid: mp 220e222 ꢀC; 1H
3.28. Dimethyl 2-amino-3-cyano-4H-chromen-4-
ylphosphonate 6l from 3b (through transesterification)
NMR (300 MHz, acetone-d6)
d
8.23 (1H, d, J¼8.7 Hz), 7.92 (2H, d,
J¼8.4 Hz), 7.63e7.58 (1H, m), 7.52e7.47 (1H, m), 7.26 (1H, d,
J¼8.7 Hz), 6.81 (2H, br s), 4.65 (1H, d, 2JPH¼16.5 Hz), 4.00e3.83 (4H,
To a solution of salicylaldehyde (5a) (122 mg, 1.0 mmol), malo-
nonitrile (2a) (66 mg, 1.0 mmol), and triphenyl phosphite (3b)
(310 mg, 1.0 mmol) in 5 mL of methanol was added 20 mol % of
EDDA (36 mg). The reaction mixture was stirred at room temper-
ature for 12 h. After completion of the reaction, the mixture was
evaporated under reduced pressure and crude product was purified
by column chromatography on silica gel using hexane/ethylacetate
(3:7) gave product 6l (154 mg, 55%) as a solid: mp: 160e162 ꢀC; 1H
m), 1.16e1.09 (6H, m); 13C NMR (75 MHz, DMSO-d6)
d 163.3, 148.5,
130.7, 130.3, 129.6, 128.0, 126.6, 125.2, 124.9, 120.3, 116.7, 112.0, 62.4
2
2
2
(d, JCP¼7.1 Hz), 62.1 (d, JCP¼6.6 Hz), 48.2 (d, JCP¼7.1 Hz), 31.9 (d,
1JCP¼145.5 Hz), 16.3 (d, JCP¼5.5 Hz), 16.2 (d, JCP¼5.5 Hz); IR (KBr)
3361, 3169, 2981, 2191, 1660, 1418, 1237, 1035, 812 cmꢁ1; HRMS m/z
(Mþ) calcd for C18H19N2O4P: 358.1082; found: 358.1080.
3
3
NMR (300 MHz, DMSO-d6)
d 7.44e7.36 (m, 2H), 7.26e7.21 (m, 1H),
7.10 (d, 1H, J¼7.8 Hz), 6.81 (s, 2H), 4.14 (d, 1H, 2JPH¼17.7 Hz), 3.77 (d,
3.25. Ethyl 2-amino-4-(diethoxyphosphoryl)-4H-chromene-
3-carboxylate (6j)23
2
2
3H, JPH¼11.1 Hz), 3.72 (d, 3H, JPH¼10.5 Hz); 13C NMR (75 MHz,
acetone-d6) d 163.6, 151.1, 130.4, 129.6, 125.2, 120.2, 118.4, 117.0, 53.7
(d, JCP¼7.2 Hz), 53.5 (d, JCP¼7.1 Hz), 49.5, 35.6 (d, 1JCP¼146.1 Hz);
IR (KBr) 3401, 3293, 3138, 2955, 2856, 2181, 1653, 1417, 1235,
1040 cmꢁ1; HRMS m/z (Mþ) calcd for C12H13N2O4P: 280.0613;
found: 280.0613.
A mixture of salicylaldehyde (5a) (122 mg, 1.0 mmol), ethyl-
cyanoacetate (2b) (113 mg, 1.0 mmol), and triethyl phosphite (3a)
(166 mg, 1.0 mmol) in ethanol (5 mL) in the presence of 20 mol % of
EDDA (36 mg) was stirred at room temperature for 3 h. After
completion of the reaction, the mixture was evaporated under re-
duced pressure and crude product was purified by column chro-
matography on silica gel using hexane/ethylacetate (3:2) gave
2
2
3.29. Dipropyl 2-amino-3-cyano-4H-chromen-4-
ylphosphonate 6m from 3b (through transesterification)
product 6j (267 mg, 75%) as an oil: 1H NMR (300 MHz, CDCl3)
d 7.30
(1H, d, J¼7.5 Hz), 7.20e7.13 (1H, m), 7.05 (1H, t, J¼7.5 Hz), 6.91 (1H,
To a solution of salicylaldehyde (5a) (122 mg, 1.0 mmol), malo-
nonitrile (2a) (66 mg, 1.0 mmol), and triphenyl phosphite (3b)
(310 mg, 1.0 mmol) in 5 mL of 1-propanol was added 20 mol % of
EDDA (36 mg). The reaction mixture was stirred at room temper-
ature for 12 h. After completion of the reaction, the mixture was
evaporated under reduced pressure and crude product was purified
by column chromatography on silica gel using hexane/ethylacetate
(2:3) gave product 6m (134 mg, 40%) as a solid: mp: 113e115 ꢀC; 1H
2
d, J¼8.1 Hz), 6.49 (2H, br s), 4.35 (1H, d, JPH¼19.5 Hz), 4.23e4.08
(2H, m), 4.02e3.92 (2H, m), 3.88e3.67 (2H, m), 1.26 (3H, t,
J¼7.2 Hz), 1.19 (3H, t, J¼7.2 Hz), 1.06 (3H, t, J¼7.2 Hz); 13C NMR
(75 MHz, CDCl3)
d 168.7, 161.9, 150.8, 129.6, 128.4, 124.5, 120.0,
116.0, 70.7, 62.8 (d, 2JCP¼7.6 Hz), 62.5 (d, 2JCP¼7.1 Hz), 59.8, 35.1 (d,
1JCP¼144.5 Hz), 16.5 (d, JCP¼6.0 Hz), 16.4 (d, JCP¼5.5 Hz), 14.7; IR
(neat) 3380, 3278, 2982, 1678, 1627, 1528, 1482, 1305, 1238,
1046 cmꢁ1; MS (m/z, EI) 355 (Mþ, 1), 219 (17), 218 (100), 173 (10),
172 (38), 145 (5), 118 (6), 116 (4), 89 (4), 81 (2).
3
3
NMR (300 MHz, acetone-d6)
d
7.25 (d, 1H, J¼7.5 Hz), 7.16 (t, 1H,
J¼7.8 Hz), 7.02 (t, 1H, J¼7.5 Hz), 6.87 (d, 1H, J¼7.8 Hz), 6.30 (s, 2H),
3.93e3.65 (m, 5H),1.56e1.49 (2H, m),1.45e1.39 (2H, m), 0.79 (t, 3H,
J¼7.2 Hz), 0.72 (t, 3H, J¼7.5 Hz); 13C NMR (75 MHz, acetone-d6)
3.26. Ethyl 2-amino-4-(diethoxyphosphoryl)-6-methyl-4H-
chromene-3-carboxylate (6k)
d 163.4, 151.2, 130.7, 129.6, 125.2, 120.1, 118.7, 116.9, 68.7 (d,
2JCP¼7.7 Hz), 68.6 (d, 2JCP¼7.1 Hz), 50.8, 36.3 (d, 1JCP¼146.1 Hz), 24.7,
24.6, 10.4, 10.3; IR (KBr) 3315, 3180, 2966, 2190, 1655, 1412, 1235,
1009 cmꢁ1; HRMS m/z (Mþ) calcd for C16H21N2O4P: 336.1239;
found: 336.1237.
A mixture of 5-methylsalicylaldehyde (5c) (136 mg, 1.0 mmol),
ethylcyanoacetate (2b) (113 mg, 1.0 mmol), and triethyl phosphite
(3a) (166 mg,1.0 mmol) in ethanol (5 mL) in the presence of 20 mol
% of EDDA (36 mg) was stirred at room temperature for 2 h. After
completion of the reaction, the mixture was evaporated under re-
duced pressure and crude product was purified by column chro-
matography on silica gel using hexane/ethylacetate (1:1) gave
product 6k (240 mg, 65%) as an oil: 1H NMR (300 MHz, acetone-d6)
3.30. Dimethyl 2-amino-3-cyano-4H-chromen-4-
ylphosphonate 6l from 3a (through transesterification)
To a solution of salicylaldehyde (5a) (122 mg, 1.0 mmol), malo-
nonitrile (2a) (66 mg, 1.0 mmol), and triethyl phosphite (3a)
(166 mg, 1.0 mmol) in 5 mL of methanol was added 20 mol % of
EDDA (36 mg). The reaction mixture was stirred at room temper-
ature for 12 h. After completion of the reaction, the mixture was
evaporated under reduced pressure and crude product was purified
by column chromatography on silica gel using hexane/ethylacetate
(3:7) gave product 6l (182 mg, 65%) as a solid. All spectral data of 6l
are the same as described above.
d
7.14 (1H, s), 7.06 (1H, d, J¼8.1 Hz), 6.88 (1H, d, J¼8.1 Hz), 4.27 (1H,
2
d, JPH¼19.5 Hz), 4.23e3.77 (6H, m), 2.30 (3H, s), 1.28 (3H, t,
J¼6.9 Hz), 1.19 (3H, t, J¼6.9 Hz), 1.11 (3H, t, J¼7.2 Hz); 13C NMR
(75 MHz, acetone-d6) d 163.5, 149.9, 134.3, 130.8, 130.7, 129.6, 129.5,
121.1, 116.3, 62.8 (d, 2JCP¼7.6 Hz), 62.7 (d, 2JCP¼7.1 Hz), 59.9, 35.9 (d,
1JCP¼143.9 Hz), 20.7, 16.9, 16.8, 15.0; IR (neat): 3388, 3288, 2982,
2931, 1676, 1627, 1532, 1492, 1412, 1308, 1204, 1046 cmꢁ1; HRMS m/
z (Mþ) calcd for C17H24NO6P: 369.1341; found: 369.1340.

S.R. Kolla, Y.R. Lee / Tetrahedron 68 (2012) 226e237
237
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(166 mg, 1.0 mmol) in 5 mL of 1-propanol was added 20 mol % of
EDDA (36 mg). The reaction mixture was stirred at room temper-
ature for 12 h. After completion of the reaction, the mixture was
evaporated under reduced pressure and crude product was purified
by column chromatography on silica gel using hexane/ethylacetate
(2:3) gave product 6m (208 mg, 62%) as a solid. All spectral data of
6m are the same as described above.
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