Lewis Acid-Catalyzed Malonate Addition onto 3-Hydroxy-2-oxindoles

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Cite This: J. Org. Chem. 2018, 83, 12664−12682

Lewis Acid-Catalyzed Malonate Addition onto 3‑Hydroxy-2oxindoles: Mechanistic Consideration and Synthetic Approaches to the Pyrroloindoline Alkaloids K. Naresh Babu, Nikhil Raj Kariyandi, Saina Saheeda M. K., Lakshmana K. Kinthada, and Alakesh Bisai*

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Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal Bypass Road, Bhopal, Madhya Pradesh 462 066, India S Supporting Information *

ABSTRACT: Metal triflate-catalyzed reactions of 3-hydroxy2-oxindoles with a variety of malonates have been developed under mild conditions. The reaction afford a variety of 2oxindoles sharing a C-3 quaternary center at the pseudobenzylic position in an operationally simple procedure. Control experiments using enantioenriched 3-hydroxy/ methoxy 2-oxindoles (91% ee) afforded a malonate addition product in racemic form, clearly suggesting that the reaction proceeds through an in situ generated 2H-indol-2-one intermediate (4a). Synthetic potential of this methodology has been shown by approaching the cyclotryptamine alkaloids linked with the aryl group at the pseudobenzylic position.

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INTRODUCTION Synthesis of small organic molecules sharing a biologically active natural product skeleton1 is of crucial importance for the success of a chemical genetics/genomics-based program. In this regard, given the prevalence of 2-oxindole and their derivatives in biologically active molecules2 and pharmaceutically active ingredients,3 a significant effort has been directed toward the synthesis of this structural motif. Particularly, 2oxindoles, bearing an all-carbon quaternary stereocenter4 at the C(3a) position, constitute a common structural motif in many biologically active molecules. In fact, the construction of carbon atoms having four carbon ligands, i.e., all-carbon quaternary centers, is a daunting task to address, owing to the resultant steric congestion.4 These structural motifs are also used in the construction of complex cyclotryptamine alkaloids, such as asperazine (1a) and pestalazine (1b)5 (Figure 1) having a tricyclic C(3a)-arylpyrroloindoline core (2). 3-Hydroxy-2-oxindole has been proven as a versatile building block for the syntheses of a variety of indole-based biologically active alkaloids. They are extensively used as electron-deficient partners for a variety of nucleophilic substitution reactions to realize different C−C bond forming events. For instance, Friedel−Crafts alkylations of aromatic compounds with 3,3-disubstituted 2-oxindole6 as an electrondeficient partner is one of the fundamental reactions. In this regard in 1985, Baeyer and Lazarus7a accessed symmetrical 3,3disubstituted 2-oxindoles starting from isatin through iterative electrophilic aromatic substitutions. Later in 1998, Olah and co-workers7b reported a general synthetic route to symmetrical 3,3-disubstituted oxindoles from isatins in superacidic triflic acid (CF3SO3H, TfOH). However, 3,3-unsymmetrically © 2018 American Chemical Society

disubstituted 2-oxindoles are the most demanding since they create an all-carbon quaternary stereocenter at the pseudobenzylic C-3 position.4 In this regard, in 2004, while working on the total synthesis of diazonamide A and related structures, Nicolaou et al.7c demonstrated that 3-hydroxy-2-oxindole could be activated under the influence of trifluoromethanesulfonic acid (TfOH), leading to the formation of an all-carbon quaternary center at the pseudobenzylic C-3 position of the 2oxindole derivative. Later, in 2011, Neuville and Zhu et al.8a had reported that trifluoroacetic acid promoted intramolecular double Friedel−Crafts alkylations to access a variety of spirooxindole structural motifs. In 2013, Zhu and co-workers8b reported a one-pot integrated Brønsted base-catalyzed trichloroacetimidation of 3-hydroxyoxindoles followed by a Brønsted acid-catalyzed nucleophilic substitution reaction to access a variety of unsymmetrically substituted 2-oxindoles. Interestingly, the Lewis acid-activation strategy has also been applied in the synthesis of a variety of 2-oxindoles containing a heteroatom at the 3-position.9 In 2012, our group showed an efficient Lewis acid-catalyzed Friedel−Crafts alkylation of phenols with 3-alkyl-3-hydroxy-2oxindoles.10a10b The methodology was applied for the synthesis of a tetracyclic core of azonazine.10a We have also utilized other electron-rich species, such as terminal alkynes (and acetophenone)11a and allyltrimethylsilane11b as nucleophiles for C−C bond forming reactions with 3-hydroxy-2oxindoles. In the case of Lewis acid-catalyzed Friedel−Crafts reactions of 3-hydroxy-2-oxindoles, it is believed to be Received: August 4, 2018 Published: September 21, 2018 12664

DOI: 10.1021/acs.joc.8b02017 J. Org. Chem. 2018, 83, 12664−12682

Article

The Journal of Organic Chemistry

Figure 1. Asperazine (1a), pestalazine (1b), and C(3a)-pyrroloindoline core (2).

Scheme 1. Proposed Synthesis of Cyclotryptamine Alkaloids Core (2) via Lewis Acid-Catalyzed Malonate addition

proceeded through the formation of a 2H-indol 2-one (4) intermediate (Scheme 1). Interestingly, a species like 4 is also reported to be formed under base-mediated elimination of 3halo 2-oxindoles for a C−C bond forming reaction.12 These reactions are well utilized in the total synthesis of complex indole alkaloids via formal cycloaddition processes.13,14 We envisioned that a Lewis acid-catalyzed reaction of 3hydroxy-2-oxindoles could be realized with malonates as nucleophiles in the presence of catalytic metal triflate under mild conditions (Scheme 1). On the basis of the well precedence by Stoltz and co-workers,13a malonates can be served as 2 carbon units after a selective hydrolysis of one of two ester functionalities (see, 5). Therefore, synthesis of the C(3a)-hexahydropyrroloindoline core (2)15,16 can be achieved from malonate addition products 5 (Scheme 1). In view of the demand for efficient, economic, and environmentally friendly processes, the development of direct catalytic C−C bond-forming reactions of 3-hydroxy-2oxindoles15,16 with prior unmodified substrates is an important area of research. Herein, we report that metal triflate catalyzed an inexpensive and environmentally benign malonate addition on a variety of 3-hydroxy-2-oxindoles for the synthesis of various 3,3-disubstituted 2-oxindoles and its application to pyrroloindoline scaffolds.

Table 1. Optimization of Malonate Addition on 3-Hydroxy2-oxindole 3aa,b

RESULTS AND DISCUSSION The Lewis acid activation of 3-hydroxy-2-oxindoles followed by a reaction with a suitable nucleophile gives access to 2oxindoles sharing an all-carbon quaternary stereocenter at the C-3 position. We thought of exploring Lewis acid-catalyzed activation of 3-hydroxy-3′-aryl-2-oxindoles, such as 3a, and subsequent reactions with malonates for the synthesis of these 2-oxindole-based structures, such as 5a. Toward this, we selected 3-aryl-3-hydroxy-2-oxindole (3a) as an electrondeficient partner with diethyl malonate as the electron-rich species, respectively, in the presence of a catalytic amount of metal triflate as the Lewis acid (Table 1). Our initial optimization with 0.3 mmol of 3a and 0.9 mmol of diethyl malonate in the presence of 20 mol % of Lewis acids,

a

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S. No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Lewis acids

catalyst loading (mol %)

solvent

temp (°C)

time (h)

yield (%)

BF3·OEt2 In(OTf)3 In(OTf)3 In(OTf)3 Bi(OTf)3 Fe(OTf)3 Sc(OTf)3 Yb(OTf)3 Zn(OTf)2 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 In(OTf)3 Sc(OTf)3 In(OTf)3

20 20 20 10 10 10 10 10 10 10 10 10 10 5 5

CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 MeCN PhMe (CH2Cl)2 (CH2Cl)2 (CH2Cl)2 (CH2Cl)2

25 25 40 40 40 40 40 40 40 65 100 80 80 80 80

12 12 10 12 1 12 15 20 20 15 15 1 1 6 6

tracesc 26c 89 87 58d 42 83 29c 35c tracesd 12c 94 92 85 82

Reactions were carried out using 0.3 mmol of 3a (1 equiv) with 0.9 mmol of diethylmalonate (3 equiv) in 2.0 mL of solvent at specified temperatures. bIsolated yields after column chromatography. cThe rest of the mass recovered as starting material. dThe rest of the mass decomposed.

such as BF3·OEt2 in 2 mL of dichloromethane at 25 °C, afforded only a trace amount of the product (92% of recovered starting material) (entry 1). When the reaction was carried out using 20 mol % of In(OTf)3, 5a was obtained in 26% yield at 25 °C (entry 2), and in 89% yield at refluxing dichloromethane (entry 3). Importantly, by reducing the catalyst loading to 10 mol % of In(OTf)3, 5a was obtained in 87% yield in 12 h (entry 4). 12665


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The Journal of Organic Chemistry Scheme 2. Substrate Scope Using Different Malonates on 3a−3da,b

a Reactions were carried out using 0.3 mmol of 3 (1 equiv) with 0.9 mmol of malonate (3 equiv) in 2.0 mL 1,2-dichloroethane at 80 °C. bIsolated yields after column chromatography.

ditions A [10 mol % of Sc(OTf)3] and B [10 mol % of In(OTf)3] afforded product 6a in 90 and 85% yields, respectively (Scheme 3). To our delight, a range of 3-aryl-3methoxy-2-oxindoles (3e−3g) underwent malonate addition to afford a wide range of 2-oxindoles having an all-carbonquaternary center (such as 6a−6f) in good to excellent yields (Scheme 3). Further, we turned our attention to the exploration of 3-(3′indolyl) 3-hydroxy-2-oxindoles of type 7 as electron-deficient partners, as the products from these reactions have a huge potential for the synthesis of dimeric pyrroloindoline alkaloids.11b These substrates are challenging in a sense, since they have both electron-deficient centers (hydroxyl group at C-3 position) as well as electron-rich centers (indole C-2 position). Therefore, not many reports are available for the reaction of 3-(3′-indolyl)3-hydroxy-2-oxindoles as electrondeficient partners (of type 7) with nucleophiles. To our delight, it was found, that our optimized conditions could be extended to a variety of 3-(3′-indolyl)3-hydroxy-2oxindoles of type 7 with functionalization on both scaffolds, namely, 2-oxindole as well as the indole part of 7 (Scheme 4). As a result, a wide range of 3-(3′-indolyl)3-malonyl-2oxindoles bearing all-carbon-quaternary centers at the pseudobenzylic position are obtained in good yields (8a−8h; Scheme 4). Gratifyingly, 2-oxindole as well as the indole part containing a deactivating halogen group, such as the bromo

A quick Lewis acid optimization revealed that diethyl malonate addition onto 3-aryl-3-hydroxy-2-oxindole (3a) was effective in the presence of 10 mol % of Sc(OTf)3 and In(OTf)3 at 40 °C in dichloromethane as compared to other Lewis acids (entries 4−9). Following exhaustive optimization, it was found, that 3-aryl-3-hydroxy-2-oxindole (3a) reacts with diethylmalonate efficiently in the presence of 10 mol % of Sc(OTf)3 and In(OTf)3 in refluxing 1,2-dichloroethane (entries 13−14). Among different Lewis acids employed, Sc(OTf)3 and In(OTf)3 were found to be superior over other metal triflates, such as Bi(OTf)3, Yb(OTf)3, Zn(OTf)2, and Sc(OTf)3 (entries 5−9). Further, on lowering catalyst loading to 5 mol % of Sc(OTf)3 and In(OTf)3, the malonate addition product 5a was obtained in up to 85 and 82% yields, respectively (entries 14−15). Therefore, on the basis of the optimization, two conditions with 10 mol % of Sc(OTf)3 (condition A) and In(OTf)3 (condition B) were chosen as standard conditions to carry out the malonate addition. Subsequently, we tested reactions of 3hydroxy-2-oxindole 3a as electron-deficient partners with a variety of malonates, which afforded products 5a−5d in 75− 91% yields in 1 h (Scheme 2). Next, we attempted to explore the substrate scope using a variety of 3-aryl-3-hydroxy-2oxindoles to afford the products 5e−5i in up to 90% yield (Scheme 2). Gratifyingly, it was found that diethyl malonate addition onto 3-aryl-3-methoxy-2-oxindole (3e) under con12666


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The Journal of Organic Chemistry Scheme 3. Substrates Scope Using a Variety of 3-Aryl-3-hydroxy-2-oxindoles (3e−3g)a−b

Reactions were carried out using 0.3 mmol of 3e−3g (1 equiv) with 0.9 mmol of malonate (3 equiv) in 2.0 mL 1,2-dichloroethane at 80 °C. Isolated yields after column chromatography.

a

b

Scheme 4. Substrates Scope Using a Variety of 3-Indolyl-3-hydroxy-2-oxindoles (7a−7f)a,b

Reactions were carried out using 0.3 mmol of 8 (1 equiv) with 0.9 mmol of malonate (3 equiv) in 2.0 mL 1,2-dichloroethane at 80 °C. bIsolated yields after column chromatography. a

functionality (see, 8f−8h), also afforded products in 70−77% yields. Next, we tested the substrate scope using various Nsubstituted 3-(3′-indolyl)3-hydroxy-2-oxindoles of type 7g−7l with a variety of malonates under the optimized conditions (Scheme 5). To our delight, a wide variety of 3-(3′-indolyl)3-

malonyl-2-oxindoles bearing all-carbon quaternary centers at the pseudobenzylic position were obtained in high yields (9a− 9g; Scheme 5). A variety of N-alkyl groups, such as methyl, ethyl, allyl, and cinnamyl, on the 2-oxindole part were well tolerated under the standard conditions. It is noteworthy to observe, that 2-oxindole starting materials containing electron12667


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The Journal of Organic Chemistry Scheme 5. Substrates Scope Using a Variety of 3-(N-Substituted indolyl)3-hydroxy-2-oxindoles (7g−7l)a,b

Reactions were carried out using 0.3 mmol of 7g−7l (1 equiv) with 0.9 mmol of malonate (3 equiv) in 2.0 mL 1,2-dichloroethane at 80 °C. Isolated yields after column chromatography.

a

b

Further, active methylene groups containing a substrate such as tert-butyl acetoacetate (11) were utilized as nucleophiles to react with 3-(3′-indolyl)3-hydroxy-2-oxindole 7a (Scheme 7). Therefore, the 3,3 disubstituted 2-oxindoles product 12 was obtained in excellent yields; however, no diastereoselectivity was observed under the conditions of A and B (Scheme 7). A plausible mechanism of Lewis acid-catalyzed activation of 3-hydroxy/methoxy-2-oxindoles (3, 7, and 10) with malonate is shown in Scheme 8. Mechanistically,10a the reaction could proceed through the formation of a common 2H-indol-2-one (4a) generated in situ upon treatment with a 3-methoxy/3hydroxy-2-oxindole in the presence of catalytic metal triflates. The malonate could directly react with 2H-indol-2-one (4a or 4b) to afford 3,3-disubstituted 2-oxindoles having an all-carbon quaternary stereocenter (Scheme 8). However, if this proposed pathway goes through 2H-indol-2one (4a), then enantioenriched 3-hydroxy/methoxy-2-oxindoles (such as 3, 7, and 10) could afford a product in racemic form via the intermediary of type 4a or carbocataion 4b. Toward this direction, we synthesized enantioenriched 7a (91% ee) via organocatalytic enantioselective addition of indole onto isatin in the presence of the 10 mol % cinchona catalyst 15 (Scheme 9).17a Later, a one-pot N- and Omethylation of (+)-7a with methyl iodide in the presence of NaH afforded (+)-10c in 88% yield with 91% ee (Scheme 9). Additionally, as per the literature report by Chimni et al.,17b we have synthesized 3-aryl-3-methoxy-2-oxindole (−)-3e utilizing the organocatalytic enantioselective addition of sesamol in the presence of the cinchona-based catalyst 17 (10 mol %) in methyl tert-butylether (MTBE) solvent (Scheme 10). This reaction afforded enantioenriched (+)-16

donating and deactivating halogen groups, such as 9f and 9g, as well as the indole part containing an electron-donating group, such as 9e, were obtained in 75−80% isolated yields (Scheme 5). Interestingly, one of the malonate addition products 9d (CCDC 1859924) gave a suitable crystal for X-ray analysis (Figure 2), which unambiguously proved the formation of the all-carbon quaternary center at the pseudobenzylic position.

Figure 2. X-ray structure of compound 9d (CCDC 1859924).

Later, the methodology was extended with 3-methoxy/ benzyloxy-2-oxindoles, such as 10a−10c, as electron-deficient partners with diethyl and dimethyl malonates under optimized conditions (Scheme 6). These reactions afforded 3-(3′indolyl)3-malonyl 2-oxindoles bearing all-carbon quaternary centers in synthetically useful yields (8a and 8i−8l; Scheme 6). 12668


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The Journal of Organic Chemistry Scheme 6. Substrates Scope Using a Variety of 3-Methoxy/benzyloxy-2-oxindoles 10a−10ca,b

Reactions were carried out using 0.3 mmol of 10a−10c (1 equiv) with 0.9 mmol of malonate (3 equiv) in 2.0 mL 1,2-dichloroethane at 80 °C. Isolated yields after column chromatography.

a

b

investigated (Schemes 9 and 10). Toward this direction, we reacted enantioenriched compound (+)-7a, (+)-10c, and (−)-3e with diethyl malonate under the standard conditions (conditions A and B). Interestingly, as per our hypothesis, these reactions furnished racemic products (±)-8a, (±)-8j, and (±)-6a in good yields (79−91%), indicating the involvement of the intermediate of type 4a (Scheme 1). This result proves that the Lewis acid-catalyzed reaction of 3hydroxy-/methoxy-2-oxindoles with malonates probably proceeds through the SN1 pathway (Schemes 9 and 10). We then moved toward the synthesis of C(3a)-arylpyrroloindoline scaffolds (Scheme 11). Toward this end, the Krapcho reaction of 5g was carried out using LiCl in DMSO:H2O at 160 °C to give the ester compound 18 in 85% yield, which underwent reductive cyclization in the presence of LiAlH4 at 0 °C to furnish the furoindoline scaffold 19 in 94% yield. In another sequence, the ester compound (18) was converted to primary alcohol (20) by using LiBH4 in 67% yield, which was further oxidized by using the Swern oxidation to give the aldehyde intermediate 21 (Scheme 11). This crude aldehyde was converted into tricyclic C(3a)-aryl pyrroloindoline (22) through imine formation using methyl-

Scheme 7. Substrates Scope Using a Variety of Alkyl Acetoacetates on Compound 7aa,b

a Reactions were carried out using 0.3 mmol of 7a (1 equiv) with 0.9 mmol of β-ketoesters (3 equiv) in 2.0 mL 1,2-dichloroethane at 80 °C. bIsolated yields after column chromatography.

in 90% yield with 90% ee, from where methylations of the hydroxyl groups afforded (−)-3e in 90% yield with 90% ee (Scheme 10).17b With enantioenriched 3-indolyl-3-hydroxy-2-oxindole (+)-7a, 3-(N-methylindolyl)3-methoxy-N-methyl-2-oxindole (+)-10c, and 3-aryl-3-methoxy-2-oxindole (−)-3e in hand, an indirect evidence for the formation of a 2H-indol-2-one intermediate (see intermediate 4a in Scheme 8) was

Scheme 8. Proposed Mechanism of Malonate Addition with 3-Hydroxy/3-Methoxy-2-oxindoles

12669


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The Journal of Organic Chemistry Scheme 9. Control Experiments Using 3-Hydroxy/Methoxy-2-oxindoles

Scheme 10. Synthesis of Enantioenriched 3e

Scheme 11. Synthesis of C(3a)-Arylpyrroloindoline Core 22

stituted 3-methoxy-2-oxindoles with various active methylene carbons as nucleophilic partners. Lewis acid-catalyzed malonate additions on to enantioenriched 3-hydroxy-2oxindoles (+)-7a and (−)-3e and 3-methoxy 2-oxindole (+)-10c suggest that the reaction involves the intermediacy of a carbocation, which is responsible for the formation of the 2H-indol-2-one ring system (4a) (Schemes 9 and 10). Utilizing the aforementioned strategy, we have demonstrated

amine hydrochloride, followed by reductive cyclization in the presence of LiAlH4 in THF under refluxing conditions in 79% over two steps (Scheme 11).

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CONCLUSIONS In summary, we developed an efficient method for the synthesis of 2-oxindoles sharing an all-carbon quaternary center at the pseudobenzylic position by a Lewis acid-catalyzed reaction of 3-substituted 3-hydroxy-2-oxindoles and 3-sub12670


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to the solution. The reaction was allowed to stir for 1 h at 0 °C, and then, it was brought to room temperature. The reaction mixture was quenched with a slow addition of water and diluted with 50 mL of EtOAc after completion of the reaction (monitored by TLC). The reaction mixture was put into a separatory funnel and extracted with 50 mL of water. The organic filtrate was dried over anhydrous Na2SO4 and concentrated in a rotary evaporator under vacuum. The crude products were purified by flash chromatography to afford alkylated products. 1-Allyl-3-methoxy-3-(6-methoxybenzo[d][1,3]dioxol-5-yl)indolin-2-one.

the synthesis of C(3a)-pyrroloindoline structural motifs 2, which are present in a number of cyclotryptamine alkaloids.

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EXPERIMENTAL SECTION

Material. Unless otherwise stated, reactions were performed in oven-dried glassware fitted with rubber septa under an inert atmosphere and were stirred with Teflon-coated magnetic stirring bars. Liquid reagents and solvents were transferred via syringe using standard Schlenk techniques. Tetrahydrofuran (THF) and diethyl ether (Et2O) were distilled over sodium/benzophenone ketyl. Dichloromethane (CH2Cl2), toluene, and benzene were distilled over calcium hydride. All other solvents and reagents were used as received unless otherwise noted. Reaction temperatures above 23 °C refer to the oil bath temperature. Thin layer chromatography (TLC) was performed using silica gel 60 F-254 precoated plates (0.25 mm) and visualized by UV irradiation, anisaldehyde stain, and other stains. Silica gel with a particle size 100−200 mesh was used for flash chromatography. Melting points were recorded on a digital melting point apparatus and are uncorrected. 1H and 13C NMR spectra were recorded on 400 and 500 MHz spectrometers with 13C operating frequencies of 100 and 125 MHz, respectively. Chemical shifts (δ) are reported in ppm relative to the residual solvent (CDCl3) signal (δ = 7.26 for 1H NMR and δ = 77.0 for 13C NMR). Data for 1H NMR spectra are reported as follows: chemical shift (multiplicity, coupling constants, and number of hydrogen). Abbreviations are as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad). IR spectra were recorded on an FT-IR system (Spectrum BX) and are reported in frequency of absorption (cm−1). Only selected IR absorbencies are reported. High-resolution mass spectrometry (HRMS) and low-resolution mass spectrometry (LRMS) data were recorded on a MicrOTOF-Q-II mass spectrometer using methanol as the solvent. General Procedure for the Synthesis of 3-Hydroxy-3substituted-2-oxindoles (3a−3d). An oven-dried round-bottom flask under argon atmosphere was charged with isatin (1.0 g; 6.8 mmol; 1.0 equiv) in dry THF (30 mL) at 0 °C. To this reaction mixture (15.0 mmol, 2.2 equiv. in case of 3a−3c preparation and 7.5 mmol for 3d), aryl magnesium bromide was added dropwise over a period of 10 min. The reaction mixture was then allowed to stir for 3 h. Upon completion of the starting material (judged by TLC analysis under UV light and I2 stain), the reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and diluted with EtOAc (50 mL). The whole reaction mixture was taken into the separatory funnel to separate the organic layer, and the aqueous layer was washed with EtOAc (2 × 40 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified through column chromatography using a hexane−EtOAc system as the eluent to afford the desired product (3a−3d). For characterization of compounds 3a−3d, see the refs 10, 11. General Procedure for the Synthesis of Compounds 3e−3g. Step 1. An oven-dried round-bottom flask was charged with isatin derivative (6.8 mmol; 1.0 equiv) in methyl tert-butyl ether (15 mL). To this reaction mixture, sesamol (8.2 mmol, 1.2 equiv) and Et3N (1.3 mmol, 20 mol %) were added at RT. Then, the reaction mixture was allowed to stir for 15 h (TLC showed complete consumption of starting materials under UV light and I2 stain). After complete consumption of starting materials, water (20 mL) was added to quench the reaction and diluted with EtOAc (40 mL). The whole reaction mixture was put into a separatory funnel to separate the organic layer. Then, the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. This crude product was used for next step without purification. Step 2. The crude product of 3-hydroxy-2-oxindoles (∼5.4 mmol; 1.0 equiv) was dissolved in DMF solvent under an N2 atmosphere, and this was done in an oven-dried round-bottom flask equipped with a magnetic stir bar at room temperature. To this reaction mixture, NaH (2.5 equiv, 13.5 mmol) was added portion-wise at 0 °C. Alkyl halide (2.5 equiv, 13.5 mmol) was then added dropwise with a syringe

The compound 3f was obtained as a light yellow solid (6.8 mmol scale; 1.5 g; 74% over two steps). mp 180−182 °C. Rf = 0.50 (30% EtOAc in hexane). 1H NMR (400 MHz, CDCl3, δ): 7.44 (s, 1H), 7.24 (td, J = 7.2, 2.0 Hz, 1H), 7.00−6.94 (m, 2H), 6.84 (d, J = 7.8 Hz, 1H), 6.37 (s, 1H), 5.94−5.84 (m, 3H), 5.36 (dd, J = 17.2, 1.5 Hz, 1H), 5.31−5.25 (m, 1H), 4.41 (q, J = 3.4, 2.5 Hz, 2H), 3.32 (s, 3H), 3.15 (s, 3H). 13C NMR (100 MHz, CDCl3, δ): 174.8, 150.9, 147.7, 144.2, 141.8, 131.9, 129.4, 128.4, 124.4, 122.7, 121.4, 117.9, 108.6, 107.3, 101.3, 95.9, 80.3, 56.8, 51.7, 42.6. IR (film) υmax 3370, 2920, 2350, 1713, 1614, 1460, 1149, 1027, 803, 723, 705, 620 cm−1. HRMS (ESI-TOF) (m/z): [M + H]+ Calcd for C20H20NO5, 354.1336; found, 354.1317. 1-Benzyl-3-methoxy-3-(6-methoxybenzo[d][1,3]dioxol-5yl)indolin-2-one.

The compound 3g was obtained as a light yellow solid (6.8 mmol scale; 2.0 g; 72% over two steps). mp 170−172 °C. Rf = 0.40 (20% EtOAc in hexane). 1H NMR (400 MHz, CDCl3, δ): 7.5 (s, 1H), 7.46−7.44 (m, 2H), 7.35−7.31 (m, 2H), 7.30−7.24 (m, 1H), 7.19 (td, J = 7.6, 1.6 Hz, 1H), 6.97 (dtd, J = 14.7, 7.3, 1.3 Hz, 2H), 6.78 (d, J = 7.8 Hz, 1H), 6.37 (s, 1H), 6.00−5.80 (m, 2H), 5.04−4.90 (m, 2H), 3.19 (s, 3H), 3.14 (s, 3H). 13C NMR (100 MHz, CDCl3, δ): 175.3, 151.0, 147.8, 144.3, 141.8, 136.2, 129.4, 128.7, 128.5, 127.9, 127.7, 124.4, 122.8, 121.3, 108.6, 107.4, 101.3, 95.9, 80.3, 56.7, 51.8, 44.2. IR (film) υmax 3368, 2930, 2340, 1718, 1624, 1440, 1129, 1007, 883, 720, 725, 621 cm−1. HRMS (ESI-TOF) (m/z): [M + H]+ Calcd for C24H22NO5, 404.1492; found, 404.1505. For characterization of compound 3e, see ref 10b. Synthetic Procedure for Compound 3h. An oven-dried roundbottom flask was charged with isatin (1g; 6.8 mmol; 1.0 equiv) in methyl tert-butyl ether (15 mL) under an N2 atmosphere at 25 °C. To this solution, sesamol (8.2 mmol, 1.2 equiv) and Et3N (1.3 mmol, 20 mol %) were added sequentially, and the reaction mixture was allowed to stir for 15 h. Upon completion of the starting material (judged by TLC analysis), the reaction mixture was quenched with water (20 mL), and the organic compound was extracted with ethyl acetate (2 × 30 mL). Then, the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. This crude product was used for the next step without purification. To the crude product of 3-hydroxy-2-oxindoles (∼6.3 mmol; 1.0 equiv) in dichloromethane (30 mL) under an N2 atmosphere at 25 °C, a Lewis acid (∼0.63 mmol, 10 mol %) and MeOH (∼31.5 mmol, 5.0 equiv) were added. Then, the reaction mixture was allowed to stir for 12 h. Upon completion of the starting material (judged by TLC analysis under UV light and I2 stain), the reaction mixture was 12671


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Hz, 1H), 6.96 (d, J = 7.8 Hz, 1H), 3.81 (dp, J = 32.3, 7.1 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H). 13C NMR (125 MHz, CDCl3, δ): 176.9, 142.2, 136.9, 131.5, 129.7, 125.2, 124.7, 123.4, 123.2, 122.2, 120.1, 119.9, 115.2, 111.6, 108.7, 75.7, 35.0, 12.6. IR (film) υmax 3435, 3115, 2931, 2245, 2113, 1661, 1471, 1366, 1290, 1180, 1007, 811, 601 cm−1. HRMS (ESI-TOF) (m/z): [M + H]+ Calcd for C18H17N2O2, 293.1285; found, 293.1276. 1-Allyl-3-hydroxy-3-(5-methoxy-1H-indol-3-yl)indolin-2one.

quenched with water (30 mL), and the organic compound was extracted with ethyl acetate (2 × 40 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified through column chromatography using 30−40% (EtOAc/hexane) as the eluent to afford the desired product. 3-(6-Hydroxybenzo[d][1,3]dioxol-5-yl)-3-methoxyindolin-2one.

Compound 3h was obtained as an orange solid (6.8 mmol scale of reaction, 1.8 g of product, 88% yield over two steps). mp 120−122 °C. Rf = 3.3 (50% EtOAc in hexane). 1H NMR (500 MHz, DMSO-d6, δ): 10.50 (s, 1H), 9.19 (s, 1H), 7.21 (ddd, J = 7.8, 5.9, 3.0 Hz, 1H), 7.16 (s, 1H), 6.91−6.89 (m, 2H), 6.84 (d, J = 7.7 Hz, 1H), 6.27 (s, 1H), 5.93 (d, J = 8.6 Hz, 2H), 3.46 (Water), 3.04 (s, 3H). 13C NMR (125 MHz, DMSO-d6, δ): 176.3, 148.9, 147.2, 144.2, 140.0, 129.8, 128.7, 124.8, 122.1, 118.8, 109.7, 106.9, 101.2, 98.0, 81.0, 51.4. IR (film) υmax 3382, 2916, 2255, 1722, 1631, 1614, 1568, 1452, 1390, 1105, 1002, 911, 720 cm−1. HRMS (ESI-TOF) (m/z): [M + Na]+ Calcd for C16H13NO5Na, 322.0686; found, 322.0697. For the synthetic procedure and characterization of compounds 7a−7f, see ref 15c. General Procedure for the Synthesis of Compounds 7g−7l. In a round-bottom flask charged with isatin (1.0 equiv) in MeOH (30 mL) under an N2 atmosphere at 25 °C, indole (1.2 equiv) and KOH (0.2 equiv) were added successively. Then, the reaction mixture was allowed to stir for 5−6 h. Upon completion of the starting material (judged by TLC analysis under UV light and I2 stain), the reaction mixture was quenched with water (20 mL), and the organic compound was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified through column chromatography using hexane−EtOAc as the eluent to afford the desired product (7g−7l). 3-Hydroxy-3-(1H-indol-3-yl)-1-methylindolin-2-one.

The compound 7i was obtained as a yellow solid (5.3 mmol scale of reaction, 1.6 g of product, 91% yield). mp 160−162 °C. Rf = 0.38 (50% EtOAc in hexane). 1H NMR (500 MHz, CDCl3, δ): 8.22 (s, 1H), 7.52 (dd, J = 7.4, 1.3 Hz, 1H), 7.35 (td, J = 7.8, 1.3 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 7.15−7.07 (m, 2H), 7.02 (d, J = 2.4 Hz, 2H), 6.94 (d, J = 7.8 Hz, 1H), 6.84 (dd, J = 8.8, 2.4 Hz, 1H), 5.88 (ddt, J = 17.0, 10.5, 5.3 Hz, 1H), 5.48−5.14 (m, 2H), 4.47 (ddt, J = 16.3, 5.3, 1.7 Hz, 1H), 4.30 (ddt, J = 16.3, 5.5, 1.6 Hz, 1H), 3.78 (s, 3H). 13C NMR (125 MHz, CDCl3, δ):176.8, 154.2, 142.5, 132.0, 131.2, 131.1, 129.7, 125.2, 125.0, 123.9, 123.2, 117.9, 115.0, 112.9, 112.2, 109.4, 102.2, 75.6, 55.7, 42.6. IR (film) υmax 3480, 3120, 2921, 2200, 2105, 1660, 1460, 1309, 1221, 1119, 1006, 990, 814, 780 cm−1. HRMS (ESI-TOF) (m/z): [M + H]+ Calcd for C20H19N2O3, 335.1390; found, 335.1411. 1-Cinnamyl-3-hydroxy-3-(1H-indol-3-yl)indolin-2-one.

The compound 7j was obtained as a colorless solid (3.8 mmol scale; 1.3 g, 87%). mp 155−157 °C. Rf = 0.50 (50% EtOAc in hexane). 1H NMR (500 MHz, CDCl3, δ): 8.37 (s, 1H), 7.48 (dd, J = 11.2, 7.7 Hz, 2H), 7.33 (d, J = 8.2 Hz, 1H), 7.30 (d, J = 3.2 Hz, 2H), 7.29 (s, 1H), 7.26 (dd, J = 5.5, 3.0 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.11 (d, J = 2.6 Hz, 1H), 7.04 (dt, J = 14.6, 7.5 Hz, 2H), 6.99 (d, J = 7.8 Hz, 1H), 6.63 (d, J = 15.9 Hz, 1H), 6.21 (dt, J = 15.9, 5.9 Hz, 1H), 13C NMR (125 MHz, CDCl3, δ): 177.1, 142.3, 136.9, 136.1, 133.1, 131.3, 129.7, 128.5, 127.9, 126.5, 125.1, 124.7, 123.5, 123.3, 122.5, 122.3, 120.2, 120.0, 115.2, 111.6, 109.4, 75.7, 42.2. IR (film) υmax 3470, 3100, 2991, 2290, 2115, 1620, 1400, 1389, 1201, 1189, 1016, 890, 700 cm−1. HRMS (ESI-TOF) (m/z): [M + H]+ Calcd for C25H21N2O2, 381.1598; found, 381.1610. 3-Hydroxy-3-(1H-indol-3-yl)-5-methoxy-1-methylindolin-2one.

The compound 7g was obtained as a light yellow solid (6.2 mmol scale of reaction, 1.5 g of product, 87% yield). mp 182−184 °C. Rf = 0.30 (50% EtOAc in hexane). 1H NMR (400 MHz, 0.4 mL CDCl3,0.1 mL CD3OD, δ): 8.62 (d, J = 24.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 7.4 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.27 (d, J = 4.3 Hz, 1H), 7.10 (d, J = 4.6 Hz, 2H), 7.06−7.01 (m, 2H), 6.90 (t, J = 3.7 Hz, 2H), 3.21 (s, 3H). 13C NMR (100 MHz, CDCl3,1 drop CD3OD, δ): 175.3, 144.0, 136.9, 130.0, 128.1, 125.5, 124.9, 124.0, 123.0, 122.3, 121.2, 120.0, 113.4, 108.5, 108.5, 50.6, 26.2. IR (film) υmax 3406, 3380, 2999, 2911, 1701, 1678, 1201, 866 cm−1. HRMS (ESI-TOF) (m/z): [M + H]+ Calcd for C17H15N2O2, 279.1128; found, 279.1102. 1-Ethyl-3-hydroxy-3-(1H-indol-3-yl)indolin-2-one.

The compound 7k was obtained as a yellow solid (5.1 mmol scale of reaction, 1.4 g of product, 87% yield). mp 157−159 °C. Rf = 0.41 (50% EtOAc in hexane). 1H NMR (400 MHz, DMSO-d6, δ): 11.02 (s, 1H), 7.40−7.19 (m, 2H), 7.09−6.59 (m, 9H), 3.61 (s, 3H), 3.07 (s, 3H), 2.46 (s, 1H). 13C NMR (100 MHz, DMSO-d6, δ): 176.8, 155.9, 137.2, 136.8, 134.4, 125.1, 124.1, 121.6, 120.4, 119.1, 115.5, 113.8, 112.0, 111.9, 109.5, 75.4, 55.9, 26.5. IR (film) υmax 3465, 3175, 2991, 2225, 2183, 1631, 1451, 1356, 1200, 1180, 1017, 891, 701 cm−1. HRMS (ESI-TOF) (m/z): [M + H]+ Calcd for C18H17N2O3, 309.1234; found, 309.1218.

The compound 7h was obtained as a yellow solid (5.7 mmol scale of reaction, 1.5 g of product, 91% yield). mp > 250 °C. Rf = 0.35 (50% EtOAc in hexane). 1H NMR (500 MHz, CDCl3, δ): 8.41 (s, 1H), 7.48−7.43 (m, 2H), 7.36 (td, J = 7.8, 1.3 Hz, 1H), 7.30−7.27 (m, 1H), 7.16−7.13 (m, 1H), 7.04 (q, J = 8.0 Hz, 2H), 7.00 (d, J = 2.6 12672


Article

The Journal of Organic Chemistry 5-Chloro-3-hydroxy-3-(5-methoxy-1H-indol-3-yl)-1-methylindolin-2-one.

Dimethyl-2-(3-(4-methoxyphenyl)-2-oxoindolin-3-yl)malonate.

The compound 7l was obtained as a yellow solid (5.2 mmol scale of reaction, 1.4 g of product, 89% yield). mp 195−197 °C. Rf = 0.250 (50% EtOAc in hexane). 1H NMR (400 MHz, DMSO-d6, δ): 10.93− 10.78 (m, 1H), 7.40 (dd, J = 8.3, 2.2 Hz, 1H), 7.26 (d, J = 2.2 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 7.10 (d, J = 8.3 Hz, 1H), 7.00 (d, J = 2.6 Hz, 1H), 6.78 (d, J = 2.4 Hz, 1H), 6.68 (dd, J = 8.8, 2.5 Hz, 1H), 6.53 (s, 1H), 3.60 (s, 3H), 3.13 (s, 3H). 13C NMR (101 MHz, DMSO-d6, δ): 176.6, 153.3, 142.4, 135.1, 132.4, 129.4, 126.9, 125.5, 124.7, 114.4, 112.7, 111.6, 110.6, 102.6, 75.1, 55.6, 26.5, 14.5. IR (film) υmax 3412, 3379, 2739, 2703, 1695, 1501, 1028, 911 cm−1. HRMS (ESI-TOF) (m/z): [M + H]+ Calcd for C18H16ClN2O3, 343.0844; found, 343.0847. For the synthetic procedure and characterization of compound 10a, see ref 15c. For the synthesis and characterization of compounds 10b and 10c, see ref 10c. For the synthesis and characterization of compounds (+)-7a and (+)-10c, see refs 17a, 11b. For the synthesis and characterization of compounds (+)-16 and (−)-3e, see refs 17b, 11a. General Procedure for the Synthesis of Compounds 5a−5g. 3-Hydroxy-2-oxindole (8) (1 equiv) was dissolved in 1,2-dichloroethane (CH2Cl)2 in an oven-dried round-bottom flask at 25 °C. To this reaction mixture, 10 mol % of a Lewis acid (In(OTf)3 in the case of condition A and Sc(OTf)3 in the case of condition B) was added, and the solution was stirred for 5 min. Afterward, dialkyl malonate (3 equiv) was added dropwise by a syringe to the solution. Then, the reaction mixture was transferred to an oil bath,and stirring was continued for respective times at 80 °C. Upon completion of the reaction (monitored by TLC under UV light and I2 stain), the reaction mixture was quenched with water and diluted with 5 mL of CH2Cl2. The organic layer was separated with a separatory funnel, dried over anhydrous Na2SO4, and concentrated in a rotary evaporator. The crude product was purified by flash chromatography to afford the required products (5a−5g). Diethyl-2-(3-(4-methoxyphenyl)-2-oxoindolin-3-yl)malonate.

The product 5b was obtained as a colorless solid (0.3 mmol scale; 95 mg, 86% under condition A). Rf = 0.35 (40% EtOAc in hexane). 1H NMR (400 MHz, CDCl3, δ): 8.74 (s, 1H), 7.96 (d, J = 7.5 Hz, 1H), 7.32−7.18 (m, 3H), 7.10 (t, J = 7.6 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 6.76 (d, J = 9.0 Hz, 2H), 4.87 (s, 1H), 3.72 (s, 3H), 3.57 (s, 3H), 3.35 (s, 3H). 13C NMR (100 MHz, CDCl3, δ): 179.3, 179.3, 167.7, 167.2, 159.1, 141.8, 129.0, 128.9, 128.8, 128.2, 128.0, 122.5, 113.8, 110.2, 58.3, 56.0, 55.2, 52.5, 52.5. IR (film) υmax 3366, 2926, 2800, 1612, 1686, 1420, 1357, 1234, 1089, 910, 701 cm−1. mp 175−177 °C. HRMS (ESI-TOF) (m/z): [M + H]+ Calcd for C20H20NO6, 370.1285; found, 370.1286. Diisopropyl-2-(3-(4-methoxyphenyl)-2-oxoindolin-3-yl)malonate.

The product 5c was obtained as a colorless solid (0.3 mmol scale; 99 mg, 78% under condition A). mp 140−142 °C. Rf = 0.48 (40% EtOAc in hexane). 1H NMR (400 MHz, CDCl3, δ): 8.15 (s, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.30−7.21 (m, 9H), 7.15−7.13 (m, 2H), 7.09−7.01 (m, 3H), 6.75−6.73 (m, 3H), 5.08−4.99 (m, 3H), 4.84 (s, 2H), 3.75 (s, 3H). 13C NMR (100 MHz, CDCl3, δ): 178.9, 167.0, 166.6, 159.1, 141.6, 135.1, 134.6, 129.0, 128.9, 128.6, 128.4, 128.3, 128.3 (two carbons), 128.2, 128.2, 128.2, 128.1, 122.5, 113.9, 110.1, 67.4, 67.2, 58.5, 55.9, 55.1. IR (film) υmax 3388, 2920, 2885, 1660, 1611, 141, 1390, 1285, 1052, 983, 701 cm−1. HRMS (ESI-TOF) (m/z): [M + Na]+ Calcd for C24H27NO6Na, 448.1731; found, 448.1760. Dibenzyl-2-(3-(4-methoxyphenyl)-2-oxoindolin-3-yl)malonate.

The product 5d was obtained as a colorless solid (0.3 mmol scale; 133 mg, 85% under condition A). mp 143−145 °C. Rf = 0.50 (40% EtOAc in hexane). 1H NMR (400 MHz, CDCl3, δ): 8.15 (s, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.30−7.21 (m, 9H), 7.15−7.13 (m, 2H), 7.09−7.01 (m, 3H), 6.75−6.73 (m, 3H), 5.08−4.99 (m, 3H), 4.84 (s, 2H), 3.75 (s, 3H). 13C NMR (100 MHz, CDCl3, δ): 178.9, 167.0, 166.6, 159.1, 141.6, 135.1, 134.6, 129.0, 128.9, 128.6, 128.4, 128.3, 128.3 (two carbons), 128.2, 128.2, 128.2, 128.1, 122.5, 113.9, 110.1, 67.4, 67.2, 58.5, 55.9, 55.1. IR (film) υmax 3377, 2922, 2845, 1697, 1611, 1431, 1308, 1205, 1072, 920, 731 cm−1. HRMS (ESI-TOF) (m/z): [M + H]+ Calcd for C32H28NO6, 522.1911; found, 522.1924. Diethyl-2-(3-(3,4-dimethoxyphenyl)-2-oxoindolin-3-yl)malonate.

The product 5a was obtained as a colorless solid (0.3 mmol scale; 109 mg, 91% under condition A). mp 150−152 °C. Rf = 0.50 (40% EtOAc in hexane). 1H NMR (400 MHz, CDCl3, δ): 8.33 (brs, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H), 7.23−7.22 (m, 2H), 7.11 (t, J = 7.6 Hz, 1H), 6.91 (d, J = 7.7 Hz, 1H), 6.77−6.75 (m, 2H), 4.83 (s, 1H), 4.04 (q, J = 7.1 Hz, 2H), 3.90−3.76 (m, 2H), 3.72 (s, 3H), 1.07 (t, J = 7.1 Hz, 3H), 0.85−0.80 (m, 3H). 13C NMR (100 MHz, CDCl3, δ): 179.3, 167.2, 166.8, 159.1, 141.8, 129.3, 128.9, 128.9, 128.3, 128.3, 122.6, 113.8, 109.9, 61.7, 61.4, 58.5, 56.0, 55.2, 13.8, 13.3. IR (film) υmax 3383, 2926, 2825, 1680, 1621, 1421, 1380, 1266, 1080, 913, 761 cm −1 . HRMS (ESI-TOF) (m/z): [M + Na]+ Calcd for C22H23NO6Na, 420.1418; found, 420.1429. 12673


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Diethyl-2-(3-(6-methoxybenzo[d][1,3]dioxol-5-yl)-1-methyl2-oxoindolin-3-yl)malonate.

The product 5e was obtained as a colorless solid (0.3 mmol scale; 115 mg, 90% under condition A). Rf = 0.40 (40% EtOAc in hexane). 1H NMR (400 MHz, CDCl3, δ): 8.73 (s, 1H), 8.03 (s, 1H), 7.29 (s, 1H), 7.12 (s, 1H), 7.00−6.93 (m, 2H), 6.75−6.71 (m, 2H), 4.86 (s, 1H), 4.06 (s, 2H), 3.88−3.57 (m, 8H), 1.28−1.10 (m, 3H), 0.95−0.83 (m, 3H).13C NMR (100 MHz, CDCl3, δ): 179.3, 167.2, 166.8, 148.7, 141.9, 129.7, 128.9, 128.8, 128.2, 122.1, 119.8, 110.7, 110.4, 110.0, 99.9, 61.7, 61.4, 58.5, 56.2, 55.8, 13.9, 13.3. IR (film) υmax 3373, 2916, 2815, 1679, 1601, 1411, 1392, 1265, 1082, 903, 781 cm−1. mp 118− 120 °C. HRMS (ESI-TOF) (m/z): [M + Na] + Calcd for C23H25NO7Na, 450.1523; found, 450.1512. Dimethyl-2-(3-(benzo[d][1,3]dioxol-5-yl)-2-oxoindolin-3-yl)malonate.

The product 6a was obtained as a colorless solid (0.3 mmol scale; 118 mg, 90% under condition A). mp 120−122 °C. Rf = 0.50 (20% EtOAc in hexane). 1H NMR (400 MHz, CDCl3, δ): 7.76 (dd, J = 7.6, 1.2 Hz, 1H), 7.29−7.24 (m, 1H), 7.02 (td, J = 7.6, 1.1 Hz, 1H), 6.79 (d, J = 7.8 Hz, 1H), 6.49 (s, 1H), 6.17 (s, 1H), 5.79 (s, 2H), 5.37 (s, 1H), 4.14−4.05 (m, 2H), 3.82−3.74 (m, 5H), 3.18 (s, 3H), 1.14 (t, J = 7.1 Hz, 3H), 0.85 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3, δ): 176.8, 167.9, 167.7, 153.9, 147.5, 144.4, 141.1, 130.6, 128.9, 126.7, 122.8, 118.8, 108.6, 107.8, 101.3, 95.8, 61.2, 60.9, 56.5, 56.2, 56.2, 26.6, 13.9, 13.5. IR (film) υmax 3360, 2926, 2235, 1712, 1611, 1501, 1412, 1370, 1125, 1022, 901, 720 cm−1. HRMS (ESI-TOF) (m/z): [M + Na]+ Calcd for C24H25NO8Na, 478.1472; found, 478.1498. Enantiomeric peaks of the pure compound were determined via HPLC analysis using a Chiralpak AD-H column; solvent, hexane/2propanol = 60/40; flow rate, 1.0 mL/min; detection, at 254 nm; tR1 = 7.35 min; and tR2 = 8.80 min (for 0% ee). Diethyl-2-(1-allyl-3-(6-methoxybenzo[d][1,3]dioxol-5-yl)-2oxoindolin-3-yl)malonate.

The product 5f was obtained as a colorless solid (0.3 mmol scale; 93 mg, 81% under condition A). Rf = 0.41 (40% EtOAc in hexane). 1H NMR (400 MHz, CDCl3, δ): 8.30 (brs, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.29 (t, J = 7.7 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 6.91 (d, J = 7.8 Hz, 1H), 6.83 (s, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.66 (d, J = 8.3 Hz, 1H), 5.89 (s, 2H), 4.81 (s, 1H), 3.63 (s, 3H), 3.38 (s, 3H). 13C NMR (100 MHz, CDCl3, δ): 178.8, 167.6, 167.1, 147.8, 147.2, 141.6, 130.9, 129.1, 128.6, 128.1, 122.7, 120.7, 110.1, 108.1, 107.7, 101.2, 58.3, 56.2, 52.5. IR (film) υmax 3374, 2914, 2813, 1688, 1622, 1401, 1390, 1245, 1080, 983, 780 cm−1. mp 120−122 °C. HRMS (ESI-TOF) (m/ z): [M + Na]+ Calcd for C20H17NO7Na, 406.0897; found, 406.0920. Diethyl-2-(3-(4-methoxyphenyl)-1-methyl-2-oxoindolin-3yl)malonate.

The product 6b was obtained as a yellow solid (0.3 mmol scale; 127 mg, 89% under condition A). mp 126−128 °C. Rf = 0.50 (20% EtOAc in hexane). 1H NMR (400 MHz, CDCl3, δ): 7.77 (dd, J = 7.6, 1.3 Hz, 1H), 7.25−7.20 (m, 1H), 7.01 (td, J = 7.6, 1.1 Hz, 1H), 6.79 (d, J = 7.8 Hz, 1H), 6.49 (s, 1H), 6.18 (s, 1H), 5.84−5.76 (m, 3H), 5.38 (s, 1H), 5.27−5.15 (m, 2H), 4.46−4.40 (m, 1H), 4.20−4.05 (m, 3H), 3.85−3.75 (m, 5H), 1.14 (t, J = 7.1 Hz, 3H), 0.83 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl3, δ): 176.5, 167.9, 167.6, 153.9, 147.5, 143.6, 141.2, 131.6, 130.6, 128.7, 126.7, 122.7, 118.9, 117.7, 108.7, 108.5, 101.3, 95.8, 56.2, 56.1, 42.8, 13.9, 13.5. IR (film) υmax 3353, 2961, 2202, 1732, 1601, 1501, 1452, 1320, 1115, 1052, 901, 780 cm −1 . HRMS (ESI-TOF) (m/z): [M + Na] + Calcd for C26H27NO8Na, 504.1629; found, 504.1655. Diethyl-2-(1-benzyl-3-(6-methoxybenzo[d][1,3]dioxol-5-yl)2-oxoindolin-3-yl)malonate.

The product 5g was obtained as a colorless solid (0.3 mmol scale; 107 mg, 87% under condition A). mp 120−122 °C. Rf = 0.52 (40% EtOAc in hexane). 1H NMR (500 MHz, CDCl3, δ): 8.1 (dd, J = 7.5, 1.3 Hz, 1H), 7.39 (td, J = 7.8, 1.3 Hz, 1H), 7.30−7.28 (m, 2H), 7.18 (td, J = 7.6, 1.1 Hz, 1H), 6.90 (dd, J = 7.8, 1.0 Hz, 1H), 6.80−6.78 (m, 2H), 4.87 (s, 1H), 4.07 (q, J = 7.1 Hz, 2H), 3.89−3.80 (m, 2H), 3.75 (s, 3H), 3.20 (s, 3H), 1.10 (t, J = 7.1 Hz, 3H), 0.87 (t, J = 7.1 Hz, 3H). 13 C NMR (125 MHz, CDCl3, δ): 177.2, 167.8, 166.8, 159.1, 144.7, 129.4, 128.9, 128.4, 128.3, 128.0, 122.6, 113.8, 108.1, 61.5, 61.3, 58.8, 55.4, 55.2, 26.7, 13.8, 13.5. IR (film) υmax 3360, 2910, 2810, 1629, 1600, 1419, 1382, 1245, 1002, 953, 721 cm−1. HRMS (ESI) (m/z) [M + H]+ Calcd for C23H26NO6, 412.1755; found, 412.1778. General Procedure for the Synthesis of Compounds 6a−6f. 3-Aryl-2-oxindole (3) (1 equiv) was dissolved in 1,2-dichloroethane (CH2Cl)2 in an oven-dried round-bottom flask at 25 °C. To this reaction mixture, 10 mol % of a Lewis acid (In(OTf)3 in the case of condiitin A and Sc(OTf)3 in the case of condition B) was added, and the reaction was stirred for 5 min. Afterward, dialkyl malonate (3 equiv) was added dropwise by a syringe to the solution. Then, the reaction mixture was allowed to stir for respective times at 25 °C. Upon completion of the reaction (monitored by TLC under UV light and I2 stain), the reaction mixture was quenched with water and diluted with 5 mL of CH2Cl2. The organic layer was separated with a separatory funnel, dried over anhydrous Na2SO4, and concentrated in a rotary evaporator. The crude product was purified by flash chromatography to afford the required products (6a−6f).

The product 6c was obtained as a colorless solid (0.3 mmol scale; 146 mg, 92% under condition A). mp 110−112 °C. Rf = 0.50 (20% EtOAc in hexane). 1H NMR (400 MHz, CDCl3, δ): 7.78 (dd, J = 7.6, 1.3 Hz, 1H), 7.32−7.13 (m, 6H), 6.99 (td, J = 7.6, 1.1 Hz, 1H), 6.70 (d, J = 7.8 Hz, 1H), 6.51 (s, 1H), 6.18 (s, 1H), 5.83−5.80 (m, 2H), 5.43 (s, 1H), 5.01 (d, J = 15.6 Hz, 1H), 4.73 (d, J = 15.6 Hz, 1H), 4.20−4.06 (m, 2H), 3.80−3.65 (m, 5H), 1.15 (t, J = 7.1 Hz, 3H), 0.70 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3, δ): 176.9, 167.9, 167.7, 153.9, 147.6, 143.6, 141.2, 136.0, 130.6, 128.7, 128.6, 127.6, 127.5, 126.8, 122.8, 119.0, 108.8, 108.6, 101.4, 95.8, 61.3, 61.0, 56.5, 56.2, 44.3, 12674


Article

The Journal of Organic Chemistry 14.0, 13.4. IR (film) υmax 3343, 2951, 2212, 1721, 1641, 1551, 1402, 1330, 1125, 1012, 931, 740 cm−1. HRMS (ESI-TOF) (m/z): [M + Na]+ Calcd for C30H29NO8Na, 554.1785; found, 554.1804. Dimethyl-2-(3-(6-methoxybenzo[d][1,3]dioxol-5-yl)-1methyl-2-oxoindolin-3-yl)malonate.

ethane (CH2Cl)2 in an oven-dried round-bottom flask at 25 °C. To this reaction mixture, 10 mol % of a Lewis acid (In(OTf)3 in the case of condition A and Sc(OTf)3 in the case of condition B) was added, and the reaction was stirred for 5 min. Afterward, dialkyl malonate (3 equiv) was added dropwise by a syringe to the solution. Then, the reaction mixture was allowed to stir for respective times at 25 °C. Upon completion of the reaction (monitored by TLC under UV light and I2 stain), the reaction mixture was quenched with water and diluted with 5 mL of CH2Cl2. The organic layer was separated with a separatory funnel, dried over anhydrous Na2SO4, and concentrated in a rotary evaporator. The crude product was purified by flash chromatography to afford the required products (8a−8j). Diethyl-2-(3-(1H-indol-3-yl)-2-oxoindolin-3-yl)malonate.15c

The product 6d was obtained as a colorless solid (0.3 mmol scale; 115 mg, 90% under condition A). mp 118−120 °C. Rf = 0.47 (20% EtOAc in hexane). 1H NMR (400 MHz, CDCl3, δ): 7.73 (dd, J = 7.6, 1.3 Hz, 1H), 7.26 (td, J = 7.7, 1.2 Hz, 1H), 7.02 (td, J = 7.6, 1.1 Hz, 1H), 6.80 (d, J = 7.8 Hz, 1H), 6.50 (s, 1H), 6.19 (s, 1H), 5.79 (q, J = 1.5 Hz, 2H), 5.39 (s, 1H), 3.79 (s, 3H), 3.62 (s, 3H), 3.33 (s, 3H), 3.19 (s, 3H). 13C NMR (100 MHz, CDCl3, δ): 176.8, 168.4, 167.9, 153.8, 147.6, 144.2, 141.2, 130.6, 128.9, 126.4, 122.8, 118.5, 108.5, 107.8, 101.4, 95.9, 56.6, 56.3, 55.8, 52.3, 52.2, 26.6. IR (film) υmax 3368, 2906, 2245, 1722, 1717, 1621, 1612, 1561, 1422, 1380, 1115, 1022, 911, 710 cm−1. HRMS (ESI-TOF) (m/z): [M + Na]+ Calcd for C22H21NO8Na, 450.1159; found, 450.1185. Dimethyl-2-(1-allyl-3-(6-methoxybenzo[d][1,3]dioxol-5-yl)2-oxoindolin-3-yl)malonate.

Compound 8a was obtained as a yellow solid (0.3 mmol scale; 102 mg, 84% under condition A). mp 170−172 °C. Rf = 0.50 (50% EtOAc in hexane). 1H NMR (400 MHz, 0.4 mL CDCl3, 0.1 mL DMSO-d6, δ): 9.63 (brs, 1H), 9.49 (brs, 1H), 7.80 (d, J = 7.2 Hz, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.10 (t, J = 8.3 Hz, 2H), 6.91−6.80 (m, 3H), 6.76 (d, J = 7.7 Hz, 1H), 6.51−6.50 (m, 1H), 4.99 (s, 1H), 3.77−3.66 (m, 4H), 0.76 (t, J = 14.2 Hz, 3H), 0.62 (t, J = 14.2 Hz, 3H). 13C NMR (100 MHz, 0.4 mL CDCl3, 0.1 mL DMSO-d6, δ): 178.4, 167.3, 166.9, 142.5, 136.9, 129.8, 128.3, 126.9, 124.9, 124.2, 121.7, 121.4, 121.3, 118.8, 111.9, 111.2, 109.5, 61.1, 60.6, 56.4, 53.4, 13.2, 13.1. IR (film) υmax 3375, 2989, 2359, 1724, 1615, 1265, 1034, 747, 700 cm−1. HRMS (ESI-TOF) (m/z): [M + H]+ Calcd for C23H23N2O5, 407.1601; found, 407.1604. Enantiomeric peaks of the pure compound were determined via HPLC analysis using a Chiralpak AD-H column; solvent, hexane/2-propanol = 70/30; flow rate, 1.0 mL/min; detection, at 254 nm; tR1 = 16.14 min; and tR2 = 28.70 min (for 0% ee). 1-Benzyl-3-ethyl-2-(−3-(1H-indol-3-yl)-2-oxoindolin-3-yl)malonate.15c

The product 6e was obtained as a colorless solid (0.3 mmol scale; 123 mg, 91% under condition A). mp 125−127 °C. Rf = 0.50 (20% EtOAc in hexane). 1H NMR (400 MHz, CDCl3, δ): 7.74 (dd, J = 7.6, 1.2 Hz, 1H), 7.24 (td, J = 7.5, 1.3 Hz, 1H), 7.02 (td, J = 7.6, 1.1 Hz, 1H), 6.81 (d, J = 7.8 Hz, 1H), 6.50 (s, 1H), 6.18 (s, 1H), 5.86−5.79 (m, 3H), 5.42 (s, 1H), 5.30−5.18 (m, 2H), 4.39−4.24 (m, 2H), 3.80 (s, 3H), 3.64 (s, 3H), 3.33 (s, 3H). 13C NMR (100 MHz, CDCl3, δ): 176.5, 168.4, 167.9, 153.9, 147.6, 143.4, 141.3, 131.5, 130.5, 128.8, 126.5, 122.8, 118.6, 117.9, 108.7, 108.4, 101.4, 95.9, 56.5, 56.2, 55.9, 52.2, 52.2, 42.8. IR (film) υmax 3370, 2906, 2215, 1723, 1641, 1541, 1432, 1310, 1105, 1002, 931, 700 cm−1. HRMS (ESI-TOF) (m/z): [M + H]+ Calcd for C24H24NO8, 454.1496; found, 454.1491. Diethyl-2-(3-(6-hydroxybenzo[d][1,3]dioxol-5-yl)-2-oxoindolin-3-yl)malonate.

Compound 8b was obtained as ayellow solid (0.3 mmol scale; 112 mg, 80% under condition A). mp 191−193 °C. Rf = 0.42 (40% EtOAc in hexane). 1H NMR for 1:1 mixture of diastereomers (400 MHz, DMSO-d6, δ): 10.97 (brs, 1H for major diastereomer +1H for minor diastereome), 10.47 (brs,1H for minor diastereomer), 10.46 (s, 1H for major diastereomer), 7.76 (d, J = 7.3 Hz, 1H for minor diastereomer), 7.71 (d, J = 7.3 Hz, 1H for major diastereomer), 7.53 (d, J = 8.0 Hz, 1H for major diastereomer), 7.49 (d, J = 8.1 Hz, 1H for minor diastereomer), 7.36−7.22 (m, 3H for major diastereomer +3H for minor diastereomer), 7.27−7.16 (m, 2H for major diastereomer +2H for minor diastereomer), 7.04−6.95 (m, 3H for major diastereomer +3H for minor diastereomer), 6.90−6.83 (m, 3H for major diastereomer +3H for minor diastereomer), 6.66 (s, 1H for minor diastereomer), 6.63 (s, 1H for major diastereomer), 5.02 (s, 1H for major diastereomer), 5.01 (s, 1H for minor diastereomer), 4.93− 4.81 (m, 2H for major diastereomer +2H for minor diastereomer), 3.81−3.80 (m, 2H for major diastereomer +2H for minor diastereomer), 0.80 (t, J = 6.9 Hz, 3H for major diastereomer), 0.65 (t, J = 6.8 Hz, 3H for for minor diastereomer). 13C NMR (100 MHz, DMSO-d6, δ): 178.1, 177.9, 167.4, 167.3, 166.90, 166.87, 143.5, 143.4, 137.4, 137.3, 135.7, 135.5, 130.2, 130.1, 129.13, 129.11, 128.8, 128.6, 128.5, 128.2, 127.9, 127.7, 127.2, 127.0, 125.3, 125.2, 124.92, 124.91, 121.8, 121.75, 121.72, 121.67, 121.63 (2 C), 119.2, 119.0, 112.5, 112.1, 111.9, 111.8, 110.2, 110.1, 66.9, 66.7, 61.7, 61.1, 56.65, 56.61, 53.5, 53.4, 13.7, 13.6. IR (film) υmax 3700, 3464, 2918, 2352,

Compound 6f was obtained as a colorless solid (0.3 mmol scale; 108 mg, 85% under condition A). mp 135−137 °C. Rf = 0.52 (40% EtOAc in hexane). 1H NMR (400 MHz, chloroform-d, δ): 9.90 (s, 1H), 8.74 (s, 1H), 8.01 (d, J = 7.2 Hz, 1H), 7.30 (td, J = 7.7, 1.3 Hz, 1H), 7.16 (td, J = 7.7, 1.2 Hz, 1H), 6.93 (d, J = 7.7 Hz, 1H), 6.51 (s, 1H), 6.32 (s, 1H), 5.80 (dd, J = 20.8, 1.5 Hz, 2H), 5.33 (s, 1H), 4.06 (q, J = 7.1 Hz, 2H), 3.82 (qd, J = 7.1, 4.7 Hz, 2H), 1.09 (t, J = 7.1 Hz, 3H), 0.85 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, chloroform-d, δ): 182.0, 167.2, 166.6, 152.4, 148.5, 141.6, 140.7, 129.5, 128.3, 123.5, 113.6, 110.7, 108.7, 101.9, 101.3, 61.8, 61.5, 57.8, 54.4, 13.3, 13.4. IR (film) υmax 3355, 3264, 2920, 2884, 1719, 1622, 1451, 1465, 1311, 1273, 1217, 1155, 742, 696 cm−1. HRMS (ESI-TOF) (m/z): [M + H]+ Calcd for C22H22NO8, 428.1340; found, 428.1331. General Procedure for the Synthesis of Compounds 8a−8j. 3-Methoxy 2-oxindole (7) (1 equiv) was dissolved in 1,2-dichloro12675


Article

The Journal of Organic Chemistry 1725, 1458, 1322, 1241, 1148, 738 cm−1. HRMS (ESI) (m/z) [M + Na]+ Calcd for C28H24N2O5Na, 491.1577; found, 491.1602. Diethyl −2-(5-chloro-3-(1H-indol-3-yl)-2-oxoindolin-3-yl)malonate.15c

Diethyl-2-(3-(5-bromo-1H-indol-3-yl)-2-oxoindolin-3-yl)malonate.15c

Compound 8f was obtained as a brown solid (0.3 mmol scale; 101 mg, 70% under condition A). mp 123−125 °C. Rf = 0.56 (50% EtOAc in hexane). 1H NMR (500 MHz, CDCl3, δ): 9.25 (s, 1H), 9.12 (s, 1H), 8.00 (s, 1H), 7.93 (d, J = 7.5, 1H), 7.24 (t, J = 7.5, 1H), 7.15− 7.06 (m, 2H), 7.02 (t, J = 7.6, 1H), 6.88 (d, J = 7.7, 1H), 6.59 (s, 1H), 5.08 (s, 1H), 3.90−3.78 (m, 4H), 0.83 (t, J = 7.1, 3H), 0.78 (t, J = 7.0, 3H). 13C NMR (125 MHz, 0.4 mL CDCl3, 0.1 mL DMSO-d6, δ): 178.6, 167.4, 166.9, 142.5, 135.8, 129.6, 128.7, 127.1, 127.1, 126.6, 125.8, 124.4, 121.9, 113.0, 112.4, 111.9, 109.9, 61.5, 60.9, 56.5, 53.4, 13.4, 13.3. IR (film) υmax 3250, 3053, 2920, 2350, 1712, 1616, 1469, 1217, 1097, 1018, 746 cm−1. HRMS (ESI-TOF) (m/z): (ESI) (m/z) [M + Na]+ Calcd for C23H21BrN2O5Na, 507.0526; found, 507.0534. Diethyl-2-(5-bromo-3-(1H-indol-3-yl)-2-oxoindolin-3-yl)malonate.15c

Compound (8c) was obtained as a yellow solid (0.3 mmol scale; 102 mg, 78% under condition A). mp 192−194 °C. Rf = 0.50 (50% EtOAc in hexane). 1H NMR (500 MHz, CDCl3, δ): 8.15 (brs, 1H), 8.09− 8.08 (m, 1H), 8.05−8.04 (m, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.25 (s, 1H), 7.23 (s, 1H), 7.14−7.05 (m, 2H), 6.77 (d, J = 8.3 Hz, 1H), 6.68−6.63 (m, 1H), 5.19 (s, 1H), 3.96−3.87 (m, 4H), 0.94 (t, J = 7.1 Hz, 3H), 0.76 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, DMSO, δ): 178.1, 167.2, 166.8, 140.3, 136.9, 131.5, 128.7, 127.7, 127.6, 124.8, 124.1, 122.4, 122.1, 119.6, 111.9, 111.3, 110.6, 61.8, 61.2, 56.4, 53.8, 13.5, 13.3. IR (film) υmax 3349, 2980, 1721, 1620, 1461, 1381, 1289, 1256, 1159, 1011, 870, 800, 761, 720 cm−1. HRMS (ESI) (m/z) [M + H]+ Calcd for C23H22ClN2O5, 441.1212; found, 441.1236. Diethyl-2-(3-(1H-indol-3-yl)-2-oxo-5-phenylindolin-3-yl)malonate.15c

Compound 8g was obtained as a brown solid (0.3 mmol scale; 103 mg, 71% under condition A). mp 182−184 °C. Rf = 0.60 (50% EtOAc in hexane). 1H NMR (400 MHz, CDCl3, δ): 8.38 (brs, 1H), 8.17 (d, J = 1.6 Hz, 1H), 8.12 (brs, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.38 (dd, J = 8.2, 1.8 Hz, 1H), 7.24 (s, 1H), 7.13−7.04 (m, 2H), 6.70 (d, J = 8.2 Hz, 1H), 6.60 (d, J = 2.4 Hz, 1H), 5.18 (s, 1H), 3.94−3.86 (m, 4H), 0.91 (t, J = 7.1 Hz, 3H), 0.77 (t, J = 7.1 Hz, 3H). 13C NMR (10 MHz, CDCl3, δ): 178.2, 167.3, 166.8, 140.9, 137.0, 131.9, 131.7, 130.4, 124.8, 124.2, 122.4, 122.1, 119.9, 115.0, 111.9, 111.4, 111.3, 61.8, 61.3, 56.4, 53.8, 13.5, 13.3. IR (film) υmax 3381, 2982, 1715, 1471, 1371, 1299, 1246, 1189, 1031, 860, 816, 741 cm−1. HRMS (ESITOF) (m/z): [M + Na]+ Calcd for C23H21BrN2O5Na, 507.0526; found, 507.0530. Dibenzyl-2-(3-(5-bromo-1H-indol-3-yl)-2-oxoindolin-3-yl)malonate.15c

Compound 8d was obtained as a colorless solid (0.3 mmol scale; 115 mg, 80% under condition A). mp 180−182 °C. Rf = 0.49 (40% EtOAc in hexane). 1H NMR (500 MHz, 0.5 mL CDCl3, 0.1 mL DMSO-d6, δ): 9.72−9.68 (m, 2H), 8.29−8.28 (m, 1H), 7.86−7.85 (m, 1H), 7.61−7.48 (m, 3H), 7.42−7.35 (m, 2H), 7.31−7.24 (m, 2H), 7.06− 6.97 (m, 3H), 6.73−6.71 (m, 1H) 5.21 (s, 1H), 3.94−3.83 (m, 4H), 2.73 (Water), 0.92−0.87 (m, 3 H), 0.78−0.75 (m, 3H). 13C NMR (125 MHz, 0.5 mL CDCl3, 0.1 mL DMSO-d6, δ): 178.6, 167.4, 167.0, 142.1, 141.1, 137.2, 134.7, 130.6, 128.6, 127.2, 126.6, 126.5, 125.5, 125.1, 124.4, 121.9, 121.5, 119.1, 111.5, 110.0, 61.4, 60.8, 56.6, 53.7, 13.4, 13.2. IR (film) υmax 3390, 3052, 2936, 2340, 1722, 1650, 1423, 1357, 1230, 893, 746 cm−1. HRMS (ESI) (m/z) [M + H]+ Calcd for C29H27N2O5, 483.1914; found, 483.1906. Diethyl-2-(3-(5-methoxy-1H-indol-3-yl)-2-oxoindolin-3-yl)malonate.15c

Compound 8h was obtained as a brown solid (0.3 mmol scale; 140 mg, 77% under condition A). mp 159−161 °C. Rf = 0.55 (50% EtOAc in hexane). 1H NMR (500 MHz, DMSO-d6, δ): 7.75 (d, J = 1.9, 1H), 7.70 (dd, J = 7.6, 1.2, 1H), 7.36−7.30 (m, 2H), 7.28 (dd, J = 5.0, 1.8, 3H), 7.25−7.14 (m, 4H), 7.07−6.97 (m, 3H), 6.91 (dd, J = 7.8, 1.1, 1H), 6.83−6.77 (m, 2H), 6.71 (s, 1H), 5.06 (s, 1H), 4.96−4.78 (m, 4H). 13C NMR (125 MHz, DMSO, δ): 177.7, 167.3, 166.6, 142.9, 135.9, 135.3, 129.4, 129.4, 128.8, 128.7, 128.5, 128.4, 127.9, 127.7, 126.9, 126.7, 126.6 (2 C), 124.4, 123.8, 121.9, 114.3, 112.1, 111.3, 110.4, 67.2, 66.9, 56.5, 53.1. IR (film) υmax 3391, 2925, 2257, 1728, 1621, 1471, 1379, 1312, 1266, 1147, 1025, 1005, 755, 698 cm−1. HRMS (ESI-TOF) (m/z): [M + Na]+ Calcd for C33H25BrN2O5Na, 631.0839; found, 631.0867. General Procedure for the Synthesis of Compounds 9a−9g. 3-Hydroxy 2-oxindole (7) (1 equiv) was dissolved in 1,2-dichloroethane (CH2Cl)2 in an oven-dried round-bottom flask at 25 °C. To this reaction mixture, 10 mol % of a Lewis acid (In(OTf)3 in the case of condition A and Sc(OTf)3 in the case of condition B) was added, and the reaction was stirred for 5 min. Afterward, dialkyl malonate (3

Compound 8e was obtained as an orange solid (0.3 mmol scale; 104 mg, 80% under condition A). mp 130−132 °C. Rf = 0.56 (50% EtOAc in hexane). 1H NMR (500 MHz, DMSO-d6, δ): 10.86 (d, J = 2.8, 1H), 10.50 (s, 1H), 7.80 (dd, J = 7.5, 1.2, 1H), 7.31 (td, J = 7.7, 1.3, 1H), 7.20 (d, J = 8.8, 1H), 7.05 (td, J = 7.6, 1.1, 1H), 6.94 (dd, J = 7.8, 1.0, 1H), 6.80 (d, J = 2.4, 1H), 6.74−6.56 (m, 2H), 4.90 (s, 1H), 3.98−3.86 (m, 2H), 3.86−3.78 (m, 2H), 3.62 (s, 3H), 0.84 (t, J = 7.1, 3H), 0.79 (t, J = 7.1, 3H). 13C NMR (125 MHz, DMSO-d6, δ): 178.1, 167.4, 166.9, 153.1, 143.6, 132.3, 130.2, 129.1, 127.3, 125.6, 125.3, 121.7, 112.6, 111.6, 111.4, 109.9, 103.6, 61.6, 61.0, 56.5, 55.6, 53.3, 13.7, 13.7. IR (film) υmax 3381, 2982, 1715, 1471, 1371, 1299, 1246, 1189, 1031, 860, 816, 741 cm−1. HRMS (ESI) (m/z) [M + Na]+ Calcd for C24H24N2O6Na, 459.1527; found, 459.1551. 12676


Article


7.13 m, 4H), 7.09 (d, J = 7.1 Hz, 1H), 7.02 (t, J = 7.4 Hz, 3H), 6.97 (dt, J = 10.3, 7.3 Hz, 2H), 6.92−6.82 (m, 2H), 6.72 (d, J = 7.2 Hz, 1H), 6.6 (d, J = 7.5 Hz, 1H), 6.46 (s, 1H), 5.28 (s, 1H), 4.76 (s, 4H), 3.46 (dd, J = 14.2, 7.2 Hz, 1H), 3.33 (dq, J = 14.2, 7.3 Hz, 1H), 0.95 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3, δ): 176.2, 167.5, 166.8, 143.7, 137.1, 135.1, 134.9, 129.3, 128.8, 128.7, 128.5, 128.4, 128.3, 128.2, 128.0, 127.9, 127.4, 125.1, 124.2, 122.4, 122.5, 122.2, 120.1, 112.8, 111.4, 108.5, 67.3, 67.1, 56.9, 53.1, 34.9, 12.1. IR (film) υmax 3312, 2932, 2241, 2249, 1729, 1628, 1411, 1340, 1301, 1240, 1110, 1002, 788, 629 cm−1. HRMS (ESI-TOF) (m/z): [M + Na]+ Calcd for C35H30N2O5Na, 581.2047; found, 581.2077. Dibenzyl 2-(1-cinnamyl-3-(1H-indol-3-yl)-2-oxoindolin-3yl)malonate.

equiv) was added dropwise by a syringe to the solution. Then, the reaction mixture was allowed to stir for respective times at 25 °C. Upon completion of reaction (monitored by TLC under UV light and I2 stain), the reaction mixture was quenched with water and diluted with 5 mL of CH2Cl2. The organic layer was separated with a separatory funnel, dried over anhydrous Na2SO4, and concentrated in a rotary evaporator. The crude product was purified by flash chromatography to afford the required products (9a−9g). Dibenzyl 2-(3-(1H-indol-3-yl)-1-methyl-2-oxoindolin-3-yl)malonate.

The compound 9a was obtained as a light yellow solid (0.3 mmol; 134 mg, 82% under condition A). mp 188−189 °C. Rf = 0.60 (50% EtOAc in hexane). 1H NMR (400 MHz, CDCl3) 7.96 (d, J = 7.4, 1H), 7.83 (d, J = 7.5, 2H), 7.24 (d, J = 7.6, 1H), 7.19 (d, = 6.4, 4H), 7.11 (d, J = 7.0, 1H), 7.06 (t, J = 7.5, 3H), 6.98 (dd, J = 14.43 7.0, 2H), 6.95−6.85 (m, 2H), 6.73 (d, J = 7.4, 2H), 6.59 (d, J = 7.6, 1H), 6.51 (d, J = 2.9, 1H), 5.27 (s, 1H), 4.78 (d, J = 2.7, 2H), 4.76−4.61 (m, 2H), 2.71 (s, 3H). 13C NMR (100 MHz, CDCl3, δ): 176.8, 167.7, 167.2, 144.8, 137.3, 135.4, 134.9, 129.3, 129.1, 128.8, 128.7, 128.6, 128.3, 127.4, 125.3, 124.4, 122.7, 122.7, 122.5, 120.4, 111.7, 108.6, 77.7, 77.4, 77.0, 67.8, 67.4, 57.2, 53.4, 26.6. IR (film) υmax 3404, 3010, 2975, 2911, 1710, 1690, 1608, 1451, 1203, 805 cm−1. HRMS (ESITOF) (m/z): [M + H]+ Calcd for C34H29N2O5, 545.2071; found, 545.2086. Bis(4-fluorobenzyl) 2-(3-(1H-indol-3-yl)-1-methyl-2-oxoindolin-3-yl)malonate.

The compound 9d was obtained as a yellow solid (0.04 mmol scale; 22 mg, 83%). mp 96−98 °C. Rf = 0.50 (50% EtOAc in hexane). 1H NMR (400 MHz, CDCl3, δ): 8.03 (d, J = 7.5 Hz, 1H), 7.97 (s, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.32−7.24 (m, 5H), 7.23−7.11 (m, 9H), 7.09−6.96 (m, 5H), 6.84 (d, J = 7.1 Hz, 2H), 6.80 (d, J = 7.8 Hz, 1H), 6.66 (d, J = 2.7 Hz, 1H), 6.41 (d, J = 15.9 Hz, 1H), 6.01 (dt, J = 16.0, 5.7 Hz, 1H), 5.38 (s, 1H), 5.01−4.76 (m, 4H), 4.37 (dd, J = 5.4, 1.8 Hz, 1H), 3.96 (dd, J = 16.8, 5.8 Hz, 1H). 13C NMR (100 MHz, CDCl3, δ): 176.3, 167.4, 166.7, 143.7, 136.9, 136.3, 135.0, 134.8, 132.3 (2 C), 129.0, 128.7, 128.5, 128.4, 128.3, 128.2, 128.1, 127.9, 127.6, 127.2, 126.4, 125.0, 124.1, 123.0, 122.4, 122.3, 121.9, 120.1, 112.7, 111.4, 109.2, 67.3, 67.0, 56.9, 53.1, 42.0. IR (film) υmax 3362, 2922, 2264, 2209, 1716, 1610, 1410, 1340, 1301, 1249, 1100, 1012, 798, 629 cm−1. HRMS (ESI) (m/z) [M + Na]+ Calcd for C42H34N2O5Na, 669.2360; found, 669.2388. Dibenzyl-2-(1-allyl-3-(5-methoxy-1H-indol-3-yl)-2-oxoindolin-3-yl)malonate.

The compound 9b was obtained as a yellow solid (0.3 mmol scale; 142 mg, 82% under condition A). Rf = 0.42 (40% EtOAc in hexane). 1 H NMR (500 MHz, CDCl3, δ): 8.03 (dd, J = 7.5, 1.2, 1H), 7.96 (t, J = 6.3, 2H), 7.34 (td, J = 7.7, 1.2, 1H), 7.28 (s, 1H), 7.25 (s, 1H), 7.20−7.13 (m, 1H), 7.08 (dtd, J = 13.3, 7.3, 1.1, 2H), 6.97−6.95 (m, 4H), 6.80 (t, J = 8.7, 2H), 6.74 (dd, J = 8.6, 5.6, 2H), 6.69 (d, J = 7.8, 1H), 6.57 (d, J = 2.6, 1H), 5.34 (s, 1H), 4.88−4.69 (m, 4H), 2.86 (s, 3H). 13C NMR (125 MHz, CDCl3, δ): 176.4, 167.3, 166.7, 144.3, 136.9, 130.8, 130.5, 129.8, 129.8, 128.8, 127.0, 124.9, 124.1, 122.4, 122.4, 122.2, 120.1, 115.5, 115.3, 115.2, 115.0, 112.5, 111.4, 108.2, 66.6, 66.3, 56.6, 53.0, 26.3. IR (film) υmax 3385, 2920, 2231, 2219, 1715, 1702, 1660, 1452, 1398, 1274, 1160, 1022, 988, 889 cm−1. HRMS (ESI-TOF) (m/z): [M + Na]+ Calcd for C34H26F2N2O5Na, 603.1702; found, 603.1706. Dibenzyl-2-(1-ethyl-3-(1H-indol-3-yl)-2-oxoindolin-3-yl)malonate.

The compound 9e was obtained as a yellow solid (0.3 mmol; 136 mg, 76% under condition A). mp 75−77 °C. Rf = 0.45 (30% EtOAc in hexane). 1H NMR (500 MHz, CDCl3) 8.14 (d, J = 7.6, 1H), 7.93 (s, 1H), 7.44−7.35 (m, 4H), 7.32 (d, J = 7.2, 1H), 7.29−7.21 (m, 4H), 7.18 (t, J = 7.5, 1H), 7.12−7.05 (m, 2H), 6.97 (d, J = 7.5, 2H), 6.89 (dd, J = 8.8, 2.5, 1H), 6.84 (d, J = 7.7, 1H), 6.74 (d, J = 2.6, 1H), 5.70 (ddt, J = 15.6, 10.3, 5.1, 1H), 5.43 (s, 1H), 5.15 (dd, J = 25.6, 13.0, 2H), 4.98 (s, 2H), 4.94 (s, 2H), 4.30 (dd, J = 16.5, 5.1, 1H), 3.90 (dd, J = 16.4, 5.5, 1H), 3.77 (s, 3H). 13C NMR (125 MHz, CDCl3, δ): 176.6, 167.5, 166.9, 154.2, 143.9, 135.2, 134.9, 132.1, 131.7, 129.3, 128.8, 128.7, 128.5, 128.5, 128.5, 128.3, 128.2, 127.3, 125.5, 124.8, 122.6, 117.5, 113.4, 112.6, 112.2, 109.4, 103.3, 67.6, 67.3, 56.9, 55.7, 53.6, 53.2, 42.7. IR (film) υmax 3382, 2932, 2241, 2229, 1726, 1622, 1420, 1350, 1388, 1264, 1120, 1012, 798, 689 cm−1. HRMS (ESITOF) (m/z): [M + H]+ Calcd for C37H33N2O6, 601.2333; found, 601.2315.

The compound 9c was obtained as a yellow solid (0.3 mmol; 137 mg, 82% under condition A). mp 72−74 °C. Rf = 0.40 (30% EtOAc in hexane). 1H NMR (400 MHz, CDCl3, δ): 7.98 (s, 1H), 7.93 (d, J = 7.3 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.18− 12677


Article

The Journal of Organic Chemistry Dibenzyl-2-(3-(1H-indol-3-yl)-5-methoxy-1-methyl-2-oxoindolin-3-yl)malonate.

168.0, 167.3, 144.7, 137.7, 129.3, 128.9, 128.5, 127.0, 125.5, 122.4, 121.9, 121.8, 119.5, 110.7, 109.4, 108.1, 56.7, 53.0, 52.5, 52.2, 32.8, 26.7. IR (film) υmax 3370, 2956, 2820, 1662, 1601, 1401, 1380, 1225, 1062, 883, 701 cm−1. HRMS (ESI-TOF) (m/z): [M + H]+ Calcd for C23H23N2O5, 407.1601; found, 407.1599. Diethyl 2-(1-methyl-3-(1-methyl-1H-indol-3-yl)-2-oxoindolin-3-yl)malonate.

The compound 9f was obtained as a yellow solid (0.3 mmol; 138 mg, 80% under condition A). mp 90−92 °C. Rf = 0.60 (50% EtOAc in hexane). 1H NMR (400 MHz, CDCl3) 8.03 (s, 1H), 7.88 (d, J = 8.1, 1H), 7.74 (d, J = 2.7, 1H), 7.30−7.22 (m, 4H), 7.18−7.14 (m, 4H), 7.08−7.02 (m, 3H), 6.90−6.83 (m, 3H), 6.76−6.40 (m, 2H), 5.38 (s, 1H), 4.89−4.80 (m, 4H), 3.73 (s, 3H), 2.81 (s, 3H). 13C NMR (100 MHz, CDCl3, δ): 176.3, 167.4, 166.8, 155.7, 138.0, 136.9, 135.0, 134.6, 130.0, 128.5, 128.5, 128.4, 128.3 (2C), 127.9, 124.9, 124.0, 122.3, 122.1, 120.1, 114.0, 113.8, 112.6, 111.4, 108.6, 67.4, 67.1, 56.9, 55.7, 53.5, 26.3. IR (film) υmax 3388, 2938, 2253, 1722, 1631, 1420, 1361, 1310, 1255, 1110, 1002, 766, 708 cm−1. HRMS (ESI) (m/z) [M + H]+ Calcd for C35H31N2O6, 575.2177; found, 575.2194. Dibenzyl-2-(5-chloro-3-(5-methoxy-1H-indol-3-yl)-1-methyl-2-oxoindolin-3-yl)malonate.

The product 8j was obtained as a colorless solid (0.3 mmol; 104 mg, 80% under condition A). mp 185−187 °C. 1H NMR (400 MHz, CDCl3, δ): 8.08 (dd, J = 7.6, 1.3 Hz, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.38 (td, J = 7.7, 1.3 Hz, 1H), 7.20−7.10 (m, 3H), 7.06 (ddd, J = 8.1, 6.5, 1.6 Hz, 1H), 6.88 (d, J = 7.7 Hz, 1H), 6.52 (s, 1H), 5.21 (s, 1H), 4.00−3.76 (m, 4H), 3.59 (s, 3H), 3.17 (s, 3H), 0.88 (t, J = 7.2 Hz, 3H), 0.77 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3, δ): 176.9, 167.6, 167.0, 144.7, 137.7, 129.4, 128.8, 128.5, 127.2, 125.6, 122.4, 122.3, 121.8, 119.4, 110.9, 109.3, 107.9, 61.4, 60.9, 56.9, 53.1, 32.7, 26.7, 13.6, 13.4. IR (film) υmax 3388, 2966, 2880, 1620, 1661, 1481, 1300, 1211, 1012, 893, 781 cm−1. HRMS (ESI-TOF) (m/z): [M + Na]+ Calcd for C25H26N2O5Na, 457.1734; found, 457.1754. Enantiomeric peaks of the pure compound were determined via HPLC analysis using a Chiralpak AD-H column; solvent, hexane/2propanol = 70/30; flow rate, 1.0 mL/min; detection, at 254 nm; tR1 = 15.70 min; and tR2 = 28.55 min (for 0% ee). Diethyl-2-(1-benzyl-3-(1-benzyl-1H-indol-3-yl)-2-oxoindolin-3-yl)malonate.

The compound 9g was obtained as a light yellow solid (0.3 mmol; 142 mg, 78% under condition A). mp 195−197 °C. Rf = 0.55 (50% EtOAc in hexane). 1H NMR (400 MHz, CDCl3, δ): 8.15 (d, J = 2.1 Hz, 1H), 7.95 (s, 1H), 7.40−7.31 (m, 5H), 7.28−7.18 (m, 4H), 7.08 (dd, J = 6.7, 2.8 Hz, 2H), 6.90−6.85 (m, 3H), 6.64−6.62 (m, 2H), 5.37 (s, 1H), 4.95−4.87 (m, 4H), 3.77 (s, 3H), 2.87 (s, 3H). 13C NMR (100 MHz, CDCl3, δ): 176.3, 167.2, 166.7, 154.2, 143.2, 134.9, 134.5, 132.0, 130.6, 128.8, 128.7, 128.6, 128.5, 128.2, 128.1, 127.8, 127.7, 125.2, 124.7, 113.5, 112.2, 111.5, 109.2, 103.2, 67.7, 67.4, 56.7, 55.7, 53.3, 26.5. IR (film) υmax 3421, 3328, 3102, 3035, 2979, 2811, 1701, 1695, 1678, 1201, 978 cm−1. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for C35H29ClN2O6Na, 631.1606; found, 631.1614. General Procedure for the Synthesis of Compounds 8a and 8i−8l. 3-Substituted 2-oxindole (9) (1 equiv) was dissolved in 1,2dichloroethane (CH2Cl)2 in an oven-dried round-bottom flask at 25 °C. To this reaction mixture, 10 mol % of a Lewis acid (In(OTf)3 in the case of condition A and Sc(OTf)3 in the case of condition B) was added, and the reaction was stirred for 5 min. Afterward, dialkyl malonate (3 equiv) was added dropwise by a syringe to the solution. Then, the reaction mixture was allowed to stir for respective times at 25 °C. Upon completion of the reaction (monitored by TLC under UV light and I2 stain), the reaction mixture was quenched with water and diluted with 5 mL of CH2Cl2. The organic layer was separated with a separatory funnel, dried over anhydrous Na2SO4, and concentrated in a rotary evaporator. The crude product was purified by flash chromatography to afford the required products (8a, 8i−8l). Dimethyl-2-(1-methyl-3-(1-methyl-1H-indol-3-yl)-2-oxoindolin-3-yl)malonate.

The product 8k was obtained as a colorless solid (0.3 mmol; 143 mg, 81% under condition A). mp 139−141 °C. 1H NMR (400 MHz, CDCl3, δ): 8.09 (d, J = 7.5 Hz, 1H), 7.88−7.86 (m, 1H), 7.25−7.18 (m, 9H), 7.14−7.03 (m, 4H), 6.96−6.93 (m, 2H), 6.75 (d, J = 7.8 Hz, 1H), 6.69 (s, 1H), 5.29 (s, 1H), 5.23−5.13 (m, 2H), 4.98 (d, J = 15.7 Hz, 1H), 4.81 (d, J = 15.8 Hz, 1H), 3.94−3.84 (m 3H), 3.74 (dq, J = 10.6, 7.1 Hz, 1H), 0.77−0.73 (m, 6H). 13C NMR (100 MHz, CDCl3, δ): 176.9, 167.5, 166.9, 143.7, 137.3, 135.9, 129.4, 128.6, 128.6, 128.1, 127.5 (two carbons), 127.4, 127.3, 126.9, 126.3 (two carbons), 125.9, 122.5, 122.5, 122.1, 119.7, 112.2, 109.9, 109.1, 61.5, 61.0, 56.9, 53.2, 50.0, 44.2, 13.4, 13.4. IR (film) υmax 3353, 2926, 2805, 1679, 1621, 1441, 1342, 1245, 1072, 923, 761 cm−1. HRMS (ESI-TOF) (m/z): [M + H]+ Calcd for C37H35N2O5, 587.2540; found, 587.2545. Dimethyl-2-(1-benzyl-3-(1-benzyl-1H-indol-3-yl)-2-oxoindolin-3-yl)malonate.

The product 8l was obtained as a colorless solid (0.3 mmol; 117 mg, 70% under condition A). mp 130−132 °C. 1H NMR (400 MHz, CDCl3, δ): 8.08 (d, J = 7.6 Hz, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.32− 7.27 (m, 8H), 7.20−7.07 (m, 4H), 7.00−6.99 (m, 2H), 6.85−6.81 (m, 2H), 5.35 (s, 1H), 5.24 (s, 2H), 4.95 (s, 2H), 3.46 (s, 3H), 3.35 (s, 3H). 13C NMR (100 MHz, CDCl3, δ): 176.9, 167.9, 167.3, 143.7, 137.3, 137.3, 135.9, 129.3, 128.8, 128.1, 128.6, 128.1, 127.5, 127.5, 127.5, 127.2, 126.3, 125.8, 122.6, 122.1, 122.0, 119.7, 111.9, 109.9, 109.1, 56.8, 53.1, 52.4, 52.1, 50.0, 44.3. IR (film) υmax 3388, 2996, 2825, 1692, 1611, 1410, 1372, 1295, 1022, 953, 701 cm−1. HRMS (ESI-TOF) (m/z): [M + H]+ Calcd for C35H31N2O5, 559.2227; found, 559.2215.

The product 8i was obtained as a colorless solid (0.3 mmol; 91 mg, 75% under condition A). mp 180−182 °C. 1H NMR (400 MHz, CDCl3, δ): 8.06 (d, J = 7.5 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.43 (t, J = 7.7 Hz, 1H), 7.24−7.17 (m, 3H), 7.11−7.07 (m, 1H), 6.94 (d, J = 7.8 Hz, 1H), 6.61 (s, 1H), 5.28 (s, 1H), 3.64 (s, 3H), 3.50 (s, 3H), 3.47 (s, 3H), 3.22 (s, 3H). 13C NMR (100 MHz, CDCl3, δ): 176.8, 12678


Article

The Journal of Organic Chemistry Synthesis of Compound 12. 3-Hydroxy 2-oxindole (7) (1 equiv) was dissolved in 1,2-dichloroethane (CH2Cl)2 in an oven-dried round-bottom flask at 25 °C. To this reaction mixture, 10 mol % of a Lewis acid (In(OTf)3 in the case of condition A and Sc(OTf)3 in the case of condition B) was added, and the reaction was stirred for 5 min. Afterward, compound 11 (3 equiv) was added dropwise by a syringe to the solution. Then, the reaction mixture was allowed to stir for respective times at 25 °C. Upon completion of the reaction (monitored by TLC under UV light and I2 stain), the reaction mixture was quenched with water and diluted with 5 mL of CH2Cl2. The organic layer was separated with a separatory funnel, dried over anhydrous Na2SO4, and concentrated in a rotary evaporator. The crude product was purified by flash chromatography to afford the required product (12). tert-Butyl-2-(3-(1H-indol-3-yl)-2-oxoindolin-3-yl)-3-oxobutanoate.

The product (±)-18 was obtained as a colorless solid (0.28 mmol scale; 81 mg, 85%). mp 110−112 °C. Rf = 0.43 (20% EtOAc in hexane). 1H NMR (400 MHz, CDCl3, δ): 7.34−7.18 (m, 2H), 7.12 (td, J = 7.7, 1.3 Hz, 1H), 6.97 (dd, J = 7.3, 1.3 Hz, 1H), 6.82 (d, J = 8.8 Hz, 2H), 6.67 (td, J = 7.4, 1.0 Hz, 1H), 6.44 (d, J = 7.8 Hz, 1H), 5.35 (s, 1H), 4.11 (ddd, J = 8.4, 7.2, 1.0 Hz, 1H), 3.76 (s, 3H), 3.52 (ddd, J = 11.5, 8.5, 4.6 Hz, 1H), 2.95 (s, 3H), 2.69 (td, J = 11.7, 7.2 Hz, 1H), 2.43 (dd, J = 11.8, 4.5 Hz, 1H). 13C NMR (100 MHz, CDCl3, δ):157.9, 152.2, 138.9, 135.3, 127.9, 127.6, 124.4, 117.7, 113.7, 106.6, 98.4, 60.7, 55.2, 53.4, 39.8, 38.5, 35.9. IR (film) υmax 3055, 2921, 2359, 1716, 1608, 1504, 1370, 1306, 1251, 1167, 1140, 1037, 935, 756, 673, 540 cm−1. HRMS (ESI-TOF) (m/z): [M + H]+ Calcd for C20H22NO4, 340.1543; found, 340.1553. Synthetic Procedure for Compound (±)-19. Compound (±)-18 (1.0 equiv., 0.14 mmol) was dissolved in dry THF (2 mL) in a flame-dried round-bottomed flask under an N2 atmosphere. LiAlH4 (5 equiv., 0.73 mmol) was added at 0 °C in an ice bath, and then the mixture was stirred for 2 h. When TLC showed that the reaction was complete, the reaction mixture was quenched by the addition of ethyl acetate at 0 °C. The mixture was then treated with water (slow and dropwise addition) until a clear organic layer formed. The organic layer was separated with a separatory funnel. The organic phase was dried with anhydrous Na2SO4 and concentrated in a rotary evaporator under vacuum. The crude product was purified by flash chromatography to give (±)-19 (94%) as a colorless solid. 3a-(4-Methoxyphenyl)-8-methyl-3,3a,8,8a-tetrahydro-2Hfuro[2,3-b]indole.

Compound 12 was obtained as a colorless solid (0.3 mmol; 112 mg, 92% under condition A). mp 120−122 °C. dr = 1.1:1 (determined from the unpurified reaction mixture] of (±)-14a. Rf = 0.51 (40% EtOAc in hexane). 1H NMR (400 MHz, CDCl3, spectrum contains ∼1.1:1 diastereomers, δ): 8.57 (d, J = 9.4, 1H for minor diastereomer), 8.44 (d, J = 8.7, 1H for major diastereomer), 8.20− 8.17 (m, 2H for major + minor diastereomers), 8.06−8.02 (m, 2H for major + minor diastereomers), 7.93 (d, J = 7.5, 1H for major diastereomer), 7.85 (d, J = 7.5, 1H for minor diastereomer), 7.25− 7.16 (m, 4H), 7.16−6.99 (m, 6H for major + minor diastereomers), 6.81−6.76 (m, 2H for major + minor diastereomers), 6.52 (s, 1H for minor diastereomer), 6.41 (s, 1H for major diastereomer), 5.43 (s, 1H for major diastereomer), 5.07 (s, 1H for minor diastereomer), 2.08− 2.04 (m, 7H for major + minor diastereomers), 1.04−1.02 (m, 9H for major diastereomer), 0.99 (s, 9H for minor diastereomer). 13C NMR (100 MHz, CDCl3, spectrum contains ∼1.1:1 diastereomers, δ): 202.5, 201.5, 179.4, 178.9, 168.1, 166.7, 141.8, 141.5, 137.2, 137.1, 130.4, 130.1, 128.5, 128.4, 128.0, 126.5, 125.4 (two carbons), 124.9, 124.4, 122.6 (two carbons), 122.4, 122.1 (two carbons), 122.1, 121.7 (two carbons), 119.7, 119.6, 111.8, 111.3, 110.1, 109.8, 83.1, 81.9, 65.0, 61.4, 54.2, 53.5, 32.4, 29.3, 27.2, 27.2, 27.1. IR (film) υmax 3455, 3364, 3220, 2884, 2019, 1722, 1711, 1665, 1461, 1223, 1207, 1185, 702, 606 cm−1. HRMS (ESI-TOF) (m/z): [M + Na]+ Calcd for C24H24N2O4Na, 427.1628; found, 427.1606. The procedures for the synthesis of compounds (+)-7a, (+)-10c, and (−)-3e were done as described in refs 11a,b,17a,b. Synthetic Procedure for Compound (±)-18. To a stirred solution of (±)-5g (300 mg, 0.6 mmol; 1.0 equiv) in DMSO (5 mL) at 25 °C was added lithium chloride (96 mg, 2.3 mmol, 4.0 equiv) and H2O (104 μL, 5.6 mmol, 10.0 equiv). After being stirred for 5 min, the reaction mixture was transferred to a preheated oil bath (140 °C), and stirring was continued for 24 h. After complete consumption of the starting material (as judged by running TLC), reaction mixture was cooled down to 25 °C and quenched with water (4 mL). The organic compound was extracted with ethyl acetate (2 × 10 mL). Then, the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography by using 20−30% (EtOAc/ hexane) to afford compound (±)-18 as a colorless solid. (±)-Ethyl 2-(3-(4-methoxyphenyl)-1-methyl-2-oxoindolin-3yl)acetate.

The product (±)-19 was obtained as a colorless solid (0.14 mmol scale; 37 mg, 94%). mp 80−84 °C. Rf = 0.42 (30% EtOAc in hexane). 1 H NMR (400 MHz, CDCl3): δ 7.34−7.18 (m, 2H), 7.12 (td, J = 7.7, 1.3 Hz, 1H), 6.97 (dd, J = 7.3, 1.3 Hz, 1H), 6.82 (d, J = 8.8 Hz, 2H), 6.67 (td, J = 7.4, 1.0 Hz, 1H), 6.44 (d, J = 7.8 Hz, 1H), 5.35 (s, 1H), 4.11 (ddd, J = 8.4, 7.2, 1.0 Hz, 1H), 3.76 (s, 3H), 3.52 (ddd, J = 11.5, 8.5, 4.6 Hz, 1H), 2.95 (s, 3H), 2.69 (td, J = 11.7, 7.2 Hz, 1H), 2.43 (dd, J = 11.8, 4.5 Hz, 1H). 13C NMR (100 MHz, CDCl3, δ): 158.3, 150.9, 136.1, 133.4, 128.4, 127.3, 124.1, 117.7, 113.9, 105.5, 105.5, 68.1, 60.2, 55.3, 40.8, 30.7. IR (film) υmax = 2931, 1606, 1490, 1387, 1297, 1260, 1182, 1037, 950, 798, 740, 662, 608, 578 cm−1. HRMS (ESI-TOF) (m/z): [M + H]+ Calcd for C18H20NO2, 282.1489; found, 282.1505. Synthetic Procedure for Compound (±)-20. Compound (±)-18 (1.0 equiv., 1.47 mmol) was dissolved in diethyl ether (7 mL) in a flame-dried round-bottomed flask under an N2 atmosphere. The reaction mixture was treated with MeOH (5 equiv., 7.37 mmol) at room temperature. Then, the solution was cooled down to 0 °C, and LiBH4 (2.5 equiv., 3.67 mmol) was added at the same temperature. After 45 min, the reaction mixture was allowed to reach room temperature. When TLC showed that the reaction was complete, the excess LiBH4 was quenched by the addition of ethyl acetate at 0 °C. The mixture was then treated with water (slow and dropwise addition) until a clear organic layer formed. The organic layer was separated with a separatory funnel. The organic phase was dried with anhydrous Na2SO4 and concentrated in a rotary evaporator under vacuum. The crude product was purified by flash chromatography to give (±)-20 (67%) as a colorless solid. 12679


Article

The Journal of Organic Chemistry 3-(2-Hydroxyethyl)-3-(4-methoxyphenyl)-1-methylindolin2-one.

(s, 3H), 2.90−2.83 (m, 1H), 2.76−2.61 (m, 2H), 2.52 (s, 3H), 2.30− 2.19 (m, 1H). 13C NMR (125 MHz, CDCl3, δ): 157.9, 152.2, 138.9, 135.3, 127.9, 127.6, 124.4, 117.7, 113.7, 106.6, 98.4, 60.7, 55.2, 53.4, 39.8, 38.5, 35.9. IR (film) υmax 3412, 2932, 1715, 1606, 1487, 1373, 1250, 1183, 1123, 1037, 950, 830, 750, 604, 569 cm−1. HRMS (ESITOF) (m/z): [M + H]+ Calcd for C19H23N2O, 295.1805; found, 295.1783.

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ASSOCIATED CONTENT

S Supporting Information *

The product (±)-20 was obtained as a colorless solid (1.47 mmol scale; 292 mg, 67%). mp 143−146 °C. Rf = 0.3 (70% EtOAc in hexane). 1H NMR (400 MHz, CDCl3, δ): 7.31 (td, J = 7.7, 1.3 Hz, 1H), 7.28−7.24 (m, 2H), 7.24−7.20 (m, 1H), 7.14−7.05 (m, 1H), 6.88 (d, J = 7.8 Hz, 1H), 6.84−6.78 (m, 2H), 3.74 (s, 3H), 3.43 (ddt, J = 25.1, 11.5, 6.2 Hz, 2H), 3.19 (s, 3H), 2.70 (dt, J = 14.0, 7.0 Hz, 1H), 2.50−2.29 (m, 1H), 2.18 (brs, 1H). 13C NMR (100 MHz, CDCl3, δ): 179.4, 158.8, 143.6, 132.1, 131.9, 128.3, 127.8, 124.6, 122.7, 114.0, 108.6, 59.4, 55.3, 54.4, 40.3, 26.5. IR (film) υmax 3422, 2933, 1697, 1610, 1512, 1471, 1373, 1253, 1185, 1096, 1034, 829, 754 cm−1. HRMS (ESI-TOF) (m/z): [M + H]+ Calcd for C18H20NO3, 298.1438; found, 298.1453. Procedure for the Synthesis of Compound (±)-22. DMSO (0.68 mmol, 5 equiv) was dissolved in dry dichloromethane (5 mL) in a flame-dried round-bottomed flask, and the mixture was cooled to −78 °C. A solution of (COCl)2 (0.50 mmol, 1.5 equiv) in dichloromethane (2 mL) was then added dropwise to the reaction mixture at −78 °C. The reaction mixture was stirred for 30 min. Then, a solution of compound (±)-20 (0.33 mmol, 5 equiv) in dry dichloromethane (2 mL) at −78 °C was added. The reaction mixture was stirred for 2 h, and then Et3N (1.68 mmol, 5 equiv) was added. The mixture was then stirred for a further 3 h, and then the temperature was slowly allowed to increase from −78 to 0 °C. When TLC showed that the reaction was completed, water and dichloromethane were added. The mixture was then separated using a separatory funnel. The combined organic layers were dried with anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was used in the next step without further purification. Next, crude aldehyde (±)-21 (0.40 mmol, 1 equiv) was taken up in dry THF (8 mL) in a flame-dried round-bottomed flask under an inert atmosphere at room temperature. MgSO4 (180 mg) was added, followed by Et3N (4.0 mmol, 10.0 equiv) and MeNH2·HCl (4.0 mmol, 10.0 equiv). The reaction mixture was stirred vigorously at room temperature for 12 h. After this time, solid LiAlH4 (4.0 mmol, 10.0 equiv) was added at room temperature. The reaction mixture was placed in a preheated oil bath, and it was heated at 70 °C for 1.5 h. When TLC showed that the reaction was complete, the reaction mixture was cooled down to room temp., and the reaction was quenched by the careful addition of EtOAc (5 mL) and then saturated aq. NaHCO3 (8 mL). The mixture was filtered through a Celite pad, which was then washed with EtOAc. The organic layer was separated with a separatory funnel. The aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography to give (±)-22 (78%) as a yellow liquid. 3a-(4-Methoxyphenyl)-1,8-dimethyl-1,2,3,3a,8,8ahexahydropyrrolo[2,3-b]indol.

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b02017. X-ray crystallographic data for compound 9d (CIF) Copies of 1H and 13C NMR spectra for all products, Xray crystal structure of 9d (CCDC 1859924), and HPLC chromatograms (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Alakesh Bisai: 0000-0001-5295-9756 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from the Science Engineering Research Board (SERB), DST [EMR/2016/000214], Ministry of Earth Sciences [MoES (09-DS/11/2018-PC-IV)], and Council of Scientific and Industrial Research [CSIR (02(0295)/17/EMRII)], Govt. of India, is gratefully acknowledged. We thank Ms. Anusha Upadhyay, IISER Bhopal, for X-ray structure analysis. K.N.B. and L.K.K. thank the CSIR, New Delhi, for Senior Research Fellowships (SRFs). Facilities from the Department of Chemistry, IISER Bhopal, are gratefully acknowledged.

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REFERENCES

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The product (±)-22 was obtained as a colorless solid (0.33 mmol scale; 79 mg, 79%). Rf = 0.42 (50% EtOAc in hexane). 1H NMR (400 MHz, CDCl3, δ): 7.23−7.15 (m, 2H), 7.09 (td, J = 7.7, 1.3 Hz, 1H), 6.88 (dd, J = 7.4, 1.3 Hz, 1H), 6.85−6.77 (m, 2H), 6.65 (td, J = 7.4, 1.0 Hz, 1H), 6.46 (d, J = 7.9 Hz, 1H), 4.44 (s, 1H), 3.76 (s, 3H), 2.97 12680


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Lewis Acid-Catalyzed Malonate Addition onto 3-Hydroxy-2-oxindoles

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