Microwave-assisted improved synthesis of pyrrolo[2,3,4-kl]acridine and dihydropyrrolo[2,3,4-kl]acridine derivatives catalyzed by silica sulfuric acid

Article abstract of DOI:10.3390/molecules18021613

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.

Full text of DOI:10.3390/molecules18021613

Molecules 2013, 18, 1613-1625; doi:10.3390/molecules18021613
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
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
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
†
These authors contributed equally to this work.
* Authors to whom correspondence should be addressed; E-Mails: dqshi@suda.edu.cn (D.S.);
wyc9999@126.com (Y.W.); Tel.: +86-512-6588-0049 (D.S.); Fax: +86-512-6588-0089 (D.S.);
Tel./Fax: +86-010-6316-5263 (Y.W.).
Received: 29 November 2012; in revised form: 21 December 2012 / Accepted: 5 January 2013 /
Published: 28 January 2013
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.
Keywords: pyrrolo[2,3,4-kl]acridine; silica sulfuric acid; microwave irradiation

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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 [1–3].
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 [21–23], 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.
Scheme 1. The model reaction.

Molecules 2013, 18
Table 1. Optimization of the reaction conditions for the synthesis of 3a.
1615
Entry
1
Solvent
ethanol
ethanol
AcOH
Catalyst
-
T (°C) Time (min) Yield a (%)
110
110
110
110
110
110
110
110
110
110
110
110
110
90
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
8
23
91
85
81
87
91
78
59
73
40
90
91
76
71
85
87
77
87
91
89
2
SSA (0.02 g)
SSA (0.02 g)
SSA (0.02 g)
SSA (0.02 g)
SSA (0.02 g)
HCl (0.5 mL)
H2SO4 (0.5 mL)
I2 (0.02 g)
3
4
H2O
5
ethylene glycol
toluene
ethanol
ethanol
ethanol
ethanol
ethanol
ethanol
ethanol
ethanol
ethanol
ethanol
ethanol
ethanol
ethanol
ethanol
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
L-proline (10 mol%)
SSA (0.03 g)
SSA (0.04 g)
SSA (0.01 g)
SSA (0.02 g)
SSA (0.02 g)
SSA (0.02 g)
SSA (0.02 g)
SSA (0.02 g)
SSA (0.02 g)
SSA (0.02 g)
100
120
110
110
110
110
10
12
20
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

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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 2. Synthesis of dihydropyrrolo[2,3,4-kl]acridines 3.
Entry Product R1
R2
Time (min) Isolated Yield (%)
1
2
3a
3b
3c
3d
3e
3f
H
H
4-t-BuC6H4
12
12
12
15
12
12
12
15
12
15
12
12
12
15
12
12
12
15
12
12
15
91
92
92
89
90
91
92
90
93
89
92
91
91
90
92
92
93
90
90
91
92
3,5-(CH3)2C6H3
2-CH3CH2C6H4
3-Cl-4-FC6H3
4-CH3OC6H4
4-t-BuC6H4
3
H
4
H
5
5-Cl
5-Cl
6
7
3g
3h
3i
5-Cl 3,5-(CH3)2C6H3
5-Cl 3-Cl-4-FC6H3
5-Cl 2-CH3CH2C6H4
8
9
10
11
12
13
14
15
16
17
18
19
20
21
3j
5-Cl
5-F
5-F
n-C4H9
4-CH3C6H4
4-ClC6H4
3k
3l
3m
3n
3o
3p
3q
3r
3s
5-F 2,4-(CH3)2C6H3
5-F
5-F
3-Cl-4-FC6H3
4-t-BuC6H4
5-F 2-CH3CH2C6H4
5-Br 4-ClC6H4
5-Br 3-Cl-4-FC6H3
5-Br 4-BrC6H4
5-Br 3,5-(CH3)2C6H3
5-Br n-C4H9
3t
3u
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
1
were not obtained. In the corresponding H-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).

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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 3. Synthesis of pyrrolo[2,3,4-kl]acridine derivatives 5.
Entry Product R1
R2
R3 Time (min) Isolated Yield (%)
1
2
5a
5b
5c
5d
5e
5f
5-F
5-F
5-F
5-Cl
5-F
5-F
5-F
H
4-ClC6H4
2,4-Cl2C6H3
C6H5
H
H
15
15
15
15
15
15
15
15
15
15
15
15
15
15
87
88
87
88
86
87
84
88
85
87
85
84
85
85
3
H
4
4-BrC6H4
4-t-BuC6H4
4-ClC6H4
3-Cl-4-FC6H3
C6H5
H
5
H
6
Ph
Ph
Ph
7
5g
5h
5i
8
9
5-F 2,4-(CH3)2C6H3 Ph
10
11
12
13
14
5j
H
4-BrC6H4
4-t-BuC6H4
C6H5
Ph
Ph
Ph
Ph
5k
5l
5-Cl
5-F
5m
5n
5-Br
4-CH3C6H4
5-Br 4-OCH3C6H4 CH3
The structures of the products 3 and 5 were identified from their IR, 1H-NMR, and HRMS spectra.
The structure of compound 3k was further confirmed by X-ray analysis (Figure 1).
Figure 1. Molecular structure of compound 3k.

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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
1
absorptions in cm−1. H-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,

Molecules 2013, 18
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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.
1
168–169 °C; IR (KBr, cm−1) 2958, 1710, 1462, 1356, 1171, 1100, 880, 755; H-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,

Molecules 2013, 18
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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.
1
192–195 °C; IR (KBr, cm−1) 2957, 1703, 1508, 1360, 1223, 1110, 825, 699; H-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.
1
204–206 °C; IR (KBr, cm−1) 2950, 1707, 1639, 1493, 1348, 1201, 1086, 1017, 955, 833; H-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.
1
166–168 °C; IR (KBr, cm−1) 2949, 1699, 1514, 1353, 1196, 1098, 1017, 943, 843, 785; H-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.
1
192–194 °C; IR (KBr, cm−1) 2949, 1705, 1499, 1351, 1102, 961, 826, 740; H-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),

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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).
1
M.p. 168–170 °C; IR (KBr, cm−1) 2950, 1704, 1588, 1495, 1439, 1347, 1084, 822, 702; H-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;
1
IR (KBr, cm−1) 2938, 1699, 1510, 1450, 1356, 1245, 1126, 1028, 831, 789; H-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,
1
cm−1) 3022, 1716, 1638, 1185, 1074, 874; H-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
1
(KBr, cm−1) 3050, 1723, 1639, 1182, 1089, 785; H-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,
1
1716, 1673, 1262, 1185, 1074, 874; H-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.

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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
1
(KBr, cm−1) 2951, 1710, 1628, 1512, 1353, 1205, 1096, 830, 718; H-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
1
(KBr, cm−1) 2930, 2352, 1710, 1640, 1503, 1384, 1092, 805; H-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,
1
1637, 1496, 1103, 1008, 761; H-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,
1
cm−1) ν2987, 1703, 1636, 1501, 1253, 1181, 1085, 832. H-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.

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9-Fluoro-2,4-diphenylpyrrolo[2,3,4-kl]acridin-1(2H)-one (5l). M.p. 218–219 °C; IR (KBr, cm−1)
1
2957, 1705, 1633, 1322, 1173, 1096, 854; H-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
1
(KBr, cm−1) 2921, 1706, 1635, 1384, 1129, 1092, 820; H-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
1
(KBr, cm−1) 2916, 1718, 1637, 1516, 1384, 1124, 1080, 849; H-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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