Some reactions of 6,8-dimethoxypyrrolo[3,2,1-hi]indoles

Article abstract of DOI:10.1016/j.tet.2009.01.011

Two 6,8-dimethoxypyrrolo[3,2,1-hi]indole carboxylic esters were hydrolyzed and decarboxylated. In an investigation of their electrophilic substitutions, some pyrroloindoles were formylated using the Vilsmeier reagent, and acylated with oxalyl chloride fol

Full text of DOI:10.1016/j.tet.2009.01.011

Tetrahedron 65 (2009) 2059–2066
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Some reactions of 6,8-dimethoxypyrrolo[3,2,1-hi]indoles
*
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
Two 6,8-dimethoxypyrrolo[3,2,1-hi]indole carboxylic esters were hydrolyzed and decarboxylated. In an
investigation of their electrophilic substitutions, some pyrroloindoles were formylated using the Vils-
meier reagent, and acylated with oxalyl chloride followed by quenching with dimethylamine to give the
glyoxylic amides. The electrophilic substitutions occur at the C2 or C4 position (a to the nitrogen atom)
rather than the C1 or C5 position ( to the nitrogen atom). Four of the formyl and acyl products were
b
reduced to the corresponding methanol derivatives. These compounds reacted on treatment with a range
of acids, but pure products could not be separated from the complex mixtures.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Pyrroloindoles
Formylation
Acylation
Decarboxylation
1. Introduction
hydrolyzed readily with 20% aqueous sodium hydroxide, the de-
carboxylation of the resulting 2-carboxylic acid to afford the
The synthesis of pyrrolo[3,2,1-hi]indoles has been achieved by
the aldol cyclization of 7-formyl-N-indolylacetates,1 the cyclization
of N-phenacyl-indole-7-carbaldehydes,1 and by dehydrogenation
of a tetrahydropyrroloindole formed from a related indoline.2 As
a result of the different synthetic methods used, a variety of sub-
stituentsdin addition to the two methoxy groupsdappear on the
pyrroloindoles. These are typically carboxylic esters, aroyl, or aryl
groups. It was of particular interest to investigate the directing
influences at work in substitution reaction of the various pyrro-
loindoles, and this paper described a selection of such reactions.
unsubstituted pyrrolo[3,2,1-hi]indole required heating in quinoline
in the presence of copper(II) oxide.
Treatment of pyrroloindoles 1 and 2 with 10 equiv of 0.5 M
ethanolic potassium hydroxide at reflux for 1.5 h followed by
acidification with 5% hydrochloric acid gave the related acids
3 and 4, respectively, in very high yield (Scheme 1). The reaction
was efficient and pure products were simply obtained by re-
crystallization from chloroform/light petroleum. In both cases, the
potassium salt intermediates crystallized out on cooling. However,
filtration of these salts was not the preferred work-up procedure as
better yields of the acids were achieved by removal of the solvent
under reduced pressure followed by dilution with water and
acidification. The 1H NMR spectra of pyrroloindoles 3 and 4 showed
singlets for H7 (6.68 and 6.69 ppm) and H5 (7.45 and 7.73 ppm) and
broad singlets for COOH (12.65 and 13.30 ppm). The singlet H2
resonance for pyrroloindole acid 3 appeared at 8.12 ppm. A signif-
icant decrease of the carbonyl stretching frequency from 1710 cmꢀ1
in the ester precursor 1 to 1670 cmꢀ1 in pyrroloindole acid 3 was
observed in the infrared spectrum.
2. Results and discussion
2.1. Hydrolysis and decarboxylation of pyrroloindole
carboxylic esters
It has been reported that dimethyl 4,6-dimethoxyindole-2,3-
dicarboxylate undergoes hydrolysis by treatment with ethanolic
potassium hydroxide to give an excellent yield of the related di-
carboxylic acid.3 However, when the reaction was conducted using
20% sodium hydroxide for a longer period of time, hydrolysis and
single decarboxylation occurred to afford the corresponding 2-
carboxylic acid in quantitative yield. The latter finding was in ac-
cordance with one reported by Paudler and Shin,4 who showed that
although ethyl pyrrolo[3,2,1-hi]indole-2-carboxylate could be
The decarboxylation of pyrroloindoles 3 and 4 was achieved by
treatment with 4.5 equiv of copper(II) oxide in quinoline at reflux
under a nitrogen atmosphere for 30 min to afford pyrroloindoles 5
and 6, respectively, in high yield (Scheme 1). The reaction was very
efficient and only a single product was observed. However, com-
plete removal of the quinoline during work-up was important to
avoid difficulties in the chromatographic purification.
The 1H NMR spectra of pyrroloindoles 5 and 6 showed singlets
for H7 (6.47–6.48 ppm), doublets for H5 (6.86–6.90 ppm) and
doublets for H4 (7.36–7.48 ppm). In the case of pyrroloindole 5, the
* 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.2009.01.011

2060
Jumina et al. / Tetrahedron 65 (2009) 2059–2066
R1
MeO
Br
R1
Br
MeO
KOH / EtOH
92%
R2
R2
MeO
MeO
MeO
N
MeO
N
POCl3 / DMF
75-94%
CHO
CO2Et
R2
CO2H
R2
MeO
N
R
MeO
N
R
R1
R1
1
2
4-BrC6H4
Ph
H
Ph
3
4
4-BrC6H4
Ph
H
Ph
R
CO2Et
R
7
1
5
CO2Et
H
8
9
H
CHO
CuO / quinoline 73-94%
Scheme 2.
R1
MeO
R1
R2
5
6
4-BrC6H4
Ph
H
Ph
R2
7.61 and 10.57 ppm corresponding to H7, H5 and CHO, respectively.
Evidence for substitution at C2 rather than at C5 was obtained via
an NOE experiment in which irradiation of the formyl proton gave
positive NOE for the bromophenyl protons (7.53–7.62 ppm) and
vice versa.
MeO
N
Scheme 1.
singlet resonance for H2 appeared at 7.50 ppm. An X-ray crystal
structure of pyrroloindole 5 (Fig. 1) showed that the pyrroloindole
ring is approximately planar, but the benzene ring of the bromo-
phenyl substituent is twisted out of plane with the pyrroloindole
ring by 31.4ꢁ. It is also interesting to note that the 8-methoxy group
is directed away from the phenyl ring, which indicates that a sig-
nificant degree of steric hindrance exists between it and the C1
substituent. The crystal data also showed that there is no real dif-
ference in the bond lengths of all C–C bonds of the pyrroloindole
ring, and in particular there is no difference between the length of
the C1–C2 and C4–C5 double bonds. In addition, no prediction
about the reactive centres of pyrroloindole 5 could be made as the
bond angles of the two pyrrolic rings are also similar.
Moreover, the X-ray crystal structure of pyrroloindole carbal-
dehyde 7 (Fig. 2) confirmed that the formyl group is at the 2-po-
sition. It is also interesting to note that the orientation of all
substituents in the crystal structure of aldehyde 7 is similar to those
of the starting pyrroloindole 1, except for the phenyl ring, which is
twisted out of plane with the pyrroloindole ring by 41.8ꢁ.
The more reactive pyrroloindole 5 underwent reaction with
1.5 equiv of the Vilsmeier reagent at room temperature in 1 h to
afford the corresponding 2-carbaldehyde 8 and 2,4-dicarbaldehyde
9 in 75 and 17% yields, respectively (Scheme 2). The reaction was
very clean and the crude product contained only those two com-
pounds. The mass spectrum of aldehyde 8 revealed a molecular ion
at 385 (81Br, 96%) and the infrared spectrum showed the presence
of a carbonyl stretching frequency at 1650 cmꢀ1. The 1H NMR
spectrum gave clear evidence for formylation at C2 as the two
typical doublets for H5 (6.85 ppm) and H4 (7.90 ppm) were still
present. The resonances for H7 and the formyl proton appeared as
singlets at 6.35 and 9.76 ppm, respectively. The mass spectrum of
2.2. Formylation of 6,8-dimethoxypyrroloindoles
Pyrroloindole ester 1 remained intact in the presence of the
Vilsmeier reagent at room temperature overnight, presumably
deactivated to some extent by the carbethoxy group. However,
treatment of pyrroloindole ester 1 with 1.5 equiv of Vilsmeier re-
agent at 50 ꢁC for 1 h gave the corresponding 2-carbaldehyde 7 in
94% yield (Scheme 2).
Br1A
C14A
The reaction was clean and the crude product was sufficiently
pure for further reaction. The mass spectrum of pyrroloindole
carbaldehyde 7 revealed a molecular ion at 457 (81Br, 17%), while
the 1H NMR spectrum showed the presence of three singlets at 6.37,
C18A
C13A
C15A
O2A
C5A
C12A
C2A
C3A
C8A
C4A
C16A
C17A
C11A
O3A
C7A
C17
C18
C6A
C19A
N1A
O1A
C1A
C5
C7
O2
C4
C8
O1
C3
C10A
C9A
C6
C13
C12
C20A
C2
O4A
Br1
O5A
C11
C14
C10
C9
N1
C1
C21A
C16
C15
C22A
Figure 1. ORTEP diagram derived from the single-crystal X-ray analysis of compound 5.
Figure 2. ORTEP diagram derived from the single-crystal X-ray analysis of compound 7.

Jumina et al. / Tetrahedron 65 (2009) 2059–2066
2061
dialdehyde 9 revealed a molecular ion at 413 (81Br, 16%), whereas
the 1H NMR spectrum showed four singlets at 6.45, 7.76, 9.80 and
10.92 ppm corresponding to H7, H5 and the two formyl protons,
respectively.
Treatment of diphenylpyrroloindole 6 with 1.5 equiv of the
Vilsmeier reagent at 60 ꢁC for 2 h gave the corresponding 4-car-
baldehyde 10 in 71% yield (Scheme 3). The 1H NMR spectrum
showed three singlets at 6.50, 7.68 and 9.69 ppm corresponding to
H7, H5 and the formyl proton, respectively. Conclusive evidence
for the structure of compound 10 was obtained by its reduction to
the related alcohol 11, which was identical to the product of
reduction of pyrroloindole ester 2 with lithium aluminium hydride
(Scheme 3).
correlation for H4 originating from its interaction with H5. The
presence of a long range coupling between H1 and H5, which
involves seven atoms, was interesting. Furthermore, it is worth
mentioning that the NOESY spectrum of pyrroloindole 13 pro-
vides a useful basis for the assignment of the resonances for H2,
H4 and H5 of related pyrroloindoles.
2.3. Acylation of 6,8-dimethoxypyrroloindoles
with oxalyl chloride
The reactions of activated indoles give rise to useful products
and also involve subtle regiochemistry, controlled to some extent
by solvent.5–7 It was therefore of interest to investigate the reaction
of pyrroloindoles with oxalyl chloride, with the aim of determining
the reactive centres of these molecules.
MeO
MeO
Ph
Ph
Treatment of pyrroloindole 5 with 2 equiv of oxalyl chloride in
benzene at room temperature for 1.5 h followed by addition of
excess dimethylamine gave the related 2-glyoxylamide 14 in 90%
yield: no other by-product was detected (Scheme 5).
POCl3 / DMF
71%
Ph
Ph
MeO
MeO
N
N
CHO
6
10
Br
Br
70%
Ph
NaBH4
MeO
MeO
MeO
MeO
Ph
1. (COCl)2
2. Me2NH
90%
COCONMe2
Ph
Ph
LiAlH4
67%
MeO
N
MeO
N
MeO
MeO
N
N
5
14
CO2Et
CH2OH
Scheme 5.
2
11
Scheme 3.
This is interesting as the related formylation also yielded 2,4-
dialdehyde 9 in addition to 2-aldehyde 8. Presumably this reflects
the stronger electron withdrawing capacity of the glyoxyloyl group
compared to the iminium ion functionality, as well as a greater
steric footprint. The 1H NMR spectrum shows the two typical
doublets for H4 and H5 at 7.95 and 6.85 ppm, respectively, and the
singlet resonance for H7 at 6.30 ppm. The 13C NMR spectrum
showed signals at 166.1 and 183.4 ppm corresponding to the two
glyoxylamide carbonyl carbons, and the mass spectrum revealed
a molecular ion at 456 (81Br, 25%). More vigorous conditions were
required for the less reactive diphenylpyrroloindole 6, and treat-
ment of this compound with 2 equiv of oxalyl chloride in benzene
at reflux for 3 h, followed by addition of excess dimethylamine
afforded the related 4-glyoxylamide 15 in 63% yield (Scheme 6).
Treatment of the parent 6,8-dimethoxypyrroloindole 12 with
1.5 equiv of the Vilsmeier reagent at 0 ꢁC for 1 h afforded the related
2-carbaldehyde 13 in 54% yield (Scheme 4).
MeO
MeO
POCl3 / DMF
54%
CHO
MeO
MeO
N
N
12
13
Scheme 4.
MeO
Ph
MeO
Only a moderate yield could be obtained as the reaction also
produced two other products, which seemed to be the related
2,4-dialdehyde (21%) and 7-carbaldehyde (13%) on the basis of
the 1H NMR spectra. However, both by-products could not be
well characterized and the mass spectra indicated that the
compounds were contaminated with other substances having
higher molecular ions. The mass spectrum of aldehyde 13 showed
a molecular ion at 229 (100%) and the 1H NMR spectrum showed
two singlets at 6.40 and 9.83 ppm corresponding to H7 and the
formyl proton, respectively. Evidence for formylation at C2 rather
than at C1 was given by the NOESY 1H NMR spectrum, which
showed correlation between H1 and the protons of the
8-methoxy group. The resonances for H1 and H4 appeared as
doublets at 7.51 and 7.82 ppm, respectively, since these were
coupled to H5 arising as a doublet of doublets at 6.86 ppm. This
latter proton gave two correlations in the NOESY spectrum,
resulting from its interaction with H4 and the protons of the
6-methoxy group. The NOESY spectrum also displayed a single
Ph
1. (COCl)2
2. Me2NH
Ph
Ph
MeO
N
MeO
N
63%
COCONMe2
6
15
Scheme 6.
Pyrroloindole 15 revealed a molecular ion at 453 (100%) in its
mass spectrum and the infrared spectrum confirmed the presence
of carbonyl groups. The 1H NMR spectrum of glyoxylamide 15
showed singlets at 7.55 and 6.37 ppm for H5 and H7, respectively.
An X-ray crystal structure of pyrroloindole 15 (Fig. 3) established
that the glyoxylamide group is at the 4-position. Again, the crystal
data showed that the pyrroloindole ring is approximately planar
and that the 1- and 2-phenyl rings are out of plane with the pyr-
roloindole ring by 41.2ꢁ and 55.8ꢁ, respectively.

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Jumina et al. / Tetrahedron 65 (2009) 2059–2066
group is at the 2-position. It was also interesting to note that the
two carbonyl groups of the glyoxylamide substituent of pyrro-
loindole 16 are oriented at 125.2ꢁ to each other, as compared to an
orientation of 93.7ꢁ for those in glyoxylamide 15.
C28
C26
C27
C23
C16
C5
O4
C8
C25
2.4. Formation of hydroxymethyl-6,8-dimethoxy-
pyrroloindoles and their treatment with acid
C7
C10
C24
C6
O2
C21
C20
C22
O3
C17
C3
C2
N1
C1
C11
It has been shown that 2- and 7-hydroxymethyl-4,6-dime-
thoxyindoles undergo reaction under a variety of acidic conditions
to give interesting macrocyclic structures such as calixindoles.8,9 It
was therefore of interest to obtain similar hydroxymethyl-
pyrroloindoles and investigate their behaviour with acids.
C9
C4
C15
O1
C18
C19
C12
Four representative examples were chosen. Reduction of
diphenylpyrroloindole-4-carbaldehyde 10 with sodium borohy-
dride in a mixture of absolute ethanol and tetrahydrofuran, or re-
duction of the related carboxylic ester 2 with lithium aluminium
hydride gave 4-methanol 11 in approximately 70% yield (Scheme 3).
Similar lithium aluminium hydride reduction of pyrroloindole ester
1 resulted in debromination, and thus the formation of 1-phenyl-
pyrroloindole-4-methanol 17 in 79% yield (Scheme 8).
N2
C13
C14
Figure 3. ORTEP diagram derived from the single-crystal X-rayanalysis of compound 15.
Pyrroloindole 12 also underwent substitution with oxalyl chlo-
ride and dimethylamine under similar conditions to afford 2-
glyoxylamide 16 in 53% yield (Scheme 7).
Br
MeO
MeO
MeO
MeO
1. (COCl)2
2. Me2NH
53%
LiAlH4
79%
COCONMe2
MeO
N
MeO
N
MeO
N
MeO
N
CH2OH
CO2Et
12
16
1
17
Scheme 7.
Scheme 8.
Only a moderate yield was obtained as the reaction also formed
some minor products, which were not isolated. The 1H NMR
spectrum of glyoxylamide 16 showed a singlet at 6.39 ppm corre-
sponding to H7, and doublet resonances for H1 and H4 at 7.61 ppm
and 7.88 ppm, respectively, resulting from coupling with H5, which
appeared as a doublet of doublets at 6.88 ppm. Again, the unusual
coupling between H1 and H5, which involves seven atoms, as
previously seen in the related 2-formyl compound was observed in
the 1H NMR spectrum of glyoxylamide 16. An X-ray crystal struc-
ture of pyrroloindole 16 (Fig. 4) confirmed that the glyoxylamide
Treatment of pyrroloindole-2-carbaldehyde 8 and the corre-
sponding glyoxylamide 14 with sodium borohydride gave the cor-
responding pyrroloindole-2-methanols 18 and 19 in 93 and 78%
yields, respectively (Scheme 9).
Br
Br
MeO
MeO
LiAlH4
R
R
78-93%
MeO
MeO
N
N
O1
C11
C5
C3
C2
R
R
18 CH2OH
19 CH(OH)CONMe2
C4
C7
C12
8
CHO
N1
C9
14 COCONMe2
C6
C8
C1
O2
Scheme 9.
C13
C14
C10
O3
O4
These four pyrroloindole methanols were submitted to a wide
range of acidic conditions suitable for the formation of structures
similar to the calixindoles. While there were some spectroscopic
indications of the formation of interesting, possibly macrocyclic
structures, pure compounds could not be obtained from the com-
plex reaction mixtures.
N2
C16
C15
3. Conclusions
The main conclusion that can be drawn from the formylation
Figure 4. ORTEP diagram derived from the single-crystal X-rayanalysis of compound 16.
and acylation reactions of a range of pyrrolo[3,2,1-hi]indoles is that

Jumina et al. / Tetrahedron 65 (2009) 2059–2066
2063
the most reactive centre is at C2 or at C4, rather than at C1 or C5.
Thus the pyrroloindoles behave like pyrroles, which undergo 2-
substitution, rather than indoles, which undergo 3-substitution.
requires C, 73.6; H, 5.0; N, 3.4%. lmax 212 nm (
3
13,900 cmꢀ1 Mꢀ1),
247 (14,300), 327 (17,600). nmax 3370, 1680, 1660, 1330, 1260, 1215,
1000, 720 cmꢀ1. 1H NMR spectrum (300 MHz, DMSO-d6):
d
3.95 and
Electrophilic attack
20, which would show greater resonance stability than cation 21,
which would be formed from electrophilic attack to the nitrogen
a
to the nitrogen atom would generate cation
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,
b
DMSO-d6): d 56.6 and 58.2 (OMe), 95.7 (C7), 117.3 (C5), 126.6, 127.6,
atom. Cation 20 is benzylic, and in the case of a 1-arylpyrroloindole
even doubly benzylic, whereas cation 21 resembles an anti-
aromatic cyclopentadienyl cation.
127.7, 128.0, 130.7 and 131.5 (ArCH), 101.6, 103.3, 123.0, 128.3, 132.4,
133.4, 134.6, 140.0, 157.5 and 157.8 (ArC), 161.4 (COOH).
Mass spectrum: m/z 398 (Mþ1, 24%), 397 (M, 100), 353 (33), 105
(24), 69 (25).
MeO
MeO
H
E
4.4. 1-(40-Bromophenyl)-6,8-dimethoxypyrrolo[3,2,1-
hi]indole (5)
H
E
MeO
N
MeO
N
Copper(II) oxide (0.30 g, 3.83 mmol) was suspended in a solu-
tion of pyrroloindole 3 (0.34 g, 0.85 mmol) in quinoline (10 mL)
under nitrogen. The mixture was heated at reflux for 30 min, then
allowed to cool and diluted with chloroform (70 mL). The resulting
mixture was washed with 5% hydrochloric acid (3ꢂ40 mL) followed
by water, dried over magnesium sulfate and evaporated to leave
a brown oil. Flash chromatography and elution with dichloro-
methane/light petroleum (2:3) afforded pyrroloindole 5 as a white
solid (0.22 g, 73%), mp 126–128 ꢁC. Found: C, 60.9; H, 4.1; N, 3.8.
20
21
4. Experimental
4.1. General
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)
spectrometer. 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. Col-
umn chromatography was carried out using Merck 230–400 mesh
ASTM silica gel, whilst preparative thin layer chromatography was
C18H14BrNO2 requires C, 60.7; H, 4.0; N, 3.9%. lmax 213 nm (
9100 cmꢀ1 Mꢀ1), 248 (9100), 280 (9900), 309 (10,500). nmax 1660,
1595, 1520, 1340, 1230, 1180, 1090, 725 cmꢀ1 1H NMR spectrum
(300 MHz, CDCl3): 3.96 and 4.20 (6H, 2s, OMe), 6.47 (1H, s, H7),
3
.
d
6.86 (1H, d, J 3.1 Hz, H5), 7.36 (1H, d, J 3.1 Hz, H4), 7.50 (1H, s, H2),
7.52 and 7.76 (4H, 2d, J 8.5 Hz, ArH). 13C NMR spectrum (75 MHz,
CDCl3): d 56.2 and 57.7 (OMe), 95.1 (C7), 109.1 (C5), 117.4 (C2), 121.4,
129.4 and 131.4 (ArCH), 102.0, 102.5, 120.2, 125.8, 134.1, 140.7, 155.7
and 155.9 (ArC). Mass spectrum: m/z 358 (Mþ1, 81Br, 19%), 357 (M,
81Br, 98), 355 (M, 79Br, 100), 261 (57), 246 (24), 190 (28), 101 (28), 95
(31). Crystals for X-ray determination were obtained by re-
crystallization from chloroform/ethanol.
performed using Merck silica gel 7730 60GF254
.
4.2. 1-(40-Bromophenyl)-6,8-dimethoxypyrrolo[3,2,1-
hi]indole-4-carboxylic acid (3)
A mixture of pyrroloindole 1 (0.40 g, 0.93 mmol) in 0.5 M
ethanolic potassium hydroxide (20 mL, 10 mmol) was heated at
reflux for 1.5 h. The mixture was allowed to cool, then the solvent
removed under reduced pressure. The residue was diluted with
water (30 mL), then acidified with 5% hydrochloric acid. The
resulting precipitate was filtered, washed with water and dried to
afford pyrroloindole carboxylic acid 3 as a yellow solid (0.34 g, 92%),
mp 265–267 ꢁC (from chloroform/light petroleum). Found: C, 56.7;
H, 3.8; N, 3.4. C19H14BrNO4 requires C, 57.0; H, 3.8; N, 3.4%. lmax
4.5. 4,6-Dimethoxy-1,2-diphenylpyrrolo[3,2,1-hi]indole (6)
A mixture of copper(II) oxide (0.35 g, 4.31 mmol), pyrroloindole
4 (0.38 g, 0.96 mmol) and quinoline (20 mL) was heated at reflux
under nitrogen for 30 min, and further treatment was in accor-
dance with the method of preparation of compound 5. Flash
chromatography and elution with light petroleum/dichloro-
methane (1:1) afforded pyrroloindole 6 as a white solid (0.32 g,
94%), mp 162–164 ꢁC. Found: C, 81.7; H, 5.6; N, 3.8. C24H19NO2 re-
210 nm (
(30,700). nmax 1670, 1645, 1580, 1505, 1345, 1300, 1210, 1010,
745 cmꢀ1. 1H NMR spectrum (300 MHz, DMSO-d6):
4.09 and 4.27
3
29,700 cmꢀ1 Mꢀ1), 244 (21,500), 277 (19,600), 328
quires C, 81.6; H, 5.4; N, 4.0%. lmax 209 nm (
(7900), 316 (8100). nmax 1650, 1590, 1505, 1345, 1325, 1230, 1210,
1180, 1130, 700 cmꢀ1. 1H NMR spectrum (300 MHz, CDCl3):
3.89
3
13,200 cmꢀ1 Mꢀ1), 246
d
d
(6H, 2s, OMe), 6.69 (1H, s, H7), 7.67 and 7.98 (4H, 2d, J 7.9 Hz, ArH),
and 4.23 (6H, 2s, OMe), 6.48 (1H, s, H7), 6.90 (1H, d, J 3.1 Hz, H5),
7.73 (1H, s, H5), 8.12 (1H, s, H2), 12.81–14.10 (1H, br s, COOH). 13C
7.48 (1H, d, J 3.1 Hz, H4), 7.26–7.58 (10H, m, ArH). 13C NMR spec-
NMR spectrum (75 MHz, DMSO-d6):
d
56.6 and 58.1 (OMe), 95.8
trum (75 MHz, CDCl3): d 56.4 and 57.7 (OMe), 95.4 (C7), 108.7 (C5),
(C7), 115.9 (C5), 119.3 (C2), 129.7 and 131.4 (ArCH), 101.6, 101.9,
119.7, 125.0, 126.2, 133.6, 140.4, 157.8 and 158.1 (ArC), 162.2 (COOH).
Mass spectrum: m/z 402 (Mþ1, 81Br, 18%), 401 (M, 81Br, 98), 399 (M,
79Br, 100), 357 (35), 355 (37), 305 (42), 261 (21), 201 (22), 190 (27),
95 (28), 43 (33).
121.2 (C4), 126.4, 127.5, 127.9, 128.6, 129.4 and 130.8 (ArCH), 102.6,
104.6, 121.8, 131.0, 132.1, 135.1, 139.4, 155.5 and 155.9 (ArC). Mass
spectrum: m/z 354 (Mþ1, 24%), 353 (M, 100), 338 (21), 84(22).
4.6. Ethyl 1-(40-bromophenyl)-6,8-dimethoxy-2-
formylpyrrolo[3,2,1-hi]indole-4-carboxylate (7)
4.3. 6,8-Dimethoxy-1,2-diphenylpyrrolo[3,2,1-hi]indole-4-
carboxylic acid (4)
A cooled solution of phosphoryl chloride (0.06 mL, 0.63 mmol)
in dry dimethylformamide (0.5 mL) was added dropwise into
a cooled solution of pyrroloindole 1 (0.18 g, 0.42 mmol) in dry
dimethylformamide (3 mL). The mixture was stirred at 0 ꢁC for
15 min, then at 50 ꢁC for 1 h, cold water (10 mL) was added, fol-
lowed by 2 M sodium hydroxide until the mixture was strongly
basic. The resulting suspension was stirred at room temperature
overnight, and the precipitate filtered, washed with water and
A mixture of pyrroloindole 2 (0.50 g, 1.18 mmol) in 0.5 M etha-
nolic potassium hydroxide (23.5 mL, 11.76 mmol) was heated at
reflux for 1 h. Further treatment was according to the method of
preparation of compound 1 to give pyrroloindole carboxylic acid 4
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

2064
Jumina et al. / Tetrahedron 65 (2009) 2059–2066
dried. The solid was recrystallized from dichloromethane/light
formylpyrroloindole 10 as a yellow solid (0.27 g, 71%), mp 189–
petroleum to give formylpyrroloindole
7
as
a
yellow solid
191 ꢁC. Found: C, 78.5; H, 5.3; N, 3.4. C25H19NO3 requires C, 78.7; H,
(0.18 g, 94%), mp 207–210 ꢁC. Found: C, 52.7; H, 4.2; N, 2.6.
5.0; N, 3.7%. lmax 213 nm (
(12,600), 340 (16,200), 359 (16,700). nmax 1680, 1650, 1585, 1340,
1210, 1070, 1130, 725, 700 cmꢀ1 1H NMR spectrum (300 MHz,
CDCl3): 3.92 and 4.21 (6H, 2s, OMe), 6.50 (1H, s, H7), 7.22–7.48
(10H, m, ArH), 7.68 (1H, s, H5), 9.69 (1H, s, CHO). 13C NMR spectrum
(75 MHz, CDCl3): 56.3 and 57.8 (OMe), 95.5 (C7), 118.3 (C5), 126.4,
3
12,700 cmꢀ1 Mꢀ1), 258 (13,600), 294
C22H18BrNO5$2.4H2O requires C, 52.9; H, 4.6; N, 2.8%. lmax 209 nm
(3
16,600 cmꢀ1 Mꢀ1), 226 (15,400), 247 (14,800), 269 (12,600), 363
.
(17,500). nmax 1710, 1660, 1590, 1440, 1335, 1265, 1220, 1190, 1135,
d
750 cmꢀ1 1H NMR spectrum (300 MHz, CDCl3):
.
d
1.43 (3H, t, J
7.2 Hz, Me), 3.85 and 4.23 (6H, 2s, OMe), 4.44 (2H, q, J 7.2 Hz, CH2),
d
6.37 (1H, s, H7), 7.53–7.62 (4H, m, ArH), 7.61 (1H, s, H5), 10.57 (1H, s,
127.6, 128.3, 128.5, 130.5 and 131.1 (ArCH), 102.8, 104.0, 123.4, 132.1,
132.7, 134.1, 135.7, 141.0, 158.4 and 159.2 (ArC), 180.5 (CHO).
Mass spectrum: m/z 382 (Mþ1, 27%), 381 (M, 100), 105 (62), 77
(33), 57 (27).
CHO). 13C NMR spectrum (75 MHz, CDCl3):
d 14.3 (Me), 56.2 and
58.3 (OMe), 61.4 (CH2), 96.4 (C7), 117.7 (C5), 130.6 and 132.8 (ArCH),
101.1, 103.7, 122.7, 128.4, 130.1, 131.4, 133.5, 160.5, 161.2 and 161.4
(ArC), 183.6 (CO), 196.2 (CHO). Mass spectrum: m/z 457 (M, 81Br,
17%), 455 (M, 79Br, 17), 428 (15), 426 (15), 376 (16), 331 (22), 330
(100), 230 (19), 202 (22), 201 (30), 188 (43), 174 (32). Crystals for
X-ray determination were obtained from chloroform/ethanol.
4.9. 6,8-Dimethoxypyrrolo[3,2,1-hi]indole-2-
carbaldehyde (13)
Pyrroloindole 12 (0.21 g, 1.05 mmol) was dissolved in dry
dimethylformamide (4.0 mL), then reacted with phosphoryl chlo-
ride (0.15 mL, 1.57 mmol) in dry dimethylformamide (0.5 mL) at
0 ꢁC according to the method of preparation of compound 7. The
resulting solid was purified by means of thin layer chromatography,
and elution with ethyl acetate in dichloromethane (1:9) gave for-
mylpyrroloindole 13 as a yellow solid (0.13 g, 54%), mp 135–138 ꢁC.
Found: C, 67.8; H, 5.2; N, 5.8. C13H11NO3 requires C, 68.1; H, 4.8; N,
4.7. Formylation of 1-(40-bromophenyl)-6,8-
dimethoxypyrrolo[3,2,1-hi]indole (5)
A cooled solution of phosphoryl chloride (0.06 mL, 0.63 mmol)
in dry dimethylformamide (0.50 mL) was added dropwise into an
ice-cooled solution of pyrroloindole 5 (0.15 g, 0.42 mmol) in dry
dimethylformamide (5.0 mL). The mixture was stirred at 0 ꢁC for
1 h, then at room temperature for another 1 h and further treat-
ment was in accordance with the method of preparation of com-
pound 7. Thin layer chromatography and elution with
dichloromethane gave two products.
6.1%. 1H NMR spectrum (300 MHz, CDCl3):
d 4.09 and 4.19 (6H, 2s,
OMe), 6.40 (1H, s, H7), 6.86 (1H, dd, J 3.1 and 1.3 Hz, H5), 7.51 (1H, d,
J 1.3 Hz, H1), 7.82 (1H, d, J 3.1 Hz, H4), 9.83 (1H, s, CHO). Mass
spectrum: m/z 229 (M, 100%), 214 (22), 186 (30), 171 (23).
4.7.1. 1-(40-Bromophenyl)-6,8-dimethoxypyrrolo[3,2,1-hi]indole-2-
carbaldehyde (8)
4.10. N,N-Dimethyl{1-(40-bromophenyl)-6,8-dimethoxy-
pyrrolo[3,2,1-hi]indol-2-yl}glyoxylamide (14)
Monoaldehyde 8 was isolated as a bright yellow solid (0.12 g,
75%), mp 209–212 ꢁC. Found: C, 59.6; H, 3.9; N, 3.5. C19H14BrNO3
Oxalyl chloride (0.06 mL, 0.67 mmol) was added dropwise into
a solution of pyrroloindole 5 (0.12 g, 0.34 mmol) in dry benzene
(7.0 mL) under nitrogen. The mixture was stirred at room temper-
ature for 1 h, then aqueous dimethylamine (40%, 0.51 mL,
4.02 mmol) was added and the stirring continued for 30 min. The
mixture was diluted with chloroform (70 mL), then washed with
water, dried over magnesium sulfate and evaporated to leave
a sticky yellow oil. Preparative thin layer chromatography and
elution with dichloromethane in ethyl acetate (1:3) afforded
glyoxylamide 14 as a yellow solid (0.14 g, 90%), mp 89–91 ꢁC.
Found: C, 52.9; H, 4.4; N, 5.3. C22H19BrN2O4$2.5H2O requires C,
requires C, 59.4; H, 3.8; N, 3.7%. lmax 211 nm (
(4400), 362 (5400). nmax 1650, 1590, 1320, 1235, 1210, 1135,
800 cmꢀ1. 1H NMR spectrum (300 MHz, CDCl3):
3.88 and 4.23 (6H,
3
5700 cmꢀ1 Mꢀ1), 253
d
2s, OMe), 6.35 (1H, s, H7), 6.85 (1H, d, J 3.1 Hz, H5), 7.58 and 7.61
(4H, 2d, J 8.8 Hz, ArH), 7.90 (1H, d, J 3.1 Hz, H4), 9.76 (1H, s, CHO). 13C
NMR spectrum (75 MHz, CDCl3):
d 56.1 and 58.2 (OMe), 96.4 (C7),
101.5, 103.5, 122.9, 129.1, 131.4, 136.4, 140.7, 158.6 and 160.2 (ArC),
109.5 (C5), 124.1 (C4), 131.2 and 132.4 (ArCH), 181.5 (CHO). Mass
spectrum: m/z 386 (Mþ1, 81Br, 18%), 385 (M, 81Br, 96), 384 (Mþ1,
79Br, 52), 383 (M, 79Br, 100), 382 (36), 289 (38), 246 (27), 190 (49),
152 (52), 69 (66).
52.8; H, 4.8; N, 5.6%. lmax 213 nm (
340 (9400), 386 (10,600), 391 (10,600). 1H NMR spectrum
(300 MHz, CDCl3): 2.50 and 2.76 (6H, 2s, NMe2), 3.78 and 4.23
3
7300 cmꢀ1 Mꢀ1), 257 (7900),
4.7.2. 1-(40-Bromophenyl)-6,8-dimethoxypyrrolo[3,2,1-hi]indole-
2,4-dicarbaldehyde (9)
d
(6H, 2s, OMe), 6.30 (1H, s, H7), 6.85 (1H, d, J 3.1 Hz, H5), 7.42 and
Dialdehyde 9 was obtained as a pale yellow solid (30 mg, 17%),
mp 296–298 ꢁC. Found: C, 58.0; H, 3.7; N, 3.1. C20H14BrNO4 requires
7.55 (4H, 2d, J 8.2 Hz, ArH), 7.95 (1H, d, J 3.1 Hz, H4). 13C NMR
spectrum (75 MHz, CDCl3):
d 33.4 and 36.8 (NMe2), 56.1 and 58.3
C, 58.3; H, 3.4; N, 3.4%. 1H NMR spectrum (300 MHz, CDCl3):
d
3.93
(OMe), 96.6 (C7), 109.4 (C5), 124.8 (C4), 130.4 and 132.2 (ArCH),
101.3, 122.7, 126.4, 131.6, 132.1, 134.2, 140.6, 158.9 and 160.6 (ArC),
166.1 (COCONMe2), 183.4 (COCONMe2). Mass spectrum: m/z 456
(M, 81Br, 25%), 454 (M, 79Br, 25), 385 (22), 383 (82), 382 (86), 304
(38), 303 (100), 288 (39), 260 (31), 202 (30), 188 (28), 72 (84).
and 4.29 (6H, 2s, OMe), 6.45 (1H, s, H7), 7.56 and 7.63 (4H, d, J
8.5 Hz, ArH), 7.76 (1H, s, H5), 9.80 and 10.92 (2H, 2s, CHO). Mass
spectrum: m/z 413 (M, 81Br, 16%), 411 (M, 79Br, 15), 333 (20), 332
(100), 289 (47), 274 (22), 246 (28), 201 (23), 190 (41), 166 (41), 123
(22), 69 (28).
4.11. N,N-Dimethyl(6,8-dimethoxy-1,2-diphenylpyrrolo[3,2,1-
hi]indol-4-yl)glyoxylamide (15)
4.8. 6,8-Dimethoxy-1,2-diphenylpyrrolo[3,2,1-hi]indole-4-
carbaldehyde (10)
Oxalyl chloride (0.05 mL, 0.56 mmol) was added dropwise into
a solution of pyrroloindole 6 (0.10 g, 0.28 mmol) in dry benzene
(8 mL) under nitrogen. The mixture was heated at reflux for 3 h,
then allowed to cool, aqueous dimethylamine (40%, 0.43 mL,
3.36 mmol) was added and further treatment was according to the
method of preparation of compound 14. Thin layer chromatography
and elution with ethyl acetate in dichloromethane (1:9) afforded
glyoxylamidopyrroloindole 15 as a yellow solid (80 mg, 63%), mp
A cooled solution of phosphoryl chloride (0.14 mL,1.49 mmol) in
dry dimethylformamide (0.5 mL) was added dropwise into an ice-
cooled solution of pyrroloindole 6 (0.35 g, 0.99 mmol) in dry
dimethylformamide (5.0 mL). The mixture was stirred at 0 ꢁC for
15 min, then warmed at 60 ꢁC for 2 h and further treatment was
according to the method of preparation of compound 7. Flash
chromatography and elution with dichloromethane afforded

Jumina et al. / Tetrahedron 65 (2009) 2059–2066
2065
181–183 ꢁC. Found: C, 74.3; H, 5.5; N, 6.0. C28H24N2O4 requires C,
74.3; H, 5.4; N, 6.2%. lmax 212 nm (
7600 cmꢀ1 Mꢀ1), 227 (7300),
256 (7300), 279 (6600), 363 (9400). nmax 1645, 1580, 1340, 1220,
1180, 1130, 1035, 855, 740 cmꢀ1 1H NMR spectrum (300 MHz,
CDCl3): 2.84 and 2.94 (6H, 2s, NMe2), 3.81 and 4.09 (6H, 2s, OMe),
6.37 (1H, s, H7), 7.11–7.27 (10H, m, ArH), 7.55 (1H, s, H5). 13C NMR
spectrum (75 MHz, CDCl3): 34.4 and 37.4 (NMe2), 56.4 and 57.8
hydroxymethylpyrroloindole 11 as a white solid (0.12 g, 67%), mp
158–160 ꢁC. Found: C, 77.7; H, 5.6; N, 3.6. C25H21NO3$0.1H2O re-
3
quires C, 77.9; H, 5.6; N, 3.6%. lmax 212 nm (
(1400), 311 (1500). nmax 3290, 1655, 1600, 1505, 1335, 1210, 1120,
700 cmꢀ1. 1H NMR spectrum (300 MHz, DMSO-d6):
3.93 and 4.23
3
1600 cmꢀ1 Mꢀ1), 244
.
d
d
(6H, 2s, OMe), 4.45 (2H, d, J 5.6 Hz, CH2), 5.22 (1H, t, J 5.6 Hz, OH),
d
6.59 (1H, s, H7), 6.96 (1H, s, H5), 7.24–7.58 (10H, m, ArH). 13C NMR
(OMe), 95.2 (C7), 122.8 (C5), 126.3, 127.5, 127.6, 128.1, 130.7 and
131.4 (ArCH), 102.9, 103.9, 123.6, 132.3, 132.7, 134.2, 134.3, 141.5,
158.6 and 159.7 (ArC), 166.8 (COCONMe2), 180.4 (COCONMe2). Mass
spectrum (ES): 475 (MþNaþ, 27%), 453 (M, 100), 380 (23). Crystals
for X-ray determination were obtained from chloroform/ethanol.
spectrum (75 MHz, DMSO-d6): d 56.1 (CH2), 56.3 and 57.8 (OMe),
95.1 (C7), 107.4 (C5), 126.3, 127.8, 128.4, 128.5, 130.4 and 130.9
(ArCH), 101.9, 103.5, 121.8, 128.4, 131.8, 134.7, 138.7, 139.2, 154.9 and
155.1 (ArC). Mass spectrum: m/z 384 (M, 34%), 383 (100), 366 (27),
139 (27).
4.12. N,N-Dimethyl(6,8-dimethoxypyrrolo[3,2,1-hi]indol-2-
4.14.2. Method B
yl)glyoxylamide (16)
Sodium borohydride (4 0 mg, 1.05 mmol) was added into
a cooled solution of pyrroloindole 10 (0.10 g, 0.26 mmol) in a mix-
ture of absolute ethanol and tetrahydrofuran (1:1, 8 mL). The
mixture was stirred at 0 ꢁC for 30 min, then at room temperature
for another 15 min. The solvent was removed and the residue
diluted with water to give hydroxymethylpyrroloindole 11 as
a white solid (70 mg, 70%).
Pyrroloindole 12 (100 mg, 0.50 mmol) in dry benzene (6 mL)
was reacted with oxalyl chloride (0.08 mL, 0.94 mmol) and aqueous
dimethylamine (40%, 0.64 mL, 5.01 mmol) according to the method
of preparation of compound 14. Thin layer chromatography and
elution with ethyl acetate in dichloromethane (1:4) afforded
glyoxylamide 16 as a yellow solid (80 mg, 53%), mp 148–150 ꢁC.
Found: C, 64.0; H, 5.6; N, 9.0. C16H16N2O4 requires C, 64.0; H, 5.4; N,
4.15. 1-(40-Bromophenyl)-6,8-dimethoxy-2-hydroxy-
methylpyrrolo[3,2,1-hi]indole (18)
9.3%. 1H NMR spectrum (300 MHz, CDCl3):
d 3.09 and 3.13 (6H, 2s,
NMe2), 4.09 and 4.20 (6H, 2s, OMe), 6.39 (1H, s, H7), 6.88 (1H, dd, J
1.0 and 3.1 Hz, H5), 7.61 (1H, d, J 1.0 Hz, H1), 7.88 (1H, d, J 3.1 Hz,
H4). Mass spectrum: m/z 300 (M, 24%), 229 (20), 228 (100), 200
(22), 72 (37). Crystals for X-ray determination were obtained from
chloroform/ethanol.
A solution of formylpyrroloindole 8 (0.15 g, 0.39 mmol) in
a mixture of absolute ethanol and tetrahydrofuran (1:1, 8 mL) was
reacted with sodium borohydride (0.06 g, 1.58 mmol) according to
the method of preparation of compound 11. Recrystallization from
dichloromethane/light petroleum afforded the hydroxy-
methylpyrroloindole as a white solid (0.14 g, 93%), mp 168–171 ꢁC.
Found: C, 59.2; H, 4.5; N, 3.3. C19H16BrNO3 requires C, 59.1; H, 4.2;
4.13. 6,8-Dimethoxy-4-hydroxymethyl-1-phenylpyrrolo[3,2,1-
hi]indole (17)
N, 3.6%. lmax 210 nm (
(31,100), 308 (44,800). nmax 3260, 1590, 1330, 1220, 1170, 1130 cmꢀ1
1H NMR spectrum (300 MHz, DMSO-d6):
3.95 and 4.22 (6H, 2s,
3
50,600 cmꢀ1 Mꢀ1), 244 (36,600), 276
Bromophenylpyrroloindole 1 (0.14 g, 0.33 mmol) was added into
an ice-cooled suspension of lithium aluminium hydride (0.13 g,
3.30 mmol) in dry tetrahydrofuran under nitrogen. The mixture was
stirred at 0 ꢁC for 1 h, then at room temperature for another 2 h and
then excess hydride was destroyed by cautiously adding cold water
(5 mL). The solvent was removed under reduced pressure, and the
residue extracted with dichloromethane (3ꢂ60 mL). The combined
organic layers were washed with water, dried over magnesium
sulfate, evaporated and recrystallized from dichloromethane/light
petroleum to afford the hydroxymethylpyrroloindole 17 as white
needles (0.08 g, 79%), mp 167–170 ꢁC. Found: C, 74.4; H, 5.8; N, 4.4.
.
d
OMe), 4.83 (2H, d, J 5.4 Hz, CH2), 5.65 (1H, t, J 5.4 Hz, OH), 6.58 (1H,
s, H7), 7.06 (1H, d, J 2.8 Hz, H5), 7.67 and 7.73 (4H, d, J 8.5 Hz, ArH),
7.81 (1H, d, J 2.8 Hz, H4). 13C NMR spectrum (75 MHz, DMSO-d6):
d
54.3 (CH2), 56.2 and 57.6 (OMe), 94.9 (C7), 96.1, 102.3, 119.8, 120.5,
132.1, 133.8, 138.5, 155.2 and 155.4 (ArC), 108.8 (C5), 122.2 (C4),
130.9 and 131.8 (ArCH). Mass spectrum: m/z 388 (Mþ1, 81Br, 21%),
387 (M, 81Br, 100), 386 (Mþ1, 79Br, 27), 385 (M, 79Br, 98), 370 (53),
368 (53), 289 (35), 274 (33), 259 (27), 196 (52), 157 (44), 139 (62),
107 (44), 43 (70).
C19H17NO3 requires C, 74.3; H, 5.6; N, 4.6%. lmax 212 nm (
16,000 cmꢀ1 Mꢀ1), 241 (12,900), 267 (11,400), 309 (15,500). nmax
3355, 1660, 1610, 1515, 1360, 1340, 1230, 1160, 1010, 740 cmꢀ1 1H
NMR spectrum (300 MHz, DMSO-d6): 4.04 and 4.21 (6H, 2s,
3
.
4.16. N,N-Dimethyl 2-{1-(40-bromophenyl)-6,8-dimethoxy-
pyrrolo[3,2,1-hi]indol-2-yl}-2-hydroxyacetamide (19)
d
OMe), 4.88 (2H, d, J 5.6 Hz, CH2), 5.59 (1H, t, J 5.6 Hz, OH), 6.59
(1H, s, H7), 6.91 (1H, s, H5), 7.35 (1H, t, J 7.4 Hz, H40), 7.51 (2H, t, J
7.4 Hz, H30, H50), 8.01 (2H, d, J 7.4 Hz, H20, H60), 8.03 (1H, s, H2). 13C
Pyrroloindole 14 (100 mg, 0.22 mmol) in a mixture of absolute
ethanol and tetrahydrofuran (1:1, 8.0 mL) was reacted with sodium
borohydride (40 mg, 1.06 mmol) according to the method of prep-
aration of compound 11 to give hydroxyacetamidopyrroloindole 19
as a white solid (80 mg, 78%), mp 110–113 ꢁC (from dichloro-
methane/light petroleum). Found: C, 53.3; H, 4.7; N, 5.1.
C22H21BrN2O4$0.67CH2Cl2 requires C, 53.0; H, 4.4; N, 5.4%. lmax
NMR spectrum (75 MHz, DMSO-d6):
d 56.0 and 56.4 (OMe), 58.0
(CH2), 95.1 (C7), 106.2 (C5), 118.0 (C2), 126.3, 127.4 and 128.5
(ArCH), 102.1, 125.3, 132.3, 135.0, 137.3, 140.3, 155.0 and 155.3
(ArC). Mass spectrum: m/z 308 (Mþ1, 20%), 307 (M, 100), 290 (60),
69 (22), 43 (23).
213 nm (
nmax 3400, 1655, 1590, 1510, 1330, 1210, 1130, 1060, 1015, 720 cmꢀ1
1H NMR spectrum (300 MHz, DMSO-d6):
3.0 and 3.3 (6H, 2s,
3
12,400 cmꢀ1 Mꢀ1), 246 (11,900), 269 (9700), 310 (13,900).
4.14. 4,6-Dimethoxy-1,2-diphenyl-4-hydroxymethyl-
pyrrolo[3,2,1-hi]indole (11)
.
d
NMe2), 4.35 and 4.63 (6H, 2s, OMe), 5.95 (1H, s, CHOH), 6.46 (1H, s,
CHOH), 6.99 (1H, s, H7), 7.44 (1H, d, J 3.1 Hz, H5), 8.0 (1H, d, J 3.1 Hz,
H4), 8.07 and 8.20 (4H, 2d, J 8.2 Hz, ArH). 13C NMR spectrum
4.14.1. Method A
Pyrroloindole 2 (0.20 g, 0.47 mmol) was added into a cooled
suspension of lithium aluminium hydride (90 mg, 2.35 mmol) in
dry tetrahydrofuran (8.0 mL) under nitrogen. The mixture was
stirred at 0 ꢁC for 1.5 h, and further treatment was according to
(75 MHz, DMSO-d6):
d 35.2 (NMe2), 55.7 and 57.2 (OMe), 63.0
(CHOH), 94.5 (C7), 108.5 (C5), 122.4 (C4), 130.8 and 131.3 (ArCH),
101.4, 120.0, 121.3, 128.6, 132.8, 138.2, 155.0, 155.5 and 169.5 (ArC),
176.0 (CONMe2). Mass spectrum: m/z 458 (M, 81Br, 8%), 456 (M, 79Br,
method
A for the preparation of compound 17 to give

2066
Jumina et al. / Tetrahedron 65 (2009) 2059–2066
8), 387 (27), 386 (93), 385 (36), 384 (100), 305 (24), 262 (28), 190
(26), 72 (82).
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
4.17. Crystallographic studies
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
4.17.1. Crystal data for compound 5
dispersion parameters were from International Tables for X-ray
Crystallography.10 Structure solutions were by SIR9211 and re-
finement used RAELS.12 ORTEP-II13 running on an eMac was used
for the structural diagrams, and the eMac was also used for
calculations.
C18H14BrNO2,
M 356.2, orthorhombic, space group Pbcm,
a 20.985(4), b 9.719(2), c 7.438(2) Å, V 1517.0(5) Å3, Dc 1.56 g cmꢀ3, Z
4, mMo 26.90 cmꢀ1, 2qmax 50ꢁ. The number of reflections was 818
considered observed out of 1455 unique data. The molecule lies
across the mirror plane at z¼1⁄4 , and hence is disordered. Final
residuals R, Rw were 0.037, 0.041 for the observed data.
Atomic coordinates, bond lengths and angles, and displacement
parameters have been deposited at the Cambridge Crystallographic
Data Centre (CCDC 694315 for structure 5, CCDC 694316 for struc-
ture 7, CCDC 694317 for structure 15, CCDC 694318 for structure 16).
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
Rd, Cambridge CB2 1EZ, UK; fax: þ44 1223 336033.
4.17.2. Crystal data for compound 7
(C22H18BrNO5)2$CHCl3, M 1032.0, triclinic, space group P-1,
a 7.677(2), b 10.657(5), c 28.673(11) Å,
a 81.63(2), b g
85.59(2)ꢁ,
68.83(3)ꢁ, V 2164(1) Å3, Dc 1.58 g cmꢀ3, Z 2, mCu 46.86 cmꢀ1, 2qmax
140ꢁ. The number of reflections was 5645 considered observed out
of 7346 unique data. Final residuals R, Rw were 0.058, 0.103 for the
observed data. The chloroform was disordered over two sites with
occupancies of 0.52, 0.48.
Acknowledgements
Financial support from the Australian Research Council is
gratefully acknowledged. Jumina acknowledges receipt of a post-
graduate scholarship from the Australian Government.
4.17.3. Crystal data for compound 15
C28H24N2O4,
M 452.5, orthorhombic, space group P212121,
a 9.082(1), b 9.214(2), c 27.052(5) Å, V 2263.8(7) Å3, Dc 1.33 g cmꢀ3
,
Z 4, mCu 7.22 cmꢀ1, 2qmax 140ꢁ. The number of reflections was 2183
considered observed out of 2462 unique data. Final residuals R, Rw
were 0.033, 0.050 for the observed data.
References and notes
1. Jumina; Keller, P. A.; Kumar, N.; Black, D. StC. Tetrahedron, 2008, 64,
11603–11610.
2. Jumina; Kumar, N.; Black, D. StC. Tetrahedron, in press. doi:10.1016/j.tet.2009.01.
010.
3. Black, D. StC.; Kumar, N.; Wong, L. C. H. Aust. J. Chem. 1986, 39, 15–20.
4. Paudler, W. W.; Shin, H. G. J. Heterocycl. Chem. 1969, 6, 415–417.
5. Black, D. StC.; Craig, D. C.; Kumar, N.; McConnell, D. B. Tetrahedron Lett. 1996, 37,
241–244.
6. Black, D. StC.; Kumar, N.; McConnell, D. B. Tetrahedron 1996, 52, 8925–8936.
7. Black, D. StC.; Kumar, N.; McConnell, D. B. Tetrahedron 2000, 56, 8513–8524.
8. Black, D. StC.; Bowyer, M. C.; Kumar, N.; Mitchell, P. S. R. J. Chem. Soc., Chem.
Commun. 1993, 819–821.
9. Black, D. StC.; Craig, D. C.; Kumar, N. Tetrahedron Lett. 1995, 36, 8075–8078.
10. International Tables for X-ray Crystallography; Ibers, J. A., Hamilton, W. C., Eds.;
Kynoch: Birmingham, 1974; Vol. 4.
11. Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G.; Giacovazzo, C.; Guagliardi,
A.; Polidori, G. J. Appl. Crystallogr. 1994, 27, 435–440.
12. Rae, A. D. RAELS. A Comprehensive Least Squares Refinement Program; University
of New South Wales: Sydney, 1996.
13. Johnson, C. K. ORTEP-II; Oak Ridge National Laboratory: TN, USA, 1976.
4.17.4. Crystal data for compound 16
C16H16N2O4, M 300.3, monoclinic, space group P21/c, a 9.576(6),
b 7.784(2), c 19.918(9) Å,
b ,
102.65(2)ꢁ, V 1449(1) Å3, Dc 1.38 g cmꢀ3
Z 4, mCu 8.29 cmꢀ1, 2qmax 140ꢁ. The number of reflections was 1501
considered observed out of 2742 unique data. Final residuals R, Rw
were 0.078, 0.096 for the observed data.
4.17.5. Structure determination
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-
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