Palladium-catalyzed C-7 alkenylation of indolines using molecular oxygen as the sole oxidant

Abstract

A general and efficient method for the intermolecular direct C-7-selective C–H alkenylation of indolines using palladium(II) as the catalyst and molecular oxygen as the sole oxidant has been developed. The reaction showed complete regio- and stereoselectivity. All products were E-isomers at the C-7 position, and no Z-isomers or other position substituted products could be detected. The approach also presented an efficient route for the synthesis of C-7 alkenylated indoles.

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Introduction

The indoline ring is a ubiquitous structural unit in bioactive natural products, pharmaceuticals, and organic materials.¹ The development of efficient strategies for the functionalization of indoline nucleus has been received considerable attention in organic synthesis.² Among them metal-catalyzed direct C-7 C–H alkenylation is an attractive approach due to 7-vinylindoline motifs found in numerous bioactive moleculars and important synthetic intermediates.³ However, to date efficient direct regioselective C-7 alkenylation of indoline has been limited. In 2011, Caretero et al. reported an elegant Pd(II)-catalyzed ortho C–H olefination of aniline and arylalkamine derivatives with electron-poor alkenes using the 2-pyridylsulfonyl group as a removable directing group with N-fluoro-2,4,6-trimethylpyridiniumtriflate (2.0 equiv.) as the oxidant.^4a Later in 2013, with the similar reaction conditions they disclosed a pioneering example of Pd(II)-catalyzed direct C-7 C–H alkenylation of N-(2-pyridyl)-sulfonyl indoline with butyl acrylate.^4b Then Oestreich et al. employed urea units as directing group to realize an elegant Pd(II)-catalyzed C-7 alkenylation of indolines using 1,4-benzoquinone (BQ, 2.0 equiv.) as the oxidant.⁵ Almost at the same time, with the similar urea directing group, Antonchick et al. disclosed a Rhodium(III)-catalyzed C-7 alkenylation of indolines using AgSbF₆ (20 mol%) as an activator and Cu(OAc)₂ (2.5 equiv.) as the oxidant, followed by one-pot subsequent oxidation to provide 7-vinylindoles.⁶ Despite these important advances, some challenging issues still remain: for example, (1) large excess of oxidants was utilized to regenerate the catalyst;⁶ (2) stoichiometric amounts of reduced products of the oxidants were produced as waste which increased work-up cost; and (3) substrate scope was limited and some cases were of poor yield.⁵ Herein, we report a general, efficient and structurally versatile palladium(II)-catalyzed intermolecular C-7-selective C–H alkenylation of indolines, characterized by using molecular oxygen as the sole oxidizing agent, complete regio- and stereoselectivity. Compared with N-fluoro-2,4,6-trimethyl-pyridiniumtriflate, Cu(OAc)₂ and BQ, oxygen is an ideal oxidant and offers attractive industrial prospects in terms of green and sustainable chemistry while no reduced waste is produced.⁷

Results and discussion

Initially, we chose Pd(OAc)₂ as catalyst. Considering trifluoroacetic acid (TFA) and Pd(OAc)₂ can facilitate the generation of more electropositive [Pd(II)O₂CCF₃]⁺ species which, compared with [Pd(II)OAc]⁺, possesses higher activity for electrophilic substitution of C–H bonds to form σ-indoline–Pd complex,⁸ TFA was introduced as the additive. The study commenced by investigating the indoline N-protecting groups which have potential directing feature for the C-7 position. A set of protecting groups were tested for the reaction of indoline derivatives (1) and ethyl acrylate (2a) using 10 mol% Pd(OAc)₂ as catalyst, trifluoroacetic acid (TFA, 4 equiv.) as the additive and oxygen as the oxidant in 1,2-dichloroethane (DCE) at 80 °C (Table 1). The reaction was found to proceed in low conversion (<10%) when the N-protecting group was Ts, Ac or 2-pyridylcarbonyl (Table 1, entries 1–3). To our delight, the N-(2-pyridyl)sulfonyl protecting group gave the desired product 3da in 62% conversion and 55% isolated yield (Table 1, entry 4). Moreover, the reaction possessed complete C-7 regioselectivity and E stereoselectivity by analyzing the reaction mixtures. Then the palladium source was investigated (Table 1, entries 5–6), Pd(TFA)₂ or PdCl₂ did not improve the yield of the desired product. In the absence of palladium catalyst, the reaction would not occur (Table 1, entry 7). After careful solvent screening, anisole/AcOH (10 : 1) proved to be the best solvent to give complete conversion and excellent yield (Table 1, entries 8–12). Finally we checked the amount of the additive TFA and the catalyst Pd(OAc)₂. TFA (2 equiv.) provided almost the same results, but less amount of TFA led to incomplete reaction (Table 1, entry 13). The conversion decreased remarkably while Pd(OAc)₂ was reduced to 5% (Table 1, entry 14).

Table 1 Optimization of reaction conditions^a

Entry	Indoline	Cat.	Solvent	Time (h)	Yield^b (%)
a Reaction conditions: 1 (1.0 mmol), 2a (2.0 mmol), catalyst (0.1 mmol), O2 (1 atm) and TFA (4.0 mmol) in solvent (10 mL) at 80 °C.b Isolated yield after purification by flash column chromatography.c Solvents: 1,4-dioxane, DMSO, MeOH, CH3CN, THF, CH3NO2.d TFA (2.0 mmol).e Catalyst (0.05 mmol).f The conversion. The yield was in parentheses.
1	1a	Pd(OAc)2	DCE	16	—
2	1b	Pd(OAc)2	DCE	16	—
3	1c	Pd(OAc)2	DCE	16	—
4	1d	Pd(OAc)2	DCE	16	62^f (55)
5	1d	Pd(TFA)2	DCE	16	45
6	1d	PdCl2	DCE	16	<10
7	1d	—	DCE	16	—
8	1d	Pd(OAc)2	Anisole	16	52
9	1d	Pd(OAc)2	Toluene	16	30
10	1d	Pd(OAc)2	AcOH	16	47
11	1d	Pd(OAc)2	Solvents^c	16	<20
12	1d	Pd(OAc)2	Anisole : AcOH (10 : 1)	12	100^f (95)
13^d	1d	Pd(OAc)2	Anisole : AcOH (10 : 1)	12	100^f (93)
14^d^e	1d	Pd(OAc)2	Anisole : AcOH (10 : 1)	12	<30

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Accordingly, the reaction conditions were optimized as follows: Pd(OAc)₂ (10% mol), TFA (2 equiv.) under oxygen atmosphere in the solvent (anisole/AcOH = 10 : 1) at 80 °C.

After identifying the optimized conditions, we moved on to explore the scope of the transformation. First, we studied the effect of electronic and structural variations on the alkene (Table 2). The present reaction tolerated a variety of alkenes. Monosubstituted alkenes, not only electrophilic alkenes but also the more challenging non-activated styrene derivatives, reacted with 1d to give the corresponding C-7 alkenylation products in good to excellent yields (72–95%) with complete regio- and stereoselectivity (Table 2, entries 1–9). Indoline phosphonate 3dj could also be generated from vinyl phosphonate 2j in excellent yield (Table 2, entry 10). Pleasedly, 1,1-disubstituted alkenes successfully coupled with indoline at C-7 position to give the corresponding double-bond-isomerized product in high yield (Table 2, entry 11). Particularly noticeable is the performance of 1,2-disubstituted alkenes, given the few precedents and lower reactivity of this kind of olefin in oxidative alkenylation (Fujiwara–Moritani) reactions.⁹ Under this reaction conditions, (E)-methyl crotonate and dimethyl maleate underwent smooth reaction with 1d to afford the corresponding trisubstituted alkene products 3dl and 3dm in excellent yields, respectively (Table 2, entries 12 and 13). The molecular structures of compound 3da and 3dk were confirmed by X-ray crystallographic analysis (Fig. 1).²⁰

Table 2 C-7-alkenylation of indoline (1d) with alkenes^a

Entry	Alkene	Product	Time (h)	Yield^b (%)
a Reaction conditions: 1d (1.0 mmol), 2 (2.0 mmol), Pd(OAc)2 (0.1 mmol), O2 (1 atm) and TFA (2.0 mmol) in anisole/AcOH (10 : 1, 10 mL) at 80 °C.b Isolated yield.c Anisole/AcOH (2 : 1).d Double bond isomer of the alkenylation product.
1			12	95
2			16	88
3^c			26	91
4			30	79
5			24	92
6			20	83
7			20	72
8			20	86
9			20	82
10			20	94
11^d			20	80
12			16	85
13			24	95

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Fig. 1 X-ray of 3da and 3dk.

Next, we explored the reaction of various indoline derivatives with n-butyl acrylate (2b) and 4-fluorostyrene (2g) (Table 3). We chose 4-fluorostyrene as model substrate due to organofluorine molecules possessing distinctive properties and having many valuable applications in medicinal chemistry, agrochemistry, and materials science.¹⁰ Indolines, bearing either electron-withdrawing groups or electron-donating groups, all reacted smoothly and provided C-7 alkenylation products 3 in moderate to good yields (50–83%). Many functional substituents such as F, Cl, Br and MeO were compatible with these conditions, which could be further transformed into other functionalities.

Table 3 C-7-alkenylation of various indoline derivatives with ethyl acrylate and 4-fluorostyrene^ab

Indoline	Product of 2b	Product of 2g
a Reaction conditions: 1 (1.0 mmol), 2b or 2g (2.0 mmol), Pd(OAc)2 (0.1 mmol), O2 (1 atm) and TFA (2.0 mmol) in anisole/AcOH (10 : 1, 10 mL) at 80 °C.b Isolated yield after purification by flash column chromatography.

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A plausible mechanism for the reaction is showed in Scheme 1. Pd(OAc)₂ is treated with TFA to get active Pd(O₂CCF₃)⁺,^8,11 which affords the C-7-palladated cyclopalladation species I through coordination of palladium(II) to the nitrogen in the 2-pyridylsulfonyl group. Then coordination of alkene (intermediate II) and insertion of C=C bond result in the palladium(II) complex III. Indoline/alkene adduct would be released from III upon β-H elimination, and the Pd(0) can be re-oxidized to Pd(O₂CCF₃)⁺ by O₂ in the presence of TFA to complete the catalytic cycle.¹²

Scheme 1 Plausible mechanism for the transformation.

After developing efficient approach for synthesis of 7-vinylindolines, we were interested in synthesizing 7-vinylindoles because the motifs are also prevalent in many natural products and pharmaceutical targets.^3b–d Delightedly, indoline derivatives could be easily oxidized with DDQ (1.2 equiv.) to generate 7-substituted indole derivatives (Scheme 2). The 2-pyridylsulfonyl group in indolines (3) or indoles (4) can be facilely removed under mild conditions with the stereochemistry of the olefin moiety untouched. The reaction was carried out with zinc in NH₄Cl (aq.)/THF (1 : 1) at room temperature to afford the product in good yield.

Scheme 2 Deprotection and synthesis of 7-vinylindoles.

Experimental

General information

All commercial reagents and solvents were used as received without further purification. Reactions were followed with TLC (0.254 mm silica gel 60 F plates). Visualization was accomplished with UV light. Flash chromatographies were carried out on silica gel 200–300 mesh. All NMR spectra were obtained at ambient temperature using Varian INOVA-400 MHz or Bruker-400 MHz spectrometer. ¹H NMR and ¹³C NMR spectra were recorded using CDCl₃ as solvent. Spectra were referenced internally to the residual proton resonance in CDCl₃ (δ 7.26 ppm) with tetramethylsilane (TMS, δ 0.00 ppm) as the internal standard. Chemical shifts (δ) were reported as part per million (ppm) in δ scale downfield from TMS. Multiplicities are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. Infrared (IR) spectra were recorded using KBr Solid on a Bruker EQUINOX55 instrument. High resolution mass spectrometry data were obtained on a micro TOF-QII (hybrid quadrupolar/time-of-flight) API US system by electrospray ionization (ESI) in the positive ion mode using a Bruker instrument. X-ray crystal structure analyses were measured on Bruker Smart APEXIICCD instrument using Mo-Kα radiation. The structures were solved and refined using the SHELXTL software package.

General experimental procedure for synthesis

Synthesis of substituted indolines⁶. Substituted indole (1.5 mmol) was dissolved in glacial acetic acid (6 mL) and cooled in an ice bath just until the solution began to become partially frozen. At this point, the solution was treated portion-wise with sodium cyanoborohydride (4.5 mmol), then allowed to warm to room temperature and stir for 15 hours. The reaction mixture was concentrated to a thick residue and diluted with saturated aqueous NaHCO₃. The resulting solution was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO₃ and brine, then dried over anhydrous Na₂SO₄ and concentrated. Then product was purified by normal silica gel column chromatography with EtOAc/petroleum ether as eluent.

Synthesis of 1-tosylindoline (1a)¹³. To a vigorously stirring solution of indoline (240 mg, 2.0 mmol) and tetrabutylammonium hydrogen sulfate (TBAHS) (33.6 mg, 0.2 mmol) in CH₂Cl₂ (5 mL) at 0 °C was added 50% aqueous sodium hydroxide (3 mL) and sulfonyl chloride (419 mg, 2.2 mmol). The resultant solution was stirred at room temperature until completion of the reaction (TLC). After this time, the organic layer was separated, washed with 1 M HCl, saturated aqueous NaHCO₃, water and brine; dried over MgSO₄ and concentrated under reduced pressure. The residue was purified by flash chromatography to afford 1a; white solid; yield: (182 mg, 76%).

Synthesis of 1-(indolin-1-yl)ethanone (1b)¹⁴. Acetyl chloride (237 mg, 3.0 mmol) was added to a solution of indoline (240 mg, 2.0 mmol) in acetic acid (5 mL), and the reaction mixture was refluxed for 3 h. After removing the solvent afforded N-acetyl indoline 1b; yield: (216 mg, 90%).

Synthesis of N-(2-pyridyl) carbonyl indoline (1c)¹⁵. The indoline (119 mg, 1 mmol) were added to pyridine-2-carboxylic acid (111 mg, 0.9 mmol), triethylamine (0.16 mL) and TBTU (312 mg, 0.97 mmol) in THF(10 mL). The reaction mixture was stirred for 3 h at RT, diluted with EtOAc and washed with 15% potassium carbonate solution, saturated sodium chloride solution and 1 M hydrochloric acid. The organic phase was dried over MgSO₄ and the volatiles were removed under reduced pressure. The residue was purified by flash chromatography to afford 1c. yield: (67 mg, 56%).

Synthesis of starting materials (N-(2-pyridyl)sulfonylindoline) derivatives.
2-Pyridylsulfonyl chloride¹⁶. To a solution of 2-mercaptopyridine (1.5 g, 13.5 mmol) in conc. H₂SO₄ (40 mL) was added dropwise a commercially available bleach solution (roughly 5% NaClO, 150 mL). The resulting mixture was stirred at 0 °C for 15 min before it was extracted with CH₂Cl₂ (3 × 25 mL). The combined organic phase was dried (Na₂SO₄) and concentrated under reduced pressure at 20 °C (caution: in a fume hood because of the presence of Cl₂) to afford the 2-pyridylsulfonyl chloride as a colorless oil. This compound is relatively unstable at room temperature and it was immediately used without further purification.
N-(2-Pyridyl)sulfonylindoline derivatives¹⁷. A mixture of indoline (2.2 g, 18.0 mmol) and sodium hydride (860 mg, 36.0 mmol) was stirred in dry THF at 0 °C for 30 min. To the resulting solution was slowly added at 0 °C 2-pyridylsulfonyl chloride (6.4 g, 36.0 mmol) and the resulting mixture was stirred at room temperature overnight. The mixture was quenched with saturated aqueous NH₄Cl solution and extracted with EtOAc. The combined organic phase was dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by flash chromatography.
Synthesis of the C-7 alkenylation of indolines. A seal tube containing the N-(2-pyridyl)sulfonylindoline derivative 1 (0.2 mmol), Pd(OAc)₂ (6.0 mg, 10 mol%) was evacuated and filled with dioxygen gas using an oxygen containing balloon. Then, anisole/AcOH (10 : 1, 1 mL), alkene 2 (0.4 mmol) and trifluoroacetic acid (TFA, 0.4 mmol) were sequentially added to the system via syringe under an oxygen atmosphere (if alkene 2 is response to a solid, it can be charged with N-(2-pyridyl)sulfonylindoline derivative 1 in the full oxygen tube). The mixture was heated to 80 °C for 12–48 h (indicated in each case). It was allowed to reach room temperature, diluted with EtOAc (30 mL) and washed with saturated aqueous NaHCO₃ (3 × 2 mL). The combined organic phase was dried (Na₂SO₄) and concentrated under reduced pressure. Purification by flash chromatography afforded the C-7 alkenylated indoline derivative 3.
Oxidation of indoline derivatives¹⁸. Indoline derivative (150 mg, 0.42 mmol) was dissolved in dry toluene (2 mL) in a round bottomed flask equipped with a reflux condenser and DDQ (125 mg, 0.55 mmol) was added. The reaction mixture was heated to reflux under an argon atmosphere for 12 hours. The reaction was then cooled to RT, diluted with EtOAc, washed with water and brine and dried over anhydrous MgSO₄. The solvent was removed in vacuo and purification of the crude reaction mixture by flash chromatography to afford the product.
Removing the directing group⁴. A suspension of indoline or indole derivative (36 mg, 0.1 mmol) and activated Zn powder (327 mg, 5 mmol, 50 equiv.) in a 1 : 1 mixture of THF and sat aq. NH₄Cl solution (5 mL) was stirred at room temperature until consumption of the starting material (TLC monitoring). The mixture was diluted with EtOAc (15 mL) and filtered over a pad of Celite to remove the Zn. The filtrate was washed with a saturated aqueous solution of ammonium chloride and brine. The combined organic phase was dried over MgSO₄ and concentrated to dryness. The residue was purified by flash chromatography to afford the product.

Product characterization data.
3-Methylindoline⁶. ¹H NMR (400 MHz, CDCl₃) δ 7.05 (d, J = 8.0 Hz, 1H), 7.00 (t, J = 8.0 Hz, 1H), 6.71 (t, J = 8.0 Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H), 3.65–3.58 (m, 2H), 3.34–3.29 (m, 1H), 3.04 (t, J = 8.0 Hz, 1H), 1.29 (d, J = 8.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 151.2, 134.2, 127.2, 123.3, 118.6, 109.4, 55.3, 36.5, 18.6.
5-Methylindoline⁶. ¹H NMR (400 MHz, CDCl₃) δ 6.94 (s, 1H), 6.82 (d, J = 4.0 Hz, 1H), 6.55 (d, J = 8.0 Hz, 1H), 3.52–3.48 (m, 3H), 2.97 (t, J = 8.0 Hz, 2H), 2.24 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 149.2, 129.3, 128.1, 127.5, 125.4, 109.5, 47.6, 30.0, 20.8.
5-Methoxyindoline. ¹H NMR (400 MHz, CDCl₃) δ 6.74 (s, 1H), 6.56 (s, 2H), 3.71 (s, 4H), 3.48 (t, J = 8.0 Hz, 2H), 2.97 (t, J = 8.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 153.4, 145.2, 131.11, 112.0, 111.4, 110.1, 55.8, 47.7, 30.4.
5-Chloroindoline⁶. ¹H NMR (400 MHz, CDCl₃) δ 7.17 (s, 1H), 7.07 (d, J = 8.0 Hz, 1H), 6.47 (d, J = 8.0 Hz, 1H), 3.58–3.51 (m, 3H), 2.99 (t, J = 8.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 150.7, 131.8, 129.8, 127.6, 110.6, 110.1, 47.6, 29.7.
5-Bromoindoline⁶. ¹H NMR (400 MHz, CDCl₃) δ 7.15 (s, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.44 (d, J = 8.0 Hz, 1H), 3.73 (s, 1H), 3.50 (t, J = 8.0 Hz, 2H), 2.96 (t, J = 8.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 150.6, 131.7, 129.7, 127.5, 110.5, 109.98, 47.5, 29.6.
1-Tosylindoline (1a)¹³. ¹H NMR (400 MHz, CDCl₃) δ 7.67–7.63 (m, 3H), 7.22–7.16 (m, 3H), 7.06 (d, J = 8.0 Hz, 1H), 6.96 (t, J = 8.0 Hz, 1H), 3.89 (t, J = 8.0 Hz, 2H), 2.86 (t, J = 8.0 Hz, 2H), 2.35 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 144.2, 141.9, 133.8, 131.8, 129.6, 127.7, 127.3, 125.1, 123.7, 114.9, 49.9, 27.8, 21.5.
1-(Indolin-1-yl)ethanone (1b)¹⁴. ¹H NMR (400 MHz, CDCl₃) δ 8.20 (d, J = 8.0 Hz, 1H), 7.19–7.14 (m, 2H), 7.00 (d, J = 8.0 Hz, 1H), 3.99 (t, J = 8.0 Hz, 2H), 3.15 (t, J = 8.0 Hz, 2H), 2.19 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 168.7, 142.8, 131.1, 127.4, 124.5, 123.5, 116.8, 48.7, 27.9, 24.2.
N-(2-Pyridyl) carbonyl indoline (1c)¹⁵. ¹H NMR (400 MHz, CDCl₃) δ 8.62 (d, J = 4.0 Hz, 1H), 8.32 (d, J = 4.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.38 (s, 1H), 7.27–7.21 (m, 2H), 7.09–7.07 (m, 1H), 4.33 (t, J = 8.0 Hz, 2H), 3.13 (t, J = 8.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 166.1, 154.5, 148.0, 143.2, 137.1, 132.2, 127.4, 125.0, 124.6, 124.3, 124.1, 117.9, 50.1, 28.6.
N-(2-Pyridyl)sulfonylindoline (1d)¹⁷. IR (KBr, cm⁻¹): 3056, 2969, 2927, 2857, 1599, 1570, 1481, 1454, 1350, 1178, 752; ¹H NMR (400 MHz, CDCl₃) δ 8.61 (d, J = 4.0 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.82 (t, J = 8.0 Hz, 1H), 7.47–7.43 (m, 2H), 7.10–7.08 (m, 2H), 6.93 (t, J = 8.0 Hz, 1H), 4.33 (t, J = 8.0 Hz, 2H), 3.05 (t, J = 8.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 156.2, 150.2, 141.5, 137.8, 132.0, 127.5, 127.0, 125.2, 123.7, 123.1, 114.5, 51.4, 28.1; HRMS (ESI): exact mass calcd for C₁₃H₁₂N₂NaO₂S⁺ [M + Na]⁺: 283.0517. Found: 283.0513.
2-Methyl-1-(pyridin-2-ylsulfonyl)indoline (1e). White solid; mp = 96–97 °C; IR (KBr, cm⁻¹): 3023, 2961, 2919, 1576, 1474, 1347, 1175, 763; ¹H NMR (400 MHz, CDCl₃) δ 8.57 (d, J = 4.0 Hz, 1H), 7.87 (d, J = 4.0 Hz, 1H), 7.77 (t, J = 8.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.40–7.37 (m, 1H), 7.12–7.06 (m, 2H), 6.95 (t, J = 8.0 Hz, 1H), 5.01–4.98 (m, 1H), 3.31–3.25 (m, 1H), 2.57 (d, J = 16.0 Hz, 1H), 1.45 (d, J = 4.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 156.6, 150.0, 140.3, 137.7, 131.6, 127.4, 126.8, 125.3, 124.2, 122.8, 116.0, 59.9, 36.3, 23.6; HRMS (ESI): exact mass calcd for C₁₄H₁₅N₂O₂S⁺ [M + H]⁺: 275.0849. Found: 275.0860.
3-Methyl-1-(pyridin-2-ylsulfonyl)indoline (1f)¹⁸. Pale yellow oil; IR (KBr, cm⁻¹): 3053, 2963, 2927, 2875, 1507, 1477, 1454, 1354, 1177, 752; ¹H NMR (400 MHz, CDCl₃) δ 8.60 (d, J = 4.0 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.83 (t, J = 8.0 Hz, 1H), 7.48–7.41 (m, 2H), 7.13–7.06 (m, 2H), 6.96 (t, J = 8.0 Hz, 1H), 4.47 (t, J = 8.0 Hz, 1H), 3.85–3.80 (m, 1H), 3.39–3.34 (m, 1H), 1.22 (d, J = 8.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 155.9, 150.1, 140.9, 137.8, 136.8, 127.6, 127.0, 123.9, 123.7, 122.9, 114.1, 58.7, 34.7, 19.3; HRMS (ESI): exact mass calcd for C₁₄H₁₄N₂NaO₂S⁺ [M + Na]⁺: 297.0668. Found: 297.0674.
5-Methyl-1-(pyridin-2-ylsulfonyl)indoline (1g). White solid; mp = 95–96 °C; IR (KBr, cm⁻¹): 3088, 2956, 2921, 2855, 1615, 1576, 1484, 1453, 1352, 1178, 815, 782, 744; ¹H NMR (400 MHz, CDCl₃) δ 8.58 (d, J = 4.0 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.82–7.80 (m, 1H), 7.40–7.33 (m, 2H), 6.89 (s, 2H), 4.29 (t, J = 8.0 Hz, 2H), 2.97 (t, J = 8.0 Hz, 2H), 2.20 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 155.9, 150.0, 138.9, 137.7, 133.3, 132.1, 127.8, 126.9, 125.7, 122.9, 114.2, 51.4, 27.9, 20.7; HRMS (ESI): exact mass calcd for C₁₄H₁₄N₂NaO₂S⁺ [M + Na]⁺: 297.0668. Found: 297.0682.
5-Methoxy-1-(pyridin-2-ylsulfonyl)indoline (1h)¹⁸. White solid; mp = 92–94 °C; IR (KBr, cm⁻¹): 3097, 2954, 2838, 1601, 1574, 1486, 1429, 1351, 1241, 1177, 857, 815, 780, 745; ¹H NMR (400 MHz, CDCl₃) δ 8.60 (d, J = 4.0 Hz, 1H), 7.89–7.81 (m, 2H), 7.42–7.37 (m, 2H), 6.64–6.62 (m, 2H), 4.30 (t, J = 8.0 Hz, 2H), 3.70 (s, 3H), 2.96 (t, J = 12.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 156.6, 156.0, 150.0, 137.7, 134.7, 133.9, 126.9, 123.0, 115.7, 112.3, 111.0, 55.4, 51.6, 28.4; HRMS (ESI): exact mass calcd for C₁₄H₁₄N₂NaO₃S⁺ [M + Na]⁺: 313.0617. Found: 313.0634.
5-Chloro-1-(pyridin-2-ylsulfonyl)indoline (1i)¹⁸. Pale yellow oil; IR (KBr, cm⁻¹): 3056, 2920, 2851, 1603, 1574, 1472, 1426, 1355, 1176, 876, 817, 776, 745; ¹H NMR (400 MHz, CDCl₃) δ 8.61 (s, 1H), 7.94–7.85 (m, 2H), 7.47–7.37 (m, 2H), 7.05 (s, 2H), 4.32 (t, J = 8.0 Hz, 2H), 3.04 (d, J = 8.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 155.8, 150.2, 140.3, 137.9, 133.9, 128.7, 127.4, 127.2, 125.2, 123.0, 115.3, 51.5, 27.8; HRMS (ESI): exact mass calcd for C₁₃H₁₂ClN₂O₂S⁺ [M + H]⁺: 295.0303. Found: 295.0308.
5-Bromo-1-(pyridin-2-ylsulfonyl)indoline (1j)¹⁸. Pale yellow oil; IR (KBr, cm⁻¹): 3089, 2918, 2849, 1604, 1526, 1458, 1423, 1350, 1174, 867, 807, 775, 744; ¹H NMR (400 MHz, CDCl₃) δ 8.61 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.89–7.87 (m, 1H), 7.46 (s, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.21 (s, 2H), 4.33 (t, J = 8.0 Hz, 2H), 3.05 (t, J = 8.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 155.9, 150.3, 140.9, 137.9, 134.3, 130.4, 128.2, 127.2, 123.1, 116.3, 115.9, 51.6, 27.9; HRMS (ESI): exact mass calcd for C₁₃H₁₂BrN₂O₂S⁺ [M + H]⁺: 338.9797. Found: 338.9795.
(E)-Ethyl 3-(1-(pyridin-2-ylsulfonyl)indolin-7-yl)acrylate (3da). White solid; yield: 95%; mp = 113–115 °C; IR (KBr, cm⁻¹): 3093, 3054, 2975, 2919, 1707, 1638, 1578, 1512, 1450, 1428, 1360, 1177, 846, 786, 744; ¹H NMR (400 MHz, CDCl₃) δ 8.65 (d, J = 4.0 Hz, 1H), 8.16 (d, J = 16.0 Hz, 1H), 7.77 (t, J = 8.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 4.0 Hz, 2H), 7.14–7.09 (m, 2H), 6.42 (d, J = 16.0 Hz, 1H), 4.28 (t, J = 8.0 Hz, 4H), 2.53 (t, J = 6.0 Hz, 2H), 1.34 (t, J = 8.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 166.9, 155.8, 150.1, 141.9, 141.4, 137.8, 137.7, 127.7, 127.2, 126.8, 126.0, 125.4, 123.3, 117.8, 60.4, 53.2, 29.2, 14.3; HRMS (ESI): exact mass calcd for C₁₈H₁₈N₂NaO₄S⁺ [M + Na]⁺: 381.0879. Found: 381.0880.
(E)-Butyl 3-(1-(pyridin-2-ylsulfonyl)indolin-7-yl)acrylate (3db)⁴. White solid; yield: 88%; mp = 108–110 °C; IR (KBr, cm⁻¹): 3064, 2957, 2922, 2851, 1706, 1636, 1570, 1464, 1428, 1363, 1337, 1176, 849, 782, 743; ¹H NMR (400 MHz, CDCl₃) δ 8.65 (d, J = 4.0 Hz, 1H), 8.16 (d, J = 16.0 Hz, 1H), 7.76 (t, J = 8.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.48 (t, J = 6.0 Hz, 2H), 7.12–7.09 (m, 2H), 6.42 (d, J = 16.0 Hz, 1H), 4.28 (t, J = 8.0 Hz, 2H), 4.22 (t, J = 6.0 Hz, 2H), 2.53 (t, J = 8.0 Hz, 2H), 1.70 (t, J = 6.0 Hz, 2H), 1.46–1.44 (m, 2H), 0.97 (t, J = 8.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 167.1, 155.9, 150.1, 141.9, 141.5, 137.8, 137.7, 127.8, 127.2, 126.8, 126.0, 125.5, 123.3, 117.9, 64.3, 53.3, 30.8, 29.2, 19.2, 13.8; HRMS (ESI): exact mass calcd for C₂₀H₂₂N₂NaO₄S⁺ [M + Na]⁺: 409.1192. Found: 409.1204.
(E)-2-Acetoxyethyl 3-(1-(pyridin-2-ylsulfonyl)indolin-7-yl)acrylate (3dc). White solid; yield: 91%; mp = 116–119 °C; IR (KBr, cm⁻¹): 3064, 2957, 2923, 1735, 1709, 1660, 1633, 1570, 1514, 1450, 1428, 1355, 1253, 1187, 849, 784, 745; ¹H NMR (400 MHz, CDCl₃) δ 8.65 (d, J = 4.0 Hz, 1H), 8.21 (d, J = 16.0 Hz, 1H), 7.77 (t, J = 8.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.13–7.09 (m, 2H), 6.45 (d, J = 16.0 Hz, 1H), 4.42–4.27 (m, 6H), 2.53 (t, J = 6.0 Hz, 2H), 2.12 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 171.0, 166.6, 155.8, 150.2, 142.8, 141.6, 137.8, 137.7, 127.5, 127.2, 126.8, 126.2, 125.5, 123.3, 117.0, 62.3, 62.1, 53.2, 29.2, 20.9; HRMS (ESI): exact mass calcd for C₂₀H₂₀N₂NaO₆S⁺ [M + Na]⁺: 439.0934. Found: 439.0941.
(E)-1-(1-(Pyridin-2-ylsulfonyl)indolin-7-yl)pent-1-en-3-one (3dd). White solid; yield: 79%; mp = 112–114 °C; IR (KBr, cm⁻¹): 3026, 2973, 2927, 1775, 1660, 1623, 1580, 1477, 1446, 1422, 1352, 1191, 845, 789, 744; ¹H NMR (400 MHz, CDCl₃) δ 8.65 (d, J = 4.0 Hz, 1H), 8.10 (d, J = 16.0 Hz, 1H), 7.77 (t, J = 8.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.54–7.46 (m, 3H), 7.14–7.08 (m, 2H), 6.64 (d, J = 16.0 Hz, 1H), 4.31 (t, J = 8.0 Hz, 2H), 2.90–2.85 (m, 2H), 2.56 (t, J = 6.0 Hz, 2H), 1.20 (t, J = 6.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 202.4, 155.7, 150.2, 141.5, 140.5, 137.9, 137.8, 127.9, 127.3, 127.0, 126.7, 126.1, 125.3, 123.5, 53.5, 32.0, 29.2, 8.3; HRMS (ESI): exact mass calcd for C₁₈H₁₈N₂NaO₃S⁺ [M + Na]⁺: 365.0930. Found: 365.0944.
(E)-N,N-Diethyl-3-(1-(pyridin-2-ylsulfonyl)indolin-7-yl) acrylamide (3de). White solid; yield: 92%; mp = 118–120 °C; IR (KBr, cm⁻¹): 3069, 2971, 2931, 1647, 1603, 1480, 1452, 1424, 1356, 1178, 828, 784, 743; ¹H NMR (400 MHz, CDCl₃) δ 8.65 (d, J = 4.0 Hz, 1H), 7.95 (d, J = 16.0 Hz, 1H), 7.80 (t, J = 6.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.50–7.45 (m, 2H), 7.11–7.04 (m, 2H), 6.84 (d, J = 16.0 Hz, 1H), 4.24 (t, J = 6.0 Hz, 2H), 3.50 (d, J = 8.0 Hz, 4H), 2.53 (t, J = 6.0 Hz, 2H), 1.28–1.19 (m, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 166.0, 155.9, 150.0, 141.2, 138.8, 137.9, 137.6, 128.9, 127.1, 126.6, 125.6, 125.1, 123.3, 118.4, 53.0, 42.3, 40.7, 29.3, 15.0, 13.2; HRMS (ESI): exact mass calcd for C₂₀H₂₄N₃O₃S⁺ [M + H]⁺: 386.1533. Found: 386.1549.
(E)-1-(Pyridin-2-ylsulfonyl)-7-styrylindoline (3df). White solid; yield: 83%; mp = 150–152 °C; IR (KBr, cm⁻¹): 3056, 2956, 2921, 1715, 1572, 1495, 1451, 1425, 1355, 1178, 846, 778, 738; ¹H NMR (400 MHz, CDCl₃) δ 8.63 (d, J = 4.0 Hz, 1H), 7.72 (d, J = 16.0 Hz, 1H), 7.64–7.53 (m, 4H), 7.42–7.35 (m, 3H), 7.26 (d, J = 4.0 Hz, 1H), 7.10–7.06 (m, 2H), 6.93 (d, J = 8.0 Hz, 1H), 4.29 (t, J = 8.0 Hz, 2H), 2.47 (t, J = 8.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 155.8, 150.1, 134.0, 137.6, 130.7, 128.6, 128.2, 127.6, 127.1, 126.9, 126.8, 126.3, 124.2, 123.5, 53.5, 29.3; HRMS (ESI): exact mass calcd for C₂₁H₁₈N₂NaO₂S⁺ [M + Na]⁺: 385.0981. Found: 385.0986.
(E)-7-(4-Fluorostyryl)-1-(pyridin-2-ylsulfonyl)indoline (3dg). Brown solid; yield: 72%; mp = 123–125 °C; IR (KBr, cm⁻¹): 3056, 2956, 2921, 1734, 1682, 1643, 1594, 1507, 1426, 1355, 1226, 1177, 824, 778, 741; ¹H NMR (400 MHz, CDCl₃) δ 8.65 (d, J = 4.0 Hz, 1H), 7.79–7.48 (m, 6H), 7.49–7.37 (m, 1H), 7.17–6.99 (m, 4H), 6.94 (d, J = 8.0 Hz, 1H), 4.30 (t, J = 8.0 Hz, 2H), 2.48 (t, J = 8.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 162.4 (d, J = 245 Hz), 155.9, 150.2, 140.0, 137.6, 133.9, 130.6, 128.4 (d, J = 8 Hz), 127.2, 127.0, 126.9, 126.2, 124.1, 123.6, 115.6 (d, J = 22 Hz), 53.6, 29.4; HRMS (ESI): exact mass calcd for C₂₁H₁₇FN₂NaO₂S⁺ [M + Na]⁺: 403.0887. Found: 403.0901.
(E)-7-(2-Chlorostyryl)-1-(pyridin-2-ylsulfonyl)indoline (3dh). White solid; yield: 86%; mp = 155–157 °C; IR (KBr, cm⁻¹): 3058, 2955, 2921, 1653, 1566, 1426, 1352, 1176, 846, 777, 744; ¹H NMR (400 MHz, CDCl₃) δ 8.65 (d, J = 4.0 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.69–7.64 (m, 3H), 7.55 (d, J = 8.0 Hz, 1H), 7.50 (s, 1H), 7.44–7.41 (m, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.29–7.26 (m, 1H), 7.19 (t, J = 8.0 Hz, 1H), 7.10 (t, J = 8.0 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 4.32 (t, J = 8.0 Hz, 2H), 2.50 (t, J = 8.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 155.8, 150.1, 140.1, 137.6, 137.6, 135.7, 133.3, 130.4, 129.6, 128.8, 128.5, 127.3, 127.2, 127.1, 126.9, 124.6, 124.0, 123.6, 53.6, 29.3; HRMS (ESI): exact mass calcd for C₂₁H₁₇ClN₂NaO₂S⁺ [M + Na]⁺: 419.0591. Found: 419.0605.
(E)-7-(3-Chlorostyryl)-1-(pyridin-2-ylsulfonyl)indoline (3di). White solid; yield: 82%; mp = 132–134 °C; IR (KBr, cm⁻¹): 3057, 2958, 2919, 1643, 1590, 1567, 1427, 1357, 1178, 848, 782, 739; ¹H NMR (400 MHz, CDCl₃) δ 8.66 (s, 1H), 7.72–7.68 (m, 2H), 7.88–7.53 (m, 3H), 7.47–7.40 (m, 2H), 7.27 (t, J = 6.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.09 (t, J = 8.0 Hz, 1H), 6.97 (t, J = 8.0 Hz, 2H), 4.29 (t, J = 8.0 Hz, 2H), 2.53 (t, J = 8.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 156.0, 150.2, 140.3, 139.6, 137.7, 137.6, 134.5, 130.1, 129.9, 127.8, 127.4, 127.1, 126.9, 126.7, 125.1, 124.3, 124.0, 123.5, 53.6, 29.5; HRMS (ESI): exact mass calcd for C₂₁H₁₇ClN₂NaO₂S⁺ [M + Na]⁺: 419.0591. Found: 419.0606.
(E)-Diethyl2-(1-(pyridin-2-ylsulfonyl)indolin-7-yl)vinylphos-phonate (3dj). Yellow oil; yield: 94%; IR (KBr, cm⁻¹): 3056, 2982, 2907, 1619, 1579, 1429, 1392, 1359, 1178, 856, 781, 744; ¹H NMR (400 MHz, CDCl₃) δ 8.65 (d, J = 4.0 Hz, 1H), 7.87–7.76 (m, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.15–7.07 (m, 2H), 6.29 (t, J = 18.0 Hz, 1H), 4.27–4.17 (m, 6H), 2.50 (t, J = 8.0 Hz, 2H), 1.38 (t, J = 8.0 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 155.8, 150.2, 145.4 (d, J = 8 Hz), 141.2, 137.9, 137.70, 128.3 (d, J = 24 Hz), 127.2, 126.9, 125.9, 125.4, 123.5, 113.4 (d, J = 190 Hz), 62.1 (d, J = 5 Hz), 53.2, 29.2, 16.5 (d, J = 6 Hz); HRMS (ESI): exact mass calcd for C₁₉H₂₃N₂NaO₅PS⁺ [M + Na]⁺: 445.0958. Found: 445.0972.
Methyl 2-((1-(pyridin-2-ylsulfonyl)indolin-7-yl)methyl)-acrylate (3dk). White solid; yield: 80%; mp = 144–146 °C; IR (KBr, cm⁻¹): 3015, 2954, 2922, 2849, 1710, 1630, 1570, 1430, 1350, 1284, 1178, 843, 781, 743; ¹H NMR (400 MHz, CDCl₃) δ 8.66 (s, 1H), 7.74 (t, J = 8.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.28 (s, 1H), 7.03 (d, J = 12.0 Hz, 2H), 6.91 (d, J = 4.0 Hz, 1H), 6.28 (s, 1H), 5.58 (s, 1H), 4.22 (t, J = 8.0 Hz, 2H), 4.07 (s, 2H), 3.69 (s, 3H), 2.41 (t, J = 6.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 167.5, 156.0, 150.2, 141.0, 139.4, 137.7, 137.5, 132.6, 129.1, 127.1, 126.9, 123.5, 122.8, 53.5, 51.9, 35.0, 29.5; HRMS (ESI): exact mass calcd for C₁₈H₁₈N₂NaO₄S⁺ [M + Na]⁺: 381.0879. Found: 381.0888.
(E)-Methyl 3-(1-(pyridin-2-ylsulfonyl)indolin-7-yl)but-2-enoate (3dl). Colorless oil; yield: 85%; IR (KBr, cm⁻¹): 3055, 2951, 2849, 1715, 1634, 1573, 1431, 1356, 1263, 1176, 840, 784, 742; ¹H NMR (400 MHz, CDCl₃) δ 8.63 (s, 1H), 7.71 (t, J = 4.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 4.0 Hz, 1H), 7.10–7.06 (m, 3H), 5.96 (s, 1H), 4.33 (t, J = 6.0 Hz, 2H), 3.72 (d, J = 4.0 Hz, 3H), 2.64–2.61 (m, 5H); ¹³C NMR (100 MHz, CDCl₃) δ 167.2, 157.4, 156.3, 150.1, 138.8, 137.6, 136.3, 127.9, 127.0, 126.6, 124.8, 123.1, 117.9, 52.9, 51.0, 29.4, 19.1; HRMS (ESI): exact mass calcd for C₁₈H₁₈N₂NaO₄S⁺ [M + Na]⁺: 381.0879. Found: 381.0885.
(E)-Dimethyl 2-(1-(pyridin-2-ylsulfonyl)indolin-7-yl)maleate (3dm). White solid; yield: 95%; mp = 114–116 °C; IR (KBr, cm⁻¹): 3013, 2958, 2921, 1722, 1716, 1645, 1574, 1433, 1351, 1263, 1174, 837, 780, 744; ¹H NMR (400 MHz, CDCl₃) δ 8.65 (d, J = 4.0 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.45–7.42 (m, 1H), 7.12–7.02 (m, 2H), 7.01 (d, J = 8.0 Hz, 2H), 4.46 (s, 1H), 4.12 (d, J = 8.0 Hz, 1H), 3.88 (s, 3H), 3.60 (s, 3H), 2.58 (d, J = 8.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 166.1, 165.1, 155.9, 149.9, 143.5, 140.0, 137.6, 136.7, 129.0, 127.0, 127.0, 126.3, 125.8, 125.1, 123.6, 53.0, 52.8, 51.7, 29.3; HRMS (ESI): exact mass calcd for C₁₉H₁₈N₂NaO₆S⁺ [M + Na]⁺: 425.0778. Found: 425.0784.
(E)-Butyl 3-(2-methyl-1-(pyridin-2-ylsulfonyl)indolin-7-yl)acrylate (3eb). White solid; yield: 80%; mp = 113–115 °C; IR (KBr, cm⁻¹): 3056, 2922, 1704, 1634, 1570, 1513, 1427, 1361, 1279, 1176, 854, 776, 739; ¹H NMR (400 MHz, CDCl₃) δ 8.64 (d, J = 4.0 Hz, 1H), 8.15 (d, J = 16.0 Hz, 1H), 7.81–7.70 (m, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 4.0 Hz, 1H), 7.12–7.08 (m, 2H), 6.43 (d, J = 16.0 Hz, 1H), 4.99–4.96 (m, 1H), 4.23 (t, J = 6.0 Hz, 2H), 2.68–2.63 (m, 1H), 2.26 (d, J = 16.0 Hz, 1H), 1.73–1.70 (m, 2H), 1.48–1.45 (m, 2H), 1.27 (d, J = 6.0 Hz, 3H), 0.98 (t, J = 6.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 167.2, 156.0, 150.1, 142.2, 140.0, 137.8, 136.7, 128.3, 127.1, 126.7, 126.5, 125.6, 123.3, 117.6, 64.4, 60.8, 36.1, 30.8, 21.8, 19.2, 13.8; HRMS (ESI): exact mass calcd for C₂₁H₂₄N₂NaO₄S⁺ [M + Na]⁺: 423.1349. Found: 423.1349.
(E)-7-(4-Fluorostyryl)-2-methyl-1-(pyridin-2-ylsulfonyl)-indoline (3eg). Brown oil; yield: 70%; IR (KBr, cm⁻¹): 3032, 2924, 1648, 1597, 1493, 1452, 1357, 1172, 814, 759, 720; ¹H NMR (400 MHz, CDCl₃) δ 8.64 (s, 1H), 7.67–7.51 (m, 6H), 7.43 (d, J = 12.0 Hz, 1H), 7.12–7.03 (m, 4H), 6.93 (d, J = 8.0 Hz, 1H), 5.03–4.96 (m, 1H), 2.61–2.55 (m, 1H), 2.21 (d, J = 16.0 Hz, 1H), 1.29 (d, J = 8.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 162.4 (d, J = 246 Hz), 155.9, 150.1, 138.4, 137.6, 136.6, 134.0, 131.1, 128.4 (d, J = 8 Hz), 127.0, 126.7, 127.6, 126.4, 124.2, 124.1, 123.5, 115.6 (d, J = 21 Hz), 60.9, 36.1, 21.9; HRMS (ESI): exact mass calcd for C₂₂H₁₉FN₂NaO₂S⁺ [M + Na]⁺: 417.1043. Found: 417.1050.
(E)-Butyl 3-(3-methyl-1-(pyridin-2-ylsulfonyl)indolin-7-yl)acrylate (3fb). White solid; yield: 80%; mp = 132–133 °C; IR (KBr, cm⁻¹): 3061, 2956, 2924, 1706, 1637, 1572, 1513, 1458, 1427, 1358, 1281, 1177, 875, 785, 749; ¹H NMR (400 MHz, CDCl₃) δ 8.66 (s, 1H), 8.13 (d, J = 16.0 Hz, 1H), 7.79 (t, J = 8.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.17 (t, J = 8.0 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.42 (d, J = 16.0 Hz, 1H), 4.67–4.62 (m, 1H), 4.20 (t, J = 6.0 Hz, 2H), 3.54 (t, J = 12.0 Hz, 1H), 2.85–2.83 (m, 1H), 1.72–1.68 (m, 2H), 1.48–1.42 (m, 2H), 1.13 (d, J = 8.0 Hz, 3H), 0.97 (t, J = 6.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 167.0, 156.0, 150.1, 142.3, 141.9, 141.3, 137.9, 127.3, 127.2, 126.8, 125.5, 124.7, 123.2, 117.9, 64.3, 60.6, 35.5, 30.7, 19.1, 17.0, 13.8; HRMS (ESI): exact mass calcd for C₂₁H₂₄N₂NaO₄S⁺ [M + Na]⁺: 423.1349. Found: 423.1373.
(E)-7-(4-Fluorostyryl)-3-methyl-1-(pyridin-2-ylsulfonyl)-indoline (3fg). Yellow solid; yield: 70%; mp = 119–120 °C; IR (KBr, cm⁻¹): 3053, 2962, 2928, 1634, 1596, 1507, 1455, 1427, 1355, 1178, 870, 781, 751; ¹H NMR (400 MHz, CDCl₃) δ 8.65 (s, 1H), 7.75–7.54 (m, 6H), 7.43 (d, J = 4.0 Hz, 1H), 7.18–7.11 (m, 1H), 7.05–7.01 (m, 3H), 6.89 (d, J = 8.0 Hz, 1H), 4.70–4.66 (m, 1H), 3.52 (t, J = 12.0 Hz, 1H), 2.79 (s, 1H), 1.12 (d, J = 4.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 162.4 (d, J = 246 Hz), 156.0, 150.1, 142.4, 139.9, 137.7, 133.9, 130.2, 128.4 (d, J = 8 Hz), 127.1, 127.0, 126.2, 124.3, 123.5, 122.3, 115.5 (d, J = 21 Hz), 61.0, 35.5, 17.1; HRMS (ESI): exact mass calcd for C₂₂H₁₉FN₂NaO₂S⁺ [M + Na]⁺: 417.1043. Found: 417.1060.
(E)-Butyl-3-(5-methyl-1-(pyridin-2-ylsulfonyl)indolin-7-yl)-acrylate (3gb). White solid; yield: 83%; mp = 122–123 °C; IR (KBr, cm⁻¹): 3056, 2956, 2926, 1707, 1634, 1570, 1509, 1462, 1425, 1359, 1278, 1178, 851, 824, 780, 739; ¹H NMR (400 MHz, CDCl₃) δ 8.65 (d, J = 4.0 Hz, 1H), 8.15 (d, J = 16.0 Hz, 1H), 7.78 (t, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.51–7.49 (m, 1H), 7.29 (s, 1H), 6.90 (s, 1H), 6.41 (d, J = 16.0 Hz, 1H), 4.27–4.20 (m, 4H), 2.45 (t, J = 8.0 Hz, 2H), 2.29 (s, 3H), 1.72–1.70 (m, 2H), 1.46–1.43 (m, 2H), 0.97 (t, J = 8.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 167.0, 155.7, 150.0, 141.9, 139.1, 137.8, 136.6, 127.2, 126.9, 125.7, 123.3, 117.5, 64.2, 53.3, 30.7, 29.0, 21.0, 19.1, 13.7; HRMS (ESI): exact mass calcd for C₂₁H₂₄N₂NaO₄S⁺ [M + Na]⁺: 423.1349. Found: 423.1330.
(E)-7-(4-Fluorostyryl)-5-methyl-1-(pyridin-2-ylsulfonyl)-indoline (3gg). Brown oil; yield: 72%; IR (KBr, cm⁻¹): 3050, 2955, 2921, 1597, 1507, 1458, 1426, 1355, 1178, 853, 823, 781, 740; ¹H NMR (400 MHz, CDCl₃) δ 8.65 (s, 1H), 7.70–7.64 (m, 2H), 7.60–7.53 (m, 3H), 7.44 (d, J = 4.0 Hz, 1H), 7.36 (s, 1H), 7.05–7.01 (m, 3H), 6.75 (s, 1H), 4.27 (t, J = 8.0 Hz, 2H), 2.42 (t, J = 6.0 Hz, 2H), 2.30 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 162.3 (d, J = 246 Hz), 155.9, 150.1, 137.7, 137.6, 136.7, 134.0, 130.1, 128.4 (d, J = 8 Hz), 127.1, 126.7, 126.2, 124.6, 124.5, 123.7, 115.5 (d, J = 21 Hz), 53.7, 29.3, 21.3; HRMS (ESI): exact mass calcd for C₂₂H₁₉FN₂NaO₂S⁺ [M + Na]⁺: 417.1043. Found: 417.1056.
(E)-Butyl 3-(5-methoxy-1-(pyridin-2-ylsulfonyl)indolin-7-yl)acrylate (3hb). Brown oil; yield: 55%; IR (KBr, cm⁻¹): 3053, 2956, 2923, 1707, 1636, 1604, 1466, 1427, 1355, 1172, 855, 820, 778, 741; ¹H NMR (400 MHz, CDCl₃) δ 8.66 (d, J = 4.0 Hz, 1H), 8.15 (d, J = 16.0 Hz, 1H), 7.76–7.74 (m, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.48 (t, J = 6.0 Hz, 1H), 6.90 (s, 1H), 6.64 (s, 1H), 6.41 (d, J = 16.0 Hz, 1H), 4.28–4.21 (m, 4H), 3.78 (s, 3H), 2.45 (t, J = 6.0 Hz, 2H), 1.71 (t, J = 8.0 Hz, 2H), 1.49–1.43 (m, 2H), 0.96 (t, J = 6.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 167.0, 158.5, 155.9, 150.2, 141.8, 139.4, 137.8, 135.0, 128.4, 127.2, 123.5, 118.2, 112.9, 109.0, 64.4, 55.6, 53.5, 30.8, 29.5, 19.2, 13.8; HRMS (ESI): exact mass calcd for C₂₁H₂₄N₂NaO₅S⁺ [M + Na]⁺: 439.1298. Found: 439.1326.
(E)-7-(4-Fluorostyryl)-5-methoxy-1-(pyridin-2-ylsulfonyl) indoline (3hg). Brown oil; yield: 75%; IR (KBr, cm⁻¹): 3053, 2938, 2927, 1598, 1507, 1466, 1427, 1353, 1225, 1171, 847, 823, 781, 740; ¹H NMR (400 MHz, CDCl₃) δ 8.66 (s, 1H), 7.69–7.61 (m, 2H), 7.56–7.53 (m, 3H), 7.53–7.44 (m, 1H), 7.05–7.01 (m, 4H), 6.51 (s, 1H), 4.28 (t, J = 6.0 Hz, 2H), 3.80 (s, 3H), 2.41 (t, J = 6.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 162.4 (d, J = 246 Hz), 158.6, 155.9, 150.2, 139.3, 137.6, 133.8, 133.7, 131.3, 128.5 (d, J = 8 Hz), 127.2, 127.1, 126.1, 123.8, 115.6 (d, J = 21 Hz), 110.3, 108.0, 55.7, 53.8, 29.6; HRMS (ESI): exact mass calcd for C₂₂H₁₉FN₂NaO₃S⁺ [M + Na]⁺: 433.0993. Found: 433.1013.
(E)-Butyl 3-(5-chloro-1-(pyridin-2-ylsulfonyl)indolin-7-yl)acrylate (3ib). Yellow oil; yield: 70%; IR (KBr, cm⁻¹): 3071, 2959, 2928, 1710, 1638, 1580, 1453, 1424, 1361, 1251, 1177, 862, 806, 779, 742; ¹H NMR (400 MHz, CDCl₃) δ 8.66 (s, 1H), 8.07 (d, J = 16.0 Hz, 1H), 7.89–7.79 (m, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.52–7.45 (m, 2H), 7.06 (s, 1H), 6.40 (d, J = 16.0 Hz, 1H), 4.31–4.20 (m, 4H), 2.57–2.54 (m, 2H), 1.72–1.68 (m, 2H), 1.46–1.42 (m, 2H), 0.97 (t, J = 8.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 166.7, 155.8, 150.3, 140.7, 140.2, 139.7, 138.1, 132.2, 128.8, 127.4, 125.9, 125.3, 123.4, 119.0, 64.5, 53.5, 30.7, 29.3, 19.2, 13.8; HRMS (ESI): exact mass calcd for C₂₀H₂₁ClN₂NaO₄S⁺ [M + Na]⁺: 443.0803. Found: 443.0807.
(E)-5-Chloro-7-(4-fluorostyryl)-1-(pyridin-2-ylsulfonyl) indoline (3ig). Colorless oil; yield: 50%; IR (KBr, cm⁻¹): 3062, 2956, 2922, 1641, 1589, 1507, 1426, 1356, 1178, 857, 820, 777, 737; ¹H NMR (400 MHz, CDCl₃) δ 8.65 (d, J = 4.0 Hz, 1H), 7.74 (t, J = 8.0 Hz, 1H), 7.66–7.45 (m, 6H), 7.07–6.99 (m, 3H), 6.90 (s, 1H), 4.30 (t, J = 8.0 Hz, 2H), 2.49–2.48 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 162.5 (d, J = 246 Hz), 155.7, 150.2, 139.5, 138.7, 137.9, 133.4, 132.3, 131.7, 128.6 (d, J = 8 Hz), 128.1, 127.3, 125.0, 123.9, 123.6, 123.5, 115.6 (d, J = 21 Hz), 53.8, 29.3; HRMS (ESI): exact mass calcd for C₂₁H₁₆ClFN₂NaO₂S⁺ [M + Na]⁺: 437.0497. Found: 437.0503.
(E)-Butyl 3-(5-bromo-1-(pyridin-2-ylsulfonyl)indolin-7-yl)acrylate (3jb). Brown oil; yield: 70%; IR (KBr, cm⁻¹): 3065, 2958, 2928, 1710, 1638, 1578, 1542, 1425, 1362, 1334, 1251, 1177, 861, 821, 784, 743; ¹H NMR (400 MHz, CDCl₃) δ 8.66 (s, 1H), 8.05 (d, J = 16.0 Hz, 1H), 7.83–7.81 (m, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.61 (s, 1H), 7.50 (d, J = 4.0 Hz, 1H), 7.21 (s, 1H), 6.39 (d, J = 16.0 Hz, 1H), 4.30 (t, J = 6.0 Hz, 2H), 4.22 (t, J = 8.0 Hz, 2H), 2.58 (t, J = 8.0 Hz, 2H), 1.72–1.68 (m, 2H), 1.46–1.43 (m, 2H), 0.97 (t, J = 8.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 166.7, 156.0, 150.3, 140.8, 140.6, 139.9, 138.1, 129.3, 128.8, 128.4, 127.4, 123.4, 120.0, 119.2, 64.6, 53.5, 30.8, 29.3, 19.2, 13.8; HRMS (ESI): exact mass calcd for C₂₀H₂₁BrN₂NaO₄S⁺ [M + Na]⁺: 487.0298. Found: 487.0299.
(E)-5-Bromo-7-(4-fluorostyryl)-1-(pyridin-2-ylsulfonyl)-indoline (3jg). Yellow oil; yield: 50%; IR (KBr, cm⁻¹): 3068, 2956, 2923, 1633, 1583, 1507, 1450, 1426, 1359, 1179, 854, 821, 775, 737; ¹H NMR (400 MHz, CDCl₃) δ 8.65 (s, 1H), 7.75–7.72 (m, 1H), 7.67–7.63 (m, 2H), 7.60–7.51 (m, 3H), 7.48 (d, J = 4.0 Hz, 1H), 7.11–6.97 (m, 4H), 4.30 (s, 2H), 2.51 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 162.6 (d, J = 246 Hz), 155.8, 150.3, 139.8, 139.2, 137.9, 133.4, 132.2, 128.6 (d, J = 8 Hz), 128.2, 127.3, 127.0, 126.4, 124.9, 123.6, 120.2, 115.7 (d, J = 21 Hz), 53.8, 29.3; HRMS (ESI): exact mass calcd for C₂₁H₁₇BrFN₂O₂S⁺ [M + H]⁺: 459.0173. Found: 459.0175.
(E)-Ethyl 3-(1-(pyridin-2-ylsulfonyl)-1H-indol-7-yl)acrylate (4da)¹⁹. White solid; yield: 75%; mp = 160–161 °C; IR (KBr, cm⁻¹): 3045, 2974, 2923, 1710, 1645, 1638, 1575, 1508, 1461, 1423, 1359, 1255, 1178, 871, 786, 744; ¹H NMR (400 MHz, CDCl₃) δ 8.58–8.54 (m, 2H), 8.32 (d, J = 8.0 Hz, 1H), 7.91–7.88 (m, 2H), 7.60 (d, J = 8.0 Hz, 1H), 7.46–7.44 (m, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.24–7.21 (m, 1H), 6.75 (d, J = 4.0 Hz, 1H), 6.08 (d, J = 16.0 Hz, 1H), 4.31–4.26 (m, 2H), 1.37 (t, J = 8.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 166.7, 155.9, 150.4, 144.2, 138.2, 133.0, 133.0, 130.5, 127.8, 124.8, 123.8, 123.4, 123.2, 122.8, 120.2, 108.2, 60.5, 14.5; HRMS (ESI): exact mass calcd for C₁₈H₁₆N₂NaO₄S⁺ [M + Na]⁺: 379.0723. Found: 379.0737.
(E)-1-(Pyridin-2-ylsulfonyl)-7-styryl-1H-indole (4df)¹⁹. White solid; yield: 74%; mp = 163–165 °C IR (KBr, cm⁻¹): 3428, 3158, 2921, 1577, 1342, 1249, 1178, 1128, 958, 794, 730, 661, 576; ¹H NMR (400 MHz, CDCl₃) δ 8.37 (d, J = 6.0 Hz, 1H), 8.08 (d, J = 16.0 Hz, 1H), 7.90 (d, J = 4.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.44–7.43 (m, 2H), 7.41–7.28 (m, 5H), 7.25–7.20 (m, 2H), 6.75 (d, J = 4.0 Hz, 1H), 6.44 (d, J = 16.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 156.0, 150.1, 137.7, 137.5, 133.0, 132.8, 131.7, 130.3, 128.8, 128.2, 127.9, 127.4, 126.9, 126.2, 124.6, 124.0, 123.0, 121.2, 108.3; HRMS (ESI): exact mass calcd for C₂₁H₁₆N₂NaO₂S⁺ [M + Na]⁺: 383.0825. Found: 383.0800.
(E)-Ethyl 3-(indolin-7-yl)acrylate (5da). Yellow oil; yield: 82%; IR (KBr, cm⁻¹) 3364, 2923, 2853, 1692, 1649, 1608, 1462, 1361, 1304, 1240, 1176, 1049, 992, 855, 742, 591; ¹H NMR (400 MHz, CDCl₃) δ 7.73 (d, J = 16.0 Hz, 1H), 7.19–7.13 (m, 2H), 6.70 (t, J = 8.0 Hz, 1H), 6.30 (d, J = 16.0 Hz, 1H), 4.31–4.26 (m, 2H), 3.65 (t, J = 8.0 Hz, 2H), 3.10 (t, J = 8.0 Hz, 2H), 1.36 (t, J = 8.0 Hz, 3H), 1.29 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 167.7, 151.4, 141.8, 130.7, 127.1, 126.4, 118.8, 116.7, 116.0, 60.5, 47.3, 29.5, 14.5; HRMS (ESI): exact mass calcd for C₁₃H₁₆NO₂⁺ [M + H]⁺: 218.1176. Found: 218.1174.
(E)-7-Styrylindoline (5df). Colorless oil; yield: 80%; IR (KBr, cm⁻¹) 3337, 3268, 2921, 2856, 1006, 1508, 1452, 1245, 1110, 956, 831, 769, 696, 617; ¹H NMR (400 MHz, CDCl₃) δ 7.49 (d, J = 8.0 Hz, 2H), 7.36 (t, J = 8.0 Hz, 2H), 7.26–7.10 (m, 2H), 7.10–6.97 (m, 3H), 6.75 (t, J = 8.0 Hz, 1H), 3.62 (t, J = 12.0 Hz, 2H), 3.08 (t, J = 8.0 Hz, 2H), 1.25 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 149.4, 137.8, 130.2, 128.7, 127.4, 126.3, 125.5, 125.4, 123.8, 119.8, 119.2, 47.4, 29.8; HRMS (ESI): exact mass calcd for C₁₆H₁₆N⁺ [M + H]⁺: 222.1277. Found: 222.1268.
(E)-Ethyl 3-(1H-indol-7-yl)acrylate (6da). Yellow oil; yield: 80%; IR (KBr, cm⁻¹) 3373, 3018, 2921, 2905, 1691, 1636, 1509, 1472, 1435, 1336, 1274, 1187, 858, 792, 714; ¹H NMR (400 MHz, CDCl₃) δ 8.79 (s, 1H), 8.07 (d, J = 16.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.25 (s, 1H), 7.13 (t, J = 8.0 Hz, 1H), 6.61–6.51 (m, 2H), 4.33–4.28 (m, 2H), 1.36 (t, J = 8.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 167.5, 141.2, 134.4, 129.0, 124.9, 123.4, 122.3, 120.2, 118.3, 118.0, 103.3, 60.7, 14.4; HRMS (ESI): exact mass calcd for C₁₃H₁₃NNaO₂⁺ [M + Na]⁺: 238.0838. Found: 238.0847.
(E)-7-Styryl-1H-indole (6df)⁶. White solid; yield: 82%; mp = 160–162 °C; IR (KBr, cm⁻¹) 3739, 3407, 2923, 2852, 2495, 1600, 1456, 1390, 1268, 1064, 958, 788, 723, 472; ¹H NMR (400 MHz, CDCl₃) δ 8.47 (s, 1H), 7.60–7.54 (m, 3H), 7.40–7.36 (m, 4H), 7.30–7.24 (m, 2H), 7.17–7.13 (m, 2H), 6.61–6.60 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 137.6, 133.9, 129.9, 128.9, 128.6, 127.9, 126.5, 125.2, 124.4, 121.5, 120.6, 120.4, 103.4; HRMS (ESI): exact mass calcd for C₁₆H₁₃NNa⁺ [M + Na]⁺: 242.0940. Found: 242.0943.

Conclusions

We have developed a general and efficient method for the intermolecular direct C-7-selective C–H alkenylation of indolines using palladium(II) as the catalyst and molecular oxygen as the sole oxidant. The reaction showed complete regio- and stereoselectivity. All products were E-isomers at C-7 position, and no Z-isomers or other position substituted product could be detected. The approach also presented an efficient route for synthesis of C-7 alkenylation of indoles. The method should have many applications in organic and medical chemistry. Detailed mechanistic investigations and application to other types of heteroaromatic compounds are currently underway.

Acknowledgements

We are grateful for financial support from National Natural Science Foundation of China (NSFC-20972126, 21272185), the Program for New Century Excellent Talents in University of the Ministry of Education China (NCET-10-0937).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: ¹H and ¹³C NMR spectra. CCDC 1046800 and 1046801. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra02245b

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