Synthesis of 2-amino-3-cyano-4H-chromen-4-ylphosphonates and 2-amino-4H-chromenes catalyzed by tetramethylguanidine

Article abstract of DOI:10.1016/j.tet.2013.10.052

Synthesis of 2-amino-4H-chromen-4-ylphosphonates and 2-amino-4H-chromenes has been accomplished by the reaction of salicylaldehyde, malononitrile, dialkyl/diphenylphosphites catalyzed by 1,1,3,3-tetramethylguanidine (TMG) under neat conditions at room tem

Full text of DOI:10.1016/j.tet.2013.10.052

Tetrahedron 69 (2013) 10544e10551
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 2-amino-3-cyano-4H-chromen-4-ylphosphonates and
2-amino-4H-chromenes catalyzed by tetramethylguanidine
*
Reddi Mohan Naidu Kalla, Seong Jin Byeon, Min Seon Heo, Il Kim
The BK21 PLUS Program for Advanced Chemical Technology, Department of Polymer Science and Engineering, Pusan National University,
Busan 609-735, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of 2-amino-4H-chromen-4-ylphosphonates and 2-amino-4H-chromenes has been accom-
plished by the reaction of salicylaldehyde, malononitrile, dialkyl/diphenylphosphites catalyzed by 1,1,3,3-
tetramethylguanidine (TMG) under neat conditions at room temperature. The applicability of catalytic
TMG for the synthesis of 2-amino-4H-chromenes also has been described. The mild reaction conditions,
simple work-up procedure, and use of TMG as an inexpensive catalyst provides an economical protocol
for the preparation of important phosphorus-containing compounds.
Received 3 September 2013
Received in revised form 14 October 2013
Accepted 16 October 2013
Available online 23 October 2013
Keywords:
Solvent-free reaction
One-pot synthesis
Ó 2013 Elsevier Ltd. All rights reserved.
Multi-component reactions
Phosphorus-containing chromenes
Tetramethylguanidine
1. Introduction
phosphonates and related compounds through CeP bond-forming
reactions, are an important tools for the synthetic chemist.10 Im-
The development of operationally simple and eco-friendly
routes for the synthesis of organic and medicinal compounds
with important biological properties are the most significant ob-
jectives in synthetic chemistry. Conducting reactions in the absence
of a solvent (i.e., neat conditions) is an important research field in
green (or sustainable) chemistry,1e3 in addition, the accomplish-
ment of various transformations in a single operation is highly
compatible with the goals of green chemistry. One-pot reaction in
which three or more reactants are combined to forma new pre-
ferred compound without isolation of any intermediate is, known
as multi-component reactions (MCRs),4 are highly attractive in
terms of their ability to fabricate two or more CeC, CeP, CeN, or
CeS bonds in a single step.
Phosphorus compounds play an important role in medicinal
chemistry because of their wide range of biological activities;5 P-
containing natural products exhibit significant biological activities.6
Among these, phosphonates are an important intermediates in or-
ganic synthesis and are used widely as enzyme inhibitors
and metabolic probes,7 peptide mimetics,8 antibiotics, and phar-
macological agents,9 due to wide range of applications the contin-
ued development of efficient protocols for the synthesis of
portant CeP bond-forming protocols include the Kabachnik-Field,11
Michaelis-Arbuzov,11 Michaelis-Becker,12 and phospha-Michael re-
actions.13 A number of methods have been reported for the syn-
thesis of 2-amino-3-cyano-4H-chromen-4-ylphosphonates, some of
which involve phospha-Michael addition catalyzed by diethyl-
amine,14 ethylenediaminediacetate,15 K3PO4,16 I2,17 PEG,18
b-cyclo-
dextrin,19 InCl3,20 and silica-bonded 2-hydroxyethylammonium
acetate (HEAA)21 (Scheme 1). These methods show varying de-
grees of success as well as limitations, such as prolonged reaction
times, low yields, requirement of excess reagent or catalyst, use of
toxic solvent, and laborious work-up procedures; based on this still
they need alternate milder and environmentally sustainable pro-
cedures for the synthesis of 2-amino-3-cyano-4H-chromen-4-
ylphosphonates.
Guanidine compounds, which have been known to chemists for
over 150 years, organic super bases possessing great utility in organic
synthesis; inparticular, guanidine are recently drawn much attention
because of their outstanding roles in organocatalysis.22 From a struc-
tural point of view, guanidine organo-catalysts can be classified based
upon the inclusion of a guanidine group either as open-chain or ring
structures(monoorbicyclic). Generalstructuresof guanidine organo-
catalysts are illustrated in Fig. 1; typical open-chain guanidine is
1,1,3,3-tetramethylguanidine (TMG), whereas monocyclic guanidine
isimidazolidin-2-imine (IMI) and bicyclic guanidine general structure
is 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD).
* Corresponding author. E-mail addresses: ilkim@pusan.ac.kr, ilkim59@gmail.
com (I. Kim).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.10.052

R.M.N. Kalla et al. / Tetrahedron 69 (2013) 10544e10551
10545
Scheme 1. Earlier reported methods for the synthesis of 2-amino-3-cyano-4H-choromenyl-4-ylphosphonates.
2. Results and discussion
In general, MCRs often times require high reaction tempera-
tures, long reaction times, and high catalyst loadings to promote
the formation of the desired product. Attempts at a one-pot three-
component reaction of SA, MN, and DAP (1 mmol each) were first
performed using various types of catalysts at rt in an ethanol sol-
vent Table 1. First, acidic species, such as BF3$OEt2, BF3$SiO2, silica-
supported H2SO4, and trifluoroacetic acid (10 mol %) were exam-
ined at rt over 3e4 h of reaction. Compound 1 was obtained in 40%,
20%, 30% and 10% yields, respectively (entries 1e4), whereas in the
presence of base catalysts, such as NEt3, NH4OH, KOH, and DMAP at
rt, a mixture of products chromenylphosphonate and iminocou-
marin (IC) was observed in all cases based on the TLC analysis of the
reaction mixture after 5 h. After stirring continuously for an addi-
tional 5 h, this mixture of products remained, and very low yields of
products were obtained (entries 5e8). Next, we attempted to carry
out the reaction in the presence of metal salts Mg(ClO4)2 and
Y(CF3OOC)3$nH2O no product was observed under these condi-
tions; however, intermediate IC was isolated in almost quantitative
yield 90% (entries 9 and 10). We then examined the polymer-based
catalysts Amberlyst-15 and PEGeSO3H for their potential re-
activity; again, intermediate IC was obtained in acceptable yields
with these catalysts 75% and 65% (entries 11 and 12). Finally, we
attempted the three-component reaction in the presence of
3.5 mmol (TMG), an efficient Lewis base as well as a hydrogen-bond
donor and acceptor. Initially, the reaction was carried out in etha-
nol; we were pleased to see that the TMG catalyst facilitated the
formation of 2-amino-3-cyano-4H-chromen-4-ylphosphonate in
good yields 85% but required long reaction times 3e4 h (entry 13).
It was decided to carry out the reaction under neat conditions in the
presence of the TMG catalyst, and the reaction was found to be
completed within 30 min in quantitative yield 96% (entry 14). In-
terestingly, the super base TMG was found to be superior to com-
mon catalytic species, including Lewis acids, heterogeneous acids,
Brønsted bases, and metal salts.
Fig. 1. Structures of open-chain (TMG), monocyclic (IMI) and bicyclic (TBD) guanidines.
An extensive survey of the literature has revealed that there are
(to the best of our knowledge) no reports on the synthesis of 2-
amino-3-cyano-4H-chromen-4-ylphosphonates are promoted by
TMG. As part of our research program focusing on the discovery and
applications of green synthetic protocols,23,24 our aim was to de-
velop and expand upon an environment-friendly reaction meth-
odology toward this end. Herein, we report an eco-friendly one-pot
synthesis of 2-amino-3-cyano-4H-chromen-4-ylphosphonates
through a three-component condensation of salicylaldehyde (SA),
malononitrile (MN), dialkylphosphite (DAP), and diphenylphos-
phite (DPP) in the presence of TMG under neat conditions at room
temperature Scheme 2.
To determine the appropriate concentration of TMG, we in-
vestigated the model reaction at different catalyst loadings: 1.0, 1.5,
Scheme 2. Synthesis of 2-amino-3-cyano-4H-choromenyl-4-ylphosphonates.

10546
R.M.N. Kalla et al. / Tetrahedron 69 (2013) 10544e10551
Table 1
nitro) produced good yields, with reactions typically completed
within 30 min (compounds 5e16). In all cases, the 2-amino-3-
cyano-4H-chromen-4-ylphosphonates were obtained in a short
time in high yields. Next, we investigated the replacement of DMP
with DEP, DBP, and DPP. The reaction was observed to proceed
smoothly for all DAPs in good yield; while the reaction with DPP
also proceeded smoothly but in a comparatively lower yield than
that of DAPs. The structures of compound 2 were elucidated by the
NMR analysis and direct comparison with the reported data.15 The
1H NMR spectrum of compound 2 showed the characteristic
Influence of various catalyst systems for the production of compound 1 in ethanol
solvent at room temperaturea
Entry
Catalyst used
Time (h)
Product
Yield (%)b
1
2
3
4
5
6
7
8
BF3O(Et)2
BF3eSiO2
SiO2eSO3H
H3BO3
Et3N
NH4OH
4
4
6
5
6
5
7
5
2
1
2
3
4
0.25
1
1
1
1
40
20
30
10
10þ50
20þ60
15þ55
30þ60
85
90
75
65
85
1þICc
1þIC
1þIC
1þIC
IC
KOH
DMAP
methine peak of the CeP proton at d 4.31e3.99 as multiplet because
9
Mg(ClO4)2
Y(CF3OOC)3$nH2O
Amberlyst-15
PEGeSO3H
TMG
of the overlapping of this signal with the two ethoxymethylene
10
11
12
13
14
IC
IC
IC
1
protons, whereas in the 13C NMR spectrum, the characteristic car-
bon peak of the CeP bond appeared at
d 35.3 as a doublet with
a coupling constant of 147.4 Hz.
TMG, neatd
1
95
Subsequent to this initial success in the improvement of a one-
pot synthesis of 2-amino-3-cyano-4H-chromen-4-ylphosphonates,
we attempted to expand the applicability of this protocol towards
the preparation of a few biologically active compounds. In this
context, we directed our interest to the synthesis of 2-amino-4H-
chromenes Fig 3.
a
Reaction conditions: ethanol¼5 mL, catalyst¼10 mol %, SA¼1 mmol,
MN¼1 mmol, and DAP¼1 mmol.
b
Yields based upon TLC comparison with authentic samples.
Iminocoumarin.
Reaction at neat condition with 3.5 mmol of TMG.
c
d
2.0, 2.5, 3.0, 3.5, and 4.0 mmol, which gave product yields of 65%,
72%, 78%, 83%, 90%, 96, and 96%, respectively. The product yield
remained constant at 96% when the catalyst was increased from 3.5
to 4.0 mmol, indicating that a 3.5 mmol loading was sufficient for
optimal results considering the reaction time and product yield.
The results are summarized in Fig. 2.
Fig. 3. Structures of a few biologically active 2-amino-4H-chromenes.
2-Amino-4H-chromenes are widely employed as pigments,
cosmetics,25 and potential biodegradable agrochemicals.26 Fused-
chromenes are also used as anticancer,27 antiviral,28 anti-in-
flammatory,29 and pesticidal compounds.30 In spite of such im-
portant biological properties of 2-amino-4H-chromenes, it remains
a challenging task to develop an easy and efficient method for their
synthesis. Synthesis of various 2-amino-4H-chromene derivatives
have been previously reported using diethylamine,31 KF,32 and
Amberlyst-2133 as catalysts. We envisaged that the TMG catalysis of
the MCR of SA and 2 equiv of ethyl-cyanoacetate (ECA) would easily
afford 25. The reaction is depicted in Scheme 3.
Fig. 2. Effect of the amount of TMG catalyst on the yield of compound 1. Conditions:
salicylaldehyde (1 mmol), malononitrile (1 mmol), dialkylphosphite (1 mmol), TMG
(3.5 mmol), neat, rt.
In order to establish the generality of this methodology, addi-
tional reactions employing various substituted SAs with MN and
various DAPs were carried out in the presence of 3.5 mmol TMG
under neat conditions. The results are summarized in Experimental
section. Reaction with 3-methyl SA (compounds 17e20) produced
the corresponding phosphonates in good yields (80e86%) because
of the electron-donating methyl group at the 3-position of SA;
similarly, in the case of reactions using 3-tert-butyl SA with DAPs,
excellent yields were obtained (91%, 95%, 93%) within 10 min
(compounds 21, 22, and 23) because of the highly reactivity of
DAPs. Reaction with DPP did not yield product because of its re-
duced reactivity, in addition to the highly hindered SA. Conversely,
substituted SAs with electron-withdrawing groups (bromo, chloro,
The synthesis of 25 was achieved by the reaction of SA and ECA
(1:2 equiv) in the presence of TMG as a catalyst at rt. An exothermic
reaction took place upon the addition of the catalyst. After com-
pletion of the reaction (TLC), water was added and the solution was
stirring continuously until a solid was obtained; the solid was fil-
tered, washed with water (15 mL) four times, and dried in air. The
comparison with the previously reported 1H NMR data showed that
the resultant product was obtained as a single diastereoisomer
having an erythro configuration (1H NMR). In order to extend
the above reaction Scheme 3 to compile a compound library,
SAs (1 equiv) were allowed to react with ECA (2 equiv). In all
cases, the products were obtained in good yield and as a single
diastereoisomer.

R.M.N. Kalla et al. / Tetrahedron 69 (2013) 10544e10551
10547
Scheme 3. TMG catalyzed synthesis of 2-amino-4H-chromenes.
Treatment of SA with MN under similar conditions gave the
4. Experimental
4.1. General
corresponding 2-amino-4H-chromene derivative 28 in good yield
with high diastereoselectivity. The reactions proceeded efficiently
with different SAs in high yields at rt in all cases. The extent of
electron density and nature of the substituent on the aromatic ring
exhibited some effects on this conversion. SAs carrying electron-
withdrawing substituent, such as halide or nitro groups gave the
products in high yields in a short reaction time. In contrast, un-
substituted and electron-rich SAs required longer reaction times
and gave lower yields compared to those of their electron-deficient
counterparts.
The formation of 1 can be explained by the plausible mechanism
shown in Scheme 4. Reaction of SA and MN in the presence of TMG
first 2-(2-hydroxybenzylidene)malononitrile through a Knoevena-
gel-condensation; the newly-formed hydroxy cyano olefin un-
dergoes an intramolecular Pinner reaction to form iminocoumarin.
Subsequent phospha-Michael addition of DAP provides the target
compound 1.
Various substituted SAs, phosphites (dimethyl, diethyl, and
diphenyl), ethyl-cyanoacetate (SigmaeAldrich Co), dibutylphos-
phite, MN (Thermo Fisher Scientific Inc.), and TMG (Alfa-Aesar)
were used as received. All experiments were carried out under neat
conditions; pre-coated silica gel plates (Merck Chemicals) de-
veloped with iodine was used for the analytical TLC. Melting points
were uncorrected and determined on a digital Stuart SMP3 appa-
ratus (Bibby Scientific Limited, Staffordshire, UK). The 1H NMR
(400 MHz), 13C NMR (100 MHz), and 31P NMR (161.9 MHz) spectra
were recorded on a Varian INOVA 400 NMR spectrometer at rt.
Chemical shift values were relative to Me4Si. Data are presented as
follows: chemical shift (parts per million), multiplicity (s¼singlet,
d¼doublet, dd¼doublet of doublet, t¼triplet, m¼multiplet, br
s¼broad singlet, coupling constant J (Hertz)). FTIR spectra were
Scheme 4. Plausible mechanism for the formation of 2-amino-3-cynao-4H-chromen-4-ylphosphonates.
3. Conclusions
recorded on a Shimadzu IR Prestige 21 spectrometer at rt. The
spectra were taken in KBr discs in the range 3500e500 cmꢀ1. Ele-
mental analyses were performed on a Vario EL III Element Analyzer
(Elementar Analysensysteme GmbH, Germany).
In conclusion, the development of a simple, procedure for the
synthesis of 2-amino-3-cyano-4H-chromen-4-ylphosphonates
and 2-amino-4H-chromenes under TMG catalysis and solvent-
free conditions has been described. This low-cost protocol has
several advantages, including a cleaner reaction medium (sol-
vent-free), use of easily available chemicals, high yields, and easy
work-up procedures. This protocol provides the synthetic
chemist with a rapid method for preparing both phosphorus-
containing heterocycles and biologically important 2-amino-
4H-chromenes.
4.2. General procedure for synthesis of (2-amino-3-cyano-4H-
chromene-4-yl)phosphonates (1e24) and 2-amino-4H-chro-
menes (25e32)
TMG (3.5 mmol) was added to a mixture of SA (1 mmol), MN
(1 mmol) and DAP (1 mmol) in neat condition. The resulting mix-
ture was stirred at room temperature. After completion of the

10548
R.M.N. Kalla et al. / Tetrahedron 69 (2013) 10544e10551
reaction (monitored by TLC), distilled water (15 mL) was added to
the reaction mixture and stirring continued till a free flowing solid
was obtained. It was filtered and then washed successively with
water, n-hexane. The crude product was purified by re-
crystallization from ethanol solution. For this, the crude product
was saturated in boiling ethanol and then the solution mixture was
filtered when it was hot to remove the undissolved solid. The hot
filtrate cooled down to room temperature to afford elemental an-
alytically pure crystalline product. The similar experimental pro-
cedures were adopted for the synthesis of all the 2-amino-4H-
chrormens.
CDCl3): d (ppm) 161.5, 148.8, 132.1, 132.0, 131.9, 118.7, 118.2, 117.5,
1
53.8, 53.5, 34.8 (d, JCP¼148.4 Hz); 31P NMR (161.9 MHz, CDCl3):
d
(ppm) 23.3; FTIR (KBr):
n
¼3329, 3175, 2980, 2184, 1646, 1452,
1241, 1032, 895 cmꢀ1. Anal. Calcd for C12H12BrN2O4P: C, 40.13; H,
3.37; N, 7.80. Found: C, 39.79; H, 3.63; N, 8.06.
4.2.6. Diethyl 2-amino-6-bromo-3-cyano-4H-chromen-4-
ylphosphonate (6). 95% yield in 9 min of reaction; Solid, mp
177e178 ꢁC (180e182 ꢁC);14 1H NMR (400 MHz, CDCl3):
d (ppm)
8.25 (t, 1H, J¼2.6 Hz, AreH), 8.17 (t, 1H, J¼2.4 Hz, AreH), 7.12 (d, 1H,
J¼8.8 Hz, AreH), 4.86 (br s, 2H, eNH2), 4.13e4.09 (m, 4H, eOCH2),
3.93 (d, 1H, J¼18.8 Hz, ePeCH), 1.33 (t, 3H, J¼7.0 Hz, eCH3), 1.27 (t,
4.2.1. Dimethyl 2-amino-3-cyano-4H-chromen-4-ylphosphonate
3H, J¼7.0 Hz, eCH3); 13C NMR (100 MHz, CDCl3):
d (ppm) 161.3,
(1). 90% yield in 15 min of reaction; Solid, mp 156e158 ꢁC; 1H
148.9, 132.2, 131.9, 118.8, 118.7, 117.5, 117.4, 63.3, 51.9, 35.2 (d,
NMR (400 MHz, CDCl3):
d
(ppm) 7.33 (d, 1H, J¼7.6 Hz, AreH), 7.27
1JCP¼149.0 Hz), 16.3; 31P NMR (161.9 MHz, CDCl3):
d (ppm) 20.8;
(d, 1H, J¼8.0 Hz, AreH), 7.14 (t, 1H, J¼7.2 Hz, AreH), 6.98 (d, 1H,
J¼8.4 Hz, AreH), 4.84 (br s, 2H, eNH2), 3.92 (d, 1H, J¼17.6 Hz,
ePeCH), 3.76 (d, 3H, J¼10.4 Hz, eOCH3), 3.64 (d, 3H, J¼10.4 Hz,
FTIR (KBr):
n
¼3335, 3150, 2975, 2167, 1656, 1474, 1248, 1034,
876 cmꢀ1. Anal. Calcd for C14H16BrN2O4P: C, 43.43; H, 4.17; N, 7.24.
Found: C, 46.25; H, 2.28; N, 9.21.
eOCH3); 13C NMR (100 MHz, CDCl3):
d (ppm) 161.6, 149.7, 129.5,
129.1, 125.1, 119.1, 116.5, 109.5, 53.8, 51.8, 35.0 (d, 1JCP¼146.1 Hz); 31
P
4.2.7. Dibutyl 2-amino-6-bromo-3-cyano-4H-chromen-4-
NMR (161.9 MHz, CDCl3):
d
(ppm) 24.2; FTIR (KBr): v¼3340, 3162,
ylphosphonate (7). 96% yield in 10 min of reaction; Solid, mp
2971, 2192, 1651, 1492, 1241, 1030, 981 cmꢀ1
.
Anal. Calcd
148e150 ꢁC; 1H NMR (400 MHz, CDCl3):
d (ppm) 7.45 (t, 1H,
for C12H13N2O4P: C, 51.43; H, 4.68; N,10.00. Found: C, 51.39; H, 4.52;
N, 9.95.
J¼2.2 Hz, AreH), 7.36 (t, 1H, J¼1.8 Hz, AreH), 6.85 (d, 1H, J¼8.8 Hz,
AreH), 4.82 (br s, 2H, eNH2), 4.11e3.90 (m, 4H, eOCH2), 3.82 (d, 1H,
J¼18.4 Hz, ePeCH), 1.67e1.23 (m, 8H, e(CH2)4), 0.92 (t, 3H,
J¼7.4 Hz, eCH3), 0.87 (t, 3H, J¼7.4 Hz, eCH3); 13C NMR (100 MHz,
4.2.2. Diethyl 2-amino-3-cyano-4H-chromen-4-ylphosphonate
(2). 93% yield in 10 min of reaction; Solid, mp 152e153 ꢁC
CDCl3): d (ppm) 161.3, 148.8, 132.1, 131.8, 118.8, 118.7, 118.0, 117.4,
(140e142 ꢁC);14 1H NMR (400 MHz, CDCl3):
d
(ppm) 7.43e6.97 (m,
66.9, 51.9, 34.5 (d, JCP¼140.2 Hz), 32.6, 18.5, 13.5; 31P NMR
1
4H, AreH), 4.81 (br s, 2H, eNH2), 4.31e3.99 (m, 5H, eOCH2, and
(161.9 MHz, CDCl3):
d
(ppm) 21.3; FTIR (KBr):
n
¼3352, 3158, 2969,
PeCH), 1.33 (t, 3H, J¼7.2 Hz, eCH3), 1.16 (t, 3H, J¼7.2 Hz, eCH3); 13
C
2159, 1654, 1462, 1249, 1050, 975 cmꢀ1
18H24BrN2O4P: C, 48.77; H, 5.46; N, 6.32. Found: C, 48.63; H, 5.24;
N, 6.58.
. Anal. Calcd for
NMR (100 MHz, CDCl3):
d
(ppm) 161.6, 149.7, 129.6, 129.5, 128.9,
C
125.0, 119.2, 116.4, 63.2, 52.2, 35.3 (d, 1JCP¼147.4 Hz), 16.3; 31P NMR
(161.9 MHz, CDCl3):
d
(ppm) 21.6; FTIR (KBr):
n
¼3341, 3165, 2898,
2184, 1640, 1495, 1248, 1034, 961 cmꢀ1
.
Anal. Calcd for
4.2.8. Diphenyl 2-amino-6-bromo-3-cyano-4H-chromen-4-
C
8.97.
14H17N2O4P: C, 54.55; H, 5.56; N, 9.09. Found: C, 54.50; H, 5.49; N,
ylphosphonate (8). 86% yield in 25 min of reaction; Solid, mp
165e166 ꢁC; 1H NMR (400 MHz, CDCl3):
d
(ppm) 8.18 (br s, 2H,
eNH2), 7.29e7.02 (m, 13H, AreH), 3.46 (d, 1H, J¼16.5 Hz, ePeCH);
13C NMR (100 MHz, CDCl3):
(ppm) 160.8, 157.6, 155.6, 153.3, 150.2,
4.2.3. Dibutyl 2-amino-3-cyano-4H-chromen-4-ylphosphonate
d
(3). 94% yield in 10 min of reaction; Solid, mp 146e148 ꢁC; 1H
138.1, 131.2, 118.4, 117.6, 112.9, 108.7, 104.4, 61.0, 30.6 (d,
NMR (400 MHz, CDCl3):
d
(ppm) 7.31e6.93 (m, 4H, AreH), 5.02 (br
1JCP¼143.4 Hz); 31P NMR (161.9 MHz, CDCl3):
d (ppm) 30.9; FTIR
s, 2H, eNH2), 4.11e3.81 (m, 5H, eOCH2, and PeCH), 1.65e1.16 (m,
8H, e(CH2)4), 0.89 (t, 3H, J¼7.2 Hz, eCH3), 0.82(t, 3H, J¼7.2 Hz,
(KBr):
n
¼3326, 3155, 2985, 2186, 1646, 1485, 1246, 1042, 892 cmꢀ1
.
Anal. Calcd for C22H16BrN2O4P: C, 54.68; H, 3.34; N, 5.80. Found: C,
54.60; H, 3.32; N, 5.77.
eCH3); 13C NMR (100 MHz, CDCl3):
d (ppm) 161.8, 149.8, 129.5,
1
128.9, 124.9, 119.4, 116.4, 116.3, 66.7, 51.6, 36.1 (d, JCP¼140.2 Hz),
32.4, 18.6, 13.5; 31P NMR (161.9 MHz, CDCl3):
d
(ppm) 21.8; FTIR
4.2.9. Dimethyl 2-amino-6-chloro-3-cyano-4H-chromen-4-
(KBr):
n
¼3339, 3172, 2964, 2174, 1644, 1492, 1320, 1020, 970 cmꢀ1
.
ylphosphonate (9). 92% yield in 10 min of reaction; Solid, mp
Anal. Calcd for C18H25N2O4P: C, 59.33; H, 6.92; N, 7.69. Found: C,
59.59; H, 7.02; N, 7.70.
166e168 ꢁC; 1H NMR (400 MHz, CDCl3):
d (ppm) 7.30 (t, 1H,
J¼2.4 Hz, AreH), 7.21 (t, 1H, J¼2.2 Hz, AreH), 6.93 (d, 1H, J¼8.8 Hz,
AreH), 4.84 (br s, 2H, eNH2), 3.86 (d, 1H, J¼18.8 Hz, ePeCH), 3.77
(d, 3H, J¼10.8 Hz, eOCH3), 3.70 (d, 3H, J¼10.8 Hz, eOCH3); 13C NMR
4.2.4. Diphenyl 2-amino-3-cyano-4H-chromen-4-ylphosphonate
(4). 86% yield in 25 min of reaction; Solid, mp 158e160 ꢁC; 1H
(100 MHz, CDCl3): d (ppm) 161.7, 148.3, 130.2, 129.2, 129.0, 118.9,
NMR (400 MHz, DMSO-d6):
d
(ppm) 8.37 (br s, 2H, eNH2), 7.74e7.02
118.0, 117.9, 53.9, 50.9, 34.9 (d, 1JCP¼148.4 Hz); 31P NMR (161.9 MHz,
(m,14H, AreH), 5.82 (d,1H, J¼16.5 Hz, ePeCH); 13C NMR (100 MHz,
CDCl3):
d
(ppm) 23.3; FTIR (KBr):
n
¼3360, 3184, 2972, 2188, 1596,
CDCl3):
d
(ppm) 163.8, 151.3, 139.3, 131.6, 130.2, 128.9, 125.8, 124.9,
1460, 1310, 1051, 956 cmꢀ1. Anal. Calcd for C12H12ClN2O4P: C, 45.80;
H, 3.84; N, 8.90. Found: C, 42.30; H, 4.31; N, 8.03.
121.0, 120.1, 118.2, 117.2, 49.9, 33.4 (d, JCP¼140.2 Hz); 31P NMR
1
(161.9 MHz, CDCl3):
d
(ppm) 16.0; FTIR (KBr):
n
¼3320, 3182, 2983,
2179, 1654, 1440, 1224, 1039, 965 cmꢀ1
22H17N2O4P: C, 65.35; H, 4.24; N, 6.93. Found: C, 65.30; H, 4.21;
N, 6.95.
.
Anal. Calcd for
4.2.10. Diethyl 2-amino-6-chloro-3-cyano-4H-chromen-4-
C
ylphosphonate (10). 94% yield in 12 min of reaction; Solid, mp
148e150 ꢁC (150e152 ꢁC);14 1H NMR (400 MHz, CDCl3):
d (ppm)
7.30 (t, 1H, J¼3.4 Hz, AreH), 7.19 (t, 1H, J¼2.2 Hz, AreH), 6.90 (d, 1H,
J¼8.8 Hz, AreH), 4.94 (br s, 2H, eNH2), 4.14e4.01 (m, 4H, eOCH2),
3.81 (d, 1H, J¼18.4 Hz, ePeCH), 1.32 (t, 3H, J¼7.0 Hz, eCH3), 1.22 (t,
4.2.5. Dimethyl 2-amino-6-bromo-3-cyano-4H-chromen-4-
ylphosphonate (5). 94% yield in 10 min of reaction; Solid, mp
160e161 ꢁC; 1H NMR (400 MHz, CDCl3):
d
(ppm) 7.44 (s, 1H, AreH),
3H, J¼7.0 Hz, eCH3); 13C NMR (100 MHz, CDCl3):
d (ppm) 161.5,
7.37 (d, 1H, J¼8.8 Hz, AreH), 6.87 (d, 1H, J¼8.8 Hz, AreH), 4.94 (br s,
2H, eNH2), 3.85 (d, 1H, J¼18.0 Hz, ePeCH), 3.77 (d, 3H, J¼10.8 Hz,
eOCH3), 3.71 (d, 3H, J¼10.8 Hz, eOCH3); 13C NMR (100 MHz,
148.3, 130.0, 129.9, 129.1, 118.9, 118.3, 117.7, 63.3, 51.4, 35.3 (d,
1JCP¼146.7 Hz), 16.4; 31P NMR (161.9 MHz, CDCl3):
d (ppm) 20.8;
¼3325, 3164, 2965, 2172, 1670, 1491, 1309, 1062,
FTIR (KBr):
n

R.M.N. Kalla et al. / Tetrahedron 69 (2013) 10544e10551
10549
920 cmꢀ1. Anal. Calcd for C14H16ClN2O4P: C, 49.06; H, 4.71; N, 8.17.
Found: C, 49.22; H, 4.65; N, 7.93.
150e151 ꢁC; 1H NMR (400 MHz, DMSO-d6):
d
(ppm) 9.27 (br s, 2H,
eNH2), 8.62e6.68 (m, 13H, AreH), 5.82 (dd, 1H, J¼16.5, 12.3 Hz,
ePeCH); 13C NMR (100 MHz, DMSO-d6):
d
(ppm) 163.9,157.6,154.2,
4.2.11. Dibutyl 2-amino-6-chloro-3-cyano-4H-chromen-4-
144.2, 130.2, 129.7, 126.8, 125.9, 120.1, 118.6, 117.7, 115.3, 49.0, 33.5
ylphosphonate (11). 96% yield in 10 min of reaction; Solid, mp
(d, 1JCP¼142.4 Hz); 31P NMR (161.9 MHz, DMSO-d6):
d (ppm) 24.2;
138e140 ꢁC; 1H NMR (400 MHz, CDCl3):
d
(ppm) 7.31 (t, 1H,
FTIR (KBr):
n
¼3376, 3184, 2976, 2169, 1648, 1462, 1254, 1048,
J¼2.4 Hz, AreH), 7.20 (t, 1H, J¼2.4 Hz, AreH), 6.91 (d, 1H, J¼8.8 Hz,
AreH), 4.80 (br s, 2H, eNH2), 4.07e3.91 (m, 4H, eOCH2), 3.82 (d,1H,
J¼18.4 Hz, ePeCH),1.71e1.29 (m, 8H, e(CH2)4), 0.92 (t, 3H, J¼7.4 Hz,
eCH3), 0.87(t, 3H, J¼7.4 Hz, eCH3); 13C NMR (100 MHz, CDCl3):
912 cmꢀ1. Anal. Calcd for C22H16N3O6P: C, 58.80; H, 3.59; N, 9.35.
Found: C, 58.79; H, 3.21; N, 9.04.
4.2.17. Dimethyl 2-amino-8-methyl-3-cyano-4H-chromen-4-
d
(ppm) 161.3,148.2,130.0,129.3,128.8,118.8,118.4,117.6, 66.9, 52.0,
ylphosphonate (17). 84% yield in 10 min of reaction; Solid, mp
36.0 (d, 1JCP¼148.4 Hz), 32.5,18.6,13.6; 31P NMR (161.9 MHz, CDCl3):
148e150 ꢁC; 1H NMR (400 MHz, CDCl3):
d (ppm) 7.14 (d, 1H,
d
(ppm) 20.9; FTIR (KBr):
n
¼3362, 3156, 2956, 2173,1682,1425,1325,
J¼6.8 Hz, AreH), 7.10 (d, 1H, J¼7.6 Hz, AreH), 7.02 (t, 1H, J¼7.4 Hz,
AreH), 4.79 (br s, 2H, eNH2), 3.90 (d, 1H, J¼18.0 Hz, ePeCH), 3.74
(d, 3H, J¼10.8 Hz, eOCH3), 3.65 (d, 3H, J¼10.8 Hz, eOCH3), 2.25 (s,
1065, 932 cmꢀ1. Anal. Calcd for C18H24ClN2O4P: C, 54.21; H, 6.07; N,
7.02. Found: C, 53.79; H, 5.93; N, 7.04.
3H, eCH3); 13C NMR (100 MHz, CDCl3):
d (ppm) 161.7, 131.2, 125.8,
1
4.2.12. Diphenyl 2-amino-6-chloro-3-cyano-4H-chromen-4-
124.6, 119.1, 118.4, 117.4, 115.6, 56.5, 45.7, 35.8 (d, JCP¼148.0 Hz),
ylphosphonate (12). 80% yield in 25 min of reaction; Solid, mp
15.7; 31P NMR (161.9 MHz, CDCl3):
d (ppm) 24.2; FTIR (KBr):
158e160 ꢁC; 1H NMR (400 MHz, DMSO-d6):
d
(ppm) 8.33 (br s, 2H,
eNH2), 7.75e6.71 (m, 13H, AreH), 4.35 (dd, 1H, J¼16.5, 10.0 Hz,
ePeCH); 13C NMR (100 MHz, DMSO-d6):
(ppm) 164.8,151.3,149.4,
n
¼3358, 3168, 2986, 2176, 1674, 1486, 1256, 1064, 936 cmꢀ1. Anal.
Calcd for C13H15N2O4P: C, 53.06; H, 5.14; N, 9.52. Found: C, 53.71; H,
5.38; N, 9.17.
d
146.5, 132.6, 130.2, 128.2, 125.8, 120.1, 119.6, 118.6, 115.3,49.4, 32.6
(d, 1JCP¼141.2 Hz); 31P NMR (161.9 MHz, DMSO-d6):
d
(ppm) 23.2;
4.2.18. Diethyl 2-amino-8-methyl-3-cyano-4H-chromen-4-
FTIR (KBr):
n
¼3346, 3176, 2968, 2185, 1659, 1452, 1310, 1062,
ylphosphonate (18). 85% yield in 12 min of reaction; Solid, mp
936 cmꢀ1. Anal. Calcd for C22H16ClN2O4P: C, 60.22; H, 3.68; N, 6.38.
Found: C, 60.24; H, 3.63; N, 6.40.
158e160 ꢁC (161e164 ꢁC);14 1H NMR (400 MHz, CDCl3):
d (ppm)
7.13 (d, 1H, J¼7.6 Hz, AreH), 7.08 (d, 1H, J¼7.6 Hz, AreH), 7.04 (t, 1H,
J¼7.4 Hz, AreH), 4.90 (br s, 2H, eNH2), 4.11e3.90 (m, 4H, eOCH2),
3.85 (d, 1H, J¼18.0 Hz, ePeCH), 2.24 (s, 3H, eCH3) 1.31 (t, 3H,
J¼7.2 Hz, eCH3), 1.18 (t, 3H, J¼7.2 Hz, eCH3); 13C NMR (100 MHz,
4.2.13. Dimethyl 2-amino-6-nitro-3-cyano-4H-chromen-4-
ylphosphonate (13). 95% yield in 10 min of reaction; Solid, mp
216e218 ꢁC; 1H NMR (400 MHz, DMSO-d6):
d
(ppm) 8.21 (br s, 2H,
CDCl3): d (ppm) 161.8, 148.2, 130.5, 127.1, 125.6, 124.4, 119.3, 116.1,
eNH2), 8.14 (t,1H, J¼4.0 Hz, AreH),7.40 (d,1H, J¼7.2 Hz, AreH), 7.24
(t, 1H, J¼4.4 Hz, AreH), 4.48 (d, 1H, J¼18.8 Hz, ePeCH), 3.61 (d, 3H,
J¼1.2 Hz, eOCH3), 3.59 (d, 3H, J¼1.2 Hz, eOCH3); 13C NMR (100 MHz,
63.2, 52.0, 36.4 (d, 1JCP¼148.9 Hz), 16.4, 15.5; 31P NMR (161.9 MHz,
CDCl3):
d
(ppm) 21.8; FTIR (KBr):
n
¼3346, 3179, 2948, 2153, 1692,
1458, 1276, 1068, 940 cmꢀ1. Anal. Calcd for C15H19N2O4P: C, 55.90;
H, 5.94; N, 8.69. Found: C, 57.38; H, 6.04; N, 8.68.
DMSO-d6):
d (ppm) 162.2, 154.7, 1v43.9, 125.5, 125.2, 119.8, 117.9,
1
117.8, 53.6, 47.3, 33.9 (d, JCP¼149.8 Hz); 31P NMR (161.9 MHz,
DMSO-d6):
d
(ppm) 13.9; FTIR (KBr):
n
¼3319, 3124, 2958, 2167,1656,
4.2.19. Dibutyl 2-amino-8-methyl-3-cyano-4H-chromen-4-
1467,1298,1030, 925 cmꢀ1. Anal. Calcd for C12H12N3O6P: C, 44.32; H,
3.72; N, 12.92. Found: C, 44.28; H, 3.75; N, 12.85.
ylphosphonate (19). 86% yield in 14 min of reaction; Solid, mp
134e136 ꢁC; 1H NMR (400 MHz, CDCl3):
d (ppm) 7.14 (d, 1H,
J¼7.6 Hz, AreH), 7.08 (d, 1H, J¼7.2 Hz, AreH), 7.01 (t, 1H, J¼7.6 Hz,
AreH), 4.78 (br s, 2H, eNH2), 4.04e3.80 (m, 4H, eOCH2), 3.73 (d,
1H, J¼16.4 Hz, ePeCH), 2.24 (s, 3H, eCH3), 1.67e1.22 (m, 8H,
e(CH2)4), 0.91 (t, 3H, J¼7.4 Hz, eCH3), 0.84 (t, 3H, J¼7.4 Hz, eCH3);
4.2.14. Diethyl 2-amivno-6-nitro-3-cyano-4H-chromen-4-
ylphosphonate (14). 96% yield in 10vmin of reaction; Solid, mp
222e224ꢁC(216e218 ꢁC);14 1HNMR(400MHz, CDCl3):
d(ppm) 7.46 (t,
1H, J¼2.4 Hz, AreH), 7.36 (t,1H, J¼4.0 Hz, AreH), 6.85 (d,1H, J¼12.0 Hz,
AreH), 4.81 (br s, 2H, eNH2), 4.14e3.98 (m, 4H, eOCH2), 3.81 (d, 1H,
J¼16.0 Hz, ePeCH), 1.33 (t, 3H, J¼8.0 Hz, eCH3), 1.22 (t, 3H, J¼8.0 Hz,
13C NMR (100 MHz, CDCl3):
d (ppm) 161.5, 148.1, 130.4, 125.6, 124.5,
119.2, 116.4, 116.2, 66.7, 52.5, 34.6 (d, 1JCP¼140.2 Hz), 32.5, 18.6, 15.5,
13.5; 31P NMR (161.9 MHz, CDCl3):
n
d (ppm) 22.0; FTIR (KBr):
eCH3); 13C NMR (100 MHz, CDCl3):
d
(ppm) 160.7, 153.8, 144.4, 125.5,
¼3380, 3192, 2965, 2092, 1645, 1476, 1193, 1045, 890 cmꢀ1. Anal.
124.7,118.3,118.1,117.9, 63.6, 52.0, 36.1 (d,1JCP¼146.2Hz),16.4; 31PNMR
Calcd for C19H27N2O4P: C, 60.31; H, 7.19; N, 7.40. Found: C, 60.79; H,
7.29; N, 7.35.
(161.9 MHz, CDCl3):
d
(ppm) 21.5; FTIR (KBr):
n¼3346, 3145, 2965, 2178,
1648,1485,1286,1086, 886 cmꢀ1. Anal. CalcdforC14H16N3O6P: C, 47.60;
H, 4.57; N, 11.89. Found: C, 47.62; H, 4.53; N, 11.80.
4.2.20. Diphenyl 2-amino-8-methyl-3-cyano-4H-chromen-4-
ylphosphonate (20). 80% yield in 30 min of reaction; Solid, mp
4.2.15. Dibutyl 2-amino-6-nitro-3-cyano-4H-chromen-4-
214e216 ꢁC; 1H NMR (400 MHz, DMSO-d6):
d
(ppm) 7.29e7.02 (m,
13H, AreH), 6.69 (br s, 2H, eNH2), 4.84 (d, 1H, J¼16.5 Hz, ePeCH),
2.26 (s, 3H, eCH3); 13C NMR (100 MHz, DMSO-d6):
(ppm) 160.9,
ylphosphonate (15). 91% yield in 15 min of reaction %; Solid, mp
148e150 ꢁC; 1H NMR (400 MHz, CDCl3):
d
(ppm) 8.24 (d, 1H,
d
J¼3.2 Hz, AreH), 8.16 (d, 1H, J¼4.8 Hz, AreH), 7.12 (d, 1H, J¼9.6 Hz,
AreH), 4.97 (br s, 2H, eNH2), 4.08e3.92 (m, 4H, eOCH2), 3.79 (d,
1H, J¼18.2 Hz, ePeCH), 1.71e1.28 (m, 8H, e(CH2)4), 0.80 (t, 6H,
157.3,150.0,140.8,138.6,126.1,124.3,123.3,120.2,118.8,116.2,114.0,
71.0, 31.6 (d, 1JCP¼142.4 Hz), 15.7; 31P NMR (161.9 MHz, DMSO-d6):
d
(ppm) 16.3; FTIR (KBr):
n
¼3346, 3194, 2960, 2094, 1686, 1489,
J¼7.2 Hz, eCH3); 13C NMR (100 MHz, CDCl3):
d
(ppm) 160.7, 155.6,
1143, 1086, 976 cmꢀ1. Anal. Calcd for C23H19N2O4P: C, 66.03; H,
4.58; N, 6.70. Found: C, 63.81; H, 4.39; N, 6.68.
153.8, 144.5, 125.3, 124.7, 118.1, 117.3,67.1, 51.9, 35.2 (d,
1JCP¼148.4 Hz), 32.4, 18.6, 13.5; 31P NMR (161.9 MHz, CDCl3):
d
(ppm) 21.4; IR (KBr):
n
¼3385, 3168, 2974, 2154, 1632, 1492, 1265,
4.2.21. Dimethyl 2-amino-8-tert-butyl-3-cyano-4H-chromen-4-
1044, 892 cmꢀ1. Anal. Calcd for C18H24N3O6P: C, 52.81; H, 5.91; N,
10.26. Found: C, 51.22; H, 5.85; N, 9.93.
ylphosphonate (21). 91% yield in 10 min of reaction; Solid, mp
205e207 ꢁC; 1H NMR (400 MHz, CDCl3):
d (ppm) 7.27e7.25 (m, 1H,
AreH), 7.18e7.16 (m, 1H, AreH), 7.07 (t, 1H, J¼7.8 Hz, AreH), 4.85
(br s, 2H, eNH2), 3.89 (d, 1H, J¼17.6 Hz, ePeCH), 3.75 (d, 3H,
J¼10.4 Hz, eOCH3), 3.58 (d, 3H, J¼10.4 Hz, eOCH3), 1.38 (s, 9H,
4.2.16. Diphenyl 2-amino-6-nitro-3-cyano-4H-chromen-4-
ylphosphonate (16). 88% yield in 20 min of reaction; Solid, mp

10550
R.M.N. Kalla et al. / Tetrahedron 69 (2013) 10544e10551
e(CH3)3); 13C NMR (100 MHz, CDCl3):
d
(ppm) 161.3, 148.8, 137.5,
4.33e4.24 (m, 4H, eOCH2), 4.02 (d, 1H, J¼3.6 Hz), 1.34 (t, 3H,
J¼7.0 Hz, eCH3), 1.29 (t, 3H, J¼7.0 Hz, eCH3); 13C NMR (100 MHz,
127.7, 126.7, 124.6, 119.0, 116.8, 53.2, 52.3, 36.3, 34.8 (d,
1JCP¼142.1 Hz), 30.1; 31P NMR (161.9 MHz, CDCl3):
d
(ppm) 24.2;
CDCl3): d (ppm) 167.4, 164.5, 161.3, 154.6, 144.2, 125.1, 124.4, 121.2,
FTIR (KBr):
n
¼3325, 3165, 2956, 2085, 1689, 1456, 1265, 1070,
117.6, 114.8, 72.9, 63.3, 60.7, 46.6, 36.6, 14.4, 13.9; FTIR (KBr):
985 cmꢀ1. Anal. Calcd for C16H21N2O4P: C, 57.14; H, 6.29; N, 8.33.
Found: C, 56.77; H, 6.34; N, 8.13.
n
¼3345, 2845, 2357, 2240, 1725, 1664, 720 cmꢀ1. Anal. Calcd for
C
17H17N3O7: C, 54.40; H, 4.57; N, 11.20. Found: C, 54.34; H, 4.65; N,
11.10.
4.2.22. Diethyl 2-amino-8-tert-butyl-3-cyano-4H-chromen-4-
ylphosphonate (22). 95% yield in 10 min of reaction; Solid, mp
4.2.28. 2(-2-Amino-3-cyano-4H-chromen-4-yl)malononitrile
235e237 ꢁC; 1H NMR (400 MHz, CDCl3):
d
(ppm) 7.25 (s, 1H, AreH),
(28). 95% yield in 25 min of reaction; Solid, mp 156e158 ꢁC; 1H
7.18 (d, 1H, J¼7.6 Hz, AreH), 7.06 (t, 1H, J¼7.8 Hz, AreH), 4.78 (br s,
2H, eNH2), 4.15e3.82 (m, 4H, eOCH2), 3.03 (s, 1H, ePeCH), 1.37 (s,
9H, e(CH3)3), 1.33 (t, 3H, J¼7.2 Hz, eCH3), 1.13 (t, 3H, J¼7.2 Hz,
NMR (400 MHz, DMSO-d6): d (ppm) 7.56e7.05 (m, 4H, AreH), 5.82
(br s, 2H, eNH2), 5.02 (d, 1H, J¼4.0 Hz, ePeCH), 4.55 (d, 1H,
J¼4.0 Hz); 13C NMR (100 MHz, CDCl3):
d (ppm) 163.8, 150.1, 147.3,
eCH3); 13C NMR (100 MHz, CDCl3):
d
(ppm) 161.2,148.7,137.3,127.8,
130.5, 129.2, 125.4, 119.7, 118.3, 116.7, 37.5, 32.8; FTIR (KBr):
n¼3359,
126.5,124.5,119.1,117.1, 63.1, 52.8, 36.6, 34.9 (d, 1JCP¼148.9 Hz), 30.1,
2876, 2363, 2209, 1643, 827 cmꢀ1. Anal. Calcd for C13H8N4O: C,
66.10; H, 3.41; N, 23.72. Found: C, 65.85; H, 3.30; N, 23.60.
16.4; 31P NMR (161.9 MHz, CDCl3):
n
d (ppm) 21.8; FTIR (KBr):
¼3342, 3162, 2985, 2068, 1692, 1458, 1285, 1040, 939 cmꢀ1. Anal.
Calcd for C18H25N2O4P: C, 59.33; H, 6.92; N, 7.69. Found: C, 59.65; H,
7.14; N, 7.87.
4.2.29. 2(-2-Amino-6-bromo-3-cyano-4H-chromen-4-yl)malononi-
trile (29). 98% yield in 34 min of reaction; Solid, mp 160e162 ꢁC; 1H
NMR (400 MHz, DMSO-d6):
d
(ppm) 7.67 (d, 1H, J¼4.0 Hz, AreH),
4.2.23. Dibutyl 2-amino-8-tert-butyl-3-cyano-4H-chromen-4-
7.58 (t, 1H, J¼2.4 Hz, AreH), 7.55 (br s, 2H, eNH2), 7.08 (d, 1H,
ylphosphonate (23). 93% yield in 9 min of reaction; Solid, mp
J¼8.8 Hz, AreH), 5.10 (d, 1H, J¼4.0 Hz), 4.58 (d, 1H, J¼4.0 Hz); 13C
180e182 ꢁC; 1H NMR (400 MHz, CDCl3):
d
(ppm) 7.25 (t, 1H,
NMR (100 MHz, DMSO-d6): d (ppm) 163.6, 149.4, 132.0, 131.2120.7,
J¼1.8 Hz, AreH), 7.20e7.17 (m, 1H, AreH), 7.06 (t, 1H, J¼7.8 Hz,
AreH), 4.73 (br s, 2H, eNH2), 4.07e3.73 (m, 5H, eOCH2 &ePeCH),
1.70e1.40 (m, 8H, e(CH2)4), 1.37 (s, 9H, e(CH3)3), 0.91 (t, 3H,
J¼7.2 Hz, eCH3), 0.83 (t, 3H, J¼7.2 Hz, eCH3); 13C NMR (100 MHz,
119.5, 119.2, 116.8, 113.4,48.8, 37.0, 32.4; FTIR (KBr):
n
¼3351, 2879,
2366, 2206, 1642, 826 cmꢀ1. Anal. Calcd for C13H7BrN4O: C, 49.55;
H, 2.24; N, 17.78. Found: C, 49.42; H, 2.18; N, 17.62.
CDCl3):
d
(ppm) 161.3, 148.7, 137.3, 127.8, 126.5, 124.4, 119.2, 117.3,
4.2.30. 2(-2-Amino-6-chloro-3-cyano-4H-chromen-4-yl)malononi-
1
66.7, 52.4, 36.6, 34.9 (d, JCP¼142.8 Hz), 33.2, 32.4, 18.6, 13.5; 31P
trile (30). 99% yield in 40 min of reaction; Solid, mp 158e160 ꢁC; 1H
NMR (161.9 MHz, CDCl3):
d
(ppm) 21.7; FTIR (KBr):
n
¼3362, 3129,
NMR (400 MHz, DMSO-d6): d (ppm) 7.55 (br s, 2H, eNH2), 7.45 (d,
2896, 2085, 1694, 1492, 1286, 1040, 958 cmꢀ1. Anal. Calcd for
22H33N2O4P: C, 62.84; H, 7.91; N, 6.66. Found: C, 63.57; H, 8.21; N,
1H, J¼1.6 Hz, AreH), 7.43 (d, 1H, J¼2.4 Hz, AreH), 7.14 (d, 1H,
C
J¼8.8 Hz, AreH), 5.10 (d, 1H, J¼4.0 Hz), 4.58 (d, 1H, J¼3.6 Hz); 13C
6.76.
NMR (100 MHz, DMSO-d6): d (ppm) 163.6, 148.9, 130.1, 129.0, 128.8,
128.6, 120.3, 119.5, 113.7 48.8, 37.3, 32.5; FTIR (KBr):
n
¼3351, 2888,
4.2.24. Diphenyl 2-amino-8-tert-butyl-3-cyano-4H-chromen-4-
2189, 1650, 817 cmꢀ1. Anal. Calcd for C13H7ClN4O: C, 57.69; H, 2.61;
N, 20.70. Found: C, 56.95; H, 2.49; N, 20.52.
ylphosphonate (24)a. aNot formed.
4.2.25. Ethyl
mene-3-carboxylate (25). 95% yield in 40 min of reaction; Solid, mp
144e146 ꢁC; 1H NMR (400 MHz, CDCl3):
(ppm) 7.30e7.28 (m, 1H,
2-amino-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chro-
4.2.31. 2(-2-Amino-6-nitro-3-cyano-4H-chromen-4-yl)malononitrile
(31). 97% yield in 40 min of reaction; Solid, mp 166e168 ꢁC; 1H
d
NMR (400 MHz, DMSO-d6):
d
(ppm) 8.47 (d, 1H, J¼2.8 Hz, AreH),
AreH), 7.27 (br s, 2H, eNH2), 7.09e7.05 (m, 3H, AreH), 4.70 (d, 1H,
J¼3.6 Hz, eCH), 4.27e4.20 (m, 4H, eOCH2), 3.95 (d, 1H, J¼3.6 Hz,
eCH), 1.32 (t, 3H, J¼7.0 Hz), 1.26 (t, 3H, J¼7.0 Hz); 13C NMR
8.26 (d, 1H, J¼2.4 Hz, AreH), 7.74 (br s, 2H, eNH2), 7.36 (d, 1H,
J¼9.2 Hz, AreH), 5.18 (d, 1H, J¼4.0 Hz), 4.76 (d, 1H, J¼3.6 Hz); 13C
NMR (100 MHz, DMSO-d6): d (ppm) 163.1, 154.5, 144.2, 126.2, 125.7,
(100 MHz, CDCl3):
d
(ppm) 168.0, 165.0, 162.4, 150.4, 129.2, 128.1,
119.6, 118.5, 113.2, 113.0, 48.9, 37.2, 32.7; FTIR (KBr):
n
¼3317, 2896,
124.6, 120.1, 116.5, 115.4, 73.4, 62.6, 59.9, 46.7, 36.8, 14.5, 13.9; FTIR
2206, 1659, 767 cmꢀ1. Anal. Calcd for C13H7N5O3: C, 55.52; H, 2.51;
N, 24.90. Found: C, 55.50; H, 2.49; N, 24.89.
(KBr):
n
¼3348, 2874, 2365, 2209, 1720, 1643, 827 cmꢀ1. Anal. Calcd
for C17H18N2O5: C, 61.81; H, 5.49; N, 8.48. Found: C, 61.75; H, 5.69;
N, 8.40.
4.2.32. 2(-2-Amino-8-methyl-3-cyano-4H-chromen-4-yl)malononi-
trile (32). 95% yield in 36 min of reaction; Solid, mp 178e180 ꢁC; 1H
4.2.26. Ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-
NMR (400 MHz, acetone-d6):
d
(ppm) 7.38 (d, 1H, J¼7.6 Hz, AreH),
4H-chromene-3-carboxylate (26). 94% yield in 35 min of reaction;
7.29 (d, 1H, J¼7.2 Hz, AreH), 7.16 (t, 1H, J¼7.4 Hz, AreH), 6.81 (br s,
Solid, mp 135e136 ꢁC; 1H NMR (400 MHz, CDCl3):
d (ppm) 7.40 (d,
2H, eNH2), 4.73 (d, 1H, J¼3.6 Hz), 4.53(d, 1H, J¼3.2 Hz), 2.0 (s, 3H,
1H, J¼2.8 Hz, AreH), 7.38 (d, 1H, J¼2.0 Hz, AreH), 7.25 (br s, 2H,
eNH2), 6.96 (d, 1H, J¼8.8 Hz, AreH), 4.66 (d, 1H, J¼3.6 Hz, eCH),
4.32e4.22 (m, 4H, eOCH2), 3.96 (d, 1H, J¼3.6 Hz), 1.34e1.28 (m, 6H,
eCH3); 13C NMR (100 MHz, acetone-d6):
d (ppm) 163.6, 148.5, 146.5,
131.4,126.4,126.0,124.6,118.0,112.2, 51.0, 38.5, 32.2,14.6; FTIR (KBr):
n
¼3315, 2898, 2203, 1649, 763 cmꢀ1. Anal. Calcd for C14H10N4O: C,
eCH3); 13C NMR (100 MHz, CDCl3):
d
(ppm) 167.7, 164.8, 162.1,
67.19; H, 4.03; N, 22.39. Found: C, 67.22; H, 4.05; N, 22.36.
149.5, 132.2, 130.9, 122.1, 118.3, 116.9, 115.1, 73.0, 63.0, 60.0, 46.5,
36.7, 14.5, 14.0; FTIR (KBr):
n
¼3336, 2854, 2375, 2219, 1735, 1649,
Acknowledgements
828 cmꢀ1. Anal. Calcd for C17H17BrN2O5: C, 49.89; H, 4.19; N, 6.85.
Found: C, 49.76; H, 4.08; N, 6.71.
This work was supported by a two-year research grant from
Pusan National University. The authors also thank to BK21 PLUS
Program for the financial support.
4.2.27. Ethyl 2-amino-6-nitro-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-
chromene-3-carboxylate (27). 95% yield in 35 min of reaction; Solid,
mp 141e142 ꢁC; 1H NMR (400 MHz, CDCl3):
d (ppm) 8.20 (dd, 1H,
References and notes
J¼2.8, 2.8 Hz, AreH), 8.07 (d, 1H, J¼2.8 Hz, AreH), 7.21 (d, 1H,
J¼8.8 Hz, AreH), 5.28 (br s, 2H, eNH2), 4.79 (d, 1H, J¼3.2 Hz, eCH),
1. Xiao, F.; Liao, Y.; Wu, M.; Deng, G.-J. Green. Chem. 2012, 14, 3277.

R.M.N. Kalla et al. / Tetrahedron 69 (2013) 10544e10551
10551
2. Bala, B. D.; Rajesh, S. M.; Perumal, S. Green. Chem. 2012, 14, 2484.
3. Alonso, F.; Moglie, Y.; Radivoy, G.; Yusa, M. Green. Chem. 2012, 14, 2699.
4. Orru, R. V. A.; de Greef, M. Synthesis 2003, 10, 147.
5. Smith, J. D. In The Role of Phosphonates in Living Systems; Hilderbrand, R. L., Ed.;
CRC: Boca Raton, FL, 1983; pp 31e53.
18. Das, B.; Balasubramnyam, P.; Reddy, G. C.; Salvanna, N. Helv. Chim. Acta 2011, 94,
1347.
19. Murthy, S. N.; Madhav, B.; Reddy, V. P.; Nageswar, Y. V. D. Tetrahedron Lett. 2010,
51, 3649.
20. Jayashree, P.; Shanthi, G.; Perumal, P. T. Synlett 2009, 917.
21. Sobhani, S.; Honarmand, M. Catal. Lett. 2013, 143, 476.
22. Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138.
23. Kalla, R. M. N.; Khalivulla, S. I.; Rasheed, S.; Fakurazi, S.; Arulselvan, P.; Lasekan,
O.; Abas, F. Int. J. Mol. Sci. 2013, 14, 1843.
6. Fields, S. C. Tetrahedron 1999, 55, 1237.
7. (a) Allen, M. C.; Fuhrer, W.; Tuck, B.; Wade, R.; Wood, J. M. J. Med. Chem. 1989,
32, 1652; (b) Patel, D. V.; Rielly-Gauvin, K.; Ryono, D. E. Tetrahedron Lett. 1990,
31, 5587; (c) Stowasser, B.; Budt, K. H.; Li, J. Q.; Peyman, A.; Ruppert, D. Tetra-
hedron Lett. 1992, 33, 6625.
24. Kalla, R. M. N.; Krishna, B. S.; Kumar, M. A.; Arulselvan, P.; Khalivulla, S. I.;
8. Kafarski, P.; Lejczak, B. Phosphorus, Sulfur Silicon Relat. Elem. 1991, 63, 193.
9. (a) Baylis, E. K.; Campbell, C. D.; Dingwall, J. G. J. Chem. Soc., Perkin Trans. 1
1984, 1, 2845; (b) Atherton, F. R.; Hassal, C. H.; Lambert, R. W. J. Med. Chem.
1986, 29, 29.
10. Hayashi, M.; Matsuura, Y.; Nishimura, Y.; Yamasaki, T.; Imai, Y.; Watanabe, Y. J.
Org. Chem. 2007, 72, 7798; (b) Kalek, M.; Stawinski, J. Organometallics 2007, 26,
5840.
11. (a) Kabaschnik, M. I.; Medved, T. L. Izv. Akad. Nauk. SSSR 1953, 6, 1126; (b)
Michaelis, A.; Kaehne, R. Ber. Dtsch. Chem. Ges. 1898, 31, 1048; (c) Fields, E. K. J.
Am. Chem. Soc. 1952, 74, 1528; (d) Arbusov, A. E. J. Russ. Phys.-Chem. Soc. 1906,
38, 687.
12. Keglevich, G.; Sipos, M.; Takacs, D.; Ludanyi, K. Heteroat. Chem. 2008, 19, 288.
13. (a) Enders, D.; Tedeschi, L.; Bats, J. W. Angew. Chem., Int. Ed. 2000, 39, 4605; (b)
Enders, D.; Saint-Dizier, A.; Lannou, M. I.; Lenzen, A. Eur. J. Org. Chem. 2006, 29.
14. Kulakarni, M. A.; Pandurangi, V. R.; Desai, U. V.; Wadgaonkar, P. P. C.R. Chim.
2012, 15, 745.
Lasekan, O. Molecules 2012, 17, 7543.
25. Ellis, G. P. In The Chemistry of Heterocyclic Compounds; Weissberger, A., Taylor,
E. C., Eds.; John Wiley: New York, NY, 1977; (Chapter II).
26. Hafez, E. A. A.; Elangdi, M. H.; Elgamey, A. G. A.; El-Taweel, F. M. A. A. Hetero-
cycles 1987, 26, 903.
27. (a) Li, C. J.; Li, Y. L. U. S. Patent Appl. Publ. U.S. 2,005,222,246 Al 20,051,006,
2005. (b) Ough, M.; Lewis, A.; Bey, E. A.; Gao, J.; Ritchie, J. M.; Bornmann, W.;
Boothman, D. A.; Oberley, L. W.; Cullen, J. J. Cancer Biol. Ther. 2005, 4, 95.
28. Hiramoto, J.; Nasuhara, A.; Michiloshi, K.; Kato, T.; Kikugawa, K. Mutat. Res.
1997, 395, 47.
29. Moon, D.-O.; Choi, Y. H.; Kim, N.-D.; Park, Y. M.; Kim, G. Y. Int. Im-
munopharmacol. 2007, 7, 506.
30. Shestopalov, A. M.; Emelianova, Y. M.; Nesterov, V. N. Russ. Chem. Bull. 2003, 52,
1164.
31. Kulkarni, M. A.; Pandit, K. S.; Desai, U. V.; Lad, U. P.; Wadgaonkar, P. P. C.R. Chim.
2013, 16, 689.
15. Kolla, S. R.; Lee, Y. R. Tetrahedron 2012, 68, 226.
32. Elinson, M. N.; Ilovaisky, A. I.; Merkulova, V. M.; Belyakov, P. A.; Chizhov, A. O.;
Nikishin, G. I. Tetrahedron 2010, 66, 4043.
33. Yadav, J. S.; Reddy, B. V. S.; Gupta, M. K.; Prathap, I.; Pandey, S. K. Catal. Commun.
16. Gaikwad, D. S.; Undale, K. A.; Shaikh, T. S.; Pore, D. M. C.R. Chim. 2011, 14, 865.
17. Rajasekhar, M.; Rao, K. U. M.; Sundar, C. S.; Reddy, N. B.; Nayak, S. K.; Reddy, C. S.
Chem. Pharm. Bull. 2012, 60, 854.
2007, 8, 2208.