Multicomponent synthesis of substituted 3-styryl-1H-quinoxalin-2-ones in an aqueous medium

Article abstract of DOI:10.1016/j.tetlet.2018.09.048

A multicomponent synthesis of substituted 3-styryl-1H-quinoxalin-2-ones is described. Sequential reactions of o-phenylenediamine with sodium pyruvate and aldehydes in 20% aqueous acetic acid containing sodium acetate provided the target products in good to high yields. The reaction is proposed to proceed via initial condensation of the diamine and pyruvate partners followed by an aldol condensation-type mechanism.

Full text of DOI:10.1016/j.tetlet.2018.09.048

Accepted Manuscript
Multicomponent synthesis of substituted 3-styryl-1H-quinoxalin-2-ones in an
aqueous medium
Erivaldo P. da Costa, Sara E. Coelho, André H. de Oliveira, Renata M. Araújo,
Livia N. Cavalcanti, Josiel B. Domingos, Fabrício G Menezes
PII:
S0040-4039(18)31152-3
https://doi.org/10.1016/j.tetlet.2018.09.048
TETL 50287
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
22 August 2018
13 September 2018
18 September 2018
Please cite this article as: da Costa, E.P., Coelho, S.E., de Oliveira, A.H., Araújo, R.M., Cavalcanti, L.N., Domingos,
J.B., Menezes, F.G., Multicomponent synthesis of substituted 3-styryl-1H-quinoxalin-2-ones in an aqueous medium,
Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.09.048
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Multicomponent synthesis of substituted 3-styryl-1H-
quinoxalin-2-ones in an aqueous medium
Erivaldo P. da Costaa, Sara E. Coelhob, André H. de Oliveiraa, Renata M. Araújoa, Livia
N. Cavalcantia, Josiel B. Domingosb and Fabrício G Menezesa*
a Instituto de Química, Universidade Federal do Rio Grande do Norte, Natal, RN,
59072-970, Brazil.
b Departamento de Quimica, Universidade Federal de Santa Catarina, Florianópolis,
SC, 88040-900, Brazil
*Corresponding author:
Fabrício Gava Menezes
Phone: +55 84 33422323
e-mail: fgmenezes10@gmail.com

Abstract
A multicomponent synthesis of substituted 3-styryl-1H-quinoxalin-2-ones is described.
Sequential reactions of o-phenylenediamine with sodium pyruvate and aldehydes in
20% aqueous acetic acid containing sodium acetate provided the target products in
good to high yields. The reaction is proposed to proceed via initial condensation of the
diamine and pyruvate partners followed by an aldol condensation-type mechanism.
Keywords: multicomponent synthesis; green chemistry; 3-styryl-1H-quinoxalin-2-ones.
Graphical Abstract

The development of efficient and green protocols is an important area of
research in modern organic chemistry.1 One-pot multicomponent reactions (MCRs)
represent one of the main strategies for obtaining highly functionalized heterocyclic
compounds in a single step. The use of water or aqueous media as solvents, atom
economy, reduced waste generation, and catalysis comprise some of the principles of
green chemistry associated with MCR chemistry.
Compounds containing the quinoxaline moiety are of significant interest in
medicinal chemistry due to their potent activity against several targets.2–4 Quinoxaline
derivatives are also found in studies involving synthetic dyes5 and chemosensors,6
especially due to the luminescent properties of some of their derivatives.7 Several well-
established synthetic methodologies for the synthesis of quinoxaline derivatives have
been described.8 Recently, MCR concepts have also been applied to the synthesis of
this heterocyclic unit.9–13
The 3-styryl-1H-quinoxalin-2-one (SQXO) scaffold is found in many biologically
relevant molecules, such as those presenting anticancer activity,14,15 as well as
luminescent molecular probes for detecting amyloid β-fibrils.16 On the other hand,
SQXO derivatives are also interesting in the area of materials chemistry (Fig. 1).17–19
O
N
O
15
Br
N
N
N
N
H
O
N
H
O
N
H
O
precursor of supramolecular
chiral material18
anticancer activity15
fluorescent probe16
Figure 1. Selected SQXO derivatives and their applications.
Various synthetic methodologies have been reported for obtaining SQXO
derivatives (2), mostly proceeding via the reactions of 3-methyl-1H-quinoxaline-2-one

(1) with aldehydes in organic solvents, such as glacial acetic acid (Scheme 1).14 Due to
the role of green MCR-based protocols for modern organic synthesis and the relevance
of the SQXO scaffold in different areas, herein we report the one-pot, three-component
synthesis of a series of SQXO derivatives in an aqueous medium.
Previous study:
R
N
N
ArCHO, AcOH, H2SO4, 118 oC
65-78%
11 examples
N
H
O
N
H
O
1
2
Scheme 1. Standard protocol for the synthesis of SQXO derivatives (2) from precursor 1.14
We began optimizing the reaction conditions for the MCR-based synthesis of
SQXO derivatives in water using o-phenylenediamine, sodium pyruvate and
benzaldehyde (Table 1). The reaction in water with no additives was inefficient at both
room temperature and at 120 oC (Entries 1 and 2) after 48 h. The addition of 20%
aqueous acetic acid at room temperature or 120 oC was also tested. Under these
reaction conditions, the o-phenylenediamine was consumed in less than 3 h at room
temperature; however only compound 1 was observed and isolated in 90-92% yield,
even after heating for 48 h (Entries 3 and 4). Transition metal additives including
CuSO4, NiCl2, Al(NO3)3 and Zn(OAc)2 were tested in an attempt to promote the
formation of 2a, however, only compound 1 was observed by TLC, and isolated in 86-
90% yield after 48 h (Entries 5-8). Finally, the addition of sodium acetate was
investigated as an additive (Entry 9). The combination of 20% aqueous acetic acid and
o
sodium acetate (5 equiv.) in a MCR approach at 120 C provided the expected product
2a in 85% yield after 10 h. Lower concentrations of acetic acid provided 2a in lower
yields even after extended reaction times (Entries 10 and 11). Thus, the reaction of o-

phenylenediamine, sodium pyruvate and benzaldehyde with sodium acetate (5 equiv.)
in 20% AcOH(aq) at 120 ºC was selected as the optimised reaction conditions for this
transformation.
Table 1. Optimization of the reaction conditions.a
Entry Conditions
Time (h) Yield (%)b Yield (%)b
1
2a
c
c
c
1
H2O, rt
H2O, 120 oC
48
48
48
48
48
48
48
48
─
─
─
c
2
─
d
3
20% AcOH(aq), rt
92
90
90
88
86
90
─
d
4
20% AcOH(aq), 120 oC
20% AcOH(aq), CuSO4,e 120 oC
20% AcOH(aq), NiCl2,e 120 oC
20% AcOH(aq), Al(NO3)3,e 120 oC
20% AcOH(aq), Zn(OAc)2,e 120 oC
─
d
5
─
d
6
─
d
7
─
d
8
─
g
9
20% AcOH(aq), AcONa (5 equiv.) 120 oC 10
10% AcOH(aq), AcONa (5 equiv.) 120 oC 14
─
85
78
65
g
10
─
g
11
5% AcOH(aq), AcONa (5 equiv.) 120 oC
24
─
a Reagents and conditions: o-phenylenediamine (0.20 g, 1.85 mmol), sodium pyruvate (1.85
mmol), benzaldehyde (2.00 mmol), solvent (25 mL).
b Isolated yield.
c No reaction.
d o-Phenylenediamine was consumed but without SQXO formation (TLC).
e Metal additive in 20 mol% loading relative to o-phenylenediamine.
With the optimised reaction conditions in hand, twelve SQXO derivatives were
obtained in 75-92% yield (Table 2). In general, the SQXO derivatives were isolated by

filtration, except those derived from ortho- and para-hydroxybenzaldehyde, which were
isolated after column chromatography using hexane-ethyl acetate as eluent.
The scope of the reaction includes commercially available benzaldehydes
bearing nitro, hydroxyl, and methoxy groups as well as halogens in different positions.
In general, the role of the substituent is related to their electronic effects. Thus, strongly
electron withdrawing nitro groups provide faster reactions, while electron-releasing
groups such as methoxy react more slowly. Furthermore, the nature of the substituent
does not significantly affect the yield, except for the product from the reaction of 2-
hydroxybenzaldehyde (Table 2, entry 6), which was obtained in 65% yield.

Table 2. Scope for the one-pot MCR synthesis of SQXO derivatives.
R1
R2
AcOH, AcONa, H O,
O
2
R1
R2
O
NH2
NH2
o
N
120 C, 8-14 h
H
ONa
+
+
(65-92%)
N
H
O
O
2
Entry
Product
Time (h)
Yielda
Entry
Product
Time (h)
Yielda
N
N
1
10
85
7
8
12
81
OH
N
H
O
N
H
O
2a
2g
N
2
9
82
10
80
NO
2
N
H
O
2b
NO
2
N
3
4
8
92
89
9
12
10
78
88
N
H
O
2c
F
N
12
10
N
H
O
2d
Br
N
5
6
12
12
79
65
11
12
90
N
H
O
2e
a Isolated yield.
A mechanistic proposal for the formation of SQXO derivatives is presented in
Scheme 2. An initial acid catalyzed reaction between pyruvic acid and o-
phenylenediamine affords 2-(2-amino-phenylimino)-propionic acid (3), which is

subsequently converted into 1 via intramolecular nucleophilic substitution. Since this
latter heterocyclic compound has an enolizable methyl hydrogen, the key-intermediate
(3-methylene-3,4-dihydro-1H-quinoxalin-2-one – 4) is formed which then reacts with
the aldehyde to afford the product 2a via nucleophilic addition to the carbonyl carbon
followed by dehydration.
Scheme 2. Mechanistic proposal for the one-pot synthesis of SQXO derivatives.
Thus, we report herein the one-pot synthesis of a series of substituted 3-styryl-
1H-quinoxalin-2-ones in an aqueous medium. This MCR-based protocol was easily
performed and applied to a variety of SQXO derivatives in good to high yields.
Acknowledgements
This work has been financially supported by the Brazilian entities: Coordenação
de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de

Desenvolvimento Científico e Tecnológico (CNPq), Financiadora de Estudos e Projetos
(FINEP) and Fundação de Amparo à Pesquisa do Estado do Rio Grande do Norte
(FAPERN). Authors gratefully acknowledge the Editor for the valuable contribution.
Supplementary data
Supplementary data associated with this article can be found, in the online
version, at http://dx.doi.org/
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Highlights
● One-pot synthesis of 3-styryl-1H-quinoxalin-2-ones in an aqueous medium is
described
● Reaction medium consists in o-phenylenediamine, sodium pyruvate and aldehydes
● Procedure is easily performed and applied to an interesting scope with good yields
● A mechanistic proposal involved sequential condensation reactions is presented