Next Article in Journal
Identification and Validation of SAA4 as a Rheumatoid Arthritis Prescreening Marker by Liquid Chromatography Tandem-mass Spectrometry
Previous Article in Journal
Antigiardial Activity of Podophyllotoxin-Type Lignans from Bursera fagaroides var. fagaroides
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 22
Issue 5
10.3390/molecules22050801
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

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

by
Bing Lin
1,†,
Zhi-Yong Chen
1,†,
Huan-Huan Liu
1,
Qi-Di Wei
1,
Ting-Ting Feng
1,
Ying Zhou
1,*,
Can Wang
1,
Xiong-Li Liu
1,* and
Wei-Cheng Yuan
2
1
Guizhou Medicine Edicine Edible Plant Resources Research and Development Center, College of Pharmacy, Guizhou University, Guiyang 550025, China
2
Key Laboratory for Asymmetric Synthesis & Chirotechnology of Sichuan Province, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
*
Authors to whom correspondence should be addressed.
†
These two authors contributed equally to this work.
Molecules 2017, 22(5), 801; https://doi.org/10.3390/molecules22050801
Submission received: 20 April 2017 / Revised: 11 May 2017 / Accepted: 12 May 2017 / Published: 13 May 2017
(This article belongs to the Section Organic Chemistry)
Browse Figures
Versions Notes

Abstract

:
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.

Graphical Abstract

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].
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.

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.
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.
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).
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).
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).

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 3

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

Molecules 22 00801 i012
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.
Molecules 22 00801 i013
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.
Molecules 22 00801 i014
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.
Molecules 22 00801 i015
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.
Molecules 22 00801 i016
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.
Molecules 22 00801 i017
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.
Molecules 22 00801 i018
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.
Molecules 22 00801 i019
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, JCF = 20.8 Hz), 117.4 (d, JCF = 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, JCF = 245.8 Hz), 178.5; HRMS (ESI-TOF) m/z: Calcd. for C16H14FNNaO2 [M + Na]+: 294.0906; Found: 294.0908.
Molecules 22 00801 i020
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.
Molecules 22 00801 i021
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.
Molecules 22 00801 i022
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.
Molecules 22 00801 i023
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.
Molecules 22 00801 i024
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.
Molecules 22 00801 i025
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.
Molecules 22 00801 i026
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.
Molecules 22 00801 i027
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.
Molecules 22 00801 i028
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.
Molecules 22 00801 i029
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, JCF = 21.3 Hz), 122.7, 125.1, 126.3, 126.4, 126.8, 128.9 (d, JCF = 8.8 Hz), 129.8, 136.6 (d, JCF = 7.5 Hz), 140.9, 162.1 (d, JCF = 243.8 Hz), 178.7; HRMS (ESI-TOF) m/z: Calcd. for C17H16FNNaO2 [M + Na]+: 308.1063; Found: 308.1067.
Molecules 22 00801 i030
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.
Molecules 22 00801 i031
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.
Molecules 22 00801 i032
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.
Molecules 22 00801 i033
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.
Molecules 22 00801 i034
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.
Molecules 22 00801 i035
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.
Molecules 22 00801 i036
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.
Molecules 22 00801 i037
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.
Molecules 22 00801 i038
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.
Molecules 22 00801 i039
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.
Molecules 22 00801 i040
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.
Molecules 22 00801 i041
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.
Molecules 22 00801 i042
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.
Molecules 22 00801 i043
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.
Molecules 22 00801 i044
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.
Molecules 22 00801 i045
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.
Molecules 22 00801 i046
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.
Molecules 22 00801 i047
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.
Molecules 22 00801 i048
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, JCF = 21.1 Hz), 117.4 (d, JCF = 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, JCF = 243.8 Hz), 178.9; HRMS (ESI-TOF) m/z: Calcd. for C19H20FNNaO2 [M + Na]+: 336.1376; Found:336.1377.
Molecules 22 00801 i049
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.
Molecules 22 00801 i050
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.
Molecules 22 00801 i051
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.
Molecules 22 00801 i052
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.
Molecules 22 00801 i053
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.
Molecules 22 00801 i054
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.
Molecules 22 00801 i055
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.
Molecules 22 00801 i056
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, JCF = 20.1 Hz), 117.4 (d, JCF = 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, JCF = 243.8 Hz), 178.2; HRMS (ESI-TOF) m/z: Calcd. for C22H18FNNaO2 [M + Na]+: 370.1219; Found:370.1221.
Molecules 22 00801 i057
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.
Molecules 22 00801 i058
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.
Molecules 22 00801 i059
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.
Molecules 22 00801 i060
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.
Molecules 22 00801 i061
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.

Supplementary Materials

Supplementary materials are available online.

Acknowledgments

We are grateful for the financial support from the National Natural Science Foundations of China (No. 81560563, No. 81660576 and No. 81603390); Excellent Creative Talents of Science and Technology Support Plan in Guizhou Province Colleges and Universities ([(2015)491] Qian Jiao He KY Zi); Guizhou Chinese Medicine and Pharmaceutical Engineering Professional Degree Graduate Student Workstation (JYSZ [2014]002); Major Project of the Graduate Student Education Teaching Reform (Qian Jiao Yan He JG Zi)[2016]06; Science and Technology Major Project of Guizhou Province (Qian Ke He J Zhong Da Zi ([2015]6009-5)and Guizhou Education Research Together KYJJ Word ([2016]07).

Author Contributions

B.L. and Z.-Y.C. conceived and designed the experiments; H.-H.L. and Q.-D.W. performed experiments; T.-T.F. and C.W. analyzed data; W.-C.Y. and Y.Z. contributed reagents/materials/analysis tools; X.-L.L. wrote the paper.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Marti, C.; Carreira, E.M. Construction of Spiro[pyrrolidine-3,3′-oxindoles]-Recent Applications to the Synthesis of Oxindole Alkaloids. Eur. J. Org. Chem. 2003, 12, 2209–2219. [Google Scholar] [CrossRef]
  2. Trost, B.M.; Brennan, M.K. Asymmetric Syntheses of Oxindole and Indole Spirocyclic Alkaloid Natural Products. Synthesis 2009, 18, 3003–3025. [Google Scholar] [CrossRef]
  3. Klein, J.E.M.N.; Taylor, R.J.K. Transition-Metal-Mediated Routes to 3,3-Disubstituted Oxindoles through Anilide Cyclisation. Eur. J. Org. Chem. 2011, 34, 6821–6841. [Google Scholar] [CrossRef]
  4. Zhou, F.; Liu, Y.-L.; Zhou, J. Catalytic Asymmetric Synthesis of Oxindoles Bearing a Tetrasubstituted Stereocenter at the C-3 Position. Adv. Synth. Catal. 2010, 352, 1381–1407. [Google Scholar] [CrossRef]
  5. Ball-Jones, N.R.; Badillo, J.J.; Franz, A.K. Strategies for the enantioselective synthesis of spirooxindoles. Org. Biomol. Chem. 2012, 10, 5165–5181. [Google Scholar] [CrossRef] [PubMed]
  6. Dalpozzo, R.; Bartolib, G.; Bencivenni, G. Recent advances in organocatalytic methods for the synthesis of disubstituted 2- and 3-indolinones. Chem. Soc. Rev. 2012, 41, 7247–7290. [Google Scholar] [CrossRef] [PubMed]
  7. Shen, K.; Liu, X.; Lin, L.; Feng, X. Recent progress in enantioselective synthesis of C3-functionalizedoxindoles: Rare earth metals take action. Chem. Sci. 2012, 3, 327–334. [Google Scholar] [CrossRef]
  8. Cheng, D.; Ishihara, Y.; Tan, B.; Barbas, C.F., III. Organocatalytic Asymmetric Assembly Reactions: Synthesis of Spirooxindoles via Organocascade Strategies. ACS Catal. 2014, 4, 743–762. [Google Scholar] [CrossRef]
  9. Galliford, C.V.; Scheidt, K.A. Pyrrolidinyl-Spirooxindole Natural Products as Inspirations for the Development of Potential Therapeutic Agents. Angew. Chem. Int. Ed. 2007, 46, 8748–8758. [Google Scholar] [CrossRef] [PubMed]
  10. Vine, K.L.; Matesic, L.; Locke, J.M.; Ranson, M.; Skropeta, D. Cytotoxic and Anticancer Activities of Isatin and Its Derivatives: A Comprehensive Review from 2000 to 2008. Anti-Cancer Agents Med. Chem. 2009, 9, 397–414. [Google Scholar] [CrossRef]
  11. Badillo, J.J.; Hanhan, N.V.; Franz, A.K. Enantioselective Synthesis of Substituted Oxindoles and Spirooxindoles with Applications in Drug Discovery. Curr. Opin. Drug Discovery Dev. 2010, 13, 758–776. [Google Scholar]
  12. Singh, G.S.; Desta, Z.Y. Isatins as Privileged Molecules in Design and Synthesis of Spiro-Fused Cyclic Frameworks. Chem. Rev. 2012, 112, 6104–6155. [Google Scholar] [CrossRef] [PubMed]
  13. Hong, L.; Wang, R. Recent Advances in Asymmetric Organocatalytic Construction of 3,3′-Spirocyclic Oxindoles. Adv. Synth. Catal. 2013, 355, 1023–1052. [Google Scholar] [CrossRef]
  14. Hinman, R.L.; Bauman, C.P. Reactions of 3-Bromooxindoles. The Synthesis of 3-Methyleneoxindole. J. Org. Chem. 1964, 29, 2431–2437. [Google Scholar] [CrossRef]
  15. Fuchs, J.R.; Funk, R.L. Indol-2-one Intermediates: Mechanistic Evidence and Synthetic Utility. Total Syntheses of (±)-Flustramines A and C. Org. Lett. 2005, 7, 677–680. [Google Scholar] [CrossRef] [PubMed]
  16. Fuchs, J.R.; Funk, R.L. Total Synthesis of (±)-Perophoramidine. J. Am. Chem. Soc. 2004, 126, 5068–5069. [Google Scholar] [CrossRef] [PubMed]
  17. Zuo, J.; Liao, Y.-H.; Zhang, X.; Yuan, W.-C. Organocatalyzed Enantioselective Decarboxylative Stereoablation Reaction for the Construction of 3,3′-Disubstituted Oxindoles Using β-Ketoacids and 3-Halooxindoles. J. Org. Chem. 2012, 77, 11325–11332. [Google Scholar] [CrossRef] [PubMed]
  18. Liao, Y.-H.; Wu, Z.-J.; Han, W.-Y.; Zhang, X.-M.; Yuan, W.-C. Organocatalytic Enantioselective Stereoablative Hydroxylation of 3-Halooxindoles: An Effective Method for the Construction of Enantioenriched 3-Substituted 3-Hydroxy-2-Oxindoles. Chem. Eur. J. 2012, 18, 8916–8920. [Google Scholar] [CrossRef] [PubMed]
  19. Ma, S.; Han, X.; Krishnan, S.; Virgil, S.C.; Stoltz, B.M. Catalytic Enantio selective Stereoablative Alkylation of 3-Halooxindoles: Facile Access to Oxindoles with C3 All-Carbon Quaternary Stereocenters. Angew. Chem. Int. Ed. 2009, 48, 8037–8041. [Google Scholar] [CrossRef] [PubMed]
  20. Zhang, H.; Hong, L.; Kang, H.; Wang, R. Construction of Vicinal All-Carbon Quaternary Stereocenters by Catalytic Asymmetric Alkylation Reaction of 3-Bromooxindoles with 3-Substituted Indoles: Total Synthesis of (+)-Perophoramidine. J. Am. Chem. Soc. 2013, 135, 14098–14101. [Google Scholar] [CrossRef] [PubMed]
  21. Zuo, J.; Wu, Z.-J.; Zhao, J.-Q.; Zhou, M.-Q.; Xu, X.-Y.; Zhang, X.-M.; Yuan, W.-C. Preparation of 3-Sulfonylated 3,3-Disubstituted Oxindoles by the Addition of Sulfinate Salts to 3-Halooxindoles. J. Org. Chem. 2015, 80, 634–640. [Google Scholar] [CrossRef] [PubMed]
  22. Krishnan, S.; Stoltz, B.M. Preparation of 3-Sulfonylated 3,3-Disubstituted Oxindoles by the Addition of Sulfinate Salts to 3-Halooxindoles. Tetrahedron Lett. 2007, 48, 7571–7573. [Google Scholar] [CrossRef]
  23. Zhao, M.; Li, N.-K.; Zhang, Y.-F.; Pan, F.-F.; Wang, X.-W. Construction of 3-amino-2-oxindoles by direct amination of aniline or α-amino-acid derivatives to 3-bromooxindoles. Tetrahedron 2016, 72, 1406–1414. [Google Scholar] [CrossRef]
  24. Zhang, H.; Kang, H.; Hong, L.; Dong, W.; Li, G.; Zheng, X.; Wang, R. Construction of the N1–C3 Linkage Stereogenic Centers by Catalytic Asymmetric Amination Reaction of 3-Bromooxindoles with Indolines. Org. Lett. 2014, 16, 2394–2397. [Google Scholar] [CrossRef] [PubMed]
  25. Wu, C.; Li, G.; Sun, W.; Zhang, M.; Hong, L.; Wang, R. Organocatalytic Highly Enantioselective Monofluoroalkylation of 3-Bromooxindoles: Construction of Fluorinated 3,3′-Disubstituted Oxindoles and Their Derivatives. Org. Lett. 2014, 16, 1960–1963. [Google Scholar] [CrossRef] [PubMed]
  26. Bai, X.; Jing, Z.; Liu, Q.; Ye, X.; Zhang, G.; Zhao, X.; Jiang, Z. l-Amino Acid Based Urea–Tertiary Amine-Catalyzed Chemoselective and Asymmetric Stereoablative Carboxylation of 3-Bromooxindoles with Malonic Acid Half Thioesters. J. Org. Chem. 2015, 80, 12686–12696. [Google Scholar] [CrossRef] [PubMed]
  27. Frederick, W.; Goldberg, P.M.; Rachel, T. A Mild Thermal and Acid-Catalyzed Rearrangement of O-Aryl Ethers intoortho-HydroxyArenes. Org. Lett. 2005, 7, 4531–4534. [Google Scholar]
  28. Dyachenko, V.I.; Peregudov, A.S.; Chkanikov, N.D. Trifluoromethyl-containing N-acylmethylenequinone imines as novel highly electrophilic agents. J. Fluor. Chem. 2007, 128, 868–878. [Google Scholar] [CrossRef]
  29. Wang, Y.; Tang, X.; Shao, Z.; Ren, J. Indole-based alkaloids from deep-sea bacterium Shewanellapiezotolerans with antitumor activities. J. Antibiot. 2014, 67, 395–399. [Google Scholar] [CrossRef] [PubMed]
  30. Subba Reddy, B.-V.; Rajeswari, N.; Sarangapani, M.; Prashanthi, Y.; Ganji, R.-J.; Addlagatta, A. Iodine-catalyzed condensation of isatin with indoles: A facile synthesis of di(indolyl)indolin-2-ones and evaluation of their cytotoxicity. Bioorg. Med. Chem. Lett. 2012, 22, 2460–2463. [Google Scholar] [CrossRef] [PubMed]
  31. Kamal, A.; Srikanth, Y.-V.-V.; Khan, M.-N.-A.; Shaik, T.-B.; Ashraf, M. Synthesis of 3,3-diindolyl oxyindoles efficiently catalysed by FeCl3 and their in vitro evaluation for anticancer activity. Bioorg. Med. Chem. Lett. 2010, 20, 5229–5231. [Google Scholar] [CrossRef] [PubMed]
  32. Paira, P.; Hazra, A.; Kumar, S.; Paira, R.; Sahu, K.-B.; Naskar, S.; Saha, P.; Mondal, S.; Maity, A.; Banerjee, S.; et al. Efficient synthesis of 3,3-diheteroaromatic oxindole analogues and their in vitro evaluation for spermicidal potential. Bioorg. Med. Chem. Lett. 2009, 19, 4786–4789. [Google Scholar] [CrossRef] [PubMed]
  33. Hibino, S.; Choshi, T. Simple indole alkaloids and those with a nonrearranged monoterpenoid unit. Nat. Prod. Rep. 2001, 18, 66–87. [Google Scholar] [CrossRef] [PubMed]
  34. Marsden, S.P.; Watson, E.L.; Raw, S.A. Facile and General Synthesis of Quaternary 3-Aminooxindoles. Org. Lett. 2008, 10, 2905–2908. [Google Scholar] [CrossRef] [PubMed]
  35. Snell, R.-H.; Woodward, R.-L.; Willis, M.-C. Catalytic Enantio selective Total Synthesis of Hodgkinsine B. Angew. Chem. Int. Ed. 2011, 50, 9116–9119. [Google Scholar] [CrossRef] [PubMed]
  36. Boyer, N.; Movassaghi, M. Concise total synthesis of (+)-gliocladins B and C. Chem. Sci. 2012, 3, 1798–1803. [Google Scholar] [CrossRef] [PubMed]
  37. Luo, L.; Zhang, J.-J.; Ling, W.-J.; Shao, Y.-L.; Wang, Y.-W.; Peng, Y. Unified Synthesis of (–)-Folicanthine and (–)-Ditryptophenaline Enabled by a Room Temperature Nickel-Mediated Reductive Dimerization. Synthesis 2014, 46, 1908–1915. [Google Scholar] [CrossRef]
  38. Li, T.-Z.; Wang, X.-B.; Sha, F.; Wu, X.-Y. Catalytic enantioselective addition of alcohols to isatin-derived N-Bocketimines. Tetrahedron 2013, 69, 7314–7319. [Google Scholar] [CrossRef]
  39. Jhan, Y.-H.; Kang, T.-W.; Hsieh, J.-C. Efficient copper-catalyzed intramolecular N-arylation for the synthesis of oxindoles. Tetrahedron Lett. 2013, 54, 1155–1159. [Google Scholar]
  40. Hsieh, J.-C.; Cheng, A.-Y.; Fu, J.-H.; Kang, T.-W. Copper-catalyzed domino coupling reaction: An efficient method to synthesize oxindoles. Org. Biomol. Chem. 2012, 10, 6404–6409. [Google Scholar] [CrossRef] [PubMed]
  41. Piemontesi, C.; Wang, Q.; Zhu, J. Synthesis of 3,3-disubstituted oxindoles by one-pot integrated Brønsted base-catalyzed trichloroacetimidation of 3-hydroxyoxindoles and Brønsted acid-catalyzed nucleophilic substitution reaction. Org. Biomol. Chem. 2013, 11, 1533–1536. [Google Scholar] [CrossRef] [PubMed]
Sample Availability: Samples of the compounds 3aa–3ah are available from the authors.
Molecules 22 00801 g001 550
Figure 1. Strategies for the synthesis of 3,3′-disubstituted oxindoles.
Figure 1. Strategies for the synthesis of 3,3′-disubstituted oxindoles.
Molecules 22 00801 g001
Molecules 22 00801 g002 550
Figure 2. Representatives of the 3-alkoxylated-2-oxindolederivatives.
Figure 2. Representatives of the 3-alkoxylated-2-oxindolederivatives.
Molecules 22 00801 g002
Molecules 22 00801 sch001 550
Scheme 1. Construction of 3,3′-disubstituted oxindoles using 3-halooxindoles as electrophiles.
Scheme 1. Construction of 3,3′-disubstituted oxindoles using 3-halooxindoles as electrophiles.
Molecules 22 00801 sch001
Molecules 22 00801 sch002 550
Scheme 2. Contrast experiments with different types of substrate oxindoles 1 using MeOH as substrate and solvent.
Scheme 2. Contrast experiments with different types of substrate oxindoles 1 using MeOH as substrate and solvent.
Molecules 22 00801 sch002
Molecules 22 00801 sch003 550
Scheme 3. Bromooxindole 1′a as a test substrate for this transformation.
Scheme 3. Bromooxindole 1′a as a test substrate for this transformation.
Molecules 22 00801 sch003
Molecules 22 00801 sch004 550
Scheme 4. The alkoxylation of chloroxindole 1a on a gram scale.
Scheme 4. The alkoxylation of chloroxindole 1a on a gram scale.
Molecules 22 00801 sch004
Table
Table 1. Optimization of reaction conditions a.
Table 1. Optimization of reaction conditions a.
Molecules 22 00801 i001
Entry aSolventCatalyst (20 mol %)Time (h)Yield b (%)
1 cMeOHDABCO24trace
2 cMeOHDBU2454
3 cMeOHEt3N2473
4 cMeOHK2CO32487
5 cMeOHNaHCO32476
6 cMeOHNa2CO32494
7MeOHNone24<10
8tolueneNa2CO32461
9DCMNa2CO32459
10EtOAcNa2CO32410
11THFNa2CO32413
12 cCH3CNNa2CO32451
13 cMeOHNa2CO3463
14 cMeOHNa2CO3679
15 c,dMeOHNa2CO31596
16 c,eMeOHNa2CO34878
17 c,fMeOHNa2CO37261
a 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. b Isolated yield after flash chromatography. c The reaction was carried out using MeOH as substrate and solvent. d The reaction was carried out using 100 mol % of base Na2CO3. e The reaction was carried out using 10 mol % of base Na2CO3. f The reaction was carried out using 5 mol % of base Na2CO3.
Table
Table 2. Synthesis of 3-alkoxylated-2-oxindoles 3 a,b.
Table 2. Synthesis of 3-alkoxylated-2-oxindoles 3 a,b.
Molecules 22 00801 i062
Molecules 22 00801 i002
Molecules 22 00801 i003
Molecules 22 00801 i004
Molecules 22 00801 i005
Molecules 22 00801 i006
Molecules 22 00801 i007
Molecules 22 00801 i008
Molecules 22 00801 i009
Molecules 22 00801 i010
Molecules 22 00801 i011
a 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. b Isolated yield after flash chromatography. c This reaction was carried out in oil bath at 45 °C for 24 h.

Share and Cite

MDPI and ACS Style

Lin, B.; Chen, Z.-Y.; Liu, H.-H.; Wei, Q.-D.; Feng, T.-T.; Zhou, Y.; Wang, C.; Liu, X.-L.; Yuan, W.-C. Alcohols as Substrates and Solvents for the Construction of 3-Alkoxylated-2-Oxindoles by Direct Alkoxylation of 3-Halooxindoles. Molecules 2017, 22, 801. https://doi.org/10.3390/molecules22050801

AMA Style

Lin B, Chen Z-Y, Liu H-H, Wei Q-D, Feng T-T, Zhou Y, Wang C, Liu X-L, Yuan W-C. Alcohols as Substrates and Solvents for the Construction of 3-Alkoxylated-2-Oxindoles by Direct Alkoxylation of 3-Halooxindoles. Molecules. 2017; 22(5):801. https://doi.org/10.3390/molecules22050801

Chicago/Turabian Style

Lin, Bing, Zhi-Yong Chen, Huan-Huan Liu, Qi-Di Wei, Ting-Ting Feng, Ying Zhou, Can Wang, Xiong-Li Liu, and Wei-Cheng Yuan. 2017. "Alcohols as Substrates and Solvents for the Construction of 3-Alkoxylated-2-Oxindoles by Direct Alkoxylation of 3-Halooxindoles" Molecules 22, no. 5: 801. https://doi.org/10.3390/molecules22050801

Article Metrics

Back to TopTop