Synthesis of 4-azo-butenolides

Article abstract of DOI:10.1080/00397911.2017.1354380

An efficient, catalyst-free, microwave-assisted approach has been developed for the synthesis of 4-azo-butyenolides derivatives by condensing tetronic acid with various anilines. This approach exhibited good functional group compatibility and produced the

Full text of DOI:10.1080/00397911.2017.1354380

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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Synthesis of 4-azo-butenolides
Ana Paula da Rocha Pissurno & Rosangela da Silva de Laurentiz
To cite this article: Ana Paula da Rocha Pissurno & Rosangela da Silva de Laurentiz (2017):
Synthesis of 4-azo-butenolides, Synthetic Communications, DOI: 10.1080/00397911.2017.1354380
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1354380
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Date: 24 July 2017, At: 03:09

Synthesis of 4-azo-butenolides
Ana Paula da Rocha Pissurno
Physics and Chemistry Department, São Paulo State University (UNESP), Ilha Solteira, São
Paulo, Brazil
Rosangela da Silva de Laurentiz
Physics and Chemistry Department, São Paulo State University (UNESP), Ilha Solteira, São
Paulo, Brazil
Address correspondence to Rosangela da Silva de Laurentiz, Physics and Chemistry Department,
São Paulo State University (UNESP), 15385–000, Ilha Solteira, São Paulo, Brazil
ABSTRACT
An efficient, catalyst free, microwave assisted approach has been developed for the
synthesis of 4-azo-butyenolides derivatives by condensing tetronic acid with various anilines.
This approach exhibited good functional group compatibility and produced the desired products
in good to excellent yields in just 30–40 minutes. This approach can be seen as a better
alternative to protocols with long reaction times used for the synthesis of these compounds,
which are synthons for the obtaining of quinolines.
Graphical Abstract
1

KEYWORDS: microwave irradiation, quinolines synthons, short reaction time, substrate scope
Introduction
Heterocyclic natural or synthetic compounds are an important class of molecules for
development of new drugs.[1–3] Several of these compounds containing the quinoline nucleus
display innumerous biological properties and are used as drugs against malaria, cardiovascular
diseases, allergies, and vasodilators.[4–15] The search for new drugs more potent and with less
side effects requires chemical strategies of synthesis that facilitate the obtaining of intermediates
for the construction of heterocycles in a quick way and in smaller reactional times, speeding up
the process of the synthesis until the biological evaluation.[16]
4-Azo-butenolides are synthons for the synthesis of quinolines, dihydroquinolines,
lactones and a large amount of derivatives of great pharmacological interest.[17–20] Despite the
importance of these compounds, the syntheses described in the literature use reactional
conditions that involve long reaction times and expensive purification processes.[20] These
conditions make it difficult to obtain these intermediates for the construction of more complex
molecules in quantity and structural variety for biological evaluation. In this work, a new method
for synthesis of 4-azo-butenolide derivatives from reaction between tetronic acid (1) and anilines
promoted by microwave is described.
Result and Discussion
2

Firstly, the reaction between equimolar quantity of tetronic acid (1) and 4-bromoaniline
(2a) was used as a model to evaluation of better solvent and temperature for the synthesis
(Scheme 1). Dioxane, water, ethanol, acetonitrile and trifluoroacetic acid (Table 1) were
evaluated as solvent at room temperature and under microwave heating. Results are summarized
in Table 1. The product 3a was purified its structure was confirmed by 1H NMR and 13C NMR.
Table 1 shows that in the reaction with dioxane was obtained good yield at room
temperature (entries 1, Table 1), but with a reaction time of 144 h. Under microwave heating at
200W the reaction time decreases, however, the yield also decreases with the formation of by-
products as seen by thin layer chromatography (entry 2, Table 1). Microwave heating of dioxane
occurs due the polarity of the starting materials. Water, ethanol and trifluoracetic acid at room
temperature furnished the product 3a in yield varying between 60 at 70% with reaction time of
72h. Under microwave irradiation these solvents provided the product 3a in shorter reaction
times in yields similar to those obtained at room temperature but with by-products formation.
Acetonitrile in room temperature furnished the product 3a in better yield in the time of 48h and
98% of yield after 30 minutes under microwave heating. In protic solvents used part of the
aniline is ionized while in acetonitrile no there ionization and nucleophilic character of nitrogen
is maintained. In dioxane also no there ionization, however the starting materials are insoluble,
therefore the time reactional is longer.[21]
Based on these results, it was established a time of 30–40 min using acetonitrile as
solvent under microwave heating for the others reactions performed.
After optimization of the reaction conditions, other anilines (2b–j) were examined for the
synthesis of 4-azo-butenolides derivatives (3b-j) (Table 2).
3

The results in Table 2 show that by use of CH3CN/MW in a time reaction of 30–40 min,
it was possible to obtain 4-azo-butenolides derivatives (3b-j) with high yields (84–91%). Large
yield differences was observed for aniline 2d which furnished the product 3d in yield of 74 %.
The inductively electron withdrawing methoxy group in the position 3 of the aniline 2d removes
electron density from nitrogen, making it less nucleophilic.[22]
The nucleophilic attack of the nitrogen in the carbonyl of the tetronic acid (1) furnish the
intermediate I. The MW heating causes increased of the molecular kinetic energy turning faster
the reaction[23–26] and the acetonitrile (Lewis base) promote the remoting of proton α-carbonyl
and subsequent loss of H2O with formation of the product 3.
There are in the literature methodologies describing the synthesis of 4-azo-butenolides
derivatives, [27–31] however, most of them use anhydrous and toxic solvents such as benzene, low
yields, long reaction times and chromatographic purification methods. Our methodology has the
advantage not only of the higher yield, but also of the shortest reaction time and the higher purity
of the products that do not require chromatographic purification.
Experimental
General procedure for synthesis of 4-azo-butenolides 3a
A mixture of tetronic acid (1.0 mmol) and anilines (1.2 mmol) in acetonitrile (2 mL) was
taken in a reaction flask equipped with a small magnetic stirring bar, and the reflux condenser. The
mixture was then irradiated in a microwave reactor for 40 min (reflux temperature of the solvent)
4

at a power of 200 W. Completion of the reaction was monitored by TLC (20 % ethyl acetate in
hexane). The reaction mixture was then cooled to room temperature and the solvent was removed
on rota-evaporator. The precipitated crude product was washed with mixture of hexane-ethyl
acetate (8:2) and dried under vacuum to give 3a (31.1 mg, 98%) as a yellow solid; mp 239–241 °C.
It was obtained as brown solid having m. p. 247–249 °C in 98% yield. 1H NMR (400 MHz,
DMSO-d6): δ (ppm) 9.83 (s, 1 H, NH), 7.53 (d, 2H arom, J = 8.8 Hz), 7.16 (d, 2H arom, J = 8.8
Hz), 5.36 (s, 1H), 4.87 (s, 2H). NMR 13C (100 MHz, DMSO-d6): δ (ppm) 174.80, 162.32,
+
+
139.52, 132.18, 120.47, 114.58, 84.47, 68.04. HRMS (ESI ): m/z [M + H] calculated for
C10H9NBrO2: 253.9816; found: 253.9810.
Conclusion
Finally, we can conclude that the use acetonitrile and MW heating in the reaction
between tetronic (1) and aniline derivatives (2a–j) produces new 4-azo-butenolides derivatives
with excellent yields, in a very efficient manner. This reaction condition can be applied using
anilines with electron-withdrawing as well as electron-donating substituents at different positions
on the aromatic ring.
Supporting Information
1
Full experimental detail, H and 13C NMR spectra have been provided in supporting
information. This material can be found via the “Supplementary Content” section of this article’s
webpage.
Acknowledgements
5

The authors would like to thank Fundação de Amparo à Pesquisa do Estado de São Paulo
(FAPESP) (Proc. 2014/07493–5), for their financial support and Coordenacão de
Aperfeiçoamento de Pessoal de Nível Superior (CAPES) for scholarship.
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7

Table 1. Results obtained to the reaction between tetronic acid (1) and Br-aniline (2a) in
different solvents
Entry
Solvente
DX
Temperatureb
r.t.
Time (h)
144
2
Yielda %
86
1
2
3
4
5
MW
r.t.
MW
r.t.
MW
r.t.
68
60
65
68
60
70
H2O
EtOH
TFA
72
0.5
72
0.6
72
6
7
8
9
MW
r.t.
0.6
48
60
75
CH3CN
10
MW
0.5
98
a Isolated product. b MW- reflux temperature of the solvent, 200 W, open vessel
8

Table 2. Results obtained by reaction between tetronic acid (1) and anilines derivatives (2a–j)
promoted by MW
Entry
Aniline
Product
3a
Yielda (%)
1
2
4-Br* (2a)
98
97
90
74
84
84
96
93
89
88
3,4 (OC2H4O) (2b)
4-(OCH3) (2c)
3-(OCH3) (2d)
4-Cl (2e)
3b
3c
3
4
3d
3e
5
6
4-CH(CH3)2 (2f)
3,4 (OCH2O) (2g)
3,4-(OCH3)2 (2h)
3,4,5-(OCH3)3 (2i)
4-CF3 (2j)
3f
7
3g
8
3h
3i
9
10
3j
a Isolated yields. b MW- Microwave reflux, 200 W, open vessel
9

Scheme 1. Reaction between tetronic acid (1) and benzaldehyde derivatives (2a–j) promoted by
microwave.
10

Scheme 2. Mechanistic proposal for reaction between tetronic acid and aniline.
11