Mechanisms of cyclisation of indolo oxime ethers. Part 2: Formation of?ethyl 6,8-dimethoxypyrazolo[4,5,1-hi]indole-5-carboxylates

Article abstract of DOI:10.1016/j.tet.2008.01.100

The cyclisation of a series of ethyl 3′-phenyl-4′,6′-dimethoxyindol-7′-yl-2-(hydroxyimino)acetates was investigated using ¹H NMR spectroscopy to determine the mechanism of formation of the corresponding ethyl 6,8-dimethoxypyrazolo[4,5,1-hi]indo

Full text of DOI:10.1016/j.tet.2008.01.100

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 3183e3189
www.elsevier.com/locate/tet
Mechanisms of cyclisation of indolo oxime ethers. Part 2: Formation
of ethyl 6,8-dimethoxypyrazolo[4,5,1-hi]indole-5-carboxylates
*
Kylie A. Clayton, David StC. Black, Jason B. Harper
School of Chemistry, University of New South Wales, UNSW, Sydney, NSW 2052, Australia
Received 12 October 2007; received in revised form 8 January 2008; accepted 24 January 2008
Available online 31 January 2008
Abstract
The cyclisation of a series of ethyl 30-phenyl-40,60-dimethoxyindol-70-yl-2-(hydroxyimino)acetates was investigated using 1H NMR spectros-
copy to determine the mechanism of formation of the corresponding ethyl 6,8-dimethoxypyrazolo[4,5,1-hi]indole-5-carboxylates. The electronic
requirements of the reaction were determined and used, along with the effect of removing the ester functionality, to determine that the reaction
proceeds through a concerted intramolecular substitution.
Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
Keywords: Indole; Cyclisation; Mechanism determination
1. Introduction
isomeric case has been shown in the preceding paper in this
series2 to proceed through an electrocyclic mechanism.
As for the series investigated previously (Scheme 2),2 sev-
eral mechanistic pathways may be considered for the reaction
outlined in Scheme 1. There is literature precedent for an
intramolecular concerted substitution process3 and this has
been suggested previously for this system.1 A polar mecha-
nism that proceeds stepwise through a nitronium ion must
also be considered. Rather than a polar mechanism, radical
mechanisms need also to be considered, as both one-step4
and two-step5 radical processes have been reported for related
systems. While an electrocyclic mechanism, which was found
to be the case for the isomeric oxime cyclisation (Scheme 2),2
is not possible in this case, a conjugate addition mechanism
Recently, we have reported the cyclisation of chlorophenyl
oxime ether 1c to the corresponding tricycle 2c (Scheme 1).1 It
is of interest to determine the mechanism of this process, both
in an effort to extend the methodology involved in the synthe-
ses of these novel tricycles and also as a comparison to when
the indoles are substituted at the 2-position (Scheme 2). This
Cl
Cl
O
O
base
THF, Δ
N
H
O
N
O
EtO2C
N
O
N
R
R
NO2
NO2
EtO2C
2c
1c
O
O
O2N
NO2
NEt3
N
N
O
THF, Δ
Scheme 1. Cyclisation of the oxime ether 1c to give the corresponding
tricycle 2c.
CO2Et
N
H
N
H
CO2Et
O
O
Scheme 2. Cyclisation of ethyl 30-aryl-40,60-dimethoxyindol-20-yl-2-(hydroxy-
imino)acetates, which has been shown to proceed through an electrocyclic
mechanism.2
* Corresponding author. Tel.: þ61 2 9385 4692; fax: þ61 2 9385 6141.
E-mail address: j.harper@unsw.edu.au (J.B. Harper).
0040-4020/$ - see front matter Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.100

3184
K.A. Clayton et al. / Tetrahedron 64 (2008) 3183e3189
R
R
R
R
O
O
O
O
O
i)
ii)-iv)
v), vi)
N
H
O
O
N
H
Br
3
N
H
O
6
EtO2C
O
4
5
vii)
R
R
R
O
O
a R = CN
b R = Br
c R = Cl
d R = H
e R = Me
O
viii), ix)
x)
N
O
N
H
O
N
N
O
EtO2C
N
O
H
EtO2C
7
EtO2C
N
2
1
OH
O2N
NO2
Scheme 3. Syntheses of the tricycles 2aee. Reagents: (i) 3,5-dimethoxyaniline, EtOH, NaHCO3, D; (ii) (CF3CO)2O; (iii) CF3CO2H; (iv) KOH, MeOH; (v)
(COCl)2; (vi) EtOH; (vii) NH2OH$HCl, pyridine, EtOH, D; (viii) Na, EtOH; (ix) 2,4-fluorodinitrobenzene; (x) NEt3, THF, D.
(which is formally equivalent to the electrocyclic mechanism
in the previous case) is also possible.
NMR spectroscopy, specifically the disappearance of the
0
signals due to H5 of the precursors 1aee and appearance of
In this paper, we describe the synthesis and cyclisation of
a series of analogues of the oxime ether 1c. Through variation
of the substituent on the phenyl ring, the electronic demand of
the reaction was determined and used, along with observation
of the effect of varying the ester substituent, to elucidate the
mechanism.
the signals due to H7 of the products 2aee. Each of these pro-
tons had previously been shown to have the same relaxation
time and hence integration of these signals was an appropriate
quantitative measure.
Initial analysis of the rate data showed that the cyclisation
of the precursors 1aee followed first order kinetics. This
allowed the straightforward calculation of the rate constants
for the cyclisation of the precursors 1aee to the corresponding
tricycles 2aee (Table 1). The trend in the rate constants for the
cyclisation of the precursors 1aee is clear, with the rate of
reaction being faster for electron donating substituents and
slower for electron withdrawing substituents. The values
calculated give rise to a linear Hammett plot (Fig. 1) with a
r value of ꢀ0.98ꢁ0.07.
2. Results and discussion
Indole oxime ethers 1aee were synthesised as outlined in
Scheme 3 from the corresponding acetophenones 3aee. Bis-
chler-like conditions were used to convert the ketones 4aee to
the phenylindoles 5aee, which were subsequently acylated
and esterified. This gave a mixture of the desired 7-substituted
indoles 6aee, which were separated from the corresponding 2-
isomers that were also produced, using column chromatography.
Conversion to the corresponding oximes 7aee using hydroxyl-
amine was followed by reaction with fluorodinitrobenzene to
give the cyclisation precursors 1aee. It is interesting to note
that spectroscopic analysis of both the oximes 7aee and the ox-
imeethers 1aeedidnotshow anyindicationthatboththe synand
theantiformswerepresent, aswasthecaseforthecorresponding
isomers substituted at the 2-position of the indole.2 This is con-
sistent with hydrogen bonding seen previously, suggesting that
onlythe anti form is present in each case.6 The corresponding tri-
cycles2aeewereformedthroughheating theprecursors1aee at
reflux in tetrahydrofuran in the presence of triethylamine.
Each of the precursors 1aee was treated under the same
conditions as described in Scheme 3. Samples of the reaction
were taken at regular intervals, immediately cooled to 77 K
and the solvent removed in vacuo. The rate of disappearance
of each of the starting materials 1aee and the rate of forma-
While several of the possible mechanisms might be antici-
pated to be favoured by electron donating groups, the large
value for the reaction constant is consistent with significant
decrease in electron density in the transition state, as occurs
in a polar mechanism. The distance of the substituents on
the phenyl group in the precursors 1aee from the imino nitro-
gen atom would likely result in their change having little effect
on the formation of a nitronium ion intermediate, suggesting
that a stepwise polar mechanism is not operating. Both the in-
tramolecular concerted substitution process and the conjugate
Table 1
Rate constants for the cyclisation of the precursors 1aee
Compound
R
Rate constant (sꢀ1
)
1a
1b
1c
1d
1e
CN
Br
Cl
(2.04ꢁ0.01)ꢂ10ꢀ6
(5.22ꢁ0.14)ꢂ10ꢀ6
(4.53ꢁ0.11)ꢂ10ꢀ6
(8.36ꢁ0.30)ꢂ10ꢀ6
(13.9ꢁ0.1)ꢂ10ꢀ6
H
Me
1
tion of each of the tricycles 2aee were followed using H

K.A. Clayton et al. / Tetrahedron 64 (2008) 3183e3189
3185
0.3
0.2
0.1
0
It is not possible to follow the reaction using the same sig-
1
nals in the H NMR spectra as for the conversion of the pre-
cursors 1aee to the tricycles 2aee as in the case of the
cyclisation of the oxime ether 8 the signals overlap.1 As
such, the cyclisation of the ether 8 was followed using the sig-
nals corresponding to the protons on the chlorophenyl substit-
uent. Under identical conditions to those used for the
cyclisation of the precursors 1aee, the reaction was found to
go to completion in less than 12 h. This corresponds to
a rate at least five times than that for the cyclisation of the fast-
est of the precursors 1aee and is consistent with the results
reported previously.1
These results indicate that the cyclisation of the ethers
1aee proceeds through a concerted intramolecular cyclisation,
as shown in Scheme 4. The process is shown as proceeding
through the indole anion rather than the neutral indole, as
the reaction has been shown not to proceed in the absence
of a base but to proceed faster in the presence of a stronger
base.1
-0.4
-0.2
0
0.2
0.4
0.6
0.8
-0.1
-0.2
-0.3
-0.4
-0.5
-0.6
-0.7
Figure 1. Hammett plot for the cyclisation of the precursors 1aee under the
conditions outlined in Scheme 1.
addition mechanism would be anticipated to result in a nega-
tive r value. While no values of the reaction constant have
been reported for reaction of styrylamines or related com-
pounds, it is possible to use r values reported for the reaction
of aniline derivatives and the attenuation ratio developed for
the insertion of a vinyl group to predict r values for such a
reaction. The reaction constants for the reaction of anilino
derivatives range from ꢀ2.1 to ꢀ4.2,7 depending on reaction
conditions, though the comparison may be narrowed to the
lower end of this range by recognising that the r value is
dependent on temperature and dielectric constant of the me-
dium.8 Using this and the attenuation value for a vinyl group
(0.48ꢁ0.079) suggests a reaction constant of ca. 1e1.5 for
both the intramolecular concerted substitution and the conju-
gate addition mechanisms, which, given the approximations
involved, is in reasonable agreement with that observed.
In order to distinguish these mechanistic possibilities, the
oxime ether 8, which is related to the ether 1c through replace-
ment of the ester moiety with a methyl group, was prepared by
a method analogous to that described in Scheme 3. The removal
of the ester group would be expected to have the greatest effect
on the rate of cyclisation if the reaction proceeded through
a conjugate addition mechanism, essentially halting the reac-
tion. In the case of the intramolecular concerted processes,
while removing the ester group might be expected to alter the
electron density on the oxime ether nitrogen, the effect on the
rate of reaction would not be expected to be as great.
R
R
O
O
base
N
H
N
O
O
EtO2C
N
O
EtO2C
N
O
O2N
NO2
O2N
NO2
1
R
O
N
O
N
EtO2C
2
Scheme 4. Cyclisation of the precursors 1 proceeding through a concerted
intramolecular substitution.
3. Conclusions
Cl
Oxime ethers 1aee cyclise through a concerted intramolec-
ular substitution mechanism to give the indoles 2aee, a pro-
cess for which there is literature precedent.3
O
N
O
4. Experimental
H
N
O
4.1. General
O2N
NO2
Melting points were determined on a Kofler hot stage appa-
¨
ratus and are uncorrected. Elemental analyses and electrospray
8

3186
K.A. Clayton et al. / Tetrahedron 64 (2008) 3183e3189
mass spectra were performed by Marianne Dick at the Camp-
bell Microanalytical Laboratory, University of Otago, New
Zealand. High-resolution mass spectra were recorded on
a Bruker BioApex IIe 7T FT-ICRMS with an Analytico electro-
spray ionisation source operating in positive ion mode. Ultra-
violet spectra were recorded 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
74.9 mmol) was added. The mixture was then stirred for 1 h
and water was added, causing precipitation. The solid was
then extracted with dichloromethane until the organic extracts
were colourless. The organic extracts were then combined,
dried over magnesium sulfate and the solvent removed in va-
cuo. This gave the indole 5a, which was used without further
purification. 3-(40-Cyanophenyl)-4,6-dimethoxyindole 5a. 1H
NMR (300 MHz, CDCl3) d 3.81 (s, 3H, OMe), 3.84 (s, 3H,
OMe), 6.27 (d, 1H, J¼1.9 Hz, H5), 6.51 (d, 1H, J¼1.9 Hz,
H7), 7.07 (d, 1H, J¼2.3 Hz, H2), 7.67 (d, 2H, J¼8.3 Hz,
1
between sodium chloride plates unless otherwise stated. H
NMR spectra were recorded at 300 MHz and 13C NMR spectra
were recorded at 75.5 MHz using a Bruker AC300F spectro-
meter with the residual protio solvent as an internal standard.
Chemical shifts are reported in parts per million downfield
from TMS and coupling constants (J) in hertz (Hz). Compounds
1c, 2c, 4bee, 5bee, 6c, 7c and 8 were prepared as described
previously.1,2,10,11
0
0
H3 ), 7.79 (d, 2H, J¼8.3 Hz, H2 ), 8.35 (br s, 1H, NH).
Oxalyl chloride (1.26 mL, 14.7 mmol) was added to a mix-
ture of the indole 5a (3.40 g, 12.2 mmol) partially dissolved in
dry diethyl ether (105 mL). This mixture was stirred for 3 h at
room temperature and the solvent was then removed in vacuo.
Absolute ethanol (52 mL) was then added to the solid and the
mixture stirred for further 2 h, whereupon the solvent was
again removed in vacuo. The residue was purified using col-
umn chromatography (methanol/chloroform, 1:1000) to give
the indole ester 6a as a yellow solid (0.70 g, 12%). Mp
186e187 ꢃC; 1H NMR (300 MHz, CDCl3) d 1.38 (t, 3H,
J¼7.2 Hz, CH3), 3.92 (s, 3H, OMe), 3.93 (s, 3H, OMe),
4.2. Preparation of novel indole precursors
4.2.1. 1-(40-Cyanophenyl)-2-[(300,500-dimethoxy-
phenyl)amino]ethanone (4a)
3,5-Dimethoxyaniline (3.46 g, 22.6 mmol), 2-bromo-40-cya-
noacetophenone 3a (5.06 g, 22.6 mmol) and sodium hydrogen
carbonate (2.37 g, 28.3 mmol) in absolute ethanol (75 mL)
were heated under reflux with stirring until TLC analysis con-
firmed the consumption of the starting materials (ca. 4 h). The
mixture was then removed from heating and allowed to cool.
The solvent was removed in vacuo and the residue recrystallised
from ethyl acetate/light petroleum to yield amino ketone 4a as
a yellow solid (4.64 g, 70%). Mp 158e159 ꢃC; 1H NMR
(300 MHz, CDCl3) d 3.78 (s, 6H, OMe), 4.54 (s, 2H, CH2),
0
4.40 (q, 2H, J¼7.2 Hz, CH2), 6.20 (s, 1H, H5 ), 7.14 (d, 1H,
0
00
00
J¼2.3 Hz, H2 ), 7.61 (br s, 4H, H2 , H3 ), 10.66 (br s, 1H,
NH); 13C NMR (75.5 MHz, CDCl3) d 14.1 (CH3), 55.5, 56.9
0
(OMe), 61.5 (CH2), 87.7 (C5 ), 100.9 (C7 ), 109.3 (C3 ),
0
0
0
00
0
110.3 (C3a ), 117.7 (C4 ), 119.3 (CN), 122.9 (C2 ), 129.7
00
(C2 ), 131.4 (C3 ), 138.7 (C7a ), 140.1 (C1 ), 161.8 (C4 ),
00
0
00
0
0
162.2 (C6 ), 165.9 (CO), 185.1 (OCO); nmax 3390, 2223,
1737, 1608 cmꢀ1; lmax (CHCl3) 360 nm (3 10,000 cmꢀ1 Mꢀ1),
325 (17,000); m/z (ESI) 379 ([MþH], 100%), 357 (12), 305
(47), 279 (47). Found: C, 66.5; H, 5.0; N, 7.3. Calcd for
C21H18N2O5: C, 66.7; H, 4.8; N, 7.4.
00
00
5.87 (s, 2H, H2 ), 5.88 (br s, 1H, H4 ), 7.49 (d, 2H, J¼8.7 Hz,
H3 ), 7.93 (d, 2H, J¼8.7 Hz, H2 ); 13C NMR (75.5 MHz,
0
0
00
CDCl3) d 50.8 (CH2), 55.2 (OMe), 90.5 (C4 ), 92.4 (C2 ), 117.1
00
0
(CN), 117.5 (C4 ), 128.1 (C2 ), 132.7 (C3 ), 137.7 (C1 ), 148.3
0
0
0
4.3.2. General procedure for the formation of the
substituted indoles 6b, d and e
(C1 ), 161.8 (C3 ), 193.7 (CO); nmax 3396, 1682, 1618 cmꢀ1
;
00
00
lmax (CHCl3) 368 nm (3 770 cmꢀ1 Mꢀ1), 259 (2900); m/z (ESI)
297 ([MþH]þ, 100%). Found: C, 67.4; H, 5.4; N, 9.1. Calcd for
C17H16N2O3$0.05CHCl3: C, 67.7; H, 5.4; N, 9.3.
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 indole 5) was then added to the solid
and the mixture stirred for further 2 h, whereupon the solvent
was again removed in vacuo. Indole esters 6b, d and e were
then purified using column chromatography (methanol/chloro-
form, 1:100). Elemental analyses indicated chloroform of
crystallisation in one case.
4.3. Preparation of substituted indole esters
4.3.1. Ethyl 2-(30-(400-cyanophenyl)-40,60-dimethoxyindol-70-
yl)glyoxylate (6a)
1-(40-Cyanophenyl)-2-[(300,500-dimethoxyphenyl)amino]-
ethanone 4a (4.57 g, 15.4 mmol) and triethylamine (4.26 mL,
30.8 mmol) in dry tetrahydrofuran (70 mL) were stirred in
an ice bath before trifluoroacetic anhydride (4.32 mL,
30.8 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
(21 mL) was added to the oil and the mixture heated under re-
flux for 15 min. The mixture was then removed from heating,
allowed to cool and poured into ice water (ca. 100 mL) result-
ing in a green precipitate. The solid was collected and left
to dry in a desiccator. The dried precipitate was dissolved
in methanol (42 mL) and potassium hydroxide (4.2 g,
4.3.2.1. Ethyl 2-[30-(400-bromophenyl)-40,60-dimethoxyindol-70-
yl]glyoxylate (6b). 3-(40-Bromophenyl)-4,6-dimethoxyindole
5b: 2.34 g, 7.04 mmol, yield: 0.48 g, 16%, mp 162e163 ꢃC,
appearance: yellow solid; 1H NMR (300 MHz, CDCl3)
d 1.42 (t, 3H, J¼7.1 Hz, CH3), 3.92 (s, 3H, OMe), 3.94 (s,
0
3H, OMe), 4.40 (q, 2H, J¼7.1 Hz, CH2), 6.18 (s, 1H, H5 ),
0
00
00
7.09 (d, 1H, J¼2.3 Hz, H2 ), 7.45 (m, 4H, H2 , H3 ), 10.56
(br s, 1H, NH); 13C NMR (75.5 MHz, CDCl3) d 14.1 (CH3),
0
55.4, 56.9 (OMe), 61.4 (CH2), 87.7 (C5 ), 100.8 (C7 ), 110.6
0

K.A. Clayton et al. / Tetrahedron 64 (2008) 3183e3189
3187
0
(C3 ), 118.0 (C1 ), 120.1 (C4 ), 121.9 (C2 ), 130.7 (C2 ), 131.0
00
00
0
00
give the oximes 7, which were characterised using NMR spec-
troscopy and used without further purification.
00
0
0
0
0
(C3 ), 134.1 (C3a ), 138.5 (C7a ), 162.0 (C4 ), 162.1 (C6 ), 165.9
(CO), 185.1 (OCO); nmax 3426, 1728, 1615 cmꢀ1; lmax
(CHCl3) 368 nm (3 11,000 cmꢀ1 Mꢀ1), 258 (22,000); m/z
(ESI) 432/434 ([MþH], 100%), 404/406 (47), 358/360 (23).
Found: C, 55.3; H, 4.2; N, 3.2. Calcd for C20H18BrNO5: C,
55.6; H, 4.3; N, 3.2.
The appropriate indole oxime 7 (1 mol equiv) was dissolved
in absolute ethanol (38 L per mole of oxime 7) and sodium
metal (1.5 mol equiv) was added. This mixture was stirred for
30 min to ensure complete reaction of sodium. The mixture
was then cooled in an ice bath before 2,4-fluorodinitrobenzene
(1.5 mol equiv) was added dropwise, resulting in immediate
precipitation of a yellow-brown solid. The reaction mixture
was stirred overnight whereupon the solid was collected under
suction and washed with absolute ethanol. The resulting solid
was recrystallised from either chloroform or chloroform/light
petroleum to yield the appropriate cyclisation precursor 1.
The yields calculated are based upon two steps from the ester.
Elemental analyses indicated chloroform of crystallisation.
4.3.2.2. Ethyl 2-[30-phenyl-40,60-dimethoxyindol-70-yl]glyoxy-
late
(6d). 4,6-Dimethoxy-3-phenylindole
5d:
1.64 g,
6.48 mmol, yield: 0.37 g, 16%, mp 134e135 ꢃC, appearance:
pale yellow solid; 1H NMR (300 MHz, CDCl3) d 1.42 (t,
3H, J¼7.2 Hz, CH3), 3.92 (s, 3H, OMe), 3.93 (s, 3H, OMe),
0
4.42 (q, 2H, J¼7.1 Hz, CH2), 6.19 (s, 1H, H5 ), 7.11 (d, 1H,
0
00
J¼2.3 Hz, H2 ), 7.28 (tt, 1H, J¼1.5, 8.7 Hz, H4 ), 7.37 (m,
00
00
2H, H3 ), 7.61 (dd, 2H, J¼1.5, 7.2 Hz, H2 ), 10.56 (br s, 1H,
NH); 13C NMR (75.5 MHz, CDCl3) d 14.1 (CH3), 53.3, 55.4
4.4.1.1. Ethyl 30-(400-cyanophenyl)-40,60-dimethoxyindol-20-yl-
2-(hydroxyimino)acetate (7a). Ethyl 2-[30-(400-cyanophenyl)-
40,60-dimethoxyindol-20-yl]glyoxylate 6a: 0.19 g, 0.50 mmol,
appearance: yellow solid; 1H NMR (300 MHz, CD3OD)
d 1.35 (t, 3H, J¼7.2 Hz, CH3), 3.93 (br s, 6H, OMe), 4.35
0
0
0
(OMe), 61.4 (CH2), 87.4 (C5 ), 100.8 (C7 ), 110.8 (C3 ),
00
119.2 (C1 ), 121.9 (C4 ), 126.0 (C2 ), 127.6 (C2 ), 128.7
00
0
00
00
0
0
0
0
(C3 ), 135.1 (C3a ), 138.5 (C7a ), 162.1 (C4 ), 162.2 (C6 ),
166.0 (CO), 185.0 (OCO); nmax 3409, 1746, 1728,
1625 cmꢀ1; lmax (CHCl3) 378 nm (3 5700 cmꢀ1 Mꢀ1), 341
(9600), 265 (12,000); m/z (ESI) 354 ([MþH], 100%), 282
(14), 254 (19). Found: C, 67.8; H, 5.8; N, 3.6. Calcd for
C20H19NO5: C, 68.0; H, 5.4; N, 4.0.
0
0
(q, 2H, J¼7.2 Hz, CH2), 6.40 (s, 1H, H5 ), 7.26 (s, 1H, H2 ),
00
00
7.70e7.90 (m, 4H, H2 , H3 ), 10.35 (br s, 1H, NH).
4.4.1.2. Ethyl 30-(400-cyanophenyl)-40,60-dimethoxyindol-70-yl-
2-(O-2,4-dinitrophenoxyimino)acetate (1a). Yield: 0.10 g,
1
4.3.2.3. Ethyl 2-[40,60-dimethoxy-30-(400-methylphenyl)indol-70-
yl]glyoxylate (6e). 4,6-Dimethoxy-3-(40-methylphenyl)indole
5e: 2.60 g, 9.73 mmol, yield: 0.13 g, 4%, mp 134e136 ꢃC, ap-
pearance: yellow solid; 1H NMR (300 MHz, CDCl3) d 1.42 (t,
3H, J¼7.2 Hz, CH3), 2.40 (s, 3H, 400-Me), 3.90 (s, 3H, OMe),
3.91 (s, 3H, OMe), 4.42 (q, 2H, J¼7.2 Hz, CH2), 6.17 (s, 1H,
36%, mp 131e133 ꢃC, appearance: orange solid; H NMR
(300 MHz, CDCl3) d 1.43 (t, 3H, J¼7.2 Hz, CH3), 3.85 (s,
3H, OMe), 3.86 (s, 3H, OMe), 4.43 (q, 2H, J¼7.2 Hz, CH2),
0
6.25 (s, 1H, H5 ), 7.05 (br s, 1H, H2 ), 7.60e7.70 (m, 4H,
0
00
00
000
H2 , H3 ), 8.16 (d, 1H, J¼9.4 Hz, H6 ), 8.43 (dd, 1H, J¼2.6,
000
000
9.4 Hz, H5 ), 8.96 (d, 1H, J¼2.6 Hz, H3 ), 10.12 (br s, 1H,
0
0
00
H5 ), 7.07 (d, 1H, J¼2.3 Hz, H2 ), 7.18 (d, 2H, J¼7.9 Hz, H3 ),
NH); 13C NMR (75.5 MHz, CDCl3) d 13.8 (CH3), 55.0, 57.4
7.45 (d, 2H, J¼7.9 Hz, H2 ), 10.54 (br s, 1H, NH); 13C NMR
00
0
(OMe), 60.6 (CH2), 88.9 (C5 ), 90.0 (C7 ), 106.5 (C3a ),
0
0
(75.5 MHz, CDCl3) d 14.1 (CH3), 21.0 (400-Me), 55.5, 56.8
00
0
113.8 (C4 ), 117.5 (C3 ), 117.6 (CN), 117.7 (C6 ), 122.0
000
0
(OMe), 61.3 (CH2), 87.3 (C5 ), 100.7 (C7 ), 110.9 (C3 ),
0
0
000 0 00 00 000
(C3 ), 123.1 (C2 ), 126.1 (C2 ), 129.6 (C3 ), 129.9 (C5 ),
00
119.1 (C1 ), 122.2 (C4 ), 122.7 (C2 ), 128.4 (C2 ), 129.2
00
0
00
000 0 00 000
135.9 (C2 ), 136.0 (C7a ), 139.5 (C1 ), 140.2 (C4 ), 156.6
00
0
0
0
0
0
000
0
(C3 ), 135.6 (C3a ), 138.4 (C7a ), 162.0 (C4 ), 162.3 (C6 ),
166.0 (CO), 185.0 (OCO); nmax 3775, 3684, 3621, 1708,
1603 cmꢀ1; lmax (CHCl3) 335 nm (3 4300 cmꢀ1 Mꢀ1), 259
(8100), 265 (12,000); m/z (ESI) 354 ([MþH], 100%), 282
(14), 254 (19). Found: C, 66.4; H, 5.8; N, 3.3. Calcd for
C21H21NO5$0.1CHCl3: C, 66.8; H, 5.6; N, 3.7.
(C6 ), 157.0 (C1 ), 157.9 (C4 ), 164.7 (C]N), 175.1 (OCO);
nmax (CHCl3) 3684, 3620, 1736, 1712, 1603 cmꢀ1; lmax
(CHCl3) 260 nm (3 6900 cmꢀ1 Mꢀ1), 385 (5200); m/z (ESI)
560 ([MþH], 5%), 376 (100). HRMS found: 560.1426. Calcd
for C27H22N5O9 ([MþH]þ): 560.1418. Found: C, 56.3; H, 3.5;
N, 11.9. Calcd for C27H21N5O9$0.2CHCl3: C, 56.0; H, 3.7; N,
12.0.
4.4. Preparation of 3-arylindole-7-ketoxime ethers
4.4.1.3. Ethyl 30-(400-bromophenyl)-40,60-dimethoxyindol-70-yl-
2-(hydroxyimino)acetate (7b). Ethyl 2-[30-(400-bromophenyl)-
40,60-dimethoxyindol-70-yl]glyoxylate 6b: 0.11 g, 0.25 mmol,
appearance: yellow solid; 1H NMR (300 MHz, CD3OD)
d 1.35 (t, 3H, J¼7.1 Hz, CH3), 3.74 (s, 3H, OMe), 3.76 (s,
4.4.1. General procedure for the formation of the
cyclisation precursors 1
The appropriate indole ester 6 (1 mol equiv) and hydroxyl-
amine hydrochloride (2.1 mol equiv) were dissolved in a mix-
ture of pyridine (4.4 L per mole of indole ester 6) and absolute
ethanol (2.8 L per mole of indole ester 6). The mixture was
heated under reflux until TLC analysis confirmed consumption
of the starting material 6. The solvent was then removed in va-
cuo, the residue dissolved in dichloromethane and the organic
layer extracted twice with water, once with 1 M hydrochloric
acid and then dried. The solvent was removed in vacuo to
0
3H, OMe), 4.35 (q, 2H, J¼7.1 Hz, CH2), 6.29 (s, 1H, H5 ),
0
00
00
7.10 (s, 1H, H2 ), 7.36 (br s, 4H, H2 , H3 ), 10.51 (br s, 1H,
NH); 13C NMR (75.5 MHz, CDCl3) d 13.2 (CH3), 54.4, 56.8
0
(OMe), 61.1 (CH2), 88.0 (C5 ) 89.0 (C7 ), 110.8 (C3a ), 117.0
0
0
0
(C3 ), 119.0 (C2 ), 122.1 (C4 ), 126.9 (C2 ), 130.2 (C3 ),
0
00
00
00
00
135.4 (C1 ), 135.6 (C7a ), 156.1 (C4 ), 156.8 (C6 ), 165.3
0
0
0
(C]N), 165.5 (OCO).

3188
K.A. Clayton et al. / Tetrahedron 64 (2008) 3183e3189
1
appearance: yellow solid; H NMR (300 MHz, CD3COCD3)
4.4.1.4. Ethyl 30-(400-bromophenyl)-40,60-dimethoxyindol-70-yl-
2-(O-2,4-dinitrophenoxyimino)acetate (1b). Yield: 0.09 g,
d 1.35 (t, 3H, J¼6.8 Hz, CH3), 2.13 (s, 3H, 400-Me), 3.80 (br s,
1
59%, mp 197e198 ꢃC, appearance: orange solid; H NMR
6H, OMe), 4.45 (q, 2H, J¼6.8 Hz, CH2), 6.35 (s, 1H, H5 ),
0
0
6.90e7.30 (m, 5H, H2 , H2 , H3 ), 10.42 (br s, 1H, NH).
00
00
(300 MHz, CDCl3) d 1.45 (t, 3H, J¼7.2 Hz, CH3), 3.91 (s,
3H, OMe), 3.92 (s, 3H, OMe), 4.53 (q, 2H, J¼7.2 Hz, CH2),
0
0
6.28 (s, 1H, H5 ), 7.14 (d, 1H, J¼7.2 Hz, H2 ), 7.43 (d, 2H,
4.4.1.8. Ethyl 40,60-dimethoxy-30-(400-methylphenyl)indol-70-yl-
00
00
J¼8.3 Hz, H2 ), 7.51 (d, 2H, J¼8.3 Hz, H3 ), 7.86 (d, 1H,
2-(O-2,4-dinitrophenoxyimino)acetate (1e). Yield: 0.04 g,
1
000
000
J¼9.0 Hz, H6 ), 8.49 (dd, 1H, J¼2.6, 9.0 Hz, H5 ), 8.91 (d,
74%, mp 170e171 ꢃC, appearance: yellow-orange solid; H
1H, J¼2.6 Hz, H3 ), 9.82 (br s, 1H, NH); 13C NMR
NMR (300 MHz, CDCl3) d 1.43 (t, 3H, J¼7.2 Hz, CH3),
000
(75.5 MHz, CDCl3) d 13.3 (CH3), 54.8, 57.0 (OMe), 61.5
2.41 (s, 3H, 400-Me), 3.91 (s, 3H, OMe), 3.92 (s, 3H, OMe),
0
0
0
(CH2), 89.4 (C5 ) 93.7 (C7 ), 110.9 (C3a ), 117.4 (C6 ), 117.7
000
0
4.31 (q, 2H, J¼7.2 Hz, CH2), 6.26 (s, 1H, H5 ), 7.12 (s, 1H,
0
(C3 ), 121.2 (C3 ), 122.8 (C2 ), 127.2 (C2 ), 129.2 (C5 ),
00
131.0 (C3 ), 134.3 (C4 ), 134.7 (C1 ), 135.2 (C7a ), 136.5
000
0
00
000
0
00
H2 ), 7.16 (d, 2H, J¼7.9 Hz, H3 ), 7.46 (d, 2H, J¼7.9 Hz,
00
00
0
0
0
0
0
0
H2 ), 7.87 (d, 1H, J¼9.4 Hz, H6 ), 8.41 (dd, 1H, J¼2.6,
13
000
000
000
0
0
0
0
0
0
0
0
(C2 ), 141.8 (C4 ), 155.6 (C1 ), 159.0 (C4 ), 159.7 (C6 ),
160.1 (C]N), 161.6 (OCO); nmax 3733, 1733, 1716,
1657 cmꢀ1; lmax (CHCl3) 376 nm (3 8400 cmꢀ1 Mꢀ1), 334
(10,000), 256 (15,000); m/z (ESI) 613/615 ([MþH], 8%),
429/431 (100), 368 (22), 338 (10). Found: C, 44.0; H, 3.2;
N, 8.0. Calcd for C26H21BrN4O9$1CHCl3: C, 44.3; H, 3.0;
N, 7.6.
9.4 Hz, H5 ), 8.72 (d, 1H, J¼2.6 Hz, H3 ), 9.75 (br s, 1H,
NH); C NMR (75.5 MHz, CDCl3) d 14.0 (CH3), 21.1 (400-
0
0
Me), 55.3, 57.4 (OMe), 62.3 (CH2), 85.4 (C5 ) 88.7 (C7 ),
000
103.0 (C3a ), 116.5 (C3 ), 119.7 (C6 ), 121.4 (C3 ), 122.0
00
(C2 ), 127.7 (C5 ), 128.4 (C2 ), 129.2 (C3 ), 129.4 (C1 ),
000
132.1 (C4 ), 135.8 (C2 ), 136.1 (C7a ), 141.0 (C4 ), 156.7
(C6 ), 159.2 (C1 ), 160.0 (C4 ), 166.9 (C]N), 169.9 (OCO);
nmax 3776, 3684, 3621, 1708, 1598 cmꢀ1; lmax (CHCl3)
386 nm (3 1400 cmꢀ1 Mꢀ1), 329 (2800), 243 (4700). HRMS
found: 549.1625. Calcd for C27H25N4O9 ([MþH]þ):
549.1616.
0
0
000
0
000
00
00
00
000
0
0
000
0
4.4.1.5. Ethyl 30-phenyl-40,60-dimethoxyindol-70-yl-2-(hydroxy-
imino)acetate (7d). Ethyl 2-(30-phenyl-40,60-dimethoxyindol-
70-yl)glyoxylate 6d: 0.27 g, 0.75 mmol; appearance: yellow
solid; 1H NMR (300 MHz, CD3COCD3) d 1.36 (t, 3H,
J¼7.5 Hz, CH3), 3.85 (br s, 6H, OMe), 4.36 (q, 2H,
4.5. Preparation of pyrrolo[3,2,1-hi]indazoles
0
0
J¼7.5 Hz, CH2), 6.41 (br s, 1H, H5 ), 7.17 (br s, 1H, H2 ),
00
00
00
7.25e7.38 (br s, 3H, H3 , H4 ), 7.56 (d, 2H, J¼7.1 Hz, H2 ),
4.5.1. General preparation of the tricycles 2
11.29 (br s, 1H, NH); 13C NMR (75.5 MHz, CD3COCD3)
The appropriately substituted cyclisation precursor 1
(1 mol equiv) and triethylamine (10 mol equiv) in dry tetrahy-
drofuran (42 L per mole of cyclisation precursor 1) were
heated at reflux until TLC analysis showed consumption of
the starting material. The solvent was then removed in vacuo,
and the solid dissolved in dichloromethane before extracting
with water, followed by 2 M sodium hydroxide, 2 M hydro-
chloric acid and finally 2 M sodium hydroxide again. Each ex-
traction was performed until the aqueous layer was no longer
coloured. The organic layer was dried over magnesium sulfate
and the solvent removed in vacuo. The remaining solid was
then purified using preparative TLC (methanol/chloroform,
1:100). Due to the small amounts of the tricycles 2 produced,
they were characterised using NMR spectroscopy and HRMS.
0
d 13.4 (CH3), 54.5, 57.0 (OMe), 61.2 (CH2), 89.0 (C5 ), 96.6
00
(C7 ), 110.9 (C3 ), 122.0 (C2 ), 125.4 (C2 ), 129.2 (C3 ),
00
132.7 (C4 ), 135.9 (C1 ), 135.9 (C7a , C3a ), 156.0 (C4 ),
0
156.9 (C6 ), 165.2 (C]N), 166.1 (OCO).
0
0
0
00
00
0
0
0
4.4.1.6. Ethyl 30-phenyl-40,60-dimethoxyindol-70-yl-2-(O-2,4-di-
nitrophenoxyimino)acetate (1d). Yield: 0.15 g, 37%, mp 192e
193 ꢃC, appearance: yellow solid; 1H NMR (300 MHz,
CDCl3) d 1.43 (t, 3H, J¼7.2 Hz, CH3), 3.90 (s, 3H, OMe),
3.92 (s, 3H, OMe), 4.53 (q, 2H, J¼7.2 Hz, CH2), 6.27 (s,
0
0
00
00
1H, H5 ), 6.91 (s, 1H, H2 ), 7.15e7.50 (m, 5H, H2 , H3 ,
00
000
H4 ), 7.88 (d, 1H, J¼9.4 Hz, H6 ), 8.50 (dd, 1H, J¼2.6,
000
000
9.4 Hz, H5 ), 8.92 (d, 1H, J¼2.6 Hz, H3 ), 9.81 (br s, 1H,
NH); 13C NMR (75.5 MHz, CD3COCD3) d 13.4 (CH3),
4.5.1.1. Ethyl 1-(40-cyanophenyl)-6,8-dimethoxypyrazolo[4,5,
1-hi]indole-5-carboxylate (2a). Ethyl 30-(400-cyanophenyl)-
40,60-dimethoxyindol-70-yl-2-(O-2,4-dinitrophenoxyimino)ace-
tate 1a: 0.098 g, 0.175 mmol, yield: 0.030 g, 45%, appearance:
yellow solid; 1H NMR (300 MHz, CDCl3) d 1.39 (t, 3H,
J¼7.2 Hz, CH3), 3.88 (s, 3H, OMe), 3.93 (s, 3H, OMe),
4.35 (q, 2H, J¼7.2 Hz, CH2), 6.55 (s, 1H, H7), 7.72 (d, 2H,
0
54.8, 57.2 (OMe), 61.7 (CH2), 89.5 (C5 ) 93.6 (C7 ), 111.2
0
0
000
0
000
0
(C3a ), 117.8 (C6 ), 118.8 (C3 ), 121.1 (C3 ), 122.7 (C2 ),
00
00
00
125.7 (C4 ), 127.3 (C3 ), 129.4 (C2 ), 129.8 (C5 ), 135.2
000
00
(C1 ), 135.6 (C7a ), 135.6 (C2 ), 141.7 (C4 ), 156.1 (C1 ),
0
000
000
000
0
0
159.4 (C4 ), 159.9 (C6 ), 160.0 (C]N), 161.5 (OCO); nmax
3440, 1732, 1600 cmꢀ1
lmax (CHCl3) 395 nm (3
;
8500 cmꢀ1 Mꢀ1), 334 (13,000), 258 (17,000); m/z (ESI) 535
([MþH], 8%), 385 (27), 252 (100), 280 (24). Found: C,
38.7; H, 3.1; N, 6.7. Calcd for C26H22N4O9$3CHCl3: C,
39.0; H, 2.8; N, 6.3.
0
J¼8.7 Hz, H3 ), 7.74 (s, 1H, H2), 7.87 (d, 2H, J¼8.7 Hz,
0
H2 ); nmax (CHCl3) 3687, 3614, 1814, 1794, 1713, 1647,
1602 cmꢀ1. HRMS found: 376.1303. Calcd for C21H18N3O4
([MþH]þ): 376.1297.
4.4.1.7. Ethyl 40,60-dimethoxy-30-(400-methylphenyl)indol-70-yl-
2-(hydroxyimino)acetate (7e). Ethyl 2-[40,60-dimethoxy-30-
(400-methylphenyl)indol-70-yl]glyoxylate 6e: 0.02 g, 0.07 mmol,
4.5.1.2. Ethyl 1-(40-bromophenyl)-6,8-dimethoxypyrazolo[4,5,1-
hi]indole-5-carboxylate (2b). Ethyl 30-(400-bromophenyl)-

K.A. Clayton et al. / Tetrahedron 64 (2008) 3183e3189
3189
40,60-dimethoxyindol-70-yl-2-(O-2,4-dinitrophenoxyimino)ace-
tate 1b: 0.040 g, 0.065 mmol, yield: 0.0052 g, 19%, appear-
1
ance: orange solid; H NMR (300 MHz, CDCl3) d 1.42 (t,
then removed in vacuo at that temperature. The aliquots were
1
subsequently analysed using H NMR spectroscopy. The ex-
tent of reaction in each case was calculated by comparing
0
the integrations corresponding to the H5 signal in the precur-
3H, J¼7.2 Hz, CH3), 4.09 (s, 3H, OMe), 4.24 (s, 3H, OMe),
4.54 (q, 2H, J¼7.2 Hz, CH2), 6.47 (s, 1H, H7), 7.56 (d, 2H,
sors 1aee and 8, and the H7 signal in the corresponding tricy-
cles. The data were then fitted to a first order exponential
decay curve to obtain the rate constant for the formation of
the tricycles.
0
0
J¼8.7 Hz, H3 ), 7.70e7.80 (m, 3H, H2, H2 ); nmax (CHCl3)
3686, 3604, 1817, 1794, 1722, 1644 cmꢀ1; HRMS found:
429.0442. Calcd for C20H18BrN2O4 ([MþH]þ): 429.0445.
4.5.1.3. Ethyl 6,8-dimethoxy-1-phenylpyrazolo[4,5,1-hi]indole-
5-carboxylate (2d). Ethyl 30-phenyl-40,60-dimethoxyindol-
70-yl-2-(O-2,4-dinitrophenoxyimino)acetate 1d: 0.021 g,
0.039 mmol, yield: 0.0044 g, 32%, appearance: yellow solid;
1H NMR (300 MHz, CDCl3) d 1.42 (t, 3H, J¼7.2 Hz, CH3),
4.08 (s, 3H, OMe), 4.13 (s, 3H, OMe), 4.54 (q, 2H, J¼
Acknowledgements
The advice of Dr. James Hook and the other staff of the
UNSW NMR Facility is gratefully acknowledged, as are the
particularly helpful discussions with Dr. Rebecca Wilson and
the financial support of the Australian Research Council and
UNSW.
0
7.2 Hz, CH2), 6.48 (s, 1H, H7), 7.60e7.80 (m, 6H, H2, H2 ,
0
0
H3 , H4 ); nmax (CHCl3) 3688, 3614, 1818, 1794, 1713, 1647,
1601 cmꢀ1. HRMS found: 373.1162. Calcd for C20H18N2O4
([MþNa]þ): 373.1164.
References and notes
1. Wahyuningsih, T. D.; Pchalek, K.; Kumar, N.; Black, D. StC. Tetrahedron
2006, 62, 6343e6348.
4.5.1.4. Ethyl 6,8-dimethoxy-1-(40-methylphenyl)pyrazolo[4,5,1-
hi]indole-5-carboxylate (2e). Ethyl 40,60-dimethoxy-30-(400-
methylphenyl)indol-70-yl-2-(O-2,4-dinitrophenoxyimino)acetate
1e: 0.030 g, 0.055 mmol, yield: 0.0059 g, 20%, appearance:
yellow solid; 1H NMR (300 MHz, CDCl3) d 1.42 (t, 3H,
J¼7.2 Hz, CH3), 2.41 (s, 3H, 400-Me), 4.07 (s, 3H, OMe),
4.13 (s, 3H, OMe), 4.53 (q, 2H, J¼7.2 Hz, CH2), 6.47 (s, 1H,
2. Clayton, K. A.; Black, D. StC.; Harper, J. B. Tetrahedron 2007, 63,
10615e10621.
3. For examples, see: Narasaka, K. Pure Appl. Chem. 2003, 75, 19e28 and
references cited therein.
4. Mikami, T.; Narasaka, K. Chem. Lett. 2000, 338e339.
5. Uchiyama, K.; Ono, A.; Hayashi, Y.; Narasaka, K. Bull. Chem. Soc. Jpn.
1998, 71, 2945e2955.
6. Black, D. StC.; Kumar, N.; McConnell, D. B. Tetrahedron 1996, 52,
8925e8936.
´
7. See for examples: Jaffe, H. H. Chem. Rev. 1953, 53, 191e261 and refer-
0
H7), 7.56 (d, 2H, J¼7.9 Hz, H3 ), 7.70 (s, 1H, H2), 7.77 (d,
0
2H, J¼7.9 Hz, H2 ); nmax (CHCl3) 3687, 3609, 1818, 1794,
1712, 1646, 1602 cmꢀ1. HRMS found: 365.1495. Calcd for
ences cited therein; Wells, P. R. Chem. Rev. 1963, 63, 171e219 and refer-
ences cited therein; Arcoria, A.; Fisichella, S.; Scarlata, G.; Sciotto, D.
J. Org. Chem. 1973, 38, 32e36; Arcoria, A.; Maccarone, E.; Musumarra,
G.; Tomaselli, G. A. J. Org. Chem. 1973, 38, 2457e2460; Arcoria, A.;
Fisichella, S. J. Org. Chem. 1973, 38, 3774e3777.
C21H21N2O4 ([MþH]þ): 365.1496.
4.6. Calculation of rate constants for the cyclisation of
3-arylindole-7-ketoxime ethers
8. For the original discussion of the importance of reaction conditions, see:
Hammett, L. P. J. Am. Chem. Soc. 1937, 59, 96e100.
9. Hammett, L. P. Physical Organic Chemistry; McGraw-Hill: Tokyo, 1970.
´
10. Black, D. StC.; Gatehouse, B. M. K. C.; Theobald, F.; Wong, L. C. H.
Aust. J. Chem. 1980, 33, 343e350.
Each of the precursors 1aee and 8 (1 mol equiv) was added
to a solution of triethylamine (10 mol equiv) in tetrahydro-
furan (42 L per mole of precursor 1) being heated at reflux.
Aliquots of the reaction mixtures (ca. 0.3 ml) were taken peri-
odically, cooled to 77 K to quench the reaction and the solvent
11. 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,
1741e1750.