Combinatorial synthesis of spiro[indoline-3,2′-pyrrole] derivatives via a three-component reaction under catalyst-free conditions

Abstract

Reported here is a convenient catalyst-free method for preparing a series of spiro[indoline-3,2′-pyrroles] from a three-component reaction of isatins, α-amino acid and phenylpropiolic acid esters in refluxing isopropanol with high regioselectivity and yields. A plausible mechanism for this process was proposed. In addition, this protocol permitted the facile construction of spiro[indoline-3,2′-pyrroles] through an expanded scope of substrates.

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Introduction

The ability to access spirocyclic nitrogen-containing heterocycles has always remained a great inspiration for organic chemists because of their widespread prevalence in nature.¹ As one of the most important class of spirooxidoles,² the spiro[indoline-3,2′-pyrrole] derivatives exhibited promising pharmaceutical activities such as antimicrobial,³ anticancer,⁴ antitumor,⁵ antioxidant,⁶ and many others⁷ and were cytotoxic to MCF-7 cells.⁸ Therefore, intensive efforts have been made to design and develop new methods for the construction of novel synthetic spirooxindole-fused-heterocycles.⁹ Recent synthetic methods were completed in racemic manners¹⁰ or employed chiral starting materials,¹¹ and catalytic asymmetric transformations to access this spirooxindole scaffold have sporadically been described in the literature.¹²

Multicomponent reactions (MCRs) have gained tremendous attention from medicinal and organic chemists because they offerred highly convergent routes to complex molecules. Additionally, MCRs did not require the isolation and purification intermediates thereby reduced the time, cost, and waste production.¹³ Therefore, the MCRs were attractive in the area of organic/medicinal/pharmaceutical chemistry.¹⁴ As part of our program on the study of developing new multicomponent reactions for the synthesis of heterocyclic compounds,¹⁵ herein we wish to report the efficient synthesis of spiro[indoline-3,2′-pyrrole] derivatives from the three-component reactions of isatins, α-amino acid and phenylpropiolic acid esters under catalyst-free conditions (Scheme 1).

Scheme 1 Synthesis of spiro[indoline-3,2′-pyrrole] derivatives by the three-component reactions of isatins, α-amino acid and phenylpropiolic acid esters.

Results and discussion

We initiated the investigation using 5-methylindoline-2,3-dione (1b), sarcosine (2a), and methyl 3-phenylpropiolate (3a) in acetonitrile under refluxing for 10 h (Table 1, entry 1). To our delight, the desired product 4b was obtained in 71% yield. The reaction was further carried out in various solvents and temperatures to improve the yield, the results were summarized in Table 1. Among the examined solvents, isopropanol provided an optimum isolated yield of 85% for 4b (Table 1, entry 5), whereas methanol, ethanol, 1,2-dichloroethane (DCE), tetrahydrofuran (THF), dimethylformamide (DMF), toluene, and 1,4-dioxane gave low yields (Table 1, entries 2–4, 6–9). When H₂O, diethyl ether (Et₂O) or dichloromethane (DCM) was used as the solvent, a lower yield of the product was obtained (Table 1, entries 10–12). The influence of the reaction time and temperature were also investigated, but the results were negative (Table 1, entries 13–18). Thus, the isopropanol was considered to be the best solvent and the optimum refluxing time was 8 h (Table 1, entry 5).

Table 1 Optimization of the reaction conditions^a

Entry	Solvent	Temp (°C)	Time (h)	Yield^b (%)
a Reaction conditions: 5-methylindoline-2,3-dione 1a (0.1 mmol), sarcosine 2a (0.12 mmol), and methyl 3-phenylpropiolate 3a (0.1 mmol), solvent (5 mL).b Isolated yield.
1	Acetonitrile	Reflux	10	71
2	MeOH	Reflux	8	72
3	EtOH	Reflux	8	71
4	DCE	Reflux	8	63
5	Isopropanol	Reflux	8	85
6	THF	Reflux	8	55
7	DMF	Reflux	8	68
8	Toluene	Reflux	8	75
9	1,4-Dioxane	Reflux	8	78
10	DCM	Reflux	8	Trace
11	Et2O	Reflux	8	Trace
12	H2O	Reflux	8	Trace
13	Isopropanol	r.t.	8	Trace
14	Isopropanol	40	8	Trace
15	Isopropanol	60	8	60
16	Isopropanol	Reflux	4	40
17	Isopropanol	Reflux	6	65
18	Isopropanol	Reflux	12	83

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Under the optimal conditions, various isatins 1, α-amino acids 2 and phenylpropiolate esters 3 were examined to test the scope and limitation of this three-component reaction, and the results were summarized in Table 2.

Table 2 Synthesis of spiro[indoline-3,2′-pyrrole] derivatives via three-component reaction of isatins, β-amino acid, and phenylpropiolate esters^a

Entry	R1, R2, R3, R4	R5	R6	Product	Yield^b (%)
a Reaction conditions: isatins 1 (0.1 mmol), α-amino acid 2 (0.12 mmol), and phenylpropiolate esters 3 (0.1 mmol), isopropanol (5 mL) at refluxing.b Isolated yields.
1	1a (H, H, H, H)	CH3 (2a)	OCH3 (3a)	4a	85
2	1b (CH3, H, H, H)	CH3 (2a)	OCH3 (3a)	4b	83
3	1c (CH3CH2, H, H, H)	CH3 (2a)	OCH3 (3a)	4c	82
4	1d ((CH3)2CH, H, H, H)	CH3 (2a)	OCH3 (3a)	4d	81
5	1e (CH3O, H, H, H)	CH3 (2a)	OCH3 (3a)	4e	63
6	1f (F, H, H, H)	CH3 (2a)	OCH3 (3a)	4f	90
7	1g (Cl, H, H, H)	CH3 (2a)	OCH3 (3a)	4g	88
8	1h (Br, H, H, H)	CH3 (2a)	OCH3 (3a)	4h	87
9	1i (I, H, H, H)	CH3 (2a)	OCH3 (3a)	4i	86
10	1j (H, H, CH3, H)	CH3 (2a)	OCH3 (3a)	4j	81
11	1k (H, H, F, H)	CH3 (2a)	OCH3 (3a)	4k	88
12	1l (H, Br, H, H)	CH3 (2a)	OCH3 (3a)	4l	86
13	1m (H, H, H, CH3)	CH3 (2a)	OCH3 (3a)	4m	55
14	1n (CH3CH2, H, H, CH3)	CH3 (2a)	OCH3 (3a)	4n	57
15	1o (CH3O, H, H, CH3)	CH3 (2a)	OCH3 (3a)	4o	47
16	1a (H, H, H, H)	H (2b)	OCH3 (3a)	4p	85
17	1b (CH3, H, H, H)	H (2b)	OCH3 (3a)	4q	83
18	1f (F, H, H, H)	H (2b)	OCH3 (3a)	4r	88
19	1a (H, H, H, H)	CH3CH2 (2c)	OCH3 (3a)	4s	86
20	1b (CH3, H, H, H)	CH3CH2 (2c)	OCH3 (3a)	4t	82
21	1f (F, H, H, H)	CH3CH2 (2c)	OCH3 (3a)	4u	84
22	1a (H, H, H, H)	CH3 (2a)	OCH2CH3 (3b)	4v	73
23	1b (CH3, H, H, H)	CH3 (2a)	OCH2CH3 (3b)	4w	72
24	1f (F, H, H, H)	CH3 (2a)	OCH2CH3 (3b)	4x	87
25	1a (H, H, H, H)	CH3 (2a)	CH3 (3c)	4y	52
26	1b (CH3, H, H, H)	CH3 (2a)	CH3 (3c)	4z	50
27	1f (F, H, H, H)	CH3 (2a)	CH3 (3c)	4aa	51

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In most cases, the reactions of isatins, sarcosine 2a, and methyl 3-phenylpropiolate 3a were proceeded smoothly, and the yields were very good (up to 90% yield). It was observed that the nature of the substituent on the benzene ring of isatins affected the yields of the products. As illustrated in Table 2, isatins with electron-withdrawing R₁ groups (e.g. –F, Cl, –Br, –I) resulted in higher yields than when with electron-donating groups (e.g. –CH₃, –CH₂CH₃, –CH(CH₃)₂) (Table 2, entries 2–4, 6–9). When isatin with a strong electron-donating group (–OCH₃) was subjected to this reaction, the yield of the desired product 4e decreased to 63% (Table 2, entry 5). However, when protected isatins were used as substrates under the optimal reaction conditions, only moderate yields were achieved (Table 2, entries 13–15). When other position substituent of isatins with R₂, R₃ groups were applied to this reaction (Table 2, entries 10–12), the yields (4j to 4l) were 81%, 88%, and 86%, respectively. The structure of the product 4b was confirmed by X-ray crystallographic analysis as shown in Fig. 1.

Fig. 1 X-ray crystal structure of product 4b.¹⁶

To further demonstrate the versatility of the present method, other common α-amino acids such as 2-aminoacetic acid (2b), 2-(ethylamino)acetic acid (2c) and other phenylpropiolate ester such as ethyl 3-phenylpropiolate (3b), were also used in the three-component reaction under standard reaction conditions. The reactions usually produced the corresponding spiro[indoline-3,2′-pyrroles] 4p–4x as the main product in satisfactory yields. The scope and generality of the developed reaction were further tested by using 4-phenylbut-3-yn-2-one (3c) in the three-component reaction. Under the same reaction conditions, the yield of the desired products 4y, 4z, and 4aa could reach to 52%, 50%, and 51%, respectively.

Based on the above results and literature reports,¹⁷ a plausible mechanism for this multicomponent reaction was proposed. First, the condensation of isatin 1a with sarcosine 2a afforded the corresponding azomethine ylide A, which was formed by migration of a proton. Subsequently, the protic solvent of isopropanol would promote the decarboxylation of azomethine ylid A to form the 1,3-dipole B. Then, the 1,3-dipolar cycloaddition of intermediate B with methyl 3-phenylpropiolate 3a results in the final product spiro[indoline-3,2′-pyrrole] 4a (Scheme 2).

Scheme 2 Proposed reaction mechanism of the multicomponent reaction.

Conclusions

In conclusion, we developed a novel method for the synthesis of spiro[indoline-3,2′-pyrrole] derivatives without any catalysts or external additives. The reaction was believed to be proceeded with sequential generation of azomethine ylide and 1,3-dipolar cycloaddition reaction. In comparison to the metal-catalyzed reactions, this effective method was an environmentally friendly process. This simple synthesis with the ability to incorporate multiple functional groups into a desired spiro[indoline-3,2′-pyrrole] ring system provided an attractive strategy for pharmaceutical building blocks and medicinal chemistry applications.

Experimental section

General

Unless otherwise specified, all reagents and starting materials were purchased from commercial sources and used as received, and the solvents were purified and dried by standard procedures. The chromatography solvents were technical grade and distilled prior to use. Flash chromatography was performed using 200–300 mesh silica gel with the indicated solvent system according to standard techniques. The ¹H and ¹³C NMR data were recorded on 400 MHz NMR spectrometers, unless otherwise specified. Chemical shifts (δ) in parts per million are reported relative to the residual signals of chloroform (7.26 ppm for ¹H and 76.1 ppm for ¹³C). Multiplicities are described as s (singlet), d (doublet), t (triplet), q (quartet), or m (multiplet), and coupling constants (J) are reported in hertz. HRMS analysis with a quadrupole time-of-flight mass spectrometer yielded ion mass/charge (m/z) ratios in atomic mass units. IR spectra were measured as dry films (KBr), and peaks are reported in terms of wave number (cm⁻¹).

General procedure for the synthesis of methyl 1′,5-dimethyl-2-oxo-3′-phenyl-1′,5′-dihydrospiro[indoline-3,2′-pyrrole]-4′-carboxylate 4b

A mixture of isatin 5-methylindoline-2,3-dione 1b (0.1 mmol), sarcosine 2a (0.12 mmol) and methyl 3-phenylpropiolate 3a (0.1 mmol) in isopropanol (5 mL) was heated at refluxing for 8 h in an oil bath. Upon completion of the reaction, the mixture was cooled to room temperature, and then evaporated in vacuum. The residue was purified by flash column chromatography on silica gel with ethyl acetate and petroleum ether (3 : 1, v/v) as the eluting solvent to produce product 4b at a yield of 83%.

Methyl 1′-methyl-2-oxo-3′-phenyl-1′,5′-dihydrospiro[indoline-3,2′-pyrrole]-4′-carboxylate (4a)

White solid; mp 73–75 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 7.27 (d, J = 7.2 Hz, 1H), 7.18–7.12 (m, 4H), 6.97 (t, J = 7.2 Hz, 1H), 6.85–6.84 (m, 2H), 6.68 (d, J = 7.6 Hz, 1H), 4.07 (s, 2H), 3.59 (s, 3H), 2.17 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 174.99, 163.29, 158.99, 151.16, 142.21, 133.18, 132.84, 131.55, 130.44, 129.79, 128.93, 128.81, 128.20, 127.81, 114.31, 112.39, 83.25, 60.27, 51.94, 35.26 ppm; IR (KBr) ν: 3250, 1724, 1618, 1469, 1441, 1315, 1225, 1192, 755, 697 cm⁻¹; HRMS (ESI) calcd for C₂₀H₁₈N₂O₃ ([M + H]⁺) 335.1396, found 335.1389.

Methyl 1′,5-dimethyl-2-oxo-3′-phenyl-1′,5′-dihydrospiro[indoline-3,2′-pyrrole]-4′-carboxylate (4b)

White solid; mp 85–87 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 10.42 (s, 1H), 7.21–7.15 (m, 4H), 7.02 (d, J = 8.0 Hz, 1H), 6.86 (t, J = 6.4 Hz, 2H), 6.62 (d, J = 8.0 Hz, 1H), 4.21–4.13 (m, 2H), 3.55 (s, 3H), 2.25 (s, 3H), 2.24 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 174.45, 163.18, 159.03, 158.66, 151.47, 140.52, 132.62, 131.77, 131.12, 130.61, 128.87, 128.14, 127.90, 127.02, 126.10, 110.35, 83.11, 60.17, 52.00, 35.43, 21.00 ppm; IR (KBr) ν: 3435, 1686, 1627, 1494, 1414, 1206, 1137, 1075, 546, 518 cm⁻¹; HRMS (ESI) calcd for C₂₁H₂₀N₂O₃ ([M + H]⁺) 349.1552, found 349.1544.

Methyl 5-ethyl-1′-methyl-2-oxo-3′-phenyl-1′,5′-dihydrospiro[indoline-3,2′-pyrrole]-4′-carboxylate (4c)

White solid; mp 85–87 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 10.32 (s, 1H), 7.18–7.13 (m, 4H), 7.02 (t, J = 6.0 Hz, 1H), 6.84 (d, J = 7.2 Hz, 2H), 6.61–6.58 (m, 1H), 4.16 (s, 2H), 3.54 (s, 3H), 2.56–2.50 (m, 2H), 2.24 (s, 3H), 1.14 (t, J = 7.6 Hz, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 175.80, 163.66, 162.58, 140.60, 138.01, 133.42, 131.24, 129.19, 128.51, 128.15, 127.95, 127.91, 125.55, 109.93, 83.41, 60.26, 51.82, 53.13, 28.18, 16.43 ppm; IR (KBr) ν: 3114, 2969, 1736, 1674, 1627, 1494, 1461, 1428, 1292, 1250, 1199, 1137, 833, 697 cm⁻¹; HRMS (ESI) calcd for C₂₂H₂₂N₂O₃ ([M + H]⁺) 363.1709, found 363.1700.

Methyl 5-isopropyl-1′-methyl-2-oxo-3′-phenyl-1′,5′-dihydrospiro[indoline-3,2′-pyrrole]-4′-carboxylate (4d)

White solid; mp 73–75 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 10.38 (s, 1H), 7.21–7.12 (m, 4H), 7.05 (d, J = 8.0 Hz, 1H), 6.83 (d, J = 6.4 Hz, 2H), 6.60 (d, J = 8.4 Hz, 1H), 4.18–4.16 (m, 2H), 3.54 (s, 3H), 2.84–2.81 (m, 1H), 2.27 (s, 3H), 1.16 (d, J = 6.8 Hz, 6H) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 174.47, 163.17, 159.06, 158.68, 151.73, 143.07, 140.78, 132.74, 130.70, 128.75, 128.43, 128.02, 127.89, 126.17, 124.56, 110.24, 83.34, 60.17, 51.99, 35.54, 33.45, 24.60, 24.22 ppm; IR (KBr) ν: 3442, 1709, 1491, 1438, 1234, 1138, 1068, 953, 837, 722, 698, 516 cm⁻¹; HRMS (ESI) calcd for C₂₃H₂₄N₂O₃ ([M + H]⁺) 377.1865, found 377.1855.

Methyl 5-methoxy-1′-methyl-2-oxo-3′-phenyl-1′,5′-dihydrospiro[indoline-3,2′-pyrrole]-4′-carboxylate (4e)

White solid; mp 101–103 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 7.20–7.16 (m, 3H), 6.91–6.87 (m, 3H), 6.74–6.72 (m, 1H), 6.61 (d, J = 8.4 Hz, 1H), 4.13–4.05 (m, 2H), 3.69 (s, 3H), 3.55 (s, 3H), 2.19 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 175.28, 163.18, 155.04, 151.95, 135.66, 132.95, 130.94, 129.01, 128.15, 128.07, 127.55, 127.46, 114.68, 111.95, 110.21, 83.26, 59.81, 55.42, 51.33, 34.61 ppm; IR (KBr) ν: 3250, 2949, 2224, 1723, 1605, 1489, 1438, 1291, 1202, 1171, 1029, 760, 690 cm⁻¹; HRMS (ESI) calcd for C₂₁H₂₀N₂O₄ ([M + H]⁺) 365.1501, found 365.1495.

Methyl 5-fluoro-1′-methyl-2-oxo-3′-phenyl-1′,5′-dihydrospiro[indoline-3,2′-pyrrole]-4′-carboxylate (4f)

White solid; mp 90–92 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 10.62 (s, 1H), 7.19–7.15 (m, 4H), 7.01–6.96 (m, 1H), 6.89–6.73 (m, 2H), 6.72–6.70 (m, 1H), 4.12–4.04 (m, 2H), 3.59 (s, 3H), 2.19 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 175.808, 175.795, 163.50, 159.72, 157.35, 151.93, 139.21, 139.19, 133.20, 131.64, 129.98, 129.91, 128.60, 128.08, 127.83, 116.61, 116.38, 113.74, 113.50, 111.22, 111.15, 83.64, 83.62, 79.72, 60.23, 51.84, 35.05 ppm; IR (KBr) ν: 3262, 1724, 1629, 1485, 1441, 1281, 1236, 1185, 1135, 698 cm⁻¹; HRMS (ESI) calcd for C₂₀H₁₇FN₂O₃ ([M + H]⁺) 353.1301, found 353.1293.

Methyl 5-chloro-1′-methyl-2-oxo-3′-phenyl-1′,5′-dihydrospiro[indoline-3,2′-pyrrole]-4′-carboxylate (4g)

White solid; mp 89–90 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 10.52 (s, 1H), 7.33 (d, J = 2.4 Hz, 1H), 7.22–7.18 (m, 4H), 6.88–6.86 (m, 2H), 6.68 (d, J = 8.0 Hz, 1H), 4.13–4.04 (m, 2H), 3.54 (s, 3H), 2.18 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 175.62, 163.46, 151.57, 141.75, 133.12, 131.75, 130.18, 130.08, 128.70, 128.15, 127.80, 126.55, 126.07, 111.73, 83.39, 60.27, 51.89, 35.10 ppm; IR (KBr) ν: 3438, 1725, 1618, 1474, 1437, 1228, 1183, 698 cm⁻¹; HRMS (ESI) calcd for C₂₀H₁₇ClN₂O₃ ([M + H]⁺) 369.1006, found 369.1001.

Methyl 5-bromo-1′-methyl-2-oxo-3′-phenyl-1′,5′-dihydrospiro[indoline-3,2′-pyrrole]-4′-carboxylate (4h)

White solid; mp 91–92 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 10.59 (s, 1H), 7.47 (d, J = 5.6 Hz, 1H), 7.37–7.34 (m, 1H), 7.21–7.18 (m, 3H), 6.88–6.86 (m, 2H), 6.67 (d, J = 8.4 Hz, 1H), 4.17–4.07 (m, 2H), 3.54 (s, 3H), 2.21 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 174.99, 163.29, 158.99, 151.16, 142.21, 133.18, 132.84, 131.55, 130.44, 129.79, 128.93, 128.81, 128.20, 127.81, 114.31, 112.39, 83.25, 60.27, 51.94, 35.26 ppm; IR (KBr) ν: 3442, 1736, 1671, 1618, 1474, 1438, 1138, 1077, 838, 721, 696, 537 cm⁻¹; HRMS (ESI) calcd for C₂₀H₁₇BrN₂O₃ ([M + H]⁺) 413.0501, found 413.0492.

Methyl 5-iodo-1′-methyl-2-oxo-3′-phenyl-1′,5′-dihydrospiro[indoline-3,2′-pyrrole]-4′-carboxylate (4i)

Gray solid; mp 105–106 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 10.51 (s, 1H), 7.55 (s, 1H), 7.51–7.48 (m, 1H), 7.20–7.16 (m, 3H), 6.87–6.84 (m, 2H), 6.55 (d, J = 8.4 Hz, 1H), 4.12–4.03 (m, 2H), 3.53 (s, 3H), 2.18 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 175.12, 163.44, 151.48, 142.64, 138.75, 134.31, 133.06, 131.66, 130.57, 130.44, 128.74, 128.16, 127.81, 127.46, 112.76, 85.38, 83.13, 60.29, 51.91, 35.15 ppm; IR (KBr) ν: 3538, 3405, 3314, 1726, 1701, 1468, 1444, 1427, 1239, 1183, 1146, 1122, 694 cm⁻¹; HRMS (ESI) calcd for C₂₀H₁₇IN₂O₃ ([M + H]⁺) 461.0362, found 461.0355.

Methyl 1′,7-dimethyl-2-oxo-3′-phenyl-1′,5′-dihydrospiro[indoline-3,2′-pyrrole]-4′-carboxylate (4j)

Yellow solid; mp 83–85 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 10.57 (s, 1H), 7.20–7.12 (m, 4H), 7.02–7.00 (m, 1H), 6.92–6.84 (m, 3H), 4.16 (s, 2H), 3.54 (s, 3H), 2.25 (d, J = 10 Hz, 3H), 2.07 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 174.91, 163.16, 159.04, 151.48, 141.63, 132.65, 132.14, 130.69, 128.87, 128.14, 127.88, 125.62, 123.88, 122.68, 119.91, 83.18, 60.09, 52.00, 35.43, 16.58 ppm; IR (KBr) ν: 3439, 1678, 1626, 1604, 1439, 1137, 1072, 989, 860, 545 cm⁻¹; HRMS (ESI) calcd for C₂₁H₂₀N₂O₃ ([M + H]⁺) 349.1552, found 349.1546.

Methyl 7-fluoro-1′-methyl-2-oxo-3′-phenyl-1′,5′-dihydrospiro[indoline-3,2′-pyrrole]-4′-carboxylate (4k)

White solid; mp 62–63 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 10.96 (s, 1H), 7.19–6.98 (m, 6H), 6.86 (d, J = 7.6 Hz, 2H), 4.10 (s, 2H), 3.58 (s, 3H), 2.19 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 175.74, 163.51, 151.86, 147.75, 145.33, 133.10, 131.66, 131.02, 130.98, 129.96, 129.83, 128.69, 128.10, 127.80, 123.41, 123.36, 122.23, 122.20, 117.20, 117.03, 83.46, 83.44, 79.59, 60.21, 51.87, 35.06 ppm; IR (KBr) ν: 3538, 3230, 2955, 1719, 1654, 1492, 1259, 1231, 1195, 1132, 799 cm⁻¹; HRMS (ESI) calcd for C₂₀H₁₇FN₂O₃ ([M + H]⁺) 353.1301, found 353.1293.

Methyl 6-bromo-1′-methyl-2-oxo-3′-phenyl-1′,5′-dihydrospiro[indoline-3,2′-pyrrole]-4′-carboxylate (4l)

White solid; mp 89–90 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 10.55 (s, 1H), 7.25–7.13 (m, 5H), 6.86–6.83 (m, 3H), 4.13–4.06 (m, 2H), 3.54 (s, 3H), 2.20 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 175.61, 172.25, 162.08, 159.06, 148.28, 142.86, 132.21, 131.65, 130.43, 129.49, 129.30, 128.40, 128.16, 127.97, 127.81, 126.98, 123.64, 123.10, 111.14, 82.96, 77.99, 52.45, 51.92, 51.90, 35.07 ppm; IR (KBr) ν: 3435, 1678, 1621, 1473, 1438, 1138, 1974, 989, 860, 545 cm⁻¹; HRMS (ESI) calcd for C₂₀H₁₇BrN₂O₃ ([M + H]⁺) 413.0501, found 413.0498.

Methyl 1,1′-dimethyl-2-oxo-3′-phenyl-1′,5′-dihydrospiro[indoline-3,2′-pyrrole]-4′-carboxylate (4m)

White solid; mp 122–124 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 7.32 (d, J = 7.6 Hz, 1H), 7.27 (t, J = 7.2 Hz, 1H), 7.16–7.11 (m, 3H), 7.05 (t, J = 7.6 Hz, 1H), 6.89 (d, J = 7.6 Hz, 1H), 6.79 (d, J = 6.4 Hz, 2H), 4.10 (s, 2H), 3.54 (s, 3H), 3.01 (s, 3H), 2.12 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 174.08, 163.53, 152.25, 144.27, 133.15, 131.45, 130.21, 128.57, 128.02, 127.71, 127.29, 125.73, 123.15, 109.15, 82.90, 60.27, 51.90, 35.05, 26.34 ppm; IR (KBr) ν: 3435, 1729, 1709, 1611, 1468, 1434, 1366, 1341, 1301, 1288, 1169, 1125, 1078, 983, 738, 699 cm⁻¹; HRMS (ESI) calcd for C₂₂H₂₂N₂O₄ ([M + H]⁺) 379.1658, found 379.1648.

Methyl 5-ethyl-1,1′-dimethyl-2-oxo-3′-phenyl-1′,5′-dihydrospiro[indoline-3,2′-pyrrole]-4′-carboxylate (4n)

White solid; mp 97–99 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 7.16–7.07 (m, 5H), 6.78 (t, J = 5.6 Hz, 3H), 4.09 (s, 2H), 3.54 (s, 3H), 2.97 (s, 3H), 2.58–2.52 (m, 2H), 2.12 (s, 3H), 1.14 (t, J = 7.6 Hz, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 174.02, 163.57, 152.40, 142.08, 138.81, 133.19, 131.35, 129.23, 128.55, 127.96, 127.73, 127.32, 127.22, 125.23, 108.91, 83.05, 60.29, 51.87, 35.11, 28.17, 26.33, 16.47 ppm; IR (KBr) ν: 3435, 2947, 1707, 1618, 1599, 1496, 1442, 1238, 1192, 1074, 1037, 696 cm⁻¹; HRMS (ESI) calcd for C₂₃H₂₄N₂O₃ ([M + H]⁺) 377.1865, found 377.1863.

Methyl 5-methoxy-1,1′-dimethyl-2-oxo-3′-phenyl-1′,5′-dihydrospiro[indoline-3,2′-pyrrole]-4′-carboxylate (4o)

Yellow solid; mp 97–98 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 7.15–7.11 (m, 3H), 6.91 (s, 1H), 6.83–6.79 (m, 4H), 4.14–4.05 (m, 2H), 3.71 (s, 3H), 3.53 (s, 3H), 2.98 (s, 3H), 2.13 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 173.76, 163.53, 156.05, 152.24, 137.62, 133.19, 131.48, 128.71, 128.57, 128.03, 127.75, 114.76, 112.37, 109.66, 83.28, 60.28, 55.94, 51.88, 35.05, 26.39 ppm; IR (KBr) ν: 3392, 2919, 2848, 1724, 1645, 1469, 1435, 1382, 1357, 1287, 1234, 1035 cm⁻¹; HRMS (ESI) calcd for C₂₀H₁₈N₂O₃ ([M + H]⁺) 335.1396, found 335.1389.

Methyl 2-oxo-3′-phenyl-1′,5′-dihydrospiro[indoline-3,2′-pyrrole]-4′-carboxylate (4p)

White solid; mp 75–77 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 10.99 (s, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.32–7.18 (m, 4H), 7.09 (t, J = 7.6 Hz, 1H), 6.84–6.78 (m, 3H), 4.60–4.47 (m, 2H), 3.59 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 175.24, 163.31, 151.39, 144.57, 132.91, 131.50, 128.77, 128.43, 128.18, 127.97, 127.82, 126.69, 125.28, 122.94, 113.23, 82.90, 60.17, 51.93, 35.17 ppm; IR (KBr) ν: 3054, 2916, 2848, 1743, 1612, 1462, 1265, 1193, 704 cm⁻¹; HRMS (ESI) calcd for C₁₉H₁₆N₂O₃ ([M + H]⁺) 321.1239, found 321.1235.

Methyl 5-methyl-2-oxo-3′-phenyl-1′,5′-dihydrospiro[indoline-3,2′-pyrrole]-4′-carboxylate (4q)

White solid; mp 51–53 °C.¹H NMR (400 MHz, DMSO-d₆) δ 10.85 (s, 1H), 7.44 (s, 1H), 7.29–7.20 (m, 3H), 7.13 (d, J = 8.0 Hz, 1H), 6.84–6.81 (m, 2H), 6.70 (d, J = 8.0 Hz, 1H), 4.61–4.43 (m, 2H), 3.59 (s, 3H), 2.28 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 172.91, 162.36, 148.77, 140.24, 136.72, 132.19, 132.15, 130.79, 129.53, 129.38, 128.36, 127.99, 127.11, 110.75, 78.38, 52.38, 52.28, 20.97 ppm; IR (KBr) ν: 3446, 1730, 1673, 1625, 1494, 1440, 1294, 1286, 1201, 1139, 698 cm⁻¹; HRMS (ESI) calcd for C₂₀H₁₈N₂O₃ ([M + H]⁺) 335.1396, found 335.1391.

Methyl 5-fluoro-2-oxo-3′-phenyl-1′,5′-dihydrospiro[indoline-3,2′-pyrrole]-4′-carboxylate (4r)

Gray solid; mp 52–54 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 10.89 (s, 1H), 7.53–7.51 (m, 1H), 7.28–7.21 (m, 3H), 7.15–7.09 (m, 1H), 6.87 (d, J = 6.4 Hz, 2H), 6.78–6.74 (m, 1H), 4.57–4.41 (m, 2H), 3.58 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 173.67, 162.42, 159.65, 157.29, 148.63, 138.95, 138.93, 130.92, 130.40, 129.27, 128.38, 127.95, 118.20, 117.96, 114.59, 111.88, 111.81, 78.82, 52.65, 52.30 ppm; IR (KBr) ν: 3450, 1735, 1707, 1664, 1490, 1441, 1308, 1244, 1190, 1146, 799, 724, 700, 597 cm⁻¹; HRMS (ESI) calcd forC₁₉H₁₅FN₂O₃ ([M + H]⁺) 339.1145, found 339.1144.

Methyl 1′-ethyl-2-oxo-3′-phenyl-1′,5′-dihydrospiro[indoline-3,2′-pyrrole]-4′-carboxylate (4s)

White solid; mp 84–55 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 10.35 (s, 1H), 7.31 (d, J = 7.2 Hz, 1H), 7.18–7.12 (m, 4H), 6.98 (t, J = 7.6 Hz, 1H), 6.84–6.82 (m, 2H), 6.68 (d, J = 7.6 Hz, 1H), 4.16–4.04 (m, 2H), 3.53 (s, 3H), 2.56–2.51 (m, 1H), 2.37–2.33 (m, 1H), 0.93 (t, J = 7.2 Hz, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 176.21, 163.65, 152.30, 142.70, 133.18, 130.84, 129.99, 128.54, 128.48, 127.94, 127.91, 126.08, 122.43, 110.16, 83.04, 58.00, 51.80, 43.36, 40.54, 40.33, 40.13, 39.91, 39.71, 39.49, 39.29, 14.30 ppm; IR (KBr) ν: 3247, 1724, 1617, 1519, 1470, 1442, 1372, 1318, 1281, 1211, 754, 697 cm⁻¹; HRMS (ESI) calcd for C₂₁H₂₀N₂O₃ ([M + H]⁺) 349.1552, found 349.1543.

Methyl 1′-ethyl-5-methyl-2-oxo-3′-phenyl-1′,5′-dihydrospiro[indoline-3,2′-pyrrole]-4′-carboxylate (4t)

White solid; mp 67–69 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 10.23 (s, 1H), 7.19–7.14 (m, 4H), 6.98 (d, J = 7.6 Hz, 1H), 6.84 (d, J = 6.4 Hz, 2H), 6.58 (d, J = 8.0 Hz, 1H), 4.16–4.04 (m, 2H), 3.55 (s, 3H), 2.54–2.50 (m, 1H), 2.39–2.34 (m, 1H), 2.25 (s, 3H), 0.95 (t, J = 7.2 Hz, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 176.22, 163.69, 152.35, 140.22, 133.20, 131.29, 130.69, 130.30, 128.52, 128.50, 127.94, 126.56, 109.90, 83.06, 58.02, 58.00, 51.79, 43.36, 21.06, 14.28 ppm; IR (KBr) ν: 3374, 1723, 1623, 1490, 1436, 1294, 1232, 1194, 1137, 697 cm⁻¹; HRMS (ESI) calcd for C₂₂H₂₂N₂O₃ ([M + H]⁺) 363.1709, found 363.1695.

Methyl 1′-ethyl-5-fluoro-2-oxo-3′-phenyl-1′,5′-dihydrospiro[indoline-3,2′-pyrrole]-4′-carboxylate (4u)

White solid; mp 72–74 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 10.41 (s, 1H), 7.22–7.15 (m, 4H), 7.01–6.96 (m, 1H), 6.87–6.85 (m, 2H), 6.67–6.64 (m, 1H), 4.18 (d, J = 13.2 Hz, 1H), 4.05 (d, J = 12.8 Hz, 1H), 3.54 (s, 3H), 2.57 (m, 1H), 2.29 (m, 1H), 0.94 (t, J = 6.8 Hz, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 176.25, 163.51, 159.72, 157.35, 151.71, 138.83, 132.99, 131.18, 130.53, 130.46, 128.56, 128.03, 127.87, 127.80, 127.87, 116.55, 116.32, 113.72, 113.48, 110.07, 110.99, 83.38, 58.00, 51.81, 51.77, 43.38, 43.34, 14.27 ppm; IR (KBr) ν: 3241, 3058, 2972, 2949, 1724, 1628, 1521, 1483, 1372, 1236, 1184, 1074, 817, 800, 698, 594 cm⁻¹; HRMS (ESI) calcd for C₂₁H₁₉FN₂O₃ ([M + H]⁺) 367.1458, found 367.1445.

Ethyl 1′-methyl-2-oxo-3′-phenyl-1′,5′-dihydrospiro[indoline-3,2′-pyrrole]-4′-carboxylate (4v)

White solid; mp 77–79 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 10.38 (s, 1H), 7.30 (d, J = 7.2 Hz, 1H), 7.18–7.13 (m, 4H), 6.99 (t, J = 7.2 Hz, 1H), 6.86 (d, J = 6.4 Hz, 2H), 6.69 (d, J = 8.0 Hz, 1H), 4.08 (s, 2H), 4.01–3.59 (m, 2H), 2.23 (s, 3H), 0.98 (t, J = 6.8 Hz, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 175.87, 163.24, 152.17, 142.88, 133.52, 131.81, 130.06, 128.44, 128.08, 127.92, 126.18, 122.47, 115.64, 110.19, 83.34, 60.38, 60.21, 35.09, 14.04 ppm; IR (KBr) ν: 3417, 2976, 2871, 2798, 1715, 1621, 1472, 1291, 1229, 1171, 1071, 1021, 750, 698, 614 cm⁻¹; HRMS (ESI) calcd for C₂₀H₁₈N₂O₃ ([M + H]⁺) 335.1396, found 335.1389.

Ethyl 1′,5-dimethyl-2-oxo-3′-phenyl-1′,5′-dihydrospiro[indoline-3,2′-pyrrole]-4′-carboxylate (4w)

Gray solid; mp 73–74 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 10.27 (s, 1H), 7.19–7.13 (m, 4H), 6.98 (d, J = 7.6 Hz, 1H), 6.87 (t, J = 6.0 Hz, 2H), 6.59 (d, J = 8.0 Hz, 1H), 4.08 (s, 2H), 4.01–3.95 (m, 2H), 2.23 (s, 3H), 2.17 (s, 3H). 0.99 (t, J = 7.2 Hz, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 175.85, 163.29, 152.17, 140.41, 133.54, 131.70, 131.35, 130.33, 128.45, 128.18, 127.96, 127.91, 126.67, 115.64, 109.91, 83.38, 60.37, 60.26, 35.11, 21.03, 14.04 ppm; IR (KBr) ν: 3249, 2979, 1720, 1623, 1522, 1490, 1377, 1295, 1231, 1130, 1072, 697 cm⁻¹; HRMS (ESI) calcd for C₂₀H₁₈N₂O₃ ([M + H]⁺) 335.1396, found 335.1389.

Ethyl 5-fluoro-1′-methyl-2-oxo-3′-phenyl-1′,5′-dihydrospiro[indoline-3,2′-pyrrole]-4′-carboxylate (4x)

White solid; mp 66–67 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 10.51 (s, 1H), 7.26–7.17 (m, 4H), 7.04–6.99 (m, 1H), 6.91–6.88 (m, 2H), 6.71–0.68 (m, 1H), 4.19–4.11 (m, 2H), 4.02–3.96 (m, 2H), 2.26 (s, 3H), 0.99 (t, J = 6.8 Hz, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 175.31, 162.90, 159.77, 158.64, 157.40, 151.14, 139.10, 139.07, 133.01, 131.87, 129.08, 128.65, 128.06, 127.89, 117.01, 116.76, 114.06, 113.82, 111.31, 111.25, 83.61, 83.59, 60.53, 60.21, 35.25, 13.99 ppm; IR (KBr) ν: 3346, 1708, 1525, 1486, 1444, 1382, 1289, 1187, 1138, 801, 698 cm⁻¹; HRMS (ESI) calcd for C₂₁H₁₉FN₂O₃ ([M + H]⁺) 367.1458, found 367.1453.

4′-Acetyl-1′-methyl-3′-phenyl-1′,5′-dihydrospiro[indoline-3,2′-pyrrol]-2-one (4y)

White solid; mp 73–74 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 10.30 (s, 1H), 7.34 (d, J = 7.2 Hz, 1H), 7.25–7.20 (m, 3H), 7.17–7.13 (m, 1H), 7.00–6.96 (m, 1H), 6.91–6.89 (m, 2H), 6.65 (d, J = 7.6 Hz, 1H), 4.05 (s, 2H), 2.18 (s, 3H), 1.75 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 196.07, 175.90, 151.14, 142.74, 140.71, 133.67, 130.06, 128.98, 128.56, 128.24, 127.91, 126.29, 122.43, 110.16, 84.35, 60.38, 35.24, 29.85 ppm; IR (KBr) ν: 3437, 1719, 1663, 1617, 1469, 1376, 1223, 1185, 751, 700 cm⁻¹; HRMS (ESI) calcd for C₂₀H₁₈N₂O₂ ([M + H]⁺) 319.1447, found 319.1439.

4′-Acetyl-5-methyl-3′-phenyl-1′,5′-dihydrospiro[indoline-3,2′-pyrrol]-2-one (4z)

White solid; mp 82–83 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 10.19 (s, 1H), 7.24 (d, J = 6.0 Hz, 3H), 7.16 (s, 1H), 6.96 (d, J = 7.6 Hz, 1H), 6.91 (t, J = 6.0 Hz, 2H), 6.54 (d, J = 8.4 Hz, 1H), 4.05 (s, 2H), 2.25 (s, 3H), 2.17 (s, 3H), 1.74 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 196.09, 175.83, 151.24, 140.63, 140.31, 133.71, 131.27, 130.32, 128.98, 128.57, 128.27, 128.01, 126.80, 109.87, 84.41, 60.42, 35.28, 29.86, 21.08 ppm; IR (KBr) ν: 3404, 1720, 1663, 1624, 1491, 1383, 1296, 1233, 1200, 1121, 700 cm⁻¹; HRMS (ESI) calcd for C₂₁H₂₀N₂O₂ ([M + H]⁺) 333.1603, found 333.1592.

4′-Acetyl-5-fluoro-3′-phenyl-1′,5′-dihydrospiro[indoline-3,2′-pyrrol]-2-one (4aa)

White solid; mp 78–79 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 10.37 (s, 1H), 7.26 (d, J = 2.8 Hz, 4H), 6.98–6.95 (m, 3H), 6.65–6.62 (m, 1H), 4.07 (d, J = 5.2 Hz, 2H), 2.20 (s, 3H), 1.75 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 195.94, 175.92, 159.72, 157.35, 150.49, 140.91, 138.92, 138.91, 133.49, 129.84, 129.78, 129.06, 128.66, 128.21, 116.63, 116.40, 113.97, 113.73, 111.07, 110.99, 84.72, 60.41, 35.23, 29.87 ppm; IR (KBr) ν: 3438, 1719, 1664, 1485, 1443, 1382, 1283, 1211, 1185, 1211, 1074, 801, 701, 596 cm⁻¹; HRMS (ESI) calcd for C₂₀H₁₇FN₂O₂ ([M + H]⁺) 337.1352, found 337.1350.

Acknowledgements

This work was partially supported by the National Natural Science Foundation of China (No. 21172001, 21372008).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: ¹H and ¹³C NMR spectra of all products, and crystal data and structure refinement for 4b. CCDC 1436295. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra23860a

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