Three component synthesis of 2-oxindole via sequential Michael addition, intramolecular cyclization and aromatization

Article abstract of DOI:10.1039/c4ra02091j

An easy metal free access to the synthesis of medicinally promising 2-oxindole derivatives via a tandem enamine formation-Michael addition-regiospecific intramolecular cyclization-aromatization sequence promoted by trifluoroacetic acid has been described. This three component reaction is regiospecific with good yield and satisfactory atom economy.

Full text of DOI:10.1039/c4ra02091j

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Three component synthesis of 2-oxindole via
sequential Michael addition, intramolecular
Cite this: RSC Adv., 2014, 4, 18549
cyclization and aromatization†
a
a
a
*
Muthusamy Boominathan, Muthupandi Nagaraj, Shanmugam Muthusubramanian
and Nattamai Bhuvaneshb
Received 10th March 2014
Accepted 7th April 2014
An easy metal free access to the synthesis of medicinally promising 2-oxindole derivatives via a tandem
enamine formation – Michael addition – regiospecific intramolecular cyclization – aromatization
sequence promoted by trifluoroacetic acid has been described. This three component reaction is
regiospecific with good yield and satisfactory atom economy.
DOI: 10.1039/c4ra02091j
www.rsc.org/advances
development of metal free strategies for the assembly and
derivatization of 2-oxindole from readily available starting
Introduction
materials would be a signicant contribution to biomedical
community. Multicomponent reactions29,30 allow the generation
of complex structures involving the simultaneous formation of
two or more bonds in a single step from readily available
precursors providing opportunities for the construction of new
rings with molecular diversity.
The 2-oxindole core is an important privileged heterocyclic
scaffold in numerous biologically active pharmacophores and
natural products. Hence, new selective methods for the
synthesis of 2-oxindole derivatives assume importance in
organic and pharmaceutical chemistry.1 The 2-oxindole skel-
eton is found in many natural products like notamide C, ela-
comine, alstonisine, surugatoxin, welwitindolinone A, salacin,
uncarine E, spirotryprostatin A, coerulescine, horsline, mar-
emycins A and convolutamydines and biologically active mole-
cules like AG-041R, SSR-149415, SU4984, GW491619, SU11248,
WAY-255348, CX-6258, chaperone and tenidap (Fig. 1).2–10 2-
Oxindole derivatives also exhibit anti-anxiety, anti-depression,
antiangiogenic, anticancer and other biological activities.11–17
Structure–activity relationship studies have also been carried
out with this nucleus.18
Results and discussion
Recently, a sequential one-pot six-component reaction to
generate 2-oxindoles using palladium catalyst has been repor-
ted.31 Similarly, a copper catalyzed three component reaction
towards the synthesis of 2-oxindole involving N-methyl isatin,
phenylacetylene and aniline derivatives has also been devel-
oped.32 As part of our continuing interest in proposing newer
2-Oxindole derivatives can be accessed through Heck reac-
tion,19 Stille coupling in carbamoyl chloride,20 radical cycliza-
tion,21 Pd- or Rh-catalyzed cyclization,22 carbonylation of 2-
alkynylanilines,23 transition metal catalyzed cyclization of a,b-
acetylenic amides24,25 and nucleophilic addition of oxoindoles
to carbonyl compounds.26 Most of these protocols suffer from
limitations such as the utilization of expensive metal catalysts,
use of additives and cofactors, complex starting materials,
harsh reaction conditions, long reaction times, multistep
syntheses or difficult purication.18,24–28 Therefore, the
aSchool of Chemistry, Madurai Kamaraj University, Madurai – 625 021, India. E-mail:
muthumanian2001@yahoo.com; Fax: +91-452-2459139; Tel: +91-452-2458246
bX-ray Diffraction Laboratory, Department of Chemistry, Texas A&M University,
College station, Texas 77842, USA
† Electronic supplementary information (ESI) available: 1H and 13C NMR spectral
data, NMR spectra, mass spectra and crystal data. CCDC 976050. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c4ra02091j
Fig. 1 Representative examples of biologically active molecules with
2-oxindole moiety.
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Scheme 1 Metal free synthesis of new 2-oxindole derivatives (4a–u).
Table 2 Screening of the acid catalysts for the synthesis of 2-oxindole
4a (R1 ¼ CH2Ph and R2 ¼ OEt)
routes for the construction of heterocycles, we decided to
explore a viable metal free synthesis of 2-oxindoles and thus the
present investigation reports a regiospecic, three component,
triuoroacetic acid mediated synthesis of medicinally prom-
ising 2-oxindoles (4) from cyclohexane-1,3-dione (1), primary
amine (2) and diethyl/methyl acetylenedicarboxylate (3)
involving enamine formation – Michael addition – intra-
molecular regiospecic cyclization – aromatization sequence
(Scheme 1).
The reaction has been carried out with cyclohexane-1,3-
dione (1), benzylamine (2, R1 ¼ CH2Ph) and diethyl acetylene-
dicarboxylate (3, R2 ¼ OEt) in different solvents to choose the
appropriate solvent system for this transformation. It is found
that the reaction produced relatively poor yield in solvents like
THF, acetonitrile, 1,2-dichloroethane, ethanol and dimethyl
sulfoxide, while the use of aromatic solvents like benzene,
toluene and p-xylene is found to be successful ending up in
good to excellent yield of 2-oxindole as a single regioisomer.
Ultimately, toluene is found to be the solvent of choice,
requiring shorter reaction time and providing higher yield than
the other examined solvents. The various attempts are
summarized in Table 1.
Entry
Catalyst (0.3 equiv.)
Yield (%)
1
2
3
4
5
6
7
Polyphosphoric acid
Phosphorus oxychloride
Phosphorus pentoxide
Titanium(IV) chloride
p-Toluenesulfonic acid
Camphorsulfonic acid
Triuoromethane sulphonic
acid
27
34
25
48
40
62
78
8
9
10
Acetic acid
Trichloroacetic acid
Triuoroacetic acid
83
86
92
Under the optimized conditions, a library of unknown
2-oxindole derivatives (4a–u, Table 3) has been generated. Even
when equimolar amounts of 1, 2 and 3 were employed in the
reaction, a trace amount of 5 has also been noticed in all the
cases along with the major product 4. The trace compound 5a
has been identied as ethyl 2-(1-benzyl-4-(benzylamino)-2-
oxoindolin-3-yl)acetate (Scheme 2). The synthesis of 2-oxindole
4a can also be achieved by the reaction of 3-(benzylamino)
cyclohex-2-enone (6) and diethyl acetylenedicarboxylate yielding
ethyl 2-(1-benzyl-4-hydroxy-2-oxoindolin-3-yl)acetate (4a) as the
single product (Scheme 3) with comparable yield. Compound 6
was prepared separately by the reaction of cyclohexane-1,3-
dione with benzylamine in ethanol with catalytic amount of
acetic acid.
It must be mentioned that under a different condition with
different mole ratio of the substrates, we have noticed the
formation of pyrroloquinone-2,4-dione from the related starting
materials.33 It is found that the aliphatic primary amines react
rapidly and smoothly yielding 4 compared to aromatic primary
amines. This may be due to the higher nucleophilicity of
aliphatic primary amines over aromatic amines. When the
model reaction was carried out with 5,5-dimethyl-1,3-cyclo-
hexanedione in the place of cyclohexane-1,3-dione, the reaction
ended with diethyl 2-(2-(benzylamino)-4,4-dimethyl-6-oxocyclo-
hex-1-enyl)maleate (7a) (Scheme 4), though the reaction with 5-
phenyl-1,3-cyclohexanedione instead of cyclohexane-1,3-dione
went in the expected manner resulting in 4u (Scheme 4), indi-
cating that aromatization may be a driving force in the forma-
tion of 4.
Similarly, the effect of various acid catalysts on the reaction
has also been investigated and it has been noticed that the use
of inorganic acid derivatives of phosphorous and titanium
resulted in relatively poor yield. It was also found that cam-
phorsulfonic
acid,
p-toluenesulfonic
acid
and
tri-
uoromethanesulfonic acid have led to moderate productivity,
compared to acetic acid, trichloroacetic acid and triuoroacetic
acid. Triuoroacetic acid has been identied as the suitable
acid for this reaction, which effectively catalyzing the reaction
with quantitative yield (Table 2).
Table 1 Screening of the solvents for the synthesis of 2-oxindole 4a
(R1 ¼ CH2Ph and R2 ¼ OEt)
Entry
Solvent
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
THF
3.50
3.00
3.50
2.00
3.00
0.75
0.75
0.50
40
36
22
48
60
80
85
92
CH3CN
C2H4Cl2
Ethanol
DMSO
Benzene
p-Xylene
Toluene
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Table 3 Three component synthesis of 2-oxindole derivatives (4a–u)
Scheme 2 The formation of trace compound 5a.
Scheme 3 Two component synthesis of 2-oxindole 4a.
It must be admitted that the structure of the major product 4 ring product (2-oxindole derivative) and also the six membered
could not be unambiguously assigned by NMR spectral data. It ring product, 2-oxo-1,2,3,4-tetrahydroquinoline-4-carboxylate, 8
can be seen that both the one dimensional and two dimensional (Fig. 2). It is to be noted that compound 8 can also be theoret-
NMR spectral data could be matched with the ve membered ically obtained as the product from this multicomponent
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Scheme 4 Three component reaction with dimedone and 5-phenyl-1,3-cyclohexanedione.
Fig. 2 HMBC spectrum of compound 4a (two bond and three bond connections are shown in red and blue arrows respectively).
tautomerisation and aromatization to provide the target
product, 3-substituted-2-oxindole 4.
Conclusions
A new route to the biologically relevant 2-oxindole scaffolds via
new metal free, one-pot enamine formation/Michael addition/
intramolecular regiospecic cyclization/aromatization reaction
sequence has been described. This one-pot multi-component
Fig. 3 Single crystal structure of 4a.
procedure has many advantages with easy workup and a good
atom economy avoiding transition metal catalysts, additives
and cofactors.
reaction. However, the single crystal X-ray analysis (Fig. 3) came
to the rescue in identifying the product 4 to be a benzfused ve
membered ring system and not a six membered one.
Experimental section
General information and materials
On the basis of the above experimental results, a plausible
mechanism for this one pot three-component heteroannulation All the reagents were obtained commercially or synthesized
is outlined in Scheme 5. In this process, triuoroacetic acid according to literature procedures. Nuclear Magnetic Reso-
plays a signicant role in increasing the electrophilicity of the nance (1H and 13C NMR) spectra were recorded on a 300 MHz
electrophile. Initially the nucleophilic attack of amine on cyclic spectrometer in CDCl3 using TMS as internal standard. Chem-
1,3 diketone occurs resulting in the formation of enamine. ical shis are reported in parts per million (d), coupling
Subsequently, Michael addition with acetylene dicarboxylate constants (J values) are reported in Hertz (Hz). 13C NMR spectra
and intermolecular cyclization take place one aer another were routinely run with broadband decoupling. Melting points
leading to the formation of the ve membered intermediate A were determined on a melting point apparatus equipped with a
with the elimination of ethanol. Intermediate A then undergoes thermometer and were uncorrected. Column chromatography
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Scheme 5 Plausible mechanism for the formation of 2-oxindole (4a–u).
was carried out in silica gel (60–120 mesh) using pet. ether–ethyl 8.1 Hz, 1H), 7.19–7.45 (m, 5H), 8.43 (s, 1H); 13C NMR (75 MHz,
acetate as eluent. Elemental analyses were performed on a CDCl3) d ¼ 35.9, 40.1, 44.1, 53.0, 101.4, 111.9, 112.0, 127.2,
CHNS analyzer.
127.6, 128.7, 129.8, 135.6, 144.6, 153.5, 176.1, 176.4; MS (M + 1)
312.25. Anal. calcd for C18H17NO4: C, 69.44, H, 5.50, N, 4.50;
found: C, 69.40, H, 5.47, N, 4.48%.
General procedure for the synthesis 3-substituted-2-
oxindole (4)
Ethyl 2-(4-hydroxy-1-(4-methylbenzyl)-2-oxoindolin-3-yl)-
acetate (4c)
Cyclohexane-1,3-dione (1 mmol) dissolved in minimum amount
of dry toluene was added to diethyl/methyl acetylenedicarbox-
ylate (1 mmol) followed by the addition of primary amine Colorless solid: mp 120–122 ꢀC; 1H NMR (300 MHz, CDCl3) d ¼
(1 mmol) with catalytic amount of triuoroacetic acid 1.33 (t, J ¼ 7.2 Hz, 3H), 2.33 (s, 3H), 2.69 (dd, J ¼ 18.2, 10.5 Hz,
(0.3 equiv.). Then the reaction mixture was reuxed and the 1H), 3.41 (dd, J ¼ 18.2, 1.5 Hz, 1H), 3.82 (dd, J ¼ 10.5, 1.5 Hz,
progress of the reaction was monitored in TLC using pet. ether– 1H), 4.31 (q, J ¼ 7.2 Hz, 2H), 4.82 (d, J ¼ 16.5 Hz, 1H), 4.91 (d, J ¼
ethyl acetate (3 : 2) mixture as eluting medium. Aer the 16.5 Hz, 1H), 6.36 (d, J ¼ 9.0 Hz, 1H), 6.59 (d, J ¼ 9.0 Hz, 1H),
completion of the reaction, the reaction mixture was quenched 7.07–7.21 (m, 5H), 8.61 (s, 1H); 13C NMR (75 MHz, CDCl3) d ¼
with water and the organic layer was separated. The crude 14.0, 21.0, 36.5, 40.1, 43.9, 62.5, 101.4, 111.9, 112.0, 127.2, 129.4,
sample got aer the removal of the solvent was puried using 129.8, 132.6, 137.3, 144.6, 153.6, 176.0, 176.4; MS (M + 1) 340.42.
column chromatography.
Anal. calcd for C20H21NO4: C, 70.78, H, 6.24, N, 4.13; found: C,
70.72, H, 6.19, N, 4.10%.
Ethyl 2-(1-benzyl-4-hydroxy-2-oxoindolin-3-yl)acetate (4a)
Methyl 2-(4-hydroxy-1-(4-methylbenzyl)-2-oxoindolin-3-yl)-
acetate (4d)
Colorless solid: mp 129–131 ꢀC; 1H NMR (300 MHz, CDCl3): d ¼
1.27 (t, J ¼ 7.1 Hz, 3H), 2.73 (dd, J ¼ 18.0, 9.9 Hz, 1H), 3.37 (dd, J
¼ 18.0, 2.4 Hz, 1H), 3.81 (dd, J ¼ 9.9, 2.4 Hz, 1H), 4.24 (q, J ¼ 7.1 Colorless solid: mp 132–134 ꢀC; 1H NMR (300 MHz, CDCl3) d ¼
Hz, 2H), 4.84 (d, J ¼ 15.6 Hz, 1H), 4.92 (d, J ¼ 15.6 Hz, 1H), 6.32 2.31 (s, 3H), 2.68 (dd, J ¼ 18.3, 10.6 Hz, 1H), 3.41 (dd, J ¼ 18.3,
(d, J ¼ 8.0 Hz, 1H), 6.56 (d, J ¼ 8.0 Hz, 1H), 7.05 (t, J ¼ 8.0 Hz, 2.0 Hz, 1H), 3.79–3.83 (m, 4H), 4.80 (d, J ¼ 15.0 Hz, 1H), 4.88 (d,
1H), 7.19–7.52 (m, 5H), 8.56 (s, 1H); 13C NMR (75 MHz, CDCl3) d J ¼ 15.0 Hz, 1H), 6.34 (d, J ¼ 7.5 Hz, 1H), 6.57 (d, J ¼ 7.5 Hz, 1H),
¼ 13.9, 36.0, 40.1, 44.1, 62.2, 101.3, 111.8, 112.0, 127.1, 127.5, 7.05–7.18 (m, 5H), 8.43 (s, 1H); 13C NMR (75 MHz, CDCl3) d ¼
128.6, 129.7, 135.6, 144.5, 153.5, 175.7, 176.2; MS (M + 1) 326.33; 21.0, 35.9, 40.1, 43.9, 53.0, 101.4, 111.8, 111.9, 127.2, 129.4,
anal. calcd for C19H19NO4: C, 70.14, H, 5.89, N, 4.31; found: C, 129.8, 132.6, 137.3, 144.6, 153.5, 176.1, 176.4; MS (M + 1) 326.17.
70.09, H, 5.85, N, 4.27%.
Anal. calcd for C19H19NO4: C, 70.14, H, 5.89, N, 4.31; found: C,
70.11, H, 5.85, N, 4.27%.
Methyl 2-(1-benzyl-4-hydroxy-2-oxoindolin-3-yl)acetate (4b)
Ethyl 2-(4-hydroxy-2-oxo-1-(4-(triuoromethyl)benzyl) indolin-
3-yl) acetate (4e)
Colorless solid: mp 140–142 ꢀC; 1H NMR (300 MHz, CDCl3) d ¼
2.70 (dd, J ¼ 18.3, 10.5 Hz, 1H), 3.38 (dd, J ¼ 18.3, 2.0 Hz, 1H),
3.77–3.84 (m, 4H), 4.85 (d, J ¼ 16.5 Hz, 1H), 4.93 (d, J ¼ 16.5 Hz, Isolated yield 0.308 g (88%); colorless solid: mp 170–172 ꢀC; 1H
1H), 6.33 (d, J ¼ 8.1 Hz, 1H), 6.58 (d, J ¼ 8.1 Hz, 1H), 7.08 (t, J ¼ NMR (300 MHz, CDCl3) d ¼ 1.30 (t, J ¼ 7.2 Hz, 3H), 2.72 (dd, J ¼
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18.3, 10.2 Hz, 1H), 3.39 (dd, J ¼ 18.0, 2.1 Hz, 1H), 3.84 (dd, J ¼
10.2, 2.1 Hz, 1H), 4.28 (q, J ¼ 7.2 Hz, 2H), 4.89 (d, J ¼ 15.9 Hz,
1H), 4.98 (d, J ¼ 15.9 Hz, 1H), 6.28 (d, J ¼ 8.4 Hz, 1H), 6.60 (d, J ¼
8.4 Hz, 1H), 7.10 (t, J ¼ 8.4 Hz, 1H), 7.45–7.55 (m, 4H), 8.54 (s,
1H); 13C NMR (75 MHz, CDCl3) d ¼ 13.9, 36.2, 40.2, 43.8, 62.4,
101.0, 112.0, 112.3, 124.6, 129.0, 129.3, 129.9, 130.4, 136.8,
144.2, 153.8, 175.9, 176.2; MS (M + 1) 394.25. Anal. calcd for
Methyl 2-(4-hydroxy-2-oxo-1-propylindolin-3-yl)acetate (4j)
Colorless solid: mp 101–103 ꢀC; 1H NMR (300 MHz, CDCl3) d ¼
0.95 (t, J ¼ 7.5 Hz, 3H), 1.70 (m, 2H), 2.69 (dd, J ¼ 18.0, 9.9 Hz,
1H), 3.32 (dd, J ¼ 18.0, 2.4 Hz, 1H), 3.63–3.72 (m, 2H), 3.73 (dd, J
¼ 9.9, 2.4 Hz, 1H), 3.79 (s, 3H), 6.43 (d, J ¼ 7.5 Hz, 1H), 6.61 (d, J
¼ 7.5 Hz, 1H), 7.17 (t, J ¼ 7.5 Hz, 1H), 8.51 (s, 1H); 13C NMR (75
MHz, CDCl3) d ¼ 11.2, 20.7, 35.8, 40.2, 42.1, 52.9, 100.7, 111.7,
112.2, 129.8, 145.0, 153.6, 176.1, 176.3; MS (M + 1) 264.32. Anal.
calcd for C14H17NO4: C, 63.87, H, 6.51, N, 5.32; found: C, 63.84,
H, 6.47, N, 5.27%.
C
20H18F3NO4: C, 61.07, H, 4.61, N, 3.56; found: C, 61.02, H, 4.58,
N, 3.51.
Ethyl 2-(4-hydroxy-1-(2-methoxybenzyl)-2-oxoindolin-3-yl)-
acetate (4f)
Ethyl 2-(1-butyl-4-hydroxy-2-oxoindolin-3-yl)acetate (4k)
Colorless solid: mp 150–152 ꢀC; 1H NMR (300 MHz, CDCl3) d ¼
1.24 (t, J ¼ 7.2 Hz, 3H), 2.79 (dd, J ¼ 18.2, 10.2 Hz, 1H), 3.34 (dd,
J ¼ 18.0, 2.1 Hz, 1H), 3.81–3.86 (m, 4H), 4.20 (q, J ¼ 7.2 Hz, 2H),
4.86 (d, J ¼ 15.9 Hz, 1H), 4.95 (d, J ¼ 15.9 Hz, 1H), 6.33 (d, J ¼ 8.4
Hz, 1H), 6.55 (d, J ¼ 8.4 Hz, 1H), 6.85 (m, 2H), 7.05 (m, 2H), 7.20
(t, J ¼ 7.2 Hz, 1H), 8.57 (s, 1H); 13C NMR (75 MHz, CDCl3) d ¼
13.8, 35.5, 38.8, 40.3, 55.1, 61.9, 101.4, 110.1, 111.4, 111.9, 120.4,
123.4, 127.7, 128.5, 129.5, 144.7, 153.2, 156.8, 175.0, 176.6; MS
(M + 1) 356.33. Anal. calcd for C20H21NO5: C, 67.59, H, 5.96, N,
3.94; found: C, 67.55, H, 5.90, N, 3.89%.
Colorless solid: mp 126–128 ꢀC; 1H NMR (300 MHz, CDCl3) d ¼
0.86 (t, J ¼ 7.2 Hz, 3H), 1.25–1.33 (m, 5H), 1.63–1.70 (m, 2H),
2.70 (dd, J ¼ 18.0, 9.6 Hz, 1H), 3.27–3.30 (m, 2H), 3.64–3.76 (m,
2H), 4.23 (q, J ¼ 7.2 Hz, 2H), 6.42 (d, J ¼ 9.0 Hz, 1H), 6.60 (d, J ¼
9.0 Hz, 1H), 7.16 (t, J ¼ 9.0 Hz, 1H), 8.63 (s, 1H); 13C NMR (75
MHz, CDCl3) d ¼ 14.1, 14.2, 20.2, 29.6, 36.0, 38.6, 40.3, 62.2,
100.7, 111.6, 112.3, 129.8, 145.1, 153.8, 175.6, 176.1; anal. calcd
for C16H21NO4: C, 65.96, H, 7.27, N, 4.81; found: C, 65.90, H,
7.24, N, 4.77%.
Methyl 2-(1-butyl-4-hydroxy-2-oxoindolin-3-yl)acetate (4l)
Ethyl 2-(4-hydroxy-1-methyl-2-oxoindolin-3-yl)acetate (4g)
Colorless solid: mp 144–146 ꢀC; 1H NMR (300 MHz, CDCl3) d ¼
0.94 (t, J ¼ 7.5 Hz, 3H), 1.35–1.41 (m, 2H), 1.61–1.66 (m, 2H),
2.66 (dd, J ¼ 18.1, 10.1 Hz, 1H), 3.33 (dd, J ¼ 18.0, 3.0 Hz, 1H),
3.64–3.73 (m, 3H), 3.79 (s, 3H), 6.42 (d, J ¼ 7.5 Hz, 1H), 6.64 (d, J
¼ 7.5 Hz, 1H), 7.16 (t, J ¼ 7.5 Hz, 1H), 8.49 (s, 1H); 13C NMR (75
MHz, CDCl3) d ¼ 13.5, 20.0, 29.4, 35.5, 40.2*, 52.7, 100.6, 111.5,
112.2, 129.7, 144.9, 153.6, 175.9, 176.0; anal. calcd for
Colorless solid: mp 164–166 ꢀC; 1H NMR (300 MHz, CDCl3) d ¼
1.33 (t, J ¼ 7.1 Hz, 3H), 2.62 (dd, J ¼ 18.3, 10.7 Hz, 1H), 3.20 (s,
3H), 3.34 (d, J ¼ 18.3 Hz, 1H), 3.72 (d, J ¼ 10.7 Hz, 1H), 4.29 (q, J
¼ 7.1 Hz, 2H), 6.42 (d, J ¼ 9.0 Hz, 1H), 6.63 (d, J ¼ 9.0 Hz, 1H),
7.20 (t, J ¼ 9.0 Hz, 1H), 8.67 (s, 1H); 13C NMR (75 MHz, CDCl3) d
¼ 13.8, 26.5, 36.2, 40.6, 62.3, 100.1, 111.9, 112.0, 129.8, 145.4,
153.5, 175.7, 176.3; MS (M + 1) 250.25. Anal. calcd for
C
15H19NO4: C, 64.97, H, 6.91, N, 5.05; found: C, 64.94, H, 6.87,
C
13H15NO4: C, 62.64, H, 6.07, N, 5.62; found: C, 62.59, H, 6.02,
N, 5.01%. (*Two carbons merged here.)
N, 5.59%.
Ethyl 2-(1-hexadecyl-4-hydroxy-2-oxoindolin-3-yl)acetate (4m)
Methyl 2-(4-hydroxy-1-methyl-2-oxoindolin-3-yl)acetate (4h)
1
ꢀ
Colorless solid: mp 55–57 C; H NMR (300 MHz, CDCl3) d ¼
0.87 (t, J ¼ 7.0 Hz, 3H), 1.25–1.31 (m, 31H), 2.60 (dd, J ¼ 18.3,
10.7 Hz, 1H), 3.33 (dd, J ¼ 18.3, 1.8 Hz, 1H), 3.66–3.72 (m, 3H),
4.28 (q, J ¼ 7.1, Hz, 2H), 6.41 (d, J ¼ 9.0 Hz, 1H), 6.60 (d, J ¼ 9.0
Hz, 1H), 7.17 (t, J ¼ 9.0 Hz, 1H), 8.63 (s, 1H); 13C NMR (75 MHz,
CDCl3) d ¼ 14.0, 14.1, 22.6, 26.8, 27.4, 29.2, 29.3*, 29.4, 29.5,
29.6, 31.8, 36.3, 40.1, 40.5, 62.4, 100.6, 111.7, 112.2, 129.8, 144.9,
153.7, 175.8, 176.4; anal. calcd. for C28H45NO4: C, 73.16, H, 9.87,
N, 3.05; found: C, 73.12, H, 9.85, N, 2.98%. (*More carbons
merged here.)
Colorless solid: mp 157–159 ꢀC; 1H NMR (300 MHz, DMSO) d ¼
2.69 (dd, J ¼ 18.2, 10.5 Hz, 1H), 3.24 (s, 3H), 3.37 (dd, J ¼ 18.2,
2.0 Hz, 1H), 3.76 (broadened doublet, J ¼ 10.5 Hz, 1H), 3.85 (s,
3H), 6.45 (d, J ¼ 9.0 Hz, 1H), 6.66 (d, J ¼ 9.0 Hz, 1H), 7.22 (t, J ¼
9.0 Hz, 1H), 8.56 (s, 1H); 13C NMR (75 MHz, CDCl3) d ¼ 26.7,
35.8, 40.1, 53.1, 100.4, 111.9, 112.0, 129.9, 145.5, 153.5, 175.9,
176.6; MS (M + 1) 236.22. Anal. calcd for C12H13NO4: C, 61.27, H,
5.57, N, 5.95; found: C, 61.25, H, 5.51, N, 5.91%.
Ethyl 2-(4-hydroxy-2-oxo-1-propylindolin-3-yl)acetate (4i)
1
Ethyl 2-(1-cyclopropyl-4-hydroxy-2-oxoindolin-3-yl)acetate (4n)
ꢀ
Colorless solid: mp 85–87 C; H NMR (300 MHz, CDCl3) d ¼
1
ꢀ
0.96 (t, J ¼ 7.2 Hz, 3H), 1.31 (t, J ¼ 6.9 Hz, 3H), 1.66–1.76 (m, 2H), Colorless solid: mp 84–86 C; H NMR (300 MHz, CDCl3) d ¼
2.63 (dd, J ¼ 18.3, 10.5 Hz, 1H), 3.34 (dd, J ¼ 18.3, 2.1 Hz, 1H), 0.88–1.88 (m, 4H), 1.26 (t, J ¼ 7.2 Hz, 3H), 2.62–2.74 (m, 2H),
3.30–3.68 (m, 3H), 4.28 (m, 2H), 6.43 (d, J ¼ 7.8 Hz, 1H), 6.62 (d, J 3.27 (dd, J ¼ 18.0, 2.4 Hz, 1H), 3.67 (dd, J ¼ 9.6, 2.4 Hz, 1H), 4.22
¼ 7.8 Hz, 1H), 7.18 (t, J ¼ 7.8 Hz, 1H), 8.64 (s, 1H); 13C NMR (75 (q, J ¼ 7.2 Hz, 2H), 6.61 (d, J ¼ 8.1 Hz, 1H), 6.69 (d, J ¼ 7.5 Hz,
MHz, CDCl3) d ¼ 11.3, 14.0, 20.7, 36.3, 40.1, 42.0, 62.4, 100.7, 1H), 7.17 (t, J ¼ 7.8 Hz, 1H), 8.54 (s, 1H); 13C NMR (75 MHz,
111.7, 112.2, 129.8, 144.9, 153.7, 176.0, 176.2; MS (M + 1) 278.42. CDCl3) d ¼ 6.0, 13.9, 22.4, 35.7, 40.3, 62.1, 101.6, 111.5, 111.6,
Anal. calcd for C15H19NO4: C, 64.97, H, 6.91, N, 5.05; found: C, 129.6, 145.8, 153.3, 175.5, 177.0; anal. calcd for C15H17NO4: C,
64.95, H, 6.87, N, 4.99%.
65.44, H, 6.22, N, 5.09; found: C, 65.39, H, 6.19, N, 5.04%.
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1H); 13C NMR (75 MHz, CDCl3) d ¼ 14.2, 36.3, 40.4, 62.4, 101.5,
112.1, 112.3, 116.6, 116.7, 128.6, 129.8, 145.5, 152.6, 153.8,
175.7, 175.8; anal. calcd for C18H16FNO4: C, 65.65, H, 4.90, N,
4.25; found: C, 65.59, H, 4.86, N, 4.22%.
Ethyl 2-(1-cyclohexyl-4-hydroxy-2-oxoindolin-3-yl)acetate (4o)
1
ꢀ
Colorless solid: mp 91–93 C; H NMR (300 MHz, CDCl3) d ¼
1.01–1.26 (m, 8H), 1.65–1.80 (m, 6H), 2.77–2.83 (m, 1H), 3.33
(dd, J ¼ 17.1, 2.7 Hz, 1H), 3.5 (d, J ¼ 7.2 Hz, 2H), 3.82 (dd, J ¼ 8.7,
3.3 Hz, 1H), 4.26 (q, J ¼ 7.2 Hz, 2H), 6.49 (d, J ¼ 8.1 Hz, 1H), 6.57
(d, J ¼ 8.4 Hz, 1H), 7.20 (t, J ¼ 8.1 Hz, 1H), 8.68 (s, 1H); 13C NMR
(75 MHz, CDCl3) d ¼ 13.8, 25.5, 26.1, 30.7, 35.3, 36.1, 40.2, 46.6,
53.2, 61.6, 100.8, 111.2, 112.1, 129.3, 145.3, 153.4, 174.5, 176.6;
anal. calcd for C18H23NO4: C, 68.12, H, 7.30, N, 4.41; found: C,
68.06, H, 7.24, N, 4.40%.
Ethyl 2-(1-(3,5-dichlorophenyl)-4-hydroxy-2-oxoindolin-3-yl)-
acetate (4t)
Colorless solid: mp 175–177 ꢀC; 1H NMR (300 MHz, CDCl3) d ¼
1.23 (t, J ¼ 7.5 Hz, 3H), 2.65 (dd, J ¼ 18.0, 9.6 Hz, 1H), 3.32 (dd, J
¼ 18.0, 2.4 Hz, 1H), 3.82 (dd, J ¼ 9.6, 2.4 Hz, 1H), 4.20 (q, J ¼ 7.5
Hz, 2H), 6.30 (d, J ¼ 8.1 Hz, 1H), 6.57 (d, J ¼ 8.1 Hz, 1H), 7.06 (t, J
¼ 8.1 Hz, 1H), 7.28 (d, J ¼ 1.8 Hz, 2H), 7.33 (d, J ¼ 1.8 Hz, 1H),
8.33 (s, 1H); 13C NMR (75 MHz, CDCl3) d ¼ 14.0, 36.1, 40.4, 62.4,
101.5, 112.0, 112.6, 125.3, 128.4, 129.9, 135.8, 136.4, 144.4,
153.9, 175.3, 175.4; anal. calcd for C18H15Cl2NO4: C, 56.86, H,
3.98, N, 3.68; found: C, 56.82, H, 3.93, N, 3.64%.
Ethyl 2-(1-(3-bromophenethyl)-4-hydroxy-2-oxoindolin-3-yl)-
acetate (4p)
Isolated yield 0.335 g (88%); colorless solid: mp 160–162 ꢀC; 1H
NMR (300 MHz, CDCl3) d ¼ 1.31 (t, J ¼ 7.2 Hz, 3H), 2.54 (dd, J ¼
18.3, 10.5 Hz, 1H), 2.92 (t, J ¼ 7.5 Hz, 2H), 3.22 (dd, J ¼ 18.3, 1.8
Hz, 1H), 3.67 (dd, J ¼ 10.5, 1.8 Hz, 1H), 3.80–4.00 (m, 2H), 4.22–
4.33 (m, 2H), 6.41 (d, J ¼ 7.8 Hz, 1H), 6.62 (d, J ¼ 7.8 Hz, 1H),
7.09–7.35 (m, 5H), 8.68 (s, 1H); 13C NMR (75 MHz, CDCl3) d ¼
13.8, 33.0, 36.3, 39.9, 41.3, 62.3, 100.3, 111.9, 112.0, 122.4, 127.3,
128.8, 129.8, 130.0, 131.7, 140.1, 144.3, 153.8, 175.6, 176.3; anal.
calcd for C20H20BrNO4: C, 57.43, H, 4.82, N, 3.35; found: C,
57.39, H, 4.79, N, 3.32%.
Ethyl 2-(1-benzyl-4-hydroxy-2-oxo-6-phenylindolin-3-yl)-
acetate (4u)
Colorless solid: mp 154–156 ꢀC; 1H NMR (300 MHz, CDCl3) d ¼
1.31 (t, J ¼ 7.2 Hz, 3H), 2.71 (dd, J ¼ 18.3, 10.5 Hz, 1H), 3.42 (dd,
J ¼ 18.3, 2.1 Hz, 1H), 3.85 (dd, J ¼ 10.5, 2.1 Hz, 1H), 4.40 (q, J ¼
7.2 Hz, 2H), 4.88 (d, J ¼ 15.6 Hz, 1H), 4.94 (d, J ¼ 15.6 Hz, 1H),
6.55 (s, 1H), 6.82 (s, 1H), 7.25–7.43 (m, 10H), 8.75 (s, 1H); 13C
NMR (75 MHz, CDCl3) d ¼ 13.9, 36.5, 40.1, 44.2, 62.4, 100.4,
110.8, 111.0, 126.9, 127.2, 127.6, 127.7, 128.6, 128.7, 138.7,
140.6, 143.6, 145.1, 153.7, 176.2, 176.6; anal. calcd for
Ethyl 2-(4-hydroxy-2-oxo-1-(thiophen-2-ylmethyl)indolin-3-yl)-
acetate (4q)
Colorless solid: mp 154–156 ꢀC; 1H NMR (300 MHz, CDCl3) d ¼
1.29 (t, J ¼ 7.2 Hz, 3H), 2.64 (dd, J ¼ 18.3, 10.5 Hz, 1H), 3.35 (dd,
J ¼ 18.0, 1.8 Hz, 1H), 3.76 (dd, J ¼ 10.5, 1.8 Hz, 1H), 4.27 (q, J ¼
7.2 Hz, 2H), 5.03 (d, J ¼ 15.9 Hz, 1H), 5.09 (d, J ¼ 15.9 Hz, 1H),
6.49 (d, J ¼ 7.8 Hz, 1H), 6.60 (d, J ¼ 7.8 Hz, 1H), 6.69–6.94 (m,
C
25H23NO4: C, 74.79, H, 5.77, N, 3.49; found: C, 74.73, H, 5.74,
N, 3.45%.
Acknowledgements
1H), 7.04 (d, J ¼ 2.7 Hz, 1H), 7.16–7.20 (m, 2H), 8.59 (s, 1H); 13
C
The authors thank DST, New Delhi for assistance under the
IRHPA program for the NMR facility. Financial support from
UGC, New Delhi to Mr M. Boominathan was gratefully
acknowledged.
NMR (75 MHz, CDCl3) d ¼ 13.9, 36.3, 39.0, 40.0, 62.4, 101.0,
112.1*, 125.3, 126.5, 126.8, 129.9, 138.1, 144.1, 153.8, 175.6,
176.2; anal. calcd for C17H17NO4S: C, 61.61, H, 5.17, N, 4.23;
found: C, 61.57, H, 5.13, N, 4.18%. (*Two carbons merged here.)
Ethyl 2-(4-hydroxy-2-oxo-1-phenylindolin-3-yl)acetate (4r)
Notes and references
Colorless solid: mp 165–167 ꢀC; 1H NMR (300 MHz, CDCl3) d ¼
1.37 (t, J ¼ 7.2 Hz, 3H), 2.89 (dd, J ¼ 18.0, 9.9 Hz, 1H), 3.41 (dd,
J ¼ 18.0, 2.4 Hz, 1H), 3.91 (dd, J ¼ 9.9, 2.4 Hz, 1H), 4.27 (q, J ¼
7.2 Hz, 2H), 6.34 (d, J ¼ 9.0 Hz, 1H), 6.62 (d, J ¼ 9.0 Hz, 1H), 7.09
(t, J ¼ 9.0 Hz, 1H), 7.38–7.44 (m, 5H), 8.54 (s, 1H); 13C NMR (75
MHz, CDCl3) d ¼ 13.9, 36.5, 40.4, 62.5, 101.7, 111.9, 112.0, 126.5,
126.7, 129.5, 129.6, 134.5, 145.6, 153.7, 175.5, 175.6; anal. calcd
for C18H17NO4: C, 69.44, H, 5.50, N, 4.50; found: C, 69.39, H,
5.46, N, 4.47%.
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