Expedient, one-pot preparation of fused indoles via CAN-catalyzed three-component domino sequences and their transformation into polyheterocyclic compounds containing pyrrolo[1,2-a]azepine fragments

Article abstract of DOI:10.1039/c004703a

The CAN-catalyzed three-component between reaction between primary amines, β-dicarbonyl compounds and naphthoquinones or 2-bromonaphthoquinones afforded, respectively, 5-hydroxybenzo[g]indoles and benzo[f]indole-4,9-diones, the former of which were transformed into tetracyclic azepino[1,2-a]benzo[g] indole systems through a γ-alkylation/ring-closing metathesis sequence. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/c004703a

Organic &
Biomolecular
Chemistry
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Volume 8 | Number 15 | 7 August 2010 | Pages 3345–3580
ISSN 1477-0520
FULL PAPER
PERSPECTIVE
Alessandro Dondoni
Heterocycles in organic synthesis:
thiazoles and triazoles as exemplar
cases of synthetic auxiliaries
J. Carlos Menéndez et al.
One-pot preparation of fused indoles
via CAN-catalyzed three-component
domino sequences

PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Expedient, one-pot preparation of fused indoles via CAN-catalyzed
three-component domino sequences and their transformation into
polyheterocyclic compounds containing pyrrolo[1,2-a]azepine fragments†
Padmakar A. Suryavanshi, Vellaisamy Sridharan and J. Carlos Mene´ndez*
Received 29th March 2010, Accepted 19th May 2010
First published as an Advance Article on the web 9th June 2010
DOI: 10.1039/c004703a
The CAN-catalyzed three-component between reaction between primary amines, b-dicarbonyl
compounds and naphthoquinones or 2-bromonaphthoquinones afforded, respectively,
5-hydroxybenzo[g]indoles and benzo[f ]indole-4,9-diones, the former of which were transformed into
tetracyclic azepino[1,2-a]benzo[g]indole systems through a g-alkylation/ring-closing metathesis
sequence.
fold mission of promoting the formation of enamines from 1,3-
Introduction
dicarbonyl compounds and primary amines and facilitating the
The indole ring system is a widespread structural motif found in a
subsequent Michael addition to quinones. Cerium(IV) ammonium
large number of naturally occurring molecules and it can perhaps
nitrate (CAN) was our initial choice because of its low cost, non-
be considered as the most important single class of heterocyclic
toxicity, and moisture tolerance, together with its good Lewis
systems.1 Indole derivatives possess a wide range of powerful
and therapeutically interesting biological activities,2 and indeed
indole derivatives have been included in the “privileged scaffolds”
category3 because they comply with the definition proposed by
Evans in that they constitute “a molecular framework able to
provide ligands for diverse receptors”.4 Consequently, the develop-
ment of new synthetic methodologies and the improvement of the
existing synthetic routes for the construction of the indole scaffold
is a very important topic in organic synthesis. The most common
and traditional methods for the synthesis of indoles5 include the
Fischer, Bischler, Reissert, Madelung and Smith methodologies.
In addition, organometallic reagents, particularly palladium com-
pounds, have found widespread application in modern indole
syntheses.6 Among the available synthetic methodologies leading
to indoles, the Nenitzescu reaction, i.e. the reaction between 1,4-
benzoquinones and b-enaminones to afford 5-hydroxyindoles, has
remained relatively unexplored despite its experimental simplicity
and the pharmaceutical applications of some of the products
derived from it.7–9 The main drawbacks of this methodology
include the problems associated with the purification of the acid-
sensitive enaminones and the poor yields normally observed for
the final products.
acidity,11 and also because there is literature precedent for the
use of CAN as a catalyst in b-enaminone synthesis.11e
We started our study by conducting the reaction of n-butylamine
1a and ethyl acetoacetate 2a in ethanol in the presence of a
catalytic amount of CAN (5 mol%) followed by the addition of
1,4-naphthoquinone 3a, which was chosen because it has received
relatively little attention as a Nenitzescu substrate. After stirring
the reaction mixture at room temperature for 2 h, the fused indole
4a was isolated in 27% yield together with quinone 5a (63%) (see
Scheme 1). An increase of the reaction time to 24 h furnished a
complex mixture that contained only small amounts of 4a and 5a.
Gratifyingly, we found subsequently that, under reflux conditions,
the reaction afforded compound 4a in 93% yield as a single
product in only one hour. As mentioned below (see Scheme 3),
we propose that the use of reflux conditions deviates the reaction
Results and discussion
The first purpose of our work was to overcome the problems
associated with the Nenitzescu reaction and to extend its range of
synthetic applications. As the main difficulty lies in the purification
of the enaminones, we planned to carry out the reaction in a one-
pot multicomponent fashion10 using a Lewis acid with the two-
Departamento de Qu´ımica Orga´nica y Farmace´utica, Facultad de Farmacia,
Universidad Complutense, 28040 Madrid, Spain. E-mail: josecm@farm.
ucm.es; Fax: +34 91 3941823; Tel: +34 913941840
† Electronic supplementary information (ESI) available: Copies of spectra
of all compounds. See DOI: 10.1039/c004703a
Scheme 1 CAN-catalyzed three-component reaction between primary
amines, b-dicarbonyl compounds and 1,4-naphthoquinone.
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Table 1 Solvent optimization for the CAN-catalyzed reaction between
electron-releasing groups as the amine. All these substrates gave
compounds 4 in good to excellent yields with the sole exception
of arylamines (entries 11–15), for which yields were lower in
the one-pot reaction due to the low reactivity of these amines
with 1,3-dicarbonyls in the enamine formation step.11e However,
the problem could be solved by use of isolated, crude enamines
as starting materials. An attempt to use a a-branched primary
amine, namely cyclohexylamine, afforded only the corresponding
intermediate 5 (72% yield after 1 h reaction time in the presence
of 5 mol% CAN), and all attempts to effect its cyclization were
unsuccessful. Regarding the scope of the method in terms of the
R2 substituent, we verified that the reaction gave good results with
alkyl substituents, but not when R2 was aryl.
butylamine, ethyl acetoacetate and 1,4-naphthoquinone
Entry
Solvent
Yield of 4a (%)
1
2
3
4
5
6
7
8
9
Ethanol
CH3CN
Methanol
THF
93
92
57
66
57
93
67
90
28
CH2Cl2
(CH2Cl)2
Toluene
1,4-Dioxane
CHCl3
from the expected mechanistic pathway, explaining its very high
efficiency and cleanliness. We next examined the model reaction
in different solvents under the previously established time and
temperature conditions. As shown in Table 1, ethanol, acetonitrile,
1,2-dichloroethane, and 1,4-dioxane were found to be excellent
solvents for the reaction while methanol, THF, dichloromethane,
toluene and (specially) chloroform were less effective. Ethanol was
chosen as the optimal solvent for subsequent studies because of
its low cost and toxicity.
The reaction between n-butylamine, ethyl 5-hydroxy-3-oxo-5,5-
diphenylpentanoate 2e and 1,4-naphthoquinone did not afford
the expected product, but gave instead the C2-methyl derivative
4a in 55% yield (Scheme 2). This reaction probably proceeded
through the formation of the expected product 6, which would
be activated by CAN by coordination with the ester carbonyl to
facilitate the elimination a molecule of benzophenone to give the
observed indole 4a via intermediate 7.
The application of the optimized conditions (5 mol% CAN,
1 h reflux in ethanol) to a number of 1,3-dicarbonyl compounds
allowing structural variation at R1, R2 and R3 is summarized in
Scheme 1 and Table 2. We initially sought to further optimize
the model reaction, and found that an increase of the reflux time
to 1.5 h led only to a slight improvement of the yield (entry 2),
and also that the substitution of CAN by InCl3 (10 mol%) as an
alternative Lewis acid furnished the same product after a 2 h reflux
without any significant change in the yield. We considered these
improvements to have little significance and hence we retained
for our subsequent reactions the 1 h reflux time and CAN as
a catalyst because of its many previously mentioned advantages.
The scope of the reaction included the use of b-keto esters and
b-keto thioesters as the dicarbonyl component and aliphatic
primary amines (n-butyl, allyl, propargyl, and benzyl amines,
entries 3–10) or anilines having either electron-withdrawing or
Table 2 Scope and yields of the three-component reaction between
primary amines, b-dicarbonyl compounds and 1,4-naphthoquinone
Entry
Cmpd.
R1
R2
R3
Yield (%)
Scheme 2 Loss of benzophenone in the reaction involving 5-hydroxy-
3-oxo-5,5-diphenylpentanoate as the b-dicarbonyl component.
1
2
3
4
5
6
7
8
4a
4a
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4j
nBu
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
nPr
OEt
OEt
OEt
OMe
OEt
OEt
OMe
S-tBu
S-tBu
OEt
OEt
OEt
OEt
OEt
OEt
S-tBu
OEt
93
96a
95b
96
90
90
89
87
88
75
65
55
73c
50
76c
70
52
nBu
nBu
nBu
Regarding the mechanism of the three-component reaction, a
detailed literature search on the mechanism of the Nenitzescu
reaction showed that there are two possible routes to explain the
observed product. The first one (mechanism a) is initiated by
the formation of a carbon–carbon bond by a Michael addition
of the enaminone to the quinone followed by a nucleophilic
cyclization that generates a carbon–nitrogen bond. The second
possibility involves the initial formation of a carbon–nitrogen
bond by condensation of the enamine with the quinone carbonyl,
and subsequent cyclization to form the carbon–carbon bond
(mechanism b).7 In our experimental conditions, we can rule out
mechanism b in view of our isolation of compounds 5 on many
occasions. The mechanism normally accepted for route a conven-
tionally involves a redox process which, applied to our case, would
allyl
Bn
allyl
allyl
propargyl
propargyl
Ph
9
10
11
12
13
14
15
16
17
p-OMeC6H4
p-OMeC6H4
p-ClC6H4
p-ClC6H4
nBu
4k
4k
4l
4m
nBu
a Reaction time, 1.5 h. b InCl3 (10 mol%) was used as a catalyst (2 h reaction
time). c Isolated, crude enamines were used as starting materials.
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Org. Biomol. Chem., 2010, 8, 3426–3436 | 3427
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Scheme 3 Non-redox mechanistic proposal for the CAN-catalyzed three-component benzo[g]indole synthesis.
Table 3 Scope and yields of the three-component reaction between
primary amines, b-dicarbonyl compounds and 1,4-benzoquinone
start by an initial Michael addition followed by tautomerism to
the corresponding hydroquinone species. Its oxidation by air to
quinone 5, even in trace amounts, is enough to trigger a redox
cycle in which 5 is cyclized to an iminium derivative, which is
then reduced by the hydroquinone to give another molecule of 5
and the observed product 4.7,12 However, this mechanism seems
not to be in operation in our case since treatment of isolated
quinone 5a with one equivalent of externally added hydroquinone
under our standard reaction conditions (5 mol% of CAN in
refluxing ethanol) did not afford compound 4a. Based on these
observations, we propose an alternative mechanism not involving
any redox reaction, where the enamine formed by reaction between
amines 1 and 1,3-dicarbonyl compounds 2 adds to the CAN-
activated naphthoquinone to afford intermediate 8, which at room
temperature is slowly converted by air oxidation into the p-quinone
derivative 5. On the other hand, under our optimized conditions,
which involve reflux temperature, intermediate 8 undergoes a
fast intramolecular nucleophilic cyclization before tautomerism,
prompted by coordination of Ce(IV) to its carbonyl group,13 and
this is followed by elimination of a molecule of water to furnish
the observed fused indoles 4 (Scheme 3).
Entry
Compd
R1
R2
R3
Yield (%)
1
2
3
4
5
6
7
8
10a
10b
10c
10d
10e
10f
10g
10h
nBu
allyl
Bn
Me
Me
Me
Me
Me
Me
nPr
nPr
OEt
OEt
OEt
OEt
S-tBu
S-tBu
OEt
OEt
78
75
73
69
86
81
82
78
propargyl
nBu
allyl
nBu
allyl
Scheme
4 CAN-catalyzed three-component synthesis of 5-hydro-
xyindoles.
In order to further probe the generality of our three-component
methodology, and also to facilitate its comparison with the
standard Nenitzescu reaction, we studied its applicability to the
reaction using p-benzoquinone 3b, the most common substrate
for the Nenitzescu reaction. Again, the expected 5-hydroxyindoles
10 were obtained in very good yields and the reaction had a
similar scope to the one starting from naphthoquinone (Scheme 4,
Table 3). The reaction between amines, ethyl 3-oxohexanoate and
p-benzoquinone gave particularly good yields of the correspond-
ing indoles having a propyl substituent at position 2, showing
an enhanced reactivity for p-benzoquinone compared with 1,4-
naphthoquinone (entries 7 and 8).
reaction mode to a Michael–Michael domino sequence, leading
to a method for the preparation of linear tricyclic systems. Hence,
we applied our three-component protocol to butylamine 1a,
ethyl acetoacetate 2a, and 2-bromonaphthoquinone 3c14 as the
Michael acceptor and observed the formation of indolequinone
11a as the main product together with compound 12a, which can
be regarded as an intermediate of the pathway leading to 11a
(Scheme 5). Changes in the reflux time and catalyst load led to very
similar results (Table 4), and indeed we found that the reaction
could be performed at room temperature with little change in
the final results (entry 4). When acetylacetone was used as the
starting material, fused indolequinone 11b was isolated as the
only product in 67% yield (entry 7). It is noteworthy that literature
precedent of a Nenitzescu reaction between 2-chloroanthracene-
1,4,9,10-tetraone and a b-enaminone proceeded through the
As an additional refinement of our study, we next briefly
examined how the presence of a leaving group at the C-2 position
of the starting quinone affected our three-component reaction,
based on the hypothesis that this modification could change the
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Table 4 Conditions and yields for the three-component reaction be-
tween primary amines, b-dicarbonyl compounds and 2-bromo-1,4-
naphthoquinone
Entry
R1
R2
CAN (%) Time/h
% 11 % 12
1
2
3
4
5
6
7
8
a
a
a
a
a
a
b
c
nBu
nBu
nBu
nBu
nBu
nBu
nBu
Bn
OEt
OEt
OEt
OEt
5
5
5
5
1
3
1
1
2.5
24
1
1
1
50
39
54a
51b
50
0c
67
51
44
42
21
17
18
17
12
0
0
0
0
0
OEt 15
OEt
Me
Me
Me
5
5
5
5
5
9
10
d
e
allyl
propargyl Me
1
a Isolated, crude enamine was used. b Isolated enamine was used and the
reaction was carried out at room temperature. c Decomposed.
Scheme
5
Three-component synthesis of benzo[f ]indolequinones
from primary amines, b-dicarbonyl compounds and 2-bromo-1,
4-naphthoquinone.
idea into practice, we examined the possibility of using the acidity
of the carbonyl-conjugated 2-methyl group of fused indoles 4 to
introduce terminal alkenyl and alkynyl chains by a deprotonation–
nucleophilic substitution sequence, although this type of depro-
tonation of 2-methylindoles has received little attention in the
literature.16 In the event, we discovered that treatment of N-
allyl derivatives of compounds 4 with LDA in THF followed by
addition of allyl iodide smoothly afforded the desired metathesis
precursors 13 in high yields (Scheme 6). These alkylation reactions
can be presumed to occur on dianion species generated by
deprotonation of both the phenol and the C2-methyl group and,
interestingly, were completely regioselective in favour of the latter.
All efforts to achieve the ring-closing metathesis (RCM) and
ring-closing enyne metathesis (RCEYM) reaction of 13 using
Grubbs catalysts were unsuccessful. However, as shown in
standard pathway, affording an angular fused indole related to
the anthracyclines.15a On the other hand, a few examples of two-
component reactions between b-enaminones and bromoquinones
that give linear products related to ours are known in the
literature, but they required Ullman-type conditions (K2CO3,
CuBr2) and proceed only in 15–25% yields.15b Further studies on
this transformation are in progress in our laboratory.
Finally, we reasoned that the functionality present in com-
pounds 4 should allow their use as starting materials for novel
routes to structurally complex nitrogen heterocycles. For instance,
a ring-closing metathesis reaction between suitable substituents
placed at the indole nitrogen and the adjacent methyl group
should provide ready access to unusual tetracyclic compounds
bearing a bridgehead nitrogen atom. In order to translate this
Scheme 6 Synthesis of 9,12-dihydro-8H-azepino[1,2-a]benzo[g]indoles by ring-closing metathesis.
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Scheme 6, the O-acetylated and benzoylated derivatives 14a–d
underwent smooth ring-closing reaction in the presence of 10
mol% of Grubbs 1st generation catalyst under mild experimen-
tal conditions in dichloromethane to give very good yields of
compounds 15, which are derivatives of the hitherto unknown
9,12-dihydro-8H-azepino[1,2-a]benzo[g]indole ring system and
are of potential biological interest in view of the varied biolog-
ical activities known for pyrrolo[1,2-a]azepine derivatives.17 This
efficient transformation is noteworthy in view of the difficulties
often associated with the construction of medium-sized rings
by RCM, specially from acyclic precursors, owing to entropic
factors and transannular repulsions that develop as the ring is
formed.18 Indeed, to our knowledge, the synthesis of compounds
15 constitutes the first example of the preparation of a pyrrolo[1,2-
a]azepine system by a metathesis strategy. On the other hand, the
RCEYM reactions of 14e and 14f gave only traces of the desired
products, even after assaying a variety of commercially available
metathesis catalysts in different solvents including the highly
effective fluorinated aromatic hydrocarbon metathesis solvents,19
and also failed under an ethylene atmosphere, which is often used
to promote ene-yne metathesis reactions.20
de Microana´lisis Elemental, Universidad Complutense, using a
Leco 932 CHNS combustion microanalyzer.
General procedure for the synthesis of benzo[g]indoles 4 and
p-quinone derivatives 5
To a stirred mixture of primary amines 1 (3 mmol) and 1,3-
dicarbonyl compounds 2 (3 mmol) in ethanol (6 mL) was added
CAN (5 mol%) and stirring was continued for 30 min at room
temperature. 1,4-Naphthoquinone 3a (3 mmol) was then added
and the mixture was refluxed for further 30 min. After completion
of the reaction, as indicated by tlc, dichloromethane (20 mL) was
added to the mixture and the resulting solution was washed with
water (5 mL), dried over anhydrous Na2SO4 and the solvent was
evaporated under reduced pressure. The crude reaction mixture
was purified by silica column chromatography using petroleum
ether–ethyl acetate mixture (80 : 20, v/v) as eluent. Characteriza-
tion data for compounds 4 follow, and also for compound 5a,
which was isolated in 72% yield after 1 h reaction time at room
temperature in the presence of 5 mol% CAN.
Ethyl 1-butyl-5-hydroxy-2-methyl-1H-benzo[g]indole-3-carbo-
xylate (4a). Off-white solid; mp 191–192 ◦C; IR (KBr) 3266,
1
2963, 2933, 1646, 1599, 1521, 1415, 1334, 1247, 1123 cm-1; H
Conclusions
NMR (DMSO-d6, 250 MHz) d 0.94 (t, J = 7.2 Hz, 3H), 1.37–1.48
(m, 5H), 1.73–1.84 (m, 2H), 2.77 (s, 3H), 4.28–4.36 (q, J = 7.1 Hz,
2H), 4.48–4.54 (t, J = 7.5 Hz, 2H), 7.43 (dd, J = 7.8, 7.1 Hz,
1H), 7.60 (dd, J = 8.3, 7.1 Hz, 1H), 7.72 (s, 1H), 8.26–8.31 (m,
2H), 9.76 (s, 1H); 13C NMR (DMSO-d6, 63 MHz) d 12.0, 14.0,
14.9, 19.7, 31.8, 40.8, 59.3, 102.0, 104.0, 120.6, 122.5, 122.8, 123.2,
123.6, 123.8, 124.8, 126.7, 143.0, 148.6, 165.6; Anal. Calcd for
C20H23NO3: C, 73.82; H, 7.12; N, 4.30. Found: C, 73.53; H, 6.95;
N, 4.19%.
In summary, we have developed an efficient methodology for
the synthesis of benzo[g]indoles and 5-hydroxyindoles based on
a CAN-catalyzed, three-component enamine formation–Michael
addition–intramolecular imine formation domino sequence start-
ing from amines, b-dicarbonyl compounds and quinones, in a
three-component variation of the Nenitzescu indole synthesis. The
conventional oxidation–reduction mechanism normally accepted
for the Nenitzescu reaction was ruled out under our conditions
and the available experimental evidence led us to propose a non-
redox mechanism different from the one commonly accepted for
this reaction. The three-component protocol was also extended
to the synthesis of linear benzo[f ]indolequinones by using 2-
bromoquinones as the starting materials. The benzo[g]indole
derivatives were transformed into 9,12-dihydro-8H-azepino[1,2-
a]benzo[g]-indoles, a new class of fused indole derivatives, using a
C-alkylation/ring-closing metathesis strategy.
Methyl 1-butyl-5-hydroxy-2-methyl-1H-benzo[g]indole-3-carbo-
xylate (4b). Off-white solid; mp 221–222 ◦C; IR (KBr) 3281,
1
2954, 1654, 1598, 1522, 1441, 1333, 1248, 1199, 1121 cm-1; H
NMR (DMSO-d6, 250 MHz) d 0.95 (t, J = 7.2 Hz, 3H), 1.38–1.50
(m, 2H), 1.74–1.83 (m, 2H), 2.78 (s, 3H), 3.86 (s, 3H), 4.53 (t,
J = 7.6 Hz, 2H), 7.44 (dd, J = 7.8, 7.2 Hz, 1H), 7.62 (dd, J =
7.8, 7.6 Hz, 1H), 7.69 (s, 1H), 8.27–8.34 (m, 2H), 9.79 (s, 1H); 13
C
NMR (DMSO-d6, 63 MHz) d 12.1, 14.0, 19.7, 31.8, 45.4, 50.9,
101.9, 103.9, 120.6, 122.5, 122.9, 123.2, 123.4, 123.8, 124.7, 126.8,
143.1, 148.6, 166.0; Anal. Calcd for C19H21NO3: C, 73.29; H, 6.80;
N, 4.50. Found: C, 73.08; H, 6.67; N, 4.23%.
Experimental section
General experimental information
Ethyl 1-allyl-5-hydroxy-2-methyl-1H-benzo[g]indole-3-carbo-
xylate (4c). Off-white solid; mp 218–219 ◦C; IR (KBr) 3259,
All reagents (Aldrich, Fluka, SDS, Probus) and solvents (SDS)
were of commercial quality and were used as received. Reactions
were monitored by thin layer chromatography, on aluminium
plates coated with silica gel with fluorescent indicator (SDS
CCM221254). Separations by flash chromatography were per-
formed on silica gel (SDS 60 ACC 40–63 mm) or neutral alumina
(Merck S22). Melting points were measured on a Reichert 723
hot stage microscope, and are uncorrected. Infrared spectra were
recorded on a Perkin Elmer Paragon 1000 FT-IR spectrophotome-
ter, with all compounds examined as KBr pellets or as thin films
on NaCl disks. NMR spectra were obtained on a Bruker Avance
250 spectrometer operating at 250 MHz for 1H and 63 MHz
for 13C (CAI de Resonancia Magne´tica Nuclear, Universidad
Complutense). Elemental analyses were determined by the CAI
1
2981, 1644, 1597, 1529, 1418, 1336, 1245, 1131 cm-1; H NMR
(DMSO-d6, 250 MHz) d 1.41 (t, J = 7 Hz, 3H), 2.73 (s, 3H), 4.33
(q, J = 7.0 Hz, 2H), 4.65 (d, J = 17.2 Hz, 1H), 5.17–5.22 (m, 3H),
6.21–6.38 (m, 1H), 7.42 (dd, J = 7.8, 7.1 Hz, 1H), 7.54 (dd, J =
7.7, 6.8 Hz, 1H), 7.72 (s, 1H), 8.21–8.28 (m, 2H), 9.79 (s, 1H);
13C NMR (DMSO-d6, 63 MHz) d 11.7, 14.9, 48.0, 59.4, 101.9,
104.3, 116.0, 120.9, 122.3, 122.9, 123.3, 123.6, 123.8, 124.4, 126.4,
133.9, 143.3, 148.6, 165.6; Anal. Calcd for C19H19NO3: C, 73.77;
H, 6.19; N, 4.53. Found: C, 73.48; H, 6.16; N, 4.54%.
Ethyl 1-benzyl-5-hydroxy-2-methyl-1H-benzo[g]indole-3-carbo-
xylate (4d). Off-white solid; mp 240–241 ◦C; IR (KBr) 3264,
1
2928, 1641, 1599, 1523, 1416, 1336, 1293, 1247, 1124 cm-1; H
3430 | Org. Biomol. Chem., 2010, 8, 3426–3436
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NMR (DMSO-d6, 250 MHz): d 1.43 (t, J = 7.0 Hz, 3H), 2.74 (s,
3H), 4.35 (q, J = 7.0 Hz, 2H), 5.90 (s, 2H), 7.05 (d, J = 7.4 Hz,
2H), 7.25–7.37 (m, 5H), 7.76 (s, 1H), 8.07–8.10 (m, 1H), 8.22–8.25
(m, 1H), 9.83 (s, 1H); 13C NMR (DMSO-d6, 63 MHz): d 11.9, 14.9,
49.1, 59.5, 101.9, 104.6, 120.7, 122.3, 122.9, 123.4, 123.6, 123.8,
124.7, 125.9, 126.4, 127.6, 129.3, 137.4, 143.6, 148.8, 165.6; Anal.
Calcd for C23H21NO3: C, 76.86; H, 5.89; N, 3.90. Found: 76.50; H,
6.05; N, 3.78%.
(dd, J = 8.3, 7.0 Hz, 1H), 7.31 (dd, J = 8.0, 7.2 Hz, 1H), 7.51–7.54
(m, 2H), 7.72–7.75 (m, 4H), 8.22 (d, J = 8.3 Hz, 1H), 9.87 (s, 1H);
13C NMR (DMSO-d6, 63 MHz): d 13.0, 15.0, 59.5, 101.7, 105.1,
119.9, 122.3, 123.1, 123.4, 123.7, 124.2, 124.8, 125.9, 129.2, 130.2,
130.8, 139.3, 143.5, 148.9, 165.6; Anal. Calcd for C22H19NO3: C,
76.50; H, 5.54; N, 4.06. Found: C, 76.47; H, 5.56; N, 4.15%.
Ethyl 5-hydroxy-1-(4-methoxyphenyl)-2-methyl-1H-benzo[g]-
indole-3-carboxylate (4j). Pale brown solid; mp 216–217 ◦C;
IR (KBr) 3273, 2928, 1652, 1514, 1384, 1298, 1249, 1176, 1136,
1033 cm-1; 1H NMR (DMSO-d6, 250 MHz): d 1.41 (t, J = 7.0 Hz,
3H), 2.43 (s, 3H), 3.93 (s, 3H), 4.35 (q, J = 7.0 Hz, 2H), 6.94 (d,
J = 8.4 Hz, 1H), 7.15–7.46 (m, 6H), 7.74 (s, 1H), 8.22 (d, J =
8.3 Hz, 1H), 9.84 (s, 1H); 13C NMR (DMSO-d6, 63 MHz): d 13.0,
14.9, 55.9, 59.4, 101.7, 104.9, 115.8, 119.9, 122.4, 123.0, 123.4,
123.6, 124.0, 125.0, 125.9, 130.2, 131.7, 143.9, 148.9, 160.1, 165.6;
Anal. Calcd for C23H21NO4: C, 73.58; H, 5.64; N, 3.73. Found: C,
73.28; H, 5.77; N, 3.85%.
Methyl 1-allyl-5-hydroxy-2-methyl-1H-benzo[g]indole-3-carbo-
xylate (4e). Off-white solid; mp 220–221 ◦C; IR (KBr) 3256,
2980, 1644, 1623, 1597, 1530, 1415, 1335, 1245, 1130, 1071 cm-1;
1H NMR (DMSO-d6, 250 MHz): d 2.74 (s, 3H), 3.88 (s, 3H), 4.36
(d, J = 17.2 Hz, 1H), 5.19–5.24 (m, 3H), 6.25–6.36 (m, 1H), 7.44
(dd, J = 7.6, 7.1 Hz, 1H), 7.56 (dd, J = 7.5, 6.9 Hz, 1H), 7.71
(s, 1H), 8.23–8.30 (m, 2H), 9.81 (s, 1H); 13C NMR (DMSO-d6, 63
MHz): d 11.7, 48.1, 50.9, 101.8, 104.1, 116.0, 120.9, 122.3, 123.0,
123.4, 123.6, 123.8, 124.3, 126.5, 133.9, 143.4, 148.7, 165.9; Anal.
Calcd for C18H17NO3: C, 73.20; H, 5.80; N, 4.74. Found: C, 72.96;
H, 6.17; N, 4.52%.
Ethyl
1-(4-chlorophenyl)-5-hydroxy-2-methyl-1H-benzo[g]in-
dole-3-carboxylate (4k). Off-white solid; mp 250–251 ◦C; IR
(KBr) 3282, 2927, 1649, 1493, 1386, 1339, 1259, 1137, 1090,
1015 cm-1; 1H NMR (DMSO-d6, 250 MHz): d 1.41 (t, J = 7.0 Hz,
3H), 2.42 (s, 3H), 4.36 (q, J = 7.0 Hz, 2H), 6.88 (d, J = 8.5 Hz,
1H), 7.21 (dd, J = 8.2, 7.0 Hz, 1H), 7.33 (dd, J = 8.1, 7.0 Hz,
1H), 7.57–7.61 (m, 2H), 7.74–7.81 (m, 3H), 8.23 (d, J = 8.2 Hz,
1H), 9.90 (s, 1H); 13C NMR (DMSO-d6, 63 MHz): d 13.0, 14.8,
59.5, 101.6, 105.4, 119.7, 122.2, 123.2, 123.5, 123.8, 124.3, 124.9,
126.2, 130.8, 131.1, 134.9, 138.4, 143.5, 149.2, 165.3; Anal. Calcd
for C22H18ClNO3: C, 69.57; H, 4.78; N, 3.69. Found: C, 69.27; H,
4.94; N, 3.84%.
S-tert-Butyl 1-allyl-5-hydroxy-2-methyl-1H-benzo[g]indole-3-
◦
carbothioate (4f). Pale brown solid; mp 107–108 C; IR (KBr)
3377.8, 2963, 1622, 1597, 1512, 1401, 1363, 1265, 1091, 982 cm-1;
1H NMR (CDCl3, 250 MHz): d 1.68 (s, 9H), 2.72 (s, 3H), 4.90
(d, J = 17.5 Hz, 1H), 5.02 (s, 2H), 5.29 (d, J = 12.5 Hz, 1H),
6.13–6.25 (m, 1H), 7.43–7.55 (m, 2H), 7.90 (s, 1H), 8.13 (d, J =
8.0 Hz, 1H), 8.36 (d, J = 7.0 Hz, 1H); 13C NMR (CDCl3, 63
MHz): d 12.9, 30.9, 48.5, 48.9, 103.2, 115.9, 117.9, 120.9, 122.5,
122.9, 123.4, 123.6, 123.7, 125.4, 126.6, 132.4, 141.0, 147.4, 189.3;
Anal. Calcd for C21H23NSO2: C, 71.36; H, 6.56; N, 3.96; S, 9.07.
Found: C, 71.08; H, 6.36; N, 4.16; S, 8.73%.
S-tert-Butyl 1-butyl-5-hydroxy-2-methyl-1H-benzo[g]indole-3-
carbothioate (4l). Dark brown viscous liquid; IR (neat) 2968,
S-tert-Butyl
5-hydroxy-2-methyl-1-(prop-2-ynyl)-1H-benzo-
[g]indole-3-carbothioate (4g). Pale brown solid; mp 168–169 ◦C;
IR (KBr) 3296, 2964, 2923, 1668, 1652, 1512, 1455, 1364, 1264,
1083, 989 cm-1; 1H NMR (CDCl3, 250 MHz): d 1.66 (s, 9H), 2.20
(s, 1H), 2.86 (s, 3H), 5.16 (s, 2H), 7.28 (s, 1H), 7.51–7.64 (m, 2H),
7.83 (s, 1H), 8.38 (d, J = 7.5 Hz, 1H), 8.47 (d, J = 7.5 Hz, 1H);
13C NMR (CDCl3, 63 MHz): d 13.1, 30.8, 36.6, 48.9, 74.8, 76.6,
103.0, 116.3, 121.0, 122.5, 122.8, 123.4, 123.7, 123.8, 125.1, 126.9,
140.0, 147.6, 189.3; Anal. Calcd for C21H21NSO2: C, 71.76; H,
6.02; N, 3.99; S, 9.12. Found: C, 71.48; H, 5.72; N, 4.17; S, 8.92%.
2871, 1668, 1597, 1504, 1456, 1364, 1248, 1166, 1079 cm-1; H
1
NMR (CDCl3, 250 MHz): d 1.04 (t, J = 7.2 Hz, 3H), 1.52–1.61
(m, 2H), 1.67 (s, 9H), 1.89–1.95 (m, 2H), 2.80 (s, 3H), 4.43 (t, J =
7.3 Hz, 2H), 5.43 (s, 1H), 7.48–7.62 (m, 2H), 7.90 (s, 1H), 8.20
(d, J = 8.4 Hz, 1H), 8.39 (d, 8.2 Hz, 1H); 13C NMR (CDCl3, 63
MHz): d (one aromatic carbon signal is merged with others) 13.3,
14.2, 20.5, 30.9, 32.2, 46.0, 48.9, 103.2, 115.8, 120.6, 122.9, 123.7,
123.4, 123.9, 124.8, 126.8, 140.5, 147.3, 189.4; Anal. Calcd. for
C22H27NO2S: C, 71.51; H, 7.36; N, 3.79; S, 8.68. Found: C, 71.25;
H, 7.15; N, 3.58; S, 8.46%.
Ethyl 5-hydroxy-2-methyl-1-(prop-2-ynyl)-1H-benzo[g]indole-3-
carboxylate (4h). Off-white solid; mp 235–236 ◦C; IR (KBr)
3305, 2976, 2924, 1635, 1598, 1525, 1457, 1418, 1336, 1244,
1133 cm-1; 1H NMR (DMSO-d6, 250 MHz): d 1.41 (t, J = 7.0 Hz,
3H), 2.81 (s, 3H), 3.53 (s, 1H), 4.33 (q, J = 7.0 Hz, 2H), 5.40 (s,
2H), 7.46 (dd, J = 7.8, 7.7 Hz, 1H), 7.62 (dd, J = 7.9, 7.8 Hz, 1H),
7.70 (s, 1H), 8.29 (d, J = 8.1 Hz, 1H), 8.50 (d, J = 8.6 Hz, 1H), 9.84
(s, 1H); 13C NMR (DMSO-d6, 63 MHz): d 11.9, 14.8, 36.3, 59.5,
76.8, 79.2, 101.8, 104.7, 121.2, 122.4, 123.2, 123.4, 123.5, 123.6,
124.4, 126.5, 142.8, 148.8, 165.4; Anal. Calcd for C19H17NO3: C,
74.25; H, 5.58; N, 4.56. Found: C, 74.01; H, 5.70; N, 4.34%.
Ethyl 1-butyl-5-hydroxy-2-propyl-1H-benzo[g]indole-3-carbo-
xylate (4m). Brown solid; mp 166–167 ◦C; IR (KBr) 2959, 2870,
1
1654, 1600, 1513, 1450, 1332, 1245, 1124, 1070 cm-1; H NMR
(CDCl3, 250 MHz): d 1.03–1.14 (m, 6H), 1.48–1.58 (m, 5H),
1.67–1.77 (m, 2H), 1.91–1.98 (m, 2H), 3.22 (t, J = 7.5 Hz, 2H),
4.46–4.55 (m, 4H), 6.59 (br-s, 1H), 7.46–7.64 (m, 2H), 8.02 (s,
1H), 8.25 (dd, J = 8.5 Hz, 1H), 8.46 (d, J = 8.3 Hz, 1H); 13C
NMR (CDCl3, 63 MHz): d 14.2, 14.7, 14.9, 20.5, 24.0, 28.3, 32.8,
46.0, 60.2, 102.9, 104.5, 120.5, 123.0, 123.2, 123.6, 124.1, 124.6,
125.5, 126.7, 147.3, 148.0, 166.9; Anal. Calcd. for C22H27NO3: C,
74.76; H, 7.70; N, 3.96. Found: C, 74.37; H, 7.43; N, 4.29%.
Ethyl 5-hydroxy-2-methyl-1-phenyl-1H-benzo[g]indole-3-carbo-
xylate (4i). Pale brown solid; mp 230–231 ◦C; IR (KBr) 3420,
2931, 1648, 1596, 1496, 1411, 1337, 1246, 1196, 1177, 1071 cm-1;
1H NMR (DMSO-d6, 250 MHz): d 1.42 (t, J = 7.0 Hz, 3H), 2.43
(s, 3H), 4.36 (q, J = 7.0 Hz, 2H), 6.81 (d, J = 8.5 Hz, 1H), 7.13
(E)-Ethyl 3-(butylamino)-2-(1,4-dioxo-1,4-dihydronaphthalen-2-
yl)but-2-enoate (5a). Brownish viscous liquid; IR (neat, NaCl):
2960, 2931, 1706, 1652, 1594 cm-1; 1H NMR (CDCl3, 250 MHz):
0.99 (t, J = 7.2 Hz, 3H), 1.11 (t, J = 7.1 Hz, 3H), 1.40–1.54
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The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 3426–3436 | 3431
©

(m, 2H), 1.60–1.71 (m, 2H), 1.97 (s, 3H), 3.31 (q, J = 6.8 Hz,
2H), 4.06 (q, J = 7.1 Hz, 2H), 6.76 (s, 1H), 7.71–7.78 (m, 2H),
8.07–8.15 (m, 2H), 9.77 (s, 1H); 13C NMR (CDCl3, 63 MHz): 14.2,
14.7, 17.6, 20.5, 32.4, 43.8, 59.7, 89.7, 126.2, 127.2, 132.8, 133.3,
133.7, 133.8, 137.5, 149.4, 162.0, 169.2, 185.9, 186.0; Anal. Calcd.
For C20H23NO4: C, 70.36; H, 6.79; N, 4.10; Found: C, 70.10; H,
6.41; N, 4.01%.
S-tert-Butyl
1-butyl-5-hydroxy-2-methyl◦-1H-indole-3-carbo-
thioate (10e). Off-white solid; mp 133–134 C; IR (KBr) 3438,
2959, 2870, 1627, 1596, 1587, 1495, 1459, 1412, 1362, 1321, 1197,
1163, 1067 cm-1; H NMR (CDCl3, 250 MHz): d 0.97 (t, J =
1
7.1 Hz, 3H), 1.32–1.47 (m, 2H), 1.64 (s, 9H), 1.69–1.74 (m, 2H),
2.74 (s, 3H), 4.06 (t, J = 7.4 Hz, 2H), 5.05 (s, 1H), 6.83 (dd, J =
2.3, 8.6 Hz, 1H), 7.16 (d, J = 8.7 Hz, 1H), 7.80 (d, J = 2.1 Hz,
1H); 13C NMR (CDCl3, 63 MHz): d 13.4, 14.2, 20.6, 30.9, 32.2,
43.5, 48.5, 107.4, 110.6, 111.6, 114.0, 126.5, 131.4, 143.7, 151.7,
188.6; Anal. Calcd for C18H25NO2S: C, 67.67; H, 7.89; N, 4,38; S,
10.04. Found: C, 67.48; H, 7.72; N, 4,65; S, 9.90%.
Synthesis of 5-hydroxyindole derivatives 10
The general procedure for the synthesis of compounds 4 was
employed for the reaction between primary amines 1, 1,3-
dicarbonyl compounds 2 and p-benzoquinone 3b for the synthesis
of 5-hydroxyindole derivatives 10.
S-tert-Butyl
1-allyl-5-hydroxy-2-methyl-1H-indole-3-carbo-
thioate (10f). Pale brownish viscous liquid; IR (neat) 2962,
2922, 1622, 1597, 1501, 1473, 1409, 1362, 1219, 1164, 1085, 1065,
Ethyl
1-butyl-5-hydroxy-2-methyl-1H-indole-3-carboxylate
1
1021 cm-1; H NMR (CDCl3, 250 MHz): d 1.64 (s, 9H), 2.70
(10a). Off-white solid; mp 145–146 ◦C; IR (KBr) 2965, 2927,
(s, 3H), 4.65–4.67 (m, 2H), 4.84 (d, J = 17.1 Hz, 1H), 5.16 (d,
J = 10.3 Hz, 1H), 5.57 (s, 1H), 5.82–5.97 (m, 1H), 6.82 (dd, J =
2.3, 8.7 Hz, 1H), 7.09 (d, J = 8.7 Hz, 1H), 7.82 (d, J = 2.3 Hz.
1H); 13C NMR (CDCl3, 63 MHz): d 13.1, 30.8, 45.6, 48.6, 107.4,
110.6, 111.9, 114.3, 117.3, 126.5, 131.4, 132.1, 143.9, 152.0, 188.9;
Anal. Calcd for C17H21NO2S: C, 67.29; H, 6.98; N, 4.62; S, 10.57.
Found: C, 67.03; H, 6.96; N, 4.63; S, 10.36%.
2863, 1652, 1621, 1520, 1469, 1440, 1379, 1283, 1245, 1185, 1157,
1116 cm-1; H NMR (CDCl3, 250 MHz): d 0.98 (t, J = 7.2 Hz,
1
3H), 1.33–1.49 (m, 5H), 1.75 (m, 2H), 2.76 (s, 3H), 4.09 (t, J =
7.4 Hz, 2H), 4.41 (q, J = 7.1 Hz, 2H), 4.98 (s, 1H), 6.81 (dd, J =
2.3, 8.7 Hz, 1H), 7.18 (d, J = 8.7 Hz, 1H), 7.63 (d, J = 2.4 Hz,
1H); 13C NMR (CDCl3, 63 MHz): d 12.6, 14.2, 14.9, 20.6, 32.3,
43.6, 60.0, 103.6, 106.7, 110.4, 111.7, 128.3, 131.3, 145.5, 152.1,
167.0; Anal. Calcd for C16H21NO3: C, 69.79; H, 7.69; N, 5.09.
Found: C, 69.51; H, 7.52; N, 5.30%.
Ethyl
1-butyl-5-hydroxy-2-propyl-1H-indole-3-carboxylate
(10g). Off-white solid; mp 124–125 ◦C; IR (KBr) 3336, 2961,
2872, 1688, 1651, 1521, 1470, 1444, 1379, 1296, 1245, 1180, 1147,
Ethyl
1-allyl-5-hydroxy-2-methyl◦-1H-indole-3-carboxylate
1
1111, 1035 cm-1; H NMR (CDCl3, 250 MHz): d 0.99 (t, J =
(10b). Pale brown solid; mp 132–133 C; IR (KBr) 3288, 2986,
7.5 Hz, 3H), 1.07 (t, J = 7.3 Hz, 3H), 1.35–1.50 (m, 2H), 1.45
(t, J = 7.1 Hz, 3H), 1.65–1.83 (m, 4H), 3.09–3.15 (m, 2H), 4.08
(t, J = 7.3 Hz, 2H), 4.41 (q, J = 7.1 Hz, 2H), 5.79 (s, 1H), 6.84
(dd, J = 2.4, 8.7 Hz, 1H), 7.18 (d, J = 8.7 Hz, 1H), 7.74 (d, J =
2.4 Hz, 1H); 13C NMR (CDCl3, 63 MHz): d 14.2, 14.7, 14.9,
20.7, 23.7, 28.4, 32.6, 43.7, 60.0, 103.0, 106.8, 110.7, 111.8, 128.5,
131.2, 149.7, 152.3, 166.8; Anal. Calcd C18H25NO3: C, 71.26; H,
8.31; N, 4.62. Found: C, 71.00; H, 8.11; N, 4.66%.
1655, 1620, 1522, 1471, 1433, 1379, 1292, 1249, 1185, 1155, 1120,
1034 cm-1; H NMR (CDCl3, 250 MHz): d 1.35 (t, J = 7.1 Hz,
1
3H), 2.62 (s, 3H), 4.31 (q, J = 7.1 Hz, 2H), 4.58–4.61 (m, 2H),
4.74 (dq, J = 0.85, 17.1 Hz, 1H), 5.07 (dq, J = 0.85, 10.3 Hz, 1H),
5.75–5.92 (m, 2H), 6.72 (dd, J = 2.5, 8.7 Hz, 1H), 7.02 (d, J =
8.7, 1H), 7.62 (d, J = 2.4 Hz, 1H); 13C NMR (CDCl3, 63 MHz):
d 12.3, 15.0, 45.8, 60.0, 104.0, 106.8, 110.5, 111.9, 117.2, 128.2,
131.4, 132.3, 145.7, 152.1, 166.9; Anal. Calcd for C15H17NO3: C,
69.48; H, 6.61; N, 5.40. Found: C, 69.20; H, 6.63; N, 5.49%.
Ethyl
1-allyl-5-hydroxy-2-propyl◦-1H-indole-3-carboxylate
(10h). Pale brown solid; mp 116–117 C; IR (KBr) 3362, 2964,
Ethyl
1-benzyl-5-hydroxy-2-methyl-1H-indole-3-carboxylate
2870, 1691, 1659, 1525, 1470, 1378, 1247, 1182, 1148, 1115,
(10c). Off-white solid; mp 191–192 ◦C; IR (KBr) 3291, 2971,
1
1031 cm-1; H NMR (CDCl3, 250 MHz): d 1.06 (t, J = 7.2 Hz,
2926, 1644, 1623, 1520, 1475, 1438, 1358, 1293, 1249, 1180, 1142,
3H), 1.46 (t, J = 7.0 Hz, 3H), 1.62–1.72 (m, 2H), 3.10 (t, J =
7.6 Hz, 2H), 4.41 (q, J = 7.0 Hz, 2H), 4.73 (s, 2H), 4.88 (d, J =
17.4 Hz, 1H), 5.19 (d, J = 10.0 Hz, 1H), 5.65 (s, 1H), 5.89–6.00
(m, 1H), 6.82 (d, J = 8.6 Hz, 1H), 7.13 (d, J = 8.6 Hz, 1H), 7.72
(s, 1H); 13C NMR (CDCl3, 63 MHz): d 14.6, 14.9, 23.5, 28.2, 45.9,
60.0, 103.6, 106.8, 110.9, 111.9, 117.3, 128.4, 131.4, 132.8, 149.9,
152.3, 166.6; Anal. Calcd for C17H21NO3: C, 71.06; H, 7.37; N,
4,87. Found: C, 70.86; H, 7.13; N, 5.11%.
1120, 1032 cm-1; H NMR (CDCl3, 250 MHz): d 1.48 (t, J =
1
7.1 Hz, 3H), 2.74 (s, 3H), 4.42 (q, J = 7.1 Hz, 2H), 5.34 (s, 2H),
6.78 (dd, J = 2.5, 8.7 Hz, 1H), 7.00 (dd, J = 2.4, 7.8 Hz, 1H),
7.12 (d, J = 8.7 Hz, 1H), 7.29–7.35 (m, 5H), 7.66 (d, J = 2.5 Hz,
1H); 13C NMR (CDCl3, 63 MHz): d 12.5, 15.0, 47.0, 60.0, 104.4,
106.9, 110.7, 111.9, 126.3, 128.0, 128.2, 129.4, 131.9, 136.7, 146.0,
151.9, 166.7. Anal. Calcd. for C19H19NO3: C, 73.77; H, 6.19; N,
4.53. Found: C, 73.42; H, 6.37; N, 4.47%.
Synthesis of indolequinones 11 and the bromoquinone
intermediates 12
Ethyl 5-hydroxy-2-methyl-1-(prop-2-ynyl)-1H-indole-3-carbo-
xylate (10d). Off-white solid; mp 201–202 ◦C; IR (KBr) 3285,
2985, 1654, 1622, 1528, 1486, 1434, 1378, 1348, 1292, 1249, 1184,
The general procedure for the synthesis of compounds 4 was
employed for the reaction between butylamine 1a, 1,3-dicarbonyl
compounds 2 and 2-bromo-1,4-naphthoquinone 3c for the syn-
thesis of compounds 11 and 12. See Table 4 for reaction times and
catalyst load.
1
1151, 1126, 1034 cm-1; H NMR (DMSO-d6, 250 MHz): d 1.41
(t, J = 6.9 Hz, 3H), 2.14 (s, 1H), 2.78 (s, 3H), 3.42 (s, 2H), 5.15 (q,
J = 7 Hz, 2H), 6.75 (d, J = 7.6 Hz, 1H), 7.44 (s, 2H), 9.08 (s, 1H);
13C NMR (DMSO-d6, 63 MHz): d 12.4, 15.3, 33.1, 59.7, 75.9,
79.5, 103.8, 106.4, 111.4, 112.5, 127.9, 130.5, 145.4, 153.7, 165.9;
Anal. Calcd for C15H15NO3: C, 70.20; H, 5.88; N, 5.44; found: C,
69.90; H, 5.55; N, 5.20%.
Ethyl 1-butyl-2-methyl-4,9-dioxo-4,9-dihydro-1H-benzo[f ]in-
dole-3-carboxylate (11a). Dark brown viscous liquid; IR (neat)
3432 | Org. Biomol. Chem., 2010, 8, 3426–3436
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©

1
2960, 2931, 2865, 1706, 1652, 1273 cm-1; H NMR (CDCl3, 250
General procedure for the introduction of substituents on the C-2
methyl group of 4: synthesis of compounds 13
MHz): d 1.01 (t, J = 4.2 Hz, 3H), 1.39–1.54 (m, 5H), 1.70–1.82
(m, 2H), 2.51 (s, 3H), 4.41–4.50 (m, 4H), 7.65–7.72 (m, 2H),
8.11–8.22 (m, 2H); 13C NMR (CDCl3, 63 MHz): d (two carbons
are merged with others) 11.2, 14.1, 14.6, 20.4, 32.9, 46.2, 61.6,
114.5, 126.2, 126.6, 127.1, 130.4, 133.3, 133.6, 134.2, 165.2, 176.4,
179.9. Anal. Calcd. for C20H21NO4: C, 70.78; H, 6.24; N, 4.13.
Found: C, 70.53; H, 5.98; N, 3.81%.
A solution of compounds 4 (1 mmol) in dry THF (4 mL)
was added to LDA (3 mmol), prepared from BuLi (3.3 mmol)
and diisopropylamine (3 mmol) in dry THF (4 mL), slowly at
-20 ◦C and the reaction mixture was stirred for 30 min at the
same temperature. Allyl iodide or propargyl bromide (2.2 mmol)
was then added and stirring was continued for further 2 h.
The reaction was quenched by adding saturated NH4Cl solution
and extracted with dichloromethane (2 ¥ 10 mL). The organic
layer was washed with brine, dried over anhydrous Na2SO4 and
the solvent was evaporated. The crude mixture was purified by
silica column chromatography eluting with petroleum ether-ethyl
acetate mixture (80 : 20, v/v).
3-Acetyl-1-butyl-2-methyl-1H-benzo[f ]indole-4,9-dione (11b).
Pale yellow solid; mp 115–116 C; IR (KBr) 2960.8, 2930, 2870,
◦
1652, 1592, 1495, 1469, 1433, 1354, 1269, 1210, 1096, 1000 cm-1;
1H NMR (CDCl3, 250 MHz): d 0.86 (t, J = 7.3 Hz, 3H), 1.25–1.40
(m, 2H), 1.55–1.67 (m, 2H), 2.29 (s, 3H), 2.58 (s, 3H), 4.32 (t, J =
7.5 Hz, 2H), 7.55 (dd, J = 3.3, 5.7 Hz, 2H), 7.98 (dd, J = 3.2,
5.8 Hz, 2H); 13C NMR (CDCl3, 63 MHz): d 11.2, 14.2, 20.5, 30.1,
32.1, 32.8, 46.1, 123.2, 125.6, 126.7, 127.0, 129.9, 133.6, 133.7,
133.9, 141.6, 176.4, 181.1, 199.8; Anal. Calcd for C19H19NO3: C,
73.77; H, 6.19; N, 4.53. Found: C, 73.57; H, 6.32; N, 4.15%.
Ethyl
1-allyl-2-(but-3-enyl)-5-hydroxy-1H-benzo[g]indole-3-
carboxylate (13a). Off-white solid; mp 181–182 ◦C; IR (KBr)
3288, 2984, 1635, 1622, 1599, 1512, 1450, 1128, 1072, 987 cm-1;
1H NMR (CDCl3, 250 MHz): d 1.50 (t, J = 7.1 Hz, 3H), 2.46 (q,
J = 6.7 Hz, 2H), 3.29 (t, J = 6.8 Hz, 2H), 4.49 (q, J = 7.1 Hz,
2H), 4.90 (d, J = 17.1 Hz, 1H), 5.09 (d, J = 14.2 Hz, 2H), 5.20 (s,
3H), 5.32 (d, J = 9.4 Hz, 1H), 5.89–6.05 (m, 1H), 6.21–6.32 (m,
1H), 7.46–7.60 (m, 2H), 7.96 (s, 1H), 8.21 (d, J = 8.2 Hz, 1H),
8.42 (d, J = 8.2 Hz, 1H); 13C NMR (CDCl3, 63 MHz): d 15.0,
25.7, 34.4, 48.3, 60.2, 102.8, 105.1, 115.8, 117.9, 120.9, 122.7,
123.5, 123.6, 123.9, 124.9, 125.2, 126.6, 133.0, 137.8, 146.7, 147.9,
166.6; Anal. Calcd for C22H23NO3: C, 75.62; H, 6.63; N, 4.01.
Found: C, 75.36; H, 6.53; N, 3.74%.
3-Acetyl-1-benzyl-2-methyl-1H-benzo[f ]indole-4,9-dione (11c).
Yellow solid; mp 163–164 ◦C; IR (neat) 1651, 1591, 1496,
1269 cm-1; H NMR (CDCl3, 250 MHz): d 2.39 (s, 3H), 2.76
1
(s, 3H), 5.86 (s, 3H), 7.11 (d, J = 8.0 Hz, 2H), 7.29–7.38 (m,
3H), 7.70–7.74 (m, 2H), 8.12–8.20 (m, 2H); 13C NMR (CDCl3, 63
MHz): d 11.3, 32.1, 49.2, 123.5, 125.7, 126.6, 126.8, 127.1, 128.2,
129.4, 130.2, 133.6, 133.7, 133.8, 133.9, 135.9, 142.4, 176.6, 181.1,
199.6; Anal. Calcd. for C22H17NO3: C, 76.95; H, 4.99; N, 4.08.
Found: C, 76.72; H, 4.82; N, 4.01%.
3-Acetyl-1-allyl-2-methyl◦-1H-benzo[f ]indole-4,9-dione (11d).
Methyl 1-allyl-2-(but-3-enyl)-5-hydroxy-1H-benzo[g]indole-3-
carboxylate (13b). Off-white solid; mp 181–182 ◦C; IR (KBr)
Yellow solid; mp 117–118 C; IR (neat) 1652, 1591, 1496, 1430,
1
1270, 1210 cm-1; H NMR (CDCl3, 250 MHz): d 2.42 (s, 3H),
1
3311, 2985, 1638, 1598, 1450, 1334, 1243, 1126, 999 cm-1; H
2.74 (s, 3H), 4.97 (d, J = 17.1 Hz, 1H), 5.21 (t, J = 12.3 Hz, 3H),
5.94–6.09 (m, 1H), 7.69 (m, 2H), 8.10–8.16 (m, 2H); 13C NMR
(CDCl3, 63 MHz): d 10.9, 32.1, 48.0, 117.6, 123.2, 125.5, 126.7,
127.0, 129.9, 132.2, 133.5, 133.6, 133.7, 133.9, 142.1, 176.4, 181.0,
199.6; Anal. Calcd. for C18H15NO3: C, 73.71; H, 5.15; N, 4.78.
Found: C, 73.45; H, 5.06; N, 4. 68%.
NMR (CDCl3, 250 MHz): d 2.46 (q, J = 6.7 Hz, 2H), 3.28 (t,
J = 5.4 Hz, 2H), 4.03 (s, 3H), 4.90 (d, J = 17.1 Hz, 1H), 5.09
(d, J = 10.1 Hz, 1H), 5.19 (s, 3H), 5.33 (d, J = 10.5 Hz, 1H),
5.89–6.05 (m, 1H), 6.19–6.33 (m, 1H), 6.58 (s, 1H), 7.47–7.60
(m, 2H), 8.02 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.45 (d, J =
8.2 Hz, 1H); 13C NMR (CDCl3, 63 MHz): d 25.7, 34.4, 48.3, 51.5,
102.8, 104.9, 115.9, 117.9, 121.0, 122.8, 123.4, 123.6, 123.9, 124.9,
125.2, 126.6, 133.0, 137.8, 146.9, 148.1, 167.0; Anal. Calcd for
C21H21NO3: C, 75.20; H, 6.31; N, 4.18. Found: C, 74.84; H, 6.28; N,
4.02%.
3-Acetyl-2-methyl-1-(prop-2-ynyl)-1H-benzo[f ]indole-4,9-dione
(11e). Yellow solid; mp 194–195 ◦C; IR (neat) 1668, 1653, 1592,
1494, 1267, 1210, 1104 cm-1; 1H NMR (CDCl3, 250 MHz): d 2.40
(t, J = 2.3 Hz, 1H), 2.55 (s, 3H), 2.75 (s, 3H), 5.44 (d, J = 2.3 Hz,
2H), 7.71–7.77 (m, 2H), 8.15–8.20 (m, 2H); 13C NMR (CDCl3, 63
MHz): d 10.6, 31.6, 34.8, 73.5, 121.1, 122.8, 125.1, 126.2, 126.6,
128.8, 132.8, 133.2, 133.4, 141.6, 176.1, 180.4, 198.8; Anal. Calcd.
for C18H13NO3: C, 74.22; H, 4.50; N, 4.81. Found: C, 73.92; H,
4.39; N, 4.78%.
Ethyl
1-allyl-2-(but-3-ynyl)-5-hydroxy-1H-benzo[g]indole-3-
carboxylate (13c). Off-white solid; mp 201–202 ◦C; IR (KBr)
3302, 2982, 1646, 1624, 1600, 1518, 1450, 1334, 1244, 1128,
1
1074 cm-1; H NMR (CDCl3, 250 MHz): d 1.50 (t, J = 7.1 Hz,
3H), 2.03 (q, J = 2.6 Hz, 1H), 2.67 (t, J = 7.7 Hz, 2H), 3.43 (t,
J = 7.5 Hz, 2H), 4.50 (q, J = 7.0 Hz, 2H), 4.85 (d, J = 17.8 Hz,
1H), 5.32 (s, 3H), 6.22–6.34 (m, 1H), 7.47–7.61 (m, 2H), 7.99 (s,
1H), 8.21 (d, J = 8.2 Hz, 1H), 8.43 (d, J = 8.0 Hz, 1H); 13C NMR
(CDCl3, 63 MHz): d 14.9, 19.5, 25.3, 48.5, 60.5, 69.9, 83.6, 102.6,
105.4, 117.9, 120.9, 122.8, 123.6, 123.8, 123.9, 124.9, 125.3, 126.7,
133.0, 144.9, 148.3, 166.5; Anal. Calcd for C22H21NO3: C, 76.06;
H, 6.09; N, 4.03. Found: C, 75.86, H, 5.85; N, 4.05%.
(E)-Ethyl 2-(3-bromo-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-3-
(butylamino)but-2-enoate (12a). Pale brown solid; mp 98–99 ◦C;
IR (KBr) 2962, 2929, 1682, 1599, 1464, 1382, 1278, 1242, 1160,
1
1067 cm-1; H NMR (CDCl3, 250 MHz): d 0.99 (t, J = 7.2 Hz,
3H), 1.10 (t, J = 7.1 Hz, 3H), 1.40–1.55 (m, 2H), 1.61–1,72 (m,
2H), 1.87 (s, 3H), 3.32 (q, J = 6.7 Hz, 2H), 4.07 (q, J = 7.1 Hz,
2H), 7.73–7.81 (m, 2H), 8.13–8.23 (m, 2H), 9.67 (s, 1H); 13C NMR
(CDCl3, 63 MHz): d 14.2, 14.8, 17.4, 20.5, 32.4, 43.7, 59.6, 90.9,
124.6, 127.7, 127.8, 131.9, 132.5, 134.0, 134.4, 150.1, 161.6, 168.1,
179.1, 182.8. Anal. Calcd. for C20H22BrNO4: C, 57.15; H, 5.28; N,
3.33. Found: C, 57.07; H, 5.20; N, 3.52%.
Methyl 1-allyl-2-(but-3-ynyl)-5-hydroxy-1H-benzo[g]indole-3-
carboxylate (13d). Pale brown solid; mp 160–161 ◦C; IR (KBr)
3299, 2984, 1648, 1624, 1600, 1522, 1449, 1407, 1335, 1244, 1124,
1
1072 cm-1; H NMR (CDCl3, 250 MHz): d 2.02 (s, 1H), 2.66
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(t, J = 7.1 Hz, 2H), 3.43 (t, J = 7.3 Hz, 2H), 4.02 (s, 3H), 4.88
(d, J = 17.2 Hz, 1H), 5.16–5.33 (m, 3H), 6.23–6.34 (m, 1H), 7.47–
7.60 (m, 2H), 7.90 (s, 1H), 8.21 (d, J = 8.2 Hz, 1H), 8.42 (d, J =
8.1 Hz, 1H); 13C NMR (CDCl3, 63 MHz): d 19.3, 25.0, 48.6, 51.5,
69.9, 83.6, 102.8, 105.4, 117.9, 121.0, 122.8, 123.6, 123.7, 123.9,
124.6, 125.4, 126.8, 132.9, 145.3, 148.0, 166.7; Anal. Calcd for
C21H19NO3: C, 75.66; H, 5.74; N, 4.20. Found: C, 75.34; H, 5.92;
N, 4.21%.
125.2, 126.7, 128.2, 129.1, 130.0, 130.8, 132.9, 134.0, 137.7, 142.8,
147.7, 165.9, 166.2; Anal. Calcd for C29H27NO4: C, 76.80; H, 6.00;
N, 3.09. Found: C, 76.64; H, 5.97; N, 3.26%.
Methyl
1-allyl-5-(benzoyloxy)-2-(but-3-enyl)-1H-benzo[g]in-
dole-3-carboxylate (14d). Off-white solid; mp 118–119 ◦C; IR
(KBr) 2930, 1734, 1697, 1623, 1526, 1246, 1192, 1115, 1088,
1
1068 cm-1; H NMR (CDCl3, 250 MHz): d 2.47 (q, J = 6.9 Hz,
2H), 3.34 (t, J = 7.8 Hz, 2H), 3.98 (s, 3H), 4.94 (d, J = 17.2 Hz,
1H), 5.10 (d, J = 15.6 Hz, 1H), 5.21 (d, J = 15.7 Hz, 3H), 5.35
(d, J = 10.6 Hz, 1H), 5.90–6.06 (m, 1H), 6.22–6.36 (m, 1H),
7.44–7.76 (m, 5H), 8.03 (d, J = 8.1 Hz, 1H), 8.23–8.31 (m, 2H),
8.40 (d, J = 7.4 Hz, 2H); 13C NMR (CDCl3, 63 MHz): d 25.5,
34.3, 48.4, 51.4, 106.2, 113.9, 116.0, 118.2, 121.7, 122.7, 123.0,
123.6, 124.6, 125.2, 126.7, 128.2, 129.1, 130.0, 130.8, 132.8, 134.1,
137.7, 142.9, 148.1, 166.2, 166.3; Anal. Calcd for C28H25NO4: C,
76.52; H, 5.73; N, 3.19. Found: C, 76.31; H, 5.91; N, 3.32%.
General procedure for the acetylation and benzoylation of
compounds 13: synthesis of compounds 14
To a stirred suspension of compound 13 (1 mmol) and BiOCl
(5–10 mol%) in dichloromethane (3 mL) under argon was added
acetyl or benzoyl chloride (2 mmol) at room temperature. The
reaction was completed in 20 min as indicated by tlc. The
mixture was diluted with dichloromethane (10 mL), washed with
saturated NaHCO3 solution, water and brine. The organic layer
was dried over anhydrous Na2SO4 and the solvent was evaporated.
Purification of the crude mixture by Al2O3 (neutral, activity grade
II-III) column chromatography eluting with petroleum ether–ethyl
acetate mixture (85 : 15, v/v) gave the compounds 14.
Ethyl
5-acetoxy-1-allyl-2-(but-3-ynyl)-1H-benzo[g]indole-3-
carboxylate (14e). Pale brown viscous liquid; IR (neat) 2984,
1
1760, 1694, 1625, 1527, 1418, 1366, 1208, 1112, 1058 cm-1; H
NMR (CDCl3, 250 MHz): d 1.52 (t, J = 7.1 Hz, 3H), 2.03 (d,
J = 2.5 Hz, 1H), 2.55 (s, 3H), 2.70 (t, J = 7.2 Hz, 2H), 3.45 (t,
J = 6.9 Hz, 2H), 4.49 (q, J = 7.1 Hz, 2H), 4.90 (d, J = 16.7 Hz,
1H), 5.33 (s, 3H), 6.24–6.36 (m, 1H), 7.49–7.59 (m, 2H), 7.98
(d, J = 7.8 Hz, 1H), 8.18 (s, 1H), 8.27 (d, J = 8.0 Hz, 1H); 13C
NMR (CDCl3, 63 MHz): d 13.5, 17.9, 20.0, 23.5, 47.1, 58.8, 68.6,
82.0, 105.2, 112.2, 116.6, 120.2, 121.2, 121.5, 122.1, 123.2, 123.7,
125.3, 126.8, 131.3, 141.3, 144.7, 164.2, 169.1; Anal. Calcd for
C24H23NO4: C, 74.02; H, 5.95; N, 3.60. Found: C, 73.85; H, 5.88;
N, 3.47%.
Ethyl
5-acetoxy-1-allyl-2-(but-3-enyl)-1H-benzo[g]indole-3-
carboxylate (14a). Off-white solid; mp 101–102 ◦C; IR (KBr)
2982, 1761, 1693, 1527, 1418, 1365, 1206, 1149 cm-1; H NMR
1
(CDCl3, 250 MHz): d 1.49 (t, J = 7.1 Hz, 3H), 2.41–2.53 (m, 5H),
3.31 (t, J = 7.6 Hz, 2H), 4.46 (q, J = 7.1 Hz, 2H), 4.91 (d, J =
17.1 Hz, 1H), 5.05 (d, J = 10.8 Hz, 1H), 5.19 (d, J = 10.6 Hz,
3H), 5.33 (d, J = 10.5 Hz, 1H), 5.88–6.04 (m, 1H), 6.22–6.33
(m, 1H), 7.47–7.60 (m, 2H), 7.96 (d, J = 7.9 Hz, 1H), 8.18 (s,
1H), 8.27 (d, J = 8.7 Hz, 1H); 13C NMR (CDCl3, 63 MHz): d
15.0, 21.5, 25.5, 34.3, 48.3, 60.1, 106.3, 113.7, 115.9, 118.2, 121.6,
122.6, 122.9, 123.8, 124.5, 125.0, 126.6, 128.2, 132.8, 137.7, 142.6,
147.7, 165.8, 170.6; Anal. Calcd for C24H25NO4: C, 73.64; H, 6.44;
N, 3.58. Found: C, 73.39; H, 6.40; N, 3.71%.
Methyl 5-acetoxy-1-allyl-2-(but-3-ynyl)-1H-benzo[g]indole-3-
carboxylate (14f). Off-white solid; mp 95–96 ◦C; IR (KBr) 3294,
2950, 1760, 1698, 1624, 1528, 1435, 1397, 1365, 1268, 1207, 1150,
1
1115, 1058 cm-1; H NMR (CDCl3, 250 MHz): d 2.01 (t, J =
2.6 Hz, 1H), 2.52 (s, 3H), 2.68 (t, J = 7.2 Hz, 2H), 3.45 (t, J =
7.3 Hz, 2H), 4.00 (s, 3H), 4.90 (d, J = 17 Hz, 1H), 5.32–5.35 (m,
3H), 6.22–6.36 (m, 1H), 7.48–7.61 (m, 2H), 7.97 (d, J = 8.0 Hz,
1H), 8.13 (s, 1H), 8.27 (d, J = 8.1 Hz, 1H); 13C NMR (CDCl3,
63 MHz): d 19.2, 21.5, 24.8, 48.6, 51.5, 70.1, 83.5, 106.5, 113.7,
118.1, 121.7, 122.7, 122.9, 123.4, 124.7, 125.2, 126.8, 128.3, 132.8,
142.8, 146.5, 166.2, 170.6; Anal. Calcd for C23H21NO4: C, 73.58;
H, 5.64; N, 3.73. Found: C, 73.24; H, 5.65; N, 3.98%.
Methyl 5-acetoxy-1-allyl-2-(but-3-enyl)-1H-benzo[g]indole-3-
carboxylate (14b). Off-white solid; mp 115–116 ◦C; IR (KBr)
2949, 1760, 1698, 1528, 1435, 1397, 1365, 1207, 1113, 1058 cm-1;
1H NMR (CDCl3, 250 MHz): d 2.41–2.53 (m, 5H), 3.32 (t, J =
7.7 Hz, 2H), 3.99 (s, 3H), 4.91 (d, J = 17.0 Hz, 1H), 5.06 (d, J =
10.4 Hz, 1H), 5.20 (d, J = 10.9 Hz, 3H), 5.34 (d, J = 10.7 Hz,
1H), 5.88–6.01 (m, 1H), 6.22–6.33 (m, 1H), 7.47–7.60 (m, 2H),
7.97 (d, J = 7.9 Hz, 1H), 8.15 (s, 1H), 8.26 (d, J = 8.3 Hz, 1H);
13C NMR (CDCl3, 63 MHz): d (one aromatic carbon is merged
with others) 22.2, 26.2, 34.9, 49.0, 52.0, 114.4, 116.7, 118.9, 122.4,
123.4, 123.6, 124.2, 125.2, 125.7, 127.3, 128.9, 133.4, 138.3, 143.3,
148.7, 166.9, 171.3; Anal. Calcd for C23H23NO4: C, 73.19; H, 6.14;
N, 3.71. Found: C, 72.90; H, 6.20; N, 3.83%.
General procedure for the ring-closing metathesis reaction of
compounds 14: synthesis of 9,12-dihydro-8H-
azepino[1,2-a]benzo[g]indole derivatives 15
To a stirred solution of compounds 14 (0.5 mmol) in dry
dichloromethane (2 mL) was added Grubbs 1st generation catalyst
(10 mol%) and stirring was continued for 3 h at room temperature
under argon atmosphere. After completion of the reaction the
solvent was evaporated and the crude mixture was purified by
Al2O3 (neutral, activity grade II–III) column chromatography
using petroleum ether–ethyl acetate mixture (80 : 20, v/v) as
eluent.
Ethyl 1-allyl-5-(benzoyloxy)-2-(but-3-enyl)-1H-benzo[g]indole-
3-carboxylate (14c). Off-white solid; mp 115–116 ◦C; IR (KBr)
3073, 2981, 1738, 1694, 1527, 1451, 1418, 1247, 1192, 1112, 1087,
1
1021 cm-1; H NMR (CDCl3, 250 MHz): d 1.49 (t, J = 7.1 Hz,
3H), 2.48 (q, J = 6.7 Hz, 2H), 3.30–3.36 (m, 2H), 4.45 (q, J =
7.1 Hz, 2H), 4.90–5.37 (m, 6H), 5.90–6.05 (m, 1H), 6.22–6.35 (m,
1H), 7.43–7.64 (m, 4H), 7.75 (tt, J = 1.3, 8.6 Hz, 1H), 8.03 (dd,
J = 1.1, 8.2 Hz, 1H), 8.28 (d, J = 8.0 Hz, 2H), 8.42 (dd, J = 1.5,
8.5 Hz, 2H); 13C NMR (CDCl3, 63 MHz): d 15.0, 25.6, 34.3, 48.3,
60.1, 106.4, 113.9, 115.9, 118.1, 121.6, 122.7, 123.0, 123.8, 124.5,
Ethyl 5-acetoxy-9,12-dihydro-8H-azepino[1,2-a]benzo[g]indole-
7-carboxylate (15a). Off-white solid; mp 138–139 ◦C; IR (KBr)
3436, 3023, 2901, 1762, 1619, 1623, 1542, 1450, 1364, 1204, 1107,
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1
1058 cm-1; H NMR (CDCl3, 250 MHz): d 1.44 (t, J = 7.1 Hz,
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Kunkel, J. P. Springer and J. Hirshfield, J. Med. Chem., 1988, 31, 2235–
2246.
5 For selected reviews on indole synthesis, see: (a) G. W. Gribble, J. Chem.
Soc., Perkin Trans. 1, 2000, 1045–1075; (b) G. R. Humphrey and J. T.
Kuethe, Chem. Rev., 2006, 106, 2875–2911; For a recent review on
more sustainable approaches for the synthesis of N-based heterocycles
including indoles, see: (c) N. R. Candeias, L. C. Branco, P. M. P. Gois,
C. A. M. Afonso and A. F. Trindade, Chem. Rev., 2009, 109, 2703–2802.
6 For a comprehensive review on the synthesis and functionalization of
indoles through palladium-catalyzed reactions, see: S. Cacchi and G.
Fabrizi, Chem. Rev., 2005, 105, 2873–2920.
3H), 2.52 (s, 5H), 3.76 (s, 2H), 4.45 (q, J = 7.1 Hz, 2H), 5.30 (s,
2H), 5.87 (d, J = 11.3 Hz, 1H), 6.01 (s, 1H), 7.46–7.60 (m, 2H),
7.96 (d, J = 8.0 Hz, 1H), 8.11 (s, 1H), 8.32 (d, J = 8.3 Hz, 1H); 13
C
NMR (CDCl3, 63 MHz): d 15.0, 21.5, 23.0, 28.8, 44.3, 60.1, 105.4,
113.9, 121.0, 122.5, 122.8, 123.1, 123.2, 124.4, 125.0, 126.4, 128.2,
134.9, 142.3, 149.9, 166.2, 170.6; Anal. Calcd for C22H21NO4: C,
72.71; H, 5.82, N, 3.85. Found: C, 72.52; H, 5.90; N, 3.89%.
Methyl 5-acetoxy-9,12-dihydro-8H-azepino[1,2-a]benzo[g]in-
dole-7-carboxylate (15b). Off-white solid; mp 167–168 ◦C; IR
(KBr) 3430, 3028, 2944, 1753, 1693, 1622, 1543, 1430, 1396, 1365,
1205, 1111, 1059 cm-1; H NMR (CDCl3, 250 MHz): d 2.53 (s,
5H), 3.77 (q, J = 5.6 Hz, 2H), 3.99 (s, 3H), 5.31 (d, J = 7.3 Hz,
2H), 5.89 (d, J = 11.3 Hz, 1H), 6.01 (s, 1H), 7.47–7.61 (m, 2H),
7.97 (d, J = 8.1 Hz, 1H), 8.10 (s, 1H), 8.33 (s, 1H); 13C NMR
(CDCl3, 63 MHz): d (one aromatic carbon is merged with others)
21.5, 23.0, 28.8, 44.3, 51.4, 105.2, 113.9, 121.0, 122.5, 122.8, 123.1,
124.5, 125.0, 126.4, 128.2, 134.8, 142.3, 150.0, 166.6, 170.7; Anal.
Calcd for C21H19NO4: C, 72.19; H, 5.48; N, 4.01. Found: C, 71.84;
H, 5.55; N, 4.01%.
1
Ethyl 5-(benzoyloxy)-9,12-dihydro-8H-azepino[1,2-a]benzo[g]in-
dole-7-carboxylate (15c). Off-white solid; mp 168–169 ◦C; IR
(KBr) 2978, 2926, 1737, 1694, 1623, 1540, 1450, 1402, 1301, 1247,
1179, 1111, 1088 cm-1; H NMR (CDCl3, 250 MHz): d 1.46 (t,
J = 7.0 Hz, 3H), 2.58 (m, 2H), 3.81 (t, J = 6.0 Hz, 2H), 4.44 (q,
J = 7.0 Hz, 2H), 5.36 (m, 2H), 5.88–5.94 (m, 1H), 6.02–6.09 (m,
1H), 7.43–7.76 (m, 5H), 8.02 (d, J = 8.2 Hz, 1H), 8.22 (s, 1H),
8.36–8.42 (m, 3H); 13C NMR (CDCl3, 63 MHz): d (four aromatic
carbons are merged with others) 15.0, 23.0, 28.8, 44.3, 60.1, 105.5,
114.0, 121.0, 122.6, 122.9, 123.3, 124.5, 125.2, 126.4, 128.2, 129.1,
130.0, 130.8, 134.0, 134.9, 142.5, 149.9, 166.2; Anal. Calcd for
C27H23NO4: C, 76.22; H, 5.45; N, 3.29; found: C, 75.97; H, 5.48;
N, 3.30%.
1
7 For a review of Nenitzescu reaction, see: S. A. Patil, R. Ratil and D. D.
Miller, Curr. Org. Chem., 2008, 12, 691–717.
8 For selected examples of the Nenitzescu reaction, see: (a) J. M. Pawlak,
V. V. Khau, D. R. Hutchison and M. J. Martinelli, J. Org. Chem., 1996,
61, 9055–9059; (b) D. M. Ketcha, L. J. Wilson and D. E. Portlock,
Tetrahedron Lett., 2000, 41, 6253–6257.
9 For some medicinal applications of 5-hydroxyindole derivatives, see:
(a) Shefali, S. K. Srivastava, S. M. Husbands and J. W. Lewis, J. Med.
Chem., 2005, 48, 635–638; (b) J. Landwehr, S. George, E.-M. Karg, D.
Poeckel, D. Steinhilber, R. Troschu¨tz and O. Werz, J. Med. Chem., 2006,
49, 4327–4332; (c) E.-M. Karg, S. Luderer, C. Pergola, U. Bu¨hring, A.
Rossi, H. Northoff, L. Sautebin, R. Troschu¨tz and O. Werz, J. Med.
Chem., 2009, 52, 3474–3483.
10 For selected reviews and monographs on multicomponent reactions,
see: (a) A. Do¨mling and I. Ugi, Angew. Chem. Int. Ed., 2000, 39, 3168–
3210; (b) D. J. Ramo´n and M. Yus, Angew. Chem., Int. Ed., 2005, 44,
1602–1634; (c) Multicomponent Reactions, ed. J. Zhu and H. Bienayme´,
Wiley-VCH: Weinheim, 2005; (d) A. Do¨mling, Chem. Rev., 2006, 106,
17–89.
Methyl 5-(benzoyloxy)-9,12-dihydro-8H-azepino[1,2-a]benzo-
[g]indole-7-carboxylate (15d). Off-white solid; mp 199–200 ◦C;
IR (KBr) 2926, 1734, 1698, 1623, 1601, 1542, 1450, 1396, 1248,
1190, 1114, 1087, 1068, 1020 cm-1; 1H NMR (CDCl3, 250 MHz):
d 2.58–2.60 (m, 2H), 3.82 (t, J = 6.0 Hz, 2H), 3.96 (s, 3H), 5.36 (d,
J = 5.0 Hz, 2H), 5.88–5.96 (m, 1H), 6.03–6.11 (m, 1H), 7.43–7.76
(m, 5H), 8.01 (d, J = 8.4 Hz, 1H), 8.19 (s, 1H), 8.37–8.42 (m,
3H); 13C NMR (CDCl3, 63 MHz): d 23.0, 28.8, 44.3, 51.3, 105.3,
114.1, 121.0, 122.5, 122.9, 123.2, 123.3, 124.5, 125.3, 126.5, 128.2,
129.1, 130.0, 130.8, 134.0, 134.9, 142.6, 150.1, 166.3, 166.6; Anal.
Calcd for C26H21NO4: C, 75.90; H, 5.14; N, 3.40. Found: C, 75.64;
H, 5.38; N, 3.35%.
Acknowledgements
11 For recent selected examples of CAN-catalyzed reactions, see: (a) V.
Sridharan, S. Maiti and J. C. Mene´ndez, J. Org. Chem., 2009, 74, 9365–
9371; (b) V. Sridharan, P. Ribelles, M. T. Ramos and J. C. Mene´ndez,
J. Org. Chem., 2009, 74, 5715–5718; (c) V. Sridharan, S. Maiti and J. C.
Mene´ndez, Chem.–Eur. J., 2009, 15, 4565–4572; (d) V. Sridharan and
J. C. Mene´ndez, Org. Lett., 2008, 10, 4303–4306; (e) V. Sridharan, C.
Avendan˜o and J. C. Mene´ndez, Synlett, 2007, 881–884; For a review,
see: (f) V. Sridharan and J. C. Mene´ndez, Chem. Rev., 2010, 110,
DOI: 10.1021/cr100004p.
Financial support from MICINN (grant CTQ2009-12320-BQU)
and UCM (Grupos de Investigacio´n, grant 920234) is gratefully
acknowledged.
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