Facile synthesis of novel indeno[1,2-b]indol-10-one derivatives by the oxidation with DDQ

Article abstract of DOI:10.1081/SCC-200049795

The synthesis of indeno[1,2-b]indol-10-one analogues with a wide range of biological activities was described. They are also important intermediates of some selective estrogen receptor modulators (SERMs).

Full text of DOI:10.1081/SCC-200049795

Synthetic Communicationsw, 35: 581–588, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200049795
Facile Synthesis of Novel
Indeno[1,2-b]indol-10-one
Derivatives by the Oxidation with DDQ
Jun-Bo Wang, Qing-Gang Ji, Jing Xu, Xi-Han Wu,
and Yu-Yuan Xie
State Key Lab of Drug Research, Shanghai Institute of Materia Medica,
SIBS, CAS, Shanghai, P.R. China
Abstract: The synthesis of indeno[1,2-b]indol-10-one analogues with a wide range of
biological activities was described. They are also important intermediates of some
selective estrogen receptor modulators (SERMs).
Keywords: 5,10-dihydroindeno[1,2-b]indole, Indeno[1,2-b]indol-10(5H)-one, oxida-
tion, DDQ
Radical processes play an important role in many commondiseases. Free radical-
derived reactive oxygen species are constantly generated in a living system and
giverisetothe damage ofDNA, proteins, and lipids, which leadtothe occurrence
of numerous degenerative or chronic diseases. So much effort is currently in
progress to synthesize the antioxidants with different structures. Indeno
[1,2-b]indoles and Indeno[1,2-b]indole-10-ones are among the most potent
nontoxic antioxidants known.[1] What’s more, they also act as membrane
stabilizing agents[2] and protect against chemical mediated hepatotoxicity,
etc.[3,4] They are also the key intermediates of some selective estrogen
receptor modulators.[5,6]
Received in the UK 1 September 2004
Address correspondence to Xi-Han Wu, State Key Lab of Drug Research, Shanghai
Institute of Materia Medica, SIBS, CAS, Shanghai 201203, P.R. China. Tel.: 8621-
54920507. E-mail: xhwu@mail.shcnc.ac.cn

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J. Wang et al.
In view of the potential applications of these compounds, we were inter-
ested in the synthesis of indeno[1,2-b]indol-10-one derivatives.
Indeno[1,2-b]indol-10-ones have previously been obtained by complex or
specific synthetic sequences in only poor to moderate yields.[7,8] Besides, there
is no report on the synthesis of indeno[1,2-b]indol-10-ones with substituting
groups at 2- or 3- position. We now describe the synthesis of these families
from the readily available materials through a shot route.
Indeno[1,2-b]indol-10-ones were obtained as a result of a three-step
procedure shown in Scheme 1.
The starting compounds 1a, b, c were prepared by a literature
procedure.[9] The building of the indenoindole cycle was accomplished
through Fischer indole synthesis. First, the hydrazones 3a, b c were
prepared in high yields catalyzed by small amount of acetic acid. Second,
the indenoindoles 4a, b, c were obtained by the intramolecular cyclization
Scheme 1.

New Method to Indeno[1,2-b]indole-10-one Derivatives
583
of 3a, b c in the presence of Lewis acid (ZnCl2) at reflux temperature in
moderate yields.
In the last step of the synthesis, the formation of carbonyl group was
accomplished by the oxidation of DDQ at 08C in the solvent system THF/
H2O(9/1). The carbonyl band was observed in the IR spectra of these
compounds. The oxidation reaction utilizing SeO2 was not successful.
The method described in this article is quite convenient for the synthesis
of indeno[1,2-b]indol-10-ones substituted at 2-, 3-,7- or 8-position. These
compounds are interesting with their potential pharmacological activities or
as important intermediates in the synthesis of some SERMs for the prevention
of postmenopausal syndromes.
EXPERIMENTAL
Melting points were determined on Fisher-Johns Melting Point Apparatus and
are uncorrected. The 1HNMR spectra were taken on a Mercury-400 (400 Mz)
with TMS as internal standard; the values of chemical shifts (d) are given in
ppm and coupling constants (J ) in Hz. The IR spectra were recorded on a
Nicolet Magna FTIR-750 spectrometer. The course of the reactions was
monitored by TLC on silica gel plates (Merck, GF254) using petroleum
ether/ethyl acetate (1 : 10) solvent system for compounds 4 and petroleum
ether/ethyl acetate (1 : 4) solvent system for compounds 5. Mass spectra
were obtained on MAT-95 (EI-70 ev).
General Synthetic Method
Step 1. 5-Methoxy-1-Indanone (4-phenyl)-hydrazone (3a)
To a solution of phenylhydrazine (5 g, 47 mmol) and 5-methoxy indanone
(8.1 g, 50 mmol) in ethanol (100 mL) was added a few drops of acetic acid.
The mixture was refluxed for 1.5 h. The reaction mixture was then cooled
and a solid precipitated out. The solid was filtered to give an pale yellow
solid. Yield: 10 g, (84.7%). M.p.: 109–118C.
1HNMR (400 MHz, DMSO-d6) d 2.81 (t, 2H, J ¼ 6.8 Hz, CH2),
3.06 (t, 2H, J ¼ 6.8 Hz, CH2), 3.79 (s, 3H, OCH3), 6.69 (dd, 1H, J ¼ 4,
6 Hz, ArH), 6.85 (dd, 1H, J ¼ 2.4, 8.4 Hz, ArH), 6.90 (s, 1H, ArH), 7.15–7.20
(m, 4H, ArH), 7.55 (d, 1H, J ¼ 8.4 Hz, ArH).
Step 2. 5,10-Dihydro-2-methoxyindeno[1,2-b]indole (4a)
A mixture of 5-methoxy-1-indanone (4-phenyl)-hydrazone (from previous
step) (1.2 g, 4.8 mmol) and ZnCl2 (1.5 g, 11 mmol) in AcOH (15 mL) was

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J. Wang et al.
heated to 1208C for 2 h. The mixture was then poured into water, extracted
with ethyl acetate. The organic phase was dried with MgSO4 and concen-
trated. The product was purified by flash chromatography (ethyl acetate/
petroleum, 1/12) to give a white solid. Yield: 0.95 g, (89.9%). M.p.: 190–58C.
1HNMR (400 MHz, CDCl3) d 4.35 (s, 2H, CH2), 4.48 (s, 3H, OCH3),
6.94 (dd, 1H, J ¼ 2, 6.8 Hz, ArH), 7.16 (dd, 3H, J ¼ 2.8, 4.8 Hz, ArH),
7.34 (d, 1H, J ¼ 2.8 Hz, ArH), 7.38 (m, 1H, ArH), 7.53 (dd, 1H, J ¼ 2.8,
4.8 Hz, ArH). MS (EI): m/e (%) 235 (100 Mþ), 220 (100), 191 (60).
Step 3. 2-Methoxyindeno[1,2-b]indol-10(5H)-one (5a)
To a solution of 5,10-dihydro-2-methoxyindeno [1,2-b]indole (521 mg,
2.2 mmol) in THF/H2O (40 mL, 9/1) at 2108C under the atmosphere of
Ar2 was added a solution of 2,3-Dichloro-5,6-dicyanobenzoquinone (DDQ)
(1 g, 4.4 mmol) in THF (2 mL). The reaction mixture was allowed to warm
to room temperature over a period of 2.5 h and then concentrated under
reduced pressure, followed by the addition of EtOAc. The organic layer was
washed with aqueous Na2CO3 (saturated, 3 ꢀ 20 mL) and brine
(2 ꢀ 20 mL), dried (Na2SO4), and the solvent was removed. The product
was purified by flash chromatography (ethyl acetate/petroleum, 1/5) to give
a red solid. Yield: 200 mg, (36.2%). M.p.: 210–28C.
1HNMR (400 MHz, DMSO-d6) d 3.82 (s, 3H, OCH3), 6.85 (dd, 1H,
J ¼ 2.4, 8 Hz, ArH), 6.93 (d, 1H, J ¼ 6 Hz, ArH), 7.12 (m, 2H, ArH),
7.21 (d, 1H, J ¼ 8 Hz, ArH), 7.42 (dd, 1H, J ¼ 2, 7.6 Hz, ArH),
7.53 (d, 1H, J ¼ 2 Hz, ArH). 13C-NMR (DMSO-d6) d 184.3, 162.9, 156.7,
156.5, 141.5, 141.3, 136.8, 132.5, 124.1, 122.8, 119.2, 115.2, 113.6, 111.1,
107.8 and 55.6. IR spectra: 3220 (NH), 1668 (CO). MS (EI): m/e 249 (100
Mþ), 234 (60), 206 (18), 178 (20).
6-Methoxy-1-indanone(4-phenyl)-hydrazone (3b)
Yield: 10.5 g, (88.7%), straw yellow solid. M.p.: 140-28C. 1HNMR (400 MHz,
DMSO-d6) d 2.81 (t, 2H, J ¼ 6.7 Hz, CH2), 3.0 (t, 2H, J ¼ 6.9 Hz, CH2),
3.79 (s, 3H, OCH3), 6.73 (dd, 1H, J ¼ 4.4, 8.4 Hz, ArH), 6.83 (dd, 1H,
J ¼ 2.6 Hz, ArH), 7.13 (d, 1H, J ¼ 2.5 Hz, ArH), 7.20–7.23 (m, 5H, ArH),
9.05 (s, 1H, NH).
5,10-Dihydro-3-methoxyindeno[1,2-b]indole (4b)
1
Yield: 2.2 g, (76.7%), pale green solid. M.p.: 213-58C. HNMR (400 MHz,
DMSO-d6) d 3.59 (s, 2H, CH2), 3.81 (s, 3H, OCH3), 6.74 (dd, 1H, J ¼ 2.4,
8 Hz, ArH), 6.81 (dd, 1H, J ¼ 2.2, 8 Hz, ArH), 6.99–7.09 (m, 2H, ArH),

New Method to Indeno[1,2-b]indole-10-one Derivatives
585
7.15 (d, 1H, J ¼ 2.4 Hz, ArH), 7.41 (2H, t, J ¼ 8 Hz, ArH), 7.52 (d, 1H,
J ¼ 8 Hz, ArH). MS (EI): m/e (%) 235 (100 Mþ), 220 (45), 204 (50), 191 (40).
3-Methoxyindeno[1,2-b]indol-10(5H)-one (5b)
Yield: 173 mg, (47.5%), red solid. M.p.: 214-68C. 1HNMR(400 MHz, CDCl3)
d 3.86 (s, 3H, OCH3), 6.57 (dd, 1H, J ¼ 2, 8 Hz, ArH), 6.70 (d, 1H, J ¼ 2 Hz,
ArH), 7.15–7.19 (m, 2H, ArH), 7.33 (d, 1H, J ¼ 7.2 Hz, ArH), 7.38 (d, 1H,
J ¼ 8 Hz, ArH), 7.78 (d, 1H, J ¼ 8.8 Hz, ArH). 13C-NMR (DMSO-d6)
d 183.5, 161.2, 159.6, 159.4, 143.2, 141.5, 141.4, 126.1, 123.1, 122.6,
120.2, 119.0, 114.6, 113.5, 110.9 and 55.6. IR spectra: 3178 (NH),
1668 (CO). MS (EI): m/e 249 (100 Mþ), 234 (60), 206 (25), 149 (40), 57 (80).
5,6-Dimethoxy-1-indanone(4-phenyl)-hydrazone (3c)
1
Yield: 7.64 g, (90.3%), yellow solid. M.p.: 180–38C. HNMR (400 MHz,
DMSO-d6) d 2.76 (2H, t, J ¼ 6.4 Hz), 2.98 (2H, t, J ¼ 6 Hz), 3.76 (3H, s),
3.79 (3H, s), 6.67 (1H, m), 6.91 (1H, s), 7.09 (1H, s), 7.16 (4H, m),
8.82 (1H, s).
5,10-Dihydro-2,3-dimethoxyindeno[1,2-b]indole (4c)
Yield: 0.98 g, (30.9%), pale green solid. M.p.: 234–68C. 1HNMR (400 MHz,
CDCl3) d 3.66 (2H, s), 3.95 (3H, s), 3.96 (3H, s), 7.06 (1H, s), 7.14 (3H, m),
7.41 (1H, t, J ¼ 4, 5.2 Hz), 7.6 (1H, d, J ¼ 4.8 Hz), 8.28 (1H, br). MS (EI):
m/e (%) 265 (100 Mþ), 250 (60), 222 (35), 192 (25), 178 (25), 149 (30).
2,3-Dimethoxyindeno[1,2-b]indol-10(5H)-one (5c)
Yield: 50 mg, (41.3%), red solid. M.p.: .2508C. 1HNMR (400 MHz, CDCl3)
d 3.95 (3H, s), 3.96 (3H, s), 7.06 (1H, s), 7.14 (3H, m), 7.41 (1H, t, J ¼ 4,
5.2 Hz), 7.6 (1H, d, J ¼ 4.8 Hz), 8.28 (1H, br). 13C-NMR (DMSO-d6) d
184.5, 160.3, 157.4, 157.1, 152.7, 145.3, 137.2, 132.9, 127.4, 122.2, 118.7,
116.3, 113.6, 111.7, 108.5, and 55.6. IR spectra: 3224 (NH), 1670 (CO).
MS (EI): m/e (%) 279 (100 Mþ), 266 (40), 251 (25).
6-Methoxy-1-indanone (4-methoxyphenyl)-hydrazone (3d)
1
Yield: 9.5 g, (81.5%), yellow crystal. M.p.: 105–88C. HNMR (400 MHz,
DMSO-d6) d 2.79 (t, 2H, J ¼ 2.4 Hz, CH2), 2.99 (t, 2H, J ¼ 2.4 Hz, CH2),

586
J. Wang et al.
3.69 (3H, s, OCH3), 3.80 (3H, s, OCH3), 6.8 (t, 3H, J ¼ 2.4 Hz, ArH), 7.13 (td,
3H, J ¼ 2, 2.4 Hz, ArH), 7.20 (d, 1H, J ¼ 8 Hz, ArH).
5,10-Dihydro-3, 8-dimethoxyindeno[1,2-b]indole (4d)
Yield: 552 mg, (50.8%), pale green solid. M.p.: 212–38C. 1HNMR (400 MHz,
CDCl3) d 3.62 (s, 2H, CH2), 3.85 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 6.73 (dd,
1H, J ¼ 2.2, 8 Hz, ArH), 6.81(dd, 1H, J ¼ 2.2, 8 Hz, ArH), 6.99 (d, 1H,
J ¼ 2.8 Hz, ArH), 7.05 (d, 1H, J ¼ 2.8 Hz, ArH), 7.29 (d, 1H, J ¼ 8.8 Hz,
ArH), 7.38 (d, 1H, J ¼ 8.4 Hz, ArH), 8.16 (s, 1H, NH). MS (EI): m/e 278
(10 Mþ), 223 (40), 149 (100).
3,8-Dimethoxyindeno[1,2-b]indol-10(5H)-one (5d)
Yield: 120 mg, (45.7%), red solid. M.p.: 225–78C. 1HNMR (400 MHz,
CDCl3) d 3.83 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 6.56 (dd, 1H, J ¼ 2,
8 Hz, ArH), 6.65 (d, 1H, J ¼ 2.4 Hz, ArH), 6.78 (dd, 1H, J ¼ 2.4, 8.8 Hz,
ArH), 7.20–7.27 (m, 2H, ArH), 7.38 (d, 1H, J ¼ 8.4 Hz, ArH). 13C-NMR
(DMSO-d6) d 183.4, 161.2, 159.7, 159.1, 155.9, 142.3, 136.2, 136.0, 127.3,
121.2, 115.3, 114.6, 111.3, 110.7, 102.5, 55.6 and 55.3. IR spectra:
3222 (NH), 1678 (CO). MS (EI): m/e 278 (5 M–Hþ), 223 (10), 149 (100).
5-Methoxy-1-indanone (4-methoxyphenyl)-hydrazone (3e)
1
Yield: 3.9 g, (52.1%), yellow crystal. M.p.: 104–68C. HNMR (400 MHz,
DMSO-d6) d 2.78 (t, 2H, J ¼ 6.4 Hz, CH2), 3.04 (t, 2H, J ¼ 6.4 Hz, CH2),
3.69 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 6.81 (dd, 1H, J ¼ 2, 2.4 Hz, ArH),
6.89 (dd, 1H, J ¼ 2 Hz, ArH), 7.10 (dd, 2H, J ¼ 2, 2.4 Hz, ArH),
7.51 (d, 1H, J ¼ 8 Hz, ArH), 8.61 (br, 1H, NH).
5,10-Dihydro-2,8-dimethoxyindeno[1,2-b]indole (4e)
Yield: 514 mg, (51.8%), pale green solid. M.p.: 203–58C. 1HNMR (400 MHz,
CDCl3) d 3.67 (2H, s), 3.86 (3H, s), 3.87 (3H, s), 6.78 (1H, dd, J ¼ 2.4,
8.8 Hz), 6.85 (1H, dd, J ¼ 2.8, 4 Hz), 7.04 (1H, d, J ¼ 2.8 Hz), 7.13 (1H, d,
J ¼ 1.6 Hz), 7.28–7.34 (2H, m), 8.15 (1H, br). MS (EI): m/e 278 (5 Mþ),
223 (10), 149 (100).
2,8-Dimethoxyindeno[1,2-b]indol-10(5H)-one (5e)
Yield: 34 mg, (52.9%), red solid. M.p.: 248–508C. 1HNMR (400 MHz,
DMSO-d6) d 3.75 (3H, s), 3.78 (3H, s), 6.69 (1H, dd, J ¼ 2.4, 8.4 Hz),

New Method to Indeno[1,2-b]indole-10-one Derivatives
587
6.83 (1H, dd, J ¼ 2.4, 8 Hz), 6.89 (1H, d, J ¼ 2.4 Hz), 6.97 (1H, d,
J ¼ 2.8 Hz), 7.16 (1H, d, J ¼ 8 Hz), 7.29 (1H, d, J ¼ 9.2 Hz), 12.3 (1H, s).
13C-NMR (DMSO-d6) d 183.3, 161.1, 159.3, 159.1, 156.3, 143.3, 136.2,
136.0, 126.3, 120.1, 114.7, 113.6, 111.7, 110.7, 101.5, 55.6 and 55.3. IR
spectra: 3199 (NH), 1674 (CO). MS (EI): m/e (%) 279 (5 M–Hþ), 223
(10), 149 (100).
5,6-Dimethoxy-1-indanone(4-methoxyphenyl)-hydrazone (3f)
1
Yield: 6.8 g, (67.8%), yellow crystal. M.p.: 142–38C. HNMR (400 MHz,
DMSO-d6) d 2.76 (t, 2H, J ¼ 6.4 Hz, CH2), 2.99 (t, 2H, J ¼ 6 Hz, CH2),
3.68 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 3.80 (s, 3H, OCH3), 6.81 (dd,
2H, J ¼ 2, 7.2 Hz, ArH), 6.92 (s, 1H, ArH), 7.09–7.12 (m, 3H, ArH), 8.59
(s, 1H, NH).
5,10-Dihydro-2,3,8-trimethoxyindeno[1,2-b]indole (4f)
Yield: 0.9 g, (30.4%), pale green solid. M.p.: 228–308C. 1HNMR (400 MHz,
CDCl3) d 3.64 (s, 2H, CH2), 3.89 (s, 3H, OCH3), 3.95 (s, 3H, OCH3),
3.96 (s, 3H, OCH3), 6.80 (dd, 1H, J ¼ 2.4, 8.4 Hz, ArH), 7.06 (d, 2H,
J ¼ 2.4 Hz, ArH), 7.15 (s, 1H, ArH), 7.30 (d, 1H, J ¼ 9.6 Hz, ArH),
8.18 (br, 1H, NH). MS (EI): m/e (%) 295 (30 Mþ), 280 (20), 192 (30),
165 (50), 149 (70), 123 (60), 108 (100).
2,3,8-Trimethoxyindeno[1,2-b]indol-10(5H)-one (5f)
Yield: 60 mg, (44.3%), red solid. M.p.: 245–88C. 1HNMR (400 MHz, CDCl3)
d 3.84 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 6.73 (dd, 2H,
J ¼ 2.4, 8.8 Hz, ArH), 7.11 (s, 1H, ArH), 7.17 (m, 2H, ArH), 8.54 (br, 1H,
NH). 13C-NMR (DMSO-d6) d 184.4, 159.3, 155.6, 154.4, 152.7, 149.2,
136.1, 135.4, 127.4, 126.9, 122.4, 121.7, 115.3, 112.1, 104.3, 55.6 and 55.2.
IR spectra: 3237 (NH), 1666 (CO). MS (EI): m/e (%) 309 (100 Mþ),
294 (35), 266 (40), 251 (25), 223 (25).
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