This document describes a three-component reaction to synthesize novel 2-(3-chromonyl)-2-acyloxycarboxamide derivatives. 3-Formylchromone, an alkyl isocyanide, and a carboxylic acid react in dichloromethane at room temperature to form these products in good yields. A variety of carboxylic acids and isocyanides were tested in the reaction, producing diverse derivatives. The reaction proceeds via initial formation of an adduct between the chromone and acid, followed by addition of the isocyanide and intramolecular rearrangement to form the final product.

1. 1 3
J IRAN CHEM SOC
DOI 10.1007/s13738-015-0769-7
ORIGINAL PAPER
Synthesis of 2‑(3‑chromonyl)‑2‑acyloxycarboxamides
via multicomponent reactions of isocyanides
Mohammad Bagher Teimouri1
· Foad Mashayekhi1
· Elham Alishaei2
Received: 26 December 2014 / Accepted: 2 November 2015
© Iranian Chemical Society 2015
in fruits, vegetables, nuts, seeds, flowers, and barks [1].
They are an integral part of the human diet and have been
reported to exhibit a wide range of biological effects. They
display not only spasmolytic, diuretic, clotting, antibacte-
rial, antiviral, anti-tumoral, anti-inflammatory, and anti-
anaphylactic activity, but can also be used as antioxidants,
pigments, photo-active materials, and biodegradable agro-
chemicals [2].
The peptide bond is an important functional group in
organic chemistry, biochemistry, and medicine [3–5]. Pep-
tides play crucial roles in the human body and other organ-
isms [6–8]. Due to the biological significance of molecules
with the chromone moiety, we have combined amides and
chromones as molecular entities through carbon–carbon
bond formation to create new molecules. Considering the
versatile activities of these structures, we think it would be
of interest to combine the chromone moiety and the peptide
bond in view of their promising applications in medicinal
chemistry and biological investigations.
Peptide bond is traditionally synthesized by the reac-
tion of an amine with an activated carboxylic acid [9–12].
Among the protocols for the synthesis of peptide bond, one
of the important methods is the Passerini three-component
reaction (P-3CR) [13]. The most commonly used P-3CR,
in which a carboxylic acid, an oxo compound and an iso-
cyanide are reacted results in α-acyloxycarboxamide prod-
ucts. This group of compounds is present in the structures
of many natural products, such as the pharmacologically
active depsipeptides [14, 15]. Also, the P-3CR reaction can
lead to interesting and potentially bioactive peptidomimetic
compounds and offers an inexpensive and rapid way to
generate compound libraries [16].
3-Formylchromone is a highly reactive and well studied
compound which can serve as the starting material for the
syntheses of a whole series of heterocyclic systems due to
Abstract A three-component reaction between a 3-for-
mylchromone, an alkyl isocyanide, and a carboxylic acid
which affords novel 2-(3-chromonyl)-2-acyloxycarboxam-
ide derivatives is reported. This cascade reaction sequence
represents an atom-economic route to biologically interest-
ing molecules.
Graphical Abstract
Electronic supplementary material The online version of this
article (doi:10.1007/s13738-015-0769-7) contains supplementary
material, which is available to authorized users.
* Mohammad Bagher Teimouri
mbteimouri@yahoo.com; teimouri@khu.ac.ir
1
Faculty of Chemistry, Kharazmi University, Mofateh Ave.,
Tehran, Iran
2
Faculty of Chemistry, Omidiyeh Branch, Islamic Azad
University, Omidiyeh, Iran
CH2Cl2, rt
+ + R4
N C
OH
O
R3O
CHO
O
R2
R1
O
O
R2
R1
CONHR4
R3
OCO
Keywords Carboxylic acid · 3-Formylchromone ·
Isocyanide · Passerini reaction
Introduction
Chromones (4H-chromen-4-one derivatives) are an impor-
tant moiety which forms the nucleus of a class of heterocy-
clic natural products called flavonoids that occur naturally

2. J IRAN CHEM SOC
1 3
the presence of three electrophilic centers at C-2, C-4, and
formyl group in this molecule [17]. 3-Formylchromone
can give access to compounds where the chromone ring is
retained or to 2-hydroxybenzoyl derivatives resulting from
the opening of the pyran-4-one ring.
In 2008 [18], 3-formylchromone was used as the oxo
component in Passerini reactions with tosylmethyl isocya-
nide (TosMIC) to yield chromenyl-amidoesters. In continu-
ation of our research in the synthesis of chromone-contain-
ing molecules [19–22], herein, this was taken advantage in
the formation of poly-functional 2-(3-chromonyl)-2-acy-
loxycarboxamides via a three-component condensation
reaction of alkyl isocyanides as an expanded report that
includes more results to another report [18].
Result and discussion
The one-pot three-component condensation reactions of
3-formylchromone derivatives 1 with various carboxylic
acids 2 in the presence of alkyl isocyanides 3 proceeded at
room temperature in dichloromethane and were complete
after 24 h to afford corresponding 2-(3-chromonyl)-2-acy-
loxycarboxamides 4, in good yields (Table 1). 1
H and 13
C
NMR spectra of the crude products clearly indicated the
formation of 2-(3-chromonyl)-2-acyloxycarboxamides 4.
Any other products could not be detected by NMR spec-
troscopy. All products 4a–p are new stable solid com-
pounds whose structures were established by IR, 1
H, 13
C
NMR spectroscopy, and elemental analysis. The full results
are summarized in Table 1.
To survey the generality and scope of this one-pot three-
component protocol, the methodology was applied to the
synthesis of a variety of 2-(3-chromonyl)-2-acyloxycar-
boxamide derivatives 4a–p. With the optimal condition in
hand, we extended the reaction to other carboxylic acid
compounds, and results are indicated in Table 1. Ten deriv-
atives of carboxylic acids including aromatic, heterocyclic,
aliphatic and α,β-unsaturated carboxylic acids, afforded
2-(3-chromonyl)-2-acyloxycarboxamides from good to
excellent isolated yields. Four derivatives of 3-formylchr-
omones underwent the one-pot reaction smoothly without
using any catalyst. To explore the scope of this reaction
with respect to reactive isocyanides, we have examined
four alkyl isocyanides. We have found that the reactions
proceed very efficiently with both sterically hindered and
less hindered alkyl isocyanides.
A probable mechanistic rationale portraying sequence
of events for this three-component coupling is postulated
in Scheme 1 [15]. The first step is believed to be the for-
mation of a loosely hydrogen-bonded adduct 5 from 3-for-
mylchromone derivative and a carboxylic acid followed
by α-addition of the electrophilic carbonyl carbon and the
nucleophilic oxygen atom of the carboxylic acid to the
isocyanide carbon atom under formation of a cyclic transi-
tion state 6 with all three parent compounds. The α-adduct
which cannot be isolated, rearranges in an intramolecular
transacylation to the stable 2-(3-chromonyl)-2-acyloxycar-
boxamides 4.
Conclusions
In summary, 3-formylchromone was introduced as a novel
oxo component in Passerini reactions. Several carboxylic
acids and alkyl isocyanides were compatible under these
reaction conditions to afford diverse 2-(3-chromonyl)-
2-acyloxycarboxamides of potential synthetic and phar-
maceutical interest in good to excellent yields. The present
method carries the advantage of being performed under
neutral conditions and requires no activation or modifica-
tion of the educts.
Experimental
Apparatus
Melting points were measured on a Electrothermal 9100
apparatus and are uncorrected. Elemental analyses were
performed using a Heraeus CHN–O-rapid analyzer. IR
spectra were measured on a Shimadzu IR-460 spectrom-
eter. 1
H and 13
C NMR spectra were recorded on a Bruker
DRX-300 Avance spectrometer at 300.1 and 75.5 MHz,
respectively, with CDCl3 or CD3SOCD3 as solvents and
calibrated using residual undeuterated solvent as an inter-
nal reference. Chemical shifts are reported in parts per mil-
lion (ppm) relative to TMS as internal reference. Analytical
TLC was carried out on pre-coated plates (Merck silica gel
60, F254) and visualized with UV light. All chemical rea-
gents were obtained from Merck, Fluka or Acros and were
used without further purification.
Typical procedure for the preparation of 2‑(benzylam
ino)‑1‑(6‑methyl‑4‑oxo‑4H‑chromen‑3‑yl)‑2‑oxoethyl
benzoate (4a)
To a magnetically stirred solution of 3-formyl-6-methyl-
chromone (0.188 g, 1.0 mmol) and benzoic acid (0.122 g,
1.0 mmol) in anhydrous dichloromethane (10 mL) was
added benzyl isocyanide (0.117 g, 1.0 mmol) at room tem-
perature (25 °C). The reaction mixture was then stirred
for 24 h. After complete conversion, as monitored by TLC
using EtOAc/hexane 1:1 as eluent, the mixture was con-
centrated in vacuo and the solid residue was washed with
diethyl ether and crystallized from CH2Cl2/hexane (1:4)

3. J IRAN CHEM SOC
1 3
Table 1 Synthesis of
compounds 4a–p
CH2Cl2, rt
+ + R4
N C
OH
O
R3O
CHO
O
R2
R1
O
O
R2
R1
CONHR4
R3
OCO
1
2 3
4
Entry R1
R2
R3
R4
Product Yield (%)a
1 CH3 H
O
O O
NH
O
O
CH3
4a
89
2 CH3 H
O
O O
NH
O
O
CH 3
4b
85
3 CH3 H
Cl
Cl
CH3
CH3
3
CH3
CH
CH3
CH3 CH3
O
O O
NH
O
O
CH3
Cl
Cl
CH3
CH3
CH3
4c
92
4 CH3 H
NO2
O
O O
NH
O
O
CH3
NO2
4d
95
5 CH3 H
O
O
O O
O
O
NH
CH3
O
4e
79
6 CH3 H
O
O O
NH
O
O
CH3
4f
86
7 CH3 H
Cl
O
O O
NH
O
O
CH3
Cl
4g
89

4. J IRAN CHEM SOC
1 3
Table 1 continued
8 CH3 H
Cl
O
O O
O
O
NH
CH3
Cl
4h
83
9 CH3 H
Br
O
O O
O
O
NH
CH3
Br
4i
86
10 CH3 H
Br
O
O O
O
O
NH
CH3
Br
4j
91
11 CH3 H
O
O O
O
O
NH
CH3
4k
81
12 H H
O
O O
NH
O
O
4l
92
13 H H
O
O
O O
NH
O
O
O
4m
82
14 H H
Br
3
CH3
CH
CH3
CH3 CH3
O
O O
NH
O
O
CH3
Br
CH3
4n
80
15 Cl H
O
O O
NH
O
O
Cl
4o
90
16 Cl Cl
NO2
O
O O
NH
O
O
Cl
NO2
Cl 4p
87
Entry R1
R2
R3
R4
Product Yield (%)a
a
Refers to purified yield. Puri-
ties were >95 % according to
1
H NMR spectroscopy

5. J IRAN CHEM SOC
1 3
to afford pure product. The dried product thus obtained
showed a single spot on TLC and was pure enough for all
analytical purposes.
Pale yellow powder; m.p. 196–198 °C (dec.); IR
(KBr) (νmax, cm−1
): 3343 (N–H), 1717, 1687, 1634
(C=O), 1610 (C=C); 1
H NMR (CDCl3, 300.1 MHz): δH
2.45 (3 H, s, CH3), 4.46 and 4.58 (2 H, doublet of AB-q,
2
JHH = 15.1 Hz, 3
JHH = 5.7 Hz, NH–CHAHB–Ph), 6.38 (1
H, s, O=C–CH), 7.18–7.60 (11 H, m, arom. H+NH), 7.99
(1 H, br. s, arom. H), 8.09–8.11 (2 H, m, arom. H), 8.32 (1
H, s, C=CH–O); 13
C NMR (CDCl3, 75.5 MHz): δC 176.5,
167.5, 165.2, 155.4, 154.6, 137.8, 135.8, 135.5, 133.6,
129.9, 129.1, 128.6, 128.5, 127.4, 127.3, 125.1, 123.4,
119.4, 118.0, 69.2, 43.5, 20.9; Anal. Calcd for C26H21NO5
(427.44) C 73.06, H 4.95, N 3.28 %; Found C 72.87, H
4.93, N 3.30 %.
2‑(Cyclohexylamino)‑1‑(6‑methyl‑4‑oxo‑4H‑chromen‑3‑
yl)‑2‑oxoethyl benzoate (4b)
White powder; m.p. 163–165 °C (dec.); IR (KBr) (νmax,
cm−1
): 3314 (N–H), 1714, 1662, 1644 (C=O), 1609
(C=C); 1
H NMR (CDCl3, 400.2 MHz): δH 1.22–2.19 (10
H, m, 5 CH2), 2.48 (3 H, s, CH3), 3.77 (1 H, m, NH–CH),
6.31 (1 H, s, O–CH), 6.84 (1 H, d, 3
JHH = 8.0 Hz, NH–
CH), 7.41–8.14 (8 H, m, arom. H), 8.33 (1 H, s, C=CH–O);
13
C NMR (CDCl3, 100.6 MHz): 176.5, 166.5, 165.3, 155.3,
154.6, 135.7, 135.5, 133.6, 129.9, 129.3, 128.6, 125.1,
123.6, 119.6, 118.1, 69.3, 48.4, 33.5, 32.8, 32.6, 25.5, 24.6,
21.0; Anal. Calcd for C25H25NO5 (419.46) C 71.58, H 6.01,
N 3.34 %; Found C 71.34, H 5.98, N 3.33 %.
1‑(6‑Methyl‑4‑oxo‑4H‑chromen‑3‑yl)‑2‑oxo‑2‑[(1,1,3,3‑t
etramethylbutyl)amino]ethyl 2,4‑dichlorobenzoate (4c)
White powder; m.p. 255–257 °C (dec.); IR (KBr) (νmax,
cm−1
): 3385 (N–H), 1727, 1676, 1645 (C=O), 1608
(C=C); 1
H NMR (CDCl3, 400.2 MHz): δH 0.90 (9 H, s,
CMe3), 1.37 (6 H, s, CMe2), 1.61 and 1.77 (2 H, AB-q sys-
tem, 2
JHH = 14.9 Hz, CH2), 2.43 (3 H, s, CH3), 6.22 (1 H,
s, O–CH), 7.24–7.49 and 7.89–8.04 (6 H, 2 m, arom. H),
8.23 (1 H, s, C=CH–O); 13
C NMR (CDCl3, 100.6 MHz):
177.4, 166.1, 164.2, 155.8, 155.3, 139.7, 136.6, 136.4,
135.7, 134.1, 131.8, 128.4, 128.0, 125.9, 124.2, 120.0,
118.9, 70.7, 56.4, 52.4, 32.3, 32.1, 30.0, 29.7, 21.8; Anal.
Calcd for C27H29Cl2NO5 (518.42) C 62.55, H 5.64, N
2.70 %; Found C 62.40, H 5.66, N 2.73 %.
2‑(Cyclohexylamino)‑1‑(6‑methyl‑4‑oxo‑4H‑chromen‑3‑
yl)‑2‑oxoethyl 4 nitrobenzoate (4d)
White powder; m.p. 254–256 °C (dec.); IR (KBr) (νmax,
cm−1
): 3274 (N–H), 1724, 1654, 1625 (C=O), 1619 (C=C)
1
H NMR (DMSO-d6, 300.1 MHz): δH 1.06–1.76 (10 H, m,
5 CH2), 2.43 (3 H, s, CH3), 3.50–3.60 (1 H, m, NH–CH),
6.28 (1 H, s, O=C–CH), 7.59–7.69 (2 H, m, arom. H), 7.87
(1 H, s, arom. H), 8.14 (1 H, d, 3
JHH = 7.8 Hz, NH–CH),
8.20 and 8.33 (4 H, m, C6H4NO2), 8.48 (1 H, s, C=CH–O);
13
C NMR (DMSO-d6, 75.5 MHz): δC 174.8, 165.1, 163.6,
156.8, 154.1, 150.4, 135.8, 135.7, 134.6, 131.0, 124.3,
123.9, 123.0, 119.0, 118.4, 69.0, 48.0, 32.1, 25.1, 24.6,
24.5, 20.4; Anal. Calcd for C25H24N2O7 (464.46) C 64.65,
H 5.21, N 6.03 %; Found C 64.78, H 5.20, N 6.00 %.
Scheme 1 Plausible reaction
mechanism
R4
N C
R3
OH
O
O
O
O
H
O
O H
O
O
R3
N
R4
R3
NHR4
O
O R3
5
64
1
2
3
O
O
R1
R2
H
O
O
O
R1
R2
O
O
R1
R2
O
O
R1
R2

6. J IRAN CHEM SOC
1 3
2‑(Cyclohexylamino)‑1‑(6‑methyl‑4‑oxo‑4H‑chromen‑3‑
yl)‑2‑oxoethyl 2‑furoate (4e)
White powder; m.p. 202–204 °C (dec.); IR (KBr) (νmax,
cm−1
): 3297 (N–H), 1724, 1690 (C=O); 1
H NMR (CDCl3,
400.2 MHz): δH 1.14–2.05 (10 H, m, 5 CH2), 2.48 (3 H, s,
CH3), 3.74–3.85 (1 H, m, NH–CH), 6.26 (1 H, s, O–CH),
6.55 (1 H, dd, 3
JHH = 3.6 Hz, 3
JHH = 1.6 Hz, OCH=CH–
CH of furan moiety), 6.83 (1 H, br d, 3
JHH = 8.0 Hz, NH–
CH), 7.33 (1 H, d, 3
JHH = 3.2 Hz, OCH=CH–CH of furan
moiety), 7.41 (1 H, t, 3
JHH = 8.4 Hz, CH of chromone moi-
ety), 7.53 (1, d, 3
JHH = 8.8 Hz, 3
JHH = 1.6 Hz, CH of chr-
omone moiety), 7.63 (1 H, app. s, OCH=CH–CH of furan
moiety), 8.03 (1 H, s, CH of chromone moiety), 8.32 (1
H, s, C=CH–O); 13
C NMR (CDCl3, 100.6 MHz): 176.4,
166.1, 157.1, 155.5, 154.6, 147.0, 143.8, 135.8, 135.5,
125.1, 123.5, 119.4, 119.3, 118.1, 112.1, 69.0, 48.4, 32.8,
32.6, 25.5, 24.6, 21.0; Anal. Calcd for C23H23NO6 (409.43)
C 67.47, H 5.66, N 3.42 %; Found C 67.69, H 5.70, N
3.39 %.
2‑(Cyclohexylamino)‑1‑(6‑methyl‑4‑oxo‑4H‑chromen‑3‑
yl)‑2‑oxoethyl phenylacetate (4f)
White powder; m.p. 120–122 °C (dec.); IR (KBr) (νmax,
cm−1
): 3312 (N–H), 1732, 1664, 1643 (C=O), 1555
(C=C); 1
H NMR (CDCl3, 300.1 MHz): δH 0.99–1.97 (10
H, m, 5 CH2), 2.46 (3 H, s, CH3), 3.65–3.73 (1 H, m, NH–
CH), 3.79 (2 H, s, O=CCH2), 6.03 (1 H, s, O=C–CH),
6.59 (1 H, d, 3
JHH = 8.1 Hz, NH–CH), 7.28–7.53 (7 H, m,
arom. H), 8.00 (1 H, br. s, arom. H), 8.05 (1 H, s, C=CH–
O); 13
C NMR (CDCl3, 75.5 MHz): δC 176.4, 170.0, 166.2,
155.4, 154.5, 135.7, 135.4, 133.4, 129.3, 128.7, 128.5,
127.3, 125.0, 123.5, 119.2, 118.0, 69.0, 48.2, 41.1, 32.7,
32.5, 25.4, 24.6, 20.9; Anal. Calcd for C26H27NO5 (433.49)
C 72.04, H 6.28, N 3.23 %; Found C 71.91, H 6.32, N
3.20 %.
2‑(Cyclohexylamino)‑1‑(6‑methyl‑4‑oxo‑4H‑chromen‑3‑
yl)‑2‑oxoethyl chloroacetate (4g)
White powder; m.p. 159–161 °C (dec.); IR (KBr) (νmax,
cm−1
): 3295 (N–H), 1741, 1661, 1645 (C=O), 1619
(C=C); 1
H NMR (CDCl3, 300.1 MHz): δH 1.07–1.99
(10 H, m, 5CH2), 2.46 (3 H, s, CH3), 3.72–3.75 (1 H,
m, NH–CH), 4.20 and 4.25 (2 H, AB-q, 2
JHH = 15.0 Hz,
O=CCH2), 6.13 (1 H, s, O=C–CH), 6.82 (1 H, d,
3
JHH = 7.9 Hz, NH–CH), 7.38–7.54 (2 H, m, arom. H),
7.99 (1 H, br. s, arom. H), 8.20 (1 H, s, C=CH–O); 13
C
NMR (CDCl3, 75.5 MHz): δC 176.3, 166.0, 165.5, 155.1,
154.7, 154.5, 135.9, 135.6, 125.0, 123.3, 118.8, 118.0,
69.8, 48.5, 40.6, 32.7, 32.5, 25.4, 24.5, 20.9; Anal. Calcd
for C20H22ClNO5 (391.87) C 61.30, H 5.66, N 3.57 %;
Found C 61.45, H 5.61, N 3.60 %.
2‑(Cyclohexylamino)‑1‑(6‑methyl‑4‑oxo‑4H‑chromen‑3‑
yl)‑2‑oxoethyl 3‑chloropropanoate (4h)
White powder; m.p. 155–157 °C (dec.); IR (KBr) (νmax, cm−1
):
3306 (N–H), 1731, 1661, 1645 (C=O), 1620 (C=C); 1
H
NMR (CDCl3, 300.1 MHz); δH 1.10–2.00 (10 H, m, 5 CH2),
2.46 (3 H, s, CH3), 2.94–3.01 (2 H, m, O=C–CH2), 3.80–3.82
(1 H, m, NH–CH), 3.82–3.84 (2 H, m, ClCH2), 6.13 (1 H, s,
O=C–CH), 6.82 (1 H, d, 3
JHH = 7.9 Hz, NH–CH), 7.39 (1
H, 3
JHH = 8.6 Hz, arom. H), 7.52 (1 H, dd, 3
JHH = 8.6 Hz,
4
JHH = 1.9 Hz, arom. H), 7.99 (1 H, app. s, arom. H), 8.18
(1 H, s, C=CH–O); 13
C NMR (CDCl3, 75.5 MHz): δC 176.4,
168.9, 166.0, 155.1, 154.5, 135.7, 135.5, 125.0, 123.4, 119.1,
118.0, 68.9, 48.4, 38.8, 37.4, 32.7, 32.5, 25.4, 24.6, 20.9;Anal.
Calcd for C21H24ClNO5 (405.87) C 62.14, H 5.96, N 3.45 %;
Found C 62.02, H 6.00, N 3.40 %.
2‑(Cyclohexylamino)‑1‑(6‑methyl‑4‑oxo‑4H‑chromen‑3‑
yl)‑2‑oxoethyl bromoacetate (4i)
White powder; m.p. 158–160 °C (dec.); IR (KBr) (νmax,
cm−1
): 3300 (N–H), 1732, 1663, 1645 (C=O), 1619
(C=C); 1
H NMR (CDCl3, 300.1 MHz): δH 1.12–2.00
(10 H, m, 5 CH2), 2.46 (3 H, s, CH3), 3.70–3.76 (1 H,
m, NH–CH), 3.98 (2 H, app. s, O=CCH2), 6.09 (1 H, s,
O=C–CH), 6.80 (1 H, d, 3
JHH = 7.8 Hz, NH–CH), 7.38–
7.54 (2 H, m, arom. H), 7.99 (1 H, br. s, arom. H), 8.19 (1
H, s, C=CH–O); 13
C NMR (CDCl3, 75.5 MHz): δC 176.3,
165.8, 165.6, 155.2, 154.5, 135.8, 135.6, 125.0, 123.4,
118.8, 118.0, 69.9, 48.4, 32.7, 32.5, 25.4, 25.3, 24.5,
20.9; Anal. Calcd for C20H22BrNO5 (436.29) C 55.06, H
5.08, N 3.21 %; Found C 54.91, H 5.07, N 3.18 %.
2‑(Cyclohexylamino)‑1‑(6‑methyl‑4‑oxo‑4H‑chromen‑3‑
yl)‑2‑oxoethyl 5‑bromopentanoate (4j)
Pale yellow powder; m.p. 138–140 °C (dec.); IR (KBr)
(νmax, cm−1
): 3321 (N–H), 1725, 1663, 1640 (C=O),
1618 (C=C); 1
H NMR (CDCl3, 300.1 MHz): δH 1.07–
2.68 and 2.47–2.68 (19 H, 2 m, 8 CH2+CH3), 3.43 (1 H,
t, 3
JHH = 6.4 Hz, CH2Br), 3.70–3.77 (1 H, m, NH–CH),
6.08 (1 H, s, O=C–CH), 6.77 (1 H, d, 3
JHH = 7.7 Hz, CH–
NH), 7.39–7.42 and 7.51–7.54 (2 H, 2 m, arom. H), 8.01
(1 H, app. s, arom. H), 8.20 (1 H, s, C=CH–O); 13
C NMR
(CDCl3, 75.5 MHz): δC 176.5, 171.7, 166.3, 155.0, 154.5,
135.7, 135.5, 125.0, 123.4, 119.3, 118.0, 68.4, 48.3, 33.1,
33.0, 32.7, 32.6, 31.7, 25.4, 24.6, 23.3, 21.0; Anal. Calcd
for C23H28BrNO5 (478.37) C 57.75, H 5.90, N 2.93 %;
Found C 57.83, H 5.85, N 2.90 %.

7. J IRAN CHEM SOC
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2‑(Cyclohexylamino)‑1‑(6‑methyl‑4‑oxo‑4H‑chromen‑3‑
yl)‑2‑oxoethyl (2E)‑3‑phenylacrylate (4k)
White powder; m.p. 159–161 °C (dec.); IR (KBr) (νmax,
cm−1
): 3318 (N–H), 3087 (=C–H), 1704, 1662, 1642
(C=O), 1619 (C=C); 1
H NMR (CDCl3, 300.1 MHz): δH
1.16–2.05 (10 H, m, 5 CH2), 2.46 (3 H, s, CH3), 3.78–3.81
(1 H, m, NH–CH), 6.20 (1 H, s, O=C–CH), 6.59 (1 H, d,
3
JHH = 16.0 Hz, HC=CH), 6.82 (1 H, br. d, 3
JHH = 8.1 Hz,
NH–CH), 7.39–7.41 (4 H, m, arom. H), 7.49–7.56 (3 H, m,
arom. H), 7.79 (1 H, d, 3
JHH = 16.0 Hz, HC=CH), 8.01
(1 H, br. s, arom. H), 8.27 (1 H, s, C=CH–O); 13
C NMR
(CDCl3, 75.5 MHz): δC 176.4, 166.4, 165.5, 155.3, 154.5,
146.5, 135.6, 135.4, 134.0, 130.6, 128.9, 128.2, 125.0,
123.5, 119.5, 118.0, 116.8, 116.7, 68.7, 48.4, 32.8, 32.6,
25.4, 24.6, 20.9; Anal. Calcd for C27H27NO5 (445.50) C
72.79, H 6.11, N 3.14 %; Found C 72.59, H 6.08, N 3.19 %.
2‑(Cyclohexylamino)‑2‑oxo‑1‑(4‑oxo‑4H‑chromen‑3‑yl)
ethyl benzoate (4l)
White powder; m.p. 165–167 °C (dec.); IR (KBr) (νmax,
cm−1
): 3290 (N–H), 1720, 1684, 1633 (C=O), 1610
(C=C); 1
H NMR (CDCl3, 400.2 MHz): δH 1.13–2.01 (10
H, m, 5 CH2), 3.70–3.80 (1 H, m, NH–CH), 6.22 (1 H, s,
O–CH), 6.78 (1 H, d, 3
JHH = 7.6 Hz, NH–CH), 7.39–7.68
and 8.08–8.31 (9 H, 2 m, arom. H), 8.33 (1 H, s, C=CH–
O); 13
C NMR (CDCl3, 100.6 MHz): 177.2, 167.2, 166.0,
157.1, 156.3, 135.0, 134.4, 130.7, 130.1, 129.4, 126.7,
126.4, 124.7, 120.7, 119.1, 70.1, 49.3, 33.6, 33.4, 26.3,
25.4; Anal. Calcd for C24H23NO5 (405.44) C 71.10, H 5.72,
N 3.45 %; Found C 70.82, H 5.68, N 3.44 %.
2‑(Cyclohexylamino)‑2‑oxo‑1‑(4‑oxo‑4H‑chromen‑3‑yl)
ethyl 2‑furoate (4m)
White powder; m.p. 183–185 °C (dec.); IR (KBr) (νmax,
cm−1
): 3305 (N–H), 1720, 1687, 1636 (C=O), 1607 (C=C);
1
H NMR (CDCl3, 400.2 MHz): δH 1.18–2.05 (10 H, m, 5
CH2), 3.77–3.83 (1 H, m, NH–CH), 6.26 (1 H, s, O–CH),
6.55 (1 H, dd, 3
JHH = 3.2 Hz, 3
JHH = 1.6 Hz, OCH=CH–
CH of furan moiety), 6.81 (1 H, d, 3
JHH = 8.0 Hz, NH–
CH), 7.33 (1 H, d, 3
JHH = 3.2 Hz, OCH=CH–CH of furan
moiety), 7.45 (1 H, t, 3
JHH = 7.2 Hz, CH of chromone moi-
ety), 7.51 (1 H, d, 3
JHH = 8.4 Hz, CH of chromone moi-
ety), 7.63 (1 H, d, app. s, OCH=CH–CH of furan moiety),
7.72 (1 H, t, 3
JHH = 7.6 Hz, CH of chromone moiety), 8.24
(1 H, d, 3
JHH = 8.0 Hz, CH of chromone moiety), 8.34 (1
H, s, C=CH–O); 13
C NMR (CDCl3, 100.6 MHz): 176.3,
166.0, 157.1, 156.3, 155.7, 147.0, 143.7, 134.3, 125.9,
125.7, 123.9, 119.5, 119.3, 118.3, 112.1, 77.0, 69.0, 48.5,
32.7, 32.6, 25.5, 24.6; Anal. Calcd for C22H21NO6 (395.40)
C 66.83, H 5.35, N 3.54 %; Found C 67.03, H 5.38, N
3.50 %.
2‑(Tert‑butylamino)‑1‑(6‑methyl‑4‑oxo‑4H‑chromen‑3‑y
l)‑2‑oxoethyl bromoacetate (4n)
White powder; m.p. 128–130 °C (dec.); IR (KBr) (νmax,
cm−1
): 3300 (N–H), 1762, 1685, 1634 (C=O), 1621
(C=C); 1
H NMR (CDCl3, 300.1 MHz): δH 1.35 (9 H, s,
C(CH3)3), 3.98 (2 H, app. s, O=CCH2), 6.03 (1 H, s, O=C–
CH), 6.75 (1 H, s, NH), 7.42–7.52 (2 H, m, arom. H), 7.69–
7.75 (1 H, m, arom. H), 8.21 (1 H, s, C=CH–O), 8.21–
8.24 (1 H, m, arom. H); 13
C NMR (CDCl3, 75.5 MHz):
δC 176.3, 165.7, 165.4, 156.2, 155.3, 134.3, 125.8, 125.7,
123.7, 119.2, 118.3, 69.9, 51.7, 28.6, 25.3; Anal. Calcd for
C18H20BrNO5 (410.25) C 52.70, H 4.91, N 3.41 %; Found
C 52.58, H 4.88, N 3.40 %.
1‑(6‑Chloro‑4‑oxo‑4H‑chromen‑3‑yl)‑2‑(cyclohexylamin
o)‑2‑oxoethyl benzoate (4o)
White powder; m.p. 191–193 °C (dec.); IR (KBr) (νmax,
cm−1
): 3297 (N–H), 1713, 1660, 1645 (C=O), 1610
(C=C); 1
H NMR (CDCl3, 400.2 MHz): δH 1.19–2.07 (10
H, m, 5 CH2), 3.80–3.86 (1 H, m, NH–CH), 6.28 (1 H, s,
O–CH), 6.71 (1 H, d, 3
JHH = 8.4 Hz, NH–CH), 7.48–7.52
(5 H, m, Phenyl), 8.12 and 8.13 (2 H, 2 d, 3
JHH = 7.2 Hz,
CH=CH of chromone moiety), 8.22 (1 H, d, 4
JHH = 2.8 Hz,
ClC=CH of chromone moiety), 8.34 (1 H, s, C=CH–O);
13
C NMR (CDCl3, 100.6 MHz): 178.1, 166.1, 165.2, 155.7,
154.6, 134.5, 133.7, 131.7, 129.9, 129.2, 128.6, 125.3,
124.9, 120.1, 120.0, 69.2, 48.5, 32.8, 32.7, 29.7, 25.5, 24.6;
Anal. Calcd for C24H22ClNO5 (439.88) C 65.53, H 5.04, N
3.18 %; Found C 65.74, H 5.00, N 3.20 %.
2‑(Cyclohexylamino)‑1‑(6,8‑dichloro‑4‑oxo‑4H‑chrome
n‑3‑yl)‑2‑oxoethyl 4‑nitrobenzoate (4p)
White powder; m.p. 258–260 °C (dec.); IR (KBr) (νmax,
cm−1
): 3279 (N–H), 1732, 1654 (C=O), 1599 (C=C);
1
H NMR (CDCl3, 300.1 MHz): δH 1.10–1.76 (10 H, m, 5
CH2), 3.52–3.60 (1 H, m, NH–CH), 6.27 (1 H, s, O=C–
CH), 7.98 (1 H, d, 3
JHH = 2.2 Hz, arom. H), 8.08 (1 H, d,
3
JHH = 7.7 Hz, CH–NH), 8.20–8.35 (3 H, 2 m, arom. H),
8.68 (1 H, s, C=CH–O); 13
C NMR (CDCl3, 75.5 MHz):
δC 173.4, 164.6, 163.5, 157.3, 150.4, 134.5, 134.2, 131.0,
130.2, 125.4, 124.0, 123.8, 123.3, 119.6, 68.8, 48.2, 32.0,
25.1, 24.5; Anal. Calcd for C24H20Cl2N2O7 (519.33)
C 55.51, H 3.88, N 5.39 %; Found C 55.42, H 3.90, N
5.35 %.

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Acknowledgments The authors thank Kharazmi University
Research Council for financial support of this research.
References
1. G.P. Ellis, I.M. Lockhart, Chemistry of heterocyclic compounds,
chromenes, chromanones, and chromones, vol. 31, ed. by G.P.
Ellis (Wiley–VCH, London, 2007)
2. R.S. Keri, S. Budagumpi, R.K. Pai, R.G. Balakrishna, Eur. J.
Med. Chem. 78, 340 (2014)
3. T. Cupido, J. Tulla-Puche, J. Spengler, F. Albericio, Curr. Opin.
Drug Discov. Dev. 10, 768 (2007)
4. J.W. Bode, Curr. Opin. Drug Disco. Dev. 9, 765 (2006)
5. J.M. Humphrey, A.R. Chamberlin, Chem. Rev. 97, 2243 (1997)
6. F.-F. Tian, P. Zhou, Z.-L. Li, J. Mol. Struct. 830, 106 (2007)
7. M. Shu, H. Mei, S.Yang, L. Liao, Z. Li, Q.S.A.R. Comb, Sci. 28,
27 (2009)
8. T. Day, S.A. Greenfield, Exp. Brain Res. 155, 500 (2004)
9. R.C. Larock, Comprehensive organic transformations (VCH,
New York, 1999)
10. E. Valeur, M. Bradley, Chem. Soc. Rev. 38, 606 (2009)
11. S.Y. Han, Y.A. Kim, Tetrahedron 60, 2447 (2004)
12. C.A.G.N. Montalbetti, V. Falque, Tetrahedron 61, 10827 (2005)
13. L. Banfi, R. Riva, Org. React. 65, 1 (2005)
14. A. Dömling, Chem. Rev. 106, 17 (2006)
15. A. Dömling, I. Ugi, Angew. Chem. Int. Ed. 39, 3168 (2000)
16. I. Ugi, S. Heck, Comb. Chem. High Throughput Screen. 4, 1
(2001)
17. G. Sabitha, Aldrichim. Acta 29, 15 (1996)
18. M.A. Terzidis, J. Stephanidou-Stephanatou, C.A. Tsoleridis,
Open Org. Chem. J. 2, 88 (2008)
19. M.B. Teimouri, P. Akbari-Moghaddam, G. Golbaghi, A.C.S.
Comb, Science 13, 659 (2011)
20. M.B. Teimouri, Tetrahedron 67, 1837 (2011)
21. M.B. Teimouri, M. Eskandari, J. Chem. Res. 500 (2011)
22. M.B. Teimouri, B. Asnaashari, Tetrahedron Lett. 55, 2249 (2014)