Synthesis of 2,2-Disubstituted Indolin-3-ones via Enolonium Species

Abstract

Herein, we present an efficient and operationally simple one-pot synthesis of a broad range of 2,2-disubstituted indolin-3-ones via the double umpolung reaction of 2-aminophenyl-3-oxopropanoate. The 2-substituent introduced in the reaction may be hydroxy or acetamide. The products can then be functionalized further. The procedure has a broad scope and functional group tolerance. Importantly, density functional theory (DFT) calculations provide novel mechanistic insight into both this and related reactions and reveal that two C-enolonium species are key intermediates of this transformation.

Functionalized oxindoles are an integral part of a wide spectrum of alkaloid natural products and serve as key building blocks for the synthesis of pharmaceutically relevant compounds. Particularly, 2,2-disubstituted indolin-3-ones are commonly encountered structural components in bioactive alkaloids. Notably, indolin-3-ones bearing a hydroxy or amine group at the C2-position, such as matemone, cephalinone B, secoleuconoxine, and melochicorin (Figure A), have been found to exhibit a broad range of biological activities. ,

1.

Selected examples of natural products containing indolin-3-ones and methods for their preparation.

Currently, the most used method for synthesizing 2-hydoxy-indolin-3-ones is the oxidation of indoles. This oxidation can be performed using various oxidants including dimethyldioxirane (DMDO), Pd­(acac)₂/H₂O₂, and several others. − Another reliable strategy involves the intramolecular cyclization of either amino acetophenone derivatives or nitrogen-containing phenyl acetylene derivatives to produce the corresponding 2-hydoxy-indolin-3-ones. Notably, Yang reported on the oxidative cyclization of 2-aminophenyl-1,3-dione using a combination of ceric ammonium nitrate (CAN) and TEMPO as oxidants for the construction of 2-hydroxy-indolinones (Figure B). Recently, Wu and co-workers demonstrated the copper-catalyzed oxidative cyclization of 2-arylethynylanilines for accessing 2-hydroxy indolinones. Of particular relevance to this work, Fan et al. reported on the cyclization of anilines using PIDA as an oxidant for the construction of indolinones (Figure B). Fan reported 8 examples of which one (R¹, R² = H) produced in 50% yield was converted into a variety of benzene derivatives via Friedel-Craft-type chemistry with the acetate function as the leaving group. Formation of quaternary centers from other products was not possible. While a mechanism was proposed, no supporting evidence was provided.

Our group has pioneered the preparation of semistable enolonium species from hypervalent iodine reagents and carbonyl enolates and studied their structure spectroscopically and mechanistically. We − and other groups , have also demonstrated the broad applicability of these in situ generated electrophilic enolonium species in various umpolung intermolecular α-functionalization reactions. −

We have previously shown that β-keto esters can form enolonium species when treated with hypervalent iodine reagents. , We hypothesized that substrates such as 2-aminophenyl-3-oxopropanoate (Figure C), where β-keto ester and nucleophilic amino group are tethered in the same molecule, could engage in intramolecular cyclization via enolonium species to produce the indolin-3-one. This compound could then be oxidized in a second step, possibly again via an enolonium species, to afford the 2,2-disubstituted indolin-3-ones.

Thus, we commenced our studies with 2-aminophenyl-3-oxopropanoate 1a as a model substrate. First, we screened various hypervalent iodine reagents in dichloromethane (DCM) as a solvent at room temperature (Table ). Naturally at least two equivalents of hypervalent iodine reagent would be required to enable the two oxidation events. Surprisingly, commercially available PIDA did not produce product 2a (entry 1). To our delight, PIFA produced the anticipated intramolecular cyclized product 2a in an excellent isolated yield of 97% (entry 2). Commercially available Koser’s reagent and iodosobenzene delivered product 2a in inferior yields when compared to PIFA (entries 3 and 4). Zhang’s reagent did not afford the desired product (entry 5). Either increasing or reducing the stoichiometry of PIFA reagent was found to be detrimental and delivered the product in low yields (entries 6 and 7). Using PIFA as an oxidant and screening other solvents such as DCE, THF, or methanol did not yield the product (entries 8–10). Testing other N-protecting groups such as N-Ac or N-Boc indicated that N-Ts protection was essential for successful oxidative cyclization.

1. Optimization of Cyclization of 2-Aminophenyl-3-oxopropanoate .

entry	iodine(III) reagent (equiv)	solvent	% yield
1	PIDA (2.0)	CH2Cl2
2	PIFA (2.0)	CH2Cl2	97
3	Koser's reagent (2.0)	CH2Cl2	<10
4	Ph-I = O (2.0)	CH2Cl2	50
5	Zhang's reagent (2.0)	CH2Cl2
6	PIFA (1.3)	CH2Cl2	59
7	PIFA (2.5)	CH2Cl2	73
8	Koser's reagent (2.0)	DCE	<30
9	PIFA (2.0)	THF
10	PIFA (2.0)	MeOH

^aConditions: 100 mg scale, 0.025 M of DCM as a solvent at 25 °C for 14–20 h under nitrogen atmosphere; yields were determined by ¹H NMR with 1,3,5-trimethoxybenzene as an internal standard.

^bIsolated yields.

With the optimized conditions in hand, the generality of the new protocol was explored, and the results are shown in Scheme . A variety of substituted 2-aminophenyl-3-oxopropanoate with a range of electron-deficient or electron-donating groups were successfully converted into the corresponding 2-hydroxy-indolin-3-ones 2a–n in good yields. 2-Aminophenyl-3-oxopropanoate bearing a phenyl ring or a methyl group at the 4-position produced the corresponding cyclized product (2b, 2c) in 80 and 62% yields, respectively. The series of halogen (F, Cl, Br, I)-substituted 2-aminophenyl-3-oxopropanoate at the 4-position were tolerated under the reaction conditions.

1. Umpolung Oxidative Cyclization: Scope of the Reaction.

Especially remarkable are p-Br- and p-F-aminophenyl-3-oxopropanoate, delivering the corresponding products (2d–g) in 73–97% yield. Reactant 1 with an electron-withdrawing cyano group at the 4-position afforded the corresponding product 2h in 87% yield. 5-Halogen substitutions on the phenyl ring were also well tolerated under the reaction conditions and delivered the desired products (2i, 2j) in 92 and 75% yields, respectively. Having an electron-withdrawing CF₃ substituent at the 5-position provided the cyclized product (2k) in 98% yield. Reactants with a 4-electron-donating methoxy group underwent the reaction, albeit in a reduced yield of 65% yield (2l). Reactant 1 with a methyl substituent at the 2-position also underwent the reaction, producing the corresponding product 2m in 92% yield. 5-Chloro-substituted 1 furnished the corresponding indolin-3-one product (2n) in 85% yield. Interestingly, changing from ethyl ester to methyl ester produced the desired product (2o) in 88% yield. Additionally, β-diketone afforded 2-benzoyl-2-hydroxy-1-tosylindolin-3-one (2p) in 60% yield.

Next, we turned our focus to evaluate the feasibility of the reaction in acetonitrile as a solvent. We speculated that acetonitrile might act as a nucleophile to attack a second enolonium species (Int6, Figure ), producing after aqueous workup hydrolysis, the 2-acetamido-indolin-3-one (Figure C). Using 2 equiv of PIFA and now using acetonitrile as a solvent, we expanded the scope, and the results are summarized in Scheme . Compound 1a afforded the desired 2-amino-indolin-3-one 2q in 65% yield. Compounds 1 with 4-phenyl and -methyl groups provided the corresponding products (2r, 2s) in 55 and 54% yields, respectively. Reactant 1 with a chloride atom at the 4-position underwent the reaction and provided the corresponding product (2t) in 58% yield. Halogen substitution (Br or Cl) at the 5-position was tolerated under the reaction conditions and provided the corresponding indolin-3-one products (2u, 2v) in 46 and 77% yield, respectively. The electron-withdrawing CF₃ group at the 5-position afforded cyclized product 2w in 70% yield.

2.

(A) Free energy (kcal/mol) profile for the formation of 2-trifluoroacetoxy-indolin-3-one (Int7) or product 2a obtained at the SMD_(DCM)/B3LYP/6-31G, LANL2DZ, level of theory. (B) Transition state structures (hydrogens are omitted for clarity).

To demonstrate the practicability of the newly developed approach, we carried out a gram-scale reaction (Scheme ). Under the standard conditions, 2a was isolated in 63%.

To illustrate the potential of 2-hydroxy-indolin-3-one to create diverse motifs, several downstream transformations of 2a were carried out (Scheme ). Esterification with acetyl chloride in reflux CH₂Cl₂ produced 2-acetoxy-indolin-3-one 3 in 69% yield. Chlorination with thionyl chloride and imidazole furnished 2-chloro-indolin-3-one 4 in 40% yield. Etherification with dimethylsulfate and cesium carbonate in a mixture of acetonitrile and DMF as solvent provided 2-methoxy-indolin-3-one 5 in 81% yield. Subsequent Corey-Chaykovsky reaction of 5 with TMSOI and sodium hydride in DMSO generated epoxide 6 at position 3 in 37% yield. N-Tosyl deprotection was performed using magnesium metal in methanol, and a subsequent third umpolung reaction employing PIFA as an oxidant and indole as the nucleophile provided C–C bond in the sterically hindered C2-position. This product (7) was obtained in an overall yield of 56%. Importantly, the yield of the third umpolung reaction furnished product 7 with a densely substituted quaternary center in a yield of 92%. Amide hydrolysis of 2q with HCl produced 2-amino-indolin-3-one 8 in 61% yield.

2. Synthetic Transformations.

To shed light on the possible reaction mechanism, we performed DFT calculations using Gaussian16. , For the standard reaction, computational studies were done at the SMD_(DCM)/B3LYP/LANL2DZ, 6-31G level of theory (see the SI for computational details). The reaction can begin with a nucleophilic attack of the carbonyl oxygen of the ester moiety on the hypervalent iodine center, leading to Int1 (ΔG° = −20.2 kcal/mol). Since most of the reactions with PhIL₂ and a nucleophile follow a heterolytic pathway, and the bonding situation in neutral I­(III) compounds is accurately described as an ionic pair in two mesomeric species, , PIFA was considered as an ion pair of [Ph-I-O₂CCF₃]⁺[O₂CCF₃]⁻. Natural Bond Orbital (NBO) analysis revealed a more negative charge on the carbonyl oxygen of the ester moiety (−0.598 au) than that of the ketone (−0.594 au). Thus, the carbonyl ester moiety attacks preferentially the [Ph-I-O₂CCF₃]⁺ species. The resulting adduct (Int1) is an iodinated intermediate interacting with trifluoroacetate (CF₃COO^–) through acidic methylene hydrogen. Ensuing deprotonation of the methylenic C–H of Int1 by the CF₃COO^– via a transition state barrier (TS1) of 6.62 kcal/mol leads to the formation of an O-iodoenolate Int2 (ΔG° = 6.14 kcal/mol). Along this path, 1,3-migration of the [Ph-I-O₂CCF₃]⁺ fragment from the O-iodoenolate to the α C-iodoenolate generates a lower-energy C-iodoenolate species Int3 without a barrier (ΔG° = −11.65 kcal/mol). Int3 subsequently undergoes intramolecular cyclization by a nucleophilic attack of the ortho-NH group on the α C-iodoenolate, resulting in C–N bond formation. This exergonic step triggers the formation of intermediate Int4 (ΔG° = −51.9 kcal/mol) with an energy barrier of 5.28 kcal/mol (TS2). The change in the oxidation state of iodine (III to I) and the expulsion of neutral species (PhI and CF₃COOH) provide a noticeable thermodynamic drive for this reaction. Int4 further interacts with a second equivalent of PIFA to form another O-iodoenolate species Int5 (ΔG° = −23.3 kcal/mol) through TS3. The activation energy barrier for this step is 6.72 kcal/mol. Important to note, in this step, the enolonium species is formed with the carbonyl ketone and not with the carbonyl ester moiety since it forms a product (Int5) which is lower in energy (see the SI for comparison). In addition, this enolonium species (Int5) is an aromatic structure, while enolonium species of the carbonyl ester is not. Succeeding 1,3-migration of [Ph–I-O₂CCF₃]⁺ from the O-iodoenolate to the α C-iodoenolate atom generates a lower-energy C-iodoenolate Int6 (ΔG° = −8.0 kcal/mol). This step is barrierless. Attack of the CF₃COO^– ion on enolonium species Int6 through TS4 readily gives Int7 (ΔG° = −34.21 kcal/mol). This step is quite fast, as it exhibits a low barrier of only 9.92 kcal/mol, and results in the formation of PhI, CF₃COO^–, and the final 2-trifluoroacetoxy-indolin-3-one (Int7). Although CF₃COO^– is a weak nucleophile, since no other nucleophile exists in the reaction mixture, it is feasible to get Int7 as an intermediate. Int7 was not detected experimentally; it may be attributed to the fast reaction from Int6 to Int7, but it cannot be excluded that Int7 is not formed during the process. Upon water workup, hydrolysis of the trifluoroacetate moiety furnishes the final hydroxy product (2a). The second pathway is H₂O attack on Int6 during the workup process that will lead directly to product 2a.

In summary, we have developed an efficient one-pot approach for the cyclization of 2-aminophenyl-3-oxopropanoate via an umpolung reaction, yielding synthetically valuable 2,2-disubstituted indolin-3-ones. In comparison to other methods, this protocol relies on simple substrates and has a broad substrate scope (23 examples). DFT calculations provided insight into the reaction mechanism and support the formation of key C-enolonium species.

Experimental Section

General Information

Unless otherwise noted, all reagents were purchased from commercial suppliers and used without further purification. All solvents were dried according to standard procedures and techniques before use. Column chromatography was performed on silica gel. ¹H NMR spectroscopy measurements were carried out on Bruker 400 MHz NMR spectrometers with CDCl₃ (δ 7.26) as an internal standard unless otherwise stated. The ¹³C NMR spectra were recorded on a 101 MHz NMR spectrometer with CDCl₃ (δ 77.16) as an internal standard unless otherwise stated. HRMS spectra were acquired on an Xevo G2-XS QTof device mass spectrometer. IR spectra were obtained using an FT/IR-4700 type A with a resolution of 16 cm^–1. Melting point was measured on Stuart SMP50 version 1.12.

Caution! PIFA is an oxidizing agent. While no data exist for PIFA, some hypervalent iodine reagents are potentially explosive. , PIFA is a mild irritant. Appropriate precautions should be taken.

General Procedure A for the Umpolung Oxidative Cyclization in CH₂Cl₂

Compounds 1a–n (1 equiv) were dissolved in 12 mL of dry DCM (0.02 M). PIFA (2 equiv) was added portion-wise to the reaction mixture at room temperature. The reaction was allowed to stir overnight. The mixture was extracted 3 times with 10 mL water and DCM (3 × 30 mL) and dried over sodium sulfate. The product was purified by silica gel column chromatography using EtOAc/Hexane as eluents.

General Procedure B for the Umpolung Oxidative Cyclization in CH₃CN

Compounds 1a–c, 1e, and 1i–k were dissolved in 12 mL of dry CH₃CN (0.02–0.03 M). PIFA (2 equiv) was added portion-wise at room temperature. The reaction was allowed to stir overnight. Next, 10 mL of water was added to the mixture and allowed to stir for 30 min. The mixture was extracted 3 times with 10 mL of water and DCM (3 × 30 mL) and dried over sodium sulfate. The product was purified by column chromatography with ethyl acetate and hexane as the eluents. Ethyl 2-hydroxy-3-oxo-1-tosylindoline-2-carboxylate (2a). According to general procedure A, 1(a) (100 mg, 0.27 mmol) and PIFA (238 mg, 0.54 mmol, 2 equiv) were used in 12 mL of dry DCM (0.02 M). The crude residue was purified by silica gel column chromatography using EtOAc:hexane (20:80, v:v) to afford a brown color solid, 101 mg, 97% yield. ¹ H NMR (400 MHz, CDCl₃) δ 7.98 (m, 2H), 7.70 (m, 1H), 7.63–7.51 (m, 2H), 7.31 (m, 2H), 7.17–7.11 (bs, 1H), 5.33 (s, 1H), 4.43 (m, 1H), 4.31 (m, 1H), 2.40 (s, 3H), 1.29 (t, J = 8 Hz, 3H). ¹³ C­{ ¹ H} NMR (101 MHz, CDCl₃) δ: 191.2, 167.3, 152.4, 145.1, 138.3, 136.1, 129.9, 128.0, 125.9, 123.9, 120.3, 87.3, 64.5, 21.7, 14.0. HRMS (ESI) m/z: [M + Na]⁺ Calcd for C₁₈H₁₇NNaO₆S 398.0674; found: 398.0668. mp 108–111 °C.

Ethyl 2-Hydroxy-3-oxo-5-phenyl-1-tosylindoline-2-carboxylate (2b)

According to general procedure A, 1(b) (100 mg, 0.23 mmol) and PIFA (197 mg, 0.46 mmol, 2 equiv) were used in 12 mL of dry DCM (0.02 M). The crude residue was purified by silica gel column chromatography using EtOAc:hexane (20:80, v:v) to afford an amorphous yellow color solid, 82 mg, 80% yield. ¹ H NMR (400 MHz, CDCl₃) δ 8.01 (m, 2H), 7.90 (m, 1H), 7.85 (m, 1H), 7.64 (m, 1H), 7.53–7.49 (m, 2H), 7.46–7.41 (m, 2H), 7.39–7.31 (m, 3H), 5.42 (s, 1H), 4.45 (m, 1H), 4.33 (m, 1H), 2.41 (s, 3H), 1.31 (t, J = 8 Hz, 3H). ¹³ C­{ ¹ H} NMR (101 MHz, CDCl₃) δ: 191.3, 167.2, 151.5, 145.2, 138.8, 137.5, 137.3, 136.1, 130.0, 129.1, 128.0, 126.8, 123.8, 120.8, 114.1, 87.8, 64.6, 21.7, 14.0. HRMS (ESI) m/z: [M + Na]⁺ Calcd for C₂₄H₂₁NNaO₆S 474.0987; found: 474.0998. IR 3031, 1761, 1725, 1611, 1470, 1355, 1261, 1157, 1084, 958 cm^–1.

Ethyl 2-Hydroxy-5-methyl-3-oxo-1-tosylindoline-2-carboxylate (2c)

According to general procedure A, 1(c) (100 mg, 0.27 mmol) and PIFA (229 mg, 0.54 mmol, 2 equiv) were used in 12 mL of dry DCM (0.02 M). The crude residue was purified by silica gel column chromatography using EtOAc:hexane (15:85, v:v) to afford a yellow color solid, 64 mg, 62% yield. ¹ H NMR (400 MHz, CDCl₃) δ 7.96 (m, 2H), 7.44 (m, 3H), 7.30 (m, 2H), 5.33 (s, 1H), 4.41 (m, 1H), 4.30 (m, 1H), 2.39 (s, 3H), 2.32 (s, 3H), 1.28 (t, J = 8 Hz, 3H). ¹³ C­{ ¹ H} NMR (101 MHz, CDCl₃) δ: 191.3, 167.3, 150.5, 145.0, 139.4, 136.2, 133.9, 129.9, 128.0, 125.5, 120.3, 113.6, 87.5, 64.4, 21.7, 20.6, 13.9. HRMS (ESI) m/z: [M + Na]⁺ Calcd for C₁₉H₁₉NNaO₆S 412.0831; found: 412.0843 IR 2926, 2848, 2304, 1761, 1724, 1617, 1487, 1362, 1247, 1141, 916, 672 cm^–1. mp 109–112 °C.

Ethyl 5-Bromo-2-hydroxy-3-oxo-1-tosylindoline-2-carboxylate (2d)

According to general procedure A, 1(d) (100 mg, 0.23 mmol) and PIFA (195 mg, 0.46 mmol, 2 equiv) were used in 12 mL of dry DCM (0.02 M). The crude residue was purified by silica gel column chromatography using EtOAc:hexane (20:80, v:v) to afford a light orange color solid, 100 mg, 97% yield. ¹ H NMR (400 MHz, CDCl₃) δ 7.98–7.93 (m, 2H), 7.82–7.78 (m, 1H), 7.68 (m, 1H), 7.50–7.45 (m, 1H), 7.32 (m, 2H), 5.37 (s, 1H), 4.42 (m, 1H), 4.31 (m, 1H), 2.41 (s, 3H), 1.29 (t, J = 8 Hz, 3H). ¹³ C­{ ¹ H} NMR (101 MHz, CDCl₃) δ: 190.1, 166.8, 151.2, 145.4, 140.8, 135.8, 130.0, 128.3, 128.0, 121.8, 116.8, 115.4, 87.6, 64.7, 21.7, 14.0. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₁₈H₁₇BrNO₆S 453.9960; found: 453.9954. IR 2926, 2853, 1759, 1730, 1593, 1453, 1364, 1247, 1150, 1128, 1079, 951 cm^–1. mp 114–117 °C.

Ethyl 5-Chloro-2-hydroxy-3-oxo-1-tosylindoline-2-carboxylate (2e)

1(e) (100 mg, 0.25 mmol) and PIFA (218 mg, 0.5 mmol, 2 equiv) were used in 12 mL of dry DCM (0.02 M). The crude residue was purified by silica gel column chromatography using EtOAc:hexane (12:82, v:v) to afford an orange color solid, 76 mg, 73% yield. ¹ H NMR (400 MHz, CDCl₃) δ 7.95 (m, 2H), 7.64 (m, 1H), 7.57–7.51 (m, 2H), 7.31 (m, 2H), 5.40 (s, 1H), 4.42 (m, 1H), 4.31 (m, 1H), 2.40 (s, 3H), 1.29 (t, J = 8 Hz, 3H). ¹³ C­{ ¹ H} NMR (101 MHz, CDCl₃) δ: 190.2, 166.8, 150.7, 145.4, 138.0, 135.8, 130.0, 129.7, 128.0, 125.2, 121.4, 115.1, 87.7, 64.7, 21.7, 13.9. HRMS (ESI) m/z: [M + Na]⁺ Calcd for C₁₈H₁₆ClNNaO₆S 432.0284; found: 432.0286. IR 3358, 3009, 1729, 1738, 1364, 1150, and 963 cm^–1. mp 117–120 °C.

Ethyl 2-Hydroxy-5-iodo-3-oxo-1-tosylindoline-2-carboxylate (2f)

According to general procedure A, 1(f) (100 mg, 0.21 mmol) and PIFA (176 mg, 0.42 mmol, 2 equiv) were used in 12 mL of dry DCM (0.02 M). The crude residue was purified by silica gel column chromatography using EtOAc:hexane (20:80, v:v) to afford a yellow color solid, 85 mg, 82% yield. ¹ H NMR (400 MHz, CDCl₃) δ 7.97 (m, 3H), 7.85 (m, 1H), 7.38–7.28 (m, 3H), 5.34 (s, 1H), 4.42 (m, 1H), 4.31 (m, 1H), 2.41 (s, 3H), 1.29 (t, J = 8 Hz, 3H). ¹³ C­{ ¹ H} NMR (101 MHz, CDCl₃) δ: 189.9, 166.8, 151.8, 146.4, 145.4, 135.8, 134.3, 130.0, 128.0, 122.3, 115.8, 87.3, 86.4, 64.7, 21.7, 14.0. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₁₈H₁₇INO₆S 501.9821; found: 501.9823 IR 3235, 3040, 1752, 1728, 1591, 1450, 1357, 1252, 1128, 1078, 1007, 949 cm^–1. mp 125–128 °C.

Ethyl 5-Fluoro-2-hydroxy-3-oxo-1-tosylindoline-2-carboxylate (2g)

According to general procedure A, 1(g) (100 mg, 0.26 mmol) and PIFA (226 mg, 0.52 mmol, 2 equiv) were used in 12 mL of dry DCM (0.02 M). The crude residue was purified by silica gel column chromatography using EtOAc:hexane (15:85, v:v) to afford a yellow color solid, 101 mg, 97% yield. ¹ H NMR (400 MHz, CDCl₃) δ 7.99–7.92 (m, 2H), 7.55 (m, 1H), 7.38–7.28 (m, 4H), 5.35 (s, 1H), 4.43 (m, 1H), 4.32 (m, 1H), 2.41 (s, 3H), 1.30 (t, J = 8 Hz, 3H). ¹³ C­{ ¹ H} NMR (101 MHz, CDCl₃) δ: 190.7, 190.7, 166.9, 160.3, 157.8, 148.7, 148.7, 145.3, 135.9, 130.0, 128.0, 125.8, 125.6, 121.3, 121.3, 115.3, 115.2, 111.6, 111.3, 87.9, 64.6, 21.7, 14.0. ¹⁹ F NMR (376 MHz, CDCl₃) δ −118.01. HRMS (ESI) m/z: [M + Na]⁺ Calcd for C₁₈H₁₆FNNaO₆S 416.0580; found: 416.0589. IR 3372, 2928, 1739, 1729, 1477, 905 cm^–1. mp 131–134 °C.

Ethyl 5-Cyano-2-hydroxy-3-oxo-1-tosylindoline-2-carboxylate (2h)

According to general procedure A, 1(h) (100 mg, 0.26 mmol) and PIFA (222 mg, 0.52 mmol, 2 equiv) were used in 12 mL of dry DCM (0.02 M). The crude residue was purified by silica gel column chromatography using EtOAc:hexane (20:80, v:v) to afford an orange color oil, 90 mg, 87% yield. ¹ H NMR (400 MHz, CDCl₃) δ 8.00–7.93 (m, 3H), 7.84 (m, 1H), 7.68 (m, 1H), 7.36–7.31 (m, 2H), 4.44 (m, 1H), 4.31 (m, 1H), 2.41 (s, 3H), 1.29 (t, J = 8 Hz, 3H). ¹³ C­{ ¹ H} NMR (101 MHz, CDCl₃) δ: 189.7, 166.3, 154.4, 145.9, 141.0, 135.2, 130.2, 130.1, 128.0, 120.6, 117.3, 114.6, 107.6, 87.8, 64.9, 21.7, 13.9. HRMS (ESI) m/z: [M + Na]⁺ Calcd for C₁₉H₁₆N₂NaO₆S 423.0627; found: 423.0621. IR 3312, 3028, 2233, 1741, 1616, 1580, and 900 cm^–1.

Ethyl 6-Bromo-2-hydroxy-3-oxo-1-tosylindoline-2-carboxylate (2i)

According to general procedure A, 1(i) (100 mg, 0.22 mmol) and PIFA (195 mg, 0.44 mmol, 2 equiv) were used in 12 mL of dry DCM (0.02 M). The crude residue was purified by silica gel column chromatography using EtOAc:hexane (25:75, v:v) to afford an orange color solid, 95 mg, 92% yield. ¹ H NMR (400 MHz, CDCl₃) δ 7.99–7.94 (m, 2H), 7.76 (m, 1H), 7.54 (m, 1H), 7.37–7.31 (m, 2H), 7.28 (m, 1H), 5.39 (bs, 1H), 4.42 (m, 1H), 4.30 (m, 1H), 2.41 (s, 3H), 1.29 (t, J = 8 Hz, 3H). ¹³ C­{ ¹ H} NMR (101 MHz, CDCl₃) δ 190.2, 166.8, 152.8, 145.4, 135.7, 134.0, 130.1, 128.0, 127.5, 126.6, 119.1, 117.2, 87.6, 64.6, 21.7, 13.9. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₁₈H₁₇BrNO₆S 453.9960; found: 453.9954. IR 3434, 3109, 1722, 1589, 1153, 952 cm^–1.

Ethyl 6-Chloro-2-hydroxy-3-oxo-1-tosylindoline-2-carboxylate (2j)

According to general procedure A, 1(j) (100 mg, 0.25 mmol) and PIFA (218 mg, 0.5 mmol, 2 equiv) were used in 12 mL of dry DCM (0.02 M). The crude residue was purified by silica gel column chromatography using EtOAc:hexane (17:83, v:v) to afford an orange color solid, 78 mg, 75% yield. ¹ H NMR (400 MHz, CDCl₃) δ 7.97 (d, 2H), 7.64–7.60 (m, 1H), 7.59–7.57 (m, 1H), 7.34 (m, 2H), 7.12 (m, 1H), 4.43 (m, 1H), 4.31 (m, 1H), 2.42 (s, 3H), 1.29 (t, J = 8 Hz, 3H). ¹³ C­{ ¹ H} NMR (101 MHz, CDCl₃) δ: 189.9, 166.9, 152.9, 145.5, 145.1, 135.7, 130.1, 128.0, 126.7, 124.6, 118.7, 114.3, 87.8, 64.7, 21.7, 14.0. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₁₈H₁₇ClNO₆S 410.0465; found: 410.0479. IR 3449, 3014, 1733, 1599, 1153, 955 cm^–1. mp 122–125 °C.

Ethyl 2-Hydroxy-3-oxo-1-tosyl-6-(trifluoromethyl)­indoline-2-carboxylate (2k)

According to general procedure A, 1(k) (100 mg, 0.23 mmol) and PIFA (200 mg, 0.46 mmol, 2 equiv) were used in 12 mL of dry DCM (0.02 M). The crude residue was purified by silica gel column chromatography using EtOAc:hexane (14:86, v:v) to afford an orange color solid, 102 mg, 98% yield. ¹ H NMR (400 MHz, CDCl₃) δ 8.00–7.95 (m, 2H), 7.85–7.78 (m, 2H), 7.39 (m, 1H), 7.34 (m, 2H), 5.46 (s, 1H), 4.44 (m, 1H), 4.32 (m, 1H), 2.42 (s, 3H), 1.30 (t, J = 8 Hz, 3H). ¹³ C­{ ¹ H} NMR (101 MHz, CDCl₃) δ: 190.8, 166.7, 152.2, 145.7, 139.6, 139.3, 139.0, 138.6, 135.5, 130.1, 128.0, 126.5, 122.6, 121.6, 120.7, 120.7, 111.1, 111.0, 111.0, 111.0, 87.6, 64.8, 21.7, 14.0. ¹⁹ F NMR (376 MHz, CDCl₃) δ −63.49. HRMS (ESI) m/z: [M + Na]⁺ Calcd for C₁₉H₁₆F₃NNaO₆S 466.0548; found: 466.0557. IR 3420, 2985, 1748, 1604, 1157, 972 cm^–1. mp 125–128 °C.

Ethyl 2-Hydroxy-6-methoxy-3-oxo-1-tosylindoline-2-carboxylate (2l)

According to general procedure A, 1(l) (100 mg, 0.25 mmol) and PIFA (220 mg, 0.5 mmol, 2 equiv) were used in 12 mL of dry DCM (0.02 M). The crude residue was purified by silica gel column chromatography using EtOAc:hexane (25:75, v:v) to afford a light yellow color solid, 67 mg, 65% yield. ¹ H NMR (400 MHz, CDCl₃) δ 7.97 (m, 2H), 7.61 (m, 1H), 7.31 (m, 2H), 7.00 (m, 1H), 6.65 (m, 1H), 5.34 (s, 1H), 4.42 (m, 1H), 4.30 (m, 1H), 3.87 (s, 3H), 2.40 (s, 3H), 1.29 (t, J = 8 Hz, 3H). ¹³ C­{ ¹ H} NMR (101 MHz, CDCl₃) δ: 188.8, 168.2, 167.4, 154.6, 145.1, 136.1, 129.9, 128.0, 127.6, 113.4, 111.6, 98.5, 88.1, 64.4, 56.1, 21.7, 14.0. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₁₉H₂₀NO₇S 406.0960; found: 406.0956. IR 3396, 3034, 1724, 1604, 1585, 967 cm^–1. mp 133–136 °C.

Ethyl 2-Hydroxy-7-methyl-3-oxo-1-tosylindoline-2-carboxylate (2m)

According to general procedure A, 1(m) (100 mg, 0.26 mmol) and PIFA (229 mg, 0.52 mmol, 2 equiv) were used in 12 mL of dry DCM (0.02 M). The crude residue was purified by silica gel column chromatography using EtOAc:hexane (20:80, v:v) to afford a yellow color solid, 95 mg, 92% yield. ¹ H NMR (400 MHz, CDCl₃) δ 7.98–7.92 (m, 2H), 7.63 (m, 1H), 7.38–7.29 (m, 3H), 7.09 (m, 1H), 5.37 (s, 1H), 4.44 (m, 1H), 4.27 (m, 1H), 2.42 (s, 3H), 2.16 (s, 3H), 1.29 (t, J = 8 Hz, 3H). ¹³ C­{ ¹ H} NMR (101 MHz, CDCl₃) δ: 191.7, 167.2, 151.4, 144.6, 142.6, 138.5, 130.0, 127.1, 125.5, 124.6, 123.7, 122.5, 88.6, 64.3, 21.7, 21.7, 13.9. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₁₉H₂₀NO₆S 390.1011; found: 390.1000. IR 3436, 3040,1753, 1722, 1148, 967 cm^–1. mp 131–134 °C.

Ethyl 4-Chloro-2-hydroxy-3-oxo-1-tosylindoline-2-carboxylate (2n)

According to general procedure A, 1(n) (100 mg, 0.24 mmol) and PIFA (218 mg, 0.48 mmol, 2 equiv) were used in 12 mL of dry DCM (0.02 M). The crude residue was purified by silica gel column chromatography using EtOAc:hexane (17:83, v:v) to afford a yellow color solid, 88 mg, 85% yield. ¹ H NMR (400 MHz, CDCl₃) δ 8.00–7.96 (m, 2H), 7.50–7.43 (m, 2H), 7.32 (m, 2H), 7.08 (m, 1H), 5.42 (s, 1H), 4.46 (m, 1H), 4.31 (m, 1H), 2.41 (s, 3H), 1.31 (t, J = 8 Hz, 3H). ¹³ C­{ ¹ H} NMR (101 MHz, CDCl₃) δ: 188.5, 166.9, 153.5, 145.4, 138.2, 135.7, 134.0, 130.0, 128.1, 125.2, 117.1, 111.9, 87.3, 64.7, 21.7, 14.0. HRMS (ESI) m/z: [M + Na]⁺ Calcd for C₁₈H₁₆ClNNaO₆S 432.0284; found: 432.0291. IR 3378, 2932, 1786, 1750, 1080, and 957 cm^–1. mp 124–127 °C.

Methyl 2-Hydroxy-3-oxo-1-tosylindoline-2-carboxylate (2o)

According to general procedure A, 1(o) (100 mg, 0.28 mmol) and PIFA (247 mg, 0.56 mmol, 2 equiv) were used in 12 mL of dry DCM (0.02 M). The crude residue was purified by silica gel column chromatography using EtOAc:hexane (35:65, v:v) to afford a yellow color solid, 92 mg, 88% yield. ¹ H NMR (400 MHz, CDCl₃) δ 7.98 (m, 2H), 7.71–7.55 (m, 3H), 7.31 (m, 2H), 7.18–7.11 (m, 1H), 5.35 (s, 1H), 3.87 (s, 3H), 2.39 (s, 3H). ¹³ C­{ ¹ H} NMR (101 MHz, CDCl₃) δ: 191.0, 167.7, 152.3, 145.2, 138.4, 135.9, 129.9, 128.0, 125.9, 124.0, 120.2, 113.8, 87.3, 54.7, 21.7. HRMS (ESI) m/z: [M + Na]⁺ Calcd for C₁₇H₁₅NNaO₆S 384.0518; found: 384.0507. IR 2925, 1749, 1593, 1246, and 951 cm^–1. mp 149–152 °C.

2-Benzoyl-2-hydroxy-1-tosylindolin-3-one (2p)

According to general procedure A, 1(p) (26 mg, 0.07 mmol) and PIFA (58 mg, 0.14 mmol, 2 equiv) were used in 12 mL of dry DCM (6 mM). The crude residue was purified by silica gel column chromatography using EtOAc:hexane (15:85, v:v) to afford an amorphous yellow color solid, 16 mg, 60% yield. ¹ H NMR (400 MHz, CDCl₃) δ 8.02–7.95 (m, 2H), 7.86–7.76 (m, 3H), 7.73–7.68 (m, 2H), 7.60–7.54 (m, 1H), 7.40–7.33 (m, 2H), 7.29 (m, 2H), 7.25–7.21 (m, 1H), 6.47 (s, 1H), 2.40 (s, 3H). ¹³ C­{ ¹ H} NMR (101 MHz, CDCl₃) δ: 191.7, 191.0, 152.1, 145.2, 138.5, 135.7, 134.7, 131.7, 129.8, 129.2, 129.1, 128.4, 126.3, 124.4, 120.8, 114.6, 90.4, 21.7. HRMS (ESI) m/z: [M + Na]⁺ Calcd for C₂₂H₁₇NO₅SNa 430.0725; found: 430.0706. IR 3070, 2923, 1732, 1683, 1359, 753 cm^–1.

Ethyl 2-Acetamido-3-oxo-1-tosylindoline-2-carboxylate (2q)

According to general procedure B, 1(a) (140 mg, 0.39 mmol) and PIFA (333 mg, 0.78 mmol, 2 equiv) were used in 12 mL of dry DCM (0.03 M). The crude residue was purified by silica gel column chromatography using EtOAc:hexane (40:60, v:v) to afford a white color solid, 105 mg, 65% yield. ¹ H NMR (400 MHz, CDCl₃) δ 7.79–7.72 (m, 4H), 7.63 (m, 1H), 7.36 (s, 1H), 7.28 (m, 2H), 7.17 (m, 1H), 4.37 (m, 1H), 4.27–4.18 (m, 1H), 2.39 (s, 3H), 1.76 (s, 3H), 1.24 (t, J = 8 Hz, 3H). ¹³ C­{ ¹ H} NMR (101 MHz, CDCl₃) δ: 188.9, 168.9, 164.9, 151.6, 144.9, 137.3, 137.2, 130.0, 126.6, 125.0, 123.6, 122.2, 113.6, 77.7, 64.3, 22.1, 21.7, 13.8. HRMS (ESI) m/z: [M + Na]⁺ Calcd for C₂₀H₂₀N₂NaO₆S 439.0940; found: 439.0948 IR 2249, 1759, 1728, 1666, 1602, 1458, 1357, 1214, 1153, 1081 cm^–1. mp 209–212 °C.

Ethyl 2-Acetamido-3-oxo-5-phenyl-1-tosylindoline-2-carboxylate (2r)

According to general procedure B, 1(b) (130 mg, 0.29 mmol) and PIFA (256 mg, 0.58 mmol, 2 equiv) were used in 12 mL of dry DCM (0.02 M). The crude residue was purified by silica gel column chromatography using EtOAc:hexane (40:60, v:v) to afford a yellow color solid, 81 mg, 55% yield. ¹ H NMR (400 MHz, CDCl₃) δ 7.94 (m, 1H), 7.86 (m, 2H), 7.80 (m, 2H), 7.57–7.53 (m, 2H), 7.49–7.41 (m, 3H), 7.38–7.33 (m, 1H), 7.31–7.28 (m, 2H), 4.39 (m, 1H), 4.25 (m, 1H), 2.39 (s, 3H), 1.77 (s, 3H), 1.27 (t, J = 8 Hz, 3H). ¹³ C­{ ¹ H} NMR (101 MHz, CDCl₃) δ: 188.9, 169.0, 164.8, 150.7, 145.0, 139.2, 137.1, 137.1, 136.3, 130.0, 129.0, 127.8, 126.9, 126.6, 123.0, 122.7, 113.9, 78.1, 64.3, 22.0, 21.6, 13.8. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₂₆H₂₅N₂O₆S 493.1433; found: 493.1473. IR 3365, 3180, 1755, 1738, 1654, 1144, and 961 cm^–1. mp 180–183 °C.

Ethyl 2-Acetamido-5-methyl-3-oxo-1-tosylindoline-2-carboxylate (2s)

According to general procedure B, 1(c) (130 mg, 0.35 mmol) and PIFA (298 mg, 0.7 mmol, 2 equiv) were used in 12 mL of dry DCM (0.03 M). The crude residue was purified by silica gel column chromatography using EtOAc:hexane (40:60, v:v) to afford a white color solid, 80 mg, 54% yield. ¹ H NMR (400 MHz, CDCl₃) δ 7.77–7.73 (m, 2H), 7.65 (m, 1H), 7.52 (m, 1H), 7.43 (m, 1H), 7.37 (s, 1H), 7.28–7.24 (m, 2H), 4.35 (m, 1H), 4.22 (m, 1H), 2.38 (s, 3H), 2.35 (s, 3H), 1.74 (s, 3H), 1.24 (t, J = 8 Hz, 3H). ¹³ C­{ ¹ H} NMR (101 MHz, CDCl₃) δ: 188.9, 168.8, 165.0, 149.7, 144.7, 138.42, 137.37, 133.53, 129.92, 126.60, 124.82, 122.30, 113.41, 77.9, 64.2, 22.0, 21.6, 20.6, 13.8. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₂₁H₂₃N₂O₆S 431.1277; found: 431.1290. IR 3309, 3034, 1753, 1662, 1620, 1150, and 965 cm^–1. mp 210–213 °C.

Ethyl 2-Acetamido-5-chloro-3-oxo-1-tosylindoline-2-carboxylate (2t)

According to general procedure B, 1(e) (140 mg, 0.35 mmol) and PIFA (304 mg, 0.7 mmol, 2 equiv) were used in 12 mL of dry DCM (0.03 M). The crude residue was purified by silica gel column chromatography using EtOAc:hexane (40:60, v:v) to afford a white color solid, 92 mg, 58% yield. ¹ H NMR (400 MHz, CDCl₃) δ 7.73–7.67 (m, 3H), 7.65–7.63 (m, 1H), 7.53 (m, 1H), 7.35 (s, 1H), 7.25 (m, 2H), 4.33 (m, 1H), 4.20 (m, 1H), 2.37 (s, 3H), 1.70 (s, 3H), 1.21 (t, J = 8 Hz, 3H). ¹³ C­{ ¹ H} NMR (101 MHz, CDCl₃) δ: 187.8, 169.0, 164.4, 149.9, 145.2, 137.0, 136.9, 130.0, 129.3, 126.6, 124.5, 123.4, 114.9, 78.1, 64.4, 21.9, 21.7, 13.8. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₂₀H₂₀ClN₂O₆S 451.0731; found: 451.0764. IR 3014, 2921, 1759, 1684, 1607, 1461, 1364, 1269, 1210, 1163, 1086, 1011, 886 cm^–1. mp 192–195 °C.

Ethyl 2-Acetamido-6-bromo-3-oxo-1-tosylindoline-2-carboxylate (2u)

According to general procedure B, 1(i) (130 mg, 0.29 mmol) and PIFA (254 mg, 0.58 mmol, 2 equiv) were used in 12 mL of dry DCM (0.02 M). The crude residue was purified by silica gel column chromatography using EtOAc:hexane (35:65, v:v) to afford a white color solid, 68 mg, 46% yield. ¹ H NMR (400 MHz, CDCl₃) δ 8.00 (m, 1H), 7.77–7.73 (m, 2H), 7.59–7.55 (m, 1H), 7.35–7.28 (m, 4H), 4.37 (m, 1H), 4.23 (m, 1H), 2.41 (s, 3H), 1.73 (s, 3H), 1.26 (d, J = 8 Hz, 3H). ¹³ C­{ ¹ H} NMR (101 MHz, CDCl₃) δ: 187.9, 168.9, 164.5, 152.1, 145.2, 136.9, 132.7, 130.1, 127.2, 126.6, 125.9, 121.1, 117.0, 77.9, 64.5, 22.0, 21.7, 13.9. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₂₀H₂₀BrN₂O₆S 495.0226; found: 495.0241. IR 3299, 3007, 1741, 1660, 1596, 955 cm^–1. mp 229–232 °C.

Ethyl 2-Acetamido-6-chloro-3-oxo-1-tosylindoline-2-carboxylate (2v)

According to general procedure B, 1(j) (130 mg, 0.33 mmol) and PIFA (282 mg, 0.66 mmol, 2 equiv) were used in 12 mL of dry DCM (0.03 M). The crude residue was purified by silica gel column chromatography using EtOAc:hexane (40:60, v:v) to afford a light orange color solid, 114 mg, 77% yield. ¹ H NMR (400 MHz, CDCl₃) δ 7.81 (m, 1H), 7.75 (m, 2H), 7.65 (m, 1H), 7.34 (s, 1H), 7.33–7.28 (m, 2H), 7.15 (m, 1H), 4.37 (m, 1H), 4.23 (m, 1H), 2.41 (s, 3H), 1.73 (s, 3H), 1.25 (t, J = 8 Hz, 3H). ¹³ C­{ ¹ H} NMR (101 MHz, CDCl₃) δ: 187.6, 168.9, 164.5, 152.2, 145.2, 143.9, 136.9, 130.1, 126.6, 125.8, 124.3, 120.7, 114.1, 78.1, 64.4, 22.0, 21.7, 13.8. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₂₀H₂₀ClN₂O₆S 451.0731; found: 451.0755. IR 3316, 3016, 1781, 1748, 1656, 1071, 967 cm^–1. mp 216–219 °C.

Ethyl 2-Acetamido-3-oxo-1-tosyl-6-(trifluoromethyl)­indoline-2-carboxylate (2w)

According to general procedure B, 1(k) (130 mg, 0.3 mmol) and PIFA (260 mg, 0.6 mmol, 2 equiv) were used in 12 mL of dry DCM (0.03 M). The crude residue was purified by silica gel column chromatography using EtOAc:hexane (30:70, v:v) to afford an orange color solid, 103 mg, 70% yield. ¹ H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.83 (m, 1H), 7.78–7.72 (m, 2H), 7.45–7.41 (m, 2H), 7.31 (m, 2H), 4.38 (m, 1H), 4.25 (m, 1H), 2.41 (s, 3H), 1.74 (s, 3H), 1.26 (t, J = 8 Hz, 3H). ¹³ C­{ ¹ H} NMR (101 MHz, CDCl₃) δ: 188.2, 169.2, 164.3, 151.3, 145.4, 138.7, 138.3, 138.0, 137.7, 136.7, 130.1, 126.6, 125.5, 124.6, 124.5, 121.9, 120.5, 120.5, 110.9, 110.8, 110.8, 78.0, 64.6, 21.8, 21.7, 13.8. ¹⁹ F NMR (376 MHz, CDCl₃) δ −63.16. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₂₁H₂₀F₃N₂O₆S 485.0994; found: 485.1038. IR 3288, 3019, 1744, 1709, 1654, 943 cm^–1. mp 203–206 °C.

Procedures for Synthetic Transformations

Ethyl 2-Acetoxy-3-oxo-1-tosylindoline-2-carboxylate (3)

Compound 2a (300 mg, 0.8 mmol) was dissolved in 5 mL of dry DCM (0.16 M). Triethylamine (4 mL) was added, and the mixture was stirred at room temperature for 10 min. Acetyl chloride (1.17 mL) was added, and the mixture was stirred at reflux for 2 h. The crude mixture was extracted 3 times with water and DCM and dried over sodium sulfate. The product was purified by silica gel column chromatography using EtOAc/Hexane (25:75 v:v) to afford a yellow color solid, 233 mg, 69% yield. ¹ H NMR (400 MHz, CDCl₃) δ 7.86–7.81 (m, 3H), 7.71 (m, 1H), 7.65 (m, 1H), 7.31 (m, 2H), 7.19 (m, 1H), 4.33 (m, 1H), 4.22 (m, 1H), 2.41 (s, 3H), 1.88 (s, 3H), 1.25 (t, J = 8 Hz, 3H). ¹³ C­{ ¹ H} NMR (101 MHz, CDCl₃) δ: 188.2, 168.0, 162.5, 151.5, 145.3, 137.6, 137.0, 130.1, 126.8, 125.1, 123.9, 121.7, 113.7, 87.9, 63.6, 21.7, 20.0, 13.8. HRMS (ESI) m/z: [M + Na]⁺ Calcd for C₂₀H₁₉NNaO₇S 440.0780; found: 440.0781. IR 3115, 1764, 1642, 1603, 1087, and 950 cm^–1. mp 131–134 °C.

Ethyl 2-Chloro-3-oxo-1-tosylindoline-2-carboxylate (4)

Imidazole (72 mg, 1 mmol, 8 equiv) was dissolved in 3 mL of dry DCM (0.33 M). Thionyl chloride (25 μL, 0.32 mmol, 2.5 equiv) was added at 0 °C. The mixture was stirred at that temperature for 10 min, and then compound 2a (50 mg, 0.13 mmol) dissolved in 1 mL dry DCM was added dropwise. The mixture was stirred at 0 °C for 1 h. The crude mixture was extracted 3 times with water and DCM and dried over sodium sulfate. The product was purified by silica gel column chromatography using EtOAc/Hexane (18:82 v:v) to afford an amorphous yellow solid. 21 mg, 40% yield. ¹ H NMR (400 MHz, CDCl₃) δ 8.07–8.01 (m, 2H), 7.78 (m, 1H), 7.67 (m, 1H), 7.60–7.56 (m, 1H), 7.36 (m, 2H), 7.24–7.19 (m, 1H), 4.44 (m, 1H), 4.35 (m, 1H), 2.43 (s, 3H), 1.34 (t, J = 8 Hz, 3H). ¹³ C­{ ¹ H} NMR (101 MHz, CDCl₃) δ: 187.2, 162.4, 151.7, 145.8, 138.5, 135.6, 130.1, 128.4, 126.7, 124.5, 119.6, 114.2, 79.8, 64.7. HRMS (ESI) m/z: [M + Na]⁺ Calcd for C₁₈H₁₆ClNNaO₅S 416.0335; found: 416.0342. IR 2922, 1746, 1177, 950 cm^–1.

Ethyl 2-Methoxy-3-oxo-1-tosylindoline-2-carboxylate (5)

Compound 2a (0.8 g, 2.1 mmol) was dissolved in a CH₃CN:DMF (2:1) mixture (0.21 M). Cs₂CO₃ (2.43 g, 7.4 mmol, 3.5 equiv) was added, followed by dropwise addition of dimethylsulfate (1.6 mL, 17 mmol, 8 equiv). The mixture was stirred at room temperature overnight. Solvents were evaporated, and the product was purified by silica gel column chromatography using EtOAc/hexane (20:80 v:v) to afford a yellow color solid, 678 mg, 81% yield. ¹ H NMR (400 MHz, CDCl₃) δ 8.03–7.97 (m, 2H), 7.84–7.79 (m, 1H), 7.71–7.64 (m, 2H), 7.34 (m, 2H), 7.16 (m, 1H), 4.37–4.29 (m, 1H), 4.29–4.21 (m, 1H), 2.94 (s, 3H), 2.42 (s, 3H), 1.26 (t, J = 8 Hz, 3H). ¹³ C­{ ¹ H} NMR (101 MHz, CDCl₃) δ: 191.2, 164.1, 153.3, 145.2, 138.6, 136.5, 130.0, 127.7, 125.4, 123.8, 120.9, 113.9, 93.0, 63.2, 52.8, 21.7, 14.0. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₁₉H₂₀NO₆S 390.1011; found: 390.1000. IR 3028, 1731, 1587, 1157, and 950 cm^–1. mp 112–115 °C.

Ethyl 2-Methoxy-1-tosylspiro­[indoline-3,2′-oxirane]-2-carboxylate (6)

TMSOI (367 mg, 1.6 mmol, 5 equiv) was dissolved in 3 mL of dry DMSO (0.5 M). NaH (48 mg, 2 mmol) was added, and the mixture was stirred at room temperature for 5 min. Compound 5 (130 mg, 0.3 mmol) dissolved in 1 mL dry DMSO was added dropwise. The mixture was stirred at room temperature for 3 h. The crude mixture was extracted 3 times with NH₄Cl and ethyl acetate and dried over sodium sulfate. The product was purified by silica gel column chromatography using EtOAc/Hexane (40:60 v:v) to afford an amorphous yellow solid. 50 mg, 37% yield. ¹ H NMR (400 MHz, CDCl₃) δ 8.06–8.01 (m, 2H), 7.34 (m, 4H), 7.06–6.98 (m, 2H), 4.37–4.29 (m, 2H), 3.53 (m, 1H), 3.46 (m, 1H), 3.03 (s, 3H), 2.41 (s, 3H), 1.31 (t, J = 8 Hz, 3H). ¹³ C­{ ¹ H} NMR (101 MHz, CDCl₃) δ: 165.0, 144.8, 144.4, 136.4, 131.4, 129.8, 128.1, 123.4, 123.2, 122.6, 112.2, 97.5, 63.8, 62.7, 51.8, 51.8, 41.0, 21.7, 14.1. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₂₀H₂₂NO₆S 404.1168; found: 404.1171. IR 2923, 1765, 1677, 1355, 1163, 1016 cm^–1.

Ethyl 2-(1H-Indol-3-yl)-3-oxoindoline-2-carboxylate (7)

Compound 5 (188 mg, 0.48 mmol) and magnesium turnings (586 mg, 24 mmol, 50 equiv) were dissolved in 12 mL of dry MeOH (0.04 M) under N₂ atmosphere. The suspension was placed in an ultrasonicator at room temperature and sonicated for 30 min, with the flask being manually shaken every minute for the first 5 min to ensure thorough mixing. The suspension was poured over ethyl acetate with vigorous shaking to prevent a thick gel from forming. The crude mixture was extracted 3 times with ammonium chloride solution and ethyl acetate and dried over sodium sulfate. The product was purified by silica gel column chromatography using EtOAc/Hexane (9:91 v:v) to afford a purple solid, 60 mg, 61% yield. ¹ H NMR (400 MHz, CDCl₃) δ 7.83 (s, 1H), 7.73 (m, 1H), 7.33 (m, 1H), 7.25 (m, 1H), 7.08 (m, 1H), 4.42 (q, J = 8 Hz, 2H), 1.41 (t, J = 8 Hz, 3H). ¹³ C­{ ¹ H} NMR (101 MHz, CDCl₃) δ: 163.5, 147.5, 135.4, 127.3, 120.2, 119.8, 117.9, 112.0, 108.2, 60.8, 14.6. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₁₁H₁₂NO₃ 206.0817; found: 206.0825. IR 3507, 3337, 2920, 1674, 1617, 1327, 1232, 1012, 742 cm^–1. mp 93–96 °C. The deprotected indole from the previous step (30 mg, 0.15 mmol) was dissolved in 12 mL of dry DCM (1.3 mM). PIFA (62 mg, 0.15 mmol, 1 equiv) was added. The solution was stirred at room temperature for 5 min and indole (42 mg, 0.36 mmol, 2.5 equiv) was added. The solution was stirred at room temperature for 1 h and extracted 3 times with water and DCM and dried over sodium sulfate. Product was purified by silica gel column chromatography using EtOAc/Hexane (20:80 v:v) to afford 43 mg of yellow solid, 43 mg, 92% yield. ¹ H NMR (400 MHz, CDCl₃) δ 8.40 (s, 1H), 7.69 (m, 1H), 7.62–7.57 (m, 1H), 7.52 (m, 1H), 7.33–7.28 (m, 2H), 7.17 (m, 1H), 7.08 (m, 1H), 6.99 (m, 1H), 6.95–6.90 (m, 1H), 5.73 (s, 1H), 4.27 (q, J = 8 Hz, 2H), 1.23 (t, J = 8 Hz, 3H). ¹³ C­{ ¹ H} NMR (101 MHz, CDCl₃) δ: 195.0, 168.5, 161.2, 137.9, 136.6, 125.5, 125.4, 123.7, 122.6, 120.3, 120.3, 119.9, 119.6, 113.6, 111.7, 111.6, 72.7, 63.1, 14.1. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₁₉H₁₇N₂O₃ 321.1239; found: 321.1257. IR 3390, 3348, 2917, 1726, 1676, 1232, and 744 cm^–1. mp 189–192 °C.

Ethyl 2-Amino-3-oxo-1-tosylindoline-2-carboxylate (8)

2q (42 mg, 0.1 mmol) was dissolved in 10 mL of ethanol (0.01 M). 2 mL of conc. HCl was added, and the mixture was stirred at 100 °C overnight. Then, pH was adjusted to 7 by adding solid NaHCO₃ and extracted 3 times with water and ethyl acetate. The organic layer was dried over sodium sulfate, and the product was purified by silica gel column chromatography using ethyl acetate and hexane as eluents (13:87, v:v). The desired product was obtained as a white solid, 61% yield. ¹ H NMR (400 MHz, CDCl₃) δ 8.00–7.94 (m, 2H), 7.70 (m, 1H), 7.61 (m, 1H), 7.54 (m, 1H), 7.31 (m, 2H), 7.14 (m, 1H), 5.35 (s, 1H), 4.43 (m, 1H), 4.31 (m, 1H), 2.40 (s, 3H), 1.63 (s, 1H), 1.29 (t, J = 8 Hz, 3H). ¹³ C­{ ¹ H} NMR (101 MHz, CDCl₃) δ: 191.3, 167.2, 152.4, 145.1, 138.3, 136.1, 129.9, 128.0, 125.9, 123.9, 120.3, 113.8, 87.3, 64.5, 21.7, 14.0. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₁₈H₁₉N₂O₅S 375.1015; found: 375.1009. IR 3435, 3410, 2988, 1599, 1456, 1249, and 743 cm^–1. mp 132–135 °C.

The data underlying this study are available in the published article and its Supporting Information.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.5c00873.

• Synthetic procedures and characterization data for all new compounds, computational details, and optimized geometries (PDF)

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

The authors declare no competing financial interest.