One-pot synthesis of coumarin-3-carboxamides containing a triazole ring via an isocyanide-based six-component reaction

Article abstract of DOI:10.1021/co4001259

A facile, efficient, and environmentally friendly approach has been developed for the diversity oriented synthesis of trifunctional coumarin-amide-triazole containing compounds. A wide variety of pharmacologically significant and structurally interesting compounds were synthesized via a one-pot, six-component, tandem Knoevenagel/Ugi/click reaction sequence from readily available starting materials in ethanol at room temperature in excellent overall yields. Substituents could be independently varied at five different positions.

Full text of DOI:10.1021/co4001259

Research Article
pubs.acs.org/acscombsci
One-Pot Synthesis of Coumarin-3-carboxamides Containing a
Triazole Ring via an Isocyanide-Based Six-Component Reaction
Shabnam Shaabani,† Ahmad Shaabani,*,† and Seik Weng Ng‡,§
†Faculty of Chemistry, Shahid Beheshti University, G. C., P.O. Box 19396-4716, Tehran, Iran
‡Department of Chemistry, University of Malaya, 50603, Kuala Lumpur, Malaysia
§Chemistry Department, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah, Saudi Arabia
S
* Supporting Information
ABSTRACT: A facile, efficient, and environmentally friendly
approach has been developed for the diversity oriented
synthesis of trifunctional coumarin-amide-triazole containing
compounds. A wide variety of pharmacologically significant
and structurally interesting compounds were synthesized via a
one-pot, six-component, tandem Knoevenagel/Ugi/click re-
action sequence from readily available starting materials in
ethanol at room temperature in excellent overall yields.
Substituents could be independently varied at five different
positions.
KEYWORDS: coumarin, triazole, multicomponent reaction, click chemistry, isocyanide
INTRODUCTION
■
Coumarin (2H-1-benzopyran-2-one) and its derivatives are
important compounds due to their presence in naturally
occurring aromatic products found in plants1 and cinnamon-
flavored foods.2 It has been reported that coumarin derivatives
exhibit anticancer,3 anti-influenza,4 anti-HIV,5 antialzheimer,6
anti-inflammatory,7 antituberculosis,8 antiviral,9 and antimicro-
Figure 1. Examples of some biologically active 1,2,3-triazole-
bial activities.10 Novobiocin is a coumarin-derived antibiotic
coumarins.
used as a competitive inhibitor of the bacterial ATP binding
gyrases B subunit, blocking the negative supercoiling of relaxed
Multicomponent reactions (MCRs) are useful and powerful
DNA.11 Moreover, coumarins constitute an important class of
tools in which three or more different starting materials react to
organic fluorescent dyes. These fluorescent properties have
form novel and complex molecules in a one-pot strategy with
great efficiency and atom economy. The development of such
been used to study proteins and nucleic acids.12 It is important
to note that the existence of the amide groups in coumarin-3-
processes in which several bonds are formed without isolation
carboxamides improves the biological activity of these
of intermediates receives considerable attention for the
compounds.13
preparation of structurally diverse libraries of drug-like
polyfunctinal compounds.19 Although reports on novel MCRs
In recent years, some works have manifested that a coumarin
backbone in combination with some nitrogen-containing
heterocyclic moieties such as azetidine, thiazolidine, thiazole,
and so on could significantly increase the antimicrobial
efficiency and broaden their antimicrobial spectrum.14 In this
context, considerable efforts have been made to develop
synthetic strategies to join two structural units, such as
coumarin scaffold and triazole moiety, in order to make a
new potential therapeutic agent.15,10 For example, compounds
of formula I are useful as pharmaceutical agents to slow or halt
atherogenesis,16 II is a potent 5-lipoxygenase (5-LO)
inhibitor,17 and III is an antiflammatory agent (Figure 1).18
appear regularly in the recent literature, MCRs using more than
five components are very rare. A landmark in this context is the
seven component reaction (7CR) reported by Domling and
Ugi,20 in which thiazolidines are efficiently produced from two
different aldehydes, NaSH, NH3, an isocyanide, CO2, and a
primary alcohol. However, NaSH, NH3, and CO2 are invariable
components in this reaction.
Received: September 29, 2013
Revised: February 13, 2014
Published: February 14, 2014
© 2014 American Chemical Society
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Research Article
Scheme 1. Synthesis of Coumarin-3-carboxamide Derivatives Bearing Substituted 1,2,3-Triazole Moiety 7
The Ugi four-component reaction (U-4CR) is one of the
most commonly used MCRs, in which a carboxylic acid, an
amine, a carbonyl compound, and an isocyanide are reacting to
result in peptide-like products.21 The combination of U-4CR
with secondary transformations is a powerful approach to
access highly functionalized heterocyclic structures in few steps.
There are some literature examples of using an Ugi reaction in
conjunction with click chemistry.22 “Click” chemistry is a highly
effective method for functionalization which was coined in 2001
by Sharpless et al.23 to describe an ideal set of near perfect
reactions. Among the various click reactions, the copper(I)-
catalyzed 1,3-dipolar azide−alkyne cycloaddition (CuAAC) is a
reliable means to form 1,4-disubstiuted triazoles24 that has been
widely used in synthetic and medicinal chemistry.25 1,2,3-
Triazoles are present in many drugs26 and, because of their
interesting biological properties such as antibacterial,25b
antiallergic,27 and anti-HIV activity,28 are an important class
of target molecules. Compounds with 1,2,3-triazole could
actively participate in hydrogen bonding and dipole−dipole
interactions due to their strong dipole moments; moreover it is
extremely hard to be hydrolyzed and remain stable under
oxidative or reductive conditions.25a
Some articles exposed the use via click chemistry of some
coumarin derivatives.29 The well-known biological properties of
coumarins and 1,2,3-triazoles prompted us to synthesize
molecules in which both nuclei exist. As a part of our ongoing
research program on the isocyanide-based MCRs,30 here we
report the synthesis of coumarin-3-carboxamides containing
triazole ring 7 by a one-pot, six-component, condensation
reaction of salicylaldehydes 1, Meldrum’s acid 2, aromatic
propargyloxy aldehydes 3, amines 4, isocyanides 5, and azides
6, in the presence of catalytic amounts of Cu(OAc)2 (10 mol
%) and sodium ascorbate (20 mol %) as a reducing agent for
the reduction of Cu(II) to Cu(I) in ethanol at room
temperature (Scheme 1). Recently, Balalaie et al. synthesized
coumarin-3-carboxamides containing lipophilic spacers through
the U-4CR.31 In this paper, we report the synthesis of
coumarin-3-carboxamides containing a triazole ring by
preparing the starting coumarine-3-carboxylic acid and a
terminal triazole ring in situ. It is worth mentioning that in
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Figure 2. continued
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Figure 2. Structure and isolated yields of products 7.
the course of our reaction, two C−C bonds and six heteroatom-
C bonds are formed. Also, a triazole ring, a lactose ring, and two
amide groups are formed.
5.67 ppm), and CH (δ = 6.42 ppm); a multiplet for aromatic
porotons (6.68−8.13 ppm, 19H); and a singlet for NH (δ =
1
8.45 ppm). Also, the H decoupled 13C NMR spectrum of
7{2,1,1,1,1} is completely consistent with the product structure.
The mass spectra of these compounds displayed molecular ion
peaks at the appropriate m/z values. Finally, the structure of the
products 7{2,1,2,1,1}, 7{2,1,2,1,3}, and 7{2,2,1,1,1} was
confirmed unambiguously by single-crystal X-ray analysis
(Figure 3 and SI).
RESULTS AND DISCUSSION
■
In a pilot experiment, 5-bromosalicylaldehyde 1{2} reacts with
Meldrum’s acid 2 in EtOH to afford 6-bromo-coumarin-3-
carboxylic acid. Then, aniline 4{1}, propargyloxy aldehyde
3{1}, and cyclohexyl isocyanide 5{1} were added and the
mixture stirred at room temperature. After completion of the
reaction, benzyl azide 6{1} and a catalytic amount of Cu(OAc)2
(10 mol %) and sodium ascorbate (20 mol %) were added.
After completion of the reaction (24 h), the desired product
7{2,1,1,1,1} was isolated in 92% yield.
The reaction did not require any optimization. In view of the
success of the above reaction, we explored the scope and
limitations of this reaction, by extending the procedure to
various salicylaldehydes 1{1−4}, aromatic propargyloxy
aldehydes 3{1−3}, amines 4{1−4}, isocyanides 5{1−4}, and
azides 6{1−5}. As indicated in Figure 2, the reactions proceed
very efficiently at room temperature and led to the formation of
a new class of the amidated coumarin derivatives containing
triazole ring 7 in excellent yields. It is noteworthy that the Ugi
and click reaction cannot usually be performed directly in one
step. It is well-known that isocyanides are good ligands for
transition metals.32 Therefore, copper will be coordinated to
the isocyanide C atom, and this complex is not effective as a
catalyst for the Huisgen 1,3-dipolar cycloaddition.
Figure 3. ORTEP diagram for 7{2,1,2,1,1}.
A possible mechanism for the formation of products 7 is
shown in Scheme 2. The reaction may be rationalized as by the
initial formation of conjugated electron-deficient heterodiene 8
by a standard Knoevenagel condensation of the salicylaldehyde
1 and Meldrum’s acid 2. Then nucleophilic attack of the
phenolic group onto the carbonyl carbon of Meldrum’s acid
resulted in the opening of Meldrum’s acid ring, and a
The structures of products 7 were deduced from their IR, 1H
NMR, 13C NMR, mass spectra, and CHN analysis data. The 1H
NMR spectrum of 7{2,1,1,1,1} consisted of a multiplet for the
methylene protons of the cyclohexyl ring (δ = 1.04−1.71 ppm,
10H); a broad singlet for the NH−CH cyclohexyl (δ = 3.64
ppm); three singlets for OCH2 (δ = 5.21 ppm), NCH2 (δ =
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Scheme 2. Proposed Mechanism for the Formation of Products 7
subsequent loss of acetone leads to the formation of coumarin-
3-carboxylic acid.33 According to the commonly accepted Ugi-
4CR mechanism, the amines, aldehydes, and acids are in
equilibrium with iminium carboxylates 9 in the reaction
medium. The addition of the carbenoid C atom of the
isocyanides onto the iminium group followed by the addition of
the carboxylate ion onto the C atom of the nitrillium ion leads
to the formation of the adduct 10, which undergoes an
intramolecular acylation known as Mumm rearrangement to
give the stable Ugi adduct 11. Finally, the Huisgen 1,3-dipolar
cycloaddition reaction between the propargyloxy group of 11
and azide 6 takes place to produce the bifunctional coumarin-
triazole products 7 (Scheme 2).
trifunctional containing coumarin-amide-triazole compounds
starting from simple and readily available inputs. The reaction
shows good functional group tolerance and is high-yielding, and
product isolation is very straightforward. The broader substrate
scope of this reaction makes it a useful and attractive process
for the synthesis of a great library of these important
compounds. The potential uses of this route in synthetic and
medicinal chemistry may be significant, since the products share
structural and functional group properties of the biologically
active molecules.
EXPERIMENTAL PROCEDURES
■
General. Melting points were measured on an Electro-
thermal 9200 apparatus. IR spectra were recorded on a
Shimadzu IR-470 spectrometer. 1H NMR spectra were
recorded on a Bruker DRX-300 Avance spectrometer at
300.13 MHz; chemical shifts (δ scale) are reported in parts
CONCLUSION
■
In conclusion, we have successfully developed a novel one-pot
six-component condensation reaction strategy leading to
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per million (ppm). H NMR spectra are reported in order:
number of protons, multiplicity, and approximate coupling
constant (J value) in hertz (Hz); signals were characterized as s
(singlet), d (doublet), t (triplet), m (multiplet), br s (broad
signal), and Ar (aryl). 13C NMR spectra were recorded on
Bruker DRX-400 and DRX-300 Avance spectrometers at
100.64 and 75.47 MHz; chemical shifts (δ scale) are reported
in parts per million (ppm). The mass spectra were recorded on
an Agilent 5973 mass spectrometer operating at an ionization
potential of 70 eV. The elemental analyses were performed with
an ElementarAnalysensysteme GmbH VarioEL. All of the
products are new compounds, which were characterized by IR,
mass, H NMR, and 13C NMR spectra.
1
General Procedure for the Synthesis of 1,2,3-Triazole-
coumarin-3-carboxamides 7. A mixture of salicylaldehyde (1
mmol) and Meldrum’s acid (1 mmol) in EtOH (5 mL) was
stirred for 10 h. Then, amine (1 mmol), propargyloxy aldehyde
(1 mmol), and isocyanide (1 mmol) were added and the
mixture stirred at ambient temperature for 8 h. After
completion of the reaction, as indicated by TLC, aryl azide
(1.2 mmol), Cu(OAc)2 (0.02 g, 10 mol %), and sodium
ascorbate (0.04g, 20 mol %) were added. Then, the resulting
mixture was stirred for 6 h at room temperature. After
completion of the reaction, as indicated by TLC, the product
was filtered off. Then, it was stirred in a solution of ammonia
and water for 30 min. Then, the solid was filtered and washed
with EtOH and water to give the pure product.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures; characterization data and spectra of
products; IR, mass, and H and 13C NMR spectra for 7; and
1
crystallographic data for 7{2,1,2,1,1}, 7{2,1,2,1,3}, and
7{2,2,1,1,1} (CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Tel.: +98-21-29902800. Fax: +98-21-22431671. E-mail: a-
■
shaabani@sbu.ac.ir.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from the Iran
National Science Foundation (INSF) and Research Council of
Shahid Beheshti University.
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