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Lewis-acid Catalyzed Malonate Addition onto 3Hydroxy 2-Oxindoles: Mechanistic Consideration and Synthetic Approaches to the Pyrroloindoline Alkaloids K. Naresh Babu, Nikhil Raj Kariyandi, Saina Saheeda M. K., Lakshmana Kumar KINTHADA, and Alakesh Bisai J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02017 • Publication Date (Web): 21 Sep 2018 Downloaded from http://pubs.acs.org on September 21, 2018

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The Journal of Organic Chemistry

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*

Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal Bypass Road, Bhopal, Madhya Pradesh - 462 066, INDIA

TOC GRAPHIC

ABSTRACT Metal triflate catalyzed reactions of 3-hydroxy-2-oxindoles with a variety of malonate have been developed under mild condition. The reaction affords a variety of 2-oxindoles 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 malonate addition product in racemic form, clearly suggesting that the reaction proceeds through in situ generated 2H-indol-2-one intermediate (4a). Synthetic potential of this methodology has been shown by approaching the cyclotryptamine alkaloids linked with aryl group at the pseudobenzylic position.

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INTRODUCTION Synthesis of small organic molecules sharing the biologically active natural product skeleton1 is of crucial 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 ingredients3 significant effort has been directed toward the synthesis of this structural motif. Particularly, 2-oxindoles bearing an all-carbon quaternary stereocenter4 at the C-3(a) 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), pestalazine (1b)5 (Figure 1) having a tricyclic C(3a)-arylpyrroloindoline core (2).

Figure 1: Asperazine (1a), pestalazine (1b) and C(3a)-pyrroloindoline 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 electrondeficient 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 electron-deficient 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 disubstituted 2-oxindoles is most demanding since


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they create an 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 trifluoromethane sulfonic acid (TfOH) leading to the formation of an allcarbon quaternary center at the pseudobenzylic C-3 position of 2-oxindole 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 have reported a one-pot integrated Brønsted base-catalyzed trichloroacetimidation of 3-hydroxyoxindoles followed by a Brønsted acidcatalyzed 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 have shown efficient Lewis acid catalyzed Friedel–Crafts alkylations of phenols with 3-alkyl 3-hydroxy 2-oxindoles.10a,b 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 2-oxindoles. In the case of Lewis acid catalysed Friedel–Crafts reactions of 3-hydroxy-2-oxindoles, it is believed to be 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 3-halo 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

Scheme 1: Proposed synthesis of cyclotryptamine alkaloids core (2) via Lewis acid catalysed malonate addition. We envisioned that a Lewis acid catalysed reaction of 3-hydroxy 2-oxindoles can be realized with malonates as nucleophiles in the presence of catalytic metal triflate under mild condition



(Scheme 1). Based on 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 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-2-oxindoles15, 16 with prior unmodified substrates is an important area of research. Herein, we report metal triflate catalyzed an inexpensive and environmentally benign malonate addition on to a variety of 3-hydroxy 2-oxindoles for the synthesis of various 3,3-disubstituted 2-oxindoles and its application to pyrroloindoline scaffolds.

RESULTS AND DISCUSSION Lewis acid activation of 3-hydroxy-2-oxindoles followed by reaction with a suitable nucleophile gives access to 2-oxindoles 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-oxindole such as 3a and subsequent reaction with malonates for the synthesis of these 2oxindole based structures such as 5a. Towards this, we selected 3-aryl 3-hydroxy 2-oxindole (3a) as an electron-deficient partner with diethyl malonate as the electron-rich species, respectively, in the presence of catalytic amount of metal triflate as Lewis acid (Table 1). Our initial optimization with 0.3 mmol of 3a and 0.9 mmol of diethyl malonate in presence of 20 mol% of Lewis acids such as BF3.OEt2 in 2 mL of dichloromethane at 25 °C afforded only trace amount of 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). Table 1: Optimization of malonate addition on 3-hydroxy 2-oxindole 3a.a-b


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a

S. No.

Lewis acids

solvent

temp

time

yield (%)

BF3.OEt2

catalyst loading 20 mol%

1.

CH2Cl2

25 ºC

12 h

tracesc

2.

In(OTf)3

20 mol%

CH2Cl2

25 ºC

12 h

26%c

3.

In(OTf)3

20 mol%

CH2Cl2

40 ºC

10 h

89%

4.

In(OTf)3

10 mol%

CH2Cl2

40 ºC

12 h

87%

5.

Bi(OTf)3

10 mol%

CH2Cl2

40 ºC

1h

58%d

6.

Fe(OTf)3

10 mol%

CH2Cl2

40 ºC

12 h

42%

7.

Sc(OTf)3

10 mol%

CH2Cl2

40 ºC

15 h

83%

8.

Yb(OTf)3

10 mol%

CH2Cl2

40 ºC

20 h

29%c

9.

Zn(OTf)2

10 mol%

CH2Cl2

40 ºC

20 h

35%c

10.

Sc(OTf)3

10 mol%

MeCN

65 ºC

15 h

tracesd

11.

Sc(OTf)3

10 mol%

PhMe

100 ºC

15 h

12%c

12.

Sc(OTf)3

10 mol%

(CH2Cl)2

80 ºC

1h

94%

13.

In(OTf)3

10 mol%

(CH2Cl)2

80 ºC

1h

92%

14.

Sc(OTf)3

5 mol%

(CH2Cl)2

80 ºC

6h

85%

15.

In(OTf)3

5 mol%

(CH2Cl)2

80 ºC

6h

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.c rest of the mass recovered as starting material. drest of the mass decomposed.

A quick Lewis acid optimization revealed that diethyl malonate addition onto 3-aryl 3hydroxy 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 the 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, malonate addition product 5a was obtained in up to 85% and 82% yields, respectively (entries 14-15). Scheme 2: Substrate scope using different malonates on 3a-d.a-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 ºC. bisolated yields after column chromatography.

Therefore, based on optimization, two conditions viz. 10 mol% of Sc(OTf)3 (condition A) and In(OTf)3 (condition B) were chosen as standard conditions to carry out malonate addition. Subsequently, we tested reactions of 3-hydroxy 2-oxindole 3a as electron-deficient partners with a variety of malonates, which afforded products 5a-d in 75–91% yields in 1 h


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(Scheme 2). Next, we have attempted to explore substrate scope using variety of 3-aryl 3hydroxy 2-oxindoles to afford the products 5e-i in up to 90% yield (Scheme 2). Gratifyingly, it was found that diethyl malonate addition onto 3-aryl 3-methoxy 2-oxindole (3e) under conditions A [10 mol% of Sc(OTf)3] and B [10 mol% of In(OTf)3] afforded product 10a in 90% and 85% yields, respectively (Scheme 4). To our delight, a range of 3-aryl 3-methoxy 2oxindoles (3e-g) underwent malonate addition to afford a wide range of 2-oxindoles having an all-carbon-quaternary center (such as 6a-f) in good to excellent yields (Scheme 3).

Scheme 3: Substrates scope using variety of 3-aryl 3-hydroxy 2-oxindoles (3e-g).a-b

a

reactions were carried out using 0.3 mmol of 3e-g (1 equiv.) with 0.9 mmol of malonate (3 equiv.) in 2.0 mL

1,2-dichloroethane at 80 ºC. bisolated yields after column chromatography.

Further, we turned our attention for exploration of 3-(3’-indolyl) 3-hydroxy 2-oxindoles of type 7 as electron-deficient partners, as the products from these reactions have huge potential for the synthesis of dimeric pyrroloindoline alkaloids.11b These substrates are challenging in a sense that, they have both electron-deficient center (hydroxyl group at C-3 position) as well



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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 electron-deficient 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-2-oxindoles of type 7 with functionalization on both scaffolds namely 2-oxindole as well as indole part of 7 (Scheme 4). As a result, a wide range of 3-(3’indolyl)-3-malonyl-2-oxindoles

bearing

an

all-carbon-quaternary

centers

at

the

pseudobenzylic position are obtained in good yields (8a-h; Scheme 4). Gratifyingly, 2oxindole as well as indole part containing a deactivating halogen group such as bromo functionality (see, 8f-h) also afforded products in 70-77% yields. Scheme 4: Substrates scope using variety of 3-indolyl 3-hydroxy 2-oxindoles (7a-f).a-b

a

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 ºC. bisolated yields after column chromatography.


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Next, we tested substrate scope using various N-substituted 3-(3’-indolyl) 3-hydroxy-2oxindoles of type 7g-l with a variety of malonates under the optimized condition (Scheme 5). To our delight, a wide variety of 3-(3’-indolyl) 3-malonyl 2-oxindoles bearing an all-carbonquaternary centers at the pseudobenzylic position are obtained in high yields (9a-g; Scheme 5). A variety of N-alkyl groups such as methyl, ethyl, allyl, cinnamyle on 2-oxindole part well tolerated under the stand condition. Noteworthy to observe was that, 2-oxindole starting materials containing electron-donating and deactivating halogen group such as 9f and 9g as well as indole part containing electron-donating group such as 9e was obtained in 75-80% isolated yields (Scheme 5). Scheme 5: Substrates scope using variety of 3-(N-substituted indolyl) 3-hydroxy 2-oxindoles (7g-l).a-b

a

reactions were carried out using 0.3 mmol of 7g-l (1 equiv.) with 0.9 mmol of malonate (3 equiv.) in 2.0 mL




Interestingly, one of the malonate addition product 9d (CCDC 1859924) gave a suitable crystal for X-ray analysis (Figure 2), which unambiguously proved the formation of allcarbon 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-c 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-l; Scheme 6).

a

reactions were carried out using 0.3 mmol of 10a-c (1 equiv.) with 0.9 mmol of malonate (3 equiv.) in 2.0 mL


Scheme 6: Substrates scope using variety of 3-methoxy/benzyloxy-2-oxindoles 10a-c.a-b


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Further, active methylene group containing substrate such as tert-butyl acetoacetate (11) were utilized as nucleophile to react with 3-(3’-indolyl)-3-hydroxy-2-oxindole 7a (Scheme 7). Therefore, products 3,3 disubstituted 2-oxindoles 12 were obtained in excellent yields, however, no diastereoselectivity were observed under the condition of A and B (Scheme 7).

a

reactions were carried out using 0.3 mmol of 7a (1 equiv.) with 0.9 mmol of b-ketoesters (3 equiv.) in 2.0 mL


Scheme 7: Substrates scope using variety of alkyl acetoacetates on compound 7a.a-b A plausible mechanism of Lewis acid catalyzed activation of 3-hydroxy/methoxy-2oxindoles (3, 7, and 10) with malonate has been 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 of 3-methoxy/3-hydroxy-2-oxindole in presence of catalytic metal triflates. The malonate could directly react with 2H-indol-2-one (4a or 4b) to afford 3,3disubstituted 2-oxindoles having an all-carbon quaternary stereocenter (Scheme 8).

Scheme 8: Proposed mechanism of malonates addition with 3-hydroxy/3-methoxy-2oxindoles.



However, if this proposed pathway goes through 2H-indol-2-one (4a), then enantioenriched 3-hydroxy/methoxy 2-oxindoles (such as 3, 7, 10) should afford 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 10 mol % of cinchona catalyst 15 (Scheme 10).17a Later, a one-pot Nand O-methylation of (+)-7a with methyl iodide in the presence of NaH afforded (+)-10c in 88% yield in 91% ee (Scheme 9).

Scheme 9: Control experiments using 3-hydroxy/methoxy-2-oxindoles.

Additionally, as per literature report by Chimni et al.,17b we have synthesized 3-aryl 3methoxy-2-oxindole (–)-3e utilizing organocatalytic enantioselective addition of sesamol in the presence of cinchona based catalyst 17 (10 mol%) in methyl tert-butylether (MTBE) solvent (Scheme 11). This reaction afforded enantioenriched (+)-16 in 90% yield with 90% ee, from where methylations of hydroxyl groups afforded (-)-3e in 90% yield with 90% ee (Scheme 10).17b


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Scheme 10. Synthesis of enantioenriched 3e. With enantioenriched, 3-indolyl 3-hydroxy-2-oxindole (+)-7a, 3-(N-methylindolyl) 3methoxy 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 investigated (Schemes 9 and 10). Towards 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 intermediate of type 4a (Scheme 1). This result proves that the Lewis-acidcatalyzed reaction of 3-hydroxy-/methoxy-2-oxindoles with malonates probably proceeds through the SN1 pathway (Schemes 9-10). We then moved towards the synthesis of C(3a)-arylpyrroloindoline scaffolds (Scheme 11). Towards this end, Krapcho reaction of 5g was carried out using LiCl in DMSO:H2O at 160 °C to give ester compound 18 in 85% yield, which underwent reductive cyclisation in the presence of LiAlH4 at 0 °C to furnish furoindoline scaffold 19 in 94% yield. In another sequence, ester compound (18) was converted to primary alcohol (20) by using LiBH4 in 67% yield, which was further oxidized by using Swern oxidation to give aldehyde in intermediate 21 (Scheme 11). This crude aldehyde was converted into tricyclic C(3a)-aryl pyrroloindoline (22) through imine formation using methylamine hydrochloride followed by reductive cyclisation in the presence of LiAlH4 in THF under refluxing condition in 79 % over two steps (Scheme 11).



Scheme 11: Synthesis of C(3a)-arylpyrroloindoline core 2.

CONCLUSIONS In summary, we developed an efficient method for synthesis of 2-oxindoles sharing an allcarbon quaternary center at the pseudobenzylic position by Lewis acid catalysed reaction of 3-substituted 3-hydroxy 2-oxindoles and 3-substituted 3-methoxy 2-oxindole with various active methylene carbons as nucleophilic partners. Lewis acid catalyzed malonate additions on to enantioenriched 3-hydroxy 2-oxindoles (+)-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 the synthesis of C(3a)pyrroloindoline structural motifs 2, which are present in a number of cyclotryptamine alkaloids.

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.


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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 oil bath temperature. Thin layer chromatography 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 of 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

13

C NMR spectra were recorded 400, 500 MHz

spectrometers with 13C operating frequencies of 100, 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), br (broad). IR spectra were recorded on a FT-IR system (Spectrum BX) and are reported in frequency of absorption (cm1

). Only selected IR absorbencies are reported. High-Resolution Mass Spectrometry (HRMS)

and Low-Resolution Mass Spectrometry (LRMS) data were recorded on MicrOTOF-Q-II mass spectrometer using methanol as solvent. General Procedure for the synthesis of 3-hydroxy-3-substituted-2-oxindoles (3a-d): In 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 ºC. To this reaction mixture (15.0 mmol, 2.2 equiv. in case of (3a-c) preparation and 7.5 mmol for (3d) aryl magnesium bromide was added drop-wise over a period of 10 minutes. The reaction mixture was then allowed to stir for 3 h. Upon completion of 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 aqueous layer was washed with EtOAc (2 X 40 mL). The combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified through column chromatography using hexane-EtOAc system as eluent to afford the desired product (3a-d). For characterization of compounds (3a-d) see the reference 10, 11



General Procedure for the synthesis of compound (3e-g): Step 1: In 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%) was 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 taken in a separatory funnel to separate the organic layer. Then the combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure. This crude product was used for next step without purification. Step 2: To the crude product of 3-hydroxy 2-oxindoles (~5.4 mmol; 1.0 equiv) was dissolved in DMF solvent under N2 atmosphere which was taken 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 in portion-wise at 0 ˚C. Alkyl halide (2.5 equiv, 13.5 mmol) was then added dropwise with a syringe to the solution. The reaction was allowed to stir for 1h at 0 ˚C and then bring it to room temperature. The reaction mixture was quenched with slow addition of water and diluted with 50 mL of EtOAc after completion of reaction (monitored by TLC). The reaction mixture was taken in 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 compound (3f) was obtained as 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


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– 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);

13

C 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-5-yl)indolin-2-one: The compound (3g)was obtained as 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 reference 10b. Synthetic procedure for the compound (3h): In an oven-dried round bottom flask was charged with isatin (1g; 6.8 mmol; 1.0 equiv) in methyl tert-butyl ether (15 mL) under nitrogen atmosphere at 25 ºC. To this solution, sesamol (8.2 mmol, 1.2 equiv) and Et3N (1.3 mmol, 20 mol%) was added sequentially and the reaction mixture was allowed to stir for 15 h. Upon completion of starting material (judged by TLC analysis), the reaction mixture was quenched with water (20 mL) and organic compound was extracted with ethyl acetate (2 X 30 mL). Then the combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure. This crude product was used for next step without purification.



Page 18 of 49

To the crude product of 3-hydroxy 2-oxindoles (~6.3 mmol; 1.0 equiv) in dichloromethane (30 mL) under nitrogen atmosphere at 25 ºC Lewis acid (~0.63 mmol, 10 mol %) and MeOH (~31.5 mmol, 5.0 equiv) was added. Then the reaction mixture was allowed to stir for 12 h. Upon completion of starting material (judged by TLC analysis under UV light and I2 stain), the reaction mixture was quenched with water (30 mL) and organic compound was extracted with ethyl acetate (2 X 40 mL). The combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified through column chromatography using 30-40% (EtOAc/Hexane) as eluent to afford the desired product.

3-(6-Hydroxybenzo[d][1,3]dioxol-5-yl)-3-methoxyindolin-2-one:

Compound

(3h)was

obtained as 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, DMSOd6) 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 synthetic procedure and characterization of compounds 7a-f, see the reference 15c. General procedure for the synthesis of compound (7g-l): In a round-bottom flask was charged with isatin (1.0 equiv) in MeOH (30 mL) under nitrogen atmosphere at 25 ºC indole (1.2 equiv) and KOH (0.2 equiv) were added successively. Then the reaction mixture was then allowed to stir for 5-6 h. Upon completion of starting material (judged by TLC analysis under UV light and I2 stain), the reaction mixture was quenched with water (20 mL) and organic compound was extracted with ethyl acetate (2 X 50 mL). The combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure.


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The crude product was purified through column chromatography using hexane-EtOAc as eluent to afford the desired product (7g-l).

3-Hydroxy-3-(1H-indol-3-yl)-1-methylindolin-2-one: The compound (7g) was obtained as 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 CDCl3,0.1mL 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);

13

C 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 (ESITOF) 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 (7h) was obtained as a yellow solid (5.7 mmol scale of reaction, 1.5 gm 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 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 cm1

. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H17N2O2 293.1285; Found 293.1276.



Page 20 of 49

1-Allyl-3-hydroxy-3-(5-methoxy-1H-indol-3-yl)indolin-2-one: The compound (7i) was obtained as a yellow solid (5.3 mmol scale of reaction, 1.6 gm 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);

13

C NMR (125 MHz, CDCl3)

δ176.8, 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 gm, 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.


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3-Hydroxy-3-(1H-indol-3-yl)-5-methoxy-1-methylindolin-2-one: The compound (7k) was obtained as a yellow solid (5.1 mmol scale of reaction, 1.4 gm 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.

5-Chloro-3-hydroxy-3-(5-methoxy-1H-indol-3-yl)-1-methylindolin-2-one: The compound (7l) was obtained as a yellow solid (5.2 mmol scale of reaction, 1.4 gm of product, 89% yield); mp = 195 – 197 °C; Rf = 0.250 (50% EtOAc in hexane); 1H NMR (400 MHz, DMSOd6) 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 synthetic procedure and characterization of compound 10a, see the reference 15c. For synthesis and characterization of compounds 10b-c, see the reference10c. For synthesis and characterization of compounds (+)-7a, (+)-10c see the reference 17a, 11b. For synthesis and characterization of compounds (+)-16, (-)-3e, see the references 17b and 11a.



Page 22 of 49

General Procedure for the synthesis of compounds (5a-g): 3-Hydroxy 2-oxindole (8) (1 equiv) was dissolved in 1,2-dichloroethane (CH2Cl)2 in an oven dried round bottom flask at 25 ºC. To this reaction mixture, 10 mol% of Lewis acid (In(OTf)3 in case of condiitin A and Sc(OTf)3 in case of condition B) was added and stirred it for 5 minutes. Afterwards, dialkyl malonate (3 equiv) was added drop wise by a syringe to the solution. Then the reaction mixture was transferred to oil bath and stirring was continued for respective times at 80 ºC. 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 and dried over anhydrous Na2SO4, concentrated in a rotary evaporator. The crude product was purified by flash chromatography to afford required products (5a-g).

Diethyl-2-(3-(4-methoxyphenyl)-2-oxoindolin-3-yl)malonate:

The

product

(5a)

was

obtained as 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.

Dimethyl-2-(3-(4-methoxyphenyl)-2-oxoindolin-3-yl)malonate: The product (5b) was obtained as colorless solid (0.3 mmol scale; 95 mg, 86% under Condition A); Rf = 0.35 (40%


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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 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 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 (5e) was obtained as 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 (5f) was obtained as 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.


Page 24 of 49

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Diethyl-2-(3-(4-methoxyphenyl)-1-methyl-2-oxoindolin-3-yl)malonate: The product (5g) was obtained as 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); 13C 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-f): 3-aryl-2-oxindole (3) (1 equiv) was dissolved in 1,2-dichloroethane (CH2Cl)2 in an oven dried round bottom flask at 25 ºC. To this reaction mixture, 10 mol% of Lewis acid (In(OTf)3 in case of condiitin A and Sc(OTf)3 in case of condition B) was added and stirred it for 5 minutes. Afterwards, dialkyl malonate (3 equiv) was added drop wise by a syringe to the solution. Then the reaction mixture was allowed to stir for respective times at 25 ºC. 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 and dried over anhydrous Na2SO4, concentrated in a rotary evaporator. The crude product was purified by flash chromatography to afford required products (6a-f).

Diethyl-2-(3-(6-methoxybenzo[d][1,3]dioxol-5-yl)-1-methyl-2-oxoindolin-3-yl)malonate: The product (6a) was obtained as 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 pure compound was determined via HPLC analysis using a Chiralpak AD-H column; solvent: hexane/2-propanol = 60/40; flow rate: 1.0 mL/min; detection: at 254 nm): tR1 = 7.35 min, tR2 = 8.80 min. for 0% ee).

Diethyl-2-(1-allyl-3-(6-methoxybenzo[d][1,3]dioxol-5-yl)-2-oxoindolin-3-yl)malonate: The product (6b) was obtained as 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); 13C 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.


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Diethyl-2-(1-benzyl-3-(6-methoxybenzo[d][1,3]dioxol-5-yl)-2-oxoindolin-3-yl)malonate: The product (6c) was obtained as 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, 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)-1-methyl-2-oxoindolin-3yl)malonate: The product (6d) was obtained as 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);

13

C 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: The product (6e) was obtained as 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 (6f) was obtained as a colourless solid (0.3 mmol scale; 108 mg, 85% under Condition A); 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; MP 135 - 137 ºC. General Procedure for the synthesis of compounds (8a-j): 3-Methoxy 2-oxindole (7) (1 equiv) was dissolved in 1,2-dichloroethane (CH2Cl)2 in an oven dried round bottom flask at 25 ºC. To this reaction mixture, 10 mol% of Lewis acid (In(OTf)3 in case of condiitin A and Sc(OTf)3 in case of condition B) was added and stirred it for 5 minutes. Afterwards, dialkyl malonate (3 equiv) was added drop wise by a syringe to the solution. Then the reaction mixture was allowed to stir for respective times at 25 ºC. Upon completion of reaction (monitored by TLC under UV light and I2 stain), the reaction mixture was quenched with


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water and diluted with 5 mL of CH2Cl2. The organic layer was separated with a separatory funnel and dried over anhydrous Na2SO4, concentrated in a rotary evaporator. The crude product was purified by flash chromatography to afford required products (8a-j).

Diethyl-2-(3-(1H-indol-3-yl)-2-oxoindolin-3-yl)malonate:15c Compound (8a) was obtained as yellow solid (0.3 mmol scale; 102 mg, 84% under Condition A); 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; MP 170 - 172 ºC; Enantiomeric peaks of pure compound was 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, tR2 = 28.70 min (for 0% ee).

1-Benzyl-3-ethyl-2-(-3-(1H-indol-3-yl)-2-oxoindolin-3-yl)malonate:15c

Compound

(8b)

was obtained as yellow solid (0.3 mmol scale; 112 mg, 80% under Condition A); 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, 1725, 1458, 1322, 1241, 1148, 738 cm-1; HRMS (ESI) m/z [M + Na]+ Calcd for C28H24N2O5Na 491.1577; Found 491.1602; MP 191 - 193 ºC.

Diethyl -2-(5-chloro-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); 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; MP 192 - 194 ºC.


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Diethyl -2-(3-(1H-indol-3-yl)-2-oxo-5-phenylindolin-3-yl)malonate:15c Compound (8d) was obtained as a colorless solid (0.3 mmol scale; 115 mg, 80% under Condition A); 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; MP 180 - 182 ºC.

Diethyl -2-(3-(5-methoxy-1H-indol-3-yl)-2-oxoindolin-3-yl)malonate:15c Compound (8e) was obtained as a orange solid (0.3 mmol scale; 104 mg, 80% under Condition A); 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; MP 130 - 132 ºC.



Page 32 of 49

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); 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; MP 123 - 125 ºC.

Diethyl-2-(5-bromo-3-(1H-indol-3-yl)-2-oxoindolin-3-yl)malonate:15c Compound (8g) was obtained as a brown solid (0.3 mmol scale; 103 mg, 71% under Condition A); 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);

13

C 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 (ESI-TOF) m/z: [M + Na]+ Calcd for C23H21BrN2O5Na 507.0526; Found 507.0530; MP 182 - 184 ºC.

Dibenzyl-2-(3-(5-bromo-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 =


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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 cm1

; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C33H25BrN2O5Na 631.0839, Found:

631.0867. General Procedure for the synthesis of compounds (9a-g): 3-Hydroxy 2-oxindole (7) (1 equiv) was dissolved in 1,2-dichloroethane (CH2Cl)2 in an oven dried round bottom flask at 25 ºC. To this reaction mixture, 10 mol% of Lewis acid (In(OTf)3 in case of condiitin A and Sc(OTf)3 in case of condition B) was added and stirred it for 5 minutes. Afterwards, dialkyl malonate (3 equiv) was added drop wise by a syringe to the solution. Then the reaction mixture was allowed to stir for respective times at 25 ºC. 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 and dried over anhydrous Na2SO4, concentrated in a rotary evaporator. The crude product was purified by flash chromatography to afford required products (9a-g).

Dibenzyl 2-(3-(1H-indol-3-yl)-1-methyl-2-oxoindolin-3-yl)malonate: The compound (9a) was obtained as 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,



Page 34 of 49

2975, 2911, 1710, 1690, 1608, 1451, 1203, 805 cm-1; HRMS (ESI-TOF) 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 (9b) was obtained as a yellow solid (0.3 mmol scale; 142 mg, 82% under Condition A); Rf = 0.42 (40% EtOAc in hexane); 1H 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);

13

C 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 (9c) was obtained as yellow solid (0.3 mmol; 137 mg, 82% under Condition A); mp = 72 - 74 ºC; 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 - 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,


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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-3-yl)malonate: The compound (9d) was obtained as yellow solid (0.04 mmol scale; 22 mg, 83%); mp = 96 - 98 ºC; 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 (9e) was obtained as yellow solid (0.3 mmol; 136 mg, 76% under Condition A); mp 75 - 77 ºC; 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 =



Page 36 of 49

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 (ESI-TOF) m/z: [M + H]+ Calcd for C37H33N2O6 601.2333; Found 601.2315.

Dibenzyl-2-(3-(1H-indol-3-yl)-5-methoxy-1-methyl-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 ºC; 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);

13

C 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 compound (9g) was obtained as 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,


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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, 8i-l): 3-substituted 2-oxindole (9) (1 equiv) was dissolved in 1,2-dichloroethane (CH2Cl)2 in an oven dried round bottom flask at 25 ºC. To this reaction mixture, 10 mol% of Lewis acid (In(OTf)3 in case of condiitin A and Sc(OTf)3 in case of condition B) was added and stirred it for 5 minutes. Afterwards, dialkyl malonate (3 equiv) was added drop wise by a syringe to the solution. Then the reaction mixture was allowed to stir for respective times at 25 ºC. 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 and dried over anhydrous Na2SO4, concentrated in a rotary evaporator. The crude product was purified by flash chromatography to afford required products (8a, 8i-l).

Dimethyl-2-(1-methyl-3-(1-methyl-1H-indol-3-yl)-2-oxoindolin-3-yl)malonate:

The

product (8i) was obtained as 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);

13

C

NMR (100 MHz, CDCl3) δ 176.8, 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.



Page 38 of 49

Diethyl 2-(1-methyl-3-(1-methyl-1H-indol-3-yl)-2-oxoindolin-3-yl)malonate: The product (8j) was obtained as 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 pure compound was 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 = 15.70 min, tR2 = 28.55 min (for 0% ee).

Diethyl-2-(1-benzyl-3-(1-benzyl-1H-indol-3-yl)-2-oxoindolin-3-yl)malonate: The product (8k) was obtained as 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);

13

C 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 HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C37H35N2O5 587.2540; Found 587.2545.


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Dimethyl-2-(1-benzyl-3-(1-benzyl-1H-indol-3-yl)-2-oxoindolin-3-yl)malonate:

The

product (8l) was obtained as 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);

13

C 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. Synthesis of compound (12): 3-Hydroxy 2-oxindole (7) (1 equiv) was dissolved in 1,2dichloroethane (CH2Cl)2 in an oven dried round bottom flask at 25 ºC. To this reaction mixture, 10 mol% of Lewis acid (In(OTf)3 in case of condiitin A and Sc(OTf)3 in case of condition B) was added and stirred it for 5 minutes. Afterwards, compound 11 (3 equiv) was added drop wise by a syringe to the solution. Then the reaction mixture was allowed to stir for respective times at 25 ºC. 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 and dried over anhydrous Na2SO4, concentrated in a rotary evaporator. The crude product was purified by flash chromatography to afford required products (12).

tert-Butyl-2-(3-(1H-indol-3-yl)-2-oxoindolin-3-yl)-3-oxobutanoate: Compound (12) was obtained as a colourless solid (0.3 mmol; 112 mg, 92% under Condition A); dr = 1.1:1 (determined from un purified reaction mixture] of (±)-14a; Rf = 0.51 (40% EtOAc in hexane); 1

H 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

13

C 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; MP 120 122 ºC. Procedure for the synthesis of compound (+)-7a, (+)-10c and (-)-3e followed as described in references 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 ºC was added lithium chloride (96 mg, 2.3 mmol, 4.0 equiv) and H2O (104 µL, 5.6 mmol, 10.0 equiv). After 5 minutes starring, the reaction mixture was transferred to a pre-heated oil bath (140 ºC) and stirring was continued for 24 h. After complete consumption of starting material (as judged by running TLC), reaction mixture was cooled down to 25 ºC and quenched with water (4 mL). The organic compound was extracted with ethyl acetate (2 X 10 mL). Then the combined organic layers were dried over anhydrous sodium sulphate 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 colourless solid.

(±)-Ethyl 2-(3-(4-methoxyphenyl)-1-methyl-2-oxoindolin-3-yl)acetate: The product (±)-18 was obtained as 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 =


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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) δ157.9, 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 a nitrogen 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-2H-furo[2,3-b]indole: The product (±)-19 was obtained as colorless solid (0.14 mmol scale; 37 mg, 94%. mp = 80 – 84 °C; Rf = 0.42 (30 % 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 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.



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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 a nitrogen 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 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.

3-(2-Hydroxyethyl)-3-(4-methoxyphenyl)-1-methylindolin-2-one: The product (±)-20 was obtained as colorless solid (1.47 mmol scale; 292 mg, 67%); Rf = 0.3 (70 % EtOAc in hexane). M.P. 143 – 146 °C; 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);

13

C 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 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. The reaction mixture was stirred for 2 h, and then Et3N


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(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,8,8a-hexahydropyrrolo[2,3-b]indol:

The

product (±)-22 was obtained as colourless 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 (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) 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 (ESI-TOF) m/z: [M + H]+ Calcd for C19H23N2O 295.1805; Found 295.1783. ASSOCIATED CONTENT Supporting Information Copies of 1H and

13

C NMR spectra for all products, X-ray crystal structure of 9d (CCDC

1859924) and HPLC chromatograms. This material is available free of charge via the Internet at http://pubs.acs.org AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] Notes The authors declare no competing financial interest. ACKNOWLEDGEMENTS Financial supports 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/EMR-II)], Govt. of India, are 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 is gratefully acknowledged. REFERENCES AND NOTES 1. (a) Nicolaou, K. C.; Montagnon, T. Molecules That Changed the World: A Brief History of the Art and Science of Synthesis and Its Impact on Society; Wiley: Weinheim, 2008. (b) Dewick, P. M. Medicinal Natural Products; Wiley: West Sussex, 2009.


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