Alcohols as Substrates and Solvents for the Construction of 3-Alkoxylated-2-Oxindoles by Direct Alkoxylation of 3-Halooxindoles.

Described herein is an environmentally benign method for the synthesis of multisubstituted 3-alkoxylated-2-oxindoles 3 via direct alkoxylation of 3-halooxindoles 1. A wide variety of such multisubstituted 3-alkoxylated-2-oxindole scaffolds were smoothly obtained in good yields (up to 94%) by heating in an oil bath at 35 °C for 24 h. A particularly valuable feature of this method was the development of environment-friendly chemistry using alcohols 2 as both the substrates and solvents in the presence of a catalytic amount of base.

1. Introduction

3,3′-Disubstituted oxindoles are embedded in the indole alkaloids and various clinical pharmaceuticals [1,2,3,4,5,6,7,8,9,10,11]. Significant efforts have been devoted by many research groups to the synthesis of 3,3′-disubstituted oxindoles. Among them, the most important and efficient approaches involve the use of electrophilic isatins/isatinimines and nucleophilic 3-monosubstituted oxindoles for the synthesis of 3,3′-disubstituted oxindoles (Figure 1) [2,3,4,5,12,13]. Despite these advances, however, the use of indol-2-ones (generated in situ from 3-halooxindoles) as electrophiles has been limited [14,15,16,17,18,19,20,21,22,23,24,25,26,27,28].

Figure 1

Strategies for the synthesis of 3,3′-disubstituted oxindoles.

On the other hand, as 3,3′-disubstituted oxindole scaffolds, 3-alkoxylated-2-oxindoles possessing interesting structural properties were found in a number of biologically active synthetic and natural products (Figure 2) [29,30,31,32,33,34,35,36,37] Therefore, methods for alkoxylation of the oxindole nucleus are of value in medicinal chemistry and natural product synthesis. Over the past several years, although many synthetic methods have been developed for the synthesis of 3-hydroxy-2-oxindoles, existing catalytic syntheses of substituted 3-alkoxylated-2-oxindoles from simple substrates and catalysts are very few [38,39,40,41]. Worthy of note is that in 1964, Hinman and Bauman, et al. reported only a single example that described the synthesis of 3-methoxy-3-methyloxindole from 3-bromo-3-methyloxindole by treatment with 1 equivalent of NaHCO3 in MeOH/water (10/1). Prompted by this precedent, we have recently expanded the scope of this type of electrophile to synthesize a wide variety of 3-sulfonylated 3,3-disubstituted oxindole derivatives (Scheme 1) [21]. In this context, considering the high solubility of HCl in the alcoholic solvent, we supposed that a stoichiometric amount of base may be not necessary in alkoxylation of 3-halooxindoles in alcoholic solvents. We present herein the use of alcohols as both the substrates and solvents for the synthesis of 3-alkoxylated-2-oxindoles by direct alkoxylation of 3-halooxindoles using a catalytic amount of base.

Figure 2

Representatives of the 3-alkoxylated-2-oxindolederivatives.

Scheme 1

Construction of 3,3′-disubstituted oxindoles using 3-halooxindoles as electrophiles.

2. Results and Discussion

In our initial endeavor, the 3-chloroxindole 1a was prepared via a three-step approach (Knoevenagel condensation, reduction and chlorination) using benzaldehyde and 2-oxindole as the starting materials [17]. We then investigated 3-chloroxindole 1a as a starting substrate to substantiate the feasibility of the strategy under various reaction conditions, as shown in Table 1. The tertiary amine catalyst DABCO (entry 1, Table 1) failed to afford the desired product 3aa, providing an intractable product mixture from which no product could be identified by HRMS analysis. We then screened other different tertiary amines and inorganic bases (e.g., Et3N, DBU, Na2CO3, K2CO3 and NaHCO3) as catalysts in the reaction, and found that they can catalyse the reaction successfully leading to the desired product 3aa in moderate to good yields (entries 2–6, Table 1). In the absence of catalyst, the reaction did not well occur under otherwise identical conditions, and only starting materials remained (Table 1, entry 7). Further solvent screening demonstrated that the reaction could deliver the product 3aa preferentiallys (94% yield) with MeOH as the solvent (Table 1, entry 6). When the reaction was performed in EtOAc and THF, only 10% and 13% yields of 3aa were obtained, respectively (Table 1, entries 10 and 11). Considering the environmental friendliness of this chemistry and good solubility of the substrates in alcohols, we chose to use alcohols as both the substrates and solvents in the alkoxylation reactions of 3-halooxindoles.Shortening the reaction time led to the desired product 3aa in the relatively lower yields, along with some remaining starting materials (Table 1, entries 13 and 14). Further screening of the amount of the base demonstrated that the reaction could deliver the product 3aa in 94% yield when a catalytic amount (20 mol %) of Na2CO3 was employed (Table 1, entry 6 and entries 15–17). Thus, the optimal reaction conditions we established were: 3-chloroxindole 1a (0.40 mmol), 20 mol % of Na2CO3 (0.08 mmol) in 4.0 mL of MeOH 2a in an oil bath at 35 °C for 24 h.

Table 1

Optimization of reaction conditions .

Entry a	Solvent	Catalyst (20 mol %)	Time (h)	Yield b (%)
1 c	MeOH	DABCO	24	trace
2 c	MeOH	DBU	24	54
3 c	MeOH	Et3N	24	73
4 c	MeOH	K2CO3	24	87
5 c	MeOH	NaHCO3	24	76
6 c	MeOH	Na2CO3	24	94
7	MeOH	None	24	<10
8	toluene	Na2CO3	24	61
9	DCM	Na2CO3	24	59
10	EtOAc	Na2CO3	24	10
11	THF	Na2CO3	24	13
12 c	CH3CN	Na2CO3	24	51
13 c	MeOH	Na2CO3	4	63
14 c	MeOH	Na2CO3	6	79
15 c,d	MeOH	Na2CO3	15	96
16 c,e	MeOH	Na2CO3	48	78
17 c,f	MeOH	Na2CO3	72	61

Unless otherwise noted, reactions were carried out with 0.4 mmol of 1a, 2.0 mmol of 2a, 20 mol % of catalyst in the 4.0 mL of solvent for the specified time. Isolated yield after flash chromatography. The reaction was carried out using MeOH as substrate and solvent. The reaction was carried out using 100 mol % of base Na2CO3. The reaction was carried out using 10 mol % of base Na2CO3. The reaction was carried out using 5 mol % of base Na2CO3.

With the best reaction conditions in hands, we next turned our interest to the reaction scope, and the results are summarized in Table 2. MeOH (2a) was first used as a standard substrate to probe the reactivity of different 3-chloroxindoles 1 in this reaction. Significant structural variation in the oxindole system could be accommodated in this reaction. For example, electron-rich (Table 2, 3ba and 3ca) and electron-poor (Table 2, 3da–3ja) substituents incorporated on the phenyl group or the benzo moiety of the oxindole core were perfectly tolerated under the conditions.

Table 2

Synthesis of 3-alkoxylated-2-oxindoles 3 .

Unless otherwise noted, reactions were carried out with 0.4 mmol of 1 and 20 mol % of catalyst Na2CO3 in the 4.0 mL of alcohol 2 in oil bath at 35 °C for 24 h. Isolated yield after flash chromatography. This reaction was carried out in oil bath at 45 °C for 24 h.

The generality of the reaction was further demonstrated by using a variety of alcohols 2, clearly indicating that all of the reactions proceeded smoothly under the optimal conditions, producing the desired products 3 in moderate to good yields (Table 2, 3ab–3ah), regardless of the electronic nature of the chloroxindoles 1. It is noteworthy that the bulky isopropyl alcohol (2d) led to deleterious effects on the reactivity, affording the desired products in moderate yields (Table 2, 3dd–3gd). In addition, our attempts to identify the alkoxylation reactions of 3-aryl or 3-arylmethyl substituted N-Boc-oxindoles 1 using MeOH as substrate and solvent were in vain (Scheme 2). Furthermore, using 3-aryl substituted N-Me-oxindole 1m as substrate it proved difficult to obtain the pure compound 1ma, and we always obtained an intractable product mixture (Scheme 2).

Scheme 2

Contrast experiments with different types of substrate oxindoles 1 using MeOH as substrate and solvent.

In order to further explore the scope of the substrates, we also chose bromooxindole 1′a as a test substrate for this transformation. To our delight, the reaction proceeded well to give the desired product 3aa in good yield (88%) under the standard reaction conditions (Scheme 3).

Scheme 3

Bromooxindole 1′a as a test substrate for this transformation.

The significance and the high efficiency of the current protocol were demonstrated by a gram-scale synthesis of 3aa. The alkoxylation of 3-chloroxindole 1a proceeded cleanly on a 4.0 mmol scale (1.03 g of 1a) in oil bath at 35 °C for 48 h. As outlined in Scheme 4, the corresponding adduct 3aa was obtained smoothly in 92% yield, which was similar to those observed in a previous investigation (entry 1 of Table 2).

Scheme 4

The alkoxylation of chloroxindole 1a on a gram scale.

3. Experimental Section

3.1. General

The 1H and 13C NMR spectra were recorded on Bruker Avance DMX 400 MHz or 500 M NMR spectrometers (Bruker, Billerica, MA, USA) in CDCl3 using TMS as internal standard. Chemical shifts were reported as δ values (ppm). High-resolution mass spectra (HRMS-ESI) were obtained on a Micro™ Q-TOF Mass Spectrometer (Waters, Milford, MA, USA). Melting points were uncorrected and recorded on an Electothermal 9100 digital melting point apparatus (Electothermal, Stone, UK). Reagents were purchased from commercial sources and were used as received unless mentioned otherwise. Reactions were monitored by thin layer chromatography using silica gel GF254 plates. Column chromatography was performed on silica gel (300–400 mesh).

3.2. General Experimental Procedures for Synthesis of 3-Alkoxylated-2-Oxindoles

In an ordinary vial equipped with a magnetic stirring bar was added 3-chloroxindole 1 (0.4 mmol), 20 mol % of catalyst Na2CO3 (8.5 mg, 0.08 mmol) and 4.0 mL of alcohol 2. The reaction mixture was stirred in oil bath at 35 °C for 24 h. After completion of the reaction, as indicated by TLC, the removal of solvent and purification by flash column chromatography (hexane/EtOAc = 10:1~6:1) was carried out to furnish the corresponding products 3.

3.3. Characterization Data of Compounds

3-Benzyl-3-methoxyindolin-2-one (3aa). Light orange solid, m.p. 120.3–122.5 °C; yield 94%; 1H-NMR (CDCl3) δ: 3.08 (s, 3H), 3.11 (d, J = 12.8 Hz, 1H), 3.32 (d, J = 12.8 Hz, 1H), 6.80–6.83 (m, 1H), 6.93–6.96 (m, 2H), 7.02–7.11 (m, 5H), 7.22–7.26 (m, 1H), 9.13 (br s, 1H); 13C-NMR (CDCl3) δ: 43.6, 5.3.3, 84.2, 110.4, 122.6, 125.3, 126.3, 126.7, 127.6, 129.8, 130.6, 133.9, 141.2, 178.6; HRMS (ESI-TOF) m/z: Calcd. for C16H15NNaO2 [M + Na]+: 276.1000; Found: 276.1004. Spectra are in Supplementary Materials.

3-Methoxy-3-(4-methoxybenzyl)indolin-2-one (3ba). Light orange solid, m.p. 142.3–144.1 °C; yield 92%; 1H-NMR (CDCl3) δ: 3.03 (d, J = 12.8 Hz, 1H), 3.05 (s, 3H), 3.23 (d, J = 12.8 Hz, 1H), 3.66 (s, 3H), 6.57–6.61 (m, 2H), 6.79–6.85 (m, 3H), 7.01–7.03 (m, 2H), 7.20–7.25 (m, 1H), 8.98 (br s, 1H); 13C- NMR (CDCl3) δ: 42.9, 53.4, 55.1, 84.4, 110.5, 113.1, 122.7, 125.4, 126.0, 126.6, 129.9, 131.7, 141.4, 158.5, 178.8; HRMS (ESI-TOF) m/z: Calcd. for C17H17NNaO3 [M + Na]+: 306.1106; Found: 306.1107.

3-Methoxy-3-(4-methylbenzyl)indolin-2-one (3ca). Light orange solid, m.p. 130.7–134.2 °C; yield 91%; 1H-NMR (CDCl3) δ: 2.13 (s, 3H), 2.97–3.01 (m, 4H), 3.19 (d, J = 12.8 Hz, 1H), 6.72–6.81 (m, 5H), 6.94–6.99 (m, 2H), 7.13–7.18 (m, 1H), 8.94 (br s, 1H); 13C-NMR (CDCl3) δ: 21.0, 43.2, 53.2, 84.2, 110.4, 122.5, 125.3, 126.5, 128.3, 129.7, 130.4, 130.7, 136.2, 141.2, 178.7; HRMS (ESI-TOF) m/z: Calcd. for C17H17NNaO2 [M + Na]+: 290.1157; Found: 290.1154.

3-(4-Bromobenzyl)-3-methoxyindolin-2-one (3da). Light orange solid, m.p. 120.3–122.4 °C; yield 91%; 1H-NMR (CDCl3) δ: 3.05 (d, J = 13.2 Hz, 1H), 3.08 (s, 3H), 3.26 (d, J = 13.2 Hz, 1H), 6.81–6.84 (m, 3H), 7.03–7.06 (m, 2H), 7.20–7.26 (m, 3H), 8.82 (br s, 1H); 13C-NMR (CDCl3) δ: 43.0, 53.3, 83.8, 110.5, 121.0, 122.7, 125.2, 126.0, 130.0, 130.8, 132.3, 132.9, 141.0, 178.2; HRMS (ESI-TOF) m/z: Calcd. for C16H14BrNNaO2 [M + Na]+: 354.0106; Found: 354.0106.

3-(2-Bromobenzyl)-3-methoxyindolin-2-one (3ea). Light orange solid, m.p. 184.5–187.1 °C; yield 91%; 1H- NMR (CDCl3) δ: 3.09 (s, 3H), 3.36 (d, J = 11.2 Hz, 1H), 3.48 (d, J = 11.2 Hz, 1H), 6.68 (d, J = 6.0 Hz, 1H), 6.89–6.95 (m, 2H), 7.05–7.09 (m, 1H), 7.20–7.27 (m, 2H), 7.40–7.42 (m, 1H), 7.48–7.50 (m, 1H), 9.32 (br s, 1H); 13C-NMR (CDCl3) δ: 42.0, 53.2, 83.2, 110.5, 122.6, 125.6, 126.8, 128.5, 129.8, 132.4, 132.8, 134.4, 140.9, 179.0; HRMS (ESI-TOF) m/z: Calcd. for C16H14BrNNaO2 [M + Na]+: 354.0106; Found: 354.0105.

3-(2-Chlorobenzyl)-3-methoxyindolin-2-one (3fa). Light orange solid, m.p. 138.2–139.8 °C; yield 93%; 1H-NMR (CDCl3) δ: 3.09 (s, 3H), 3.35 (d, J = 13.5 Hz, 1H), 3.47 (d, J = 13.5 Hz, 1H), 6.77 (d, J = 7.2 Hz, 1H), 6.89–6.97 (m, 2H), 7.13–7.26 (m, 4H), 7.42–7.44 (m, 1H), 9.40 (br s, 1H); 13C-NMR (CDCl3) δ: 39.4, 53.2, 83.3, 110.4, 122.6, 125.5, 125.9, 126.2, 128.3, 129.1, 129.8, 132.5, 132.7, 135.3, 140.5, 141.0, 179.0; HRMS (ESI-TOF) m/z: Calcd. for C16H14ClNNaO2 [M + Na]+: 310.0611; Found: 310.0614.

3-(4-Chlorobenzyl)-3-methoxyindolin-2-one (3ga). Light orange solid, m.p. 125.2–127.3 °C; yield 91%; 1H-NMR (CDCl3) δ: 3.05 (d, J = 12.8 Hz, 1H), 3.08 (s, 3H), 3.27 (d, J = 12.8 Hz, 1H), 6.83 (d, J = 7.6 Hz, 1H), 6.88 (d, J = 8.4 Hz, 2H), 7.02–7.08 (m, 4H), 7.24–7.28 (m, 1H), 8.93 (br s, 1H); 13C-NMR (CDCl3) δ: 42.9, 53.3, 83.9, 110.5, 122.8, 125.3, 126.1, 127.8, 130.0, 131.9, 132.4, 132.8, 141.1, 178.3; HRMS (ESI-TOF) m/z: Calcd. for C16H14ClNNaO2 [M + Na]+: 310.0611; Found: 310.0610.

3-(3-Fluorobenzyl)-3-methoxyindolin-2-one (3ha). Light orange solid, m.p. 135.7–138.2 °C; yield 90%; 1H-NMR (CDCl3, 500 MHz) δ: 3.07 (d, J = 13.5 Hz, 1H), 3.09 (s, 3H), 3.31 (d, J = 13.5 Hz, 1H), 6.70–6.75 (m, 2H), 6.83–6.85 (m, 2H), 6.98–7.06 (m, 3H), 7.24–7.27 (m, 1H), 9.12 (br s, 1H); 13C-NMR (CDCl3, 125 MHz) δ: 43.2, 53.3, 83.8, 110.5, 110.6, 113.7 (d, J = 20.8 Hz), 117.4 (d, J = 21.3 Hz), 122.7, 125.3, 126.0, 126.3, 126.4, 128.9, 129.0, 130.0, 136.5, 136.6, 141.1, 141.2, 162.1 (d, J = 245.8 Hz), 178.5; HRMS (ESI-TOF) m/z: Calcd. for C16H14FNNaO2 [M + Na]+: 294.0906; Found: 294.0908.

3-Benzyl-5-chloro-3-methoxyindolin-2-one (3ia). Light orange solid, m.p. 130.4–133.3 °C; yield 90%; 1H-NMR (CDCl3) δ: 3.00 (s, 3H), 3.03 (d, J = 12.8 Hz, 1H), 3.21 (d, J = 12.8 Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), 6.87–6.92 (m, 3H), 7.01–7.08 (m, 3H), 7.13–7.19 (m, 1H), 8.83 (br s, 1H); 13C-NMR (CDCl3) δ: 43.6, 53.5, 84.3, 111.4, 125.6, 127.0, 127.8, 128.2, 128.3, 129.8, 130.5, 133.4, 139.6, 178.2; HRMS (ESI-TOF) m/z: Calcd. for C16H14ClNNaO2 [M + Na]+: 310.0611; Found: 310.0611.

3-Benzyl-6-chloro-3-methoxyindolin-2-one (3ja). Light orange solid, m.p. 198.4–201.9 °C; yield 91%; 1H-NMR (DMSO-d6) δ: 2.91 (s, 3H), 3.00 (d, J = 12.8 Hz, 1H), 3.20 (d, J = 12.8 Hz, 1H), 6.66 (s, 1H), 6.67–6.90 (m, 2H), 7.03 (d, J = 2.0 Hz, 1H), 7.09–7.13 (m, 4H), 10.5 (br s, 1H); 13C-NMR (DMSO-d6) δ: 42.3, 52.3, 83.1, 109.9, 121.5, 125.0, 126.6, 126.8, 127.7, 130.3, 134.0, 134.1, 143.9, 176.2; HRMS (ESI-TOF) m/z: Calcd. for C16H14ClNNaO2 [M + Na]+: 310.0611; Found: 310.0611.

3-Benzyl-3-ethoxyindolin-2-one (3ab). Light orange solid, m.p. 112.0–113.8 °C; yield 89%; 1H-NMR (CDCl3) δ: 1.14–1.18 (m, 3H), 3.10–3.15 (m, 2H), 3.22–3.26 (m, 1H), 3.31 (d, J = 12.8 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.92–6.93 (m, 2H), 6.94–7.10 (m, 5H), 7.20–7.26 (m, 1H), 9.01 (br s, 1H); 13C- NMR (CDCl3) δ: 15.3, 43.8, 61.2, 83.6, 110.3, 122.5, 125.1, 126.7, 127.1, 127.6, 129.6, 130.5, 134.0, 141.0, 179.0; HRMS (ESI-TOF) m/z: Calcd. for C17H17NNaO2 [M + Na]+: 290.1157; Found: 290.1154.

3-Ethoxy-3-(4-methoxybenzyl)indolin-2-one (3bb). Light orange solid, m.p. 151.2–153.1°C; yield 92%; 1H-NMR (CDCl3) δ: 1.12–1.16 (m, 3H), 3.02–3.12 (m, 2H), 3.19–3.26 (m, 2H), 3.65 (s, 3H), 6.56–6.58 (m, 2H), 6.76–6.84 (m, 3H), 7.01–7.06 (m, 2H), 7.18–7.25 (m, 1H), 8.93 (br s, 1H); 13C-NMR (CDCl3) δ: 15.5, 43.1, 55.1, 61.3, 83.8, 110.4, 113.1, 122.6, 125.2, 126.1, 127.5, 129.7, 131.6, 141.2, 158.4, 179.1; HRMS (ESI-TOF) m/z: Calcd. for C18H19NNaO3 [M + Na]+: 320.1263; Found: 320.1263.

3-Ethoxy-3-(4-methylbenzyl)indolin-2-one (3cb). Light orange solid, m.p. 138.8–141.9 °C; yield 91%; 1H-NMR (CDCl3) δ: 1.07–1.10 (m, 3H), 2.13 (s, 3H), 2.99–3.07 (m, 2H), 3.14–3.22 (m, 2H), 6.69–6.79 (m, 5H), 6.94–7.01 (m, 2H), 7.12–7.18 (m, 1H), 8.82 (br s, 1H); 13C-NMR (CDCl3) δ: 15.3, 21.0, 43.4, 61.1, 83.6, 110.2, 122.5, 125.1, 127.3, 128.3, 129.6, 130.4, 130.8, 136.1, 141.0, 178.9; HRMS (ESI-TOF) m/z: Calcd. for C18H19NNaO2 [M + Na]+: 304.1313; Found: 304.1315.

3-(4-Bromobenzyl)-3-ethoxyindolin-2-one (3db). Light orange solid, m.p. 142.1–144.6 °C; yield 90%; 1H-NMR (CDCl3) δ: 1.15–1.18 (m, 3H), 3.04 (d, J = 13.2 Hz, 1H), 3.11–3.15 (m, 1H), 3.22–3.28 (m, 2H), 6.78–6.84 (m, 3H), 7.03–7.05 (m, 2H), 7.18–7.27 (m, 3H), 8.82 (br s, 1H); 13C-NMR (CDCl3) δ: 15.3, 43.2, 61.3, 83.2, 110.4, 120.9, 122.7, 125.1, 126.8, 129.8, 130.7, 132.3, 133.0, 140.8, 178.6; HRMS (ESI-TOF) m/z: Calcd. for C17H16BrNNaO2 [M + Na]+: 368.0262; Found: 368.0265.

3-(2-Bromobenzyl)-3-ethoxyindolin-2-one (3eb). Light orange solid, m.p. 185.1–186.2 °C; yield 88%; 1H-NMR (CDCl3) δ: 1.14–1.18 (m, 3H), 3.07–3.11 (m, 1H), 3.23–3.28 (m, 1H), 3.32 (d, J = 13.6 Hz, 1H), 3.47 (d, J = 13.6 Hz, 1H), 6.65 (d, J = 7.2 Hz, 1H), 6.86–6.92 (m, 2H), 7.05–7.07 (m, 1H), 7.18–7.25 (m, 2H), 7.38–7.40 (m, 1H), 7.49–7.52 (m, 1H); 13C-NMR (CDCl3) δ: 15.4, 42.2, 61.2, 82.7, 110.5, 122.6, 125.6, 126.5, 126.7, 126.9, 128.6, 129.7, 132.4, 132.9, 134.7, 140.9, 179.4; HRMS (ESI-TOF) m/z: Calcd. for C17H16BrNNaO2 [M + Na]+: 368.0262; Found: 368.0262.

3-(2-Chlorobenzyl)-3-ethoxyindolin-2-one (3fb). Light orange solid, m.p. 207.1–209.2 °C; yield 90%; 1H-NMR (DMSO-d6) δ: 1.01–1.05 (m, 3H), 2.91–2.95 (m, 1H), 3.05–3.08 (m, 1H), 3.14 (d, J = 12.8 Hz, 1H), 3.32 (d, J = 12.8 Hz, 1H), 6.72 (d, J = 7.8 Hz, 1H), 6.80–6.87 (m, 2H), 7.14–7.28 (m, 5H), 10.5 (br s, 1H); 13C-NMR (DMSO-d6) δ: 15.3, 40.1, 60.0, 82.0, 109.8, 121.5, 124.8, 126.5, 128.6, 129.0, 129.7, 132.2, 132.5, 142.0, 176.7; HRMS (ESI-TOF) m/z: Calcd. for C17H16ClNNaO2 [M + Na]+: 324.0767; Found: 324.0769.

3-(4-Chlorobenzyl)-3-ethoxyindolin-2-one (3gb). Light orange solid, m.p. 154.1–156.2 °C; yield 91%; 1H-NMR (CDCl3) δ: 1.14–1.18 (m, 3H), 3.06 (d, J = 12.8 Hz, 1H), 3.11–3.15 (m, 1H), 3.21–3.25 (m, 1H), 3.28 (d, J = 12.8 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 6.88 (d, J = 8.4 Hz, 2H), 7.02–7.05 (m, 4H), 7.22–7.27 (m, 1H), 9.04 (br s, 1H); 13C-NMR (CDCl3) δ: 15.3, 43.1, 61.3, 83.3, 110.4, 122.7, 125.1, 126.9, 127.7, 129.8, 131.9, 132.5, 132.7, 140.9, 178.7; HRMS (ESI-TOF) m/z: Calcd. for C17H16ClNNaO2 [M + Na]+: 324.0767; Found: 324.0766.

3-Ethoxy-3-(3-fluorobenzyl)indolin-2-one (3hb). Light orange solid, m.p. 118.3–119.8 °C; yield 89%; 1H-NMR (CDCl3, 500 MHz) δ: 1.16–1.19 (m, 3H), 3.08 (d, J = 13.0 Hz, 1H), 3.12–3.15 (m, 1H), 3.24–3.27 (m, 1H), 3.31 (d, J = 13.0 Hz, 1H), 6.69–6.75 (m, 2H), 6.80–6.83 (m, 2H), 7.00–7.05 (m, 3H), 7.22–7.26 (m, 1H), 9.10 (br s, 1H); 13C-NMR (CDCl3, 125 MHz) δ: 15.3, 43.4, 61.2, 83.2, 110.4, 110.5, 113.6, 113.7, 117.4 (d, J = 21.3 Hz), 122.7, 125.1, 126.3, 126.4, 126.8, 128.9 (d, J = 8.8 Hz), 129.8, 136.6 (d, J = 7.5 Hz), 140.9, 162.1 (d, J = 243.8 Hz), 178.7; HRMS (ESI-TOF) m/z: Calcd. for C17H16FNNaO2 [M + Na]+: 308.1063; Found: 308.1067.

3-Benzyl-3-propoxyindolin-2-one (3ac). Light orange solid, m.p. 146.1–148.3 °C; yield 86%; 1H-NMR (CDCl3) δ: 0.84–0.88 (m, 3H), 1.54–1.60 (m, 2H), 2.95–3.01 (m, 1H), 3.08 (d, J = 12.8 Hz, 1H), 3.15–3.20 (m, 1H), 3.33 (d, J = 12.8 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.96–7.13 (m, 7H), 7.19–7.26 (m, 1H), 8.90 (br s, 1H); 13C-NMR (CDCl3) δ: 10.5, 23.1, 43.8, 67.2, 83.4, 110.2, 122.5, 125.3, 126.7, 127.2, 127.6, 129.6, 130.7, 134.1, 140.9, 178.9; HRMS (ESI-TOF) m/z: Calcd. for C18H19NNaO2 [M + Na]+: 304.1313; Found: 304.1315.

3-(4-Methoxybenzyl)-3-propoxyindolin-2-one (3bc). Light orange solid, m.p. 145.5–146.9 °C; yield 82%; 1H-NMR (CDCl3) δ: 0.81–0.85 (m, 3H), 1.52–1.56 (m, 2H), 2.94–3.02 (m, 2H), 3.12–3.15 (m, 1H), 3.25 (d, J = 12.8 Hz, 1H), 3.66 (s, 3H), 6.57–6.60 (m, 2H), 6.78 (d, J = 7.6 Hz, 1H), 6.84–6.87 (m, 2H), 6.97–7.00 (m, 2H), 7.19–7.25 (m, 1H), 8.99 (br s, 1H); 13C-NMR (CDCl3) δ: 10.7, 23.2, 43.0, 55.1, 67.3, 83.6, 110.4, 113.1, 122.6, 125.4, 126.2, 127.5, 129.7, 131.7, 141.2, 158.4, 179.3; HRMS (ESI-TOF) m/z: Calcd. for C19H21NNaO3 [M + Na]+: 334.1419; Found: 334.1415.

3-(4-Methylbenzyl)-3-propoxyindolin-2-one (3cc). Light orange solid, m.p. 75.1–76.8 °C; yield 83%; 1H-NMR (CDCl3) δ: 0.76–0.80 (m, 3H), 1.46–1.53 (m, 2H), 2.15 (s, 3H), 2.89–2.93 (m, 1H), 2.98 (d, J = 12.8 Hz, 1H), 3.08–3.11 (m, 1H), 3.21 (d, J = 12.8 Hz, 1H), 6.68 (d, J = 7.6 Hz, 1H), 6.76–6.82 (m, 4H), 6.92–6.97 (m, 2H), 7.12–7.19 (m, 1H), 8.41 (br s, 1H); 13C-NMR (CDCl3) δ: 10.5, 21.0, 23.1, 43.4, 67.2, 83.3, 110.1, 122.4, 125.3, 127.4, 128.3, 129.5, 130.5, 130.9, 136.1, 140.9, 178.7; HRMS (ESI-TOF) m/z: Calcd. for C19H21NNaO2 [M + Na]+: 318.1470; Found: 318.1472.

3-(4-Bromobenzyl)-3-propoxyindolin-2-one (3dc). Light orange solid, m.p. 143.3–144.8 °C; yield 82%; 1H-NMR (CDCl3) δ: 0.84–0.87 (m, 3H), 1.53–1.59 (m, 2H), 2.95–3.02 (m, 2H), 3.14–3.19 (m, 1H), 3.27 (d, J = 12.8 Hz, 1H), 6.81–6.86 (m, 3H), 6.94–6.96 (m, 1H), 7.01–7.04 (m, 1H), 7.20–7.24 (m, 3H), 8.88 (br s, 1H); 13C-NMR (CDCl3) δ: 10.5, 23.0, 43.1, 67.2, 83.0, 110.4, 120.9, 122.6, 125.2, 126.9, 129.8, 130.7, 132.4, 133.2, 140.8, 178.7; HRMS (ESI-TOF) m/z: Calcd. for C18H18BrNNaO2 [M + Na]+: 382.0419; Found: 382.0417.

3-(2-Bromobenzyl)-3-propoxyindolin-2-one (3ec). Light orange solid, m.p. 153.1–154.9 °C; yield 81%; 1H-NMR (CDCl3) δ: 0.85–0.88 (m, 3H), 1.54–1.62 (m, 2H), 2.95 (d, J = 6.0 Hz, 1H), 3.21 (d, J = 6.4 Hz, 1H), 3.32 (d, J = 11.2 Hz, 1H), 3.48 (d, J = 11.2 Hz, 1H), 6.59 (d, J = 6.0 Hz, 1H), 6.89–6.92 (m, 2H), 7.07–7.09 (m, 1H), 7.21–7.26 (m, 2H), 7.41 (d, J = 6.4 Hz, 1H), 7.56 (d, J = 6.0 Hz, 1H), 9.22 (br s, 1H); 13C-NMR (CDCl3) δ: 10.6, 23.1, 42.1, 67.0, 82.3, 110.3, 122.5, 125.5, 126.5, 126.6, 126.7, 128.4, 129.6, 132.3, 133.0, 134.7, 140.7, 179.2; HRMS (ESI-TOF) m/z: Calcd. for C18H18BrNNaO2 [M + Na]+: 382.0419; Found: 382.0421.

3-(2-Chlorobenzyl)-3-propoxyindolin-2-one (3fc). Light orange solid, m.p. 160.3–161.9 °C; yield 80%; 1H-NMR (CDCl3) δ: 0.85–0.88 (m, 3H), 1.56–1.62 (m, 2H), 2.94–2.98 (m, 1H), 3.18–3.22 (m, 1H), 3.33 (d, J = 13.6 Hz, 1H), 3.46 (d, J = 13.6 Hz, 1H), 6.69 (d, J = 7.2 Hz, 1H), 6.86–6.94 (m, 2H), 7.13–7.26 (m, 4H), 7.51 (d, J = 4.0 Hz, 1H), 9.15 (br s, 1H); 13C-NMR (CDCl3) δ: 10.6, 23.1, 39.6, 67.1, 82.4, 110.2, 122.5, 125.4, 126.0, 126.7, 128.2, 129.0, 129.6, 132.8, 135.3, 140.8, 179.2; HRMS (ESI-TOF) m/z: Calcd. for C18H18ClNNaO2 [M + Na]+: 338.0924; Found: 338.0924.

3-(4-Chlorobenzyl)-3-propoxyindolin-2-one (3gc). Light orange solid, m.p. 158.1–161.2 °C; yield 84%; 1H-NMR (CDCl3) δ: 0.84–0.87 (m, 3H), 1.53–1.60 (m, 2H), 2.96–3.00 (m, 1H), 3.03 (d, J = 12.8 Hz, 1H), 3.14–3.18 (m, 1H), 3.29 (d, J = 12.8 Hz, 1H), 6.81 (d, J = 7.6 Hz, 1H), 6.89–6.97 (m, 3H), 7.01–7.07 (m, 3H), 7.22–7.26 (m, 1H), 8.90 (br s, 1H); 13C-NMR (CDCl3) δ: 10.5, 23.0, 43.1, 67.3, 83.0, 110.3, 122.6, 125.2, 126.9, 127.7, 129.8, 132.0, 132.7, 140.8, 178.7; HRMS (ESI-TOF) m/z: Calcd. for C18H18ClNNaO2 [M + Na]+: 338.0924; Found: 338.0927.

3-(4-Bromobenzyl)-3-isopropoxyindolin-2-one (3dd). Light orange solid, m.p. 148.1–150.1 °C; yield 77%; 1H-NMR (CDCl3, 500 MHz) δ: 1.01 (d, J = 6.5 Hz, 3H), 1.10 (d, J = 6.0 Hz, 3H), 2.97 (d, J = 13.0 Hz, 1H), 3.23 (d, J = 13.0 Hz, 1H), 6.78–6.83 (m, 3H), 6.98–7.02 (m, 2H), 7.19–7.27 (m, 3H), 8.57 (br s, 1H); 13C-NMR (CDCl3, 125 MHz) δ: 23.1, 24.1, 43.8, 69.5, 82.7, 110.3, 120.9, 122.4, 125.6, 127.3, 129.8, 130.6, 132.4, 133.2, 140.6, 179.3; HRMS (ESI-TOF) m/z: Calcd. for C18H18BrNNaO2 [M + Na]+: 382.0419; Found: 382.0419.

3-(2-Bromobenzyl)-3-isopropoxyindolin-2-one (3ed). Light orange solid, m.p. 182.0–183.3 °C; yield 74%; 1H-NMR (CDCl3) δ: 0.99 (d, J = 6.0 Hz, 3H), 1.10 (d, J = 6.0 Hz, 3H), 3.24 (d, J = 14.0 Hz, 1H), 3.40–3.44 (m, 2H), 6.53 (d, J = 7.2 Hz, 1H), 6.84–6.89 (m, 2H), 7.03–7.08 (m, 1H), 7.18–7.25 (m, 2H), 7.37–7.41 (m, 1H), 7.55–7.57 (m, 1H), 9.16 (br s, 1H); 13C-NMR (CDCl3) δ: 23.2, 24.0, 42.7, 69.3, 82.1, 110.5, 122.4, 126.1, 126.7, 126.8, 126.9, 128.5, 129.7, 132.3, 133.1, 134.9, 140.6, 180.4; HRMS (ESI-TOF) m/z: Calcd. for C18H18BrNNaO2 [M + Na]+: 382.0419; Found: 382.0422.

3-(2-Chlorobenzyl)-3-isopropoxyindolin-2-one (3fd). Light orange solid, m.p. 197.2–198.7 °C; yield 70%; 1H-NMR (CDCl3) δ: 1.01 (d, J = 6.0 Hz, 3H), 1.12 (d, J = 6.0 Hz, 3H), 3.27 (d, J = 13.6 Hz, 1H), 3.40–3.45 (m, 2H), 6.66 (d, J = 7.2 Hz, 1H), 6.87–6.92 (m, 2H), 7.12–7.26 (m, 4H), 7.49–7.52 (m, 1H), 9.16 (br s, 1H); 13C-NMR (CDCl3) δ: 23.1, 24.0, 40.1, 69.2, 82.1, 110.3, 122.2, 125.9, 126.0, 127.0, 128.1, 128.9, 129.6, 132.9, 135.4, 140.5, 180.1; HRMS (ESI-TOF) m/z: Calcd. for C18H18ClNNaO2 [M + Na]+: 338.0924; Found: 338.0925.

3-(4-Chlorobenzyl)-3-isopropoxyindolin-2-one (3gd). Light orange solid, m.p. 198.2–201.3 °C; yield 72%; 1H-NMR (CDCl3) δ: 1.01 (d, J = 6.4 Hz, 3H), 1.08 (d, J = 6.0 Hz, 3H), 2.98 (d, J = 12.8 Hz, 1H), 3.25 (d, J = 12.8 Hz, 1H), 3.38–3.45 (m, 1H), 6.81 (d, J = 7.6 Hz, 1H), 6.86–6.89 (m, 2H), 6.97–7.04 (m, 4H), 7.22–7.27 (m, 1H), 8.97 (br s, 1H); 13C-NMR (CDCl3) δ: 23.1, 24.1, 43.7, 69.5, 82.8, 110.4, 122.4, 125.6, 127.3, 127.7, 129.8, 132.0, 132.6, 132.7, 140.6, 179.6; HRMS (ESI-TOF) m/z: Calcd. for C18H18ClNNaO2 [M + Na]+: 338.0924; Found: 338.0926.

3-Benzyl-3-butoxyindolin-2-one (3ae). Light orange solid, m.p. 125.5–126.7 °C; yield 80%; 1H-NMR (CDCl3) δ: 0.82–0.85 (m, 3H), 1.28–1.36 (m, 2H), 1.49–1.54 (m, 2H), 3.01–3.09 (m, 2H), 3.16–3.20 (m, 1H), 3.32 (d, J = 12.8 Hz, 1H), 6.78–6.81 (m, 1H), 6.95–7.11 (m, 7H), 7.19–7.26 (m, 1H), 9.01 (br s, 1H); 13C-NMR (CDCl3) δ: 13.8, 19.1, 31.8, 43.8, 65.3, 83.4, 110.3, 122.4, 125.2, 126.7, 127.2, 127.5, 129.6, 130.6, 134.1, 141.0, 179.1; HRMS (ESI-TOF) m/z: Calcd. for C19H21NNaO2 [M + Na]+: 318.1470; Found: 318.1473.

3-Butoxy-3-(4-methoxybenzyl)indolin-2-one (3be). Light orange solid, m.p. 139.5–141.7 °C; yield 83%; 1H-NMR (CDCl3) δ: 0.81–0.85 (m, 3H), 1.28–1.34 (m, 2H), 1.48–1.52 (m, 2H), 6.59 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 7.6 Hz, 1H), 6.87 (d, J = 8.8 Hz, 2H), 6.97–7.04 (m, 2H), 7.20–7.24 (m, 1H), 9.08 (br s, 1H); 13C-NMR (CDCl3) δ: 13.8, 19.1, 31.8, 42.9, 54.9, 65.2, 83.5, 110.3, 112.9, 122.4, 125.2, 126.1, 127.3, 129.5, 131.5, 141.0, 158.2, 179.1; HRMS (ESI-TOF) m/z: Calcd. for C20H23NNaO3 [M + Na]+: 348.1576; Found:348.1576.

3-Butoxy-3-(4-methylbenzyl)indolin-2-one (3ce). Light orange solid, m.p. 105.1–107.7 °C; yield 85%; 1H-NMR (CDCl3) δ: 0.74–0.78 (m, 3H), 1.22–1.25 (m, 2H), 1.43–1.48 (m, 2H), 2.13 (s, 3H), 2.93–2.98 (m, 2H), 3.10–3.13 (m, 1H), 3.20 (d, J = 13.2 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 6.75–6.81 (m, 4H), 6.90–6.94 (m, 2H), 7.12–7.18 (m, 1H), 8.87 (br s, 1H); 13C-NMR (CDCl3) δ: 13.8, 19.1, 21.0, 31.9, 43.3, 65.2, 83.4, 110.2, 122.4, 125.2, 127.3, 128.2, 129.5, 130.5, 130.9, 136.1, 141.0, 179.0; HRMS (ESI-TOF) m/z: Calcd. for C20H23NNaO2 [M + Na]+: 332.1626; Found:332.1629.

3-(4-Bromobenzyl)-3-butoxyindolin-2-one (3de). Light orange solid, m.p. 136.0–138.1 °C; yield 84%; 1H-NMR (CDCl3) δ: 0.82–0.85 (m, 3H), 1.30–1.35 (m, 2H), 1.48–1.54 (m, 2H), 2.99–3.03 (m, 2H), 3.17–3.19 (m, 1H), 3.27 (d, J = 13.0 Hz, 1H), 6.80–6.86 (m, 3H), 6.94–6.96 (m, 1H), 7.01–7.04 (m, 1H), 7.20–7.27 (m, 3H), 8.93 (br s, 1H); 13C-NMR (CDCl3) δ: 13.8, 19.1, 31.8, 43.1, 65.3, 83.0, 110.4, 120.9, 122.6, 125.2, 126.9, 129.8, 130.7, 132.4, 133.2, 140.8, 178.7; HRMS (ESI-TOF) m/z: Calcd. for C19H20BrNNaO2 [M + Na]+: 396.0575; Found: 396.0578.

3-(2-Bromobenzyl)-3-butoxyindolin-2-one (3ee). Light orange solid, m.p. 98.9–99.3 °C; yield 80%; 1H-NMR (CDCl3) δ: 0.82–0.85 (m, 3H), 1.25–1.36 (m, 2H), 1.45–1.51 (m, 2H), 3.00–3.01 (m, 1H), 3.22–3.24 (m, 1H), 3.32 (d, J = 11.2 Hz, 1H), 3.48 (d, J = 11.2 Hz, 1H), 6.59 (d, J = 6.0 Hz, 1H), 6.89–6.92 (m, 2H), 7.07–7.08 (m, 1H), 7.20–7.25 (m, 2H), 7.40–7.42 (m, 1H), 7.55 (d, J = 6.0 Hz, 1H), 9.55 (br s, 1H); 13C-NMR (CDCl3) δ: 13.8, 19.2, 31.8, 42.1, 65.1, 82.4, 110.4, 122.4, 125.4, 126.5, 126.6, 126.7, 128.4, 129.5, 132.3, 132.9, 134.7, 140.8, 179.4; HRMS (ESI-TOF) m/z: Calcd. for C19H20BrNNaO2 [M + Na]+: 396.0575; Found: 396.0575.

3-Butoxy-3-(2-chlorobenzyl)indolin-2-one (3fe). Light orange solid, m.p. 142.1–144.0 °C; yield 81%; 1H-NMR (CDCl3) δ: 0.82–0.86 (m, 3H), 1.33–1.38 (m, 2H), 1.49–1.57 (m, 2H), 2.97–3.03 (m, 1H), 3.20–3.25 (m, 1H), 3.32 (d, J = 13.6 Hz, 1H), 3.46 (d, J = 13.6 Hz, 1H), 6.69 (d, J = 7.6 Hz, 1H), 6.87–6.94 (m, 2H), 7.13–7.26 (m, 4H), 7.47–7.50 (m, 1H), 9.29 (br s, 1H); 13C-NMR (CDCl3) δ: 13.8, 19.2, 31.8, 39.6, 65.1, 82.5, 110.3, 122.5, 125.4, 126.0, 126.7, 128.2, 129.0, 129.6, 132.8, 132.9, 135.3, 140.7, 179.2; HRMS (ESI-TOF) m/z: Calcd. for C19H20ClNNaO2 [M + Na]+: 352.1080; Found:352.1082.

3-Butoxy-3-(4-chlorobenzyl)indolin-2-one (3ge). Light orange solid, m.p. 142.1–144.3 °C; yield 83%; 1H-NMR (CDCl3) δ: 0.81–0.85 (m, 3H), 1.30–1.34 (m, 2H), 1.50–1.54 (m, 2H), 3.00–3.05 (m, 2H), 3.16–3.21 (m, 1H), 3.28 (d, J = 12.8 Hz, 1H), 6.80–6.83 (m, 1H), 6.89–6.96 (m, 3H), 7.01–7.06 (m, 3H), 7.21–7.27 (m, 1H), 9.09 (br s, 1H); 13C-NMR (CDCl3) δ: 13.7, 19.1, 31.8, 43.1, 65.3, 83.1, 110.4, 122.6, 125.1, 126.9, 127.7, 129.7, 132.0, 132.7, 140.9, 178.8; HRMS (ESI-TOF) m/z: Calcd. for C19H20ClNNaO2 [M + Na]+: 352.1080; Found:352.1083.

3-Butoxy-3-(3-fluorobenzyl)indolin-2-one (3he). Light orange solid, m.p. 129.0–131.1 °C; yield 74%; 1H-NMR (CDCl3, 500 MHz) δ: 0.82–0.86 (m, 3H), 1.26–1.35 (m, 2H), 1.45–1.57 (m, 2H), 3.02–3.05 (m, 2H), 3.19–3.22 (m, 1H), 3.32 (d, J = 13.5 Hz, 1H), 6.72–6.76 (m, 2H), 6.80–6.84 (m, 2H), 6.91–6.95 (m, 1H), 7.01–7.05 (m, 2H), 7.22–7.26 (m, 1H), 9.18 (br s, 1H); 13C-NMR (CDCl3, 125 MHz) δ: 13.7, 19.1, 31.8, 43.4, 65.3, 83.0, 110.4, 113.6 (d, J = 21.1 Hz), 117.4 (d, J = 21.2 Hz), 122.6, 125.1, 126.4, 126.9, 128.8, 128.9, 129.8, 136.7, 136.8, 140.9, 162.1 (d, J = 243.8 Hz), 178.9; HRMS (ESI-TOF) m/z: Calcd. for C19H20FNNaO2 [M + Na]+: 336.1376; Found:336.1377.

3-Benzyl-3-(benzyloxy)indolin-2-one (3af). Light orange solid, m.p. 168.8–170.3 °C; yield 84%; 1H-NMR (CDCl3) δ: 3.18 (d, J = 12.8 Hz, 1H), 3.41 (d, J = 12.8 Hz, 1H), 4.12 (d, J = 8.2 Hz, 1H), 4.25 (d, J = 12.8 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.97–7.10 (m, 7H), 7.21–7.29 (m, 6H), 8.97 (br s, 1H); 13C-NMR (CDCl3) δ: 43.8, 67.8, 83.8, 110.4, 122.6, 125.4, 126.8, 127.6, 127.7, 127.8, 128.2, 129.9, 130.7, 133.9, 137.5, 141.1, 178.4; HRMS (ESI-TOF) m/z: Calcd. for C22H19NNaO2 [M + Na]+: 352.1313; Found:352.1313.

3-(Benzyloxy)-3-(4-methoxybenzyl)indolin-2-one (3bf). Light orange solid, m.p. 218.1–219.8 °C; yield 85%; 1H-NMR (CDCl3) δ: 3.12 (d, J = 13.2 Hz, 1H), 3.34 (d, J = 13.2 Hz, 1H), 3.64 (s, 3H), 4.11 (d, J = 10.8 Hz, 1H), 4.23 (d, J = 10.4 Hz, 1H), 6.58–6.61 (m, 2H), 6.79–6.81 (m, 1H), 6.87–6.89 (m, 2H), 7.05–7.10 (m, 2H), 7.22–7.29 (m, 6H), 8.88 (br s, 1H); 13C-NMR (CDCl3) δ: 43.0, 55.1, 68.0, 84.0, 110.6, 113.2, 122.8, 125.5, 126.0, 127.1, 127.8, 128.0, 128.3, 130.0, 131.8, 137.7, 141.2, 158.5, 178.7; HRMS (ESI-TOF) m/z: Calcd. for C23H21NNaO3 [M + Na]+: 382.1419; Found:382.1421.

3-(Benzyloxy)-3-(4-methylbenzyl)indolin-2-one (3cf). Light orange solid, m.p. 132.2–134.3 °C; yield 80%; 1H-NMR (CDCl3) δ: 2.10 (s, 3H), 3.06 (d, J = 13.2 Hz, 1H), 3.28 (d, J = 12.8 Hz, 1H), 4.03 (d, J = 10.4 Hz, 1H), 4.16 (d, J = 10.8 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 6.78 (s, 4H), 6.96–7.02 (m, 2H), 7.14–7.20 (m, 6H), 8.93 (br s, 1H); 13C-NMR (CDCl3) δ: 21.0, 43.3, 67.8, 83.8, 110.4, 122.6, 125.3, 126.9, 127.6, 127.8, 128.2, 128.4, 129.8, 130.5, 130.7, 136.2, 137.6, 141.1, 178.5; HRMS (ESI-TOF) m/z: Calcd. for C23H21NNaO2 [M + Na]+: 366.1470; Found:366.1474.

3-(Benzyloxy)-3-(4-bromobenzyl)indolin-2-one (3df). Light orange solid, m.p. 201.2–203.2 °C; yield 82%; 1H-NMR (DMSO-d6) δ: 3.08 (d, J = 10.0 Hz, 1H), 3.27 (d, J = 10.0 Hz, 1H), 3.99 (d, J = 8.4 Hz, 1H), 4.12 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 6.0 Hz, 1H), 6.86 (d, J = 6.4 Hz, 1H), 7.19–7.22 (m, 1H), 7.26–7.31 (m, 9H); 13C-NMR (DMSO-d6) δ: 41.4, 66.1, 82.3, 109.5, 119.5, 121.4, 124.5, 125.6, 127.0, 127.1, 127.7, 129.5, 130.0, 132.0, 133.2, 137.2, 141.8, 175.6; HRMS (ESI-TOF) m/z: Calcd. for C22H18BrNNaO2 [M + Na]+: 430.0419; Found:430.0423.

3-(Benzyloxy)-3-(2-bromobenzyl)indolin-2-one (3ef). Light orange solid, m.p. 158.8–160.1 °C; yield 81%; 1H-NMR (CDCl3) δ: 3.42 (d, J = 14.0 Hz, 1H), 3.58 (d, J = 14.0 Hz, 1H), 4.12 (d, J = 10.8 Hz, 1H), 4.30 (d, J = 10.8 Hz, 1H), 6.70 (d, J = 7.6 Hz, 1H), 6.91–6.95 (m, 2H), 7.07–7.09 (m, 1H), 7.21–7.30 (m, 7H), 7.42 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 9.35 (br s, 1H); 13C-NMR (CDCl3) δ: 42.2, 67.8, 82.9, 110.7, 122.8, 125.8, 126.3, 126.6, 127.0, 127.7, 127.8, 128.3, 128.7, 130.0, 132.5, 133.1, 134.6, 137.8, 141.0, 179.0; HRMS (ESI-TOF) m/z: Calcd. for C22H18BrNNaO2 [M + Na]+: 430.0419; Found:430.0418.

3-(Benzyloxy)-3-(2-chlorobenzyl)indolin-2-one (3ff). Light orange solid, m.p. 145.3–147.2 °C; yield 82%; 1H-NMR (CDCl3) δ: 3.42 (d, J = 14.0 Hz, 1H), 3.56 (d, J = 13.6 Hz, 1H), 4.12 (d, J = 10.8 Hz, 1H), 4.29 (d, J = 10.8 Hz, 1H), 6.80 (d, J = 7.2 Hz, 1H), 6.89–6.96 (m, 2H), 7.12–7.15 (m, 2H), 7.20–7.28 (m, 7H), 7.48–7.50 (m, 1H), 9.34 (br s, 1H); 13C-NMR (CDCl3) δ: 39.6, 67.7, 82.9, 110.5, 122.6, 125.5, 126.1, 126.3, 127.6, 128.2, 128.3, 129.1, 129.9, 132.6, 132.9, 135.3, 137.6, 140.8, 178.7; HRMS (ESI-TOF) m/z: Calcd. for C22H18ClNNaO2 [M + Na]+: 386.0924; Found:386.0925.

3-(Benzyloxy)-3-(4-chlorobenzyl)indolin-2-one (3gf). Light orange solid, m.p. 110.3–112.8 °C; yield 83%; 1H-NMR (DMSO–d6) δ: 3.09 (d, J = 12.8 Hz, 1H), 3.29 (d, J = 12.8 Hz, 1H), 3.99 (d, J = 10.8 Hz, 1H), 4.13 (d, J = 10.8 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 8.4 Hz, 2H), 7.00–7.03 (m, 1H), 7.15–7.30 (m, 9H), 10.5 (br s, 1H); 13C-NMR (DMSO-d6) δ: 41.4, 66.1, 82.4, 109.5, 121.4, 124.5, 125.7, 127.0, 127.1, 127.7, 129.5, 131.0, 131.6, 132.9, 137.2, 141.8, 175.6; HRMS (ESI-TOF) m/z: Calcd. for C22H18ClNNaO2 [M + Na]+: 386.0924; Found:386.0924.

3-(Benzyloxy)-3-(3-fluorobenzyl)indolin-2-one (3hf). Light orange solid, m.p. 153.2–155.1 °C; yield 75%; 1H-NMR (CDCl3, 500 MHz) δ: 3.16 (d, J = 10.4 Hz, 1H), 3.39 (d, J = 13.4 Hz, 1H), 4.13 (d, J = 11.0 Hz, 1H), 4.27 (d, J = 10.5 Hz, 1H), 6.72–6.74 (m, 1H), 6.76–6.78 (m, 1H), 6.81–6.84 (m, 2H), 7.04–7.06 (m, 3H), 7.23–7.29 (m, 6H); 13C-NMR (CDCl3, 125 MHz) δ: 43.4, 67.9, 83.4, 110.5, 113.7 (d, J = 20.1 Hz), 117.4 (d, J = 21.3 Hz), 122.8, 125.3, 126.5, 127.7, 127.8, 128.3, 129.0, 129.1, 130.1, 136.5, 137.4, 141.0, 162.1 (d, J = 243.8 Hz), 178.2; HRMS (ESI-TOF) m/z: Calcd. for C22H18FNNaO2 [M + Na]+: 370.1219; Found:370.1221.

3-Benzyl-3-(benzyloxy)-5-chloroindolin-2-one (3if). Light orange solid, m.p. 217.3–220.5 °C; yield 82%; 1H-NMR (DMSO–d6) δ: 3.09 (d, J = 12.4 H, 1H), 3.33 (d, J = 12.8 Hz, 1H), 4.03 (d, J = 10.8 Hz, 1H), 4.16 (d, J = 10.8 Hz, 1H), 6.68 (d, J = 8.8 Hz, 1H), 6.92–6.95 (m, 2H), 7.11–7.13 (m, 3H), 7.22–7.32 (m, 7H), 10.6 (br s, 1H); 13C-NMR (DMSO-d6) δ: 42.4, 66.8, 83.2, 111.3, 125.2, 125.9, 126.8, 127.5, 127.6, 127.7, 128.2, 128.5, 129.7, 130.3, 133.9, 137.6, 141.2, 176.0; HRMS (ESI-TOF) m/z: Calcd. for C22H18ClNNaO2 [M + Na]+: 386.0924; Found:386.0926.

3-Benzyl-3-(benzyloxy)-6-chloroindolin-2-one (3jf). Light orange solid, m.p. 165.1–168.5 °C; yield 85%; 1H-NMR (CDCl3) δ: 3.04 (d, J = 13.2 Hz, 1H), 3.31 (d, J = 13.2 Hz, 1H), 4.01 (d, J = 10.8 Hz, 1H), 4.16 (d, J = 10.8 Hz, 1H), 6.75–6.76 (m, 1H), 6.84–6.94 (m, 4H), 7.00–7.06 (m, 3H), 7.16–7.23 (m, 5H), 9.04 (br s, 1H); 13C-NMR (CDCl3) δ: 43.6, 67.9, 83.4, 111.2, 122.7, 125.1, 126.4, 127.0, 127.8, 128.3, 130.7, 133.6, 135.5, 137.2, 142.1, 178.5; HRMS (ESI-TOF) m/z: Calcd. for C22H18ClNNaO2 [M + Na]+: 386.0924; Found: 386.0925.

3-(2-Hydroxyethoxy)-3-(4-methylbenzyl)indolin-2-one (3cg). Light orange solid, m.p. 211.6–213.4 °C; yield 83%; 1H-NMR (DMSO-d6) δ: 2.14 (s, 3H), 2.95–3.03 (m, 2H), 3.08–3.12 (m, 1H), 3.17 (d, J = 10.0 Hz, 1H), 3.38–3.42 (m, 2H), 4.57 (br s, 1H), 6.61 (d, J = 6.4 Hz, 1H), 6.73 (d, J = 6.4 Hz, 2H), 6.86 (d, J = 6.0 Hz, 2H), 6.96–6.99 (m, 1H), 7.14–7.17 (m, 1H), 7.21 (d, J = 5.6 Hz, 1H), 10.3 (br s, 1H); 13C-NMR (DMSO-d6) δ: 20.1, 41.7, 59.6, 65.9, 82.5, 109.2, 121.2, 124.5, 126.3, 127.7, 129.2, 129.6, 130.6, 135.0, 141.8, 175.8; HRMS (ESI-TOF) m/z: Calcd. for C18H19NNaO3 [M + Na]+: 320.1263; Found:320.1267.

3-(4-Chlorobenzyl)-3-(2-hydroxyethoxy)indolin-2-one (3gg). Light orange solid, m.p. 205.3–207.3 °C; yield 87%; 1H-NMR (CDCl3) δ: 2.93–2.97 (m, 1H), 3.03 (d, J = 6.4 Hz, 1H), 3.07–3.11 (m, 1H), 3.21 (d, J = 6.4 Hz, 1H), 3.39–3.43 (m, 2H), 4.56–4.58 (m, 1H), 6.64–6.65 (m, 1H), 6.88 (d, J = 6.4 Hz, 2H), 6.97–7.00 (m, 1H), 7.13–7.19 (m, 4H), 10.4 (br s, 1H); 13C-NMR (CDCl3) δ: 41.3, 59.5, 66.0, 82.2, 109.3, 121.3, 124.5, 125.9, 127.1, 129.4, 130.9, 131.5, 132.9, 141.7, 175.7; HRMS (ESI-TOF) m/z: Calcd. for C17H16ClNNaO3 [M + Na]+: 340.0716; Found:340.0716.

3-Benzyl-3-(2,3-dihydroxypropoxy)indolin-2-one (3ah). Light orange oil; yield 51%, 1:1dr; 1H-NMR (CDCl3) δ: 3.03–3.10 (m, 2H), 3.12–3.18 (m, 1H), 3.21–3.32 (m, 2.6 H), 3.45–3.49 (m, 1H), 3.59–3.84 (m, 2.6 H), 6.74–6.77 (m, 1H), 6.92–7.04 (m, 4H), 7.07–7.15 (m, 3H), 7.19–7.23 (m, 1H), 8.65 (br s, 1H); 13C -NMR (CDCl3) δ: 43.6, 63.4, 63.5, 66.7, 67.7, 70.4, 70.7, 83.6, 83.7, 110.6, 110.7, 122.8, 126.9, 127.7, 130.0, 130.5, 130.6, 133.6, 140.8, 178.7, 178.8; HRMS (ESI-TOF) m/z: Calcd. for C18H19NNaO4 [M + Na]+: 336.1212; Found:336.1215.

4. Conclusions

In conclusion, we have developed a highly efficient and eco-friendly method for the synthesis of multisubstituted 3-alkoxylated-2-oxindoles 3 via direct alkoxylation of 3-halooxindoles 1. A wide variety of multisubstituted 3-alkoxylated-2-oxindole scaffolds were obtained smoothly in good yields (up to 94%) by simple heating in an oil bath at 30 °C for 24 h. A particularly valuable feature of this method was the development of environmentally-friendly chemistry using alcohols 2 as both the substrates and solvents. Moreover, only a catalytic amount of Na2CO3, a very cheap buck chemical, was used as the catalyst in this transformation, which made this chemistry exceptionally appealing for practical application.