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

Abstract

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.

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Introduction

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 skeleton is found in many natural products like notamide C, elacomine, alstonisine, surugatoxin, welwitindolinone A, salacin, uncarine E, spirotryprostatin A, coerulescine, horsfiline, maremycins A and convolutamydines and biologically active molecules 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

Fig. 1 Representative examples of biologically active molecules with 2-oxindole moiety.

2-Oxindole derivatives can be accessed through Heck reaction,¹⁹ Stille coupling in carbamoyl chloride,²⁰ radical cyclization,²¹ Pd- or Rh-catalyzed cyclization,²² carbonylation of 2-alkynylanilines,²³ transition metal catalyzed cyclization of α,β-acetylenic amides^24,25 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 purification.^18,24–28 Therefore, the development of metal free strategies for the assembly and derivatization of 2-oxindole from readily available starting materials would be a significant contribution to biomedical community. Multicomponent reactions^29,30 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.

Results and discussion

Recently, a sequential one-pot six-component reaction to generate 2-oxindoles using palladium catalyst has been reported.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 developed.³² As part of our continuing interest in proposing newer 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 regiospecific, three component, trifluoroacetic acid mediated synthesis of medicinally promising 2-oxindoles (4) from cyclohexane-1,3-dione (1), primary amine (2) and diethyl/methyl acetylenedicarboxylate (3) involving enamine formation – Michael addition – intramolecular regiospecific cyclization – aromatization sequence (Scheme 1).

Scheme 1 Metal free synthesis of new 2-oxindole derivatives (4a–u).

The reaction has been carried out with cyclohexane-1,3-dione (1), benzylamine (2, R₁ = CH₂Ph) and diethyl acetylenedicarboxylate (3, R₂ = 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.

Table 1 Screening of the solvents for the synthesis of 2-oxindole 4a (R₁ = CH₂Ph and R₂ = OEt)

Entry	Solvent	Time (h)	Yield (%)
1	THF	3.50	40
2	CH3CN	3.00	36
3	C2H4Cl2	3.50	22
4	Ethanol	2.00	48
5	DMSO	3.00	60
6	Benzene	0.75	80
7	p-Xylene	0.75	85
8	Toluene	0.50	92

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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 camphorsulfonic acid, p-toluenesulfonic acid and trifluoromethanesulfonic acid have led to moderate productivity, compared to acetic acid, trichloroacetic acid and trifluoroacetic acid. Trifluoroacetic acid has been identified as the suitable acid for this reaction, which effectively catalyzing the reaction with quantitative yield (Table 2).

Table 2 Screening of the acid catalysts for the synthesis of 2-oxindole 4a (R₁ = CH₂Ph and R₂ = OEt)

Entry	Catalyst (0.3 equiv.)	Yield (%)
1	Polyphosphoric acid	27
2	Phosphorus oxychloride	34
3	Phosphorus pentoxide	25
4	Titanium(IV) chloride	48
5	p-Toluenesulfonic acid	40
6	Camphorsulfonic acid	62
7	Trifluoromethane sulphonic acid	78
8	Acetic acid	83
9	Trichloroacetic acid	86
10	Trifluoroacetic acid	92

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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 identified 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.

Table 3 Three component synthesis of 2-oxindole derivatives (4a–u)

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Scheme 2 The formation of trace compound 5a.

Scheme 3 Two component synthesis of 2-oxindole 4a.

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-cyclohexanedione in the place of cyclohexane-1,3-dione, the reaction ended with diethyl 2-(2-(benzylamino)-4,4-dimethyl-6-oxocyclohex-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), indicating that aromatization may be a driving force in the formation of 4.

Scheme 4 Three component reaction with dimedone and 5-phenyl-1,3-cyclohexanedione.

It must be admitted that the structure of the major product 4 could not be unambiguously assigned by NMR spectral data. It can be seen that both the one dimensional and two dimensional NMR spectral data could be matched with the five membered ring product (2-oxindole derivative) and also the six membered ring product, 2-oxo-1,2,3,4-tetrahydroquinoline-4-carboxylate, 8 (Fig. 2). It is to be noted that compound 8 can also be theoretically obtained as the product from this multicomponent reaction. However, the single crystal X-ray analysis (Fig. 3) came to the rescue in identifying the product 4 to be a benzfused five membered ring system and not a six membered one.

Fig. 2 HMBC spectrum of compound 4a (two bond and three bond connections are shown in red and blue arrows respectively).

Fig. 3 Single crystal structure of 4a.

On the basis of the above experimental results, a plausible mechanism for this one pot three-component heteroannulation is outlined in Scheme 5. In this process, trifluoroacetic acid plays a significant role in increasing the electrophilicity of the electrophile. Initially the nucleophilic attack of amine on cyclic 1,3 diketone occurs resulting in the formation of enamine. Subsequently, Michael addition with acetylene dicarboxylate and intermolecular cyclization take place one after another leading to the formation of the five membered intermediate A with the elimination of ethanol. Intermediate A then undergoes tautomerisation and aromatization to provide the target product, 3-substituted-2-oxindole 4.

Scheme 5 Plausible mechanism for the formation of 2-oxindole (4a–u).

Conclusions

A new route to the biologically relevant 2-oxindole scaffolds via new metal free, one-pot enamine formation/Michael addition/intramolecular regiospecific cyclization/aromatization reaction sequence has been described. This one-pot multi-component procedure has many advantages with easy workup and a good atom economy avoiding transition metal catalysts, additives and cofactors.

Experimental section

General information and materials

All the reagents were obtained commercially or synthesized according to literature procedures. Nuclear Magnetic Resonance (¹H and ¹³C NMR) spectra were recorded on a 300 MHz spectrometer in CDCl₃ using TMS as internal standard. Chemical shifts are reported in parts per million (δ), coupling constants (J values) are reported in Hertz (Hz). ¹³C NMR spectra were routinely run with broadband decoupling. Melting points were determined on a melting point apparatus equipped with a thermometer and were uncorrected. Column chromatography was carried out in silica gel (60–120 mesh) using pet. ether–ethyl acetate as eluent. Elemental analyses were performed on a CHNS analyzer.

General procedure for the synthesis 3-substituted-2-oxindole (4)

Cyclohexane-1,3-dione (1 mmol) dissolved in minimum amount of dry toluene was added to diethyl/methyl acetylenedicarboxylate (1 mmol) followed by the addition of primary amine (1 mmol) with catalytic amount of trifluoroacetic acid (0.3 equiv.). Then the reaction mixture was refluxed and the progress of the reaction was monitored in TLC using pet. ether–ethyl acetate (3 : 2) mixture as eluting medium. After the completion of the reaction, the reaction mixture was quenched with water and the organic layer was separated. The crude sample got after the removal of the solvent was purified using column chromatography.

Ethyl 2-(1-benzyl-4-hydroxy-2-oxoindolin-3-yl)acetate (4a)

Colorless solid: mp 129–131 °C; ¹H NMR (300 MHz, CDCl₃): δ = 1.27 (t, J = 7.1 Hz, 3H), 2.73 (dd, J = 18.0, 9.9 Hz, 1H), 3.37 (dd, J = 18.0, 2.4 Hz, 1H), 3.81 (dd, J = 9.9, 2.4 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 4.84 (d, J = 15.6 Hz, 1H), 4.92 (d, J = 15.6 Hz, 1H), 6.32 (d, J = 8.0 Hz, 1H), 6.56 (d, J = 8.0 Hz, 1H), 7.05 (t, J = 8.0 Hz, 1H), 7.19–7.52 (m, 5H), 8.56 (s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ = 13.9, 36.0, 40.1, 44.1, 62.2, 101.3, 111.8, 112.0, 127.1, 127.5, 128.6, 129.7, 135.6, 144.5, 153.5, 175.7, 176.2; MS (M + 1) 326.33; anal. calcd for C₁₉H₁₉NO₄: C, 70.14, H, 5.89, N, 4.31; found: C, 70.09, H, 5.85, N, 4.27%.

Methyl 2-(1-benzyl-4-hydroxy-2-oxoindolin-3-yl)acetate (4b)

Colorless solid: mp 140–142 °C; ¹H NMR (300 MHz, CDCl₃) δ = 2.70 (dd, J = 18.3, 10.5 Hz, 1H), 3.38 (dd, J = 18.3, 2.0 Hz, 1H), 3.77–3.84 (m, 4H), 4.85 (d, J = 16.5 Hz, 1H), 4.93 (d, J = 16.5 Hz, 1H), 6.33 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 7.08 (t, J = 8.1 Hz, 1H), 7.19–7.45 (m, 5H), 8.43 (s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ = 35.9, 40.1, 44.1, 53.0, 101.4, 111.9, 112.0, 127.2, 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%.

Ethyl 2-(4-hydroxy-1-(4-methylbenzyl)-2-oxoindolin-3-yl)acetate (4c)

Colorless solid: mp 120–122 °C; ¹H NMR (300 MHz, CDCl₃) δ = 1.33 (t, J = 7.2 Hz, 3H), 2.33 (s, 3H), 2.69 (dd, J = 18.2, 10.5 Hz, 1H), 3.41 (dd, J = 18.2, 1.5 Hz, 1H), 3.82 (dd, J = 10.5, 1.5 Hz, 1H), 4.31 (q, J = 7.2 Hz, 2H), 4.82 (d, J = 16.5 Hz, 1H), 4.91 (d, J = 16.5 Hz, 1H), 6.36 (d, J = 9.0 Hz, 1H), 6.59 (d, J = 9.0 Hz, 1H), 7.07–7.21 (m, 5H), 8.61 (s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ = 14.0, 21.0, 36.5, 40.1, 43.9, 62.5, 101.4, 111.9, 112.0, 127.2, 129.4, 129.8, 132.6, 137.3, 144.6, 153.6, 176.0, 176.4; MS (M + 1) 340.42. Anal. calcd for C₂₀H₂₁NO₄: C, 70.78, H, 6.24, N, 4.13; found: C, 70.72, H, 6.19, N, 4.10%.

Methyl 2-(4-hydroxy-1-(4-methylbenzyl)-2-oxoindolin-3-yl)acetate (4d)

Colorless solid: mp 132–134 °C; ¹H NMR (300 MHz, CDCl₃) δ = 2.31 (s, 3H), 2.68 (dd, J = 18.3, 10.6 Hz, 1H), 3.41 (dd, J = 18.3, 2.0 Hz, 1H), 3.79–3.83 (m, 4H), 4.80 (d, J = 15.0 Hz, 1H), 4.88 (d, J = 15.0 Hz, 1H), 6.34 (d, J = 7.5 Hz, 1H), 6.57 (d, J = 7.5 Hz, 1H), 7.05–7.18 (m, 5H), 8.43 (s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ = 21.0, 35.9, 40.1, 43.9, 53.0, 101.4, 111.8, 111.9, 127.2, 129.4, 129.8, 132.6, 137.3, 144.6, 153.5, 176.1, 176.4; MS (M + 1) 326.17. Anal. calcd for C₁₉H₁₉NO₄: C, 70.14, H, 5.89, N, 4.31; found: C, 70.11, H, 5.85, N, 4.27%.

Ethyl 2-(4-hydroxy-2-oxo-1-(4-(trifluoromethyl)benzyl) indolin-3-yl) acetate (4e)

Isolated yield 0.308 g (88%); colorless solid: mp 170–172 °C; ¹H NMR (300 MHz, CDCl₃) δ = 1.30 (t, J = 7.2 Hz, 3H), 2.72 (dd, J = 18.3, 10.2 Hz, 1H), 3.39 (dd, J = 18.0, 2.1 Hz, 1H), 3.84 (dd, J = 10.2, 2.1 Hz, 1H), 4.28 (q, J = 7.2 Hz, 2H), 4.89 (d, J = 15.9 Hz, 1H), 4.98 (d, J = 15.9 Hz, 1H), 6.28 (d, J = 8.4 Hz, 1H), 6.60 (d, J = 8.4 Hz, 1H), 7.10 (t, J = 8.4 Hz, 1H), 7.45–7.55 (m, 4H), 8.54 (s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ = 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 C₂₀H₁₈F₃NO₄: 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)

Colorless solid: mp 150–152 °C; ¹H NMR (300 MHz, CDCl₃) δ = 1.24 (t, J = 7.2 Hz, 3H), 2.79 (dd, J = 18.2, 10.2 Hz, 1H), 3.34 (dd, J = 18.0, 2.1 Hz, 1H), 3.81–3.86 (m, 4H), 4.20 (q, J = 7.2 Hz, 2H), 4.86 (d, J = 15.9 Hz, 1H), 4.95 (d, J = 15.9 Hz, 1H), 6.33 (d, J = 8.4 Hz, 1H), 6.55 (d, J = 8.4 Hz, 1H), 6.85 (m, 2H), 7.05 (m, 2H), 7.20 (t, J = 7.2 Hz, 1H), 8.57 (s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ = 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%.

Ethyl 2-(4-hydroxy-1-methyl-2-oxoindolin-3-yl)acetate (4g)

Colorless solid: mp 164–166 °C; ¹H NMR (300 MHz, CDCl₃) δ = 1.33 (t, J = 7.1 Hz, 3H), 2.62 (dd, J = 18.3, 10.7 Hz, 1H), 3.20 (s, 3H), 3.34 (d, J = 18.3 Hz, 1H), 3.72 (d, J = 10.7 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 6.42 (d, J = 9.0 Hz, 1H), 6.63 (d, J = 9.0 Hz, 1H), 7.20 (t, J = 9.0 Hz, 1H), 8.67 (s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ = 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 C₁₃H₁₅NO₄: C, 62.64, H, 6.07, N, 5.62; found: C, 62.59, H, 6.02, N, 5.59%.

Methyl 2-(4-hydroxy-1-methyl-2-oxoindolin-3-yl)acetate (4h)

Colorless solid: mp 157–159 °C; ¹H NMR (300 MHz, DMSO) δ = 2.69 (dd, J = 18.2, 10.5 Hz, 1H), 3.24 (s, 3H), 3.37 (dd, J = 18.2, 2.0 Hz, 1H), 3.76 (broadened doublet, J = 10.5 Hz, 1H), 3.85 (s, 3H), 6.45 (d, J = 9.0 Hz, 1H), 6.66 (d, J = 9.0 Hz, 1H), 7.22 (t, J = 9.0 Hz, 1H), 8.56 (s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ = 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)

Colorless solid: mp 85–87 °C; ¹H NMR (300 MHz, CDCl₃) δ = 0.96 (t, J = 7.2 Hz, 3H), 1.31 (t, J = 6.9 Hz, 3H), 1.66–1.76 (m, 2H), 2.63 (dd, J = 18.3, 10.5 Hz, 1H), 3.34 (dd, J = 18.3, 2.1 Hz, 1H), 3.30–3.68 (m, 3H), 4.28 (m, 2H), 6.43 (d, J = 7.8 Hz, 1H), 6.62 (d, J = 7.8 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 8.64 (s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ = 11.3, 14.0, 20.7, 36.3, 40.1, 42.0, 62.4, 100.7, 111.7, 112.2, 129.8, 144.9, 153.7, 176.0, 176.2; MS (M + 1) 278.42. Anal. calcd for C₁₅H₁₉NO₄: C, 64.97, H, 6.91, N, 5.05; found: C, 64.95, H, 6.87, N, 4.99%.

Methyl 2-(4-hydroxy-2-oxo-1-propylindolin-3-yl)acetate (4j)

Colorless solid: mp 101–103 °C; ¹H NMR (300 MHz, CDCl₃) δ = 0.95 (t, J = 7.5 Hz, 3H), 1.70 (m, 2H), 2.69 (dd, J = 18.0, 9.9 Hz, 1H), 3.32 (dd, J = 18.0, 2.4 Hz, 1H), 3.63–3.72 (m, 2H), 3.73 (dd, J = 9.9, 2.4 Hz, 1H), 3.79 (s, 3H), 6.43 (d, J = 7.5 Hz, 1H), 6.61 (d, J = 7.5 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 8.51 (s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ = 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%.

Ethyl 2-(1-butyl-4-hydroxy-2-oxoindolin-3-yl)acetate (4k)

Colorless solid: mp 126–128 °C; ¹H NMR (300 MHz, CDCl₃) δ = 0.86 (t, J = 7.2 Hz, 3H), 1.25–1.33 (m, 5H), 1.63–1.70 (m, 2H), 2.70 (dd, J = 18.0, 9.6 Hz, 1H), 3.27–3.30 (m, 2H), 3.64–3.76 (m, 2H), 4.23 (q, J = 7.2 Hz, 2H), 6.42 (d, J = 9.0 Hz, 1H), 6.60 (d, J = 9.0 Hz, 1H), 7.16 (t, J = 9.0 Hz, 1H), 8.63 (s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ = 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)

Colorless solid: mp 144–146 °C; ¹H NMR (300 MHz, CDCl₃) δ = 0.94 (t, J = 7.5 Hz, 3H), 1.35–1.41 (m, 2H), 1.61–1.66 (m, 2H), 2.66 (dd, J = 18.1, 10.1 Hz, 1H), 3.33 (dd, J = 18.0, 3.0 Hz, 1H), 3.64–3.73 (m, 3H), 3.79 (s, 3H), 6.42 (d, J = 7.5 Hz, 1H), 6.64 (d, J = 7.5 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 8.49 (s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ = 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 C₁₅H₁₉NO₄: C, 64.97, H, 6.91, N, 5.05; found: C, 64.94, H, 6.87, N, 5.01%. (*Two carbons merged here.)

Ethyl 2-(1-hexadecyl-4-hydroxy-2-oxoindolin-3-yl)acetate (4m)

Colorless solid: mp 55–57 °C; ¹H NMR (300 MHz, CDCl₃) δ = 0.87 (t, J = 7.0 Hz, 3H), 1.25–1.31 (m, 31H), 2.60 (dd, J = 18.3, 10.7 Hz, 1H), 3.33 (dd, J = 18.3, 1.8 Hz, 1H), 3.66–3.72 (m, 3H), 4.28 (q, J = 7.1, Hz, 2H), 6.41 (d, J = 9.0 Hz, 1H), 6.60 (d, J = 9.0 Hz, 1H), 7.17 (t, J = 9.0 Hz, 1H), 8.63 (s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ = 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.)

Ethyl 2-(1-cyclopropyl-4-hydroxy-2-oxoindolin-3-yl)acetate (4n)

Colorless solid: mp 84–86 °C; ¹H NMR (300 MHz, CDCl₃) δ = 0.88–1.88 (m, 4H), 1.26 (t, J = 7.2 Hz, 3H), 2.62–2.74 (m, 2H), 3.27 (dd, J = 18.0, 2.4 Hz, 1H), 3.67 (dd, J = 9.6, 2.4 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H), 6.61 (d, J = 8.1 Hz, 1H), 6.69 (d, J = 7.5 Hz, 1H), 7.17 (t, J = 7.8 Hz, 1H), 8.54 (s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ = 6.0, 13.9, 22.4, 35.7, 40.3, 62.1, 101.6, 111.5, 111.6, 129.6, 145.8, 153.3, 175.5, 177.0; anal. calcd for C₁₅H₁₇NO₄: C, 65.44, H, 6.22, N, 5.09; found: C, 65.39, H, 6.19, N, 5.04%.

Ethyl 2-(1-cyclohexyl-4-hydroxy-2-oxoindolin-3-yl)acetate (4o)

Colorless solid: mp 91–93 °C; ¹H NMR (300 MHz, CDCl₃) δ = 1.01–1.26 (m, 8H), 1.65–1.80 (m, 6H), 2.77–2.83 (m, 1H), 3.33 (dd, J = 17.1, 2.7 Hz, 1H), 3.5 (d, J = 7.2 Hz, 2H), 3.82 (dd, J = 8.7, 3.3 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H), 6.49 (d, J = 8.1 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H), 7.20 (t, J = 8.1 Hz, 1H), 8.68 (s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ = 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-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) δ = 1.31 (t, J = 7.2 Hz, 3H), 2.54 (dd, J = 18.3, 10.5 Hz, 1H), 2.92 (t, J = 7.5 Hz, 2H), 3.22 (dd, J = 18.3, 1.8 Hz, 1H), 3.67 (dd, J = 10.5, 1.8 Hz, 1H), 3.80–4.00 (m, 2H), 4.22–4.33 (m, 2H), 6.41 (d, J = 7.8 Hz, 1H), 6.62 (d, J = 7.8 Hz, 1H), 7.09–7.35 (m, 5H), 8.68 (s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ = 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-(4-hydroxy-2-oxo-1-(thiophen-2-ylmethyl)indolin-3-yl)acetate (4q)

Colorless solid: mp 154–156 °C; ¹H NMR (300 MHz, CDCl₃) δ = 1.29 (t, J = 7.2 Hz, 3H), 2.64 (dd, J = 18.3, 10.5 Hz, 1H), 3.35 (dd, J = 18.0, 1.8 Hz, 1H), 3.76 (dd, J = 10.5, 1.8 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 5.03 (d, J = 15.9 Hz, 1H), 5.09 (d, J = 15.9 Hz, 1H), 6.49 (d, J = 7.8 Hz, 1H), 6.60 (d, J = 7.8 Hz, 1H), 6.69–6.94 (m, 1H), 7.04 (d, J = 2.7 Hz, 1H), 7.16–7.20 (m, 2H), 8.59 (s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ = 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)

Colorless solid: mp 165–167 °C; ¹H NMR (300 MHz, CDCl₃) δ = 1.37 (t, J = 7.2 Hz, 3H), 2.89 (dd, J = 18.0, 9.9 Hz, 1H), 3.41 (dd, J = 18.0, 2.4 Hz, 1H), 3.91 (dd, J = 9.9, 2.4 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 6.34 (d, J = 9.0 Hz, 1H), 6.62 (d, J = 9.0 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 7.38–7.44 (m, 5H), 8.54 (s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ = 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%.

Ethyl 2-(1-(4-fluorophenyl)-4-hydroxy-2-oxoindolin-3-yl)acetate (4s)

Colorless solid: mp 168–170 °C; ¹H NMR (300 MHz, CDCl₃) δ = 1.31 (t, J = 7.5 Hz, 3H), 2.82 (dd, J = 18.0, 9.6 Hz, 1H), 3.40 (dd, J = 18.0, 1.2 Hz, 1H), 3.90 (dd, J = 9.6, 1.2 Hz, 1H), 4.28 (q, J = 7.5 Hz, 2H), 6.28 (d, J = 8.4 Hz, 1H), 6.63 (d, J = 8.4 Hz, 1H), 7.10 (t, J = 8.4 Hz, 1H), 7.17–7.26 (m, 2H), 7.35–7.39 (m, 2H), 8.47 (s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ = 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-(3,5-dichlorophenyl)-4-hydroxy-2-oxoindolin-3-yl)acetate (4t)

Colorless solid: mp 175–177 °C; ¹H NMR (300 MHz, CDCl₃) δ = 1.23 (t, J = 7.5 Hz, 3H), 2.65 (dd, J = 18.0, 9.6 Hz, 1H), 3.32 (dd, J = 18.0, 2.4 Hz, 1H), 3.82 (dd, J = 9.6, 2.4 Hz, 1H), 4.20 (q, J = 7.5 Hz, 2H), 6.30 (d, J = 8.1 Hz, 1H), 6.57 (d, J = 8.1 Hz, 1H), 7.06 (t, J = 8.1 Hz, 1H), 7.28 (d, J = 1.8 Hz, 2H), 7.33 (d, J = 1.8 Hz, 1H), 8.33 (s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ = 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-benzyl-4-hydroxy-2-oxo-6-phenylindolin-3-yl)acetate (4u)

Colorless solid: mp 154–156 °C; ¹H NMR (300 MHz, CDCl₃) δ = 1.31 (t, J = 7.2 Hz, 3H), 2.71 (dd, J = 18.3, 10.5 Hz, 1H), 3.42 (dd, J = 18.3, 2.1 Hz, 1H), 3.85 (dd, J = 10.5, 2.1 Hz, 1H), 4.40 (q, J = 7.2 Hz, 2H), 4.88 (d, J = 15.6 Hz, 1H), 4.94 (d, J = 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) δ = 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 C₂₅H₂₃NO₄: C, 74.79, H, 5.77, N, 3.49; found: C, 74.73, H, 5.74, N, 3.45%.

Acknowledgements

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.

Notes and references

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Footnote

† 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

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