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Synthesis 2015; 47(04): 562-568
DOI: 10.1055/s-0034-1379584
paper
© Georg Thieme Verlag Stuttgart · New York

Copper(I) Iodide Catalyzed Synthesis of Fused Hexacyclic Pyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-ones under Ligand-Free Conditions

Wen-Ting Zhang
School of Chemistry and Chemical Engineering, Jiangsu Key Laboratory of Green Synthesis for Functional Materials, Jiangsu Normal University, Xuzhou Jiangsu 221116, P. R. of China   Fax: +86(516)83500065   Email: xswang@jsnu.edu.cn
,
Dong-Sheng Chen
School of Chemistry and Chemical Engineering, Jiangsu Key Laboratory of Green Synthesis for Functional Materials, Jiangsu Normal University, Xuzhou Jiangsu 221116, P. R. of China   Fax: +86(516)83500065   Email: xswang@jsnu.edu.cn
,
Chao Li
School of Chemistry and Chemical Engineering, Jiangsu Key Laboratory of Green Synthesis for Functional Materials, Jiangsu Normal University, Xuzhou Jiangsu 221116, P. R. of China   Fax: +86(516)83500065   Email: xswang@jsnu.edu.cn
,
Xiang-Shan Wang*
School of Chemistry and Chemical Engineering, Jiangsu Key Laboratory of Green Synthesis for Functional Materials, Jiangsu Normal University, Xuzhou Jiangsu 221116, P. R. of China   Fax: +86(516)83500065   Email: xswang@jsnu.edu.cn
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Further Information

Publication History

Received: 21 August 2014

Accepted after revision: 31 October 2014

Publication Date:
14 November 2014 (online)

 
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Abstract

The three-component reaction of an o-halogenated benzaldehyde, 1H-indazol-6-amine, and cyclohexane-1,3-dione is described for the construction of fused hexacycles catalyzed by copper(I) iodide under ligand-free conditions. This is a domino reaction that constructs two new heterocycles and six new bonds in a one-pot reaction, and provides an efficient method for the synthesis of pyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-ones in good yields.


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Key words

1H-indazol-6-amine - pyrazoloquinolinoacridine - domino reaction - copper(I) iodide - ligand-free

It is well known that fused polycyclic heterocycles possess good biological and pharmacological activity.[1] Pyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one (Figure [1], left) is a fused hexacyclic heterocycle that contains acridine, pyrazole, and quinoline rings. Of these, acridine is a fused tricyclic heterocycle containing a nitrogen atom; it is ubiquitous heterocycle because of the broad spectrum of biological activity of its derivatives.[2] Amsacrine (Figure [1], middle) is a representative drug based on the acridine moiety on the market, it is an antineoplastic agent used in the treatment of acute lymphoblastic leukemia.[3] In addition, quinoline is also an important alkaloid in natural products with significant bioactivity.[4] A well-known example is chloroquine (Figure [1], right) which is effective for the treatment of malaria.[5] Combining two of these heterocyclic systems also gives compounds with biological activity, for example pyrazoloquinoline and pyrazoloacridine derivatives also have anti-inflammatory[6] and anticancer activity,[7] respectively. However, there are few reports of the synthesis of quinolinoacridines.[8] Furthermore, it should be noted that there are no reports on the synthesis of pyrazoloquinolinoacridinones which potentially have unique activities. Therefore, a one-pot, efficient, and green method for the synthesis of pyrazoloquinolinoacridinones is very necessary.

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Figure 1 Pyrazoloquinolinoacridinone, amsacrine, and chloroquine

The Ullmann reaction is an efficient method for the construction of carbon–heteroatom bonds, including C–O, C–S, and C–N bonds;[9] it is achieved using various metal catalysts containing palladium or copper.[10]

In our previous study, copper(I) was shown to be an efficient catalyst for the promotion of Csp2–N bond formation.[11] As part of our continued study of the synthesis of polycyclic heterocycles via Ullmann-type reactions, herein, we would like to report the copper(I) iodide catalyzed reaction of an o-halogenated benzaldehyde, 1H-indazol-6-amine, and cyclohexane-1,3-dione under ligand-free conditions for the construction of fused hexacyclic pyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one derivatives.

2-Bromobenzaldehyde (1a), 1H-indazol-6-amine (2a), and 5,5-cyclohexane-1,3-dione (3a) were used as substrates in a model reaction to optimize the reaction conditions (Equation 1). An extensive investigation of the catalyst, catalyst amount, base, and solvent was carried out. When the reaction was performed in the absence of a base, the simple condensation product 11-(2-bromophenyl)-8,8-dimethyl-7,8,9,11-tetrahydro-1H-pyrazolo[3,4-a]acridin-10(6H)-one (5) was isolated in 92% yield (Table [1], entry 1). In the presence of a base the formation of 4a was observed; the bases examined include potassium carbonate, cesium carbonate, sodium carbonate, sodium hydrogen carbonate, and triethylamine (entries 2–6). The highest yield (83%) of 4a was obtained using two equivalents of cesium carbonate as the base in dioxane (entry 3).

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Equation 1 The model reaction

Table 1 Optimization of the Model Reaction for the Formation of 4a (Equation 1)a

Entry

Catalyst (mol%)

Base

Temp (°C)

Solvent

Yieldb (%)

1

CuI (5)

–

100

dioxane

0c

2

CuI (5)

K2CO3

100

dioxane

76

3

CuI (5)

Cs2CO3

100

dioxane

83

4

CuI (5)

Na2CO3

100

dioxane

72

5

CuI (5)

NaHCO3 d

100

dioxane

73

6

CuI (5)

Et3N

100

dioxane

76

7

CuI (10)

Cs2CO3

100

dioxane

86

8

CuI (20)

Cs2CO3

100

dioxane

85

9

CuI (5)

Cs2CO3

100

DMSO

86

10

CuI (5)

Cs2CO3

80

MeCN

65

11

CuI (5)

Cs2CO3

65

THF

68

12

CuI (5)

Cs2CO3

100

toluene

62

13

CuBr (5)

Cs2CO3

100

DMSO

85

14

CuCl (5)

Cs2CO3

100

DMSO

75

a Reaction conditions: 1a (0.185 g, 1.0 mmol), 2a (0.133 g, 1.0 mmol), 3a (0.140 g, 1.0 mmol), base (2 mmol), solvent (10 mL), reflux.

b Isolated yields.

c Product of simple condensation reaction was isolated in 92% yield.

d 4 mmol.

Then, the influence of various solvents, including dimethyl sulfoxide, acetonitrile, tetrahydrofuran, and toluene, on the yield of 4a was studied (entries 3, and 9–12). Using cesium carbonate as the base, dimethyl sulfoxide at 100 °C was found to be the best solvent for this reaction and gave 4a in the highest yield of 86% (entry 9). In addition, other copper(I) catalysts, such as copper(I) bromide and copper(I) chloride (entries 9, 13, and 14) were also examined, but copper(I) iodide was established to be superior.

With the optimized the reaction conditions in hand, we then explored the scope and limitations of this reaction with variety of o-halogenated benzaldehydes 1 (Equation 2, Table [2]). Reactions with both electron-donating (alkoxy) and electron-withdrawing (halogen and nitro) groups all proceeded efficiently at 100 °C to give the corresponding products 4a–h in good yields (entries 1–8). The reaction was, therefore, not significantly affected by the substituents on the o-halogenated benzaldehyde. It should be noted that using 2-chloro-5-nitrobenzaldehyde (X = Cl) as a reactant also gave a good result (entry 8). To our satisfaction, the optimized reaction conditions were also suitable for other cyclohexane-1,3-dione derivatives, such as cyclohexane-1,3-dione (3b) (entries 9–13) and 5-methylcyclohexane-1,3-dione (3c) (entries 14–18); they all reacted well with 1 and 2 to afford fused pyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-ones 4i–r in good yields under ligand-free conditions. In addition, 3-methyl-1H-indazol-6-amine (2b) also reacted with 1 and 3a to give 4s and 4t in 82% and 84% yields, respectively (entries 19 and 20).

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Equation 2 Synthetic route to 4

Table 2 Formation of Fused Pyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-ones 4 (Equation 2)a

Entry

R1

R2

R3

R4

Product

Time (h)

Yieldb (%)

1

H

H

Me

Me

4a

12

86

2

3-Cl

H

Me

Me

4b

10

89

3

2-Cl

H

Me

Me

4c

10

85

4

3-F

H

Me

Me

4d

12

82

5

2-F

H

Me

Me

4e

12

87

6

2-MeO

H

Me

Me

4f

14

79

7

2,3-(MeO)2

H

Me

Me

4g

16

80

8

2-O2Nc

H

Me

Me

4h

10

86

9

3-Cl

H

H

H

4i

12

90

10

2-Cl

H

H

H

4j

15

83

11

2-MeO

H

H

H

4k

18

82

12

2,3-(MeO)2

H

H

H

4l

18

76

13

3-F

H

H

H

4m

12

86

14

2-Cl

H

Me

H

4n

12

84

15

3-F

H

Me

H

4o

16

78

16

2-F

H

Me

H

4p

15

84

17

2-MeO

H

Me

H

4q

12

79

18

2,3-(MeO)2

H

Me

H

4r

16

72

19

3-Cl

Me

Me

Me

4s

16

82

20

4,5-OCH2O

Me

Me

Me

4t

13

84

a Reaction conditions: 1 (1.0 mmol), 2 (0.133 g, 1.0 mmol), 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0 mmol), DMSO (10 mL), X = Br.

b Isolated yields.

c X = Cl.

In conclusion, a new procedure for the synthesis of pyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one derivatives catalyzed by copper(I) iodide under ligand-free conditions has been established. This procedure involves the three-component reaction of an o-halogenated benzaldehyde, 1H-indazol-6-amine, and cyclohexane-1,3-dione and provides an expedient route for the synthesis of fused hexacyclic heterocycles in one-pot by an Ullmann-type Csp2–N bond coupling reaction.

Melting points were determined in open capillaries and are uncorrected. IR spectra were recorded on a TENSOR 27 spectrophotometer as KBr pellets. 1H and 13C NMR spectra were obtained in CDCl3 solution with TMS as internal standard using a Bruker-400 spectrometer. HRMS and LCMS analyses were carried out using Bruker micro-TOF-Q-MS and LCQ Advantate analyzers, respectively.


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Pyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one Derivatives 4; General Procedure

A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0 mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0 mmol), and DMSO (10 mL). The mixture was stirred at reflux until completion (TLC monitoring). The solid was filtered off, and the filtrate was distilled under reduced pressure to recover the solvent; the residue was purified by chromatography (silica gel, EtOAc–petroleum ether, 1:2) to give 4.


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12,12-Dimethyl-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one (4a)

Pale yellow solid; yield: 292 mg (86%); mp 194–195 °C.

IR (KBr): 2949, 2869, 1678, 1660, 1595, 1532, 1514, 1455, 1374, 1337, 1305, 1239, 1194, 1102, 1036, 988, 870, 826, 758, 739, 717 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.68–8.64 (m, 2 H, HAr), 8.57 (d, J = 5.2 Hz, 1 H, HAr), 8.27–8.23 (m, 1 H, HAr), 7.89–7.85 (m, 2 H, HAr), 7.49 (t, J = 8.0 Hz, 1 H, HAr), 3.42 (s, 2 H, CH2), 2.94 (s, 2 H, CH2), 1.26 (s, 6 H, 2 CH3).

13C NMR (100 MHz, CDCl3): δ = 200.5, 163.0, 149.4, 137.1, 136.1, 134.8, 132.6, 131.6, 131.0, 126.4, 124.1, 122.1, 121.4, 119.6, 115.7, 114.7, 112.8, 55.0, 49.4, 33.1, 28.7.

MS (ESI): m/z = 340.3 (100) [M + H]+.

HRMS (TOF, ESI): m/z [M + H]+ calcd for C22H18N3O: 340.1450; found: 340.1449.


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3-Chloro-12,12-dimethyl-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one (4b)

Pale yellow solid; yield: 332 mg (89%); mp 224–226 °C.

IR (KBr): 2950, 2868, 1674, 1660, 1594, 1526, 1465, 1373, 1339, 1271, 1235, 1194, 1095, 1036, 974, 865, 812, 768 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.67 (d, J = 2.4 Hz, 1 H, HAr), 8.67 (d, J = 9.2 Hz, 1 H, HAr), 8.58 (s, 1 H, HAr), 8.26 (d, J = 8.8 Hz, 1 H, HAr), 7.90 (d, J = 8.8 Hz, 1 H, HAr), 7.45 (dd, J = 9.2 Hz, J′ = 2.4 Hz, 1 H, HAr), 3.44 (s, 2 H, CH2), 2.94 (s, 2 H, CH2), 1.28 (s, 6 H, 2 CH3).

13C NMR (100 MHz, CDCl3): δ = 200.5, 163.2, 149.4, 138.9, 137.6, 136.6, 134.1, 132.3, 131.7, 126.4, 124.5, 122.4, 121.1, 118.0, 115.6, 114.8, 112.5, 55.0, 49.4, 33.2, 28.6.

MS (ESI): m/z = 374.3 (100) [M + H]+.

HRMS (TOF, ESI): m/z [M + H]+ calcd for C22H17N3OCl: 374.1060; found: 374.1072.


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2-Chloro-12,12-dimethyl-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one (4c)

Pale yellow solid; yield: 317 mg (85%); mp 218–219 °C.

IR (KBr): 2947, 2884, 1670, 1658, 1596, 1537, 1512, 1449, 1406, 1372, 1338, 1299, 1222, 1189, 1173, 1138, 1095, 1030, 1000, 902, 876, 831, 800, 743 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.69 (d, J = 2.4 Hz, 1 H, HAr), 8.64–8.59 (m, 2 H, HAr), 8.27 (t, J = 8.8 Hz, 1 H, HAr), 7.91 (d, J = 8.8 Hz, 1 H, HAr), 7.83 (dd, J = 8.8 Hz, J′ = 2.0 Hz, 1 H, HAr), 3.44 (s, 2 H, CH2), 2.98 (s, 2 H, CH2), 1.28 (s, 6 H, 2 CH3).

13C NMR (100 MHz, CDCl3): δ = 200.3, 163.2, 149.4, 137.4, 134.5, 133.6, 132.7, 131.4, 130.5, 129.7, 126.5, 122.3, 121.4, 120.8, 116.9, 114.7, 112.7, 54.9, 49.5, 33.1, 28.6.

MS (ESI): m/z = 374.3 (100) [M + H]+.

HRMS (TOF, ESI): m/z [M + H]+ calcd for C22H17N3OCl: 374.1060; found: 374.1051.


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3-Fluoro-12,12-dimethyl-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one (4d)

Pale yellow solid; yield: 293 mg (82%); mp 210–211 °C.

IR (KBr): 2957, 2871, 1672, 1661, 1619, 1597, 1520, 1467, 1374, 1341, 1274, 1239, 1194, 1182, 1098, 1039, 979, 888, 862, 816, 794, 778 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.69 (dd, J = 9.2 Hz, J′ = 6.0 Hz, 1 H, HAr), 8.56 (s, 1 H, HAr), 8.29 (dd, J = 9.2 Hz, J′ = 2.4 Hz, 1 H, HAr), 8.22 (d, J = 9.2 Hz, 1 H, HAr), 7.87 (d, J = 8.8 Hz, 1 H, HAr), 7.22–7.17 (m, 1 H, HAr), 3.41 (s, 2 H, CH2), 2.92 (s, 2 H, CH2), 1.26 (s, 6 H, 2 CH3).

13C NMR (100 MHz, CDCl3): δ = 200.5, 164.8 (d, J F-C = 254.0 Hz), 163.3, 149.5, 137.9 (d, J F-C = 11.8 Hz), 137.7, 134.4, 133.7 (d, J F-C = 9.9 Hz), 131.9, 126.3, 122.4, 121.0, 116.1 (d, J F-C = 3.0 Hz), 114.8, 112.37 (d, J F-C = 22.4 Hz), 112.39, 102.3 (d, J F-C = 26.4 Hz), 55.0, 49.5, 33.1, 28.6.

MS (ESI): m/z = 358.3 (100) [M + H]+.

HRMS (TOF, ESI): m/z [M + H]+ calcd for C22H17N3OF: 358.1356; found: 358.1357.


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2-Fluoro-12,12-dimethyl-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one (4e)

Pale yellow solid; yield: 310 mg (87%); mp 234–235 °C.

IR (KBr): 2961, 2869, 1679, 1661, 1596, 1537, 1513, 1468, 1449, 1374, 1336, 1302, 1240, 1219, 1192, 1095, 1037, 959, 874, 796, 717 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.63 (dd, J = 9.2 Hz, J′ = 5.6 Hz, 1 H, HAr), 8.55 (s, 1 H, HAr), 8.37 (dd, J = 11.2 Hz, J′ = 2.8 Hz, 1 H, HAr), 8.25 (d, J = 9.2 Hz, 1 H, HAr), 7.88 (d, J = 8.8 Hz, 1 H, HAr), 7.62–7.57 (m, 1 H, HAr), 3.42 (s, 2 H, CH2), 2.95 (s, 2 H, CH2), 1.26 (s, 6 H, 2 CH3).

13C NMR (100 MHz, CDCl3): δ = 200.3, 163.1, 158.4 (d, J F-C = 242.4 Hz), 149.4 (d, J F-C = 1.2 Hz), 136.9, 133.9, 132.6, 131.1, 126.4, 122.1, 121.4, 120.9 (d, J F-C = 9.0 Hz), 120.6 (d, J F-C = 24.2 Hz), 117.2 (d, J F-C = 8.4 Hz), 116.7 (d, J F-C = 25.5 Hz), 114.5, 112.5, 54.9, 49.4, 33.1, 28.6.

MS (ESI): m/z = 358.3 (100) [M + H]+.

HRMS (TOF, ESI): m/z [M + H]+ calcd for C22H17N3OF: 358.1356; found: 358.1348.


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2-Methoxy-12,12-dimethyl-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one (4f)

Pale yellow solid; yield: 292 mg (79%); mp 237–238 °C.

1H NMR (400 MHz, CDCl3): δ = 8.54 (d, J = 8.8 Hz, 1 H, HAr), 8.51 (s, 1 H, HAr), 8.22 (d, J = 8.8 Hz, 1 H, HAr), 8.06 (d, J = 2.8 Hz, 1 H, HAr), 7.28 (d, J = 8.8 Hz, 1 H, HAr), 7.46 (dd, J = 9.2 Hz, J′ = 2.8 Hz, 1 H, HAr), 3.95 (s, 3 H, CH3O), 3.42 (s, 2 H, CH2), 2.95 (s, 2 H, CH2), 1.27 (s, 6 H, 2 CH3).

13C NMR (100 MHz, CDCl3): δ = 200.7, 162.9, 155.7, 149.5, 136.5, 134.2, 130.70, 130.65, 126.4, 121.8, 121.32, 121.31, 120.6, 116.7, 114.4, 113.4, 112.7, 55.8, 55.1, 49.5, 33.1, 28.7.

MS (ESI): m/z = 370.3 (100) [M + H]+.

HRMS (TOF, ESI): m/z [M + H]+ calcd for C23H20N3O: 370.1556; found: 370.1553.


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2,3-Dimethoxy-12,12-dimethyl-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one (4g)

Pale yellow solid; yield: 319 mg (80%); mp 223–224 °C.

IR (KBr): 2952, 2862, 1683, 1657, 1595, 1565, 1530, 1469, 1448, 1374, 1337, 1291, 1235, 1194, 1146, 1097, 1049, 967, 862, 836, 809, 691 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.57 (s, 1 H, HAr), 8.25 (d, J = 8.8 Hz, 1 H, HAr), 8.11 (d, J = 2.4 Hz, 2 H, HAr), 7.88 (d, J = 8.8 Hz, 1 H, HAr), 4.19 (s, 3 H, CH3O), 4.03 (s, 3 H, CH3O), 3.42 (s, 2 H, CH2), 2.93 (s, 2 H, CH2), 1.25 (s, 6 H, 2 CH3).

13C NMR (100 MHz, CDCl3): δ = 200.7, 163.3, 153.7, 149.6, 145.8, 136.7, 134.2, 132.3, 130.9, 126.2, 122.1, 120.2, 114.4, 112.7, 112.14, 112.10, 97.1, 56.6, 65.4, 55.2, 49.7, 33.1, 28.6.

MS (ESI): m/z = 400.3 (100) [M + H]+.

HRMS (TOF, ESI): m/z [M + H]+ calcd for C24H22N3O3: 400.1661; found: 400.1671.


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12,12-Dimethyl-2-nitro-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one (4h)

Pale yellow solid; yield: 330 mg (86%); mp 237–238 °C.

IR (KBr): 2955, 2868, 1676, 1662, 1620, 1595, 1533, 1490, 1464, 1374, 1338, 1237, 1143, 1120, 1079, 964, 875, 839, 784, 754 cm–1.

1H NMR (400 MHz, CDCl3): δ = 9.73 (d, J = 2.0 Hz, 1 H, HAr), 8.75 (d, J = 9.2 Hz, 1 H, HAr), 8.68–8.66 (m, 2 H, HAr), 8.30 (d, J = 8.8 Hz, 1 H, HAr), 7.97 (d, J = 8.8 Hz, 1 H, HAr), 3.48 (s, 2 H, CH2), 3.03 (s, 2 H, CH2), 1.29 (s, 6 H, 2 CH3).

13C NMR (100 MHz, CDCl3): δ = 200.1, 163.9, 149.5, 143.3, 139.4, 139.2, 134.0, 132.5, 127.7, 126.8, 126.6, 123.1, 121.7, 119.8, 116.5, 115.4, 112.9, 54.9, 49.5, 33.2, 28.6.

MS (ESI): m/z = 385.4 (100) [M + H]+.

HRMS (TOF, ESI): m/z [M + H]+ calcd for C22H17N4O3: 385.1301; found: 385.1290.


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3-Chloro-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one (4i)

Pale yellow solid; yield: 311 mg (90%); mp 263–264 °C.

IR (KBr): 2947, 2875, 1673, 1659, 1605, 1551, 1526, 1510, 1466, 1454, 1372, 1341, 1293, 1267, 1234, 1188, 1171, 1096, 997, 879, 864, 816, 717 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.69 (d, J = 2.0 Hz, 1 H, HAr), 8.61 (d, J = 9.2 Hz, 1 H, HAr), 8.60 (s, 1 H, HAr), 8.27 (d, J = 8.8 Hz, 1 H, HAr), 7.91 (d, J = 8.8 Hz, 1 H, HAr), 7.46 (dd, J = 9.2 Hz, J′ = 2.0 Hz, 1 H, HAr), 3.45 (t, J = 6.0 Hz, 2 H, CH2), 3.05 (t, J = 6.8 Hz, 2 H, CH2), 2.42–2.35 (m, 2 H, CH2).

13C NMR (100 MHz, CDCl3): δ = 200.2, 164.8, 149.1, 138.9, 137.6, 136.6, 134.4, 132.1, 131.7, 126.5, 124.6, 122.3, 121.9, 117.9, 115.6, 114.7, 112.6, 40.6, 35.4, 21.2.

MS (ESI): m/z = 346.4 (100) [M + H]+.

HRMS (TOF, ESI): m/z [M + H]+ calcd for C20H13N3OCl: 346.0747; found: 346.0754.


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2-Chloro-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one (4j)

Pale yellow solid; yield: 286 mg (83%); mp 273–274 °C.

IR (KBr): 2948, 2850, 1674, 1659, 1594, 1531, 1510, 1459, 1396, 1372, 1337, 1298, 1237, 1177, 1109, 1028, 995, 944, 888, 831, 799 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.57 (d, J = 2.0 Hz, 1 H, HAr), 8.52 (s, 1 H, HAr), 8.48 (d, J = 8.8 Hz, 1 H, HAr), 8.22 (d, J = 8.8 Hz, 1 H, HAr), 7.84 (d, J = 9.2 Hz, 1 H, HAr), 7.74 (dd, J = 8.8 Hz, J′ = 2.4 Hz, 1 H, HAr), 3.43 (t, J = 6.0 Hz, 2 H, CH2), 3.07 (t, J = 6.8 Hz, 2 H, CH2), 2.42–2.35 (m, 2 H, CH2).

13C NMR (100 MHz, CDCl3): δ = 200.0, 164.8, 149.1, 137.4, 134.4, 133.9, 132.7, 131.4, 130.3, 129.8, 126.6, 122.2, 122.1, 120.7, 116.9, 114.6, 112.8, 40.5, 35.4, 21.2.

MS (ESI): m/z = 346.4 (100) [M + H]+.

HRMS (TOF, ESI): m/z [M + H]+ calcd for C20H13N3OCl: 346.0747; found: 346.0746.


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2-Methoxy-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one (4k)

Pale yellow solid; yield: 280 mg (82%); mp 187–188 °C.

IR (KBr): 2941, 2856, 1672, 1658, 1598, 1563, 1535, 1470, 1449, 1373, 1337, 1297, 1235, 1176, 1119, 1086, 1043, 900, 873, 827, 673 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.60 (d, J = 9.2 Hz, 1 H, HAr), 8.55 (s, 1 H, HAr), 8.26 (d, J = 8.8 Hz, 1 H, HAr), 8.05 (d, J = 2.4 Hz, 1 H, HAr), 7.87 (d, J = 9.2 Hz, 1 H, HAr), 7.49 (dd, J = 9.2 Hz, J′ = 2.8 Hz, 1 H, HAr), 3.96 (s, 3 H, CH3O), 3.44 (t, J = 6.0 Hz, 2 H, CH2), 3.06 (t, J = 6.8 Hz, 2 H, CH2), 2.42–2.35 (m, 2 H, CH2).

13C NMR (100 MHz, CDCl3): δ = 200.3, 164.5, 155.8, 149.2, 136.5, 134.6, 130.7, 130.6, 126.6, 122.0, 121.8, 121.4, 120.5, 116.8, 114.3, 113.2, 112.8, 55.8, 40.7, 35.4, 21.2.

MS (ESI): m/z = 342.4 (100) [M + H]+.

HRMS (TOF, ESI): m/z [M + H]+ calcd for C21H16N3O2: 342.1243; found: 342.1248.


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2,3-Dimethoxy-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one (4l)

Pale yellow solid; yield: 282 mg (76%); mp 273–274 °C.

IR (KBr): 2955, 2838, 1687, 1606, 1581, 1545, 1505, 1461, 1439, 1397, 1362, 1327, 1267, 1245, 1181, 1152, 1036, 975, 939, 867, 832, 802 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.09 (s 1 H, HAr), 8.07 (d, J = 9.2 Hz, 1 H, HAr), 7.81 (d, J = 8.8 Hz, 1 H, HAr), 7.30 (s, 1 H, HAr), 6.74 (s, 1 H, HAr), 4.03 (s, 3 H, CH3O), 3.79 (s, 3 H, CH3O), 3.46–3.42 (m, 2 H, CH2), 2.79–2.68 (m, 2 H, CH2), 2.33–2.27 (m, 2 H, CH2).

13C NMR (100 MHz, CDCl3): δ = 197.2, 162.4, 150.1, 149.94, 149.91, 146.3, 136.5, 135.3, 131.4, 126.2, 123.8, 123.4, 120.5, 116.1, 114.8, 111.0, 110.8, 56.3, 56.2, 40.2, 34.2, 21.4.

MS (ESI): m/z = 372.3 (100) [M + H]+.

HRMS (TOF, ESI): m/z [M – H]– calcd for C22H16N3O3: 370.1186; found: 370.1187.


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3-Fluoro-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one (4m)

Pale yellow solid; yield: 283 mg (86%); mp 203–204 °C.

IR (KBr): 2945, 2846, 1656, 1620, 1597, 1530, 1520, 1469, 1374, 1343, 1303, 1275, 1239, 1183, 1119, 1103, 1002, 899, 871, 827, 692 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.68 (dd, J = 8.8 Hz, J′ = 6.0 Hz, 1 H, HAr), 8.57 (s, 1 H, HAr), 8.30 (dd, J = 8.8 Hz, J′ = 2.8 Hz, 1 H, HAr), 8.23 (d, J = 9.2 Hz, 1 H, HAr), 7.87 (d, J = 8.8 Hz, 1 H, HAr), 7.23–7.18 (m, 1 H, HAr), 3.45–3.42 (m, 2 H, CH2), 3.06–3.02 (m, 2 H, CH2), 2.41–2.35 (m, 2 H, CH2).

13C NMR (100 MHz, CDCl3): δ = 200.3, 164.8 (d, J F-C = 254.0 Hz), 164.9, 149.2, 137.8 (d, J F-C = 11.7 Hz), 137.7, 134.7, 133.5 (d, J F-C = 9.8 Hz), 131.9, 126.5, 122.4, 121.7, 116.0 (d, J F-C = 2.8 Hz), 114.7, 112.51 (d, J F-C = 22.4 Hz), 112.47, 102.4 (d, J F-C = 26.4 Hz), 40.6, 35.4, 21.2.

MS (ESI): m/z = 330.4 (100) [M + H]+.

HRMS (TOF, ESI): m/z [M + H]+ calcd for C20H13N3OF: 330.1043; found: 330.1029.


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2-Chloro-12-methyl-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one (4n)

Pale yellow solid; yield: 302 mg (84%); mp 238–239 °C.

IR (KBr): 2954, 2869, 1676, 1656, 1596, 1531, 1496, 1459, 1398, 1373, 1337, 1267, 1235, 1198, 1152, 1107, 1031, 910, 883, 832, 797, 780 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.63 (d, J = 2.0 Hz, 1 H, HAr), 8.56–8.54 (m, 2 H, HAr), 8.24 (d, J = 9.2 Hz, 1 H, HAr), 7.87 (d, J = 8.8 Hz, 1 H, HAr), 7.78 (dd, J = 8.8 Hz, J′ = 2.0 Hz, 1 H, HAr), 3.56–3.51 (m, 1 H, CH), 3.23–3.11 (m, 2 H, CH2), 2.73–2.64 (m, 2 H, CH2), 1.32 (d, J = 6.4 Hz, 3 H, CH3).

13C NMR (100 MHz, CDCl3): δ = 200.2, 164.0, 149.2, 137.3, 134.4, 133.7, 132.6, 131.4, 130.3, 129.7, 126.5, 122.2, 121.8, 120.7, 116.9, 114.6, 112.7, 48.8, 43.7, 28.9, 21.2.

MS (ESI): m/z = 360.3 (100) [M + H]+.

HRMS (TOF, ESI): m/z [M + H]+ calcd for C21H15N3OCl: 360.0904; found: 360.0918.


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3-Fluoro-12-methyl-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one (4o)

Pale yellow solid; yield: 268 mg (78%); mp >300 °C.

IR (KBr): 2951, 2869, 1677, 1660, 1619, 1596, 1528, 1520, 1469, 1453, 1374, 1340, 1274, 1239, 1196, 1160, 1107, 1036, 903, 884, 863, 826 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.71 (dd, J = 9.2 Hz, J′ = 6.0 Hz, 1 H, HAr), 8.59 (s, 1 H, HAr), 8.33 (dd, J = 8.8 Hz, J′ = 2.8 Hz, 1 H, HAr), 8.25 (d, J = 9.2 Hz, 1 H, HAr), 7.89 (d, J = 8.8 Hz, 1 H, HAr), 7.23–7.18 (m, 1 H, HAr), 3.56–3.51 (m, 1 H, CH), 3.21–3.12 (m, 2 H, CH2), 2.72–2.63 (m, 2 H, CH2), 1.32 (d, J = 6.0 Hz, 3 H, CH3).

13C NMR (100 MHz, CDCl3): δ = 200.5, 164.8 (d, J F-C = 254.2 Hz), 164.1, 149.3, 137.9 (d, J F-C = 11.7 Hz), 137.7, 134.6, 133.6 (d, J F-C = 9.9 Hz), 131.9, 126.5, 122.4, 121.4, 116.0 (d, J F-C = 2.9 Hz), 114.8, 112.50 (d, J F-C = 22.3 Hz), 112.47, 102.3 (d, J F-C = 26.4 Hz), 48.9, 43.7, 28.9, 21.2.

MS (ESI): m/z = 344.4 (100) [M + H]+.

HRMS (TOF, ESI): m/z [M + H]+ calcd for C21H15N3OF: 344.1199; found: 340.1188.


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2-Fluoro-12-methyl-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one (4p)

Pale yellow solid; yield: 288 mg (84%); mp 262–263 °C.

IR (KBr): 2956, 2867, 1669, 1657, 1622, 1602, 1520, 1496, 1453, 1377, 1340, 1286, 1236, 1206, 1154, 1107, 1041, 1024, 1000, 855, 834, 792 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.63 (dd, J = 9.2 Hz, J′ = 5.2 Hz, 1 H, HAr), 8.55 (s 1 H, HAr), 8.35 (dd, J = 11.2 Hz, J′ = 2.4 Hz, 1 H, HAr), 8.25 (d, J = 8.8 Hz, 1 H, HAr), 7.87 (d, J = 8.8 Hz, 1 H, HAr), 7.62–7.57 (m, 1 H, HAr), 3.56–3.52 (m, 1 H, CH), 3.21–3.11 (m, 2 H, CH2), 2.73–2.63 (m, 2 H, CH2), 1.32 (d, J = 6.0 Hz, 3 H, CH3).

13C NMR (100 MHz, CDCl3): δ = 200.3, 163.9, 158.5 (d, J F-C = 242.6 Hz), 149.3, 137.1, 134.2, 132.7 (d, J F-C = 1.6 Hz), 131.2, 126.7, 122.2, 121.8, 121.0 (d, J F-C = 9.0 Hz), 120.8 (d, J F-C = 24.3 Hz), 117.3 (d, J F-C = 8.5 Hz), 116.6 (d, J F-C = 25.5 Hz), 114.6, 112.7, 48.8, 43.7, 28.9, 21.2.

MS (ESI): m/z = 344.4 (100) [M + H]+.

HRMS (TOF, ESI): m/z [M + H]+ calcd for C21H15N3OF: 344.1199; found: 340.1192.


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2-Methoxy-12-methyl-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one (4q)

Pale yellow solid; yield: 280 mg (79%); mp 206–207 °C.

IR (KBr): 2938, 2828, 1672, 1656, 1596, 1564, 1531, 1469, 1448, 1374, 1337, 1291, 1237, 1195, 1122, 1100, 1049, 927, 872, 855, 834, 799 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.59 (d, J = 9.2 Hz, 1 H, HAr), 8.54 (s, 1 H, HAr), 8.24 (d, J = 9.2 Hz, 1 H, HAr), 8.07 (d, J = 2.4 Hz, 1 H, HAr), 7.86 (d, J = 8.8 Hz, 1 H, HAr), 7.48 (dd, J = 9.2 Hz, J′ = 2.4 Hz, 1 H, HAr), 3.95 (s, 3 H, CH3O), 3.55–3.50 (m, 1 H, CH), 3.20–3.11 (m, 2 H, CH2), 2.73–2.61 (m, 2 H, CH2), 1.31 (d, J = 6.0 Hz, 3 H, CH3).

13C NMR (100 MHz, CDCl3): δ = 200.5, 163.7, 155.7, 149.3, 136.4, 134.4, 130.7, 130.6, 126.5, 121.8, 121.7, 121.3, 120.5, 116.7, 114.3, 113.2, 112.7, 55.8, 49.0, 43.7, 28.9, 21.2.

MS (ESI): m/z = 356.4 (100) [M + H]+.

HRMS (TOF, ESI): m/z [M + H]+ calcd for C22H18N3O2: 356.1399; found: 356.1393.


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2,3-Dimethoxy-12-methyl-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one (4r)

Pale yellow solid; yield: 277 mg (72%); mp 237–238 °C.

IR (KBr): 2948, 2849, 1669, 1660, 1623, 1598, 1518, 1494, 1435, 1371, 1341, 1286, 1240, 1213, 1119, 1084, 1026, 872, 854, 826, 789 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.58 (s, 1 H, HAr), 8.25 (d, J = 8.8 Hz, 1 H, HAr), 8.10 (s 1 H, HAr), 8.06 (s, 1 H, HAr), 7.88 (d, J = 8.8 Hz, 1 H, HAr), 4.19 (s, 3 H, CH3O), 4.04 (s, 3 H, CH3O), 3.56–3.51 (m, 1 H, CH), 3.20–3.11 (m, 2 H, CH2), 2.71–2.63 (m, 2 H, CH2), 1.31 (d, J = 6.0 Hz, 3 H, CH3).

13C NMR (100 MHz, CDCl3): δ = 200.4, 164.1, 153.8, 149.4, 145.9, 136.8, 134.5, 132.3, 130.9, 126.4, 122.1, 120.5, 114.4, 112.7, 112.3, 111.8, 97.2, 56.6, 56.4, 49.0, 43.9, 28.9, 21.2.

MS (ESI): m/z = 386.4 (100) [M + H]+.

HRMS (TOF, ESI): m/z [M + H]+ calcd for C23H20N3O3: 386.1505; found: 386.1508.


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3-Chloro-7,12,12-trimethyl-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one (4s)

Pale yellow solid; yield: 318 mg (82%); mp 230–231 °C.

IR (KBr): 3091, 2954, 2867, 1676, 1652, 1603, 1524, 1469, 1439, 1350, 1329, 1271, 1173, 1095, 973, 952, 866, 817, 770 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.57 (d, J = 6.4 Hz, 1 H, HAr), 8.56 (s, 1 H, HAr), 8.16 (d, J = 8.8 Hz, 1 H, HAr), 7.83 (d, J = 8.8 Hz, 1 H, HAr), 7.39 (dd, J = 9.2 Hz, J′ = 2.0 Hz, 1 H, HAr), 3.41 (s, 2 H, CH2), 2.93 (s, 2 H, CH2), 2.90 (s, 3 H, CH3), 1.29 (s, 6 H, 2 CH3).

13C NMR (100 MHz, CDCl3): δ = 200.4, 163.2, 149.4, 148.2, 138.8, 136.5, 134.3, 132.5, 132.3, 125.9, 123.9, 121.4, 120.7, 117.4, 115.2, 114.3, 112.5, 54.9, 49.4, 33.1, 28.5.

MS (ESI): m/z = 388.3 (100) [M + H]+.

HRMS (TOF, ESI): m/z [M + Na]+ calcd for C23H18ClN3ONa: 410.1036; found: 410.1036.


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3,3,8-Trimethyl-3,4-dihydro[1,3]dioxolo[4,5-b]pyrazolo[1,5,4-fg]quinolino[2,3,4-kl]acridin-1(2H)-one (4t)

Pale yellow solid; yield: 333 mg (84%); mp >300 °C.

IR (KBr): 2953, 2924, 1677, 1666, 1608, 1592, 1529, 1500, 1489, 1351, 1331, 1257, 1219, 1036, 973, 940, 866, 851, 835, 737 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.17 (d, J = 8.8 Hz, 1 H, HAr), 7.97 (s, 1 H, HAr), 7.91 (s, 1 H, HAr), 7.81 (d, J = 8.8 Hz, 1 H, HAr), 6.21 (s, 2 H, CH2), 3.39 (s, 2 H, CH2), 2.91 (s, 5 H, CH2, CH3), 1.27 (s, 6 H, 2 CH3).

13C NMR (100 MHz, CDCl3): δ = 200.2, 163.1, 152.1, 149.6, 147.4, 144.6, 134.8, 133.6, 131.8, 125.8, 121.0, 119.9, 113.8, 113.5, 112.2, 108.6, 102.5, 95.3, 54.9, 49.5, 33.1, 28.6.

MS (ESI): m/z = 398.3 (100) [M + H]+.

HRMS (TOF, ESI): m/z [M + H]+ calcd for C24H20N3O3: 398.1505; found: 398.1487.


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Acknowledgment

We are grateful to the National Natural Science Foundation of China (20802061), the Major Natural Science Foundation of Jiangsu Province (14KJA150004), a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions and College Industrialization Project (JHB2012-31) of Jiangsu Province for financial support.

Supporting Information

    Supporting information for this article is available online at http://dx.doi.org.accesdistant.sorbonne-universite.fr/10.1055/s-0034-1379584. Included are copies of the 1H NMR and 13C NMR spectra for compounds 4a–t.
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Zoom Image
Figure 1 Pyrazoloquinolinoacridinone, amsacrine, and chloroquine
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Equation 1 The model reaction
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Equation 2 Synthetic route to 4