An Expeditious One-Pot Synthesis of N-Substituted 6-Nitroindoles from Indolines

Article abstract of DOI:10.1007/s00706-003-0005-5

This paper reports an one-pot method for the concomitant alkylation - oxidation (aromatization) of indolines, particularly effective to get easy access to N-alkyl-6-nitroindoles, which are useful platforms in medicinal chemistry. N-alkyl-6-nitroindoles are obtained in good yield (64-91%) by reaction at room temperature in non-degassed DMF of 6-nitroindoline, an alkyl halide, and NaH as base. The presence of NaH appears to be essential for a high yield conversion.

Full text of DOI:10.1007/s00706-003-0005-5

Monatshefte f€ur Chemie 134, 1037–1043 (2003)
DOI 10.1007/s00706-003-0005-5
An Expeditious One-Pot Synthesis
of N-Substituted 6-Nitroindoles from Indolines
Guillaume Laconde1, Pascal Carato2, Jacques H. Poupaert3,
1
Pascal Berthelot2, Patrick Depreux1;ꢀ, and Jean-Pierre Henichart
´
1
Institut de Chimie Pharmaceutique Albert Lespagnol, F-59006 Lille, France
2
ꢀ
Laboratoire de Pharmacie Chimique, Faculte de Pharmacie, F-59006 Lille, France
Ecole de Pharmacie, Universite Catholique de Louvain, B-1200, Bruxelles, Belgium
3
ꢀ
Received December 3, 2002; accepted December 9, 2002
Published online May 26, 2003 # Springer-Verlag 2003
Summary. This paper reports an one-pot method for the concomitant alkylation – oxidation (aroma-
tization) of indolines, particularly effective to get easy access to N-alkyl-6-nitroindoles, which are
useful platforms in medicinal chemistry. N-alkyl-6-nitroindoles are obtained in good yield (64–91%)
by reaction at room temperature in non-degassed DMF of 6-nitroindoline, an alkyl halide, and NaH as
base. The presence of NaH appears to be essential for a high yield conversion.
Keywords. Heterocycles; Indole; Indoline; Oxydation; Aromatization.
Introduction
Indole represents a privileged structural element in medicinal chemistry with a
considerable number of applications in drug discovery [1]. Indole templates con-
stitute a major family of targets with a broad array of pharmacological activities,
which have made them medicinally important and synthetically challenging. In this
connection, we recently developed tetracyclic structures with a central N-substi-
tuted indole moiety in order to design products with anti-proliferative activity
against cancer cells (Scheme 1, structure B, structure D [2]). The central indole
system, because of its inherent poor chemical stability, had to be generated at the
end of the scheme from an indoline precursor.
Various methods can effectively be employed to synthesize indoles from indo-
lines such as oxidation by MnO2 [3], CuCl2 [4], DDQ [5], trichloroisocyanuric acid
(TCCA) [6], phenylseleninic anhydride [7], or catalytic dehydrogenation using a
metal catalyst such as Pd=C [8] or Raney nickel [9]. Taken together, these results
suggest that a feasible approach to N-substituted indolic derivatives may consist in
the concomitant alkylation – oxidation (aromatisation) of indolines [10].
ꢀ
Corresponding author. E-mail: pdepreux@phare.univ-lille2.fr

1038
G. Laconde et al.
Scheme 1
Results and Discussion
In this approach applied to structure A, among the various methods to alkylate
indoline [11], we first used K2CO3 in acetone and, after a long reaction time (4
days), we obtained the corresponding N-substituted indolines. In order to reduce
the reaction time, we decided to use NaH as base in DMF which, surprisingly
enough, was found to promote access to N-substituted indoles (structure B) in an
extremely efficient one-pot N-substitution – oxidation process (80–90%, Scheme 1).
However, upon application of the same procedure to compounds of structure C
(which are closely related to B), use of NaH in DMF did not lead to the desired the
N-substituted indoles but rather the N-substituted indolines (structure D). It was
consequently anticipated that the electronic demand of the substituents was of
major importance for the success of this concomitant N-substitution – oxidation
process.
In an effort to ascertain the synthetic value of this procedure, a study involving
simple indoline model compounds (Table 1) was undertaken to investigate the ap-
plication of this substitution – oxydation. From commercially available indolines,
the corresponding N-methyl indoles (2a–2d) and=or N-methyl indolines (3a–3d)
were obtained in the presence of NaH (1.5 equiv.) and methyl iodide (1.5 equiv.) in
DMF [12]. As indicated in Table 1, indoline 1a gave a ꢁ50:50% (1H NMR) ratio of
the N-substituted indole 2a [13] and N-substituted indoline 3a [14]. In contrast, the
electron-withdrawing nitro group in position 5 (1c) and electron-donating methoxy
Scheme 2

An Expeditious One-Pot Synthesis of N-Substituted 6-Nitroindoles
Table 1. NaH-mediated alkylation – oxydation of indolines (1a–1d)
1039
Indoline
R
Substituted indole, yield %
Substituted indoline, yield %
1a
1b
1c
1d
H
2a: 50
2b: 0
2c: 0
3a: 50
3b: 75
3c: 90
3d: 0
5-OMe
5-NO2
6-NO2
2d: 83
group in position 5 (1b) gave exclusively N-substituted indolines 3b [15] and 3c
[16, 17] in 75 and 90% yield. In accordance with this observation, a previous ob-
servation [12] indicated that 5-bromoindoline with alkyl halides in the presence of
NaH gave exclusively N-alkyl-5-bromoindolines. Indoline substituted with a strong
electron-withdrawing substituent such as the nitro group in position 6 (1d) clearly
promoted this concomitant substitution – oxidation process giving 2d with 83%
yield. All these facts underscore the importance of the positioning of the electron-
withdrawing substituent for the success of the aromatisation.
It is noteworthy that 1c and 1d show opposite behavior (Table 1) and this
provides further insight into the mechanistic aspect of these transformations. The
more acidic 1c is selectively N-methylated while 1d, with the 6-NO2 group acti-
vating the benzylic methylene in position 3, undergoes both methylation and ox-
idation. Moreover, 1a is selectively N-methylated (and not oxidized) when treated
with methyl iodide in the presence of potassium carbonate in acetone or DMF. It
should be kept in mind also that oxidized compounds are always isolated in their
N-alkylated form. Consequently, it can be advanced that N-alkylation is a primary
event in the overall process. Effectively, N-methyl-6-nitroindoline was oxidized
into N-methyl-6-nitroindole in the presence of NaH. On the basis of all the afore-
mentioned arguments, we can therefore propose a tentative mechanism (Scheme 3)
Scheme 3. Mechanism of the one-pot oxidation – N-substitution process

1040
G. Laconde et al.
involving air oxygen. It is known, indeed, that DMF is a good solvent of oxygen.
This mechanism proposed here appears in clear agreement with Cannon’s previous
observation that indolines are air oxidized in strongly basic media [18].
In this mechanism, the first reaction is the nucleophilic substitution of the in-
dole. In the second step, NaH initiates the oxidation by withdrawing a proton in the
benzylic position 3 of the N-substituted indoline 3 to give the corresponding anion
4. Structure 4 (in resonance with 5) combines with molecular oxygen via a single
electron transfer to produce the radical species 6. This radical 6 then interacts with
another oxygen molecule, which leads to the peroxyradical 7. Subsequent recom-
bination of 7 with 4 generates the peroxyanion 8 simultaneously with the produc-
tion of 6. Elimination of the peroxydianion from 8 affords the iminium 9, which is
then converted to indole 2 by the abstraction of a proton by the peroxydianion,
giving rise to a hydroperoxide anion.
A key feature in this mechanism is the proposal of a benzylic radical. Quantum-
mechanical calculations at AM1 and PM3 level show that the 6-NO2 substitution
favors the radical species 6 while the 5-NO2 substitution destabilizes the same rad-
ical species. Semi-empirical quantum-mechanical calculations were performed with
MOPAC 6.0 using the AM1 and PM3 Hamiltonians for 1c and 1d. Atom-centered
partial charges and molecular electrostatic potentials (ESP) were calculated by the
method of Mulliken as implemented in MOPAC 6.0. A conformational search was
performed for each compound. The capto-dative stabilisation of the benzylic radical
could be appreciated by calculating the partial charge difference (Dq) of the carbon
neighboring the benzylic carbon [19]. Indeed, in 5-nitroindoline, Dq was equal to
0.014 while for the 6-nitro species this figure was 0.056, which represents a 4.1 fold
increase.
Scheme 4
Table 2. N-Alkylindoles 2d–2i synthesis from 6-nitroindoline (1) and alkyl halides
Products
R-X
Yield %
2d
2e
2f
CH3–I
83
86
91
88
75
C2H5–I
C3H7–I
2g
2h
C4H9–I
C6H5–CH2–Br
2i
64

An Expeditious One-Pot Synthesis of N-Substituted 6-Nitroindoles
1041
The reaction was exemplified with several alkyl halides and the results are pre-
sented in Table 2. All N-alkyl-6-nitroindoles 2d–2i were obtained in fair to good
yields (64–91%). As 6-nitroindoline is effectively obtained by nitration of indoline
in 90% yield [20] by a simple nitration in HNO3–H2SO4 in the presence of a radical
scavenger, the method reported here clearly offers a viable route to N-alkyl-6-
nitroindoles and subsequent key applications in medicinal chemistry as illustrated
by several recent disclosures [21, 22]. Our finding is in the line of a recent report by
Samet et al. who described the aromatisation of the strongly electron-deficient
4,6-dinitro-1-(p-toluenesulfonyl)indoline by air oxidation at 70ꢂC in pyridine.
Conclusion
In conclusion, we have developed a one-pot method for alkylation – oxydation of
N-substituted indolines that is especially effective to get access to N-alkyl-6-
nitroindoles in good yield by reacting at room temperature in DMF 6-nitroindoline,
an alkyl halide, and NaH as base. The reaction was found to proceed smoothly and
is likely to be extended to other indoline derivatives bearing electron-withdrawing
groups in position 6. In view of the simplicity of the procedure and the high yields
obtained, the procedure has some value for the production of indole compound
ensembles using fast parallel synthesis techniques.
Experimental
€
Melting points were determined with a Buchi 535 capillary melting point apparatus and are uncor-
rected. H NMR (300MHz) spectra were obtained from solutions in CDCl3 on a Bruker AC 300P
1
apparatus. The NMR spectra were recorded at ambient temperature using TMS as internal reference. IR
spectra were recorded using a dispersion of the product in KBr disks by means of a Perkin-Elmer
Model 297 spectrometer. Rf values refer to thin layer chromatography plates (5.0ꢃ 10cm, 250 ꢀm,
silica gel 60 F254), developed in the solvent system indicated. Mass spectra were recorded on a Mat
1
SSQ710 mass spectrometer. All compounds reported had IR, H and 13C NMR, MS, and elemental
analysis data consistent with their structures. The experimental elemental analysis figures were found
to be within 0.4% of the calculated values. All reagents were purchased from Aldrich. 2a, 3a, 3b, and
3c mentioned in the text were identical with the compounds already described in Refs. [13–16].
Preparation of N-Substituted Indoles
A solution of 1.0 g of 6-nitroindoline (6 mmol) in 10 cm3 of anhydrous DMF was added dropwise to a
solution of 0.27 g of NaH (9 mmol) in 5 cm3 of DMF. The solution was stirred at room temperature
while a red color slowly developed. After 3 h, 0.56 cm3 of CH3I (9mmol) diluted in 5 cm3 of anhydrous
DMF was added dropwise over 10 min and the mixture was stirred for 16h at room temperature. The
solution was evaporated in vacuo to dryness and 50cm3 of H2O were added. The resulting precipitate
was collected by filtration, washed with 100 cm3 of H2O, and recrystallized from ethanol.
N-Methyl-6-nitroindole (2d, C9H8N2O2)
1
Yield 0.9 g (83%), mp 73–74ꢂC, TLC: Rf (CH2Cl2) ¼ 0.75; H NMR: ꢁ ¼ 3.90 (s, 3H), 6.60 (d,
J ¼ 2.72Hz, 1H), 7.36 (d, J ¼ 2.72 Hz, 1H), 7.66 (d, J ¼ 8.72Hz, 1H), 8.02 (dd, J ¼ 2.18, 8.72 Hz,
1H), 8.33 (d, J ¼ 2.18 Hz, 1H) ppm; MS (70 eV): m=z ¼ 176 (Mþ ).

1042
G. Laconde et al.
N-Ethyl-6-nitroindole (2e, C10H10N2O2)
Yield 0.94g (86%), mp 78–79ꢂC, TLC: Rf (CH2Cl2) ¼ 0.78; 1H NMR: ꢁ ¼ 1.02 (m, 3H), 4.05 (m, 2H),
6.61 (d, J ¼ 3.10 Hz, 1H), 7.41 (d, J ¼ 3.10Hz, 1H), 7.67 (d, J ¼ 8.55 Hz, 1H), 8.03 (dd, J ¼ 1.93,
8.55Hz, 1H), 8.33 (d, J ¼ 1.93 Hz, 1H); MS (70 eV): m=z ¼ 190 (Mþ ).
N-Propyl-6-nitroindole (2f, C11H12N2O2)
Yield 0.95 g (91%), mp 65–66ꢂC, TLC: Rf (CH2Cl2) ¼ 0.8; 1H NMR: ꢁ ¼ 0.99 (m, 3H), 1.92 (m, 2H),
4.19 (m, 2H), 6.60 (d, J ¼ 3.37 Hz, 1H), 7.41 (d, J ¼ 3.37Hz, 1H), 7.67 (d, J ¼ 8.65Hz, 1H), 8.02 (dd,
J ¼ 1.93, 8.65 Hz, 1H), 8.33 (d, J ¼ 1.93 Hz, 1H); MS (70 eV): m=z ¼ 204 (Mþ ).
N-Butyl-6-nitroindole (2g, C12H14N2O2)
Yield 0.94g (88%), mp 60–61ꢂC, TLC: Rf (CH2Cl2) ¼ 0.81; 1H NMR: ꢁ ¼ 0.99 (m, 3H), 1.38 (m, 2H),
1.88 (m, 2H), 4.21 (m, 2H), 6.60 (d, J ¼ 3.27Hz, 1H), 7.40 (d, J ¼ 3.27 Hz, 1H), 7.66 (d, J ¼ 8.72 Hz,
1H), 8.02 (dd, J ¼ 1.64, 8.72Hz, 1H), 8.30 (d, J ¼ 1.64 Hz, 1H); MS (70 eV): m=z ¼ 218 (Mþ ).
N-Benzyl-6-nitroindole (2h, C15H12N2O2)
1
Yield 0.84g (75%), mp 72–73ꢂC, TLC: Rf (CH2Cl2) ¼ 0.81; H NMR: ꢁ ¼ 4.81 (s, 2H), 6.60 (d,
J ¼ 3.27Hz, 1H), 7.40 (d, J ¼ 3.27Hz, 1H), 7.52 (m, 3H), 7.66 (d, J ¼ 8.72Hz, 1H), 7.88 (m, 2H), 8.02
(dd, J ¼ 1.64, 8.72 Hz, 1H), 8.30 (d, J ¼ 1.64Hz, 1H); MS (70 eV): m=z ¼ 252 (Mþ ).
N-(3,4,5-Trimethoxybenzyl)-6-nitroindole (2i, C18H18N2O5)
Yield 1.46 g (64%), mp 95–96ꢂC, TLC: Rf (CH2Cl2) ¼ 0.65; 1H NMR: ꢁ ¼ 3.78 (s, 6H), 3.81 (s, 3H),
5.34 (s, 2H), 6.36 (s, 2H), 6.67 (d, J ¼ 3.08Hz, 1H), 7.42 (d, J ¼ 3.08Hz, 1H), 7.70 (d, J ¼ 8.78 Hz,
1H), 8.04 (dd, J ¼ 1.76, 8.78Hz, 1H), 8.34 (d, J ¼ 1.76 Hz, 1H); MS (70 eV): m=z ¼ 342 (Mþ ).
Acknowledgements
Thanks are due to Prof. S. Z. Zard (Ecole Polytechnique, Palaiseau, France) and Prof. C. Amatore (ENS
Chimie, Paris, France) for their valuable contributions and helpful discussions.
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