Synthesis of pyrrolo[3,4- c ]carbazole-1,3(2 H,6 H )-diones via addition/cyclization reactions between 3-chloro-4-indolylmaleimides and alkynes

Abstract

3-Chloro-4-indolylmaleimides and two different alkynes are used as the starting materials in a novel and highly effective Pd-catalyzed addition/C–H activation/cyclization sequence for the synthesis of pyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones. The desired products are obtained in moderate to excellent yields. Such compounds show a wide range of biological activities.

Introduction

Pyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones have attracted significant attention in pharmaceutical chemistry because of their wide range of biological activities, for example, inhibition of PARP-1, ¹ Chk 1,^2,3 and D1-CDK4, ⁴ JNK, ⁵ GSK-3.^6,7 Relatively, few synthetic methods for the synthesis of pyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones have been reported. The main previously reported methods are as follows: (1) A 2-vinylindole derivative is synthesized via a Wittig reaction between an indolaldehyde and phosphorus ylides. The 2-vinylindole derivative then undergoes a Diels–Alder reaction with maleimide, and the product is oxidized by MnO₂ or DDQ (2,3-Dichloro-5,6-dicyano-1,4-benzoquinone) to form the target compound (Scheme 1(a)). ² (2) 3-Bromo-4-indolylmaleimide is reacted with o-bromophenylboronic acid via a Suzuki reaction to obtain a diarylmaleimide derivative, which is then cyclized via a Heck reaction to form the product (Scheme 1(b)). ⁸ (3) Condensation of indole-3-acetamide with methyl 2-(1H-indol-3-yl)-2-oxoacetate in the presence of potassium t-butoxide gives a diarylmaleimide, which is then converted into the target product using DDQ, I₂, ⁹ Pd(OAc)₂, ¹⁰ or PdCl₂ (Scheme 1(c)). ¹¹ In the current study, a novel highly effective Pd-catalyzed addition/C–H activation/cyclization of 3-chloro-4-indolylmaleimides and alkynes is used to synthesize pyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones. Such compounds have a wide spectrum of biological activities. The procedure is high-yielding and also easy to operate (Scheme 1(d)).

Scheme 1.

Synthesis of pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione: (a)–(c) Current synthetic strategies and (d) this work.

Results and discussion

Synthesis

Initially, 3-chloro-4-indolylmaleimide and diphenylacetylene were used as model substrates to investigate the effects of factors such as the base, ligand, solvent, and reaction time (Table 1). Pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione was obtained in 50% yield via the reaction between 1a (0.2 mmol) and diphenylacetylene (2a)(0.4 mmol), with N, N-diisopropylethylamine (0.6 mmol) as the base, Pd(OAc)₂ (20 mol%) as the catalyst, PCy₃·HBF₄ (40 mol%) as the ligand, and anhydrous DMF (dimethylformamide) (1 mL) as the solvent. The reaction was performed at 135°C for 20 h under a nitrogen atmosphere. Because of the large amounts of Pd catalyst and ligand required and the low yield obtained in the initial trial, the reaction conditions were further studied. First, the amount of the Pd(OAc)₂ catalyst and the PCy₃·HBF₄ ligand were decreased to 5 mol% and 10 mol%, respectively, and the reaction time was extended to 40 h. The effect of the base on the reaction was then investigated. Diisopropylamines proved to be efficient and gave a 59% yield of 3a (Table 1, entries 2–10). Solvent screening showed that dimethyl sulfoxide was the best solvent giving a yield of 63% (Table 1, entries 10–17). There were still some unreacted starting materials in the reaction system after 40 h; therefore, the reaction time was extended to 52 h. A yield of 94% was achieved; however, the yield decreased to 87% when the reaction time was increased to 72 h (Table 1, entries 15, 18, and 19). The effects of various ligands and catalysts on the reaction were also investigated. The results indicated that the target product was obtained effectively with PtBu₃, PPh₃, or DPPE (1,2-Bis(diphenylphosphino)ethane) as the ligand and Pd(OAc)₂ or Pd(PPh₃)₄ as the catalyst. However, the yields were reduced (Table 1, entries 20–23).

Table 1.

Optimization of the reaction conditions ^a .

Entry	Base	Solvent	Pd-cat.	Ligand	Time (h)	Yield (%) b
1 c	DIPEA	DMF	Pd(OAc)2	PCy3·HBF4	20	50
2	CsCO3	DMF	Pd(OAc)2	PCy3·HBF4	40	trace
3	K2CO3	DMF	Pd(OAc)2	PCy3·HBF4	40	trace
4	NaOAc	DMF	Pd(OAc)2	PCy3·HBF4	40	20
5	t-BuOK	DMF	Pd(OAc)2	PCy3·HBF4	40	11
6	DBU	DMF	Pd(OAc)2	PCy3·HBF4	40	trace
7	Pyridine	DMF	Pd(OAc)2	PCy3·HBF4	40	trace
8	Et3N	DMF	Pd(OAc)2	PCy3·HBF4	40	37
9	DIPEA	DMF	Pd(OAc)2	PCy3·HBF4	40	49
10	DIPA	DMF	Pd(OAc)2	PCy3·HBF4	40	59
11	DIPA	NMP	Pd(OAc)2	PCy3·HBF4	40	41
12	DIPA	THF	Pd(OAc)2	PCy3·HBF4	40	33
13	DIPA	toluene	Pd(OAc)2	PCy3·HBF4	40	34
14	DIPA	1,4-dioxane	Pd(OAc)2	PCy3·HBF4	40	37
15	DIPA	DMSO	Pd(OAc)2	PCy3·HBF4	40	63
16	DIPA	DCE	Pd(OAc)2	PCy3·HBF4	40	59
17	DIPA	CH3CN	Pd(OAc)2	PCy3·HBF4	40	27
18	DIPA	DMSO	Pd(OAc)2	PCy3·HBF4	52	94
19	DIPA	DMSO	Pd(OAc)2	PCy3·HBF4	72	87
20	DIPA	DMSO	Pd(OAc)2	PtBu3·HBF4	52	71
21	DIPA	DMSO	Pd(OAc)2	PPh3	52	67
22	DIPA	DMSO	Pd(OAc)2	DPPE	52	29
23	DIPA	DMSO	Pd(PPh)4	/	52	38

DIPEA: N,N-Diisopropylethylamine; DMF: dimethylformamide; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; DIPA: diisopropylamine; NMP: N-Methyl-2-pyrrolidone; DMSO: dimethyl sulfoxide; DCE: 1,2-dichloroethane; DPPE: 1,2-Bis(diphenylphosphino)ethane.

a

Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), Pd-cat. (5 mol%), ligand (10 mol%), base (0.6 mmol), solvent (0.2 M), N₂ atmosphere, 135°C.

b

Isolated yields.

c

Pd(OAc)₂ (20 mol%) and PCy₃·HBF₄ (40 mol%) were used for 20 h.

The optimized conditions for the model reaction were therefore 3-chloro-4-indolylmaleimide (1a)(1.0 equiv.) and diphenylacetylene (2a) (2.0 equiv.) as the reactants, diisopropylamine (3.0 equiv.) as the base, Pd(OAc)₂ (0.05 equiv.) as the catalyst, PCy₃·HBF₄ (0.1 equiv.) as the ligand and dimethyl sulfoxide as the solvent, a reaction temperature of 135°C, a reaction time of 52 h, and nitrogen as an inert atmosphere. These conditions gave an isolated yield of product 3a of 94% (Table 1, entry 18).

Further investigations were performed under the optimized reaction conditions to determine the substrate scope of the reaction. First, the effect of the substituent on the indole ring in the 3-chloro-4-indolylmaleimide was investigated. The electronic properties of the R¹ group greatly affected the reaction yield (Table 2, products 3a–g). A high yield was obtained when R¹ was an electron-donating group such as methyl or methoxy (Table 2, products 3e and 3f). When R¹ was a fluorine atom, which is an electron acceptor, the yield was considerably lower (Table 2, product 3b). The use of chlorine as R¹ also decreased the yield (Table 2, products 3c and 3d). This could be because of competition from an alkenyl chloride intermediate during the oxidative-addition stage, which would lead to by-product formation. In addition, the introduction of a large benzyl group (R ² ) on the nitrogen atom of the indole ring did not affect the reaction yield (Table 2, product 3h). This suggests that this site has good potential for modification. The use of 4-octyne rather than diphenylacetylene as the alkyne substrate gave product 3i in 95% yield (Scheme 2). This indicates that, similarly to an arylalkyne, an alkylalkyne reacts with 3-chloro-4-indolylmaleimide to form the target product in high yield.

Table 2.

Scope of substituted indoles ^a .

DIPA: diisopropylamine; DMSO: dimethyl sulfoxide.

a

Reaction conditions: 1a–h (0.2 mmol), 2a (0.4 mmol), Pd(OAc)₂ (5 mol%), PCy₃·HBF₄ (10 mol%), DIPA (0.6 mmol), DMSO (0.2 M), N₂ atmosphere, 135°C.

Scheme 2.

4-Octyne as the alkyne substrate for the construction of a carbazole derivative.

Scheme 3.

Transformations of the carbazole.

Scheme 4.

The proposed reaction pathway.

The use of this reaction to obtain structurally diverse pyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones was explored by investigating transformations of products 3a, 3c, and 3e(Scheme 3).

Compounds 3a, 3c, and 3e were aminolyzed by ammonia to give maleimide compounds 4a–c in high yields. Aminolysis of 3a with a methylamine–ethanol solution at room temperature gave N-methylmaleimide 4d. This indicates high potential for subsequent product modification.

On the basis of relevant literature reports^12–15 and our experimental results, the following possible reaction mechanism is proposed (Scheme 4). In the first step, Pd(0) catalyzes an oxidative-addition reaction of the C–Cl bond in substrate 1a to give intermediate A. In the second step, Pd coordinates with the C–C triple bond in alkyne 2a to form complex B. In the third step, alkyne insertion leads to chloroalkenyl–palladium intermediate C. In the fourth step, Pd(II) participates in electrophilic substitution with the indole to form intermediate D. In the fifth step, intramolecular C–H activation leads to formation of a seven-membered palladium-containing ring E. Finally, product 3a is obtained via reductive elimination, and the regenerated Pd(0) participates in the next catalytic cycle.

Conclusion

In the current study, a novel and highly effective Pd-catalyzed addition/C–H activation/cyclization strategy, with 3-chloro-4-indolylmaleimides and alkynes as starting materials, has been used for the synthesis of pyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones. These compounds have been previously shown to demonstrate a wide range of biological activities.^1–7 The method gives high yields and tolerates a wide range of functional groups. The obtained target compounds have high conversion potential.

Experimental section

Experimental

All reagents used in the synthesis were obtained commercially and used without further purification, unless otherwise specified. Melting points were determined with a BÜCHI Melting Point B-450 apparatus (BüchiLabortechnik, Flawil, Switzerland) and are uncorrected. The ¹H NMR (500 MHz) and ¹³C NMR (125 MHz) spectra were recorded on a Bruker ANANCE III spectrometer using TMS as the internal standard, and the coupling constants are reported in hertz. CDCl₃ or DMSO (dimethyl sulfoxide) was used as the solvent, and chemical shifts (δ) are reported in parts per million (ppm). The reactions were followed by thin-layer chromatography (TLC) on GF-254 glass-packed precoated silica gel plates and visualized in an iodine chamber or with a ultraviolet (UV) lamp. Column chromatography purifications were performed on silica gel (200–300 mesh). High-resolution mass spectra (HRMS) were recorded on a Thermo Scientific LTQ Orbitrap XL mass instrument (ESI). Anhydrous THF and toluene were distilled from sodium-benzophenone. Anhydrous CH₂Cl₂, DMF, and DMSO were distilled from calcium hydride.

General procedure for the synthesis of pyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones 3a–i

To a dried Schlenk tube were added 3-chloro-4-indolylmaleimide 1 (0.2 mmol), Pd(OAc)₂ (0.01 mmol), PCy₃·HBF₄ (0.02 mmol), and alkyne 2 (0.4 mmol) under N₂. DIPA (diisopropylamine) (0.6 mmol) and DMSO (1.0 mL) were then introduced via syringe. The mixture was stirred at 135°C for 52 h. After cooling to room temperature, the mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL × 3). The organic phase was combined, dried over anhydrous sodium sulfate, and filtered. Evaporation of the solvent under reduced pressure yielded the crude product, which was then purified by silica gel column chromatography, eluting with petroleum ether/dichloromethane/ethyl acetate 200: 100:1 (v/v/v) to afford the product.

6-Methyl-2,4,5-triphenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (3a)

Yellow solid, 94% yield, m.p.: >250°C. ¹H NMR (500 MHz, CDCl₃): δ 9.31 (d, J = 7.9 Hz, 1H), 7.67–7.59 (m, 1H), 7.57–7.45 (m, 4H), 7.42–7.46 (m, 3H), 7.33–7.27 (m, 3H), 7.26–7.19 (m, 5H), 7.15 (dd, J = 6.6, 2.9 Hz, 2H), 3.25 (s, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 168.0, 167.6, 144.2, 142.8, 137.8, 136.3, 136.1, 132.2, 131.3 (2C), 130.2, 130.1 (2C), 128.8 (2C), 128.5, 127.8, 127.7 (2C), 127.6, 127.2 (2C), 127.0, 126.8 (2C), 126.3, 125.2, 121.2, 120.5, 120.3, 120.1, 109.0, 32.6; HRMS (ESI): m/z calcd for C₃₃H₂₃N₂O₂ [M + H]⁺: 479.1754, found: 479.1767.

8-Fluoro-6-methyl-2,4,5-triphenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (3b)

Yellow solid, 68% yield, m.p.: >250°C. ¹H NMR (500 MHz, CDCl₃): δ 9.24 (dd, J = 8.8, 5.7 Hz, 1H), 7.53–7.44 (m, 4H), 7.41–7.33 (m, 1H), 7.33–7.26 (m, 3H), 7.25–7.16 (m, 5H), 7.14–7.09 (m, 3H), 7.03 (dd, J = 9.7, 2.3 Hz, 1H), 3.19 (s, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 167.9, 167.4, 164.5 (d, J = 246.5 Hz), 145.3 (d, J = 12.1 Hz), 143.3, 137.6, 136.0, 135.8, 132.1, 131.2 (2C), 130.3, 130.0 (2C), 128.8 (2C), 127.9, 127.8 (d, J = 10.4 Hz), 127.7 (2C), 127.6, 127.2 (2C), 127.1, 126.8 (2C), 124.7, 120.5, 120.0, 116.9, 109.4 (d, J = 23.7 Hz), 96.1 (d, J = 27.2 Hz), 32.8; HRMS (ESI): m/z calcd for C₃₃H₂₂FN₂O₂ [M + H]⁺: 497.1655, found: 497.1661.

8-Chloro-6-methyl-2,4,5-triphenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (3c)

Yellow solid, 66% yield, m.p.: >250°C. ¹H NMR (500 MHz, CDCl₃): δ 9.20 (d, J = 8.4 Hz, 1H), 7.53–7.44 (m, 4H), 7.42–7.33 (m, 3H), 7.33–7.26 (m, 3H), 7.26–7.17 (m, 5H), 7.17–7.09 (m, 2H), 3.21 (s, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 167.9, 167.4, 144.8, 143.1, 138.1, 136.0, 135.8, 134.5, 132.0, 131.2 (2C), 130.5, 130.0 (2C), 128.8 (2C), 128.0, 127.8 (2C), 127.7, 127.3 (2C), 127.2, 127.1, 126.8 (2C), 125.2, 121.7, 120.6, 119.7, 119.1, 109.3, 32.8l; HRMS (ESI): m/z calcd for C₃₃H₂₂ClN₂O₂ [M + H]⁺: 513.1370, found: 513.1363.

9-Chloro-6-methyl-2,4,5-triphenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (3d)

Yellow solid, 58% yield, m.p.: >250°C. ¹H NMR (500 MHz, CDCl₃): δ 9.29 (d, J = 2.1 Hz, 1H), 7.55 (dd, J = 8.7, 2.2 Hz, 1H), 7.53–7.45 (m, 4H), 7.41–7.34 (m, 1H), 7.32–7.26 (m, 5H), 7.26–7.17 (m, 5H), 7.17–7.09 (m, 2H), 3.23 (s, 3H). ¹³ C NMR (125 MHz, CDCl₃): δ 167.8, 167.4, 143.0, 142.4, 138.3, 136.0, 135.8, 132.0, 131.3 (2C), 130.6, 130.0 (2C), 128.9 (2C), 128.6, 127.9, 127.75 (2C), 127.7, 127.3, 127.2, 126.8 (2C), 126.6 (2C), 125.6, 125.5, 121.4, 120.5, 119.2, 110.1, 32.8. HRMS (ESI): m/z calcd for C₃₃H₂₂ClN₂O₂ [M + H]⁺: 513.1370, found: 513.1377.

6,8-Dimethyl-2,4,5-triphenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (3e)

Yellow solid, 96% yield, m.p.: >250°C. ¹H NMR (500 MHz, CDCl₃): δ 9.16 (d, J = 8.1 Hz, 1H), 7.54–7.43 (m, 4H), 7.40–7.32 (m, 1H), 7.32–7.26 (m, 2H), 7.28–7.13 (m, 8H), 7.18–7.09 (m, 2H), 3.22 (s, 3H), 2.61 (s, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 168.1, 167.7, 144.7, 142.9, 139.2, 137.3, 136.5, 136.2, 132.3, 131.3 (2C), 130.1 (2C), 130.0, 128.8 (2C), 127.7, 127.6 (2C), 127.5, 127.2 (2C), 127.0, 126.9 (2C), 125.9, 124.6, 122.8, 120.5, 119.9, 118.3, 109.2, 32.6, 22.5; HRMS (ESI): m/z calcd for C₃₄H₂₅N₂O₂ [M + H]⁺: 493.1916, found: 493.1922.

9-Methoxy-6-methyl-2,4,5-triphenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (3f)

Orange solid, 88% yield, m.p.: >250°C. ¹H NMR (500 MHz, CDCl₃): δ 8.88 (d, J = 2.4 Hz, 1H), 7.54–7.45 (m, 4H), 7.41–7.33 (m, 1H), 7.30–7.27 (m, 5H), 724–7.18 (m, 5H), 7.16–7.11 (m, 2H), 4.02 (s, 3H), 3.22 (s, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 168.2, 167.6, 154.9, 143.0, 139.1, 137.5, 136.3, 136.1, 132.2, 131.3, 130.2, 130.1 (2C), 128.9 (2C), 127.8, 127.7, 127.6 (2C), 127.2 (2C), 127.1 (2C), 127.0, 125.3, 120.8, 120.2, 119.7, 118.8, 109.9, 107.3, 56.0, 32.7; HRMS (ESI): m/z calcd for C₃₄H₂₅N₂O₃ [M + H]⁺: 509.1865, found: 509.1859.

9-(Benzyloxy)-6-methyl-2,4,5-triphenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (3g)

Yellow solid, 82% yield, m.p.: >250°C. ¹H NMR (500 MHz, CDCl₃): δ 9.02 (d, J = 2.4 Hz, 1H), 7.60–7.54 (m, 2H), 7.55–7.45 (m, 4H), 7.46–7.32 (m, 5H), 7.34–7.24 (m, 4H), 7.25–7.17 (m, 5H), 7.16–7.12(m, 2H), 5.29 (s, 2H), 3.23 (s, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 168.2, 167.6, 154.0, 143.0, 139.2, 137.5, 137.2, 136.3, 136.1, 132.2 (2C), 131.3 (2C), 130.2, 130.1, 128.9 (2C), 128.5 (2C), 128.0 (2C), 127.9, 127.8, 127.7, 127.6 (2C), 127.2 (2C), 127.1, 127.0 (2C), 125.3, 120.8, 120.2, 119.7, 119.3, 110.0, 108.7, 70.8, 32.7; HRMS (ESI): m/z calcd for C₄₀H₂₉N₂O₃ [M + H]⁺: 585.2178, found: 585.2176.

6-Benzyl-2,4,5-triphenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (3h)

Yellow solid, 95% yield, m.p.: >250°C. ¹ H NMR (500 MHz, CDCl₃): δ 9.40 (d, J = 7.9 Hz, 1H), 7.60–7.41 (m, 6H), 7.41–7.34 (m, 1H), 7.29 (d, J = 10.6 Hz, 1H), 7.18–7.07 (m, 9H), 7.04–6.97 (m, 2H), 6.95–6.89 (m, 2H), 6.56–6.49 (m, 2H), 5.04 (s, 2H). ¹³C NMR (125 MHz, CDCl₃): δ 168.0, 167.5, 143.9, 142.2, 138.1, 136.8, 136.0, 135.5, 132.2, 130.8 (2C), 130.6, 129.9 (2C), 128.8 (2C), 128.7 (2C), 128.3 (2C), 127.6, 127.5, 127.4 (2C), 127.1 (2C), 127.0, 126.9, 126.8 (2C), 126.4, 125.3, 125.2, 121.6, 120.8, 120.7, 120.5, 109.8, 47.8; HRMS (ESI): m/z calcd for C₃₉H₂₇N₂O₂ [M + H]⁺: 555.2073, found: 555.2064.

6-Methyl-2-phenyl-4,5-dipropylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (3i)

Yellow solid, 95% yield, m.p.: >250°C. ¹H NMR (500 MHz, CDCl₃): δ 9.22 (d, J = 7.9 Hz, 1H), 7.63–7.56 (m, 1H), 7.55 (d, J = 4.3 Hz, 4H), 7.48–7.38 (m, 2H), 7.34 (d, J = 7.3 Hz, 1H), 4.15 (s, 3H), 3.35–3.30 (m, 2H), 3.27–3.19 (m, 2H), 1.81–1.66 (m, 4H), 1.19 (t, J = 7.3 Hz, 3H), 1.15 (t, J = 7.3 Hz, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 168.9, 168.2, 144.0, 143.9, 139.4, 132.4, 130.0, 128.9 (2C), 128.0, 127.6, 127.0 (2C), 126.0, 124.4, 120.8 (2C), 120.6, 119.8, 108.8, 32.8, 29.9, 29.6, 25.8, 25.2, 14.7, 14.2; HRMS (ESI): m/z calcd for C₂₇H₂₇N₂O₂ [M + H]⁺: 411.2073, found: 411.2072.

6-Methyl-4,5-diphenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (4a)

To a Schlenk tube was added compound 3a (20 mg, 0.04 mmol) under N₂, followed by ammonium hydroxide (1.0 mL) and DMF (2.0 mL) via syringe. The mixture was stirred at 90°C (oil bath) until the reaction was complete (monitored by TLC). After cooling to room temperature, the mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL × 3). The organic phase was combined, dried over anhydrous sodium sulfate, and filtered. Evaporation of the solvent under reduced pressure yielded the crude product, which was purified by silica gel column chromatography, eluting with petroleum ether/dichloromethane/ethyl acetate 200:100:1 (v/v/v) to afford 16 mg (96%) of 4a as a yellow solid, m.p.: >250°C. ¹H NMR (500 MHz, DMSO-d₆): δ 11.10 (s, 1H), 9.08 (dt, J = 8.0, 1.0 Hz, 1H), 7.65–7.53 (m, 2H), 7.39–7.33 (m, 1H), 7.31–7.27 (m, 3H), 7.22–7.17 (m, 2H), 7.15–7.10 (m, 3H), 7.11–7.03 (m, 2H), 3.11 (s, 3H). ¹³ C NMR (125 MHz, DMSO-d₆): δ 169.6, 169.1, 143.6, 141.7, 136.52, 136.1, 135.9, 131.2 (2C), 130.0 (2C), 128.2, 127.6, 127.3 (2C), 126.7 (2C), 126.6, 125.9, 125.0, 121.1, 120.6, 119.5, 118.6, 118.0, 109.9, 32.1; HRMS (ESI): m/z calcd for C₂₇H₁₉N₂O₂ [M + H]⁺: 403.1447, found: 403.1454.

8-Chloro-6-methyl-4,5-diphenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (4b)

According to the procedure used to prepare 4a, reaction of 3c with ammonium hydroxide provided 4b in 89% yield as a yellow solid, m.p.: >250°C. ¹H NMR (500 MHz, DMSO-d₆): δ 11.16 (s, 1H), 9.03 (d, J = 8.5 Hz, 1H), 7.76 (d, J = 1.8 Hz, 1H), 7.41 (dd, J = 8.5, 1.9 Hz, 1H), 7.30–7.27 (m, 3H), 7.25–7.21 (m, 2H), 7.16–7.11 (m, 3H), 7.11–7.05 (m, 2H), 3.12 (s, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 169.5, 169.0, 144.3, 142.2, 137.0, 135.9, 135.7, 135.6, 133.0 (2C), 131.2 (2C), 130.1, 130.0, 128.7, 127.8, 127.4 (2C), 126.8 (2C), 126.6, 126.0, 121.6, 118.3, 118.0, 110.2, 32.4; HRMS (ESI): m/z calcd for C₂₇H₁₈ClN₂O₂ [M + H]⁺: 437.1057, found: 437.1053.

6,8-Dimethyl-4,5-diphenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (4c)

According to the procedure used to prepare 4a, reaction of 3e with ammonium hydroxide provided 4c in 89% yield as a yellow solid, m.p.: >250°C. ¹H NMR (500 MHz, DMSO-d₆): δ 11.06 (s, 1H), 8.92 (d, J = 8.1 Hz, 1H), 7.39 (s, 1H), 7.30–7.23 (m, 3H), 7.23–7.17 (m, 3H), 7.16–7.10 (m, 3H), 7.10–7.03 (m, 2H), 3.08 (s, 3H), 2.53 (s, 3H). ¹³C NMR (125 MHz, DMSO-d₆): δ 169.7, 169.1, 144.1, 141.8, 138.4, 136.2, 136.1, 136.0, 131.2 (2C), 130.0 (2C), 129.5, 127.6, 127.3 (2C), 126.7 (2C), 126.5, 125.3, 124.7, 122.1, 120.9, 118.8, 117.3, 109.9, 32.0, 22.0; HRMS (ESI): m/z calcd for C₂₈H₂₁N₂O₂ [M + H]⁺: 417.1603, found: 417.1608.

2,6-Dimethyl-4,5-diphenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (4d)

A mixture of 3a (20 mg, 0.04 mmol) and 32% CH₃NH₂ in methanol (5 mL) was stirred at room temperature until the reaction was complete (monitored by TLC). Evaporation of the solvent under reduced pressure yielded the crude product, which was then purified by silica gel column chromatography, eluting with petroleum ether/dichloromethane/ethyl acetate 200: 100:1 (v/v/v) to afford 14 mg (82%) of 4d as a yellow solid, m.p.: >250°C. ¹H NMR (500 MHz, CDCl₃): δ 9.27 (d, J = 7.9 Hz, 1H), 7.66–7.59 (m, 1H), 7.46–7.41 (m, 1H), 7.38 (d, J = 8.1 Hz, 1H), 7.31–7.19 (m, 6H), 7.23–7.15 (m, 2H), 7.14–7.07 (m, 2H), 3.23 (s, 3H), 3.19 (s, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 169.1, 168.9, 144.1, 142.6, 137.3, 136.4, 136.2, 131.3 (2C), 130.0 (2C), 129.4, 128.4, 127.7, 127.6 (2C), 127.2 (2C), 127.0, 126.1, 125.7, 121.0, 120.8, 120.5, 120.1, 109.0, 32.6, 23.8; HRMS (ESI): m/z calcd for C₂₈H₂₁N₂O₂ [M + H]⁺: 417.1603, found: 417.1601.