Effective synthetic routes to activated pyrrolo[3,2,1-hi]indoles

Article abstract of DOI:10.1016/j.tet.2008.10.025

Pyrrolo[3,2,1-hi]indoles have been formed by the aldol cyclisation of 7-formyl-N-indolylacetates. The synthetic sequence incorporates three steps from suitably activated indoles: these are alkylation at nitrogen with a bromoacetic ester, formylation at C7 and an aldol condensation between these two substituents. An X-ray crystal structure of pyrrolo[3,2,1-hi]indole 24 is described. Crown Copyright

Full text of DOI:10.1016/j.tet.2008.10.025

Tetrahedron 64 (2008) 11603–11610
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Effective synthetic routes to activated pyrrolo[3,2,1-hi]indoles
*
Jumina, Paul A. Keller, 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:
Pyrrolo[3,2,1-hi]indoles have been formed by the aldol cyclisation of 7-formyl-N-indolylacetates. The
synthetic sequence incorporates three steps from suitably activated indoles: these are alkylation at
nitrogen with a bromoacetic ester, formylation at C7 and an aldol condensation between these two
substituents. An X-ray crystal structure of pyrrolo[3,2,1-hi]indole 24 is described.
Received 8 August 2008
Received in revised form
26 September 2008
Accepted 9 October 2008
Available online 15 October 2008
Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
Keywords:
Indoles
Pyrroloindoles
Aldol reaction
Cyclisation reactions
1. Introduction
structure 1a). Using a similar route from N-aminoindoline, Paudler
and Shin7 constructed the parent compound 1. Cyclisation of N,N-
Pyrrolo[3,2,1-hi]indoles 1a,b are indoles bearing an etheno link
between the indole N1 and C7 positions. The numbering system for
the pyrroloindoles is different from that of simple indoles, as shown
in structure 1a. Pyrrolo[3,2,1-hi]indoles can be considered to be
benzo-analogues of pyrrolizidines, heterocycles found in the
structures of numerous biologically active alkaloids.1,2 The funda-
mental structure is also of interest in connection with the effects of
aromaticity on its reactions. In addition to its aromaticity by virtue
of being an ‘oscillating’ indole, the effect of a zwitterionic resonance
disubstituted anilines, derived from aniline and phenacyl bromide
or bromoacetone, with polyphosphoric acid also gave
pyrroloindoles.8,9
It was of particular interest to investigate synthetic routes to
6,8-dimethoxypyrrolo[3,2,1-hi]indoles, making use of the specific
reactivity of 4,6-dimethoxyindoles at C7. Although the Fischer
synthetic methodology seemed attractive, it is known that aryl-
hydrazones bearing electron-donating groups, especially ortho- or
para- to the hydrazine unit, perform very poorly in the Fischer
synthesis.10,11 We therefore concentrated on cyclisation processes
involving activated indoles.
structure 1b could be to confer a 10
p
peripheral conjugated system
on the molecule.
7
8
6
2. Results and discussion
1
5
N
N
2
4
2.1. Reactions of diphenacylanilines
3
1a
1b
In principle, cyclisation of N,N-disubstituted anilines should be
an attractive option, and should be facilitated by the presence of
additional electron-donating groups.
Although some examples are known, these heterocyclic
compounds have been rather neglected. Anet et al.3 prepared
1,2,4,5-tetramethylpyrrolo[3,2,1-hi]indole by oxidation of a dihy-
dropyrroloindole formed by a Fischer synthesis4–6 starting with an
N-aminoindoline. NMR spectroscopic data clearly showed that the
molecule contained an axis of symmetry along N3 to C7 (see
Reaction of 3,5-dimethoxyaniline with 2 equiv of phenacyl bro-
mide or 4-bromophenacyl bromide gave the disubstituted anilines,
which were cyclised directly with trifluoroacetic acid to give the
respective N-phenacylindoles 2 and 3 (Scheme 1). Attempts to
achieve the second cyclisation through reaction with stronger acids,
such as polyphosphoric acid, failed to form pyrroloindoles. By con-
trast, the spectroscopic evidence indicated the formation of poor
yields of indolo-isoquinolines, as a result of migration of the C3-aryl
* 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 Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.025

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Jumina et al. / Tetrahedron 64 (2008) 11603–11610
group to C2, followed by cyclisation to form a six-membered ring.
Consequently this approach was not investigated further.
indoles 4 and 5 were sufficiently acidic to undergo deprotonation
with aqueous sodium hydroxide, used for the hydrolysis of the
iminium salt intermediate in the Vilsmeier reaction.
MeO
MeO
O
2.2.2. Aldol cyclisation of N-phenacylindole-7-carbaldehydes
As sodium hydroxide seemed to be a useful base for the intra-
molecular aldol condensation of formylindoles 4 and 5, the actual
condensation was carried out by treating the formylindoles in
dimethylformamide with excess saturated sodium hydroxide in
methanol to afford pyrroloindoles 6 and 7 in 63–64% yield. Although
the reactions were fast and simple, and the majority of the pyrro-
loindoles crystallised out after stirring for 15 min, the N-unsub-
stituted indole-7-carbaldehydes were also produced as minor
products. The use of alternative bases still gave rise to product
mixtures. A one-pot technique, combining the formylation and aldol
cyclisation reaction, also gave mixtures of the same types of
products.
R
RCOCH2Br
N
NH2
MeO
MeO
R
O
31-44% overall
MeO
MeO
R
N
R
POCl3 / DMF
58-69%
N
MeO
MeO
R
R
CHO
Compounds 6 and 7 were fully characterised by analytical and
spectroscopic data. For example, the 1H NMR spectrum of com-
pound 6 showed the presence of three singlets at 6.65, 7.66 and
8.22 ppm corresponding to H7, H5 and H2, respectively.
O
O
R
R
4
5
Ph
4-BrC6H4
2
3
Ph
4-BrC6H4
2.3. Preparation and formylation of N-indolylacetates
NaOH / MeOH
DMF
63-64%
R
Given the product mixtures obtained from the phenacylindole
carbaldehydes, it was decided to investigate the slightly less re-
active ester systems derived from a-haloacetates. The N-indolyl-
acetates 12–15 were obtained in 70–78% yield by the treatment of
the respective 3-aryl-4,6-dimethoxyindoles 8and 9 with potassium
hydroxide in dimethylsulfoxide followed by ethyl or methyl 2-
bromoacetate (Scheme 2). Formylation of indoles 12–14 using the
MeO
MeO
R
N
R
6
Ph
4-BrC6H4
7
R1
MeO
R1
MeO
BrCH2CO2R3
KOH / DMSO
70-86%
O
R2
R2
Scheme 1.
N
N
MeO
MeO
H
2.2. Cyclisation of 1,7-disubstituted indoles
CO2R3
R1
R2
R1
R2
R3
The most accessible cyclisation route would involve the aldol
condensation of an active methylene group on the indole nitrogen
atom with a carbonyl substituent at the indole C7 position. Elec-
trophilic substitution of 3-aryl-4,6-dimethoxyindoles occurs
predominantly at C7, with Vilsmeier formylation readily affording
the 7-carbaldehydes. Formylation at C7 should be preceded by the
8
9
4-BrC6H4
Ph
Ph
H
H
Ph
12
13
4-BrC6H4
4-BrC6H4
Ph
Ph
Ph
H
H
H
H
Ph
Et
Me
Et
Me
Et
10
14
15
19
CO2Me CO2Me
11
20 CO2Me CO2Me Et
alkylation with an a-halocarbonyl compound at the indole nitro-
21
Me
CO2Me CO2Me
gen. Not only would the N-alkylated indole be more reactive
towards the Vilsmeier reagent, but a 7-carbaldehyde would be less
reactive towards alkylation: indeed it has been found that N-al-
kylation of 4,6-dimethoxy-2,3-diphenylindole-7-carbaldehyde
could not be effected.12
POCl3 / DMF
MeO
54-81%
MeO
R1
R1
2.2.1. Formylation of N-phenacylindoles
Formylation of N-phenacylindoles 2 and 3 with 1.5 equiv of the
Vilsmeier reagent afforded 7-carbaldehydes 4 and 5 in 58 and 69%
yield, respectively. Only moderate yields were obtained as the
formyl compounds underwent further cyclisation to the ultimately
desired pyrroloindoles 6 (10%) and 7 (18%) (Scheme 1). While for-
mylation of 4,6-dimethoxyindoles has been reported to occur at
0 ꢀC or room temperature,12–14 heating at 80 ꢀC was required for
the formylation of indoles 2 and 3. This lower reactivity is pre-
sumably caused by the steric effect of the relatively bulky phenacyl
substituent at N1. The 1H NMR spectra of compounds 4 and 5
displayed singlets for H5 (6.25–6.28 ppm), singlets for H2 (6.79–
6.84 ppm) and downfield singlets for CHO (10.24–10.30 ppm). The
fact that pyrroloindoles 6 and 7 were already found in the for-
NaH / THF
30-78%
R2
R2
N
MeO
N
MeO
CO2R3
CHO
CO2R3
R2
R1
R3
R1
R2
H
H
H
R3
Et
Me
Et
Et
16
17
18
22
4-BrC6H4
4-BrC6H4
Ph
24
25
4-BrC6H4
4-BrC6H4
Ph
H
H
H
Ph
Ph
Et
Me
Et
Et
H
26
27
28
Ph
Ph
Ph
Ph
23 CO2Me CO2Me Et
29 CO2Me CO2Me Et
mylation stage of the sequence indicated that the
a
-CH2 protons of
Scheme 2.

Jumina et al. / Tetrahedron 64 (2008) 11603–11610
11605
4. Experimental
C17
4.1. General
O1
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-
C5
C15
O2
Br
C4
C7
C3
C8
C14
C16
C6
C13
C2
N1
C11
C18
C12
C1
C10
C9
C19
formed using Merck silica gel 7730 60GF254
.
O3
O4
4.2. 4,6-Dimethoxy-1-phenacyl-3-phenylindole (2)
C20
A mixture of 3,5-dimethoxyaniline (3.0 g, 19.6 mmol),
a-bro-
C21
moacetophenone (7.80 g, 39.2 mmol) and sodium carbonate
(8.30 g, 78.4 mmol) in 95% ethanol (50 mL) was heated at reflux for
4 h. The mixture was allowed to cool, the resulting precipitate was
filtered, washed with water and recrystallised from chloroform/
light petroleum to give the diphenacylaniline as a brown solid
(2.74 g, 36%), mp 130–133 ꢀC. 1H NMR spectrum (300 MHz, CDCl3):
Figure 1. ORTEP diagram derived from the single-crystal X-rayanalysisof compound 24.
Vilsmeier reagent at 0 ꢀC was regioselective and gave the related
indole-7-carbaldehydes 16–18 in 54–81% yield, without formation
of the 2-isomers. The 1H NMR spectroscopic data showed the re-
placement of the H5 and H7 doublets of the starting materials with
an H5 singlet and a formyl proton. 2,3-Diphenyl-4,6-dimethoxy-
indole 10 and dimethyl 4,6-dimethoxyindole-2,3-dicarboxylate 11
were also converted to the related indolylacetates 19–21 in 80–86%
yield, and compounds 19 and 20 were formylated to give the 7-
aldehydes 22 and 23 in 78–79% yield (Scheme 2).
Treatment of the 7-formyl-N-indolylacetates 16–18, 22 and 23
with sodium hydride in boiling tetrahydrofuran gave only moder-
ate yields of the pyrroloindoles 24–27 and 29 (Scheme 2). The
starting aldehydes were relatively insoluble and some ester hy-
drolysis also occurred. The use of weaker bases (triethylamine, or
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)) was ineffective, while
stronger bases (potassium hydride or n-butyllithium) resulted in
removal of the carboxymethyl group and formation of the re-
spective indole-7-aldehyde.
d
3.67 (6H, s, OMe), 4.9 (4H, s, CH2), 5.72 (2H, d, J 2.5 Hz, H2,6), 5.92
(1H, t, J 2.5 Hz, H4), 7.51, 7.61 and 8.01 (10H, m, ArH). 13C NMR
spectrum (75 MHz, CDCl3): 55.0 (OMe), 58.0 (CH2), 89.6 (C4), 92.4
d
(C2,6), 127.8, 128.8 and 133.6 (ArCH), 135.1, 150.4 and 161.6 (ArC),
196.4 (CO). Mass spectrum: m/z 389 (M, 8%), 284 (62), 166 (22), 105
(84), 91 (100), 84 (30), 77 (74).
The diphenacylaniline (0.20 g, 0.51 mmol) was added into ice-
cooled trifluoroacetic acid (4.0 mL), then the mixture was heated at
70 ꢀC for 1 h. The mixture was allowed to cool, diluted with ice-
water (15 mL) and the resulting precipitate was filtered, washed
with water and dried. Thin layer chromatography and elution with
chloroform afforded the phenacylindole 2 as a brown solid (0.17 g,
87%), mp 96–98 ꢀC. (Found: C, 77.5; H, 6.0; N, 3.6. C24H21NO3 re-
quires C, 77.6; H, 5.7; N, 3.8%.) lmax 210 nm (
241 (70,600), 282 (39,000). nmax 1700, 1620, 1600, 1220, 1200,
1140 cmꢁ1 1H NMR spectrum (300 MHz, CDCl3):
3.80 and 3.81
(6H, 2s, OMe), 5.39 (2H, s, CH2), 6.25 (1H, d, J 2.3 Hz, H5), 6.28 (1H,
d, J 2.3 Hz, H7), 6.89 (1H, s, H2), 7.36 and 7.51 (6H, 2 t, J 7.3 Hz, meta,
para-ArH), 7.63 and 8.00 (4H, 2d, J 7.3 Hz, ortho-ArH). 13C NMR
3
63,900 cmꢁ1 Mꢁ1),
.
d
Compounds 24–26 and 29 were fully characterised and the 1H
NMR spectroscopic data for compounds 24–26 showed the pres-
ence of three singlets at 6.4–6.5, 7.3–7.6 and 7.4–7.9 ppm corre-
sponding to H7, H5 and H2, respectively. The infrared carbonyl
stretching frequency of the aldehyde at 1750 cmꢁ1 in the starting
material was no longer observed.
spectrum (75 MHz, CDCl3):
d 52.5 (CH2), 55.1 and 55.7 (OMe), 85.3
(C5), 92.3 (C7), 111.0, 118.8, 134.8, 135.9, 139.2, 155.2 and 157.8 (ArC),
125.1, 125.6, 127.5, 128.1, 129.0 and 129.6 (ArCH), 134.0 (C2), 192.9
(CO). Mass spectrum: m/z 372(Mþ1, 13%), 371 (M, 53), 266 (100),
250 (21), 105 (27), 77 (28), 69 (30).
An X-ray crystal structure of compound 24 (Fig. 1) showed that
the pyrroloindole ring is essentially planar and that the bond
lengths and bond angles of the two pyrrolic rings are similar. The C6
methoxy group is unusually angled away from C7, while the C8
methoxy group is angled towards C7. Crystallographic data for 4,6-
dimethoxyindoles invariably show both methoxy groups angled
towards C5. Compound 27 could not be obtained analytically pure,
but was hydrolysed to the related carboxylic acid 28, which was
fully characterised.
4.3. 1-(40-Bromophenacyl)-3-(40-bromophenyl)-
4,6-dimethoxyindole (3)
A mixture of 3,5-dimethoxyaniline (5.0 g, 32.6 mmol), a-bromo-
40-bromoacetophenone (18.2 g, 65.3 mmol) and sodium carbonate
(13.8 g,130.4 mmol) in 95% ethanol (80 mL) was heated at reflux for
4 h. The mixture was allowed to cool, and the resulting precipitate
was filtered, washed with water and recrystallised from chloro-
form/light petroleum to give a yellow solid. This diphenacylaniline
was reacted with cooled trifluoroacetic acid (15 mL) according to
the method of preparation of compound 2. The resulting solid was
flash chromatographed with light petroleum/dichloromethane
(1:2) as eluent afforded the bromophenacylindole 3 as a pale-yel-
low solid (7.60 g, 44%), mp 185–188 ꢀC. (Found: C, 54.8; H, 3.8; N,
3. Conclusions
A series of pyrrolo[3,2,1-hi]indoles has been formed by the aldol
cyclisation of 7-formyl-N-indolylacetates, which have in turn been
obtained by the N-alkylation of indole-7-carbaldehydes. This se-
quence is more general and effective than a related one involving
the cyclisation of N-phenacyl-indole-7-carbaldehydes.
2.5. C24H19Br2NO3 requires C, 54.5; H, 3.6; N, 2.7%.) lmax 206 nm (
3
38,700 cmꢁ1 Mꢁ1), 215 (33,200), 247 (29,400), 276 (20,100), 296

11606
Jumina et al. / Tetrahedron 64 (2008) 11603–11610
(13,900). nmax 1710, 1630, 1600, 1560, 1230, 1210, 1150, 1000 cmꢁ1
1H NMR spectrum (300 MHz, CDCl3):
3.79 (6H, s, OMe), 5.35 (2H,
.
C25H17Br2NO3 requires C, 55.7; H, 3.2; N, 2.6%.) lmax 210 nm (3
d
20,200 cmꢁ1 Mꢁ1), 221 (15,700), 267 (10,500), 281 (9200), 365
s, CH2), 6.19 (1H, d, J 1.8 Hz, H5), 6.27 (1H, d, J 1.8 Hz, H7), 6.85 (1H, s,
(10,100). nmax 1630, 1590, 1520, 1350, 1230, 1180, 1160, 980 cmꢁ1. 1H
NMR spectrum (300 MHz, DMSO-d6): d 4.04 and 4.19 (6H, 2s, OMe),
H2), 7.46 (4H, s, ArH), 7.65 and 7.84 (4H, 2d, J 8.2 Hz, ArH). 13C NMR
spectrum (75 MHz, CDCl3):
d
52.3 (CH2), 55.1 and 55.6 (OMe), 85.3
6.65 (1H, s, H7), 7.61, 7.81 and 7.91 (8H, m, ArH), 7.66 (1H, s, H5),
8.22 (1H, s, H2). The compound was not sufficiently soluble to
obtain a 13C NMR spectrum. Mass spectrum: m/z 542 (Mþ1, 81Br,
13%), 541 (M, 81Br, 51), 540 (Mþ1, 79,81Br, 33), 539 (M, 79,81Br, 73),
537 (M, 79Br, 30), 188 (22), 185 (94), 183 (54), 182 (80), 158 (98), 155
(100), 76 (58), 75 (78), 69 (34), 55 (22), 43 (40).
When the formylindole 5 (0.11 g, 0.20 mmol) was dissolved in
dimethylformamide (4 mL), then reacted with a saturated solution
of sodium hydroxide in methanol according to the method of
preparation of compound 6, the pyrroloindole 7 was obtained as
a bright yellow solid (69 mg, 64%), mp 251–253 ꢀC.
(C5), 92.4 (C7),117.7,119.7, 125.0, 133.3, 134.7,139.2, 155.0,158.0 and
192.0 (ArC), 125.0 (C2), 129.5, 130.6, 131.1 and 132.3 (ArCH), 209.6
(CO). Mass spectrum: m/z 531(M, 81Br, 19%), 530 (Mþ1, 79,81Br, 18),
529 (M, 79,81Br, 58), 528 (Mþ1, 79Br, 11), 527 (M, 79Br, 23), 346 (87),
345 (42), 344 (100), 207 (32), 185 (37), 185 (39), 156 (62), 155 (65),
76 (68), 75 (58), 69 (53), 43 (47).
4.4. 4,6-Dimethoxy-1-phenacyl-3-phenylindole-7-
carbaldehyde (4)
A cooled solution of phosphoryl chloride (0.19 mL, 2.03 mmol)
in dry dimethylformamide (1.0 mL) was added dropwise to a cooled
solution of the phenacylindole 2 (0.5 g, 1.35 mmol) in dry dime-
thylformamide (4 mL). The mixture was stirred at 0 ꢀC for 15 min,
then warmed at 80 ꢀC for another 30 min. Cold water (10 mL) was
added, followed by excess 2 M sodium hydroxide solution until the
mixture was strongly basic. The suspension was stirred at room
temperature overnight, the resulting precipitate was filtered,
washed with water and dried. The resulting solid was flash chro-
matographed with dichloromethane elution and yielded the for-
mylindole 4 as a white solid (0.37 g, 69%), mp 208–211 ꢀC. (Found:
C, 75.4; H, 5.3; N, 3.5. C25H21NO4 requires C, 75.2; H, 5.3; N, 3.5%.)
4.6. 4-Benzoyl-6,8-dimethoxy-1-phenylpyrrolo[3,2,1-hi]-
indole (6)
Excess saturated solution of sodium hydroxide in methanol was
added dropwise to a solution of formylindole 4 (0.1 g, 0.25 mmol)
in dimethylformamide (4 mL) until the mixture was strongly basic.
The mixture was stirred at room temperature for 30 min, the
resulting yellow precipitate was filtered, washed with water and
dried. Thin layer chromatography and elution with dichloro-
methane gave the pyrroloindole 6 as a yellow solid (60 mg, 63%),
mp 160–163 ꢀC. (Found: C, 78.5; H, 5.3; N, 3.7. C25H19NO3 requires
lmax 214 nm (
(5400), 353 (5500). nmax 1700, 1650, 1590, 1550, 1270, 1220, 1060,
1030, 610 cmꢁ1 1H NMR spectrum (300 MHz, CDCl3):
3.90 and
3
5000 cmꢁ1 Mꢁ1), 252 (6500), 268 (6800), 340
C, 78.7; H, 5.0; N, 3.7%.) lmax 207 nm (
(25,000), 255 (18,700), 277 (10,800), 362 (22,200). nmax 1720, 1650,
1620, 1590, 1340, 1230, 1200 cmꢁ1 1H NMR spectrum (300 MHz,
CDCl3): 4.03 and 4.17 (6H, 2s, OMe), 6.48 (1H, s, H7), 7.32, 7.43,
7.53, 7.60 and 7.97 (10H, m, ArH), 7.39 (1H, s, H5), 8.15 (1H, s, H2).
13C NMR spectrum (75 MHz, CDCl3):
56.2 and 57.5 (OMe), 94.9
3
43,600 cmꢁ1 Mꢁ1), 220
.
d
.
3.98 (6H, 2s, OMe), 6.18 (2H, s, CH2), 6.28 (1H, s, H5), 6.84 (1H, s,
d
H2), 7.31, 7.55 and 8.05 (10H, m, ArH), 10.30 (1H, s, CHO). 13C NMR
spectrum (75 MHz, DMSO-d6):
d 55.3 and 56.8 (OMe), 58.0 (CH2),
d
87.8, 125.5, 127.2, 127.6, 128.5, 129.1, 129.8 and 133.0 (ArCH), 106.0,
112.0, 117.7, 134.7, 135.1, 136.2, 160.5 and 164. 4 (ArC), 186.8 (CHO),
193.2 (CO). Mass spectrum: m/z 400 (Mþ1, 12%), 399 (M, 51), 295
(16), 294 (100), 279 (32), 264 (17), 236 (23), 208 (13), 105 (21), 77
(31).
(C7), 119.1 (C5), 120.3 (C2), 126.5, 127.8, 128.3, 128.4, 128.8 and 131.9
(ArCH), 102.4, 102.9, 127.0, 132.8, 134.7, 138.6, 141.5, 158.6 and 158.9
(ArC),186.7 (CO). Mass spectrum: m/z 382 (Mþ1, 27%), 381 (M,100),
105 (81), 77 (53).
4.5. 1-(40-Bromophenacyl)-3-(40-bromophenyl)-4,6-dimeth-
oxyindole-7-carbaldehyde (5) and 4-(40-bromobenzoyl)-1-
(40-bromophenyl)-6,8-dimethoxypyrrolo[3,2,1-hi]indole (7)
4.7. Ethyl 3(40-bromophenyl)-4,6-dimethoxyindol-
1-ylacetate (12)
A mixture of powdered potassium hydroxide (0.12 g, 2.1 mmol)
and dimethylsulfoxide (10 mL) was stirred at room temperature for
10 min, indole 8 (0.50 g, 2.0 mmol) was added, and the mixture was
Indole 3 (1.61 g, 3.05 mmol) was dissolved in dry dime-
thylformamide (15 mL), then reacted with a solution of phosphoryl
chloride (0.42 mL, 4.58 mmol) in dry dimethylformamide (1 mL)
according to the method of preparation of compound 4. The
resulting brown precipitate was filtered, washed with water and
dried. Flash chromatography and elution with dichloromethane
gave two products. The first product was the formylindole 5 as
a pale-yellow solid (0.98 g, 58%), mp 210–212 ꢀC. (Found: C, 54.2; H,
3.6; N, 2.2. C25H19Br2NO4 requires C, 53.9; H, 3.4; N, 2.5%.) lmax
stirred for another 30 min. Ethyl
a-bromoacetate (0.4 mL,
3.6 mmol) was added dropwise, and the mixture was stirred
overnight. The resulting brown-yellow mixture was diluted with
water (70 mL), extracted with dichloromethane (3ꢂ60 mL) and the
combined organic layers were washed with water, dried over
magnesium sulfate and evaporated to give a brown oil. Flash
chromatography and elution with dichloromethane afforded the
ethyl indolylacetate 12 as an off-white solid (0.63 g, 78%), mp 104–
105 ꢀC. (Found: C, 57.1; H, 4.6; N, 3.1. C20H20BrNO4 requires C, 57.4;
213 nm (
nmax 1720, 1670, 1590, 1570, 1270, 1230, 1170 cmꢁ1. 1H NMR spec-
trum (300 MHz, CDCl3): 3.88 and 3.95 (6H, 2s, OMe), 6.07 (2H, s,
CH2), 6.25 (1H, s, H5), 6.79 (1H, s, H2), 7.42 and 7.77 (8H, m, ArH),
10.24 (1H, s, CHO). 13C NMR spectrum (75 MHz, DMSO-d6):
55.8
3
14,300 cmꢁ1 Mꢁ1), 260 (19,000), 336 (6200), 351 (6200).
d
H, 4.8; N, 3.4%.) lmax 208 nm (
(25,400), 284 (13,500), 299 (12,100). nmax 1740, 1620, 1280, 1220,
1200, 1160, 790 cmꢁ1. 1H NMR spectrum (300 MHz, CDCl3):
1.28
3
29,800 cmꢁ1 Mꢁ1), 223 (31,000), 231
d
d
and 57.3 (OMe), 58.1 (CH2), 88.7, 129.9, 130.3, 130.5, 131.3 and 131.9
(ArCH), 106.0, 111.8, 116.2, 119.2, 127.6, 133.8, 134.5, 136.2, 160.6 and
164.6 (ArC), 187.0 (CHO), 192.9 (CO). Mass spectrum: m/z 559 (M,
81Br, 16%), 558 (Mþ1, 79,81Br, 18), 557 (M, 79,81Br, 32), 556 (Mþ1,
79Br, 15), 555 (M, 79Br, 22), 375 (20), 374 (100), 373 (14), 372 (84),
359 (22), 357 (21), 314 (18), 220 (29), 207 (34), 185 (43), 182 (42),
157 (89), 155 (88), 76 (72), 75 (58), 50 (36).
(3H, t, J 7.1 Hz, CH2CH3), 3.80 and 3.86 (6H, 2s, OMe), 4.24 (2H, q, J
7.1 Hz, CH2CH3), 4.76 (2H, s, CH2), 6.28 (1H, d, J 2.0 Hz, H5), 6.31 (1H,
d, J 2.0 Hz, H7), 6.91 (1H, s, H2), 7.47 (4H, s, ArH). 13C NMR spectrum
(75 MHz, CDCl3):
d 14.2 (CH2CH3), 48.1 (CH2), 55.2 and 55.7 (OMe),
61.8 (CH2CH3), 85.2 (C5), 92.5 (C7), 124.9 (C2), 110.7, 117.7, 119.7,
134.8, 139.0, 155.0 and 158.0 (ArC), 130.6 and 131.1 (ArCH), 168.3
(CO). Mass spectrum: m/z 419 (M, 81Br, 13%), 417 (M, 79Br, 15), 185
(93), 183 (100), 157 (29), 155 (31), 76 (37), 75 (32), 69 (39), 57 (41),
55 (36).
The second product was the pyrroloindole 7 as a bright yellow
solid (0.31 g, 20%), mp 250–253 ꢀC. (Found: C, 55.8; H, 3.3; N, 2.4.

Jumina et al. / Tetrahedron 64 (2008) 11603–11610
11607
4.8. Methyl 3(40-bromophenyl)-4,6-dimethoxyindol-
1-ylacetate (13)
CDCl3): d 14.2 (CH2CH3), 53.2 (CH2), 55.3 and 57.0 (OMe), 61.3
(CH2CH3), 87.9 (C5), 129.1 (C2), 106.9, 113.0, 118.0, 120.2, 134.2,
136.7, 160.8, 165.1 (ArC), 130.5 and 131.4 (ArCH), 169.5 (CO), 188.2
(CHO). Mass spectrum: m/z 448 (Mþ1, 81Br, 10%), 447 (M, 81Br, 62),
446 (Mþ1, 79Br, 10), 445 (M, 79Br, 67), 374 (45), 372 (49), 344 (27),
220 (28), 207 (33), 192 (33), 178 (32), 163 (36), 151 (39), 69 (69), 55
(100), 54 (100).
This was prepared by reacting a suspension of potassium hy-
droxide (0.35 g, 6.33 mmol) in dimethylsulfoxide (25 mL) with in-
dole 815,16 (1.50 g, 4.52 mmol) and methyl
a-bromoacetate (1.1 mL,
11.30 mmol) according to the method of preparation of compound
12. The resulting brown solid was flash chromatographed, and
elution with light petroleum in dichloromethane (3:7) gave the
methyl indolylacetate 13 as an orange solid (1.28 g, 70%), mp 123–
125 ꢀC. (Found: C, 56.5; H, 4.5; N, 3.4. C19H18BrNO4 requires C, 56.5;
4.11. Methyl 3-(40-bromophenyl)-7-formyl-4,6-dimethoxy-
indol-1-ylacetate (17)
H, 4.5; N, 3.5%.) lmax 210 nm (
(10,600), 298 (9300). nmax 1740, 1620, 1590, 1330, 1280, 1210, 1170,
1140, 1010 cmꢁ1. 1H NMR spectrum (300 MHz, CDCl3):
3.77, 3.80
3
19,300 cmꢁ1 Mꢁ1), 230 (19,500), 280
Indole 13 (0.65 g, 1.61 mmol) in dry dimethylformamide
(3.5 mL) was reacted with phosphoryl chloride (0.25 mL,
2.41 mmol) in dry dimethylformamide (1.0 mL) according to the
method of preparation of compound 16. The resulting solid was
flash chromatographed, and elution with dichloromethane/chloro-
form (1:1) yielded the formylindole 17 as a brown solid (0.51 g,
73%), mp 243–245 ꢀC. (Found: C, 55.3; H, 4.3; N, 3.1. C20H18BrNO5
d
and 3.87 (9H, 3s, OMe), 4.77 (2H, s, CH2), 6.30 (1H, br s, H5), 6.32
(1H, br s, H7), 6.89 (1H, s, H2), 7.47 (4H, s, ArH). 13C NMR spectrum
(75 MHz, CDCl3):
d 47.9 (CH2), 52.6, 55.1 and 55.7 (OMe), 85.1 (C5),
92.4 (C7), 124.8 (C2), 110.6, 117.7, 119.7, 134.7, 139.0, 155.0 and 158.0
(ArC), 130.6 and 131.1 (ArCH), 168.8 (CO). Mass spectrum: m/z 406
(Mþ1, 81Br, 20%), 405 (M, 81Br, 97), 404 (Mþ1, 79Br, 20), 403 (M,
79Br, 100), 346 (33), 344 (31), 309 (45), 207 (30), 174 (30), 152 (28),
69 (40), 59 (29), 43 (35).
requires C, 55.6; H, 4.2; N, 3.2%.) lmax 212 nm (
227 (17,200), 257 (10,300), 281 (5800). nmax 1770, 1600, 1590, 1570,
1280, 1225 cmꢁ1 1H NMR spectrum (300 MHz, DMSO-d6):
3.63,
3
18,400 cmꢁ1 Mꢁ1),
.
d
3.90 and 3.98 (9H, 3s, OMe), 5.33 (2H, s, CH2), 6.54 (1H, s, H5), 7.24
(1H, s, H2), 7.38 and 7.53 (4H, 2d, J 7.8 Hz, ArH), 10.23 (1H, s, CHO).
4.9. Methyl 4,6-dimethoxy-3-phenylindol-1-ylacetate (15)
13C NMR spectrum (75 MHz, DMSO-d6):
d 52.0, 55.8 and 57.3 (OMe),
52.4 (CH2), 88.9 (C5),130.3 (C2),130.5 and 131.3 (ArCH),106.0,111.8,
116.4, 119.3, 134.4, 135.9, 160.5 and 164.5 (ArC), 169.8 (CO), 187.1
(CHO). Mass spectrum: m/z 433 (M, 81Br, 14%), 432 (Mþ1, 79Br, 12),
431 (M, 79Br, 28), 361 (100), 359 (95), 265 (53), 194 (23), 178 (27),
150 (36), 139 (38), 83 (48), 69 (28), 59 (22).
A
suspension of powdered potassium hydroxide (0.16 g,
2.8 mmol) in dimethylsulfoxide (10 mL) was reacted with indole
916,17 (0.50 g, 2.0 mmol) followed by methyl
-bromoacetate
a
(0.4 mL, 4.3 mmol) according to the method of preparation of
compound 12. The resulting brown oil was flash chromatographed,
and elution with dichloromethane gave the methyl indolylacetate
15 as a white solid (0.47 g, 72%), mp 103–105 ꢀC. (Found: C, 70.5; H,
6.2; N, 4.4. C19H19NO4 requires C, 70.1; H, 5.9; N, 4.3%.) lmax 208 nm
4.12. Ethyl 4,6-dimethoxy-7-formyl-3-phenylindol-1-
ylacetate (18)
(3
23,200 cmꢁ1 Mꢁ1), 224 (27,640), 269 (10,800), 279 (11,280). nmax
1750, 1580, 1270, 1210, 1200, 1160, 1040, 770, 700 cmꢁ1 1H NMR
spectrum (300 MHz, CDCl3): 3.64, 3.69, 3.76 (9H, 3s, OMe), 4.64
Indole 916,17 (0.66 g, 2.61 mmol) was reacted with a suspension
of powdered potassium hydroxide (0.21 g, 3.65 mmol) in dime-
thylsulfoxide (12 mL) followed by ethyl a-bromoacetate (0.7 mL,
.
d
(2H, s, CH2), 6.19 (1H, d, J 2.0 Hz, H5), 6.22 (1H, d, J 2.0 Hz, H7), 6.79
(1H, s, H2), 7.16 (1H, t, J 7.1 Hz, H40), 7.26 (2H, t, J 7.1 Hz, H30), 7.53
6.53 mmol) according to the method of preparation of compound
12. The resulting brown oil (0.67 g), presumably compound 14, was
dissolved in dry dimethylformamide (4 mL), cooled in ice, then
a cooled solution of phosphoryl chloride (0.3 mL, 2.94 mmol) in dry
dimethylformamide (1.0 mL) was added dropwise. Work-up
according to the method of preparation of compound 16 afforded
the formylindole 18 as a brown solid (0.52 g, 54%), mp 135–137 ꢀC.
(Found: C, 68.5; H, 5.8; N, 3.6. C21H21NO5 requires C, 68.7; H, 5.8; N,
(2H, d, J 7.1 Hz, H20). 13C NMR spectrum (75 MHz, CDCl3):
d 47.9
(CH2), 52.6, 55.2 and 55.7 (OMe), 85.1 (C5), 92.3 (C7), 124.8 (C2),
110.9, 118.9, 135.7, 139.0, 155.2 and 157.9 (ArC), 125.7, 127.5 and
129.5 (ArCH), 168.9 (CO). Mass spectrum: m/z 326 (Mþ1, 20%), 325
(M, 100), 310 (20), 266 (48), 250 (29), 208 (21), 152 (25), 134 (36),
105 (56), 83 (20), 77 (34), 69 (46), 57 (47).
3.8%.) lmax 216 nm (
337 (7200). nmax 1755, 1650, 1590, 1570, 1555, 1280, 1225,
1210 cmꢁ1 1H NMR spectrum (300 MHz, CDCl3):
1.29 (3H, t, J
3
9900 cmꢁ1 Mꢁ1), 233 (9900), 262 (11,000),
4.10. Ethyl 3-(40-bromophenyl)-7-formyl-4,6-dimethoxy-
indol-1-ylacetate (16)
.
d
8.2 Hz, CH2CH3), 3.82 and 3.93 (6H, 2s, OMe), 4.22 (2H, q, J 8.2 Hz,
CH2CH3), 5.33 (2H, s, CH2), 6.21 (1H, s, H5), 6.80 (1H, s, H2), 7.31 (4H,
m, H20,30), 7.51 (1H, d, J 9.1 Hz, H40), 10.39 (1H, s, CHO). 13C NMR
Indole 12 (0.60 g, 1.50 mmol) was dissolved in dry dime-
thylformamide (4 mL), the solution cooled in ice, then a cooled
solution of phosphoryl chloride (0.2 mL, 2.25 mmol) in dry dime-
thylformamide (1.0 mL) was added dropwise. The mixture was
stirred at 0 ꢀC for 1 h, then at room temperature for another 30 min.
Cold water (10 mL) was added, followed by excess 2 M sodium
hydroxide solution until the mixture was strongly basic. The sus-
pension was stirred at room temperature overnight, the resulting
precipitate was filtered, washed with water and dried. Flash chro-
matography and elution with dichloromethane afforded the for-
mylindole 16 as a white solid (0.54 g, 81%), mp 209–211 ꢀC. (Found:
C, 56.5; H, 4.5; N, 3.0. C21H20BrNO5 requires C, 56.5; H, 4.5; N, 3.1%.)
spectrum (75 MHz, CDCl3):
d 14.1 (CH2CH3), 53.1 (CH2), 55.1 and
56.8 (OMe), 61.1 (CH2CH3), 87.7 (C5), 126.0 (C2), 106.6, 112.9, 119.1,
135.1, 136.5, 160.9 and 164.9 (ArC), 127.4, 129.1 and 129.7 (ArCH),
169.5 (CO), 188.1 (CHO). Mass spectrum: m/z 368 (Mþ1, 18%), 367
(M, 100), 310 (22), 294 (57), 236 (27), 69 (22).
4.13. Ethyl 4,6-dimethoxy-2,3-diphenylindol-1-ylacetate (19)
A
suspension of powdered potassium hydroxide (0.24 g,
4.2 mmol) in dimethylsulfoxide (2 mL) was reacted with indole 1016
(1.0 g, 3.0 mmol) followed by ethyl -bromoacetate (1.35 mL,
lmax 208 nm (
(4100). nmax 1750, 1650, 1580, 1550, 1270, 1210, 810, 780 cmꢁ1. 1H
NMR spectrum (300 MHz, CDCl3): 1.28 (3H, t, J 7.1 Hz, CH2CH3),
3
10,700 cmꢁ1 Mꢁ1), 234 (8700), 259 (11,200), 333
a
12.2 mmol). After 4 h, water (100 mL) was added to the stirred
mixture and the resulting solid was collected to give ethyl indolyl-
acetate 19 as a white solid (1.09 g, 86%), mp 190–192 ꢀC (from
ethanol). (Found: C, 75.3; H, 6.0; N, 3.4. C26H25NO4 requires C, 75.2;
H, 6.1; N, 3.4%.) nmax 1752, 1622, 1609, 1595, 1579, 1507, 1467, 1457,
d
3.86 and 3.96 (6H, 2s, OMe), 4.22 (2H, q, J 7.1 Hz, CH2CH3), 5.33 (2H,
s, CH2), 6.24 (1H, s, H5), 6.79 (1H, s, H2), 7.35 and 7.46 (4H, 2d, J
8.5 Hz, ArH), 10.71 (1H, s, CHO). 13C NMR spectrum (75 MHz,

11608
Jumina et al. / Tetrahedron 64 (2008) 11603–11610
1342,1271,1203,1154,1052, 706 cmꢁ1.1H NMR spectrum (300 MHz,
CDCl3): 1.25 (3H, t, J 7.1 Hz, CH2CH3), 3.72 and 3.88 (6H, 2s, OMe),
125.6, 126.8, 128.1, 128.2, 131.3 and 131.5 (ArCH), 169.5 (CO), 188.1
(CHO). Mass spectrum: m/z 443 (M, 100%), 370 (32), 354 (14).
d
4.22 (2H, q, J 7.1 Hz, CH2CH3), 4.65 (2H, s, CH2), 6.29 (1H, d, J 1.6 Hz,
H5), 6.34 (1H, d, J 2.0 Hz, H7), 7.20 (10H, m, ArH). 13C NMR spectrum
4.17. Ethyl 1-(40-bromophenyl)-6,8-dimethoxypyrrolo[3,2,1-
(75 MHz, CDCl3):
d
14.2 (CH2CH3), 46.3 (CH2), 55.3 and 55.7 (OMe),
hi]indole-4-carboxylate (24)
61.5 (CH2CH3), 85.4 (C5), 92.7 (C7), 111.7, 116.1, 131.6, 135.8, 138.6,
155.2, 157.2, 157.8 (ArC), 125.4, 126.8, 127.8, 128.3, 131.3 and 131.5
(ArCH), 167.0 (CO). Mass spectrum: m/z 415 (M, 100%), 400 (18), 342
(14).
Sodium hydride (80% in paraffin oil, 0.16 g, 5.38 mmol) was
added into an ice-cooled solution of formylindole 16 (1.50 g,
4.20 mmol) in dry tetrahydrofuran (100 mL). The mixture was
heated at reflux for 2 h, then allowed to cool and excess sodium
hydride was destroyed by cautious treatment with ice-water
(120 mL). The resulting suspension was extracted with dichloro-
methane (3ꢂ90 mL), and the combined organic layers were washed
with water, dried over magnesium sulfate and evaporated to give
a brown solid. Flash chromatography and elution with light pe-
troleum in dichloromethane (1:3) afforded the pyrroloindole 24 as
a light yellow solid (0.55 g, 48%), mp 164–166 ꢀC. (Found: C, 58.8; H,
4.1; N, 3.2. C21H18BrNO4 requires C, 58.9; H, 4.2; N, 3.3%.) lmax
4.14. Dimethyl 4,6-dimethoxy-1-ethoxycarbonylmethylindol-
2,3-dicarboxylate (20)
This was prepared from the indole diester 1117 (1.0 g, 3.4 mmol),
50% sodium hydride (0.2 g, 4.0 mmol) and ethyl a-bromoacetate
(0.4 mL, 3.6 mmol) in dry tetrahydrofuran (80 mL). After 4 h, ice-
water (10 mL) was added and the solvent was evaporated to give
a residue, which was recrystallised from dichloromethane/light
petroleum to give the ethyl indolylacetate 20 as a white solid
(1.05 g, 81%), mp 160–162 ꢀC. (Found: C, 56.7; H, 5.5; N, 3.8.
C18H21NO8 requires C, 57.0; H, 5.6; N, 3.7%.) nmax 1763, 1744, 1717,
205 nm (
nmax 1710, 1580, 1350, 1300, 1260, 1230, 1210 cmꢁ1. 1H NMR spec-
trum (300 MHz, CDCl3): 1.50 (3H, t, J 7.1 Hz, CH2CH3), 4.03 and
3
5000 cmꢁ1 Mꢁ1), 245 (2600), 263 (2000), 334 (2800).
d
1631, 1541, 1279, 1243, 1210, 1169, 1157 cmꢁ1
(300 MHz, CDCl3): 1.25 (3H, t, J 7.1 Hz, CH2CH3), 3.84, 3.86 and
3.94 (12H, 3s, OMe), 4.22 (2H, q, J 7.1 Hz, CH2CH3), 5.17 (2H, s, CH2),
6.21 (2H, br s, H5, H7). 13C NMR spectrum (75 MHz, CDCl3):
15.3
.
1H NMR spectrum
4.26 (6H, 2s, OMe), 4.49 (2H, q, J 7.1 Hz, CH2CH3), 6.52 (1H, s, H7),
7.57 and 7.81 (4H, 2d, J 6.7 Hz, ArH), 7.63 (1H, s, H5), 7.92 (1H, s, H2).
d
13C NMR spectrum (75 MHz, CDCl3):
d 14.5 (CH2CH3), 56.3 and 58.0
d
(OMe), 61.0 (CH2CH3), 74.3, 102.3, 120.5, 125.7, 133.8, 139.4, 153.1,
154.4 and 155.6 (ArC), 95.7 (C7), 115.9 (C5), 119.2 (C2), 129.8 and
131.5 (ArCH), 158.3 (CO). Mass spectrum: m/z 430 (Mþ1, 81Br, 19%),
429 (M, 81Br, 92), 428 (Mþ1, 79Br, 20), 427 (M, 79Br, 100), 401 (25),
399 (26), 305 (30), 69 (41).
(CH2CH3), 47.1 (CH2), 52.4 and 53.0 (CO2Me), 56.0 and 56.2 (OMe),
61.8 (CH2CH3), 84.0 (C5), 93.5 (C7), 109.4, 116.1, 120.9, 138.8, 159.5,
159.6 (ArC), 153.4, 165.5, 166.6 (CO). Mass spectrum: m/z 379 (M,
100%), 306 (21).
4.15. Dimethyl 4,6-dimethoxy-1-methoxycarbonylmethy-
lindol-2,3-dicarboxylate (21)
4.18. Methyl 1-(40-bromophenyl)-6,8-dimethoxypyrrolo[3,2,1-
hi]indole-4-carboxylate (25)
This was prepared as described for compound 20 from the in-
dole diester 1117 (1.0 g, 3.4 mmol), 50% sodium hydride (0.2 g,
4.0 mmol) and methyl a-bromoacetate (0.4 mL, 4.2 mmol) in dry
tetrahydrofuran (80 mL) to give the methyl indolylacetate 21 as
a white solid (1.0 g, 80%), mp 156–158 ꢀC. (Found: C, 55.8; H, 5.1; N,
3.9. C17H19NO8 requires C, 55.9; H, 5.2; N, 3.9%.) nmax 1751, 1735,
1713, 1627, 1546, 1514, 1269, 1238, 1209, 1171, 1154, 1016 cmꢁ1. 1H
This was prepared by reacting sodium hydride (80% in paraffin
oil, 14 mg, 0.47 mmol) with a solution of the formylindole 17
(0.10 g, 0.23 mmol) in dry tetrahydrofuran (15 mL) according to the
method of preparation of compound 24. Thin layer chromatogra-
phy and elution with dichloromethane afforded the pyrroloindole
25 as a yellow-greenish solid (30 mg, 30%), mp 132–134 ꢀC. (Found:
C, 58.1; H, 4.3; N, 3.2. C20H16BrNO4 requires C, 58.0; H, 3.9; N, 3.4%.)
NMR spectrum (300 MHz, CDCl3):
4s, OMe), 5.19 (2H, s, CH2), 6.21 (1H, br s, H5), 6.22 (1H, br s, H7). 13
NMR spectrum (75 MHz, CDCl3): 47.0 (CH2), 52.5, 52.9 and 53.0
d
3.74, 3.84, 3.86 and 3.94 (15H,
lmax 211 nm (
1350, 1270, 1240, 1220, 1180 cmꢁ1
CDCl3): 3.98, 3.99 and 4.20 (9H, 3s, OMe), 6.47 (1H, s, H7), 7.53
(2H, d, J 8.7 Hz, H20), 7.58 (1H, s, H5), 7.77 (2H, d, J 8.7 Hz, H3’), 7.87
(1H, s, H2). 13C NMR spectrum (75 MHz, CDCl3):
51.9, 56.2 and 57.8
3
78,700 cmꢁ1 Mꢁ1), 329 (21,800). nmax 1720, 1600,
1H NMR spectrum (300 MHz,
C
.
d
d
(CO2Me), 56.0 and 56.2 (OMe), 83.9 (C5), 93.6 (C7), 109.3, 116.1,
120.8, 138.8, 159.5, 159.6 (ArC), 153.4, 165.5, 167.2 (CO). Mass
spectrum: m/z 365 (M, 100%), 332 (31), 331 (29), 306 (31), 276 (24),
274 (31).
d
(OMe), 95.4 (C7), 115.9 (C5), 119.0 (C2), 129.3 and 131.3 (ArCH),
102.2, 102.4, 120.4, 125.2, 125.8, 133.7, 141.1 and 158.2 (ArC), 161.8
(CO). Mass spectrum: m/z 416 (Mþ1, 81Br, 20%), 415 (M, 81Br, 99),
414 (Mþ1, 79Br, 18), 413 (M, 79Br, 100), 319 (22), 201 (23), 188 (29),
183 (22), 149 (21), 59 (28).
4.16. Ethyl 4,6-dimethoxy-7-formyl-2,3-diphenylindol-1-
ylacetate (22)
Indole 19 (0.35 g, 0.34 mmol) was dissolved in dry dime-
thylformamide (1.0 mL), cooled in ice, then a cooled solution of
phosphoryl chloride (0.1 mL, 1.0 mmol) in dry dimethylformamide
(1.0 mL) was added dropwise. Work-up according to the method of
preparation of compound 15 afforded the formylindole 22 as white
crystals (0.30 g, 80%), mp 218–219 ꢀC (from dichloromethane/light
petroleum). (Found: C, 72.9; H, 5.6; N, 3.2. C27H25NO5 requires C,
4.19. Ethyl 6,8-dimethoxy-1-phenylpyrrolo[3,2,1-hi]indole-4-
carboxylate (26)
This was prepared by reacting sodium hydride (80% in paraffin
oil, 0.25 g, 8.33 mmol) with a solution of the formylindole 18
(1.50 g, 4.20 mmol) in dry tetrahydrofuran (100 mL) according to
the method of preparation of compound 24. Thin layer chromato-
graphy and elution with light petroleum in dichloromethane (1:9)
gave the pyrroloindole 26 as a yellow solid (0.88 g, 60%), mp 148–
151 ꢀC. (Found: C, 71.9; H, 5.6; N, 3.9. C21H19NO4 requires C, 72.2; H,
73.1; H, 5.7; N, 3.3%.) lmax 258 nm (
360 (7200). nmax 1758, 1649, 1587, 1576, 1560, 1271, 1220, 1210, 1170,
1120, 820, 725, 701 cmꢁ1 1H NMR spectrum (300 MHz, CDCl3):
1.19 (3H, t, J 7.1 Hz, CH2CH3), 3.78 and 3.98 (6H, 2s, OMe), 4.11 (2H,
q, J 7.1 Hz, CH2CH3), 5.19 (2H, s, CH2), 6.26 (1H, s, H5), 7.21 (10H, m,
ArH), 10.44 (1H, s, CHO). 13C NMR spectrum (75 MHz, CDCl3):
14.1
3
21,700 cmꢁ1 Mꢁ1), 325 (9200),
.
d
5.5; N, 4.0%.) lmax 212 nm (
(24,000), 333 (52,500). nmax 1700, 1595, 1230, 1200, 1180 cmꢁ1. 1H
NMR spectrum (300 MHz, CDCl3): 1.41 (3H, t, J 7.1 Hz, CH2CH3),
3
58,000 cmꢁ1 Mꢁ1), 236 (45,500), 265
d
d
(CH2CH3), 50.3 (CH2), 55.3 and 57.0 (OMe), 60.9 (CH2CH3), 88.2 (C5),
106.8, 113.5, 117.1, 135.4, 137.0, 139.3, 161.0, 165.0 and 170.1 (ArC),
3.93 and 4.16 (6H, 2s, OMe), 4.41 (2H, q, J 7.1 Hz, CH2CH3), 6.41 (1H,
s, H7), 7.25 (1H, t, J 7.7 Hz, H40), 7.38 (2H, t, J 7.7 Hz, H30), 7.52 (1H, s,

Jumina et al. / Tetrahedron 64 (2008) 11603–11610
11609
H5), 7.83 (1H, s, 2), 7.84 (2H, t, J 7.7 Hz, H20). 13C NMR spectrum
(75 MHz, CDCl3): 14.5 (CH2CH3), 56.3 and 57.9 (OMe), 61.0
(CH2CH3), 93.50, 103.62, 104.04, 122.44, 126.82, 127.40, 134.25 and
158.05 (ArC), 95.6 (C7), 115.9 (C5), 119.2 (C2), 126.7, 128.0 and 128.4
(ArCH). Mass spectrum: m/z 350 (Mþ1, 22%), 349 (M,100), 321 (27),
190 (29), 163 (29), 69 (28).
A mixture of formylindole 23 (0.15 g, 0.37 mmol) and 1,8-di-
azabicyclo[5.4.0]undec-7-ene (0.28 mL, 1.85 mmol) in dry acetoni-
trile (10 mL) was heated at reflux for 16 h. The mixture was allowed
to cool, then diluted with dichloromethane (80 mL), washed with 5%
hydrochloric acid (2ꢂ20 mL) followed by water, dried over magne-
sium sulfate and evaporated to leave an off-white solid. Preparative
thin layer chromatography and elution with ethyl acetate in
dichloromethane (1:12) gave the pyrroloindole 29 as a white solid
(0.050 g, 35%), mp 143–145 ꢀC. (Found C, 58.6; H, 5.2; N, 3.4.
d
4.20. Ethyl 4,6-dimethoxy-1,2-diphenylpyrrolo[3,2,1-hi]-
indole-4-carboxylate (27)
C19H19NO8 requires C, 58.6; H, 4.9; N, 3.6%.) lmax 208 nm (
3
41,500 cmꢁ1 Mꢁ1), 239 (31,700), 310 (24,100), 349 (33,100). nmax
Sodium hydride (80% in paraffin oil, 1.0 g, 33.3 mmol) was added
into an ice-cooled solution of formylindole 22 (2.95 g, 6.66 mmol)
in dry tetrahydrofuran (170 mL) containing dry dimethylforma-
mide (6.8 mL). The mixture was heated at reflux for 4 h, and further
treatment was according to the method of preparation of
compound 24. Flash chromatography and elution with light pe-
troleum in dichloromethane (1:3) gave the pyrroloindole 27 as
1750, 1715, 1660, 1590, 1345, 1220 cmꢁ1. 1H NMR spectrum (CDCl3):
d
1.38 (3H, t, J 7.2 Hz, CH2CH3), 3.90, 4.01, 4.05 and 4.16 (12H, s, OMe),
4.37 (2H, q, J 7.2 Hz, CH2CH3), 6.44 (1H, s, H7), 7.63 (1H, s, H5). 13
NMR spectrum (CDCl3): 14.4 (CH2CH3), 52.0, 53.1, 56.7 and 58.0
C
d
(OMe), 61.2 (CH2CH3), 96.9 (C7), 119.4 (C5), 100.9, 101.1, 114.8, 126.5,
130.9,139.8,159.2 and 159.4 (ArC),160.3,163.0 and 163.7 (CO). Mass
spectrum: m/z 389 (M, 66%), 358 (24), 328 (30), 286 (43), 254 (100),
242 (36), 225 (53), 184 (57), 155 (69), 127 (78), 115 (60), 59 (98).
a yellow solid (2.20 g, 78%), mp 164–166 ꢀC. lmax 244 nm (
23,900 cmꢁ1 Mꢁ1), 329 (26,000). 1H NMR spectrum (300 MHz,
CDCl3): 0.95 (3H, t, J 7.1 Hz, CH2CH3), 3.88 and 4.23 (6H, 2s, OMe),
3.94 (2H, q, J 7.1 Hz, CH2CH3), 6.49 (1H, s, H7), 7.26 (10H, m, ArH),
7.68 (1H, s, H5). 13C NMR spectrum (75 MHz, CDCl3):
13.8
3
d
4.23. Crystallographic study on compound 24
d
4.23.1. Crystal data
(CH2CH3), 56.3 and 57.9 (OMe), 60.6 (CH2CH3), 95.5 (C7), 101.6,
103.9, 123.6, 127.6, 132.9, 133.4, 134.6, 140.7, 157.3 and 158.0 (ArC),
117.7 (C5), 126.2, 127.4, 127.5, 127.8, 130.8 and 131.3 (ArCH), 161.0
(CO). Mass spectrum: m/z 425 (M, 31%), 424 (100), 396 (19). This
material could not be obtained analytically pure and was hydro-
lysed directly to the carboxylic acid (29).
C21H18BrNO4,
a 23.543(9), b 4.545(2), c 17.226(9) Å,
M
428.3, monoclinic, space group P21/c,
96.50(3)ꢀ, V 1831(2) Å3, Dc
b
1.55 g cmꢁ3, Z 4, mCu 33.34 cmꢁ1, 2qmax 140ꢀ. The number of re-
flections was 2690 considered observed out of 3485 unique data.
Final residuals R, Rw were 0.055, 0.074 for the observed data.
4.23.2. Structure determination
4.21. 6,8-Dimethoxy-1,2-diphenylpyrrolo[3,2,1-hi]indole-4-
carboxylic acid (28)
Reflection data were measured with an Enraf-Nonius CAD-4
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
l
l
0.7107) Å. Re-
A mixture of pyrroloindole 27 (0.50 g, 1.18 mmol) in 0.5 M
ethanolic potassium hydroxide (23.5 mL, 11.76 mmol) was heated
at reflux for 1 h. The mixture was allowed to cool and the solvent
removed under reduced pressure. The residue was diluted with
water (30 mL) and acidified with 5% hydrochloric acid. The result-
ing precipitate was collected, washed with water and dried to af-
ford the pyrroloindole carboxylic acid 28 as a yellow solid (0.43 g,
92%), mp 217–219 ꢀC (from chloroform/light petroleum). (Found: C,
73.6; H, 5.1; N, 3.2. C25H19NO4.0.6H2O requires C, 73.6; H, 5.0; N,
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.
Reflection weights used were 1/s s(Fo) being derived
2(Fo), with
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 dis-
/S
3.4%.) lmax 212 nm (
nmax 3370, 1680, 1660, 1330, 1260, 1215, 1000, 720 cmꢁ1
spectrum (300 MHz, DMSO-d6): 3.95 and 4.27 (6H, 2s, OMe), 6.68
(1H, s, H7), 7.23–7.39 (10H, m, ArH), 7.45 (1H, s, H5), 12.65 (1H, br s,
COOH). 13C NMR spectrum (75 MHz, DMSO-d6):
56.6 and 58.2
3
13,900 cmꢁ1 Mꢁ1), 247 (14,300), 327 (17,600).
1H NMR
persion parameters were from International Tables for X-ray Crys-
tallography.18 Structure solutions were by SIR9219 and refinement
used RAELS.20 ORTEP-II21 running on an eMac was used for the
structural diagrams, and the eMac was also used for calculations.
Atomic coordinates, bond lengths and angles, and displacement
parameters have been deposited at the Cambridge Crystallographic
Data Centre (CCDC 694313). 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
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ,
UK; fax: þ44 1223 336033.
.
d
d
(OMe), 95.7 (C7), 117.3 (C5), 101.6, 103.3, 123.0, 128.3, 132.4, 133.4,
134.6, 140.0, 157.5 and 157.8 (ArC), 126.6, 127.6, 127.7, 128.0, 130.7
and 131.5 (ArCH), 161.4 (CO). Mass spectrum: m/z 398 (Mþ1, 24%),
397 (M, 100), 353 (33), 105 (24), 69 (25).
4.22. Dimethyl, ethyl 6,8-dimethoxypyrrolo[3,2,1-hi]indole-
1,2,4-tricarboxylate (29)
Acknowledgements
Indole 20 (0.20 g, 0.54 mmol) was dissolved in dry dime-
thylformamide (1.0 mL), cooled in ice, then a cooled solution of
phosphoryl chloride (0.1 mL, 1.0 mmol) in dry dimethylformamide
(1.0 mL) was added dropwise. Work-up according to the method of
preparation of compound 16 afforded the formylindole 23 as white
crystals (0.18 g, 78%), mp 146–147 ꢀC. nmax 1755, 1714, 1663, 1583,
1547, 1285, 1267, 1232, 1220, 1208, 1195, 1143 cmꢁ1. 1H NMR spec-
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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