Copper(II) catalyzed expeditious synthesis of furoquinoxalines through a one-pot three-component coupling strategy

Article abstract of DOI:10.1021/ol502072k

Microwave assisted one-pot transformation has been developed for the synthesis of biologically significant polysubstituted furoquinoxalines in good to excellent yields through a copper(II) catalyzed three-component coupling of o-phenylenediamine, ethylglyoxalate, and terminal alkyne, known as A³-coupling, followed by 5-endo-dig cyclization.

Full text of DOI:10.1021/ol502072k

Letter
pubs.acs.org/OrgLett
Copper(II) Catalyzed Expeditious Synthesis of Furoquinoxalines
through a One-Pot Three-Component Coupling Strategy
Gunaganti Naresh,† Ruchir Kant,§ and Tadigoppula Narender*,†
§
†Medicinal and Process Chemistry Division, Molecular and Structural Biology Division, CSIR-Central Drug Research Institute,
Lucknow-226 031, India
S
* Supporting Information
ABSTRACT: Microwave assisted one-pot transformation has
been developed for the synthesis of biologically significant
polysubstituted furoquinoxalines in good to excellent yields
through a copper(II) catalyzed three-component coupling of o-
phenylenediamine, ethylglyoxalate, and terminal alkyne,
known as A3-coupling, followed by 5-endo-dig cyclization.
olycyclic fused nitrogen containing heterocyclic com-
pounds are found in many biologically significant natural
The existing methods for the synthesis of quinoxaline fused
heterocycles involve multiple steps (Scheme 1) and prefunc-
P
products and pharmaceuticals.1 Synthesis of these motifs in a
single step through C−C and C−heteroatom bond formation is
challenging as well as an emerging field in current organic
synthesis. Various domino/cascade reactions have been
developed to address this challenge.2 Among these, in recent
years, transition metal catalyzed three-component coupling of
an aldehyde amine and terminal alkyne (A3-coupling) has
gained sizable attention,3 since it allows the fast and short
synthesis of highly functionalized heterocycles in a complete
atom economic fashion. Distinct transition metals such as
gold,3b silver,4 copper,5 and iron6 have been successfully utilized
for these transformations in the past decade. In general, A3
coupling (amine, aldehyde, and alkyne) furnishes propargyl-
amines as final products and introduction of additional reactive
functionality in aldehyde or amine source could result in the
formation of diversified heterocycles.7 Very limited reports are
available in the literature in which an aldehyde having another
nucleophile5 was used for A3-coupling, whereas no reports were
found on an amine with another nucleophile for A3-coupling
reactions. With this concept in mind, we planned to synthesize
the biologically important furoquinaxaline heterocyclic motifs
in a single step by using o-phenylenediamine as an amine
source (amine with additional nucleophile) in A3-coupling for
the first time.
Scheme 1. Approach for the Synthesis of Furoquinoxalines
tionalization of starting materials. Therefore, simple and
straightforward strategies from readily available starting
materials are highly acceptable. In continuation of our efforts
toward the development of new synthetic methodologies for
the construction of biologically important heterocycles and
carbocycles,18 herein, we disclose an efficient approach for the
synthesis of furoquinoxalines from o-phenylenediamines, ethyl-
glyoxalate, and terminal alkynes with a one-pot strategy in good
to excellent yields.
Our initial attempt for the synthesis of furoquinoxaline began
with commercially available o-phenylenediamine (1a), an
ethylglyoxalate 50% solution in toluene (2a), phenylacetylene
(3a), and copper(II) trifluoromethanesulfonate (10 mol %) as
the catalyst at 80 °C in a microwave reactor for 5 min. This
resulted in a 50% conversion of the starting materials, and the
desired furoquinoxaline (4aaa) was isolated in a 35% yield
(Table 1, entry 1). When we introduced toluene as the solvent
in the reaction medium, we were pleased to observe the notable
Quinoxaline and its derivatives are an important class of
nitrogen heterocycles originating in many natural products and
pharmaceuticals and exhibit a broad spectrum of biological
activities.8 Quinoxaline derivatives are also significant in
materials science such as luminescent materials9 and
polymers.10 Several synthetic methods exist in the literature
for the construction of quinoxaline and its derivatives.11−13
Most of them are limited to the synthesis of simple
quinoxalines, and very few strategies are available for bio-
logically active complex quinoxaline fused derivatives such as
indole,14 furan,15 pyrrole,16 and pyrazole17 heterocycles.
Received: July 15, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol502072k | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
After attaining the optimal conditions (Table 1, entry 10), we
examined various electron-rich and -deficient substituted o-
phenylenediamines (1a−h), which afforded the desired
furoquinoxalines in good to excellent yields (Scheme 2,
Table 1. Optimization of the Reaction Conditions for the
Synthesis of Furoqinoxalines
a
Scheme 2. Substrate Scope of o-Phenylenediamine for the
a
Synthesis of Furoquinaxalines with Optimized Conditions
b
temp time (min) microwave/ yield
entry
catalyst
solvent
(°C)
conventional
(%)
c
1
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OAc)2
CuBr2
−
80
80
05/120
05/120
05/120
10/120
05/120
10/120
10/120
10/120
10/120
10/120
15/150
10/120
10/120
10/120
10/120
10/120
35
50
55
55
62
70
70
55
50
87
85
85
40
25
0
c
2
toluene
toluene
toluene
toluene
toluene
toluene
DCE
c
3
100
100
100
100
110
110
110
110
110
120
110
110
110
110
c
4
d
d
d
d
d
e
e
e
e
e
e
e
5
6
7
8
9
ACN
10
11
12
13
14
15
16
toluene
toluene
toluene
toluene
toluene
toluene
toluene
a
CuI
Conditions: 1a−1h (0.46 mmol), 2a (0.93 mmol), 3a (0.46 mmol),
CuCl
0
Cu(OTf)2 (20 mol %), Toluene (3 mL); isolated yields in
a
parentheses. # = isolated yields of mixture of two isomers.
Reaction conditions: 1a (0.46 mmol), 2a (0.93 mmol), 3a (0.46
mmol) catalyst, solvent (3 mL); in microwave vial (2−5 mL) sealed
and placed in microwave reactor (450 W); DCE = 1,2-Dichloroethane,
4aaa−4haa). The electron-rich diamines gave marginally better
yields when compared to electron-deficient diamines (4faa).
The reaction of monosubstituted phenylenediamines (1b−f)
with terminal alkynes gave a mixture of two separable isomers
in an 80:20 ratio with respect to the isolated yields (Scheme 2,
4baa−4faa); however in the case of 3,4-diaminotoluene (1d),
an inseparable mixture of 4daa was obtained.
b
c
d
ACN = Acetonitrile. Isolated yields. 10 mol % catalyst loading. 15
mol % catalyst loading. 20 mol % catalyst loading.
e
progress in yield (Table 1, entry 2). The same reaction was
carried out with conventional heating at 80 °C for 2 h;
however, it was not helpful in increase the yield. We then
carried out the experiment with an elevated temperature at 100
°C in a microwave as well as conventional system and found a
slight improvement in the yield (Table 1, entry 3). Further
improvement in yield (62%) was observed, when we increased
the catalyst loading to 15 mol % (Table 1, entry 5). All these
preliminary experiments suggested that the amount of catalyst
and the temperature play crucial roles in yield improvement.
We therefore increased the catalyst loading to 20 mol % and
the temperature to 110 °C in the microwave for 10 min; to our
delight, we observed remarkable improvement in the yield to
87% (Table 1, entry 10). Other copper salts such as Cu(II)
bromide, Cu(OAc)2, CuI, and CuCl were also employed in the
reaction medium (Table 1, entries 13−16); however, we found
that only Cu(OTf)2 was efficient for this domino strategy.
Various solvent systems were also screened, and it was found
that toluene was the most effective in the synthesis of the
desired furoquinoxaline in high yield. The formation of
furoquinoxaline (4aaa) was unambiguously confirmed by
various 2D-NMR spectral data and subsequently by the 2D-
NMR spectral data and single crystal X-ray structure of
compound 4aaf (Figure 1).19
We next investigated the scope of the reaction toward the
substitution tolerance of terminal alkynes (3b−3o), and the
results are summarized in Scheme 3. Both the electron-rich
and-withdrawing substituted aromatic alkynes produced the
target furoquinoxalines smoothly in high yield. Even the strong
electron-withdrawing substituted terminal alkyne 3l (Scheme 3,
4aal) and heteroaromatic terminal alkyne 3n (Scheme 3, 4aan)
were successfully utilized to furnish the desired furoquinoxa-
lines in good yields. The reaction between substituted o-
phenylenediamines (4g−h) and aromatic terminal alkynes
(3b−c) gave excellent yields (4gab−4hac). The aliphatic
terminal alkyne (3o), however, failed to produce the desired
furoquinoxalines (4aao) under similar reaction conditions.
Aliphatic terminal alkynes have low boiling points when
compared to the aromatic terminal alkynes; due to this reason,
they might fail to produce the desired furoquinoxalines at high
temperature. When we carried out the same reaction at rt, the
o-phenylenediamine and ethylglyoxalate mixture was not
soluble and the reaction failed to give furoquinoxaline 4aao.
Encouraged by the above results, we focused on synthesizing
more structurally diversified furoquinoxalines using non-
commercial phenyl acetylenes. We synthesized a few phenyl
acetylenes (3n−s) by using known protocols20 and subjected
them to the optimized conditions, which resulted in the
synthesis of diversified furoquinoxalines in good to excellent
yields (Scheme 4, 4aap−4han).
A possible reaction mechanism for the formation of
furoquinoxalines appears to be tandem C−C bond formation
followed by a 5-endo-dig cyclization reaction as outlined in
Figure 1. ORTEP diagram of compound 4aaf.
B
dx.doi.org/10.1021/ol502072k | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Substrate Scope for the Synthesis of
Scheme 5. Possible Reaction Mechanism for the Tandem A3-
Coupling and 5-endo-dig Cyclization
Furoquinaxalines with Terminal Alkynes under Optimized
a
Conditions
furoquinoxaline. Further studies, however, are required to
confirm the exact reaction mechanism.
In conclusion, we have developed a simple, novel, and
efficient protocol for the copper(II) catalyzed synthesis of
furoquinaxalines from readily available 2-amino substituted
anilines, ethyl glyoxalate, and terminal alkynes through tandem
A3-coupling followed by a 5-endo-dig cyclization process in a
single step to produce good to excellent yields under
microwave and also conventional conditions (data not
presented). This novel method involves the formation of four
new bonds (2C−C, C−N, and C−O) in a cascade pathway.
ASSOCIATED CONTENT
* Supporting Information
General experimental procedure and spectroscopic data of all
the compounds; 2D-NMR spectral data for 4aaa, 4aaf; and X-
ray analysis data for 4aaf. This material is available free of
charge via the Internet at http://pubs.acs.org.
■
a
Conditions: 1 (0.46 mmol), 2 (0.93 mmol), 3 (0.46 mmol),
S
Cu(OTf)2 (20 mol %), Toluene (3 mL); isolated yields in
parentheses.
Scheme 4. Synthesis of Furoquinaxalines with Diversified
Terminal Alkynes under Optimized Conditions
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: t_narendra@cdri.res.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Authors are thankful to the Director, CDRI, Lucknow, India for
constant encouragement for the program on the synthesis of
Natural products analogues. We thank Dr. Tejender S. Thakur
of the Molecular and Structural Biology Division, CSIR-Central
Drug Research Institute for supervising the X-ray data
collection and structure determination of a compound (4aaf);
G. Naresh is thankful to the CSIR, New Delhi, India for a
fellowship and research grant (BSC-0102: THUNDER). This is
CDRI communication No.8758.
Scheme 5. Generally, in A3-coupling reactions, the amine (I)
reacts with aldehyde (II) and forms the imine which is further
transformed to iminium ion A; at the same time the in situ
generated copper acetylide B from terminal alkyne and
copper(II) trifluoromethanesulfonate attacks the intermediate
(A) to produce the propargylamine C.3a The resulting
propargylamine C further attacks the ester functionality
intramolecularly, leading to the generation of intermediate D.
Since intermediate D is easily enolizable in an acidic medium, it
provides cyclized intermediate 3-(alkynyl)-3,4-dihydro-
quinoxalin-2(1H)-one (E) and further cleavage of the metal
π-complex occurs followed by oxidation furnishing the target
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