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Article

Microwave-Assisted Improved Synthesis of Pyrrolo[2,3,4-kl]acridine and Dihydropyrrolo[2,3,4-kl]acridine Derivatives Catalyzed by Silica Sulfuric Acid

by
Chengpao Cao
1,†,
Changliang Xu
2,†,
Wei Lin
1,
Xuemei Li
3,
Minghua Hu
1,
Juxian Wang
2,
Zhibin Huang
1,
Daqing Shi
1,* and
Yucheng Wang
2,*
1
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, China
2
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union, Medical College, Beijing 100050, China
3
Center for Drug Evaluation, State Food and Drug Administration Office of Generic Drug Pharmaceutical Science, Beijing 100038, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Molecules 2013, 18(2), 1613-1625; https://doi.org/10.3390/molecules18021613
Submission received: 29 November 2012 / Revised: 21 December 2012 / Accepted: 5 January 2013 / Published: 28 January 2013
(This article belongs to the Section Organic Chemistry)
Browse Figures
Versions Notes

Abstract

:
An improved synthesis of multifunctionalized pyrrolo[2,3,4-kl]acridine derivatives with different substituted patterns using silica sulfuric acid (SSA) as a heterogeneous catalyst under microwave irradiation conditions was developed. The reaction could be conducted by using readily available and inexpensive substrates within short periods of 12–15 min. under microwave irradiation. Compared with the conventional methods, the remarkable advantages of this method are milder reaction conditions, operational simplicity, higher yields, short reaction times, and an environmentally friendly procedure.

1. Introduction

Acridine derivatives were primarily used as stains for dye manufacturing (e.g., acridine orange) until their fluorescence and chemiluminescence properties found numerous other applications [1,2,3]. Such acridines have demonstrated important biological activity [4], including activity against cancer [5] due to their ability to intercalate into DNA and disrupt unwanted cellular processes [6]. This unique property of acridines has been exploited in many areas of medicine. As a result, significant biological activity toward viruses [7], bacteria [8], parasites [9,10], fungus [11], Alzheimer’s disease [12], and HIV/AIDS [13] has also been reported. Pyrrolo[2,3,4-kl]acridine derivatives have been isolated from a Plakortis sponge and showed biological activities [14,15]. Although there have been some reports on the synthesis of these molecules [16,17], those methods require multistep syntheses. Recently, we [18] and Tu [19] reported the one-pot synthesis of pyrrolo[2,3,4-kl]acridine derivatives catalyzed by L-proline or AcOH, respectively. However, these methods required the use of toluene or acetic acid as solvents. Thus, there is a need for the development of concise and green methods for the construction of this heterocyclic skeleton.
The need to reduce the amount of toxic waste and by-product arising from chemical process requires increasing emphasis on the use of less toxic and environmentally compatible materials in the design of new synthetic methods. One of the most promising approaches in organic synthesis is the use of reusable heterogeneous catalysts because of their environmental, economical, and industrial aspects [20]. The development of efficient methods using recoverable and reusable catalysts is an important goal in organic synthesis. Up to now, several reusable and heterogeneous catalysts have been designed and used. One useful example is silica sulfuric acid (SSA), which has been widely studied in recent years [21,22,23], in a variety of reactions such as cross-Aldol condensation [24], deacylation [25], selective oxidation [26], Michael addition [27] and functional group protection [28]. In our previous works, SSA was used as an efficient catalyst for the acetylation of aldehydes and sugars [29]. As a continuation of our interest in organic reactions catalyzed by solid acids [29,30], herein, we report the microwave-assisted green synthesis of pyrrolo[2,3,4-kl]acridine-1-one derivatives catalyzed by SSA in ethanol.

2. Results and Discussion

In a preliminary study, we optimized the reaction conditions, including reaction solvents, temperature, catalyst and amount of SSA catalyst using isatin (1a), and 3-(4-t-butylphenylamino)-5,5-dimethylcyclohex-2-enone (2a) as model reactants (Scheme 1). The reaction mixture, which was composed of a 1:1 mixture of 1a to 2a, was tested under different conditions. The results are summarized in Table 1.
Molecules 18 01613 g002 550
Scheme 1. The model reaction.
Scheme 1. The model reaction.
Molecules 18 01613 g002
Table
Table 1. Optimization of the reaction conditions for the synthesis of 3a.
Table 1. Optimization of the reaction conditions for the synthesis of 3a.
EntrySolventCatalyst T (°C)Time (min)Yield a (%)
1ethanol-1101523
2ethanolSSA (0.02 g)1101591
3AcOHSSA (0.02 g)1101585
4H2OSSA (0.02 g)1101581
5ethylene glycolSSA (0.02 g)1101587
6tolueneSSA (0.02 g)1101591
7ethanolHCl (0.5 mL)1101578
8ethanolH2SO4 (0.5 mL)1101559
9ethanolI2 (0.02 g)1101573
10ethanolL-proline (10 mol%)1101540
11ethanolSSA (0.03 g)1101590
12ethanolSSA (0.04 g)1101591
13ethanolSSA (0.01 g)1101576
14ethanolSSA (0.02 g)901571
15ethanolSSA (0.02 g)1001585
16ethanolSSA (0.02 g)1201587
17ethanolSSA (0.02 g)110877
18ethanolSSA (0.02 g)1101087
19ethanolSSA (0.02 g)1101291
20ethanolSSA (0.02 g)1102089
a Yield was determined by HPLC-MS.
The optimization process revealed that the reactions did not proceed in ethanol under catalyst-free conditions (Table 1, entry 1). Pleasingly, the target compound 3a was obtained in ethanol with 0.02 g SSA as catalyst (Table 1, entry 2). To improve the yield, different solvents were evaluated. The results indicated that ethanol provided much better results than AcOH, ethylene glycol or water (Table 1, entries 2–5). The non-polar solvent toluene gave the same yield (Table 1, entry 6). Considering the toxicity of toluene, ethanol was selected as the preferred reaction solvent. Several other catalysts were also evaluated for their catalytic efficiency in the current reaction. Common acids (H2SO4 and HCl) and other catalysts (I2 or L-proline) can catalyze this reaction with low yields (Table 1, entries 7–10). The results revealed that SSA was the optimal catalyst with the product being isolated in 91% yield (Table 1, entry 2). Subsequently, we proceeded to evaluate the amount of SSA required for this reaction. When 0.02 g of silica gel was used, the reaction of 3a proceeded in good yield (91%, Table 1, entry 2). The reaction yield remained unchanged when we increased the amount of SSA (Table 1, entries 11 and 12), but the yield was lower when the amount of SSA was decreased (Table 1, entry 13), therefore, 0.02 g of SSA is sufficient to initiate the reaction. To identify the optimum reaction temperature, the reaction was carried out with 0.02 g SSA at 90 °C, 100 °C, 110 °C and 120 °C, providing the product 3a in yields of 71%, 85%, 91% and 87% (Table 1, entries 14, 15, 2 and 16), respectively, so the most suitable reaction temperature for this reaction is 110 °C. Finally, to optimize the reaction time, the reaction was carried out with 0.02 g SSA at 110 °C and the reaction time used was 8 min, 10 min, 12 min, 15 min and 20 min, respectively. It was found that the reaction can proceed smoothly in 12 min (Table 1, entry 19), while prolonging the reaction time did not enhance the yield of the product (Table 1, entries 2 and 20). Thus, the optimum conditions required the use of 0.02 g SSA as catalyst in ethanol as solvent at 110 °C and a reaction time of 12 min.
Having established the optimal conditions we proceeded to investigate the substrate scope of the transformation. As shown in Table 2, substituents such as bromo, chloro, fluoro on the isatin ring, and t-butyl or phenyl groups bearing either electron-withdrawing or electron-donating groups on the enaminone ring, were well tolerated under these reaction conditions, leading to the final products in satisfactory yields (up to 93%).
Table
Table 2. Synthesis of dihydropyrrolo[2,3,4-kl]acridines 3.
Molecules 18 01613 i001
Table 2. Synthesis of dihydropyrrolo[2,3,4-kl]acridines 3.
Molecules 18 01613 i001
EntryProductR1R2Time (min)Isolated Yield (%)
13aH4-t-BuC6H41291
23bH3,5-(CH3)2C6H31292
33cH2-CH3CH2C6H41292
43dH3-Cl-4-FC6H31589
53e5-Cl4-CH3OC6H41290
63f5-Cl4-t-BuC6H41291
73g5-Cl3,5-(CH3)2C6H31292
83h5-Cl3-Cl-4-FC6H31590
93i5-Cl2-CH3CH2C6H41293
103j5-Cln-C4H91589
113k5-F4-CH3C6H41292
123l5-F4-ClC6H41291
133m5-F2,4-(CH3)2C6H31291
143n5-F3-Cl-4-FC6H31590
153o5-F4-t-BuC6H41292
163p5-F2-CH3CH2C6H41292
173q5-Br4-ClC6H41293
183r5-Br3-Cl-4-FC6H31590
193s5-Br4-BrC6H41290
203t5-Br3,5-(CH3)2C6H31291
213u5-Brn-C4H91592
To expand the scope of the present method, N-substituted 3-aminocyclohex-2-enone, N-substituted 3-amino-5-phenylcyclohex-2-enones or N-substituted 3-amino-5-methylcyclohex-2-enones (4) were examined to replace the N-substituted 3-amino-5,5-dimethylcyclohex-2-enones (2), to our surprise, under the above optimized conditions, the desired 4,5-dihydropyrrolo[2,3,4-kl]acridine products 3 were not obtained. In the corresponding 1H-NMR spectra, the methylene group signals could not be detected, however a new aromatic proton could be detected easily. This result indicated that the corresponding oxidation products, the pyrrolo[2,3,4-kl]acridine derivatives 5 were produced (Table 3). The reason is that when there is no substituent or only one substituene (phenyl or methyl) on the C5 position of N-substituted 3-aminocyclohex-2-enone, the 4,5-dihydropyrrolo[2,3,4-kl]acridine derivatives would be oxidized by oxygen in the air to give pyrrolo[2,3,4-kl]acridine derivatives. The reaction pathways could therefore be controlled by varying the enaminones with different substitution patterns to give a series of novel 4,5-dihydropyrrolo[2,3,4-kl]acridin-1-ones 3 and pyrrolo[2,3,4-kl]acridin-1-ones 5 selectively.
Table
Table 3. Synthesis of pyrrolo[2,3,4-kl]acridine derivatives 5.
Molecules 18 01613 i002
Table 3. Synthesis of pyrrolo[2,3,4-kl]acridine derivatives 5.
Molecules 18 01613 i002
EntryProductR1R2R3Time (min)Isolated Yield (%)
15a5-F4-ClC6H4H1587
25b5-F2,4-Cl2C6H3H1588
35c5-FC6H5H1587
45d5-Cl4-BrC6H4H1588
55e5-F4-t-BuC6H4H1586
65f5-F4-ClC6H4Ph1587
75g5-F3-Cl-4-FC6H3Ph1584
85hHC6H5Ph1588
95i5-F2,4-(CH3)2C6H3Ph1585
105jH4-BrC6H4Ph1587
115k5-Cl4-t-BuC6H4Ph1585
125l5-FC6H5Ph1584
135m5-Br4-CH3C6H4Ph1585
145n5-Br4-OCH3C6H4CH31585
The structures of the products 3 and 5were identified from their IR, 1H-NMR, and HRMS spectra. The structure of compound 3k was further confirmed by X-ray analysis (Figure 1).
Molecules 18 01613 g001 550
Figure 1. Molecular structure of compound 3k.
Figure 1. Molecular structure of compound 3k.
Molecules 18 01613 g001

3. Experimental

3.1. General

All reagents were purchased from commercial suppliers and used without further purification. Melting points are uncorrected. IR spectra were recorded on Varian F-1000 spectrometer in KBr with absorptions in cm−1. 1H-NMR (300 MHz or 400 MHz) spectra were recorded on a Varian Inova-300 MHz and Varian Inova-400 MHz (Palo Alto, CA, USA) in DMSO-d6 or CDCl3 solution. J values are in Hertz. Chemical shifts are expressed in parts per million downfield from internal standard TMS. High-resolution mass spectra (HRMS) for all the compounds were determined on Bruker MicrOTOF-QII mass spectrometer with ESI resource (Billerica, MA, USA). X-ray crystallographic analysis was performed with a Rigaku Mercury CCD/AFC diffractometer (Tokyo, Japan). Microwave irradiation was carried out with an Initiator EXP Microwave Synthesizer from Biotage (Uppsala, Sweden). The reaction temperature was measured by an infrared detector during microwave heating.

3.2. General Procedure for the Synthesis of Compounds 3 and 5

Isatin (1, 1.0 mmol) was introduced in a 10-mL Initiator reaction vial, and enaminone 2 or 4 (1.0 mmol) and 0.02 g of silica sulfuric acid as well as ethanol (3 mL) were then successively added. Subsequently, the reaction vial was closed and prestirred for 10 s. The mixture was irradiated (time, 12 or 15 min; temperature, 110 °C; absorption level, high; fixed hold time) until TLC (petroleum ether/ethyl acetate 3:1) revealed that convension of the starting material 1 was complete. The reaction mixture was then cooled to room temperature and concentrated. The solid was collected by Büchner filtration and purified by flash column chromatography (silica gel, mixture of petroleum ether/ethyl acetate, 3:1, v/v) to afford the desired products 3 or 5.
2-(4-tert-Butylphenyl)-4,5-dihydro-4,4-dimethylpyrrolo[2,3,4-kl]acridin-1(2H)-one (3a). M.p. 168–170 °C; IR (KBr, cm−1) 2930, 1690, 1448, 1332, 1075, 959, 891, 831, 700; 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 1.28 (s, 6H, 2 × CH3), 1.34 (s, 9H, (CH3)3), 3.33 (s, 2H, CH2), 5.80 (s, 1H, CH), 7.44 (d, J = 8.4 Hz, 2H, ArH), 7.59 (d, J = 8.4 Hz, 2H, ArH), 7.77 (t, J = 7.6 Hz, 1H, ArH), 7.84–7.88 (m, 1H, ArH), 8.16 (d, J = 8.8 Hz, 1H, ArH), 8.57 (d, J = 8.0 Hz, 1H, ArH). HRMS (ESI): m/z calcd. for C26H27N2O [M+H]+, 383.2123; found, 383.2103.
4,5-Dihydro-4,4-dimethyl-2-(3,5-dimethylphenyl)pyrrolo[2,3,4-kl]acridin-1(2H)-one (3b). M.p. 205–207 °C; IR (KBr, cm−1) 3064, 1717, 1634, 1499, 1386, 1327, 1257, 1186, 1092, 1018, 777; 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 1.20 (s, 6H, 2 × CH3), 2.30 (s, 6H, 2 × CH3), 3.07 (s, 2H, CH2), 5.64 (s, 1H, CH), 7.02–7.04 (m, 3H, ArH), 7.64 (t, J = 7.2 Hz, 1H, ArH), 7.72 (t, J = 7.6 Hz, 1H, ArH), 8.04 (d, J = 8.0 Hz, 1H, ArH), 8.46 (d, J = 7.6 Hz, 1H, ArH). HRMS (ESI): m/z calcd. for C24H23N2O [M+H]+, 355.1810; found, 355.1811.
2-(2-Ethylphenyl)-4,5-dihydro-4,4-dimethylpyrrolo[2,3,4-kl]acridin-1(2H)-one (3c). M.p. 196–198 °C; IR (KBr, cm−1) 2957, 1708, 1646, 1500, 1348, 1146, 1083, 1016, 896, 830, 738; 1H-NMR (300 MHz, CDCl3): δ (ppm) 1.39–1.40 (m, 9H, 3 × CH3), 2.39–2.43 (m, 2H, CH2), 3.32 (s, 2H, CH2), 5.82 (s, 1H, CH), 7.33–7.39 (m, 2H, ArH), 7.59–7.60 (m, 1H, ArH), 7.73–7.82 (m, 3H, ArH), 8.27–8.30 (m, 1H, ArH), 8.72–8.74 (m, 1H, ArH). HRMS (ESI): m/z calcd. for C24H23N2O [M+H]+, 355.1810; found, 355.1823.
2-(3-Chloro-4-fluorophenyl)-4,5-dihydro-4,4-dimethylpyrrolo[2,3,4-kl]acridin-1(2H)-one (3d). M.p. 168–169 °C; IR (KBr, cm−1) 2958, 1710, 1462, 1356, 1171, 1100, 880, 755; 1H-NMR (300 MHz, CDCl3): δ (ppm) 1.34 (s, 6H, 2 × CH3), 3.26 (s, 2H, CH2), 5.60 (s, 1H, CH), 7.31–7.38 (m, 2H, ArH), 7.56 (s, 1H, ArH), 7.69–7.78 (m, 2H, ArH), 8.20–8.21 (m, 1H, ArH), 8.69–8.70 (m, 1H, ArH). HRMS (ESI): m/z calcd. for C22H17ClFN2O [M+H]+, 379.1013; found, 379.1015.
9-Chloro-4,5-dihydro-2-(4-methoxyphenyl)-4,4-dimethylpyrrolo[2,3,4-kl]acridin-1(2H)-one (3e). M.p. 162–164 °C; IR (KBr, cm−1) 2954, 1704, 1494, 1342, 1121, 1009, 819; 1H-NMR (300 MHz, CDCl3): δ (ppm) 1.32 (s, 6H, 2 × CH3), 3.18 (s, 3H, OCH3), 3.87 (s, 2H, CH2), 5.59 (s, 1H, CH), 7.04 (d, J = 6.6 Hz, 2H, ArH), 7.38 (d, J = 6.6 Hz, 2H, ArH), 7.65 (d, J = 7.2 Hz, 1H, ArH), 8.05 (d, J = 8.7 Hz, 1H, ArH), 8.66 (s, 1H, ArH). HRMS (ESI): m/z calcd. for C23H20ClN2O2 [M+H]+, 391.1213; found, 391.1194.
2-(4-Tert-butylphenyl)-9-chloro-4,5-dihydro-4,4-dimethylpyrrolo[2,3,4-kl]acridin-1(2H)-one (3f). M.p. 182–184 °C; IR (KBr, cm−1) 2947, 1575, 1485, 1392, 1319, 1253, 1077, 989, 833, 717; 1H-NMR (300 MHz, CDCl3): δ (ppm) 1.33 (s, 6H, 2 × CH3), 1.38 (s, 9H, (CH3)3), 3.19 (s, 2H, CH2), 5.68 (s, 1H, CH), 7.42 (s, 2H, ArH), 7.56–7.57 (m, 2H, ArH), 7.66–7.68 (m, 1H, ArH), 8.08–8.09 (m, 1H, ArH), 8.69 (s, 1H, ArH). HRMS (ESI): m/z calcd. for C26H26ClN2O [M+H]+, 417.1734; found, 417.1768.
9-Chloro-4,5-dihydro-4,4-dimethyl-2-(3,5-dimethylphenyl)pyrrolo[2,3,4-kl]acridin-1(2H)-one (3g). M.p. 178–180 °C; IR (KBr, cm−1) 2928, 1705, 1636, 1521, 1474, 1396, 1254, 1176, 1109, 1035, 803; 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 1.11 (s, 6H, 2 × CH3), 2.21 (s, 6H, 2 × CH3), 2.97 (s, 2H, CH2), 5.61 (s, 1H, CH), 6.94 (s, 3H, ArH), 7.61–7.65 (m, 1H, ArH), 7.91 (d, J = 8.8 Hz, 1H, ArH), 8.23 (s, 1H, ArH). HRMS (ESI): m/z calcd. for C24H22ClN2O [M+H]+, 389.1421; found, 389.1405.
9-Chloro-2-(3-chloro-4-fluorophenyl)-4,5-dihydro-4,4-dimethylpyrrolo[2,3,4-kl]acridin-1(2H)-one (3h). M.p. 164–166 °C; IR (KBr, cm−1) 2944, 1634, 1484, 1369, 1288, 1182, 1093, 951, 818, 693; 1H-NMR (300 MHz, CDCl3): δ (ppm) 1.34 (s, 6H, 2 × CH3), 3.20 (s, 2H, CH2), 5.63 (s, 1H, CH), 7.32–7.37 (m, 2H, ArH), 7.57 (s, 1H, ArH), 7.69 (d, J = 7.8 Hz, 1H, ArH), 8.09 (d, J = 7.8 Hz, 1H, ArH), 8.66 (s, 1H, ArH). HRMS (ESI): m/z calcd. for C22H16 Cl2FN2O [M+H]+, 413.0624; found: 413.0608.
9-Chloro-2-(2-ethylphenyl)-4,5-dihydro-4,4-dimethylpyrrolo[2,3,4-kl]acridin-1(2H)-one (3i). M.p. 198–200 °C; IR (KBr, cm−1) 2948, 1703, 1638, 1516, 1457, 1351, 1209, 1087, 910, 879, 804; 1H-NMR (300 MHz, CDCl3): δ (ppm) 1.14–1.16 (m, 3H, CH3), 1.31 (s, 6H, 2 × CH3), 2.56 (s, 2H, CH2), 3.20 (s, 2H, CH2), 5.29 (s, 1H, CH), 7.27 (s, 1H, ArH), 7.36 (s, 1H, ArH), 7.45 (s, 2H, ArH), 7.67 (d, J = 8.1 Hz, 1H, ArH), 8.09 (d, J = 6.9 Hz, 1H, ArH), 8.69 (s, 1H, ArH). HRMS (ESI): m/z calcd. for C24H22ClN2O [M+H]+, 389.1421; found, 389.1416.
2-Butyl-9-chloro-4,5-dihydro-4,4-dimethylpyrrolo[2,3,4-kl]acridin-1(2H)-one (3j). M.p. 148–149 °C; IR (KBr, cm−1) 2950, 1706, 1500, 1346, 1240, 1091, 956, 890, 824, 697; 1H-NMR (300 MHz, CDCl3): δ (ppm) 0.92–0.94 (m, 3H, CH3), 1.29–1.36 (m, 8H, CH2 + 2 × CH3), 1.66–1.67 (m, 2H, CH2), 3.09–3.10 (m, 2H, CH2), 3.73–3.74 (m, 2H, CH2), 5.51 (s, 1H, CH), 7.57–7.58 (m, 1H, ArH), 7.96–7.98 (m, 1H, ArH), 8.56 (s, 1H, ArH). HRMS (ESI): m/z calcd. for C20H22ClN2O [M+H]+, 341.1421; found, 341.1412.
2-(4-tert-Butylphenyl)-9-fluoro-4,5-dihydro-4,4-dimethylpyrrolo[2,3,4-kl]acridin-1(2H)-one (3k). M.p. 168–170 °C; IR (KBr, cm−1) 3079, 1711, 1635, 1504, 1403, 1256, 1119, 1063, 775, 707; 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 1.24 (s, 6H, 2 × CH3), 2.38 (s, 3H, CH3), 3.08 (s, 2H, CH2), 5.70 (s, 1H, CH), 7.31–7.36 (m, 4H, ArH), 7.60 (s, 1H, ArH), 8.00–8.09 (m, 2H, ArH). HRMS (ESI): m/z calcd. for C23H20FN2O [M+H]+, 359.1560; found, 359.1544.
2-(4-Chlorophenyl)-9-fluoro-4,5-dihydro-4,4-dimethylpyrrolo[2,3,4-kl]acridin-1(2H)-one (3l). M.p. 192–195 °C; IR (KBr, cm−1) 2957, 1703, 1508, 1360, 1223, 1110, 825, 699; 1H-NMR (300 MHz, CDCl3): δ (ppm) 1.32 (s, 6H, 2 × CH3), 3.19 (s, 2H, CH2), 5.63 (s, 1H, CH), 7.44–7.52 (s, 5H, ArH), 8.12–8.16 (m, 1H, ArH), 8.28–8.31 (m, 1H, ArH). HRMS (ESI): m/z calcd. for C22H17ClFN2O [M+H]+, 379.1013; found, 379.1005.
9-Fluoro-4,5-dihydro-4,4-dimethyl-2-(2,4-dimethylphenyl)pyrrolo[2,3,4-kl]acridin-1(2H)-one (3m). M.p. 148–150 °C; IR (KBr, cm−1) 2940, 1697, 1602, 1454, 1354, 1251, 1096, 970, 896, 834, 707; 1H-NMR (300 MHz, CDCl3): δ (ppm) 1.28 (s, 6H, 2 × CH3), 2.06 (s, 3H, CH3), 2.35 (s, 3H, CH3), 3.17 (s, 2H, CH2), 5.28 (s, 1H, CH), 7.13 (s, 1H, ArH), 7.24 (s, 2H, ArH), 7.46–7.48 (m, 1H, ArH), 8.12–8.14 (m, 1H, ArH), 8.28–8.31 (m, 1H, ArH). HRMS (ESI): m/z calcd. for C24H22FN2O [M+H]+, 373.1716; found, 373.1699.
2-(3-Chloro-4-fluorophenyl)-9-fluoro-4,5-dihydro-4,4-dimethylpyrrolo[2,3,4-kl]acridin-1(2H)-one (3n). M.p. 172–173 °C; IR (KBr, cm−1) 2958, 1613, 1473, 1363, 1273, 1171, 1070, 998, 910, 827, 701; 1H-NMR (300 MHz, CDCl3): δ (ppm) 1.33 (s, 6H, 2 × CH3), 3.22 (s, 2H, CH2), 5.63 (s, 1H, CH), 7.30–7.36 (m, 2H, ArH), 7.48–7.57 (m, 2H, ArH), 8.14–8.18 (m, 1H, ArH), 8.25–8.27 (m, 1H, ArH). HRMS (ESI): m/z calcd. for C22H16ClF2N2O [M+H]+, 397.0919; found, 397.0927.
2-(4-tert-Butylphenyl)-9-fluoro-4,5-dihydro-4,4-dimethylpyrrolo[2,3,4-kl]acridin-1(2H)-one (3o). M.p. 204–206 °C; IR (KBr, cm−1) 2950, 1707, 1639, 1493, 1348, 1201, 1086, 1017, 955, 833; 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 1.19 (s, 6H, 2 × CH3), 1.27 (s, 9H, (CH3)3), 3.04 (s, 2H, CH2), 5.70 (s, 1H, CH), 7.36–7.37 (m, 2H, ArH), 7.51–7.59 (m, 3H, ArH), 7.97 (s, 1H, ArH), 8.07 (s, 1H, ArH). HRMS (ESI): m/z calcd. for C26H26FN2O [M+H]+, 401.2029; found, 401.2034.
2-(2-Ethylphenyl)-9-fluoro-4,5-dihydro-4,4-dimethylpyrrolo[2,3,4-kl]acridin-1(2H)-one (3p). M.p. 166–168 °C; IR (KBr, cm−1) 2949, 1699, 1514, 1353, 1196, 1098, 1017, 943, 843, 785; 1H-NMR (300 MHz, CDCl3): δ (ppm) 1.12–1.17 (m, 3H, CH3), 1.30 (s, 6H, 2 × CH3), 2.53–2.56 (m, 2H, CH2), 3.20 (s, 2H, CH2), 5.28 (s, 1H, CH), 7.27 (s, 1H, ArH), 7.35 (s, 1H, ArH), 7.44–7.46 (m, 2H, ArH), 7.50–7.53 (m, 1H, ArH), 8.15–8.18 (m, 1H, ArH), 8.33 (d, J = 6.3 Hz, 1H, ArH). HRMS (ESI): m/z calcd. for C24H22FN2O [M+H]+, 373.1716; found, 373.1712.
9-Bromo-2-(4-chlorophenyl)-4,5-dihydro-4,4-dimethylpyrrolo[2,3,4-kl]acridin-1(2H)-one (3q). M.p. 192–194 °C; IR (KBr, cm−1) 2949, 1705, 1499, 1351, 1102, 961, 826, 740; 1H-NMR (300 MHz, CDCl3): δ (ppm) 1.32 (s, 6H, 2 × CH3), 3.17 (s, 2H, CH2), 5.64 (s, 1H, CH), 7.44–7.49 (m, 4H, ArH), 7.80 (s, 1H, ArH), 7.97 (s, 1H, ArH), 8.81 (s, 1H, ArH). HRMS (ESI): m/z calcd. for C22H17BrClN2O [M+H]+, 439.0213; found, 439.0197.
9-Bromo-2-(3-chloro-4-fluorophenyl)-4,5-dihydro-4,4-dimethylpyrrolo[2,3,4-kl]acridin-1(2H)-one (3r). M.p. 168–170 °C; IR (KBr, cm−1) 2950, 1704, 1588, 1495, 1439, 1347, 1084, 822, 702; 1H-NMR (300 MHz, CDCl3): δ (ppm) 1.33 (s, 6H, 2 × CH3), 3.18 (s, 2H, CH2), 5.63 (s, 1H, CH), 7.30–7.36 (m, 2H, ArH), 7.56 (s, 1H, ArH), 7.79 (d, J = 6.6 Hz, 1H, ArH), 7.98 (d, J = 8.4 Hz, 1H, ArH), 8.77 (s, 1H, CH). HRMS (ESI): m/z calcd. for C22H16BrClFN2O [M+H]+, 457.0119; found, 457.0103.
9-Bromo-2-(4-bromophenyl)-4,5-dihydro-4,4-dimethylpyrrolo[2,3,4-kl]acridin-1(2H)-one (3s). M.p. 182–184 °C; IR (KBr, cm−1)2955, 1709, 1590, 1459, 1343, 1159, 1013, 889, 832, 766, 705; 1H-NMR (300 MHz, CDCl3): δ (ppm) 1.32 (s, 6H, 2 × CH3), 3.18 (s, 2H, CH2), 5.64 (s, 1H, CH), 7.37–7.39 (m, 2H, ArH), 7.65 (s, 2H, ArH), 7.79–7.82 (m, 1H, ArH), 7.99 (d, J = 6.9 Hz, 1H, ArH), 8.82 (s, 1H, CH). HRMS (ESI): m/z calcd. for C22H17 Br2N2O [M+H]+, 482.9708; found, 482.9693.
9-Bromo-4,5-dihydro-4,4-dimethyl-2-(3,5-dimethylphenyl)pyrrolo[2,3,4-kl]acridin-1(2H)-one (3t). M.p. 164–166 °C; IR (KBr, cm−1) 2958, 1915, 1612, 1550, 1445, 1318, 1229, 1101, 984, 823, 715; 1H-NMR (300 MHz, CDCl3): δ (ppm) 1.31 (s, 6H, 2 × CH3), 2.39 (s, 6H, 2 × CH3), 3.16 (s, 2H, CH2), 5.63 (s, 1H, CH), 7.03–7.07 (m, 3H, ArH), 7.22 (d, J = 6.0 Hz, 1H, ArH), 7.96–7.98 (m, 1H, ArH), 8.83 (s, 1H, CH). HRMS (ESI): m/z calcd. for C24H22BrN2O [M+H]+, 433.0916; found, 433.0906.
9-Bromo-2-butyl-4,5-dihydro-4,4-dimethylpyrrolo[2,3,4-kl]acridin-1(2H)-one (3u). M.p. 156–158 °C; IR (KBr, cm−1) 2938, 1699, 1510, 1450, 1356, 1245, 1126, 1028, 831, 789; 1H-NMR (300 MHz, CDCl3): δ (ppm) 0.95 (s, 3H, CH3), 1.32–138 (m, 8H, CH2 + 2 × CH3), 1.69–1.70 (m, 2H, CH2), 3.11–3.12 (m, 2H, CH2), 3.77 (s, 2H, CH2), 5.54 (s, 1H, CH), 7.74 (d, J = 7.2 Hz, 1H, ArH), 7.94 (d, J = 8.7 Hz, 1H, ArH), 8.78 (s, 1H, ArH). HRMS (ESI): m/z calcd. for C20H22BrN2O [M+H]+, 385.0916; found, 385.0917.
2-(4-Chlorophenyl)-9-fluoropyrrolo[2,3,4-kl]acridin-1(2H)-one (5a). M.p. 237–238 °C; IR (KBr, cm−1) 3022, 1716, 1638, 1185, 1074, 874; 1H-NMR (400 MHz, CDCl3): δ (ppm) 7.02–7.04 (m, 1H, ArH), 7.56–7.59 (m, 4H, ArH), 7.69–7.73 (m, 2H, ArH), 7.90 (d, J = 9.2 Hz 1H, ArH), 8.44–8.50 (m, 2H, ArH). HRMS (ESI): m/z calcd. for C20H10ClFN2NaO, 371.0363, [M+Na]+; found, 371.0345.
2-(2,4-Dichlorophenyl)-9-fluoropyrrolo[2,3,4-kl]acridin-1(2H)-one (5b). M.p. 248–250 °C; IR (KBr, cm−1) 3050, 1723, 1639, 1182, 1089, 785; 1H-NMR (400 MHz, CDCl3): δ (ppm) 6.66 (d, J = 6.8 Hz 1H, ArH), 7.43–7.45 (m, 1H, ArH), 7.58 (d, J = 8.0 Hz, 2H, ArH), 7.69–7.73 (m, 2H, ArH), 7.92 (d, J = 8.8 Hz 1H, ArH), 8.49–8.53 (m, 2H, ArH). HRMS (ESI): m/z calcd. for C20H9Cl2FN2NaO, 404.9974, [M+Na]+; found, 404.9989.
9-Fluoro-2-phenylpyrrolo[2,3,4-kl]acridin-1(2H)-one (5c). M.p. 228–230 °C; IR (KBr, cm−1) 2978, 1716, 1673, 1262, 1185, 1074, 874; 1H-NMR (400 MHz, CDCl3): δ (ppm) 7.03 (d, J = 6.8 Hz 1H, ArH), 7.46–7.47 (m, 1H, ArH), 7.60–7.76 (m, 6H, ArH), 7.87 (d, J = 8.8 Hz 1H, ArH), 8.43–8.50 (m, 2H, ArH). HRMS (ESI): m/z calcd. for C20H11FN2NaO, 337.0753, [M+Na]+; found, 337.0769.
2-(4-Bromophenyl)-9-chloropyrrolo[2,3,4-kl]acridin-1(2H)-one (5d). M.p. 218–220 °C; IR (KBr, cm−1) 2978, 1706, 1632, 1503, 1130, 1118 1096, 854; 1H-NMR (400 MHz, CDCl3): δ (ppm) 6.70–6.71 (m, 1H, ArH), 7.48–7.59 (m, 3H, ArH), 7.64–7.71 (m, 3H, ArH), 7.87–7.89 (m, 1H, ArH), 8.43–8.49 (m, 2H, ArH). HRMS (ESI): m/z calcd. for C20H10BrClN2NaO, 430.5963, [M+Na]+; found, 430.5978.
2-(4-tert-Butylphenyl)-9-fluoropyrrolo[2,3,4-kl]acridin-1(2H)-one (5e). M.p. 162–164 °C; IR (KBr, cm−1) 2951, 1710, 1628, 1512, 1353, 1205, 1096, 830, 718; 1H-NMR (300 MHz, CDCl3): δ (ppm) 1.42 (s, 9H, C(CH3)3), 7.04–7.06 (m, 1H, ArH), 7.57–7.71 (m, 6H, ArH), 7.85–7.89 (m, 1H, ArH), 8.44–8.51 (m, 2H, ArH). HRMS (ESI): m/z calcd. for C24H20FN2O, 370.1481, [M+H]+; found, 371.1537.
2-(4-Chlorophenyl)-9-fluoro-4-phenylpyrrolo[2,3,4-kl]acridin-1(2H)-one (5f). M.p. 238–240 °C; IR (KBr, cm−1) 2930, 2352, 1710, 1640, 1503, 1384, 1092, 805; 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.46–7.69 (m, 11H, ArH), 8.04–8.05 (m, 1H, ArH), 8.41–8.42 (m, 2H, ArH). HRMS (ESI): m/z calcd. for C26H15ClFN2O, 425.0857, [M+H]+; found, 425.0846.
2-(3-Chloro-4-fluorophenyl)-9-fluoro-4-phenylpyrrolo[2,3,4-kl]acridin-1(2H)-one (5g). M.p. 230–232 °C; IR (KBr, cm−1) 3069, 2926, 2354, 1716, 1639, 1499, 1087, 812; 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.29–7.54 (m, 6H, ArH), 7.70–7.76 (m, 4H, ArH), 8.01–8.02 (m, 1H, ArH), 8.42–8.45 (m, 2H, ArH). HRMS (ESI): m/z calcd. for C26H14 ClF2N2O, 443.0763 [M+H]+; found, 443.0770.
2,4-Diphenylpyrrolo[2,3,4-kl]acridin-1(2H)-one (5h). M.p. 220–221 °C; IR (KBr, cm−1) 2921, 1718, 1637, 1496, 1103, 1008, 761; 1H-NMR (400 MHz, CDCl3): δ (ppm) 7.27 (s, 1H, ArH), 7.45–7.53 (m, 4H, ArH), 7.60–7.73 (m, 6H, ArH), 7.80 (t, J = 8.0 Hz, 1H, ArH), 7.93 (t, J = 8.4 Hz, 1H, ArH), 8.06 (s, 1H, ArH), 8.42 (d, J = 8.8 Hz, 1H, ArH), 8.89 (d, J = 8.0 Hz, 1H, ArH). HRMS (ESI): m/z calcd. for C26H16N2NaO, 395.1160 [M+Na]+; found, 395.1182.
9-Fluoro-2-(2,4-dimethylphenyl)-4-phenylpyrrolo[2,3,4-kl]acridin-1(2H)-one (5i). M.p. 188–190 °C; IR (KBr, cm−1) 2990, 1705, 1633, 1131, 1066, 854; 1H-NMR (400 MHz, CDCl3): δ (ppm) 2.08 (s, 3H, CH3), 2.26 (s, 3H, CH3), 6.72–6.73 (m, 1H, ArH), 7.03–7.16 (m, 3H, ArH), 7.22–7.29 (m, 3H, ArH), 7.47–7.49 (m, 3H, ArH), 7.82–7.84 (m, 1H, ArH), 8.22–8.27 (m, 2H, ArH). HRMS (ESI): m/z calcd. for C28H20FN2O, 419.1560, [M+H]+; found, 419.1559.
2-(4-Bromophenyl)-4-phenylpyrrolo[2,3,4-kl]acridin-1(2H)-one (5j). M.p. 234–235 °C; IR (KBr, cm−1) ν2987, 1703, 1636, 1501, 1253, 1181, 1085, 832. 1H-NMR (CDCl3-d1, 400 MHz) δ : 7.22 (s, 1H, ArH), 7.40–7.56 (m, 5H, ArH), 7.69–7.79 (m, 5H, ArH), 7.91 (t, J = 7.6 Hz, 1H, ArH), 8.05 (s, 1H, ArH), 8.40 (d, J = 8.8 Hz, 1H, ArH), 8.83 (d, J = 8.4 Hz, 1H, ArH). HRMS (ESI): m/z calcd. for C26H16BrN2O, 451.0446, [M+H]+; found, 451.0409.
2-(4-tert-Butylphenyl)-9-chloro-4-phenylpyrrolo[2,3,4-kl]acridin-1(2H)-one (5k). M.p. 222–223 °C; IR (KBr, cm−1) 2922, 1719, 1634, 1383, 1171, 1077, 822; 1H-NMR (400 MHz, CDCl3): δ (ppm) 1.42 (s, 9H, (CH3)3), 7.19–7.22 (m, 1H, ArH), 7.42–7.68 (m, 9H, ArH), 7.75–7.80 (m, 1H, ArH), 7.92–7.96 (m, 1H, ArH), 8.27–8.31 (m, 1H, ArH), 8.73–8.78 (m, 1H, ArH) HRMS (ESI): m/z calcd. for C30H24ClN2O, 463.1577, [M+H]+; found, 463.1570.
9-Fluoro-2,4-diphenylpyrrolo[2,3,4-kl]acridin-1(2H)-one (5l). M.p. 218–219 °C; IR (KBr, cm−1) 2957, 1705, 1633, 1322, 1173, 1096, 854; 1H-NMR (400 MHz, CDCl3): δ (ppm) 7.43–7.51 (m, 4H, ArH), 7.59–7.70 (m, 8H, ArH), 8.01–8.02 (m, 1H, ArH), 8.41–8.43 (m, 2H, ArH). HRMS (ESI): m/z calcd. for C26H16FN2O, 391.1247, [M+H]+; found, 391.1229.
9-Bromo-4-phenyl-2-p-tolylpyrrolo[2,3,4-kl]acridin-1(2H)-one (5m). M.p. 220–222 °C; IR (KBr, cm−1) 2921, 1706, 1635, 1384, 1129, 1092, 820; 1H-NMR (400 MHz, CDCl3): δ (ppm) 2.45 (s, 3H, CH3), 7.17 (s, 1H, ArH), 7.38–7.50 (m, 7H, ArH), 7.65 (d, J = 7.6 Hz, 2H, ArH), 7.89–7.95 (m, 2H, ArH), 8.21 (d, J = 9.2 Hz, 1H, ArH), 8.98 (s, 1H, ArH). HRMS (ESI): m/z calcd. for C27H17BrN2NaO, 487.0422, [M+H]+; found, 487.0403.
9-Bromo-2-(4-methoxyphenyl)-4-methylpyrrolo[2,3,4-kl]acridin-1(2H)-one (5n). M.p. 216–218 °C; IR (KBr, cm−1) 2916, 1718, 1637, 1516, 1384, 1124, 1080, 849; 1H-NMR (400 MHz, CDCl3): δ (ppm) 2.50 (s, 3H, CH3), 2.60 (s, 3H, OCH3), 6.82 (s, 1H, ArH), 7.41–7.60 (m, 5H, ArH), 7.93–7.96 (m, 1H, ArH), 8.24–8.26 (m, 1H, ArH), 9.03–9.04 (m, 1H, ArH). HRMS (ESI): m/z calcd. for C22H15BrN2NaO2, 441.0215, [M+Na]+; found, 441.0218.

4. Conclusions

In conclusion, we have developed a procedure for the simple synthesis of a variety of potential biologically active pyrrolo[2,3,4-kl]acridines based on a novel domino reaction. Using this method, a library of molecularly diverse pyrrolo[2,3,4-kl]acridine derivatives was rapidly assembled (12–15 min) with excellent yields (84%–93%) by using readily available and inexpensive substrates under microwave irradiation.

Acknowledgments

We gratefully acknowledge the Natural Science Foundation of China (No. 81072577, 81102376, 21072144), the Major Basic Research Project of the Natural Science Foundation of the Jiangsu Higher Education Institutions (No. 10KJA150049), the Priority Academic Project Development of Jiangsu Higher Education Institutions and Key Laboratory of Organic Synthesis of Jiangsu Province (No. KJS0812) and the National S&T Major Special Project on Major New Drug Innovation (No. 2012ZX093101002-001-017) for support of this research.

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  • Sample Availability: Samples of the compounds 3 and 5 are available from the authors.

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MDPI and ACS Style

Cao, C.; Xu, C.; Lin, W.; Li, X.; Hu, M.; Wang, J.; Huang, Z.; Shi, D.; Wang, Y. Microwave-Assisted Improved Synthesis of Pyrrolo[2,3,4-kl]acridine and Dihydropyrrolo[2,3,4-kl]acridine Derivatives Catalyzed by Silica Sulfuric Acid. Molecules 2013, 18, 1613-1625. https://doi.org/10.3390/molecules18021613

AMA Style

Cao C, Xu C, Lin W, Li X, Hu M, Wang J, Huang Z, Shi D, Wang Y. Microwave-Assisted Improved Synthesis of Pyrrolo[2,3,4-kl]acridine and Dihydropyrrolo[2,3,4-kl]acridine Derivatives Catalyzed by Silica Sulfuric Acid. Molecules. 2013; 18(2):1613-1625. https://doi.org/10.3390/molecules18021613

Chicago/Turabian Style

Cao, Chengpao, Changliang Xu, Wei Lin, Xuemei Li, Minghua Hu, Juxian Wang, Zhibin Huang, Daqing Shi, and Yucheng Wang. 2013. "Microwave-Assisted Improved Synthesis of Pyrrolo[2,3,4-kl]acridine and Dihydropyrrolo[2,3,4-kl]acridine Derivatives Catalyzed by Silica Sulfuric Acid" Molecules 18, no. 2: 1613-1625. https://doi.org/10.3390/molecules18021613

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