One-pot synthesis of 6,11-dihydro-5H-indolizino[8,7-b]indoles via sequential formation of β-enamino ester, Michael addition and Pictet–Spengler reactions

Abstract

β-Enamino esters generated from addition of tryptamines to alkyl propiolates reacted with 3-phenacylideneoxindoles in the presence of anhydrous ZnCl₂ to give functionalized 2-pyrrolo-3′-yloxindoles in satisfactory yields, which can be further converted to the corresponding 6,11-dihydro-5H-indolizino[8,7-b]indoles in good yields through a CF₃SO₃H catalyzed Pictet–Spengler cyclization process. Under similar conditions, when arylamines were used to replace tryptamine, the one-pot domino reaction afforded the functionalized 2-pyrrolo-3′-yloxindoles.

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Introduction

The Pictet–Spengler reaction has long been known as an efficient method for the preparation of tetrahydro-β-carboline frameworks.^1,2 In recent years, many developments have been made to incorporate Pictet–Spengler reaction into cascade sequence or multicomponent reactions based on the use of tryptamine-derived substrates.^3–7 In this respect, β-enamino esters generated from reaction of tryptamines with alkyl propiolates were widely used as the valuable building blocks for sequential Pictet–Spengler reaction to construct versatile indole-annulated heterocyclics.^8–11 Practically, Wu and Zhao successfully developed an organocatalytic three-component synthesis of indoloquinolizidines based on conjugate addition of β-enamino ester to α,β-enals and subsequent substrate controlled Pictet–Spengler cyclization.¹² Recently, we also successfully developed facile synthetic procedure for the functionalized 1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizines by one-pot domino reactions of tryptamines, propiolate and α,β-unsaturated aldehydes as well as arylideneacetones with Lewis acid catalyst.¹³ In order to develop the potential values of this one-pot domino reaction in synthetic chemistry and to hunt for new efficient domino reactions, we envisioned that spiro-indolo[2,3-a]quinolizine-oxindoles would be synthesized from the similar reactions of in situ generated β-enamino esters with 3-phenacylideneoxindoles (Scheme 1). The obtained results indicated that the domino reaction of tryptamine, alkyl propiolate and 3-phenacylideneoxindoles resulted in the functionalized 6,11-dihydro-5H-indolizino[8,7-b]indoles instead of the desired spiro-indolo[2,3-a]quinolizine-oxindole system. Herein we wish to report these interesting results.

Scheme 1 Reaction of β-enamino esters with 3-phenacylideneoxindoles.

Results and discussion

According to the established reaction conditions for synthesis of the functionalized 1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizines from the one-pot reaction of tryptamine, propiolates and arylideneacetones,¹³ At first, tryptamine reacted with methyl propiolate in ethanol at room temperature in about twenty minutes to give the expected reactive intermediate β-enamino ester. Then, under the catalysis of anhydrous zinc chloride, the sequential reaction of the in situ generated β-enamino esters with 3-phenacylideneoxindoles resulted in the functionalized 2-pyrrolo-3′-yloxindoles 1a–1d in satisfactory yields (Table 1), not the expected Pictet–Spengler cyclized products as that in the previous reported reactions of β-enamino esters with arylideneacetones.¹³ The structures of functionalized 2-pyrrolo-3′-yloxindoles 1a–1d were established on the spectroscopy. The molecular structure of 1d was also determined by X-ray diffraction method (Fig. 1). The functionalized 2-pyrrolo-3′-yloxindoles 1a–1d are very interesting molecules, in which the three rings of indole, pyrrole and oxindole were connected each other with C–C single bond and ethylene bridge. ¹H NMR spectra of compounds 1a–1d indicated that two isomers with a ratio of 4 : 1 or 7 : 3 exist in the products, which is attribute to the equilibrium of the keto-enol tautomers existing in the oxindole moiety. This phenomenon has been reported in the known functionalized 2-pyrrolo-3′-yloxindoles.¹⁴

Table 1 One-pot synthesis of functionalized 2-pyrrolo-3′-yloxindoles 1a–1d^a

Entry	Compd	R^1	R^2	R^3	R^4	Ar	Yield^b (%, keto–enol)
a Reaction condition: 1, tryptamines (1.0 mmol), propiolate (1.0 mmol) in EtOH (5.0 mL), rt, 20 min; 2, 3-phenacylideneoxindole (1.0 mmol), ZnCl2 (0.5 mmol), rt, 12 h.b Isolated yield.
1	1a	H	CH3	Cl	H	C6H5	87 (4 : 1)
2	1b	H	CH3	Cl	Bn	p-CH3C6H4	92 (4 : 1)
3	1c	H	CH3	CH3	H	p-ClC6H4	85 (7 : 3)
4	1d	CH3O	CH2H3	Cl	H	C6H5	90 (4 : 1)

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Fig. 1 Molecular structure of compound 1d.

In order to finish the Pictet–Spengler cyclization of the above prepared functionalized 2-pyrrolo-3′-yloxindoles, many screening experiments were carried out. Finally, we found that the functionalized 2-pyrrolo-3′-yloxindoles in acetic acid at 60–70 °C in the presence of trifluoromethansulfonic acid could be successfully transferred to polysubstituted 6,11-dihydro-5H-indolizino[8,7-b]indoles 2a–2j in good yields (Table 2). The structures of 2a–2j were characterized with IR, HRMS, ¹H and ¹³C NMR spectra and were confirmed by determination of single crystal of compound 2i (Fig. 2). It should be pointed out that acid catalyzed Pictet–Spengler cyclization of functionalized 2-pyrrolo-3′-yloxindole did no result in the expected heterocyclic spirooxindole system. The oxindole moiety is only a substituent on the core of the obtained 6,11-dihydro-5H-indolizino[8,7-b]indole.

Table 2 One-pot synthesis of 6,11-dihydro-5H-indolizino[8,7-b]indoles 2a–2j^a

Entry	Compd	R^1	R^2	R^3	Ar	Yield^b (%)
a Reaction condition: 1, tryptamines (1.0 mmol), propiolate (1.0 mmol) in EtOH (5.0 mL), rt, 20 min; 2, 3-phenacylideneoxindole (1.0 mmol), ZnCl2 (0.5 mmol), rt, 12 h. 3, CF3SO3H (0.1 mmol), AcOH (5.0 mL), 60–70 °C, 6 h.b Isolated yield.
1	2a	H	CH3	Cl	C6H5	70
2	2b	H	CH3	F	p-CH3C6H4	65
3	2c	H	CH3	Cl	p-CH3OC6H4	68
4	2d	CH3O	CH3	H	p-CH3C6H4	67
5	2e	CH3O	CH3	CH3	p-ClC6H4	70
6	2f	CH3O	CH3	CH3	p-CH3C6H4	66
7	2g	CH3O	CH3	CH3	C6H5	63
8	2h	CH3O	CH3	F	p-CH3C6H4	71
9	2i	CH3O	CH3	Cl	p-CH3OC6H4	65
10	2j	CH3O	C2H5	Cl	C6H5	65

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Fig. 2 Crystal structure of compound 2i.

In order to explain the mechanism of this one-pot sequential reaction, we proposed a plausible reaction mechanism on the basis of our previously reported reactions containing tryptamine⁹ or 3-phenacylideneoxindoles^10c (Scheme 2). At first, the nucleophilic addition of tryptamine to methyl propiolate gives the expected reactive intermediate β-enamino ester (A). Secondly, Michael addition of β-enamino ester (A) to the exocyclic carbon atom of 3-phenacylideneoxindole affords a adduct (B). Thirdly, under the catalysis of anhydrous zinc chloride, the intramolecular condensation of amino group with carbonyl group results in the intermediate (C), which in turn transferred to the functionalized 2-pyrrolo-3′-yloxindole 1 by elimination of water. Then, in the presence of trifluoromethanesulfonic acid, a new iminium intermediate (D) was formed by protonation of the functionalized 2-pyrrolo-3′-yloxindole 1. Finally, 6,11-dihydro-5H-indolizino[8,7-b]indoles 2 was formed through the well-known Pictet–Spengler cyclization process.

Scheme 2 Proposed formation mechanism for 6,11-dihydro-5H-indolizino[8,7-b]indoles.

In order to shed the light of the proposed reaction mechanism, ethyl 2-(2-oxoindolin-3-ylidene)acetates were also utilized to react with the in situ generated β-enamino ester under similar reaction conditions and the polyfunctionalized open-chain products 3a and 3b were successfully separated in 60% and 65% yields, respectively (Scheme 3). The products 3a and 3b can be considered as the intermediate B in the above proposed reaction mechanism (Scheme 2). Because there is no reactive carbonyl group in ethyl 2-(2-oxoindolin-3-ylidene)acetates, the pyrrole ring could not be formed in the sequential reaction. Thus, the reaction stopped at the second step of the proposed reaction mechanism to give the open-chain product. This result provided stronger evidence to our proposed reaction mechanism. The molecular structures of 3a and 3b were also successfully determined by X-ray diffraction method (Fig. 3 and S1†).

Scheme 3 Synthesis of the open-chain products 3a and 3b from one-pot reaction.

Fig. 3 Crystal structure of intermediate 3a.

Finally, arylamines were also introduced to replace cryptamine in the domino reaction under similar conditions. The reaction of arylamine with methyl propiolate at room temperature for about 24 hours resulted in desired β-enamino ester, which in turn reacted with 3-phenacylideneoxindole in the presence of ZnCl₂ as catalyst in refluxing ethanol for about six hours. The expected functionalized 2-pyrrolo-3′-yloxindoles 4a–4f can be obtained in good yields (Table 3). ¹H NMR spectra also indicated the a mixture of keto-isomer and enol-isomer with ratio of 3 : 1 to 5 : 1 exit in products 4a–4f as that in the products 1a–1d. The molecular structures of the compound 4b (Fig. 4) and 4e (Fig. S2†) were also successfully determined by X-ray diffraction method. This experiment also added conventional evidence for the proposed domino reaction mechanism in Scheme 2.

Table 3 One-pot synthesis of functionalized 2-pyrrolo-3′-yloxindoles 4a–4f^a

Entry	Compd	R^1	R^2	R^3	Ar	Yield^b (%, keto–enol)
a Reaction condition: 1, arylamine (1.0 mmol), propiolate (1.0 mmol) in EtOH (5.0 mL), rt, 24 h; 2, 3-phenacylideneoxindole (0.8 mmol), ZnCl2 (0.5 mmol), reflux, 6 h.b Isolated yield.
1	4a	CH3	H	H	p-ClC6H5	76 (3 : 1)
2	4b	CH3	Cl	H	p-CH3OC6H4	74 (5 : 1)
3	4c	OCH3	Cl	H	p-CH3OC6H4	80 (5 : 1)
4	4d	CH3	Cl	H	p-CH3C6H4	70 (5 : 1)
5	4e	OCH3	F	H	p-CH3C6H5	76 (3 : 1)
6	4f	OCH3	CH3	H	p-ClC6H4	77 (3 : 1)

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Fig. 4 Crystal structure of intermediate 4b.

Conclusion

In summary, we have successfully developed a convenient procedure for synthesis of polysubstituted 6,11-dihydro-5H-indolizino[8,7-b]indoles by one-pot sequential reaction of tryptamines, alkyl propiolates and 3-phenacylideneoxindoles. The reaction mechanism involved generation of β-enamino ester, Michael addition and Pictet–Spengler cyclization process, which were stronger supported by the comparable experiments and characterization of the structures of the similar possible intermediates. This protocol has advantages of mild reaction conditions, easily accessible starting materials, easy purification of the products and wide range of substrates, which makes it a useful and attractive method for the synthesis of the complex indolizino[8,7-b]indoles in synthetic and medicinal chemistry.

Experimental section

1. General procedure for the one-pot synthesis of functionalized 2-pyrrolo-3-yloxindoles 1a–1d

A mixture of tryptamines (1.0 mmol) and methyl or ethyl propiolate (1.0 mmol) in 5.0 mL absolute ethanol was stirred at room temperature for 20 minutes. Then, 3-phenacylideneoxindole (1.0 mmol) and anhydrous zinc chloride (0.5 mmol) were added. The mixture was stirred at room temperature for additional twelve hours. The resulting precipitate was collected by filtration and washed with cold alcohol to give the pure product.

Methyl 1-(2-(1H-indol-3-yl)ethyl)-4-(5-chloro-2-oxoindolin-3-yl)-5-phenyl-1H-pyrrole-3-carboxylate (1a). White solid, 87%, m.p. 190–192 °C; ¹H NMR (600 MHz, DMSO-d₆) δ: keto-form: 10.82 (s, 1H, NH), 10.43 (s, 1H, NH), 7.67 (s, 1H, ArH), 7.52–7.51 (m, 3H, ArH), 7.45–7.44 (m, 2H, ArH), 7.31 (d, J = 8.4 Hz, 1H, ArH), 7.08–7.00 (m, 2H, ArH), 6.98 (brs, 1H, ArH), 6.90–6.86 (m, 1H, ArH), 6.83–6.79 (m, 1H, ArH), 4.20 (s, 1H, CH), 4.14–4.07 (m, 2H, CH), 3.38 (s, 3H, OCH₃), 3.01–2.96 (m, 1H, CH), 2.94–2.89 (m, 1H, CH); enol-form: 10.77 (s, 1H, NH), 10.09 (s, 1H, NH), 7.26 (d, J = 7.2 Hz, 2H, ArH), 7.16–7.15 (m, 3H, ArH), 6.90–6.86 (m, 2H, ArH), 6.52 (d, J = 8.4 Hz, 1H, ArH), 5.51 (s, 1H, CH), 3.90 (t, J = 7.2 Hz, 2H, CH), 3.78 (s, 3H, OCH₃), 2.85 (t, J = 7.2 Hz, 2H, CH); keto–enol = 4 : 1; ¹³C NMR (150 MHz, DMSO-d₆) δ: 177.7, 163.4, 142.0, 136.3, 136.0, 133.1, 130.8, 130.0, 128.8, 128.6, 128.1, 127.0, 126.8, 124.8, 123.0, 122.5, 121.0, 118.3, 117.9, 115.3, 111.3, 111.2, 110.2, 109.9, 56.0, 50.0, 48.2, 44.7, 26.8, 18.5; IR (KBr) ν: 3548, 3010, 2355, 1694, 1622, 1585, 1537, 1476, 1453, 1406, 1373, 1333, 1244, 1173, 1097, 1066, 1017, 884, 825 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₃₀H₂₄ClN₃NaO₃ ([M + Na]⁺): 532.1397. Found: 532.1398.

Methyl 1-(2-(1H-indol-3-yl)ethyl)-4-(1-benzyl-5-chloro-2-oxoindolin-3-yl)-5-p-tolyl-1H-pyrrole-3-carboxylate (1b). White solid, 92%, m.p. 149–151 °C; ¹H NMR (600 MHz, DMSO-d₆) δ: keto-form: 10.83 (brs, 1H, NH), 7.67 (s, 1H, ArH), 7.41–7.40 (m, 2H, ArH), 7.37–7.36 (m, 2H, ArH), 7.34–7.30 (m, 4H, ArH), 7.28–7.24 (m, 2H, ArH), 7.06–6.99 (m, 3H, ArH), 6.95–6.93 (m, 1H, ArH), 6.88 (t, J = 7.2 Hz, 2H, ArH), 6.81 (d, J = 8.4 Hz, 1H, ArH), 5.05–5.03 (m, 1H, CH), 4.79–4.76 (m, 1H, CH), 4.43 (s, 1H, CH), 4.12–4.11 (m, 2H, CH), 3.31 (s, 3H, OCH₃), 3.00–2.92 (m, 2H, CH), 2.39 (s, 3H, CH₃); enol-form: 10.77 (s, 1H, NH), 7.18 (d, J = 7.8 Hz, 6H, ArH), 7.12 (d, J = 7.2 Hz, 1H, ArH), 6.95–6.92 (m, 4H, ArH), 6.59 (d, J = 7.8 Hz, 1H, ArH), 6.55 (brs, 1H, ArH), 4.57–4.54 (m, 1H, CH), 4.15 (brs, 1H, CH), 3.89 (brs, 2H, CH), 3.79 (s, 3H, OCH₃), 2.86–2.84 (m, 2H, CH), 2.29 (s, 3H, CH₃). keto–enol = 4 : 1; ¹³C NMR (150 MHz, DMSO-d₆) δ: 176.0, 163.4, 142.5, 138.2, 136.5, 136.0, 136.0, 132.3, 130.8, 129.5, 128.5, 128.4, 128.0, 127.4, 127.2, 127.2, 127.0, 126.9, 126.8, 125.7, 123.0, 122.4, 120.9, 118.2, 118.0, 114.9, 113.0, 111.0, 110.2, 109.5, 50.1, 48.2, 44.2, 43.2, 26.8, 20.9; IR (KBr) ν: 3561, 2946, 2355, 1692, 1618, 1560, 1527, 1476, 1454, 1396, 1336, 1099, 1014, 930, 877, 815, 769 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₃₈H₃₂ClN₃NaO₃ ([M + Na]⁺): 636.2020. Found: 636.2024.

Methyl 1-(2-(1H-indol-3-yl)ethyl)-5-(4-chlorophenyl)-4-(5-methyl-2-oxoindolin-3-yl)-1H-pyrrole-3-carboxylate (1c). White solid, 85%, m.p. 190–192 °C; ¹H NMR (600 MHz, DMSO-d₆) δ: keto-form: 10.84 (s, 1H, NH), 10.19 (s, 1H, NH), 7.67 (s, 1H, ArH), 7.54 (d, J = 7.8 Hz, 2H, ArH), 7.41 (d, J = 7.8 Hz, 2H, ArH), 7.32 (d, J = 8.4 Hz, 1H, ArH), 7.06–7.01 (m, 2H, ArH), 6.97 (brs, 1H, ArH), 6.91–6.86 (m, 1H, ArH), 6.67 (d, J = 7.8 Hz, 1H, ArH), 6.59 (s, 1H, ArH), 4.13–4.11 (m, 3H, CH), 3.34 (s, 3H, OCH₃), 2.99–2.96 (m, 1H, CH), 2.94–2.90 (m, 1H, CH), 2.19 (s, 3H, CH₃); enol-form: 10.78 (s, 1H, NH), 9.88 (s, 1H, NH), 7.69 (brs, 1H, ArH), 7.28 (d, J = 8.4 Hz, 1H, ArH), 7.13 (brs, 2H, ArH), 6.71 (brs, 1H, ArH), 6.46 (d, J = 7.8 Hz, 1H, ArH), 5.43 (s, 1H, CH), 3.88 (t, J = 7.2 Hz, 2H, CH), 3.78 (s, 3H, OCH₃), 2.85 (t, J = 7.2 Hz, 2H, CH); keto–enol = 7 : 3; ¹³C NMR (150 MHz, DMSO-d₆) δ: 177.9, 177.1, 164.9, 163.4, 140.6, 136.1, 136.0, 134.7, 133.5, 132.5, 132.4, 130.9, 129.5, 129.2, 129.0, 128.8, 128.3, 127.6, 127.5, 127.3, 126.8, 126.7, 123.3, 123.0, 122.9, 121.0, 118.2, 118.1, 116.6, 111.6, 111.4, 111.3, 110.1, 108.4, 50.7, 49.8, 48.1, 47.7, 44.6, 42.9, 42.9, 26.8, 26.7, 20.7; IR (KBr) ν: 3548, 3231, 3005, 2930, 2895, 2335, 1689, 1626, 1556, 1458, 1428, 1397, 1335, 1243, 1120, 1091, 1011, 978, 876, 812 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₃₁H₂₆ClN₃NaO₃ ([M + Na]⁺): 546.1555. Found: 546.1555.

Ethyl 4-(5-chloro-2-oxoindolin-3-yl)-1-(2-(5-methoxy-1H-indol-3-yl)ethyl)-5-phenyl-1H-pyrrole-3-carboxylate (1d). White solid, 90%, m.p. 190–192 °C; ¹H NMR (600 MHz, DMSO-d₆) δ: keto-form: 10.67 (s, 1H, NH), 10.42 (s, 1H, NH), 7.72 (s, 1H, ArH), 7.50–7.51 (m, 1H, ArH), 7.49–7.45 (m, 2H, ArH), 7.42–7.40 (m, 1H, ArH), 7.23–7.20 (m, 1H, ArH), 7.18–7.15 (m, 1H, ArH), 6.94 (brs, 1H, ArH), 6.78 (d, J = 8.4 Hz, 1H, ArH), 6.76 (brs, 1H, ArH), 6.63 (brs, 1H, ArH), 4.37 (s, 1H, CH), 3.86 (t, J = 6.6 Hz, 2H, CH), 3.66 (s, 3H, OCH₃), 3.00–2.85 (m, 2H, CH), 0.97 (t, J = 7.2 Hz, 3H, CH₃); enol-form: 10.62 (s, 1H, NH), 10.06 (s, 1H, NH), 7.12 (brs, 1H, ArH), 7.06–7.05 (m, 1H, ArH), 6.87 (brs, 1H, ArH), 6.83 (brs, 1H, ArH), 6.66–6.65 (m, 1H, ArH), 6.51–6.49 (m, 2H, ArH), 5.51 (s, 1H, CH), 4.27 (t, J = 7.2 Hz, 2H, CH), 3.64 (s, 3H, OCH₃), 1.31 (t, J = 6.6 Hz, 3H, CH₃); keto–enol = 4 : 1; ¹³C NMR (150 MHz, DMSO-d₆) δ: 178.1, 163.5, 153.5, 142.4, 136.9, 133.6, 131.6, 131.2, 130.5, 129.2, 129.1, 128.4, 127.6, 127.4, 125.3, 124.1, 123.0, 115.4, 112.2, 111.9, 110.5, 110.4, 100.0, 58.9, 55.8, 48.6, 45.3, 27.3, 14.5; IR (KBr) ν: 3320, 3180, 3057, 2996, 2740, 1964, 1698, 1618, 1559, 1527, 1477, 1443, 1380, 1328, 1296, 1239, 1173, 1091, 1068, 1032, 927, 891, 765 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₃₂H₂₈ClN₃NaO₄ ([M + Na]⁺): 576.1665. Found: 576.1661.

2. General procedure for the one-pot synthesis of 6,11-dihydro-5H-indolizino[8,7-b]indoles 2a–2j

A mixture of tryptamines (1.0 mmol) and methyl or ethyl propiolate (1.0 mmol) in 5.0 mL absolute ethanol was stirred at room temperature for 20 minutes. Then, 3-phenacylideneoxindole (1.0 mmol) and anhydrous zinc chloride (0.5 mmol) were added. The mixture was stirred at room temperature for additional twelve hours. The solvent was removed by rotatory evaporation at reduced pressure. Acetic acid (5.0 mL) and trifluoromethanesulfonic acid (0.1 mmol) were added to the residue. The resulting mixture was heated to 60–70 °C for six hours. The solvent was removed at reduced pressure. The residue was subjected to preparative thin-layer chromatography with a mixture of light petroleum and ethyl acetate (v/v = 3 : 1) as developing reagent to give the pure product fro analysis.

Methyl 2-(5-chloro-2-oxoindolin-3-yl)-3-phenyl-6,11-dihydro-5H-indolizino[8,7-b]indole-1-carboxylate (2a). Brown solid, 68%, m.p. 282–284 °C; ¹H NMR (600 MHz, DMSO-d₆) δ: 10.94 (s, 1H, NH), 10.52 (s, 1H, NH), 7.65–7.51 (m, 7H, ArH), 7.19 (d, J = 8.4 Hz, 1H, ArH), 7.14 (d, J = 7.8 Hz, 1H, ArH), 7.05 (t, J = 7.2 Hz, 1H, ArH), 6.94 (s, 1H, ArH), 6.87 (d, J = 8.4 Hz, 1H, ArH), 4.38 (s, 1H, CH), 4.11–4.06 (m, 2H, CH), 3.34 (s, 3H, OCH₃), 3.18–3.10 (m, 2H, CH); ¹³C NMR (150 MHz, DMSO-d₆) δ: 177.9, 165.1, 141.6, 137.1, 136.0, 133.4, 130.7, 129.5, 128.9, 127.1, 126.0, 125.3, 125.1, 122.5, 122.3, 119.5, 118.5, 118.3, 114.9, 112.4, 110.1, 108.8, 106.4, 50.1, 45.1, 43.7, 19.9s; IR (KBr) ν: 3926, 3746, 2947, 2371, 2343, 1871, 1847, 1831, 1796, 1773, 1703, 1686, 1656, 1637, 1621, 1576, 1560, 1543, 1522, 1475, 1455, 1365, 1334, 1269, 1216, 1169, 1133, 1033, 895, 819, 788 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₃₀H₂₁ClN₃NaO₃ ([M + Na]⁺): 530.1232. Found: 530.1242.

Methyl 2-(5-fluoro-2-oxoindolin-3-yl)-3-p-tolyl-6,11-dihydro-5H-indolizino[8,7-b]indole-1-carboxylate (2b). Brown solid, 65%, m.p. 190–194 °C; ¹H NMR (600 MHz, DMSO-d₆) δ: 10.95 (s, 1H, NH), 10.45 (s, 1H, NH), 7.62 (d, J = 8.4 Hz, 1H, ArH), 7.55–7.54 (m, 2H, ArH), 7.49–7.48 (m, 1H, ArH), 7.38 (d, J = 7.8 Hz, 2H, ArH), 7.13 (t, J = 7.8 Hz, 1H, ArH), 7.05 (d, J = 7.8 Hz, 2H, ArH), 6.99–6.96 (m, 1H, ArH), 6.85–6.81 (m, 2H, ArH), 4.36 (s, 1H, CH), 4.09 (d, J = 7.2 Hz, 2H, CH), 3.32 (s, 3H, OCH₃), 3.16–3.09 (m, 2H, CH), 2.39 (s, 3H, CH₃); ¹³C NMR (150 MHz, DMSO-d₆) δ: 178.1, 165.2, 138.8, 138.4, 137.0, 136.0, 133.1, 130.6, 129.8, 129.4, 126.6, 126.0, 125.3, 122.3, 119.5, 118.3, 115.0, 113.3, 113.1, 112.4, 108.7, 106.5, 50.0, 45.4, 43.6, 28.9, 20.9, 19.9; IR (KBr) ν: 3615, 2922, 2852, 2367, 1712, 1618, 1483, 1454, 1366, 1332, 1267, 1180, 1138, 1114, 943, 814, 780 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₃₁H₂₄FN₃NaO₃ ([M + Na]⁺): 528.1682. Found: 528.1694.

Methyl 2-(5-chloro-2-oxoindolin-3-yl)-3-(4-methoxyphenyl)-6,11-dihydro-5H-indolizino[8,7-b]indole-1-carboxylate (2c). Brown solid, 68%, m.p. 190–191 °C; ¹H NMR (600 MHz, DMSO-d₆) δ: 10.93 (s, 1H, NH), 10.51 (s, 1H, NH), 7.62–7.51 (m, 4H, ArH), 7.19 (d, J = 8.4 Hz, 1H, ArH), 7.13–7.12 (m, 3H, ArH), 7.05 (t, J = 7.8 Hz, 1H, ArH), 6.93 (brs, 1H, ArH), 6.87 (d, J = 8.4 Hz, 1H, ArH), 4.37 (s, 1H, CH), 4.08 (d, J = 6.6 Hz, 2H, CH), 3.82 (s, 3H, OCH₃), 3.34 (s, 3H, OCH₃), 3.17–3.08 (m, 2H, CH), 2.39 (s, 3H, CH₃); ¹³C NMR (150 MHz, DMSO-d₆) δ: 178.0, 165.2, 159.7, 141.6, 137.0, 136.0, 133.5, 132.0, 129.8, 127.0, 126.1, 125.3, 125.1, 122.5, 122.3, 121.5, 119.5, 118.3, 114.8, 114.3, 112.4, 110.0, 108.7, 106.3, 55.2, 50.0, 45.2, 43.6, 19.9; IR (KBr) ν: 3055, 2949, 2838, 2374, 1712, 1687, 1615, 1592, 1500, 1476, 1452, 1365, 1332, 1268, 1249, 1214, 1174, 1136, 1115, 1087, 1032, 945, 886, 838, 814, 790 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₃₁H₂₄ClN₃NaO₄ ([M + Na]⁺): 560.1341; Found: 560.1361.

Methyl 8-methoxy-2-(2-oxoindolin-3-yl)-3-p-tolyl-6,11-dihydro-5H-indolizino[8,7-b]indole-1-carboxylate (2d). Brown solid, 67%, m.p. 198–200 °C; ¹H NMR (600 MHz, DMSO-d₆) δ: 10.82 (s, 1H, NH), 10.45 (s, 1H, NH), 7.52–7.51 (m, 3H, ArH), 7.39–7.37 (m, 2H, ArH), 7.14 (t, J = 7.2 Hz, 1H, ArH), 7.03 (brs, 1H, ArH), 6.91–6.90 (m, 1H, ArH), 6.86 (d, J = 8.4 Hz, 2H, ArH), 6.77–6.76 (m, 1H, ArH), 4.34 (s, 1H, CH), 4.08–4.07 (m, 2H, CH), 3.78 (s, 3H, OCH₃), 3.28 (s, 3H, OCH₃), 3.15–3.06 (m, 2H, CH), 2.39 (s, 3H, CH₃); ¹³C NMR (150 MHz, DMSO-d₆) δ: 183.6, 170.5, 159.0, 147.9, 143.6, 142.0, 136.4, 135.2, 134.7, 132.4, 131.9, 131.9, 130.9, 127.7, 126.3, 120.9, 118.4, 118.1, 113.9, 113.6, 111.7, 104.9, 60.5, 55.2, 50.3, 48.9, 26.1, 25.3; IR (KBr) ν: 3748, 2941, 2832, 2365, 1710, 1685, 1620, 1574, 1520, 1471, 1454, 1364, 1330, 1296, 1267, 1218, 1170, 1130, 1032, 964, 928, 822, 786, 751 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₃₂H₂₇N₃NaO₄ ([M + Na]⁺): 540.1884. Found: 540.1894.

Methyl 3-(4-chlorophenyl)-8-methoxy-2-(5-methyl-2-oxoindolin-3-yl)-6,11-dihydro-5H-indolizino[8,7-b]indole-1-carboxylate (2e). Brown solid, 70%, m.p. 196–198 °C; ¹H NMR (600 MHz, DMSO-d₆) δ: 10.82 (s, 1H, NH), 10.34 (s, 1H, NH), 7.65 (s, 4H, ArH), 7.52 (d, J = 8.4 Hz, 1H, ArH), 7.04 (s, 1H, ArH), 6.95–6.94 (m, 1H, ArH), 6.78–6.73 (m, 3H, ArH), 4.30 (s, 1H, CH), 4.09 (brs, 2H, CH), 3.78 (s, 3H, OCH₃), 3.29 (s, 3H, OCH₃), 3.15–3.08 (m, 2H, CH), 2.18 (s, 3H, CH₃); ¹³C NMR (150 MHz, DMSO-d₆) δ: 178.2, 165.2, 153.8, 140.2, 135.4, 133.7, 132.5, 131.2, 131.2, 130.3, 130.0, 129.0, 128.5, 127.4, 126.4, 125.6, 123.1, 116.2, 113.2, 113.0, 108.6, 108.5, 106.4, 99.6, 55.3, 50.0, 44.9, 43.7, 20.6, 20.0; IR (KBr) ν: 3687, 2947, 2392, 2355, 2330, 1841, 1711, 1649, 1624, 1573, 1555, 1537, 1518, 1488, 1472, 1453, 1365, 1331, 1296, 1269, 1220, 1171, 1135, 1032, 1013, 964, 818 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₃₂H₂₆ClN₃NaO₄ ([M + Na]⁺): 574.1497. Found: 574.1504.

Methyl 8-methoxy-2-(5-methyl-2-oxoindolin-3-yl)-3-p-tolyl-6,11-dihydro-5H-indolizino[8,7-b]indole-1-carboxylate (2f). Brown solid, 66%, m.p. 244–246 °C; ¹H NMR (600 MHz, DMSO-d₆) δ: 10.81 (s, 1H, NH), 10.27 (s, 1H, NH), 7.50 (brs, 3H, ArH), 7.38 (brs, 2H, ArH), 7.03 (brs, 1H, ArH), 6.94 (brs, 1H, ArH), 6.78–6.72 (m, 3H, ArH), 4.31 (brs, 1H, CH), 4.08 (brs, 2H, CH), 3.78 (s, 3H, OCH₃), 3.10 (brs, 2H, CH), 2.37 (s, 3H, CH₃), 2.18 (s, 3H, CH₃); ¹³C NMR (150 MHz, DMSO-d₆) δ: 178.3, 165.3, 153.8, 140.2, 138.3, 136.7, 131.3, 131.2, 130.0, 130.0, 129.4, 127.4, 126.7, 126.6, 125.7, 123.1, 115.8, 113.2, 112.8, 108.4, 106.5, 99.6, 56.0, 55.3, 49.9, 45.0, 43.7, 20.8, 20.6, 20.0, 18.5; IR (KBr) ν: 3818, 3747, 3029, 2919, 1710, 1687, 1623, 1591, 1543, 1491, 1474, 1455, 1366, 1332, 1296, 1265, 1277, 1134, 1110, 1031, 963, 817 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₃₃H₂₉N₃NaO₄ ([M + Na]⁺): 554.2041. Found: 554.2050.

Methyl 8-methoxy-2-(5-methyl-2-oxoindolin-3-yl)-3-phenyl-6,11-dihydro-5H-indolizino[8,7-b]indole-1-carboxylate (2g). Brown solid, 63%, m.p. 208–210 °C; ¹H NMR (600 MHz, DMSO-d₆) δ: 10.84 (s, 1H, NH), 10.33 (s, 1H, NH), 7.65–7.57 (m, 4H, ArH), 7.53–7.51 (m, 2H, ArH), 7.04 (brs, 1H, ArH), 6.94 (d, J = 7.8 Hz, 1H, ArH), 6.78–6.74 (m, 3H, ArH), 4.31 (s, 1H, CH), 4.12–4.09 (m, 2H, CH), 3.78 (s, 3H, OCH₃), 3.30 (s, 3H, OCH₃), 3.15–3.08 (m, 2H, CH), 2.18 (s, 3H, CH₃); ¹³C NMR (150 MHz, DMSO-d₆) δ: 178.3, 165.3, 153.7, 140.2, 136.7, 131.2, 131.1, 130.1, 129.9, 129.6, 128.9, 128.8, 127.4, 126.5, 123.1, 115.9, 113.3, 112.9, 108.5, 108.4, 106.5, 99.5, 55.2, 50.0, 45.0, 43.7, 20.6, 20.0; IR (KBr) ν: 3346, 2947, 1716, 1624, 1575, 1489, 1455, 1365, 1268, 1136, 964, 810 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₃₂H₂₇ClN₃NaO₄ ([M + Na]⁺): 540.1891. Found: 540.1894.

Methyl 2-(5-fluoro-2-oxoindolin-3-yl)-8-methoxy-3-p-tolyl-6,11-dihydro-5H-indolizino[8,7-b]indole-1-carboxylate (2h). Brown solid, 71%, m.p. 189–191 °C; ¹H NMR (600 MHz, DMSO-d₆) δ: 10.84 (s, 1H, NH), 10.44 (s, 1H, NH), 7.53–7.48 (m, 3H, ArH), 7.38–7.37 (m, 2H, ArH), 7.03 (brs, 1H, ArH), 6.97 (t, J = 7.8 Hz, 1H, ArH), 6.84–6.76 (m, 3H, ArH), 4.35 (s, 1H, CH), 4.07 (brs, 2H, CH), 3.78 (s, 3H, OCH₃), 3.35 (s, 3H, OCH₃), 3.11–3.08 (m, 2H, CH), 2.39 (s, 3H, CH₃); ¹³C NMR (150 MHz, DMSO-d₆) δ: 178.2, 165.2, 153.8, 138.8, 138.4, 136.9, 133.2, 133.1, 131.2, 130.6, 130.1, 129.4, 126.6, 126.6, 125.6, 114.9, 113.3, 113.2, 113.2, 112.9, 110.4, 109.3, 109.2, 108.5, 106.3, 99.6, 55.3, 50.0, 45.5, 43.7, 20.9, 20.0; IR (KBr) ν: 3747, 2949, 2833, 2372, 2309, 1869, 1845, 1714, 1685, 1653, 1623, 1575, 1541, 1521, 1484, 1456, 1383, 1365, 1331, 1396, 1268, 1219, 1186, 1135, 1032, 962, 819, 777, 750 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₃₂H₂₆FN₃NaO₄ ([M + Na]⁺): 558.1792. Found: 558.1800.

Methyl 2-(5-chloro-2-oxoindolin-3-yl)-8-methoxy-3-(4-methoxyphenyl)-6,11-dihydro-5H-indolizino[8,7-b]indole-1-carboxylate (2i). Brown solid, 65%, m.p. 270–272 °C; ¹H NMR (600 MHz, DMSO-d₆) δ: 10.83 (s, 1H, NH), 10.55 (s, 1H, NH), 7.59–7.49 (m, 3H, ArH), 7.20 (d, J = 7.8 Hz, 1H, ArH), 7.13 (brs, 2H, ArH), 7.03 (brs, 1H, ArH), 6.94 (s, 1H, ArH), 6.87 (d, J = 7.8 Hz, 1H, ArH), 6.77 (dd, J₁ = 1.8 Hz, J₂ = 1.2 Hz, 1H, ArH), 4.37 (s, 1H, CH), 4.06 (t, J = 7.2 Hz, 2H, CH), 3.82 (s, 3H, OCH₃), 3.78 (s, 3H, OCH₃), 3.32 (s, 3H, OCH₃), 3.15–3.05 (m, 2H, CH); ¹³C NMR (150 MHz, DMSO-d₆) δ: 178.0, 165.1, 159.7, 153.8, 141.6, 136.9, 133.5, 132.0, 131.2, 123.0, 127.0, 126.6, 125.7, 125.1, 122.4, 121.5, 114.8, 114.3, 113.2, 112.9, 110.0, 108.4, 106.1, 99.6, 55.3, 55.2, 50.0, 45.2, 43.6, 20.0; IR (KBr) ν: 3616, 3167, 2950, 2833, 2369, 1709, 1682, 1619, 1592, 1574, 1500, 1475, 1454, 1364, 1333, 1290, 1268, 1249, 1222, 1174, 1132, 1032, 966, 882, 838, 816, 780 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₃₂H₂₆ClN₃NaO₅ ([M + Na]⁺): 590.1445. Found: 590.1457.

Ethyl 2-(5-chloro-2-oxoindolin-3-yl)-8-methoxy-3-phenyl-6,11-dihydro-5H-indolizino[8,7-b]indole-1-carboxylate (2j). Brown solid, 65%, m.p. 197–199 °C; ¹H NMR (600 MHz, DMSO-d₆) δ: 10.94 (s, 1H, NH), 10.57 (s, 1H, NH), 7.65 (brs, 1H, ArH), 7.57–7.52 (m, 5H, ArH), 7.21 (d, J = 7.2 Hz, 1H, ArH), 7.04–6.98 (m, 2H, ArH), 6.86–6.77 (m, 2H, ArH), 4.38 (s, 1H, CH), 4.08 (brs, 2H, CH), 3.90–3.86 (m, 2H, CH), 3.78 (s, 3H, OCH₃), 3.12 (brs, 2H, CH), 0.84 (s, 3H, CH₃); ¹³C NMR (150 MHz, DMSO-d₆) δ: 177.9, 164.7, 153.8, 141.5, 137.1, 133.5, 131.1, 130.7, 130.4, 129.6, 128.9, 127.0, 126.6, 125.6, 125.1, 122.5, 114.6, 113.2, 113.0, 110.2, 108.6, 106.7, 99.6, 59.1, 55.3, 45.3, 43.8, 20.0, 13.7; IR (KBr) ν: 3448, 3187, 2982, 2827, 2366, 1711, 1620, 1574, 1475, 1450, 1371, 1332, 1299, 1264, 1221, 1172, 1130, 1073, 1029, 921, 884, 843, 820, 790, 770 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₃₂H₂₆ClN₃NaO₄ ([M + Na]⁺): 574.1499. Found: 574.1504.

3. General procedure for the one-pot synthesis of functionalized succinates 3a–3b

A mixture of tryptamines (1.0 mmol) and methyl or ethyl propiolate (1.0 mmol) in 5.0 mL absolute ethanol was stirred at room temperature for 20 minutes. Then, ethyl 2-(2-oxoindolin-3-ylidene)acetates (1.0 mmol) and anhydrous zinc chloride (0.5 mmol) were added. The mixture was stirred at room temperature for additional twelve hours. The solvent was removed at reduced pressure. The residue was subjected to preparative thin-layer chromatography with a mixture of light petroleum and ethyl acetate (v/v = 3 : 1) as developing reagent to give the pure product.

4-Ethyl 1-methyl 2-((2-(1H-indol-3-yl)ethylamino)methylene)-3-(5-fluoro-2-oxoindolin-3-yl)succinate (3a). White solid, 60%, m.p. 70–71 °C; ¹H NMR (600 MHz, DMSO-d₆) δ: 10.83 (s, 1H, NH), 10.39 (s, 1H, NH), 8.02 (brs, 1H, NH), 7.53 (d, J = 7.2 Hz, 1H, ArH), 7.32 (d, J = 8.4 Hz, 1H, ArH), 7.11 (s, 1H, ArH), 7.06 (d, J = 8.4 Hz, 1H, ArH), 7.00–6.96 (m, 1H, ArH), 6.89 (d, J = 13.2 Hz, 1H, ArH), 6.74–6.73 (m, 1H, ArH), 4.11 (t, J = 6.6 Hz, 2H, CH), 3.91–3.80 (m, 2H, CH), 3.40–3.36 (m, 2H, CH), 3.31 (s, 3H, OCH₃), 2.83 (t, J = 6.0 Hz, 2H, CH), 1.60 (t, J = 6.6 Hz, 3H, CH₃); ¹³C NMR (150 MHz, DMSO-d₆) δ: 177.2, 172.7, 168.0, 158.1, 156.5, 153.8, 139.2, 136.2, 129.2, 129.1, 127.0, 122.8, 120.9, 118.3, 118.2, 114.0, 113.8, 113.7, 113.6, 111.3, 110.9, 109.5, 109.4, 87.2, 60.3, 56.0, 49.6, 48.7, 48.6, 46.0, 27.1, 18.5, 14.0; IR (KBr) ν: 3307, 2917, 2849, 1715, 1668, 1607, 1484, 1445, 1381, 1308, 1227, 1193, 1183, 1040, 932 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₆H₂₆FN₃NaO₅ ([M + Na]⁺): 502.1760. Found: 502.1749.

4-Ethyl 1-methyl 2-((2-(1H-indol-3-yl)ethylamino)methylene)-3-(1-butyl-5-fluoro-2-oxoindolin-3-yl)succinate (3b). White solid, 65%, m.p. 102–103 °C; ¹H NMR (600 MHz, DMSO-d₆) δ: 10.84 (s, 1H, NH), 8.01–7.99 (m, 1H, NH), 7.52 (d, J = 7.8 Hz, 1H, ArH), 7.32 (d, J = 7.8 Hz, 1H, ArH), 7.11–7.05 (m, 4H, ArH), 6.97–6.93 (m, 2H, ArH), 6.83 (d, J = 13.2 Hz, 1H, ArH), 4.15–4.10 (m, 2H, CH), 3.97 (d, J = 4.8 Hz, 1H, CH), 3.85 (d, J = 5.4 Hz, 1H, CH), 3.68–3.63 (m, 1H, CH), 3.59–3.51 (m, 1H, CH), 3.39–3.34 (m, 2H, CH), 3.29 (s, 3H, OCH₃), 2.82 (t, J = 7.2 Hz, 2H, CH), 1.47 (t, J = 7.8 Hz, 3H, CH), 1.25–1.21 (m, 2H, CH), 1.16 (t, J = 7.2 Hz, 3H, CH₃), 0.85 (t, J = 7.8 Hz, 3H, CH); ¹³C NMR (150 MHz, DMSO-d₆) δ: 175.1, 172.6, 168.0, 158.4, 156.9, 153.8, 140.2, 136.3, 128.5, 128.4, 127.0, 122.7, 121.0, 118.2, 114.0, 113.9, 113.8, 113.7, 111.3, 110.8, 108.7, 108.6, 86.9, 60.4, 48.5, 48.7, 48.1, 46.4, 29.0, 27.1, 19.3, 14.0, 13.4; IR (KBr) ν: 3315, 2917, 2850, 1730, 1684, 1665, 1616, 1486, 1465, 1382, 1207, 1227, 1198, 1152, 1102, 1039, 1001, 889 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₃₀H₃₄FN₃NaO₅ ([M + Na]⁺): 558.2386. Found: 558.2375.

4. General procedure for the one-pot synthesis of functionalized 2-pyrrolo-3-yloxindoles 4a–4f

A mixture of arylamine (1.0 mmol) and methyl propiolate (1.0 mmol) in 5.0 mL absolute ethanol was stirred at room temperature for 24 hours. Then, 3-phenacylideneoxindole (0.8 mmol) and anhydrous zinc chloride (0.5 mmol) were added. The mixture was refluxed for six hours. The solvent was removed under reduced pressure. The residue was titrated with alcohol to give the pure product.

Methyl 5-(4-chlorophenyl)-4-(2-oxoindolin-3-yl)-1-p-tolyl-1H-pyrrole-3-carboxylate (4a). White solid, 76%, m.p. 250–252 °C; ¹H NMR (400 MHz, DMSO-d₆) δ: keto-form: 10.39 (s, 1H, NH), 7.70 (s, 1H, CH), 7.43 (d, J = 8.4 Hz, 2H, ArH), 7.28 (d, J = 8.4 Hz, 2H, ArH), 7.19 (d, J = 8.4 Hz, 2H, ArH), 7.13 (d, J = 8.0 Hz, 2H, ArH), 7.03–7.00 (m, 1H, ArH), 6.94 (d, J = 7.2 Hz, 1H, ArH), 6.85 (t, J = 8.4 Hz, 2H, ArH), 4.35 (s, 1H, CH), 3.37 (s, 3H, OCH₃), 2.30 (s, 3H, CH₃); enol-form: 10.13 (s, 1H, NH), 7.73 (s, 1H, CH), 7.43 (d, J = 8.4 Hz, 2H, ArH), 7.28 (d, J = 8.4 Hz, 2H, ArH), 7.19 (d, J = 8.4 Hz, 2H, ArH), 7.13 (d, J = 8.0 Hz, 2H, ArH), 7.03–7.00 (m, 1H, ArH), 6.94 (d, J = 7.2 Hz, 1H, ArH), 6.85 (t, J = 8.4 Hz, 2H, ArH), 5.55 (s, 1H, CH), 3.79 (s, 3H, OCH₃), 2.21 (s, 3H, CH₃). Keto–enol = 3 : 1. ¹³C NMR (100 MHz, DMSO-d₆) δ: 128.3, 163.7, 143.5, 137.6, 136.5, 135.1, 133.5, 132.7, 131.0, 130.2, 130.0, 129.4, 129.3, 129.1, 127.7, 125.8, 123.1, 121.3, 118.1, 113.0, 109.2, 50.6, 45.0, 20.9; IR (KBr) ν: 3135, 3080, 3033, 2944, 2891, 2843, 1701, 1653, 1618, 1519, 1457, 1253, 1232, 1197, 1105, 1085, 879, 831, 752 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₇H₂₁ClN₂O₃ ([M + Na]⁺): 479.1140. Found: 479.1133.

Methyl 4-(5-chloro-2-oxoindolin-3-yl)-5-(4-methoxyphenyl)-1-p-tolyl-1H-pyrrole-3-carboxylate (4b). White solid, 74%, m.p. 250–253 °C; ¹H NMR (400 MHz, DMSO-d₆) δ: keto-form: 10.50 (s, 1H, NH), 7.66 (s, 1H, CH), 7.21–7.15 (m, 7H, ArH), 6.97 (brs, 2H, ArH), 6.92 (d, J = 8.4 Hz, 2H, ArH), 6.83 (d, J = 8.4 Hz, 1H, ArH), 4.36 (s, 1H, CH), 3.73 (s, 3H, OCH₃), 3.41 (s, 3H, OCH₃), 2.29 (s, 3H, CH₃); enol-form: 10.18 (s, 1H, NH), 7.13 (brs, 1H, ArH), 7.80 (d, J = 7.6 Hz, 2H, ArH), 7.01 (brs, 1H, ArH), 6.63 (d, J = 8.4 Hz, 2H, ArH), 6.45 (d, J = 8.0 Hz, 2H, ArH), 5.56 (s, 1H, CH), 3.81 (s, 3H, OCH₃), 3.64 (s, 3H, OCH₃), 2.24 (s, 3H, CH₃). Keto–enol = 5 : 1. ¹³C NMR (100 MHz, CDCl₃) δ: 178.1, 163.8, 159.5, 142.5, 137.4, 136.8, 136.6, 133.4, 132.4, 130.0, 128.7, 127.5, 125.8, 125.3, 123.1, 122.5, 116.6, 114.4, 113.3, 110.5, 55.5, 50.6, 45.2, 20.9; IR (KBr) ν: 3178, 3123, 3034, 2946, 2918, 2860, 1698, 1625, 1518, 1490, 1248, 1204, 1123, 1096, 1024, 836, 810 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₈H₂₃ClN₂O₄ ([M + Na]⁺): 509.1235. Found: 509.1239.

Methyl 4-(5-chloro-2-oxoindolin-3-yl)-1,5-bis(4-methoxyphenyl)-1H-pyrrole-3-carboxylate (4c). White solid, 80%, m.p. 245–248 °C; ¹H NMR (400 MHz, DMSO-d₆) δ: keto-form: 10.49 (s, 1H, NH), 7.63 (s, 1H, CH), 7.21–7.18 (m, 5H, ArH), 6.97 (brs, 1H, ArH), 6.93–6.91 (m, 4H, ArH), 6.88 (d, J = 8.0 Hz, 1H, ArH), 4.34 (s, 1H, CH), 3.75 (s, 3H, OCH₃), 3.72 (s, 3H, OCH₃), 3.41 (s, 3H, OCH₃); enol-form: 10.17 (s, 1H, NH), 7.05 (d, J = 8.4 Hz, 2H, ArH), 6.64 (d, J = 8.4 Hz, 2H, ArH), 6.50 (m, 5H, ArH), 5.56 (s, 1H, CH), 3.81 (s, 3H, OCH₃), 3.70 (s, 3H, OCH₃), 3.63 (s, 3H, OCH₃). Keto–enol = 5 : 1. ¹³C NMR (100 MHz, DMSO-d₆) δ: 178.1, 163.8, 159.5, 158.7, 142.5, 136.8, 133.5, 132.5, 132.2, 128.8, 127.5, 127.5, 127.4, 125.3, 123.1, 122.5, 116.4, 114.6, 114.4, 113.1, 110.5, 55.8, 55.5, 50.6, 45.3; IR (KBr) ν: 3309, 3123, 3002, 2932, 2836, 1733, 1699, 1653, 1616, 1558, 1540, 1508, 1251, 1199, 1177, 1094, 1027, 813 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₈H₂₃ClN₂O₅ ([M + Na]⁺): 525.1184. Found: 525.1188.

Methyl 4-(5-chloro-2-oxoindolin-3-yl)-1,5-dip-tolyl-1H-pyrrole-3-carboxylate (4d). White solid, 70%, m.p. 240–242 °C; ¹H NMR (400 MHz, DMSO-d₆) δ: keto-form: 10.50 (s, 1H, NH), 7.67 (s, 1H, CH), 7.19–7.12 (m, 8H, ArH), 6.96 (brs, 1H, ArH), 6.83 (d, J = 8.4 Hz, 1H, ArH), 4.37 (s, 1H, CH), 3.41 (s, 3H, OCH₃), 2.29 (s, 3H, CH₃), 2.27 (s, 3H, CH₃); enol-form: 10.21 (s, 1H, NH), 7.12 (brs, 1H, ArH), 7.08 (d, J = 8.0 Hz, 2H, ArH), 6.70 (brs, 2H, ArH), 6.79 (d, J = 7.2 Hz, 2H, ArH), 6.64 (d, J = 8.0 Hz, 1H, ArH), 6.42 (d, J = 6.8 Hz, 2H, ArH), 5.59 (s, 1H, CH), 3.81 (s, 3H, OCH₃), 2.24 (s, 3H, CH₃), 2.15 (s, 3H, CH₃). Keto–enol = 5 : 1. ¹³C NMR (100 MHz, DMSO-d₆) δ: 178.0, 163.8, 142.5, 138.0, 137.4, 136.7, 136.7, 133.4, 131.0, 130.0, 129.6, 128.9, 127.5, 127.4, 125.9, 125.3, 123.1, 116.7, 113.4, 110.5, 56.5, 50.7, 45.2, 21.2, 20.9, 19.0; IR (KBr) ν: 3341, 3184, 3130, 3034, 2948, 2921, 2857, 1695, 1653, 1618, 1558, 1518, 1476, 1257, 1231, 1199, 1113, 1091, 823 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₈H₂₃ClN₂O₃ ([M + Na]⁺): 493.1258. Found: 493.1397.

Methyl 4-(5-fluoro-2-oxoindolin-3-yl)-1-(4-methoxyphenyl)-5-p-tolyl-1H-pyrrole-3-carboxylate (4e). White solid, 76%, m.p. 245–248 °C; ¹H NMR (400 MHz, DMSO-d₆) δ: keto-form: 10.38 (s, 1H, NH), 7.64 (s, 1H, CH), 7.19–7.16 (m, 6H, ArH), 6.97–6.90 (m, 3H, ArH), 6.82–6.78 (m, 2H, ArH), 4.34 (s, 1H, CH), 3.75 (s, 3H, OCH₃), 3.40 (s, 3H, OCH₃), 2.27 (s, 3H, CH₃); enol-form: 10.10 (s, 1H, NH), 7.04 (d, J = 8.4 Hz, 2H, ArH), 6.83 (brs, 2H, ArH), 6.61 (brs, 1H, ArH), 6.44 (d, J = 7.2 Hz, 1H, ArH), 5.60 (s, 1H, CH), 3.81 (s, 3H, OCH₃), 3.70 (s, 3H, OCH₃), 2.14 (s, 3H, CH₃). Keto–enol = 5 : 1. ¹³C NMR (100 MHz, DMSO-d₆) δ: 178.3, 163.8, 158.8, 157.1, 139.7, 138.0, 136.9, 132.2, 131.0, 129.5, 129.0, 127.5, 127.4, 116.6, 114.6, 114.5, 113.8, 113.6, 113.3, 111.1, 110.9, 109.7, 109.6, 55.7, 50.6, 45.6, 21.2; IR (KBr) ν: 3178, 3139, 2948, 2920, 2867, 2838, 1703, 1653, 1627, 1611, 1559, 1515, 1483, 1459, 1296, 1249, 1235, 1197, 1124, 1105, 1082, 1033, 928, 828 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₈H₂₃FN₂O₄ ([M + Na]⁺): 493.1529. Found: 493.1534.

Methyl 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-4-(5-methyl-2-oxoindolin-3-yl)-1H-pyrrole-3-carboxylate (4f). White solid, 77%, m.p. 230–232 °C; ¹H NMR (600 MHz, CDCl₃) δ: keto-form: 8.58 (s, 1H, NH), 7.56 (s, 1H, CH), 7.28–7.27 (m, 3H, ArH), 7.05 (d, J = 8.4 Hz, 2H, ArH), 6.96 (d, J = 7.8 Hz, 1H, ArH), 6.83 (d, J = 8.4 Hz, 2H, ArH), 6.79 (d, J = 7.8 Hz, 1H, ArH), 6.73–6.72 (m, 2H, ArH), 4.61 (s, 1H, CH), 3.80 (s, 3H, OCH₃), 3.46 (s, 3H, OCH₃), 2.25 (s, 3H, CH₃); enol-form: 8.41 (s, 1H, NH), 7.25 (brs, 2H, ArH), 6.99 (brs, 1H, ArH), 6.20 (d, J = 9.0 Hz, 1H, ArH), 6.87 (d, J = 8.4 Hz, 2H, ArH), 6.62 (d, J = 7.8 Hz, 1H, ArH), 6.52 (d, J = 7.8 Hz, 2H, ArH), 5.80 (s, 1H, CH), 3.89 (s, 3H, OCH₃), 3.74 (s, 3H, OCH₃), 2.27 (s, 3H, CH₃). Keto–enol = 3 : 1; ¹³C NMR (100 MHz, DMSO-d₆) δ: 178.3, 163.7, 158.8, 141.0, 135.2, 133.5, 132.7, 132.5, 131.9, 131.1, 130.1, 129.5, 129.4, 129.0, 127.9, 127.8, 127.8, 127.4, 123.8, 117.9, 114.8, 114.6, 113.7, 109.0, 55.8, 50.6, 45.1, 21.1; IR (KBr) ν: 3197, 3077, 3038, 2945, 2918, 2864, 1703, 1652, 1624, 1558, 1520, 1490, 1252, 1201, 1117, 1093, 818, 773 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₈H₂₃ClN₂O₄ ([M + Na]⁺): 509.1238. Found: 509.1239.

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (Grant no. 21272200) and the Priority Academic Program Development of Jiangsu Higher Education Institutions. We also thank Analysis and Test Center of Yangzhou University providing instruments for analysis.

References

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Footnote

† Electronic supplementary information (ESI) available: ¹H and ¹³C NMR spectra for all new compounds are available. CCDC 1013721–1013724, 1022835 and 1022862. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra10355f

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