Metal-free regioselective construction of indolin-3-ones via hypervalent iodine oxidation of N-substituted indoles

Abstract

A metal-free method for the regioselective construction of 2-acetoxy indolin-3-ones from N-substituted indoles with PhI(OAc)₂ as the oxidant was developed under mild reaction conditions. A range of functionalized 2-acetoxy indolin-3-ones were readily accessed by this strategy with moderate to good yields.

---

Introduction

Indolin-3-ones (3-oxyindoles) are unique structural motifs with frequent occurrence in the structures of a large variety of natural alkaloids and biologically active molecules.¹ Over the past few decades, research showed that indolin-3-ones have great promise in medicine² and polymers.³ Although some C-2 substituted indolin-3-one derivatives have been used in the total synthesis of molecules, such as iboluteine,⁴ (+)-isatisine A,⁵ fistulosin,⁶ brevianamide B,⁷ (+)-austamide⁸ and so on⁹ (Fig. 1), comparing with the construction of indolin-2-one derivatives,¹⁰ reports about syntheses of intricate indolin-3-one derivatives are still limited. Most of the methods rely on either transformations of pre-existing indolin-3-ones¹¹ or tandem cyclization with complicated substrates,¹² moreover, the use of precious or toxic metal catalysts, such as Au,^12a,12f Ag,^12c Al,^12d Pd,¹³ Ru¹⁴ has accounted for a great proportion. In 2014, Ye and co-workers reported a new way towards the flexible and practical synthesis of indolin-3-ones catalysed by Au (Scheme 1a).^12b These insufficiences have hindered further application in pharmaceutical synthesis of existing methods. As a result, it is very urgent to develop straightforward and efficient methods with simple substrates and transition-metal-free procedure.

Fig. 1 Selected natural products with indolin-3-one motifs.

Scheme 1 The synthesis of indolin-3-ones.

In recent years, transition-metal-free C–H bond functionalization has attracted a great deal of attention.¹⁵ In this research direction, hypervalent iodine system occupied a very important role for their benign environmental character and ready availability.¹⁶ Some properties, similar to transition metals, which are easy to undergo ligand exchange and reductive elimination, make hypervalent iodine a good choice for carbon–carbon, carbon–heteroatom, or hetero–heteroatom bond formations to construct various carbon- and heterocycles.¹⁷ In 2010, Fan's group reported a new way to the construction of indolin-3-ones via tandem oxidative cyclization–acetoxylation of o-acyl anilines (Scheme 1b),^12h and 2-acetoxy indolin-3-ones could be synthesized, which is the fundamental structure of fistulosin. This result inspired us to think the feasibility of constructing indolin-3-ones directly from the indole motif using hypervalent iodine as oxidant, and fortunately, we found PhI(OAc)₂ could achieve the goal after a careful study of reaction conditions (Scheme 1c).

Results and discussion

We chose N-(2-pyrimidyl)indole (1a) as the model substrate in the initial study and the results were summarized in Table 1. Using 3 equivalents of PhI(OAc)₂ in AcOH/Ac₂O for the reaction, 2a was observed in 62% yield along with 13% yield of 4a in 12 hours (entry 1). Comparing this interesting result with Lei's¹⁸ and Punji's¹⁹ work (Scheme 2), increasing the amount of hypervalent iodine oxidant and reaction time shifted the product formation towards the desired 2a, which was not mentioned under their reaction conditions. Further increase of reaction time led to 2a in 65% yield without the formation of 3a and 4a. This observation indicated 2a is the thermodynamically stable product under the reaction conditions compared with 3a and 4a observed under Lei's and Punji's conditions. Further optimization including different hypervalent iodine oxidants (PhI(TFA)₂, PhI(OTs)OH, PhIO, and NaIO₃) and other oxidant (m-CPBA, K₂S₂O₈) proved to be less efficient (entries 3–8). The equivalence of oxidants also affected the product distribution. When 2 equivalents of PhI(OAc)₂ was used, 2a was isolated in a slightly higher yield, but a significant amount of 4a was also observed (entry 9). Increasing the amount of PhI(OAc)₂ dropped down the yield (entry 10). Lowering the reaction temperature promoted the formation of 3a (entry 11), and higher temperature decreased the yield (entry 12).

Table 1 Optimization studies for 2-acetoxy indolin-3-ones^a

Entry	Oxidant	T (°C)	2a (%)	3a (%)	4a (%)
a Unless otherwise noted, the reactions were carried out with compound 1a (0.30 mmol), oxidant (3 eq.), AcOH/Ac2O = 7 : 3 (2.0 mL), 24 h. Yields of isolated compounds.b Reaction for 12 h.c PhI(OAc)2 = 2 eq.d PhI(OAc)2 = 4 eq.
1^b	PhI(OAc)2	60	62	Trace	13
2	PhI(OAc)2	60	65	Trace	0
3	PhI(TFA)2	60	9	0	0
4	PhI(OTs)OH	60	11	0	0
5	PhIO	60	58	Trace	7
6	NalO3	60	35	0	7
7	m-CPBA	60	15	Trace	Trace
8	K2S2O8	60	5	—	5
9^c	PhI(OAc)2	60	71	Trace	17
10^d	PhI(OAc)2	60	60	Trace	0
11	PhI(OAc)2	20	53	25	Trace
12	PhI(OAc)2	80	42	0	0

---

Scheme 2 (a) Lei's and (b) Punji's work of indole oxidation with PhI(OAc)₂.

Further optimization of the N-substituted groups suggested pyrimidyl group on indole nitrogen was essential to afford the desired product (Table 2). In the reaction of N-substituted indoles containing N-phenyl,²⁰ N-methyl and N-(2-pyridyl), neither 2 or 3 were not detected in the reaction (entries 1–3). At the same time, the indole substrates substituted by acetyl and tosyl on nitrogen gave 3 in 76% and 74% yields, respectively (entry 4 and 5).¹⁸ When there is no substituent group on the nitrogen atom of indole, the reaction also failed (entry 6).

Table 2 Effect of N-substituents on the formation of 2-acetoxy indolin-3-ones^a,b

Entry	R	SM	2 (%)	3 (%)
a Isolated yield based on 1.b Detected based on TLC and ^1H NMR analysis.c No protect group.d Decomposed into intractable products.
1	Ph	1q	0	0
2	CH3	1r	0	0
3	2-Py	1s	0	0
4	Ac	1t	0	76 (3t)
5	Tosyl	1u	0	74 (3u)
6^c	—	—	—	—^d

---

With the optimized reaction conditions in hand, we then extended the reaction with a range of substrates (Table 3). The reaction was compatible with different substituents at C4-, C5-, C6- or C7-positions, and afforded 2-acetoxy indolin-3-ones with high regioselectivity. Substrates containing electron-donating groups (EDG) or electron-withdrawing groups (EWG) all afforded 2-acetoxy indolin-3-one products predominately. Indoles with electron-donating methyl (2b, 2f and 2p), benzyloxy groups (2c) usually gave better yields than those with electron-withdrawing ester (2l), halogen groups (2d, 2e, 2h–2k and 2m–2o). This might be due to the increased electron-density and reactivity of indoles with EDG towards PhI(OAc)₂ oxidation. For indole substrates containing EWG, they tended to generate 3-acetoxy by-products (4d, 4h and 4j). Perplexing, although methoxy is a strong electron-donating group, substrate 1g only gave a low yield of 2g.

Table 3 The scope of 2-acetoxy indolin-3-ones^a,b

a Reaction conditions: substrate (0.3 mmol), PhI(OAc)₂ (0.9 mmol), AcOH : Ac₂O = 7 : 3 (2.0 mL), 60 °C, 24–36 h (to ensure the completion).b Isolated yield.c Isolated yield of the 3-OAc product.

---

Other acids and their anhydrides were tested as the mixed solvents for the reaction (Scheme 3). Employing n-propionic acid and propionic anhydride gave the corresponding 2-propionyloxy indolin-3-one (2aa) in 40% yield, along with the 3-propionyloxy indole product in 40% yield (4aa) (eqn (1)). However, when n-butyric acid and butyric anhydride were used as the solvents, 2-butyroyloxy indolin-3-one product (2ab) were observed in a low yield together with some intractable by-products (eqn (2)). For both reactions, trace amount of 2-acetoxy indolin-3-one (2a) could be observed in the end of the reaction. The formation of 2aa and 2ab might result from the exchange of alkyl acids with acetoxy group either in PhI(OAc)₂ or in the 2a.

Scheme 3 Diversified acyloxylated indolin-3-ones.

To explore the reaction path, a few control experiments were conducted to monitor the probable intermediates in the reaction (Scheme 4). When 1a reacted with 1.1 equivalents of PhI(OAc)₂ at room temperature for 1 hour, diacetoxylated indoline 3a was isolated in 50% yield (Scheme 4a). Then simply heating compound 3a in AcOH/Ac₂O for 3 hours led to the 3-acetoxylated indole 4a in 95% yield (Scheme 4b). Both products 3a and 4a have been observed as the major products under Lei's and Punji's conditions respectively.^18,19 When 4a was heated with more PhI(OAc)₂ for prolonged time, 2a was formed in 52% yield (Scheme 4c). These experiments indicated the reaction from 1a to 2a might go through intermediates 3a and 4a gradually.

Scheme 4 Control experiments addressing intermediate species.

On the basis of the above observation and literature evidence,^18,19 we propose the reaction pathways as shown in Scheme 5. The C-3 acetoxylated product 4a reacts further with PhI(OAc)₂ to form the hyperiodination intermediate A, which readily undergoes an intramolecular attack by the acetate to give unstable intermediate B accompanied by the reductive elimination of PhI. B undergoes intramolecular nucleophilic attack to generate cis oxygen cation intermediate C. Then C is attacked by acetate to afford the final product 2a. The structure of the products were confirmed by the single-crystal diffraction analysis of 2j as shown in Fig. 2.²¹

Scheme 5 Proposed mechanism for the construct of 2-acetoxy indolin-3-ones.

Fig. 2 X-ray diffraction structure of 2j.

Inspired by Fan's work,^12h the 2-acetoxy indolin-3-ones structure might be reactive to undergo the Friedel–Crafts reaction with p-xylene to afford 3-indolone derivatives (Scheme 6). In the presence of 2 equivalents of trifluoromethane sulfonic acid, reaction of 2a with p-xylene gave 2-(2,5-dimethylphenyl)-1-(pyrimidin-2-yl)indolin-3-ones (5a) in 50% yield.

Scheme 6 Friedel–Crafts reaction of 2-acetoxy indolin-3-ones.

Conclusions

In conclusion, we have discovered a reaction for the selective construction of 2-acetoxy indolin-3-ones through control of the amount of PhI(OAc)₂ oxidants and the reaction time. Comparing with the previous work related to indole oxidation, 2-acetoxy indolin-3-ones are believed to be the thermodynamic product under the reaction conditions. The method features the selective formation of 2-acetoxy indolin-3-ones instead of its isomeric 3-acetoxy indolin-2-one.

Experimental section

General information

All reagents and metal catalysts were obtained from commercial sources without further purification. Representative starting compounds 1, PhI(OAc)₂ and AcOH/Ac₂O were analysed by ICP-AES, which showed only trace amount of transition metals (<0.1 ppm Fe, Co, Ni, Cu, Pd). Analytical thin layer chromatography (TLC) was performed on precoated silica plates. Yields of the products refer to purification by silica-gel column chromatography. Silica gel 60H (200–300 mesh) manufactured by Qingdao Haiyang Chemical Group Co. (China) was used for general chromatography. Mass spectra were recorded with a TSQ Quantum-LC/MS/MS of Finnigan using Electron spray ionization (ESI) techniques. ¹H and ¹³C NMR spectra were recorded with a Bruker AV-300 and AV-500 spectrometer operating at 300 MHz/500 MHz and 75 MHz/125 MHz, respectively, with chemical shift values being reported in ppm relative to chloroform (δ = 7.26 ppm) for ¹H NMR, and chloroform (δ = 77.16 ppm) for ¹³C NMR.

The N-substituted indoles 1a–1p were prepared according to reported literature procedures.²² Phenyl-1H-indole, methyl-1H-indole, 1-(pyridin-2-yl)-1H-indole, 1-(1H-indol-1-yl) ethan-1-one, 1-tosyl-1H-indole (1q–1u) were prepared according to other known literature procedures.^18,23

Representative procedure for 2-acetoxy indolin-3-ones of N-substituted indole. The mixture of PhI(OAc)₂ (289.8 mg, 0.9 mmol), substrate (0.3 mmol) and AcOH : Ac₂O = 7 : 3 (2 mL) were added under air to a high pressure tube (35 mL). After sealing the tube, the mixture was stirred at 60 °C for 24–36 h. Then the reaction mixture was cooled to ambient temperature, poured into H₂O (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic phase was washed with H₂O (3 × 20 mL) and saturated NaHCO₃ solution (15 × 2 mL), then dried over Na₂SO₄. After filtration and evaporation of the solvents in vacuo, then purified directly via chromatography on silica gel with (EA : petroleum ether = 2 : 8) to provide the corresponding product.

3-Oxo-1-(pyrimidin-2-yl)indolin-2-yl acetate (2a). Yield: 65%, yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.74 (d, J = 8.4 Hz, 1H), 8.59 (d, J = 4.8 Hz, 2H), 7.76 (d, J = 7.6 Hz, 1H), 7.68 (s, 1H), 7.16 (d, J = 7.4 Hz, 1H), 6.94 (t, J = 4.8 Hz, 1H), 6.90 (s, 1H), 2.13 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 193.17, 169.18, 157.86, 157.63, 153.73, 137.61, 124.36, 122.76, 121.98, 117.24 (s), 114.56 (s), 79.54 (s), 20.65 (s). IR (neat): 2979, 2848, 1754, 1723, 1559, 1461, 1461, 1428, 1012, 745. HRMS (ESI) calcd for C₁₄H₁₂N₃O₃ [M + H]⁺: 270.0879, found 270.0879.

1-(Pyrimidin-2-yl)indoline-2,3-diyl diacetate (3a). White solid. ¹H NMR (500 MHz, CDCl₃) δ 8.55 (d, J = 4.7 Hz, 2H), 8.44 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 7.4 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.22 (s, 1H), 7.07 (t, J = 7.5 Hz, 1H), 6.86 (t, J = 4.7 Hz, 1H), 6.01 (s, 1H), 2.07 (s, 3H), 2.05 (s, 3H). The spectral data of the product were in accordance with those reported in the literature.¹⁹

1-(Pyrimidin-2-yl)-1H-indol-3-yl acetate (4a). White solid. ¹H NMR (300 MHz, CDCl₃) δ 8.82 (d, J = 8.4 Hz, 1H), 8.66 (d, J = 4.8 Hz, 2H), 8.44 (s, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.43–7.33 (m, 1H), 7.31–7.21 (m, 1H), 7.00 (t, J = 4.8 Hz, 1H), 2.40 (s, 3H). The spectral data of the product were in accordance with those reported in the literature.¹⁹

4-Methyl-3-oxo-1-(pyrimidin-2-yl)indolin-2-yl acetate (2b). Yield: 65%, yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.65–8.46 (m, 3H), 7.63–7.35 (m, 1H), 6.92 (dd, J = 6.2, 3.4 Hz, 1H), 6.89 (d, J = 6.6 Hz, 2H), 2.62 (d, J = 8.5 Hz, 3H), 2.11 (d, J = 9.9 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 193.76, 169.22, 157.73 (3C, for three carbons on pyrimidine), 154.17, 139.95, 136.84, 124.63, 119.78, 114.42 (2C), 79.39, 20.68, 18.29. IR (neat): 2931, 2849, 1745, 1718, 1597, 1574, 1558, 1410, 1207, 779. HRMS (ESI) calcd for C₁₅H₁₄N₃O₃ [M + H]⁺: 284.1035, found 284.1029.

4-(Benzyloxy)-3-oxo-1-(pyrimidin-2-yl)indolin-2-yl acetate (2c). Yield: 71%, yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.57 (d, J = 4.7 Hz, 2H), 8.31 (d, J = 8.3 Hz, 1H), 7.54 (dd, J = 11.4, 7.9 Hz, 3H), 7.38 (t, J = 7.4 Hz, 2H), 7.31 (d, J = 7.2 Hz, 1H), 6.95–6.89 (m, 2H), 6.60 (d, J = 8.3 Hz, 1H), 5.28 (s, 2H), 2.12 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 190.05, 169.15, 157.74, 154.50, 139.19, 136.06, 128.52, 127.76, 126.49, 114.60, 110.99, 109.39, 106.35, 79.59, 70.06, 20.71, 0.95. IR (neat): 2923, 2851, 1752, 1715, 1619, 1584, 1560, 1450, 1416, 1146, 191. HRMS (ESI) calcd for C₂₁H₁₈N₃O₄ [M + H]⁺: 376.1297, found 376.1290.

4-Chloro-3-oxo-1-(pyrimidin-2-yl)indolin-2-yl acetate (2d). Yield: 51%, yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.70 (d, J = 8.5 Hz, 1H), 8.59 (d, J = 4.8 Hz, 2H), 7.55 (t, J = 8.2 Hz, 1H), 7.07 (d, J = 7.9 Hz, 1H), 6.97 (t, J = 4.8 Hz, 1H), 6.87 (s, 1H), 2.12 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 190.25, 168.97, 157.83, 157.47, 154.91, 137.55, 132.31, 123.99, 118.57, 115.40, 115.00, 79.48, 20.57. IR (neat): 2924, 2852, 1744, 1728, 1599, 1575, 1559, 1448, 1206, 963, 781. HRMS (ESI) calcd for C₁₄H₁₁ClN₃O₃ [M + H]⁺: 304.0489, found 304.0483.

4-Chloro-1-(pyrimidin-2-yl)-1H-indol-3-yl acetate (4d). Yield: 20%, white solid. ¹H NMR (300 MHz, CDCl₃) δ 8.78 (d, J = 8.1 Hz, 1H), 8.69 (d, J = 4.8 Hz, 2H), 8.30 (s, 1H), 7.26 (s, 1H), 7.22 (d, J = 5.9 Hz, 1H), 7.07 (s, 1H), 2.40 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 169.29, 157.96, 157.14, 134.48, 132.13, 124.87, 124.14, 123.20, 121.30, 116.77, 116.45, 115.17, 20.90. IR (neat): 2922, 2846, 1738, 1669, 1771, 1561, 1456, 830. HRMS (ESI) calcd for C₁₄H₁₁ClN₃O₂ [M + H]⁺: 288.0540, found 288.0534.

4-Bromo-3-oxo-1-(pyrimidin-2-yl)indolin-2-yl acetate (2e). Yield: 48%, yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.81–8.68 (m, 1H), 8.58 (d, J = 4.8 Hz, 2H), 7.45 (t, J = 8.1 Hz, 1H), 7.30–7.16 (m, 1H), 6.96 (t, J = 4.8 Hz, 1H), 6.86 (s, 1H), 2.10 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 190.70, 169.01, 157.86, 157.43, 155.33, 137.58, 131.88, 130.32, 127.39, 115.96, 115.01, 79.53, 20.59. IR (neat): 2982, 2929, 1741, 1728, 1572, 1447, 1408, 1206, 958, 777. HRMS (ESI) calcd for C₁₄H₁₁BrN₃O₃ [M + H]⁺: 347.9984, found 347.9979.

5-Methyl-3-oxo-1-(pyrimidin-2-yl)indolin-2-yl acetate (2f). Yield: 70%, yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.61 (s, 1H), 8.57 (d, J = 4.8 Hz, 2H), 7.56 (s, 1H), 7.49 (d, J = 8.1 Hz, 1H), 6.91 (t, J = 4.8 Hz, 1H), 6.87 (s, 1H), 2.38 (s, 3H), 2.12 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 193.19, 169.21, 157.76 (3C, for three carbons on pyrimidine), 151.88, 138.62, 132.58, 124.10, 117.05, 114.27, 79.83, 20.64, 20.50. IR (neat): 2924, 2850, 1756, 1715, 1621, 1581, 1560, 1417, 1191, 1146, 788. HRMS (ESI) calcd for C₁₅H₁₄N₃O₃ [M + H]⁺: 284.1035, found 284.1033.

5-Methoxy-3-oxo-1-(pyrimidin-2-yl)indolin-2-yl acetate (2g). Yield: 25%, green yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.66 (d, J = 9.1 Hz, 1H), 8.55 (d, J = 4.8 Hz, 2H), 7.32–7.27 (m, 1H), 7.20 (d, J = 2.7 Hz, 1H), 6.90 (t, J = 4.7 Hz, 1H), 6.86 (s, 1H), 3.84 (s, 3H), 2.13 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 193.13, 169.21, 157.77, 155.59, 148.53, 126.32, 122.61, 118.62, 114.12, 105.40, 80.09, 55.72, 20.65. IR (neat): 2922, 2853, 1761, 1730, 1578, 1556, 1468, 1426, 1246. HRMS (ESI) calcd for C₁₅H₁₄N₃O₄ [M + H]⁺: 300.0984, found 300.0980.

5-Fluoro-3-oxo-1-(pyrimidin-2-yl)indolin-2-yl acetate (2h). Yield: 56%, yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.80–8.70 (m, 1H), 8.58 (d, J = 4.8 Hz, 2H), 7.41 (d, J = 7.7 Hz, 2H), 6.95 (s, 1H), 6.85 (s, 1H), 2.13 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 192.47, 169.09, 157.84, 157.64, 157.19 (d, J = 245.7 Hz), 150.06 (s), 124.56 (d, J = 23.6 Hz), 123.06 (d, J = 7.5 Hz), 118.81 (d, J = 6.5 Hz), 114.62, 109.86 (d, J = 23.3 Hz), 80.06, 20.56. IR (neat): 2979, 1754, 1727, 1621, 1579, 1556, 1418, 1210, 1133, 882. HRMS (ESI) calcd for C₁₄H₁₁FN₃O₃ [M + H]⁺: 288.0784, found 288.0780.

5-Fluoro-1-(pyrimidin-2-yl)-1H-indol-3-yl acetate (4h). Yield: 11%, white solid. ¹H NMR (300 MHz, CDCl₃) δ 8.77 (dd, J = 9.1, 4.6 Hz, 1H), 8.67 (d, J = 4.8 Hz, 2H), 8.47 (s, 1H), 7.20 (dd, J = 8.6, 2.4 Hz, 1H), 7.10 (dd, J = 9.2, 2.4 Hz, 1H), 7.04 (t, J = 4.8 Hz, 1H), 2.39 (s, 3H). The spectral data of the product were in accordance with those reported in the literature.¹⁹

5-Chloro-3-oxo-1-(pyrimidin-2-yl)indolin-2-yl acetate (2i). Yield: 55%, yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.69 (d, J = 8.9 Hz, 1H), 8.58 (d, J = 4.8 Hz, 2H), 7.68 (s, 1H), 7.58 (d, J = 8.9 Hz, 1H), 6.96 (t, J = 4.8 Hz, 1H), 6.83 (s, 1H), 2.11 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 192.0, 169.05, 157.87, 157.4, 152.01, 137.09, 128.35, 123.71, 123.23, 118.59, 114.82, 79.81, 20.55. IR (neat): 2922, 2846, 1752, 1733, 1669, 1771, 1561, 1456, 834, 700. HRMS (ESI) calcd for C₁₄H₁₁ClN₃O₃ [M + H]⁺: 304.0489, found 304.0485.

5-Bromo-3-oxo-1-(pyrimidin-2-yl)indolin-2-yl acetate (2j). Yield: 57%, yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.63 (d, J = 8.9 Hz, 1H), 8.58 (d, J = 4.8 Hz, 2H), 7.82 (d, J = 1.9 Hz, 1H), 7.71 (dd, J = 8.9, 2.1 Hz, 1H), 6.96 (t, J = 4.8 Hz, 1H), 6.81 (s, 1H), 2.11 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 191.85, 169.02, 157.87, 157.54, 152.40, 139.85, 126.79, 123.65, 118.95, 115.55, 114.84, 79.66, 20.55. IR (neat): 2921, 2852, 1734, 1574, 1463, 1232, 1044, 733. HRMS (ESI) calcd for C₁₄H₁₁BrN₃O₃ [M + H]⁺: 347.9984, found 347.9980. The structure of 2j was confirmed by the single-crystal diffraction analysis (CCDC deposition number: 1495548†).

5-Bromo-1-(pyrimidin-2-yl)-1H-indol-3-yl acetate (4j). Yield: 6%, white solid. ¹H NMR (300 MHz, CDCl₃) δ 8.71–8.59 (m, 3H), 8.43 (s, 1H), 7.68 (d, J = 1.7 Hz, 1H), 7.43 (dd, J = 8.9, 1.8 Hz, 1H), 7.05 (t, J = 4.8 Hz, 1H), 2.39 (s, 3H). The spectral data of the product were in accordance with those reported in the literature.¹⁹

5-Iodo-3-oxo-1-(pyrimidin-2-yl)indolin-2-yl acetate (2k). Yield: 45%, yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.59 (d, J = 4.8 Hz, 2H), 8.54 (d, J = 8.8 Hz, 1H), 8.05 (d, J = 1.8 Hz, 1H), 7.92 (dd, J = 8.8, 1.9 Hz, 1H), 6.96 (d, J = 4.8 Hz, 1H), 6.83 (s, 1H), 2.12 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 191.64, 169.02, 157.81, 157.54, 152.97, 145.56, 132.86, 124.08, 119.35, 114.86, 85.31, 79.39, 20.57. IR (neat): 2981, 2919, 2849, 1750, 1734, 1568, 1461, 1192, 809. HRMS (ESI) calcd for C₁₄H₁₁BrN₃O₃ [M + H]⁺: 395.9845, found 395.9840.

Methyl 2-acetoxy-3-oxo-1-(pyrimidin-2-yl)indoline-5-carboxylate (2l). Yield: 40%, yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.78 (d, J = 8.8 Hz, 1H), 8.62 (d, J = 4.8 Hz, 2H), 8.41 (d, J = 1.1 Hz, 1H), 8.34 (dd, J = 8.8, 1.8 Hz, 1H), 7.02 (d, J = 4.8 Hz, 1H), 6.91 (s, 1H), 3.93 (s, 3H), 2.12 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 192.33, 168.98, 165.72, 157.93, 157.48, 156.29, 138.69, 126.20, 124.60, 121.97, 116.82, 115.30, 79.90, 52.20, 20.54. IR (neat): 2916, 2848, 1735, 1703, 1622, 1579, 1558, 1418, 1211, 1012, 763. HRMS (ESI) calcd for C₁₆H₁₄N₃O₅ [M + H]⁺: 328.0933, found 328.0930.

6-Fluoro-3-oxo-1-(pyrimidin-2-yl)indolin-2-yl acetate (2m). Yield: 60%, yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.60 (d, J = 4.8 Hz, 2H), 8.49 (dd, J = 11.0, 2.2 Hz, 1H), 7.76 (dd, J = 8.4, 5.9 Hz, 1H), 6.98 (t, J = 4.8 Hz, 1H), 6.89 (s, 1H), 6.88–6.79 (m, 1H), 2.12 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 191.25, 169.03, 168.81 (d, J = 255.7 Hz), 157.87, 157.46, 155.41 (d, J = 14.9 Hz), 126.49 (d, J = 11.8 Hz), 118.43, 114.99, 110.72 (d, J = 24.5 Hz), 105.04 (d, J = 29.7 Hz), 79.86, 20.58. IR (neat): 2919, 2850, 1748, 1717, 1618, 1576, 1555, 1456, 1435, 793. HRMS (ESI) calcd for C₁₄H₁₁FN₃O₃ [M + H]⁺: 288.0784, found 288.0780.

6-Chloro-3-oxo-1-(pyrimidin-2-yl)indolin-2-yl acetate (2n). Yield: 59%, yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.80 (d, J = 1.4 Hz, 1H), 8.61 (d, J = 4.8 Hz, 2H), 7.67 (d, J = 8.2 Hz, 1H), 7.12 (dd, J = 8.2, 1.4 Hz, 1H), 6.97 (d, J = 4.8 Hz, 1H), 6.87 (s, 1H), 2.12 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 191.76, 169.02, 157.88, 157.46, 154.05, 144.00, 125.14, 123.31, 120.46, 117.51, 114.99, 79.75, 20.57. IR (neat): 2997, 2840, 1750, 1732, 1603, 1574, 1554, 1417, 1065, 786. HRMS (ESI) calcd for C₁₄H₁₁ClN₃O₃ [M + H]⁺: 304.0489, found 304.0484.

6-Bromo-3-oxo-1-(pyrimidin-2-yl)indolin-2-yl acetate (2o). Yield: 55%, yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.99 (t, J = 7.5 Hz, 1H), 8.62 (dd, J = 12.4, 4.8 Hz, 2H), 7.59 (d, J = 8.1 Hz, 1H), 7.28 (dd, J = 8.2, 1.6 Hz, 1H), 6.97 (t, J = 4.8 Hz, 1H), 6.84 (s, 1H), 2.11 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 192.00, 169.02, 157.89, 157.45, 153.95, 132.97, 126.19, 125.15, 120.84, 120.42, 115.00, 79.64, 20.55. IR (neat): 2921, 2852, 1730, 1574, 1463, 1232, 1044, 733, 650. HRMS (ESI) calcd for C₁₄H₁₁BrN₃O₃ [M + H]⁺: 347.9984, found 347.9980.

7-Methyl-3-oxo-1-(pyrimidin-2-yl)indolin-2-yl acetate (2p). Yield: 59%, yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.56 (d, J = 4.8 Hz, 2H), 7.60 (d, J = 7.4 Hz, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.18 (d, J = 7.5 Hz, 1H), 6.98 (t, J = 4.8 Hz, 1H), 6.64 (s, 1H), 2.24 (s, 3H), 2.19 (d, J = 3.7 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 194.46, 169.12, 159.95, 157.98 (for three carbons on pyrimidine), 154.08, 139.77, 129.34, 124.66, 122.00, 115.77, 84.52, 20.90, 20.79. IR (neat): 2927, 1744, 1723, 1591, 1575, 1562, 1409, 1277, 1018, 759. HRMS (ESI) calcd for C₁₅H₁₄N₃O₃ [M + H]⁺: 284.1035, found 284.1031.

Acetylindoline-2,3-diyl diacetate (3t). Yield: 76%, yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.18 (s, 1H), 7.49 (d, J = 7.5 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 6.66 (s, 1H), 5.91 (s, 1H), 2.29 (s, 3H), 2.12 (s, 3H), 2.09 (s, 3H). The spectral data of the product were in accordance with those reported in the literature.¹⁸

1-Tosylindoline-2,3-diyl diacetate (3u). Yield: 74%, white solid, ¹H NMR (300 MHz, CDCl₃) δ 7.66 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 8.6 Hz, 1H), 7.38–7.24 (m, 2H), 7.18 (d, J = 7.9 Hz, 2H), 7.02 (d, J = 0.7 Hz, 1H), 6.58 (s, 1H), 5.69 (s, 1H), 2.30 (s, 3H), 2.03–1.97 (m, 3H), 1.78 (s, 3H). The spectral data of the product was in accordance with that reported in the literature.¹⁸

3-Oxo-1-(pyrimidin-2-yl)indolin-2-yl propionate (2aa). Yield: 40%, yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.72 (d, J = 8.5 Hz, 1H), 8.57 (d, J = 4.8 Hz, 2H), 7.75 (d, J = 7.6 Hz, 1H), 7.71–7.62 (m, 1H), 7.13 (dd, J = 11.1, 3.8 Hz, 1H), 6.93 (t, J = 4.8 Hz, 1H), 6.86 (s, 1H), 2.39 (q, J = 7.5 Hz, 2H), 1.14 (t, J = 7.5 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 193.27, 172.68, 157.77, 153.68, 137.56, 124.33, 122.74, 122.04, 117.23, 114.54, 79.58, 27.26, 8.86. IR (neat): 2988, 1762, 1732, 1467, 1422, 1077, 753, 634. HRMS (ESI) calcd for C₁₅H₁₄N₃O₃ [M + H]⁺: 284.1035, found 284.1030.

1-(Pyrimidin-2-yl)-1H-indol-3-yl propionate (4aa). Yield: 40%, white solid. ¹H NMR (300 MHz, CDCl₃) δ 8.81 (d, J = 8.4 Hz, 1H), 8.68 (d, J = 4.8 Hz, 2H), 8.45 (s, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.36 (d, J = 7.3 Hz, 1H), 7.29–7.23 (m, 2H), 7.03 (t, J = 4.8 Hz, 1H), 2.70 (q, J = 7.5 Hz, 2H), 1.34 (t, J = 7.5 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 171.60, 157.94, 157.61, 133.42, 132.73, 124.50, 122.05, 117.36, 116.39, 115.92, 114.45, 27.61, 9.18. IR (neat): 2982, 1749, 1564, 1433, 1147, 732, 640, 591. HRMS (ESI) calcd for C₁₅H₁₄N₃O₂ [M + H]⁺: 268.1086, found 268.1081.

3-Oxo-1-(pyrimidin-2-yl)indolin-2-yl butyrate (2ab). Yield: 29%, yellow oil. ¹H NMR (300 MHz, CDCl₃) δ 8.73 (d, J = 8.4 Hz, 1H), 8.57 (d, J = 4.8 Hz, 2H), 7.75 (d, J = 7.6 Hz, 1H), 7.67 (s, 1H), 7.14 (s, 1H), 6.93 (s, 1H), 6.89 (s, 1H), 2.35 (t, J = 7.3 Hz, 2H), 1.72–1.58 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 193.27, 171.80, 157.76, 153.70, 137.55, 124.34, 122.72, 122.02, 117.22, 114.53, 79.47, 35.79, 18.23, 13.42. IR (neat): 2959, 2921, 1739, 1437, 1425, 1237, 1043, 736, 650. HRMS (ESI) calcd for C₁₆H₁₆N₃O₃ [M + H]⁺: 298.1192, found 298.1190.

2-(2,5-Dimethylphenyl)-1-(pyrimidin-2-yl)indolin-3-one (5a). Yield: 50%, white solid. ¹H NMR (300 MHz, CDCl₃) δ 8.89 (d, J = 8.5 Hz, 1H), 8.46 (d, J = 4.7 Hz, 2H), 7.84–7.67 (m, 2H), 7.15 (dd, J = 15.0, 7.5 Hz, 2H), 6.93 (d, J = 7.7 Hz, 1H), 6.77 (t, J = 4.8 Hz, 1H), 6.69 (s, 1H), 5.94 (s, 1H), 2.66 (s, 3H), 2.10 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 197.77, 157.76, 157.61, 154.85, 136.95, 135.31, 134.45, 133.94, 130.85, 128.40, 124.56, 123.43, 122.29, 117.15, 113.61, 66.39, 20.91, 19.47. IR (neat): 2918, 2855, 1716, 1586, 1466, 1429, 1310, 752, 598. HRMS (ESI) calcd for C₂₀H₁₈N₃O [M + H]⁺: 316.1450, found 316.1443.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (NSFC) (Grant No. 21402092), Natural Science Foundation of Jiangsu Province – China (Grant No. BK20140775), Nanjing University of Science and Technology – China (“Zijin Star Program”), the Priority Academic Program development of Jiangsu Higher Education Institutions – China (PAPD).

Notes and references

1. (a) W. Gu, Y. Zhang, X. J. Hao, F. M. Yang, Q. Y. Sun, S. L. Morris-Natschke, K. H. Lee, Y. H. Wang and C. L. Long, J. Nat. Prod., 2014, 77, 2590; (b) T. Mohn, I. Plitzko and M. Hamburger, Phytochemistry, 2009, 70, 924; (c) H. Fujii, R. Ogawaa, K. Ohata, T. Nemoto, M. Nakajima, K. Hasebe, H. Mochizuki and H. Nagase, Bioorg. Med. Chem., 2009, 17, 5983; (d) R. Abonia, P. Cuervo, J. Castillo, B. Insuasty, J. Quiroga, M. Nogueras and J. Cobo, Tetrahedron Lett., 2008, 49, 5028; (e) I. Nakamura and Y. Yamamoto, Chem. Rev., 2004, 104, 2127; (f) H. Takayama, H. Ishikawa, M. Kurihara, M. Kitajima, N. Aimi, D. Ponglux, F. Koyama, K. Matsumoto, T. Moriyama, L. T. Yamamoto, K. Watanabe, T. Murayama and S. Horie, J. Med. Chem., 2002, 45, 1949.
2. (a) J. A. Campbell, V. Bordunov, C. A. Broka, M. F. Browner, J. M. Kress, T. Mirzadegan, C. Ramesha, B. F. Sanpablo, R. Stabler, P. Takahara, A. Villasenor, K. A. Walker, J. H. Wang, M. Welch and P. Weller, Bioorg. Med. Chem., 2004, 14, 4741; (b) J. F. Dropinski, T. Akiyama, M. Einstein, B. Habulihaz, T. Doebber, J. P. Berger, P. T. Meinke and G. Q. Shi, Bioorg. Med. Chem., 2005, 15, 5035.
3. P. N. Wyrembak and A. D. Hamilton, J. Am. Chem. Soc., 2009, 131, 4566.
4. G.-Y. Zhao, X.-G. Xie, H.-Y. Sun, Z.-Y. Yuan, Z.-L. Zhong, S.-C. Tang and X.-G. She, Org. Lett., 2016, 18, 2447.
5. A. Karadeolian and M. A. Kerr, J. Org. Chem., 2010, 75, 6830.
6. Y. Terada, M. Arisawa and A. Nishida, J. Org. Chem., 2006, 71, 1269.
7. L. A. Adams, M. W. N. Valente and R. M. Williams, Tetrahedron, 2006, 62, 5195.
8. P. S. Baran and E. J. Corey, J. Am. Chem. Soc., 2002, 124, 7904.
9. (a) K. Higuchi, Y. Sato, M. Tsuchimochi, K. Sugiura, M. Hatori and T. Kawasaki, Org. Lett., 2009, 11, 197; (b) Y.-H. Liu and W. W. McWhorter Jr, J. Am. Chem. Soc., 2003, 125, 4240; (c) D. Stoermer and C. H. Heathcock, J. Org. Chem., 1993, 58, 564; (d) K. Yamada, T. Kurokawa, H. Tokuyama and T. Fukuyama, J. Am. Chem. Soc., 2003, 125, 6630.
10. (a) F. Zhou, Y. L. Liu and J. Zhou, Adv. Synth. Catal., 2010, 352, 1381; (b) C. V. Galliford and K. A. Scheidt, Angew. Chem., Int. Ed., 2007, 46, 8748; (c) H. Lin and S. J. Danishefsky, Angew. Chem., Int. Ed., 2003, 42, 36.
11. (a) J.-Y. Xu, S.-H. Hu, Y.-Y. Lu, Y. Dong, W.-F. Tang, T. Lu and D. Du, Adv. Synth. Catal., 2015, 357, 923; (b) Y.-Y. Lu, W.-F. Tang, Y. Zhang, D. Du and T. Lu, Adv. Synth. Catal., 2013, 355, 321; (c) J. X. Liu, Q. Q. Zhou, J. G. Deng and Y. C. Chen, Org. Biomol. Chem., 2013, 11, 8175; (d) A. Parra, R. Alfaro, L. Marzo, A. Moreno-Carrasco, J. L. Garcia Ruano and J. Aleman, Chem. Commun., 2012, 48, 9759; (e) M. Rueping, R. Rasappan and S. Raja, Helv. Chim. Acta, 2012, 95, 2296; (f) C. Y. Jin, Y. Wang, Y. Z. Liu, C. Shen and P. F. Xu, J. Org. Chem., 2012, 77, 11307; (g) Q. Yin and S. L. You, Chem. Sci., 2011, 2, 1344; (h) W.-S. Sun, L. Hong and R. Wang, Chem.–Eur. J., 2011, 17, 6030; (i) M. Rueping, S. Raja and A. Núñez, Adv. Synth. Catal., 2011, 353, 563; (j) Y. Z. Liu, J. Zhang, P. F. Xu and Y. C. Luo, J. Org. Chem., 2011, 76, 7551; (k) K. Higuchi, K. Masuda, T. Koseki, M. Hatori, M. Sakamoto and T. Kawasaki, Heterocycles, 2007, 73, 641; (l) Y.-Y. Liu and W. W. McWhorter Jr, J. Org. Chem., 2003, 68, 2618.
12. (a) R. R. Liu, S. C. Ye, C. J. Lu, G. L. Zhuang, J. R. Gao and Y. X. Jia, Angew. Chem., Int. Ed., 2015, 54, 11205; (b) C. Shu, L. Li, X. Y. Xiao, Y. F. Yu, Y. F. Ping, J. M. Zhou and L. W. Ye, Chem. Commun., 2014, 50, 8689; (c) S. R. Mothe, M. L. Novianti, B. J. Ayers and P. W. H. Chan, Org. Lett., 2014, 16, 4110; (d) M. Shimizu, Y. Takao, H. Katsurayama and I. Mizota, Asian J. Org. Chem., 2013, 2, 130; (e) P. Kothandaraman, B. Q. Koh, T. Limpanuparb, H. Hirao and P. W. H. Chan, Chem.–Eur. J., 2013, 19, 1978; (f) A. Wetzel and F. Gagosz, Angew. Chem., Int. Ed., 2011, 50, 7354; (g) K. Okuma, N. Matsunaga, N. Nagahora, K. Shioji and Y. Yokomori, Chem. Commun., 2011, 47, 5822; (h) Y. Sun and R.-H. Fan, Chem. Commun., 2010, 46, 6834.
13. (a) S. K. Guchhait, V. Chaudhary, V. A. Rana, G. Priyadarshani, S. Kandekar and M. Kashyap, Org. Lett., 2016, 18, 1534; (b) T. G. Chen, P. Fang, X. L. Hou and L. X. Dai, Synthesis, 2015, 47, 134.
14. W. Ding, Q. Q. Zhou, J. Xuan, T. R. Li, L. Q. Lu and W. J. Xiao, Tetrahedron Lett., 2014, 55, 4648.
15. (a) C. L. Sun and Z. J. Shi, Chem. Rev., 2014, 114, 9219; (b) V. P. Mehta and B. Punji, RSC Adv., 2013, 3, 11957.
16. (a) V. V. Zhdankin, Chem. Rev., 2008, 108, 5299; (b) V. V. Zhdankin, Chem. Rev., 2002, 102, 2523; (c) R. M. Moriarty, J. Org. Chem., 2005, 70, 2893; (d) P. J. Stang, J. Org. Chem., 2003, 68, 2997; (e) V. V. Grushin, Chem. Soc. Rev., 2000, 29, 315; (f) P. J. Stang, Chem. Rev., 1996, 96, 1123.
17. L. F. Silva Jr, Molecules, 2006, 11, 421.
18. Q. Liu, Q. Y. Zhao, J. Liu, P. Wu, H. Yi and A.-W. Lei, Chem. Commun., 2012, 48, 3239.
19. V. Soni, U. N. Patel and B. Punji, RSC Adv., 2015, 5, 57472.
20. The 1-(pyridin-2-yl)indoline-2,3-dione was isolated. The spectral data of the product was in accordance with those reported in the literature. ( J. Sun, Q.-T. Tan, W.-S. Yang, B.-X. Liu and B. Xu, Adv. Synth. Catal., 2014, 356, 388 .)
    .
21. I. Mutule, E. Suna, K. Olofsson and B. Pelcman, J. Org. Chem., 2009, 74, 7195.
22. (a) L. Ackermann and A. V. Lygin, Org. Lett., 2011, 13, 3332–3335; (b) Z. Ding and N. Yoshikai, Angew. Chem., Int. Ed., 2012, 51, 4698; (c) J. Shi, B. Zhou, Y. Yang and Y. Li, Org. Biomol. Chem., 2012, 10, 8953; (d) S. Xu, X. Huang, X. Hong and B. Xu, Org. Lett., 2012, 14, 4614; (e) P.-J. Feng, Y.-K. Fan, F.-Z. Xue, W.-G. Liu, S. L. Li and Y. Shi, Org. Lett., 2011, 13, 21; (f) K. S. Feldman and P. Ngernmeesri, Org. Lett., 2010, 12, 20; (g) J. Zhao, X. Cheng, J. Le, W. Yang, F. Xue, X. Zhang and C. Jiang, Org. Biomol. Chem., 2015, 13, 9000.
23. (a) Q.-C. Yang, Y.-F. Wang, B.-J. Zhang and M.-J. Zhang, Chin. J. Chem., 2012, 30, 2389; (b) V. K. Tiwari, N. Kamal and M. Kapur, Org. Lett., 2015, 17, 1766; (c) J. M. Fraile, K. L. Jeune, J. A. Mayoral, N. Ravasio and F. Zaccheria, Org. Biomol. Chem., 2013, 11, 4327.

---

Footnote

† Electronic supplementary information (ESI) available. CCDC 1495548. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra19741h

---