Convenient synthesis of functionalized pyrrolo[3,4-b]pyridines and pyrrolo[3,4-b]quinolines via three-component reactions

Abstract

A simple protocol for convenient construction of pyrrolo[3,4-b]pyridine skeleton was successfully developed by base promoted three-component reaction of β-enamino imide, aromatic aldehydes and malononitrile as well as its ester and amide derivatives. The similar three-component reaction of β-enamino imide, aromatic aldehydes and cyclic diketones such as dimedone and cyclohexane-1,3-dione afforded functionalized pyrrolo[3,4-b]quinolines in good yields.

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Introduction

Pyrrolo[3,4-b]pyridine is the core structure of many pharmacological agents and natural alkaloids displaying promising biological activities as indole and purine bioisosteres.¹ Several pyrrolo[2,3-b]pyridines have been reported as selective inhibitors of different isoforms of Janus kinase (JAK).² Particularly, moxifloxacin is one of the most widely used fourth generation fluoroquinolones antibacterial agents with well tolerated drug developed by Bayer AG.³ As a consequence, many efficient synthetic methods and elegant procedures have been developed for the construction of pyrrolo[3,4-b]pyridine system and its functionalized derivatives.^4–7 The reported synthetic methods for pyrrolo[2,3-b]pyridines were mostly started from the substituted pyridine precursors, while the syntheses starting from pyrrole precursors were not attracted much attention. Recently, we reported that β-enamino ester generated in situ from the addition of arylamine to dialkyl acetylenedicarboxylate reacted with aromatic aldehydes and malononitrile to give polysubstituted 1,4-dihydropyridine derivatives.⁸ In these years, the reactive β-enamino esters generated from the addition of aliphatic and aromatic amines to electron-deficient alkynes have been emerged as one of most valuable tools for the preparation of structurally diverse carbocyclic and heterocyclic molecules.^9–12 In this respect, β-enamino imide, which could be easily formed from the sequential reaction of dimethyl acetylenedicarboxylate with arylamine and methylamine,¹³ maintains the structural character of β-enaminone and β-enamino ester, is also proved to be one of potential synthons for construction of diverse heterocyclic systems.¹⁴ In continuation of our aim of developing domino multicomponent reaction for versatile nitrogen-containing heterocyclic systems,^15,16 herein we wish to provide one efficient synthetic procedure for the synthesis of functionalized pyrrolo[3,4-b]pyridines and pyrrolo[3,4-b]quinolines by the three-component reactions of 3-arylamino-1-methyl-1H-pyrrole-2,5-diones with aromatic aldehydes and reactive methylene compounds such as malononitrile and dimedone.

Results and discussion

According to our previously established reaction conditions for the synthesis of 1,4-dihydropyridines by the reaction of aromatic aldehydes, malononitrile and β-enamino esters,^8a,13d an equivalent amount of 3-arylamino-1-methyl-1H-pyrrole-2,5-dione, aromatic aldehyde and malononitrile in ethanol in the presences of triethylamine as base catalyst was refluxed for about five hours, the expected pyrrolo[3,4-b]pyridines 1a–1j were obtained in satisfactory yields (Table 1, entries 1–10). It should be pointed out that the reaction afforded very pure products after filtration and no need further separation with chromatography. When ethyl cyanoacetate and cyanoacetamide were employed in the reaction, the corresponding functionalized pyrrolo[3,4-b]pyridines 1k–1p were also obtained in good yields (Table 1, entries 11–17). These results indicated that this three-component reaction has a wide variety of substrates and with high efficiency. The structures of the products 1a–1p were fully characterized by spectroscopic methods. The single crystal structures of the compounds 1a (Fig. 1) and 1p (Fig. S1†) were determined by X-ray diffraction method. It is interesting to find that 1,4-dihydropyridyl ring exists in a slightly distortional plane and the two aryl groups at 1,4-positions stretched to the same side of ring.

Table 1 Synthesis of 4,5,6,7-tetrahydro-1H-pyrrolo[3,4-b]pyridines 1a–1q^a

Entry	Compd	R (Ar)	Ar′	E	Yield^b (%)
a Reaction conditions: β-enamino imide (0.5 mmol), aromatic aldehyde (0.5 mmol) and malononitrile (0.5 mmol), Et3N (0.5 mmol), EtOH (15.0 mL), reflux, 5 h.b Isolated yields.
1	1a	Bn	p-CH3C6H4	CN	90
2	1b	Bn	p-CH3OC6H4	CN	88
3	1c	Bn	p-ClC6H4	CN	81
4	1d	p-CH3C6H4	p-CH3C6H4	CN	92
5	1e	p-CH3C6H4	p-ClC6H4	CN	65
6	1f	p-CH3C6H4	p-BrC6H4	CN	70
7	1g	p-ClC6H4	C6H5	CN	72
8	1h	p-ClC6H4	p-ClC6H4	CN	95
9	1i	p-BrC6H4	C6H5	CN	85
10	1j	p-BrC6H4	p-ClC6H4	CN	75
11	1k	p-CH3C6H4	m-NO2C6H4	CO2Et	62
12	1l	p-ClC6H4	m-NO2C6H4	CO2Et	52
13	1m	p-BrC6H4	m-NO2C6H4	CO2Et	78
14	1n	Bn	C6H5	CONH2	55
15	1o	Bn	p-ClC6H4	CONH2	68
16	1p	p-CH3C6H4	p-ClC6H4	CONH2	85
17	1q	p-BrC6H4	p-ClC6H4	CONH2	82

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Fig. 1 ORTEP-drawings of the crystal structures of 1a.

For further demonstrating the synthetic values of β-enamino imide, the similar three-component reaction of 3-arylamino-1-methyl-1H-pyrrole-2,5-dione, aromatic aldehydes and dimedone was also investigated. When the reaction was carried out in ethanol with triethylamine, DABCO, DBU and K₂CO₃ as base promoter, the reaction resulted in complicate mixture of products. Then, some acid was employed in the reaction. After careful examination, we were pleased to find that the chain products 2a and 2b can be obtained in good yields when the reaction is conducted in ethanol at room temperature by using acetic acid as promoter (Scheme 1). The single crystal structure of the compound 2b was successfully determined by X-ray diffraction method (Fig. 2). The products 2a and 2b obviously came from the addition of β-enamino imide to the in situ generated arylidene dimedone. However, the further annulation process was not accomplished under the above mentioned reaction conditions.

Scheme 1 Synthesis of chain products 2a and 2b from three-component reaction.

Fig. 2 ORTEP-drawings of the crystal structures of 2b.

In order to get the annulation product, the harsh reaction conditions were employed in the three-component reaction. When the three-component reaction was carried out with acetic acid both as catalyst and solvent at about 100 °C for ten hours, all cyclization reaction proceeded smoothly and the expected functionalized pyrrolo[3,4-b]quinolines 3a–3j were obtained in moderate to good yields (Table 2). The structures of pyrrolo[3,4-b]quinolines 3a–3j were established by HRMS, IR, ¹H and ¹³C NMR spectra, and were further confirmed by single-crystal X-ray diffraction studies performed for compounds 3a (Fig. 3), 3g and 3j (Fig. S2 and S3†).

Table 2 Synthesis of 5,6,7,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline 3a–3j^a

Entry	Compd	Ar	Ar′	R	Yield^b (%)
a Reaction conditions: β-enamino imide (0.5 mmol), aromatic aldehyde (0.5 mmol), dimedone (0.5 mmol), AcOH (10.0 mL), reflux, 10 h.b Isolated yields.
1	3a	p-CH3C6H4	C6H5	H	74
2	3b	p-CH3C6H4	p-CH3C6H4	CH3	80
3	3c	p-CH3C6H4	p-(CH3)3CC6H4	CH3	66
4	3d	p-CH3C6H4	p-NO2C6H4	CH3	74
5	3e	p-CH3C6H4	p-NO2C6H4	H	78
6	3f	p-CH3OC6H4	C6H5	H	70
7	3g	p-CH3OC6H4	p-NO2C6H4	CH3	72
8	3h	p-ClC6H4	p-CH3C6H4	H	72
9	3i	p-ClC6H4	p-NO2C6H4	CH3	75
10	3j	p-BrC6H4	p-CH3C6H4	H	68

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Fig. 3 ORTEP-drawings of the crystal structures of 3a.

Another common cyclic 1,3-dikeone, 4-hydroxy-2H-chromen-2-one, was also employed in the three-component reaction. The chain products 4a and 4b could be obtained in good yields when the three-component reaction was carried out in ethanol at room temperature with acetic acid as catalyst (Scheme 2). However, when the reaction was carried out in refluxing acetic acid, the expected annulated cyclic products did not formed and the chain products were observed to decompose slowly to give complicate mixture. We could not get the desired cyclized products after testing many different reaction conditions. This result displays that the sequential cyclization process is very sensitive to the structure of the substrates and reaction conditions.

Scheme 2 Synthesis of chain products 4a and 4b from three-component reaction.

For explaining the reaction mechanism, a tandem reaction mechanism is proposed in Scheme 3. In acidic system, aromatic aldehyde condensates with dimedone to give arylidene dimedone (A). Then, nucleophilic addition of β-enamino imide to intermediate (A) results in a open chain product 2. Finally, the intramolecular condensation of reaction of amino group with one of carbonyl group in product 2 affords 1H-pyrrolo[3,4-b]quinoline (3). Obviously, the three-component reaction for formation of pyrrolo[3,4-b]pyridine 1 has similar reaction mechanism as showed in Scheme 3.

Scheme 3 Proposed reaction mechanism for three-component reaction.

Conclusion

In summary, we have successfully developed convenient procedures for the synthesis of functionalized pyrrolo[3,4-b]pyridines and pyrrolo[3,4-b]quinolines via the three-component reaction of β-enamino imides with aromatic aldehydes and reactive methylene compounds such as malononitrile and dimedone. The advantages of this reaction included using readily available starting substrates, milder reaction conditions, simple separation process, satisfactory yields and diverse molecular outcome. This reaction also explored the versatile applications of reactive synthons of β-enaminone and its ester, amide derivatives for the synthesis of heterocycles. The potential uses of the reaction in synthetic and medicinal chemistry might be quite significant.

Experimental section

1. General procedure for the synthesis of functionalized pyrrolo[3,4-b]pyridines 1a–1q

A mixture of 3-arylamino-1-methyl-1H-pyrrole-2,5-dione (0.5 mmol), aromatic aldehyde (0.5 mmol), malononitrile (0.5 mmol, 0.033 g) and triethylamine (0.5 mmol, 0.050 g) in ethanol (15.0 mL) was refluxed for five hours. TLC monitor indicated that the reaction has finished. After removing the solvent by rotator evaporation at reduced pressure, the resulting solid was titrated by alcohol to give the pure product for analysis.

2-Amino-1-benzyl-4-(4-methoxyphenyl)-6-methyl-5,7-dioxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,4-b]pyridine-3-carbonitrile (1a). Yellow solid, 0.176 g, 88%, mp 198–200 °C; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.41–7.37 (m, 2H, ArH), 7.33–7.31 (m, 1H, ArH), 7.26 (d, J = 7.6 Hz, 2H, ArH), 6.99 (d, J = 8.0 Hz, 2H, ArH), 6.80 (d, J = 8.0 Hz, 2H, ArH), 6.38 (s, 2H, NH₂), 5.54 (d, J = 16.4 Hz, 1H, CH), 5.29 (d, J = 16.4 Hz, 1H, CH), 4.44 (s, 1H, CH), 3.72 (s, 3H CH₃), 2.78 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ: 168.7, 165.7, 158.7, 152.7, 138.3, 137.3, 136.5, 129.1, 128.9, 128.0, 127.4, 121.7, 114.2, 113.0, 62.2, 55.5, 46.6, 36.0, 23.8; IR (KBr) ν: 3458, 3337, 3241, 2896, 2189, 1764, 1708, 1666, 1564, 1509, 1429, 1380, 1250, 1172, 1110, 1034, 980, 844, 751 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₃H₂₀N₄NaO₃ ([M + Na]⁺): 423.1428. Found: 423.1437.

2-Amino-1-benzyl-6-methyl-5,7-dioxo-4-(p-tolyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,4-b]pyridine-3-carbonitrile (1b). Yellow solid, 0.173 g, 90%, mp 210–212 °C; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.40–7.31 (m, 3H, ArH), 7.28–7.26 (m, 2H, ArH), 7.05 (d, J = 7.6 Hz, 2H, ArH), 6.95 (d, J = 7.6 Hz, 2H, ArH), 6.39 (s, 2H, NH₂), 5.55 (d, J = 16.4 Hz, 1H, CH), 5.29 (d, J = 16.4 Hz, 1H, CH), 4.44 (s, 1H, CH), 2.78 (s, 3H CH₃), 2.25 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ: 168.6, 165.7, 152.8, 141.4, 138.5, 137.3, 136.6, 129.4, 129.1, 128.0, 127.7, 127.4, 121.6, 112.9, 62.1, 46.6, 36.4, 23.8, 21.0; IR (KBr) ν: 3438, 3358, 3253, 2190, 1765, 1706, 1669, 1554, 1510, 1428, 1381, 1234, 1172, 1111, 1060, 984, 954, 844, 788, 763, 743 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₃H₂₀N₄NaO₂ ([M + Na]⁺): 407.1487. Found: 407.1485.

2-Amino-1-benzyl-4-(4-chlorophenyl)-6-methyl-5,7-dioxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,4-b]pyridine-3-carbonitrile (1c). Yellow solid, 0.164 g, 81%, mp 207–209 °C; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.41–7.37 (m, 2H, ArH), 7.34–7.31 (m, 3H, ArH), 7.26 (d, J = 7.6 Hz, 2H, ArH), 7.12 (d, J = 7.6 Hz, 2H, ArH), 6.47 (s, 2H, NH₂), 5.53 (d, J = 16.4 Hz, 1H, CH), 5.32 (d, J = 16.4 Hz, 1H, CH), 4.55 (s, 1H, CH), 2.78 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ: 168.5, 165.5, 153.0, 143.2, 138.9, 137.2, 132.1, 129.7, 129.1, 128.8, 128.0, 127.3, 121.5, 112.1, 61.4, 46.6, 36.2, 23.8; IR (KBr) ν: 3440, 3360, 3252, 3044, 2945, 2852, 2187, 1764, 1706, 1668, 1551, 1428, 1381, 1239, 1171, 1095, 985, 837, 736 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₂H₁₇N₄NaO₂ ([M + Na]⁺): 427.0932. Found: 427.0931.

2-Amino-6-methyl-5,7-dioxo-1,4-di-p-tolyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,4-b]pyridine-3-carbonitrile (1d). Yellow solid, 0.177 g, 92%, mp 243–245 °C; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.33–7.28 (m, 4H, ArH), 7.27–7.25 (m, 2H, ArH), 7.18–7.16 (m, 2H, ArH), 5.54 (s, 2H, NH₂), 4.55 (s, 1H, CH), 2.66 (s, 3H CH₃), 2.39 (s, 3H, CH₃), 2.30 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ: 168.9, 163.8, 152.2, 141.7, 139.5, 138.0, 136.7, 132.8, 130.5, 129.6, 128.0, 121.4, 111.3, 61.1, 36.7, 23.6, 21.3, 21.1; IR (KBr) ν: 3470, 3029, 2875, 2178, 1772, 1717, 1671, 1613, 1553, 1508, 1385, 1285, 1185, 1074, 982, 839, 761 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₃H₂₀N₄NaO₂ ([M + Na]⁺): 407.1478. Found: 407.1487.

2-Amino-4-(4-chlorophenyl)-6-methyl-5,7-dioxo-1-(p-tolyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,4-b]pyridine-3-carbonitrile (1e). Yellow solid, 0.131 g, 65%, mp 246–248 °C; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.43 (s, 4H, ArH), 7.31 (s, 4H, ArH), 5.62 (s, 2H, NH₂), 4.65 (s, 1H, CH), 2.67 (s, 3H CH₃), 2.39 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ: 168.8, 163.7, 152.3, 143.4, 139.6, 138.4, 132.6, 132.2, 130.5, 130.1, 129.6, 128.9, 121.2, 110.4, 60.5, 36.5, 23.6, 21.3; IR (KBr) ν: 3436, 3027, 2874, 2176, 1776, 1717, 1670, 1661, 1551, 1503, 1385, 1327, 1282, 1187, 1087, 983, 840, 791 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₂H₁₇ClN₄NaO₂ ([M + Na]⁺): 427.0932. Found: 427.0933.

2-Amino-4-(4-bromophenyl)-6-methyl-5,7-dioxo-1-(p-tolyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,4-b]pyridine-3-carbonitrile (1f). Yellow solid, 0.157 g, 70%, mp 243–245 °C; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.58 (d, J = 7.6 Hz, 2H, ArH), 7.38 (d, J = 7.6 Hz, 2H, ArH), 7.31 (s, 4H, ArH), 5.64 (s, 2H, NH₂), 4.65 (s, 1H, CH), 2.68 (s, 3H CH₃), 2.40 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ: 168.8, 163.7, 152.3, 143.9, 139.6, 138.4, 132.6, 131.9, 130.5, 130.4, 129.6, 121.2, 120.8, 110.4, 60.4, 36.6, 23.6, 21.3; IR (KBr) ν: 3470, 3025, 2876, 2177, 1775, 1717, 1672, 1611, 1553, 1505, 1384, 1283, 1187, 1072, 985, 838, 703 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₂H₁₇BrN₄NaO₂ ([M + Na]⁺): 471.0427. Found: 471.0424.

2-Amino-1-(4-chlorophenyl)-6-methyl-5,7-dioxo-4-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,4-b]pyridine-3-carbonitrile (1g). Yellow solid, 0.140 g, 72%, mp 240–242 °C; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.56 (d, J = 8.8 Hz, 2H, ArH), 7.48 (d, J = 8.8 Hz, 2H, ArH), 7.40–7.35 (m, 4H, ArH), 7.29–7.25 (m, 1H, ArH), 5.79 (s, 2H, NH₂), 4.59 (s, 1H, CH), 2.67 (s, 3H CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ: 168.9, 163.9, 152.0, 144.5, 138.0, 134.6, 134.3, 132.4, 131.8, 130.2, 129.6, 128.7, 128.5, 121.4, 110.0, 60.8, 37.0, 23.9, 23.3; IR (KBr) ν: 3452, 3098, 2941, 2876, 2184, 1771, 1716, 1676, 1626, 1559, 1489, 1417, 1379, 1280, 1181, 1079, 980, 839, 758 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₁H₁₅ClN₄NaO₂ ([M + Na]⁺): 413.0776. Found: 413.0779.

2-Amino-1,4-bis(4-chlorophenyl)-6-methyl-5,7-dioxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,4-b]pyridine-3-carbonitrile (1h). Yellow solid, 0.210 g, 95%, mp 248–250 °C; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.56 (d, J = 8.8 Hz, 2H, ArH), 7.48 (d, J = 8.8 Hz, 2H, ArH), 7.45–7.41 (m, 4H, ArH), 5.84 (s, 2H, NH₂), 4.65 (s, 1H, CH), 2.67 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ: 168.8, 163.9, 152.1, 143.5, 138.2, 134.7, 134.1, 132.4, 132.2, 131.8, 130.5, 130.2, 129.9, 129.6, 129.2, 128.6, 121.3, 110.3, 60.8, 36.6, 23.9, 23.3; IR (KBr) ν: 3412, 2947, 2882, 2187, 1894, 1772, 1708, 1562, 1486, 1384, 1284, 1084, 982, 842, 753 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₁H₁₆Cl₂N₄NaO₃ ([M + Na]⁺): 465.0492. Found: 465.0493.

2-Amino-1-(4-bromophenyl)-6-methyl-5,7-dioxo-4-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,4-b]pyridine-3-carbonitrile (1i). Yellow solid, 0.184 g, 85%, mp 244–246 °C; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.70–7.68 (m, 2H, ArH), 7.42–7.34 (m, 6H, ArH), 7.28–7.25 (m, 1H, ArH), 5.79 (s, 2H, NH₂), 4.59 (s, 1H, CH), 2.67 (s, 3H CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ: 168.9, 163.9, 152.0, 144.5, 138.0, 134.7, 133.1, 132.7, 132.0, 129.3, 128.7, 128.6, 127.9, 123.4, 121.4, 110.0, 60.8, 37.1, 23.9, 23.3; IR (KBr) ν: 3452, 3093, 2939, 2873, 2183, 1771, 1715, 1674, 1625, 1558, 1487, 1417, 1378, 1282, 1181, 1068, 980, 856, 757 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₁H₁₅BrN₄NaO₂ ([M + Na]⁺): 457.0271. Found: 457.0277.

2-Amino-1-(4-bromophenyl)-4-(4-chlorophenyl)-6-methyl-5,7-dioxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,4-b]pyridine-3-carbonitrile (1j). Yellow solid, 0.176 g, 75%, mp 243–245 °C; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.69 (d, J = 8.8 Hz, 2H, ArH), 7.43–7.40 (m, 6H, ArH), 5.84 (s, 2H, NH₂), 4.65 (s, 1H, CH), 2.67 (s, 3H CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ: 168.8, 163.8, 152.1, 143.4, 138.2, 134.6, 133.1, 132.6, 132.2, 130.5, 129.9, 129.2, 128.6, 123.4, 121.3, 110.3, 60.4, 36.6, 23.9, 23.3; IR (KBr) ν: 3454, 3093, 2940, 2885, 2180, 1774, 1716, 1675, 1627, 1557, 1484, 1418, 1377, 1278, 1149, 1074, 984, 837, 790 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₁H₁₄BrClN₄NaO₂ ([M + Na]⁺): 490.9881. Found: 490.9885.

Ethyl 2-amino-6-methyl-4-(3-nitrophenyl)-5,7-dioxo-1-(p-tolyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,4-b]pyridine-3-carboxylate (1k). Yellow solid, 0.143 g, 62%, mp 216–218 °C; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.14 (s, 1H, ArH), 8.09–8.07 (m, 1H, ArH), 7.86–7.84 (m, 1H, ArH), 7.64–7.61 (m, 1H, ArH), 7.37 (s, 4H, ArH), 4.97 (s, 1H, CH), 3.90–3.88 (m, 2H, CH), 2.67 (s, 3H CH₃), 2.42 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ: 168.9, 163.8, 154.0, 149.0, 147.9, 139.7, 138.0, 135.1, 132.3, 130.6, 130.2, 129.7, 122.7, 121.9, 112.2, 77.8, 59.2, 35.7, 23.6, 21.3, 14.4; IR (KBr) ν: 3414, 2989, 1718, 1687, 1600, 1523, 1486, 1374, 1352, 1308, 1223, 1073, 1017, 975, 847, 700 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₄H₂₂N₄NaO₆ ([M + Na]⁺): 485.1432. Found: 485.1440.

Ethyl 2-amino-1-(4-chlorophenyl)-6-methyl-4-(3-nitrophenyl)-5,7-dioxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,4-b]pyridine-3-carboxylate (1l). Yellow solid, 0.125 g, 52%, mp 258–260 °C; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.14–8.13 (m, 1H, ArH), 8.09–8.06 (m, 1H, ArH), 7.87 (d, J = 7.2 Hz, 1H, ArH), 7.65–7.62 (m, 3H, ArH), 7.60–7.54 (m, 2H, ArH), 7.34 (brs, 2H, NH₂), 4.96 (s, 1H, CH), 3.89 (q, J = 6.8 Hz, 2H, CH), 2.67 (s, 3H CH₃), 0.99 (t, J = 6.0 Hz, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ: 169.0, 168.9, 163.9, 153.7, 148.9, 147.9, 137.7, 135.2, 134.3, 133.0, 132.4, 130.2, 123.6, 122.8, 121.9, 112.2, 77.8, 59.2, 35.7, 23.6, 14.4; IR (KBr) ν: 3437, 3093, 2985, 1774, 1718, 1686, 1653, 1595, 1496, 1441, 1379, 1345, 1316, 1221, 1099, 1070, 1019, 986, 923, 899, 847, 785 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₃H₁₉BrN₄NaO₆ ([M + Na]⁺): 505.0885. Found: 505.0882.

Ethyl 2-amino-1-(4-bromophenyl)-6-methyl-4-(3-nitrophenyl)-5,7-dioxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,4-b]pyridine-3-carboxylate (1m). Yellow solid, 0.205 g, 78%, mp 233–235 °C; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.15–8.14 (m, 1H, ArH), 8.08–8.06 (m, 1H, ArH), 7.87 (d, J = 7.6 Hz, 1H, ArH), 7.78–7.75 (m, 2H, ArH), 7.62 (d, J = 8.0 Hz, 1H, ArH), 7.49–7.47 (m, 2H, ArH), 7.33 (brs, 2H, NH₂), 4.96 (s, 1H, CH), 3.89 (q, J = 6.8 Hz, 2H, CH), 2.67 (s, 3H CH₃), 0.99 (t, J = 7.2 Hz, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ: 169.0, 168.9, 163.9, 153.7, 148.9, 147.9, 137.7, 135.2, 134.3, 133.0, 132.4, 130.2, 123.6, 122.8, 121.9, 112.2, 77.8, 59.2, 35.7, 23.6, 14.4; IR (KBr) ν: 3437, 3093, 2985, 1774, 1718, 1686, 1653, 1595, 1496, 1441, 1379, 1345, 1316, 1221, 1099, 1070, 1019, 986, 923, 899, 847, 785 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₃H₁₉BrN₄NaO₆ ([M + Na]⁺): 549.0380. Found: 549.0370.

2-Amino-1-benzyl-6-methyl-5,7-dioxo-4-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,4-b]pyridine-3-carboxamide (1n). Yellow solid, 0.107 g, 55%, mp 194–196 °C; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.06 (s, 2H, NH₂), 7.36–7.34 (m, 2H, ArH), 7.31–7.28 (m, 3H, ArH), 7.13 (s, 5H, ArH), 6.37 (s, 2H, NH₂), 5.56 (d, J = 16.4 Hz, 1H, CH), 5.23 (d, J = 16.4 Hz, 1H, CH), 4.84 (s, 1H, CH), 2.78 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ: 172.1, 169.1, 165.9, 152.4, 152.3, 145.5, 137.8, 137.6, 129.0, 128.4, 127.9, 127.8, 127.6, 126.7, 114.1, 81.6, 45.9, 34.7, 23.7; IR (KBr) ν: 3431, 3168, 1763, 1682, 1603, 1477, 1427, 1378, 1232, 1067, 983, 830, 743 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₂H₂₀N₄NaO₃ ([M + Na]⁺): 411.1428. Found: 411.1436.

2-Amino-1-benzyl-4-(4-chlorophenyl)-6-methyl-5,7-dioxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,4-b]pyridine-3-carboxamide (1o). Yellow solid, 0.144 g, 68%, mp 170–172 °C; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.10 (s, 2H, NH₂), 7.39–7.32 (m, 3H, ArH), 7.28–7.26 (m, 2H, ArH), 7.22–7.19 (m, 2H, ArH), 7.13–7.12 (m, 2H, ArH), 6.42 (s, 2H, NH₂), 5.53 (d, J = 16.4 Hz, 1H, CH), 5.24 (d, J = 16.4 Hz, 1H, CH), 4.88 (s, 1H, CH), 2.78 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ: 172.0, 169.1, 165.8, 152.5, 144.5, 138.1, 137.5, 131.4, 129.8, 129.0, 128.3, 128.0, 127.8, 127.6, 113.6, 81.2, 46.0, 34.2, 23.8; IR (KBr) ν: 3499, 3442, 3140, 2944, 1763, 1682, 1677, 1608, 1479, 1424, 1381, 1232, 1172, 1088, 983, 841, 749 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₂H₁₉ClN₄NaO₃ ([M + Na]⁺): 445.1038. Found: 445.1041.

2-Amino-4-(4-chlorophenyl)-6-methyl-5,7-dioxo-1-(p-tolyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,4-b]pyridine-3-carboxamide (1p). Yellow solid, 0.179 g, 85%, mp 232–234 °C; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.48–7.46 (m, 2H, ArH), 7.38–7.36 (m, 2H, ArH), 7.33–7.28 (m, 4H, ArH), 6.44 (s, 2H, NH₂), 4.98 (s, 1H, CH), 2.65 (s, 3H CH₃), 2.40 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ: 171.9, 169.3, 164.0, 151.8, 145.2, 139.3, 137.5, 132.9, 131.5, 130.4, 130.0, 129.7, 128.6, 112.1, 79.8, 34.5, 23.5, 21.3; IR (KBr) ν: 3506, 3459, 3125, 1770, 1694, 1627, 1577, 1470, 1412, 1377, 1260, 1177, 1056, 982, 833, 748 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₂H₁₉ClN₄NaO₃ ([M + Na]⁺): 445.1038. Found: 445.1050.

2-Amino-1-(4-bromophenyl)-4-(4-chlorophenyl)-6-methyl-5,7-dioxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,4-b]pyridine-3-carboxamide (1q). Yellow solid, 0.199 g, 82%, mp 243–245 °C; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.72–7.70 (m, 2H, ArH), 7.48–7.46 (m, 2H, ArH), 7.43–7.40 (m, 4H, ArH), 6.54 (s, 2H, NH₂), 4.97 (s, 1H, CH), 2.66 (s, 3H, CH₃); ¹³C NMR (150 MHz, DMSO-d₆) δ: 171.5, 168.8, 163.6, 151.1, 144.6, 136.7, 134.4, 132.3, 132.0, 131.0, 129.6, 128.1, 122.7, 111.8, 79.4, 34.1, 23.1; IR (KBr) ν: 3502, 3460, 3121, 1769, 1692, 1627, 1579, 1473, 1381, 1265, 1065, 984, 838, 750 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₁H₁₆BrClN₄NaO₃ ([M + Na]⁺): 508.9987. Found: 508.9988.

2. General procedure for the synthesis of chain products 2a,2b and 4a,4b

A mixture of 3-arylamino-1-methyl-1H-pyrrole-2,5-dione (0.5 mmol), aromatic aldehyde (0.5 mmol) dimedone or 4-hydroxy-2H-chromen-2-one (0.5 mmol) and acetic acid (5.0 mL) in ethanol (10.0 mL) was stirred at room temperature for about eight hours. TLC monitor indicated that the reaction has finished. After removing the solvent by rotator evaporation 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 agents to give the pure product for analysis.

3-((4-Chlorophenyl)amino)-4-((2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-en-1-yl)(4-methoxyphenyl)methyl)-1-methyl-1H-pyrrole-2,5-dione (2a). Yellow solid, 0.163 g, 66%; mp 152–154 °C; ¹H NMR (600 MHz, CDCl₃) δ: 8.93 (s, 1H, OH), 7.91 (s, 1H, NH), 7.26 (s, 2H, ArH), 7.08–7.05 (m, 4H, ArH), 6.86–6.84 (m, 2H, ArH), 5.51 (s, 1H, CH), 3.80 (s, 3H, OCH₃), 3.01 (s, 3H, CH₃), 2.39–2.30 (m, 4H, 2CH₂), 1.15 (s, 3H, CH₃), 1.11 (s, 3H, CH₃); ¹³C NMR (150 MHz, CDCl₃) δ: 199.1, 175.1, 173.1, 166.7, 158.2, 140.7, 137.3, 129.9, 129.8, 128.4, 128.2, 122.6, 114.0, 109.3, 58.4, 55.2, 50.2, 43.7, 31.3, 31.1, 29.5, 27.2, 23.8, 18.4; IR (KBr) ν: 3212, 3102, 3039, 2959, 1767, 1688, 1647, 1598, 1504, 1453, 1383, 1291, 1246, 1169, 1099, 1030, 964, 826, 750 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₇H₂₇ClN₂NaO₅ ([M + Na]⁺): 517.1501. Found: 517.1511.

3-((4-Chlorophenyl)amino)-4-((2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-en-1-yl)(p-tolyl)methyl)-1-methyl-1H-pyrrole-2,5-dione (2b). Yellow solid, 0.167 g, 70%; mp 156–158 °C; ¹H NMR (400 MHz, CDCl₃) δ: 8.92 (s, 1H, OH), 7.91 (s, 1H, NH), 7.20–7.18 (m, 2H, ArH), 7.11 (d, J = 8.0 Hz, 2H, ArH), 7.06–7.03 (m, 4H, ArH), 5.52 (s, 1H, CH), 3.00 (s, 3H, CH₃), 2.38–2.36 (m, 2H, CH₂), 2.32 (s, 3H, CH₃), 2.30–2.28 (m, 2H, CH₂), 1.15 (s, 3H, CH₃), 1.10 (s, 3H, CH₃); ¹³C NMR (150 MHz, CDCl₃) δ: 195.6, 168.3, 163.7, 151.6, 151.0, 146.8, 137.6, 136.0, 135.4, 130.2, 130.0, 128.9, 123.9, 113.98, 113.1, 50.0, 40.6, 34.4, 32.4, 29.2, 27.1, 23.5; IR (KBr) ν: 3246, 3103, 3032, 2957, 1764, 1695, 1646, 1600, 1501, 1450, 1388, 1244, 1155, 1095, 1011, 824, 750; IR (KBr) ν: 3246, 3103, 3032, 2957, 1764, 1695, 1646, 1600, 1501, 1450, 1388, 1244, 1155, 1095, 1011, 824, 750 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₇H₂₇Cl₂NaO₄ ([M + Na]⁺): 501.1552; found: 501.1560.

3-((4-Hydroxy-2-oxo-2H-chromen-3-yl)(phenyl)methyl)-1-methyl-4-(p-tolylamino)-1H-pyrrole-2,5-dione (4a). Red solid, 0.144 g, 62%, mp 228–230 °C; ¹H NMR (600 MHz, DMSO-d₆) δ: 11.04 (s, 1H, OH), 7.77 (d, J = 7.8 Hz, 1H, ArH), 7.38–7.35 (m, 1H, ArH), 7.15–7.14 (m, 2H, ArH), 7.11–7.08 (m, 4H, ArH), 7.01–6.98 (m, 1H, ArH), 6.95–6.94 (m, 2H, ArH), 6.83–6.82 (m, 2H, ArH), 5.77 (s, 1H, CH), 2.84 (s, 3H, CH₃), 2.19 (s, 3H, CH₃); ¹³C NMR (150 MHz, DMSO-d₆) δ: 176.7, 176.2, 171.4, 169.6, 157.4, 147.0, 146.2, 142.7, 135.0, 134.0, 133.0, 131.7, 131.2, 128.8, 128.7, 127.5, 126.0, 124.4, 119.5, 118.1, 102.5, 83.4, 83.2, 83.0, 37.9, 27.6, 24.6; IR (KBr) ν: 3068, 2933, 2855, 1764, 1684, 1639, 1512, 1451, 1386, 1282, 1239, 1159, 110, 1035, 912, 811, 759 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₈H₂₂N₂NaO₅ ([M + Na]⁺): 489.1421; found: 489.1425.

3-((4-Hydroxy-2-oxo-2H-chromen-3-yl)(4-nitrophenyl)methyl)-1-methyl-4-(p-tolylamino)-1H-pyrrole-2,5-dione (4b). Red solid, 0.174 g, 68%, mp 242–244 °C; ¹H NMR (600 MHz, DMSO-d₆) δ: 10.94 (s, 1H, OH), 8.00 (d, J = 9.0 Hz, 2H, ArH), 7.75 (d, J = 7.2 Hz, 1H, ArH), 7.42–7.38 (m, 3H, ArH), 7.13–7.10 (m, 2H, ArH), 6.96–6.95 (m, 2H, ArH), 6.88–6.86 (m, 2H, ArH), 5.82 (s, 1H, CH), 2.86 (s, 3H, CH₃), 2.20 (s, 3H, CH₃); ¹³C NMR (150 MHz, DMSO-d₆) δ: 170.3, 172.2, 167.2, 165.6, 153.7, 152.6, 145.4, 142.8, 138.4, 131.8, 130.6, 129.2, 128.5, 124.9, 123.4, 123.3, 122.6, 121.0, 115.9, 111.8, 110.0, 98.4, 55.5, 34.6, 23.9, 20.8, 19.0; IR (KBr) ν: 3188, 2921, 1762, 1697, 1643, 1601, 1514, 1447, 1388, 1344, 1243, 1198, 1158, 1112, 1045, 990, 907, 860, 811, 761 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₈H₂₁N₃NaO₇ ([M + Na]⁺): 534.1272; found: 534.1268.

3. General procedure for the synthesis of functionalized pyrrolo[3,4-b]quinoline 3a–3j

A mixture of 3-arylamino-1-methyl-1H-pyrrole-2,5-dione (0.5 mmol), aromatic aldehyde (0.5 mmol) and dimedone (cyclohexane-1,3-dione) (0.5 mmol) in acetic acid (10.0 mL) was refluxed for about ten hours. TLC monitor indicated that the reaction has finished. After removing the solvent by rotator evaporation 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 agents to give the pure product for analysis.

2-Methyl-9-phenyl-4-(p-tolyl)-6,7,8,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,5(2H,4H)-trione (3a). Yellow solid, 0.149 g, 74%, mp 230–232 °C; ¹H NMR (600 MHz, CDCl₃) δ: 7.41–7.40 (m, 2H, ArH), 7.33–7.31 (m, 4H, ArH), 7.21–7.16 (m, 3H, ArH), 5.20 (s, 1H, CH), 2.80 (s, 3H, CH₃), 2.45 (s, 3H, CH₃), 2.42–2.38 (m, 1H, CH), 2.33–2.30 (m, 1H, CH), 2.28–2.26 (m, 2H, CH₂), 1.96–1.93 (m, 2H, CH₂), 1.88–1.82 (m, 1H, CH); ¹³C NMR (150 MHz, CDCl₃) δ: 196.0, 168.9, 164.4, 153.4, 144.5, 139.8, 137.3, 134.8, 130.3, 128.6, 128.5, 127.8, 115.1, 114.6, 36.8, 33.6, 27.2, 23.3, 21.4, 21.0; IR (KBr) ν: 3071, 3030, 2950, 2884, 1763, 1710, 1668, 1569, 1508, 1443, 1368, 1252, 1160, 1106, 1060, 1017, 975, 831, 776, 740, 703 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₅H₂₂N₂NaO₃ ([M + Na]⁺): 425.1523; found: 425.1533.

2,7,7-Trimethyl-4,9-di-p-tolyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,5(2H,4H)-trione (3b). Yellow solid, 0.176 g, 80%, mp 216–218 °C; ¹H NMR (400 MHz, CDCl₃) δ: 7.34–7.28 (m, 4H, ArH), 7.16–7.12 (m, 4H, ArH), 5.10 (s, 1H, CH), 2.70 (s, 3H, CH₃), 2.47 (s, 3H, CH₃), 2.30 (s, 3H, CH₃), 2.26–2.22 (m, 1H, CH), 2.20–2.27 (m, 1H, CH), 2.15–2.14 (m, 1H, CH), 2.08–2.04 (m, 1H, CH), 1.00 (s, 3H, CH₃), 0.92 (s, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ: 195.8, 168.9, 164.5, 151.3, 141.7, 139.7, 136.5, 134.8, 130.4, 129.3, 127.8, 121.9, 115.2, 113.8, 50.3, 40.5, 33.5, 32.3, 29.4, 27.1, 23.3, 21.4, 21.1; IR (KBr) ν: 3268, 3029, 2953, 2923, 2874, 1761, 1693, 1651, 1604, 1518, 1448, 1395, 1334, 1240, 1154, 994, 821, 749 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₈H₂₈N₂NaO₃ ([M + Na]⁺): 463.1992; found: 463.1995.

9-(4-(tert-Butyl)phenyl)-2,7,7-trimethyl-4-(p-tolyl)-6,7,8,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,5(2H,4H)-trione (3c). Yellow solid, 0.159 g, 66%, mp 182–184 °C; ¹H NMR (400 MHz, CDCl₃) δ: 7.34–7.31 (m, 6H, ArH), 7.17–7.15 (m, 2H, ArH), 5.12 (s, 1H, CH), 2.80 (s, 3H, CH₃), 2.47 (s, 3H, CH₃), 2.23–2.10 (m, 2H, CH₂), 2.17–2.14 (m, 1H, CH), 2.08–2.04 (m, 1H, CH), 1.27 (s, 9H, 3CH₃), 1.00 (s, 3H, CH₃), 0.94 (s, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ: 195.9, 169.0, 164.5, 151.5, 149.5, 141.5, 139.7, 137.3, 134.8, 130.4, 127.4, 125.6, 118.8, 115.4, 113.7, 50.3, 40.6, 34.4, 33.3, 32.3, 29.4, 27.7, 23.3, 21.4; IR (KBr) ν: 3043, 2953, 1768, 1712, 1664, 1577, 1508, 1445, 1365, 1320, 1252, 1150, 1111, 1028, 978, 928, 836, 744 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₃₁H₃₄N₂NaO₃ ([M + Na]⁺): 505.2462; found: 505.2475.

2,7,7-Trimethyl-9-(4-nitrophenyl)-4-(p-tolyl)-6,7,8,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,5(2H,4H)-trione (3d). Yellow solid, 0.175 g, 74%, mp 224–226 °C; ¹H NMR (400 MHz, CDCl₃) δ: 8.20 (J = 8.8 Hz, 2H, ArH), 7.58 (d, J = 8.8 Hz, 2H, ArH), 7.35 (d, J = 8.8 Hz, 2H, ArH), 7.16 (d, J = 8.8 Hz, 2H, ArH), 5.26 (s, 1H, CH), 2.61 (s, 3H, CH₃), 2.48 (s, 3H, CH₃), 2.77–2.20 (m, 2H, CH), 2.16–2.07 (m, 2H, CH₂), 1.00 (s, 3H, CH₃), 0.92 (s, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ: 195.7, 168.5, 168.8, 152.3, 151.4, 146.8, 140.1, 138.0, 134.2, 130.5, 128.8, 123.9, 113.2, 112.8, 50.0, 40.5, 34.4, 32.3, 29.3, 27.1, 23.4, 21.4; IR (KBr) ν: 3443, 2958, 1769, 1713, 1668, 1574, 1516, 1446, 1353, 1251, 1154, 1103, 1035, 977, 862, 828, 742, 700 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₇H₂₅N₃NaO₅ ([M + Na]⁺): 494.1686. Found: 494.1689.

2-Methyl-9-(4-nitrophenyl)-4-(p-tolyl)-6,7,8,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,5(2H,4H)-trione (3e). Yellow solid, 0.173 g, 78%, mp 216–218 °C; ¹H NMR (600 MHz, CDCl₃) δ: 8.19 (d, J = 6.0 Hz, 2H, ArH), 7.57 (d, J = 6.0 Hz, 2H, ArH), 7.34–7.33 (m, 2H, ArH), 7.18–7.16 (m, 2H, ArH), 5.30 (s, 1H, CH), 2.81 (s, 3H, CH₃), 2.46 (s, 3H, CH₃), 2.42–2.38 (m, 1H, CH), 2.35–2.32 (m, 1H, CH), 2.30–2.28 (m, 2H, CH₂), 2.00–1.96 (m, 1H, CH), 1.86–1.84 (m, 1H, CH); ¹³C NMR (150 MHz, CDCl₃) δ: 195.8, 168.6, 163.9, 154.2, 151.4, 146.9, 140.1, 137.8, 134.4, 130.5, 128.9, 128.4, 124.0, 113.7, 113.5, 36.6, 34.3, 27.3, 23.5, 21.4, 21.0; IR (KBr) ν: 3071, 2931, 2880, 1925, 1769, 1713, 1671, 1604, 1567, 1517, 1442, 1355, 1272, 1247, 1162, 1105, 1060, 1016, 973, 905, 826, 775, 740, 704 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₅H₂₁N₃NaO₅ ([M + Na]⁺): 466.1373; found: 466.1374.

2-Methyl-9-(4-methoxyphenyl)-4-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,5(2H,4H)-trione (3f). Yellow solid, 0.145 g, 70%, mp 216–218 °C; ¹H NMR (600 MHz, CDCl₃) δ: 7.40–7.39 (m, 2H, ArH), 7.32–7.31 (m, 2H, ArH), 7.20–7.19 (m, 3H, ArH), 7.10–6.99 (m, 2H, ArH), 5.20 (s, 1H, CH), 3.87 (s, 3H, OCH₃), 2.80 (s, 3H, CH₃), 2.42–2.39 (m, 1H, CH), 2.32–2.30 (m, 1H, CH), 2.28–2.26 (m, 2H, CH₂), 1.98–1.94 (m, 1H, CH), 1.88–1.84 (m, 1H, CH); ¹³C NMR (150 MHz, CDCl₃) δ: 195.9, 168.9, 164.4, 160.2, 153.7, 144.5, 137.4, 129.9, 128.6, 127.8, 126.6, 115.0, 114.7, 114.6, 35.6, 36.8, 33.7, 27.2, 23.3, 21.1; IR (KBr) ν: 3072, 3027, 2946, 2892, 2829, 1887, 1764, 1711, 1668, 1571, 1507, 1446, 1369, 1286, 1244, 1159, 1105, 1068, 1025, 975, 917, 841, 777, 741, 701 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₅H₂₂N₂NaO₄ ([M + Na]⁺): 437.1472; found: 437.1484.

4-(4-Methoxyphenyl)-2,7,7-trimethyl-9-(4-nitrophenyl)-6,7,8,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,5(2H,4H)-trion (3g). Yellow solid, 0.175 g, 72%, mp 208–210 °C; ¹H NMR (400 MHz, CDCl₃) δ: 8.20 (d, J = 8.0 Hz, 2H, ArH), 7.57 (d, J = 8.0 Hz, 2H, ArH), 7.20–7.17 (m, 2H, ArH), 7.05–7.03 (m, 2H, ArH), 5.26 (s, 1H, CH), 3.90 (s, 3H, OCH₃), 2.82 (s, 3H, CH₃), 2.28–2.20 (m, 2H, CH₂), 2.16–2.08 (m, 2H, CH₂), 1.01 (s, 3H, CH₃), 0.92 (s, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ: 191.0, 163.8, 159.2, 155.5, 147.9, 146.6, 142.0, 133.2, 124.5, 124.1, 119.2, 110.2, 108.5, 108.0, 50.8, 45.3, 35.7, 29.7, 27.6, 18.7; IR (KBr) ν: 3068, 2950, 1767, 1710, 1668, 1575, 1516, 1449, 1352, 1303, 1247, 1156, 1101, 1025, 974, 835, 746, 703 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₇H₂₅N₃NaO₆ ([M + Na]⁺): 510.1636. Found: 510.1633.

4-(4-Chlorophenyl)-2-methyl-9-(p-tolyl)-6,7,8,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,5(2H,4H)-trione (3h). Yellow solid, 0.156 g, 72%, mp 240–242 °C; ¹H NMR (600 MHz, CDCl₃) δ: 7.50–7.48 (m, 2H, ArH), 7.28–7.26 (m, 2H, ArH), 7.25–7.24 (m, 2H, ArH), 7.13–7.12 (m, 2H, ArH), 5.15 (s, 1H, CH), 2.80 (s, 3H, CH₃), 2.41–2.38 (m, 1H, CH), 2.33–2.27 (m, 1H, CH), 2.25–2.24 (m, 2H, CH₂), 1.98–1.94 (m, 1H, CH), 1.88–1.84 (m, 1H, CH); ¹³C NMR (150 MHz, CDCl₃) δ: 195.8, 168.7, 164.4, 152.5, 141.4, 136.8, 136.7, 135.9, 135.7, 130.3, 129.9, 129.4, 127.7, 115.7, 115.0, 36.8, 33.2, 27.3, 23.4, 21.1, 21.0; IR (KBr) ν: 3088, 2953, 2882, 1912, 1763, 1709, 1668, 1568, 1485, 1368, 1263, 1155, 1095, 1057, 1014, 973, 844, 776, 735 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₅H₂₁ClN₂NaO₃ ([M + Na]⁺): 455.1133; found: 455.1132.

4-(4-Chlorophenyl)-2,7,7-trimethyl-9-(4-nitrophenyl)-6,7,8,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,5(2H,4H)-trione (3i). Yellow solid, 0.184 g, 75%, mp 226–228 °C; ¹H NMR (400 MHz, CDCl₃) δ: 8.21 (s, 1H, ArH), 8.19 (s, 1H, ArH), 7.58 (s, 1H, ArH), 7.56 (d, J = 8.8 Hz, 2H, ArH), 7.52 (s, 1H, ArH), 7.24–7.22 (m, 2H, ArH), 5.25 (s, 1H, CH), 2.82 (s, 3H, CH₃), 2.28–2.24 (s, 1H, CH), 2.21–2.18 (m, 1H, CH), 2.17–2.14 (m, 1H, CH), 2.08–2.04 (m, 1H, CH), 1.02 (s, 3H, CH₃), 0.93 (s, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ: 195.6, 168.3, 163.8, 151.6, 146.8, 137.6, 136.0, 135.4, 130.2, 130.0, 128.9, 124.0, 113.8, 113.1, 50.0, 40.6, 34.4, 32.4, 29.2, 27.1, 23.5; IR (KBr) ν: 3438, 2957, 1771, 1715, 1669, 1570, 1517, 1443, 1356, 1254, 1155, 1096, 1025, 976, 835, 743, 703 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₆H₂₂CN₃NaO₅ ([M + Na]⁺): 514.1140; found: 514.1139.

4-(4-Bromophenyl)-2-methyl-9-(p-tolyl)-6,7,8,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,5(2H,4H)-trione (3j). Yellow solid, 0.162 g, 68%, mp 238–240 °C; ¹H NMR (600 MHz, CDCl₃) δ: 7.65 (d, J = 8.4 Hz, 2H, ArH), 7.28–7.26 (m, 2H, ArH), 7.18 (d, J = 8.4 Hz, 2H, ArH), 7.13–7.12 (m, 2H, ArH), 5.15 (s, 1H, CH), 2.80 (s, 3H, CH₃), 2.42–2.38 (m, 1H, CH), 2.33–2.28 (m, 1H, CH), 2.30 (s, 3H, CH₃), 2.25–2.23 (m, 2H, CH₂), 1.98–1.94 (m, 1H, CH), 1.90–1.84 (m, 1H, CH); ¹³C NMR (150 MHz, Hz, CDCl₃) δ: 195.8, 168.7, 164.4, 152.4, 141.4, 136.7, 136.5, 132.9, 13.6, 129.4, 127.7, 123.8, 115.7, 115.1, 36.8, 33.2, 30.9, 27.3, 23.4, 21.1, 21.0, 18.5; IR (KBr) ν: 3068, 3018, 2950, 1909, 1801, 1764, 1709, 1669, 1639, 1568, 1486, 1474, 1368, 1260, 1157, 1104, 1059, 1014, 976, 915, 831, 775, 740 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₅H₂₁BrNNaO₃ ([M + Na]⁺): 499.0628; found: 499.063.

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (Grant No. 21172189, 21572196) and the Priority Academic Program Development of Jiangsu Higher Education Institutions. We also thank the 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. CCDC 1a (CCDC 1451318), 1p (CCDC 1451319), 2b (CCDC 1451320), 3a (CCDC 1451321), 3g (CCDC 1451322), and 3j (CCDC 1451323). For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra03165j

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