Ultrasound-assisted synthesis of azlactone and its reactions with nucleophiles

Article abstract of DOI:10.1016/j.mencom.2012.09.016

4-(2-Oxoindolin-3-ylidene)-2-phenyl-5(4H)-oxazolone (azlactone) was synthesized as a mixture of E- and Z-isomers by ultrasound-assisted Erlenmeyer-Pl?chl reaction between isatin and N-benzoylglycine. Treatment of azlactone with nucleophiles causes opening of its oxazolone moiety.

Full text of DOI:10.1016/j.mencom.2012.09.016

Mendeleev
Communications
Mendeleev Commun., 2012, 22, 273–274
Ultrasound-assisted synthesis of azlactone
and its reactions with nucleophiles
Boris V. Paponov,*a Sergey V. Lvov,b Ekaterina V. Ichetovkina,a
Ilya A. Panasenkoa and Stepan G. Stepanianc
a School of Chemistry, V. N. Karazin Kharkov National University, 61077 Kharkov, Ukraine.
E-mail: paponov_borya@mail.ru
b Research Institute of Biology, V. N. Karazin Kharkov National University, 61077 Kharkov, Ukraine
c B. I. Verkin Institute for Low Temperature Physics and Engineering, National Academy of Sciences of Ukraine,
61103 Kharkov, Ukraine
DOI: 10.1016/j.mencom.2012.09.016
4-(2-Oxoindolin-3-ylidene)-2-phenyl-5(4H)-oxazolone (azlactone) was synthesized as a mixture of E- and Z-isomers by ultrasound-
assisted Erlenmeyer–Plöchl reaction between isatin and N-benzoylglycine. Treatment of azlactone with nucleophiles causes opening
of its oxazolone moiety.
4-Substituted 2-phenyl-5-(4)-oxazolones (azlactones) are highly
demanded building blocks for the synthesis of various biologi-
cally active compounds, including potential anti-cancer agents.1
The most important route for their preparation is the Erlenmeyer–
Plöchl reaction2 comprising condensation of carbonyl compounds
with hippuric acid (N-benzoylglycine). Thermal3 or microwave4
activation of this condensation are reported. On the other hand,
indolin-2-one moiety is one of the most important structure
subunits in the modern medicinal chemistry.5–7
Surprisingly, 2,3-dioxindole (isatin) is not studied enough as
the carbonyl counterpart in the Erlenmeyer–Plöchl reaction. There-
fore, the structure and chemical properties of the thus obtained
product should be clarified.8
Herein, we report on the efficient synthesis of azlactone 1 and
some its reactions leading to its oxazolone ring transformations
(Scheme 1). Previously, the synthesis of N-acetyl derivative of com-
pound 1 under thermal activation was reported.8 However, after
deacetylation the yield of azlactone 1 did not exceed 45%. In
our experiments, sonication of the reactants 2 and 3 raised the
yield of product 1 to 95%.† This procedure is the first successful
application of ultrasound to promote Erlenmeyer–Plöchl reaction
(see Scheme 1).
Due to the exocyclic double bond between 3-position of
oxindole moiety and 4-position of oxazolone ring, structure 1
can be either 4-Z or 4-E isomer. In our experiments, it was formed
in a ratio of 2:1, respectively. This isomerism was also observed
when thermal activation was applied to the reactants 2 + 3. How-
ever, this fact was not noted earlier. The preferred formation of
Z-isomer can be explained by the mutual repulsion of the oxindole
and oxazolone moieties carbonyl groups in the E-isomer mole-
Me
N
O
OR
N
H
O
Ph
NH
NH
O
O
Ph
NH
Ph
NH
O
HO
O
NH
O
O
N
O
H
NH
Z-isomer
Z-isomer
5a R = Me
5b R = Et
6
Z-isomer
Me
N
4
AcOH
ROH
O
NH2
O
N
H
O
Ph
N
H
Ph
+
O
O
N
Ac2O,
2
N
ultrasound
O
room
temperature
HO
O
O
O
NH
NH
E-isomer
Z-isomer
NH2
NH2
NH
O
†
Hippuric acid 3 (9.49 g, 53 mmol) and isatin 2 (7.8 g, 53 mmol) in 25 ml
NH2
Ph
of acetic anhydride were sonicated at 40°C for 90 min (TLC control). After
completion of the reaction, the mixture was filtered and the precipitate
was washed with 100 ml of sodium bicarbonate solution (5%) and recrys-
tallized from acetonitrile to afford product 1 as a mixture of Z- and
E-isomers (2:1). Reddish brown powder, 14.6 g (95%), mp 224–226°C
HN
H2N
3
S
N2H4·H2O
HN
O
O
1
(lit.,8 mp 235°C). MS (EI, 70 eV) m/z: 290 (M+). H NMR (400 MHz,
NH
O
N
NH2
O
N
DMSO-d6) d: 10.79 (s, 0.31H), 10.68 (s, 0.69H), 8.66 (d, 0.31H, J 7.9 Hz),
8.42 (d, 0.69H, J 7.7 Hz), 8.27–8.17 (m, 2×0.69H), 8.13 (d, 2×0.31H,
J 7.7 Hz), 7.79–7.75 (m, 1H), 7.68–7.63 (m, 2H), 7.39–7.34 (m, 1H),
7.09–7.01 (m, 1H), 6.85 (t, 1H, J 7.9 Hz). 13C NMR (100 MHz, DMSO-d6)
d: 167.0, 166.7, 165.9, 165.5, 160.8, 159.1, 145.2, 145.0, 141.8, 139.7,
135.0, 134.7, 133.8, 132.8, 129.9, 129.1, 129.0, 128.8, 127.9, 125.2, 125.1,
123.0, 122.9, 122.1, 121.9, 110.3, 110.1. Found (%): C, 70.37; H, 3.39;
N, 9.61. Calc. for C17H10N2O3 (%): C, 70.34; H, 3.47; N, 9.65.
Ph
N
H
HN
N
H
NH
O
Z-isomer
Z-isomer
Z-isomer
9
Scheme 1
© 2012 Mendeleev Communications. All rights reserved.
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Mendeleev Commun., 2012, 22, 273–274
cule of azlactone 1. This hypothesis was confirmed by computa-
replacement of cycle oxygen by nitrogen was observed, and
(Z)-3-[4-oxo-2-phenyl-1H-imidazol-5(4H)-ylidene]indolin-2-one
9 was isolated in a moderate yield.
In summary, the ultrasound-assisted Erlenmeyer–Plöchl reac-
tion between hippuric acid and isatin made azlactone available,
which may promote its further studying in the fields of hetero-
cyclic and medicinal chemistry.
tional methods.‡
(Z)-2-Benzamido-2-(2-oxoindolin-3-ylidene)acetic acid 4 and
its esters 5a,b were formed from azlactone 1 via oxazolone
moiety cleavage by heating in acetic acid or alkanols, respectively
(Scheme 1).
The formation of azolopyrimidinones was described for reac-
tion of 4-benzylidene azlactone with aminoazoles.9 However,
only heterocyclic amides of N-benzoyl-2-(2-oxoindolin-3-ylidene)-
2-aminoacetic acid can be formed. In our investigations, reaction
of azlactone 1 with 5-amino-3-methylpyrazole was provided as
an example, amide 6 being obtained in a good yield (similarly to
the case with anilines10).
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2012.09.016.
References
Compounds 4, 5a,b and 6 were formed only as Z-isomers
from a mixture E,Z-1.§ Apparently, these Z-isomers were stabilized
by intramolecular hydrogen bond between the carbonyl oxygen
in the oxindole moiety and the benzamide NH group.
3-(2-Oxoindolin-3-ylidene)-3,4-dihydroquinoxalin-2(1H)-one
7 identical to the described previously11 was formed in the reac-
tion of 1,2-diaminobenzene with azlactone 1. In this case, the
benzamide moiety in the molecule 1 was cleaved. Product 7 was
obtained in excellent yield as the Z-isomer only. Similar trans-
formation was proposed earlier for the classical Erlenmeyer
reaction of 4-benzylidene azlactone.12
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Treatment of lactone 1 with hydrazine-hydrate gave (Z)-3-hy-
drazonoindolin-2-one 8 as the product of oxazolone ring opening.
When thiosemicarbazide was used as the nucleophile, formal
‡
For the computational data, see Online Supplementary Materials.
A typical procedure of oxazolone ring opening. A solution of 200 mg
§
(0.67 mmol) of compound 1 in 10 ml of acetic acid or corresponding
alcohol was refluxed for 1 h, then the solid product was filtered off.
For 4: yellow needles, 195 mg (92%), mp > 300°C. MS (EI, 70 eV)
m/z: 308 (M+). 1H NMR (400 MHz, DMSO-d6) d: 12.86 (s, 1H), 11.28 (s,
1H), 8.01 (d, 2H, J 7.7 Hz), 7.68 (d, 1H, J 7.7 Hz), 7.61 (t, 2H, J 7.7 Hz),
7.29 (d, 1H, J 7.4 Hz), 7.14 (t, 1H, J 7.4 Hz), 7.08–6.92 (m, 2H), 3.32 (s,
1H, H2O exchange). 13C NMR (100 MHz, DMSO-d6) d: 170.7, 167.4,
162.0, 139.7, 137.1, 134.0, 133.3, 130.2, 129.0, 128.7, 128.4, 121.9, 121.2,
118.8, 110.9. Found (%): C, 66.27; H, 3.90; N, 9.01. Calc. for C17H12N2O4
(%): C, 66.23; H, 3.92; N, 9.09.
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m/z: 322 (M+). 1H NMR (400 MHz, DMSO-d6) d: 12.70 (s, 1H), 11.21 (s,
1H), 7.96 (d, 2H, J 7.4 Hz), 7.65 (d, 1H, J 7.4 Hz), 7.58 (t, 2H, J 7.4 Hz),
7.25 (d, 1H, J 7.4 Hz), 7.17 (t, 1H, J 7.4 Hz), 7.06–6.91 (m, 2H), 4.01
(s, 3H). 13C NMR (100 MHz, DMSO-d6) d: 172.0, 164.7, 162.8, 139.8,
137.7, 133.8, 133.2, 129.9, 129.1, 128.7, 128.1, 122.3, 121.5, 119.2, 111.7,
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C, 67.07; H, 4.38; N, 8.69.
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For characteristics of compounds 5b, 6–9, see Online Supplementary
Materials.
Received: 28th February 2012; Com. 12/3882
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