Journal of Chemistry

Volume 2013 (2013), Article ID 262580, 12 pages

http://dx.doi.org/10.1155/2013/262580

Research Article

Synthesis of Pyrroloquinones via a CAN Mediated Oxidative Free Radical Reaction of 1,3-Dicarbonyl Compounds with Aminoquinones

Thao Nguyen,¹ Dwayaja Nadkarni,¹ Shilpa Dutta,1,2 Su Xu,¹ Sanghun Kim,¹ Srinivasan Murugesan,¹ and Sadanandan Velu1,2,3

¹Department of Chemistry, University of Alabama at Birmingham, 901 14th Street South, Birmingham, AL 35294-1240, USA

²Center for Biophysical Sciences and Engineering, University of Alabama at Birmingham, 901 14th Street South, Birmingham, AL 35294-1240, USA

³Comprehensive Cancer Center, University of Alabama at Birmingham, 901 14th Street South, Birmingham, AL 35294-1240, USA

Received 31 May 2013; Accepted 15 July 2013

Academic Editor: Suleyman Goksu

Copyright © 2013 Thao Nguyen et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Pyrroloquinone ring systems are important structural units present in many biologically active molecules including a number of marine alkaloids. For example, they are found in a series of marine metabolites, such as tsitsikammamines, zyzzyanones, wakayin, and terreusinone. Several of these alkaloids have exhibited antimicrobial, antimalarial, antifungal, antitumor, and photoprotecting activities. Synthesis of pyrroloquinone unit is the key step in the synthesis of many of these important organic molecules. Here, we present a ceric (IV) ammonium nitrate (CAN) mediated oxidative free radical cyclization reaction of 1,3-dicarbonyl compounds with aminoquinones as a facile methodology for making various substituted pyrroloquinones. 1,3-dicarbonyl compounds used in this study are ethyl acetoacetate, acetylacetone, benzoyl acetone, and N,N-dimethyl acetoacetamide. The aminoquinones used in this study are 2-(benzylamino)naphthalene-1,4-dione and 6-(benzylamino)-1-tosyl-1H-indole-4,7-dione. The yields of the synthesized pyrroloquinones ranged from 23–91%.

1. Introduction

Pyrroloquinone is a pharmacophore present in many biologically important molecules. For example, a family of marine alkaloids that include zyzzyanones, tsitsikammamine, and wakayin contains the pyrroloquinone skeleton [1–4]. These alkaloids are metabolites of marine sponges Latrunculia, Zyzzya and ascidian species Clavelina [1, 4–6]. In addition to antimicrobial, antimalarial, and antifungal activities, these alkaloids have notable antitumor properties, which are derived from their unique fused ring structure. Tsitsikammamine A derivatives, for example, inhibit indoleamine-2,3-dioxygenase, an important enzyme contributing to tumor immune invasion [7]. Tsitsikammamines A-B also exhibit antimicrobial, antimalarial, and antifungal properties, cytotoxicity, and topoisomerase inhibition [8]. Additionally, marine alkaloid wakayin inhibits topoisomerase II, damages DNA, exhibits strong antimicrobial property against Bacillus subtilis, and is potent toward human colon cancer cell lines [1]. Zyzzyanones A-D contain a bispyrroloquinone ring system and have exhibited cytotoxicity against Ehrlich carcinoma cells at micromolar range [2, 3]. Moreover, bispyrroloquinone is also the core structure of the marine fungus metabolite terreusinone (1), which is a potent UV-A protectant [9]. The photoprotecting activity of terreusinone is stronger than that of the commercial sunscreen ingredient oxybenzone [10]. For these reasons, pyrroloquinone alkaloids are regarded as a source of new antitumor and dermatological drugs [11–17]. In addition to this, 3-methyl-1H-benz[f] indole-4,9-dione (3) is a natural product isolated from the barks of G. tapis and G. uvaroides containing pyrrolonaphthaquinone ring system. This compound shows strong inhibitory effects on platelet-activating factor (PAF) receptor [18]. Selected few examples of the natural products containing pyrroloquinone units are given in Figure 1.

Figure 1: Selected natural products containing pyrroloquinone units.

Unfortunately, these natural products are isolated from natural sources only in minute quantities, which impose a limitation on their thorough biological evaluation. Additionally, the unique fused-ring aromatic structure poses a challenge in the total synthesis of these natural products. Several efforts have been made towards achieving the synthesis of these natural products [8, 10, 17, 19]. Our group has recently used an oxidative free radical cyclization reaction as a key step in the synthesis of zyzzyanones and the intermediates [19, 20].

Oxidative free radical reactions facilitated by transition metals have been known to promote carbon-carbon bond formation. In these reactions, the electron transfer between the radical precursor and metal complex generates electrophilic radicals, which ultimately react with alkenes, alkynes, or quinones to form carbon-carbon bonds [21–26]. Among the metal salts that have been investigated in the past two decades for facilitating oxidative free radical cyclization, Mn-(OAc)₃ and ceric (IV) ammonium nitrate (CAN) were proven to be the most efficient catalysts. A proposed mechanism of action for these reagents for effecting oxidative free radical cyclization has also been reported [21, 27, 28]. Mn-(OAc)₃ and CAN have been extensively used in the synthesis of naphthoquinone, which is an important skeleton of natural products, such as mitosenes, kinamycins, and murrayaquinones [29, 30]. The synthesis of bispyrroloquinone by a CAN mediated oxidative free radical cyclization has been reported from our lab [20]. An Mn (OAc)₃ mediated oxidative free radical cyclization leading to the total synthesis of zyzzyanones A-D has also been reported from our lab [19]. As an extension of these studies, herein, we demonstrate the general synthetic utility of CAN mediated oxidative free radical cyclization of various aminoquinones with 1,3-dicarbonyl compounds to form 24 new substituted pyrroloquinones.

2. Results and Discussion

The oxidative free radical reaction leading to the formation of pyrroloquinones is shown in the general Table 1. Substituted benzylaminoquinones such as 2-(benzylamino)naphthalene-1,4-dione (8) and 6-(benzylamino)-1-tosyl-1H-indole-4,7-dione (10) are treated with various 1,3-dicarbonyl compounds in the presence of CAN to afford 24 pyrroloquinone derivatives (4a-l and 5a-l) in moderate to excellent yields.

Table 1: General scheme for the oxidative free radical cyclization.

Compd no.
R
X
Y
Z

4a
Benzyl
CH₃
OCH₂CH₃
I

4b
4-Nitrobenzyl
CH₃
OCH₂CH₃
I

4c
4-Methoxybenzyl
CH₃
OCH₂CH₃
I

4d
Benzyl
CH₃
CH₃
I

4e
4-Nitrobenzyl
CH₃
CH₃
I

4f
4-Methoxybenzyl
CH₃
CH₃
I

4g
Benzyl
CH₃
C₆H₅
I

4h
4-Nitrobenzyl
CH₃
C₆H₅
I

4i
4-Methoxybenzyl
CH₃
C₆H₅
I

4j
Benzyl
CH₃
N(CH₃)₂
I

4k
4-Nitrobenzyl
CH₃
N(CH₃)₂
I

4l
4-Methoxybenzyl
CH₃
N(CH₃)₂
I

5a
Benzyl
CH₃
OCH₂CH₃
II

5b
4-Nitrobenzyl
CH₃
OCH₂CH₃
II

5c
4-Methoxybenzyl
CH₃
OCH₂CH₃
II

5d
Benzyl
CH₃
CH₃
II

5e
4-Nitrobenzyl
CH₃
CH₃
II

5f
4-Methoxybenzyl
CH₃
CH₃
II

5g
Benzyl
CH₃
C₆H₅
II

5h
4-Nitrobenzyl
CH₃
C₆H₅
II

5i
4-Methoxybenzyl
CH₃
C₆H₅
II

5j
Benzyl
CH₃
N(CH₃)₂
II

5k
4-Nitrobenzyl
CH₃
N(CH₃)₂
II

5l
4-Methoxybenzyl
CH₃
N(CH₃)₂
II

We used various 2-benzylaminonaphthalene-1,4-diones (8a–c) and N-Tosyl-6-benzylaminoindole-4,7-quinones (10a–c) as starting substrates for our oxidative free radical reactions yielding pyrroloquinones. Three 2-benzylamino naphthalene-1,4-diones (8a–c) used in these studies were prepared as outlined in Scheme 1. Naphthalene-1,4-dione (7) was treated with substituted benzyl amines (6a–c) in a mixture of MeOH and THF to afford 2-benzylamino naphthalene-1,4-diones (8a–c) in 50–86% yield.

Scheme 1: Synthesis of 2-benzylaminonaphthalene-1,4-diones.

The three N-Tosyl-6-benzylaminoindole-4,7-quinones (10a–c) used in these studies were prepared as outlined in Scheme 2. Previously reported [31], N-Tosyl-6-methoxyindole-4,7-quinone (9) was treated with substituted benzyl amines (6a–c) in a mixture of MeOH and THF to afford N-Tosyl-6-benzylaminoindole-4,7-quinones (10a–c) in 70–94% yield.

Scheme 2: Synthesis of 6-(benzylamino)-1-tosyl-1H-indole-4,7-quinones.

Yields and the specific reaction conditions used for the oxidative free radical cyclization of the aminoquinones (8a–c and 10a–c) with four 1,3-dicarbonyl compounds are summarized in Figure 4. 1,3-dicarbonyl compounds used in this study are ethyl acetoacetate, acetylacetone, benzoyl acetone and N,N-dimethyl acetoacetamide. The reactions resulted in the formation of 24 new substituted pyrroloquinones with yields ranging from 23% to 91%. Most of these reactions were carried out in CH₂Cl₂ and MeOH, except for entries 2 and 3 where a combination of CH₂Cl₂ and EtOH was used as solvent. Initially, the reaction of 8a with 4 equivalents of ethyl acetoacetate yielded the expected product 4a in good yield (80%, entry 1). However, latter reactions employed fewer equivalents of β-carbonyl compounds, which tended to result in cleaner reactions and made purification easier. Unfortunately, when compound 8b reacted with ethyl acetoacetate in CH₂Cl₂ and MeOH, the reaction proceeded well, but a mixture of methyl and ethyl esters was obtained due to transesterification. So, a combination of CH₂Cl₂ and EtOH was used in these cases to obtain the products, 4b and 4c in 35% and 82%, respectively (entries 2 and 3).

The majority of pyrroloquinones 4a-l were obtained in good yields regardless of the types of β-carbonyl starting materials used. The products 4a-l were usually yellow compared to the red orange starting materials 8a–c. Additionally, we experimented with 1, 1.8, and 4 equivalents of β-carbonyl compounds and found that only 1 equivalent of β-carbonyl compounds was sufficient to bring the reaction to the completion. Highest yields were obtained when the electron donating methoxy group was present on the benzyl substituent (entries 3, 6, 9, and 12, 82–91% yield). In contrast, the presence of nitro group on the benzyl group resulted in significantly lower yields (entries 2, 5, 8, and 11, 31–38% yield). Entries with unsubstituted benzyl substituents resulted in moderate yields (entries 1, 4, 7, and 10, 51–80%). The reactions of 8b with all four 1,3-dicarbonyl compounds proved to be difficult. This is due to several reasons, firstly, poor solubility of 8b in CH₂Cl₂ and MeOH which required the usage of triple amount of solvent volume and heating to dissolve the starting material. Secondly, the reaction did not proceed at room temperature as in the other cases and needed refluxing to force the reactions to go to completion. In addition, more CAN (1.5–2.5 equiv) and longer reaction times were required for the reaction to go to completion. Finally, the reactions always resulted in a significant amount of side products, which ultimately led to low product yields.

When 1,3-diketones such as acetylacetone and benzoylacetone are used in these experiments, theoretically, two regioisomeric products are possible. The two possible products (A and B) for the reaction between benzoylacetone and 2-benzylamino naphthalene-1,4-dione mediated by CAN are illustrated in Figure 2. However, only one product (4g) was formed in this reaction, and it was proved to be the isomer A by ¹H-NMR, ¹³C-NMR, and NOESY experiments. In the NOESY NMR experiment of compound 4g as indicated in Figure 3, the methyl group (CH₃; singlet; 2.18 ppm) clearly had a NOESY correlation with the benzyl methylene group (CH₂; singlet; 5.76 ppm). The experiment clearly establishes that the product formed is regioisomer A. The absence of the regioisomer B is perhaps due to the steric hindrance between the two bulky phenyl groups, which makes the structure significantly more unstable.

(a)

(b)

Figure 2: Two possible regioisomers of compound 4g.

Figure 3: NOESY spectrum of compound 4g.

Figure 4: CAN-mediated oxidative free radical cyclization reaction of benzylamino quinones yielding substituted N-benzyl pyrroloquinones. aisolated yields; *EtOH/CH₂Cl₂ mixture was used instead of MeOH/CH₂Cl₂ to avoid transesterification; †triple volume of solvents and heating was used to dissolve starting materials.

Compounds 10a–c were reacted with the 1,3-dicarbonyl reagents, including ethyl acetoacetate, benzoyl acetone, N,N-dimethyl acetoacetamide, and acetylacetone. The reactions were carried out in the 1 : 5 ratio mixtures of CH₂Cl₂ and MeOH. The yields and reaction condition to obtain the final products 5a-l are given in Figure 4. In this study, four equivalents of CAN were necessary for the reactions to complete while less equivalents or absence of CAN resulted in the incomplete or no reactions. The types of 1,3-dicarbonyl reagents did not affect the outcome of the reaction as there were no trends affecting percent yields when different β-carbonyl reagents were used. Interestingly, the reaction of 6-(benzylamino)-1-tosyl-1H-indole-4,7-dione with 1,3-diketones is expected to yield two regioisomeric products, but only one product was formed as in the case of 2-(benzylamino)naphthalene-1,4-dione system.

Although the trend is not as strong as in previous 2-(benzylamino)naphthalene-1,4-dione system, the yields of the methoxybenzyl-substituted products 5c, f, i, and l (entries 15, 18, 21, and 24, 65–71%) are slightly higher than those of the nonsubstituted counterparts 5a, d, g, and j (entries 13, 16, 19, and 22, 67-68%). In addition, the nonsubstituted bispyrroloquinones 5a, d, g, and j were achieved in better yields compared to their equivalent nitrobenzyl substituted compounds 5b, e, h, and k (entries 14, 17, 20, and 23, 52–60%). These results were consistent with our earlier observation in the reactions of 2-benzylaminonaphthalene-1,4-diones.

3. Conclusions

Synthesis of pyrroloquinone unit is the key step in the synthesis of several biologically important organic molecules. A CAN mediated oxidative free radical cyclization reaction of 1,3-dicarbonyl compounds with aminoquinones leading to the formation of various substituted pyrroloquinones is presented. 1,3-dicarbonyl compounds used in this study are acetylacetone, benzoyl acetone, ethyl acetoacetate, and N,N-dimethyl acetoacetamide. The aminoquinones used in this study are 2-(benzylamino)naphthalene-1,4-dione and 6-(benzylamino)-1-tosyl-1H-indole-4,7-dione. The yields of the synthesized pyrroloquinones ranged from 23 to 91%. Interestingly, we found that only one regioisomer was formed even when 1,3-diketones like benzoyl acetone were used. Finally, the majority of the oxidative free radical cyclized products were isolated as yellow solids in good yields.

4. Experimental

4.1. General Considerations

The NMR spectra were recorded on a Bruker DPX 300, DRX 400, or AVANCE 700 spectrometers. Chemical shifts are reported in ppm relative to TMS or CDCl₃ as internal standard. The values of chemical shift (δ) and coupling constants were given in parts per million and in Hz, respectively. Mass spectra were recorded using an Applied Biosystems 4000 Q Trap and Micromass Platform LCC instruments. Thin-layer chromatography was performed with silica gel plates with fluorescent indicator (Whatman, silica gel, UV254, and 25 μm plates) and visualized by UV (wavelengths 254 and 365 nm). The reaction mixture was purified by column chromatography using silica gel (32–63 μm) from Dynamic Absorbent Inc. Melting points were uncorrected and obtained from Mel-Temp II apparatus. Solvents were removed in vacuo by using rotatory evaporator. The recrystallization was assisted by Fisher Scientific FS30 sonicator. Anhydrous solvents were purchased in Sure-Seal bottles from Aldrich chemical company. Other reagents were obtained from Aldrich and Acros chemical companies.

4.1.1. 2-(Benzylamino)naphthalene-1,4-dione (8a)

To a solution of 1,4-naphthoquinone 7 (5.0 g, 31.62 mmol) in THF (50 mL), a solution of benzylamine 6a (6.91 mL, 63 mmol) in MeOH (50 mL) was added. The reaction was refluxed under N2 atm for 36 h. Upon the completion of the reaction as indicated by TLC (100% CH₂Cl₂), the solvents were removed in vacuo. The residue obtained was dissolved in EtOAc (700 mL) and washed with water (2 200 mL), brine (200 mL) and dried over Na₂SO₄. The drying agent was filtered off, and the solution was concentrated under reduced pressure to obtain the crude product which was then purified by chromatography over silica gel using 100% CH₂Cl₂ as eluent to afford compound 8a as a red solid (6.5 g, 80%); Mp: 137–141°C; ¹H NMR (CDCl₃, 300 MHz) δ 4.37 (d, 2H, J = 5.7 Hz), 5.78 (s, 1H), 6.26 (bs, 1H), 7.25–7.44 (m, 5H), 7.61 (t, 1H, J = 7.5 Hz), 7.73 (t, 1H, J = 7.5 Hz), and 8.01–8.12 (m, 2H); ¹³C NMR (CDCl₃, 75 MHz) δ 46.9, 101.9, 126.3, 126.4, 127.8 (2C), 128.3, 129.2 (2C), 130.6, 132.2, 133.7, 134.9, 136.1, 147.9, 182.0, and 183.2; MS (ES+): m/z = 264 [].

4.1.2. 2-(4-Nitrobenzylamino)naphthalene-1,4-dione (8b)

To a solution of 1,4-naphthoquinone 7 (0.30 g, 1.90 mmol) in THF (7 mL), a mixture of 4-nitrobenzylamine hydrochloride 6b (0.54 g, 2.84 mmol) and Et₃N (0.383 g, 3.79 mmol) in MeOH and CH₂Cl₂ (1 : 1, 14 mL) was added. The reaction was stirred under N2 atm overnight at room temperature. After the TLC analysis (EtOAc/hexanes, 1 : 2) showed the completion of the reaction, the solvents were removed in vacuo. The residue obtained was dissolved in CH₂Cl₂ (300 mL) and washed with water ( mL), brine (100 mL) and dried over Na₂SO₄. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to obtain the crude product which was purified by chromatography over silica gel using 100% CH₂Cl₂ as eluent to afford compound 8b as a red solid (0.292 g, 50%); Mp: 225–228°C; ¹H NMR (CDCl₃, 300 MHz) δ 4.54 (d, 2H, J = 8.4 Hz), 5.67 (s, 1H), 6.32 (bs, 1H), 7.45–7.53 (m, 2H), 7.66 (dt, 1H, = 1.3 Hz, = 7.7 Hz), 7.75 (dt, 1H, = 1.3 Hz, = 7.7 Hz), 8.08 (d, 1H, J = 1.1 Hz), 8.10 (d, 1H, J = 1.1 Hz), and 8.22–8.27 (m, 2H); ¹³C NMR (CDCl₃, 75 MHz) δ 46.2, 102.8, 124.5 (2C), 126.6 (2C), 128.1 (2C), 130.6, 132.6, 133.5, 135.2, 143.5, 147.7, 148.0, 181.9, and 183.2; MS (ES+): m/z = 309 [].

4.1.3. 2-[(4-Methoxybenzyl) amino]naphthalene-1, 4-dione (8c)

The compound was prepared using a procedure similar to the one used in the preparation of compound 8a using 1,4-naphthoquinone 7 (5.0 g, 31.62 mmol) in THF (50 mL) and 4-methoxybenzylamine 6c (6.15 mL, 47.42 mmol) dissolved in MeOH (50 mL). Compound 8c was obtained as a red solid (7.95 g, 86%); Mp: 138–141°C; ¹H NMR (CDCl₃, 300 MHz) δ 3.79 (s, 3H), 4.28 (d, 2H), 5.78 (s, 1H), 6.15 (bs, 1H), 6.85–6.92 (m, 2H), 7.19–7.28 (m, 2H), 7.58 (dt, 1H, = 1.5 Hz, = 7.6 Hz), 7.71 (dt, 1H, = 1.5 Hz, = 7.6 Hz), 8.03 (dd, 1H, = 1.11 Hz, = 7.7 Hz), and 8.08 (dd, 1H, = 1.1 Hz, = 7.7 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 46.5, 55.5, 101.8, 114.6 (2C), 126.4, 126.5, 128.1, 129.3 (2C), 130.7, 132.2, 133.8, 134.9, 147.9, 159.7, 182.1, and 183.2; MS (ES+): m/z = 294 [].

4.1.4. Ethyl 1-benzyl-2-methyl-4,9-dioxo-4,9-dihydro-1H-benzo[f]indole-3-carboxylate (4a)

To a solution of compound 8a (0.080 g, 0.30 mmol) and ethyl acetoacetate (0.158 g, 1.21 mmol) in MeOH and CH₂Cl₂ (7 : 3, 10 mL), CAN (0.584 g, 1.06 mmol) was added in four portions at 10 min intervals. After another 10 min of stirring at room temperature, TLC analysis (100% CH₂Cl₂) revealed the completion of the reaction. The solvents were removed in vacuo. Water (50 mL) was added to the residue and extracted with CH₂Cl₂ ( mL). The combined CH₂Cl₂ layer was washed with water ( mL), brine (20 mL) and dried over Na₂SO₄. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to obtain the crude product which was purified by column chromatography over silica gel using EtOAc/hexanes (1 : 3) as eluent to furnish the product 4a as a yellow solid (0.091 g, 80%); Mp: 157–160°C; ¹H NMR (CDCl₃, 300 MHz) δ 1.44 (t, 3H, J = 7.2 Hz), 2.40 (s, 3H), 4.43 (q, 2H, J = 7.2 Hz), 5.81 (s, 2H), 7.06 (d, 2H, J = 7 Hz), 7.22–7.36 (m, 3H), 7.60–7.71 (m, 2H), and 8.03–8.19 (m, 2H); ¹³C NMR (CDCl₃, 75 MHz) δ: 11.2, 14.4, 49.0, 61.4, 114.7, 126.2 (2C), 126.4, 126.5, 126.9, 128.0, 129.2 (2C), 130.5, 133.1, 133.4, 133.5, 134.0, 135.8, 142.5, 164.8, 176.4, and 179.6; MS (ES+): m/z = 374 [].

4.1.5. Ethyl 1-(4-nitrobenzyl)-4,9-dihydro-2-methyl-4,9-dioxo-1H-benzo[f]indole-3-carboxylate (4b)

Compound 8b (0.050 g, 0.16 mmol) and ethyl acetoacetate (0.021 g, 0.16 mmol) were dissolved in a mixture of EtOH and CH₂Cl₂ (7 : 3, 33 mL) by heating the solution for 15 min. After the removal of heating, CAN (0.388 g, 0.71 mmol) was added in four installments at 10 min intervals. After 16 h of stirring at room temperature, TLC analysis (100% CH₂Cl₂) showed the completion of reaction. After the solvents were removed in vacuo, water (50 mL) was added to the residue and extracted with CH₂Cl₂ ( mL). The combined CH₂Cl₂ layer was washed with water ( mL), brine (20 mL) and dried over Na₂SO₄. The drying agent was filtered off, and the crude product obtained was purified by column chromatography over silica gel using 100% CH₂Cl₂ and recrystallized with CH₂Cl₂/hexanes to isolate compound 4b as a yellow solid (0.023 g, 35%); Mp: 96–98°C; ¹H NMR (CDCl₃, 700 MHz) δ 1.46 (t, 3H, J = 7.0 Hz), 2.44 (s, 3H), 4.47 (q, 2H, J = 7.0 Hz), 5.91 (s, 2H), 7.25 (d, 2H, J = 3.3 Hz), 7.68 (t, 1H, J = 3.2 Hz), 7.71 (t, 1H, J = 3.2 Hz), 8.07 (d, 1H, J = 3.3 Hz), 8.19 (d, 1H, J = 3.2 Hz), and 8.21 (d, 2H, J = 3.3 Hz); ¹³C NMR (CDCl₃, 175 MHz) δ 11.1, 14.4, 48.6, 61.6, 115.2, 124.6 (2C), 126.5 (2C), 127.1, 127.2 (2C), 130.4, 133.1, 133.4, 133.9, 134.0, 142.0, 143.2, 147.9, 164.5, 176.6, and 179.6; MS (ES+): m/z = 419 [].

4.1.6. Ethyl 1-(4-methoxybenzyl)-4,9-dihydro-2-methyl-4,9-dioxo-1H-benzo[f]indole-3-carboxylate (4c)

To a solution of compound 8c (0.080 g, 0.27 mmol) in a mixture of EtOH and CH₂Cl₂ (7 : 3, 10 mL), ethyl acetoacetate (0.036 g, 0.27 mmol) was added, and the solution was charged with CAN (0.523 g, 0.96 mmol) in four portions at 10 min intervals and stirred at room temperature for another 10 min. TLC analysis (100% CH₂Cl₂) indicated the reaction was complete. After the solvents were removed under reduced pressure, water (50 mL) was added to the residue. It was extracted with CH₂Cl₂ ( mL), washed with water (2 × 30 mL), brine (20 mL) and dried over Na₂SO₄. Drying agent was filtered off, and the filtrate was concentrated in vacuo to obtain the crude product, which was purified by column chromatography over silica gel (eluted with 100% CH₂Cl₂) and recrystallized with CH₂Cl₂/hexanes to isolate compound 4c as a yellow solid (0.090 g, 82%); Mp: 127–129°C; ¹H NMR (CDCl₃, 300 MHz) δ 1.44 (t, 3H, J = 7.1 Hz), 2.43 (s, 3H), 3.77 (s, 3H), 4.44 (q, 2H, J = 7.1 MHz), 5.76 (s, 2H), 6.85 (d, 2H, J = 8.0 Hz), 7.04 (d, 2H, J = 8.0 Hz), 7.67-7.68 (m, 2H), and 8.10–8.15 (m, 2H); ¹³C NMR (CDCl₃, 75 MHz) δ 11.3, 14.4, 48.6, 55.5, 61.4, 114.6 (2C), 114.7, 126.2, 126.5, 126.9, 127.9, 128.0 (2C), 130.4, 133.2, 133.5 (2C), 134.0, 142.4, 159.4, 164.8, 176.4, and 179.7; MS (ES+): m/z = 404 [].

4.1.7. 3-Acetyl-1-benzyl-2-methyl-1H-benzo[f]indole-4,9-dione (4d)

Compound 8a (0.080 g, 0.3 mmol) and acetylacetone (0.031 g, 0.3 mmol) were dissolved in a mixture of MeOH and CH₂Cl₂ (7 : 3, 10 mL). The reaction mixture was charged with CAN (0.523 g, 1.06 mmol) in four installments at 10 min intervals. After stirring at room temperature for another 10 min, the reaction was complete as shown by TLC (100% CH₂Cl₂). The solvents were removed under reduced pressure. Water (50 mL) was added to the residue and extracted with CH₂Cl₂ ( mL). The combined CH₂Cl₂ layer was washed with water ( mL), brine (20 mL) and dried over Na₂SO₄. The drying agent was filtered off, and the solvent was removed in vacuo. The crude product thus obtained was purified by column chromatography over silica gel using 100% CH₂Cl₂ and recrystallized with CH₂Cl₂/hexanes to isolate compound 4d as a yellow solid (0.065 g, 62%); Mp: 203–205°C; ¹H NMR (CDCl₃, 300 MHz) δ 2.35 (s, 3H), 2.73 (s, 3H), 5.81 (s, 2H), 7.06 (d, 2H), 7.22–7.36 (m, 3H), 7.62–7.69 (m, 2H), and 8.04–8.17 (m, 2H); ¹³C NMR (CDCl₃, 75 MHz) δ 11.1, 31.9, 49.0, 123.3, 125.5, 126.5 (3C), 126.6, 126.9, 128.0, 129.2 (2C), 130.0, 133.4, 133.6, 133.7, 135.8, 142.2, 176.3, 180.9, and 199.3; MS (ES+): m/z = 344 [].

4.1.8. 1-(4-Nitrobenzyl)-3-acetyl-2-methyl-1H-benzo[f]indole-4,9-dione (4e)

Compound 8b (0.080 g, 0.26 mmol) and acetylacetone (0.026 g, 0.26 mmol) were dissolved in a mixture of MeOH and CH₂Cl₂ (7 : 4, 33 mL) by refluxing for 15 min. The solution was removed from heat and added with CAN (0.642 g, 1.16 mmol) in four portions at 10 min intervals. After overnight stirring at room temperature, the reaction was complete as indicated by TLC analysis (100% CH₂Cl₂). Upon removing solvents under reduced pressure, water (50 mL) was added and extracted with CH₂Cl₂ ( mL). The combined CH₂Cl₂ layer was washed with water ( mL), brine (20 mL) and dried over Na₂SO₄. After removing the drying agent, the filtrate was removed in vacuo to obtain the crude product, which was purified by column chromatography over silica gel (eluted with 100% CH₂Cl₂) and recrystallized with CH₂Cl₂/hexanes to isolate compound 4e as a yellow solid (0.023 g, 23%); Mp: 205-206°C; ¹H NMR (CDCl₃, 300 MHz) δ 2.38 (s, 3H), 2.76 (s, 3H), 5.91 (s, 2H), 7.24 (d, 2H, J = 8.1 Hz), 7.60–7.90 (m, 2H), and 8.07–8.22 (m, 4H); ¹³C NMR (CDCl₃, 75 MHz) δ 11.1, 31.9, 48.5, 123.6, 124.5 (2C), 125.8, 126.6, 127.1, 127.2, 129.9 (2C), 133.2, 133.6, 133.7, 133.9, 141.8, 143.1, 147.8, 176.5, 180.7, and 199.1; MS (ES+): m/z = 389 [].

4.1.9. 1-(4-Methoxybenzyl)-3-acetyl-2-methyl-1H-benzo[f]indole-4,9-dione (4f)

The compound 4f was prepared following a procedure similar to the one used in the preparation of compound 4d using compound 8c (0.080 g, 0.27 mmol), acetylacetone (0.0545 g, 0.54 mmol), and CAN (0.523 g, 0.96 mmol to obtain compound a yellow solid (0.087 g, 85%); Mp: 172-173°C; ¹H NMR (CDCl₃, 300 MHz) δ 2.38 (s, 3H), 2.73 (s, 3H), 3.77 (s, 3H), 5.76 (s, 2H), 6.85 (d, 2H, J = 8.4 Hz), 7.05 (d, 2H, J = 8.4 Hz), 7.68–7.71 (m, 2H), and 8.12–8.17 (m, 2H); ¹³C NMR (CDCl₃, 75 MHz) δ 11.2, 31.9, 48.5, 55.5, 114.3, 114.5, 123.3, 125.5, 126.6, 126.9, 127.8, 128.0, 129.9 (2C), 133.4, 133.5 (2C), 133.7, 142.2, 159.4, 176.4, 180.9, and 199.4; MS (ES+): m/z = 374 [].

4.1.10. 1-Benzyl-2-methyl-3-(phenylcarbonyl)-1H-benzo[f]indole-4,9-dione (4g)

The compound 4g was prepared following a procedure similar to the one used in the preparation of compound 4d using compound 8a (0.080 g, 0.3 mmol), benzoylacetone (0.050 g, 0.3 mmol), and CAN (0.584 g, 1.06 mmol) to afford a yellow solid (0.063 g, 51%); Mp: 213–215°C; ¹H NMR (CDCl₃, 400 MHz) δ 2.19 (S, 3H), 5.77 (s, 2H), 7.05 (d, 2H, J = 7.3 Hz), 7.16–7.30 (m, 3H), 7.35 (t, 2H, J = 7.3 Hz), 7.44–7.59 (m, 3H), 7.81 (d, 2H, J = 7.6 Hz), 7.88 (d, 1H, J = 7.2 Hz), and 8.02 (d, 1H, J = 7.2 Hz); ¹³C NMR (CDCl₃, 100 MHz) δ 11.2, 49.3, 121.7, 126.8 (3C), 126.9, 127.0, 127.1, 128.3, 128.9, 129.5 (2C), 129.7 (2C), 130.0 (2C), 133.6 (2C), 133.7, 134.0, 134.1, 138.7, 141.3, 176.5, 180.2, and 193.4; MS (ES+): m/z = 406 [].

4.1.11. 1-(4-Nitrobenzyl)-2-methyl-3-(phenylcarbonyl)-1H-benzo[f]indole-4,9-dione (4h)

The compound 4h was prepared following a procedure similar to the one used in the preparation of compound 4e using compound 8b (0.050 g, 0.16 mmol), benzoylacetone (0.026 g, 0.16 mmol), and CAN (0.400 g, 0.73 mmol) to furnish a yellow solid (0.028 g, 38%); Mp: 231-232°C; ¹H NMR (CDCl₃, 300 MHz) δ 2.31 (s, 3H), 5.95 (s, 2H), 7.32 (d, 2H, J = 8.6 Hz), 7.47 (t, 2H, J = 7.6 Hz), 7.58–7.70 (m, 3H), 7.91 (d, 2H, J = 7.8 Hz), 8.00 (d, 1H, J = 7.0), 8.11 (d, 1H, J = 7.0), and 8.25 (d, 2H, J = 8.4 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 10.9, 48.6, 121.8, 124.6 (2C), 126.7, 127.0, 127.3 (3C), 128.7 (2C), 129.5, 129.7 (2C), 133.4, 133.5 (2C), 133.6, 133.8, 138.3, 140.6, 143.2, 147.8, 176.4, 179.7, and 192.8; MS (ES+): m/z = 451 [].

4.1.12. 1-(4-Methoxybenzyl)-2-methyl-3-(phenylcarbonyl)-1H-benzo[f]indole-4,9-dione (4i)

The compound 4i was prepared following a procedure similar to the one used in the preparation of compound 4d using compound 8c (0.080 g, 0.27 mmol), benzoylacetone (0.0885 g, 0.54 mmol), and CAN (0.523 g, 0.96 mmol) to obtain a yellow solid (0.092 g, 91%); Mp: 233–235°C; ¹H NMR (CDCl₃, 300 MHz) δ 2.31 (s, 3H), 3.80 (s, 3H), 5.80 (s, 2H), 6.87–6.91 (m, 2H), 7.12 (d, 2H, J = 8.4 Hz), 7.45 (t, 2H, J = 7.7 Hz), 7.55–7.70 (m, 3H), 7.88–7.91 (m, 2H), 7.99 (dd, 1H, = 7.3 Hz, = 1.7 Hz), and 8.15 (dd, 1H, = 7.3 Hz, = 1.7 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 11.1, 48.7, 55.5, 114.7 (2C), 121.5, 126.8 (2C), 126.9 (2C), 127.9, 128.1 (3C), 128.7 (2C), 129.5, 129.8, 133.4, 133.5 (2C), 133.9, 138.6, 141.0, 159.5, 176.4, 180.0, and 193.3; MS (ES+): m/z = 436 [].

4.1.13. 1-Benzyl-N,N,2-trimethyl-4,9-dioxo-4,9-dihydro-1H-benzo[f]indole-3-carboxamide (4j)

The compound 4j was prepared following a procedure similar to the one used in the preparation of compound 4d using compound 8a (0.080 g, 0.3 mmol), N,N-dimethylacetoacetamide (0.040 g, 0.3 mmol), and CAN (0.584 g, 1.06 mmol) to obtain a yellow solid (0.079 g, 70%); Mp: 163-164°C; ¹H NMR (CDCl₃, 400 MHz) δ 2.18 (s, 3H), 2.87 (s, 3H), 3.12 (s, 3H), 5.63–5.80 (m, 2H), 7.04 (d, 2H), 7.15–7.30 (m, 3H), 7.59 (t, 2H, J = 3.9 Hz), and 8.04 (t, 2H, J = 3.9 Hz); ¹³C NMR (CDCl₃, 100 MHz) δ 11.1, 35.3, 38.5, 49.3, 118.4, 125.2 (2C), 126.8 (2C), 127.0, 128.2, 129.4 (3C), 129.9, 133.6 (2C), 134.2, 136.2, 138.8, 166.1, 176.2, and 180.8; MS (ES+): m/z = 373 [].

4.1.14. 1-(4-Nitrobenzyl)-4,9-dihydro-N,N,2-trimethyl-4,9-dioxo-1H-benzo[f]indole-3-carboxamide (4k)

The compound 4k was prepared following a procedure similar to the one used in the preparation of compound 4e using compound 8b (0.050 g, 0.16 mmol), N,N-dimethylacetoacetamide (0.020 g, 0.16 mmol), and CAN (0.400 g, 0.73 mmol) to afford a yellow solid (0.021 g, 31%); Mp: 187–189°C; ¹H NMR (CDCl₃, 400 MHz) δ 2.29 (s, 3H), 2.97 (s, 3H), 3.22 (s, 3H), 5.87 (s, 2H), 7.28 (d, 2H, J = 8.5 Hz), 7.69 (d, 2H, J = 2.7 Hz), 8.09–8.14 (m, 2H), and 8.21 (d, 2H, J = 8.5 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 10.8, 35.2, 38.3, 48.6, 118.5, 124.5 (2C), 125.2, 126.7, 126.8, 127.4 (3C), 129.5, 133.4, 133.6, 133.7, 138.2, 143.2, 147.8, 165.5, 176.1, and 180.4; MS (ES+): m/z = 418 [].

4.1.15. 1-(4-Methoxybenzyl)-4,9-dihydro-N,N,2-trimethyl-4,9-dioxo-1H-benzo[f]indole-3-carboxamide (4l)

The compound 4l was prepared following a procedure similar to the one used in the preparation of compound 4d using compound 8c (0.080 g, 0.27 mmol), N,N-dimethylacetoacetamide (0.0705 g, 0.54 mmol), and CAN (0.523 g, 0.96 mmol) to obtain a yellow solid (0.092 g, 84%); Mp: 224–226°C; ¹H NMR (CDCl₃, 300 MHz) δ 2.27 (s, 3H), 2.93 (s, 3H), 3.19 (s, 3H), 3.75 (s, 3H), 5.63–5.77 (m, 2H), 6.83 (d, 2H, J = 8.7 Hz), 7.01 (d, 2H, J = 8.7 Hz), 7.62–7.68 (m, 2H), and 8.08–8.13 (m, 2H); ¹³C NMR (CDCl₃, 75 MHz) δ 10.9, 35.0, 38.2, 48.6, 55.4, 114.5 (2C), 118.1, 124.8, 126.5, 126.7, 127.9, 128.1 (3C), 129.5, 133.3 (2C), 134.0, 138.4, 159.3, 165.9, 175.9, and 180.5; MS (ES+): m/z = 403 [].

4.1.16. 6-Benzylamino-1-tosyl-1H-indole-4,7-dione (10a)

To a solution of 6-methoxy-1-tosyl-1H-indole-4,7-dione 9 (1.2 g, 3.3 mmol) in a mixture of MeOH and THF (1 : 1, 50 mL) at room temperature, a solution of benzyl amine 6a (0.5 g, 5 mmol) in MeOH (4 mL) was added and stirred at room temperature for 20 hours. TLC analysis (EtOAc/CHCl₃, 1 : 1) revealed that the reaction was complete. The solvent was removed under reduced pressure to obtain the crude product as a reddish brown residue. It was purified by column chromatography over silica gel using EtOAc/CHCl₃ (1 : 10) as eluent to furnish the pure compound 10a (1.3 g, 88%); ¹H NMR (CDCl₃, 300 MHz) δ 2.43 (s, 3H), 4.24 (d, 2H, J = 5.7 Hz), 5.35 (s, 1H), 6.06 (bt, 1H, J = 5.7 Hz), 6.71 (d, 1H, J = 3.0 Hz), 7.15–7.20 (m, 2H), 7.25–7.45 (m, 4H), 7.8 (d, 1H, J = 3.0 Hz), and 7.99 (d, 2H, J = 8.4 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 21.8, 47.3, 97.5, 108.6, 127.0, 127.8 (2C), 128.2, 128.9 (2C), 129.0 (2C), 129.8 (2C), 131.3, 134.0, 134.4, 135.7, 146.2, 147.9, 170.2, and 181.4; MS (ES+) m/z 407 [].

4.1.17. 6-(4-Nitrobenzylamino)-1-tosyl-1H-indole-4,7-dione (10b)

To a solution of 6-methoxy-1-tosyl-1H-indole-4,7-dione 9 (0.700 g, 2.16 mmol) in MeOH and THF (1 : 1, 100 mL) at room temperature, a solution of 4-nitrobenzylamine hydrochloride 6b (0.540 g, 3.24 mmol) in MeOH (4 mL) and Et₃N (0.330 g, 3.24 mmol) was added and stirred for 20 hours. TLC analysis (EtOAc/CHCl₃, 1 : 1) revealed that the reaction was complete. The solvent was removed under reduced pressure, and the reddish yellow residue was purified by column chromatography over silica gel using EtOAc/CHCl₃ (1 : 10) as eluent to furnish pure compound 10b (0.700 g, 70% yield); ¹H NMR (CDCl₃, 300 MHz) δ 2.45 (s, 3H), 4.42 (d, 2H, J = 6.0 Hz), 5.23 (s, 1H), 6.19 (bt, 1H, J = 6.0 Hz), 6.72 (d, 1H, J = 3.0 Hz), 7.37 (d, 2H, J = 8.4 Hz), 7.42 (d, 2H, J = 8.7 Hz), 7.82 (d, 1H, J = 3.0 Hz), 8.01 (d, 2H, J = 8.4 Hz), and 8.21 (d, 2H, J = 8.7 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 21.8, 46.4, 98.5, 108.7, 124.2 (2C), 126.9, 128.0, 129.0 (2C), 129.8 (2C), 131.5 (2C), 133.9, 134.1, 143.2, 146.4, 147.6, 147.8, 170.1, and 181.4; MS (ES+) m/z 451 [].

4.1.18. 6-(4-Methoxybenzylamino)-1-tosyl-1H-indole-4,7-dione (10c)

To a solution of 6-methoxy-1-tosyl-1H-indole-4,7-dione 9 (1.13 g, 3.41 mmol) in a mixture of MeOH and THF (1 : 1, 100 mL) at room temperature, a solution of 4-methoxybenzylamine 6c (0.70 g, 5.1 mmol) in MeOH (4 mL) was added, and the reaction mixture was stirred at room temperature for 20 hours. TLC analysis (EtOAc/CHCl₃, 1 : 1) revealed that the reaction was complete. The solvent was removed under reduced pressure, and the reddish yellow residue obtained was purified by column chromatography over silica gel using EtOAc/CHCl₃ (1 : 10) as eluent to furnish pure compound 10c (1.40 g, 94%); ¹H NMR (CDCl₃, 300 MHz) δ 2.43 (s, 3H), 3.80 (s, 3H), 4.16 (d, 2H, J = 6.0 Hz), 5.35 (s, 1H), 5.99 (bt, 1H, J = 6.0 Hz), 6.72 (d, 1H, J = 3.0 Hz), 6.87 (d, 2H, J = 8.7 Hz), 7.18 (d, 2H, J = 8.7 Hz), 7.34 (d, 2H, J = 8.4 Hz), 7.80 (d, 1H, J = 3.0 Hz), and 7.98 (d, 2H, J = 8.4 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 21.8, 46.8, 55.3, 97.3, 108.6, 114.4 (2C), 126.9, 127.7, 128.9 (2C), 129.2 (2C), 129.8 (2C), 131.3, 134.0, 134.4, 146.2, 147.8, 159.5, 170.2, and 181.4; MS (ES+) m/z 434 [].

4.2. CAN Mediated Oxidative Cyclization for 16–19: General Procedure

To a solution of bicyclic quinone 10a–c (1 equiv) and β-dicarbonyl compound (4 equiv) in MeOH and CH₂Cl₂ (5 : 1), CAN (4 equiv) was added in four equal portions at 10 min intervals. The reaction mixture was stirred for another 10 min at room temperature. TLC analysis (EtOAc/hexanes, 1 : 1) revealed completion of the reaction. Solvent was completely removed under reduced pressure, and the residue was dissolved in CH₂Cl₂ (75 mL), washed with water ( mL), brine ( mL) and dried over anhydrous Na₂SO₄. The drying agent was filtered off, and the solvent was evaporated under reduced pressure. The crude product obtained was purified by column chromatography over silica gel using EtOAc/hexanes (1 : 10) as eluent to obtain the pure bispyrroloquinones 5a-l in 52–71% yield.

4.2.1. 1-Benzyl-2-methyl-4,8-dioxo-7-tosyl-1,4,7,8-tetrahydropyrrolo[3,2-f]indole-3-carboxylic Acid Ethyl Ester (5a)

Following the general procedure, compound 10a (0.094 g, 0.23 mmol) was treated with ethyl acetoacetate (0.12 g, 0.92 mmol) and CAN (0.51 g, 0.92 mmol) in anhydrous MeOH and CH₂Cl₂ (5 : 1, 12 mL) to furnish compound 5a (0.081 g, 68%); ¹H NMR (CDCl₃, 300 MHz) δ 1.39 (t, 3H, J = 7.2 Hz), 2.32 (s, 3H), 2.39 (s, 3H), 4.37 (q, 2H, J = 7.2 Hz), 5.66 (s, 2H), 6.73 (d, 1H, J = 3.2 Hz), 6.95–7.05 (m, 2H), 7.20 (d, 2H, J = 8.4 Hz), 7.25–7.30 (m, 3H), 7.71 (d, 1H, J = 3.2 Hz), and 7.90 (d, 2H, J = 8.4 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 10.9, 14.1, 21.7, 48.5, 61.1, 108.3, 113.9, 124.4, 126.5 (2C), 127.6, 128.7 (2C), 128.9 (2C), 129.4 (3C), 129.6, 130.1, 132.6, 134.0, 135.6, 141.2, 145.7, 164.5, 167.1, and 177.0; MS (ES+) m/z 515 [].

4.2.2. 1-(4-Nitrobenzyl)-2-methyl-4,8-dioxo-7-tosyl-1,4,7,8-tetrahydropyrrolo[3,2-f]indole-3-carboxylic Acid Ethyl Ester (5b)

Following the general procedure, compound 10b (0.050 g, 0.11 mmol) was treated with ethyl acetoacetate (0.058 g, 0.44 mmol) and CAN (0.24 g, 0.44 mmol) in anhydrous MeOH and CH₂Cl₂ (5 : 1, 12 mL) to furnish compound 5b (0.037 g, 60%); ¹H NMR (CDCl₃, 300 MHz) δ 1.40 (t, 3H, J = 7.2 Hz), 2.35 (s, 3H), 2.37 (s, 3H), 4.39 (q, 2H, J = 7.2 Hz), 5.72 (s, 2H), 6.76 (d, 1H, J = 3.3 Hz), 7.12 (d, 2H, J = 8.7 Hz), 7.17 (d, 2H, J = 8.3 Hz), 7.72 (d, 1H, J = 3.3 Hz), 7.86 (d, 2H, J = 8.3 Hz), and 8.13 (d, 2H, J = 8.7 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 10.8, 14.2, 21.6, 48.1, 61.2, 108.5, 114.4, 124.0 (2C), 124.7, 127.2 (2C), 128.9 (2C), 129.4 (3C), 129.7, 129.9, 132.9, 134.0, 140.8, 143.1, 146.1, 147.4, 164.2, 166.9, and 176.7; MS (ES+) m/z 562 [].

4.2.3. 1-(4-Methoxybenzyl)-2-methyl-4,8-dioxo-7-tosyl-1,4,7,8-tetrahydro-pyrrolo[3,2-f]indole-3-carboxylic Acid Ethyl Ester (5c)

Following the general procedure, compound 10c (0.054 g, 0.12 mmol) was treated with ethyl acetoacetate (0.064 g, 0.50 mmol) and CAN (0.27 g, 0.50 mmol) in anhydrous MeOH and CH₂Cl₂ (5 : 1, 12 mL) to furnish compound 5c (0.047 g, 71%); ¹H NMR (CDCl₃, 300 MHz) δ 1.38 (t, 3H, J = 7.2 Hz), 2.33 (s, 3H), 2.41 (s, 3H), 3.78 (s, 3H), 4.35 (q, 2H, J = 7.2 Hz), 5.58 (s, 2H), 6.74 (d, 1H, J = 3.2 Hz), 6.77 (d, 2H, J = 8.7 Hz), 6.91 (d, 2H, J = 8.7 Hz), 7.24 (d, 2H, J = 8.1 Hz), 7.71 (d, 1H, J = 3.2 Hz), and 7.93 (d, 2H, J = 8.1 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 11.0, 14.2, 21.7, 48.1, 55.3, 61.0, 108.3, 114.0, 114.1 (2C), 124.5, 127.8, 128.1 (2C), 129.0 (2C), 129.4, 129.5 (2C), 129.6, 130.2, 132.6, 134.2, 141.1, 145.8, 159.1, 164.5, 167.1, and 176.9; MS (ES+) m/z 546 [].

4.2.4. 3-Acetyl-1-benzyl-2-methyl-7-tosyl-1H,7H-pyrrolo[3,2-f]indole-4,8-dione (5d)

Following the general procedure, compound 10a (0.050 g, 0.12 mmol) was treated with acetyl acetone (0.049 g, 0.48 mmol) and CAN (0.27 g, 0.48 mmol) in anhydrous MeOH and CH₂Cl₂ (5 : 1, 12 mL) to furnish compound 5d (0.040 g, 67%); ¹H NMR (CDCl₃, 300 MHz) δ 2.26 (s, 3H), 2.40 (s, 3H), 2.65 (s, 3H), 5.66 (s, 2H), 6.74 (d, 1H, J = 2.4 Hz), 6.90–7.00 (m, 2H), 7.21 (d, 2H, J = 8.0 Hz), 7.20–7.40 (m, 3H), 7.73 (d, 1H, J = 2.4 Hz), and 7.93 (d, 2H, J = 8.0 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 10.9, 21.8, 31.6, 48.5, 108.2, 122.6, 123.7, 126.5 (2C), 127.6, 128.7 (2C), 129.0 (2C), 129.5 (3C), 129.6, 130.1, 132.3, 133.9, 135.6, 140.8, 145.9, 167.0, 178.3, and 199.1; MS (ES+) m/z 487 [].

4.2.5. 3-Acetyl-2-methyl-1-(4-nitrobenzyl)-7-tosyl-1H,7H-pyrrolo[3,2-f]indole-4,8-dione (5e)

Following the general procedure, compound 10b (0.045 g, 0.10 mmol) was treated with acetyl acetone (0.040 g, 0.40 mmol) and CAN (0.22 g, 0.40 mmol) in anhydrous MeOH and CH₂Cl₂ (5 : 1, 12 mL) to furnish compound 5e (0.027 g, 58%); ¹H NMR (CDCl₃, 300 MHz) δ 2.30 (s, 3H), 2.37 (s, 3H), 2.67 (s, 3H), 5.72 (d, 2H), 6.75 (d, 1H, J = 3.3 Hz), 7.14 (d, 2H, J = 8.7 Hz), 7.19 (d, 2H, J = 8.1 Hz), 7.74 (d, 1H, J = 3.3 Hz), 7.88 (d, 2H, J = 8.1 Hz), and 8.14 (d, 2H, J = 8.7 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 10.8, 21.6, 31.7, 48.0, 108.5, 122.9, 124.0, 124.1, 127.2 (2C), 128.9, 129.0 (2C), 129.4 (2C), 129.7 (2C), 129.9, 132.5, 133.7, 140.4, 143.0, 146.2, 147.4, 166.9, 178.1, and 198.8; MS (ES+) m/z 532 [].

4.2.6. 3-Acetyl-1-(4-methoxybenzyl)-2-methyl-7-tosyl-1H,7H-pyrrolo[3,2-f]indole-4,8-dione (5f)

Following the general procedure, compound 10c (0.070 g, 0.16 mmol) was treated with acetyl acetone (0.064 g, 0.64 mmol) and CAN (0.35 g, 0.64 mmol) in anhydrous MeOH and CH₂Cl₂ (5 : 1, 12 mL) to furnish compound 5f (0.056 g, 68%); ¹H NMR (CDCl₃, 300 MHz) δ 2.28 (s, 3H), 2.41 (s, 3H), 2.63 (s, 3H), 3.78 (s, 3H), 5.58 (s, 2H), 6.73 (d, 1H, J = 3.0 Hz), 6.78 (d, 2H, J = 8.0 Hz), 6.93 (d, 2H, J = 8.5 Hz), 7.25 (d, 2H, J = 8.0 Hz), 7.73 (d, 1H, J = 3.0 Hz), and 7.95 (d, 2H, J = 8.5 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 10.9, 21.7, 31.6, 48.0, 55.3, 108.2, 114.1 (2C), 122.7, 123.8, 127.7, 128.1 (2C), 129.0, 129.1 (2C), 129.5 (2C), 129.6, 130.3, 132.3, 134.1, 140.7, 145.9, 159.1, 167.1, 178.3, and 199.0; MS (ES+) m/z 517 [].

4.2.7. 3-Benzoyl-1-benzyl-2-methyl-7-tosyl-1H,7H-pyrrolo[3,2-f]indole-4,8-dione (5 g)

Following the general procedure, compound 10a (0.10 g, 0.25 mmol), 1-phenyl-2-propanone (0.16 g, 0.99 mmol) and CAN (0.47 g, 0.99 mmol) in anhydrous MeOH and CH₂Cl₂ (5 : 1, 12 mL) to furnish compound 5 g (0.090 g, 67%); ¹H NMR (CDCl₃, 300 MHz) δ 2.19 (s, 3H), 2.41 (s, 3H), 5.69 (s, 2H), 6.59 (d, 1H, J = 2.4 Hz), 6.90–7.10 (m, 2H), 7.20–7.35 (m, 5H), 7.40 (t, 2H, J = 7.2 Hz), 7.54 (t, 1H, J = 7.2 Hz), 7.68 (d, 1H, J = 2.4 Hz), 7.82 (d, 2H, J = 7.5 Hz), and 7.95 (d, 2H, J = 8.1 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 10.7, 21.8, 48.7, 108.2, 120.9, 125.1, 126.6 (2C), 127.7, 128.4 (2C), 128.7, 128.8 (2C), 128.9, 129.0 (2C), 129.2 (2C), 129.5 (2C), 130.6, 132.0, 133.1, 134.1, 135.7, 138.4, 139.7, 145.8, 167.0, 177.3, and 192.9; MS (ES+) m/z 549 [].

4.2.8. 3-Benzoyl-2-methyl-1-(4-nitrobenzyl)-7-tosyl-1H,7H-pyrrolo[3,2-f]indole-4,8-dione (5h)

Following the general procedure, compound 10b (0.050 g, 0.11 mmol) was treated with 1-phenyl-2-propanone (0.072 g, 0.44 mmol) and CAN (0.24 g, 0.44 mmol) in anhydrous MeOH and CH₂Cl₂ (5 : 1, 12 mL) to furnish compound 5h (0.034 g, 52%); ¹H NMR (CDCl₃, 300 MHz) δ 2.23 (s, 3H), 2.39 (s, 3H), 5.76 (s, 2H), 6.61 (d, 1H, J = 2.4 Hz), 7.15–7.25 (m, 4H), 7.43 (t, 2H, J = 8.0 Hz), 7.57 (t, 1H, J = 7.6 Hz), 7.69 (d, 1H, J = 2.4 Hz), 7.82 (d, 2H, J = 7.6 Hz), 7.90 (d, 2H, J = 8.0 Hz), and 8.18 (d, 2H, J = 8.4 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 10.6, 21.6, 48.1, 108.4, 121.1, 124.1 (2C), 125.3, 127.3 (2C), 128.4, 128.6 (2C), 129.0 (2C), 129.2 (2C), 129.4 (2C), 129.8, 130.2, 132.2, 133.3, 133.9, 138.1, 139.2, 143.1, 146.1, 147.5, 166.9, 177.0, and 192.5; MS (ES+) m/z 594 [].

4.2.9. 3-Benzoyl-1-(4-methoxybenzyl)-2-methyl-7-tosyl-1H,7H-pyrrolo[3,2-f]indole-4,8-dione (5i)

Following the general procedure, compound 10c (0.080 g, 0.18 mmol) was treated with 1-phenyl-2-propanone (0.090 g, 0.72 mmol) and CAN (0.36 g, 0.22 mmol) anhydrous MeOH and CH₂Cl₂ (5 : 1, 12 mL) to furnish compound 5i (0.074 g, 70%); ¹H NMR (CDCl₃, 300 MHz) δ 2.21 (s, 3H), 2.43 (s, 3H), 3.8 (s, 3H), 5.61 (s, 2H), 6.59 (d, 1H, J = 3.3 Hz), 6.81 (d, 2H, J = 8.4 Hz), 7.01 (d, 2H, J = 8.4 Hz), 7.25–7.30 (m, 2H), 7.40 (t, 2H, J = 8.0 Hz), 7.54 (t, 1H, J = 8.0 Hz), 7.68 (d, 1H, J = 3.3 Hz), 7.81 (d, 2H, J = 8.0 Hz), and 7.97 (d, 2H, J = 8.0 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 10.8, 21.8, 48.1, 55.3, 108.2, 114.1 (2C), 120.8, 125.1, 127.8, 128.2 (2C), 128.3 (2C), 128.6, 129.1 (2C), 129.2 (2C), 129.4, 129.5 (2C), 130.6, 131.9, 133.1, 134.1, 138.3, 139.7, 146.0, 159.1, 167.1, 177.3, and 192.9; MS (ES+) m/z 579 [].

4.2.10. 1-Benzyl-2-methyl-4,8-dioxo-7-tosyl-1,4,7,8-tetrahydropyrrolo[3,2-f]indole-3-carboxylic Acid Dimethylamide (5j)

Following the general procedure, compound 10a (0.050 g, 0.12 mmol) was treated with N,N-dimethylacetoacetamide (0.064 g, 0.49 mmol) and CAN (0.27 g, 0.49 mmol) in anhydrous MeOH and CH₂Cl₂ (5 : 1, 12 mL) to furnish compound 5j (0.043 g, 68%); ¹H NMR (CDCl₃, 300 MHz) δ 2.15 (s, 3H), 2.41 (s, 3H), 2.88 (s, 3H), 3.13 (s, 3H), 5.55–5.75 (m, 2H), 6.70 (d, 1H, J = 3.0 Hz), 6.90–7.10 (m, 2H), 7.20–7.30 (m, 5H), 7.71 (d, 1H, J = 3.0 Hz), and 7.93 (d, 2H, J = 8.4 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 10.6, 21.8, 34.8, 38.0, 48.6, 108.0, 117.5, 123.3, 126.7 (2C), 127.6, 128.5, 128.7 (2C), 129.0 (2C), 129.4 (3C), 131.0, 131.9, 134.0, 135.8, 137.1, 145.8, 165.5, 167.0, and 178.0; MS (ES+) m/z 516 [].

4.2.11. 2-Methyl-1-(4-nitrobenzyl)-4,8-dioxo-7-tosyl-1,4,7,8-tetrahydropyrrolo[3,2-f]indole-3-carboxylic Acid Dimethylamide (5k)

Following the typical procedure, compound 10b (0.045 g, 0.10 mmol) was treated with N,N-dimethylacetoacetamide (0.051 g, 0.40 mmol) and CAN (0.22 g, 0.40 mmol) in anhydrous MeOH and CH₂Cl₂ (5 : 1, 12 mL) to furnish compound 5k (0.031 g, 58%); ¹H NMR (CDCl₃, 300 MHz) δ 2.20 (s, 3H), 2.38 (s, 3H), 2.90 (s, 3H), 3.15 (s, 3H), 5.60–5.80 (m, 2H), 6.71 (d, 1H, J = 3.3 Hz), 7.15–7.25 (m, 4H), 7.72 (d, 1H, J = 3.3 Hz), 7.88 (d, 2H, J = 8.4 Hz), and 8.14 (d, 2H, J = 8.7 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 10.5, 21.6, 34.9, 38.1, 48.1, 108.1, 117.9, 123.6, 124.0 (2C), 127.4, 128.4 (2C), 129.0, 129.4 (2C), 129.7 (2C), 130.4, 132.1, 133.9, 136.8, 143.1, 146.1, 147.4, 165.1, 166.7, and 177.7; MS (ES+) m/z 561 [].

4.2.12. 1-(4-Methoxybenzyl)-2-methyl-4,8-dioxo-7-tosyl-1,4,7,8-tetrahydro-pyrrolo[3,2-f]indole-3-carboxylic Acid Dimethylamide (5l)

Following the typical procedure, compound 10c (0.070 g, 0.16 mmol) was treated with N,N-dimethylacetoacetamide (0.083 g, 0.64 mmol) and CAN (0.35 g, 0.64 mmol) in anhydrous MeOH and CH₂Cl₂ (5 : 1, 12 mL) to furnish compound 5l (0.063 g, 68%); ¹H NMR (CDCl₃, 300 MHz) δ 2.17 (s, 3H), 2.42 (s, 3H), 2.86 (s, 3H), 3.13 (s, 3H), 3.79 (s, 3H), 5.40–5.60 (m, 2H), 6.69 (d, 1H, J = 3.3 Hz), 6.78 (d, 2H, J = 7.6 Hz), 6.96 (d, 2H, J = 8.5 Hz), 7.2-7.3 (m, 2H), 7.71 (d, 1H, J = 3.3 Hz), and 7.95 (d, 2H, J = 8.5 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 10.7, 21.7, 34.8, 38.0, 48.1, 55.3, 107.9, 114.1 (2C), 117.6, 123.3, 127.9 (2C), 128.3 (2C), 128.4, 129.0, 129.4 (3C), 131.0, 131.9, 134.2, 137.0, 145.8, 159.1, 165.6, 167.0, and 178.0; MS (ES+) m/z 546 [].

Acknowledgments

The authors also wish to acknowledge the financial support by the Collaborative Programmatic Development Grant from the University of Alabama at Birmingham (UAB) Comprehensive Cancer Center and the financial support from UAB Department of Chemistry. Beginning, Grant-in-Aid (AHA0865323E) from the American Heart Association Greater Southeast Affiliate is also acknowledged.

References

B. R. Copp, C. M. Ireland, and L. R. Barrows, “Wakayin: a novel cytotoxic pyrroloiminoquinone alkaloid from the ascidian Clavelina species,” The Journal of Organic Chemistry, vol. 56, no. 15, pp. 4596–4597, 1991.

N. K. Utkina, A. E. Makarchenko, and V. A. Denisenko, “Zyzzyanones B-D, dipyrroloquinones from the marine sponge Zyzzya fuliginosa,” Journal of Natural Products, vol. 68, no. 9, pp. 1424–1427, 2005.

N. K. Utkina, A. E. Makarchenko, V. A. Denisenko, and P. S. Dmitrenok, “Zyzzyanone A, a novel pyrrolo[3,2-f]indole alkaloid from the Australian marine sponge Zyzzya fuliginosa,” Tetrahedron Letters, vol. 45, no. 40, pp. 7491–7494, 2004.

G. J. Hooper, M. T. Davies-Coleman, M. Kelly-Borges, and P. S. Coetzee, “New alkaloids from a South African latrunculid sponge,” Tetrahedron Letters, vol. 37, no. 39, pp. 7135–7138, 1996.

E. M. Antunes, B. R. Copp, M. T. Davies-Coleman, and T. Samaai, “Pyrroloiminoquinone and related metabolites from marine sponges,” Natural Product Reports, vol. 22, no. 1, pp. 62–72, 2005.

D. J. Faulkner, “Marine natural products,” Natural Product Reports, vol. 19, no. 1, pp. 1–48, 2002.

E. Dolusic, P. Larrieu, C. Meinguet et al., “Indoleamine 2, 3-dioxygenase inhibitory activity of derivatives of marine alkaloid tsitsikammamine A,” Bioorganic & Medicinal Chemistry Letters, vol. 23, no. 1, pp. 47–54, 2013.

A. Rives, T. Delaine, L. Legentil, and E. Delfourne, “Total synthesis of the marine pyrroloiminoquinone alkaloid tsitsikammamine A,” Tetrahedron Letters, vol. 50, no. 10, pp. 1128–1130, 2009.

S. M. Lee, X. F. Li, H. Jiang et al., “Terreusinone, a novel UV-A protecting dipyrroloquinone from the marine algicolous fungus Aspergillus terreus,” Tetrahedron Letters, vol. 44, no. 42, pp. 7707–7710, 2003.

C. Wang and J. Sperry, “Total synthesis of the photoprotecting dipyrrolobenzoquinone (+)-terreusinone,” Organic Letters, vol. 13, no. 24, pp. 6444–6447, 2011.

V. Bénéteau and T. Besson, “Synthesis of novel pentacyclic pyrrolothiazolobenzoquinolinones, analogs of natural marine alkaloids,” Tetrahedron Letters, vol. 42, no. 14, pp. 2673–2676, 2001.

V. Bénéteau, A. Pierré, B. Pfeiffer, P. Renard, and T. Besson, “Synthesis and antiproliferative evaluation of 7-aminosubstituted pyrroloiminoquinone derivatives,” Bioorganic and Medicinal Chemistry Letters, vol. 10, no. 19, pp. 2231–2234, 2000.

J. M. Kokoshka, T. L. Capson, J. A. Holden, C. M. Ireland, and L. R. Barrows, “Differences in the topoisomerase I cleavage complexes formed by camptothecin and wakayin, a DNA-intercalating marine natural product,” Anti-Cancer Drugs, vol. 7, no. 7, pp. 758–765, 1996.

R. Zhao, B. Oreski, and J. W. Lown, “Synthesis and biological evaluation of hybrid molecules containing the pyrroloquinoline nucleus and DNA-minor groove binders,” Bioorganic and Medicinal Chemistry Letters, vol. 6, no. 18, pp. 2169–2172, 1996.

L. Legentil, L. Benel, V. Bertrand, B. Lesur, and E. Delfourne, “Synthesis and antitumor characterization of pyrazolic analogues of the marine pyrroloquinoline alkaloids: wakayin and tsitsikammamines,” Journal of Medicinal Chemistry, vol. 49, no. 10, pp. 2979–2988, 2006.

L. Legentil, B. Lesur, and E. Delfourne, “Aza-analogues of the marine pyrroloquinoline alkaloids wakayin and tsitsikammamines: synthesis and topoisomerase inhibition,” Bioorganic and Medicinal Chemistry Letters, vol. 16, no. 2, pp. 427–429, 2006.

C. Wang and J. Sperry, “Total syntheses of the dipyrrolobenzoquinone (+)-terreusinone enabled by an evaluation of 4-methylpent-1-yn-3-ols in the Larock indole synthesis,” Tetrahedron, vol. 69, no. 23, pp. 4563–4577, 2013.

B. A. Moharam, I. Jantan, J. Jalil, and F. Ahmad, “Inhibitory effect of compounds from Goniothalamus tapis Miq. and Goniothalamus uvaroides King on platelet-activating factor receptor binding,” Phytotherapy Research, vol. 26, no. 5, pp. 687–691, 2012.

D. H. Nadkarni, S. Murugesan, and S. E. Velu, “Total synthesis of zyzzyanones A-D,” Tetrahedron, vol. 69, no. 20, pp. 4105–4113, 2013.

S. Murugesan, D. H. Nadkarni, and S. E. Velu, “A facile synthesis of bispyrroloquinone and bispyrroloiminoquinone ring system of marine alkaloids,” Tetrahedron Letters, vol. 50, no. 25, pp. 3074–3076, 2009.

J. Iqbal, B. Bhatia, and N. K. Nayyar, “Transition metal-promoted free-radical reactions in organic synthesis: the formation of carbon-carbon bonds,” Chemical Reviews, vol. 94, no. 2, pp. 519–564, 1994.

C.-C. Tseng, Y.-L. Wu, and C.-P. Chuang, “Cerium salts in the oxidative free radical reactions between 2-amino-1,4-naphthoquinones and β-dicarbonyl compounds,” Tetrahedron, vol. 58, no. 38, pp. 7625–7633, 2002.

C.-P. Chuang and Y.-L. Wu, “A novel oxidative free radical reaction between 2-hydroxy-1,4-naphthoquinone and β-enamino carbonyl compounds,” Tetrahedron Letters, vol. 42, no. 9, pp. 1717–1719, 2001.

C.-P. Chuang and A.-I. Tsai, “Oxidative free radical reactions between 2-amino-1,4-benzoquinones and carbonyl compounds,” Tetrahedron, vol. 63, no. 48, pp. 11911–11919, 2007.

C.-M. Tseng, Y.-L. Wu, and C.-P. Chuang, “Solvent effects on the oxidative free radical reactions of 2-amino-1,4-naphthoquinones,” Tetrahedron, vol. 60, no. 52, pp. 12249–12260, 2004.

Y.-L. Wu, C.-P. Chuang, and P.-Y. Lin, “Oxidative free radical reactions between 2-amino-1,4-naphthoquinones and carbonyl compounds,” Tetrahedron, vol. 57, no. 26, pp. 5543–5549, 2001.

R. Mohan, S. A. Kates, M. A. Dombroski, and B. B. Snider, “Manganese (III) based oxidative free-radical cyclizations. 3. Polycyclization reactions proceeding through secondary radicals,” Tetrahedron Letters, vol. 28, no. 8, pp. 845–848, 1987.

B. B. Snider and J. J. Patricia, “Manganese(III)-based oxidative free-radical cyclizations. Oxidative cyclization and aromatization of 3-oxo-6-heptenoate esters,” The Journal of Organic Chemistry, vol. 54, no. 1, pp. 38–46, 1989.

S. Patai and Z. Rappoport, The Chemistry of Functional Groups: The Chemistry of the Quinoid Compounds, Wiley, New York, NY, USA, 1988.

R. H. Thomson, Natural Occurring Quinones IV: Recent Advances, Chapman & Hall, London, UK, 1997.

E. V. Sadanandan, S. K. Pillai, M. V. Lakshmikantham, A. D. Billimoria, J. S. Culpepper, and M. P. Cava, “Efficient syntheses of the marine alkaloids makaluvamine D and discorhabdin C: the 4,6,7-trimethoxyindole approach,” The Journal of Organic Chemistry, vol. 60, no. 6, pp. 1800–1805, 1995.