Synthesis of 1,3-di[alkoxy(aryloxy)carbonyl]-2-oxo-2,3-dihydroindoles

Article abstract of DOI:10.1016/S0040-4020(00)00477-4

Two protocols have been developed for the synthesis of 1,3-di[alkoxy(aryloxy)carbonyl]-2-oxo-2,3-dihydroindoles starting from the corresponding N,O-diacyl derivatives obtained by treatment of 2-oxindoles with chloroformic acid esters and triethylamine. Th

Full text of DOI:10.1016/S0040-4020(00)00477-4

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 5893±5903
Synthesis of 1,3-Di[alkoxy(aryloxy)carbonyl]-2-
oxo-2,3-dihydroindoles
a
Marta Porcs-Makkay, Gyula Argay, Alajos Kalman and Gyula Simig
b
b
a,
*
Â
Â
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aChemical Research Division, EGIS Pharmaceuticals Ltd., P.O. Box 100, H-1475 Budapest, Hungary
bInstitute of Chemistry, Chemical Research Center of the Hungarian Academy of Sciences, P.O. Box 17, H-1525 Budapest, Hungary
Received 14 March 2000; revised 8 May 2000; accepted 25 May 2000
AbstractÐTwo protocols have been developed for the synthesis of 1,3-di[alkoxy(aryloxy)carbonyl]-2-oxo-2,3-dihydroindoles starting from
the corresponding N,O-diacyl derivatives obtained by treatment of 2-oxindoles with chloroformic acid esters and triethylamine. The ®rst is
rearrangement of N,O-diacylated compounds in the presence of 4-dimethylaminopyridine to give N,C(3)-diacylated products with identical
acyl groups in the two positions. The second involves O-deacylation of the N,O-diacylated compounds, followed by O-acylation and
rearrangement resulting N,C(3)-diacylated 2-oxindoles with different acyl groups in the two positions. q 2000 Elsevier Science Ltd. All
rights reserved.
Introduction
O±C(3) Acyl migrations were carried out in quantitative
yields by heating 3 (Ar: 2-thienyl, and 1-carbethoxy-2-
indolyl) in dichloromethane in the presence of a catalytic
amount of 4-dimethylaminopyridine (DMAP).
As a part of our program in medicinal chemistry we required
1,3-di[alkoxy(aryloxy)carbonyl]-2-oxo-2,3-dihydroindoles
(exempli®ed by compounds 11 and 12, Scheme 2) as start-
ing material, containing identical or different alkoxy(aryloxy)-
carbonyl groups in the two positions.
There are very few examples in the literature for the acyla-
tion of 2-oxindoles unsubstituted in the 3-position. Treat-
ment of 2-oxindole with sodium hydride and ethyl
chloroformate in THF gave the N-acylated derivative in
20% yield.7 In a patent application8 we described N,O-
diacylation of 5-chloro-2-oxindole with alkyl- and aryl-
chloroformates and the conversion of the N,O-diacylated
compounds to N-acylated ones.
Several papers dealt with the reactions of 3-substituted-2-
oxindole derivatives and alkyl chloroformates under various
conditions, encountering the formation of product mixtures
and low yield of the required regioisomer.1±5 In the most
instructive paper in this ®eld, Beccalli and Marchesini
described the reactions of 3-aroylmethyl-2-oxo-2,3-dihydro-
indoles (1) with ethyl chloroformate.6 When compounds 1
were treated with excess of ethyl chloroformate and triethyl-
amine in dichloromethane at 08C, in addition to the expected
product 2, derivatives 3 and 4 were formed in some cases
(Scheme 1). If the acylation reaction of 1 (ArˆPh) was
carried out by re¯uxing after the ethyl chloroformate
addition, compound 4 (ArˆPh) was obtained as the single
product. Treatment of type 3 N,O-diacylated compounds
with ethyl chloroformate and triethylamine resulted in the
formation of 2 and 4 in some cases. The results were
rationalized as follows: attack of ethyl chloroformate at
the nitrogen atom is followed by acylation of the oxygen
at C(2). Acylation at the oxygen of the side chain carbonyl
leads to compounds 2. Derivatives 4 arise from compounds
3 by O±C(3) acyl migration.
Keywords: acylation; indolinones; rearrangements; regio control;
tautomerism.
* Corresponding author. Tel.: 136-1-2655543; fax: 136-1-2655613.
Scheme 1.
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00477-4

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M. Porcs-Makkay et al. / Tetrahedron 56 (2000) 5893±5903
Scheme 2.
In a recent communication9 2-oxindole and 3-methyl-2-
oxindole were shown to have different reactivities in acyl-
ation reactions under similar conditions. Treatment of
2-oxindole with benzyl chloroformate and triethylamine in
THF gave only the N,O-diacylated derivative. 3-Methyl-2-
oxindole did not react under the same conditions, however,
its treatment with benzyl chloroformate and DMAP gave
N,C(3)-diacylated derivative in moderate yield.10 We are
unaware, however, of any examples of N,C(3)-diacylation
of 2-oxindoles unsubstituted in the 3-position.
reaction with ammonium carbonate in DMF to give N-
[alkoxy(aryloxy)carbonyl]-2-oxo-2,3-dihydroindoles 7 with
good yields.8,11 The reaction of N-acylated derivatives 7
with 1.1 equiv. of chloroformic acid esters and triethylamine
in THF afforded mixed N,O-diacylated derivatives 8.
Attempts to rearrange compounds 6a and 8a to 11a and 12a
using catalytic amounts of triethylamine or DMAP as well
as equivalent amount of triethylamine afforded product
mixtures. Treatment of 6a with 1 equiv. of DMAP followed
by acidic work-up resulted in the formation of 11a in good
yield. Derivatives 11 and 12 with aryl- or benzyloxycar-
bonyl group in the 3-position were unstable towards the
acidic work-up. However, 4-dimethylaminopyridinium
salts of 11 and 12, namely enolates 9 and 10 were easily
accessible by addition of water to the reaction mixture in
DMF. The structures of enolates 9 and 10 shown in Scheme
2 are assigned on the bases of single crystal X-ray analysis
of 9d (Fig. 1).
After consideration of the information provided by the
literature we reasoned that N,O-diacylated compounds 6
and 8 could serve as the appropriate precursors of the
desired N,C(3)-diacylated products 11 and 12 (Scheme 2).
In this paper we describe the reaction conditions where the
required rearrangement proceeds smoothly and the products
are obtained in high yield. Recently, we have reported the
application of a similar strategy in our synthesis of anti-
8,11
rheumatic drug tenidap.
The formation of salts 9 and 10 points to the different role
played by DMAP in the rearrangement of 3-substituted and
3-unsubstituted N,O-diacylated 2-oxindoles. Rearranged
products obtained from 3-substituted N,O-diacylated
2-oxindoles using a catalytic amount of DMAP do not
exhibit an acidic hydrogen in the 3-position.6 However, in
the case of the corresponding 3-unsubstituted derivatives
Results and Discussion
Treatment of 2-oxindoles 5 with 2.2 equiv. of chloroformic
acid esters and triethylamin in THF afforded N,O-diacylated
derivatives 6.8,9,11 The O-acyl moiety was removed by

M. Porcs-Makkay et al. / Tetrahedron 56 (2000) 5893±5903
5895
Figure 2. ORTEP drawing of 11b. Displacement ellipsoids correspond to
50% probability.
medicinal chemistry for the preparation of various 1- and
3-carboxamide derivatives of 2-oxindoles.
Crystal structures
The 1,3-di(ethoxycarbonyl) derivative 11bÐapart from the
chemically non-equivalent N(1) and C(3) positions of the
indole moietyÐtheoretically has Cs or C2 molecular
symmetry. In the crystal lattice this pseudosymmetry is
further diminished by the asymmetric orientation of the
central OH group closing an intramolecular OH´´´O hydro-
gen bond with the carbonyl group bound to C(3). This
de®nes the ®nal asymmetric stretching of the molecule
(Fig. 2).
Figure 1. Perspective view of 9d showing atomic numbering. The posi-
tional disorder of N(1) vs. C(3) and Cl(5) with 82:18 (A:B) ratio are labelled
(£) in structure B.
The 1,3-di(benzyloxycarbonyl) derivative 9d is chlorinated
on C(5) and forms a salt with DMAP. The proton of the
cation is bifurcated and donates two almost symmetrical
NH´´´O bonds to the charged central oxygen and one of
the neighbouring carbonyl oxygens (geometry parameters
the reaction is accomplished by the formation of enolates 9
and 10 with the equivalent amount of DMAP present
(Scheme 2).
Ê
in A and 8) (Table 1).
As mentioned above, addition of aqueous hydrogen chloride
solution to the reaction mixture containing 9 and 10 enolates
in DMF did not afford conjugate acids 11 and 12 in all cases
with preparatively useful yields. On treatment with aqueous
acid, 3-aryl- and 3-benzyloxycarbonyl groups underwent
hydrolysis and decarboxylation. However, selected type
11 and 12 compounds containing 3-alkyloxycarbonyl
The above described pseudosymmetry of 11b retained in 9d
enables the anion to assume a stretched array between the
terminal C(16) and C(36) phenyl carbons in such a way that
N(1) and C(3) are swapped with a probability 0.82:0.18.
This gives also rise to a positional disorder of the chlorine
atom (Fig. 1).
1
group were isolated in good yield (Table 7). The H NMR
spectra of 11 and 12 indicated an equilibrium between the
keto and enol forms in solution, while single crystal X-ray
analysis has shown that 11b exhibits enol form in crystalline
state (Fig. 2).
Table 1. Hydrogen bond parameters for compound 9d
Ê
H´´´A (A)
Ê
D´´´A (A)
D±H
A
DHA (8)
N44±H44
N44±H44
O2
O31
2.00
2.16
2.710(2)
2.816(2)
139.4
132.4
Enolates 9 and 10 are useful synthetic intermediates in

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M. Porcs-Makkay et al. / Tetrahedron 56 (2000) 5893±5903
5903
Experimental
After stirring for 30 min at room temperature, the solvent
was evaporated. Water (100 mL) was added to the residue
and the mixture was stirred for 2 h at 0±58C. The crystalline
product was ®ltered and recrystallized to give 8. For the
yields, mp's, solvents of recrystallization, elemental
Melting points are uncorrected. 1H NMR spectra were
recorded at 200 or 400 MHz. All unspeci®ed reagents
were from commercial sources.
1
analyses and H NMR data see Table 4.
Structure determination of 9d and 11b by X-ray crystal-
lography. Intensity data were collected on an Enraf Nonius
CAD4 diffractometer. The structures were solved by direct
methods.12
General procedure for the synthesis of N,3-diacylated 2-
oxindole-4-dimethylamino-pyridinium salts 9 and 10. To
a solution of 6 or 8 (0.1 mol) in DMF (100 mL) was added a
solution of 4-dimethylaminopyridine (0.1 mol) in DMF
(100 mL) at 0±28C. The mixture was stirred for 10 min
and ice-water (400 g) was added. The crude product was
®ltered, washed with water and recrystallized to give 9 or
10, respectively. For the yields, mp's, solvents of recrystal-
lization, elemental analyses and 1H NMR data see Tables 5
and 6, respectively.
9d. C31H28ClN3O5; Mrˆ558.01, crystallized from ethyl
acetate as colourless crystals. The triclinic cell parameters
Ê
and calculated cell volume are aˆ10.568(1) A, bˆ
Ê
Ê
11.274(1) A, cˆ12.151(2) A, aˆ93.07(1)8, bˆ97.60(1)8,
Ê 3
gˆ106.16(1)8, Vˆ1372.1(2) A . Space group: P-1. Re®ne-
ment on F2 values for all non-hydrogen atoms yielded
R1ˆ0.0438 and wR2ˆ0.1287 for 4391 [I.2s(I)] observa-
tions.
General procedure for the synthesis of N,3-diacylated 2-
oxindoles 11 and 12. To a solution of 6 or 8 (0.1 mol) in
DMF (100 mL) was added a solution of 4-dimethylamino-
pyridine (0.1 mol) in DMF (100 mL) at 0±28C. It was stirred
for 10 min and a mixture of concentrated HCl (8.2 mL) and
ice-water (400 g) was added. The crude product was ®ltered,
washed with water and recrystallized to give 11 or 12,
respectively. For the yields, mp's, solvents of recrystalliza-
11b. C14H15NO5; Mrˆ277.27, crystallized from ethanol as
colourless crystals. The triclinic cell parameters and calcu-
Ê
Ê
lated cell volume are aˆ4.993(1) A, bˆ9.184(2) A,
Ê
cˆ15.145(1) A, aˆ99.78(1)8, bˆ92.51(1)8, gˆ95.51(1)8,
Ê 3
2
Vˆ679.95(16) A . Space group: P-1. Re®nement on F
values for all non-hydrogen atoms yielded R1ˆ0.0414 and
wR2ˆ0.1284 for 1943 [I.2s(I)] observations.
1
tion, elemental analyses and H NMR data see Table 7.
General procedure for the synthesis of N,O-diacylated 2-
oxindoles 6. To a solution of 2-oxindole 5 (0.10 mol) and
triethylamine (0.22 mol) in THF (360 mL) was added
chloroformic acid ester (0.22 mol) dropwise. The tempera-
ture was kept below 308C during the addition. After stirring
for 30 min at room temperature, the solvent was evaporated.
Water (100 mL) was added to the residue and the mixture
was stirred for 2 h at 0±58C. The crystalline product was
®ltered and recrystallized to give 6. For the yields, mp's,
solvents of recrystallization, elemental analyses and 1H
NMR data see Table 2.
References
1. Beccalli, E. M.; Marchesini, A. Tetrahedron 1995, 51, 2353.
2. Beccalli, E. M.; Marchesini, A. Synth. Comm. 1993, 23, 2945.
3. Beccalli, E. M.; Marchesini, A.; Pilati, T. J. Chem. Soc., Perkin
Trans. 1 1994, 579.
4. Beccalli, E. M.; Marchesini, A.; Pilati, T. Tetrahedron 1994, 50,
12697.
5. Beccalli, E. M.; Marchesini, A.; Pilati, T. Synthesis 1992, 891.
6. Beccalli, E. M.; Marchesini, A. Tetrahedron 1993, 49, 4741.
7. Caramella, P.; Coda Corsico, A.; Corsaro, A.; Del Monte, D.;
Marinone Albini, F. Tetrahedron 1982, 38, 173.
General procedure for the synthesis of N-acylated
2-oxindoles 7. To a solution of 6 (0.1 mol) in DMF
(200 mL) was added ®nely powdered ammonium carbonate
(7.80 g, NH3 content 22%, 0.1 mol) at 0±58C. The mixture
was stirred for 6 h at room temperature then poured into ice-
water (400 g). The crude product was ®ltered, washed with
water and recrystallized to give 7. For the yields, mp's,
solvents of recrystallization, elemental analyses and 1H
NMR data see Table 3.
Â
Â
 Â
8. Blasko, G.; Lukacs, Gy.; Reiter, J.; Florian, E.; Porcs-Makkay,
M.; Mezei, T.; Simig, Gy. WO 97 36,895 (to Egis Pharmaceuticals
Ltd., ®led on 3 April 1997), Chem. Abstr. 1997, 127, 318879z.
9. Rajeswaran, W. G.; Cohen, L. A. Tetrahedron 1998, 54, 11375.
10. For similar reactions of 3-alkyloxindoles see Beccalli, E. M.;
Marchesini, A. Synthesis 1992, 265.
11. Porcs-Makkay, M.; Simig, Gy. Org. Process Res. Dev. 2000,
4, 10.
General procedure for the synthesis of `mixed' N,O-
diacylated 2-oxindoles 8. To a solution of 7 (0.10 mol)
and triethylamine (0.11 mol) in THF (360 mL) was added
chloroformic acid ester 2 (0.11 mol) dropwise. The
temperature was kept below 308C during the addition.
12. The authors have deposited atomic coordinates with the
Cambridge Crystallographic Data Centre. The coordinates can be
obtained, on request, from the Director, Cambridge Crystallo-
graphic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.
Ref. No. for 9d CCDC 143819 and for 11b CCDC 143820.