Synthesis of methyl 5- and 6-nitroindole-2-carboxylates by nitration of indoline-2-carboxylic acid

Article abstract of DOI:10.1055/s-2002-20043

Indoline-2-carboxylic acid was transformed into 6-nitroindoline-2-carboxylic acid, the methyl ester of which was easily dehydrogenated by DDQ to methyl 6-nitroindole-2-carboxylate (total yield: 67%). Methyl 5-nitroindole-2-carboxylate was obtained by the nitration of methyl 1-acetylindoline-2-carboxylate acid followed by dehydrogenation with MnO₂ in toluene in 40% total yield.

Full text of DOI:10.1055/s-2002-20043

320
SHORT PAPER
Synthesis of Methyl 5- and 6-Nitroindole-2-carboxylates by Nitration of
Indoline-2-carboxylic Acid
Synthesis of
5
e
and 6-Nitr
r
oindole-
g
2-carboxylat
e
es i N. Lavrenov, Sergei A. Lakatosh, Ludmila N. Lysenkova, Alexander M. Korolev, Maria N.
Preobrazhenskaya*
G.F. Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, B. Pirogovskaya 11, Moscow 119992, Russia
Fax +7(095)2450295; E-mail: lcta@space.ru
Received 6 November 2001; revised 15 December 2001
Abstract: Indoline-2-carboxylic acid was transformed into 6-ni-
COOH
COOMe
troindoline-2-carboxylic acid, the methyl ester of which was easily
dehydrogenated by DDQ to methyl 6-nitroindole-2-carboxylate (to-
tal yield: 67%). Methyl 5-nitroindole-2-carboxylate was obtained
by the nitration of methyl 1-acetylindoline-2-carboxylate acid fol-
lowed by dehydrogenation with MnO2 in toluene in 40% total yield.
N
H
N
R
1
8. R = H
HNO3
9. R = Ac
Extraction
at pH 4.5
72 %
HNO3
63 %
Extraction
at pH<2
Key words: methyl 5- and 6-nitroindole-2-carboxylate, indoline-
indole method, indoles
O2N
O2N
COOH
+
2
COOH
COOCH3
O2N
N
N
H
N
H
5
2
Nitroindole-2-carboxylic acids are the precursors of cor-
responding aminoindole carboxylic acids, which can be
used as building blocks in the synthesis of analogs of the
antibiotics containing carboxamide moieties (e.g. CC-
1065, distamycin, and netropsin) capable of sequence se-
lective DNA interaction. Whereas ethyl 5-nitroindole-2-
carboxylate was obtained by Fischer indole synthesis
from the 4-nitrophenylhydrazone of ethyl pyruvate in 50–
60% yields, ethyl 6-nitroindole-2-carboxylate was ob-
tained from the 3-nitrophenylhydrazone of ethyl pyruvate
in 8% yield as a mixture with the 4-nitro isomer.1–3 Methyl
4,5,6, and 7-nitroindole-2-carboxylates were also ob-
tained by condensation of the corresponding nitrobenzal-
dehydes with methyl 2-azidoacetate followed by
thermolysis.4 Nitration of protonated indoline leads selec-
tively to 6-nitroindoline, whereas nitration of 1-acetylin-
doline produces 1-acetyl-5-nitroindoline as protonated
nitrogen gives meta-direction whereas the non-protonated
N-acetyl group in indoline shows para-direction.5 We
used here this indoline-indole approach for the prepara-
tion of nitroderivatives of indole-2-carboxylic acid. Nitra-
tion of commercially available indoline-2-carboxylic acid
with concentrated HNO3 in concentrated H2SO4 led to a
mixture of 6- and 5-nitroindoline-2-carboxylic acids 2 and
5, in which the 6-nitro derivative 2 was the predominant
compound (Scheme). Compound 5 admixed with 2 was
extracted with EtOAc at pH < 2, then the aqueous phase
was adjusted to pH 4.5–5.0 and extracted with EtOAc, to
give 72% of pure 6-nitroindoline-2-carboxylic acid (2),
which was esterified to give methyl 6-nitroindoline-2-car-
boxylate (3). Additional amounts of 3 (6%) and 6 (10%)
were obtained after esterification of the products extracted
from the reaction mixture at pH < 2, followed by column
COCH3
10
MeOH, H+
chromatography
MeOH, H+
90 %
5 % from 1
1. 1N HCl
10 % from 1
2. MeOH, H+
83 %
O2N
COOMe
COOMe
N
N
O2N
3
H
6
H
MnO2
94 %
DDQ
94 %
,
O2N
COOMe
COOMe
N
O2N
N
H
H
4
7
Scheme Synthesis of methyl 6- and 5-nitroindole-2-carboxylates
chromatography. Dehydrogenation of 3 proceeded under
unexpectedly mild conditions (refluxing with DDQ in a
EtOAc–benzene mixture) to give the target methyl 6-ni-
troindole-2-carboxylate (4) in 95% yield.
For the preparation of methyl 5-nitroindole-2-carboxylate
(7) we used methyl 1-acetylindoline-2-carboxylate (9),
which was obtained by the acetylation of methyl indoline-
2-carboxylate (8) (Scheme). Nitration of 9 in concentrated
HNO3–Ac2O mixture gave methyl 1-acetyl-5-nitroindo-
line-2-carboxylate (10) (63% after column chromatogra-
phy). Hydrolysis of 10 led to 5-nitroindoline-2-carboxylic
acid, which was reesterified without isolation to give ester
6. All attempts to dehydrogenate compound 6 using DDQ
under various conditions were unsuccessful, but refluxing
6
of 6 with fresh -MnO2 in toluene gave methyl 5-nitroin-
dole-2-carboxylate (7) in 78% yield (40% from 1). The
molecular structures of the compounds obtained were
supported by 1H NMR spectroscopy (Table). A significant
NOE between NH and 7-H, as well as between 3-H and 4-
H for compounds 4 and 7 are strongly indicative for the
Synthesis 2002, No. 3, 18 02 2002. Article Identifier:
1437-210X,E;2002,0,03,0320,0322,ftx,en;Z11901SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

SHORT PAPER
Synthesis of 5- and 6-Nitroindole-2-carboxylates
321
Table 1H NMR Spectra of Compounds 3,4,6,7,10
Compd (Solvent) Chemical Shifts ( ) and Spin-Coupling Constants J (Hz)
H-7
[J7,6
(J7,5
H-6
[J6,5
(J6,4
H-5
[J5,4
(J5,7
H-4
[J4,5
(J4,6
H-3a
[J3a,3b
(J3a,2
H-3b
[J3b,3a
(J3b,2
H-2
[J2,3a]
(J2,3b )
Other Signals
]
)
]
)
]
)
]
)
]
]
)
)
{J6,7
}
3
7.43 d
(2.15)
7.60 dd
[8.06]
(2.01)
7.14 d
[8.14]
3.36 m
[16.78]
(5.35)
3.43 m
[17.21]
(10.11)
4.43 dd
[5.37]
(10.12)
CO2CH3: 3 H, s 3.76
(CDCl3)
–
4
8.33 d
(2.08)
7.91dd
[8.89]
(2.08)
7.86 d
[8.91]
7.29 s
NH: s, 12.3
CO2CH3: 3 H, s 3.95
(DMSO-d6)
–
–
–
6
7.46 d
[8.24]
8.12 dd
(2.16)
{8.29}
8.67 d
(2.16)
3.63 dd
[17.86]
(10.72)
3.29 dd
[17.86]
(4.58)
5.17 dd
[10.76]
(4.58)
CO2CH3: 3 H, s 3.74
(CDCl3)
–
–
–
7
7.60 d
[9.15]
8.17 dd
{9.15}
(2.34)
8.74 d
(1.97)
7.43 s
NH: s, 12.3
CO2CH3: 3 H, s, 3.95
(DMSO-d6)
–
–
10
8.31d
[8.8]
8.16 dd
(2.42)
{8.8}
8.1s
3.77 m
3.48 d
[16.53]
5.43
d [10.1]
COCH3 : 3 H, s, 2.23
CO2CH3: 3 H, s, 3.81
(acetone-d6)
Methyl 6-Nitroindoline-2-carboxylate (3) and Methyl 5-Nitro-
indoline-2-carboxylate (6)
position of the nitro groups: irradiation of 3-H atom (7.39
ppm) in compound 4 led to the enhancement of intensity
of the 4-H signal (7.86 ppm, J4,5 = 8.91 Hz) by 7%, and
irradiation of the 1-H atom increased the 7-H signal (8.33
ppm, d, J7,5 = 2.08 Hz) by 20%. Similarly, irradiation of
the 3-H atom (7.43 ppm) of 7 increased the intensity of the
4-H signal (8.74 ppm, J4,6 = 1.97 Hz) by 8%, and irradia-
tion of the 1-H atom increased the intensity of the 7-H
doublet (7.60 ppm, J7,6 = 9.15 Hz) by 10%.
A solution of 2 (23 g, 111 mmol) and p-toluenesulfonic acid mono-
hydrate (11 g) in MeOH (100 mL) was refluxed for 30 min, then the
solvent was removed in vacuo and the resulting dark solid was dis-
solved in EtOAc. The solution was washed with sat. aq NaHCO3 so-
lution and then with H2O until the pH was neutral. The dried
solution was evaporated to give methyl 6-nitroindoline-2-carboxy-
late (3; 22 g, 90%) as dark yellow crystals; mp 102–104 °C
(MeOH). Additional amounts of 3 and methyl 5-nitroindoline-2-
carboxylate (6) were obtained from the extract (a) after evaporation
and stirring in MeOH with p-toluenesulfonic acid monohydrate (5
g) for 20 h. After evaporation, the residue was dissolved in EtOAc
and washed with aq NaHCO3 solution, dried (Na2SO4), and evapo-
rated. The products were isolated by column chromatography (silica
gel, n-heptane–acetone, 4:1); the fractions with Rf 0.24 (in the same
system) gave 6 (2.67 g, 10% from 1) as yellow powder; mp 124–
126 °C (n-heptane–acetone) and fractions with Rf 0.32 gave 3 (1.33
g, 5%) (Table).
In conclusion, we have developed a convenient method
for the synthesis of methyl 6-nitroindole-2-carboxylate
starting from indoline-2-carboxylic acid. A new method
for the synthesis of methyl 5-nitroindole-2-carboxylate
was also developed.
Analytical TLC was performed on Kieselgel F254 plates (Merck)
and column chromatography on silica gel 60 (Merck). Melting
points were determined on a Büchi SMP-20 apparatus and are un-
corrected. 2-Carboxyindoline was purchased from Aldrich.
3
Anal. Calcd for C10H10N2O4 (222.2): C, 54.05; H, 4.54; N, 12.61.
Found: C, 54.06; H, 4.43; N, 12.75.
6-Nitroindoline-2-carboxylic Acid (2)
Methyl 6-Nitroindole-2-carboxylate (4)
Indoline-2-carboxylic acid (1; 25 g, 153 mmol) was dissolved in
98% H2SO4 (200 mL) at –5 °C. Concd HNO3 (d 1.5 g/cm3, 6.93 mL,
165 mmol) was slowly added at –20 to –10 °C to the stirred solu-
tion. After 30 min of stirring, the reaction mixture was poured into
crushed ice (500 g) and extracted with EtOAc. The extract (a) was
collected for the isolation of 5-nitroindoline-2-carboxylic acid (5)
(see below). The aqueous phase was adjusted to pH 4.5–5.0 with aq
NaOH solution, extracted with EtOAc, and the organic extract was
dried (Na2SO4). The extract (b) was evaporated in vacuo at a tem-
perature below 45 °C (to prevent decarboxylation) to give 2 (23 g,
72%) as a dark yellow oil, which was used for esterification.
A solution of 3 (22 g, 100 mmol) and DDQ (25 g, 110 mmol) in
EtOAc–benzene (1:2, 100 mL) was refluxed for 30 min and then di-
luted with of EtOAc (400 mL). The resulting solution was washed
several times with the sat. aq NaHCO3 solution, dried (Na2SO4), and
evaporated to give 4 (20.7 g, 94%) as yellow powder; Rf 0.80 (n-
heptane–EtOAc, 2:1); mp 225–227 °C (EtOAc) (Table).
Anal. Calcd for C10H8N2O4 (220.2) : C, 54.5; H, 3.66; N, 12.72.
Found: C, 54.35; H, 3.68; N, 12.65.
Methyl 1-Acetyl-5-nitroindoline-2-carboxylate (10)
Methyl indoline-2-carboxylate (8; 800 mg, 4.5 mmol) was dis-
solved in Ac2O (5 mL) and Et3N (800 L, 1 equiv) was added. The
reaction mixture was stirred at r.t. for 1 h and then poured into a
Synthesis 2002, No. 3, 320–322 ISSN 0039-7881 © Thieme Stuttgart · New York

322
S. N. Lavrenov et al.
SHORT PAPER
mixture of ice and aq NaHCO3, and the product was extracted with
EtOAc. The extract was washed subsequently with sat. aq citric acid
(20 mL), aq NaHCO3, H2O, brine, then dried and evaporated to give
9 as a brown oil, which was used in the next step without further pu-
rification. It was dissolved in Ac2O (10 mL) and a solution of conc.
HNO3 (300 L) in Ac2O (5 mL) was added dropwise at 0 °C. The
mixture was stirred for 1.5 h and then poured into a mixture of ice
and aq NaHCO3. The product was extracted with EtOAc (100 mL),
washed with sat. aq NaHCO3 solution, H2O and brine, dried, evap-
orated, and purified by column chromatography (SiO2, n-heptane–
EtOAc, 1.5:1) to give 10 as a yellowish solid (750 mg, 63% from
8); Rf 0.41 (n-heptane–EtOAc, 1:1); mp 122–125 °C (n-heptane–
EtOAc) (Table).
pared -MnO2 (1 g) for 1 h. The reaction mixture was filtered and
the filter cake was washed with EtOAc. The washings and the fil-
trate were colleced and evaporated to give a solid residue, which
was washed with Et2O and dried in vacuo. Recrystallization from
toluene gave 7 (40 mg, 78%); mp 290–292 °C (dec.) (Table).
Anal. Calcd for C10H8N2O4 (220.2): C, 54.55; H, 3.66; N, 12.72.
Found: C, 54.67; H, 3.43; N, 12.75.
Acknowledgement
This work was supported by Russian Fund of Fundamental Rese-
arch (project 01-03-33-028).
Anal. Calcd for C12H12N2O5 (264.2): C, 54.55; H, 4.58; N, 10.60.
Found: C, 54.38; H, 4.51; N, 10.68.
References
(1) Parmerter, S. M.; Cook, A. G.; Dixon, W. B. J. Am. Chem.
Soc. 1958, 80, 4621.
(2) Cavallini, G.; Ravenna, F. Farmaco Ed. Sci. 1958, 1, 105;
Chem. Abstr. 1958, 52, 20126.
(3) Kost, A. N.; Sagittulin, R. S.; Gorbunov, V. I.; Barinova, G.
I. Khim. Farm. Zh. 1967, 3, 14; Chem. Abstr.1967, 67,
67532.
(4) Boger, D. L.; Yun, W.; Han, N.; Johnson, D. S. Bioorg. Med.
Chem. 1995, 3, 611.
Methyl 5-Nitroindoline-2-carboxylate (6)
Methyl 1-acetyl-5-nitroindoline-2-carboxylate (10; 500 mg, 1.9
mmol) was refluxed in 1 N HCl (25 mL) until dissolution was com-
pleted. The reaction mixture was evaporated and dissolved in anhyd
MeOH (50 mL), cooled to –10 °C, and treated with SOCl2 (5 mL).
It was then left to stir at r.t. overnight. The mixture was evaporated,
the residue was dissolved in EtOAc (100 mL), the EtOAc solution
was washed with aq NaHCO3, then with H2O and brine, dried
(Na2SO4) and evaporated to give crude 6 (350 mg, 83%) (Table).
(5) Preobrazhenskaya, M. N. Russ. Chem. Rev. 1967, 36, 753.
(6) Fatiadi, A. J. Synthesis 1976, 133.
Methyl 5-Nitroindole-2-carboxylate (7)
Methyl 5-nitroindoline-2-carboxylate (6; 50 mg, 0.23 mmol) was
dissolved in anhyd toluene (30 mL) and refluxed with freshly pre-
Synthesis 2002, No. 3, 320–322 ISSN 0039-7881 © Thieme Stuttgart · New York