- Email: [email protected]
l -proline
Accepted Manuscript Domino Synthesis of Fused Hexacyclic Imidazoquinolinoacridinones Catalyzed by CuI/L-Proline Chao Li, Wen-Ting Zhang, Xiang-Shan Wang PII:
S0040-4020(14)01401-X
DOI:
10.1016/j.tet.2014.09.084
Reference:
TET 26058
To appear in:
Tetrahedron
Received Date: 7 July 2014 Revised Date:
17 September 2014
Accepted Date: 26 September 2014
Please cite this article as: Li C, Zhang W-T, Wang X-S, Domino Synthesis of Fused Hexacyclic Imidazoquinolinoacridinones Catalyzed by CuI/L-Proline, Tetrahedron (2014), doi: 10.1016/ j.tet.2014.09.084. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Domino Synthesis of Fused Hexacyclic Imidazoquinolinoacridinones Catalyzed by CuI/L-Proline
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Chao Li, Wen-Ting Zhang, Xiang-Shan Wang* R
O
CHO X
H2N
O
N
+
+ N H
CuI, L-proline Cs2CO3
N
1
R
R2
N
SC
R
O
R1 R2
N
One-Pot, Fused Hexacycle 2 New Heterocycles
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6 New Bonds
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Domino Synthesis of Fused Hexacyclic Imidazoquinolinoacridinones Catalyzed by CuI/L-Proline
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Chao Li, Wen-Ting Zhang, 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. China
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E-mail: [email protected]
Abstract—A three-component reaction of 2-halogenated aromatic aldehydes, 1H-benzo[d]
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imidazol-5-amine and cyclohexane-1,3-diones is described, and gives imidazoquinolinoacridinone derivatives in good yields catalyzed by CuI/L-proline. This Domino reaction constructs a fused hexacyclic skeleton in one-pot containing two new rings, six new bonds and an Ullmann-type C-N bond coupling reaction.
Introduction
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Keywords: Domino reaction, imidazoquinolinoacridine, Ullmann reaction, CuI
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Acridine occurs in a large number of natural products and attracts much attention
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due to its wide biological activities. A well-known example is Amsacrine, it is an antineoplastic agent used in the treatment of acute lymphoblastic leukemia.1 Another
useful drug on the market is Ethacridine lactate,2 which has strong killing effects on
gram positive bacteria and a few gram-negative bacteria. Although a number of useful synthetic procedures to prepare these compounds have been developed in recent years,3 still several limitations remain, as well. For example, most of the procedures
involve several steps, low yields or costly metal catalysts. Thus, simple, efficient, and
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versatile preparation of acridine derivatives in one-pot reaction is still highly desirable,
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especially for novel fused acridine, it may possess new bio-activity for screening.
Figure 1. The marketed drugs containing acridine analogue
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The traditional Ullmann reaction named after Fritz Ullmann4 in 1901 is a coupling reaction between aryl halides catalyzed by copper under harsh reaction conditions. In modern organic synthesis, it has been developed to Pd-catalyzed coupling reactions gradually, such as the Heck reaction,5 the Hiyama coupling6 and
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the Sonogashira coupling.7 However, copper-catalyzed Ullmann-type reaction has been received much attention due to its lower price in catalysts, and it has been used
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to synthesize the products of structural diversity.8 As a continuation of our research devoted to the new methods for the preparation
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of fused polycyclic heterocycles via Ullmann-type reaction catalyzed by copper (I) and its compound,9 we describe here the synthesis of fused hexacyclic skeleton
containing acridine analogue by a three-component Domino reaction of 2-halogenated aromatic aldehydes, 1H-benzo[d]imidazol-5-amine and cyclohexane-1,3-diones
catalyzed by CuI/L-proline. Results and discussion Treatment of 2-bromobenzaldehyde 1a, 5,5-dimethylcyclohexane-1,3-dione 2a,
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and 1H-benzo[d]imidazol-5-amine 3 in refluxing dioxane in the presence of CuI and Cs2CO3, resulted in the corresponding 12,12-dimethyl-12,13-dihydroimidazo[4,5,1-de]
+ O
N
+
N H
2a
CuI Cs2CO3
3
N
N
N
4a
SC
H2 N
Br
1a
O
O
CHO
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quinolino[4,3,2-mn]acridin-14(11H)-one 4a in 68 % yield (Scheme 1).
Scheme 1. Reaction of 1a, 2a and 3
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Taking the reaction of 2-bromobenzaldehyde 1a, 2a, and 3 as a model, several parameters including catalysts, ligands, bases and solvents, were optimized first in our lab. The reaction was carried out in the absence of catalysts; it was found that no 4a was observed at refluxing dioxane, and simple condensation product of
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11-(2-bromophenyl)-8,8-dimethyl-6a,7,8,9,10a,11-hexahydro-1H-imidazo[4,5-a]acri din-10(6H)-one was obtained in 87 % yield, and the subsequent Ullmann-type
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reaction did not take place without CuI and base. Different ligands, for example, PPh3, CH3NHCH2CO2H and L-proline were used to promote the reaction, and the L-proline
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gave the best result. Various kinds of bases, such as Na2CO3, K2CO3, Cs2CO3, and NaHCO3 (Table 1, entries 5, 10-12) were used to promote this reaction. It was found
that Cs2CO3 was the best base to give 4a in the highest yields for its slightly stronger
alkaline. In addition, other solvents, such as THF, CH3CN and toluene (entries 13-15),
were also tested but dioxane proved to be superior. Table 1. Synthetic results of 4a under different reaction conditionsa
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Ligands(mol%)
Bases
Solvents
Yields (%)b
1
-
-
-
Dioxane
87c
2
CuI(5)
-
Cs2CO3
Dioxane
68
3
CuI(5)
PPh3(10)
Cs2CO3
Dioxane
72
4
CuI(5)
CH3NHCH2CO2H(10)
Cs2CO3
Dioxane
76
5
CuI(5)
L-proline(10)
Cs2CO3
Dioxane
86
6
CuI(10)
L-proline(20)
Cs2CO3
Dioxane
85
7
CuI(20)
L-proline(40)
Cs2CO3
Dioxane
86
8
CuBr(5)
L-proline(10)
Cs2CO3
Dioxane
82
9
CuCl(5)
L-proline(10)
Cs2CO3
Dioxane
78
10
CuI(5)
L-proline(10)
K2CO3
Dioxane
82
11
CuI(5)
L-proline(10)
Na2CO3
Dioxane
76
12
CuI(5)
L-proline(10)
NaHCO3d
Dioxane
70
13
CuI(5)
L-proline(10)
Cs2CO3
CH3CN
72
14
CuI(5)
L-proline(10)
Cs2CO3
THF
67
15
CuI(5)
Cs2CO3
Toluene
80
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Catalysts (mol%)
L-proline(10)
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a
Entry
Reagents and conditions: 1a (0.185 g, 1.0 mmol), 2a (0.140 g, 1.0 mmol), 3 (0.133 g, 1.0 mmol),
solvent (10 mL), 2 mmol base, refluxing. b Isolated yields. c The product is simple condensation one without Ullmann reaction. d 4 mmol.
Subsequently, various kinds of 2-halogenated aromatic aldehydes were used to react with 2a and 3 at the same optimized conditions first. It was found that this process
could
tolerate
both
electron-donating,
such
as
alkoxy,
and
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electron-withdrawing (halogen and nitro) substituents on the 2-halogenated aromatic aldehydes (Table 2). In all cases, they all carried out smoothly to give
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imidazoquinolinoacridinone derivatives in good yields (Table 2, entries 1~11). The halogen in the 2-position of benzaldehyde is usually bromine (Table 2, entries 1-7). It also
can
be
a
chlorine
atom
(Table
2,
entries
8-9),
for
example,
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2-chloro-5-nitrobenzaldehyde or 2-chloro-5-(trifluoromethyl)benzaldehyde was used as a reactant, they all reacted well to give desired products in 83 % and 79 % yields,
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respectively. It was found in surprised that the 2-halogenated aromatic aldehyde also could be 4-bromo-2-fulorobenzaldehyde, and the reaction gave 4j in 75 % yield. This data indicated that the fluoride could also be used as a leaving group in this CuI-catalyzed Ullmann-type reaction. In addition, it should be noted that when
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2-bromothiophene-3-carbaldehyde was charged with 2a and 3 at the same reaction condition, the expected product of 11,11-dimethyl-11,12-dihydroimidazo[4,5,1-ij] quinolino[4,3,2-de]thieno[2,3-b]quinolin-13(10H)-one was obtained in good yield
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(Table 2, entry 11). Cyclohexane-1,3-dione 2b and 5-methylcyclohexane-1,3-dione 2c also gave the good results (Table 2, entries 12~18). All the structures of the products
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were characterized by NMR, IR and HRMS; their data were in good agreement to the preconceived structures. The structure of 4h was confirmed by X-ray diffraction analysis, and its crystal structure is shown in Figure 2.
Scheme 2. Reaction of 1, 2 and 3
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Table 2. The reaction time and yields of the products 4a R
X (in 1)
R1
R2
Time (h)
Products
Yieldsb (%)
1
H
Br
Me
Me
15
4a
86
2
3-Cl
Br
Me
Me
12
4b
82
3
2-Cl
Br
Me
Me
12
4c
84
4
2,3-OCH2O
Br
Me
Me
18
4d
78
5
2,3-(MeO)2
Br
Me
Me
18
4e
76
6
3-F
7
2-F
8
2-NO2
9
2-CF3
10
Me
Me
12
4f
89
Br
Me
Me
12
4g
86
Cl
Me
Me
10
4h
83
Cl
Me
Me
10
4i
79
3-Br
F
Me
Me
16
4j
75
11
2-Thienylc
Br
Me
Me
16
4k
84
12
H
Br
H
H
16
4l
83
13
3-F
Br
H
H
14
4m
84
14
2-MeO
Br
H
H
18
4n
85
15
H
Br
H
Me
16
4o
75
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Br
AC C
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Entry
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3-Cl
Br
H
Me
12
4p
82
17
2-Cl
Br
H
Me
12
4q
83
18
2,3-OCH2O
Br
H
Me
18
4r
74
a
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16
Reaction condition: dioxane (10 mL), 1 (1.0 mmol), 2 (1.0 mmol) and 3 (1.0 mmol), CuI (10 mg),
L-proline (6 mg), Cs2CO3 (650 mg), reflux. b Isolated yields. c 2-Bromothiophene-3-carbaldehyde
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was used as 2-halogenated aromatic aldehyde.
Figure 2. The crystal structure of 4h
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According to the structure 4 and the references,8,9 subsequent condensation, aromatization and Ullmann-type C-N bond coupling reaction may take place. The key
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step is the Csp2-N coupling of imidazole and aryl halide. The possible reaction
mechanism is outlined in Scheme 3.
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O L-Proline + CuI + Base N O H Cu CHO
Br HN
O O
NH2 +
+
CuI
N
N
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H N
Br
O
N H
O
Cs2CO3 Aromatization
O NH Cu N Oxidative addition
Br O
O N
N O H Cu
-Br
N
O
N
O
-
N
O
Cu O
Cs2CO3
HN
N
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N H
SC
Br HN
O
N
Reductive elimination
N
N
N
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Scheme 3. The possible reaction mechanism
Conclusion
In summary, a three-component Domino reaction of 2-halogenated aromatic
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aldehydes, 1H-benzo[d]imidazol-5-amine and cyclohexane-1,3-diones catalyzed by
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CuI/L-proline was studied. This procedure provided an expedient route for the synthesis fused hexacyclic skeleton in one-pot containing two new heterocycles, six new bonds and an Ullmann-type C-N bond coupling reaction. Experimental
Melting points were determined in open capillaries and are uncorrected. IR spectra were recorded on a Tensor 27 spectrometer in KBr pellet. 1H NMR spectra was obtained from a solution in DMSO-d6 with Me4Si as internal standard using a
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Bruker-400 spectrometer. HRMS analyses were carried out using a Bruker-microTOF-Q-MS analyzer.
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General procedure for the syntheses of 4. A dry 50 mL flask was charged with 2-halogenated aromatic aldehyde 1 (1.0 mmol), 1H-benzo[d]imidazol-5-amine (0.133 g, 1.0 mmol), cyclohexane-1,3-diones
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(1.0 mmol), CuI (10 mg), L-proline (6 mg), Cs2CO3(650 mg) and dioxane (10 mL).
The reaction mixture was stirred at reflux for 10-18 h. After completion of the
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reaction, as indicated by TLC, the solid was filtered off by a fast and hot filtration, and the products of 4 were obtained as pale yellow powder or crystals, when the mixture was allowed to cool down to room temperature.
12,12-Dimethyl-12,13-dihydroimidazo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-
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one (4a): Yield 86 % (292 mg). Pale yellow solid, m.p.: 277~279 °C; 1H NMR (CDCl3, 400 MHz): δH 1.28 (s, 6H), 2.96 (s, 2H), 3.43 (s, 2H), 7.51~7.55 (m, 1H), 7.81~7.85 (m, 1H), 8.05 (d, J = 8.8 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 8.44 (d, J = 8.8
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Hz, 1H), 8.66 (dd, J = 8.4 Hz, J’ = 0.8 Hz, 1H), 9.04 (s, 1H). 13C NMR (CDCl3, 100 MHz): δC 28.7, 33.2, 49.4, 55.1, 113.0, 116.0, 120.8, 121.0, 122.0, 125.1, 126.4, 131.9,
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132.4, 133.6, 134.3, 136.9, 140.2, 142.8, 146.9, 161.7, 201.0. IR (KBr): ν 3081, 2956,
2869, 1683, 1595, 1530, 1510, 1469, 1379, 1348, 1302, 1243, 1209, 1169, 1098, 1092, 827, 810, 768, 741 cm-1. HRMS (TOF, ESI, m/z): Calcd for C22H18N3O [M + H]
340.1444, found 340.1440. 3-Chloro-12,12-dimethyl-12,13-dihydroimidazo[4,5,1-de]quinolino[4,3,2-mn]acridin14(11H)-one (4b): Yield 82 % (306 mg). Pale yellow solid, m.p.: > 300 °C; 1H NMR
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(CDCl3, 400 MHz): δH 1.27 (s, 6H), 2.95 (s, 2H), 3.44 (s, 2H), 7.46 (dd, J = 8.8 Hz, J’ = 2.0 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 8.12 (d, J = 2.0 Hz, 1H), 8.43 (d, J = 9.2 Hz,
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1H), 8.61 (d, J = 8.8 Hz, 1H), 8.97 (s, 1H). 13C NMR (CDCl3, 100 MHz): δC 28.6, 33.2, 49.4, 55.1, 112.8, 116.1, 119.3, 120.8, 122.3, 124.9, 125.5, 126.5, 133.0, 133.1,
133.6, 134.3, 134.6, 138.4, 146.9, 162.0, 200.9. IR (KBr): ν 3089, 2954, 2868, 1681,
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1625, 1590, 1549, 1530, 1505, 1468, 1403, 1373, 1332, 1288, 1228, 1173, 1092, 1038, 981, 876, 848, 822, 768 cm-1. HRMS (TOF, ESI, m/z): Calcd for C22H17ClN3O [M +
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H] 374.1060, found 374.1046.
2-Chloro-12,12-dimethyl-12,13-dihydroimidazo[4,5,1-de]quinolino[4,3,2-mn]acridin14(11H)-one (4c): Yield 84 % (313 mg). Pale yellow solid, m.p.: 189~191 °C; 1H NMR (CDCl3, 400 MHz): δH 1.16 (s, 3H), 1.21 (s, 3H), 2.61 (s, 2H), 3.33 (s, 2H),
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7.28 (d, J = 1.6 Hz, 1H), 7.51 (dd, J = 8.4 Hz, J’ = 1.6 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 8.40 (b, 2H). 13C NMR (CDCl3, 100 MHz): δC 27.6, 28.9, 32.4, 47.9, 53.7, 119.8, 121.9, 123.0, 123.9, 126.8, 127.5, 128.7, 130.4, 134.6, 134.9, 135.1,
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135.6, 142.3, 146.9, 148.3, 159.8, 197.8. IR (KBr): ν 3081, 2951, 2867, 1687, 1575, 1552, 1465, 1448, 1371, 1301, 1289, 1273, 1211, 1098, 1034, 912, 841, 829, 813 cm-1.
AC C
HRMS (TOF, ESI, m/z): Calcd for C22H17ClN3O [M + H] 374.1060, found 374.1076.
3,3-Dimethyl-3,4-dihydro-[1,3]dioxolo[4,5-b]imidazo[1,5,4-fg]quinolino[2,3,4-kl]acri
din-1(2H)-one (4d): Yield 78 % (299 mg). Pale yellow solid, m.p.: > 300 °C; 1H NMR (CDCl3, 400 MHz): δH 1.25 (s, 6H), 2.92 (s, 2H), 3.39 (s, 2H), 6.18 (s, 2H), 7.40 (s, 1H), 7.88 (s, 1H), 8.01 (d, J = 8.8 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H), 8.82 (s, 1H). 13C NMR (CDCl3, 100 MHz): δC 28.6, 33.1, 49.5, 55.1, 95.9, 102.8, 109.6, 112.3,
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115.0, 119.9, 121.8, 124.5, 126.1, 130.1, 132.6, 134.2, 134.3, 145.4, 146.7, 151.5, 161.8, 200.8. IR (KBr): ν 3088, 3056, 2954, 2907, 2869, 1688, 1605, 1592, 1532,
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1505, 1483, 1388, 1369, 1330, 1268, 1239, 1140, 1117, 1082, 1043, 940, 866, 850, 833 cm-1. HRMS (TOF, ESI, m/z): Calcd for C23H18N3O3 [M + H] 384.1348, found 384.1367.
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2,3-Dimethoxy-12,12-dimethyl-12,13-dihydroimidazo[4,5,1-de]quinolino[4,3,2-mn]a
cridin-14(11H)-one (4e): Yield 76 % (303 mg). Pale yellow solid, m.p.: 255~257 °C; H NMR (CDCl3, 400 MHz): δH 1.25 (s, 6H), 2.93 (s, 2H), 3.41 (s, 2H), 4.01 (s, 3H) ,
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1
4.14 (s, 3H), 7.43 (s, 1H), 8.00 (d, J = 8.8 Hz, 1H), 8.04 (s, 1H), 8.38 (d, J = 8.8 Hz, 1H), 8.91 (s, 1H). 13C NMR (CDCl3, 100 MHz): δC 28.6, 33.1, 49.6, 55.4, 56.4, 56.5, 97.2, 112.3, 113.0, 113.8, 119.7, 121.8, 124.6, 126.1, 129.1, 132.4, 134.0, 134.2, 146.2,
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146.8, 153.0, 161.9, 201.2. IR (KBr): ν 3035, 2950, 2897, 2869, 2825, 1678, 1665, 1618, 1595, 1535, 1492, 1458, 1381, 1364, 1327, 1274, 1254, 1238, 1209, 1105, 1038, 1009, 983, 847, 824, 795 cm-1. HRMS (TOF, ESI, m/z): Calcd for C24H22N3O3 [M + H]
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400.1661, found 400.1662.
3-Fluoro-12,12-dimethyl-12,13-dihydroimidazo[4,5,1-de]quinolino[4,3,2-mn]acridin-
AC C
14(11H)-one (4f): Yield 89 % (318 mg). Pale yellow solid, m.p.: > 300 °C; 1H NMR
(CDCl3, 400 MHz): δH 1.25 (s, 6H), 2.92 (s, 2H), 3.41 (s, 2H), 7.19~7.24 (m, 1H), 7.78 (dd, J = 8.8 Hz, J’ = 1.6 Hz, 1H), 8.03 (d, J = 8.8 Hz, 1H), 8.40 (d, J = 8.8 Hz,
1H), 8.69 (dd, J = 9.2 Hz, J’ = 1.6 Hz, 1H), 8.91 (s, 1H). 13C NMR (CDCl3, 100 MHz):
δC 28.6, 33.2, 49.4, 55.1, 103.0 (d, JF-C = 25.6 Hz), 112.7, 113.2 (d, JF-C = 21.6 Hz), 117.3 (d, JF-C = 3.0 Hz), 120.6, 122.3, 125.0, 126.5, 133.1, 133.8, 134.4 (d, JF-C = 9.7
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Hz), 134.6, 135.1 (d, JF-C = 10.5 Hz), 146.9, 162.0, 164.2 (d, JF-C = 254.6 Hz), 201.0. IR (KBr): ν 3081, 3047, 2954, 2870, 1675, 1621, 1592, 1569, 1529, 1514, 1472, 1380,
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1352, 1332, 1296, 1272, 1247, 1198, 1174, 1097, 1086, 980, 890, 868, 845, 817 cm-1. HRMS (TOF, ESI, m/z): Calcd for C22H17FN3O [M + H] 358.1356, found 358.1350.
2-Fluoro-12,12-dimethyl-12,13-dihydroimidazo[4,5,1-de]quinolino[4,3,2-mn]acridin-
SC
14(11H)-one (4g): Yield 86 % (307 mg). Pale yellow solid, m.p.: 254~256 °C; 1H NMR (CDCl3, 400 MHz): δH 1.26 (s, 6H), 2.94 (s, 2H), 3.41 (s, 2H), 7.52~7.56 (m,
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1H), 8.03 (d, J = 8.8 Hz, 1H), 8.11 (dd, J = 8.8 Hz, J’ = 4.8 Hz, 1H), 8.36~8.43 (m, 2H), 8.96 (s, 1H). 13C NMR (CDCl3, 100 MHz): δC 28.6, 33.2, 49.4, 55.1, 112.8, 117.4 (d, JF-C = 8.6 Hz), 118.0 (d, JF-C = 25.4 Hz), 120.2(d, JF-C = 24.3 Hz), 121.1, 122.1, 122.6 (d, JF-C = 8.9 Hz), 124.7, 126.6, 130.1, 133.0, 133.4 (d, JF-C = 2.4 Hz),
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134.5, 146.9, 158.8 (d, JF-C = 244.1 Hz), 161.8, 200.9. IR (KBr): ν 3063, 3045, 2956, 2870, 1681, 1666, 1591, 1545, 1508, 1474, 1413, 1379, 1331, 1298, 1230, 1208, 1160, 1091, 970, 872, 827 cm-1. HRMS (TOF, ESI, m/z): Calcd for C22H17FN3O [M + H]
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358.1356, found 358.1342.
12,12-Dimethyl-2-nitro-12,13-dihydroimidazo[4,5,1-de]quinolino[4,3,2-mn]acridin-1
AC C
4(11H)-one (4h): Yield 83 % (319 mg). Pale yellow solid, m.p.: 282~284 °C; 1H
NMR (CDCl3, 400 MHz): δH 1.26 (s, 6H), 3.00 (s, 2H), 3.45 (s, 2H), 8.07 (d, J = 8.8 Hz, 1H), 8.23 (d, J = 9.2 Hz, 1H), 8.43 (d, J = 8.8 Hz, 1H), 8.63 (dd, J = 9.2 Hz, J’ =
2.4 Hz, 1H), 9.03 (s, 1H), 9.68 (d, J = 2.4 Hz, 1H). 13C NMR (CDCl3, 100 MHz): δC 28.6, 33.3, 49.4, 55.0, 112.9, 116.7, 121.2, 121.5, 122.9, 124.8, 126.7, 126.8, 128.1, 133.1, 133.4, 134.8, 137.2, 143.9, 147.0, 162.5, 200.6. IR (KBr): ν 3098, 2963, 2948,
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2862, 1681, 1670, 1617, 1589, 1574, 1528, 1480, 1468, 1339, 1298, 1284, 1255, 1222, 1161, 1120, 1092, 1084, 1036, 987, 967, 889, 869, 837, 790 cm-1. HRMS (TOF, ESI,
RI PT
m/z): Calcd for C22H17N4O3 [M + H] 385.1301, found 385.1301. 12,12-Dimethyl-2-(trifluoromethyl)-12,13-dihydroimidazo[4,5,1-de]quinolino[4,3,2-
mn]acridin-14(11H)-one (4i): Yield 79 % (322 mg). Pale yellow solid, m.p.:
SC
279~280 °C; 1H NMR (CDCl3, 400 MHz): δH 1.47 (s, 6H), 3.49 (s, 2H), 3.71 (s, 2H),
8.10 (d, J = 8.8 Hz, 1H), 8.13 (dd, J = 8.4 Hz, J’ = 1.6 Hz, 1H), 8.27 (d, J = 8.4 Hz,
M AN U
1H), 8.48 (d, J = 9.2 Hz, 1H), 9.05 (s, 1H), 11.15 (s, 1H). 13C NMR (CDCl3, 100 MHz): δC 25.9, 45.4, 46.4, 67.1, 112.7, 116.0, 119.5, 122.6, 122.7, 125.1, 125.6, 127.5, 128.4 (q, JF-C = 33.3 Hz), 129.6, 132.1, 133.2, 134.6, 135.0, 135.2, 149.4, 171.5, 210.1. IR (KBr): ν 3090, 2971, 2931, 2868, 1699, 1666, 1626, 1592, 1545, 1527,
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1473, 1432, 1413, 1350, 1335, 1257, 1226, 1168, 1150, 1124, 1091, 1078, 969, 956, 917, 873, 831 cm-1. HRMS (TOF, ESI, m/z): Calcd for C23H17F3N3O [M + H] 408.1324, found 408.1331.
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3-Bromo-12,12-dimethyl-12,13-dihydroimidazo[4,5,1-de]quinolino[4,3,2-mn]acridin14(11H)-one (4j): Yield 75 % (313 mg). Pale yellow solid, m.p.: > 300 °C; 1H NMR
AC C
(CDCl3, 400 MHz): δH 1.25 (s, 6H), 2.93 (s, 2H), 3.42 (s, 2H), 7.61 (dd, J = 9.2 Hz, J’
= 2.0 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 8.43 (d, J = 8.8 Hz, 1H), 8.54 (d, J = 8.8 Hz, 1H), 8.98 (s, 1H). 13C NMR (CDCl3, 100 MHz): δC 28.6, 33.2, 49.4, 55.1, 112.9, 119.1, 119.8, 120.8, 122.3, 126.6, 126.7, 128.4, 133.2, 133.8, 134.4, 134.7, 138.6, 144.9, 147.0, 162.0, 200.9. IR (KBr): ν 3077, 2954, 2936, 2868, 1680, 1669, 1600, 1590, 1549, 1529, 1506, 1467, 1372, 1331, 1302, 1287, 1250, 1227,
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1174, 1088, 1082, 979, 875, 848, 821, 750 cm-1. HRMS (TOF, ESI, m/z): Calcd for C22H17BrN3O [M + H] 418.0555, found 418.0554.
RI PT
11,11-Dimethyl-11,12-dihydroimidazo[4,5,1-ij]quinolino[4,3,2-de]thieno[3,2-b]quino lin-13(10H)-one (4k): Yield 84 % (290 mg). Pale yellow solid, m.p.: 284~286 °C; 1H
NMR (CDCl3, 400 MHz): δH 1.75 (s, 6H), 2.83 (s, 2H), 3.41 (s, 2H), 7.81 (d, J = 8.4
SC
Hz, 1H), 8.00 (d, J = 6.0 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 8.44 (d, J = 8.8 Hz, 1H), 8.87 (s, 1H). 13C NMR (CDCl3, 100 MHz): δC 28.2, 32.3, 49.7, 54.1, 111.5, 114.8,
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115.2, 122.57, 122.62, 125.0, 126.4, 132.8, 134.2, 135.1, 135.5, 136.7, 147.6, 162.4, 199.9. IR (KBr): ν 3080, 2951, 2867, 1672, 1656, 1590, 1531, 1509, 1456, 1397, 1370, 1337, 1315, 1235, 1174, 1109, 959, 867, 823, 741 cm-1. HRMS (TOF, ESI, m/z): Calcd for C20H16N3OS [M + H] 346.1014, found 346.1019.
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12,13-Dihydroimidazo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one (4l): Yield 83 % (258 mg). Pale yellow solid, m.p.: 278~280 °C; 1H NMR (CDCl3, 400 MHz): δH 2.37~2.44 (m, 2H), 3.08 (t, J = 5.6 Hz, 2H), 3.45 (t, J = 6.0 Hz, 2H), 7.51~7.55 (m,
EP
1H), 7.80~7.84 (m, 1H), 8.04 (d, J = 8.8 Hz, 1H), 8.15 (dd, J = 8.4 Hz, J’ = 1.2 Hz, 1H), 8.43 (d, J = 8.8 Hz, 1H), 8.64 (dd, J = 8.4 Hz, J’ = 1.2 Hz, 1H), 9.02 (s, 1H). 13C
AC C
NMR (CDCl3, 100 MHz): δC 21.3, 35.4, 40.7, 113.1, 116.0, 120.8, 121.8, 121.9, 125.2, 126.5, 127.6, 128.7, 131.6, 132.4, 133.0, 133.5, 134.5, 146.6, 163.2, 200.9. IR (KBr):
ν 3045, 2952, 2885, 1674, 1588, 1530, 1509, 1471, 1377, 1340, 1298, 1228, 1163,
1100, 1093, 1038, 994, 922, 827, 767 cm-1. HRMS (TOF, ESI, m/z): Calcd for C20H14N3O [M + H] 312.1137, found 312.1138. 3-Fluoro-12,13-dihydroimidazo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one
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(4m): Yield 84 % (276 mg). Pale yellow solid, m.p.: > 300 °C; 1H NMR (CDCl3, 400 MHz): δH 2.35~2.42 (m, 2H), 3.05 (t, J = 6.8 Hz, 2H), 3.44 (t, J = 6.4 Hz, 2H),
RI PT
7.22~7.25 (m, 1H), 7.81 (dd, J = 8.8 Hz, J’ = 1.6 Hz, 1H), 8.04 (d, J = 9.2 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 8.70 (dd, J = 9.2 Hz, J’ = 2.0 Hz, 1H), 8.94 (s, 1H). 13C
NMR (CDCl3, 100 MHz): δC 21.2, 35.4, 40.7, 103.1 (d, JF-C = 25.6 Hz), 112.8, 113.3
SC
(d, JF-C = 21.8 Hz), 117.3 (d, JF-C = 3.1 Hz), 121.4, 122.3, 125.0, 126.6, 133.0, 134.1,
134.3 (d, JF-C = 9.7 Hz), 134.6, 135.1 (d, JF-C = 10.8 Hz), 146.7, 163.5, 164.3 (d, JF-C
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= 254.8 Hz), 200.8. IR (KBr): ν 3089, 3062, 2884, 1672, 1661, 1624, 1591, 1533, 1511, 1472, 1350, 1334, 1295, 1248, 1195, 1164, 1103, 1036, 1013, 990, 887, 832, 826 cm-1. HRMS (TOF, ESI, m/z): Calcd for C20H13FN3O [M + H] 330.1043, found 330.1042.
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2-Methoxy-12,13-dihydroimidazo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one (4n): Yield 85 % (290 mg). Pale yellow solid, m.p.: 283~285 °C; 1H NMR (CDCl3, 400 MHz): δH 2.35~2.41 (m, 2H), 3.05 (t, J = 6.4 Hz, 2H), 3.42 (t, J = 6.0 Hz, 2H),
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3.92 (s, 3H), 7.30 (dd, J = 9.2 Hz, J’ = 2.8 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.97~7.99 (m, 2H), 8.39 (d, J = 8.8 Hz, 1H), 8.88 (s, 1H). 13C NMR (CDCl3, 100
AC C
MHz): δC 21.2, 35.5, 40.8, 55.9, 113.0, 114.5, 117.0, 117.4, 117.7, 120.4, 121.7, 121.9, 126.5, 127.7, 132.8, 134.2, 134.4, 146.6, 156.3, 163.2, 201.0. IR (KBr): ν 3104, 2957,
2948, 1665, 1592, 1563, 1538, 1508, 1486, 1461, 1377, 1333, 1296, 1231, 1181, 1166, 1124, 1098, 1044, 998, 938, 896, 871, 831, 800 cm-1. HRMS (TOF, ESI, m/z): Calcd
for C21H16N3O2 [M + H] 342.1242, found 342.1242. 12-Methyl-12,13-dihydroimidazo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one
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(4o): Yield 75 % (244 mg). Pale yellow solid, m.p.: 261~263 °C; 1H NMR (CDCl3, 400 MHz): δH 1.32 (d, J = 6.4 Hz, 3H), 2.67~2.73 (m, 2H), 3.10~3.20 (m, 2H),
RI PT
3.51~3.56 (m, 1H), 7.48~7.53 (m, 1H), 7.78~7.82 (m, 1H), 8.01 (d, J = 9.2 Hz, 1H), 8.13 (d, J = 7,6 Hz, 1H), 8.41 (d, J = 8.8 Hz, 1H), 8.63 (dd, J = 8.4 Hz, J’ = 1.2 Hz, 1H), 9.00 (s, 1H). 13C NMR (CDCl3, 100 MHz): δC 21.3, 29.0, 43.6, 49.0, 113.0,
SC
116.0, 120.7, 121.3, 121.9, 124.8, 125.1, 126.4, 131.6, 132.3, 133.0, 133.5, 134.3, 134.4, 146.6, 162.4, 201.0. IR (KBr): ν 3048, 3033, 2963, 2894, 2869, 1659, 1590,
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1541, 1506, 1490, 1470, 1377, 1341, 1303, 1274, 1244, 1227, 1189, 1177, 1102, 857, 834, 765, 742 cm-1. HRMS (TOF, ESI, m/z): Calcd for C21H16N3O [M + H] 326.1293, found 326.1293.
3-Chloro-12-methyl-12,13-dihydroimidazo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(1
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1H)-one (4p): Yield 82 % (294 mg). Pale yellow solid, m.p.: 265~267 °C; 1H NMR (CDCl3, 400 MHz): δH 1.31 (d, J = 6.0 Hz, 3H), 2.67~2.72 (m, 2H), 3.11~3.17 (m, 2H), 3.51~3.56 (m, 1H), 7.43 (dd, J = 9.2 Hz, J’ = 2.0 Hz, 1H), 8.02 (d, J = 8.8 Hz,
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1H), 8.08 (d, J = 2.0 Hz, 1H), 8.40 (d, J = 8.8 Hz, 1H), 8.56 (d, J = 8.8 Hz, 1H), 8.93 (s, 1H). 13C NMR (CDCl3, 100 MHz): δC 21.2, 28.9, 43.7, 49.0, 112.7, 116.0, 119.1,
AC C
121.1, 122.2, 124.7, 125.4, 126.5, 132.8, 133.0, 133.5, 134.1, 134.5, 138.3, 146.7, 162.6, 200.9. IR (KBr): ν 3099, 3038, 2956, 2924, 2868, 1679, 1605, 1591, 1550, 1530, 1506, 1470, 1434, 1376, 1334, 1295, 1265, 1225, 1177, 1120, 1091, 1027, 989, 880, 858, 819, 767 cm-1. HRMS (TOF, ESI, m/z): Calcd for C21H15ClN3O [M + H] 360.0904, found 360.0901. 2-Chloro-12-methyl-12,13-dihydroimidazo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(1
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1H)-one (4q): Yield 83 % (298 mg). Pale yellow solid, m.p.: 260~262 °C; 1H NMR (CDCl3, 400 MHz): δH 1.34 (d, J = 6.4 Hz, 3H), 2.65~2.76 (m, 2H), 3.13~3.25 (m,
RI PT
2H), 3.53~3.58 (m, 1H), 7.78 (dd, J = 8.8 Hz, J’ = 2.0 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 8.44 (d, J = 9.2 Hz, 1H), 8.66 (d, J = 2.4 Hz, 1H), 8.97 (s, 1H). 13C NMR (CDCl3, 100 MHz): δC 21.2, 28.9, 43.7, 48.9, 112.8, 117.1, 121.4,
SC
122.0, 122.1, 124.5, 126.5, 130.7, 131.2, 131.8, 132.2, 132.9, 133.1, 134.4, 146.6,
162.6, 200.7. IR (KBr): ν 3092, 2956, 2926, 2871, 1676, 1591, 1537, 1505, 1483,
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1467, 1378, 1330, 1294, 1226, 1195, 1168, 1116, 1096, 1028, 970, 879, 828 cm-1. HRMS (TOF, ESI, m/z): Calcd for C21H15ClN3O [M + H] 360.0904, found 360.0897. 3-Methyl-3,4-dihydro-[1,3]dioxolo[4,5-b]imidazo[1,5,4-fg]quinolino[2,3,4-kl]acridin1(2H)-one (4r): Yield 74 % (273 mg). Pale yellow solid, m.p.: 275~277 °C; 1H NMR
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(CDCl3, 400 MHz): δH 1.33 (d, J = 6.0 Hz, 3H), 2.67~2.72 (m, 2H), 3.10~3.22 (m, 2H), 3.50~3.54 (m, 1H), 6.20 (s, 2H), 7.34 (s, 1H), 7.84 (s, 1H), 8.01 (d, J = 8.8 Hz, 1H), 8.41 (d, J = 8.8 Hz, 1H), 8.79 (s, 1H). 13C NMR (CDCl3, 100 MHz): δC 21.2,
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28.9, 43.8, 49.0, 96.0, 102.9, 103.0, 109.5, 109.8, 112.3, 115.0, 120.3, 121.8, 126.2, 130.2, 132.6, 134.5, 145.5, 146.6, 151.6, 162.5, 200.8. IR (KBr): ν 3086, 3043, 2954,
AC C
2905, 2871, 1666, 1605, 1591, 1535, 1504, 1481, 1458, 1387, 1371, 1326, 1286, 1265, 1236, 1193, 1142, 1117, 1044, 1016, 943, 933, 870, 852, 833 cm-1. HRMS (TOF, ESI,
m/z): Calcd for C22H16N3O3 [M + H] 370.1192, found 370.1192. Acknowledgement: We are grateful to the National Natural Science Foundation of China (20802061), a project funded by the Priority Academic Program Development of Jiangsu Higher
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Education Institutions, Qing Lan Project (10QLD008, GSFM2011003) and College Industrialization Project (JHB2012-31) of Jiangsu Province for financial support.
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References 1. Horstmann, M. A.; Hassenpflug, W. A.; zur Stadt, U.; Escherich, G.; Janka, G.; Kabisch, H.
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S0040-4020(14)01401-X
DOI:
10.1016/j.tet.2014.09.084
Reference:
TET 26058
To appear in:
Tetrahedron
Received Date: 7 July 2014 Revised Date:
17 September 2014
Accepted Date: 26 September 2014
Please cite this article as: Li C, Zhang W-T, Wang X-S, Domino Synthesis of Fused Hexacyclic Imidazoquinolinoacridinones Catalyzed by CuI/L-Proline, Tetrahedron (2014), doi: 10.1016/ j.tet.2014.09.084. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Domino Synthesis of Fused Hexacyclic Imidazoquinolinoacridinones Catalyzed by CuI/L-Proline
RI PT
Chao Li, Wen-Ting Zhang, Xiang-Shan Wang* R
O
CHO X
H2N
O
N
+
+ N H
CuI, L-proline Cs2CO3
N
1
R
R2
N
SC
R
O
R1 R2
N
One-Pot, Fused Hexacycle 2 New Heterocycles
AC C
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6 New Bonds
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Domino Synthesis of Fused Hexacyclic Imidazoquinolinoacridinones Catalyzed by CuI/L-Proline
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Chao Li, Wen-Ting Zhang, 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. China
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E-mail: [email protected]
Abstract—A three-component reaction of 2-halogenated aromatic aldehydes, 1H-benzo[d]
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imidazol-5-amine and cyclohexane-1,3-diones is described, and gives imidazoquinolinoacridinone derivatives in good yields catalyzed by CuI/L-proline. This Domino reaction constructs a fused hexacyclic skeleton in one-pot containing two new rings, six new bonds and an Ullmann-type C-N bond coupling reaction.
Introduction
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Keywords: Domino reaction, imidazoquinolinoacridine, Ullmann reaction, CuI
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Acridine occurs in a large number of natural products and attracts much attention
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due to its wide biological activities. A well-known example is Amsacrine, it is an antineoplastic agent used in the treatment of acute lymphoblastic leukemia.1 Another
useful drug on the market is Ethacridine lactate,2 which has strong killing effects on
gram positive bacteria and a few gram-negative bacteria. Although a number of useful synthetic procedures to prepare these compounds have been developed in recent years,3 still several limitations remain, as well. For example, most of the procedures
involve several steps, low yields or costly metal catalysts. Thus, simple, efficient, and
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versatile preparation of acridine derivatives in one-pot reaction is still highly desirable,
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especially for novel fused acridine, it may possess new bio-activity for screening.
Figure 1. The marketed drugs containing acridine analogue
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The traditional Ullmann reaction named after Fritz Ullmann4 in 1901 is a coupling reaction between aryl halides catalyzed by copper under harsh reaction conditions. In modern organic synthesis, it has been developed to Pd-catalyzed coupling reactions gradually, such as the Heck reaction,5 the Hiyama coupling6 and
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the Sonogashira coupling.7 However, copper-catalyzed Ullmann-type reaction has been received much attention due to its lower price in catalysts, and it has been used
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to synthesize the products of structural diversity.8 As a continuation of our research devoted to the new methods for the preparation
AC C
of fused polycyclic heterocycles via Ullmann-type reaction catalyzed by copper (I) and its compound,9 we describe here the synthesis of fused hexacyclic skeleton
containing acridine analogue by a three-component Domino reaction of 2-halogenated aromatic aldehydes, 1H-benzo[d]imidazol-5-amine and cyclohexane-1,3-diones
catalyzed by CuI/L-proline. Results and discussion Treatment of 2-bromobenzaldehyde 1a, 5,5-dimethylcyclohexane-1,3-dione 2a,
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and 1H-benzo[d]imidazol-5-amine 3 in refluxing dioxane in the presence of CuI and Cs2CO3, resulted in the corresponding 12,12-dimethyl-12,13-dihydroimidazo[4,5,1-de]
+ O
N
+
N H
2a
CuI Cs2CO3
3
N
N
N
4a
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H2 N
Br
1a
O
O
CHO
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quinolino[4,3,2-mn]acridin-14(11H)-one 4a in 68 % yield (Scheme 1).
Scheme 1. Reaction of 1a, 2a and 3
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Taking the reaction of 2-bromobenzaldehyde 1a, 2a, and 3 as a model, several parameters including catalysts, ligands, bases and solvents, were optimized first in our lab. The reaction was carried out in the absence of catalysts; it was found that no 4a was observed at refluxing dioxane, and simple condensation product of
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11-(2-bromophenyl)-8,8-dimethyl-6a,7,8,9,10a,11-hexahydro-1H-imidazo[4,5-a]acri din-10(6H)-one was obtained in 87 % yield, and the subsequent Ullmann-type
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reaction did not take place without CuI and base. Different ligands, for example, PPh3, CH3NHCH2CO2H and L-proline were used to promote the reaction, and the L-proline
AC C
gave the best result. Various kinds of bases, such as Na2CO3, K2CO3, Cs2CO3, and NaHCO3 (Table 1, entries 5, 10-12) were used to promote this reaction. It was found
that Cs2CO3 was the best base to give 4a in the highest yields for its slightly stronger
alkaline. In addition, other solvents, such as THF, CH3CN and toluene (entries 13-15),
were also tested but dioxane proved to be superior. Table 1. Synthetic results of 4a under different reaction conditionsa
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Ligands(mol%)
Bases
Solvents
Yields (%)b
1
-
-
-
Dioxane
87c
2
CuI(5)
-
Cs2CO3
Dioxane
68
3
CuI(5)
PPh3(10)
Cs2CO3
Dioxane
72
4
CuI(5)
CH3NHCH2CO2H(10)
Cs2CO3
Dioxane
76
5
CuI(5)
L-proline(10)
Cs2CO3
Dioxane
86
6
CuI(10)
L-proline(20)
Cs2CO3
Dioxane
85
7
CuI(20)
L-proline(40)
Cs2CO3
Dioxane
86
8
CuBr(5)
L-proline(10)
Cs2CO3
Dioxane
82
9
CuCl(5)
L-proline(10)
Cs2CO3
Dioxane
78
10
CuI(5)
L-proline(10)
K2CO3
Dioxane
82
11
CuI(5)
L-proline(10)
Na2CO3
Dioxane
76
12
CuI(5)
L-proline(10)
NaHCO3d
Dioxane
70
13
CuI(5)
L-proline(10)
Cs2CO3
CH3CN
72
14
CuI(5)
L-proline(10)
Cs2CO3
THF
67
15
CuI(5)
Cs2CO3
Toluene
80
EP
TE D
M AN U
SC
RI PT
Catalysts (mol%)
L-proline(10)
AC C
a
Entry
Reagents and conditions: 1a (0.185 g, 1.0 mmol), 2a (0.140 g, 1.0 mmol), 3 (0.133 g, 1.0 mmol),
solvent (10 mL), 2 mmol base, refluxing. b Isolated yields. c The product is simple condensation one without Ullmann reaction. d 4 mmol.
Subsequently, various kinds of 2-halogenated aromatic aldehydes were used to react with 2a and 3 at the same optimized conditions first. It was found that this process
could
tolerate
both
electron-donating,
such
as
alkoxy,
and
ACCEPTED MANUSCRIPT
electron-withdrawing (halogen and nitro) substituents on the 2-halogenated aromatic aldehydes (Table 2). In all cases, they all carried out smoothly to give
RI PT
imidazoquinolinoacridinone derivatives in good yields (Table 2, entries 1~11). The halogen in the 2-position of benzaldehyde is usually bromine (Table 2, entries 1-7). It also
can
be
a
chlorine
atom
(Table
2,
entries
8-9),
for
example,
SC
2-chloro-5-nitrobenzaldehyde or 2-chloro-5-(trifluoromethyl)benzaldehyde was used as a reactant, they all reacted well to give desired products in 83 % and 79 % yields,
M AN U
respectively. It was found in surprised that the 2-halogenated aromatic aldehyde also could be 4-bromo-2-fulorobenzaldehyde, and the reaction gave 4j in 75 % yield. This data indicated that the fluoride could also be used as a leaving group in this CuI-catalyzed Ullmann-type reaction. In addition, it should be noted that when
TE D
2-bromothiophene-3-carbaldehyde was charged with 2a and 3 at the same reaction condition, the expected product of 11,11-dimethyl-11,12-dihydroimidazo[4,5,1-ij] quinolino[4,3,2-de]thieno[2,3-b]quinolin-13(10H)-one was obtained in good yield
EP
(Table 2, entry 11). Cyclohexane-1,3-dione 2b and 5-methylcyclohexane-1,3-dione 2c also gave the good results (Table 2, entries 12~18). All the structures of the products
AC C
were characterized by NMR, IR and HRMS; their data were in good agreement to the preconceived structures. The structure of 4h was confirmed by X-ray diffraction analysis, and its crystal structure is shown in Figure 2.
Scheme 2. Reaction of 1, 2 and 3
RI PT
ACCEPTED MANUSCRIPT
SC
Table 2. The reaction time and yields of the products 4a R
X (in 1)
R1
R2
Time (h)
Products
Yieldsb (%)
1
H
Br
Me
Me
15
4a
86
2
3-Cl
Br
Me
Me
12
4b
82
3
2-Cl
Br
Me
Me
12
4c
84
4
2,3-OCH2O
Br
Me
Me
18
4d
78
5
2,3-(MeO)2
Br
Me
Me
18
4e
76
6
3-F
7
2-F
8
2-NO2
9
2-CF3
10
Me
Me
12
4f
89
Br
Me
Me
12
4g
86
Cl
Me
Me
10
4h
83
Cl
Me
Me
10
4i
79
3-Br
F
Me
Me
16
4j
75
11
2-Thienylc
Br
Me
Me
16
4k
84
12
H
Br
H
H
16
4l
83
13
3-F
Br
H
H
14
4m
84
14
2-MeO
Br
H
H
18
4n
85
15
H
Br
H
Me
16
4o
75
EP
Br
AC C
TE D
M AN U
Entry
ACCEPTED MANUSCRIPT
3-Cl
Br
H
Me
12
4p
82
17
2-Cl
Br
H
Me
12
4q
83
18
2,3-OCH2O
Br
H
Me
18
4r
74
a
RI PT
16
Reaction condition: dioxane (10 mL), 1 (1.0 mmol), 2 (1.0 mmol) and 3 (1.0 mmol), CuI (10 mg),
L-proline (6 mg), Cs2CO3 (650 mg), reflux. b Isolated yields. c 2-Bromothiophene-3-carbaldehyde
TE D
M AN U
SC
was used as 2-halogenated aromatic aldehyde.
Figure 2. The crystal structure of 4h
EP
According to the structure 4 and the references,8,9 subsequent condensation, aromatization and Ullmann-type C-N bond coupling reaction may take place. The key
AC C
step is the Csp2-N coupling of imidazole and aryl halide. The possible reaction
mechanism is outlined in Scheme 3.
ACCEPTED MANUSCRIPT
O L-Proline + CuI + Base N O H Cu CHO
Br HN
O O
NH2 +
+
CuI
N
N
RI PT
H N
Br
O
N H
O
Cs2CO3 Aromatization
O NH Cu N Oxidative addition
Br O
O N
N O H Cu
-Br
N
O
N
O
-
N
O
Cu O
Cs2CO3
HN
N
M AN U
N H
SC
Br HN
O
N
Reductive elimination
N
N
N
TE D
Scheme 3. The possible reaction mechanism
Conclusion
In summary, a three-component Domino reaction of 2-halogenated aromatic
EP
aldehydes, 1H-benzo[d]imidazol-5-amine and cyclohexane-1,3-diones catalyzed by
AC C
CuI/L-proline was studied. This procedure provided an expedient route for the synthesis fused hexacyclic skeleton in one-pot containing two new heterocycles, six new bonds and an Ullmann-type C-N bond coupling reaction. Experimental
Melting points were determined in open capillaries and are uncorrected. IR spectra were recorded on a Tensor 27 spectrometer in KBr pellet. 1H NMR spectra was obtained from a solution in DMSO-d6 with Me4Si as internal standard using a
ACCEPTED MANUSCRIPT
Bruker-400 spectrometer. HRMS analyses were carried out using a Bruker-microTOF-Q-MS analyzer.
RI PT
General procedure for the syntheses of 4. A dry 50 mL flask was charged with 2-halogenated aromatic aldehyde 1 (1.0 mmol), 1H-benzo[d]imidazol-5-amine (0.133 g, 1.0 mmol), cyclohexane-1,3-diones
SC
(1.0 mmol), CuI (10 mg), L-proline (6 mg), Cs2CO3(650 mg) and dioxane (10 mL).
The reaction mixture was stirred at reflux for 10-18 h. After completion of the
M AN U
reaction, as indicated by TLC, the solid was filtered off by a fast and hot filtration, and the products of 4 were obtained as pale yellow powder or crystals, when the mixture was allowed to cool down to room temperature.
12,12-Dimethyl-12,13-dihydroimidazo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-
TE D
one (4a): Yield 86 % (292 mg). Pale yellow solid, m.p.: 277~279 °C; 1H NMR (CDCl3, 400 MHz): δH 1.28 (s, 6H), 2.96 (s, 2H), 3.43 (s, 2H), 7.51~7.55 (m, 1H), 7.81~7.85 (m, 1H), 8.05 (d, J = 8.8 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 8.44 (d, J = 8.8
EP
Hz, 1H), 8.66 (dd, J = 8.4 Hz, J’ = 0.8 Hz, 1H), 9.04 (s, 1H). 13C NMR (CDCl3, 100 MHz): δC 28.7, 33.2, 49.4, 55.1, 113.0, 116.0, 120.8, 121.0, 122.0, 125.1, 126.4, 131.9,
AC C
132.4, 133.6, 134.3, 136.9, 140.2, 142.8, 146.9, 161.7, 201.0. IR (KBr): ν 3081, 2956,
2869, 1683, 1595, 1530, 1510, 1469, 1379, 1348, 1302, 1243, 1209, 1169, 1098, 1092, 827, 810, 768, 741 cm-1. HRMS (TOF, ESI, m/z): Calcd for C22H18N3O [M + H]
340.1444, found 340.1440. 3-Chloro-12,12-dimethyl-12,13-dihydroimidazo[4,5,1-de]quinolino[4,3,2-mn]acridin14(11H)-one (4b): Yield 82 % (306 mg). Pale yellow solid, m.p.: > 300 °C; 1H NMR
ACCEPTED MANUSCRIPT
(CDCl3, 400 MHz): δH 1.27 (s, 6H), 2.95 (s, 2H), 3.44 (s, 2H), 7.46 (dd, J = 8.8 Hz, J’ = 2.0 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 8.12 (d, J = 2.0 Hz, 1H), 8.43 (d, J = 9.2 Hz,
RI PT
1H), 8.61 (d, J = 8.8 Hz, 1H), 8.97 (s, 1H). 13C NMR (CDCl3, 100 MHz): δC 28.6, 33.2, 49.4, 55.1, 112.8, 116.1, 119.3, 120.8, 122.3, 124.9, 125.5, 126.5, 133.0, 133.1,
133.6, 134.3, 134.6, 138.4, 146.9, 162.0, 200.9. IR (KBr): ν 3089, 2954, 2868, 1681,
SC
1625, 1590, 1549, 1530, 1505, 1468, 1403, 1373, 1332, 1288, 1228, 1173, 1092, 1038, 981, 876, 848, 822, 768 cm-1. HRMS (TOF, ESI, m/z): Calcd for C22H17ClN3O [M +
M AN U
H] 374.1060, found 374.1046.
2-Chloro-12,12-dimethyl-12,13-dihydroimidazo[4,5,1-de]quinolino[4,3,2-mn]acridin14(11H)-one (4c): Yield 84 % (313 mg). Pale yellow solid, m.p.: 189~191 °C; 1H NMR (CDCl3, 400 MHz): δH 1.16 (s, 3H), 1.21 (s, 3H), 2.61 (s, 2H), 3.33 (s, 2H),
TE D
7.28 (d, J = 1.6 Hz, 1H), 7.51 (dd, J = 8.4 Hz, J’ = 1.6 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 8.40 (b, 2H). 13C NMR (CDCl3, 100 MHz): δC 27.6, 28.9, 32.4, 47.9, 53.7, 119.8, 121.9, 123.0, 123.9, 126.8, 127.5, 128.7, 130.4, 134.6, 134.9, 135.1,
EP
135.6, 142.3, 146.9, 148.3, 159.8, 197.8. IR (KBr): ν 3081, 2951, 2867, 1687, 1575, 1552, 1465, 1448, 1371, 1301, 1289, 1273, 1211, 1098, 1034, 912, 841, 829, 813 cm-1.
AC C
HRMS (TOF, ESI, m/z): Calcd for C22H17ClN3O [M + H] 374.1060, found 374.1076.
3,3-Dimethyl-3,4-dihydro-[1,3]dioxolo[4,5-b]imidazo[1,5,4-fg]quinolino[2,3,4-kl]acri
din-1(2H)-one (4d): Yield 78 % (299 mg). Pale yellow solid, m.p.: > 300 °C; 1H NMR (CDCl3, 400 MHz): δH 1.25 (s, 6H), 2.92 (s, 2H), 3.39 (s, 2H), 6.18 (s, 2H), 7.40 (s, 1H), 7.88 (s, 1H), 8.01 (d, J = 8.8 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H), 8.82 (s, 1H). 13C NMR (CDCl3, 100 MHz): δC 28.6, 33.1, 49.5, 55.1, 95.9, 102.8, 109.6, 112.3,
ACCEPTED MANUSCRIPT
115.0, 119.9, 121.8, 124.5, 126.1, 130.1, 132.6, 134.2, 134.3, 145.4, 146.7, 151.5, 161.8, 200.8. IR (KBr): ν 3088, 3056, 2954, 2907, 2869, 1688, 1605, 1592, 1532,
RI PT
1505, 1483, 1388, 1369, 1330, 1268, 1239, 1140, 1117, 1082, 1043, 940, 866, 850, 833 cm-1. HRMS (TOF, ESI, m/z): Calcd for C23H18N3O3 [M + H] 384.1348, found 384.1367.
SC
2,3-Dimethoxy-12,12-dimethyl-12,13-dihydroimidazo[4,5,1-de]quinolino[4,3,2-mn]a
cridin-14(11H)-one (4e): Yield 76 % (303 mg). Pale yellow solid, m.p.: 255~257 °C; H NMR (CDCl3, 400 MHz): δH 1.25 (s, 6H), 2.93 (s, 2H), 3.41 (s, 2H), 4.01 (s, 3H) ,
M AN U
1
4.14 (s, 3H), 7.43 (s, 1H), 8.00 (d, J = 8.8 Hz, 1H), 8.04 (s, 1H), 8.38 (d, J = 8.8 Hz, 1H), 8.91 (s, 1H). 13C NMR (CDCl3, 100 MHz): δC 28.6, 33.1, 49.6, 55.4, 56.4, 56.5, 97.2, 112.3, 113.0, 113.8, 119.7, 121.8, 124.6, 126.1, 129.1, 132.4, 134.0, 134.2, 146.2,
TE D
146.8, 153.0, 161.9, 201.2. IR (KBr): ν 3035, 2950, 2897, 2869, 2825, 1678, 1665, 1618, 1595, 1535, 1492, 1458, 1381, 1364, 1327, 1274, 1254, 1238, 1209, 1105, 1038, 1009, 983, 847, 824, 795 cm-1. HRMS (TOF, ESI, m/z): Calcd for C24H22N3O3 [M + H]
EP
400.1661, found 400.1662.
3-Fluoro-12,12-dimethyl-12,13-dihydroimidazo[4,5,1-de]quinolino[4,3,2-mn]acridin-
AC C
14(11H)-one (4f): Yield 89 % (318 mg). Pale yellow solid, m.p.: > 300 °C; 1H NMR
(CDCl3, 400 MHz): δH 1.25 (s, 6H), 2.92 (s, 2H), 3.41 (s, 2H), 7.19~7.24 (m, 1H), 7.78 (dd, J = 8.8 Hz, J’ = 1.6 Hz, 1H), 8.03 (d, J = 8.8 Hz, 1H), 8.40 (d, J = 8.8 Hz,
1H), 8.69 (dd, J = 9.2 Hz, J’ = 1.6 Hz, 1H), 8.91 (s, 1H). 13C NMR (CDCl3, 100 MHz):
δC 28.6, 33.2, 49.4, 55.1, 103.0 (d, JF-C = 25.6 Hz), 112.7, 113.2 (d, JF-C = 21.6 Hz), 117.3 (d, JF-C = 3.0 Hz), 120.6, 122.3, 125.0, 126.5, 133.1, 133.8, 134.4 (d, JF-C = 9.7
ACCEPTED MANUSCRIPT
Hz), 134.6, 135.1 (d, JF-C = 10.5 Hz), 146.9, 162.0, 164.2 (d, JF-C = 254.6 Hz), 201.0. IR (KBr): ν 3081, 3047, 2954, 2870, 1675, 1621, 1592, 1569, 1529, 1514, 1472, 1380,
RI PT
1352, 1332, 1296, 1272, 1247, 1198, 1174, 1097, 1086, 980, 890, 868, 845, 817 cm-1. HRMS (TOF, ESI, m/z): Calcd for C22H17FN3O [M + H] 358.1356, found 358.1350.
2-Fluoro-12,12-dimethyl-12,13-dihydroimidazo[4,5,1-de]quinolino[4,3,2-mn]acridin-
SC
14(11H)-one (4g): Yield 86 % (307 mg). Pale yellow solid, m.p.: 254~256 °C; 1H NMR (CDCl3, 400 MHz): δH 1.26 (s, 6H), 2.94 (s, 2H), 3.41 (s, 2H), 7.52~7.56 (m,
M AN U
1H), 8.03 (d, J = 8.8 Hz, 1H), 8.11 (dd, J = 8.8 Hz, J’ = 4.8 Hz, 1H), 8.36~8.43 (m, 2H), 8.96 (s, 1H). 13C NMR (CDCl3, 100 MHz): δC 28.6, 33.2, 49.4, 55.1, 112.8, 117.4 (d, JF-C = 8.6 Hz), 118.0 (d, JF-C = 25.4 Hz), 120.2(d, JF-C = 24.3 Hz), 121.1, 122.1, 122.6 (d, JF-C = 8.9 Hz), 124.7, 126.6, 130.1, 133.0, 133.4 (d, JF-C = 2.4 Hz),
TE D
134.5, 146.9, 158.8 (d, JF-C = 244.1 Hz), 161.8, 200.9. IR (KBr): ν 3063, 3045, 2956, 2870, 1681, 1666, 1591, 1545, 1508, 1474, 1413, 1379, 1331, 1298, 1230, 1208, 1160, 1091, 970, 872, 827 cm-1. HRMS (TOF, ESI, m/z): Calcd for C22H17FN3O [M + H]
EP
358.1356, found 358.1342.
12,12-Dimethyl-2-nitro-12,13-dihydroimidazo[4,5,1-de]quinolino[4,3,2-mn]acridin-1
AC C
4(11H)-one (4h): Yield 83 % (319 mg). Pale yellow solid, m.p.: 282~284 °C; 1H
NMR (CDCl3, 400 MHz): δH 1.26 (s, 6H), 3.00 (s, 2H), 3.45 (s, 2H), 8.07 (d, J = 8.8 Hz, 1H), 8.23 (d, J = 9.2 Hz, 1H), 8.43 (d, J = 8.8 Hz, 1H), 8.63 (dd, J = 9.2 Hz, J’ =
2.4 Hz, 1H), 9.03 (s, 1H), 9.68 (d, J = 2.4 Hz, 1H). 13C NMR (CDCl3, 100 MHz): δC 28.6, 33.3, 49.4, 55.0, 112.9, 116.7, 121.2, 121.5, 122.9, 124.8, 126.7, 126.8, 128.1, 133.1, 133.4, 134.8, 137.2, 143.9, 147.0, 162.5, 200.6. IR (KBr): ν 3098, 2963, 2948,
ACCEPTED MANUSCRIPT
2862, 1681, 1670, 1617, 1589, 1574, 1528, 1480, 1468, 1339, 1298, 1284, 1255, 1222, 1161, 1120, 1092, 1084, 1036, 987, 967, 889, 869, 837, 790 cm-1. HRMS (TOF, ESI,
RI PT
m/z): Calcd for C22H17N4O3 [M + H] 385.1301, found 385.1301. 12,12-Dimethyl-2-(trifluoromethyl)-12,13-dihydroimidazo[4,5,1-de]quinolino[4,3,2-
mn]acridin-14(11H)-one (4i): Yield 79 % (322 mg). Pale yellow solid, m.p.:
SC
279~280 °C; 1H NMR (CDCl3, 400 MHz): δH 1.47 (s, 6H), 3.49 (s, 2H), 3.71 (s, 2H),
8.10 (d, J = 8.8 Hz, 1H), 8.13 (dd, J = 8.4 Hz, J’ = 1.6 Hz, 1H), 8.27 (d, J = 8.4 Hz,
M AN U
1H), 8.48 (d, J = 9.2 Hz, 1H), 9.05 (s, 1H), 11.15 (s, 1H). 13C NMR (CDCl3, 100 MHz): δC 25.9, 45.4, 46.4, 67.1, 112.7, 116.0, 119.5, 122.6, 122.7, 125.1, 125.6, 127.5, 128.4 (q, JF-C = 33.3 Hz), 129.6, 132.1, 133.2, 134.6, 135.0, 135.2, 149.4, 171.5, 210.1. IR (KBr): ν 3090, 2971, 2931, 2868, 1699, 1666, 1626, 1592, 1545, 1527,
TE D
1473, 1432, 1413, 1350, 1335, 1257, 1226, 1168, 1150, 1124, 1091, 1078, 969, 956, 917, 873, 831 cm-1. HRMS (TOF, ESI, m/z): Calcd for C23H17F3N3O [M + H] 408.1324, found 408.1331.
EP
3-Bromo-12,12-dimethyl-12,13-dihydroimidazo[4,5,1-de]quinolino[4,3,2-mn]acridin14(11H)-one (4j): Yield 75 % (313 mg). Pale yellow solid, m.p.: > 300 °C; 1H NMR
AC C
(CDCl3, 400 MHz): δH 1.25 (s, 6H), 2.93 (s, 2H), 3.42 (s, 2H), 7.61 (dd, J = 9.2 Hz, J’
= 2.0 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 8.43 (d, J = 8.8 Hz, 1H), 8.54 (d, J = 8.8 Hz, 1H), 8.98 (s, 1H). 13C NMR (CDCl3, 100 MHz): δC 28.6, 33.2, 49.4, 55.1, 112.9, 119.1, 119.8, 120.8, 122.3, 126.6, 126.7, 128.4, 133.2, 133.8, 134.4, 134.7, 138.6, 144.9, 147.0, 162.0, 200.9. IR (KBr): ν 3077, 2954, 2936, 2868, 1680, 1669, 1600, 1590, 1549, 1529, 1506, 1467, 1372, 1331, 1302, 1287, 1250, 1227,
ACCEPTED MANUSCRIPT
1174, 1088, 1082, 979, 875, 848, 821, 750 cm-1. HRMS (TOF, ESI, m/z): Calcd for C22H17BrN3O [M + H] 418.0555, found 418.0554.
RI PT
11,11-Dimethyl-11,12-dihydroimidazo[4,5,1-ij]quinolino[4,3,2-de]thieno[3,2-b]quino lin-13(10H)-one (4k): Yield 84 % (290 mg). Pale yellow solid, m.p.: 284~286 °C; 1H
NMR (CDCl3, 400 MHz): δH 1.75 (s, 6H), 2.83 (s, 2H), 3.41 (s, 2H), 7.81 (d, J = 8.4
SC
Hz, 1H), 8.00 (d, J = 6.0 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 8.44 (d, J = 8.8 Hz, 1H), 8.87 (s, 1H). 13C NMR (CDCl3, 100 MHz): δC 28.2, 32.3, 49.7, 54.1, 111.5, 114.8,
M AN U
115.2, 122.57, 122.62, 125.0, 126.4, 132.8, 134.2, 135.1, 135.5, 136.7, 147.6, 162.4, 199.9. IR (KBr): ν 3080, 2951, 2867, 1672, 1656, 1590, 1531, 1509, 1456, 1397, 1370, 1337, 1315, 1235, 1174, 1109, 959, 867, 823, 741 cm-1. HRMS (TOF, ESI, m/z): Calcd for C20H16N3OS [M + H] 346.1014, found 346.1019.
TE D
12,13-Dihydroimidazo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one (4l): Yield 83 % (258 mg). Pale yellow solid, m.p.: 278~280 °C; 1H NMR (CDCl3, 400 MHz): δH 2.37~2.44 (m, 2H), 3.08 (t, J = 5.6 Hz, 2H), 3.45 (t, J = 6.0 Hz, 2H), 7.51~7.55 (m,
EP
1H), 7.80~7.84 (m, 1H), 8.04 (d, J = 8.8 Hz, 1H), 8.15 (dd, J = 8.4 Hz, J’ = 1.2 Hz, 1H), 8.43 (d, J = 8.8 Hz, 1H), 8.64 (dd, J = 8.4 Hz, J’ = 1.2 Hz, 1H), 9.02 (s, 1H). 13C
AC C
NMR (CDCl3, 100 MHz): δC 21.3, 35.4, 40.7, 113.1, 116.0, 120.8, 121.8, 121.9, 125.2, 126.5, 127.6, 128.7, 131.6, 132.4, 133.0, 133.5, 134.5, 146.6, 163.2, 200.9. IR (KBr):
ν 3045, 2952, 2885, 1674, 1588, 1530, 1509, 1471, 1377, 1340, 1298, 1228, 1163,
1100, 1093, 1038, 994, 922, 827, 767 cm-1. HRMS (TOF, ESI, m/z): Calcd for C20H14N3O [M + H] 312.1137, found 312.1138. 3-Fluoro-12,13-dihydroimidazo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one
ACCEPTED MANUSCRIPT
(4m): Yield 84 % (276 mg). Pale yellow solid, m.p.: > 300 °C; 1H NMR (CDCl3, 400 MHz): δH 2.35~2.42 (m, 2H), 3.05 (t, J = 6.8 Hz, 2H), 3.44 (t, J = 6.4 Hz, 2H),
RI PT
7.22~7.25 (m, 1H), 7.81 (dd, J = 8.8 Hz, J’ = 1.6 Hz, 1H), 8.04 (d, J = 9.2 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 8.70 (dd, J = 9.2 Hz, J’ = 2.0 Hz, 1H), 8.94 (s, 1H). 13C
NMR (CDCl3, 100 MHz): δC 21.2, 35.4, 40.7, 103.1 (d, JF-C = 25.6 Hz), 112.8, 113.3
SC
(d, JF-C = 21.8 Hz), 117.3 (d, JF-C = 3.1 Hz), 121.4, 122.3, 125.0, 126.6, 133.0, 134.1,
134.3 (d, JF-C = 9.7 Hz), 134.6, 135.1 (d, JF-C = 10.8 Hz), 146.7, 163.5, 164.3 (d, JF-C
M AN U
= 254.8 Hz), 200.8. IR (KBr): ν 3089, 3062, 2884, 1672, 1661, 1624, 1591, 1533, 1511, 1472, 1350, 1334, 1295, 1248, 1195, 1164, 1103, 1036, 1013, 990, 887, 832, 826 cm-1. HRMS (TOF, ESI, m/z): Calcd for C20H13FN3O [M + H] 330.1043, found 330.1042.
TE D
2-Methoxy-12,13-dihydroimidazo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one (4n): Yield 85 % (290 mg). Pale yellow solid, m.p.: 283~285 °C; 1H NMR (CDCl3, 400 MHz): δH 2.35~2.41 (m, 2H), 3.05 (t, J = 6.4 Hz, 2H), 3.42 (t, J = 6.0 Hz, 2H),
EP
3.92 (s, 3H), 7.30 (dd, J = 9.2 Hz, J’ = 2.8 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.97~7.99 (m, 2H), 8.39 (d, J = 8.8 Hz, 1H), 8.88 (s, 1H). 13C NMR (CDCl3, 100
AC C
MHz): δC 21.2, 35.5, 40.8, 55.9, 113.0, 114.5, 117.0, 117.4, 117.7, 120.4, 121.7, 121.9, 126.5, 127.7, 132.8, 134.2, 134.4, 146.6, 156.3, 163.2, 201.0. IR (KBr): ν 3104, 2957,
2948, 1665, 1592, 1563, 1538, 1508, 1486, 1461, 1377, 1333, 1296, 1231, 1181, 1166, 1124, 1098, 1044, 998, 938, 896, 871, 831, 800 cm-1. HRMS (TOF, ESI, m/z): Calcd
for C21H16N3O2 [M + H] 342.1242, found 342.1242. 12-Methyl-12,13-dihydroimidazo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one
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(4o): Yield 75 % (244 mg). Pale yellow solid, m.p.: 261~263 °C; 1H NMR (CDCl3, 400 MHz): δH 1.32 (d, J = 6.4 Hz, 3H), 2.67~2.73 (m, 2H), 3.10~3.20 (m, 2H),
RI PT
3.51~3.56 (m, 1H), 7.48~7.53 (m, 1H), 7.78~7.82 (m, 1H), 8.01 (d, J = 9.2 Hz, 1H), 8.13 (d, J = 7,6 Hz, 1H), 8.41 (d, J = 8.8 Hz, 1H), 8.63 (dd, J = 8.4 Hz, J’ = 1.2 Hz, 1H), 9.00 (s, 1H). 13C NMR (CDCl3, 100 MHz): δC 21.3, 29.0, 43.6, 49.0, 113.0,
SC
116.0, 120.7, 121.3, 121.9, 124.8, 125.1, 126.4, 131.6, 132.3, 133.0, 133.5, 134.3, 134.4, 146.6, 162.4, 201.0. IR (KBr): ν 3048, 3033, 2963, 2894, 2869, 1659, 1590,
M AN U
1541, 1506, 1490, 1470, 1377, 1341, 1303, 1274, 1244, 1227, 1189, 1177, 1102, 857, 834, 765, 742 cm-1. HRMS (TOF, ESI, m/z): Calcd for C21H16N3O [M + H] 326.1293, found 326.1293.
3-Chloro-12-methyl-12,13-dihydroimidazo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(1
TE D
1H)-one (4p): Yield 82 % (294 mg). Pale yellow solid, m.p.: 265~267 °C; 1H NMR (CDCl3, 400 MHz): δH 1.31 (d, J = 6.0 Hz, 3H), 2.67~2.72 (m, 2H), 3.11~3.17 (m, 2H), 3.51~3.56 (m, 1H), 7.43 (dd, J = 9.2 Hz, J’ = 2.0 Hz, 1H), 8.02 (d, J = 8.8 Hz,
EP
1H), 8.08 (d, J = 2.0 Hz, 1H), 8.40 (d, J = 8.8 Hz, 1H), 8.56 (d, J = 8.8 Hz, 1H), 8.93 (s, 1H). 13C NMR (CDCl3, 100 MHz): δC 21.2, 28.9, 43.7, 49.0, 112.7, 116.0, 119.1,
AC C
121.1, 122.2, 124.7, 125.4, 126.5, 132.8, 133.0, 133.5, 134.1, 134.5, 138.3, 146.7, 162.6, 200.9. IR (KBr): ν 3099, 3038, 2956, 2924, 2868, 1679, 1605, 1591, 1550, 1530, 1506, 1470, 1434, 1376, 1334, 1295, 1265, 1225, 1177, 1120, 1091, 1027, 989, 880, 858, 819, 767 cm-1. HRMS (TOF, ESI, m/z): Calcd for C21H15ClN3O [M + H] 360.0904, found 360.0901. 2-Chloro-12-methyl-12,13-dihydroimidazo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(1
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1H)-one (4q): Yield 83 % (298 mg). Pale yellow solid, m.p.: 260~262 °C; 1H NMR (CDCl3, 400 MHz): δH 1.34 (d, J = 6.4 Hz, 3H), 2.65~2.76 (m, 2H), 3.13~3.25 (m,
RI PT
2H), 3.53~3.58 (m, 1H), 7.78 (dd, J = 8.8 Hz, J’ = 2.0 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 8.44 (d, J = 9.2 Hz, 1H), 8.66 (d, J = 2.4 Hz, 1H), 8.97 (s, 1H). 13C NMR (CDCl3, 100 MHz): δC 21.2, 28.9, 43.7, 48.9, 112.8, 117.1, 121.4,
SC
122.0, 122.1, 124.5, 126.5, 130.7, 131.2, 131.8, 132.2, 132.9, 133.1, 134.4, 146.6,
162.6, 200.7. IR (KBr): ν 3092, 2956, 2926, 2871, 1676, 1591, 1537, 1505, 1483,
M AN U
1467, 1378, 1330, 1294, 1226, 1195, 1168, 1116, 1096, 1028, 970, 879, 828 cm-1. HRMS (TOF, ESI, m/z): Calcd for C21H15ClN3O [M + H] 360.0904, found 360.0897. 3-Methyl-3,4-dihydro-[1,3]dioxolo[4,5-b]imidazo[1,5,4-fg]quinolino[2,3,4-kl]acridin1(2H)-one (4r): Yield 74 % (273 mg). Pale yellow solid, m.p.: 275~277 °C; 1H NMR
TE D
(CDCl3, 400 MHz): δH 1.33 (d, J = 6.0 Hz, 3H), 2.67~2.72 (m, 2H), 3.10~3.22 (m, 2H), 3.50~3.54 (m, 1H), 6.20 (s, 2H), 7.34 (s, 1H), 7.84 (s, 1H), 8.01 (d, J = 8.8 Hz, 1H), 8.41 (d, J = 8.8 Hz, 1H), 8.79 (s, 1H). 13C NMR (CDCl3, 100 MHz): δC 21.2,
EP
28.9, 43.8, 49.0, 96.0, 102.9, 103.0, 109.5, 109.8, 112.3, 115.0, 120.3, 121.8, 126.2, 130.2, 132.6, 134.5, 145.5, 146.6, 151.6, 162.5, 200.8. IR (KBr): ν 3086, 3043, 2954,
AC C
2905, 2871, 1666, 1605, 1591, 1535, 1504, 1481, 1458, 1387, 1371, 1326, 1286, 1265, 1236, 1193, 1142, 1117, 1044, 1016, 943, 933, 870, 852, 833 cm-1. HRMS (TOF, ESI,
m/z): Calcd for C22H16N3O3 [M + H] 370.1192, found 370.1192. Acknowledgement: We are grateful to the National Natural Science Foundation of China (20802061), a project funded by the Priority Academic Program Development of Jiangsu Higher
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Education Institutions, Qing Lan Project (10QLD008, GSFM2011003) and College Industrialization Project (JHB2012-31) of Jiangsu Province for financial support.
RI PT
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