Straightforward selective preparation of nitro- or amino-indoles from 2-halonitroanilines and alkynes. First synthesis of 7-amino-5-nitroindoles

Article abstract of DOI:10.1016/j.tetlet.2009.05.027

A one-pot selective synthesis of 2-substituted C5-, C6-, and C7-nitro- or amino-indoles has been developed from 2-halonitroanilines. These two types of nitrogen-substituted indoles have been selectively obtained by only varying the solvent used in the tandem Sonogashira coupling/heteroannulation reaction. Moreover, from commercially available 2-bromo-4,6-dinitroaniline an unprecedented in situ selective reduction of one of the nitro groups has allowed the synthesis of new 7-amino-5-nitro-2-substituted indoles.

Full text of DOI:10.1016/j.tetlet.2009.05.027

Tetrahedron Letters 50 (2009) 4423–4426
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Straightforward selective preparation of nitro- or amino-indoles from
2-halonitroanilines and alkynes. First synthesis of 7-amino-5-nitroindoles
*
Roberto Sanz , Verónica Guilarte, Antonio Pérez
Área de Química Orgánica, Departamento de Química, Facultad de Ciencias, Universidad de Burgos, Pza. Misael Bañuelos, s/n, 09001 Burgos, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-pot selective synthesis of 2-substituted C5-, C6-, and C7-nitro- or amino-indoles has been devel-
oped from 2-halonitroanilines. These two types of nitrogen-substituted indoles have been selectively
obtained by only varying the solvent used in the tandem Sonogashira coupling/heteroannulation reac-
tion. Moreover, from commercially available 2-bromo-4,6-dinitroaniline an unprecedented in situ selec-
tive reduction of one of the nitro groups has allowed the synthesis of new 7-amino-5-nitro-2-substituted
indoles.
Received 2 April 2009
Revised 5 May 2009
Accepted 13 May 2009
Available online 18 May 2009
Keywords:
Ó 2009 Elsevier Ltd. All rights reserved.
Nitroindoles
Aminoindoles
Reduction
Coupling
Cyclization
Indoles bearing nitrogen substituents on the benzenoid moiety
are often found to exhibit biological activity,1 and so the develop-
ment of synthetic methodologies that allow the easy access to
this type of compounds is of current interest. Among them,
nitroindoles2 are useful starting materials to a wide range of nitro-
gen-substituted indole derivatives such as aminoindoles and
azidoindoles.3 Considering the many methods available for the
indole-ring synthesis, the cyclization under basic conditions of
o-alkynylanilines, usually prepared from o-haloanilines via the
Sonogashira reaction, is a valuable methodology.4 In this context,
the synthesis of different 2-substituted-nitroindoles derivatives
has been reported from commercially available 2-haloanilines,4b–d
or 2-amino-nitrophenols by this cross-couplingÀheteroannulation
approach.5 Following our interest in the development of new meth-
ods for the synthesis of regioselectively functionalized indoles,6 we
have recently developed an efficient route to 2-substituted indoles
from 2-iodoanilines and terminal alkynes, using a NaOH-mediated
5-endo-dig cyclization as the key step.7 Herein, we wish to report a
novel one-pot procedure for the synthesis of 2-substituted indoles
possessing selectively a nitro or an amino substituent at the C5,
C6, or C7 positions.
We thought that the formation of 4 could be due to competitive
hydrogenation of intermediate 2-alkynylaniline 5 under the reac-
tion conditions. Surprisingly, we observed that a simple solvent
change from DMF to N,N-dimethylacetamide (DMA) completely
avoided the formation of the side product 4 allowing the isolation
of 2-phenylindole 3 in 76% yield (Scheme 1).
This result suggests that when the reaction is performed in DMF
an ammonium formate derivative, which is known to act as a
source of hydrogen,8 is generated under the basic reaction
conditions.
Having in mind that a simultaneous reduction of nitro- to ami-
no-group has been observed in a Pd-catalyzed Suzuki cross-cou-
pling reaction,9 and taking advantage from the finding that a
hydrogen source must be generated under our reaction conditions
in DMF as solvent, we reasoned that nitroindoles or aminoindoles
When we attempted the synthesis of 2-phenylindole from
2-iodoaniline 1a and phenylacetylene 2a under our previously re-
ported conditions,7 we observed the formation of 2-(2-phenyl-
ethyl)aniline 4 (48% yield) along with the expected 2-phenylindole
3 (25% yield) (Scheme 1).
* Corresponding author. Tel.: +34 947 258036; fax: +34 947 258831.
E-mail address: rsd@ubu.es (R. Sanz).
Scheme 1. One-pot Sonogashira coupling/NaOH-mediated reactions of 2-iodoan-
iline 1a with phenylacetylene 2a.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.027

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R. Sanz et al. / Tetrahedron Letters 50 (2009) 4423–4426
Table 1
Synthesis of nitroindoles 6 and aminoindoles 7 from 2-halonitroanilines 1 and terminal alkynes 2
Entry
Starting aniline
Alkyne
R
Solvent
Product
6ba: R = Ph
Yielda (%)
1
2
3
4
2a
2b
2c
2d
Ph
c-C6H9
n-Bu
DMA
DMA
DMA
DMA
84
76
89c
81
b
6bb: R = c-C6H9
6bc: R = n-Bu
6bd: R = n-C5H11
n-C5H11
5
6
7
8
9
2a
2b
2c
2d
2e
Ph
c-C6H9
n-Bu
n-C5H11
DMF
DMF
DMF
DMF
DMF
7ba: R = Ph
7bb: R = c-C6H9
7bc: R = n-Bu
7bd: R = n-C5H11
7be: R = 4-F-3-MeC6H3
55
48
65
66
44c
b
4-F-3-MeC6H3
10
11
2c
2f
n-Bu
3-ClC6H4
DMA
DMA
6cc: R = n-Bu
6cf: R = 3-ClC6H4
55c
76c
b
12
13
14
2b
2c
2d
c-C6H9
n-Bu
DMF
DMF
DMF
7cb: R = c-C6H9
7cc: R = n-Bu
7cd: R = n-C5H11
40
46
n-C5H11
45c
15
16
2a
2d
Ph
n-C5H11
DMA
DMA
6da: R = Ph
6dd: R = n-C5H11
69
52c
b
17
2b
c-C6H9
DMF
7db: R = c-C6H9
30
18
19
2a
2d
Ph
n-C5H11
DMA
DMA
6ea: R = Ph
6ed: R = n-C5H11
60
47
20
21
22
2a
2d
2g
Ph
n-C5H11
4-MeC6H4
DMF
DMF
DMF
7ea: R = Ph
7ed: R = n-C5H11
7eg: R = 4-MeC6H4
45
32
43
a
Isolated yield after column chromatography.
1-Cyclohexenyl.
Carried out under microwave irradiation (140 °C, maximum wattage supplied 80 W): 20 min for the cyclization step and 30 min for the reduction.
b
c
could be selectively synthesized from the same starting 2-haloni-
troanilines 1 by a simple selection of the reaction solvent. To our
delight, we found that whereas the use of DMA as solvent allowed
the preparation of expected nitroindoles 6 in good yields, when
DMF was employed a simultaneous reduction of the nitro- to the
corresponding amino-group took place allowing the preparation
of aminoindoles 7 in moderate yields10 (Table 1). In some cases,
when DMF was used, the reduction of the intermediate nitroin-
doles 6 takes place slowly. However, we found that the addition
of Pd/C (5 mol %) to the reaction mixture allowed the complete
reduction in reasonable times. Aryl-, alkyl-, and alkenyl-groups
could be placed at the C-2 of the final indoles 6 and 7 starting from
different alkynes 2a–g (Table 1). Regarding the starting 2-halonit-
roaniline, the use of commercially available 1b allows the synthe-
sis of 4-nitroindoles 6ba–d in high yields (entries 1À4) and 4-
aminoindoles 7ba–e in moderate to good yields (entries 5À9). On
the other hand, C7-nitroindoles 6cc, f and 6da, d (entries 10À11,
15À16) as well as C7-aminoindoles 7cb–d and 7db (entries
12À14, 17) were obtained from 2-iodoanilines 1c and 1d11 in mod-
erate yields. Finally, C6-nitrogen-substituted indoles 6ea, d and
7ea–g (entries 18À22) were also synthesized from commercially
available 2-bromoaniline 1e in moderate yields. We have also
found that the reaction times for the NaOH-mediated cyclization
and the simultaneous reduction of the nitro groups could be dra-
matically reduced by carrying out the process under microwave
irradiation.12

R. Sanz et al. / Tetrahedron Letters 50 (2009) 4423–4426
4425
Table 2
Synthesis of 7-amino-5-nitro-2-substituted indoles 9 from 2-bromo-4,6-dinitroani-
line 1f and terminal alkynes 214
Entry
Alkyne
R
Product
Yielda (%)
1
2
3
4
5
6
2a
2b
2c
2d
2f
Ph
c-C6H9
n-Bu
n-C5H11
3-ClC6H4
4-MeC6H4
9a
9b
9c
9d
9e
9f
46
36
40
50
44
43
b
Scheme 3. Preparation of 7-amino-5-nitroindole derivatives 10 and 11.
2g
a
Isolated yield after column chromatography.
1-Cyclohexenyl.
b
In order to further evaluate the scope of the process, we decided
to use commercially available 2-bromo-4,6-dinitroaniline 1f as
starting 2-halonitroaniline. Due to the strong electron-withdraw-
ing effect of the two nitro groups, the cyclization of intermediate
o-alkynylanilines to the corresponding 2-substituted 5,7-dinitroin-
doles 8 took place without the addition of base (Scheme 2). This
process could also be carried out under microwave irradiation
affording compounds 8 in good yields and in short reaction times
(Scheme 2).
Surprisingly, when we carried out the same reaction between 1f
and terminal alkynes 2 under the reaction conditions described
above for the synthesis of aminoindoles 7, (i.e., by using DMF as
solvent instead of DMA and with the addition of NaOH after the
Sonogashira coupling), we obtained the indole derivatives 9 where
only one of the two nitro groups had been reduced to the corre-
sponding amino group. In this case the reaction does not require
the additional treatment with Pd/C catalyst.13 Although at the mo-
ment we have no explanation for this selective reduction and the
yields of the isolated compounds 9 are moderate, this result is very
interesting because to the best of our knowledge there is no meth-
od described in the literature for the synthesis of 7-amino-5-
nitroindoles.
We have also prepared some derivatives of these interesting in-
doles 9. A complete methylation reaction was observed upon treat-
ment of aminonitroindole 9b with excess of methyl iodide that
allowed the isolation of trimethyl derivative 10 (Scheme 3). Grati-
fyingly, the indole derivative 11, obtained from 9f by sulfonamide
formation, could be crystallized and its structure confirmed by sin-
gle-crystal X-ray diffraction analysis (Scheme 3 and Fig. 1).15
The relevance of this new synthesis of 7-amino-5-nitroindoles 9
is supported by the fact that reduction of 5,7-dinitroindole 8a un-
der conventional conditions (H2 with Pd/C in EtOH) gave rise to the
corresponding 5,7-diaminoindole derivative in 80% yield.16
To sum up, we have described a useful new approach to the syn-
thesis of 2-substituted indoles bearing an amino or a nitro group at
the benzenoid moiety based on a simultaneous reduction of nitro-
Figure 1. Crystal structure of compound 11 (a molecule of Et2NH has been omitted
for clarity).
to amino-group when DMF was used as solvent. Although in some
cases the yields are moderate, this methodology easily allows the
synthesis of regioselectively nitrogen-functionalized indoles in a
one-pot procedure from commercially or easily available starting
materials. An unprecedented selective synthesis of new 7-amino-
5-nitroindoles from 2-bromo-4,6-dinitroaniline has also been
developed.
Acknowledgments
We gratefully thank Ministerio de Educación y Ciencia (MEC)
and FEDER (CTQ2007-61436/BQU) and Junta de Castilla y León
(BU021A09) for financial support. V.G. thanks MEC for a FPU pre-
doctoral fellowship. Many thanks are due to Dr. F. Rodríguez (Uni-
versidad de Oviedo) for helpful comments.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.05.027.
References and notes
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Scheme 2. Synthesis of 5,7-dinitroindoles 8.

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13. The likely intermediate 5,7-dinitroindoles 8 were detected by GC-MS but after
completion of the cyclization, only the final 7-amino-5-nitroindoles 9 were
isolated.
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entry 1): A mixture of 2-bromo-4,6-dinitroaniline 1f (262 mg, 1 mmol),
phenylacetylene 2a (153 mg, 1.5 mmol), PdCl2(PPh3)2 (21 mg, 0.03 mmol),
CuI (9.5 mg, 0.05 mmol), and Et2NH (110 mg, 1.5 mmol) in DMF (3 mL) was
stirred under N2 at 70 °C for 2 h (the consumption of the starting material was
monitored by GC-MS). Then, freshly powdered NaOH (400 mg, 10 mmol) was
added to the reaction mixture, and it was heated to 140 °C for 3 h (the end of
the cyclization was monitored by GC-MS). The reaction was cooled to rt. and
then, CH2Cl2 (20 mL) was added. The separated aqueous phase was extracted
with CH2Cl2 (3 Â 20 mL) and the combined organic layers were washed with
water (2 Â 60 mL) and dried over anhydrous Na2SO4. The solvent was removed
under reduced pressure and the residue was purified by silica gel column
chromatography (eluent: hexane/EtOAc, 3/2) to afford 9a (116 mg, 46%) as a
brown solid; mp 244À246 °C. 1H NMR (300 MHz, DMSO-d6): d = 11.58 (s, 1H),
7.88À7.79 (m, 3H), 7.48 (t, J = 7.5 Hz, 2H), 7.39À7.31 (m, 1H), 7.24 (d, J = 2.0 Hz,
1H), 7.02 (s, 1H), 5.82 (br s, 2H); 13C NMR (75.4 MHz, DMSO-d6) d = 142.5 (C),
139.5 (C), 134.4 (C), 131.4 (C), 129.4 (C), 129.1 (2 Â CH), 128.1 (CH), 127.8 (C),
125.1 (2 Â CH), 105.8 (CH), 101.5 (CH), 98.6 (CH); EI-LRMS m/z 253 (M+, 9), 231
(44), 207 (100), 191 (12); HRMS calcd for C14H11N3O2, 253.0851; found,
253.0854.
9. Wang, H.-S.; Wang, Y.-C.; Pan, Y.-M.; Zhao, S.-L.; Chen, Z.-F. Tetrahedron Lett.
2008, 49, 2634–2637.
10. The moderate yields obtained could be due to the prolonged reaction times
under basic conditions. Also, in some cases we observed small amounts of by-
products derived from partial or total reduction of the triple bond in o-
alkynylanilines intermediates such as 5. However, aniline derivatives from
reduction of the corresponding halides were never detected, see: Zawisza, A.
M.; Muzart, J. Tetrahedron Lett. 2007, 48, 6738–6742.
11. These o-iodoanilines were obtained from commercially available 4-chloro-2-
nitroaniline and 4-methyl-2-nitroaniline, respectively, by iodination with ICl in
AcOH.
15. CCDC 725042 contains the supplementary crystallographic data for compound
11ÁEt2NH. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
16. See, also: Saleha, S.; Siddiqui, A. A.; Khan, N. H. Indian J. Chem. 1980, 19B, 81–82.
12. The mixture was charged under air in a 35-mL thick-walled glass sealed tube
and irradiated, under stirring, at 70 °C in the microwave cavity for 10 min