Synthesis of 4- and 6-substituted nitroindoles

Article abstract of DOI:10.1016/j.tet.2003.11.011

Enolizable ketones react with m-nitroaniline in the presence of strong base such as t-BuOK to give 4- and 6-substituted nitroindoles. The reaction proceeds via oxidative nucleophilic substitution of hydrogen in m-nitroaniline with enolate anions in positions ortho to the amino group giving anionic σ^H adducts that are additionally stabilized by intramolecular interaction between the amino and the carbonyl group. Spontaneous oxidation of the σ^H adducts followed by the Bayer type condensation of the produced ortho-aminonitrobenzyl ketones gives 4- and 6-substituted nitroindoles. The scope of this reaction and its basic mechanistic features are discussed.

Full text of DOI:10.1016/j.tet.2003.11.011

Tetrahedron 60 (2004) 347–358
Synthesis of 4- and 6-substituted nitroindoles
*
Nikolai Moskalev, Michał Barbasiewicz and Mieczysław Ma˛kosza
Institute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44, PO Box 58, 01-224 Warszawa 42, Poland
Received 5 September 2003; revised 17 October 2003; accepted 6 November 2003
Abstract—Enolizable ketones react with m-nitroaniline in the presence of strong base such as t-BuOK to give 4- and 6-substituted
nitroindoles. The reaction proceeds via oxidative nucleophilic substitution of hydrogen in m-nitroaniline with enolate anions in positions
ortho to the amino group giving anionic sH adducts that are additionally stabilized by intramolecular interaction between the amino and the
carbonyl group. Spontaneous oxidation of the sH adducts followed by the Bayer type condensation of the produced ortho-aminonitrobenzyl
ketones gives 4- and 6-substituted nitroindoles. The scope of this reaction and its basic mechanistic features are discussed.
q 2003 Elsevier Ltd. All rights reserved.
Numerous important natural products, drugs, plant protec-
tion agents, dyes, etc.1,2 contain the indole ring system and,
therefore, great attention is continuously directed towards
novel, efficient methods of indole synthesis.3 Although
many methods of construction of the indole ring system are
known, new and simple processes serving this purpose are
in great demand.4 Of particular interest are simple and
efficient methods of the synthesis of indoles containing
various substituents in defined positions of the five and six
membered rings of the indole. Since the nitro group is one of
the most versatile substituents, which can be converted into
many other functionalities and also can promote numerous
reactions,5 synthesis of nitroindoles deserves special atten-
tion.6 There are many ways of synthesising nitroindoles: via
nitration of indoles under various conditions,7 Fischer
cyclization of starting materials containing the nitro
group,8 Bergman approach, utilizing 2-methyl-3-nitroani-
lines, etc.9 One of the most general and versatile approach to
the nitroindole ring construction appears to be nucleophilic
substitution of hydrogen (NSH) in nitroarenes with carbon
nucleophiles and subsequent cyclizations.10 Thus, vicarious
nucleophilic substitution of hydrogen (VNS) in m-nitro-
benzoisonitriles with chloromethyl aryl sulfones followed
by cyclization directly gives substituted 4- and/or 6-nitro-
indoles.11a To this category belongs the cyclization of
3-nitroanilides of chloroacetic acid via intramolecular
VNS,11b and intramolecular oxidative nucleophilic substi-
tution of hydrogen (ONSH) in m-nitroacetanilides and their
analogues, leading to nitrooxindoles.11c
simpler method of synthesis of 4- and/or 6-nitroindoles—
the direct condensation of 3-nitroanilines with ketones.12
A similar reaction of 3-nitroaniline 1a with aliphatic nitriles
results in formation of 2-amino-4-nitro- and 2-amino-6-
nitroindoles.13 The reaction apparently proceeds via ONSH
in the nitroaromatic ring with the respective carbanions,
followed by intramolecular reaction of the amino group with
the carbonyl or the cyano groups. The process seems to be
directed and assisted by an interaction between these groups
within the sH adduct and/or in the course of the addition
process.
In this paper, a full account of our studies on the synthesis of
nitroindoles via this interesting and useful reaction between
ketones and nitroanilines is presented.
Nucleophilic substitution of hydrogen in nitroarenes with
carbon, nitrogen or oxygen nucleophiles is a well known
and established process. Formation of anionic sH adducts
and further oxidative or eliminative transformations of
these short lived intermediates are accepted mechanistic
features.14,15
Reactions of enolate anions with nitroarenes have been
studied for more than 100 years. Reaction of acetone enolate
with m-dinitrobenzene to form a sH adduct and its subse-
quent oxidation with an excess of the nitroarene to
dinitrobenzyl methyl ketone are known as the Janovsky
and the Zimmerman reactions, respectively.16 ONSH in
simple mononitroarenes: nitrobenzene, p-chloronitrobenzene
etc. with the enolate of acetophenone was reported by
Hamana.17 Fluoride anion promoted reaction of trimethyl-
silyl enol ethers with nitroarenes produces sH adducts of the
respective enolates that appear to be additionally stabilized
by O-silylation of the nitro group. These sH adducts can be
In our preliminary communication, we reported a much
Keywords: Enolates; Indoles; Nitroarenes; Nucleophilic addition.
*
Corresponding author. Tel.: þ48-22-6318788; fax: þ48-22-6326681;
e-mail address: icho-s@icho.edu.pl
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.11.011

348
N. Moskalev et al. / Tetrahedron 60 (2004) 347–358
Scheme 1.
further oxidized to give products of ONSH in nitroarenes
with enolate anions.18 Reductive cyclization of the o-
nitrobenzyl ketones obtained in this way provides the
corresponding indoles.18 Addition of enolates of some a-
haloketones to nitroarenes leads to sH adducts that undergo
base induced b-elimination of hydrogen halide giving
products of VNS–nitrobenzyl ketones.19 There are many
examples of reactions of polynitroarenes with ketones
producing bi- and tricyclic adducts, some of them found
application in synthesis.20 However, to the best of our
knowledge, there are no preceeding reports on reactions of
enolates with m-nitroanilines.
3- we have observed a strong preference for replacement of
hydrogen in position 2- for Z¼halogens, OMe, Me, NMe2,
etc. and discussed reasons for such orientation.21
Under similar conditions a variety of other ketones react
with 1a giving 4- and 6-nitroindoles. The DMSO/t-BuOK
system appears to be a reagent of choice for this
transformation. Indeed, acetophenone reacts satisfactorily
with 1a in the presence of t-BuOK in DMSO, whereas in
THF, Et2O, PhCl and CH2Cl2 only traces of the expected
indoles were produced, and most of the reactants were
recovered. DMF and HMPT are acceptable, but less
practical solvents, because of decomposition of the former
and toxicity of the latter. The reactions of 1a with a variety
of ketones 2–16 in DMSO are presented in Scheme 1 and
Table 1.
1. Results and discussion
Treatment of a solution of 3-nitroaniline 1a and acetone 2 in
DMSO with t-BuOK results in a moderately exothermic
reaction and dark-red coloration of the mixture. Acidifica-
tion of the mixture and standard work up gave 2-methyl-4-
nitroindole 2a with a minor amount of the isomeric 6-
nitroindole. Thus, the overall result is that hydrogen in
position 2- and 6- of 1a (ortho- and para- to the NO2 and
ortho- to the NH2 group) has been replaced with the acetone
moiety. This unusual orientation in the reaction-preference
of the nucleophilic addition of the enolate to the most
hindered position 2- of 3-nitroaniline is well precedented in
the nucleophilic substitution of hydrogen in nitroarenes.
During our previous studies of the VNS reaction in
nitroarenes containing a variety of substituents Z in position
All methyl ketones CH3COR in which R does not contain
acidic hydrogen atoms, in the reaction with 1a form
predominantly 4-nitro-2-R-indoles 2a–9a resulted from
addition of the enolates to position 2- of 3-nitroaniline.
The observation that these ketones react exclusively in
position 2-, reported in our preliminary communication,12
was only partially confirmed in the present studies. Thus, in
the reaction of 1a with acetone 2 and acetophenone 5 we
were also able to isolate minor quantities (7 and 8%), of 6-
nitro-2-methyl and 6-nitro-2-phenyl-indoles 2a6 and 5a6.
One cannot exclude that in the reactions of 1a with some
other methyl ketones small quantities of substituted 6-
nitroindoles are also formed, but they were not isolated in

N. Moskalev et al. / Tetrahedron 60 (2004) 347–358
349
Table 1. Substituted 4- and 6-nitroindoles obtained from 1a and ketones 2–
16 as in Scheme 1
an intermediate stage, whereas the final products—the
chloronitroindoles are stable under the reaction conditions.
As one could expect the dehalogenation process proceeded
to a much higher degree in the case of the analogous
bromoaniline. The reaction of 6-bromo-3-nitroaniline 1c
with acetophenone 5 gave the expected 2-phenyl-4-nitro-7-
bromoindole 5c and the debrominated product 5a in almost
equal amounts. Similarly to chloroindole 5b, bromoindole
5c was stable under the reaction conditions, and the
debromination product 5a was not detected by TLC when
5a was treated with t-BuOK in DMSO.
Ketone
Products and
yields (%)
Ketone
Products and yields
(%)
2
3
4
5
2a, 58
2a6, 7
10
11
12
13
14
15
16
10a, 32
11a, 33
12a, 16
13a, 16
14a, 34
15a, 23
16a, 24
10a6, 26
11a6, 30
12a6, 38
13a6, 12
14a6, 13
15a6, 13
16a6, 12
a
3a, 60
4a, 42
5a, 67
6a, 53
7a, 50
8a, 50
9a, 12
a
5a6, 8
a
6
7b
8b
9c
a
a
a
a
Small amounts (,5%) of 6-nitroindoles are perhaps formed but not
isolated and identified.
Reactions were performed with 3-fold excess of 1a to ketone.
Reaction with 2-acetylpyrrole failed, ketone was N-methylated with CH3I
and then reaction with 1a and t-BuOK was performed.
The reactions of enolates with fluoronitro anilines were
somewhat more complicated, because of the competing
process of nucleophilic substitution of halogen. The
observed formation of the expected fluoronitroindoles via
ONSH reaction was the major process, however, nitro-
indoles derived from SNAr of fluorine were also isolated.
Thus, in the reaction of 6-fluoro-3-nitro aniline 1d with
acetophenone 5 besides the expected 7-fluoro-2-phenyl-4-
nitro-indole 5d some amount of 6-nitro-2-phenylindole 5a,
identical to that obtained from 1a and 5, was produced
(Scheme 2, Table 2).
b
c
routine column chromatography separation technique.
Interestingly, the reaction of 1a with methyl ethyl ketone
10, gave two isomeric products, 4- and 6-nitro-2,3-
dimethylindoles 10a, and 10a6, derived from the secondary
enolate, produced via deprotonation of the methylenic
group. We failed to find any evidence of the presence of 4-
or 6-nitro-2-ethyl-indoles, which would be derived from the
reaction of the isomeric primary enolate. Preference for the
reactions of thermodynamically controlled secondary
enolates over those kinetically controlled is a well
established phenomenon.22 The addition of the more
sterically demanding secondary enolate occurs in both
positions 2- and 6- of 1a giving a mixture of 2,3-
dimethyl-4-nitro- and 2,3-dimethyl-6-nitro indoles 10a and
10a6. Similarly, diethyl ketone 11 and propiophenone 12 in
the reaction with 1a gave two isomeric products:
2-ethyl-3-methyl-4-nitro- and -6-nitroindoles 11a and
11a6 and 3-methyl-4-nitro-2-phenyl- and -6-nitroindoles
12a and 12a6, respectively. Interestingly, the ratio of the
two isomeric 4- and 6-nitroindoles produced from the
aliphatic ketones 10 and 11 was close to 1 (1.2 and 1.1),
whereas in the reaction of propiophenone 12 the 6-
nitroisomer was the major product, ratio 12a/12a6<0.4.
The reaction of secondary enolates of cyclic ketones 13, 14,
15 and 16 also proceeds via the addition to positions
2-and 6- of 3-nitroaniline giving substituted 4- and
6-nitroindoles, always the 4-nitroisomer being isolated in
larger yield (ratio 4-/6-nitro between 1.5 and 2.6). Thus,
even sterically bulky secondary enolates attack preferen-
tially the more sterically hindered position 2- of 3-nitro-
aniline.
On the other hand, the reaction of 4-fluoro-3-nitroaniline 1e
with enolate anions via ONSH process can occur at
positions 2- or 6- giving 5-fluoro-4- and 6-nitroindoles.
Acetone was found to react with 1e in the same manner as
with 1a, via addition to the most sterically hindered position
giving 5-fluoro-2-methyl-4-nitroindole 2e, whereas second-
ary enolates of diethyl ketone 11 and butyrophenone 22
gave predominantly or exclusively 6-nitroindoles 11e6 and
22e6 (Scheme 3, Table 2).
Usually the reaction of enolates with fluoro nitro anilines
gave lower yields of nitroindoles, perhaps because of some
competing reactions of substitution of fluorine by other
nucleophiles present in the system. It is worth noting, that in
the reaction of fluoronitroanilines 1d and 1e dehalogenation
Table 2. Substituted halonitroindoles obtained from halo-m-nitroanilines
1b–e and ketones 2–21 as in Schemes 2 and 3
Aniline
Ketone
Products and yields (%)
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1c
1d
1d
1d
1d
1d
1e
1e
1e
2
5
7
8
11
14
16
17
18
19
20
21
5
2b, 51
5b, 61
7b, 43
8b, 60
11b, 61
14b, 30
16b, 50
17b, 55
18b, 46
19b, 42
20b, 27
21b, 23
5c, 37
2d, 33
5d, 50
11d, 40
22d, 34
19d, 34
1e, 21
5a, 5
7a, 13
8a, 7
11a, 7
14a, 1
16a, 13
3-Nitroanilines containing halogens also enter the reaction
with a variety of enolates giving the corresponding
halonitroindoles. Thus, in the reaction of 6-chloro-3-
nitroaniline 1b with ketones substituted 4-nitro-7-chloroin-
doles were produced. In no cases did we observe formation
of the indoles resulting from nucleophilic displacement of
the halogen in 1b, namely 6-nitroindoles. However, in the
majority of experiments some amounts of side products of
dechlorination, 4-nitroindoles, were obtained. These com-
pounds were identical to the indoles produced in the
analogous reaction of 1a itself. In separate experiments,
chloronitroindole 5b was subjected to the standard reaction
conditions and was recovered unreacted, without loss of Cl.
Therefore, we concluded that dechlorination took place at
18a, 16
19a, 9
5a, 33
2a6, 3a
2
5
5a6, 7a
11
22
19
2
18
22
11a6, 15a
22a6, 12a
19a6, 12a
18e, 5
18e6, 20
22e6, 22
a
Formed via substitution of F.

350
N. Moskalev et al. / Tetrahedron 60 (2004) 347–358
Scheme 2.
was not observed. Indoles 2a6–22a6 that do not contain
fluorine were formed as the result of nucleophilic substi-
tution of fluorine and further cyclization.
initial condensation of the amino functionality with the
carbonyl group of the ketones giving 3-nitroaryl imines,
which upon treatment with base form carbanions that enter
intramolecular ONSH resulting in the indole ring closure;
(b) initial addition of the enolate anions to the nitroaromatic
ring (ortho- or para- to the nitro group and ortho- to the
Formation of the indole ring in the base-induced reaction of
ketones with 1a can, in principle, occur in two ways: (a)
Scheme 3.

N. Moskalev et al. / Tetrahedron 60 (2004) 347–358
351
Scheme 4.
amino group) followed by oxidation of the produced sH
adducts resulting in ONSH to form ortho-aminonitrobenzyl
ketones, further intramolecular condensation of which gives
nitroindoles.23 These alternative pathways are shown in
Scheme 4.
of the sH adducts gives the corresponding ONSH products–
nitrobenzyl ketones which subsequently undergo the Baeyer
type cyclisation23 to give nitroindoles. Oxidation of the sH
adducts in the form of aminal should give the same final
results. Differentation between these two possible ways of
stabilization of sH adducts was not attempted in our studies.
In order to clarify which of these alternative series of
transformations is the actual reaction pathway, the corre-
sponding imine 23 was prepared from acetophenone and
3-nitroaniline and subjected to the reaction conditions
(Scheme 5).
Additional stabilization of the sH adducts explains the
relatively high activity of 3-nitroanilines as electrophilic
partners in the reaction with enolate anions. It was observed
earlier that 1a is of rather low activity in its reactions with
carbanions, due to the presence of the strong electrondonat-
ing amino group that deactivates the aromatic ring towards
nucleophilic addition. Moreover, partial deprotonation of
the amino group should enhance this effect substantially.
The hypothesis that there is a specific tendency to form and
stabilize sH adducts of enolates to 1a in vicinity of the
amino groups was verified experimentally in competitive
experiments. In these experiments, we have directly
compared rates of the VNS reaction in nitrobenzene and
1a with the carbanion of chloromethyl phenyl sulfone,
which is unable to form intramolecular bonding with the
amino group, and rates of the ONSH reaction in nitro-
benzene and 1a with acetophenone (Scheme 6).
However, the expected 4-nitro-2-phenylindole 5a was found
in the reaction mixture in less than 6% overall yield,
moreover, it appears that in this case the indole was formed
due to decomposition of the imine to the aniline and ketone
followed by the reaction as in Scheme 1. This result
indicates that the path a (Scheme 4), including initial
condensation between the amino and the carbonyl group is
not the reaction pathway and should be excluded from
further consideration. The alternative path b, should,
therefore, be considered as an actual reaction pathway.
The absence of acylic products of this reaction ortho- to the
nitro group and para- to the amino group indicates that there
is a strong preference for the ONSH reaction in the vicinity
of the amino group. This can be rationalized by the
supposition that formation of a sH adduct is assisted by
either non-covalent interaction between the amino and the
carbonyl group or stabilization of the sH adduct by
formation of cyclic aminal takes place. Further oxidation
Results of these competitive experiments, presented in
Scheme 6, indicate that the rate of VNS in nitrobenzene with
the carbanion of chloromethyl phenyl sulfone is more than
100 times higher than the rate of this reaction with 1a. In
fact, the product of the latter process was not detected in the
reaction mixture. On the other hand, the ONSH reaction
with the enolate of acetophenone in nitrobenzene is only
about two times faster than formation of the nitroindole via
ONSH in 1a, which suggests that the deactivating effect of
the amino group on the electrophilic activity of 1a is
compensated by the additional stabilization of the sH
adduct. Thus, as we have supposed, addition of the enolate
to 1a is favored, apparently because the corresponding sH
adduct is additionally stabilized, and upon its oxidation
forms 4-nitro-2-phenylindole. Although these data are only
qualitative they indicate unambiguously that there is a
strong effect promoting addition of enolates to 1a. Such an
effect does not operate in the reaction of carbanions unable
to experience additional interactions with amino groups, for
Scheme 5.

352
N. Moskalev et al. / Tetrahedron 60 (2004) 347–358
Scheme 6.
Scheme 7.
instance, those generated from chloromethyl phenyl
sulfone.
nitrobenzyl phenyl ketones. Some discrepancy in the
orientation of ONSH in nitrobenzene with acetophenone
enolate is apparently due to the differences in the conditions.
The results presented in Scheme 6 indicate that there is an
effect promoting the reaction of enolates with 1a which does
not operate in the case of nitrobenzene and which we assign
to an interaction between the carbonyl and the amino groups
as shown in Scheme 4.
The carbanion of chloromethyl phenyl sulfone is our
standard nucleophile for the VNS reaction with nitroarenes.
In the presence of t-BuOK in DMSO and also in other base–
solvent systems it reacts with nitrobenzene to give a mixture
of ortho- and para-nitrobenzyl phenyl sulfones 24.24
Since the VNS reaction of this sulfone with 1a was not
reported (we reported earlier that this reaction does occur
with 3-nitro-N,N-dimethylaniline)21 we have shown in a
separate experiment that the VNS reaction of chloromethyl
phenyl sulfone with 1a proceeds satisfactorily giving a
single product 25 (Scheme 7).
Another important question is identity of the oxidant
oxidizing the sH adducts of enolates to 1a. We believe
that these sH adducts are oxidized by the air oxygen always
present in the reaction mixtures. Indeed when the reaction of
acetophenone 5 with 1a was carried out in the strictly
deoxygenated solvent under argon yields of the indoles were
substantially lower. On the other hand saturation of the
system with oxygen does not change the outcome
substantially as shown in Scheme 9
For unambiguous identification, compound 25 was diazo-
tized and the diazonium salt reduced in situ with hypo-
phosphorous acid, giving para-nitrobenzyl phenyl sulfone
24, identical to that reported in our early paper.24 Thus, VNS
in 1a proceeded in a position para- to the nitro group giving
2-amino-4-nitrobenzyl phenyl sulfone 25. Under similar
conditions, nitrobenzene reacts with acetophenone to give
para-nitrobenzyl phenyl ketone 26 (Scheme 8).
The identity of the oxidizing agents and effect of conditions
on the oxidation process need further studies.
This reaction under somewhat different conditions, was
reported by Hamana17 to give a mixture of ortho- and para-
Scheme 9.
Scheme 8.

N. Moskalev et al. / Tetrahedron 60 (2004) 347–358
353
In conclusion, the reported method of synthesis of
2.1. General procedure
nitroindoles from inexpensive and readily available starting
materials offers the simplest and the most efficient approach
to these valuable intermediates, particularly taking into
account that as well as of standard transformations of the
nitro group, further reactions of nucleophilic substitution of
hydrogen such as VNS in nitroindoles25 are possible so
polycyclic heterocyclic systems can be readily produced.26
To a stirred solution of m-nitroaniline (5 mmol) and ketone
(7 mmol) in DMSO (15 mL) at 15–20 8C (water bath),
t-BuOK (12 mmol) was added in one portion. All operations
were made in open flask under air. Deep red or red-violet
colour indicated the reaction progress. After 2 h of stirring
aqueous NH4Cl (60 mL) was added, the mixture was
extracted with ethyl acetate (3£50 mL) and the extract
dried with MgSO4. Chromatographic separation on silica
gel with hexane–toluene (1:1) eluent, then pure toluene on
20 cm£5 cm column is efficient for 5 mmol scale prepara-
tions. We do not recommend hexane–ethyl acetate eluent
for separation of crude reaction mixtures after workup. For
reaction of 1a with methylaryl ketones 5–9 procedure for
isolation of minor amounts of 6-NO2 isomers is
recommended. Analytical samples were finally purified by
recrystallization from heptane–toluene mixture.
2. Experimental
Unless otherwise noted all reagents and solvents were used
commercial without further purification. Chromatographic
columns were filled with silica gel 60 (0.040–0.063 mm,
230–400 mesh). 1H NMR spectra were recorded at
200 MHz.
The nitroindoles are stable yellow to dark-red crystalline
compounds, however some of them show instability in
solution on prolonged storage. 4-Nitroisomers are usually
less soluble and produce orange to brown spots on TLC,
while 6-nitroisomers are better soluble and produce lighter
spots on TLC. Halogenated indoles are less polar (TLC) and
better soluble.
2.2. General procedure for isolation of minor amounts of
6-NO2 isomers
Reaction was performed as in general procedure. Combined
extracts were dried with MgSO4, filtered, silica gel was
added to the solution and solvent was evaporated. Gel was
put on chromatographic column with toluene (5£5 cm,
silica gel). Large amount (up to 1 L) of toluene was passed
through and solvent was evaporated. Residue was crystal-
lized from heptane–toluene mixture (left in well isolated
can in refrigerator for slow cooling). Precipitated crystals
were filtered, washed with heptane–toluene mixture and
dried to obtain 4-nitroindole derivatives (for 5a 57%).
Solution was evaporated with silica gel and put on
chromatographic column with hexane–ethyl acetate (4:1
then 1:1) (5£15 cm, silica gel). After collection and
evaporation of fractions 6-nitroindole derivatives (for
5a6 8%) (first eluted product) and 4-nitroindole
derivatives (for 5a 10%) (second eluted product) were
obtained.
The reactions were monitored by TLC (aluminium sheets,
silica gel 60 F254, Merck) using toluene as eluent. For the
reaction with N-methyl-4-piperidone, methylene chloride–
methanol, (4:1) was used as eluent. Samples of the reaction
mixtures for TLC were treated with aqueous NH4Cl and
extracted with EtOAc. Usually, all the reactions were
complete within 2 h, however, we recommend stopping the
reaction when starting m-nitroaniline is not detected by TLC
in the reaction mixture.
Typical TLC retention factors (Rf, toluene) components of
the reaction mixture: m-nitroaniline¼0.25 (yellow spot, UV
lamp helps to find trace amounts), 6-NO2 indoles¼0.30–
0.40 (yellow to orange spots), 4-NO2 indoles¼0.40–0.45
(orange to brown spots).
2.2.1. Reaction with N-methyl-2-acetylpyrrole. To a
stirred mixture of 2-acetylpyrrole (597 mg, 5.5 mmol) and
t-BuOK (614 mg, 5.5 mmol) in DMSO (10 mL) at 20 8C,
CH3I (2.5 g, 17.6 mmol) was added in one portion. Reaction
was moderately exothermic. After 1.5 h, TLC showed that
reaction was completed and excess of CH3I was removed
in vacuo. To this solution m-nitroaniline 1a (765 mg,
5.5 mmol) and t-BuOK (1368 mg, 12.2 mmol) were added
consecutively. After 2 h of stirring in open flask under air
aqueous NH4Cl (60 mL) was added and product isolated as
in general procedure to give 4-nitro-2-(N-methyl-pyrrol-2-
yl)-indole 9a (150 mg, 12%).
For methyl aryl ketones (for example see reaction of 1a with
5), retention factors of the both isomers are very close. Due
to low abundance of 6-NO2 isomer in the reaction mixture
and low solubility of 4-nitroisomer (‘diffusion’ of sample)
detection of 6-NO2 isomer often becomes difficult. For these
cases hexane–ethyl acetate (2:1) should be used as an
eluent, where order of elution of isomers is reversed (Rf,
hexane–ethyl acetate, 2:1): 4-NO2 indoles¼0.35–0.40
(orange to brown spots), 6-NO2 indoles¼0.45–0.50 (yellow
to orange spots).
2.2.2. Reactions with 2-acetylthiophene and 2-acetyl-
furan. Reactions were performed as in general procedure,
but 3-fold excess of m-nitroaniline was used (15 mmol) on
ketone (5 mmol).
2-Bromo-5-nitroaniline 1c was obtained by simple bromin-
ation of 1a in glacial acetic acid at 10 8C and subsequent
recrystallization from ethanol (yield 25%) mp 136–139 8C
(lit.27 140 8C) similarly to the procedure described.27
2.2.3. Reaction with a-tetralone. To a stirred solution of
m-nitroaniline 1a (693 mg, 5 mmol) and a-tetralone 16
(1040 mg, 7.1 mmol) in DMSO (15 mL) at 17 8C, t-BuOK
(1127 mg, 10.1 mmol) was added in one portion. Deep blue
colour appeared and after 45 min of stirring in open flask
Chloromethylphenylsulfone was obtained from bromo-
chloromethane and benzenesulfinic acid sodium salt.28
Ethylene glycol monoacetal of dimedone (2,2-dimethyl-
cyclohexane-1,3-dione) 21 was prepared as reported.29

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N. Moskalev et al. / Tetrahedron 60 (2004) 347–358
1
under air aqueous NH4Cl (60 mL) was added. Insoluble
solid product was filtered and dried. Filtrate was extracted
with ethyl acetate (2£25 mL) and dried with MgSO4. Dried
solid was added to extracts, silica gel was added to the
mixture and then solvent was evaporated. Residue adsorbed
on gel was put on 3 cm layer of silica gel. Then toluene and
ethyl acetate was passed through. Solvent was evaporated
and 40 mL of toluene was added. Mixture was heated to
boiling for 10 min, then cooled, and the precipitate was
filtered, washed with toluene and dried to obtain 5,6-dihydro-
7-nitrobenzo[a]carbazole 16a (416 mg, 31%). Organic solu-
tions were put on chromatographic column with toluene and
separated to obtain: 5,6-dihydro-7-nitrobenzo[a]carbazole
16a (78 mg, 6%) and 5,6-dihydro-9-nitrobenzo[a]carbazole
16a6 (249 mg, 19%).
with m-nitroaniline (25) was not detected by TLC and H
NMR in organic phase nor in aqueous extracts.
2.2.6. Competitive reaction of 1a and nitrobenzene with
5 (Scheme 6). To a solution of nitrobenzene (370 mg,
3 mmol), m-nitroaniline 1a (414 mg, 3 mmol) and aceto-
phenone 5 (119 mg, 1 mmol) in DMSO (9 mL), t-BuOK
(224 mg, 2 mmol) was added in one portion and the mixture
was stirred at open flask under air for 20 min at 20 8C. The
mixture was diluted with aqueous NH4Cl (60 mL), extracted
with ethyl acetate (3£25 mL), the combined extracts were
treated with HClaq (1:1, 2£100 mL), washed with water and
dried with MgSO4. After evaporation of the solvent residue
was separated on short column (toluene then toluene–ethyl
acetate 10:1) to give mixture of nitroindoles (5a, 5a6)
and p-nitrobenzyl phenyl ketone 26 (166 mg, about 60% of
all compounds). Basification of the acidic solution with
KOH and extraction with ethyl acetate (3£25 mL) gave
m-nitroaniline 1a (330 mg, 80%).
2.2.4. Synthesis of imine 23 and attempts of cyclization
(Scheme 5). m-Nitroaniline 1a (416 mg; 3 mmol), aceto-
phenone 5 (127 mg; 1.06 mmol) and p-toluenesulphonic
acid (TsOH; 7 mg; 3%) in toluene (50 mL) were refluxed
overnight with Soxlet apparatus filled with well-dried
molecular sieves. The solvent was evaporated and the
residue separated by flash chromatography (toluene, silica
gel (25 g) treated with NEt3 (5 g) in 50 mL toluene over-
night, then washed with 200 mL toluene on column).
Evaporation of solvent and recrystallization from hexane
gave N-(3-nitrophenyl)-N-[(E)-1-phenylethylidene]amine
23 as yellow-brown crystals (0.108 g; 43%), mp 90–
1H NMR analysis of the crude reaction mixture showed
p-nitrobenzyl phenyl ketone 26 to nitroindoles (5a, 5a6)
ratio close to 2:1.
2.2.7. Reaction of 1a with chloromethylphenylsulfone
(synthesis of 25, Scheme 7). m-Nitroaniline 1a (416 mg,
3 mmol) and chloromethylphenylsulfone (193 mg, 1 mmol)
were dissolved in degassed DMSO (9 mL) under argon and
t-BuOK (225 mg, 2 mmol) was added in one portion. The
mixture was stirred for 20 min at 20 8C, aqueous NH4Cl
(60 mL) was added and extracted with ethyl acetate
(3£30 mL). Separation on short column with toluene then
toluene–ethyl acetate (10:1) gave 5-nitro-2-[(phenyl
sulfonyl)methyl]aniline 25 (164 mg, 56%) as yellow solid.
Mp 216–218 8C. 1H NMR (500 MHz, DMSO-d6) d 4.74 (s,
2H), 5.80 (s, 2H), 7.06 (d, J¼8.4 Hz, 1H), 7.24 (dd, J¼8.4,
2.4 Hz, 1H), 7.44 (d, J¼2.4 Hz, 1H), 7.58–7.62 (m, 2H),
7.70–7.75 (m, 1H), 7.78–7.82 (m, 2H). EIMS m/e (relative
intensity): 292 (Mþ, 8), 151 (100). IR (cm21, KBr): 3473,
3390, 1636, 1510, 1353, 1300, 1145, 1081, 750, 725, 694,
594, 517. Anal. Calcd for C13H12N2O4S: C, 53.42; H,
4.14; N, 9.58; S 10.97. Found: C, 53.42; H, 4.06; N; 9.58; S
10.91.
1
91 8C, H NMR d (500 MHz, CDCl3) 2.27 (s, 3H, CH3),
7.13 (ddd, J¼7.9, 2.0, 2.0 Hz, 1H), 7.45–7.54 (m, 3H), 7.67
(dd, J¼2.0, 2.0 Hz, 1H), 7.95 (ddd, J¼8.0, 2.0, 2.0 Hz, 1H),
7.97–8.00 (m, 2H). EIMS m/e (relative intensity): 240
(Mþ, 54), 225 (100), 179 (55). Anal. Calcd for C14H12N2O2:
C, 69.99; H, 5.03; N, 11.66. Found: C, 70.15; H, 4.96; N,
11.58.
To a solution of N-(3-nitrophenyl)-N-[(E)-1-phenylethyl-
idene]amine 23 (119 mg; 0.5 mmol) in DMSO (5 mL),
t-BuOK (133 mg; 1.2 mmol) was added in one portion and
the mixture was stirred for 2 h in open flask under air,
aqueous NH4Cl (25 mL) was added, extracted with ethyl
acetate (2£25 mL) and combined organic layers were dried
with MgSO4. Separation by column chromatography on
toluene gave 4-nitro-2-phenylindole 5a (7 mg; 6%, structure
1
confirmed by H NMR) as the only isolable product.
2.2.8. Conversion of 25 into 24 (Scheme 7). To a
suspension of 5-nitro-2-[(phenylsulfonyl)methyl]aniline 25
(97 mg, 0.33 mmol) in a mixture of 36% aqueous HCl
(3.3 g) and 50% aqueous H3PO2 (3.2 g) at 25 8C aqueous
solution of NaNO2 (120 mg, 1.7 mmol in 600 mg of water)
was added slowly. The mixture was warmed to room
temperature during 1 h. Water (50 mL) was added and the
mixture was extracted with ethyl acetate (2£30 mL) com-
bined organic layers were washed with brine (2£100 mL)
and dried with MgSO4. Column chromatography (toluene
then toluene–ethyl acetate 10:1) gave 4-nitrobenzyl phenyl
sulfone 24 (42 mg, 46%) mp 210–210.5 8C (lit.24 207 8C)
2.2.5. Competitive reaction of 1a and nitrobenzene with
chloromethyl phenyl sulfone (Scheme 6). Nitrobenzene
(375 mg, 3 mmol), m-nitroaniline 1a (416 mg, 3 mmol) and
chloromethylphenylsulfone (208 mg, 1 mmol) were dis-
solved in degassed DMSO (9 mL) under argon. Then t-BuOK,
0.224 g (2 mmol) was added in one portion and the mixture
was stirred at 20 8C for 20 min. After this aqueous NH4Cl
(60 mL) was added and the mixture was extracted with ethyl
acetate (2£30 mL), and extracts were treated with 2£100 mL
HClaq (1:1), washed with water dried with MgSO4. After
evaporation of solvent residue was separated on short
column (toluene then toluene–ethyl acetate 10:1) to give the
mixture of ortho- and para-nitrobenzyl phenyl sulfones
(194 mg, 70%, detected by TLC and confirmed by 1H
NMR). The acidic solution was made alkaline with KOH
and extracted with ethyl acetate (3£25 mL) to give
m-nitroaniline 1a (394 mg, 95%). Product of the reaction
1
(confirmed by H NMR spectrum).
2.2.9. Reaction of 5 with nitrobenzene (synthesis of 26,
Scheme 8). To a solution of nitrobenzene (373 mg, 3 mmol)
and acetophenone 5 (117 mg, 1 mmol) in DMSO (9 mL)
t-BuOK (233 mg, 2.1 mmol) was added in one portion. The
mixture was stirred in open flask under air for 20 min at

N. Moskalev et al. / Tetrahedron 60 (2004) 347–358
355
20 8C and then aqueous solution of NH4Cl (50 mL) was
added, the whole was extracted with ethyl acetate
(2£30 mL) and dried. Separation on short column with
hexane–ethyl acetate (20:1 to 4:1) gave p-nitrobenzyl
phenyl ketone 26 as white solid (151 mg, 64%), mp 141.5–
2.3.6. 2-Cyclopropyl-4-nitroindole (3a). Mp 192–193 8C.
1H NMR d (CDCl3) 0.87–1.01 (m, 2H), 1.03–1.17 (m, 2H),
1.96–2.11 (m, 1H), 6.88–6.92 (m, 1H), 7.16 (dd, J¼8.0,
8.0 Hz, 1H), 7.57 (ddd, J¼8.0, 0.9, 0.9 Hz, 1H), 8.09 (dd,
J¼8.1, 0.9 Hz, 1H), 8.42 (br s, 1H). EIMS m/e (relative
intensity): 202 (Mþ, 100), 185 (89), 155 (95), 128 (64).
Anal. Calcd for C11H10N2O2: C, 65.34; H, 4.98; N, 13.85.
Found: C, 65.23; H, 4.87; N, 14.04.
1
143 8C (lit.30 138–140 8C). H NMR d (CDCl3) 4.42 (s,
2H), 7.40–7.67 (m, 5H), 7.98–8.06 (m, 2H), 8.16–8.24 (m,
2H). LSIMS m/z: 242 [Mþþ1]. Anal. Calcd for C14H11NO3:
C, 69.70; H, 4.60; N, 5.81. Found: C, 70.07; H, 4.59; N, 5.92
and unidentified yellow product (EIMS: Mþ343) (19 mg).
2.3.7. 2-tert-Butyl-4-nitroindole (4a). Mp 173 8C (lit.12
173 8C).
2.2.10. Influence of oxygen on the reaction (Scheme 9).
The reactions 1a with 5 were performed according to the
general procedure for isolation of minor amounts of 6-NO2
isomers. For experiment without oxygen, DMSO was dried
with CaH2 overnight, distilled in a stream of argon under
reduced pressure, degassed by 3-fold repeated freeze–
pump–thaw technique (see Ref. 31) and argonated before
experiment. Experiment with oxygen was performed with
continuous bubbling of oxygen through the reaction mixture
10 min before and during the reaction.
2.3.8. 2-Phenyl-4-nitroindole (5a). Mp 205 8C (lit.9b 203–
206 8C). IR (cm21, KBr): 3339, 1500, 1481, 1454, 1374,
1325, 1272, 983, 766.
2.3.9. 2-Phenyl-6-nitroindole (5a6). Mp 214.5–216 8C. 1H
NMR (DMSO-d6) d 7.16 (s, 1H), 7.38–7.60 (m, 3H), 7.72
(d, J¼8.8 Hz, 1H), 7.82–7.99 (m, 3H), 8.29 (d, J¼2.0 Hz,
1H), 12.36 (s br, 1H). EIMS m/e (relative intensity): 238
(Mþ, 100), 208 (35), 192 (44), 165 (28). IR (cm21, KBr):
3323, 1502, 1487, 1461, 1298, 1065, 757, 731. Anal. Calcd
for C14H10N2O2: C, 70.58; H, 4.23; N, 11.76. Found: C,
71.47; H, 4.29; N, 11.62.
2.3. Physicochemical and spectral data
Representative IR spectra are given for compounds 2a, 2a6,
5a, 5a6, 12a and 12a6.
2.3.10. 7-Chloro-4-nitro-2-phenylindole (5b). Mp 200–
1
202 8C. H NMR d (DMSO-d6) 7.40 (d, J¼8.6 Hz, 1H),
2.3.1. 2-Methyl-4-nitroindole (2a). Mp 202 8C (lit.9b 197–
198 8C). IR (cm21, KBr): 3301, 1580, 1505, 1478, 1321,
1231, 980, 779, 735.
7.43–7.60 (m, 4H), 8.07 (d, J¼8.6 Hz, 1H), 8.06–8.14 (m,
2H), 12.42 (br s, 1H). EIMS m/e (relative intensity): 272,
274 (Mþ, 100, 37), 242, 244 (25, 9), 226, 228 (21, 7), 191
(27). Anal. Calcd for C14H9ClN2O2: C, 61.66; H, 3.33; N,
10.27. Found: C, 61.81; H, 3.01; N, 10.08.
2.3.2. 2-Methyl-6-nitroindole (2a6). Mp 118–119 8C (lit.32
113.5–114.5 8C). IR (cm21, KBr): 3314, 1589, 1543, 1501,
1
1463, 1316, 1069, 821, 733. H NMR (CDCl3) d 2.55 (d,
2.3.11. 7-Bromo-4-nitro-2-phenylindole (5c). Mp 197.5–
198 8C. 1HNMR(CDCl3)d7.43(d, J¼8.6 Hz,1H), 7.42–7.60
(m, 3H), 7.67 (d, J¼2.5 Hz, 1H), 7.78–7.85 (m, 2H), 8.05 (d,
J¼8.6 Hz, 1H), 8.81 (s br, 1H). EIMS m/e (relative intensity):
316, 318 (Mþ, 100, 97), 286, 288 (28, 27), 270, 272 (25, 24),
191 (99). Anal. Calcd for C14H9N2O2Br: C, 53.02; H, 2.86; N,
8.83; Br, 25.20. Found: C, 53.30; H, 2.67; N, 8.84; Br, 24.76.
J¼0.8 Hz, 3H), 6.35–6.37 (m, 1H), 7.53 (d, J¼8.8 Hz, 1H),
8.01 (dd, J¼8.8, 2.2 Hz, 1H), 8.29–8.31 (m, 1H), 8.55 (s br,
1H). EIMS m/e (relative intensity): 176 (Mþ, 100), 146 (28),
130 (55). Anal. Calcd for C9H8N2O2: C, 61.36; H, 4.58; N,
15.90. Found: C, 61.51; H, 4.41; N, 15.80.
2.3.3. 7-Chloro-2-methyl-4-nitroindole (2b). Mp 208–
209 8C. 1H NMR d (CDCl3) 2.57 (d, J¼0.9 Hz, 3H), 7.03–
7.06 (m, 1H), 7.17 (d, J¼8.7 Hz, 1H), 8.05 (d, J¼8.7 Hz,
1H), 8.50 (br s, 1H). EIMS m/e (relative intensity): 210, 212
(Mþ, 100, 34), 180, 182 (40, 14), 164, 166 (47, 15). Anal.
Calcd for C9H7ClN2O2: C, 51.32; H, 3.35; N, 13.30. Found:
C, 51.45; H, 3.23; N, 13.06.
2.3.12. 7-Fluoro-4-nitro-2-phenylindole (5d). Mp 204–
1
206 8C. H NMR d (DMSO-d6) 7.19 (dd, J¼10.2, 8.9 Hz,
1H) 7.41–7.60 (m, 4H), 8.03–8.10 (m, 2H), 8.11 (dd,
J¼8.9, 4.1 Hz, 1H), 12.77 (br s, 1H). EIMS m/e (relative
intensity): 256 (Mþ, 100), 226 (27), 210 (42). Anal. Calcd
for C14H9FN2O2: C, 65.62; H, 3.54; N, 10.93. Found: C,
65.53; H, 3.29; N, 10.78.
2.3.4. 7-Fluoro-2-methyl-4-nitroindole (2d). Mp 228–
1
229 8C. H NMR (CDCl3) d 2.56 (d, J¼0.8 Hz, 3H), 6.89
2.3.13. 4-Nitro-2-(2-pyridyl)indole (6a). Mp 167 8C (lit.12
167 8C).
(dd, J¼9.7, 8.9 Hz, 1H), 7.02–7.07 (m, 1H), 8.09 (dd,
J¼8.9, 4.3 Hz, 1H), 8.45 (br s, 1H). EIMS m/e (relative
intensity): 194 (Mþ, 100), 164 (28), 148 (52). Anal. Calcd
for C9H7N2O2F: C, 55.67; H, 3.63; N, 14.43. Found: C,
55.87; H, 3.50; N, 14.30.
2.3.14. 2-(Furan-2-yl)-4-nitroindole (7a). Mp 211–212 8C.
1H NMR (DMSO-d6) d 6.73(dd, J¼3.4, 1.8 Hz, 1H), 7.17(dd,
J¼3.4, 0.6 Hz, 1H), 7.32 (dd, J¼8.0, 8.0 Hz, 1H), 7.33 (dd,
J¼2.2, 0.8 Hz, 1H), 7.85 (dt, J¼8.0, 0.9 Hz, 1H), 7.92
(dd, J¼1.8, 0.7 Hz, 1H), 8.07 (dd, J¼8.0, 0.8 Hz, 1H), 12.49
(s, 1H). EIMS m/e (relative intensity): 228 (Mþ, 100), 198
(8), 182 (34). Anal. Calcd for C12H8N2O3: C, 63.16; H,
3.53; N, 12.28. Found: C, 63.30; H, 3.32; N, 12.30.
2.3.5. 5-Fluoro-2-methyl-4-nitroindole (2e). Mp 194–
195 8C. 1H NMR d (DMSO-d6) 2.48 (s, 3H), 6.65–6.69 (m,
1H), 7.20 (dd, J¼12.5, 8.7 Hz, 1H), 7.68 (ddd, J¼8.7, 3.8,
0.8 Hz, 1H), 11.94 (br s, 1H). EIMS m/e (relative intensity):
194 (Mþ, 100), 164 (42), 148 (69). Anal. Calcd for
C9H7FN2O2: C, 55.67; H, 3.63; N, 14.43. Found: C,
55.66; H, 3.39; N, 14.26.
2.3.15. 7-Chloro-2-(20-furyl)-4-nitroindole (7b). Mp 209–
1
210 8C. H NMR d (CDCl3) 6.60 (dd, J¼3.4, 1.7 Hz, 1H),

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N. Moskalev et al. / Tetrahedron 60 (2004) 347–358
6.92 (dd, J¼3.4, 0.6 Hz, 1H), 7.24 (d, J¼8.6 Hz, 1H),
7.49–7.62 (m, 2H), 8.10 (d, J¼8.6 Hz, 1H), 8.97 (br s,
1H). EIMS m/e (relative intensity): 262, 264 (Mþ, 100,
34), 232, 234 (22, 7), 216, 218 (47, 16). Anal. Calcd for
C12H7ClN2O3: C, 54.88; H, 2.69; N, 10.67. Found: C,
54.60; H, 2.53; N, 10.52.
2.3.25. 2-Ethyl-5-fluoro-3-methyl-4-nitroindole (11e).
1
Mp 162–163 8C. H NMR d (CDCl3) 1.30 (t, J¼7.6 Hz,
3H), 2.11 (s, 3H), 2.78 (q, J¼7.6 Hz, 2H), 6.92 (dd, J¼10.4,
8.8 Hz, 1H), 7.33 (dd, J¼8.8, 3.9 Hz, 1H), 8.10 (br s, 1H).
EIMS m/e (relative intensity): 222 (Mþ, 50), 205 (48), 175
(100). Anal. Calcd for C11H11FN2O2: C, 59.46; H, 4.99; N,
12.61. Found: C, 60.48; H, 5.15; N, 12.45.
2.3.16. 4-Nitro-2-(20-thienyl)-indole (8a). Mp 220–221 8C.
1H NMR (DMSO-d6) d 7.24 (dd, J¼5.0, 3.7 Hz, 1H), 7.29
(dd, J¼2.2, 0.8 Hz, 1H), 7.31 (dd, J¼8.0, 8.0 Hz, 1H), 7.72
(dd, J¼5.0, 1.2 Hz, 1H), 7.75 (dd, J¼3.7, 1.2 Hz, 1H), 7.85
(ddd, J¼8.0, 0.8, 0.8 Hz, 1H), 8.07 (dd, J¼8.0, 0.8 Hz, 1H),
12.50 (s br, 1H). EIMS m/e (relative intensity): 244 (Mþ,
100), 214 (27), 198 (44). Anal. Calcd for C12H8N2O2S: C,
59.01; H, 3.30; N, 11.47. Found: C, 59.20; H, 3.14; N, 11.42.
2.3.26. 2-Ethyl-5-fluoro-3-methyl-6-nitroindole (11e6).
1
Mp 197–198 8C. H NMR d (CDCl3) 1.32 (t, J¼7.7 Hz,
3H), 2.21 (s, 3H), 2.82 (q, J¼7.7 Hz, 2H), 7.21 (d,
J¼12.1 Hz, 1H), 8.09 (d, J¼6.1 Hz, 1H), 8.23 (br s, 1H).
EIMS m/e (relative intensity): 222 (Mþ, 100), 207 (48), 192
(31), 161 (51). Anal. Calcd for C11H11FN2O2: C, 59.46; H,
4.99; N, 12.61. Found: C, 60.49; H, 5.24; N, 12.18.
2.3.17. 7-Chloro-4-nitro-2-(20-thienyl)indole (8b). Mp
211–213 8C. 1H NMR d (acetone-d6) 7.21 (dd, J¼5.1,
3.7 Hz, 1H), 7.36 (d, J¼8.6 Hz, 1H), 7.43 (d, J¼2.0 Hz,
1H), 7.66 (dd, J¼5.1, 1.1 Hz, 1H), 7.82 (dd, J¼3.7, 1.1 Hz,
1H), 8.08 (d, J¼8.7 Hz, 1H), 11.50 (br s, 1H). EIMS m/e
(relative intensity): 278, 280 (Mþ, 100, 37), 248, 250 (40,
15). Anal. Calcd for C12H7ClN2O2S: C, 51.71; H, 2.53; N,
10.05. Found: C, 51.63; H, 2.26; N, 10.02.
2.3.27. 3-Methyl-4-nitro-2-phenylindole (12a). Mp 207–
1
208 8C (lit.35 205–206 8C), H NMR d (CDCl3) 2.43 (s,
3H), 7.20 (d, J¼8.0 Hz, 1H), 7.40–7.62 (m, 5H), 7.62
(dd, J¼8.1, 0.9 Hz, 1H), 7.78 (dd, J¼7.9, 0.9 Hz, 1H),
8.40 (br s, 1H). EIMS m/e (relative intensity): 252 (Mþ,
63), 235 (37), 205 (100). IR (cm21, KBr): 3357, 1504,
1328, 1286, 1055, 993, 810, 764, 772, 700. Anal. Calcd
for C15H12N2O2: C, 71.42; H, 4.79; N, 11.10. Found: C,
71.25; H, 4.64; N, 10.97.
2.3.18. 4-Nitro-2-(1-methyl-1H-pyrrol-2-yl)-1H-indole
(9a). Mp 216–218 8C. 1H NMR (DMSO-d6) d 3.91 (s,
3H), 6.18 (dd, J¼3.8, 2.6 Hz, 1H), 6.71 (dd, J¼3.8, 1.8 Hz,
1H), 7.02 (dd, J¼2.1, 2.0 Hz, 1H), 7.17 (d, J¼1.5 Hz, 1H),
7.26 (dd, J¼8.0, 8.0 Hz, 1H), 7.79 (d, J¼7.9 Hz, 1H), 8.03
(dd, J¼8.1, 0.7 Hz, 1H), 12.03 (s, 1H). EIMS m/e (relative
intensity): 241 (Mþ, 100), 195 (36). Anal. Calcd for
C13H11N3O2: C, 64.72; H, 4.60; N, 17.42. Found: C,
64.48; H, 4.42; N, 17.57.
2.3.28. 3-Methyl-6-nitro-2-phenylindole (12a6). Mp 208–
1
210 8C (lit.35 205–206 8C), H NMR d (CDCl3) 2.48 (s,
3H), 7.39–7.66 (m, 6H), 8.06 (dd, J¼8.8, 2.0 Hz, 1H), 8.34
(dd, J¼2.0, 0.5 Hz, 1H), 8.45 (br s, 1H). EIMS m/e (relative
intensity): 252 (Mþ, 100), 222 (23), 206 (24). IR (cm21
,
KBr): 3339, 1495, 1464, 1297, 1238, 1062, 775, 755, 709.
Anal. Calcd for C15H12N2O2: C, 71.42; H, 4.79; N, 11.10.
Found: C, 71.69; H, 4.46; N, 10.82.
2.3.19. 2,3-Dimethyl-4-nitroindole (10a). Mp 173 8C (lit.33
175 8C).
2.3.29. 8-Nitro-1,2,3,4-tetrahydro-cyclopent[b]indole
(13a). Mp 198–199 8C (lit.36a 199 8C).
2.3.20. 2,3-Dimethyl-6-nitroindole (10a6). Mp 142 8C
(lit.34 142 8C).
2.3.30. 6-Nitro-1,2,3,4-tetrahydro-cyclopent[b]indole
(13a6). Mp 139–141 8C (lit.36a 153 8C), 1H NMR
(DMSO-d6) d 2.41–2.58 (m, 2H), 2.72–2.85 (m, 2H),
2.85–2.97 (m, 2H), 7.45 (d, J¼8.8 Hz, 1H), 7.85 (dd,
J¼8.8, 2.2 Hz, 1H), 8.22 (d, J¼2.2 Hz, 1H), 11.69 (s, 1H).
EIMS m/e (relative intensity): 202 (Mþ, 100), 172 (13), 156
(35). Anal. Calcd for C11H10N2O2: C, 65.34; H, 4.98; N,
13.85. Found: C, 65.36; H, 5.21; N, 13.76.
2.3.21. 2-Ethyl-3-methyl-4-nitroindole (11a). Mp 175 8C
(lit.8d 175 8C).
2.3.22. 2-Ethyl-3-methyl-6-nitroindole (11a6). Mp 165 8C
(lit.8d 164 8C).
2.3.23. 7-Chloro-2-ethyl-3-methyl-4-nitroindole (11b).
1
2.3.31. 5-Nitro-1,2,3,4-tetrahydrocarbazole (14a). Mp
152 8C (lit.36b 153–156 8C).
Mp 150–151 8C. H NMR d (CDCl3) 1.34 (t, J¼7.6 Hz,
3H), 2.29 (s, 3H), 2.85 (q, J¼7.6 Hz, 2H), 7.11 (d,
J¼8.5 Hz, 1H), 7.72 (d, J¼8.5 Hz, 1H), 8.35 (br s, 1H).
EIMS m/e (relative intensity): 238, 240 (Mþ, 41, 14), 221,
223 (69, 25), 191, 193 (100, 39). Anal. Calcd for
C11H11ClN2O2: C, 55.36; H, 4.65; N, 11.74. Found: C,
55.64; H, 4.78; N, 11.59.
2.3.32. 7-Nitro-1,2,3,4-tetrahydrocarbazole (14a6). Mp
169 8C (lit.36b 170–171 8C).
2.3.33. 8-Chloro-5-nitro-1,2,3,4-tetrahydrocarbazole
1
(14b). Mp 208–209 8C (lit.37 214 8C), H NMR d (CDCl3)
1.77–2.00 (m, 4H), 2.79–2.96 (m, 4H), 7.10 (d, J¼8.5 Hz,
1H), 7.79 (d, J¼8.5 Hz, 1H), 8.35 (br s, 1H). MS: 250, 252
(Mþ, 32, 10), 233, 235 (100, 32), 203, 205 (77, 26). Anal.
Calcd for C12H11ClN2O2: C, 57.50; H, 4.42; N, 11.17.
Found: C, 57.46; H, 4.19; N, 11.10.
2.3.24. 2-Ethyl-7-fluoro-3-methyl-4-nitroindole (11d).
1
Mp 155–156 8C. H NMR d (CDCl3) 1.33 (t, J¼7.7 Hz,
3H), 2.30 (s, 3H), 2.84 (q, J¼7.6 Hz, 2H), 6.82 (dd, J¼9.5,
8.8 Hz, 1H), 7.78 (dd, J¼8.8, 4.5 Hz, 1H), 8.40 (br s, 1H).
EIMS m/e (relative intensity): 222 (Mþ, 44), 205 (62), 175
(100). Anal. Calcd for C11H11FN2O2: C, 59.46; H, 4.99; N,
12.61. Found: C, 59.41; H; 4.84; N, 12.61.
2.3.34. 1-Nitro-5,6,7,8,9,10-hexahydro-cyclohepta[b]in-
dole (15a). Mp 147–148 8C (lit.35 148–149 8C).

N. Moskalev et al. / Tetrahedron 60 (2004) 347–358
357
2.3.35. 3-Nitro-5,6,7,8,9,10-hexahydro-cyclohepta[b]
indole (15a6). Mp 134–136 8C (lit.35 135–136 8C).
2H), 4.96–5.03 (m, 1H), 5.05–5.08 (m, 1H), 5.84–6.06 (m,
1H), 7.50 (d, J¼8.8 Hz, 1H), 7.98 (dd, J¼8.8, 2.0 Hz, 1H),
8.25 (d, J¼2.0 Hz, 1H), 8.37 (br s, 1H). EIMS m/e (relative
intensity): 216 (Mþ, 100), 201 (20), 189 (51). Anal. Calcd
for C12H12N2O2: C, 66.65; H, 5.59; N, 12.95. Found: C,
66.51; H, 5.56; N, 12.82.
2.3.36. 5,6-Dihydro-7-nitrobenzo[a]carbazole (16a). Mp
1
258–259 8C (dec.). H NMR (DMSO-d6) d 2.93–3.15 (m,
4H), 7.25 (dd, J¼8.0, 8.0 Hz, 1H), 7.30–7.41 (m, 3H),
7.70–7.78 (m, 2H), 7.82 (dd, J¼8.0, 1.0 Hz, 1H), 12.36 (br
s, 1H). EIMS m/e (relative intensity): 264 (Mþ, 32), 247
(68), 217 (100). Anal. Calcd for C16H12N2O2: C, 72.72; H,
4.58; N, 10.60. Found: C, 72.57; H, 4.28; N, 10.41.
2.3.44. 3-Allyl-7-chloro-2-methyl-4-nitroindole (19b).
1
Mp 136–137 8C. H NMR d (CDCl3) 2.48 (s, 3H), 3.53–
3.58 (m, 2H), 4.71–4.84 (m, 1H), 4.87–4.96 (m, 1H), 5.81–
6.02 (m, 1H), 7.13 (d, J¼8.5 Hz, 1H), 7.71 (d, J¼8.5 Hz,
1H), 8.49 (br s, 1H). EIMS m/e (relative intensity): 250, 252
(Mþ, 54, 18), 233, 235 (83, 38), 209, 211 (100, 32). Anal.
Calcd for C12H11ClN2O2: C, 57.50; H, 4.42; N, 11.17.
Found: C, 57.31; H, 4.24; N, 11.00.
2.3.37. 5,6-Dihydro-9-nitrobenzo[a]carbazole (16a6). Mp
1
253–254 8C (lit.38 226–228 8C), H NMR (DMSO-d6) d
2.96–3.16 (m, 4H), 7.30–7.48 (m, 3H), 7.72 (d, J¼8.8 Hz,
1H), 7.76–7.83 (m, 1H), 7.97 (dd, J¼8.8, 2.1 Hz, 1H), 8.32
(d, J¼2.1 Hz, 1H), 12.35 (br s, 1H). EIMS m/e (relative
intensity): 264 (Mþ, 100), 234 (22), 217 (90). Anal. Calcd
for C16H12N2O2: C, 72.72; H, 4.58; N, 10.60. Found: C,
72.71; H, 4.37; N, 10.69.
2.3.45. 3-Allyl-7-fluoro-2-methy-4-nitroindole (19d). Mp
1
119–120 8C. H NMR d (CDCl3) 2.47 (s, 3H), 3.55–3.62
(m, 2H), 4.70–4.84 (m, 1H), 4.87–4.97 (m, 1H), 5.82–6.04
(m, 1H), 6.84 (dd, J¼9.3, 8.9 Hz, 1H), 7.78 (dd, J¼8.8,
4.5 Hz, 1H), 8.52 (br s, 1H). EIMS m/e (relative intensity):
234 (Mþ, 37), 217 (70), 186 (100). Anal. Calcd for
C12H11FN2O2: C, 61.53; H, 4.73; N, 11.96. Found: C,
61.31; H, 4.62; N, 11.82.
2.3.38. 10-Chloro-5,6-dihydro-7-nitrobenzo[a]carbazole
(16b). Mp 206–207 8C. 1H NMR d (DMSO-d6) 2.91–3.11
(m, 4H), 7.33 (d, J¼8.5 Hz, 1H), 7.31–7.38 (m, 3H), 7.84
(d, J¼8.5 Hz, 1H), 8.06–8.14 (m, 1H), 12.35 (br s, 1H).
MS: 298, 300 (Mþ, 38, 13), 281, 283 (100, 33), 251, 253
(65, 23). Anal. Calcd for C16H11ClN2O2: C, 64.33; H, 3.71;
N, 9.38. Found: C, 64.61; H, 3.62; N, 9.01.
2.3.46. 8-Chloro-5-nitro-1,2,3,4-tetrahydro-g-carboline
1
(20b). Mp 189–190 8C. H NMR d (CDCl3) 2.57 (s, 3H),
2.78–2.87 (m, 2H), 2.93–3.03 (m, 2H), 3.91 (t, J¼1.6 Hz,
2H), 7.14 (d, J¼8.6 Hz, 1H), 7.91 (d, J¼8.6 Hz, 1H), 8.65
(br s, 1H). EIMS m/e (relative intensity): 265, 267 (Mþ, 9,
3), 248, 250 (100, 32), 218, 220 (88, 30). Anal. Calcd for
C12H12ClN3O2: C, 54.25; H, 4.55; N, 15.81. Found: C,
54.48; H, 4.48; N, 15.59.
2.3.39. 7-Chloro-2-(10-naphtyl)-4-nitroindole (17b). Mp
1
213–214 8C. H NMR d (DMSO-d6) 7.36 (d, J¼2.1 Hz,
1H), 7.47 (d, J¼8.6 Hz, 1H), 7.58–7.86 (m, 4H), 8.05–8.20
(m, 3H), 8.13 (d, J¼8.6 Hz, 1H), 12.80 (br s, 1H). EIMS m/e
(relative intensity): 322, 324 (Mþ, 100, 34), 276, 278 (20,
6). Anal. Calcd for C18H11ClN2O2: C, 66.99; H, 3.44; N,
8.68. Found: C, 67.14; H, 3.20; N, 8.42.
2.3.47. Ethylene glycol monoacetal of 8-chloro-1,1-
dimethyl-5-nitro-1,2,3,4-tetrahydro-carbazol-2-one
(product of reaction of ethylene glycol monoacetal of
dimedone with 2-chloro-5-nitroaniline) (21b). Mp 234–
236 8C. 1H NMR (CDCl3) d 1.44 (s, 6H), 2.04 (t, J¼6.6 Hz,
2H), 3.07 (t, J¼6.6 Hz, 2H), 3.99–4.15 (m, 4H), 7.14 (d,
J¼8.5 Hz, 1H), 7.82 (d, J¼8.5 Hz, 1H), 8.28 (br s, 1H).
EIMS m/e (relative intensity): 336, 338 (Mþ, 41, 14), 319,
321 (25, 9), 250, 252 (100, 33). Anal. Calcd for
C16H17N2O4Cl: C, 57.06; H, 5.09; N, 8.32. Found: C,
57.05; H, 5.17; N, 8.11.
2.3.40. 3-Ethyl-4-nitro-2-n-propylindole (18a). Mp 144–
1
145 8C. H NMR d (CDCl3) 0.98–1.11 (m, 6H) 1.61–1.81
(m, 2H), 2.72–2.86 (m, 4H), 7.12 (dd, J¼7.9 Hz, 1H), 7.52
(dd, J¼7.9, 1.0 Hz, 1H), 7.74 (dd, J¼7.9, 1.0 Hz, 1H), 8.27
(br s, 1H). EIMS m/e (relative intensity): 232 (Mþ, 100),
215 (65). Anal. Calcd for C13H16N2O2: C, 67.22; H, 6.94; N,
12.06. Found: C, 67.42; H, 6.98; N, 12.05.
2.3.41. 7-Chloro-3-ethyl-4-nitro-2-n-propylindole (18b).
1
Mp 151–152 8C. H NMR d (CDCl3) 0.98–1.11 (m, 6H),
1.65–1.86 (m, 2H), 2.73–2.87 (m, 4H), 7.12 (d, J¼8.5 Hz,
1H), 7.72 (d, J¼8.5 Hz, 1H), 8.38 (br s, 1H). EIMS m/e
(relative intensity): 266, 268 (Mþ, 100, 33), 249, 251 (70,
23), 221, 223 (39, 14). Anal. Calcd for C13H15ClN2O2: C,
58.54; H, 5.67; N, 10.50. Found: C, 58.38; H, 5.70; N, 10.51.
2.3.48. 3-Ethyl-5-fluoro-6-nitro-2-phenylindole (22e6).
1
Mp 164–165 8C. H NMR d (CDCl3) 1.31 (t, J¼7.6 Hz,
3H), 2.87 (q, J¼7.6 Hz, 2H), 7.40 (d, J¼12 Hz, 1H), 7.44–
7.61 (m, 5H), 8.19 (d, J¼6.1 Hz, 1H), 8.37 (br s, 1H). EIMS
m/e (relative intensity): 284 (Mþ, 71), 269 (100), 223 (48).
Anal. Calcd for C16H13FN2O2: C, 67.60; H, 4.61; N, 9.85.
Found: C, 67.77; H, 4.39; N, 9.89.
2.3.42. 3-Allyl-2-methyl-4-nitroindole (19a). Mp 129–
1
130 8C. H NMR d (CDCl3) 2.44 (s, 3H), 3.54–3.59 (m,
2H), 4.71–4.84 (m, 1H), 4.86–4.95 (m, 1H), 5.82–6.03 (m,
1H), 7.12 (dd, J¼8.0 Hz, 1H), 7.52 (dd, J¼8.0, 1.0 Hz, 1H),
7.74 (dd, J¼8.0, 1.0 Hz, 1H), 8.35 (br s, 1H). EIMS m/e
(relative intensity): 216 (Mþ, 27), 199 (64), 168 (100). Anal.
Calcd for C12H12N2O2: C, 66.65; H, 5.59; N, 12.95. Found:
C, 66.47; H, 5.65; N, 12.75.
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1
121 8C. H NMR d (CDCl3) 2.45 (s, 3H), 3.41–3.50 (m,

358
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