Synthesis of pyrrolo[3,2,1-hi]indazoles from indole-7-ketoximes

Article abstract of DOI:10.1016/j.tet.2006.04.041

Treatment of the 2,4-dinitrophenyl ethers of some indole-7-ketoximes with base results in a cyclisation reaction to yield pyrrolo[3,2,1-hi]indazoles.

Full text of DOI:10.1016/j.tet.2006.04.041

Tetrahedron 62 (2006) 6343–6348
Synthesis of pyrrolo[3,2,1-hi]indazoles from indole-7-ketoximes
*
Tutik Dwi Wahyuningsih, Karin Pchalek, Naresh Kumar and David StC. Black
School of Chemistry, University of New South Wales, UNSW Sydney NSW 2052, Australia
Received 6 February 2006; revised 26 March 2006; accepted 11 April 2006
Available online 19 May 2006
Abstract—Treatment of the 2,4-dinitrophenyl ethers of some indole-7-ketoximes with base results in a cyclisation reaction to yield
pyrrolo[3,2,1-hi]indazoles.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
only a 51% yield of the oxime 12 (Scheme 1). The reactions
were considerably slower than those for the related
aldehydes,1 requiring approximately two days instead of 2 h
for completion. In each case only one isomer was observed,
and the structures were confirmed by their spectroscopic
data as the respective anti-isomers. In particular the imine
infrared stretching frequencies5 were consistent with that
We have previously reported that indole-7-carbaldehydes
can be converted into the corresponding indole-7-carbo-
nitriles by treatment of carbaldoxime 2,4-dinitrophenyl ether
intermediates with base.1 The related ketoximes can be
derived from 7-acyl-, 7-aroyl- and 7-glyoxyloyl-indoles,
and we wished to investigate the behaviour of their 2,4-di-
nitrophenyl ethers under similar conditions. One possible
outcome could in principle be a Beckmann rearrangement
leading to a 7-amidoindole, an extremely useful addition to
the range of indole functionality. Two other possibilities
might becyclisationprocesseseitherdirectlyontoaninterme-
diate electron-deficient nitrogen atom arising from the loss of
a 2,4-dinitrophenolate anion or radical, or alternatively onto
an electron-deficient carbon atom generated by a Beckmann
rearrangement process. In any cyclisation process, the most
likely event wouldbe bond formation with the indole nitrogen
atom, leading to formation of either a pyrazole or an imida-
zole ring, respectively, in the above two scenarios.
R1
R1
MeO
MeO
NH2OH.HCl
10% NaOH
R2
R2
N
N
MeO
MeO
H
H
R3
R3
O
NOH
R2
R3
R2
R3
R1
R1
Yield %
______________________
____________________________
81
80
78
85
99
51
Me Me
Me Me
1
2
3
4
5
6
4-BrC6H4
4-ClC6H4
Ph
7
4-BrC6H4
4-ClC6H4
Ph
H
Me
H
Me
8
Me 4-ClC6H4
Me CF3
Me 4-ClC6H4
Me CF3
9
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
10
Me CO2Et
Me CONMe2
Me CO2Et
Me CONMe2
11 4-BrC6H4
12 4-BrC6H4
NaOEt
fluoro-2,4-
dinitrobenzene
2. Results and discussion
R1
MeO
R3
2.1. Formation of indole-7-ketoximes and ketoxime
ethers
R2
R1
MeO
N
MeO
H
NaH or
Et3N
R2
N
O
The various 7-acyl-, 7-aroyl- and 7-glyoxyloyl-indoles 1 and
3–6 have already been reported.2,3 The 7-acetylindole 2 is
detailed here for the first time, although closely related to
several known compounds.4,5 Treatment of these compounds
with hydroxylamine hydrochloride and sodium hydroxide
generally gave high yields (78–99%) of the indole-7-ketox-
imes 7–12, except for the glyoxylic amide 6, which gave
N
MeO
N
R3
O2N
R2
NO2
R2
R3 Yield %
R3
R1
R1
Yield %
____________________________
___________________________
Me Me
49
64
Me Me
13 4-BrC6H4
14 4-ClC6H4
19 4-BrC6H4
20 4-ClC6H4
63
69
10
29
21
30
H
Me
H
Me
Me 4-ClC6H4
Me CF3
78
Me 4-ClC6H4
Me CF3
Ph
15
Ph
21
100
100
2 100
4-BrC6H4
16
4-BrC6H4
22
Me CO2Et
Me CO2Et
Me CONMe2
17 4-BrC6H4
18 4-BrC6H4
23 4-BrC6H4
24 4-BrC6H4
Me CONMe
Keywords: Indoles; Oxime ethers; Pyrazoles; Pyrroles; Pyrrolo-indazoles.
* Corresponding author. Tel.: +61 2 9385 4657; fax: +61 2 9385 6141;
e-mail: d.black@unsw.edu.au
Scheme 1.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.04.041

6344
T. D. Wahyuningsih et al. / Tetrahedron 62 (2006) 6343–6348
assignment, which was further supported by 1H NMR spec-
troscopic data showing hydrogen bonding of the indole NH
to the oxime N atom. For example, in oxime 7, the two reso-
nances at 10.49 and 10.89 ppm were unequivocally assigned
to the indole NH and oxime OH protons, respectively, on the
basis of NOE experiments. Irradiation of the C2-methyl pro-
tons affected the indole NH and C3-aryl proton resonances;
irradiation of the ketoxime methyl protons affected the
methoxy, H5, NH and OH resonances; irradiation of the 6-
methoxy protons affected the methyl ketoxime and H5
resonances.
and some kind of cyclisation had taken place onto the indole
N atom. Two options were considered. Direct cyclisation
would result in bond formation between the oxime and indole
nitrogen atoms to give the pyrrolo-indazole 19. On the other
hand, if a Beckmann rearrangement preceded cyclisation, the
pyrrolo-benzimidazole 25 could be formed.
The pyrrolo-indazole structure 19 was confirmed by NMR
spectroscopy. Initial analysis with NOESY H NMR spec-
1
troscopy failed to give any useful information, and HMBC
1H–13C NMR spectra could only differentiate between the
resonances of the two methyl groups. However, analysis
with 1H–15N correlations (HSQC-HMBC NMR spectra)
gave clear evidence that the methyl group of the ketoxime
ether has a correlation with its nitrogen atom at 216 ppm,
while the C2-methyl group protons correlate with the nitro-
gen atom of the indole. These data are consistent with the
structure 19, but not with structure 25, in which the ketoxime
ether methyl group would be expected to correlate with each
of the nitrogen atoms. The yield of compound 19 was 63%.
Treatment of the indole-7-ketoximes 7–12 with sodium in
absolute ethanol, followed by addition of fluoro-2,4-dinitro-
benzene at room temperature, yielded the oxime ethers
13–18 in 49–100% yield (Scheme 1). Except for the amido-
substituted compound 18, all of these oxime ethers showed
only one isomer with an anti-configuration, based on infra-
1
red6 and H NMR spectroscopic data. This assignment is
also logical for steric reasons as the bulky ether group would
probably tend to be away from the NH of the indole ring.
The other oxime ethers 14–18 were also treated with base
and converted into the pyrrolo-indazoles 20–24 in somewhat
variable yields ranging from 10–69%. It was observed that
different bases could be utilised for the cyclisation reaction.
If an electron-donating R3 substituent was present on the
oxime ether, cyclisation occurred readily with the use of a
weak base such as triethylamine. If an electron-withdrawing
group was present, cyclisation required a stronger base such
as sodium hydride. It was found that the indole oxime ether
15 could only be converted into its geometrical syn-isomer
when heated under reflux with triethylamine for two days,
while treatment with sodium hydride gave a low yield of
the pyrrolo-indazole 21 together with the syn-isomer.
Cl
MeO
Me
N
MeO
N
Me
25
2.2. Formation of pyrrolo-indazoles
Treatment of the indole ketoxime ether 13 with triethylamine
in tetrahydrofuran under reflux for 6 h gave a white solid as
the major product after chromatography. The mass spectrum
of the product showed a molecular ion at m/e 384 (79Br,
23%), while its infrared spectrum showed that there was no
NH stretching frequency present. The 1H NMR spectrum dis-
played two singlet resonances at 2.67 and 2.75 ppm for pro-
tons of the two methyl groups and a singlet at 6.29 ppm
corresponding to H5 of the starting indole. It was clear that
the elimination of the dinitrophenoxy group had occurred
The pyrrolo-indazoles 19–24 all exhibited a bright yellow
fluorescence under long-wavelength ultraviolet light.
Narasaka and co-workers have investigated various cyclisa-
tion reactions of oxime ethers.7,8 The cyclisation of either
the syn- or anti-isomer of the 2-(3-hydroxyphenyl)ethyl
ketone O-2,4-dinitrophenyloxime 26 on treatment with
sodium hydride gave a mixture of the quinoline 27 and the
tetrahydroquinoline 28, proceeded via a radical mechanism
involving an alkylideneaminyl radical (Scheme 2). While
electron
NaH
N
O
Me
N
O
Me
N
O
Me
transfer
O
O
OH
O2N
NO2
O2N
NO2
O2N
NO2
26
NO2
O
O2N
+
N
Me
N
Me
N
Me
H
OH
O
OH
27
28
Scheme 2.

T. D. Wahyuningsih et al. / Tetrahedron 62 (2006) 6343–6348
6345
such a radical mechanism is possible for the conversion of
indole oxime ethers 13–18 into the pyrrolo-indazoles 19–24,
the presence of the anti-configuration supports a displace-
ment mechanism, with attack of the indole anion on the
nitrogen atom of the oxime ether with simultaneous release
of the dinitrophenoxide anion (Scheme 3).
50–60 ꢀC, stirred at this temperature overnight and quenched
with ice/water. Aqueous sodium hydroxide (2 M) was added
until a pH of 14 was reached, followed by 3 h of stirring at
room temperature. The precipitate was filtered off and puri-
fied by chromatography (dichloromethane) yielding com-
pound 2 (0.30 g, 52%) as a white solid, mp 202–204 ꢀC.
(Found: C, 65.5; H, 4.9; N, 4.3. C18H16ClNO3 requires C,
65.6; H, 4.9; N, 4.3%). nmax: 3328, 2942, 2844, 1624, 1585,
1561, 1343, 1272, 1216, 1093, 965, 796 cmꢁ1. lmax: 232 nm
(3 22,300 cmꢁ1 Mꢁ1), 250 (24,500), 323 (13,200). 1H NMR
spectrum (300 MHz, CDCl3): d 2.69 (3H, s, Me), 3.90 (3H, s,
OMe), 4.01 (3H, s, OMe), 6.23 (1H, s, H5), 7.08 (1H, d, J
1.9 Hz, H2), 7.32, 7.49 (4H, AA0BB0, Ar), 11.06 (1H, br s,
NH). 13C NMR spectrum (75 MHz, CDCl3): d 33.1 (Me),
55.1 (OMe), 56.2 (OMe), 87.3 (C5), 121.7 (C2), 127.6,
130.6 (ArCH), 104.8, 110.2, 117.1, 131.6, 134.2, 139.0,
159.3, 161.0 (ArC), 198.6 (CO).
R1
MeO
R1
MeO
R2
R2
N
-BH
N
MeO
MeO
H
B
R3
N
O
R3
N
O
O2N
NO2
O2N
NO2
NO2
O
O2N
MeO
4.1.2. 1-[3-(4-Bromophenyl)-4,6-dimethoxy-2-methyl-
indol-7-yl]ethanone oxime (7). The 7-acetylindole 12
(0.88 g, 2.28 mmol), hydroxylamine hydrochloride (0.25 g,
3.60 mmol) and potassium hydroxide (0.5 g, 8.93 mmol) in
95% ethanol (50 mL) were heated under reflux for 45 h.
After cooling, cold water was added and the mixture was
acidified with 1 M HCl. The solution was cooled and
the resulting white precipitate was filtered off and dried.
Column chromatography (dichloromethane/ethyl acetate,
95:5) yielded the oxime 7 (0.74 g, 81%) as a white solid,
mp 221–222 ꢀC. (Found: C, 56.9; H, 4.8; N, 6.9.
R1
R2
N
MeO
N
R3
Scheme 3.
C19H19BrN2O3 requires C, 56.6; H, 4.7; N, 6.9%). nmax
:
:
3. Conclusions
3380, 1596, 1289, 1140, 1001, 912, 824, 782 cmꢁ1. lmax
1
231 nm (3 27,100 cmꢁ1 Mꢁ1), 313 (9250), 398 (4150). H
NMR spectrum (300 MHz, DMSO-d6): d 2.12 (3H, s, Me),
2.23 (3H, s, MeC]N), 3.69, 3.79 (6H, 2s, 2ꢂOMe), 6.36
(1H, s, H5), 7.24, 7.48 (4H, AA0BB0, ArH), 10.49 (1H, s,
NH), 10.88 (1H, s, OH). 13C NMR spectrum (75 MHz,
DMSO-d6): d 12.1 (Me), 16.1 (MeC]N), 55.5, 57.3
(OMe), 89.8 (C5), 130.2, 132.9 (ArCH), 103.7, 111.4,
111.5, 118.6, 131.4, 135.1, 135.8, 152.3, 153.5 (ArC),
153.9 (C]N). Mass spectrum (EI): m/z 405 (M+1, 81Br,
17%), 404 (99), 403 (M+1, 79Br, 15), 402 (100), 371 (23),
276 (25), 275 (28).
The treatment of 2,4-dinitrophenyl ethers to a range of
indole-7-ketoximes with base provides an effective method
for the synthesis of the novel pyrrolo[3,2,1-hi]indazoles.
4. Experimental
4.1. General
Melting points were measured using a Mel-Temp melting
point apparatus, and are uncorrected. Microanalyses were
performed on a Carlo Erba Elemental Analyser EA 1108 at
the Campbell Microanalytical Laboratory, University of
Otago, New Zealand. 1H and 13C NMR spectra were obtained
on a Bruker DPX300 spectrometer. Mass spectra were re-
corded on either a Bruker FT-ICR MS (EI) or a Micromass
ZQ2000 (ESI) at UNSW, or a Shimadzu LCMS QP 8000
(ESI) at the University of Otago, New Zealand. Infrared
spectra were recorded with a Thermo Nicolet 370 FTIR
Spectrometer using KBr discs. Ultraviolet–visible spectra
were recorded using a Varian Cary 100 Scan Spectrometer.
Column chromatography was carried out using Merck
230–400 mesh ASTM silica gel, whilst preparative thin layer
chromatography was performed using Merck silica gel 7730
4.1.3. 1-[3-(4-Chlorophenyl)-4,6-dimethoxyindol-7-yl]-
ethanone oxime (8). This was prepared as described for
the oxime 7 from the 7-acetylindole 2 (0.50 g, 1.52 mmol),
hydroxylamine hydrochloride (0.17 g, 2.45 mmol) and
potassium hydroxide (0.33 g, 5.88 mmol) in 95% ethanol
(30 mL) under reflux for 45 h. After filtration the product
was chromatographed (dichloromethane/ethyl acetate, 95:5)
to yield oxime 8 (0.52 g, 80%) as a white solid, mp 171 ꢀC.
(Found: C, 62.1; H, 4.8; N, 8.1. C18H17ClN2O3$0.2H2O re-
quires C, 62.1; H, 5.0; N, 8.0%). nmax: 3418, 3353, 1585,
1349, 1285, 1213, 1089, 994 cmꢁ1
. lmax: 230 nm
(3 24,700 cmꢁ1 Mꢁ1). 1HNMRspectrum(300 MHz, DMSO-
d6): d 2.15 (3H, s, Me), 3.80, 3.84 (6H, 2s, 2ꢂOMe), 6.44
(1H, s, H5), 7.16 (1H, d, J 2.6 Hz, H2), 7.34, 7.51 (4H,
AA0BB0, ArH), 10.67 (1H, br, NH), 10.88 (1H, s, OH). 13C
NMR spectrum (75 MHz, DMSO-d6): d 15.9 (Me), 55.5,
57.3 (OMe), 89.9 (C5), 123.4 (C2), 127.8, 130.9 (ArCH),
103.9, 110.2, 115.8, 130.1, 135.4, 136.6, 152.5, 154.4
(ArC), 154.7 (C]N). Mass spectrum (EI): m/z 346 (M,
37Cl, 35%), 344 (M, 35Cl, 100), 313 (23), 311 (34).
60GF254
.
4.1.1. 1-[3-(4-Chlorophenyl)-4,6-dimethoxyindol-7-yl]-
ethanone (2). To a solution of 3-(4-chlorophenyl)-4,6-
dimethoxyindole9 (0.50 g, 1.74 mmol) at 0 ꢀC in N,N-
dimethylacetamide (1 mL) was slowly added phosphoryl
chloride (1.1 mL, 11.8 mmol). The mixture was heated to

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T. D. Wahyuningsih et al. / Tetrahedron 62 (2006) 6343–6348
4.1.4. 1-[4,6-Dimethoxy-2-methyl-3-phenylindol-7-yl]-1-
[4-chlorophenyl]methanone oxime (9). Indole 32 (0.31 g,
0.76 mmol), hydroxylamine hydrochloride (0.11 g,
1.58 mmol), pyridine (3 mL) and absolute ethanol (3 mL)
were heated under reflux for 24 h. After cooling, the solvent
was evaporated off under reduced pressure. The residue was
dissolved in dichloromethane, acidified with 1 N HCl,
washed with water and dried. The solvent was evaporated
off and the residue was chromatographed (dichloro-
methane/ethyl acetate, 95:5) to give the oxime 9 (0.25 g,
78%) as a light brown solid, mp 128 ꢀC. (Found: C, 68.1;
H, 5.1; N, 6.8. C24H21ClN2O3$0.1H2O requires C, 68.2; H,
5.1; N, 6.6%). nmax: 3422, 1599, 1574, 1289, 1213, 1148,
1091, 991 cmꢁ1. lmax: 247 nm (3 38,650 cmꢁ1 Mꢁ1), 314
(10,700). 1H NMR spectrum (300 MHz, DMSO-d6): d 2.18,
2.22 (3H, 2s, syn and anti Me), 3.55, 3.63, 3.67, 3.70 (6H,
4s, syn and anti OMe), 6.33, 6.39 (1H, 2s, syn and anti H5),
7.18–7.58 (9H, m, syn and anti ArH), 10.43, 10.64 (1H, 2s,
syn and anti NH), 11.27, 11.40 (1H, 2s, syn and anti OH).
13C NMR spectrum (75 MHz, DMSO-d6): d 12.2 (Me),
55.5, 57.1 (OMe), 89.4 (C5), 125.3, 127.4, 128.2, 128.5,
130.9 (ArCH), 98.5, 111.7, 112.7, 131.3, 133.3, 134.6,
136.0, 136.5, 150.4, 152.4 (ArC), 154.1 (C]N). Mass spec-
trum (EI): m/z 422 (M, 37Cl, 32%), 420 (M, 35Cl, 100), 404
(24), 389 (28), 387 (65), 291 (21), 267 (44).
OMe), 4.23 (2H, m, syn and anti OCH2), 6.35, 6.39 (1H,
2s, syn and anti H5), 7.27–7.51 (4H, 2d, J 8.7 Hz, syn and
anti ArH), 10.29, 10.39 (1H, 2s, syn and anti NH), 11.35,
12.17 (1H, 2s, syn and anti OH). 13C NMR spectrum
(75 MHz, DMSO-d6): d 12.1, 12.2 (Me), 14.4, 14.5 (CH2–
Me), 55.5, 55.6, 57.0, 57.9 (OMe), 60.8, 60.9 (OCH2),
88.9, 90.0 (C5), 130.3, 130.4, 132.9, 133.0 (ArCH), 96.7,
96.9, 111.2, 111.3, 111.9, 112.3, 118.6, 119.0, 131.2,
131.4, 133.7, 134.5, 135.3, 135.8, 145.7, 149.4, 153.6,
154.6 (ArC), 155.3, 155.7 (C]N), 164.1, 164.4 (C]O).
Mass spectrum (EI): m/z 463 (M+1, 81Br, 17%), 462 (100),
461 (M+1, 79Br, 13), 460 (95), 444 (29), 430 (41), 371
(52), 357 (89), 276 (91), 261 (85).
4.1.7. N,N-Dimethyl-2-[3-(4-bromophenyl)-4,6-dimeth-
oxy-2-methylindol-7-yl]-2-(hydroxyimino)acetamide
(12). This was prepared as described for the oxime 7 from
indole 62 (0.50 g, 1.1 mmol), hydroxylamine hydrochloride
(0.14 g, 2.01 mmol) and pyridine (5 mL) in absolute ethanol
(5 mL) under reflux for 48 h. After extraction and concentra-
tion, the residue was chromatographed (dichloromethane/
methanol, 95:5) to give the oxime 12 (0.26 g, 51%) as a white
solid, mp 256–257 ꢀC. (Found: C, 54.5; H, 4.8; N, 9.2.
C21H22BrN3O4 requires C, 54.8; H, 4.8; N, 9.1%). nmax
:
:
3386, 3153, 1636, 1585, 1213, 1127, 1002 cmꢁ1. lmax
231 nm (3 29,000 cmꢁ1 Mꢁ1), 326 (13,250). 1H NMR spec-
trum (300 MHz, DMSO-d6): d 2.27 (3H, s, Me), 2.88, 2.93
(6H, 2s, NMe2), 3.71, 3.73 (6H, 2s, 2ꢂOMe), 6.36 (1H, s,
H5), 7.26, 7.50 (4H, 2d, J 8.7 Hz, ArH), 10.34 (1H, br,
NH), 11.17 (1H, s, OH). 13C NMR spectrum (75 MHz,
DMSO-d6): d 12.2 (Me), 33.6, 36.7 (NMe2), 55.6, 58.1
(OMe), 90.2 (C5), 130.3, 133.1 (ArCH), 98.4, 111.8, 112.1,
118.9, 131.0, 134.3, 135.4, 151.9, 155.2 (ArC), 155.4
(C]N), 165.5 (C]O). Mass spectrum (EI): m/z 462 (M+1,
81Br, 18%), 461 (100), 460 (M+1, 79Br, 16), 459 (97), 443
(26), 372 (62), 371 (45), 370 (58), 276 (45), 261 (59).
4.1.5. 1-[3-(4-Bromophenyl)-4,6-dimethoxy-2-methyl-
indol-7-yl]-2,2,2-trifluoroethanone oxime (10). This was
prepared as described for oxime 7 from 7-trifluoroacetyl-
indole 42 (0.50 g, 1.13 mmol), hydroxylamine hydrochloride
(0.10 g, 1.44 mmol) and pyridine (5 mL) in absolute ethanol
(2.5 mL) under reflux for 24 h. After extraction and concen-
tration, the residue was chromatographed (dichloromethane/
ethyl acetate, 95:5) to give the oxime 10 (0.44 g, 85%) as a
white solid, mp 212–214 ꢀC. (Found: C, 50.2; H, 3.6; N,
6.1. C19H16BrF3N2O3 requires C, 49.9; H, 3.5; N, 6.1%).
nmax: 3516, 3361, 1594, 1370, 1347, 1194, 1139, 988 cmꢁ1
.
lmax: 231 nm (3 24,200 cmꢁ1 Mꢁ1), 319 (10,300). H NMR
spectrum (300 MHz, DMSO-d6): d 2.22 (3H, 2s, Me), 3.72,
3.78 (6H, 2s, 2ꢂOMe), 6.40 (1H, s, H5), 7.26, 7.49 (4H,
AA0BB0, ArH), 10.75 (1H, s, NH), 12.37 (1H, s, OH). 13C
NMR spectrum (75 MHz, DMSO-d6): d 12.1 (Me), 55.5,
57.1 (OMe), 88.8 (C5), 92.3 (CF3), 130.3, 132.9 (ArCH),
111.2, 111.5, 131.8, 134.6, 135.6, 142.3, 142.8, 153.8
(ArC), 155.1 (C]N). Mass spectrum (EI): m/z 459 (M+1,
81Br, 16%), 458 (100), 457 (M+1, 79Br, 13), 456 (96), 372
(24), 370 (23), 362 (21), 345 (24), 276 (49), 261 (41).
4.1.8. 1-[3-(4-Bromophenyl)-4,6-dimethoxy-2-methyl-
indol-7-yl]ethanone O-2,4-dinitrophenyloxime (13).
Indole oxime 7 (0.20 g, 0.49 mmol) was dissolved in abso-
lute ethanol (20 mL) and sodium (18 mg, 0.78 mmol) was
added. The solution became clear and was stirred at room
temperature for 30 min. The mixture was cooled in an ice-
bath, and fluoro-2,4-dinitrobenzene (0.1 mL, 0.83 mmol)
was added dropwise. The mixture was stirred for another 2 h
and the resulting precipitate was filtered off, washed with
absolute ethanol and dried to yield the oxime ether 13
(0.14 g, 49%) as an orange solid, which could not be fully
1
1
4.1.6. Ethyl 2-[3-(4-bromophenyl)-4,6-dimethoxy-2-
methylindol-7-yl]-2-(hydroxyimino)acetate (11). This
was prepared as described for oxime 7 from indole 52
(0.40 g, 0.90 mmol), hydroxylamine hydrochloride (0.13 g,
1.87 mmol) and pyridine (4 mL) in absolute ethanol
(2.5 mL) under reflux for 16 h. After extraction and concen-
tration, the residue was chromatographed (dichloromethane/
ethyl acetate, 95:5) to give the oxime 11 (0.41 g, 99%) as
a yellow solid, mp 182–184 ꢀC (dec). (Found: C, 54.6; H,
4.6; N, 6.1. C21H21BrN2O5 requires C, 54.7; H, 4.6; N,
6.1%). nmax: 3400, 3330, 1732, 1595, 1357, 1210, 998,
911, 787 cmꢁ1. lmax: 231 nm (3 26,350 cmꢁ1 Mꢁ1), 252
(24,800), 329 (14,100). 1H NMR spectrum (300 MHz,
DMSO-d6): d 1.24 (3H, m, syn and anti CH2–Me), 2.21,
2.28 (3H, 2s, syn and anti Me), 3.73 (6H, m, syn and anti
purified. H NMR spectrum (300 MHz, CDCl3): d 2.67,
2.74 (6H, 2s, 2ꢂMe), 3.92, 4.03 (6H, 2s, 2ꢂOMe), 6.29
(1H, s, H5), 7.32 (1H, d, J 9.4 Hz, ArH), 7.46–7.56 (4H,
m, ArH), 8.44 (1H, dd, J 9.4, 2.6 Hz, ArH), 9.06 (1H, d, J
2.6 Hz, ArH), 11.0 (1H, br, NH). The sample was not soluble
enough for 13C NMR measurement.
4.1.9. 1-[3-(4-Chlorophenyl)-4,6-dimethoxyindol-7-yl]-
ethanone O-2,4-dinitrophenyloxime (14). This was pre-
pared as described for indole 13 from indole oxime 8
(0.18 g, 0.54 mmol), absolute ethanol (20 mL), sodium
(18 mg, 0.78 mmol) and fluoro-2,4-dinitrobenzene (0.1 mL,
0.83 mmol). After filtration, washing and chromatography
(dichloromethane) it was dried to yield the oxime ether
14 (0.17 g, 64%) as an orange solid, mp 102 ꢀC (dec).

T. D. Wahyuningsih et al. / Tetrahedron 62 (2006) 6343–6348
6347
(Found: C, 49.0; H, 3.1; N, 9.3. C24H19ClN4O7$1.3CH2Cl2
requires C, 48.9; H, 3.5; N, 9.0%). nmax: 3396, 1607, 1530,
lmax: 230 nm (3 39,900 cmꢁ1 Mꢁ1), 257 (38,400). 1H
NMR spectrum (300 MHz, CDCl3): d 1.39 (3H, t,
J 7.2 Hz, CH2Me), 2.37 (3H, s, Me), 3.78, 3.86 (6H, 2s,
OMe), 4.41 (2H, q, J 7.2 Hz, OCH2), 6.23 (1H, s, H5),
7.28, 7.49 (4H, 2d, J 8.6 Hz, ArH), 8.00 (1H, d, J 9.4 Hz,
ArH), 8.42 (1H, s, NH), 8.47 (1H, dd, J 9.4, 2.6 Hz, ArH),
8.79 (1H, d, J 2.6 Hz, ArH). The sample was not soluble
enough for 13C NMR measurement. Mass spectrum (EI):
m/z 629 (M+1, 81Br, 26%), 627 (M+1, 79Br, 26) 583 (12),
446 (100), 371 (55).
1462, 1340, 1214 cmꢁ1 1H NMR spectrum (300 MHz,
.
CDCl3): d 2.74 (3H, s, Me), 4.04, 4.06 (6H, 2s, 2ꢂOMe),
6.35 (1H, s, H5), 7.36, 7.47 (4H, AA0BB0, ArH), 7.67 (1H,
s, H2), 7.80 (2H, d, J 8.7 Hz, ArH and NH), 8.44 (1H, dd,
J 9.4, 2.6 Hz, ArH), 9.06 (1H, d, J 2.6 Hz, ArH). The sample
was not soluble enough for 13C NMR measurement. Mass
spectrum (EI): m/z 345 (100%), 327 (37).
4.1.10. 1-(4-Chlorophenyl)-1-[4,6-dimethoxy-2-methyl-
3-phenylindole]methanone O-2,4-dinitrophenyloxime
(15). This was prepared as described for indole 13 from in-
dole oxime 9 (0.24 g, 0.57 mmol), absolute ethanol (25 mL),
sodium (24 mg, 1.04 mmol) and fluoro-2,4-dinitrobenzene
(0.1 mL, 0.83 mmol). After filtration, washing and chroma-
tography (dichloromethane) it was dried to yield the oxime
ether 15 (0.25 g, 78%) as an orange solid, mp 158–160 ꢀC.
(Found: C, 51.3; H, 3.3; N, 7.9. C30H23ClN4O7$1.8CH2Cl2
requires C, 51.6; H, 3.6; N, 7.6%). nmax: 3419, 1600, 1541,
4.1.13. N,N-Dimethyl-2-[3-(4-bromophenyl)-4,6-di-
methoxy-2-methylindol-7-yl]-2-(O-2,4-dinitrophenyloxy-
imino)acetamide (18). This was prepared as described for
indole 13 from indole oxime 12 (0.15 g, 0.33 mmol), abso-
lute ethanol (15 mL), sodium (0.02 g, 0.87 mmol) and fluoro-
2,4-dinitrobenzene (0.06 mL, 0.50 mmol). After filtration
and washing, it was dried to yield the oxime ether 18 (0.20 g,
100%) as an orange solid, mp 162 ꢀC (dec). (Found: C, 50.5;
H, 3.8; N, 10.3. C27H24BrN5O8$1H2O requires C, 50.3; H,
4.0; N, 10.8%). nmax: 3428, 1646, 1585, 1515, 1343, 1296,
1215 cmꢁ1. lmax: 230 nm (3 45,650 cmꢁ1 Mꢁ1), 255
(42,800), 364 (18,850). 1H NMR spectrum (300 MHz,
CDCl3): d 2.32, 2.37 (3H, s, syn and anti Me), 2.99–3.18
(6H, m, syn and anti NMe2), 3.75–3.88 (6H, m, syn and
anti OMe), 6.20, 6.23 (1H, s, syn and anti H5), 7.46–7.52
(4H, m, syn and anti ArH), 7.83, 7.86 (1H, d, J 9.4 Hz, syn
and anti ArH), 8.39–8.50 (1H, m, syn and anti ArH), 8.72,
8.90 (1H, d, J 2.6 Hz, ArH), 9.66 (1H, s, syn and anti NH).
The sample was not soluble enough for 13C NMR measure-
ment. Mass spectrum (EI): m/z 509 (12%), 463 (46), 461
(41), 445 (100), 443 (98), 289 (47).
1526, 1469, 1341, 1264, 1215, 1149, 924 cmꢁ1. lmax
:
228 nm (3 32,250 cmꢁ1 Mꢁ1), 242 (32,100), 311 (24,650).
1H NMR spectrum (300 MHz, CDCl3): d 2.27 (3H, s, Me),
3.66, 3.79 (6H, 2s, 2ꢂOMe), 6.31 (1H, s, H5), 7.28–7.68
(10H, m, ArH and NH), 8.01 (1H, d, J 9.4 Hz, ArH), 8.44
(1H, dd, J 9.4, 2.6 Hz, ArH), 8.76 (1H, d, J 2.6 Hz, ArH).
13C NMR spectrum (75 MHz, CDCl3): d 12.0 (Me), 55.2,
56.3 (OMe), 88.3 (C5), 118.3, 121.6, 125.6, 127.1, 128.7,
128.9, 129.4, 130.9 (ArCH), 95.5, 112.2, 114.3, 130.6,
132.5, 134.4, 135.5, 137.1, 137.2, 141.2, 154.3, 156.3,
157.0, 160.3 (ArC). Mass spectrum (EI): m/z 589 (M+1,
37Cl, 2%), 588 (6), 587 (M+1, 35Cl, 6), 586 (17), 513 (26),
294 (100), 293 (45).
4.1.14. 5-(4-Bromophenyl)-6,8-dimethoxy-1,4-dimethyl-
pyrrolo[3,2,1-hi]indazole (19). A mixture of indole oxime
ether 13 (0.14 g, 0.24 mmol) and triethylamine (0.75 mL)
in dry tetrahydrofuran (15 mL) was heated under reflux for
6 h with stirring. The solvent was evaporated off and the
residue was dissolved in dichloromethane. The organic layer
was washed with 2 M NaOH and water, dried and concen-
trated. Column chromatography (dichloromethane) yielded
compound 19 (0.06 g, 63%) as a white solid, mp 180–
181 ꢀC. (Found: C, 59.1; H, 4.5; N, 7.4. C19H17BrN2O2
requires C, 59.2; H, 4.5; N, 7.3%). nmax: 1682, 1603, 1511,
1234, 1122, 1000 cmꢁ1. lmax: 229 nm (3 25,500 cmꢁ1 Mꢁ1),
4.1.11. 1-[3-(4-Bromophenyl)-4,6-dimethoxy-2-methyl-
indol-7-yl]-2,2,2-trifluoroethanone O-2,4-dinitrophenyl-
oxime (16). This was prepared as described for indole 13
from indole oxime 10 (0.15 g, 0.33 mmol), absolute ethanol
(15 mL), sodium (0.02 g, 1.07 mmol) and fluoro-2,4-dinitro-
benzene (0.06 mL, 0.33 mmol). After filtration and washing,
it was dried to yield the oxime ether 16 (0.20 g, 100%) as an
orange solid, mp 189 ꢀC (dec). (Found: C, 48.3; H, 2.8; N,
8.7. C25H18BrF3N4O7 requires C, 48.2; H, 2.9; N, 9.0%).
nmax: 3420, 1603, 1541, 1469, 1345, 1221, 1153, 1123,
1
933 cmꢁ1. lmax: 233 nm (3 35,750 cmꢁ1 Mꢁ1). H NMR
1
spectrum (300 MHz, CDCl3): d 2.33 (3H, s, Me), 3.79, 3.88
(6H, 2s, OMe), 6.28 (1H, s, H5), 7.28, 7.49 (4H, AA0BB0,
ArH), 7.92 (1H, d, J 9.0 Hz, ArH), 7.94 (1H, br, NH), 8.48
(1H, dd, J 9.0, 2.6 Hz, ArH), 8.78 (1H, d, J 2.6 Hz, ArH).
The sample was not soluble enough for 13C NMR measure-
ment. Mass spectrum (EI): m/z 624 (M, 81Br, 1%), 622 (M,
79Br, 1), 440 (95), 371 (100).
270 (13,450), 329 (15,900). H NMR spectrum (300 MHz,
CDCl3): d 2.67 (3H, s, Me), 2.75 (3H, s, MeC]N), 3.91,
4.03 (6H, 2s, 2ꢂOMe), 6.29 (1H, s, H7), 7.48, 7.55 (4H,
AA0BB0, ArH). 13C NMR spectrum (75 MHz, CDCl3):
d 10.7 (Me), 15.2 (MeC]N), 56.2, 56.7 (OMe), 92.1 (C7),
131.0, 131.2 (ArCH), 101.4, 103.5, 118.4, 119.9, 129.8,
134.1, 142.9, 151.1, 156.3, 158.4 (ArC). Mass spectrum
(EI): m/z 387 (M+1, 81Br, 20%), 386 (99), 385 (M+1, 79Br,
23), 384 (100), 369 (55), 275 (90).
4.1.12. Ethyl 2-[3-(4-bromophenyl)-4,6-dimethoxy-2-
methylindol-7-yl]-2-(O-2,4-dinitrophenyloxyimino)-
acetate (17). This was prepared as described for indole 13
from indole oxime 11 (0.20 g, 0.43 mmol), absolute ethanol
(20 mL), sodium (27 mg, 1.17 mmol) and 2,4-dinitrofluoro-
benzene (0.08 mL, 0.66 mmol). After filtration and washing,
it was dried to yield the oxime ether 17 (0.27 g, 100%) as an
orange solid, mp 179–180 ꢀC. (Found: C, 51.4; H, 3.6; N,
8.7. C27H23BrN4O9 requires C, 51.7; H, 3.7; N, 8.9%).
4.1.15. 5-(4-Chlorophenyl)-6,8-dimethoxy-1-methylpyr-
rolo[3,2,1-hi]indazole (20). This was prepared as described
for indole 19 from indole oxime ether 14 (0.15 g,
0.29 mmol) and triethylamine (0.75 mL) in dry tetrahydro-
furan (15 mL) under reflux for 6 h. After extraction and
concentration, the residue was chromatographed (dichloro-
methane) to give the pyrrolo-indazole 20 (0.07 g, 69%)
as a white solid, mp 198–200 ꢀC. (Found: C, 66.0; H,
nmax: 3434, 1743, 1591, 1542, 1342, 1208, 1159 cmꢁ1
.

6348
T. D. Wahyuningsih et al. / Tetrahedron 62 (2006) 6343–6348
4.6; N, 8.7. C18H15ClN2O2 requires C, 66.2; H, 4.6; N,
8.6%). nmax: 3102, 1675, 1604, 1505, 1333, 1220, 1176,
1117, 1067 cmꢁ1. lmax: 230 nm (3 20,200 cmꢁ1 Mꢁ1), 274
(OMe), 61.6 (OCH2), 93.9 (C5), 131.1, 131.2 (ArCH),
100.5, 102.7, 120.8, 122.5, 129.9, 133.1, 142.1, 142.6,
156.6, 158.8 (ArC), 162.0 (C]O). Mass spectrum (EI): m/z
444 (M, 81Br, 35%), 442 (M, 79Br, 28), 372 (23), 371 (100),
369 (96).
1
(12,400). H NMR spectrum (300 MHz, CDCl3): d 2.74
(3H, s, Me), 4.03, 4.05 (6H, 2s, 2ꢂOMe), 6.34 (1H, s,
H7), 7.67 (1H, s, H2), 7.36, 7.80 (4H, AA0BB0, ArH). 13C
NMR spectrum (75 MHz, CDCl3): d 15.2 (Me), 56.3, 56.5
(OMe), 91.7 (C7), 118.6 (C2), 128.4, 128.6 (ArCH),
100.5, 103.4, 123.9, 132.0, 133.2, 144.4, 151.7, 157.2,
159.2 (ArC). Mass spectrum (EI): m/z 328 (M, 37Cl, 31%),
326 (M, 35Cl, 100), 311 (57), 261 (32).
4.1.19. N,N-Dimethyl-5-(4-bromophenyl)-6,8-di-
methoxy-4-methylpyrrolo[3,2,1-hi]indazole-1-carbox-
amide (24). This was prepared as described for indole 19
from indole oxime ether 18 (0.20 g, 0.32 mmol) and sodium
hydride (0.12 g, 80% dispersion in oil, 4.0 mmol) in dioxane
(4 mL) under reflux for 1 h. After extraction and concentra-
tion, the residue was chromatographed (dichloromethane)
to give the pyrrolo-indazole 24 (42 mg, 30 %) as a pale yel-
low solid, mp 230–232 ꢀC. (Found: C, 55.3; H, 4.4; N, 9.2.
C21H20BrN3O3$0.7H2O requires C, 55.4; H, 4.7; N, 9.2%).
nmax: 1677, 1627, 1596, 1515, 1327, 1225, 1132, 1077,
1005 cmꢁ1. lmax: 231 nm (3 27,900 cmꢁ1 Mꢁ1), 329
(8250). 1H NMR spectrum (300 MHz, CDCl3): d 2.67 (3H,
s, Me), 3.21 (6H, s, NMe2), 3.92, 4.04 (6H, 2s, OMe), 6.36
(1H, s, H5), 7.48, 7.56 (4H, 2d, J 8.3 Hz, ArH). 13C NMR
spectrum (75 MHz, CDCl3): d 10.5 (Me), 35.4, 38.7
(NMe2), 56.7, 56.9 (OMe), 94.0 (C5), 131.1, 131.2 (ArCH),
100.7, 101.8, 120.5, 120.7, 129.6, 133.5, 141.6, 145.8,
156.3, 158.8 (ArC), 164.1 (C]O). Mass spectrum (EI):
m/z 444 (M+1, 81Br, 27%), 443 (100), 442 (M+1, 79Br, 20),
441 (90), 372 (38), 371 (68), 370 (22), 369 (71), 275 (32).
4.1.16. 1-(4-Chlorophenyl)-6,8-dimethoxy-4-methyl-5-
phenylpyrrolo[3,2,1-hi]indazole (21). This was prepared
as described for indole 19 from indole oxime ether 15
(0.30 g, 0.51 mmol) and sodium hydride (0.12 g, 80% dis-
persion in oil, 4.0 mmol) in dioxane (7.5 mL) under reflux
for 1 h. After extraction and concentration, the residue was
chromatographed (dichloromethane) to give the pyrrolo-
indazole 21 (20 mg, 10%) as a yellow solid, mp 190–192 ꢀC.
(Found: C, 70.5; H, 4.9; N, 6.7. C24H19ClN2O2$0.3H2O
requires C, 70.6; H, 4.8; N, 6.9%). nmax: 1675, 1600, 1518,
1325, 1299, 1234, 1216, 1134, 1013 cmꢁ1. lmax: 231 nm (3
1
31,350 cmꢁ1 Mꢁ1), 246 (31,200), 318 (12,100). H NMR
spectrum (300 MHz, CDCl3): d 2.75 (3H, s, Me), 3.92, 4.06
(6H, 2s, 2ꢂOMe), 6.37 (1H, s, H7), 7.30–7.66 (7H, m,
ArH), 8.35 (1H, part of AA0BB0, ArH). 13C NMR spectrum
(75 MHz, CDCl3): d 10.6 (Me), 56.2, 56.8 (OMe), 92.8
(C7), 126.3, 127.9, 128.6, 129.4, 129.7 (ArCH), 101.6,
120.5, 129.6, 131.7, 134.4, 134.8, 142.7, 151.7, 155.4,
158.4 (ArC). Mass spectrum (EI): m/z 404 (M, 37Cl, 35%),
402 (M, 35Cl, 100), 387 (43), 291 (20), 220 (22).
Acknowledgements
Financial support from the Australian Research Council is
gratefully acknowledged. T.D.W. and K.P. acknowledge
receipt of an Indonesian Government Quality of Under-
graduate Education (QUE) Scholarship and an International
Postgraduate Scholarship, respectively.
4.1.17. 5-(4-Bromophenyl)-6,8-dimethoxy-4-methyl-1-
trifluoromethylpyrrolo[3,2,1-hi]indazole (22). This was
described as prepared for indole 19 from indole oxime ether
16 (0.20 g, 0.32 mmol) and sodium hydride (97 mg, 80%
dispersion in oil, 3.23 mmol) in dioxane (5 mL) under reflux
for 1 h. After extraction and concentration, the residue was
chromatographed (dichloromethane) to give the pyrrolo-
indazole 22 (41 mg, 29%) as a pale yellow solid, which
References and notes
1. Wahyuningsih, T. D.; Kumar, N.; Nugent, S. J.; Black, D. StC.
Tetrahedron 2005, 61, 10501–10506.
2. Jones, A. W.; Wahyuningsih, T. D.; Pchalek, K.; Kumar, N.;
Black, D. StC. Tetrahedron 2005, 61, 10490–10500.
3. Black, D. StC.; Kumar, N.; McConnell, D. B. Tetrahedron 1996,
52, 8925–8936.
4. Black, D. StC.; Deb-Das, R. B.; Kumar, N. Aust. J. Chem. 1992,
45, 1051–1056.
5. Black, D. StC.; Kumar, N.; Mitchell, P. S. R. J. Org. Chem. 2002,
67, 2464–2473.
6. Cho, B. R.; Park, C. W.; Je, J. T. J. Chem. Res., Synop. 1995,
200–201.
7. Uchiyama, K.; Hayashi, Y.; Narasaka, K. Synlett 1997, 445–446.
8. Uchiyama, K.; Ono, A.; Hayashi, Y.; Narasaka, K. Bull. Chem.
Soc. Jpn. 1998, 71, 2945–2955.
9. Black, D. StC.; Bowyer, M. C.; Bowyer, P. K.; Ivory, A. J.;
Kim, M.; Kumar, N.; McConnell, D. B.; Popiolek, M. Aust.
J. Chem. 1994, 47, 1741–1750.
1
could not be fully purified. H NMR spectrum (300 MHz,
CDCl3): d 2.68 (3H, s, Me), 3.95, 4.05 (6H, 2s, 2ꢂOMe),
6.37 (1H, s, H7), 7.47, 7.58 (4H, AA0BB0, ArH).
4.1.18. Ethyl 5-(4-bromophenyl)-6,8-dimethoxy-4-
methylpyrrolo[3,2,1-hi]indazole-1-carboxylate (23).
This was prepared as described for indole 19 from indole
oxime ether 17 (0.27 g, 0.43 mmol) and triethylamine (1 mL)
in dry tetrahydrofuran (20 mL) under reflux overnight. After
extraction and concentration, the residue was chromato-
graphed (dichloromethane) to give the pyrrolo-indazole 23
(40 mg, 21%) as a yellow solid, which could not be fully pu-
rified. 1H NMR spectrum (300 MHz, CDCl3): d 1.49 (3H, t,
J 7.1 Hz, OCH2Me), 2.70 (3H, s, Me), 3.94, 4.08 (6H, 2s,
2ꢂOMe), 4.54 (2H, q, J 7.1 Hz, OCH2), 6.38 (1H, s, H5),
7.48, 7.57 (4H, AA0BB0, ArH). 13C NMR spectrum
(75 MHz, CDCl3): d 10.5 (Me), 14.3 (OCH2Me), 56.6, 56.7