Mechanisms of cyclisation of indolo oxime ethers I. Formation of ethyl 9,11-dimethoxy indolo[2,3-c]quinoline-6-carboxylates

Article abstract of DOI:10.1016/j.tet.2007.08.026

The cyclisation of a series of ethyl 3′-aryl-4′,6′-dimethoxyindol-2′-yl-2-(hydroxyimino)acetates was investigated using ¹H NMR spectroscopy to determine the mechanism of formation of the corresponding ethyl 9,11-dimethoxy indolo[2,3-c]quinoline

Full text of DOI:10.1016/j.tet.2007.08.026

Tetrahedron 63 (2007) 10615–10621
Mechanisms of cyclisation of indolo oxime ethers I.
Formation of ethyl 9,11-dimethoxy indolo[2,3-c]quinoline-
6-carboxylates
*
Kylie A. Clayton, David StC. Black and Jason B. Harper
School of Chemistry, University of New South Wales, UNSW, Sydney NSW 2052, Australia
Received 8 May 2007; revised 17 July 2007; accepted 8 August 2007
Available online 14 August 2007
Abstract—The cyclisation of a series of ethyl 30-aryl-40,60-dimethoxyindol-20-yl-2-(hydroxyimino)acetates was investigated using 1H NMR
spectroscopy to determine the mechanism of formation of the corresponding ethyl 9,11-dimethoxy indolo[2,3-c]quinoline-6-carboxylates.
The electronic requirements of the reaction were determined and, along with the observation of an intermediate in the process, indicated
that the reaction proceeds through an electrocyclic mechanism. The importance of the ester moiety in such a process is discussed.
Crown Copyright Ó 2007 Published by Elsevier Ltd. All rights reserved.
1. Introduction
systems and hence clearly need to be considered also. Fi-
nally, the reaction may proceed through an electrocyclic
mechanism, followed by the elimination of 2,4-dinitrophe-
nol. It is important to note that formally the first step in
this process is equivalent to conjugate addition of the aro-
matic ring onto the nitrogen centre, since the reaction pro-
ceeds through the same intermediate.
We have recently observed the cyclisation of the chloro-
phenyl ester 1b to give the tetracycle 2b (Scheme 1).1 Since
structures related to the indoloquinoline 2b have been found
to have antitumour activity,2 it is of interest to extend the
synthetic methodology associated with these compounds.
In order to do so, we have undertaken mechanistic studies
to determine how this cyclisation occurs.
In this paper we describe the synthesis and cyclisation of
a series of analogues of the oxime ether 1b. Through varia-
tion of the substituent on the phenyl ring, the electronic de-
mand of the reaction was determined and the mechanism
elucidated.
Cl
Cl
NO2
NO2
O
O
NEt
3
N
N
O
THF, Δ
2. Results and discussion
CO2Et
N
H
N
H
CO2Et
O
O
2b
The indole oxime ethers 1a–e were synthesised as outlined
in Scheme 2 from the corresponding acetophenones 3a–e.
The amino ketones 4a–e were cyclised under Bischler-like
conditions to give the phenylindoles 5a–e. Treatment with
oxalyl chloride and then ethanol gave a mixture of the de-
sired 2-substituted keto esters 6a–e and the corresponding
7-substituted isomer, which could be separated using col-
umn chromatography. The ketones 6a–e were converted to
the corresponding oximes 7a–e using hydroxylamine, fol-
lowed by reaction with dinitrofluorobenzene to give the cyc-
lisation precursors 1a–e. Spectroscopic studies on each of
the oximes 7a–e and the oxime ethers 1a–e showed the pres-
ence of both syn and anti forms in solution. The correspond-
ing quinolines 2a–e were formed through heating the
precursors 1a–e at reflux in tetrahydrofuran in the presence
of triethylamine.
1b
Scheme 1. Cyclisation of the oxime ether 1b to give the corresponding tetra-
cycle 2b.
Several mechanistic pathways might be considered for this
reaction. While substitution at an sp2 hybridised centre is
not common, significant literature precedent exists for an in-
tramolecular concerted substitution process in closely re-
lated oxime ether systems.3 A stepwise polar mechanism
can also be envisaged, in which the reaction proceeds
through a nitrenium ion intermediate. Similar one-4 and
two-step5 radical processes have been observed for related
Keywords: Indole; Cyclisation; Mechanism determination.
* Corresponding author. Tel.: +61 2 9385 4692; fax: +61 2 9385 6141;
e-mail: j.harper@unsw.edu.au
0040–4020/$ - see front matter Crown Copyright Ó 2007 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.08.026

10616
K. A. Clayton et al. / Tetrahedron 63 (2007) 10615–10621
R
R
R
R
O
O
O
O
O
ii)-iv)
v), vi)
i)
O
O
N
H
Br
N
H
O
N
H
CO2Et
O
3
4
5
6
vii)
R
R
R
NO2
NO2
a
b
c
d
e
R = Br
R = Cl
R = H
O
O
O
x)
viii), ix)
R = Me
R = OMe
N
N
OH
N
O
CO2Et
N
H
CO2Et
N
N
H
O
CO2Et
O
O
H
7
1
2
Scheme 2. Syntheses of the tetracycles 2a–e. Reagents: (i) 3,5-dimethoxyaniline, EtOH, NaHCO3, D; (ii) (CF3CO)2O; (iii) CF3CO2H; (iv) KOH, MeOH; (v)
(COCl)2; (vi) EtOH; (vii) NH2OH$HCl, NaCH3CO2, EtOH, D; (viii) Na, EtOH; (ix) 2,4-dinitrofluorobenzene and (x) NEt3, THF, D.
Each of the precursors 1a–e was treated under the same con-
ditions as those used in the initial cyclisation studies.1 Sam-
ples of the reaction were taken at regular intervals,
immediately cooled to 77 K and the solvent removed in va-
cuo. The rate of disappearance of each of the starting mate-
rials 1a–e and the rate of appearance of each of the
tetracycles 2a–e were followed using 1H NMR spectroscopy.
intermediate containing the dinitrophenoxide moiety is be-
ing formed in the reaction.
Therefore, the reaction was analysed assuming that, once it
had formed, the intermediate could decompose to either
starting material or product, but product formation was irre-
versible. The data sets fit well into this model and were inte-
grated numerically, with the rates of formation of the
intermediate calculated for the cyclisation of each of the pre-
cursors 1a–e. These are summarised in Table 1 and show
a clear trend, with the rate of reaction faster for electron do-
nating substituents and slower for electron withdrawing sub-
stituents. The difference in the rate constant between the two
extreme cases was a factor of ca. 3.
00
00
Specifically the signals due to H5 and H7 of the precursors
1a–e and H1 of the products 2a–e were followed using the
protons on the methoxyindole moiety as the internal stan-
dard. Each of these protons had previously been shown to
have the same relaxation time, and hence integration of the
signals was an appropriate quantitative measure.
Initial analysis showed that the rate of consumption of each
of the starting materials 1a–e did not follow first order kinet-
ics. In addition, signals were observed, which could not be
attributed to either the starting materials 1a–e or the products
2a–e. Further, these signals did not correspond to the nitro-
phenoxide that might be expected to be liberated during the
reaction. A sample spectrum is shown in Figure 1, for the
cyclisation of the methyl substituted case 1e. The coupling
pattern of the highlighted signals is characteristic of
a 1,2,4-trisubstituted aromatic system and suggests that an
The importance of the base was also probed, with the above
kinetic analyses repeated for the chloro derivative 1b in ei-
ther the absence of triethylamine or with either 0.5 or 1 equiv
of triethylamine present. In the absence of triethylamine, no
1
trace of the product 2b was evident by H NMR spectro-
scopy, though there was indication of the intermediate iden-
tified earlier. In the presence of either 0.5 or 1 equiv of the
base, the reaction was observed to proceed at the same initial
rate as when an excess was present, however the reaction
stopped at an extent of conversion of ca. 50% and 95%, re-
spectively, and the rate slowed as the limiting yield was
approached.
The effect on the reaction of altering the concentration of the
base, the observation of an intermediate and the electronic
requirements of the reaction allows the mechanistic pathway
Table 1. Rate constants for the cyclisation of the precursors 1a–e
Compound
R
Rate constant (ꢀ10ꢁ5 sꢁ1
)
9.6
9.4
9.2
9.0
8.8
8.6
(ppm)
8.4
8.2
8.0
7.8
1a
1b
1c
1d
1e
Br
Cl
H
Me
OMe
(1.14ꢂ0.17)
(1.09ꢂ0.27)
(1.77ꢂ0.17)
(2.78ꢂ0.06)
(3.61ꢂ0.29)
Figure 1. 1H NMR spectrum of the cyclisation reaction of the precursor 1e.
The highlighted signals do not correspond to starting material, product,
nitrophenol or its deprotonated form.

K. A. Clayton et al. / Tetrahedron 63 (2007) 10615–10621
10617
R
NO2
R
O
O
NO2
O
N
O
NO2
N
N
O
H
N
H
CO2Et
CO2Et
NO2
O
1
R
N
R
O
O
O
NO2
N
N
H
O
CO2Et
N
H
O
NO2
O
OEt
2
Scheme 3. Cyclisation of the precursors 1 proceeding through an electrocylic mechanism.
to be elucidated. The cyclisation of the precursors 1a–e
occurs through an electrocyclic process, which proceeds
through an intermediate that contains the dinitrophenoxide
moiety followed by elimination to give the aromatic species
2a–e (Scheme 3). A significant resonance contributor to this
intermediate is also shown with a negative charge localised
on the ester oxygen. The presence of an electron donating
substituent at the 400 position of the starting material stabil-
ises this resonance form and hence the intermediate itself.
This results in an increase in the rate of cyclisation, while
conversely an electron withdrawing substituent at the 400 po-
sition of the starting material destabilises the intermediate
and decreases the rate of cyclisation.
Chemical shifts are reported in parts per million downfield
from TMS and coupling constants (J) in hertz (Hz). The
compounds 1b, 2b, 4a,c,e, 5a–c,e, 6b and 7b were prepared
as described previously.1,6,7
4.2. Preparation of novel indole precursors
4.2.1. 1-(40-Chlorophenyl)-2-[(300,500-dimethoxyphenyl)-
amino]ethanone (4b). 3,5-Dimethoxyaniline (1.98 g,
12.9 mmol), 2-bromo-40chloroacetophenone 3b (3.01 g,
12.9 mmol) and sodium hydrogen carbonate (1.37 g,
16.1 mmol) in absolute ethanol (50 mL) were heated under
reflux with stirring until TLC analysis confirmed the con-
sumption of the starting materials (ca. 4 h). The mixture
was then removed from the heat and allowed to cool. The
solvent was removed in vacuo and the residue was purified
using column chromatography (ethyl acetate/light petro-
leum, 3:7) to yield the amino ketone 4b as a yellow solid
(3.60 g, 92%). Mp 114–116 ꢃC; 1H NMR (300 MHz,
CDCl3) d 3.78 (s, 6H, OMe), 4.56 (s, 2H, CH2), 5.88 (s,
3. Conclusions
In conclusion, it can be seen that the key portion of the pre-
cursors 1a–e is the ester moiety. The presence of this group
stabilises the intermediate in the electrocyclic process, facil-
itating the reaction. Further, it suggests that related groups
might be able to perform a similar role; an amide in this
position has been shown to facilitate the cyclisation.1 The
importance of the ester functionality is currently being
investigated through the study of related cyclisations.
00
00
0
2H, H2 ), 5.93 (s, 1H, H4 ), 7.49 (d, 2H, J¼8.7 Hz, H3 ),
7.95 (d, 2H, J¼8.7 Hz, H2 ); 13C NMR (75.5 MHz, CDCl3)
0
00
d 50.5 (CH2), 55.1 (OMe), 90.3 (C4 ), 92.1 (C2 ), 129.1
00
0
0
0
0
00
(C3 ), 129.2 (C2 ), 133.1 (C1 ), 140.3 (C4 ), 148.6 (C1 ),
161.8 (C3 ), 193.6 (CO); nmax 3396, 1682, 1618 cmꢁ1
;
00
lmax (CHCl3) 262 nm (3 8600 cmꢁ1 Mꢁ1); m/z (ESI) 305/
307 ([M+H], 100%); found: C, 62.9; H, 5.3; N, 4.4. Calcd.
for C16H16ClNO3: C, 62.9; H, 5.3; N, 4.6.
4. Experimental
4.1. General
4.2.2. 4,6-Dimethoxy-3-(40-methylphenyl)indole (5d). 3,5-
Dimethoxyaniline (1.48 g, 9.67 mmol), 2-bromo-40-methyl-
acetophenone 3d (2.00 g, 6.94 mmol) and sodium hydrogen
carbonate (1.02 g, 12.1 mmol) in absolute ethanol (35 mL)
were heated under reflux with stirring until TLC analysis
confirmed the consumption of the starting materials (ca.
4 h). The mixture was then removed from the heat and al-
lowed to cool. 1H NMR spectroscopic analysis of the crude
reaction mixture indicated the presence of the indole 5d and,
as such, a small portion of the crude reaction mixture was pu-
rified using column chromatography (light petroleum/ethyl
acetate, 7:3) and the amino ketone 4d isolated. 2-[(300,500-
Dimethoxyphenyl)amino]-1-(40-methylphenyl)ethanone 4d:
€
Melting points were determined on a Kofler hot stage appa-
ratus and are uncorrected. Elemental analyses and electro-
spray mass spectra were performed by Marianne Dick at
the Campbell Microanalytical Laboratory, University of
Otago, New Zealand. Ultraviolet spectra were measured
on a Carey 100 spectrophotometer and refer to solutions in
chloroform. IR spectra were obtained on a Mattson Genesis
series FTIR spectrometer as Nujol mulls between sodium
1
chloride plates unless otherwise stated. H NMR spectra
were recorded at 300 MHz and 13C NMR spectra were re-
corded at 75.5 MHz using a Bruker AC300F spectrometer
with the residual protio solvent as an internal standard.
1
mp 114–116 ꢃC; H NMR (300 MHz, CDCl3) d 2.44 (s,

10618
K. A. Clayton et al. / Tetrahedron 63 (2007) 10615–10621
00
00
3H, 4-Me), 3.78 (s, 6H, OMe), 4.57 (s, 2H, CH2), 5.94 (br s,
0
2H, J¼8.5 Hz, H3 ), 7.48 (d, 2H, J¼8.5 Hz, H2 ), 9.35 (br
00
00
3H, H2 , H4 ), 7.31 (d, 2H, J¼8.3 Hz, H3 ), 7.90 (d, 2H,
s, 1H, NH); 13C NMR (75.5 MHz, CDCl3) d 13.5 (CH3),
0
55.1, 55.6 (OMe), 61.9 (CH2), 85.6 (C7 ), 93.8 (C5 ), 113.3
0 00 00 0 0
(C3a ), 121.9 (C4 ), 127.0 (C2 ), 128.5 (C3 ), 130.0 (C2 ),
13
J¼8.3 Hz, H2 ); C NMR (75.5 MHz, CDCl3) d 21.6 (40-
0
0
00
Me), 50.2 (CH2), 55.1 (OMe), 90.2 (C4 ), 92.0 (C2 ),
00
0
127.8 (C2 ), 129.5 (C3 ), 132.3 (C1 ), 144.8 (C4 ), 148.8
0
0
0
00
00
132.4 (C1 ), 132.5 (C3 ), 139.7 (C7a ), 157.0 (C4 ), 162.4
0
0
00
00
0
(C1 ), 161.8 (C3 ), 194.3 (CO); nmax 3392, 1682, 1621,
1600 cmꢁ1; lmax (CHCl3) 260 nm (3 9400 cmꢁ1 Mꢁ1); m/z
(ESI) 286 ([M+H], 100%); found: C, 71.8; H, 6.4; N, 4.9.
Calcd for C17H19NO3: C, 71.6; H, 6.7; N, 4.9.
(C6 ), 163.9 (CO), 176.7 (OCO); nmax 3000, 1739,
1630 cmꢁ1; lmax (CHCl3) 363 nm (3 16,000 cmꢁ1 Mꢁ1),
264 (19,000); m/z (ESI) 432/424 ([M+H], 100%), 404/406
(9); found: C, 53.8; H, 4.5; N, 3.0. Calcd for
C20H18BrNO5$0.125CHCl3: C, 54.1; H, 4.1; N, 3.1.
The remainder of the mixture and triethylamine (1.94 mL,
14 mmol) in dry tetrahydrofuran (32 mL) was stirred in
an ice bath before trifluoroacetic anhydride (1.98 mL,
14 mmol) was added. The mixture was allowed to come to
room temperature, stirred for 1 h and the solvent was then re-
moved in vacuo yielding a yellow oil. Trifluoroacetic acid
(9.58 mL) was added to the oil and the mixture heated under
reflux for 15 min. The mixture was then removed from the
heat, allowed to cool and poured into ice-water (ca.
100 mL) resulting in a green precipitate. The solid was col-
lected and left to dry in a dessicator. The dried precipitate
was dissolved in methanol (19.2 mL) and potassium hydrox-
ide was (2.03 g, 36.2 mmol) added. The mixture was then
stirred for 1 h and water was added, causing precipitation.
The solid was then extracted with dichloromethane and the
solvent removed in vacuo to give the title compound as
a grey/black solid (2.64 g, 100%) a small sample of which
was recrystallised from chloroform for elemental analysis.
4.3.1.2. Ethyl 2-[30-phenyl-40,60-dimethoxyindol-20-yl]-
glyoxylate (6c). 4,6-Dimethoxy-3-phenylindole 5c: 1.64 g,
6.48 mmol, yield: 0.84 g, 37%, mp 138–139 ꢃC, appearance:
pale yellow solid; 1H NMR (300 MHz, CDCl3) d 1.08 (t, 3H,
J¼7.1 Hz, CH3), 3.62 (s, 3H, OMe), 3.66 (q, 2H, J¼7.1 Hz,
0
CH2), 3.92 (s, 3H, OMe), 6.11 (d, 1H, J¼1.9 Hz, H5 ), 6.40
0
00
00
00
(d, 1H, J¼1.9 Hz, H7 ), 7.34–7.45 (m, 5H, H2 , H3 , H4 ),
9.21 (br s, 1H, NH); 13C NMR (75.5 MHz, CDCl3) d 13.5
0
(CH3), 55.1, 55.5 (OMe), 61.8 (CH2), 85.5 (C7 ), 93.6
0
0
00
00
00
(C5 ), 113.5 (C3a ), 126.8 (C2 ), 127.2 (C3 ), 127.5 (C4 ),
0
130.0 (C2 ), 130.8 (C3 ), 130.9 (C1 ), 139.7 (C7a ), 157.2
00
00
0
0
0
(C4 ), 162.3 (C6 ), 164.0 (CO), 177.5 (OCO); nmax 3340,
1730, 1612 cmꢁ1; lmax (CHCl3) 365 nm (3 6600 cmꢁ1 Mꢁ1),
261 (6900); m/z (ESI) 354 ([M+H], 100%); found: C, 65.9;
H, 5.4; N, 3.8. Calcd for C20H19NO5$0.125CHCl3: C,
65.6; H, 5.2; N, 3.8.
1
Mp 114–116 ꢃC; H NMR (300 MHz, CDCl3) d 2.39 (s,
4.3.1.3. Ethyl 2-[40,60-dimethoxy-30-(400-methylphenyl)-
indol-20-yl]glyoxylate (6d). 4,6-Dimethoxy-3-(40-methyl-
phenyl)indole 5d: 2.60 g, 9.73 mmol, yield: 1.57 g, 44%,
mp 181–183 ꢃC, appearance: yellow solid; 1H NMR
(300 MHz, CDCl3) d 1.08 (t, 3H, J¼7.2 Hz, CH3), 2.40 (s,
3H, 400-Me), 3.64 (s, 3H, OMe), 3.68 (q, 2H, J¼7.2 Hz,
3H, 4-Me), 3.80 (s, 3H, OMe), 3.85 (s, 3H, OMe), 6.26
(d, 1H, J¼2.1 Hz, H5), 6.49 (d, 1H, J¼2.1 Hz, H7), 6.98
0
(d, 2H, J¼8.5 Hz, H2), 7.18 (d, 2H, J¼8.1 Hz, H3 ), 7.90 (d,
2H, J¼8.1 Hz, H2 ), 8.06 (br s, 1H, NH); 13C NMR
0
(75.5 MHz, CDCl3) d 21.0 (40-Me), 55.0 (6-OMe), 55.5 (4-
OMe), 86.8 (C7), 92.1 (C5), 110.4 (C3a), 118.9 (C3), 120.1
0
CH2), 3.86 (s, 3H, OMe), 6.11 (d, 1H, J¼1.9 Hz, H5 ),
0
0
0
0
0
00
(C2), 128.2 (C2 ), 129.3 (C3 ), 133.0 (C1 ), 135.1 (C4 ),
138.3 (C7a), 154.9 (C4), 157.5 (C6); nmax 3357, 1618,
1580 cmꢁ1; lmax (CHCl3) 260 nm (3 9400 cmꢁ1 Mꢁ1); m/z
(ESI) 268 ([M+H], 100%); found: C, 73.0; H, 6.3; N, 5.0.
Calcd for C17H17NO2$0.125CHCl3: C, 72.9; H, 6.1; N, 5.0.
6.39 (d, 1H, J¼1.9 Hz, H7 ), 7.16 (d, 2H, J¼7.9 Hz, H3 ),
7.31 (d, 2H, J¼7.9 Hz, H2 ), 9.20 (br s, 1H, NH); 13C
00
NMR (75.5 MHz, CDCl3) d 13.4 (CH3), 21.2 (400-Me),
0
0
55.1, 55.5 (OMe), 61.9 (CH2), 85.5 (C7 ), 93.5 (C5 ), 113.4
0
(C3a ), 127.3 (C3 ), 127.6 (C2 ), 130.2 (C2 ), 130.8 (C3 ),
0
00
00
00
00
134.2 (C1 ), 137.2 (C4 ), 139.8 (C7a ), 157.3 (C4 ), 162.2
00
0
0
0
4.3. Preparation of substituted indole esters
(C6 ), 164.1 (CO), 176.4 (OCO); nmax 3301, 1739,
1630 cmꢁ1; lmax (CHCl3) 358 nm (3 8600 cmꢁ1 Mꢁ1), 261
(8400); m/z (ESI) 368 ([M+H], 100%), 268 (8); found: C,
67.1; H, 5.5; N, 3.7. Calcd for C21H21NO5$0.1CHCl3: C,
66.8; H, 5.6; N, 3.7.
4.3.1. General procedure for the formation of the
substituted indoles 6. Oxalyl chloride (1.2 mol equiv) was
added to a mixture of the appropriately substituted indole
5 (1 mol equiv) partially dissolved in dry diethyl ether
(8.6 L per mole of indole 5). This mixture was stirred for
3 h at room temperature and the solvent was then removed
in vacuo. Absolute ethanol (4.3 L per mole of substituted in-
dole 5) was then added to the solid and the mixture stirred for
a further 2 h, whereupon the solvent was again removed in
vacuo. The indole esters 6a–e were then purified using col-
umn chromatography (methanol/chloroform, 1:100). Ele-
mental analyses indicated chloroform of crystallisation.
4.3.1.4. Ethyl 2-[40,60-dimethoxy-30-(400-methoxyphe-
nyl)indol-20yl]glyoxylate (6e). 4,6-Dimethoxy-3-(40-meth-
oxyphenyl)indole 5e: 1.90 g, 6.71 mmol, yield: 2.08 g,
1
81%, mp 182–183 ꢃC, appearance: yellow solid; H NMR
(300 MHz, CDCl3) d 1.11 (t, 3H, J¼7.2 Hz, CH3), 3.65 (s,
3H, OMe), 3.74 (q, 2H, J¼7.2 Hz, CH2), 3.85 (s, 3H,
00
0
OMe), 3.87 (s, 3H, 4 -OMe), 6.11 (d, 1H, J¼1.7 Hz, H5 ),
0
00
6.39 (d, 1H, J¼1.7 Hz, H7 ), 6.90 (d, 2H, J¼8.7 Hz, H3 ),
7.35 (d, 2H, J¼8.7 Hz, H2 ), 9.21 (br s, 1H, NH); 13C
00
4.3.1.1. Ethyl 2-[30-(400-bromophenyl)-40,60-dimethoxy-
indol-20-yl]glyoxylate (6a). 3-(40-Bromophenyl)-4,6-di-
methoxyindole 5a: 2.34 g, 7.04 mmol, yield: 0.54 g, 18%,
mp 187–188 ꢃC, appearance: yellow solid; 1H NMR
(300 MHz, CDCl3) d 1.14 (t, 3H, J¼7.7 Hz, CH3), 3.64 (s,
3H, OMe), 3.66 (m, 2H, CH2), 3.85 (s, 3H, OMe), 6.11 (d,
NMR (75.5 MHz, CDCl3) d 13.4 (CH3), 55.1, 55.5 (OMe),
00
(C2 ), 113.5 (C3a ), 125.5 (C3 ), 127.3 (C2 ), 130.0 (C1 ),
0
55.2 (4 -OMe), 61.9 (CH2), 85.5 (C7 ), 93.5 (C5 ), 112.4
0
00
0
0
0
00
00
0
0
0
132.2 (C3 ), 139.8 (C7a ), 157.3 (C4 ), 159.2 (C6 ), 162.2
00
(C4 ), 164.1 (CO), 177.4 (OCO); nmax 3295, 1739,
1620 cmꢁ1; lmax (CHCl3) 409 nm (3 4300 cmꢁ1 Mꢁ1), 314
(5400), 264 (6300); m/z (ESI) 384 ([M+H], 100%), 312
0
0
1H, J¼1.9 Hz, H5 ), 6.39 (d, 1H, J¼1.9 Hz, H7 ), 7.30 (d,

K. A. Clayton et al. / Tetrahedron 63 (2007) 10615–10621
10619
(6), 284 (9); found: C, 64.5; H, 5.4; N, 3.5. Calcd for
C20H18BrNO5$0.1CHCl3: C, 64.1; H, 5.4; N, 3.5.
4.4.1.3. Ethyl 40,60-dimethoxy-30-(400-methylphenyl)
indol-20-yl-2-(hydroxyimino)acetate (7d). Ethyl 2-[40,60-
dimethoxy-30-(400-methylphenyl)indol-20-yl]glyoxylate 6d:
1.28 g, 3.48 mmol, yield: 1.02 g, 77%, mp 98–99 ꢃC, ap-
pearance: yellow solid; 1H NMR (300 MHz, CDCl3)
d 1.00 (m, 6H, CH3), 2.40 (s, 3H, 400-Me), 3.69 (m, 16H,
4.4. Preparation of 3-arylindole-2-ketoximes
4.4.1. General procedure for the formation of the indole
oximes 7. The appropriate indole ester 6 (1 mol equiv),
hydroxylamine hydrochloride (5.2 mol equiv) and sodium
acetate (2.9 mol equiv) in absolute ethanol (40 L per mol
of indole ester 6) were heated under reflux for 7 h. The
mixture was allowed to cool to room temperature and wa-
ter (50 L per mol indole ester 6) was added. The aqueous
layer was extracted with dichloromethane, washed with
water and dried. The solvent was removed in vacuo and
1H NMR analysis of the crude reaction mixture was per-
formed. If there was evidence of the ester 6, the reaction
was repeated. Upon consumption of the starting material,
the crude oxime mixture was purified using column chro-
matography (chloroform/methanol, 9.7:0.3). It should be
noted that due to the presence of the syn and anti forms
of the oximes 7a–e, signals in the NMR spectra are
doubled. Elemental analyses indicated chloroform of
crystallisation.
0
OMe, CH2), 6.10, 6.16 (2d, 2H, J¼1.9 Hz, H5 ), 6.35, 6.40
0
00
00
(2d, 2H, J¼1.9 Hz, H7 ), 7.11–7.34 (m, 8H, H2 , H3 ),
8.97, 9.67 (2br s, 2H, NH); 13C NMR (75.5 MHz, CDCl3)
d 13.4, 13.4 (CH3), 21.1, 21.2 (400-Me), 55.0, 55.1 (40-
OMe), 55.4, 55.4 (60-OMe), 61.7, 62.1 (CH2), 86.1, 86.2
0
0
0
(C7 ), 92.5, 92.9 (C5 ), 111.0, 113.0 (C3a ), 120.2, 123.1
0
(C3 ), 121.8, 122.2 (C2 ), 127.4, 127.8 (C2 ), 130.7, 131.9
0
00
00
(C4 ), 131.1, 131.3 (C3 ), 136.2, 138.1 (C1 ), 144.4, 146.1
00
00
0
0
0
(C7a ), 155.8, 155.8 (C4 ), 159.3, 159.4 (C6 ), 162.0, 163.7
(C]N), 175.9, 177.5 (OCO); nmax 3416, 1717,
1627 cmꢁ1; lmax (CHCl3) 329 nm (3 12,000 cmꢁ1 Mꢁ1),
262 (18,000); m/z (ESI) 383 ([M+H], 100%), 365 (11),
293 (34); found: C, 63.1; H, 5.57 N, 6.8. Calcd for
C21H22N2O5$0.15CHCl3: C, 63.2; H, 5.6; N, 7.0.
4.4.1.4. Ethyl 40,60-dimethoxy-30-(400-methoxyphenyl)-
indol-20-yl-2-(hydroxyimino)acetate (7e). Ethyl 2-[40,60-
dimethoxy-30-(400-methylphenyl)indol-20-yl]glyoxylate 6e:
1.98 g, 5.17 mmol, yield: 1.17 g, 57% (recovered 0.22 g,
0.57 mmol starting material), mp 89–90 ꢃC, appearance:
4.4.1.1. Ethyl 30-(400-bromophenyl)-40,60-dimethoxy-
indol-20-yl-2-(hydroxyimino)acetate (7a). Ethyl 2-[30-(400-
1
bromophenyl)-40,60-dimethoxyindol-20-yl]glyoxylate
6a:
yellow solid; H NMR (300 MHz, CDCl3) d 1.02 (m, 6H,
CH3), 3.71 (m, 22H, 40-, 60- and 400-OMe), 6.08, 6.15 (2d,
0.45 g, 1.05 mmol, yield: 0.45 g, 96%, mp 128–129 ꢃC, ap-
pearance: yellow solid; 1H NMR (300 MHz, CDCl3) d 1.06
(m, 6H, CH3), 3.72 (m, 16H, OMe, CH2), 6.11, 6.17 (2d, 2H,
0
0
2H, J¼1.5 Hz, H5 ), 6.31, 6.40 (2d, 2H, J¼1.5 Hz, H7 ),
00
00
6.87 (m, 4H, H2 ), 7.31 (m, 4H, H3 ), 9.03, 9.66 (2br s,
2H, NH); 13C NMR (75.5 MHz, CDCl3) d 13.5, 13.6
(CH3), 55.0, 55.1 (60-OMe), 55.2 (400-OMe), 55.5, 55.5 (40-
0
0
J¼1.9 Hz, H5 ), 6.36, 6.43 (2d, 2H, J¼1.9 Hz, H7 ), 7.24 (m,
4H, H2 ), 7.38 (m, 4H, H3 ), 8.85, 9.62 (2br s, 2H, NH); 13C
NMR (75.5 MHz, CDCl3) d 13.4, 13.5 (CH3), 55.0, 55.0 (60-
OMe), 55.5, 55.5 (40-OMe), 61.9, 62.2 (CH2), 86.0, 86.1
00
00
0
OMe), 61.6, 62.0 (CH2), 86.0, 86.0 (C7 ), 92.5, 92.6 (C5 ),
0
0
111.2, 113.1 (C3a ), 112.2, 112.5 (C2 ), 120.1, 122.8 (C3 ),
00
0
0
0
0
(C7 ), 92.6, 92.8 (C5 ), 110.8, 112.7 (C3a ), 120.1, 122.2
0 00 00
121.4, 122.2 (C2 ), 126.1, 127.2 (C1 ), 132.3, 132.4 (C3 ),
0
(C3 ), 120.9, 121.5 (C2 ), 129.8, 130.1 (C2 ), 132.7, 132.9
0
00
00
137.9, 138.1 (C4 ),144.7, 146.0 (C7a ), 155.7, 155.9 (C4 ),
0
0
00
00
00
(C3 ), 133.0, 133.9 (C4 ), 137.9, 138.1 (C1 ), 144.0, 145.7
0
158.6, 159.5 (C6 ), 161.4, 164.1 (C]N), 170.7, 179.1
(C7a ), 155.1, 155.3 (C4 ), 159.6, 159.6 (C6 ), 161.6, 163.2
(C]N), 175.6, 177.3 (OCO); nmax 3419, 1733, 1716,
1683 cmꢁ1; lmax (CHCl3) 326 nm (3 11,000 cmꢁ1 Mꢁ1),
264 (19,000); m/z (ESI) 446/448 ([M+H], 100%), 429/431
(34), 356/358 (27); found: C, 48.4; H, 3.8; N, 5.5. Calcd
for C20H19BrN2O5$0.5CHCl3: C, 48.6; H, 3.9; N, 5.5.
(OCO); nmax 3420, 1716, 1646 cmꢁ1; lmax (CHCl3)
358 nm (3 9500 cmꢁ1 Mꢁ1), 329 (15,000), 260 (20,000);
m/z (ESI) 399 ([M+H], 100%), 381 (23), 309 (42); found:
C, 60.3; H, 5.3; N, 6.2. Calcd for C21H22N2O6$0.2CHCl3:
C, 60.3; H, 5.3; N, 6.6.
0
0
0
4.5. Preparation of 3-arylindole-2-ketoxime ethers
4.4.1.2. Ethyl 30-phenyl-40,60-dimethoxyindol-20-yl-
2-(hydroxyimino)acetate (7c). Ethyl 2-[30-phenyl-40,60-di-
methoxyindol-20-yl]glyoxylate 6c: 0.58 g, 1.65 mmol, yield:
4.5.1. General procedure for the formation of the cyclisa-
tion precursors 1. The appropriate indole oxime 7 (1 mol
equiv) was dissolved in absolute ethanol (38 L per mol of
oxime 7) and sodium metal (1.5 mol equiv) was added.
This mixture was stirred for 30 min to ensure complete re-
action of the sodium. The mixture was then cooled in an
ice bath before 2,4-dinitrofluorobenzene (1.5 mol equiv)
was added dropwise, resulting in immediate precipitation
of a yellow-orange solid. The reaction mixture was stirred
until TLC analysis confirmed consumption of the indole
oxime 7 whereupon the solid was collected under suction
and washed with absolute ethanol. The solid was dried in
a dessicator and reacted further without the need for puri-
fication (a small sample was recrystallised from chloro-
form for elemental analysis). It should be noted that due
to the presence of the syn and anti forms of the cyclisa-
tion precursors 1a–e, signals in the NMR spectra may
be doubled.
1
0.59 g, 97%, mp 92–93 ꢃC, appearance: yellow solid; H
NMR (300 MHz, CDCl3) d 1.00 (m, 6H, CH3), 3.73 (m,
0
16H, OMe, OCH2), 6.10, 6.16 (2d, 2H, J¼1.9 Hz, H5 ),
0
00
6.36, 6.43 (2d, 2H, J¼1.9 Hz, H7 ), 7.31 (m, 10H, H2 ,
H3 , H4 ), 8.86, 9.67 (2br s, 2H, NH); 13C NMR
(75.5 MHz, CDCl3) d 13.3, 13.5 (CH3), 55.0, 55.0 (60-
OMe), 55.4, 55.5 (40-OMe), 61.7, 62.1 (CH2), 86.0, 86.1
00
00
0
(C7 ), 92.5, 92.7 (C5 ), 111.0, 113.0 (C3a ), 120.2, 123.0
0
0
0
0
00
(C3 ), 121.7, 122.1 (C2 ), 126.7, 126.8 (C2 ), 126.8, 127.0
00
(C3 ), 131.2, 131.4 (C4 ), 137.9, 138.1 (C1 ), 144.3, 146.0
00
00
0
0
0
(C7a ), 155.6, 155.8 (C4 ), 159.4, 159.4 (C6 ), 161.9, 163.2
(C]N), 176.8, 177.6 (OCO); nmax 3419, 1716, 1634 cmꢁ1
;
lmax (CHCl3) 359 nm (3 7600 cmꢁ1 Mꢁ1), 331 (12,000),
262 (15,000); m/z (ESI) 369 ([M+H], 100%), 351 (17),
279 (18); found: C, 60.7; H, 5.4; N, 6.8. Calcd for
C20H20N2O5$0.25CHCl3: C, 61.1; H, 5.1; N, 7.0.

10620
K. A. Clayton et al. / Tetrahedron 63 (2007) 10615–10621
4.5.1.1. Ethyl 30-(400-bromophenyl)-40,60-dimethoxyin-
00
127.6 (C2 ), 129.1, 129.6 (C4 ), 130.2, 130.7 (C5 ), 131.0,
00
00
dol-20-yl-2-(O-2,4-dinitrophenoxyimino)acetate (1a). Ethyl
30-(400-bromophenyl)-40,60-dimethoxyindol-20-yl-2-(hydroxy-
imino)acetate 7a: 0.28 g, 0.63 mmol, yield: 0.29 g, 75%,
mp 214–215 ꢃC, appearance: yellow-orange solid; 1H NMR
(300 MHz, CDCl3) d 1.13–1.27 (m, 6H, CH3), 3.58–3.93
00
000
00
131.4 (C3 ), 135.9, 137.1 (C2 ), 139.0, 139.21 (C1 ),
0
139.8, 140.1 (C7a ), 140.1, 141.4 (C4 ), 149.4, 151.6 (C6 ),
000
0
0
000
155.1, 155.3 (C4 ), 156.8, 157.0 (C1 ), 160.0, 161.1
(C]N), 161.5, 173.5 (OCO); nmax 3385, 1739, 1626,
1607 cmꢁ1; lmax (CHCl3) 408 nm (3 29,000 cmꢁ1 Mꢁ1),
333 (50,000), 252 (53,000); m/z (ESI) 549 ([M+H], 9%),
365 (100), 293 (13); found: C, 58.3; H, 4.5; N, 9.9. Calcd
for C27H24N4O9$0.1CHCl3: C, 58.1; H, 4.3; N, 10.0.
0
(m, 16H, OMe, CH2), 6.15 (br s, 2H, H5 ), 6.47, 6.61 (2d,
0
00
2H, J¼1.9 Hz, H7 ), 7.26 (m, 4H, H2 ), 7.48–7.61 (m, 4H,
00
000
H3 ), 7.90, 8.23 (2d, 2H, J¼9.4 Hz, H6 ), 8.45, 8.53 (2dd,
000
2H, J¼2.6, 9.4 Hz, H5 ), 8.30, 9.12 (2d, 2H, J¼2.6 Hz,
H3 ), 8.70, 10.77 (2br s, 2H, NH); 13C NMR (75.5 MHz,
4.5.1.4. Ethyl 40,60-dimethoxy-30-(400-methoxyphenyl)-
indol-20-yl-2-(O-2,4-dinitrophenoxyimino)acetate (1e).
Ethyl 40,60-dimethoxy-30-(400-methoxyphenyl)indol-20-yl-2-
(hydroxyimino)acetate 7e: 0.78 g, 1.95 mmol, yield: 0.78 g,
000
CDCl3) d 13.5, 14.6 (CH3), 55.7, 55.8 (40-OMe), 56.1, 56.4
0
(C5 ), 106.1 (C3a ), 117.4 (C6 ), 119.7 (C3 ), 121.3, 122.2
0
(4 -OMe), 62.0, 62.7 (CH2), 86.7, 88.7 (C7 ), 93.1, 93.2
0
0
000
000
1
71%, mp 173–174 ꢃC, appearance: yellow-orange solid; H
0
(C2 ), 124.0, 125.3 (C4 ), 126.8, 127.8 (C1 ), 130.1, 130.2
00
00
00
000
00
000
(C2 ), 130.3, 130.7 (C5 ), 132.9, 133.5 (C3 ), 136.2 (C2 ),
NMR (300 MHz, CDCl3) d 1.10–1.26 (m, 6H, CH3), 3.56–
3.92 (m, 22H, 40-, 60- and 400-OMe), 6.10, 6.12 (2d, 2H,
0
139.8 (C7a ), 141.4, 141.6 (C4 ), 151.2 (C6 ), 155.6, 155.7
000
0
0
000
0
0
(C4 ), 160.1 (C1 ), 160.6, 161.9 (C]N), 165.6, 170.8 (OCO);
nmax 3382, 1738, 1626, 1606 cmꢁ1; lmax (CHCl3) 386 nm (3
16,000 cmꢁ1 Mꢁ1), 262 (23,000); m/z (ESI) 614/616 ([M+H],
4%), 429/431 (100); found: C, 42.3; H, 2.9; N, 7.5. Calcd for
C26H21BrN4O9$1.4CHCl3: C, 42.2; H, 2.9; N, 7.2.
J¼1.9 Hz, H5 ), 6.42, 6.58 (2d, 2H, J¼1.9 Hz, H7 ), 6.89 (m,
0
0
0
0
4H, H2 ), 7.30 (m, 4H, H3 ), 7.90, 8.21 (2d, 2H, J¼9.4 Hz,
000
000
H6 ), 8.39, 8.50 (2dd, 2H, J¼2.6, 9.4 Hz, H5 ), 8.87, 9.09
(2d, 2H, J¼2.6 Hz, H3 ), 8.72, 10.69 (2br s, 2H, NH); 13C
000
NMR (75.5 MHz, CDCl3) d 13.4, 13.5 (CH3), 55.0, 55.1 (40-
OMe), 55.2 (400-OMe), 55.5, 55.7 (60-OMe), 62.7, 62.8
4.5.1.2. Ethyl 30-phenyl-40,60-dimethoxyindol-20-yl-2-
(O-2,4-dinitrophenoxyimino)acetate (1c). Ethyl 30-phen-
yl-40,60-dimethoxyindol-20-yl-2-(hydroxyimino)acetate 7c:
0.37 g, 1.01 mmol, yield: 0.23 g, 43%, mp 165–166 ꢃC, ap-
pearance: yellow-orange solid; 1H NMR (300 MHz, CDCl3)
d 1.08–1.27 (m, 6H, CH3), 3.47–3.97 (m, 16H, OMe,
0
(CH2), 85.6, 85.7 (C7 ), 93.0, 93.4 (C5 ), 112.2, 112.3 (C3 ),
0
00
0
000
112.4, 113.7 (C3a ), 116.6 (C6 ), 118.0, 118.3 (C3 ), 121.9,
0
0
122.5 (C2 ), 124.9, 126.0 (C1 ), 129.0, 130.2 (C5 ), 132.2,
00
000
00
132.7 (C2 ), 135.4, 135.9 (C2 ), 139.8, 139.9 (C7a ), 141.0,
000
0
000
0
0
141.5 (C4 ), 149.4, 151.6 (C6 ), 155.3, 156.1 (C4 ), 157.0
000
00
(C1 ), 159.1, 160.2 (C4 ), 161.1, 161.2 (C]N), 161.6, 173.0
(OCO); nmax 3388, 1739, 1605 cmꢁ1; lmax (CHCl3) 333 nm
(3 7000 cmꢁ1 Mꢁ1), 248 (12,000); m/z (ESI) 565 ([M+H],
8%), 381 (100); found: C, 54.3; H, 4.4; N, 8.9. Calcd for
C21H22N2O6$0.33CHCl3: C, 54.3; H, 4.1; N, 9.3.
0
OCH2), 6.13 (br s, 2H, H5 ), 6.46, 6.61 (2d, 2H, J¼1.9 Hz,
0
00
00
00
H7 ), 7.24–7.43 (m, 10H, H2 , H3 , H4 ), 7.90, 8.23 (2d,
000
2H, J¼9.4 Hz, H6 ), 8.42, 8.52 (2dd, 2H, J¼2.6, 9.4 Hz,
000
000
H5 ), 8.30, 9.12 (2d, 2H, J¼2.6 Hz, H3 ), 8.73, 10.77 (2br
s, 2H, NH); 13C NMR (75.5 MHz, CDCl3) d 13.3, 13.4
(CH3), 55.0, 55.1 (40-OMe), 55.5, 55.7 (60-OMe), 62.7,
4.6. Preparation of indolo[2,3-c]quinolines
0
62.8 (CH2), 85.6, 85.7 (C7 ), 93.1, 93.5 (C5 ), 110.5, 112.3
0
0
(C3a ), 116.7, 116.8 (C6 ), 118.0, 118.3 (C3 ), 119.2, 119.4
000
0
4.6.1. General procedure for the formation of the tetra-
cycles 2. The appropriate cyclisation precursor 1 (1 mol
equiv) and triethylamine (10 mol equiv) in dry tetrahydrofu-
ran (42 L per mole of cyclisation precursor 1) were heated at
reflux until TLC analysis showed consumption of the start-
ing material. The solvent was then removed in vacuo and
the residue dissolved in dichloromethane whereupon it was
slowly added to 2 M hydrochloric acid resulting in precipi-
tation. The precipitate was collected and the aqueous layer
separated. The organic layer was again extracted with 2 M
hydrochloric acid and the aqueous washings and the precip-
itate combined. Dichloromethane was added to the aqueous
mixture, which was subsequently adjusted to pH 12 with con-
centrated sodium hydroxide solution, resulting in the sus-
pended solid dissolving. The organic phase was separated
and the aqueous layer was then extracted again with dichloro-
methane. The combined organic phases were dried over mag-
nesium sulfate and the solvent removed in vacuo to yield the
tetracycles 2a–e. Where necessary a small sample was re-
crystallised from chloroform for elemental analysis.
000
0
00
(C3 ), 122.0, 122.6 (C2 ), 126.8, 127.0 (C2 ), 129.1, 130.2
000
(C5 ), 131.2, 131.4 (C3 ), 132.8, 133.7 (C4 ), 135.5 (C2 ),
00
00
000
00
0
000
138.9, 139.8 (C1 ), 140.7 (C7a ), 141.6 (C4 ), 149.2, 151.5
0
0
000
(C4 ), 155.1, 155.3 (C6 ), 156.0, 156.1 (C1 ), 160.1, 161.3
(C]N), 161.4, 173.3 (OCO); nmax 3380, 1726, 1624,
1608 cmꢁ1; lmax (CHCl3) 385 nm (3 16,000 cmꢁ1 Mꢁ1),
257 (23,000); m/z (ESI) 535 ([M+H], 9%), 451 (6), 351
(100), 279 (6); found: C, 57.2; H, 4.5; N, 9.9. Calcd for
C26H22N4O9$0.125CHCl3: C, 57.1; H, 4.1; N, 10.2.
4.5.1.3. Ethyl 40,60-dimethoxy-30-(400-methylphenyl)-
indol-20-yl-2-(O-2,4-dinitrophenoxyimino)acetate (1d).
Ethyl 40,60-dimethoxy-30-(400-methylphenyl)indol-20-yl-2-
(hydroxyimino)acetate 7d: 1.01 g, 2.65 mmol, yield:
1.07 g, 74%, mp 170–171 ꢃC, appearance: yellow-orange
1
solid; H NMR (300 MHz, CDCl3) d 1.09–1.27 (m, 6H,
CH3), 2.40 (s, 6H, 400-Me), 3.50–3.95 (m, 16H, OMe,
0
CH2), 6.11, 6.14 (2d, 2H, J¼1.5 Hz, H5 ), 6.44, 6.60 (2d,
0
00
00
2H, J¼1.5 Hz, H7 ), 7.14–7.31 (m, 8H, H2 , H3 ), 7.90,
000
8.23 (2d, 2H, J¼9.4 Hz, H6 ), 8.41, 8.52 (2dd, 2H, J¼2.6,
000
000
9.4 Hz, H5 ), 8.83, 9.11 (2d, 2H, J¼2.6 Hz, H3 ), 8.71,
10.73 (2br s, 2H, NH); 13C NMR (75.5 MHz, CDCl3)
d 13.3, 13.4 (CH3),0 21.1, 21.2 (400-Me), 55.0, 55.1 (40-
4.6.1.1. Ethyl 3-bromo-9,11-dimethoxy indolo[2,3-c]-
quinoline-6-carboxylate (2a). Ethyl 30-(400-bromophenyl)-
40,60-dimethoxyindol-20-yl-2-(O-2,4-dinitrophenoxyimino)-
acetate 1a: 0.0503 g, 0.082 mmol, yield: 0.033 g, 94%, mp
199–200 ꢃC, appearance: yellow-orange solid; 1H NMR
(300 MHz, CDCl3) d 1.24 (t, 3H, J¼7.2 Hz, CH3), 3.95,
0
OMe), 55.5, 55.7 (6 -OMe), 62.6, 62.8 (CH2), 85.7 (C7 ),
0
93.0, 93.4 (C5 ), 113.5, 113.6 (C3a ), 116.6 (C6 ), 118.0,
0
000
0
00
118.3 (C3 ), 119.3, 119.5 (C3 ), 121.9, 122.5 (C2 ), 127.5,
0

K. A. Clayton et al. / Tetrahedron 63 (2007) 10615–10621
10621
4.12 (2s, 6H, OMe), 4.67 (q, J¼7.2 Hz, OCH2), 6.42 (d, 1H,
J¼1.9 Hz, H10), 6.67 (d, 1H, J¼1.9 Hz, H8), 7.68 (dd, 1H,
J¼1.9, 9.4 Hz, H2), 8.57 (d, 1H, J¼1.9 Hz, H4), 9.38 (d,
1H, J¼9.4 Hz, H1), 10.37 (br s, 1H, NH); 13C NMR
(75.5 MHz, CDCl3) d 14.3 (CH3), 55.4, 55.6 (OMe), 62.4
(CH2), 86.9 (C8), 92.9 (C10), 119.8 (C6a), 124.0 (C3), 125.6
(C11c), 128.6 (C1), 130.6 (C4), 132.0 (C11a), 132.4 (C7a,
C11b), 132.9 (C2), 142.7 (C4a), 143.4 (C6), 155.9 (C9), 162.1
(C11), 166.7 (OCO); nmax 3411, 1690, 1614 cmꢁ1; lmax
(CHCl3) 404 nm (3 1900 cmꢁ1 Mꢁ1), 363 (3300), 275
(8400); m/z (ESI) 429/431 ([M+H], 100%); found: C, 46.4;
H, 3.7; N, 5.2. Calcd for C20H17BrN2O4$CHCl3: C, 46.0;
H, 3.3; N, 5.1.
1H, J¼1.5 Hz, H10), 6.61 (d, 1H, J¼1.5 Hz, H8), 7.33 (dd,
1H, J¼3.0, 9.4 Hz, H2), 8.16 (d, 1H, J¼3.0 Hz, H4), 9.39
(d, 1H, J¼9.4 Hz, H1), 10.37 (br s, 1H, NH); 13C NMR
(75.5 MHz, CDCl3) d 14.4 (CH3), 55.3 (3-OMe), 55.4,
55.6 (OMe), 62.3 (CH2), 86.9 (C8), 92.5 (C10), 108.6 (C4),
120.6 (C11c), 120.7 (C1), 125.4 (C6a), 128.2 (C2), 131.2
(C11a), 131.6 (C7a, C11b), 143.0 (C4a), 144.3 (C6), 156.2
(C9), 158.0 (C3), 162.0 (C11), 166.9 (OCO); nmax 3431,
1726, 1687, 1620 cmꢁ1
; lmax (CHCl3) 416 nm (3
5000 cmꢁ1 Mꢁ1), 363 (8300), 260 (13,000); m/z (ESI) 365
([M+H], 100%); found: C, 58.7; H, 5.0; N, 6.4. Calcd for
C21H20N2O5$0.5CHCl3: C, 58.7; H, 4.7; N, 6.4.
4.7. Calculation of rate constants for the cyclisation of
3-arylindole-2-ketoxime ethers
4.6.1.2. Ethyl 9,11-dimethoxy indolo[2,3-c]quinoline-
6-carboxylate (2c). Ethyl 30-phenyl-40,60-dimethoxyindol-
20-yl-2-(O-2,4-dinitrophenoxyimino)acetate 1c: 0.052 g,
0.098 mmol, yield: 0.034 g, 99%, mp 189–191 ꢃC, appear-
ance: yellow-orange solid; 1H NMR (300 MHz, CDCl3)
d 1.41 (t, 3H, J¼7.1 Hz, CH3), 3.90, 4.14 (2s, 6H, OMe),
4.68 (q, J¼7.1 Hz, OCH2), 6.43 (s, 1H, H10), 6.70 (s, 1H,
H8), 7.68 (m, 2H, H3, H4), 8.43 (m, 1H, H2), 9.53 (d, 1H,
J¼7.9 Hz, H1), 10.40 (br s, 1H, NH); 13C NMR
(75.5 MHz, CDCl3) d 14.3 (CH3), 55.5, 55.6 (OMe), 62.4
(CH2), 87.0 (C8), 92.9 (C10), 125.8 (C6a), 126.3 (C1),
127.1 (C2), 127.7 (C3), 127.8 (C4), 131.0 (C11a), 132.1
(C7a), 132.2 (C11b), 135.1 (C11c), 143.7 (C4a), 145.0 (C6),
156.1 (C9), 162.0 (C11), 166.8 (OCO); nmax 3430, 2693,
1620 cmꢁ1; lmax (CHCl3) 398 nm (3 750 cmꢁ1 Mꢁ1), 359
(1200), 272 (3000); m/z (ESI) 351 ([M+H], 100%); found:
C, 60.7; H, 7.4; N, 6.5. Calcd for C20H18N2O11$3.5CHCl3:
C, 61.0; H, 7.0; N, 6.1.
The precursors 1a–e (1 mol equiv) were each added to a
solution of triethylamine (10 mol equiv) in tetrahydrofuran
(42 L per mol of precursor 1) being heated at reflux. Aliquots
of the reaction mixture (ca. 0.3 mL) were taken periodically,
cooled to 77 K to quench the reaction and the solvent then
removed in vacuo at that temperature. The aliquots were sub-
sequently analysed using 1H NMR spectroscopy. The extent
of reaction in each case was calculated by comparing the in-
000
tegrations corresponding to either the H5 or H6 signal in
000
0
0
the precursor 1, the H5 or H6 signal in the intermediate
and the H1 signal in the tetracycle 2. The data was fitted
using a numerical integration to obtain the rate constant for
the formation of the intermediate from each of the starting
materials 1a–e.
Acknowledgements
4.6.1.3. Ethyl 9,11-dimethoxy-3-methyl indolo[2,3-
c]quinoline-6-carboxylate (2d). Ethyl 40,60-dimethoxy-
30-(400-methylphenyl)indol-20-yl-2-(O-2,4-dinitrophenoxyimi-
no)acetate 1d: 0.308 g, 0.055 mmol, yield: 0.20 g, 100%,
mp 181–183 ꢃC, appearance: yellow-orange solid; 1H NMR
(300 MHz, CDCl3) d 1.24 (t, 3H, J¼7.1 Hz, CH3), 3.94,
4.13 (2s, 6H, OMe), 4.65 (q, J¼7.1 Hz, OCH2), 6.42 (d,
1H, J¼1.9 Hz, H10), 6.68 (d, 1H, J¼1.9 Hz, H8), 7.52 (dd,
1H, J¼1.9, 8.7 Hz, H2), 8.16 (br s, 1H, H4), 9.41 (d, 1H,
J¼8.7 Hz, H1), 10.33 (br s, 1H, NH); 13C NMR (75.5 MHz,
CDCl3) d 14.3 (CH3), 21.3 (3-Me), 55.4, 55.6 (OMe), 62.2
(CH2), 86.9 (C8), 92.6 (C10), 123.5 (C11c), 125.6 (C6a),
126.8 (C1), 130.0 (C2), 130.2 (C4), 131.9 (C11a), 132.0 (C7a,
C11b), 135.9 (C3), 142.6 (C4a), 143.2 (C6), 156.1 (C9), 161.8
(C11), 167.1 (OCO); nmax 3424, 1698, 1623 cmꢁ1; lmax
(CHCl3) 406 nm (3 3400 cmꢁ1 Mꢁ1), 262 (4400); m/z (ESI)
381 ([M+H], 100%); found: C, 60.4; H, 5.3; N, 6.9. Calcd
for C21H20N2O11$0.8CHCl3: C, 60.6; H, 5.0; N, 6.5.
The helpful advice of Dr. James Hook and the other staff of
UNSW NMR Facility is gratefully acknowledged, as is the
financial support of the Australian Research Council and
UNSW. JBH would like to acknowledge the receipt of a
visiting fellowship from the University of Melbourne.
References and notes
1. Wahyuningsih, T. D.; Kumar, N.; Black, D., StC. Tetrahedron
2007, 63, 6713–6719.
2. Sugumi, H.; Niijima, J.; Kotake, Y.; Okada, T.; Kamata, J.-i.;
Yoshimatsu, K.; Nagasu, T.; Nakamura, K.; Uenaka, T.;
Yamaguchi, A.; Yoshino, H.; Koyanagi, N.; Kito, K. Int.
Patent 9638446, 1996; Chem. Abstr. 1996, 126, 89394.
3. For examples, see: Narasaka, K. Pure Appl. Chem. 2003, 75,
19–28 and references cited therein.
4. Mikami, T.; Narasaka, K. Chem. Lett. 2000, 338–339.
5. Uchiyama, K.; Ono, A.; Hayashi, Y.; Narasaka, K. Bull. Chem.
Soc. Jpn. 1998, 71, 2945–2955.
4.6.1.4. Ethyl 3,9,11-trimethoxy indolo[2,3-c]quino-
line-6-carboxylate (2e). Ethyl 40,60-dimethoxy-30-(400-
methoxyphenyl)indol-20-yl-2-(O-2,4-dinitrophenoxyimino)-
acetate 1e: 0.195 g, 0.035 mmol, yield: 0.066 g, 51%, mp
159–161 ꢃC, appearance: yellow-orange solid; 1H NMR
(300 MHz, CDCl3) d 1.57 (t, 3H, J¼7.2 Hz, CH3), 3.92,
4.09 (2s, 6H, OMe), 4.66 (q, J¼7.2 Hz, OCH2), 6.36 (d,
ꢀ
6. Black, D. StC.; Gatehouse, B. M. K. C.; Theobald, F.; Wong,
L. C. H. Aust. J. Chem. 1980, 33, 343–350.
7. Black, D. StC.; Bowyer, M. C.; Bowyer, P. K.; Ivory, A. J.; Kim,
M.; Kumar, N.; McConnell, D. B.; Popiolek, M. Aust. J. Chem.
1994, 47, 1741–1750.