Synthesis of indolo[1,2-b]indazole derivatives via copper(I)-catalyzed intramolecular amination reaction

Article abstract of DOI:10.1080/00397910903043017

A versatile method for preparation of indolo[1,2-b]indazole derivatives was developed by using an intramolecular amination reaction of 1-aminoindoline derivatives in reaction with CuI/PHAN/K₂CO₃ (250mol%) in 1,4-dioxane at 105°C. The method provides indoles fused with indazole rings in good yields.

Full text of DOI:10.1080/00397910903043017

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Synthesis of Indolo[1,2-b]indazole
Derivatives via Copper(I)-Catalyzed
Intramolecular Amination Reaction
Jianwen Chi a , Chenchen Hang a , Yongming Zhu a & Hajime
Katayama b
a College of Pharmacy, Soochow University , Suzhou, China
b College of Pharmacy, Kinjo Gakuin University , Nagoya, Japan
Published online: 12 Mar 2010.
To cite this article: Jianwen Chi , Chenchen Hang , Yongming Zhu & Hajime Katayama (2010)
Synthesis of Indolo[1,2-b]indazole Derivatives via Copper(I)-Catalyzed Intramolecular Amination
Reaction, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 40:8, 1123-1133, DOI: 10.1080/00397910903043017
To link to this article: http://dx.doi.org/10.1080/00397910903043017
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Synthetic Communications1, 40: 1123–1133, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903043017
SYNTHESIS OF INDOLO[1,2-b]INDAZOLE
DERIVATIVES VIA COPPER(I)-CATALYZED
INTRAMOLECULAR AMINATION REACTION
Jianwen Chi,1 Chenchen Hang,1 Yongming Zhu,1 and
Hajime Katayama2
1College of Pharmacy, Soochow University, Suzhou, China
2College of Pharmacy, Kinjo Gakuin University, Nagoya, Japan
A versatile method for preparation of indolo[1,2-b]indazole derivatives was developed by
using an intramolecular amination reaction of 1-aminoindoline derivatives in reaction with
CuI/PHAN/K2CO3 (250 mol%) in 1,4-dioxane at 105 ꢀC. The method provides indoles
fused with indazole rings in good yields.
Keywords: Anticancer activity; Cu(I)-catalysis; indolo[1,2-b]indazole; intramolecular amination
The construction of substituted pyrazolo[1,5-a]indole 1 has been of long-standing
interest because pyrazolo[1,5-a]indole derivatives such as 2 (Fig. 1) have fairly
potent inhibitory activity against DNA topoisomerases I and II.[1] In this study,
the ring of E and F of 2 was crucial for activities.[2] Potential anticancer activity
of pyrazolo[1,5-a]indole derivatives prompted us to examine the activity of the
related structure 3, indolo[1,2-b]indazole, in the hope of expanding the scope of
the series of compounds. We already have reported a new method of synthesizing
indolo[1,2-b]indazole derivatives via a palladium-catalyzed intramolecular aromatic
amination reaction.[3,4] Here, we report an alternative method to construct the struc-
ture of indolo[1,2-b]indazoles via the copper(I)-catalyzed intramolecular reaction of
1-acetylamino-2-(2-bromophenyl)indulines (Scheme 1).
The starting material 4 was prepared from 2-(2-bromophenyl)indole deriva-
tives by a modification of literature procedures[5–8] and acetylated to 5 because of
the instability of the hydrazine derivative, 4. By using 5a, we investigated in detail
on the copper(I)-catalyzed intramolecuar amination in a pressure tube at elevated
temperature. The results are summarized in Table 1.
We used CuI as catalyst because it was shown to be efficient for the intermo-
lecular amination of aryl halides with amides.[9–13] Our previous reports support the
efficiency of this catalyst for an intramolecular amination reaction for the prep-
aration of 1-aryl-1H-indazole and 2-aryl-2H-indazole derivatives.[14,15] Because of
Received March 25, 2009.
Address correspondence to Yongming Zhu, College of Pharmacy, Soochow University, Suzhou
215123, China. E-mail: zhuyongming@suda.edu.cn
1123

1124
J. CHI ET AL.
Figure 1. Skeletal structure of potential anticancer agents.
Scheme 1. Synthetic route of indolo[1,2-b]indazoles.
the previous experiences, we sought to find efficient reaction conditions that could
solve the difficulties expected for steric hindrance of 5a. By using 5a, we investigated
the effects of solvents, ligands, and bases (Scheme 1). Basicity was crucial. Weak
bases such as K2CO3 provided better yield, and strong bases such as t-BuONa led
to poor yield. Effects of ligands were investigated with 1,10-phenanthroline (PHAN),
ethylenediamine (EDA), trans-1,2-cyclohexanediamine (TCHDA), and N,N0-
dimethylenediamine (DMEDA) in combination with CuI, and PHAN offered the
best result. Without ligand, the yield was moderate (65%). As the catalyst, CuBr
Table 1. Effects of the reaction conditions in the reaction of Cu(I)-catalyzed intramolecular aminationa
Solvent
Metal
Ligand
Base (250 mol %)
Yield (%)b
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Toluene
Dioxane
Dioxane
Dioxane
Dioxane
CuI
CuI
PHAN
PHAN
K2CO3
Cs2CO3
t-BuONa
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
95
88
22
68
80
71
83
52
65
<10
0
CuI
CuI
PHAN
EDA
CuI
CuI
TCHDA
DMEDA
PHAN
CuI
CuBr
CuI
PHAN
No ligand
PHAN
No ligand
No metal
No metal
aReaction conditions: A mixture of 5a (1 mmol), CuI (0.05 mmol), ligand (0.1 mmol), base (2.5 mmol),
and solvent (3 mL) in a pressure tube was heated at 110 ꢀC for 20 h.
bIsolated yields after silica gel chromatography.
Notes. PHAN, 1,10-phenanthroline; TCHDA, trans-1,2-cyclohexanediamine; EDA, ethylenediamine;
and DMEDA, N,N0-dimethylenediamine.

INDOLO[1,2-b]INDAZOLE DERIVATIVES
1125
was usable but the yield was less than that with CuI. Without copper(I) catalyst,
almost no reaction was observed. Optimal reaction conditions for the synthesis of
indolo[1,2-b]indazole were found to be a combination of CuI, PHAN, and K2CO3
in anhydrous 1,4-dioxane as a solvent.
Table 2. Synthesis of indolo[1,2-b]indazole derivatives by copper(I)-catalyzed intramolecular aminationa
Entry
1
5
7
Yield (%)b
8
Yield (%)b
95
94
2
3
4
5
86
80
90
94
97
87
95
88c
6
97
92
7
8
85
95
91
78c
aReaction conditions: A mixture of 5 (1 mmol), CuI (0.05 mmol), PHAN (0.1 mmol), K2CO3 (2.5 mmol),
and 1,4-dioxane (3 mL) was reacted in a pressure tube at 110 ꢀC for 20 h.
bYields are isolated yields after chromatography.
cTime was prolonged to 40 h.

1126
J. CHI ET AL.
Optimal reaction conditions were adapted to the preparation of methyl-,
methoxy-, chloro-, and fluoro-substituted indolo[1,2-b]indazoles, and the results
are summarized in Table 2. Virtually no obvious drop of the yields was observed
by introduction of a functional group to either ring A or D. The chloro group
was tolerable in the reaction. Hydrolysis of 7 and subsequent air oxidation of the
product 6 allowed the formation of the desired product 8 in good yield.
In summary, we have demonstrated a straightforward method for the synthesis
of indolo[1,2-b]indazole 8 from indoline derivatives 5 via copper(I)-catalyzed intra-
molecular cyclization. Intramolecular CꢁN bond formation catalyzed by CuI was
used as a key reaction to transfer 5 to 7. This method provides a readily operable
pathway for the formation of pharmacologically attractive compounds. Applications
of this method to the synthesis of potential biological active compounds are now
under way, and the results will be reported in due course.
EXPERIMENTAL
General Procedure for the Preparation of 5 from 4
A solution of 4 (1 mmol) and Ac2O (2 mmol) in CH2Cl2 (5 mL) was stirred
overnight at room temperature. The solution was neutralized using saturated
Na2CO3 and extracted three times with CH2Cl2. The organic layer was dried over
Na2SO4, and the solvent was removed under reduced pressure. The residue was pur-
ified by chromatography on silica gel with ethyl acetate=petroleum ether to provide
the desired product as a white solid.
General Procedure for the Synthesis of 7 from 5
An oven-dried resealable Schlenk tube was charged with CuI (10 mg,
0.05 mmol, 5 mol%), 1,10-phenanthroline (18 mg, 0.1 mmol, 10 mol%), K2CO3
(345 mg, 2.5 mmol), and 1-acetylamino-2-(2-bromophenyl)indoline 5 (1.0 mmol),
then evacuated and backfilled with argon. Anhydrous 1,4-dioxane (3 mL) was added
under argon. The Schlenk tube was sealed, and the reaction mixture was stirred at
110 ꢀC for 20 h. The resulting suspension was cooled to room temperature and
filtered through a pad of silica gel, eluting with ethyl acetate. The filtrate was concen-
trated. Purification of the residue by chromatography on silica gel with ethyl acetate=
petroleum ether provided the product 7 as a white solid.
General Procedure for the Synthesis of 8
NaOH (5 mol=L, 1.5 mL) was added to a solution of 7 (0.5 mmol) in MeOH
(8 mL) and the mixture was heated to 70 ꢀC for 30 min under a nitrogen atmosphere.
The reaction mixture was poured into ice water (20 g), and the suspension was
extracted with CH2Cl2 (25 mL ꢂ 3). The organic layer was washed with brine
(30 mL ꢂ 3) and dried over Na2SO4. The solution was left stirring at room tempera-
ture overnight to complete air oxidation. After filtration, the filtrate was concen-
trated, and the residual crude product was purified by chromatography on silica
gel with ethyl acetate=petroleum ether to provide the product 8 as white crystals.

INDOLO[1,2-b]INDAZOLE DERIVATIVES
1127
SPECTRAL DATA
1-Acetylamino-2-(2-bromophenyl)indoline 5a
White solid (EtOAc); mp 186.5–187.8 ꢀC; IR (KBr) cmꢁ1: 3229, 1667, 1488,
1254, 1023, 762. 1H NMR (400 MHz, DMSO-d6) d: 1.81 (s, 3H), 2.55 (dd,
J ¼ 15.6, 11.5 Hz, 1H), 3.62 (dd, J ¼ 14.9, 9.1 Hz, 1H), 5.26 (s, 1H), 6.57 (d,
J ¼ 7.1 Hz, 1H), 6.8 (d, J ¼ 6.7 Hz, 1H), 7.11 (s, 1H), 7.24 (m, 1H), 7.41 (t,
J ¼ 7.21 Hz, 1H), 7.62 (d, J ¼ 7.8 Hz, 1H), 7.91 (d, J ¼ 4.6 Hz, 1H), 9.76 (s, 1H).
13C NMR (400 MHz, DMSO-d6) d: 20.9, 35.7, 69.6, 109.3, 120.5, 122.7, 124.5,
125.4, 127.4, 128.2, 128.5, 129.3, 132.6, 140.7, 151.2, 168.6. HRMS: calcd. for
C16H15 79BrN2O: 330.0368; found: 330.0375.
6-Acetyl-10b,11-dihydro-6H-indolo[1,2-b]indazole 7a
White crystals (EtOAc); mp 130.3–132.1 ꢀC; IR (KBr) cmꢁ1: 1662, 1596, 1482,
1
1465, 1392, 1318, 1278, 757; H NMR (400 MHz, CDCl3) d: 2.57 (s, 3H), 3.45 (d,
J ¼ 15.6 Hz, 1H), 3.55 (dd, J ¼ 15.6, 8.1 Hz, 1H), 5.27 (d, J ¼ 7.9 Hz, 1H),
6.93–7.41 (m, 7H), 7.76 (d, J ¼ 7.6 Hz, 1H). 13C NMR (400 MHz, CDCl3) d:
20.93, 35.69, 69.61, 109.31, 120.52, 122.68, 124.53, 125.39, 127.44, 128.17, 128.49,
129.32, 132.62, 140.67, 151.22, 168.58. HRMS: calcd. for C16H14N2O: 250.1106;
found: 250.1103.
11H-Indolo[1,2-b]indazole 8a
Yellow crystals (EtOAc); mp 168.7–170.3 ꢀC; IR (KBr) cmꢁ1 2928, 1716, 1635,
1
1519, 1472, 1398, 1370, 739.1. H NMR (400 MHz, CDCl3) d: 4.11 (s, 2H), 7.11 (t,
J ¼ 7.1 Hz, 1H), 7.32 (t, J ¼ 8.1 Hz, 2H), 7.48 (t, J ¼ 7.3 Hz, 1H), 7.56 (d, J ¼ 7.2 Hz,
1H), 7.69 (d, J ¼ 8.4 Hz, 1H), 7.79 (d, J ¼ 8.8 Hz, 1H), 7.88 (d, J ¼ 7.6 Hz, 1H), 13C
NMR (400 MHz, CDCl3) d: 29.14, 112.62, 117.43, 118.71, 120.09, 122.02, 126.10,
126.49, 126.93, 128.76, 134.95, 137.76, 140.91, 153.51. HRMS: calcd. for
C14H10N2: 206.0844; found: 206.0853.
1-Acetylamino-5-methyl-2-(2-bromophenyl)indoline 5b
White solid (EtOAc); mp 185.8–188.1 ꢀC, IR (KBr) cmꢁ1: 566, 597, 762, 1023,
1
1253, 1369, 1487, 1542, 1662, 3228; H NMR (400 MHz, DMSO-d6) d: 1.86 (s, 3H),
2.22 (s, 3H), 2.72 (d, J ¼ 16.0 Hz, 1H), 3.78 (dd, J ¼ 10.1, 16.3 Hz, 1H), 5.76 (d,
J ¼ 9.7 Hz, 1H), 6.89 (d, J ¼ 7.6 Hz, 1H), 6.98 (s, 1H), 7.03 (d, J ¼ 8.2 Hz, 1H),
7.29 (t, J ¼ 7.3, 7.3 Hz, 1H), 7.22 (dd, J ¼ 6.3, 7.5 Hz, 1H), 7.69 (d, J ¼ 7.6 Hz,
1H), 8.04 (d, J ¼ 8.2 Hz, 1H), 9.87 (s, 1H). 13C NMR (400 MHz, DMSO-d6) d:
20.93, 23.34, 35.60, 109.28, 120.47, 124.52, 125.22, 125.36, 125.79, 127.41, 127.68,
129.99, 137.98, 141.16, 151.26, 168.39, 168.47. HRMS: calcd. for C17H17 79BrN2O:
344.0524; found: 344.0530.
6-Acetyl-2-methyl-10b,11-dihydro-6H-indolo[1,2-b]indazole 7b
White crystals (EtOAc); mp 136.8–128.5 ꢀC, IR (KBr) cmꢁ1: 1667, 1475, 1388,
1
749, 593, 566; H NMR (400 MHz, CDCl3) d: 2.25 (s, 3H), 2.57 (s, 3H), 3.41 (d,

1128
J. CHI ET AL.
J ¼ 15.5 Hz, 1H), 3.52 (dd, J ¼ 15.6, 8.1 Hz, 1H), 5.26 (d, J ¼ 8.0 Hz, 1H), 6.84–7.31
(m, 6H), 7.76 (d, J ¼ 7.6 Hz, 1H). 13C NMR (400 MHz, CDCl3) d: 21.37, 23.16,
33.81, 68.23, 114.55, 118.31, 122.59, 125.55, 126.14, 128.72, 129.03, 129.12, 134.16,
134.63, 139.53, 149.21, 171.72. HRMS: calcd. for C17H16N2O: 264.1263; found:
264.1263.
2-Methyl-11H-indolo[1,2-b]indazole 8b
White crystals (EtOAc); mp 195.7–197.3 ꢀC; IR (KBr) cmꢁ1: 3041, 2901, 1670,
1486, 1364, 1157, 818, 734. 1H NMR (400 MHz, CDCl3) d: 2.44 (s, 3H), 4.08 (s, 2H),
7.11 (t, J ¼ 15.1, 7.3 Hz, 1H), 7.19–7.44 (m, 3H), 7.69 (d, J ¼ 8.4 Hz, 1H), 7.79 (dd,
J ¼ 12.1, 8.0 Hz, 2H). 13C NMR (400 MHz, CDCl3) d: 21.91, 28.99, 112.19,
117.52, 118.71, 119.97, 121.89, 125.55, 126.68, 127.21, 135.17, 136.51, 137.49,
138.84, 153.43. HRMS: calcd. for C15H12N2: 220.1000; found: 220.1002.
1-Acetylamino-5-methoxy-2-(2-bromophenyl)indoline 5c
White solid (EtOAc); mp 196.8–198.2 ꢀC; IR (KBr) cmꢁ1: 3201, 2846, 1659,
1
1477, 1296, 1246, 1116, 1212, 809, 757. H NMR (400 MHz, DMSO-d6) d: 1.82 (s,
3H), 2.27 (dd, J ¼ 11.7, 15.5 Hz, 1H), 3.62 (dd, J ¼ 8.9, 16.1 Hz, 1H), 3.59 (s, 3H),
5.13 (s, 1H), 6.44 (d, J ¼ 8.2 Hz, 1H), 7.01 (td, J ¼ 4.7, 4.7, 9.1 Hz, 2H), 7.12–7.47
(m, 3H), 7.58 (s, 1H), 9.77 (s, 1H); 13C NMR (400 MHz, DMSO-d6) d: 20.01,
35.49, 55.43, 61.36, 108.43, 109.56, 112.67, 114.56, 118.84, 122.72, 126.68, 127.55,
131.87, 146.64, 151.23, 155.09, 168.66. HRMS: calcd. for C17H17 79BrN2O2:
360.0473; found: 360.0473.
6-Acetyl-2-methoxy-10b,11-dihydro-6H-indolo[1,2-b]indazole 7c
White crystals (EtOAc); mp 137.3–138.7 ꢀC; IR (KBr) cmꢁ1: 1624, 1596, 1482,
1
1389, 1283, 1266, 1024, 810, 775, 726; H NMR (400 MHz, CDCl3) d: 2.54 (s, 3H),
3.41 (d, J ¼ 15.6 Hz, 1H), 3.53 (dd, J ¼ 8.1, 15.6 Hz, 1H), 3.72 (s, 3H), 5.25 (d,
J ¼ 7.9 Hz, 1H), 6.74 (d, J ¼ 10.9 Hz, 2H), 6.99 (m, 2H), 7.65 (d, J ¼ 8.3 Hz, 2H),
7.15 (t, J ¼ 7.07, 7.07 Hz, 1H); 13C NMR (400 MHz, CDCl3) d: 22.77, 33.68,
55.89, 68.53, 109.17, 112.96, 115.35, 118.04, 124.83, 125.41, 128.23, 128.59, 134.28,
136.05, 151.64, 158.02, 171.36. HRMS: calcd. for C17H17N2O2: 280.1212; found:
280.1201.
2-Methoxy-11H-indolo[1,2-b]indazole 8c
Yellow solid (EtOAc); mp 210.3–211.8 ꢀC; IR (KBr) cmꢁ1: 3063, 1603, 1634,
1
1485, 1435, 1264, 1246, 825, 742; H NMR (400 MHz, CDCl3) d: 3.88 (s, 3H),
4.13 (s, 2H), 7.01 (dd, J ¼ 2.3, 8.6 Hz, 1H), 7.11 (t, J ¼ 7.6, 7.6, 7.6 Hz, 1H), 7.16
(d, J ¼ 2.1 Hz, 1H), 7.31 (ddd, J ¼ 1.1, 6.7, 8.8 Hz, 1H), 7.70 (d, J ¼ 8.4 Hz, 1H),
7.80 (d, J ¼ 8.9 Hz, 1H), 7.81 (d, J ¼ 8.9 Hz, 1H); 13C NMR (400 MHz, CDCl3) d:
28.91, 55.88, 112.64, 112.83, 113.12, 115.5, 117.34, 118.28, 119.34, 126.11, 126.07,
134.56, 136.34, 152.98, 158.58. HRMS: calcd. for C15H12N2O: 236.0950; found:
236.0925.

INDOLO[1,2-b]INDAZOLE DERIVATIVES
1129
1-Acetylamino-5-fluoro-2-(2-bromophenyl)indoline 5d
White solid (EtOAc); mp 170.5–171.9 ꢀC; IR (KBr) cmꢁ1: 3235, 2923, 1662,
1
1541, 1481, 1236, 1026, 761; H NMR (400 MHz, DMSO-d6) d: 1.81 (s, 3H), 2.57
(dd, J ¼ 11.6, 15.6 Hz, 1H), 3.63 (dd, J ¼ 8.8, 15.9 Hz, 1H), 5.28 (s, 1H), 6.54 (dd,
J ¼ 8.4, 12.8 Hz, 1H), 6.91–7.63 (m, 5H), 7.89 (d, J ¼ 7.1 Hz, 1H), 9.78 (s, 1H); 13C
NMR (400 MHz, DMSO-d6) d: 20.92, 35.45, 69.98, 109.82, 122.61, 127.31, 128.17,
128.52, 129.38, 132.62, 140.36, 147.52, 155.83, 158.94, 168.47, 168.55. HRMS: calcd.
for C16H14 79BrFN2O: 348.0274; found: 348.0270.
6-Acetyl-2-fluoro-10b,11-dihydro-6H-indolo[1,2-b]indazole 7d
White crystals (EtOAc); mp 174.3–175.6 ꢀC, IR (KBr) cmꢁ1: 1681, 1483, 1381,
1
1343, 1244, 1178, 1127, 760; H NMR (400 MHz, CDCl3) d: 2.55 (s, 3H), 3.44 (d,
J ¼ 15.8 Hz, 1H), 3.54 (dd, J ¼ 8.1, 15.8 Hz, 1H), 5.29 (d, J ¼ 8.1 Hz, 1H), 6.85 (t,
J ¼ 7.6, 7.6 Hz, 2H), 6.93 (dd, J ¼ 4.4, 9.5 Hz, 1H), 7.12 (t, J ¼ 7.3, 7.3 Hz, 1H),
7.25 (m, 2H), 7.76 (d, J ¼ 7.7 Hz, 1H); 13C NMR (400 MHz, CDCl3) d: 23.16,
33.81, 68.23, 114.55, 118.31, 122.59, 125.55, 126.14, 128.72, 129.03, 129.12, 134.16,
134.63, 139.53, 149.21, 171.72; HRMS: calcd. for C16H13FN2O: 268.1012; found:
268.1013.
2-Fluoro-11H-indolo[1,2-b]indazole 8d
White crystals (EtOAc); mp 124.5–126.8 ꢀC; IR (KBr) cmꢁ1: 3273, 2924, 1481,
1
1445, 1273, 1228, 757, 733. H NMR (400 MHz, CDCl3) d: 4.03 (s, 2H), 6.93–7.32
(m, 6H), 7.62 (d, J ¼ 8.4 Hz, 1H). 13C NMR (400 MHz, CDCl3) d: 29.16, 113.19,
114.61, 117.23, 118.65, 119.85, 122.09, 122.88, 124.21, 126.87, 129.02, 130.13,
135.02, 147.64; HRMS: calcd. for C14H9FN2: 224.0750; found: 224.0750.
1-Acetylamino-5-chloro-2-(2-bromophenyl)indoline 5e
Yellow solid (EtOAc); mp 185.3–187.1 ꢀC, IR (KBr) cmꢁ1: 3073, 2927, 1645,
1
1602, 1463, 1390, 1267, 1217, 1172, 1030, 811, 751; H NMR (400 MHz, DMSO-
d6) d: 1.88 (s, 3H), 2.61 (d, J ¼ 16.6 Hz, 1H), 3.75 (dd, J ¼ 10.2, 16.6 Hz, 1H), 5.34
(s, 1H), 6.93 (d, J ¼ 7.4 Hz, 1H), 7.06 (t, J ¼ 8.3, 8.3 Hz, 2H), 7.29 (td, J ¼ 7.1, 7.1,
31.6 Hz, 2H), 7.71 (d, J ¼ 7.8 Hz, 1H), 8.15 (dd, J ¼ 5.2, 8.6 Hz, 1H), 9.60 (s, 1H);
13C NMR (400 MHz, DMSO-d6) d: 23.19, 37.11, 62.64, 113.77, 116.99, 120.80,
125.48, 128.59, 129.75, 131.80, 133.39, 139.55, 141.38, 157.19, 160.37, 168.48.
HRMS: calcd. for C16H14 79Br35ClN2O: 363.9978; found: 363.9970.
6-Acetyl-2-chloro-10b,11-dihydro-6H-indolo[1,2-b]indazole 7e
Yellow crystals (EtOAc); mp 166.8–171.2 ꢀC; IR (KBr) cmꢁ1: 1592, 1480, 1350,
1
1285, 1224, 1173, 1040, 812, 742; H NMR (400 MHz, CDCl3) d: 2.43 (s, 3H), 3.35
(d, J ¼ 15.6 Hz, 1H), 3.46 (dd, J ¼ 8.7, 15.8 Hz, 1H), 5.32 (d, J ¼ 8.5 Hz, 1H), 6.95 (d,
J ¼ 7.8 Hz, 1H), 7.01 (d, J ¼ 7.6 Hz, 1H), 7.06–7.21 (m, 3H), 7.21 (d, J ¼ 7.1 Hz, 1H),
7.45 (d, J ¼ 14.9, 1H), 7.51–7.68 (m, 1H); 13C NMR (400 MHz, CDCl3) d: 23.09,

1130
J. CHI ET AL.
38.13, 62.91, 109.70, 113.36, 115.01, 119.66, 125.14, 127.98, 128.15, 133.73, 144.76,
150.80, 159.62, 167.44, 173.45. HRMS: calcd. for C16H13 35ClN2O: 284.0716; found:
284.0721.
2-Chloro-11H-indolo[1,2-b]indazole 8e
Mp 145.2–146.8 ꢀC; IR (KBr) cmꢁ1: 1601, 1517, 1474, 1445, 1409, 1372, 1272,
1228, 816, 732. 1H NMR (400 MHz, CDCl3) d: 4.07 (s, 2H), 7.11 (t, J ¼ 9.2, 18.5 Hz,
1H), 7.25 (d, J ¼ 10.3 Hz, 1H), 7.32 (t, J ¼ 7.5, 15.0 Hz, 1H), 7.48 (t, J ¼ 7.7, 15.3 Hz,
1H), 7.55 (d, J ¼ 7.4 Hz, 1H), 7.75 (dd, J ¼ 4.5, 9.3 Hz, 1H), 7.86 (d, J ¼ 7.8 Hz, 1H);
13C NMR (400 MHz, CDCl3) d: 28.96, 112.56, 116.63, 117.98, 118.26, 120.62,
126.51, 128.79, 134.87, 137.71, 140.73, 145.61, 150.75, 157.38. HRMS: calcd. for
C14H9 35ClN2: 240.0454; found: 240.0458.
1-Acetylamino-2-(2-bromo-5-fluorophenyl)indoline 5f
White solid (EtOAc); mp 206.8–208.7 ꢀC; IR (KBr) cmꢁ1: 3264, 1661, 1541,
1
1469, 1370, 1296, 1263, 1156, 1107, 1024, 748; H NMR (400 MHz, DMSO-d6) d:
1.82 (s, 3H), 2.59 (dd, J ¼ 11.7, 15.4 Hz, 1H), 3.64 (dd, J ¼ 8.8, 15.6 Hz, 1H), 5.18
(s, 1H), 6.58 (d, J ¼ 8.1 Hz, 1H), 6.83 (t, J ¼ 7.35, 7.35 Hz, 1H), 7.14 (m, 3H), 7.69
(m, 2H), 9.81 (s, 1H); 13C NMR (400 MHz, DMSO-d6) d: 20.93, 35.33, 59.89,
109.50, 120.83, 124.62, 125.32, 127.55, 134.32, 134.43, 143.32, 143.41, 150.98,
160.21, 163.45, 168.68. HRMS: calcd. for C16H14 79BrFN2O: 348.0274; found:
348.0276.
6-Acetyl-9-fluoro-10b,11-dihydro-6H-indolo[1,2-b]indazole 7f
White crystals (EtOAc); mp 136.2–137.3 ꢀC; IR (KBr) cmꢁ1: 1672, 1475, 1384,
1
1351, 1254, 1156, 1109, 780. H NMR (400 MHz, CDCl3) d: 2.57 (s, 3H), 3.43 (d,
J ¼ 15.6 Hz, 1H), 3.56 (dd, J ¼ 8.3, 15.7 Hz, 1H), 5.27 (d, J ¼ 8.3 Hz, 1H), 6.99 (m,
4H), 7.21 (dd, J ¼ 12.6, 19.8 Hz, 2H), 7.70 (dd, J ¼ 12.6, 19.8 Hz, 1H); 13C NMR
(400 MHz, CDCl3) d: 22.82, 33.69, 67.99, 109.92, 114.77, 115.47, 115.78, 119.38,
125.12, 125.58, 128.46, 135.68, 151.32, 159.19, 162.43, 171.76. HRMS: calcd. for
C16H13FN2O: 268.1012; found: 268.1012.
9-Fluoro-11H-indolo[1,2-b]indazole 8f
Yellow solid (EtOAc); mp 187.2–188.4 ꢀC; IR (KBr) cmꢁ1: 3066, 2918, 1646,
1
1525, 1473, 1298, 1170, 754. H NMR (400 MHz, CDCl3) d: 4.08 (s, 1H), 7.09 (dt,
J ¼ 2.4, 9.3, 9.3 Hz, 1H), 7.25 (m, 1H), 7.33 (t, J ¼ 7.5, 7.5 Hz, 1H), 7.52 (m, 2H),
7.79 (m, 2H); 13C NMR (400 MHz, CDCl3) d: 28.97, 112.58, 117.95, 118.33,
120.54, 120.67, 126.72, 128.81, 134.89, 137.64, 140.74, 150.77, 156.99, 160.17.
HRMS: calcd. for C14H9FN2: 224.0750; found: 224.0752.
1-Acetylamino-2-(2-bromo-5-methoxyphenyl)indoline 5g
White solid (EtOAc); mp 179.8–180.7 ꢀC; IR (KBr) cmꢁ1: 3031, 2840, 1598,
1
1478, 1367, 1240, 1128, 1012, 757; H NMR (400 MHz, DMSO-d6) d: 1.83 (s, 3H),

INDOLO[1,2-b]INDAZOLE DERIVATIVES
1131
2.56 (dd, J ¼ 12.4, 16.0 Hz, 1H), 3.60 (dd, J ¼ 8.6, 15.5 Hz, 1H), 3.76 (s, 3H), 5.12 (s,
1H), 6.58 (d, J ¼ 7.9 Hz, 1H), 6.82 (dd, J ¼ 4.6, 13.1 Hz, 2H), 7.12 (td, J ¼ 3.7, 3.7,
7.1 Hz, 2H), 7.49 (d, J ¼ 8.8 Hz, 1H), 7.57 (d, J ¼ 1.5 Hz, 1H), 9.76 (s, 1H); 13C
NMR (400 MHz, DMSO-d6) d: 20.99, 35.48, 55.42, 59.93, 109.60, 112.52, 113.43,
115.67, 120.82, 124.64, 125.53, 127.55, 133.33, 141.68, 151.23, 159.15, 168.63.
HRMS: calcd. for C17H17 79BrN2O2: 360.0473; found: 360.0478.
6-Acetyl-9-methoxy-10b,11-dihydro-6H-indolo[1,2-b]indazole 7g
White solid (EtOAc); mp 137.3–138.6 ꢀC; IR (KBr) cmꢁ1: 1664, 1482, 1437,
1
1389, 1327, 1281, 1154, 868, 774; H NMR (400 MHz, CDCl3) d: 2.55 (s, 3H),
3.42 (d, J ¼ 15.6 Hz, 1H), 3.52 (dd, J ¼ 8.2, 15.7 Hz, 1H), 3.73 (s, 3H), 5.23 (d,
J ¼ 8.0 Hz, 1H), 6.75 (m, 2H), 7.00 (dd, J ¼ 5.1, 7.9 Hz, 2H), 7.16 (t, J ¼ 6.9,
6.9 Hz, 2H), 7.66 (d, J ¼ 8.3 Hz, 1H). 13C NMR (400 MHz, CDCl3) d: 22.86,
33.67, 56.09, 68.06, 108.82, 113.49, 114.67, 118.86, 124.86, 125.49, 128.28, 128.39,
133.15, 135.78, 151.56, 157.93, 171.47. HRMS: calcd. for C17H16N2O2: 280.1212;
found: 280.1213.
9-Methoxy-11H-indolo[1,2-b]indazole 8g
Yellow solid (EtOAc); mp 199.5–201.1 ꢀC; IR (KBr) cmꢁ1: 2999, 1641, 1462,
1
1348, 1217, 1020, 809, 754. H NMR (400 MHz, CDCl3) d: 3.87 (s, 3H), 4.08 (s,
2H), 7.00 (dd, J ¼ 7.1, 21.2 Hz, 2H), 7.30 (dd, J ¼ 8.3, 15.9 Hz, 1H), 7.40–7.78 (m,
3H), 7.85 (d, J ¼ 7.7 Hz, 1H); 13C NMR (400 MHz, CDCl3) d: 28.86, 55.82, 96.53,
112.27, 117.15, 120.03, 121.49, 121.68, 126.18, 128.70, 134.88, 136.64, 140.98,
150.19, 155.34. HRMS: calcd. for C15H12N2O: 236.0950; found: 236.0954.
1-Acetylamino-2-(2-bromo-3-methylphenyl)indoline 5h
Mp 188.7–191.3 ꢀC; IR (KBr) cmꢁ1: 3191, 3049, 1666, 1545, 1475, 1373, 1248,
1
1255, 1020, 781, 760; H NMR (400 MHz, DMSO-d6) d: 1.81 (s, 3H), 2.54 (dd,
J ¼ 9.6, 13.6 Hz, 1H), 3.66 (dd, J ¼ 8.9, 15.6 Hz, 1H), 5.33 (s, 1H), 6.56 (d, J ¼ 7.9 Hz,
1H), 6.81 (t, J ¼ 7.3, 7.3 Hz, 1H), 7.04–7.40 (m, 4H), 7.73 (d, J ¼ 5.9 Hz, 1H), 9.72 (s,
1H); 13C NMR (400 MHz, DMSO-d6) d: 20.79, 23.11, 35.52, 70.00, 109.05, 120.31,
124.36, 125.06, 125.23, 125.69, 127.25, 127.49, 129.82, 137.81, 141.11, 151.14,
168.29. HRMS: calcd. for C17H17 79BrN2O: 344.0524, found: 344.0513.
6-Acetyl-7-methyl-10b,11-dihydro-6H-indolo[1,2-b]indazole 7h
Mp 171.7–173.8 ꢀC, IR (KBr) cmꢁ1: 1691, 1593, 1477, 1368, 1309, 1253, 1108,
1
1024, 820, 761; H NMR (400 MHz, CDCl3) d: 2.31 (s, 3H), 2.56 (s, 3H), 3.36 (d,
J ¼ 15.6 Hz, 1H), 3.48 (dd, J ¼ 8.3, 15.6 Hz, 1H), 5.23 (d, J ¼ 8.1 Hz, 1H), 6.97 (t,
J ¼ 7.3, 7.3 Hz, 1H), 7.01–7.07 (m, 3H), 7.10 (dd, J ¼ 7.6, 13.4 Hz, 2H), 7.16 (t,
J ¼ 7.6, 7.6 Hz, 1H); 13C NMR (400 MHz, CDCl3) d: 20.48, 23.51, 33.99, 68.34,
114.61, 119.84, 124.44, 125.48, 126.69, 128.23, 129.77, 131.05, 136.26, 139.90,
151.50, 153.98, 175.10. HRMS: calcd. for C17H16N2O: 264.1263; found: 264.1266.

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J. CHI ET AL.
7-Methyl-11H-indolo[1,2-b]indazole 8h
Mp 111.6–112.2 ꢀC; IR (KBr) cmꢁ1: 2904, 1690, 1616, 1475, 1363, 1146, 831,
1
753; H NMR (400 MHz, CDCl3) d: 2.70 (s, 3H), 3.99 (s, 2H), 6.98 (dd, J ¼ 6.9,
8.4 Hz, 1H), 7.05 (d, J ¼ 6.8, 1H), 7.25 (dd, J ¼ 6.8, 14.3 Hz, 1H), 7.40–7.52 (m,
3H), 7.91 (d, J ¼ 7.8 Hz, 1H). 13C NMR (400 MHz, CDCl3) d: 17.83, 28.91 112.58,
117.08, 117.40, 122.07, 125.92, 126.17, 126.31, 128.49, 128.67, 134.89, 137.94,
141.00, 153.82. HRMS: calcd. for C15H12N2: 220.1000; found: 220.1000.
ACKNOWLEDGMENTS
This work was partially supported by the National Natural Science
Foundation of China (Grants 20472062 and 20672079) and the Natural Science
Foundation of Jiangsu Province (No. BK2006048).
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