Pseudo-five-component reaction between 3-formylchromones, Meldrum's acid, isocyanides and primary arylamines: Diversity-oriented synthesis of novel chromone-containing peptidomimetics

Article abstract of DOI:10.1021/co200125a

An efficient and practical method has been developed for the diversity-oriented synthesis of chromone-containing tripeptides via pseudo-five-component reaction between 3-formylchromones, Meldrum's acid, isocyanides and primary aromatic amines for the generation of a wide range of structurally interesting and pharmacologically significant compounds at ambient temperature. It is worth mentioning that in the course of this reaction, five new bonds (two C-C bonds, two C-N bonds and one C=O bond) are formed. In the present reaction three amide bonds are newly formed.

Full text of DOI:10.1021/co200125a

RESEARCH ARTICLE
pubs.acs.org/acscombsci
Pseudo-Five-Component Reaction between 3-Formylchromones,
Meldrum’s Acid, Isocyanides and Primary Arylamines:
Diversity-Oriented Synthesis of Novel Chromone-Containing
Peptidomimetics
Mohammad Bagher Teimouri,*,† Peyman Akbari-Moghaddam,† and Golara Golbaghi‡
†Petrochemical Department, Iran Polymer and Petrochemical Institute, P.O. Box 14965-115, Tehran, Iran
‡Department of Chemistry, School of Sciences, Alzahra University, Vanak, Tehran, Iran
S Supporting Information
b
ABSTRACT: An efficient and practical method has been
developed for the diversity-oriented synthesis of chromone-
containing tripeptides via pseudo-five-component reaction be-
tween 3-formylchromones, Meldrum’s acid, isocyanides and
primary aromatic amines for the generation of a wide range of
structurally interesting and pharmacologically significant compounds at ambient temperature. It is worth mentioning that in the
course of this reaction, five new bonds (two CꢀC bonds, two CꢀN bonds and one CdO bond) are formed. In the present reaction
three amide bonds are newly formed.
KEYWORDS: 3-formylchromone, isocyanide, Meldrum’s acid, multicomponent reaction, triamide
’ INTRODUCTION
hetero- andcarbo-annulated chromonederivatives whichareuseful
antiplatelet,24 antifungal25 and anticancer agents.26 They display
not only spasmolytic, diuretic, clotting, antiviral, antitumoral, and
antianaphylactic activity, but can also be used as pigments, photo-
active materials, and biodegradable agrochemicals.27
Considering the versatile bioactivities of the above-mentioned
structures, we hypothesize that the integration of chromone
scaffold with a triamide segment may result in the discovery of
new drug candidates with unknown bioactivities. However, the
design of triamide compounds implanted with chromone frame-
works for medicinal purpose has been less recognized. Therefore,
the development of a facile approach to access these novel targets
with structural diversity is highly desirable and valuable for
medicinal chemistry and drug discovery.
Peptides are traditionally synthesized by the reaction of
amines with activated carboxylic acid derivatives.28 Among the
protocols for the synthesis of peptides, one of the important
methods is the Ugi four-component reaction (U-4CR).29 The
most commonly used U-4CR, in which a carboxylic acid, an
amine, a carbonyl compound and an isocyanide are reacted to
result in peptide-like products, has come into widespread use for
generating large collections of molecules in combinatorial synth-
esis. Of notable outcome, although the Ugi four-component
condensation was successfully performed by employing carboxylic
acids as starting materials, in the course of our investigations30 into
the reactions between isocyanides and carbonyl compounds in
The peptide bond is an important functional group in
organic chemistry, biochemistry, and medicine.1 Peptides play
crucial roles in the human body and other organisms.2 Among
them, di- and tripeptides and their analogues have exhibited
a wide spectrum of important bioactivities such as antibacterial,3
antitumor,4 anticarcinogenic,5 neuroprotective,6 and anti-
diabetic7 activities. Because of the good affinity of the peptides
toward cells and nucleic acids, the introduction of a peptide
segment onto drugs can facilitate their interactions with cells and
tissues and thereby provide a robust strategy to design new drugs
or lead compounds. Heterocyclic compounds have distinguished
themselves from other small molecules because of their profound
bioactivities. The practice of attaching heterocyclic skeletons
and peptides onto one molecule has received much attention
from synthetic and medicinal chemists for the discovery of
novel compounds with unknown or improved pharmacological
properties.8,5b However, the scopes of bioactive small molecules,
especially heterocyclic molecules used for incorporation with
tripeptide segments are rather limited. As a result, it is a
formidable and urgent task to synthesize a new class of tripeptide
compounds containing bioactive skeletons.
The chromone moiety forms the nucleus of a class of hetero-
cyclic natural products called flavanoids that occur naturally in
fruits, vegetables, nuts, seeds, flowers, and barks.9ꢀ11 They are an
integral part of the human diet and have been reported to exhibit
a wide range of biological effects.12ꢀ19 Chromone is also part of
pharmacophores of a large number of molecules of medicinal
significance20,21 including anticancer agents such as psorosper-
min and pluramycin A.22,23 Some other recent examples include
Received: August 2, 2011
Revised:
September 11, 2011
Published: September 15, 2011
r
2011 American Chemical Society
659
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RESEARCH ARTICLE
Scheme 1. Synthesis of Tripeptide-Bound Chromones 5
Figure 1. 3-Formylchromones 1{1ꢀ4}.
Figure 2. Isocyanides 3{1ꢀ10}.
presence of CH-acids it is found that one of the useful modifica-
tions of this synthetic methodology can be the use of Meldrum’s
acid as the acid component. We envisaged that the combination
of a chromone system with the peptide bonds would allow
the development of a new class of biologically active molecules
and useful synthetic building blocks in organic and medicinal
chemistry.
’ RESULTS AND DISCUSSION
When a mixture of 3-formylchromones 1 and Meldrum’s acid
2 as acid component in dry CH2Cl2 is treated with primary
arylamines 4 in the presence of alkyl or aryl isocyanides 3 the
reaction leads to N2-alkyl or aryl-2-(4-oxo-4H-chromen-3-yl)-
N1,N1-diarylethane-1,1,2-tricarboxamide derivatives 5. The reac-
tion allows the creation of three peptide bonds in a single
operation.
Figure 3. Arylamines 4{1ꢀ9}.
The elucidation of the structure of 5 using 1H and 13C NMR
spectroscopic data is discussed with 5{1,1,1} as an example. The
1H NMR spectrum of 5{1,1,1} consisted of multiplet signals for
the cyclohexyl rings (δH 0.91ꢀ1.58 ppm) and the NHꢀCH
resonance (δH 3.30ꢀ3.42 ppm) and an AB system (JAB = 11.6
Hz) for the two methine (δH 4.41 and 4.52 ppm) protons. A
fairly broad doublet resonance (δH 7.99 ppm) was observed for
the cyclohexyl-NH group and the aromatic protons gave rise to
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RESEARCH ARTICLE
multiplets in the aromatic region of the spectrum (δH 6.94ꢀ7.74
ppm). The vinylic methine gives rise to a sharp singlet signal (δH
8.37 ppm). Two broad singlets (δH 9.76 and 9.97 ppm) were
followed by a [1 + 4] cycloaddition reaction32 with isocyanide 3
to afford an iminolactone intermediate 7. It is well-known that
acylated Meldrum’s acids33 and also arylidene Meldrum’s acids34
can readily lose acetone in the presence of nucleophiles, so it is
reasonable to assume that the reaction of fused iminolactone 7
with arylamine and subsequently loss of acetone from 8 leads to
formation of iminolactone 8. Finally, nucleophilic attack of the
second molecule of arylamine to the activated carbonyl moiety
of 8, yields product 5.
1
observed for the two Ph-NH protons. The H decoupled 13C
NMR spectrum of 5{1,1,1} showed 26 distinct resonances in
agreement with the suggested structure. The 1H and 13C NMR
spectra of 5{1,2,1}-5{4,1,1} are similar to those of 5{1,1,1}
except for the R1, R2, R3 or Ar groups, which exhibit characteristic
signals with appropriate chemical shifts.
The formation of tripeptide-bound chromone 5 could be
accounted for by a plausible reaction pathway outlined in
Scheme 2. The reaction may be rationalized as by initial forma-
tion of conjugated electron-deficient heterodiene by Knoevenogel
condensation of the 3-formylchromone 1 and Meldrum’s acid 2,
To gain an insight into a possible reaction mechanism, the
5-[(4-oxo-4H-chromen-3-yl)methylene]-Meldrum’s acid as a
representative Knoevenagel condensation adduct was synthe-
sized separately by the condensation of 3-formylchromone and
Meldrum’s acid.31 Then we examined the reaction of the isolated
5-[(4-oxo-4H-chromen-3-yl)methylene]-Meldrum’s acid with
one equivalent of cyclohexyl isocyanide in the presence of two
equivalents of aniline in anhydrous CH2Cl2 at room temperature,
and we obtained the product 5{1,1,1} in excellent yield.
Table 1. Pseudo-Five-Component Condensation Reactions
of 3-Formylchromones, Meldrum’s Acid and Alkyl or Aryl
Isocyanides in the Presence of Primary Arylamines in Anhy-
drous Dichloromethane
To survey the generality and scope of this one-pot pseudo
five-component protocol, the methodology was applied to the
synthesis of a variety of N2-alkyl or aryl-2-(4-oxo-4H-chromen-3-yl)-
N1,N1-diarylethane-1,1,2-tricarboxamide derivatives 5{1,1,1}ꢀ
5{4,1,1}. With the optimal condition in hand, we extended the
reaction to other 3-formylchromone compounds, and results are
indicated in Table 1. Four derivatives of 3-formylchromones
afforded tripeptide-bound chromones from good to excellent
isolated yields. The yield of the product seems to be affected by
the nature of substituents at C-6 and C-8, and increases when
electron- withdrawing substituents are present. To explore the
scope of this reaction with respect to reactive isocyanides, we
have examined ten alkyl or aryl isocyanides. We have found that
the reaction proceeds very efficiently with both sterically hin-
dered and less hindered alkyl or aryl isocyanides. A variety of aryl
amines carrying different functional groups were subjected to the
coupling reactions and in all cases the desired product was
obtained in reasonable yields. It was observed that under similar
conditions, a wide range of anilines containing electron-donating
as well as electron-withdrawing groups, such as methoxy, methyl,
ethyl, phenyl, fluoro, and nitro underwent condensation with
good isolated yields. It seems that the groups attached on the
aromatic ring of aryl amine do not affect the reaction significantly.
Encouraged by the above results, we continued our task to
explore the reactivity of different aliphatic primary and secondary
amines with 3-formylchromone, Meldrum’s acid and cyclohexyl
isocyanide under similar reaction conditions. The reaction
entry formylchromone isocyanide arylamine product yield a (%)
1
1{1}
1{1}
1{1}
1{1}
1{1}
1{1}
1{1}
1{2}
1{2}
1{2}
1{2}
1{2}
1{2}
1{2}
1{2}
1{3}
1{3}
1{3}
1{4}
1{4}
3{1}
3{2}
3{3}
3{4}
3{5}
3{1}
3{3}
3{1}
3{3}
3{6}
3{3}
3{1}
3{7}
3{8}
3{7}
3{9}
3{10}
3{7}
3{5}
3{1}
4{1}
4{1}
4{1}
4{1}
4{2}
4{3}
4{4}
4{2}
4{2}
4{5}
4{6}
4{6}
4{7}
4{8}
4{3}
4{5}
4{5}
4{9}
4{8}
4{1}
5{1,1,1}
5{1,2,1}
5{1,3,1}
5{1,4,1}
5{1,5,2}
5{1,1,3}
5{1,3,4}
5{2,1,2}
5{2,3,2}
5{2,6,5}
5{2,3,6}
5{2,1,6}
5{2,7,7}
5{2,8,8}
5{2,7,3}
5{3,9,5}
5{3,10,5}
5{3,7,9}
5{4,5,8}
5{4,1,1}
95
86
78
78
83
80
75
88
85
90
78
87
75
90
92
87
86
84
77
80
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
a Refers to purified yield, which is >95% as determined by H NMR
1
spectroscopy.
Scheme 2. Possible Mechanism for the Formation of Products 5
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RESEARCH ARTICLE
system did not work well with aliphatic amines, such as iso-
butylamine, benzylamine, 1-adamantylamine, morpholine, and
diethyl amine, to generate the corresponding desired products,
but only an intractable mixture was obtained in each case. This
would be probably attributed to the higher nucleophilicity of the
aliphatic primary and secondary amines toward the formylchro-
mones-Meldrum’s acid Knoevenogel adducts than aryl amines
which can compete with isocyanides in attacking the above-
mentioned adducts to produce complex reaction mixtures.
Anal. Calcd. for C30H29N3O5 (511.56) C 70.43, H 5.71, N
8.21%; Found C 70.61, H 5.69, N 8,18%.
N2-{[(4-Methylphenyl)sulfonyl]methyl}-2-(4-oxo-4H-chro-
men-3-yl)-N1,N1-diphenylethane-1,1,2-tricarboxamide (5{1,3,1}):
Cream powder (0.243 g, 78%); mp 276ꢀ278 °C; Rf (30%
n-hexane/EtOAc) 0.65; IR (KBr) (νmax, cmꢀ1) 3340 and 3312
(NꢀH), 1692, 1656, and 1630 (CdO), 1599 (CdC), 1324 and
1143 (SO2); 1H NMR (400.1 MHz, DMSO-d6) δH 2.18 (3 H, s,
Me), 4.42ꢀ4.53 (4 H, m, CH2 + CHꢀCH), 6.92ꢀ8.65 (20 H,
arom. +NH + dCHꢀO), 9.73 and 9.96 (2 H, 2 br s, 2 NH), 13C
NMR (100.6 MHz, DMSO-d6) δC 176.7, 171.3, 166.9, 166.4,
157.9, 156.7, 145.4, 140.1, 139.5, 136.0, 135.6, 130.5, 130.1, 130.0,
129.5, 127.0, 126.4, 125.0, 124.8, 124.5, 120.4, 120.3, 119.6, 61.7,
55.7, 43.5, 22.3; Anal. Calcd for C34H29N3O7S (623.67) C 65.48,
H, 4.69; N, 6.74%; Found C 65.62, H 4.70, N 6.76%.
’ CONCLUSION
In summary, we have developed a pseudo-five-component
condensation reaction for the formation of biologically interest-
ing tripeptide-bound chromones, which is one-pot and atom and
step economic. The reaction proceeds along a rather complex
pathway but it is very simple from the experimental point of view
and allows the creation of three peptide groups with concomitant
formation of five new CꢀC and C-heteroatom bonds in a single
operation.
N2-(2,6-Dimethylphenyl)-2-(4-oxo-4H-chromen-3-yl)-N1,N1-
diphenylethane-1,1,2-tricarboxamide (5{1,4,1}): White pow-
der (0.218 g, 78%); mp 280ꢀ282 °C; Rf (30% n-hexane/EtOAc)
0.80; IR (KBr) (νmax, cmꢀ1) 3271 and 3295 (NꢀH), 1676 and
1647 (CdO), 1600 (CdC); 1H NMR (400.1 MHz, DMSO-d6)
δH 1.94 (6 H, s, 2 Me), 4.69 and 4.72 (2 H, AB-system, 3JHH
=
6.0 Hz, CHꢀCH), 6.93ꢀ7.58 (17 H, m, arom.), 8.52 (1 H, s,
dCHꢀO), 9.14 (1 H, br s, NH), 9.80 and 10.05 (2 H, 2 br s, 2
NH); 13C NMR (100.6 MHz, DMSO-d6) δC 177.1, 169.7, 167.3,
166.7, 158.1, 156.8, 140.2, 139.6, 136.8, 136.2, 135.6, 130.0,
128.8, 127.7, 126.9, 126.3, 125.0, 124.7, 124.6, 121.1, 120.4,
120.2, 119.7, 56.3, 44.2, 19.0; Anal. Calcd for C34H29N3O5
(559.61) C 72.97, H 5.22, N 7.51%; Found C 73.16, H 5.20,
N 7.48%.
’ EXPERIMENTAL PROCEDURES
General Procedure for Preparation of the Tripeptide-
Bound Chromone Derivatives 5. The appropriate 3-formyl-
chromone (0.5 mmol) and Meldrum’s acid (0.5 mmol) were
dissolved in 5 mL of anhydrous dichloromethane, and the mixture
was stirred at room temperature for 3 h. To this solution
arylamine (1.0 mmol) and the isocyanide (0.5 mmol) were added
successively. The reaction mixture was stirred at ambient tem-
perature for 12 h, and the completion of reaction was confirmed
by TLC (EtOAc/n-hexane 1:1). Subsequently, the precipitated
product was filtered off and the solid washed with diethyl ether
several times to give 5. The crude product was purified by
crystallization from hot ethanol to yield pure 5{1,1,1}ꢀ5{4,1,1}.
The air-dried product thus obtained showed a single spot on TLC
and was pure enough for all analytical purposes.
Methyl N-[4-[(4-methylphenyl)amino]-3-{[(4-methylphenyl)-
amino]carbonyl}-4-oxo-2-(4-oxo-4H-chromen-3-yl)butanoyl]-
glycinate (5{1,5,2}): White powder (0.230 g, 83%); mp 278ꢀ
280 °C; Rf (50% n-hexane/EtOH) 0.81; IR (KBr) (νmax, cmꢀ1
)
3330 and 3295 (NꢀH), 1758, 1699, 1656, and 1633 (CdO),
1607 (CdC); 1H NMR (400.1 MHz, DMSO-d6): δH 2.13 and
2.21 (6 H, 2 s, 2 Me), 3.47 (3 H, s, OMe), 3.71 and 3.76 (2 H, m,
CH2), 4.51 (2 H, s, CHꢀCH), 6.95ꢀ8.01 (13 H, m, arom. +
NH), 8.42 (1 H, s, dCHꢀO), 9.59 and 9.92 (2 H, 2 br s, 2 NH);
13C NMR (100.6 MHz, DMSO-d6) δC 176.9, 171.7, 171.3, 167.1,
166.5, 157.8, 156.8, 137.8, 137.1, 135.5, 133.9, 133.5, 130.4, 130.3,
126.8, 126.4, 124.5, 121.0, 120.4, 120.3, 119.6, 56.0, 52.8, 43.5,
42.1, 21.7, 21.6; Anal. Calcd. for C31H29N3O7 (555.57) C 67.02,
H 5.26,; N 7.56%; Found C 66.78, H 5.28, N 7.59%.
N2-Cyclohexyl-2-(4-oxo-4H-chromen-3-yl)-N1,N1-diphenyle-
thane-1,1,2-tricarboxamide (5{1,1,1}): White powder (0.255 g,
95%); mp 278ꢀ280 °C; Rf (50% n-hexane/EtOAc) 0.52; IR
(KBr) (νmax, cmꢀ1) 3294 (NꢀH), 1680 and 1647 (CdO), 1600
1
(CdC); H NMR (400.1 MHz, DMSO-d6) δH 0.91ꢀ1.58
(10 H, m, 5 CH2), 3.30ꢀ3.42 (1 H, m, NCH), 4.41 and 4.52
(2 H, AB-system, 3JHH = 11.6 Hz, CHꢀCH), 6.94ꢀ7.74 (14 H,
N2-Cyclohexyl-N1,N1-bis(3-nitrophenyl)-2-(4-oxo-4H-chromen-
3-yl)ethane-1,1,2-tricarboxamide (5{1,1,3}): Light orange pow-
der (0.251 g, 80%); mp 264ꢀ266 °C; Rf (30% n-hexane/EtOAc)
0.74; IR (KBr) (νmax, cmꢀ1) 3294 (NꢀH), 1698 and 1625
(CdO), 1599 (CdC), 1530 and 1349 (NO2); 1H NMR (400.1
MHz, DMSO-d6) δH 0.09ꢀ1.59 (10 H, m, 5 CH2), 3.38ꢀ3.43
(1H, m, NCH), 4.48 and 4.53 (2 H, AB-system, 3JHH = 11.2 Hz,
CHꢀCH), 7.35ꢀ8.37 (13 H, m, arom. +NH), 8.60 (1 H, s,
dCHꢀO), 10.20and 10.61 (2 H, 2 br s, 2 NH); 13C NMR (100.6
MHz, DMSO-d6) δC 176.8, 170.0, 167.9, 167.5, 157.7, 156.7,
149.1, 149.0, 141.2, 140.5, 135.5, 131.5, 131.4, 126.8, 126.6, 126.5,
126.2, 124.4, 120.9, 119.6, 119.2, 114.8, 114.6, 57.3, 49.3, 43.8,
33.3, 26.4, 25.9, 25.7; Anal. Calcd. for C32H29N5O9 (627.60) C
61.24, H 4.66, N 11.16%; Found C 61.48, H 4.64, N 11.11%.
N2-{[(4-Methylphenyl)sulfonyl]methyl}-N1,N1-bis(2-nitrop-
henyl)-2-(4-oxo-4H-chromen-3-yl)ethane-1,1,2-tricarboxamide
(5{1,3,4}): White powder (0.268 g, 75%); mp 274ꢀ276 °C; Rf
(50% n-hexane/EtOH) 0.36; IR (KBr) (νmax, cmꢀ1) 3337 and
3312 (NꢀH), 1692, 1656, and 1630 (CdO), 1599 (CdC), 1526
3
m, arom.), 7.99 (1 H, d, JHH = 7.6 Hz, NH), 8.37 (1 H, s,
dCHꢀO), 9.76 and 9.97 (2 H, 2 br s, 2 NH); 13C NMR (100.6
MHz, DMSO-d6) δC 176.9, 170.0, 167.4, 166.9, 157.6, 156.7,
140.2, 139.6, 135.5, 130.0, 126.8, 126.3, 125.0, 124.7, 124.5,
121.3, 120.4, 120.3, 119.6, 56.6, 49.1, 43.9, 33.3, 26.4, 25.8, 25.7;
Anal. Calcd for C32H31N3O5 (537.60) C 71.49, H 5.81, N 7.82%;
Found C 71.32, H 5.79, N 7.85%.
N2-(tert-Butyl)-2-(4-oxo-4H-chromen-3-yl)-N1,N1-diphenyl-
ethane-1,1,2-tricarboxamide (5{1,2,1}): White powder (0.220
g, 86%); mp 286ꢀ288 °C; Rf (50% n-hexane/EtOAc) 0.54; IR
(KBr) (νmax, cmꢀ1) 3302 and 3291 (NꢀH), 1679, 1649, and
1635 (CdO), 1600 (CdC); 1H NMR (400.1 MHz, DMSO-d6)
δH 1.09 (9H, s, 3 Me), 4.43 and 4.53 (2 H, AB-system, 3JHH
=
11.7 Hz, CHꢀCH), 6.95ꢀ8.01 (15 H, m, arom. +NH), 8.38
(1 H, s, dCHꢀO), 9.86 and 9.90 (2 H, 2 br s, 2 NH); 13C NMR
(100.6 MHz, DMSO-d6) δC 176.9, 170.3, 167.2, 166.9, 157.0,
156.6, 140.1, 139.6, 135.6, 130.1, 130.0, 126.9, 126.4, 125.0,
124.8, 124.4, 121.6, 120.5, 120.4, 119.6, 57.1, 51.5, 43.9, 29.6;
662
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RESEARCH ARTICLE
and 1355 (NO2), 1324 and 1143 (SO2); 1H NMR (400.1 MHz,
DMSO-d6) δH 2.17 (3 H, s, CH3), 4.28ꢀ4.71 (4 H, m, CHꢀCH +
SO2CH2), 6.95ꢀ8.07 (16 H, m, arom.), 8.19 (1 H, s, dCHꢀO),
8.87 (1 H, t, 3JHH = 6.7 Hz, CH2NH), 10.25 and 10.41 (2 H, 2 s, 2
NH); 13C NMR (100.6 MHz, DMSO-d6) δC 176.7, 172.4, 170.4,
167.1, 166.3, 156.9, 156.8, 156.0, 145.6, 135.9, 135.7, 135.6,
135.2, 132.3, 130.7, 130.5, 129.7, 129.5, 126.8, 126.4, 126.3,
126.2, 126.1, 126.0, 124.5, 122.4, 119.7, 61.7, 55.2, 39.3, 37.7,
22.3; Anal. Calcd for C34H27N5O11S (713.67) C 57.22, H 3.81,
N 9.81%; Found C 57.37, H 3.80; N 9.77%.
CH3), 2.36ꢀ2.48 (7 H, m, 2 CH2CH3 + CH3), 4.38ꢀ4.48 (4 H,
2 m, CHꢀCH + SO2CH2), 6.91ꢀ7.76 (18 H, m, arom.), 8.21 (1
H, s, dCHꢀO), 8.58 (1 H, t, 3JHH = 5.4 Hz, NH), 9.58 and 9.81
(2 H, 2 br s, 2 NH); 13C NMR (100.6 MHz, DMSO-d6) δC
176.6, 171.3, 166.7, 166.2, 157.7, 154.9, 145.3, 140.4, 140.2,
137.8, 137.2, 136.6, 136.5, 136.0, 130.5, 129.4, 129.2, 129.1,
125.6, 124.3, 120.4, 120.3, 120.2, 119.4, 61.6, 55.5, 43.4, 28.8,
28.7, 22.2, 21.7, 17.0, 16.9; Anal. Calcd for C39H39N3O7S
(693.80) C 67.51, H, 5.67, N 6.06%; Found C 67.70, H 5.65;
N 6.02%.
N2-Cyclohexyl-2-(6-methyl-4-oxo-4H-chromen-3-yl)-N1,N1-
bis(4-methylphenyl)ethane-1,1,2-tricarboxamide (5{2,1,2}):
White powder (0.255 g, 88%); mp 294ꢀ296 °C; Rf (70% n-
hexane/EtOAc) 0.74; IR (KBr) (νmax, cmꢀ1) 3291 (NꢀH),
N2-Cyclohexyl-N1,N1-bis(4-ethylphenyl)-2-(6-methyl-4-oxo-
4H-chromen-3-yl)ethane-1,1,2-tricarboxamide (5{2,1,6}):
White powder (0.264 g, 87%); mp 270ꢀ272 °C; Rf (30% n-
hexane/EtOAc) 0.83; IR (KBr) (νmax, cmꢀ1) 3314 (NꢀH),
1
1
1677 and 1646 (CdO), 1600 (CdC); H NMR (400.1 MHz,
1675 and 1652 (CdO), 1609 (CdC); H NMR (400.1 MHz,
DMSO-d6) δH 0.87ꢀ1.58 (10 H, m, 5 CH2), 2.12, 2.20, and 2.38
CDCl3) δH 1.02ꢀ2.16 (10, m, 5 CH2), 1.11 (6 H, t, 2 CH2CH3),
(9 H, 3 s, 3 Me), 3.34ꢀ3.42 (1 H, m, NCH), 4.39 and 4.46 (2 H,
2.43ꢀ2.52 (4 H, m, 2 CH2CH3), 3.57 (1 H, s, NCH), 5.19 and
3
3
AB-system, JHH = 11.4 Hz, CHꢀCH), 6.95ꢀ7.55 (11 H, m,
5.29 (2 H, AB-system, JHH = 11.3 Hz, CHꢀCH), 6.79ꢀ7.57
arom.), 7.75 (1 H, br s, NH), 8.33 (1 H, s, dCHꢀO), 9.66 and
9.86 (2 H, 2 br s, 2 NH); 13C NMR (100.6 MHz, CDCl3) δC
176.9, 170.1, 167.2, 166.7, 157.4, 154.1, 137.8, 137.1, 136.5,
136.4, 133.9, 133.6, 130.3, 125.5, 124.2, 121.1, 120.4, 119.4, 56.5,
49.0, 43.8, 33.3, 26.4, 25.8, 25.7, 21.8, 21.7, 21.6; Anal. Calcd for
C35H37N3O5 (579.68) C 72.52, H 6.43, N 7.25%; Found C
72.23, H 6.40, N 7.29%.
(12 H, m, dCHꢀO + arom.), 9.03, 10.07, and 10.51 (3 H, 3 br s,
3 NH); 13C NMR (100.6 MHz, CDCl3) δC 178.2, 171.9, 167.6,
167.1, 158.2, 155.5, 140.7, 140.1, 137.2, 137.0, 135.7, 135.6,
128.6, 128.3, 125.9, 124.2, 121.3, 121.2, 121.0, 118.7, 56.0, 49.7,
45.3, 33.3, 33.2, 29.1, 26.2, 25.5, 25.4, 21.5, 16.59; Anal. Calcd for
C37H41N3O5 (607.73) C 73.12, H 6.80, N 6.91%; Found C
72.88, H 6.83, N 6.95%.
2-(6-Methyl-4-oxo-4H-chromen-3-yl)-N1,N1-bis(4-methylphenyl)-
N2-{[(4-methylphenyl)sulfonyl]methyl}ethane-1,1,2-tricarboxamide
(5{2,3,2}): White powder (0.283 g, 85%); mp 252ꢀ254 °C;
Rf (25% n-hexane/EtOAc) 0.70; IR (KBr) (νmax, cmꢀ1) 3319
(NꢀH), 1688, 1647, and 1630 (CdO), 1600 (CdC), 1321 and
1143 (SO2); 1H NMR (400.1 MHz, DMSO-d6) δH 1.94 (12 H, 4
s, 4 Me), 4.40ꢀ4.50 and 4.67ꢀ4.70 (4 H, 2 m, CHꢀCH + CH2),
6.94ꢀ7.79 (15 H, m, arom.), 8.23 (1 H, s, dCHꢀO), 8.60 (1 H,
N1,N1-Bis(2,4-dimethoxyphenyl)-2-(6-methyl-4-oxo-4H-chr-
omen-3-yl)-N2-(1,1,3,3-tetramethylbutyl)ethane-1,1,2-tricarb-
oxamide (5{2,7,7}): Dark violet powder (0.263 g, 75%); mp
238ꢀ240 °C; Rf (50% n-hexane/EtOAc) 0.46; IR (KBr)
(νmax, cmꢀ1) 3218 (NꢀH), 1658 and 1614 (CdO), 1574
1
(CdC); H NMR (400.1 MHz, CDCl3) δH 0.78 (9 H, s,
C(Me)3), 1.24 and 1.25 (6 H, 2 s, C(Me)2), 1.50 and 1.72 (2
3
H, AB-system, JHH = 14.8 Hz, CH2), 2.40 (3 H, s, Me), 3.68,
t, 3JHH = 6.0 Hz, NH), 9.59 and 9.82 (2 H, 2 br s, 2 NH); 13
C
3.70, 3.76, and 3.78 (12 H, 4 s, 4 OMe), 4.26 and 4.71 (2 H, AB-
system, 3JHH = 12.0 Hz, CHꢀCH), 6.26ꢀ8.21 (9 H, m, arom.),
6.51 (1 H, br s, NH), 8.25 (1 H, s, dCHꢀO), 8.44 and 8.81 (2 H,
2 br s, 2 NH); 13C NMR (100.6 MHz, CDCl3) δC 178.1, 169.7,
167.6, 165.8, 157.7, 155.9, 155.2, 151.3, 150.7, 136.0, 135.9,
126.0, 124.0, 122.4, 121.9, 121.7, 121.3, 119.8, 118.9, 104.5,
104.3, 99.4, 99.3, 57.8, 56.6, 56.5, 56.3, 56.2, 52.1, 45.3, 32.2, 32.0,
29.8, 29.6, 21.7; Anal. Calcd for C39H47N3O9 (701.80) C 66.74,
H 6.75, N 5.99%; Found C 66.50, H 6.79, N 6.01%.
NMR (100.6 MHz, DMSO-d6) δC 176.6, 171.4, 166.7, 157.7,
155.0, 145.3, 137.7, 137.0, 136.7, 136.5, 136.0, 134.0, 133.7,
130.5, 130.4, 130.3, 129.4, 125.6, 124.3, 120.3, 120.2, 119.4, 61.6,
55.6, 43.4, 22.3, 21.8, 21.7, 21.6; Anal. Calcd for C37H35N3O7S
(665.75) C 66.75, H 5.30, N 6.31%; Found C 66.94, H 5.33,
N 6.26%.
2-(6-Methyl-4-oxo-4H-chromen-3-yl)-N1,N1-bis(2-methylp-
henyl)-N2-2-naphthylethane-1,1,2-tricarboxamide (5{2,6,5}):
White powder (0.280 g, 90%); mp 274ꢀ276 °C; Rf (25% n-
hexane/EtOAc) 0.79; IR (KBr) (νmax, cmꢀ1) 3281 (NꢀH),
N2-Butyl-2-(6-methyl-4-oxo-4H-chromen-3-yl)-N1,N1-di-1-
naphthylethane-1,1,2-tricarboxamide (5{2,8,8}): Light pink
powder (0.281 g, 90%); mp 240ꢀ242 °C; Rf (30% n-hexane/
EtOAc) 0.72; IR (KBr) (νmax, cmꢀ1) 3280 (NꢀH), 1675, 1649,
and 1623 (CdO), 1600 (CdC); 1H NMR (400.1 MHz, DMSO-
d6) δH 0.73 (3 H, t, 3JHH = 7.2 Hz, Me), 1.14 (2 H, sex., 3JHH = 7.1
Hz, CH2CH3), 1.28 (2 H, quin., 3JHH = 7.1 Hz, CH2CH2CH3),
2.39 (3 H, s, Me), 3.00 (2 H, q, 3JHH = 6.4 Hz, NCH2), 4.48 and
5.05 (2 H, 2 d, 3JHH = 11.2 Hz, CHꢀCH) 7.14ꢀ8.18 (18 H, m,
arom. +NH), 8.46 (1 H, s, dCHꢀO), 9.93 and 10.07 (2 H, 2 br s,
2 NH); 13C NMR (100.6 MHz, DMSO-d6) δC 177.1, 171.1,
168.4, 168.1, 157.8, 155.2, 136.6, 136.4, 135.0, 134.9, 134.7,
134.1, 129.5, 129.4, 129.0, 127.4, 127.3, 127.2, 127.1, 127.0,
126.9, 126.8, 126.7, 125.6, 124.5, 123.9, 123.3, 122.8, 122.6,
121.3, 119.4, 55.7, 44.4, 39.9, 32.4, 21.7, 20.6, 14.9; Anal. Calcd
for C39H35N3O5 (625.71) C 74.86, H 5.64, N 6.72%; Found C
74.63, H 5.62, N 6.75%.
1
1672 and 1641 (CdO), 1600 (CdC); H NMR (400.1 MHz,
DMSO-d6) δH 1.88, 2.20, and 2.36 (9 H, 3 s, 3 Me), 4.61 and 4.90
(2 H, AB-system, 3JHH = 11.2 Hz, CHꢀCH), 7.04ꢀ8.14 (18 H,
m, arom.), 8.48 (1 H, s, dCHꢀO), 9.40, 9.43, and 9.92 (3 H, 3 s,
3 NH); 13C NMR (100.6 MHz, DMSO-d6) δC 177.1, 170.3,
167.7, 167.2, 158.5, 155.1, 137.9, 137.3, 136.9, 136.7, 136.5,
134.5, 132.7, 132.5, 131.7, 131.6, 131.0, 129.4, 128.7, 128.5,
127.6, 127.3, 126.8, 126.5, 125.8, 125.7, 125.6, 125.5, 124.4,
121.6, 120.4, 119.4, 116.9, 54.9, 45.7, 21.7, 19.0, 18.6; Anal. Calcd
for C39H33N3O5 (623.69) C 75.10, H 5.33 N 6.74%; Found C
74.87, H 5.35, N 6.71%.
N1,N1-Bis(4-ethylphenyl)-2-(6-methyl-4-oxo-4H-chromen-
3-yl)-N2-{[(4-methylphenyl)sulfonyl]methyl}ethane-1,1,2-tri-
carboxamide (5{2,3,6}): White powder (0.270 g, 78%); mp
254ꢀ256 °C; Rf (30% n-hexane/EtOAc) 0.65; IR (KBr)
(νmax, cmꢀ1) 3308 (NꢀH), 1677, 1655, and 1640 (CdO),
2-(6-Methyl-4-oxo-4H-chromen-3-yl)-N1,N1-bis(3-nitrophe-
nyl)-N2-(1,1,3,3-tetramethylbutyl)ethane-1,1,2-tricarboxamide
(5{2,7,3}): White powder (0.309 g, 92%); mp 276ꢀ278 °C; Rf
1
1603 (CdC), 1328 and 1144 (SO2); H NMR (400.1 MHz,
DMSO-d6) δH 0.97ꢀ1.08 (6 H, m, 2 CH2CH3), 2.14 (3 H, s,
663
dx.doi.org/10.1021/co200125a |ACS Comb. Sci. 2011, 13, 659–666

ACS Combinatorial Science
RESEARCH ARTICLE
(50% n-hexane/EtOAc) 0.58; IR (KBr) (νmax, cmꢀ1) 3286
(NꢀH), 1708, 1655, and 1619 (CdO), 1604 (CdC), 1530
and 1351 (NO2); 1H NMR (400.1 MHz, DMSO-d6) δH 0.71 (9
H, s, C(Me)3), 1.13 (6 H, s, C(Me)2), 1.48ꢀ1.60 (2 H, AB-
system, 3JHH = 24.0 Hz, CH2), 2.32 (3 H, s, Me), 4.45ꢀ4.62 (2
H, AB-system, 3JHH = 9.2 Hz, CHꢀCH), 7.15 (1 H, br s, NH),
7.45ꢀ8.62 (11 H, m, arom.), 8.35 (1 H, s, dCHꢀO), 10.31 and
10.46 (2 H, 2 br s, 2 NH); 13C NMR (100.6 MHz, DMSO-d6) δC
169.7, 167.6, 167.4, 156.7, 155.0, 149.1, 141.2, 140.5, 136.7,
136.5, 131.5, 126.7, 125.5, 119.6, 119.3, 114.8, 57.5, 55.6, 51.7,
43.8, 32.3, 32.2, 30.3, 29.7, 21.6; Anal. Calcd for C35H37N5O9
(671.69) C 62.58, H 5.55, N 10.43%; Found C 62.74, H 5.58, N
10.39%.
(νmax, cmꢀ1) 3273 (NꢀH), 1747, 1667, and 1655 (CdO), 1596
1
(CdC); H NMR (400.1 MHz, DMSO-d6) δH 3.31 (3 H, s,
Me), 3.71ꢀ3.85 (2 H, m, CH2), 4.61 and 5.06 (2 H, AB-system,
3JHH = 11.2 Hz, CHꢀCH), 7.21 (1 H, t, 3JHH = 7.2 Hz, NH),
7.43ꢀ8.46 (16 H, m, arom.), 8.69 (1 H, s, dCHꢀO), 9.93 and
10.12 (2 H, 2 br s, 2 NH)); 13C NMR (100.6 MHz, DMSO-d6)
δC 175.5, 171.5, 171.3, 168.2, 167.8, 158.7, 151.3, 135.1, 135.0,
134.9, 134.7, 134.0, 131.3, 129.6, 129.5, 129.0, 128.9, 127.4,
127.3, 127.2, 127.1, 126.9, 126.8, 126.7, 126.6, 125.0, 124.7,
123.8, 123.1, 122.8, 122.7, 121.8, 112.5, 55.2, 52.9, 44.0, 42.3;
Anal. Calcd for C37H27Cl2N3O7 (696.53) C 63.80, H 3.91, N
6.03%; Found C 63.98, H 3.90, N 6.05%.
N2-Cyclohexyl-2-(6,8-dichloro-4-oxo-4H-chromen-3-yl)-N1,
>N1-diphenylethane-1,1,2-tricarboxamide (5{4,1,1}): White
powder (0.243 g, 80%); mp 277ꢀ279 °C; Rf (50% n-hexane/
EtOAc) 0.75; IR (KBr) (νmax, cmꢀ1) 3287 (NꢀH), 1679 and
1649 (CdO), 1599 (CdC); 1H NMR (400.1 MHz, DMSO-d6)
δH 0.88ꢀ1.58 (10 H, m, 5 CH2), 3.30ꢀ3.42 (1 H, m, NCH),
2-(6-Chloro-4-oxo-4H-chromen-3-yl)-N1,N1-bis(2-methylph-
enyl)-N2-(3-phenylpropyl)ethane-1,1,2-tricarboxamide (5{3,9,9}):
White powder (0.277 g, 87%); mp 240ꢀ242 °C; Rf (50% n-
hexane/EtOAc) 0.63; IR (KBr) (νmax, cmꢀ1) 3283 (NꢀH),
1
1673 and 1651 (CdO), 1600 (CdC); H NMR (400.1 MHz,
3
DMSO-d6) δH 1.55ꢀ1.56 (2 H, m, CH2CH2Ph), 1.89 and 2.20
4.40 and 4.56 (2 H, AB-system, JHH = 10.8 Hz, CHꢀCH),
3
(6 H, 2 s, 2 Me), 2.40 (2 H, t, JHH = 7.7 Hz, CH2CH2Ph),
6.95ꢀ8.12 (12 H, m, arom.), 7.47 (1 H, d, 3JHH = 6.8 Hz, NH),
8.49 (1 H, s, dCHꢀO), 9.70 and 9.99 (2 H, 2 s, 2 NH); 13C
NMR (100.6 MHz, DMSO-d6) δC 175.3, 169.5, 167.3, 166.7,
158.1, 151.2, 140.2, 139.5, 135.0, 131.1, 130.1, 130.0, 126.4,
125.0, 124.7, 124.5, 121.7, 120.4, 120.3, 56.4, 49.2, 43.9, 33.3,
26.4, 25.9, 25.8; Anal. Calcd for C32H29Cl2N3O5 (606.49) C
63.37, H 4.82, N 6.93%; Found C 63.17; H 4.80, N 6.89%.
2.92ꢀ3.07 (2 H, m, NCH2), 4.39 and 4.75 (2 H, AB-system, 3JHH
= 11.2 Hz, CHꢀCH), 6.97ꢀ7.97 (17 H, m, arom. + NH), 8.47
(1 H, s, dCHꢀO), 9.30 and 9.36 (2 H, 2 br s, 2 NH); 13C NMR
(100.6 MHz, DMSO-d6) δC 176.0, 170.8, 167.7, 167.3, 158.4,
155.4, 143.2, 137.5, 136.9, 135.5, 132.6, 132.5, 131.6, 131.3,
129.5, 129.4, 127.3, 127.2, 126.9, 126.7, 126.4, 125.8, 125.7,
125.4, 125.2, 122.2, 121.6, 55.1, 44.4, 39.7, 33.6, 32.3, 19.0, 18.5;
Anal. Calcd for C37H34ClN3O5 (636.13) C 69.86, H 5.39, N
6.61%; Found C 70.06, H 5.36, N 6.59%.
’ ASSOCIATED CONTENT
N2-Benzyl-2-(6-chloro-4-oxo-4H-chromen-3-yl)-N1,N1-bis(2-
methylphenyl)ethane-1,1,2-tricarboxamide (5{3,10,9}): White
powder (0.261 g, 86%); mp 278ꢀ280 °C; Rf (50% n-hexane/
EtOAc) 0.55; IR (KBr) (νmax, cmꢀ1) 3281 (NꢀH), 1676 and
1653 (CdO), 1600 (CdC); 1H NMR (400.1 MHz, DMSO-d6)
δH 1.89 and 2.19 (6 H, 2 s, 2 Me), 4.19- 4.22 (2 H, m, CH2), 4.45
S
Supporting Information. Experimental procedures, char-
b
acterization data, and FT-IR, H, and 13C NMR spectra of
1
compounds 5. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
3
and 4.81 (2 H, AB-system, JHH = 11.2 Hz, CHꢀCH),
3
6.98ꢀ7.99 (16 H, m, arom.), 8.20 (1 H, JHH = 5.9 Hz, NH),
Corresponding Author
*Phone: 0098-21-44580000. Fax: 0098-21-44580021. E-mail:
m.teimouri@ippi.ac.ir.
8.48 (1 H, s, dCHꢀO), 9.30 and 9.37 (2 H, 2 br s, 2 NH)); 13C
NMR (100.6 MHz, DMSO-d6) δC 176.1, 171.0, 167.8, 167.2,
158.6, 155.4, 140.7, 137.5, 136.9, 135.5, 132.6, 132.4, 131.6,
131.5, 131.4, 129.3, 128.1, 127.8, 127.4, 127.3, 126.7, 126.4,
125.8, 125.7, 125.4, 125.1, 122.3, 121.4, 55.0, 44.5, 43.6, 19.0,
18.6; Anal. Calcd for C35H30ClN3O5 (608.08) C 69.13, H 4.97,
N 6.91%; Found C 68.91, H 4.96, N 6.94%.
Funding Sources
We would like to thank Iran Polymer and Petrochemical Institute
(IPPI) Research Council for the financial support.
2-(6-Chloro-4-oxo-4H-chromen-3-yl)-N1,N1-bis(4-fluoroph-
enyl)-N2-(1,1,3,3-tetramethylbutyl)ethane-1,1,2-tricarboxamide
(5{3,7,10}): White powder (0.267 g, 84%); mp 270ꢀ272 °C; Rf
(50% n-hexane/EtOAc) 0.37; IR (KBr) (νmax, cmꢀ1) 3329 and
3305 (NꢀH), 1702, 1655, and 1622 (CdO), 1598 (CdC); 1H
NMR (400.1 MHz, CDCl3) δH 0.73 (9 H, s, C(Me)3),
1.17ꢀ1.23 (6 H, m, C(Me)2), 1.45ꢀ1.73 (2 H, m, CH2),
4.85ꢀ4.90 (2 H, m, CHꢀCH), 6.67ꢀ7.62 (12 H, m, arom. +
dCHꢀO), 8.75 (1 H, br s, NH), 9.90 and 10.29 (2 H, 2 br s, 2
NH); 13C NMR (100.6 MHz, CDCl3) δC 177.0, 170.4, 167.0,
159.1, 155.4, 135.6, 135.2, 134.5, 132.5, 124.9, 123.1, 123.0,
122.6, 122.5, 121.1, 116.3, 116.1, 115.8, 115.5, 56.7, 56.1, 53.2,
32.2, 32.1, 29.9; Anal. Calcd for C34H34ClF2N3O5 (638.10) C
64.00, H 5.37, N 6.59%; Found C 63.87, H 5.39, N 6.60%.
Methyl N-{2-(6,8-Dichloro-4-oxo-4H-chromen-3-yl)-4-(1-
naphthylamino)-3-[(1-naphthylamino)carbonyl]-4-oxobuta-
noyl}glycinate (5{4,5,8}): Brown powder (0.268 g, 77%);
mp 240ꢀ242 °C; Rf (50% n-hexane/EtOAc) 0.32; IR (KBr)
’ REFERENCES
(1) (a) Bode, J. W. Emerging Methods in Amide- and Peptide-
Bond Formation. Curr. Opin. Drug Discovery Dev. 2006, 9, 765–775.
(b) Humphrey, J. M.; Chamberlin, A. R. Chemical Synthesis of Natural
Product Peptides: Coupling Methods for the Incorporation of Non-
coded Amino Acids into Peptides. Chem. Rev. 1997, 97, 2243–2266.
(c) Cupido, T.; Tulla-Puche, J.; Spengler, J.; Albericio, F. The Synthesis
of Naturally Occurring Peptides and Their Analogs. Curr. Opin. Drug
Discovery Dev. 2007, 10, 768–783.
(2) (a) Tian, F.-F.; Zhou, P.; Li, Z.-L. T-scale as A Novel Vector of
Topological Descriptors for Amino Acids and Its Application in QSARs
of Peptides. J. Mol. Struct. 2007, 830, 106–115. (b) Shu, M.; Mei, H.;
Yang, S.; Liao, L.; Li, Z. Structural Parameter Characterization and
Bioactivity Simulation Based on Peptide Sequence. QSAR Comb. Sci.
2009, 28, 27–35. (c) Day, T.; Greenfield, S. A. Bioactivity of A Peptide
Derived from Acetylcholinesterase in Hippocampal Organohpic Cul-
tures. Exp. Brain Res. 2004, 155, 500–508.
(3) Strom, K.; Sjogren, J.; Broberg, A.; Schnurer, J. Lactobacillus
plantarum MiLAB 393 Produces the Antifungal Cyclic Dipeptides
664
dx.doi.org/10.1021/co200125a |ACS Comb. Sci. 2011, 13, 659–666

ACS Combinatorial Science
RESEARCH ARTICLE
Cyclo(L-Phe-L-Pro) and Cyclo(L-Phe-trans-4-OH-L-Pro) and 3-Phenyl-
lactic Acid. Appl. Environ. Microbiol. 2002, 68, 4322–4327.
(4) Tan, C.; Zhang, X.; Jiang, Y.; Zhang, D.; Chen, J. Antitumor
Activity of Vilon Dipeptide Lys-Glu. Chin. Pharmacol. Bull. 2007,
23, 233–236.
Substituents for the Cleavage of DNA in the Presence of Cu(II).
Phytother. Res. 1999, 13, 609–612.
(19) Yamada, J.; Tomita, Y. Antimutagenic Activity of Water Ex-
tracts of Black Tea and Oolong Tea. Biosci., Biotech., Biochem. 1994,
58, 2197–2200.
(5) (a) Cui, C. B.; Kakeya, H.; Okada, G.; Onose, R.; Ubukata, M.;
Takahashi, I.; Isono, K.; Osada, H. Tryprostatins A and B, Novel
Mammalian Cell Cycle Inhibitors Produced by Aspergillus fumigatus.
Antibiotics 1995, 48, 1382–1384. (b) Cui, C. B.; Kakeya, H.; Osada, H.
Novel Mammalian Cell Cycle Inhibitors, Cyclotryprostatins A-D,
Produced by Aspergillus Fumigatus, Which Inhibit Mammalian Cell
Cycle at G2/M Phase. Tetrahedron 1997, 53, 59–72.
(6) (a) Faden, A. I.; Movsesyan, V. A.; Knoblach, S. M.; Ahmed, F.;
Cernak, I. Neuroprotective Effects of Novel Small Peptides in vitro and
after Brain Injury. Neuropharmacology 2005, 49, 410–424. (b) Hlinak,
Z.; Vinsova, J.; Kasafirek, E. Effect of Alaptide, Its Analogues and
Oxiracetam on Memory for An Elevated Plus-Maze in Mice. Eur. J.
Pharmacol. 1996, 314, 1–7.
(7) Tang, X.; Fan, L.; Yu, H.; Liao, Y.; Yang, D. Facile Synthesis of
Dipeptidomimetics of p-Aminobenzoic Acid and Their Antidiabetic
Activity. Chin. J. Org. Chem. 2009, 29, 595–600.
(8) (a) Barros, T. G.; Pinheiro, S.; Williamson, J. S.; Tanuri, A.;
Pereira, H. S.; Brindeiro, R. M.; Neto, J. B. A.; Antunes, O. A. C.; Muri,
E. M. F. Novel Peptides Mimetic Inhibitors of Hepatitis C Serine
Protease Derived from Isomannide. Synthesis 2009, 620–626. (b) Girgis,
A. S.; Ellithey, M. Facile Synthesis of Non-steroidal Anti-inflammatory
Active Bisbenzamide-containing Compounds. Bioorg. Med. Chem. 2006,
14, 8527–8532.
(9) Malikov, V. M.; Yuldashev, M. P. Phenolic Compounds of Plants
of the Scutellaria. Distribution, Structure and Properties. Chem. Nat.
Compd. 2002, 38, 358–406.
(10) Huck, C. W.; Huber, C. G.; Ongania, K.-H.; Bonn, G. K.
Isolation and Characterization of Methoxylated Flavones from the
Flowers of Primula Veris by Liquid Chromatography and Mass Spectro-
metry. Chromatogr. A 2000, 870, 453–462.
(11) Nagao, T.; Abe, F.; Kinjo, J.; Okabe, H. Antiproliferative
Constituents in Plants. 10. Flavones from the Leaves of Lantana
Montevidensis BRIQ. and Consideration of Structure-Activity Relation-
ship. Biol. Pharm. Bull. 2002, 25, 875–879.
(20) (a) Hurley, L. H. DNA and Its Associated Process as Targets for
Cancer Therapy. Nat. Rev. Cancer 2002, 2, 188–200. (b) Hurley, L. H.
Secondary DNA Structures as Molecular Targets for Cancer Therapeu-
tics. Biochem. Soc. Trans. 2001, 29, 692–696. (c) Kupchan, S. M.;
Streelmann, D. R.; Sneden, A. T. Psorospermin, A New Antileukemic
Xanthone from Psorospermum febrifugum. J. Nat. Prod. 1980,
43, 296–301. (d) Hansen, M. R.; Hurley, L. H. Pluramycins. Old Drugs
Having Modern Friends in Structural Biology. Acc. Chem. Res. 1996,
29, 249–258. (e) Bocian, W.; Kawechi, R.; Bednarek, E.; Sitkowski, J.;
Ulkowska, A.; Kozerski, L. Interaction of Flavonoid Topoisomerases I
and II Inhibitors with DNA Oligomers. New J. Chem. 2006, 30, 467–472.
(f) Mukherjee, A. K.; Basu, S.; Sarkar, N.; Ghosh, A. C. Advances in
Cancer Therapy with Plant Based Natural Products. Curr. Med. Chem. 2001,
8, 1467–1486. (g) Shi, Y.-Q.; Fukai, T.; Sakagami, H.; Chang, W.-J.; Yang,
P.-Q.; Wang, F.-P.; Nomura, T. Cytotoxic Flavonoids with Isoprenoid
Groups from Morus mongolica. J. Nat. Prod. 2001, 64, 181–188.
(21) (a) Korkina, G. L.; Afanas’ev, I. B. Antioxidant and Chelating
Properties of Flavonoids. In: Antioxidants in Disease Mechanisms and
Therapy. In Advances in Pharmacology; Sies, H., Ed.; Academic: San
Diego, CA, 1997; Vol. 38, pp 151ꢀ163; (b) Hansch, C., Sammes, P. G.,
Taylor, J. B., Eds.; Comprehensive Medicinal Chemistry; Pergamon: New
York, NY, 1990; Vol. 6.
(22) (a) Kim, M. Y.; Na, Y.; Vankayalapati, H.; Gleason-Guzman,
M.; Hurley, L. H. Design, Synthesis, and Evaluation of Psorospermin/
Quinobenzoxazine Hybrids as Structurally Novel Antitumor Agents.
J. Med. Chem. 2003, 46, 2958–2972. (b) Mitscher, L. A. Bacterial
Topoisomerase Inhibitors: Quinolone and Pyridone Antibacterial
Agents. Chem. Rev. 2005, 105, 559–592.
(23) (a) Cassady, J. M.; Baird, W. M.; Chang, C. J. Natural Products
as A Source of Potential Cancer Chemotherapeutic and Chemopreven-
tive Agents. J. Nat. Prod. 1990, 53, 23–41. (b) Kupchan, S. M.;
Streelman, D. R.; Sneden, A. T. Psorospermin, A New Antileukemic
Xanthone from Psorospermum febrifugum. J. Nat. Prod. 1980, 43,
296–301.
(12) Chan-Bacab, M. J.; Pe~na-Rodríguez, L. M. Plant Natural Pro-
ducts with Leishmanicidal Activity. Nat. Prod. Rep. 2001, 18, 674–688.
(13) Harborne, J. B. Recent Advances in Chemical Ecology. Nat.
Prod. Rep. 1999, 16, 509–523.
(24) (a) Morris, J.; Wishka, D. G.; Lin, A. H.; Humphrey, W. R.;
Wiltse, A. L.; Gammil, R. B.; Judge, T. M.; Bisaha, S. L.; Olds, N. L.;
Jacob, C. S.; Bergh, C. L.; Cudahy, M. M.; Williams, D. J.; Nishizawa,
E. E.; Thomas, E. W.; Gorman, R. R.; Benjamin, C. W.; Shebuski, R. J.
Synthesis and Biological Evaluation of Antiplatelet 2-Aminochromones.
J. Med. Chem. 1993, 36, 2026–2032. (b) Mazzei, M.; Balbi, A.; Roma, G.;
Di Braccio, M.; Leoncini, G.; Buzzi, E.; Maresca, M. Synthesis and Anti-
Platelet Activity of Some 2-(Dialkylamino]chromones. Eur. J. Med.
Chem. 1988, 23, 237–242. (c) Mazzei, M.; Sottofattori, E.; Di Braccio,
M.; Balbi, A.; Leoncini, G.; Buzzi, E.; Maresca, M. Synthesis and
Antiplatelet Activity of 2-(Diethylamino)-7-ethoxychromone and Re-
lated Compounds. Eur. J. Med. Chem. 1990, 25, 617–622. (d) Leoncini,
G.; Maresca, M.; Colao, C.; Buzzi, E.; Mazzei, M. Mode of Action of
2-(Diethylamino)-7-ethoxychromone on Human Platelets. Cell Bio-
chem. Funct. 1991, 9, 79–85.
(25) (a) Wang, H.-J.; Gloer, J. B.; Scott, J. A.; Malloch, D.
Coniochaetones A and B: New Antifungal Benzopyranones from the
Coprophilous Fungus Coniochaeta saccardoi. Tetrahedron Lett. 1995,
36, 5847–5850. (b) Fujimoto, H.; Ingaki, M.; Satoh, Y.; Yoshida, E.;
Yamazaki, M. Monoamine Oxidase-Inhibitory Components from An
Ascomycete, Coniochaeta tetraspora. Chem. Pharm. Bull. 1996,
44, 1090–1092. (c) Graham, J. G.; Zhang, H.; Pendland, S. L.; Santal-
siero, B. D.; Mesecar, A. D.; Cabieres, F.; Farnsworth, N. R. Antimyco-
bacterial Naphthopyrones from Senna obliqua. J. Nat. Prod. 2004,
67, 225–227.
(14) (a) Rowley, D. C.; Hansen, M. S. T.; Rhodes, D.; Sotriffer,
C. A.; Ni, H.; McCammon, J. A.; Bushman, F. D.; Fenical, W.
Thalassiolins AꢀC: New Marine-Derived Inhibitors of HIV cDNA
Integrase. Bioorg. Med. Chem. 2002, 10, 3619–3625. (b) Xu, H.-X.; Wan,
M.; Dong, H.; But, P. P.-H.; Foo, L. Y. Inhibitory Activity of Flavonoids
and Tannins Against HIV-1 Protease. Biol. Pharm. Bull. 2000,
23, 1072–1076. (c) Wu, J.-H.; Wang, X.-H.; Yi, Y.-H.; Lee, K.-H. Anti-
AIDS Agents 54. A Potent Anti-HIV Chalcone and Flavonoids from
Genus Desmos. Bioorg. Med. Chem. Lett. 2003, 13, 1813–1815.
(15) Pꢀerez-Vizcaíno, F.; Ibarra, M.; Cogolludo, A. L.; Duarte, J.;
Zaragozꢀa-Arnꢀaez, F.; Moreno, L.; Lꢀopez-Lꢀopez, G.; Tamargo, J. En-
dothelium-Independent Vasodilator Effects of the Flavonoid Quercetin
and Its Methylated Metabolites in Rat Conductance and Resistance
Arteries. J. Pharmacol. Exp. Ther. 2002, 302, 66–72.
(16) (a) Sꢀanchez, I.; Gꢀomez-Garibay, F.; Taboada, J.; Ruiz, B. H.
Antiviral Effect of Flavonoids on the Dengue Virus. Phytother. Res. 2000,
14, 89–92. (b) Bae, E.-A.; Han, M. J.; Lee, M.; Kim, D.-H. In Vitro
Inhibitory Effect of Some Flavonoids on Rotavirus Infectivity. Biol.
Pharm. Bull. 2000, 23, 1122–1124.
(17) Matsuo, N.; Yamada, K.; Yamashia, K.; Shoji, K.; Mori, M.;
Sugano, M. Inhibitory Effect of Tea Polyphenols on Histamine and
Leukotriene B4 Release from Rat Peritoneal Exudate Cells. In Vitro Cell
Dev. Biol. 1996, 32, 340–344.
(26) Ishar, M. P. S.; Singh, G.; Singh, S.; Sreenivasan, K. K.; Singh, G.
Design, Synthesis, and Evaluation of Novel 6-Chloro-/fluorochromone
Derivatives as Potential Topoisomerase Inhibitor Anticancer Agents.
Bioorg. Med. Chem. Lett. 2006, 16, 1366–1370.
(18) Jain, A.; Martin, M. C.; Parveen, N.; Khan, N. U.; Parish, J. H.;
Hadi, S. M. Reactivities of Flavonoids with Different Hydroxyl
665
dx.doi.org/10.1021/co200125a |ACS Comb. Sci. 2011, 13, 659–666

ACS Combinatorial Science
RESEARCH ARTICLE
(27) (a) Ellis, G. P.; Lockhart, I. M. In The Chemistry of Heterocyclic
Compounds, Chromenes, Chromanones, and Chromones; Ellis, G. P., Ed.;
Wiley-VCH: New York, 2007; Vol. 31, pp 1ꢀ1196. (b) Hepworth, J. D.;
Gabbutt, C. D.; Heron, B. M. In Comprehensive Heterocyclic Chemistry II:
Pyrans and their Benzo Derivatives: Synthesis; Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.; Pergamon Press: Oxford, U.K., 1996; Vol. 5,
pp 351ꢀ468. (c) Geen, G. R.; Evans, J. M.; Vong, A. K. In Compre-
hensive Heterocyclic Chemistry II: Pyrans and their Benzo Derivatives:
Applications; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Pergamon Press: Oxford, U.K., 1996; Vol. 5, pp 469ꢀ500.
Reusable Catalyst for the Knoevenagel Condensation. Cent. Eur. J.
Chem. 2010, 8, 12–18.
(32) (a) Hazeri, N.; Maghsoodlou, M. T.; Habibi-Khorassani, S. M.;
Marandi, G. Synthesis of 3-Hydroxy-2H-iminolactones and 3-Hydroxy-
2H-pyrrol-2-ones from Reaction between Isocyanides and Methyl
2-Acetylacetoacetate. ARKIVOC 2008, xiv, 282–288. (b) Umkehrer,
M.; Ross, G.; J€ager, N.; Burdack, C.; Kolb, J.; Hu, H.; Alvim-Gaston, M.;
Hulme, C. Expeditious Synthesis of Imidazo[1,2-c]pyrimidines via A
[4 + 1]-Cycloaddition. Tetrahedron Lett. 2007, 48, 2213–2216. (c)
Wehner, V.; Stilz, H.-U.; Osipov, S. N.; Golubev, A. S.; Sieler, J.; Burger,
K. Trifluoromethyl-Substituted Hydantoins, Versatile Building Blocks
for Rational Drug Design. Tetrahedron 2004, 60, 4295–4302. (d) Nair,
V.; Mathew, B.; Vinod, A. U.; Mathen, J. S.; Ros, S.; Menon, R. S.; Varma,
R. L.; Srinivas, R. [4 + 1] Cycloaddition Reactions of o-Thioquinones
with Isocyanides: Novel Syntheses of 2-Imino-1,3-oxathioles. Synthesis
2003, 662–664. (e) Chatani, N.; Oshita, M.; Tobisu, M.; Ishii, Y.; Murai,
S. A GaCl3-Catalyzed [4 + 1] Cycloaddition of α,β-Unsaturated
Carbonyl Compounds and Isocyanides Leading to Unsaturated
γ-Lactone Derivatives. J. Am. Chem. Soc. 2003, 125, 7812–7813. (f)
Ito, Y.; Kato, H.; Saegusa, T. A New Approach for Stereoselective
Synthesis of γ-Butyrolactones. J. Org. Chem. 1982, 47, 741–743.
(33) (a) Oikawa, Y.; Hirasawa, H.; Yonemitsu, O. Meldrum’s Acid in
Organic Synthesis. 1. A Convenient One-pot Synthesis of Ethyl In-
dolepropionates. Tetrahedron Lett. 1978, 19, 1759–1762. (b) Oikawa,
Y.; Sugano, K.; Yonemitsu, O. Meldrum’s Acid in Organic Synthesis. 2. A
General and Versatile Synthesis of β-Keto Esters. J. Org. Chem. 1978,
43, 2087–2088.
(34) (a) Subba Reddy, B. V.; Majumder, N.; Hara Gopal, A. V.;
Chatterjee, D.; Kunwar, A. C. Ugi-type Four-component Reaction for a
Novel Synthesis of 5-Oxo-perhydrofuro[3,2-b]pyran Carboxylate Deri-
vatives. Tetrahedron Lett. 2010, 51, 6835–6838. (b) Shaabani, A.;
Soleimani, E.; Rezayan, A. H.; Sarvary, A.; Khavasi, H. R. Novel
Isocyanide-Based Four-Component Reaction: A Facile Synthesis of
Fully Substituted 3,4-Dihydrocoumarin Derivatives. Org. Lett. 2008,
10, 2581–2584. (c) Shaabani, A.; Yavari, I.; Teimouri, M. B.; Bazgir, A.;
Bijanzadeh, H. R. New and Efficient Synthesis of Dialkyl 2-[1-p-
nitrophenyl-2-(alkylamino)-2-oxoethyl]malonates. Tetrahedron 2001,
57, 1375–1375. (d) Shaabani, A.; Teimouri, M. B.; Bijanzadeh, H. R.
Russ. J. Org. Chem. 2004, 40, 976–981. (e) Shaabani, A.; Teimouri, M. B.
The Reaction of Alkyl Isocyanides and Arylidene Meldrum’s acid
Derivatives in the Presence of Water: One-pot Synthesis of 4--
(alkylamino)-3-(aryl)-4-oxobutanoic Acids. J. Chem. Res. (S) 2002,
433–435.
(28) (a) Larock, R. C. In Comprehensive Organic Transformations;
VCH: New York, 1999. (b) Valeur, E.; Bradley, M. Amide Bond
Formation: Beyond the Myth of Coupling Reagents. Chem. Soc. Rev.
2009, 38, 606–631. (c) Han, S. Y.; Kim, Y. A. Recent Development of
Peptide Coupling Reagents in Organic Synthesis. Tetrahedron 2004,
60, 2447–2467. (d) Montalbetti, C. A. G. N.; Falque, V. Amide Bond
Formation and Peptide Coupling. Tetrahedron 2005, 61, 10827–10852.
(29) (a) Park, W. K. C.; Auer, M.; Jaksche, H.; Wong, C. H. Rapid
Combinatorial Synthesis of Aminoglycoside Antibiotics Mimetics: Use
of A Polyethylene Glycol-Linked Amine and Neamine Derived Alde-
hyde in Multicomponent Condensation as A Strategy for the Discovery
of New Inhibitors of the HIV RNA Rev Response Element. J. Am. Chem.
Soc. 1996, 118, 10150–10155. (b) Bauer, S. M.; Armstrong, R. W. Total
Synthesis of Motuporin (Nodularin-V). J. Am. Chem. Soc. 1999,
121, 6355–6366. (c) Hebach, C.; Kazmaier, U. Via Ugi-Reaction to
Conformational Fixed Cyclic Peptides. Chem. Commun. 2003, 596–597.
(d) Wessjohann, L. A.; Voigt, B.; Rivera, D. G. Diversity Oriented One-
Pot Synthesis of Complex Macrocycles: Very Large Steroid-Peptoid
Hybrids from Multiple Multicomponent Reactions Including Bifunc-
tional Building Blocks. Angew. Chem., Int. Ed. 2005, 44, 4785–4790.
€
(e) El Kaim, L.; Grimaud, L.; Oble, J. Phenol Ugi-Smiles Systems:
Strategies for the Multicomponent N-Arylation of Primary Amines with
Isocyanides, Aldehydes, and Phenols. Angew. Chem., Int. Ed. 2005,
44, 7961–7964. (f) Giovenzana, G. B.; Tron, G. C.; Di Paola, S.;
Menegotto, I. G.; Pirali, T. Split the Primary Amine in Two: Secondary
Diamines May Play the Role of the Primary Amine in the Ugi 4CR.
Angew. Chem., Int. Ed. 2006, 45, 1099–1102. (g) D€omling, A. Recent
Advances in Isocyanide-Based Multicomponent Chemistry. Curr. Opin.
Chem. Biol. 2002, 6, 306–313. (h) D€omling, A. Recent Developments in
Isocyanide Based Multicomponent Reactions in Applied Chemistry.
Chem. Rev. 2006, 106, 17–89. (i) Ngouansavanh, T.; Zhu, J. IBX-
Mediated Oxidative Ugi-Type Reaction: Application to the N- and
C1-functionalization of Tetrahydroisoquinoline. Angew. Chem., Int. Ed.
2007, 46, 5775–5778.
(30) (a) Teimouri, M. B.; Mansouri, F. Simple Synthesis of 7H-
Phenaleno[1,2-b]furan-7-oneDerivativesbyOne-Pot, Three-Component
Reactions. J. Comb. Chem. 2008, 10, 507–510. (b) Teimouri, M. B.;
Bazhrang, R. Shaken Not Stirred: A Facile Synthesis of 1,4-Bis(furo[2,3-
d]pyrimidine-2,4(1H,3H)-dione-5-yl)benzenes by One-Pot Reaction of
Isocyanides, N,N0-Dimethylbarbituric Acid and Terephthaldialdehyde.
Bioorg. Med. Chem. Lett. 2006, 16, 3697–3701. (c) Shaabani, A.; Teimouri,
M. B.; Samadi, S.; Soleimani, K. Microwave-Assisted Three-Component
Condensation Reactions on Montmorillonite K10: Solvent-Free Synth-
esis of Furopyrimidines, Furocoumarines and Furopyranones. Synth.
Commun. 2005, 35, 535–541. (d) Shaabani, A.; Teimouri, M. B.; Bijanza-
deh, H. R. A Novel Three-Component Tetrahydrobenzofurans Synthesis.
Monatsh. Chem. 2004, 135, 441–446. (e) Shaabani, A.; Teimouri, M. B.;
Bijanzadeh, H. R. One-Pot Three-Component Condensation Reactions in
Water: An Efficient and Improved Procedure for the Synthesis of Furan
Annulated Heterocycles. Monatsh. Chem. 2004, 135, 589–593. (f) Shaa-
bani, A.; Teimouri, M. B.; Bazgir, A.; Bijanzadeh, H. R. Introducing A
Novel Class of Four-Component Reactions. Mol. Diversity 2003,
6, 199–206. (g) Shaabani, A.; Teimouri, M. B.; Bijanzadeh, H. R. One-
Pot Three Component Condensation Reaction in Water: An Efficient and
Improved Procedure for the Synthesis of Furo[2,3-d]pyrimidine-
2,4(1H,3H)-diones. Tetrahedron Lett. 2002, 43, 9151–9154.
(31) Shelke, K. F.; Sapkal, S. B.; Niralwad, K. S.; Shingate, B. B.;
Shingare, M. S. Cellulose Sulphuric Acid as A Biodegradable and
666
dx.doi.org/10.1021/co200125a |ACS Comb. Sci. 2011, 13, 659–666