Pronounced ionic liquid effect in the synthesis of biologically active isatin-3-oxime derivatives under acid catalysis

Article abstract of DOI:10.1016/j.tetlet.2008.07.067

An efficient method was developed for the preparation of isatin-3-oxime derivatives with Bronsted and/or Lewis acids in imidazolium-based ionic liquids. Isatin-3-oxime bearing the electron donating methoxy group was equally obtained in good yields. The pr

Full text of DOI:10.1016/j.tetlet.2008.07.067

Tetrahedron Letters 49 (2008) 5639–5641
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Pronounced ionic liquid effect in the synthesis of biologically
active isatin-3-oxime derivatives under acid catalysis
Angelo C. Pinto a, , Alexandre A. Moreira Lapis b,d, Barbara Vasconcellos da Silva a, Renato S. Bastos a,
*
Jaïrton Dupont b, Brenno A. D. Neto c,
*
a Departamento de Química Orgânica, Instituto de Química, Universidade Federal do Rio de Janeiro (UFRJ), 21945-970, Rio de Janeiro, RJ, Brazil
b Laboratory of Molecular Catalysis, IQ-UFRGS, Porto Alegre, RS, Brazil
c Pharmacy Department, PUCRS, Porto Alegre, RS, Brazil
d Universidade Federal do Pampa, Unipamapa, Bagé, RS, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient method was developed for the preparation of isatin-3-oxime derivatives with Bronsted and/
or Lewis acids in imidazolium-based ionic liquids. Isatin-3-oxime bearing the electron donating methoxy
group was equally obtained in good yields. The pronounced ionic liquid effect avoids the direct formation
of isatin in the acidified media and the reaction leads exclusively to isatin-3-oxime derivatives.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 23 June 2008
Revised 8 July 2008
Accepted 10 July 2008
Available online 16 July 2008
1a X = InCl , BMI.InCl
4
Isatins are synthetically versatile substrates that display diverse
biological and pharmacological properties.1,2 These substances
were found in urine and brain regions associated with hunger,
but their endogenous role has not been fully clarified yet.2 More-
over, isatins can be found in nature. Recently, 6-methoxy-1-meth-
ylisatin was isolated from the plant Boronella koniambiensislies.3
Isatin-3-oximes are useful antiallergic agents with potent and pro-
longed action. Derivatives of these compounds are also potassium
channel openers for treatment of respiratory diseases, convulsions,
renal disorders, urinary incontinence and diarrhea.4
The most common route to prepare isatins is the Sandmeyer
method that involves the reaction of anilines, chloral hydrate and
hydroxylamine hydrochloride in the presence of sodium sulfate
solution, followed by treatment of the formed isonitrosoacetani-
lides with concd sulfuric acid.5 Several modifications have been
introduced in the original methodology to prepare this class of bio-
logically active compounds.6 Nevertheless, the methodologies fail
in the preparation of isonitrosoacetanilides bearing electro donat-
ing groups. Those cases require a five-step procedure and, in all
cases, nitrone intermediates are involved.7 Normally, isatin-3-oxi-
mes systems are prepared from respective isatins upon treating
them with hydroxylamine hydrochloride in ethanol in the pres-
ence of a base.8 The only procedure described in the literature
not passing through isatin intermediates, consists of the hydro-
lyses reactions of 1-arylamine-1-methylthio-2-nitroethenes that
allow the obtainment of 2-nitroacetanilides, which in turn afford
isatin 3-oxime in the presence of strong acids.9
4
1b X = PF , BMI.PF
6
6
_
1c X = BF , BMI.BF
4
4
X
+
N
N
1d X = Cl, BMI.Cl
1e X = AlCl , BMI.AlCl
4
4
1f X = NTf , BMI.NTf
2
2
Figure 1. Structure of some imidazolium-based ILs.
applied in catalysis.10 ILs have been efficiently used in biphasic
catalysis. Moreover, it was shown in several cases that ILs have a
salutary effect on the reaction rate and selectivity. Besides, they
can also promote reactions that are not easy to take place in clas-
sical organic solvents.11 ILs are also very effective media for ‘clas-
sic’ acid catalysis and the acidity of acids normally increases
when dissolved in ILs.12 Furthermore, ILs are less solvating than
water.13
Recently, we have successfully used ILs for the preparation
of synthetic intermediates of biologically active molecules14a and
explored their effect to promote reactions under catalytic acidic
conditions.15 Due to our interest in biologically active com-
pounds14 and the preparation of isatin-3-oximes derivatives,2 we
describe herein the use of ILs as great media to support different
Lewis and Bronsted acids and to promote direct formation of isat-
in-3-oximes derivatives from substituted isonitrosoacetanilides
(Scheme 1).
Isonitrosoacetanilides were prepared, in good yields, upon
treatment of anilines with chloral hydrate and hydroxylamine
hydrochloride, in a saturated aqueous sodium sulfate medium,
according to a previous report.5b Preliminary studies with isonitro-
soacetanilide were carried out using different acids and ILs. The
results are summarized in Table 1.
Ionic liquids (ILs), especially those based in 1-n-butyl-3-methyl-
imidazolium cation (BMI, Fig. 1), are among the most studied and
* Corresponding authors. Tel.: +55 51 33203512; fax: +55 51 3320 3612.
E-mail address: brenno.ipi@gmail.com (B. A. D. Neto).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.067

5640
A. C. Pinto et al. / Tetrahedron Letters 49 (2008) 5639–5641
NOH
O
H
H
NOH
O
Lewis acid
or
Bronsted acid
BMI.X
NOH
NOH
Difficult
ion-pair
formation
R
+
+
R
N
H
Anion high
coordinative ability
N
N
H
O
N
H
+
O
IL
o
H
135
C
(Charged intermediate)
2
Isatin-3-oxime 3
_
+
_
X
derivative
+
N
N
X
+
Scheme 1. Cyclization promoted in ILs under acid conditions.
N
N
Table 1
Conditions for the cyclization isonitrosoacetanilide (R = H, Scheme 1)a
_
Entry
IL
Acids (5 mol %)
Yieldb (%)
H
X
BMI.X
H
NOH
Easy
ion-pair
formation
1
2
3
4
5
6
7
8
9
BMIÁNTf2 1f
BMIÁNTf2 1f
BMIÁNTf2 1f
BMIÁNTf2 1f
BMIÁNTf2 1f
BMIÁNTf2 1f
BMIÁInCl4 1a
BMIÁInCl4 1a
BMIÁBF4 1c
CF3CO2H
CH3SO3H
p-TolSO3H
PhB(OH)2
HBF4
BF3.OEt2
—
InCl3
61
88
31
0
96
95
15
31
25
+
NOH
+
Anion low
coordinative ability
N
H
O
N
H
O
(Charged intermediate)
+
+
_
X
+
+
N
N
HBF4
N
N
a
See Ref. 19 for the best condition used.
Isolated yield.
Scheme 2. Anion stabilizing effect of the charged intermediate.
b
It is possible to observe that the use of BMIÁBF4 1c and HBF4
Table 2
Cyclization reactions using BMIÁNTf2 and HBF4 (5 mol %)a
gave a low yield of the product (Table 1, entry 9). The inherent
Lewis acid nature of BMIÁInCl4 1a16 resulted in the formation of
the desired compound in low yields (Table 1, entry 7), despite
the fact that no additional Lewis or Bronsted acid was required
to promote the reaction. When additional InCl3 as Lewis acid was
added, it was not effective enough to promote a high yield forma-
tion of the isatin-3-oxime (Table 1, entry 8). Once we had in mind
that the coordinative ability of the anion has a major role in acid-
catalyzed reactions in ILs,15 we decided to test the use of BMIÁNTf2
1f, a poorly coordinating anion, as the medium to promote the
reaction. In fact, the choice showed to be appropriate and we could
test different acids to promote the reaction. Even in the case of
choice of BMIÁNTf2 1f some acids gave poor results, for example,
phenylboronic acid (Table 1, entry 4) and p-toluenesulfonic acid
(Table 1, entry 3). Nevertheless, the use of CF3CO2H (Table 1, entry
1), CH3SO3H (Table 1, entry 2), HBF4 (Table 1, entry 5) and BF3ÁOEt2
(Table 1, entry 6) gave the respective isatin-3-oxime in good to
excellent yields in short reaction time (90 min).
It is worth noting that the use of the same acid (HBF4—Table 1,
entries 5 and 9) gave very distinct results just switching the anion
of the IL. The use of BMIÁNTf2 1f gave the product in 96% (Table 1,
entry 5) while the use of BMIÁBF4 1c resulted in only 25% yield
(Table 1, entry 9). The drastic difference in the yields clearly indi-
cates the importance of the anion to ion pair formation of charged
intermediates and their stabilization. The divergence in the ob-
served behavior of both ILs 1c and 1f can be explained in terms
of the coordinative ability of the anion. Upon increasing the anion
coordinative ability (OTf > PF6 > BF4 > InCl4 > NTf2),17 the probabil-
ity of ion pair formation among the anion and the protonated sub-
strate decreases (the charged intermediate) and, thereby, the
reaction yield decreases too, as a consequence of lack of stabiliza-
tion of the reaction intermediate, as seen in Scheme 2. If the anion
has a low coordinative ability it will be more available to stabilize
the charged intermediate, facilitating its formation/stabilization
and increasing the reaction yield. In the opposite case, the anion
will prefer to be stacked in the well-organized ionic channels of
the three-dimensional structural arrangement of imidazolium-
based ILs.18
Entry
R
Yieldb (%)
1
2
3
4
5
6
7-CF3
7-Cl
7-I
7-OMe
6-OMe
5-OMe
73
12
72
83
81
78
a
See Ref. 19 for the best condition used.
Isolated yield.
b
ates. InClÀ4 (low coordinative ability anion) was sufficient to pro-
mote the reaction by ion pair formation and stabilization of the
charged intermediate. In this case, BMIÁInCl4 1a showed a dual
function: Lewis acid property and ion pair formation. Upon
increasing the reaction time using IL 1a, it was possible to observe
an increase in the yield. For instance, if the reaction was carried out
over a period of 6 hours, the yield increased from 15% (Table 1,en-
try 7) to 41% without the addition of other Lewis or Bronsted acid.
In order to gain insight as to the generality of this catalytic
cyclization reaction, it was performed on several other derivatives
using the established best reaction conditions (BMIÁNTf2, HBF4).
Other isatin-3-oximes derivatives were prepared varying the sub-
stituent in the aromatic ring (as seen in Scheme 1, Table 2).
Over a period of 90 min, we observed a poor result only when
R = Cl (Table 2, entry 2). The high electronegativity of the element
consistently decreased the charge density of the aromatic ring,
turning its nucleophilic character lower than the other examples
tested. Still, under the developed conditions, this effect was not
very pronounced when the substituent is a CF3 group and the isat-
in-3-oxime derivative was obtained in 73% (Table 2, entry 1). Inter-
estingly, better results were obtained using OMe group as
substituent in the aromatic ring. In all cases, (Table 2, entries
4–6) we observe good yields (78–83%) using the developed condi-
tions. The donating effect of methoxy groups allows an easy nucleo-
philic attack on the electrophilic carbon of the oxime resulting in
the desired isatin-3-oxime.
Our results illustrate a case where the pronounced ionic liquid
effect was essential to form and stabilize the charged intermedi-
In conclusion, we developed a novel, efficient, and fast method-
ology for preparation of isatin-3-oximes under Lewis or Bronsted

A. C. Pinto et al. / Tetrahedron Letters 49 (2008) 5639–5641
5641
acid catalysis in different imidazolium-based ILs.19 Moreover, this
approach also proved to be useful when the aromatic ring has an
electron withdrawing group, except when the substituent is a chlo-
rine. The results suggest that the ionic nature of BMIÁNTf2, associ-
ated with the low coordinative ability of the anion, is a powerful
combination capable of co-promoting the formation and stabiliza-
tion of different types of intermediates through supramolecular ion
pairs formation. The pronounced ionic liquid effect was responsi-
ble for a fast, selective, and efficient synthesis of isatin-3-oximes
derivatives.
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Acknowledgments
The authors thank Brazilian agencies Conselho Nacional de
Desenvolvimento Científico e Tecnológico (CNPq), Coordenação
de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fun-
dação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ)
and Pronex-FAPERJ for financial support. We also thank Roxzana
Sudo (USA) for a critical reading of the manuscript. BAD Neto is
fully grateful to Pharmacy Department (PUCRS) for unconditional
support to the development of this new research line.
13. Thornazeau, C.; Olivier-Bourbigou, H.; Magna, L.; Luts, S.; Gilbert, B. J. Am.
Chem. Soc. 2003, 125, 5264.
14. (a) Pilli, R. A.; Robello, L. G.; Camilo, N. S.; Dupont, J.; Lapis, A. A. M.; Neto, B. A.
D. Tetrahedron Lett. 2006, 47, 1669; (b) Russowsky, D.; Neto, B. A. D.
Tetrahedron Lett. 2004, 45, 1437; (c) Russowsky, D.; Neto, B. A. D. Tetrahedron
Lett. 2003, 44, 2923; (d) Neto, B. A. D.; Lapis, A. A. M.; Mancilha, F. S.;
Vasconcelos, I. B.; Thum, C.; Basso, L. A.; Santos, D. S.; Dupont, J. Org. Lett. 2007,
9, 4001.
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19. General procedure for the preparation of isatin-3-oximes derivatives:
Isonitrosoacetanilide (1 mmol), BMIÁNTf2 (0.5 mL) and acid catalyst
2. Da Silva, J. M.; Garden, S. J.; Pinto, A. C. J. Braz. Chem. Soc. 2001, 12, 273. and
references cited therein.
(0.050 mmol) were added to
a sealed tube. The reaction was stirred for
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Teuber, L.; Olesen, S. P. WO 00/69794, November 23, 2000.
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90 min and the temperature maintained at 135 °C. After, Et2O (2 Â 10 mL) was
used to extract organic compounds from the ionic liquid phase and the
combined organic layers were concentrated under reduced pressure. Product
purification was performed by column chromatography (silica gel, gradients of
hexane/Et2O). Overall yields were determined by a combination of isolated
products.