Synthetic approaches to activated pyrrolo[3,2,1-hi]indoles: synthesis of 6,8-dimethoxy pyrrolo[3,2,1-hi]indole

Article abstract of DOI:10.1016/j.tet.2009.01.010

6,8-Dimethoxypyrrolo[3,2,1-hi]indole 25 has been formed by the dehydrogenation of the related tetrahydro compound 23, which in turn was formed by reduction of the related isatin 22. Approaches to achieve the cyclisation of N-hydroxyethylindoles, N-dimethy

Full text of DOI:10.1016/j.tet.2009.01.010

Tetrahedron 65 (2009) 2591–2598
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthetic approaches to activated pyrrolo[3,2,1-hi]indoles: synthesis
of 6,8-dimethoxy pyrrolo[3,2,1-hi]indole
*
Jumina, Naresh Kumar, David StC Black
School of Chemistry, University of New South Wales, UNSW Sydney, NSW 2052, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 August 2008
Received in revised form 5 December 2008
Accepted 5 January 2009
Available online 9 January 2009
6,8-Dimethoxypyrrolo[3,2,1-hi]indole 25 has been formed by the dehydrogenation of the related tetra-
hydro compound 23, which in turn was formed by reduction of the related isatin 22. Approaches to
achieve the cyclisation of N-hydroxyethylindoles, N-dimethylacetamidoindoles, and C7-substituted
chloroacetylindoles were unsuccessful.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Indoles
Pyrroloindoles
Dehydrogenation
Isatins
1. Introduction
2. Results and discussion
The synthesis of pyrrolo[3,2,1-hi]indoles can be achieved ef-
fectively by the aldol cyclisation of 7-formyl-N-indolylacetates,
derived from the formylation of N-alkyl indoles.1 The related, but
less effective, cyclisation of N-phenacylindole-7-carbaldehydes
has also been reported.1 These cyclisation processes made the
final connection between substituents at N1 and C7: functional-
isation at C7 was made possible by the use of specifically acti-
vated indoles. Given such activation, it is also possible in principle
to complete a cyclisation by a direct connection between the N1
substituent and C7 itself. Indeed various cyclisations of this type
are worthy of investigation. Additionally, there is also the po-
tential cyclisation of a C7 substituent directly onto N1. This paper
deals with investigations of some of these strategies, which al-
though found to be unsuccessful, helped to define the scope of
pyrrolo[3,2,1-hi]indole synthesis. The strain factor involved in
a 6,5,5-fused ring system2 can be reduced by a strategy that in-
volves the cyclisation on an indoline framework: subsequent
dehydrogenation is then required to form the pyrrolo[3,2,1-
hi]indole. A successful example of this approach is also described
herein.
2.1. Reactions of N-phenacylindoles
It has been previously reported1 that the reaction of 3,5-dime-
thoxyaniline with 2 equiv of 4-bromophenacyl bromide gave a di-
substituted aniline, which was cyclised directly with trifluoroacetic
acid to give N-phenacylindole 1. Attempts to achieve the second
cyclisation through reaction with stronger acids, such as poly-
phosphoric acid, failed to form pyrroloindoles. However, during
formylation of indole 1 with the Vilsmeier reagent, a pyrroloindole
was obtained as a byproduct in poor yield.1
In order to aim for a less strained dihydropyrroloindole ring
system, the phenacylindole was reduced with sodium borohydride
to give benzylic alcohol 2, which was then subjected to a variety of
acidic conditions capable of generating a benzylic cation for intra-
molecular substitution at C7. Cyclisation could not be achieved and
in most cases the reactions gave complex product mixtures. How-
ever, treatment of alcohol 2 with boron trifluoride etherate in
boiling benzene gave the phenyl substituted product 3 in 63% yield,
but no cyclisation was observed (Scheme 1). Similar treatment in
other solvents gave no reaction.
2.2. Reactions of N-indolylacetamides
Indoles 4–8 were reacted with N,N-dimethylchloroacetamide
and potassium hydroxide in dimethylsulfoxide at room tempera-
ture for 30 min to give the corresponding N-substituted indoles
* Corresponding author. Tel.: þ61 2 9385 4657; fax: þ61 2 9385 6141.
E-mail address: d.black@unsw.edu.au (D.StC Black).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.01.010

2592
Jumina et al. / Tetrahedron 65 (2009) 2591–2598
MeO
MeO
R1
R1
MeO
MeO
R
R
KOH / THF
NaBH4
ClCH2CONMe2
THF / EtOH
R2
R2
NMe2
77-90%
83%
N
N
N
N
MeO
MeO
MeO
MeO
R
R
H
O
OH
O
1
2
R1
Ph
R2
H
R1
Ph
R2
H
9
BF3.Et2O
benzene
4
5
6
7
R = 4-BrC6H4
4-BrC6H4
Ph
CO2Me CO2Me
H
Ph
10
11
12
4-BrC6H4
Ph
CO2Me CO2Me
H
Ph
63%
8
H
H
13
H
H
MeO
R
N
MeO
R
82-83%
POCl3 / DMF
R1
3
MeO
Scheme 1.
R2
NMe2
N
MeO
CHO
9–13 in 77–90% yield. In the case of the less reactive indole diester
7, the addition of potassium iodide was essential for the sub-
stitution to proceed. In general the reactions of these indoles with
O
R2
H
Ph
R1
Ph
Ph
14
15
the
a-chloroacetamide were much more effective than those with
a
-bromoacetates,1 as they rapidly went to completion and usually
gave pure products without the need for chromatography. Pre-
sumably the acetamide reagent and products were more stable
than the related acetates under the basic conditions involved. The
1H NMR spectra of the N-substituted indoles 9–13 showed singlet
resonances for the acetyl methylene protons at around 4.7 ppm,
pairs of singlets for the N-methyl protons at 2.8–3.1 ppm, and
typical doublets at 6.1–6.4 ppm for H5 and H7.
Scheme 2.
the two adjacent substituents does not allow appropriate attack of
the carbanion on the carbonyl carbon. This information is indicated
by an X-ray crystal structure of compound 16 (see Fig. 1).
All attempts to cyclise the indolyl acetamides by treatment even
with excess phosphoryl chloride to generate the electrophilic imi-
nium salts failed. No reaction could be observed at room temper-
ature, while at higher temperatures inseparable product mixtures
were obtained. None of the product mixtures were highly coloured,
ruling out the formation of an indigo-like product that could arise
by oxidative dimerisation of the desired cyclised pyrro-indolone
product. Replacement of phosphoryl chloride by trifluoromethane-
sulfonic anhydride3 yielded similar product mixtures.
MeO
MeO
MeO
Ph
Ph
Ph
Ph
R1
Ph
Ph
N
N
N
MeO
O
MeO
MeO
H
H
O
O
OH
O
R2
Cl
Cl
Given that the 7-formyl N-indolyl acetates undergo ready aldol
cyclisation to give pyrroloindoles,1 the two N-indolyl acetamides 9
and 11 were formylated at C7 by typical Vilsmeier conditions to give
aldehydes 14 and 15 in high yield (Scheme 2). The Vilsmeier reagent
is known to react at the methylene position of acetamides to give
dimethylaminomethylene amides,4 but no reaction was observed in
these examples, probably because of the superior reactivity at the
indole C7 position.
R1
NMe2 NMe2
OMe
R2
18
19
16
17
OEt
2.3. Reactions of 7-chloroacetylindoles
Aldol cyclisation of compounds 14 and 15 could not be achieved,
despite the investigation of numerous bases. In many cases no re-
action was observed. Treatment with sodium hydride in dime-
thylformamide gave the related indole 7-aldehydes, resulting from
the loss of the acetylacetamide group. Similar treatment in tetra-
hydrofuran additionally gave N-indolyl acetamides 9 and 11,
resulting from the loss of the formyl group. Presumably the reduced
acidity of the acetamide methylene protons, compared with those
of the acetates, led to the failure to effect cyclisation.
7-Glyoxylic amide 16, readily prepared from N-indolyl acet-
amide 11, also failed to undergo cyclisation. Similarly, 7-glyoxylic
ester 17 was also subjected to the standard cyclisation conditions
without success.1 These results can be explained by the geometry of
compounds 16 and 17, which because of steric hindrance between
Alternative potential precursors for the formation of pyrrolo-
indolones are the 7-chloroacetylindoles. 2-Acylaminochloroaceto-
phenones have been shown to undergo cyclisation on treatment
with base, followed by dehydration, to give N-acetylindolones.5
Reduction of such products gives N-acetylindoles. Treatment of
indole 6 with excess of a reagent formed from phosphoryl chloride
and N,N-dimethylchloroacetamide at 80 ꢀC afforded 7-chloro
acetylindole 18 in 90% yield. The reaction of indole with N,
N-dimethylchloroacetamide under Vilsmeier conditions has been
reported to give the 3-acetylated indole in 37% yield.6 Treatment of
indole 18 with either sodium hydride in tetrahydrofuran or po-
tassium hydroxide in dimethylsulfoxide gave only polymeric ma-
terial, and the application of milder bases such as triethylamine or

Jumina et al. / Tetrahedron 65 (2009) 2591–2598
2593
MeO
MeO
NaBH3CN
HOAc
C22
C23
C24
C25
93%
N
H
N
H
MeO
MeO
C21
O2
20
8
C20
C19
NaNO2
HCl
C4
C5
HCl
48%
C3
ClCOCOCl
C2
90%
MeO
C26
MeO
C1
N1
C13
C18
C17
C6
C7
C8
O3
N
NO
MeO
C14
MeO
O
N
O
C16
C15
O1
C10
21
C27
O4
C29
C9
C28
O5
22
N3
C30
N2
NaBH(CF3CO2)3
C12
MeO
MeO
C11
+
Figure 1. ORTEP diagram derived from the single-crystal X-ray analysis of compound
16.
MeO
N
MeO
N
Pd / C
toluene
24
19%
23
52%
pyridine also failed to initiate any reaction. The alcohol reduction
products of 2-acylaminochloroacetophenones have also been
reported to undergo cyclisation to give N-acetylindoles directly.5
Consequently, indole 18 was reduced by sodium borohydride to
give alcohol 19 in 86% yield. Although this material could not be
fully purified, attempts were made to effect cyclisation using a va-
riety of bases and elevated temperatures, but no cyclic products
could be identified.
62%
Pd / C
56%
MeO
nitrobenzene
MeO
N
25
2.4. Approaches from 4,6-dimethoxyindoline
Scheme 3.
In order to minimise problems involving strain in the cyclisation
process, 4,6-dimethoxyindoline 20 became a desirable starting
material. This can be produced from the known 4,6-dimethoxy
indole 8,7,8 but here we describe an improved synthesis for this
compound (see Experimental). Indoles can be effectively reduced to
indolines by reaction with sodium cyanoborohydride in acetic
acid.9–13 Using these conditions, indole 8 was readily reduced to
indoline 20 in 94% yield (Scheme 3). However, fairly swift purifi-
cation of the product was necessary to prevent re-oxidation oc-
curring. In an attempt to apply the Fischer synthesis to form
a dihydropyrroloindole, indoline 20 was nitrosated by treatment
with nitrous acid in ethanol and gave N-nitroso-indole 21 in 90%
yield. However, attempted reduction of the nitroso compound to
the related hydrazine only generated complex product mixtures, so
this approach was not viable. An alternative approach via an isatin
was then investigated. Indoline 20 was converted into its hydro-
chloride salt, which was reacted with excess oxalyl chloride at
140 ꢀC to give the bright yellow indoline isatin 22 in 48% yield.
Treatment of the isatin 22 with lithium aluminium hydride led to
products of ring opening, which could not be purified satisfactorily.
This reaction once again illustrates the issue of strain in the 6,5,5-
fused ring system. Ring opening was also observed when sodium
borohydride or sodium acetoxyborohydride was used. However,
to 19%. Treatment of tetrahydropyrroloindole 23 with palladium on
charcoal in nitrobenzene at reflux under a nitrogen atmosphere for
4 h gave pyrroloindole 25 in 56% yield (Scheme 3). It was observed
that the first dehydrogenation forming indole 24 occurred at ap-
proximately 120 ꢀC and was complete in less than an hour. How-
ever, the second dehydrogenation leading to pyrroloindole 25
required heating at 210 ꢀC and still did not reach completion after
4 h. This indicates that the activation energy involved for the con-
version of tetrahydropyrroloindole 23 to indole 24 is less than that
involved for the conversion of indole 24 to pyrroloindole 25. The
synthesis of indole 24 was also carried out by treatment of tetra-
hydropyrroloindole 23 with palladium on charcoal in toluene at
reflux under a nitrogen atmosphere for 2.5 h. Indole 24 was
obtained in 62% yield, but could not be obtained analytically pure.
The mass spectrum of pyrroloindole 25 revealed a molecular ion at
201 (100%) and its elemental analysis was in agreement with the
structure. The 1H NMR spectrum established that the molecule is
symmetrical (and therefore aromatic according to Paudler and
Shin16), as H2 and H4 were identical (doublet at 6.85 ppm, J 3.0 Hz),
as well as H1 and H5 (doublet at 7.36 ppm, J 3.0 Hz), and also the
protons of the two methoxy groups (singlet, 4.13 ppm). Further-
more, the 13C NMR spectrum showed only one methoxy peak, three
CH signals, and three quaternary carbon resonances.
treatment of isatin 22 with
a large excess of sodium tri-
fluoroacetoxyborohydride gave tetrahydropyrrolo indole 23 in 52%
yield, together with a trace of indole 24 (Scheme 3). As sodium
trifluoroacetoxyborohydride is known to be
a
hydroborating
3. Conclusions
agent,14,15 it was found to be advantageous to add hydrogen per-
oxide during work-up. Although the yield of the tetrahydro com-
pound 23 was not increased, that of the dihydrocompound 24 rose
Although it was not possible to cyclise N-hydroxyethylindoles,
N-dimethylacetamidoindoles or C7-substituted chloroacetylindoles to

2594
Jumina et al. / Tetrahedron 65 (2009) 2591–2598
form pyrrolo[3,2,1-hi]indoles, the simple 6,8-dimethoxypyrrolo[3,2,
1-hi]indole 25 could be readily prepared via isatin 22 and indoline 23.
added dropwise and then stirring continued for another 2 h. Water
(100 mL) was added and the resulting precipitate was filtered,
washed with water and dried to afford indolylacetamide 9 as
a yellow solid (1.54 g, 77%), mp 143–145 ꢀC (from dichloromethane/
light petroleum). (Found: C, 70.7; H, 6.7; N, 8.1. C20H22N2O3 re-
quires: C, 71.0; H, 6.6; N, 8.2%.) nmax 1660, 1325, 1200, 1150,
4. Experimental
4.1. General
1040 cmꢁ1 1H NMR spectrum (300 MHz, CDCl3):
. d 2.98 and 3.00
Melting points were measured using a Mel-Temp melting point
apparatus, and are uncorrected. Microanalyses were performed by
Dr H.P. Pham at UNSW. 1H and 13C NMR spectra were obtained on
a Bruker AC300F (300 MHz) or a Bruker AM500 (500 MHz) spec-
trometer. Mass spectra were recorded on either a VG Quattro MS
(EI) or a Finnegan MAT (MALDI). Infrared spectra were recorded
with a Perkin Elmer 298 IR spectrometer. Ultraviolet-visible spectra
were recorded using a Hitachi U-3200 spectrometer. Column
chromatography was carried out using Merck 230–400 mesh ASTM
silica gel, whilst preparative thin layer chromatography was per-
(6H, 2s, NMe2), 3.83 and 3.89 (6H, 2s, OMe), 4.79 (2H, s, CH2), 6.31
(1H, d, J 1.8 Hz, H5), 6.40 (1H, d, J 1.8 Hz, H7), 6.92 (1H, s, H2), 7.29
(1H, t, J 7.2 Hz, H40), 7.39 (2H, t, J 7.2 Hz, H30), 7.64 (2H, d, J 7.2 Hz,
H20). 13C NMR spectrum (75 MHz, CDCl3):
d 35.9 and 36.5 (NMe2),
48.4 (CH2), 55.0 and 55.6 (OMe), 85.3 (C5), 92.0 (C7), 124.7, 125.4,
127.3 and 129.3 (ArCH), 110.6, 118.4, 135.7, 139.0, 155.0 and 157.6
(ArC), 167.0 (CONMe2). Mass spectrum: m/z 339 (Mþ1, 23%), 338
(M, 85), 267 (30), 266 (100), 250 (49), 208 (28), 152 (22), 72 (83).
4.1.4. N,N-Dimethyl-3-(40-bromophenyl)-4,6-dimethoxyindol-1-
formed using Merck silica gel 7730 60GF254
.
ylacetamide (10)
A
suspension of powdered potassium hydroxide (0.030 g,
4.1.1. 3-(40-Bromophenyl)-1-{2-(40-bromophenyl)-2-hydroxy
ethyl}-4,6-dimethoxyindole (2)
0.54 mmol) in dimethyl sulfoxide (4 mL) was reacted with bromo
phenylindole 517,19 (0.10 g, 0.30 mmol) and N,N-dimethyl-
chloroacetamide (0.060 g, 0.45 mmol) according to the method of
preparation of compound 9. The resulting precipitate was filtered,
washed with water, dried and recrystallised from dichloro-
methane/light petroleum to give indolylacetamide 10 as a white
solid (0.11 g, 88%), mp 195–197 ꢀC. (Found: C, 57.4; H, 5.3; N, 6.5.
Sodium borohydride (0.086 g, 2.28 mmol) was added into
a cooled solution of phenacylindole 1 (0.30 g, 0.57 mmol) in
a mixture of absolute ethanol and tetrahydrofuran (1:1, 10 mL). The
mixture was stirred at 0 ꢀC for 45 min and then at room tempera-
ture for another 30 min. The solvent was removed under reduced
pressure and the residue was diluted with water (40 mL). The
resulting precipitate was filtered, washed with water, and dried to
give hydroxyindole 2 as a white solid (0.25 g, 83%), mp 97–99 ꢀC
(from dichloromethane/light petroleum). (Found: C, 53.9; H, 4.2; N,
C20H21BrN2O3 requires: C, 57.6; H, 5.1; N, 6.7%.) lmax 213 nm (
3
8600 cmꢁ1 Mꢁ1), 248 (9200), 287 (9400), 303 (9300). nmax 1650,
1620, 1580, 1545, 1330, 1205, 1145, 1050, 795 cmꢁ1. 1H NMR spec-
trum (300 MHz, CDCl3):
d 2.97 and 2.98 (6H, 2s, NMe2), 3.78 and
2.3. C24H21Br2NO3 requires: C, 54.3; H, 4.0; N, 2.6%.) lmax 214 nm (
4700 cmꢁ1 Mꢁ1), 315 (5600). nmax 3200, 1620, 1590, 1545, 1340,
1205, 1165, 1060, 1010, 800 cmꢁ1 1H NMR spectrum (300 MHz,
CDCl3): 2.06 (1H, br s, OH), 3.78 and 3.85 (6H, 2s, OMe), 4.16 (2H,
3
3.84 (6H, 2s, OMe), 4.77 (2H, s, CH2), 6.25 (1H, d, J 2.0 Hz, H5), 6.33
(1H, d, J 2.0 Hz, H7), 6.86 (1H, s, H2), 7.44 (4H, s, ArH). 13C NMR
.
spectrum (75 MHz, CDCl3): d 36.0 and 36.6 (NMe2), 48.3 (CH2), 55.1
d
and 55.6 (OMe), 85.4 (C5), 92.2 (C7), 124.8 (C2), 130.5 and 131.0
(ArCH), 110.4, 117.3, 119.5, 134.8, 139.1, 154.9 and 157.8 (ArC), 166.9
(CO). Mass spectrum: m/z 418 (M, 81Br, 64%), 416 (M, 79Br, 66), 346
(78), 344 (83), 330 (22), 207 (22), 72 (100).
d, J 6.2 Hz, CH2), 4.98 (1H, d, J 6.2 Hz, CH), 6.26 (1H, br s, H5), 6.35
(1H, br s, H7), 6.82 (1H, s, H2), 7.17–7.51 (8H, m, ArH). 13C NMR
spectrum (75 MHz, CDCl3):
d 54.0 (CH2), 55.1 and 55.7 (OMe), 72.8
(CH), 85.6 (C5), 92.1 (C7),110.6,117.0,119.6,122.2,134.7,138.7,140.0,
155.0 and 157.7 (ArC), 125.0 (C2), 127.6, 130.6, 131.0 and 131.8
(ArCH). Mass spectrum: m/z 533 (M, 81Br, 21%), 531 (M, 79,81Br, 42),
529 (M, 79Br, 21), 347 (20), 346 (97), 344 (100), 77 (28).
4.1.5. N,N-Dimethyl-4,6-dimethoxy-2,3-diphenylindol-1-
ylacetamide (11)
This was prepared by reacting a suspension of potassium hy-
droxide (0.72 g, 12.77 mmol) in dimethyl sulfoxide (40 mL) with
diphenylindole 617 (3.0 g, 9.12 mmol) and N,N-dimethyl-
chloroacetamide (1.66 g, 13.68 mmol) according to the method of
preparation of compound 9. The resulting precipitate was filtered,
washed with water, dried and recrystallised from dichloro-
methane/light petroleum to give indolylacetamide 11 as a white
solid (3.41 g, 90%), mp 168–171 ꢀC. (Found: C, 75.2; H, 6.5; N, 6.6.
C26H26N2O3 requires: C, 75.3; H, 6.3; N, 6.8%.) nmax 1650, 1580, 1330,
4.1.2. 3-(40-Bromophenyl)-4,6-dimethoxy-1-(1-phenyl-40-
bromophenethyl)indole (3)
Boron trifluoride etherate (four drops) was added into a cooled
solution of indole 2 (0.20 g, 0.35 mmol) in dry benzene (10 mL). The
mixture was heated at reflux for 2 h, allowed to cool, diluted with
chloroform (80 mL), washed with water, dried over magnesium
sulfate, and evaporated to leave a brown oil. Thin layer chroma-
tography and elution with light petroleum in dichloromethane
(1:4) afforded phenethylindole 3 as a yellow solid (0.13 g, 63%), mp
87–89 ꢀC. (Found: C, 61.7; H, 4.9; N, 2.0. C30H25Br2NO2$0.3C5H12
requires: C, 61.7; H, 4.7; N, 2.3%.) 1H NMR spectrum (300 MHz,
.
1270, 1215, 1140, 1060, 805, 760, 700 cmꢁ1 1H NMR spectrum
(300 MHz, CDCl3): 2.87 and 2.99 (6H, 2s, NMe2), 3.72 and 3.90
d
(6H, 2s, OMe), 4.73 (2H, s, CH2), 6.29 (1H, d, J 1.3 Hz, H5), 6.37 (1H, d,
J 1.3 Hz, H7), 7.10–7.40 (10H, m, ArH). 13C NMR spectrum (75 MHz,
CDCl3):
d
3.80 and 3.82 (6H, 2s, OMe), 4.45 (1H, t, J 7.4 Hz, CH), 4.60
CDCl3): d 36.0 and 36.3 (NMe2), 46.3 (CH2), 55.3 and 55.7 (OMe),
and 4.63 (2H, 2d, J 7.4 Hz, CH2), 6.25 (1H, d, J 1.8 Hz, H5), 6.27 (1H, d,
J 1.8 Hz, H7), 6.40 (1H, s, H2), 6.99–7.43 (13H, m, ArH). Mass spec-
trum (MALDI): m/z 590 (Mþ1, 79Br, 47%), 400 (32), 379 (46), 190
(95), 172 (95), 146 (52).
85.9 (C5), 92.5 (C7), 125.2, 126.7, 127.6, 128.2, 131.2 and 131.5
(ArCH), 111.7, 115.8, 131.9, 135.7, 135.8, 139.1, 155.1 and 157.6 (ArC),
167.5, CO. Mass spectrum: m/z 414 (M, 49%), 342 (22), 327 (24), 210
(67), 209 (44), 151 (100), 83 (48), 72 (33).
4.1.3. N,N-Dimethyl-4,6-dimethoxy-3-phenylindol-1-
ylacetamide (9)
4.1.6. Dimethyl 4,6-dimethoxy-1-(N,N-dimethylacetamido)indolyl-
2,3-dicarboxylate (12)
A
mixture of powdered potassium hydroxide (0.47 g,
Method A. Sodium hydride (80% in paraffin oil, 29 mg,
0.96 mmol) was added into an ice-cooled solution of indole diester
718 (0.20 g, 0.68 mmol) in dry tetrahydrofuran (10 mL) under ni-
trogen. The mixture was stirred at 0 ꢀC for 15 min, then N,N-
dimethylbromoacetamide (0.17 g, 1.02 mmol) was added dropwise
5.93 mmol) and dimethyl sulfoxide (20 mL) was stirred at room
temperature for 10 min, then phenylindole 417,18 (1.50 g,
5.93 mmol) was added and the mixture was stirred for another
30 min. N,N-Dimethylchloroacetamide (1.10 g, 8.90 mmol) was

Jumina et al. / Tetrahedron 65 (2009) 2591–2598
2595
and stirring continued at room temperature overnight. Excess hy-
dride was destroyed by the slow addition of cold water (40 mL) and
the resulting precipitate was filtered, washed with water and dried.
Thin layer chromatography and elution with dichloromethane in
ethyl acetate (1:3) gave indolylacetamide 12 as a white solid (0.18 g,
70%), mp 227–229 ꢀC. (Found: C, 57.5; H, 5.8; N, 7.3. C18H22N2O7
d 35.6 and 36.1 (NMe2), 53.1 (CH2), 55.1 and 56.8 (OMe), 87.4 (C5),
125.7, 127.2, 129.5 and 129.6 (ArCH), 106.7, 112.9, 118.7, 135.4, 136.7,
160.9, 164.9 and 168.2 (ArC), 188.4 (CHO). Mass spectrum: m/z 366
(M, 49%), 294 (100), 266 (68), 236 (22), 84 (27), 72 (96).
4.1.9. N,N-Dimethyl-4,6-dimethoxy-7-formyl-2,3-diphenylindol-1-
ylacetamide (15)
requires: C, 57.1; H, 5.9; N, 7.4%). lmax 213 nm (
249 (15,900), 312 (16,500). nmax 1705, 1665, 1625, 1580, 1535, 1280,
1240, 1210, 1160 cmꢁ1. 1H NMR spectrum (300 MHz, CDCl3):
2.96
3
14,800 cmꢁ1 Mꢁ1),
This was prepared by reacting a cooled solution of phosphoryl
chloride (0.33 mL, 3.62 mmol) in dry dimethylformamide (1.0 mL)
with an ice-cooled solution of indole 11 (1.0 g, 2.41 mmol) in dry
dimethylformamide (15 mL) according to the method of prepara-
tion of compound 14. The resulting precipitate was filtered, washed
with water and dried. Flash chromatography and elution with ethyl
acetate in dichloromethane (1:9) afforded formylindole 15 as
a white solid (0.88 g, 82%), mp 216–218 ꢀC. (Found: C, 73.5; H, 6.2;
N, 6.3. C27H26N2O4 requires C, 73.3; H, 5.9; N, 6.3%.) lmax 211 nm
d
and 3.10 (6H, 2s, NMe2), 3.78, 3.79, 3.83 and 3.90 (12H, 4s, OMe and
CO2Me), 5.15 (2H, s, CH2), 6.15 (1H, s, H5), 6.18 (1H, s, H7). 13C NMR
spectrum (75 MHz, CDCl3): d 35.8 and 36.3 (NMe2), 46.3 (CH2), 51.8,
52.4, 55.5 and 55.7 (OMe), 84.4 (C5), 93.7 (C7), 110.0, 116.5, 121.7,
140.4, 154.7 and 160.8 (ArC), 161.4, 167.0 and 167.5 (CONMe2 and
CO2Me). Mass spectrum: m/z 379 (Mþ1, 22%), 378 (M, 100), 347
(21), 306 (90), 276 (37), 72 (39).
Method B. Sodium hydride (80% in paraffin oil, 20 mg,
0.48 mmol) was added into an ice-cooled solution of indole diester
718 (0.010 g, 0.34 mmol) in dry tetrahydrofuran (6 mL) under ni-
trogen. The mixture was stirred at 0 ꢀC for 15 min, then potassium
iodide (0.090 g, 0.51 mmol) was added followed by N,N-dimethyl-
chloroacetamide (80 mg, 0.68 mmol) dropwise and then stirring
continued at room temperature for 4 h. Further treatment and
purification according to method A afforded indolylacetamide 12 as
a white solid (0.010 g, 78%), mp 227–230 ꢀC.
(3
24,000 cmꢁ1 Mꢁ1), 259 (21,800), 329 (10,700), 355 (9100). nmax
3310, 1665, 1575, 1265, 1220, 1170, 1050, 755, 700 cmꢁ1 1H NMR
spectrum (300 MHz, CDCl3): 2.84 and 2.88 (6H, 2s, NMe2), 3.76
.
d
and 3.96 (6H, 2s, OMe), 5.41 (2H, s, CH2), 6.23 (1H, s, H5), 7.13–7.28
(10H, m, ArH), 10.41 (1H, s, CHO). 13C NMR spectrum (75 MHz,
CDCl3):
d 35.6 and 36.1 (NMe2), 49.8 (CH2), 55.2 and 56.9 (OMe),
87.9 (C5), 125.4, 126.6, 127.8, 128.0, 131.3 and 131.5 (ArCH), 106.8,
113.5, 116.8, 131.8, 135.6, 137.2, 139.4, 161.0, 165.0 and 168.3 (ArC),
188.5 (CHO). Mass spectrum: m/z 442 (M, 48%), 370 (52), 342 (24),
72 (100), 58 (33).
4.1.7. N,N-Dimethyl-4,6-dimethoxyindol-1-ylacetamide (13)
This was prepared by reacting a suspension of powdered po-
tassium hydroxide (0.090 g, 1.61 mmol) in dimethyl sulfoxide
(4 mL) with 4,6-dimethoxyindole 87,8 (0.19 g, 1.06 mmol) and N,N-
dimethylchloroacetamide (0.21 g, 1.70 mmol) according to the
method of preparation of compound 9. The resulting precipitate
was filtered, washed with water and dried to afford indolylaceta-
mide 13 as a white solid (0.23 g, 82%), mp 176–178 ꢀC (from
dichloromethane/light petroleum). (Found: C, 64.0; H, 7.2; N, 10.5.
C14H18N2O3 requires: C, 64.1; H, 6.9; N, 10.7%.) lmax 212 nm
4.1.10. N,N-Dimethyl-4,6-dimethoxy-1-(N,N-dimethylacetamido)-
2,3-diphenylindol-7-yl-glyoxylamide (16)
Oxalyl chloride (0.08 mL, 0.96 mmol) was added dropwise into
a solution of indole 11 (0.20 g, 0.48 mmol) in dry benzene (10 mL)
under nitrogen. The mixture was stirred at room temperature for
2 h, then aqueous dimethylamine (40%, 0.37 mL, 2.88 mmol) was
added and the stirring continued for another 30 min. The mixture
was diluted with chloroform (80 mL), then washed with water,
dried over magnesium sulfate and evaporated to leave a yellow
solid. Recrystallisation from dichloromethane/light petroleum
afforded indolylglyoxylamide 16 as a bright yellow solid (0.22 g,
89%), mp 243–245 ꢀC. (Found: C, 68.8; H, 6.2; N, 7.8. C30H31N3"-
O5$0.5H2O requires C, 69.0; H, 6.2; N, 8.0%.) lmax 214 nm
(3
7400 cmꢁ1 Mꢁ1), 232 (7300), 269 (7500). nmax 1650, 1585, 1340,
1310, 1270, 1200, 1145, 1045, 810, 700 cmꢁ1 1H NMR spectrum
(300 MHz, CDCl3): 2.94 and 2.97 (6H, 2s, NMe2), 3.84 and 3.90
.
d
(6H, 2s, OMe), 4.78 (2H, s, CH2), 6.22 (1H, d, J 1.8 Hz, H5), 6.35 (1H, d,
J 1.8 Hz, H7), 6.55 (1H, d, J 3.1 Hz, H3), 6.85 (1H, d, J 3.1 Hz, H2). 13C
(3
14,100 cmꢁ1 Mꢁ1), 240 (13,900), 264 (14,800), 333 (8300), 364
(6700). nmax 1645, 1570, 1260, 1215, 1120, 1150, 760, 700 cmꢁ1. 1H
NMR spectrum (300 MHz, CDCl3): 2.81, 2.87, 2.99 and 3.06 (12H,
NMR spectrum (75 MHz, CDCl3):
d 36.0 and 36.6 (NMe2), 48.7
(CH2), 55.3 and 55.7 (OMe), 85.4, 91.6, 99.6 and 125.4 (ArCH), 113.5,
137.9, 153.8 and 157.8 (ArC), 167.3, CO. Mass spectrum: m/z 262
(M, 66%), 190 (100), 175 (32), 132 (30), 72 (38).
d
4s, NMe2), 3.73 and 3.86 (6H, 2s, OMe), 4.93 (2H, s, CH2), 6.21 (1H,
s, H5), 7.11–7.28 (10H, m, ArH). 13C NMR spectrum (75 MHz,
CDCl3): d 34.2, 35.8, 36.2 and 37.1 (NMe2), 48.6 (CH2), 55.3 and 57.5
4.1.8. N,N-Dimethyl-4,6-dimethoxy-7-formyl-3-phenylindol-1-
ylacetamide (14)
(OMe), 88.6 (C5), 125.4, 126.6, 127.8, 127.9, 131.3 and 131.6 (ArCH),
105.5, 114.4, 116.7, 131.7, 135.6, 137.5, 140.0, 160.2 and 161.3 (ArC),
168.0 and 169.6 (CONMe2), 189.8 (COCONMe2). Mass spectrum: m/z
514 (M, 13%), 513 (34), 441 (60), 413 (21), 72 (78), 58 (100). Crystals
for X-ray determination were obtained from isopropanol/
chloroform.
A cooled solution of phosphoryl chloride (0.31 mL, 3.33 mmol)
in dry dimethylformamide (1.0 mL) was added dropwise into an
ice-cooled solution of indole 9 (0.75 g, 2.22 mmol) in dry dime-
thylformamide (15 mL). The mixture was stirred at 0 ꢀC for 30 min
and then at room temperature for another 1 h. Cold water (10 mL)
was added, followed by 2 M aqueous sodium hydroxide, until the
mixture was strongly basic. The suspension was stirred at room
temperature overnight, the resulting precipitate was filtered,
washed with water, dried and recrystallised from dichloro-
methane/light petroleum to give formylindole 14 as a yellow solid
(0.67 g, 83%), mp 223–225 ꢀC. (Found: C, 69.0; H, 6.1; N, 7.5.
C21H22N2O4 requires C, 68.8; H, 6.1; N, 7.7%). lmax 212 nm
4.1.11. Methyl 1-carbethoxymethyl-2,3-diphenylindol-7-
ylglyoxylate (17)
Oxalyl chloride (0.10 mL, 1.08 mmol) was added dropwise into
a
solution of ethyl 2,3-diphenylindol-1-ylacetate1 (0.15 g,
0.36 mmol) in dry benzene (7 mL) under nitrogen. The mixture was
stirred at room temperature for 15 min and then warmed at 70 ꢀC
for 2 h. The mixture was allowed to cool, excess methanol was
added and stirring continued for 30 min. The resulting precipitate
was filtered, washed with dichloromethane/light petroleum (1:1)
(20 mL) and dried to give indolylglyoxylate 17 as a light yellow solid
(0.080 g, 44%), mp 185–187 ꢀC. (Found: C, 69.6; H, 5.6; N, 2.7.
C29H27NO7 requires C, 69.5; H, 5.4; N, 2.8%.) lmax 213 nm
(3
15,100 cmꢁ1 Mꢁ1), 228 (13,600), 260 (15,900), 340 (8800). nmax
1660, 1570, 1550, 1335, 1270, 1220, 1070 cmꢁ1 1H NMR spectrum
(300 MHz, CDCl3): 2.92 and 3.08 (6H, 2s, NMe2), 3.81 and 3.90
.
d
(6H, 2s, OMe), 5.48 (2H, s, CH2), 6.18 (1H, s, H5), 6.78 (1H, s, H2),
7.23 (1H, t, J 7.2 Hz, H40), 7.31 (2H, t, J 7.2 Hz, H30), 7.49 (2H, d, J
7.2 Hz, H20), 10.34 (1H, s, CHO). 13C NMR spectrum (75 MHz, CDCl3):
(3
14,200 cmꢁ1 Mꢁ1), 245 (14,600), 267 (15,200), 325 (10,100), 371

2596
Jumina et al. / Tetrahedron 65 (2009) 2591–2598
(7900). nmax 1740, 1660, 1580, 1305, 1245, 1210, 1160, 1055,
705 cmꢁ1 1H NMR spectrum (300 MHz, CDCl3):
1.17 (3H, t, J
4,6-Dimethoxyisatin (12.0 g, 58.0 mmol) was added in portions
over a period of 2 h into a mixture of lithium aluminium hydride
(11.0 g, 289.9 mmol) in dry dioxane (300 mL) at reflux. Heating was
continued for another 10 h, then the mixture was cooled and excess
hydride was destroyed by cautious treatment with cold water
(60 mL). The solvent was removed under reduced pressure and the
residue was extracted with dichloromethane (3ꢂ90 mL). The
combined organic layers were washed once with brine (40 mL),
dried over magnesium sulfate and evaporated to leave a purple
solid. Flash chromatography and elution with dichloromethane
gave indole 8 as a white solid (4.98 g, 49%), mp 118–120 ꢀC
(lit.7 119–120.5 ꢀC).
.
d
6.9 Hz, CH2CH3), 3.74, 3.88 and 3.90 (9H, 3s, OMe), 4.11 (2H, q, J
6.9 Hz, CH2CH3), 4.82 (2H, s, CH2), 6.24 (1H, s, H5), 7.13–7.28 (10H,
m, ArH). 13C NMR spectrum (75 MHz, CDCl3):
d 14.0 (CH2CH3), 49.1
and 61.2 (CH2), 52.4, 55.3 and 57.4 (OMe), 88.6 (C5), 125.6, 126.7,
128.2, 128.4, 131.2 and 131.4 (ArCH), 104.3, 114.1, 117.0, 131.1, 135.1,
136.4, 139.2, 160.3 and 161.6 (ArC), 165.3 and 169.1 (CO2Et and
COCO2Me), 185.1 (COCO2Me). Mass spectrum: m/z 502 (M, 26%),
501 (82), 443 (30), 442 (100), 399 (23), 355 (24), 254 (31), 59 (49).
4.1.12. 2-Chloro-(40,60-dimethoxy-20,30-diphenylindol-70-
yl)ethanone (18)
Phosphoryl chloride (0.70 mL, 7.60 mmol) was added dropwise
into cooled N,N-dimethylchloroacetamide (1.85 g, 15.20 mmol) and
then diphenylindole 617 (0.50 g, 1.52 mmol) was added. The mix-
ture was stirred at 0 ꢀC for 15 min, then heated at 80 ꢀC for 2 h and
further treatment was according to the method of preparation of
compound 15. Flash chromatography and elution with dichloro-
methane yielded chloroacetylindole 18 as a yellow solid (0.56 g,
90%), mp 233–235 ꢀC. (Found: C, 70.1; H, 5.1; N, 3.3. C24H20"-
4.1.15. 4,6-Dimethoxyindoline (20)
Method A. Sodium cyanoborohydride (6.41 g, 101.7 mmol) was
added into a solution of 4,6-dimethoxyindole 8 (6.0 g, 33.9 mmol)
in glacial acetic acid (120 mL) at 15 ꢀC under nitrogen. The mixture
was stirred for 45 min, then diluted with water (250 mL), cooled in
an ice bath and made strongly basic by slowly adding sodium hy-
droxide pellets. The resulting white suspension was extracted with
ether (3ꢂ90 mL) and the combined ethereal layers were washed
with water, dried over magnesium sulfate and evaporated to give
an off-white solid. Recrystallisation from dichloromethane/light
petroleum afforded the indoline 20 as a white solid (5.70 g, 94%),
mp 60–62 ꢀC. (Found: C, 67.0; H, 7.4; N, 7.8; C10H13NO2 requires C,
ClNO3$0.2H2O requires C, 70.4; H, 5.0; N, 3.4%.) lmax 213 nm (
3
900 cmꢁ1 Mꢁ1), 269 (900), 304 (900), 330 (1000), 358 (900). nmax
3410, 1635,1590, 1215, 1160, 1140, 990, 700 cmꢁ1. 1H NMR spectrum
(300 MHz, CDCl3):
6.22 (1H, s, H5), 7.26–7.44 (10H, m, ArH), 11.15 (1H, s, NH). 13C NMR
spectrum (75 MHz, CDCl3): 52.2 (CH2), 55.4 and 56.3 (OMe), 86.8
d 3.85 and 4.08 (6H, 2s, OMe), 4.97 (2H, s, CH2),
67.0; H, 7.3; N, 7.8%). lmax 214 nm (
285 (2000). nmax 3280, 1610, 1500, 1350, 1200, 1140, 1100, 1040, 800,
780 cmꢁ1 1H NMR spectrum (300 MHz, CDCl3):
2.92 (2H, t, J
3
6100 cmꢁ1 Mꢁ1), 230 (5900),
d
(C5), 126.1, 127.1, 127.4, 127.6, 128.3 and 131.2 (ArCH), 102.2, 128.0,
128.7, 132.2, 133.2, 135.5, 138.0, 160.7 and 160.8 (ArC), 190.1 (CO).
Mass spectrum: m/z 407 (Mþ1, 37%), 406 (M, 32), 405 (100), 357
(20), 356 (76), 254 (38), 178 (38), 133 (39), 49 (44).
.
d
8.5 Hz, H3), 3.39 (1H, s, NH), 3.56 (2H, t, J 8.5 Hz, H2), 3.74 and 3.80
(6H, 2s, OMe), 5.90 (1H, d, J 2.1 Hz, H5), 5.94 (1H, d, J 2.1 Hz, H7). 13C
NMR spectrum (75 MHz, CDCl3):
d 26.3 (C3), 47.7 (C2), 55.3 and
55.5 (OMe), 89.1 and 89.6 (C5,7), 108.1, 153.4, 156.7 and 161.3 (ArC).
Mass spectrum: m/z 179 (M, 100%), 178 (93), 163 (20), 150 (24), 148
(40), 147 (26), 136 (22).
4.1.13. 2-Chloro-(40,60-dimethoxy-20,30-diphenylindol-70-yl)
ethanol (19)
Sodium borohydride (60 mg, 1.59 mmol) was added into
a cooled solution of indole 18 (0.15 g, 0.37 mmol) in 5% aqueous
dioxane (10 mL). The mixture was stirred at 0 ꢀC for 30 min, then at
room temperature for another 2 h and further treatment was
according to the method of preparation of compound 2. Recrys-
tallisation from dichloromethane/light petroleum gave the
hydroxyethylindole as a white solid (0.13 g, 86%), but it was un-
stable and could not be obtained pure. 1H NMR spectrum (300 MHz,
Method B. Palladium on charcoal (10%, 1.00 g) was added into
a solution of 4,6-dimethoxyindole 8 (1.89 g, 10.68 mmol) in formic
acid (90%, 35 mL) under nitrogen. The mixture was heated at 70 ꢀC
for 1.5 h, then the catalyst was filtered and washed with 80%
aqueous methanol (100 mL). The combined filtrate was evaporated,
and the resulting reddish-oily residue of the N-formylindoline was
heated at reflux for 2 h with a solution of potassium hydroxide
(6.00 g, 106.80 mmol) in methanol (100 mL). The solvent was re-
moved under reduced pressure and the residue diluted with water
(60 mL). The resulting brown precipitate was filtered, washed with
water and dried. Flash chromatography and elution with ethyl ac-
etate in dichloromethane (3:17) afforded indoline 20 as a pale
yellow solid (0.67 g, 35%, mp 58–62 ꢀC).
CDCl3): d 3.73 and 3.96 (6H, 2s, OMe), 3.89 (1H, m, CH2), 4.10 (1H, t, J
10.5 Hz, CH2), 5.48 (1H, qt, J 4.9 Hz, CH), 6.04 (1H, d, J 4.9 Hz, OH),
7.35 (10H, br s, ArH), 10.35 (1H, s, NH). 13C NMR spectrum (75 MHz,
CDCl3):
d 49.0 (CH2), 55.3 and 56.9 (OMe), 68.1 (CH), 89.4 (C5),
104.5, 113.2, 113.4, 132.5, 132.6, 135.7, 136.2, 152.9 and 154.0 (ArC),
126.0, 127.0, 127.3, 128.2, 128.3 and 131.3 (ArCH).
4.1.16. 4,6-Dimethoxy-N-nitrosoindoline (21)
4.1.14. 4,6-Dimethoxyindole (8)
A solution of sodium nitrite (0.25 g, 3.63 mmol) in water (1 mL)
was added dropwise into a cooled solution of indoline 20 (0.50 g,
2.79 mmol) in absolute ethanol (15 mL) containing concentrated
hydrochloric acid (0.3 mL). The mixture was stirred at 0 ꢀC for
45 min and then at room temperature for another 1 h. The mixture
was poured into cold water (50 mL) and the resulting suspension
was extracted with dichloromethane (3ꢂ50 mL). The combined
organic layers were washed with water, dried over magnesium
sulfate and evaporated to give nitrosoindoline 21 as a grey solid
(0.52 g, 90%), mp 134–136 ꢀC (from isopropanol/chloroform).
(Found: C, 57.8; H, 5.6; N, 13.2. C10H12N2O3 requires C, 57.7; H, 5.8;
The original procedure7 for the preparation of this compound
was as follows: to an ice cold, stirred suspension of lithium alu-
minium hydride (4.62 g, 122.0 mmol) in dioxane (200 mL) was
slowly added 4,6-dimethoxyisatin (5.0 g, 24.0 mmol). The mixture
was cautiously heated to boiling over a 5 h period and then main-
tained at reflux for 15 h. The mixture was cooled and treated with
absolute ethanol and water followed by removal of the solvent in
vacuo. The residue was thrice extracted with chloroform and the
combined extracts were dried over magnesium sulfate and evap-
orated in vacuo to leave a purple solid residue. Chromatography on
silica gel with elution by chloroform gave 1.82 g (43%) of white
crystals, mp 119–120.5 ꢀC (from benzene/cyclohexane).
N, 13.5%.) lmax 213 nm (
325 (5900). nmax 1630,1610,1510,1300,1265,1240,1210,1160,1035,
820 cmꢁ1 1H NMR spectrum (300 MHz, CDCl3):
2.96 (2H, t, J
3
4600 cmꢁ1 Mꢁ1), 242 (4800), 282 (5000),
Some difficulties leading to an uncontrolled reaction were found
when this procedure was used for the reduction of more than 10 g
of 4,6-dimethoxyisatin. The following procedure was found to be
safer and gave comparable yields.
.
d
7.7 Hz, H3), 3.79 and 3.80 (6H, 2s, OMe), 4.06 (2H, t, J 7.7 Hz, H2),
6.26 (1H, d, J 2.0 Hz, H5), 6.90 (1H, d, J 2.0 Hz, H7). 13C NMR spec-
trum (75 MHz, CDCl3):
d 22.7 (C3), 46.9 (C2), 55.4 and 55.7 (OMe),

Jumina et al. / Tetrahedron 65 (2009) 2591–2598
2597
88.6 and 97.0 (ArCH), 112.1, 142.3, 156.9 and 161.7 (ArC). Mass
spectrum (ES): m/z 209 (Mþ1, 92%), 179 (100).
62%), which could not be obtained analytically pure. Mp 126–
128 ꢀC. lmax 215 nm ( 2700 cmꢁ1 Mꢁ1), 241 (2800), 267 (3000),
291 (3200). nmax 1645, 1610, 1525, 1500, 1430, 1325, 1270, 1210,
1200, 1170, 1105, 1070, 725 cmꢁ1 1H NMR spectrum (300 MHz,
CDCl3): 3.85 (2H, t, J 7.2 Hz, H5), 3.91 and 3.95 (6H, 2s, OMe), 4.43
3
4.1.17. 4,5-Dihydro-6,8-dimethoxy-1,2-dioxopyrrolo[3,2,1-hi]
indole (22)
.
d
Hydrogen chloride gas was passed through a solution of indo-
line 20 (4.75 g, 26.50 mmol) in diethyl ether (200 mL) at room
temperature for 1.5 h. The resulting white precipitate was filtered,
washed with diethyl ether (80 mL) and dried. This indoline hy-
drochloride salt (5.42 g) was added in portions with stirring into
oxalyl chloride (15.82 mL, 185.5 mmol) over a period of 30 min and
then the mixture was heated directly at 135–140 ꢀC for 2 h. The
resulting green solid was washed with light petroleum (150 mL),
then flash chromatographed and eluted with ethyl acetate in
dichloromethane (1:9) to give dihydrodioxopyrroloindole 22 as
a bright yellow solid (2.83 g, 48%), mp 212–214 ꢀC. (Found: C, 60.7;
H, 5.1; N, 5.8. C12H11NO4$0.2H2O requires C, 60.9; H, 4.9; N, 5.9%.)
(2H, t, J 7.2 Hz, H4), 6.04 (1H, s, H7), 6.42 (1H, d, J 2.8 Hz, H1), 6.92
(1H, d J 2.8 Hz, H2). Mass spectrum: m/z 203 (M, 100%), 188 (95),
145 (27), 117 (24).
4.1.20. 6,8-Dimethoxypyrrolo[3,2,1-hi]indole (25)
Palladium on charcoal (10%, 2.0 g) was added into a solution of
tetrahydropyrroloindole 23 (0.87 g, 4.24 mmol) in nitrobenzene
(30 mL) under nitrogen. The mixture was brought to reflux over
a period of 1.5 h and then heated at that temperature for another
4 h. The mixture was allowed to cool, then the catalyst was fil-
tered off and washed with quinoline (10 mL). The combined fil-
trate was distilled under reduced pressure and the residue was
dissolved in dichloromethane (90 mL), washed with 5% hydro-
chloric acid (2ꢂ30 mL) followed by water, dried over magnesium
sulfate and evaporated to leave a brown oil. Flash chromatography
and elution with dichloromethane in light petroleum (2:3) affor-
ded pyrroloindole 25 as a pale yellow solid (0.48 g, 56%) mp 64–
66 ꢀC. (Found: C, 71.3; H, 5.8; N, 7.0. C12H11NO2 requires C, 71.6; H,
lmax 211 nm (
(10,800), 350 (4300). nmax 1730, 1675, 1590, 1310, 1260, 1225 cmꢁ1
1H NMR spectrum (300 MHz, CDCl3):
3.29 (2H, t, J 7.4 Hz, H5), 3.89
and 4.10 (6H, 2s, OMe), 4.12 (2H, t, J 7.4 Hz, H4), 5.82 (1H, s, H7). 13C
NMR spectrum (75 MHz, CDCl3): 29.4 (C5), 46.3 (C4), 56.2 and
3
14,900 cmꢁ1 Mꢁ1), 228 (12,400), 249 (94,00), 300
.
d
d
59.0 (OMe), 94.1 (C7), 94.6, 103.6, 157.3, 157.7, 161.1 (ArC), 163.2 and
178.6 (CO). Mass spectrum: m/z 233 (M, 14%), 207 (43), 205 (100),
204 (65), 178 (30), 177 (21), 148 (25), 120 (33), 69 (32).
5.5; N, 7.0%.) lmax 209 nm (
(14,400). nmax 1650, 1590, 1500, 1350, 1265, 1190, 1140 cmꢁ1
NMR spectrum (300 MHz, CDCl3): 4.13 (6H, s, OMe), 6.44 (1H, s,
H7), 6.85 (2H, d, J 3.0 Hz, H1,5), 7.36 (2H, d, J 3.0 Hz, H2,4). 13C
NMR spectrum (75 MHz, CDCl3): 57.3 (OMe), 96.7 (C7), 108.7
3
13,200 cmꢁ1 Mꢁ1), 232 (13,200), 293
1H
.
d
4.1.18. 6,8-Dimethoxy-1,2,4,5-tetrahydropyrrolo[3,2,1-hi]
indole (23)
d
A solution of trifluoroacetic acid (14.81 mL, 192.30 mmol) in
dioxane (30 mL) was added dropwise over a period of 45 min into
a stirred suspension of sodium borohydride (7.27 g, 192.30 mmol)
in dioxane (220 mL) at 10–15 ꢀC under nitrogen. Indoline isatin 22
(2.24 g, 9.61 mmol) was added and then the mixture was heated
at 70 ꢀC for 2 h. The mixture was concentrated under reduced
pressure, diluted with water (200 mL) and extracted with
dichloromethane (3ꢂ80 mL). The combined organic layers were
washed once with brine (70 mL), dried over magnesium sulfate
and evaporated to leave an orange oil. This oil was dissolved in
tetrahydrofuran (60 mL), then a solution of sodium hydroxide
(2.69 g, 67.27 mmol) in water (14 mL) was added, followed by
hydrogen peroxide (27.5%, 7.49 mL, 67.27 mmol). The mixture was
stirred at room temperature for 3 h, then the organic layer was
separated and the aqueous phase was extracted with ether
(3ꢂ70 mL). The combined organic layers were washed once with
brine (80 mL), dried over magnesium sulfate and evaporated to
(C1,5), 120.8 (C2,4), 102.6, 140.2 and 155.5 (ArC). Mass spectrum:
m/z 202 (Mþ1, 20%), 201 (M, 100), 186 (57), 158 (49), 143 (32), 101
(24).
4.2. Crystallographic study on compound 16
4.2.1. Crystal data
C30H31N3O5, M 513.6, triclinic, space group Pꢁ1, a 10.652(3),
b 11.222(3), c 12.014(4) Å,
a b g
80.63(2)ꢀ, 86.21(2)ꢀ, 71.14(2)ꢀ, V
1340.6(7) Å3, Dc 1.27 g cmꢁ3, Z 2, mCu 7.08 cmꢁ1, 2qmax 140ꢀ. The
number of reflections was 4199 considered observed out of 5076
unique data. Final residuals R, Rw were 0.046, 0.082 for the
observed data.
4.2.2. Structure determination
Reflection data were measured with an Enraf–Nonius CAD-4
give
a
brown oil. Flash chromatography and elution with
diffractometer in
copper ( 1.5418 Å) or molybdenum radiation (
flections with I>2 (I) were considered observed. The structures
q
/2
q
scan mode using graphite monochromatized
dichloromethane afforded dihydropyrroloindole 24 as a white
solid (0.36 g, 19%), mp 127–130 ꢀC. Further elution with ethyl ac-
etate in dichloromethane (1:19) gave tetrahydropyrroloindole 23
as a colourless oil (1.02 g, 52%). (Found: C, 70.0; H, 7.6; N, 6.7.
C12H15NO2 requires C, 70.2; H, 7.4; N, 6.8%.) 1H NMR spectrum
l
l
0.7107 Å). Re-
s
were determined by direct phasing and Fourier methods. Hydrogen
atoms were included in calculated positions and were assigned
thermal parameters equal to those of the atom to which they were
bonded. Positional and anisotropic thermal parameters for the non-
hydrogen atoms were refined using full matrix least squares.
(300 MHz, CDCl3):
s, H5); (C6D5CD3):
d
3.24 (8H, m, CH2), 3.81 (6H, s, OMe), 5.75 (1H,
d
2.87 (4H, t, J 7.2 Hz, H1,5), 3.11 (4H, t, J 7.2 Hz,
H2,4), 3.47 (6H, s, OMe), 5.80 (1H, s, H7). 13C NMR spectrum
Reflection weights used were 1/s s(Fo) being derived
2(Fo), with
(75 MHz, CDCl3):
101.7, 156.1 and 167.7 (ArC). Mass spectrum: m/z 205 (M, 100%),
204 (51), 190 (27), 69 (38), 43 (23).
d
32.8 (C1,5), 56.2 (OMe), 58.1 (C2,4), 90.4 (C7),
from
Rw¼(
s
(Io)¼[
s
2(Io)þ(0.04Io)2]1/2. The weighted residual is defined as
S
w
D2 wFo2)1/2. Atomic scattering factors and anomalous
/S
dispersion parameters were from International Tables for X-ray
Crystallography.20 Structure solutions were by SIR9221 and re-
finement used RAELS.22 ORTEP-II23 running on an eMac was used
for the structural diagrams, and the eMac was also used for
calculations.
4.1.19. 4,5-Dihydro-6,8-dimethoxypyrrolo[3,2,1-hi]indole (24)
Palladium on charcoal (10%, 1.74 g) was added to a suspension
of tetrahydropyrroloindole 23 (0.77 g, 3.76 mmol) in toluene
(35 mL) under nitrogen. The mixture was heated at reflux for 2.5 h,
then the catalyst was filtered off and washed with dichloro-
methane (70 mL). The combined filtrate was evaporated to leave
a brown solid. Flash chromatography and elution with dichloro-
methane gave dihydropyrroloindole 24 as a white solid (0.47 g,
Atomic coordinates, bond lengths and angles, and displacement
parameters have been deposited at the Cambridge Crystallographic
Data Centre (CCDC 694314). These data can be obtained free-of-
charge via www.ccdc.cam.ac.uk/data_request/cif, by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge

2598
Jumina et al. / Tetrahedron 65 (2009) 2591–2598
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Crystallographic Data Centre, 12 Union Rd, Cambridge CB2 1EZ, UK;
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Financial support from the Australian Research Council is
gratefully acknowledged. Jumina acknowledges receipt of a post-
graduate scholarship from the Australian Government.
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