New routes to oxindole derivatives

Article abstract of DOI:10.1007/s00706-003-0127-9

A new, practical synthesis of the antirheumatic oxindole derivative, tenidap, has been elaborated. The new approach has initiated studies on the mechanism of the acylation reactions of oxindoles. Methods have been developed for the synthesis of 1-[alkoxy(or aryloxy)carbonyl]- and 1,3-di[alkoxy(or aryloxy)carbonyl]oxindoles starting from oxindoles. The route designed for tenidap has provided a facile access to several analogues, too. On another front, new reaction conditions are described, which turn Wenkert's synthesis of 3-alkyloxindoles (by Raney nickel induced alkylation of oxindoles with alcohols) into a highly efficient synthetic tool. The method has been extended to the synthesis of 3-alkyloxindoles from isatins and to the preparation of 3-(ω-hydroxyalkyl)oxindoles from oxindoles and isatins. Springer-Verlag 2004.

Full text of DOI:10.1007/s00706-003-0127-9

Monatshefte f€ur Chemie 135, 697–711 (2004)
DOI 10.1007/s00706-003-0127-9
New Routes to Oxindole Derivatives
´
Marta Porcs-Makkay, Balazs Volk, Rita Kapiller-Dezsofi,
Tibor Mezei, and Gyula Simig
´
¨
ꢀ
Chemical Research Division, EGIS Pharmaceuticals Ltd., 1475 Budapest, Hungary
Received October 1, 2003; accepted October 15, 2003
Published online January 27, 2004 # Springer-Verlag 2004
Summary. A new, practical synthesis of the antirheumatic oxindole derivative, tenidap, has been
elaborated. The new approach has initiated studies on the mechanism of the acylation reactions of
oxindoles. Methods have been developed for the synthesis of 1-[alkoxy(or aryloxy)carbonyl]- and 1,3-
di[alkoxy(or aryloxy)carbonyl]oxindoles starting from oxindoles. The route designed for tenidap has
provided a facile access to several analogues, too.
On another front, new reaction conditions are described, which turn Wenkert’s synthesis of 3-
alkyloxindoles (by Raney nickel induced alkylation of oxindoles with alcohols) into a highly efficient
synthetic tool. The method has been extended to the synthesis of 3-alkyloxindoles from isatins and to
the preparation of 3-(!-hydroxyalkyl)oxindoles from oxindoles and isatins.
Keywords. Acylation; Alkylation; Isatins; Oxindoles; Regioselectivity.
Introduction
The biological activity of oxindole (2-oxo-2,3-dihydroindole, 1,3-dihydro-2H-
indol-2-one) derivatives and their structural relationship to indoles makes these
compounds important targets in medicinal and synthetic organic chemistry [1–
4]. Oxindoles showing cyclooxygenase inhibiting activity and cytokine modulating
properties have been developed for the treatment of rheumatoid arthritis and
osteoarthritis. An outstanding representative of these antirheumatic oxindoles, teni-
dap (2, (Z)-5-chloro-3-[1-hydroxy-1-(2-thienyl)methylene]-2-oxo-2,3-dihydro-1H-
indole-1-carboxamide), was discovered and developed by Pfizer and regulatory
approval was granted for its sodium salt in several countries [4–6]. Despite the
very high market expectations, finally it was not launched because of concerns
about reduced bone mineral density associated with its use.
The methods previously described for the synthesis of tenidap are shown in
Scheme 1. Two routes were elaborated starting from 5-chlorooxindole (1a) [7, 8]
just differing in the sequence of introduction of substituents. According to the first
procedure, the thienoylation of compound 1a with thiophene-2-carbonyl chloride
ꢀ
Corresponding author. E-mail: simig.gyula@egis.hu

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M. Porcs-Makkay et al.
Scheme 1. The 3-acylated oxindoles may exist either in oxo or in enol form; in addition, the enol
form may adopt an E or a Z configuration
to compound 3 [8] is followed by N-amidation performed with chlorosulfonyl
isocyanate and subsequent hydrolysis [9]. The second route involves the prepara-
tion of the 1-carbamoyl derivative 4 in the first step by the reaction of oxindole 1a
with chlorosulfonyl isocyanate and subsequent hydrolysis. Thienoylation of com-
pound 4 afforded tenidap (2) [9, 10].
In the late nineties we were interested in the elaboration of a new patentable
manufacturing synthesis of tenidap (2). Our activity in the field of oxindole chem-
istry has been initiated by this project.
Results and Discussions
New Practical Synthesis of Tenidap
The concept of our new synthetic route has been strongly influenced by the deci-
sion that we wanted to avoid the use of chlorosulfonyl isocyanate in our manufac-
turing process. Therefore our strategy for the new synthesis was to use the
appropriate N-carboxylate as the precursor of the N-carbamoyl functionality, i.e.
to introduce the N-carbamoyl moiety via alkoxy(or aryloxy)carbonylation of the
oxindole nitrogen followed by treatment with ammonia. Compounds 3 and 4 could
not be used in our synthesis for patent reasons. Therefore the N-carbamoyl group of

New Routes to Oxindole Derivatives
699
Scheme 2
tenidap (2) would have to be introduced in the last step by ammonolysis of the key
N-carboxylate 6 (Scheme 2) prepared by thienoylation of compound 5 [11, 12].
First we addressed the task of preparing N-alkoxy(or aryloxy)carbonylox-
indoles 5. The reaction of oxindole (1b) with one equivalent of ethyl chloroformate
in the presence of triethylamine in THF is reported to give the corresponding N-
ethoxycarbonyl derivative after chromatographic separation [13]. The low yield
(20%) can be attributed to the simultaneous formation of N,O-diethoxycarbony-
lated product as indicated by our experiments.
N,O-Diethoxycarbonylation of some 3-substituted oxindoles with an excess of
ethyl chloroformate has also been reported [14]. Considering these data we decided
to carry out the synthesis of compounds 5 in a new two-step sequence starting from
the readily available 5-chlorooxindole (1a) [7, 8]. In the first step, oxindole 1a was
treated with 2.2 equiv of ethyl chloroformate in the presence of triethylamine in
THF to afford 5-chloro-1-ethoxycarbonyl-2-(ethoxycarbonyloxy)indole (7a) in
excellent yield (Scheme 3). The corresponding methyl and phenyl esters (7b and
7c) were obtained similarly. In the second step, selective O-ammonolysis of com-
pounds 7 was accomplished with ammonium carbonate in DMF under mild con-
ditions (0–6ꢁC, ꢂ3 h, 25ꢁC, ꢂ3 h, one equivalent of ammonium carbonate) to
furnish oxindole-1-carboxylates 5 in good yield.
It is suggested in the patent literature that 3-thienoylation can be carried out in
the presence of various amines, however, 4-(dimethylamino)pyridine (DMAP) is
obviously preferred [9, 10]. Our observations, which helped us to understand the
nature of the reaction, are summarized in Scheme 4.
Thienoylation of the phenyl carbamate 5c in the presence of 1.1 equiv of
DMAP gave a mixture of the starting compound and the 3-thienoyl derivative
6c. When the same reaction was carried out in the presence of 1.1 equiv of triethyl-
amine, the O-thienoyl derivative 8c was obtained. Treatment of the O-thienoyl
Scheme 3

700
M. Porcs-Makkay et al.
Scheme 4
derivative 8c with 1.1 equiv of DMAP afforded the required C(3)-thienoyl deriva-
tive 6c. It is important to note that a catalytic amount of DMAP is not sufficient for
the reaction.
The multistep reaction sequence of the thienoylation reaction is summarized in
Scheme 5. Treatment of the oxindole-N-carboxylate 5 in the presence of one equiv
Scheme 5

New Routes to Oxindole Derivatives
701
of triethylamine or DMAP affords the O-thienoylated derivative 8. The rearrange-
ment to the C(3)-thienoylated product 6 takes place only in the presence of DMAP.
Because of the ꢀ-keto amide structure of the product 6, the O ! C rearrangement
should be reversible in the presence of a base, in principle. In spite of this fact the
reaction can be accomplished, the equilibrium is driven by enolisation to the right
as demonstrated by the isolation of the dimethylaminopyridinium enolate salts 9,
which were converted to the corresponding enols 6 by acidification (Scheme 5).
The X-ray structure analysis of compound 9a revealed that the salt adopts an E
configuration in the crystalline state [12]. The protonated DMAP cation
(DMAPHþ) is linked with hydrogen bonds to the oxygen of the ring and the
carbamate carbonyls. However, the temperature dependence of the chemical shifts
of oxindole C(4) and thiophene C(3) hydrogen and the NOE observed between
1
them in H NMR studies shows the presence of the Z isomer in CDCl3 solution,
indicating the possibility of a rotation around the bond between oxindole C(3) and
the carbon attached to the ring. The E isomer is expected to be the more stable one
due to the electrostatic repulsion between the oxygens in the Z isomer.
The 3-thienoyl derivatives 6 obtained from the enolate salts 9 by acidification
exhibit a Z enol structure both in solution and in the crystalline form as indicated
1
by H NMR and single crystal X-ray studies of compound 6a [12]. A significant
NOE between oxindole C(4) and thiophene C(3) hydrogens was detected.
Attempts to convert ethyl carbamate 6a to tenidap (2) failed. The reaction with
ammonium carbonate in DMF at ambient temperature for 2 h resulted in the for-
mation of the ammonium salt 10a (Scheme 6). The starting material was recovered
after further treatment of this ammonium salt with ammonium carbonate in DMF at
80ꢁC for 6 h followed by acidification. The application of other ammonia sources
and more vigorous reaction conditions resulted in the formation of substantial
amounts of deethoxycarbonylated product and experiments with the methyl carba-
mate 6b gave similar results: the initially formed ammonium salt could not be
converted to tenidap (2).
However, the phenyl carbamate 6c could be converted to tenidap (2) under
simple conditions. Thus, treatment with 2 equiv of ammonium carbonate in
DMF at 75–80ꢁC for 5 h, followed by acidic work-up gave tenidap (2) in excellent
yield (Scheme 6). An important requirement for a smooth reaction is an adequate
solubility of the initially formed ammonium salt. Therefore the use of DMF as the
reaction solvent is crucial. In less polar solvents the ammonium salt crystallizes out
and does not react further.
These studies allowed the development of a patent-free one-pot process for the
preparation of tenidap (2) starting from N,O-di(phenoxycarbonyl)-5-chlorooxindole
(7c) by successive treatment in DMF with ammonium carbonate, thiophene-2-
carbonyl chloride in the presence of DMAP, and once more with ammonium
carbonate, in an optimized overall yield of 75% (Scheme 7). An appropriate one-
pot treatment of the phenyl carbamate 5c gave tenidap (2) in 79% overall yield.
New Synthesis of Oxindole-1-carboxamides
Together with tenidap (2), several oxindole-1-carboxamides have been described in
the patent literature [4–6, 15]. The 1-carbamoyl moiety was introduced exclusively

702
M. Porcs-Makkay et al.
Scheme 6
by treating an N-unsubstituted oxindole with alkyl, aryl, or acyl isocyanate. The
use of isocyanates for the introduction of the 1-carbamoyl moiety has two major
disadvantages: relatively few organic isocyanates are commercially available and
N,N-disubstituted oxindole-1-carboxamides can not be synthesized by this method.
Taking advantage of our new key intermediate 6c used in the synthesis of
tenidap (2) we prepared a series of oxindole-1-carboxamides 11 by amidation of
the phenyl carbamate 6c with various amines (Scheme 8) [16]. For the most part,
these compounds cannot be synthesized by the isocyanate method.
Aminolysis of compound 6c with various amines is expected to follow a similar
pathway as shown in Scheme 6. Therefore at least two equivalents of the amine
have to be used in the reactions.
Synthesis of 1,3-Di[alkoxy(or aryloxy)carbonyl]oxindoles
Oxindole-1,3-dicarboxamides are also interesting targets in medicinal chemistry.
According to the procedure described in the patent literature [10, 17], the two
carbamoyl moieties were introduced successively into the oxindole. Refluxing
with alkyl, aryl, or acyl isocyanates in toluene afforded oxindole 1-carboxamides.
The 3-carbamoyl group was then introduced by further treatment with an isocya-
nate in DMF in the presence of a base. Based on the experience obtained
in the course of the synthesis of tenidap (2), we decided to synthesize new

New Routes to Oxindole Derivatives
703
Scheme 7
Scheme 8

704
M. Porcs-Makkay et al.
Scheme 9
oxindole-1,3-dicarboxamides starting from the corresponding oxindole-1,3-dicar-
boxylates. Since these latter compounds had not been described in the literature,
we have set as an aim to synthesize 1,3-di[alkoxy(or aryloxy)carbonyl]oxindoles
(exemplified by compounds 17 and 18, Scheme 9), containing identical or different
alkoxy(or aryloxy)carbonyl groups in these two positions.
Similarly to the synthesis of compounds 6 and 7 (Scheme 3), oxindoles 1 were
treated with 2.2 equiv of chloroformic acid esters and triethylamine in THF afford-
ing N,O-diacylated derivatives 12. The O-acyl moiety was removed by reaction
with ammonium carbonate in DMF to give N-[alkoxy(or aryloxy)carbonyl]oxin-
doles 13 in good yields. The reaction of the N-acylated derivatives with 1.1 equiv
of chloroformic acid esters and triethylamine in THF afforded mixed N,O-diacy-
lated derivatives 14. Attempts to rearrange the N,O-diacylated compounds 12
and 14 to the desired N,C(3)-diacylated derivatives using catalytic amounts of

New Routes to Oxindole Derivatives
705
triethylamine or DMAP as well as one equivalent of triethylamine resulted in
formation of product mixtures. Treatment of 12 and 14 with one equivalent of
DMAP in DMF followed by addition of water gave the N,C(3)-diacylated di-
methylaminopyridinium enolate 15 and 16 in good yields (Scheme 9).
The stereostructure of compounds 15 and 16 depicted in Scheme 9 corresponds
to the structure of the dibenzyloxycarbonyl derivative determined by single crystal
X-ray study [18].
The acidic treatment of the enolate of diesters having an alkoxycarbonyl group
in the 3-position results in the conjugate acids 17 and 18 (Scheme 9), which exist
as oxo-enol mixtures in CDCl3 solutions as demonstrated by the NMR spectra.
However, derivatives with aryl- or benzyloxycarbonyl group in the 3-position were
unstable towards the acidic work-up. Hydrolysis and decarboxylation was observed
[18].
Single crystal X-ray analysis of the bis(ethoxycarbonyl) compound 17 has
shown that it exhibits the enol form in the crystalline state [18].
We have recently started studying the amidation reactions of oxindole-1,3-
dicarboxylates. Several unexpected reactions have been observed and the elabora-
tion of the project is in progress.
Raney Nickel Induced 3-Alkylation of Oxindole with Alcohols and Diols
In continuation of our studies on acylation reactions of oxindoles we sought a
simple method for the synthesis of 3-alkyl- and 3-(!-hydroxyalkyl)oxindoles.
Direct alkylation of deprotonated oxindole (1b) has been studied in detail [19].
However, the lack of regioselectivity and the formation of dialkylated products
have rendered this synthetic route limited use.
The two-step reductive alkylation of oxindole (1b) with ketones and aromatic
aldehydes through 3-alkylideneoxindoles is a convenient method for the prepara-
tion of 3-alkyloxindoles. However, in the case of aliphatic aldehydes the yields are
moderate because of aldol-type side reactions [20].
Wenkert has described the formation of 3-alkyloxindoles 19 by long refluxing
(>70 h) of oxindole (1b) in alcohols in the presence of ten fold mass of Raney
nickel (Ra-Ni) [21]. Raney nickel plays various roles in this multistep reaction
(Scheme 10): it acts as the oxidizing agent in the transformation of the alcohol
to the corresponding carbonyl compound, as the base in the condensation of ox-
indole (1b) with the carbonyl compound to form 3-alkylideneoxindoles, and as the
reducing agent in the last step, affording 3-alkyloxindoles 19.
In a later publication Wenkert remarked that ‘dependence on heterogenous
catalysis for success of the alkylations could be predicted to make the results
erratic’ [22]. This might explain why the method has not been mentioned later
in the literature for the synthesis of 3-alkyloxindoles.
We managed to elaborate new reaction conditions, which turned Wenkert’s
synthesis of 3-alkyloxidoles 19 into a reproducible and highly efficient synthetic
tool. The reactions of oxindole (1b) with various primary and secondary alcohols
were carried out by heating the mixture in an autoclave at 150–220ꢁC for 1–5
hours in the presence of less than one mass equivalent (0.1 g=mmol of oxindole) of
Raney nickel (Scheme 11) [23].

706
M. Porcs-Makkay et al.
Scheme 10
Scheme 11
We succeeded in extending the Raney nickel induced 3-alkylation reactions of
oxindole (1b) to the preparation of 3-(!-hydroxyalkyl)oxindoles 20 in good yields.
The treatment of oxindole with diols under the conditions shown in Scheme 12
afforded the !-hydroxyalkyl compounds, which are convertible into a range of new
derivatives. Alternative methods for the preparation of 3-(2-hydroxyethyl)oxindole
(20a) involve complicated multistep procedures [24].
Byproduct 21 (ꢂ5%, mixture of diastereomers) was isolated when the reaction
of oxindole (1b) was performed with ethylene glycol. The formation of a similar
byproduct has not been observed in the case of butane-1,4-diol (Scheme 12).
We tried to extend the reaction to the 3-aminoalkylation of oxindole. The
reaction of oxindole (1b) with 2-(dimethylamino)ethanol and 2-(diisopropylami-
no)ethanol under various conditions (Ra-Ni, 120–180ꢁC, 2–9 h) afforded 3-(2-
hydroxyethyl)oxindole (20a) and the dimeric byproduct 21 (Scheme 13). The
expected 3-(2-dialkylaminoethyl)oxindoles could not be detected in the product

New Routes to Oxindole Derivatives
707
Scheme 12
Scheme 13
mixture. Higher temperatures and longer reaction times led to an increased amount
of 21.
Preliminary studies have been carried out on the stereochemical aspects (pos-
sibility of asymmetric induction) of the alkylation reaction. The alkylation of
oxindole (1b) with (ꢃ)-2-butanol (Ra-Ni, 180ꢁC, 6 h) gave practically equal
amounts (47:53, 49:51, and 53:47 molar ratio in three runs, measured by
1H NMR) of the two expected diastereomeric racemates 19h (Scheme 14). How-
ever, this result might be the consequence of an epimerization at C(3) due to the
basicity of Raney nickel and the high reaction temperature. Further investigations
regarding the stereochemical control of this reaction type are in progress in our
laboratory.
Scheme 14

708
M. Porcs-Makkay et al.
One-pot Synthesis of 3-Alkyl- and 3-(!-Hydroxyalkyl)oxindoles
from Isatins
Since oxindoles can be prepared by catalytic reduction of easily available isatins
[25], an opportunity arose that the complex reaction sequence, which involves the
reduction of isatin (22a) to oxindole (1b) and the regioselective alkylation of
oxindole at the 3-position with alcohols in the presence of Raney nickel, might
be carried out in one pot.
Therefore, the reaction of isatin (22a) with ethanol was performed by heating
the reactants in an autoclave at 150ꢁC for 5 h in the presence of Raney nickel. As
expected, 3-ethyloxindole (19b) was obtained as the main product. However, the
conversion of isatin (22a) to 3-ethyloxindole (19b) was substantially lower than the
conversion of oxindole (1b) to 3-ethyloxindole (19b) under the same conditions
[23], which indicates that the multistep reaction sequence suffers from the slow
reduction of isatin (22a) to oxindole (1b). Although longer reaction times and
higher temperatures resulted in better conversions, the yield of the isolated product
was unsatisfactory because of the formation of unidentified impurities.
It was reasoned that the use of hydrogen atmosphere could accelerate the rate
of the first two, reductive steps of the complex reaction sequence (22a ! 23 !
1b ! 19b, Scheme 15). Detailed experiments have shown that 3-hydroxyoxindole
(23) is formed from isatin (22a) in EtOH in the presence of Raney nickel under 15
bar hydrogen (25ꢁC, 15 min). More vigorous conditions (80ꢁC, 1 h, Ra-Ni, 15 bar
hydrogen) lead to the formation of oxindole (1b). As described above [23], at
higher reaction temperatures (150ꢁC, 5 h, Ra-Ni) oxindole (1b) can be transformed
to 3-ethyloxindole (19b). These results demonstrate that the introductory reaction
steps of the overall transformation of isatin to 3-alkyloxindole are faster in hydro-
gen atmosphere than the final step, i.e. the 3-alkylation of oxindole. This relation of
the individual reaction rates is supposed to facilitate the overall reaction. Indeed,
the reaction of isatin with ethanol in the presence of Raney nickel at 180ꢁC under
Scheme 15

New Routes to Oxindole Derivatives
709
15 bar hydrogen affords a high yield (88%) of 3-ethyloxindole after 4 h reaction
time.
The reaction studied above can be applied to other alcohols and isatins. A new
and efficient one-pot procedure has been developed for the synthesis of 3-alkylox-
indoles 24 from isatins 22 by treatment with alcohols in the presence of Raney
nickel, under hydrogen atmosphere [26]. The reactions of isatins 22 with various
primary and secondary alcohols were accomplished in an autoclave at 140–220ꢁC
for 2–5 h in the presence of less than one mass equivalent of Raney nickel under 15
bar hydrogen, and the corresponding 3-alkyloxindoles 24 were isolated in high
yields (Scheme 16).
The alkylation reaction of isatins with alcohols under hydrogen atmosphere, in
the presence of Raney nickel has also been extended to the synthesis of 3-(!-
hydroxyalkyl)oxindoles 25 by treatment of isatins with diols under the conditions
shown in Scheme 17 [26].
This publication gives an overview on our recent achievements in the field of
oxindole chemistry. In connection with our novel manufacturing route to tenidap,
new methods have been developed for the preparation of 1-acylated and 1,3-dia-
cylated oxindoles. Furthermore, we have studied the alkylation reactions of this
family in detail, elaborating the first one-pot synthesis of 3-alkyl- and 3-(!-hydro-
xyalkyl)oxindoles from isatins.
Scheme 16
Scheme 17

710
M. Porcs-Makkay et al.
Acknowledgements
´ ´
We are grateful to Prof. A. Kalman and Dr. Gy. Argay for the X-ray crystallography studies of several
compounds mentioned in this paper.
References
[1] Howard HR, Prakash C, Seeger TF (1994) Drugs Future 19: 560
[2] DeMarinis RM, Hieble JP (1989) Drugs Future 14: 781
[3] Robertson DW, Hayes JS (1986) Drugs Future 11: 377
[4] Robinson C (1990) Drugs Future 15: 898
[5] (1993) Drugs Future 18: 875
[6] Robinson RP, Reiter LA, Barth WE, Campeta AM, Cooper K, Cronin BJ, Destito R, Donahue
KM, Falkner FC, Fiese EF, Johnson DL, Kuperman AV, Liston TE, Malloy D, Martin JJ, Mitchell
DY, Rusek FW, Shamblin SL, Wright CF (1996) J Med Chem 39: 10
[7] Junge H (1973) Ger Offen 2158955; (1973) Chem Abstr 79: 66169z
[8] Kadin SB (1985) EP 153818; (1986) Chem Abstr 104: 88427u
[9] Crawford ThCh (1985) EP 155828; (1986) Chem Abstr 104: 109466y
[10] Kadin SB (1985) EP 156 603; (1986) Chem Abstr 104: 109468a
´
[11] Blasko G, Lukacs Gy, Reiter J, Florian E, Porcs-Makkay M, Mezei T, Simig Gy (1997) WO
´
ꢀ
ꢀ
9736895; (1997) Chem Abstr 127: 318879z
[12] Porcs-Makkay M, Simig Gy (2000) Org Process Res Dev 4: 10
[13] Caramella P, Coda Corsico A, Corsaro A, Del Monte D, Marinone Albini F (1982) Tetrahedron
38: 173
[14] a) Beccalli EM, Marchesini A (1992) Synthesis 265; b) Beccalli EM, Marchesini A, Pilati T
(1992) Synthesis 891; c) Beccalli EM, Marchesini A (1992) Tetrahedron 48: 5359; d) Beccalli
EM, Marchesini A, Pilati T (1993) Tetrahedron 49: 4741; e) Beccalli EM, Marchesini A (1993)
Synth Comm 23: 2945; f) Beccalli EM, Marchesini A, Pilati T (1994) Tetrahedron 50: 12697; g)
Beccalli EM, Marchesini A, Pilati T (1994) J Chem Soc Perkin Trans 1 579; h) Beccalli EM,
Marchesini A (1995) Org Prep Proc Int 27: 113; i) Beccalli EM, Marchesini A, Pilati T (1996)
Tetrahedron 52: 3029
[15] Robinson RP, Donahue KM (1994) J Het Chem 31: 1541
[16] Porcs-Makkay M, Simig Gy (2001) J Het Chem 38: 451
[17] a) Kadin SB (1986) EP 208510; (1987) Chem Abstr 106: 138254z; b) Kadin SB (1987) US
4725616; (1989) Chem Abstr 110: 23728x
´ ´
[18] Porcs-Makkay M, Kalman A, Argay Gy, Simig Gy (2000) Tetrahedron 56: 5893
€
[19] a) Gruda I (1972) Can J Chem 50: 18; b) Reisch J, Muller M, Labitzke H (1984) Arch
Pharm (Weinheim, Germany) 317: 639; c) Kende AS, Hodges JC (1982) Synth Commun
12: 1
€
[20] a) Nozoye T, Nakai T, Kubo A (1977) Chem Pharm Bull 25: 196; b) Mertens A, Muller-
Beckmann B, Kampe W, Holck JP, von der Saal W (1987) J Med Chem 30: 1279; c) Tacconi G,
€
Maggi LD, Righetti P, Desimoni G, Azzolina O, Ghislandi V (1976) J Chem Soc Perkin Trans 2
150
[21] Wenkert E, Bringi NV (1958) J Am Chem Soc 80: 5575
[22] Wenkert E, Bringi NV, Choulett HE (1982) Acta Chem Scand Ser B 36: 348
[23] Volk B, Mezei T, Simig Gy (2002) Synthesis 595
[24] a) McEvoy FJ, Allen GR Jr (1973) J Org Chem 38: 3350; b) Wenkert E, Bindra JS, Chang CJ,
Cochran DW, Rearick DE (1974) J Org Chem 39: 1662; c) Nozoye T, Shibanuma Y (1975)
Yakugaku Zasshi 95: 710; (1975) Chem Abstr 83: 131400; d) Rajanbabu TV, Chenard BL,
Petti MA (1986) J Org Chem 51: 1704; e) Rasmussen HB, MacLeod JK (1997) J Nat Prod 60:
1152

New Routes to Oxindole Derivatives
711
[25] a) Karp GM (1993) Org Prep Proc Int 25: 481 and references cited therein; b) Muchowski JM
(1969) Can J Chem 47: 857; c) Wells AS, Lewis NJ, Walsgrove TC, Oxley P, Fortunak JM (1994)
WO 9415918; (1994) Chem Abstr 121: 179494f
[26] Volk B, Simig Gy (2003) Eur J Org Chem 3991.