Convenient one-step synthesis of pyrrolo[3,4-c]quinolin-1-ones via TMSCl-catalyzed cascade reactions of isatins and β-enamino ketones

Abstract

An efficient and facile synthesis of pyrrolo[3,4-c]quinoline-1-ones by TMSCl-catalyzed reaction of easily available substituted isatins and β-enamino ketone derivatives has been developed. This cascade reaction has shown good functional group tolerance, operational simplicity, and proceeded smoothly in good to excellent yields via a one-step method under mild conditions. Preliminary experiments on oxidative cleavage of the C=C bond have been applied.

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Introduction

Pyrrolo[3,4-c]quinoline is an important structural unit which exists in natural products and biologically active molecules.¹ Their biological activities include antitumor activity (Fig. 1, Alpkinidine 1, isolated from Xestospongia cf. carbonaria and X. cf. exigua),² caspase-3 inhibition (Fig. 1, compound 2),^1a,3 hepatitis C virus (HCV) inhibition (Fig. 1, compound 3),⁴ anti-tuberculosis,⁵ ADAMTS-4/5 inhibition,⁶ anti-fungal,⁷ anti-inflammatory,⁸ anti-Alzheimer's disease⁹ and others.¹⁰ Due to these diverse activities, the synthesis of pyrrolo[3,4-c]quinoline derivatives has attracted increasing attention from synthetic and medicinal chemists.¹¹ Isatin and its C-3 derivatives (e.g. methyleneindolinones) are the most employed starting materials for constructing various pyrrolo[3,4-c]quinoline-1-ones¹² due to their easy synthesis and versatile reactivity. The traditional synthetic routes for pyrrolo[3,4-c]quinoline-1-ones utilize isatins as starting materials, and typically involve tedious multi-step procedures based on the Pfitzinger reaction.^{3a–c,6,11f,13} Consequently, efficient and flexible synthetic methods for this motif are still highly desired.

Fig. 1 Representative biologically active pyrrolo[3,4-c]quinoline-1-one derivatives.

Recently, several one-step methods for the construction of pyrrolo[3,4-c]quinoline-1-ones have been developed. The Jia group¹⁴ reported a BF₃-catalyzed strategy for constructing pyrrolo[3,4-c]quinoline-1,3-diones via isocyanide-based cascade cycloaddition reaction with methyleneindolinones (Scheme 1a). The groups of Lee^1h,15 and Yadla¹⁶ developed a synthesis of pyrrolo[3,4-c]quinoline-1,3-diones through microwave-assisted cascade reactions of isatin and β-ketoamides in the presence of ethylenediamine diacetate (EDDA), 4-dimethylaminopyridine (DMAP) or [Bmim]BF₄ (Scheme 1b). However, these procedures could only generate products with a C=O/C=S bond at the 3-position of pyrrol-1-one ring, thus the molecular diversity are limited. We recently developed a novel synthesis of pyrrolo[3,4-c]quinoline-1-one derivatives, using a trifluoroacetic acid (TFA)-catalyzed three-component cascade reaction of amines, isatins and N,N-dimethylenaminones (Scheme 1c).^12g As a part of our continuing efforts towards developing new synthetic methods for increasing the structural diversity of pyrrolo[3,4-c]quinoline-1-one system, herein we wish to report a trimethylchlorosilane (TMSCl)-catalyzed cascade reaction between isatins and β-enamino ketones, which generates a methylene group (=CH₂) at the 3-position of pyrrol-1-one ring (Scheme 1d).

Scheme 1 One-step protocol synthesis of pyrrolo[3,4-c]-quinoline-1-ones.

Results and discussion

Initially, isatin (4a) and β-enamino ketone (5a) were used as model substrates for the optimization of reaction conditions. Under a reaction condition similar to our previous work (2.0 mmol TFA, xylene, 120 °C, 2.5 h),^12g the desired product 6a was isolated in 18% yield (entry 1). The catalyst, solvent, reaction temperature and time were screened. Firstly, various catalysts were investigated in xylene at 120 °C for 2.5 h. CeCl₃, CoCl₃, MgCl₂, KHSO₄ and Cu(OAc)₂ afforded only trace amounts of the desired product 6a (entries 4–8). To our delight, formation of 6a were observed in reactions catalyzed by AcOH and p-toluenesulfonic acid (p-TSA) (44% and 46%, entries 2–3), and TMSCl was found more efficient (56%, entry 9). Next, the solvent effects were studied using TMSCl as the catalyst. The desired reaction was completely inhibited in protic solvents such as water and MeOH (entries 12–13). Formation of the dimethyl ketal of isatin was detected for the reaction in MeOH. Among the nonprotic solvents tested, CH₃CN was found the most efficient as the reaction afforded good yield in only 1.0 h (74%, entry 14 vs. entries 9–11). The role of reaction temperature was also screened in the presence of TMSCl in CH₃CN for 1.0 h (entries 14–17). We found that the reaction at 60 °C provided the best result (91%, entry 16 vs. entries 14, 15, 17) (Table 1). Further investigation of the catalyst amounts showed that the reaction with 1.0 equiv TMSCl could not reach complete conversion (entry 19), but higher catalyst loading (3.0 mmol) had little impact on the results (entry 18). Thus, the reaction with 2.0 mmol of TMSCl in CH₃CN at 60 °C was found the optimal condition.

Table 1 Optimization of the reaction conditions^a

Entry	Solvent	Catalyst [mmol]	T [°C]	Time [h]	Yield^b [%]
a Reaction conditions: isatins 4a (0.5 mmol) and β-enamino ketone 5a (0.5 mmol) in 3.0 mL solvent.b Isolated yield based on β-enamino ketone 5a.c Not detected.
1	Xylene	TFA (2.0)	120	2.5	18
2	Xylene	AcOH (2.0)	120	2.5	44
3	Xylene	p-TSA (2.0)	120	2.5	46
4	Xylene	CeCl3 (1.0)	120	2.5	Trace
5	Xylene	CoCl3 (1.0)	120	2.5	Trace
6	Xylene	MgCl2 (1.0)	120	2.5	Trace
7	Xylene	KHSO4 (1.0)	120	2.5	Trace
8	Xylene	Cu(OAc)2 (1.0)	120	2.5	Trace
9	Xylene	TMSCl (2.0)	120	2.5	56
10	1,4-Dioxane	TMSCl (2.0)	Reflux	2.5	54
11	Toluene	TMSCl (2.0)	Reflux	2.5	44
12	Water	TMSCl (2.0)	Reflux	2.5	ND^c
13	MeOH	TMSCl (2.0)	Reflux	2.5	ND^c
14	CH3CN	TMSCl (2.0)	Reflux	1	74
15	CH3CN	TMSCl (2.0)	70	1	88
16	CH3CN	TMSCl (2.0)	60	1	91
17	CH3CN	TMSCl (2.0)	50	1.5	83
18	CH3CN	TMSCl (3.0)	60	1	92
19	CH3CN	TMSCl (1.0)	60	1	80

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With the optimal reaction condition in hand, the scope of substrates was then explored. The results are summarized in Table 2. Electron-neutral (5-H) and halogenated (5-Br, 5-Cl, 5-F) isatins were smoothly converted to the corresponding products 6a–6z in good to excellent yields (62–93%). When the substituent of isatins was changed to strong electron-withdrawing groups (5-NO₂, 5-(morpholine-4-sulfonyl), 7-F and 7-CF₃), low to moderate yields were obtained in certain cases (6a′–6c′, 6f′–6h′, 31–58%), though good yields could also be observed sometimes (6d′, 75%, 6e′, 62%). On the other hand, β-enamino ketones bearing N-aryl or alkyl substituents are all effective substrates and able to generate the expected 6 in moderate to excellent yields. A variety of substituents on the N-aryl group, including electron-rich (4-OMe), electron- neutral (4-H, 4-Me) and halogen (2-Cl, 2-Br, 3-F, 3-Br, 4-Cl and 4-F), showed little impact on the results, except that 4-acetamino-substituted β-enamino ketone gave a lower yield. The reactions of β-enamino ketones bearing N-alkyl groups (n-butyl, cyclohexyl, 2-furylmethyl and 2-tetrahydrofurfuryl) also proceeded smoothly and afforded the desired products in moderate yields (6a′–6f′). The structure of 6p was unambiguously confirmed by X-ray single-crystal diffraction analysis (Fig. 2, CCDC 1438897).¹⁷

Table 2 Synthesis of the 3-methylene pyrrolo[3,4-c]quinoline-1-one derivatives^a,b

a General conditions: isatins 4 (0.5 mmol) and β-enamino ketone 5 (0.5 mmol), and TMSCl (2.0 mmol) mixed in 3.0 mL of CH₃CN, stirred at 60 °C for 1.0 h.b Isolated yield based on β-enamino ketone 5.

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Fig. 2 X-ray structure of compound 6p.

Notably, this reaction produces products bearing a C=C bond on the pyrrol-1-one ring, providing opportunities for further functionalization. For example, 3-methylene pyrrolo[3,4-c]quinoline-1-one derivatives could be converted to pyrrolo[3,4-c]quinoline-1,3-dione compounds, which exhibited caspase-3 and HCV inhibition activities (Fig. 1, compound 2 and 3).^3,4 As shown in Scheme 2, oxidative cleavage of the C=C bond of 6d and 6f with 1.5 equiv of KMnO₄/Al₂O₃ in acetone¹⁸ smoothly afforded the corresponding 1,3-dione products 7a and 7b in 53% and 55% yields, respectively.

Scheme 2 Synthesis of pyrrolo[3,4-c]quinoline-1,3-dione derivatives.

On the basis of the previous reports,^12,14–16 a plausible reaction mechanism is proposed in Scheme 3. The 3-carbonyl of isatin first reacts with TMSCl to give an activated form 8, which is attacked by β-enamino ketone. Subsequent imine–enamine tautomerization and cyclization of 10 give rise to tricyclic intermediate 11, which then experiences ring-opening, re-cyclization and dehydration to form pyrroloquinoline 15. Finally, one molecule of hydroxytrimethylsilane and a proton are eliminated to yield the desired product 6.

Scheme 3 Proposed mechanism of the formation of 6.

Conclusions

In conclusion, we have developed an efficient, facile and practically useful one-step procedure for the synthesis of 3-methylene pyrrolo[3,4-c]quinoline-1-one derivatives starting from isatins and β-enamino ketones by a TMSCl-catalyzed cascade reaction under mild reaction conditions. With this simple procedure, structurally diverse 3-methylene pyrrolo[3,4-c]quinoline-1-one compounds were rapidly obtained in usually moderate to excellent yields. Oxidative cleavage of the C=C bond afforded pyrrolo[3,4-c]quinoline-1,3-dione derivatives, which showed multiple bioactivities. The study on the functionalization of the C=C bond and the bioactivity of the newly synthesized pyrrolo[3,4-c]quinoline-1-one derivatives are currently underway in our laboratory.

Experimental section

All compounds were fully characterized by spectroscopic data. The NMR spectra were recorded on a Bruker Avance 400 (¹H: 400 MHz, ¹³C: 100 MHz) and Bruker DRX500 (¹H: 500 MHz, ¹³C: 125 MHz), chemical shifts (δ) are expressed in ppm, and J values are given in Hz, and deuterated CDCl₃ and DMSO-d₆ were used as solvent. IR spectra were recorded on a FT-IR Thermo Nicolet Avatar 360 using KBr pellet. The reactions were monitored by thin layer chromatography (TLC) using silica gel GF₂₅₄. The melting points were determined on XT-4A melting point apparatus and are uncorrected. HRMs were performed on a Agilent LC/MS TOF instrument. All chemicals and solvents were used as received without further purification unless otherwise stated. Compounds 5 were prepared according to the literature.¹⁹

General procedure for the synthesis of 3-methylene-pyrrolo[3,4-c]quinoline-1-ones (6)

Isatins 4 (0.5 mmol) and β-enamino ketones 5 (0.5 mmol), acetonitrile (3.0 mL), TMSCl (2.0 mmol) were placed into a 10 mL round-bottom flask and the mixture was stirred at 60 °C for 1.0 h, and monitored by TLC until the β-enamino ketone substrate was used up. The mixture was cooled to room temperature, neutralized with a saturated solution of Na₂CO₃ to pH 8–9, and then EtOAc (30 mL × 2) were added. The organic phase was washed with water (20 mL), dried over Na₂SO₄, concentrated and purified by flash column chromatography to afford the product 6 in a 31–93% yield. The products were further identified by FT-IR, NMR and HRMS, being in good agreement with the assigned structures (see ESI†).

2-(4-Methoxyphenyl)-4-methyl-3-methylene-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-one (6a). Yellow solid; mp 199–201 °C; IR (KBr): 1701, 1630, 1511, 1443, 1337, 1253, 1165, 1140, 1033, 844, 787, 750 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 3.00 (s, 3H, C–CH₃), 3.87 (s, 3H, ArOCH₃), 5.06 (d, J = 2.4 Hz, 1H, C=CH₂), 5.54 (d, J = 2.0 Hz, 1H, C=CH₂), 7.06 (d, J = 8.8 Hz, 2H, ArH), 7.31 (d, J = 8.8 Hz, 2H, ArH), 7.64–7.68 (m, 1H, ArH), 7.76–7.80 (m, 1H, ArH), 8.12 (d, J = 8.4 Hz, 1H, ArH), 9.01 (d, J = 8.4 Hz, 1H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ = 25.2, 55.7, 97.9, 115.0, 115.0, 122.0, 124.5, 126.6, 127.6, 128.1, 128.8, 129.9, 129.9, 130.6, 131.3, 143.3, 148.2, 153.3, 159.7, 166.4; HRMS (TOF ES⁺): m/z calcd for C₂₀H₁₇N₂O₂ [(M + H)⁺], 317.1285; found, 317.1282.

4-Methyl-3-methylene-2-(p-tolyl)-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-one (6b). Yellow solid; mp 201–203 °C; IR (KBr): 1721, 1704, 1633, 1515, 1388, 1249, 1153, 1130, 1068, 873, 781, 704 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ = 2.41 (s, 3H, ArCH₃), 2.91 (s, 3H, C–CH₃), 4.97 (d, J = 2.4 Hz, 1H, C=CH₂), 5.65 (d, J = 2.4 Hz, 1H, C=CH₂), 7.32 (d, J = 8.4 Hz, 2H, ArH), 7.40 (d, J = 8.0 Hz, 2H, ArH), 7.70–7.74 (m, 1H, ArH), 7.82–7.86 (m, 1H, ArH), 8.08 (d, J = 8.8 Hz, 1H, ArH), 8.81 (d, J = 8.4 Hz, 1H, ArH); ¹³C NMR (100 MHz, DMSO-d₆): δ = 21.7, 25.6, 99.6, 122.0, 124.3, 128.1, 129.0, 129.5, 129.5, 129.6, 130.9, 130.9, 131.0, 131.5, 132.1, 139.1, 142.9, 148.3, 154.4, 166.1; HRMS (TOF ES⁺): m/z calcd for C₂₀H₁₇N₂O [(M + H)⁺], 301.1335; found, 301.1334.

4-Methyl-3-methylene-2-phenyl-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-one (6c). Yellow solid; mp 212–215 °C; IR (KBr): 1712, 1625, 1499, 1384, 1335, 1278, 1244, 1153, 839, 793, 770, 713 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ = 3.06 (s, 3H, C–CH₃), 5.15 (d, J = 5.0 Hz, 1H, C=CH₂), 5.62 (d, J = 5.0 Hz, 1H, C=CH₂), 7.46 (d, J = 7.75 Hz, 2H, ArH), 7.51–7.54 (m, 1H, ArH), 7.60–7.63 (m, 2H, ArH), 7.70–7.74 (m, 1H, ArH), 7.82–7.86 (m, 1H, ArH), 8.17–8.19 (m, 1H, ArH), 9.06–9.08 (m, 1H, ArH); ¹³C NMR (125 MHz, CDCl₃): δ = 25.6, 98.3, 122.3, 124.8, 128.0, 128.5, 129.0, 129.1, 129.1, 129.1, 130.0, 130.0, 130.9, 131.5, 134.4, 143.2, 148.5, 156.3, 166.5; HRMS (TOF ES⁺): m/z calcd for C₁₉H₁₅N₂O [(M + H)⁺], 287.1179; found, 287.1178.

2-(2-Bromophenyl)-4-methyl-3-methylene-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-one (6d). Yellow solid; mp 222–225 °C; IR (KBr): 1713, 1638, 1477, 1383, 1327, 1165, 1058, 1027, 859, 771 cm⁻¹; ¹H NMR (500 MHz, DMSO-d₆): δ = 3.10 (s, 3H, C–CH₃), 4.85 (d, J = 3.4 Hz, 1H, C=CH₂), 5.82 (d, J = 3.3 Hz, 1H, C=CH₂), 7.57–7.61 (m, 1H, ArH), 7.66–7.71 (m, 2H, ArH), 7.87–7.91 (m, 1H, ArH), 7.96–8.03 (m, 2H, ArH), 8.29 (d, J = 8.5 Hz, 1H, ArH), 8.94 (d, J = 8.0 Hz, 1H, ArH); ¹³C NMR (125 MHz, DMSO-d₆): δ = 24.2, 99.7, 121.6, 123.8, 123.9, 123.9, 127.9, 127.9, 129.2, 129.6, 131.8, 131.9, 132.3, 133.4, 133.9, 133.9, 140.9, 154.3, 164.7; HRMS (TOF ES⁺): m/z calcd for C₁₉H₁₄BrN₂O [(M + H)⁺], 365.0290; found, 365.0293.

2-(3-Bromophenyl)-4-methyl-3-methylene-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-one (6e). White solid; mp 211–213 °C; IR (KBr): 1706, 1634, 1477, 1334, 1278, 1148, 1126, 854, 773, 720, 680 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 3.02 (s, 3H, C–CH₃), 5.13 (d, J = 2.4 Hz, 1H, C=CH₂), 5.60 (d, J = 2.4 Hz, 1H, C=CH₂), 7.37 (d, J = 7.6 Hz, 1H, ArH), 7.42–7.46 (m, 1H, ArH), 7.60–7.63 (m, 2H, ArH), 7.66–7.70 (m, 1H, ArH), 7.79–7.82 (m, 1H, ArH), 8.14 (d, J = 8.4 Hz, 1H, ArH), 8.99 (d, J = 8.4 Hz, 1H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ = 25.3, 98.1, 121.9, 123.0, 124.4, 127.5, 127.6, 128.3, 128.9, 130.8, 130.9, 130.9, 131.9, 132.0, 135.4, 142.5, 148.3, 153.3, 166.0; HRMS (TOF ES⁺): m/z calcd for C₁₉H₁₄BrN₂O [(M + H)⁺], 365.0284; found, 365.0281.

2-(2-Chlorophenyl)-4-methyl-3-methylene-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-one (6f). White solid; mp 217–219.5 °C; IR (KBr): 1713, 1638, 1595, 1482, 1385, 1250, 1170, 1059, 858, 771, 688 cm⁻¹; ¹H NMR (500 MHz, DMSO-d₆): δ = 3.18 (s, 3H, C–CH₃), 4.94 (d, J = 3.4 Hz, 1H, C=CH₂), 5.86 (d, J = 3.4 Hz, 1H, C=CH₂), 7.66–7.70 (m, 3H, ArH), 7.83–7.84 (m, 1H, ArH), 7.93–7.96 (m, 1H, ArH), 8.06–8.09 (m, 1H, ArH), 8.44 (d, J = 8.6 Hz, 1H, ArH), 8.96 (d, J = 8.2 Hz, 1H, ArH); ¹³C NMR (125 MHz, DMSO-d₆): δ = 23.1, 100.4, 121.7, 124.0, 126.2, 128.2, 129.1, 129.8, 130.8, 131.4, 131.9, 131.9, 132.2, 132.6, 133.1, 140.4, 144.3, 154.5, 164.3; HRMS (TOF ES⁺): m/z calcd for C₁₉H₁₄ClN₂O [(M + H)⁺], 321.0795; found, 321.0797.

2-(4-Chlorophenyl)-4-methyl-3-methylene-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-one (6g). White solid; mp 236–238 °C; IR (KBr): 1708, 1634, 1494, 1390, 1253, 1087, 834, 769, 737, 684 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 3.00 (s, 3H, C–CH₃), 5.09 (d, J = 2.4 Hz, 1H, C=CH₂), 5.57 (d, J = 2.4 Hz, 1H, C=CH₂), 7.36 (d, J = 8.8 Hz, 2H, ArH), 7.53 (d, J = 8.4 Hz, 2H, ArH), 7.65–7.68 (m, 1H, ArH), 7.77–7.81 (m, 1H, ArH), 8.12 (d, J = 8.4 Hz, 1H, ArH), 8.98 (d, J = 8.4 Hz, 1H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ = 25.2, 97.9, 121.9, 124.4, 127.6, 128.3, 128.9, 129.9, 129.9, 130.1, 130.1, 130.7, 131.0, 132.6, 134.6, 142.6, 148.2, 153.3, 166.0; HRMS (TOF ES⁺): m/z calcd for C₁₉H₁₄ClN₂O [(M + H)⁺], 321.0789; found, 321.0789.

2-(4-Fluorophenyl)-4-methyl-3-methylene-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-one (6h). Pink solid; mp 189–191 °C; IR (KBr): 1698, 1633, 1509, 1385, 1224, 1150, 1097, 833, 773, 726 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 3.01 (s, 3H, C–CH₃), 5.06 (d, J = 2.8 Hz, 1H, C=CH₂), 5.57 (d, J = 2.4 Hz, 1H, C=CH₂), 7.23–7.27 (m, 2H, ArH), 7.37–7.41 (m, 2H, ArH), 7.65–7.69 (m, 1H, ArH), 7.77–7.82 (m, 1H, ArH), 8.13 (d, J = 8.4 Hz, 1H, ArH), 8.99 (d, J = 8.4 Hz, 1H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ = 25.2, 97.9, 116.7 (d, J = 22.8 Hz), 116.7 (d, J = 22.8 Hz), 121.9, 124.4, 127.6, 128.3, 128.9, 130.0 (d, J = 3.2 Hz), 130.6 (d, J = 8.6 Hz), 130.6 (d, J = 8.6 Hz), 130.7, 131.1, 143.0, 148.3, 153.3, 162.5 (d, J = 247.1 Hz), 166.3; HRMS (TOF ES⁺): m/z calcd for C₁₉H₁₄FN₂O [(M + H)⁺], 305.1085; found, 305.1082.

2-(3-Fluorophenyl)-4-methyl-3-methylene-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-one (6i). White solid; mp 233–235 °C; IR (KBr): 1706, 1626, 1590, 1497, 1450, 1224, 1145, 849, 808, 771, 748, 715, 687 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 3.08 (s, 3H, C–CH₃), 5.21 (d, J = 2.8 Hz, 1H, C=CH₂), 5.67 (d, J = 2.8 Hz, 1H, C=CH₂), 7.23–7.31 (m, 3H, ArH), 7.58–7.61 (m, 1H, ArH), 7.73–7.76 (m, 1H, ArH), 7.85–7.89 (m, 1H, ArH), 8.20 (d, J = 8.4 Hz, 1H, ArH), 9.06 (d, J = 8.4 Hz, 1H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ = 25.2, 98.1, 115.8 (d, J = 20.8 Hz), 116.3 (d, J = 22.9 Hz), 121.9, 124.4, 124.6 (d, J = 3.3 Hz), 127.6, 128.3, 128.9, 130.7, 130.8 (d, J = 9.3 Hz), 130.9, 135.5 (d, J = 9.8 Hz), 142.5, 148.2, 153.3, 163.1 (d, J = 246.7 Hz), 165.9; HRMS (TOF ES⁺): m/z calcd for C₁₉H₁₄FN₂O [(M + H)⁺], 305.1085; found, 305.1086.

N-(4-(4-Methyl-3-methylene-1-oxo-1H-pyrrolo[3,4-c]quinolin-2(3H)-yl)phenyl)acetamide (6j). Pink solid; mp 302.5–304.5 °C; IR (KBr): 1703, 1668, 1532, 1517, 1391, 1313, 1154, 839, 772, 744, 671 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 2.10 (s, 3H, C–CH₃), 2.91 (s, 3H, C–CH₃), 4.98 (s, 1H, C=CH₂), 5.64 (s, 1H, C=CH₂), 7.36 (d, J = 8.0 Hz, 2H, ArH), 7.71–7.73 (m, 1H, ArH), 7.79 (d, J = 8.0 Hz, 2H, ArH), 7.82–7.84 (m, 1H, ArH), 8.06 (d, J = 8.0 Hz, 1H, ArH), 8.80 (d, J = 8.0 Hz, 1H, ArH), 10.20 (s, 1H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ = 25.0, 25.6, 99.6, 120.6, 120.6, 122.0, 124.3, 128.1, 129.0, 129.2, 129.6, 130.1, 130.1, 131.0, 131.5, 140.4, 142.9, 148.3, 154.4, 166.2, 169.6; HRMS (TOF ES⁺): m/z calcd for C₂₁H₁₈N₃O₂ [(M + H)⁺], 344.1394; found, 344.1399.

8-Bromo-2-(4-methoxyphenyl)-4-methyl-3-methylene-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-one (6k). Yellow solid; mp 230–232.5 °C; IR (KBr): 1705, 1634, 1518, 1498, 1303, 1256, 1171, 1042, 987, 829, 726 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 2.98 (s, 3H, C–CH₃), 3.88 (s, 3H, ArOCH₃), 5.11 (d, J = 2.4 Hz, 1H, C=CH₂), 5.58 (d, J = 2.4 Hz, 1H, C=CH₂), 7.06 (d, J = 8.8 Hz, 2H, ArH), 7.29 (d, J = 8.8 Hz, 2H, ArH), 7.82–7.85 (m, 1H, ArH), 7.96 (d, J = 8.8 Hz, 1H, ArH), 9.16 (d, J = 2.0 Hz, 1H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ = 25.2, 55.7, 98.7, 115.0, 115.0, 122.6, 123.0, 126.3, 126.8, 128.2, 129.9, 129.9, 130.3, 130.4, 134.1, 143.0, 146.7, 153.8, 159.8, 165.8; HRMS (TOF ES⁺): m/z calcd for C₂₀H₁₆BrN₂O₂[(M + H)⁺], 395.0390; found, 395.0393.

8-Bromo-4-methyl-3-methylene-2-(p-tolyl)-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-one (6l). White solid; mp 231–233.5 °C; IR (KBr): 1704, 1631, 1514, 1375, 1333, 1264, 1170, 1061, 874, 814, 796, 656 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 2.45 (s, 3H, ArCH₃), 2.98 (s, 3H, C–CH₃), 5.14 (d, J = 2.4 Hz, 1H, C=CH₂), 5.58 (d, J = 2.4 Hz, 1H, C=CH₂), 7.27 (d, J = 8.0 Hz, 2H, ArH), 7.36 (d, J = 8.0 Hz, 2H, ArH), 7.82–7.85 (m, 1H, ArH), 7.97 (d, J = 8.8 Hz, 1H, ArH), 9.17 (d, J = 2.4 Hz, 1H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ = 21.4, 25.2, 98.7, 122.6, 123.0, 126.8, 128.2, 128.4, 128.4, 130.3, 130.3, 130.3, 130.4, 131.2, 134.1, 138.8, 142.8, 146.7, 153.8, 165.7; HRMS (TOF ES⁺): m/z calcd for C₂₀H₁₆BrN₂O [(M + H)⁺], 379.0441; found, 379.0440.

8-Bromo-4-methyl-3-methylene-2-phenyl-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-one (6m). White solid; mp 235–237.5 °C; IR (KBr): 1721, 1634, 1497, 1384, 1335, 1185, 1067, 988, 785, 719 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 2.99 (s, 3H, C–CH₃), 5.15 (d, J = 2.8 Hz, 1H, C=CH₂), 5.60 (d, J = 2.8 Hz, 1H, C=CH₂), 7.39–7.41 (m, 2H, ArH), 7.46–7.50 (m, 1H, ArH), 7.55–7.58 (m, 2H, ArH), 7.83–7.86 (m, 1H, ArH), 7.97 (d, J = 8.8 Hz, 1H, ArH), 9.16 (d, J = 2.0 Hz, 1H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ = 25.2, 98.8, 122.6, 122.9, 126.7, 128.2, 128.7, 128.7, 128.8, 129.7, 129.7, 130.2, 130.4, 133.9, 134.1, 142.6, 146.7, 153.8, 165.6; HRMS (TOF ES⁺): m/z calcd for C₁₉H₁₄BrN₂O [(M + H)⁺], 365.0284; found, 365.0283.

8-Bromo-2-(3-bromophenyl)-4-methyl-3-methylene-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-on (6n). White solid; mp 223.5–225.5 °C; IR (KBr): 1707, 1631, 1586, 1476, 1441, 1371, 1333, 1171, 886, 865, 682 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 2.99 (s, 3H, C–CH₃), 5.17 (d, J = 2.8 Hz, 1H, C=CH₂), 5.64 (d, J = 2.8 Hz, 1H, C=CH₂), 7.37 (d, J = 8.0 Hz, 1H, ArH), 7.42–7.46 (m, 1H, ArH), 7.59–7.63 (m, 2H, ArH), 7.84–7.87 (m, 1H, ArH), 7.98 (d, J = 9.2 Hz, 1H, ArH), 9.14 (d, J = 2.0 Hz, 1H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ = 25.3, 98.9, 122.8, 122.9, 123.0, 126.7, 127.4, 128.2, 129.9, 130.5, 130.9, 131.9, 132.0, 134.3, 135.2, 142.2, 146.8, 153.8, 165.4; HRMS (TOF ES⁺): m/z calcd for C₁₉H₁₃Br₂N₂O [(M + H)⁺], 442.9389; found, 442.9387.

8-Bromo-2-(4-chlorophenyl)-4-methyl-3-methylene-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-one (6o). White solid; mp 244–246 °C; IR (KBr): 1704, 1634, 1496, 1378, 1333, 1174, 1089, 1016, 863, 830, 774, 736 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 2.99 (s, 3H, C–CH₃), 5.14 (d, J = 2.8 Hz, 1H, C=CH₂), 5.62 (d, J = 2.8 Hz, 1H, C=CH₂), 7.35 (d, J = 8.8 Hz, 2H, ArH), 7.55 (d, J = 8.8 Hz, 2H, ArH), 7.84–7.87 (m, 1H, ArH), 7.97 (d, J = 9.2 Hz, 1H, ArH), 9.13 (d, J = 2.0 Hz, 1H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ = 25.3, 98.7, 122.8, 122.9, 126.7, 128.3, 130.0, 130.0, 130.0, 130.0, 130.0, 130.5, 132.4, 134.3, 134.7, 142.4, 146.7, 153.8, 165.5; HRMS (TOF ES⁺): m/z calcd for C₁₉H₁₃BrClN₂O [(M + H)⁺], 398.9894; found, 398.9890.

8-Bromo-2-(4-fluorophenyl)-4-methyl-3-methylene-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-one (6p). Pink solid; mp 230.5–233 °C; IR (KBr): 1702, 1633, 1512, 1393, 1222, 1182, 1160, 1061, 865, 831, 733, 699 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 2.97 (s, 3H, C–CH₃), 5.10 (s, 1H, C=CH₂), 5.60 (s, 1H, C=CH₂), 7.23–7.27 (m, 2H, ArH), 7.36–7.40 (m, 2H, ArH), 7.84 (d, J = 9.2 Hz, 1H, ArH), 7.95 (d, J = 9.2 Hz, 1H, ArH), 9.11 (s, 1H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ = 25.2, 98.6, 116.8 (d, J = 22.7 Hz), 116.8 (d, J = 22.7 Hz), 122.7, 122.8, 126.6, 128.2, 129.7, 130.0, 130.5 (d, J = 12.3 Hz), 130.5 (d, J = 12.3 Hz), 130.5, 134.2, 142.6, 146.7, 153.8, 162.5 (d, J = 247.2 Hz), 165.7; HRMS (TOF ES⁺): m/z calcd for C₁₉H₁₃BrFN₂O [(M + H)⁺], 383.0190; found, 383.0194.

8-Bromo-2-(3-fluorophenyl)-4-methyl-3-methylene-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-one (6q). White solid; mp 226.5–230 °C; IR (KBr): 1702, 1629, 1496, 1393, 1334, 1218, 1146, 890, 857, 827, 673 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 2.99 (s, 3H, C–CH₃), 5.19 (d, J = 2.8 Hz, 1H, C=CH₂), 5.64 (d, J = 2.8 Hz, 1H, C=CH₂), 7.14–7.23 (m, 3H, ArH), 7.51–7.57 (m, 1H, ArH), 7.84–7.87 (m, 1H, ArH), 7.97 (d, J = 8.8 Hz, 1H, ArH), 9.14 (d, J = 2.0 Hz, 1H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ = 25.3, 98.9, 115.9 (d, J = 20.9 Hz), 116.2 (d, J = 22.9 Hz), 122.8, 122.9, 124.5 (d, J = 3.4 Hz), 126.7, 128.2, 130.0, 130.5, 130.9 (d, J = 8.7 Hz), 134.3, 135.3 (d, J = 9.8 Hz), 142.2, 146.7, 153.8, 163.1 (d, J = 247.0 Hz), 165.4; HRMS (TOF ES⁺): m/z calcd for C₁₉H₁₃BrFN₂O [(M + H)⁺], 383.0190; found, 383.0192.

8-Chloro-4-methyl-3-methylene-2-(p-tolyl)-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-one (6r). White solid; mp 223–225 °C; IR (KBr): 1702, 1626, 1499, 1402, 1340, 1169, 1071, 873, 796, 742 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 2.50 (s, 3H, ArCH₃), 3.04 (s, 3H, C–CH₃), 5.19 (d, J = 2.4 Hz, 1H, C=CH₂), 5.63 (d, J = 2.4 Hz, 1H, C=CH₂), 7.32 (d, J = 8.0 Hz, 2H, ArH), 7.41 (d, J = 8.0 Hz, 2H, ArH), 7.74–7.76 (m, 1H, ArH), 8.08 (d, J = 9.2 Hz, 1H, ArH), 9.03 (d, J = 2.4 Hz, 1H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ = 21.3, 25.1, 98.6, 122.4, 123.3, 128.1, 128.3, 128.3, 130.2, 130.2, 130.2, 130.3, 131.0, 131.4, 134.1, 138.7, 142.6, 146.3, 153.5, 165.6; HRMS (TOF ES⁺): m/z calcd for C₂₀H₁₆ClN₂O [(M + H)⁺], 335.0946; found, 335.0946.

8-Chloro-4-methyl-3-methylene-2-phenyl-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-one (6s). Red solid; mp 231–233 °C; IR (KBr): 1702, 1629, 1496, 1388, 1331, 1184, 1071, 897, 873, 720, 695 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 3.00 (s, 3H, C–CH₃), 5.15 (d, J = 2.4 Hz, 1H, C=CH₂), 5.60 (d, J = 2.4 Hz, 1H, C=CH₂), 7.40 (d, J = 7.6 Hz, 2H, ArH), 7.46–7.50 (m, 1H, ArH), 7.55 (d, J = 7.6 Hz, 2H, ArH), 7.69–7.72 (m, 1H, ArH), 8.04 (d, J = 9.2 Hz, 1H, ArH), 8.98 (d, J = 2.4 Hz, 1H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ = 25.1, 98.7, 122.4, 123.3, 128.2, 128.6, 128.6, 128.6, 128.7, 129.6, 129.6, 130.2, 131.4, 133.8, 134.2, 142.5, 146.3, 153.5, 165.5; HRMS (TOF ES⁺): m/z calcd for C₁₉H₁₄ClN₂O [(M + H)⁺], 321.0789; found, 321.0788.

2-(3-Bromophenyl)-8-chloro-4-methyl-3-methylene-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-one (6t). White solid; mp 193.5–195 °C; IR (KBr): 1704, 1630, 1475, 1369, 1334, 1171, 1075, 865, 782, 748, 684 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 2.97 (s, 3H, C–CH₃), 5.16 (d, J = 2.4 Hz, 1H, C=CH₂), 5.62 (d, J = 2.4 Hz, 1H, C=CH₂), 7.36 (d, J = 8.0 Hz, 1H, ArH), 7.42 (d, J = 8.0 Hz, 1H, ArH), 7.59–7.62 (m, 2H, ArH), 7.68–7.71 (m, 1H, ArH), 8.01 (d, J = 8.8 Hz, 1H, ArH), 8.91 (d, J = 2.0 Hz, 1H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ = 25.1, 98.8, 122.2, 122.9, 123.1, 127.3, 128.1, 129.9, 130.3, 130.8, 131.5, 131.7, 131.8, 134.3, 135.0, 142.1, 146.3, 153.5, 165.3; HRMS (TOF ES⁺): m/z calcd for C₁₉H₁₃BrClN₂O [(M + H)⁺], 398.9900; found, 398.9904.

8-Chloro-2-(3-fluorophenyl)-4-methyl-3-methylene-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-one (6u). Yellow solid; mp 238–240 °C; IR (KBr): 1702, 1630, 1593, 1387, 1333, 1160, 1021, 883, 831, 692 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ = 3.06 (s, 3H, C–CH₃), 5.25 (d, J = 2.8 Hz, 1H, C=CH₂), 5.70 (d, J = 2.8 Hz, 1H, C=CH₂), 7.21–7.32 (m, 3H, ArH), 7.57–7.62 (m, 1H, ArH), 7.77–7.79 (m, 1H, ArH), 8.11 (d, J = 8.95 Hz, 1H, ArH), 9.02 (d, J = 2.15 Hz, 1H, ArH); ¹³C NMR (125 MHz, CDCl₃): δ = 25.5, 99.0, 116.2 (d, J = 20.8 Hz), 116.5 (d, J = 23.0 Hz), 122.7, 123.6, 123.6, 124.8, 128.6, 130.4, 130.6, 131.1 (d, J = 8.9 Hz), 132.0, 134.8, 135.6 (d, J = 5.8 Hz), 142.5, 146.8, 153.9, 163.4 (d, J = 250.6 Hz), 165.7; HRMS (TOF ES⁺): m/z calcd for C₁₉H₁₃ClFN₂O [(M + H)⁺], 339.0695; found, 339.0695.

8-Fluoro-2-(4-methoxyphenyl)-4-methyl-3-methylene-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-one (6v). Yellow solid; mp 200–202 °C; IR (KBr): 1703, 1634, 1515, 1387, 1252, 1193, 1036, 873, 867, 810, 786, 662 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ = 3.05 (s, 3H, C–CH₃), 3.94 (s, 3H, ArOCH₃), 5.16 (d, J = 2.4 Hz, 1H, C=CH₂), 5.64 (d, J = 2.3 Hz, 1H, C=CH₂), 7.12 (d, J = 8.75 Hz, 2H, ArH), 7.36 (d, J = 8.75 Hz, 2H, ArH), 7.58–7.62 (m, 1H, ArH), 8.16–8.19 (m, 1H, ArH), 8.67–8.69 (m, 1H, ArH); ¹³C NMR (125 MHz, CDCl₃): δ = 25.3, 56.0, 98.8, 108.5 (d, J = 23.8 Hz), 115.3, 115.3, 121.0 (d, J = 26.3 Hz), 123.0 (d, J = 11.3 Hz), 126.7, 128.5, 130.2, 130.2, 131.2 (d, J = 6.3 Hz), 131.5 (d, J = 10 Hz), 143.4, 145.6, 152.8, 160.1, 161.5 (d, J = 250.0 Hz), 166.4; HRMS (TOF ES⁺): m/z calcd for C₂₀H₁₆FN₂O₂ [(M + H)⁺], 335.1190; found, 335.1194.

8-Fluoro-4-methyl-3-methylene-2-(p-tolyl)-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-one (6w). Yellow solid; mp 165.5–167 °C; IR (KBr): 1717, 1634, 1514, 1374, 1341, 1243, 1210, 1093, 873, 804, 784, 753 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 2.45 (s, 3H, ArCH₃), 3.00 (s, 3H, C–CH₃), 5.13 (d, J = 2.8 Hz, 1H, C=CH₂), 5.59 (d, J = 2.4 Hz, 1H, C=CH₂), 7.28 (d, J = 8.4 Hz, 2H, ArH), 7.36 (d, J = 8.0 Hz, 2H, ArH), 7.52–7.57 (m, 1H, ArH), 8.10–8.14 (m, 1H, ArH), 8.62–8.65 (m, 1H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ = 21.4, 25.1, 98.6, 108.2 (d, J = 23.7 Hz), 120.7 (d, J = 25.9 Hz), 122.7 (d, J = 11.6 Hz), 128.2, 128.5, 128.5, 130.4, 130.4, 130.9 (d, J = 5.8 Hz), 131.2, 131.3, 133.8, 142.9, 145.3, 152.6 (d, J = 2.9 Hz), 161.6 (d, J = 248.5 Hz), 165.9; HRMS (TOF ES⁺): m/z calcd for C₂₀H₁₆FN₂O [(M + H)⁺], 319.1241; found, 319.1245.

8-Fluoro-4-methyl-3-methylene-2-phenyl-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-one (6x). White solid; mp 204.5–206 °C; IR (KBr): 1702, 1633, 1602, 1512, 1373, 1341, 1270, 1211, 1095, 870, 840, 692 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 3.00 (s, 3H, C–CH₃), 5.14 (d, J = 2.8 Hz, 1H, C=CH₂), 5.60 (d, J = 2.4 Hz, 1H, C=CH₂), 7.39–7.41 (m, 2H, ArH), 7.48–7.50 (m, 1H, ArH), 7.52–7.58 (m, 3H, ArH), 8.10–8.13 (m, 1H, ArH), 8.61–8.64 (m, 1H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ = 25.1, 98.6, 108.2 (d, J = 23.7 Hz), 120.8 (d, J = 25.9 Hz), 122.7 (d, J = 11.6 Hz), 128.3, 128.7, 128.7, 128.8, 129.7, 129.7, 130.9 (d, J = 6.0 Hz), 131.3 (d, J = 9.4 Hz), 133.9, 142.7, 145.3, 152.6 (d, J = 2.9 Hz), 161.7 (d, J = 248.6 Hz), 165.8; HRMS (TOF ES⁺): m/z calcd for C₁₉H₁₄FN₂O [(M + H)⁺], 305.1085; found, 305.1089.

2-(3-Bromophenyl)-8-fluoro-4-methyl-3-methylene-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-one (6y). White solid; mp 197–199 °C; IR (KBr): 1705, 1635, 1514, 1478, 1375, 1340, 1241, 1194, 870, 798, 772, 679 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 2.99 (s, 3H, C–CH₃), 5.16 (d, J = 1.6 Hz, 1H, C=CH₂), 5.63 (s, 1H, C=CH₂), 7.26–7.36 (m, 1H, ArH), 7.42–7.46 (m, 1H, ArH), 7.53–7.63 (m, 3H, ArH), 8.10–8.13 (m, 1H, ArH), 8.56–8.60 (m, 1H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ = 25.1, 98.8, 108.1 (d, J = 23.8 Hz), 120.9 (d, J = 25.9 Hz), 122.6 (d, J = 11.7 Hz), 123.0, 127.5, 128.2, 130.5, 130.9, 131.4 (d, J = 9.4 Hz), 131.9, 131.9, 135.2, 142.3, 145.3, 152.5 (d, J = 2.9 Hz), 161.7 (d, J = 249 Hz), 165.6; HRMS (TOF ES⁺): m/z calcd forC₁₉H₁₃BrFN₂O [(M + H)⁺], 383.0190; found, 383.0187.

8-Fluoro-2-(3-fluorophenyl)-4-methyl-3-methylene-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-one (6z). White solid; mp 221–223 °C; IR (KBr): 1700, 1633, 1596, 1514, 1494, 1376, 1344, 1223, 865, 775, 681 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 3.00 (s, 3H, C–CH₃), 5.18 (d, J = 2.4 Hz, 1H, C=CH₂), 5.63 (d, J = 2.4 Hz, 1H, C=CH₂), 7.15–7.26 (m, 3H, ArH), 7.53–7.57 (m, 2H, ArH), 8.10–8.13 (m, 1H, ArH), 8.57–8.60 (m, 1H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ = 25.1, 98.7, 108.1 (d, J = 23.7 Hz), 115.9 (d, J = 20.8 Hz), 116.3 (d, J = 23.0 Hz), 120.9 (d, J = 26.0 Hz), 122.6 (d, J = 11.7 Hz), 124.5 (d, J = 3.3 Hz), 128.2, 130.6 (d, J = 6.1 Hz), 130.9 (d, J = 9.0 Hz), 131.4 (d, J = 9.2 Hz), 135.3 (d, J = 9.9 Hz), 142.3, 145.3, 152.5 (d, J = 2.8 Hz), 161.7 (d, J = 248.7 Hz), 163.1 (d, J = 247.0 Hz), 165.3; HRMS (TOF ES⁺): m/z calcd for C₁₉H₁₃F₂N₂O [(M + H)⁺], 323.0990; found, 323.0996.

2-Butyl-6-fluoro-4-methyl-3-methylene-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-one (6a′). White solid; mp 90–92 °C; IR (KBr): 1699, 1510, 1469, 1227, 1089, 831, 758, 631 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ = 0.98–1.01 (m, 3H, CH₃), 1.41–1.48 (m, 2H, CH₂), 1.68–1.75 (m, 2H, CH₂), 3.03 (s, 3H, CH₃), 3.86–3.89 (m, 2H, CH₂), 5.28 (d, J = 2.8 Hz, 1H, C=CH₂), 5.62 (d, J = 2.8 Hz, 1H, C=CH₂), 7.44–7.48 (m, 1H, ArH), 7.57–7.61 (m, 1H, ArH), 8.78 (d, J = 8.5 Hz, 1H, ArH); ¹³C NMR (125 MHz, CDCl₃): δ = 14.1, 20.6, 25.6, 31.0, 39.6, 97.1, 114.9 (d, J = 20.0 Hz), 120.5 (d, J = 5.0 Hz), 123.8, 128.2 (d, J = 8.8 Hz), 128.8, 131.9, 138.2 (d, J = 11.3 Hz), 141.5, 154.0, 157.8 (d, J = 253.8 Hz), 166.3; HRMS (TOF ES⁺): m/z calcd for C₁₇H₁₈FN₂O [(M + H)⁺], 285.1398; found, 285.1399.

2-Cyclohexyl-4-methyl-3-methylene-6-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-one (6b′). White solid; mp 164–166 °C; IR (KBr): 1691, 1511, 1375, 1303, 1133, 845, 767 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ = 1.33–1.38 (m, 1H, CH₂), 1.41–1.49 (m, 2H, CH₂), 1.77–1.80 (m, 1H, CH₂), 1.86–1.89 (m, 2H, CH₂), 1.89–1.98 (m, 2H, CH₂), 2.34–2.41 (m, 2H, CH₂), 3.05 (s, 3H, CH₃), 4.12–4.15 (m, 1H, CH), 5.46 (d, J = 2.9 Hz, 1H, C=CH₂), 5.69 (d, J = 2.9 Hz, 1H, C=CH₂), 7.68–7.71 (m, 1H, ArH), 8.11 (d, J = 7.3 Hz, 1H, ArH), 9.26 (d, J = 8.1 Hz, 1H, ArH); ¹³C NMR (125 MHz, CDCl₃): δ = 25.8, 26.0, 26.8, 26.8, 30.3, 30.3, 53.5, 97.7, 122.8, 124.3 (J = 271.3 Hz), 126.7, 127.8 (J = 30.0 Hz), 128.4, 128.6, 128.9, 131.7, 141.2, 144.4, 154.4, 166.7; HRMS (TOF ES⁺): m/z calcd for C₂₀H₂₀F₃N₂O [(M + H)⁺], 361.1522; found, 361.1526.

2-Butyl-4-methyl-3-methylene-6-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-one (6c′). White solid; mp 113–115 °C; IR (KBr): 1701, 1578, 1510, 1452, 1348, 1300, 1130, 840, 675 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ = 0.99–1.02 (m, 3H, CH₃), 1.42–1.49 (m, 2H, CH₂), 1.70–1.76 (m, 2H, CH₂), 3.05 (s, 3H, CH₃), 3.88–3.91 (m, 2H, CH₂), 5.30 (d, J = 2.9 Hz, 1H, C=CH₂), 5.65 (d, J = 2.9 Hz, 1H, C=CH₂), 7.69–7.72 (m, 1H, ArH), 8.12 (d, J = 7.3 Hz, 1H, ArH), 9.24 (d, J = 8.2 Hz, 1H, ArH); ¹³C NMR (125 MHz, CDCl₃): δ = 14.2, 20.6, 25.8, 31.0, 39.6, 97.2, 122.8, 124.4 (J = 271.3 Hz), 126.8, 127.8 (J = 28.8 Hz), 128.5, 128.7, 128.8, 131.8, 141.4, 145.8, 154.5, 166.5; HRMS (TOF ES⁺): m/z calcd for C₁₈H₁₈F₃N₂O [(M + H)⁺], 335.1366; found, 335.1374.

4-Methyl-3-methylene-2-((tetrahydrofuran-2-yl)methyl)-6-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-one (6d′). White solid; mp 146–148 °C; IR (KBr): 1695, 1581, 1395, 1349, 1305, 1120, 1085, 873, 786, 680, 559 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ = 1.76–1.81 (m, 1H, CH₂), 1.92–1.98 (m, 2H, CH₂), 2.05–2.10 (m, 1H, CH₂), 3.04 (s, 3H, CH₃), 3.76–3.80 (m, 1H, CH₂), 3.91–3.96 (m, 2H, CH₂), 4.03–4.07 (m, 1H, CH₂), 4.28–4.30 (m, 1H, CH), 5.55 (d, J = 2.7 Hz, 1H, C=CH₂), 5.69 (d, J = 2.7 Hz, 1H, C=CH₂), 7.69–7.72 (m, 1H, ArH), 8.12 (d, J = 7.3 Hz, 1H, ArH), 9.23 (d, J = 8.3 Hz, 1H, ArH); ¹³C NMR (125 MHz, CDCl₃): δ = 25.9, 26.0, 29.7, 44.1, 68.7, 98.6, 122.7, 124.4 (J = 272.5 Hz), 126.8, 127.8 (J = 30.0 Hz), 128.7, 128.7, 128.8, 129.0, 131.5, 141.7, 144.5, 154.6, 166.8; HRMS (TOF ES⁺): m/z calcd for C₁₉H₁₈F₃N₂O₂ [(M + H)⁺], 363.1315; found, 363.1314.

2-(Furan-2-ylmethyl)-4-methyl-3-methylene-6-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-one (6e′). White solid; mp 141–143 °C; IR (KBr): 1705, 1630, 1509, 1346, 1135, 1083, 1011, 952, 848, 771, 676, 642 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ = 3.02 (s, 3H, CH₃), 5.08 (s, 2H, CH₂), 5.50 (d, J = 3.0 Hz, 1H, C=CH₂), 5.66 (d, J = 3.0 Hz, 1H, C=CH₂), 6.35 (d, J = 4.2 Hz, 2H, CH), 7.38 (s, 1H, CH), 7.69–7.72 (m, 1H, ArH), 8.12 (d, J = 7.3 Hz, 1H, ArH), 9.24 (d, J = 8.4 Hz, 1H, ArH); ¹³C NMR (125 MHz, CDCl₃): δ = 25.8, 36.6, 98.2, 108.8, 111.0, 122.7, 124.3 (J = 271.3 Hz), 126.9, 127.8 (J = 28.8 Hz), 128.6, 128.9, 129.0, 131.4, 140.9, 142.9, 144.5, 150.0, 154.6, 166.1; HRMS (TOF ES⁺): m/z calcd for C₁₉H₁₄F₃N₂O₂ [(M + H)⁺], 359.1002; found, 359.1005.

2-Butyl-4-methyl-3-methylene-8-nitro-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-one (6f′). Yellow solid; mp 203–205 °C; IR (KBr): 1698, 1634, 1495, 1395, 1229, 1080, 913, 845, 760, 633, 573 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ = 0.99–1.02 (m, 3H, CH₃), 1.42–1.49 (m, 2H, CH₂), 1.71–1.77 (m, 2H, CH₂), 3.04 (s, 3H, CH₃), 3.90–3.93 (m, 2H, CH₂), 5.37 (d, J = 2.9 Hz, 1H, C=CH₂), 5.69 (d, J = 2.9 Hz, 1H, C=CH₂), 8.19 (d, J = 8.3 Hz, 1H, ArH), 8.50–8.52 (m, 1H, ArH), 9.86 (d, J = 2.4 Hz, 1H, ArH); ¹³C NMR (125 MHz, CDCl₃): δ = 14.2, 20.6, 25.7, 31.0, 39.8, 98.1, 121.2, 121.6, 124.1, 129.5, 130.7, 133.4, 141.1, 146.8, 149.9, 157.5, 165.6; HRMS (TOF ES⁺): m/z calcd for C₁₇H₁₈N₃O₃ [(M + H)⁺], 312.1343; found, 312.1349.

4-Methyl-3-methylene-8-nitro-2-phenyl-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-one (6g′). Yellow solid; mp 226–228 °C; IR (KBr): 1700, 1528, 1498, 1379, 1337, 1117, 917, 887, 723 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ = 3.10 (s, 3H, CH₃), 5.27 (d, J = 2.7 Hz, 1H, C=CH₂), 5.73 (d, J = 2.7 Hz, 1H, C=CH₂), 7.43 (d, J = 7.6 Hz, 2H, ArH), 7.51–7.54 (m, 1H, ArH), 7.59–7.62 (m, 2H, ArH), 8.25 (d, J = 9.35 Hz, 1H, ArH), 8.54–8.56 (m, 1H, ArH), 9.90 (d, J = 2.5 Hz, 1H, ArH); ¹³C NMR (125 MHz, CDCl₃): δ = 25.8, 100.2, 121.3, 121.6, 124.3, 128.9, 128.9, 129.3, 129.4, 130.1, 130.1, 130.8, 132.8, 133.9, 142.5, 146.9, 150.1, 157.7, 165.3; HRMS (TOF ES⁺): m/z calcd for C₁₉H₁₄N₃O₃ [(M + H)⁺], 332.1030; found, 332.1032.

4-Methyl-3-methylene-8-(morpholinosulfonyl)-2-phenyl-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-one (6h′). Yellow solid; mp 224–226 °C; IR (KBr): 1708, 1631, 1499, 1265, 1163, 1112, 947, 839, 741, 635, 599 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ = 3.10 (s, 3H, CH₃), 3.11–3.13 (m, 4H, CH₂), 3.74–3.76 (m, 4H, CH₂), 5.25 (d, J = 2.8 Hz, 1H, C=CH₂), 5.72 (d, J = 2.8 Hz, 1H, C=CH₂), 7.43 (d, J = 7.5 Hz, 2H, ArH), 7.50–7.53 (m, 1H, ArH), 7.58–7.61 (m, 2H, ArH), 8.10–8.12 (m, 1H, ArH), 8.29 (d, J = 8.9 Hz, 1H, ArH), 9.47 (d, J = 2.0 Hz, 1H, ArH); ¹³C NMR (125 MHz, CDCl₃): δ = 25.7, 46.5, 46.5, 66.5, 66.5, 100.0, 121.6, 125.7, 128.3, 128.9, 128.9, 129.3, 130.1, 130.1, 130.1, 130.5, 132.2, 133.9, 135.3, 142.7, 149.4, 157.0, 165.6; HRMS (TOF ES⁺): m/z calcd for C₂₃H₂₁N₃NaO₄S [(M + Na)⁺], 458.1145; found, 458.1149.

General procedure for the synthesis of pyrrolo[3,4-c]quinoline-1,3-diones (7)

The 3-methylene pyrrolo[3,4-c]quinolin-1-one 6d/6f (0.2 mmol) is then dissolved in acetone, and the KMnO₄/Al₂O₃ powder (90 mg supported reagent, 0.3 mmol KMnO₄) added room temperature. After five hours of vigorous stirring, the reaction mixture is filtered and the acetone filtrate condensed. The residue is taken up into EtOAc, washed with dilute hydrochloric acid, dried over Na₂SO₄, concentrated and purified by flash column chromatography to give the product 7a/7b.

2-(2-Bromophenyl)-4-methyl-1H-pyrrolo[3,4-c]quinoline-1,3(2H)-dione (7a). White solid; mp 202–204 °C; IR (KBr): 1712, 1625, 1476, 1371, 1126, 1096, 1028, 754, 737, 665 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 3.10 (s, 3H, C–CH₃), 7.38–7.42 (m, 2H, ArH), 7.48–7.52 (m, 1H, ArH), 7.72–7.79 (m, 2H, ArH), 7.89–7.94 (m, 1H, ArH), 8.17 (d, J = 8.4 Hz, 1H, ArH), 8.84 (d, J = 8.4 Hz, 1H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ = 22.3, 120.8, 121.8, 123.4, 125.1, 128.5, 129.2, 129.4, 131.0, 131.0, 131.2, 133.0, 133.7, 135.8, 151.8, 155.4, 166.6, 166.8; HRMS (TOF ES⁺): m/z calcd for C₁₈H₁₂BrN₂O₂ [(M + H)⁺], 367.0082; found, 367.0085.

2-(2-Chlorophenyl)-4-methyl-1H-pyrrolo[3,4-c]quinoline-1,3(2H)-dione (7b). White solid; mp 184–186 °C; IR (KBr): 1714, 1624, 1483, 1373, 1115, 1065, 1029, 754, 737, 691 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 3.10 (s, 3H, C–CH₃), 7.40–7.47 (m, 3H, ArH), 7.59–7.61 (m, 1H, ArH), 7.71–7.75 (m, 1H, ArH), 7.89–7.93 (m, 1H, ArH), 8.16 (d, J = 8.8 Hz, 1H, ArH), 8.83 (d, J = 8.4 Hz, 1H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ = 22.3, 120.8, 121.8, 125.1, 127.8, 129.2, 129.2, 129.4, 130.5, 130.8, 130.9, 133.0, 133.3, 135.9, 151.8, 155.4, 166.6, 166.8; HRMS (TOF ES⁺): m/z calcd for C₁₈H₁₂ClN₂O₂ [(M + H)⁺], 323.0587; found, 323.0588.

Acknowledgements

We are grateful for the financial support from the National Natural Science Foundation of China (21402070), the Personnel Training Foundation of Kunming University of Science and Technology (14118841) and The Analytical & Testing Foundation of Kunming University of Science and Technology (20150751, 20150742).

Notes and references

1. (a) I. Okun, S. Malarchuk, E. Dubrovskaya, A. Khvat, S. Tkachenko, V. Kysil, D. Kravchenko and A. Ivachtchenko, J. Biomol. Screening, 2006, 11, 694; (b) V. Gasparotto, I. Castagliuolo, G. Pezzi, V. Chiarelotto, G. Montanaro, P. Brun, G. Palu and M. G. Ferlin, J. Med. Chem., 2006, 49, 1910; (c) Y. Sangnoi, O. Sakulkeo, S. Yuenyongsawad, A. Kanjanaopas, K. Ingkaninan, A. Plubrukarn and K. Suwanborirux, Mar. Drugs, 2008, 6, 578; (d) V. Estévez, M. Villacampa and J. C. Menéndez, Chem. Soc. Rev., 2010, 39, 4402; (e) A. R. Carroll, S. Duffy and V. M. Avery, J. Org. Chem., 2010, 75, 8291; (f) P. W. Okanya, K. I. Mohr, K. Gerth, R. Jansen and R. Muller, J. Nat. Prod., 2011, 74, 603; (g) T. H. Brown, R. J. Ife, D. J. Keeling, S. M. Laing, C. A. Leach, M. E. Parsons, C. A. Price, D. R. Reavill and K. J. Wiggall, J. Med. Chem., 1990, 33, 527; (h) L. Xia, A. Idhayadhulla, Y. R. Lee, S. H. Kim and Y.-J. Wee, ACS Comb. Sci., 2014, 16, 333.
2. Z. Thale, T. Johnson, K. Tenney, P. J. Wenzel, E. Lobkovsky, J. Clardy, J. Media, H. Pietraszkiewicz, F. A. Valeriote and P. Crews, J. Org. Chem., 2002, 67, 9384.
3. (a) D. V. Kravchenko, V. V. Kysil, A. P. Ilyn, S. E. Tkachenko, S. Maliarchouk, I. M. Okun and A. V. Ivachtchenko, Bioorg. Med. Chem. Lett., 2005, 15, 1841; (b) C.-H. Tseng, Y.-L. Chen, P.-J. Lu, C.-N. Yang and C.-C. Tzeng, J. Med. Chem., 2005, 48, 3680; (c) D. V. Kravchenko, V. M. Kysil, S. E. Tkachenko, S. Maliarchouk, I. M. Okun and A. V. Ivachtchenko, Farmaco, 2005, 60, 804; (d) D. V. Kravchenko, V. M. Kysil, S. E. Tkachenko, S. Maliarchouk, I. M. Okun and A. V. Ivachtchenko, Eur. J. Med. Chem., 2005, 40, 1377; (e) S. Sharma, K. Sahu, P. Jain, V. K. Mourya and R. K. Agrawal, Med. Chem. Res., 2008, 17, 399.
4. V. Summa, P. Pace, M. E. Di Francesco, J. I. Martin Hernando and E. Nizi, Brit. UK Pat. Appl., GB-2450771, 2009.
5. S. Eswaran, A. V. Adhikari and R. A. Kumar, Eur. J. Med. Chem., 2010, 45, 957.
6. C. Andrea, N. Chiara, V. Salvatore, G. Germano, A. Maurizio, M. Laura, G. Antonio, C. Gianfranco, P. S. Luigi, M. Francesco, G. Gianluca and V. Salvatore, ChemMedChem, 2010, 5, 739.
7. A. H. Kategaonkar, R. U. Pokalwar, S. S. Sonar, V. U. Gawali, B. B. Shingate and M. S. Shingare, Eur. J. Med. Chem., 2010, 45, 1128.
8. Y.-L. Chen, I.-L. Chen, C.-M. Lu, C.-C. Tzeng, L.-T. Tsao and J.-P. Wang, Bioorg. Med. Chem., 2004, 12, 387.
9. P. Camps, X. Formosa, C. Galdeano, D. Muñoz-Torrero, L. Ramírez, E. Gomez, N. Isambert, R. Lavilla, A. Badia, M. V. Clos, M. Bartooini, F. Mancini, V. Andrisano, M. P. Arce, M. I. Rodíguez-Franco, O. Huertas, T. Dafni and F. J. Luque, J. Med. Chem., 2009, 52, 5365.
10. (a) J. B. J. Milbank, R. J. Stevenson, D. C. Ware, J. Y. C. Chang, M. Tercel, G. O. Ahn, W. R. Wilson and W. A. Denny, J. Med. Chem., 2009, 52, 6822; (b) F. A. Valeriote, K. Tenney, J. Media, H. Pietraszkiewicz, M. Edelstein, T. A. Johnson, T. Amagata and P. Crews, J. Exp. Ther. Oncol., 2012, 10, 119.
11. (a) R. Di Santo, R. Costi, M. Forte and C. Galeffi, ARKIVOC, 2004, 181; (b) G. Furlotti, M. A. Alisi, C. Apicella, A. Capezzone de Joannon, N. Cazzolla, R. Costi, G. C. Crucitti, B. Garrone, A. Iacovo, G. Magarò, G. Mangano, G. Miele, R. Ombrato, L. Pescatori, L. Polenzani, F. Rosi, M. Vitiello and R. Di Santo, J. Med. Chem., 2012, 55, 9446; (c) X. Ma, Y. Vo, M. G. Banwell and A. C. Willis, Asian J. Org. Chem., 2012, 1, 160; (d) R. Wang, X.-P. Xu, H. Meng, S.-Y. Wang and S.-J. Ji, Tetrahedron, 2013, 69, 1761; (e) X.-M. Lu, J. Li, Z.-J. Cai, R. Wang, S.-Y. Wang and S.-J. Ji, Org. Biomol. Chem., 2014, 12, 9471; (f) Y. Zhao, Q. Duan, Y. Zhou, Q. Yao and Y. Li, Org. Biomol. Chem., 2016, 14, 2177.
12. (a) F.-C. Yu, S.-J. Yan, L. Hu, Y.-C. Wang and J. Lin, Org. Lett., 2011, 13, 4782; (b) B. Jiang, X. Wang, M.-Y. Li, Q. Wu, Q. Ye, H.-W. Xu and S.-J. Tu, Org. Biomol. Chem., 2012, 10, 8533; (c) H.-Y. Wang, L.-L. Li, W. Lin, P. Xu, Z.-B. Huang and D.-Q. Shi, Org. Lett., 2012, 14, 4598; (d) B. Jiang, X. Wang, H.-W. Xu, M.-S. Tu, S.-J. Tu and G.-G. Li, Org. Lett., 2013, 15, 1540; (e) W.-J. Hao, J.-Q. Wang, X.-P. Xu, S.-L. Zhang, S.-Y. Wang and S.-J. Ji, J. Org. Chem., 2013, 78, 12362; (f) C.-P. Cao, C.-L. Xu, W. Lin, X.-M. Li, M.-H. Hu, J.-X. Wang, Z.-B. Huang, D.-Q. Shi and Y.-C. Wang, Molecules, 2013, 18, 1613; (g) F.-C. Yu, B. Zhou, H. Xu, Y.-M. Li, J. Lin, S.-J. Yan and Y. Shen, Tetrahedron, 2015, 71, 1036.
13. (a) A. Mortoni, M. Martinelli, U. Piarulli, N. Regalia and S. Gagliardi, Tetrahedron Lett., 2004, 45, 6623A. Godard and G. Queguiner, J. Heterocycl. Chem., 1980, 17, 465; (b) D. V. Kravchenko, Y. A. Ivanenkov, K. V. Balakin, V. M. Kisil, S. E. Tkachenko, I. M. Okun and A. V. Ivashchenko, Pharm. Chem. J., 2006, 40, 127; (c) D. V. Kravchenko, V. M. Kysil, A. P. Ilyn, S. E. Tkachenko, S. Maliarchouk, I. M. Okun and A. V. Ivachtchenko, Synth. Commun., 2006, 36, 911; (d) M. S. T. Makki, D. A. Bakhotmah and R. M. Abdel-Rahman, Int. J. Org. Chem., 2012, 2, 49.
14. J. Li, S. Su, M. Huang, B. Song, C. Li and X. Jia, Chem. Commun., 2013, 49, 10694.
15. L. Xia and Y. R. Lee, Org. Biomol. Chem., 2013, 11, 5254.
16. S. Avula, S. Koppireddi, J. R. Komsani, J. B. Nanubolu and R. Yadla, RSC Adv., 2013, 3, 20990.
17. CCDC 1438897 contain the supplementary crystallographic data for compound 6p.
18. C. E. Harris, W. Chrisman, S. A. Bickford, L. Y. Lee, A. E. Torreblanca and B. Singaram, Tetrahedron Lett., 1997, 38, 981.
19. (a) Z. Duan, T. Li, X. J. Xuan and Y. J. Wu, Chin. Chem. Lett., 2006, 17, 1566; (b) M. M. Khodaei, A. R. Khosropour and C. Cardel, J. Chin. Chem. Soc., 2008, 55, 217.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 6p (1438897). For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra15492a

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